Document jgmEjxBep1gkaMZeJw0eXdwEp

oauict --rT e. a. MBS? Beta i .. _.i DUfMlUMI tigfBir IMS Mk-IM MUii ar trayj 4a aot nun iifut. IB-JJ 5'. i'. nLar/t j. jMNiKki r. J. MUatwt/B. B. Belaaa C. L. Jaaeaa. CMS j. *. am, CMC a. L. adliM. rat C. a. BaaM c. b. atfiiu A. 8. SaySar B. J. anti L. am - Uwia. Kt 4. 0. CaalStr. Ott electric rawer aaaearc* (actuate BUttiAatin Uat Pair* . C. BUMUI L. B. fruit . r. Ivary A. B. Mir B. A. w*llent J. B. a. a. scKt/aiA B. L. Wllllae. (US Beytea Baytaa ft. law St. law tt. IH St. dm tt. (Ml Baytaa Atts.yu(*Ml St. (Ml ru Alta Baytaa Baytaa Baytaa BBaayttta*a* St. ~ St. (Ml St. taaia aay iiy 0J44/B-2 .1 a can fraa tfce Baytaa ceatxal file Offtea. i r^M................*-- n. - I L.! .11, i.................... tiUI J HONS 025035 w rm mmn * whomitwib iiiu n mil >wml by . eart.A.jtellUa. MwwSy J. Mraa* 3mm > Drtnbn, nl UtMri Staayar eta*, mats-u frayf>4 far Uactri* laai baaamb laatitsta MU ttUaiaa Aaaaca Pala Alt*. caltfamalOM Oil Viajact OKicav Balyfe T. laaai uaa Mviaiaa Oaytaa. Ohia 4SW> woks 025036 *UBM> HT1CS* IMa nfNt m nyin4 to tka araaalaatloa iaM Maw aa aa aaaaaat af wrt tptattrti to tka Slaatria law toaiwat lWaaMtWitaWu,, lIMacS.. <|WI#NU|>>. amtiitfklaKr DVMll,, aaakara Uof mVUi., UtkNa iriMHiUNtil aaa-- kalaw. aar aa? rtrtta actiaa aa tkair kakalfi (a) aakaa aa aarraaty, am--a ar lialM, *itk raayact ta tka aaa af aay i--acaatlaa. atyarataa, aatk--. ac rracaaa iatlaaat la tkia rafart ar tkat aack aaa aaa aat ialriaaa ariaataly a--4 rtfhu; ar Ikl aaaaaia aar llakiliuaa witk raafact U tka aaa af. ar far fan aat raaalti-- fraa tka aaa af. aaa iafaraauaa. aaaarauu. aatk--. ar iractu tiaclaa-- ia this rtpart. . kaaaarak Caryarauia Baytaa ukaratarr Diyua. aaa 44497 HONS 025037 __ __ niiti te npit _________i.f.tsssttL'SE cUwimM kiflMli C8e) to ImU mmIm. towtopto far Uda win that wnlifa a*f af aa avaaaaaa aiif un aiiiann mi ___ . ___ tilt rtaantiaa fiaa toa aula aaarayad a aauvaiaat K> caacaauatiaa af ft ffm. itt a rmft af 10 w to It mm. no aaljiio of apikad aailo afcoaad a raeavary af Kt t far itoKHMaa pUad. ' iii HONS 025038 1 1. IMntKtta rnpa MU tUMiy al Mina............................................. VvvptfiM Mils*...................................... alactiaa M l iiwilaia far res jaaatiutiaa. Uaaarity af Uw Aradara................................... daa a aatariala................................................ falacttaa af aatractiaa aalvaat........................ Kffatta af varyiag Ua amactiaa udaiya . . J. Caaaaata aa halwaui af riaal aaUada far ICBa ia tail........................................................... Cnucal ranaw af Ua praltaiaary aaUad . . . . miuuHT aaalaattaa af Ua furl nUaf. . . . Caalaattaa af ftaal aaUad aaiay a aartaty aatl ty>--.............................................................. 1 K 11 N n at 31 A***a4ta A. faruMa aluratalat uat aaUaf far |al|(UariaM kiflafta aatl........................................................... * HONS 025039 salts af JUaalaa Chin Mm........................ is imlu af Mm MiKtin Mliwi................. it Iiim| la ta|lM MncM hr liM MlUtiw . it hwwq af lTlM bttKta hy nuasaUcstiM. is Cffacts tf in Wh MUUsa ts Ml S--ai*a bUirtW Sy Wmaaaintin................................ M hiain ttm tasln --SJsctsS ts Mil Mtstisa si nunmciUm.......................... is NmSRiUUty la Bscaasiy fna castiaa* hasssl tttlKUW/WtllMIHHW..................... is suaSart Cans saS last Basalts far a Ssayl* Baas* SaSacaS Ml lafl* Sus............................ naliaiaary taslastiaa af tfca riaal BathsS. ... a Caaatal Daacriyuaaa af Ml Tyyas........................ M Syacafic OMractaristica af Mia 0as4 fa* taalaauaa........................................................ aaalytical Malts far ISar Ml lyyaa.................. It vii HONS 025040 ocnai i Mjn KM. cmwmUw. tkcmUm mIUI* ta> cwt rwuM* fiBTpi to MriMW tow) ft nUmhUn ( Mil. mum asst to Mat tor minis to latoratoty ton tto pstaatial Hlia| um tor rasalta cm tonick m nak. Mays is site ilw^ era jwn ynllat u casual ( tto caataiaata4 m A tortus* is u*M far tto tail aaaatiricatiaa ( KBs at tto tan tost stto ia tto fislS. Ito taatita aaat to rail, mmrato, partakls, aat sasily asa4 By yrnmal tovias m (facial CteMMl UAUttlf. tto atoactm M tkia prsaraa ns to stefacs aa toaapsaa m pmaMs rnairil tost kit stilisiaa sluavislat 1ST) mu tor tto (ail. accsrau aMatificatua st KBs is ntl. na laaaata a tkia tot aaaM to toaiyiaS to to raatoly aaafcla to trna(< yarsaaaal. Ito yayai af tkia nysrt is ta saaaam tto rasalta af tkia HONS 025041 SECTION 2 data simiam and analyses PREPARING SPIKED SOILS During th development vork, both individually spikad toil plat and a largo aaattr batch of PCB-tpikad toil wat uatd. For any of the teata for aatbod davtlopatnt, individually tpikad toil aaaples wtrt uttd. That# vert prepared in the following anner. Tor the aatter batch, a staple of huait rich garden toil wat hoBogenixed by nixing in a Roto-vap with hexane. The PCB taaple in hexane wat added to the toil Mixture, and the retulting taaple wat dried. Aliquot* of thit toil vere then uted in the experiaents. For the individually tpiked taaplet, a 10-qrtB taaple of air-dried toil wat weighed into a 40-bL Teflon! teptun-lined tcrew-capped vial. A 1-bL aliquot of a 541 pg/aL Aroclor 1254 in hexane stand ard wat pipetted onto the toil taaple. The taaple wat allowed to etand uncapped prior to aaalytit until all of the hexane bad evaporated. SELECTION OF A VAVELENCTH FOR PCS QUANTITATION At thown in Figure! 1. 2. and 3, all three Aroclor formulations (1242.12S4, and 1260) abtorb in the 200-to 300-na range. A wave length of 2S0 na wat aelected becaute all three Aroclota can be aeatured at concentrations of S to SO ppa in that region. In addition, three peaticides, endrin, lindance, and acthoxychlor. were analyzed by UV (Figure 4) and found to abtorb strongly in the 230-to 260-na range. Herbicides and pesticides are potential contaainantt at sites where toil analytes for PCBs nay be desired. LINEARITY OF THE AROCLORS The analytical linearity of the three coaaercially available Aroclora (1242, 12S4, and 1260) wat investigated. Figures S. 6. and 7 show the UV absorbance of Aroclors 1242, 1254, and 1260 in hexane, respectively, at a function of concentration in hexane. Figure R shows thit relationship for all three Aroclors on on* graph. No probleat in linearity for the analysis of PCBs using ultraviolet detection were encountered between one and greater 2 HONS 025062 WAVELENGTH, nm Fi9Ure i- W Absorption , 1 for Aroclor 1242 in bsuas --1|i HONS 025043 ABSORPTION, chart unlit Fiqure 2. UV absorption spectra for Aroclor 12S4 in hasaoa (rang* l.t), NONS 025044 WAVELENGTH, nm rigure 3. uv absorption spectra for Aroclor 1260 in henano (rang* 2.0). HONS 025045 AISOamON. Chart Untti rigira 4. UV absorption spectra for nistures of endrin, lindane, and nethoxyctilor. HONS 025046 SOMANCt. d w t UflMs Figaro S. UV abcorbanca at 2S0 m of Aroclor 1242 in hexane aa a function of Aroclor concentration. HONS 025047 chart units Figure *. UV absorbance at 280 m of Aroclor 1254 in hexane as a function of Aroclor concentration. MQN5 025048 Flour* 7. UV aboorbanca at 280 m of Aroclor 1260 in hexan* aa a function of Aroclor concentration. MONS 025049 V 50 <o n coNcofflunoN or moclo* in houni. m Figure 6 UV absorbance at 280 m of Ardor* 1242, 1254, and 1260 (individual) in hexane a* a function of Aroclor concentration. HONS 025050 than 500 M(IOi. Althea* ceaceatratlea is linsar itt respect to abaofbaneo. tkiMviM Aroelor (militicM aimt eoaswhat dlfftmUy for the nm relative caacaatratisa. Itia ttaoMcasssnr to km oriorkaovledge of which VCBo or oiatons f KSa nay be |tmt la wta U iemitoly determine the!* m. castration directly.froa these analytical curves. rutiiirainl results, shown inhgure . indicate that oiataras of Aroclors (total concentration) also ara lioaar at. absorbance. figures 10 "fll show the li2f raapeoao for theW absorbanca of Aroclors 1242 and 12(0 respectively, la aeotooltrlla. If tbo idoatlty of tha KBs la aakaoan, a acaa of tbo vavolaagtha between 2(0 m and 200 no will anablo Aroelor 12(0 to bo identi fied duo to tbo absorption ainiauo at 2(0 an. As aaaa ia Figaro 0, this ia significant boeaoao tbo absorption of Aroelor 12(0 differa tbo aoat frea tbo otbor KBs. Id tbo absonco of tbo 2(S-na absorp tion ainiaua, tbo aao of an average of tbo Aroelor 1242 and tbo Aroelor 12(4 calibration curves could bo uaad living an error that ia insignificant coaparod to the inharaot error in tbo overall aathed (e.g. percent recovery variability). AltemaUly, tbo aethod can be used assuaing that the least sensitive PCD is pres ent to give a aaxiaua possible KB concentration in the soil. CUAN-UP MATERIALS Several packing aatorials were investigated to deteraine which aaterials would be suitable for resowing interferences froa the soil. Florisil, silica gal, charcoal, a Cu-Bonapak resin, and aluaina were studied. riorisil, silca gel, charcoal, and the Cn-packing were not found to be suitable. Mien a clean soil extract (analysed by gas chroaatography/nass spectroaetxy and found to contain less than 0.1 ppa of any KB, pesticide, herbicide, or identifiable extract able organic) was passed through a saall chroaatographic coluan packed with any of those four packings, a UV response greater than that of a 50-pea Aroelor standard was obtained. Only aluaina (deactivated (X with deionised water) provided sufficient cleanup of the blank soil extract. Subsequent studies were conducted using hand-packed aicro-coluana of 5% (N/V) deactivated aluaina. Four replicate saaples (5 aL each) of a 54.1-pps Aroelor 1254 Standard were run through an aluaina clean-up coluan followed by three 5-al hexane rinees. Tha concentration of each extract was neasured using both GC/EC and UV to deteraine the volume of eluant necessary to rinss the KBs froa the coluan. Results are shown in Table 1. It can be seen that virtually all of the KBs were recovered in the first two S-aL rinses. 11 HONS 025051 AISOMANCE, chart units Figure 9. 1242 AND 1X0 OR AROCIORS 1254 ANO12H, ff* UV absorbance at 280 rat of mixtures of Aroclors 1242, 12S4. and 1240 (individual) in hexane as a function of Aroclor concentration. HONS 025052 Figure 10. UV abaorbance at 200 na and at 24S na Aroclor 1242 in acatonitrile a* a function of Aroclor concentration. 13 HONS 025053 Figure 11. UV abiorbince it 280 na of Aroclor 1260 in acetonitrile is i function of Aroclor concentration. 14 HONS 025054 TABU 3. INSULTS Of ALUMINA CLZAN-OT COUNM Suoll No. rrtctlaa 1 SH Staplt riMt 5-oL riiiM Second S-aL rim* Third S-aL rinit 2 5-oL Saflt Tint 5-oL rim* Second S-aL rinit Third S-oL riou 3 S-aL Staple Tint S-aL rinit Second S-oL rinit Third S-aL rinM 4 S-aL Staple Firit S-aL rinit Stcaod S-aL rinit Third S-aL rinit rractlto rtcmry, 0 47 30 0 47 78 12 0 33 S3 4 0 i 42 2 0 lattl rtnvtry, % ' ' 1 HI Friction Total rtcovtry. ncwiry, \\ 0 77 48 28 0 41 137 41 i 111 0 50 42 Sf 2 in 0 75 103 85 175 11 4 Fraction S-aL Staplt Firit S-aL rinit Stcaod S-aL rinit third S~nL rint* TOTAL Avcrtot rieovtrr. \ cute UV 30 41 40 40 12 13 01 102 123 15 HONS 025055 SUCTION OP DOMCTION tOiVWT Several extraction Mlveatx wn tried in an attempt to reprodac ibly remove tha Aroclora (m the Mil. TImm inclw acetonitrile. methanol, benzene, ethyl ether. chloroform, Mthylana chloride, tetrahydrofuran and the m of sodium aulfata with hexane. Ten-gran samples of Mil vara apikad with Ml pg of Aroclor MM IM-I pg/g. Duplicate analyse* with aach aolvant worn performed aftar extracting tha saaple with 20 aL of Mlvant. Tha extraction conaiatad of manually ahakinq the aaapla and then placing tha aaapla in an ultraaonic bath for ainutea with annual agitation every ainute. The extract waa decanted and aaved. A aecond extraction waa parforaad uainq an additional 10 aL of aolvant, with ultraaonication for 2 ainutea and annual agitation every 30 aeeonda. The two extraeta were contained and analyzed by electron capture ga> chroaatography. Reaulta are ahown in Table 2. Wetting th toil with a polar aolvant (acetone or diaethyl sulfoxide} prior to extraction with a nonpolar aolvant (hexane) alto waa mveatiqated. Acetone reaoved ao aany interference* froa the toil that the extract waa coapletely opaque in tha UV region (2S0 na). Diaethyl aulfoxide yielded "recoveries* of 144 to 1S9% on triplicate aaaplea, after correction by aubtracting an untpiked toil blank. Hexane wax ahown to be a relatively good extraction tolvent for FCBa while not extracting a great nuaber of poten tially interfering coapounda froa the toil. EFFECTS OF VARYINC THE EXTRACTION TECHNIQUE The effeett of hand agitation and ultraaonication on recovery were inveatigated in an atteapt to find the faataat method for reproducibly removing the Aroclora froa the toil uainq hexane aa an extraction tolvent. In one experiaent, 10-graa aaaplea of aoil were epiked with S41 pg (54.1 pg/q) of Aroclor 1254. Then, 20-nI. of hexane waa added to each aaapla, and each waa hand-agitated for ainutea. The reaultant extract waa decanted and analyzed by UV apectroacopy. A aecond aliquot of hexane, S aL, waa added to the aoil and anaken for one ainute. It waa dacanted and aaved. A third aliquot, 5 mL. waa added and ahaken for one ainute. Thia extract waa com bined with the aecond aliquot and analyzed by UV. Reaulta are provided in Table 3. Ultraaonication waa atudied aa a mean* of reaoving the Aroclora froa aoil. Ten-graa aaaplea apiked with 541 pg of Aroclor 1254 (54.1 pg/g) were extracted uaing lS-mL aliquot* of hexane and placed in an ultraaonic bath for varying tinea. The reaulting extract* were analyzed by UV and a high degree of variability waa noted a* shown in Table 4. 16 HONS 025056 tau 2. usutn or various extraction savors Solvent Acetonitrile Acetonitrile Benzene Benzene Ethyl ether Ethyl ether Hexane Hexane Hexane NaSO Hexane HaSOe Methanol Methanol Tetrahydrofuran Tetrahydrofuran Methylene chloride? Methylene chloride* Chloroforn* Chlorofora* Rocovety. 98 7S 78 72 78 90 75 84 72 74 76 70 104 90 b b *Could not be analyzed by CC/EC; was analyzed by UV. ^Opaque to UV at 280 na after soil extraction. TABLE 3. RECOVERY IN SAMPLES EXTRACTED BY HAND-AGITATION Slavic No. 1 2 3 4 Extract 20-el Extract 20-el Original extract Tee 5-el subsequent extracts 20-aL Original extract Two 5-el subsequent extracts 20-aL Original extract One S-al subsequent extract* Extract recovers, \ 33 44 9 30 u 24 10 Total recovers, t 33 S3 41 34 `staple performed to aiaBino affect of using only on* subsequent extraction. 17 MONS 025057 TABU 4. RECOVERY M SAMPLES BIMCRD BY UUAAS0MCA7ICN Extraetloa time, Recovery? No. sis 1 1 120 2 5 72 3 10 24 4 20 120 The im experiment was rtftiUd by first mixing the spiked soil with 10% (W/V) distilled water (1 >L per lOg saaple). The results also were highly variable aa shown in Table S. Four additional samples were analysed (without water additions) to determined whether shaking manually for 10 ninutes and than placing the sanples in an ultrasonic bath for 10 ainutes would significantly improve the extraction efficiency and reproduci bility over the 10-ninute ultraaonic extraction, Resulta are shown in Table 6. Six spiked soil saaples (S4.1 vg/g Aroclor 1254) were analyzed in the following aannaer to evaluate the reproducibility of the com bined hand-agitation/ultrasonication method. Twenty ailliliters of hexane was added to each saaplei it was shaken for 8 ainutes and ultrasonicated for 8 ainutes. The extract was decanted and analyzed by UV. Two subsequent 5-aL aliquots of hexane were added to the soil; each was shaken for one ainute and placed in an ultrasonic bath for one ainute. The resultant extracts were com bined and analyzed by UV. The results froa the original and com bined subsequent analyses suasurized in Table 7. Reproducibility was still found to be a problem. TABLE 5. EFFECTS OF 10* WATER ADDITION TO SOIL SAMPLES EXTRACTED BY ULTRASON1CATION SftBplO NO. 1 2 3 4 Extraction uoe. ain 1 s 10 20 Recovery. X 48 12 84 132 18 HONS 025058 TABLE I. RBCOVBST IMN SAIVLBS SUBJECTED TO MANUAL AGITATION AM> UUIRSOMCKTICN sangle NO. 1 2 3 4 Extraction tin. nin Homoi UltrlXMUC 10 10 10 10 0 10 0 10 Mcovtiy, 40 170 100 100 TABLE 7. REPRODUCIBILITY IN RECOVERY FROM COMBINED MANUAL EXTRACTION/ULTRASCM1CAT1CM Saaple No. 1 2 3 4 5 4 Extract 20-aL Original extract Two S-aL aubaaguant axtracta Extract " "Rial rcovtry. rteovtry, XX 54 28 20-mL Original extract Two 5-L subsequent extracts S9 22 81 20-oL Original extract Two S-oL subsequent extracts 41 13 S4 20-aL Original extract ' Two S-aL subsequent extracts 41 11 52 20-aL Original extracts . Two 5-aL subsequent extracts* 20-aL Original extract Two S-aL subsequent extracts 30 94 17 113 *Saaple lest. 19 MOMS 025059 SECTION 3 COMMENTS ON PRELIMINARY AND FINAL METHODS FOR PCBs IN SOIL CRITICAL REVIEW OF THE FREL1HINART METHOD A1 though the preliainary method of hexane extraction of FCBi froa soli with ultraaonie enhancement followed by SX water deactivated aluaina cleanup and UV detection ahowed promise, reproduebility waa a major problea. At that point, the preliainary method was written and circulated among varioua MRC reeearchere for coamenta. The significant pointa of concern were aa follows: * The preliainary aethod contained several steps in which extracts were combined and an aliquot was taken for subse quent processing. The aethod was revised to start with a smaller soil saaple (froa 10 grau to 2 graas) such that all processing steps could use the entire extract. This elimi nated the need for combining fractions and taking aliquots and also resulted in increasing the ratio of hexane-to-soil from. 2 aL of hexane per gram soil to 6 iL hexane per graa soil. The amount and activity of the deactivated aluaina used in the method could have been a significant source of vari ability. Regular aluaina (activated by heating to 400*C for 4 hours) is a good sorbent for PCBs and is sometimes used to remove FCB interferences froa samples for other analyses. After deactivation with 5X water, the alumina passes PCBs in hexane but retains many other interferences. Discussions with the aethod development technician indicated that de activated aluaina on hand froa another project was used to dry pack one of two types of columns requiring approximately 3 graas or 4 graas of aluaina, respectively. Freshly pre pared deactivated aluaina was specified in the method. For the cleanup column, the 11 an x 85 am column was selected with 2.00 graas of alumina. Acetonitrile is used in the method to clean the alumina immediately prior to hexane. Because acetonitrile and hexane are not miscible, this might create a problea with wetting the aluaina with hexane. In one experiment, a small quantity of acetone, an intermediate solvent miscible with both acetonitrile and hexane, was run through the column between the acetonitrile and the hexane. Unfortunately, small traces 20 HONS 025060 of mteM raaaiaiag oa the alaniaa aad eluting vita the hexene bad a high enough W aatlaetlaa coefficient ta iaterfere with saaple analyses. The final aethod resulting frea the above caaaaau (given la tha Appendix) was then evaluated ta deteniae if it was accurate aad reproducible. PRELIMINARY EVALUATION OF TBS PIBAL HEIBOD Saaplei were prepared by apiking 2.00 grans of aoil with a known Mount of Aroclor 1200 in hexane. The blanks warn spiked with aa equal voluae of hexane solvent. The hexane was allowed ta evap orate. Alunina cleanup coluans were aade by placing 2.00 grns of SX water-deactivated aluaina in 11 aa x 85 aa coluans. Each sanple was first extracted by adding 4 L of hexane, nanually shaking ten tines, and sonicating for 2 ainutes. This shaking/ sonicating was repeated five tines. The extract was decanted and started through the aluaina eoluan. The saaple was then extracted twice aore by adding 4 aL of hexane, aanually shaking six tines, sonicating for 30 seconds, and repeating the shaking/sonicating sequence four tiaes. The second and third extracts were placed sequentially on the aluaina cleanup eoluan. The first 10 aL eluting froa the aluaina eoluan was collected in a voluaetric flask (includes aost of the third extract) for UV analysis at 281 na. The results of the analysis of one saaple and blank are given in Table 8. Results for three additional saaples and three addi tional blanks analyzed IS days later are shown in Table 9. These tests indicate that the problems in recovery reproducibility en countered earlier have been resolved by the changes incorporated in the final aethed. EVALUATION OF FINAL METHOD UING A VARIETY OF SOIL TYPES Any aethod for analyzing PCBs in soil oust be useful with a variety of soil types. During the aethods developaent phase of this work, it was assuaed that PCBs would be aost difficult to extract froa a huais-rich black soil. This type of soil also would be expected to contain the potentially aost interfering areaatic organic ceapouads. Because the aethod was developed with this type of soil, the aethod was expected to handle soil types with high sand or clay content. A series of tests were conducted to confira that the PCBs could be recovered froa a variety of soil types in a consistent Banner and to deteraine the range of ultra violet absorbing background interfences that would be encountered in soil analyses not reaoved by the aluaina clean-up eoluan. 21 HONS 025001 TABU a. BWMBD CUBVX ANDTBST BSSOUS VUI A BAMHS USMC BBVCD SOU, UIMI BIB Stall identification Standard 1 Standard 2 standard 3 Standard 4 standard 5 Blank Saaple spika 1 Absorbance 0.0590 0.1110 0.2049 0.350S 0.5088 0.0650 0.2860 comwmtlw of Aroelor 12*0, ______ M/1.,, 9.6 (Known; 19.2 (Known 38.4 (Known; 67.2 (Known; 96.0 (Known; 10 54 Aaount tpiked: 4S vg/g Racovtry: 92X TABLE 9. PRELIMINARY EVALUATION OF THE FINAL METHOD Saaple identification Standard 1 Standard 2 Standard 3 Standard 4 Standard 5 Blank 1 Blank 2 Blank 3 Saaple apike 1 Saaple spika 2 Saaple spika 3 Abaorbanca 0.0590 0.0175 0.2026 0.3522 0.5006 0.0790 0.1153 0.0957 0.3610 0.3305 0.3278 concentration of Aroelor 1260, uq/q 9.6 (Known) 19.2 (Known) 38.4 (Known) 67.2 (Known) 96.0 (Known) 14 21 17 69 63 62 Aaount apiked: 48 m9/9 Average blank value: 17 m9/9 Average analyzed value: 65 pg/g Average recovery: 99% 22 MONS 025062 ...._____Mriedtml Mi MtitlMl Project* cmm (NMK) MlaUiaaa supply ef itaM, nU cteietiriM MUteitt roMtrcb Mi amlnat hnw. faaplM of four Mila m obtained (gratia) am wreT a general deecriptiaa of tea aail typaa used la sImmi la Ml* lOi specific-analysed characteris tics ef these Mila ara shewn la Table 11. fach aoil blank was analysed la triplicate Ming tea Mthod akoaa la tha Appandia. These tests vara conducted to datoxaiaa tea range el eoacaatratlea of altraviolat absorbing species teat weald be extracted free the Mil and net rcaoved by the clean-up proce dure. Iba rasulta of these taata ara shown la Table 12. tea potentially interfering background absorption extracted froa tea four aoila was found to vary froa an equivalent KB concentration of 15 pen to 19 ppa. Preliminary testa with the garden Mil used for Mthods developaent (Tablet I and 9 showed background absorp tion equivalent to 10 pan and 19 ppu. Considering tea wide range of toil types tested, the background absorption vaa found to be relatively consistent Iron one soil type to another. A potential reproducibility probleu within soil type blanks was encountered, but probably involved familiarity with the Mthod because it did not occur in the analysis of the spiked sanples. tee four soil types were spiked with 48 ppu of Aroclor 1260 and analysed in triplicate with the final Mthod shown in the Appendix. These tests were conducted to determine if sowe soil (e.g.. bite organic content) edMrbed tha KBs Mrs strongly than others: this feature would reduce the recovery of the spiked KBs. The results of these analyses, presented in Table, shew that the percent recovery of the spike varied froa soil to soil froa 89% to 9SX- Preliminary tests of the Mthod (Tables 8 and 9) showed recoveries of 92% and 99% with the garden soil. Clearly, this Mthod is capable of reproducibility extracting the KBs froa the soils. The variability within triplicate analyses also is reason able. The grand average for recovery of the Aroclor 1260 spikes frea the four soil types was 92% 3%. , The Mthod in its present fon could be used in the field to deteraine the extent of clean-up required after a spill ox it could easily be put into kit for*. Further areas of potential iaproveaent for the Mthod could in clude a detailed analysis of the shaking and ultrasonic agita tion in the Mthod to reduce operator tiM (e.g., it nay be possible to elininate soae of the aanual shaking). A layered alumina coluan could be evaluated to deteraine if a combination of acidic, neutral, and basic aluainas would reduce the soil background. CC/MS might be used to identify the interfering species so that specific modification to the clean-up procedure would be aade to remove these interferences. 23 MOWS 025003 TABU 10. GEKRAL BUOUPTIOHS Of SOIL TTTfS* Drainage and peraeability - Well drained; aurface runoff ranges iron slew to aeoius; paneanility is aoderately rapid. Use and Veqatation - Generally used for growing bay and pas ture, with ssall part in corn, wheat, soybeans, and orchards; large part of steeper areas is in forest or permanent pas tures; native vegetation was forest, doainantly oaks and hickories. Distributation and Extent - Southern Michigan and northwestern Ohio; series is ot noderate extent. setting - In aoraipes, till, plains, outvash plains, and beach ridges within lake plains of Wisconsin age; dominant slopes froe 2 to 18 percent, ranging froa 0 to 40 percent. DRUMMER SILTY CLAY LOAM - Dniester series is fine-silty, nixed, esie Typic Hapiaquoits. Drainage and Perseability - Poorly drained; surface runoff is slow or ponded; peraability is aoderate. Use and Vegetation - Largely cropped to corn and soybeans; sons snail grain and acadow also grown; native vegetation was probably aarsh grasses and sedges. Distribution and Extent - Northern and eastern Illinois; extent is aoderate. Setting - Occur on nearly level parts and in depressions of till and outvash plains; slopes range froa 0 to 2 percent; foraed in 40 to 00 inches of loess or waterlaid silty aaterial and underlying stratified outvash and glacial drift. (continued) 24 HONS 025064 TABLE 10 (continued) DWO SILT LOW! - Dupo series is maber of course-silty over ciayey, sixtd, nonacid, msic fanily of Aquic Udifluvents. Drainage and Permeability - Somewhat poorly drained; nulici runon it slow; permeability is uoderately (low to alow. Uao and Vegetation - Mainly cultivated to corn, aoyboana, and aaan grains; native vegetation vas probably nixed daeidoua hardwooda and sedges or graaata. Distribution and Extant - Central and southern Illinoia; eatent is aaail. Setting - On floodplains on slope gradients lass than 2 per cent; xoroed in 20 to 40 inches of recent light colored silty alluviua overlying dark colored silty clay or clay. HODGE nm SAMP - Bodge series is nixed, nesic Typic UdipsaaMnCs: Drainage and Permeability - Somewhat excessively drained; runoti is slow; permability is rapid; Hodge soils are frequently flooded where not protected by levees. Use and Vegetation - Commonly cropped to corn, wheat, soy beans and nay; native vegetation is nostly cottonwood and oak trees with sosm interspersed tall grasses. Distribution and Extent - Mainly along the Missouri River in Missouri and possibly along aajor stream in Iowa and Nebraska; extent is Moderate. Setting - On nearly level to gently undulating floowplains; slope gradients doainantly less than 2 percent but range to S percent in sons pedons; foned in calcareous sandy alluvial sedimnts. information free National Cooperative Soil Survey, U.S.A. 25 HONS 025065 TABLE 11. SPECIFIC CHARACTERISTICS OF SOILS USED FOR EVALUATION Composition X Ocquiic natter Sand Silt Clay Other characteristics pH CEC, M9/100 9 Bulk density, 9/cc One-third bar, X spin** loaey land 2.4 75.1 17.8 4.8 4.7 11.1 1.41 17.9 ; brumer Gupo silty elr loan silt lose 3.4 2.4 68.8 25.3 1.2 4.6 84.2 10.0 6.2 24.6 1.16 28.8 8.1 10.4 1.13 23.9 8535* fine snd 0.3 61.2 28.0 10.8 7.2 7.3 1.4 8.9 HONS 025066 table 13. AMUTicju. mom rat rant ton Tim Parameter Standard curvet Aroclor 12(0 concentration. _ me .( 19.2 30.4 67.2 96.0 Absorption at 201 an* Background____ flee 0.036 0.090 0.1(2 0.341 0.S2B 0.041 0.091 0.104 0.346 0.534 (continued) TABLE 12 (continued) Paranatert Spinkt background Average Drunaer background Averse Dupo background Average Hodge background Average Abtorption at 281 na Equivalent Aroclor 1260 cone., Don 0.052 0.182 0.023 8.6 36.5 8.1 17.7 0.062 0.099 0.022 15.0 21.6 8.0 14.9 0.047 0.186 (0.130 rerun) 0.019 12.5 37.1 7,5 19.0 0.076 0.056 0.070 17.6 13.9 16.5 16.0 (continued) 27 MOMS 025067 TABU 12 (contimed) Paraueteri Spinks vith 41-ppu tpikt Average Dnaaer with 41-ppu ipiko Avr*9 Dupo with 44-ppu ipikt Avr9 Hodge with 4t-ppu ipiko tmigt Overall mm recovery of pike freu four Milo khtorptian it 211 lotoi oquiwolMt kroclor 1240 concentration, nm CanrntritiM ltM mrm bictywwl, vem Nremt rccovtnr 0.282 0.234 0.208 42.9 59.9 58.2 45.2 42.2 40.5 94 M 84 89 0.251 0.229 0.255 00.9 59.4 41.2 44.0 44.7 44.3 90 93 97 95 0.292 0.271 0.270 03.5 42.2 02.2 44.2 43.2 43.2 92 90 90 91 0.27S 0.271 0.225 12.0 42.2 59.3 40.0 44.2 43.2 97 90 90 94 92 `standard eunrt hi generated on two different daye. 28 MOWS 025068 Amu romau ultmviout tut tcraco rat rourouiiiMTiD iiraorru in soil 29 MONS 025069 rat i > SIMBffU l SOIL 1. Scope and Application 1.1 Thio netted covort the qualitative and sasd-quanti tative determination of polychlorinated biphenyls (FCBs) in aoil saaples by tho ultraviolet absorbance spsctroptetcaatric analyais of hoxaao soil a*tracts. 1.2 The eethod ia designed for the rapid field dottruination of whether rc>s occur in test soils at levels greater than the SO parts per Billion (ppa) specified in aany spill clean-up operations. 1.3 The method detection liait (tDL), defined as the aininua con centration of a substance that can be aeasured and reported with I9{ confidence that the value is above xero, was calculated to be 4.5 ppa for Aroclor 1260 froa replicate analyses with this aethod. 1.4 Different FCBs have ultraviolet extinction coefficients that vary by a factor of almost two. Aroclor 1260 differs the aost in 201-na absorption froa Ardors 1254 and 1242. However, it can be differentiated froa Ardors 12S4 and 1242 by an absorption ainiaun that occuis at 260 na for Aroclor 1260. In cases where the iden tity of the FCBs present is unknown (or nixed), standards of the least-UV-absorbing PCS (Aroclor 1260) should be used to calculate the naxinun possible FCB concentration for the sample. 2. Summary of the Method' Approxisately 2-g saaples of soil are extracted three times by 4-aL portions of hexane. The hexane extracts are passed in series through an aluaina coluan to ainiaite potential interferants and collected in a volumetric flask for analysis via ultraviolet absorbance spectrophotometry at a wavelength of 281 na. 3. Interferences 3.1 Ultraviolet (UV) absorption at 281 na is generally due to the presence of arcaatic compounds. Extraction of soil saaples with hexane removes not only any FCBs present, but also aany other UVabsorbing ceapounds. Although the aluaina coluan retains aany of these coapounds while passing the FCBs, some species elute with the FCBs and give a background signal from 'clean" soils. 3.2 In five different soil types analysed, the UV-absorbing background interferences ranged froa an equivalent PCB concentra tion of 10 ppa to 19 ppa, with an average equivalent concentration of 16 ppm. 10 HONS 025070 4. MMi Althea* FCBshave low acata toxicity ad hm aot booo found t ka cstoiaogealit by etaadard ketleaal Caacor laotitate Moaaaeyo. tkoy ora regelated oo carcinogens. All appropriate paatlia koeld bo takaa by personnel cuedsctiag aaalyaos to follow OOk regulations oat to avoid eoatoet witk fcao or PCB-containing loo or extracts. S. Apparatus and Materials 5.1 Extraction Taboo -- Coming, It an n 100 aa, Pyres* calturo tuboa with Taflon-Uaod scrow cap (riahor 982S-16 or equivalent). 5.2 Voluaotric Flaaks -- 10 aL. S.l voluaotric Pipettes or Solvent Diaponaor -- Capable of * aL voluaea. 5.4 Clean-up Coluana -- 11 aa x 85 m. 5.5 Sonicator -- Branaon. Bronxonic Hodol 12 uonic bath or oguivalont. S.t Laboratory Analytical Balance -- 0.0001-g aenaitivity for preparation of atandards. 5.7 Field Balance -- 0.1-g aenaitivity for weighing 2-g aanplea of toila. 5.8 Ultraviolet Spectrophotoaetar -- Capable of analyeee at 281 na. 6. Keagenta t.l Aroclor 12to -- chea Service Stock Mo. FLZ-110 or equiva lent and other PCB standards as required. 6.2 Hexane -- Fisher, HPLC-grade or equivalent. t.l Acetonitrile -- Burdick and Jackson, UV quality or equivalent. 6.4 Alenina -- Bio-Bad, neutral, AC* 7, 100 to 200 nesh or equivalent. ' t.S Standard Solutions -- Stock standard solutions nay be pre pared by addition of weighed quantities of Aroclor 1260 to hexane In voluaotric flasks, or they nay be purchased aa certified solutions. 31 HONS 025071 1.1 Secondary Dilation Itudirti -- Mia* stock standard solu tions, prepare seeandery fllsuas standards in barana sack that, ths standards sill, bracket tbs expected concantratiso of vet in tbs btxaae extracts of tbs sail saa^les. 7. Calibration 7.1 Prepare calibration standards at a minimum of fear concentre* lion levels, bracketing tbs expected concentration of PCS in tbs final bexane extract. 7.2 Determine tbs absorbance of each solution using an ultra* violet spectropheneter at a wavelength of 2(1 no. 7.3 Prepare the calibration curve by plotting FCB concentration versus ultraviolet absorbance. 7.4 Determine tbs least-squares*fit of data points to tha best straight line plot. S. Quality Control 1.1 Each new analyst should analyze a number of blank and spiked soils to become familiar with the method prior to the analysts of field samples. 8.2 An ongoing progran of performance checks is recoanended to assure that results are within the accuracy and precision Units expected for the method. 9. Sample Collection, Preservation, and Handling Soil samples for PCS analyses ara not expected to degrade signifi* cantly under any normal sample collection or storage conditions. 10. Sample Extraction and Ultraviolet Spectrophotometry 10.1 Approximately 2 g of soil is placed in a Pyrex culture tube supplied with a Teflon-lined screw cap. Each sample is extracted three times with 4-nL portions of hexane. 10.2 For the first extraction, the hexane soil mixture is manual ly shaken ten times followed by sonication for 2 minutes. This Process is repeated four more tines for a total of SO shakes and 0 minutss of sonication and then the hexane extract is decanted onto the alumina column (sea 10.3). For the second and third extractions, the nixtures are annually shaken six tiatts followed by sonication for 30 seconds. This shaking/sonication process is repeated three norm tines for a total of 24 shakes and 2-minute sonication for both the second and third extractions. These 32 HONS 025072 10 at eletlngfreo tbs aluaina csluaa lii collected la a iviaiSt flask for analysis. 10.3 Tbs 11 a i H alanine colasos ars prepared by filllas yitkj 0 of almina (iio-ed . neutral AO 7? 100 to 200 aask) that baa baan activated by beating for boars at 400*C, deacti4atad by tbs addition of SI (sgw) vatar. no colons ars further conditiond in tha fiald bywashiag with 3 inL of acotonitriio and than with 3 nL of beaana laaadiataly prior to ass. 10.4 Tha baaana aatracts fraa tbs alaaina colunns ara analysad for absorbancy using an ultraviolst spectrophotooetar at a wavelangtb of 201 na. 10.S A Corning It aa x 100 na ultraviolet call (Fisbar 9125-14 or aquivalant) ia nsad for tbs analyaas. 11. Calculations 11.1 Tbs concentration of FCB is obtained by direct interpolation iron tha calibration curve. 11.2 Whan blanks, duplicates, or spikad staples ara used, all data obtained with the saaple results should be reported. 12. Method Ferfoxnance 12.1 The aethod detection Unit (HDL) is defined as tha aasinua concentration of a substance that can bo naasurad and reported with tty confidence that the valua is above taro. 12.2 An MDL nay ha computed iron tha variability of replicate analyses conducted near tha detection liaits of a nethod. This is accoaplished by Multiplying tha standard deviation of repli cate analyses tines the Student's t-value appropriate for a 99% confideca level with n-1 degrees of freedoa. 12.3 A worst case MIL waa computed using triplicate analyses froa four different soil typos spiked at 40 ppa with Aroclor 1240. The average analysed value for the 12 analyses was 41.2 ppa with a standard deviation of 1.65 pea. The Student's t-value at the 99X confidence level for 12 replicate analyses (11 degrees of freedoa) of 2.73 tines the 1.45 ppa standard deviation gives a coaputed MIL of 4.5 ppa (2.73 s 1.45 ppa) for Aroclor 1240. 33 MONS 025073 m*-13J771 Mmcii Id bpcnn, Baalch aad Iwrlto--iatal Uftcu ItadlN ot FCSa ZULU Ufa lrita>. lac. Cleveland, OUi tl Hay lM .. imimr of combbe MmhI TmMhI htmnttai fenric* mons 02*032 JdfeSystems. Me. ?oo4- U577I TR.S07-137B ADVANCES IN EXPOSURE, HEALTH AND ENVIRONMENTAL EFFECTS STUDES OF PCBs SYMPOSIUM PR0CEE0M6S May 12*13.1962 Pnpand Undar Contract No. 68-01 -66 Pro** 1247 EMRWMk AaUgnmanl No: 30 *v ICAIB fjkSmtemJm. CtaMtond, OH 44122 lor OHlea ol 'tade SuMaraaa mm m pmionninw mmw iwwon lvl<#9> cnjM--o----rm--nw rimuionaM- --m--cy- WtoaNngtcn, DC 20460 NAflONAl TtCHNICAL INFORMATION SERVICE "KSSIMBT HONS 026033 ttmKLMr-aocwxT*no*i i. :_____ ________ ___ l ui-at-i07-n7 Ii, m laMM Advances In Exposure* Health and Environmental I iff*cca Studies of PCie: Synposlia Pppceedlngs H 8. J. Davenport and I. K. lernerd (Edo.) ;cai* Ufa Systene* Inc. 2*733 Ulghpoint load Clavtiand, Olio 44122 Office of Toxle Subotancee a**lcfc and Environmental laview Division }.i. Environmental Protection Ageney '%ihlngton, DC 20460 i ?M*-IJJ77l 12/83 tPaca of PubUca-.ul) 12-307-1371 * NwQTwwawii 1HMI.1.39 68-01-8334 Final QUil - / miumwi The Proceedings is * compilation of daea presented and dloeuaaad during > jvpfeiiM hold nay 12-13* 1982 la Dethesde* naryland, to provida aa lsforaacioa opdaea ?v; 'aa Environmental Protactlon Agency's Polychlorlaaead Biphenyls Program. Kina pepora . ' .3 diseuaolou itwrlM and concluding rairki address data* published or (ton studies progress tinea 1978* la tha following topic araaat Analytical Methodologies; Exposure Studios: Environmental Kaslduaa and lloeecumulaclon; Exposure Studiosx Industrial Procassaa; Health tffects: Epidemiology; Health Effectsi Lahoretory Studies; Caviroamentel Iffacta; and Bisk Aasasanant I.ch contributed paper Includes a significant bibliography of cited and related jciaoclflc literature reforeaeee for those seeking greater detail. lolyefclordlnoted Biphenyls lytwsatal Besldues lloeccunwlaclon Industrial Processes Health Effects Epidmdology Esvlroamental Effects Bisk Assessment Analytical Methodologies laboratory Studies Exposure Studies a ccaen aewow Beleeee unlimited, available from Metlonel Technical Infer itpftee, Sprlngflold TA . 12181_________ Symposia Proceedings PCS anti 363 m> Mm HONS 02603N TV*307*1371 ADVANCES IN EXF0SU1E, ItALTH AND ENVIBONHENTAL effects studies or rcs Syvpoolw FrocMNlngt May U-U, IM2 Ftt?or4 <Mt Centroct No. M-Ol-6334 Frojoot 1247 ICAI1 Work AislfMMe No.: 30 by ICAIl Lift SyatCM, Inc. ClovoUrt, OS 44122 for Offleo of Toxic SoWtoocoo iMlth nl twlriMiitil Itrlav Divtotoo i*S. bfiroaaatal hotiatlo* Agoacy Mkift|to, DC 20400 14/ *OHs 0*6035 DISCLAIM! Although tilt Vvocoodlftga DoevBMt reporta tha prtttotaelooa aod dlacoaalon tlat acnrti4 1% tha VCD S^aate (wSa4 Vy tha Suited Stataa tavlmantal hotactlaa tfaacj tktaa^ Camaee la. M-OI-65S4 vie! Ufa Syataaa, In.# tka emaaci af tka fmaWliga ata tha Mafaafaae vim of aclaoelaca aat aaaaelatd vttk IVA. Caaaaywatly, tha fraaafta|i Daoaaat baa aat haaa aabjoctod to tha Ifaacf'i poor ravlaa procoaa. It 4aai aat oaeaaaarllf rafiaat tha Tlarvo of tho Agoarcy aaf oo official oodoraaaoac should bo lafamf.ll ll MONS 026036 FOREWORD Alaest anyone *ho le likely to open this kook trill know cbo beele facto about polychlorinated biphenyl* (PCDs)t first described In the lsts 19th century, they hav boon produced on an Industrial nIi elec* about 1930. ta ths subsequent AO year* they have been Nl extonelraly in a variety of ipfll* cations because of thalr chemical and tharnal stability and good dielectric properties. Slnca the dlffarane canmereiel PCS products sra not slnpls antltlas but families of compounds, tka picture is complicated baeanaa Individnal conpooonta of tkasa mixture* differ in thalr chemical, physical and biological properties. Tka Initial concern about chlorinated aromatic compound* originated free riports around 1940 of cblorecne and. tloor change* m workers aha cam* le contact with thaaa aacarlala during production or handling. Worldwide etteotlon es not glean to PCla, hasten*, until 1Mb vban the Journal* N Aclaatlat. rsportod on Soeon Jenson's finding of PCS* la pika fron Swedish letss, In tka huuan brain end in an aagla which was found dead lo the Seockhola area. During the year# that followad, FCSs vara found In environmental samples In aearal parte of the world. It baeaaa evident Chet thoea persistent and bleaeeumulatlog compounds were ubiquitously distributed] biological natetlal frea polar reglono end othar nnlnhablead end remote areas eoatalned tracaa af PCls. Tka 0.S. neanfactnrers raepondsd ta thaaa findings by Halting ealee af PCla to veto la ancloaad syttane oaly. Tka praeanca af PCSa ta mm laoUtad environmental etaplat fron twadan might kaea raaalnad an analytical eurlaelty far sons tint kad oat laehaal Careen's book, "Silent Spring", alartad environ mental eelaatlate - end tka gonaral public - seat years bafara ta tha poaalbla dangar af arganacblorloa caapounda. In HAS accidental lngastlan af PCls through eontoalnotod rleo oil rseoalod awake* of toxic affocta af PCls la a group of Japanoao people. This Incident aloe ostabilohad placental tranafar of thaaa compound* and paraleeanco In the allk ef eontealnoted mothers. Coaporeble effects ware observed in the 1979 PCla poisoning Incident in Taiwan. tn the early I970e It wee elan shewn that humane were directly caponed ta PCls fron ouch diverse sources as food packaging aatarlala and carbonless copying paper. Tha aaaa tlao period alee aaw the beginning af Inteaelve scientific efforts te understand the route of exposure end the fate and affocta af PCla. Long tin exposure* at lew levolo wore studied sod the phenomena of bloaccwualaclon and feed-chain magnification wore olao Investigated. Prior to studies with KSs, little was known ea photochemical behavior aad aotakeLie pattern* of chlorooroaatlc compound*. PCS* production and laport la elthor forbidden or Halted in neat Industrialised eewatrlee. Bouev*r. neat af tha total PCls produced to date are either selll in service or found In dumps and land fill*. To avoid further environmental contamination, aafo mothoda for nltlaato dlapoeal have .to be founds 111 HONS 02603? The PCIi profclen *111 net dleeppaar overnight. Thera nap ba motional reaction end eofoonded foor concerning fC8a. bat there le eleo the possibility el reel envlromootal prehlene with potsmtiallf heaardowa coest^uences. m nest look et the facte* avalnata then and conduct Investigations In areas where additional aelantlfle roeeareh la required, a sclanrlficellp toned beele <ot prudent political decisions nut bo dnvalopod. The Q.S. tnvlronnoneal Frocscclon Agency and Life Spatana, Inc. ara to bo cnmtnJod for organising tbls laportant Synpoalun. 0. lutslageT Ihiiarfltp oi iayxeoeh lepra*eh* Garneny lv MOWS 026038 ACXMOVIZDGEMEHTS Tho aympoelun tron which this docunont vat prepared, "tacant Advancao la Ixpoeure. Health, and Cnvlroweental Efface* Studlec of PCla," woo ha W Kay 12-13. 1962 at tha Holiday inn la Betheede, Karyland. Tha eynpoalun vaa orianltad by ICAll of Ufa Syataaa, Inc. Tha affore vaa parfomed uadar Contract Ho. $1-01-633* fron tha 0.$. Envlrouaantal Protection Aganey, Office of Paotlcldao and Toale Snbatancaa. Va vlah to gratefully ecknovlodga tha odnlnletrotlvo eervlcae of tha following tndlviduula ruopenalblu fat tha prograa otBaaltatlon. execution, and unMoquunt preparation of thoaa procaadlngat Dr. tnrlu Bowaal, Or. Million Parland and Hr. I. Clam VtlUma of tha Office of Paatleldna and Toxic Subatancoa, and Mr. Michael Kangaa, Ma. Cynehta Patrick, Dr. toy tauter, Mr. Crag fchlcfer, Ma. Patricia Sweeney and Ma. Cynthia tfaalay of tCAIX. Special appraclatlon la axtanded to the aynpoalua partlelpanta for the excellent cuallty of the preaoncaeloaa* the profeeelooal aannar In vhleh the aaaalona were conducted, and the emulating nature of the dlacnaalona. It wee tha eoublned effotta of all theca Individual* ehleh entered tha auccaaa af thla aynpoalua and tha raanltant contribution of koovlndgo to the acionelflc cowntnlty. I. J. Davenport I. K. Sornard HQhS 026039 cowrorrs lielalMr...................................................................................................................... PotwoH.......................................................................................................................... jkkMvUd|Moei................................. ...................................................................... Chapter 1 INT1000CTI0* .............................................................................................. Chapter 2 AKALTT1CAL HCTB0D0106ICS..................................................................... Recent Advance* on the Asalyals of FCBa in Savlroweantal llolo|lcal MU. I. 0. Falllaaerl, M. A. Moeeley, I. D. Cooper* J. f, ferry, B. A. Dealan............................. Olecnaoloe Sanaary. Mary $. Wolff.............................................................. Chapter 3 OCFOmi STVBIU - DTUKMHEVTAL MS IMIS AJID B10ACC0H0UT10W...................................................................................... Dlatrlbutlon end Fata of Chlorohtphonyla la the Eavlroaaeat. B. J. Noelenaer.................................................................. Factor* Affectlnf the lloeccnralotion and Ferelateace of Folychlerlaated llphonyla. M. J. Tadlcslk......................................... Oiacnaelom Naary. If. Balance* .................................................................. Chapter 4 KZF04QU ITUDIKS - tSDOSTiXALFB0CBS9M...................................... Sspoovro India* Bolotins to ladnatrial Frocoaaoa Contelalai lacldontal KB. K. 1. Bod|e*. T. A. Boblaeoa, C. J. loonier, B. C. Beley, I. Caepere. F. Maid, A. B. Flttevay.................................................................................................. Dlaonaaloo Iwary. I. C. Kaley ................................................. .... Chapter 5 HALTS tFFICTS - tFIDDUOLOGT........................................................ Bocont tpldonleloflc Itadloa of FCBa. W. B. Gaffey......................... Dlacoealoa haary. B. D. Uabrai|b.......................................................... Chaptav 4 HALTS BFFBCTS - LABORATOBT ST0D1BS............................................ Facaatlal Boalth Bffacta fro* Kspoenre to Folyehlorlnatad Blpbenylei Laboratory Stndloa. I. L. Frloaa, 9. A. 9rlU. B. . lay*. T. A. Uoala, C. I. Ichaffer............................................. FCBei Itractore-Activlty BaUtlooablpa. I. fafo. A. Farklnaon. L. Bobortaoa, T. lawyer, S. landlore. 1. tafo. M. A. Coapholl, N. Mallla.......................................................... Dlaenaalon Suaeary. B. 0. Klahroofb.......................................................... r 11 Ill v 1 4 4 41 44 47 97 124 134 137 112 1M 119 202 211 212 229 249 contioeodvi *0HS *60+o Concrete t - concieurrf Prtr Chrptrr ? WVI10HHWTAL OTICT*................................................................................. cavlroMMacal Sfftecr of Polychiorlaretd UphrnyLrt Irporerrc leologicrl Alpcti.I. C. Kuactr......................................... OUcunlor Swirr, w. Hrlrneor................................................ rhrpcrr I XISK ASStSSNBrr ................................................................................................... Arrrmtac ot thr Iuhq Kirk* cr Kir Artaclrctd vleh etir Bxprccrd tnyiro--rcX Sxporttrrr. I. C. Jm. I. I. Irrblm...................................................... Dlreutrler SrMry. K. I. Irbl*n................................................. Chrocrr 9 COHCUTStGMS........................................................................................................ Stsavary rf Irene Mvmcm in hpemti Irrlth ml Invlrrnarnerl Iffrcer Stvdlrr rf Kir* 0. ftseslrgrr ...... AectnOrrr....................................................................................................................................... InJrx................................................................................................................................................ 2(4 2(5 292 MO MO 337 340 340 344 351 m HONS 026041 CHAPTER 1 IRTIOOOCTXOV This publication Is coaplUtloa of dots prosoneod and discussed during the ayvpotlim neleUd, "Roceac Advenes* In Exposure, Boalth tad Invlcoweetal Efface* Scudloo of PCBs,* hold May 12-15, 1982 In Seehesdo, Maryland. Tho ayapoalua orgoalfod specifically ao or Information update for eha Envlroaaencal Protaecloa Agency's (EPA's) Polyclrlorloacad Biphenyls (PC) ?rogT*. In aora gaearal earaa, the syapoalua provided aa opportunity far the exchange of information baevaaa Pda raaaarehar* froa acadaala. govirwac agencies, Industry tad lndapandanr rasaareh Institutions. The PCSa Program waa teplenoneed by eha Offlea of Paatleidas aad Toaie Subetaneae (OPTS) to carry out eha apeelfle raqulraaanea of Section 8(a) of eha Toaie Subaeaaeao Coaerol Aee (TSCA). Saeeioa 8(a) aaadaeoa eha promulgation of rulaa by cha DA for eha dlepeoal aad aarklng of PCBa. aad aacaollahao a eiaecable for controlling eha osa of PCBa. aad for eliminating eha aauufaeturo, precasting aad dlierlbucloa of PCBa la eoomeree. Ao part of eho eoaelaulag apdaeo procaoo for acquiring relevant data for cha PC8a Program, eha OPTS roqueaeed that a two-day eympoeium ba aadartakaa which voald provide a form for a fall aad fraa dlaeaaoloa of scientific lasuaa ralaead to PCSa. Stoopstun Seoao and Objoctlvaa Tba data prasaacad la eha aynpotlms vas llaltad to that which baa lacema available alaea 1978, lacladlag bach pwbllahad data aad data fraa atwdlaa chat ara atlll In progress, So formal eoaaldaratloa waa glraa tha DA'a paat or potaatlal ragulatovy scclvltleo coocaralag PCSa. Tha following objoetlvoo won ootabllohod for tho syapooloa: 1. To ravlov, dlocaoo aad Incarptat PCBa aeltnclfle data pwbllahad tinea 1978 oed pnllalnary PCBa data froa ongoing work. 2. To provlda for aa eschangs of vlaws batvaon selontlata who ara kaowUdgoakla aboat exposers, baalch and environmental offacta, aad Immo baalth atwdlaa aaaoelatad with PCSa. 5. To Idootlfy tooooreh gaps ond oroao of ogrooaont and controversy. Sraaoalaa Partlcltoata Tho followlag iadlrldwols portlelpocod os tho Chairperson* os Spoohoro or ao Dlseasaloa Loodorot MONS 026042 Chairperson: Dr. Otto Rutsingtr* Unlrsrslty of Amsterdam The Metherlend* Author*: Dt. Seynoar fries* 3rltl, frlM. Bays, loetii 4 Seluffir, lac. Arlington, TA 22209 Dr. Vllllaa Caffay Monsanto Conpeny St. tout*. MO 43147 Mr. Kent lodges Dev Chemical Coupany Midland, MX 44440 Mr. Bleherd hatar 0.1. Any Cory* of b|inri Tulsa, OK 74121 Dr. lobart Jamest Ecology and environment, lac. Buffalo* VT 14253 Dlscnasloa lenders: Dr. laymsnd lerblson University of Arkansas for Radical Sciences tlctla keek, AX 72205 Dr. lobart Xalay Monsanto C--yany It. Unit, NO 4)147 Dr. tout. Utomtht Cantor for Manaoa Control ChambUa, A 30)41 Dr. lobart Hooleaeer Dov Chemical Company Midland, MX 44440 Dr. (do Palllttarl lesearch Trlanglo Institute laaaarcb Trlanglo Park* DC 27704 Dr. Stephan Safe Tanas ASM Culverslty Collage Station, TX 7714) Dr. Mary Jo Vodlcalk Radical Collage of Vlsesnale Hllvankaa, VI 53224 Dr. Mark Halancon Madleat Collage of Viaconala Mllvaukao, VI 5)224 Dr. Mary Wolff Renat Sinai School of Hodlelao lav fork, MI 10029 *Mov at University of Bayranth, Bayraoth. federal lapublle af Casnaoy. tgav at Bnlvnrslty of Arkansan, Dirtsion of Tonleology, Little teak, AB 72203. agav at Cantor .for tavirowmeuts1 Booltk, Arlaaea. CA 50333. 2 HOMS 026043 CvfjnKieten of Sropotiuo tn order ee achieve the above arspoelu* objectives, the *yvpo*luo vat lut4ad into aavao **silons. Tba leu coplea, la order of presentation are aa follovti Analytical Methodologies Ixposure Studio*: Environmental Residues tod lloeceunulatloo Exposure Studio*: Industrial Processes aalth Effects: Epidemiology Health Effects: Laboratory Studio* Environments! Effaets Risk Assessment Each seaslce coaoutod of Che presentation of papers by one to thro* tpasksr*. followed by o discussion period. During tho dlacuoolou period, o ilolofuo i ootoblltkod hetvaan tho tpukm and tho symposium ottoodoos. bastion* wort outvoted, and dot* and tho Intarprataelona of data vora xenauged. Etch Discussion loadar moderated tho discussion period for oaa or tvo aaaaloot. following tha symposium. tho Discussion Loadar* proporod tuomerlee of tho dlaeuaalOM from thalr uota* and tTMterlpto node during tha symposium. Tha chaptoti that follow art arranged la tho ardor of tho som aa*looa. Each chapcar contains tho popart that vora pro*aotad and tho discussion auaaary. praparod by too Discussion Loadar. Tha late ehepttr (Chapctr 9) It t sutmary of tho accomplishments oud :`*'jlt* of tho work praaancod and dltcvtoad during tho tyvpotlvo. Although 'rlecon frov tho cachoolo|lc*l vlovpolut of a tingle participant (tho symposium Chairperson, Dr. Otto Hettinger), it prorldaa a ooadad interprets* clou of tho uauy fact*, vacant technical advances tnd tdontlflod daea |tpt that vara praaaotad and dloeuaaad during thl* tvo-day parlod. 3 026044 hons aunt* 2 ABALTTICAL METHODOLOGIES This chapter revieve certain analytical advances m PCBa detection. Hiatlflcatlon, and quantification. Sigh roaoiutloo gee chromatography la covered In detail, vith specific references to capillary columo development end anppertlng 'phase' eecbodolaglce, detector lyitm, and tbo eomparaclvo advantages and llnltatloaa of aaeh combination. Problems aaaoclatad vlth instrument calibration arc generally caused bp tha nonavailability or lack of primary PCIa atandarda, and tha possibility of using secondary ataodarda ouch aa vaUndefined eonmerelal PCIa mixtures. Tha application of ehoao navar method* to environmental, biological, and procoaa acraan samples aro discussed. tbi dlacuaaion twary la a review of tbo advantages and lUltationa of tbo various mathod*loglas. Topics Include procoduraa for analyala of PCBa contaminants, validation methodology, liate* af detection, PCIa pattern recognition, and tbo cooc/beneflc ratio of packad versus capillary eoltm gaa chromatography. UCtBt A9TAIKU IB TVS AKALTSIS OP POLTCBLOtUUTO BIPBIVTU l* BfVIBOBMElfTAL ADD BIOLOGICAL MEDIA I. D. Palllsaarl, M. A. Moealay, B. D. Cooper, J. T. Barry, B. Damian Analytical and Chemical Sciences Baaaarch Triangle laatltuca Baaaarch Trlangla Park, DC 2770* *. D. HaIlia tf.g. tnvlronmantal Prataeclon Agency Large Lake* laaaarcb Station Croeae IU. MI 4SIM IMTtOOOCTIOB Polyehlorlnatad blphonyla (PCBa), tarphanyla (PCTa) and quedphenyls (PCQa) bad bean manufeetnred aa commercial mixture* (Aroclortm (OS), elephant (Germany), and Kauoclar# (Japan)) far eort than font daeadaa before they vara beanad in the OS la 1970. Baeauam af tbalr long-tarn heavy naaga aa dlelectrie flalda. In trantformoro and capacitors. In hydraulic flnlda, fire ratardamts, ate*, and chair poraleceace, PCBa have permeated Into practically every environmental median throughout tha world (Ruttlngcr at ai. 1974). Icceuoc af their ubiquity PCBa have received considerable attention la recant ynata In thn erne of analytical measurement* and toxicology. Slnea anvlronaantal pollatlon by PCBa flrat became apparane, a plethora af purification procedures, gaa chromatographic eyeearns, detectors and nethoda far quantifying gaa chromatographic reapor.ee* has bean reported to dototnino aha coacanlaatltfo of anvlrecmnetal and biological samples (Hutslnger ot el. 1974, Sharma 1975, Chau and Sampton 1975, Lao at al. 1976, Krull 1977, Irishman at al. 1971, Pemnraota at al. 1976, Stalling at al* lf79a,h, Shnrma HONS 026045 1981, Albro at al. 1979). Rovevar, until racenc advances in analytical Instrumentation, aote of tha conventional necbodology yielded only senlquantitative data wttb virtually no qualitative or quantitative Information oo tha Homer competition for PCIe In cha aanpla. Tha analytical problems ara complicatad by tha face chat chart ara 209 Individual ehlorlnacad biphenyl laomera (Rallsehalteer and 2all 1980) spanning 10 homologous aarlaa (1 to 10 chlorlnaa par blphanyl). A cowerclel mixture (a.|., Aroclor) ltaalf nay contain aa aaoy aa 80 chloroblphaayl iaoaara representing aavaraL honologs (Ballochnlttor and tall 1980). Tha conventional quantification nothod la baaad upon packed column (aa chromatography (GC) and raporta tha PCI contone In environmental and blolofleal temples by referring le to a particular Aroclor mixture Aroclor 1242, 1254 or 1280). Tha CC daeaceor la flrat eallbratad ualng coumerclal Aroclor alxcurca, aod tbaa tha approprlaca commarclal Aroclor proflla la maeehad to eho tampIt profile. Oalog tho Vebb-McCall technique or o variation of It tho total PCS contant la calculated (Vehb and McCall 1973). Thla approach, however, la potantlally aubjacc to conaldarabla arrer. Environmental eontamlaatlon may ba darlvad from Aroclor nixturea or from Incidentally gaaaracad chleroblphenyla uhaaa proflloo do aot raaamhla Aroclor patterns (Pittaway at cl. 1981). In ottbar capo* tha convancional quantifi cation nathod la inadequate. Aa tlma peseta, cha "Areelor patterns" undorgo alteration In tho onvlroamaot atnea aalactlvo weathering and bietranaformaclon and bloaccumulaelon in living organlama parturb tbaaa pactarns. Tha problam of Aroclor pattam dlcalmlUrlty will ba further aggrtvatad aa PCI monitoring caatlnuaa into tha futura. Tha quantification problam la further exacerbated by production of chlorebtphanyl laamara la ekemleal precast ttrsamt. Inclaaratloa, ate., win chamical or pyrolyala raactlama which ara aot tha cams at tha chamlcal rasetloaa onca uatd for tha maaufactura of Aroclor* (Plttavay ot al. 1981). Tharo la aa raaaoa to ballava that Incideatal gamaraelan praducaa aay fixad pactarn of chlerehlphanyl laamara which cha analyte can waa to Idenelfy and quantify chleroblphenyla baaad open pattern recognition from cha packad coluam gaa chromatogram. Thus, the qualitative and quantitative analysis of PCBt la environmental and biological aamplaa tad la aamplaa from procooa acroama Involve# tho difficult leouo of having to dotoct. Identify aod quantify each Individual laemar. Tha accuracy of PCI determination la environmental, biological and procaaa atraam aamplaa It, la addition to tha raa*ona glvao above, also rolattd to tha dagrot of variability it tha analytical response of each chlaroblphemyl Isomer to tha dataatar amplayad (Vmtalagar at al. 1974, Boa and tgaac 1179, Albro at al. 1981, Safa at al. 1975). Recant theoretical and axparlmaatal atudlaa have lndleacad that cha blelaglcal propartloa of chlerebipheeyl laamara ara aigmlflcancly inflmamaad by tha number and biphenyl ring petition of tha chlorine ateme (McKinney and tlngh 1991, Poland and Glover 1977, Matthew at al. 1978# Kimbrough 1980). lecture tha toxleological proparelaa vary conaidarably among laomara (MeKlamay and Slr.gh 1981, Poland and Glowr 1977), moro oophlatleatad mochada oapabla of yielding information about tbm-~chaaleal composition at tha leonerle level ara 5 MOMS 0260+6 required In order to precisely investigate and aaaaaa the toricologieel consequences of PCI pollution. Obviously, the Ideal analytical procedure le one whleh Idenclflee end meeaures each Individual chloroblpheoyl isomer. Thle chapter esamleae the noet recent advances which strive to neat the objective of Individual chloroblpheoyl looser Identification end qoenelflcsdon. The ereee dlecueeed ere: (e) high rooolutlon geo ehronecogrephy; (b) detection systems; (c) availability of chloroblphenyl looser standards; end (d) application of etece-of-the-art notbode to the anelyolo of envlroasootal and biological oaspleo. Zt le beyond the aeopo of thle paper to Include easyllog techniques and loolaelon end purification nethodo. Theoe have boon adequately reviewed elsewhere. HICH IISOLPTIOH CAS CWOKAIOClAFHtC TICHWOtOCT In order to analyse for 209 Individual chloroblphenyl laosora the uao of high rooolutlon chrosecogrephle techniques lo sendatory. In thle respect, CC currently la far enperlor to high resolution chin-layer and high reooLutlon liquid chromatography fot FCI analyela. The relative serlte ef peeked colw (leu resolution) versus capillary colusn (high roaolutlon) 6C analyala of FCSo have boon euceloctly reported by Hhllln end Fllkloo (INI). Their work provided the tapetea for further rooearch into the dotarnlnotlon of as optlsa copillary eolm(a) for the onolyolo of individual looaaro of PCle, polyhroslnotod biphenyle, pestleIdas and other halogeneted hydrocerhone in hielog ical and anvlrouaontal asaplea. Peveloosent of Caalllar? Cohans Noaeley and Pelllcceri have recently reported on ostenelve lnvaetlgetlon lata flva varlebloe which affact eaplllary porfersenca far tha analyela af PCls Ofeeeley and Pelllaaarl 1942e,b, Pelllaaarl at el. INI). These variables ere: (e) notarial af caaatrwctleas (b) pretreetxenc/deectlveties precednreei (e) stationery phase type; (d) stationary phase fils thickness; end () capillary dlsenelone. Ivelneelon criteria esployed were: (a) aaparatlon onsber (It) between 2,2',4',3-tttrechloroblphenyl end 22't4,4',i,4'-hexechleveblphenyl; (b) reeolotion bntvnon 2.2*.S.f'-cetrachloroblphenyl end 1,2'.4 *.3-tetrachlarahlphany1; (c) height equivalent to an effective theoret ical plate (ItSTF) for 1,2',4*v5-tetrachlerehlphenyl; (d) adsorpelou character istics; (a) thermal stability; and (f) general performance on an Aroelor 1242/1240 mixture (111. w/w). Ceplllarlafl sura made Iran pyres and soft glens, quarts, vitreous allies ad fused silica matarlala (Naaalay and Ptlllsterl 1942a,h, Pelllaaarl et al. INI). The abjective ef thle facet of the study wee to determine the moot eultahla Mterlal far construction, protreatmont/doectlvetlon, end emanehlllty to tooting ef e thin, vnlfetm, table film of atetlouery pbeee. It was recognised early ta this work that theee variables ware not Independent ef each ether. Incept far C-47, ell stationary phases evaluated could ha coated an the flexible elllea capillaries (Pelllaaarl et el. 1941). Preference for cbe silica capillaries was attributed te tbeir flexible nature facilitating their eeeemhly Into CC# even by the nnvlee. Thus, e major impediment te the bM of coptturloo by tbe smvtycleal esnmsnlty had been removed. 4 HOMS 026047 Hany pTt*atn*ut/dasctlvatloe procedures wri Investigated tinea Che rev constructleo notarial vtt net suitable for dlreetly casting vlth stationary thee* Otocelcy t4 felllsserl I992a,b. FtlUiiatl it el. 1981). The procedure* vert: (a) berlua carbonate treaeaoat: (b) Carbowes 20Hj (e) tupre*-4; <d) WC1 etching; () peTollylatloo; eed () thetnelly laduced polyslloxane (SC-52 or 07-101) bonding. The preferred atehodc vre polyclloxene deactivation on allies and pyre* aod persilylaclon on pyrex (Moseley end ftllltttrl 1982b, fellisssrl tc el. 1981). Although |lttt ceplllerlee coeced vlth C-87 stationary phee* provide exeelleet ra*oluiion of individual cfcloroblpbenyl teeners, ate of C-87 enereoely It Halted by tvo factors - lte teaperaturo eteblUcy ^>220*0 ted eb* current inability to aveeooofnUy coat e nalfoca file to elllea. Secauee ag the upper eeeperacur* Halt Che C-87 phete coeced ceplllerlee are inadequate tor the analytle of KTc, FCQe, Till end Maple extract* whieh ere very "dirty" (e.|.t flab), for there reason* eltorneto stationery phaoao vert sought. The current literature reporta aevoral different pboooe oeed in eeplllary OC for oeelyole of fCle (Albte oc el. 1981, Mollio end Filklaa 1981. CrapeIk at el. 1978 Irupelk at el. 1980. Albro-et el. 1977. teelllnt et el. 1978. Truaetre et el. 1981): bovever. until our retoerek ehoro use not e eoueortod effort to tyeteMtleeily ovelneto pbeeoe Otoeeley end Volllsserl 1982a,b, FolHsxerl at el. 1981). Being the pruvlouely aentloned erlterla e ontrlx deolgeod etudy m executed in eoeeert end while asking e eouperleon ef phase selectivity (Ikfteyuolde' eooetente) to guide the overall laveetlgetleu toward the "eptlaa" phase. Among the phases evaluated vers C-87, ll-)4, P-2100, 07-1. 88-52. 07-101, Dexell 410, Apioson N end Apleson l. terly reeulte pTtdieted (Iron Meteymoldo* eonateate) that Apiesoa N would aoet eleeely alale the excellent nnperetlen pntcern nf C-87 (fnlUxterl nt el. 1981). In feet, thle eorreeptndence wee experlaentelly deaoeetrated (Hoseley and Felllsserl 1982a). Several advantages of Aplosoa II veto rocognltod and will he dlecuoMd later, finally, eoaploaeutary stationery phase to Apleson M vac caught eo that one phase could carve aa a prlaary eealytlcel eatwan aod tho other e reference calaaa. 81-54 coated capillaries provided e signifi cantly different resolution pntturn cenpartd to Apleson K and SI-54 wet also elected In nut roeosreh (Waneley and felUssarl 1982a,b). It has long boat recognised that tho thloaer tha taclonary flla thicknooa tho hlghar tha nee* treaefer eanfflclant. Tha aaapla capacity, however, dacroaaaa. Thai, monarch was patterned te deteralen e flla thickness which had e vary high aeaa transfer coefficient (as aaaaurad hy I88TT), adequate aaple capacity far tha datectieu aystaa to ha eaplayed, and stability te leaf perleds ef usage Qleealey end falllssarl I982e,b, felllsserl at el, 1981). Stability (to ealvent and tberaal aback) could, of course, he lap*rted by iMobllisiag the flla on tho silica surface by a erosellaklug/flurfece bonding reaction (Meteley and PoUisserl 1982b). Tun anthode ware reported whleb iasoblllsed phases to elllea (Moseley end felllsserl 1982b). One utilised e thermal technique (88-52) the second e dlceayl peroxide reaction (88-54). The first astbnd easily produced the desired (L821.ii flla capillaries for see vlth electros capture (1C) sad negative ioe ehealeel looiaatloe (VtCI) aaee tpectreaatrle (MS) deteetlou ef 0260*8 HONS fCla. Those capillaries exhibited e bleed of 0.7 pA (fleas loeltatloe detec tion) ot 520*C. Tbo iko4 aotbed yieldod thicker f 11m (0.1 v) for higher capacity for with electron lapoct MS. An Agioson M photo taaoblltsed to tlllco has not boon reported. Tm results of these Investigations which specifically focused on resolu tion, of KBs Indicated that A slUen capillary, polyslloxane deactivated, 0.2-* tD x 50-n la length, eoeeed with Apeixon H (0.025 u ftla) or St-54 (0,925-y flla) la preferred (Moaoloy end felllsserl 1902a.b. folllsaarl at al. 1901). An Aplesoe N sooted flltca eeplllary allows tha elution of PCIe to aeenr approxlaaealy 50-40*6 lover than other ececlouery phaaaa (Moaoloy and folllxssrl 1902a.b, Felllstarl st al. 1901) and la ehemally stable to *215*6. Connarlaon of focltod and Capillary Colons Profiles The loharane dlffaroneaa boevean low end high resolution gas rhrcraa tographle eolnana are exanpUfiad by figures. 1 and 2. figure l eeaperea tha prefllaa for a standard mixture of Aroclor 1242/1200.. Figure 2 deplete toe profiles for a stack (otscionary source) aanple (Nellis 19011. loth high resoihtlon analyses vers performed on SI-54 fused allies capillaries. It is evident lx figure 2 that the loo resolution profile does not readily reenable a ewerelsl Aroclor sixturn. Thus, It would be highly Inaccurate to guentlfy the lev resolution profile using a coanerclal Aroclor standard fox lastnaant calibration and tha Vabb-McCall nathod (Vabb end NeCall 1975). Several exanpleo danonstratlng the performance of Aplaaon M silica capillaries vlll be discussed later In this chapter. pcncncN mip Bedes of Detection Use of several types of detectors has been reported over the years in tha analysis of PCOe. Oowower, only a few have ends significant recant advaacas that are noteworthy. These am electron capture, negative ion cbenlcsl loelestlsn ness epeettonetry (VXCX-Mf) end selected ten nenleorlng (SXM), a variant af electron lapact uses spectrometry. Ilectmn Capture Oetectlon The electron captort deteeter ccntlnoee to ho one of tho noot oonsltlva and hanen valeabla aalactlva detectors for fCB dotsctlon. It Is only rscsntly, housvsr, that Its full petsntlsl has boon realised sad incorporated into coMorc&sl nyttsas. fron a guancltatlvo standpoint, one of the llaltetleno of the electron septum detector in past has bean nonllnssrlty of rsspenss. Until the sN19r0f tan tCP la nan had r linear dynaalo rsnge of approxlastely 50-100. Poverol pepero hauo doslt with dotornlnlng tho propor function vhlefa would give s linear rslstlsnshlp with coocsntratlon (FoUlrssrl 1974, Vsntworth andI I HONS 026049 Fackad colon rtfun I. Ckroaaeanrau at Araclar 1242/1264. Tat taeltad colaaa. kattaa - catlllaty. 1 moms 026050 -1______________ _L34 INJ TIm, ala i --.i 100 70 TIm. ala 30 i X1U Flfara 2. ChroMtotriaa of stack oaa^lo, Tot " Mcfcod eolw, boetoa - capillary. 10 HONS 026051 Chvo 1979). It baa been auggaatad that tha reepoaae vu legarlthale by Hilatjp to light abeorptloa (Vaetvatth and Chn 1979). Imvtr. vtaa tbt IGD vaa opiratid la the pulse iplla| node tha reaction# aceartad prinrilp la tha Hold free ptl4. an that tha analogy vaa not eoealdared vary appropriate (Vaaevorch aad Chan 1979). Onca a valid kinetic nodal for the aiaeeroa capture procaaaea far eheraal reaction* vaa darlvad by Uentvorcb at al. (1979) and tba raaaareh la atveepherle procure levitation Mat apactronetry gave direct evidence an eagatlva aad poaltlva loa formation fuadar ECD eoadleloaa). tba aolutloa to aiaeeroa capture detector noallnaarlvy vaa la band, Ateeeelon yaa faevaad an tba tCD'a eoneantratlen dapandaaea vbleb baa beta of great concern ea analytical ebanlatry. Aaalyala of tba klaatle nodal vaa earrlad out by ouMTleal eolation of dlfferuatlal aquation* vbleb allavlatad mm of cba early oathanaelee-l ainnitliiii Aa a ratals of tba asparlaaatal vark an alactron eaptura Meemia*, ubeegueet raporta appeared la tba Utaratvra daacrlblag an altanaca oatbad if linearisation of raaponaa Ofagga at al. 1971, Fattereoa ae at. 1976). rba fuedenental prlaelpla vaa baaed apov nodnlatlng tha fraguvecy af pvlatag tba detector alaecrodaa ao Chat tba plaint evrraac vaa nalatalaad eooataat. Tbla function la given by where F tba fregaeeey giving tba baa# current la tba ebeeoce of 9 eaptarlag apaclaa F tba fregueney giving tba beta torrent in tba praeanca of a eaptarlag apaclaa Initially there vara raporta af a Vnk" la llnaarity, but vltb lnprovad laatrvnaat daalga paraaetera tbla prablaa vaa ellalnated (Fattaraav at al. 1979). Thai, cba aadarn KD.ntlllaaa aadvlated pvltad fregeeoey to acblave a dynaale ranga af appro*Inately four order# af aegnltvde, ea laprovanant vbleb la neeaaaarr for tbn aaalyaia af FCla la anvironaancal and biological anaplaa. A aecoad limitation vna tba fCD call vaSaaa. Tbla prablaa did aac urfece until analyata bagaa laveetigatlng tba van of high raaolatiov capil lary coluanf (Fnlllaanri 197A). Tbn original call valuaaa af 2-4-nL vara ade quate vban nsad vltb packed catenae abate (leva vara high tad ebronatograpblc peak abapa aad afflelaacy vara praaarved. A lav itainted raporta appeared in tbn lltntntara addranaing Improved tall daalga, la pertlcalar lav valaaa cella, far aaa vltb taplllarlee. KCD call volnai batvnaa ISO and S00-*i etlllelag a coaxial daalga trill regvlrad a *cavenger gat after tba capillary catena to reduce tba raaldaaca tiaa la cba ICO call aad praaerra tba alertklgb tbaaratleal pUtca vbleb vara nttn&nnbla by capillar!#* (Pnlllatarl 1974). Bavavar* it vaa only recently that eoaaarelal OC ayataaa baeana routlaaly available vltb lOe covpatlbla vltb capillary flov rataa. Wick thaaa tvo parallel davolopaaoca it la nav faaalble to pnefaen elegeac gueaUtatlvo electro* eaptura datactloa af FC9. 11 HONS 026*>5i UtMttH loo Chonlcol Iwliulw Kiu <wettc--trt This 4titiN MtM ta virlnt of poiltlv* loo ehraleil tonlratloa Mii opectrooecry. The eclated alactroalca eo ragvlato, facoa and peat aagaclva Ion# Co to appropriately polarlaod oloeeroa aultlpllor vara developed la tha aid-1970#: Iwwrar, 1c a aoc aacll ncactlf that too soarca ted raagoat |aa cooditloea vara lavaotlgatad far optimising PCI analysis (Pallltsarl ac al. I9l). HlCl-W la aalgeoly suited to naasartag eraea guantltlas af polyhalotaiatcf ebenlcali la tavlrn--atal atopies hatmia af tta high sensitivity far these cheaietls sod lea virtual transparency co ocharvlaa potentially lacarfarlaf solecnUe (bahl at al. I9B0). le alaa provides, la addition t sensitivity, Mlaevlir laa information oad tka a verification of tbo struc ture! aatlty belag aaaaarad, a hl|hly desirable faatura vbaa txealnlnt eeaplas tavlroamontal aid blalagleal oamplao. RICJH0 is vary slaaaly analogous to electron capture daeactloa la cbac the laa fatalag raaecloaa ara com to both, lha loa faming raaetloaa that ata Uporteat far polychlorinated nolocales hm baaa daacrlbad (laahl at al. 19B0). Thay Includes (a) tha raaldaot eaptara of tbanal alactraaa; (b) eblaclda attechmaari (a) dopratoeatlooj til (d) oxygon axebongo. Bacaaaa I1CI-W la a mtII tachnlgoo* tha operating paraaaters vbleh optInis* tha teehalgne prafaraatlaily to aaa af tha abora sschoelms for PCI aaalyala hm rataatly baaa atadlad la oat laboratory. lavtatlgatlraa la this laboratory boot eoatorad oo tbo aao of blgb roaolatloa gaa chromatography is combination vltb BlCl-tfl ablla olaeldatlag and cbaractarlalag Instrumental parameter# oaltablo far fCB analyaaa (Felllsserl at at. 1911), Tbasa lnvaatlgatlana hm Isclndadt (a) asanlalag tba parfananca af tvo dlffarant loa ooarea designs; O) tbo offoct of ooorto praaooro on oonoltlvlty and spectral alcantnrot and (e) tbo offoct of various roogenc gaaoa on oonoltlvlty and ffpmiutloc of KB loemoro. Conporod to eonvootloool oloetroo Impact Ml* loot Infonatloo aboot tbo atrnetato of tbo tangBind la obcalnod. Thai, tbo apoclfle ala af tbo lovoatlgatloaa voa eo tody aaoaral nodaratlog and raagant gnaaa ta anbancat (l) tha fornatlon af nalacalar anlana af tba individual eblocabipbanyl Isomers; or (2) tbalr dissociation ta ytald ablaHda 33 and 37 isotopic anlona (Pallltsatl at al. IW1). teegOot gaa atndlao vara condnctad vltb natbona* oxygon/nltrogen, altrova vsldo/altrepan, altraaa anlda/natbaaa. dlfUerodiehloromsthsos, and tatraflmrmthm. fhio variety of raagoat gaaoa voa nacaaaory bacavao a najor problan anaooatarod in BIC1-MS analysis af KBa bod boon tbo laek of aolaevUr valght infanation abtalaad far tba laoar nalacalar valght KBa (C.-C.) vndar natbaoa nadaratad alactran captwra conditions, tinea tba lovsr nolocular valght KBa wsdargo dlaaaclatlvo alactraa eaptara to fan Cl" laaa vndar these cooditloea, voa af a raagant goo vblcb ebanleally react* vltb Individual ebleroblpbaeyl laooor* rather than Just aodaratlag alactraa energy lad ta tbo observation of etaful nolocoUr valght lafonation la tba apoctral slgnatura. Plaid at al.* (Salt tad Plaid 1990) had ohaerved that a nlxture of alcrovo aside and ootheaa prodvcod abvadaat fit" lose voder negative laa HONS 026053 eoedltlona. Tha hydroxide Iona vara ebaarved<>to react vleh a vide variety of conpounda by proton abatractloo to fora (M-l)" looa. Therefore. thla raatane gaa nlxtura vaa atudlad tn mr laboratory aa a llkaly candidate to provide olacular velghc laforaatlon for Indlvldnal chloroblpheoyl laonara. Experlneoca vara conducted vieb an 1X1 2091 nagnetlc aactor tnctrunooe vtth a relatively opan aanrca daclgo. Figures 3-7 depict naaa spectra of noeochloroblphanyl, trlebloroblpfceeyl, bexachloroblpbaoyl, oceaeblorobtpheayl, and dacaehloroblpbaeyt obtataad aodar P.O/CV. VtCl condition*. Nitrone omlda vaa introduced through a loageut gsa.lnlat (5 x 10*3 Torr aa Maaorad at tha Fanning gauge) an* nathana O 10* Tan) vaa paaaad into cba lav aoureo ala a CC nake-up Una and teperator. Baaed on ealenlatlona mada for positive ion nathana Cl.tba attmLwaret- ptsacnao-enartsd -by both--reagent gaaee vaa 0.2-0.3 Torr. Tha MS ayaton vaa optlalaad for n/a, 17 (OB ). A 2-Mi lojac tion (MOO-pg) of a atandard aalvtian of FCBa vaaTaedo vttb a 3<1 apllt ratio. Aa indlcatad in Flgura 3 tha tpectrun of 2-cblarablpbanyl exhibited CM-*)* tana. Tha peak at n/a, ISO la no largar than expected fron iJC laocopa abnndanca. In addltlea,~vary lov lntanaicy Iona vara fonnd for tbo (H*R*0)~ loo at e/a. 203, (K-S^lIjO)* i at a/a 231, and (M-I*M* Ion at n/a. 217. Tba high naaa region far trlehloroblpbeoyl ( a/a AO, flgora A) mm apactrua vaa donlnatad by tba (M-l)" Iona at n/ 257,7257, and 259. Tba MA latanalty vaa greater than predicted an tbn baaTa af AJC laocopa ebvndoaco (241 ti. 13%) avggaatiag that aaaa atablliaatloo of IP- aa oecnrrlng. Alao, (M-CD* Iona vnrt avldant at n/a 221 and 223. for basacbXoroblpbanyl (Figure 5) cba (M-*)" Iona at n/x, 357, 359, Ml, and 34) vara present. AXaa, anbacaneiai abondanea of IP- Ionia vaa eboerved (531 observed va. 13% ealenlatad at WC). Ion eXnatara far tbn Una af ana chlorine (n/ 323) and tvo cklerinea (i/i 244) fron tbo poront nolocnlo voro datoctad. Tbn lateroatlng_lee cXnatav Toraad by tba Uaa af cblarlna and tba addition af oxygen (H-19) vaa abaarvad (n/j* 330). The naaa spectra af ectacblaroblpbanyl (Flgura 4) exhibited negligible hydrogen abstraction bet vaa certainly donlnatad by SH- Iona. Sines that* are aly two hydrogen# available for abstraction on tbla FOB bonolog, thla raanlc vaa unexpected. Decachlorebipbeayl (Figure 7) vlth no bydrogono available for abatractloo yla Ida a spectra that is dna to electron captnra (foraaclon of W-) and Cl*. Tba above observations far V. 0/Cl. reagent gas indicate that varlflaatlan af tba neUcnUt vnlgbt ef'tbe cnUtabipbanyl laonat ean be achieved in high raeolation OC BICI-MS. Fvrthoraora, tha henegenolty af gaa chrenatograpblc peak* in esnplax nlxtura analyala can be aatabllabad ainca non-FCl aebataucaa or nonbonologons KB laonara can be dlstlagvlobed. BICI-MB vill tbva provide nalacvlar veigbc infacnacian, vhftcb baa bean ana af tha ttroeg vita cUiaad far XX-M. Another nedarating gaa typically need la IICI-MS la nathaoa. Sxperlnonca in enr laboratories an tba affects af aanrea presents an sensitivity Indicated that aa tba nathana praaannn-4acraaaad aa alao did aanalcivley. Ac a conprenlaa between nail-- aanaltlvlty and aseaaalva praaanra, a raagant gaa proa- 13 HONS 026054 la lM iit lacoM lty in _____________ L_ IS 100 200 M/l Flguro 2. MjO/Cl^ MIC1 alia spaeirui of oonochloroblpbonyl. n HONS 026055 80 I r 5 *0 20 0 ur100 nn 1 300 Flgvrt 4, fjO/Ct^ RICI Hit ptcirva tYlcfclftTOfcltltmyl. 15 HGKS 0*6056 HONS 02605?  CJ 100 300 M/Z 0rt|ra . RjO/CN^ WCI mm iptctruM of octoctilorobtplioAyl. HONS 026058 0 ! 5 * a J5 100 luO ' M/2 jfo l *ioT MO 7Figure . N^O/CII^ NICI uaa apactiw of docachloroblphenyl. MOMS 026059 L *5aura of * i iO Torr la tonally employed (aeoearcd at ilflMlot rm* threat, actual aourea preoeora say be higher). Of the reagent and lodiratlng gaaaa mflH. Mthm gmlfM oua of the tore coeltlwc node* of fincloe. Iemr, tbo erlaclpcl mochonlom of reaetlou la dleeoclatlve oloctroa capture toadlog to a/ 33 emd 3? vbieh cau bo uaed for quaeclfleatloe. "" The ebaadeal thermodyeamlco tu iICI*MS la alao affected by the physical design of the CC/HS aourea where the Cl takas place. Tba iitiTlami coo* ducted with a relatively epee aad eleeed aourea daalgaa gare parallel veoelta. The principal feature of the ogee aourea wee that It uae leee auhjaat to filament carhoelaatloe an4 lea eemeltlvlty waa aalmtalnod atthle far a few woofca. Consldorehla abaoluea dlffaraacaa la eba Units of detection ware obeerred botvaaa two dlffaraat laattuaent oakao. Oua ayataa in tlacrly capable of detecting la tba blgb fautograa regloo, ufclle tba oth*r required two otdata of magnitude more TCI notarial. That* tba UmtigH of both aeaaltlwlty aad aoleeular weight lafenetieu cat bo realised wlcb VIC1-HS, Tba roeoat atudlaa bare provided a baaie for cboeelag the opyropriata oparatiag pazaaetete (at aaalyaia of KM. lolactod loo Wooieerlaa PMUrlmg P-tt Electron Impact mii apectronetry baa baaa a vary papular aaalytleal tool* la addltlao to SCO, at a PC detector (or KM. Tba oao of tba eaowao tleoal acatalog uoda auffara fm aa laedognate Unit of detoetioa for cblerehlpheoyl isomers. Tba Units of datoctioo say differ hotwoeo 11-M aad BO by aocb aa tbroo ordara af aagaitoda (Talllatarl till)* Far tble raaaao* II-IB got, H baa aot baaa vldoly auceeoaful ualooa tboro aro large quantities af PCBe preeeat la oowireaaeafl aad biological soaploo. Tbara bava baaa report*. bouovar* af a apaelallaad appllcatloa af IX-M. Selectad loa aoaltorlag (SXK) bad baaa prlaarlly developed fat drug aaalyaia* but recently it baa baaa applied to varifyiag aad guaatifylag PCBo (Tiadall aad Vtalapar 1990* Kartalll at al. Ittl* klbro cad Parker 19SO, Irtekaoa oad Polllaaarl 1979). Xaprovod llalta af detectlea are raallsad. Another variant of Bl-M la liaitod nans acanalog (UK). Tba too af IZM (progrannad uoda) and IM permits tba spectrometer to opeed aero time trooeaittlng tbrnogb tba aaalyiar to tba alactroa aaltipliar laaa af ftncaraat t* yield lover llalta af datoctioo (Tiadall aad Vinluger 1940). Sorb af tbeee toebalgoaa are uadar ebaputor eoattal aad are alao awollablo to tbo analyat oboa oporatlog la tbo VICl-Mi nedo. Blood Feoltivo loa gotatlvo Iaa Chemical Ionlaatlon (PPIMICI) Mate ssssassa During tba peat fan yoara FFXB1CI baa booo developed: rapid avltcklag botvaaa poaltlvo and nngatlvn Cl (Uhb) allaua alaultaoaooa laformotlon te be acquired (Patliaaarl and Mono lay 1991). Little raaoareh baa bean porfataad am lta iptNuaim dad application to Kb aaalyaia. 19 HONS 0260*0 Ccablastlon of Hth iesolqtloft Caa Chroaegoirawtr and Cltratanaltlvt iVltMtlW 2l d iflet the eonblnatlon of high rteolw- Cloo chromatography and electros capture detection. it la elearly ovldont fro* ebeoo profiles that aodern EC deeoececo t doolgaed to preserve cbe high roeoleeloe efcleh capillary eoltaaa art oow capable of delivering. The direct coopting of high reooletlon CC caplllarlaa with cho to* aowree of moo spectrometers haa alao baoo eaceeeofelly accomplished. Tha flexible spiers of allien caplllarlaa baa greatly facilitated tbia accomplishment, Inca Boat MS ayaca*a are aot wall engineered to accept tha rigid glaaa caplllarlaa. Plgata S deplete an enaapla af analysis of an Aroclor tOlt/1234/12tO alatnra (2.5t2.0tl,0 #/w/w) utilising bn Aplaaoa M phaaa coated (0.025-n fit*), MO alUca capillary and MCt-MS daeaetlon. Table l Hate tha opera*lag conditions which ware opclatsad for dleaociatlwa alactroa captnra (l.o., enhancement of j/a 39 end 37). The *aaa chro*atogra* (/t 15) exemplifies tha claaa similarity between the proportloMl raapoaaa fas TaJlvidnal chloroblphanyl laoaaca wodar naebaae tftCI coadltleaa and tboaa abtalnad with ICO. An expanded version af ehla ebromategram la given la Figaros HI. Chrometegvaphla paaha 3* 33* aad 103 are tha Internal standards, 1,2-dlcblore- naphthalene, 1,2,3,4-tatrnchlorweaphthalsne, and actachlaronaphthalaaa, raapactlvaly. Tha chreaacofTephle paaha depleted la Plgwraa 9*11 ladleata Ideal aytry aad that tha chromatography waa preserved. Tha peak raaldaaca tlaaa are generally Mi. laeaaaa tha ICO and ftlCX-M profllaa ate sapertmpeeable, tha awhbarlng scheme ehewn In Tlgasna 9-11 waa atandntdlsad far ear characterisation raaaarch aad far ear eroos-rafaronelag aad varlflcatftaa affarta. Tha Identity of aavaral af tha peaks will ha dlacnaaad hale*. Another aaaaa af rapraaaatlag ItCZ-NI lafat*atlaa la depleted by Figaros 12 aad 13. Tha top tracing la tha aaa ahowa in Plgara 0 hat It la cemslderahly radacad. Tha raaalalag profllaa la flgare 12 are aaaa chromatograms far a/i 1M (Cl.), 222 (Cl,). 23b (Cl,). 292 (Cl.), aad 320 (Cl ) rapraaaatlag tha ?lve homologous aortas. It la lapertaat to aoca that emdsr machame VICX condltlona, tha Intensity af molacelar aalean far Cl.-Cl, la vary weak ca nonaalatant. It la asrs appraprlata to aoo f.O/Cl. for sotoctlng which chromatographic peak baleens to a he*elog. ftgare'U abawa aaaa chm4H|TIM (at ,/ IM (Cl.). 1*4 (Cl.). 42* (Cl.). 4*2 (Cl.), art 4H (Cl m kWM) ri,r.MCla| tkl rartlala,Wl.iH. Mrl... If tkl* cm 114f tha iklmhl.haajl Imki Mr. (mkM 1. th, 4roelor alstur,. Tarlatlov af titwiw Uwmil 4 mm *taia. *itii to, nei-M art ii-m dot. us) ,, iKtn, u th l*r* varlatlm Sick 1, ataam. hataaaa tha MlfMul ckUnkiH--)l iaaMta, hath vithi. art hatvxv tMalafava .aria. Otvtslng.r at al. 1*74, laa in4 Ijaaa 1*7*. Alhra at al. 1MI, Ma at al. 1*7]). Tha ralattva ra4*oM* (....ca (SI ) (a, , (n iui.i^il thloT'>l*hav*l iNtm obtalart with high 7-a.oUrlvC CC-Kl [(SC)'-ICO) haa hm ra*tta4. * MJarlt* af tha IaaMta hav. h# aaalya.4 la Mr labc*cor . tha IS. eosm. (Tahla 2). Tha t**g ... ealcvlata* aa follovat HONS 026061 rifura . Mm ekrowtofraa (/ 33) / Aroelor 1016/1254/ 1260 attalaa* by OI4 21 HONS 026062 TibU 1. {GC)^/HCI-SS Paraaetar GC Capillary ID Ua|U Dcactlvaelaa Statloaar? pkaaa rila UlckMaa la earrlar Spllelaaa/aplit Taaparatura m laagaat gaa Ftripriiitn 11g* vacwa praaaara HnlfbU tflpantan laaltar Mftraun laiuiM aurrtat lltetm aatrgy Scaa cycla ku raaga Ctmdltlona (Tlaaigas 4021) Coa41cioa rutd atllca 0.23 m 45 a Polyalloxaoa Aplasoa H 0.025 n 0.6 aL/aia (32 ea/aac) 40 aac; 10:1 100*C/0.1 ala + 260*C fl.S*C/ala 4 0.2 torr , *.* x 10'1 torr 120*C 2M*C 0.5 It 70 1.0 MC 30-700 Idtm 22 HONS 026063 't<m inniHi *haHw mIi.MiM UPM> m*.mt,t#m Mimp> . I.P wi an. aI m kfri|M 9. Nsm ckrMt*grM (/ 99) of Areclor 1019/1294/ 1240 Iu1m4 CI^ 1ICI-K* (Tlfirt sp44). 23 HQHS Q16Q6H Flfun 10. Maaa ekaaaatafraa </ 15) af Araalar 1014/1154/11*0 aktalaa* kj Ol^ IICI-KI (fign, I asoaa4a4--al*41. aoitloo). 14 HONS 026065 / ;-/> ASSESSMENT OF CAP.CINOCENiC RISKS FROM PCS IK FOOD Prepared for United States Congress offset of Technoloty Asseajsient Onder Contract No. 933.1350.0 Raney S. Crunp, Ph.D. Marjory D. Nasteraan, B.S. science research systems, ikc. Boa 7356 Button, LA 71272 April. 1979 HONS 025108 TABLE or CONTENTS Bag* 1. Chlalcal Properties ............................................................................................ 1 2. Food and Environaental Contacination................................................... 5 2.1 Routes of Contamination and Environmental Distribution .................................... 6 2.2 Levels in Food from the FDA Total Diet Program ... 9 2.3 Levels in Fish............................................................................................ 11 2.A Human Exposure from Consuming Lalte Michigan Sport Fish...................................................................................................... 16 2.5 PCB Levels in Human Milk................................................................... 18 3. Carcinogenic Effects............................................................................................ 21 3.1 Human Data....................................................................................................... 21 3.2 Data from Lifetime AnimalFeeding Experiments. ... 23 3.2.1 The Experiment of Kimbrough e: el. (1975) on the Effect of Aroclor 1260 on Female Sherman Hat*............................................................................ 24 3.2.2 The National Cancer Institute (1978) Bloassay of the Carcinogenic Effect of . Aroclor 1254 in Fisher 344 Rats............................... 26 3.2.3 Industrial Bio-Test Experiment with Charles River Rats....................................................................................... 28 3.3 Synergistic Effects.................................................................................. 4. Quantification of Carcinogenic Risk.................................................... 30 31 4.1 Calculation of Virtually Safa Doses from Different Mathematical Model*.................................................................. 31 4.2 Estimates of Risk from PCBs in Diets of U.S. Adults................................................................................................................. 35 4.3 Estimates of Risk to Breast-Fed Infants............................... 39 Appendix: Review and Evaluation of Methods of Determining Risks From Chronic Lou-Lcvel Carcinogenic Insult..................... 46 References......................... ............................................................................................... 80 HONS 025109 1. Chemical Properties Polychlorinated biphenyls (PCBs) are a family of cocpounds produced by the total or partial chlorination of biphenyl. There are ten pos sible hydrogen bonds vhlch can acccsaodate chlorine substitution in a biphenyl molecule. A specific chloroblphenyl molecule aay be referred to by naming the positions of the chlorine atoms according to the dia gram in Figure 1 (National Institute for Occupational Safety and Health (NIOSH), 1977). In naming a particular molecule, the lowest possible nuebers are assigned and the ring with the fewest chlorine substitutions Is assigned primed numbers. See Figure 2 for examples of the naming convention. When two compounds have the same number of chlorine substituents on the biphenyl molecule but the substitutions occur In different locations, the two compounds are called Isomers. The class of chloroblphenyls consisting of one type of isomers is referred to using a prefix denoting the number of chlorine substituents, e.g. pentachloroblphenyls. There are ten possible chloroblphcnyls and 209 possible individual lsomera. The term PCBs is used to refer to a complex mix ture of different chloroblphcnyls and their isomers (Nlsbet, 1976a). The synthesis of a pure sample of a specific chloroblphenyl In the laboratory is quite difficult because the chlorination process of biphenyl naturally forms mixtures of many PCBs. Because some chlorine substitution patterns are more likely than others, some Isomers are mare likely to occur than others and this In turn causes some of the 1 HONS 025110 32 figure 1; Biphenyl molecule end ring numbering system S.S'.t-trieh'.orobiphenyl 2\3.*\5-t.triehlorobiph,nyl Flgur* 2: Example* ef th numbering aysten for ehlorobiphenyl* HONS 025111 ehlorcbiphenyls to be pore abundant than others. For example, a chlorobiphenyl completely chlorinated on one ring and unchlorinated on tht ether is net likely to appear (Environmental Protection Agency (EPA). 1976). PCls are produced commercially by the chlorination of biphenyl vith anhydrous chlorine in the presence of a catalyst, usually iron (illngt or ferric chloride (EPA, 1976). The chlorination process is terolnatcd at a particular step in order to produce a mixture of chlorinated biphenyls vith an average percentage of chlorine. These crude isomeric mixtures are further refined to remove color, traces of hydrogen and the catalyst by a distillation process (EPA, 1976). PCI products made by Monsanto are called by the trade name "Aroclor". Varying kinds of Aroclors are designated by a four-digit number, e.g. Aroclor 1254 or Aroclor 1242. The first tvo digits refer to the fact that biphenyl is cede up of twelve carbon stems, and the second tvo digits refer to the approximate percent by velght of chlorine in the mixture. Thus, Aroclor 1254, a mixture of chlorinated biphenyls, voold contain by veight, 54Z chlorine and 46Z carbo'n, hydrogen and trace elements. Aroclor 1254 would not always contain the exact same amount of a particular compound since commercial mixtures vill vary from batch to batch, but the relative amounts of the ten isomer classes will stay the assn from batch to batch. One. exception to the usual Aroclor nomenclature is Aroclor 1016, which vas Introduced in 1971 to gradually replace Aroclor 1242. Aroclor 1016 is cooprised mainly of tri- and tatrachlorobiphenyl compounds and contains 411 chlorine by weight. It differs from Aroclor 1242 in that HONS 0251U 4 the latter contains a grt-ater percentage of the more highly chlorinated compounds (KIOSK, 1977). In Japan other PCB products were marketed under the trade names "Santotherc" and "Kanechors" 300, 400, 300, and 600. In Cernany PCB products were marketed under the trade name "Clophens" A50 and A60, and in France under the names "Phenoclors" and "Pyralenes" (K30SH, 1977). Studies of the commercial preparations vith PCBs have turned up two interesting facts. First, about half of the 209 possible isoaiera do not occur in the coraercial mixtures. In fact, Aroclor 124S contains lets than 50 separable isomers. Second, trace contaminants such as polychloro naphthalenes and polychloro dibenzofursns (PCOF) have been found in some samples of PCSs. The contamination cay occur during the manufacturing process (KIOSK, 1977). PCBs have several physical and chemical properties of both in dustrial and environmental, interest. Even through the basic properties of the different commercial PCB mixtures depend on the particular mixture of chlorobiphcnyls in the specific preparations, the mixtures are enough alike that the Aroclors can be used ns a basis for discussion of these properties (EPA, 1976). Commercial PCB mixtures can be mobile oils, viscous liquids, sticky resins or crystalline solids at room temperature. Their color ranges from clear to yellow to yellow-green to black. A more complete listing of physical properties is given in EPA (1976), p. 40. Chemically, PCBs are very stable organic compounds, exhibiting a high heat capacity, low electrical conductivity, a resistance to oxidation, low vapor pressure and excellent dielectric properties. HONS 0251k3 3 PCBs ere quite stable to long heating and those PCI liquids with lour or more chlorine ato^s are non*flarjrjble as are their vapors. Al though PCSs are not very soluble in water, with this solubility decreas ing with increasing clorine content, PCEs are quite soluble in hydro carbon .solvents, lipids and in oils. Also the adsorption rate of PC3s onto plastic, glass, dust particles, silt and sand is high. Because of these "attractive" checical properties, industry has siade exten sive use of PCSs, aostly in "closed" or "seal-closed" systess such as electrical transforcers and capacitors, and in heat transfer systess (EPA, 1976). When it becaae evident in the late 1960*0 that PCBs had become an envlronscntal pollutant, Monsanto Co. voluntarily phased out pro duction of Arodors 1232, 1268, 1260, 1262 and 126S in 1971. Konssnto also began selling PCSs for use in "clcsed" electrical systess only and, as of 1973, was producing only Aroclors 1221, 1016, 1242 and 1234 OUsbec, 1976a). 2. Food and Environmental Contaclnatlon The particular ceabination of physical and chemical properties in chloreblphanyls that led to such a widespread usage of PCBs in Industry is also an inportant factor in the process of PCBs beconing environmental pollutants (IPA, 1976). Some of the more significant properties Include low solubility in water, high solubility in lipids and high specific gravity. To delernine the lnpsct of PCBs as eovironmental pollutants and food contaainants, it is necessary to deterstine first how they are released into the environoent and, secondly, how they arc dispersed throughout the environoent. HONS 02SH* 6 2.1 Koutcs of Ccntaninntion and Environngnfil Distribution There ere basically three vays that PCEs can be released Into the environment. First, there is Intentional disposal of PCBs and products containing PCBs, mostly into dumps and landfills. Second, there is disposal into vater, including losses of industrial fluids and deliberate dumping of industrial vastes. Third, PCBs are released into the air, including vaporization from plasticized products, releases from incomplete burning in dumps or incinerators, and re leases from burning scrap products (Klsbet, 1976b). There are tvo major methods of transport once the PCBs are in the environment. PCBs ere transported aerially in the form of a vapor or because they are trapped on airborne dust particles (EPA, 1976), and eventually return to earth in rain or dustfall. PCBs are trans ported through vater in several vsys including the movement of sediment containing PCBs, dumping sewage sludge in the ocean and direct leaks from coastal industries (Klsbet, 1976b). Due to the low solubility of PCBs in vater and/or the high specific gravity of PCBs, most of the PCBs discharged into the vater vill either be ab sorbed into the sediment at the bottom of the body of water or evaporate into the air. The latter possibility is evidenced by a co-evaporadon study on Aroclor solutions, and since each Aroclor is aiade up of dif ferent isomers of several ehlorobiphenyls, the vapor prassure or solubility of a particular Aroclor really represents an average over its various isomeric components (EPA, 1976). The former possibility is evidenced in a study ef drainage basins in the United States and Puerto Rico where it was apparent that bottom sediments contained much higher concentrations of PCBs than did overlying vater (EPA, 1976), HOMS 026115 7 presumably because of the high specific gravity and low solubility In vater of PCBs (Dennis, 1976). PCBs are available for introduction into food chains through the above methods of release into the environment. The PCBs are taken in by biota directly, through absorption, or indirectly, through a food chain. That biological signification can occur has been ob served in the wide ranging accumulation of PCBs within the biota, where extreaely large loads are found in the highest members of the food chain (EPA, 1976). It has been demonstrated in the laboratory that fish can accumulate PCBs to concentrations as much as 274,000 tiaes the concentration of PCSs in water (Nisbct, 1976a). Food nay be contaminated by PCBs also through nachinc leaks, such as heat transfer equipment leaking during pasteurization, contamination of packaging materials (recycled paper) and contamination of animal feed which leads to contamination of meat and poultry. Mothers' milk has also been found to contain PCBs. Polychlorinated biphenyls are very persistent in the environment. The sere highly chlorinated biphenyls arc more resistant to degradation, resulting in a "differential persistence" of PCBs. The selective degrada tion of PCBs has an effect on which of the Aroclors are aost persistent in air, vater, fish, and in humans. Most of the PCBs found in dry HONS 02511b s fallout and In the ait resenble Aroclor 1254 (Nisbct, 1976c). In a study done by the U.S.Department of Interior's ecological Survey on PCBs contained in whole water samples and in bottom sediments in the major drainage basins of the United States and Puerto Rico for 1971 1974, the predominant PCB detected was Aroclor 1254 (Dennis, 1976). In other studies though, combinations of PCBs are reported: in samples of both bottom and suspended sediment taken from the upper Chesapeake Bay Aroclors 1254, 1262, 1242 and 1246 were found (Munson, et al.. 1976). A study by Sanborn jet. al. (1976) on the green sunfish demonstrated that in fish a main difference in metabolism comes between triehloro- blphenyls end tetrachloroblphenyls, with a relatively efficient storage of tetrachloroblphenyls. This is also evident in data from the 1970 Kational Pesticide Residue Monitoring Program in which substantial fractions of Aroclor 1248 occurred in fish taken from the Ohio and Hudson Rivers (Valkar, 1976). McDermott, _al. (1976) found that Aroclors 1254 and 1242 were present in Dover sole taken near discharge points of southern California vastewater plants in the ratio of 2:1 while the ratio in Che wastewater was about 3:8. This last example vould imply that other factors such as the sediment load or solubility of a particular PCB are involved in determining the levels of PCBs in fish. Another factor is the phenomenon of bioaccumulation, the con centration of PCBs in the tissues at much higher levels than in the surrounding water. This is due primarily to the fact that PCBs are highly soluble in lipids and not very soluble in water. In humans there is differential storage of the more highly chlorinated biphenyls, and the less chlorinated isomers are either metabolised or excreted. Results of studies on residues in human HONS 025117 9 adipose tissue indicate that the chiorobiphenyl confounds most often found were the penta-, hexa-, and heptachlorobiphenyl compounds, in amount most comparable to those prevalent in Arodors 1254 and 1260 (Kutz and Strasr-an, 1926). But herder. food monitoring indicates that most humans are exposed to PCBs through diet, and that most PCSs in human food are in fish. This would apparently contradict the fact that substantial quantities of tetrachlorobiphenyls are found in fish. What apparently happens is that humans may be exposed to these less highly chlorinated biphenyls but do not retain them (Kisbet, 1976c). 2.2 Levels in rood from the FDA Total Piet Program In the PDA Total Piet Program (Johnson and Manske, 1977), a mar ket basket of food representing the basic 2-week diet of a 16-to-19ysar-old male is collected in each of several geographic areas. Ihe various foods are prepared in the manner in which they would normally be eaten and are then analyzed for the presence of various substances including PCBs. The lowest concentration at which it is possible to quantify the level of PCSs present is .05 ppm. Levels detected belov this level arc recorded as "trace". The results of these studies pertaining to PCBs for the fiscal years 71-76 are summarized in Table 1. HONS 025118 10 1 * Total Diet Studiea-Amcriean teenage melt Percent of composites containing PCB's Food class composites fiscal Vrar Oils, Dairy |',eat. Grain legume Root fats Sugars pro- fish l l cereal vege- vege- Garden & short and ducts poultry .products Potatoes tables tables fruits ening adjuncts 1S71 47 1972 6 46 1973 10 33 13 6 17 3 6 3 3 17 3 1974 43 1975 Pst half) 1976 40 15* r Hsnsks (1979), personal conenunic scion Source: Jellnek end Corneliussen (1976) 6 3 (Ko entries signify zeros) Table 2: Estimates of daily PCS intakes (Total Diet Study-teenage oiale) Fiscal year Averaoe daily intake of PCB's* Total diet (ug/day) Kieat-fish-poultry food (pg/day) 1971 1972 1973 1974 1975 {1st half) 1976 15.0 12.6 13.1 8.8 8.7 3.3* 9.5 9.1 8.7 8.8 8.7 3.3* *Lower limit of quantitative reporting analytical method employed. * Ksnske (1979),personal communication Source: Jellnek and Cerneliusscn (1976) 0.05 ppm with HONS 025119 11 The only food clast in which TCEs were detected in 1975 or 1976 was Mae, fish and poultry and all of Che posiciv* observations vara trace values. It is likely that these positive finds ere all due to PCS* in fish samples. JelineV and Corneliussen (1976) estimated Che microgran per day intake of FCEs based upon the FDA Total Diet Program These values vhich arc listed in Table 2, must be viewed as only very crude estisstes since, in order to obtain then, numerical values had to be assigned to trace observations. For those levels vhich were reported as trsce, the decision was made to consider them to be at one-half the quantitative lower level of detection, i.e., .025 ppm (Kisbet, 1976a). 2.3 Levels in Fish based upon the FDA Total Diet Study (Johnson and Kanaka, 1977), it appears that, for the U. S. population as a whole, the most signif icant exposure to PCBs from food is through fish. It does not seem possible to evaluate adequately at this' tiDe the overall distribution of exposures to PCBs through eating fish. The distribution of total fish consumption and consumption of tuna can be calculated froa the Seafood Consumption Study (National Marine Fisheries Service, 1976), but the distribution of consumption of other species is not available. Moreover, the concentration of PCBs in fish is highly variable, both between species and vlthin a single species. Fish caught further offshore tend to have smaller amounts of FCBs than estuarine fish, and MOMS 025120 12 fr*h valor fish caught in areas of high I'Ct pollution lend to have the highest concentrations of ?CBs. Sutler and Schutimann (1976) reported on PCB residues in Juvenile estuarine fish as part of the Rational Pesticide Monitoring Program. This report is Based upon 1524 analyses collected in 144 estuaries nation-uide during the period 1972 to 1976. The annual incidence of PCB residues and the average residue discovered are given In Table 3. These data indicate a possible gradual decline in both the maximum residues observed and average concentrations. This is likely due to the general curtailment in production and use of these compounds. It appears from Table 3, hovcver, that PCBs vill continue to cost tanlnate estuarine fish for cany years to come. Table 4 indicates the geographical distribution of PCB residues in estuarine fish, k'e note that average concentration? vary videly froa crate to state. Although these data are indicative of geographical distribution and tine trends of PCB concentrations, they only represent a lower bound to concentra tions of PCBs in fi.h caught in these waters for human consumption, Ihla is because the fish sampled were generally no more than one vest old. Pish caught for human consumption ste usually older and eon-, seguently more haavily contaminated with PCBt. Walker (1976) summarized the PCB levels in freshvatar fish as determined by the Rational Fish and Wildlife Monitoring Program. Geographically, the higher concentrations appear to be associated with certain river systems having industrial activity .... PCB residues expressed at Aroclor 1254 were found in five major river systems In the Atlantic coastal region, with residues exceeding 5 mg/kg. Four of these stations had residues exceeding 10 mg/kg during the last 5 years. Fish in four cf the Great Lakes stations had PCB concentrations exceeding the 5 ng/kg level and all stations reported concentrations HONS 025121 3 3?b)c Annuil incidence of rrci, pcb, and dieldrin residues in juvenile vhole fi*h samples, 1972-76 ftlb>*tlg, ,4/i DOT kiT" Yot K* * fnnii Ritwi A Iiimm' % Wmiwi'I tltiM ll) It) 41 14)3 43 J4 It?) l> >4 MV St IS DM )M M I MO 4} ft ttn }H 34 *M) i* JO iiw in x nu at n <W S70M71I Ml* issa AhtlMlil eia** * iM nN * m>in b**ir`* Ittu* Mk tninl AMlill tll<M;i' MO ?0JI J 0 ssi % liMti'l T 4 a I o IlliM 140 4140 IJ IS -- CtMMM x at SO is 14 -- Source Sutler and Schutsnann (197S) Table 4: frequency and average concentration of PCB residues in Juvenile eatuarlne fish by coastal area, 1972-76 CWTai AM* Fmmmmv ft Ctktm A*a Co'fiK- iaa1s*s. CMMnkM ft*** IblsM K* YmK Viefiate* len lift CftMoefti* FMeeOa ' Tiim Alabtau Vligia Il|e4i WgAiegna him H-*fi OttfM Keseefc f h4hu Oet StVb C *<* AM* M*a*iaa aa 7S S3 SI SI JSJ4 Sl M S4 33 I# IT 14 ) 9 ) a | 0 0 WMbieriMiisie D*>>' VwpWbia Vw|i Itliadi UK** liliai Cmmimmi Cf>|U M*s>|* Ke- Vtk lauhiaaa fw>* Keg Ha- aU K*e*>C>'*l>M CMmw* Oi.-ga Sdeig (atidiat AblMM Tern F Meats 1474 7M 439 )70 sso 333 333 304 343 394 343 3*4 34? 370 |03 113 14) l)| 83 HOT4 (sasngAi Sit liemtl Mb tbit the niiWKei gl >a.y*lp. *mMe 1 geaeafj--C isseegMg, pie-1 <}f>* ) 9I e*^4aag. leg Mfin Of fcefc 4.f.er I-- (Mb iwitll gist * Aaiefcaneitf Ha(t gt (>gMUH wgv < gguit ta-flei m M MM tli-- fSIII. Source: Butler and Schutzmann (1978) HONS 029122 14 exceeding 0.5 mg/l-.g. In the Mississippi River system, the Allegheny and Chio were the hot spots, with seven nut of the eight stations reporting residue coneentretidns in excess of 5 ng/kg. Thirty-one of thirty-five stations in this river system reported residues in excess of .15 ng/kg in the 1970-73 sapling programs. The highest residues, often exceeding 10 ag/kg were found in the Allegheny, Kanasha, Cumberland, Tennessee, and Ohio Rivers along vith stations on the Mississippi River at Memphis, Tennessee, and the Mis souri River at Mercian, Missouri. Other monitoring stations that vere found to have residue levels ex ceeding 5 ng/kg during the sampling periods 1970-73 included: the Villiaaette River on the Columbia spates; the Rouge River in the Pacific coastal drainage; the Sacramento River in California; the Cnena River tributary of the Yukon in Alaska; and the Rio Crande, Alabama, and Mississippi Rivers in the Gulf States region. Only in tuo sample periods of 1972-73 and in the current monitoring samples, which are still yet to be fully analyzed, has there been a downward trend, hut this occura only is those samples where residues are not being detected. The stations where high residues hava been noted in the past still remain relatively contaminated with PCS. Unlike the decline of DOT in Crest Lakes fishes, PCS concentrations do not show significant changes tnd say trend upward in salaonida. As analysis of PCS levels in fresh-vater fish in He* York State froa 1971 through 1975 by the Kev York State Department of Environ mental Conservation (Spagnoli and Skinner, 1977) indicated that Hudson River fish contained the highest known PCS concentrations with in th* United States. Levels in Individual fish were often found to exceed 100 ppa. The highest individual concentration recorded was 559.25 ppa in a large eel. Lake Michigan it another body of water that has a high level of contamination by PCBs. Table 5 shows data froa a three-year study of two species of Lake Michigan fish by the U. S. Fish and Wildlife Service Laboratory (Humphrey, 1977). Aa shown, the PCS levels in lake trout rote, during the three year period and levels in Coho salaon did not change appreciably. HOMS 025123 15 Tab)* 5: PCI contamination in whole fish* Species Location Collection Length Year (inches) Sample Size Kean PCB Value (ppm) Lake Trout near South Haven 1972 1973 1974 20 - 28 20 - 28 20 - 28 0 12.86 t 4.75 30 18.93 t 2.08 30 22.91 t 3.75 Coho Salmon near Ludington 1972 1973 1974 20 - 32 20 - 32 20 - 32 10 10.93 Z 2.12 29 12.17 t 0.77 30 10.45 t 0.92 *Data from the Great Lakes rishery Laboratory, U.S. Bureau of Sport Fisheries and Wildlife. Source: Humphrey (1977) MOMS 025124 li 2.4 Human Exposure from Consuclnr. Lake Mlchir.an Snort Fish A tvo year study (1972-1974) via made under an FDA contract (Humphrey, 1977) of persons vho regularly consumed PCB-contaminated Lake Michigan sport fish and randomly selected persons vho did not consume such fish. A total of ISO adults participated in the study including 91 who consumed more fish than recommended by the Michigan Department of Public health (no more than one meal per week or 24 pounds per year), 31 vho consumed less than 6 pounds per year, another group vho consumed an intermediate amount, and 19 fish eaters vho consumed fish primarily from Lake St. Clair'vhich are not as heavily contaainated vith PCBs as fish from Lake Michigan. A medical record, a dietary record, and blood specimens vere obtained for all participants. Summaries of mean PCS levels of participants arranged by city of residence and level of fish consumption is shovn in Table 6. In 1973 those vho annually consumed 24 or more pounds of sport fish from Lake Michigan had a mean blood PC3 level of 0.073 ppm; persons annually eating S pounds or less had a mean level of 0.020 ppm; persona eating no fish had averaged 0.017 ppm; and persons eating 24 or more pounds from Lake St. Clair (vho resided in Algonac) had an average blood level of .023 ppm. A comparison of PCI blood levels in persons in the group vith highest consumption of Lake Michigan fish to PCS levels in these vho are no fish revealed a highly significant difference in mean PCS levels (p << .001). A similar comparison between persons vho occasionally ate Lake Michigan fish (1-6 pounds per year) vith those vho ate no fish also indicated a highly significant difference (p .002). The level of PCBs found in the blood of participants did not change significantly from year to year, nor did it dlminlah MONS 025125 1. 6: Year to year comparison of moon PCS blood levels for consumers of Lake Kichigsn fish City Kean Total PCS Value (ppm) 1973 1 Participant Group Control Inter mediate ! Exposed Kean Total PC3 Value (ppm) 197V Participant Group Inter Control mediate Exposed Traverse City 0.017 0.026 0.060 0.019 0.036 0.061 .`Unittee 0.026 0.068 0:109 0.028 0.029 0.120 Udinjton 0.021 0.0M8 0.062 0.021 0.0SB O.OSS South Haven 0.028 0.036 0.083 Aljonac - 0.021 0.023 troup Kean Pirst 1 Citias 0.020 **.: Humphrey (1977) 0.0WM 0.073 0.073 0.011 C.07S HONS 025126 18 slsnificantly when fish consumption was eliminated for up to nine months. PCB levels measured during the study in cooked lake Michigan fish are*exhibited in table 7. A comparison vith Table 3 reveals that levels in cooked fish appear to be only 1/6 to 1/4 the levels in raw fish. Tne quantity of PCB invested fron eating Lake Michigan fish averaged 46.3 ag/year and ranged froa 14.17 to 114.31 ng/year for the 91 participants eating rare than 24 pounds per year. Vithln this sane heavily exposed group, the PCB dose averaged 1.7 ug/kg/day (mlcrograss PCS per kilograa body ueight per day) and ranged froa .490 to 3.940 wg/kg/day. One participant in the study gave birth to a child in January of 1979. A ailk speciaen froa this individual contained 4 ppa PCB (fat basis--the speciaen had 21 fat content), whereas a blood speci men collected at the same tine contained .033 ppa total PCB. As a group, che exposed participants had no health problcas or medical conditions that could be correlated vith PCS blood levels, exposure to Lake Michigan fish, or known symptoms of PCB poisoning. 2.5 PCB Levels in Human Milk Savage (1979) reported on levels of PCSs in human milk sampled froa 1038 individuals residing in 44 different states. Of the 1038 samples, PCBs were detected in all but 9 camples. Trace values were separated for 720 samples and the concentrations in the other 309 samples ranged froa e low of 0.3 ppm (fat basis) to 16.92 ppm (fat basis). Eighty-one or 7.SZ of the samples contained residues in excess of 2.5 ppm (fat basis) which was the temporary tolerance set by PDA for TCB levels in commercial milk. HONS 025127 19 Ibl 7: KCB levels in cooked Li.e Michigan fish 10CA11 OH Traverse City: Keen Me. Senplcs Manistee: Kean No. Seir-piej ludlngson: Mean NO. .Semples lauth Haven: Keen Ko. Samples LAJCl 7 ROUT PCS 1251 (p?) 1973 '57* 1 1573-7* risH setcics SALMON PC# 125* !pp0 1573 157* 1573-7* otmir* PCS 125* Iso*) 1573 197* 1572-7* 3. SO 2.22 2.52 3.78 3-*3 3-28 l.*3 1. M 1.35 II 10 21 37 10 8 u 2-85 2.*0 2.0 3.7* 2.20 3.8 0.38 0.53 0.78 5 II 3* 7 22 * 3-36 k.02 3-58 2.50 2.5 2.55 l.0 0.86 0.53 .3 9 7* n 3- 1 * k. I I 2.51 1.17 2 'liKlvtfti;, fikt, Whittfish, Smelt, Chubs, Menominee and Perch ^wre*: Humphrey ( 197^ HOftS 025128 20 To estimate the average concentration of PCSs in human milk, wt took natural logarithms of the reported concentrations in whole milk. Estimates i and o2 of the mean and variance of the log-conc,entratloa of PCSs in whole milk were calculated using the method of Cohen (1961) for estimating the mean and variance of a normal distribution from censored data. We then estimated the mean concentration of PCZs in whole human milk to be exp(u + c2/2) - exp(-3.4124 + .6337/2) - .0453 ppo. Since the average percent lipid content in the 309 samples was cal culated as 4.497Z ue estimated the average concentration of PCSs In human milk to be .0453/.04497 - 1.007 ppm (fat basis). By uay of con trast, the temporary tolerance set by FDA for infant and Junior food la 0.2 ppm. Based upon our use of the log-normal distribution for PCB concentration in whole milk samples, we estimate that approximately 952 of the 1036 human milk samples had PCB concentrations in excess of 0.2 ppm (faC basis). Ue. likewise estimate that the percent of human ilk samples having more than 2.5 ppm, 5.0 ppm, 10 ppo is 72, 12, .052, respectively. It vould be difficult to estimate precisely the proportion of PCB contamination of human milk that is due to FCBs in food, but most of the contamination is likely due to dietary exposure. The single measurement of 4 ppm (fat basis) of PCB in human milk of a consumer of Lake Michigan fish in the FDA study (Humphrey, 1977) indicates that consumers of PCB contaminated sport fish may have significantly higher levels of PCBs in their milk than women in generel. To corroborate this single measurement, ve considered comparisons of PCB levels in human blood plasma and milk made by Pollshuk, (1977) in a study involving 29 Israeli women. Average PCB levels measured were .0193 * .0126 ppm in plasma, and .0442 - .0412 ppm in whole *0NS 025129 milk. Consequently, the concentration of PCEs in whole milk was 71 ,0442/.019 2.33 times the avenge concentration in plasma. If this ratio holds for th most heavily exposed group of fish caters then the average concentration of PCSs In whole milk of humane who consume PCS* from fish at ths same level ss this htavily exposed group should be about (.073)(2.33) * .170 ppm. If further, ve assume the average lipid content of vholc milk is 4.4972 (Savage, 1979), then the average concentration of FCSs in milk from these heavily exposed individuals should be about .170/.04497 3.78 ppm (fat basis). The level of uncertainty associated vith this calculated value if fairly high* However, it does agree nicely vith the value of 4 ppm measured in the single sample obtained in the FDA study (Humphrey, 1S77). Since high consumers of Lake Michigan fish were purposefully re* crulted for the study, it is not possible to estimate from the study the number of people is Michigan vho consume such high levels of contaminated fish. However, based upon the information in the study, it seems reasonable to assume there is a sizable population of women who consume fairly high levels of PC8 contaminated sport fish and vho consequently have PCB levels in milk which average about four times ~ ( 4 ppm vs. 1 ppm) the levels in the general population. 3. Carcinogenic Effects 3.1 Human Data In the early part of 1968 the accidental contamination of edible Pica-bran oil lad to an epidemic poisoning of the Japanese families consumed this oil. The disease later became known as Yusbo or Pice-oil disease. The contamination of the rice-oil was due to a leak in a heat-exchange unit while the eil was being heated to remove of its odcrous components (KIOSK, 1977). The chief symptoms of Tush disease were ehloracne and eye discharges while other symptoms HONS 025130 2: included discoloration of the skin, headaches, fatigue, abdominal pain, menstrual changes and liver disturbances. Sables born to mothers who consumed the rice-oil were snall-for-date and had temporary skin discoloration. The first symptoms of Yusho disease were registered on June 7, 1968 and 1291 cases had been reported as of May, 1975 (N10SH, 1977). The concentration of PCBa in the oil varied according to date of production and method of shipment. For canned oil produced on February 5, 1968, the PCB concentration ranged from 2000 to 3000 ppm, while the hot tied oil produced on February 10, 1966 eoneelned 134 ppa and only a trace vas detected in samples of oil produced after February 19, 1968 (Cordla, a_l., 1978). The main contaminant of the rica-oil vas Xanechlor 400, but one important "minor" contaminant vas polychlorinated dihenaofuran, present at about 1/200 the concentration of FCEs in the rice-oil (KIOSK, 1977). An analysis of 146 of the total 1291 reported cases of Yusho disease vas done In 1971. It vas estimated that the lowest dose pro* ducinj overt effects vas 0.5 g (Cordla, et, al., 1976) while the average Ingestion producing these same symptoms vas 2.0 g and the average volume consumed vas 800 ml (K10SH, 1977), But tha question arises as to whether the effects noted ere due In fact to the PCBs alone. The ratio of PCBs to PCDFs in the Yusho oil (containing "used" Kancchlor 400) vae 200:1 whereas the ratio of PCBs to PCDFs In "unused** (unheated) Kanechlor 400 is 50,000:1. Thus with respect to PCBs the ratio of PCDFs In Yusho oil to PCDFs In rice-oil is 250:1. Also, the toxicity of PCDFs ranges from 200 to 500 times that of PCBs (Cordla, et a].. 1970). Thus for equal.amounts of rlec-oll and pure Kanechlor 400, the HONS 025131 toxicity of the rice-oil would range from 2 to 3.5 times that expected from its FCB content alone. Because of the uncertainty about the confounding of effects be tween PCBs and PCDfs, it is difficult to determine from the Yusho data exactly vhat effect(s) exposure to PCBs alone could have on humans. Careful records of the 1291 Yusho patients have been kept in an ef fort to determine possible long term effects. At least 9 out of the 2? deaths that occurred as of Kay, 1975, vere attributed to malignant neoplasms (N10SH, 1977.), but s causal relationship between PCBs and cancer can necessarily be inferred because of the high concentration of PCDF In the oil. The Yusho study, nevertheless, had two important results: first, the information established that PCBs can be trans ferred from mother to fetus snd from mother to child through breast feeding, and second, highly chlorinated PCB compounds are excreted more slowly from the body than the less chlorinated ones (N10SH, 1977). 2n a study of chemical workers (Bahn, e al., 1976, 1977), two malignant melanomas vere diagnosed in 31 workers heavily exposed to Arochlor 1256 (and also exposed to other chemicals that could possibly causa cancer). It was estimated chat .04 malignant melanomas would have been expected from this group of individuals. Among 41 other workers also, but less heavily, exposed to Aroclor 1254, one additional melanoma was diagnosed. 3.2 gata from Lifetime Animal Feedlns Experiments There have been a number of studies on neoplastic effects resulting from feeding PCBs to experimental rata or mice (Ito, 1973, Linder, et, el., 1974, Kimbrough, et al., 1973, 1974, 1975, Calandra, 1976, KCI, 1978). Although each of these studies provides some evidence chat HON5 025132 2L pCfift induce neoplastic lesions in rodents, only three of these experi ments were of sufficient duration to be classified as lifetime feeding experiments. These three long-term experiments vlll be summarized below*. 3.2,1 The Experiment of Kicbrough et el. (197S) on the Iffeet of Aroelor 1260 on Ferela Shtrr.an Rats Tour hundred weanling Sherman strain COES female rats 21-26 days old were divided randomly into two groups of 200 animals each. One group vas maintained as controls and the animals In the other group' were fed ad libitua a diet containing 100 ppm Aroelor 1260. Exposure vas continued until 6 weeks prior to the termination of the experiment. When the anitAt were 23 months old all surviving animals were sacrificed and autopsied. A total of 164 dosed rets and 173 controls survived to the end of the experiment. Pathologic findings sre sussarlsmd in Table C. Of the three studies discussed in this section, this study provides the most convincing evidence of the carcinogenicity of PCBs. This study involved a relatively large number of animals and the increased Incidence of hepatocellular carcinomas in the treated group is highly significant. Following are excerpts from the analysis of this study In the Criteria Document for PCBs (Klsbet, 19?6n). This was a well-designed and vcll-conducted study, deviating from recommended protocols in only one respect: its limitation to female rats. . . . Two other limitations may be noted: (a) the rats were not exposed prior to weaning, although the authors . . . had indicated the rats exposed to PCB*s during gestation and nursing showed early liver changes at much lower dietary levels; (b) the rets were killed at 23 months, relatively early in com parison to the 26-30 month expected life span. Each of these design features of the experiment, although com mon practice in carcinogenesis bioassays, is likely to have reduced its sensitivity in demonstrating carcinogenic effects. HONS 025133 23 .Me 8: Incidence end type of liver lesions end tumors of other or$ens txemined histologically (MM CelroW 'bptft* BCMal U*ti Adttntl tlind Crviu? bUddtr .tW Siuy tliad U-i AdtMM liu Bniit 0'i7 HiatUpMtic j*Um Ktp*:vnt1vlks ni(i(iest ne-4u) Tefi 9t ttU if CYtfc. plum* il;nt>oe Pjrw'c^i-ula* <iil igmi CK>6A`-e^><wK 3<.<467^* Camf-ema sdart-t.~.iJ jol)-p Adl*MtMiKrtb Suts ( tftdeealrial trema TrarjiUe'*.' nil ptpi'ltma Ttb^idfAtet ribfrii4Ri Adf**ma Lipera* Chema C>w<uli ilna nit tuner Pipillirv idiaonu CnivlKylk lu*t.*nU Tkyw*m fun*]?**d tW h >nL';<CQi TbyfMRt* ACrnema T.bnse 1/173 0/173 2S/173 37/1W 1/173 41.1A3 0/119 10/140 0/140 3/149 1/107 17/173* 3/173* 1/173* 2/173 0/173* 0/173 3/140 1/140 1/173 0/173 0/173 1/173* 0/173 0/173* w 4>Mib >ltt bAmiH 20/104 I44/1S0 113/.54 1S/1M 1/167 33/130 1/130 23/163 3/113 7/163 0/100 13/134* 1/1S4* e/i?4* 3/104 3/1*4* 3/104 0/10 3/163 0/104 3/154 1/154 0/154* a/104 1/1S4* Seurct: Klabrouth, t 1..C1973) HONS 025134 26 3.2.2 The National Ccnccr Institute Q97S) Bionrsay of the Carcinorenic Effect of Aroclor 1234 in fisher 344 Eats Croups of 24 Fisher 344 rots of each sex were administered Aroclor 1234 at one of three doses, either 25, 50, or 100 ppm ad libitum for 104-105 weeks. Matched controls consisted of groups of 24 untreated rats of each sex. All animals were 53 * 2 days of age when placed on study. All surviving animals were sacrificed 104-105 weeks after the aniseIs were placed on study. It ves concluded that "under the condi tions of this bioassay, Aroclor 1254 vas not carcinogenic in Fisher 344 rats; however, a high incidence of hepatocellular proliferative lesions in both sale and female rets vas related to the adnir.istretion of the eheolcal. In addition, the careionnat of the gastrointestinal tract say be associated with the administration of Araclor 1254 in both males and females." The observed incidences of leukemias, lymphomas, and hepatocellular carcinomas are listed in Table 9. Although Aroclor 1254 vas not shown to be carcinogenic in Fischer 344 rats by the KCI Bioassay, it must be kept in mind that this vas a relatively small experiment utilising only 24 animals per dose group. The usual number of animals per group for an NCI bloassay appears to be 50. This study vss psrt of s larger study designed to assess the combined affects of s group of chemicals which is likely the reason this biosssay is smaller than most. Overlooking for the moment the fact that the protocols were different and different Aroclors were tested, the results of the NCI bioasssy and the Kimbrough study are not all that inconsistent. A x**tes that the risk of hepatocellular carcinoma at 100 ppm was the sane for Kimbrough study as for the female rats in the NCI study was barely significant at the .05 level. The corresponding MONS 025135 27 Table 9: Incidences of leukemias and hepatocellular carcinomas in rats from KCI (1978) Sioassay of Aroclor 1254. Data is reported as no. animals vith condition/no. animals examined for condition. Dose (ppo) 0 25 50 100 Leukemias Hale 3/24 2/24 5/24 8/24 Female 4/24 6/24 5/24 4/24 Hepatocellular Carcinomas Hale Female 0/24 0/24 0/24 0/24 1/24 0/24 2/24 0/24 HONS 025136 X?-tcst applied to Che Kimbrough study and the male rats in the NCI study was not significant (p > 0.3). Thu*, because this experiment involved relatively few animals, it is simultaneously consistent with both no carcinogenic effect as veil as an affect approaching that observed in the Kimbrough (197S) study. 3.2.3 Industrial Bio-Test Experiment vith Charles River Rats This experiment vae described in an unpublished report (Industrial Bio-Test Laboratories, 1971) end e brief susaary of results was presented at the National Conference on Polychlorinated Biphenyls (Calandra, 1970). The following comments on the experiment are taken from the EPA Criteria Document on ?C3s (Nisbet, 1976a). One thousand Charles River strain albino rats were divided into 10 treatment groups. One hundred rets (50 sale end 50 female) served as controls end 100 rats (50 sale end 50 female) were Included in each of nine exposed groups which were fed diets containing 1, 10, and 100 ppm of Aroclors 1242, 1254 end 1260 respectively. Dosage started when the animals were about 4-6 weeks old end continued for 24 months. The liver slides from this study have been examined twice by the original pathologist, once in the original re port (Industrial Bio-Test Laboratories, 1971) end in a later report (Honsanto, 1975). The diagnoses in these two examinations were markedly different. Tor example, In the animals dosed at 100 ppm the earlier examination diagnosed one hepatoma and two animals with nodular hyperplasia, whereas the later examination diagnosed eleven animals with hepatomas and twenty-eight animals with modular hyperplasia. A suraary of the results of the latter pathological examination as given by Nisbet (1976a) is listed in Table 10. HONS 025137 pjble 10: Liver pathology reported in Industrial Sio-Ttst rat experlawnt: 1975 re-diagnosis Control Aroclor 1242 rata (pro):_________ _____________1 10 100 el anieals 23 31 30 20 l ;i(uolsr change 1 76 9 ;,(tl hypertrophy itVular hyperplasia 0 23 8 1 02 8 eye t ona 0 00 2 hxtular hyperplasia 5 33 3 fnolanglo-hcpatoBa 0 00 1 lipstocellular necrosis 1 110 Aroclor 1234 1 10 100 31 26 27 8 10 13 3 3 13 0 3 13 004 634 0 02 3 12 Aroelor 1230 1 10 100 23 23 27 56 3 10 09 00 63 00 42 10 11 7 5 14 2 6 Source: Nlsbet (1976a) MOWS 02S136 30 For some reason Chit vis not explained, there vis unusually high mortality among the racs in the experiment. The numbers of rats were further reduced by interim sacrifices during the course of the experi ment. For example, only 6-21 ar.ir.als out of the initial 100 in each treatment/sex subgroup fed 100 ppm survived to che terminal sacrifice. Even so, the re-diagnosis of the liver pathology (Table 10) indicates a significant tumorlgenic effect. The incidence of nodular hyperplasia is significantly elevated in the group fed 10 ppm Aroclor 1260 over the incidence in the control group (p <<.005, Fisher's exact test). There ere a total of 9 hepatomas in the groups fed 100 ppm of one of the three Aroclors, but none in the groups fed lesser concentrations of PCBs. 9.3 Svnercistic Effects The synergistic effects of PCBs acting in conjunction with other chemicals may be quite significant in some instances, although quantita tive estimates of these effects et environmental levels of exposure, would be quite tenuous. Xto e_t al. (1973) reported on experiments in which groups of 12 30 dd male mice were exposed to verious levels of PCBs (Kanechlors XC-300, XC-400, KC-500 at 100-300 ppm in the diet) alone or in combina tion with one of three isomers of BHC (hexachlorocyclohexane ft-BHC, P-BHC, y-BHC at 50-250 ppm in the diet). In the groups exposed to PCBs a)one, only the group exposed to 500 ppm KC-500 developed hepato cellular carcinomas (5 animals out of 12 exposed). In the groups ex posed to BHC alone, only the group exposed to 250 ppm o-BHC developed hepatocellular carcinomas (8 animals out of 30). however, carcinoeaa HONS 025139 31 vre induced vithin 24 weeks by joint feeding of PCEs end BHC at levels below those which had no effect when fed independently. The cosbina- tions of 100 ppa o-BHC and 230 ppa KC-500 produced 1 hepatocellular careinoca in 23 animals; 30 ppa c-EHC and 230 ppm KC-500 produced 2 hepatocellular carcinomas in 30 animals, 230 ppa each of ft-SKC and KC-500 produced 6 hepatocellular carcinomas in 29 animals. The authors concluded that PCEs promoted the induction of tumors by o-EHC and ft-BHC. Other experiments have produced negative and even antagonistic results. In an experiment with mice (Uchlyama, el., 1974), FCBs (KC-4C0) fed in the diet did not appear to accelerate the development of cervical carcinoma induced by methylcholanthrene. In another study in rats (Kakiura, 1974), feeding with PC3s for 24 weeks appeared to inhibit the induction of hepatocellular carcinoma by three other car cinogens. Vd (vinyl chloride) is a known human liver carcinogen and is also a mutagen, but both its carcinogcniciey and mutagenicity appear to depend on metabolism in the liver to an active metabolite (Rannug, et si., 1974). The mutagenicity of VO! has been demonstrated only in the presence of liver mierosonal preparations, including those stimulated by PCBs (Kisbet, 1976a). This strongly suggests that there may be a synergistic effeet between PCBs and VCM In the production of tumors. 4. Quantification of Carcinogenic Risk 4.1 Calculation of Virtually Safe Poses from Different Mathematical Models To illustrate the computation of virtually safe doses (VSPs) by extrapolation of the results of animal experiments to low dose levels. HONS 025140 3; v* have (elected the three data sets listed In Table 11. To this date we have applied three dose response nodels and related extrapolation procedures;-the probit isodel (yantel, 51^1*, 1575). la-tbLocjgd ?(d) - C + (l-C)j (2x)_1/2exp(-y2/2)dy |1] the one-stage or one-hit model (Crump l., 1977) F<d) - l-exp{-(q0 + qjd)), qo>93 - 0. end the multistage model (Crump, e el., 1977) P(d) - l-exp{-(qo + 51<> + q2<iJ + + ). 9o...........qk 2 0 12) [3] The farms nultihit model (Rai and Van Ryzin, 1978) vas also considered. This model requires at least two positive experimental doses and eould not be applied to the first two data sets. Vhen applied to the third data set, the cosputer algorithm for computing the estimates failed to converge (Van Ryzin, parsonal communication). For eaeh of these models, P(d) represents the probability of a particular tuaorignic response in a single animal fed a test substance at s dose-rate d during the course of a lifetime feeding experiment. A discussion of these models and their theoretical rational# is given in the Appendix. The results of applying these extrapolation procedures to the data sets in Table 31 are eurnmaflzcd in Tsble 12. In this table are computed maximum likelihood (best-fit) estimates of the dose required to produce extra risks over background risk of 10~*, 10"*, 10~*, respectively. Lover 95Z confidence bounds for each of these doses ere also computed from the various models. Maximum estimates are ncc recorded for the method based upon the problc model since this method was not designed to fit data. As explained in the Appendix, the HONS Q251*1 33 Table 11: Data seta used for calculating virtually safe doses in Table 12. Data Set fl-~Kir.brough et al. (1975) rat study vith Aroclor 1260-Hepatocellular carcinomas Dietary level (ppn) 0. 100 So. of animals 173 184 No. animals vith Hcpstocellulor carcinomas 1 36 Data Set 92--Kimbrough et^ al. (1975) rat study with Aroclor 1260-- liver neoplastic nodules Dietary level (PP) 0 100 No. of animals 173 1S4 No. animals vith Ktoplastie Nodules 0 144 Data Sec 3--Industrial Bio-Teat rat experiment vith Aroclor 1260-- liver neoplastic nodules Dietary level <pp) 0 1 10 100 No. of animals 23 25 23 27 No. animals vith Neoplastic Nodules 1 0 9 7 HONS 02 5142 34 Table 13: Virtual? Safe Doses computed from data in Table V Data See Analytic Method Maximus likelihood estimates of dose in ppb. corresponding to extra risk of 10-' 10*s 10* 5 Virtually safe doses (lover 952 confidence bounds -for dose) in ppb. corresponding to extra risk of 6* o1 io- 10* 5 1 Probit 1.96 14.2 43.6 I One-Hit and .0069 .686 6.86 .0051 .511 5.11 Multistage II Probit .025 .180 .552 II One-Hit and .00063 .063 .634 .00055 .0551 .551 Multistage III Probit .178 1.29 3.97 III One-Hit .0046 .465 4.65 .00235 .235 2.35 111 Multistage .0046 .465 4.65 .00205 .205 2.05 HONS 025143 35 parameter b appearing in this model it set equal to unity regardless of the data. This designation precludes the model from providing an adequate fit to most data sets. Likewise, the gamma multlhle model is applied only to data set 111 since this model cannot be applied to data containing only one experimental dose. These models yield quite different values for the lover confidence bounds on dose. These divergent results are predicted by and, to some extent, explained by the discussion in the Appendix. The probit procedure will typically estimate virtually safe doses larger than those predicted by the multistage models for extra risks below about 10"*. Virtually safe doses based upon the multlstsge model are Identical vlth those based upon the one-hit model when there is only ona positive experimental dose. This is illustrated vlth data sets 1 and 11. The multistage procedure also yields virtually the same values as the one-hit model for data set III since Introduction of the parameters q2, q$> etc. into the model cannot Improve the fit to this data. Bewever, as explained in the Appendix, the multistage can yield higher values for the V5D than the one-hit model whenever the data exhibit upward curvature and are inconsistent vlth the one-hit model. To compare with the VSDs in Table 12, we estimate from Table 2, that the average consumption of ?C3s in the I'nlted States In 1976 was about 3.3 wg/day * 1S37 gm/day 2.1 ppb of PCS, assuming an average daily food Intake of 1337 grams. 4.2 Estimates of Bisk from PCIs in Diets of U.5. Adults Next we shall astlmate levels of risk for the general U.S. popula tion and for the population of consumers of fresh water fish. The M0N3 025144 36 risks from consuming human milk In Infancy present some special dif ficulties and will be dealt with separately. The data of Kimbrough #t el. (1975) on the increased incidence of hepatacellular carcinomas in rats fed Aroclor 1260 provides the most convincing evidence of carcinogenicity of PCBs. Our estimates of risks to human populations will therefore be based upon this data. The feet that only one dose level of PCBs was used In this experiment means that the one hit is the only one of the models discussed previously that can be utilised. The Mantel et al.(1975) procedure based upon the probit model (!) la an operetional procedure for calculating a virtually safe dose. Sinee the parameter b in the model is not chosen besed upon the data, the method should not be used to calculate "best" estimates (e.g., max imum likelihood estimates) or risk at a given dose. Except for the one-hit model the other models require at least two positive experi mental doses for their utilisation. Zn Table 13 arc exhibited lifetime risks of cancer based upon extrapolating the Kimbrough data from the experimental doses to PCB exposure levels in humans. This process Involved :->o steps. First, exposure levels in humans were converted to equivalent exposure levels in rats. Bcsults are given for two methods for making this conver sion: 1) on a ppm of PCBs in total diet basis and 2) on a mg intake of PCBs per kg body weight oer day basis. The next step is to cal culate the extra risk of hepatocellular carcinoma at this dose based upon a one-hit model fit to the animal data. The risks exhibited in Table 13 are based upon the one-hit model which fits the animal data beat. Upper confidence bounds on these risks sre not listed but an upper 9SX confidence bound is given by multiplying all corresponding risks in the table by 1.5. HONS 025145 Tht estimates of dose from th total diet study (Table 2) ore tenuous. The estimates for the years 1975 end 1976 ere based upon 8 and 3. respectively* trace findings of PCBs in 20 samples fro the neat* fish, and poultry food class and no findings at all in samples fro* other food classes. The PCB levels in Table 2 were estimated by assuming that .023 ppm PCB (1/2 of .05 ppm, the lover limit of PCB quantification) were present in ell food samples in which trace amounts of PCBs were found (Xlsbet, 1976a). Ib computing the risk estimates, no allowance was made for the composition of PCBs in food to which humans are exposed being different from the composition of Aroclor 1260 used in the experiment. As in dicated in an earlier section, however, it appears that the higher clorlnated biphenyls predominate in the environment and consequently the composition of PCBs in food should not be too different from Aroclor 1260. Also, no allowance was made for the fact that PCB lcvals la human adiposa tissue are likely much greater than corresponding levels in rats for a given level of dietary exposure. The risk estimates are computed for a hypothetical human popula tion exposed throughout their lifetime to current levels of PCBs in food. In actuality, PCB levels appear to be decreasing. Based upon the estimates in Tdble 13 the expected number of extra cases of hepatocellular carcinoma par year resulting from a nationwide exposure at the dietary level detected In the 1976 Total Diet Study (3.3 vg/day) would range between 220,030,000/(7.36,000 * 70) ll.l cases/ year and 220,000,000/(764,000 * 70) - 4.1 casea/year. Using the assumptions of s one-hit model, figures on total catch of lake Michigan fish (Humphrey, 1977) and estimates of PCB levels In HONS 025146 35 Lake Michigan fish, we can estimate the total expect number of Hepato cellular carcinomas among residents of Michigan from consuming PCBs in Lake Michigan fish. From Table 2 in Humphrey (1977) we estimate that in 1974, Michigan sport fishermen caught 4,065,930 lbs. of lake trout, 6,979,500 lbs. of salmon, and 2,930,220 of other spore fish from Lake Michigan. From Tablt 7 it is estimated that cooked portions of these fish contained an average of 3.26 ppo, 2.88 ppm, and 1.0 ppm PCBs, respectively. Assuming that 1/3 of the total of weight of these fish were injested by humans, it follows that a total of approximately (4,065,930 * 3.28 + 6,979,500 * 2.83 + 2,930,220 1.16] * 10* * .333 12.28 lbs. of PCBs ware injested by humans from eating these fish. Since, according to Table 12 injecting 127 ug/day of PCB (127 * 10~* 365 * 70 - 3.2 gm in a lifetime) would produce on the average about 1/8,000 tumors, 12.28 lba. * 5575 grs of PCBs would produce (1/6000) * (5575/3.2) - .22 hepatocellular carcinomas/year. 4.3 Estimates of Risk to Breast-Fed Infanta The population of Infants vhose diet during early life consists wholly or at least in large pert of human milk has a much higher ex posure to PCBs through food than the general population. As estimated In Section 2.5, human milk in the United States contains an average of 1 ppm (fat basis) PCBs with 72 of the samples containing pore than 2.5 ppm (fat basis) PCBs. Further, it was estimated that there is a population of consumers of fresh water fish whose milk samples could contain on the average four times the levels in the general population. ftisks from exposures at such an early age arc difficult to quantify. Studies on similar exposure patterns In animals have apparently not been done. HONS 0251*7 There arc a number of animal studies in which various acute ef fects were detected with 1-10 ppm exposure to PCS* In food. Linder 9 al. (1974) exposed rats for two Generations to 1, 5, 20 and 100 ppm PCBs. Significant Increases in liver weights were observed in 21-dayold Tj male weanlings at the 1 ppn level of Aroclor 1254 end in either sex of Fj end Fg weanlings at 5 ppn or higher levels of both Aroeler 1254 and 1260. It Bust be kept in Bind, however, that because of bloBagnificaeion, concentrations of PCBs In Bilk say have been nuch greater then the levels in feed. Rhesus monkeys ere considerably sore sensitive to PCBs than rodents; Rhesus nonkeys fed 3 ppm PCBs all died after 8 months (McNulty, 1976). Female Rhesus monkeys given 2.5 and 5.0 ppm Aroclor 1246 in their dicta developed facial edena, swollen eyelids, erythema, loss of hair and acne within two months (Baraotti, 1976). Following 6 months of PCB exposure the female monkeys vere bred to control males. There was a significant reproduc tive effect of the FCB in the diet as shown in Table 14. The six infant monkeys vere permitted to nurse their mothers for 4 months. The mothers' milk contained 0.15-0.40 ppm of PCBs (whole milk basis). Within 2 month* focal areas of hyperpigmentation, swollen lips and eyelids, lots of eyelashes, and acne form lesions of the faee developed. Within four months, 3 of the 6 infants died due to PCB intoxication. From tho data of Savage (1979) it is estimated that approximately 32 of human milk samples in the United States have FCB levels in excess of .15 ppm.(whole milk basis). Any estimates of carcinogenic risk from exposures to PCBs in human milk on the basis ef existing animal data must be regarded as extremely tenuous. Wot only does one have to contend with the MOMS 025146 41 Tablt H : Modification in reproduction In primates that vara exposed to Aroelor 1248 in the diet Control 2.5 ppm 5.0 ppm Total impregnated (no./no. animals) 12/12 8/8 6/8 Resorptions or abor tions (no./ no. animals) 0/12 3/8 </8 Stil Iborn (no./no. animals) 0/12 0/8 1/8 Normal births (no./ no. animals) 12/12 5/8 1/8 Source: Allan and Norbaek (1976) HONS 025149 42 uncertainties of extrapolation iron high doses in animals to low doses in humans, it is also necessary to make assumptions regarding the effect of a time-varying dosage. The effeet of dosages early in life on carcinogenicity could be such different from equivalent doses later in life. To illustrate vhst such an effect sight be, ve shall calculate sose hypothetical risks of hepatocellular careinoaa by relating the cancer incidence observed in the Kimbrough je el. (1975) study to husan PCB exposure levels in human silk. The calculation will be based upon the multistage aodel of cancer. Peto (1977b) indicates that this nodel may be particularly applicable to carcinoaas. The swdel ia capable of explaining observed high rates of Increase of cancer vlth age without having to specifically posit an aging mechanise. Zn applying tha model ve aust decide which stages PCBs might effeet and the nature of the effect. Let us assume in the absence of evidence to the contrary, that PCBs affect only the first stage end that the effect la to increase the rate at which cells pass through this stage by an amount proportional to the quantity of PCBs present in the diet t the time. This assumption is s "worse ease" assumption because with the particular multistage model v have in mind, cells pass through tha stages In a prescribed order on their way to becoming cancerous. Consequently, exposures at infancy will have the greatest overall effect if they set upon the first stage. Vlth such a model, it can be argued that when exposure to PCBs la at a level 0 from birth to an age which represents an age-fraction i of the normal life span, with no exposure for the remainder of tha lifetime, then the extra llfc-tim risk of hepatocellular carcinoma MQNS 025150 over risk sl sero dose should be approximately of the form ?(b.O - i-.*r{-sti-(i-f)k]) IS] where k is the number of states in the multistage model. Ue estimate 0 - .147 * 10"2 Iron the Kimbrough t^ al_. (1973) data by taking f 1 and D 100 ppm. This method of estimating 0 should tend to under* estimate the carcinogenic risk since the rats in this experiment were exposed only after vesning and prior to 21.3 months of age, and were sacrificed at 23 months of age. With 0 estimated in this fashion ve can new calculate theoretical extra lifetime risks of hepatocellular carcinoma from [3] for different values of 0, f and k. The results of some such calculations are tabulated in Table 14. These estimates are based upon unverlfiable assumptions and should be regarded as hypothetical. They do illustrate, however, the carcino genic effect that night result from doses of a carcinogen applied early in life, such as PCBs in human milk. Some of the assuaptlcns made in constructing there estimates were conservative In that other assumptions which are equally reasonable would prediet even higher cancer risks. For example, if we had converted dose from rata to humans on a mg/kg/day basis rather than on a ppm basis, the estimated risks would likely be greater. Cells in Infants are going through mitosis much more often than cells in adults which might imply that they are at a greater risk per unit time from a carcinogenic intuit than cells in adults. However, this possibility was not reflected in the model. It should perhaps be pointed out that with this model (as well as possibly In real life), even though carcinogenic dose la very early HONS 025151 44 in life, a cancer eventually resulting Iron this oosc can occur at any age. The risks tabulated in Table 15 are perhaps rare useful for com parative purposes rather than in an absolute sense. By comparing these values vlth those In Table 13, it appears that the subpopulaclon of breast-fed Infants could be at mueh higher levels of risk of hepato cellular carcinoma from PCBs than the U.S. population in general. HONS 025152 45 Tibia 15: Theeretical extra lifetime risks of hcpaioeciluiar carcinoma in breast-fed infants based upon Kimbrough al. 0975) rat data. A k-stage modal of cancer is assumed with dose effecting the first stage only (Equation [5]). Conversion of dose from rats to humans is by assuming ppn of PCB in rat diet is equivalent to ppn (fat basis) in human silk. Extra risk to infant in general population (0 1.0 ppn) Age at Vanning K 6 month. 12 month. (-1/140) (-1/70) 1 1/93000 1/48000 3 1/32000 1/16000 S 1/19000 1/9800 Extra risk to offspring of consumers of aore than 24 lbs./ year of Lake Michigan sport fish (D 4.0 ppo) Age at Vanning 6 month. 12 months 1/140) f-1/70) 1/24,000 1/12,000 1/8000 1/4000 1/4800 1/2300 HONS 025153 37 Table 13: Estimates of lifetime extra rial: to humans of hepatocellular carcinoma based upon applying a one-hit model [2] to the Kimbrough et al. (1975) rat study. Hunan RCB Dosage 8.7 Vf/day (1975 Total Diet Study, Table 2) 3.3 vg/day (1976 Total Diet Study, Tabla 2) 127 vg/day (Avg. Intake of people consuming mere than 24 lba./yr. Lake Michigan fish, Humphrey (1977) Risks calculated from converting human dose to animal dose on the basis of ppm in diet rc/k/dav 1/123,000 1/288,000 1/328,000 1/764,000 1/8,000 1/20,000 HONS 025154 APPENDIX * ,r;;rw AND EVALUATION OF METHODS OF DETERMINING RISKS FROM CHRONIC LOW-LEVEL CARCINOGENIC INSULT Buie Principles end Considerations To aid in determining a proper regulatory action regarding ::r.;;en that is present in man's environment, whether it be * additive, industrial polutant, or otherwise, it is help : lave some Knowledge about the number of extra cancers c* likely to be caused by the presence of the carcinogen i tr.vironment. It is also helpful to have some knowledge i likely change in number of extra cancers that would my some projected increase or decrease in the level of 'tposure occuring either as a result of regulatory action ,;iion. This kind of information is usually impossible to : directly from human data. For this reason it is often :*-y to use data from animal feeding experiments to estimate ;lsk. This procedure involves two difficult steps, 1) re< tht animal risk at high deses to doses very near to aero " relating the animal risk to risk in humans. "ypically, animal experiments use on the order of 100 * t each experimental dose. If a particular experimental fles a lifetime increase in cancer risk of 1/10, this 025155 HONS *7 ,.eise can be measured with a small degree of accuracy using .) sninals. But if the increased cancer risk is less than 1/100 increase will often not even be detectable by an animal `:<iing experiment. For example, if the true risk is 1/100 it .-;ld require that ever 400 animals be tested at that dose in :'tr to be 99% sure of detecting any carcinogenic response at ;l (i.e., for there to be a probability of .99 that at least one .pal gets cancer). Xf background or spontaneous carcinogenesis j present even larger numbers of animals will be required. On ut other hand, the extra human risk that we may want to csti- it resulting from environmental exposure is usually (and hopc- hllv) much smaller than 1/100 for any given chemical, perhaps s the order of 1/1,000,000. It is clear that it would not be '-.'ictical to conduct an experiment with enough animals to measure :;;tctly an increase in risk this small. For these seasons the procedure has been developed of ''ducting lifetime animal feeding experiments using, in addition 3 a control dose of zero, several doses at which the projected ut;i cancer risk may be 1/10 or larger. This high dose data is -a used to estimate the extra risk at a dose where the extra *>% may be no larger than, say, 1/1,000,000. An equally import- variant to this problem is the calculation of the so-called fa' dose, that is, a dose for which there is some measure of '`tistical assurance that the extra risk at that dose is no <r than, say, 1/1,000,000. These problems are often referred 13 collectively in the literature as the 'low dose extrapolation '!Men." HONS 025156 Importance of the Mathematical Model Performing a low-dose extrapolation involves the choice : a mathematical function to model the dose-carcinogenic response .relationship and the choice of statistical procedures to apply t the mathematical function. The choice for this mathematical function turns out to be extremely crucial to the outcome of Ic--dose risk estimation. If the assumed relationship between turner occurrence and dose does not apply in the regions to which the extrapolation is being made, a serious overestimate of the 'safe dose may result (Mantel and Bryan, 1961, p. 458). Chand and Hr * (1974) compared five standard dose response models and observed that they could differ by many orders of magnitude at low dcse levels for which extra risks are on the order of 1/100,000,OCC. It laight be supposed that it should be possible to dis criminate among the various potential dose response functions rr the basis of experimental data but, unfortunately, two differer.t dose response functions can often fit experimental data equally well but still differ by several orders of magnitude at very lrdoses. Moreover, even if a particular dose response function were to give a significantly better fit to data than several Others this would still not furnish assurance that this functir." would necessarily correlate in any way with the true dose response at very low doses where it is not feasible to measure the true extra risk directly. As a consequence of the great disparity of dose response functions at low doses it is impera tive that the dose response function be selected, neither arbi trarily nor solely on the basis of hew well it can be made to HONS 025157 *9 f*perimental data, but, insofar as is possible, it should reflect I laovn or at least plausible information regarding the biological ueehanisms through which a chemical induces or promotes cancer. What Shaoe Should be Expected for the Dose Besponse Curve at Low poses? Tumors of so many different types arise in such a diver sity of different tissues, their etiology is so little understood, and the agents that cause tumors affect a subject in such diverse ways, that it might seem that no general conclusions can be drawn. However, for a certain broad class of 'directly-acting* chemical carcinogens the range of uncertainty associated with the shape of the dose response curve at low doses can be greatly narrowed. As osed in this paper, the term 'directly-acting carcinogen* encom passes (Guess, Crump and Peto, 1977) carcinogenic agents for which either the agent itself or a metabolite acts directly at the cellular level and produces a hereditable change which eventually leads to the formation of a tumor. Carcinogens which are carcino genic by reason of their mutagenicity should fall into the cate gory of 'directly-acting carcinogens.' Accordingly, carcinogens which test positively using the Ames mutagenicity screening test for carcinogenicity are very likely to be directly-acting. (See KcCann and Ames, 1976). In a recent study (McCann, Choi, Yamasaki and Ames, 1975) in which about 300 carcinogens and non carcinogens were tested using the Ames Test, 901 (157 out of 175) of the carcinogens were mutagenic including almost all of the MONS 025158 JO known human carcinogens. This indicates that the class of directlyacting carcinogens may encompass most of the known carcinogens. A partial solution to the low-dose extrapolation problem for the case of directly-acting chemical carcinogens has been given in Peto (1977), Crump, Boel, Langley and Peto (1976), and Guess, et al. (1976). The key result is that, at least as long as background carcinogenesis is present, we should expect the dose response curve not to be absolutely flat at zero dose. What this means is simply that when risk is plotted against dose response on ordinary linear scales, the tangent line to the dose response curve at zero dose should have a positive slope. When a dose re sponse function has this property we will say it is linear at lev dose. This simple property can have far-reaching consequences on low-dose extrapolation. For example, consider the two potential dose response functions 1) 0.1Ijpf d + d2) and 2) .Id2 for the dose interval 0 d 3. Both of the curves give a risk of 1/10 at a dose of d 1 and are practically indistinguishable at higher doses. However, at a dose of d - 1/1,000 1) predicts a risk of 1/100,000 and 2) predicts a risk of 1/10,000,000, a dif ference of two orders of magnitude. We note also that 1) has a tangent line with a positive slope at d 0 whereas 2) does not. One explanation of why the dose response function should be linear at low dose when background is present may be found in Crump, et al. (1976) and Peto (1977) and will be briefly outlined here. When background carcinogenesis is present, the cellular mechanism through which the test agent produces cancer should HONS 025159 31 already be operative in producing background tumors. i.Tien this is true the effect cf the test agent is to add to an already on going process. The result of this additive effect is illustrated in Figure 1. The dose response curve is for all tumors produced through the mechanism through which the test agent acts. Back ground carcinogenesis is allowed for in the Figure by an effec tive background dose de. We see that, in this case, the added risk caused by a dose d of the test agent should be expected to increase approximately linearly near d - 0 (i.e., the tangent line at d 0 will have a positive slope). Implicitly assumed by the way Figure 1 is drawn is the fact that an added dose of a carcinogen aeting through this mechanism does not produce a smaller risk. If background carcinogenesis is allowed for as in Figure 1 by positing an effective background dose dQ which is estimated from the data then the wide range of risks obtained using different models effectively disappears (Feto, 1977). We note that the existence of a tangent line with a positive slope at zero dose does not, in itself, imply any lower bound for extra risk at low doses since the slope of the tangent line could possibly be very small. The evidence given above for a positive slope to the dose response function at zero dose applies particularly to the case in which .background carcinogenesis is operative. This does not ieply that we expect the dose response curve not to be linear at low dose in the absence of background carcinogenesis. For exam ple, the multistage models of cancer (Armitage and Doll, 191) *te a fairly broad class of models in which it is assumed that HONS 029160 Figure 1. Illustration of why the dose response cu; ve should be linear at low dose in the presence of background ear cinogenesis. d is the effective background dose and d is ths dose of the carcinogen of interest. HONS 025161 a number of ivtnts >: required to occur at the cellular level to initiate cancer. Although all models in this class are linear at low dose provided background carcinogenesis is present, a sizable subclass of them are linear at low dose in the absence of back ground carcinogenesis (Crump, et al., 1976). Watson (1977) has recently proposed a more specialized model for cancer induction and promotion based upon reversible epigenetic cellular changes. Watson concludes that his model supports the low-dose-linearity hypothesis and states *as sug gested by a different argument of Crump, et al. . . . , it is reasonable to assess the risk due to an additional carcinogen at low constant dosage by a linear relation.* The evidence for low-dose-linearity given above applies mainly to directly-acting carcinogens. An indirectly acting car cinogen might be one which causes some gross physiological change such as suppression of ovulation which could predispose the sub ject to cancer. For such carcinogens the shape of the dose re sponse curve at low dose is highly speculative. There could possibly be a threshold dose below which the agent has no car cinogenic effect at all on an individual. Hcwever even if a threshold mechanism is operative, there is likely to be con siderable variation in individual thresholds in a large popula tion. Consequently the dose response curve for the entire population could still exhibit a linear trend at risks as low as 1/1,000,000 or lower. The effects of metabolic activation and detoxification upon carcinogenic dose response have been recently considered by HONS 025162 54 Cornfield (1977) through a kinetic model that encompasses free toxic substance, metabolite, deactivator, and the interactions of these substances. Only a steady state situation is studied in that variation over time o' the concentrations of these agents is not considered. The model predicts a threshold dose below which there is no carcinogenic risk under the assumption that the de activator is lOOt efficient in deactivating the carcinogen. How ever, in a naturally occurring process it is liksly that deacti vation would not be perfect and would be less than 100% effective in always combining with 1001 of the carcinogen before an amount ef the active metabolite reaches a cancer target site. Any of a number of modifications to the model to allow for non-perfect deactivation would rule cut a threshold and would lead directly to a model for which carcinogenic response varies linearly with dose at low doses. Cornfield's own modification of perfect de activation, that of allowing the deactivating reaction to be reversible, leads, as Cornfield points out, to a model which is linear at low dose. This occurs regardless of how slowly the reverse reaction takes place, as long as the possibility is not eliminated entirely. Furthermore, even in the extremely unlikely case of perfect deactivation, an otherwise realistic model should still imply low-dose-linearity since the theoretical time re quired for perfect deactivation would not be zero and would likely be infinite. For most, perhaps all, carcinogens, the mechanisms through uhich cancer is produced is not sufficiently understood so that the shape of the carcinogenic response curve can be theoretically HONS 025163 55 predicted with certainty. As pointed out earlier, neither can experiments of sufficient site be conducted that would permit direct experimental investigation of the dose response curve at low dose, we have noted that there are plausible arguments that the dose response curve is linear at low dose for many carcino gens. On the other hand, this author knows of no serious pro posal of a mechanism that would lead to a more conservative dose response relationship such as the risk varying approximately as the square root of dose at low dose. In view of these uncertain ties it would seem reasonable to base estimates of added risk of canear upon a mathematical model that encompasses low-doselinsarity unless, of course, the mechanism through which the carcinogen operates is sufficiently understood so that lov-doselinearity can be conclusively ruled out. Once the principle of low-dose-linearity is accepted the problem of estimation of risks at low dose is nearly solved. This is because the dis agreement between the upper statistical confidence bounds on risk at low doses based upon a model that incorporates low-doselinearity and one that does not is typically several orders of Bagnitude whereas the corresponding disagreement between two reasonable models both of which incorporate lcw-dose-linearity usually much less than this. HONS 025164 Specific Methods for Low Dose Risk Estimation A. Mantel-3rvan The Mantel-Bryan procedure (Mantel and Bryan, 1961 and Mantel, Bohidar, Brown, Cirainera and Tukey, 1975) nas been selected by the food and Drug Administration as part of their procedures for evaluating assays for carcinogenic residues in edible products of animals. Before the Mantel-Bryan procedure HONS 025165 57 itself is discussed, the "Sensitivity of Method" (SOM) document (Federal Register, Vol. 42, No. 35 - Tuesday, Feb. 22, 1977, p. 10412) will be reviewed briefly so that the role of the Mantel-Bryan procedure in official FDA policy can be understood and appreciated. The so-called Delaney clause of Section 409 of the Federal rood. Drug and Cosmetic Act of 1958 prohibited the approval of any food additive that "is found to induce dancer when ingested by oan or animal, or if it is found, after tests which are ap propriate for the evaluation of safety of food additivies, to induce cancer in man or animal .... This language was inter preted as forbidding. FDA to approve the use of a carcinogenic substance as a feed additive for food-producing animals whether of not the compounds night leave any residues in the edible pro ducts of the animals. However, in 1962 Congress modified this prohibition as part of the Drug Amendments of 1962. Section 409(c)(3)(A) now reads in part: . . . [N)o additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additivies, to in duce cancer in man or animal, except that this proviso shall not apply with respect to the use of a substance as an ingredient of feed for animals which are raised for food production, if the Secretary finds (i) thatT uncer the cbncrtions of use and feeding specified in pro posed labeling and reasonably certain to be followed In practice, such additive will not adversely affect the animals for which such feed is intended, and (ii) that no residue of the additive will be found (by methods of examination prescribed or approved by the Secretary by regulations, which regulations shall not be subject to subsections (f) and (g)) in any edible portion of such animal after slaughter or in any food yielded by or derived from the living animal ... * HONS 025166 SI Originally, th FDA applied this so-called "DES proviso* on a case-by-case basis without published criteria. However the rBA on February 22, 1977 published the 'Sensitivity of Method* document which established objective criteria for acceptance of in assay method for detecting residues of a carcinogenic feed idditive and for establishing post-administration withdrawal per iods for these additives. Thus the document furnished an operaiional definition of the no-residue requirement of the DES iroviso. This operational definition involves the application t the Mantel-Bryan procedure to animal experimental dose rejonse data. The test-animal specics/strains to be utilized are > have *the greatest possible susceptibility to the test coa ted* while at the same time being 'appropriate models for sail.' deral Register, vol. 42, 1977, p. 10418). The Mantelyen procedure is applied to the animal test data to detenaine residue level, designated S0< corresponding to a risk of '',000,000 in test animals (i.e., S0 is the 'safe* dose level trained by the Mantel-Bryan procedure). The level S0 is (eased as a fraction of the total diet (i.e., parts per lion). This level is adjusted to account for the respective fertions of the human diet that is represented by the various ! products containing residues of the carcinogen being tested, transfer from animals to man being made on a fraction of H diet basis. The resulting dose level S_ is 'the level of 1 residues of carcinogenic concern that can be operationally 'ed as satisfying the no-residue requirement of the act for fic tissues* (Federal Register, Vol. 42, 1977, - MONS 025167 3) The dose level S_ thus represents the upper bound to the lowest IB limit of reliable meesuremcnt that an approved assay method must satisfy. The Mantel-Bryan procedure is thus an integral- part of the 'Sensitivity of Method* document. The procedure as originally set forth (Mantel and Bryan, 1961) and "improved* (Mantel, et el, 1975) is for the purpose of conservatively choosing a "safe* dose of a carcinogen, a 'safe* dose being defined as one for which it ean be expected that, with a given level of statistical assur ance (e.g., 99%), the true dose producing a preassigned *safe* level (e.g., 1/1,000,000) of risk will lie above the 'safe* dose. Zn the Kantel-Bryen procedure the mathematical model used for the dose response model is the probit function P(d) - C (1-C) ^e+^g*(2,j-l/2 exp {_x2/2} a* where d represents the dose of the carcinogen and ? (d) represents the probability of a cancerous response in an animal subjected to a dose d. The parameters in the model are an intercept parameter a, a probit slope parameter b, and C, which represents the probability of a response in untreated animals. The parameter b is not estimated from the data but rather is arbitrarily set equal to 1. This choice is stated as being conservative (Mantel and Bryan, 1961), the argument for this being that typical dose data exhibit a probit slope in the experimentally observable region above 1% incidence that is greater than one. In Mantel and Schneiderman (197S) it was observed that a set of DBS data (Cass, C. H., Coats, D., Graham, N., 1964, C3H females) exhibited MOMS 025168 60 probit slop* of 1/2, but the general use of a probit slope of bl was still suggested. A slope of b"l was adopted in the SOM document unless the experimental data exhibit a smaller slope, in which case the smaller value would be used. With the probit slope parameter fixed at bl the remaining parameters, a and C, are estimated from the data and then ad justed so as to produce a higher level of risk as a given dose that corresponds to a upper 9St statistical limit on the true risk at a given dose. The value 991 is the one used in the SOM document but the choice is arbitrary. The safe dose is then de termined to be the one producing a given low risk (e.g., 1/1,000,000) based upon the adjusted values of a and C. The risk value of 1/1,000,000 was also adopted in the SOM document. As pointed out in Mantel, et al. (1975), the Mantel-3ryan procedure rewards larger and better experiments in that the more evidence there is of safety, the higher the calculated safe dose will be. However this advantage should be shared by any extra polation method that uses reasonable statistical procedures. Some have considered the Mantel-Bryan procedure as adopted in the SOM document to be too conservative (Federal Register, Vol. 42, 1977, p. 10419} in that it involves three conservative choices (991 statistical assurance, lifetime risk of 1/1,000,000, and probit slope set equal to 1) and that any one of these assuaiptions alone could provide adequate protection to the public. The first two of these choices are regulatory decisions that would have to be made with any extrapolation procedure. However, the arbitrary selection for the slope parameter seems to be peculiar HONS 025169 61 to the Mantel-Bryan procedure. To Investigate its effect upon the extrapolation procedure a typical fit is presented in Figure 2 (from Crump, 19 77b) of the Mantel-3rvan probit curve [All to experimental carcinogenicity data when the probit slope para meter is fixed at b 1. As can be readily seen the probit curve typically provides a very poor fit, curving downward even when th --ir.e of the data is toward an increasingly upward curvature. This typically bad fit to data of the probit curve raises serious questions regarding the validity of statistical procedures asso ciated with the Mantel-Bryan method. (See Salsburg, 1977 and Crump, 1977b.) On the other hand, the Mantel-Bryan procedure utilizing the choice b 1 was put forth as conservative procedure and it gives that appearance in Figure 1 since the probit curve appears to lie far above the trend of the data at the lowest doses. How ever es mentioned earlier and also pointed out by Mantel (Mantel and Bryan, 1961, p. 4SB) a procedure may, while appearing con servative at experimental dose levels, at the same time seriously overestimate the 'safe* dose (i.e., be seriously anticonservative) if the assumed dose response relationship does not apply at the low risk levels to which extrapolation is being made. Thus, before the degree of conservation can be evaluated for any pro cedure, the properties of the dose response curve at very low doses must be evaluated. As described earlier, there are strong arguments that indi cate the dose response curve should be 'linear at low dose* (see p.50 for the definition of this concept) particularly for 62 o o indicates data point (no. responders/no. animals tested) Mantel Bryan 0 1-------------------------------------------------------------------------------------------------------------------------- ' 0 2 46 Dose FiV- 2. typical fit of Msntel-2ryan curva to *??DerijTcntal data (frcrn Cr\rrp, 1177b). " HONS 025171 <3 directly acting carcinogens in the presence of background carcino genesis. This has led Peto (1974 ) to recommend extrapolation pro cedures using only dose response functions from a class containing only dose response functions which are linear at low dose. At the very least, however, it would seen prudent not to go to the opposite extreme and use a dose response function which rules out linearity at low dose by assumption. However, the Mantel-Bryan procedure, through its use of the probit curve [A1J rules out linearity at low dose in favor of a 'flatness property* (see Hartley and Sielken, 1977, Kantel, 1977, and Crump, 1977b) at low dose which is anticonservative to the extreme. This property im plies that mathematical derivatives of all orders of the probit curve approach zero (through positive values) as the dose approaches zero. This unusual property is most often discussed within the context of mathematical oddities rather than in con nection with a scientific investigation. It implies that if the true dose response curve comes from an extremely broad class of functions known as analytic functions and which pervade scienti fic applications of mathematics, then the probit curve will eventually underestimate the true risk at low doses. Further more, at low enough doses, the degree to which the risk will be underestimated will be arbitrarily large (i.e., the ratio of the true risk to the probit estimate will grew arbitrarily large). It was emphasized earlier that it is important when, extra polating to low doses for the assumed dose response function to Incorporate known or at least plausible facts about the mecha nisms of carcinogenesis. In neither the original paper HONS 025172 64 (Mantel and Bryan, 1961) nor in the paper outlining the improved version is biological justification given for the selection of a curve having the above described "flatness property." It should be mentioned at this point that the incorporation of background carcinogenesis into the Mantel-3ryan probit model [Al] using the parameter C implies that the mechanism through which the test carcinogen produces cancer is independent of the mechanisms through which all of the background cancers are produced (Crump, et al, 197S). In keeping with the discussion in the last seeticr. it would seem : moror: proper to incorporate background into the probit model by positing an effective background dose dQ which adds to the dose d of the test carcinogen. If background is incorporated in this way the probit curve no longer has the "flatness property" and becomes linear at low dose (Guess, et al, 1977). In fact, with background incorporated in this way, the probit curve assumes a shape similar to the one-hit model, sometimes referred to as the most conservative of all procedures (e.g., Mantel, 1977). Even though the "flatness property" implies the probit curve should at suitably low doses be anticonservative to the extreme, the "flatness" property holds only for doses approaching sero and the feature of arbitrarily fixing the prebit slope at 1 mitigates the anticonservativeness implied by the "flatness" property at any given low dose (although the property itself- will hold for all choices of the parameters a, b, c). The cancer risks that are typically extrapolated to are in the risk ranees 1/10,000 to 1/100,000,000. We will examine the outcome of MONS 025173 ti Nantel-Bryan extrapolations to these risk levels in a later sec tion when we compare several different extrapolation procedures. B. Linear Extrapolation The technique for linear extrapolation was recommended by Kocl, Gaylor, Xirschstein, Safiotti and Schneiderman (1975) for use on an interim basis until better procedures could be devel oped. The procedure is straightforward and is based upon an assumed linear relationship between dose and response at low dose. The procedure utilizes only the data for the group of control ani mals and a single other dose group, usually either the highest dose that elicits no response or else the lowest dose that elicits soma response. In the case there are no cancers in the control animals the 'safe* dose, based upon a maximum risk of 1/1,000,000 and $9% statistical assurance, is calculated as follows: An upper 99t confidence bound is calculated for the cancer risk in the dose group of animals. From this risk and dose one extrapolates back toward zero dose and zero risk using a straight line relationship. The dose corresponding to a risk of 1/1,000,000 on this straight line is taken to be the `safe* dose. If there are cancers in the control animals this procedure is modified to allow for the sta tistical treatment of the response in the control group while re taining the straight line relationship, when data at other experimental doses are available this method of linear extrapola tion has the obvious shortcoming of not fully utilizing the available data. A linear dcse response curve is linear at low dose but the converse is noe necessarily true. A curve can be linear at HONS 025174 66 low dose and still have a hi;h desrea of nonlinearity at higher doses. Linear extrapolation is viewed by some as a very conserva tive procedure. For example, comments were made during the decision on which extrapolation procedure to incorporate into the SOM document to the effect that linear extrapolation is the most conservative of all procedures. Crump, et al (1976) examined the extent of the conservatism of a linear dose response function when compared with a multistage dose response model (Armitage and Doll, 1961). The multistage model assumes that a cell must go through a number of different stages before cancer is initiated in that cell and the model can encompass a high degree of nonlinearity. It was determined that the maximum pos sible degree of conservatism of a linear model relative to a multistage model depended rather heavily upon the incidence at the experimental dose relative to the background incidence. (This is consistent with the general relationship between back ground carcinogenesis and linearity at low dose as discussed earlier.) For example, when the incidence at the experimental dose is four times the incidence at zero dose the extra incidence at low doses derived from the linear dose response differs from the incidence derived frem the multistage model by, at most, less than a factor of 2.5 regardless of the number of stages in the multistage process. Thus, when background carcinogenesis is present, the linear dose response curve is not overly conserva tive relative to the multistage dose response curve. In fact the linear dose response curve is anticonservativo when compared to HONS 025175 67 the one-stage or one-hit models. Linear extrapolation has long been proposed Cor use in radiation carcinogenesis (see Brown, J. M., 1976, Cor a review of the relevant reports). The BIJl (1972) report on radiation risks from the National Academy of Science recommended linear extra polation as a "best estimate* approach as opposed to a conserva tive approach. Brown reviewed arguments both for and against linearity and concluded that 'linear extrapolation of human data from high doses of low LET radiation cannot be said to overesti mate the risk at low doses. In fact, there is some doubt as to whether the risk is not underestimated.* Certainly much remains to be learned about both radiation and chemical carcinogenesis. However, if both radiation and chemicals cause cancer through similar mechanisms then it should be expected that there would also be similarities between the respective carcinogenesis dose response functions. Direct damage to DNA by the carcinogenic agent has been implicated as one cancer, initiating mechanism for both radiation and chemicals (Brown, J. H., 1976 and McCann and Ames, 1976). Thus, the findings related to the potential linearity of the dose response function for radia tion has implications for chemical carcinogens as well, particu larly for "directly-acting" carcinogens. The results of linear extrapolation will be compared with ether methods in a later section. HONS 02517* C. Extrapolation Methods Based Poon the Multistace Modal Two methods of low dose extrapolation which are alterna tive* to the Mantel-Bryan or linear procedures have recently been proposed independently by Guess, Crump, and Deal (Guess and Crump, l>7t, 1978 and Crump, Guess and Deal, 1977) and Hartley and Sielkin, 1977. Both of these methods utilize a multistage dose response function of the form P(d) - l-exp{-[qe + <jjd + q2d2 + + q^d*] } (A?,' where qe, q^ , q^ are all nonnegative parameters to be astiMted from the data. This dose response function is general nough to yield a considerably wide range of responses at low dose. On the one hand, if q^>o and q^-o for i>3 the dose response function [A2] becomes the one-stage model which yields risks at lewdoses comparable to what would be obtained with linear extrapola tion. On the other hand, the model can produce risks even as low as the probit curve [Al] down to any fixed positive low dose. Thus this model is capable of fitting both highly linear and highly nonlinear dose response relations. Since the model has the property of 'linear at low dose' if q^>o and does not have this property if q^o, use of this model does away with having to make the arbitrary but crucial decision of having to either assume linear at low dose as in linear extrapolation or else assume a highly nonlinear dose response relationship at low dose as in Mantel-Bryan extrapolation. Thus 'safe' doses computed using this model should provide a more realistic measure of the true un certainty of low dose extrapolation than would 'safe' doses based HONS 025177 9 en cither an assumed linear curve shape or an assumed highly nonlinear curve shape. The dose response relation [A2] contains all of the Armitage and Doll (1961) multistage dose response models as special cases hut also contains curves which are much flatter at low dose than any of the multistage curves. The two extrapolation procedures based upon [A2] have some features which are different. When computing "most likely* esti mates the procedure of Guess, Crump and Seal uses an infinite dimensional maximisation procedure so that it is not necessary to specify a value of k, the degree of the polynomial in [A2]. How ever, the two methods differ chiefly in the way the statistical conficence intervals are computed. There have not yet been suf ficient comparative calculations made to determine how safe doses may differ using the two approaches. Mantel (1977) has made a critical review of the statistical procedure used by Hartley and Sielkin for calculating the 'safe' dose. Both the Hartley and Sielkin and the Guess, Crump and Deal (as extended by Crump, 1977) procedures can utilize times at which cancer is detected in the experimental animals rather than just the dichotomous information of whether or not an animal contracted cancer before it died of some other cause or before the termination of the experiment. The utilization of time data la low dose extrapolation is important for at least two reasons: 0 The age at which cancers occur should be important in assessing the magnitude of the harmful effect of a carcinogen upon man (*.g., cancers that occur early in life should be viewed as more HONS 025178 70 rious than those which occur in extreme old ace) . 2) In many animal carcinogenicity experiments the response data at the highest doses lies below the trend of the lower dose data. This sometimes appears to be due to the fact that at the highest doses some of the animals are being poisoned by the chemical before they have a chance to develop cancer. Khen this occurs the high dose date is often Just deleted from the analysis. However if the times at which the animals die is properly used the high dose data slight net appear anosiolous. Mora research needs to be dene on the proper utilisation of animal time of death data to assess the harmful effects of chemicals to man. D. The Gamma -Multihlt Carcinogenesis Dose Besoonse Model Bai and Van Ryrin (1978) have proposed basing risk estima tion on the gamma multihit model fld uk-l -u ?(d) - C + (l-C)J du k20 - C + (l-C){l-e"*djl + Id + + ... k 1,2,... (A3) where Ptd) is the lifetime probability of cancer in a tissue when subjected to a constant dose-rate d of the carcinogen. This model is obtained by assuming that cancer due to the carcinogen occurs when the tissue has been hit k times, these hits occurring randomly according to a Poisson distribution. The manner in which background carcinogenesis is incorporated into the model is MONS 025179 71 equivalent to assuming that the event 'cancer occurs due to the action of the carcinogen" is independent of the event 'cancer occurs spontaneously.* This assumption would not apply, for example, to processes in which the effect of the carcinogen is to speed up the rate at which the 'spontaneous' events occur which lead to the background cancers. At low dose rates, the response is approximately given by P(d) X^Vkl. Consequently, this dose response model is linear at low dosa rates when and only when k * 1. Rai and Van Ryzin calculate confidence intervals for added risk at a given dosa and for the dose producing a fixed added risk using asymptotic maximum likelihood theory. Although in the theoretical development k must be an integer, in the applications k is allowed to assume any positive value. Upper statistical confidence intervals on extra risk at a given low dose computed using this procedure can be compared with those computed from the multistage model [a2) by considering two general classes of data. If the data exhibit a general downward curvature as illustrated in Figure 3a, upper confidence bounds on extra risk computed from the gamma multihit model [A31 should generally be greater than or equal to corresponding upper confidence bounds computed from ehe multistage model [A2]. In certain instances the gamma multihit upper bounds could be much greater than the corresponding multi stage upper bounds. This could occur when the data is consistent HONS 025180 7: with k < 1 in the gamma multihit model {presumably correspond;, to a fraction of a hit). On the other hand, if the data exhibit a general upward curvature as illustrated in Figure 3b the reverse situation wi. hold; gamma multihit upper confidence bounds on extra risk vii: generally be less than or equal to corresponding multistage bounds. Camma multihit bounds will not in general share the low-dose-linearity of multistage bounds and because of this may be saialler than the multistage bounds by orders of magnitude at low doses. The reason these large differences can occur is as fdllows. The multistage family of models contains members whic: are simultaneously linear at low dose and exhibit upward curvac. at moderate doses, For example, the particular multistage model ^-(qid + q*d*) <Jlq2 0 is linear at low dose since q; > 0 and still can exhibit upward curvature at moderate doses since qa > 0. This means there are dose response curves in the multistage class which are both linear at low dose and can adequately describe data of the type exemplified by Figure 3b. On the other hand, this will generally not be true of gamma multihit models. All dose-respcr.s curves in the gamma multihit class which are linear at lew dose must exhibit downward curvature and consecuently would generally not be consistent with the data in Figure 3b. When this is true gamma multihit confidence upper bounds will be sublinear (e.g., quadratic) at low dose and consequently much smaller than the multistage confidence bounds. HONS 025181 73 Fiyur *. Exarapla of Data Exhibiting Upward Curvature c 8. mX X rigura 3>. Dos* Ex tup la of Data Exhibitinc Downward Curvatura ' HONS 025182 74 Confidence bounds based upon the passim multihit modal will be approximately correct whenever this model is the correct mods A similar statement could be made for the probit model, multi stage model, or any other modal to which reasonable statistical methods are applied. However, there may be considerable uncer tainty as to what the true model may be in a particular situatic Hie multistage model not only reflects some reasonable assumptic regarding the carcinogenic process which dovetail nicely with epidemiological data for many cancers (Peto, 1977b), but it also reflects soma of the uncertainty with regard to the true model by virtue of encompassing a relatively large class of doseresponse functions. For example, as noted earlier, the multista class contain* dose response functions which are linear at low dose and also exhibit upward curvature at moderate doses. On the ether hand, the gamma multihit class is more restrictive at this point in that it does not permit such behaviour. Is this extra restrictiveness of the gamma multihit model justified? TO help answer this question, consider the following modifica tion to this model. Suppose that the hits (phenomenological events which are required to occur in a tissue in order that a cancer appear) can possibly occur spontaneously in the absense of the carcinogen. Part of the affect of the carcinogen would then be to speed up tho races at which the spontaneous hits ere occurring. For example, if one of the 'hits' is an in correct base substitution in DNA during mitosis, the carcinogen could speed up the rate at which these "hits' are occurring in individual cl! : ^ ^ --, - - - HONS 02513 73 n incorrect substitution. With this modification to the model, the gamma multihit upper confidence bounds will no longer be sublinear at low dose and will likely be very close to corre sponding bounds calculated from the multistage model [A3], Ob the other hand, versions of the gamma model which incorporate such an assumption as this could still be consistent with data with strong upward curvature as exemplified by Figure 3b. Thus, in order to obtain sublinear upper confidence intervals with the gamma multihit model a modification such as the one described above must be ruled out, not on the basis of data, but by assumption. By was of summary, confidence intervals based upon the multi stage model will always be linear at low dosa. Confidence inter vals based upon the gamma multihit model may be either 'super linear* (corresponding to X < 1) or 'sublinear* (corresponding to k > 1). Superlinearity is achieved by making the model too broad in that a fraction of a hit is allowed which has no bio logical basis. On the other hand, sublinearity is achieved by making the model possibly too restrictive in that models which are reasonable from a biclogical viewpoint are ruled out by assumption. Comparisons and Discussion To compare low dose extrapolations using the Mantel-Brysn probit model (All with those using the multistage model [A2] we present Figure 4 based upon the same data as Figure 2. In this HONS 025184 76 Dose Figure Comparisons of 'safe' doses computed from the Mentei- Bryen procedure and from a procedure based upon the multistage model (from Crump, 1977b). HONS 025185 77 Figure are plotted on a log-log scale the Mantel-Bryan 'safe' dose as well as both the multistage 'most likely' curve based upon fcaj and the 'safe' dose based upon [A2j and computed as outlined in Crump, at al. <1977). A 99% statistical assurance was used for both 'safe' dose curves. We note that the Mantel-3ryan 'safe' dose lies above the multistage safe dose curve at values of added risk below S x 10~*. The Mantel-Bryan "safe" dose curve lies above the multistage 'safe' dose curve by a factor greater than 20 for an added risk of 10" and by a factor greater than 300 for an added risk of 10~8 Because of the 'flatness' property Of the Mantel-Bryan probit function (Al) described earlier, the Mantel-Bryan 'safe' dose curve will lie above the multistage safe dose curve by arbitrarily large factors at extreme low doses. Guess, et al. (1977) have compared the Mantel-Bryan 'safe' dose curves to the multistage 'safe' dose curves and found this to be a typical situation. Thus it is clear that if the true dose re sponse curve could be similar to the multistage dose response function (All then the Mantel-Bryan procedure could not be justi fiably called conservative. (See also Crump 1977 for further discussion of this point.) On the other hand, we have seen that there are quite plausible arguments for the true dose response curve to have the same shape at low dose (linear) as the estimated ultistage curve. We note that both the multistage 'safe' dose curve and 'most likely' curve have a slope 1 in Figure 4 as plotted on the log-log scales which is equivalent to the curves being linear at low dose. The fact that the 'most likely' curve has slope 1 is HONS 025186 due to the fact that with this particular data sat tha linaar coefficient q^ in (A2] was estimated to ba positive. However ti safe' dose curve using the multistage model (A2J will always -< linear at low dose regardless of whether or not the linear ecef ficient is estimated to be positive. This property should i shared by any valid statistical procedure based upon a dose re sponse function that does not rule out linearity at low dose by assumption as Mantel-Bryan does. Just as it is not possible tc prove statistically the existence of a threshold, it is likewis not* possible to rule out the possibility that the true dose response curve is linear at low dose on the basis of statistics analysis. (See Guess, et al. (1977) for a thorough discussion this important point.) The Mantel-Bryan obtains 'safe' dose estimates which are considerably higher -than those obtained usi: the multistage model because it assumes away linearity at low dose, an assumption that we have seen is probably unwarrented z that majority of carcinogens which are classified as 'directly- acting' carcinogens. Since extrapolation based upon a model such as tha multi stage model must always be linear at low dose, the question arises as to how different the result will be from simple linear extrapolation. For some data the difference will be minimal. For example, for the data upon which Figure 2 is based, 'safe doses' computed using the multistage model is almost identical with 'safe' doses based upon linear extrapolation. For some data sets, however, the difference could be considerable. example, with the Cass, et al. (1964) DES usinn tS- nv Tor HONS 0251*7 It mica, the 'safe' dose based upon linear extrapolation is lower than the 'safe' dose based upon the multistage model by a factor of about five and there are doubtless cases where this difference could be greater than an order of magnitude. HONS 02518 REFERENCES Allan, 1. F. and KorbacV. (1976). Fathobiological response of primates to polychlorinated bipher.vl exposure. Proceedings of the Katirnal Conference on Polychlorinated Eiehenvls (Nov. 19-21, "'1976, . Chicago, 111.) E?A-560/6-75-004. Armltage, F. and Doll, R. (1961). Stochastic models for carcinogenesis. In Proceedings of the Fourth Berkeley Symposium on hiatheaatical Statistics and Probability. 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Environmental Protection Agency (1976). PCBs in the United States industrial use and environmental distribution, task I. EPA 560/6-76-005. Food Safety Council (197S). Proposed system for food safety assessment. Food and Cosmetic Toxicology (December). Cass, C. H., Costs, D. and Graham, K. (1964). Carcinogenic doseresponse curve to oral diethylstilbestrol. J. Katl. Cancer Inst. 33: 971-977. Cuess, H. A. and Crump, X.S. (1976). Lov-dose rate extrapolation of data from animal carcinogenicity experiments--analysis of a new statistical technique. Mathcsstlcsl Biosciences 30, 15-36. Cuess, H. A. and Cruop, X. S., (1978). Kaximua likelihood estimation of dose-rosponre functions subject to absolutely nonctonlc constraints. Annals of Statistics 6. 101-111. Cuess, H. A., Crump, K. S., and Peto, R., (1977). Uncertainty estimates for low-dose rate-extrapolations of animal carcinogenicity data. Cancer Research 37:3475-3483. Hartley, H. 0. and Sielken, R. L. (1977). Estimation of "safe doses'* in carcinogenic experiments. Biomctrics 33:1-30. ts \j Hoel, D. G., Caylor, D. V., Klrschsteln, R. L., Saffiotti, U. and Schneidcrman, >1. A. (1975). Estimation of risks of irreversible, delayed toxicity. J, of Toxirolorv and Environmental Health 1:133-151. HONS 025190 Humphrey, H. E. B. (1577). Evaluation of changes of tlie level of polychlerinared biphenyls (PC3) in human tissue. Final Report on FDA Contract 233-73-2709. 1ARC (197S). Polychlorinated biphenyls and polybromatcd biphenyls. 1AKC (Internaticnal Agency for Research on Cancer) Monographs on the Evaluation of the Carcinogenic Fisk of Chemicals to Humans, Vol. 16; WHO Publications Centre, Albany, K.Y. Industrial Bio-Test Laboratories, Inc. (1971). Reports to Monsanto Company. Tve-year chronic toxicity vith Arcchlor 1242, 1254, and 1260 in albino rats. Unpublished reports, November 12, 1971. 1ST No. B7298. Ito, K.t Nagasaki, H., Aral, M., Makiura, S., Sugihara, S., and Hirao, K. (1973). Hlsopachologic studies on liver tumorlgenasis induced by mice by technical polychlorinated biphenyls and its promoting effect on liver tunors induced by beneaene hexachlerlde. Journal of the National Cancer Institute 51. 163 7-164 6. Jelinek, C. and Corneliussen, P. E. (1976). Levels of PCEs in.tbe. U.S. food supply. Proceedints of the Kational Conference on Polychlorinated Blobenvls (Nov. 15-21, 1975, Cnicago, 111.) EPA-560/6-75-004, 147-154. Johnson, X. D. and Kaske, D. D. (1977). Pesticide and Othar Chemical Residues in Total Diet Samples (XI) . Pesticide Monitoring Journal 11. 116-131. Kimbrough, R. D., Linder, R. E., Bursa, V. V. and Jennings, R. V. (1973). Adanoflbrosis in the rat liver, with persistence of polychlorinated biphenyls in adipose tissue. Archives of Environmental Health 27. 390-395. Kimbrough, K. D. and Linder, P.. E. (1974). The induction of adenoflbrosls and hepatomas of the liver in mice of the BALB/cJ strain by polychlorinated biphenyls (Aroclor 1254). Journal of the Rational Cancer Institute 53, 544-552. Xinbrouth, R. D., Squire, R. A., Linder, R. E., Strandburg, J. D., Montali, R. J., and Burse, V. U. (1975). Induction of liver tunors in Sherman strain female rats by polychlorinated biphenyl Aroclor 1260. Journal of the Kational Cancer Institute 55. 1453-1459. ` ' Ruts, F. V. and Strassnan, S. C. (1976). Residues of polychlorinated biphenyls in the genetal population of the United States. Proceeding. of the National Conference on Pclvchlorinated Bi phenyls (Nov. 19-21, 1975, Chicago, 111.) El'A--560/6-75-004, 139-143. Linder, R. E., Caines, T. B., and Kimbrough, R. D. (1974). The effect of polychlorinated biphenyls on rat reproduction. Food and Cosmetic Toxicnlorv 12. 63-77. HONS 025191 63 Maklurs, I'., Aoe, H., Sugihara, S., Ilirao, K. Aral. >:., and Ito, IS. (1974). Inhibitory effects of polychlorinated biphenyls oti livtr tumorigenesis in rata treated vich 3'-nthyl-i-dimaihylacinoaaobtr-cnc, K-2-fluorenylacetamide, and dicthylnitroaanina. Journal of the National Cancer Institute 53. 1253-1257. Mantel. N. and Bryan, V. R. (19C1). Safety testing of carcinogenic agents. J. Natl. Cancer Inst. 27:455-470. Mantel, N. and Schneiderian, (1975). Estimating 'safe* levels, a haxardous undertaking. Cancer Research 35:1379-1386. Mantel, N., Bahidar, K. R., Brown, C. C., ClRinera, J. L. and Tukey, J. W. (1975). An improved Mantel-Bryan procedure for the "safety" testing of carcinogens. Cancer Research 35:665-872. Mantel, N. (1977). Aspects of the Kartley-Sielken approach for setting "safe doses" of carcinogens. In Origins of Human Cancer Booh C. Hunan Risk Assessment. H. H. Hiatt, J. D. Watson, and J. A. Vinsten (eds.) Cold Springe Harbcr, K.V., Cold Springs Berber Laboratory, 1397-1401. McCann, J., Choi, E., Yanasski, E. and Aces, B. K. (1975). Detection of carcinogens as nucegens in the Saleonells/iticreseme teat: Assay of 300 cheaicals. Proc. Nat. Acad. Sci. USA 72:5135-5139. McCann, J. and Anes, E. K. (1976). Detection of carcinogens as mutagens in the Salmonella/microsone test: Assay of 300 cheaicals: Dis cussion. Proc. Nat. Acad. Sci. USA 73:950-954. KcDeraott, D. J., Young, D. R., and Heescn, T. C. (1976). PCB con tamination of southern California marine organisms. Proce6dincs of the Rational Conference on Polychlorinated Eiohenrls (Nov. 19-21, 1975, Chicago, 111.) EPA-560/6-75-004, 209-217! McNulty, V. T. (1976). Use of the rhesus monkey as a model for human toxicity vith polychlorinated biphenyls. Proceedings of the National Conference on Polvchlorlr.ated Binhenvls (Nov. 19-21, 1975, Chicago, 111.) EPA-560/6-75-004, 332-333. Monsanto (1975). Industrial Rio-Test l.cheraterJes, Inc. Reports. Hlstopathological evaluation of additional liver sections. Mareh 24, 1975. Unpublished reports, Monsanto Co., St. Louis, Missouri. Munson, T. 0., Palmer, H. D., and Porns, J. M. (1976). Transport of chlorinated hydrocarbons in the upper Chesapeake tay. Pro ceedings of the National Conference on Tolvchlorlnatcd Binhenvls (Nov. 19-21, 1975, Chicago, 111.) EPA-560/6-75-004, 21E-2l7! National Marine Fisheries Service (1976). Compendium of PCB data. N0AA, U.S. Dept, of Commerce, Washington, D.C. 02S192 HOMS 64 National Institute for Occupational Safety and Health (1977). Criteria lor a recommended standard . . . occupational exposure to poly chlorinated biphenyls (PCSs). DHEV (NIOSli) Publication Ho. 77-225. NCI (National Cancer Institute) (1978). Bloassay of Aroeler 1254 for possible carcinogenicity. Carcinogenesis Technical Report Series No. 38. CAS No. 27323-18-8 NCI-CG-TK-3B. Kisbet, I. C. T. (1976a). Protection Agency. PB-253-397. Criteria document lor PC5s. Environmental National Technical Information Service Nltbet, I. C. T. (1976b). Introductory remarks, session 111. Pro ceedings of the National Conference on Polvchlorinsted Eionenvls (Nov. 19-21, 1975, Chicago, 111.) EPA-560/6-75-00*. 137-138. Xlsbet, I. C. T. (1976c). Environmental transport and occurrtnce of PCBs in 1975. Procetdlncs ol the National Conference on Poly chlorinated Biphenyls (Nov. 19-21, 1975, Chicago, 111.) EPA-560/6-75-004, 254-256. Pato, X. (1974). (Paper delivered at the N1EHS Vrlghtsvllle Beech conference on Low--Dose Risk Estimation). Pato, X. (1977). The carcinogenic effects of chronic exposure to vary low levels of toxic substances. Presented at an K1EK5 con ference on cancer risk estimation, Pinehurat, N.C., March 10 - 12, 1976. Environmental Health Perspectives. Pato, X. (1977b). Epidenology, multistage models, and short-term mutagenicity tests. In Origins of Hunsn Cancer Book C. Human Risk Assessment. H. H. Hiatt, J. D. Watson, and J. A. Vinsten (eda.) Cold Springs Harbor, N.Y., Cold Springs Harbor Laboratory, 1397-1*01. Pollshuk, Z. W., Xon, K., Vasserman, M., Cucos, Slsl, Vasserman, Dora, and Lcscsch, C. (1977). Organoclorine compounds in htnan blood places and nilk. Pesticides Monltorine Journal 10. 121-129. --------------- Kai, K. and Van Xyxin, J. (1978). Risk assessment of toxic substances based on a generalised multihit dose response model. Tree. SIMS Conference, Alta, Utah, June 26-30. Xannug, U., Johansson, A., Hand, C., and Vachtmeiater, C. A. (1974). The mutagenicity of vinyl chloride afLer metabolic activation. Ambio 3. 194-197. Salaburg, D. S. (1977). Open query: Theoretical problems in the modified Mantel-Bryan procedure. Biometrics 33:419-421. Sanborn, J. X., Childers, V. F., and Metcalf, X. L. (1976). Uptake of three polychlorinated biphenyls, DDT and DDE by the green sunfish, Lcpcmis Cyanellur. Raf. Prc-ccedinrs of the national Conference on Pnlvchlorlnatcd Biphenyls (Nov. 19-21, 1973, Chicago. 111.) El'A-360/6-75-004, 236-2*2. HONS 025193 Savage, E. P. 0979). (Personal communication). Spagnoli, J. J. and SV.inner, L. C. (1977). I'CE's in fish from selected voters of Kev York State. Pesticide Hcnitorinr Journal 11. 69-67. UcMya.ni, M., Chiba, T., and Koda, K. (1974). Co-carcinogenic effect of DDT and PCS feedings on methylchloanthrene-lnduced chemical carcinogenesis. Bulletin of Enviror.-.entt 1 Contamination and Toxicology 12. 687-693. ValV.tr, C. *. (1976). The occurrence of PCS in the National Pish and Wildlife Monitoring Program. Proceedings of the Rational Con ference on Polychlorinated Biphenyls (Kov. 19-21, 1975 Chicago TU.) EPA-360/6-75-004, 161-176. ' Watson, C. S. (1977). Age incidence curves for cancer. Proc. Hat. Acad. Sci. USA 74^, 1341-1342. -------------------- HONS 025194 3r'urr'ri fir; 7C CALI!-' THE TOXICOLOGY OF PCB'S An Ovanriaw with Emphasis on Human Haatth Effaets and Occupational Expoauras '983 Evaluation Syttam and Information Sarvica Stata of California Haalth Saryieaa/Dapartmant of Industrial Raiations January, 1981 (Updatad Fabruary 1982) HONS 025195 J THE TOXICOLOGY OP PCBs An Overview with Emphasis on Human HeaJth Effects and Occupational Exposures Prepared by Gideon lets, M.O., M.P.H. Hazard Evaluation System and Information Service State of California Department of Health Services/Department of Industrial Relations 2131 Berkeley Way Berkeley, California 90704 (413) 340-2113 HOWS 025196 THE TOXICOLOGY OF PCS* Table of Contents I. INTRODUCTION..........................................................................................* D. GENERAL BACKGROUND INFORMATION................................................t m. PHARMACOKINETICS................................................................................... Absorption..........................................................................................................g Distribution, Accumulation (Mammals)...........................................................I Transplacental Exposure, Secretion in Milk................................................ Metabolism......................................................................................................... IV. ANIMAL TOXICOLOGY............................................................................. .... Acute ............................................................................................................... Subacute, Chronic............................................................................................. Reproductive Effects................................................................................... .... Other Immunoauppresive, Endocrine......................................................... II V. CARCINOGEN1CTTY/MUTAGEN1CITY.........................................................20 Carcinogenicity.................................................................................................. 20 Test Results.................................................................................................. 20 Mutagenicity.................................................................................................. 23 VL BIOCHEMICAL EFFECTS................................................................................. 2J Enzyme Induction............................................................................................ 23 Porphyria........................................................................................................ 2< VE. HUMAN TOXICOLOGY AND EPIDEMIOLOGY........................................2* Dermatologic Effects...................................................................................... 2S Systemic Symptoms...................................................................................... 29 Liver Damage.................................................................................................. 29 Yusho............................. 29 Neurotoxicity .................................................................................................. 31 Cancer................................................................. 32 Ongoing Occupational Studies .... 33 VIE. MEDICAL SURVEILLANCE AND BIOLOGIC MONITORING . . . 3S IX. SUMMARY AND CONCLUSIONS............................................................... 3* -2- HONS 025197 Table of Contents REFERENCES...............................................................................................................3 Table I. Dose-Response for Animal Toxicology............................................ *J Table D. Occupational Exposure to PCBs...................................................... eg Table 111. Percent Distribution ofSymptoms ofYusho Reported by 119 Patients ExaminedBefore October 3, 1962...................................50 Figure l........................................................................................................................ 51 Figure n........................................................................................................................52 Figure 111....................................................................................................................... 52 Figure IV....................................................................................................................... 53 -3- HONS 025198 L INTRODUCTION As a consequence of the Environmental Protection Agency (EPA) ban on further manufacture of polychlorinated biphenyls (PCBs) in 1977, occupational exposures to these compounds have been drastically reduced. However, significant exposures may remain for particular occupational groups. Utility workers, for example, may experience sporadic but potentially massive exposures when cleaning up spills, or when servicing and dismantling transformers and capacitors that still contain PCB fluid. Electricians, appliance service workers and firefighters also may have continued occupational exposure. The National Institute of Occupational Safety and Health (NIOSH) estimates that 12,000 workers have potential exposure as a result of current uses of PCBs (NIOSH, 1977). Despite the vast scientific literature on the toxicology of PCBs, the human health effects likely to result from such exposure remain illdefined. The Hazard Evaluation System and Information Service (HES1S) has reviewed the literature on PCB toxicology in response to inquiries about worker health. Requests lor information have come from tsiions and workers who handle PCB fluids in cleanup of spills, in maintenance work, and in transportation, storage and disposal of used equipment. Toxicology information has also been requested by medical professionals evaluating the clinical significance of PCB exposures, and public health officials who are attempting to set standards far occupational and environmental exposures. Our primary goal has been to review the data relevant to the human health effects of PCBs especially those resulting from occupational exposures. Since the published epidemiologic evidence is limited we have utilized animal toxicology studies where appropriate in anticipating potential biologic effects in humans. Ve have not attempted to summarize the extensive literature on PCB toxicology, but the reader is referred -*- HONS 025199 to numbor of roetnt review! (DHEV, 197*J IARC, 1978; Fishbein, 1970; Kimbrough, 1970; BPA, I >77; Neloon, 1972; NIOSH, 1977). -3- HONS 025200 U. GENERAL BACKGROUND INFORMATION In all animal spades that have been studied PCBs have a very low acute toxicity. They are readily absorbed across biological membranes, poorly metabolized and only very slowly eliminated. Because PCBs persist in the environment and accumulate in living tissue, they are concentrated fbiomagnified") in the food chain in a similv manner to other organochlorine compounds like DDT. Concern about exposure to PCBs has, therefore, focused on their resistance to biodegradation with the comequent potential for long-term or delayed health effects. A number of published reports have established "background" levels of PCBs in the blood and tissues of human populations with no previous history of exposure. Surveys in vsrlous geographical areas have found detectable residues in blood, (at and mothers' milk. Measurable levels of PCBs are typically found in greater than 30% of subjects tested with maximum blood levels generally less than 20 ppb (Finklea, 1972). The levels reported from adipose tissue are typically somewhat higher, in the range of 1-2 ppm (Kutz, 1973). Residues of PCBs in human milk have ranged from 40-100 ppb in whole milk (New York State Health Council, 1977). Two facts complicate the documentation of the human and animal toxicology of PCBs: 1. Commercial products are rarely single agents, but rather are complex mixtures of chlorinated biphenyls with different numbers and arrangements of attached chlorine atoms (see Figure IX The metabolism and toxicology of PCBs seem to vary with the percent of chlorination and with the isomeric structure of the PCB molecule.2 2. All commercial products are potentially contaminated with chlori nated naphthalenes and polychlorinated dibenzofurans (PCDFsX The degree of this contamination varies with different commercial mixtures (see Figure III). - 6- HONS 025201 Contamination by dibenzofuran* (PCDFj) is of particular concern because of the structural similarity of these compounds to the highly toxic dibenzodioxins (see Figure M. The pattern of observed effects in animals exposed to PCDFs closely resembles that seen following exposure to 2,3,7,S tetrachlorodibenzodioxin (TCDD). In comparative animal studies the toxicity of PCOFs is much greater than the PCBs, particularly in the thymus, skin (acne), Uver and hematopoetic system (Oishl et si.. 197t| Moore et^ aU, 1979X In addition, PCOFs are 1000 times more potent than PCBs as enzyme inducers (see Section VI). Uncertainties in the analytic methods used for detection of PCBs must be considered when reviewing the published data on PCB toxicoiogyt Monitoring PCBs in environmental or biological samples by gas-liquid chromatography/mass spectrometry (GC/MS) is made difficult by the presence of other chlorinated hydrocarbons (e.g., pesticides) which are commonly present at similar concentrations (Stalling et ai.. 1979). Because of the difficulties in the interpretation of CC/MS spectra and other methodologic problems btdudlry extraction and cleanup, the PCB levels reported from different laboratories may show considerable variation. -7- hons 025202 m. PHARMACOKINETICS Absorption There is relatively little information on the rate or degree of absorption of PCBs by any route for any species of animaL Since similar systemic toxicity has been observed In rodents alter dermal, oral and inhalational adminstration of comparable doses, it is likely that PCBs are easily absorbed by all routes. The few quantitative measurements of relative absorption rates indicate that most, if not all, PCBs which contain six or fewer chlorine atoms are efficiently absorbed from the gastrointestinal (Cl) tract (Albro and Fishbein, 1972| Van Miller et ai. 1973| Matthews and Anderson, 1973). Distribution. Accumulation (Mammals) As with other heavily chlorinated chemicals the major storage tissue for PCBs is body fat. The concentration in adipose tissue is 10-1000 times that found in other tissues, both following single oral doses (Grant et ah, 1971) and after chronic administration. (Curley et at, 1971) The lowest concentrations are found in whole blood and plasma where levels are usually several fold lower than in other tissues examined. This preferential distribution of PCBs into fat has been well documented after intravenous (Lv.) dosing in tha rat (Lutz et aL. 1977). Results are consistent with the high distribution coefficient of PCBs in fat and low perfusion of adipose tissue compared to skin, liver, muscle and blood (Anderson et aL. 1977). Two important pharmacokinetic questions cannot now be resolved on the basis of available datat 1. Doas the concentration of PCBs reach steady state with constant exposure? -S- HONS 025203 2. Will mobilization of adipose tissue after starvation or illness lead to a transient increase in PCB concentrations in blood and other tissues ? Like most heavily chlorinated hydrocarbons the half-life of PCBs in animal tissue is quite long. In a chronic feeding study with Arodor 1234 at 100 ppm in the diet of rats, a steady build-up of PCBs occurred in all tissues analyzed without a plateau level even after 240 days of treatment. By comparison, in a similar rat dietary study using DDT, plateaus in fat were attained after 90-140 days (Curley et a!., 1971). In dairy cows a steady state was reached in 40-60 days (Fries, 1972), probably due to mobilization into fat micelles and secretion into milk. Thus, PCBs are unlikely to reach steady state levels In nonlactatlng animals* and fat mobilization or lactation may be expected to result in release ol stored PCBs. Transplacental Exposure. Secretion in Milk Transplacental exposure of PCBs has been documented in mammals. Term fetuses taken from rats exposed to 10 mg/kg/day during days 7-19 gestation contained 0.63 ppm PCB, or about 1/60 the maternal dose. When the dose to the mother was increased five fold, the concentration in the fetuses increased two lold (Curley et aU 1973). The hyperpigmented babies observed in the Yusho incident (see Section VII) represent additional circumstantial evidence of transplacental passage of PCBs, although it is imdev whether these effects were related to PCB or to the PCDF contamination. Secretion of PCBs into milk has also been observed. In mice, little passage of PCBs occurred across the placenta once PCBs had been sequestered into maternal adipose tissue, but they were readily transferred to suckling offspring through the milk (Vodicnik and Lech, 19*0). These observations suggest that secretion of PCBs into milk may be quantitatively much more important as a source of exposure in newborns than is -9- HONS 025204 transplacental passage. Thu has recently been documented in a prospective study of Japanese mothers end their infants (Hirokadzu and Ota, 1980). Metabolism PCBs are metabolized primarily by hydroxylation and conjugation with glucuronic acid. The primary site of biotransformation is assumed to be the liver, although no data is available currently on the possible role of peripheral metabolism, e.g., skin. Many experimental feeding studies in both mammals and birds have shown an inverse relationship between percent chlorination and rates of metabolism. Less chlorinated PCBs are more readily metabolized than are more chlorinated ones, the rate of metabolism and excretion decreasing sharply as the number of chlorine atoms increases above five (EPA, 1977). The metabolism of the higher chlorinated biphenyls is also dependent on the position of chlorine atom substitution. The presence of two adjacent, unsubstituted carbon atoms is needed lor the rapid enzymatic hydroxylation reaction (Jansen and Swdstrom, 1974). Since the more highly chlorinated biphenyls have a very much slower metabolic rate and longer hall-life, they are more generally found as residues in human and animal tissues. This relationship alters with PCBs above 94% chlorination, presumably as a result of lower absorption from the gastrointestinal tract. Arena oxide intermediates have been described in a major pathway of the metabolic transformation of PCBs by hepatic mixed function oxidases (Safe et aL, 1979) Gardner ot aL. 1973). These intermediates are of particular concern since they are capable of direct interaction with ONA and may be the active form of carcinogenic polyacyclic hydrocarbons (Jcrina and Daly, 1974). The PCB molecules which are more readily metabolized and excreted also are more likely to form these arene oxides. It does 10 - HONS 025205 net necessarily follow, however, that those compounds which persist in tissue and are more likely to be measured in population sampling, are less important in terms of their carcinogenic potential. From the limited data available, it appears that significant differences exist between nonhuman primates and rodents in the metabolism and pharmacokinetics of PCBs. The marked variation observed in PCS toxicity between rodents and primates may be explained by such differences. Primates appear to be more susceptible to the toxic effects of PCBs than ire rats or mice (see Section IV and Figure IV). When single doses of radiolabeled PCB were administered by gastric intubation to infant monkeys, the metabolites measired in urine, tissue (liver) and serum included hydroxylation products derived from arene oxide intermediates while in the rat, direct hydroxylation is the rule (Hsu et al. 1973). There is virtually no pharmacokinetic data in humans. A lew generalizations can be made, however, based on studies reporting PCB blood levels: the higher the exposure levels, the higher blood concentration of PCBs (Hera et al. 1973; Inoue et ah. 1973; Kvppanan and Lolho, 1973; Baker et at, 1980); and the higher the environmental concentration and/or the longer the period of exposure, the longer the Mood levels of PCBs remain elevated (Harm et al., 1973; Baker et aU 1980). However, there are a few reports which are inconsistent with this latter trend (Bumgarrcr et al.. 1973; Hasetawm et aU 1972; Kitamura et al., 1973). PCB levels have also been correlated with race and geographic residence (NIOSH, 1977) and with age and dietary intake of fish (Kimbrough, 1980). -H- HONS 025206 Comments Certain generalizations can be made from the limited pharmacokinetic data that is available) 1. Absorption occurs by all routes (skin. Cl, inhalation). 2. Distribution is primarily into fat. 3. Metabolism and excretion are dependent on specific molecular structure, varying inversely with percent chlorination. . Excretion is in general quite slow so that Moaccumulation occurs even at low exposure levels. 3. Trans^acental transfer occurs but may be quantitatively less significant than secretion into milk. . Arene oxide metabolites are found in the metabolic transformation of PCBs. These compounds are highly reactive and may represent the active carcinogens (see Section VV 7. The relationship between percent chlorination and potency as carcinogen has not been established.S. S. There are essentially no pharmacokinetic data in humans; it is not known, for example, 11 intermittent high doses are more or less hazardous than low level chronic exposures to the same total dose. - 12 - HONS 025207 FV. ANIMAL TOXICOLOCY Acute Toxicity When given a* a single dose, the acute oral LDJQ of PCBs in rats, rabbits and mice ranges from 1-10 g/kg of body weight. According to the American Industrial Hygiene Association classification system for acute toxicity, PCBs are classified as "slightly toxic" (0.5-3 g/kg), or "practically nontoxic" <5-13 g/kg). There is some evidence that young animals are more sensitive than adults, and that females are more susceptible than males to the acute effects of PCBs (Kimbrough et at. 1971). In rodents, the acute oral toxicity appears to decrease with increasing chlorine content of the administered PCBs. This may be secondary to decreased absorption of the higher chlorinated compounds or to the differences in metabolic transformation previously discussed. Although few clinical signs of toxicity have been reported in experimental animals, pathologic findings are extensively documented. Central Nervous System (CNS) depression (decreased pain response and diminished exploratory behavior), anorexia and oliguria lollowed by ataxia, coma and death have been observed in rats following acute administration ol large doses of PCBs (Brackner et ai.. 1973). Consistent pathologic findings associated with death in rats, rabbits and guinea pigs include liver damage with fatty infiltration, centrolobular atrophy, and in some cases necrosis. Pathologic changes in other organs in these species are not often described, except for chloracnellke lesions which occur at the site of skin or intradermal application. 13 - HONS 025208 Comments The low order of acute toxicity in experimental animals is consistent with the lack of acute effects observed in workers exposed to PCBs. Reporter symptoms alter occupational exposures include mild irritation of the skin and eyes at levels above 0.1 mg/m3 with unbearable irritation occurring above 10 mg/m3 (ACG1H, 1974). Systemic symptoms of nausea and headache have been reported but may be secondary to the solvents (such as trichlorobenzene) in the PCB mixtures. Subacute and Chronic Toxicity In contrast to the low order of acute toxicity, effects from chronic exposures to relatively low doses of PCBs have been consistently observed and are of far greater concern. These subacute effects show appreciable variation among species, but liver damage is again the prominent finding. The major changes in rats fed Arodor 1248, 1254, and 1262 at 100 ppm in their diet for six weeks induded liver hypertrophy, marked fatty infiltration and degeneration of parenchymal cells. As in acute toxidty studies, PCB mixtures with lower chlorine content were more toxic (Allen and Abrahamson, 1973). In 8-12 month feeding studies increased serum lipids and focal areas of liver damage were observed (Allen et aL. 1976 Kimbrough et aL, 1972). Nonhuman primates are more sensitive than rodents to the toxic effects of PCBs (see Table 1 and Figure IV). Adult female monkeys exposed to dietary levels of 2.3 ppm lor 12 months (>O.OS mg/kg/day) developed facial edema, alopecia, acne, gastritis with ulceration, anemia, hypoproteinemia and bone marrow hypoplasia. At 100 ppm (10 mg/kg/day) there wia considerably more evidence of tissue damage than in rats, '1 - HONS 025309 including marked hepatic hypertrophy with litrastructiral abnormalities (Allen, 197H Based on extrapolation from the Yusho data, PCBj may cause symptoms to human at levels (0.2 mg/kg/day) which are comparable to the lowest doses which produce effects in nonhuman primates (see Table 0. Most of the animal data are derived from feeding or oral intubation studies. Tfare are relatively few reports of dermal or inhalation experiments. Inhalation studies again revealed liver damage to be the prominent finding in rodents. Far summary of irhaiation data see the NIOSH criteria document, page 123 (NIOSH, 1977). Dermal toxicity studies in rabbits have produced skin lesions at the site ol application as well a systemic effects including liver and kitbiey damage, thymic atrophy, lymphopenia and Increased fecal porphyrins (Vos and Beams, 1971). Comments Liver ckmage, documented histologically, is the most consistent finding among the many laboratory animals spades tested. Effects of low level chronic exposure does show appreciable variation among species, but liver damage has been, observed in all spades and is usually the most sensitive indication of PCB exposure. The fact that liver dysfunction has been inconsistently observed in humans may be an artifact ol the relative insensitivity of the standard liver function tests (SCOT, SCPT) as compared to biopsy and histologic analysis (see Sec. VD, p. 23). Reproductive Effects Adverse reproductive effects of PCBs have been noted in many mammalian and avian spades. The pattern of reproductive effects indude alterations in estrue cydes, failure of implantation, increased frequency of spontaneous abortions, low birth weitfu oilspring HONS 02S210 and decreased poet-natal survival. No specific teratogenic effects of PCBi have been observed in a variety of avian spedes. Transplacental effects, however, have been ttocumented in both animals and humans (see Section vn). PCBs given to mice for 10 weeks at dosage of 1.0 mg/kg/day lengthened the estrus cycle by more than two days and decreased the number of successfully implaited ova (Orberg and Kihlstrom, 1973). Similarly, mice that received PCBs as sucklings in a long-term trinsgenerational study showed subsequent alterations in estrus cycles, decrease in implantations, and when mated to each other (FI studies), reduced number of offspring per litter (Kihlstrom et aL. 1973). In rats, studies suggest that reproductive effects of PCBs dacrass* at chlorination increases. No reproductive effects have been fouid with Arodor 1260 (60 percam chlorination) at 1, 10, 100 ppm, but siptificant effects have been noted with Arodor 1262 and 1236 (62 and 36 percent chlorination, respectively) at doses of 20 and 100 ppm. Arodor 1260 began to exert toxic effects at doses of 300 ppm. Rats chronically fed from 20 to 100 ppm Arodor 1262 and 1236 had reduced numbers of offspring. .Surviving newborns showed increased mortality, with only 30 percent sirviving to weaning. Five ppm of either Arodor 1262 or 1236 produced no effects over two generations. Thus, the minimum effective doses ranged from 20 ppm for the lower Chlorination mixtures to 100-300 ppm of the more highly chlorinated compounds (Keplinger et aL. 197I{ Linder, et aL. 1976). Evidence of adverse reproductive effects is also available far nonhuman primates. Rhesus monkeys fed 2.3 and 3.0 ppm Arodor 1261 for IS months in the diet showed diangea in menstrual cycles in addition to other systemic signs of toxidty. Evidence was also obtained for frequent resorptions and spontaneous abortions following breeding - 16 - HONS 025211 to normal males. In all, six infants were carried successfully to term out of 1* pregnancies. The offspring were of low birth weight and by two montfo began to show evidence of PCB toxicity, presumably from PCBs in the maternal milk; only tfree infants survived to six months. Behavioral tests in the three surviving animals showed marked deficits in several learning tasks, with increasing errors correlated with Increasing body burdens of PCBs (Allen and Barsottl, 1976; Bowman et_aL, 197S; Barsottl et aL. 1976). The effect of PCBs on the male reproductive system is not known. There is one report of four male Rhesus monkeys exposed to 9.0 ppm Arodor 1248 in the diet for II months. Alter 12 months, one of four animals developed clinical signs of PCB Intoxication, showed marked sperm count depression and was functionally sterile. A testicular biopsy revealed a marked decrease in spermatogonia. A second biopsy one year altar exposure showed complete recovery (Allen et aL, 1979). PCBs are negative In the mouse sperm morphology assay (Heddle and Bruce, 1977). Comments PCBs show significant effects on reproductive competence in a variety of species. These effects increase in intensity with increasing dosage and decrease with increasng tfilorinatien of the PCB isomers. PCBs do not appear to be mammalian teratogens. A reasonable explanation for most of the reproductive effects of PCBs could be based on their estrogenic activity (see below). PCBs lave been detected in humen semen (Dougherty et aL. 1980), but there have been no studies of semen quality in relation to PCB exposure in humans. The eflects of PCBs on the male reproductive system in animals or humans has not been adequately - 17 - HOMS 0252X2 studied. The only other evidence to date on reproductive tonicity in human come from the Yusho incident and is summarized in Section VO. Other 1. Immunosuppressive Effects A number of reports implicate PCBs as immunosuppressants (Fishbein, 197*). Lymphoid atrophy has been observed in rabbits, chicken* and guinea pigs. Suppression of humoral immune responses to several antigens was observed in rabbits and guinea pigs, and decreased cell-mediated immune resporae followed PCB exposix* in guines pigs. A decreased tolerance to hepatitis virus was seen in ducklings without apparent intoxication. In monkeys exposed trains piacentally and through contaminated milk, the lymph nodule* of the spleen were extremely small and without germinal centers (Allen and Barsotti, 1976)) morphologic changes were indicative of reduced immunologic compe tence. 2. Endocrine Effects Subcutaneous administration of Arodar compounds with lower chlorination produced an estrogenic effect on the rat uterus which was not shown with Arodors of hi^ner dnlorination (Bitman and Ceal, 1970). Female monkeys led Arodar 12S for six months showed an increase in concentration of ixinary ketosteroidi and a prolongation of their menstrual cycles with increased bleeding (Barsotti et al, 1976). Antiandrogenic effects have been described in birds although the mechanism is not dear. It may be secondary to an increased rate of androgen metabolism in the liver by induction of microsomal enzymes (see Section VI), or by virtue of PCBs exerting estrogenic effects. - 18 - HONS 025213 Comment* Tht ell(CT ol PCB expo*ire on imrrune and endocrine system function has not been carelully studied in humans, so the relevance ol these animal observation* to human health remains inknown. There is one cross-sectional study ol occupational exposire to PCBs which will include analysis ol scrum hormone levels and urinary metabolites, but results have not yet been published (Selikoli et al.. in progress). - 19 HONS 02521* V. CARCINOGENICITY/MUTAGENICITY Cardnotenicity Several PCS mixtures are dearly carcinogenic in rodent bioassays, producing liver turnon (hepatocellular cardnomasX Kanechlor 500 and Arodor 1254 are carcinogenic In male mice (lto et aL. 1973} Kimbrough and Linder, 1974)} and Arodor 12(0 is carcinogenic in separate studies in two strains of female rats (Kimbrough et aL. 1975; Norback et aL. 19*0). In addition, a purified component of a PC8 mixture, 2,4,5,7,V,5' hexaehlorobiphenyl, has recently been found to be cardnogenic in female rats, causing hepatocellular cardnomas (Norback et aL, 1980L Because hi^i doses of PCBs are known to cause extensive injury to liver tissue it is Important to consider the dose levels at which liver cardnomas were produced in the rodent bioassays. In two studies in rats, significant increases in hepatocellular erdnomas were present at doses which did not produce gross histologic changes. Hepetocytcs ware somewhat enlarged (probably due to microsomal enzyme induction), but no extensive fany Infiltration or necrosis occurred, as was characteristic of bioassays at hitter dose levels (Kimbrough et aL. 1975L Test Results 1. Mice (Male) A. Kanechlor 300, 400, and 500 fed to groups of 12 eight-week-old male mice at 100; 250, and 500 ppm in the diet for 32 weeks produced hepatocellular cardnomas in 5 of 12 sirvivors in the high dose group led Kanechlor 500. The remaining 7 mice in this group had nodular hyperplasia (neoplastic nodules). No metastases or other tumors were - 20 - HONS 025215 present in this or other dosed groups. The control group (6 mice) was likewise tumor-lree (lto et aL. 1973). B. A rodor 123* administered to groups of 30 five to six-week-old male BALB/c3 mice at dietary levels of 0 or 300 ppm (about 30 mg/kg body weight during the exposure) lor 11 months produced neoplastic nodules (hepatomas or hyperplastic nodules) in 9 of 22 sirvivors in the dosed group. Other liver lesions (adenofibrosis) were present in all 22 survivors. Additional morphological changes in the livers of these animals induded picomor phism and areas of necrosis. Such changes and tumors were absent among sirvivors (2*) in the control group (Kimbrough and Linder, 197*)t 2. Rats A. Kanechlor *00 administered to ten-week-old Donryu rats (10 males and 10 females) at dietary levels whidi varied from *0-000 ppm during the *00-day study produced liver tumors (multiple adenomatous nodules) in 6/10 treated female rats. Such lesions were absent from the controls (3 males and 3 females) end the treated males (Kimtra and Baba, 1973). B. Kanechlor 300, *00, or 300 administered to groupe of 30 eight-week-old male Wlstar rats at dietary levels of 0, 100, 300, or 1000 ppm produced increases in the incidence of cholangiofibrosis at the highest dose level of all Kanechlars (2/13, 2/10, and */13, respectively). All three compoinds also produced hepatic nodular hyperplasia, the incidence of which increased with dose and extent of chlorination (Kanechlor 300 at - 21 - HONS 025216 100 ppmt 1/22; Kanechlor 400 at 100 ppm: 2/16, and 1000 ppm: 3/10; Kanechlor 300 at 100 ppm: 3/23, at 300 ppm: 3/16, and at 1000 ppm: 3/13); (Ito t_aL, 197*). C. Arodor 1260 administered to groups of 200 three to four-week-old female Sherman rats at 0 and 100 ppm in the diet (varying between 3-10 mg/kg body weiit Airing the 21-month exposure) produced at 23 months among the dosed survivors dearly significant increases of hepatocellular cardnomas (controls 1/173; dosed group 26/184) as well as neoplastic nodules (hyperplastic nodules: controls 0/173; dosed group 146/184). The incidences of nonhepatic tumors did not differ between the dosed and control groups (Kimbrough et at, 1973). D. Arodor 123* administered to groups of 2* eight-week-old Fisher 3** rats of either sex at dietary levels of 0, 23, 30, or 100 ppm for 103 weeks was not cardnogenic to any of the treated groups under the test conditions. It is important to note that two of the dose levels used were lower than those which produced a positive response in Sherman rats. Rare adenocarcinomas and cardnomas of the gastrointestinal tract appeared in both sexes and may be related to the administration of the PCBs (males: historical controls 6/600, dosed group 2/2*). In addition a high inddence of hyperplasia was present among the dosed poups (males: controls 0/24, low-dose 3/24, mid-dose S/2*, hi^i-dose 12/24; females: controls 0/23, low-dose 6/24, mid-dose 9/22, and highdose 17/24); (NCI, 1978). - 22 - HONS 025217 E. Arodor 1260 administered to groups of 30 male and female SpragueDawley rats at dietary levels of 0 and 100 ppm for 103 weeks was carcinogenic in female rats, causing significant increases in liver hepatocellular carcinomas (Norback and Weltman, 19*0). F. A purified component of a PCB mixture, 2,*,3,2`,',3'-hexachlorobiphenyl administered to groups of 30 male and female Sprague-Dawley rats at dietary levels of 0 and 100 ppm for 103 weeks was carcinogenic in female rats, producing an increased incidence of liver hepatoceUdv carcinomas among the dosed animals (Norback and Weltman, 1910), Mutaeenicity PCB mixtures have not been observed to have mutagenic activity nor to measirably affect chromosomes in repeated studies using a variety of in vitro or in vivo test systems Evidence of genetic damage from PCBs in laboratory test systems induding diromesemal aberrations, nondisj inction, loss of sex chromosomes or increased frequency of sister chromatid exchange has not been observed. Report of a weak effect of Arodor 1221 and of a stronger effect of a-dilorobiphenyl in Salmonella using PCBinduced rabbit liver homogenate as a Uvcr activation system appears unfounded (Wyndtam et at. 1976). Father attempts to repeat these results have been insuccessiu! using a variety of Salmonella tester strains and liver activation systems (Katzenellcnbogan and Ames, 1980) Safe, 197S). However, PCBs belong to the class of heavily chlorinated animal cardnogens, most of which are not positive in short-term tests for mutagenicity. Examples in this class include dield'in, chlordane, kepone, mirex, TCDD*, chloroform, and carbon tetrachloride. HONS 023218 Whether this is because the in vitro metabolic activation systems do not produce the same spectrum of metabolites that occur in vivo or because heavily chlorinated compounds such as PCBs art carcinogenic by nonmutagerac mechanisms is not known at this time. Validation oi the carcinogenic efleets in rodents is provided by a positive cell trans formation assay using C3H10T1/2 done eight mouse fibroblast cells in culture by two separate PCB mixtires (Arocior 123b and 1260) and a purified component 2,0,3,2*,S',3* -hexachlorobi phenyl (Norbeck and Weltman, I960). Comments A wide variety of PCB mixtures have been subjected to rodent cancer bioassays nd to numerous In vitro and in vivo short-term tests for mutagenicity. Several of these PCB mixtures are carcinogenic. None of the PCB mixtures are active in short-term tests for mutagenicity, a finding that holds true for most heavily chlorinated carcinogens. However, siiistantial confirming evidence lor cardnogenidty is provided by positive cell transformation assays using these same PCB mixtures. Thus, under OSHA published criteria, PCB mixtures should be considered Category I* carcinogens. Both IARC (IARC, 197S) and EPA (EPA, 1971) have concluded that based on available animal data PCBs should be considered as potential human carcinogens. Category li Human evidence or two positive mammalian bioassays or 1 positive mammalian bioessay with supporting results in short-term tests. Catexorv lit One positive mammalian bioassay. (Source: Occupational Health and Safety Letter VeL 9, No. 2b November S, 1979) - 24 - HONS 025219 VI. BIOCHEMICAL EFFECTS OF PCBs Enzyme Induction The principal biochemical ellect o< PCBs is the stimulation and induction oi certain enzyme systems. Enzyme induction occurs in both the microsomal monooxygenase or cytochrome P-430 system and the aryl hydrocarbon hydroxylase or cytochrome P-44S system, and it has been observed in both man and experimental animals. Induction is not restricted to the liver. It occurs in numerous other organs including Id(hey, adrenal, ling, gut, skin, and testes. Fetal enzyme induction may occur via transplacental exposure, and induction may also occur by exposure to contaminated milk (Alvaras td Kappas, 1973)l Identification of structure-activity relationships for enzyme induction is difficult because of the lvge number of isomers in commercially prepared PCBs and because all commercial products contain trace amounts of polychlorinated dibenzolurans (PCDFs) which are orders of magnitude more potent as enzyme inducers than PCBs (Matthews at aL. 197*). In early studies using commercial Arodors, potency for enzyme induction was loend to be dependent on chlorination of the PCB mixture. Later, when purified isomers were tested, potency was found to vary with the position of chlorine atom substitution (Ecobichon and Comeau, 1973; and see Section IU). Since rate of metabolism is also known to vary with isomeric configuration of the PCB molecule, it may be that potency for enzyme induction is simply a function of the relative rate of metaboiisn and excretion. HONS 025220 - 23 - The enzyme induction properties of PCBs are utilized in the metabolic activation ayatam of in vitro bioassays for mutagenicity. It it unlikely, however, that enzyme induction would oonaistently enhance the effects of carcinogens or pro-carcinogenst it might function synergistically to activate a chemical, but they also might function to deactivate reactive carcinogens. Both phenomena have been observed in rodent cancer bioassays. Porohvria Porphyria cutanea tarda (PCT) in humans is an acquired delect in hepatic porphyrin metabolisn characterized by uroperphorinuria, photosensitivity and mechanical fragility o< the skin. PCT can be produced experimentally by a number of <frugs, indudiiy tetrachlorodibcnzodioxins and PCBs. All of these agents have the ability to stimulate the activity of 2-aminolevulinic acid (ALA) synthetase whidi is the initial enzyme in the heme synthetic pathway. Experimental hepatic porphyria was observed in Sherman rats exposed to Arodor 12)4 in the diet. At doses of 100 ppm the animals became porphyric after a delay of approximately 2-4 months. The porphyria resembled hexachlorobenzene poisoning and human PCT (Goldstein et aL. 197)). In dironlc feeding studies ALA-synthetase induction occurs after rats have become porphyric, although with large single doses the enzyme induction is seen almost immediately after dosing the animals (Goldstein et aL. 197)). It hu not bei established whether only certain isomers in the PCB mixtures or - 26 hONS 02)221 contamination with PCOFi is responsible lor the production ol hepatic PCT. Porphyria has not bean reported in humans exposed to PCBs. Comments Enzyme induction has two important implications lor human health! 1. the occurrence ol disease secondary to the increased metabolism ol endogenous or exogenous substances, and 2. the interference with medical therapy due to increased metabolism ol administered (tugs. PCBs are more potent snzyme inducers than phonobarbital, a *ug that occasionally causes clinical problems due to is enzyme inducing eflects. While the ellects of phenobarbital decline alter administration ceases, enzyme induction from PCBs persists long alter cessation of exposure. - 27 - HONS 025222 VU. HUMAN TOXICOLOGY AND EPIDEMIOLOGY Few good epidemiologic studies oi the health effects of PCBs are available. Most studies reported in the literature have been characterized by one or more of the following shortcomings! 1. small study populations, 2. lack of accurate exposure data, 3. simultaneous exposixe ol workers to other potentially harmful chemicals, S. lack of control for confotmding variables, such as alcohol consumption, and 3. inability to separate PCBs from contaminants ahd/or difficulty in comparing PCBs manufactured by different firms. In spite of these problems, some health effects have been consistently reported in Studies of workers occupationally exposed to PCBs. In addition, a large-scale poisoning whidt resulted from ingestion ol PCB/PCOF-contaminated rice oil has been well documented and resulted in multiple signs and symptoms attributable to PCBs and/or PCDFs. The health effects identified in a review of the epidemiologic literatire are summarized below, and Table n briefly describes the major epidemiological studies from 1930 through 19S0. Dermatolotic Changes Chicracnc, contact or allergic dermatitis, and brown chromodermatosis have been consistently reported in studies of workers exposed to PCBs (Hara ct aL. 1973; Hasegawa et aL. 1972; Inoue et aL, 1973} Kitamura et aL. 1973; Baker ct aL. 1980; Meigs et aL, 193*1 Ouw et aL, 1976; Schwartz, 1936). - 21 - MOWS 025223 Systemic Symptomi Nausea, digestive disturbances, headaches, upper respiratory problems, id persistent body odor have been reported as a result of occupational exposures (Ouw et aL. 1976; Schwartz, 1936; Warshaw et aL. 1979). Liver Parnate Abnormal liver finction tests have been reported in a number of occupational studies and clinical hepatitis was observed in the Yusho epidemic. However, some of the earlier investigations reporting abnormal liver finction did not control for exposixe to additional chemicals, previous medical history or drinking pattern and some of the marginal differences observed could have been related to these confounding variables. More recently, Fbchbeln et aL, (1979) found no significant differences in LFTs between capacitor manufacturing workers with low level chronic exposure and nonexposed controls. However, in a cross-sectional survey by Maroni et aL, (19S1 a * b) abnormal LFTs were observed and seemed to correlate with serum PCB levels. With the exception of a lew cases of dtloracne, these workers had no other symptoms, sipis or laboratory abnormalities. Yusho (Japanese word translated as "oil disease") Both dermal and systemic health effects are well documented in the epidemiologic study of a poisoning epidemic in Japan caused by ingestion of contaminated rice oil in 1961 (Hlguchi, 1976| Kiratstne et aL. 1972). - 29 - HONS 025224 It 1$ not dear how much the health ellects observed in Yusho victims can be extrapolated to occupational expoaures lor the following reasons: 1. The average amount ol PCB (Kanechlor *00) ingested was estimated to be 2 grams and the minimum, 0.3 gram (Kuratsune etaL, 1972). This i$ a higher dose than has been reported in most occupational exposures. In addition, the PCBs were ingested as opposed to inhaled or skin-absorbed as is the case with occupational expoaures. 2. The contaminated oil contained "used" Kanechlor *00, the exact chemical com positon ol which is uiknown. 3. Frying ol foods with the rioe oil oould have produced new compounds which may have altered the toxicity of the PCBs or the toxicity of possible contaminants. *. Yusho oil was shown to oontain high concentrations of dibenzofurans. 3. Reported concentration of PCBs in the oil may not have been accurate enough to permit a rigorous <fjantitative analysis since the methods for estimating PCBs in foods were not fully developed at the time. Clinical featixes of the Yusho patients are listed in Table III. The Yusho incident is also important because it clearly documents the potential for reproductive and transplacental effects in humans. A study was made of the 13 infwits ol 11 mothers affected by Yusho and of 2 taiaffacted wives of patients: 2 of the Yusho mothers had stillbirths; 10 of the babies had transient greyish or dark-brown pigmentation of the skin, and 3 had similar pigmentation of the gingiva and/or nails; increased ocular discharge was present in 9; and 12 ol the 13 infants were small when compared with the national average (Ftstatsu et aU 1972; Kikuchi et aL, 1969; Kuratsune, 1976; Tald et aL, 1969). Babies born to patterns even 3 years after severe PCB exposure tended to show pigmentation of the sldn on the back and the gingiva, although the degree of pigmentation was lass than that of babies bom to the same mothers up to one year after the poisoning (Kuratsvxie, 1976). - 30 HONS 025225 Congenital abnormalities have also been observed in PCB-intoxicated infants. In the population of 13 offspring of Yusho mothers, premature eruption of teeth was observed in 2 cases, and larger than normal frontal and occipital tontanelles, exophthalmos and the persistence of an abnormally wide sagittal suture were observed in 3 others. No other gross malformations were reported nor was any relationship between dose and outcome considered (Funtasu et al.. 1972). Mothers' milk contaminated with PCBs also appears to be a source of exposure lor infantsi one baby showed signs of poisoning even though the mother had ingested the contaminated rice oil only after the baby was delivered. The infant began to show signs of PCB intoxication alter 3-0 months of breast feeding (Kuratsune, 1972; Yoshimura, 1970). Neurotoxicity Paresthesias were reported in over 30% of Yusho patients (see Table III). In the Yusho epidemic more detailed neurologic examinations were performed in 21 cases admitted to a university hospital in northern Japan. Ten of the patients complained of numbness or pain in the distal extremities, and in five cases decreased pain, touch and temperature sensations were observed. Sensory conduction velocity in sural and radial nerves was below normal in 6 of 10 individuals with neuropathic symptoms (Murai and Kuroiwa, 1971). A decrease in amplitude of muscle action potential evoked by nerve stimulation, and a decrease in sciatic nerve conduction velocity has been reported in rats intoxicated with tetrachlorobiphenyL Thus, PCBs can affect peripheral nerve function in both - 31 - HONS 025220 humans and experimental animals, but these have been reported only at doses which cause other systemic signs of poisoning. Cancer There is too little epidemiological evidence available yet to evaluate the potential of PCBs as human carcinogens (Bahn et al., 1910; Brown and Jones, 1980). A follow-up of the Yusho patients through 1977 has reported 91 deaths (31 with cause of death confirmed) of the 1,(63 identified victims. There were 11 deaths from neoplasms, or 33.996 of the total. While this rate is higher than the 21.196 in the population of the same prefecture in 1977, these data were not age-adjusted. No particular site was elevated, and there were no deaths from malignant melanoma, a tumor previously suspected to be linked to PCB exposure (Bahn et al.. 1976). Two liver cancers and two lung cancers were reported but smoking and drinking patterns were not available (Urabe et al, 1979). A retrospective cohort mortality study of 2,367 workers in two capacitor manufacturing plants was recently completed by NIOSH. The report did not find any statistically Significant SMR for any cause of death among exposed workers. Deaths from liver cancer, cirrhosis of the liver and rectal cancer were slightly higher than expected, though these excesses were not statistically significant and no information was available on medical histories, drinking patterns, etc. There was no relationship between increased mortality from all causes of cancer, rectal cancer or liver cancer, and length of exposure to PCBs. Limitations in the study design, however, might have obscured a true association. In particular, there was a relatively small sample followed over time thereby limiting the statistical power of this study. Second, there were on the average - 32 - HONS 025227 only 13.19 yurt ol lollow-up lor each exposed worker in the study. Usually the latent period between exposures and deaths Iron) cancer is longer. Third, exposure to PCBs was quantised (or March 1977 only; there was no data on actual PCB exposures during the time when most ol the population at risk was working with PCBs. Finally, over 30% ol the sample has exposure to PCB lor only two years or less. Ontoint Occupational Studies Two additional cohort mortality studies are currently underway. The lirst is a mortality survey ol the entire worldore* employed between 1932-1937 at the largest United States' lacility that manulactured capacitors and transformers. There is detailed lnlormation available on exposure levels in the plant. While the duration Irom onset ol exposure is shorter than optimal (only 23 years in some cases), the information will at least give data on the short-term mortality experience ol a heavily exposed occupational group (Selikoff et ai, in progress). The second is a similar occupational mortality study, also ol workers exposed in capacitor and transformer manufacturing. Over 2,000 workers have been identified for this study but no ftrther details are yet available (Bertazzi et aL. in progress). On* case control study is currently being conducted to assess whether there is excess risk ol malignant melanoma among PCB-exposed workers. This data will not be available until March, 19S2 (Bahn et al., 1976). - 33 - HONS 025228 There is also one cross-sectional clinical Held survey o{ 326 capacitor manufacturing workers at two sites, encompassing a total workforce oi S00 (Fischbein eteL, 1979). Exposures were classified as none, low, medium, and high based on job description at the time of the survey (1975). Researchers were able to identify the PCBs used and had some data on environmental air levels in the plants. A number of parameters were measured, including complete history and physical examinations, SMA panels and pulmonary function tests. Results have been published on respiratory function (Warshaw at al., 1979) and general signs/symptoms, and results of serum lipids, endocrine function and dermatologic findings are forthcoming. To date, the only positive association involves dermatologic signs and symptoms. Further investigations of the effects of PCB exposure on serum lipids have been done in both occupational and general environmental exposure settings. Smith et al.. (1978), reported some statistically significant differences between exposed and nonexposed workers at two sites. They reported higher serum triglycerides and lower levels ol high density Upo-proteins in the exposed group. Whether the magnitude of the difference is biologically significant is not clear from this study. For example, the nonexposed group at site #1 compared to the nonexposed group at site *2 showed a greater difference than the exposed and nonexposed comparison at either site, in another study (Baker et al- 1980) workers and community residents with exposure to fertilizer Warshaw et ai (1979) concluded that there was also an association between PCB exposure and impaired pulmonary function (restrictive pattern). However, there were major methodoiogic problems with the data: the particular spirometer used (heated wire flow sensor) is notoriously inaccurate; it was not possible to link exposure data with particular PFT results; there was no information on race, and finally the magnitude of the observed effects was low and no statistical comparisons were done with nonexposed controls. - 36 HONS 025229 made from sewage sludge contaminated with PCBs were studied. Plasma triglyceride levels were tound to increase significantly with serum PCB concentration (both in drinkers and nondrinkers), and the authors concluded that PCBs may alter lipid metabolism at levels of exposure and bioaccumulation insufficient to produce other identifiable signs of toxicity. Comments Although many problems have been identified in the studies evaluating the health effects of PCBs, it is dear that occupational exposure, at a minimum, can produce dermatologic effects. The long half-life of PCBs and their bioaccumulation in various humw tissues leaves open the possibility of substantial chronic and delayed effects analogous to those seen in animal bioessays. These eflects have only recently begun to be studied in a rigorous manner, and although the epidemiological evidence is neither complete nor entirely consistent there can be no question ol the necessity to protect the worker from exposure. - }} - AONS 0i5i30 VUI. MEDICAL SURVEILLANCE AND BIOLOGIC MONITORING Medical surveillance and biologic monitoring are o< limited usefulness in predicting health hazards if dose-response relationships are not known. This certainly is the case with PCBs. Based on animal toxicology, there are many suspected adverse effects of PCBs which might result from exposure in occupational settings, but very lew have been documented well enough to give even rough estimates of "no-effect" or "sale" levels. A large percentage of nonoccupationally exposed people have detectable pcb levels In body fat, blood and milk. However, any attempt to estimate an adverse health effect associated with increases above this background level necessarily involves extrapolation from animal data and, therefore, is subject to considerable error, especially when the marked variation in sensitivity of various animal species is appreciated. Furthermore, not enough is known regarding the relative dose-response characteristics of the various documented effects (e.g., liver damage, skin changes) to state that in the absence of a particular sign, symptom or laboratory abnormality, the risk of long-term effect (cancer, reproductive toxicity) will be negligible (see Table I). Far the clinician confronted with a worker who has a history of exposure to PCBs the approach to management cannot be easily outlined. Given the current analytic methodology, residues can be meastred in blood or tissue in the ppb range and compared to background; but assigning a health risk to a given level is virtually impossible, especially given the lack of pharmacokinetic data. Often patients are being evaluated after a considerable lag period (years) since last exposure occurred and extrapolation to peak blood levels is not possible. In fact, it may be that residue levels bear little relationship to the health risk. For example, the lower chlorinated compounds may be more toxic but they are more rapidly metabolized and excreted and, therefore, less likely to persist in blood or fat. Further, with the possible exception of chioracne, - 36 - HONS 025231 the presence of specific signs, symptoms or laboratory abnormalities is very difficult to definitely relate to PCB exposure in any given patient. Given these uncertainties and the potential for serious health effects, the approach to monitoring should emphasize environmental sampling and every attempt should be made to minimize exposure by engineering controls or personal protective measures in those settings where occupational exposure still occurs (e.g., utility repair workers). Biologic monitoring may be used to assess the effectiveness of environmental control, but it is really best utilized within a specific research protocol and probably has little value in the routine work-up of individual patients. - 37 - ftQHS 015232 SUMMARY AND CONCLUSIONS PCBj have low acute toxicity but are ol public health concern because oi their persistence in the environment and in human tissues and their demonstrated potential for chronic or delayed toxicity. They are potent inhibitors of reproductive function in both rodents and nonhuman primates and are positive in animal cancer bioassays. As potent inducers of hepatic enzyme systems, PCBs may have additional unpredictable long-term health effects. Some of the conflicting reports in the toxicology literature are undoubtedly related to the variable composition and trace chemical contamination of the tested mixtures. Occupational and environmental exposure is usually to those mixtures; but if we are to accurately assess the associated health hazards, further animal studies are needed which carefully define the toxicology of the individual agents. Epidemiologic studies of occupational exposures to PCBs to date have failed to detect serious adverse effects but are considered insufficient, and further studies are clearly needed. Of particular interest is the continued exposure among utility workers. Because of the potential ability to cause cancer and other long-term adverse effects such as infertility and hepatic injury, human exposure to PCBs should be kept to the lowest level technically passible. The persistence of PCBs in the body and the irreversibility of some of its ellects make it necessary to act now, rather than to wait until more definitive data are available. - 38 - HONS 025233 REFERENCES ACGIH. Chiorodlphenyl - *2% chlorine. Documentation of the TLVs for substances in workroom air. 3rd ed., pp31-2. Cincinnati, 1976. Albro, PV and Fishbein L. Intestinal absorption of PCBs in rats. Bull Environ Contam Toxicol St26, 1972. Allen, 3R and Abrahamson, U. Morphologic and biochemical changes in the liver of rats fed PCBs. Arch Environ Contam Toxicol h263, 1973. Alien, 3R. Response of the nonhuman primate to PCB exposure. Fed Proc 36:1673, 1973. -- Allen, 3R and Barsotti, DA. The effects of transplacental and mammary movement of PCBs on infant rhesus monkeys. Toxicol 6:331, 1976. Allen, 3R et al Response of rats exposed to PCBs lor 33 weeks. Arch Environ Toxicol :e*TT976. Allan, 3R et al Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. Ann NYAS 320:619, 1979. Alvares, AP and Kappas, A. Induction of aryl hydrocarbon hydroxylase by PCBs in the retroplacental unit and neonatal liven during lactation. Fed Europ Biochem Soc Letters 30:172, 1973. Anderson, MV et aL The construction of a pharmacokinetic model for the disposition of PCBs in the rat. Clin Pharm Therap 22:763, 1977. Bahn, AK et aL Melanoma after exposure to PCBs (letter to the editor). N Engl 3 Med 2931*30976. Baker, E et aL Metabolic consequences of exposure to polychlorinated biphenyls (PCB) In sewage sludge. Amer 3 Epldm 112:333, I960. Barsotti, DA et aL Reproductive dysfuKtion in rhesus monkeys exposed to low levels of PCBs (Arocior 12**). Food Coamet Toxicol j*:99, 1976. Bertazzi, PA et aL Mortality experience among PCB workers. Univ of Milano, Inst Occ Health, Milan, Italy, in progress. Bitman, 3 and Ceal, HC. Estrogenic activity of DDT analogs and PCBs. 3 Ag Food Chem UU110*, 197a Bowman, R et aL Correlation of PCB body burden with behavioral toxicology in monkeys. Pharmocol Biochem Behav 9:69-36, 197*. - 39 HONS 025234 Braekner, 3V et al. Biological response ol the rat to PCBs. Tox Appl pharm 24:434, Brown, OP and Jones, M. Mortality and industrial hygiene study ot workers exposed to polychlorinated biphenylv Draft report, NIOSH Division of Surveillance, Hazard Evaluation and Field Studies 1980. Bumgarner, 3E et al Polychlorinated biphenyl residues in refuse workers. National Institute of Environmental Health Sciences (as reported in NIOSH Criteria Document), 1973. Burse, VW et al PCBs - storage, distribution, excretion and recovery; liver morphology after prolonged dietary ingestion. Arch Environ Health 29:301, 1974. Curley, A et al PCBs - distribution and'storage in body fluids and tissues of Sherman rats. Environ Res 4:481, 1971. Curley, A et al. PCBs evidence of transplacental passage in the Sherman rat. Food Cesm ToxiSni;471, 1973. DHEVi Subcommittee on health effects of PCBs and PBBs - series of articles appearing in Env Health Persp 24:146-198, 1978. Dougherty, RC et al Sperm density and toxic substances; a potential key to environmental health hazard, submitted to Env Health Chem, 1980. Ecobichon, DO and Comeau, AM. Isomerically pure chiorobiphenyl congenes and hepatic fmction in the rat; influence of position and degree ol chlorination. Tox Appl Pharm 33;94, 1973. EPA: Halogenated polyaromatics, mi L Fishbein, Potential industrial carcinogens and mutagens, pub #360/3-77-003, Oflice of Toxic Substances EPA, Washington, DC ppl73197, 1977. Finklee, 3 et al PCB residues in human plasma expose a major urban pollution problem Amer 3 PuCCc Health 62; 643, 1971. Fisdibein, A et al. Clinical findings among PCB-exposed capacitor manufacturing workers. AixTRYAS 320; 203, 1979. Fries, CF. PCB residues In milk of environmentally and experimentally contaminated cows. Env Health Persp. _1:33, April 1972. Fimatsu, I et ai. Polychlorobiphenyls (PCB) induced fetophathy. 1 Clinical observation (Abstract l'JoT'72-2360). Kurume Med 3 _19:43-31, 1972. Gardner, AM et__aL PCBs hydroxylated urinary metabolites of 2,5,2',3,-tetrachlorobiphenyl identified in rabbits. Biochem Biophys Res Comm 33:1377, 1973. Goldstein, 3A et aL A comparative study of two PCB mixtures on induction of hepatic porphyria and Tug metabolizing enzymes. Tox Appl Pharm 32:461, 1973. - 40 - HONS 025235 Grant, Dl t al Metabolism oi PCB (Arocior 123*) mixture in the rt. Bull Environ Contain Tox (>102, 1971. Mari, I et al FoUow-^ study ol condenser factory alter use ol PCB discontinued. (As reported NIOSH Criteria Document) 3pn 3 Ind Health ^7:371-372, 17> (3ap). Hasegawa, H et al Report on survey ol work area environment where PCB is handled and ol the health ol workers handling PCS, in special research report on prevention of environmental pollution by PCB-like substances. (As reported in NIOSH Criteria Document) Japan, Research Coordination Bureau, Science and Technology Agency, pp. 1*1-99, 1972. * Heddle, 3A and Bruce, WR. Comparison of tests lor mutagenicity or carcinogenicity using assays for sperm abnormalities, formation of micronuclei and mutations in Salmonella. Origin* of Human Cancer, Cold Spring Harbor Lab., pp!3%9, 1973. Hlguchl, K ed. PCB poboning and pollution. Academic Press, NY 1976. Hirokadzu, D and Ota H. Transfer ol PCBs to infants lrom their mothers. Arch Environ Health 35:(2) 93, 1980. Hsu, IC et al Metabolic fate if ^H2,3,2',3,-tetrachlorobiphenyl in infant nonhuman primates. Bull Environ Contam Toxicol U:233, 1973. LARCi Working group on the evaluation of the carcinogenic risk of chemicals to human* - polychlorinated biphenyls, Vol 18, 1978. Inoue, Y et al Discovery of PCB pollution in textile factory--I. PCB level in blood serum of laborers and results of physical examination (as reported in NIOSH Criteria Document) Jpn. 3 Public Health 22:1637, 1973 (Jap). I to, N et al Histopadwlogical studies on liver tumorigenesis in rats treated with PCB*. fiimn"63:3%3, 197%. Jensen, S and Sundstron, G. Structure and levels ol most chlorobiphenyls in two technical PCB products and in human adipose tissue. Ambio 3:70, 197%. Jerina, DM and Daly, JT. Arena oxides: a new aspect of drug metabolism. Science .183:373, 197%. Karppanen, E and Kolha, L. The concentration of PCB in human blood and adipose tissue in three different research groups. In, PCB Conference II, Stockholm 1972 (as reported in NIOSH Criteria Document) Sana, Sweden National Swedish Environment Protection/Publications, %E, pp 126-128, 1973. Katzenellenbogen, J and Ames, BN. Personal communication, 1980. Keplinger, M et al Taxicologic studies with PCBs (abstract). Tox Appi Pharmocol _19t%02-%03, 19717" Kihlstrom, JE et al Sexual function of mice neonatally exposed to DDT or PCB. Environ Phys Biochem 3:3%, 1973. - 01 HONS 02523b Kikuchi, M et ! An autopsy case of stillborn ol dilorobiphenyls poisoning. Fukuoka Acta Med 1969. Kimbrough, RD et aL Morphologic changes in liver oi rats fed PCBs. Arch Ind Health 23034, 1972. Kimbrough, RD. The toxicity of polychlorinated polycyclic compounds and related chemicals. Crit Rev Toxicol 2:643, 1974. Kimbrough, RD and Linder, RE. Induction of adenofibrosis and hepatomas of the liver In BALC/c3 mice by PCBs (Arolcor 1234). 3 Natl Cancer Inst 33:347, 1974. Kimbrough, RD et aL Induction of liver tumors in Sherman strain female rats by PCB (Aroclor 1260}. TRatl Cancer Inst 33:1433, 1973. Kimbrough, RD et aL Animal toxicology, DHEW Subcommittee on Health Eflects of PCBs and PBBs.~fnv Health Persp 24:173, 1971. Kimbrough, RD. Chronic toxicity of halogenated biphenyls and related compounds in animals and health effects in humans. Presentation at the American Chemical Society meeting, August I960. Las Vegas, Nevada. Kimura, NT and Baba, T. Neoplastic changes in the rat liver induced by PCB. Gann gilOS, 1973. Kitamura, M et aL PCB in blood of workers employed in an electrical parts manufacturing plant. (As reported in NIOSH Criteria Document) 3pn 3 Ind Health _13t339, 1973 (3ap). Kuratsune, M et aL Epidemiologic study on Yusho, a poisoning caused by ingestion of rice oU contaminated with a commercial brand of PCBs. Environ Health Persp ill 19, 1972. Kutz, FV and 5 trassman, SC. Residues ol PCBs in the general population of the U.S. Proceedings ol the national conference on PCB, Chicago, EPA-360/6-73-004, Washington DC, pp 139. Linder, R et aL The effect of PCBs on rat reproduction. Food Comet Toxicol JJ:63, 1974. Lutz, R3 et aL Preliminary pharmacokinetic model lor several chlorinated biphenyls in the rat. 6rug Mctab Dis 3:316, 1977. Maroni, M et aL Occupational exposure to PCBs in electrical workers 1. Environmental and blood PC6 concentrations. Brit 3 Ind Med 31:49-34, 1911 a. Maroni, M et aL Occupational exposure to PCBs in electrical workers II. Health effects. BrlTTInd Med 31:33-60, 1911 b. Matthews, HB et aL Metabolism and biochemical toxicology of PCBs and PBBs. Env Health Persp 247177, 1971. - 42 - HONS 025237 Matthews, HB and Anderson, NV. Effect of chlorination on the distribution and excretion of PCBs. Drug Metab Dis 3:371, 1973. Meigs, 3V et aL Chloracne from and unusual exposure to Arocior. 3AMA 134:1*17. IBU -- ' MUIcr, 3*. Pathologic changes in animals exposed to a commercial chlorinated biphenyl. Public Health Rep 39:1063, 194*. Moore, 3A et at Comparative toxicity of three halogenated dibenxofuran* in guinea pigs, mice and rhesus monkeys. Ann NYAS 320:131, 1979. Mural, Y and Yoshigoro, K. Peripheral neuropathy In chlorobiphenyl poisoning. Neurol 21iH73, 1971. NCh Carcinogenesis technical report series #31, DHEW pubUcation #(N1H) 7I-(3S, 1976. Nelson, N et aL PCBs - environmental impact. Environ Res 3:249, 1972. NIOSHi Criteria lor a recommended standard - occupational exposure to PCBs N10SH, Cincinnati, 1977. Norbeck, OH and Veltman, R. Personal commuiication 19S0. New York State Health Planning Commission. Report of the ad hoc committee on the health implications of PCBs in mother# milk. Albany Health "Advisory Council, 1977. Oishi, S et ai Comparative toxicity of PCBs and dibenzofurans in rats. Tox Appl Pharm *3TT3T 197. Orbarg, 3 and Klhlstrom, 3E. Effects of long-term feeding of PCB, Clophen A-60 on length of estrus cycle and frequency of implanted ova in the mouse. Environ Res it 176, 1973. Ouw, HD et aL The use and health effects of Arocior 1242, a polychlorinated biphenyl, in an electrical industry. Arch Environ Health 31:169, 1976. Sato; M and Haaegawa, H. Amount of PCB in blood of laborers. (As reported in NIOSH Criteria Document) 3pn 3 Ind Health if: 363, 1974 (3ap). Safe, S et at The metabolism of *-chiorobiphenyl in the pig. Can 3 Phys Pharmacol 33:392, TO7J. Schwartz, L. Dermatitis from synthetic resins and waxes. Dermatitis 26:366, 1936. Selikoff, et aL Mortality experience of factory workers exposed to PCBs in the manufacture of transformers and capacitors. Mt. Sinai School of Med, Env Sciences Lab, New York, NY, in progress, 1960. HONS 025238 Shiota, K. postnatal behavioral ellecu of prenatal treatment with PCBs in rats. (As reported in IARC, 197SX. Okajimas Pol Anat Jpn 53:103, 1976. Smith, AB etal. Lipid and lipoprotein alteration occupational exposures to PCS Clinical Reslfrto, 1978. Stalling, OL et ai An expanded approach to the study and measurement of PCBs and selected planar halogenated aromatic environmental pollutants. Am NYAS 520:01. 1979. -- Takl, I et at Report on Yusho (chlorobiphenyls poisoning)! pregnant women and their fetuses. Fukuoka Acta Med 60:071, 1969 (Jap). Treon, 3F etaL The toxicity of the vapors of Aroclor 1202 and Aroclor 1250. Am Ind Hyg QTTTJoo, 1936. Urabe, H et aL Present state of Yusho patients. Am NYAS 320:273, 1979. Vodioiik, MJ and Lech, 33. The transfer of 2,0,5,7,0,,5,-hexachlorobiphenyl to fetuses and nursing offspring. Tox Appl Pharm 30:293, 19*0. Vm Miller, 3P et aL Distribution and metabolism of 3H-2,3,7,3'-tetrachlorobiphenyl in rats. Proc Soc Exp Biol Med 108:6*2, 1975. Vos, JG and Seems, RB. Dermal toxicity studies of technical PCBs and fractions thereof in rabbits. Tox Appl Pharm .19:617, 1971. Varshaw, R et aL Decrease in vital capacity in PCB-exposed workers in a capacitor manufacturing facility. Ann NYAS 320:277. 1979. Wyndham, C et aL The in vitro metabolism, macromotecuiar binding and bacterial mutagenicity of O-chlerobipEenyi, a model PCS substrate. Res Commun Cham Pathol Pharmacol .13:363, 1976. Yoshknura, T. Epidemiological study on Yusho babies born to mothers who had consumed oil contaminated by PCS. Fukuoka Acta Med 63:70, 1970 (Jap). - 00 - HONS 025239 TABLE I iudmu na imi mtcouer HONS 025240 tour II - ocoAToau woww 10 feu wir Mar HM feM* f 4MN* NMteh MMt liMWf* UmI Tl-- llwiy hytlMlM liyinl CNiiil nwl IIImii a k/.s MmIN * > ! 19 M* IMW* UHM Mft* MM tfcMMflfl Nftf InN|I U NtM* tuily >--< 7 ail* ' w4MM ffclMMM, ClMMl IttMlUtl STm.. RS* k MKiBl ylNM KM* IkICIVM iNNIlNt WKllll> ami HUM* Mil MS |/ ) NwIwUilii Hirii,nr I* iHU) <1 M M ywn 99 a liitm Ur fuMIlN Mrwl, 1 MrMrlt-- iWwimI Ugliity iNiml m m > wvim iw*i t NpNM Mt wyimi * HW bllNto IHNW u 111 MwMinli, * SIS mm. nywt*l IJS IrtUMlN riail^a UK C--MMft'l-- Cmcm/ MMUlllJ Cmmi tWn m m a --i wmlNlw WWM> >> f|TN ri Nf^ MM --* ----top* MM M *I|M at m Niminm4i M If* h|Nili NM ffk ImmI ilnm MM WNlNli l Wm4 MNINlMI NN4 n ) Mm, iNn m rtU* ii--Kir if M--4 --| -- UM|M, In MlMlN M* fVMNIty *IImIN. UInu mw Inn lih tot* il at Ha lNN IN KB Mll-UU la kUN. HONS 025241 UK! II* OCCOtiTIMAl ttttaMt 10 PCS* (cmc'J) mum Ntto tatat al Mkm to --f--4--* OMOWliO flMf Iqiiiu toot 1) Mt r--wtii to MOM Crt- uto tacwMtt tafMIta 1.1 |ff Imm ill.. Ittto TE3 al a fataIt aaoMta tattoo Ml* tot ra--nai to MOO* Crtlatto ImmI ptaiir aataari Mi | OalM*' UttMt rrOM. UlfiWt tU. toail OH tuti A--ra--i ffO m -2100 MO) 1)0*110 MO to-- Hf4 hta-- -- tattoo urtar MtaMtaM* 0.1) - 4.4 o/ 1 tot rifwui art Mil - 1.1s to MM* Uaa--tta t it* Cvltatto ptat OCi m) ftMMMt SETST toO a# I b wlHlMl too iMt Mil-- Mi toon rnjTi <iu Ota pi* IMlw) Mali HfMMII MlM 4 l--lll ItaMtot lMl) iMtoMMii MU M M total t*fi IlfiMf1 i* ItaffMil M MO i ).* It mO NNIw 04) M l HIIMI 74-MOO M* IMMIlIU tMtMMtM I* ! Ik* M rtf-- wrUn (4-14 M0> to --totlMtato M toMi OtaMM NUMMtal to OtMi Mi totaltai f IflMI. Kli mm tmm0 to MOM** to* to Mthiit aifaat iiiwi. f--urutM Mt --l| Ui UU HONS 025242 TAIU || OCCSPATIMAl IS Kb (! *4) tbttjlil NNOMr 4 --IN I1UI l.l - 1.4 J (It artan)!* -a ! 1 (II artlnj (Mbfl MM M HMMllN M TIm 1 M. M 1) fti* Mb 4|lii mnOirii nAmiS Aimtor 11*4 mm t ?* SI MlM Ml 41 ImaIm N imlM ISM Hm Ii turn li *M ntmi MS rum Si rum Si US-IMS*/,* lSM MM bn* lag* todUIlM *1 l--r, *yn mS 4M| 1 AM nikM 1 lUMMMa mmm! bnilUU tit (Ihmh la 4 d dta IInI ImIi > m9r* hywili IM - Ml (MM *0S *) Ii Mlllf>c|. tfMMto dlMM IlfMUl Ml M MM Mi M** IMM Mf UNt IA*m m* m li--fM MMMM M AkMi MM* iraatoM bln SM MA. I MllfMM TAm* MM mImmm IIMmt? mMm ilnnil, NfMlil to S4 MfMtll IM4M U (At (AmM m M(M. MWm no Amu) mm Im m- mmA m Mr amimIi. Mr to to pmmii. All <-- Mtflliy h Iwtr iIm mt* perlii (141 (M, . 114 ?) All (Mtir |* Mi Um n (Am fMiil |M n 4S. .) IwMl MS ItMV (MM Ml* II|M1? IlMlH M MC fl|K(lMMlyi Uwi ilfiriM MUIIIf UrthrtiM* I* ib Wu irtw* lUm. IMn I* IlIlM b aftolll? Mbrtmi* HONS 0252*3 tt mmU| ptoM MM) CMNlMtM (UmIn 11*1) mm m M# m miw nm wta mv m* ID.) fm M IttMM Mil (m ii.i mi Rat, toa. wMa. M|k toM* m JM ttoaUtoMla tmi * atllir to* (I4to t^-n nij W) MmmTm > ytto mTt)n. Mt wrntt* ir iiiMi if vtilrtM Cnm tortit toM tala n~r~~n toiftltt Inc mm aato yftlHg ml* MN4). ffATtout amw n tea* (omU) Atm, ImmmM Hpiauil* to 4 Mftoi Mmwm umm to fVf nIMM tt Ml* Im tomiato* |tt mmUImi ImMIii M Uk klMary ti mm iton m M tt flay itoiMIt Mlk mm(mi in* a mmI* Mttoa. tuitoiltil la|IMa*a MNlllM Wit* fCMT With HIM tl K tot IM Iwf Mat tt *rtMmr aim) a mimUUm with Mtor liar aayat Nkm imMi towto lawim* MiM* IIumId Ml* irMtoaa. lato to* 4M* MM VO* MtMMIftf iMmIMi tolNg Min, tt *- arrtai *Mm- mini wiw HONS 025244 TABLE SI PERCENT DISTRIBUTION OF SYMPTOMS OF YUSHO REPORTED BY 119 PATIENTS EXAMINED BEFORE OCTOBER 31, IMS. Symptoms Dork brown pigmentation ot nails Distinctive hair loilides Increased sweating at palms AcneUke skin eruptions Rad plaques on limbs Itching Pigmentation of skin Swelling of limbs Stiffened soles in feet and palms of hands Pigmented mucous membrane Increased eye discharge Hyperemia of conjunctiva Transient visual disturbance Jaundice Swelling of upper eyelids Peeling of weakness Numbness in limbs Fever Haering difficulties Spasm of limbs Headache Vomiting Diarrhea Males (N-19) Females (N- 100) 13.1 64.0 30.4 17.4 20.2 *2.7 73J 20.2 2*.7 34.2 11.1 70.1 34.2 11.2 71.) 31.* 32.4 14.) 11.0 7.) 30.3 23.4 l).l 73.0 54.Q 33.6 12.0 14.0 32.0 72.0 *1.0 2).0 *7.0 13.0 71.0 33.0 11.0 7*.0 32.0 33.0 19.0 19.0 1.0 39.0 21.0 17.0 Sources KurotuiM et al, 1)72 -50- HONS 0232*5 FICURE I IZFHim MOLECULE Aid) RIMS NUMBERING SYSTEM 3-chloroblphonjrl a 2,2',3,*',3-pontehloroblphByl or-EXAMPLES NOMENCLATURE SYSTEM OF CHLOROIIFHENYL CONFOUNDS BOJORSANO PERCENT CHLORINE FOR THE 10 CHLOROMPHENYL (PCB) CLASSES Chlorobiphenyl mono di tri tetr* pent* hex* hept* oct* non* dec* Empiric*! FormuU No. of Isomers c uH,a c >iH,a 2 c iiH7ci 3 c uH,ci * c ijHjCI 5 c llHCl 6 c uHjCl 7 c uH.a 1 c >>HC1 9 c i.ci 10 3 12 2* *2 46 *2 2* 12 3 1 -51- Weight % Cl IS. 79 31.77 *1.30 4S.S6 3*. 30 31.93 62.77 63.91 61.73 71.IS MOMS 0i5^A6 ricuu II MycMerliuM HHun/li (Kl'i) *v , 'v *. , M KJ" NljptfilarliMM TvrfftMjrii CHiHmM m-llhrwi Source Klobrough, 1974 1Cmr a*M WmMImIi NlirtliHnHd nniiHnlim FICTJSX III CHLORODIBENZOFURAN TYPES AND CONCENTRATIONS (lig g) IN COMMERCIAL PCS PREPARATIONS Chlorodibenzoiurans Mixture* dl tri tetra penta hexa hepta Total (1) 10 It (1) 10 It (1) 12*1 (1) 123* (1) 123* (1) 1240 (1) 12(0 (2) A-tO (3) DP-4 (*) K300 (*) K*00 (*) K300 (*) KtOO 0.3 (c)*** (e) <0.0001 0.3 0.1 0.2 0.1 0.2 1.* 0.7 (a) (e) (a) <0.0001 1.2 0.2 o. 0.4 0.3 3.0 10.0 (a) (c) (a) (a) <0.0001 0.3 1.4 0.9 0.3 0.3 2.2 Z9 (c) (b) (a) (b) *(1) Aroclor, (2) aophon. (3) Phenoclor,, (*) Kanechlor **(). (b). (c), (d), (e) represent relative mounts in increasing order 0.3 2.0 1.7 1.3 1.0 OLS l( 13.4 1-1.3 17--IS 2,3-4 3-3 HONS 025247 ncuu iv Responses el primates and rats to PCB** Response Susceptibility to toxicity Acne Hyperpigmentation of skin Alopecia Hyperactive Meibomian (lands ConjunctWit is Oedema oI eyelids Subcutaneous oedtma Keratin cysts in hair follicles Hyperplasia of hair follicle epithelium Gastric hyperplasia Thymic atrophy Hepatic hypertrophy Liver enzyme change Decreased no. of red-blood ceils Decreased haemoglobin Serum hyperlipidaemia Leucoeytosii Man Monkey Rat High Yes Yes NA Yes Yes Yes Yes Yes Yes NA NA Yes NA Yes Yes Yes Yes High Yes Only infants Yes Yes Yes Yes Yes Yes Yes Yes NA Yes Yes Yes Yes Hypolipidaemia Yes Moderate No No No No No No No No No No Yes Yes Yes No No Yes No Sourcet IARC, 197S * This table summarizes acute and subacute clinical effects but does not include chronic or delayed effects such as reproductive effects or cancer. -53- HONS 025248 AiHsnx.rr or the wmui tens to pen associates urn TU EXPECTS) ESVtIOWBSTAt EXPOSOUS UtR C. Jot, Ph.D. Dapartaoac of laurdliclpllaiip Taatealegjr Ihlnrltt; of. Arkansas for Radical Sdancaa A301 if'. Martha* UCllt lock, Arkanaaa 72203 tajMad 0. larklMo, Pti.D. Bapmam of lacardiaciplioary T*UaU|7 Silnniip of Arkaoaaa for !Mlcal Seiantaa 4301 H. Markkas Unit Irak, Arkanaaa 7Z203 HONS 025249 During cr.i put dacatai. i combination of "opin" lyieana c-r loppy or illegal diipotal practical h*e raiulced in the raiaaaa of lar|a guaaciciaa e( thoaicala into tha environment. Co cha lato 1940a, Whan it bocau apparanc that pariutint chlorinated hydrocarbon polychlorinated biphanyli (PCll) wart ubipuitoua environmental caatminaoti which cook yaara to biodegrade, actaacioa waa focuaad oo choir pocaatial to bioancuaulata to what waa believed to bo toaie lawali ia aaiaala ant hiaaaa. Aa a remit, gueetiona araaa regarding the chronic aide effect! cauial by long-term aapoaura to chaaa chovicala. Reflecting public eoatarn, Con|taaa aaaecaO chi Toaie Subatancaa Con trol Ait in 1974, which mandated a phaaaout of PCX aaaufaccuriag aaa uaa. At chat tiaa, PCIa wore coaaidarad a highly toaio aaO Oaagaraua chemical bacauaa of thoir eaviroaaaacal paxaiacaaco act choir pocaatial far laualag permanent aOwarao health affaota, inch aa caaaac. la raaaat yoara, howavor, a aubataatial lacraaaa ia aciaatific 4act baa raoulted ia a battar ua4arataa4iag of bath tha actual affacca of kuaaa expoaura ca TCle aa4 tha chaaically-ia4uca4 praeaiaaa leading to caaaar. While it waa apprapriaca a faw yoara ago te act aa tha praaiaa that all pocaacially aaxciaagaaic chaaieala rapraiencad aiailar haaarda, raaaat experience haa ahawa chat chart ara ispartaac chaoracital aaf practical 4iffaraacaa ia tha actual haxard each "carciccgaaH rapraaaaca ta public health. Similarly, chart haa baaa a aubataatial iaeroaaa la tha amount ef 4ata raflactiog tha toxicity of PCJo ia aaiaala aa4 hwaaaa. Caaai4aring the'national concern oxpraaao4 for eavironaaatal cenraninanti, aa4 in particular for PCIa, it enema both apprapriaca tab nacaaaary ca raowaluaca the haar4 aa4 riaka paaa4 by PCIa aaw chat wa have core lafaraaciaa. HONS 025250 te it cha purest at edit- papar ca pravida iraaavar* for .; * - diving cha important coxicologictl canaidaraciana uaad in inctrrrt:in| cha riaka infarrad by eexieiey oica, at vail u ca pravida a aitcuaiian aa cha PCS data within chit frtaauark ia aa ca arriva ac ar. aaaaaaaanc af cha tiah ca huaan haalch. ocramoMS an iasic nuemis or Asnssiw >isu A coaieanc ia a ehaoical aganc chat can product an advaraa affac: in a bielaiieal ayacaai. Such an advaraa affaee aay ba an alcaracian a( narmal function ar daacrucciaa af Ufa. TMi dafinieian ia braad inaa all ahaaiaala ara conic at aoaa daaa, t.a., all chamicala ara capahla of alcarini aaaa fuaacloa or praduciai daach la cam biologi cal ariaaiaa. Ohlla chia acaeaaaac aay aaaa ahvlaua, it aarvaa ta aaphtaita tha kaaia af riak aaaaaaaaat, i.a., chaaa tiraaaataadaa and aaadicioaa uadar uhith aa advaraa affacc aaa ba praducad. Aa fail Mrah atatad yaart ago, "chart ara no hatalaaa tubacaacaa; chart ara aaly haralaaa vaya af uaing tubacaacaa.'* A chaaical la canie and fraduaaa hats only within praacrihad candlciana of utaga. Siah la dafiaad aa cha prabahilicy chat a aubtcaaca will produea hats aadar tyaaiflad candlciana (1); l.a., ic ia a practical can* aldaraciaa ta dataruiaa whathar ar nac aaaa harm will ha alleicad traa a apaaitla ahaaiaal anpaawva. Safacy ia tha ratipracal af riak, ar tha probability that a aubaeanca will nac produaa ham uadar cha apt* cl flad aaaditiaaa. Thua, whan dacaraining cha riak ar aafaty af a ahaaiaal, cha aritiaal faatar ia not nacaatarily tha intrinaic eomicicy af tha chaaical par aa, but cha Likalihead that tha laval af aapaawra ca cha chamieal ia aufficianc ca axprata ita lncrinait coaicicy. HONS 025251 In {ar.aral oral. than, cha risk is approxiaaeat yy cna nua:-.:: X T *t whare R is risk, T it coxieicy, an* t is exposure. "ora accurately, Che aquation for risk is equal to cha toxicity at a function (() of cha axpoaura, or: R TfCt) This hector tafiaes cha axcrspoIstiax, ainaa untar corrals caakitiasa tho risk ia ooc always liooax ovar cha aaclra Oosa--raspasaa curra-, ask aisea, Soyasalni an hew osa laflaai fusedos (f), ehrasheik or aouthnshelk kesa-raapouss earraa say ha fitcek ta chip apauias. lever*r, retardate at haw ana chaaaaa ta express tha riaka ta chauical axpoaura. It ia claar that: (a) the actual rlak la kapeataac spas hath tha toxicity (l.a., hatark) ask tha axpoaura (l.a., ausuat of ehasical) ask (h) ta chaafa aithar altera cha riak. Therafare, ta sake a rlak asaeaaaaat, asa suat taxpara cha axpoaura prsbablllty with tha various kaaataapaaaa eurraa far each toxicity ta tec cruise uhachar or sat a haruful raapease ia likaly ta ha iakucak. Is araluaalag cha riak aaaeciacak with axpowra ta PCla, so will attaupt ta aaawur two quartleas. rlrat, la the Laral af oxpaasra at a euffialaac aagsituka such that a hatark axiaeat Racaak, It aa, ahsr ia cha hatark or uskaairahla response axpaacak for chat laval af axpatura. Ta answer hath quasiions it ia aacasaary ta first evaluate tha hasarts aasaciacak with PCla; i.a., what ara cha toxic rospaaaaa ask at what lavala af axpoaura will char ocaurt HONS 025252 'lay aapaeca nuae : conaidarad and vaijnad Decora eno hatarca co huoana aaaociacad i:.i PCS anpoauro can da avalauced. an evaiuecion of aha huaan haaard and lubiaouanc dale aacixacian for any chacsical nuae addraai cha data Saaa utilizing choroufh coaparacive taxi* calasid aaaoaaxanca. Thia oaaaa chat cha aninal and huaun data availahla auae ha carefully canaidarad in cam of: (a) cha hraadch tad variety af cha caxie raapaaaaa aanifeacad; <h> cha degree a! apaaiaa variaeioa ar apaaiaa coaaiacency ia cha af facta aoaicared; Cc) Cha paaaihla and/or propoaad oechaniaaa af caxicicy; (d) cha validity of cha taaca patterned and chair ralavanca tar aacrapalacioaa to aaa; (a) tha dotage uaed in aaiaal eaata veraua cha axpactad laval af huaaa axpaauraa; and, finally, ca tha axtanc chat cha data arc avallahla, (f) cha aucaamaa af aariaua poiaouinga and lonf-tarx occupational axpaauraa aa a soldo ca cha axpoaead huaaa conaaauaacaa and aa a caat af tha ancrapalatiaaa aada fraa aaiaal data. Only haa a aaaaiataat patcarn af caxicicy in aniaala coiacidaa with huaaa axpariaacaa can accuraca and aafa fuidalinaa ha praauliacad. Tha fallowing aactiona af chip chapcar will diaeuaa cha hatard aaaociacad with PCS axpoaura aa iacarpracad ftna tha aniaal and huaaa data; cha chaica and uaa af riak aaaaaaaant aadala ca dafina cha dale ca Kti fraa variaua aaviroaaancal axpaauraa; cha accuracy vich uhich cha haalch riaka far a fCl axpaaura can ha eac lanced at cha praaasc ciaa; and cha caactuaiaaa raachad ky chip atudy. tvAU'Anne in acctz haia*d associated wit* pcs exposes: rsca AhtffAL BATA Sawaral raviawa at cha aaaaaalian eaxicicy of PCSa have Seen puhliahad within cha laac dacada (2*7). Since ouch of chia HONS 025253 information has already been given is the previous chiocsrt, i rurttrSlattery rather than an exhaustive review is prevised hr. This se nary presents aha types of hasards to be expected and bocueencs che extrapolations ona night nake to the high exposure htaia situation baaad an cha aninal data. It am first ba stattd that PCIs have a law order af acuta tonicity aa aaaaurad by tha cadian lathal daaaa (ta 302 of tha populatian) (LOjga) for rodant ipaciaa. Aa shown in Tabla l, tha aadiaa lathal daaaa for various eouoercial PCI niaturaa lia between 1.3 and H.l |/kg of body weight, hadlea lethal daaaa aa high aa thaaa claaaify PCI aixturaa, aspacialy tha highar chlariaatad daturas, aa only slightly conic chaaicals (1). PCla produce a variety of physiologic changes in animals. Pot example. in cha liver, PCla increase tha eoaunc of aadeplaaaic ratieuLutt, resulting io aalarged hapatocyeas sad thereby increasing livar sioa and weight. Higher daaaa can causa livar danaga and aacrasia. PCla applied directly ta cha akin ef rabbits have produced hyperkera tosis , erechywa, blisters, and deopuvacion. Ia priaacas, oral doses of PCla hava lad ta facial adaaa, hair loss, and acas-lika pustules, aa wall aa prolonged anascruel cyelaa and increased bleeding in feasts aniaala. Additional tyapcaaa tapartad in various apaciea include gastric hyperplasia, dacraaaaa in rad and whits blood calls, atrophy of tha chynua and spleen, sad increases ia sarua lavals af phospholi pids, triglycerides, and cholesterol. However, aa with lethality, cha daaaa repaired to cause thaaa acuta effaces era generally high. Tha daaaa repaired to causa sub chronic affects can alas be considered high whan cha alass rata af sMtabeliaa, and therefore a tendency to bioeccuatlace, ia taken into consideration, while a nwaher of effects have been reported for PCIs, HONS 025254 rait i 'TOM* UThai oous rot vtflftS CCttTUCU. ^ MUTUKCS i1 KMM (oral) R*C (oral) AabblU Cabin) CMWll ran* ir acta AmUr 1234 lorwcmar Amlor 'm AmUr 1232 AmUr 1242 *miw 1240 Amin 1294 Amlor 1240 AmUr 1212 Amin 1240 *mUr 4449 AinU 3440 AinIn 1221 AmUr 1232 Amur 1242 AmUr 12*1 AmUr 12M AmUr 1242 Amu 12U U)M (*v/tat mv 141* > 2,000 >1,179 4,000 4,900 0,700 11,000 4,000-10,300 10,300 11,300 10,900 14,000 If,200 3,200 2,000 1,300 1,300 1,300*2,000 1,300*2,000 2,900 HONS 025255 theta of cha liver (i.a., anlargeoent and necrosis) are cha seat esalisceacly reported, is sre theta of cha shia (i.a., ehloracna ar Oaraacicii). Thaaa phyiiolagie raipaatat abaarvad ia cha lirar aad bin ara fairly predictable affacca af aany chlorinated caopouadt. In aaaaaalag cha acuta aad subcbreaic eaata af aaiaala, fda da nac appear ta ba raaurkably eaait ehaaicala. The danal icricaeioa cawaad by Kla la aac an uauaual yhyalalagla raayaaaa tar an argaaie, tslveac-llha chemical. Iha chlaracaa ebaarrad ia aaiaala aad humans ia alaa a fragaaacly abaarvad affacc af ochar cKlariaacad ahuicals aad ia ravaraibla ia cases where Kla ara cha only rurpacc agant. Tha abaarvad Uvar affacca (i.a., laaraaaad livar weight, proliferation af aadaplaamic ratlculia, deposition af fag, eall death, aad cleave aaaraala) ara comm responses ca yaraiataac, chlariaacad hydrasarbaaa, vhlth ia gaaaral ara aaayaa inducing agaaca at Isaac daaaa aad hapatocoaias at higher daaaa. haay achar chamieals ahara aaa ar bach af Chase charaatarlaclaa. Milla aaayaa iaduatlaa any iaaraasa tha eeaiciey af raaa ehaaicala aad lavar cha daaa pradaalag taxiciey, chia la asc a gaaaral phaaaaaaaa. Ia aaay iaacoacaa, aa iaaraasa ia aaraballaa dacraaaaa tha taaicicy af other ehaaicala. Similarly, induing agaaca efcaa Iaaraasa achar raataa af biacraarfaraaciaa chat deconify taxis ehaaicala. Ia fact, aaayaa loducciea ia aoaaciaca aaad chare* poetically. Hardfara, iadasdsa by icaalt caaaac ba caaaidarad a Cede rsapeaaa, aar aaa its caoaaauaacas ba accuracaly pradlctad ia Ia asahayp, PCIa causa a coavariiaa af cha gastric apichaliaa chat caa ba described aa a dyaplaatic graved pactera. this dsaa nac caaaclcuca a naaplascie craaataraaciaa (If). Whila Kla hava beae raparcsd aa iahiblciag cha iaaaaa ayacaa ia aaoaalr, this aaevra ac high daaaa at which gaaaral taxiaicy laada ts a reduced food inaaha HONS 025256 ini thui i reduced nutritional itacui. tn sou cite trj, product change! in rcpreduccivi pcrfornanci, but again uiuill/ it sign dotoi. tn acnkayo, chi* problin occuri only vieh thn female mini11 ini it dam clearly producing general tonicity ini aigni ini aympcoai of ineosicicion. Siproduct!vo dyifunction during chemical ineoaica- eien ii nnc i pirticulirly unuiunl finding. Thnrnforn, ic la con cluded chic cha icuta coniclcy of PCSa in ininali ii not pirticulirly ranarhahll, nor iana tha chemical rapraaaac an uauiuil aeuca hatari. enmie imcxs or rein Mutagenicity A ganateai! chemical la any eanpouai capable of iainciai a paraaaaac, inheritable chaaga in tha gaaacla compaelclon at a call. Canacanic affaatl arc iiriiai Inca three typaa, iapaaiing an cha aallular level af cha gaaacla laaien. Mutagnaeala rafara ca naaatiani or atruatural changaa aa tha IM level, called nlcralaalena (1). Iha athar tea eypaa af geaacanic affacci arc: claacagenaaii, uhich reterc te ettwctueel changea ac tha chrameeemal level, and aaaeploidlaatiaa, uhiah refara ca a chaaga in ehreaaaemal number, lath claacaganaail and aaaapleiiliation can clear the emetine or anpranian af ganacic aatarial; hath eypaa af chaageg are referred ea a aaaralailana (l). far eha lake af iiicaaolen, all ganacanicicy eaaca arc referred ca in chia paper aa ancagaaiciey eaaca. Tha "Anal tact," which uiaa nutiac ceraiaa af eha hcccaria JalaencJUi trjhianriim chat have lace eha ability ca lyncheaite chair own hlatiiina, ic prebchly tha aaat papalar and baac kaeva caac for QNS 025257 sutiftoic activity. Sine* ton iuu acid is iapercanc to procs:- svnehtsit, aad charafart growth, chasa edit tan pn only n his::- diat is tddtd ta cha culture radius. A ehtaieal aucsfsa cm bt idte- tifltd by t tutscion ia cht laces of cht histidine dtftct which reverts cht btctttit to cht isnsl sctct, chut allowing easily idanti- fitbls btcctritl colonies CO (in it t hiscidiaa-defieisnc aadlia. Wyadhaa tad ca-ntarkari (1), using cht Jtst Silly, cttctd cht aavaral chltriatetd biphenyl aiacurtt tad repertad that chay wart weakly autt|taie. k review of chair data ladleaaad chat 4- chlara- biphaayl had significant activity. , Atm lor 1221, uhlsh hat a chloriaa coactac of 1.13 chlorlot a par aalacnla aad it tharafara largely a oeneehlorobiphanyl aiacisre, shavad a greatly rtdacad activ ity. this weald seta ca ladleaca chad tithtr cha "heavier" Kg aflr culta vara inhibiting aacagaaicity ar chat cha aecirity ia graacatt far cha 4-chlere-iaeaar of cha aaaeahlerekiphaayl cospsaada. Tha cats raaalct far tha pelyehlariaatad klphaayl ca^aaada 1,1' tacrachlerabiphaayl aad Areelsr 1200 teas ca ladicata aa tukscsacial anergasia acciaicy. Sabaagaaat stcsspcs ct repredieee cha Wyodhas ac al. rantlct haaa failed (HU) (taa Takla 2). Tha aajericy af aaaaya ditaaaac aay aaggaaciaa chat Kit ar aaaachlarakiphaayl ara aacaiaaie ia tha imto ataay, taaaral tcadlaa haaa dasaastraced chat FCla laah cha akility ta dasaga ar altar chraseaaaaa. Octan tc al. (14) looked far al|aifiaaac ckraaaeaaal dtaiga ia cha kerne narrow aad spars sails af raca adsis- iscarad cha fallaslag daaaga ragiaaaa: a tiagla data af areolar 124! tc 1230, 2300, tad 3000 ag/kg; ar 300 ag/kg par day far fire dayt. tvea chaogh saaa af cha aniaals dtaeatcracad daflalca tigaa af tacaai- ratios, chars aas aa aaidaaaa af chraaaaeaal akasisalitiaa. Thaaa fiodlagt art caotiataac with cha rttulcs rtportad by Oikahith tc tl. HONS 025258 nmi !+' t f mnmtft witn wen? itsm t. rail II. HONS 02S259 UJ) or uarchoff al. (13) in rac u< the cuey reyorcit s? Kaeplegarhcr or li. CIS) mini cuUunj husan '.rjMOtii. Keddle 3rues < 11) reported e-no: Aroelor 133- woo negative in the eicroauc'. s.i CMC, which HUcrti clMCojinic sceivicy (chreuesenal breakage) by censuring enrnaatin bodies in rad blood cam. uraea c cl. (I*), using chc dooiacnc lechal esse, which smiucm nucagenic ivscei ia Ira e lie by eha eaatyoeoxieiey ic inducts, reported tht Aroelor 1242 sad Aroelor 1234 gsva M|li results in rtes. Zaplinger sc el. (II) sad Calaadra (19) els* reported s siailtr Ueh of aucstsnie activity in aics using chs dominant lachal east. LavinskM (13) his racancly raviavad cha xucaganiciey data for PCIa. Jaaidas cha abeva-eancioaad eases, laviaskaa discusses aaay addiciaaal, chough la several cases laaa eftaa used, precaduraa. la his review ha refara ca a study by Odashiaa ia whisk laaacblar 300 sad 300 Mrs nagstiva ia cha standard scraiaa at iaineaalla tvwhlanriua uaad la cha Aaas assay, as wall as savaral addiciaaal bacterial scraiaa. However, (anachlor 300 was rsparead pasicIra ia aaa or earn at four addiciaaal scraiaa, while Kaaachler 300 was listed as sags* tire. 0a cha haaia at sadiaaacacioa races, Stadnicki ac al. (13) have raparcsd chat cha apaaida of cacraehlorebipaeayl caused singlastraadad chraaaaausl braaka la cha OKA of L-929 calls ac caaaaacraclaaa raagisg (rsa 1 >ig/al ca 100 >if/al. 4 aiscura af ewe hydresy aataholltas, sad ca a leaser axeane eecrachlorsaiphaayl, easead asue daaMga ac 20 >ig/al sad signifisaac dauaga ac 100 jag/ul. Iha eigniiicaace at this case at chasa high in vicra cancascraciaaa ia gueeciaaabla. '.'sing Oreseahelia nelasotaeter and ioerbvn vorl as eha eukaryote cast species, neither cha french K3 aixturas. C'.opben JO and Ctoyhar. MONS 025260 50, Or tha JrjtMll aiaturea, iCsnechLor 300 and 540, vert eueageni:. Muhiu (7, ,3) ittidied chraaoaaaal aberrationa in Toihida aatcoaa eelli at PCS concentricione caul inf 501 growth inhibition: tanachlar 300 gave a poncivi raiponao and Xanechler 500 a negative ona. Odaihina reported cyta|tnecic aaalyeia o( bon# narrow calla in aiea aapaaed ca PCle at a naar latteal doaa. Thia taat live paradoxical ratalea. Odaahiaa liiead expeeere to Xanachlor 500 aa poaltive and expoaura to Kanoahlor 300 aa negative (7, 13). Xorbaak at al. (13) raportad that Aroolar 1254 cranafonad C3I10T11/2 calla to Typo III loci attar six woaka at ceaciauoua expeaora to 10 og/oL of Aroolar 1234, while a caacoatratian at 1 ug/aL waa aagativa. Norback and eo-vorkara baggaatad thaa tha attacts at KSa la taltara inclada proaetioo. Ia aaotraat to thia aeudy, Fiante (13) raportad Araalar 1234 aa aagativa la tha Syrian hmater call traaa(araatlaa eaac. Paakall (13) raportad chroaaaeaal aharratiaaa la daraa (ad a 10--ppw diaa al ICIa. lit fregaeaey ahaagad (roa 0.IX la caaarala ca l.M la traaaad blrda. Tha araraga rata el chraaaaaaal abarratiaaa aaaag traaaad agga waa higher thaa tha higheat eaatrel value ia 0017 4 al 17 pratraated aebryea. Ia toacraat, ICIa injected lata white leg horn egga ap ta aaaaantratlaaa al 20 ppa, while toxic, vote not elaecagaaia. A thorough review al tha eutagenicicy taata rawoala that FCgo gaaa prlaarlly aagativa reepoaaee. While tana paaitlva reauita wra reported, thaaa were largely la vitre taata and tar tha Saaaehler braada, wklah gave iaaaaaiatant and alaad raaalta tar tha 300 and 500 bread aiateree. Tha ralewanaa at saaa at tha In vitro caeca chat taaad paaitlva eearea only at ceacencracieae at 10 ug/aL or greater HONS 025261 Nicy hijti and unli'caly la vino eoneinerieioni) ia cunciaaioli. 7--;, iatarjTiCieion it iupfrc4 b tlt flee chic in w|r cun i oinilaxicrininc jin eatTtapoadir.tl* ecyoiiei, i, nifitivi, mulct. According ca Liviatkaa, "eoniidirint chi Urn nunbar if cci coaduecad, ic ii uc lurpr-.iLQf chic m occaaional auaiicioua paiiclm (lading riaulcid, imply on a tcaciacical baaia" <I3). a caayaritan f chi auaber at Ami ciici unable co npmduea chi nialei ( Vyadhm ic il. (I) lupptrtl hii ciaciatiaa. 1C li chi cmiiaiui a( chli nviav chac fell la uc rapritiac i alfhlflcinc iuci|ialc riik to huaiai; a fact bona me tad niifirciC by chi auMTiua nagicin eircinoiiaie tcudiaa it Kli In aaiaali. TititijmicUT A ciracifm ii i|ac chac prodocn congenital deficit. Although eiricagmle riapoani in generally identified by diflaici eaataaicdl defied la chi affigxiig, luehorieiii alia rifarl fuacclnal ir blaihaaical chaacn w ewtdaaaa al centegoalilcy. Aa laporxaac caaillaraclaa ia analuatlag tencogeniclcy data, amcimaa raftered ca aa 'Unallky'l tala,'* la chac "any ceagouad edniniteered ac iha prayer deeege, at tha proper ecaga < danalapuaac, to aabryM af cha piyat ipeeiei, will ba effective ia cmaiat dinar* banana ia mbryeaie davalapaaoc." Mine raraefiky'i rula cilia at cam ella ca U tha (act chac uaciruilly toxic daiai nyahla ( killiai cha fatal ar predating cincatmic ifficti in cha effaprlag an af auch ini cancan chan chaia chaaicali cam lag cha saaa iffacca at daiai far balaw a aatacailly tonic lival. If tha pregnant fmala ii nadc ilk, than cha dalicaca halaaci bacvaia anchor cad facaa it llkaviia afficcid or diiruycid end aa advirn fecal efface can ha (CONS 0252*2 Dayandihg 3ft -.in iti|t 3' ena f, chic liirutivi ,r..iuc> ba uni/aiead ift aony vaya. *or axaoyla, diaaaaa, aalnucricion, i-: ccraaa ftava all baan mown to produca changai In cha nunkar ana ^ualLey of offiprlng produead. E-/n ravaraibla acuca affacca oa ana aochar'i canctal narwoua lyttaa, chough ol abort duraeion, any disrupt (adding enough ea cauaa undaairabla raipomai in cha uaharn. There fore, facotoaieicy ia al aaac concern only whan ic aceura u daaaa car balaw choaa eliciting coaicicy in cha aoehar. In any study, naichar daath of cha (acua (i.a., facocoaleicy) nor a mailer birth aim ara acaacad with birth dafacta (i.a., earataiaaiciey). Tha acudiaa eoneamad with cha caracaiaaicicy at ?C3 ia aica ara caatradiccary. Taaraah (20) raaartad Chat PCI* ara not caracatana in aiaa at daaafaa <ia to 500 ag/kg. gowarer, aara raaaac atadiaa kava ravaalad chaaically-laduaad effect* la cha (acaa at in aaabana ac laaar daaaa. Mtaaaha aad Sugthara (21) lajattad aica with toaachlor 500 at daaagaa (pyraaiaating 2d ca 1(2 ag/kg/day an day* d through 1} of gaacaciaa. At cha highar daaaa, cha pregnancy raca daclinad co ona third af cha taatral raluas, tha ember of raaarbad facuaaa doablad, aad tha rata at fatal elaft palataa raachad 3.St. Tha authora seacad that alaaa chara way aa thaaga in aacaraal sr fatal weight gain, cha PCXa uaad had a aye*ifla earatagaaic affaec not dua co gaaaral caciroal caticlcy. Havener, chair ova raaulca da not auyyarc chia coecaneiaa. AC cha highar daaagaa, cha aacaraal aortalicy waa highar chan cha rata af alaft yalacaa aaang cha aawbora (lit ra. ft). Alta, cha authora aacad akin laaiana. alayacia, aad anlargad livara la cha Jam, ladiaaclag aigaifleaac ahaaieal ineaaiaatiaa. Marka ac al. (22) rayarcad caracagaaia aifaata Car cha specific chlarinacad biyhaayl caeyound 3,3',4,4',5,2"-he**chloreblyhcnyl. HONS 025263 Ac asset's af Z -.a 16 =*, leg/day an days 6 threugte 13 at {taca- tian chari war* iijai!i:s ir.:raaiaa in the asreancat* at rssargccam as* fatal sal fame iana. Liver dasaga aceurrad ia the dan* aad con sist'd af aiagla-aall etnecolobuLar necrosis and aieroabscaases. Tha fatal iivars had ava* a aera pronounced injury, iaeiudiag aaaaiT* naaraata aad eha faraacian af cuhuia-li'sa pactan af hsgatecytas. TUaaa at al. (13) ragartad that 31 ug/kg/day af tha 3,3' ,6,6'catrachlarahlghaayl, whan givaa aa daya 10 ehraugh It af gaaeatiaa, iaduaad alga* af aaurataaieity ia tha affagriag. Saa af tha aawharn wan lakalad "spinners" bacaua* at chair iaaraaaad aatar activity and agissda* of haad bobhiag aad ratatianal aevQuanta. Tha spianars had daaraaaad fanliah grig icraagth aad all eraatad aaInals had diffi culty ia craaalag vir* rada. Suhsaguant studlaa (Id) ravaalad that thla aagaaur* lava! af catrachlanbighcnyl aigaificaatly altarad tha ftyina bladlag sitaa aad tha dagaaiaa lavala (a tha cargaa atriatua af aaabarn aica. Caacrary ea harks at al. (11), .lactase* at al. (13) ragartad chat data* af aggraaiaataly 30 ag/kg/day af 2,1',6,4',3,3'-h*aachlereblghaayl did act iaeraaaa tha raaargcia* freguaaey, aad aa fatal affaata war* aatad achar than aalargad livers. Likewise, Caltarc aad Wilaaa (It) ragartad that a* ragraduaciva af facta war* saaa ia tha affagriag af aica axgased ea Areclara 1111, 1161, aad UtO at dssagaa af 30 ag/kg/day aa day* 16 thraugh 10 af gaaeatiaa. lata hav* alaa bean aataaaivaly studied uaiag daaagaa eg ca 100 ag/hg gar day. Althaugh chase studies indicate chat fatacaaicicy increase* with data, an tavatogaaicity haa been ragartad (it, it, 1T-H). HONS 025266 Malformations (carats) have been rep-oread in dags and pt{, i, abatracc by Earl at <1. (29). however. the dosagaa of C3* used resulted in a severely reduced food aonaunpcien in bath tha dags and pigs and cha authors reported clue cRara nay hava baan an underlying fanatic deface chac contributed ca cha caracagaaie raipanaa in dogi (39). Several acudiaa Rava baan publiahad uaiag monkeys aa caac apaaiaa (31-34). rat aia faaalaa fad 23 ppn af ICIa far tv* aaacha, conaap- cian vaa inhibited (31). Of cha l ix, anly ana ana abla ca give birch; all faaala aainala vara clearly iacaxieacad and ana diad. * aacand cudy (32) taacad It fanala aainals fad diata of 2.3 ar 3.0 ppa of Araclar 124*. Aftar aaran nancha' axpaaura, cha aight aurvivars traa aaad daaaga laval vara brad. *11 aainala aa cha Lovdoaa diat <ar chived. there warn chraa raaarpciona and five bircha. of cheaa aniaala given the higher daaa diat, an* raiorpeioa, chraa akarCiena, an* dif dealt dalivery and suhaagwaat death, and ana aarnal birth **torrid. *11 aaabaraa war* aaall la lira and ahawod hyparpigmaacactan, bee war* achanria* aarnal (32). In a nanbar af apaaiaa (a.g., aica, rabbit a, rua, and noakaya), Kba ahawad a* ar eancradiccary carataganie activity, tha atudy con duce ad by lari at al. (30), acill uapobliahad, pravidaa uncaoviaciag data aiaca it in pnaaibl* chac cha aalfacnatiana abaarvad in cha affapriag war* cha raaolt af aavara aacarnal malnutrition. Ihia eancluaian wan aobataatlacad by Kansan *c al. (33), <di* tailed ca find carataganie afftnta in piga whan tha aachara warn fad a diat af 20 ppn af Araalar 12*2 during gaacaeien and mining. PCS* have producad eancradiccary raaulca in nice. Taata caudoctad by harks at al. (22) and Tilaan and caunrhara (23, 24) indicate hac cha recorded effaces arc aaan only wich avwcrisally chlorinated HONS 025265 biphenyl cssaauada *nd chic chlorination in the chraa and fpur jon- tioaa it critical, this say axnlain why Toarjak (20) ana achara (2). It) law na or laaaar ailacei with nixturea containing mall aaaaaca of tha (pacific iaeaara ar wish achar hexachlerobiphanyl iaowarf at hi|har daaaa. Hawawar, atudiaa by liocea at al. (It), like tha negctiva data, treacly laaaaa eha iafacc ot tha caracegeaie findlsja la aica. Thaaa auchara danonitraced chac tha 21-day LOjg for 3,3', *,*',3,3'-nexechlerablpheoyl ia chant If ug/kg/day (ranging baewaaa U thraafh 31 ng/kg/day). Moreover, extending tha abaarracioa Interval ta SO daya, it waa found that tha daoagn levala 10 ciaaa lower cauaad 1042 aartality. Dlapeeicloa atudiaa ravoalad chat tha casiclcy at tha iaaaara waa related ta ciaaua aacianalacioa and that far che 20-day interval tha adlyaaa tlaawa levala at cha Ujg doaaga vara appraalaacely 2,000 yyau Thaaa data reveal chat cha taratataaia effaat aaam by SUrha at al. (22) attar at daaaa treater chaa thaaa that allev far threaic aurrlval. T3lia ia caaaiataat with cha fladiaga of Vacaaabe aad Sutahara (21) for which cha teratogenic af-^lcci of rest In aica ayyaar at daaaa af aignificaat aataraal tamieicy aad lachnlicy. In aiamary, than, cha aaiaal data do aac Indicate chat PCle rayraaaat a i|aiftcaac terataganic rich ac daaaa oat cauaiag algniflcanc aataraal toxicity, furthanara, cha data awggtata chat prevealing tubchroeic Owe lethality ar^argaa toxicity would praveet teratogenic affacta. Thua, cha riah ta hwaaa la axyectad ta be aiaiaal, caaaidatiag cha aach lever daaaa chat hwaaa art tantrally axpaced ta la tha environmental aad tha apparent lack af toxicity expected ac chaaa daaaa. SCedlaa in aaiaala aiailarly daaaaatrata chat ICla rapraaaac a aiaiaal reproductive and fecocoxic haaard (39, 30). -hilt affaaca ou rapraduacian ar facacaxlcicy Have been reported, the daaaa cauaiag uch affacta are generally high, kata are fairly raaiatanc, while MONS 025200 3VRM se co id particularly sensitive. Aulerieh *nd :unjr reeorttc shat sinks fad 2 pea Aroelor 1234 in chair discs hid da- trossed reproductive suceass. The ecfsce ae this livi specific Jar Aroelor 1224 and v not aaan far Aroelor* LOU, 1221 or 1242. The reproductive iapainenc va* not paraaoaat and eeneistsr.cly oc curred ac aacsrnaUv lethal dosee. Orberg (37) has demonstrated an iaaraaaed metabolism of progesterone, aacradial, and testosterone va eniaala pracraacad with pegs. It up be proposed, chan, chat doses (hag greatly increase the utibsliss of important hormones could altar the normal hormone homeostasis and result in reproductive problems. The series of studies by Alloa sod co*vorkers (31*34) have demon* aerated that PCfts may disrupt senscruel cycle* aad significantly alter reproductive success in monkeys. However, the doses used were dearly maternalLy tonic, facetonie, and eosie to the offspring. Studios sim ilar to those in mice indicate that the body burdona in monkeys at the time of death are quite high (41). Since (a) high, nacarsally tonic or lethal doses were generally required, (b) there are a muber of negative studies, (c) the general hinsea environmental tapesure is very lev, aad (d) no reproductive problems in humans have boon associated with espesures to PCla only, PCSe do sot appear to represent a signif icant reproductive risk to humans sc cho low exposure levels generally occurring via the environment (39). Cortimotmititv The carcinogenicity of PCIa has recently been reviewed by several authors (6, 7, 13, 3S, 39). The following paragraphs provide a stu* nary of the data. Studies repeating the tumoriganicity of PCBo era HONS 025267 liatad ia Tabic J. .Tula stay invaui|Hi9iu > 9aan conducccc, ratapc ccudltc have ineoeicuccnc 1/ resorted e ci|nificcnc incrctca haatcictllular ecrsiaesa. ::a cc cl. (12) reported hepatocellular ctrcir.oxc is nice if car 12 aoncha' axpocura Co a diet o f 300 ppa o! 'tioaenlar 300. Xiabrouph and ca-vorkarc (13) alaa reported hapacocallular ccrcinooa ia fcaala raca !ad 100 ppo of Araclar 1230 far 21 Matm. Hawavar, contrary ca chaca ftsdinpa, aaay ciailar ccudiea have haw aa ability af fCla eo produce eaacar. Kiabrsuah aad Linder (14) feuod chat 300 ppa af Araalar 1234 failad ta prodoca hapacaealtular carcisonaa ia alee afcar 11 aaatha. Studied uaiop laaa chlariaacad Kaaechlore vara ciailarlv uaahla ta preduca caaaar (11). Likoniea, Calaadra (If), Lavioakaa (13), aad cha laclaaa1 Caaaar laatltata (SCI) (43) bna ra pare ad caata aa bath Araalar 1234, Araalar 12(0, aad 1C1 ia rata at daaaa up 100 to 200 ppa: aoaa vara fouad ta ha aartlaapaait. Calaadra (If) haa alaa rapartad a evo-year atady af dapa pivaa daaaa af 1, 10, aad 100 ppa that vaa atpatlva. Studiaa of rhaaaa noakaya vara alaa aapatlva (3f, 44). PCI aiaturaa praaaat a dittlaat prahlaa vhaa attaaptiap to aatiaata tha caaaar haaard, aad tharafara cha aaacar riak, ca hiaaaa baaad aa data davalapad la radaat acvdlaa. Tha trua of tha prahlaa it tha ralavaaaa placad aa aa latraaaa ia radaat livar Ciaara Mian iacarpraciap tha hMoa rlah. Thia dilaaaa ia aatually tvafald. Plrat, chart haa haaa caatravarty avar tha ralavaaaa and aaaanclatura af radaat hapatid laaiaaa. Saaa af chit caatravarty ralataa ta cha criteria ucad to diapaaaa caacar. Tha XI haa ramMinded a chaaa far tha claaaiflcatiaa af hapacacallular tuoarc cad ralatad laaiaaa ia raet (17). Thia ratfiadation haa not haaa univaraally ettepted, and ic ucad ia anly aone af ehc raporca af PCS carciaa* HONS 02520 JWImmm iMftMft M* Ml. K*|wfti Ml *1. AIM* I ** M* m !. MImm 4 ftwftv* IlMf * Mw Mm fti Mm Ml ftl. UnpAI M l. Kk!MMM#I Ml Ml. Ifr| I IIMMIKfMC irncts m n-te Vmmt IfIt IfIt 1*1 i)l )*) BaU UK* *elr 1241, liMI, m4 IIMi Ml *W>' m*i. KiManfetar* M, MM, iwl AtmcImcm IW, in*, mM IIUi ft. 12/4 wm* Knurlliar Mfta iriwu M*|Mr*rM lk^Mkw ) Hnflrii|*| r*><HiruKM ih,M.u fit Iffft ftaU Mm Ifttft 19H 1I4 Hft Nicft toB(r mat M MM ftWH HIM MmIIm* Mft, M mm imi II MM ilMTM Mft. M> mWM i Ulr Ifti MM | II mmIIm IIUMFfllU M * i Mill* lllini Ml M||m4 l IMMHk mIIm I Imw wll NNtrwIa MhImIm* k| Mm/iIimim IMibilM II* ImMiim W Iiw Imw, hy UlNMlnllM tWtlMMI Mri| l# iMMihlm >m HrfMiuullHl*r 1411'IIMM, tf/M*l kw* !Imci||< mmImImm IU/M*| at'MNlilwMMi. HONS 025269 I |IM.) imnm m ! IwM* nn iii* IMt Ml Ida atmiw tmi MINI IM, I2M, Ml 1MM Mi unfit mhUm tflMa niHiaaim IhMiMtMw I ImM# ^<11 025210 mows Ihe SCI eUtaificaeian achaiaa ia tncanaive and tpacific -.a i*f_-ing naoplaac-C iaalona. 1: vaa concluded by NCI chat baaiga iija:-.: call cuaara (i.a., cuwra vichaue cha potential lot oalignaac behav ior) could noc ba diagnoaad eonaiatently. Therefore, a cars auch at 'tdtnonawhich rafera ca a benign eunor, vaa not reeoownded. Is waa alaa deeomiaad chat cha can "hapacoaauaed ca danata a benign liver tuner, vaa inpreeiie and chut waa noc racomanded ca daacriba any of cha Indiana under diacuaaien. Contrary ca cradleian, chan, dataatlaa at vaaaular lavaaiaa at aataacaaaa waa aac eanaidatad by MCI ca ba aaaeacial far cba diagnoaia at hapaeaaallular carciaosa. loacaad, cha uaa of iaeluaiva aycalatical cticatia deaeribing chaagaa that nay at aay aac hawa cha potential ca baaaaa cha diaaaaa precaaa wa call caaaar, lac lad lag aaay reapenaaa chat will aawar pro(rate ca caaaar, waa accepted at cha axyaaaa of cha am definitive critatia af adignaat at laraaiwa aaaylaama. Than, it law chat cha cticatia far aatabliahiag livar caaaar aay vary aaaag pathelegiaca. Only PCSi with a chlariaa eaacaac af (OX produced callular mor phological chaagaa ia rat livar chat vara elaacifiad aa hapaeaaallular carcinaaa uciag PCX gaidaliaaa. however, chic aaw PCI aixcvra vaa caacad ia aaachar atraia at rat cad did aac clgaificaacly tacraaaa cha iaaidaaaa af ewar faraatiaa. toward achat acadiaa claw failed ca ahaa aay PO-ladweud ewara, laaludiag a acady perfomed by .VCT. Siaaa theta la aaly aaa repeat af PCVladacad hapaeaaallular eareiaeaa ia rata, wa aaac weigh chia tiagla raparc agaiaac cha aojaricy of eaaca, whlah wara aagaclva. Ac praviaaaly acatad, cha uaa af iaeluaiva eytelagisal criteria will dafiaa aa caaaar aaw hepatocellular chaagaa chat will aawar protract ca cancer, furthanaon, the livar chaagaa aaaaciacad with HONS 025271 ?C3 n^nn were tipariri cs rtgraaa after the anioal in been raeawad ttv.t the chamieal axpoaura (HI. '-'hi-.* Iona lavaacigacori hare uaed the ineluaire eycalagieal criteria tat eleaaifyiag hcpacocalWlar laaiena, achar invaacijeeora faal chi* claaaificacion jehaxa lacka aufflcicne diagnoaeie diacriainatioa. TTiua, cha aingla ripir: ( KHUiuad caacar la rata tap uac a patkal|ical deacripciaa chat dlffcra tram cha taninalofy uid far deacribing cha banifn e-jaara aaaa in cha ochar aeudlaa. Tha aecend problaa acaaa frea tha oaed ca daccraiaa cha aachaaiaa hr which a chaaical induces eaaear. Chaaical ly-laduccd carciaoganesii la a special aapecc at caaiealaip, a lata chaaical careiaogoaa u< ar aay aac ehey cradlelanal caaicalatic priaclpla*. Tot axaapla, although earclaagcac thaw daae-ratpaaaa tcletleaahipa, aay undergo blacraaafaraaclaa ca actIra ar iaaatlra aacahallcaa, aaC daaeascraca specific a trueCara accbltp ralaclaaahipa aa achar toxicaaca da, they aay claa ha aallha achar csaicaacas chay aay aae daaaaaeraca chraahalda aad than aay axiac a long end ladafiaica lacaacy period between the critical biachcaical efface aad aay cellular ar phyiialotie exprcccira. la ncaac yoacc, cha acicatific cenaalcy haa coaelodad chat even aaaai chaaical carcinagaaa than arc rut dlffcraaaaa la cha aachaolaaa by which caacar la ladacad. Chaaical carcioogana <*r aracad lata caa grewpai aaa which abaya cradiclaaal cealcela|ic prin cipled aad aaa which daaa aac. Weliburger aad Uilliaaa, in Caaarcee aad DcaUa' Taxicelerr; the laatc Scltacc of Means (1), aapcraca carciaaiaaa aa cithar paaecexic (iaitiacor) ar epigenatie (prcaacar), Che dlatiactiaa being chat gaaecexic carciaegeaa induce caacar by ialciccihg a pcnanaac change ia D!A. 'plgenaclc chcaicala crapriae HONS 025272 :!. cheeieali vhieh altar the aaniftacaelon of eaacar by other :-.m Janatie naana and include homonaa, itaunaauppreaiaaea, eacareinagent, and pranetrs. Thia diaeiaecisn baevaan typee of eareinafaaa ia accreaaly inpor- :anc (1, 4S, 50), aiaea initiating (genatoxic) eareiaagaaa nay causa i;;averatble ilaljl and amp nae have thresholds. Hia concept vaa gen erally proposed for all eareiaagaaa eerly in eha laat daeada aad vaa tha baala far davaloping eariata aaathraahald riak assessnnc aadala far vnieh aaal riak ia preaaac at aay laval at aapaaara. On eha atha* hand, ehaaical eareiangana chat pronto calla already pradiapaiad ta aaaaar ta hava danaaatrahla ehraahald lavala. Therefore, eha riak aaaaaiatad with praaacara dilfera tron iaieiacara at lav daaaa ia that eha riak axiaea only far eha duration that eha laval af tha praaatar axtaada tha ehraahaU. Ltdaaia vend ia eaaear eaaea hava a high apaaeaaaana lacidaaca far liver ctaart. Therefora, if a aeatiaeieally algaifleant iatraaaa ia aaaa after chaaieal axpaaare, it ia lapettant ta daearaiaa ahathar ar aat thia phaaaaanan rapraaaata true iaitiatiaa or aataly praaatiaa af tha hachgraaad laeidaaea. Such ia tha prahlaa far KSa. Ta aaka eha diatiaetiaa katvaaa laieiateri aad proncara, tha autagaaieity data and achor characteristics af eha ehaaical or tha earciaagaaia raapaaaa heccn arlclaally dacataiaaae factara. Iaitlatara are dafinad aa theta agaaea producing daaaga ta MU vhich panic call aucvival hut prediepoea tha call for uaaoacrellad gravth. Therefore, iaitlatara anal paaaaaa algalflecat aatagaaic activity. There are aeveral other eharaccariaeiea aaperatiag initiat ing earciaageaa aad prenting agent; thaaa art liatad la Tahla 4. Tha eharaccariaeiea af KSa arc alaa Liatad la Tibia 4. It caa ha HOMS 025273 c*actcst;c c/rccn cr c*tcx cmcmgcsns urissu !iutiori ^raMin c!i O**Mm4 iwmw iwww m HUilll UtM. niimiiM tm Omtin twin Mli|wr. frtMttl fflMl tiMt (W1| 0f ttanwlwtt* tin. ,,,, * " owiiii it rrMU * wwini hm. CNM--1 My MUM IM iffMl fUf IM|U Mw. CWI MhU iflmiai IM iffm tf Ht ctrMMjM mui m tfm ttfftt fM. PnjrtMMft / MWUMil HfftrMClMlM Mat Mt rttnit tra iihim iiwm m immi. pmiUy * t Mll MMV HONS 025274 ton tHu tha thuacnriicici at Kit ruNtU thorn of < oronotitj agaat ind oat thorn of in inidttor. In hii roviov of c!io octagon.: ind ctrdaaganie pattndtl of PCSt, Ltvintktt (13) lUtviia dm tovoril tutkort and anporiaantt mppordng the cone melon :hic K3i have prorating tctlviep, including :ho KCC blotattp (451. Ik imr. ohm allotting the carcinogenic htaard of Klo, ono wit dooido whit weight to give inch portion at tho dm. While ono euioc lgnoro tho flct that poaitiva eudnagmic activity hu bom reportad la rodaatl, ma wl taka lata eoaoldandoa tha aukaaia of ehli tatpa*** oinaa it van not raproducad la aevoral aubaeguant indlu. Parchetrare, thara It a grade dial of avidaaca to tuggaat tklt If Kla Induct chtagaa, It It bp way of a promcion aachtalta. That, on chn kttit of tha taiaal data tad eaaaldarlag tho iacaaalataaap of tha ratpanta. PCla, at waak prorating agaata, at law daaaa atkld rapraamt a ralatlvalp aaall caaaar haaard la aaa. laoafaialag tha praklaaa aaaaalaead with accavaea Ip inearpraeinj tha ralavtana of tad rlak Infarrad bp taiaal earciaaganaaia bioaaaapa. Mart Sgeirt, fotrar acting director of tha Carclaogaaaala Tcatlag Prograa tad head of HCI'a Turat Patbologp Scctioa, haa propoaad a raakiag achara far tha aaiaal avidaaca (it), Sgaira prapotaa chat tha kaaia for docoraiaiag tha atraagth at a poaitiva taac raoidaa la ahachor tha "ratface carcinogen": la poaitiva ia a nrahor at apoclaa, glvoa rite to klatagaaadcallp diffaroot tppaa of aaaplaaaa ia ono or non apooiaa, ladacaa aalignaat rather than bmiga eraara, tad la eontlataaclp pociclvo ia an tppropritca battery of taata naaaoriag geaacoaicitp. Tha daaa ragairad to iadneo traara aa vail ta tha apoataaaaaa lacidaaca of aaaplaaaa In tha caatral aaiaala art alaa aritaria. HONS 025275 Sy ran'cisg th* ( iiu for taeh criteria according * pai.-.t ayttaa 4*v*lo?*4 by Spuirt, on* ( (a avarall tear* co tha atrtngch of tha ovi*nc*. Spuir*'i approach it appealing bacausa i: racagaiaaa aararal (latum oi an tniaal bioajaay that (haul4 b* eonaUata* whan accaapciag ta aatiaaca tha LikaUhso* that th* hatt raapanaa ia aiallar. Sinca thara aro aavarcl caacar taaca in aaiaala (a* Kit, ch* aggregate tear* that PCla wmld ratal** dapanda on th* eight aaaifna* la tha paaiti** aa* a*fati*a Par a. aewower, tha total tare (a* PCle, ragarblaoe *( tha acacia*, mil probably ba abaat II at laa*. Jpuira tlaiaieiaa a chaalcal ratalrlai a taara at laaa than 41 aa a tlaa* V cartinaaaa, a tlaaa tar which ha tugsaats chat th* regulatory apeiana era aany oa4 tar laa* raatricclra chaa tar chaalaala ttarin* hl|hr la th* ranking aahaaa. Tbaa, ataartin* to tbit cabana, *** ch* "paaltl**" arUaaa* tar ICIa 4a*a cat raak chaa aa a hwaaa caaaar haaar* that la aa algalfitaac aa naay achar chaaltala, aaaa at which ar* ttill coaaaaly tttaC. ITOtWOLOCT Acuta an* chamta ihataa Bata la raaaat tcuAiaa at accupational axpaawra, PCI* hoc* act baaa preran ta ba a rfar*ably taxic chaaital t* paraaaa la tha warh place, wh* bar* prabcbly raaalrah eh* wait ilgaiflcaat axpatwr* c* PCI*. Oww ta* ca-warkari (11) tt*41*4 JA warhara traa a aia(la capacitor pleat ualag Araalar llAJ. ot thia grawp, U war* *xp*a*4 far aara chaa an* year e*4 lb tar fir* yaara or aara. Although la4*atrial hygiaa* ct tha pleat h*4 baaa gaaarally poor prior ta chair acu4y <*> air HONS 025276 concentration* vara l!Ot ea 1213 of cha aliovaaLa varhroon <i; i:ine. ard a( 1.0 |/a^), eh* clinical etsea did not identify any ligatf-.eaal haaleh yroblaaa. &:* easa of chloraene vaa reyorcad aa vail aa flva dial at an actaaacaua raah. (van chough cha avorago KB blaad Uvala of tha irony vara avor 400 pyo coayartd ea non* daeaccad in :ha cancral icudy irony, eha clinical eaaca *aaaucia| livar funceian ravaalad ehac hiliruhia, alkalina yhsayhacaaa, linn yroctin, albn- ia, sen, and lunglabullna tor cha irouy of faccary var'aari vara wichld eha uraal llaie* far each taac. In addition, braaaaulyhalain claaranca did not carralaea vail vith aichar K1 blood lavala or lta|th of anyWynont. A noro rtcdnc aeudy of a far larger irony of anylaynna fran a aayaaicar ylasc raynread a aimilar lack af uaaavard fiadia|a (51). Baaad an chla aendy at )U aaylayaaa, 1c vaa ynaaihla ea aayaraca eha ylajaai racarda lata eh* following catagoriaa tar yaar* *! axyat'lrai 10X had boon aayasad fa* 5 yaara ar lata; 20.ft 5 ca 10 yaara; 17.3X 10 ta IS yaara; 11.4S IS ca IQ yeara; If.IS IO ce 15 yaara; and HZ had beaa axynand far aara ehaa IS yacrr. A naaiy af eha akia caaylaiaca ravaalad ehac 10.TX af eha aaylayaaa rayartad raaha* and IA.IS rayarcad burning aanaacinn of eh* akia. fhyoieal uxasinacian further revealed aaaa radaaaa, avnlllni, dryueaa, or thiekaaiai of eha akia In ayyraaiauaiy JO* af tha iadlridnala, vAila IX axyoriancad abaarnal aaarnclan* traa cha ayam. thu clinical chaalacry af eha aeudy vaa innarally uaruaarScabla. aad cha rtaaarchan cawaiad an eha "fancier af abaarnal raanlea." Of 321 yaraaaa avaninad, eha yaraaacaia af aanylaa aucaida af cha aatnal ranga vara: MB S.3Z; araaclnlaa 1 .IX; SCOT I.IS; SCIT 7.IT; 1M 2.St; alkalina yhoaykacaan 1.23; SCOT 1.13; bilirubin 0.03; HONS 025277 cholesterol I7.il; triglycerides 10.31; and total lipids 3.at. rhtia data can ba canaidarad indicative of tha typo of random taae results to bo eapoccal whoo 321 poraooa art coacod vichooc iiaulttnaeusly running a control jroup to coupara a|ainat tha itandardUad ''(lamal" values usad to indicate an abnormal finding. likewise, tha naoroloiie anamindtioni failod to produce any prevalence of abnormal findicia. Thera "a a dacraaaa in tha forced rical capacity of tha luaa in 14Z of thaao werhars compared to only S.tX la tho normal popalatiaa (33). While thin la an uauaual fLading, thin cheapo woo not aoon in ana group, i.a., the non-smoking uoaoa taatad. tha aignificanca of thin finding la unknown at thin tiaa and raguires rorificatlom from othor todioa. Moroni at al. (34, 33) haoa raportad am Itallaa rtudy of amployaaa la a aapaaitor plant azpoaod to a foreign fCl aiatnra aiailar to Areolar 1241. Tha aaaa ago and employment of the 10 employee* axaaiaad mao JM and 12H ymart, roapoctiroly. PCI air eoacaacratlea* ramgod from .04* to .273 mg/m3, aad all taatad aarfacaa ooro heavily aoataminntod, indicating that employee azpmaaraa mar* bath dermal aad iahalatiaa. Tha roaulta ahaurnd that ICS blood eaacaatratlent ranged from II to 1313 pph. fourteen uorhora vara found eo have akia diaardaro ceaalatiag of docnatitia, folllculitla, or chloracao. Sintaon aaployaea eera raportad ta have abnormal liver affaett, ceaolating of hepatomegaly aad aaaatiaaa am lacraaao in aormo level at liver ensyaaa. Tha liver findlaga did not earralat* wall with either tha duration of employment or tha K1 blood lavola, aad tha pattern far hapatic anajma chaagaa wot a random finding Inaoaalatent with hepatotaalc chmeicala. It la avidaat from thaaa data that tha cllaical chaagaa vara uaramnrkabla. furthermore, central subjects vara not HONS 0252?8 '.eaat thru nencha in areas of -*C3 exposure. The vital scocua of ii~. of tut population * decarair.ea and 39,018 person y-aare wort tcc-.--lacad. The types o< K3 used uere Aroclor 1015, 1242, and 1254. The major eauaaa of death far the 183 persona vno had diad 0* ;'i tiu of cha reoert at* separately liacad in Table 3. The only acaciacieally ai|niflcaac diffaranca obaarvad vaa for cancar of the rseeun, but only if ebd faula population of plant #2 waa eonaidarad aland. Hawevar, cha plaaca aeudiad ara lecacad in aa araa where mereslicy fraa raatal cancer ia iraacar chan tha Baicad Stataa average (]). as aaatianad, ehla umiaual incraaaa seaaud from a high auber of deaths la cha faula yayalacioa af plane 2; aiailar findioga ward noc rafleetad la tha faula poyolacion af plant l aar ia cha ula papulaelan af aithar plant. While cha lirer eaacar incidence waa higher chan expected, 1: vaa not aignificaac. Ohara waa aa relacieaahip between dnraciea af aapleyuac inwnlwing PCI exposure and the rish of urtaliey dun ca cancar or cirhnaia af cha liwnr. There waa aa seaciacically significant relationship far aay cauaa af death whan cha tatal axpasad pepelatiea waa cauidared. lartaui at al. (70) aeudiad 27 daacha ia 1310 warkare axpaaad :n Rla far 20,343 paraan yeara. Mortality waa aeudiad far cha 23-year patiad baewaaa 1134 and 117* far eapleyneat baewue 1144 and 1170. The study group had beaa aapleyed for at laaat six aaochs and cha txpeeare waa largely ta Arular 1234. Far all caacara, the ebaarwad eartality waa 14 waraua 1.83 axpeccad. This ineraaaa, however, was eignlfleaaa aaly far the ula pepulaciau. Higher chan axpeccad incidaaaaa ia cancer af Che dlgaativa organa and in cancer af tha lye* phatlc ar hautapeiatic ayacua vers alaa ebaerved, alchaugh chase vara nac aignificaac. There vara na raparta af livar cancer. HONS 02S279 ru > eiutts c7 :c,;in cwsc r- *ocu* 1014, tj'.:, ic nu OHirM/CimtN *U Cm-- 411 atUfrant mminm Oimii f ntmw lyMW OH-- / tyita WOlU AH MMr (MM AU IMN 39/43.79 11/11.33 40/41.9) 13/10.J9 40/M.79 141/101.J1 Cow Of UMMI iMMUfl* Mtu Uot Niwm Hwiioarr 0m-- lydMll OMWf aiuasjssias 1/1.40 4/4.03 4/1.19 VI .07 1/1.90 T/7.90 7/4.04 2/4.34 10/14.70 Wltw 47 StMM wtUty Him tm ;> (99) cm (001 (19) (40) (991 034) (210) 03) Oil (102) (44) (40) MANS 025280 includad :s 4<tinini tha aortal cate variationi aaong gna.ipo.ad toaa of aioilar i|aa Soria bilirubin and alialina pnotanacua LavaU uara within tha normal ranja of variation far all tubjocca. Soma of :ha conclutio.-.i rttenad in cuo raeanc raviava of cha varioua atudiaa of PC* aapaaaraa to data (J, 57) ara nocnworchy. Plrac, while higher aapoaurai CO PCJ* land co aaaa a higher body burdam, than vaa a laoaral lack of earralactan between aspaaure duractao ad body burdaa. Seamed, although not all atudiaa agrao, chara waa alaa a aunaaciaa that tha hlghur thlarlnatad PCI* uara aara li'aaly to aectanilata in adipota tiaaua, iu|iaatin| a alower aatakaliam rata. Third, tha gaaaral haalch of tha occupationally axpaaad group waa canidarad goad. While ewe of tha atudiaa reviewed failad to rapart tliaital findlage (othar than etaciug that tha aarkara uara ia (bad haalth), aaa aaaaurad 1C* blaad lauala of up ta 1*00 ppb la riaaiah uarkara. Of 15 atudiaa rapartlop tliaital aaanraanti, 11 rapartad danatal|it afftdta, 1 rapartad Uvar fuaetiaa caata, i rapartad lipid maaauraaaata, aad 9 rapartad aa blaad ehaaiatry. Oaffay caacludad that ahila thara ia aa claar earralatiaa batmaaa PC* blaad leveli aad chloraana, tha atudiaa teggoat that ahaa PC* blaad lauala aaaaad 130 ta 100 ppb, thlaracua taa occur (90). la alaa caacludad that daraatitia, lika ehlaraaaa, waa a frageaotly obaaruad affact. aad that it aay ba aaaaciatad with tha kighar chlariaatad PC* compounda (5d). Of tha aiaa rapartad atudiaa at llwar fuaetiaa, only fiwa found aaaa aild thanga ia livar fuaetiaa caata. No taaaiataat pattern waa idaatiflad, nor was aa aaaaelaeioa hotwooa thaaa chaagoa and Kg blood lauala idaatiflad. ta adoataa haalth affact was aaaaaiatad with fC* txpaaura in aay af tha atudiaa. Of tha aix atudiaa that eunaidarad HONS 025281 lipid atcabolisa, no eanaitcane pattern tuaeiuii vich K1 u^n;,: on* itudy, by reporting a dacraaae in all paraaatera, contradicted all o< tha tcudiaa reporting an iacraasa. Moat acudiaa ala eaaociate increaead triglyaiaa vies the PCS eapaaura, buc tba raaulca for cSolaacaral vara iaconaitctnt. So cllaieal tlgalfleaaeu haa baaa attached to cheat finding*. of tha five saudiaa af blaad chaaiaery. aaaa reported aay rclatlaaahip bataaaa tha caaca aad PCS blaad level*. Of tha tw atudla* that aaaaurad blaad prauure, aaa foviad aa aaaaaiatlaa, vhlla aaa rapertad aa aaaaaiatlaa batman PCS lamia aad diaacolia blaad praaavra (30. ta turnery, a raviaw af tha huaaa data froa atudiaa of peraoaa accapaalaaally aapaaad or uhaaa PCS lamia vara laaraaaad via fun coaauaptlea ramala that tha eoablaad raaalta at all atodiaa, vhlla daaaaatratiag PCla eaaaad daraal prablaaa, fallad ta ldaatlfy aay aidalfltaat a1laical dlaaaaa aaaanlatad with cicatrical (rada PCla. bhlle aaaa phyaialasla ehaagaa mra aatad, aa allalaal altalfleaaaa eaald ba attached to aay af thaaa. particularly the ehaagaa ia lIvor function, vhich mra nloinal aad gaaarally aat eonparad to aa appraprlata caatral group. It haa alaa baaa noted that PCSa can induct ealdatim nataballan la paraana acaupaelaaally aapaaad ta than (30. Aaiaal atudiaa auggaat ghat induelag agaata can lacracaa aarua traaa--i-- lamia, a.g., KR (31, 10) aad trlglytaridaa (10). Shut, tha randan, alaiaal laaraaaaa la aarua treatanlaaaa lamia aad laaraaaad trlglynaridaa fauad ia paraana accupatianally aapaaad ta PCla nay rcpraaaat tha pradlctabla pheaaaaaa af aadaat aaapaa iaduetlaa. Tha national Inatltuta at Oteupatiaaal Safety aad Saalth (XIOSS) atudy (37) llkawiaa iadicataa that ehraaia limr, aarmaa, or clrculacary dlaaaaaa are aat aaaeaiacad vith Looptin tapeaura to lamia af PCSa MONS 025282 uhUh ucrt aueh higher than ehoen encountered l3 tht environcane. Thera tore, it ;he envirofcseneal expoeurc ca PC3 U isauitleient ca indues chloracne (the noec t request I jr abaarvad efface), acuta, aubehranie, ar chronic coxieicy it probably nac ca ba expected ia hisaoa. Yuaha la 1111 a can oucbraak cl chlaracaa and ocher ajaitaaa, lacar tamed "Yuaha," aa eauaad by cha ia|aacisa al coating ail cancmi* sated by KSa and other chlorinated coapnunds. Hitachi (61) and Kuratauna (tl) reported chat appcoxiaataly halt at tha patience ca*ylained at a variety at nauralatie dlacraaaas aach aa headaches, matnaaa, hypothetic, aad neuralgia. Msec at cha haadachaa ware eraa~ aiact, but acc racuxrad aver a period at aaacha ca yeara. lUguchi (tl) aacclodad that tha aajarily at thaaa haadachaa probably ateaa traa aaaclaaal atraaa ar ai{raise ceadlcieaa, aad aura sac related ca PCI axpaaura, heaauraaaaca at narra eaaduccioc raleciciaa ia Yuaha patlaaca revealad, hovover, chat up ca 30Z at the 20 patiaata acudied had lauar chaa aaraal aaaaary narra conduction valaciciaa, chaufh chair aatar narra caaducclaa valaciciaa warn seraxl (tl). raaala paciaaca, tOZ, aettarad akaaraal nanscruel cyulaa, thauth tha ntfacca varied. Saaa uaaaa auffarad pralaapad incarvnla at aeaatruaeiaa, ahiln athaxa had thereanad ar irrtfvlar incarrala. Oacarainaciona a! uriaary aacrataaa ravealad a dacraaaa. A paaaibla axplaaaciaa tar thie eauld ka aa lacraaaad degradation at aacrapaaa dua ca iacraaaad Uvar aataka lisa (tl). Heaacelecic axnainatiana at Yuaha pacieaca revealed a alight leukocycosie and aonacytoaia, aad term lavala at IgA and IgM warn MOMS 025283 |taorall;' decreased. Sursriaingly, lerua indicator* of liver ii-ajt inch is COT, '7T, and bilirubin war* norsal. Thus, although K3* can cauao liver injury in enpariaancal annals, aa aaay halogenaead hydrocarbons Co, cha clinical evidence af Yuahe indicates :hac [hu is nat a praainanc tonicity in huaans (41, *1). hleroocoplc changes vara observed in livar biopsy aanples. The aajar finding, aa Uaraasa in cha aaaacb anSaplaaaia recieuluu, is interpreted aa repraaanciv* at cha induction af Ota hapatlc ana pana for exidacIve aacabaliaa, a find ing pradlccad (ran aniaal acudiaa and noc an indication af toaieicy. Analysis af other laria parmetars alaa suggested a diaruption af aoraal lipid aacabaliaa. Sana triglycerides vara alavacad, while chelaataral on* nat. Of 4) affected ahildraa araninad, 23 bays shoved traaaicarp daaraaaaa in height and weight gain when Caspar*d ta aaaffatted child ren, while It girl* did ant differ teas cha canard group- Alan, tcan cf (ha infanta barm ta weaaa affatted bp Tuaha warn anal1-fordata. Ochar a pup row a la newborn, included dark-brown plpnaoeatlen, pacahnaac-lika akin, empties af taath, and larger than eaual fontauallas, iadicatiag transplacental paaaaga af KBs to cha facu* during gactation. Prebablp cha aaat cannon apuptoaa and cha anna largely reaponsihlc far Cha Idastiflcaciaa of Yuaha's diaaaca were aye and a'aia prablsao. That# caaaiaccd of ecae-lUc eruption*, follicular accanCuatiaa, cualliag cf (ha ayalida with discharge free cha eye*, acd increased pipnancacioa of cha akia. 'Mfortunaeely, swan though the chlaracaa waa not a pataaaeac condition, ic uaa a diacanfartiag diafigaraneai chat laacad for a period ef nonch* ta yaara. HONS 025284 y.Uraba a: <1. (43) havo reported on cha causa o! cha daachs or ol cha SI parsons who died during cha firse dacada after cha Yuaho incidanc. Haven daachs rasulcad (roo various naoplasaa; a 13.41 eancar raca, which is highar chan cha 21.1! raca ganorall/ roporead far chac araa of Japan. ho caaalusioa can ba drawn from chic ac prasaac, tinea cha Yuaho raca waa aac aga-adjusead aad furchar analyaia at Cha fuaho diaoaao auac bo deao ac a laear daca. Of cha rasore ad canoara, cha cypaa of naoplaaoa variad. The niabara of eancar far aaoh claauo ooro: cwo acouooh, ona scouaeh and livor, evo livar, chrat lung, ona braaac, tad cwo mali|habc lyuphoaa. Whllo Cha abavo affaees doacribod is Yuaho paciaaca give soaa Idas of cha poatibia conaaauancas of ovaraxposura to ICIa, cha axaee causa of chain i/apeout is dabatabli. Tho typo of FCI oixeura eoneaolaaciat eh* rica ail, Xaaachlar 400, had boam dlacavaxad Co coocain polythloriaacad dibaaaofuraaa (KSfa) at coaaancraciona aa high aa if ppa (61, 64). haaauraooaes of cha rica oil uaod by Yuaho paciaaca ravaalad chut tc eoucainad Kla ranging froa l Co 1000 ppm, S spa oc KOfi, aud approxiaacaly 1000 ppa at polychlorinucod guotarphinyls (ICQa) (62, 63, 66). Thoroforo, is La noc kaota whiah of cha Yuaho aida affaaca eaa bo accribacad aolaly ce fCXa (64, 67) and, if eancar la faaad la cha fucura CO hava boon significantly ineraaaad in this group, tho aaatto of eaaaor iadoecioa will raaaia unknown. (Boca: Tho K9Fa found la cho Yuaho FCIa aro about 1000 ciaaa higher chan choao usually uooaurid in hnorican aourcaa of Kla). lacancly, XuracauM (64) raviavod cha Yuaho apiaoda aad suggoscad chat cha lavols of rcla aad caoCMinanca wora aecoolly abouc half of cho toaunc peaviaualy raporcad. Ha also auggaacad chat aiaco a aouaidarabla nuobor of vitciaa did not racovor fraa chair syopcooa aftor chair lavols of HONS 0*5205 TCSa ht4 4:bppa4 :a near umi level*, cti high lavtl* al caneasiaaac* icill yrotaae ia cha viceiaa u; ba the aara likal/ cauaal factor* of :h* Yuaba probloa (it). aorttlicv 5cu4io* *ari at high eancar rata* aaaag MU oil oaployaa* ixfaitl ta Rla (Arcelor 1Z3*) ac Mobil'* Paalaharo, Xaw Jorioy, rallaory have baa* iuatyncri at laUutin o( a paaalbla link bacvaaa K1 aiyaiara a* akla (aalaaoaa) ar paacraatlc caoaar (If). Tha prolleiaary Mohil tu4y raparccO eight eaacara vhich 4avalepe4 bacvaaa lf)7 aa4 1173 aaag *2 research aa4 Cevelepaene aa4 rolleary worker* azyaaa4 ta vtryiag laaala al Aroclar 1224 far flaa ar aii yaara la tha lata ltao* oa4 aarly 1730a. Of tha aigha aaaaara, thraa aara aallgaaat aalaaoaa* ni tva vara caacar* al tha peseta**. Aaaarllag to non, "Thia ia ignifitaacLy aan akla eaaaar (aalaaoaa) aa4 paaereatle aaaaaa thaa voal4 ba aspaetaO la a papalacioa at thia aiaa, b*aa4 oa cha YhlrO katloeal Caaaax Sumy." Savant, it ia iifliault ta 4xav any coacliiaiaaa Iraa thia ltu4y baeauaa el tha avail auahara al Ia4ivi4aala aapaaaO aa4 tha variety al other chaaitale ta blch they vara ospeteO. Ia aay caaa, tha ata4y vaa vith4rava tar raviaiaa aa4 hat aat yet kaaa ra-ralaaa4 (SO). 01 tha atu4iaa reporting tha alltcta al KSa aa cha ehraaic 111-- aaaaaa ar tha aertality laciOanc* ia hnaaa, only cva proviOa largo papslatlaa* al ayyaraatly a lagla chaaieal txpoiure. trava aa4 Jaaaa (Of) cea4uata4 a retreapactive cohort aertality aeu4y al 23*7 oaplay aat Itva tva plaata vhara KSa vara vaa4 ta aaaaiaatvra electrical capacicora. *11 varkarr lael4a4 ta cha atvCy wore oaployo* lor ac HONS 025286 In aataaaiag the apedaoiolegie aridanea far eareinegenieit/, :: suae in raaeoberad that in any apidaaielogic study it nay ba inpoasible to aliainaca all of efta unrelated but confounding variablaa in t."ia obaarvad populations. ^oreornr, it ia not uncoooen ca fan aeasurabla incraaaaa in ana typa af caaear avar vhae ia nathaaacically expaeted, aiaea va eaiuioc chaosa a aubpopwlatian chat raflaeea aaactly tha baaaltna eancar racae of tha total population. In fact, ie la all known chat different ataaa of cha United Itataa hero different backgrounds far many of tha apaaific cypun af eancar. Ail thia Boat ba eonaldarad carafaliy, and na caneluaieas ihould ba aada concerning any finding af axcaaa eancar which ia nac aeaclatieally aignifieant. bat only above aapacead raluas, anlaaa chla lot axcaaa far that ayacifla cyyo af aanaar la rapaacadly deoanatracad la aubaaauanc atadlaa. A poeitivo aamlaciac baewaaa axpaaora ta a ehaalcal and a raaultaat advaraa haalch afface raliaa ao cha fallowing canditlaaa (6b): a A poaitiva aaaaaiaciao auac ba tarn in lndlrldnala with known axpoawraa; a The paaitira aaaadiatian casaoc bo axplaincd by blaa in recording, detection, ar axporioantal daaign; a The paaitira aaeaciatioo ouac ba aeatiaeically aignifieant; a Tha paaitira aeeoeiatioa ahauld ahoo both daao and axyoeare period dependency; and HONS 0252*7 boticiva attoeiat ion mat bo abtarvad rapaacadly is susittuant atudiaa and cinno: ba < aingla, confounding, raritbla obaarvat -bn. Ts data, tha mortality atudiaa canearsad with PCJ utcaurti prtant aawaral Proliant at intarpratatian, tha Mat aboioua and important of uhlch la tha dlfiatant laertaana in aaaaar typo rtportad. Takan aa a dula, chaaa atudiaa pravlda no aupport (or aaaortioaa that FCla atm a cancar-causlng ehanieal. Tha wariaty at taaat altaa Sound ta bo oC Mat eoscora within oaoh ttudy laa|al)r dlffars from tha aniaal data and la laeomalatont with tha aalactlrlty of turrantly known praaotlng agaata or initiating cartinogoaa. la aiaatr, apidaaiologit atmdiaa harm daMnatiatad that coMortial fCla art not raaarkably taaia chaaitala altar acuta aapoaura and that, dna axcaaa aapoaura data occur, tha uaual caaaanuaacaa arm dor* natalogia aad oat of a lorioua or pornamong natnrt. Data fraa iavaatlgatlona Inoaloing throaie axpoanraa yiald alailar conalualana. Tha majority af atudiaa haa m idaatifiad a allaiaal dlaaaaa aaaaciatad with PCI aapoaura, nor haa it prnwidad portuaaiwa awidanca of haalth inpaimant. Thara ia no poronaaiva aoidanea of aa oaaaaa in total aactality or ia Morality dun to caaur, cardlowaacular dlaooao, or narrnua ayaaaa dlaaaaa aaaMiatad with Mtapational axpaaurn ta fCla. Pda harm wt haoa llakad ta aay haaaa cancar. faturn inmatigationa of MaapatiOMlly expoand popnlationa will no dauht furtbar clarify thla laaM aa tha tatal Morality within tha tatt group incraaiaa with tiM and yialda a largnr Mrtality data baaa. HONS 02aa JHOCISVSIS '0* AJStSSISC arsx (a ICCtapein| ca ttcrapnlaet cha huaan risk fret chaaical aapaturt using tniatl toxicicy tt the basis far cha risk extrapolation, chart trt savarat aadala cs ehsata Iron. Tht total charts it priaarilp teearaiut hr cha type at httlch haiart at aoic conearn. How ever, ipathinf is (tnaral carat, chart art only two crpta used. Tht first typt ettaiaca at chaat aathods uaat tor axcrapalacini cha huaan riak tiraaelr traa cha tosa tar thick chart vaa at observable aniaal toxicity. This atthat eat ha applied ca aaac eaxiciciaa (atcape cancar} , tinea thraahoIta art assisted for chaat raapataaa. Tht second typo at total it tiaaraUy tact to aaataa cha risk aaaociacat with carciatttna. Slnet amp acitnciaca aaaaat at idtacitiahla threshold tar chit toaieicp, chart it aoaa riak aceachat ca tap aapamra. Thia caattpc ticcacta chat aacktaatical aadala bt uaat to attraptlaca to ttptauraa far balm chaat tootles inducing obaarrabla raapaaaaa it cha eaae aaiaal populaclon. far aoacamcar catieieiaa (i.a., chraahoU eaxiciciaa), cha totals for attrapaiaciai riak art ralativaly siapla and aiailar ca cha Suglaacad la Adverse katpaaaa Laval (SMIL) proposed bp cha .rational Sataarch Cattail at cha national Acadaap at Science (72). ar cha Lavaas Ohaarvabla Stfaac LlaiB (LOIL) uaad bp cha tfaicad Scacaa Enviraaamtal Iracaacim agency (!M) (7). Saaicallp, chit eppa at caltulaciaa it caapucad bp aaauaiag chat huaaaa ara at sensitive aa cha caac apaaiaa uaad. Iharafara, cha aswuat iageacad bp cha taac aaiaal chat |ivaa at catic raapoaae it cha safe uppar Hale at axpoaura tor huaaaa, l.t.. cha huaan chraahold data. 0NS 025289 Tha calculation taaantiali/ aakaa cha canvariiaa on tha Utii z: chi l'.at diiiartncial bdtvaan iiiaani and cha caae ipacin, uauaU/ a body weight eoagariaoa rather than surface araa. Ic should ala* taka iaca canaidaraciea chaia (acton that affaet a truly caayarativa data, a.|., akiapclaa (actara it cha huaaa aipanta dlffari fraa tha late ctadlclaaa ar It tha aalaal daaaga raglaaa alttars fraa tha "------eageaura interval. Tha aalealatisa la alailar ta tha tollsviag: Safa luaaa Data TSo.elag/ kg) a 70(kg) a r a g.X. a tl/I . s.r. T9o.a chreaneld, ar a* abaarrabla aftacc data la tha taac Malaa; r akaaryclea faatar, ar taala at aalmal akeoreciea dirliad by tha huaaa abaeryciea (tbaeryclan aaiaa1/ abaarytlan huaaa); t.g. axfasura rat la (doaaga raglaaa iniaal/eagaeura raglaaa htaaa); tl/S raala at ellainatien (half-llfa la aalaal/ halt-llfa la hiaaaa); tad g.f. aafacy factor, which deyaada aa tha rallablllty at cha data uaad far xcripoUclaa. HONS 025290 Typically, tha lafety (actor uaad variaa (too 19 to 1000, (atone.-; Clio oxcane a( aniaal data availtblt and vhecher or sot chore it an/ human data to aubacaaciaca cha relicbtlicy o( cha number, of eourao, cha maker calculated ahould uio chronic data vhara chronic axpoeurei arc oxpoccad. fhia typo of modal caleularoo ono value, fxpeeuro at or balav ckia value ia ceeaidared aafa. The aecend type ef calculatien alae haa tavaral eecheda or medala free which te cheeaa. Rewewar, all differ in their haaic ceeiapciona or in cha macheoaciael axpreaaien uaed. Hence, ac tha lew axpeaeraa la enaction, their aaelaacion ef riak cam vary dramatically (OB), Regulatory ageaclaa curranely uaa the multiacate medal prepeaad by Cramp (7, 73). Dainf chip medal, the riak ia linearly proportional to the anpeaure at lew deaea. While each expeaura la ceeaidared te carry aama riak, the acceptable riak er aafa deee ia eaeally euggeecad aa cha ampaaura range far a 10"* ta 10** riak. Thia aeaaa that daily espeaure ca that dean wewld incraaaa caaaar by 1 paraea in 100,090 ompaaad (l.a., 10**) er l in 10,000,000 peraona (10**) with a lifer cima ampaaura. kiak ta TCTa Aa ataxad earlier ia chla chapter, tha determinant factor far aaaaaaimi cha riaka aaaaaiacad with chemical expeaura la uaually tha eamiaity (aauta er chrealc) ef moat ceacara chat can be expected te eacar ia Insane. With PCSe, aa for aay ehaaieal, determiner.; cha eamiaity ef meat ceacara la extremely iaparcaat ee totting aafa expeeura limica. Ukawiaa, determining cha ceaiaiey ef meat concern alae MQNS 025291 ieteniacs the public's perception a( the ban of iri>poiurt :3 Kla.'whieh ia cun affects risk aascasaent. A* kenonscrated by the types aC Analysis used, eha difference of whether or not a chaaical is careinegenic can translate iaca aagnicukea of differences in cha calculated kasa coasikarak ea ba aafa. Xla ara a (oak eaaaple of chla kllesaaa. Aa saaa in tha tVs aakianc watar duality ericaria far Kla (7), tba aafa kasa caicuiatak if Kla ara nac eonaikarak ea ba carcinogenic ia 110 ut/kay; if Kla ara eanalkarak ea ba carcinatanic. Cha 10** risk kaaata ia appreuiaatsd at ltO ng/kay. this la (raaaar than a 1000-folk klffaraaca ia eha "safe" exposure baaak aa cha cbaaical's carcinatanic patential. Thus, kacarainint cha aaraiaataaic paeaacial at Kla actaracaly baa a large lapaee aa ica perceived risk. Ivan chanth many aigiaasu nay ba aaka rsgarkiag eha aaraiaataaic pecaatlal af ICla, cha aaaver ce cha euastee retardiag uhich level aay ba aafa caa ba fauak by a stapler, aara klracc aachak. While cha precekiat axcrapalatiaas aighc provide uaaful guidelines far sate enpesuras when aaly aataal kata ara available, they eaa ba aak should ba esaporak by cha huaaa axpariaaca uhaaavar paaaibla. While huaaa kata aay eat peeve that eha excrapolscien* free aataal kata ara aarrac:, ebay caa bo acillaek la aaaa instaacaa ta kacaraiaa if theca eacrapvlaciaaa ara iaearraat. Such ia eha caaa far Kgs. Tha aakal proklcctat cha caaear risk fraa PCla baaak aa cha kata froa tba lUbraagh ac al. study (7) is liaaar ia cha kaaata range calculated far acceptable risks. Therefore, linear exerapelaciea to that kaaa appeeataatiag a 1008 cancer incidence la husiaaa uaiag cha alapo tar cha curve ia chat partiaa af eha kaaa reapaaao far lav risks provided an overaactaatien af tha actual kasa required for a high 02S2 HONS a actual mm or mia m aaaoct b imvoumimii fum inw miow 0A ACTIMl DOM MMUIMIBII IBM MU O* CAMCfA Ob CXfDAPOlATtOMM MPM1BMVM0 MW MM OB CANCCB Figwrt 1 EXTRAPOLATION FROM LOW CANCER RISK EXPOSURE TO IIIOII CANCER RISK EXPOSURE MOWS 025293 incidence oJ cancer (ri;ura l). .'erforatnf tail excrapolac;c?C3a it.a.. 10*J tick i< loO ng/day, ta a risk of 1 ii 10s a ISO ng, di aeuala lo a*/day), u* ehouid expect a eaacar incidence of :c:; ia eh* axpaead population ac abouc a to Bg/day-axooaura af ?C3a if law axpaaura pareapcton oi cat risk ia eorraec. Xovaver, else Occupational Sefacy and Health Adainteracion (OSIU) Uaie far occupational expoaure ca 7Cla vaa 0.3 ug/a3 (or Aroclor 1234 and 1.0 ag/a3 far Aroalar L242 aad ochar, lover ehlorinacad biphenyla until 7C3a vara banned. Aaaaaiag that cha average veluaa a< air iakalad par uorkday ia appraaiaacaly 10 a3, caaa the elloveble uerkday iacaka at Kle could appraaiaaca 3 ca 10 ag. Sraacad chat parhapa nac ovary worker vaa aapaaad daily ta ehaaa lavaia, raparca each ag Ouv ac al. (31) er Irova and Jaaaa (*) illuacraca that la aavaral iaacaacaa axpaaurae vara highar; chernfor*, ua caa aaaaaa chac tba daily expoeura appraaiaacaa of oar aaaiaagciaa ara a practical eaaaidaratlaa. Alaa, cha alapa of cha extrapolated llae oaald ba aach chat tba eaacar rich abort 1 ag/day at K1 axpaaura vault ba aaaily ebaenrtble. Siacc cha largcac acudy, by Irova aad Jooaa (U), did ooc flad any acaclatically inertaaad Uvar eaacar, and could nac daaanacraco any caaacr rich, ooo auac aaaaluda cbac cha aaoaar riak extra polated fraa cha animal data far lav data axpaaura ia uraag aad by ac laaac tea ta chraa ardara of aagaicuda or grcacar. ly comparing eba riak caleulatad uaiag animal data ca ckac fauad ia 2317 capaaitar uerkara (67), ua oigkc conclude chac ana at chraa poaaikiliciaa or a combination at all three axlata ca axplain ebia arrar la aar talculaaiaaa: (a) cha aadal ia vraag, (b) cha aaiaal epaciaa uaad daaa not rapraaant aan, or (c) PCIa ara nac carclaagaaic HONS 025294 in huaani. Tha tint poaaible applanation sty coneributt :3 ::r:. lu, Sue i> lint li'ul< :a n tit ewul factor tot, it rtaaaaa : i-; 3 wart fill*, than cat occupational cncir would harp boon oaaaurao.t. Therefor*. ono eon conclude choc otther 2 or 3 ia cho ooro likely r*atoil far Clio diierepaney. lagardlaaa of cho cauaa for cno diacroponey, ic can Pa doom traced cnac, ae cho war? laaac, cho roaulea of cho animal coaca of Siabrough ac al, (13) da noc appoor co rrprpaooc an animal nodal colavoot far aaaaaaiaf cho cancor riak la busana uaing cho entrapdlaclaa poaad by Crap (II). lacoroaciifly, if cho data au||tacin| that PCIa art promocini a|anca art ignored and if cho aaara modal ia adapead for cho human data (cha eampariaam ia flgura l damaa* acracaa haw cha modal ia aaeaaaira by aavaral ordara of aagaicuda at laaac), wa raaah am appraaisaca 10--3 riak at caacar that it agmivalaat to cha LOtt aalculatad by tha CM of 110 u|/day. It might alia bt natad that chit tana tttt of tha 10'* riak baaad upon animal data far DOT and thlardana ahawa a largo evereaciaaelam of tha riak for thaaa chamieala aa wall. Thma, thia typo of aatrapalatiam aaana ta ha inappropriate far acker ahleriaatad, partittamt chamieala which anhamaa ar produce liver tunerigetteaia ia ra- damta. IREUT103 or m NZALia IISX1 AJSOCIATID WITS gHTMOWEITAI. ECJOJUKJ larly ia chip paper ic vaa acatad chat a charongh avaluatiaa of tha haaarda aaaaaiatad with PCI aapeattraa nuac caaaidar and wai|h ait dlffaraat charaatariaciaa ef cha data. Tha fine two factara daal with tha braadch and variety at conic caapanaaa produced and cha dagrao of apaaiaa variation aaaaaiatad wick cha affacta aonicorad. Many of cha PCI-inducad advataa affaetd are HONS 025295 chartccarisuo of a entariascas organic conseund ef ehs PCS eyes, ;r at laast offsets art niur.tl|r praductd S cany chlenaa:u organics. 7>.ta effaces include Uvar injury, Uvar anlargenenc, Uvar ansyne induction, irricaeinn whan ippUld cn cha akin, chloraene. and (possibly) a .iiarupeian at cha aacrafanic balance in (analaa dua ca incraaiad Uvar aacabeliam. Although chaaa nay indaad ba eanaidarad advaraa effaces, all chemicals ara capabla at clearing aana physiologic function at a high anaugfa doaa. In tha note ralavaat reproductive autogenic, tarataganie, and careinogaalc taata, caata of chlorinated hlphanyla wara canalacantly nagativa, with only a tav antaptiana. Saaa of tha axcaptiana can ba dlicountad bacauaa at inadequate study daaign, diaputabla intarpratatiaaa, ar uaa at unusual tast nathodalogy. [t it uanatasaary ta display a disproportiaaataly high caaaarn tar ehota tav patitlaa studlas whan chair findings cannot ba rapradutad la a ntabar of subsequent studlas eonducctd uodar siai- lar ar ldaatlcal candleiana. Third, ragardlng naahaaisas, suffleiant avidanaa anises ta indi cats chat PCI* hsva tha paeaatisl ta pranoca ctnear rsthar than inlci- tta ciaara. Similarly, cha aacabatiaai tad aliniaatian af PCls in prinasaa is far lauar than that of radanct, suggaseiag ehse nan it far lass likaly ta ganaraca toxic xacabalitaa chan rodoncs, i.a., nan is prabahly laaa suaaapcibla ta Uvar injury and say lapacc this nay hsva on evasriganasis. Tha faurth factar ragardt cha ralavaaca of cha parfornad tats. Par cha nasc part, this was nee a factar whan considering tha rasulct af neat easts. Thara ara, hovevar, tana problems in sttschiag cha HONS 025296 list aipniiUaeea to all af aha autapsoicicy cates. T>.a human n:vanea of aintla*tcrsiifaP broths in ON* at hi|ti in vitro PCS coneancracioas or cat applicability al Etta chreaoteasl cotta in birPa it puaacionabla unto coaysraP to cka sort ofcan uaap anp baccar tacabliobap caoca for aucspaaic or tlastapanic activity ia aanaliaa anp baatarial taac ayatana. Thus, va hava concluPaP chat cka aucapanic, anp cktrafara initiacioj, activity af PCla in huaaas ia ainiaal, i.a., it ia aat a aianiflaant kanarp ca htaana coaaiParlap tha ovarvhalaimply nspaciva caaa ratponsas aaP cka lowar kuaaa rata af PCS aataboliia. Tha ralavanca af axcrapalacinp ana paaitiva carsiaopsnstis bioaaaay vithoat balaaciap it apaiaat oiaaroua aapativa aaaa alia aaaiaa iaapprapriaca conaiParinp tha likalihaaP ckac PCla ara proaotara; that tha arpaa raapanaa (i.a., livar eaacar) haa a hiph bashpnvnp laeiPaata ia raPaaca (7*) aaP ia aaacaptikla ca praaaiiaa by auch affacta aa inpuatiaa (75, 7t) tap raturrtac livar injury (77-7*7 (cna known affaati af fCla); tha attain prafaranca af tha paaitiva affact; anp ckt irrtpnPacikility of tkia nffacc. ConaiParinp cka pranecinp praaanxna chat kiph, chronic Paana af PCla eenlP anart, it is probably asrs unaaual ca flap tha nsjavicy af raapanaaa in tha rat napaciva. Tha fifth factor Paala with tha Posapaa rapniraP ca proPues uiaal tonialtlaa aa aanparaP ta tha aapaatap bnaa axpoanra. In anisola, Kla an acacaly conic only at hiph Paaaa. Similarly, chair thrnait affaata paanrally occur at ralativaly hiph Paaaa or hiph bapy buypaas. Thaa, cahiap ints eoaaiParatiaa tha anpaataP low anvirsnaaatal axpaamraa ta hiaaas, PCla Pn aac appsar ta psaa a aipnificaat riah. If ahia PianrPara ara aet iaPocsP (hiphly uallkaly), athsr affacta aaaa unraaliacic. MOWS 025291 Utc factor daala with risxa daterainee by huaan ai;tig:n Thu apidtsialatic itudiua hm daaanactatad chat PCle ara not rasaraakly toxic ehaaitala dfter acuta aapaaura and Chat, uhan axeaao msura deaa oeeur, cha uaual coniaavoneae ara doraatalO|ic and oac of a ;aiaanaac natura. to spite of ovar 30 years of uaa, FC3 chrome expo sure* have addad Uttla or aa additional adverts affacta of nota to ckia picture. The aajericy af atadiaa haa not idaaciflad a cllaioal diaoaaa aaaaaiacod with K> expoaura achar thaa chlaracaa, nor haa i: provided persuasive aoidaaca of aa aaaaaal haalth inpairuesc. Thera ia aa avldaaea af aa axeaaa ia total oartallty or la aartality doa ta caoaar, cardiovascular diaaaaa, or aarraaa syscen diaaaaa that eaa ba aaaaaiatad with occupational axyoaura to fCla. FCta hava act boon Uakod to any huaan caocar. ThereCot*, it ayyaara that fCla ara nt a ranarkahla toxicaat. but chaaicals that rayulra hifh daaao to yroduca hamtul affacta. la avaluatiot tha riak aoaociatod with tho cuvlraaaaatal aapaaura to fCIo, ua ahaald aaavar eua tuaetioas. first, ia tho laval af aapa aura of a aufficiaat aafnituda to ceoatituca a haaord? Sacond, if 13, vhac ia cha axpoctad hssard? Jollook aad Caraolluaaoa (fO) tatiaccod that tha doily fC> lataha far 0 young nolo adult dropped Cron approxiaataly IS uf/doy ia 1S71 Co (.7 ug/day ia H73. This aatinaca vaa booad on tho aaouapciaa choc aaac of tho latoko uauld cano fron aaisclag fCS-caacaaiaacad flah (an ualikaly coaoidaratioo for noat II.J. cltitaaa). Tho aatinaca uould oat ba accurata for people uha vara oat catlag auph flah. ar vara aaciag Larger anauaca of flah, ar far thaac vha vara axpaaad ta vaata aitaa, cootaaiaatad vatar, ar other uauaual aaurcaa. HONS 025298 naelaad (JU aora recently reported that i.-idaor jir gollu:::vich fCJj li graacar thin ouedaor ir pollution, and afran nr.;., ;r;0.1 ug/a- 9 0.2 ug/o^ af air car cany of cha locaciona caacad. thia approxixacae tJ l 1,0 Co 2.0 ug/day axgaaura eo K2< frou :u> indoor <ir murcaa. thia axgaaura alia appraxioacaa the currenel-f tuggeacad XI0S1 axgaaura laval far induacry (32). thua, ic aggaara Chat paraana within cha United Scacaa axa, in gaoaral, anviranaaneally xpoiad ca aicxegraa aaaaaca of Kla gar day ia due art probably the higher axgaaara iaacanaaa (axaludlag uauaual caadlciaaa). Thia axgaaura ia approxiaacaly 1000 ciaaa lavar chaa (araai occupational axpoaaraa, which, atcording ca raeaat evidence, gradocad aa identifiable prablaoe ackar chaa chlaracaa. Ic would adwo chat a 1000-fold raductiaa ia axgaaara would ba a auffieiewc aargia of aafacy far aay vaak chraakald affaata ekac wara idaaciftad, a.g., akia diaardart and ladaatiaa af livar aatyaaa. While cha VI0SI laval ia lawar chaa cha 0H1 aeaadard. ic vault aaaa char cha aid liaic raaaaaably gracaccad cha aaaupttiaaally axgaaad garaaaa. Thia bodaa wall tar cha rate at ua caaa Ida ring our far lauar axgaccad axgaaura froa cha anviransaac. Furtharaora, calculaciaaa ravaal chat PCI axgeauraa af aicrograaa gar day art not likaly ca elgnifleantly altar a garaoa'a acaady-acata ciiaa cenaaacratlaaa. Per axaagla, cha avaraga 70-kg aaa ia xada ug af 13S or graatar body fat. Ia achar vorda, ha haa at laaac 10.3 ig of fat la which ta ctora Kla. Siaca nea-aacugatieaally axgaaad paraana caatala 2 ppo or lata af Kla ia chair body fat, ac 2 gga cha avaraga aaa would caacala 21,000 ug or laaa af Kla. If aaa atauaad a woratcaaa aaciaata without ceaaidariag aacabaliaa, .xcracinn, achar ciaauae ca., ic would caka 21.1 yaara ac a daily axgaaura at 2 ug/day ca daubla hia fae lavala af Kla. Ac 10 ug/day, ic would taka 3.1 yaara; at 30 ug/day, ic would caka 1.2 yvara; and ac 100 ug/day, it would HONS 025299 i,caka 0.5 'Old. Ua eha fcalc-lito o( C3t probes!-.- -s ,3.... chin i tiorcn or :uo, cha iccual cist to double cha bo</ buriai: -.1 laager this the above ee leant iona and would never 3a reached Irr :r.< lover axpoaurea. Thua, eha axpoeura to KJa (acad by :0a general pap ulation, aicinaeed at about ] ug/day or laaa (or chore arpoiad, -oc liaa:y to have ouch a( an isoace upon the law body lavala at coseani- nation chat hava baan anaaurad in nonoacupacionally anpoaod parsona. Sinca chaaa lavala art (ar lowor than cha tiaaua coneancraciana expariancad by aapaaicar warkara, it U ualikaly chat any untoward conaa- gueacea can ba expected in cha tnnaral population, tha talsulatiana alao danenacrata chat oeaaaional aapaauraa to ouch higher lavala ara not likaly to inaraaan a paraan'a adipoaa lavala abova cha 1 co 2 ppn coMonly naaaurad. rran cha aPava diacuaaioo, it can ba aaaa chat cha curraae daily aavlraiManaal axpoauro naat likaly oncouncarad tran cha envireisoat la nat at a ewfiltlent magnitude co aaaatlcuca am additional haaard baaauaa It la not likaly to altmiCleaacly altar our currant body bur- daaa. Tha aaiaal data haa identified cartain haiarda, but cha eagaciva data auggeac char chaaa haaarda ara not eanaiacanc or pocaac raaponaaa la ivory apaalaa. While wa night apaculata that vary largo daaaa of Kla nay cauaa variaua datriaancal eCecee, cha higheec anpaaura group, aapaaicar warkara, appaara co hava baan axpaaarad at lavala balav chaaa that would cauaa aarioua advaraa attaaca in hiaano. Than, tha currant aaviraanancat oxpoauroi to Kla, which an such lsoar chan pravlaua oaaapatiaoal axpaouraa, da aac appaar to bo aaaa* ciaaod with on identifiable haaard, and 00 cha huaaa riak comma ca bo aininal or inaignidcanc. la ardor that chic paper ia aac niaincarpracad, it ia aaphaaicad chat chia eonaluoion doom not apply ca cancontracod waacaa or ahanical vaate aicaa uhara cha anpoaura nay ba HONS 025300 M|Rr Jt e: lUJinnE nitun. it it ilit esphasitet :-t: hijaor t.-.an sicrofram~?tr-day exposures to "pu?" ?C3e <9 aoc aieii- tartly carry an added risk. The federal Orug Administration (nu) l^idolises 0i l ug/fc|/4ay, or 0 >ia|lo exposure of 130 ug of PCS*, it still far below the previous CSKA regulation or ovon cho S?A't con servative estisate of cho LQSL* Until definitive evidence clearly demonstrates a chronic coxicit7 in espscitor workers or ocher exposed persons, environmental exposures co cowereial grade K3e (with loss levels of PCOFe). which ere far Lees chan cho former occupational exposure levels, appear co carry a minimal risk co honei. HONS 025301 uhumcss (1) Dottll, J.. C.S. Hulun, uU M.o. 4a4*x. eiwut'i tn4 SouU'i twttilap; Th* Uic itimi ( Mwi (tow ^otk: LiacailUn-- Twkliahiag Ca., 1*40). (2) Uahkala, l. "Toaleicp at Chlariaae*4 liphaarla." Aoa. to*. Thamaaal. 14;13* am). (]) Matpaafk. *.0. "Thk Toxieicp at 7*lr*hloriaac*4 TolpcpaUe eam~ a*--4* aa4 tolaca4 ChaaUal*.'' C1C Crlt. to*. la Toxical. 2:**4 (1*74). --------------------------------------------- (4) Faakall, 9.1. "TCI* aa4 Tbair tanriranaaacal Iff****." C1C Crlc. to*. t*ltax. Coat. 1:441 (1*73). ----------------- (3) National Inaclckti law Oceopatioaal Salat? aa4 toalth CHOU). "Ctiaaria la* hainlii 4caa4**4, Ocaafitiml lapaawr* to Talr<hlorla*t*4 liphaarla (TCla)," DUB Takl. to. * 77 (1*77). (4) tacaraaclaaal A|a**7 *or tosaarcb on Caoaa* (UK). "U1C toaarrapha aa cka Ivalxacian at ch* Caralaagaaic li*k at ChaaiaaU to Huaaaa: 7at]rchlariaaca4 liph*n?U." ttarU llaalch Orjanisaeion Twhllaaciaa* (1*71). (7) twlmwml rtatacelan Atantp (04). "Aoklant data* Qaallip Crltarla (a* Nlpcfclarla*ta4 liphaarla," 9SUA topart 4*0/3-10044 (1*40). (I) VyuOtm, C.i J. Savanlah, aa4 1. Safa. *tta la Viera Matakallaa, Maaraaalaaalar liaOix* aa4 laccarial Muta|aiaiC7 at 4-Olarakipkaarl. a to4al 7C3 Sukacrata." to* Caaaa. Chaa. lath. Thaaaaaal. 13:341 (1*74). ------ (*) Metohia, I.I., J.C. Cllaa, aa4 C.Z. Thoaaaaa. "Aaaap at 1*3 Taat Ctaaicala ia Taa Taaear Seraiaa tlaiag a tow M*4illtacioa at eh* Aaaa Taat for laccarial Matagaa*," Caaaar to*. )f:442 (l*7f). HONS 025302 CIO) Sat*. S. "ukiau u*t* Ovality Crictri* tor Polychlariaatac Hpoaayla," t'SIPA layarc 113/3-IO-OM (1910). (U) Haiti*. J.A., aad v.l. Jruc*. "Coaparitoa at Taaca tar .Hutafar.lci:7 ar Carciaoiaaicicy Uaiaj aaaaya tor }**rv Abaaraalitiaa, Paraatia* at Micraavclai, aad Mucatioa is Salaaaalla," ia Oriliaa at !>** Caatat. I.i, Hiatt at al. tt. (Cali Spriag Hara#r, Nov tor a: Cola Spriat Harbor Laaaratary, 1777), Vol. a, .. 1319. (11) Sakaany, S.S., C.C. Saith, act J.C. Upa*. "Maa --tagralclty tat Salaaaalla at tk* CBlariaatad Xytraearbaaa Araalar 1231,' 1.2.1-Tritkl*rakaasaaa. Miraa. aat laaraa." Matatian Hat. 11: 123 (1979). (13) lavlaakaa, a. "A tvriav aat fraloatiaa at Caniaataaieity stadlaa la Mica aat lata aad Matapaaicity Stollaa vitk Palycklariaatad lipkaayla," Maaaaata pakliaatira (1911). (U) Craaa, t., J.V. Carr. I.A. Falaar, aad f.J. Oavald. "lack at Cytataaia tltaaca ia lava Maarav aad fpataatatraial Call* ia lata Traatad vita talyahlariaaaad lipkaayla (Ataaara 1112 aad 1130," lvlli^B*ir*a;_CoataBi_To*l**l;_ 13:11 (1973). (13) Slkakitk, T.S.I., u. laakaaad, 1. Afcrakaa, aad r. Caalacaa. "tffact at Palyaklarlaatad llpkaapl (Araalar 1231) aa lat Taatia," tap. Mai. Patk. 22:371 (1973). (11) laapiagaraar. 1., 1. laaaal, aad B. Kraaaa. "Talyaklariaatad llpkaayl lataraatiaaa vitk Tiaaaa Cultvra Call*," laairaa. Haiti Tarapact. 1:133 (1972). (17) Craaa, I., F.H. Saara, aad l. friadaaa. "lack at Baataaat Utkality la lat* Traatad vitk Falyaklariaatad lipkaayla, . Araalara 1112 aad 1234," Fd. Caaaat. Toxicol 13:307 (1379). (II) lapliaiar, H.L., 0.1. taaakat, aad J.C. Calaadra. "Traiaalagital Stvdlaa vitk Palyaklarlaatad lipkaayla," payar ptuaatad at PCI Caataraaaa, Qaail laatt Caataraaca Caatar, laacaaaat, Sarth Carallaa (1971). (19) Calaadra, J.C. "fanary at Taalaalatiaal Stadia* aa Caaaarcial TCla," ia Ftaatadlaar at tka Oatiaaal Cratarraaa a* Palyaklariratad^lljkaarl* (Meat*. tlUaala, 1173). PA tapart 3*a/k- (20) Taaraak, f. "Itfatt at TCI an Oavalapiag Maaaa," Ciaaaaahat* 2:173 (1973). (21) Vataaafca,.I. aad T. Svgakara, "laparlaaatal Faraatiaa at Clatt Pa lat* la ttaa vitk Palyckiariaacad lipkaayla," Tralaalray. 19:19 (1911). MOMS 023303 (22) Kirks, T.A., C.L. liaii, n( X.E. staples. "(n/Utnc. 3; : nacrical Falychlarinacad llphanyl tiowrt an bkryo and !(;i. Davtlapntnc of Mica, l. Tarscajcaiei:;/ of 3,3' ,4,4* clorobiphanyl," Tokicol- Aosl. Fhsmstol. l:2il (mi). (21) Tilm, R.A., C.J. Bii, 3.A. Me Lachlan, and G.w. Lueiar. "l>.a Effaces af Fo lychloriaacad Sisheeyli Clean Franceally an the Maurobahsviorcl Oavalaynaac af Mica," Environ. Eas, 11:4*4 (1171). ----------------------- (24) Ajrival, A.X., H.A. Tilsan ud J.C. londy. "3. 4, 1`, *- Tacrachlacabiphcayl Clean to Mica Franacally Produces Lonf-Tani Dacracsaa in leriscad Doyaniaa and beapeor Sindia* Sicca in tha Caudate bunions," Tonical. Ucearc 7:417 (llll). (23) Msttcan, X., A. ruction, J.x. Kihlitran and X. Lindahl* XiasaliM. "tffnccc at a buachlarinaced biphenyl an Lynpheid Or(ia* and Caaneytian of Faacnsas U Frafnanc Mica," Arch. Environ. Cancan. Tanical. 10:2X1 (1111). --" (2*) Callart, X.J., and c. uiloan. "bpraduaelee function in Caci Exposed Fanatally ea Faacicidas and Falychlarinacad llphanyti," Environ. Xaa. 11:437 (1171). (27) Under, E.E., T.l. Cainar, and l.S. Kinkron|h. "Tha Efface af Polrealarieased lithanyli an be larrodnccion." fd. Carnet. Tanical. 12:3 (1174). ------------------- (21) Tillaanurc, B.C., 0.1. Grant, X. Xhjara, D.J. Cle*|, * bar, and W.J. FhiUia. "Tha Facaeexieley af a Falychlarinacad lifhaayl Mixture (Aranlar 1U4) U tha Uhhlc and in tha be," Environ. Fhvaial. 1:7 (1171). (21) bylinfor, M.L., o.X. rancher, and J.C. Calandrc. "Torieoloiie SCndiaa With Polychlorinated Sisbnrls," Tanical. Aral. Phamacnl. lli*02 (1172). (30) Earl, F.I., J.L. Cane111Ian, d E.J. Tan Loan. "Tha byrodac* tiea Iffont* af FC2 123* in ba(l* Oats and Niniacur* Svina," Tanical. Anal. Phnruncol. 21:10* (1174). (31) Allan, J.X., L.A. Caracaa* and O.A. brcaccl. "bsidual Effacts at Sheet-Tern, Lav-Laval Inyaansn af lanhnnsn Frinacas ta Pely- chlarinacad Uyhanyls Tanical, Aval. Fharnacat. 30:4*0 (1174). (31) Allan, J.X. and D.A. larsocci. "Tha Effaces af Trsnsylscancsl and Msnnary Mavansnc at FCSs an Infanc Ihasas Monkaya" Toxicol*Hi331 (1170). (33) lartnctl, O.A., 2.3. Marlsr, sad 3.2. Allan, "byreductlve Dysfunction in basue Maokayb Exyasad ca Lon Levels af Palychlarinatsd liyhanyls (Arcelor 124*)," fd. Casnac. Tanleal. 14:11 (117*). HONS 025304 (34) Aliad, J.2., D.A. tarascei, u4 L.A. Caraeana. "Haaitual llftcts ( folyehlorinacea liphaayla an Mule Msahuun ?risa:et a>4 Their OttiTrinj,'' J. Toxical. Curiron. Saalrh 4:33 (1340). (33) Kaaaan. L.S.. C.S. Byarly. i.l. Metcalf, tad t.y. levila. "ttface a( folychloTiaacea Iiphenyl MixCura aa Svina ReproCueeiea ana Tlceua ReeiCuee,'' Aa. J. Tat. Hat. 34:13 (1373). (34) iiaaca, M., 4.4. Cupca, K. Chao, J.9. McXiaaey an4 J.A. Naara. "Toxicity at SelactaC Syuatrical Haxathlerohipheayl daam ia cka Meuae," Taxital. Aaal. fharucal. 34:441 (1311). (37) Ortery, 3. "Ufeet at Twa Chlereaiaheayla a* the RspreCuxciva Cayaclcy is 7aula Mica," Acta. Thatu. Toxical. 42:313 (1374). (31) Jm, 4.C., M.f. Craaur, ana 4.D. harhiaea. "Health effaces at Kiel Sauary as4 laehaiaal lariw,' report auhaiccat ca Otaoical Maufaatiuara Assatieties (1311). (33) Drill, V.A., S.L. Fraiaa, H.V. laya, T.A. Locals, an* C.l. Shatter. "Tecaerial aaalth Ufuxa ia aha luu (rax tapamre ta ralyehlsriucei tlphesyls (PCM) aaO RalacaC lapariclas,' rapart aahaiitaa ca aha (Clean Ilaatria tascitata (13(2). (40) Aalarith, 4.J. CM 4.4. klafar. "Carraac Statu at TCS Tasiaity ta Miak, aaO Ufaat aa Thair RaprcCecrlea" Arab. Caviren. Can tu. Taxiul. 1:273 (1377). ---------------------------------- (41) Milay, J., t. Caaai, H. Mullar md V. taint. "Transfer at laxashlarahaaaaM saC TolynhleriaacaC liphaayla ta Oaraiai latau (Mans Kashayat tabauaC Tonicity." lariraa. taa. 21:130 (1310). (42) Its, 4., I. Mtuaki. S. Makiara, ut M. Aril. "Hlaeopatholocical Stahlaa aa Liver Tiaaritaaaeis ia lata TraacaO With TalyahlarlaUaO tiphaayls," Cans 43:343 (1374). (43) Kiahrenyh, h.O., h.A. Haira, t.I. UaOar, J.D. StaUhart, t.J. Matall, aaO T.H. laraa. "!nCaction at Liver Twara ia Sharaaa ftraia TaaaAa tata hy TelychleriaacaC tlphaayl (Arealer 1240)," J. hat. ftaaeT lut. 33:1433 (1373). (44) Klahraafh, 4.D., aaO 4.4. Liahar. "InCecciea at ACaaafihraais aa< taper--aa at cka Livar ia MLWc4 Mica hy TelychlerinateC Mphasyl (Areolar 1234)," J. Oat. Cauar last, 33:347 (1374). (43) tatiaail Cauar lutltuta, "lieaasay at Arealor* 1234 tar faeoikla Csrsiaeoaaisity," CaraiMtaaaaia Taatlat Trafru Diviaiaa at Cauar Caaaa aU Travaatiaa, 0M Teh. 4a. (X14) 74. (44) Allas, J.4., aaO O.k. Xarhaak. "TalvchleriaataO tiphoayl aaC Triphoayl IftCuceO Sea trie Mucaaai Nyparylaaia ia Triutaa,* Saleses 173:434 (1373). HOMS 025305 I'*' Sduira, I.A., and M.K. Invite. "Claaaiiieacisn of Spec:.':; Hagaeaeellular Letiont," Caactr^lee^ 33:3214 (1373). (Ad) June, , t.D. Xiakraugh, E.C. JUlmwt, E.. Jtaaisga, E.C. Linder. and CSatocoo(. "falychlariaacad lipaaayla: Sterag*, Diatrikutisa, Carteun and lacavary: Urn Margkalagy Altar frelaagad Ingeeciaa," Arch. Cirriraw. Health 21:301 (lf74). (43) Sauirt, . "leaking Aniaal Carcinagana: A Frapotad UpluaTr Approach," Scienca 114:177 (1311). (30) tfaiekurcar, J.O., and C..1. UUliaaa. "Ctrclaage* Tatting: Cur rant Fraklaaa and At* Appvaachae," Stltaca 214:401 (1301). (31) Otar, E.E.. 0.0. Siagaaa, and 0.1. Slyali. "Da* aad Health Effacta ai Araalar 1242, a Fvlychloriaatad llphaayl. ia tha Ilaatrical Wtttry," Arc*, environ. Health H:l*f (1371). (31) flachbala, A.. H.S. Uallf, 1. Ullt, J. Thomtan, aad t. lalikafl. "Clinical finding! aneng KS Espaaad Capaaltac Maamlaccuring Warkare," Ann. Il.T. Aaad. let. 320:703 (1373). (33) Warthaw, .. A. riackbain, J. Thancon, A. Millar, and I. lallkalf. "Oaaraaaa la Vital Capacity in PCI-Expatad Uerkarl la a Cagacicar Maanlaacnring faculty," Aaa. H.T. Acad, lal. 320:277 (1373). (31) Manai, H., A. Calaaki, g. Caatcai, E. fcrlall, ad V. faa. 'Occngatiaaal Ixgatnra ta falycklarinacad ligkaayll la Ilaarri- cal Varkava, I. (avlreaaaacal aad Hand falycklarlaaacd llphcnylt Caacnatraclana," grit. J. lad. Mad. 30:13 (1301). (33) Marnai, M.. A. Calaaki, 1. Caactai, I. ftrial!, aad v. faa. "Occngatiaaal Expeaura ca falycklarlaacad llghcaylt la ElactTical Utrkart. IX. Health glftttt." Irit. J. lad. Mad. 30:33 ' (1301). (31) Safety, V. "Tha Igldaaialagy al fCOa," Maaeaac* gaklicaciaa (1301). (37) Irwva, 3.f., J.T. Caa, aad 0.0. facack, Jr. Caaaral Electric p*llcaclaa (1301). (30) Alvar**, A.F., A. fiackkaia, E.E. Aadaraaa, aad A. Caggaa. "Altaraclaa ia Drag Matakallaa in Warhart Eagatad ta felycklariaatad lipfcaayta," Clin, fkataacal. Tktr. 22:110 (1377). (33) Whitfield, J.I., E.E. ftaadar, S. Oaala, aad B.S. Matt, 'bna ffmna Clutaayl Traaagagtidaa* Activity ia Liter Dlaaaaa," Cat. 13:702 (1372). (10) Marcia, F.J., J.V. Marcia, aad O.M. Caldkarg. "rft-01ataat( Trentgagcidaaa, Trlglycaridac aad Eaxyna Indactiaa," Erie. Med. J. 1:17 (1373). aiiiob HONS (11) Hifvehi, K. 70 Poiaeaiat n4 Pollution. (lev fork: Acia-.: hail, 197*). <i:> Kuracsuaa, M. "Scan o( eh* Ikmi 7ia4icfi Caacarnin* Tush*, Maclaual Caaiaraaaa * P*ljr*hla*iaata4 Jiphaapl.," L'SZPA *a*ar? 510/1-75-004 (1171), p. 14. (in Ural*. H., H. Kata, u>4 M. Asshi. "Trasant Kata at Tuaha Patianea," Aan. l.T. .tea*, lei. ]20sl73-271 (1171). (64) Kuracsuaa, K., T. Toshiaura, J. Macsusaha, aal 4. Taaachi. "IpUaaialagic Stu4y * Tuaha, a Paiaaaiat Causal hp lu*sci*a t lie* Oil CaatMloacal with a Caaaartial traua at palpchlaria- ac4 Uphaapla," larlrea. Oaalth Tarttact. 1:111 (1171). (41) Kacapaaa. J., M. Zurataoaa. aa4 T. Hastes. "Datataiaatlaa *{ Chlarioacte DlhaasaTuraaa la taaaahlara ate Tuaha Oil." lull. tarlrau. Ctataa. Taulaal. 13:1 (1170). ------------ (It) Kuracsuaa, M. "Tuaha,'' la talaoanacte llahaarla, Trlahaauls. laahchalaaaa. Dlh*aae4l*uiaa aah lalatte Praauscs. 1. KiaarauiH U. (Htw Uik, ' laaaiaryUaru lallaai, 1111), ,. 207. (17) Tut, J.o., 7.1. Kaaaaa, l.l. Taa lar itaaa, H.C. Taa teavar aa Iran, au4 1.4. 4* aa. "Usaalllaatiaa aa4 T*aiaal*(laal hil- uatlaa *1 Chlariaatte Uhaatsfuraa a*4 ChU*laata4 laphlhalaaa la Tua Caaarcial Palpahlariuacte llfhaaplt," 74. Caaaat. Taal- aal. 1:115 (1170). -- (Ml lata, 4.1., I. laaaaaaika, I. terraaaa, at al. "Malaaaaa altar tapaaura ta Kla," tea teal. J. Mte.. oTTiW (1171). (11) Iraaa, 0.7. aa4 M. Jaaaa. "tertallcp aa4 Ialoatrial lptlaaa Sttep al Uarkars lapasal ca 7*lpchlariaaca4 Uphaapla," Arch. tar. Haalch. (54)110 (1101). - (70) lartaaal, 7.4., C. Zaathattl, 1. Ouarcllaaa, K.S. Paglla, a. Taaatarl, aa4 1. Ill*141. "tertalitp Utep *1 tela aa4 laaal* nathara tapnal ca reia," pa*ar pr*aaata4 at tta lotaraatlaeal parasite aa fraraaclaa al Octu*atiaaal Caatar, Ralaiaki, Tialaa4, April 11-24, 1101. (71) Dali, I. "lalaraaca al IpU*ai*l*tp t* TalUlaa tar tha Irtraatlaa al Gtaaar," Aaarlcan la4u*crial Ipsitaa Aaaaalatlaa, taa Iraaalaa*, Calllarala (1100). (71) lata Driakiac Watar Coni: tat, Drlahtaa Watar aa4 tetlih. Talus* ^ (ttaablactaa, D.C.: aatiaaal Aateaap Praaa, 1110). (71) Olllta *1 Taahaaltfp Aaaaisaaut. "Aaaaaaaaat *1 T*ahaaltla* lar Dataraiaiat Caatar list* fraa tha Eoviraaaaat," (till). (74) llckartaa, 1.7. "Spaataaatu* Tuaart aa4 telat*4 rathalatic Chaaiaa," la Caraiaaaaaaala Tattlaa al Chaalaala, L. Callhar*. t4. (Claralaaa, aui cac rraaa, i7J7. *. Jl. HOMS 025307 (73) Paraiaa, C., 2.J.M. Try, Mid I. Statfaldt. "lahaaetranc i Spancaaaaua Hayacic TuaB*i|taaaia in CjH Mica by Dia c try Pkaaabacital.'' J. Sari. Caacar Inat. 51:1349 (1973). (74) facica, C., I.J.M. Try, tad J.P. Chriatapkar. "Inhaneinj Iftact: at Phdaabarbitaaa tad lutylatad Hydraxytsluana on 2-Aaacylaaiaotluarana tnduead Hayttlc T.jaari|anai it in tha Hie, fd. Caaiaat Taaieel. 13:93 (1977). (77) Oata. P.M.. S.V. Catkaakar, and S.V. Jhida. "It fact a a! Facial Htfatlcctijr an Tuaar Incidanca tad Macaboliia at Mica fad TMaacacaaida," J. Matt. Caacar Iaatit. 34:493 (1974). (70 laraakltaa, I. "Tuaar roraaciaa Pallaviat Fraaaiaf with Carbaa Olaalda Saav," Irlc. J. taaar. back. 10:179 (1919). (79) hkaiaa! A.M., i.T. Quaai aa4 P.C. Vataaaka, "Tha Phamaaakiaaclca and Maarabalacular Incaraxciaaa at Parchloroachylana in Mica aad taca aa lalatad to Oncataaicity," Taaical. Anal. Hiarcaaal. 33:207 (19*0). (40) Jalinak, C. aad p.c. Carnaliuaaaa, "tavaia at PCIa ia cka ll.S. Paad Supply", national Cantataaaa aa Polychlarlaatad Sipkanyla, cklaata. tlllaaia, (1979) p. 147. (ID mtUad. K.l., "Polyaklarlnatad llykaayla la ladaar Air. "Inriraa. Sciaaaa Tack. 13:924 (1911). (ID HtOia Crltaria Oatitat. "A latavaad Standard tar Oacupaciaaal tapaaura ta Palyahlarlaatad Biykaayla1* MTOM #77-223 (1977). HONS 025300 Comments and Studies on the Use of Polychlorinated Biphenyls in Response to an Order of the United States Court of Appeals for the District of Columbia Circuit Tka IMBtr MM Waata ActfoMaa Ocaa* Tka FlUaa Baefcla laatkata Tka KiMml nl BnUfa CaaywHaa toidwln Tka IhM 9alaa El lafl fwlatHia Agany Faknwiy IS, IMS vkM n I B--MS Marti h S< DRILL, FRIESS, HAYS, LOOMIS A SHAFFER. INC. Caamtaau Im raefcafagy 1901 N. Fort Mytr Drive -- Suite JO* -- Arlington. VA 22209 HONS 02539 TABLE OF CONTENTS Executive Summary .......................................................................................... I. Introduction ....................................................................................... II. Yuno Episode ..................................................................................... [II. Body Burdens, Metabolism, andkinetics............................ tv. General Toxicity ............................................ V. Skin and Other Cutanaoua Tiaauaa .................................... VI. Ettact ot pCBs on Liver ........................................................... VII. Gastric Lesions ................................................................................ VIII. Carcinoganeslst Experimentaland Clinical .............. IX. Reproductive Effaces ..................................................... X. Mutagenesis ....................... XI. Other Health Effects ............................................................. XII. Epidemiology ..................................................................... XIII. References .................................................................................... XIV. Glossary of Tens .......................................................................... Curricula vitae - Category I Teas Curricula vleae - Category II Teas 1 17 23 23 si S3 61 S3 S3 10] 117 12] 143 IBS 203 HONS 025310 -I- EXECUTIVE SUMMARY The present study on th potential health effects in human populations from exposure to commercial polychlorinated biphenyl (PCS) mixtures under occupational or other environmental conditions was conducted by a team of specialists in the medical, toxicological, and epidemiological sciences designated as the Category I team. Draft material for the study report was reviewed by a second group of specialists designated as the Category i: team, and other scientists, leading to comments and suggestions for improvement which were incorporated into the draft report. The available body of scientific literature on health effects of pels in humans and in test animal systems was reviewed and analysed with emphasis on the relationships linking exposure, dosage to the biological target, and occurrence of specific health effects in the animal or human. Both the toxicological and epidemiological data from acute and chronic animal and human exposures were considered in generating assessments of the prob ability of occurrence of any specific health affect in humans. The results of these assessments are summarised below, separately Itemised under each major health effect. It should be noted that each assessment applies to the potential for development of that effect under the type and level of human exposures actually encountered in the O.S. during the past decades, with the most intensive integrated exposures having occurred in manufacturing operatlone that worm terminated in this country in 1977. HONS 025311 2 Yusho Disease Separate consideration was devoted Co the Yusho episode recogmrinq the special character of the human exposures co high conesncrat ions of nixturas of PC8s and chair charmsI degradation products, polychlorinatad dibenxofurans (PCDFs) and polychlorinatad quaterphenyls (PCOa). Several conclusions reached by cha Category I caaa ara of importance: (a) ic is impossible co stipulate whether any of the health effects observed is causally related to PCS exposure, since the ocher haloqenated compounds are also biologically active; (b) the dosaqe patterns axpertanced by Yusho patients and u.S. industrial workers (PCB-expoaed) are not at all comparable; the latter qroup experienced low level, lonq time period exposures primarily via inhalation and akin contact, with only minimal oral ingestion; (c) the similar health effects assn in Yusho patients from the Japanese and Taiwanese episodes of exposure to contaminated cooking oils point to the same type of toxic mixtures resulting from thermal heat ex changer action in tho two avants; (d) because of points ta)-<c) above, and tho fact that at least the PCDPa in tha Yusho oils are potentially more toxic than the pCBs on the basis of animal data, it la not possible to extrapolate the Yusho experience to prediction of acute and sub-chronic affects of commercial PCS mixtures in the human; (a) finally, with respect to predic tions of human carcinogenesis from the Yusho type of exposure the data are so incomplete that conclusions regarding any types and amounts of excess cancers attrlbuttable to those exposures have to await further definitive study. HONS 025312 -3- aajv Burdens, Metabolism, and Kinetics Some general observations derive from consider ation of the data on the storage, distribution, metabolise, and eseretlon of coeaercial PCB mixtures (with associated impurities such as the PCOFs) in mammalian systems. The dynamics of the pathways by which these processes occur in test animal models have been explored intensively and have been fairly well worked out. The variability of PCI effects with species of test animal model has been investigated for a number of important effects, and some general structure versus activity rules have emerged from these studies. There thus exists a conceptual framework, but not experimental data, for describing such phenomena in humans. Further, important data on the biochemical interactions of pels, poors, and metabolites with tissues have been obtained that bear dlreetly on Interpretation of toxic affects in these tissues. General Toxicity Tran acute, subehronic, and chronic studies of PCB affects in test animal models, a general summary of health affects encountered lncludesi (a) a low order of acute toxicity; (b) akin lesions; (e) affects on liver tissue that are generally reversible at lovor doses but that trend toward irreversibility with increased doming; (d) effects on the gastric mucosa; (e) offsets on the menstrual cycle and on reproduction; HONS 025313 -4- (f) porphyria; (g) effacts on tht kidney; and (Ml miscellaneous changes including hamatologic alterations, thymic atrophy, and lymphatic changes. There is a considerable range o species susceptibil ity to biological activity of the PCBs, with one representative comparison of order of decreasing activity being mink, monkey, rat. It is concluded that there is no basis for determining which species most accurately serves as a model for prediction of general subchronic/chronic toaicity in man; rathec, the judg ment of the moat suitable surrogate for man must be made indepen dently for each major health effect. Finally, it is noted that although there is some similarity between acute health effect phenomena produced by PCB eaposure in the monkey and human yuaho disease, it would be Incorrect to equate Yusho disease with pea intosieation because of the much more ccmples mlsture of compounds encountarad in Yusho oil than In a commarcial pea mlsture. Shin end Other Cutaneous Tleeuee Commercial PCBs ars capable of producing ekin leeione In the monkey model end in expoeed humane. Chronic edalniatratlon of PCaa to the monkey produces chloracne. In humans occu pationally espoeed to PCBs skin disorders including cbloracnc have occasionally been observed, these skin disorders have been shown to be reversible In some of the anlnal and human studies. WOKS 02531* -5- t.lvar Effects PCB mixtures in capable of generating important effaces on liver tissue in animal models. These effects include: (a) increase in liver weights; <b) histopathologic changes in liver including enlarged hepatocytes, deposition of fat droplets in tissue, and tissue necrosis and cell death: (cl enlargement of the liver: (d) the occurrence of adenofibrosis, a benign lesion; and (a) an increase in proliferative lesions of the liver, including increases in hyperplastic foci and nodular hyperplasia. These increases in proliferative lesions appear to increase in severity with Increasing degree of chlorination of the PCB mixture, as seen in the greater potency of Aroclor 12*0 over Aroclor 1254. The effects on liver tissue are gen erally reversible at lover doses but trend tovard irreversibility with increased dosing. However, in contrast with the positive findings of PCB effects on liver tissue in animal models, no significant effects on liver function teats have been observed from clinical data on human populations exposed to PCls in the occupational setting, further, there ham been no epidemiological finding of liver disease in O.S. oecupaelonally-expoeed personnel. Also, as noted in the Yuaho discussion about persons exposed to contami nated cooking oil with a PCI content of 1000 ppm, there was no finding of liver disease in the categories of either jaundice or hepatocellular Injury. HONS 025315 -S- Gastric lesions when teeted in monkeys and rodents. PCS* show species specrticity with respect to e toxic effect on the gastric epithelium, or stomach lininq. m the monkey, with Aroclor 1242, there is a mucous conversion of the gaetric epithelium that can bast bo described as a dysplastic growth pattern. This growth pattern does not constituta a neoplastic transformation. In rodents, PCM do not evoke this effect on the gastric mucosa. In human* occupationally exposed to PCM there are no clinical findings to data of gastric lesions, and no evidence of stomach cancer due to this exposure. Carcinogenesist Experiments! and Clinical A sixeable volume of aniaal experimental work has been dlractad toward chronic studies in several speciesi the mouse, the rat, and tha dog. Thors are some areas of interpretation that are still under debate by the investigators concerned, but in ths opinion of the Category I taaa the following represents conclusions that can be drawn from presently available data: (a) the evidence on carcinogenicity is negative for gastrointes tinal carcinoma and bladder carcinoma in rata'and hepatocellular carcinoma in the dog: (b) soma studies have reported an increase in hepatocellular carcinoma in mice and rats exposed to commer cial PCM chronically, wboreaa other studies have afforded nega tive results. HONS 02531b -7 - With respect to the possibility of cancer linked to exposure of humans to PCBs, epidemiological studies show to date usmiiilly negative results for hepacoeeilular carcinoma, gaatrointtstinal carcinoma and all othar fonts of cancsr. There is a single praliminary study that purports to show an incraasa in aalanoma (skin cancar) In occupationally axposad paopla, but tha full data display and analysis haws not boon mads for this study, in contrast, in two larger and nora datailad studias, this finding has not baan confirmed; no axcass incidanca of isalanoma in axposad parsonnal has baan obaarvad. Retrospective mortality studias of PCS-axposed human populations hava not demonstrated a conslstant relationship between extant of expoaure and tha development of any par ticular type of cancer. The huaan studias in hepatocellular esreincaa are not coaiprehanslva, but to the extant that they have been developed tha results do not confirm tha projection of a risk for liver cancer based on tha animal studias. Some findings of increases in lymphatic and hematopoietic malignancies were below the level of statistical significance, and wars refuted by observations of changes in the opposite direction in other epidemiological studies. Evan findings of statistically signif icant differences between exposed and control populations with rsspset to tha incidence of rectal cancar in woman at one plant have net bean confirmed by observations in other studias. Tha variance in these findings points up tha important principle that tbe Standard Mortality Ratio (SHR) may vary widely in different MQNS 02531V -a- studies, end that undue emphasis should not be placed on the SNR found in one study unless it has been confirmed by similar findinqs in repeat or parallel studies. Reproductive Effects Experimental worlt with commercial PCD mixtures and animal models has been directed to the reproductive process itself, to teratogenesis in the offspring, and to possible fetotoxiclty. In most test species PCBs produce deletenoue effects on reproduction at high dosages. In the female monkey at relatively high dosages, difficulties are encountered m con ception, in implantation of the fertilized ovum, and in carrying the fetus to term. Similarly dosed, the male monkey does not transmit these difficulties to the reproductive process. In the human, axposed occupationally or otherwise to PCBs, there is in general no evidence for adverse effects on the reproductive process, although there are little data froai which to draw con clusions. In the very special case of Yusho exposure to high levels of PCBs and other polychlorinated hydrocarbons, the new born in significant proportion were pigmented, small, and showed a retarded rata of growth. However, this pigmentation disappearad six! the infants caught up with control population infants in total growth. The potential for PCB-induced teratogenesis, or produc tion of defects in the embryo or fetus, has been investigated in aeveral species of test animals. Host animal teats have yielded negative results when PCBs were administered to pregnant females during the critical periods for organogenesis. MONS 025318 9 Several posaibla axeaptiona eo this statsmwne might ba nottd. IB mica, a sinqla eonganar, 3,,3',4'-tatrachlorobiphenyl, in due ad- a behavioral detact ("vaitsing syndrome") that may ba related to an anatomical defect In the inner ear. PCB in mica ay produce soma delay in implantation. In rata, no groaa taratoiogleal changes wars observed, but soma alterations in tbyroid atructure or function produced by pcb administration sight fall under the definition of tarata. In dogs and in swine, no teratologlcal affects were noted at lowar PCB dosas; however at the highest doses of PCB in the feed, at which the daa suffers marked reduction in food consumption and is therefore nutritionally deficient, there are doee-related teratoloqieal effects in the offspring. In monkeys dosed with PCBe, there are no doee-related abnormalities in the offspring, but they are aaaller in else. Based on those observations, it is the Cate gory 1 team's conclusion that comaMrcial PCBs present no appreci able risk of teratogenicity in offspring of human females exposed under occupational conditions. in teat animals, Us. rats, dogs, and rabbits, PCBs are fetotoxie when administered at relativeiy high domes to the pregnant female. In the human, the only reported epidemiological evidence for fatotoslelty in exposed populations sterna from the unique yusbo event, in which causation may not be linked to KBs. HONS 025319 10 Mutagenesis Investigations of possible mutagenesis from acute or chronic exposures co cowurcul PCBs have shown negative results in * ssnss of ui vitro and i_n vivo tsst systems. Isolated bacterial teat systems (Ames til) and human lymphocytes in cul ture showed no evidence for PCB-induced mutation or transformation. With in vivo systems in intact animals: (a) cytogenetic tests for alterations of cell structures or for induction of chromosome abnormalities yielded negative results; and (b) both the mouse micronucleus test and the dominant lethal test demonstrated negative results. Incubation of human lymphocytes in culture with pCBs caused an alteration in glucose transport through the csll membranes. Thera is no significant evidence that PCBs are mutagenic in teat systems, and no reports of such activity in huaian populations. It is quite unlikely that commercial PCS mixtures would sxert mutagenic activity in humans. This conclu sion is consistent with the lack of axcass cancer incidence observed in PCB-exposed human populations. other Health Bffecta This grouping includes ensyma induction, immunocempstance, and porphyria. PCla indues mixed function oxidases (NPO) in the liver of test animals. The important issue is whether or not this process includes the specific induction of cytochrosM P-44S as a general property of ths PCBs, with ths added implication that same oxidase system is being induced that HONS 025320 u- eoul4 b# involved in chsaicbl carcinogsnssis. Ssvsral concluionfl wsr rtschsd with rcspsct to this issus: (*) th pro* doMirmnt timer, of comAsrcitl PCB* vs cytochrom* p-450 induction, not P-441; (b) coa*rci*l PCB* in th U.S. can contain up to bout 2 ppo ot PCors; and (c) tho poors can induct cytochrome p->44t. From chtst observations in anioal model systems and our Jud*me nt. it is concluded that under conditions of U.S. occu pational axpoaura to PCBa, nona oC tha Mro-inducing actions of the eoaaarcial nixturse will ba of toxicological significance owar tha lifatiaa of a PCB-axposad parson. with raspact to potantial PCB offsets on tneunacaepetanca in taat anlaal systaas, soara obsarvations ara parttnant to tha assasaaant of probabla hasard in tha huaan. it haa baan obaerrad in chicks that if tha PCI doaagas ara high enough, atrophy of tha aplenlc pulp and nocroals of the lyaphold syataa ean ba daaonatratad. siailar indicators of change in laaunocoapetance can alao bo produced in duckllnga, ales, and aonkaya as a conaeguanca of asaara change in nutritional atatua. High doeas of PCBa loading to narked reduction of food intake and utilisation can load to such changes in nutritional status. These eonalderatlons lead to two general conclusions relative to the PCB-axposad huoanst (a) as projectad free animal studies, if tha PCB dosage is high enough to load to general toxicity in tha huaan (a.., deereaaad food intake, fall in body weight, fall in weight gain), HONS 025321 12 immunosuppression nay be demonstrable secondary to malnutrition; and (b) at lower dos* levels, there is no likelihood of signifi cant immunosuppression. Porphyria, or deposition of porphyrin-derived pigments in liver and urine, has been observed in experimental animals such as the rat and rabbit dosed with PCBe. The effect has a delayed onset, and, especially in the rat, seems to take place by mechanisms dlffsrent from those employed by known chemical porphyria-producers in the human. It is concluded that, aside from the unique case of Yusho disease, no evidence has accrued for the occurrence of porphyria in populations exposed to pCBs even under hiqh level occupational exposure conditions. Ipldsmiology This section (XXI) of the study presents a separate, independent assessment of the recorded epidemiological literature and data bases on human exposures to commercial PCBs, and on the significance of the health effects attributed to these exposures. Summary points in this assessment Include the following: (a) mortality data, baaed on very small numbers of deaths, do not confirm a carcinogenic effect of PCBa in mam (b) data on human skin lesions in relation to PCB expoeures have shorn variability in incidence of this effect with geographical locus and with in creasing blood level indicators of exposuret (c) data from studies of liver ansymas and liver function suggest changes in one or more ensymes related to PCB exposure that are not associated HONS 025322 13 with liver disease and chit occur at levels below those at which chloracns occurs; (d) thsrs is frequently a positive cor relation between PCB levels and triglyceride levels in blood; and () epidemiological data on reproductive effects, hematology and immunology in humane exposed to PCBs do not suggest abnorsalities in these systems or processes. Buwan Occupational Exposure Levels Of the various effects noted in animal test systems, only dermatological effects, including some chloracns, have been clearly demonatrated in human populations at the dosage levels associated with occupational exposures. Table 1 summarises the nature and intensity of some exposures that have occurred to per sonnel involved occupationally with PCBs and the biological Indices that have accompanied these exposures, measured as PCB contsnt in blood and adipose tissue. Sines the risk to human health from even high level occu pational exposures has been shown by the studies available to be low. it may be concluded that much lower human exposure levels do not present significant risks. HONS 025323 mwiniia immi utni nmu UM Oft* 41*22) 11922) 4197ft) utm Uf (UUI -- 41*1) MU (1UU) 55SSfa?]3g,S /asgsjr tmma\ nUooIfmt iI ini r MUh*` im i-- k 4PCftto|.) 9ft- Jftft sift* in l 2ftft-17ftft w M m M- 42ft <-- U 11 Uft-aaa 1H M i mm ift ! is* toft. ' 41ft- Mi 42 Mi " MftUftl 41 24- Ml 179-12M ft.D.- 244 Vftft 2ft 14 12 U 44ft llft-IMft 20 Mft-llftft 40ft Tt.-I2ftft lH-- 4n1 L-in II- 29 L-244 H- *2 L- ft] U- 14 2li-1f4t12 b-Ml 21A-1U* Ift 44 2ft- 19ft IbI--2191? M-240B 10- 29ft ic'fl (7--I9liMft NRapi Mllmf* I Uft Mft-419 2*ft f*t'-"4 2-271 .1-19 HONS 025324 1 1 a mui* !< 17- 215 3414 L- 33 5- 52 a- 7- 74 L- It l- 52 L- 14 23- 53 N- 10 7- 17 13 L- 34 13- K 1- 10 L- 11 1- M N- t 4- 10 13 L- 33 3- 47 10 L- 33 12- 40 H- 3t 7-250 13 L- 33 !J- 53 0- 5- 35 L- 13 13- 42 N- t 3- 11 ni (Ml) Bm Mil UmaUa s^atrl r m-m am 40 13 vaa 15 377 00-1)13 300 41-470 31.4 1^)12 14.3 10- 10 jo 5.4 l.a-ji.a 5 1.4 1.0- 1.0 KB piama NiyWi M i^nMl u parts par QllUm liaeliriiK ame Mlaiifw Uaaa aalyiu ra sapaaaaaO u parts pac tUm , Panar ari Im^c jaa daoatop^Mc mmtai Uaaaaa Uaa Ua car atutaiiu p,p^iwi) -at. L" KBs --]4di WM Mas. pirn aam MOu IT KBa utrlucfe 5-OCfe ml fcMhar. pt M 4-KBa. HONS 025325 17 - l. INTRODUCTION A. Origin! and Methodology of the Study In August 1981, th! (Ira of consultants in toxicology. Drill, Frisss, Hays, Loom it and Shaffer, Inc., Arlington, Virginia, (DPHL3) entered into a contract with tha Edison Electric Institute (**1) and tha National Elaetrical Manufacturer* Association (TOM) wtaaraby OFHLS agreed to axaaina tha toxicological and epidemiological literature on polychlorinated biphenyls (PCSs) and provide EEZ and NEKA with DPHLS* independent, professional opinion on the huaian health effects of PCBs at varying dosages or exposure levels. TO this end, the principal scientific stadias and data coapilations available on toxicological and apldaaiological offsets of pels, aa ceaaereial sixturas and as pariflad slngla congeners, have boon rsviawad by a teas of ssiantista designated aa tha Category I teas. Members of tha Category I teas are Dr*. v.A. Drill, s.L. Frleas, a.a. Bays, T.A. boaaia, and C.S. Shaffar from OFHLS. Additionally, Dr. e. Matanoakl of tha Johns Hopkins university has acted as an independent aeaber of tha Category 1 teas charged with study of the pertinent epidoaiologleal literature on peas and their human health effects, leading to an independent assesaaent and evalu ation of tha probability, cauaallty, and reality of these offsets. Category I teas review of the aniaal and huaan data resulted In draft aatarlal on the relationships between PCI exposure and apeelfie health effects in test aniaals and in MONS 025326 13 exposed human populations. Further, where human data were Lack ing or incomplete, the Category I team members developed specific projections or opinions as to the probability of occurrence of certain health effects m exposed humans, based on the existing animal/human data bases. Health effect areas scrutinized in cluded: general toxicity; effects on skin and other cutaneous tissues; effects on liver; effects on gastric tissues; carcino genesis (experimental and clinical observations); reproductive effects including fetotoxlcity and teratogenicity; mutagenesis; Yusho disease and occurrence of cancer; and other health effects including enzyme induction, changes in immunocompetence, and porphyria. Or. Hatanoski's treatment of epidemiological obser vations constituted an independent section of the draft report. Draft sections from the Category I taam vers than re viewed tor content, conclusions, and opinions by the members of a scientific team of pharmacologists and toxicologists deslgnatsd as the Category II team Or. r.G. Standaert (Georgetown univer sity), Or. A. Alvsres (Uniformed Services University of the Health Sciences), Or. J.A. Thomas (West Virginia university), and Or. p.e. Enterline (university of Pittsburgh). Or. Cnterline was the prime reviewer of the epldemiologlcsl contribution made by Or. Hatanoeki. Comments and critique from Category II team members, singly and as a group, were then transmitted to the Category I team for consideration, leading to revisions and amplifications HONS 025327 19 t]Mt are in place in the final drafe of this study. Coauants airi suggestions from scientists representing the sponsors of this.study. eei and NEMA, were also considered. In the final version of the study, to the extent possible, a section on summary and opinion is appended to each dleeueeion of a potential human health effect attributable to KB expoaure. The primary responsibility for each of these eections is assumed by the Category I team, even though the con tent may have beneflttad from useful contributions by Category It personnel. B. Commercial KB Mixtures Polychlorinated biphenyls (KBs) are members of a class of nan-polar chlorinated hydrocarbons based on the biphenyl nucleus, in uhleh multiple chlorine atone are substituted on HONS 025328 20 either or both the primed and unprimed aromatic ring*. Certain individual members of the PCB family have baan praparad in a ralativaly pura atata, with substitution of ring positions by chlonna ranging from dichloro isoaiars (symbolizad as 2-CB1 up to tha nonochloro (9-CB) and dacachloro (10-CB) danvativas. Commarcially, PCBs wara marketed in tha United statas undar tha trada narna of Aroelors. Thay wara also aanufacturad abroad undar tha tradanamas "Phenoclor* and *Pyralene* (Franca). Clophan" (Canaany). and Kanachlor (Japan). Thay ara comprisad of mixtures of ehlorinatad biphanyls. Tha last two digits of tha u.S. coanaareial naaa danota tha parcantaga of chlorina in aach mistura, a.., Aroclor 1242 contains 42% by waight of Cl corraspondlng to an avaraga of approsimataly thraa chlorlnas par biphanyl molacula. Likewise, Aroclor 1234, Clophan A30, and Kanachlor 500 all contain 34% chlorina corraspondlng to fiva chlorina atoas par molacula on tha avaraga. Caaaerclally usaful mlxturaa of PCBs hava baan widaly dlstributad ovar tha world In tha past faw dacadas. usually in applications that hava pracludad axcasalva axposuras of uaar populations. Bouavat. bacausa of tha graat chaaical stability of thasa polychlorinatad aolaculas, thalr paraistanca in tha anvlronaant aftar accidantal ralaasa can ba langthy leading to poaslbla axpoauraa of paopla and biota In tha blosphara. Tha raaults of thasa axposuras, as wall as those of personnel occu pationally exposed to PCBs In the course of chaaical synthesis HONS 0253*9 21 alri manufacturing operations, are of great importance from the staitfpoint of potentially harmful health effects that might oceur on an acute or chronic basis. c. PCB Impurities Commercial PCB mistures are truly couples, containing variable numbers and amounts of congeners within a given family of compounds, and traces of impurities, all of which are poten tially tosie to hmeans and animals. Impurities that have been Identified in PCBs as msnufactured are polychlorinated derivatives of napthalene (PCNa), terphenyls (PCTs), methylbiphenyls. and dlbenaofurans (PCOPs). The occurrence of PCDrs is particularly noteworthy in view of the higher tonicity for certain congeners, relative to teas. It is Important to note that there are theoretically 1J3 pomslbla PCDP congeners, a few of which are believed to be highly tosie. While reviewing PCB toaieological or epidemiological data, a number of factors related to the actual material involved east be considered. The PCDP content of commercial PCBs variesi for Aroclors the reported range is 0-2 ppm of total PCDP congeners, for European and Japanese PCBs, the reported range for pear con tent is 3-20 ppm. The impurity levels can alao be affected by eapoaura to high temporaturee and oaygen. ror esample. hroclor 12*4 la converted to 2-]t PCDPs at 330-400 degreee C. These earns conditions result In the formation of polychlorinated gnaterphenyls (PCQs). HONS 025330 23 II. Yusho Episode In 1961 a mass outbreak of food poisoning occurred in japan, following ingestion of a cooking oil contaminated with PCM and other compounds, that aroused worldwide concern over the potential human health effects from exposure to PCBa. However, this poisoning, which became known as Yusho disease, differs sig nificantly in several ways from occupational exposure to PCBs in the united States so that data from the Yusho incident cannot be extrapolated to indicate the effects of PCBS in industrial situations. Secant studies of the rice oil involved in the Yusho poisoning show that the oil contained relatively large amounts of other chlorinated hydrocarbons such as pcors and FCQs (see Xuratsune et al., 1976; and Rayabuchi et aU, 1979). The rice oil that caused the diseaae vaa found to contain about 1000 ppm of PCBs, 9 ppm of PCDTs, and 1000 ppm of PCQS; the amounts of the latter two claaaaa of chlorinated hydrocarbons in the rice oil are higher than in the Aroclors used in the United States. Rayabuchi reanalysad the intake data for the Yusho patient, and calculated that the average intake for the mean latent period was PCB 466 eg, PCDP 2.5 mg, and PCQ 439 mg; the smallest Intake by a patient was estimated to be 111, 0.6, and 10S eg respectively. KB concentrations in the tissues of Yusho patients ere much lower than those of asymptomatic individuals with body MOWS 025331 24 burdens of PCS* resulting from occupational exposure. Furttlr, PCS fraction* of blood, cimuii, and braaae milk of Yusho patiant* yielded gas chromatographic pattarns showing a largr amount of late-eluting peaks than do PCB fractions of tiasuas of individuals subject to other types of PCB exposure (rods and Masuda, 1975). These patterns have never been obeerved in indi viduals Ihuun or animal) exposed to PCBs in other situations. They are unique to Yusho disease. Also, PCDrs have been found in tissues of Yusho patients. Further evidence for the uniqueness of the syndrome in humans exposed to the Yusho oil is furnished in two recent studies. Hayabuchl et al. (19(1) in follow-up studies on these patients five or more years after the poisoning found signifi cant positive correlations for the years 1973-197S between blood concentrations of PCBs and the total amount of rice oil con sumed, but not with the dosage of rice oil conaused per unit of body weight per day. Kasbiaoto et al.. (1911) found that Yusho is quite different from ordinary KB toxicity in the sense that, even 12 years after the first outbreak, KQs have been found in the patients' blood and both KQs and PCDP* have been found in their tissues and organa. It is obvious from this brief review that Yusho cannot be considered a aodel to reflect the possible effects of the PCB exposure in aan. Although such can be learned from the Yusho HONS 025332 25 Incident, it would Be misleading to attempt to interpret the observations on Yusho patients as valid signs and symptoms of overexposure to PCBs or to attempt to quantify the possiBle effects of PCS exposure based on Yusho disease. h. Yuetio Disease Yusho disease is characterised by the ingestion of a mixture of chlorinated hydrocarbons containing PCBs in large amounts over a relatively short period of time (latent period from start of ingestion to onset of the disease averaged 71 days), in contrast, the studies of PCB exposure in workers in the united States have been concerned with the possible effects of chronic exposure to small amounts of PCBS through inhalation or akin contact. The principal signs of Yusho disease are skin conditions such as senators eruptions, pigmentation of the akin and naila, and hypersecretion of the meibomian glands. Chloracne and hyperaeerstion of tha Meibomian glands are believed now to be caused predominantly by PCDfs. Hyperpigmentation of the skin is observed rarely, if ever, in human populations with heavy occupational exposure to primarily teas. Tha actions of poors appear to differ in several ways from those of the PCBs. Kuratsune at al. (1*70 showed, for example, that tha liver appears to concentrate PCOPs selectively relative to PCBs. It was also found that relative to PCBs. the concentration of pCDPs was about 250 tines higher in the rice oil than in unused Kaneehlor-400. Additionally, the PCOPs appear to HONS 025333 26 - be highly toxic, at least in the rabbit; a single oral dose of 0.5-1 mg/kg of tha tri- and tatrachlorodibanzofurana cauaad 19aevere_and often lethal necrosia in the rabbit (Hofmann, J|, Bauer il., 1961), B. Tuaho Oisease and Liver Function In view of the effect of PCBe on the liver of the rat and the highly toxic action of Poors on the liver of the rabbit, it waa anticipated that the Yusho patient would have severe liver damage, but such has not been found. In their review of Yusho disease, Kuratsune at al. (1972) list "the subjective symptoms of Yusho aa stated by 1B9 patients* i Lit report jaundice. Data to confirm the patients* subjective symptoms" are not provided, nor is the presence of this "symptom" confirmed by other statements of clinical findings. Prof. Urabe (Chief of the Study Group) did not list jaundice as a sign or symptom of Yusho disease and tha diagnostic criteria adopted in 1972 do not make reference to jaundice or the need for a liver function test in these patients (see Kuratsune at al., 1970. The following two papers on Yusho disesse and liver function are in Japanese and the brief stumsary given below is taken from the report of Kuratsune at al. (197S). Okumars and Kataukl (1969)i They examined 24 patients soon after the onset of the diseasei HONS 025334 27 (i) There were no objective sign* of liver disorders; (ii) No patients war* jaundiced and only three had paipa&le livers (in one patient examinations of a liver biopsy showed marked hypertrophy of the smooth endoplasmic reticulum). Okunara 11972): Liver function casts were performed in 38 Yusho patients with various subjective symptoms, kn increase in lactic dehydrogenase IU3H-S) and in thymol turbidity titer was observed in some of the severe esses, 'but no definite evidence for liver disorders was obtsined.* In a follow-up study of 121 Yusho pstients the mean Serum bilirubin was 0.48 og/100 ml compsred with 0.87 mg/100 ml la eontrol patients (Blrayama at si., 1874). The difference vee statistically significant and the authors suggest that there asy be accelerated bilirubin disposal from the blood. It nay be concluded that the Japanese findings do not provide evidence for the development of hepatocellular injury or jaundice in patients with yusho disease. C. Yuaho aleeeee and Carcinogenicity Urabe and co-workers (1879) report that SI of 737 Yusho patients in the Fukuoka district had died and they list the cause of death for 11 of the patients. There were 11 deaths (lS.4t) frea neoplasms which they state is substantially higher than the H.lt rate that is 'the mortality rate from neoplasms in the HONS 025335 - 28 saow prefecture this year." A further analysts is not provided. The following malignant neoplasm* were listed as the cause of deatrr for the 11 patients with cancer. Anatomical Site No. of Cases Stomach Cancer 2 Stomach Cancer a Liver Cancer 1 Liver cancer a Liver Cirrhosis Lung Cancer 2* 2* Lung Tumor 1 Breast Cancer Malignant Lymphoma 1 _2 TOTAL* 11 *Autopsied information on age and other relevant epldamlologlcal data are not given, and even a tentative conclusion regarding Yusho disease and any malignancy must await further analysis. HONS 025336 - 29 - III. Body Burdens. Metabolism, and Kinetics A. Introduction The degree of chlorination (two to 10 atoms of Cl par pO molecule) and tha positions of tha ehlonna substituants on tbs biphenyl ringe both arart a profound influanca on how mam>Hllin aystasa handle any given PCB nolacula. Tha decree and position of chlorination play a major rola in determining tha pathways for sstabolisn and elimination of tha parent nolecules nd chair metabolites by aniasl models and tha huaan. These Structural factors also bear on lipid solubility of tha molecules, and therefore influanca to sosm extant the kinetics of PCB tissue distribution and storage. The following sections deal with the present state of knowlege on those PCB handling mechanisaa em ployed by anlaal models and tha huaan. recognising that there is a strong linkage in tha dynamic processes beginning with exposure and ending in excretion. Thasa topics will be treated in three groupings! (1) distribution and storage of PCB metabolites in tlssuasi (2) metabolism and excretion) and (}) kinetics or tha dynamics of PCB turnover in anlaal nodels and the husun. fraaantly, some generalisations emerge with regard to PCB struc ture versus reactivity relationships and mechanisms for handling KBs in test animal systems that make reasonable extrapolation to potential events la the human organism possible, even when direct evidence for actions of a glvan compound or PCB mixture la human populations is not available. HOMS 025337 30 Additional attention haa baan directed to available information on the aetiona of PCDFa in animal nodala and tha hunan, and to a variety of biochaaical affacts raeordad for PCBa and thair laatabolltas in maaaalian ayiteaa. PCOfa may ba contaminanta of aoaa caaaereially uaed PCBa. although 10-20 ppn of thaaa cantaalnanta have baan found in PCBa aanufaeturad in Europe and Japan, only traca aaounta on tba ordar of ona or two alcrograaa of total PCOP conganari par graa of PCI have baan raportad in tha American aanufaeturad aiatura Aroeior 1254 (Bowea at al., 1975). B. PCB Olatributlon and Storaaa in Tlaauaa K eonaidarabla body of lltaratura aaiata on atudlaa of tha tlaa dapandanca of tha diatrtbutlon, aoveaent, and atoraga of PCBa and their aatabolitaa in eha tlaauaa of erpariaental aniaal aodala and of humane, following eapoaurea to chlorlnatad biphanyla aa pura caapounda or alaturaa. in eaat aniaal aodala ualng unlabalad or radlolabelad (!*C or 3| PCBa, con trolled axpoauraa wara ganarally by tha oral routa (atoaach tuba, or in tha faad) or by intravenoua Injection, followed by atudy of the changing dlatrlbution of the agent and ita aatabo litaa in the circulating blood, in tlaauaa, in bile fluid, and in aaerata aa a function of elapeed tlaa after deeing. In tba huaan, aapeeuraa with reeultlng body burdene of PCBa were gan arally of the aubchronic typa ateaalng either froa aaaalve polaonlng aventa, aa in tba Yuaho aventa, froa chronic occupational aapeeuraa in air and via akin contact, and via PCB contaainanta in air, water, food, and aurfaca contact* in tha aablent. Humane HONS 025338 - 31 - also have been exposed to PCBa occupationally in tha chaaicn manufacturing pcocaaa, in tha manufacture of capacitora, and in 12a manufacture and repair of tranaformars. Until recently, Peveral microscope immersion oils contained 10-40* PCBa as AroBlor 1234, causing potential exposures of students, pathologists, plcroacopista. etc. i the degree of expoaure is low and the pene tration through akin from these products may not be as extensive So in large scale manufacturing procasees. In human atudiea, PC8 distribution and storage in readily obtained tissues was generally followed epidemlologically la expoeed populations by monitoring levels in blood, soawtiaea la Bother's milk as a function of time and sometimes by measuring, teas In adipose and other tissue samples obtained clinically and post sortam. Animal model assults The picture of distribution and storage of PCBa and thalr metabolites In tissues over tins has baan developed moat completely from controlled does experiments in animal models. Osnarally, rats and alee were the animals of choice for this work (Surse at el., l7i Gayer at al., HIOi Quinsy at al.. 1*7B| Kattewe and Anderson, 1*75i Morales and Matthews, 13731 Albro and riahbein, 1*72i auras at al., 137), but the dog, as ell as the monkey, has also been used (Hsu at al., 137 Sa > Hilling at al., l*79t Slpea at al., 1110). Tha dynemica of tiesus distribution vary with different iaosars and congeners, and depend In lirfjt Miiufc OB vhtthtr or bob tho opodflc Kl HONS 025339 32 molecular structure allows rapid macaboliam and excretion of polar metabolites via blla, feces, and urina lulling e al., 1974; Safa at al., 1975; Sipa* at al., 1990; Matthews at al., 1979; Guiney t al., 1979; Guialian, 1979) or slower eetobo11am with ratantlon of parent compounds and matabolitaa in tisauas. AS will ba discussed in the following section, metabolic transformation in the liver is particularly facile for those PCBs with lower chlorine content (2-CB through 4-C9, .e. 2-4 chlorines per ?CB molecule) and with adjacent ring carbon atoms unsubstituted by chlorine atoms {Matthews and Tuey, 1990; Sundstroe et al^., 1979; Rato at ol^., 1990; Jensen and Sundatreo at al., 1974b; Ghiaauddln et al., 1974; Matthews et al., 1970). for many pea molecules in Mich metabolic transformation and excretion is not excessively rapid, the dy namic distribution of parent compounds and matabolitaa in tis sues following dosing has been studied carefully (Mlsutani et al., 1900; Safe et al., 1975; Sipes it il., 1990). The fol lowing generalisations appear valid In animal models tor struc tures ranging from 1-CB to 4-CB and higher. Pint, the PCBs are readily absorbed from the gut following oral administration and appear rapidly in the blood stream IAlbro and Plabbain, 1972; Berlin et al., 1975; Cbaa and Matthews, 1974). Within minutes to hours, the naterlals largely clear from the blood and accumulate in the liver and in nusela tissue (Berlin et al., 1975; Burse et al., 1974; Chen and Hatthane, 1974). However, traces of PCBs have been found in the HONS 025340 33 blood of humans. probably by redistribution froa other tissues, years after exposure. The liver is the primary locus for metab olism of the PCBa, especially for reactive species, leading to ixtures of parent molecules and metabolites that then either translocate to other tissues or are excreted by both bile/gut. lumen/feces, and urinary pathways. As translocation tram liver and muscle occurs in the rodent model and other species over time periods ranging from hours to many days, the ultimate depots for major amounts of the non-polar PCBs and their polar natabolites appear to be adipose tissue and skin (Berlin et al., 1975t Hansen, 19791 Gulney et al., 1978; Burse at al.. 1974). Tbs general distribution pathway in rodants nay therefore be characterised as sequential migration froa gut and bloodstream entry points to liver and muscle tissues, in a rapid process, and thanes to depot storage in body fat and skin. Mien the PCB structure is such as to permit ready aatabollaa to polar hydroxy, dthydroxy or dlol derivatives, the aetabolic process aay be closely linked in tlae with excretion of ths metabolites (Jansen and Sundstroa, 197i Lay et al., 1979i Matthews and Tuay, 1980) Matthews tt d,, 1978 Matthews and Anderson, 1978), Animal studies on urinary and fecal ex cretion of PCSs (Guselian, 1979i Matthews and Anderson, 197Ji srlln st al., 1975; Lay at al., 1979i Chen at al., 197ft Van tiler at al., 1979), and ratss of elialnation of PCBs froa liver into bile and than into gut/faces, show that the larger HONS 025341 34 proportion of excretion in rodents is by focal elimination (Kato at al.. 19*0: Lay at al.. 1979; Chon at al., 1976; von Hiller ot l.. 1979; Chon and Matthews, 1974) of polar metab olites, mostly glucuronides, eliminated via the bile. Tho dynamics of dlotribution and elimination ot PCBo in two monkey opacioa have boon otudiad (Heu. ot al.. 1979a; Sipoa at al., 1900; Hau at aK, 197 5B), and are found to follow a aimilarly eoaplox pathway, but with widar tleaua dlotribution ultiaatoLy than that loan in tho rat. In our opinion, thia difference nay ralata in part to the ability to analyse aoro tiaauae in larger aniaala. With fat tioauoo presont in only aaall proportions in tho Infant Rhesus aonkay, tho ultiaata depots included bone narrow and the adrenal 9lands, in addition to okln Ulou at al., l!7Sa). Long-term studies involving chronic adalnistretion of PCBs at low doaeqe levels to animal models for significant tractions ot their lifetimes, with determinations of total bur dens and tissue distributions achieved over time periods of one to two years of ingestion, are lacking. Human Bode Burden hssults from Epidemiological studies experimental data on body burdens and tissue distribu tions of PCBs in humans as a result of precisely-measured in takas are not available. However, there are several population sectors tor which exposures to PCBs can be at least roughly esti mated, and from which tissue samples (blood, subcutaneous and other fatty tissue, etc.) have been taken to obtain indices of HONS 025342 35 l^y burden. These sectors include: (1) humans occupationally exposed to peas during years in which they were employed in manufacturing processes (Karppanen et aU. 1972; Hasegawa at al., 1972; Kitamura at al., 1973 ; Ouw at al., 197*; Pisehbein at al., 1*79; Wolff at al., 1981; Maroni at al., 1981a, b; Smith at *K, 1981a, 0; Chase et al., 1981); (2) humans accidentally poisoned by fCBa ingested in contaminated foods, as in the Yusho experience In 19(8 and in corresponding ingestions of contaminated rice oil in Taiwan (Chen, 1980; EP8 summary, 1980); and (3) humans living in areas in which PCBs have somehow entered the food chain or water supply in measurable amounts, leading to long term, lox^level body burdens in adults that may also be present In the human milk supply for transmission to infants (Humphrey, 197}, 1910; Ruwabara at al., 1979a; Ruwabara at al., 1979b; Mm and Oaviea, 1979; Watanaba aU, 1980). in additional source of eapoaure that is more difficult to characterise quantitatively sterna from the espoouro of families to contaminated clothing of PCI workers. Survey work has boon done In all of these popula tion sectors worldvlda. The results are sketchy, but tentative qualitative generalisations can bo drawn. Blood or plamaui levels of PCBs aro moat readily followed in potanttally exposed population data using highly amities analytical techniques such as gas chromatography and ass spectrometry. Por occupationally exposed people (fllOSH, 1*77; balth at al., 1910a) values ranging from 10 ppb up to a naxloum of 3330 ppb havo boon observed, with the additional HONS 025343 36 qualitative findinq from Japanese references that the haif-nf* for disappearance of PCS* from Olood following cimtian of exposure rang** from three to 30 months. PCS olood level* were higher with increased duration of exposure. For Yusho victim* in Japan, with Olood samples taken five to seven years following ex posure to PCS*. in the 1973-1375 tin* frame (NIOSH, 1977) values In the ranqe 3-3 3 ppb were observed. Enhancement factors over control group levels (mean, 3 ppb) as great as 10 were calcu lated, but the observed blood levels were still nuch lower than levels found in Japanese capacitor workers. It is of interest to note the observation of Humphrey (1*75) on the very slow clearance of PCla from the tissues of humans exposed by eating fish. In general populations, blood plasma or serum levels of PCU In the range 5- 29 ppb have been found IHXOSR, summary p. 30. k current and well-documented study of body burdens of PCla In persona employed tor many yeara in capacitor manu facturing (Wolff at al., 1111) Is of special value from the standpoint of its correlations of tiaaus concentrations with estent of exposures. with highly chlorinated PCla (H-PCla), plasma concentrations of 1-54* ppb In exposed personnel corre lated with total accumulated exposure time. For the less highly chlorinated (CM (b-PCBS), plasma levels In tha range (-2330 ppb correlated better with specific tasks of Individuals working with these z-Ch to 4-CS molecules. Also observed in this study was a correlation of levels in plasma with levels in adipose MQNS 0253V* 37 tissue for cl> class of PCBe, With H-pCBs and l-pcbs taken as Boparate classes, and an overall adiposc/plasma partition coef ficient of 190. The lavala of PCSs and metabolites in subcutaneous fat In huaans haws also baan survayad in general populations (niOSH. Jp77), in groups such as Yuaho patiants with high exposures, and in boss occupationally exposed individuals. For tha general papulation, lavala in fat ranqa fro* lass than L ppm to greater than 2 PP<*. For Yuaho individuals, alavatad fat PCS lavals in tha ranga 13-75 ppai hava baan obsarvad, corraaponding to paak enhanceaant factors as high aa 10 ovar tha population at largo. It Should also ha not ad that tha spactrua of coapounds in huiaan tlaauaa is not nacaaaarily idantical with tha spactrua in tha alstura to which a givan papulation was axpoaad (Kuwabara at al.. 1971a). Ranges of adipoaa tissue PCB lavala in occupationally axpoaad individuals have baan reported as 1(0-12} ppa (Karppanan at al., 1972), 1-12.0 ppa (Chase il., 1911), and 2-271 ppa (Holff at al., 1901). Spocial surveys hava baan aada of PCI lavals in tha silk of lactating buaan aethers (Nos and Oaviaa, 1979 Matanabe * al., 19S0| BI0S8 auaaary) and of lavala in huaan aabryonic *Bh fatal tissues resulting froa in utaro transfer froa yuaho fasalas (MOM, 1977). Huaan silk saaplas with values of PCBs the range 0.000-0.1 ppa hava baan obsarvad. Clearly, eonaaatrationa in silk are higher than those in blood priaarily ****uae silk is rich in fat. Organs froa tha aabryonic and HONS 025245 38 fatal tiaaua diaplayed PCS lavala in the range 0.002-0.750 ppa for whole tiaauee, with fat darivad iron thaaa organa yielding levela in tha ranga 0.04-1.14 ppm. C. PCB Hetaboliaa and excretion Aniaal aapariaanta involving expoaure By faading, in tubation, or injaetion of purified PCB iaoaara in taat aniaal nodala hava yialdad aoaa iaportant ganaralizationa on tha aachaniaaa aaployad by aaaaalian apaciaa to aataboliza PCBa to mora polar derivativaa, and to azerata both parant caapounda and Mtabolitea. Bag inning with raady abaorption Cram tha gut and tranafar to circulating blood, or with direct injaetion in to tha bloodatreaa, a given PCB Molecule ultiaataly reaches tha llvar where major natabolic actIona are initiated. The proceeaaa of aetaboliae and aacratlon aa a raault of thaaa actiona are couple*, and dependent on the eolecolar atructure of the PCB. Canaral featurea of thaaa proceaaaa include tha following point!i (1) variable aaounta of PCS eetabolitae are excratad via tha facaa after delivery to the gat luaan via tha bile flow pathway. Unchanged PCBa can occur and be diecharged in allk. Relatively leaver aaounta are excreted aa polar Mtabolitaa in urine than in feoaa in Met aniaal nodela (Kate at al., IBSOt Lay at al., lPTPi Chen at al., l7*j van Hiller at al., 175 Chan and Hetthewe, 1174). (2) Mtabolitaa are fonaad in pattarne that differ quantitatively or qualitatively aaang naneallan apaciaa. They are generally foxMd by oxidative proceaaaa that are thought 39 to involve an arena oxide formation that results in monohydroxylation, dihydroxylation, hydroxylstion and methylation, or dial formation accompanied by partial reduction of an aromatic ring <Berlin et al., 1975; Lay _t al., 1979; Lucier et al., 197*; Hilling et al., 1979; Sundstrom at l., 197*; Gardner et al.. 1973; Chen al., 197; Matthews at al., 197*; van Miller at el., 1975; Hsu at al., 1975a; Hsu et aJL., 1975b; Burse at al., 2971) Evidence also exists for dechlorination of a PCB in the process of mtabolisa (Kato at al., 1910; Hutiinger at_ al., 1974b). For some PCI structures, the process of oxidative eetabolism may be closely followed by excretion via the liver-bilefeces pathway (Chen and Matthews, 1974). (3) Compounds with lower levels of chlorination I2-CB to 3 or 4-CB) generally undergo metabolism more readily, and faetar than the more highly chlorinated PCBs. The nore highly chlorinated PCBs nay persist in tissues for years because they ere not metabolized. Indeed, 10-CB is virtually inert. (4) In the case of metabolism by oxidstlve pathways, the moot facile process involving formation of hydrosylated products occurs when one or both aroautic rings contains adjacent pairs of ring carbon atoms (ealled vicinal ring atone) that ace oamebstituced by chlorine atoms. In the absence of unsubetltutad vicinal positlone, direct hydroxylation can occur in the ring, bet with greater difficulty (Gayer at al., 19B0; Matthews and Tesy. 19*0). HONS 025347 40 - The importance of vicinal unsubstitoted positions an PCB rinqs in facilitating oxidative metabolism in the livar it explained by a mechanism chat involves an arena oxide interne* diata (Daly at al., U72). whan aithar or both of tha vicinal poaltiona contain cnlorina. raaction rataa will ba lower, but tha machaniaa ia not antiraly ruled out. Additional aolacular rearrangements, including tha so-called Nth (National tnatitutas of Haalth) shift of a ring aubatltuant (Daly at al.. 1473), nay ba involvad. Laaa is known about nachantaas of diract anxyaatie hydroaylation that do not procaad through an arana oaida intermadiata. (51 Hydroxylstad aatabolitaa of tha PCa and thair conjugates will generally display diffarant ordars of toxicity than thoaa shown by tha parent aolecules. () A general point of intarast with raapact to PCS aatabolitaa lias in tha obaarvatlon that they are usually aore polar than thair parent eeapounda. Conjugation of tha hydroxy and dlhydroxy aatabolitaa as glueuronides or sulfates can occur, loading to polar conjugates that can readily ba axcratad. Tha polar character of aatabolitaa, in contrast with tha non-polar HONS 025348 1 - CharactsriJCicx of Che atctinq PCBs, can lead to differing dis tribution, storage, and excretion patterns for tne two classes Of chemical compounds. Polar metabolites are not readily par titioned into fat or reabsorbed from the urinary or gastrointes tinal tracts. Therefore they are excreted relatively rapidly. D. PCB Kinetics Profiles of the dynamic growth and decay of PCB/metabollte concentrations in each key tissue can be drawn from controlled toxicological experiments. The distribution of a given KB and its metabolites in the blood, tissues, and excreta of test animals is followed as a function of time after administration. Tissues are viewed as body compartments into which materials are delivered from the arterial blood supply, in which some metabolic processes may occur, and from which materials are delivered into the venous drainage systems. * collection of such compartments communicating with the blood supply and controlled by rates of (low through the compartments, with postulated equilibration of any given chemical in a compartment with its venous blood (low, constitutes an appropriate nodeling system for correlating PCB distribution, storage, metabolism, and excretion kinetics in an animal ovsr time. This multi-compartment model has bean employed by Matthews and co-workars and othars (Anderson at al., 1*77> Bungay at al., 1*7*> Tuny and Matthews, l77j Luts at al., 1*^7), to sort out the kinetics of specific KB isomers in rodent models. The PCB administration can be either direct MOWS 025349 - 42 - injection of a PCB into the blood circulation, or it* absorp tion into blood from the gut aftar feeding or intubation of the-compound. excretory pathways ara via tha liver/blle/gut routa or tha blood/kidney/urinary elimination systam. Tha succasa of a modal aquation aystaa in fittinq analytical data tor a <31 van PCB and predicting tha shapa of ita coneantration varsua tima curva for aach organ or compart ment dapanda in larqa maaaura on aavaral factors, includlnq: (1) tha asaiqnaant of suitable valuas Cor distribution coef ficients of PCB compounda in aach coaipartaant> (2) tha dif ferential blood flow to various organs) and (3) the clearance from organs and tha body. This fittinq process has now bean carried out for a number of PCBs for which kinetic data ara available (Anderson at el., 1*771 Chakraborty, 17). Tha qoodneas of fit of the model to each aet of PCB kinetic data availabla attests to the validity of tha aaaumptlon that matarlale partition at equilibrium between blood and tisaue ac cording to purely physical properties involving solubility parameters of tha chemicals. (. Miscellaneous Biochemical effects of PCBs Studies of the actions of PCBs In animal models and hiaane asposed to these chemical aqents accidentally or In the occupational setting have revealed a variety of biochemical at facts on mammalian organlsma. Some, such as alteration of drug aotaboliao by virtue of PCB induction of microsomal oised function osldaaas (HPO), are treated elsewhere in this documen HOHS 0*5350 43 effects appear to be unrelated to MFO actions, and have ^9 detected in the course of acute or chronic toxicological ^periments with laboratory animal models or epidemiological ^rveys of exposed human populations. In an animal study (Bastomsky et aK, 1973) aimed at robing the previous evidence on reduced serum bilirubin levels ^ ruaho patients, it was found that Aroclor 1254-treated rats mowed Increased liver microsomal protein, as expected, but with 0 significant elevaelon in liver bilirubin UDP-glucuronyl trans ferase activity that could have accounted for reduced serum Avels. Other studies (Grote at al., 1975; Cake et al., 1979) tee shown enhanced levels of this transferase activity. At pres- Bet therefore, the mechanism underlying the hypobilirubinemia 1 Tuaho patients remains speculative. Prom epidemiological studies of yuaho patients (Strik, 1*79), a rather general biochemical finding has bean the obser vation of porphyrins in urine and porphyrin accumulation in liver, as a result of asposura to chlorinated hydrocarbons Including tCSs. chronic hepatic porphyria is the designated condition, sblch increases with exposure and can thereforebe taken as an Indicator of the extant of PCI exposure, Isswhere in this text (section xi). porphyria is discussed A biochemical factor that may bear on the toxicity ot Kba in certain sensitive human populations, e.j., fetuses, neo- stes, enxyma deficient adults, etc., is related to the ability to **crsta the toxic phenolic metabolites rapidly and efficiently. HQHS 025351 - 44 - Sine* a cannon roue* of excretion involves preliminary conjuga tion of eh* phenolic hydroxyl groups with glucuronic acid in eh* oody, or sulfae* conjugation, it has b**n pointed out (Calabrese, 1977b) that human groups that are biochemically deficient in the ability to conjugate could be predisposed to accumulate PCS* and metabolite* because of this deficiency. * more serious consequence of altered liver capability would be a reduced capacity to deal with arene oxide intermediates effec tively. An interesting biochemical defect in human lymphocytes has been studied (tea and Park. 19(0) that can be attributed to direct action of PCI* on these white blood cells. Por both human lymphocytes and monocytes, it has been found that incuba tion of the calls with Aroelor 1234 In culture eedlua causes a decrease In their ability to take up glucoae from the medium. A non-motabolixabl* analog of glueoee, 2-deoxyglucosa, was used to detect the biochemical defect, which was attributed to PCS exposure but which say well be aora general for any organic chemical that concentrates in the fat of the call wall. It may entail direct action of PCSs on an active transport process in cell membranes. In this regard, liver glucoae-S-phoephataae na been found to be inhibited in rats fed various Aroelor mixtures (Utterest et al., 1*72). The processes by which PCS pretreetment Influences rates of protein and nucleic acid I AHA) synthesis and turnover in rat liver tissues have been investigated systematically HONS 0*53*2 45 Ufcrbonne, 19794# b* c, e), using radiolabeled substrates. u fp clear that Uvir tissue, iri vivo and _in vitro, responds to pS treatment (Phenochlor 0F6) by increasing the protein synehssis Is liver microsomal erections in a process that is both age and ex dependent. Concomitant increases in liver (at are also --an in vivo, as well as changes in levels of WA synthesis in parlous liver fractions and increases m liver weights. From UM turnover experiments in rats, it is also observed that micro somal membrane protein metabolism is enhanced by ingestion of Pbenochlor DP6. Some further biochemical effects of PCB exposures on human are seen in workers occupationally exposed to these tfttmieals for extended periods of time (Smith et el., 197$). fbm findings, as yet unexplained In terme of requisite doeages or underlying mechanisms, srs that! (l) the circulating tri glyceride levels in blood plasms are eleveted for exposed workers over controls, but ere still within normal Levels; and (2) the circulating levels of high daneity lipoprotein are lowered in --posed groups of workers. Another biochemical effect seen in FCB-treated rats is worthy of nots# slnco it rolatoo to an impairment of exeretion ot an Important drug and its motabolieos (Schmoldt et al., 1979). Zs the Hlstar rat pretreated with Aroclor 124S, the drug dlgitomin and its metabolites were blocked to a eignifiesne degree from exeretion via tho bile. The results suggest thst the 025353 HONS 46 block*?* i* due at leaat in part to * pCB-induced impairment of th* cleavage of on* of th# auqar* fro* digitoxin. Finally, th* action of KB* laid in? to induction of nixed function oxidaa** (tiro*) in th* liver, with elevation of aaaociated cytochrome* P-450 or P-44S, haa potential conaequenee*. The** are diacuaaad elaewher* (aectlon XI). F. Some Obaervationa on Polychlorinated Dibenxofurana The PCOfa are of apeeial inter*#t ainc* they are known to be highly toxic In their own riqbt, and the degree to which, *a contaminant*, they add to th* potanciea of PCB mixture* in production of adverae health effect* in animal model* and human* haa not been fully evaluated. However, toxicological atudiee in animal* with PCDra containing one to four or nor* Cl atom* par aolcule (Morlta and Olahl, 1977) Soldateln at al., 197(i Veerkamp at al., 19*1) have ahown that th* PCSPa are qualitatively quit* almilar to their atructural PCB analog* with reapect to propertiaa of tlaaua dlatrtbution, mataOoliaa, and excretion, in the aouae, tba haavily chlorinated laemera locallx* in liver, apleen, and fat (Morlta and Olahl, 1977), with a half-life for clearance from the body of about two weak*. in th* rat, matabollaa oc cur* by oxidatlv* pathway* leading to mono- and dlhydroaylatad derivative* (veerkamp *t al., 19*1), with a wide variation in ring poaltlon by tba hydroxy function among th* lower chlori nated PCCP*. The oetachloro derivative yield* no metabolic product* in tlaaua* or excreta (veerkamp at al., 19(1). In HONS 025354 47 the chick (Goldstein et 1., 1976), the 2,3,7,8-tetracnlorodiOsnsofuran ITCOF) has scan shown Co be relatively poor m entyme induction. However, Goldstein at al. (1979, 1979a) hava shown that 2,3,7,8-TCDF is a potant inducar of cytochrome p-450 and aryl hydrocarbon hydrosylata. Soaa important data on PCor matabolisa and aacration in tha human wara obcainad IRappe at al_., 1979) by analysis of llvar tlsaua from two dacaasad patlancs in tha rusho disaasa group in Japan. From tha diffarancas in PCDF structural relatlonahipa in tha contaminated rlea oil and in tha PCOr fractions Isolated from tha livers, infarancas could bo drawn with respect to PCDF structure (all containing four to sis chlorine atoms par oolacula) retained by the liver versus those that had disappeared from liver by processes of aatabolisa/eliminatlon. In striking psrallelisn with KB disposition in oaaaalian tissues, it was found that none of the PCDFs retained in liver had two vicinal unaubstitutad (by Cl) positions in cither aromatic ring, apparent ly, all such oolaculas had baen sufficiently susceptible to osidatlve metabolism to be hydromylated and sseratad from liver in the blla. The above observations are not to ba taken as allinclusive with respect to the body of Information that must be developed in the torlcology of the PCDFs. This class of com pounds, even at low contaminant levels, is an important contrib utor to the total spectrum of tonic effects from commercial pcb statures. MOWS 025355 48 - G. Summary and Opinion Son* general reflections end opinions can reasonably be drawn from the previous discussion regarding the use of animal-derived biochemical and Kinetic information to predict certain events and hazards in human PCS intoxications. (1) Pathways of absorption, distribution, metabolism, and excretion have been explored fairly extensively in animal models. Prom the species variability seen, coupled with limited observations in the husin, educated guesses and predictions can be made on the occurrence of certain toxic effects and processes in the human. (2) Mathematical analyses of kinetic data from animal modeling experiments lead to some generalisations (Luts et al.. 1977) that could apply to PCI turnover kinetics in the humani (1) kinetic rate constants for metabolism of PCBs by the liver decrease as the degree of chlorination increases! (2) rate con stants for biliary clearance of PCS metabolites from the liver are nearly the same for all PCSs; (3) urinary clearance rates for PCBs deerease as the degree of chlorination of the parent molecules increases! and, (4) for each PCS, the value of the distribution coefficient between fat and blood is greater than that in any other major tissue, indicating that tne fat compart ment of all tissues nay constitute the major PCS depot. (3) Kinetic models derived from animal data may be use ful tor prediction of time courses of action in the human once HONS 025356 49 ^dltional data on metabolism and claaranc* races for individual Ida in Human tissues aca obtained. (4) Soma general pea structure versus activity rela tionships nave emerged from animal studies, particularly rodents, (feat can nave useful predictive power for the human. (5) There is some relevance of the features of the Morptlon/diseribution/metabolism/clearance processes discussed |a. this seceion to the toxicology of PCBs in animals and humans, lot example: (a) The possibility that an arena oxide intermedi ate can occur in PCB metabolism has special significance in tans of potential reactions with protein, RNA, or DMA to cause tissue damage or damage to a cell's nuclear functions. (B) The retention of PCBs in adipose or other tissue can have major significance by creating reservoirs from vbich material can be leached over tine for reaction at other tissue sites. (e) There is little evidence in humans for acute cytotoxicity of the kind usually associated with reactive metabolites. Bather, seam of the adverse effects of PCBs, a.., Shloracne, could stem from the physical presence of unreacted material In the cells along with oils and/or seDacsous aatarlala pf ths skin. HONS 023357 51 IV. General Toxicity A. General Considerations Any attempt to undertake a systematic evaluation of the fcokicity of PCBa xe confounded by a number and variety of factors Chat complicate the interpretation of the findinqa and limit Chair generalization. Therefore, these factors should be recog nised at the outset of consideration of the available body of Coslcoloqieal literature. The more important of these factors ass listed as followsi (a) The multiplicity of commercial products of both 7,5 end foreign manufacture! (b) -rne multiplicity of isoaeric forms of PCBa in aeesrclal products; (c) Qualitative and quantitative differences in metab olism of different iaoaers within the same species! (d) Qualitative and quantitative differences in metab olise of the sane isoaer between species; (e) olffareneea in rates of metabolise of different iaoeers within the saae species; (f) Differences in rates of metabolise of the saae iheaer between species; (4) Differences in the biological half-lives of different iaoeers within the saae species; (h) Dlffarsncas in the biological half-life of the ana Isoear between species; HONS 025358 52 (i) The presence in cosmiercial product* of impuritia* of ouch greater toxicity than that of PCBsi (j) Tha variability between coxuxercial products of tha Sana typa U.e., Sana degree of chlorination) in tha concantration of topuritias of auch greater toxicity than that of PCBSi (hi Tha variability between coauaercial products of tha diffarant types (i.-a.. diffarant degrees of chlorination) in tha concentrations of iapuritisa of ouch greater toxicity than that of PCBai and (1) Oiftarancas batwaan spaciaa in suacaptibility to tha toxic action of (i) individual iconsra and thair oatabolitaa, and (11) tha lapurltles that aay bo prssant in eooaarcial products. Tha preceding factors aay underlie the conclusion reached by the Panel of Haiardous Trace Substances (1972) that *(t)here la no consistent relationship between toxicity and degree of chlorination which la valid for different species and different routes of exposure.* To this sight be added the ob servation that there is often no consistent relationship between the results of investigations on products of the saaa degree of chlorination froa different aanufacturers. These observations constitute caveats that should be borne in alnd as individual toxicological esperlaenta and results are evaluated. B. ISBurltles in Co--erclal Products The work of Voe and his associates (Voe and Roeaan, 1970i voe at al., l70i voe and Peeaa, 1*71) led to a recognition HONS 025359 - 53 ^the significant role played by tracts ot impurities in com^rctal PCBs in influencing the apparent toxicity of the Utter. Ip studies involving three coauaercial PCBs of the same degree of Ihlormation, these investigators found marked differences in fjxieity that were traced to the presence, in two of the products, tr small amounts of chlorinated dibenzofurans (PCDFs) and ehloHnated naphthalenes. The PCDFs are related closely, both struc turally and toxicoloqlcally, to the chlorinated dibenzodioxins. |be 2,3,7,8-tetrachlorodlbenzo-p-dioxin isomer is an extremely potent toxicant in mammals, especially for the fetus. The chlotlnated naphthalenes are less toxic than the chlorinated dioxins. But nevertheless cause ehloracne and other symptoms in man flmilar to those produced by PCDrs. The extent of the contribution made by contaminants to the toxicity of commercial PCBs is uncertain, but the consensus le that it is substantial. There seems little doubt that the Uin lesions, including ehloracne, are caused by PCDFs. The Panel on Hazardous Trace Substances (1972) states that the PCDFs 9are probably the chief if not exclusive cause of ehloracne in an.* Flshbeln (1974), in his review of the toxicity ot chlo rinated biphenyls, observes that '(lllver damage and skin lesions are believed to be caused primarily by chlorinated dibensofuran contaminants and to a minor extent by KB itself.* Furthermore, since the chlorinated dibenzodioxins exhibit pronounced embryotoxldty, it is not unreasonable to expect that the KDPs share this property and, hence, are largely responsible for the fatal HONS 025360 54 daatha and raiorptiona chat have baan obaarved experimentally wien commercial PCBa. An appreciation of eha rola playad by contaminanta in eha toxicity of eoaMretil PCBa la important for two reaaona. rirat, it may axplain dlacrapanciaa between eha reaulta of atudiea of apparantly eiailar commercial producea. Sacond, ie poinea up tha difficulty of attempting eo uaa pcb eiaaua lavala eo correlate tha raaulta of laboratory atudlaa with obaarvatlona of occupationally or anvironaantally axpoaad populationa. For axaapla, aoma aniaal populationa in eha environaant appaar to ba unatfactad by PCB tiaaua larala that ara equal to or greater than thoaa aaaociaead with adwaraa affacta on coaparabla apaclaa in eha laboratory. C. General Toxicology 1. Acuta Toxicity Tha Aroclora of tha PCB claaa hava a low ordar of acuta toxicity. Tha acuta oral LOSOa for rata ranqe from 1-10 g/kg. Tha u>30e by eingle application eo ena akin of rabbita ara approxiaataly 1-] g/kg. Oral and darual LOSO data hawa naan an--iTliad by Plahbaln (1974), kiabrough at al. (1978). and tha Banal on Naaardoua Traea Subatancaa (1972). 2. Subchronic and Chronic Toxicity (a) General Subchronic and chronic toxicity ara groupad togathar tor purpoaaa of thia dlacuaaion aInca tha affacta of chronic HONS 0253b! 55 - wpsur to PCBs *c ssstntiaLly extinsions of thoss obssrvsd gc0A rspsstsd exposures of shorter duration. There ara numarous published stadias m wtucn corner* Iclal PCSs (Aroclors) hava taan administered by various routas tfbr varying pariods of tins to moat common mammalian species of Bjtioraeory animals. Out of this mass of obsarvatxons. ona may gSantify two principal classas of biological affacts of thasa abstancas. Thasa classas ara (a) altarationa in the Liver, and D ) akin 1.aiona. (b) Alterations In the Liver Enlargement of th. liv.r, both In absolute terms and S a percentage at body weight, h.a D..n oba.rv.d consistently a.Mat species consequent to repeated eapoaure to PCSs, although fit la sore pronounced in rodents then In others. This phenomenon Me been reported (or sice (Kimbrough and Linder, 1974), rata Klruckner at al., 1973, 1974a, b), guinea plga (Voa and Van =BBlel-Grootenhula, 1972), rabbita (roller and Zlnkl, 1973). dog a (Calandra, 197), and eonkays (Allan at al., 1973). Early enlargement of the liver Is prleerlly the result at an incraaaa in the alia of the hepatocyte associated with an incraaaa in the eaount of the smooth endoplasmic reticulum (SEk). These develop ment* are aaaoelatad also with incraasad aniymatie activity of the liver (hruckner at al., 1973). A detailed dlacuaaion of the affects of PCla on liver test animal systems is given in aaetlon VI. HONS 025362 56 (c) Skin Lesions Cutaneous effaces from repeated exposure eo commer cial PCBs can be elicited by feeding to monkeys or skin appli cation to rabbits, although the results are somewhat more dramatic in the former. The results of these animal studies are discussed in section v. (d) Miscellaneous Effects Hyperplasia and dysplasia of the gastric mucosa have been observed in monkeys fed a diet containing 300 ppm of Aroclor 1241 for three months (Allen and Norback. 1973). Gas trointestinal lesions do not appear to occur in rodents, except at very large single doses by mouth (Kimbrough, 1979). A dietary concentration of 2.1 ppm of Aroclor 1241 produced alterations in the menstrual cycles of adult, female rhesus monkeys (Allen et al.. 1979). Menses were prolonged, and there was an Increase in menstrual bleeding, Hepatic porphyria has been demonstrated in mice after feeding Aroclor 1254 (Kimbrough and binder, 1974). in cats aftar feeding Axoclors 1254 ox 1240 (Kimbrough, et al.. 1972), and in rabbits after repeated skin application of Aroclor 12*0 (Vos and Seems, 1971). Urinary excretion of coproporphyrin was incressed in rsts fad Aroclor 1242 (Sruckner et al., 1974), and both urinary and fecal excretion of porphyrins was increased in rabbits receiving repeated skin applications of Aroclor 12*0 <Voa and Seams, 1971). other effects reported for one species or another Include structural cnanges in the kidney (Voe and Seems, 1971i Sruckner et al., 1974a, b), hematologic alterations MOMS 025363 - 57 ^ruekn.c t l.. 1974*, t>), and thymic atrophy toqathar wicn 1 Ruction in the number of germinal centers in the spleen and gnpft nodes (Vos and Beams, 1971). 0. Summary and Opinion Voluminous liter.cure establishes chat commercial RBs are capable of producing a variety of biological effects jmen administered in large quantities to experimental animals. |ha majority of these effects can be grouped into two categories, fcamely, those involving the skin and those involving the liver. J[ number of miseellaneous effects that have been observed in one Species or another can be eoneidered secondary to the action of tie subetancee on the liver. In general, theee effects are only elicited by relatively high dosages of the PCBe. refleeting the l&w order of acute toxicity of the U.S. commercial mixtures. There is a considerable range of species susceptibility to the biological activity of PCBe as measured by the site of the doeage, the duration of the exposure, and the severity of the effect. Mink appear to be the most susceptible, monkeys somewhat iees so, and rodents the most resistant. There is no basis for e judgment as to which species most accuratsly servss as a model for man, A comparison of the observations on humans in the Yuaho Incident with those on monkeys fed relatively email amunts of KBs has led some investigators to conclude that the latter pscies is an appropriate surrogate for man. Although there are ome similarities between Yuaho disease and the findings in "tonkays, they are not sufficient to justify such a conclusion. HONS 025364 - 58 There 11 evidence throughout the literature that some of tha biological effects observed experimentally with commercial PCB mixtures ara caused not by ?CBs themselves but by other chlorinated aromatic compounds present as impurities, such as the PCOFs. The significance of this finding is that PCB levels resulting from occupational or environmental expo sures cannot be interpreted in the same way as those observed in experimental animals. A broader implication of this cir cumstance is that the results of laboratory studies are not necessarily predictive of what may be expected from inciden tal exposures since the nature of the exposure may have dif fered in the two instances. As is always the case In experimental toxicology, the validity of test results as predictors of hasard to man must await confirmation or denial by observations of exposed human populations. Fortunately, the reports of actual injury to man from PCB exposure are few, although extensive epidemio logical surveys have been conducted and others are in progress. An evaluation of the epidemiology of exposure to PCls is the subject of section XXI of this report. Still oehsr sections of the report deal with specific potential health effects In greater detail. HONS 0253*5 59 - V. Skin and Other Cutaneous Tissues Epithelial and follicular hyperplasia and hyper keratosis Hava been raportad to occur following tha application of PCB on tha skin of raobits (Voa and Beams, 1971). skin laaiona hava also baan obsarvad in rats and guinea pigs from tna Ipplication of PCBa. Repeated application of Aroclor 1260 to tha akin of rabbits causad thickamng of tha skin as a rasult of hyparplaaia and hyparkaratoaia of tha apithalium (Voa and Baams. 1*71). Cutanaous affacta hava baan alicitad in mala rhaaua aonkays tad a diat containing 300 ppm Aroclor 1241. Within ona month tha aniaala loot consldarabla hair from tha haad, naek. and Back (Allan jt il., 1973. 1973). Similar affacta hava baan obaarvad in famala rhaaua aonkays fad a diat containing 23 ppm Aroclor 1241 for two montha (Allan at al., 1974). Within six waaka tha aniaala bagan to loaa hair and davalopad obvious signs af adama of tha llpa and ayalida. Small pustulna involving hair faillelas appeared about tha mouth, chaaka, and naek. Abraham and Allan (1971) shoved that the Infant monkey was able to talarata domas of PCBa that produce extrema morbidity in adult aankaya. nay suggested that there may be variations in absorp tion, distribution, metabolism, storage, and excretion in adult and infant aonkays that may account for thaas differences. Follicular hyparkaratoaia la an important faatura of the occupational dlaaaae known aa sens, which la characterised by tha appearance of papules, comadonas. and cyata. Industrial HONS 02536* 60 darmatosia of the senators type has Daan obxervtd amen; workeri axcoaed to chlorinated hydrocacbona (Jonai and Aldan, 1934; flayers and Silverberq, 1938; Maroni jl., 1981). Savan caaaa of chloracna of the faca and haad have baan reported aaonq 14 chaaical operators exposed froa 9-19 month a intermittently to low concentrations ot chlorinated biphenyls (neiqs and Alboo. 1994). Pueelnalll (1994) and Hofman il. (1942) report cbloracna in aavaral capacitor workers, whereas Smith at al. (1981) notad that nona of tha capacitor workers aaaninad in this racant survey wara found to hava acnaform laaiona suqqestive of chloracna. Tha acnaform aruptlons that occur in tha akin of both monkaya and rabbita may bo cauaod by a aquamoua aetaplastle chanqe in tha apithalloa llnlnq tha aobacaoua qlanda, which raault in a chanqe in tha charaetar of tha aacratlon froa nor mal oily to karatlnaeooua. Thia condition frequently raaulta in pluqqinq and rupturo of tha qlanda with consequent inflam matory raactlona (aeno). Tha question of whathar a aiailar condition can occur in man froa axpooura to Kla will ba daalt with in anotbar aactlon of thia raport. It ham boon suqqested that tha cutanaoua aruptlona that occur in both animala and man from exposure to commercial preparations of teas may ba duo to certain impurities. Chemical analysis of tha pels that contaminated tha rice oil that cauaad the Tuaho dlaaaaa in japan showed hlqh levels ot polychlorinated dibonsofurans (Kuratsune, 1974). HONS 025367 61 VI Effect off PCBs on Liver A. Euptrtwtntil Data 1. Livtr weight The idmimitratiori of PCBs mey indue* an inertot in llvir weight (Table 2). The effect is more prominent at the plgher dose levels; the lower doses of PCBs do not increase ri*r weight. The detailed data of Kinbrough al. (1972) (tea not included in the tabla. may found tnat Aroclor 1260, adainisterad with the diat in doaaa of 900 and 1000 ppa for eight Maths, significantly incraasad llvar weight in nala and faiaala tratsi dosas of 20 and 100 ppai wars affaetiva only in nala rats. Aroclor 1294 inersasas livar weight in both nala and fanala rats at dosas of 20, 100, and 900 ppn. Although tha data in Tabla 2 illustrata tha affact obtained in subchronic and chronic studies, it should ba noted that llvar weight nay also bo Increased in acuta toxicity studies. KB congeners (penta-, haxa-, and heptachlorobiphenyls) given in a high single dose of 90 ng/kg, can increase livar weight in tha rat; in coot but not all teats, livar triglyearidas, cholesterol, and phospholipids wars incraasad (Yoshihara at al., 1979). In the aonkay a single oral doaa of 1.9 g or 3.0 g/kg of Aroclor 1294 produced slight anlargaaant of tho livar in 4 days (Allan, torback, and asu, 1974). Tha incraaaa in livar weight is correlated with hepatic coll hypertrophy and an incraasa in snooth andoplasnic reticulua HONS 025368 -42* Tal 2 tflmt o< fO on Livr mht iM HofBfcalogy Wtiffet CkilHM ea--M mj* Miatalov* iei IlMim* siMraufii 4 i if74* UMlM 1214 M. C *1., I. 4S4 Ci kya to k iM 4aya tMlly m H. IN wm JlMlM US4, UM ! rm i tm ilt4l4t U42 IN. it. i wm U MN 11 HU. It MU UtlMWt M a.. UTS Antlit U42, U4fl US4, UM SM M NM sm m 4 MU 4 Ml 4 Ml klXm UTS, f.lt to. NM AlflW UN, US4* UM Ml r * *1., umi UWlM U4S IM Mr toi Mr to al.. UT4 mm. * MB 2,4,4 Ik 0 9 4 * * eaua mu, iqraUM yriMiM r "INmilllli m m ** ass mu. iMNm UfM NB IM it ran HONS 025369 -1- Tikia i cconimnoi ({fact of K9a on Li--r Mlkt IM NMftMlocv Htm *1., imur usa ioit to* *t *i.. IlMlM UII to--m*r*HpN*ar1 toU *i*nX, 1ST! to--lor 1294 imlir 123 Inalu 1291 tolffct Ch*iM}a *-iaerao an cftaao* Stoll** la tot* (CoatlaoaO) **7*r m*tolo~ ie*l fliiOia** LM p-- *9 io --min Stoll** ST I s 0 tala-- n* taaytaa. y-- KM eytoflMB. diiiMteniO a* all* e--to 120 teiMl 4 --00* 1 m tnak H--if <*** ration, --ii "-7MO Of ; lalto--4 hafato" 8|M0 --i* ftUurt to** ayto. a--a aaot--4* 0 to UMflfflMl HONS 025370 i 1 a I a Table 2A Uvr uaioM in Albino Anta Treated with Aroclora for 2 Ynara (Data (rca Laviaakaa, 1901) Mot level, ppn control 23 I 1 n 9--anlar d-|i Natl lycpbeid infiltration fbMl hypertrophy hepatoeytee mik knaitUiii 0. * .1 hypecplaela --y iff OdlaNfiotaHUM Mepatoceilalar eareinona 1 1 1 1 5 0 Arcelor 1242 1 10 100 32 29 7a 1l 00 23 11 33 0 00 0 1ft 9 0 0 0 0 3 3 1 0 Aroelor 1294 11 100 30 2 2ft 7 11 11 201 3 14 0 14 ft 14 04 02 00 *Tbn reaulta of thii atndy Mr* pronnntnd in a atnaariiad (on by Calandra (1979) and mr latnr rnnnalynnd and tabulated bv Lavinahaa II90H Aroelor 12M 1 10 100 2ft 2% 25 57 4J 9 ft oio 1 11 07 ft 7 9 ft 12 01 7 00 4 00 0 MOMS 0^5371 65 - Mtth* rat, rabbit, and monkey (Voa at al., 1372; Allan and ^Kanaaaon, 1973; Bruckner at al., 1974a; Allan, Norback, and Hsu, Pti Allan, Carscani, and Barsotti, 1974). Ecobichon and Coaeau ^^74a, b) found that tha affact of PCBs administered intraperineally on livar weight and on hepatic enzymas associated with bade endoplasmic ratlculum waa ralatad to tha poaition of ehlorlna aubatitution on tha biphanyl nuclaua. However, all B'Cba congeners and isomers adainlatarad at a doaa of SO mg/kg ^traperitoneally for thraa daya produead an incraaaa in smooth pdoplaamc, lipid droplata and microbodies, although tha quantifciva raaponaa varlad (lianaa11 and ecobichon, 1974). 2. General Histology Tha adainiatratlon of PCBa to axpariMntal anlaala will Bbducs hlstopathological changes in tha liaar. Tha aain atfacta htainad ara tha production of enlarged hapatocytaa, fat droplata. Sad alight dagraa of nacroaia; tha occurranca of thaaa changaa depend particularly on tha doaa of tha PCI and to some aatant on the particular Aroclor (Tablaa 2 and 2A1. Nacroaia aaaaa to ea Sara aavara in tha rabbit than in tha rat. in ganaral, tha parpholog leal changaa observed in tha livar of peb-traatad amaala ara aiailar to thaaa found aftar traataant with othar chlorinatad tydrocarbona. In a datailad etudy, Kimbrough at al. (19721 found that ;icoclor 12a0 (20, 100, S00, and 1000 ppa) and Aroclor 12S4 (20. 100. ^ad 300 ppa), given in tha diet of rata for eight aontha, produead HONS 025372 66 enlarged liver cell* end cytoplasmic inclusions. At the higher doaes. there waa evidence ot lipid accumulation, which waa aaaociatad with a foamy cytoplasm, and pigment accumulation in the Kupffer calla. The piqment qave a poet- tiva Ptuaaian-blue reaction, indicating the preaenca of hemoaiderin. Studies of rata four to air months after expo- aura to different doaea of Aroclora 1016 and 1243 indicated that the morphological changes are reversible and disappear gradually after doalng la atoppedt the hepatocytee were still larger than controls, but the frequency of vacuolated cytoplaam or Indus iona within the cytoplaam had decreaaad (Suraa at al., 1S74). Aroclor 13S4 waa evaluated by the national Cancer Institute <1370. Pischar rats receiving 23 ppm in the diet for eight weeks had enlarged livers, but without evidence of histological abnormality. The administrations of doaea of 23, 30, and 100 ppm for 104-103 weeks did not increase the frequency of liver lesions such as congestion, inflammation, necrosis, or anglsctaais. 3. Adenofibroaia Adenofibrosls (synonyms: bile duct proliferation, bile duct adenomatosis, ebolanglotibrosls, fibroadenoma) has been observed in some rats receiving peas. Adenofibroaia is generally regarded as a benign lesion, in ehalr review of experimental tumors, Stewart and Snell (1337) stated that there is no convincing evidence that adenofibroaia la a precancerous lesion. HONS 023373 67 - it should b noted, however, that Reuber (1968), studying 2aeetamidofluorene and 2-diacetanudotluorene, suggested that adenofibrosis is a precancerous lesion for the development of cholang loearei noma. (i) Studies in mice. Kimbrough and Linder (197,1 observed foci of adanofibrosis in the liver oC some me* with 300 ppm of Aroeior US, in the diet for 11 months. [to et si. (1974) commant that thay did not obaarva cholangiofibroais in aiea receiving Kanechlor. (ii) Studias in rats. Kimbrough at al. (19721 obaarvad adanofibrosis in rats traatad with Aroeior 1260 and 1294i tha at fact was obaarvad at tha higher dose levels and particularly in animals racaiving Aroeior 1294. Whan tha faeding of 900 ppm of Aroeior 1294 was discontinued and tha animals studied up to 10 additional months, tha fat and livar content of ,CS remained high and tha adanof ibrosis persisted (Kimbrough ait al.. 1973). In a latar paper involving treatment with Aroeior 1290 at 100 ppm for 21 months, mention is only made that a few rata showed areas of adenofibrosis. indicating a low degree of response, but data are not tabulated (Kimbrough at al.. 1979). In further studies by the same group adenofibrosis was not ob served in rats fed Aroeior 1014 or 1242 (100 ppm) for up to 10 months (Purse it al., 1974). In a study with three Aroclors, administration of 100 ppm in the diet for 24 months produced a low incidence of MOWS 025374 68 cholsngiohepatoma (Table 2A), but concentrations o( L ppm or 10 ppm were without effect (Calender, 1976; Levinskss. 1961). Treatment did not significantly affect ductal hyperplasia. The study of the national Cancer Institute (1976) did not observe adenofibroeis in raes receiving Aroclor 1194 at doses of 21, 90, and 100 ppm for 104-109 weeks. In studies with various Kanechlors, Ito at. al. (1974) administered Kanecdor 900, 400, and 300 in the diet at concentrations of 1000, 900, and 100 ppm. At the concentra tion of 1000 ppm of the Kanechlors, the incidence of eholangioflbroais ranged from 13 to 30% in tne rats; cholangiofibrosis did not occur at levels of 900 or 100 ppm. Klmura at al. (1976) also reported cholangiofibroeis in rats treated with Kanechlor 400. 4. Hyperplastic roei and Modular Hyperplasia in the Hear Hyperplastic foci or hyperplastic areas represent minimal changes in the hepatocytes. Such foci or areas of hy perplastic changes arm uncommon in untreated young rats, but increase with age. The hyperplastic areas or foci eay cooslet with nodular hyperplasia and/or hepatocellular carcinoma. The significance of hyperplastic foci is that they eay be part of a spectrum cepeble of progressing to a nodule (Sgulre and Levitt, 1979). The hyperplastic nodule (nodular hyperplasia, neoplas tic nodule, hepatcsw) is generally as large or larger than the area of several lobulea, and the lesion is sometimes elevated HONS 025375 69 the surface of the lwr. The lesion is frequently re_Brctd to ss * neoplastic nodule and some consider it to be a manifestation of a carcinogenic process, the earlier staqes which may be represented by the hyperplastic foci discussed pUbve. The use of these terms in the literature is confusing, ms some who use the word 'hyperplastic nodule* reqard the Htaion to be part of the neoplastic process whereas others Consider it to be unrelated to neoplasia. Some investigators mee the terms adenoma or hepatoma to designate the lesion, implying that it is a benign neoplasm. Despite the differing terminology, it may be considered that the hyperplastic foci and nodular hyperplasia (neoplastic modules) occurring In the liver are benign lesions rather than ICarelnoaaa. However, such nodules may be part of a sequence of hooplastic changes that eventually progress on to hepatocellular carcinomas. Although the data on hyperplastic foci and nodular hyperplasia are discussed In this section and hepatocarcinogenen are discusaed in eectlon VIII, the eaperimental data on the inc. dance of benign and malignant lealona are given in the same table so that the overall biological effect of the treataient can be observed as a unit. (1) Studies in mice. Ito et al. (1*73) observed edular hyperplasia in nice only at the highest dose level of Kaaachlor 300. (Nagasaki et al., 1972, reported the same data.) Mtoraas Kanechlor 500 produced nodular hyperplasia at 300 ppm, lesser doses were not active and Kanechlor 400 or Kanechlor 300 HOMS 025376 70 was inactive at ail doses studisd (Table 31. There was moss evTdence that tne administration of Kanechlor 500 increased tne nodular hyperplastic rasponss induced By X or p isomers of benzene hexachloride. Kimbrough and Linder (1974) observed adenofibrosls and hepatoisaa in nine of 24 mica fed Aroclor 12S4 (300 ppm in the diet) tor 11 months) in animals ted Aroclor for only sis months followed by a five month recovery there was no adenofibrosls and the incidence of hepatoma was only 1/24 mice. (li) Studies in rats. Keplinger et si. (1971) did not observe hepatic lesions in rats receiving different Aroclor* for It months) however, re-evaluation of the slides indicated a significant increase of nodular hyperplasia in the treated animals (see national Cancer Institute, 1970. Ito et al. (1974) observed nodular hyperplasia in rats receiving 100, S00, or 1000 ppm of Kanechlor SOOi a lesssr effect was observed with Kanechlor 400 and there was no signi ficant affect of Kanmehlor 300. Klabrough et al. (197S) reported a significant in crease in the incidence of hyperplastic foci or areas and neo plastic nodules in tamale rats given 100 ppm of Aroclor 1200, mlssd with tbs diet for 21 months (Table 4). In another study, the dietary administration of 100 ppm of Aroclor 1242, 1294, and 1200 for 24 months inersasad the incidence of nodular hy perplasia (Table 2A)i a leaser affect was obtained with 10 ppm. HOMS 025377 -71- TABLE 3 Incidence of Liver Lesions in Mala Mice Treated with PCBs for 14 Waaks (Data of Ito at al, 1973) ppn in diet Incidence Modular Hyperplasia Hepatocellular Carcinoma (hmechlor 500 (aaechlor 400 Kaoechlor 300 Controls SOO 250 100 7/12 0 0 500 0/12 250 0 100 0 500 0/12 250 0 100 0 0/6 S/12 0 0 0/12 0 0 0/12 a o 0/6 *ONS 025378 -72- TABLE 4 Incidence of Liver Lesions in female Sets Treated with Aroclor 1250 (Oat* from Kimbrough et al., 1975} Lesion Hyperplastic foci or areas .isoplastic Nodules Hepatocellular Carcinon* Incidence Controls Experimental 29/173 0/173 1/173 192/194 144/194 29/194 HONS 025379 -73- TABLE 5 Incidanca oS Livar Lasions in Mala and rentals Rati Treated with Aroelor 1143, 1254 and 1260 100 ppm in Diet for 24 months (Data from Calandra. 1975) Modular hyparplasia Hepatomas Hepatocellular carcinoma 1242* 8/20 2/20 0/20 Aroelor 1254** 13/27 4/27 0/27 1260 7/27 5/27 0/27 10 malaa and 10 (aulas **13 malaa and 14 faaulas HOHS 0*5380 -74- TABLE * Incidence of Liver Lesions in Male and Female Rats Treated with Aroelor 1254 (Oata from National Cancer Institute, 1778)* ** Number of animals necropsied * Hyperplastic foci or areas Adenoma, NOS* Hepatocellular carcinoma Low Dose Males_______________ Females Mid Ooso High Dose Low Mid Do. Dose High Ooi. 24 24 24 24 22 24 58 00 01 12 1 2 6 9 17 0L 2 00 3 Hyperplastic foci, hepatocellular adenomas or carcinomas were not diagnosed in the controls. + Not otherwise specified ** As defined in report MGNS 0*5361 75 - 1 1 pp* did not product a positive response (Calandra, 1976; |lnakas, 19*1). All three Aroelors produced an increased r of hepatoiaas at the high doaa (Tapla 5). mart was no Mldanca of metastasis or invaslvenasa, and tha lasions wara Bearded by tna pathologists as beniqn tuaors. Tha rasults of a Bioassay of Aroclor 1254 for carcmogpnlclty, using doaas of 25, 50, and 100 ppa in tha diat, art Ksaiarixsd in Tabla 6 (National Cancac Institute, 19761 . Thair gw of tarns is confusing, for although thay usa tha words 'nodular gyperplasla* in thair tabla, thay atata in tha taxt that *tha grass of nodular hyperplasia appaarad to ba microscopically Uallar to what Is eurrantly tstSMd 'focal araas of callular Iteration." Thus, wa havs usad tha tarn 'hyperplastic foci or rasa' in Tabla ( to dascrlba thair rssults. It is aaldant fron lbs data in Tabla ( that tha hyparplastlc foci wars prasant in a Boss-ralatad fraguancy. Although tha lncldanca of tha hyperlastic foci did not differ significantly fron tha controls, this Incidence appaarad to ba related to traataant. The biological ignifleance of tha increase in 'focal araas of callular altera* Bias* is not clear aa relatively fa* adenoaaa wara found. aetb tha above atudies (Klabrough at al^, 19751 National fsneer institute, 1971) desnnatrate an lncreaaa in prollfarativa taaiana of tha llvari tha affect is grastar with Aroclor 12(0 Man with Aroclor 1254. (ill) Studies in docs. Hepatic nodular hyperplasia id net occur in the dogs receiving dietary levels of 1, 10, or 100 HONS 025382 76 ppm of Aroclor 1242. 1254, or 1260, respectively, Cor two years (Calandra, 1076). Each treatment group consisted of eight dog* (Cour female and four male). 5. Summary and Coament The administration of high doaas of PCBs to animal* can produce hepatic enlargement and an increase in liver weights, which 1* associated with an increase in smooth endo plasmic reticulum. Other effects include a alight degree of necrosis and the presence of fat droplets and a vacuolated cytoplasm. These changes, which are similar to those found after treatment with other chlorinated hydrocarbons, are readily induced by high doses of PCBs, but are absent when lower doees of PCBs are given. The response appears to be greater with Increased chlorination of the biphenyl nucleus but, depending on dose, even the high chlorinated derivatives may not produce a positive response. Treatment with PCBs usually increases the occurrence of hyperplastic foci. The nodular hyperplasia, neoplastic nodules or hepatomas have been reported to be-increased in some studies, but other evaluations have not confirmed these effects. The effoots of PCBs on the occurrence of nodular hyperplasia, neoplastic nodules, hepatomas, or adenoflbroais is highly variable! some studies have reported a positive effect whereas others failed to show an effect of treetment. Again the change In histological response or In frequency of benign hepatic tumors Is related to both the dose of PCB administered and the degree of chlorination of the PCB. MOWS 025383 77 Dta on hopaeoctllular carcinoma in PCB-craacad animals r( discussed in section VIII. a. Clinical Oats 1. Uvtr function in PCB-exposed workers Baaed on results in animals, it was expected that if IPCB* produced a significant degree of injury in man, it would be to tha livar. Such has not baan tha caaa, as the clinical studies suaaarixed below have provided little evidence for the occurrence of hepatic dysfunctions in PCB-esposed workers even thouqh the blood .aval of PC* aay be relatively high. (11 Ouv et al. (1976) studied liver functions in 3 workers exposed to Aroclor 1242 for one nonth up to 2] yearsi 31 were exposed for eore than one year and 16 for five or ixore years. :icatterad individual abnoraal test results were obtainedi serue bilirubin was noneal and in all 34 subjects, alkaline phosphatase was elevated in one of ]4 subjects and sarua transaainase (SGPT) V wee increased in five teats." there was no relationship of the results to the blood level of FCB and the mean of each hepatic function test for the whole group was within normal liaits. BSPV V Tha abbreviations used in this section are as followsi SOOT sense qlutaoie oxaloacetic transaainase MPT sense glutaaic pyruvic transaainase SHOT serua gaaaa glutaayltranapeptidaee LOG - serua lactic dehydrogenase AST aspartate aainotranaferase ALT - serua alanine aainotransferase 90CT serua ornlthln-carbaanyltransferase MP broasulfonpbthaleln HONS 025384 test* vara <lio performed on seven workers with nlitioiy nign blood PCB; four of tna seven testa wart slightly abova the normal limit of 5* but, aa the authora acata, alnca other conditiona auch aa fevar may ineraaaa BSP retention, thaaa raaulca by ehaaaalvaa could not ba takan aa proof of hepatic damage. rha BSP ttat raaulta did not show a significant corralation with blood PCB lavala or tha length of aaposura. (fiva to 23 yaars) to pcs. <tt) fischbain at al. (1*7*) studiad llwar func tion taata in 321 workars axpoaad to PCBa in an alactrical manu facturing plant for last than fiva yaara to iaora than 29 yaara. Tha parcant of taata that gave an abnormal taat raault was SOOT 2.2*. SGPT 7.2*. COR 2.9%, alkalina phosphataaa 1.2, and Sanaa bilirubin 9.3%, and indicatad a 'vary low pravalanca of abnoraal livar findings.' Thara was no coaaaant or analysis to atata that a cartain nuabar of tha subjects showad a pattarn of abnoraal livar function taata indieativa of hapatic dysfunction. Thaaa data can ba takan to rapraaant a aarlas of randoa taat raaulta that alght ba oapoctad in a population of 321 individuals rang ing in aga team laaa than 30 yaara to ovor 70 years. Control subjects or non-aaposad workars wars not included for compari son. There was perhaps seas indication of a relationship of SCOT levels to plasaa lavala of PCBa, but tha two exposure categories of PCB levels are toe broad and require a finer analysis. (ill) Baker at al. (IPSO) atudlad liver function in 14* individuals with various dagraaa of exposure to PCBsi tha HONS 025385 79 g^n Kl run level* Cor the Cour test groups varied froei 17.4 gh-to 75.1 ppb. mere was no change in liver function tests 00?. SGPT, LDH. alkaline phosphataae, or serum bilirubin) n tion to PCB Blood levels in either drinkers or nondrinkers of Alcohol. Serum GGTP (gamma glutamyl transpeptidase) correlated Mth serum PCB, but a correlation did not exist when alcohol (Sinkers were removed from the analysis. (lv) Heron1 at al. (19tla, b) studied liver function in-10 workers exposed to PCBs for an average of 12 years and sported that It Individuals had an abnormal liver finding as asdged by clinical examination or by laboratory teste. Inspection of the data shows relatively few instances f abnormal liver function tests. The most frequently altarsd laboratory tests wore as followsi f of (0 subjects with increase of SCGT activity 7 of 10 subjects with Increased eerum amino- trenaferaae activity (AST or ALT) f of SO subjects with increase of socr activity. It is evident from their data that many of the changes are slight, and as tsst results from control subject* wore not included, we do not know what the normal tsst variations asy be for to control Bubjects of a similar ago. Further, examination of the data for tbs 14 subjects with clinical hepatomegaly shows only one subject with an abnormal test in three types of teats (SCOT, AST/ ALT, and OCT)i only two of tha subjects gave a positive response in two of HOhS 025386 80 - the teat typeej eight eubjects had an abnormality m only on tastu three subject* had normal ease results. Sarum bilirubin and alkaline phosphatase activity war* within th* normal rang* in all subjects. Sasad on tha above review, it is evident that only one of th* 80 subjects showed a pattern of test results indi cative of abnormal liver functloni the other test results reflect only random variations from normal. naronl at al. also reported that tha aean level of blood pesa in tha 18 workers with abnormal liver findings was signifleantly higher than that of 84 workers without abnormal liver findings, but the ranges for the two groups show consid erable overlapping and the two subjects with tbs highest blood PCS level* had normal liver function tests. Th* only control w* can use to evaluate the suggested relationship between PCS blood level and liver function are the 10 subjects with chloracne, these 10 individuals had normal liver test results despite the fact that their mean blood PCb concentration waa high and not significantly different from th* mean blood PCS level found in the IS workers discussed above. Thus, it cannot be said that this study demonstrates a relationship between a high blood PCS level and abnormal liver function tests, attest ing further to the randomness of the liver function test results in th* study. (v> Smith at al. IlSSla, b, c) evaluated liver function testa in PCS-exposed employees from an electrical manufacturing plant, a municipal electric utility company, and HONS 0253S7 81 ^privately-owned electric utility company, The data on SCOT |M carr ace difficult to evaluate as the results of tne mea- graments are not given, and therefore may be assumed to Be thin normal population levels; rather, the authors sought (^relations Between the log of SCOT and CGTP with the log of gpe lower serum PCSs and the log of high serum PCBs. Calcula- XJbns Include simple correlations, separate regressions with Iks confoundsrs as predictors, and squared partial correlation, Una other computations to see if associations existed. Their fkblea i, 7, and 8 summarize many of their calculations, and Iste for transaminases from table 7 are sumsMrized below. Correlation With Serum log L-PCB Serum log H-PCB llectric equipment company log SCOT log GOT? municipal electric utility company log SOOT log CCPT frslvtaly-owned utility company log SCOT log CCTP NS Sig NS NS Sig NS Sig Sig NS NS NS NS Sit statistically significant * not significant L-FCB lower chlorinated biphenyls H-PCB higher chlorinated biphenyls MOMS 025388 32 Correlation* (associations) were found at tn* equip, ment company but the data cannot be examined to determine if the calculated value haa any medical sigmficance. Correiationa at the publicly-owned utility company were not signifi cant. At the privately-owned utility company, the only poeitise finding was a positive association of SCOT with serum l-pcb. It is not clear what the change in this on* test result means as the serum L-PCBa were not significantly different between the exposed and nonexposad groups. The test results for total Bilirubin, alkaline phoaphastasa, and lactic dehydrogenase are not discussed, and it ia presumed that these measurements of liver function were not abnormal. 2. Liver Disease in PCB-fxpoaed workers Nedleal examination of PCB-exposed workers has not shown the presence of liver disease. In the study of Pischbein et *1. (1*7), physical examination of 32S individuals (age less than 30 to over 70 years) revealed four Individuals with abnormal liver size, two of whom had a history of heavy alcohol intakes one of the four had a slight elevation of one liver function test (SOOT of S3). in another study of 14B individuals with varying de grees of PCS eapoeure, there was no evidence of liver disease as determined by medical history and physical examinations (Baker et al., IftO). Smith et al. (lll) did not find evidence for liver MOMS 025389 - 93 Slseaee in their subjects, there being no significant findings on physical examination of workers at an electrical equipment manu facturing plant who were heavily exposed to PCBs, or workers at iiaunieipal utility company or a private utility company who were jess heavily exposed. Deaths from cirrhosis of the Liver were not increased by exposure to PCS (brown and Jones, 1991); six deaths were observed (three of the six consumed alcohol regularly) versus fit expected. 3. Summary and Opinion The review of clinical data demonstrates that exposure to PCBs does not significantly affect liver function tests. Liver function remains normal in individuals with measurable, and freq* osntly high levels of serum pCB. Also, exposure to PCBs does net result in the production of clinically detectable liver disease. The induction of enxyme systems in the liver and the biological significance of this process, as mediatsd by PCBs, are discussed in section XI. HONS Of5390 *ONS 0*5391 as VII. CHtnc Lesions The oral administration of ?CBs to nonhuman primataa Has been shown by Mian and co-worksrs to induca hypertrophy and pyparpiasia of tha gastric mucosa. Nucosal cysts may ba praaant plthin tha apithalium of tha atoaiach, but in tha mucosal lining and tha submucoaa, thara may ba adama of tha submucosa of tha Stomach. In addition, thara is frequently invasion of tha under lying mucosa by iaolatad glandular alamants of tha mucosal apithalium. Ganaral affacta of this natura hava baan producad in tha monkey byt (1) A aingla oral doss of 1.5 g or 3 g of Aroclor 1241 (Allan, Norback, and Hsu, 1974). (11) Aroclor 1241, 300 ppm and Aroclor 5400 (a polychlorinated trlphenyl), 5000 ppm In the diet for 90 days (Allan, Abrahamson, and Norback, 1973) Allan and Norback, 1973). (Ill) Aroclor 1240, 25 ppm In tha diet for 2 months (Allan, Carstans, and (araottl, 1974). (la) Aroclor 1240, 100 ppm in the diet for 2-3 months (Allan, 1979). (a) Aroclor 1240, 2.9 ppm and 9.0 ppm in the dlat for up to ana year (Oaraotti and Mian, 1975). (Gastric changes vara not listed for thasa domes in Mian's reelow.) HONS 025392 86 (vi) The hyperplastic qaatritis may persist tor over one year following discontinuance of PCS exposure (Allen. 1979). A mixture of Ion chlorinated biphenyl (Clophen A-30) was not observed to produce gastrle lesions in the monkey (latropouloa et el., 1977). The findings of Allen et al. were recently confirmed and extended by Becker et a^. (1979). Their study involved six monkeys, one untreated and one each receiving a diet containing 3. 30, or 300 mg/kg of PCS (Aroclor 1242) i two monkeys received a diet containing 10 ag/kg. Monthly biopsies tskan from the greater curvature of the stomach showed a drasMtic decrease in the number of perietal cells with a concomitant increase in the number of mucous neck cells. The syaogenle (chief) cells were also reduced in number. This was followed in all treated animals by a mucous conversion of the gastric epithelium, with downgrowth of the gastric glands into the sutamucoaa and the eventual formation of cysts, it is noteworthy that the lesions were confined to the stomacbr no changes were found lit other regions of the gastrointestinal tract. The gastric changes can be described as a dyaplaatie growth pattern, bat there is no neoplastic transformation (Allen and norbaek, 1973). Sowersr, the authors speculate that they are 'suggestive* of an eventual neoplastic transformation. Analysis of the results obtained in the monkey indicates that the PCS-induced morphologic changes in the gastric mucosa HONS 025393 87 OS *pacific to this species and not predictive of possinla |f(acts in man. (i) Evan within tha monkey a specificity of action ia present, aa tha laaion induced by PCBa 1* found only along tha greater curvatura of tha stomach; naithar tha cardiac nor pyloric portions wara affactad (Becker t_ al., 1979). tii) Hypertrophy and hyperplaaia of tha gastric mucosa hsva not baan raportad in tha rodant (Allan and Abrahamaon, 1971), rabbit (vos, 1972), or in othar specias (Vos and Koeraan, 1970). Clinical findings to data hava not auggaatad or indieatad that exposure to PCBa incraaaaa tha occurranca of cancer of tha atoeach in tha human (saa also aaction VIII, relating to carcinogenicity), HONS 02539* VIII. Carcinogenesis: Experiments! and Clinical A. Experimental Studies Ail authors do not uss ths words tumorigeneeis and neoplasia to indicata ths saias typ of response. Tumocigenesn Is a general tarn that rafars to both benign growths and malig nant growths; coapounds may affact tha occurranca of banign tumors without inducing cancar. Naoplaaia maans simply a ntw growth. Tha tan "neoplasia* can rafar to a banign or malignant growth. Oftantlnaa authors may combine data relative to banign and malignant growths so that whan tha tarns tumorigenesis or naoplasia ara used, they must be carefully defined. 1. Hepatocellular Carcinoma (I) Studies in mica. Ito at al. (1973) ob served hepatocellular earelnomas in mica only in the high dose group givan Kanechlor 500; lower doses of Kanechlor 300 or tha other Kanachlora did not produce a carcinogenic response (Table 3). Tha administration of 300 ppm of Aroclor 1234 in tha diet tor 11 months did not induce hepatocallular carcinomas in sice (Kimbrough t Under. 1974). (II) Studies in rats. The administration of Kanechlor 400 for 400 days did not indues hepatocellular carcinoma (Klmura 4 Saba, 1973), hue tha period of treatment nay have bean too brief to detect a carcinogenic affect, in a further study Klmura at al. (1974) admlnisterad Kanechlor to rats for sis mont-i but due to body weight changes a variable dosage schedule was employed. Following the cessation of treatment, the rata ware 025395 - 90 - fed on a normal diet for 270*410 days; autopsy, aftsr a coral xpaximantal period of 450-590 daya. did not ravaal hepatocel lular carcinoma in any of 12 raca. Ito at el. 11974) traatad raca with diffarant doaaa of Kanechlor 500, 400, and 300 for parloda up to 52 weeks; napatocallular careinomaa wara not observed, but tha duration of traataant was probably toe abort to rula out tha possibility of a positive response. The three major atudlea pertaining to PCBa and hepa tic careinoaa in tha rat are those of Kiabrough at al. (1575), Calandra (19751, and the National Cancer Institute (197N). Kimbrough and co-workers, using the Sharaan strain of rat, found that 100 ppa of Aroclor 12(0 in the diet for 21 months producsd a significant Increase In the incidence of hepatocel lular carelnesM In feaale rats (section VI, Table 4). Hale rats wara not atudiad. The administration of three different Aroclors at a dose of 100 ppa to rats for 2t aontha (Table 5) did not induce hepatocellular cardneaa (Calandra, 1575), Tha author states that this negative finding was based on evsluaclon of the liver sections by throe pathologists, who resd tha slides independently and separately. Be states further that Professor P. Pour re evaluated the Kiabrough slides and did not agree with the reported findings (see also section VI, Table 2*). The results of the National Cancer institute (1P7I) bloaaaay of hroclor 1254 for possible carcinogenicity are shown in section VI, Table (. riacher 344 rats were used and the PCS HONS 02539b - 91 - ^sture waa administered et three dose levels (25, 90, end 100 ppm) gB ths diet for I0a-105 weeks. The effect of the treetment on Body weight end mortality et the higher dose levels demonstrated ^at maximum tolereted doees were used, thus providing e satisBctory tett of carcinogenic potential. A sufficient number of lata of both aesaa was available for meaningful statistical Belyeas of the incidence of late-developing tumors. Treatment a associated with only three hepatocellular carcinomas in male kata, which waa not significantly different from the controls. Bad It was concluded that Aroclor 1234 waa not carcinogenic in the Moassay. (ill) Studies In does. Hepatocellular carcinoaa did Bet occur in dogs (four aale and tour fasiale par group) receiving ft, 10, or 100 ppai of Aroclor 1242, 1234, and 1200, respectively, in fthelr diets for two yean (Calandra, 1)73). (iv) Placuaaion. Data free the souse provide only Halted and restricted evidence for a carcinogenic effect of the Japanese eoapound Kanechlor 300 (Table 3). Studies on the rat give conflicting results on hepatic careinosu. (Section Vl deals with the benign hepatic proliferative lesions found in the treat ed rats, which aay or say not indicate carcinogenic potential.) IlaOrough et al. (1)73) reported an increase of hepatocellular earelncaaa in faaala rats receiving Aroclor 1200, whereas the studies of Calandra (1)73) and the National Cancer Institute (1)70) did not observe a significant increase in hepatocellular carelnooaa in rata receiving different Aroclora. Miether the MONS 025397 - 92 - divergent reaulta arc related to the different stralna of rata that were uaed, repreaent dlfferencea in the effect of the two Aroclara, or are doe to other faetora ia not known, it ia obvioua, however, that in view of the differing reaulta obtained it la not poaaible to extrapolate or project poaaible effecta in man. Hepatocellular earcinaaaa did not develop in doqa treated with aroclor for two yeara. 2. gladder Cancer Riabrough (1972) obeerved bladder cancera in two rata fed 1Q0 ppa of Aroclor 12(0 for eiqht montha. In a later atudy with 200 rata receiving 100 ppa of Aroclor 12(0 for 21 montha the only bladder tuaor obeerved (a tranaltional cell papilleaa) waa in a control animal, and It waa concluded that `the occur rence of the bladder tumor in the previoua experiment waa ap parently unrelated to tna lngeation of Aroclor 12(0* (riabrough et al.. 1979). Thia type of variation deaonatratee the un reliability of attaching aignificance to email ebangee in tuaor incidence in a given experiment, particularly when the inci dence doea not ahow a atatietically aignifleant difference from a control group. benign or aallgnant bladder tuaora did not occur in rata treated with Aroelora 1294 (29, 90, and 100 ppa) for 104 109 weoka (Motional Cancer Xnatltuta, 1970. The above atudlee do not deaonatrate that adalnletration of Aroclor 1234 or Aroclor 12(0 Inducea bladder cancer in the rat. HONS 025398 93 3. Stomach, Intestinal Tract Cancer Treatment of female rata with Aroclor 1280 (100 ppm in (flat) for 21 months did not Induce tumors m the gastrointestinal [Erect (Kimbrough at al., 1975). Treatment of rats with Aroclor 1254 (25, 50, and 100 ppm jtA the diet) for 104-105 weeks did not induce gastrointestinal carcinomas (National Cancer Institute, 1978). Tumors occurred in random manner as illustrated in Table 7. 4. Carcinogenesis - Other Organa Studies with PCBs in relation to cancer of the liver, yastrointeatinal tract, and urinary bladder have been discussed separately above* In the studies with PCBs other organs have bsen evaluated in detail without finding any effect of chronic administration of Aroclors on the incldanca of benign or malignant neoplasms. The following appraisals rsfsr to tumors of those other organs. Kimbrough at al. (1975) found that tha chronic administration of Aroclor 12(0 to rata did not affect tha incidence of benign tumors or carcinomas of tha thyroid gland, adrenal gland, starus, lung, and otbor organs, rraquanely investigator* look only for Increases In tumor Incidence, when in fact decreases are often obtained. It is worth noting that mammary adenocarcinoma occurred In 5/173 control animals versus an incldanca of 1/184 in treated animals. If the incldanca had bean reversed, acme authors may haws commented or suggested that PCBs may increase the occurrence of mamawry cancer, but such would not have bean HONS 025399 tneilanei of SttuolnuttiMl Ctmiwut la tan rttaiM uii Acoeloc L4J4 (0m from NetoiMl Cmimc iti Mai-- CfflSLSi mr *e Cweiiwif Obw im Ob-- huh Po-- 44 44 44 4 1 01 4 MGAS 025400 95 can aa the number of mammary adenocarcinomas in control groups can vary sigmficantly from study to study. if the inci dence of spontaneous tumors can vary, then the number of malig nancies in the treated group will vary with each esperiment Independent of the treatment given. An additional illustration of turner variability is the incidence of ovarian granulosa theca cell tumors which was S/149 in controls versus 0/143 in the treated animals. in the National Cancer Institute (1978) study, the chronic administrations of Aroclor 1254 was without effect on the developmsne of benign or malignsnt neoplasms in the various body organs of tha rat (the liver, gastrointestinal tract, and urinary bladder wars discussed separately above). In the study, interstitial cell tumors of the testes were present in nearly all control and treated animals, there being no effect of treatment. Leukemias, which were the second most common neo plasma, were found in 13* of control males and 17% of control females. A statistically significant doee-relatsd trsnd for leukamia was present in the treated males but not in the female rats. However, direct dome ceawarisons between each treatment group (male or female) and the control group were not statisti cally significant, so that an affect in males could not be clearly related to the administration of Aroclor 1234. Adding the few lymphomas to the leukemias for the analysis did not change the HONS 025401 - 9( conclusion. Kimbrough st aK (1975) also did not find a 119. nifleant sffset of Aroclor 12(0 on leukemia incidsncs (1/17} m controls vsrsus 0/104 in traatad animals). It may be concluded from these studies that the chronic oral administration of high doses of Aroclors 12(0 or 1254 does not induce benign or malignant tumors of the thyroid gland, adrenal gland, uterus, lung, hematopoietic system, pituitary gland, thymus, kidney, and other orqans in rats. 5. Summary and Opinion Animal studies do not provide convincing evidence that pCOs Induce liver cancer. Of the major studies in the rat, one has been judged positive and two have been negative. Hepatic carcinoma was not produced in the dog. Chronic administration of Aroclors in the rat did not induce bladder cancar, gastrointestinal carcinomas, or cancer of the thyroid gland, pituitary gland, adrenal gland, uterus, lung, hematopoietie system, or other organs. a. Clinical Studies The studies of Brown and Jones (ItSU and Bertatsl and co-workers (19*1) have evaluated the relationship between eapoeurs to PCS* and the subsequent development of cancer. Both analyses are retrospective aortality studies of workers to determine the cause of the death and, for malignancies, the specifle type of cancer causing the death) the deaths are designated as 'observed cases.* The person-years of esposure HONS 025402 - 97 pf the workers to PCB were dtttnumd and combined into calendar tise period* and five-year ape groups to calculate from mortality varieties the number of 'expected* deaths. The number of ob served versus expected deaths was then compared. Background data relative to these studies are summarized Briefly, as follows: ft) Brown and Jones (1981). The authors analyzed It] known deaths occurring among 2,567 workers exposed to PCBs for 39,019 person-years. Exposure to PCBS rangsd from three months to over 20 years. The type of PCBs used at the plants were Aroclor 1234, 1242, and 1016. (11) Bertaul et al. (HS1). The authors analyxsd 27 deaths occurring In 1,310 workers exposed to PCBs for 20,MS psrson-years, detsrainlng 'observed* versus `sxpectsd* ratss for malignancies. Mortality was studied for a 25-year period (1SS4-197B). Exposure up to 1964 was ssinly to Aroclor 12S4 and Pyraline 1476; starting in 1965 mixtures with 421 chlorine were used (mainly pyraline 3010 and 3011). (ill) Bahn et al. (l7t, 1977). These authors report two cases of malignant melanoma in 31 .men exposed to Aroclor 1234. It is not clear free their studies if they are discussing morbidity or mortality; Brown and Jones (19B1) interpret the report as mortality. Pertinent data on tho mortality from malignancies are summarised in Table B and ars discussed below. 025903 KQNS 98 All Hal tenancies. Brown and Jones reported 39 obnrvM cases of cancer versus 93.8 expected cases. whereas Bartam at al. found a statistically significant increase l(1 mala*, but not in feeale workers (Tabla 8). Thara waa no incraaaa in tha risk of aortality froa all malignancies with length of axpoaura or with tha number of yaara of employment (Brown and Jonas, 1911). Baetua. The only atatlatleally significant differanea obsarvad in tha atudy of Brown and Jonas was for racial eancsc in faaalas froa Plant 2 (Tabla 8). Thara was no significant finding for faaalas in Plant 1, aalss in Plant l or 2, or for tha coabinad data for aalas and faaalas. Tha incidanca of ractal cancar showad a alight, but statistically Insignificant, ineraaaa with Inctaaaa in latencyi no direct relationship with Increased length of exposure la apparent. Bertasil at al. (1911) did not report a csss of ractal cancer in pCB-exposed individuals. Stosach, Pancreas. Tha studies did not deaonstrace an increased risk for stoaMCh or pancreatic canear (Tabla 8). Hepatocellular Caret no--. Three eases of liver cancer were observed in the atudy of Brown and Jones (1911), but tha difference froa the control rate waa not reported to be statistically significant (Table 8). Bertassi and co workers did not aantion observing any case of hepatic cancar. Ixaaination of the data for latency affact or for length of axpoaura to PCBs did not show any relationship to developawnt of livar cancer (Brawn and Jones, 1981). HONS 025404 40 ttbla I QFtaw ftbOCiHc Tvoai of Ctncar Coaparnan of Obaarvaa Oaatns in PCI Honiara MICA Cxpactaa OaatAa Nua--or of Caaaa aafaranca 1 2 3 Malianaaev iU !! Otaarv-- laoact 14.F 3* 41.79 H 3.32 F 4 2.33 V aeti ft l 4.91 1 Ffplaat 1) 0 0.11 rtpiaat 21 ) 0.S9 l n.t 4 1.19 1 fUMM n.t 1 i.oo i fanoraaa n.t 1 l.M 2 Difootiva Ocfoao Utara*. paaaraaa, biliary traati H T ) 0.19 0- l M090CU ClrtiMM n.t 3 1.07 l LjMObatla l ianMPMU 2 2 n.t n t 2 4.34 2 0.49 2 0.4ft ) Will- N 1 n.r 2 n.t 2 0.04 0- lumtieai a Sianifleanea 10 NS 241 P0.04 230 NO NO NO MO.OS 33ft NO 40 NO 93 NO 340 NO * NO 210 NO 40 NO 419 NO 444 I-- MO.001 - NO ` NO M 1. M 2. M ] Ml* 1-- i 3mm, 1901 artaasl o al.. 1901 Ma at l., 1971, 19J7 IUbIu^Iim --miiiy ratio (abaarwao OaatM/aNpaota* <MtM ISO) IN llpiliiMt HOMS 025405 100 Lynphltic and Hematopoietic Cancer. The two studies show diametrically opposite risk values, although nsithsr is ststisticslly significant (Table 81. Helanoma. 8shn il. <1976, 1977) rsportsd two essss of malignant malanoaia occurring among 01 man who had hasn exposed to Aroclor 1254. Basad on tha Third National Canear Survey incidence rates. Bahn at al. calculate for a person-year analysis that only 0.04 malignant melanomas would be expected, the difference being statistically significant (P*0.fl01). The extensive studies of Brown and Jones and of Bertassi at al^. fail to confirm the increased risk of mortality tor malignant melanoma reported by Bahn and co-workers (Table 8). raising doubts about the significance of the Bahn studies. Even an association with the low p value of 0.001 hae not been con firmed. Summary. the clinical evaluation of PCSs relative to cancer la currently baeed on a limited amount of data, and any concluaion regarding their effects must be regarded as tentative. Neverthelees, ease detailed analyeee are available and conclualone beeed on them, as listed below, are of seme significance. 1. Retrospective mortality studies have not demon strated a consistent relationship between exposure to PCBs and the development of a particular type of cancer. 2. The clinical findings on hepatocellular carcinoma are of great interest as some experlamntal studies report an HONS 025406 101 - lncraaaa in Unr cancer In rodenta receiving PC8a. Although Brown and Jonaa (19*1) obaarvad theta caaaa varsua 1.07 expected eaiat, tha difference ia not statistically significant. Thtir analyala of PCS exposure and rlak of mortality from liver cancar ia alao noteworthy ainca it did not danonatrata an affaet of latancy (nuabar of yaara froai data flrat amployad) ar a ralatlonablp to lneraaaad duration of aaploynant in Joba Involving PCB aapoaura. Thaaa lattar obaarvationa ara, howaaar. baaad on aaall nuabara. Bertaxxi at al. (1981) did not raport any significant ralationahip batwaan PCB aapoaura and liver cancar. Taken together thaaa atudiaa do not confirm tba projection of a riak for livar cancar in humana baaad on tha animal atudiaa. J. Tba SUB (Standard Mortality Ratio) may vary aidaly in diffarant atudiaa. and amphaala ahould not ba plaead on an lncraaaa in tha SMB found in ona atudy unlaaa a significant change in SMB can ba confirmed in aavaral repeat atudiaa. Por example, Brown and jonaa found the SMB for lymphatic and hematopoietic malignancy to ba decreaaed while Bertaaal at al. reportad an lncraaaa. although neither raault waa atatiatieally algnlfleanc (Table a). 4. Broma aad jonaa obaarvad a atatiatieally aignifleant inereaae la SMB tor rectal cancar in woman at ona plant, but net in a different plant, and no algnlfleant attact in mala workara at altbor plant waa obaarvad. tortaxxl at al. HONS 02540? 102 did not capoct any cactal caneac (Tabla g). Ovarall, ttiarafora, a convincing damanatration of racial cancar aa a raault of axtandad axpoaura to PCBa hat not baan mada. HONS 025*08 103 - IX. Reproductive Effects _ A. Reproduction Numerous reports have appeared in the literature on Uh effects of polychlorinated biphanyla on reproduction in pnimals. Gallart and Wilson (1979) shoved that female Spraguapavley rata givan 30 mg/kg Aroclor 1221. 1242, and 1260 By gavaga during daya 14 througb 20 of pregnancy bad no effect on the reproductive function of the offspring aa judged by (a) normal aatrua cycles, (bl normal appaaranca of ovaries and uteri, and (c) fertility of males. Feeding 550 ppm of Aroclor 12S4 for 67 days to Sherman rats resulted in fewer litters, smaller litter aiaa, and 104% mortality by day three of the ria pupa. At 100 ppm survival of both ria and Flp offspring was reduced. The pups were smaller than controls but appeared nonaal at weaning. Aroclor 1260 fed at a dieeary level of S00 ppm (35.4 mg/kg) for 67 days prior to mating markedly reduced litter else and survival-to-weaning in the Fla and Flp generation. Dietary levels of S ppm Aroclor 1234 and 100 ppm Aroclor 1260 had no effect on reproduction in rats exposed through two generations (Under at aU, 1976). A dietary concentration of 2.S ppm of Aroclor 1269 produced alteration in the menstrual cycle of adult female rhesus monkeys. (lenses were prolonged and menstrual bleeding was increased (Allen et al., 1979). Kapilnger tt il. (1971) fad rats and dogs Aroclor 1242, 1234, and 1260 at doses of 1.0, 10.0, and 100 ppm. mo adverse MOMS 025409 104 - affect on reproduction was observed in rata given 1,0 and 10 ppn Aroclor 1242, but there waa a decreaae in survival of pupa at loo ppm of Aroclor 1242, 1254, and 12(0 as well as a decrease in mating indices. The effect of PCBs on reproduction in beagle dogs and swine has been studied by Earl at al. (1974), Aroclor 1254 interfered significantly with reproduction m dogs at doses above 2.5 mg/kg/day while in swine 10.0 mg/kg/day lowered fertility and survivability of neonataa. The reproduce tive effects In doge are questionable because of unesplalned changes in the reproduction pattern aaong controls. 8. Teratogenicity 1. Introduction Teratogenicity la that property of an agent whereby it is capable of inducing congenital defects in the developing embryo. Such agones that ars chaaical substances are known as 'teratogens* and the defects they Induce are known as 'terata.* Although teratogenicity is considered generally to involve only anatoaical detects, soae authorities regard functional or biocheaical changes as aanitestations of teratogenicity, A distinction aust be made between teratogenicity and Iatotoxiclty, l^e., toxicity to the fetus. The finding of dead or reaorblng fetuaea In the uterus of an experiaantal aniaal is not evidence of a teratogenic action of the test substance. Slailarly, a smaller else of the newborn is indicative of fetotoxlcity rather than teratogenicity. HONS 025410 105 A substance may appear to be teratogenic 1! it proluces severe toxic ffacts on tna pregnant femala. maternal llsease and malnutrition affact the number and quality of the Offspring. Defaces in tha offspring that are secondary to toxic if facts of the substance on the mother are not considered teraea. Teratogens produce their harmful effects during the period of formation of cells* tissues* and organs. Hence* once davelopaMnt of the fetus has been completed, a teratogenic vent can no longer occur. Chemical substances administered to tha mother can be transmitted, together with their metabolites, ela tha milk to the suckling young, and may produce toxic effects in the latter. However, such effects are not indications of teratogenicity. Conventional teats for the detection of teratogenicity Ineolve administration of the test substance to pregnant females at repeated intervals throughout the period of organogenesis, j.j., days ala through IS of the gestation in the rat. The treated females ars sacrificed on the day prior to parturition, and the fetuses removed from the uterus aurgicslly tor examination, alternatively, tha test substance nay be administered over rela tively long periods of time, and the animals allowed to breed normally as la the usual one- to three-generation reproduction studies. Os appearance of aalfomad offspring among the succeeding generations would be evidence of teratogenicity. In ordur for a chemical substance to which the aothar Is exposed to exert a direct action on tha concaptua, it or one HONS 025411 106 or mort of its metabolites muse os able to cross ths placental barrier. Trsnsplscsntsi passaqs of PCBs ns bssn demonstrated in scvsrsl snimsl spsciss (Allen st al_., 1980; Curlsy se si., 1973; Couwillion st si., 1974; Cianc sc il., 1971), snd is known to occur in ths human (Funatsu st si., 1972). 1. Hies PCBs wars noe teratoqenie in mica st dosaqss up to ;oo mg/kg given on days ona through six or days savan through 11 of gestation (TosrusX. 1973). Howavar, a raesnt study (Harks at si. 1981) with ths hexachloroconqanar 3.3 , 4,4 , J,S'-hssschlorosiphsnyl in mica at dosaqss in ths range of 0.1-18 ng/kg/day dur ing days six through IS of gestation produced a significant In crease in fatal malformation, a significant decrease in average fatal weighe, and an increase in the percentage resorptions. Torok (1870 reported that oral administration of 375 mg/kg or 7S0 mg/kg of 2.2'-dlehlorobiphenyl to mice on days ona through three of gestation resulted In prolongation of the interval between breeding and parturition. He attributed this observation to delayed implantation, although the treated animals had fewer litters and lesser mean litter sites, there was no indication of teratogenicity. Boats mice exposed to 3,4,3'4'-tetrachlorobiphenyl were reported to exhibit a 'waitsing syndraoa* (Davis at al., 1979; Tilson at al., 1979). The dosage vas 32 aq/kg administered by gavage to the mothers on days 10 through 18 of gestation. The HONS 025412 107 pyndroee consisted of ineraaaad motor activity, hyperreflexia, and apiaodaa of haad bobbing and rotational movements that wart present Up to at laaat eight montha of age. Not all axpoaad mica vara at factad similarly, but avan thoaa that did not exhibit the pyndroao howad diainlahad performance in varloua naurobanavioral tlata. Ttlaon at al. (1171) rafar to thaaa obaarvationa as tha 'behavioral teratology* of -CB. 3. tttl Thara ara a plethora of studies in which tha reproduc tive affects of feeding various Aroclors to rata have bean in vestigated (Calandra, 117* > Gellert and Wilson, 1171, Keplinger jt al., 1*71) Keplinger at al., 1171> Linder n il., 17, villeneuva at al., 1171a). Collectively, these studies rsportsd fatotosiclty as the dosage was lncrsased, but no taratogenicity was daaonatratad. It say be useful to note tha order of aagnltude of the doaagaa Involved. Vllleneuva at al. (1171a) found no effect fros the adalnistratlon of doaages of up to 100 eg/kg per day orally to pregnant feaales froe the sixth through tha fifteenth day of gestation. ultraatsuctural lesions in thyroid follicular cells sad a reduction In same thyroid hormones have been reported in neonstel and sosnllng rats whose aethers had been fsd a diet esntainlng SO ppa or S00 ppa of Aroclor 1194 throughout the psrlsd of gestation (Collins and Capon, 1100). The authors suggest that alterations in thyroid structure and function in the fetus or neonate aay be related to subsequent disturbances la growth or davelopsMnt. HONS 025413 In tn study conducted by Earl at al. (19T), preqnant biechas war* given doaaqes of 0.25, 1.0, or 5.0 aq/kq of Aroclor 1254 from tha day of breedtnq to tha day on which thay were nacropaiad. At 5,0 aq/kq, thara waa an incraaaa in tha percentaqe of raaorptiona, a dacraaaa in tha number of liva pupa par Uttar at birth, and a raduction in tha percentaqe of thoaa aurvivinq to two waaka. Tha tarata obaarvad conalatad of enlarqed fontanallaa, cleft palataa, and auparfluoua phalanqee. This doaaga waa aaid to limit dial conauaption aevereW. Tha authors stata that ona Uttar of tha controls *may hava had a qenetie dafact that causad an unusually niqh insldanca of tarata.* 5. Swine Earl at al. (1*74) includad alniatura awlna (Horae1 strain) In tha lnvestlqatlon daacribad iamadiataly aboaa. preqnant sows wars qlven daily oral dosaqas of 1 aq/kq, 10 aq/kq, or 10 aq/kq of Aroclor 1254. Oosinq baqan 21 days bafora breedinq and waa continuad until the day of nacropsy. Tha authors concludad that doaa>ralatad affacta wara saan at all traataont lavala aa evidenced by dacraaaaa in tha nuabar of praqnanclaa. nuabar of lira plqa farrowed par littar, and parcantaqa of Uv offsprlnq after two waaka of aqa. Syndactyly and claft palataa ware obaarvad in tha younq of sows racaivinq 10 aq/kq, and patent fontanallaa and claft palataa in tha offsprlnq of those racaivinq 30 aq/kq. as in tha caaa of tha doqs, tha hlqhar dosaqas caused a aarkad raduction in food consumption. HONS 025414 109 6. Monkeys In * study rtporesd by Alien ct al. (1974), sis adult, feaele rhesus monkeys wars sd a diet containing 25 ppm of Aroclor 1248 (or two months. During this period, all animals developed characteristic signs of tosicity, although they main* pained a regular menstrual cycle. One animal died. At the beginning of the fifth month, or three months after discontinu ance of exposure to the teat substance, an attempt was made to breed the survivors. Three animals appeared to conceive, but only one succeeded in carrying her fetus to term. Although this infant was well developed, its body weight was considerably lower than that of the average rhesus infant. Examination of tha tissues showed no gross or microscopic lesions. In a second study by tha Wisconsin group (Barsottl et al., 1970 involving It adult, fesala rhesus monkeys, nine were fed a dice containing 2.5 ppm, and nine were fed a diet containing 5 ppa of Aroclor 1248. After seven months on these diets, the eight surviving anisals from the 2.S ppm group and eight from the 9 ppm group were mated with control males. All animals in the 2.5 ppm group became pregnant, but three of these resorbad their eabryosi tbs remaining five gave birth to live infants. In tha 5 ppm group six animals became pregnant. Theea lapragnatlons reaulted In three abortions, one resorption, one stillbirth (suffocation during difficult delivery), and one un complicated birth. At birth, the six Infants were small) how ever, other than their aaull stature and focal areas of dermal HONS 025415 uo hyparpigmantation, thair gtnaral appoaranca, hasngraa*. and osseous dsvslopnent as evaluated radiographically wars normal. Tha adult, tamala rhaaua monkeys that were tha ori ginal subjects in tha study discusaad abova vara (ad tha diats containing 2.5 ppm or 5 ppm of Aroelor 1241 (or aia months prior to breeding, throughout gustation, and for thraa aontha aftar delivery for a total of about IS Months (Alien at.. 19(0). Only It fasalaa vara brad, inasmuch as ona had diad and anothar was droppad from tha study (or soma raaaon not axplainad. About ona yaar aftar dlacontinuanca of tha Aroelorcontaining diats, tha animals wars brad again to control aalas. All of tha savan survivors in tha S ppm group conesivad, but only four gava birth to liva infants. In tha 2.1 ppm group, ona animal had an abortion and tha raoaining savan had uncom plicated dalivorias. Apart from thalr aomawhat smallar sirs comparad to tha young of tha control animals, tha Infanta appaarad normal. Analysss of adlpoma tlaauo from two stillborn Infanta of motbars in tha s ppm group showad tha pramanco of PCBm, but histological evaluation of adipoaa and othar tiaauaa ahownsd no abnormalItiaa. 7. Clinical Data runatsu ot al. (1972) atudlad in datall four bablas born to notbars who had lngostad rlcm oil contamlnatad with a haat-oachango fluid containing PCSm, PCOPm, and fCQa. Tha notbara wars among tha papulation sspomod In eho `Tumho* apiaoda. Thrss of tha four bablas asbibltad soma avldsnca of intrsutmrlno mal nutrition or ratardation of growth, and all four had dark brown HONS 025416 Ill - piaaentation of the akin that was most pronounced at the qenikalla, axillae, and near the finqarnails. The lama pigmentation fees notad-on the lips, qums, and palata. while ona or mors of the Infants displayad other clinical signs, no neuroioqical or cardiovascular abnormalities, nor any malformations wars obsarvad. Sfea pigmentation of tha akin and mucous isambranas disappaarad slabin two to fiva months of aga In all casas. . Summary and Opinion (a) In a variaty of tasta, coanaarcial PCS mixtures .(Aroclors) showad no taratoqanic activity in mica, rata, rabbits, and aonkays. (b) earl at al. t1*74) hava not damonstratad convinc ingly a taratoqanic action of Aroclor 1254 in doqs or swina. Ml svsluation of thalr work auffara from a paucity of information and tba peaaibla praaanea of a qanatic dafact in tha doq colony. Iba publlshad abstract tanda to bo aialaadlnq. eaaninatlon of tba unpublished manuscript shows that tha authors did not raqard tha two lowar doaaqaa as taratoqanic for althar spacias. Tha hlqhast doaa la aald to limit food consumption severaly in both apacisa Therefore, it ia likely that tha defects obsarvad in tha offspring ware tba result of severe maternal malnutrition, eases at el. (l7i) failed to find taratoqanic affects in swina <*en tha mothers were ted a diet eentainlnq soma 20 ppm of Aroclor 1243 throuqhout qeatation And nursinq. (c) The observations of Collins and Capan (10) on ultrsstructural alterations in tha thyroid qlanda of perinatal HONS 025417 112 cat* whose mothers were exposed to Aroclor 1254 are indicative of functional change* rather than of teratogenicity. (d) The occurrence of a "valtjing syndrome* in mice exposed prenatally to 3.4.3',4'-tetrachloroblphenyl might rep resent a true teratogenic effect (Davis et al.. 1979). this phenomenon usually results from a structural or funetionel defect of the middle ear. The dosage used to produce the syn drome is relatively high. While the expoeed animals were not uniformly affected Insofar a* the overt sign* are concerned. Ttlson et al. (1479) presented evidence to show a wider pre valence of more eubtle neuro-behavloral effects. It is not known whether this condition could be induced by a commercial PCI mixture. (a) The scientific literature presently supports the conclusion that PCS* present no appreciable risk of teratogeni city for humane, in our opinion, in view of the essentially negative teet results in tour test species and the questionable positive findings in the dog and in swine. c. fototoiicltv rabbits given 1.0 mq/kg of hroclor 1234 daily for 20 daya of gestation had no affect on the developing fetus but doses of 12.3 to 30 mg/kg were fetotoxlc. Rats appear to be more resistant than rabbits, as doses up to 100 mg/kg do not cause fatal deaths or malformations (Villenauve et *1,., l*71a). taferyotoslc effects of Mnaehlor 200 and 900 were produced in HONS 025418 113 - gpragua-Dawlty JC1 rata whan Cad ac lavals of 500 ppm in eha flat throughout qascation (Shiota, 1976b). Olats containing 0 ppn of Aroclor 1248 wara fetotoxic to rhaaus aonkeya. Fatuaaa and naonataa of mothars with Yuaho diaaaaa (pve davalopad aoaa of tha charactariatic aigna of diaaaaa aa Bftraault of tranafar of PCM to tha fatua and infant through Ua placanta and braaat faading (Yaaaahita, 1977i Hatauda, at ai.. 197li Yakuahljji at al., 197). studlaa in aica on tha tranafar of PCIa to fatuaaa and offapring indicata that tha aaount tranafarrad dapanda upon tha chaaical atructura of tha individual coapounda and tha poaitlon of tha chlorina atoaa within tha chaaical atructura (Hatauda at al., 1978, 1979). Aroclora 1242 and 12S4 ara potant lnducara of hapatie aieroaoaal anayaaa. A alnglo intraparitonaal injection of 1(0 ag/kg of Aroclor 1242 to rata incraaaad llvar waight, total aieroaoaal activity, aa aaaeured by hydroaylation of acetani lide and N-daaathylation of aalnopyiana, and hepatic cytochroaa P-490 Orucknar at al., 1972). The breakdown of endogenoua aubataneea auch aa progaaterone, eatradiol, and teatoatarone haa bean ebovn to be incraaaad in aniaala pretraatad with ehlorlnatad blphanyla (Ortoarg, 1078). It ia poaaibla that altarationa In tha aatabaliaa of tha andoganoua aubataneaa by PCM aay upaat tha noaaal balance that ia aaaantlal for iaplantatlon of the fertlllaad ova in the utarue (Saith, 1900). Paading a PCI alxtura containing 808 chlorine aignificantly incraaaad tha uterine waight of gulnaa plga (Voa, 1972). HONS 025419 114 - Yamashita 11977) studied the clinical features of PCS. pcop, end peg induced fetopathy in four babies born free mothers poisoned by contaminated rice oil. There was intra uterine retardation of growth, dark brown pigmentation on the skin and mucous membranes, edematous face, and exopchalmus. tn some cases the retardation persisted for many months but the infants eventually gained their weight for the age group. although over 100 nursing mothers residing in michi gan during 1977-1978 had residues of PCBs in breast milk rang ing froai 1.0 ppm to over 3 ppm, there have been no reports of serious adverse effects on reproduction or infant mortality (Micklxer, 1981). Suaaaary and Opinion 1. It is apparent from studies on humans and animals thae certain classes of polychlorinated biphenyls are more toxic than others and that the degree of chlorination is one of the determinant factors in their toxicity. But, as stated previously under cutaneous toxicity, the presence of contami nants may be responsible for the adverse effects on reproduction Oishi e al. (1978, 1910) compared the activities of PCBs and dibenxofurans in rats and found that dibensofurans markedly depressed body weight, decreased weights of the thymus, ventral prostrate, end seminal vesicles and reduced hemoglobin and hornet ocrlt values, while PCBs had little or no effect. HONS 025420 115 2. On the question of fetotoxicity in pcB-expoaed females, positive reaults art seen in certain test animals (rats, jogs, rabbits) whan the PCBs are administered at relatively high doses (greater than 10 mg/kg) to pregnant animals. In the human, the only reported evidence for fetotoxicity in exposed popula tions stems from the unique Yusho event, in which causation may not be linked to PCBs. No such reports have been mads on other exposed human populations, suggesting the absence of this effect in the human under occupational exposure conditione. HONS 025421 117 X. Mutagenesis A. Ctntril _ The term 'mutagenesis' refers to any promt chat Induces * permanent change (mutation) in the genetic composition ofca cell, thereby causing that cell to differ in a consistent pay from its parent. II a mutation occurs in a germ cell, the Offspring resulting from the union ol that cell with another Pill nave an altered genetic composition that will persist in the germ line unless the alteration ia lethal. Mutations occur spontaneously through unknown mechanisms, but they also may be caused by radiation or chemical substances (mutagens), while In a strict sense the tern 'mutation* applies only to changes In the DM* at the molecular level, it Is considered broadly to Include alterations In the number and atructure of chromosoaMs. Mutagenicity is the property of an agent, chemical or physical, to induce mutations. Chemical substances may be tested tor mutagenicity by a variety of methods, among which are those that employ (a) bacterial test systems, (b) cytogenetic analysis In vivo, (e) cytogenetic analysis In vitro, and (d) dominant lethality in a rodent. l, hactorlal Test Systems The 'Ames teat* Is the moat popular test of mutagenesis employing a bacterial teat system, rt ia a so-called 'backward' nutation system that uses a series of mutant atralns of salmonella tyshimurlum that have lost the ability to ayntheaise the amino HONS 025422 118 acid histidine. Hence, they can grow only if aaoqenous histi dine 11 supplied. A nutation has occurred if, aftir upoiura to tn chemical aubatanec, the organisms regain the ability to grow in tha absence of niatidina, Aroclors 1221, 1234, and 1260 shoved littla muta genic activity in tha Anas taat (Wyndhaa at al., 1976) vtth indieationa that Aroclors with lover chlorina contanta ara weekly positive in tha Salnonalla taat ayatana. However, thaaa raaulta nuat ba diacountad alnea thay could not ba replicatad (McMahon jl., 1979) Safa, I960). As a general finding, Haddla and Bruce (1977), neflahon at al. (1979), Schoany at^ al. (1979), and Safa (19B0) wara unabla to find avidanca of autaganlcity of PCBa in baetarial taat systems. C. Cytoganatlc Analysis in Vivo In this procadura, tha axpariaantal anlaal is traatad with tha taat aubatanca and, aftar a suitable period of time, sacrificed for examination of rapidly dividing tissues, lone narrow and tha seminiferous tubules ara generally tha noat frequently used tissues for this purpose, tt is customary to inject the animals vleh colchicine several hours before sacri fice in order to promote the accumulation of cells in the aataphase stage of division. In this stage, the chromosome can be examined more readily for abnormalities. In two investigations, PCBa ware judged not to have produced chromosomal abnormalities. Dlkshlth at al. 11973) HONS 025*23 119 examined aeainlferoua tubulea of rata at different intervale attar dally doaaqaa of 90 mg/kg ot Aroclor 1294. Green at al. (1979a) examined both bona marrow and epermatoqomal calli of rata aftar either a aingle doaa of 9000 mg/kg of aroclor 1242. or four dally doaaa of 900 mq/kg. in all eaaaa, it waa concluded that no alqnif leant ehromoaoaal daiaaqa had oecurrad. Tha micronuclaua taat la a taat for aqanta that tand to braak chroiaoaoaaa (elaatoqana). A micronuclaua ia a fraqmant of chromatin that haa brokan away froai a chromoeome during call dlvlalon and haa tailed to bo included in aithar ot tha dauqhter nuclei. Tha phenomenon can ba obaarvad beat in newly fonaad arythrocytea aInca thoaa ataln differently from tha matura arythrocytaa in that thay aahlbit polychroaaala tor a period of 24 houra or ao. rurthonaoro. the nuclaua haa bean extruded at tha laat maturation dlvlalon ao that tha alcronuclel. which remain behind, ara readily vlalble in an otlterwiae ehrematinfraa call. Micronuclei occur in a aaal1 fraction of normal rad calla, but their incidence ia incraaaad by tha action of claatogeno. The toot ia carried out by adalniaterinq tha agent to the taat aniiaal, and examining tha polychromatic arythrocytea in bona aarrow aaaara aftar aoaw interval of tlaa haa bean allowed for aieronuolal to fora. addle and Oruco (1977) reported Aroclor 1294 aa nega tive in a micronuclaua taat. HONS 025429 120 0. Cytoqanatic Analysis in Vitro Hoopinqarnar at *1. (19721 activatid eulturad human lymphocytas wi.cn phytohamaqqlutinin and craatad Cham with loo ppm ot Aroclor 1214 at various scaqas of a division cycla. Tha calls than wars axaminad for chromosomal abarrations for tha diffarant ataqa traatmants. Aroclor 1254 had no apparant affact on chromosomal intaqrity as maaaurad by eytoloqical avidanca. E. Dominant lathallty in Rodants A dominant lachal mutation is ona that occurs in a qar* call. Hbila it doas not impair tha function of that call, it tills tha fartilizad ovum or tha davalopinq aabryo. Mica and rats ara tha prafarrad aaparlaantal spacias. In its aimplast tons, tha cast consists of traatinq salsa with tha suapactad mutaqan, matinq tham with normal famalas, and countinq tha numbar of viabla of fsprinq. Tha tast could ba usad to datact dominant lathal nutations in famalas, but it would ba difficult to rula out adsarsa affacta on tha aabryo that aiqht ba sacondary to non-qanatic offsets on tha notbsr. Craan at al. (1175b) concludad that Aroclors 1242 and 12S4 wars not mutaqanlc sines thay fa Had to indues domi nant lathal nutations in rata. In similar atudlas raperead both by Caplinqsr at al. (1172) and Calandra (1174), Aroclors 1242, 1214, and 1240 wara adainiatarad to mala, albino mica in a alnqla intraparltonoal doaaqa of aithar 100 nq/kq or 1000 nq/kq. Subaaquant natlnqa of thasa aniaals to control famalas HONS 025425 121 shoved no effect o treatment on eh* number of implantation or resorption sit**, number of viable embryos, or prtimplaneacion loss. F. Summary and Opinion There is no vidone* fros in vivo ease systems that any coewereial PCI mixture is mutagenic. Th* Sana obsarvation told* eru* for eh* bulk of th* investigations employing in vitro technique*. In our opinion, therefore, it is quit* unlikely that the PCS* a* a class evoke nutaqenic activity in th* huaan, either acutely or chronically. Since chesical mutagenesis and careinoqenesi* often correlate for a qiven active cheeical, this opinion is reinforced by th* essentially neqaeiv* finding* on carcinogenesis in populations occupationally exposed to PChs (sections vm and Xti). MONS 025426 123 xi. other Health Effects A. Inivw induction 1. Introduction nose chemicals that ara allowed to anter tha body ara genvertsd by tha body to a variety of different chemical entitles. In this manner, food becomes transformed into energy. Chemicals, tenor than food or those that are naturally present in the body, that are introduced into the body are generally called 'xenobiotlcs,* and they also are frequently converted by the body to deri vatives of the original compounds. The conversion processes are regulated by the enrymatic systems generally termed biotranaformailon systems. Although there are a multitude of xenobiotic sub stances to which humans ara exposed, there are only a few different onsyme systems involved. The body beslcally biotransforms chemi cals by oxidising, reducing, hydrolysing, or combining (conjugating) the agent with other chemicals. Although each of these systems la Important, of particular interest here are those systems that result in conversion of the original compound to the oxidized derivatives. It is not uncommon for the body to react to some xeno biotic compounds that it normally blotranaforma by increasing Its ability to perform tbs biotransformation function by producing an increase in the amount of ansymes available. This process, Mich is called `induction* of the enzyme system, effectively mates the body more capable of blotransfoming not only the com pound that initiated the induction but also all other compounds MONS 02542? 124 Chat ara oxidized by th* same enzymatic system. in thia sannr It 11 feasible Cor a given xinobiotic aqtnt to Indue* a bio transformation system that affects th* ability of tha body to biotransform not only th* original compound but alto a large number oC other xanobiotica as well as some naturally existing chemicals within th* body. Shortly, it will be shown that th* PCBa in general have been described as being effective, that is, potent inducers of major oxidative biotransformation sys tem* in experimental animals and in th* human, via induction of enzymes, th* concentration of various normally occurring chemicals may be altered. The scientific evidence associated with those subjects will b* evaluated in terms of th* available currant literature. __ Th* major oxidative biotransformation system in ths body, as far as xenobiotics are concerned, is present in great est activity in ths llvsr and is present in lessor activity in moot other tissues. In experimental studies, the liver gen erally serves as a monitor of drug or chemical effect on ths oxidizing enxymas. The enzymes axe located In th* *nlcroenml* fraction of ths liver cells. This is a fraction of tha call that can ha obtained by proper ultracentrifugation techniques. The biotransformation system of interact la known as the nlcroscmsl sized function oxidase system" (NfO). Functionally this system operates to Incorporate oxygen into th* xeneblotlc agent via a series of enzymatic actions. The system does this by asking an 'active* oxygen atom available via a hamaprotain enzyme. This hemsprotein is in tact a family of proteins MQNS 0.2542a 125 identified as 'cytochroms P-450.' The ability ensyme to operate as an oxldativa systain is dependent PHiths existence of savsral naturally occurring substancss ph>. in particular, on tbs existence and quantity of availablt tochrome P-450 in the microsomal fraction of the livsr. Microsomal P-450 can ba measured diractly or indirectly various substrates. Direct measurement of p-450 is based measurement of the protein system from which these enzymes Ifctained their name, that la, when the enzymes are reduced and pgmblned with carbon monoxide they exhibit, in a spectrophoto meter, maximal absorption of light energy at the wavelengths of 451 nanometers, hence tha name cytochrome P-4S0 system. The Pm430 system can also ba measured In terms of its activity on specific substrates such as ethylaorphlne and antlpyrlne. jlaductlon of this system is measured in terms of an increase in p-450 and/or its activity (based on units of protein per sample of mlcroacmes). Investigations of enzyme Induction have separated tae p-450 enzymes Into two qroups, identified as p-450 and P-441 groups, on the basis that various components of the P-450 group of enzymes are 'Induced* to different degress by different xenobiatlc agents. The P-450 enzymes are those that are mainly iladmeed by tbe barbiturates, whereas the P-44S enzymes are mainly indmead by 3-motbylebolantbrene and show maximal absorption at 44P nanometers. Tha literature Includes studies that suggest that the P-441 enzymes as well as tha P-450 enzymes are induced HONS 025429 126 by ciruin PCB* although there appears to ba soae species and tisaua specificity in thair inductive properties. Invastigation* o the efacts of PCB* on cytochroaa P-450* have cantered on two areas of interest. One involved the induction mechanism via the usa of either a commercially available sample of a single PCB congener ' luch as 2,4,5,2',4'. 5'-hesachlorobiphanyl) that was synthetically prepared and could ba tagged with a radioactive atom to facilitate analy tical work. Generally, a group of experimental animals (rats) was administered the PCB. Sample* were then obtained at vari ous levels. Livers were than examined directly for the quan tity of cytochrome P-450 or indirectly tor P-4S0 and P-44S activity via its Smyrnatic action on various substrates. The liver may also ba examined histologically and for evidence of 7 the state of protein synthesis. Induction of the P-450 enxynes in the human is estimated by measuring the plasma elimination rate (plaeaM half-life) of antipyrtne in controls as compered to exposed subjects. Antipyrine is a drug that la completely absorbed when given orally and completely metabolised by the liver P-450 microsomal system. TBs ascend area of interest concerned the ability of the liver nieroaomal system to blotranafora PCB. of particular interest van tbs nature of the intermediate and final products of the biotransformation process. This subject is important in understanding the toxicology of the PCBa because of the follow ing hypothesesi MONS 025430 127 (a) Certain PCBs indue* eh* microsomal mixed funtion tion system* thereby influencing not only their own labolism hut- also the metabolism and time course of action available endogenous hormones as well as other xenobioties eluding drugs) administered to humans. (b) Certain PCBa or contaminants of commercial rations of PCB* may lead to tha formation of intermediate ids type derivatives, and these derivatives can covalently d to macromolecules in the liver thereby leading to hepatic iclty. 2. Induction of liver tnsvmea Various studies have reported on the effect of short (pm* exposure of rets to mixtures of chlorinated biphenyls. be such study by Ecooichon et el. (1974) used the Aroclors ISentifled aa Juroclor 1014, 1221, 1242, and 12S4, and another Btady by a Trench investigator, Nerbonns (1990), used a french Reparation known as fhenoclor DPS. In both studies the sample ssterlsl consisted of a mixture of congeners of the chlorinated Mfhonyla. These studies showed that when rats were administered II ppm of ths PCBa in their diet for only one day, tha'llvers from the aniauils showed induction of P-450, aniline hydroxylase, Md amlnopyrin* s dsmsthylase. The induction of these ensymas wee maximum in about five days. if the rats were given 10 ppm e* ths PCBa in the diet for eight consecutive days, induction oc- bacied in throe to five days and to a lesser extent over the resuiln- HONS 025931 128 ing eight-day interval. In the Ecobiehon study, intraperitones! mjtction of the Aroclors in doses at 90 rag/kg was made Cor chrsa consaeucivs days. Animals wars sacrificed 96 hours later. Mixed function oxidative enzymes wars found to be induced in the liver. The greatest induction was saan with the more highly chlorinated Aroclors. The conjugation enzyme induction occurred rapidly on exposure to the Aroclors, and particularly to those Aroclors that ars more highly chlori nated. The PCBa used In these studies were coausercial grade. in order to better understand which of the P-450 cytochromes are induced by the PCBa, Ryan at al. (1575) treated qroups of rats with Aroclor 1254. phsnobarbital, or 3-methylcholanthrsne. The livers wars used to prepare three different P-450 fractions on the basis of differing molecular weights and they identified the three fractions as p-450a, P-450b, and P4S0C. All three of the P-430s were obtained fro* the KBtreated animals. P-4S0a and p-450b were obtained from the phenobsrbital-treated rats and P-4S0a and P-450e were isolated from the 1-methylcholanthrene-treatad rats. (P-450e is prob ably equivalent to P-441). Therefore, this study ehoved that the Aroclor induced at least three identified cytochrosea including the type induced by phenobarbltal and the type induced by 3-eethyleholanthrena. In 15(0 Parkinson at al. investigated the validity of the concepts that were current at that time regarding the structure-activity relationship between specific PCB congeners *ONS 0i543 129 hepatic enxyee Induction. The study was designed to yield a structure versus activity data. Basically, they conducted ueerieents-in rats using eight synthetic PCS congeners plus phenoBrbttal and methylcholanthrene as ensyne inducers. They conBadad that in order Cor a PCS to induce a methylcholantnreneggppe or a mixed-type liver ensyne system, the PCB would have lie contain chlorine substituted at specific poaitions on the Benyl rings, whereas the PCB Inducers of the phenobarbetal |ype had multiple diverse structures that could not readily be Mined. Whether PCBs are administered Cor as short a time as as to three days or whether they are administered daily for up PS a year, various liver ensyaes appear to be induced, but the (henomanon of induction does not seen to be specifically eery hareful to the animals. Allen and Abrahaason (1979) fad Bata diets containing 100 ppm of Aroclor 1241, 1294, and 12(0 for 13, 24, and 52 weeks. The growth rate of these rata was scmparable to the controls but the test animals did show liver hypertrophy, some focal cellular degeneration, and an increase in serum lipids, la gsnersl, the effects were no greater in these animals that received the diet for a year than in those that received the diet for 13 weeks. Alvaros at al. (1973) published results from experi ments that Involved treatment of rats with Aroclor 1294. latrsperltonmal Administration of 23 og/kg/day for ait days 025*33 HONS 130 produced * tripling of cytochrome P-448 content of the livers end e 10-fold increeee in the eniyme activity involving benzo(a). pyrene hydroxylation (which is a typical 3-methylcholanthrene type of induction), as well as an increase in ethylmorphine-Mdemethylation (a typical phenoherbital type of induction). They therefore concluded that Aroclor 1154 induced a nurture of both P-448 end p-490. In 1977, Alvares and Kappas described some additional work that showed the ability of Aroclor 1154 to cross the placental barrier of the rat, to be transmitted to the neonatal rat through the mother's milk, and to cause increases in blotransfonaation emymes in the fetus and newborn. Goldstein et al. (1978, 1979) attempted to resolve the question of whether pure PCS congeners had eniyme-inducing properties that were different from those produced by commercial preparations of the single congeners or the PCS commercial mix tures (such as Aroclor 1294). These author* synthesised a 'pure* sample of 2,4,9,2',4*,9'-hezachlorobiphenyl and showed that it had different enzyme Induction properties than did the aaas commercially obtainable, specially prepared, congener that was reported to be *99% pure.* The difference in the induction capability of the two preparations was primarily in regard to tha Induction of P-448 cytochromes in which the synthetically pure isomer, at doses of 290 ng/kg administered to female rats. Induced aryl hydrocarbon hydrozylaae (AHHi a P-448 enzyme system) only five-foldi whereas tha commercial isomer at a doss of 90mg/kg produced a 30-fold increase of AM. Also, a GC-HS analysis HONS 025434 m of th* two preparations of haxaehlorobiphanyl showed that the commercial preparation contained four contaminant tnat war* not peasant m th* pure conqanar. Two of the** contaminant* war* identified as a tri- and a tatracniorodlbanzofuran (TCDf). TCDF waa than shown to M i potent inducer of AHH and cyto chrome P-4S. The CD (effective dose, 50% of teat animals) for TCDf ret enzyme induction waa found to be 0.5 uq/kq for three days. Therefore, tha conclusion waa that even a 99% pur* conqanar that was coanercially obtainable can contain auffleiant dibanzofuran to altar tha anzym* Induction action. In on* report, Alvar** at al. (1977) had studied alteration* in druq metabolism in both rata and humans. In tha rat study Aroclor lOlf elicited a barbiturate type of laduetlon of hepatic anayaM*. That Aroclor did not induce cytochrome P-441> however Aroclor 1154 did induce cytochrom* P-44*. The human study involved five workers in a capacitor aanufacturlnq plant who handled primarily Aroclor loit. These aapoaed workers showed a low half-life (10.* hours) of antlpyrlne as compared to control non-aapoaed subjects (who Showed a half-lifa of 19.4 hours). The volume of distribution of tha druq in tha two qroupa waa not different, ao the com parison of the half-lives of tha druq in the two qroups la valid. Thus, ansyme induction occurs in th* human in response to occupational aspoeura to Aroclor 1014 and th* induction HOMS 015435 132 as measured by antipyrme metabolism is a P-4S0 type of induct ion. In 1975 Bickers al. rapoctad on tha effects on liver enzymes aaaociatad with topical adminiatration of immar- sion oils (aa usad in microscopy). These immaraion oils were known to contain approzimataly 30* PCBa. Ona to 10 mierolitar* of tha oils wars appliad daily for six days to tha shavad backs of rats and tha animals wars sacriflcad on tha savanth day. Tha authors found that both skin and liver anzymaa wars tnducsd. In a sacond axparimant 10 microlitars of tha oil wara topically administarad on ona occasion only, and tha animals wara aacri- ficad at various intervals following application of tha oil. P-4S0 and livar monooxyganaaas wara induced (including banaoa a-pyrene hydroxylase, a P-441 enzytse system) showing saxiaal affect in two days with a slow return to normal by 21 days. Cn this study there must have bean vary large differeneea between individuals in the control group because their data show vary large differences between groups with only a 9J* significance. The lxaaersion oils currently marketed in tha u.S. do not contain PCls. 3. metabolites of PCba Shlmada and late (19101 studied the reactive metabo lites of PCI metabolism. Their work involved tha use of isotopelabeled PCI congeners. This work suggests that PCI epoxides may be the activated forms that covalently bind the macromola- eulas in the liver calls. A hexachloxoblphenyl congener HONS 025436 133 (2,4,5.3'.4*.5'-hazachlorobiphanyl) that haa no adjacent unchlori nated atom* In tha biphenyl rint and that cannot ba eonvartad to tha epoxide waa found not to ba covalently bound although accumu lation of this PCS in tha liver waa found to occur, othar pChe ahow covalant binding that ia principally with microaomal protaina rathar than tha riboaomal rna; a conclualon baaad on tha finding that varioua protaaaaa would aelublllza tha radioactivity of tha labalad atoai. Traatmant of tha anlmala with phanobarbital producad llvara that ahowad good covalant binding to tha PC*, but traatmant of tha anlmala with mathylcholanthrana producad llvara with poor PCI binding capability. The authora concluded that PCS epoaidea wara formed by tha aonooxygenaaa ayatarn and thaaa epoxidaa ware reeponaible for tha binding of tha coapound to aieroaoaal protaina. Thoir conclualona are baaad on Indirect flndlnga. 4. Interaction* baaed on tha Induction of Enzymea by ream One report Imurphy at al., 1971) deacrlbed atudlaa that tha authora claimed Indicated tha ealatance of a drug Interaction In tha fora of potentiated lethality of fluroaane In Aroclor pre treated anlmala. The author* did ahow that tha Aroclor* induced hepatic enzyme*. Their method of aaaaurlng enzyme Induction waa to aaaaur* the aatabollam of warfarin by llvara of the Aroclortraatad anlmala according to a procedure that they had developed and that they claimed could differentiate between Induction of p-430 aa coaparad to 9-440. They found that Aroclor 1234 In rata aalnly induced cytochrome 9-440 where** Aroclor 12(0 Induced mainly HONS 025937 134 cytochrome P-450. The authori then indicated that both Aroclora caueed animala to show increased lethality on eubeaquent administration of fluroxene. We hava difficulty interpreting thia articla. Ha do not baliava that tha concluaiona ara aupportad by tha data that ara given. In ona caaa involving Aroelor 1260 tha data ara not givan in tha tabla and in tha othar caaa tha data obtainad following administration of fluroxana do not appaar to ba diffarant from tha control data. 5. Enzymes Othar Than Cvtochromaa Affactad by PCa Two additional raporta daal with an action of tha Aroclora on ATPaaa activity. Ona of thaaa raporta (Lao and Park. 1976) uaad cultured human lyaphocytaa and showed a doeeraaponaa ralation for Aroelor 1294 and inhibition of mitochon drial raspiration. Proa thia affect they indicated that there may be a dacraaaa in adanoaine triphosphate (ATP) concentration, we can aeo no way to evaluate vhat thia report meana ainca tha concantrationa of tha Aroelor uaad ara not corralatad with concentrationa that might ba involved in intact biological ayatame. Tha othar report (Lahocca and Carlaon, 1979) indicat ed that tha Aroclore produced in vitro Inhibition of rat magnaaiuai ATPaaa activity at a concentration of 30 p%m. a weak corralation woe found between incraaaing inhibition and iacreaaing chlorination. A atrong corralation waa found between PCb-inducad inhibition of the ATPaaaa and dacreaaing aquaoua aolubillty. Ha do not know what thaaa reeulta algnify HONS 025438 131 - ether chan that they seem seen to ha incidental flndlnoa many other chlorinated hydrocarbon! do cha same thine. S. Summary and Opinion The available data from experimental studies on animals IM man indicate that the coauaercially available preparations of the KBs (Aroclors) as well as some highly purified PCB congeners act to induce some of the hepatic enxyoes. Considerable effort Baa been devoted to determine which of the microsomal enxymea are induced by the Aroclors. There are some data that Indicate that the predominant Induction occurs for the P-450 type of cytochromes (Identified as a phenobarhltal-type of Induction), when expericents are conducted with the 'more pure* congeners there la very little evidence for Induction of any ensyaie systems other than the P-430 cytochromes. In qeneral, Induction is createat with the meat hlfhly chlorinated derivatives, but the lease chlorinated deriv atives also Induce the P-4S0 cytochromes. The subject of whether the 'pure* conveners of the PCSa have less action on the cytochrome systems than the ccmmarctal satertala may be only of academic Interest, since the preparations that ere available to industry and the public are the comaMrcial preparations such as the aroclors. Xt should be recognised that authors tend to describe effects due to KBs whereas they are usually referring to effects of Aroclors (such as Aroclor 1234), which are mlsturea of KSa plus various trace contaminants. The commarclally-avallable preparations of the KBs are capable of Inducing certain hepatic ensymes in the rat and there is one report suggesting that occupational exposure to HONS 025439 - US - commercial PCBa may indue* a hepatic *nxym*. Thsrs ar* no data suggesting that th* ovsrall health of th* animals or aan la influanead as a consequsnc* of PCB-Inducsd microsomal aniysta. Although it is suggested hy soma paopl* that changing th* aetabolic transformation capability is inharantly detrimental to th* animal, there is no real evidence to aupport such a hypothesis, whan ensymas ar* induced and tnay ar* than involved in th* bio activation of xanoblotle agents, such enzyme induction could be harmful depending on th* dosage sequence and th* inherent toxlcologlc properties of any specific agent. On the other hand, if th* enzymes that ar* induced ar* involved in bioinactlvatlon of xanoblotle compounds, then Induction may be beneficial to the animal again depending on the dosage sequence and inherent toxi cologic properties of any specific agent. There is no good ex perimental or clinical evidence that PCls nay act throuqh their enzyme induction capability to affect *hormone" levels and result in harmful effects on th* body. a. PO iffecta on immunocompetence A few reports appeared prior to 1970 that auggeatad indirectly that PCBs may Influence lmeunocoopstence. In 1970, vt>* and Koeoan showed that when chicks wars fad 400 ppm PCS for (0 days they showed atrophy of th* splenic pulp and lymphoid necrosin. (Chicks at higher doses all died during the test.) The chicks also showed porphyria and liver necrosis. In 1971, woe and aeons reported that coaaaareial PCS saaplaa applied to >0hS 0*5440 137 the skin of rabbiti daily five times weekly for 38 day* (27 applications aach containing 118 mg PCS) produced histologic atrophy of the cortaa of the thymus and a reduction in the niaaber of germinal centers in the spleen. At this time the animals snowed marked chloracne of the skin, increased fecal eoproporphyrin and protoporphyrin, as well as liver and kidney damage. The authors stated that these effects were strong in dicators of an iamunosuppressive action of the PCBa. In 1877, Loose and co-workers fed Aroclor 1242 to nice tor sis weeks. The animals were then immunogenleally Stimulated with sheep red blood cells as an antigen and the antibody response was measured. The method of measuring anti body sotivity Involved plaque-call estimation in the spleen and the measurement of the plasma Inmnoprotelnm. Positive findings were obtained am compared to controls and the authors particularly remarked about the reduced IgA levels found in the KB-treatsd animals. It was also noted that clinically aubtoaic levels of Aroclor 1242 wore profoundly iwanoauppresalve. These authors also cite the work of lollar and Thigpen (immunosuppres sion by a PCS to pooudornbles virus in rsbblts), vos and van Srial-ttootanhula (immunosupresslon by PC* in guinea pigs), and Mend and Trainer (increased mortality in duekllngs that had been previously esposed to Aroclor 1284 and then inoculated with duck bopmtltis virus). HONS 025441 138 - In 1976, Loosa and co-vorkars studiad tha affacta of PCIa on boat rssistanea syatams. Mica that wart fad diata conraining 167 ppm Arocior 1242 for thraa waaka and for aix waaka axhibitad incraaaad aanaitivlty to aalmonalla andotoxin and a dacraaaad aurvlval tin# to inoculation with malaria. Thua thay concludad that boat raaiatanca was impairad by prior traatmant with PCBs. Alao in 1976, Thomas and Hlndadill raportad on atudiaa in which thay fad monkaya 2.3 to 3.0 ppai PCB (Arocior 1246). Aftar aix months tha monkaya davslopad chloraena. aiopacla, and facial adaaa. Aftar 11 (nontha control and traatad monkaya wara eaatad with antigana (ahaap rad blood ealla and tatanua toxoid). Tha only peaitiva finding waa in tha 3.0 ppai aonkaya who ahowad algnificantly lowar antiahaap rad call antibodlaa aa compared tor controls. Ho affact waa obtalnad ragarding tha antibody response to tatanua toxoid. Thaaa authera alao fad mica up te iOOO ppm of tha PCB for thraa to five waaka without evidence of ovart toxicity, but thaaa animals did show a highar mortality dian ehallangad with tha pathogan salmonella tvon1murium aa compared with tha control*. in I960, olahl and Riraga raportad on thair atudiaa in which thay hod given mica PCBe (commercial product) by oral intu bation onca weakly for four waaka. othar groups of mica wars fad COP (ehlorinatad dibensofuran) or COO (chlorinetad dlbanso-p-dioxln) Only tha groups of animals that had received 10 or 100 HONS 025442 139 pg/kg CDf showed decreased thyiaus weights. All groups were Challenged with endotoxin and again only the CDP-pratraated pnlualt anowad ineraaaad lathality coaparad with tha controls. ft la notaworthy that tha authors found no daaths in thalr con trol anlisals divan endotoxin, a finding that raiaaa doubt about thalr experimental design. In thla study tha PCS pratraatad aniaala did not show ineraaaad auscaptlblllty to andotoain. tn aba aasM yaar (19(0) Inanlshi at al^. ahewad that niea tad peas for 31 daya at 100. 200, or 400 ug/gn wars significantly more aaaeaptibla to harpaa aiaplax virus and alaetroaalia virus than wars aniaala fad a PCB-frsa dlat. In 19(1, Chang at al_, raportad on tha ianunologlc avaluation of patianta froa Tainan who danolopad an aena-llks ahln dlaoaaa, taraad Tu-Chang dlsaaaa, that waa ralatad to tha ansunptlon of rlea-bran oil eontaainatad with PCBs, peers, and VCQa (in an aeeldant vary aiallar to Yuaho). The authors had } such patianta who ahewad average whole blood PCI lavala of 4S pph, with a range of IS to 90 ppb. plua an additional control groap of 33 healthy persona aatchad according to ago and sax who showed no detectable lavala of PCX in thalr blood. Tha patients had decreased concentrations of IgA and IgH lanuna globalin but not IgC. Tbolr study of subpopulations of lynphocytaa showed that tha pareantaga of B calla was not affected by the dlsaaaa but the percentage of sons apaciaa of T calls waa daereaaed as compared to tbu controls. HONS 025443 - 140 Environmental chemical affects on imjaunocompecenee have bean extensively reviewed by Faith, Lueter, end Voe (1990). A number of atudiee cited by them found PCEe to be iitvninosuppressive in various species (from due*lings end chicks to mice and monkeys), in some cases at does levels that produce little effect other than hepatocyte hypertrophy. Only one study (Street and Shanea, 1975), which involved feeding Low levels (0.19 to 6,5 mg/kg/day) of Aroclor 1254 to rabbits, showed no significant effect on humoral or cell mediated re sponse. Our review of the Street and Sharma report indicated that there was a dose-related trend toward imaunoauppreeeion in their animals and at the higher doses (2.1 and 6.5 mg/kg/day) for four to eight weeks the animals showed significant increase in liver weight. The raith. Luster, and Vos review lists several general factors (nutritional status, hormonal levels, and amounts of lmsamoregulatory proteins such as alpha-fetoprotein) thst Influence immune function. Therefore those studies in which imaame function was studied following exposure to levels of the PCBs that rosuited in overt toxicity ere meaningless from an I ifatotoxlcologlc viewpoint. In contrast. Immunosuppression at dosage levels that do not produce general toxicity would bo significant. i--rv end Opinion The overall conclusion thst can ha reached In regard to the studies on the effects of PC9s on imninocompetence let HONS 0*54*4 141 with exposure conditions that load to general toxicity, Bmunesupprejsion may Ba demenstrabla, but it may ba indirectly Qtucadi (2) with experimental conditions wharam only subclinical psicity is observed, such as hepetocyte hypertrophy, there is the BMlbllity that immunosuppression it also produced; and (}) under (till lower PCS exposure conditions it is iapoesible thst imxunogpppression is involved. Perhaps the best study to estimate a noIflect dose for exposure to PCBs would be the Thoaes and Hindsdill study whleh suggests that six months* exposure to between |X3 end S ppe of PCBs in the daily diet of eonkeys is a threshold fbr effects on the tmune system. unfortunately* there are few data lirectly concerned with the dose-response relationship for effects M the PCBs on the isaune systes in anlaal node Is or the huasn. C. porphyria Tha administration of PCBs to rata will produca a dslayad typa of porphyria, i.t., dapoaition of porphyrins and thair degra dation products in tiasuoa and axcrata. Although tha machaniaa of anion of tho pcaa la unknown, it apparently differs from that of othar porphyroganic compounds such as harachlorohanzana or iaopropylacotamldo. It has boon thought that tha affset of peas in aaimals may indicate that tbaae compounds can induce conditions seeh aa porphyria emtamaa tarda In man, but clinical data have an shown this to oeeur in PCB-exposed workers. (1) Brporlmontal Data. The fecal content of coproporpbyrln and protoporphyrin of rabbles was lneraaaad by Aroclor 12*0 HONS 142 and by hexachlorobiphenyl, but the difference was statisti cally significant only for eoproporphyrin (Vo* et al., l*72b). Bruckner et *1. (1974) observed an increased excrecion of uri nary eoproporphyrin in rat* given Aroelor 1242, 9 or 25 ppm for two, four, and ala aontha. Goldstein il. (1974) emphasised the delayed onaet of the PCS-induced porphyria> rata fed 100 ppm of Aroelor 1254 becaaie porphyrie after two or aeven aontha of treataent. Although the excretion of eoproporphyrin and other porphyrin* waa incraaaed. the largest elevation waa in the uroporphyrin fraction. There wae aleo a narked accumulation of uroporphyrin in the liver. The studies of Goldstein at al. suggest that PCBe aay effect uroporphyrin fonsation or utilisation. The induction of delta-aainolevulinlc synthetase (ALA synthetase, a rate-liaiting enxyme in heaw synthesis) dose not appear to be the aechanisa by which porphyria la Induced by PCS, as it la for aany porphyrogen1c chemical*. In their studies the in crease in ALA synthetase activity was probably secondary to the porphyria. Also, Aroelor act* to increase liver cytochrome P-430 rather than to decrease it. Msaehlorobensene is known to Induce a delayed type of hepatic porphyria similar to that produced by Aroelor 1354. however, the two responses apparently differ signifi cantly as Coldateln e al. reported that the rata fad PCha did not exhibit the nervous or cutaneous signs associated with has*chlorobansene poisoning. HONS 025446 - 14] tit) Clinical Stiiim. Some of the rusho patients ingesting rica oil contaminated with PCB reported pigmentacion of the skin and nails, but chars wars no studias to avaluata a poasibla relationship of tha reported symptoms to any chants in porphyrin mataboliso (Ruratsuna, 1972). Saith at ai. (19(1 a,a,c) datarainad urinary eoproporphyrln, uroporphyrin and porphobilinogen in PCB-expoaed workers> thay did not find a corralation batvaan tha urinary perphyrina and tha sarua lava! of tha lower chlorinatad PCBs or tha higher chlorinatad KBs. Tha aubjacts did not hava any recognisable dysfunction and thora was no clinically apparant lllnosa with hl9h lawals of PCI aapoaura or with high sarua KB. Othar invastigations evaluating tha health affects of KB asposura have not raportad caaaa of porphyrin-related dlaaaaa or caaaa of porphyria cutanea tarda (Plachbein at al., 1979i Haroni il., 19S1). Tha observation that KBs incraaae ALA synthetase in Miaala raises tha possibility that KBs can causa an attack of porphyria in patients auffaring from acuta, intermittent porphyria, however, a case of this typo has not been raportad in tha aadlcal literature. M noted above in studies on the rat, tha action of teas appeara to diffar fron that of othar porphyrlc agenes. HONS 02504? - 145 - XII. Epidemiology Although um reports of toxic effects, especially skin lesions related to exposure to chlorinated organic chemicals, pays been recorded almost from the beginning of their use (fanes and Aldan, 1936), few epidemiological studies appeared tmtil the accidental exposure of a large Japanese population to PCM, pcors. and pCQs from the contamination of rice oil. Since that time, numerous studies have been undertaken to determine fbe health affects related to exposure to PCM in the workplace had general environment. It must be remembered that there were fecoblena in these studies in assessing the effects because some ef the environmental exposures may have Involved PCM that had Men altered by processing st high temperatures (frown, J.f., jr. fetal., 19*1). The numbers of Individuals exposed occupationally are relatively small, although same may represent the heaviest and moat protracted exposures of any reported, and their added harden of PCM from the workplace must be coopered to the back* ground levels that are currently present in all populations. Many of tho commonest changes noted in biochemical and other medical meaaureaMnta obtained in screening survays have not yet Men associated with any suboeguant development of disease. In order to evaluate the epldealologleal studies that assessed tha effaces of PCSm, we win discuss the results of Mortality data, morbidity data, and screening survays separately even though many studios Include data on several outcomes. HONS 025448 146 A. Mortality Studies In 19(81 an unknown nuabar o parson* in the waatarn part of Japan ingested rica oil containing KanacRlor 400 that was contaninatad with polychlorinated dibaniofuran* (PCora) in aaounts 250 tiiaas itoca than tha usual lavals in Japanasa PCSa (IARC, 1978) and nor* than 1000 tinea tha usual lavals in u.S. Aroclors. By 1977, 18(5 casas of *Yusho* had baan racognuad basad on syaptoas of ocular dlsturbancas, skin lasions, pri marily subjective naurological syaptoaa and blood PCS lavals (Uraba, 1979). rifty-on* daaths hava occurrad in thasa patiants and tha causa* hava baan raportad to includa livar eancars and lyapheaa*. Uowavar, thara hava baan no raports on tha masbars of aspoctad daaths by specific causes baaed on the usual death ratas in slsilar Japanasa populations. Tha distri bution of causes aay siaply represent the usual distribution of daaths found in the aga groups charactaristie of Yuaho patients, and so it is iapossibls to asaeaa tha aortality patterns of these cases at the present tine. Bartersi at al. (1981) haws reported a study of 1,110 workers, prodcalnantly woaan, who, beginning in 19(8, initially war* srpoeod to Aroclor 1254 and ryralane 1478 and suOsequsntly wars eipoeed to aisturas with 428 chlorine content. Hortallty data wars collected on all individuals with sis aonths or nor* of aploymant over a 29-year period ending in 1978. The total nua bar of deaths (27) was asall but there was an assess of aortality HONS 025449 - 147 - In Canals workers eoaparad to the general population, which is un(isual Car any working group. This study damonatratas a signiCieant excess Cor aii naopiasas Cor tho conoinad saxes and an excess SpaeiCieaily oC lyaphonas. It is difCicult to interpret chaaa lata sines tha typa oC canear incrinmated seena to diCCar Cron that oC othar studias. Further, tha data oC Brown and Janas Ham fane balow, and also tha coapilation in Tibia 8, saction vim on sorktrs in two Manufacturing plants do not confini a finding of ascaas aalignancias in PCB-asposad parsonaal. Tha unusual twoCold atcass in Mortality oC Caaala workars in tha Bartazzi at al. study dasarvas Curthsr attantion. A ratroapactiva cohort aortallty study of 1,387 workars la two alactrleal capacitor aanufacturlng plants that had uaad fCha for owar 30 yaars. idantiflad 183 daaths (Brown and Jonaa. 1*11). Tha typa of PCBa uaad owar tha yaars had variad and includa Aroclors 1234, 1242, and 1018, Tha ovarall aortal tty and total canear aortality wars low, but thara wars three-fold exeaasos of eancara of both tha ractuai and tha liwar (with a total of aowan daaths) although tha raaulta wara not statistically signi ficant. Tha only significant excess was that of the subaat of raatal eaneors in faaalea in plant 2. Tha standardised Mortality ratios (IM) for raotal canear, liwar canear, or cirrhosis did not increase with increasing latency or duration of aaployaent. Daises one can daaoostrata that tha risk of canear increases in association with increasing duration of aaployawnt, which serwea HONS 025450 148 * t proxy measure of dose, it 11 difficult to suggest that the agent 1a posaiBly cauaativa for the diiaaaa. although this study has davotad strict attention to details such as tha coaplatanass of identification of workers and ascertainment of outcome it has not verified the diagnosis of cases nor investigated the pretence of confounding vari ables. Rectal cancers are often misclaaaified by location in tha intestinal tract. The classification 'liver cancers* may include cancers of tha gall bladder and biliary system as well as metastatic lesions to the liver from cancers at other sites. Therefore when one has an excess of liver cancers, verification of specific site within the liver system at well as identifi cation of primary liver lesions is extreawly important, espe cially since the number of deaths from this cause is small. Tha investigators have not verified the diagnosis of either liver or rectal cancers. Since alcohol is considered a fre quent etiological agent for cirrhosis of the liver and possibly for liver cancer, seme information on consumption would be relevant as a confounding variable. Ho data on possible con founding variables have been reported in the paper. DM mortality data from the occupational groups and the Yueho patients are baaed on very small numbers of deaths and at present do not confirm a carcinogenic effect in man. Tha observation of excess liver cancer deaths in workers occu pationally exposed to PCSs is of major interest since the liver MOWS 025451 149 M target tlt Cor changes in animals and sinca man ftaa deaonstrated avldanea of subclinieal altarationa in livar <nctIon. if livar eaneara ara to Oa tvalaatad, tna diagnosis l primary eaneara of tha hapatic calls auat Oa conflraad a tha aortallty atudlaa tinea tha nuabar of eaneara In tha group "ill bo vary atMll. Tha availabla data deaonsteste a eonalatoncy In tha eanear aortallty pattarns in tha studios aad no data on a posalbla ralatlonahtp of eaneara to dosa pf cas. Morbidity or Incldanca oats Shin Skin lotions have bean reported In association with Mposure to chlorinated aroaatlc compounds since the early 1900't tJanas and Aldan, lt3). Taylor haa aaphaalied that aenefora avaptlons are aora frequent with tha chloronaphthalenaa and tha dlbensofurans and that tha variation In tha quantity of theaa subataacaa that aay be present as contaalnants In PChs aay account to* differences In reporting of akin eruptions with eapoaures. Taylor haa also reported that the acneqenie capacity of various saapouada changed according to their fora (fuses, liquid, or solid) *nd the degree of chlorination (Taylor, 1979). These factors aay also influence the presence of reported skin disorders in atudlaa. Hot only the frequency but the characteristics of skin lasIona have differed In the various studies. Jones and Aldan's erly description of the lesions they associated with chlorinated biphenyls included 'blackheads* or 'carbon-colored* conedonee MONS 025952 - 150 (outlines distributed in unusuel areas of the body and often associated with cystic areas and yellow pus (Jones and Alden, 1936). Taylor noted that the cystic swelling and hypersecre tion of the meiboeian glands are important characteristics of the chloracnegenic effect of PCSs compared to other similar chemicals. These were the typical lesions reported by neigs et al. in seven of 14 workers exposed to a PCS vapor leak from a heat exenanger In a plant In Connecticut tnelgs et al^.. 1954) . The exposure to vapors was intermittent but of extend ed duration, elver function testa were normal in most of these workers and no PCS levels in individuals ware obtained, although an air saaiple prior to the onset of skin disease was 100 ug per m^, which warn within the accepted standards. The patients who were initially described with yusho disease had lesions siailar to that described above in about 33% and a brownish pigmentation of the skin and nails in lot of patients. These frequencies ware increased subsequently to in clude about 70 to (St of patients because of new definitions of characteristics of disease or delayed development of the signs. The eyes were also Involved, exhibiting swelling of the upper lids, hyperemia of the conjunctiva and aye discharge (Kuratsune, 1072). Pigmentation of the akin and eye discharges also occurred in newborns of affected aothers. No comparison groups have been Included in these studies of Yusho patients. Where the lesions are pathognomic of PCB-related disease this may not bo necessary MOMS 025453 151 at when the lesions are ore general, eoaparlson groups ara Msantial. There were histopethalogical changes in five patients stopsled chat aaaa to ba associated with contaainatad nca oil Pupation. These changaa includad hyperkeratosis of hair follielaa ineraaaad aalanin piquant In eha baaal layer of tha apidaraia KA(C, 1971). Ttiraa out of tha flva eaaaa alao had prolifaration > ductal apithaliua of aaophagaal glanda. it would hava baan alpful If thaaa pathological asaaaaaanta had baan aada blindly .that qualitativa judgaents auch aa 'ineraaaad aalanin* could eve baan coaparad in aapoaad and non-expoaed groups. Correlating teas pathological findings with changing levels of PCSs, PCOPa. d PCQa would alao haws baan halpful but thara ara no reported ata relating to thaaa tsauaa in tha papara available, it is (awn that tha aaount of used Kanachlor in tha rlea oil conataMd !fep tha patients was between 0.5 and 1.0 g, which would Indicate a PCI aaposura siallar to laaala In occupational aattinga. Bara at el. in two separata papers (1974, 1975) hava 'described tha akin laalona in workers in a capacitor factory Mara Kanachlor had baan uaad. Tha sarua PCSs of all workers ranged froc 7 to 300 ppb bat it is net known how these values aaamlated with tha presance of skin lesions (Sara at al., 19741 are at al., 1975), Discontinuance of tha aaposura not only decreased tha overall PCS level to 79* of tha original value but tha akin lealens disappeared to 'vestigial markings on s few individuals.* Tha aweary of the report does not indicate HONS 025454 152 the correlation of CM blood PCS and skin laaiona although thara ara data in thia papar on tha half-Ufa of PCla in ralation to duration of axpoaura. Haaagawa haa reviewed tha haalth of uorkara in fiva planta whoae induatrial procaaa ineludad axpoaura to Kanachlor (Haaagawa at al., 1972). Tha induatriaa ineludad capacitor manufacture. PCI manufacture, and biphenyl recovery. The vapor concantrationa ranged from 13 to 915 ug/aJ. Skin laaiona ware reported to be unrelated to blood PCla but generally related to direct akin contact. Tha average blood PCI level waa 170 ppe. Tha principal daraal findinga included brown chrcaedernatoaia of tha doraal jointa of handa, fingera and nail beda and acna. Thara ware no further daacnptiona of tha latter laaiona ao that tha preaence of chloracna could not bo confined, but tha brown akin diaeoloratlon certainly ta typical of tha Japaneaa worker reporta. litaaura at al. daecrlbed 13 uorkara froa an electri cal capacitor aanufacturing plant (litaaura t <1., 1973). Tha laaiona in 10 of tha uorkara daecrlbed in thia group ara avan more vague. They did not include the typical coloration of nallai chloracna waa not directly dlagnoaadi and the follicular laaiona did net occur at polnta of contact with PCla. Proa tha deacrlptlon of the atudy it la not clear that the author'a conclualona that the akin laaiona ware duo to PCla waa juatified without further Intonation on the uaual frequency of alailar typoa of akin laaiona in nonal populatlona or a daecrlptlon of typical chloracna. Tha blood PCI lawal in thia group waa 120 ppb avaraga. HONS 025*55 153 Inoua *t al. studied eh* health of workers who were Imposed to Kanachlor 500 in a thread-glossing Caetory |inou* *e pi., 1975). The frequency of skin lesions was low. The blood fCB* war* over 50 ppb in seven out of 54 individuals studied. GM person had reprssentativ* chloracne with blood pels of 190-210 **> Ouw at al. described on* case of chloracne among 34 Setters exposed to krocler 1242 in capacitor aanufactur* (Ouw g* al.. 1974). The average blood PCS was 400 ppb. In addition Civ* workers complained of ecxeaatoua rash but there was no deeription of lesions. Seven out of IS process workers and sis let of If impregnation room workers complained of burning and Irritation of the eyes. face, and skin. It la difficult to recon*11* these COTplalnts with level of espoaure since it should have lean higher in the latter group of workers than the former. How ever, Aroclor concentration* in air as high as 2220 ug/e} were measured. The investigators indicated that the 'dermatological eamplaints* occur more often among workers with higher `blood hreclor levels* but they also Indicate there is no clear corre lation. It is difficult to be suru of eh* true meaning of dermatitis as elicited by history whan the anawers can be biased and the authors do not indicate which cases are related to physlial findings only. as part of a health hasard evaluation at a facility that manufactured electrical distribution equipment, NIOSa studied the 0i^b I40HS 154 - health o eight workers and found no symptoms or physical siens of chloracne (NIOSH, 1977). There were several subjects who reported skin rashes but not those typical of PCS exposure. The mean PCS level in blood was 9i ppb with the highest value being 294 ppb. Another health hasard evaluation was done after an ac cidental spill of PCSa (NIOSH, 19S0). In this situation there were no signs of chloracne. However, the mean blood PCI level of exposed workers was only *.4 ppo> this was below the mean for unexposed workers. Husiphrey studied the PCI level of indi viduals on the basis of flab consumption (Humphrey, 1975). He found that the PCI level was correlated with fish consumption with mean blood levels ranging from 4* ppb to S2 ppb and a maximum individual level of 111 ppb. Tiers were no skin lesions or other health problems associated with pels. A medical and biochemical survey was made of 120 male workers exposed to PCSa in the maintenance of railroad cars and locomotives (Chase at al., 1M1). Among the exposed group of I* workers the 'sMdlcal histories and physical findings* revealed `several cases of chloracne* -- "with none being found in the other groups.* Mo further details are given as to whether the conditions were currently active, nor was there a description of the lesions. It would bo of interest to confirm these cases aa true chloracne since the current seen plasma PCS level in the exposed group is only 33.4 ppb (range 10-312 ppb), a very low level of PCBe to be associated with chloracne. HONS 025457 155 flachbain at al_. (1979) conpleted a aedieal aurvey of Capacitor aanufacturinq worker* who wara self-aeiectad for phyaiaal and bio-chemical exaainationa. A hlqh proportion It5-sst> of aoth mala and fenala workara coaplainad of akin dimerdara with lit qivinq a hlatory of acna baqinninq aftar the onaat of axpoaura. `Bereatoloqic findlnqa* wara praaant on phyaical exaamatlon in 31 to 41% of fenala and sale workara, raapectively. owever, thoaa laaiona included 'erythema, awallinq. drynaaa, and thickanlnq,* which would not ha laaiona charactariatie of ICt eapoaure. Five parcant of tha atudy population had acnaform aruptlona. There ia no aantion of whether thoaa wara typical Of Chloraena or wara tha uaual acna laaiona found la any aadlcal Carrey. Since akin laaiona ara common in tha qaneral population aad aince the population waa aelf-aelactad initially it ta diffi cult to evaluate thaaa findlnqa. Tha avaraqa lower rca hoaoloquaa in plaana wara 134 ppb and of hlqhar PCCa, 4t ppo. The authora report that tha akin findlnqa warn correlated with plaana n-KUa. Unfortunately, if tha aaaainatlona wara dona with the obearver kaovinq tha job hold by tha participant, all reaulta can ba biaaad, aince reportlnq alqht be related to tbe job hold and tha tea levala warn related to job. Thera waa no note of akin hyparpiqoantatlon but 1st of workara had aye abnoroalltloa ineludlnq `injected conjunctiva and palpebral hyparplqnantatlon and adaoa.* Stain, it la not elaar how frequently thaaa laaiona would have boon reported la noreal aubjecta had aaaainatlona bean dona without knowladqa of aapoaura cateqorloa. HONS 025458 156 Haroni at al. (1961) recently reported on two 9roup* ,[ workers who war* axpoaad to PCBa in th* manufacture of capacitor* On* group (A) had baan axpoaad to both 546 and 42* chlorinatad biphenyl*. Although th* lavala of th* trichlorinatad cheaical war* ainilar in currant employees in tha two plants (126 ppo (a) and 137 ppb ()). th* levels of pantaehlorinatad agent diffarad (249 ppb (A) and *6 ppb (6)). tt is of interest that 10 caaa* of acn* and folliculitis appeared in tha two plants and at least four war* entirely typical of th* condition. All four typical case* occurred in nina anployaa* who had worked in a high power capacitor iapragnation area of Plant A whar* lavala of pantaehlorinatad biphenyls war* high. Their naan blood PCI was 450 ppb, a value not different from that of tha five un affected workers but certainly higher than th* overall laval* in tha two planta. Haroni at al. also noted two csms of bleedlog haaanglaaaa, but one had axiatad froa birth and tha only diffaranc* in hi* condition was that blooding had taken place after tha job atartad and tha lasion was excised. Th* other patient had bleeding fro* the tongue and a cavernous hemangioma was discovered as well as chronic eyalocytic laukanix. Case reports such as this and particularly the unusual circw ataneea surrounding aultlple conditions in on* patiane in th* second case sake such findings difficult to interpret. The re ports of ehloracne appear valid and suggest a problem. later at al. examined aludga users, workers in a ca pacitor plant, workers' faaiilles, and cnamunlty non-sludg* users HONS 025459 157 Bakar at al., 1910). Sine* the sludge contained pcha, it It that it* uaa fertilizer might seriously affect tha pc8 aval in tha blood. Tha level of Aroclor 1242 ranqed from 7.2 a 48. ppb and for Aroclor 1254 from 10.1 to 24.5 ppb, with ha lowest lavala baing found in aludga uaars and tha highaat avail in workers. No caaaa of chloracna or othar symptoms of toxicity vara notad but only two PCI valuaa warn abova 200 ppo. Smith a al. axamlnad vorkara involved in tha maintenance, repair, and overhaul of electrical transformers and measured levels of PCM by job (Smith at al., 1981). Tha mean serum levels of L-PCls in the municipal utility workers wars ll to } ppb with a maximum of 59 ppb, and of H-PCBa of t to 24 ppb with a maximum of 74 ppb. in the privately-owned facility workin had almilar valuaa with L-PCI lavala between 19 to 22 ppb with a maximum of 52 ppb, and 8-PCI levels between < and ]l ppb with a maximum of 250 ppb. Then was no significant difference la either place in the frequency of skin leslona between those with lass than 10 ppb and those with gnater than 10 ppb a-PCM. Thera was a significant excess of symptcM of aye irritation In one and a history of bxoochltls and loss of smell in' the other ameng those with serum levels of 8-PCBa greater than or aqual to io ppb compared to less than 10 ppb. however, since these an subjective measures of disease and since workers nay have been Influenced to raport subjective symptoms dlffenntly depending on job it is Impossible to evaluate the importance ef these observations. MOMS 025460 - 158 Smith at *1. reported on the physical findinqa and symptoms in 197 workers who manufactured electrical equipment. Ths run lsvsls of L-PCBa in cho workers varied by Job, with the qsonotric uini ranging from 89 to 502 ppb, tho highest lavala (2400 to 1220 ppb) balng found in ths department whara capacitors wars procaaaad. flniahad, and tastad. and in a dapartaant that had aaaignad work throughout tha plant. Tha gaoaatric naan laval of H-PCBa rangad from 22 to 51 ppb. with tha highast valuaa (150 to 250 ppb) in thasa dapartaants. This plant had always usod 429 chlorinated biphenyls, both Aroclor 1242 and 1019. Although thara wars soae symptoas of skin and aya lesions (darkening of akin and nails, skin rash, and irri tated ayes) that appeared to ha different between the groups with b*KI 200 ppb greater than or equal to 200 ppb rnaparad to those with lower waluea, these differences diaappearad when the coapariaons ware corrected for age and job. Thee one can conclude that aysptoM were primarily related to age and job with the latter association being either real or biased. The symptoms wars net relatad to the body burden of PCha indepen dent of job. No evidence of skin lesions suggestive of chloracne was found on physical examination, in spite of ease extraordinarily high PCS blood levels. In a prallalnary report, Saha (1970 indicated tha incidence of cancer in (4 employees exposed to Aroclor 1294 in a research and developaent laboratory and 45 refinery workers HONS Q254bl 159 pith a siallar exposure from to* UM eras. The investigator ksported a significant axcaaa in the incidence of aelanoma of fcb akin aa wall aa pancraatic canear based on expected cancar gates froa the Third National Canear Survey. In a subsequent latter to tha New England Journal of Medicine, Sahn at al. have reported only on tha aacasa of aalanoaa (Bahn at al.. 1970. Mien Lawrence erltleltad tha atudy on tha baaia of tha fact Mat Individuals could have bean exposed to aultipla chemicals In tha laboratory environment (Lawrence, 1977), Bahn and col leagues suggested that tha raaaon for emphasising tha aalanoaa riaa waa the biological plauaibility of auch an aaeociation harass an axcaaa rlak of pancraatic cancera could have indi cated an aaaoclation with aultipla cheaicala (Bahn at al., 1977). The investigators themselves have dlacuaaad aavaral of. tha flawa of thla atudy. Intonation on trua axpoaura ia Halted and perhape aora iaportaatly ona-feurth of tha axpoaad wortera had to ba oaittad. The author baa alao suggested that aha undereatiaaeed tha death ratio by Including individuals Airing their early years of employment whan thare had not been a sufficiently long latency from tha time of first axpoaura of PCS to tha expected time of cancar development. Thera are other problems with this study related to the identification of caaas in tha axpoaad population and tha separability of case aacartainmant in tha Third National Cancar tansy data. Apparently the investigators Identified caaas mons 025* L60 without attempting to validate the accuracy of diagnosis. Pancreatic cancer 11 very difficult to recognise and diagnose. The diagnoses of the two cases need to he validated froa hospi tal records in order to make them comparable to data froa the survey, skin cancers such as melanomas may be diagnosed m doctors' offices. Thus, the lesions could be missed in the cancer survey data where records were obtained primarily from hospitals but identified in populations with routine medical care. It would be necessary to validate the cases in this study through the use of hospltsl and pathology records and then to compare these cases to a comparable group of employed individuals who have had active medical surveillance by physi cians. In summary, the data on skin lesions in rslation to PCI esposuras have indicated a remarkable consistency. Individ uals who have a body burden indicated by a blood level of 200 or mors ppb PCBs have an incraaaed risk of chloracna. There is littla evidence of risk below this level and thoee studies that do suggest a risk at lower levels usually do not have a compari son group or they have not collected the data in a manner sued that bias might be avoided. The data also suggest that typical akin lesions say occur more frequently in workers esposed to PCBS that have been heated and to PCBs that have S4 or sore chlorination. Since the skin lesions occur more frequently after heating, it is possible that chloracna is actually due HONS 025463 161 - as aoee alteration or contaaination of tha PCS* with more lenegenic materials auch aa dibenxofurans, aa found in tha aano Incident. Symptoms of chloracne are reported frequently Monq those who use Kanechlor; this could be related to level f exposure or Its high level of peers relative to PCBe. Such possibility could not be evaluated with the Information in (base papers. The relationship to direct skin exposure could I1H not be evaluated. C. Biochemical Changes and [.lvar function Extensive studies of liver function have been included aeong tha recant papers on PCBs. Soma of these are auaaMrtxed in able . The early study of Helps at al. involving a PCB leak see a heat exchanger indicated that there were no abnormalities a seven workers with chloracne except tor seat transient changes da liver function teats In one worker (Helps at al.. 1934) These eaanpes could not be definitely attributed to PCBs. The study of Baaepawa at al. of *P workers in six Indus trial plants in Japan indicated that increases could occur in eaaymea such as MO>> SOVT and decreases in blood cholinesteraM (Besepawe at al.. 1972) The authors reparded the changes in liver function as slid and not clinically significant. Kltaeura al. (1971) indicated that in the 11 capacitor workers the hepatle function tests were normal. HONS 0i5464 SAjttU 6MPC Ot Al,tl Wf ituan ot il.u it?) 1* Ot 0U . ItM 7 UM i*n r rtuMaia ot oLJ21 w TrtljJ tft--tcol Stoilos oJ fauwt soft Uoor foncUqo loorifti Dot# m mot CorroUtton or toution vit* *w SOFT ttTO AC LON Bthrwkin Tot. Ml * N.T. N.T. N.T. N.T. lot. no Tot. Tot. 9ft. 4 to 120 Nt At NoootU function loots OONMl N.T. H.T. N.T. N.T. N.T. N.T. Nora. Nora.. N.T. Nwm. N.T. Nmb. AfortoO S Non aorail 2.2S 7.2t ). 1.2* 2.SI 01 NMf ol si., I M sioffo lot. noon ) Motors fOB. 2? ClMlty Corrolotloat Nil Kl 17.4 (10.) 7S.1 Iff.5) Nn a.* iu.t) 24.4 (12.1) Nom On Nooo Mono sltor corwctloo IcoNol mi nl ol., If lloor # 14 liver MU. 44 Lo 214 N1 m Tot. S24 Lo 92 NT IN Tol. 29ft ? sn oit. nr*. ? Nnsltivo 4tMCt*tia iXunal Unr floiinfo one Kli nmo cloliMaUrtM In S7 portent No cohort son troop. No come lion canfoonOinf MrfMloi taolyjoN >U Mon-Orinten No otNor vorioOlo controlIc N1-K1 osoO In iMljfstt StfOtfiCMKly MfOor K* In linr cams HQNS 025465 EtnelwlcAl TABLE * (coatllUM*) ot iay-- wd Liwr runmon Iccatinuadi SMV *. SttjMtt ttm at *1. , in Ittl Awaraja Oau wo Tat. tap--4 Ott- T mm* 13.44 (10-1)2) 12.0 (10-27) SCOT Pa*. Wtt (1. . 244 IMIa La low a|Oi (ini ppo) HI nTi Pat. Stitt at al. . itttt 47 PW.la 4ft Wv. La IN ii-ift -<4 19-21 at/al ft-11 Cana) SCOT OftTP mm mm Aft LON It 1 trull* (Mat mm Naaa Dm mm Carractaft far apa Nat attar mi factar at alcatal. Carvalattaa latlwta carracttaas jj jjji JJ J ill i J IJ1J Jl J iii J f I I I ! 22 J ill 1 1 JJJi II l l i l J ill Jl J ill aaaaljraU lalttatat.,, 1 ft 2 mm Wtt at a).., IWc 224 La Ml 47 Ptt.La 4ft PH*. U Hi Aaalym tact PCS iattpaattat af attar Mlu at al. . 400 17.2 aUraa./i 1.1. 0.2-117.9) Pm. ft. T. a.r. mm rrrr -f i- HONS 025-166 164 Ouw et aK tasted the liver function of capacitor workers through the use of biochemical markers and found the overall test data for the group to be normal (Ouw at al., M7|). The 8SP liver function test was conducted only on individuals with blood PCBe above 300 ppb; four out of seven workers were above normal levels* but it is not clear whether theae valuee were above the range of error of the test or whether there were other factors that might have influenced the results. It is indicated that the blood PCS level and the BSP test do not correlate. IIIOSR (1977) evaluated the liver function of seven of eight workers axpoaed to PCBs in the manufacture of electrical equipment. The levels of SOOT. SOFT, alkaline phosphatase, and total bilirubin were normal in a group of seven workers with a mean PCI level of 99 ppb. rischbeln at al. (17) examined a group of 121 work ers from two capacitor manufacturing plants. The workers had mean levels of L-PCSs of 124 ppb and H-PCBs of 4S ppb. * small proportion of tbs workers had abnormalities In the biochemical teats. Two percent had abnormally high levels of SCOT, 7t high levels of SOP*. 2S high levels of CGTP, 1* high levels of alka line phosphatase, and 3t high levels of US. however, there were no abnormally high levels of bilirubin. The results of this study have not been corrected for important confounding variables such MOMS 025407 1S5 as age, alcohol intake, and other diseases currently or in the peat (t.j. hepatitis) that nay influence these findings. There la no unespoaed group for coaperison. The investigators have eet presented data correlating increasing ensyne levels to inaaasing PC* levels, which would be an appropriate method of pceeanting the relationship between two variables that ace eontlnuoua. The study does Include a coaperison of the data dishotoalied by two levels of SCOT, less then 50 and greater than SO i.u. and two levels of both lower and higher hoaologuee of SCM. These data indicated aignificant differences between tbs proportion of individuals with high and noraal scot levels far l-PC*s greater than 73 pp6 compared to lowor levels and for b-PC*a greater than 200 ppb coapared to lower levels. It la not clear whether these PCI levels were selected after esaalning the data. In which case the conclusions would be questionable. The If individuals Involved In a PC* spill (NIOM, 1M0) had nonal liver function tests that included total bili rubin, transaalnaae, alkaline phosphatase, and lactic dehydroge nase . Tbs triglyceride changes could not be evaluated by the investigators because of inappropriate test procedures. Choles terol levels were noraal. This group had very low blood KB levels of (.4 ppb as a assn value, a level lower than that of nan esposed groups. altar at al. (l**oi studied PC* levels in users of PO-contaalnatad sludge as a fertiliser coapared to workers in HONS 025*b6 a PCB-uainq facility, thair faailiaa, and non-aludqa uaari m tha coaaunity. Tha fCB laval vatiad from 17.4 to 75.1 ppo ln tha four qroupa with tha lowaat laval bainq found in tha aludqo uaari. Thara wara no aiqna of chanqinq lavala of SCOT, SGPT, alkalina phoaphataaa, LDH, or bilirubin in ralation to blood PCla in drlnkara and non-drinkara of alcohol. Tha CCTP laval corralatad with pci laval in tha total population but, whan aleohol eonauaiara wara raaovad, tha eorralation diaappaarad. Maroni at al^ (1911) atudiad livar abnoraalitiaa in 80 workara froa a capacitor aanufacturinq and taatinq plant. Slxtaan workara (20%) had aayaptoaatic livar abnoraalitiaa. Ovar 80% of thaaa had anlarqad 11vara, haonq thia qroup tha aoat fraquant anxyaa alavationa wara tha qaaaaa qlutaayl tranapaptidaaa (GOT*) in half tha caaaa, tha tranaaainaaaa in 44% and tha ornitbln-carbaaoyl-tranafaraaa (SOCT) in 38% of caaaa with anlarqad llvara. Tha aaan L-PC8 laval waa aiqnificantly hlqhar in workara with abnoraal livar findinqa coa^arad to con trol! (219 to 92 ppo). aaan It-PCB laval waa alqnlflcantly hlqnar (308 to 178 ppO), and total aaan PCI laval waa aiqnif icantly hlqhar (924 to 294 PPb) Tha lavala of PCla in thaaa workara ara hlqh nnaparad to valuaa froa aany of tha aapoauraa racantly raportad. It ia lntaraotinq that tha authora raport that althooqh thara ia an asaoclatlon batwaan livar diaaaaa and PCa thara waa no auch aaaociation for chloracna, but tha nunbar of caaaa waa aaallar for tha lattar paraaatar. HONS 025469 167 - Chase at a^. (19(1) exaeined tha scrum PCS Levels and the biochemical markers of liver and lipid activity m 120 aimtananca workers who had had varying exposures to PCBa in thair vorx. Pima PCBa wara eorralatad with SCOT and, afear adjusting far age, tha corralation Oatwaan thaaa two variables la atill significant. Thara la no aignlfleant corralation batwaan plaaaa KB* and CGTT or SCPT. If thia corralation la correct it iaa occurred with levels of PCBa in tha blood of aapoaed wor kers (33-4 ppb) that ara lower than those found in other stadias relating aubclinical changes in livar function with PCBa (MtoSH, 1977). However, without corrections tor other potentially con founding variables such as alcohol intake and the history of ether diseases such aa hepatitis, it la difficult to assess the finding. decently, MIOB1 has coapleted three studies repre senting cross-sectional aedlcal surveys in two groups, individ uals working in capacitor eanufscturlng (Beith at al., 19tla) and Individuals working in maintenance and repair of electrical tranafomars (Smith MU., 1901b). The third study caabtned the data tree each study in an overall analysis. In tha capacitor aanufacturlng group there were 224 participants ter whoa L-PCBs and a-PCBa were determined, aa well as biochemical studies. Several slapla correlations were cal culated and, for all those that ware aignlficant, multiple Ngnoalon aquations wara developed using all other predictor HONS 025470 168 variables far which information was avallabia. rnia included drug intaka, smoking history, othar biochemical aiarkara, ago, sax. and othars. Serum H-PCB was significantly corralatad with SCOT and GGTP. Thara wars, however, no clinical findings sug gestive of livar disaasa and no indication that tha iavals of thasa anxyeea wars abnormally high. Exposures in this plant wars high with plasma PC# Iavals baing aight to SO tlaaa tna laval found in tha community. Smith at al^. (1811b) hava raportad in tha survay in formation on 83 individuals who wars about equally dlatributad batwaan a municipal alaetric aystam and a privataly-ownad electrlc utility company. Tha lavala of H-PCBa and L-PCBa ara simi lar in tha two facllitias. Thors wars vary faw ansyma tasts ralatad to livar function that wars significantly corralatad with PCB Iavals. Tha only significant correlation was a positive relationship batwaan L-PCBa and SCOT for tha private company. Smith at al. (1881) subaaquantly raanalysad the data for tha three aitaa presenting partial correlations for L-PCBs and H-PCBs independently without correcting tha laval for alter nate homologuaa since they wore closaly interrelated. Under these clrcumstanoas, thara is not only n positive correlation batwaan H-PCBa and Boot and GOT* at tha manufacturing plant but also a correlation with L-PCB and GCTP. Tha positive correlation between L-fCB and SCOT still remained after corrections tor the private utility company. Combining the data for all sites it is HONS 025471 - 169 - potad that loq SCOT and loq CCTP deixonatrate both siqnifleant pnd hoaoqeneoua trand a in ralatlon to loq (,-PCB laval. only loq COT la ralatad to loq H-PCB and in thla eaaa tha trand for all ltaa ia hoaioqanaoua but not alqnifleant. In thaaa analyaaa. the only confoundlnq variablaa conaldarad vara aqa and aaa for poa atudy aita whereat tha analyaaa In tha pravloua papara con trol lad aultlpla variablaa such aa aaokinq and othar dlaaaaaa. Meduclnq tha nuaber of variablaa and ineraaainq tha nunbar of aabjaeta avallabla for atudy nay hava accountad for tha chanqaa la tha ralatlonahip with biochaialeal markara and ayaptoma to tha laaala of PCIa. Bacauaa of tha aany ehanqaa in ralatlonahip, it la difficult to indlcata praclaaly tha aaaoclatlon batwaan apa cific llvar anayaaa and apaclflc hoaoloquee of PCBa. it doaa appear that in thaaa atudlaa ona or aora anxyaa laaala within aaaaal raaqaa aay ba ralatad to ona or aora typaa of PCBa in tha Moad. In ordar to ldantlfy tha anxyaa ayataa that la lnducad by tha varloua chlorinated forma of blphenyla, klvarea at al. (1*77) taatad tha induction of livar cytochroaa P-450 and p-441 by Droelor 1014 in rata and in workara occupationally axpoaad to tha aqant. In rata, tha lower chlorinated PCB allcltad a barbitarata typo of effect on the oxidative anxyaa ayataa induclnq aytochraao P-490, athylaorphlna-a-daaathylaae, and alcroaoaal protain. unlike Mcoclor 1294, which inducaa both P-450 and P-440, the rata with Aroclor 1014 ahowad little affect on benxo(a)pyrena HONS 170 hydroxylase activity, which suggests llttie induction of P-44$ by the chemical. The easts in axpoaad workers ware conducted "by determining th half-life of the antipyrlna whoaa eetabolin ia stimulated by tha barbiturate claaa ot inducing aubatancaa. The workara had a significantly ahortar aatabollc haif-lifa of the drug than tha controla suggesting chat cha Aroclor iOl had induced cytochrome r-450. In a atudy of } community raaidenta in a town that had high lovala of PCaa in flab, Kralaa at al. (lil) found a correlation between PCba aa aaaaured against Aroclor 12(0 and GGTP. Thera ware no corralatlona with other liver ensynes. Corractlona were made for aeveral other varlablea auch as ape, sex, fish and alcohol consumption, and obealty. In summary, the data froe the studies of Hear en zymes and function suggest that the populations exposed to Kla usually do not have clinical liver dlaeaaa, although in ona study there was asyaptomatlc hepatomegaly (see Table >. few of the early studies allow ua to separata the various hooologues of rcia in order to correlate ensyme response to level of chlorina tion of KM. aaeent studies suggest that SCOT and/or Q6TV are tha most sensitive Barkers of change in the liver ensyme syetams relatsd to Kl exposure. In the studies that Included extensive tasting of all ensyme systama as well aa characteri sation of tha PCBa, the data have Inconsistencies that do not allow ua to judge clearly the level or the apeclfle type of hONS 025473 171 fC that la ralatad to ineraaaad lavala of (pacific livar anayaaa. nany of tha atudiaa hava not corraetad for othar con foundin'] varlablaa aucti am alcohol conaunption. Tha data ara auggaatlva that thara ara chanpaa in ona or aora livar aniyaai ralatad to PCI aapoaura that ara not aaaociatad with diaaaaa and may occur at lavala balov thoaa at which chloracna occur. o. Lipid Hatabollam Tha long-tana atudiaa of patianta with Yuaho diaaaaa bava ravaalad aavaral othar abnoraalltiaa, among which wara alovatad blood triglycorldaa (Praba at al., 1971). in racant raporta of Indivlduala axpoaad to PCBa, aaaaaamant of lipid aatabollam haa lndicatad aeaa abnoraalltiaa, but in gonaral no clinical aanifaatatlona of thoaa abnoraalltiaa auch aa Ineraaaad rtaka of cardiovaacular diaaaaa havo baan notad. loaa of thaaa atudiaa ara auaaarlsod In Tabla 10. HONS 025474 Uad* aiattBr Satjacu ____SL:t*: ST- #l **' * M mn at ai. , ion lit tajinr at al. , V lunp ftMa **k Tat. jm fat. 7-m Tat. 4 TOU 1 UliiSitffl Camlattaa ar alaaatlaa af 11*10 Trtaljrcartdat CJwlastaral a-caal. l-usI. Qacr. acr. N.T. Oacr. lacr. a.T. I. N.T. N.T. Naraal a.r N.T. hw htattala at al. J21 La 124 M 41 apart** at t ataaa mrm\ 10. SI 17.n Mar at al. \m M iladfa Man U aartars tar fas. n cmaaity Tat. 17.4 75.1 JJ.4 24.4 Nl j-*j 02.t) 9m. Naaa Salta at al.. mu 224 La S0-S02 m/mt aa. HI 22-SI 9m. mm 9m. tl . Mf. N.T (as) Mm aaa Naaa mm m caaparitaa wit* eaaaril. la camctiaa far caafaaadta* aartakl raoaria Nr -rca umi Naalysa* aaly aa aaaalcakal drtakan la attar Mriatlai caatralla*. Carracta* far atNar aartOlaa HONS 025475 TAILS 10 (continued) LlPld Studl-- Study Ttiodiir ivarf Correlation or ilivation of lipids Subjects DOM ppto Triglycerides Cboleeterol H-Chol. L-Chol. Hotss _______________________________________________________________________________________HDL- LDL-______________ Sain tt si.. two 47 NO. LS M 44 Arlv. LS HI mm at *., mu (fttMSljTMS if MM MM) C*cltor Li HI Sub. ut AH. Ml. lo Ml Li Ml kntit mi.. 444 11-34 if/Ol 4-24 Am. If-23 4-31 Am. Hi- Hmo Am. NMi Am. Mom Him 17.2 Merse/V- Mom <3.2-197.f) Mono Mm Am. Mom Nam Am. Mm Am. Am. Mm Am. Mm Mf. MM Mm Mm Mm Mom Mg. Mm MM Mm mm Mm Mm Mm Mm Mm Nam Mm Mm Mm Ao l tt vs correlation* cirroctid for itmr urutlM. Included fmr cmfmndiif HONS 025476 - 174 Haaapawa t al,. (1972) had no tad chanqaa in lipid metabolism o Yuaho patlanta aa manifested by dacraaaaa in tha blood levels ot cholesterol, triglycerides, phoapboliplda and beta-lipoproteina. othac studies such aa that ot Mara at aU (1973) on YusDo patlanta bad notad alavatad triglycerides in SSI of subject* who had blood PCBa above SO ppb. Tha lattet data wara not eorractad foe any rlak faetora auch aa age or weight. Suaparner at al. (1973) indleatad normal eholaatarol lavala in 37 rafuaa workers who had a naan PCI lawal ot 4 ppb. rlachboin at al. (1979) baa axamlnad lipid aataboliaa in 321 capacitor workara. eholaatarol lavala of 300 or more np/100 al wara found in 17.91 of workara and trlplycarlda lavala of 200 or mora eg/100 al wara raportad in 10.SI ot tha popula tion. Tha total llplda wara alavatad (abova 1 g/100 al) in 3.41 ot tha population. Thaaa nutabolic paraaatara, howavar, ara influancad by age, paraonal habita, and tha praaanca of othar dlaaaaaa> it la tharafora aaaantlal that tha data ba compared to a population with aiailar apa and aaa dlatribution and that confoundlnp varlablaa ba controlled before one can aaaaaa tha role of PCla in thaaa obaerved chanpoa. Since these compari sons ware not aado, no conclusions can bo drawn froa thaaa observations. In tha study of Baker ae al. (1990) in which PCBcontaainatad sludpa users wara coapared to exposed workers, their families, and coaaunlty controls, thora was a hipbly aipnificant HONS 029477 175 - Jbeltlve correlation of plasma triglycerides and serum h-pcb. jBi* correlation was strengthened whan alcohol consumers were removed. There waa a negative correlation of HOC. choleeterol With H-PCSs that waa not statistically significant. The investi gators suggested that the mean level of serum pcs in fasting Subjects with hypertriglyceridemia waa only 25.0 pph which is lower than the levels at which this abnormality waa noted in previous studies <50-200 ppb, HIOSH dociaent). it is not clear, lowavar, whether the other studies with higher levels have used total PCIs, whereas this study used only H-PCBs in the correla tion analyses. The H-PCBs constitute 35 to Stg of the total sen KBs in the groups. Personal characteristics may influence triglyceride levels, and many factors were apparently considered by these Investigators Including age, ser, and drinking habits, these lipid abnormalities may be occurring at the lover PCB limits, or even below those limits reported previously. Chase et al. (USD in their study of maintenance workers exposed to PCBs found that levels of plasma PCSs were significantly correlated with triglycerides but not with choles terol. adjusting for ego or length of employment dome not change too significance of this correlation. The triglycerides are not significantly correlated with fat PCB levels, as mentioned pre viously the levels of plasma PCBs in this group of workers is low (11.4 ppb). HONS 025470 176 Saitt) at al. (1981a), In the study of 22< workara fro* a capacitor manufacturing plant, found that aarua PCBs war* corralatad with measure* of lipid metabolism. Corractiona War* mad* for ralavant variable* auch aa smoking, history of diabetes and haart dlsaasa, drug usa, and othars. Tha partial corralationa indicatad a significant correlation batwaan serum h-pcb laval and total cholesterol and triglycaridea and a significant nagativa correlation of plaama triglycaridea with aerum L-PCB levels. When tha levels of H-PCB and L-PCB wars coabinad tha correlation was positive as saan in other studies whara total PCBs have bean examined. There ware no slgna of clinical dis ease in relation to tha elevated lipids. It was noted that aevaral of the lipid measurements wars corralatad with GCTP laval. is tha authors suggested, this may indicate that PCBs induce hepatic microsomal ansyaas, as has bean found in labo ratory animals and man, and these in turn nay incraaaa synthesis of specific lipids. Smith at al. (19Blb) in a health atudy of 91 workara divided between a public and private utility plant found corre lations of lipid metabolites with PCB levels that conflicted with data from the previous study. Triglycaridea ware positively corralatad with B-PCBa in one facility and negatively correlated with a-PCBs in tha other. Both correlationa were aignificant even after correction for multiple variablaa. Both triglycerides and cholaatarol war* poaltlvely associated with L-PCBa in only MONS 025479 177 - e facility even though the level* of tha Biphenyls in the Bond were einuar in the two population*. High density lipoggateins were negatively correlated with H-PCBa in only one ggtablthm*nt. In thi* caae, the other facility alao demongrated a eiailar negative relatlonehip but the level of the girrelatlon wae much lower. Smith et al. (Utlc) have combined the data from these two atudiea and corrected the reaulta for only age, aex. Bad study aits. Under theee circumstances there were leee con flicting data in the correlations, only one significant corre lation with L-PCi was noted and that was a positive correlation Mth cholesterol at the private utility. Both cholesterol and leg triglyceride were aaeociated with H-PCs at the equipment hsaufacturlng site. Trlglycerldee and d-rca ware poeltlvely correlated and ROb-cholesterol and B-PCP negatively correlated at the municipal utility site. Combining the data from all ttady sites indicated that log triglyceride was significantly associated with both L-PCB and H-PCP but the trend for all sites wee homogeneous only with L-PCh. Log dOL-cholasterol was significantly and negatively aaeociated with H-PC1* and this trend was consistent across all sites. There was no significant relationship of PCM with total cholesterol. (raise at al. IIPID have aeudled a community where high levels of POe and DOT were founds in fish. Among the Si Participants, there wee a positive correlation between cholesterol HONS 025**0 178 and PCBa iseaaured as Aroclor 1260. There was no additional contribution by serum triglyceride or HOO-cholestarol to tha prediction of sarua PCS in aultipla regression analysis. In suansary, tha studias in aan suggest that thara is frequently a positive corralation between KBs in blood and triglyceride lavals, although thara ara aany studias that daaonstrsta no ralationship. Tha corralation is o(tan to tha higher hoaoloquaa of KBs and occurs in soaa casas with blood lavals of H-PCB at 28 ppb or below. Tha data associating HOL- cholastarol and H-KBs ara not as oftan significantly corralatsd. but whan thay ara, tha ralationship is nagatlva. Lower lavals of BDL-cholestarol say bo an laportant risk factor for coronary hasrt disease but thara Is no avidanca of a ralationship of thasa lipid findings to clinical dlsaasa in thssa studios. TBs variation in tha prasanca of lipid abnoraalitloa in ralation to PCBa In tha studias and tha variation in tha spaciflc lipid changas obsarvad would suggaat that thara say ba a confounding variable that has boon Ignored and that is influencing thasa ralatlonahipe. k positive correlation of blood lipids with plana KB levels could In part ba a consequence of tha ten dency of PCBa to distribute equally aaonq all lipid pools m the body. I. haprodactive Effects vary few papers have addressed tha probleas of human reproductive affects related to KB Ingestion. Tha early paper* *0NS 025481 - 179 - by Kurataune (1972) on tha Yuaho patienta had indicated that oat of 11 wooen patlanta and two of tha wlvea of patienta aha were-axpoaad at any tlna during pregnancy, thara vara 10 live born and two atlllborn Infanta and thraa of tha llva Born Wara aaall for thalr age. Tha auchora do not provida coapariaon flgurea on raproductlva outcoaaa for that araa of Japan ao that It la lapoaalbla to aaaaaa tha manlng of thaaa flgurea. It la elaar. however, that tor all oahlaa whoae racorda wara reviewed, ahln etainlng and aya diacharga wara uaually praaant. Kreiaa at 1. (19(1) alaply lndlcatad that thara waa no aaaociation of alacarrlage, attll birth or Infant daath rata lndapandant of aga affacta In a a tody of a co--unity with high PCI levela. In genaral, tha data on raproductlva affaeta froa axpoaura to PCla ara llaltad. P. Henatology and Ifunology Mat of tha atudlaa of baaatologlcal affacta hava found no abnonaalltlaa and thaaa obaorvatlona hava boon aada In alapla atataaanta. Tha atudlaa of Xltaaura at al. (1973), tuBgarner at al. (1973), Karppanen and Kolho (1973), Plachbaln at al. (1979), akar at al. (1910), and Haronl at al. (1911) bava'not ravaalad any ahaoraalltlaa of hemoglobin or laukoeytoa. Ouw at al. (1970) taportad aovoral protoln and globulin taata on axpoead workara that wara hlgbor or lower than tha roported nonal. lowavor, tha overall lovala of globullna wara not different in two groupo of workara with high and loo axpoauraa. In the Initial abatract MOhS 025082 - i*o - relating to ttio Baker jt jl. (19*0) study, ths authors rspertsd increased hematocrit snd hemoglobin in rslation to PCB isvsIs controllsd tor age. Ths sscond complete rsport corracts tor savaral othsr variables that may account for tha diftaranca in rasulta. In tha thraa reported studias of Smith at al. (1**1), tha investigators lookad at rad call count, whits call count, hanoqlobln, and haaiatocrit and found no significant correlation with either L-PCB or B-PCB whan corrected for confounding vari ables. In tha latter studies they have also axaainad the corre lation of total protain, albuaiin, and the various globulin frac tions and found no significant correlations after correcting for othar factors. In general, there are no recent studlee that suggeet abnoraalitiee of the heme system in man related to levels of TCBs. In addition, the Smith at al. (KBlb) study of workers in electrical utilities showed no significant variation in PCBs reiated to urinary porphyrins, porphobilinogen, or 17-ketosteroids or 17-hydrosyateroids. S. Other factors Kreiss at al. lltll) in ths study of a fCB-axpoead com munity found inermased diastolic blood prassure to be correlated with PCS levels even after the correction for other variables. Ho comparison data for a control group ware given. The study of workers in tha equipment manufacturing plant also demonstrated MOMS 025413 181 g^ertelation between diastolic blood pressure and r-?cb tut ghis disappeared when corrected Cor age. Other investigators g^ee not found this relationship, so the difference nay be associated with an unrecognized Interrelated variable or a kfiance association related to the aultlpllcity of factors that See been examined. warshaw at al^. attested that workers in a capacitor lhanutacturing plant (population of flachboln at al^.) had de pressed vital capacity and restrictive lsipalrnont of lung func tion in the absence of signs of radiographic change (Warshaw at h^., 1178). They haee coapored the rvc to that of other worker populations In previous hassrdous exposure studies as well as to a non-smoking normal population. The reported percent abnor mality of PCI workers la 141 compared to 8.(1 citad for nonaaaklng populations. The comparisons do not indicate that they have been controlled for smoking habits and sax. Nest studios have reported no clinical dlseasa in pcaetpoaed populations with the exception of Tuaho disease and chlorasaa (Karppanen at al.i Humphrey, Smith it tl.t Chase at al> Brelss at al.(. Some have reported symptoms that are difficult to evaluate since moat are subjective and could be related to acker bias, rischbslm et al. suggaatad that neurological xyeptama were increased but there is no similar group with which to ampere workers and thos moke this assessment, smith et al. MONS 025484 182 (1811) in tha study of tha combinad work sitas found that couch ing at work and irritatad ayaa wara ralatad to both L-PCS and ff-PCB. Loan of appatita and parlpharal *tlnolino" wara aaaociatad only with t-PCS. History of akin rash was aaaociatad only with H-PCB. Many of thasa diffarancas wara not obsarvad whan individual work sits data wara analyaad aaparataly. Tha lack of a diffaranca in aach aita may rasult bacauaa Jobs wara includad as a contoundar variabla. Most studlas hava not avan raportad any syaptoas or history of diaaasa (Bakar at al^. and Kraiaa at al.) In all atudlas caviawad thara was littla avidanca of clinical diaaasa with tha axeaptlon of cbloracna and this condi tion sasaad to bo aost fraquont undar apacifie conditions of axposura. Tha othar coaoon but not conslstsnt f 1 nd 1 nq a wara abnoraalltias of lipid aataboliaa, aspacially blood triqlyearida lavala, and abnonsalltlas ot llvar anxyaas, aspacially SCOT and CGTP, which wars ralatad to lavala of PCSs. Tha lipid and livar chanqos appaarad to occur at lower lavols than tha skin aanitastations and wara not aaaociatad with clinical diaoaaa or syaptoais. HONS 025485 -183- ^pctfully subaitttd, Victor A. Drill, M.D., pfi.o. WySr 4g-<kCk. jWvvx* Td A. Looi, M.D., Ph.O. HONS 0254< -105- XXII. REFERENCES j. .XM, J.R. and ABRAHAMSON, L.J. (1979). 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Identification and toxicological evaluation of chlorinated dlbenzofuran and chlorinated naphthalene in two commercial polychlorinated biphenyla. Pd. Coamot. Toxicol. 8, 623-6]]. WATANABC. 1. at al. (1980). Oiatribution differencea between polychlorinated terphenyla and polychlorinated biphenyla in human tiaauae. Bull. Environ. Contan. Toxicol. 25. 810-B13. NICXIZER, T.M. at a^. (1981). Polychlorinated biphenyl con tamination of nuraing mothera' milk in Michloan. Am. J. Public Health 71, 132-137. --~ NOLFF. M.3.. FXSCK8EXN, A.. THORNTON, J., RICC. L.. LILIS. 9.. and SEX.ZKOPP, Z.G. (1981). Body burden of polychlorinated liphenyla among peraona employed in capacitor manufacturing, lubmitted for publication to Xnt. Arch. Occup. Environ. Hlth. Preeented in part at the XIX international Congraaa on Occupa tional Health, Dubrovnik, Sept.. 1978. wnDHAM. C.. OEVCNISH, J. and SAPE. S. (1978). The in vitro netaboliam, aecremelecular binding, and bacterial mutagenleity of 4-ehlorobiphenyl, a model PC8 eubetrate. Rea. Coanam. Cham. Pathol. Pharmacol, l^, 383-570. YMCU8HUJX, T. at al. (1978). Long-term atudiee of the ex cretion of polychlorinated biphenyla through the mother'a milk of an occupationally expoaad worker. Arch. Environ. Contan. Toalcol. 7 . 491-304. YAMASItXTA, P. (1977). clinical featuraa of polychlorobiphonyla (PCI)-Induced fetopathy. Pediatrician 4, 20-27. YOBRXHARA. S. 2i al. (1979). Tozicologlcal aaeoaamant of highly chlorinate!-biphenyl congenere retained in the Yuaho patlenta. Chamoaphera 8, 331-338. M0NS 025505 -205 XIV. gloatary ot Tarmt or abbreviation! alkaline phoaphataaa bromaulfonphthalaln livar function taat gaaaa glutaayl tranapeptidaea PCBa with high degree! of chlorination PCBa with lower degree! of chlorination lactic dehydrogenate polychlorinated biphanyla polychlorlnatad dibaniofurana polychlorinatad naphthalanaa polychlorlnatad quaterphenyla polychlorinatad tarphanyla aarua gluttalc oxalic tranaaaiinaaa aarua glutajalc pyruvic tranaaainaaa aarua ornithlna carbaaeyl tranafaraaa tha dlaaaaa notad in Japan following huaan ingaation of cooking oil contaalnatod with PCBa. pcora. and PCQe. parental taat anlaala littara darlvad froa flrat ganaration anlaala at Chair flrat (a) and aecead (b) natinga MONS 025506 CURRICULA VITAS CATEGORY I TEAM HONS 025507 1 of 4 COUICUUH VXTAI or MU VICTOR A. DULL SDOCATIOD aeholor of Scianca (1.9.) datraa, Loos la Land Univaratcr, 1931. Doctor ot misoophr (fh.D.) do*T*o, Frlocoton Unloortlty, 19*1. Doctor of Wodlclno (M.D.) doroo, Tolo Unl'raTaltT School of ModeLao. 19*4. --towarr laatroctor la Tharoacolop, CoUo*o of Ffcyalclaaa cod Surtoooo. Caldhla Dkloorolty, 19*9. laocroctor la Vharaacolofy, Tala Ooloaralty Schaal ot Nadlclaa. 19**-*7. Aaolataat trotoooot ot Wmitalap, Tala Dalvoralty Schaal ot Madlalaa, 19*7-**. ProfaiMr ot fhanacolofr, Iqw Dalooraltr Callaga ot nadirlac. 19*4-53. laaarlara Thyalclaa, Datrolt lacalolac 400911*1, 19*9-53. Director at Idaaatlaa, rhaliaaa of laton Caalttaa. Detroit laaalolac laorltal. 1949-53. Dlractor ot Slalaflaal laaoarcfe, 0. D. Soarla 4 Co., 1953-70. Laotarot, DaftiMt of Tharoaialap, Darthoaatara Dalooraltr edita) School. 1994-47. Staaacac 44 Sol adIflo aad trofoaoloaal Affaire, S. D. SoarLa 4 C*., 1979-74. langur la fhonacalaar, Dalooraltr of IlUaola Callata of Modfrlaa, 1994-75. frafacaao of ~ mu u Dalooraltr of llllaala Callao* of adldaa. 1974-. Dlractor; Drill, Vrlaoa, lara, Innolc 4 Shoffar, lac., 1949-. HONS 025508 Curriculum VIera of Or. Victor A. Drill 2 of 4 nornsiom. societt noamsHiFs Aloha 0H|i Alpha. Aaarlcaa Aaaaclatlon for cha Scud7 of Llvar Olaaaaaa. American Chemical Society, Dirla Ion of Medicinal Oiaaletry. Aaarlcaa Fertility Society. Aaarlcaa Fhyalologlcal Society. Aaarlcaa Society for Clinical Fhataacology and Tharapaotlca. Aawrlcaa Society far Fharaacolocy and bparlaaatal Tharapaatlca. Intarnatloaal Society of tayraduceloa Madlclno. Naa Tarfc Acadaay of Sclaocaa. Faclflc Ceaat Fertility Society, loyal Society of Nadldaa. S1H XI. Society far lapcrlaaatal Slalofy aad Madlelaa. Society af Todcolofy. Dlatlaaolahad fallaa. Society af Taalaolay. FeUaa af the leftearn! loaaareh Ceoaell. Serthoeater* Umlverelty Modi cel School. IS41-A1. Fallaa. lea Task Irafay af Sclaacaa. Fallaa, layal Saalaty af lMlclaa. loaorary IMhar, latanatloaal Family Flaaalag leeeerth Aaaaclatlon. laaarory Mer, lhaiaacaloty Soclaty af Veaaoaele. Taaahma fallaa. Friararea Oalveraity, Uhl-42. Fraaldaat, Saalaty af Tozlcaloty, 1172-73. HQN$ 025509 Currtculua Vitae of Dr. Victor A. Drill 3 of 1 ncnssiQNAL activities Maakar, Endocrine Penal, Cancer Chanotharapy National Service Caatar, National Caacar Inatltuca, 1931-41. Coaaultant, Natlaaal Canear laatltuta, 1963-47. Manber, Board of Dlraetora, larraa Foundation, 1971-71. Makar, Oru( Raaaarch Board, National Naaaarch Council-National Aeadaay of Sclaneaa, 1971-74. Maakar, Orgaalraclon Coaalttaa for tha Syapoalua on tha Fucura of lalaal Celia, Modela aad Syaraa la Baaaareh, Daaalopaant, Education and Tearing, laatltuta of Laboratory Aalaal Baaourcaa, National Baaaareh Council-National Aeadaay of Selaaeaa, 1974-76. Maakar, Sclaaca Adalaary Board, National Caatar for Toxicological Baaaareh, 1973-76. Maakar, Board of Dlraetora, International faally Planning Baaaareh Aaaoclaclon. 194g-79. (Vleo-Fraaldant, 1972-74.) Co-Oialruaa, Tha Third Confaraaca oa Cucaaaoua Toxicity, (apoaaorad ky tha Aaarlcaa Madleal Aaaocladen aad Saelaty af Toxleology), Hay 14-IB, 1976, Haahiagtoa. DC. Co-Chalraaa. Tha Fourth Confaraaca on Cutaaaaua Toxicity, (apaaaored by tha Baaclraa Madleal Aaaaelatlon aad Society of Toxicology), Hay 9-11, 1979, Haahiagtoa, DC. WUlCATIOMBt BOOKS Drill, V.A., Editor, Pharaacology la Madlelaa, MeCraa-Hlll, Nao Tort. Flrat Idltlaa, 1954 Drill'd Fharamlagy la Madlelaa, McCrar-Nlll. Nao Toth, adltad ky J.B. DIPalaa. Third Ndltloa, 1943 Fourth Idltlaa. 1971 Drill, T-A.. Oral Caatraeootlyoo. MeCraa-llU. Nao Torfc, 1144. Drill, T-A., Taxanaolanla Madlaa. la Preuea Hadlaa Mnxleaaa. Maalce, adltad ky J.B. DIPalaa, 1941. Trattata dl Fai------- hr4ii Pleela Idltora, Padova. Italy, adltad ky J.t. Dlfalaa, Tola. 1 aad 2. 1171. MOMS 025510 Corrlcul-- Vltoa of Or. Victor A. Drill of roiLianoWi moos (continuop) A. Co-- 4a Faa, V.A. Drill. H. lay--hi, W. Ia4rl(ua <b4 A.V. Schall), odltoro, towt Adroocao la ft--n Kaoreduction. Freecodings f cho drat International C--gra-- a* Asm hfnfcctlM, Us 4s Jaaslrs, Irani, Mar. 11-14, 1)74. lacarpta Hs41ea ICS No. 370, bcarpta (Mica, A--card--, 1)74. Drill. V.A., aa4 t. Laaar, Cutaasoaa ToalcltT. Acad--lc Prooo, N-- York, 1)77. Drill, V.A., mi P. laaar, Current Coacoota la Cueaaan-- Tonlcltr. Arnd--lc Pro--, N-- York, 1)10. WmlCAIIOBli BM Aorkor or ao-nuthor of appr--1--taly 110 pop--s la tka id--tide literature. (llkUofTapky a--llakla up-- rap--t.) link Aatai Jt--a 10, 1)14 Narrladi tape--k or 14, 1)40 (Sack Craig) Childreni Craig A. Of--4 it 20. 1)42) Uahard 0. (Map* 13, IMS) Soot A. (Jlp 14, 1M7) tap--t 1. 1M0 HONS 025511 1 at 3 CUUtICULUM VITA! OF on. srhook i. natst OPCAIIOW tacholor at Arts (A.i.) dofroo, Uolvaralty of California t In Aagalaa, 1IAJ. Knur of Art* (M.A.) Aafraa, Unlaaralty of Collforala at Loo Aafolao, UAA. Doctor of TMloooyhy (Fh.D.) dotrao, Onlvoroity of Collforola at Loo Anfoloo, 1*47. laooarch Chanlat, Datatla toglnaorlnQ Dlaerlct. 1*44-44. lootructor. Doyoraoat of Chanlotry, Oklaorolty of lorHooter. 1*40-31. loooorch aod AOdalotrotloa. Korol Hopleal loooorch lootlcoco, 1131-71. loooorti Sclaatlot; 1931-30. Bond, fkyolcal lloiH--lorry DItUIoo, 1*30-43. Ffcyololocltal Wo it. IMS-70. otol IS 70-79. 1"-- '-| Dlroator; Drill. Frlaaa. laya, T mini a nl Shoffar, lac., 1M0-. i OnliPl loaloty. > lootltMO of On Toromorlonol loaloty of Tanfaaloty loaloty of Tanioology The loaloty of tho Um* OpOqtooo Moil ool Society VaoUootan Inin) of Stlantoo HONS 025512 Curricula* Vlcaa of Dr. Seyaour L. frleaa 1 of j HOWOR3 Adjnet ProfMOOT, DeyarcaenC of fharaacology. Unlfornd Servlcaa llalvaralty of the Health Scloncot, The Mteal School, 1977-. Honorary Chair, Inatltute of Bloyhyalea. UnlTaralcy of Sraall ac Ml da Janeiro, aa Chlaf of cha Laboratory of Holacular rharaacoloa* 1961-. Fhl lata Layya Da font fallow la Chaalatry, 1946-47. fraaldaac. Society of Taxicology, 1975-74. Masker, Editorial Board, ToxIcoIoct aad AoallaJ --ncolorr. 1944-49 ; 4aarclata Editor, 1970-79. Makar, Editorial Board, Toxlcon. 1945-. Maakar, Editorial Beard, Toxic Sakataacaa Jooraai. 197*-. Ma^or, Editorial Board, faraaoctlraa la Toxlcolocr. 1979-. Maakar, Sdaatlfle Adrlaory Beard, fhaatcal ladaatry laatltata af Taalcelagy, 1979-. fraaldaat, kailra Board af Toxicalogy, Taa., 197V. fraaldaac, latoraartenl Oalaa af Tonoology, 1940-. Diaclngalakad fallow Board, Soclacy of Toxicology, 1941. fsomsiam dcrmros Makar. Caalttsa as Taalcalagy, Aaaaniy at Life Bclaacao, ratlaael taakgr af trlaaaaa Motional Baaaank Caaacll, 1947-74. Maakar aad ekaBaaaa, ddolasty faaala aa Baaaerth fragraaa la Span Biology, Batlaaal Aareaaeclca aad 9yaca ignry, 197V75. Mkar, TnSrology Xafaiaatlaa fragrn Canlttao, laankly of Life Balneaa. iarlnal BnaarcB raaaaM Maftaaal Beadny af falnan. 197V77. OCkalrna, 197V77.) Haksr, id Mac kdatoory Candttea n Carkn Ikanalda, noyarmar af Maaltk. llanrln aad Malfaoa. 4.4. faklla Mala* Baoaln, Baton af Canaalry Bailioaanial Maaagnnc, 1971. rhalran. Solaaclfle faaal far the MS* Apollo-Sayan Tnt fragrn. 1974-73. HONS 025513 rlculum vitae of Sayncur L. fries* 3 of 3 j^rtslIOMAl. ACTIVITIES (continued) Maker, litlwnul Protection A|ancy-Natlonal Acidar of Sciences Advisory CoaBlttaa on Tolerence for Che Pesticide Laptophos, 1971. Advisor, Sub-Committee on Profrsa Development end Adalalstredon, Bavtau Coaalttee on the National Center for Toxicological Baseareh, National Academy of Sciancaa-Naclonal Research Council. 1976-. Hanker, Bureau of Biomedical Sciences (Cossiaer Product Safety CoMlsslon) Ba*lav Coalccse, Netlonel Academy of SclanceaBatlosal Besaarch Council, 1977-78. Ualeoa Sapresentstive, Department of Defense, to the Interagency Testing CoMlttee, Advisory to the Administrator of tho Enrlrsnaental Protection Agamcy for ths Toxic Subetsscas Concrol Act, 197A-79. 9DBL1CATI0NS Author or co-author of approximately 130 papers In the scientific literature. (Bibliography available upon raguest.) fSSat ns csgeiAL IMTTMT af ''VyilUH-B Toalcslocy of ladaatrlal and military ehamcala; aaunauacnlar pbarmsrnlsgy and tanlcology; amxyme klnatlcs and earhmlMa of actios; pfeyslelagy and pathology of rbmnsrarsptors; rhamdral kinetics; hasard snaaaamant and safety evaluation; regulation of tsxle suketsncee; hyperbaric conlcmlegy and physiology. Birth data: Hamad: Children: July 1, 1921 Inly U. 1931 CMsry tugaala Tarver) Philip l. (Dncsnber 29. 1934) Martin C. (Dovbsr 23, 1934) 4322 lean Oak Court lochaada, 20034 Drill, Prlana, lays, Loomla 4 Shaffer, Inc. Suita 204 1901 March Pert Mpex Drive Arllagtaa, 9k 22209 (703)327-4430 Ingest 1, 19g0 HONS 025514 1 of ) CUMICOIUH TtTAC or 0*. HAM? U. hays PUCATIOH Socholor of Sdaaco (B.S.) 7ronkln 4 Morohdl Coll**., 19]). "actor of Sclooco (H.S.) dofrao, rrtncotoo Unlrorolcr, 1937. Doctor of mioooohr (rh.D.) do(TOO, Frlacoeoo Oolreriltj, 193*. WlflMT loooorch Pharaocolotlot, CI1A ftiarneceutled Conran?, 1939-At. Aoooelata rrofooocr of Kniol<o, Mama Stoto hlnnltr Collate of NaAlolaa, 19**-37. Director, UH0017 Contor oa Toalcole*?, Datiooal Acodo*r of SdaacaaMotload laaaarch Cooaell, 1937-M. Director, rostlelda* *a*alatloa Dlrlolea, O.S. Doportaaac of Arlcoltaro. 1904-70. Staff Offtear, rational 7ro|Ta Staff, O.S. Oapaxtaaot of A*rlcalfara, 1970-*0. Director; Drill. Frlaao, Sara, Looala 0 Shoffar, loc., 19SO-. rporosiMui soemr Mmam Martcaa Coaforoaco of flotofoanl laOaotrld *rtlaaieto. Aaarlooa lotloty of Bonwolop a* Mporlaoatal Thoro*ootlto. toploty far Mrarlaaatd Slolo*y oaf NoAlclaa. toploty at toalaalo*y. Alter, laliolop aaA Arylled rhoraocolofy, 1939-00. fraaldaat, Society of Toalcology, 19*4-43. HONS 025515 Currlculm Vitae of Dr. Harry W. Hays 2 of 3 HCMOKS (continued) Hletorlan, Society of Toxicology, 1973-. Marie Award, Saalacy of Toxicology, 1977. Dlatlngulehed fallow Award, Society of Toxicology, 1910. Praaldaac, Toxicology Laboratory Aeeradltatlon loard. 19*0-. motissioiiai acmmn Haabar, Cailetaa oa Cutanaoua laaleh and Coaoatlca, Aaerlcaa Hodltal Aaaoalatlaa, 1943-99. (Oialraan, Laglalatlxa aod Llalaoa SiOcflltw, 19*4-49.) M--bar, Frograa Cnml ctaa for Syoyoaia oa Cutanaoua Toxicity, Society of Toxicalogy, 1944-79. Maabor. Callt tea oa Cartlfleatloa of Taxicologlata and Accreditation of I abaratorlaa, Saalacy of Taxlealogy, 1973-79. Mar, laearegaoey Cal laboratlTO Giatg oa farlraoaaatal Cartloogaaaala, arlaaal Caoxar laotltato. 1973-79. Hanber. rhilral Selaatlaa BorUag Creug, Ratlaoal Center laatlexta, 1974-79. Maabor, ian Itndlaa Cailttae, 0.9. Degartaant of Agrlcnltxra, 1974-79. 990411Maabor, Toxbalcal Advisory CaHttaa to V.S. Dorertneat af tba Amy oa tba deal)1ratilatino , 1977-74. Mlbor, 0.4. delegation to tba Joint nO/n/W Coafaraate an Myoatanlaa, balrebl, Konya, 1977. .urn, bom of Trodnata lafoty Cailaali, 1977-74. for 1abaratary than 73 axlantlfla ynbllaatlana. 1 ragaaot.l HONS 025516 CurTlculuffl Vlcaa of 0*. Marry U. Mays J of 3 y^ OF STtClAL IWTPIST AMD COWgTDtCg Natural toxleanc* la food; food additives; toxicology of pooeleldos and Industrial chleals; ragulaelon of poaticldaa; hazard uiMiae and aafaty evaluation. PPtSONAl llrch data: Oecobor 23. 1909 Narrlad: Childran: Daconber 14. 1933 (Elsa C. Luts) Thoaaa Crtfory Mono addraaa: 3900 tfatson Mac* Waahlayeoa. X 20019 Business addraaa: Drill. Frlaaa, Maya, Loonla 4 Shaffer. Inc. Suita 204 1901 North Fort Myor Drive Arliafcoa, VA 22209 Business colophons: (703)327*4430 August 1, 1910 HONS 025517 1 of 4 COIftlCDUH VITAS or Oft. TZD A. LOOMIS miCATIOft Sochalor of Seine* (l.S.) dafraa, BolTr*lt7 of Hoohloftoo, 193*. Naatar of Seine* (N.S.) dafraa, Odvoralty el luffilo, 1941. Doctor of Fhiloaorhy (Sh.D.) dofroo, Udvoralty of loffaio, 1943. Doctor of Hadldaa (M.O.) dofroo, Talo Udvoralty School of Hadtclao, 1944. unarmn latan, Marla* fooyltal, O.S. MUc laalth Sorolco, Soattla, at, 1944-47. Aoalataot frofaoaor, Dopartaaot of Hloraornlofy, Odvoralty of Waahlaftoo Scftaol of Modlclao, 1947-49. laaaalata rrafoaaor, Dcooraaat of Hiaraarnlofy, Odvonlcy of Maahlaftoa School of Modirloo, 1949-53. Captala, O.S. Any Madlral Cory* (Active Doty), 1933-33. Aaooclat* Profaaoor of fhamacolofy aad State Todcoloflat. Oalvanity of MhohlafV School of Modiel*o. 1935-57. Frofaaaar of Ihanaoolofy aad Stata Tcdcelaflot, Odvonlty of Moahlaftaa School of MadSalao, 1937-74. Trafapaot ad T*tna*ol*fy aad Tnlcolafy, Ddvcnlty of Moahlaftaa Sahaal of Madirlao, 197*-. Dlrootari 9CU1. ntaaa, Maya, Loaala 4 Shoffar, la*., 1940-. Soclary far lapcrtaaotal llolafy aad Madlclaa. laalaty of Taolcolacy. Wooturn rhaaaacoloty Sodety. HONS 025518 Curtltului Vlcaa cf Ot. Tad A. Looala of 4 HOWOM Dlgloata, National iord af Mlul Ewlnirs. Dtaeingulahad Fallow, Society of Toxicology. Proaldant, Society of Toxicology, 1969*70. President, Western Pharmacology Society, 1969-70. taclplont, Toxicology education Award, Society of Toxicology and fora far Advancement of Toxicology, 1976. womnowi acrmtigg Dakar, Ci--tttM an Taata far Intoxication, Rational Safety Cowell, 19J1-. Dakar, UUorlal leard. cilnreel PhsTnaceloXT and Therseeutlcs. I960*. Dakar, Agrtealenrol Adrloory laard on Peatleidu ad laaoctlclda. State of Waafclagton, 1963-77. Dakar, Adrlaary Coatna a Tnueali fa Sofacy Imlnatlaa, 0.9. Mad and Drag Ministration, 19dd-69. Mar, Adrloory rgalgta, Fatlcldaa logoi rtf a Hrlalig, B.l. Oagarflaac of Agrlamltnm, 1966-70. Mat, fkataatalagy Toxicology laata Coalttan, iotloaol taricwa of taml Wadital Srlataa, gqrlaal Iatlcutao of laolck, 1966-70. gaaaack Affiliate, lagiaal Trlaata Caaca, OnlTaraley of daaklagtaa, 1966-. taalnta at aaltfc. 1976-74. Tealrelogy Tralatag Coaadtta, lerioool Mnl Sataaoa, latlaal laotltntaa of Mar, Candma fa Idoatfioatla at taarrk Waada la Data kgfly, kglaaatlag aad Bgka Walth 1tiara ttady Sootloa. kgrlrOBoacal Cacxal Idadalgnaila Caaaaa Tmanioa aad alnaialiJ Waoltk Samoa, Mill laaltk farrtca, B.S. miif< of laaltfc, Idaagla, aad Walfara. 1970. Mr, ddotaary raolllii ta iorla tka On at 1,4,VT, Agrlaaltaral iarrlaa, 0.9. Bagartaanr at AgnUaltara, 1970-73. to Pkanol. national laclata fa Oamgarl--1 gqfaty aad kanltk, 1973. HONS 015519 Curriculum Vital of Dr. Ted a. Loomis } of . ymressiotuu. ACTIVITIES (continue) Cenevlcant. Criteria for * Esconneodod Standard; Occupational Exposure eo formaldehyde. National Instleuto for Occupational Ssf.ty end Health, 1976. Member, Conmitten on Haaleh Hazards of Pyrolysis Produces of Polymers, National Materials Advisory loord, tfselonol Research Council-National Academy of Sciences, 197>-78. Member, Cemmietea on Oironle Toxicity Testing, Advisory Conesr on Toxicology, Notional Research Council-National Academy of Sciences, 1978. Penalise, Coaniecaa on Merino Ecoeyscwe Analysis (New York light Project), 1971-77. Henher, Advisory Board, Springer-7erlag Bandbuch Serias, 197)-. Member, Editorial Board, Coahnetlon ToxIcoIoxt. 1973-. Chairman, ComdtCM for Poor Review of NASA Ufa Sciences Proposala, Pharmacology-Toxicology Section, American Institute of Biological Sciences, 1971. Maabor, CmitCM on SvKkmie Toxicity Toot Prococola, 0.1. Erlroi--oral Protection Agency, 1979. Mrobnr, Sciontifie lavlan Panel for Bealth Boaoorch, U.$. Baiwaul Prncoctien Agency, 1990. raucttiewt bw .< Iwtortqp. U. * Ftelter. niliUpUi. fine Ultlm. UH iMri Hltla, U74 m*. uittM. an nmuasaomt town 100tatter H tarter .( ,pnlMMly H?"> la tte NlMtllu Utmnn. (MkltecraHT mUillt ufoa Tiw--t] HONS 025520 Currlculvaa Vltaa of Dr. Ted A. Looms 4 of 4 A|jftsoFjnciu_iijr|sBl_A!!0_coajnsSI OmUiMnt of biological and cbaalcal nathodclofy for tonicity testing; clinical and forensic tealcolopy Including evaluation of cauaa-offtet ' relationships and Interpretation of clinical analytical findlnps; davalopaonc and presentation of apodal proirana and Inacructlonal natarlala In corlcolopy for Industry, educational lnaclcutlona, and attorneys; effects of alcohol end drupe on autonoblla drlvlap, Includlaa blood and broach teats for lntealcaclon; anlaal and clinical drup end pastlclda coalcolopy. rOSOHAL DATA llrth data: April 1A, 1917 Married: March 19, 1904 (Marlon Adaaa) Children: Hasti 1. (Maoaahar 15, 194d) oaky A. (Saaoabor 7, 1993) aaa addraoo 2707 last lochar load Cllatoa, HA 9U3d lusloans addraaa: Drill, frlaaa. Pars, Looala A Shaffer, lac. Salta 204 1901 North Fort Mycr Drlra Arllaptoa, TA 22209 aolaaeo talaphoaai (703)327-4430 Aopuac 1, 1910 MOWS 025521 CUIUUCULUM VITA! or or. c. boyt) sium* mUCATIOW laehalor of Seloaco (I.S.) Oagraa, Lebanon Vallay Collage, 193*. Doctor of Ffclloeophy (Fh.D.) Ingres, rrlncocon University, 1941. artormiff Saaior follow, Chaalcal Hygiene followohlp, Hollos Institute of loOuocrlol research, 1941-32. Chlof Industrial Toxicaloglot, Coatrsl Radical Dofirnait, inarlcaa Cyanjnld Coapsay. 193J-3*. Olroetor of ioolrn--ootol Roslth. Ccoerxl Modicxl Daparcoast, ImiIcm Cyeoaald Coopany, 193*-44. Director of Tonicslogy, Costrol Nodical Daparronit, Anarleas Cyaamld Coopany, 1944-79. atDirector Corporota Toxicology, Cnrlroanaotal Sorrlcoo Dlrlaloo, farlcaa Cyaaanld Caapany, 1979-M. atOfmbor csrponta Label Csmttttoo at inarlcaa Cyaamld Caopaoy, 1937-*0| rial mao, lN*-*0.) Olroetor; Drill, Trlooa, lays. Toil a 4 shattar, la*., 19*0-. lari raa Tadnerrlal Dygloaa Aoaoclxtloo. laorlia foalary at ffeanacolagy as* bparlaaatal Therapeutics. loalaty far Ignfaaaul llolagy as* Kadlclaa. foalary at tamtaalagr. The loalaty at tho Sl^a Zl. atAdjunct laaariara Prsfaoaar laolreanaatal Hedicina, Diparraaat of taviroaaaootxl Madlclaa, lai Tork Oalroralcy lMlcal Caatar, 1959-*0. MONS 025522 Currlculim Vita* of Dr. C. Boyd Shoffar 2 of 3 BUMS (continual) Chaliaaa, Cordon doaaarcti Coofarcnca on Toxicology and -Salary (valuation, 19*2. CartIf lad by cha Aaarlcan loard of Induacrlal Hyglana, loe., In cha TOXICOLOGICAL ASPECTS of Induacrlal Hyglana. Praaldant, Sectary of Toxicology, 19(2-43. Editor, Toxicology and Aoollad Phataacolocy. 19*5-47. Dlatlngnlahad Polio* Auard, Society of Toxicology, 1910. PHQPissiomL Acrrrma a nw associatiom Chleal Maaafaccurara Aaaoclatloa (Potaorly Hanofaccurlng Chi tea Aaaoclatloa) Lahnla aad Pracautloaary Iafaraatloa CaHttaa (Makar tinea 19M; flilfi, 19dS-*7). Intawlttaa Taak Crony oa Traaayortatiaa laaarda, IMS. (Vtaca, mtk layac fra cha Cray, tha tea HWkll "* tka M Cara Inforation Card Traaayartaclaa laaarda lafaaaatlaa Cametoo, 1947-49. CHtota a yrayaaal aa Traaayartaclaa laaarda Iafaraatloa Syrian far aabalaalaa ta tka O.S. Dayaraaat af Traaayartaclaa.) Taola Safcaraaaa Caatral Crary, 1971-7*. (Ckalira. 1972-7*. Proaratal tka Cl taotlaaay aa Taalc Inkaraacaa Caatral laplalatlaa kafara Caaalttaaa of back loam of rrairrrt darlai tha thraa aaaalaaa af CratTtaa orar ahlah thla lailalatlaa aaa caaaldarad.) Chiral fatalarlaaa Advlaary Caomttaa,-1979-77 (Chaliaaa). lari aaa1 Ayrlaaltaral Chirrla Aeaaclatlea kaiianil Adtlu Camlttaa (Chaliaaa, 1971-74). mmnm, 'ey*TM* v wpbe MW, Clttaa an Tariralayy, Safi anal ll adam af Srlaaraa-larlrarl taaaarrk Coaacll, 19*9-73. HONS 023523 rrlculua vitae of . C. Joyd Shaffar o: ^rtssioim. ACTivnm in covnuonirr (continued) inneir. Standards Advisory Corel c coo for llaaardoua Materials Labeling, 1974-73. (Convened by cha Occupational Safety and health A^lnletraeloo of cha U.S. Dapartaaac of Labor.) Advisor on niaaroue occaalone, 1972-71, to tha Delegation free tha U.s. Dapartaonc of Transportation to nestings of tha Croup of Sapportaurs an cha Packaging of Dangerous Goods of cha Coaiccaa at laparta an cha Transport at Dangerous Csoda. (Mootings hold sanl-aaaually la Saaava, Sultsarland, uadar cha auaplcaa of tha Icaaaalc aad Social Cauacll of cha Unicod SacIona.) munnow Aachsr or co-author af approxlanealy 40 papara la tha scientific llcaracura. (llhllofraphy svallabla npoa raguaac.) CXsaasc nr srgldl. arnf" spit maun laaaarch dsaiga; toadcalogy of pyachstlc orgaale laduscrlal rhaaligig, attaalcolagy syuchacls orgaale pesticides; aafaty avaluatloa; atpracauclsaary label lag bssardaaa ladaani al rhaalrals; pracanclaaary atIsbillag haaaabsld pradurta uadar tha 7adoral lagardaaa Inbaraasaa atAac; pmaanfisnary 1 abal lag pasclaldaa uadar cha Federal Inane at mtmdclda fuaglalda, aad ladaatlclda bets regalatlea ibMliala atcha Taste tubanacaa Caatrel bets traaapartadaa baserdsua aacarlala; atpraparatlaa, anbalgalea, aad follau np foad additive patlclaas. birth data: Harried; i bagast Id, 1917 Jaa 1*. 1941 Olaty Louisa Scaaar) Idaard I. (grower 20, 1942) <" A. (Paa bar 17, 1945) 2370 11 Oaaaa llvd. b-)02 Stuart, II 33494 baaapella, U401 Drill. Trlaaa, layu, Laeals 4 Shaffer, lae. Sales 204 1901 garth Tart Myur Drive Arllagtaa, lb 22209 (703)527-4450 Aagaac 1. 1990 MONS 025524 CURRICULUM VITAE ^vltvt Ellisboth Mitinoskl (Nee Murriy) Skill Sicurity No.: 034-22-2128 8ee of 81 rth: Slim, Mossichusotts Oiti of Birth: August 28, 1330 Kitlon: Punchird High School, AndoVOr, Miss., 1947 R4dc11ff* College. Cimbrldqe, Miss., 1947-1951 Johns Hopkins School of Medicine. Biltlmoro. Md.. 1951-1955 Johns Hopkins School of Hygiene 4 Public Hoilth, Biltlmoro, Md., 1960-1984 Dofrees: Ridel Iff! College, A.B. In Chmolstry, 1951 Johns Hopkins School of Modlclno, M.O., 1955 Johns Hopkins School of Hygiene 4 Public Hoilth. M.P.H. 1962: Or.P.H. 1964 Reseerch Prosontitlon for dooroo of Doctor of Modlclno, "Prthery Bllliry Cirrhosis In Chlldron ind Adults* Cortlflod i Sooclillst In Sononl Prooontlvo Modlclno by tho Amorlcin Boird of Prooontlvo Modlclno, Ootoabir 1973 Pollom of tho Amorlcin College of Prooontlvo Modlclno. April 28. 1978 Honors: Mmnbor of tho Alphi Chiptir of tho Oolti Omooo Hononry Society. Hoy I960 Gonovlooo M. Motonoskl, H.O.. Or.P.H. Profossor Tho Johns Hopkins University School of Hygiene 4 Public Hoolth Ooportmont of Epldmelology Room 2408 615 north Holfo Struct Biltlmoro, Morylontf 21208 Telephone Moo.: (301) 988-3483 (301} 988-3692 HONS 025525 POSITIONS: Professor: Johns Hook(ns School of Hyqtn s Public Health July 1, 1976 to prisont Assoctitl Profossor: Johns Hooklns School of Health Services Sootonbor 1973-June 1978 Associate Profossor: University of Maryland Dental School October 1970 to present Coordinator 1 Evaluator of Special Projects: Evaluation 4 Biostatistics Center of the Regional Nodical Proqran March 1970 to 1973 Associate Professor: Oeeamant of Preventive Nedlclne University of Maryland 1970 to present Associate Professor of Epldaarloloqy Johns Hopkins School of Hyplene * Public Health July 1, 19(9 to present Instructor In Pepsi font of Preventive Medicine: University of Maryland 19(7*19(9 Tralnlne fellowship In ftibllc Health: Johns Hopkins School of Huelene I Public Health 1982-19(4 Assistant Professor of Epldaarioloay: Johns Hoeklns School of Hyelene 4 Public Health 1984-19(9 Instructor In EpIdswIOloqy Johns Hoeklns School of Hygiene 4 Public Health 1989-19(4 Pediatrician Out-Patient Dsoartnsnt: Johns Hoeklns Hospital 1987 te present Roseerch Assistant In Epldasrtolooy: Johns Hoeklns School of Hyolana 4 Public Health 1987a19N Assistant kasldant in Pediatrics: Johns Napkins Hospital 1988-1987 Intern In Pediatrics Johns Hopkins Hospital 1988-1988 Research Assistant Johns Hopkins School of Medicine 1988 HONS 025526 CURRICULA VITAE CATEGORY II TEAM HONS 02552* cuwiaim VITA2 llvlto Potor Alvaro**, Ffc.D. IHWM>; Ian: Dunbar 2], 1123: tubay, India Clcltonohlg: D.S.l. Hamad: no children Unlvoriley of InbOT. India, 1*31-1931 l.lc. Oogroo: Major la Oiaodatry; Klaor u Fhrolc*. 1*33 l.Sc.(Tach) Dogroa: In Qinlcal Technology, 1*37 UUnnllf of Doirelt, 1*31-1*00: H.S. Dagraa: Major In llochnlatry 1 Minor la Chaniotry, 1**1 Unlvoralty of Chlcaga, 19*0-19*3 7b.D. Dogroa; Thomcology, 1*** hoot Addraaa Dogortmnt of Thomcology Dnlfanod Servian* Unlvoralty of tba Health Seine** *301 3ano Irldgo load lacboada, Maryland 2001* Tolaghno: (202) 2*3-122* 1. Foot-doctoral Follow: Dogartnnt of Thernneology, Onlvoralty of Mlnooota Modlaal School, Hinaagolle, Min. 19*3-19*7. 2. Scalar loonitb llorlinlat: Wallen* loonreb Uboraeorloa. orroogb* Hnlleaan nd Co.. Toebobn. I.T. 1M7-1970. 3. loonreb laooclat*: The locbafollor Unlvoralty, In Toth, l.t. 1970-1972. *. Aaalatnt Profo*nr: Tho lockafallor Onlvarolt*. Sow Torb, g.T. 1971-1971. 3. l*alatent Trofoaoor: Dngorant of Thomcology, Cornoll QOlvornltT IMltal CoUtg*. No Took. I.T. 1972-1973. *. Odjont Anooat otaPTcfaoqar: Dogartont of Thomcology. Cornoll OnivorolCF Nodical Collogo, low Toth, I.T. 1973-1977. 7. Aoooclata Profooaor: 2b* laebafallar Coivorolty, loo Torb. I.T. 1979-1977. I. Adjuct frofoooor: Tba locbafollor OnlvoroltT, m Torb, I.T. 1977-1979. 9. Aooocloio Frofoooor: Dogertant of Thomcology. DOlfonod Sorvlen Unlvoralty of tbo Inolth Scloocoa, lothoado, Maryland. 1977-1979. 10. Frofoooor: Dogortnnt of Thomcology, unifomd Sorvleu Onlvoroltr of tba looltb Scloncaa, lathonda, Maryload. 1979-groonc. HONS 025528 -2- I. mortal Iraa T. Hlrochl Scholar, lf7*-197S NatUul Inaclcutaa of Railch Catwr Oavaloyiaat Award Slfwa XI tactcu tHKlatln (or eta Unacaat s< Sclaaci Haw lorl Acadmy of Scleaeoa taarlcaa Society of fharaacoloty and Inatlaaatal Thorayowtlca loKlcaa Soclacy of Biological cbmlata oaarlcaa Society to* Clioleal niaraocology aaO Therayoutlea Toolcoloty Soctloo, Iacaraatloaal Halm of Pfcarmcology (luytat) Soclacy of Toolcoloty 0. Mat leal School cat Ualwaralty ActlYltlaa: 1. Lactarm la Matleal fharaacolofy Caarm 2. Hlalcouraa la ToxlcelOfy fat 2at year aatlcal atataau 3. Cratuata Statmc Adoleery "uml nn l. Haakon ratalcy Saaata, If7S-S0 i. Chaltaaai Ctloaaaaa fraaittae. faculty Saaata, l*7f-t0 1. Haakon Saaaarth rroyaaal Marie tarlaw rnmlttaa, l9-*2. 7. Makati Blohaoarda, CmtroUat Sahataaeaa, cat Saataroaa Matarlala rnmlttaa. lftl-M. I. Cratuata Statmta cat Thaaaa: Jolla 1. Ilian. "Altaratlam la haaa mtaballm latwcat hy told H7S. 1. Mtt, Staarlat Cemlttae, Slnrhaaical Tharaaaalaty Macaaau Braaa, Maw Tack ttafmy of Salamm. H75-1177. 2. at hoc rawtaaar far llachaalcal rmraacaloty, nolacolar Itanaialap, Ufa Sdaaaaa, Sclaara, Cllalaal Pformr I logy aat Tharafawtlca, aat Joaraal of fharaataloty aat Upai I--ul Theraymtlaa. 3. Hmkar, Meritrowf of the latloaal Camlaoloa m Bltaatlre Oleaaaae. U77-1*71. . talar, ttleorlal AoarOai Cllalcal Fhaaaacolety aat tharayeuclca fharaataloty Joacaal of tawlrammtal Patholoay aat Toolcoloty HONS 025529 3- C. Participant (Invited Sgnakar) I. First International Syagoalua la Mlcroaoaas sad Drug Oxidations, lathasda. MarylMd. IMS. J. Iataraacloaal Syagoalua on Drag Tolarsms. Addiction, ASnna sad Machadoaa Traataaac, ov Orlsaaa, Lswoiaaa. 1*71. 3. Jocoad lattnacloaal SyagsalM on Mlctoaonaa sad Drag Oxidations. Stanford, California, 1*72. A, IDS Sy^oslun* Isactlon Mathaalaaa of Cytschroaa P-450 and lalstsd laxynas. Sucktela, Snadas, 1*7], J. Upjohn Confarsnea on gypaoclea and Sadatlvna. Calsnasoo, Hlehlgaa, 1974. S. guraanan Society of Padlacrlc fndaarlaology. Annual Masting, Sarlla, Vast Caranay. lt)S. 7, TMtd Iatarnatlonal Sj^oalm an MUraaanaa and Drug Onftdatlona, Sarlla, Vast Camay, 1*7*. I. Cardan laaaarHi Coafsraaca - Drag Matakollan, Plyasath, San Sanaaklra, 197*. 9. fourth Door ladga Confarsnea on Clinical fhaiaacsloggr, flathaad laka ladga. Maataaa. 1*7*. 10. Cardan Saaaarak Canfaaanoa - Tonlsslsgy. flnSall Union Acadaay, Ran lanpafelra, 1*77. 11. Synpsalxn an Drug Disposition la Man, Sarasota, Tlorlda, 1*77. 12. SingaalM an laflnaara sf Mntrttlaaal raatsts on Taaltalagy,Ingaanatlanal rangraaa sf fharnatalagy, Paris, Praaca, 1*71. II. SjMaalaa an Aaaaaonant sf Drug MataSallaa la Mm, Sasaaasa, franca, 1*79. 1*. Tataraatlaaal Caafaranca on Critical Currant lasaas la a lnaniil il Banltk Raaarda, Tal-dats, tsraal, 1*7*. IS. Ssoaacfc Inapan Mata* la Drug MataSallaa, Sarlck, Meantload, 1*M. 1*. VtrSaSag on tba Ctadlaal Iffacta sf Iona*latics, Hatlsaal Saasarcb Canaall, ottans, Canada, 1*01. 17. Cardan Caafaranca on food aad Sutrltloa, 1*S2. 025530 HONS PUBLICATIONS: Mekusick VA, Hirr GE. Peeler PC, Webb CM: Musical murmurs. Bull of Johns Hopkins Hospital 2T:U6, 1955 Prica WM, Matanoski GM. Morrison 0, Prewar a, 4*oner 5: The fractionation of seromueoids from human sarua. Bull of Johns Hook ins Hoss. 108:227, 1961 Prica WM, Matanoski GM. Prewar A, Rector L: Seromucold fraction oattams of individuals with pnaumonia or laukamia. J Sanaral Physioloay 45-205, 1982 Matanoski GM. Prica MH, Fersnez C: Eoidamiolooy of straotococcaI infactions in rhaumatic and non-rhauMtlc familtas. I. Objectives, plan of study, and comoarativa fraquancy of straotococcal isolations. Anar. J. Epid. 87:179-189, 1988 Matanoski GW. Prica WM, Farancz C: Epidamiolooy of straotococcal infactions in rhaunatlc and nonrhawatlc familias. II. Tha intar-ralationshlp of straotococcal infactlons to aoa, family transatission and tyoa of Group A. Anar. J. Epid. 87:190-208, 1988 Matanoski GW. Prica HH, Farancz C: Epidamiolooy of straotococcal Infections in rhaumatic and now rhaumatic familias. III. Comparison of tha 1manna rasponsa to straotococcal Infactlons In the tM populations. Anar. J. Enid. 87:207-225, 1988 Matanoski GM. Prica MH, Farancz C: Epldmriolooy of straotococcal Infections In rhaumatic and nonrhamaatlc familias. IV. Tha effect of tonslllactomy on streptococcal infactlons. Amor. J. Epid. 87:228-236. 1988 Matanoski 6H: Tha role of the tonsils in straotococcal infections: A comparison of tonsilleetorn!zed children and slbllnq controls. Amor. J. Epid. 96:278-291. 1972 Matanoski GH. Saltsar A, Sartuoll PE, Diamond EL. Elliott EA: Chanolm) trends In mortality of sooclallsts and U.S. white males. Proceed nos and abstracts of papers presented at the seventh annual maotlne of tha Society for Epldmaioloaic Research, Berkeley. California. June 19-22. 1974 HONS 025531 Klngvlbtrg M^tanoifcl 3W Klntell AW: Otntil carlcstiotrtcftcc In three generations of families. Journal of Public Health Oent 34:3, pages 174-180. suaaer 1974 Matanoskl 5M, Seltser R, Sartuell PE, Olanond EL. Elliott EA: rne currant aortallty ritb* of radiologists and other physician spdclallsts: Deaths fro* all causes and cancer. Anar. J. Epld. 101.:J. 188-198, March 1978 Hotanoikl 81. Seltser R, Sartuell PE. Olanond EL. Elliott EA: Tha currant aortallty ratal of radiologists and other physician spdclallsts: Spaclflc causes of death. Aoar. J. Epld. 101:3, 199-210, March 197S ----- Matanoskl GW. Sartaell PE, Elliott EA: Letter: Hodgkin's disease mortality aaang physicians. Lancet 1:928, 1978 Matanoskl 94. Landau E. Elliott C: Epidemiology Studies Pilot Study of Cancer Mortality Naer a Chartcat Plant and Other Industries in laltlaore, J.S. Envlronanntal Protaction Agency, Office of Toalc Substances, Washington. O.C. 20480. May 1978, Final Report Matannakl 6M. Henderson MM, Stlna OC, Caurpas C, Hapnar R, Walkor S: rho effectiveness of phoaacirdloacan screening for the datactIon of heart dlseaae la school-age children. AJP 87:7, (09-411, July 1977 Matanoskl SH, Landau E, Elliott E: "Progress In a Ceanmlty Arsenic 5tuey*"1a Toole lubetiaras In tha Air Enrlronaent. Air Pollution Control Association, Pittsburgh, 1977 Kaszube At, Matannakl 8M. (Ibsen (: Evaluation of tha tarponcy OaparbMnt as a site for Hypertension Screening. JACEP 7:2, pages 81-88. February 1978 Mtk H, Flynn J98, tfctaanskl EM: Oo Adelalstrstlve (gldellnes Modify the ApplIcatIM and ciinTcal benefit of Haas 0aygan7 Abstract. Anar1can barton of Respiratory Olsaaao, Supplaaat HOT April 1979 HONS 025532 -4H. Arm of Scientific Iotorooc: () Factor* infloaocini tho aotabollca aad action of dfa$*, carlrowan tol chaalcaia and carelao$oaa. (b) lataraetloaa batvaaa autrltioaol factor* aad dm* aataboiisa. () Biochoaieal and toxicological offacta of oariroaoatal rhortfli and canlaogaa. (d) Hoary aacal toxicity. (a) Iffocta of foral^ choaieal* oa Hobo bloayathosla aad hoaa aataboUia. <f) KtRMi hoBaprotoina: difference* la eoadoeltloa aad cnraeror rata*; refaiatloo by drucs, cblorlaated Hydrocarbon* aad carcinogen*. MOMS 025533 -5alvcto rtm aivams Ut of Publication*i i. Aivaroo. A. 9.: Utilisation of utti and by-produets of tho fatty oil industry. loaboy fochnolooiat. It 1.4, 1997. 2- Narbor. L. I., A. 9. Alvaros. A. Z. Jacobaoo and . j. viooki Kffoet of barblturie acid wi chlortotrocyellao upon growth, amowl o cooeontratioo wf wm activity on tto faotroiatoatlnal tract of cfcicfco. Journal of autrl*-- u> 1*9, 1943. 1. Aivaroo, A. L. . luftw and . J. vioaAt Effort of barbituric acid, chlortotrocyellao and earbohydratoo upon frovth and faa- txoiAtaatinal uroaoo activity of chieka. Joaraal of ntfitiw. 2,1 93-M, 1H4. ^ 4. Aivaroo. A. 9.. a. r. Ooodrickson and a. J. Vlaofct Sffacto of loo- nlaold, chlartatracycliaa and cappar upon frovth and paotrointootiaal aroaoo activity of ekleko. Journal of autrltlon. ait 79-d3, 1M4. rtckaoa, A r., A 9. Aivaroo and . J. viooki Sffocta of tiaal uroa kydrolyalo of rata. Joovnol of detrition. Mi 49-70 1M4. 9. Kabara. Jon j.# a. 9. Aivaroo. C. Uopol and J. f. rain cbnlootarol Xa Sffoot of arrkadollop on tbo otocol lovwrinf capability of noabylpboaldoto (Mtalia). pgaooadiwoo of tbo Till f tT Tnrmi--1 ^tt t* 7. 1, m. a. 9. Alvoroo, and 0. J. nonaarlaoi InAibitioo of drop notaboilzZt wotaballtao of l^iothylanlnnotbyl 2,2- iipbonylvoloroto K1 <0T 939-A). Wp^np^ar rtiwiol m 1 2i J2POJ4, IMP. > hfdaunflotion by hopatlr dni and 3 notkylcbolanthrano m ~nrTi" 1 mi ~ ~ 1 1' HONS 025534 Matanoski GM. Sal tsar 8, Sartwall PE, Diamond E. Elliott E: " TTjks of Radiologists Over Saven Dacades. Abstract 3resented at - SER Meeting, New Haven, Connecticut, 1979 Matanoski GM. Payton AJ: A Cohort Study of Cancer Mortality in virologists. Abstract presented at the First Annual NIOSH Scientific Symposlije 1978. Toxicological I Carcinogenic health Hazards in the Workplace, Pathotox publishers, 1979 Sandler OP, Matanoski GW. Comstock GW: Health Consequences of Nasopharyngeal Radium irradiation. Abstract presented at SER meeting. Hew Haven. Connecticut, June 1979. Amer. J. Epld. 110:3, page 358, Saeteneer 1979 Matanoski GH. Landau E, Tonascia J, Lazar C, Elliott EA, McEnroe w, Keating R, Saifter J: Lung Cancer/Mortal 1ty in Proximity to a Pesticide Plant. EPA 560/11-80-013 (Epidemiology Studies), U.S. Environmental Protection Agency, Washington. O.C., March 1980 (an interim report) Mak H, Flynn JPG, Matanoski GM: Do Clinical Guidelines Modify the Application andlenefit of Home Oxygen? Maryland State Medical Journal by the Medical and Chtrurglcal Faculty of the State of Maryland, Baltimore, Maryland, March 1980 Ferencz C, Matanoski GH. Wilson PO, Rubin JO, Neill CA, Sutberlet R: Maternal Hormone merapy and Congenital Heart Olseesa. Teratology 21:2, 225-239, April 1980 Massey RM, Crochetlere CA, Matanoski GH: Hematologic Values In Benzene Exposed Workers. Journal of Environmental Pathology and Toxicology S:2. SIS--521, Pathotox, January 1981 ~ Matanoski GH. Billings CE. Levine MS, Lees PJ. Elliott EA: Investigation of Health Hazards in the Painting Trades Industry Report. Unpublished report to NIOSH. The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland. January 1980 Matanoski GH- West S: Occupation and Environmental Exposures and the IHk of Congenital Heart Defects. Abstract presented at SER Heating, Minneapolis, Minnesota, June 1980 Altar Ml, Gerety RJ, SampIInor RE, Smallwood L. Tabor E. Matanoski GH. Nathenson N: Coamunlty Acquired Hen A Hon-* Hepatitis. Abstract presented at SER Maatlng, Minneapolis, Minnesota, June 1980 Sandler 0, Matanoski GH. Comstock G, Mitchell T: Health Consequences of the NoiopnarynggT Radium Exposure. Symposlua on Biologic Effects. Imaging Techniques and Dosimetry of Ionizing Radiation. HNS Publication (FOA) 80-8128 HONS 025535 Sandler OP, Comstock GU. Hatanoskl SH: Neoolisns Following lowOose Radius Irradiation of the hasopnaryn*. Submitted to JNCI, SeptenSer 1980 Soma metals and metal 1c Compounds. Intamatlonal Agency for Research on Cancer monographs on tha Evaluation of tha Carcinogenic Plsk of Chamlctls to Humans, Voltmm 23_, Julllet, 1980 MatanosH SH: Risk of Cancar Associated with Occupational Esposura in Radiologists and Other Radiation Workers. Procaadlngs of the 1980 International Symposium on Cancar, September 14.18, 1980. Cancar - Achievements, Challenges and Prospects for tha 1980s. Volume U241-ZS4, Grune and Stratton, 1981 Hatanoskt SH. landau E, Tonascla J, Lazar C, Elliott EA, McEnroe W, ting t: Cancer Mortality In an Industrial Area of Baltimore. Environmental Research 2S:8*28, 1981 Hatanottl GH. Elliott EA: lladdar Cancar Epidemiology. Epidemiologic Reviews vol. 3: 1981 (In Press) HONS 025536 CORSULTANT ACTIVITIES: Periodontal Olseases Advisory Cowrittoe, notional Institute of Oontol Resaarch, January 1975-Jyn* 30, 1978 Subeowiltta* on Adult Health, nodical and Chlrunjlcal faculty of the SUM of Maryland. Septaabar 197S-Juna 1978 *npran Ooveloenent Soard, American Public Haalth Association, 1977-1978 food and Oruo AWInlstratlon Sloaetrlc and Epldaoiloloqlcal Methodolopy Advisory Cawlttae. Bureau of Orups, HEM Rockvl 11a, Maryland, Movabir 1978-January 1978 Air Quality Control Advisory Council, Maryland Stata Oapartnant of Mental Hygiene, March 1978-prasant Tacbnlcal Panel on Envl rowantal Hazards. Anarlcan Public Health Association, 1978*1981 Cantor for disease Control, Beryllliaa Meeting, Atlanta, Georgia, October 1978 Central Maryland Health Systaea, Chalnaan, Technical Advisory Group on Maternal 1 Child Health, Novanher 1978-1979 Craniofacial Anoaalles Proqrea. itlOR, HEM , Oacaabor 1978 Syaeoslua on Potentiation of Iaaeme Response to Vaccines, MAID. NIH, fabruary 1979 U.S. Anay Envl rowantal Hyglana Agency, Residency Advisory Coamlttoo. Edgewood Arsenal, Maryland, 1978-present food and Orep Adelnl stration. Anesthetic 4 Life Support Drugs Advisory Coaartttw. Wrch 1979-198Z Hisaan Health Studies Propria, Division of Bloeetrlc and Envlrowantal Research, Dwt.of Enerpy SpecialCowrtttaa: Consultant to prepare a special report for HO Secretary Call fine Ravlee experlaaotal and apldaalolsplcal data on the carclnapanlclty of beryl Him. Center for Dlsaasa Control, Atlanta, geerpla. October 9, 1978 HONS 025537 CONSUL'ANT ANO MEMBER: Scitnca Projection Papnr Connttaa. CSR, Inc. Public Mnoting A Proposad Fodnral Radiation Research Aqanda hold in tha Jack Majur Adultoriun, Clinical Cantar, NIH, Bathasda. Maryland, March 10-11, 1900 Munbar oftho Pravantlva Madlclna and Public Haalth Test Caarittaa of tha National Board of Madlcal Exaarlnars, 1980-1984 Mannar of tha [ntamatlonal Agency for Rasaarch on Cancar (IARC) Working Group on tha Evaluation of tha Carclnoqanlc Rlik of Chaartcal> to Hunans: Sana Metals. World Haalth Organization, Lyon, Franca, Octobar 23-30, 1979 MMar of tha All* Ravluw Cquartttaa for tha Radiological and Envlronaanul Rataarch 01vision, Argonne National Laboratory, July 1, 1980-Junn X, 1983 Participant In tha 1980 Intamatlonal Synposlun on Cancar oraaantad by Slean-Kattartng Cancar Cantar with tha Avar!can Cancar Society and tha National Cancar tnatltuta. Naw York, Nan York Canfdranca antitlad: 'Cancar 1980: Achlavaaants, Chellangas, Protpacta* Or. Natanoakl Lactura: 'Risk of Cancar Aasaclatad with Occanatlanal Saptanbar 14-18. 1980 Expasura In Radiologists and Othar Radiation Norton* Participant and dlscwasant in tha Joint U.S.A.-CoNnlsion of tha Euroaaan Countries Saarlnar on Aaftlant and Biological Monitoring, I manhaurg, OacanPar 8-12, 1980 Mnubar of tha Madlcal Radiation Advisory Conrittaa, Bureau of Radiological Haalth, 1981- HONS 02553* -9- pgprCSSIONAC SOCIETIES: tear1c*n Association for tti Advancement of Science American Public Health Association tow fork Academy of Sciences Society for Epidamlolopicil Research Intamational Epidesilolopleal Association Association of Taacliars of Praventlve Madid no American Co II ape of Preventive Madieino RESEARCH INTERESTS: Cancar risks from occuoational and environmental exposures to radiation and other apants: evaluation of haaltn programs; family-eased oomlation studios; dantal disaasa; aspaclally oral cancar and tha rota of iwawology in pariodontal disaasa; rheumatic favor and streptococcal Infactions; Infant mortality and congenital malformations. CURRENT RESEARCH: Epidemiol ay of Infant mortality and congenital nalfonaatlons; survival rstas following dlignosls of oral cancer-relation to typo; factors associatad with risk of oral cancar; physician mortality in relation to radiation oxnosurai cancar aartallty In vlraloplsts and veterinarians; occuoational risk from ssooaura to dyas and synthetic ruhhar; health hazards from paint application; etlotopical factors in aultlpla myalona; anviroi--ntal risks fron axposura to arsanlc; the offsets of assasura to low-levels of radiation In a papulation of shipyard workers. HONS 025539 -6- 10. Alvaroa, A. f.. G. Schilling. a. Levin and n. r--n----- Aitaratian of cm aieroMMl luawprotein by 3-nethylcbolanthronet fffacta of ethlonina and actlMnycin 0. Journal of FharMrolncr m> Knaorlacntal Thattoeutlca. 143 417-4*4, 1944. ^ 11. levin, , a. 9. Alvarea, M. joeoboon, jid K. Kuntaaan> Effect of itocay f {soma 11vox tietoMHl prvparaeiona on the hyoresy- latlon of testoeterone and pentobarbital and the fiatbyU- Uon of thylnerphine. Mechanical Pharmacology. It. mi. -- -------- " 1*. Kuntaaan, R., v. LavIn, G. Schilling and A. 9. Alvaroat Ttia offacta of 3-oathyleholaathrene and pheneborbital on Um aiaroMHl haangrntalna and on tbo hydronylatlon of baaapyrono. in dlirfoan--a and Off Onldatlona. Acadanle Proae, now Tort, 349 343, 1H9. 13. Alvaree, A. G. Schilling, *. Lavin, A. PnnTtvn L. L. c. Nnaht Cytoefcrene MSO and b. in (naan llvor Clinical Ptiirnamlocv and Tharanautica. 101 ISS-4M, 14. Alvaroa, A. 9.. G. Schilling, A. Garbet and A. Aintaua on the hydrony Utlao of 1,4 banagyrana by hepatic Mi Effect of albonlw on the rata of bydaocylotion of ), lochanlcal IffTfi 1449-1499, 1970. 19. Alvaroa, A. 9. and G. J. Nanaoringt Tv anbatrato klaatlca of druynataba lining onayoo aytana of hepatic Me rhaanacolaar, 4. *04-21*, 1970. U. Levin, v., A. 9. Alvaroa and . nmfaai Dlatrlbctlon of radio active Mnagrnf In and Obindtug pipait la rongb aad March ndnplalr rotlealna of rat llvor. archive# of lochaaiatry andJ^bQiM, 139* 330-239, 1970. 17. Alvaroa, A. 9., G. Schllllag and v. Lavlai tgaalaa dlffaroncaa U tha fdMtiaa of atamail hanajrnMli and 1,4 hydranylaac by phanahorbital and ,1 naothryblyulhrhnnlMlvthbroano. Tbarwal al TharMcntlaa. 17Si 4-U, 1970? . Lavin ^ h.' Mtaaii 20i 3*9-23*, 1971. 19. Alvaroa, A. 9. g. Schilling, and a. nmaani Alteration in the Mamoaaal It--ipfoialc and tha blnatlaa of S.HMyyian by dronyiaan indaabd by 3-natbylcbnlantbatnai tin tanaan atady and affacta af piirMyrla. Llfa Sclancoa, 1*9-114, 1971, HONS 025540 -7- 20. Kunttaan, *. A. r. Altana and r. Larin i Iffacta ot indueara at lfra* alcroaaaal anrynaa aa tha conoaltlon of alcroaaaal haaoprotaln. Adrnacaa In Cytoohanarolorr. Vol. I, Ida. r. Clcaantl and a. Caccanlli, man man. a. t., pfa. 24i-2a, 1*71. 11. Alraraa, A. S. sehllllna, V. bavin and I. Haitian, inafelllty ot auhotrataa to altar tin raraan aanvldo and othyl laocyanlda dlfforonco apactra of nlcraaanal tMOoprotain. Journal of fharaacoloor and naorinanral Iharaaautlca. 17*i 1-10, 1*71. 11. Hltaai, f.. a. r. Alaaxaa, I. saaaa and A. lanui frafaratlao and yrafartiaa of a aolahiliaat form of eytochrnoi t-aso (too chick aahryo llvar mlergacoca, nalacular Hiananlorr. 7, 110-1*1. 1*71. ~ 11. Lavln, I. JCuntnaa, A. V. Alraraa and A. I. Cannayi Orittc n*rafhy of radioaatlva nl rrnaaonl haanfrntalaa on dlothyl- ninaothyl eallalaaa. nalaealar xnatnai n1nf|, 7i *00-510, 1*71. M. nitaal. r., l Mnohaotar. A. . Alaaraa. a. Man* and A. Hum lataractlao ot irytartrana *-4*0 utth aaclfeadlaa ralaad afainat a aolablllaad *-4M frafaratlao from hapatla nine apart. Halacular Fhamaralarr. 7> ta*-*t, 1*71. 1*. Alraraa, A. f. and A. laffaai Taflitnia of fhanaharbltal on tha oaraAolI ad taalfaatr affaat of aatkadana la rata. .Taaratl of lahantarv and Cllalcal Hadlrlna. 7*. 41*-4*4, 1*72. It. bavin, H., A. I. Caanay, A. . Alraraa, x. narkata and a. laffaai Tafaction of kanaalolfyrano kydranylaaa la hnaa thin. Iclanco. 17* 41-4J0. 1*72. 27. Altana, A. f. ad A. laffaai Aa laflnaano of fhaaaktrtltnl on tha la tltn and la rito natahaHat of aithaltai la rata. Xa HdtnniafCa?. i*72. 2*. Nalah. a. a.. I. M, A. . Alrona and A. I. Oaaaayi Iffact of ma lafaorlaa aa tha aatakann Of kanaa(a)fyroaa aa* *- nT lia 1*72. HONS aits'*1 ft.. 1.30. Ilckara. 0. C. Itartai. A. ftappaa and A. ft. Alvaraa. *aiT- chlorlaatta blptaaylai Coaparatlva affacta af hlyb ata law OilaclM-centainlny Araclara aa haytic airad tamiai aaldaaa. ftaaaarch rnminlcatlaaa la Qimlcal v.chi-lr aid rtititainliiai 1. 505-511, 1972. -- Alvaraa. A. f., c. 3. tarll and s. 3. Maaraxlnfi Itaactlaa at draf-mtabollao. VI. Iffacta af ptanobaxbltal ata 3-aatftyl- etelaathrana .ministration aa a-damthylatlay maym -Tna~- af rouyb ata saeoth baytlc aleroaanaa. Aloth--lcal Km- ealaav. 3J. 1037-1045. 1*73. --------------------------------- Alvaraa. A. *., A. rapya. a. Lada ata A. ft. Camay. tadacibtllty af haanoUlfyram hydracylaas la haw aftIn ay polycyclic tanearbma. Clinical vtaraacolocv ata Tharaaaatlea. 14 . 30-40. 1*7], Alvaraa, A. *., A. rap*as. a. Lavln ata A. ft. Camay. Tnfaailiiii of aryl hydra*axben hydracylaaa la hmaa akin. la ftlcraaama ta Oraa Oaldatlona. Ma. ft. >. ftataftcaak, 3. ft. Slllatta ata ft. C. taltaan. William ata wilftlaa Ca., laltlmra, af., ppo. 300-390, 1973. ftradlaw. I. a. tmott, 0. ft. fuftaaftlaa, i. oil lam, o. ft. Mata, A. . Alvaraa ata A. Hum Itaap ladaata altaratloaa af icamlf tacmaa mtaftollan la am. ftaala af tta aac larft , fclaacao. 2U> 140-194, 1*73. Alvaraa, ft. f., 0. ft. yftaayla. ft am ay Uw. FwwHiaw t Vm un-nas, itn. tolycUarlMta* ki rn MM to Jm oj Hi--79i mux rat*. Mmtmui --i IbmwImi S4> 933-m, 1979a 37. li JUi A. f. UiMMi 0. R. MMm. . lavla aai A. Qnaiyi > --la km akU a^ aiMalMlMl IMM. M. 0. I . ata ft. r. ftlvaraai Olffa ftUlty af oyaaaftram r-490 ay polyaftlarltatta blpftaayla 1,1.1 3,2-ftla(p-aftlncnptaayl)athaaa van. ~ ~ IfOl 300-300, 1*74 HONS 02554i -9- J4. A. P., D. A. Ilckara and A. Kappaa: Induction of druaatabollrlnp anrynaa and aryl hydrocarbon hydreaylaaa by alcroacepo I ManIon oil. life Iclancaa. 14. $11-440, 1*74. Alvmraa, A. p., J. Cohn and A. Kappaai Studiaa on tha affacta of aathyl narcury an athylaorphina b-dmathylaia and anilina hy- drwnrlaaa actlaltlaa and on tha comeraion of cytnchrcna MSO to cytochrcaa P-420. Oraa Matabolim and Olaaaaltlon. 2: 2SP- 244, 1*74. ------------- ~ 41. Alvaraa, A. p. i Microaoml anayna Induction by dnfa and amIron- nantal chaalcala. In aggSSisS.' **- r- KM*". T. nneod. K. Alabala, A. 0. IbadaUl and 1. Socar. blatad Praaa, b. T., *. 7., pp. 145-141, 1175. lekara. D. A., J. Claaaan. A. Kappaa and A. P. Almraai Hlcroaaapa faralrn oilai Kffacta of akin application on nitananna and hapatlc dnap aatabollAlap aniyaa. ilochmlcal PMmacolocr. J| 774-741, 1471. Kappaa, a. and A. P. Aluaraai Pa tha Lluar Hatabsllraa foralpn Pibatanraa. lalantific mm rlcan. 212 22-11, 1471. A. P., 4. Tbpalaar, 4. laaaa and a. Kappaai srap aatabollm la aacnal chlldran, laad-pnlaanad ebUdran, aad aaaml adalta. Clinical Pharaaanloay and Tlaaraaautica. 17.. 174-Ul, 1471. UfUMa A. f. N A. bfiui TnioirtlM of Alyl dytroearfeM hy- *MTlua fer niyikteiaitai OlfMoylr 1a ti footo flocMto1 anil Mi n--if1 Umi Aviav Uctotioo. rnt tottoro, $0> 172-174, 197S. -- hiloom. An F. Mi J. CoMi i* Otm fTM Mill! Mi piMtO. X. CMtMt. MV Tin ff-y >. A. aims Mi 0. D. MSp oiOnp MantSST&tMa Miotloo for aptilMia UlOff, aaCAoaiOp Map Pf. 390-3*2$ im. p aia., y>i--tlM of Mario lap If. 2*3-245. im. MioroM* A A. f. AlMMp . Mom Mi A. fotloo moo ia Availtory lupotit yoryhyrio, 4t*Mp im. Alimop A* V. A. flatOoUi t. Mom# A I* AoioroM Mi A. Ktypui Uoi iMMlootlMi Iffoota M tyfMm> MN Milotoi Nfitk im--1 irliotln. Cllatool MiomIow --i tlwr--oMito, 19i 1*3-190. 197*. HONS 025543 -10- 30. Chaag. . L.. A. V. Woog, H. t. Dtron. A. g. Coaaay, K. 1. eageraon. J- llaean and A. P. Alvaraa: Antlpyrlna: gaglalaaawaoaeaay la ' plaaaa aag aallva following agalnlatratloa of a high and law Oaoa w nan. Clinical Pharmacology aag Therapeutic.. 10: 219-226, ifjg. 31. Alvaraa. A. P., K. 1. Aagaraon. A. H. Coaaay and A. Kappaa: latar- accloaa hocwoaa awcrlcloaal factora aag grog bloeraaaforaacloaa l" Frocooglaaa of cho National Acagaav of Sclaacva. 71: 2301-2306. L976. -------------------------- ------- 32. Kappaa, A. aag A. F. Alvaraa: How the livar aataholliaa toralga auhacaaeoa. la frnaa Wiyaia^agy -m tha lavlraanaat In hn> aag Olaaaao. U. A. J. Vaagar. W. I. Fraaaaa aag Co.. Saa Fraaclaca, pp 40-69, 1976. S3. Faatuck, t. J., K.-C. latao. A. H. Coaaay. W. A. Carlaag. A. Kappaa. K. t. Aagaraoa aag A. F. Alvaraa: Iffaci of charcoal-hrollog hoof oa phaaacacla aotahallaa la aaa. Science. 19A: 1033-1017. 1976. 3A. Kappaa, A.. K. t. Aagaraoa. A. I. Coaaay, aag A. F. Alvaraa: laflaaaca of dietary prorata aag carhohygrata aa aaclpyrlaa aag tbaaphylllae aotahallaa la aaa. Clinical Fhataaaoloav aag Tharaneatlaa- 20: 663-633, 1974. 33. Coaaay, A. I. J. Faatuck, K.-c. lalaa, . A. Carlaag. K. I. Aagaraoa, A. F. Alvaraa aag A. rappeal fahaaaad phaaaaatla aatahallaa la haaaa aahjacta fag eharaaal-hrallag baaf. Cllaical QgOMHUaix-MgJEkaaaiaUcA, 30i 433-4*2, 1974. A., H. L. Iraglow, 0. g. glahara aag A. F. Alvaraa: lagactloa of a gaflclaacy of ataralg A*-3a-ragactaa activity la livar by a parphyrlaagaalc drug. Journal of Clinical lareatlaatlaa. 39: 139- 37. Caaaay, A. 1. I. J. Faataak, K.-C. lalaa, I. Tiaraa. A. F. Alvaraa legal atlaa of grag aatahallaa la aaa hy aovlroa- aaatal rhoalrala aag glat. faderatten Pracaaglaaa. 1667-1632. 1977. 36. Alvaraa, A. f.i Itlaalatary affacta of palychlarlaatag hlphaayla oa P-630 aag P >gg aaglatag alttvaaaal aaldatlaa. la a. K. I.. A. FloeMela, 0. teataaboM, 6. Saaaa, A. P. Alvaraa Mg A. Tappn: FImMm fraa alrharna laag la a flrlag raaga: Aa nananal arpaaura to a tonic heavy aatal. Tha laprlaaa Jaytaal < Magician. 61: 306-312. 1977. 60. Alvaraa, A. P. aad A. Kappaa: Tha lagaclag proportion of palychlarinatag hlphaayla (PCIa) oa hapatlc.........rygaa......... la FTOtoaglaaa < HONS 025564 -11- (1. hwu- A., A. P. Alvares, K. I. Aadsrsen, V. A. Garland, I. j. Padlock add A. , Csnaay: The regulation of huaen drug aacakallao by ootrltleoal factors. Ia ProceedInca of the Third latomaManai SvaeooliM on Hlcreaodai and Dnia Ooldaclona. Fergaaoo Praas, I. T. 703-70*. 1377. *2. Cooney. A. I., I. J. Paatock, k. Kaatsaaa, A. Kappaa, I. I. Aadersoa and A. P. alvarea; detrition and chemical hlaaraaafornaclaaa in haaaas. | freeandlnaa of Che Deer ^d| Conference on Cllalcal Pherdeceloev. Clinical Fhataacolo*y and Therapeutics 2? 707-*20, 1*77. *2. Alvarea, A. P.. A. Plachhela. (. I. aedaraon and A. Kappaa: alter ations la dnai aatahallaa la aorkers occupationally eapnaed ca polychlorinated tiphaayla (POe), Cllalcal Fhatnacolorv and Tharaaantlca. ill MO-14*. 1*77. *4. Coha. J. A.. A. P. Alvaros aad A. tappas: On tha occurranca of cytachreaa P-130 aad aryl hydraearhoa kydrerylaaa la rat brala. ;rintl *f mrloni! h*o*i*q, us mop-mu, 1177. 43. Alvaraa, A. P. aad A. Kappaa: latere*aaalty of cytochrsaa P-*SOe ladnced hy pelyehlerlaacad biphenyls. ^Tin*1 of lielogical mw-mp*. 1*77. M. Plachkala, A.. A. P. Alvaraa. K. I. Andaman. I. laaaa aad A. Kappas: lead lataalcatlaa aasap daaalltlaa earkarai Tha affect of lead aa tha hepaflr cytschraae P-A30 ayataa la aaa. Jgg^ j{ ledceloav hilUMUl 're * 411-417,1*77. *7 doraaa, K. I., C. I. Pataraaa, A. P. Alvaraa aad A. Kappaa: omdatlva drop aarahelloa aad ladaclhlllty Vy phaaaharhltal U slckln-caU i ' Of 500-3*7, 1*77. " ` '~ U o. A. A. P. Alvaraa, I. I. . I. J. Paatock. C. *. t. Chaaa and A. 1. C Kffact ef charanal-hrollad keaf ea aarlppilaa aad thaephrlHar aotakeliaa, QMal . jji 443-430. 1*7*. H. Plachhela, A.. (. . Saa, I. Daoldsv. A. P. Alvarea, S. laaaa. A. Kappaa, J. tialoper, a. I. linear* aad 1. J. Sallhotf: lead lamid amoop laeaasehara dlaaanllla* aa eldenied anhaay Uaa la an lark dtp. 1. 1. ft|-- '-------- - -* Hi 1230-123*. 1*71. 70. II far, J. U, aa* A. P. Alvarea Altnratlano ladnead la heap STutCuS! MTo"" J" * 0255A5 hqns -12- 71. Alvoroa, A. P.: Interactions beevoM anrlmi--oral i tiMli ala Mi in** bUeraufotaiCtou la m. ClUAcal BiwcokiitClM. 3: 4*2-477, Iff*, ----- " 72. Coonoy, A. I., C. J. fMtucfc, C. I. Pantuck, H. Bounin*. D. H. Jorino. J. G. Fortaor, A. P. Unna, K. C. AAbaraoa m4 a. Ufyaai tola o( MTtroMAt Mi ilat la Che regulation of huaM ini* mcaAoUm ''*lM r"~- 7}. Al.araa, A. F., A. (aggaa, l. t. Andaraea, t. 1. Fytock yd A. I. Cayayt hutrltloaal factor. nyOU| .ruf klattaaafatytlon ta aaa. ta Adttaeaa ta Fbaraacolotr tad Tharsaautlca. *ol. 1. ta., c. Oltaa, hr|iaM Fraaa. . T. yy- AJ-S1, 117*. 74. Al.araa, A. F., I. J. Fycuck, I. I. Aodaray, A. Ian Caaaay: lagalatloa of drag aatakoliaa ta aaa ky a factor., ta yncaadtaga of tha Itaaolly y Braa I ia My. Drag Hacabsllaa tarlM, i: 113-20}, irni, 7]. laaaa, J.. A. (aggaa. S. f. lamalata aad a. g. Alraraai tarn ktaaymthaala aad drag aatakaUaa ta aica ltk kandlcaxy >aaa lgtla aaaiai iaaa irygaaaaa tadactiaa aa y adagtlaa raagaaaa (or aalacalaiag cytaakraaa WM ta ckaaala haylyala. Tianial Si llalaalcal "iTTlfTTT 23*' *-*. l7g. 7*. Alcana, A. f. aad A. (aggaa: Load aad galycklartaatad klgkaayla: Ufaau a( hay aad drag aatakaUaa. ta gtataadtaga of tha l^ytaly^a gtaaaaittaa ta Ife, Dnd Matakallaa laataaa. 77. Alcana, A. F., A. faggaa, J. L. Uaaaaa, t. *. tadaraaa. c. t. (Mack. 1. J. fantaak, C.-C. lataa, . A. Earlyd yd A. I. Caaaay: tatratadlrldoal .ariaslay ta drag dtagaalataa. Fhaiaaylaar aad Tharyaattat. Jii 407-41*. 1171, 71. a, A. g. I Haay, V.I. gal. IT, iFart a, gg. 15-113, 1*71. y j* UHIB taa. aad valfan. 19. , A. F., J. L. tlayy, aad i. K. Taagi tadylkUlty af tha kaay(a)gyraw ky galycklartaatad klgkaayla (FCBa) ta Uaw aad lyg alaiaaaaal gragarattaaa fraa rasa aad takklta. ta aisra- aaay. Dna Oaldatlya aad Ckaalcal Cariityayaala. Fal. u. gg. lMT^IIia. adayc Fray, it. lift. (0. Iliya, J. 1., aad A. F. Alranai lay ytaka11 y ta tka fasa- glaaaMal talk aad aaaattal Urara durtag lattatly. iffay of gald aadly tMaaalata. ' of Miaaaaaalaar yd taaarl- aaatal Han--ai 2141 liO-il*. 1M0. HONS 025546 -13- Uanp, T.-M., J. L. Elaanan and A. P. Alvaraa: Inhibition of pulnonary cytoohrans P-450 and banco(a)pyrana hydroxylaaa In rabblta by palyehlorlnatad biphanyla (PCIa). Ilachanlcal and lloahvalcal Monarch Connicatlana. 5tl7il-17i. 1*M. Alvara*, A. f., t. J. Paacuck, A. I. Canaay and A. Kappaa: Effacta at anvlronaaatal (aetata and aatritloa an hanaa druf ancaballaa. to Ihman Epldanlalaar and aninai Laboratory Catralatlona in lical Carciaonanaala. pp. 55-72, Ablaa Pnbllahiai Carp,, H.J., Il ly, A. I., I. J. Paaanak, C. I. Pantank, J. e. Portaar. A. P. Alvaraa, E. I. Andoraoo and A. tappaa: VarUbllity in hunaa drut nacaballan. In Pyacaadlnaa of tha World Conference an Clinical Pharnacoloty and Thatapnutica. p. 11-42. Macmillan Publlahan. Ionion. lppo! Unep, T.-l. mi A. P. Alvaraai Selective laaa of pulaanary eytaehrana NASO, in rabblta pratraatad nth polychlorinated biphanyla. 1--rndl af llnlaalcal q-nrirT 32*:755d-75Al, 1M1. Alvaraa, A. P.: Cyracbranaa P-ASOt laaaarah hlahlichca of tha loot an dacadoa. Oran Watabella-mm--- il' Ol-AlC. 1M1. Alvaraa, A. P., J. L. Elaanan, T. -*. Dans and A. tappaa: Pvlychlarlaacad biphanylai Ipaalaa and tlanaa apaaifleltlaa of tha ladnaclan of aanaasypanaana la rata, aica, rabblta, and banana. In praaaadtata a( vnrhebep an Tha Caahlaad Effncta of lanablntlaa. Katlanal laanarch CaaacU, Canada, la prana. Elaanan. 1. L.. 2. von 1. and A. P. Alvaraa: Tha aftact of hanaybaa (Apia lUlliform) vaaaa an tha eonraa ot ad]vvaac-ladacad arthrltla and dapraaalaa of drac nacaballan la tha rat. la prana. Alvaraa, A. P., T. -d. I I J. L. Elaanan: Palychlortnatad biphanyla iadatibla i la rabblta and aica: Spaclaa and arpaa apaaifleltlaa. Ufa Palanaaa. la prana. Alvaraa, A.P.: Ocldatlvn htatraaafn atlan of drapa. In Tha j^jahnraraffnfh.^lfflmil^han at I. Arlan, I. Pepper. Prana, Ban lark. Za praaa. HONS 0255*7 -l- CURRICUI.UW VITAE KANE: RIRTHDATE: HRTttPUCE CITIZENSHIP: SOCIAL SECURITY NUMBER: BUSINESS ADDRESS: NOW ADDRESS: Philip E. Enctrlint 4/25/21 Kietantung, PA 141-14-5618 A315 Crabtra* Hall, CSPH 130 DaSoeo Straae Pittsburgh, PA 15261 TELEPHONE: 412/624-3013 37 St. CUlr Drlva Pittsburgh, PA 15228 TELEPHONE: 412/343-1330 EDUCATION AND TRAININC 1934-42 CtiAiif 19AB-5A 1935-40 ASM--le 1940-43 1943-47 1H7 - date 1973 Veacalnstar Coll#** BBA (1942) Eeonoaics AMTlcan Uoivarsity Aatrlem University MA (1934) Ph.D. (1940) Seaclaelca Onography (Dr. Frank Lorima APfourrwiffs and positions taMieai Oalvtfilty MeCill University University of Pittsburgh University of Michigan Professorial Lacturer Profoaoor of Nodical Statistic* Profaaaor of Blootatlaclcs faculty, hint Soooloo oa Health Cara Organisation 1942-43 1943-30 U.S. Amy D.S. Public Haalth Service Statistician HONS 025548 -2 1950-54 1954-59 1939-61 L961-65 U-S. Public Health Service Asst. Chief Prograio Analysis Section Tuberculosis end Chronic Diseases *' Chief Statistician Hoare Disease Control Progran '* Chief, Morbidity sad Health Statistics Branch. Public Health Methods " Chief. Ileewcrlee and Social Studios Breach, Occupetlonal Health WMDUHIF in FSOFUSIONAL OtCAMIZATIOMS 1946 - present Aaarlesn Public Health Association 1946 - praeant Aaarlean Statistical Asceticdo* (Treasurer Pph. Chapter 1972-74 Council Menber 1971-73) 1969 - present international EpMeatolofical Association 1973 - present Society for Occupational and Ivrlromantal Health 1933 1972 1977 1937 1937 193 C 1979-41 HOWM Fallow, Aaarlean Fwblie Health Aaacclatlaa llactad Fallow, 1--clean Seaclatleal Aaaoeiaclaa Flteakac|k Statlatlclaa of cha Tear n Daimaul Suaarlar Sarclca Jaari H DaMTtwaanl Honlim - Archer 9. Flaaaias 4war* foe Tan Maat OwtataaAlmf Tooa| Nan In Covaraaaat FI Btmm Ma (Hatlaaal Social Selaaea laaar Saclacr) Dakar, UUarlal loard, Aaarlean Sawlaw of laaFlcuorr Dlaaaaa HONS 025549 ^^hln^ (eurrent) eatatlstlcs 211 Mtatlstlcs 216 ^statistics 219 -3PROfESSIONAL ACTIVITIES Principles of Statistical Reasoning Introduce ion to Sampling Vital and Had leal Caro Statistics ^search and Training (1967 - data) Cranes and Contracts Tears Fadaral Cranes 19*1*74 Tula Training In Public Health Statistics 1972-75 Training In Industrial HlosCatlitlca 1971-73 Training in Hailcal Care Statistics 1909-7* Study of tha Cffeeta of National Health Insurance in Quebec 1970-77 Planalug Crane on Childhood Lead Paleonlng 1177-tl Caucar la Arsaalc bgnil foyulaclsns Sourca HXR NXOM HOUR HOUR nm NCI m Padoral Coatracta 1*7 V40 Haalth ol Vbrtara la Mineral tool and Plbroua Claaa toaofeccuring l7-t0 reality at Vlcknl kkrkara loaclagcan, W. Ta. 1975- Serra11lance of Health of Chlcel torkera Oner Pick Tone 1901- tortallty Hang Snelter torhera Crass-iaatlanal Study at Masonry Fuacrloa to Ursa Arkansas tbrkasa mo HQVT. ALLOTS SHILL OIL StHA ALCOA Otfcar Mon-Psdatal -- HO. *03 Anounc $131,111 91*1,40* 9274,376 17*6.532 3 71.7M 3313,170 9305.339 910S,331 9 50 T 60* 9*50.377 9 34.5*6 I- *> twtt and l*9n3nf <<>< 1IM-U Mnal IMMr, U.l. kui st Civil !<nlet Coalam tUMMUiaa) 1M4-70 latlU SwtIgh limrch Study Sactlaa, UMU lM7-data lain ddvlamy Cialnw, National hnn (or teg--1r iMacck 1M7-72 Advlaary 7*1lav, IHllsa Inatltuta -- Industrial lytlsaa Found*elan HONS 015S50 -4- 1970-72 1972-75 1972-74 1974- 76 1975- 79 1979--i0 19791979- HoAleh Services 0mocistr*tions Study Section. }i5V.A MgClonal Advisory Food and Drug Cosaice*, rBA Panol on Chromium, Cosnleee* on Biological Effaces of Aemosphoric Pollutants, National Academy of Sclancaa Chairman. Advisory Committee on Longitudinal Study of Submariners, U. S. Navy Pulaonaty Dlrani Advisory Co--ittoo. mill Talk Forca on cha Epld--iology of Respiratory Olsaaaa, :31L1I Chairman, Co--ltcaa on Otcupatlonal Agents Lltaracura lavlaver-lpIdealoUty-J. of Occupational Maduina Aaaoclaca Dir actor, Center for Environmental EpMaaiotogy Service (currant) 1. Departmental: Chairman (1976-data) School: Hmbar, Doan's Cabinet 3. local and State: Grants Ievlev Coamletea, Pennsylvania Coal uerkara laaplratory Olaaaae Program pmiCAWOW I. laferaed Articles Interline. Philip I.. end Sauer, Hnrbart 1: Co--unit y-vIda X-ray aurveya, VI, Iscorda end laparte. Pub. Health Hap, 66:1613-1621. (Daeamber 7, 19)1). later line, Philip I: Cramp Chest X-ray taamlnatinea and the Tuhaecnlaets Death late. Pub. Health Hap. 67:761-764 (Aug. 1932). Payee, Heeard H., Knterllae, Philip (., ead Houck, Julie: A Study el the Positive leeetgememraphle Pladlage let 19*6 Mahinstoa Mas Survey. --. >av. The. 64:3*0-340 (Bp*. 1*31). la--an. Wtas H.. ead Baterllna, Philip I: Delayed Used Sager Detaemlaetlona-- tvaluatlea of a Used Paesarvatlve. Pub. Health lap. 69:2*0-214 omreh 193*). Anders--, lobert j., totsrllaa, Philip I., and Turner, Otla 0.: Dndscactae TUbercnleela la Perl--a leeaealc Croupe, la. la*. The. 70:333-600 (Oet. 195*). lad--era. Mart J., Interline, Philip I., Hill, leak J., ead Inhacta, Jaan: Aa 1--1--cl-- si Tubacculaala Dec--tin by Cheat X-ray Sarvepa. Mb. Raalth lap. 63il033-10M(Ba*. 1336). Kurlander. AnaId I., Hill, Ulasbath , aad Intarllnm, Philip I: Aa --1--ticn of San Cl--aaly Dead Sera--lap Teata far Heart Dla---- aad Rypart--alan. J. Chr. Die. 2:617-633 (Oct. 1333). 025551 HONS -7" :rllne, Philip E., and Stewart, Wllllsa H: Geographic Patterns in Deaths tea Coronary Heart Olaease. Pub. Health Rep. 71:849-853 C5ept. 1956). Stsrnrt, William H., and Enterllne, Philip E: Ecology and Coronary Heart Olaease. J. Chr. Ota. 6:88-89 (July 1937). Kedeur, Araand E.. Baber. jaaaa P.. and Enterllne. Philip E: abnormalities Seen on Chast Photofluorograas and OlaRnosable Heart Disease. am. J. tonne, wd. Thar., and Nue. Had. 78:226-133 (Aug. 1937). Interline. Philip E., and tordan. Barnard: a Controlled Evaluation of Haas Surveys of Tuberculosis and Heart Olseaae. Pub. Health Rep. 73:867-673 (Oat. 1938). Eararlino, Philip E., end Caps, Katherine c: A Validation of Information Provided by Houaehold respondant i in Health Surveys, as. J. Pub. Health 49i203--212 (Tab. 1939). Eahal. William 3., Levis. labart R., Enterllne, Philip E., Painter, Robert C., alien, Lloyd S., Paveatt, Robert H., Meredith, Alla P., and Peterson, Beatrice A Short-Term Comity Study of the Epideetioloty of Coronary Heart Dtaaese. Am. J. Pub. Health 49:1930-2039 (See. 1939). Bauer, Herbert I., and Intarline, Philip E: Are Geographic Var lot tone la Death Hates for the Cardiovascular Dlaaaoaa Real? J. Chr. Die. 10:313-324 (Dae. 1939). Marline, Philip I., Rlkll, Artlair I., Sauer, Herbert I., and Hyman, Marten: each Hates for Coronary Heart Dlaaaoaa ia Metropolitan and Other Araaa. Mb. Health Hap. 73:739-766 <4u. 1960). Mrad 1th, Alla P., Enterllne, Philip t., Peterson, Beatrice, and Pehever, Jeon C: An HpldaalelOfic Slat Study ia Perch Deboer. J. Am. Dlaeet. Aeaoc. 37:339-343 (Oat. 1960). Hatarllao, Philip I., and Stsusrt, William H: tat lasted Morbidity in the Obitad States baaed am Monthly Labor Pores Report. Pub. Health Rap. 73: 1131-1160 (Dec. I960). Hatarllao, Philip I: Caaooo of Death Heapoaalhla for Roeeat Increases ia Sea natality Differentials la tha Ohitad States. Milbeak Man. Pund Quart. 39:312-326 (April 1*61). tatwllam, Philip I: Herb Loos Duo to lllaeoa in Selected Oecupatiaae sad laduatrlao. J. Otcap. Mad. 3:403-411 dope. 1961). SRemart, WUllw I., aad fcesrllne, PhUl* Si Effects of tha Rational Smrvlce am Physio lama OtUlaatiaa aad HoalRk in Easlamd aad talas. Pam England 3. of Med. 163:11*7-11N (Baa. 1961). tatarllaa, Philip B., aad stanart, WUlioa : Health Program Rogeiramenta U Oftaac Effaeta oa Lovela of Living. Am. J. Pub. Health. 32:401-40* Ohrch 1962). Cooper, W. Clark. Intarlima, Philip E.. aad tardea. Elslee T: Eetlaatlag Oeeapatlsasl Dlaaaea Eaaaxda Through Medical Cara Pleas. Pub. Health Hap. 77.1063-1070 (Das. 1962). tatarllaa, Philip I., sad tailaver, Mraaret P: Differential Mortality Ikon long Cower by Occupation. J. Occup. Med. 3:263-290 (Tama 1963). MONS 025552 -6Syne. S. Leonard, llyman. Merton J., and EntorUna, Philip E: Sum Social ond Cultural Factara Associated with cha Oceurranca at Catenary Haarc Otaaaaa. J. Chr. Ola. 17:277-200 (1964). tncerllna. Philip : Slei Absence tar Man and Honan by Marital Statua. AMA Arch. Envlran. Haalth. 9:164-470 (March 1004). Entarllne, Philip E: Mortality Rater Aaong Caal Miner a. An. J. Public Health. 54:7 50-760 (May 1964). Entarllne, Philip : Work laaa thie ta Illneaa In Certain Uaatarn Nations. Mena an (hidarnanlng. 0%y 1964). Entarllne, Philip E: Ubrk Laaa Dua ta lllnaaa. Manthly Labor keulav. 07:1101-1103 (Dee. 1964). Interline# Philip Ei Sink Abaanee In Certain uaatarn Cauntrlaa. Ind. Mad and Surgery 13:750-741 (Oct. 1964). Interline, Philip E: The Eatlaatlon of Expected Ratea in Occupational Dianaan tpIdanlalogy. rub. Health Rap. 79:973-970 (Mom. 1964). Syna, s. Leonard, Hynan, Marten R., and Eacarllna, P.E.: Sociocultural POctara and Coronary Heart Dlaaaaa. Sociological Inq. Pol. 34, Oa. 1, (Ulster, 1904). Syna, S. Leonard, Hynan, Horton M., Entarllno, Philip I: Cultural Mobility and the Oceurranca of Coronary Heart Dlaaaaa. J. of Haalth and Hunan Bahauler Voi. 6 (Ulster, 1965). Aohford, J.I., Oncarllsa, Philip E: lodlolORlc Claaolflcatlon of the Pneuaoconloose. Arch, of Environ. Hlth. Del. 12, (March 1966). Entorllsa, Philip Et Social Ceueaa af Sick Aboonco. Arch, of Envlran. Rich. VOI. 12, (April, 1966). Entacllaa, Philip E: The Effaces af Occupation on Chronic Eoaplrctery Dlaaaaa. Arch. Environ. 11th. Voi. 16. 109-200 (Jas. 1967). EaCacllaa, Philip E. and Lalabort, U.S.: the Salatlaaohlp OKvin Coal Idalag and Oran la Raaapaclfle Eoaplratory Dlaaooa. As. J. of Pub. Health Val. S7, HO. 1, 404-499 tbrak 1967). htsllaa, Philip R. and Headrick, Mildred As Asbestos-Daet Exposures sc Varlaua Lavnla and totality. Arch. Environ. Rich. val. 13, 101-106 (dap. 1967). Rarnvlta. 1. sad Estarllso. Philip S: Load Cases Among tho Jana. ha. J. af Pnb. Elth. Val. 60, Ho. 2 (Pah. 1970). btarllaa, PhUtp Et ValIdat lag IteaahaUa Dalag Industrial Hacarda. J. af Oaasp. Hod. Val. 12, Ha. 1 (Tab. 1970). tatarllaa, Philip Et tpldtoalagy of Caal ibrbar's 7nmnsranlasts. lad. Had. aad Such. Voi. 39, 115-117 (toch 1970). Henna. I. sad Hncorllaa. Philip E: Lung Caacar Aasog the Jan aad Hen-Java of Pittsburgh. AMT. J. af IpId. val. 91, Ha. 4, 333-307 (April 1970). HONS 025553 -7- ntarllna, Philip C.. OoCouflo, Plorre, and H end or so-. Vivian: Mertslicy in .station to Occupational Expoaura In cha Asbestos industry. J. Occup. Med. ;al. 1`. Ho. U (Dae. 1473). Satorllna, Philip E., DaCouflo. P. arid Handorson, V: Respiratory Cancer in Relation to Occupational Exposures Aannp Retired Asbestos Uorkers. Brit. J. taduatr. Mad., Vol. 30, 162-166 (1473). tatarllna. phUlp t., McDonald, J.C., McDonald. A.D.. and Salter. V: The Ufacts of "Proa" Medical Care on cha Practice of Medicine - The Quebec tapesience. Non England j. of Mad. 221:1132-1133 (May }1, 1973). tataoold. A.D., McDonald. J.C., ScalnaMtc, M.. tntarllna, P.E., end Salter V: Physician Service in Montreal before National Health Ineuranee. tadleal Care It (July-August 147}). Readersen, V., and Cnterllne, P.E.; An Unusual Mortality Experience in Cotton TaxtUa tarkara. J. Occup. Mad., Vol. 13, No. 4 Oaptanber 1473). tatarllna, P.R., Saltar, V.. McDonald, A.D., and McDonald, J.C.: The Harr 1but Ion of Nodical Services Before and After "free" Medical Cara--Tha Quaker Experience. Neu blaad J. Of Mad. 1M:U76-U7a (Mot. 1973). tatarllna. P. E. and Neaderson V: Type of Aabaatoi and Respiratory Cancer la the Aahaetso Industry. Arch. Environ. Hlth., Vol. 26 (Nor. 1473). taterllae, P.E., McDonald, J.C.. taPaaald, A.D. aad Henderson, V.: Physician's tarhlap (ours end Paclaata Soaa (afore and After National Health Ineuranee. Mdleal Cara, Pol. 13, Me. 2. (Tahraary 1475). tatarllna, Philip I: laaplratary Cancer Amur Chrsaaca HOrkara. J. Oeeup. tad., Vol. 16:323 (Aaf. 1*76). tatarllna, Philip (. sad laadrrsae, V; Mortality tad Morbidity Expor lonee of latlrad fibrous Clnoo tarbaro. Arch, of Environ. Hlth., Vol. 30 (March 1473). tatanald, A.D., taOoaald, J.C. (altar. V. aad tacerllae, P.E.: Effects of Qaaboc Mad If ora on Physiclaa Canaaltatlan ter Selacted Synftona. Nan Eng. J. at Mad. 241:644-632 ((opt. 2t) 1(7*. tatarllna, Philip It Pltlnllo in IpMtaleleglcal taaoareh. J. of Oecnp- Ned. Pol. 11.130-13* (talk 147*) . tatorllna, PhUlp St WtatlR* lanlth (lake la Studies of the Health Efforts of lohootoo. An. hoe. of taoplmtory Dlsanoa, Vol. 113 (147*). Plats, (.. tatarllna, PhUlp I., laadarraa, aad Varaar, Michael. 0: Mortality taperlaaca la taintinn to a tan eared Aroenle Trlaalda Exposure. Envlronaentxl Boalth PeropatrlToa, tal. 14:127-130 (tap. 1477). tatanald, J.C., tatanald, I.D., tad tatarllna. P.I.: Soaa Effects at Hadleers la Qua*as (Itadas ear 1'aaneraaca aaladla due Quebec) Seclelople ct Soc letas, U. 1. pp. 5*-7 3 Oprlap 1477). Uad, I., tatorllaa. P.E.. Paaderaaa, V: "Coacectt nlth pharnaclots bafsra tap Attor "Ttta" Madlnal Cara -- tha Qaahao Expatlance." Medical Cora. Vol. 1*. No. 3. tarah 1473. HONS 025554 -a Pinto, S., tlondarson, V. and Encarllna, ?: Morcaliey Exparuncc of Arsenic Exposed '.Jorkors. Arch, of Environ. Hlth. pp. 323-331, Mov/Oac. 1919. Marsh, C. and P.E. Encarllna: A Mac hod for Verifying cha Coapleceness of Cohorca Uaad In Occupational Mortality Studios. 3. of Oecup. Mad.. Vol. 21. 10, pp. 663-070, October 1979. Encarllna, P.E.: Accrlbucabtllcy in the Face of Uncertainty, CHBT. Vol. ;sa p. 377S-379S, Supplxenc Auguat 1990. ' 2. Procaadinga Encarllna, Philip E: A Controlled Evaluation of Caaeflnding by Choac X-ray. Procaadinga of tha Motional Tuberculosis Association (May 1937). Encarllna, Philip E: Trends and Variations In Sick Absence in cha United States Procaadinga of cha Second Inc'l Conf. on Sick Aba. Staclatlca. Anacerdaa. ' Tha Netherlande (April 22. 1999). Encarllna, Philip E: Hortalicy Aoong Aabaacaa Produces Workers in cha United States. Annals of cha N.Y. Acad, of Scl. Vol. 132 (Dae. 1999). Encarllna, Philip E: Tha Statistic tan in Epldalologlc taaaarch. Tha Proceedings of tha Canadian Asaoc. of Taachara of Soc. and Prav. Mad., Annual Heating. (Juan 3 iM 4, 1999). Interline, Philip I: Aabaatoa Oust Incrananta and Mortallty fraa Tun Diaanaar. Proceedings of the Second lnt'1 Coef. os ilolaglcal Effaces at Aabaacaa. Dreadan, Sanaa, (April 1999). Interline, Philip I: tacenc Derelopuaate In Sink Abaanee Statiaclca. Traas- actiona of tha 33rd Maating of tha Industrial gyglaaa Foundation of Anar lea, Inc. (Oat. 199*3. Enterline, Philip I: Statistical Studies of U.S. Aabaatoa Products Ubrkara. Procaadinga of Fibrosa Duet Sanlnar - Halloa Inotltute, Pittsburgh, PA (Ho*. 22, 1*9*). Interline, Philip I., Salter, Vara, HeDonald, A.D., and HeDonald, J.C.: Doctor Vlaita la Variesa Incsac Croupa Prior ca raaadlaa Medicare. Procaadinga of tha VI Ccaf. of tha Inc'l Ipidflolagtcal Assetlatlaa. Prlaoscaa, Tsgaalavla, (Aug. 1*71). ftDonald, J.D., McDaaald, A.D., 9 telenets, 1., Encarllna, P. and Salts, V: Work af Physiclass In Mutxael. Procaadinga of tha VI Conf. of tha lat'l EpIdanlalagleal Association. Prlnaatae. Yugoslavia (Aug. 1971) . bitanlino, Philip g. aad Ualll, I: Aehaeteels in Aabaatoa Caaut Workers. PrataadInga of the UtC Whrklag Croup to Aaaaaa cha Ilolaglcal Effects af Aabaatoa. him. Franca (Oct. 1*72). Encarllna, Philip I: A Envies of Mortality Data for Anarlran Coal Miners. Aauala of tha D.T. Acad, af Set., Vol. 200 (Doc. 1*. 1*72). tacerllaa, P.I.: Proceedings of tha Third Anasal ladeaery Gsssrmac CaafervAabaatas Inferaaclaa Aasee latlaa of Perth Auer lea. (Save. *-*, 1*79) pp. 1'6 Encarllna, P.I.: Procaadlags of tha Incordapartaautal SOrbar's Coupsoiscion Porca Ceafarenca so Occupactaaal Diaaaaao and khrhare Coupenactlac, U.S. Cavanuant Printing Offlca. (1979) pp. 13-19. HONS 025555 -9- Mtarline, P.E., Pinto, s., god Henderson, v.: cancar Among Arsenic Exposed Meters In a Copper Snnltcr. Proceedings of the Air Poliucion Control AssocucIon. ISscon. nov. 8-9, 1976. * ISCerllne, P E7; epidemiology in Studies of Occupational Health. Proceedings ef the Annual AHA Congress on Occupational Health, September 30, 1977. fetarllna. P.E.: Epidemiological Methods for Establishing Dose-Response golatlonehlpa in Aebescas-thise Related Diseases. Proceedings of the Asbestos Symposium, Johannesburg, South Africa, October 6, 1977. BStarline, P.E.: Epidemiologic Mathoda in Industry. Proceedings of the IPAI Health Protection Seminar. Copenhagen, Denmark, June 29, 1977. arline, P.E. and Marsh, C.M.: Environmental and Mortality of Workers from a Fibrous Usee Plant. Proceedings of cha Society for Occupational and kvlroamancal Health, Washington, DC, December 6, 1977. Eatarline, p.l. and C. Marsh: Environment and Mortality of Uorkars from a Pibeaus Class Plane. In Ousts and Diseases, 1979. tetarllna, P.E.: Sana observations on Geographic Variations in Mortality. Proceedings of cha 13th Annual Coofaronea on Trace Substances in Environmental smith, Columbia, Missouri, June S, 1979, pp. 19-27. ktarllaa, P.I.: Asbestos and Health Panel htearha, 6th Induatry and Government Conference, Aabastes Information Association, Sape. 19-20, 1979, Arlington, VA. tetarliaa, P.t. and C. Harsh: Mortality ef Mothers in cha ten-Msde Mineral Piter Industry, Proceed Inga ef the Symposium on tha Biological Iffacts of Uaaral Piters, IAdC, Lynn, Franca, September 2S-27, 1979. tetarliaa, P.t.: Sorting Out Multiple Causal teeters in Individual Casas, Pressed tegs of tha Society far Occupational and Eavlroanaatal Health, Mahlagten, DC, Dueamber 6. 1979. landerasm, V. and P.l. tetarliaa: Asbestos Exposure: racists Associated vlth Excuse Cancer and laeplratagy Disease Mortality. Ananla ef nr Academy ef Sc laneas, Vel. 13, pp. 117-126, Daeanbar 16, 1979. tetarliaa, P.I.: tetrmpalatlaa tram Occupational Stadias--A Substitute for tevlreansalsl Ipidamislogy, rresaedlagg of tha Plane Inane I Syapeeite on terireanantxl Epidemiology, Pittsburgh, PA., AprU 21, 1NO. tetarliaa. P.l.: Baa af tha tetlaaal Death Index in Occupational Ipidamialegy, Proceedlags ef tha Public ganlth Coaferaaca on Records sad Statistics, Impsos 3, 19M. tetarliaa, P.l. mad 0. Msrabi fertallty Anaag teeters in a lichal Refinery and tenafaccurlag Plant la teat Virginia, DBA. Proceedings of tha Sad Iataraatianal Rlrhal Conferante an teriresnenral and Occapstlomsl Tealcelegy ef Michel, Svaaaaa teles, OMtad llagdam, Septaaber }, 1900. tetarliaa, P.l.: Properties ef Cancer Due te fxpeaure to Asbeatee. Proceed Inga ef tha Conference ea cha Quantification ef Otcupatieaal Cnee or. teabury Center, Cold Spring Harbor Laboratory, March 30, 19*1. HONS 025556 -10- Enterlint, P.E.: Epidemiologic Dos is for the Asbestos Standard. Proceed of eho Second Annuo 1 Symposium on Environmental Epidemiology. Plee'.bursh ?\ April 28. 1981. ' Eneorlino. P.E. and C.M. Marsh: Missing Records in Occupactonal Olseose Epidemiology. Proceedings of ehe 1981 American Occuaeionsl Health Conference Atlanta, CA April 29, 1981. ' 3. Abstracts Eneerllna, P.C.: rasters Aaeociated with Ceographle Differences in Deaths from Coronary Heart 0 Useso. Circulation 14 (Nov. 1988). Symo, S. Leonard. Hyman, Morton M., and Enterline. Philip E: Sone Social and Cultural Pactors Associated with the Incidence of Coronary Heart Disease. Circulation. (Oc. 1981). Eneerllna, Philip C. and Mtaos, Nicholas E: Sea Differentials in tbrealley in England aad Usles and in the United States. Population Index (July 1983). 1. Other Cnterltne, Philip E.: Komardlng eho Sick. (Editorial) J. of Anar. Medical Aaaoe. Yol. 198, We. 3, Otay 2, 1984). Enterlino, Philip E: Asbestos and Public Health (Editorial). J. of Mmor. Medical Association, Vol. 201, No. 12, 148-147 (Sept. 18, 1987). Enterlino, Philip E.: (Haber of Cnsnitteo) Standards for Epidemiologic Surveys la Chronic lasplretory Disease. National Tuberculosis end (aspirator? Dlsaaso Association. Nov York (1989). Lainhart, U.S., Doyle, N.S., Enterline, Philip E., Henechal. A., end Kendrick, H.A.: Pw--oconlosls is Bppnlarhlen Bituminous Coal Nlnsrs. U. S. Dope, of lenltk. Education, and Welfare, Pub. ltb. Service, Publ. No. 2000, (1989). Enterllao, Philip E. and Jecobaen. M.: "Vpldwlolegy" la Mdlclae ta the Mia log Zadmocrlaa. !( Medical Books, Londoo, 1972 (J. Bo^m Id.) Bitarilaa, P.E. t tflnti of Chrsnlan Canpounda on Benoa laalth" la report oa Chrenlan prepared by the Nstlooal Ensesrch Connell, National Acadeny ef Sciences. Washington, D.C.. 1974. feitarllao, P.I.* (liltorlal) Asbaecos and Cancert Tha International Lag. im. Bov. of Easp. Die., Yel. 118:973-978 (Dacanbar 1978). Entarllaa, P.E., MtDsoald, A. sad MtDanald, J.: Sons offsets of tohoc ttwlth lasersnaa. MdBh tssaarck Olgaac Series, SUM Yah. Na. <IW> 79-3328. January 1979. HONS 025557 -1- He-- Address: lust ness Address: justness TeleeHe--: llrth--to: Itrthplics: Cltlisnshlp: Merltil Stitus: CURR1CUUIM VITAE Frink S. Standlirt 8205 Stan* Trill Drive Sethesda, Miry line 20817 3900 Reservoir RoeO, R.N, Hashington, D.C. 20007 (202) 828-783$ Rove--er 12. 1929 Peterson, Now Jersey U.S.A. MirrleO, 3 sons Mervsrd Celle--, 1947-1951, A.I. (cun lee--), Chemistry Cor--11 University Modleil College, 1951-195$, N.O. AeeeIntoents one Peeltiene: Ace--elc: The Johns Hopkins Hospital Inter-- (--Olcl--) 1955-1958 Cor--11 University M--leal College Reseereh Fell--. 1988-1957 [nstractor In Phar--celeay, 1959-1980 Assistant Professor of Pher--lo*r. 1980-1984 As--eiete Prefesser of Phemceloty. 1984-1987 gearyetown UiH--rsIty Schools of Neelei-- and Oentlstry Schorl-- FooaOetloe Pref--ser a-- Choi-- of Phamacology, 1987- Tho Memy a-- Low1o Owepen--1o Dental Clinic Lectarar to the staff. 1980-1M7 Ravel Madcol Raooorch Institute, (ethos--, Meryls-- 8--at Scle--1st. 1987-1970 Maltar Re-- Ar-- I--tltata of Dental Research Co--elta---leeterer, 1980-1972 Ravil Dentil School Consultent-lecturer, 1970-1971 HONS 025558 -2- tonotntnonts and Positions (Continued): .1). S. Government: National Institutes of Health Pharmacology and Endocrinology Fellowship Aevlew Committee, 1968-1971 Neurological Olsordtn Program Project Parlaw Coaaalttae. 1971-197$; Chalnaan 1973-197$ Pharmacology Toxicology Program Project Review Committee, 197S-1990; Chairman, 1977-1980 Fogarty International Fallowehlp Review Committee, 197$, 1976, 1979 (Chairman). 1911 (Chairman) Biotechnology Raiourcea Review Comalttee. 1981N1NC0S Comalttee to review Antleplleptle Drug Development Program, 1981-1982 Veteran's Administration Merit Review loard, Neuroblology, 1974-1977 Chairman, 1976-1977 Consultant, 1977 Congress of the United State* Comalstlon on the Federal Drug Approval Process 1981- Fedaral Trade Coamlsslon Consultant 1971-1974; 1978 Occupational Safety and Health A4a1n1strati on Consultant 197d Private: National Research Council Coamlttae an Toxicology, 1971-1977 Panel on Anticholinesterase Chemicals, 198101vlilan of Slolegy and Agriculture, Representative from American Sectety for Pharmacology and Experimental Therapy, 1987-1977 Safa Drinking Mater Cemrlttaa (consultant) 1978 Postlcldo Information Review i Evaluation Committee 1977-1981 Coamlttae an Ml11tery Environmental Proplame, (Chairmen) 1980-1981 Caaartttaa on Recoamandatlons for U. S. Army tasic Scientific Research 1981 American Heart Association Hatlamel CaplUI Affiliate High School Research Coarittae. 1970-1972 Chairmen, 1971-1972 Research Coamlttae. 1972-1977 8eerd of Directors, 1972-1978 Middle Atlantic Regional Heart Comilttan Research Review and Certification Subcewlttee, 1979-1981 U.S. Phemseopelal Convention, 1970- Exxon Health Research, toard of Scientific Advisors, 1981- MOMS 025559 -3- Preftsslonal Sociatlas: American Society for Phamacolofy and Experimental Therapeutics Comalttae on Intersoclety Relations 1944-1948 Representative to 01*. of 41ol. and Apiculture. NAS-hNC, 1948-1977 Representative to Publications Coamlttee of Foddratlon of taarlcan Societies for Csparlmdntal Slolofy, 1970-1975 Educational and Promotional Affairs Committee, 1971-1974; 1979Subcommittee on firaduatt Convocation Profran, Chairman 1972-197* Profran Com! ttea (ad hoc nmabar). 1948Ad Hoc Commlttao on loach Inf of Phamacolofy, 1970-1971 Task Foret In Support of Tratnlnf and Research, 1973-1975 Sacratary-Troasuror, 1971-1977 Committee for Liaison irlth Socloty of Toxlcolofy (Chairman) 1975-1979 Lonf Aanpa Plannlnf Comalttae. 1979- ; (Chairman) 1979-1991 Ftdtratlon of American Soclatlts for Eiporimontal Itolooy Publications CoMrtttet, 1970-1974, Chairman. 1971-1974 Lift Scltncts Atstarch Offlct-Panal for tvaluatlon of haalth haurds of Irradlattd bttf 1977-1978. Lonf Ranft Planning Group, 1980 Trtasuror El act 1981 Association for Mtdlcal School Phamacolofy, 1989Councillor, 1974-1975 Saerttary. 1975-1971 Socloty of Toxlcolofy Canalttto on Ethics of Anlntl and Human Exparlaantatlon (Co-Chalmtn, 1974-1978) Toxlcolofy-40's Comsalon, 1979 SI pat 11 1940Viee Protidant, Comall Nodical subchaptar, 1944-1947 Exacutluo Coemlttee, Gaorfoteun chapter, 1970-1973 Tha Nan fork State Society for Nodical Pasoarch Viet Pmsldsnt. 1585 flea President and Treasurer, 1988-1987 Editorial Positions: '`'liiciiiOnga.r1 'VMieia Field tdltar, bauraphamacalofy, 1971-1978 Guest Field Editor. 1978- "`fflgffl wwawnna) Science; Anasthaslaloay (ad kec) Fallauahlas and Auards; U.S.P.H.S. Camar Oaaalaeeant taerdae. 1941-1945, 1944-1947 Geldan Apple Anars, 1948 HONS 025560 -4- Mlllarv Service: U. S. Navy, 1957-19S9. It. (H.C.) U.S.N.A.. Stationed at Naval Medical Pesearot Institute. Bathesda. Maryland Professional Societies: American Associatton of Oantal Schools American Association for Laboratory Animal Science Amorlean Associatton of University Professors American Nodical Association (faculty Affiliate) American Society for Clinical Pharmacology and Therapeutics American Society for Pharmacoloty and Experimental Therapeutics Associatton of Oental Pharmacology and Therapeutics Teachers Association for Nodical School Pharmacology Drug Information Association The Harvey Society Nee fork Academic of Sciences Signs At Society for Experimental Biology and Medicine Society for Neurosctonce Society of Toxicology The Peripatetic Society Professional Licenses: District of Coluefcla Maryland New Tort Publications: See appended list HONS 025561 -5- 8IEH0GRAPHT FRANK G. STANOAERT 1. Roberts, J., F.G. Standaert. 1.1. Rio and W.F. Rlker, Jr.: The initiation . and pharmacologic reactivity of a ventricular pacemaker In the intact animal. J. Pharmacol. Cap. Ther. 117: 374-384, 1956. 2. Rlker, W.F., J. Roberts, F.G. Standaert and H. FuJImore: The motor nerve terminal as the primary focus for drug-Induced facilitation of neuromuscular transmission. J. Pharmacol. Exp. Thar. 121: 288-312, 1997. 3. Standaert, F.G., H.C. Sudduth and w.T. Hudak: A toxicological study of hydraulic fluids cellulubd 590A, Koluba 22Q and houghto-safe 109$. IWI Research Report 1*1 53 01 00.03.01, 1998. 4. Frless, S.L., F.G. St4ndatrt and L.J. Rebar: Convulsant activities of aarlnocyclanol derivatives as Influenced by stereochemical configurations (24321). Proc. Soc. Exp. Biol. N.T. 99: 277-280, 1998. i. Barr, N.L., S.E. Shepp, M. Tarcxomer and F.G. Standaert: Physiologic respontes to stressful stratosphere flights. J. Avlat. Ned. 30: 334-343. 1999. 8. Frless, S.L., F.G. Standaert, E.R. Whites*. R.F. Rlyelll, J.O. Chanley and H. Sobotka: Seme pharmacologic preparties of holothurln, an active neuro toxin from the see cucu*er. J. Pharmacol. Exp. Thar. 1J: 323-329, 1999. 7. Standaert, F.6.: Effect of pH on tultch facilitating potency of 3-hydroxyphenyl -tr lethylammonlum Ion. Proc. Soc. Exp. Biol. N.T. 102: 138-139, 1999. .8 Frless, S.L., F.G. Standaert, 8. Wittop. R.C. Ourant and L.J. Rebar: Some toxicologic properties of a nee series of aryl ethers derived from trans2-amlnocyclehexanol. Toxicol. Appl. Pharmacol. J.: <09-817, 1999. 9. Standaert. F.G.. S.L. Frless and R.O. Ooty: Comparative ganglion-blocking potencies of the geometric 1 toners of tuo cyclic 1,2-aaHna-alcohols. J. Nad. Cham. 1: 488-488, 1989. 10. Sudduth, H.O. and F.8. Standaert: Inhalation toxicity studies on a triaryl phosphate hydraulic fluid. (BUI Research Report W 008. 04-0001. 03, 1989. 11. Standaert, F.G. and S.L. Frless: Starle configuration and the activity at the aaamellan neuronucular junction of cyclic uninoalcohol derivatives. J. Pharmacol. Exp. Thar, JJt: 98-84. 1980. 12. Frless. S.L.. F.G. Standaert. E.R. Whites*. R.F. Nlgrelll, J.O. Chenely and Harry Sobotka: Same pharmacologic properties of holothurln A. a glycotldlc mixture fr* the sea cucusder. Aim. N.T. Acad. Scl. 90: 893-901, 1940. HONS 025562 -6- 11. Fr less, S.L.. L.J. Rebar. M.C. Thomnesen, L.J. Greenbeum, F.G. Stendeert end w.V. Hudak: Toilcoloqlcal properties end stereo-chemical canftauratlen in derivatives of the tropenol series. Toil col. Rani. Pharmacol 2: $74-588. I960. 14. Frless, S.L., L.J. Greenbeum, F.S. Stendeert end W.C. Thowmesen: Cantrel activity evoked In the eet by etstrenelearners of 1,2-eieinecyclaheienel derlvetlves. Toxicol. Appl. Pharmacol. 1: 636-6S3, 1961. 15. Stendeert, F.S.: Evidence far e graiyneptlc eetIon of d-tuboeurerine end suednyleballna et the neeaullen neuroeusculer Junction. Prac. 16th Patt-pred. Assenftly Anestheslalopy N.r. 23-25, Oac. 1962. 16. Alker. U.F. end F.6. Stendeert: Pharmacologic espacts af navraeMtculer trensnlsslon. Recant problems of pharmacology. Acedewy af Nodical Sciences af the USSR. Institute of Pharmacology end Chewotharepy. Vol. lit., pp. 115-137, Ed. by O.A. Kerkevlch, Netcom, 1963. 17. Stendeert, F.S.: Past-tetenlc repetitive activity In the cet salens nerve. Its origin, course end nechenlsw of genaretlan. J. Sen, Physiol. 47: 53-60, 1M3. 18. Stendeert, F.S.: The action of d-tubocurerina on the water nerve terminal. J. Phemeeol. Exp. Thar. 143:~161-1S6. 1964. 19. Stendeert, F.6.: The wechenlsae of past-tetenlc patentletlon in cat salens end gestrocnemlui miteles. J. Sen. Physiol. 47: 967-1001. 1964. 20. Stendeert. F.S. and J.C. Adame: The actions of suednylcholine on the motor nerve tersrtnel. J. Pharmacol. Exp. Thor. 149: 113. 1965. 21. Rlker, W.F., Jr. end F.6. Stendeert: The action of facllltatory drops end acetylcholine on neurooaisculer transmission. Ann. N.T. Acad. Sd. 135: 163-176. 1966. 22. Stendeert, F.6., 6. Levitt end J. Roberts: Antagonism of dial tel Is arrhythmia by pronethelal --e neural pheinwiiunT Nature 210: 742, 1966. 23. Raines, A. and F.6. Stendeert: Pro- and pest-junctlenal effects of diphenyihydantoln at the cat solees neuroaiscular Junction. J. Pharmacol. Exp. .Thor. 1: 361-366. 1966. 24. Stendeert, F 6 and J. Roberts: A neural action of pronethalel. Ann. n.t. Acad. Sd. 1309: 815-620, 1967. 25. Ratnee. A. and F.6. Stendeert: An effect of dlphenylhydentoln on the posttetanic hyperpalarlxatlen of Intramedullary nerve terminals. J. Phermeca'. Exp. Thar. .159: 591-597, 1M7. 25. Roberts. J.. 6. Levitt and F.S. Stendeert: Autenamlc nervous system control of cardiac rhythm. Retire 214: 912, 1967. HONS 025563 -7- 27. Standaart. F.G. and U.F. Rlktr: Tha constQuancas of cholinergic drug actions on motor norvo terminals. Ann. N.T. Acad. Set. 144: S17-533. 1941. 24. Aaymond. L. and F.G. Standatrt: Tha respiratory effects of carbon ploalde In tha cat. Anesthesiology 28: 974.980, 1947. 29. Aalnaa. A., 4. Levitt and F.G. Standaart: Tha affaet of spinal saction on ventricular rhythm dtsordars Induead by ouabain. Arch. lot. Pharmacodyn 170: 448-490, 1947. 30. Levitt, 4., A. Aalnaa, T.J. Sohn, F.G. Standaart: Tha physiologic and pharmacologle basis for tha sloop regiment In oyocardlal Infarction, lancot, Lattor to tho Editor, Juno 15, 1944. 31. Usublaga. J.E. and F.G. Standaart: Tha offsets of local anosthotlcs on motor nerve tanolnals. J. Pharmacol. Cap. Thor. 159: 383-341, 1944. 32. Zager, A., L. McCarty, F.G. Standaart: Tha pharmacology of 2-aalrldlnyl athanol. J. Pharmacol. Cap. Thor. 144: 204-214, 1949. 33. Aalnos, A. and F.G. Standaart: The affacts of anticonvulsant drugs on narvo terminals. Epilepsia JO: 211-227, 1949. 34. lavltt., 4., A. Aalnaa, 0. Haros, and F.G. Standaart: Tha capacity of A-lieprepyl-p-nltro-phenylethsnolnalne (IAPIA) to Influanca tlw course of ouaOaln-1nducod cardlotoslclty In tha cat. European J. Pharmacol. 4: 217-222, 1949. 34. Standaart. F.G., I. lavltt. J. Aabarts and A. Aalnaa: Antagoalsa of ventricular arrhythmia Induced by dlgltalls--a neural phenomenon. Curopaan J. Fhanaacol. 4: 209-214. 1949. 34. G1Ills, A.A., John A. Quast and F.G. Standaart: Oaprasslsa by reflesos of tha pressor and cardlataalc responses to ouahaln. J. Pharmacol. Esp. Thor. T70: 294-302, 1949. 37. Saha, Y.J., A. Aalnos. F.G. Standaart and 4. Lavltt: Tha offoct of dlphonylthlahydsntaln (DPh) on digitalis-induced cardiac arrhythmia. Arch. Inti. Pharmacoleglat 11: 244, 1949. 34. Levitt. *.. A. Aalnos. T.J. Sohn. F.G. Standaart and J.U. Hlrshfeld: Tho norveua syatom as a pita of action of digitalis and antlarrhythartc drugs. Mount Sinai J. Nad. 37: 227, 1970. 39. Standaart. F.G. and 9. Detwller: The neuromuscular pharmacology of germing 3 acetate and gnrsrino-3. -14-dlacotate. J. Pharmacol. Cap. Thor. UJ: 223-243. 1970. 40. Standaart. F.G.: The Ideal eospandlia: dhat Is 1t7 (Speaking from the standpoint of a medical educator) Orug Information lullatln 4: 204-204, 1970. HONS 025564 a- *1. Aalnes. A.. 8. Levitt. F.G. Standoert And T.J. S0IW1: The Influence of sympathetic nervous Activity on the ant I arrhythmic efficacy of diphenyl, hydontotn. European J. Pharmacol. ]j_: 293-297, 1970. *2. Glllls, A.A., J.R. McClellan, T.S. Sauer And F.G. Standaort: Depression of CArdtAC sympathetic norvo Activity by OlononylhydAntom. J. Pharmacol Exp. Thor. U3: 599-610. 1971. ' A3. Glllls, A.A., A.A. Olonne and F.S. Stondoort: Suppression by clontdino (ST-155) of dlpltalls-lnduced orrhythoiloi. J. Pharmacol. Exp. Thor. 162: 211-226. 1972. 44. Gil Ilf, A.A.. A. Raines. T.J. John, I. lovltt And F.S. Stondoort: heuro- cxcltotory offoctt of dlfltollt And tholr rolo In tlw dovolopnont of cordloc arrhythmias. J. Phonoocol. Exp. Thor. 163: 154-166, 1972. 45. Gllllt, A.A., F.H. lovlno, H. Thlbodooux, A. Aotnoi And F.G. Stondoort: A comparison of nothyllldocolno And lldocolno on arrhythmias producod by coronory occlusion In tho dop. Circulation 47: 697-703, 1973. 46. Stondoort, F.S.: Mechanism of Action of Msclo roloxonti. 1973 Lactures. Amar. Soc. Anestheslol. 117-1 to 117-3. 47. Sottroppuloi, S.S. And F.G. Stondoort: Msuroousculor offocti of aorphinc ond noloxono. J. Pharmacol. Exp. Thor. 164: 136-142, 1971. 46. Hoskmon, T.6., K.L. Orotchon ond F.S. Stondoort: Miniature ond-plotc potontlols rocordad fro* momlion myoneural Junctions In vivo. Sclonco 183: 213-215, 1974. ----------- 49. Gllllt, A.A., D.E. Evont, A. Rolnoi, 9. Lovltt and F.S. Stondoort: Slooo and ventricular praantur* boots (Lottor to tho Editor) Circulation 50: 863-664, 1974. " 50. Stondoort, F.S., K.L. Orotchon, L.A.SAIrboll and V.H. Morponroth. III: Tho offocti of cyclic nuclootldos on no--1 Ian motor norvo tonolnols. J. Phoraocol. Exp. Thor. J99: 544, 1976. 51. Stondoort, F.B., K.L. Orotchon, L.R. Sklrboll and V.H. Morponroth. 111. Tho rolo of cyclic nuclootldos In nouroousculor tronsoltslon. J. Phoraocol. Exp. Thor. J99: 553. 1976. 52. Orotchon, K.L., F.G. Stondoort, V.H. Morponroth, III ond L.R. Sklrboll: Evldonco for a prejunctional rolo of cyclic nuclootldos In neuroousculor transnrtsslon. nature 264: 78-61, 1976. 53. Orotchon, K.L., V.H. Hsrpsnroth, lit, F.G. Stondoort and L.F. Holts: Aiithloortne: effects on nouroousculor transolsslon. Anosthoslolopy 45: 604-409, 1976. HONS 025565 -9- 5*. Oretchen, K.L., F.G. Standsart and A. Raines: Effects of phenytotn on tna cyclic nucleotide system In the motor nan* tormina!. Epilepsia. lt(31: 337-3*3. 1*77. 55. Standaort, F.G.: Intaractlona amonf neuromuscular blocking aparts and othtr draft. Refresher Courses in Anestheslolofy. Ed. S.G. Harthay; J.). Llppancott, Philadelphia, Vol. f, 111-124, 1978. 58. Sklrboll, I.A., F.G. Standaort and k.l. Oretchen: Effaces of calcium on a cyclic nuclaotldm lystam in solamt motor noma terminal!. Eur. J. Pharmacol.. 54: 299-298, 1979. 57. Standaort. F.S. and k.l. Oratchmn: Cyclic naclaotldat and naurcmuscular transmliitsn. Fad. Prac.. : 2183-2192. 1979. 58. Standaort. F.G. and K.L. Oratchmn: Cyclic nuclaotldas In nauroouscular transmission. Anasth. Ana 19.. 60: 91-99. 1981. 59. Standaort, F.G.: Tha Aalaasa of Transmittar at the Neuromuscular Junction. 8r1t. J. Anaosth., 1982, (Submitted). M. Standaort, F.S. and K.O. tocher: Neuromuscular tlocklnf draft. In: CNC Nandioak an Pharmacolofy and Aflnf. Ed. K.J. Roberts; P. Goldtaff, CNC Prats. H. Palm teach. IMS. (Submitted). HONS 025566 -10- A8ST11ACTS I. Standaart. F.G.: The action of d-tuboeurarlM on tha looter norvo terminal Fad. Proc. 20: XU, 1961. " t. Standaart, F.G.: Mechant sn of post-tetanic potentiation (PTP) In eot slow and fast ausclas. Fid. Proc. 22: 309, 19*3. 3. lavltt, a., A. Raines, J. Hobart] and F.G. Standaart: Antagonisa of di|1tails arrhythmia: a naural phenomenon. Fad. Proc. 2b: 402, 4. Hal MS. A., S. lavltt and F.G. Standaart: Factors influencing dtphenylhydantoin antagonisa of ouabain-Inducad ventricular arrhythmia in tna cat. Tba Pharmacologist 9: 237, 19*7. 5. Lavltt, a., A. Ralna*. D. Moros and F.G. Standaart: Antagonism of ouebatn- tnducad vantrlcular tachycardia (VT) and daath by large dosat of b-isoorocyl p-mtrophanylathanolaalM (IMPCA) In tlM eat. Fad. Proc. 27: 34*. 19b*. a.6. Sohn, T.J., A. Ralnaa, F.G. Standaart and lavltt: Antlarrhythmtc prop- artlat of sodium 5,5-dl phony 1-2-tillohydantoin (DOTH). Tba Pharmacelegtst 10 : 221, 196*. 7. Gllllt, R.A. and F.G. Standaart: Effbct of carotid sinus and vagal norvo section on mm cardiovascular rspansao Inducad by ouabain. Tba Pharma cologist 10: 220. 19M. 8. Oatullar. P. and F.G. Standaart: Tba action of tormina aonaacetate (GNA) on cat tolaus Macias and nerves. Fad. Proc. 2: 199, 19*9. 9. Glllls. R.A., a. Lavltt, A. Raines, r.J. Sohn and F.G. Standaart: Effect of ouabain an synpathatlc, vagus and phrenic nerve activity. The Phanaacologlst 1U 244, 19*9. 10. Glllls, R.A., J. R. McClellan, T.S. Sauer and F. 6. Standaart: Effect of dlphanylhydantala on spontaneous syeoathetlc nerve activity. Pharmacolo gist 1: 30*. 1970. II. Glllls, RJL, F.H. lavl no, H. Thibodeaux. A. Raines and F.G. Standoart: Effect of anthyl1Idacalna an arrhythmias produced by coronary occlusion in the dbg. Proc. Fifth International Congress on Pharmacology, 1972. 12. naahman. T.*.. t.l. Dratchan and F.G. Standaart: In vivo intracellular recording of miniature undelete potentials from Me cat solans nuMlo. Fad. Free. 32: 771, 1973. 13. Standaart, F.6., V. H. Norgenroth. Ill, l.R. Sklrball and K.l. Oratchan: Cycltc nuclaotldas and nouroMscular traaamlsslan: prejunctional affects of cyclic nacloottdas. Pharmacologist IS: 193, 1976. MOHS 025567 -u- 1*. Morgenroth 111. V.H., L.R. Skirbell. k.L. Dretenen and F.b. Standaart: Cyclic nucleotides and neuromuscular transmission: prejunctional effects of reagents that iffiti cyclic nucleotide system. Pharmacologist 18 193. 1976. -- 15. Sklrboll. L.R., K.L. Oretehen, F.G. Standaart and V.H. Morgenroth, III: Cyclic nucleotides and neuromuscular transmission: prejunctional effects of anta9dnists of calelua flu*. Pharmacol091st Id: 193. 1976. 16. Oretehen, K.L., F.S. Stantfaart. V.H. Morgenroth, lit and L.R. Sklraoll: Cyclic nucleotides and neuromuscular transmission: prejunctional affects of physostlgmlna: inhibition of phosphodiesterase? Pharmacologist J8: 193. 1976. 17. Sklraoll, L.R.. L. la liar. H. ladarola. F.S. Standaart. V.H. Morganrotn, III and k.L. Oratcnan: The effects of calcium, magnesium, lanthanum tetraethylamonium and amlnopyrldtnes on tna cyclic nucleotide system in cne motor narua terminal. Fad. Proc. 36: 976, 1976. II. Standaart. F.5.: Structure, function and pharmacology of motor nerva terminals. In American Society of Anesthesiology: Wortshop on neuro muscular Junct ion--a caprehonstve review. Ed. J. Sayarase; boston, north, 1977. 19. Curley, H.H., K.A. Scappaticcl, R. ncSoa. k.L. Oretchen, and F.S. standaart: Cyclic AMR phosphodiesterase from cat sciatic nerve. Fad. Proc. 31: 37*. 1979. 20. Oratchan, R.L., R.A. Homerd, F.S. Standaart and C.S. Rape: Differential affects af acetylcholine and edrophonium on motor nerve endings. Soc. Hauroscl. Abst. 6: 479, 1979. 21. Curley, H.H., k.L. Oratcnan and F.S. Standaart: Inhibition by Physostipetne of Neural eAHP Phosphodiesterase. Fad. Proc. 39: 410, 19(0. 22. Stahdaort, F.S.: Neuromuscular Transalsslon - What Is a cholinergic receptor? Lectures Anar. Sac. Anusthosta, 13>l to 133-4, 1910. 23. Oay, N.S., Oratchan, N.L. and Standaart, F.6.: Comparison of Norcuron and Pancuronium am hsuramiscular Transartsslon. Fad. Proc. 141: 260. 1901. 24. Oretchoa, k.L. and Standaart, F.6.: Cyclic nucleotides and anttmgrasthanic drug*. N.V. Acad, Scl. (In Press) HONS 025568 curriculum vitae ICE AO0RE5S: Jofm flrItn Thowas O*oartint of Phar*cclogy and Tovicology *ttc Virginia Univarilty Mtaieal ctnttr Morgantown, tst Virginia 28308 T*l*pnont: (304) 293-3249 fBMC ACORESS: 881 vallay viaa Strait Morgantoan, Mast Virginia 28309 Talapnona: (304) 399-1429 H>N; La Cross*, Wisconsin April 6, 1933 La Cross* Public Scnool, LI Cross*, Wisconsin 1938-1930 Univarslty of wisconsin-La Cross*, La Cross*, Wisconsin 1931-1933; 1939-1998 Stata Univarslty of Iowa, Iowa City, Iowa 1998-1981 yCtMIC OECRCES: 8.S., Univarslty of Wisconsin, 1938 M.A., Stat* univarslty of low*. 1998 Pn.O., Stat* univarslty of Iowa, 1981 888ITAL STATUS: M*rrl*0 (1997): on* son - 008 Jun* 12, 1982; on* daughter - 008 May 31, 1984 AILITARY SERVICE: Non-coaalsslon*d Offlcar (Sorgaant) U.S. Aroy . 1993-1939 taeMtMjAMO Aaorlcan Rogistry of Physical Therapists-Stat* Univarslty of Iowa-1997 (lnactlv*) Aaarlean Aeadaay of Toxicologic Scl*nc*s - Olploaat*, 1982-1989 025^69 *Ot*S honors ano gTOFftOTijAi. RfeciCNITIONT 2 Oean's Lists, University of Wisconsin - l Cross* Gamma Alona, Science Honorary, university of Pre-coctoral Fellowsnios, University of Io*a foreign Travel Award, American Society for Pharmacology ana Experimental Theraoeutlcs Hevlco City, Mexico; San Paulo, Braril. 19 Chairman, EnOocrine Pharmacology, American Society far Pharmacology ano Experimental Theraoeutlcs (university of Minnesota, 1988) Chairman, Enflocrina Pharmacoloqy, feoetatlon of American Society for Experimental Biology (Atlantic City, n.j.) 1971 Co-Chairman, Liver Microsomal Enrymes, Society for Toxicology (Nam yore, Ne vorw) 1973 visiting Professor and Senior Research Advisor, Faculty of Meoicine, university of Ottama, Ontario, Canada 1971 McLaughlin Amard - Outstanding Teacning Award, west Virginia University Scnool of Meoicine (Shared Award) 1971 Adjunct Professor, Department or Allied Health Sclancas, Kent State university 1979-present Outstanding Teaching Award 1973-1974 west Virginia University Co-Chairman, Endocrine Pharmacology, American Society for Pharmacology and Experimental Therapeutics (University of Montreal, 1974) Co-Chairman, Endocrine Pharmacology, American Society for Pharmacology and Experimental Therapeutics (Univarsity of California, 1979) U.S. Environmental Protection Agency Certi ficate of Scientific Service, 1977 McLaughlin Awards - Outstanding Teaching Amard, west Virginia university Scnool of Medicine, (Shared Amard), 1977 National Acadeeiy of Science Travel Award, XII International Cancer Congress, Buenos Aires, Argentina, 197B Co-Organizer, Epidemiology of Toxicology, ASPCT/SOT Joint Meeting, (Unlvarsity of Texas, 1976) Maurice 0. Craff Distinguished Alumni Awsro (university of *laconsln-La Crosse), 1978 Co-Organizer, n.I.E.h.S. - sponsored Target Organ Toxicity: The Endocrlnas Symposium, west Virginia unlvarsity, i960 Organizer, ASPET/SOT - Sponsored Symposium, 'Innovating Models in Teratogenicity' (University of Louisville), 1962 0255* kohs AACH ~nTm6NT5 ; Research Associate, State University i95S-1959 visiting Senior Scientist - Travenoi Chicago, Illinois - 19*2 or leva, Laooratories, HACKING ASSISTONTSHIPS AWO ACAQEHIC APPOINTMENTS: ' fMcnTngTTsiTstantTT5o5irtieant_of Physiology, Scnool or Meaicine, State university or love. i960 Instructor, Department of Physiology, Scnool of Meaicine, State University of Iova,1961 Assistant Professor, Oeoartisent of Pharma cology, University of Virginia Scnool of Medicine, 1961-1964 . Associate Professor, Oepartnent of Physio- logy-Phareacology, Creighton university, Scnool of Medicine, 1964-1967 Associate Professor, Oeoartisent of Pharmacology, east Virginia university School of Meaicine, 1967-1969 Visiting Professor end Acting Chairman, Oaoartmant of Pharmacology, Pahlavl University School of Medicine, Shiraz, Iran, 1970 Professor, Oeoartaent of Pharmacology and Toaieology, vest Virginia University Scnool of Medicine, 1970-presant University School of Medicine, 1979-present Assistant Oman of Adalnistratlon, east Virginia University School of Medicine, 1973-1975 American Asoelatlon of Medical Collages Executive Development Seminar Program, 1976,(m.i.t. Sloan School of Management) fiscal Officer, east Virginia university Scnool of Medicine, 1973-present Promotion and Tenure, eeat Virginia University School of Medicine,1973-prasant Chief Grants ana Contracts Officer, Peat University School of Medicine,1973-present Affirmative Action Liaison, Past Virginia university School of Medicine,1973-oreeent Academic Review, eeat Virginia University Scnool of Medicine, 1973-present Biomedical Aasearch Grant Support officer, east Virginia university School of Medi cine, 1973-present facilities and Scheduling, east Virginia university School of Medicine 1973-prasant HONS 025571 4 RESEARCH activities ANO INTERESTS: Co-Investigator, National Canetr Institute, (Prostate Cancer) 1970-present Enoocrine Pharmacology/Physioipr. Reproductive System roslcity Orug-Hormcne Interactions Heavy Petal Toxicity (Zinc HetaBoiism) Peatlcioe Toxicity Gonadal Toxicants Anti-androgenic Agents Pntnalate Acid Esters ORGANIZATIONS: Aaierican Society for Pharmacology ana Exoerimental Theraoeutics Endocrine Society Society of Toxicology Pastern Pharmacology Society Sigma XI American School Health Association, elected FellOP, 1971 National Society for Medical Research Pest Virginia Association of Acaoemlc Oeans Association of American Medical Coileges- reoresentative PRESENT COMMITTEES: Executive Faculty Committee, 1973 Medical School Promotions Committee - 1973 ex-officio Medical School Admissions Committee - 1973 - ex-officio Bullying Committee for Basic Sciences - Chairman, 1973 - Medical Center Planning Committee Chairman, 197a - Educational Program Committee, 1973 Learning Reeoureee Committee. 197* - Senior Banquet Committee, 197* Asaocletlen of Aiaeriean'Medical Colleges - Planning Coordinator, 1973 Faculty Council - School of Dentistry - 197* . Medical Student Financial Aids Committee 1977 - American Society for Pharmacology and Experi mental Therapeutics - Committee on Envi ronmental Pharmacology, 1973 Computer Users Committee 1978 Medical School-Hospital Liaison to Student Body Committee, 1978 Dissertation Committees, 19<B Post-doctoral Training Grant (Endocrinology) 1977 NSF Committee to Stimulate Competitive Re search in Pest Virginia, Chairman, 1978 p.v.U. Medical Canter Blohaaarda Committee, Cna: 1980 - HONS 025572 5 SELECTEO list OF past ANO PRESENT C0NSULTANTSHIP5 ANO AOvISORy HOLES: H.E.w. - Health Manpower Sranen , Region III Environmental Protection Agency National Cancer Institute Committee on Carcinogenesis university Park Press, Baltimore, xarylano Nason Researcn Institute, worchester, "ess. asha-pma Lecturer on Drug Abuse Encyclooeaia Brltannlca Aq HO Reviewer - Journal of Animal Science Editorial Board - Journal of Toxicology ano Applied Pharmacology 1973-1981 Clinical Pharmacology - Texas Allergy Re search Foundation Baxter-Travenol Laboratories - Chicago, Illinois world Health Organisation Narcotic Oivision Ad hoc Reviewer - Science tfl hoc Reviewer - American J. School Health So hoc Reviewer - American j. Physiology *0 hoc Reviewer - Journal of National Cancer Institute Clement Associates, Inc. Scientific Regu latory Consultants, Washington, O.C. Editorial Board, Technomie Publishing Com pany (Health Scienca Oivision) Wastport.CT National Instituta Arthritis, Metabolic, and Olgastiva Oiseasas Union Carolda corporation, South Charleston, w.va. American Public Health Association urban A Schwarrenberg Medical Publishers, Baltimore, Maryland National Science Foundation-Regulatory Bio logy Program Editorial Board, J, Toxicology and Environmental Health Editorial Board, Perspectives in Toxicology Raven Press, New York, New York Professional Consultants in Occupational Health, Ine..Washington, O.C. Ad Hoc Reviewer - Proceedings Society Experleental Biology and Medicine M Hg Reviewer - Andrology National Toxicology Program (NTP) Board of Scientific Counselors Exxon Corporation, Newark, N.J. Syntax Research (Oivision of SyntextuSA], Inc.). Palo Alto, California Ad Hoc Ravlawar - National Prostatlc Cancer Project HONS 025573 6 SELECTEP LIST OF PAST COMMITTEES OHO OFFICES (ChRONQlGCICAL i President - virgin!* Academy or Sciences7 Medical Sciences, 1964 Secretary Virginia Academy of Sciences, Medical Sciences, 1942-19*3 Research Fellowship Committee, university at Virginia, 19*2-19** Secretary-treasurer, Society of Sigma *ICrelgnton university, 1945-1947 Secretary, Society or Sigma xl - est Virginia University 1949 Curriculum Committee, west Virginia univer sity School of Medicine. 1947-1949 Faculty Senate (wvu), 1949-1971; 1973-197* Feculty Senete Committee (wvu) on memoershlp and Constituencies, 1970-1971 Medical School Promotions Committee (wvu), 19*9-1973; Chairman 1970-1973 Medical School Admissions Committee (vu), 19*9-1973; vice Chairman 1970-1973 Pre-Medical Advisory Croup (wvu), 1970-1979 Sasic Science Administrator for west Virginia university Comprehensive Cancer Center Oirector of Graduate Studies in Pharmacology (WVU) 19*7-1973 President's (West Virginia university) Task Force Committee on North central Accreoitatlon, 1972-197* President's Ad hoc Council far west Virginia University Peaearcn and Graduate Education, 1972-197* Co-Oireetor, USPHS Training Grant in Pharma cology, 19*7-1973 Medical Center Long Range Planning Committee (WVU), 19S-197* American School Health Association committee on Drug Abuse, 1970-1979 Faculty Promotions and Tenure Committee (wvu School of Pharmacy) 1972-197* Graduate Faculty, Kant State university, 1979 Board of Examiners, university of Madras, India Board of Examinars, University of Ottawa, Canada Search Committee for university Comptroller (wvu) Chairman, 1978 Research Strategy Committee (wvu), Cnairman. 1977-1978 By-Laws Committee, West Virginia university School of Medicine, 197S HONS 025574 7 Selected Lilt of Past Committees and Offices (Chronological): ' Faculty of Reproductlvs Physiology[ Institute of Biological Sciences, wait Virginia University 19*7 Radiation and Isotope Comalt tee, 1968 Cancer Fellovsnip ano Research Committee, 1966 Faculty Promotions and Tenure Committee - Department of Pharmacology, 1970-1978 Inter-Disciplinary Advisory Committee - Master's Program In Nursing, 1972-1974 university Energy Committee, 1977-1979 Eaecutive Committee of the Cerontology Center 1978-1980 Thesis Committees, 1988 HONS 025575 a DUPLICATIONS (including 123 research paoers/boows/cnaote-x/r.v i... , . tapes/f 11 mi/meals : 10A abstracts); --------------------------:------ Clucose Toltranet In Rheumatoid Arthritis, J.A. Thomas, and w.o.Paul Clinical Chemistry : 338, 1958 (Abstract). ' Effect of 2430 Megacycle Microwaves in Oags, Rats and Larvae of Common Fruit Fly, o.o. Searle at.ai., 81ol. Erfeets of Microwave Radiation i. 187, mi. * CarOohyarata Metabolism in Patients .ith Rheumatoid Arthritis as Ottarmined by Oral and IV clucosa Tolerance, j.a. Thomas, m.a. rnes:s State university of loea, 1938. ' Effeet of microwave Irradiation an Spermatogenesis ana Accessory Sex Organs in the Male Albino Rat. J.A. Thomas, Doctoral Olssertation, starUniversity of loea, 1981. Olssertation Abstracts 22: 107, mi (Abstract). The Effects of Microwave Irradiation on Spermatogenesis and Accssory Se< Organs in the Male Albino Ret. J.A. Thoaaa, end J.O. Thompson, Fedaratcn Proceedings 2: *01, 1981 (Abstract). * Alterations in Clucsgen Response in Alloxan Olabetlc Orchldeetomlzed Rats by 17-ethyl-l9-nortestosterone end Estradiol Benroste. J.A. Thomas, Federation Proceedings 21: 199, 1982 (Abstract). Effect of 17-ethyl-19-nortestosterona on Blood Glucose In the Alloxan Olabetlc Rat. J.A. Thoms, Virginia Journal of Science 13: 293, 1982 (Abstract). Modification of Glucagon-induced Hyperglycemia by various steroidal Agents. J.A. Thoms, Metabolism 21: 207, 1983. The Influence of 19-nortestostorone Oorlvatlves on Clycogen and Phospnorylasa Activity in Homgonetse of Mouse Heoatlc Tissue. j.A.rncmas end J.Lomax, Federation Proceedings 22= "1* 1**3 (Abstract). The Effect of Several Steroidal Agents en Liver Phospnorylasa Activity. J.A. Thoms, Virginia Journal of Science, 1*: 331, 1983 (Abstract). Norethendraions-induced Changes In Hopatlc Phospnorylasa Activity. J.a. Thoms, Metabolism 22* *3, 19d. Effect of Testosterone Analogues on Sex Accessory Gland Fructose Levels in the Orchldoctemlted Meuse. J.A.Thoms, Federation Proceedings 22: --:1984 (Abstract). Actlen of Norethandrolone or Testosterone on mouso Sox Accessory Organ Fructose Levels. A.J. Strauss and J.A. Thoms, Virginia Journal of Science 2JL* 3*3 1><* (Abstract). The Action of Androgenic Steroids on Soma Aspects of Accessory Sex C:;s" Motebollsm. j.a. Thoms, Virginia Journal of Science 21: 3*8, 198a (Abstract). Structural Modlflcation* of the Testosterone Molecule and Its infiue-cr on Fructeso Secretion In Sex Accessory Organs of Reproduction in the Cestrsto mouse. J.A. Thomas, The Pharmacologist 4: 189, 198* (Abstract MONS 025576 9 .plications (eont.): Effect of Steroids on Meuse Sex Accissory fructose Levels. j.a. .lames ana a.j. Strauss. Acta Endocrinologies (Copenhagen) 46: 619, 1953. adogenous Histamine In Mala Organs of Saoroductlon. t.a. Assaykeen and ].. Thomas, Enoocrinology 76: 839, 1965. :(fact of Simultaneously Injected Testosterone ana Testosterone Analogues 3d Sea Accessory Organ fructose. J.A. Thomas, federation Proceedings 2a: jjl, 1965 (Aostract). TM Antagonistic Action of Estrogens on the Testosterone Oaoenoent pmecess of Sa> Accessory Organ fructose formation. J.A. Thomas. The Pharmacologist 7: 149, 1965 (Abstract). fructosa Levels In Sex Accessory Organs of Mature Coloen Hamsters. J.A. Thomas and P.v. Anortwj, Enoocrinology 7^: 1147, 1963. Antagonistic Action of Norathynoorel on the Testosterone Dependent Process of fructose formation in Mouse Sax Accessory Organs. J.A. Thomas and E.T. Knycn,Jr-, Acta Enoocrinolagica (Copennagen) 51,: 244, 1966 DM in vivo and in yttro incorporation of J2P In Mouse Prostata elands. I.T. Knycn, Jr., and J.A. Thonas, federation Proceedings 21: 314, 1966 (Abstract). Inhibitory Effects of Estrogona on the Testosterone-Dependent Process of Sob Accessory fructose Secretion. J.A. Thonas snd E.T. Knycn, Jr., Endocrinology 7j: 1064, 1964. Seme Actions of Aeserplne on Sex Accessory Orgen fructose Secretion, j.a. Thomas, The Pharmacologist 201, 1966 (Abstract). further Studios on the Influence of Estrogens on Androgen Dependent fructose fornetlon in sex Accessory organs, j.a. Thomas and E.T. Kyncn Jr., Acta Endocrinologies (Copenhagen) 3: 435, 1966. Effaets of Cyelohexlnide on Salivary Gland Protein Metabolism. J.A. ThoMS and M.f. Hill, Anatomical Accord i7: 391, 1947 (Abstract). Action of Cyelohexlnide on Prostate Gland fructeaa. J.A. Thomas, fedaratien Proceedings 446, 1947 (Abstract). Effect of Aasorplns on Prostata Cland fructosa. J.A. Thonas, A.y. Andreas and M.f. Hill, Acta Endocrinologies (Copenhagen) 52: 399, 1947. Effect of Sallvarladenectooy upon Gonadal Activity In Male hats. J.a. Thonas ana M.f. Hill, Arcnlves on Oral Biology i: 921, 1967. Action of Cyelonexlnlde on the Subaaxlllary Glands In normal and Castrate Mica. M.f. Hill snd J.A. Thomas, European Journal or Pharmacology 1.: 434, 1947. HONS 025577 Publloatlons (cont. ): 13 Some Aspect! of Prostate Clina MltUoUs* following the Aaminijtratian .. Cyclonexialde. J.A. Thomas, Th Pharmacologist 9: 232. 1987 (Abstract;. Efface of Cyelohexlmlde on Mouat Sax Accessory Organs. 3.A. Thomas, European Journal Pharmacology 2: 127, 19*7. Effect of Exogenous Oooanlne an Aat Adrenal Aseorole Aeld. A.8. King J.A. Thomas, Journal of Pharmacology ana Experimental Therapeutics 159 18. 1988. ------ Sax Accessory fructose: An Evaluation of Biocnemlcal Tecnnloues. J.A. Thomas, m. meenlnney end e. mason, Proceedings Society of Experimental Biology and Medicine ^27: 930,1988. Polatlonshlp of male Sea Hormone to Phospnorylatod and Nononosonorylated fructose. J.A. Thomas and m.c. me.nlnney, federation Proceeolngs 27: 828, 1988 (AOStract). Action of Testosterone Analogues on Prostate Clang pnospnorylaeed ana mon-pnosphorylated fructose, m.c. Meenlnney ana J.A. Thornes, The Pharmacologist 228, 1988 (Abstract). Effect of Testosterone and Estrogen on the Activity of Alkaline ana Acia Phosphatase In House Sex Accessory Organs. E.T. Knycn, Jr., and J.A. Thornes, The Pharmacologist 228, 1988 (Abstract). Changes In Submaxlllary eland Protein and Nucleic Acids follomlng Etnlonlne Administration, j.a. Thomas, . mason and m.c. meenlnney, Journal of Oental Research a: 192, 1989. Hormonal Regulation of free fructose and fructose Phosphate Esters in Prostate Glands of mice. J.A. Themes, m. meenlnney, C, eenger and E.T. mnych, Jr., federation Proceedings 2t: 77*i l*** (Abstract). Effect of a Single Injection of Testosterone and/or Ethinyl Estradiol Upon mouse Prostate Gland fructose levels. J.A. Thoaws, ". meenlnney ana C.T. Knycn, Jr., Acta Cndacrlneloglca (Copenhagen) (' 319, 1989. Action of Synthetic Steroids on the Uptake of Testosterone-1,2-mJ By mouse Prostate Glenda. J.A.Thomas, C.T. Knycn, Jr., and m.G. meenlnney. IV International Pharmacology Congress Proceeding (Basel, Seltzarlana) o. 398, 1989 (Abstract). factors Affecting the uptake and Subcallular Distribution of Radioactive Testosterone In Sox Accessory Organs of mice. C.T. Knycn, Jr., j.a. Thoaaa and C. Smith, The Pharmacologist H: 292, 1989 (Abstract), effect af 19-norstarolde on the Uptake of Trltlated Testosterone by Prostate Glands of mice. j.a. Thornes, The Pharmacologist U.: 232, 1989 (Abstract). effect of Raecrplne and Cyclohcxlmlde an mexose levels of mouse Brain. G.R. eenger, J.A. Thomas and T.J. lee. The Pharaacologlst H,: 290, 1989 (Abstract). effect of Reearplne on the Uptake of Testosterone-1.2-m7 by mouse Prostate Gland. J.A. Themes, C.T. Knycn, Jr., m.c. meenlnney, European Journal of Pharmacology 381, 1989. HONS 025978 niSLiCATIONS (cant.); 11 uDCtllular Distribution or Radioactivity In the Prostate Gland Follovlnq r Single Injection of Testosterone-1,2-hJ. J.A. Thomas. C.G. Smith, .G, mawhinney and E.T. Knycn, Jr., Acta Endocrinologies 43: joj, 1970. ictlan or various 19-norsteroids on the uptake or Radioactive Testosterone oy Sex Accessory Organs or the mouse. J.A. Thomas, <nycn, Jr., m.c. aninney and S.R. Smith, Eurooean Journal or Sfiarmacoiogy 9: 233, 1970. E.T. talatlansnlD or fructose and Fructose Phosohate Esters In Accessory Se argans or the mouse, m.c. maehinney, E.T. Knych, Jr., and J.A. Thomas, Journal or Endocrinology (Britain) a: 543, 1970. Uptake or 2-deoxyglucose-C1* (2dC) or 3-0-methyl-glucose-cl* (3mG) Dy Guinea Pig Seminal Vesicles In vitro, m.c. maehinney, J.A. Thomas and E.T. knych, Jr., Federation Proceedings 782, 1970 (Abstract). Uptake of cl*-2-deosyglucose and C^-J-O-methyl-glucose by the Rat ventral Prostate In vitro, m.c. maehinney, J.F. use, C.G. Smith, and J.A. Thomas, The Pharmacologist 1: 241, 1970 (Abstract). Cnaymatic measurement or Prostate Cland Fructose. J.A Thomas, m.c. Maehinney and G.R. eanger, Journal Reproduction and Fertility 21: 22, 1970. Aaslmllatlon of Mon-utlliieble Glucoses by Sex Accessory Organa in vitro, m.c. Maehinney, O.F. milam and J.A. Thoaas, Federation Preeaedings 2: 3it, 1971 (Abstract). Uptake of Nen-utlllxable Sugars by Culnea Pig Seminal Vesicles in vitro. M.G. Maehinney and J.A. Thomas, Journal Pharmacology and ExperlaentH Therapeutics 177: 447, 1971. The Abuse or Medicinal Products. J.A. Thomas and G.R. Knotts, American Journal of School Health 4J,: 233, 1971. Hoe do Oral Contraceptives Mark? M.G. Maehinney, J.A. Thoaas and G.R. Knotts, American Journal School Health 4^: 301, 1971. uptake of Tritium-Labeled Testosterone by Rat Femur: Effect of Olsuse ane Age. m.a. Grant, J.A. Lindsay and J.A. Thomas, Canadian Journal of Physiology and Pharmacology 4: 717, 1971. Formation of Radioactive Cyclic 3', 3' Adenosine Monophosphate (c-amp) From m'-Adenosine by Mouse Prostate Glands n vitro. Carol G. Smith, J.A. Thomas and M.G. Maeninney, The PhotmacoTogist 13: 2S7, 1971 (Abstract). Distribution of Non-utlllzable hoxosos and Amino Acids in Evortad Seminal Vaalcsl Sec of tne Guinea Pig. n.g. maehinney, J.A. Thornes and C.G. Smith, The Pharmacologist 12: 30*, 1971 (Abstract). Effect of Estrogen Pro-treatment on the uptake and Biotransformation of Testosterone-1,2-h3 by Mouse Prostata Glands. J.A. Thornes, m.t. Smith, C.G. Smith and M.C. Maehinney, The Pharmacologist 12: 2S, 1971 (Abstract). HONS 025579 PuBlicationatcant.): 12 The Action of Testosterone on tn* Assimilation of Non-utlliraola c By the Prostata. J.A. Thomas, m.c. Mavninney, T.j. Lee ano C.C. stt. Journal of Pharmacology ana Experimental Therapeutics 179: 499, 197^ ' Pesticides ana th Environment. 0. Taylor, J. Stavtni ana J.A. Thomas American Journal of Scnool Maaltn aj: 82, 1972. ' Loeallration of OOT-h3 in Malt Raoroductlva Organa and its actions uCon anaroganlc function, m.t. Smith, J.A. Tn0as, C.C. Smith, m.c. Ma.mTM.. ano J.J. McPhillios. Sociaty of Toxicology, lltn annual Matting, Marcn T 1972, 0. 101 (Abstract). Action of Oltldrln on the uptaka of Tastosterone-l,2-H3 by Prostata Clanoa of tna "ala Mousa. J.A. Tnoaas, m.t. Saltn, m.c. Mavninney anc J.J. McPhllUps, Sociaty of Toxicology, 11th Annual Matting, Marcn 1977 p. 103 (Abstract). ' Efftct of Tastostarona or Dlhydrotastosterone on tha In vitro Synthesis of laoolltd Cyclic Adtnoslna Nuclaotlda (c-amp-h3) oy"?a~lccassory Organ* of Reproduction. C.C. Saltn, J.A. Thoaas, m.c. Maahlnnty ana j.x Lloyd. Federation Proceeding* 21= 393, 1972 (Abstract). ' Effect of Tastostarona on Cyclic Adanoslna Monopnosonata-H3 (c-amp-h3) and Adenyl Cyclase Activity In Aat Saalnal veslclts. p.l. Slngnal, J.A. Thons M.A. Parulekar and C.m. Ling, v International Congress of Pnsreacology, p. 215, July 1972 (Abstract). Assimilation of Adenoslne-H3 and Its Conversion to Cyclic Adanoslna Nucleotide (c-AMP-mJ) by Norael or Hyperplastic Prostates of Dogs In vitro. m.c. Maanlnnay, C.C. Saltn, J.A. Tnoaas ano O.F. Milan, iv international Congresa of Endocrinology, p. J7i, June 1972 (Abstract). Cnaracteristlcs of Hexose uptake by tne Prostata Gland, m.c. Mawninnty, J.A. ThoaMs, C.C. Saltn and O.F. Milan, Inveatlgatlva urology 9: *39, 1972. " Failure of tf^i-adrenerglc Blocking Agents to Altar Estrogenic induction of Uterine Enxynes. A.L. Slngnal, J.A. Thomas, and m.a. Parulekar, Lift Sc lances 22: 295, 1972. Aoletlensnlp of Pituitary Hormones and Androgens on Prostata Clano Metabolism. J.A. Tnoaas, m.c. Maanlnnay and J.*. Lloyd, Proceedings 1st Annual Carcinogenesis Symposium, p. <1, October 1-a, 1972 (Abstract). Effects of OOT on Aadloactlvo Uptake from Teato*terone>l,2-M3 by Mouse Prostate Claude, m.t. Smitb, J.A. Thomas, C.C. Saltn, n.c. Mseninnty J.a. Lleyd, Toxicology and Appllad Pharmacology 22: 139, 1972. Currant Assessment of Marijuana. J.A. Thomas, M.T. Saltn and G.P. ne"; American Journal of Scnool Health *2: 3S2, 1972. utarlna c-Amp-h3 after Estradiol and/or Propranolol. J.A. Thomas, e. Crap and A.L. Slngnal, Hormones ano Metabolic Messoren *: 311, 1977. AOsnsalna uptake sno Metabolism of Cyclic 3', 3'-Adenosine Monophosci'? by Normal ano Hyperplastic Oog Prostata Glands. M.C. Maehinney. C.C. Saltn, J.A. Thomas and O.F. Milam, Investigative Urology 2fl> ^*3, 19'- MONS 025580 If notions ( cont. ): 13 mstostarons: Stimulation at Adenyl Cyclaae and c-amp-hJ Formation in It Seminal vasiclts. J.A. Thomas ano s.L. Slngnal. aiocntmical garmaeology 2: 307, 1973. a Formation and Distribution of Cyclic 3' , S'-adenosint Monoonosohat* 1 tna Evartao Gulnaa Pig Samlnal veslcla Sac. C.C. Smitn, m.g. S*ninny, s.l. Slngnal, and J.A. Thomas. Inyestlgatlve urology 10: 278, stributlon of Cl4-Alha-emlnobutyrle Acid, C14-3-o-mathyigiueosa (d Cl* Insulin In Everted Samlnal vaslela Sacs. m.5. Mswhlnney, J.A. mas, C.C. Smith and O.F. Milam. Invastlgatlva urology 282. 1973. tabollc Charactarlstlcs of Hyparplastlc Oog Prostata elands, m.c. ieninney, f.l. Scnaartz, J.A. Thomas, L.s. Olivar, . Zapo and J.a. |oyd. Proeaadlngs Annual Amariean Urology Association, 1973 (Abstract). balances Pith Abusa Potential at tha Elamantary and Hign School Laval. !A. Thomas, 73. m.c. Mawninney and C.R. Knotts. Clinical Padlatrics 12: 17. cts of Chronically Administarad Oelta*-tetranvdrocannablnol on Enal and Gonadal Activity of Mala Rats. C.M. Ling, j.a. Thomas, D.A. r and A.L. Slngnal. Intarnatlonal Journal of Clinical Pharmacology 7: 1973. " fttlona of tha Herbicide 2,,3-T on tha Uptake and Blotransformation of lotoatarone>l,2-HP by tha Mouae Prostata Gland. J.a. Lloyd, J.a. anas and M.c. Mamhlnnay. Archlvas of Envlronmantal Haalth 217, 1973. gfaet of Prolactin on tha In vitro Accumulation of Trltlatad lotaaterone (T-hJ) by tha Prostata Gland. J.a. Lloyd, J.a. Thomas, 11. Kaanan and I. Arestah, Fadaratlon Proeaadlngs 22= 298,1973 [Abstract). was Inhibitory actions of Morphine on Sax Aecassory Cland Metabolism. f.A. Thomas, m.c. Maahlnnay and J.a. Lloyd. Proe. Society of Toxicology, [2th Annual Maatlng, p. 29, 1973 (Abstract). me Actions of Organochlorlda Pastlcidas on Sax Aecassory Organs of reduction. J.A. Thaaas and J.a. Lloyd, In PEJTiciOES ano the SIAOMMCNT: A CONTINUING CONTNOVEASY, p. IT, Symposium Spaclallst, publ, th Miami, Florida, 1973. iffsets of 2,A,9-T and Other Osganochlorldas on tha Matabollam of stostarsna>l,2-MJ by Mala Organa of Reproduction. j.a. Lloyd, J.a. aaas, m.c. Maahlnnay, and C.S. Olerlnger, Society of Toxicology, 12th knual Moating, p. 3, 1973 (Abatract). rogan Matabollam by tha Epithelium or Muscle Layers of tna Guinea Pig EInal vaaiclaa. F.L. Schmartx, j.a. Thomas, J.a. Lloyd and m.g. Kinney. The Pharmacologist 237, 1973 (Abstract). Effect of Tastostarona on tha Concentration ATP in Aceassary Sex tns of the Culnsa Pig and Rat. m.c. Mamhlnnay, L.C. Oliver, J.A. *aa, c.J. Malanga and J.a. Lloyd. Tha Pharmacologist 15: 230, 1973 tract). HONS 025581 PUBLICATIONS (continued): I Differential Response of Either Bovine or Ovine Prolactin on Testosterone-nS Metabolism in various loo* of tn Rat Prostata ciane E.A. Zepp, J.. Thomas, m.g. Maaninnay ano J.a. Lloyd. Tha Pharmacologist I^i 236, i97j (Abstract). Effact of Bovina Prolactin on Anorogan Accumulation by tha Mouse Prostata Clano. C.J. Keenan, J.A. Thomas, m.g. Maaninnay ano J.a. LloyO. Tha Pharmacologist 1^: 256, 197} (Abstract). Influanca of CarBaryl on Anorogan Mataoolism in tna Prostata Clano ano Llvar. C.S. Olaringar, J.A. Thoaas, ano R.E. Stitzal. Tha Pharmacologist 1: 226, 1973 (Abstract). Olttribution of Radioactivity In Mala Reproductive Organs Artar tna Aoministratian of Citnar Carbaryl.Cl* or OOT-mj. j.a. Thomas, L.C. Scnain, ana C.S. Olaringar. Tha Pharmacologist 1: 227, 1973 (Abstract). Factors Affaetlng Cyclic Aaanoslna MonoDhosonata (c-amP) Lavals in tna Prostrata Glanos of tha Rooant. J.a. Lloyd, J.A. Thomas, and m.g. Maaninnay. Tha Pharmacologist 1_5: 231, 1973 (Abstract). Androgans and Cycllc-AMP in tha Culnaa Pig Saainal Vasicla. C.C. Smitn, J.A. Thomas and M.g. Maaninnay. Tha Pharmacologist 1^:231. 1973 (Abstract). Actions of Morphina on Mala Sas Accassory Organs of Raproduction. j.t. Oembrosay, J.A. Thomas, J.a. Lloyd and m.g. Maaninnay. Llfa Sclancas i: 796, 1973. A Oiffaranca in tha in vitro Accumulation and Matabolism of Testosterone-l,2-hj by tna Rat Prostata Cland Folloalng Incubation vitn Ovlna or Bovina Prolactin. J.a. Lloyd, J.A. Thomas and m.c. Maaninnay. Starolds a73, 1973. Hososa and Amino Acid Assimilation by tha Epithelium and Nuscls of tha Culnaa Pig Saainal vasicla. M.c. Maahlnnay, J.T. Domorosky, C.G. Smith, J.A. Thomas, J.a. Lloyd. Journal Pharmacology and Caperlmsntal Tharapautlcs U2.: *30, 1973. Actions of Ololdrln on tho Accumulation and ttotransformatlon of Radloactlva Taataatarona by Mouaa Prostata elands. J.A. Thomas, J.. Lloyd, m.c. MaoMnnmy and C.C. Smith. Toalcology and Appllad Pharmacology Ji 323, 1973. Tho Uao and Abuoo of Anabolic Starolds. J.A. Thomos, C.R. Knotts ano c.e. Erickson. Journal of Alcohol and Drug Education 1: 31, 1973. Ralationshlp of Pituitary Hormenas and Androgana on Prostata Clano Matabolism. J.A. Thomas. 2no Annual Collaboratlva Carclnoganasis Confaronco, p. 3*, Novambar 23*29, 1973 (Abstract). Passaga of Substances into tha Luman of tha Isolatad Saainal vasicla 5*: of tha Culnaa Pig. J.A. Thomas, m.c. Maaninnay and J.a. Lloyd. Urologlea International!* 1*0, 197*. HONS 025582 ubllcatlons (cont. ): 15 :lle 5', S'-Guanosln* Monophosphate (cCMP) ana Cyclic 3 ' ,5' -adenosine .,,nophooh*t* (camp) Levels In Mouse Sex Accessary Organs. E.A. Zeoc. ).. Thomas and .. Fleming. Feaaratlon Praceedings 33: 521, 197* Abstract). iffects of Prolactin and Testosterone on Mouse Prostate Olana and Seminal /ealcle. E.J. Keenan and J.A. Thomas, Federation Proceeolngs 33: 283, 197* (Aostract). ------ The EFfaet OF Prolactin on Androgen Assimilation by Eolthellum ana Muscle if tna Guinea Pig Seminal vesicle. J.A. Bells, f.l. Scn.artz, j.a. Thomas ind M.c. Meehlnney. Federation Proceedings 2i: 7*3, 197* (Aostract). Effect of Parathlon on th* uptake end Metabolism of Androgens In Rodent Sea Accessory Organs. J.A. Thomas and L.G. Scheln. Toxicology and Applied Pharmacology, 2*: 53, 197*. Effects of Carbaryl on th* Metabolism of Androgens In the Prostate ano Liver of the Mouse. C.S. Olertnger and J.A. Thomas. Environmental Reaearcn 7: 381, 197*. Prostatlc and Hepatic Testosterone.l,2-3h Metabolism as Affected by OOT Pre-treetment in th* Mouse. J.*. Lloyd, J.A. Thomas, and m.c. Naahlnnay. Toxicology and Applied Pharmacology 2*8, 197*. Effects of Carbaryl on Mouse Organs of Reproduction. J.A. Thomas, C.S. Olerlnger and L.C. Scheln. Toxicology and Applied Pharmacology 28: 1*2, 197*. Pharmacology of Morpnine and Haroln. m.c. Mamhlnney, c.R. Knotts and J.A. Thomas, Journal of Alconol and Orug Abuse, 19: 23(3), 197*. Androgan Assimilation by Normal and Hyperplastic Oog Prostate Glands. M.c. Mawhlnney, F.L. Scheartz, J.A. Thomas and J.e. Lloyd. Investigative irology 1^: 17, 197*. Androgen Assimilation by Epithelium and Muscle of the Guinea Pig Seminal vesicle. M.C. Mawhinnay, F.L. Scheartz, J.A. Thomas, J.A. Bells and J.x. Lleyo. Journal of Pharmacology and Experimental Therapeutics 188: 32*. 197*. iffeets of Acetylcholine or Isoproterenol on Sax Accessory Gland Levels jf CGMP or cAMP in vitro. E.A. Zepp and J.A. Thomas. The Pharmacologist, JJ: 310, 197* 1 Abstract). Effects of Ergoeryptin* and Prolactin on tha Mouse Anterior Prostate Glano and Seminal Vesicle. E.J. Keenan and J.A. Thomas. Tha Pharmacologist. 279, 197* (Abstract). Action of Prolactin on Oxygen Consumption by Mala Guinea Pig Sax Accessary Organs. J.A. Bells, O.F. Milam. J.A. Thomas and M.C. Maeninnay. The Pharmacologist. 279, 197* (Abstract). Relationship of Prolactin to Oxidative and Reductive Metabolism of Testosterone by Guinea Pig Sex Accessory Organs, m.c. Maanlnney, J.A. Bells, F.L. Scheartz, C.S. Olaringar and J.A. Thomas. Tha Pharmacologist. 14^ 273, 197* (Abstrsct). MONS 025583 Publications (cant.): 16 Interaction of Oleldtln and Parstnlon on Androgen uttitolim in tna Prostate ana on Hepatic P-50 activity in Mica. j.a. rno*aj l.c. Scnei1 m.O. Colby ana w.J. Canady. The Pharmacologist. 14: 229, 197* (bstrac:J Synergistic Effect of Proiactln ana Testosterone on Pat Proatata Clanc ana Nucleic ela Levels. m.s.P. Mananonar, J.A. Thomas, m.c. ianinnay E.j. Kaanan ana e.a. Zaoo. Tha Pharmacologist. l: 275 , 1974 (Abstract) Failure of Paratnion to Altar Mala Mousa Raoroauctlva Organ Activity. J.A. Thomas and m.C. Maninnay. Toxicology ana Applied Pharmacology 2V 134, 1974 (Abstract). -- Cystic Dilatation of Sax Accassory Organa In Common ana tnarco Syrian Haaatara. J.a. Balls, F.l. Schwartz, j.a. Thomas. J.. Lloyd, j.r. Oomoroaky, C.S. Olarlngar and M.C. Maehlnney. Journal of Ctrontoloay 21 312, 1974. "-- Tha Toxic Erfaeta of Marcury. E.A. Zaoo, C.N. Knotts and J.A. Thomas. Clinical Psdiatrics. 12: 9, 197a. Effaces of Tnlopnanata and Tniopnanata-Mathyl on tna Mala Paeroductiva Systam of tna mouse. J.A. Thoaas and L.C. Schsin. Toxicology and Applied Pharmacology, 129, 197s. MorPOnal Influanea an Proatata Organ Cyclic Guanoslne Monophosphate (eCMP) and Cyclle Adenosine Monophosphate (camp), j.a. Thomas and m.s.p. Manandhar. Proc. xxvi International Congress Physiological Selancas, ia Delhi, October 1974 (Abstract) Effects of Pesticides on tha Male Reproductive System, j.a. Thomas ano L.C. Schain. Proc. Satalllta Symposlum-xxvl International Congress of Physiological Sciences, Ludhiana, India, October 1974. The Effects of Testosterone and/or Prolactin on tha Incorporation of /H-thynldlna Into DMA in the Nat Prostata Cland In vivo, m.s.p. Manandhar and J.A. ThdMS. Proceedings XI International Cancer Congress. Florence, Italy, October 1974 (Abatract). Action of Peatlcldaa and Other Drugs on tha Mala Naproductive System. J.A. Thomas. Environmental Health Effects Nesesreh Sarlaa. (Nat'l. Tacn. Infora. Bar*. PW373S1 - December 1974). Effect of Prolactin on Androgen Metabolism by tha Cuinea Pig Sax Accessary Organa, m.c. Maahlnney, J.A. Balia, J.a. Thomas, and J.w. Lloyd. Journol of Phoraacology and Experiaantal Therapeutics, 192: 2^2. 197*. Effect of Prolactin and/or Testosterone on cyclle amp In tha Nat Pras-.i:e Gland. J.A. Thoaas and m.s.p. Manandhar. Hormone and Metabolic Research, 329, 1974. Changes In carabral Cortleal Cyclic AMP Formation In tha Nat After and Chronic Treatment alth Morphine. Kh.S. Shahld-Sallaa, B.k. Calasantl, C.N. Craig and J.A. Thoaas. Federation Proceedings, Ja: 197} (Abstract). HONS 025584 iftllcatiom (cont.l: 17 JSsponje of the Apt Prostate eland Following the Administration of rolaetln. J.A. Thomas, M.S.P. Mananohar and m.g. Mawhlnney. 3rd annual ;aretnogenesis Confaranca, Feb. 2-3, 1974 (Abstract). jjfects of Narcotics on the Mala Aeoroductlve System. j.a. Thomas and 2. JBmbrosky. Proceedings Toalcology Society, 14th Annual Heating, o. 97, <arcn 1973 (Aestract}. lretnlon-oielcrln Intaractlons on Androgan Metabolism In tna mouse. l.C. ifcneln and J.A. Thomas, Proceedings Society Toalcology, lath Annual seating, 0. 71, March 1973 (Abstract). JBdalum Pollution and Its Imoact on Body Metabolism. R.l. Slngnal, a. Sazall. J.A. Thomas, and G.A. Knotts. Contemporary Education, a- 10O, 1173. -- Effects of Prolactin and/or Testosterone on Nucleic Acid Levels In etaatata Glands of Normal and castrated Pats. J.a. Thomas and m.s.p. <anancnar. Journal of Endocrinology (Britain), <: U9, 1973. Effects of Morphine upon the Formation of 3m-camp in Prostata Clanos of the Mouse. J.A. Thomaa, J.T. Oombrosky, m.c. Mawhlnney, and an.s. Mease Ini. Life Sciences, 1137, 1973. Effect ef Methadone on the Male Aeproductlve System, j.a. Thomas and J.T. Oomorosky. Archlyes Internationales de Pharaacodynamle at oe Thersple, 211: 1,7S- Effects or Oleldrln on the Uptake and Metabolism of Testosterone-1,2-jm Sedant Sea Accessory Organa. L.G. Schsln and J.A. Thomas. Environmental Aesaarch, 9; 23, 1973. The Effects of Tastoatarone and Prolactin or Growth Mormons on tne Accessory Sea Organs of Castrate Mice. E.J. Keenan and J.a. Thomas. Journal of Endocrinology (Britain), 4: 111, 1973- Stimulation of Mouaa Accesaory Sea Organa by Prolactin. E.J. Keenan and J.A. Thomas. Federation Proceedings, 3a: 304, 1973 (Abstract). Effects of Crgocryptlne on Accessory Soa Organ Function in Male Mice. E.J. Keenan, s.O. Edeerds, E.A. Zepp and J.A. Thomas. The Pharaacoleglst. ^7: 242, 1973 (Abstract). Effects of Olethylstllbestrol or Estradiol--17Beta on the Accessory Sea Organs of Male Mice. J.A. Themes, m.s.p. Menandnar and E.J. Keenan, me Pheraaceloglat, 2* 3*2> 3973 (Abstract). Soma Pharmacological Aspects ef the Antihistamines. E.A. Zapp, G.s. Knotts and J.A. Thomas. Clinical Pediatrics, if: 1119, 1973. Androgens and Estrogens In the Plasma and Prostatic Tissue of Normal Ooga and Ocgs with Benign Preatatle Hypertrophy, j.s. Lloyd, J.A. Themes and M.C. Mawhlnney. Investigative Urology, ij.: 220, 1973. HONS 025585 Publications (cont.): 18 interaction of Caraaryl and Oleldrln on the Mataoolls* or JM-Testosterone. L.C. Scheln, j.a. Thomas, p.a. Kiasa and v.o. Edvards. Proceedings 15tn Annual Toxicology Society, p. iso, 1975 (Aoatract). Combined Efface* of Paratnion and CarBaryl on th Blotransformatlon of ^-Testosterone In tnt Mala Mouat. J.A. Thomas and L.C. Senain. Proceedings 15th Annual Society Toxicology, o. 150, 1976 (Aoatract). Effact of various Carclnogtns (CMBA, Emu) on Testosterone-7H Metaoclism and ONA Synthesis In tna Aat Prostata Gland, v.o. Edvards and j.a. ThoPaa, Procaaolngs 15th Annual Soclaty Toilcology, D. ial, 1976 (Abstract). An Interaction Batvean Prolactin ana Olhydrotastostarone (OhT) in tnt aat Prostata Gland and Saainal vaslclas. E.J. Keenan, p.a. Kiasa and j.a. Thoaas, fadaratlon Proceedings, 55: 270, 1976 (Abstract). Further Studies on the Role of Cycllc-Adenoslne-3',5'-onopnosonata (CAMP) In Mala Mousa Sax Accessory Organs. E.A. Zaop, J.A. Thomas ana J.C. Jones, Fadaratlon Proceedings, JJ: 7,,> l*7* (Abstract). Soae Pharmacological Asoacts of Morphine and Methadone. J.A. Thomas, Kh.S. Shanld-Sallas, B.K. Calasantl and B. Are*tan, Proc. Ten Vsnlavi Maoleal Congress, p. 2A3, April 1976, Shiraz, Iran (Abstract). Olaldrln and Parathion Interaction in the Prostata and Liver of tna Mouse. L.C. Schaln and J.A. Thomas, Journal Toxicology and Environmental Health i.: *29, 1976. Influence of Prolactin upon Nucleic Acid Metabolism in Accessory Sax Organs of Mala Mica. E.J. Keenan and J.A. Thomas, Proceedings SBtn Annual Cndrocinology Meeting, p. 328, June 1976 (Abstract). Effect of Isoproterenol and Acetylcholine Treatment in vitro on Cyclic Nuelaetldas in Mouse Sax Aeeaaaory Organs. E.A. Zspp and J.A. Thomas, Biochemical Pharmacology, 22' 919, 1976. Effect of Prolactin on the Metabolism of Androgens by the Aat ventral Prostata Cland in vitro. m.s.P. Mananenar and J.A. Thomas. Inveatlgatlva urology, is 20, 1976. Effects of Prolactin and/or Olhydrotastostarone upon the Aat Prostata Cland. J.A. Thoaes, M.S.P. Manandhar, E.J. Raenan, a.O. Edvards ana .. Kiass. urologies InternationalIs 21* 763, 1976. Saitura Olaordors In Children and Orugs used In the Management of Epllepay. J.A. Thoaas, C.R. Knotts, American Journal of School Heelt-. t 662. 1976. A Difference in the Responses of tna Mouae Prostata Cland and Seminal vesicles to Prolactin, p.a. Klase, E.J. Keenan, v.O. Edvaroa and :.> Thomas. The Pharmacologist, 21* 2A9, 1*76 (Abstract). HONS 025586 AuBl lest ion (eont. ): 19 perturoetlcn By Organoehlorlne Pesticides of 3H-testosterone Metabolis* in Rodent hepatic Mlcrosomes ana Prostate Glano l vitro. m.p. Oonovan, J.A. Thomas, L.C. Schaln, ana P.A. Klise. The Pharmacologist 18* 234 17 (Abstract). -- Effects of Olazinon, Parathlan ana CarBaryl on tha in vitro MetaDollsm of JM-testosterone oy Aodant Prostata Glands ana Haoatlc' Microsomal Enzymes. l.C. Scnein, J.A. Thomas, M.p. Donovan and P.A. Klasa. Tha Pharmacologist, 2*3, 1978 (Abstract). Seatcharo Plot Analysis of Androgan Binding In tha Mala Guinea Pig. Jcnwertr, J.A. rnomas, C.L. Robinette ana m.g. Mswninney. rna Pharmacologist, iJ: 230, 1978 (Aostract). F.i. Olhydrotastostarona and Estradlol-17 Bata Receptors in tha Pat ventral Prostata and Seminal vesicle. C.L. PoSTnette, J.A. Thomas aa m.g. Mswninney. The Pharmacologist, iSj. 2A, 1978 (Abstract). Cfftcts of Mybosla and Erythropoietin on Murine Solanlc Ornithine Oocsrboaylase Activity. M.ailson, j. Contrara and J.A. Thomas. The Pharmacologist, 1: 218, 1978 (Abstract). Cyclic AMP-Inaueed Changes in tha EEC and Behavior Effects of Morphine In tho Pat. Kh.S. Shahid-Salles, B.K. Colasantl, c.P. Craig ana J.A. Thomas. Tha Pharmacologist 1: 212, 1978 (Abstract). Cxgocryptina and Mala Acaasery Saa Organ Function. E.J. Keenan and J.A. Thamat. Proceedings 20th annual Nastarn Pharmacology Society, victoria, British Columbia, Jan. 28-29, 1977 (Abstract). Staroidophilie Proteins In Cytoplasm of tha Mouse Prostate Gland, m.p. Donovan, J.A. Thomas and L.C. Schoin. Federation Proceedings, 38: 3aa, 1977 (Abstract). Crfects of Prolactin on tha Oorsolateral Lobe of tha Pat Prostata Clano. J.A. Thomas and m.S.p. Monandhar, Investigative urology, 1: 39S, 1977. Proposed Modal for Assessing Anti-prostatlc Orugs Using a Transplant System. J.A. Thomas, P.0. Falica and a.O. Edwards. Tha Pharmacologist, 188, 1977 (Abstract). Erracta of Pestlddas on Steroid Mormons Binding In Cytoplasm of Rodent Tissues. L.C. Schaln, J.A. Thomas and m.p. Donovan. Society of Toalcelogy Procsadings, p93, March, 1977 (Abstract). Soma Actions of Parathlon and/or Oleldrln on Androgen Metabolism. J.A. Thomas, L.C. Schaln and M.P. Oonovan, Environmental Research, 13: 4*1, 1977. Morphine Analgasla and Tolerance: A Possible Pole of Cyclic amp. m.p. Oonovan, c.m. Ling and J.A. Thomas, p.h.o. Bulletin of Narcotics, 2: 9, 1977. Effects of Aging on ONA and Olhydrotastosterone-^H Formation in Pat Ventral Prostatas In situ and ventral Prostate Transplants. J.A. Thomas and *.0. Edwards. Experimental Carontology, 2*: 303, 1977. MGNS 025587 Publications (cant.): 2a Cocaine: Old Orug, Nex Problems. c.r. Keglcy ana J.A. Thomas, ;oer.;,Journal of Softool Health, *2: 600, 1977. Effects of androgens ano/or Prolactin on vantral Proitata Transplants .0. Edvards and J.A. Thomas, urolaglca Intematlonalls, 3_I: 303, 1777 A Biochemical Baals for Insactlcldo-lnducaa Cftangts In tna Mala Reproductive System. J.A. Thomas, m.p. Oonovan and L.C. Scnein, Proctaolnga 17tft Annual Soelaty of Toxicology, ol*3, 1978 (Aostract). Efftets of Zinc and Otftar Metal Ioni on tfto vitro Binding of Ancro*n to Cytoplasmic Protalns of Mouse Prostata Glana. m.p. oonovan, l.c. ' Scftaln and J.A. Tftoaas, Procaadlnga 17tft Annual Soelaty of Toxicology, 01B3, 1978 (Aostract). AOlllty of Paratftlon (P) To Lover Plasma Tastosterone and ComoetltUel, InftlBlt Binding of 01ftydrotastostarona>JH (oht-Jh) to nousa Prostata Baeaetors. L.C. Scftaln, m.p. Oonovan and J.A. Tftoaas. federation Procaadlngs j7: 286, 1978 (Abstract). Cffaeta of Androgans on Isoorotaranol-Inducad Ineraasas In Mousa Aecassory Sax Organ Cyclic AMP In vitro. E.A. Zapp and J.A. Tftoaas. Bloenaaleal Pftaraacolegy, J7: aZT, 1978. Cftaraetarliatlen of Cytoplasale Binding of Olftydrotastostarona By tna Prostata Cland and Otftar Tlaauaa of tfta Mousa. L.C. Scftaln, m.p. Oonovan and J.A. Tftoaas. Toslcalogy and Appllsd Pftaraacology, aa: la7, 1978. 01(2>otftylhaxyl) Pftthalata (OCHP) - A Report on Its Biological Effects (rev lev). J.A. Tftoaaa, T.O. Oarby, R.E. Wallin, p.j. carvln ana l. Mortis. Toxicology and Applied Pftaraacology a: 1.27, 1978. Saaa Toxicological Effaeti of fluorocarbon Aaroaols. J.A. Tftoaas ana c.r. Keglay. Tfta Aaarlcan Journal of Scneol Haaltft, a: aa3-aaa, 1978. Involvaaant of Brain Cyclic AMP in tfta Acuta and Cftronlc Effects of Merpnlna In tna Rat. Rhadljeh S. Sftanld-Sallas, Brands k. colasantl. c.R. Craig and J.A. Tftoaaa. Pftaraacology ^7: 128, 1978. Tfto Structura of U.S. Madlcal Softool Covornanca aa Oatsralnad by rnalr By.Lawa. J.A. Tftoaaa and J.t. Jonas, map Notes (Manageaant Advancanant Progrsa), Aaarlcan Association of Madlcal Collages. Suaaar, 1978. Asia of Ipldaalology In Toxicology. J.A. Tftoaas. fadaratlon Procaadlngs Jis 1879, 197*. Effsets of Postleldos on Matabollsa of Starlod Horaona By Rodent Llvar Mleroaoooa. M.P. Oonovan, L.C. Scftaln and J.A. Tftoaas. Journal of (nvironaantal Pathology and Toxicology, J: aa7, 1978. Saaa Pftoraocologle Aspects of flouridas in Oantlstry. A.A. Craca ana Tftoaas. dost Virginia Oental Journal, 22> !*** uptake of Radloactlvs Zinc (*Zn) Into Rodent Sax Accessory Tissues. M.p. Oonovan and J.A. Tftoaaa, federation Procaadlngs 21> 1979. HONS 025588 eceharln. p.R. Felice ana J.A. Thomas, American Journal of Scnool ealtn, : 28a, 1979. ffeets or Monoetnylnexyl pntnalate (mehp) on Pregnant Rabbits ana Tnir ffsorlng. j.a. Thomas, P.R. Felice, p.k. Guota, L.G. Scnein ana r.e. cCafferty, Proceealngs 18th Annual Society of Toxicology 33: 45, 1979. allure of Monoetnylnexyl Phthalate (mehp) n Offsoring of Raooits. J.A. Thomas, L.G. cCafferty, P.R. Felice, ana m.p. Oonovan. narmacology 5^: 523, 1979. to Cause Teratogenic ETfects Seheln, p.k. Guota, P.E. Toxicology ana Aoolleo loalstrlButIon of Honoethylhexyl Phthalate (MEHP) In Pregnant Rabbits nd Neonatal Pats. J.A. Thomas, L. Martls, S. Glovenetto, P.E. McCafferty >nd M.P. Oonovan. Federation Proceealngs 22:525, 1980 (Abstract). Iffeeta of Zinc Ion on Fructose in the Male Sex Accessory Organs of the touse. Michael P. Oonovan and John A. Thomas. Federation Proceedings 39: i9l, 1980 (Abstract). lame Antlsnorogenic Actions of Zinc Ion in the Mouse. M.p. Oonovan ana ).A. Thomas, Proceeding 19th Annual Society of Toxicology, 1980 lAastrsct). Inhibition of Androgen-Receptor Interaction in Mouse Prostate Gland lytosol by Divalent Metal Ions. m.p. Oonovan, L.C. Schein and J.A. Thomas. Molecular Pharmacology W.: 154, 1980. zrfeet of Prolsetln and Testosterone Adsilnlstratlon on ths Maintenance of ventral Prostate Transplants Into Intact or Conadeetomlied Mels and Fsaale Syngeneic Pets. e.O. Edeerds and J.A. Thomas, urological 'nternatlonalls 21= * 1*80. .'fact of Pharmacology Oosos of Sex Steroids on Endogenous Zlne in Rodent accessory Sex Organs, m.p. Oonovan and J.A. Thomss, Ths Pharmacologist, 22: 289, 1980 (Abstract). Morphologic and Metabolic Characteristics of ventral, Oorsal, Lateral and Anterior Prostata Loba Transplants in Pats: Effscta of Testosterone and Prolactin. e.O. Edvards and J.A. Thomas, Hormone Research, 12: 28-29, 1980. Interaction of Cadmium and Zinc in Intact and Castrate Pats. m.p. Oonovan, m.p. vaalkes, and J.A. Thomas. Federation Proceedings, A: 939, 1981 (Abstract). Effect of Cadmium on the Subcallular Distribution of Endogenous Zinc in Fetal and Meternal Rabbit Liver, m.p. vealiies, J.U. Bell, and J.a. Thomas. Feooratlon Proceedings, a: 701, 1981 (Abstract). Failure of Monethylhexyl Phthalate (mehp) to srfoct Gonadal Zinc or Ona or ana Levels In the Mouse. k.A. Curto and J.A. Thomas. Proc. Sac. Tox. 1: 103, 1981 (Abstract). Reproductive Hazards and Environmental Chamlcals. J.A. Thomas. Toxic Substances Journal, 2:319. 1981. HONS 025589 22 PuBUcatlons (eont.): Effect of Monoatnylftasyl Pnthalata (mchP) on tno Asslallatlon 0f 2^-45 By Rodent Reproductive Organs In vitro J.A. Thoaas, K.A. Curto mo * aaalkes. Elgntn Intarnatlonal Congress of Pharaacology, Tokyo, jBln 1781 (Apstract). ' ETfaet of Prolactin on ONA Synthesis and Growth of tna Accassory Se< Organs In Mala Mica. E.J. kaanan, Patricia A. Klasa ano j.a. Thoaas. Journal of Endocrinology 108:170-178. 1981. Introductory Aaaarks:Tha Tastas. J.A. Thoaas. Envlronaental Haaltn Parspactivas 21:3'*> Effacts of Cyprotarona Acatata on Rat vantral Prostata Transolsnt Croatn. J.A. Thoaas, a.O. Edwards and P.R. Failed. Endocrlnologia Eaparlaantalls, i2:171, mi. Intaractlon Bataaan Prolactin ana Androgens In tha Accassory Sax Organs of Mala Mica. C.J. Kaanan, Patricia A. Klasa and J.A. Thdaas. Journal of Enooerinology, 80:323, 1881- MONS 025590 23 ARTICLES IN PRESS: Effect of Pesticides on Metaoollsm of Sterlod Hormones oy Rodent Liver Mierosomes. m.p. Oonovan, u.C. Schein and J.A. Thomas, Journal of Toxicology ana Environmental Health ___ : ___, 1982. Effects of Pesticides on Jw-oinyorotestosterone Binding to Cytosol Proteins from various Tissues of tne Mouse. L.C. Scnein, m.p. Oonovan, J.A. Thomas and P.R. Felice, Journal of Environmental Patnology ana Toxicology ____: ____ , l82. Endocrine Toxicology. J.A. Thornes and J.u. Bell, in methOOS in TOXICOLOGY, A. xallsce Hayes, Edit., Beven Press __ :____ , 19B2. Itultary Hormones, J.A.Thomas, in PHARMACOLOGY ANO therapeutics, S.h. -chan and R.P. Malckel, edit., C.v. Mossy and Co. 1982. Male Gonadal Hormones and Anabolic Steroids, J.A. Thornes, In pharmacology ANO THERAPEUTICS, S.N. Pradhan and R.P. Malckel, edit., C.v. Mosby and CO. 1982 Electrophoretic Analysis of 3M-Olhydrotestosterone Binding In the Cytoplasm of the Mouse Prostate Gland and tha Effects of Pesticides. Pat Felice, M.p. Donovan and J.A. Thomas. Journal of Environmental Pathology and Toxicology, __ : ___ , 1982. Effect of Dlethylhexyl Phthalate (OEHP) or Monoethylhexyl Phthalate (MEHP) on Mouee Reproductive Organs. K.A. Curto and J.A. Thomas. Tealcalegy snd Applied Pharmacology,____1982. Tealclty and MettBollsm of MCMP - A Survey of Recent Literature. J.A. Themes and S. Northup. J. Toxicol. Environ. Health ____: , 1982. Assessment of Gonadal Toxicity From Chemical Exposure In tne Dork Place. Proceedings Canadian Society of Toxicology ____ :___, 1982. HONS 025591 Articles In Press (cant.): MfHP/OEMP:Conadal Toxicity and Exacts on Rodent accanery Se Organj, Jonn A. Thoaas, Karan A. Curts and Mlcnael J. Thoas. Environment*; wealth Perspectives ____:___ . 1982. Failure of Pntnalaea Acid Estars (PAE) To Stiaulate Lipid Peroxidation ,, Rat Paoroouctlva Organa, a.c. Brogan, ill, k.a. Curto and j.a. rnoeas." Procaaolnga mn Annual Soelaty of Toxicology (Apstract) 1982. furtnar Studlai on tna Effacts of tna Phtnalata Acid Estars (PAE) on sat Mala Pasroouetlva Organs. K.A. Curts, A.C. McCafferty, m.p. Oonovan ,ra J.A. Thoaas. Procaaolnga 19tn Annual Soelaty of Toiicalogy (Apstract) 1982. CsdMiua-Induced Prostata Matallotnisnain in tna Rabbit, m.p. aaalues. M.P. Oonovan and J.A. Thoaas. Tha Prostata, 1982. Effects of Lead on tna Mala Reproductive Tract, j.a. Tnooas ana Brogan, III, Aaerlcan journal Industrial Modlclna __ :___, 1982. Enftsneeaent of Iron-Induced Testicular Llold Paroxidation (lp> By 01-(2-Etnylnayl) Pntnalata (OEMP) or Otatary Zinc Oaflciancy. x.C. Brogan, III, K.A. Curto, and J.A. Tnooas. fedoration Procaadlngs (Adstract), 1982. MO NS 025592 -25- BOCKS UNO CHAPTERS: 5YNGPSIS OF ENOOCAINE PHARMACOLOGY. J.A. Thomas ana M.c. Mawhinnry, University Park Press, Baltimore, Maryland, 197?. Cyclic ? ,5'-Aaenoslne Monopnospnate-Adeny1 Cyclase System in Prostate Glands anti Otner Anaragen-Oependent Tissues. A.L. Singhal, J.A. Thomas ana O.J.B. Sutnerlana, NORMAL AnO ABNORMAL GROvTh OF The PROSTATE. Cnacter 25, p. 445, C.C. rnomas ana Co., Puol., 1974. Some Actions or Prolactin on the Metabolism of Testosterone-H? tn Prostata Claras or tnt Rat ana Oog In vitro. J.A. Thomas, *.G. a.ni-nv and J.. Lloyd, in normal ANG abnoamIl oHieTH of the prostate. Chapter 21, p. 53, C.C. Thomas ana Co., putil., 1974. MOLECULAR MECHANISMS OF CONAOAL HORMONE ACTION - Advances in Sea Hormone Msaarcn, volume I. J.A. Thomas ana a.l. Slngnal, editors, university Park Press, Baltimore, Maryland, 1979. Effect of Pesticides on the Reproductive System, j.a. Thomas, in MOLECULAR MECHANISMS ON CONAOAL HORMONE ACTION - Advances In Sei Hormone Aesearcn. J.A. Thomas ana A.L. Slngnal, editors, University Park Press, Baltimore, Maryland, 197S. Introduction to the Endrocrlnes. J.A. Thomas and J.E. Jones, in the ESSENTIALS OF PHARMACOLOCV, John A. Sevan, editor. Harper and"7oe, 197(. Pituitary noraonas, J.A Thomas and J.E. Jonas, In THE essentials of PHARMACOLOCY, John A. Bavan, editor, Harper and~Ro, 197A. Thyroid and Anti-Thyroid Oruga. J.E. Jonas and J.A. Thomas, In the essentials OF PHARMACOLOCY. J.A. Bavan, editor. Harper and Roe, 1971. Insulin end Oral Hypoglycemic Drugs. J.A. Thomas and J.E. Jones, In the ESSENTIALS OF PHARMACOLOCY. J.A. Sevan, editor, Harper and Roe, 1?T. Adrenal Cortical Steroids. J.E. Jones and J.A. Thomas, In the essentials OF PHARMACOLOGY. John A. Bavan, editor, Harper and Roe,"1976. Androgens and Estrogens. J.E. Jonas and J.A. Thomas, In THE ESSENTIALS CF PHARMACOLOCY, John A. Bavan, editor. Harper end Roe, 1776. Orel Contraceptives. J.A. Thomas and J.E. Jonas, In THE ESSENTIALS OF PHARMACOLOCY, John A. Bmvan, editor, Harper and Roe, 1976. CELLULAR MECHANISMS MOOULAT1NC CONAOAL ACTION - Advances In Sea Hormone Rasaareh, volume II. R.L. Singhal and J.A. Thomas, editors, University Park Press, Baltimore, Maryland, 1976. Prolactin Influancsa Upon Androgen Action In Mala Accessory Sea Organs. J.A. Thomas and E.J. Keenan, n CELLULAR mechanisms modulating COnaoal ACTION - Advances in Sea Hormone Research, vol. II, pp. 425-470. R.L. Singhal and J.A. Thomas, editors, university Park Press, Baltimore, Maryland, 1976. HONS 025593 26 Books and Chanters (cont.): REGULATORY MECHANISMS AFFECTING CONAOAl HORMONE ACTION - Advances ;n u. Hormone Research vol. Ill, J.A. Thoaas end r.l. Singnel, tall., university fir* Press, Saltiaore, Merylsnd, 197t. effect of Nercotics on the Reproductive System, J.A. rnoass. k.s. Shenid-Selles and H.e. Oonovsn, in REGULATORY mechanisms affecting CCnAOAl hOAnONC ACTION - Advances in Sex Horaone Reseeren, vol. Ill, Thoaas end A.L. Slngnal, editors, university Perk Press, Baltimore, "dryland, l7f. Effects of Lead on tne Aeeroouctive Systea. j.u. Sell and j.a. rnoaas ASIC AnO clinical TOXICOLOGY OF lEAO, a.l. Slngnal end J.a. rnoaas. ~ adit., uroan A Scnverienoerg Medical Publishers, Seltiadte, Maryland. IPSO. SASIC ANO CLINICAL TOXICOLOGY OF LEAO, R.L. Slnghsl and J.A. Thomas, adit., urban A Scnverienoerg Medical Publishers, Baltimore, Maryland. ipso. Soae Protein.Heavy Metal Interactions in the Rodent Prostate Cell. j.a. Thoaas, m.p. Donovan and m.p. xoalkee in the PAOSTAric cell, Murony. G.P., Sandberg, A.A. and Karr, J.P. adit., a.A. Lias Publlsners, USi. Introduction to Endocrine Therapy. J.A. Theaaa In mooean pmaamacolQGy, C.A. Craig, and R.E. Stltiel, edit.. Little Breen Publ. lMl. Estrogens, Oral Contraceptives and Progaatlns. J.A Theaas in mooern PMAAMACXOCY, C.A. Craig and R.E. Stltrel, adit., Little Brovn Pub. Isi. Thyroid and Parathyroid. J.a. Theaas, m mooean pharmacology, c.a. :rn; and R.E. Stltrel, edit.. Little Srown fuel, ifSI. MONS 025594 AUOIO-VISUAL MATERIALS: -27- Slology ana Orugs, J.A. Thomas. 38 minuets, black ana unite: video 'act e.V.U. Film, 1872. ' Pharmacologic.Actions of C.n.S. Depressants (Pharmacology laBoratory tatrclsa). J.A. Thomas and M.C. Meehinney, a7 minutes, black and unite: video Tape, u.v.u. Film, 1973. Pharmacology of Pituitary Hormones. J.A. Thomas, 58 minutes audio tape cassette. Medical Science Taoe Library, Nee Yore, n.y., 197a. 'harmacology of Thyroid Hormones, Antl-Thyrold Orugs and Parathyroid <ormone. J.A. Thomas, 98 minutes, audio tape cassette, Medical Science Taps Library, Nee York, N.y., 197a. Insulin and Hypoglycemic Agents, J.A. Thomas, 9* minutes audio taoe easaettt, Medical Science Tape Library, Nee York, n.y., 197a. Pharmacological use of Adrenocortical Steroids, J.A. Thomas, a9 minutes audio tape cassette, Medical Science Tape Library, Nee York, n.y., 197a. Pharmacological use of Androgens and Estrogens, J.A. Thomas. 92 minutes audio tape cassette, medical Sclenca Tape Library, Nee York, n.y., 197a. Oral contracsptlves, J.A. Thomas, so minutes audio tape cassette. Medical Science Tape Library, Nee York, n.y., 197A. Mlstopsthology of the Human Prostate. m.T. smith and J.A. Thomas (108-2* a 2" photomicrograph set of light and EM slides) Technomies Publishing '1 Company (Health Science Division), eestport. Conn., 1977. HONS 025595 CWA SIAFE UNIVERSITY LIBRARY -28MANUSCPIPTS SUBMITTED ANO/OP in PBEPAPATION; Effect of MCA on tno ON* Synthesis, 5H-T*stosttron# Httigollla, ano Morpnology in th* Pit Prostit*. .0. Edmaras ana J.A. Thomas. Alterations in 3h-Testosterone Metabolism, On* Synthesis, mo Morphology in th* Pat Prostit* folloulng rrntimt .itn Colliginisi and/or ^Carcinogens (OMBA and MCA). *.0. Cameras and J.A. Thomas. , `,i If Tact;of OMBA on tna aalghts, ONI Synthesis, 5M-Testost*ron* Mataoollsm, and Histology in tn* Pat Prostata. J.A. Thomas ana v.o. Donor Hoat Aga on vantral Prostata Transplant Survival. .o. J.A. ThOMI. Effect of ENU on th* Morphology and Metabolism of T*stosleron*-JH in tna,Pat Prostata. a.O. Edmsrds and J.A. Thoaas. Hormonal Influane* upon th* Morphology or Pat vantral Prostata Transolants. a.o. Edmaras and J.A. Thoaas. Crgocryotlna and Prolactin Influancas Upon Mala Aecassory $* Organs. I.J. Kaanan, p.a. kiss* and J.A. Thoaas. TEXTBOOK OP ENOOCP1NC PHAPMACOLOCT, J.A. Thoaas and E.J. Kaanan. UrOan a Sehaarianparg Madlcal Publishers, Oaltlaota, Maryland (In preparation). Effacta of Pastlcldaa on XM-Oihydrotestostaron* Binding to Cytosol Protein In various Tlssuas of tn* Mouse. L.C. Schain, m.p. Oonovan ano J.A. Thoaas. Th* induction of Tuaors In Pat vantral Prostata Epithelial Transplants. *.D. Edmaras ano J.A. Thoaas. Allergic Paactlons Caused by Hormones or Mormona-llk* Drugs. J.A. McGovern, C.P. Knotts and J.A. Thoaas. Soma Protaln.Haavy natal Interactions in th* Pat Prostatle Call. J.a. Thoaaa, m.p. Oonovan and m. aaalkas. Induction of Notallotnionoln In th* Pat Oraln by Coooar-Inplsntatlon out not by Cob*lt*!aplantatlon. M.P. aaalkas, S.n. Pass, C.P. Craig ano J.a. Thoaua. 4 irt") HONS 025596 Annual Rapoit on Carclno9na (jcdj (U.8.) National Toxleolo9y Program Kaaaarch Trianfla Park, NC Oae 17 FB]-mi5S 81. PdputMi* b< Coawwrea MM tWKM MWMMR NOflCf N! MOWS 0^559 7 BIBLIOGRAPHIC INFORMATION PB83-1358SS Annual Report on Carcinogen* (3rd). Dec 82 PERFORMERi National Toxicology Program, Reaearch Triangle Park, NC. NTP-82-330 See alao PB82-228B08. The Third Annual Report on Carcinogen*, prepared by the National Toxicology program (NTP), U.S. Public Health Service, la lamed by the Secretary of the Department of Health and Human Service* (DNHS), purauant to Public Law BS-122 of November 8, 1878. Thia law require* the Secretary to publiah an Annual Report which contain* 'a list of all substance* (1) which either are known to be carcinogen* or which may reasonably be anticipated to be carcinogens and (il) to which a significant number of persons residing in the United States are exposed)....' Annual Reports should also provide available information on the nature of exposures, the estimated number of peraora exposed, and the extant to which the implementation of Federal regulations decreases tne risk to public health from exposure to these substances. KEYWORDS: `Carcinogens, `Toxicology, `Toxic substances. Available from the National Technical Information Service, Springfield, Va. 22161 PRICE CODE: PC A1S/MT A01 1 HONS 025598 Third Annual Report on Carcinogens December 1982 VSf'ONAl TfCMNICAl INfOKMATION SfKVICf 'SSSSSi'* U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES PuMc Health Service HONS 025599 THIRD ANNUAL REPORT ON CARCINOGENS DECEMBER 1982 Pursuant to $<tlon 30lib) (4) of thf Public Health Sfvk* Act at Amcndeo by Section 2*2, PI 95*t22 Prepared by the National Tc<colofy Projram U.S. DIPAtlMCNT OF HCAtTH AND HUMAN SERVICE! Public Health Service n HONS 025600 TABLE OF CONTENTS 1. EXECUTIVE summary 11. INTRODUCTION III. SUBSTANCES LISTED A. lUt of Substence* 6. Individual Substances IV. REQUESTS TO OHMS FOR RESEARCH ANO TESTING, AND TO PROVIDE INFORMATION V. AFFENOIXES A. Alphebetlzed Synonym end Tr*d Neeie lndes to tht Subttences Listed 8. Clossery, Acronyms, end Units of Metsureaent C. List of SobstihcRS *nd Their Synonyms tnd Trede Neaes 0. Perttclpents E. Cuauletlve Index to the Annuel Reports on Cerclnogens Peje 1 S 17 17 21 285 A-l B-l C-l 0-1 E-l HONS 025601 111 EXECUTIVE SUMMARY Tht Third Annul Report on Carcinogens, prepared by the National Toxicology Program (NTP), U.S. Public Health Service, It Issued by the Secretary of the Department of Health and Human Services (dhh$), pursuant to Public lav 95-622 of Noveater t, 1978.' This lax requires the Secretaiy to publish an Annual Report which contains *a list of all substances II) which either are known to be carcinogens or which may reasonably be anticipated to be carcinogens and <11) to which a significant number of persons residing In the United States are exposed!....* Annual Reports should also provide available Information on the nature of exposures, the estimated number of persons exposed, and the extent to which the Implementation of Federal regulations decreases the risk to public health from exposure to these substances. For the purpose of this Report, `known carcinogens* are defined as those substances for which the evidence from htaaan studies indicates that there Is a causal relationship bttween exposure to the substance and taaaan cancer. Substances 'which may reasonably be anticipated to bo carcinogens* are defined as those for which there Is a limited evidence of carcinogenicity In Inaaans or sufficient evidence of carcinogenicity In experimental ontaals. Substances In the above categories, for which exposure of persons residing In the United States has been oemonstrated, are included In the Report. Also included are some substances which have been banned, or the use of which has been restricted, because people previously exposed are poterttally at risk, or because tome of those substances still remain In the envlroseent. Tht Third Annual Report does not contain all known or reatonabl) anticipated carcinogens. Additional substances with identified carcinogenic properties will be Included in the subsequent Annual Reports. Several problems are encountered in developing the Information required for the Annual Reports on Carcinogens. Estimating tht number of people exposed to a substance and identifying the nature, route, and Intensity of exposure are difficult tasks. It Is often Impossible to obtain accurate production volimus and use patterns for most chemicals. The Information that Is being collected by the U.S. Environmental Protection Agency under the Toxic Substances Control Act, at least that part which Is public recore, any assist In obtaining more accurate exposure estimates In the future. In addition, the forthcoming Nations! Occupational Exposure Survey** will provide new Information on the extent and degree of exposure for different substances and manufacturing processes. * Section 262, Paragraph (4). ** An update of the National Occupational Hazard Survey conducted from 1972 to 1974 by the Centers for Disease Control/National Institute for Occupa tional Safety and Health (CDC/N10SH). 1 HONS 025602 Perhaps the hardest task In preparing this P.eport ft to evaluate the effectiveness of Federal regulations In decreasing the risk to public bealtn. one reason is that virtually all Federal lavs concerned with reducing risk have been enacted within the last IS years. Thus, given the relatively long period between eapotwre to a carcinogen and the onset of disease, the extent to which the regulations Implemented during these IS years have reduced the risk renalns unknown. Another reason ft that reliable Information on past taposures which could be used as a baseline for estimating future risk reduction Is generally not available, nonethe less, decreasing eaposure should be considered as reducing carcinogenic risk even If the reduction cannot be quantified at present. The Third Annual Report lists 117 agents. Included are the entries free the Second Annual Report and 28 additional substances or groups of substances The new entries were chosen frost those designated by the Agencies participat ing In the preparation of the Report,* froa those tested within The National ToaleoUgy Program and the National Cancer Institute Carcinogenesis Ifoassay Program,** or from those evaluoted by the International Agency for Research on Cancer (1ARC), a part of the World Health Organization (WHO), located In Lyon, France. Of the 117 entries, nineteen substances or groups of substances and three technological processes are listed as 'known carcinogens': 4-Anlnoblphenyl Arsenic and certain arsenic ccnpounds Asbestos Auranlne oanufactura bentene benzidine N ,N-01$(2-ehlorethy1)-2-naphthyl aal ne (Chlornaphaslnc) 8fs(ehloro*ethy)lather and technical grade chloromethyl methyl ether Chlorambucil Chrcnlua and cirtaln chromium compounds Coke oven emissions Cyclophosphamide Dfethylstllbestrol Hematite underground mining Isopropyl alcohol manufacture (strong-acid, process) Melphalan Mustard gas 2-Naphthyl amine Nickel refining Soots, tars, and mineral oils Thorium dioxide Vinyl chi.ride * COC/niosh, consumer Product Safety Commission (CPSC). U.S. Environmental Protection Agency (EPA), Food and Drug Amalnlstratlon (FDA), National Institutes of Health/National Cancer Institute (N1N/NCI), National Institutes of Health/Natlonal Institute of Environmental Health Sciences (NIH/MENS), National Institutes of Health/Natlonal library of Medicine (N1H/NIM), and U.S. Department of Labor/Occupetlona! Safety and Health Adainlstretion (OOL/OSHA). ** Now part of NTP/N1EHS. 2 PICKS 0^5603 ninety-ftvt substances er groups of substances are Included because they `ay reasonably be anticipated to be carcinogens.' Nickel appears in both lists because occupational exposure asssclatsd with nickel refining is known to be carcinogenic although specific substances which nay be responsible for the carcinogenesis In humans have not yet been Identified; and elemental nickel and certain nickel compounds may reasonably be anticipated to bo carcinogens. For each substance or technological process, there Is a summary descrip tion including a synopsis of the evidence that explains inclusion In this Report. This Is followed by a collation of regulatory Information received from the participating Agencies. Among the 117 entries, two are natural substances which are not used or produced commercially: aflatoxins ind cycasin. Two are food or cosmetic additives: saccharin and safrole. Safrole has been banned for most uses. The use of saccharin has been continued by Congressional mandate. Twelve pesticides are listed: amltrole; Aramlte*: arsenical pesticides; l.t-dlbremo-3-rhloroprepene; hOMChlorobenxene; kepone"; lindane and other hexachlorocyclohexane Isomers; mlrex; nltrofen; su)fall ate; toxaphene; and l,4,*-tr1chlorofhenol. Host of these substances hare been banned or limited In use. There are IS therapeutic substances: N,M-bis(2-chloroethy11-2naphthylamine; chlorambucil; cyclophosphamide; dlethylstltbestrol; Iron dextran complex; melphalan; oxymethclone; phenccetln; phenazopyrldlne hydrochloride; phmytoin; procarbazine; reserplne; selenium sulfide; streptozotocln; and tr1s(l-az1r1d1nyl)phosph1ne sulfide. Two of these substances are no longer produced or used In the United States: u.K-bls(2-chloroethyl)-2-nephthylw<nt and streptozotocln. Six art antlcancer agents: chlorambucil, cyclophosphamide, dlethylstllbestrol, melphalan, procarbazine, and trlsll-azlrldlnylIphosphlne sulfide. The remaining (3 substancta may be classified as vsrtous Industrial chemicals and by-products (2S); dyes, dye Intermediates, and pigments <191; combustion products (13): solvents (6); eetals and metal compounds occurring In mining, extraction, and refining processes (<); analytical and research chemicals IS); and chemicals used for miscellaneous purposes (9). The three occupational exposures known to be carcinogenic are those estocl.'.tcd with the manufacture of auramlne, the underground mining of hematite, and thy manufacture of Isopropyl alcohol by the strong acid process. Scientific knowledge and judgment play Important roles In grading the available evidence of carcinogenicity as sufficient, limited, or Inadeouate. Similarly, In all but one category of substances, regulatory action is an Interpretation by the regulators of their Congressional mandates. The sole exception Is the deliberate addition of additives ar.d colors to foods. The HONS 025604 3 Delaney clause In the Food Additives Amendsent of 1954 to the Federal Food, Drug, ond Cosmetic Act retires that 'no additive snail t> deemed to be safe <f It Is found to Induce cancer ulien ingested by man or anlnal. or If It Is found, after tests which are appropriate for the evaluation of the safety of food additives, to Induce cancer In man or animals;___ "* Reguests to DHHS for conducting research, testing for carcinogenicity or providing Information on the effects of standards or regulations on public health are Included In the Report as received; this Is regulred In clause (1), subparagraph (4)(D) of Section 262. Appendix A Is an Index of synonyms and trade names to Identify substances known under a variety of different names. Appendix R contains a glossary of freguently used terms, a list of commonly used acronyms, and some coauon units of measurement. Appendix C lists the substances, group of substances, nd technological processes contained in the Report and tabulates the synonyms and trade names for each of them. Appendix 0 Is a list of partici pating Agencies and their staff sdio collaborated In the preparation of the ThlrJ Annual Report, and Appendix E contains a cumulative Index to the Annual Reports on Carcinogens, Corrections or suggestions, as well as any additional Information that the reader may have should be tent to the Director, National Toxicology Program, P.0. Pox 12233, Research Triangle Park, North Carolina 27709. Saamorles of this Repoit may be obtained from the Public Information Office, National- Toxicology Program, 02-04, P.0, lox 12233, Pcsearch Triangle Park, North Carolina 27709. Copies of the complete report are available for a fee from tkr National Technical Information Service, S29S Port Royal Road, Springfield, Virginia 22161. Reguest number PR 83-135655 should be Indicated. * So far only two substances have been banned on the basis of the Delaney clause: Flectol H In 1967 and chloronlllne In 1969. According to the FDA, both substances were used to make adhesives for food packaging material. 4 HONS 025605 INTNODUCTIOM Cancer is th* second most common cause of death in the United States. One In ever/ four Americana will suffer from cancer sometime during their lifetime; one in every live will die from cancer. In 1971, more than 400,000 Americana died of cancer.* in addition to the physical and emo tional suffering caused by cancer, this disease may cost the Nation at much at ISO billion each year in lost production and Income, medical expenses, and research resources. For these reasons, the American public It concerned about cancer and cancer haaardt, especially about ways to prevent the occur rence or decrease the incidence of cancers. Contrary to popular belief, cancer is not one but many diseases which my have different causes. Most scientists now consider that about one-third to two-thirds of all cancers are associated with the environment in which we live and work. In this context, the environment is understood as `anything that interacts withjuimans, including substances eaten, drunk, and smoked, natural and medical radiation, workplace exposures, drugs, aspects of sexual behavior, and substances in air, water, and soil.** Soma cultural and behavioral patterns, spart from defined habits of smoking and alcohol consvaption. My significantly influence the development of tiaaors in the gastrointestinal tract, breast, uterus, and prostate. These aspects of sects! environment, personal behavior, and habits are sometimes called `lifestyle.* Although we rarely know the environmental factors and condltiens which arc responsible for the development of specific cancers, in some cases we are beginning to have tome understanding. Most cancers that art associated with the environment should be avoidable, at least potentially. Development of cancer also depends on `host factors.* Host factors art attributes of human organisms associated with individual differences in the risk of developing a specified cancer. A host factor may be associated with reduced risk of a cancer, not only with Increased risk.3 Examples of host factors are immunological and endocrine (unctions, nutritional status, genetic constitution, age, and sex.4 As Americans have become more and more concerned about the enviromnent and cancer, they have repeatedly asked the Federal Government to clarify what is known about cancer-causing substances. The public wants to know and should know which substances are retarded as cancer hazards in the work place and in the general environment and how well we are protected from exposure to these substances. HONS 02560b S Section 262 of Public Low 95-62; of Hovember 9, 1978* reflect* the requests -for thli Information. Paragsaph (4) of thfi section stipulates that the `Secretary shall puOllsh an annual report which contains "(A) a list of all substances (I) uhlch either are known to be carcinogens or nay reasonably be anticipated to be carcinogens and (M) to which a signif icant hunger of persons residing In the United States are exposed; *|R) Infonoatlon concerning the nature of such exposure and the estimated nisaber of persons exposed to such substances; *{C) a statement identifying (1) each substance contained In the list under subparagraph (A) for which no effluent, ambient, or exposure standard has been established by a Federal agency; end (11) for each effluent, ambient, or exposure standard estcbllshed by a Federal agency with respect to a substance contained In the list under subparagraph (A), the extent to which, on the basis of available medical, scientific, or other data, such standard, and the Implementation of such standard by the agency, decreases the risk to public health from exposure to the substance; and "(D) a description of (I) each request received during the year Involved - *(l) from a Federal agency outside the Department of Health, Education and Welfare for the Secretary, or *(!>) from an entity within the Deparbaent of Health, Education and Welfare to any other entity within the Department, to conduct research Into, or testing for, the carcinogenicity of substances to provide Information described In clause (11) of subparagraph (C), and (11) how the Secretary and each such other entity, respectively, have responded to each request." Annual Deports on Carcinogens are Issued In response to these require ments. these reports discuss substances or technological processes which arc known to be carcinogens or which may reasonably be anticipated to be carcin ogens; they contain Information received from Federal agencies participating In the preparation of the Reports. * Community Hants! Health Centers Act, Maendnents. 6 HONS 025607 Participants Within the Department or Health and Huntn Services, th< responsibility for preparing these ennuel r*ports hot Peon delegated to the National Toxicology Program.* Other agencies participating In this effort ere: Centers for Dlseese Control/National Institute for Occupetlonal Safety and Health (C0C/W10SH) Consumer Product Safety Conmlsston (CPSC) U.S. Environmental Protection Agency (EPA) Food and Drug Aihnlnlstratlon (FDA) National Institutes of Health/Natlonal Cancer Institute (N1H/NCI) National Institutes of Health/Natlonal Institute of Environmental Health Sciences (N1H/MICHS) National Institutes of Health/National library of Medicine (NIH/NIM) U.S. Department of Ubof/Occupailonal Safety and Health Administration (OOL/OSHA) Four of these agencies -- CPSC, EPA, FDA, and OSHA -- are responsible for regulating hatardous substances and limiting the exposure to and use of such substances. Identifying Carcl-aoens For many years Government research agencies, Industries, universities, and other research organisations have studied various substances to ascertain those tdtlch might cauce cancer. Other Federal agencies have been developing Information on exposure and potential haiards and making rules and regulations to control substances which have been Identified as carcinogens. The largest single national testing effort, the National Cancer Institute's Carcinogenesis lasting Program, has now become a part of NTP/NICNS. The NCI Clearinghouse on Environmental Carcinogens, conslstl'j of a panel of experts from governmental and non-governmental Institutions, has reviewed the NCI testing results, and un analysis of results of NCI carcinogenesis bio assays of IDO chemicals has recently been published.' Tne Technical Reports Review Subcommittee of the NTP board of Scientific Counselors, augmented hy an ad hoc panel of experts In chemical carcinogenesis, has now replaced the MCrClearlnghouse as the body of non-government experts conducting peer reviews of the NTP carcinogenesis bloassay results. DHHS agencies participating In NTP are NIH/NCI; NIH/N1EHS; FOA/Natlone! Center for Toxicological Research (FOA/NCTR); and C0C/N10SH. 7 MOMS 025608 Many of the substances listed In the Third Annuel Report on Carclmgens hove been chosen fro* tne "IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans* published by the International Ag..r.cy for Research on Cancer i I ARC) In L/on, frame.* Each monograph Is the product of an indi vidual working {roup of experts In chemical carcinogenesis and related fields. The eaperts evaluate the data for each substance Included In a monograph. The evaluation Is based on the published Information available at the time the working group meets. A Joint 1ARC/WHO ad hoc Working Croup met In October 1077 to review and revise the criteria 7or~Judgtng the adequacy of available data. The terms `sufficient evidence' er.d 'limited evidence' or carcinogenicity used In these criteria refer only to the amount and adequacy of the available evidence end not to the potency of carcinogenic effect or the mechanisms Involved. An updated version of these criteria Is Included In eech 1ARC Mono graph Volume. The 1ARC Monograph Supplement 4 contains re-evaluations by an ad hoc working group of all chemicals, Industrial processes and occupations! eaposures for which some data on carcinogenicity In hunans are avelleble either In the first 29 voliaaes of monographs or In other subsequent publications.* A direct cosipartson of the 1AAC evaluations* and the evaluation of HCI/VTP bioassay results* cannot be made because different criteria were used to assess the evidence; but these criteria can be related.2 Such evaluations Involve a component of personal judgment. In some cases the available evident moy be assessed differently depending on the criteria used and the composition of the group of experts. Clause (1) In subparagraph (A)(4) of Section 262 requires *a list of all substances which are either known to be carcinogens or may reasonably be anticipated to be carcinogens.* For the purpose of this report, the fwo categories In the law -- known to be carcinogens and reasonably anticipated to be carcinogens -- relate to the IARC criteria fer the degree of evidence* as follows: 1. Known to be carcinogens: There Is "sufficient evidence of carcinogenicity* from studies in humans `which indicates a causal relationship between the agent and huaan cancer.* 2. Reasonably anticipated to be carcinogens: A. There it `limited evidence of carcinogenicity* from studies in humans, `which Indicates that causal Interpre tation is credible, but that alternative explanations, such as ohance, bias or confounding, could not adequately be excluded.* or ' * The IARC address Is: ISO, esurs Albert-Thomas, 69372 lyon Cedes 2. France. WHO/IARC Rubllcatlons may be obtained from who Publications Centre USA, 49 Sheridan Avenue, Albany, Mew fork 12210. HONS 02S6O9 8. There It "sufficient evidence of carcinogenicity* froe studies In experimental animals 'which Indictees that there It an Increased Incidence of aia)1(ntnt turnon: (a) In Multiple species or strains, or (h) In Multiple experl*entt (preferably with different routes of administration or using different dose levels), or (c) to an unusual degree with regard to Incidence, site or type of tumour, or age at onset. Additional evidence may be provided by data concerning dose response effects, as well as Inform' atfon on mutagenicity or chemical structure.* Host of the substance! contained In this Annual Report can be Identified chemically. Some carcinogens occur naturally, some are produced when materials are burned, and others are present in raw materials, or In Intermediate and final products of Industries, in sane cases only the exposure associated with a specific technological or manufacturing process, occupation, or Industry can be related to an Increased Incidence of cancer In humans, but the substances responsible cannot be Identified. Examples of such processes are the underground mining of hematite and the ttrong-aetd process for the manufacture or Isopropyl alcohol. Human and Animal Studies Some understanding of the human and animal studies used for Identifying carcinogens It necessary to clarify what Is meant by the words "known* and 'reasonably anticipated.* The strongest evidence for a relationship between exposure to a suspected substance and cancer In humans comes from epidemio logical studies. Although we have adequate epidemiological evidence only for a few carcinogens, we think the patterns seen In these studies show how other animal carcinogens might affect humans. Epidemiological Investigations give the best Information on cancer-causing agents, but such studies of groups of Individuals do have shortcomings. They may require observations over a long time because the latent period between Initial exposure and cancer occurrence may be up to 20-10 years. Intentional, long-term exposures of himan groups are, of course, unacceptable. As an alternative, scientists make educated predictions about the effects In humans, based on the effects observed In studies with experimental animals. Although test animals may respond dtfrercntly from Inmans, experience has thnwn that almost all known hisaan carcinogens also cause cancer in experimental animals If adequately tested.* This finding Is understendeole since cancer begins in Individual cells and all mammalian celis are comparable In structure and function. The basic promise of experimental carcinogenesis research Is that substances that produce cancer In rodents and other experimental animals may affect human cells In the same way. * The evidence for carcinogenicity In experimental animals of arsenic compounds it still regarded as inadequate, and the evidence for bentene Is at present limited." HONS 025610 9 Relatively lerje dotes of chemicals are used In animal studies to make up for the small number of experimental animals exposed, as compared to the site of human populations. Animal tests are costly, take years tc complete, and are often difficult to Interpret In terms of hiasan carcinogenic -Uk. They art nevertheless, the best testing tool we have. No animal test can prove beyond doubt that a substance will or will not cause cancer In humans. Even "lutrtclent evidence* of carclnoptnlclty In experimental animals may prove not to be definitive, tut if we art to prevent cancer, we cannot wait 20 tc 30 years to obtain a definitive evidence of harm to himan health. Therefore, substances which show `sufficient evidence* of cancer causation In experimental animals art considered es reasonably anticipated human carcinogens. Inclusion f Substances The Third Annual Report contains substances, (roups of substances and technological processes Milch were listed in the Second Annual Report. Mitre necessary, the Information has been updated. The Third Annual Report presents information on 2d additional substances. Each has been chosen either from substances tested by the IfCl Carcinogenesis Testing Program or the National Toxicology Program (DTP); from designations of the participating agencies, or from substances evaluated by the 1ARC working groups. Other substances from the same sources will be added to the subsequent Annual Reports. Section IMA of thi Third Annual Report lists all the substances and technological processes Included. The list is divided into two subllsts. One contains substances, groups of substances, or technological processes known to be carcinogens (22 entries). The other list of H entries Includes substances or groups of substances-whlch may reasonably be anticipated to be carcinogenic. Nickel appears In both subllsts because the nickel refining process Is known to be carcinogenic, whereas elceei.ta1 nickel and certain nickel compounds may reasonably be anticipated to be carcinogens. Section lllg contains a brief description of each substance or techno logical process together with a summary of evidence for Its carcinogenicity. References to the original papers on experimental or epidemiological studies, which can be found in the IARC Monographs or in the NCI and NTP bioassay reports, have not been Included In the Third Annual Report. A substance not listed In this Annuel Repor, may still be a known carcinogen or a reasonably anticipated carcinogen. More substances than these included nay potentially present a carcinogenic risk to persons living In the United States. These substances will be Incorporated Into subsequent Annual Reports as resources permit. Some chemicals will be Introduced at a result of testing performed by Industry In response to ERA'S requests under the Toxic Substances Control Act. The National Toxicology Program will also play a role in providing new information for these reports at further test results become available. 10 HONS 025611 Ionizing radiation. ultraviolet radiation (Including sunlight), tobacco, alcoholic beverages, and im viruses are kr.ow.i or suspected to be carcinogens, they have not been Included In this Report because Ionizing radiation Is discussed thoroughly In a General Accounting Office report,7 and a recent Surgeon General's report* reviews *he overwhelming relationship between tobacco and cancer. Several publications Issued by the National Cancer Institute" esplaln the relationship of alcolollc beverages, ultraviolet radiation, and viruses to cancer. estimating Exposure According to clause (It) of subparagraph (AKA), this Report Is required to Include those substances "to which a s'gnlflcant number of people residing In the United States are exposed." Substances to which only a few people art exposed are not Included for the most part. Tet some substances which have been banned or restricted to use are contained In the Report (e.g., tefrolc. arsenical pesticides, mtrex) either because people who were previously aspoted remain potentially at risk, or because these substances are still present In the environment. Subparagraph (d)(1) requires that the Annual Reports provide "Information concerning the nature of Mich exposure and the estimated number rf persons exposed to such substances." The determination of the nuaber of people exposed and the route, Intensity, and duration of such exposure for each substance remains a fornldaole task. This Report attempts to respond to these questions, and wherever adequate answers could bo obtained, they are Included In Section lilt. Exposure to carcinogens can occur anywhere. Some carcinogens have always been present in the environaent, and their amount varies, depending on geographical location and other environmental conditions. Every year human activities lay add more carcinogens to the ambte.it air, water, food, sol), and occupational environment. Although scientists attempt tn estimate the amount of carcinogens present In and added to the environment, there Is no reliable way to predict who Is exposed to what carcinogen and when exposure occurs. Alto, since boxen populations are always exposed to many chemicals at the same time, this may modify the effects of a specific exposure either by multiplying (synergism) or reducing Its action (antagonism). If exposure Is linked to a specific habit such as smoking, a specific use such at medical diagnosis or treatment, or a restricted environment such at the wort place, our ability to estimate exposure Improves, and In some cotes the site of population segments Involved can tc estimated. Production and sse data may alto help estimate exposure, but tnls information may not be publtcly available for many substances, and whure It Is, It may be out-dated or even contradictory. The National Occupational Hazard Survey (NOHS), conducted by CDC/NIOSH from IP7E to 1974, gave Information on the number of workers exposed and on tome broader aspects of occupational exposure. The forthcoming National Occupational Exposure Survey (a repeat of NOHS) should yield valuable Infor mation with respect to more recent exposures. Subsequent Annual Reports on Carcinogens will explore this and other available data bases, and their strengths and lie.I Cations. 11 HONS 025612 Regulatory Status Subparagraph MHC) of Section 262 ilio requires "a statement Identifying (() each substance contained In the list under subparagraph (A) for which no effluent, ambient, or exposure standard has been established by a Federal afency;....' The Third Annual Report responds to this requirement by append ing to the description of each substance In Section 11 IB a summary of federal regulations as submitted by the participating agencies. Some of these standards and regulations hare been enacted tor reasons other than the carcinogenicity of the substance, for Instance, tv prevent other adverse health effects or to Improve the environmental quality or food qualitySolid or liquid wastes or wastes discharged Into the air may contain carcinogen:, yet these may be regulated as toxic substances or hazardous pollutants and not specifically as carcinogens. But If these regulations reduce exposure to carcinogens, then the carcinogenic risk posed by such substances will also decrease. tstlmeting Risk Reduction Clause (11) In subparagraph (4)(C) requires a statement Identifying `for etch effluent, ambient, or exposure standard established by a Federal agency with respect to a substance contained in the list under subparagraph (A), the extent to which, on the basis of ovallable medical, scientific, or other data, such standard, and the Implementation of such standard by the agency, decrease the risk to public health from exposure to the substance;...? This requires quantified Information *n the amount of protection from cancer the public receives from established Federal standards. Estimating the amount of health protection Is perhaps the most difficult task In preparing the Annual Reports. One reason Is that most Federal laws concerned with reducing carcinogenic risk have been enacted within the last IS years. C1ven the long period between the Initial exposure to a ctrtlnogen and the onset of disease. It Is still too early to evaluate how much Federal standards and other regulations have decreased the risk to public health. Another reason Is thet information on past exposure levels, which could serve as a baseline for estimating future risk reduction, often Is not available or accurate. The risk the likelihood of developing cancer -- depends on the Intensity, route, and duration of exposure to a carcinogen. Individuals nay respond differently to startler expe.ures, depending on host factors such as age, sex, nutritional status, overall health and Inherited characteristics. Only In a few Insta-icet, where studies of long-term human exposures and cancer Incidence in restricted environments are available, can risk be estimated with confidence. 12 MONS 0^5613 Tin regulation of asbestos In the work piece provtaei e ood example. In IMS, under the Walsh-Hesly Act which then regulated onl the final with tovernment contrectt, the tttnderd for penalttlble exposure wet 12 fibers of eibettoi per cubic centimeter icc) of air. Under the Occupational Safety and health Act, thli standard was reduced to $ floers/cc In 1972 and to 2 flbers/cr In tbit. On April 17, 1900, a Joint N10SH-0SHA Working Croup recommended the elimination of all non-essential uses of asbestos and the Implementation of a public health program to reduce human exposures. The high risk to workers exposed prior to 196} Is well known. The actual data on exposure levels in the '40s, '60s, and '60s are fragmentary, although exposure levels were undoubtedly unacceptably high by today's standsrat. Mesothelioma (primarily an asbestos-induced cancer) and lung and other cancers, the Incidence of ditch It Increased by exposure to asbestos, generally take 20-40 years or >rt to develop and become apparent. For these reasons, wt will not know until early In the next century to what extent the series of exposure reduc tions In the '70s have reduced the cancer risk to those persons exposed to asbestos. One possible way to provide quantitative estimates of risk reduction might be to assume that the carcinogenic risk Is directly proportional to exposure. This approach also supposes that data on past and present exposure levels are available, or that conditions In all work places are In compliance with regulations. However, Information supporting these assisaptlons Is only rarely obtainable. Nevertheless, It Is reasonable and prudent to cccept that the reduction of exposure, for any reason, particularly to substances shown to be carcinogenic In experimental animals, will decrease the Incidence of cancer. This Is the basis of current regulatory policies wr.lch aimed to lower human exposure to cancer-causing substances and thereby Improve public health. For a more detailed discussion of tne Issues Involved, see tne previously cited report to Congress on the assessment of technologies for determining cancer risks from the environment.2 heouests for Research, Testing, and Information The last requirement of subparagraph (4)(0) is "a description of (1) each request received during the year Involved - "(1) from a Federal Agency outside the Depa-tment of Health, education and welfare fof tne Secretary, or "(III from an entity within the Department of Health, education, and Welfare to any ether entity within the Department, to conduct research Into, or testing for, the carcinogenicity of substances or to provide Information described In clause (II) of subparagraph (C), and (11) how the Secretary and each otner entity, respectively, have responded to each such request." IS HUNS 025614 Section IV ef the Report provides list of such requests s received from the participating agencies. The Inclusion of e substence In this ttOlt does not Imply thet It Is known or reasonably entlclpeted circinogen. Appendixes Appendix A Is an Index of synonyms and trade names of s'lbstances Included In the Third Annual Report. Appendix 1 contains a glossary of frequently usee, terms, acronyms end units of measurement. Appendix C lists in alphabet ical order the substances, groups of substances, and technological processes Included, and the synonyms and trade names for etch of then. Appendix 0 Is a '1st of participating agencies and their staff members who collaborated In preparing the Third Annual Report. Appendix E Is a cumulative Index to the Annual Reports on carcinogens. References 1. Rational Center for Health Statistics. Advance Report of Final Mortality Statistics, 1919. Monthly Vital Statistics. Report, 31. No. S, Supplement, September 30, 1902. t. Office of Technology Assessment, Congress of the United States. Assess ment of Technologies for Determining Cancer Risks from the Environment. U.S. Government Printing Office, Washington, D.C., 1961, pp. 3, 6S-109. 3. Cole, P. Epidemiological Cloes to Hcst Factors In Humen Carcinogenesis. In; H. Sartsch and 9. Armstrong, eds. Host Factors In Hiran Carcino genesis. 1ARC Scientific Publications, No. 39. Lyon, France: International Agency for Research on Cancer, 1962, p. 3. a. Dartsch, H., and 6. Armstrong, eds. Host Factors In Human Carc<no- Jenesls. 1ARC Scientific Publications, No. 39. Lyon, France: nternational Agency for Research on Cancer, 1982, p. xl. S. Grlesemer, R.A., and C. Cueto. Toward a Classification Scheme for Degrees of Experimental Evidence for the Carcinogenicity of Chemicals for An1awls. In: R. llontesano, H. Rartseh, and L. Tomatls, e'. Molecular and Cellular Aspects of Carcinogen Screening Tests, IARC Scientific Publications, No. 27. Lyon, Franca: International Agency for Research on Cancer, 1960, pp. 2S9-61. 6. International Agency for Research on Cancer. Chemicals, Industrial Processes and Industries Associated with Cancer In Humans. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1932 (In press). 14 HONS 02S6L5 7. Comptroller Control. U.S. Control Accounting Cfrlce. Problems of Assessing Cinter Risk of low level Ionising Redlotlon exposure. Report to the Congress of the United Stotts. EMO-81-1. Weshlrgton, C.C., 1981. 8. Office of Smoking end Heolth. The Heolth Conseguencts of Smoking: Center, o Report of the Surgeon Centro 1. Rockville, Meryl end: U.S. Deportment of Heolth end Maun Services, Public Heolth Service, 1982. 9. See, for exemptt, Shlmkln, M.9. Science ond Conner. M1H Publlcotlons No. 80-St8. Third Revision. Netlonol Concur Institute, Notlonol Institutes of Heolth. Rtthesde, Meryl end: U.S. Deportment of Heolth ond Humon Services, 1*80. IS HONS 025616 III. SUBSTANCES LISTED IU MOWS 025617 LIST OF SUBSTANCES' . Substances or groups of substances, and technological or manufacturing processes thet ire known to be carcinogenic** 4-Aiainobf phenyl Arsenic enil certtln ersentc compounds Asbestos Aurpmine menufpcture Benzene Benzidine N,N-b1s(2-chloroethyl)-2-naphthylam1ne (Chlomichezlne) BIsUhloromeMiyl '.ether ind technical grade ehloronethyl methyl ether Chlorambucil Chromium and certain chromium compounds Cuke oven emissions Cyclophosphamide Dipthylstllbestrol Hematite underground mining Isopropyl alcohol manufacture (strong-acid process) Melphalan Mustard gas {Naphthyl amine Nickel refining Soots, tars, and minersi oils Thorium dioxide Ylnyl chloride Bap* 31 1 47 52 57 (0 t 71 B3 85 95 102 137 U1 174 104 195 197 19$ 265 277 292 b. Substances or groups of substances that may be reasonably anticipated to be carcinogens** 2-Acetyl ami rtof1 uorene Acrylonitrile 21 23 * An alphabetised list of substances, their synonyms, and their trade names appears In Appendix A. The synonyms and trade names for each substance Included are listed In Appendix C. * For the purpose of this Nepert, "known carcinogens* are defined as those substances for which the evidence from human studies Indicates that there Is a causal relationship between exposure to the substance end human cancer. Substances 'which may reasonably be anticipated to be carcinogens* are defined as tnose for which there Is a limited evidence of carcinogenicity In humans or sufficient evidence of carcinogenicity In experimental animals. 17 HONS 025618 Aflatoxlns 2-Ant noanthragul non* 1 -An' no- 2-me thyl anthriqulrione Anltr.ile 0-Ant it dine and o-anlsldlne hydrochloride Arant to Benzlalanthracene Benzolblfluoranthene Benzol aIpyrene BerylItun and certetn beryllium compounds Cadmium and cortatn cadmium compounds Carbon tetrachloride Chloroform P-Cresldlne Cupferron Cycasln 2.4- Dtanlnosnlsole sulfate 2.4- Dlamlnotoluene DlbenaU.hlacrldlne Mbenziajjacrldlne Dlbeni(a,h(anthracene 7H-01 benzoic,(Icarbuole Dlbenaola.hlpyreno Dlbeuola.l Ipyrene 1.2- Dlbroao3-chloropropane 1.2- Olbromoethane 3.3'-01chiorebenz I di ne 1.2- blchloroethane Dlepoxybutare 01 I2-ethylhenylIphthalate 3,3'-Olmethcnybenxldlne 4-Dlnethylenlnoezobenzene 3,3'-Dimethyl bona1dlno Dimethyicarbampyl chloride Dimethyl sulfate 1.4- 0lo>ane Direct Hack 30 Direct Blue t Ethylene thiourea Frrmaldehyde Noxachlorobonxene hydrazine and hydrazine aulfato Mydrazobenzene lndeno(l,2,3-cd)pyrene Iron dextran complen Kepone" (Chlordeeone) Lead acetate and lead phosphate lindane and other hexachlorocyclohexane 1 sonars 16 !ist 27 29 33 35 37 39 54 62 64 66 75 80 85 97 99 101 104 106 108 110 112 114 116 118 120 123 126 129 132 134 139 141 143 145 147 149 151 154 156 158 162 165 168 170 172 176 178 181 HONS 025619 *.4' -Methylenebts(2-chlorotnnine) (HOC*) *. 4 '-Methylenebl s (H, N-dlmthyl Ibenzenmt ne Mtchler's ketone HI rex nickel end certtln nickel comcoundt Nltrtlotrtaeetlc eeld S-M1tro-o-en1s1d1e Hltrofen N-Hltrosod1-n-biity1ailne H-HItTsodlethenolamlne H-H1trotodlethylenlne M-nl trosodtaelhyl Ml ne p-Hl trosodlphenylaxil ne H-mtrcsodl -n-propyl ml ne H-N1 troso-H-tihylurea H-H1 troso-H-a*thy)rea H-dl troicewthyl vinyl mine H-H1trosonorphol1ne H-KItrosonorntcotlne N-Hltrojoplperldlne H-H1 trosopyrrol Hint H-H1trososercos1ne OxynethoK-ne Pheneeetln Phcnazopyrldlne and phnnazopyrldlne hydrochloride Phenytoln and sodlu* salt of phenytoln Polybroninoted biphenyls Polychlorinated biphenyls Procarbazine and procarbazine hydrochloride b-Proplolactone Reserplne Sacchjrlr. Safrole Stltnluxi Hde Streptozcui in Sulfallate Z,3,',8-1etrachlorodlbenzo-p-dlexln (TCD0) Thlnacetmide Thiourea o-Toluldtne and o-toluldlne hydrochloride Toxaphene 2,4,6-Trlehlorophenol Trlsll-aztrldlnylIphosphlne sulfide Tr1s(Z,3-d1brodopropy1Iphosphate Urethane 19 1M 19$ 191 191 199 zos ZOO 210 212 215 217 ZIP 222 224 225 22t 230 Z31 233 Z34 234 Z30 239 241 243 245 247 24P 253 255 257 2SP 252 264 268 270 271 273 275 279 281 284 286 288 290 HONS 025620 t. Individual Substances HONS 0256Z1 2-acetvlamihofiuorene Incorporation of this compound Into the food caused Increased Inc Inncts of malignant tumors In t variety of organs In the rat.1 Lons-term studies In which alee wtrt given 2-acetylMlnoMuorcnt (AAF) In the diet showed Increased Incldrncts of liver ind urinary bladder cancers. ^Wilton, K.H., f. DtCds, and A.J. Cos. The Toxicity and Carcinogenic Activity of 2-Acctylen1nofluoren. Cancer Research. Vol. 1. 1941, pp. 59S-60J. ^Staffs, J.A., and H.A. Mehlmon (eds.l. Innovations In Cancer Risk Assessment (EDgi study): Proceeding: of a Symposium. Journal of Environmental "ethology and Toxicology. Vol. J, I960, pp. 1-246. AAF was Intended for use as a pesticide, but this chemical was never marketed because it was found to be carcinogenic In experimental animals. AAF Is used as a positive control by biochemists and technicians engaged In the studr of liver enzymes and of the carcinogenicity and aeitagenlclty of aromatic amines. These research persons may be exposed to AAF. AAF Is distributed by several companies that deal In specialty chemicals. CPA reported one producer In one region (Toxic Substances Control Act, Chemical Substance Inventory, 1979, public record). Information obtained frem the distributors Indicates that AAF is Imported from Europe. A typical chemical distributor keeps approximately 10 lb of AAF In stock. Tne chemical Is usually sold In 1-, S-, or 2S-g Quantities. Based on this Information, It Is estimated that the total I'.S. usage is less than 20 lb per year. Human exposure to AAF may occur through Inhalation and skin absorption. The occupations at greatest risk to AAF exposure are organic chemists, chem ical stockroom workers, and biomedical researchers. Although neither H10SH nor OSHA has estimated the number of U.S. workers exposed to AAF, perhaps fewer than 1000 workers In 200 laboratories may come In contact with this animal carcinogen. Because AAF Is an animal carcinogen, on Febrvcry 11, 1974, OSHA promul gated a standard for this cnemicil designating protective dotning, hygiene procedures for workers, and special engineering requirements for the manufacture or processing of AAF. 21 HONS 025622 f-Actt* I Ml Hi f I .tf*** KCWUHOKl afvlattnni ana OtHar Act tana Iffatt af aafwlitlani; Ktar taaaati Cfuttei. af Nfililit* r* tarrant actita. to knaaa i la cantwar araaaeti. (tnci ISM, mi ZW. Ifltrt M Harm* uxiitem af Mtu. mttat iim u <* lil* tali efjaieat ara laajaet i Mnailra frftfltM t/)*/10. IN {miwiift KiMlWot (rwt It iNteiil t*H iMMdl Hi Hit af ear. ciaam. * raaaU af tot* Matin#. ii eaaMeal H rafatatrt Mf in iHwrti Camarrattaa aa# Uttwy *ct'i luinm atta nimil tot tffltl af flamtof **< W**>>*< H tntV#t| a (Mvtor to tM'l Omaat'taa) laNtr **) iiiaaittiat to4Uit arcatort tor diaaUiU m* tuf rnraafc Nil`> Mtirtl. I*clt1af tar<*ataM(ty U atari. 1M Wa Hal H lactatat. (CM! * cri mi.to him fratactfva clatalaf* mflratar, tjfm. iN artfeal r**air. atatt far aartari; Ntwtt fi* raaafra* Mit aaa**aiiai Ntfitiw araMfcitaa; (wimInKm tafttpal raaafrtnaw; ifan iaaatrarnt far rtfvlttta araaa; laaellnf naMmitti far caatataart. (OHM) fatal*? (Hilary: ft/lt/tt: teffmi Taaaararr SuMarat-- if era itto.iata (MM) KttKtln elatalaf ana tyfitna raaatraatru far attorn, aaa*-*aial aaaratlaaa r*tr(ct*4, aaylatarinj ratal raaanu. S/ll/74: final lUn4ar4~<*rr*nt rtfa'.a* Uni affactfva. IMM) 22 HONS 02523 ACRYLONITRILE There Is sufficient evidence frr the carcinogenicity of acrylonitrile (AN) In experimental animals; the evioence of carcinogenicity *" humans It United.1 Acrylonitrile vat carcinogenic In ratt where administered by garage and In drinking water, or by inhalation.1< An eel deniologlcal study of workert potentially exposed to acrylonitrile and observed for 20 years or anre showed an Increased Incidence of cancers of the lung, large Intestine and prostate. The aortalIty froa lung cancer was also Increased. Another tlallar study of persons occupationally exposed to acrylonitrile and followed for IP years or nore alto Indicated an Increased incidence of cancers of the stomach, colon, brain and respiratory tract.' international Agency for Research on Cancer. IARC Monographs an the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplmaent 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 19. Lyon, France: IARC, 1979, pp. 73-133. AN Is a reactive chemical that is coanerclally Important because It pelymertxet readily. It is a volatile liquid, soluble In water and 1r most coanon organic solvents. AN It used extensively In manufacturing of synthetic fibers, reslr.s, plastics, elastomers, and rubber for a variety of consumer goods such as textiles, d1n.en.rre. food containers, toys, luggage, automotive parts, smell appliances, and telephones. In 1976, about 48 percent of the AN was used to psoduce acrylic and modecryllc fibers; 21 percent to produce acrylonitrilebutadiene- styrene iABSI and styrene-acrylonitrile (SAN) resins; 19 percent to produce nitrile elastomers and latexes such as butadiene acrylonitrile copolymeis; and 12 percent to produce ediponltrlle, an Intermediate used In nylon production. AN hat keen produced in the United States since 1940. N10SH has reported that approximately l.S billion lb of AN are now manufactured annually. Exposure to AN can occur during manufacture and production. The compound Is volatile, and exposure occurs primarily through vapor Inhalation and skin absorption. OSHA estimated that approximately 278,000 persons are potentially exposed to AN. These persons work as acrylic resin makers; organic chemical synthesisers; pesticide workers; rubber, synthetic fiber, and textile makers. 23 HONS 025624 According to the Consumer Product Sofoty Commission In 19(0, direct contuner exposure to AM through consider product use It Iox. heceuse there It little nlgratlon of the awynoner fro* tuch product!. Ihe level! of AN In centner productt ore estimated to be let! thon 1 ppn In acrylic and nodacryllc flbert, 30-50 ppn In AtS copolyncrs, IS ppn In SAN copolyaert, and 0-750 ppn In nitrile rubber and latex good!. The pretence of AN. even an a trace contaal. nant, nay be caute for concern; however, data detcrlblng the actual level of residual In finished product! and the potential for centner exposure and uptake are currently lacking. The extent of exposure to AN of the general population through air nlttlont frn production, nanulecture, bulk storage, and watte disposal hat not baen determined. However, a 1977 report cited that total AN dr volitions are 2.2 percent of total production. During 197D, EPA declared AN a hazardous substance based on the reported acute toxic effects. At a result, CPA promulgated hazardous spill regulations In 1979 under the Clean Hater Act, establishing reportable quantities of 100 lb for AN. The EPA Carcinogen Assessaent Croup Included AN on Its list of carcinogens. Because AN Is an anlnal carcinogen, EPA proposed In 19(0 to reduce Uit reportable quantity of AN to 10 lb. Under the Resource Conservation and Recovery Act, EPA regulates watte products, off-spectflcatlon batches, and spill residues In excess of 2200 lb AN. FDA and OSHA have also regulated AN. During 1977, FOA banned the use of AN copolymers for beverage containers and proposed to Unit AN nlgratlon fma other food-contsct materials to SO ppb. During 1979, FDA was asked to review the ban, and this has been a continuing effort. In 19(3. the FOA Intends to review all AN regulations and bring them Into aligranent with current carcino genicity data. This review will Include an advisory opln'on and subsequently a proposal for use of a new type of container that limits AN nlgratlon. In addition, OSHA enacted regulations In 19?( to reduce worker exposure to an by establlthing ,, standard of 2 ppn (4.5 ng/n3) as a tine-weighted average. This standard requires personal protective equlpnent, training, nedlcal surveillance, signs and labeling, and engineering controls. HONS 025625 24 MnrlMitrtU kvm:im IlfltlllMI IT) l*JW' MtlMt (flNt V* IlDlHtmi ItMr (mhiu *> iifiliWfy l* it fC^SCI CM, 111: MtirMI Mlt IfitlltM CIUtllMMf 'M'MItt VVMtUr MM It. H.* l|l Mi MlttH flfMtlM MWIf*mu. inwIiitM i/mH. friMMl IV rMKI MMMU Mtt| 14 It It l.M t|l, mwvmV tn/99. tM*. Ji {ImtMM fW MtrKtM m, t/y/H. fytft, t: Hlvtuty fiKiUiiti* if mi* V4C/tlfl/Nnl,ltfMtIHtM4 tr IMtC HMHMlt Nttt I* ll. KU, Ml.Mli tHifM'IHHCMlftMiltIItMIf IMvtUJVMCtt.l HMVIMMMilVl fMcc*U-. MM tf IV MMllM MV Mtvrt irvtvMMvvmifiMill. tin MtlfMtM KiylMt'Dl 11 NMMM (IMHtMMitI.lMlMMM(iNMVtiflilMlUII*tUWMmtttlM/Mtt.MjMrttrl tm#fitl-l CiNM;MIlblmt wMmNIMWt * K(HM'MUttH- /?*. SImttlMUrMttaM<*T**l*MKtltttl1MatM(r*tMnrN, 11**1 IMM vf t(Hi; ri<KA; JiHMIfMItfH#:f fttfvltttw MtlWtMVvlyVV*rIv-UrM It't ttfKt nCUnt IMIdf Nt- Hirt PttolU I* MflU't* IbllH* torntty Witrtirt vi*muni < mitww<*f. mw'i|t*ic'it Ml tMMi M IMItUMtttt,. (KN'Ifll rwti' t.n 1 MNl'if IM MtMMt If tM CftMlVlIl MV MMll flMlt IV MVMtlM if MVlVMUl MNMni. Mtvc m cvMivvtMicttr* fctIVMl Mltn> vf MU iffMU. UMI 7?iM iIHtMbItml KiintarwiriUtrtwlitpnkmlfrititit*t> |IU - f**V. |rM] llfk Wt: Itw if UtfHI Will* IHU> ttlvMHaMlt lNtl>kyNt. MMinliHi HMfNlttMll, IrKmMfMMl> tIMMt wttcltt itHr imi **'*> tl W N Ml ttM\1fMNIMtmttt*TMIMf,$I4.MtMaMvtletCNi vfwlfH*Invt--tt*t,tt-4l-l-t-MM--ft--tP-t-lMvv;M IW>: PvtlK M#fl* M **lMltMIV. ttuttl* i iimIiiim M Cn UM, }||,|| <1 rt in, v. MOM vt ert ivi.ii i n ttnt irtut vviitvi V CM Ml.II. Ml .15 MtMTMS.ttwlMnwMn, t ||/M IIMI TCmT5***T 25 HONS 025626 VtftMM IlfltlitM 04 Mtf ht<m MMI |lft IMlIlUltlM IK jMft Im*lnlln/Mm*mul!MnN^- Kt/lMHrlti inwr IWi pmi 9* MiilMr'i .. . imt * MM nlftlft M Ml tiff IT M mrMlflH ttt\lt HfflltlM 04 MffM M WOl IHM rf M MUllI lift to*r ntllffl Mrlwltrllt war ImH aiii m Him t w nftv f M Mff inylfflffOt dNlffiM. ft nrtlTM Ww, Mt MM HM tftfttH 94 bMlfflfflf'l Mfftt ft fttlft HU wr it* ftNll ftf NMffNI m ftft W1|1 ft it tffUftni mm wm ftM ***** Iffvtt tf dfiliiimi UKr tMMl CttttH* f fftt lama * IH*1 fttrtcm W' ffttaiwwTlH* l<ff**f . *t mffUtlmtl I.NI. SMI Hit t ptft ft*ar IWillfti IS-fflt Iftft fffltft. ft lift tr ftft ftHKI lift Hffrlt NlftftltflH. ftftUtff* Mffffy: Hit: nlffMfttiy, M't tmwwiff. tin* Wttlffll ftfflltlffii NMtlft iftftlft. IftllMt. tftlffft, Mt ftfttll ftMlIlfftt natftffft Hr iffftn; ftwintff nnirt- ------- ` irt ffjlftfflft w HM frttlHt an ftMHHff tr rmllNt ftMt ftfftt IT, mil naa IffNfff HwffM" <*. Miff ft ftft> ft-*r KM. Jtntry IT, JftTftt tanner Taetranr Hiattm--8 MMrM; H ft* it** im mttaf: iftxtMrt tfffttt. iiiiftif i. nil: rift* itMftMftffMt Inti ttffftM. it cn me. ton WMI 26 HONS 02562? AFLATOXIMS There U sufficient evidence for the carcinogenicity of oflotoxins In experiments] onlmtls. The evidence of carcinogenicity In humans Is Halted.* Aflotoxlns were carcinogenic In nice, rets, fish, ducks, neraosets, tree shrews, snd monkeys by seversl routes of sdnln1;trstton I Including Orel), producing aotnly concert of the liver, colon, tnd kidney.2 epidemiologies! studies hove shown o positive correction between the o/eroge dletery concentrottont of oflotoxlns end the Incidence uf primery liver concer. No stjdlcs hove been cerrled ojt thot could link on Inc reeled risk of liver concer to octuol etlotoxln Intoke in Indlvlduols.? ^International Agency for Reseorch on Concer. IARC Homographs on the Evoluotlon or the Core I nogenie Risk of Chealcolt to Huaons. .Supplement 4. Lyon, fronce: IARC, 1982. `International Agency for Reseorch on Concer. IARC Honogrophs on the Evoluotlon of the Cerclnogcnic Risk of Chealcolt to Hon. Yol. 10. Lyon, Fronce: IARC, 1976, pp. 51-72. Aflotoxlns ore o group of toxic netobolltes produced by certoln types of fungi. They ore Intensely fluorescent In ultrovlolet light snd slightly soluble In woter. Aflotoxlns ore not coanerclolly aonufoctured; they ore noturolly occur ring contenlnonts thot ore formed by fungi on food during conditions of high tviperoture ond high humidity. Nuaen exposure to oflotoxlns occurs through Ingestion of contoalneted fond, (reins, peonuts, tree nuts, ond cottonseed aesl ore omong the no-e coemon foods on which these fungi grow. Meet, eggs, ailk, ond other edible products from entasis thot consume oflstoxln-contoalnoted feed ore oddttlonol sources of potential exposure. Anerlcons consume on estimated 0.15 to 0.50 wg of oflotoxlns dolly. Under the Resource Conservotlon tnd Recivory Act, 3001-3004, EPA regulates tfittoxlns os o hozordous constituent of waste. In Addition, the EPA Carcinogen Assessment Sroup considered oflotoxlns to be corcinogenlc. The FDA hos established enforcement levels of 0.5 ppb in ailk tnd 20 ppb for ether food product:. 27 HONS 025628 Aflatailftt KMATJONS lafalattani Otktr Actlaat tffaet #f lifvlitlMi; Hhar CaMMAts ItU, MOI-WO*! ItitH II MSlNMt UMlltotut 9* aaa. Nim imm i* can. (it* a*f nim< art aaajact ta DM r?ff|/rt(irflii|tN rtwtriMMl. frawttatal t/l/W. IKWH aflataalat *r* naturally accvrrlaf Hailaliitatt, (M Kat a IMtH i(|attiry aitkaHti mr mm misukii. Sat Carclaafta Mmwat (rw; lUtMtt alar !acav1*<MN*n*r***` ICM) AfUtaalaa an fa**4 ta at awvaiMitt UMiataMt! la fia<l. tafartraaat acttaa ktali af ft ** Itaul It, If. Ii, If) far all araHaeu m M m ahatiaia Hj la alii art la afftet. (FM) Nalli lama maun ta 1aait frKtfcalla 1ml* (FDA) Citatta* af Mfwlatlaa ae era ni.ii IlM) Caaaiianca raticy Nanaat tmaa mmn 7iit.ii, rm.os. tiit.it. 7llt.lt. ?l!t.07. 711t.ll, 71l.tt, 71Zt.) imi a2^629 28 *0>*S 2-AMN0ANTHRAQUIN0NE Techrlcel grede 2-enlnoenthrequlnone (Impurities unspecified'. Administered In the feed, wet cerclnogenlc in ule fisc her 344 rets, reusing e comblnetlon of hcpetocelluler rerclnones end neoplesttc nodules of the liver. The compound wes elsu cerclno gen1c In R5C3F1 mice, ceuslng hepetore) 1 uler cerci.iomes In both sesos end mellgnent hemetopoletlc lynphomes In fneles.l An IARC working group considered thet the evidence for the cercinogentettv In espenmentel enlmels of the meterle) tested wes limited.' In view of enother eveluetlon of NCI bloessey results, the evidence cen be considered es sufficient.' ^Netlonel Center Institute. Itoessey of Z-emlnoenthrtqulnone for Possible Cerclnogentclty. Technlcel Report Series No. 144. WEN Publlcetlon No. (N1M) 78-1399. (ethesde, Meryl end, 1978. 'internetlonel Agency for Reseerch on Cenccr. I ARC Monogrephs oo the Eveluetlon of the Cerclnogenlc Risk of Chcmlcols to Humens. Vol. 17. Lyon, Frence: 1ARC, 1962, pp. 191-98. Hrlesemer, R.A., end C. Cueto. Towerd e Clesslflcetion Scheme for Degrees or Expericcntel Evidence for the Cerclnogenlclty of Chemlceln for AnlMls. In: R. Monteteno, M. lertsch, end L. Temetls, eds. Koleculer end Celluler Aspects of Cerclnogen Screening Tests, 1ARC Scientific Publlcetlons. No. 27. Lyon, Frence: Internetlonel Agency for Reseerch on Cencer, 1980, pp. 259-81. 2-talnoenthrequlnone (AAQ), en erometlc emlne. Is Insoluble In wetyr end soluble In Alcohol. AAQ Is used es en Intermedlete In the Industriel synthesis of enthrequlnone dyes. It It the precursor of five dyes end one pigment. Including Colour Index Vet Slues 4, 6. 12, end 24; Vet fellow 1; end Pigment Slue 22. Production In 1971 wes 200,000 lb for AAQ end It: silts. Imports In 1974 were 37S.OOO lb. EPA reoorted five producers end Importers of AAQ between 1975 end 1977 (Toxic Substenccs Control Act, Chemlcel Substence Inventory, lnlttll Inventory, 1979, public record!. Production of AAQ wet not reported to the U.$. Internetlonel Trede Coemlssion In 1979-1980. Deu from NCI Indlcited thet Imports through prlnclpel U.S. customs districts In 1980 were only 250 1b. The 1982 Directory of Chntcel Producers Indicates thet only one U.S. cenpeny now produces AAQ end Its selt. Recent production figures for AAQ ere considered proprietory end ere not evelleble. 29 MONS 025630 Human axpotura to AAQ It principally through Inholotion and iktn contact. lecaute AAQ It used on a commercial tcalt tolely by tha dya Induttry, the potanilal for axpotura to tha compound It greatett for workert at dya manufacturing facllltlet. Ncwever, no additional data are available on tha number of fact 11tlai utlng AAQ. The National Occupational Naiard Survey In 1074 made no aitlmata of tha potential occupational aapotura to AAQ (N10SH). However, the Coniwer Product Safety Commit!I on ttaff ballavat that traca amount! of vnraactad AAQ may pottlbly be pratent In tome dyei bated on thlt chemical and In the final conturner product. Cxpoture even to trace amountt may be a caute for concern. Thlt concern It bated on experience with other dyet derived from aromatic am(net. Data are not available on the actual levelt of Impurltlet In the final product, the potential for coniunr. axpotura, and the uptake. |aWmMVMil*M m4 Mfr itim |9K> (Null if IU 1l ffMNIMi t wtMMtfcn+iMftf* litf fffgliMfT grlPHlp M fH. IlMgle mmM M tM tfn IlfMU IMaiVi II IMIN. KnutiM IffKt If hfltltlwn Httr Cmm (luilgi if dpiitm 30 HONS 025631 4-AM1N0BIPHCNTL There Is sufficient evidence for th carcinogenicity of 4-anlnoblphenyl both In humans end In experimental animals.1 4-Amlnobl phenyl It carcinogenic In lofct, rots, rabbits and 009s after drat administration, producing principally canctr of tht urinary bladder.2 Epidemiological studies, which aro conflneo to one series of workers occupationally exposed to commercial 4-anlnoblpheny], show a high Incidence of bladder cancer.1-3 1International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement l. Lyon, France: IARC, 1979, p. 22. `International Agency for Research on Cancel. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Tol. 1. Lyon, France: IARC, 1972, pp. 74-79. 'Melamed, M.R, Diagnostic Cytolcgy of Urinary Tract Carcinoma. European Journal of Cancer. Vol. 8, 1972, pp. 287-92. 4-Amlnoblphenyl Is an aroeiatlc amine that Is slightly soluble In water. Although formerly used as a rubber antioxidant, this compound has no current coanerclal use In the United States. Nor Is there evidence of any current commercial production. For 1975-77, EPA reported only one producer In one region, according to the Toxic Substances Control Act (TSCA), Chemical Substan-es Inventory, 1379, public record. 4-Amlnoblphenyl has been used as a research chemical and as a reagent for the detection of sulfites. The compound also occurs as a contaminant In 2-am<nobiphenyl. 2-Ami nobiphenyl, a chemical closely related to 4-amlnoblpheny). Is used In the manufacture of dyes. According to OSHA, approximately 139 workers are potentially exposed to 4-amlnobiphenyl during the production of 2-amlnoblphenyl. ERA regulates 4-amlnoblphenyl under the Resource Conservation and Recovery Act as a hazardous constituent of waste and under TSCA. The ERA Carcinogen Assessment Croup lists 4-asrinobiphenyl as a carcinogen. In February 1974, OSHA Issued a final standard requiring use of exhaust fans protective clothing, and respirators; prohibiting operation in open vessels; and requir ing control of plant contamination. 31 HONS 025632 In 1980. tt* Consuaer Froduct Sefety Comlsslon prellalnertly deteralned thot 4-aolnoblphenyl * not promt in consuoer products under Hi Juris diction. The Comission subsequently requested (45 FR 61344) public consent to verify the iccurecy of thjlr Infonutlon, end no counts uere received. Pendlnp the receipt of new Inforaetlon, the Comission plens no octlon on 4-onlnebtphcnyl. atMUTIMS IptflttlM IN Mt* k|l88l Iffaet if itfilMlaiN; IMf Ubm*u M (ITffM IN INN KMWI ! WllNir INWtU. ICMC1 eta. wat*SM4: him nmnni tw iiimh af ml*, mmi hn* a mwi lenaiiniyt m ndni h m mWVMWMNWf NNlfNMU. trmmU HIM I/I9/W. mi. Mali aaartlay ml# raafHt traihi tm *m , imiiN 1/tVMe aim nHiM a t*Mri*iiN. In (|ftlN|n MwiMM INN IWMN MN ||IWylNlNolNN. ItMl IrMKtfN ctatMafs rtaflraa**, |**N, tretataa, M iwkiI nniIUm NrtN> mm far nnin; Mmi faa MNifHlii wi-mitl Nf'itlw inMllMi atlaa cninI raarfraMira; Hp r*cM*>- mmi far Nfvlttil *r%m; NN'f^ m far (nuimn. (Ml ImliMfy nitaryi 1mm IWFfiMT furary luWN|.. fNimfw fMMi| M NffM rtaali*- jm far nMpn. aaa*-*a*ai nmtitN ItltHtM, fllllF--W. t/ll/74; flMl lUNlfl IIFNM f^ll* Um affaett**. (Haifa* f aa cm Mi ii * ft 41, a. I1M lira) if era ifM.mi (9WI 32 HOKS 025633 1-AMI N0-2-HETHU AMTHAAQUIHOKE Technlcol-gride l-ulno-2-aethylonthraqutnonc (Impurities unspecified), Administered In the feed, wot carcinogenic tn Flicker 344 rots, Inducing hepatocellular carcinomas <n ntt of both sexes, end kidney tumors (tuck ei tubular-cell edenonet nd adenocarcinomas) In nelei. The compound was carcinogenic tn feaole I6C3F1 alee, producing on Increoted combined Incidence of hopttocollular carcinomas end neoplastic nodules.I An IAAC working group considered thot the evidence for the cerclnogentclty In experimental onlnols of cite materiel tested wot limited,* but In view of Another evoluitlon of NCI bloessoy results, the evidence con be considered ss sufficient.* `National Center Institute, lloostoy of l-Amlno-2-methylonthreqwlnono for Possible Carcinogenicity. Technlcel deport Series No. 111. DHEN PubUsotlon No. (hlH) 78-13M. Washington, O.C., 1*78. `International Agency for Neteorch on Concer. IAAC Mcnogrephs on the Eveluotlon of the Corclnogenlc disk of Cheat cult tc Nunens. fol. 27.- Lyon, Fronce: IAAC, ig82, pp. igg-204. Hrlosomer, A.A., end C. Cueto. Toward o ClesslfIcetlon Scheae for Degrees of Expertaentsl Evidence for the Cerclnogenlclty of Chealcols for Anlaols. In: A. Hontesono, H. Aortsch, end l. Toaotls, eds. Molecular end Celiuler Aspects of Corel nogen Screening Tests, IAAC Scientific Pub' icottons. No. 27. tyon, Fronce: lnternotlonol Agency for Ktseorch on Concer, 1*80, pp. 250-81. 1-Aalno-2-aethylenthraqulnone Is on oroaotlc oalne thot Is Insoluble In utter end soluble In ethenol, ecetone, end bentone. l-Aalno-2-aethylonthnqulnone Is used olrsst exclusively os o dye Inter ned! etc for the production of o vorlety of onthroqulnone dyes. The Society of Dyers ond Colourists In 1*71 reported thot It con be used os o dye for o vorlety of synthetic fibers, especially scetotes, os well os wool, sheepskins, furs, ond su'fece dyeing of theraoplostics. None of the dyes thot con be prepored froa It ore presently produced In coaaercltl quantities. l-Aalno-2-aethylonthroqulnone hod been produced conmerclolly In the United Stbtes since 1(48, but production nos lost reported by one coapany in 1870. Inerts through the prlnctpol U.S. custoas districts were only 2fO lb when Tost reported In 1872, A recent study by the Consumer Product Sefety Comission (CPJC1 stiff tndlcited thot l-oalno-2-aethylonthroqulnone mot no longer either regulorly produced In coauarclol quontlttes or laported. however, In their Inventory of cheafcols In comerce (1979, public recordl. EPA reported Ouo luporters In one region. The oaount of the laports uos not reported. 33 MOMS 025634 According to NCI, no evidence wot troll obi 0 to Indlcoto that 1-amfno-J-methilenthraqulnone wot otthor produced conoerclally or loporttd In the United States. -Domestic production wot not reported to the U.S. International Trade Coaatsslon for 1979-1980. Hunan exposure to 1 -onl no-2-methylanthrequ I none It principally through Inhalation of vapors. The potential for eapoture H greatett among workers engaged In the dyeing of textiles. The National Occupational Hatard Survey Of 1974 contalnt no Information on l-amlno-2-meth, 1anthrequ1 none, but doct eitlnate that 8400 wortart may have been exposed to enthraqulnone dyet. l-Amlno-2-ncthylenthraq:i1none It not pretently uted In consumer products according to the CPSC. CPt hat proposed regulation of 1-amino-2-methylanthraqulnone under the Tonic Substances Control Act, 81a), reporting rule, which would provide detailed production and marketing data. M1>8 >.8ttl441llfH>1PImt M tnlM KMUTIMS tff*C1 9t Ilfllltl88|i IMP ttWHl CfUtlM * l(|il|tl|8 M lurrmt NtlM. (CMC) Tift, ltt: MdftlPf Mel* H* H MU. 1/tMN. ICMI p**t*tt 88*11 r*MM Mtlf Nltl lr IMII8| gfdllfl NtlX'l). vHlCfl hi it imsKirH iign* tin tw MM U UfMM8| H8P8flltlNH f ftUury r ttttr (tnrtl tCMm. ItMt il , . i)m l(M> 34 HONS 025635 AH1TR0LC There <i sufficient evidence of the carcinogenicity of amltrole In experimental animals; tne evidence of carcinogenicity In Humana It considered inadequate.1 *1trole was carcinogenic In several strains of mice and rats, producIng thyroid and liver tumors following administration in drinking water, diet, or hy stomach tube, or subcutaneous Injection. Pall road workers who were exposed to amltrole and other herbi cides showed a slight excess of cancer when all sites were considered together. Because the workers were exposed to several different herbicides, no conclusions could be made regarding the carcinogenicity of amltrole alone.1.2 1International Agency for Pesearch on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Han. Yol. 7. Lyon, France; IARC, 1974, pp. 31-47. Amltrole, a herbicide also known as amtnotrlaiole, is soluble in water and very soluble In ethanol, Amltrole Is formulated Into soluble powders, liquids, and aerosols. The na,1or use for ar.ltrole In the United States has been as a herbicide, but this use is now limited to noncrop applications. Amltrole was first patented for use In the United States In 1954. Current domestic production Is limited to approximately 40C0 Ib/yr. No reports art available an current Imports, but B93.0OO lb were Imported In the first 9 months of 1973. The potential for exposure to amltrole exists In Its manufacture and application as a herbicide. According to HIOSH, an estimated 93 pe'tons have been exposed to amltrole during Its production, but no data are available on the number of people who may be exposed during Its application or on the exposure levels In the general population. After application, amltrole will persist In soli for several weeks and In water for more than 200 days. 25 HONS 020636 Th* use of nmltrole on croplands was conceits In 1971, and CPA's Office of Pesticide Programs does not permit any residues on any food or feed crop. Under the Resource Conservation and Recovery Act, CPA also regulates the use and production of aaltrole. In addition, CPA Is reviewing Microle under the federal Insecticide, Fungicide, and Rodentlclde Act to determine if further regulation may Ur warranted. apUtia** iN ItM* M'.Im aa fcwiH aedaa. at uan amnea la ITHMf *ttr eaK JaPlMlCtltR. <easc> KW. Mt-DHi WUMU MW iwen., iif.****lffld* Nttm, IN Will Pill. *PM I* IKIH If )M* If t mNttN M H|lfVfifwttN ffnul' |MM 1/lffM. All* 1IIU Mltfill i imm>i wwtiiwM if witt Mint la Mat mdl'NlHh fVM, It VMur PI9IN I* MtlfNM If a**lIMWl mtllltl* f N ddftMM, Ifttl aariHffarM If IN flaf If Car* flNUiUilf. at tirm fa* m<itiw. tmtiM far tat a* cra*la*at. fill Wl. I (arclatfM Iiiimnm I'M* lUtiMM aaaar t*Kit;l<laHi'aM: acmATiM tffact af iiflciMi; MNf Ca--M af Mfa'atiaa n tfi m.a, HIM Un> 36 HONS 02563 7 0-M1SIDINE MO 0-ANIS1DIME HYDROCHLORIDE There It sufficient evidence tor the carcinogenicity of o-anlsldtne <n experimental animals.*<7 p-Anlstdlne hydrochloride, given In tht diet, vat carcinogenic In Fischer 344 rats and B9C3F1 ailed, Inducing transitional-cell carcinomas or papillomas of the bladder In animals of botlt teats and transitional-cell care I nomat of the pelvis and tht kidney, and follicular-cell tutors of the thyroid In male rats.3 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 27. Lyon, France: IARC, 1992. pp. 93-77. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, Fronet: IARC, 19*2. National Cancer Institute. Bloastay of o-Anitldlne Hydro chloride for Possible Carcinogenic*.ty. Technical Report Farits Ho. 89. DHEM Publication No. (UIH) 78-1339. Btthesda. Maryland, 1978- O-Anlsldlne, a derivative of aniline, Is volatile with steam; practically Insoluble in water; and miscible with alcohol, ether, aettont, and benzene. o-Anitldlne hydrochloride, reported to be used In the uanufacturt of dyes. Is a possible Ingredient, in permanent oxidation hair dyes. Chloro, nitro, alkyl, and aryl derivates of o-anlsldlne art also used in the synthesis of ato dyes. Consumer Product Safety Commission IC'SC) staff members were unable to find av suppliers for this dye Intermediate. However, the Chemical Buyer's Directory and the 1982 Chemical week Buyer t Guide list 12 suppliers for o-anlsldlne. Production of o-antsldlno hydrochloride was not reported to the U.S. International Trade Commission (USITC) In 1980, although production was reported In 1979 by one producer. Indicating an annual production greater than $000 1b. Imports of o-anlsldlne and Its meta and para Isomers for 1979 were report'd to the USITC as 3.2 million lb. Imports of e-an1t<dtne through principal U.S. customs districts In 1980 were 2.4 million 19 (NCI). Ho data are available on the importation of o-anlsldlne hydrochlorlde. o-Anfsidtne hydrochloride was not reported in the Toxic Substances Control Act, Chemical Substance Inventory, 1979, public record. 37 ttons 025638 If o-anlsldlne Is used In th manufacture of dyes, the CPSC staff State? that residual tracts of o-anlsldlne ay possibly bt present In tone of these dyes and In the final consumer product. Exposure even to trace amounts nay be a cause for concern. This concern Is based on experience with other dyes derived froai arone tic amines. No data are available on the actual levels of o-anlsldlne In the final product. The National Occupational Heiard Survey In 1974 made no estlnatt of potential sorter exposure to o-anlsldlnt hydrochloride (N10SH); however. It estimated that approximately 1800 workers were potentially at risk of exposure to anlsldtne derivatives. OSHA adopted a permissible exposure level of 0.5 mg/m3 time-weighted average, and noted a potential for skin absorption. KMiflM ImUllMI M Itkdf ktlM iffMt r iHNiitiMii MMf (MtMt W (MM KttM. KMC> Iwww Nn ffMKIlM h'M, . M *-<tr Ifdrgcklgrldi st * \m U tw. tlwy m MiMMliy IINMIMUW. tm fCPA) rtv: M wi> tw hPNtlil ** Ml* IIIMIIl* MM. tilMMP* MWtM Ilf (Mil Iffrflt MMf um tMr<) (MM) NtUttfi mivrr: . IMIs ****** if, #4 */3 TVA. ItV/Hi MM VlMff UMM - MfftM !iu iitiiM. (MM) CIUttM If tofMlMfM n <n me.two IMM) 3d HONS 025639 ARAHITE* There 1 sufficient evidence for the carclnooenlclty of Arsmlte* In experimental animals.1 Aremtte" wit carcinogenic to several trains of ratt and to tna dog when administered In the dirt. It produced liver tumors In the rot and carcinomas of the 9011 bladder and biliary ducts In the dog.` Aren1te* as tested In several strains of mice by dietary sdslnlstratlon and produced a significant Increase of hepatomas In males of one strain.- ^International Agency for Research or Cancer. IARC Monogrenhs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `Internationa* Agency for Research on Cancer. IARC Monographs on the Evaluetlon of the Carcinogenic Risk of Chemicals to Han. Vol. 5. Lyon, France: IARC, 1974, pp. 39-46. Aramlte11 Is the proprietary name for an organic aromatic compound that Is Insoluble In water but miscible with most organic solvents. Aremlte* was previously registered for use as a pesticide on 39 crops. 20 of which were fruits and nuts, but In 1970, Its use was restricted lu postharvest application on fruit trees (ERA). The single producer of Aramlte1* ceased production In 1975. prior to the 1977 voluntary cancellations of registrations by all distributors. Aramlte" Is probably not available In the United States. Although actual production volumes are not known, this pesticide wes not widely used. For example, only 20,000 lb were used on fruit and nuts grown In California In 1971. By 1977, only 13S 1b of the formulated product were available on the U.S. market, according to EPA. No data are available on the number of workers who were actually or potentially exposed to Aremlte" during Its manufacture and formulation. Mar are estimates available on direct consumer exposure to the pesticide through consumption of contaminated fruit and nut crops. Regulatory action has now eliminated the potentla* for exposure of the general public. EPA regulates Aremlte* under the Federal Insecticide, Fungicide, and Rodentlclde Act and the Resource Conservation and Recovery Act. The signifi cant regulatory action was a voluntary cancellation of the active Ingredient registration by the sole producer In 197S. One fonsulator holding remaining stockpiles was permitted to sell them through December 1977. 39 HONS 025640 A'Ml la* cuunwi M ItMf MtlKK IffaeIml Mr a(mfalmtfM; k MflH MIIM. k (MM ^IMI I* (Mt<af inkttt Mtr CMC MC flMC. It tilMk tiinll isnrkaclUwtil,MMt1W$t T. KNNMitMM. lN!iim* mUUtmMMMUHt*IM')n(UIiMUk,"M1*4lI*wkHOMt4fli kk>MMtI//mIVMMH.MN MklftkMl. kl* In kniiMM MmiimM imt iuk> MM mftr uni rt fNMlllM Ml NMtttM M NIIHMU a* iMfifIHklf fklMM MMMt KIM M U/SI/71. kiiimi*. mu 9* CftlttW ltfl|t1M t n, t. mm OS Nmlu.11 40 MONS 025641 ARSENIC AND CERTAIN ARSENIC COMPOUNDS Inform*Uon on the carcinogenicity or arsenic compounds In experimental animals is cons lotrod Inadequate for evaluation.) Tht re Is sufffcitnt evidence thot skin concer In hianans Is causally ossocloted with exposure to Inorganic trstnic compounds In drugs, drinking water, nnd the occupational environment. The risk of lung cancer was increased 4 to 12 times In certain smelter workers who Inhaled high levels of arsenic trlosldc. However, the Influence of other constituents of the working environment cannot be excluded In these studies. Case reports have suggested an association between exposure to arsenic compounds and blood dyscraslas and liver tumors.>< international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 23. lyon, France: 1M0, pp. 39*141. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Huaans. Supplement 4. Lyon, France: 1982. Arsenic Is an dement that Is used as many compounds Including arsenic trloxtde, arsenic pentoxlde, sodium arsenate, and sodium ersentte; all of these forms are soluble In water. Arsenic trioxide, referred to as white arsenic. Is the source for 97 percent of all arsenic products. Pentevalent organic arsenicals are used for animal drugs. Elemental arsenic and arsenic compounds are used in pesticides, glass, ceramics, paints, dyes, and the preservation of hides. Arsenic occurs naturally In a number of ores and In food. The chemical form of arsenic In food has not been clearly established. Metabollcally, It behaves as a pentavalent organic arsenical. Approximately 70 million 1b of arsenic and inorganic arsenic compounds are produced In the United States. Over 9$ percent of the arsenic produced Is a byproduct of copper and lead ore smelting. About 13.$ million lb cf arsenic art Imported, primarily as arsenic trioxide. EPA reported one producer of potasslw ersentte In ono region (Toxic Substances Control Act. Ohemlcal Substance Inventory, 1979, public record). 41 HONS 025642 Industrial workers tty b exposed to arsenic end Its canpounds during manufacturing snd processing operations. An estimated 545.000 workers ere potentially exposed. Hlpher-than-average worker exposure occurs durlnp the smelting of arsenic-containing ores and durlnp pesticide application. Direct consumer exposure to arsenic and arsenic compounds aay occur In tlie consimption of foods. The FDA estimates that food provides an Intake Of approximately 0.02 mg/day/person. Trace levels of arsenic have been reported In the tissues of livestock that were adalnlstered arsenic drups and feed additives. Consumer exposure to arsenic aay occur throuph the con traption of contaminated drtnklnp water. EPA has established interim repu tations to alnlalte exposure risks. The peneral population aay be exposed to arsenic coapounds throuph air emissions froa pesticide aanufacturtnp facilities, cotton pins, plats aanufactwrlnp operations, and other sources. EPA estlaeted total envlronaental ealsslons to be. *000 tons. The Consumer Product Safety Coaatsslon reports that a small number of Arsenic coapounds are used extensively as wood preservatives. In 1978, epprexlaately (3.S Billion cubic feet of wood products, which Include limber, ttaber, playground eeutpaent, and fence posts, were treated with arsenleals. A larpe portion of the total products treated was limber used for residential construction, such at decks, patios, greenhouses, and housing foundations. The CPSC staff is coordinating efforts with the CPA staff to assess the need for controls on consumer use of treated wood. EPA, FDA, and OSHA have regulated the use of arsenic and Its compounds. The EPA limits arsenic In drinking water to a maximum level of 0.0S mg/1. The Agency established effluent guidelines controlling the envlronaental release of such compounds for certain Industrial categories. CPA issued a Rebuttable Preswptlon Against Registration for 11 Inorganic arsenic pesticide products and regulates arsenic under the Resource Conservation and Recovery Act. FDA has set tolerances for residues of arsenic-containing pesticides In fruits and vegetables (0.35-7 ag/kp), field crops (cotton, 0.7-2.8 ag/kp), and livestock (cattle and horses..0.7-2.7 ag/kp). OSHA promulgated a final standard In 1978 Halting occupational exposure to Inorganic arsenic coapounds to 10 up/a3. The PEL of 9.5 ag/a* fo> organic arsenic as an 8-hour ttee-weighted average was adopted by OSHA in 1971. In addition, tnts standard requires personal protective equipment, training, aedlcal surveillance, signs end labeling, and engineering controls. 42 MOMS 025093 Mi CMMIlMl VttUfIM IN lUtr ICtlMI Mimic i ICiVcmritMitts iffma *i IH tKU/nm iuff mimi mm fw IWlnll ftr CMIMIf Mil if MM-lnitM icnci CM, Mil IfflttM flldllMI fM mui* IMlIrlll Cltrtrlt mmii irmtl. CM. MMili Mur Mllly erltirl* Mf MM M>'MI | ftMl. 11/10/00. CM. 1)1: iMTfcMC intofc Ititti ftr Nl, s/s/oo. rim MdUiiii mil mm iffNM IM emir m>mm, m if Mcft Ottti IIMimll In Mil In MUM l MllMlHIl CMlfll| IH IN MMNll CM. Hit M Mini NfflMMI itiMNi Mr Minn in mi*9 iMtN fir wtiM. uhh mcMim mm KM, m.Ml! NlffMItt M Male mmm. NMni Mttn M mwin MHM If imill. Nlttt Wttllln mine in iMjni m nnHn m nnrVntiMiiiNf ntwti. frWt|ilH l/lf/00. B&.I.CIrIsrMfrlytoiui'rr Uu/liNi/7tN*.NNf nfh am. imt mihm tf rMN wur mNm inut<MM Nnl KNdiH fn ynniii M IM). ISCI: Mtr CMtlMltf llltltot** U NMn*N If ttMr MtlrNl Mr N IfftcMt tff OUtlM If Cmni nmiiiNi wnm unitim it MCI MMIU. CtrtfmftftlcHr Ml llmi ftctrr la itutHitiat m'mIImi. i# cn m, in, l|9, IN inrtlml is ra in. i. mu CknH tMUIto. ImMIm MUMI ctrclMftalcitr* tn I| mumm tmliMi mi ifficKi if tM itatrtli Nfm nuniiiif if cm MMlU Hull M CMIftti. 41 fl. f. )MM Mh, wmmiI irujinnti. i/M IMf IHNH IM Mini MlNlH II Mil* MM If KSMTl MMli It Mt ftr tM. TMl MMlntld Mi rtMItf, If NpiI MtrttrllM, Hull to MNllUf If IM1. MOM. nntnl IMMklltN, lid M IM INN Ml Ml (M ftr Ml Nf1n| fMMMi VIMfi ftr ittrytofc tftotie. It MirN) 4Mt feM MM Mt. CMMMflttfM, l/U Mali MMtltjr INlf NM* intNn/ rtnniti facflHttt. (Mil M tniNH N #l IWNII Mir t IMClil |n;ilW tf MlltlMf CM. MOTS. NMWt (MMiutm, i/M CtoetMMtlM CHCftrltf (mMMI NN(n* M tfl ffl.N MU, l.l M/I* tllttl IMlt HIM HMMiMM IlNl tf It CM 111.11 0.01 tf/1. Im Mt MMli ctKlMfmlcltjr. IMh rt.it* far tnittlt PttlilM* Iilltlay tttoto cmttilMM Ittt* tf 0,01 af/1 rpt'N I* ftrct. Cara Naflltr> iHCltifM CirciMfttll't/. fi Mtr rrrft* MM lll N ttnlNni. icrai htomt CttMrcttMr ItmH Mtirmt(1iHmMi|NiMfiInMnNI .lUV* KtrilwMl 43 MOMS 025644 trmli m Cp>mhW I(|(l4ll4| t*4 (tNf (Vl*4| KMItlM litoct *r tos*Uifm; tMr (Mtl CtUttM a# NfH,*t*a WPlM ^M4I torMV *f Mnr NtKiM. IW.*- mm *f (N nw ImH *r***tC (PNKMI irt tlM IMI km tot* iimutii ill* NiMtltml imif. Iikm *r* HimN uaicity IMM (* 4M41U<I (IN t ** *** Nat Nil Wa Nl IKKMNIK plll|ll. <n*i Kll 1.1 MA> l-N TIM M HHt dffMUli It If/al I'M *m llwrtwlt). N Nil *e m (mik( *itt mull ui* ip ltavt* if NMinliw iwriiMi inwii mat is ih* t* uni sit* * y trrttatt**. IfMNIlN <H|l*f, flMl'lltf, kf*4*H* WltotNf, IM NlUlt Wf> *ftll*MS fMrlPMMI It* Nitifl, NlUfMt fWIfniMl, IHWH|l4| fiNlfNSMI, Slf* fNilfWlti for ntiUtM ****, iiMiM| fmifmim hr mUlNfl. MSM) VIIMrml rt(l'NMI ftr Mit*r**MClf Nll| IWNM IN UNtltilt WtM IN* IN rrfll *P* tWIIlf I* --N4l .. irwM Uf*ll far *PM*t**H. UNI Itwlilt^ ilttayi Ifit: 1s**M*ly. t.l **/) M4i* illmii nawimlw. 1/77/71: NM fMNwr tUNf^mrfwt Halt ffctlf*. I/W7I; MU) tUNiP* KyitiU Hall tftocti**. IMNO tot* *f*i( in* Nff**H |ps*at|| r* flfalttN war CM 11 IM.lt. IM.lt. M.II*. to*.IN. IM.M4, (fMI i* cm ma.iNM lN*U NIMltl II CM lilt. MM ItNffMK *ft**K) IMW) tPSMlC IHMINS CSC nil l*Jtr*Mf Will rNf*1*tl* ntNHNIlf MtsrlWU NNMt ISttt It. Ifft If) M toaastof fINftllf fnin< MtS. to*a*1f*t** //*. Nt mm* a* mtiNwiiiHy- t*c**rt*i fPNlar ini ta NaatltN *M snimIn * CMBIMlI *N IlNlI PS*1t to r***t*!*N *f cctomal mwms. niMI NMMHlI a*vltt1*M C**ulaNtMft inn l.l ****** *nni( trtoai** 1* Mas*Nl*S *N fruiN ifV*. l/w. Sm PNsctt** to m*. H*M, fcS nlIUf| CSNIIIIII** SJf iNNin *t ttfM |f**i. /*/>. NtalNl PMNItM t* all. MMI, li tfU Hi*** ri|r|*f || Iwrytilf m**l<Sl HltKINI. M/ll/71. K. N01*3t*4: lajm Milt Sf--km. *11*l**t 11lc*t1 *fi HUUI. M will r*!*MI 1* Ht*SS *f !99Ci I* MtoltM H Nlft/fKlftNll1 IN1WKI. 11m t*SlM(*4 SI MllfIMI nntIMM *1 MSU. NIUI IN* U (WWW *r**MC IPtMl** *Pf SNJttl U UN MM fWllft* ms. *p*Mlf*t** l/ll/to. Ml *MP imn WN rwwnlllit ir* sitlt *mip <*Nsi**rut*a far r*f*:*t>a*. hs I** UmIMW* IlMlMM ftp*** IIU> MM ***** l>MtVli*iNOtrtM. <'M> ft** psfvliitm imn *p**Nle. <tSM) to CM I1M, Ul.lft VrlttM Mtl* M PNflStPMU *1 ft III. p. 4SH4 o n m , p. *mi 4t CM Ml.11, Ml.U urn a CM Iftt.MM MSN) <C*aN*> 44 HONS 025645 KM (Wlllll ICmiIimO VWUTIMS fffect if lifjlitiMi; VtMr Cwatfiti IK.NUII( IWU: 'Ills UhriiNt Mill nfillKto Mtatllaftlao rmrtUU ()M0 It, IU It) w4 nyrtti| m^lnwiu. 1/19/79. KM, IrtMlKl laMimil Mt ItlltMtH WtlflM iff ItfltC 44 HilirMlf If Mill. Maittt IMM M mtMIllR My if IMM tf MkjKt M MMIIaf Mfirl/wifiiMilM riMlnarti. HmmIh'H 9/19/99. In tmtniM 4miwH Imp ataiaMM MM IMI1)ilMllWfliriM. IIM) Sm nfilitlM aafar itmI(< (9SM) Mt lltM M (IKMNMI fraattr cart la *a*4llaf aaf iMtaiaf Maluli Ml MmII remit la rvMctlaa f acctaaatal uimni. lift) nM1riillMlmRmRu:lrMi Mill rtwlaiMi mtNMitiM*f ranmiii mmuii (IM It, 414 t|| towtlaa MinlRf titMlfMM 4/19/71. nm, It VII IiimI rtfa^M laaryoafc araaatcal atatlclcaa, ll/ll/TI. Mt Mm4 aa carttaataalcltr. tacaarifa* mtfrtatvr cart la MaOftaf a*4 iM||1i| cMMcata lMii)4 tttail la rtiactlaa f acclltnui MWIMI. Npiwi favaralaatlM la aavalaaMct ill alfrtii ms alMf Maa a* a taM fniiMlln. KM) KCM, IrinUil tMMU a#t MMMHM MKlMtl IM MltM M MtlMM MMtltMMI If Mlln. MMtM l*M M (Mill Mr ^ Mm mi MljKt II fcaaOltaf Ml MMrtAlfMlkMlM MMlMMtl> TMMlfltM 9/19/44. Sm ClftlMIM IlMIMMt Irwi *IUMM aaiar tMCHjrlMlMflMMM. (IM) |M MMlitlMI mUt irmK. (OS*) ClUtfaa af lafMlatla* o era 117.11 40 cn Jii.ii 1174) 19 era 1910.1911 I9SM) era49 w.i. ip.ii 43 Ft m. 9. 44M7 40 era Ml.11 (IM) 9* era 1919.1019 ItM) (.DllMl MMlUl SZlfMvt Mill MWlMtMt atMttaMaf mmMMW MMl'V DM V, 414 l|) Mi Mm19 ratartla# Mrriw mil. towlyiiH 1/19/79. mi.rvm iMMlMlf fMWfltlMI CMtllfr. M Mr* MM 1 NflMt if araaaftt M MaiaMIM M M |Ni1| irM, 9/M. flftt, It MylstratfMi if Mm pnMtt MlMUrllf caactIM M MlMcm. 1/4/77. ttm, Ct MM IlMH M*^*t 11 (Mr. 9MK MMiltll MltUIlH, 14/10/74. Mt MM aa carclaaftalcltr* taM raMctlM la ate. MtarMaaf aat M M a mi mimmHm, Mt la aacar caaalMratlaa far rafalatiaa. 45 40 era 117.1, 117.11 Vrlttta aatica ta all iffKIM rtfiatraata 41 ft Mt, . 49947 (Cenimct) MQNS 025646 ItmoIc tM (mmi (Cw>*to) ICCOUTIOnS fttfrittlVM M< (ttMr ActlMI tffHl ClUUW Min* Amton: KwclirtN) Ml, JNl'KVIi ipimImI (iwm mi MMMh in '(itH <i kuarNi tmUtoitn ( muti kMM u cmui* W|f f Vhm HI ftojnt M ttotlftf M piHfl/norlimin nvin(Mi. FrtolftiM 9/19/00. TXI, Atilt ml# nttoHnf pnmi to m mu. NhiH 2/29/tO. to tin^miH Umiwn tn# iuu> MM tor {Mil/lMHMntrtn. UFA) to ftfvUttot tor innK. fOMit to CM Nt.ll to FI 2, 9* IM UFA) >9 era irit.Mii (SNA) triMk HmmMi: II, Jilt lUiito toll totittN nut* HlftlM torM^ to vr (Ml It, ttlt If) M MmmIm M.! VM r*toM* MU. totolttoO 1/29, KM, NM<M4i Mjnt* Mitt Ktott, lf*Hn1fttiON MttMi, ,1 toMI ml* tot to mMi 1910 If to toftAIn to riMrt/mtoiM<f nutPimu. Mu totiMtH M Mlirto ctolttomt mmi. Onto Into to imuIi mnic 9**uct* to M*Jt to to :to rotor** MMI. tottM l/)9/tt. mM, 9: niiiirifitlM to m ittW m M 1 Ml fftUmtlN, 2/19/01, <rtoM. FlfU, fi 0FAA lito nfi^M n tMrtnft mnie*i mticMn. lo/il/io. tot Cortltoto Mmiimm tow UUMM NMr ItotrlMlMflNto. 1(H) Sto MfrlitlMI tor mt(, (OSNAI Ml MlM to CirctMftMUt- Onctftofcll*. totftolclt)r, to ttnttpN Cttr. MmII fftof MirMHir tOortlol towtOntoilttMtoMvittlMnfIntoto*vtlto*otnot mnrviilff. UFA) to CM |,F.I, lir.lt to era mi.ii, H*.st to FI, 9. MOW i) ri tot. 9. toMF (CM) 19 CM 1910.1010 (MNA) Utoto tottoi. CiWw ItoMt. MNntM toMtol Iff Iftto* W tourt--l ftolltofUtt Mitt, MftM Ito to (MUto Ml tf toto to* tofitot to MMIlM to toM/rKtowiM mmuimmi. 9ntoO*MO 9/19/10. In tiniMw MHitto tom iuu* MM iMir i*tonjritort"OfHtot. MMI to era mi.u (IFF.) 46 HONS 025647 ASBESTOS Thert ft sufficient evidence for the carcinogenicity of asbestos both In humans and In experimental animals.* AT! types of coaaaerclal asbestus fibers that have been tested art carcinogenic In nice, rats, hamsters and rabbits, producing aiesothel loans and lung carcinomas after Inhalation, and after Intrapleural, Intratracheal and Intraperitonea' administration.2 Occupational exposjre to chrysotlle, aaoslte, anthophylllte, and alxtures containing crocldollte has resulted In a high Incidence of lung cancer. A predominantly treaolltlc material mixed with anthophylllte and small amounts of chrysotlle has also caused an Increased Incidence of lung cancer. Pleural and peritoneal meso theliomas have been observed after occupational exposure to cro cldollte, aaoslte and chrysotlle asbestos. Gastrointestinal tract ctncers were Increased In groups exposed occupationally to aaoslte, chrysotlle or mixed fibers containing crocldollte. An excess of cancer uf the larynx was also observed In exposed workers. Hesothalloaas have occurred In .Individuals living In the neighborhood of esbestos factories and crocldollte alnes, and In persons living with asbestos worters. Both cigarette smoking and occupational exposure to asbestos fibers Increase lung cancer Incidence Inde pendently. When present together, they act aultlpllcatlvely.*.2 ^International Agency for Besearch on Cancer. IAAC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Huatans. Supplement 1. Lyon, France: 1979. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 14. Lyon, France: 1977, pp. 1-106. Asbestos Is the generic nnme of a class of natural fibrous silicates. There are four commercially Important forms: chrysotlle, amoslte, anthophyl llte, and crocldollte. Cmysotlle represented 94 percent of U.S. consumption In 1S74. Asbestos Is currently used In more thn 5000 products, some of which are roofing, thermal and electrical insulation, cement pipe and sheet, flooring, gaskets, friction materials, coatings, plastics, textiles, and paper products. Total production of asbestos In 197t was estimated at 2SO million lb; 1979 production was reported to be 200 million 1b. Some producers are developing suitable substitutes for asbestos, and production Is expected to decline In the 1980s. 47 HONS 025648 Hunan exposure to asbestos It primarily through inhalation or Ingestion of fibers. Asbestos My occur os o contaminant of food or beverages that cent In contact with Mtcrlals such as adhesives and repeatedly used polyesterrtsln, rubber, and phenollc-resin molded plastic articles. fOA is aware that asbestos night be used In dental filling material, especially teaponry cements, exposure to asbestos In dental filling materials Is assumed to be very low to virtually nil. Asbestos is so widely used that the entire population Is exposed to tome degree. Worker exposure has been a concern In the mining and milling of asbestos, during the Mnufacture of all asbestos products, and In the construction and shipbuilding Industries. OSHA reported that about 2.5 million workers are estimated to have tome exposure to asbestos. The general population Is exposed to asbestos fibers from air, beverages, drinking water, food, phanaaceutlcal and dental preparations, and asbestos* containing ccntixaer products. Families of asbestos workers have keen exposed to high fiber levels through contaminated clothing brought home for laundering. Asbestos fibers are released Into the environment from the natural occurrence of asbestos In the earth and at a result of wear and deteriora tion of asbestos products. Asbestos minerals are emitted into the atmosahere and water systems from the mining and milling of asbestos ores. Applications of asbestos Mterials to buildings ond vehicle brake linings account for a significant amount of amissions to the atmosphere. The demolition of buildings with asbestos Insulation or firoproofing can cause high atmospheric concen trations for relatively short periods of time. The disposal of mining and building material wastes In landfills also Increases the distribution of asbestos Into the environment, but no estimates of the quantity of material released In this manner are available. The 1977 banning by the Censuaer Product Safety Commission (CPSC) of asbestos In patching compounds and In gas fireplaces prevented additional exposure of several million consianers who were exposed to asbestos from those sources. U.S. manufacturers of hand-held dryers cooperated with CPSC by voluntarily ceasing to use asbestos liners. This voluntary program resulted In the repair by manufacturers of 2 million dryers. CPSC has published advance notice of proposed rulmaaklng stating an Intent to further regulate the uses of asbestos. The Commission will convene a Chronic Hazard Advisory Panel to assess the carcinogenicity, mutagenicity, end teratogenicity of asbestos and. If feasible, estlMte the probable harm to tnxaan health that will result from exposure to asbestos. The panel will meet for the first time In January 1983. A report it expected from the panel In early summer 1983. Studies in progress are looking at asbestos release from products; another study in progress Is examining asbestos substitutes. EPA proposed an asbestos water quality criteria document for the protection of hiaan health In October 1979. CPA regulates asbestos under the Clean Air Act, the Clean Water Act, and the Resource Conservation and Recovery Act, and proposes to do so under the Toxic Substances Control Act. A voluntary EPA program Is removing or encapsulating sources of asbestos release In school buildings. 48 HONS 025649 CM published advance notices of proposed rulemaking that stated an intent to farther regulate the uses of asbestos. CM action concerning asbestos (and talc) restricted the utllltatlon of asbestos filters In the manufacture of parenteral drugs and parenteral drug ingredients. FDA has taken no action to date wlthTegard to asbestos in food, because there Is no evidence that the ingestion of small amounts of asbestos found in food poses an/ human health risk. The OSHA standard for asbestos fibers permitted In the workplace is two flbcrs/cc of air for fibers longer than S n. In addition, this standard requires personal protective equipment, training, medical surveillance, signs and labeling, and engineering controls. In April lgtO, a MOSH/OSHA work group reviewed the most recent scien tific information and recommended that a new standard for asbestos be promul gated. Receamendatlons included reduction of the current environmental limit and elimination of nonessential asbestos exposures with substitution of less haiardous alternatives. 49 025**0 HONS AtMHM KUUTiMS IffMltOWM )tMr KIlHI IfttCt if litvlntw; linr ItMitlt ClUtlM If |M 14 f>Kl * IIIIIUl. K.M fit'll mill t* Mir Hvim M!t<i f imim ndmil*| MKrl|l*| I'lMtH HTNC* I^WtttN llWMKM ' *11 nmiH i* <nii trttvcti itm M(* nttltt) ItMfl .* ri'NiH l)fl*f M. It* (ItHI M MtcttH WK'MI >M 4t l*| Mttrlilat HWUll 'flflrilli fr ttHIIII. tuft toftlttttf IMHlI U IM IMIW Htr far cwiwf hi, w> (lMMflt)| IttllMIN IMt IM If :wwi. lit'*) l.t oil Mm Mttl rvunni. Hinn l ml iillln immi m mm IINM U MUO'Of IWIMIWi M MMMaaat Minm, M i.i * if* mmi mmi u mn> l|l| litlflllti iMItllMl Mfiwnt. ICFIC) IMO CM IMt.ir It IIf1 f M. MOM IMO CM IM 1M0 CM im (OKI CM, Itti Htrmlif HHril fNHtlll IIIIHMII. IrwIflM Htn m itm/ts. (, mi tmwii h w imiw 1Mattry M In MNim 41114* W'UtlH. I/ll/ll, m it/u/7l. V t/1%/1*. CM. MHa!: t*r *l*tty .*U*rl| 0*0)11*44 t* HmI f#m, il/lt/tt. TIC*. it HlHtlf} frm ' IMtl> MM If IIMMM 1 ItlHlt, Hllllllll vwn. MM HMUf CTHI M p^ lllfl* if Hmii iiHm, ihhimi itm*i*. Hurt# III tfftJVACttM ait* CMC. NMilV* Mll'l* KM. Ml'Mf! bMKll mu ifMKU, |fl>HMlfll*M* HtlNI, wOl IMIMI I* *1 ItPO 1# II MHMil M ilH>V,KI*IMH>H 'lllfMHt, 'PMlUM l/ll/M. TIU. U Mt IW>Wt If MHiim ihwI mm htNtin m Umrtl act IMt. inmM Mi iuu iIm iMMCt KMlIl f#r mull IlMM, Mfl Milling flMI Mt lM*l Ml It Hfim *# m INI if MMUttM M mini. In (minfi* Hmuni Inn iiiimm nln I.Nit|>lMMinnn. IIMI IM nMlM Mi MflllOM linily tfcmafi MflatMf ai MKHti (Mtnlt. tanr. idl imu nn m mi Mum #f m mwi if niiili im kimmuHi *fti Miitinl mum. (Mini UnM MtCI trait iMii'M, IlMItM H Ml ilMCtljr MriltM. (nirtl f MMM hum mil <Min Mfm if mini Nir unitit. M (fl 41.20-40.20 M CM 427. 4)0.70 41 fl 2)1. . 71)10 Hfk tatirnt la ictta* It .miiwliti t mini initut-<i*iiiiii| Miniiii. 44 M M. |. 17701 nu lot. i- 4oom 40 CM til.M tin u iw# wi mm ntn ntim ti iiMitM. sitfatitM cm*Hmi nriif uMnl mtmm. UFA) 4| CM lit, 0. llOOt UFO) tCmitamf) SO *QH$ 025651 HUUIIW in (Uf ut<m (ffwt if lifilii*Ni: INf tNWMI (lUUM tf UMlflfat ft* torn* H 'Nil, fMC*: Mil NMIIM Nil tfprtttf N llMlUt Ml Ml INN M W MflUlIM If 1 IIMlMfN. *1 NM* HI ***'! trt M NV I'l.lNII 1* MUMU tM ImIi If llfrltlM {I UNUN MM full fM tut rtfllltll INI. II II INMf UMt MN Mt MMfNlNllf NN* I'M, VMM UI N `ilMMlIl mi m m lMl|* tlfTtlltt tf tfttlttV lM MM* fMI. ft* Inin if MNn) Itfiiii. fMC*: M NfllllNf IIIINf M M rVfHlltlMI IIHH U MU. (ft*) f<*rutr NMIlMI Mil NMlN lltl> MIN tf Mm Mr* IIMIIM l KlNltf frl* llf MM ftM IM MNlMUt If imillM M'tClIM MIAMI. iKfMlM NNIMH tf INMII IM mtltt* NMlfM tf IWUlIM St IMMlI MMl iMNtify. fftAI u crt i*i.im. jfr.HH. iff .tut. Iff .HOt |fM) flil f MUf|/tl !#! iNflO. -* DA. M ftm/tt >INW iMtin. dlMif. Mfllil NmOliMI NlNltl Mr mu ms MMuriat MdffWMt; mniiwim *M MM ftflf--Mu; fWKtlN tUt*ft. ftUlNMf, M M*f MM MNUMMI ta *TMf NNI ItfltlMtf M N* NKIHI IWtNll N1 Ml NffllNM U iMt ItMtlM M NNlllWl IlNlll lift rm<flN*ll ftr Mfililil nmi. IMM*I lHilN|t IW MUMMMllPt I MtCf MilM ))t> MU (MWimiM. tf cr ifii.iMi (MM) NM Ttfettttr HtMrtt--TfMtUlt M tt*f M lit t*>)/tUlt|> Mr IM: IMItM u flttf|/CC 1 |Nll Ittfl* tr 1 MMf Mr TM. linflU lirfMCf TMMftnr IttMlNI-- I flttft/u 1 U Utft* Mr fM: U flttn/tc * % m i* Utftft, t*Uit|. M tlllUM ftf Ntlll IlMIr, f tr/Mjr. t/ll/ft: ItiMiri ctttrtft MiMH U tmlvM MU rttnrlty, MltMiltl^. Wlf- lriMlt, *M iMjlMn Mrtn. wnt\ UwtMt lUMl'M**! flMM'tt I l ft Ittftfc, t-*r IkA: 19 Httr/< 1 M l IttfM. ulllaf* M\n%\ flM> SUMlM .MNIM IWt iffMlN, (MM*) SI HONS 025652 AURAMINE AND THE MANUFACTURE OF AURAMINE There Is sufficient evidence that the manufacture of auramlne ti carcinogenic In humans. The evidence for the carcinogenicity ef technical grade egrantne In humans and In experimental animals Is considered at limited.! When given in the diet, commercial auramlne of unknown purity was twnorlgenlc In two strains of mice and In WIstar rats after oral administration, producing liver tumors, and after subcu taneous Injection In rats, producing local sarcomas.! The manufacture of auramlne (which also Involves exposure to other chemicals) Is Judged to be causally associated with Increased incidence of bladder cancer. The actual carcinogenic compound(s) has not been specified precisely.'< 'international Agency For Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: 1482. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 1. Lyon, France: 1872, pp. 68-73. Auramlne (Basic fellow 2), an aromatic amine, appears as yellow leaves or needles,, which are Insoluble In water. Auramlne (hydrochloride salt) Is used industrially as a dye or dye Inter mediate for coloring Inks, textiles, wool, paper, and leather. According to 1878 U.S. International Trade Commission data, auramlne was not domestically produced: however, 165,000 lb were Imported. Htnaan exposure to auramlne occurs principally through skin absorption or vapor Inhalation. Approximately 3000 workers 1r the textile, paper, and leather Industries may be exposed to au-amine. Lew-level dermal exposure to the consumer may occur but would be limited to any migration of auramlne from fabric, leather, or paper goods. Auramlne Is regulated by the E7A under the Resource Conservation and Recovery Act. H10SH Is currently preparing a special hazard review for auramlne and the manufacture of auramlne. 62 MQNs 025653 toMtlta d Um idvfi.'toM H %r>M ItHUtllN iM ttWr MHm litM m inmu tMfem* * ;m *4 ml, mwm Nllwtt OI M HUMM It lm, IC'KI CM, kl)MU md K**Ctl. wi i mm NUHI, M Will WO* IMI if tt nwHw mw WfirV'Ni'*Wi*| wotrawNt. Mw, ll|U NllflNt (MHhiNt d wtu. MUi in* to <*ui wriuw f mi. Ml It IM MN Intm. IrtultilM 1KA, Will mil PMvIHMf tmni mw mm mu, KifttH l/lt/N. Hi im (twiMM* Hihmw Hmi luumi wmmp l**ifiMMflmrfM. (CM) IMM ifKUt NUN InM It inHrilM. UNM UUUllWl If fact *t IimIiI'mi: ttm tvwnu {lutit* r tt-tut <rt hi.u, m. <1 n 4, . UM IIMI S3 02S<>5'* HO*5 BCN2(a)ANTHRACENE There <i sufficient evidence of the carcinogenicity of bent(a)inthrecene IBAI In experimental anlnalt.1 BA given by several routes of administration hes proved to be carcinogenic In the Mute. It produced hepatomas and lung adenomas following repeated oral administration to young alee. In a parallel espertment with me thylchelenthrone, the carcinogenic effect upon the liver and lung was similar for the two compounds at the same dote level. In the same espertment, BA did not produce tuMrs of the pmrofntestfnel tract, whereas methylcholanthrene Induced tl,rm consistently.* BA Is a complete carcinogen for the Muse skin. The fact that the tuMr yield was higher when using a dodecane solution than with toluene Is related to the co-carctnogentc effect of dodecene. Benzolalpyrene given at a lower dose level produced Mre skin tumors with a shorter latency period than did BA. BA Is also an Initiator of skin carcinogenesis In mice.2 BA proJuced tumors In mice following subcutaneous Injections. Fifty g BA was the lowest dose tested, and it was effective In newborn and In adult animals. It produced bladder tuMrs In mice following implantation.* international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of who Carcinogenic Risk of Chemicals to Humans. Supplement A. Lyon, France: 1ARC, 1982. 'international Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 3. Lyon, France: IARC, 1976, pp. 45-68. BA belongs to the class of chemicals known as polycyclic aromatic hydro carbons (PAHs), which are formed under geothensal conditions leading to coal and petroleum and as a result of Incomplete combustion. BA Is slightly soluble In water and soluble in MSt organic solvents, except alcohol. BA Is a contaminant and does not have any reported cossnerclal use or application, although on* producer did report the substance for the Toxic Substances Control Act Inventory. 54 HONS 025655 IA hit b*l reported present In cigirette smote cendensite, eutjmoblle exhiust git, toot, ind emissions from colt ind git works end electric glint!, (A ilto occurs In the iromillc friction of mlnenl oil, corwierclll solvents, wixet, petrolitum, creosote, coil tir, petroleum isphilt, ind coil tir pitch. Hlcrogrim quintltlet of IA cm be found In virlous foods such it chircoil broiled, birbecued, or snaked meitt ind fish; certiln vegetibles ind vegetible oils; ind routed coffee ind coffee powders. Hunen subjects ire exposed to IA through either Inhilitlon or Ingestion. Workers it ficllltles with likely exposure to fumes from burning or betting Of orginlc miter Ills hive I potent111 for exposure to BA. Consumers cm be exposed to this chemlcil through Ingestion of virlous foods, with concentritlens of 100 g/kg In some Instmces. Cigirette smoke condensite his qumtitles of M thlt rmge from 0.03 to A.6 ug/g. IA Is found In the Atmosphere it levels thit viry with geogriphtcil (tores end cllmte. These vilues cm rmge from up to 135 ug/1000 *J In Sumer to 311 ug/1000 m3 In winter. Drinking witer simples my contiln up to II ng/1 IA, ind turfice witeru hive been found to contiln 4-115 ng/1. The toll neir Industrlil centers his been shown to contiln is much is 390 g/kg of IA, whereis sell neir highways cm hive levels of up to 1500 ug/kg, ind ireis polluted with coil tor pitch cm retch levels of 2500 mg/kg. The- Circlnogen Assessment Croup It ERA lists IA is c circlnugen, ind the witer quillty criterli for RAIIs ipply by inference to IA. There hive been few ittmpts to develop exposure stmdirds for RAHs either Indivlduilly or IS I clits; however. UlOSH his recommended I workpliee stindird for coil tir products of 0.1 mg/mo is i time-weighted ivenge for i 10-hour workshlft In i 40-hour workweek. OSMA Indirectly limits exposure to IA by requiring thit occypitloml exposure to coil tir pitch volitlles not exceed 0.2 mg/*3 over in S-hour period is i time-weighted ivertge. 55 IW1HS 025656 atbMM i ItfillUl*) IM k\Hr Icilrn irftct if M|iit'uii IIMf (RMU KM, Ml*MM: miu 10NUMt, IN nil) Nllt* Ml It IKtit < M i| u MI't M ltKn/rKH*M>l*l rntllMMI. Alt* MIHNIM It MliNMI IMIKMM |l Hill. CM, Willi MU' WAlltr I'ltl'U MllWft It IlNl UN, ll/n/M. IIUI MR INrilM; M lilldUf Mr wmtiu. TIM. Mai: ftltortf* Hit rvciilrlM MMIH M IN MU. IMMIM l/D/M. In twiMtit IiuiimiI (nm iuuhn wtif |.Mtiriii*HMNM. MM) UfvltUM UIM U (INtl( UllCll|> flltiri :r*4ttr un It UMI<N d niiii. MtoU. If MMlfiM, HIMII Mill far tictoatiM iirun. mmi Mil 14 !/* 1`M TM (tftl Ur Mu* **Mii*D ilMU, wjg)., (MtiWT iiltMyi KM TRIM', >UMir|.NiWRU IM1I tffNUN. (Ml CllltlM If llUUltM to CM Ml.I), Ml.)) p,i vi di. mi l n II. |. IM44 MM) tt crt m.it. im. itot Itowi Si HONS 02565? UHZINE The evidence that benzene 1* carcinogenic In experlmertal animals It United.1 Administered by stomach tube to rets, beniene Inert*ted tb* Incidence of lymba' gland cerclnomas. An Increised Incidence ef lymphoid tumors occurred In male mice exposed to benzene by Inhalation. In similar studies with another strain of mice and with rats, no leukemic response was observed.2 There Is sufficient evidence that benzene Is carcinogenic to man.1 Several case reports as well at an epidemiologic*1 case control study establish a relationship between benzene exposure and leukemia. Two cohort studies showed an Increased incident* of acute nonlymphecytlc leukemia In workers exposed to benzene. There has been an additional report of a large number of leukemia cases (most of which were acute nonlymphocytlc) among a group of workers exposed to benzene.1'2 international Agency for Research on Cancer. IAAC Ponographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29. Lyon, France: 1982. pp. 93-148. benzene, a volatile, colorless, flammable liquid. Is a major raw material of the chemical Industry. benzene Is used extensively as a solvent In the chemical and drug indus tries, as a starting material and Intermediate in the synthesis of numerous chemicals, and as a gasoline additive. Eighty percent of the benzene Is consumed In the production of ethylbenzene, cumene, and cyclohexane. benzene Is domesticalIv produced In the United States In over SO locations, and In 1979, approximately 12 billion lb were produced. An additional 1.8 billion 1b were Imported, whereas exports were 1.3 million lb. Benzene is expected to remain one of the Industry's most Important chemicals. Increasing market demands are forecast at approximately $ percent annually. An estlmatad 3 million workers may be exposed to benzene. Exposure may occur during the production of benzene 4r during the vse of substances con taining the chemical as an Ingredient or contaminant. Human exposure to benzene Is primarily through Inhalation of the vapor or through skin absorption. (7 HONS 025658 Out to the ubiquitous nature of benzene, over 75 percent of the popu lation hat probably been exposed to this chemical. In 1976, an eitlmated 1.3 billion lb of bencene rare released Into the atmosphere from 132 mlllijn stationary and mobile sources. This Included an estimated 240 million Ib/yr from the production, transport, storage, and use of benzene; 1 billion lb/yr from the refueling and operation of motor vehicles: and 22 million lb/yr from oil spills. It hat been estimated that (00,000 persons may be exposed to benzene from coke oven emissions at levels greater than 0.1 ppm; S million persons from petroleum refinery emissions at levels of 0.1-1.0 ppm. Information on the levels of benzene In the atmosphere Is limited, tablent monitoring data Indicate that levels of benzene range from 1 ppb to 100 ppb. The h1g.iest values were reported In metropolitan areas and may be due to exhausts from motor vehicles, benzene has been Identified in drinking water and In subsurface water at concentrations to 10 ppm. lenzene occurs In fnilts, fish, vegetables, nuts, dairy products, beverages, and eggs. The National Cancer Institute estimated that an Individual could ingest up to 2SO vg/day. In Hay 19(1, the-Consumer Product Safety Commission {CPSC) withdrew its proposed baa of consumer products, except for oesollne and laboratory reagents, which contained benzene as an Intentional Inoredlent or as a con taminant at 0.1 percent or greater by volume. The decision to withdraw the rulemaking was based on CPSC findings that benzene Is no longer used as an Intentional Ingredient In consumer products and that the contaminant levels remaining In ct'teln consumer products are unlikely to result In significant consumer exposure to benzene vapor, A labeling regulation, established in 1962 for products containing more than S percent benzene, and a 1977 safety packaging requirement for paint solvents and thlnners containing 10 percent or more of petroleum distillates, such as benzene, remains In effect. In 1977, CPA listed benzene as a hazardous air pollutant under Section 112 of the Clean Air Act. emission standards for etnylbenzenestyrene plants, benzene storage and fvglttve emissions, and coke byproduct plants were being assessed by CPA during 19S0-S1; and a standard for maleic anhydride production was proposed In 19(0. EPA also regulates benzene under the Clean Water Act; the Federal Insecticide, Fungicide, and Rodentlclde Act; and the Resource Conservation and Recovery Act. OSHA's 1971 standard limited benzene to 10 ppm In the air for an (-hour time-weighted average (TWA). This was lowered In 1977 by an emergency temporary standard to a 1 ppc TWA with a maximum of S ppm for 15 minutes. A final standard establishing a permissible exposure limit (FEl) of 1 ppm (-hour TWA with a 5 ppm upper level limited to 15 minutes has been overturned by the U.$. Supreme Court. Subsequent to this Supreme Court action, the OSHA regulation has reverted to a 10 ppm (-hour TWA PEL. $6 HONS 025659 IMW KMUTIM tafaUttaM IM ItMf tttlMI Cffacl af bti'HiMt-, ttaar (MMiti Ciutfa* af ttfaiaiiaa lift: fraaata* tH iMir CM* if NMNi | ta iMtmr i*ii< N M PMMtl 1.1 NftlN * m lr taltfaa if NMm a (iita*tnt. tlttw *IMfM II mi. at laaaa faitatitaal aic af numi i cmmn' ninn. fmitt it mmH af iracaiaa M, Mt.NMtMM HMMl #r aa iMfir iium. take ru, i*iwiU rMKti wuiiiii 1 MnMl K N't miM 4y mill Mil Mir (MitMff IraaHaf. IMfluis ta mm tm iff*ci*t*ai af tmiiaf. bfiv MCUflf rmlfM MU' WM fir MMM>I|I (Half MltHtl 1MI ttaUH II nww M tart MtMlMi tmittattl. MCI M I--MM, M M*|M Ml M*f HKMUr (Ml M Ml MS it Hr r. KMC I at MM a* itretaataatcitr. Hfiit Mfitl M*t*tat affMllvaaaii uiimM ll putan a*ar ).jra*r arita>*at uli la aamu aalaaalaf raaactfaa fro* aaacaaa pnamia car t. ICTK1 M ft. . mta sett cn iMt.se laid), laid; icto ert mt.ia lICIS) ICMf.l CM. Ill: Mmmc IMtM fir MM* fatal* UN*!, M/fl. KM* Hr MMm Mil* IlM Mi wide Mffrtii KMKttn iNlllltM rmilC 4/||/tt. IM HT HI|rlHMlM-Hr*1 fMlHlw MM* M iMrill tMm vlMlaaa fm Mar HtfaMHit wrut to mhImm. M. Mill MMr CMllH erltarla MiiiM hm) turn, iimm. M, Mil MMM Mil MilillM mmmimcm rmmiii CHWtr um H, CM mi M MmM mirtm racalra* MU. UMlflM Vtl/H. fWU. ft HlMUry BMMlSltfM If HlMrUlm If aiwtt (Mtiutif MUM M N MtfH MfTMfMt W MIN Minwi KM, MtlOtt*: bUNU MM anaaCta. ifi.im>ft*uti* tatim, mc miss mt* CMt la mcmc if ICM If U MMIIaa M rtttrt/MCCriiMttat ft<fiMii. All* tllMC M I Murcm imiimii if Mill. Mtu MM H IIMill MMM* CM MJKI M W MM MitWIlH. Mwl|IIN l/lt/M. fee M (MM|M tllflWM Inn lUtaMM Mir limylinwfmnM. IIM) Male atlMHia MMflcil Minlaa Item Ml mill fliMi aa aiiai ta icfti**t IM. kaaHlaC Hr trataaal tateaaa tarlj IMS aaf Ilaim. at fa ut. a. nut 4) ft. |. HSU at n in.. wit NS Mate aa cartlaaaaaUlqr. (acavnyai traaaar ara la MMltH *m tatwaat af cavlaala iH Hull raawlt la racacclaa af acclMaul itaiiri. at ert id.), ti7.it MM aa MMlmalM affacti. awifiaH'tr. m. SHI lialaa aa aamaaldH. taaart, It/tl Mlf affKi all art aaa raaaaar. KW H ert Ml.IS. III.U firl fatiMH HtMMUrt ftICA, Nllll. IfM) ACttaa Malt CCaflattaa af IHMIIMU tatter. KM) m> II M Mr M, it Mi Ctfllat, K IM Mil-- MM Hr M ta Mr MrlM (MMl MMliMry ttiUff! IftWU IM HiMf UcaCirC It tM Mr Ha. t/llPit Marfatr 1atrtry Slaaaar#.. 1 pta t*ar IM, 1 m IMla H* caltia|. f/Itflt: MrtM lUMH 7/t/tt* i.s. Mrm tun rtvtnta iuc ra ta M tta Mr IM. IMM) M cn IIII.IM ttMk) 59 HONS 025660 BCNIIOItt There (t sufficient evidence that benzidine li carcinogenic In experimental animalt afiar oral and subcutaneous administration, producing lty*r tumors tn mice and hamsters; liver, mammary and 7/wbel't gland tiaaori tn rati; and bladdar cancers tn dogt.l>2 There It sufficient evidence that benzidine Is carcinogenic to humans.*,* Case reports ar.d followup studies of workers provide sufficient evidence that occupational exposure to benzidine Is causally associated with an Increased risk of bladder cancer.* The causal association Is strengthened by data which suggest that the Incidence of this cancer In workers decreased after a reduction In Industrial exposure.2 ^International Agency for He search on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29. lyon, France: IAAC, 1982, pp. 149-83. ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. benzidine, an aromatic amine slightly soluble In cold water, has been used for over 60 years as an Intermediate In the production of azo dyes, sulfur dyes, fast color solts, nephthols, and other dyeing compounds. More than 2S0 benzldire-ba.ed* Cb'es have been reported. However, the general use of btnzldlne has fallen dramatically because of its carcinogenicity. Benzidine was formerly produced In the United Staves at levels of many millions of pounds per year. In 1977, U.S. production of henzidine-based dyes was reported as 1.4 million lb; 76,300 lb were Imported. The annual production of benzidine Is now about S00 1b. Human exposure to benzidine Is primarily through Inhalation or skin absorption. NIOSH hat estimated that 700 workers may be directly exposed. OSHA hat estimated that about 2200 workers are potentially exposed to benzidine. In the fall of 1980, CRSC Instructed Its staff to collect additional economic and toxicological data in order to propose a ban on the use of benzidine-based dyes In direct consumer dye products. Studies ere In progress to assess the dental penetration of benzidine congener dyes and their respective bates. Economic studies are alto In progress. * Benzidine-based means that the chemical structure of benzidine ts Included at part of a larger molecule, even though the method of synthesis may not require the use of benzidine as a starting material. 60 MOMS 025661 Residual levels or trace Impurities of benzidine may be present In benzidine-derived dyes end pigments end In the flnel consumer product. The presence of this known cereInopen, even es > trece contentn*nt. Is a cause for concern.- Available data show that benzidine residuals In benzidine dyes range from 1 to 270 ppn. CPA controls benzidine through both the 1977 toxic pollutant effluent standards and the water duality criteria proposed 1r October 197$. The OSHA standard restricts the use of benzidine In open vessels and regulres protective clothing, engineering controls, and medical surveillance of workers. SSMMtM ftl i kfilitlMi M hMf tet'wi TMtwtoftut M nimii imui in la mrtu. (PIC) (IlNI af taf*ltt<a*i; ftlMf (Mitt CttatiM af Dafaitt*** NU, hHtu NIU inintt, Off*M4tIftitum MUfttl. M *11) nil- INI In fim tf 1414 If M fetaillM Mi npirt/nwiinn nutnwm. Mat NMlfNMNfl M MMM IHtlKMOt if Mitt. MUM Up* M (Mttll MMlNlM M tafjKt IN UN MM MNlMlM. tfMalfttai l/tl/M. CM. Mil MllflM 1*111 MfwmiNN HMMiMM nN'tNlt fMNtlfp ON If. .M Ml aai MaMMf nufitif nrtn> (Ml. NpMNlfMM 0/ltfTt. CM, MM*): Salt hDUM IMllfN. CM, Mi iitif iNittr iHtifti. NNIIlferi la flam) lam. 11/14/44. In Unlnfn Iinimm Inat IUIMM UNf t-im|!*iwf1|dnAI. all*) at tatai m MniiiNiufy. Inamfit fra*tar cart t feaatltat m ia|i*| nnmMiIi Mi mn)i fatalt la fatactiM af Mditatal mmtarn. Ntaafattart feat intii cMt'itrMtr tiact Iff9 araaalftt'M. N eft mi.ii. NI.U 44 eft II?.), Il'.D ti (f lit.104 ft 41.1)1, a. It)14 icmi NfMacii** (latfehsf. MUM. trttataf m MmOiKn p*nnip* HMl M Mini NtMt f MulraiUii MM aaitfl MflllWI prMINIMi; WMlNti# taatrtl nMNWiiti Ufa naanwin Hr nNliw mu: tmaltaf MMImnuu Mr cMUiatra. IMNU tfilatafy Nlgtanr: Ifif/flt iNtrfttf TMNNftff af*Mt*M iloi| m Ngpfitaa ng/iraints far Mrtan, MM mtrl NintliM raitrictaa, taflaaaflaf faMiftatat*. UU/Hi MmI lumn tarraat ftfalatlaat ffaettva. INMU It Cft 1114.1414 <4tMl HONS 025662 HNZO(fcIFLUORANTHCKC The-e Is sufficient evidence lor the carcinogenicity of benzo(b)- fluoranthene (B(b)F) In experimental animals.1 8(b)F has ?rhoedulocwedesst kcinarctuinmoogrsenIinc mice dost following repeated for the mouse skin skin paintings, was at least ten times higher than that of benzo(a)pyrene. 6lb)F Is also an Initiator of skin carcinogenesis In mice and produces local sarcomas after subcutaneous Injection. It has not been tested by other routes In the mouse or In other species.' The Isomer of ((DIF, beniolJ)fluoranthene, has limited evidence of carcinogenicity <r experimental animals.1 international agency for Research on Cancer. IARC Monographs on the (valuation of the Carcinogenic Risk of Chemicals to Humans* Supplement 1. Lyon, France: IARC, 19(2. 'International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Tol. 1. Lyon, France: IARC, 1973, pp. 69-90. l(k)F Is a polycyclic aromatic hydrocarbon (PAH). This compound may be used as a research chemical. There Is no commercial production reported for this substance. However, this compound Is formed, as a result of Incomplete combustion of organic substances and Is found in coke even emissions and coal tar. No data are available on the amounts generated. Human exposure Is primarily through Inhalation of smoke frnm the Incomplete combustion of organic compounds. R(b)F has been detected in mg/kg quantities of particulates in air, coal tar, soot, automobile exhaust, road dust, and sewage water. It has been detected in cigarette smoke condensates, soil, drinking water, rivers and lakes, and food In microgram quantities. (PA has designated S(b)F as a carcinogen and regulates the compound under the Resource Conservation and Recovery Act. In order to minimize the risk of workplace exposure to PAMs, OSHA promulgated an exposure standard of ISO ug/m3 ((hour time-weighted average) for coke oven emissions; H10SH has recommended a workplace standard of 100 ug/m3 (10-hour time-weighted average) for coal tar products (coal tar, creosote, and coal tar pitch). OSHA has Indirectly limited exposure to l(b)F by requiring that occupational exposure to coal tar {Itch volatiles not exceed, as a time-weighted average, 0.2 mg/m3 over an hour period. 62 02Sbb3 MOMS Iwl> I nrwlM( MCUUUttt irfKt # iimmiimii MM (MMII CM, mm mhim4feit*orm*m#i llt*%, ti/n/ftto. r toMl NM mmiim; M Mlcitir n> wrmiw. II I llllHMI CMMIItwm tf Mill M WHMM mtot mm u iwuu H to MMMl| MM MMft/MCMIlhM| rtfrl'*imu. rnMl|ito to* tolMm* MHIMMl I'M IUImM mm* i**cvoIm!hOw'im. IIMI Kli t.| MM1 Mr TIM UmI tor MU* MlMltnl CM'Mii' (MHA) MmIiim atatorr l/ts/9li NM !MMf IIMtrl-nrrMt IMH IMMU tlU^M #r utt** if fa i:>. . idii i era tti.M ** n era lau.iaM. mt.itot tUtol 63 HONS 025664 BEWOlalPYAENE There It sufficient evidence for the carcinogenicity of benia(a)pyrene (B(a)P) <o experimental animals. B<a)P has produced tuners In til of the nine spec let for which dote are reported following different administrations Including oral, akin, and Intratracheal routet. It hat both a local and a tystenlc carcinogenic effect. In tubhinen primatet, there It convincing evidence of the ability of B(a)P to produce local sarcomas following repeated tubcutaneout Injection and lung carcinomas fallowing Intratracheal Inttlllatlon. It It alto an Initiator of akin carclnogenetlt in alee, and it It carcinogenic In ilngle-dotc experiments and following prenatal expoture. In tkln carclnogenetlt ttudlet In alee, B(a)P wat contlttently found to produce aore tuaort In a thorter period of time than did other polycyclic aromatic hydrocarbon, with the pottlble exception of dibenxola.hlacrldine (0B(a,h)A). In a doteretponte ttody Involving tubcutaneout Injection In alee, the alntael dote at which carcinogenicity wit detected wat higher for BlalP than for P8(a,h)A and for J-nethyl cholanthrene. The latent perlodt were thorter for B(a)P, however, tnan for DB(a,h)A. In ttudlet utlng Intratracheal adalnfttratlon, B(a)P appeared to be lett effective than 7H-rt1benzo(c,g)carbayole In the hamster.* international Agency for Research on Cancer. 1ARC Honographt on the Evaluation of the Carcinogenic Alik of Chealcalt to Humans. .Supplement . Lyon, France: IARC, 1982. `International Agency for Aetearch on Cancer. 1ARC Honographt on the Evaluation of the Carcinogenic Alik of Chemical! to Han. Vol. 3. Lyon, France: IAAC, 1P73, pp. 91-136. BlalP It a polycyclic aromatic hydrocarbon (PAH); It It not commercially produced. One chemical company manufacturer! 6(a)P, and teveral specialty chemical companlet distribute It for research purposes In quantities from IOC mg to S g. BlalP alto occurs at a product,of combustion. An estimated 1.1 mflllsr. lb/yr art released from stationary sources. Ninety-si- percent of this amount comet from coal refute piles, outer--;, abandoned coal mines, residential external combustion of bituminous coal, coke manufacture, and residential external combustion of anthracite coal. Human expoture can occur from the pretence of B(a)P In polluted air. In tome foods, and In the occupational environment. The number of persons exposed It not known. Pertont working at airports. In tarring operations. In refute Incinerator operations. In power plants, and In coke manufacturing 64 HONS 0256*5 operetlons mey be exposed to higher 8(i)P levels thin th* generel population. Scientists Involved In ctneor rcieircn or In sempllng tonic mterlels mey alto bo occupationally exposed. Ihe genersl population my be exposed to BlalP from air pollution, cigarette smoke, and food sources. 8(*)P has been detected In cigarette moke at levels ranging from 0.2 to 12.2 vg/too cigarettes. tte)P has also been detected In foods at low levels ranging from 0.1 to SO ppb. On October It, 1078, ERA Issued a notice of Rebuttable Presumption Against Registration for coal tar, creosote, or neutral oils. tla)P Is one of many constituents In these products. The CPA Carcinogen Assessment Croup hat designated IU1P as a carcinogen, and CPA regulates the compound under the Resource Conservation and Recovery Act. Under the Clean Air Act, t(a)P It considered both a surrogate for particulate organic mtter and an Indicator of coke oven maisslons. Hater quality criteria for the protection of Inman health address total pahs. OSKA indirectly limits exposure to l(e)P by requiring that occupational exposure to coal tar pitch volatiles not exceed a time-weighted average of 0.2 mg/m3 over an 8-hour period. MatafaldTraM leffleUeet M MRtf Alltel maulim Iffact at Hwlittm; tiMi Cmeti cm, smuh aur cmii* arftarta Hr 9rn WI4*M Ml **. IMJtl. fatal nn ihhH. m nmtiu me mai. attar. MIA, MJtcti am KMtcu, iff'IMtUkllltR Mtchtt. M l#lH matt. la mm if MM i| m m*<Uri m rtfart/racarmtaaiaf ii CMtCWtM MMMlIirfm M 4 MllfWdl NMtltMM |f mu, rnt MDMtl tlH im mufi (him mm ratal*- MW. NwlflM S/lf/At. ISA, Halt Nmih raaartiat *'* raaatrfnf gw w< gmeii Mia, palfMM lilt/M. (Ml CM MI am t*Mt W WUfllN Ml caatrali am mm w m mi an* itaat am at man*ttt. lwaOiirfM hi aaaa M aaraaftat far Hfywti.'i I*|M aataafo MHw tatfataar M da wwiwwiu tf mi avaa aHuim. laa Cammam Mmm*i (w# iwimw MMr 1-attltfnmfWim. IIMI Kit 1.1 atm* Mr TM lata) tar Mm aalatftai) (1WM Nmin). IMMI tmlimy iiitaf: l/tl/71 t mm fatmar lumnatrraaa Haft affac*ft. (AIM) (MeKoR af MvUiim cl n mi. . mu 40 CM Hi ll, MI.JJ at ri , f. iMac MTS. aanaMi t--[<Mimh, l/N lira) n CM IfttvIMO. lm.iMt IMA) 65 HONS 02566b BCRYLLl'JM AND CCRIAIM BCRTLUUM COMPOUNDS There <1 United evidence for the carcinogenicity of berylllun In humans, and sufficient evidence of carcinogenicity of some beryllium compounds In experimental animals.1 beryllium compounds Here carcinogenic In rats, rabbits and monkeys, beryllium metal, beryl 11 urn-aluminum alloy, beryl ore, beryllium chloride, beryllium fluoride, beryllium hydroxide, beryllium sulfate (or Its tetrakydrate) and beryllium oxide, all produced lung tumors In rats exposed by Inhalation or Intratracheally. beryllium oxide and beryllium sulfate pro duced lung tumors In monkeys after 1ntrabroi.chla1 Implantation or Inhalation, beryllium rttal, beryllium carbonate, beryllium oxide, beryllium phosphate, beryllium silicate and tine beryllium silicate all produced osteosarcomas In rabbits following Intravenous and/or intramedullary administration.* Four early epidemiological studies and three recent ones of occupational exposure to beryllium were considered to provide limited evidence that exposure to beryllium may lead to human lung cancer. The data for most of the studies were derived from two beryllium plants and from the Beryllium Case Registry. Although li new cases of beryllium disease were registered between 1173 and 1977, no further data were available on the Incidence of lung cancer. An analysis of the pathology of the 17 lung cancers noted in one study confirmed the post-mortem diagnosis of lung cancer In 32 of the 37 cases available for review. Of the 47 cases, 21 were noted to have been smokers, but the smoking histories of the other cases were not given.1 1International Agency for Research on Cancer. 1ARC Monographs on the [valuation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: 1ARC, 1982. ^International Agency for Research on Cancer. 1ARC Monographs on the [valuation of the Carcinogenic Risk of Chemicals to Humans. Vol. 23. Lyon, France: 1ARC, 1979, pp. 143-204. beryllium and Its compounds are widely distributed In nature. Beryllium compounds of commercial Importance Include beryllium oxide, beryllium sulfate, end beryl. 66 HONS 025667 .Beryllium It used extensively <n the manufacturing of electrical components, chemicals. ceramics, and X-ray tubes, a number of alloys are produced In which berylllua Is added to yield greater tensile strength, electrical conductivity, and resistance to corrosion and fatigue. The metal Is used as a neutron reflector In high-flux test reactors. Beryllium has been produced commercially In the United States since the IMOt. In 1979, two companies were reported to produce beryllium In unknown amounts. The Toxic Substances Control Act (TSCA), Chemical Substance Inventory (public record) reported six producers and Importers In 1977, with production of 74,000 lb. Imports for 1978 were approximately 1400 lb. Beryllium oxide has keen produced commercially In the United States since 19S8. In 1978, only minor amounts were produced by one producer. In 1977, EPA reported that 408.000 1b were produced domestically. Eleven other beryllium compounds are produced in small guantltles. Human exposure occurs mainly through Inhalation of beryllium dust or fumes. OSKA has estimated that approximately 75,000 workers are exposed to beryllium. Among these are beryllium ore miners, beryllium alley makers and fabricators, phosphor manufacturers, ceramic workers, missile technicians, nuclear resrtor workers, electric and electronic equipment workers, end jewelers. The major source of beryllium exposure of the general population Is through the burning of coal. Approximately 750,000 1b of beryllium Is released from coal- and oil-fired burners. EPA has estimated tlie total release of beryllium to the atmosphere from point sources Is 5530 1b per year. The principal amissions are from beryllium-copper alloy production. Approximately 771.000 persons living within 17.5 miles (70 km) of point sources are exposed to small amounts of beryllium (median concentration, 0.005 vg/n3). Small concentratlcns of beryllium have been reported In drinking water supplies and In food. In 1973, EPA promulgated a National Emissions Standard for Hazardous Air Pollutants (NESHA*) for extraction and production sites for beryllium and for beryllium oxide and beryllium rocket-motrr firing. In 1980, EPA published a water quality criteria document for beryllium for the protection of human health. In 1980, the Agency established regulations under the Resource Conservation and Aecovery Act for wastes known to contain beryllium and beryl lium compounds. These regulations were based on the Inclusion of beryllium and Its compounds In the EPA Carcinogen Assessment Group's list of chemical carcinogens. The Agency does not plan to regulate beryllium In drinking water under the Safe Drinking Water Act,-but EPA has proposed a rule under TSCA requesting production and other data. Current OSHA standards for limiting exposure to workers are a 2 ug/n3, time-weighted overage, a 5 vg/m3 celling, and 25 ug/m3 maximum peak for 10 minutes. This standard was adopted by OSHA for toxic effects other than cancer. (7 HONS 025PP Mfylllw *r (mtl* lfyUI* (< IfMMIM IlflUMMI M mttM CffMt if l*fal*|li|; MN*r Cm**ii IM* W (Mil Iff Mfylttw *M MlM, UK Ilf|i||l //). Mif mii*ii| m*w**t t* mmmim ifftCMl * **UIN* Mill MMI* *11*11* Ml <M*lfUI, I/ll. CM*, MVilt it triurU ff mWlttM NrjriltW. MltWMI 1* #W*I ft**. 11/tUM. KM, MI*M4i M)tl MUl I* ||*U(< MfylitM MW Mfylih* IMNMl M MMitM M mWHWftwiui NwlMM l/lt/M, bMNti i.rt (i Miti ifMimi III! M|MU MUNI M *UI mlMt M **4M M tow M M ft*WHw MW nwtfMHIl *w*tu W1MI. IK*. Mill NfMM Ml nMlIlM |r*> Mtm 'TW Mwf u lb*fyllti i*tfm). MM4 Mb Ml Ml MM U rtfutltt IMlIlM lb CrlNklbf MtM MCMl* tf Mum mi it it mi immm *t im |MlMl*Ul1MI tfllll. 1 IMM If I of/M* Ml mrt*f M m WMltfy I* IMt. **t Mi 'vMaMjr w* Ml* IlMI m Mt| Itttl. Me CnHiifu kiMiwM Mm iuiwm MW** l>Mtl|<MIMflMMM. tltllln If lf1*0*J> <e cn ii. *t **.; 11.*9 *t !** it ra i. . MJII m cn tit.to o cn hi.)) i n }, i. imu IM. HfHMl ewwaicitiM. I/M QMS |r|/t trllMU MCMim, J/79 'tM KLi *-m tbi 9 /> c*nt*v'. M 0) MIW* MM M M III. tiuwm MWtM fK wale ifflCtl MMf Ml CMC*r.) (MM) NiilitM nttor: 1/17/71: CM )NMtr lUMMf* ciMfit twu ifficnn. (SMI it cn itio.un iimi 68 MONS 025669 M-BIS(2-C>HM0CTm)-2-NAFHTHYlAMINC (CK10PMAPHA7INE) There It sufficient evidence of the carcinogenicity of M-bii' (2-chloroethyl)-2-naphthy1an1ne (chlornaphailne) In humans, ntf limited evidence In experimental animals.! N,N-b1s(2chloroetky1)-2-naphthy1amlne produced lung tumors In mice following Intrsperltontsl Injection, end local sarcomas In rats after subcutaneous adainlstratlon.* The afelnfstratlon of chlornaphailne together with radioactive phosphorus (3`P-sodium phosphate) caused bladder cancer In 10 of (1 patients treated for polycythemia vert. In II patients treated with <P-sgd1iaa phosphate alone, no cases of bladder cancer were found.2 international agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Hiaaans. Supplement 4. lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 4. L.'On, France: IARC, 1974. pp. 119-24. This antlneoplastlc drug, sparingly soluble In water. Is a nitrogen mustard. The drug Is cumaonly called chlornaphazlne. Chlornaphailne Is neither produced nor used commercially In the United States, although It hat been used In other countries In the treatment of leukemia and related cancers. The drug now has no wide therapeutic application. The ERA Carcinogen Assessment Group hat Included this chemical on Its list of carcinogens. Under the Resource Conservation and Recovery Act, EPA regulres that the use, handling, or disposal of wastes containing this sub stance be subject to special reporting and recordkeeping requirements. The FDA reported that N,N-bis(2-chloroethy1)-2-naphthylamlne Is not an approved drug for therapeutic use. 69 HONS 025670 I -I**%*Im'* ICfcWMftMli*> UlMTIMS (ffNl if OtMf CMIMI M (*( Mill*. > INM KMKKt It WMt prMvCtl *NI CMC JvrtMtCtlM. KfKt KM, mi'DHi MJtttl mu inMctl, MUMt. M 1*01 mt Ml ) Mill M iM l M MMHaf PM't/rKtfl|l*l PtMlPlMU. *lM iMtkflMiH n mhmw tmoiwtt K MIIM, H< M*)U MlUt Iim M tMMt* II M M IM nMlrMlU. IrMlfili* l/ll/N. |H UrtlMM IlMIMM MW* imimim mmr KM) IM rfrtt tMt |iKMII|IMm IIMM MflM M< tmi CttltlM I lOM'ltlM 10 CM 1*1.11, m.u K*) 70 HONS 025671 llS(CICO*OMETHYl)ETHER ANO TECHNICAL GRADE CHLOROMETHYL ICTHYl ETHER Tlitrt <| sufficient evidence for the carcinogenicity of these substances both In experimental animals and In humans.1 HsUhloromethyl )ether (('.ME) produced tumors at th site of application In mlc* aftar administration by Inhalation, skin application or subcutaneous Injactlon, and In rats after Inhalation and subcutaneous administration. Technical pride chloromethy'i methyl ethmr (OK) (which Is almost always contaminated with (Of.) produced local sarcomas in mice after subcutaneous administration, and was also an Initiator of skin tumors.1 Two studies of workers exposed to (CMC end technical grade CMC showed an Increased risk of lunp cancer, mainly oat-cel) carcinoma. Two subsequent studies have shown a positive association between atypical cells In bronchia) excretions (abnormal polranary cytology) and exposure to (CMC which was not related ta cigarette smoktnp. Several studies have demon strated a significant excess of lung cancer among (CMC- or CHME-exposed workers which was directly related to Intensity and duration of exposure. nat-ce)l carcinoma wos the predomi nant histological type of lung cancer. Tne excess respiratory cancer mrrtlllty was most marled In workers under SS years of age. The evaluation of CMC alone Is complicated by the pretence of 1 percent to t percent of (CMC as a contaminant.1* international Agency for research on Cancer. 1APC Monographs on the Evaluation of the Carcinogenic Disk of Chemicals to Humans. Supplement 1. Lyon, France: IARC, 1979, pp. 26-27. `International Agency for kesearch on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 4. Lyon, France: IARC, 1*74, pp. 239-4S. loth ICME and OK are water-soluble, colorless liquids. IOC and OK are used In the synthesis of other chemicals and In the manufacture of plastics and Ion exchange resins. Domestic production of ICME by one producer Is estimated by ERA to be 550,000 1b annually. IOC has been primarily used In the United States at a chemical Intermediate. There are currently four producers of CMMC In the United States, but the amount produced has not been reported. Technical grades of OK are contaminated with 1 to I percent ICME. 71 HO (US The main rout* of exposure to (CHE *nd OK It through Inhalation, and less likely through skin absorption. Potential sources of human exposure to (CHE and OK exist primarily for workers, sucn as organic chemical synthe sisers, Ion exchange resin maters, laboratory workers, and polymer makers, ho estimates of the number of workers exposed are available. Very low Incidental exposure right occur due to metabolites of some dental materials regulated by the I DA. Environmental exposure through'water pollution Is small because both chemicals rapidly decompose In water. However, the breakdown In air is less rapid. (CUE can be formed whenever formaldehyde, water, and hydrcgen chlo ride vapors are mixed at room temperature even In low concentrations. The CPA regulates (CHI under the Clean Hater Act ICWA) and the Resource Conservation and Recovery Act IRCRA). (CMC was deleted from the CWA hatardous substance list due to Us extremely short life in water and the absence of data Indicating It It a water pollution problem. RCRA lists (CHI as a hatardous constituent of waste. The CPA primarily addresses (CHE, although assessments are In progress regarding additional regulations for CMC In water and atr. OSHA Issued an emergency temporary standard covering both chemicals In 1(7) and a final standard in 1(74. This standard prohibits the operation In open vessels and regulres exhaust fans, protective clothing and devices, and warning signs and labels. The Consumer Product Safety Consistion (CPSC) staff preliminarily deter mined in 1(00 that (CHE and CMC were not present in consumer products under CPSC jurisdiction. The Commission subsegvently reguested (45 FR 61344) public comment to verify th accuracy of Its information. No comments were received on these chemicals. Pending the receipt of new Information, the Commission plans no action cn (CHE or CMC. 72 HONS 025673 UlUMirwtlirtllMf UHUTIW IffRI ** ItfiUllMi; tltor (mutl N *'* Nl<H. M tMD* prrtlHC* I* IMhM' ^riMU. (OKI CM, HHlI: Itlif crltKli r*Htoto to f(Ml to*. I1/I9/M (IOC M M iMf dlimlMl IMril. CM. Ml: tototto Irm MiNMt miu*o IHI, KW, *91 MM: UlIH II 1 KnHlil nHIHNd *t Milt, HIM IIM (Mill Kt IH MINI to MMlIf M f*to<rtotk. Irwl|u 1/19*1. |M CmlMfM IIINHMl IfNf IUIMM MHf t<NH|lHivnHN. |KM| [iUNl| iMri Ilf* li Mtor M Mmi f MU iMKillto 10V to to totor Hliitto Mhto. ItH) CM hum # IMlUl Hilttl, INCIl to mhI|iih hr CM m. |CM| toilHi mnm to tortit MiHitto wtoriiif it iiitN, tot iiHNn ti totoltoTM tollMUl. ICM) CrMMltvt iWMif. Mfftmr, nrfim, triuin +t4 toMal NtoillMtt itolfi- mu Hr Hrttni mmii to rmOtoidii HH WIHl HrnlM ItolllNl MMHlHto eMto rMlrwMt; **f* lltolr--li tor m<is Ihtoltof r*Mlr*- MU tor IMUMU. IMMI towirtonr Hn: 1/11/9)1 twfMd twnnty prMHlto tlhtotof m Hf'IN tortr*. Mtl tor Htoflj HtotoNl HTIItol rntfKM; mlwirlM m><hmU< IMM| Cttol.M *r (UfitoiiM to n ot, i. ni to r, $. wi) to era mi.u UMI 19 era 19M.IM9 (MM) 73 HONS 025674 iKtwiMt in* cmtfMtfvl **! tt*f acnurioNs ttftlttlAM M ttMf I'tltAI l tWMM KtlW. M i4W* KIHUt III CMMIIf I'MKII. icnci KM, MI-MI' M)Ktl Mill KMkII, IflMNlMImlM NIlNl, M Mill ml* Ml I* Will if MM If M NMlIill IN MNI/NWNMfli>t rnttrmMi. Alia llfMMI (K IS 1 NIINNI CtNtltolN tf Mitt IN MJMU Mlllt IWMI U MAUI* It M IN MM HNlNWU. fmIimm t/it/to. TStA, l(t)t NfrtlN mil mIHn im mi IN M Ntl, |ftHN l/M/M. |M (iKlNtN AtMUMUt INN llltMlt Nr I-kivIiNnIIntin. (IMI f*A Nnw tf Nllcil Inlets, fMCI; t llMillllN MtMlfMM It FftUM. m) tfftet tf fttMlttiMi; (INI CtWNAtl NiiictlN clatmtf* mtirtm, ttfim, INUtN IN Mini wmltlHtl nlrt* mi far itrtin, uiMt Im unInnmi, mm Misti MMittm nnimin; NMNtNtlN ttttrtl MNllINltl ftr milt iMtilt^ffMltlMttS ftr CMUlMTS. KwllMrjr Mlttry: 1/11/7): tMrjtKf Twrr; ItiNtNi** tmtctlvt llMIN MS Nl'Nt 'NVIII* MKS f*f NfUNi IH**niMl NmttlMS rtttrlctM; i|lNiflN nnIimmi. 1/12/7*: riMi ltiNtN>omn nm'i* tltAS tffMtlt*. I0SMAI ClMttM tf ItflllllN t* cr; sti.il, Itl.l) S ft |, . IMM H} it era ittt.itM USM) 74 *0NS 0^5675 CADMIUM ANO CERTAIN CADMIUM COMPOUNDS The evidence for the carcinooenlclly of cadmium end certain cadmium compound! In experimental animals it sufficient; the evidence of carcinogenicity In humans Is limited.! Cadmium chlc'lde, oxide, sulfate, and sulfide are carcinogenic In rats, causing local sarcomas after subcutaneous Injection. Cadmium powder and cadmium sulfide produce local sarcomas In rats following intramuscular administration. Cadmium chloride and cadmium sulfate produce testicular tumors in mice and rats following subcutaneous administration.1 Studies have suggested that occupational exposure to cadmium In tome form (possibly the oxide) increases the risk of prostate, respiratory, and genitourinary cancers in humans.It* international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Rumens. Supplement 4. Lyon, France; IARC, 1982. `International Agency for Research on Cancer. (ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 11. Lyon, Trance: IARC. 1576. pp. 39.7A. Cadmium and certain cadmium compounds are widely used commercially in electroplating, alloys, soldering, plastic stabilizers, batteries, fungicides, and in phosphors and pigments for television tubes, Inks, artists' rotors, glass, ceramics, textiles, and paper. The 1980 domestic production of cadmium and eight high-volume cadmium compounds was approximately 17 million 1b, whereas an additional 2 million lb were imported. Cadmium oxije accounts for approximately 10 million lb (about W percent) of the total domestic production. An estimated 4-5 million lb/yr are used exclusively for Jewelry and siIversmithing. Plastic stabilizers utilize approximately 2 million lb/yr of cadmium and cadmium compounds. Hunan exposure to cadmium and certain cadmium compounds occurs through Inhalation and Ingestion, OSMA estimates that 360,000 workers are potentially exposed to cadmium and Its compounds. The entire population Is exposed to low levels of cadmium in the diet because of the entry of cadmium into the food chain as a result of its natural occurrence. Tobacco smokers are exposed to an estimated 1.7 ug/c1fe'*tte. Cadmium Is present In relatively low amounts In the earth's crusti as a component of zinc ores, cadmium may ue released Into the environment eround smelters. 75 HONS 02567N Th* Consuaer product Safety Comalssion (CPSCI Investigated the potential contuner haiard presented by oaterlals painted with cadalua-contatntno Inks. No cadaiua was found In Inks used In printed products. The CPSC staff Indicates there Is little cadaiua found In other printed consuaer products. Th CPA has regulated cadaiua and Its coapounds under the Clean Water Act (CWA), the Resource Conservation and Recovery Act, the Safe Drinking Water Act (SOWA), and the Tonic Substances Control Act; regulation Is planned or proposed under the Clean Air Act. Under the CWA, water quality criteria for the protection of huaan health have been published that are Identical to SDWA standards of 10 g/l. The CPA has issued a Rebuttable Prcsuaptfon Against Registration of cadalun-conlatnlng pesticides, but final action has not been taken. The Carcinogen Assessaent Croup includes cednlus oxide, cadaiua sulfide, and cadalun sulfate on Its list of potential carcinogens. The PDA Halts leaching froa pottery an-1 enaael to O.S ug/al of leaching solution for pottery (flatware) and seal! hollowware (0.25 ug/al of leaching solution for large hollowware). The OSMA has adopted peraisslble exposure Halts of 0.1 ag/a3 as an t-hour thue-weighted average for fuaes, 0.3 ag/a3 as a celling for fuaes, 0.2 ag/a3 as an a-hour tlae-welghted average for dust, and O.i ag/a3 as n celling for dust. This standard was adopted by OSHA for toxic effects other than cancer. NIOSH has recouaended a standard for cadaiua and all cadaiua coapounds of 40 vg/a3 as a tlae-welghted average, and 200 vg/a3 at a IS-alnute celling. 7* HONS OiSbTI (iIm m* CnUtft () taHMtfl fll of S0 M nrni tctlot. IM. ICOSCi |HM ?- CM, M: Cfflttts ttlMlftti for rmi l<sMitriil ciUMMn Mrtu C*N<. OmvlMSN /t/?4, 4/ft/?l, ll/t/?f. ImmiH l/T/lti pnlmt* tot H.1IM tmtlftltt. CM, Mtlali ViUf *Htn1* ONOlllMt flMl f*t, U/ft/tJ. CM, *?(!)* Toalf Ml1U*t tfffvttl IIMMl Mf* In 111), M tntr Twlfittl. CM, nit luiTtHi tom rtftltfltt Stlttletltf mnttOlf tMMltr UOt 10, eft i) M taootiNf mntiof m*tm MU. OftMlftltC l/lf/tl. KM, M1*SM4: NilftttM n i stale Mitt. Ntilni ttiiiNf st ttvnt*** KeltMt. Nests cttuit!tf ciMtM rt t0|t St MMSItf rt rtont/ tctrNttoltf fttNlrettau. trtMSftSM l/lS*t. tttlfttSH M UllNMt CM1S1UMS ff tltt (CtNlM setQtNNtl. tot fSOntl:* sttcifltt). SOU. 4C04: OrotlOHtt* ft Nt* Ontltt. % tt Iota (rttlaot. tf MM tMt*1 H MtelMl |1vrt tMtfMtM Mlarttvt. leva. 40S, till MIMMV.I tfMlHtM /!)/?. CM, 4Ct: itaHttiltN ttr tnKMSritlMt If tMil M **' SMtC MtSMtH It limit iMttMt (M IN tl nil ctttf* ttmn ottn itMgr. $0M, HU: Until** tf vtttr MllM IMUillMl inti KMNiIM fn fftttttl tf t/9J. nru, It MM l|M4 *ttrsetNf mfeum otestciNs sttstitltf tmitt, lt/M/??. MOTIONS tfftes *? tefvWtitNi; son Cattmi CfUlftt tf NftUltM Cttlrtl it*Oll|ON SOrttfi Mftfiwt tf C*A41|1t*f tr VMS Otft'tt. CtrelNtftttcisr mi its ctttitertt it nt*tHstif ftfttltMI. 40 CM 41), 4)|, m |*nti*f> at ft in, p, i OrtSttSIt* tf ta*t* OtatSO (ttdtral StaltlSy) It **/l. HffktlV t* IttoSIfjrlaf stnets W tarns ftctlrtt It 1v we clitt It sot i/H Nftrrtl. NS etett tt tm<NMitiv. (tctntfti frttsn in ft MMlftf M StlttlM eNtictle in sottlt notis ft mtcsitt of tctlNtst) ttiirn. utfim ctNttt tCtStft, CitlM ctlt.*fN. CtttttSrtlltt tHfftrftf cnnHmc* t rtfilriNNi: 1.9 tf/1. 4 ft 1)1. f. ?)lt MS, onset*) ettMttctsftt, 4/Vf 4t Cft 11?.), lll.l) 4| Cl MI.14 IrtOfOlSlt* tt irtUM tst tttcIfSttUf lltuw unlit. 4t cm Ni.n at cm ft? N Nit OtNItf tntltfNNS *f t Nile? rtftftltf sltft; etttitnitf srttsttiiiv IM ettte rlifMt u ttt*cs sttrtia. . MfSNtl MtMlUtlM, 4/f) fafltltf ttafOM CNSNlMNS Inti If f.tt at/*, comic Mtltf, ItcIttlNf NSSfOlt csrcfatftofcISr* *1)1 N ettrtsstt. NMiiti unit ctmttst tot cmN ctlnlta. tvtttett ttttftittsiN la N*1N*Nt. 4t CM 141.11 N. itMlMt, 9/11 4) fl 104, f. M!?4 .ICtMlNwtO 77 M0*S ^56 fa tiM* CM4 hftol* ti*ln Camwli tCMtlMM)- ocsounons lofolitlMt ioi other Actlns CffKt of Rofolotlone: Other Conmi CltillM of koyoUtlM CM: iMir tiuimM ti f tlrttrw ufrlMi pniMU i flu MffiM* Ilf rtfilltlw. lift lHIWMI iri 1* ociytof itifii of TtCA, Melt topertlog rwt* reor?rt*C omen Mi im MU prr?iH. IKl! OMer rtvlw W If Mfltlml Nfiliury Kllw Mjr to ooffMloi. N Uffit for iiUrolMtlM IMMIIlM. t Ceetlaefo* Irwi UMit aMir I'MttylatlMMvMew- uni M0t. Hnoool (onoM'tii*, 9/00 Aiirmot ctorieo oalio ooi comim tolfoto. it n it. o. DMi lift) loeloiot COMlM tolflio ooi CiMfeo aotfoU. IIOAI IM Nmm of foeii. fOACA: CoOHm ft ee MtOeOfOMlt (UtMlNIt MIIMt it It* loeolf li oott full- (iMM ll rot # MfillM foot or fto4 etiftteo. Haiti tooch1o| lotoiloo* froa potUry ooi OOMO) 10 0.1 Og. ifBA) IN Hnu of Mltil Orelcot. fMCA: 0* fOMleioey ectloh it prooeot ootll 1 MlHIM If CliHflOi IM IM ll COlMt M OOittil OMltOi. - totttotoi I collihoritlei itoO *HA lulrtVi, iut. iK Minnitr Iim tMOltfi 10 fooi MMli WljMI to ralMtt 47*111 Mode ttrlpplhf ooltMUtry OOthOi fM Oottttlhf CMOlM |tMi CM |I|0 00 MtMOloOi theOOfh this ntthoi) 1* Mtrth 1101. firtlctMtii 1o n 1ttr*4ttor.i', colleOoritiro *b0t*1iith Itoir* M iMtMOll COMlM froo cooArOfO. fIMl mHi of ton cto< vOI M prtOMtoi it tho foil ototlo| of too Aoooclotloo of Officio) AmI|IInI CMM *tt. fortielKtoi lo m lot#root!mo* terror-- *Ao lotort itlOHOl A|fOIM*t Of (IM* follotlOM* ? Mirth 1901. Tho Itof vo* corrloi oot t? too DMitortoy ooi Atiiu* tut Mitofth Conor. CholiM Cottofo. Ohleoroltp of UiM. cn }| HIT JO (fOh) ICMImd 78 HONS 025679 t*lH <M Urtll* (t*lw C( li4Utlm iM OlMr kltw< CilinM Stall mlfinlOf M M Oaiwtr NMrtHlitM (MU IIWMil (HtrKt . 4 km (wiitN j#it cwtrKt itv^r MM m IM MWtl rnlMtl Uw taHtt M UttH If litmiritlM tMfl till tlttU fM. A HmI rtfWt Ml KIHPf<> lifMjr M mtttrtif |I 4H<KU Hr tut prtlMl f oMw Mf--M IM Villi Hit Mtfna CMtlftMf. iru) KMUTIMS IffKt If ItfllltfMl{ ttwr (MU KV> 0.1 **> f*r IMA (ftwa), . 0.) m/M ctlllaf IfMl), 0.1 M/*5 *"* 1W (Mil). 0.4 (Mill. (OMU hwMtwy Mlstonr: . IM1: MliVMiMljr. 1.1 mt/wfl miIm tUmkU WMwtnUw. l/tf/tls OH* TMmtr ItiMN arrinl ttoft iffKtirt. UimIiM mum fir MU *<fieu ttMf KM* CMCir.j (OS*) CfUtlM f tifutatt** if en iii. mo (Oft*) 79 HONS 025610 CARBON TETRACHLORIDE There It sufficient evidence far the carcinogenicity of carbon tetrachloride ICCI4> In experiment!' animals; the evidence of careinogenlcity In humans it Inadequate.* Carbon tetrachloride it carcinogenic to nice ard rati, pro ducing liver tumors after administration by varlout routet. It alto produced liver tumors in trout end hamsters following oral administration.? Three case reports describe liver tumors associated with cirrhosis in humans exposed to carbon tetrachloride. A mor tality study of laundry and drycleaning workers exposed to a variety of solvents suggested an excess of respiratory cancers, liver tumors, and leukemia.1'? IInternational Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement a. Lyon, France: IARC, 1982. ^International Agency ior Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 20. Lyon, France: IARC, 1976, pp. 371-99. CCI4 is a colorless, highly volatile liquid with a strorg ethereal odor similar to chloroform. The chemical mixes sparingly with water. Most of the CCI4 produced is used for the manufacture of Freons 11 and 12, but ft Is alto used in industrial oeqreasing operations as a general solvent and as a grain fumigant. The ERA reported 1977 domestic production as 410 million lb/yr and imports as 4 nil11on lb/yr (Toxic Substances Control Act, Chemical Substance Inventory, 1979, public record). In 1979, nearly 730 million lb were manu factured; 5.4 million lb were Imported; and 8S million 1b were exported, which Indicates a 100 percent Increase in exports since 1978. Market reports for 1979 indicate a 5-10 percent decrease in consumption as a result of discontinued uses, such as for drycleaning and fire extinguishers. Because of the increasing concern about the general toxicity of CCI4, a downward trend of consumption will probably continue. Human exposure can occur by inhalation of fumes or skin absorption. Approximately 4500 workers are exposed during production processes, and 62,000 more workers art exposed during industrial use and consuamtion of the chemical. OSHA estimated that 3.4 million workers could be exposed to CCI4 directly or indirectly. Under the authority of the Haaardous Substances Act, the Consumer Rroduct Safety Coanlsslon has banned CC14 and CCl4-m1xturts 80 HONS 025681 as hsxardous substances. This ban excludes unavoidable manufacturing residues of CCI4 In other chemicals that do not, during use, result In on otr concentrotlon of > 10 ppm. The compound could be ingested os a contaminant of foods thot were either fumigated with CC1g or Ingested In wtter contaminated with CCI4 (reported concentrations of 0.2-18 ppm). When used *s t fumigant on stored groin, residue levels can range from 3.0 to 72 mg/kg. CCI4 may also be Ingested as 4 contaminant of the chlorine used in treating drinking water. CCI4 has been found In human tissues In concentrations of 1-13 ppm. An estimated S million lh/yr of CCI4 are emitted during manufacture and processing, and approalmately 60 million lb/yr are released as solvent emlsxlons. The amount of CCI4 emitted to the environment Indicates that a largo propor tion of the general population has been eaposed. ERA estimated that 0 million people living within 12.6 miles of manufacturing sites are exposed to average levels of O.S vg/n3, with peaks of 1630 ug/nJ. CC14 has been found In 10 percent of 113 surveyed public water systems at mean concentrations ranging from 2.4 to 6.4 ug/1; In 46 percent of surface water supplies; end in 2$ percent of groundwater samples, at concentrations of 0.001-0.40 09/1. Estimates Indicate that It million people might be exposed to CCI4 through ambient air, 20 million through contaminated drinking water, and 2 million through contaminated soil or landfills. The ERA has regulated disposal and related handling of CCI4 under the Resource Conservation end Recovery Act, end effluents and spills under the Clean Mater Act. The World Health Organization recommends that no detectable residues (limit, 0.01 ppm) be allowed on food or feed, but permits SO mg/kg on cooked cereals. Under the Federal Hazardous Substances Act, FDA banned the use of CCI4 In all products except where It was an unavoidable byproduct, which would not yield ambient levels greater than in ppm. OSHA has adopted a permissible exposure level In the workplace of 10 ppm <s an 6-hour timeweighted average, a 2S-ppm celling, and a 290-ppm maximum peak for 5 minutes In any 4-hour period. This standard was adopted by O'.HA for tuxic effects other than cancer. 61 HONS 025682 dm* tttr*MBHM OtCMUTIOttS 8*4 ItMf IttlM ItMr (MNMl (MWM' lit IlMM mut f#T icrtci CM, JNMOMi WtJtCtl Mill KMKtl, r(.|HClfllUi MUM*. MM will 2|||. Ml % (Kill If IM l| U *Ml laf Mi Vtt/N. Mm mi'imM m MlMMI CMIIUMM If Milt. Nllll MM U (Min CCU in MJWt M M $m hm'mnii- fiwIpM Iflf/M. M. lilt MlMM wtll llflllllM MUtH*!* It MB*H* IMM HI Nf Mh'N nwiti| n<iMiiu. IrmulfitM t/wn. ffwM nMt nwniftW im t. imm. t CM, MM*): M**/ Hlrll MUM U MmI fM, ll/It/M. CMS llUMn NMIMM nlM> MM MMmrilM Hr ***)) nfilitiM. IMlt* HI* NMklM. IM, Mil MM HMM| Mtlllte HMfa MiM, 1/VU. nrn. : m nun ic/u/cc. fiMM niMmmn mi m MtNtr.ii MltMt M Mtltu* M IM HM N flH, Ml MMltl M U W * (IMM (Mill |MI. )M CrrftMfUl llMIMnt |M ItlMllt mmr f.nilylMii|f1i>ni. KM) M MM m nrililMitHy. Immi|H fTMUr tin | MMlIif m MHflBf iMIUtl, M4 Mill MM)t IB rMMtM f NlfMlU) IMHMI. mm m iin>M|iii)tr. MU IMUM MMUl tlMDMNt if If mini CMUMtBMl Itvd, flMMCI if wlCMCI, Ml MMf trawl If MttM, MttM lUniMI rlM HtlMMI M IMM factor** MM M MUiMfUty; MM) mi Mum MllltM' C--IM imM ilml, ll/H/tt. (mmi mm M rm/MNfM iimmt ib KBff|l. MMCtfM Imil IB fM/fM 1.11 MB. ICMI fM MMf IN MUMritji if Ml MMf IMNlf CCt < M inMItl IMIM Mf| II Ml IMIIIMIM MIMWtl, Mill **. Ml flill Mint tMll rMUf IMM IC M> ri*i Hi i UlcMiM^nNl <*mct m MM mM mm fir 1 IM M m I'M Mmtf. IM)MM IHltMy! M m M>lM Hbm*U MMMIflUM. |/t)/7l: MM TMNMr ItMirl urnl iwtl iftutfil. litMM IMM fir Male affactl ItMr MB IMIf.) IMM) CIlBlfB* If MfvUtfBB W cn IMO.Iffl)(2) (VIC) m cn hi.)] * cn id.), DM) i n IM. |. CM If M III, I. TfJtf CtiBHI. I/Ct Hr MMI D f| ), . IM t n, i. hm I9TS. CUM H Cf M Ml ten, h cn Itlt.lMC ICHBI 82 HONS 025683 CHLORAMBUCIL There It sufficient evidence * cerclnogenlclty ef chlorenbucll both in lumens end In eaperlnentel enlnels.l. Chtorembucll It cerctnogenlr. In rets end nice following Intrtptrltonei! Injection, producing lymphones in rett, end lyaphosercoaes, overlen tumors, end lung tunors in mice.* Excesses of ecote leukemia were reported in o number of epidemi ological studies of people treated with chlorenOucIl, either elone or In combination with other theroples, for both non* roll joint end nelignent ditetset. Other cencert hive el to been associated with the use of chlorenbucll ond other agents. An excess of tcute leukemia In ettoclitlon with chlorambucil wet teen In o further study In which 431 previously vntreited petlents with polycythemia vere were given phlebotoegr elone or chioraabuc11 with phlebotomy, ond followed for e mein of 6.5 yeerl. Of the 2t cites of acute leukemia thit occurred, II were In the (rosip receiving chlorenbucll. The risk Increased with Increasing dote end tine of treatment.1 1Internetlonil Agency for Reteorch on Center. IARC Monographs on the Evaluation of the Cerclhoptnlc Risk of Chenicelt to Huaent. Supplement 4. Lyon, Frence: IARC, IRK. International Agency for Rettirch on Cencer. IARC Monogrepht on the Eveluetlon of the Cerclnogenlc Risk of Chemicals to Huaent. Vo!. t. Lyon, Frence: IARC, 1901, pp. US-36. Chlorenbucll, e drug used te treet cencer, It e derlvetlve of nitrogen autterd. This drug It prlmerlly used et en intineoplistlc egent for the treetaent of lymphocytic leukcalo, nelignent lymphoaet, folllculer lyaphoae. end Hodekln't dlteete. The treetmentt ere not curetlve, but they do produce tone narked remissions. Chlorenbucll hit el to been tested for treetaent of chronic hepetltls end rheumatoid erthrltls end for use is en insect cheaotterilenv. All of the chlorenbucll used In thit country It Imported from the United Kingdom. No dete ere ivelleble on the guentlty Imported, but the FDA reported thet 1.4 alllion prescriptions were dispensed by retell pharmacies 1* IMO. Exposure In the United states would be Halted to workers forauletfng the toblets or to petlents receiving the drug. The CereInogge Assessment Sroup Includes this chealcel on its list of cerclnogens. Therefore, the EPA regulates chlorenbucll under the Resource Conservetlon end Recovery Act. The FOA epproved chlorenbucll for use es e prescription drug In IBM, noting restrictive epproved cllnlcil use for the treetment of chronic tyaphocytlc leukeale, nelignent lymphoaes, end Hodgkin's dtseise. S3 MOMS 025684 CMft'MMCt' KttUftM tfvttttWt M OIMf MtH*l l**1 If IfNiillMli ItNr (wimi eiuiiM If MfllltM M ||44*( tlH. in UM KtMWt I* WMW> nMtl DNIf CHC MMIlltl*. :traci ICtt, 1M.1M1 IrtlMli Mill pnMIt, |(f>IM(IN|llf* MWI, IN Mtn Ml IHtll If IM l| M MMttaft M mNl/WINimllf NWlfPHU. Hu MlfMMI II 1 laairlM HMlfMM If Hill, M MiNtl Ntut NM M (WUU H MIN IM IMHIMMI. Mcwl|iM t/ll/K, In* CmlNfi* iimmM Im; miwn mm jrtaMNtflwrtM* rot) m era m.n. m.j* lira) rift IvrtM if Nn, fMCftt MulNH ftr *H Irta/M. Irani IWU M UllNN if INIliM MlWNI If l*n*'l immi, mHinm ijaimii, in WNHi'i HmM. M l IWU mum miairatMtft **, m iiu> 11MM If MM M|l MM (lf|M|lMl l Ml IMrlllMi IN Mtlf clt' lCll IM|I mifMli Ml Hn If r*nrlt1* MMH fltft11 INKlIMN. irafti era ti, tMeMaw * <raft) 84 HONS 025605 CHLOROFORM There ts diffident evidence for the carcinogenicity of chloro form Inexperimental animals.! Chloroform was tested <n three experiments In aaice and In one in rats by oral admini stration. It produced hepatomas and hepatocellular carcinomas in nice (gavage of a solution in olive oil), malignant kidney tumors In male rats, and tumors of the thyroid In female rats. In another series of eperinents in male mice, chloroform administered orally (gavage in toothpaste or in arachls ill) produced benign and malignant kidney tumors.* 1 International Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk uf Chemicals to Humans. Supplement I. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 20. Lyon, France: IARC, 19/9, pp. 491-27. Chloroform is a highly volatile liguld that It slightly soluble In water. It It used primarily as an intermediate in the manufacture of fluorocarbon compounds, dyes, drugs, and pesticides; as a solvent In the attraction and purification of some antibiotics, vitamins, and flavors; ts an industrial solvent In photography and drvcleaning; and as a heat transfer medium. Its rte as an anesthetic has been largely discontinued. At least one grain fumigant miature contains chloroform with carbon disulfide, and It has been formulated with other Ingredients for screw worm control on animals. The consumption pattern for 1974 was as follows: 51 percent for fluorocarbon refrigerants, 24 percent for plastics, and 25 percent for other uses. During 1971-78, 230-350 million lb of chloroform were produced in the United States. Domestic production in 1977 was reported oy EPA (public record) as 175 million lb and imports ts 4 million lb. U.S. exports were estimated at 20 million lb In 1977. The annual growth rate for production was forecast at 7 percent. The wide industrial use of chloroform potentially exposes 360,000 workers (OSHA). Chemists and support workers as well as hospital workers art believed to be at a higher risk than the general population. Chloroform has been detected in the atmosphere at < 0.05-7.3 g/m3 (< 0.01-15 ppb); In water at < 0.1-311 wg/l; in foodstuff at SO ppm; in aguatlc lift at 7-1040 mg/kg (56-1040 ng/kg--mollusks; 7-851 eg/kg--fish) (dry weight); and in human tissue samples at 1-68 ng/kg of wet tissue. 85 HONS 025686 [PA criteria and promulgated regulations Include (1) general rule! for refolding haaardojs spills, (2) utter duality criteria doclatent for the protection of human health and assessment regarding carcinogenicity, (3) restriction of use as a pesticide under the Rebuttable Presumption Against Registration, (4) regulations regarding handling and disposal of chloroform production waste materia), and (SI the Safe Drinking Water Act In which [PA hat promulgated a regulation (i960) regarding the removal of chloroform from drinking water and established a maximum contaminant level of 100 vg/1. Chloroform was banned by fDA from use In food, drugs, and cosmetics on June 29, 19*S. Prior to being banned, chloroform had been approved for use In cough preparations, llnaments, toothpastes, cosmetics, and toothache drops. OSKA adopted a celling level of SO ppm (240 mg/H) for any 10-mlnutc period. This standard was adopted by OSHA for tonic effects other than cancer. S6 HONS 029607 (ilrtfM ** n*f tn<w UMUTIMS Iffact to a^iatftoa; (Mr C--im ClUtlto to Bafalatlaa KMCI CM. MCult Mltr cadUr CHtar'a pmtlWM fa ffwl 1t*, ll/M/M. CM, III: aaitrlaat 1*111 fMllIM HIM HwUf fmnnu i8iiir (Mil it, Itll tfi M r*tinif nwifiM. tnwitatM //. 4 |wul HOW r(HTMl Mttl m i* m.c fi, /m. MM, MI'MW: MJ1I Mill KIMII, Mimi, M IM11 r**l. Ml Ml MIM to MM t| t* IMIMI M WMTVfWItotolM TIMiTMm. aim MUMMI IklMflM* MIMM CM* I1IMM to MtW, DM Mjltll MtUI l<MI to CMWMl ft to toe MM milWMIU. fraaaltauc l/M/M. MM Mfililtoi MM1*| Will m IklMfM CM toff MNT tottoltoMMMI. Ntoultotot ll/tt/ft. IlMlfWf toCMl*to*totoC MatoM totolMM ImI to 1 >*/1. n/U, ft toM IIMH 4/l/TI. wt total cmlaafaaicftr. tout caniaaftoicM*. ImH to tocaaaMft%. (mat carta* llatal, 1/tJ/M. (MM mfaa aal Hto/toMfft mnjmM ctotlwlai. Ml Cafe laafaa Mmimh tow* IUIMM MIT |*MtolMltolMVM*. lieu K ft IJI, |. 19)11 cm iim. iif ,u i >i m. i. tiaw to VI Ml.II. Ml.19 to CM )t).U ci n.. itoM (Ml W Ixtli to Mil MnllMM mmImim mim ffMiii cUartotm tolar f/to/ff trm anrfi m iimuci im m MM fHMto #1 ttoTMftol. to* tom to iMii M f*yai** Ifni ar MitoMii to toatary immm. *M1. mvlti fr IM iriiwn to tolto** taa a mimiV to tmi> I'M) Hit M n> flto */>) ctfifH* (ItaMto* MMtf *to icait iffacia Itoto CM* CtoCto.) 1MNU ti imtat tw aMUfto to calartoar* u> faalt. Wat ttoalttoly tltotMtiac rttt. Iftoi Catalatafy afnary: illlltio:toNlc itftMocNaaitrr.ttiIaMa.pm naw MM Tatta*to ItiMirl carraat Ifait affee* flat. (MU| to cn lltl.MM (MM) 87 HONS 025688 CHROMIUM AMO CERTAIN CHROMIUM COMPOUNDS There It sufficient evidence for the carcinogenicity of chromium ontf certain chromium compounds both In humans and experimental anlaalt.1 Calclun ch.-ornate It carcinogenic In rats when given by teveral routes, producing tumors at the sites of edsilntstretton. lead chromate, sintered calcium chromate, zinc chromate, strontium chromate, sintered chromium trioxide, lead chromate oxide end cobalt-chromium alloy produce sarcoatas at the sites of their subcutaneous. Intramuscular and/or Intrapleural administration In rats: lead chremet* alto produced renal carcinomas following Its Intraaaiscular administration In rats.2 There Is sufficient evidence for Increased Incidence of lung cancer among workers In the chromate-producing Industry and possibly also among chromium platers and chromium alloy workers. There Is also a suggestion of Increased Incidence of cancers at other sites. However, the chromium confounds responsible cannot be specified.2 ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement A. Lyon, France: IARC, 1982. Mnternatlonal Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chearicals to Humans. Vol. 23. lyon, France: IARC, 1960, pp. EOS-323. Chromium Is a steel-gray, lustrous metal. Chromium and Its compounds are used In metal alloys such as stainless steel; as protective co .logs on metal; on magnetic tapes; and as pigments for paints, cement, o'- .-, rubber, composition floor covering, and other materials. These compour.,.- . re also used as oxidants In organic chemical synthesis, In photomechanl: > process ing, In Industrial water treatment, and In medicine as an astringent and antiseptic. The aggregate 1960 domestic production of chromium and 10 Important chromium compounds was over 752 million lb. Approximately 102 million lb were Imported In 1960. Sodium dlchromate Is the highest volume chea.1eal of all chromium compounds. Its domestic production In 1960 was approximately SM million 1b, and Imports totaled approximately 71 million lb. 88 HONS 025689 Chromium (In the font of unidentified chromlue compounds) Is widely distributed In dr, weter, toll, end food. In trtce mounts, the trtvolent fen neybe tn essentlel Ingredient In our diet. The entire populetton It tbue exposed to true of these compounds, but the levels of exposure very. Hextvtlent chromites compounds ore of jreeter heeltn concern then trlvelent compounds; however, hex*relent compounds ere retdlly reduced to trlvelent forms In the presence of orpensc Better. The Netlonel Occupetlcne! Hettrd Survey hes cstlmtted thet 2.5 million workers ere exposed to chromium end Its compounds. The Consumer Product Sefcty Commission (CPSC) stuff Is tnvestlgetlng the potenttel hettrd to consumers from meterlels printed with chromltescentelnlng Inks. XIthoup* chromium wes found In some Inks used in printed products, the levels found In the fine! product did not wtrrent further octtvlty. The CPSC stuff Indtceted thet there wet little chroclimi found In other printed consumer products. The CPA hes reguleted chromites end 1s compounds under the Cleon Weter Act, the Resource Conservttlon end Recovery Act, end the Toxic Substencet Control Act. the CPA nexlmue level permitted In drinking weter Is 0.0$ mp/l (Soft Drinking Utter Act, 1412). The CPA Csrclnogcn Assessment troop hot Included 10 chromium compounds on Its list of ctrclnopens. UIOSH recommends resplretcry devices, protective dothlnp, proper housekeeping, end trelnlng for persons pottntlelly exposed to hexevtlent chromites compounds. OSHA hes edopUd tn R-hour TUA exposure limit of o.t mp^H for soluble chromium compounds end 1 mg/a3 for chromium mete! end Insoluble compounds os on *-hour tlme-we1|hted oversge. For chromic Kid end chromttet, the pormlsslbl* exposure limit Is 0.1 mg/a3 celling. UIOSH rtcotaends exposure limits of 1 vg/b3 for cerclnogenlc hexevtlent cbroalitt compounds, 25 wg/m3 ts on 8-hour time-weighted evertge, end SO ug/m3 celling for other hexevelert chromium compounds. HONS 025690 Ck( H (irtlll CM< MUUf'M lafaKKaac m (liar Milan aa wriit wtiai. |f*KI Iffact af tawtatlaw: ttaar (aw*tt Citattaa af tawlattaa CirwlWi CM, mi (Iflaaal wtaaltaaa far ccruia twaatrial cattfartat aaaratt araaaaalt far aaaictaaat cataaanat: I/I, t/?, l/n. M lt/tl/lt. tracraacaaa< aart af aw caiaaary. frMiNMf tttm, latitHMat caatral taraafk VHI aawttt. Carctaavaaidly at aat atartaati ta aat*taf w*altwa. aUMaft aw yawraiiy atfaar rtaaa aaaactatar vim aaamiaat ttrai# ara aaattaarta. < Cf! fit, til. til. i|f. an. at!, ta. ai. it. in lyarttaaal ruaaaaa pi'CtHni fa* taaviaa ar tcataar taMiaf aw ftalMIW 'M. .ill aaaa caawata aa aatittla rtriMaaa af aw- aatala (a tt/Cv. All faar ara tcrtacai far yraal|iti ann atf- ar law (Ml. m rt lit. a. Jt'tl at it in. p. 1 M It IM. . UiM m rt in. a- iim CM. milll wear wall* crfttrfa wall9*aa ta fiaal law. ll/nm. fta wtlw-ttaai rritarta* la aaaaral wilc'lr ilrmlitt IM f/l; launltat M at rt mi. #. mu KM, SMOMi Nafwttai aa Mhtwi aaw*ltraM af aaw <arata aat > Wawt, tat tttMM wttffun. Maatraa tatttif ta wtawtaa artiaaaa $t mm*m. mm tawa ta cantata ww# ara aMJact ta awtltat aai raaarvracarwaaalaf Wtilruu. MwalfatM l/H/M. M, |4Ut arWary trtMtwwaer tuwari. Haal|iM It/M/Vf- Cawaatratlaa trlwartaf iw'lma naatramu ta J W>- liimai tMiaa wnMatai (aval la Ml af/i, ta*al tawt*. Ctrawc aaatafty aai tarttaafatUlM Waaralaat taraaiM aw cawliarai la aattfaf tala laval. mcmmi.u CM HI.11 Tt'Ai taaaawaat cawlatai. /H. tnalw wt tatm aaaraaaaa aart ttitrlaai w aa araiaca ralataa. ft, aaraawl taw Icatna, t/n IIM) KHI m lOTW * fNi: WKlOl 'tfill' Itm ar wl'a*CM ar Httir? twwi, ac*.ta* w mi* <* a* imw m a iM*na* whm *.*a cata M*<aia m N aiNMtt h iimii iu ity wwH itavn imwri. at awiiutu far Maury wartat. MfiUM tin art aaaat ar m in*r ttaa < ttratiar af cmiw all ae'.*. tuawelraaaiani a.iwkr far twattrta: It era I'MMt lar rwatr araarett: Miien in.m IN kriN af aaMtat Nriiar. WU: aa raw***1*** mh aaaa arwtaawa. imtea M cartirayaatc waaattal af cwaaiw tarn ttaaritaa ay carraoa* aat aaaa taiiM w aCl. irwi NiiNtia lata# Hr 90 rows 0^5691 i*4 (trull Ca*fe*fe KmiMil CCMAftWS lafelttlta* M4 hk tltlM iriNt ii iiMiitiwii fe*r tNu ctuiiM If BtfelNIw ftl: 9.1 afen* iitllN l(Mit| nM m *NNtM)i'l.l aj/a i*ar Tw IhMIi l+fmtt * (Mmi Mitt): l af/a> Mr TM IwUt m4 imliili Mill). (MM) cik-i cixwm nIN*n MIMNt: . IIM.' likNNlr. 1.1 at/n* Milts |IIm#I| INMNIMM lUNMlt m i M NNNlNl. l/lf/lls NM Miwtf Immrl-nrrwt IfNI iffutlw. (MM) IN *, JMI-J9M. infer Nraaln* In. CaNiwfe* timwtt Inn iuuwn Nfer ^ (iru Mt mmmmt <v*feN hr uni# (ll. tMMN) In NfeiitiM hr feN#. IMM) I* (fl Itll.lMO ftfcU) ii crt mi.NM (MM) CMNJn kiMk: 1(*, lilt IMINW fefll Nfet.ttN MWMlNMf W*MMr IhM *. M Ifl N^M^Nlaf Nirtiif NfelNfeNi In KM. Ml'MI Nfer NNMN. IIM) ffeNtN ClNfh nil 9t nnwr intM'i t* tlNIIW ff rtNM NfeH>U. mi NlNtlN 9* ININ 1* NNMfe tN MMfNMN MMNr NMW- (OKI IN KM. Ml.fefe. Nfer (<w. tin> MM N NNtIC Mll(Hr< flllN four UN la MMIIil Mtf talwlat CMfeuli. 119*1 < tfl ))>.. ||7.|> Kill MHWOmwtt: IN KM. NM'KN In m (.{Inn Mmimm Inn imv nM nar iNMflmnH nnn . (1941 Si HONS 025692 (krt H Ckr*l Ito'iiim m Mk# totttM to*** W, Mill to#HM mil mtHrlif prm (ttl me IM MU. tMMlto l/lt/M. tot aou, KNOMt. mm rnmlm. II) tot miniil itototo to totiiM (VII. IllMMI tot ttfttoiltti to* to#iM. MUM) tt1 cns Mfib.. IK*. M*lt totMHto "wntrMmirHtimm . 1mmmtmlM<wtuplU^mMiiwt#mMttto. tt# ItMl VMitIM IfFttt ft totoltlttoi; tUwr i'mwhI Cltotlt* tr tofviatiM n t. i)mc U'M n tn mt.itat IttMl t. *. i (IF* I Tie*. Ml): tottotllf tolt totolrltf nmi M m mu, kmhm l/tt/tc. tot {itlWMI tlKIWM tTM IUMHI mmr 4$ FI to, t. lUM ((Ml hum# (WMMi tomUMIMI. DM, Ml! mil M# HU UK* H. <U i|i mm%- to UMlnmtl. u*Ml|ttot l/tt/n. T1U, M): toihto hit Mtolrtto pr# MM tN I'M MU, MM>M< l/tt/M. Mt Uw< m iMciujHUttr. it--uftt toll# ta*t I* Itotto KM iMwto tMMMll M* iMtll PtMlt to toWII# tf MKiMMi to W 117.9. JT.| to FI <l2l,tol. IMH tot imiMito to itotiw. (Ml K l Wl Ittt.ltet IMM1 MOWS 025693 tom** * unit* U*<a Cwwo tt**ti*l VCUUUMS ItfllMlM M hMf lcttM IffltNtMtor Uantt HtrtHw Hwxnw; Im KU, Ml'NM, Mir Unnltf. tM, Hit ftlirMI Will r*t*Ut<to M*< CM, Ml imwM t**tlMS until *- iiifiM to miiim * mi ikitmii; N**tof*W* Vll/Nt MMN NMNMtl;. VtCA. llh HM-tUf MU MWlPUf *** MM IN H MM, IMIlM l/lt/M. fMtliMirMiin ihmi mMwmihmMIM*** l***ar*f** i*i*#i*j MlMlIl M IMH Mull In MKtlM *f MIMMil IMIllfM. MM )MHylMMnMM. (CHI CIUtlM Itfilltll* to era nr.\ ni.u (ira) to erv m.ta*. amil..liNu. *ll.ito. In rtfiUilnM Mr awaiw. tcm imam* ef&rss, CM, llll IMlUMI Will Vft**1*" MIMHiMm MMUItt MMIM lint ll, IM la) M MMIM riMI'M MWlMMI. H*MlttW */wm. TKA. Kill MmiIm nil watortw or*. mi m im mi, KwtiH t/n.uo- mtom* C* hmMtwiimritoMMmniiuimnnf.mi iummM lira) to* mMHMl IUWM *tr MMW (VI). tmOMfWl MlKMCMM* Mhi ni*MMH*nmtlly.tMiMpflMufflM MMllU MW MvK WMlt Ml MtotlM to acciamil mmimi. lira) to* nivtitiM Up aww. (MM Mw inwniMi to* acv. Ml'MM, ***** ***. to*, itti totnwi win wmImu* mu- < a*t ***** a* c*p*ia*a**ifUr (*c**r*a** tfaMaa nunaU mmiii (MM to, rut** on w ****11*9 M *i*>ii *H1**if*l**t*w* *tomaamtiw. mania nwnm*u. ot*Maelct*itUoa*uw) Hwniawl*ntia. ll l* n*nVn M, Mi tmm y*t*il*** mmii *- to****** to Mini# m mi# aiiMwwu. MmImm vu/Mi **--* wi*MHi. (winl to wm tor**)* mu *niB, nrai to* Caret***** amn--t awtv Cw**talM*wNfl| *w*. iaw*t era iim, nr.t) 41 rt c1,(1o4). i)Mi i> era im.im IMM) 40 era iim, liras (IM) w era m.na. 1I.tw. 411.)to. man (CHI icmiwaa) 93 HONS 025694 CkrtM* < Cirtito CkrH( CwwMi te*1M) MMATIMS M ItNP Mt<N i: iUlaNtKlPNIl P 0Nil IT1). l NflHtlWt fto |MWl. IffWt ft ItMlHNNi Will (lint bass2xJs&: Im acu. MMOOW. I CM. ):tt NIWI1 Will mm* tiiMM pwpwii iim it, 4N4WMlMl MIrt lM/nu/Mm. n*Ptl*| >Nliwli. TIC, Mill NnrtlN **' W1P1| *M * VW NN, ;WNU l/M/M. Ibu I lUNtN (tr (MM mt. W MM tiftlillnlcHy. tNNPifii pMWWUUftl<l Mr toMNiNll lPIlNffeINlt to|MMrKtatflM 4 mtMUi wyiwni. ItMJ Im ncUtlM tor Cto*<. ft IlfplltlM if cn lait.io* IWtt} cn um, ijmi 41 44!. . IM44 a era mo.MN Itoa Bwnw aw*4a: snsrsnsr. Im tMtlMpI IlMIHHl Mm ItoUMM Mar iMUrlMMlWPiN. tmi MMW toll MM ll Mt MllvM to to cMMPctoHr IMIIMI# to to* tototo Main, Ml It to pHM to Mitt mhI4 iHM topH M WNNl Mf It. W 94 HONS 02569S COKE OVEN EMISSIONS IN* overwhelming scientific evidence supports the finding thit coke oven missions ere carcinogenic, this finding rests on epidemiological surveys ns well ns animal studies and chemical analyses of coke even emissions. Coke oven workers have an Increased risk of developing cancer of the lug and urinary tract. In addition, observations on animals and of human populations have shown that skin tumors can be Induced by the products of coal combustion and distillation. Chemical analyses of coke oven missions reveal the presence of a large number of known carcinogens as well as several agents known to enhance the effect of chemical carcinogens especially on the respi ratory tract.l1 10ccupat1onal Safety and Health Adalnlstratlom Exposure to Coke Oven Emissions. Federal keel star. Vol. 41(206), 1*76, pp. 46742-90. Coke oven missions are a complex mixture of coal and coke particles, various vapors, gases, and tart that Include polycyclic aromatic hydrocarbons. OSMA defines these missions as the benzene-roiuble fraction of total partic ulate natter present during the destructive distillation or carbonisation of coal for the production of coke. Polycyclic aromatic hydrocarbons generally constitute about 7-3 percent of the total particulates and 1-6 percent of the beuene-solubie fraction. According tJ the bureau of Mines, 64 domestic plant*-operated about ll.COO coke ovens In 1970. Most of the cote produced in this country Is used In the extraction of metals from their ores, especially*Iron. As a raw mate rial, coke Is used In the synthesis of calcium carbide and In the manufacture of graphite and electrodes. Workers and those living in Industrial areas where coke oven missions occur have a high risk of exposure. Oven-charging operations and leakage around poorly sealed coke oven doors are the major sources of gaseous emissions from byproduct ovens. OSMA estimated that 10,000 coke oven workers are exposed to these missions. Worker exposures to the benzene-soluble fraction were reported in air sampling studies to range from 0.40 mg/m3 to 3.0 mg/ml. The OSMA standard for coke oven emissions, which was promulgated In 1*77, established a permissible exposure limit of 1*0 vg/m3 averaged over any (-hour period. Under this standard, specific engineering and work prac tice control regutrements became effective In January 19*0. *5 HONS 025696 Celt fet* KWLlTtfrft VfwUtlMI M QtNf fettMl fftoct if lifilttlto; ItMr Cmmmi CtuilM f Mfw'atYM (M: toll Mlittwi w altr Him* til U HUftlm If r|wiitlM m mutil mi fulfil. to to ICM) Ifwt ititwMt tomui nu nntuiriM. Itto) MM, MtoMl (MiMicnto, Ml. (tMt rut im m/>> i-f nt. JtoUfwiI bnUtto: Ntotto IM nHit wpmIUmc* *<**- mu to wrtini rnttoto totbmiu ton Mli toto ml NntoKttti cnitmt t wfmtmt r fmth'.i; tonftrit mrinnut iMcific m(mtn ntontou to mi Mto mn ttMt mcifu toilrmMi tor ctorflto, iilliif, imM|, to mImmmci am NN<r itoittoi ito nwtoMMi tor mm Ml tnu unto nffnun lMiY<*y ntotowU to toulitoi if MitatoMtol CUtoiHf ttMD 1.2tofUlMV Mitoy: INIs lltotoiiy, . /*> miImi UtoMU irtmnUw h tto tor yltti 7 7VI / U IM TUttof Sum**-- 0.2 9M*. -tr AM tor cmI tor oltrt MiiiriM. 1 29 27/ / : ritol tttorl.^ftttlH, 1 29/ /M: Metric mtoiHit Ml Mto09*1pnctki CMttol mwitoUi iftotto. ( 9 era 1190190*.1lift 9t HONS 025697 P-CRES1DINE When administered In the diet, p-cresidlne wet carcinogenic te Fischer 344 rets, cauilng Inc rent d Incidences ut cere: nomes end papUlenes of the urinary bladder In both sexes. Increased Incidences of olfactory neurobiastones In both sexes, and of lire.' tumors In nales. p-Crestdlne was also carcinogenic In BCC3F1 nice, causing caret nomai of the urinary bladders In both sexes and hepatocellular card nones In females.! national Cancer Institute. Bioassay of p-CresIdlne for Possible Carcinogenicity. CAS No. 120-71-B. Technical Report Series do. 142. OHHS Publication No. (NIH) 78-1394. Bethesda, Maryland, 1979. P-Cresidine Is an aroMtlc aaifna that Is Insoluble In water but very soluble In organic solvents. p-Crestdlne appear; to be used solely as an Intermediate In the produc tion of various aio <bres and pigments, Including 11 dyes that are produced commercially In the United States. The average annual production Is not known, but one Mnufacturer has reported a production of about 590,000 lb during 1971-76. The CPA In 1977 reported 14 manufacturers and/or Importers. Hunan exposure to p-cresIdIne occurs prlMrlly through Inhalation of vapors or skin absorption of lloulds, and this exposure Is believed to be limited to workers In dye-production facilities. The Consumer Product Safety Commission stated that residual levels or trace Impurities of p-cresidlne My possibly be present In tome dyes based on this cncmlcal and In the final consumer product. The presence of p-cresidlne, een as a trace contaminant. My be cause for concern. But no data are available describing the actual levels of Impurities In the final product, the potential for consuMr exposure, and the potential uptake. Under the Tox'c Substances Control Act. EPA has proposed a rule to ree*1re data reporting on the process and the use of p-cresidlne. p-Crestdlne Is not currently regulated under the Food, Drug, and CotMtlc Act (FMCA). The chemical Is a potential contamlMnt In the FD6CA Red 40 (AIIum Red), however, and regulatory action Is pending. 97 HONS 025698 p-Crnftiaa m< titwr ktim ltd. Mill tomtit ml* m*iiiii m<MI M IN NU^jfNNM t/M/M. M nm*Or **111*4 ntCA. toflltllt* It MNMf M M Hi tlMtltl to WIUHMU mu M -4. ir*o acttUTttt IffNt if tiNlitiwi; Itof (NWItl eiutiM if htiliiiw i n i}, i, iM4 104) M HONS 02569' CUPfiARON Cupfcrron, given In th* diet, hit carclnogenl-. to Fischer 344 rttt, causing heienglosrcons, hepatocellular carcinomas, and sguamous-cell carcinomas of the forestomich fn nln mil ftMlti, it ml) it carcinomas of tht auditory sebaceous gland In fenalcs. The chemical wit iTto carcinogenic to 86C3F1 alee, Ciutlng hantngtotircoatt In Mlct; tnd hepatocellular etretneani, circtnoait of th auditory sebaceous gttnd, combination of hamanglosareomas and hemangiomas, ind idenoatt of the Hirdcrtin gltnd In fault*.1 National Ctnctr InitltuU. Ifoittty of Cupfcrron for Potslblo Carcinogenicity. Ttchnlctl Report Strict Me. 100. DHEM Publication No. (N1H) 78-1350. tcthcidi, Maryland, 1978. Cupfcrron, I laboratory chemical, It i crystalline toll4 thtt It eery soluble In utter end ilcohol. Thtt compound It cn N-nltrotohydroxyItmlnc derive tire. Cupfcrron It uted to teperite tin frra line, ind copper and iron from other metalt. Cupfcrron alto ftndi application at a quantitative reagent for vanadate! and titanium and for the colorimetric detenu!nation ef aluminum. CPA hat indicated that tvo couvaniet currently p-oduce cupfcrron In two regies. Domestic production hat been estimated as 37,000 lb. Imoorts were not reported (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record!. The 1980 production of Cupfcrron was reported to the U.S. International Trade Commission at greater than 500C lb. Human exposure to cupfcrron occurs metnly through Ingestion or Inhala tion of the dutt from the dry salt. Skin absorption It a secondary route of exposure. The potential for exposure appears to be greatest for those engaged fn analytical or research studies Involving use of the chemical. Mortars may alto be exposed to the compound during manufacturing processes. The National 0ccunat1on.il Hazard Survey In 1974 estimated that 4000 workers were potentially expo.ed tu cupfcrron. Cupfcrron Is currently proposed for regulation by CPA under the TSCA, i(al, reporting rule, which would provide detailed production and marketing data. 99 HONS 025700 Caffarra*r IfcWUTHWS ttfVlfttlMI M OtNf *etla*4 TSCA, Malt Haaartlf ml* raanfrfaf pracaii M IM 4t4, |nftt4 t/n.10. (IW Iffaat af ftaprlatlaai; OtMr Cwm Cftatla* af ttfa>#tna 4*14 aravfda a fcattar taili far mlaatlaf tatantUI, a*It* mat fea caastatraa a)a*f all* risk fa aaunrtafnf aaaratrlataaass af rayuUtr'y ar atitar cantra! actfaa. m\ 4i , f. i344 ttM) 100 HONS 025701 CYCASIM There Is sufficient evidence fer the carcinogenicity )f cycasln In experimental animals.1 Cycasln was carcinogenic In five anlnal species. Inducing tumors in several organs. When administered In the diet, It was carcinogenic to tht rat, guineapig and fish. Administered by gavage. It was carcinogenic to the hamster. It was alto active In single-dose exper iments and following prenatal exposure. The carcinogenicity of Its metabolite, methylaioxymettonol, has been demonstrated In the rat and hamster and that of a closely related synthetic substance, methylaioxymethanol acetate. In the rat.2 ^International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk rf Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. 'International Agency for Research on Caxer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Han. Yet. 1. Lyon, France: 1ARC, 1972, pp. 1S7-63. Cycasln occurs naturally In the seeds, roots, and leaves of cycad plants, which are found In the tropical and subtropical regions of the world. Nuts from the eyeids are used to make chips, flour, and starch. Cycasln is not produced or used coawrclally. The major potential expo sure Is the Ingestion of the foods containing cycasln. It Is estimated that about SO-SS percent of the inhabitants of Swam are potentially exposed ($0,000-80,000 persons) to cycasln. Wastewater from th* preparation of the cycad nuts contains large amounts of cycasln and represents a potential secondary exposure source. The ERA regulates cycastr, under the Resource Conservation and Recovery Act. Cycasln Is designated as a hazardous constituent of waste, and wastes known to contain It are subject to handling and report/recordkeeplng requirements. trtiihi nuTtw KplMi'M mi towr ktiew KM, KM-MMt NllfUM cyCMl* < NMPdHH MNIIMR.' If Mtl, M MjKtt mM Mhi hm name I, haadllei mi HWUfWfm1*! niHfiMU- fnmil* |IM /!/. H (MlMM MWMH IfM IVMMM mat i*NHfllRflMM8, tmi IPfWt If iMlllllMt Mr C--MU ttUt'M m itMiMiM itnm.ii BW 101 HONS 025702 CYCLOPHOSPHAMIDE There 1 sufficient evidence for the carctnooenlcl ty of cyclo phosphamide both In humars end In experimental animals.1 Cyclophosphamide was carcinogenic In rats follow'ng administra tion In Printing water and Intravenous Injection, and tn mice following subcutaneous Injection. Dosages were comparable to those used In clinical practice. The chemical produced benign and malignant tumors at various sites, Including bladder tumors In the rat.2 Five epidemiological studies are available In which persons treated with cyclophosphamide for a variety of medical conditions were compared with similarly afflicted controls. These studies consistently demonstrate tn excess of various neoplasms and leukemias In the treated groups, although the iriaprr in all five studies wassawll.* ^International Agency far Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency far Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 26. Lyon. France: IARC, 1981, pp. 165-202. Cyclophosphamide, a chemical related to the nitrogen mustards. Is a widely used synthetic antlr.eoplastlc drug that is soluble In water. Cyclophosphamide Is used in the treatment of malignant lymphoma, nultlole mveloma. leukemias, and other malignant diseases. Cyclophosphrctis has been testco as an Insect chemosterllent and for use in tie chemical shearing of sheep. Cyclophosphamide Is not produced In the United States. It'It produced In the Federal Republic of Geirany and exported to the United States where one company has formulated and marketed the drug since 19S9. U.S. sales are approximately 1300 lb annually. The FDA estimates that 200,000-300,000 patients per year are treated with cyclophosphamide, which is adslnlstered orally and through Injection. The adult dosage la usually 1-S mm/kg of body weight dally o 10-1$ ng/kg administered Intravenously eve.y 7-10 days. 102 0*5703 MO**s Th* FDA requires en Insert In the drug peckige to warn of seconder/ altgnancfes thet my occur several yeers efter treatment with cydophosplwalde hes ended. The FOA Is Investigating the use of cyclophosphamide In nonaellgnent diseases. CPA regulates this chemical under the Resource Conservation and Recovery Act. M Mur AetlMi MM.AT IMS tf tNfdatit**; IlMf CURtl CfMIfM If Mfilitlid M IWPWt KttW. M IMM RflMNI ll MMHNP prMvctl Mir CMC jiriMlittw. KKIt KM. MfMlt IwtfNM N I WMHl mimrmm if uu. Hr st *mm t* wmil ylllKllKIII ll r Ajcct t* iNUtal M nwrt/ncifOiiiim miiri* MU. IrvMplH l/IVft. uImrn(Ml*MlMtMriMAiMlMfINMMMrttH. dl IttUMM (Ml M CM Kill UH) fM hnni if Urvyf, flKI: InwrlftlM Mf Mt Iff IrMMU If Mllllfll. Tm HlllH Ml dwr oinilRf f M IHMI1H I MlNlfl Hllfumn Ml Mr Ktir MNri: Ml" Ifur iriiwit III Mm DlMMIMl. TM ll MVr1M trltU l.iftrMtlM rcuvfrM fur i N**fi| tmi ri*t iimii* Mt M (Ml MtlMt. VM f MmlllRMt HlllHt ll Mlttll*- jtrfrMi*tliMMItirwM>,4|I*yM tsHMfml ifiM*tnlrti t* util Mt *11111 Mwi fun MlifnMcin. nee r**newt Mil <Mfr Mr Hirftt) I". * C/I It.imfdUi MMf 9 1C3 HONS 025704 2.4-D1AMIN0AMIS0LE SULFATE There Is sufficient evidence for th* carcinogenicity of 2.4- dlanlnoanlsole sulfate fn experimental animals.*,* in Fischer 3*4 rats, dietary administration of the technical-grad' 2.4- d1ami..oan1so1e sulfate Increased the Incidence of malignant tumors of the skin and the associated glands, and of rn.nt1g.iant thyroid tumors In each sex. In B6C3F1 mice, dietary admini stration of 2,4-dlamtncanlsole sulfate Induced thyroid tumors In tech sex. Fischer 344 female rats exposed In the feed to technical-grade 2,4-dlamlnoantsole sulfate developed tumors of the thyroid, maamiary, clltor.l, and pituitary glands.*.3 (international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1962. `International Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 27. Lyon, France: IARC, 1982, pp. 191-98. ^National Cancer Institute. 61oassay of 2,4 Clamlnoanltsole Sulfate for Possible Carcinogenicity. Technical Report Series Mo. 64. DHCW Publication Ho. (MIMI 78-1334. Rethesda, Maryland, 1978. 2,<-D(aminoan<so1e sulfate (2,4-CAA sulfate) is e phenylenedlami re derivative that Is soluble In water and ethanol. The principal use of 2,4-DAA sulfate Is as a component of oxidation ("perminent") hair- and fur-dye formulations. Approximately three-guarters of the hatr-dye formulations In 1978 contained 2,4-DAA or 2,4-DAA sulfate. These two compounds are also used as Intermediates for the production of C.l. Basic Brown 2, used to fee furs, acrylic fibers, cotton, wool, nylon, polyester, leather, suede, and as an ingredient of shoe polishes. The Consumer Prod'ict Safety Commission (CPSC) reported that currently the chemical Is not used In consumer products under CPSC jurisdiction. It Is, however, used as a component of cosmetic products under FDA Jurisdiction. Comnerclal production of 2,4-DAA sulfate was first reported In 1967 to the U.S. Tariff Commission. The estimated ennual djeestic usage of this compound In 1977 was 3C.OOO lb. The CPSC indicated that 2,4-DAA sulfate Is no lunger produced In commercial quantities or Imported. However, EPA has reported two producers and Importers of 2,4-DAA sulfate. Mo domestic pro duction data were available. Imports of 2,4-DAA sulfate were estimated as ISC 1b (Toxic Substances Control Act (TSCA), Chemical Substance Inventoiy, 1979, public record). NCI stated that production of 2,4-DAA sulfate was not 104 HONS 025705 reported to th* U.S. International Trade Commission for 1979-1980; however, the 1982 Directory of Chemical Producers Indicates that one U.S. company currently oroduces the chealcal. The one company listed stated they no longer produce this chealcal on a regular basis according to the Information received by the CPSC. Human exposure to 2,4-DM sulfate aay cccur through skin absorption at choalcal- and dye-production facilities. Dermal contact also occurs for persons using hair dyes containing 2,4-DM sulfate. The maximum concentration of the coaoound In hair-dye preparations Is about l.S percent. The National Occupational Hatard Survey In 1974 made no estimate of the potential worker exposure to 2,4-DM sulfate (N10SH). However, the survey estimated 7200 exposures for 2,4-DM. NCI states that substantial exposure of the population to 2,4-DM sulfate Is questionable. Under 21 CPU 748.18, FDA regulates 2,4-dm sulfate as a coamoncnt of hair dyes. Under 44 FP 5952,'FDA requires a warning label on cosmetic products containing 2,4-OM sulfate. However, a September 1980 court decision stayed the FDA regulation, pending a determination of the potential human health risk from dermal exposure to this compound. FOA Is continuing Its consideration of the matter. |,l44lN8l|8l( Idlfitl KUWS llfilltlm and ttMP KtIM N BfPPHt Ktfdd. :ok (ttttt NT llUlllUMi tMr {8Hli HOllUfitltMltlii ihdudl (1 ppfdKH li *Ml1 tMt It U * lau (Plllr lfllH8fy IMirnt 18 IM. ICNI M I8M\U lafftdm >P88uH, 81 I88)*UP Mir 4fM MM Pin (Mltf. 4 lMl ftwlnl N HMttC IPMttl tmmn*l4l*H thonlul. Mi Ptoplailp mi iupm in i nun nkiiinn. im> n eri m.M 4 n, p. mt iitipit, pondini gitt<Milii 8g INif MN (f NNfMl 08fPO.) IfMI 105 MONS 0*5706 2,4-OIAMlNOTOt.UENE There Is suf'lctent evidence for the carcinogenicity of 2,4-dianlnotoluene In experimental animals.3 ?,4-01m1notoluene was carcinogenic <n rats aftor adnlnlstration tn the diet, producing hepatocellular carcinomas, and after subcutaneovi Injection, Inducing local sarcomas.2 in another bloatsay. 2,4-dlaminotoluene administered In the feed of F344 rata Induced hepatocellular carcinomas or neoplastic nodules In both aiales and females ano carcinomas or adenomas of the mamaary gland In females. The test chemical also produced hepatocellular carcinomas tn female 6C3F1 mice.3 1International Agency for Research on Cancer. UPC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon. France: IARC. 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chaalcals to Hen. Vol. It. Lyon, France: IARC, 1978, pp. 83-95. 'National Cancer Institute, tioessay of 2,4-91am1notoluene for Possible Carcinogenicity. Technical Report Series No. 152. OMEN Publication No. (N!H) 79-1718. Bethesda, Maryland, 1979. 2.4-Otanlnotoluene Is a Mater-soluble crystalline solid. Most of the 2,4-dlamlnotoluenc Is used as an intermediate to produce toluene dtlsocyanete, which Is used in the production of polyurethane. Small amounts are used In the production of dyes for textiles, leathers, furs, wood, and biological stains. 2,4-01am1notoluene Is used In hair-dye formu lations, but FDA has specific labeling requlrements. 2,4-0last notoluene may be formed on hydrolysis of toluene diIsocyanate-based polyurethanes le.g., polyuretnaneadheslves). 2.4- Oiamlnotoluene has been produced coamerclally in the United States for over SO years. Approximately 14 companies currently produce and Import this chemical. Domestic production for 1980 has bean estimated at 21f million lb. Imports in 1980 were approximately 4000 lb. O'Westic production has Increased 800 percent since 19f7, with only 1979 production showing a decline. Human exposure to 2,4-dlamlnotolucne occurs by skin contact and lets frequently by inhalation. Despite a long hlgh-voluma production history, there are no data available on the number of people exposed during the pro duction or use of 2,4-dlamlnotoluene. More than 99 percent of the 2,4-dianlnotoluene produced in the United States is used captfvely to produce toluene diisocyanete, usually at the same sits; hence, exposure potential is minimised. Air emissions from production are believed to be Insignificant. Hater solubility of 2,4-diamlnotoluene nay contaminate Industrial wastewater discharges and result In exposure of the general population. I0 MOMS 025707 The Consumer Product Safety Commission staff stated that It Is possible that residual traces of 2,4-dlanlnotoluene art present In some dyes based on this chemical, and in the final consumer procuct. The presence of 2,4-dlaminotolutne, even as a tract contaminant, nay be a cause for concern. However, data describing the ectual levels cf impurities in the final product and the potential for consumer exposure art currently lackin'). The EPA regulates toluenediamine (Isomers not specified) under the Resource Conservation and Recovery Act. tMInlNMhM acuunoa IttwtMfMt M Mf Mil*# IffKI it tlfilltlMII Maf CmrU etutiwa * MfpltttM KM. M>1Mi MJwti mu mlNti, tfNstettMtaiiM Mtc***, im Milt pulMt r mnwiiwm iimmhui mi MMtftMl t* Mns inMIlH ftMOtu M PHtPMll. iHlfltn OlMKIIll M 1 MlirMI mmtumm # <mn. ItMl blH m MrMlt MdlUH. tuttn pNUr Mr* Isa Madllaf tf (Rpiul mitot. Wl CM Nt.li. ffl.M ItMl ImlUMT HIUl. tNl t*r m dm MMM unilmi MilllflM MM Mf Act M tf f IMJT inf m^nrux uihhri iMatte 025708 107 HONS D19ENZU.M ACRIDINE There U sufficient evidence of the carcinogenicity of dfbens(a.hlocrldln* (DBla.MAC) In experimental animals.* In mire, pointing with MU,MAC Inductd skin tutors. Subcutaneous aitalnlstratton to ale* Inductd local sarcoaas and Increased the Incidence of lung tutors. Intravenous aUalnlstratlon Increased the Incidence of aiultlple lung tutors.21 1 International Agency for Research on Cancer. IARC Monog'iphs on the Evaluation of the Carcinogenic Risk of Chealcals to Huaens. Supplement 4. lyon, France: IARC, 1982. `International Ageixy for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vo!. J. Lyon, France: IARC, 1973, pp. 247-53. D8(a,h)AC belongs to a class of organic chealcals known as heterocyclic compounds. The compound has limited application but it nay be used in biochemical and cancer research. DBla.MAC has been detected In air pollution emitted from coal combustion, petrolcut refineries, incinerators, and automobile exhausts. No commercial production has ever been reported. Rased on the occurrence of thlr compound In polluted air, widespread Inhalation exposure appears likely or both the occupational and the general population. The monitoring of several air pollution sources has detected DBla.MAC levels.of 17 mg/1000 *3 in domestic coal combustion stack effluents, < 0.12 mgf 1000 m-> 1 petroleum refinery Incinerator effluents, and 0.01 mg/1000 m* In air pollute! by coal-tar pitch. WU.MAC occurs In cigarette smoke condensate at concentrations up to 0.01 -g/100 cigarettes. ERA regulates DBla.MAC under the Resource Conservation and Recovery Act and the Clean Water Act. OSHA Indirectly limits exposure to OBla.MAC by requiring that occupational exposure to coal-tar pitch volatiles i.ot exceed a time-weighted average of 0.2 mg/m3 ever an 8-hour period. 108 HONS 025709  IMMU.Mit'Olna KU-llOKS 11K MNr Ktlm M. IMtilr m*r mUtf <mr1 hr MM P*mWW l Mat. *, ll/n/tC. TfUl MU iMfttIMi M Mluur Mr Nrn|4tt. KM, Ntl)NM Mil vmntM MII4NI if Mill, M mm mm u n*u* n u nniinf m itNfVmnMMi'M mtirnmi !ni IWfiM W ^rmlnM l/lt/M. Im (MiNtnu Imi tutmn ntr MimliiiMniinn. IIM| fffcct tf MplatiMt; OtMr c*mi PRl t.t Mf/* 1*^ M (ml III |IM mlatllM) 0*ttM mtr*tJ- (MM) lwln*7 iHatMnr: ft/fl/Hi MM iMMMr IIMHir*lmt Mali iflnttn. IMM1 C tali** *1 lf UtlM t* MU. f. mu <i CM Ml.II UN) It CM ItU.IM*. im.ioo* (MM) 109 HONS 0*5710 DIBENZla.JlACRIOlllC The evidence of carcinogenicity of dlbenzlajlacrldlne (DBlaJlAC) In experimental animals l considered sufficient.1 CBlaJIAC induced skin tumors In mice following topical application md produced loci) llrtmil at th highest 'lose tested following subcutaneous adetnfstraclon. It Increased the Incidence of lung tutors after subcutaneous adnintstratlon.2 international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chen teals to hiauns. Supplement 4. lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chmlcals to Man. Vol. 3. Lyon, fiance: IARC, 1973, pp. *54-59. D8(a,J)AC Is 4 heterocyclic organic compound. DBiaJlAC It used In blochintcal and toxlrologlcal research. No coasnerclal production of this chemical for other purposes has been reported, lesed on the environmental occurrence of CBUJIAC, there Is a potential of Inhala tion oapoture for the general population. MlaJIAC has been detected In air pollutants from coal combustion and petroleum rrflnery Incinerators, from automobile exhausts, and from cigarette smoke. MlaJlAC occurs In domestic coal comoustlon stack effluents at concentrations of 2 mg/1000 mJ, In petroleum refinery Incinerator effluents at concentrations of 0.15 to l.d mg/1000 m3, and In air polluted by coal-tar pitch at a concentration of 0.001 mg/1300 m2. OKaJIAC also occurs In cigarette smoke condensate at levels of 0.27 ug/100 cigarettes and in motor exhaust at le-els up to 300 vg/kg. In addition, trace amounts' have been detected In the average U.5. urban atmosphere. both tPA and USHA regulate OBla.JIAC. The EPA regulatis it under th Clean Water Act (CWAI and the Resource Conservation and Recovery Act (RCRA;. Under the CWA, EPA has published a water quality criteria documert for the protection of hunan health for PAMs, and under RCRA, EPA has designated Mla.JlAC a hazardous constituent of waste. OSHA has Indirectly limited exposure to MlaJIAC by requiring that occupational expesure to coal tar pitch volatiles not exceed a time-weighted average of 0.2 mg/e>3 over an 6-hour period. 110 HONS 025711 acfiuuno lifiUtiM " vr Kttn lfft f MmIKImi; ttMr (mtl (111. Mttit: mar Mlltr cHUfti Ik >an m*ium * MmI rn, u/tt/M. Uul flN .NniiMi M iMIllUr Mr nr< rtflU. arw, MMOOMr tailfMUl (* MM M Mtinwi (MII1MM tf Mttt. M MMtt Mltl IMM W CIMU It M MM fM*rPll, (nNlfttM l/lt/M. tM (MlMfM lltMMtt Irwt ItllMMt lM )>MttrlMlIMlWnM. M| Kir ,! im* i-m na uMi ur run NtMlUlt (lUltM IMMIfl). (MM) itMliiMy KitKr: MWU MM TakMMr HiMtH urmt ItoU trfMtlM. IMMI CIUtfM # af>*ti'j ft in. p. ?>it era Null UMI n cm mt.toM. imam ItMt} HONS 025^Z 111 OISENZfa,hIAN tHRACENE Thi- It sufficient evidence of the circ<r.cgenlelty of dlbenx(a.h)anthracene (D8(a,h|A) <n experimental animals.1 08(c,h)A has produced tumors by different routes of administration In nice, rats, guinea pigs, frog:, pigeons and chickens. It has both local and systemic carcinogenic effects. On oral admini stration In food. It produced tumors of the forestomach In the mouse; Intritrecneal administration to hamsters produced lung turners. In repeated mouse skin painting (In seera! mouse strains), D6(a,h)A And benzolalpyrene (B(a)P) appeared to be eoually effective. In a dose-response study (with C3H mice) on subcutaneous carcinogenicity with M(a,h)A, S(a)P and 3-meth.vlcholinthrene (MCI. DBla.hlA was shown tn be effective at a lower dose then that effective for 8(a)P or for MC; Its latent period, however, was longer. Dtla.hlA Induced local sarcomas and Increased the Incidence of lung adenomas following a single subcutaneous Injection In newborn mice at dose levels which were Ineffective with HC.` 1 International Agency for Research on Cancer. IARC Monogrrphs on the Evaluation of the Carcinogenic Risk of Chemicals to Hunan:. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Han. Vol. 3. lyon, France-. IARC, 1973, pp. 178-96. C9(a,h)A is a member of the class of chemicals knowr. as polycyclic aromatic hydrocarbons (PAHs), which are formed as a result of Incomplete combustion of organic compounds. There Is no reported commercial application for this compound. 08(a,h)A occurs In cigarette smoke condensate; gasoline engine exhaust; soot; saioke; coke and coai tars; various smoked, barbecued, or cnereoai-oroiieo meats ano fish; and certain vegetables and vegetable oils. EFA lists one producer for M(a,n)A, but there are no data on Its production. Exposure to this chemical would occur through Inhalation or Ingestion. Morkers near burning or energy-producing operations jre more likely to be exposed to Nla.hlA than the general public. The highest concentrations of DR(a,h)A have been reported in airborne soot and In coal tar containing 64-705 mg/1000 m* and 230 mgAg, respectively. DO(a,h)A has n widespread presence In the environment, particularly In ambient air, but It Is alto found In soils and water. Therefore, a large segment of the population could be potentially exposed to 081a,h)A from environmental sources as well as from foods and clgaratte smoke. 112 HONS 025 713 Th*rt have been few attempts to develop eaposure standards for PANs, either Individually or as a class. However, NIOSH has recommended a workplace standard for coal tar products of 0 1 ag/a3 as a time-weighted average for a 10-hour shift In a AO-hour workweek. OSHA Indirectly limits exposure to DKa.hlA by requiring that occupational exposure to coal tar pitch volatiles not exceed 0.2 ag/a3 over an 0-hour period as a time-weighted average. CPA regulates DKa.hlA under the Resource Conservation and Recovery Act, and has proposed a reporting rule requiring process and use data.under TSCA, Ola). MWm(,ftUMfcPKtM twuriws llllUlht M Mr ftct'M. Iff** *f ItftUtlMt; (Mr taNti ttfflH KtlOD. M IWM IWMM H WRWlf ffdMtl Mif 95t JtrlMKttM. ICMCI cm. mt*It wllo crlUfti lr NM HkHlM * flMl (M. Il/M/M. ini fm iMniMi; w iNtnttp mr MfUflU. . km, rm-x**: s*jtti * mku. MttMI. m Mill ml- tm MOU *f MM k* MMtM M4 PMlInwMI. AIM MMfMtM DU (MM*4 M A NltfkNI (MIlUoMl If Mttt. IfMlflM tAtfMv 'Ki, t(l; N|HM rmnN mti Pl<flk| M UU. MKtkM t/tVM. In klltllOMR IIMIMRt Irw* IU1MM (qe |-acitf(atlaoM|reu IIM) MM M r#Ml MiffMr. Fhltn frttttP firl I* MNfM| If iMMtll eOlUt. VMttf, If pfMtlfMM. Mfllt t Mill ftr nwwei. (PA) mi .l r 1m Icmi UP MU* Mlttll [IMM tWIflfl). tftltitpy Mimpjii W'/fll MM iMMIf HiMoH-coifOAt IMtt lONtin. (MNA) CttattM if atvtittiM M n |. t. Jim 0 Cft Ml.It 41 ft 19. 9. 1M4 UftU M ttf ifM.lflM 113 HONS 025714 7H-OIBNZO(c.g)CAABAZOLE There Is sufficient evidence of the carcinogenicity of 7H-d1bnnzo(c,9)carbazole (7M-DB(c.g)C) In experimental animals.1 7H-D((c,g)C was shown to bo carcinogenic In the noose, rat, hamster, and possibly In the dog. It had both a local and a systemic carcinogenic effect. Following oral adtlnlslratlon to the noose, forestonach tonors and hepatonas occurred; Intratracheal adnlnlstratlon to hansters produced tunors of the respiratory tract. In conparlson with benzole)pyrene, 7H-DB(c,g)C appears to be a stronger respiratory tract carcinogen for the hams ter.? ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chenlcals to Hunens. Supplement 4. Lyon, France: (ARC, 19(2. 'International Agency for Research on cancer. [ARC Monographs o*. the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vui. 3. Lyon, France: IARC. 1973. pp. 2S0-68. 7H-MU,g)C Is a member of the class of organic chemicals known as heterocyclic compounds. This chemical Is soluble In most organic solvents. 7H-0((c,g)C may be formed by Incomplete combustion and has been found In cigarette tar In concentrations of 0.07 ug/100 cigarettes. It Is produced as a research chemical. No case reports or epidemiologic studies have been made on huaan exposure to 7H-0l(C,g)C. But because this chemical has been detected In cigarettes, tome persons, especially smokers, may be exposed. ERA regulates 7H-DB(c,glC unoer the Resource Conservation and Recovery Act. In addition, OSMA Indirectly Units exposure to 7H-0B(c.g)C by inquiring that occupational exposure to coal tar pitch volatiles not exceed 0.2 mg/n3 over an (-hour time-weighted average. 114 025715 moms ?* !(.fata hfllltlwt Mi OtMf IttlM CM. IMIal: mir aMltty cmt'U far Mt fMMiKM 1* ftaal t*m. tt.Tt/M. Taut >M iMrtifM; IMUiltr m* urrvfau. CM. taUfMIM Uti tm- im% it i MiiriMI IMtltoNt tf aita, MtNti Mtn mm h rnuti tt u wmttit ni mmtv PKrMIH MltMMU Mini iuwtii * ( r/if/W. In UrttMfM iiwtMMt (kawt IUIMM Mr (MAI Kll l.l TM tCMl Ur Itu alttttttl (ItaiM WaaraftJ. (MM) KUMIW rrtMi af Mar CMtMt faUtta* tiMi (4 'ItMtl' tf (UTMli Muff. (CM) aaalatary DIMMyi |/tl/Tli KM TanMM IIMitrt>. urram itatt tffactiva. (MM) ClUtlM* af Mfaltttaa S tl ))ll. a. wu o crt m.ti ur*i n cn tm.ua*. IIW-WM (MM) HONS 025716 115 0IBEN20(a,h)PYREN There Is sufficient evidence for the carcinogenicity of dlbenzo(i,,h)pyrene (DB(a,h)P) In experimental animals.1 Carcinogenic effects of D6(a,h)P were demonstrated following repeated skin painting In nice and Injections In nice and rats. In the skin painting experiment, CSCa.MP was less active than benzol a Ipyrene.? 'interesttonal Agency for Research on Cancer. JARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement A. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 3. Lyon, France: IARC, 1973, pp. 707-14. D8(a,h)R Is a polycyclic aromatic hydrocarbon (PAH) that Is Insoluble In water. D6(a,h)P Is not deliberately produced; It Is a combustion product. The occurrence of 06(a,h)P In the environment is net well documented; however. It has been detected In minute amounts In coil tsr pitch, engine exhaust, ano In cigarette tar. In ig74, the National Occupational Hazard Survey estimated that approxi mately 210,000 workers were exposed to PAHs from aspnalt volatiles, coal tzr pitch volatiles, and coke oven emissions, all of which may contain D8(a,h)P. An unspecified additional number of workers may be exposed to 88(a,k)P In the products of combustion from fuel oil, diesel fuel, kerosene, and wood. Ths EPA has Included DBla.MP on the Carcinogen Assessment Group list of carcinogens, and EPA regulates this chemical under the hazardous waste disposal rule of the Resource Conservation ano Kecovery net. uorx inmrectiy Units exposure to DBla.MP by requiring that occupational exposure to coal tar pitch volatiles not exceed 0.2 mg/mv over an 8-hour period as a tine-weighted average. HONS 025717 116 IftoAMtl.hlwr** KMU'IM ItfvUtlMI IM IMf ActfWt irrtct f imiitimi: tMf Cmhu CM, m)i Mttr Mill; imiru f MtMvclw irMllc UrtnciMM MlliM < HmI f*r*. ll/WM l*Ul *W MriHW) W INIIlM Nf Mflfltt. 404RJU, H 4 HHirmi NilfMltt nt immx M)mi hum hm t* muii u v kmH*| M fmfVNnminN hmIm- HmMumI (.Hill ttMIrt r w* |lUftmClMHlWwfrHmtMHIHMt Imw HMI imiiitm urn m hhmi *; ouwih HllN. CCM Nil 1.1 */* i'lm IM m1 Ur fUft mlMIlH) (llHltM CHHIfC)* MPM am'iHnr mmy: MR'. Yiumf llMHrM nrmt IMU tVRM Cluifw *f I*|IiUh is rt mi. . ;tnt 4* C/t HI.11 tCHI intt.niatimt .im, (Mat 117 MONS 02S718 028NZ0(a,11PYRENE There it sufficient evidence of the carcinogenicity of dtbenzo(i,t)pyrene (08(1.OP) in experimental animals.! Subcutaneous Injections of D8(a,1)P resulted In i rapid appearance of local sarcomas In the hamster and the mouse. The smallest single dose which produced sarcomas In mice was SO ug. Repeated skin application In mice was also effective, but OBla.OP was less active than benzol aipyrene.* ^International Agency for Research m Cancer. IARC Monographs on the [valuation of the Carcinogenic Risk of Chemicals to Hjcans. Supplement 4. Lyon, France: lARC. 1982. International Agency for Research on Cance'. IARC Monographs on the Cvetuetlc.i of the Carcinogenic Risk of Chemicals to Ma.i. Vol. 3. Lyon, France: IARC, 1973, pp. 215-23. DR(a,1)P It a polycyclic aromatic hydrocarbon (PAH) that Is insoluble In water. DS(a,1)P It not commercially produced but Is found as a combustion product. t8(a,1)P Is the byproduct of poorly controlled combustion encoun tered In coal or refuse burning. In th exhaust of diesel-powered vehicles, and In coke oven emissions. It has also ben detected In tobacco smoke at concentrations of 0.002-0.27 eg/100 cigarettes and In smoked foods. In 1974, the National Occupational Hazard Survny estimated that about 210,000 workers were exposed to PAHs from asphalt and coal tar pitch volatiles and from coke oven emissions, ell of which contain 08(a,1)P. The EPA has Included DSla.OP on the Carclnoqen Assessment Group 1<st of carcinogens. Under the Resource conservation and Recovery Act, this chemical has been Included In the hazardous waste dlseosal rule. OSHA Indirectly i inns exposure to DSla.ilP by requiring that occupational exposure .0 toe! tar pitch volatiles not exceed 0.2 mg/m3 over an 8-hour period as a timeweighted average. 118 HONS 025219 0CM*aa<a,Of)rrfW KCUUUONS *4 9V*r ktlMl (ffut af atoUtiMi; Otfttr CnNtt C<u.4* a/ ItjaUtii* KU, 1001 nHt MjKti llti kMucu, teCMi, 1*4 aalll ml* Mi 1* umi # 1000 kf U kMU9t M mMWmK*M<*0 HWlfWMH. Mu utifuiu iiMfWlM uym at i niiuui CMttltMAi 9t mu. .**UalMM 1/17/00. Qtt, ItoUlt totte MUy rlUrt Momil ftr NlyMlur amwtic kfiruuitu MHiIM In flul fin), 11/10/00. fetal 'M MKtllM: w iMlcaUr nr wrp*|u. So CmluiM lauiwiK Irwi iutt* Mftt UK iuettrtwtunMUM. n) ifiUtlu toiM m cftmic Ualeltf. fuui irmif un i UMltay il (Nattil mtn. to tn Mt.it. ni.M to r in, nito ((Ml mi i.i uf/ai o-*r m t<Mi tor ifttk vala'lfei) (ttarftoO ttMfioa). I0M) taartatonr Milan: 0/21/71. 09U TakMm SuMar*-- carnal lurtl rffactfra. fOSM) cn miM. mo. loot tOOM) 119 HONS 025720 1,2-01 8R0M0-3-CHL0R0PR0PANE There It sufficient tv 1 denet for the carcinogenicity of 1,2-dlkromo-l-chloropropane (DBCP) In experimental animals.1 08CP administered In corn oil by gavage to Osborne-Mendel rats and B6C3FI ntca was carcinogenic, producing squamous-cell carcinomas of tha forestomach In both ttxtt and carcinomas of tha mammary gland In female rats.2 In an Inhalation experiment, ObCP was carcinogenic In male and female F344 rats. Inducing Increased Incidence of nasal cavity tutors and tutors of the tongue In both sexes, and cortical adenomas In the adrenal gland of females.3 DBCP was also carcinogenic In B6C3F1 nice of Loth sexes, producing Increased Incidence of nasal cavity tumors and lung tumors.* ^International Agency for Research on Cancer. IARC Ponographs on the Evaluation of the Carcinogenic Risk of Chemicals to (batons. Supplement a. Lyon, France: IARC, 19P2. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Mutant. Vol. 20. Lyon, France: IARC, 1979, pp. 83-86. `Motional Toxicology Program. Carcinogenesis Bioassay of l,2-01brcmo-3-Chloropropene (Cas ho. 96-12-8) In F344 Rats and 86C3F1 Mice (Inhalation Study). Technical Report Series Mo. 206. NIH Publication Mo. 82-1762. MTP, Research Triangle Park, N.C., and Sethesda. Maryland, 1982. ^National Cancer Institute. 8<oassey of Dlbromochloropropane for Possible Carcinogenicity. Technical Report Series No. 28. DHEW Publication No. (NIH) 78-028. Bethesda, Maryland, 1978. D8CP It a dark amber to oark brown liquid that Is slightly soluble in water. OKP has keen registered by CPA at a soil fumigant to control nematodes during plant growth that Include field crops, vegetables, fruits and nuts, greenhouse and nursery crept, and turf. In 1974, U.S. farmers used 9.8 million lb of DOCP on crops- In 1977, 831,000 lb were used In California alone, mostly on gropes and tomatoes. The Agency, however, suspended all registrations of end-use products during 1977, except for use on pineapples In Hawaii. 08CP was first produced commercially In the United States In 19SS. The annual production estimated during 1974 and 197S was 18-20 million lb. In 1979, CPA prohibited the sale, distribution, or movement of 08CP In commerce for all suspended uses. No data are currently available on the amount of D9CP produced In the United States nor In existing stockpiles. 120 HONS 025721 Huaan exposure to CBCP cm occur by Inhalation ontf skin contact, primarily during the pesticide's sianufacture. formulation, and storage. According to TISHA, approximately 17,500 workers have been exposed to the chemical. Pesti cide applicators at well as farm workers were the high risk exposure groups during formulation and application. Exposure of the general population through soil Is considered negligible because DICP Is moderately volatile and Is degraded In moist toll. According to a 1977 CPA report, human dietary exposure to IrlCP was estimated to be In the range of 2.2 to <1.0 x 10"* mg/kg/day. The chemical has been detected In carrots (0.009-1.5 mgAg) and In radishes (0.03-0.194 mg/kg) that were treated with DBCP. On October 29, 1979, the CPA suspended, unconditionally, all OBCPcontaining products for end uses except for nse on pineapples In Hawaii. It further Issued a notice of Intent to cancel unconditionally all runin1ng end uses of all registered OBCP-contalning pesticide products. The FOA establ'shed mailmux residue levels of l.S mg/1 In raw milk and 0.0$ mgAg In all other >aw agr`cultural commodities. The current OSHA standard for DdCP established In April 1S7B Is 1 ppb (0.01 ng/7) (l (n a-hour tlc-e-welghctd average permissible exposure limit for workers. In addition, this standard requires personal protective equipment, training, medical surveillance, signs and labeling, and engineering controls. 121 MOMS 025722 I .)|IWwa li^tiiim <m iimt mim a NWlM Mill). Il up* IWMMI t* mmmm inmu mm* (fit flMMWtlM< icraet hm wtwn, ra*t mi** K, HUM twttft am ( i rm, it eiMitfiM nmimii mm, 9aN*iM*t mju nw fMyatfftmia* Nton. m awn ------------* HIM If IMlf M MCauttM Iffact tf ItyglitfaHt; (Mr (mmi f MftUtttn tm mHmM IM iutKi/yw mil mH fm IN If Wt M IMIMNI IN illMI IWll'MlN tftiw. ' NNf imuwi M flKMKMl NlltaMi MIIHIIW M !< * *HHl tiff. InN m mi|iUlty M >nnNiHn MNUm IWNM M lim. (IM) 44 ra. i. him > era Nt.tt. ni.jj wn. fiwipwi 1/tlM. Wt, Mill Nm nuntat mmmm,9mmhNwtamfMvfwnmtf .mi m nlM IM CtfffMJM mmr nm%I4 Wi I in. tumiH i(nm|, imHnin, Hff--, wiiHf. m* Mmt Nmiiiim NNII IWWINm IM UN Hwilll NnwMiiiwnnmiiIaUmfatlaNy iimiMMiiawMo9im*mm- mttUMt. IMWI n era rni.iiM IMMI 122 HONS 025723 l,2-DIBROMOE7HANE There l> sufficient evidence lor the carcinogenicity of 1,2-dibrcmoethane (ethylene dlferoalde, EDI) In experimental animals. The evidence of carcinogenicity In humans Is Inadequate.1 When adalnlsttred by gavage In corn oil, 1,2-dlbromoethane (technical grade) was carcinogenic to Osborne-Menoel rats. Inducing squamous-cel I carcinomas of the forestomach In both sexes, hepatocellular carcinomas In females and hemanglosarcoaas In Mies. The compound Induced squemous-cel1 carcinomas of the forestomach and elveolar/hroncMolar adenomas In I6C3F1 mice of both sexes.2 Hlien Inhaled, EDI was carcinogenic In male and female F344 rats. Increasing the Incidence of nasal cavity tumors and tumors of the circulatory system. EOI also Increased the Incidence of lung tumors In both ser.es of j6C3fl mice.* Topical application to mice produced tumors of the skin, lung and forestomach.1 There was only one epidemiological study uf carcinogenic effects of occupational exposure to EOf; It did not produce adequate information.1 'international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals tc Humans. Supplement 4. Lyon, France: IARC. 1912, pp. 124-12*. Motional Cancer Institute, lioessay of 1,2-Dlbromoethene for Possible Carcinogenicity. Technical Report Series No. 16. U.S. Department of Health. Education, and Welfare, lethesda, Maryland, 1S7S. 'National Toxicology Program. Carcinogenesis lioessay of l,!-Cii,iiMuihano (CAS no. 166-yj-e) In F344 Rats and I6C3F1 Mice (Inhalation Study). Technical Report Series No. 210. U.S. Department of Health and Human Services. National Institutes of Health (N1H Publication 12-1766, HTP-80-21). Research Triangle Part, North Carolina, and lethesda, Maryland, 1982. EDI, an Industrial chemical, is a good solvent for resins, gums, waxes, and many organic chemicals; however. Its major use (IS percent) Is as an additlvo In leaded gasoline, where It scavenges lead oxide residues (rom the coabustlon chambers of gasoline engines. Other uses are In fumigants; In agricultural Insecticide formulations; and In the production of certain dyes, drugs, and vinyl bromide. 123 HONS 025724 Production of COB ii first reported In the United States In 1923. CPA Indictted In 1977 thi about 300 mil'. Ion 1b of COB were produced annually (Tonic Substances Control Act, Chemical Substance Inventory, 1979, public record). Estimated exports were 99 million lb In 1973- Imparts In 197* were reported as less than 3000 Ik. Demand for COB Is expected to fall sharply because of the decline In the consumption of gasoline lead additives. Hunan exposure Is primarily through Inhalation, Ingestion, or skin absorption. NIOSH has estimated that approximately 9000 employees at production facilities are potentially exposed to ethylene dlbromlde, OSHA l.as estimated that 21B.000 workers are potentially exposed In processes using this compound. The National Occupational Hatard Survey (1974) Indicated that 126.000 workers may be exposed. In addition to these potential Industrial exposures, NIOSH (1977) estimated that 650,000 gas station attendarts nay hnve a potential risk of exposure. Emission concentrations of ethylene dlbromlde were monitored at a bulk transfer site at levels of 0.2-17 g/m3. An CPA study (197S) measured levels of 90-11$ ug/m3 for one ethylene dlbromlde production facility. Emission samples taken adjacent to gas stations and traffic arteries contained 0.07-0.11 ug/m3. Between 13 and IS million lb are applied annually to soil as a pesticide, and It can be attuned that as a result of this application the chemical enters the environment through leaching. . Concentrations of 0.2-31 >9/1 were measured !n raw water, and finished water contained concentrations of 0.2-f vg/1. NIOSH (197B) estimated that 304,000 ib/yr were released to the atmosphere from all sources. The low vapor pressure and rather high water solubility of tkj compound tend to promote its environmental presence in air, water, and soil. However, with a half-life In the atmosphere of 4$ days and $-10 days In water, no appreciable environmental accumulation would be expected. The CPA hat regulated ethylene dlbromlde under the Resource Conservation and hexovary Act and the Clean water Act; and the Agency has Issued a notice of Rebuttable Presiaaptlon Against Registration (1977) under the federal Insecticide, Fungicide, and Rodentlclde Act, and Is considering regulation under the Clean Air Act. In 1971, OSHA adopted a permissible exposure limit of 20 ppm as an B-hour time-weighted average, a 30 ppm celling, and SO ppm maximum peak for $ minutes In an B-hour time period. This standard was adopted by OSHA for toxic effects other than cancer. 124 HONS 025725 IUMI SUUTIM IlfilltMM M MNr ktl<N Iffect ef hfiNKM; Uwr tiwm Ciutle* ef ItvrliiiM H nrfWt M Imm frtiMa fi HIMI7 KMMtl KH 9k JvHHtCtle*. itnci CM, bljKII Milt iMDtll, efMeeetricettc* Nimt. m teiu wi M* I* Mem * MM t( ' MattN M reeen/recefeeeM nwNimi. fv*. MtHH uum. 7Mt|i IMI llttM ll/H/77. CM, till iMMlM OI eeuelfuwe reeemeu (MM U, 4M Ifl M Nut! IMHIm fNilmMU, imm. CMl Mir NN>MN M tMM If Mftn MM 1 MM HiftllM M dmM Mint, MAM IicmmM Mt m *MUkl phMw te iIVm m Hull hutVM IMt |(M M M1M 1 Mfk (KM) < ere m.)> immU Meet fern rnfnN. eaeletM* ! H e* * Mil faweeet IMt); ),tnnl niirldM nr, tf/lO/**. bM M MMttC miKI)f< Mtlfl fMlir MM ta tentttef IM iM|lf tMMUH. (IMI t f*. 1. Mm h ft. 1. aim m cn iif.). uf.i) MM* lenoi) MMMlcetiee. MM (MAN: Cveleetiee ef Me Hurt le teeiMcn bnitM trm tee Me a# Whh ** Aiimm ( Mfeeec, IMf ttMJ fUt M M Mr 1M. M WMl, M Me (HUM Ml fir 1 Ml h W KM eerie*. (lUMirf MUM *tr hm effem MM imm (M*r.) mmi earieeenr M1M7: l/lfffl: CM TMMr KMlH>mM KMt effective. (MMI cm me. mm (MMI US MOMS 025726 3,3'-DIChL0R08E*IZIDlNE There (t sufficient evidence for the carcinogenicity or 3,3'-dtchlorobenj1dtni (OCB) In experimental animals. The evidence of carcinogenicity In humans It Inadequate.1 3,3'-0tchlombni1d1ne was carcinogenic In rats, hamsters, and dogs. In rats it produced twers of the skin, mammary gland, lymhal gland and hematopoietic tissues following administration in the diet or suheutaneous injection. In mice ft produced liver cell tumors and leukemias following dietary and trans placental exposure, respectively. In dogs and hamsters, It produced malignant tumors of the liver and bladder fol'owing adnlnfstietlon In the dtet.l>2 In three retrospective epidemiological studies, no bladder tumors were reported In men occupationally exposed to dfchlorobencldtne, but the studies were of Insufficient quality to permit confident exclusion of carcinogenicity. 1International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. lyon, France: IARC, 1982. 'International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29. Lyon, France: IARC, 1982, pp. 239-56. DCS Is used commercially In the United States primarily as a base (3,3'dtchlorobenzldlne) and as a salt (3,3'-dlchlorobeiu1dtne dlhydrochloride). Both are essentially Insoluble In cold water. The major uses of KB are In the manufacture of olgrents 'or --'ntlno ink, textiles, and plastics, and as a curing agent for solid urethane " plastics. OCB has been produced coaaaerclally In the United States since 1938. An estimated 9 million lb of DCS (base and salt) were produced In 1972. No production data are available after 1972. According to estimates from the U.S. International Trade Commission, 208,000 1b of OCB were Imported Into the United States In 1979. Human exposure to OCB occurs through Inhalation and probably through percutaneous absorption, primarily during industrial operations. NIOSM estimated in 1974 that 1100 people were exposed to OCB. However, no data are available on the number of workers exposed to DC8 during manufacturing, processing, storing and handling, and repackaging operations. 125 HONS 025727 According to th EPA In 1980, there trt Halted dite on the presence of DCS In the environaent. The Agency did, however, report thet e survey detected DCS levels of 0.13-1.0 ag/l et one DCS production waste disposal site. CPSC staff has stated that residual levels cr trace lapcrltles of DCI aay be present both In DC8-based dyes and plgaents and In t'.e final consuaer products. The presence of this potential carcinogen, even as a tract contaalnant, Is cause for concern. However, no data are available to describe the actual levels of lapurltles In the final product, the potential for consuaer exposure, and the potential uptake. EPA regulates DCS under the Toxic Substances Control Act (TSCA), the Clean hater Act (CUA), and the Resource Conservation and Recovery Act. Under the CUA, the Agency has published a water quality criteria docuaent for the protection of iuaian health (19801. Under TSCA, the Agency conducted a preregulatory assessaent of OCR based on Its suspected carcinogenicity. Waste disposal guidelines were proaulgeted Hay 19, 1980. for DCS. Although the PDA hat classified DCS as a carcinogen, no regulatory guidelines have been enetted by the Agency. CSMA also regulates this ci.rclnogen. The standard Includes requlreaents for personal protective agtilpaei-t, training, eedical surveillance, signs, labeling, and engineering controls. 127 HONS 025728 csmatmus Mfllltlwi IN Ctttf ICtlMI (riict tf MuiiitMt: ttM (Mill M ttfTHl MtHM. ICMCI Kit, tm*m*i tttjMI* Mtt KMKtt. ff.MMtMUItM MUM. M* k*l1t ftlt* INI I* (Mill If IM l| tt MNllM 4M mirt/miUMH<if mrirwMi. friwlNM VMM. AIM UtlmtM 1,3*. lINllUNItKN II 1 MU*NN If Mitt. IM MMU *t(tn MM U (MUM IIUM MM MWUMMI. CM. Sttflt: Mtr ttltfor ifflifU hum Mmi #m, w/n/tt. imnmi WIllUI 3.1* .milMmUWi IM NM m tmtff ittM'.i CM* Sill MIWMN Mill NNllIlN Ml|NtM| tttttttt !! Ik. I.M Ml fftmtti l/MI Im IIMf MCirlMt. INH W ttnMHMUIty. mu TSCi, Milt ImiiiiI miihIm ml* nttrlM M IM ttttttl MU. MllNN t/lyi>Tss,"KMttMittiiwi. In CmcImmu Ammmm Mm itttt* MM aattr |-MttlMM*f*IUMM. imt MWUN NU*HN. MUM, UtNUl, Ntf nttcil NMlIlMI NMlN- (Nil M NNNII MM lit In WHIN Mil Ul mill NUlNM KNUHHI (NINlMUN CMfH UNUPWIH! ttN UU'MHI fM UN'lM mm; muNnttt *M MMiiun. NblltNT Mittyt I/U/9J' ttMV**t 1MNM'T HMttrtt NMNttN M ttfUM NNl* nmi Im --mm. nimhmI nmihm ntrUM, MiNini nnunnu. 1/11/94i Cmm MglatlM* drtiN. (IUIIN f at Hi.u. hi jj i i m. mu 4t M 133. . MM4 IIM) 11 Cn I9M.IMI ICOttl ue HONS 02572* 1.2-DICHLOROETHAHE There If sufficient evidence that 1,2-dlchloroethane It car cinogenic In experimental animals.1'2 l,2-01chloroethanc (technical grade) was tested In one experiment tr. ale* and In ona In rata by gavage In corn oil. In 66C3F1 ale*. It produced benign and aallgnant tuaon of the lung and aallgnant lymphomas In anlaala of both tenet, hepatocellular carclnoaat In aalet and naaaa'y. and uterine adenocarclncaat In ftaalet. In OslorneMendel rata. It produced carclnoaat of the forotteaach In aale anlaalt, benign and aallgnant aauary tiaaors In faMlet, and heaangloiarcona' in anlaalt of both tenet.2>3 international Agency for Aesearch on Cancer. IAAC Monographi on the {valuation of the Carcinogenic Alik of Chcalcalt to Huaiani. Supplmaent 4. Lyon, France: IAAC, 1962. `International Agency for Aesearcu on Cancer. IAAC Monographs an the Evaluation of the Carcinogenic Alik of Chaalealt to Nuaant. Vol. 20. Lynn. Franca: IAAC. 1979, pp. 429-44. 'National Cancer Institute. Sloestay of I,2-D1ch1oroethane for Fottlble Carcinogenicity. Technical Aeport Series Ho. 55. OHEV Publication No. (N1H) 7S-13C1. lethatda, Maryland, 1978. 1,2-Dlchloroethane, conaonly known at ethylene dlchlorlde (EDC), It a chlorinated hydrocarbon that It sparingly soluble In water. EDC It prlaarlly used at a coaponent of leaded fuel and at an Intermed iate In the production of vinyl chloride, trlchloroethane, trichloroethylene. perchloroethylei.0, vinylideae chloride, and ethylenemalnet. Other minor utet are at an intact fumigant for stored grains and mushroom houses; at a toll fumigant In peach and apple orchards; at a cleaner for upholstery and carpers; at a solvent in textile cleaning and nets' degreasing; is s dispersant for plastics and elastomers such at synthetic rubber; at an ore flotation compound; and at an extractant In certain food processes. Commercial production of EOC was first reported In the United States in 1922. The average annual U.S. production between 1973 eiid 1976 was reported at 10 billion lb. In 1976, approximately 7.2 billion lb were produced, 400 million 1b were exported, and negligible amounts were believed to be Imported. Current production estimates are not available. 129 M01*S 02573 Hunan exposure to EDC can occur skin absorption. Inhalation, Or Ingestion. According to NIOSH, as many as 2 mil Hon workers, Including thus* eployvd In chemical manufacturing anj processing Industries, nay hare been exposed to EDC. The population at large nay also be exposed through the use of EOC In food, gasoline, and agriculture. EPA reported that EDC was identified at concentrations of 1-90 ppb In S3 of 204 surface water samples taken near heavily Industrialized areas across the United States. EPA regulates EOC under the Clean Hater Act and has assessments Ir. progress under the authority of the Clean Air Act; the Safe Drinking Hater Act; the federal insecticide. Fungicide, and Redentlclde Act; and the Toxic fubstances Control Art. The FDA, Bureau of Foods, under the Food, Drug, and Cosmetics Act, has labeled EDC as an animal carcinogen. Through regulations and other actions, FDA Is eliminating EDC residues In foods. OSHA has adopted permissible exposure levels of 50 ppm (200 mg/m3) as an S-hour time-weighted average, 100 ppm celling, 200 ppm naxlmiaa peak concentration for 5 minutes In any 3-hour period. OSHA adopted this standard for toxic effects other than cancer. 130 HONS 025731 U.'-ITIOII BffiUlltM 4 (tMr Icllw* (ffact a/ lat'iitiMt; ttar CMHti ClUtlaa ar taptatiaa MMntt K>m1< M ttaUllllH ravti* cwaiata. atiMtuiM i ihhimiiiim ti ii f>i). (CMC) cm, nii aataraav* tain raputi** nutttAtif mtriAU aaaattw m ihhih naairaaaati. Hlt/fl. )nHUl M nmt rtrwt( M, mil). Mtr ONlltr (TlUrll <a flM) fart, ll/IO/M. MMA, It Ml aatUfa IimK r%tntt (MiH affacti. uttar iaat u all nyiilfMrtl a# tMi, W.. KM, WI*M4> VrtjWtl IU >nhru, NIlMI, M mil* M1M) Mill t< IM at A Mil wt nnn/ wiMiAlH wawnmw. Ilia iI|nM m a Viliam amiUmm af atta aaa mjnii mum at m It caataia It ta im mm raaatrt- mi. r--iftat i/ii/m. CM, Ml, 1M, Uti Utatmaat tf taartaa M a .man waiatat Ml. aafvlatanr aaciUM MkiNM aartat rt*4. am, mil MM rtfaralay l,l0U0lara ataaaa M Mu atMr taliilli aryarlct fMMlNM. vast?. laa Cart'aapa Iimimh Craat ititiiit m*r |>a(atrliil1arH. (CM) ra* Ami r run. raacat n r mmm dm ata* laaaiaa m aamai IMlMM, M IM AM) Ml MlltIM mmiim a# a* raptaitaaa. tr**i rn: Nm Mr ma. Ml am calttaa, IM ta mIm pm far 9 ala aa* ) *r tanaa. (MMM Ntavl V Mil affacti attar an invar.) lama) (mtMfM'lltlf'NMI MNIll TarataiMlcftr M mMmiim iHnii law MnH Itiliaaita fa Hat af earmt nflllMlM raplf--tt. latat aa ctraalt taatcfty. lataa aa t*-aal affacti, far'aii car* titapaUHy mImI ta trait. Crtiaria team caaatatar Ml. lira) * alialaata rntan #f t.a* atcataraauiaaa ta raata. (flat taptatarv Mttanr: IMtt MiMMMalr. 71 pm aaama iflav ala taacaMrattaat. * 1/17/71: MU tpaavar ltaatarttarrtat Halt affactiia. lama? to era t)7 aa r ui, p. ram M fMlItaat la n CM HI.II, Nl.u NIH, aarttail laanluiia*. t/l 47 fl, p. M0 itaai M era m.jja. 17).HS(M)I m.no. m.aaa iraai aa era ma.iM fatM) 131 HONS 025732 oicpoxtiitamc Thtri Is sufficient evidence for th carcinogenicity of dlepoxybvtana In experlaental anlaals.l Two form of l,2:3,4-d1epo>'butane (Dl and mol were carcinogenic In alee by skin application. loth coapuundt pradictd sauaaous-eal 1 skin carcinomas. Tbt D.l-racaaata alto produced lacal sarcomas tn tea and rats by subcutaneous Injection.* ^International Agency far Research an Cancar. IARC Monograph' an the Evaluation of tbt Carcinogenic Risk of Chantcats ta Manana. Supplement 4. lyrn, Franca: iAAC, 1912. `International Agancy far Reaaarch an Cancar. IARC Monographs an tha Evaluation af tha Caret nog*,.1c Risk af Chemicals ta Han. Val. 11. Lynn, Franca: IARC, 1975, pp. 115-23. Dtapaxybutana (OCR) <a a highly rtactlvt Industrial chemical. OCI natsts In faur Itoaerlc farm (0-, L-. 01. and ata), which dl'fer In tana af thalr chaalcal and physical prapartlas. OCI It prlmrlly used in ratcarch and axparlatnul work, as a curing aiant for polymers, as a crotslInking agent for textile fabrics, and in preventing alcroblal spoilage in substances. OCI is also used coaaercially at nixed stereo Isaacm and at Individual Iseaers in tne preparation of erythrltol and other pharmaceuticals. Annual production volume are saall. CPA Indicated that 350 lb af l,2:3,4-d1opo>ybutane (1 tuner1c fame not specified) were laported by one importer (Toxic Substances Control Act ITSCA), Chaalcal Substance Inventory, IStS, pup'lc record). According to net, OCR apparently was net laported er produced coaaercially In the Unit id States In 1179-1110. Hunan exootura ta OCI Is principally through Inhalation and skin absorp tion. Tha national Occupational Hazara Survey in i7e aaee no astiaata or worker exposure ta OCu. Ho centner product use of this chaalcal was found. CPA regulates OCI under the Resource Conservation and Rece-ery Act. Regulation Is alto proposed under the TSCA, 1(a), reporting rule that would preview detailed production and aarkatir.] data. 132 HONS 025733 icTHytaiuiw rcmutiohs bfHlUlMi Ml HNr KtlMi IffHt if lajaiittoni; OtMr CmhU ClMtlM if Ilflllt'M f. nmot KllM. <cm> feu, JOHOOM: v*jcti ff-iMCftoattM MttNi, Mila mIku, Ml Mill niiiMi to MHI If tool If tl NMtlll Ml MMTt/ rwi>oin<ii nniwHU. tin MtfMm Maflil M 1 Mlirtoi MftilftM*t f mU. frwm\t*X4 l/lt/M. TSCA. Me): tiurtlm nil ftwrtrto*. mem Ml ttt HU, ftfiUl 1/09/OO. <(M) tofufattM Hill m chranlc Utility. Fatten ffiitir cart to MflUiif if CteMlCtl HIUI. 10 Cft 8ft.il, til.33 Nwll rrHc i Nltir Mill for Httottlftf Mltol pUMtlll, -<H<M Mt It CWllMUl a)Mf wUH flu 1*. Oataivtolef HfrifrlitiMii if fNlllH7 ar HNr CMtnt *ctfa. tlW) 4$ Ft. |. IM4I (IW 133 HONS 025734 DMi-ETHTlHEXTUPIITHALATE There Is sufficient evidence for the carcinogenicity of d1(2-ethylhexyllphthalate in experlaental snlaals.1,* 0112-ethylhexyl).. phthalete, |(en In tht dint, was carcinogenic to Fischer 344 rets nd WC3F1 alee, producln] Inerttied Incidence of hepato cellular cerclnoaes In feaele rets, end aale end feaale alee; end en Increised Incidence of hepatocellular cerclnoaes or neeptestte nodules In aele rats.*,3 1International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chealcals to Nutans. *0l. iS. Lyon. France: IMC. 1982, pp. 2(9-65. International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chealcals to Huaans. Supplement 4. Lyon, France: 1ARC, 1982. ^National Toxicology Progrea. Carcinogenesis Rloassay of D1(2-ethylhexyl)phthalate In F344 Rats and 8CC3F1 Mice (Feed Study). Technical Retort Series To. 217. OHMS Publication No. (N1H) 82-1773. Research Triangle Fork. North Carolina, 1982. D1(2-ethy!hetyl)phthalate (DEHP) is easily soluble In body fluids, e.g., saliva and plasaa. 008 Is aost coaaonly used as an additive to polyvinyl chloride resins for fabricating flexible products. Polyvinyl chloride polyaers plasticised with OCNP are used In aany types of products such as teething rings, pacifiers, soft tgeeese toys, and balls; In vinyl upholstery, tablecloths, shower curtains, and raincoats; and In aany other products (CPSC, CPA). DEHP is nlso used in AdhesiveI, In resins and polyaerlc coatings, In coaponents cf paper and paperboard. In dofoaalng agents. In enclosures for food containers. In anlaal glue. In surface lubricants, and In flexible devices for administering parenteral solutions iFDA). OCnP Is useo in the aanufacturlng of vinyl gloves used for nodical exaalnations and surgery. Approxlaately 800 alllion pairs of these vinyl gloves are produced annually. Three alllion flexible bags for 1v fluids and an additional 8 alllion aedlcal products both containing DEHP are used annually by physicians and hospitals. OEM* was patented In 1933 and becaae ensuercially available In the 1940s. The Society of Plastics reported 302 alllion lb of OCNP was consuaed In the United States during 1980. Approxlaately 400 alllion 1b of DEHP are produced annually. 134 MQNS 025735 CPA reported It producers and reporters In five regions, with domestic production of 278 nil I Ion lb and Imports of 1100 lb (Toxic Substances Control Act, Chemical Substance Inventory, 197}, public record). KC1 estimated 1980 production of OCHP as 257 million 1b. The entire population can potentially be exposed to this widely used phthalate. Exposure depends on the amount of OCHP that Is volatilised from vinyl products such as upholstery In automob1les, and on the ease with which OCHP Is extracted iron products Into water or saliva. The human exposure estimate from all sounds or Ingestion 1s $.8 mg/day. The FOA Is currently reviewing the data to determine If a human health hazard occurs from OCHP used In food contact Items. Urge-volume parenteral formulations are packaged In flexible containers made from polyvinyl chloride that contains OCHP as a plasticizer. Parenteral solutions are administered Intravenously. The concentration of OCHP In replenlshers (fluids, nutrients, electrolytes) Is estimated to be lets than S ppm. An Individual weighing 70 kg and receiving ) liters of a replenlther oer day gats less than 0.3 mg DC'.iP/kg/day. indlvteuxls undergoing peritoneal dialysis are expci. l to larger amounts of DCHr. gut because of losses in the dlalysls' effluent, not all OCHP in the solutions is absorbed. Pharmaceutical manufacturers, aware of the possible carcinogenic risk from OCHP exposures, ultner are shifting to other flexible plastics that require no plasticizer or ere replacing DIMP In polyvinyl chloride with other piestlclzers (FOA). The National Occupational Hazard Survey In 1974 estimated that <12,000 workers were potentially exposed to OCHP (N10SH). OCHP Is known to be widely distributed in the environment, having been detected In various forms of marine life. In soil samples, and In both animal and human tissues. The average estimated concentration of 1 ug/1 1r. surface waters is 2 to 3 times below the levels that cause harmful effects In aquatic organisms. OCHP Is biodegradable; however. It tends to partition into sediment where It Is relatively persistent. Indirect human exposure to OCHP may occur through contamination of drinking water and aquatic organises, which lead to contamination In the food chain. The leaching of OCHP from plastic articles placed In landfills Is also a potential source of exposure. CPA regulates OCHP under the Resource Conservation and Recovery Act. Regulatlen has been proposed under the Toxic Substances Control Act, 8(a). FDA regulates OCHP as an Indirect food additive. OSHA nas set a permissible exposure level of 2 ppm or 12 mg/m3 time-weighted average for phthetlc anhydride. OCHP Is the subject of a HIOSH Special Hazard Revlaw because of a 1980 NTP test In which OCHP was carcinogenic to rats and mice. Additional concern over OCHP Is due to Its use for respirator leak testing. N10SH submitted to OSHA the preliminary hazard review In September 1981. This hazard revlaw was part of OSHA's rulemaking to amend the respirator test provisions of the lead standard. 13S HONS 025736 tttuuriM dfiimiM m liNf ictiws CffMt f MfMlltlM**; Mur Cm >U C*Mtl*M If ImnIMIm NMtltt njwt I* Klftll. IMKI II MMwiM ftltiM *t Nw tnm mmi7 IMIIW'I rMXtl If ICMCI CM. mi-MM: UjKtl *<rclftcailM M(IH. HW KMMtl, M t#lll nUMl U MMI H \m If NWl Iff M NHfW timHt) i NMNMt nniiMii if wiu. NwwIftMf t/IMI. W, Mill Ifffntff mil rtfuIrMy wm M MM MM, |fNN 1/111). itw MfvtltlMM MtM M (MWiK iMidtr. (MlW fHUf urt 1m MfftlMf f IIMlul Mltll. lull *!# i mtr Mil ##* IlMIttMf MMWM IMMIll, MftfCft Mil M U*l<l*rtl l1**f Mltll fitt if ffMMtftfy Mfmriftfffti if rMMUMfy M IIW MMl UMI i c/ to.ii. m.jj II /I. t. l)Mf (t/fi MfilMM II m MIlKI (Mi m*M. imi ii e/i m.ifi. .m. .m ai era i/f.i/e, .tit, .iom tt Ctt 177.1210. .I4ff II Vt Itt.JItO. JOf II Cft 111.11 i/Mi HU 1 m MfpMMtl. TMI (MtMK tllMMU iMfMM H* Mm If lKll MMr fM IMV.) IWMI tofliwy WiMfy: Ifttt KflMMMlf. t mm III */*> * (MU) m cn mt.im <#! 136 HONS 02573 7 DIETHYLS!IlBESTROl Thr ti sufficient evidence for the carclncgenlclty or dlethylsttlbestro'i (OCS) both lit humans and In experimental animals.1 Dlethylstllbestrol, administered In several ways, was carcinogenic In alee, rats, hamsters, frogs, and squirrel monkeys, producing tumors principally In the estrogenresponsive tissues.' Dlethylsttlbestrol causes dear-cell carcinoma of the vagina In fannies exposed In utero. The evidence for an association with other hiaaan cancers Is either limited (endoaetrltas) or Inadequate (breast, ovary).' ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals tu Humans. Supplement 4. Lyon, France: IARC, 1982. 'International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Yol. 21. Lyon, France: IARC, 19/9, pp. 173-231. DCS Is a synthetic hormone that Is practically Insoluble In water but soluble in ethanol, chloroform, diethyl ether, and certain oils. DCS had been usea extensively as a growth promoter for cattle and sheep and as a treatment for estrogen-deficiency disorders In veterinary medicine. In humans DCS baa been used to prevent spontaneous abortions; to treat symp toms associated with menopause, menstrual disorders, postpartum breast engorgement, primary o-.arlan failure, and advanced breast cancer; and tc treat advanced prostate cancers In males. L'.t. production of ?EE was first reported In 1941, Put only one U.S. company now reports production of an undisclosed amount of OCS. Production data were last reported In 1952, when 3960 lb were produced, luports in 1976 were 13,000 lb. Most exposure to DCS occurs as a result of Its oral administration as a drug. OSMA hat estimated that 4000 workers are exposed during DCS manufacture or product formulation. Ac estimated 500,000 patients each year are treated with DCS. They a>e mostly moles who are treated for neoplastic disease. Dosages range from to 1 to IS mg/day. Vhen DCS was used as a growth promoter for sheep and cattle, the entire population could have been exposed to low levels of less then 10 ppb. 137 HONS 0258 The CPA Circ1nooen Assessment Group hat Included OCS on ft* list of cerclnogens. In addition, ivA regulates DCS under tht haxerdous Matta disposal rule of tht Resource Consarvatfon and Recovery Act. I'DA requires dboduct labelIng to state that OCS Is contraindicated for use during pregnancy. FDA patted a regulation In 1977 requiring a package Insert to inform patients of the risks Involved In taking OCS, and the FOA further requires srcctal labeling to Inform physicians of the risk associated with administering estrogens. In 1979, the FDA revoked all use of OCS In food-producing animals. The Court of Appeals upheld the Commissioner's decision to revoke the use of OCS In all food-producing animals on November 24, I960, and the motion to reconsider was denied on December 24, 1)60. amliUa* mi aunr Actiam la aatmat nil*, n uan amaama ta man ammeta mr CMC JtrtMlniw. icnci em, ssi-mmi mura mu imwn, aftaamtmaamaa ukm, aaa m mum la mat* aa MM l| aa mMH*v mi mmv rnaarmtaa m rnmlmatmt. Mat taatf* aataa Uawrittmtiini aa inwui aaaatimaa* aa mm. aaa aatjam mw kaaaa la aaaiaia HUM am maatmm. nwuma i/imi. mwiM imk iHIfnHvIimNfUrwi. Jtauuftea tafaat aa Uftlnims eoarCamma tiuuaa aa upiitiw a cn m.u. HI.S9IKMI let mm mm w irtimw m aamaia ae tm mm macutm mm untaMnn U WM, 4 fNHlMlM V Mhmu samnar m ttim, m mm fM MV f# s n Nii inmUM m*mu. m uvn, iur v m nntt m (MINI US (Mil 11/1/7*. M N*rw * w hum mutif. iv* twn u Innii wn m ciwHior'i wnwi m **m mmuiui* ii/m/Mi * u w<wir m n*m m tt/pm. am H MniWlf Wfil IN V KS ' *> la lam Ime* mi aarf ttMa ms mt miumi NMuhity tm annmi nwun. mm m miun n emu* sUg iuaii amamm MS w m MmnHi la mmuai mm mm* _____________ ______ rtt-W tm mat MS U wavnaUtnn tm m la mpm. mumN m nmm aatltm aarttaa imn an m mifMHt (mm a mf'*aa la r. iMiii nmm MaM. U Samaa af arms 'uu. __ In na V US it anew* aaaaa la Uim mmammrtamm ma%aiHi.f*laaamctapl ataftatataalttmncua tofaraattaa H mamma ar mmirniaa. ita aaa * am* anmrttaml aammai mil imam taut ma aatiam me m Mm m ew rtata Mtattaaai mm IKS. dt It. hacmaiar a (rati m HONS 025739 3,3*-DIMETHOXTBENZIOINE There Is sufficient evidence for the carcinogenicity of 3,3'-d<neth0xyDenitdtne (o-dlanlsldlne) In experimental animals.) 3,3'-D1methoxybenz1d1ne a<ka1 nl stared by stuMch tub* wo carcinogenic In nts. producing tuaort at various mot. Including tnttstfnbl, skin md Zymbal's gland carctnoaas. Th* findings tr. hamsters exposed to o-dlantstdlna In tht fd also suggest carcinogenicity.2 Tk* evl fence for the carcinogenicity of o-dlanlsfdlne In kuMns Is Inadeguete.1 Most of the workers exposed to this substance were also exposed to related amines, such as benaldlne, which are strongly associated with urinary bladder cancer In humans.2 international Agency for Resoarch on Career. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chealcals to Humans. Supplement 4. Lyon, France: IARC, 1982. 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 4. Lyon, France: IARC, 1974, pp. 41-47. 3,3'-01ethoxybent1dine (0H04) (o-dlanlsldlne), an aroaetlc antae. Is slightly soluble.In water and soluble In oust organic solvents and lipids. MM or Its dlhydrochlorlde Is used principally as a chemical Inter mediate for the production of azo 6es. The Society of Dyers and Colourists reported the production }f (9 dyes using DM0* as an Intermediate In 1971. About 30 percent of DIM Is used as a chemical Intermediate In the production of o-dlanlsldlne dllsocyanate (3,3'-d1methoxy-4,4'-d1lsocyanate-b1phenr1) that is used In adhesive systems and also as a component of polyurethane elastomers and resins. CMC'* Is used a i iy* iisa'if ieaihwr. paper, p)est1cs, rubber, and textiles. OHM has also been used in the detection of metals, thiocyanates, and nitrites. OHM has been produced commercially for at liast $0 years. Current production figures are net available. In 1970, only one company produced OHM, and production statistics were confidential. In 1970, the tl.S. Inter national Trade Ceanrisslea (USITC) reported 3.9 million lb of DMM produced and U,000 u imported. In 3979, USITC reported 77,000 lb of OHM and 41S.000 lb of OHM dlhydrochloride Imported. Production of OHM was not reported to the USITC In 1900; however, production of the hydrochloride salt was Indicated In 1979 by two producers, which Implied an annual production of more than 10,000 1b. Imports of OHO* through principal U.S. customs districts In 19M were 20.0C0 lb; Imports of DM0* hydrochloride were 642,000 lb. 139 HONS 025740 Human exposure to DMOB It possible throujh Inhalation of dye pertlcles from equipment vent system end throujh skin ebsorptlon from the finished dye product, textile processlnj. alxlnj operations, or pecktjlnj processes, dorters potentWily exposed to OMOB ere dye meters end o-dlenlsidlne dllsocyanote production workers. However, current dye product I on processes for DMOB end dyes aede from OWB ere jenerelly closed system with alnlael risk to workers. The Nations! Occupetlonel Hazard Survey In 1974 etime ted thet 200 workers were potentlelly exposed to OMOB. DMOB-besed dyes end ptj>nts ere meteboltzed to OMOB. The CPSC steff It concerned t*>et dyes end pljmnts based on OMOB contein residual levels or tract Impurities of OMOB In the parts-per-million ranje and that traces say be present In (he final censuaer product. At present, no data exist on the actual quantities present In the final consumer product. A study Is now In progress on the dermal penetration of OMOB and DMOB dy*s. In late 19B0, CPSC Instructed Its staff to collect data W order to propose a ban on the use of OMOB-based dyes In mass-merchandised consumer dye products. CPA rejulates OMOB under the Pesource Conservation and Recovery Act. CPA has also proposed reflation under the Toxic Substances Control Act. Bit), reporting rule that would provide detailed production and narketlnj data. i,r HltMqiMMMI-- muriMi tefuMtlMt H Mwr Artlat Ifftel ll MfiUtlMii Mur (mm.1I . CfUtfM f ItfllMtf-- A IMT ll to ffNrtll -- M AlfMl pMttft* t< ( Ml i Mini. (cnc) MM, IM1-NM: NMlMa MM KtMtU, M --111 MllMI ll NMtl If MM If M MMlt-- r< MMrt/ imnmini ntHMMti# aim 4--tfMUi MMMt M 1 MuriMi MMttMM *f Mitt. 9t*mIfMM l/lf/M. TICA, Milt mil mdrlM prmn mi im mu. iuml t/lt/10. KM) ttfrllllM ttlli M dlPWlf* ttBlfttt f# KB* CMIrtCMl. Attttrf |mttr un MMItny f (Miieil until. M tn Ml.II. HI.]) *m\4 MMvIM 1 MtUr Mill Mr BltlBBttBt MM--ft MMMlMlp tttdb m$i M imtimi *1--f tfttfc rfU t" Mt--MnprlltMtt If rwlittry *r mmt mtnl aetfM. tm> 45 n, . UMC (CM) 140 MOMS 4-OtMETHYlAMMOAZOaEMZEKE There Is sufficient evidence of carcinogenicity of 4-dlnethylaminoatobensene (0A8) In experimental aniimls. * DA8 wet warcinogenic In rats. producing liver tumors after administration by several routes (subcutaneous Injection, diet, gavage), and In dogs, producing bladder turners when administered in the diet.* PAR has also been tested by subcutaneous Injection In mice, and the results are suggestive of local end hepatic carcinogenicity. Treatment of newborn animals produced liver tutors and lung adenomas In mice. Skin-painting with OAR produced epidermal tumors In rats but not In mice.* ^International Agency for Research on Cancer. (ARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Huuns. Supplement 4. lyon, France: IARC. 108*. `International Agency fur Research on Cancer. IARC Monographs on the Evaluation of the Card iogenic Risk of Chemicals to Man. Vol. I. lyon, France: IARC, I97S, pp. 125-46. 4-01methyl aminoa/obeniene (OAR), an aromatic azo compound, Is Insoluble in water and soluble in strong mineral acids and oils. OAR is used for coloring polishes and other wax products, polystyrene, soap, and as a chemical Indicator. Ho current production or Import data on DAB are available, large-scale production in the United States was first reported In 1914. OAR was one of a grouo of at least 20 colors for which individual production data were not available, but whose U.S. production a: a group totaled 1 million lb in 1974 human exposure to OAS can uccur either through Inhalation or through skin absorption. OSMA hat estimated that 2SOO workers were exposed to OAR. ERA regulates DAR under the Resource Conservation and Recovery Act, and hat proposed a reporting rule requiring process ard use data under TSCn, Rial. In 1974, OSMA preaailgated standards for BAR based on Its carcinogenicity. The standards require protective clothing and hygiene procedures for workers sad engineering control matures for the manufacturing and processing of the them!cal. 141 MONS 025742 tuiTjaat torittlaM M *tMr iffNt f NaUUMii MMf till 1' < Im*#! M m(( ichci I* Nl. OU, Hltl Wlnu, rf^tMctftotiw Mum, in mil* mi* l MHI If IflM If t* M4<1 IN iwh/mtmniiii mitnmv. Mm mifNtn Wm MiiiNii nmumm 0 ml*. IN MlNII NIUI MM M (MUM HUM MM MlmMI. Mamlfato* l/lt/M. nU Hi': UiutlN ml* mtMiu pNdM M IN MINN t/St/M. toa (minm iuninh Mm nmmn NNT *NIV<MfNfllMN. (CM) IftVftl NmU| tUNflU lUNMl MMttN riNMtf, mifiM, iwun, ViMt|, m N<iul nmniitn mtirt* Mate Hr muni Mail to mnUwmi inmmn( amitoi mMMini mini* Ntto Mtvtl NNlNaill tor NfltltN mhi totaltto NjiMNiih tor mihmi. toarliNry Miiayt t/ll/Ms "ml HiNiN am< tiw aflactl*. ttMU (lUIlM II Ufi'ltll* to cn m.u. at.n s n t, $. mm KM# tf cm im.iitt MUM 142 MOWS 0257*3 3,3'>DIMETHriBCNZI0lN The available tut results art considered to provide sufficient evidence for the carcinogenicity o' 3,3'-d1nethylbenz1d1ne In experimental animals.1 Cocncrclal 3,3'-d1methylbenz1dlne (0-tolldlne) when given to the ret by subcutaneous Injection caused mainly Zymbel's 9'and carcinomas, but memnery and fore stomach tumors, and miscellaneous tumors at other sites were alto present. * gastric Intubation experiment with rats produced mammary carcinomas, but the result Is of doubt'd! significance because of the small number of animals Involved. In feeding experiments, the commercial product did not produce tumors In hamsters. Other experiments verified 3,3'-dlmethylbcnzldinc at a systemic carcinogen producing multiple site tumors when given subcutaneously to the rat.< international Agency foi research on Cancer. IAAC Monographs go the Evaluation of tho Carcinogenic Risk of Chemicals to moans. Supplement 4. Lyon, France: 1ARC, 1982. `International Agency for Research on Cancer. IARC Monographs on tho Evaluation of the Carcinogenic Risk of Chemicals to Man. Yol. 1. Lyon, France: IARC, 1972, pp. 87-91. 3,}'-D1aethylbenzld1nc IDM8) (o-toltdine), <h aromatic amine. Is a white to reddish crystalline powder that It slightly soluble In water and highly soluble In ethanol, ethyl ether, and dilute acids. Over 7S percent of DM8 Is used at a and as an Intermediate In the production of dyestuffs and pigments. According to the Society of Dyers and Colourists, more than 9$ Ryot are derived from DM8. Approximately 20 percent of OMR It used In the production of polyurethane-based high-strength elastomers, coatings, ana ngio piastics. uM has aiso oeen useo in snail quantities in Chlorine test kits by water companies and swlamlng pool owners and In test tapes In clinical laboratories. The major company producing DM8 ceased productI'm. In 1978; Its annual production average was approximately 200.000 lb. EPA reported five producers and Importers 4ur1ng the 197S-1977 period (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979. public record). Imports appear to ho tho only source of DMD at present. The II.S. Internationa) Trade Coamilsslon i'VSITC) reported that approximately 3.5 million 1b of OMB and 240,OOC lb of Its hydrochloride were Imported during 1979. In 1980, more than $000 1b of OMI hydrochloride wore reported to tho USITC (MCI). 143 MOMS 025704 Workers potentially exposed to 0MB include dye makers, repeckcger; ?f 0MB end dyes, workers In toluene-sitsocynnate production, md clinical and analytical chemistry laboratory porsunntl. Workers tn t variety or oecupetlons nay be esposed to smell quantities of DIB used for analytical purposes, among thea weter end sewage plant ettendints, chemical test tape or kit makers, and swimming pool ser/lce reprelentutives. NIOSW in 1?78 estimated that fewer than 100 employees were esposed to large quantities of OHB In the United States, but as many ts 200,000 may be esposed to small quantities. The National Occupational Hetard Survey In 1974 estimated tint 420 workers wer potentially esposed to IPQ. M-based dyes and pljments are matabollied to 0MB In vivo. Residual levels of 0MB may also be present In OMB-besed dyes and pigments am ir. the final consumer products. Available data Indtcate that such contaminants orn.-r In the parts-per-mtlllon range. The Consumer Product Safety CMwisslon (CPSC) bat Instructed Its staff to cellect additional dau to propose a ban on the use of OHB-based dyes in mass-merchandises consuwrdye products. 0MB Is present In swimming pool water test kits. Each kit contains 0.5-1 percent IMS. Exposure Is through dermal absorption or through Ingestion If the test solutions are emptied back Into the pool. 0MB used In swimming pool test kits Is currently being evaluated by CNBC. Oats art being collected on the dermal absorption of 0MB and on OMBbesed dyes. CM regulates 0MB under the Resource Conservation and Recovery Ret. M Hktr lctlN Vm u tvttiMftf Nit wt liu it nrmti/ Maf MlNMr (OK) KM, Ml.NMt imi(ts llKN, Mtt |fHtl, Mi Mill MltliM la mm iMMim mkiim m m$n/ AIM MHMtlt Mai t Iimmi atl taw* if itt. NaHfittl t/nm. M) tfCMUTlM trfKt ttkur CwiiRtt Cllattaa # ItfilltlM Msed mi thnnlt ImIiIii f (Mttl. (Mtta fttttr fa kaaOlliif a# OMtti aim. IIM) *o era mi.u. (CM) 144 HONS 025745 DIMETHYLCARBAHOYl CHLORIDE There It sufficient evidence 'or the carcinogenicity of dimethyl cerbemoyl chloride In experimental mintIs.1 Dlnethylcorbomoyl chloride It cerctno9entc In mice, producing local carcinomas after appllcatlen to the skin and local sarcomas after sub cutaneous or Intraperltoneal Injection,2 A study of human* exposed to dlmethylcarbamoyl chloride Is cmtloered Inadequate.1 international Agency for Research on Cancer. IARC Monogra'hs on the Evaluation of else Carcinogenic Rlsx of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1482. `International Aoency for Research on Cancer. IARC Monographs on the Evaluation of tha Carclnooe-lc Risk of Chemicals to Man. Vol. 12. Lyon, France- IARC, 197b, pp. 77-84. Olmethylcarbamoyl chloride (OtICC) Is 4 colorless liquid that rapidly hydrolyres In water. DHCC It used as a chemical Intermediate In the production of pharmaceut'cals, pesticides, rocket fuel, and In dye synthesis. The pharmaceuti cals (neostigmine bromide, neostigmine methyl sol fate, and pyridostigmine bromide) are used In the treatment of sytithenla gravis. The three U.S. registered pesticides derived from DHCC are known by the trade nanes, Tandex1*, Dlmetllan", and Plrlmor". Production data are limited; however, the Toxic Substances Control Act |TSCA|, Chemical Substance Inventory 11979) reported that there were four producers in 1977 (no production data on public record) and approximately 400 lb Imported annually. Limited human exposure Is restricted to chemical workers, pesticide formuletors, dye makers, and pharmaceutical workers. OSHA estimated that NO workers are exposed to OMCC. primarily through Inhalation. OMCC hat been found at levels up to ( ppm during the production of phthalqyl chlorides. It Is possible that levels of exposure might be higher in facilities in which tke chemical Is used for further synthesis. Mien OMCC Is used as a dye Intermediate, exposure can ocrur from residue In the product and the migration of the chemical from the product. The Consumer Product Safety Commission staff stated that residual levels or tract Impurities of OMCC aright be present In the final consumer product. The pretence of this potential carcinogen, even as a trace con taminant, Is cause for concern. However, data describing the actual levels of Impurities in the final product and the potential for consumer exposure and uptake art currently lacking. The EPA has regulated OMCC as a carcinogen under the Resouret Conservation and Recovery Act and has proposed a reporting rule under the TSCA, 8(a). 145 HONS 025740 ;.)4 #tt*f JlctlMl KM, 9Mt*9tM: M^Kti xt frMwtl, ftoMttrim;** nuki, in win rt'llMI I* MHI *r IW If t* MMlIftf K ftMfrtMwti. MM yl cl*ric n 1 IM*NM CMtltum If alltt, l* WftjKU MlUl IMM tf (Mtlll U tt IK NN tn*m. Prt|ltM TSCA. *)r MtM'tt* mil imtu M IM MU, fmfMil l/lf/M, Sm CmlNfii MHimMt :hm tiMnt iNif MitrlalmnairiM. tla> ICCUUTI0NS (ffKl if itfiiUtlMi; Ottof Claim CIUIfM f o cri Mi.u, HIM J f If, 9, 1M4* IlMI ie HONS 025747 DIMETHYL SULFATE There 1i sufficient evidence for the circlnogenlclty of dimethyl lulfete In experimental ininils. but the evidence In huaens Is considered es tnidequite.1 Dtrethyl sulfite wis circtnogenle In BD rtts ifter Inhilitlon r subc.-tineous Injection, producing aalnly locel tumors, ind ifter prenetil exposure, producing tumors of the nervous system.* Four ctscs of bronchlil circlnoms hove been reported I>. men occupettonilly exposed tc dimethyl sulfite.2 One Cise of pulmoniry cirdnomi In t tun exposed to dimethyl sulfite tnd other chemtcels, end one cise of choroldtl melinomt In men exposed six yetrs to dimethyl sulfite hive elso been repeted.1 llnternitlonel Agency for heseirch on Cencer. IARC Monogrephs on the Eviluitlon of the Ctrclnogenlc Risk of Chemlctls to Numins. Supplement 4. Lyon, Prince: IARC, 1982. `internitlonil Agency for Resetrch on Cencer. IaRC Monogrephs on the Eviluitlon of the Cerctnogenfc Risk of Ciimlwils to Min. Vol. 4. Lynn. Fnnce: IARC, 1974, pp. 271-76. Dimethyl sulfite 1s in Industrltl chcmlcil thit Is soluble In witer. It Is used Mlnly is in ilkylitlng egent for converting compounds such is phenols, wines, end thiols to the corrrspc.tdlng methyl derlvitlve:. It Is else used is i component of polyurethene bese idhestves. Dimethyl sulfite wis first produced commerclilly In the United Stites In IBID. There ire 12 producers end Importers with i combined domestic production of epproxlaitely 48 million Ib/yr. No ditl on Imports or exports ere evillible. numon exposure occurs by Inhilitlon of the vipors or by skin ibsorptlon of tho llguld it the sites where the chemlcil Is produced or where Its derlvittves ire formuliteo. N10SH his reported thit 1250 workers ire potentlllly exposed to dtwethyl sulfite. OSHA estimeted 3900 workers ire potent)illy exposed. Environment!! sources of dimethyl sulfite ire prlmirlly from the p*oductton tosses to elr ind witer. The chwlcil IMS been found In the wistewjter ttrewo end llr emissions from plints where It ms mode or used. The hydrolysis Of dimethyl sulfite In witer Is rigid; Its trinsfer from witer to llr Is not likely to occur. 147 MOHS 025748 The CPA's Carcinogen Assessment Group has included this chemical en its list of carcinonens. The CPA regulates dimethyl sulfate under the Resource Conservation and Recovery Act and proposes to require reporting under the Toxic Substances Control Act. The FDA regulates this substance under the rood. Drug, and Cosmetic Act as an optional conponent of polyurethane bate adhesives. There is no expected migration of this chemical to food under conditions of use specified 1r the adhesive regulation. OSHA hat adopted limits for the concentration of dimethyl sulfate in the eorkplace as 1 ppm (S np/n3) in an 8-hour time-ueighted average. This standard was adopted by OSHA for toxic effects other than cancer. iiaanyl Ivlf.s. uuunae M Mur ictlm: Iffact if li|iiitiMi: Uwr CMmaU ftCJU. NOI-M<: falHeti mill Sftdxti, km Min pti<- lm Ir mmi *f IM If u dkiMii mi NMPVmy*Ml| nwlrmwi. tNlfNlIt Itattiyl MlfW M kUirlNI NNittml If md, Ml MjKtl NIWI iim te nmu it u m um rvwfrwms. 1/19/90. TKAp l(lt Nil pm* tm DM *M 4aU, IMMIll */tt/N. tm m CirdNin Mmunm Imp ititmit amir ImKitolMtiifliifMi. ItM) afttWUry Avt'wltjp: fMCA; ra ll/M/71. |TM> Kit 1 pm (1 MA^I |4wp tm. tmfiimtiil itin mriMK rmh. tm(tTMin MNtu tern MMr ami CMctr.J (MM) ?mlm1|(N7 NllWIt tfil: KitiMNlifs 1 Nitm cancwitmiw. 1/17/71: OBtt TkMfr Stm4$rt~ nrmt IMt iffutln. IKNM CfUttKI if IqilHlK 40 era IK.11. HI.33 S 71 u. a. IHH (Kill n era its.ics (TM) if an (OMU 148 HONS 025749 1,4-OIOXOiE There l sufficient evldtnc' for the carcinogenicity of 1,4-dloxane In experimental enlmsls.l l,4>01oiane admin istered In drinking niter It carcinogenic In ritl mtf guinea pigs. It produced Mllgnant tumors of the nasal cavity and liver In rats and tumors of the liver and gall bladder In guinea pigs. It was also active as a promoter In a two-stage shin carcinogenesis study In mice.2 ^International Agenc/ for Research on Cancer. IMC Monographs on the Evaluation of the Carcinogenic Risk cf Chemicals to Humans. Supplement 4. Lyon, France: IARC. 1402. 'international Agency for Research on Canca.'. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Men. Vol. 11. Lyon, France: IARC, 19/E, pp. 247-56. 1.4- Otoxane Is a highly volatile liquid that Is flammable and moderately explosive. 1.4- Oioxane is used as a stabiliser for chlorinated degreasing solvents and as a solvent for lacquers, plastics, varnishes, paints, dyes, fats, greases, waxes, and resins. The chemical can occur as a contaminant In certain consumer products, and as a byproduct of reactions based on condensing ethylene oxide (EtO) or ethylr-ie glycol. The first commercial production of dtoxane In the United States occurred In 1*51. The EFA reported that 13 producers and Importers account for 7.7 million lb of domestic production and approximately 800.0W 1b of Imports. He significant change In the estimated trends for U.S. production and sales of dloaane Is forecast. Exposure to dloxane is primarily througn inneiation of tne vapors, cut the chemical Is also readily absorbed through the skin. Exposure In industry occurs when dloxane vapors are released from degreasing operations and from spent solvents. Additional workers Involved with shipping operations, primarily by rail and truck, may be exposed to dloxane through leakage from bulk loeolng lines. According to the Consumer Product Safety Comntssion (CFSC), consolers may be exposed to residual levels of 1.4-dloxane formed during the manufacture of detergents, shampoos, surfactants, and certain pharmaceuticals. ChSC has Stated that the pretence of 1,4-dioxane even as a trace contaminant Is cause for concern. However, no data are available on the actual levels of Impurities In final products or on the potential for consumer exposure and uptake. 11? HONS 025750 Th* National Occupational liaxard Survey In 1974 estlnated that 134,000 workers were potentially exposed to dloxane, 100,000 of whom were exposed ts e result of dloxane contamination of 1.1,1-trlchloroethane. Estimates tram 0SHA, however, Indicated that 466,000 workers were potentially exposed. lecause dloxane Is volatile and Infinitely soludle In water, there Is a large potential for Its presence In the environment. Emissions to the atmosphere can occur where tt Is manufactured and used, and Improperly olsposed spent solvents can contaminate ground and surface waters. The ERA regulates ioxane through the Resource Conservation and Recovery Act. The FOA has undertaken a survey of 1,4-dloxane contemlnatlvn of raw materials and products. OSHA has adopted a permissible exposure limit of 100 ppm or 360 mg/HH as an (-hour time-weighted average In the workplace for dloxane. Thl. standard was adopted by OSHA for toxic effect; other than cancer. 4l,MN N Kaunas a*)*'*** Kf M*gf Ittlm Iftact a.* ImImIm; UttT IlNMIt CM, MJNU *(*# grgdKti, W*t1 mi* Ml M UCM tf MM If ! MMIIm M mtrt/mtmmif nntnmu. m* MlfitH l/IVtt. 1KA. Milt Mfirtlf fl MMrtl| hi* mi Mi IN MU, ifiMMi l/M/M. In CniInin Mmhini Mn IIHMM |M|f iHCWylNlNllNNN. imi nt NrtM i( rMi, nacA: NNIIN KtlM NN<N: NIPMI M linMM III NNIbN. iMK'aMnr Mtaardgf^ PM Midi. fcrviT N rase lltfrllll <N kroon **- UMNtlN M*ir m* H) - mi IM *m (M> */)) Mr IM, NMIIil far ftl* nMI. 1IMMN MUM to Mad |ffttt Mu Mm mrp.1 NMt iMliNfy Mltor/s lr; M>na Wy. IM M aNtM Hamit MuMrniN. Wlt/Tli MM tNiw tu'74*<rmt Halt affactfva. ItSMl Cltltlw 9* aaf.riiM m tn ;. ft It, . |)M ttMl ti tn m.iN IPM) it tn mt.Mit (MM) 150 HONS 025751 DIRECT BUCK 38 There Is sufficient evidence that commercial Direct Slack 38 Is carcinogenic to experimental animals.1 In a thirteen-week feeding study Direct eiack 38 (technical grade) was carcinogenic in male and female Fischer 344 rats. Inducing hepatocellular carcinomas and neoplastic nodules In the liver. The test dye was not carcinogenic to 86C3F1 mice urder the sane test conditions.2 In a recent occupational hazard review,2 It was concluded that all henzI dine-based dyes, Including Olrect Black 36, regardless of their physical state or proportion In the mixture, should be recognized as potential human carcinogens. international Agency for Research on Cancer. IARC Monoeraphs. on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France; IARC, 1882. `National Cancer Institute. Thirteen-Week Subchronlr Toxicity Studies of Olrect Blua (, Olrect Block 38, and Direct Arown 95 Dyes. Technical Report Series No. 108. DHEW Publication No. (NIH) 78-1368. Bethesda, Maryland, 1978. 'National Institute of Occupatlorsl Safety and Health. Special Occupational Hazard Review for Benzidine-Based Dyes. Washington, D.C.: U.S. Covemment Printing Office, 1980. Direct Black 38 is a water-soluble azo dye derived from benzidine. It Is usually sold as a dry powder. Olrect Black 36 Is possibly being used to dye fabric, leather, cotton, cellulcslc "iterials, and paper; these are then used In consumer products. The chemical may be used by artists (CPsc. CPA). The FDA has Indicated that although Direct Black 38 Is Identified In the literature as a hair-dye component. It Is currently net used by the cosmetic Industry. U.S. manufacturers of consumer dye products stated that they havn dis continued the use of henzidine-based dyes. EPA reported six producers and importers of Direct Black 38 In one region, with domestic production of 4 million lb and Imports of 370,000 lb (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record). U.S. production Of Olroct Black 38 was reported to the U.S. International Trade Commission for 1980 as greater than 6000 lb. 1S1 MOMS 025752 In view of heelth hazard alert limed in December 1980 by OSHA, whlrn cautioned worker! and employer! of the carcinogenic effect of benildine-derlved Olrect Black 38, new nonhenztdlne Direct Black dye! have been developed and uied successfully in commercial application! by the paper and leather Industry during the pa!t year. These nonbenzidine dyes were develcped with the hope of replacing benitdlne-based dyes throughout Industry. Human exposure to Olrect Black 38 may recur through Inhalation, skin absorption, and unintentional ingestion. Consumer exposure to Direct Black 38 depends upon the ability of the dye to migrate out of consumer products and either penetrate the skin or degrade prior to penetrating the skin. No additional data quantifying the rate of migration or degradation of this dye art currently available. In the general population, unspecified exposure levels to Direct Black 38 are thought to occur through the use of textile ^ed products end retail packaged dyes for home dyeing and school use. The National Occupational Haiard Survey In 1974 estimated that approximately 16,000 workers were potentially exposed to Olrect Black 38. The population exposed consisted of dyers of leather, plastics, cotton, wool, and silks, along with makers of aqueous Inks, biological stains, typewriter ribbons, and wood stains. In late 1980, r.psc directed Its staff to collect additional scientific and economic date Ip order to propose a ban on the use of all benzidine congener dyes In consumer dye products. Currently CPSC Is studying: the skin penetration of benzidine tongener dyes and the presence of these dyts In textile, leather, and paper consumer products. EPA Is currently proooslng regulation of Direct Black 38 under the TSCA, 8(a), reporting rule that would provide detailed production and marketing data. FDA does not regulate the cosmetic use of Direct Black 38, but was petitioned to approve Olrect Black 38 far use as Indirect food additives, at dyes for paper and paperboard products. In 1973, the petition was withdrawn. HJ7SH reported that Direct Black 38 was the subject Of a November 1979 Special Hazard review and recom mended stringent work practices, material replacement, and other measures applied to carcinogens. The Special Hazard Review was based on an April 1978 joint NCI/NIOSS .-ccoanendatlon. 152 HONS 025753 Ilrtct lltrit M KUUT10H3 ItttlitMi M OtHr kttMi CMC 1l carraatlp tta*rtaf IN i<f HMtri* IlM W iMItllM tmtwr N M prtIMO af VMM %! In tactile, laatHar, HH>' Wat--if prMuc*4- ICWCI Cffaet M 9t*ar Cmw*u ClUtfaa af Ktfnlatten TICA. MtM Raaartlaf ml# ratalrlaf >whi M M MU, fraf*t4 t/tt/M. (CM) MaaW mmIM a tetter >#* far eattaatlaf MMir ictMtlil, U1< artt t* eM<4Mtl #1e*f vftt Htk la attrlalay leeraarUttaati af rfftiliiirjr ar autar eantral aettan* KM) 4i n, i. Du* (CM) HIM rmniH itrtateat Mrt prKtktl, ntirlil PtflMawat. in mi f MMr jr*tactlv* MIMfll IM"(llU U MftllltlM. (iiosm Saacfal Nuerl M, OHOSN) 153 HOMS 025754 DIRECT BLUE 6 There It sufficient evidence for the carcinogenicity of Direct Blue * (technlctl gride I In experimental animals.* In i thirteen-week feeding study Direct Blue ( dye (technical grade) was carcinogenic to sale and female fltcher 244 rats, Inducing hepatocellular carcinomas and neoplastic nodules In the liver. The test lye was not carcinogenic to 6GC3FI mice under the tame test conditions.2 In a recent occupational hazard review,3 It was concluded that all benzidine-based dyes. Including Otrect Blue S, regard less of their physical state or proportion In the mixture should be recognized as potential human carcinogens. ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of th Carcinogenic Risk of Chemicals to Humans. Supplement 4. lyon, France: IARC, 1982. `National Cancer Institute. Thirteen-week Suochronlc Toxicity Studies of Oirect Blue 6, Direct Black 3B, and Direct Brown 9$ Dyes. Technical Report Series No. 106. DHCM Publication No. (NIH) 78-1358. Betheida, Maryland, 1979. `National Institute of Occupational Safety end Health. Speclel Occupational Hazard Review for Benz1dfne-B.tsed Dyes. Washington, D.C.: U.S. Government Printing Office, 1960. Direct Blue S Is water-soluble azo (bio derived from benzidine. It It sold as a dry powder for commercial use and as a component In retail packaged ebres. Direct Blue 5 may still be used by artists. It Is potentially used to dye `sbHc. leather, ccctcn. cellulosle rateriali, and paper: thes* are then used In consumer products (CPSC, EPA). The FDA has Indicated that although Direct Blue G has been Identified In the literature at a hair dye component. It It not presently used by the cosmetic Industry. In 1976, 61,000 lb of Direct Blue 6 were produced In the United States and 120 1b were Imported. All three nanufactc'ers of consumer dye products stated that they have discontinued the use of bznzldlne-based dyes (CPSC). In their Initial Inventory of domestic predurers end users of chemicals, EPA reported five producers and Importers of Direct Blue 6 In one region, with a total domestic production of 74,000 1b and Imports of 4000 lb (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record). Production of Direct Blue 6 was not reported to the U.S. International Trade Commission In 1960; however. 154 MOWS 025755 production was reported In 1979 by one producer, which luplled an annua) production of wore than 5000 lb. The producer currently produces direct dyes; but It Is unknown whether the company actually ceased the production of this particular direct dye or simply did net produce It In 1990. Human exposure to Direct Blue * may occur through Inhalation, skin absorption. and to a lesser extent, unintentional Ingestion, wher. the dye is In the press cake or dry powder form. The primary source for exposure to Direct Blue ( Is at the production rite. The Initial production step Is In a closed system. However, other production operations, such as filter press, drying, and blending, may be performed in the open and, therefore may afford a greater potential for worker exposure. The general population nay be exposed to Direct Blue S through the use of retail packaged dyes containing this benzidine-based dye. Consumer exposure to Direct Blue f depends upon the ability of the dye to migrate out of the consumer product and either penetrate the skin or break down prior to penetrating the skin. No addliicnal data are currently available. The National Occupational Haiard Survey In 1974 estimated that 1300 workers were potentially at risk of exposure to Direct Blue e. In the late 1580s, the CPSC directed the staff to collect additional scientific and economic data In order to propose a ban on the use of all kemldlne congener dyes In consumer products. CPSC It now studying the skin penetration of beneldlne dyes and the pittance of these dyes in textile, leather, and piper consumer products. EPA Is currently proposing a reporting rale for direct Blue f under TSCA, 8(a). FDA, which do$ not regulate the cosmetic use of Direct Blue A, was petitioned to approve this chemical, among others, for use at an Indirect food additive, l.e., at a dye for paper and paperboard products, la 1979, the petition was withdrawn. N10SH has reported that Direct Blue 6 was the subject of a November 1979 Special Hazard Review. N10SH recommended stringent work practices, material replacement, end treatment of these substances at carcinogens. The Special Hazard Review was based on an April 1978 Joint NCi 'N10SH recommendation. ilpggi lloe 4 knl4twi M MNP ktlBRI PIC U PWlti lH<t M *11 PW VnlW ft QMfVNtP %tl M w pwbwm tf 9mm #*a * )MMP, * fmt RBMf IfBMU. 1PKI DM *M >*9BBK t/W/Me tint INK ittUfM um irtttWMi Moial rtKwtt aaa *9nr mtmttim BBBBIP9I UgHtMll BBrllBBgilB. mtati IffMI 4f bgaltltOMi MBbp Mn*U dlBllBR Bf a^iatlM M4 Harm MMr mH far MttMttdM BflBHI BBBiHtiBl, . M NRtMlPM |I|B| MU la MnMMai mmrtMmii # MtilM bp bBiibp aantPil t'BR. HMI n, a. mu <cm> laactal a#i*N Aaeia*. DM Wtth! 15S HONS 025756 ETHYLENE THIOUREA There ! luffIdent evidence for the carcinogenicity of ethylene thlouree IETU) In experimental anluls.* ETU 9lven In the diet to rats produced thyroid carcinomas.*.3 Increased Incidence of liver-cell tumors was reported In two strains of mice following oral administration of ETU (gavage Initially, then diet).* international Agency fer Research on Cancer. IAAC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `Graiiam, S.L., W.H. Hansen, K.J. Davis, and C.H. Perry. Effects of One-Year Administration of Ethylene Thiourea Upon tile Thyroid of the Rat. J. Agrlc. Food Chem. Yol. 21, 1973, pp. 324-29 3Gak, J.C., C. Grail lot, 0. Fournier, R. Truhaut, and 9. Radenen. Differences In Susceptibility of Hamsters and Rats to the Effects of Long-Term Administration of Ethylene Thiourea. Eur. J. Toxicol. Environ. Hyg. Yol. 9, 1976, pp. 303-12. 'International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Han. Yol. 7. Lyon, France: IARC, 1974, pp. 4S-S2. Ethylene thiourea Is a water soluble chemical, available In the United Statts as a solid powder and as an oil dispersion. ETU has been widely used in the United Statts since 1948 as an accelerator In the vulcanisation of various elastomers, ir.c:uiir.; -.;;pr;r.c Ijo'.yc.Msrojr;.?; and polyacrylate rubber. Although the curing of these rubbers converts most of the ETU to other compounds, trace amounts are still present In the cured products. Neoprene Is used almost exclusively in Industrial applications such at automotive parts, wire and cable production, construction, and adhesives. Consumer prod-icts containing neoprene include shoes and closures for containers (e.g., aerosol dispensers). The CPA has reported additional uses of ETU as an Intermediate In the manufacture of antioxidants. Insecticides, fungicides, Ares, pharmaceuticals, and synthetic resins, and as a constituent of electro plating baths. CTU Is a manufacturing, processing, and metabolic product of the ethylenebitdlthiocarbamate group of fungicides such as ma-ieb, manco.eb, metlram, and itneb. ETU appears as a stable residue or. fruit and vegetable crops that have been treated with othyleneblsdlthlocarbanate fungicides. Studies have revealed that CTU Is present In 28 different ethyleneblsdlthiocarbamate commercial products. 16 025 75 7 Conmerclel production was first reported fn the United States In 1951. Domestic production reported by (PA dual; Substances Control Act (TSCA), Chemical Substance Inventory, 1919, public record) was 375,000 lb by seven producers In four regions. U.S. production greater than 1000 lb was reported to the U.S. International Trade Commission In IPSO IhCl). CTU Is distributed and available from most major chemical companies In snail as well as bulk quantities. No data are available on current levels of Imports or exports. The National Occu-Utonal Hieard Survey In 1974 estimated that 60,000 workers were potentially exposed to CTU. The major routes of exposure are skin contact and Inhalation. N10SH estimated thit 3S00 workers are exposed to ETU In the manufacture of fabricated rubber products. In October 1978, ETU was the subject of a N10SK Special Hazard Review. NIOSH considered carcinogenic and teratogenic effects In recommending that worker exposure be minimized by using an encapsulated form of the substance In the workplace. CPA currently regulates ETU under the Resource Conservation and Recovery Act and <s proposing regulation under the TSCA, 8(a), reporting rule. FDA has prohibited the use of ETU In food. luqrlww tutsans ftajaUtlaat art ttMr ActltM Baatr avalaattaa. (CMC) KU. MCl-MMt MM AlUtif,tlu9nf Wi Oiwt Iiifctttl,iMam*flallafftMl r*frV mar* naif pffHPwmi. uh MffMtii <MUl M 4 MIIPANI (HIlttNM *f Nttt. FraMlfatM l/l/tO. ISCA> Mi): MpartlM mlc rtaafrtaf iracaaa M m fata. FM M prNlKM KM IM < attyltaa !* III Me MuuTiees Kffact af Rafalatfana; CtNr Cawaatt wltatla* af Rtfalallaa rfvlatlaa Naaa aa caraate ttilcUr* itan fmtif cart la MaOfaf af aNsiaal **. 40 CM M1.I1. rtl.JJ Mala Naataa a atttar Matt far tutaatlr-f aattura aataatfal, mate* Mat ha mmI#n alaiif tia la fataraialaf aatraartatanaa; af rayaialary ar atar- caatral actiaa. KM) at m, a. *K4f KM) tt cn i0 (FM) BIN* taatUaraf cartlnatf< H tiratnat fftttt la acMMIaf that wrtif awwri ka Mala*a* 4 hy attaf aa a*caa*lata4 fara at M NMUm la IN aarhalaaa. (BIMN) Saactal Kwfl Ravltv, iff! IIIOM) 157 HONS 025758 FORMALDEHYDE Thtrt (t sufficient evidence for the carcinogenicity of formaldehyde in experiment#) animals.1 Formeldehyoe wet tested for cerctnogenlclty by Inhelitlcn exposure In two strelns of rets end one strelr. of mice. A Significant Incidence of squamous-cel1 carcinoma* of the nose) cevtty wes Induced In both strelns of rets but not In mice. Another study In mice end one In boasters by Inhelatlcn exposure, one In rets by subcutaneous edalnlstretlon, end one In rabbits by exposure of the ore) mucosa were considered Inadequate for evaluation. Levels of forsuldebyde that caused r.esel tumors also caused acuta degeneration, necrosis, Inflaamatton and Increased call replication In the nasal mucosa o' ra*s and mice following Inhalation exposure.** The available epidemiological studies do not provide adequate evidence for assessing the carcinogenicity of formaldehyde In man.*>` 1International Agency for Research on Cancer. IARC Stenographs on the Evaluation nf the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29. Lyon, France: IARC, 1982, pp. 345-89. Formaldehyde (HCH01 Is e colorless, pungent Irritant gas that Is water :sV:ble and nest frequently marketed as 37-56 percent aquecus solutions, coraonly known at formalin. The solutions are usually stabilised with 10-15 percent methanol to prevent polymerisation. HCHO Is a hlgh-volume chemical of which 65-70 percent <s used for the production of phenolic, urea, smlemlne, and acetal resins with wide usage In the construction, automotive, and appliance Industries. HCHO also has me*? uses In products such at textiles, eehalmlng fluids, fungicides, bacteri cides, air fresheners, cosmetics, medicinal!, and toothpastes. 51xteen companies currently produce HCHO at 53 plants In the United States. Rreductlon levels for 1980 have been estimated as 6 billion 1b, while 1979 estimates were 6.5 billion lb. Imports and exports In 1980 were repotted as 10.2 mllllen and 15.6 million 1b, resreett/ely. In 1978, market analysts forecasted an average growth rate of 0-3 percent through the early 1980s; however, some analysts prtdlct production decreases of 5-30 percent. 158 HONS 025759 Hunan exposure to HCHO 1s principally throuuh Inhclztln and skin absorption or less frequently by Ingestlcr.. Most of the HCHO production In the United Starts Is from methanol In closed automated process systems. The exposure potential during transportation end storage Is likely to be minimal. Estimated emission levels from production plants range from 0.0004 to 2500 ug/H, with a median exposure of 0.01 i.g/*T. EPA estimates that 27.7 million people living within 12.5 miles of point sources may be expoted to low levels. HUSH estimates that 8000 workers are potentially exposed to HOfi during dlrvcs production. In addition, pathologists and histology technicians represent a high exposure group. In 1574. the national Occupa tional Haiard Survey estimated that 57,030 fplt-tlme and 1.7 million part time employees may have been exposed to HCHO, and CSHA estimated the number of workers exposed as 2.5 mill Iso. Most .onsumert are exposed to formaldehyde through its use In con struction materials, wood products, textiles, home furnishings, paper, cosmetics, and pharmaceuticals. The ambient air levels In the United States, ranging from about 0.001 ppm to 0.030 ppm, expose the entire population of 230 million. Two subpopulations have been Identified as having particularly high potential for HCHO exposure: 2.2 nlliicn residents of mobile homes containing particle board and plywood hr.se an average exposure of 0.* ppm HCHO, and 1.7 million perrons Using In conventional hemes insulated with urea-formaldehyde foam have a potential average exposure of 0.12 ppm. Inadvertent production of formaldehyde from combustion sources also may contribute to these exposures. An estimated ISO million persons are poten-. dally expoted to ambient air concentrations at maximum levels of 0.25 ug/sr> of HCHO. Automobiles alone emit 610 million 1b of HCHO each year. HCHO has a short half-lifa in air because It Is degraoed by pnotochamtcul processes. HCHO Is also unstable In water, and no effluent data are available. The Consumer Product Safety Commission (CPSC) requires labeling, to warn that formaldehyde Is a strong sensitizer, on household products containing 1 percent ir more of formaldehyoe. un-yr uic authority or Section 0 of the Consumer Product Safety Act, the CPSC banned the use of urea-formaldehyde foam Insulation In residences and schools (16 CFh Part 130u. Vol. 47 *64, April 2. 1902, pp. 14366-421). The Commission It currently stuping the nff-gasslr.g of formaldehyde from other products, the btoavsllabllity and derma', penetration of formaldehyde from textiles, and the sensitizing capability of formaldehyde. EPA also regulates HCHO under the Clean Hater Act, the Resource Conservation and Recovery Act (kCRA), and the Clean Air Act. The RCRA regulations are not based on carclncgentclty; however, they encourage greater car* In hrndltng and shipping of HCHO and should result In a reduction of occidental exposures. OSHA adopt'd permissible exposure levels of 3 ppm as an t-hour time-weighted average, $ ppm celling, and 10 ppm maximum peak concentration for 30 minutes In an S-hour period. This standard was adopted by OSHA for toxic effects other than cancer. Actions initiated by FCA and EPA are presently under assessment to determine what additional regulatory course. If any. should be taken. 159 HONS 025760 rwi..*rw veuAMMs bfilittiM mi Ittir Kt'Mt erract st ItMr (mini lilvlium AvVwrttf: CfU/fuZA nw: tor KtoMt cwU'Mftf 1 (Kttoi 0*a#1 D7N HI W N tPMlA II KWf WMHIltr. f 16#i i i in i if iNiwimiifirto fM IihUIIM I* KNill M NIIMNII. ItriO * llcrlllN Mat Cf CAMCf it Hlll.l AMftlAMl CAMS fr prery 10,004 MCI* tfcMi mis i*mIi:m ii** ini. fimilMrN will N llMINIM. ICfSCI CM HI: UuriNI lllll PtfoUtlM imI|miIn rmfiiilt Mtiir ||M li. IM ** IN lapatlM NtNI'N rtMP0* (Ml. PiNMlfAIH O/IO/'f. CM. Nil*N0: SMJmM Mitt pralactt , |ff-MHlfltlltl* MUNI, M Iflll rnlMl I* Mill f IM If *l MMHaf M NMVrN|r*Mto| rTylrpim. AIM M|l|NtM MfiriMS INItllMN f Nltl, M MjllU M*tSS IMM U CM* lit* It t* the MM rwlWMI. trwl* fMM l/ltftt. (Mi towiMM sf- Mvftci mo imwrii IMltlt* '/M. (MlN<N'HHtMll U MIMlN ifUllNfT MM, tl mf. Sic CirctfMM* AasttsotM Inn llltMM CMCf ItMlItolwnMNN. (IfAl ct MlM C* CAPCtMfMfCtty. (MtersfAt Mtsur (IN I* MMIlAf CM JUpplM If CMPfCAtl, AM IMvIl rtsvlt I* PMMttM Af KlIMUl MpcSaris. tCPAI IfflllUiT AilMfl^l fMCAMIfa). CwNlMttN effort l`rpif Wl. in*) MlUilivif^Mmi MlftKIMNII MM IM* CM* N MM M MUM M fPM MflItltll* l MMCVlMM. |fPA Pllt ) m Mr M, 1 M NI1M, It pp* Niton ppm. R !* la m Mr ptfMOO. (StcMcM AMpCM hr Mate fleets itkcr Ini iwtir.' *tt) ofolctpry Olstory: mil WsIsMHCAlf. 1 PM Malawi illAMOU CAMMtrStlM. IStffft: Mma TilNNt' ItMtirp.nrmt Halt cffccttM. I0MAI Otitta* f IlflllllN 1000 era ttoo.inci 11 CF Part l/N, !. ; r*. SO. MMA-llin. l/l/il ICPttl Cfl ||f.), 117.11 Cfl Ml.U. Ml.)) OAOPS, NNna) MMMtUttM. t/00 KPAI n era ifs.101. lot.ts, if) .m. m.tio. ifi.iin. 17S.1IP. Iff.NO. m.No. m.iM. IfO.lfO. Iff.ttlO. If*.100. Iff.f10. iff.iooo. m.Mo if ra mil. mm IP**) n era tfio.iooo I0SNAI HONS 025761 160 HEMATITE UNDERGROUND MINING Ther* It sufficient evidence for the carcinogenicity to hunans of underground hematite mining (with exposure to radon).1 No carcinogenic effects were observed In mice, hamsters, or guinea-pigs given ferric oxide Intratracheally.' Underground hematite miners have a high Incidence of lung cancer, whereas surface hematite miners do not. It Is not known whether this excess risk may be due tn hematite; to radon (a known lung carcinogen); to inhalation of ferric oxide or Silica; or to a combination of these or other factors. Some studies of metal workers exposed to ferric oxide dusts have shown an Increased Incidence of lung cancel, while other studies have not.1*2 The Influence of factors In the workplace other than ferric oxlrt cannot be eliminated.* international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Huetns. Supplement 4. Lyon, France: IARC, 1982. `International Agency foi Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 1. Lyon, France: IARC, 1972, pp. 29-39. Mueen exposure to hematite from underground tenet*te mining Is princi pally through Inhalation and/or ingestion of (hist. No estimates are available concerning the number of underground miners exposed. The ERA vUws heme`.It* mining ar being primarily within the jurisdiction of the Mine Safety and Health Administration of the U.S. Department of Labor. Some ERA guidelines address the ferric ore mining, milling, and refining categories but do not specifically address underground hematite mining, it Is unlikely that ERA will asstaee further jurisdiction. IMlHS |T*tffOd Wiblmf hfulillgnb ini HRer Ktlwi Mllu II8N llMd IflNM rtOTl'r *4la IN JartMtottM * MM twtrc*M M Mlllafl N Mia ftp** iriniMI. Im tWdWl piNMatf Iddretl tfw Nrrlt ifi ataidife raftMay M*M lfiw IWI1U NlOf ft 99. | file # IN NHltlfN N KW7 EMIT rift l| 99 nMFI. ft * Pltttlf mt W *111 NMN MMr JarIMKtfa*. (CM) KWUTtMS (fftet *Mf (4MMI CtUtfa* d MfuliUgo 161 MONS 025762 HEXACHLOROBCNZtNE There It turtlctcnt evidence for the carcinogenicity of hexaChlorobenztne In experimental animals.1 Hexachlorobenrene (HCB) wot totted by dlttary administration In nice, hamsters end rott (o.i experiment with tlch species). In Swiss nice, HC1 produced liver-cell tumors In animals of both tenet. In Syrian golden hamsters, HCB produced hepatoma., liver hemangioenlothellomes and thyroid adenoaiat In both sexes.? Female Agus and MAC Ulttar ratt fed hextchlorobcniene in their diet developed liver-eel1 tumori.3 Mnternat'onal Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicclt to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Ccncer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 20. Lyon, France: IARC, 1979, pp. 15S-7R. 'Smith, A.6., and J.A. Cabral. Liver-Cell tumors In Rats Fed Hexaehlorobenzene. Cancer Lett. Vol. 11, 1980, pp. 189-72. Hexachlorobenxone (MC9) It an Industrial chemlral and a byproduct from many chemical ard pesticide manufacturing processes. HCB technical-grade formulations Include wettahle powders, liquids, and dust. MCB's principal use In the United States has been as a fungicide to control wheat bunt and smut fungi on other grains. HCd has also been used as a chemical Intermediate in dye manufacture and synthesis of other organic chemicals and at a wood preservative. HCB Is formed as an Impurity during the synthesis of several herbicides and pesticides. Including the herbicide dlmethyltetrachlorotemohthallc acid I0CFA1, which may contain 10-14 percent HCB, ana tne pesticide pentaentoronltrobenzene (PCHI), which nay contain 1-8 percent HCB. HCB Is used as an Intermediate in the production of pentachlorophenol (PCP), a widely used herbicide and fungicide. PCP may ccntain up to 13 percent Impurities, part of which consist of residual HCB. Caammrclal production of HCB in the United States was first reported In 1933. Production of HCB In the United States ended In 1978. In the period between 1975 and 1977, there were three producers and Importers In three regions, with a domestic production of a.7 million lb and Imports of 3800 lb (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1*79. public recordl. NCI reported that HCB Is not now Imported or produced commer cially In the United States. Approximately 8.S million lb of HCB wastes are produced annually by 14 Industries surveyed as sources of HCB wastes. 182 HONS 025763 TIM production and use of HCt is I fungicide over the past several decades, and Its occurrence as a byproduct In the manufacture cf other chemicals, Indicate that widespread human exposure occurs In both occupa tions and nonoccupatlonal settings. Exposure to KCB may occur as a result of Its presence In wastes fro* pesticide manufacture. Contamination of the ground and of graving cattle around dumps and along roads where the watte It trucked has occurred. The National Occupational Hazard Survey In 1974 estimated that 4400 workers were potentially exposed to KCB. Occupations where the potential for human exposure exists Include fungicide workers, organic chemical synthesizers, synthetic rubber producers, >eed dlslnfectert, pesticide producers, and wood preservers. The CPA's moni toring of human adipose tissue collected across the United States has sho:n that approximately 9$ percent of the population has tram residues of HCi. KCB residues have been detected In soil, wildlife, fish, and food samples collected worldwide. In the Total Olet Program of the PDA, HCB was detected In food composites In 30 cities at levels of 0.006 to 0.040 mg/kg. The average dally Int'ke of humans In 1973 and 1974 has been calculated to be 0.04 ug/day and 0.97 ug/day, respectively. HCt was detected In most river water residues (2 /l to 90 vg/1) and srll residues ranging from traces to 1700 wgAg near Industrialized regions of the United States. HCt Is a toxicological and environmental concern due to Its bloaccumulatlon and persistence. HCt <s Insoluble In water and under most envlromaenta! conditions has a very low rate of degradation. CPA has recommended an upper limit of O.S ppm HCt In fatty tissues of cattle, pigs, and sheep, but has not promulgated a tolerance. EPA regulates HCI under the Clean Hater Act, 304 and 311, and the Resource Conservation and Recovery Act. In addition, a reporting regulation Is proposed unde.- TSC4, 1(a). 163 HONS 0257b* acevu'HNS ktiUtlWt 154 *th*r effect if "m'*'1**; Cthtr CMwiti Clin'** If a7wlitiia M ICtU*; `ifl*' rl'HtM. :cnci f*a, V*! Mttr **ih*y cm#rij 1t|ft# flMl '*, U. 11/1). 9M, )tl: "Mfcriwt ta<'>t r%vriti*N wa* \W+% "*wr*Ml* WXHf ' '*. 3.iU f m imm nr*.i4| tawiriMn. Iim <7n/>t. aCM, MUMN: M;`i MUHt. 4ltl KNtU, IM Will '*'*< ' * mm if icco *i u 44Mii<^ iih> mru tin*! tUlfTWH. ilu '(UtMttt m^icil it i HUfiMi < *<*. feMMtptH I/I1/I9. *X4, It*)? *Mlf M MM MU. XMIIM ,IH| ir*CU s n. i. uni *t;pl>ttn NtM n name tiifctty. :ir 14 kM4ll{ CM IMWIRf Cf CMHMClil. MfiilUli* Mt ** tkrtnlt if CM*KI. rMCn 7rtitcr (tr In NcMl Inf If ** CM 117. J, 117.1) 0 CM 7*1.11. 1*1.') `Mali irteftfl l Mtttr Mill fir MilMtlMf IlfllirC H4Rtlll, **<] aa$t M tmilurti itMf ltl rill la MtOfwnlnf iumriKMn 1 rtfalltiry If ItMf CMtnt KtU*. ((Ml *1 fl. $. 13tH |CM1 HONS 025765 164 HYDRAZINE AND HYDRAZINE SULFATE There Is sufficient evidence for the carcinogenicity f hydratlne In experiments! nlmals.1 Hydrazine administered l>y gavage. mainly as hydrazine sulfate, produced a high Incidence of multiple pulmonary adenomas and adenocarcinomas, and hepatomas and hepatocarclnomas In nice of several strains, low-level Inhalation exposure to hydraxlne produced lung tumors In mice, albeit In a small number of anlrats.2 Intraperftoneal Injection to several strains of mice of hydraiine In physio logical saline produced sarcomas of the mediastinum, leukemias and lung tumors. Administration of hydratlne sulfate by gavage to Cb/Se rats caused lung adenomas and adenocarcinomas, liver adenocarcinomas and mammary fibroadenomas.3 Two reports on cancer mortality of t.orkers exposed to hydratlne have been published some rears ago but the evidence provided Is considered as r.adeguate.a 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. tacEwen, J.D., E.E. McConnel, and X.C. lack. The Effect of a Six Ninth Chronic Level Inhalation Exposure to Hydratine on Animals. L-Medlcal Research Laboratory, Wrlght-Patterson Mr Force Base, Ohio. AHRl-FR-74-:25, Paper No. 16. Distributed by National Technical Information Service. li.S. Department of Commerce, Springfield, Virginia. /D-A-C11865. 1974. ^International Agency for Research on Cancer. IARC Monographs on the Evaluation cr the Carcinogenic Risk of Chemicals to Man Vol. 4. Lyon, France: IARC, 1974, pp. 127-36. Hydratlne and hydratlne sulfate are both highly soluble in water. Hydratlne Is used primarily as a chemical Intermediate and as a rocket fuel. Inc chemical has been used commercially as an oxygen scavenger in water boiler and heating system. Hydratlne Is used as an Intermediate In the production of agricultural chemicals, spandex fibers, and antioxidants; as a polymerization catalyst; as a blowing agent; as a scavenger for gases; for plating metals on glass and elastics; and In fuel celts, solder fluxes, and photographic developers. Hydrttlne sulfate Is used In refining rare metals, as an antioxidant in soldering flux for light metals. In analytical tests for blood, as a blcclde for fungi and molds, and In the preparation of hydrazina hydrate. 165 MOMS 025766 Hydrazine (I a suspoct contaminant of liquid formulations of Isonlazlde. drug uicd In treating tuberculosis. FDA It Investigating t,.e magnitude of the problem to onstiro thot tho contamination of Isonlazlde Is kept to the lorest dctoctoblo Halt. Hydrazine sulfoto bos boon Investigated os on Adjunct tu antlneoplastlc drug treatment, although extensive use Is not fortstoablo. Its carcinogenic ootantial does not necessarily preclude use for this purpose; aany antlneoplastlc aoonts are carcinogenic. EPA has estlaatad 17 producers and laporters of hydrazine In four regions, with domestic production of 7.' alllion 1b and imports of 444,000 lb. Ten producers and laporters of hydrazine sulfate were listed In the Toxic Substances Control Act. Chealc.l Substance Inventory, 19/9, public record; doaestlc production was reported at 562,000 lb; laports were not reported. Production of hydrazine was not reported to the U.S. International Trade Comission in 1979-1960. The 1M2 Directory of Chemical Producers, however, Indicates that three V,$, companies now produce hydrazine In coaaercta'. quantities. The National Occupational Hazard Survey In 1974 estimated that about 11,1(00 worters were potentially exposed to hydrazine. The environmental fate of hydrazine and Its derivatives Is largely onknown. All Vie simple hydrazine derivatives aro polar, nonvolatile, and soluble In water. The use of hydrazine In oolter water treatment right result la 1u occurrence In discharged waste, but It would rapidly react with oxygen. There Is no known presence of hydrazine in consumer products. The possible route of huaan exposure to hydrazine Is Ingestion of trace residues In processed foods. Steam in cortoct with feed oust contain no hydrazine (21 CM 173.ilO (d>). In 1979, FDA proposed to revoke the use of hydrazine as a boiler water additive for boilers In contact with food. Final action Is pending. The CPA regulates hydrazine under the Resource Conservation and Recovery Act. Hydrazine was the subject of a June 197R N10SH Criteria Document that considered a varlet- of serious health effects and recommended ; .-eduction of t,,e OJHA permissible exposure limit from 1 ppm (1.3 ag/aJ) tlae-welghtcd average to 0.04 ag/a3 celling. ICC HONS 025767 HytfrttfM Af`NyiPU<Mt Svltalt KMLATIONS tpfUtt* *d Ottor Aedt*t Cftoct tf OIMp (tantfito Cftatfaa tf lifvlitlM H etrrttt ictttit. (CMC) RCU, 300W3004: fetjtett aff-tHdftcitlta NtNt. iiU irMaett, im toll) mlMt to *c*m tf 1009 # to rvfrx/ rtetPtotnilrMii. Alto 4tdt*tot OlPkll II 1 Mlirtot (MtltMMt of Mitt. OrWtftfm* 1/19/10. 1(H) KtfilltlM Mill m cltPtntr toxicity tf totaled. f# tttop ctrt to Httdlnf tf totaled Mitn, ((H) 40 CM 191.11, (91.33 (IH1 AtfillttO M HtrHinf <|PKt t--4 lirtlH ff 9M ll lOUtf ttttP. h ft llaftoA to itf* ctotont to 'toaa to tonuct dto ftt. . (HA) 8 cm 173.319 a CH 173.319(4) (PM) Pfli 1 * (1.3 ai/a*). PilHtdl ftp itto MtrftlM ttttf. [ItiMM wftH fte toafe tfftctt ttfttr tkw ctactr.] (0**1 AtariIttry Hfitory: . IflOt Udto-Ntdy, 1 99* 11.3 af/a3) fttt. (MNU 39 CH 1919.1(99 (9SM) 199N Ttqiwiwfi nfeetlt* tf tot MHA Ki trm i.) nn n .o< uwf Ct(1f*9' INIMN) Crftopft BttoJttt, 1979 (SIMM' 167 ?68 HrCR.,.Z03EIIZENE The evidence for the carcinogenicity In experimental anlntli can be considered sufficient for hydrazobenzene.l>2 When administered In the feed, hydrszobenzene was carcinogenic to Fischer 344 rats of both sexes, causing Increased Incidences of hepatocellular carcinoma and Zymbal's gland snuamous-cell neoplasms in male rats; and neoplastic nodules of the liver, and mammary adenocarcinomas In female rats. Hydrazohenzene was also carcinogenic to female B6C3F1 mice, causing an increased Incidence of hepatocellular carcinomas. The com pound was not carcinogenic to male mice.l ^National Cancer institute. Bioassay of Hydrazohenzene for Possible Carcinogenicity. Technical Report Series No. 92. OHHS Publication Ko. (NIH) 78-1342. Bethesda, Maryland, 1978. `Grlesemer, R.A., and C. Cueto. Toward a Classification Scheme for Degrees of Experimental Evidence for the Carcino genicity of Chemicals for Animals. In: R. Montesano, H. Bartsch, and L. Tomatls, eds. Molecular and Cellular Aspects of Carcinogen Screening Tests, IARC Scientific Publi cations, No. 27. Lyon, France: International Agency for Research on Cancer, 1980, pp. 259-81. Hydrazohenzene Is Insoluble In water but soluble In ethanol and ethers. The chemical name for hydrazohenzene Is 1,2-dlphenylhydrazlne. Hydrazohenzene finds Its major use <n the dye manufacturing Industry as the precursor of the important dye Intermediate benzidine, a potent carcinogen. The chemical Is also used as an Intermediate In the production nf phenylbutazone, which Is used in the treatment of rheumatoid arthritic v* -'red rent*circs. There are seven producers and Importers of this chemical, with an annual domestic production of 373,000 lb and an annual Import of 135,000 lb. Additional unknown guantltles are produced at dye manufacturing facilities by the reduction of nitrobenzene to hydrazohenzene, prior to Its rearrangement to benzidine. The potential for exposure to hydrazohenzene Is greatest for workers In the dye Industry, although workers In the pharmaceutical Industry may also be exposed. The primary route of exposure Is through Ingestion or inhalation of the chemical. There are no data for the numbers of poisons exposed or possible levels of exposure, because there am no reliable estimates far its occurrence as an Intermediate In the production of benzidine. Because of the Importance of benzidine, the potential for exposure to Its precursor, hydrazohenzene, probably Involves many workers. 168 MON* The tPA hit published I Miter quility crlterii document for the protection f himin heilth ind hit proposed i rule under the Tonic Subttmcei Control Act thit nould require the reporting of diti concerning the processing md use of hydritobuniene. Hydriiobentene is regulited under the Resource Conservation md Recovery Act, used on chronic tonicity. llfilitleni ind ItMr Ktli l cental Ntlw. (CMC) CM Jilt Mill PtflllllM MHINtlRt rm'Ulll MMIIr iw (f.i M, |fMIH< 1/llW. l(P(f tf OfUMilrlrMlN Ml MKlHM. CM, MUIt Mir (MU;. M* Htact Mm! Hm. n/nm. KM, NM'NKi lMj(li Mitt rrMwtl. Cff*MtiriCttta MUMI, IN Mil ml* Mtt l HUM tf Itm If If NNllN M HMt/WCWftHIlN nNtfWRRIR. HavlfctM tytl/M. IK*. Mtl: Hamitf Hit rtctrt*f r* CHI CM MC HU. |fMIM I/I9/M. UMI flCUUtIMS CffMI tf Mtvl*t<t*i: MNr (Him (llltlw tf Iiniuiw Mice m df<Mir.Ri(itr. 4S ft ID, . INK i ra in. f. nut MlM tc cwiclc tcctdty. iMtif! ircctcr ccrc fa MMltai tf (MiUal min, mu C#Cf* ltl.ll. Ifl.JJ $ l. f. INN uui 025770 HONS 169 INOENO(l,2,3-cd)PrRENE There <( sufficient evidence of the carcinogenicity of this co<pouii<l to experimental animals. Indcno(1,2,3-c d)py rene (IP) was shown to bo a complete carcinogen and an Initiator gf skin carcinogenesis in the mouse (Swls'-albtno HA/ICR/M11). It produced local sarcomas In XVIInc/2 male <a1ce after subcjtaneous tJ*ct<on. It seems to be of lower potency as a sktn card nogen than benzo(a)pyrene.l>2 ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement A. ly m, France: IARC, 1902. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Del. 3. Lyon, France: IARC, 1973, pp. 229-37. IP 1s a polycyclic aromatic hydrocarbon (PAH). Although reported for the Toxic Substances Control Act Inventory, IP Is not commt'clally manufactured, and no use data are available. This compound Is widely found as a byproduct of poorly controlled combustion that occurs In refuse burning, coal furnaces, diesel-powered vehicles, forest fires, and coke ovens. IP has been measured In soot at 1$ np/kg. in coal tar pitch at 7300-8300 ng/kg, and In petroleum asphalt at 1 ng/kg. It has also been. Isolated In smoke f.-om clgaretter at concentrations ranging from O.a >g to 2.0 vg/clgarette. Fresh sausages contained 0.3 wg/kg, and low levels (0.9-1.6 ug/kg) have been detected In edible oils. The 1979 National Occupational Hazard Survey has estimated that about 210,000 workers were exposed to PAHs found In asphalt, coal-tar and pitch volatiles, and coke oven emissions, all of which contain IP. An unspecified number of workers n~ be exposed to IP In the byproducts of combustion from fuel oil, diesel fuel, kerosene, and wood. The EPA has Included IP on the Carcinogen Assessment Group list of carcinogens. EPA regulates IP under the Resource Conservation and Recovery Act. Under the Toxic fubstances Control Act, 8(a), CPA Is proposing the reporting of process end use data, and under the Clean Hater Act the Agency published a water quality criteria for the protection of human health. 170 HONS 025771 |MIM< | ,t tt'T.VIMI Nfd*llu <M tthar ictim Ifftct #f lunlitUv; war Cmnmi KM, Wt>NMi UjKM *** ihmu, MttM*. M la.tl rail* tm ( MMW *f IM If If MMl l*f M Mf|fVmifNlllf mil'MMU. Alt* frtlfWWI Mil tMMM UllUNI NMiiMm * mm. frwifiiH Mm'***** mm tMwi: iwiiiiy. llltMl |M*ttr MM * af IMUll Mitt*. IW, Mill lUMIH UMtt`f Ml* rwlrUf fnctu tm M au imm. wM. If tMwiyatM. mlt * Mil* Nr ttlaait*| a*mm. lit tMlMfM lllWINM (Mf IMM** MK t*MMflMMllwVMf. 0*. J*Mlll MK MiMM ni#rt| MftllMi * HmI Nm. n/ttm. taw (IIMUk af ItftlttiM 5 VI 1*1.It, Ml.13 i fa if. . IM4 s fa tit. . :mi Uf*l m H0I*S 0257?^ IKON PCXTRAN COMPLEX There It diffident evidence for the carcinogenicity of Iron dextrin complox in experiment*! animals; the evidence of carcinogenicity In hueans It Inadequate.* Iron dextrin complex his carcinogenic to mice and rats after subcutaneous or intramuscular Injection, producing locsl tumors.2 There have been case reports of sarcomas In human subjects asaoclated with Injections or Iron dextrin. The tumors appeared at the probable site of injections, and the similarity of the local tifeet In humans and animals wit noted.1 1 International Agency for Research on Cancer. IAAC Monogiaphs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Moncnrapns on the Evaluation of the Carcinogenic Risk of Chemicals'to Man. Vol. 2. Lyon, France: IARC. 197], pp. 161-78. Iron dextrin Is a complex af ferric hydroxide with de.tran. Oextrans are polysaccharides produced hy bacterial action on sucrose. Iron dextrin complex Is used for parenteral treatment of iron-deficiency anemia In humans and baby pigs. The product for human use Is a sterile, dark-brown colloldol solution in saline. The products designed for animal use ore more concentrated. The Iron dextrin conplvx was Introduced in the United States In 19S7. There Is no record of current U.S. production, although It Is known to be produced by two msnufacturers. Iron dextrin is available as two prescription Items, Chromagen-0 and Imferon. In 198C, 30,000 prescriptions were dispensed by pharmacies. The therapeutic dose for humans Is 1-5 ml 150-250 mg Iron) dally by deep Intramuscular Injection. Use Is advised solely for those patients who have not responded to oral adnlnlstrstlon o. Iren. Clear warning of potential Injection-site sarcoma Is included with the physician's package insert. The EPA has classified iron dextrin as a haiardous waste constituent and regulates environmental release under the Resource Conservation and Recovery Act. The FDA approved Iron dextrin in 1974 and regulates this substance as a drug under the Federal Food, Orug. and Cosmetic Act. 172 MON 3 025773 IrM NitrH CavUi KMMIOai MfaWtltM M Otfcar Actftat Cffact if Ctnar Uaaiti m nrrtM KtlM. 1 IN** li (wiMf aratacti wn* 9X JartMKtlaa. (CMC) KM, MOI'MM: imjttti NIU Ifr-KNirilHlN MIMt. 1*4 Mtll r**|. twi la aacatt T 1000 if ta m N4ft/*4WOHln nplnanti. IIm at NiKtaif (Nitluwt of hm. Maiut Inm ta aaatafa lilt aaatraa art wejact > tat laa raoalraaaatt. 2ramlata4 S/12/00. la* UnlNfa* Imirnut Orava ttataaaat a**r l-acttrlaaliiaflaartaa. KM) Malataay Mtarltirt MCI. Oartaa at )Nfi fti<raaa af Vatarfaanr iMftw rayaitua aa aa mum aatMPlat ' iNt. KM) Ota llaftaO ta Iraa Oaftctaacr mat aat aat rtnaM ta ara) trtataaatt. Otar vamlay af pata*clal tajactfa*> alta knm It farlaJa* la afr*tiia tacfcaat fata*!. irui C'Utta* af latilatlaa to cro Mi.it, m.u KM) 40 rt. . I1WO i n, a. mm k nt, a. mm 21 CM ID.IIM, 122.)IU KM) 173 HONS 025774 ISOPROPTL ALCOHOL MANUFACTURING (STRONG ACID PROCESSi There Is sufficient evidence that the me.iufactur* of lloi-ropy! aleohrl (strong acid process) Is carcinogenic In humans.1 An Increased Incidence of cancer of the paranasal sinuses was observed In workers In factories manufacturing isopropyl alcohol by the strong-acid process. The risk of laryngeal cancer may also have beer elevated. It Is not clear which substances are responsible (dllsopropyl sulfate, Isopropyl oils, or other chemicals).1-2 'international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1992. `International Agency for Research on Cancar. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Yol. IS. Lyon, France: IARC, 1977, pp. 223-43. Coancrclal Isopropyl alcohol, a water-soluble alcohol, has been produced In the United.States since 1921. There are several Industrial processes for the manufacture of isopropyl alcohol. One process using strong sulfuric acid leaves a residue ca^osed of a mixture of ma:y organic chemicals Including Isopropyl oils. No figures art available on the guantlties of isopropyl oils formed during the manufacture of Isopropyl alcohol through the strong acid process; newer processes have been replacing the strong acid method. Tim ERA reports annual production of Isopropyl alcohol to be approximately ISO million lb. The amount of Isopropyl oils produced Is unknown. Olethyl sulfate, as well as Isopropyl oils, have been suggested as a potential causative agent for the Increased Incidence of cancer In workers manufacturing Isopropyl alcohol by the strong acid process. Approximately 50 percent of the Isopropyl alcohol Is useo in acetone pro duction. Additional commercial uses are as a solvent, as a chemical Inter mediate, and In pharmaceutical and cosmetic formulations. Human exposure Is primarily through Inhalation during the manufacture of Isopropyl alcohol. NIOJN estimates that about 141,000 employees may be exposed to Isopropyl alcohol In the United States. The EFA has no data to Indicate that Isopropyl oils are present in effluents, emissions, or wastes from production facilities. 174 HONS 025775 !Mrwyl UcfM* ftftflfMlart*f (Strmt *ct| 'mm) KUUTi*S Mfdllttwi M MMf kttwi TM MPtt<*lr MllM <tM H nwum Mft M MPtftlftc*. It l| IM'ciiftft tMt M KKfll I* Mleft lupni/l t*l| art mmm m ht*mkU ncmiimIft MUM. l.ftftft II M iMItitM Ml <|ftH||< till M fftftM I* M MMmfIKmtH. imn.mim tftftftfftftr' UMl UM> IffKt # Mfiltilmi IMP MMU t<UIM ft# Mfwlttlwi HONS 025776 175 KEPOME* (CHLORDECONE) There 1$ sufficient evidence that chlordecone Is carcinogenic In experimental animals.1-2 After administration or chlcrdeccne In th< feed, a significant tncreasa was found In tha Incidence of hepatocellular carcinomas In Osborne-Mendel rats and B6C3FI mice. In addition, tha time to datactlon of tha first hepatocellular carcinoma ooserved at death was shorter for treated than control mica, and In both senes and both species, It appeared Inversely related to the dose,' in an earlier experiment In which rats, of unspecified strain, were enposec to chlordecone In the diet, hepatocellular carcinomas were seen 1r both sexes.2 1International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to hueans. Supplement 4. Lyon, ranee: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on tie Evaluation of the Carcinogenic Risk of Chemical; to Humans. Vol. EC. Lyon, France: IARC, 1979, pp. 67-81. ^National Cancer Institute, (loassay of Chlordecone (Kepone) for Possible Carcinogenicity. WHS Publication No. (tfIK) 76-1270. Sethesda, Maryland, 1976. Chlordecone Is the common name for a synthetic chlorinated organic compound, which was commercially ava'labla under the trad* name of depone*. depone*, first introduced in I960, ha; been used as an Insecticide for ieaf-eatlng Insects, ants, and cockroaches, and as a larvlcide for Ties. depone* Is not manufactured or used In the United States. In July 197S, the Virginia State Health Department ordered termination of production by the sole manufactu-rr of depone* when a nuaber of workers were found Co hsve serious neurological disorders. Before the shutdown, the average annual production was estlmatad as 882,000 lb. More than 99 percent of the production was exported, and only 0.8 percent was available for domestic use, mainly as bait In ant traps. Chlordecone Is a degradation product of the insecticide mirex. This compound has been detected In vil at a level of 0.02 vg/g of soil 12 years aftar application cf 1 ug/g mirex. In the United States, detectable levels of kepone* have been found In 400 samoles of air, drinking water, olant and aquatic life, and municipal waste wnere Kepone* was manufactured. 176 MOWS 025777 Hunan exposure tc chlordecone can occur b> inhalation, ingestion, and skin absorption. There art nan/ reports of its occurrence In Hunan body fluids. In 1976. NIOSH Had Identified SO establishuents processing or fomulatlng pesticides using Kepoe" (chlordtconei, and Had estlnated tHat about 600 workers vert potentially exposed. In 1977, fomulttors of KeponeJ voluntarily canceled prud.ictfon. CPA canceled the registration of keponcn under its federal Insecticide, Fungicide, and Rodent1cIdt nandatt. Ail registered products containing kepone* w're effectively canceled by May 1, 1978. Distribution; sale, and use of keponc' products roroulatcd prior to Hay 1, 1978, were penal tied until such stocks vtre exhausted. CPA Has also regulated this cimpound under the Clean water Act and the Resource Conservation and Recovery Act. On January 27, 1976, NIOSM recoanended that the workplace level for Kepone- be Halted to 1 ug/3 as a tiae-weighted average concentration for up to 10 novrs/t.orkday, 49 hours/workweek. iiiw1 tcatvmcww) afWUttMS hftltKM M lutr AcIltdH H ttfWK Kl<9R. M lMu yiMRCI Iff WMKRf FMU M|p UK 'MtMtCtlM. (UKI if Myiiiiitn; CtMr Umntt CfUtfM If tffil* :*M CM, 111; lilt M9 Will fMdUtlw 61M- 111* 1*1 WNTUlli MMttt? 11 It. MM If! |R4 tMtltM rtftrltaf rM<MM*U. tM* M>fMM rtru. i: wMtdw (miiuimri of pnam\ trm wwn. mhi irwi w CMtl MHMH l/ll//>: W< Mll8W< Hr) iRtHlUI. KM. J90l)60*: Mint MIU 8K8i(tt, iflvIfR'IKlI'M MURW. #M M'll Ml*- Ml | Mill If IM M IW WN9t/fK8fPWM WWfftNlU. *) MII|NUt llllW* || WUfMI NRItlfl* Ml 9f HIM, M W*lWlt Mill ** W NttIM II It IM MM ftWlMdRII, *** Wlfl'H VIVCC. 1M (*tlMM* *WMMRt irftp* llltMRt Mr WM at WiH w MnlwWiUlV. illWgf tM MMtflf irfawnif rwri!ii| MilrMRtt it *8tl tiflhfml wajp Hitt ryll. MC'ltriMl MM t Nil Mt It If MtlW iwr9**ll iflir i NtMiai- lM Ml Mr rt|t 6/ CRcr MU> t* M<y ItMl KMMMMM sMlIlil HMfl fr MWW*. \ m* fir it *r/Mr, t wiwrtwi. ICICS*) <C CM JIM, IIM) l r. $. jim 1 fi ii. i, iMrt <|M. 177 HONS 025778 LEAD ACETATE AND LEAD PHOSPHATE There It sufficient evidence for the carcinogenicity of lead acetate and Itid phosphate tn experimental intuits.1 Ltid cetitt and ltid phosphate irt carcinogenic to rits, producing btntgn md nittgnint tutors of tht kidney whtn administered In tht dltt or parenteratly. Gliomas occurred In rats given lead acetate In the dtat.2 ^International Agency for Research on Canctr. IARC Honogriphs on tht Eviluatton of the Carcinogenic Risk of Chemicals to Humans. Suoplement 4. Lyon. Prance: IARC, 198?. `International Agency for Research on Cancer. IARC Monograohs on tht Evaluation of tht Carclnogtnlc Risk of Chemicals to Humans. Vol. 23. Lyon, France: IARC, 1980, pp. 325-415. Ltad acetate Is water soluble. Lead phosphate Is a white powder Insoluble tn water. Lead acetate Is usually available commercially as hydrate (lead acetate trlhydrata). lead acetate Is used as a mordant In cotton dyes; In lead coating of metals; as a drier In paints, varnishes, and pigment Inks; and In medlctnels such as astringents. Concentrations up to 0.6 percent (weight to volume) are limited for use as color additives Is hair dyes. For 1978, sales of lead acetate hair dyes esceeded 1 million bottles. Lend phosphate Is used as a stability In styrene and casein plastics. In 1980, seven producers In three EPA regions reported domestic produc tion levels of lead acetate to be approximately 407,000 1b. U.S. Imports of lead acetate In 1978 were estimated at 2S0 1b. Imports In 197$ were approx imately 6000 16. No prrductlen figures were reported for lead phosphate, but the Toxic Substances Control Act, Chemical Substance Ir.-entory, 1979 ihium'c record, lists two producers. Human exposure to load acetate and lead phosphate occurs through Inges tion. Inhalation, snd skin absorption. Lead acetate Is absorbed at about 1.6 times the rate of other lead compounds. The National Occupational Hazard Survey (NOUS) In 1974 has estimated that 132,000 and 18,000 workers may have been exposed to lead ecetate and ltad phosphate, respectively. OSHA has estimated that 223,O^O workers may be exposed to lead acecate, with 28,000 and 27,000 workers exposed to lead phosphate dibasic and lead piiosphate trlbaslc, respectively. NWS and OSHA numbers vary due to the difference In methodology used for estimating exposure. 178 HONS 025779 The Consumer Product Safety Consulssion .'CPSC) has tunned paint end similar surface-coating uuterluls for use in consuuer products thot contain lead or leud compounds In uftten tne lead content Is In excess of 0.06 percent f the weight of the product. This bun deludes artists' paints and related materials. CPSC staff evaluated consuuer exposure to lead Inks In printed consumer products. No lead was found In printed natter Intended for children. Although lead .as found In some Inks used In printed products, the levels In the final products did not warrant further action. The C`SC staff Indicated that there was little lead found In other printed consuuer products. FUA regulates the use of lead acetate In hair dyes under the Food, Orug, and Cosmetic Act. EPA -ejulatvs lead and certain lead compounds under :he Resource Conser vation and Recovery Act (RCR*i, the Clean Water Act (CWA), and the Safe Drinking Water Act (SOWA). The dissociated lead addressed In these regulations would provide a degree of control over many lead corpounds. Including lead acetate and lead phosphate. CWA hat published a water guality criteria document for the protection of huuen health. Under RCRA, the EPA established a maxima concentration of SO ug/1 in wastes for the protection of health. Under SOWA, a primary drinking water standard of O.OS mg/1 was published December 24, 1J75. This standard was not based on carcinogenicity. OSNA has established permissible exposure levels of SO og/m3 as an l-hour timeweighted average and CO ug/100 g as the maximum permissible blood lead level. In addition, the standard requires personal protective equipment, engineering and work practice controls, and medical surveillance with provisions for medical removal. OSHA regulates lead on the basis of acute am! chronic toxic 1*7 for several ergan systems, but not on the basis of carcinogenicity. 179 MOMS 025780 UM IN Itll NlWtt uwurtois IlfNWtlWl AM Itktr JktlMi (flKt Af lAfll.ttNIi OtMr CMAtts Clutltt Af IffAlAtlAt I* If)} tM UN NlN )|<M )ri.UW Act Mt 1 il Mf((M HtH flf UN *t NUU. I IAN, UN A Ml CH II Mt tM tUNiN *t J.04 Mfttit; tMi Halt wm rrtl t flNVy |l. iMIf M NMt KtlN. CC^SCI liHUN *41 Mtt rNucN, MIN At it# lAstr Haiti AiltvAf It fflttl. am r lAAA ACAtAt* In IMS l KMsIll f#r tcrM**tf. ICflC) if cr DO) (CMC) SUM: UlNClNH llM. Prltrf itAMerf f I.OS t|/i, rMifiui KM, MI'XMi MjNlt att )NWti, ff-lftClHotll* MUIAI. M IfMl rcit* AMI l AAttll 0* 1M If II MM)Ilf AM ftOfft/flCffllfllf NNlNWItl, till KtlMtlt Oft! II MiirNM CAtttlttAttl Of anm. OMMlfltM 1/llflO. "AllftitM ft title WIN. WwlNI tAtlltf If NtmlN If util lM nmN tut IMNUIIIM. fpfMlfltM t/lt/to. CM. SH'a): Mtfr CMHHr crlttrlf Mill IMA II IinI fin, li'HVOC. CM, 111: NaiaNAai iflll rtfflttlfi ilMtluiN rtAtrUAlA fMttlty fir lN ACAtitt (MOO II) AM MWIIt rtNfl!| PMil'MMU. frMl|ltM I/2VI9. UfM, I; LAM ACCtftA Ml PtvlAMl fff Oflllllt Mf*l4tl4t AMAf flFV. 1* NHI 19'i, IVAtlflCMM Ml MIIM 14 HA (Mr < AfrAAMtt lift tM 4A4lltr*t4 Alt Ml A 4 MttrltffY 4r*A. .CM! Mt AAlAf A* CAftlMflwICHy MjAr IMNAI 9* 1<M It ArlMIty Mt*r AAfAtri tA A* flfAl, MtfAr, Atf flttartl 1* tM AlAtrtNtltt ijitAt. 10 Cfl 141.11 40 CfK HI.11. HI M CltAOlllMl A IMlM CAtCtttTAtlAt |f M N/1 ti KAitH Al crUertfA ftr Miltl (MMA At fAAtrel MaKHfl. BfCAtlA IaaA AtlMClAtAI It 4t*T, AM Atf IUMAN MilA AlflN MM NAtril A*tr tM AAtll CMtlcAl. ftltAri frfAttr CAM 1* MMlItf AM ill)* fltf Af ClMlCAll. lAIAf At MAAtlC tMl<ltr< (CM) 40 CTI HI.H r| n SSI. A. ?*)) 40 Cf* 1IM. 111..) ON, SUfAl lAMrti (IM) IN IjTHi if 0rfl. IlfCA: LMttt 1A KftftA It Mir Ml U 0.4 Nftlft (Mlflt tl M)Ml. tOMl.OO. 1*1 IIIUI tM ACftItf NMNNU fAT AM It Mir fri, l.l/fl. iron 41 FI, . Mill ii cr i)i .tiff HIM Hi: M l*M tu, to f/1M f illllN I'.AAA >tM vtl. IrMKtUl OMMM, UyflfM. %r)*>ltf, AM Mfllll MTMlIlAtC* MMlrMtttl ftr min; rmintif nninmni MM rtflMfrltf AM *N NKtltl AAttnll Mt MfflClAtt K IaaiUIa; Hfl MMlrUMU In NflUtN ama; atflctl fAMAl; imam KMAtlft (Iff IA441. (OfrAI IaaaI AtAfjr Ntttf'y: A/1V7I: 0$M TAAVAMf }UMrA }00 M.'*3 l-*r ru. }/l/)t: riM) ttiMAficNNtt rtfhlAtlAM AffACtlM (ftr IaaA). (OJMI H Cfl 1910 1029 I09MAI 180 HONS 025781 LI WANE AND OTHER HEXACHIOROCYCIOHEXANE ISOKErtj Tht evidence for tht carcinogenicity of lindane and other hexachlorocyclohexane Isomers In experimental animals was judged as limited by a recent IARC working group.1 Another working group considered thjt there was suffici-nt evidence that a-HCH, lindane, end technical HCH are carcinogenic In mice, but the evidence for the carcinogenicity of d-KCH was evaluated as Halted.' Technical and p-hexachlorocyclohexane and lindane, the r-lsoaer, were carcinogenic In alee when adminis tered In the diet, producing liver tumors. The technical-grate hexachtorocyclol.e<ene also produced neoplasms. Studies in rats and dogs were considered to 0* Inadequate, and so were tests by Skin application of technical hesachlorecyclohexane and lindane. Hexachlorocyctohexane Increased the Incidence of liver neoplasms In rats previously treated wltli R-nltrosodtethylantne.l.' Thy evidence for the carcinogenic ty of lindane a.id other hexechlorccyctoheiane Isomers In humans was judged as Inadequate.1 1 Internet Iona I Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement I. Lyon, France: IARC. 1983. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 30. Lyon, rrsnee: IARC, 1979, pp. 195-339. Llnda.it is the common name for the game 1 sneer of hexachlorocyclohexane (HCH). Technical-grade HCH Is a mixture of different Isomers. Lindane Is a colorless crystalline solid with a solubility of 11 mg/1 In water. Approximately 95 percent of the lindane and Its Isomers used In 1974 was In egr I culture -itr. the ~ 'i --C" ..sec uy -r.c-stry. ..'.a -ajcr use, o: .'.r.caur are for Insecticidal treatment of nardwoed logs and lumber, seed grains, and livestock; the minor uses are as an insecticide on several doten fruit and vegetable crops and .or personal hygiene (as a scatlcide and pediculocide) In the form of lotion, cream, or shampoo. Commercial production of lindane began In the United States in 1945 and ceased la 1976. Since 1976 linden; has been Imported In an undisclosed amount. Froductlon o; lindane.peaked in the 1950s when 15 million lb were manufactured. The chemical is rot reported to the Toxic Substances Control Act, Chemical Substance Inventory, 1979 (public record); however, ERA In 1980 estimated that 1 million lb of lindane were used annually. 1M HONS 025782 Approximately <80,000 workers were occupationally exposed to these swbstences prior to Agency regulations 11977), which Imposed Munitions on uses, Worfcpliee end residence use sites were primarily of concern as soirees of exposure. Pesticide applicators were at highest risk of exposure to lindane. The general population Is at risk of exposure through the consumption of contaminated foodstuff. Major dietary sources Include milk, eggs, da^ry products, and, to a lesser extent, seafood. The dietary Intake of lindane and Its Isomers by the U.S. population has been estimated to be In trace quantities with a significant, steady decline. CPA has regulatory authority over the use of lindane and Its Isomers. CPA has proposed to limit exposure to lindane by canceling registration for all uses except on ornamentals, pineapples, livestock, and logs. The proposed action Is scheduled to result In approximately an CO percent reduction of tho total estimated annual usago of 1 million lb. Continued use for the few permissible registrations would be restricted to certified personnel wearing appropriate protective clothing. CPA designated hcxach1orocyc1ohexane as a toxic waste constituent. The Agency established a maximum concentration of 0.4 mg/1 In wastes. During 1975, CPA promulgated drinking water standards limiting maximum contaminant levels to 0.004 mg/1. 0$HA adopted a permissible exposure limit for lindane of 0.5 mg/an as an 8-hour time-weighted average. This standard was adopted by OSHA for toxic effects other than cancer and noted lindane's potential for skin absorption. 1R2 025783 HONS 11 Ml** |M )|k(P * K^aracrc laaa'I1** IlIMfl *cuur:oas *atttiaai h (imp kmi IMnt 9* IfialitlMi; 9tatf >;m*ii eitjt'a* af itiliiii f*Wt I8M tflllKI Ifl (Mtnr KMvttl '.W jwmaicva*. ICMCI Mm. I: */U :ma t/U/. U">un mIIwn f/1/99. KM, MUNMi *aHm UIIII M KM"Mri ! hnw mim itataa 'pfkldtM l/ll/M. hljttu Htli irmrU. iffMNtIHuifN MKM1. IM l#'l PHXiN ' 8at8*l f UK || 90 tiMOlt'NyCrNPM l*4MC< M#0 tiawft) Ct aaatiaf rt TMft mvtNiN piwnmtt. :m m<f* wtn miMtlMmintHw m a niipiwi *f NttM< HiatlllH Mmwm av yixiPi ta af maam tamt 'aHr i w l l, lam fa mm m acayntiaa a< taatficacr ft MfMN IMMH. >ntiM eancaMattM a# Uni ff mu mi. ipmum I'ittt Mm* a< ar *t * layi in mpmm. HlllNUI IIN1N as * Malt ata. tlUtlliMl a miimi taaca*trat<M af 1.1 M/I af llama > aa:a n a critariaa far tMicttr* 1 M. >. Mil i a in, I. $m era Mi.) o era m.u. ni.u rim, 4: MtiPr tamiiatta* a 'ItUVrtlKN ail rnwn 711*1 WlllMIW IlMPI if <N, '/Il'TI. IM-4M i . < . < (*CtM* mMfl t* M(*l. CM, JM(a1: alt* (>' PUIp'i Mllwf llM/W. MINIMI * immh, #M Mtiw'tal ypM arMMCU. CM, 111: aaiarlMt mil *ni<ni ItMlIlMI M',.ll* M*ttl ". 1), I.lja Ml IM 48M. l/ll/M. CM, lUl MIIHM Mill malatM* MllMlIll nrt|*lf MDtllr, IHM1H, tnm imacltrtt,tI waataa mm mm HnMM). M. MU: Waam ri*i mik iuNN. MMlfllN 0M, MU: V*Ua* af teiaaim a-a* MMin * mImm*(. :tMi ar*aMaria *tt ia jrmtl 'aaffactm* mi f 'Nm4ii*ii. 4:. uu 49 m. a. MM man* Muutr. Mtt atp*mA* '*>. *****. fatltn tmtap am 'a maitaf **t i*a>1*9 af cMMMali. Mlt m o :rt 4% 7* *.)). f. MOM Maim n*t*i*al >aa> af 4.2C' a#-" auaaMMM. Sinati tai'cttr *a wm mnaMi. tiMM far aflNlll. 1/1). HMI o era ui.u 9M, WIM. I/ll Ma> Kli . nni ** **: Mtamal ft* mm MwrtttM mIM Hlatml. (hMH T ItM *t Ma*< HlKlI Mf MM nCr.i (HMI MM '(Mm' lianaanwwt iirnt tfittma. I4SMI 11 *M illl.lCN tttNAl 183 MONS 075784 ICIPHALAM Thr* It sufficient evidence for the carcinogenicity of nelphelen In humans tnd In ezperimental animals.1 Melphalan It carcino genic In nice end rets following Intraperltnnejl Injection, producing lymphosarcomas, a dose-related Increase In lung tumors In nice, and peritoneal sarcomas In rats.' Case reports of second primary malignancies (mainly acute leukemia) In patients treated with melphalan have been published. Epidemiological studies showed substantially Increased rates of leukemia In patients treated with melphalan for multiple breloma and ovarian cancer. Some of these patients were also treated with other alkylating agents and Ionizing radiation; however, sufficient numbers of patients were treated with melpnalan alone to Implicate It as the causal factor, addi tionally, the incidence of acute leukemia in patients with multiple agrelona has Increased stria the Introduction of nelphalan therapy.2 ^International Agency for Research on Cancer. 1AAC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vot. 9. Lyon, Franca: IARC, 197$, pp. 147-80. Melphalan Is a nitrogen mustard that Is practically Insoluble In water. This drug Is used In the treatment of multiple myeloma and cancer of the ovary. It Is also used In Investigation on other types of cancer and as an antlneoplrst:1: '> *nir;is Melphalan Is not produced In the United States, although one .larketer In the United SUtes has been reported. In 1979 , 3000 lb were Imported. Human erposure to melphalan occurs principally during Its use In cancer treatment. FDA estimates that 30.000 to $0,000 patients nay be treated each year. Melphalan Is administered orally or Intravenously. Adult dose rate Is 6 mg per day, S days oer month. Melphalan has been approved by the FDA for treatment of myeloma and epithelial ovarian cancer. For certain other cancers. It has been approved for Investigational use only. As with other potent antlneoplastlc agents, the likelihood of these drugs being carcinogenic Is not surprising, and Its Clinical use recognizes that risk by Its restrictive approved clinical Indications. EPA regulates melphalan under the Resource Conservation and Recovery Act. ' 184 MOMS 025785 %t|ha>ia aceuuriONS iati*tta*t m4 itMf ActtMf IffKt If IlflllttMli war CaanaaU (Haifa* if B*fniitiaa la nm*t Milan. n immi tn (Wliwr ffMMU WMf t^c JvrtM'Ct'**. ICTSCI KU MINKi MiKtl *aita ifimw, fr-tMCfflOtlM l* wit! ttfll* 4m Ht mm i! 1COO it to MMltftf * min/i>.mwii iwimmi. ItM MlfMtM M MMMNI CMttUMM tl Mill, Mi MjMtl HSttt IMM* lb NMli* It IB tfc* MM iWitn* mti. IrwIytWB 1/lt/tO. Im MmiMit Inti ititMit mmp l-Katyt--ImOmwm. tWIt m era hi.u. iii.iJ (K4*l m Mm if Hfi, ItlUi iimi< n| fir triitam if ri>m MM ftlBtl Ml MBrian emir. Iwilttfl* tIMl MB Mltjr *Bf MMlM MMf (mm. (OM) Vw mtrictM ta Imw if Iwm-HfriMf ViiwmW la iltt aWar pamt wtn^* llMik fa*t$. tM mtrtctM aa INrtta MIMIHI dal ib 4a fatla-u crwi t*i i\ Iiiomw i tm) les HONS 02S76 4,4' -HETHYLEMEbIS!2-fHLGAOANlllNE I (MOCA) Thtrt ts sufficient evidence for the carcinogenicity of 4,4'-wethylanebt s(2-ch'oroanllIne) tn experimental wImIsJ 4,4'-Methylene01s(2-chloroan11ine) was carcinoma-1c In nice and rats (several strains) after dietary adalnlstration, producing vascular, liver and lung tumors. It also produced distant tumors ,'llvtr cell carcinomas and primary lung carcinomas) In Ulster rats after subcutaneous Injection.* There art no conclusive epidemiological studies on which the evaluation of Iwaan carcinogenic risk could be based. In t study of 11 men, whose exposure to MOCA ranged from 6 months to 1( years, no cytologlcal evidence was found of bladder cancer. In addition, 17S ether MOCA workers with unstated duration of exposure were also examined cytologlcally more than 10 years after exposure had ceased, and no cases of bladder cancer were found.* ^International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to ,burner,s. Supplement 4. Lyon, France: 1ARC, 1962. `International Agency for Research or Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man Vol. 4. Lyon, France: IARC, 1974, pp. 65-71. 4,4'-Methy1eneb1s(2-ch1oroan111ne), an aromatic amine. It comaonly referred to as MOCA. It Is only slightly soluble in water, but soluble In most organic solvents end lipids. MOCA Is commercially available In pellet, liquid, and granular fore, and as a pramlied compound with pol.vhydrlc alcohols. MOCA has been used as a curing agent In urethane and epoxy resin systems containing Isocyanates, which are utilised In the manufacture of certain products, particularly Integral-skin polyurethrnc semirigid foam for crash padding, and solid urethane rubber moldings, such as gear blanks and Industrial tires. It Is also constSHd In the manufacture of gun mounts, jut engine turbine blades, radar systems, and home sppllances. In tie laboratory, MOCA has been regarded as a model compound In the study of carcinogens. Production of MOCA was first reported to the U.S. Tariff (mission tn 19SC. CPA estimated five producers and Importers of MOCA In two regions, with a domestic production of 149,000 lb; no Imports were reported (Toxic Substances Control Act (TSCA) Inventory, 1*77, public record). MOCA wes not reported to the U.S. International Trade emission In I960; however. 186 HONS 025767 production of MCCA wit Indlctted In 1979 by two producers, whlcn Implied in ennuil production of sort thin 19,000 lb. The 1902 Directory of Chemicil Producers InCIcttes thit one U.S. ecmpiny now produce: MOCA. CPSC Indlcited only one U.S. minuficturer of MOCA is of 1981. The CPSC stiff stited thit reslduil levels of MOCA niy be present In the flnil product. However, diti describing the ictuil levels of Impurities md the pntent111 for consuner exposure ire currently licking. The Nitlonil Occupit1on.il Hmrd Survey In 1974 estlmited thit 33,000 workers ere potenttilly expesed to MOCA. When used it I curing igent, MOCA Is melted before m'xlng Into elut er formulltlons end could possibly be volittltied inj emitted Into wiste gises nd vistevtter from plints where It Is being used. In 1971, MOCA wes delected In ill smells of loll tint were obtifned within e three-quirters milt ndlus of I ehemtcil plint In Adrlin, Mlchigm. Some imples token from soil on public roids In the irei conuined more thin SCO ppm MOCA. Sludge from the Adrien westewiter treitnent plint contained is much is 80 ppm MOCA, whereis simples of slodgc citilned from tho Industr'il ligoon conuined 2000 rpm. Urine from workers it tho plMt conuined levels is high is 49 ppm t.f MCCA per liter of urine. Currently MICA Is regulited by CPA wider tho Resource Conservitlon end Recovery Act, md regjiltlon Is proposed under TSCA, 8(i), thit would provide deUlled production Md mrtetlng dnU. N10SM Issued i Speclil Huird Review on MOCA In 1978, recommending sUndird of 3 ng/m? time-weighted ivenge The OSHA SUndird for MOCA wts suspended by court ictlon In 1971. 187 HONS 025788 (MOCA) USUUTtQNS tafvUttortt M- GtMr Klim Iffoct of Aifvlatioas; Other CoMoonts Citation of Atfolatioo N nrfwt action. imo O0U, JOOIOuOlt ofNSMClftcotlm hotchos mti m4wta, M still mtswi to Mttl *f 1000 kf to MMttaf on* uml/ noflnaisti. Also oiilfMtii cMofesl n s OtssfOovs cmtitom of mu. FromtfitoO S/ll/00. TSCA, Mats looortloo rvlt rtoolrlof oroeoss Ml ost otta, mmH t/29/90. UFA) lototooco KikllfM fron oso to Imm lofolstloo hosoC on cmmK tootolty of cuoalesl. fostors ffMtor coif to kdtflfof of chorteol oostos. 40 Cf* XC1.U. Hl. Houle orovlAo s Oostor hosts for ostlmtlof tsoosirs fotontial, hick mst It coosfOoroo aloof vtto risk to Ostomtolof soorspristooost Of iffvlatory or ether control actloo. H| os n. 9. ijcoi (tIM 21 CM 100 (FM) toolotofy Mttryt S/J/71: Imrfiocjr Tsiorsry StOnOor*--ffltOCtlvt CllthlOf too Ipylm roftlroaontt for onttn, rostrlettoos on ooo>*oisoi om** tloos. ooflnoortof roootroarics. 1/29/71: aovtscC stonCor* fromlfotoC. (2/7774: .$. '*in of tooools omoooO lUMtri. 10SNAI mom fscs--smio s ivimn of 9 a#/*3 tua. (moot) Sooclol NscsrC Sofiew, 1970 (otosm HONS 025709 4,4'-METHlENeiS<h,N-DIMErHrL)8f't2ENAMINE 4,4'-Methyleneb1s(N,N-dtce:hyl)berzenam1ne, administered In the feed, mi carcinogenic In nelt end female Fisci.cr 344 rati. Inducing thyroid follicular-cell carcinomas, and In female B6C3F1 mice, causing a combination of hepatocellular carcinomas and hepatocellular adenomas. There was no conclusive evidence that 4,4'-methyle.<ebis(N,N-d1methy) Ibenzenaminc was carcinogenic In male BSC3F1 mice.I An IAAC working group considered that there was Halted evidence for the carcinogenicity of this substance In experimental animals.2 In view of another evalua tion the evidence can be regarded as sufficient.3 `National Cancer Institute. Bioassay of 4,4'-Methy)eneblsIN.N-dlmcthyDbenrenamlne for Possible Carcinogenicity. Technical Report Ser'es No. IBB. DHEW Publication No. (NIH) 78-1742. Bethesda, Maryland, 1979. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 27. Iyon, France: IARC, 1982, pp. 119-24. ACrlesemer, R.A., and C. Cueto. Toward a Classification Scheme for Oegrees of Eapertaental Evidence for the Carcino genicity of Chemicals for Animals. In: R. Monteseno. H. lartsch, and l. Tcmatts (eds.l. Molecular and Cellular Aspects of Carcinogen Screening Tests, lAP.C Scientific Publi cations, No. 27. Lyon, Fra-ice: International Agency for Research on Cancer, 19C0, pp. 2S9-81. 4,4'-Methylenebls(N,N-dlmethyl)bentenem1ne, commonly referred to as Mlchler's base,' Is an aromatic amine. It is insoluble in water and soluble In benaat.e, acids, diethyl ether, and carbon disulfide. Hlcniers oase is used as an intermediate In dye manufacture ano as an analytical reagent In the determination of lead. The Society of Oyers and Colourists reported that six dyes and one pigment can be prepared from the chemical. In <979, only one of the dyes, Basic fellow 2, was being produced commercially by two companies. Mlchler's base has been commercially produced In the United States since at least 1921. EPA estimated five producers and Importers In two regions, with domestic product ion reported as 370,000 lb, and no imports (Toxic Sub stances Control Act (TSCA), Chemical Substance Inventory, 1979, public record). (I.S. production of Mlchler's base was reported to the U.S. International Trade Commission as greater than 10,000 lb In 1980. 189 025*90 *OHS According to the CP SC stiff, It Is possible that sesldual levels of Mlchler's base may b prtscnt In the final consumr product. Exposure tvtn to trice mounts My bf I cius* for concern. This concern Is based on expert met with other dyes derived froe iroMtlc mines. However, diti describing the actual levels of Impurities In the final product are currently not available. The potential for exposure Is greatest among workers In the dye and chemical manufacturing Industries. In 1974, the National Occupational Hazard Survey estimated that 1(00 workers were potentially exposed to Htchler's base. CPA Is proposing a reporting rule for Mlchler's base under TSCA, 8(a). KMUriM HillKM M ItMf l(1lM tffut of luplitlnii Mr Cmimi (UlM f l*tllHlM M limit actlw. tMCI IIU, Mtlt >Wftn nit rvwHrtcf mmi M M MU. pr-MIt t/tl/Mv uni MU #rtM i MMr Mala n> ;iaitii 8nmn wntni. *!* MM M mtlMM llaiey Plot rlM la aitmlalif awnyliMnM #f r*Ml***ry or iMf cisirgl Mtln. an) ai ft. . umi itn; 190 HONS 025791 HlCHtER'S KETONE Hlchler's Ketone, adalnlstered In the feed, wit carcinogenic In Ml* and faMle Pitcher 344 rata and fnile I6C3F1 nice, cautlnj hepatocellular carcinomas; In Mle I8C3F1 alee It produced htmanglosarcomes.1 Theta result' can be contldered at providing tufflclent evidence for the carcinogenicity of Hlchler's Ketone tn experimental animals.* 'National uncar Initltute. II oatlay of Hlchler's Ketone for Rosslble Carcinogenicity* Technical Report Serial No. 161. DHEV Publication No. (N1H) 76-1737. letheida, Maryland. ,1971. `Grtesemer, R.4.. and C. (veto. Toward a Claltlflcatlon Scheme for Oegreet of Experlaental Evidence for the Carcino- enlclty of Chealcalt for Animals. In; Hontettno, K. Sartsch, and L. Toaatlt (edt.l. Holecnlar and Cellular Aspects of Carcinogen Screening Tettt, 1ARC Scientific Publi cation!, No. 27. Lyo*. France: international Agenry fer Rotaarch on Cancer, 1160, pp. 759-81. Ml chier't ketone, a derivative of dtaetkylant line, It an aroaatlc aalne, which It practically Intoluble In water. Hlchler't ketone It uted at a chaalcal Interaedlate in tne tynthetlt of at least 13 dyet and plpaents, otpcclally suramin* derlvatlvet. ERA reported 10 producert and foportert In three region!, with a domestic production of 37,000 lb and Import! of 37,000 1b (Tcalc Substances Contrsl Act (TSCA), Chemical Substances Inventory, 1979, public record). One domestic producer manufactured a ouantlty Insufficient for reporting tv the U.S. International Trade Commission In i979-1980. but Imports of Hlchler't ketone amounted to 40,000 lb In 1900. Hunan exposure to Hlchler's ketone may occur through Inhalation and skin absorption. Occupational exposure It greatest for workers <r facilities that manufacture the compounds or any of the dyestuffs for which Nlchler's ketone Is an Intermediate. In 1974, the National Occupational Hazard Survey made no estimate on potential worker exposure to Hlchler't ketone liUOSH). . Residual levels or trace Impurities of Hlchler't ketone nay possibly be present In some dyes baaed on this chemical and In the final consuaer product. Exposure even to trace aawunts may be a cause for concern. This concern Is bated on the experience with other dyes derived from aromatic ami net. Oata are Inadepuate to describe the actual levels of Impurities In the final product, the potential for censuser exposure, and the uptake. ERA now regulates Hlchler't ketone under the Resource Conservation and Recovery Act and has proposed regulation under the Toxic Substances Control Act, dial. 191 HONS 025792 "Itlilfr'i Bt*n* K6MJITIMS MfnlitlMl iM OtMr ktlwi ** evrrtnt *ctt**. IOK) RU, )OOI*MMt MjKtl *ff-m<1fcitl*n IIUDH, MIU pfNMtl, * Off 11 W1IMI In MCtlf * 1000 kf U M4*119 ** iwt/ m**Mtft*9 rtwinaiJiu. All* *i1MCt* CMM|1 H 1 MtlN*vt C**lt1tMftt *4 *1111. 1/19/10. TSCA. I(ih l*t*ftU| mlt rtkvfrtftf pt*c*M **0 *M MU, *p***M l/lf/00. PA) tf<K\ *f Ufvt**1***; OtMf C****U out;** If l*fw1*tt*R MflllllM Ml** M c****tc U*Utty. f*<t** fft.tar (if* in knnoilnf #f CMatul Mtl. 40 Cfl tfl.11. rtl.Ji Hull frtvIM 1 Mttof Mill fir (IMWfl MtmtUl, M<k kit ft c**|tMr0 Ii*nf vft rlit ll HinprUtMtll *f flflllUf)i *r Itiff (Wtril ictlM. KM) i\ ft. |. \MH tin) 192 HONS 025793 MI REX There Is sufficient evidence thet mires Is carcinogenic In experhnentel animals.1 Mires hes been tested in too strilns of nice by garage end by administration In the diet end In rets by administration In the diet. It hes elso been tested In two strelns of nice by suhcutencous injection of single doses. In tne studies using orel ednlnlstration, It produced benign end Mlignent I'ver tienors in mice end rets of both tenet- An excess of liver tumors was elso found In Mies of one of the two strelns of mice following single SJbcuteneous injection; this esperiswnt elso suggested thet it produced retlculum-cell sercooes in Mies of both strelns.* 1 International Ager-cy for Reseerth on Cencer. 1ARC Monogrephs on the Eveluetlon of the Cerrlnogtnl: Risk of Chemlcels to Hunan'. Supplement 4. Lyon, Frence: IARC, 19(2. `International Agency for Reseerch on Cencer. IARC Monogrephs n the Eveluetlon of the Cercinogenic Risk of Chestcels to Muaans. Vol. 20. Lyon, Frence: IARC, 1979, pv>. 2(3-301. Mires, e chlorlneted cyclic hydrocerbon, is precticelly Insoluble in Mter. Mires was used estensively in the southeastern United Stetet for control of the fire ent. From 1962 to 1971, obeut 132 million ecres in 10 sutts were treeted with mires belt (consisting of 497,000 lb of mires). The belt wos etrlelly epplied In most coses. Mires wet elso used to treet other species of ents end yellow Jeckets, but it wes most effective es e species-specific pesticide. One compeny hes marketed mires es e fire-retardent additive. Mires first become commercially evolleblc in the United Stetet In 19S9. There is no current production of mires beceuse Its regittrotlons for techni cs! products were canc~leo es of becember 1977. Prior to this action, it wts Mnufactured by two U.S. producers In slgnlficent amounts end tome quantities were Imported; no specific date were available. According to tne 1974 National Occupational Heierd Survey, an estlMted 1000 workers wore potentially exposed to mires. Because Insecticidal use of mires hes been discontinued, direct human exposure Is mean. However, residues have been detected in Mter, toil, food and beverages, and hunan tissues for as long at 12 years after exposure. These residues nay result In general population exposure. Mires it known to degrade in toil to yield Xepone". In weeember 1976, ERA, under the Federal Insecticide, Fungicide, and Redenticlde Act, canceled the registrations of pesticides contaln'ng mires, effective December 1, 1977, with specified termination of uses of existing stuck. The State of Mississippi received an tMrgency exemption from ERA fer specific uses effective through June 1979. 193 HONS 025794 Hfeti CWUTtttS t*1ltfM IN ttM.* M MrrMt M l*M KIUKI 1* WlMN fPMwctl n*Mf CHC JtflUUtlM. IC7SCI Iffrn f ItfMlitiMt; tlMr (MNti flUA* It ItfllUlUlM f*r WNttil fr4. NU (MlM, 11/74; cfftctlv# It/77. AH KMKU md MM MM tactaMl. am ItKill (Mil Vt n*< ktfvn ll/JI/7). Unywy m pt'Mti wpf flMN 1 1*777I, tot kift Mm m1M ItKtf Mil tlMi IIW (tUttM f l9>1ttM l , 9. II70J l(l HONS 025795 194 MUSTARD GAS The evidence of carcinogenicity of mustard gas In humans Is sufficient; the evidence In experimental animals It llmlteo.l Mustard gas It carcinogenic In nice, the only tpedet tested, After tnhiletlon or Intrevenout Injection producing lung tumort, end After subcutaneous Injection producing local sarcomas.* Several studies have shown an Increased mortality from respire, tory tract cancer among Individuals exposed to mustard gas. This mortality was greater In those with chronic occupational exposure than In those with sporadic exposure.2 1International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic hist o' Chemicals to Hum/ns. Supplement A. Lyon, France: IARC, 1*82. 'international Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 9. Lyon, France: IARC, 1975, pp. 181-9?. Mustard gat Is a colorless, oily liquid that Is sparingly soluble In water. Mustard gas was used in chemical warfare primarily during World War I. Mustard gas hat been tested as an antineoplastic agent, hut Its clinical use at a tumor Inhibitor has been minimal. It Is used as a model compound In blolgtcxl studies of alkylating agents. Mustard gas Is not In the Toxic Substances Control Act, themlcal Substance Inventory (1879) of commercial chemicals nor Is there any Ind'catlon that there Is any manufacture or use In the United States at the present time. Production ano stockpiling of thlr chemical took place during World war II, and stocks may have existed In the United States as recently as 197A. If production of mustard gas as a chemical warfare agent were in be resumed. It would probably be excluded from regulation under the National Security Clause. However, the Resource Consenr.t<on and Recovery Act desig nates mustard get as a hazardous constituent of waste, should It be produced again. 195 MOMS 025796 btUrt hi KU, Mi'N04i lri|Mui <UN ns n MlirfMf M >u\, M Ut* Jtf Mllll lH# t* (Hill* It u lMU Im Mi rn*fi/rKftnti>f nnlnami. l/lt/to. If inMUn if murf turn rMhifect wriin *f#i nn M mml, H m*I nM>> N fWllfN frn rt|*1|||i inn* fr UOKltjT Cltt* CMUlMi ll Mill WMHtr. Im Cinlm** Cnn itiuant Mir t'KlVlMWiflMfMl. ttW tWUMONS IfftCt if lllllltlMli Mir (ijmII ttttllM f Rtfvllt'M o cn Mi ll tin) 1W HONS 025797 E-HAPHTHlflAMINE Th*r Is sufficient evidence for th carcinogenicity of E-naphthylamlne both In huaint and <n experimental animals.' E-Naphthyl amine was cardnog*nlc, producing urinary bladder carcinomas In bans tars, dogs, and non-hianan primates, and hepatomas In nice, after oral administration (by stomach tuba or In the diet)-1-* Epidemiological studies have shown that occupational exposure to E-naphthylamlne, either alone or when present as an Impurity In other compounds, Is causally associated with bladder cancer.1,* 'international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 1. Lyon, France: 1ARC, 1R7R, p. SR. `International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 4. Lyon, France: 1ARC. 1974, pp. 97-111. E-Raphthylamlne, an Industrial chemical, Is soluble In hot water, alcohol, end many organic solvents. 7-Raphthylamine has been used principally as an Intermediate In the manu facture of dyes and as an antioxidant In the rubber Industry. In recent years, other chemicals have been substituted for E-naphtl|ylam1ne, and It Is now used for research purposes only. E-Napntnylamlne nas not been produced or Imported In the unltee States since January 1, 197$. However, It had been producer coaaaerclally In sub stantial amounts for nearly SO years. United States Imports amounted to .19,000 lh In 1967. The company that had reported E-'iephthylamine for the Toxic Substances Control Act (TSCA), Chemical Substeice Inventory, 1979, withdrew their report In I960 (CPSC). The Federal Register notice of this amendment wes published In 1991 (CPSC, EPA). Huaar. exposure to E-naphthyl amine Is primarily through Inhalation. Prior to the discontinuation of domestic production and use In the dye and rubber Industries, an estimated 1000 workers were potentially exposed. E-Maphthylamlne has been reported In coal tar, cigarette smoke (0.0E ug/cigarette), and as an Impurity In commercial 1-naphthyl amine (O.S percent or less). The EPA regulates E-naphthylamlne under the Resource Conservation and Recovery Act and under the TSCA. The OSHA standard for E-naphthyl amine, promulgated In 1974, Includes protective clothing, engineering controls, and medical surveillance regelrements. 197 HONS 025798 ttOMTIMI IHilHlM Ml (tMf Klim N tMim* KUJ*. M !< KIMWI IB ttFKI IffMl Af NfillllMi; Map (amu KM| WI>>M: MJKtl Mil* ITNNtl, iff'WNlfUrtll* MWNl, M (*I1 rtH* Ml IK Mill MM l| U NNllnf M rM'l/M* rtWlNHMI. AIM AAl'fMWI (MAVylMlM M MIIMM imilMM If MU, AM WtJACll MftAA IDM M MUf* M M AM Ml nwirmiu. Nmium I/IMI. in Am fINM fM AM 1ICA iMtnif) AM MMH AM IM1. Ml Mam m m tirnm twiiiiuri, MnUtMA, r MtHt>D| # |UMWr'Ww. Iaa (MlU|N UMIIMM Imi IUUmH MAT !tU1|VlAMnNnl| UMI IMM1M CtMMAf, MIUIM^, AyfltM |P(tAtAJ. AMMTMI UMIMaKI nM* ami fit mim; aaAavx Ih haiI rwim; MMlAU rMIfttr. tAAAMIAAltAA PfMPtl MKMMU; tlfM AAIPA> AMI ft! Aftl; iMAl'M PAAAlPMMtl fAP CAAUlAAHt. (SNA) NfltiMy MMAPy: I/IC/H: (MPffMt Tmapm JliMAPA- KltKIln (UlAlAt |.M AyflAM paaa<pa> AMI <AP WAftAt 1, UAMUM mUKUl, AAflMATlM AAMlMBAAtl. flMl lUMifl-tiMM PAnf|tlAl (fffCttVA. IMMA) Af AamIMIm (II Ml.11. Hl.u ac n mi) UFA) w tn mt.icw (OlNAI 198 MGNS 025J99 NICKEI. REFINING, NICKEL, ANO CERTAIN NICKEL COMPOUNDS There It sufficient evidence that nickel refining It earctnojenle to humans.1 Epidemiological ttudlet heve demonstrted Incretted Incidences ef cancer of tlw notel cavity. lent, and possibly lar/nn In workers In nickel refineries. It It not possible, however, to specify vdtlch specific ntckel compounds art carcinogenic for humans.' The evidence of carcinogenicity ef nickel and certain nickel compounds In eiperlmental animals Is sufficient.! Nickel tvbsvlflde Is carcinogenic In rats k>' Inhalation, producing log cancer. Nickel compounds (nickel powder, subsulfide, oxide, carbonate, and nlckelocene) produced local sarcomas In mice, rats and hamsters when given intramuscularly. Inhalation of nickel carbonyl produced a low Incidence of lung tumors In rats.* 1International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: 1ARC, 1982. `International Agency for Research on Cancer. 1ARC Mpnoo-sphs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 11. Lyon, France: 1ARC, 197d, pp. 75-112. Nickel Is a metallic element used In star I and other alloy manufacturing and In electroplating. Nickel Is also used to make coins, as a chemical catalyst, In ceramics. In storaoe batteries, electric circuits, coloring glass, petroleum refining, and l.i the hardening of edible oils. The combined annual domestic production of nickel and 14 nickel compounds Is 121 million lb, and Imports total approximately 130 million lb. Human exposure to nlc>.l ana nickel compounds Is throurh Ingestion, Inha lation, and skin absorption. These exposures can occur f.om the presence of nickel In air, wettr, sell, food, and consumer products. OSHA estimates that 709,000 worxers are potentially exposed to nickel and Its compounds. ERA estimates that nearly 720,000 people living within 12.5 miet (20 km) of primary sources may be exposed to nickel at concentrations up to 15.8 ug/m3 (median, 0.2 vg/m3). As many as 15C million people live within 12.5 miles of all sources of nickel and nickel compounds, and they may be exposed to median concentrations of 0.05 up/mJ. The entire population may be exposed to low levels of nickel (300-800 vg/day) In food and water. Nickel levels In tl.S. drinking water are estimated at less tnan 10 ug/1. Food processing methods can Increase dietary nickel levels by mean* of leaching from nlckelcon*a1nlng alloys. 199 MOMS 025800 environment!) sources o' nickel Include millions from coal- and ollTlred boilers, coke ovens, diesel-fuel burning, end gray Iron foundries. Total annuel emissions from these types of sources were estimated at it.4 million lb. Soils normally contain r.lckel In the range of 5-500 ppm, and soils from serpentine rock mey contain as much as 5000 ppm. The tPA regulates nickel and nickel compounds under the Clean Water Act and the Resource Conservation and Recovery Act. Certain nickel compounds have been proposed for regulation unde' the Ionic Substances Control Act. FOA does not regulate nickel .s a fooJ additive. 05HA has adopted permissible exposure levels of 0.007 ng/m5 at an 8-hour time-weighted average for nickel carbonyl nd 1 ng/KK as an 8-hour tine-wtighted average for metal and soluble compounds. This standard was adopted by OSHA for tonic effects other than cancer. The Consumer Product Safety Commission ICPSC) staff preliminarily determined In 1880 that nickel carbonyl was not present In consumer products under CPSC Jurisdiction, The Comnlsslon subsequently requested (45 FR 163*4) public comment to verify the accu'icy of Its Information. No comments were receive4 on this chemical. Pending the receipt of new Information, the Commission plans no action on nickel ctrbonyl. 200 HONS 023801 tul ftfUI*f, *ml, *# CftU C--MmkI MCitATIONS l4f*tHtaa| v4 ItM' ActlMl (Milt d ItMr CWM IIUT M tlf>VM M'.lt*. 14 tD* MHfOCt 1* tM*WH' MMvitt. K^SC) (A, Mil tfffa*4 f*1l*lW* l#r ttrUla tIUNflil Kind. OroMlfat*# J.lf/74. /}t/H tu M(I* CM*, )!>: df M>*tr CKMiMi NltllNI la flNl ft**, ll/lt/M. ICM, M0I-M04: *<%! atctal im- HKMI Ml lIMfilll tMC^N Iff ItilH i MM'Md (Miiiiwni if mi. Mtt* IMM 0 (MUM Uld 11 MjKl U iMdflf MW ft/rKI**Nllli( PtMtraMMU. OrmwtfatM t/tf/Oo. KOA, KM: lM4 atOllmtM %* dMft Mt1 Mtr imiMKt, N*dM (OmvIOltO* 0# M cM ROHC/ 00 tlv#f. CM, 4Mi lldmtw aa cmmritff* if (((1 CM OtM* Male* In (IMMS IdlMH tar MO M Mil iMItlMfl Mir It*#/. tMi iimimm af M*nti m nwuni CMllM l#M. Mur cMttMtftf imi> am ti mmiM if nut *rrm fa#*1#* ttM. tVUMlMtlM lOIKlMWO MU IW1 d mV IMI. IM C**CtM0M MtinMit 3rji immat #i (IM| FM 1ra# 9* Fv#i: af Mltd faic*. kflt 'fMljtfl it l fiM mm*' if * *:*.! w *atla*;t. K Kim Ml lMf * fteail at MfdlMII NtlH IN* lau Ifl Mt MtMIM U Itlttt 'il ;if!llW}*ltll? llriaf KIM'; >aatf'(. .fwt Oil: 11 .1 llt-a* %*. HwvaatMM U*44'1 iaa*a#*l *(Mt tlOFtl (duiK'i 'Kiwwiimi * ftcal t**'Ma*ci. Sd*0 IN Mtt'ftf. driawl mmut datMN m a*ft f*t*<ll. d wntlMi air. awlijii iiKitm. I!9!N* Ml: 0.001 am 10.OOF (*) 0-ar :** lKMl t af/*3 0-0* lA l M MUl M# MlM> * Oiwitl. tMM*M MMIH Ur tule Hwr mm imi'.! (MM) Cdi'il ttudiikia tarawyt mt) mhii. U'dNfiafiM) hi m caaatatr*# la mmIm'M mu ywiMllwt. tf'MvIfa* Hm far taw ill accar la ta>l00i. f'UKim af omaa mafia Iftm'at uauttri H.a *o/t. N*i1nmm k Mt# h*H<1 fmaUtiaa af la IM m1q n la#fa. tent tavtaay fitr;: IMI: Nl|l*Nll;, 1 aM IlKUl U'M*)ftl antra illaNdi laacmratiaa. t/V/Hi OSM taiaN' lUaUN<"lt imi* rr*eti*t. fOSNA) 201 CIUtlM af Ki>iim as ti, #. idu ICMC) ao cn id. ais laartiMil ai n m, a. f)i* ao do tot .it 0M. MMOMt tawaiutiM, 4/U Mr, unwil canaaicjtiaa, 4/M d'HNl caawauattaa. 10/00 ((Ml to era iota.looo fOSwM llaattwa) HONS 025002 Olctal toMiltf, llttil, M (*mii l*Ml Ci INI ICMt1ftM4l hcjumoos M MMi XttMi Otalal KtUlt: HiiK Mala) iMtiul fSMu'tWtH Mi * mi an* in hu imiimi, t/lf/w. 4 4to*. 9001*1004: iml M Mini I--mo Ml HNMW mil'tH m MlMU l| kumm mmiunmi M mmi, m mini IM M 0*UI* Mt *% Mkim M MMI 1*0 M miImimi. Moml|MC l/lt/M. ! UrtiMit* tmiMM Inn tuumM mm lnnyiMHMfii. ICMI tffact f Itfilitlm; *W Clwiiti OMMl imMm iHlfaui BfriMi il IMIMM 10(11 HMHlfltlM 09MOl9tM| MOortatll MMIIi IMlt H, "" `*1 M MmiM iwM*| imin* iimifiM l/ii/n. MHlI M Mcftot CM> mi nm m MiimMftir> Ummu fMlM IM Ml IMllif M tOIOMHf Mni m m*n i*wit *-----*M MlMMIll I M<MM m nmn iwtiomi M ill. im Hum imi nmn vm ft MHCt H4MIM IM MMM/rHHM IMO 1*0 MtlMMlI. OrMllQUM. I/II/M. TIC*. Mall 4aMrt'*f *ta MIHIO mtlll IM Ml MU. ifININ 1/19/08. (CHI l Mill). law*) Wf MMlltlM Par *! (luitlk *P itfvlMlM n ri at. a. im 40 (ft Ml.II |(M| to tn nr.j, hmi 40 CM Ml.II <9 PI It. a. 1M4< (IM) 19 CPI 1910.1000 iyt tinaw; flu. Ota): (inrun *) to*trt ipkmi M *M M\*, KM>H l/tt/00. CM. 9001*9004: nml IM aim* imhm Ml MHMN NNIPlfl M HIlMUl II Ml*r4a*t COMtiUartl 0 Mitt. aM au ua* u a*ut* im an motact to mm'.im a*o Moon/marMaaoif vo*a***u. PthhIhW 9/19/00. mImooC* aM*taamtiMrUMHmMPI)MmOria*iO,rwo $Uia**at (CM) u P it. a. imu 40 CPI Ml.tl (CM. ICiatMaMI 202 HONS 025803 lint) item, h cnii itml (mmi ICwtiwuul WUfl. M IlfllltlMt HX fvxr XUlM aim* CmumI: UU IMXM NOW. n IMA UMIM' KMrfU' (C'tCt ll KM, mti lfl*U|iniltl|l MUM, W4 II rtllMil II KI If 1 l| U MMHif M M|n/N(|f*MI<lf MMlrHIMI. IlM WI<|Ntil ! itrMarl IMMMI IMIIMHI *f Mill, IN MU- MU M1III IMI IMUU II II IN MM r*MMM*tl. IfWlfl'K l/IM). TSCA, IUI: Iinmin mil pmIUn imill M aM MM, IMIIH t/tt/M. IIHI 1 NA1 ll *r? UN I*. Mill NlM kttM WUIMN MIMUMUIN fur Mill! WINllllNI. MMIIHW MilMurlUf, |I|N fur rufuUMU M*U, ruruwut KIUcIN I'MMIUI M MulfUuM. fUUMt* latuttl fbi 1 #/*) II Ml Mr TM. INM Iffuct if IimUI'ni: twr (Mm Maul ttMui W, Sill NMNNI Mill rufuUtM. MMUMlMut HturUUl# MNIIi IMO It, ttta kui in tMMtftf nwnuf umim MNI. 9rm,tpU4 tm/n. KM, ntl-Mli MA|I M ** CWUM* M MNNtN IMlflH m Mt|NUI II UINfMI NNHINMI Of WIN, M HlUi Im M HMD* IN* HI MMt ll NN< l* IN ruuurt/ IHtrUMI'N NUilrwMI. frUMlf*t*f 1TSCA. Ill): wu'UW rut* NUilMN fiKiu in * mu. ywini /W/tO. KMI Ml Mini. nmm Mi *m*i *|ulti*. tM| unit WMMIM: CM. Ill: IMINMI wilt r*fu*tl* HMlIIMN nuNNIl MMtMr (MM t*. 4*4 tl IN tMMIUf NgrtlN WMtruMKI. tWUlflM KM, MI'.IWi tlrtll IN Kail INNMI Ml iwwlw NNlllN MU MlflM II MlirMI IMtlMHU f MM. MUl UN* W COTUU MT >f MOT M MINI M MNHn MU ruUOTt/ iHlfUMlH WKlrwRIfruMtWMU I/1M0. ttUAI Hut MM M imIm*I(Ih. tiraurifi* fNIM* (MU ll INffllt M tMIUf IWM(1 M Mlf NMlI I* NMIIW Uf Kt'UMl) MfOTMH. IM| Mat MlN OT ClUNflKHU. iKIHHil INIIII (HI ll UMWllUf IN IMN*N immiKi in null mult n nMtu* Uf MtKMUl IKIUUI. imi 203 CfUtlOT f fHlUtlOT H era 1*1 -ll. m.n u n uf. . twuc HUAI It tn ItC.IHK lNU m era ur.u w cn mi.it 41 n 4|. !N4| I IfA) n in tm.iouo |M) to era iir.i, ur.u to era fM.ii |fAl tUfttlwl HONS 025S04 lUtt) tlcttl, tM ClMA** ilCtt) CwwhH iCmOMM) 1KMU W* Ifftct 11 ltnlMt|*i; ll**r (mull H#l OtiAt: CIA, MOI-NOt: hdftttt tlrttl mi iiMfviu imllM *t MltriMI (HtllMMl If Mitt. IN tMJACtl Mltll tt CMUH UN It MMlItf 8M Mmjlftttt i/lf/01. TICA, Mill lAttMltf f1t raw'Ml: |rm M tf MU, trtpMM i/hw. IIMI ttttl lutwIftM: CIA. MI.Mt: OtHfMttl MCAtl IMNNl ttt flMMltt IttCtfttA Mltrttvt M Milt. IM MHCtl Mlttt UM U (MUtl um It UtMlttf M MtttVMtMkAt#i| rttMrnttu. irtwlfaui VlMI< TKA, Mats IttOtlttf tilt rtotlrtlt| tmtll M Mt MU, IMtlW tmm. (KH) Q.l Mm: 1*000CM. Ill} NittMttt Mill rtftlAt't*. tlUtllllittf rtttMAtlt MMtity 1*. WH if) ttt toftitftf rtttrtitf ntiiH- *tl. trtMlftUt #/!. 1ttt MM tt CtMlMfttHtty. iMMMttl yrtttt* CAM It tM-AHtf AM | ft<M CMBlCtll AM ItttIA MMlt It rttWCllM *f KCiMtttt UNN'tli IfAA) CIA, MO)-MU ** Mc*t) twm. WMI Mt IMC'f'tA AM Atl'fMttA 1 Mlirttv* (IHt'lMRtt f* MUtl. M Mlttt IMM tt (t*tll* T*M <M MtffCt U mh{ **< ui*,..,*t::,*ttt:!f) 'is.i'wtr.:: Afwwtftttt l(tA) *tt Mlltl. I10SM) (tt M.TltM ftr ict) iiiMi ClttttM ft ttf'tt'M ao cm m.tt 4| M II. t. IMAf lit*) 40 Cfl HI 47 II 71 Al, f. 1M4 IIM) to cm 117*). 1174) to cm HI 41 IIMI n cm mo.iuoo ioami CIA. MOt*MO*- tM 8tl tt*. tttMl tot AUtMItt Utctritt tft ttfifMtM tl UllMMI CtMtttMttl If M*ut. tM Mlttt IMM I* (ttUll Mi IM Mtjttt tt Ntt* )<M tM Mtfn/MtMttttlfff ntflrtMU. AtWlfttM I/IUOO. IfAA) to cm hi.ii (cn> ?04 mons 025805 MtTXlLDTRIACETIC ACID Long-term feeding studies to tost the monohydrate of the trlsodiue tolt of nltrltotrfieetlc acid (NagNTA-HgO) for carcinogenicity wort conducted using Fischer 344 rtts; tnd both Fischer 344 rm end B6C3F1 alee. SlalUr bloassays, using rets end alee, were conducted with the free nltrllotrfecetlc sold (NTA). nta end MijNTA`H?0 were shown to be carcinogentc to the urinary tract and kidneys of both rats and mice.I Trlsodlua nltrflotrlacetlc add was found to be carcinogenic In t'ie kidney when adnlnlstered In drinking water to aale albino rats (Crl/COBS CU ISO) 8R1.2 National Cancer Institute. Iloassay of Nltrllotrlacetlc Acid (NTA) and Nltrllotrlecetlc Acid, Trlsodlua Salt, Mono hydrate (NajNTAHgO) fer Fosstble Carcinogenicity. Technical Report Series No. (. OHCM Fubllcation No. (N1H) 77-806. he the s.la, Maryland, 1977. `Coyer, A.A., H.L. Falk, M, Hogan, D.O. Feldaen, and W. Richter. Renal Tuaors In Rats Clean Trlsodlua Nitrllotrtacetlc Acid In Drinking Mater for Two Tears. J. Nat. Cancer Inst. Vol. M. 1981, pp. 869-80. Nltrllotrlecetlc acid (NTA) Is a chelating agent that Is Insoluble In water and aost organic solvents; however. It can fora mono-, dl-, and tri-bask salts that are soluble In water. CPA reported that NTA replaced phosphates as a detergent builder in tne late 1960s. In 1971, the use of MTA was discontinued. The possibility of resumed use arose in :sefi. The Consumer Product Safety Commission iCPSC) stated that NTA Is now used in laundry detergents in two states where phos phates are banned. FDA reported that NTA Is also used as a boiler feedwater additive at a maximum use level of S ppm of trlsodlum salt. Currently, the remaining nondetergent uses of NTA are for water treatment, textile treatment, metal plating and cleaning, and pulp and paper processing. CPA reported that the domestic production for J979 was 70-76 million lb, with 60-66 million lb exported. Estimates Indicate that reintroduction would Increase production to 260 million lb immediately and to 1 billion 1b in the near future, with most of this amount used domestically. The CPA (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record) estimated three producers and Importers In three regions. Domestic production data were not available, but Imports were 37.500 lb. Production reported to the U.S. International Trade Commission for 1980 was more than 6000 lb of NTA and more than 16,000 lb of Its trlsodlum salt. 205 HONS 026806 Tht rout* of hwian exposure it Ingestion of tract residue! that possibly remain in processed foods. In 1974, the National Occupational Haiard Survey estimated that 14.S00 writers were potentially exposed to NTs, and <(,000 workers were exposed to NT* trtsodtum salt. NT* levels in the U.S. drinking water prior to NTA's discontinued us* In detergents was estimated by (9* to have ranged from 0.20-24.S ug/1. NT* Is rapidly degraded under aerobic conditions at temperatures aoove S* C, end biodegradation does not lead to the formation of persistent intermediates. Until the spring of 1980, Industry voluntarily abstained from using N1A In detergents in the United States. At that time, CPA released a risk assess* ent on the us* of NTA in laundry detergents. In response to a request bv one manufacturer to resist use of NTA, It wot stated that '...projected levels of exposure from the use of this substance In laundry detergents are generally low, and therefore the associated risks would also be low.* CPA decided not to take regulatory action against the use of this substance for laundry detergent, but cautioned against its use In shampoos, foods, hand dishwashing detergents, and other products designed to give direct oral or dermal exposure. CPA has determined that the exposure to NTA Is low (1 ugAg/day/sdultl, but has Included some caveats as recoamndatlons to nanufactirers and processors (March 1980). The recommendations war* given under TSCA. FDA reguletes NTA at e secondary direct food additive, l.e., as a substance added to food during preparation or handling, and subsequently removed before the food Is ready for contonelIon. FDA limits the nitrllotrlacetate added to boiler feedwater to I pgm. FDA Is currently reviewing the carcinogenicity data on NTA for possible future regulatory actions- 206 025807 MOHS lUrlHviwilU teK Mi Ittof AttfMS mum Mtto*. ICTKI TKA, I, HiillMi; Nw^Klinri Mi MMMMM tNl< WlV Itrllt lotrtU If IMt WIIHlWll Atl| MX It IIH Is miwr intH K M lr*vt iril #f *rtil ihwimi. NMtMtnn Mt*1i Mrt anitiftif Mi mtimwmi lUdn u $mt%m MjMlHM if )m nMwiml tmlij IM u Hrttotou to kMfNtHIfl Mi toKNMto MlU tototo mirl %f tonni to to|iiU f lUtoKMIMN toi|i*tl. iCtti MtntMMicttiu Mi it itiitr fttiMMf t| ItMtM t* I to*. IFM) KOMTIMS IWttl if ItftlsilMS! Sttof (mmu to M1 (feiwfwrfcttr ti nttoliUH, toit (to tiwito 4ms Nt tosur it It t Mtofi* if tototofto. ttoiwi MtoitctM tototo* II Mini. iwi Iftttr Irm t.l. Mill**. It Iftcuf I tototo Mi toiiuto. uvm. u iMtitiftUms Mi Nritfit ItoCMl IlM, UUfSUtt Mi Nnlyi (Mmi (Mttos. swm if Nil iMMatiMt, inm. 1riM MSto IMItoto Mttffti |f #f ti i/nm. u cn UJJiiui (FIA) 207 HONS 025808 S-N1TR0-O-ANISI0INC 5-Nltro-o-onlsldlne, adolnfstered In th* feed, was carcinogenic (n richer 344 rett, earning turnon of the Integumentary system In males and females, and tutors of the clltoral gland In females. The compound was also carcinogenic In female B6C3F1 Ice, causing hepatocellular carcinomas.1 This evidence of carcinogenicity In experimental animals was cunsldercd as limited by an IARC working group.! In view of another evalu ation It can be regarded as sufficient.1 national Cancer Institute, lioassay of S-Nltro-o-anisld<ne for Possible Carcinogenicity. Technical Report Series No. 12?. CHEW Publication No. (N1H) 78-1312. Bethesda, Maryland, 1978. ^International Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 27. Ljron, France: IARC, 1982, pp. 133-39. ocrlesamer, R.A.. and C. Cueto. Toward a Classification Scheme for Degrees of Experimental Evidence for the Carcino genicity of Chemicals for Animals. In: It. Monteseno. H. tartsch, and l. Tomatls teds.). Molecular and Cellular Aspects of Carcinogen Screening Tests, IARC Scientific Publi cations, No. 27. lyon, France: International Agency for Research on Cancer, 1989, pp. 259-81. $-N1tro-o-an1s<dine Is a trisubstituted benzene derivative used primarily as an Intermediate In the synthesis of dyes. 5-Nltro-o-anisldlne Is an orange-reddlsh crystalline solid, highly soluble In alcohol, acetone, acetic acid, and benzene, but only slightly soluble in water. 5-Nltro-o-anlsidlne Is used in the production of C.I. Pigment Red 23; this pigment Is used in printing Inks, Interior latex paints, lacquers, rubber, plastics, floor coverings, paper coatings, and textiles. S-hltro-oenlstdlne can also be used with various coupling components to produce certain red, brown, yellow, and violet dyes for cotton, silk, acetate, and nylon. The chemical has been usea in a formulation tested for pestlcldal properties and In a formulation used to color keratin fibers, especially numan hair. 5-Nitro-o-antsidlne has been produced In this country since 1937. Two companies--both listed In Synthetic Organic Chemicals, U.S. Production and Sales, 1980--reported production or sales of this compound's stabilized dlazonlum salt, Azoic Dlazo Component 13. According to Imports of Benzenold Chemicals and Products, 83,720 lb of Azoic Dlazo Component 13 base were Imoorted Into the United States In 1980. In addition, 23,000 lb of S-nltro-oanisldine were Imported Into the United States In 1980. According to the 208 025809 HONS Consiancr Product Safety Commission (CPSC) Imports hvt significantly and steadily decreased since 1974. EPA estimated ill producers and Importers In four legions. Domestic production ui reported es 37.000 lb. end no laport dete ere trelleble (Tonic Substances Control Act (TSCA). Cheat cel Substance Inventory, 1979, public record). In 1979. 337.000 1b of Pigment bed, produced froa the dlaaonliat talt of S-nltro-o-antsIdlne, acre produced by 11 companies In the United States. U.S. production of S-nltro-n.anltiding was reported to thn U.S. International Trade Commission for 19C0 as greater than 15.000 lb. Huatn exposure to 5-nltro-o>antsld1ne Is principally through Inhalation and skin absorption. The potential for exposure to this compound is greatest for workers who aanufacture, handle, or use the dyes and pigments derived froa S>nltro>o-anit1dine- The CPSC staff Indicated that residual levels or trace taourltles of S-nltro-o-anistdlne aay possibly be present In soae dyes bated on this chaalca! and In the final consuaer product. Exposure even to trace Mounts aay be a cause for concern. This concern Is based on the experlunce with other dyes derived froa aroaetlc aalnes. However, data describing the actual levels of Impurities In the final product, the potential for conswar exposure, and the uptake are currently lacking. The 1974 National Occupational Haiard Survey made no estimate of the niaaber of workers poten tially at risk of exposure to the chemical. 5-N1tro-o-an<s1d<ne it currently proposed for regulation by EkA under the TSCA, 1(a), reporting rule. atUMTSOM a0w)sti*ftt i*i ^tNf t(tig*t if fteflit1w; CtMT CWMAts UffOH Mtlgl, ;<nt) IIU, Mil: Mfmi*| *** ffwl'lil IfKIll sag PM MU. imilH >/|tdW. (CMI l|IMItl*f HNIgfl tttmilt . MIC* Wit M (Mlftfld lllN eltt rill ii KNftiiiif wgngfimwn f r*fl4t*ry or mgr tmint mum IlfA) Cimim 9* ttml4ts*4. <1 r*. g. |)|4| ll*t ?09 MONS 025810 NITROFEN Nltrofen (technical grade)--a substituted dlp'ienyl ether--adl-. Istered In tot feeo, was carcinogenic ts B6C3T1 nice, causino hepatocellular carcinomas in both saxes. Thera was no wide ce of carcinogenicity m Fischer 344 rats.1 In another bloassay, nltrofen (technical (rade) adaln'atered In the feed ms found to Induce hepatocellular carcinomas In B6C3F1 mice of both saxes, and hmaanglnsarcomai of the liver In male 8CC3F1 mice. In addition, adenocarcinomas of the pancreas were Induced In fame'e Osbome-Mnndel rats.2 These results can be considered as providing sufficient evidence for the carcinogenicity of nltrofen In experimental animals.1 'Rational Cancer Institute, (loassay of Nltrofen for Possible Carclnotenlclty- technical Report Series No. 1M. OMEN Publi cation No. (HIM) 79-1740. bethesda, Maryland, 1979. `National Cancer Institute, tloassay of Nltrofen for Possible Carclnotenlclty- Technical Report Series No. 26. OMEN Publi cation No. (N1N) 78-826. Betheton, Maryland, 1976. 'Crlesemer, R.A., and C. Cueto. Toward a Classification Scheme far Detrees of Experimental Evidence for the Carclno tenlclty of Chemicals for Animals. In: R. Montesano, H. lartsch, and -. Tomatls (eds.l. Molecular and Cellular Aspects of Curclnopen Screenlnt Tests, IARC Scientific Publi cations, No. 27. lyon, France: International Agency for Research on Cancer, lt80, pp. 259-91. Nltrofen, the trade name for 2,4-dlchlorophenyl-p-nltrophenyl ether, is commonly referred t: a: Tor.. Nltrofen Is practically insoluble in acetone, methanol, and xylene. Nltrofen Is a contact herbicide used for pre- and postamereence control of annual grasses and broedleaf weeds on a variety of food and ornamental crops. Nltrofen hat been applied In approximately 25 states by groMrs of rice, broccoli, cauliflower, cabbage, brussel sprouts, onions, garlic, and celery. Nltrofen has also been used In nurseries growing roses and chrysan themums and rn rights-of-way. The direct crop use pf nltrofen for 1960 was estimated as 462,000 pounds. Nltrofen has not been used around homes and gardens. According to EPA, nltrofen Is produced by one company In one region (Toxic Substances Control Act (TSCA), Chemical Substances Inventory, 1979, public record). More than 5,000 1b Mre produced tn 1980, according to NCI. 210 HONS 025811 In August 1110, th* >lt manufacturer of nltrofen (T0K-E-25 md T0K-VP-50) began recalling til existing Jtocki of the herbicide from (tellers, distributors, tnd uteri. Hunan exposure to nltrofen occurs through Inhtlstlon. skin .absorption, tnd Ingestion. Occupttlontl exposure to nltrofen, primarily through Inhalatlon tnd dermal conttct, nay occur among workers at production facilities. Field handlers of the herbicide are subject to in'.lotion exposure during application procedures. The 1974 national Occupational Hazard Survey made no estimate of the number of workers potentially exposed to nltrofen. CFA has established tolerances for nltrofen residues on a variety of raw agricultural commodities, dairy products, and meat products. eitrefca WLAT1M mi mm MtlMl km M NWlllkM tr altrafaa miiMi a* i w*tr af rtm ifMvVil naMlllil Ml M i Mdito M HIf h4 mit mmu mrnmi tm/ii; /*/?:. IIHI effect ef aefvletlcft*; Mar (mu tain g ea*ent tffacta af im (Mini aaa pattern mm aatactlaa *4 M. KH) Ciutlea a# aafttaa m ere tio.m rtre) HONS 025812 211 N-NITROSODI-n-RUTTLAMINC There is sufficient evidence thet N-nltrosod<>n-butylamine I DUN) it carcinogenic in experimental animals.! DON wet carcinogenic in ell enltul species tested: nice, rets, Syrien (Olden, CMnese end European hamsters, rebbits end gulnet pigs, fter prel (diet, drinking weter and/or gastric intubation), subcutaneous, tntraperitones) or intravenous administration. It produces benign and malignant tumors in the urinary bladder, esophagus, liver, respiratory tract, stomach and Intestine, and also leukemia: It it particularly effective as a bladder carcinogen. It was carcinogenic If administered prenatally (subcutaneous injection to mothers) and In single doses.2 The two metabolites, N-nttroso-n-butyl-N-(4-hydrcxybutyl)am1ne and N-nitroso-n-butyl-N-(3-carboxypropyl)emine, were also carcinogenic, the first in pice, rats, hamsters and dogs and the second in rats. Mien given In drinking water to mice, N-nitroso-n-butyl-N-M-hydroxybutyl lamtne produced carcinomas of the urinary bladder; when given in drinking water or Intra- veslcularly to rets, it produced papillomas and carcinomas of the urinary bladder; when given subcutaneously to hassters, it produced t uxors of the urinary bladder and respiratory tract and cholangiocellular tumors; and when given subcutaneously to dogs, it produced urinary bladder tumors. N-N1troso-n-butyl-N- (3-cerbovyprnpyl)amine produced tumors of urinary bladder in rats after administration in drinking water or intravesicular instillation.2 1Interne clonal Agency for Research on Cancer. IARC Monographs or. the evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, Prance: IARC, 1962. "'international Agency for Research on Cancer. IARC Monographs on tne Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. Lyon, France: IARC, 1978, pp. S1-7S. DDK, a yellow oil that is "oloble in water, is used primarily as a research chemical and nay have limited use cs an intermediate in the organic synthesis of di-n-butylhydrazine. D8K has also been tested for fungistatic activity. Annual production of OBN is approximately 729 lh; no Imports or exports have been reported. DSN is prepared in a closed, pressurized process system. 02581.3 212 HONS The jxtent of human exposure to DBM during commercial production end use la unknown. Portont at rKk art researchers engaged in the study of DBM's biological affects and workers exposed to DBM as a contaminant. DBM may Be formeo from Ingested secondary or tertiary n-butyl amines and quarternary aaanonlue salts By reaction with nitrites. The degree of this exposure in the general population Is not known, but It Is assumed to Be sporadic and at low levels. M-nltrosamlnet are frequently produced during rubber processing and may be present as a contaminant In the final rubber product, exposure Is depen dent on the ability of the nitrosamlne to migrate out of the product ard enter the body. CPSC has a project under wjy that Is examining children's rubber pacifiers. The study will determine the presence of specific nltrosamlnes and the amounts released under normal exposure conditions. The most probable source of envlronaental nltrosamlnes Is nltrosatton of amines, irfiteh are ubiquitous In the environment. It has been estimated that air, diet, and smoking contribute to huuan exposure at leels of a few micrograms per day. Microgram quantities of DBM have been oetected In tobacco smoke, the effluents from a coke plant, a variety of cooked meat products, animal feeds, and soybean oil. CPA regulates DBM under the Resource Conservation and Recovery Act as a constituent of hazardous waste. The water quality criteria document for nltrosamlnes (Clean Water Act) published November ZB, 1P60, also includes this compound. Dtk Is regulated under the Clean Water Act hazardous spill regulation, and Is proposed for regulation under the Toxic Substances Control Act reporting rule. '13 MQNS 05fll4 MfillUMl Ml MMf KtlMI IMWMtMl Mt^Kt I* KVf'M'- llM'lUO IMt| MIW lf IM K4MU If lIlnMUM 4|t4iN fr Mttfliri, (Cl SC* cm, wuit mtM fr MifurfMi li/ll/N IMMIIMI HfllMMl. r1rt* In flat) Nt, KM, Ml*)**: Mima milt >wni, MlMh, M l|*M WllNI Hi *K*I * IM M * fcM'laf IN Ilfin/mMtMflf AIM MlIfNttl H HllMlI NMlftMH * MlU. M M)mi mm mm tmit* hum rtm AmmI|m 1/*#/*, nu, Wlh l.nmM IMMtlM Ml* rwtriiii VM MU, MlllM l/tf/N. (A, )||t *M|4M **'1l MfwUtlM tUMHiH** rmniiii wmii II i, .IM i|l. *r***i* tffm,. 8 Un- m* imhhmi m# Iti'WM MM' I.WItrlMMnMfIM. IIH> r*iio*s Kf*Ki If Mm'iUmi; lMl Um*H bill iirtfuiMidtrSCMI tlUMw If bf))nii *i til, i. >( M Ml.11. Ml.)) ! n it. . dm* *1 ra i. . imn IIM. t 214 HONS 025815 H-NITROSOOIfTHANOl AMINE There 1: sufficient evidence for the carcinogenicity of N-nltrosodlethanolanlne (NOELA) <0 experimental animals-* NOELA was carcinogenic fit rats after administration In drinking water and In hamsters after subcutaneous Injection. It produced hepatocellilar carcinomas and renal adenomas fn rats, and adenocarcinomas of the natal cavity, papillary tumrrs of the trachea, hepatocellular adenomas and ioc.'I fibrosarcomas In hamsters.* ^International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: 1ARC, 1912. `International Agency for Research on Cancer. 1ARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Mumins. Vol. 17. Lyon, France; IARC, 197R, pp. 77-62. NDCIA Is a yellow, viscous liquid miscible with water In all proportions. WCIA belongs to the group of K-nltroso compounds, which are wisely distributed In the tnvlronmont. No evidence of commercial production or use has been found; however, the ERA has reported production of 3S0 lb annually by one producer. Hunan exposure to HOELA is possible by Ingestion, skin absorption, and to a letter extent by Inhalation. It Is a known contaminant of various cosmetics, cutting fluids, certain pesticides, and tobacco. The concentrations of NKLA range from 1 ppb to 49,900 ppb. As of June 1980, FDA has analysed 335 cosmetic products for NOCIA, and 42 percent were found to be crntamlnatrd with this compound, tutting fluids have been reported to contain up to 3 percent NOElA. Atratlne, a pesticide, contained 0.5 mg/kg of NDEIA. Maleic hydraclde, a pesticide commonly applied to tobacco, has been reported to contrioute to the formation of NOCIA In tobacco at concentrations up to 173 ug/kg. The number of persons exposed to NOELA Is not known. The Consjmer Product Safety Coer'sslon (CPSC) staff preliminarily determined In I960 that NOELA was not present In consumer products under CPSC Jurisdiction. The Commission subseouently requested 146 FR 61344) public comment vc verify the accuracy of this Information. No comments were received. Pending the receipt of new information, the Commission plans no action on NOELA. Currently, this compound Is regulated by EPA under the Resource Conservation and Recovery Act as a constituent of hazardous waste. FOA has alerted the cosmetic Industry to tflf'pretence of this compound In a number of products; FOA Is also conducting a survey for product contamination. 215 MOHS 0.2 5816 llWlM H ItMr A<tff4t M nrrHt it'.lM. IM MM rtwc* (HIMr rwvttl (Mir CUC IC4K1 let!#*. KU. 2001-2004: Sfjctt mi'i frttxu, Mltk*!, tfMI rttIMt M ! ff IJfl l| If MMKnf W< pfffri/vtorfkffflnf llu fMt#Mtt Mil tl I kllMlNI (WttlMM t( Mitt, M4 MUM IMM If (MUll U U IM IM rN`i<MMti. *rw*1f|f l/lt/M. Iff tlMlMfM lllMMftt IMI IUUMM MMf 2`!>!*)MMM> IKM) mu, toiui. im) CtUUTIMS IlfMt *t ItfiUlUNIj ItMr CfMU Sfmy IMttlt mhumimd <M fliVKt rffffrctt ffr *9. |1rlM U frfflM If 44 Ft |)|| tftHf. tm) (tUIlM f# BfffUtlff 40 cn 111.11. 111.2) 1144) 216 HOWS 0*5817 M-MlTROSOOIt THYLAHIHE There is sufficient evidence for tK* carcinogenicity of H-nltrosodlethylanlne (l.'XA) In experimental onlMlt.l MOCA was carcinogenic In *11 animal species tested: mice. rats. Syr1m golden, Chinese and European hamsters, guinea pigs, rabbits, dogs, garblls, pigs, monkeys, hedgehogs, various fish, frogs and birds. It Induced benign and malignant tumors after administration by various routes. Including Ingestion, parenteral Injection, Inhalation and rectal Instillation. The major target organs were the liver, respiratory and upper digestive tracts and th* kidney. It was carcinogenic when administered prenatally I subcutaneous injection to mothers) and 1r. single doses. In several studies, dose-response relationships were established.2 H-M1troso-N-ethyl-N-(2-hydroxyethyl)am1ne, a metabolite of N-nitroso-dlethylamine, produced mainly liver tumors when given orally to >0 rats.2 I InternetIonaI Agency for detearch on Caxer. 1ARC Monographs on the Evaluation of the Carcinogenic disk of Chemicals to Humans. Supplement 4. lyon, France: IAHC, 1982. 2International Agency for detearch on Cancer. iAdr. Monographs on the Evaluation of th* Carcinogenic disk of Chemicals to Humans. Vpl. 17. Lyon. France: lAdC, 197B, pp. 77-82. HOEA Is a yellow, volatile liquid that decomposes In the presence of sunlight and ts soluble In water and organic solvents. HOEA Is predominantly used as a research chemical; minor applications Include the use In plastics, as a lubricant additive, and as an antioxidant. Two producers are listed In the EFA public records, whl.h show a domestic production of 725 lb annually. Human exposure is possible In laboratory, copolymer, lubricant, and pesticide workers. There Is no estimate of the number of people exposed. Th* general public may be potentially exposed to unknown quantities of HOEA because It occurs In the environment and Is present In food and bever ages. The concentration of HOEA In the air of a major U.S. city was esti mated as 200 hO/xw. Wastewater from chemical plants contained up to 0.24 g/1, and high nitrate well water used for drinking contained 0.01 ,,g/l; however, ft does not persist In environments exposed to sunlight. Various kinds of fish, treated or untreated meats, cheeses, and vegetable products such as soybean oil contain MOCA in th* mlcrogram per kilogram rang*. Similar concentrations have been found in alcoholic beverages and in tobacco smoke condensates. For example, up to 0.008 vg/cigarette was found In mainstream smoke and about 10 times more In sidestream smote. 217 HONS 025818 N-nltrosamlnes ere frequently produced during rubber processing end may be pretent et l contaminant In the fine) rubber product. Exposure It dependen' on the ability of the nltresanlne to migrate out of the product end enter the body. CPSC hat a project under way that It examining chlldren't rubber paclflert. The study will dctenalne the pretence of tpeclflc nltrosamlnes and the amounts released under normal exposure conditions. CPA Issued a notice In September 1177 requiring all registrants of pesticides potentially contaminated etth nltroso compounds to analyse and document the levels by specified analytical procedures. The compound Is regulated under the Clean Water Act and the Resource Conservation and Recovery Act as a hatardous uaste constituent. A water quality criteria document for the protection of hianan health has been Issued. Mlimuuwriudt m tt**p aetiwt Ktmaltdt ta fictfivri #n|ct l* KUnil, llidldf aft ihp> im mni if mmwui ftium trm ml"***. <c*v CiA, Mlili nup Mii inuftd fir MUtWlRn MHlhH ft flMl f*r*. 11/M/M. Mffiim MfwMNti|ilatRi. PH, lilt miiftNl 1*111 r*yUfn rigirvilt MHIV (1 l, t.4|4 ll, iniiilf 1/9/M. VIA. Ml'Mf: IM)NU MIU fPMKU, ifMMtfllltlM MMH. DM tt<ll ml* Mt I* MUM if MM K %8 MfU) M rMMt/p*CMmf*i Ala* (HI9WII twMVMMIrtMlMf* M A <HIPMI NMtlMM If MSU. M M)K1r nun WMi u tMUfi him m fMffWltl. IpmIiuM l/ll/M. TiiA, Ifllt friMM rwrttii I1| *M ItU, fMlIMM I'llfH, 111 UpKimi MttllMdt Irtbi IUMMM MAP lmHytMRIf1|IHRi. ItW CffMt If IlfHUtfMlI IMP C--nil titoitM if liplMlM it n ui, f. fun <S n 13), IMN it t-i tsi.ii. Ml.M 49 fl 4). i. IM44 (CPA) 218 HONS 025819 N-MITROSOOIMETMUAMINE There li sufficient evidence for the carcinogenicity of N-nitrosodtnethylamlne (DewA J In experimental animals.> DHNA was carcinogenic In all animal species tested: mice, rats, Syrian golden, Chinese and European hamsters, guinea-pigs, rabbits, ducks, mastoagrs, various fish, newts and frogs. It Induced benign and malignant tumors when administered ny various routes. Including Ingestion and Inhalation, In various organs and In various species. It produced tumors, mainly of the liver, kidney and respiratory tract. It was carcinogenic when administered prenatal1y (injection to mothers) and In s'ngle doses. In several studies dose-response relationships were established.< International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. lyon, France: IARC, 1982. 'international Agency for Research on Caver. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. lyon, France: IARC, 1978, pp. 125-75. DHNA is a yellowish oily lipoid that is very soluble In water. Prior to April 1, 1976, DMUA was used in the United States as an inter mediate In the production of 1,1-dlmethylhydrazlne, a storable liquid rocket fuel that contained approximately 0.1 percent OMHA as an Impurity. In addition, DUMA was used as a solvent in the fiber and plastics industry, as an antioxidant, at a softener of copolymers, and as an additive to lubricants. Ho evldeve has been found that OMHA is used at present except as a test chemical for research purposes. OMHA came into Industrial use In the United States In the manufacture of 1,1-dlnethylhydratlne In the mid-1950s. OMHA Is currently not produced In commercial quantities. The ERA public records Indicate previous annual domestic production at 750 lb. In 1976, the last commercial plant making OMHA was closed. Human exposure to OMHA can be by Inhalation and ingestion. The expo sure potential to H-nltroso compounds Is Mlieved to be widespread. Precursors of N-nitroso compounds, such as nitrates, nitrites, and amines, are naturally vcurving substaves, and H-nltroso compounds. Including DHNA, may be found in soil, water, air, food, and the gastrointestinal tract of humans and aniauts. 219 MOHS 025820 Workers In dlaethylemlne end dlaethylhydreilne aenuficturlng plents. Wither workers, ol) md ges function workers, pesticide workers, ind rtitirch worker! my here been occupettonelly eipoted to DHNA. iorauletions of tho peitlclde 2,3,6-tr<chlorobenio1c ectd with diaethyleaine contein bhHA it e contealnent In concentntlons up to 640 ug/1. i-nltroseatnes ere frtouently produced during rubber processing end my be present is < contealnent In the fine) rubber product. Exposure Is depen dent on the eblllty of the nltrosealne to algrete out of the product end enter the body. CfSC hes e project under wey thet Is exealnlng children's rubber peclflers. The study will detenelne the presence of specific nltrotealnet tnd the eaownts releesed under norael exposure conditions. In September 1977, EPA Issued e notice requiring ell reglstrents of pesticide products potentlelly contealneted with N-nltroso coapounds to tnelytt for the coapounds by specified enelytlcel methods to document the levels free potentlel sources. The ceapound hes been reguleted under the Resource ConservetIon end Recovery Act end the Cleen Meter Act. A weter quollty crlterle document for the protection of huaen heolth is evetleble. fM hes estebllshed Ktlon levels of 5 ppb DMMA in melt bevereges end 10 ppb In berley aelt. This Is expected to reouce or ellnlnete exposure to DMA froa these sources. In Februery 1974, OSNA pronuljeted e stenderd for RHNA, which Included protective clothing, respiretors, aedicel survelllence requirements, tnd engineering controls. 220 MONS 025021 MU EMUITIMS tifilMim tM *tn ihrttatw * Ilf M Mwftu # fm (CMC) ^jni i lfft f tuif (mtui 1*1. Willi littr Mlltf crltor lllftUIIKI NtHlMI 1* (ImI n*, 1/19/M iNTtlHI CM. lilt NliXM *#111 riyvlitll* HMlIlMM HWW> II l, .* k%\, >tw*h m/. KU, l4KtU MlU rMMtl, ff>MMtttotm MttMl, *M IM1 WlM l Mill III t| k MMltof UN finH/mMimn rttolrmcMi. Altt MI1|HMl l>ltfnHiMtf1MN Hwnwl tMTIInM MlHi MM MlKtl Mfttl M* II (Mill II tl M mu uiiiinii. imilfiwi l/ll/M. TIU, Mali IrtHUl immim rvll mikWf m MU, MAlIMM i/ll/N. Im {utimii luumH tm mimii Mir iMUVlMUAflMmm. HI Mm# w rnilfiffiltltrlitA) Arructlm ctototof. |MMU|, AM MHUl wmllllKI MlIU* mu fm mrtmi Mmt im m> mul mmiiimi imiiimi mui- miim mm) mummii i*m mim MMl m HMU UHtl'i'ilMI f*f mwioin. (OHM) Mmumr *iiMnr: I'll/llt tornnor i--mry )u*um.> lumHu iiitMif m irffm mu tor amm. m* mwi mutiiM mtrUUI, MfiMirtf nwf'MMi. l/JI/14: rtNl tumn*>rrrt fifili* turn effKtiu. I9SMA) m bun if inn. wt. irtoi TM fM Ml flUtIUM# KtlM >Wl f 1 Nl 9MA ! Mil MWIfll Mllto U Mrlay l|. ffMI (<utto* If ItuiiUM 4S ri til. *, 11)11 If ft ID, . IM4 cn ii.ii. iii.d Kill w en m.itif imm> 221 HQHS 02582i p-NITROSODIRHENYLAMIUE p-Nttrosodtphenylamtne, administered In th* fe*d, was carcino genic In male 86C3T1 alee, causing hepatocellular carcinoma!. The chemical was alio carcinogenic In male Fischer 344 rats, causing liver neoplasm. There was no evidence for the carcino genicity of p-nitrnsodiphenylamlne In female 06C3F1 mice or In female Fischer 344 rats.* Theie results mere considered as providing limited evidence or carcinogenicity In experimental animals,2 hut In view or another evaluation, they can he regarded to provide surrtclent evidence.' ^National Cancer Institute. Iloassay of p-NItrosodlphenylamtne for Posslhlo Carcinogenicity. Technical deport Series No. 190. OHEU duplication No. (NIH) 79-1746. Bethesda, Maryland, 1979. `International Agency for desearch on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 27. Lyon, France: IARC, 1982, pp. 213-25. J5r1esener, R.A., and C. Cueto. Toward a Classification Scheme for Degrees of Experimental Evidence for the Carcino genicity of Chemicals for Animals. In: R. Mo-itesano, M. lartsch, and l. Tomatls (eds.l. Molecular and Cellular Aspects of Carcinogen Screening Tests, IARC Scientific Fubllcatlons, No. 27. Lyon, France: International Agency for Research on Canctr, 1960, pp. 259-81. p-NItrosodlphenyl amine (4-nltroso-N-phenylbenzenamlne) Is an Industrial chemical that Is slightly soluble In water and petroleum ether and soluble In alcohol and benzene. p-NItrosodlphenylamlne Is used as a chemical Intermediate for dyes and pharmaceuticals and as a polymerization Inhibitor during the manufacture of vlpyl monomers. Use of p-nltrosodlphenylamine as a chemical Intermediate Is believed to be limited primarily to the production of N-phenyl-p-phenylenedlamlne and Its derivatives. p-Nitrotodlphenyl amine has also been used as an accelerator In the vulcanization of rubber. Coimaerclal production of p-nltrosodlphenylamine In the United States was first reported to the tt.S. International Trade Coanlsslon (USITC) by one company In 1975, although It Is believed to have been produced since 1970. ERA estimated one producer In one region. Domestic production was reported at 369,000 lb; Imports were not reported (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record). The U.S. production of p-nttrosodiphenylemlne was reported to the USITC as greater than SOCO lb for 1980. 222 HONS 025823 The potentUI for exposure to p-n I trosodl phenyl mine Is greetest for uortert to elestoeier, dye, phenxeceuttcel, end vinyl aonomer axnuftcturlng fecllltles. Tht 1970 Notlonol Occupation!I Hoierd Survey nod* no estlaete tf tltt number of uorkers potentlilly exposed to p-nltrosodtphenylantne. p-HItrosodlphenyljalne 1 proposed for reguletton by CPA under the TSCA, 0(o). reporting rule. Ml IfVlMI fMirI **# KIIMIIM aM t(Mf ktlm M nri*t Kttw. ItMCI Iffttt if Mitim; KM* tWM*M foe*. Itportlof mi* rugiriii M(NI Ht M MU, KIHlH UW MMtl Mflll MtUr kf It ft IIIMl1| MNIIft MtWIttl, Ul|ft Mil M MMlfN llMf Mils mm ( NUftii9 mmriitmti f nr.UUfT r KMf mifii Ktiw. IKMI (tall** # liiplaMon 'I rR. . IMatf ((HI 223 HONS 0i58ih N-NITROSCOl-n-PROPTLAMlNC There <> sufficient evidence for the cerclnoqenlcity of N-nltrosodl-n-propylemtne (HOP*) In experiments) enlmols.1 NOP* wes cerclnogcnlc In rets efter edmlnlstretion In drinking we ter end In rets end hems ters efter subcuteneots Injection. It produced benlpn end mellgnent tumors of the liver, kidney, esophequs end resplretory trect. The netebotlte N-nltroso-N(2-hydroxy-n-propy!)-n-pro?ylemine wes elso cerclnopenlc In rets end hemsters: It produced benlpn end me)Ignent tumors of the resplretory trect end liver fter subcuteneous injection.* internetlonel Agency for Reseerch on Cower. (ARC Monogrephs on the Eveluetlon of the Cerclnogenlc Risk of Chemlcels to Humens. Supplement 4. Lyon, Frence: IARC, 1962. Zlnternetlonel Agency for Reseerch on Cencer. IARC Honop'sph* on tne Eveluetlon of the Cerclnogenlc Risk of Chemlcels to Humens. Vol. 17, Lyon, Frence: IARC, 1978, pp. 177-89. MPA Is 4 yellow liquid thet hes been found es e conteminent in mlcrogrem event!ties In westeweter from chemlcel fectorles, In cheese. In brendy end liquors, end In pesticides such es Treflen end Isopropelln. Under the Tonic Substences Control Act (TSCA), Chemlcel Suhstence Inventory, 1979 (public record), EPA reported two U.S. producers with en estimeted domestic MPA production of 350 lb. The generel populetlon mey be exposed sporedicelly to low levels of NDPA. However, no exposed group sulteble for en epldemlologicel Investlgetion hes been Identified. The potentlel populetlon et risk Includes pesticide woikers end reseerch personnel. There ere no decs evelleble on the number of people exposed. CPA reguletes MPA under the Resource Conservetlon end Recovery Act. The proposed reporting rule under TSCA would require the reporting cf process end use Informetion. In 1980, CPA published wxter queMty criterie for the protection of hunen heelth. However, th- docun'nt Addressed nltrosemlnes es e dess, rether then MPA es e specific chemlcel. 224 HONS 025825 tewmiMt IN Mar ct*N KW, Mjtt mb iwn, HMHItfUltM MUNI. IN Mill nil< MM I* MtM< Mf IM If M MMI'M tM NMt^KMAlMlM NtlriMMt. lit* MlfMm a^l M MIMMM NMOMM Mill. IN M|Rtl MUM MM* M MMrta l|M IN NHMNM. N*t|KM I/II/M0. TIC*. Will NwM mmIhm kwiii im mnmMI wa mu. mU NUHlMN fmm. In tifiiMN Imhmmi Inn iminm Mr I'WIUImImIIwmm. MMI uuriM tffMI f Mar MwMi (lUIK* f MmIiIIm n cn m.u. m.n M n J, 1. ink f(MI 225 HONS 025826 N-NIIROSO-H-ETHYLURCA Th*r* fi sufficient evidence for the carcinogenicity of N-nltrosoN-ethyluree (EMU) In experimental animals.1 EMU vet carcino genic In el) animal species tetled: nice, rats, Syrian golden hamsters, rabbiti, opossum, pigs and monkeys. It produced benign and malignant tumors following administration by different routes. Including single oral doses; the main target organ appeared to vary with the route of administration. Prenatal exposure to the substance was shown to be particularly effective In producing tumors of the nervous system. In several studies, dose-response relationships were established.21 1 International Agency for Research on Cancer, 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: ]ARC, 1982. `International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. Lyon, France: IARC, 1978, pp. 191-7.5. EMU Is e water-soluble crystalline solid. ENU belongs to a group of chemicals that are widely distributed In the environment as contaminants. This compourd has been used for the laboratory syntheses of diazoethane. ENU Is produced In small quantities for research purposes. However, the Tonic Substances Control Act, Chemical Substance Inventory, 1*79 (public record). reports approximately 360 lb of EMU were produced domestically by one producer. Data on human exposure to ENU are not available, although laboratory personnel may be exposed to this compound. The ERA proposes to regulate EMU under the Safe- Drinking Mate* Act and has regulated It under tne Resource Conservation and Recovery Act es e hazardous wa-te constituent. 726 MOMS 025827 t*4 ltk(f Mlw Wit H*|W l* K*riH, l/tt. Nt|f IW4*<i KU. MM.SMtt MtU ffiMti, NUMl, Wl Will mn ! mmi ** law it I*** 4M*f *W toH< 'tolt** MM*. Ill* .**1*41*1 1** M MltrWH iwftiiMH # mim, wl iwjim *> IWM to IMtoU It to IK MM tollf*' MM. IrwIliM VIUM. IKK. Kill >H)MII r***rtlf Ml* rtvlr| wm toto. Mill to* f//W. to (**** timiMi 4mm nitwit Mf imilitwiMfiwMi. IffMi t lifii'iiwi: tow (* Ctuttto * OM MM'MM. I/M to CM lll.lt. III.)) If II <1. |. Itoto 111*1 227 HONS 025*28 M-MITROSO-H-MCTKYLVmEA There Is sufficient evidence for the carclnogsn'clty of N-nltroso-N-methylurea (NMU) In experimental animals.1 mu wt carcinogenic In all animal species tested: nice, rats, Syrian golden, Chinese and Eu'opean hamsters, guinea-pigs, rabbits, gerblls, pigs, dogs and monkeys. It Induced benign and malignant tumors following administration by different routes, Including 1ngest<on. It produced tii.no't at different sites, Including the nervous tissue, stomach, esophagus, pancreas, respiratory tract, Intestine, tynphoretlcular tissues. Skin and the kidney. It Is carcinogenic following Its adminis tration prenatally bv Injection to mothers and In single doses.* 1 International Agency for Research on Cancer. IARC Monograph; on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. lyon, France: IARC, 19(2. ^International Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. Lyon, France: IARC, 197S, pp. 227-55. MW Is soluble In water and polar organic solvents. NMU Is used for laboratory synthesis of dlazomethane, but It has been largely replaced by other reagents. It has alto been studied as a cancer chemotherapeutic agent, either alene, or in combination with cyclophosphamide. There Is no evidence of any commercial production or use of NMU; any production would be for research purposes. The EPA listed one producer, and the Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, reoorted production o' 350 lb (public record!. Few workers are exposed during the production of this compound, and only a limited number of research laboratory workers are potentially exrosed. The only direct exposure would be to cancer patients through the administra tion of NMU as a chemotherapeutic agent, but there are no reliable data for the frequency or extent of this use. Under the TSCA, 8(a), CFA has proposed a reporting rule requiring NMU use data. The ERA regulates this compound under the Resource Conservation and Recovery Act. 228 moms <u5ai9 t**l-avt* ! **UtlMt M ItMf Ictlwt KM, iMJXtl NIK IXMII, MUM*. M *mM mi* Mt U turn ! IM %% H *** ft* rtmt/mMimiM 'inimi. *Im MlfMtrt (IXI'WXI *1 M'.U, |N MfKlI NIIH INM II tNUU It U IM NNliMlltl. IrmlfilN %n*m. Ivt, ui: inhin mxttN mt NjjIHN IN M MM, INIIM4 1m UNlNfH MHUNH I'M llltMIt Ml' (lllblMMflMNW. IBM! UWktllM Iffrn *f HN' tniu (lUI'M %t im'ivi* *cri hi.ii. iii.u (t n i. i. !Mt It*) m HONS 0^5830 N-N1TROSOMETMVIY1NYIAH1MF There (t (efficient evidence for the carcinogenicity of N-n1troso*?thy1v1nylenlne INMVAi In experimental animals. W1YA was carcinogenic In roti, the only species tested. It produced carcinomas of the esophagus, tongue end pheryni after continuous administration In drinking rater end carcinomas of the nasal cavities after Inhalation exposure.? international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. lyon, France: IARC, 1982 `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. lyon, France: IARC, 1978, pp. 757-61. HHVA Is a pale yellow liquid that Is very volatile ano photolablle. MMVA Is soluble In rater, organic solvents, end lipids. It Is re'atlvely unstable In aqueous solutions. The only known use for MMVA Is limited to laboratory research. M1VA has reportedly been found at a contaminant In apple brandy. There Is no evidence that this chemical has ever been produced com mercially. The small number of researchers using NMVA could be exposed to It, and contwnert of contaminated aople brandy might be directly exposed. The ERA has Included NMVA or Its list of carcinogens and regulates It under the Resource Conservatlor jid Recovery Act. kUtltlM M tllMf Attltftf KV( Mjadi mu >ni>cUi ffmwwtfkrttui muw. m wti) wi* Ml M mtll VM l| M NMltRf UK W|inMMUM-lf Ml* IMIoRI n R|||f(NI imiMhri If mu MM MJMII OIIUI MM t *uu HUM Ml iwrtm MU. NnltiM WIIM. m tmluiN MtntMt Ifw mtlMUl MUr (NttrlMlaiMiMAi. KM t KMUTltftS t'fm If liplrtlini; MM' CiMiti (lutlin f llflllltl* * cm jM.ii. IIMI 733 HONS 025831 N-NITROSOMORPHOCINE There Is sufficient evidence for the carcinogenicity of N-nltrosomorphollne (NMOR) In experimental animals.' NMOR was carcinogenic various fish, mice, rets, and hamsters (Syrian (olden, Chineti end European). When athiinlstered In drinking water, It produced benign and malignant tumors of the liver and lung In slice, and of the liver, kidney and blood vessels In rats. After subcutaneous Injection It produced tumors of the upper digestive and respiratory tracts In hamsters; It vat carcinogenic after adolnistratlon In single doses. It produced liver tumors In rats folloving Intravenous Injection. When dissolved In tank vater. It produced liver tumors In various fish. A study In boasters has been reported In vhlch a dose-response relationship was established.2 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to (batons. Supplement 4. Lyon, France: (ARC, 1982. 'international Agency for Research on Cancer. 1AAC Monographs n the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. lyor., France: IARC, 1078, pp. 283-80. NMOR is a yellow crystalline solid that Is water soluble. NMOR belongs to the chemical group of N-nltroso compounds, which are widely distributed In the environment and can also be formed In the htrntan body. NMOR Is neither commercially produced nor used In the United States, although patents have been issued for Its use as a solvent for polyacrylo nitrile, an intermediate In the production of N-anlnomorpholine, and for application as an antimicrobial agent. NMOR has been detected as a contaminant In analytical grade dlchloromethane and chloroform. In morpholine (0.8 ug/g), and In a rubber cross-linked accelerator (0.4-0.7 ug/g). Human exposure to NMOR may occur by Inhalatlcn and less frequently through Ingestion and skin absorption. Workers In chemical research laboratories and In the rubber and tire manufacturing industry may be eapostd to the chemical. An average worker In a rubber or tire factory may be exposed to amounts In the range of P-130 up NMOR/day. Wastewater from these factories contained NMOR at levels of 0.003 ug/g. Dirt scrapings from a staircase In one of the factories revealed an NMOR level of 730 ug/g. A soli sakj'e taken outside the tame chemical plant contained NMOR at 4.4 ug/g. 231 HONS 025832 If-nitrosamlnes ara frequently produced during rubber processing and My be pretent at a contaminant In the final rubber product. Caposure Is depen dent on the ability of the nltrosaolne to olgrate out or the product and enter the body. CR$C has a project under way that Is examining children's rubber pacifiers. The study will determine the presence of specific nltrosemlnes and the amounts released under nonaal exposure conditions. The CPA regulates HMOA under the Resource Conservation and Recovery Act. < mwirmlm MfllltlMI Ml ft**' kltMt ItVMMlMI HI IH|Mt Hi llMflllf)i IMWI IW MdMpf* if HM MH*U M HtrHMlH HllliN trm NlHWri, (CMC) I0U, ItbsfMUl tl MMNM M I OMWIM MMIItaTtl f M*t, Ml MHMl MINI MM U WMM tl It MMlttf IN MfirVmMIIIMMI NMk fwlfiw l/lt/W. Ill tlM<MM MMIMMI (ffa| lUlMdM Mir IvMlllilMiRl.liirMi. IIMI C* If IlftllllMli MklP (iMMtl *t IlfdlltlM Cfl Nl.ll f(M| 232 HOMS 025833 N-H1TR0S0N0RNIC0TINI There Is sufficient evidence that N-nltrosoncrnlcotlne (NNN) Is carcinogenic In experimental animals.1 NNN was carcinogenic In rats, mlee end Syrian golden hamsters, following oral aihnlMstratlon to rats, It produced carcinomas of the upper digestive tract, mainly the esophagus, and of the nasal cavities. In hamsters, subcutaneous Injections produced mainly tracheal tumors. In mice, tntraperltoneal Injections produced lung tumors.* international Agency for Research on Cancer. IARC Monographs on the (valuation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 198c. `International Agency for Research on Cancer. IARC Monographs on the (valuation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. Lyon, France: IARC, 1R7B, pp. 281-86. MM Is a yellow oil that Is Insoluble In water. NNH reportedly does not have a commercial use, but It may be syntheslled for research purposes. No evidence was found that NNN has been manufactured commercially In the United States. Cigarette smokers, tobacco chewers, cancer researchers, and organic cher.lsts art at greatest risk of exposure to NNN. Cigarette worters and tobacco femurs have low exposure to NNN because the compound Is released during curing. Footers and persons breathing tobacco smoke may Inhale a significant amount of NNN. The amount pf the substance In commercial V.S. tobacco products varies from 1.8 to 88.6 ppm; this Is one of the highest values of an environmental nltroso corpound reported In the literature. Approximately half of the NI.'N originates in t'<e unhgrnt tobacco, whereas the remainder Is formed during burning. The Office on Smoking and Health has estimated that there are currently S4 million smok-.-rs <n .he United States. The (FA has placed KHN on Its Carcinogen Assessment Group lift of carcinogens and hat regulated It under the Resource Conservation and Recovery Act. anmwNniM*w KUUVMRS Hhgf tnttK tkw, MnMit tnifunii tn mwR< tf >8(|XWI NRttthwgl Mte Ht MfcjMtl d8Ml IR8M H C8RMU t 1 am i8M*Vmi*mi| mn$. PnmifHm 1/18/M. lit tMtMp 8|t8tt88Rt |fW Ihlwm 8dMg }>Kt()ll<aU8ri88f8|. KMI tffteHtugIef hfNllllWli at(IUI'88 Mpmiw m ckmmt;ti.n 233 MONS 02583b N-NITR0S0PIPER1DINE There Is sufficient evidence for the carcinogenicity of N-nitresoplperldine (NPIP) In experimental animals.* NPIP was carcinogenic >n nice, rets, hamsters (Syrian golden, European and Chinese), end nonkeys "hen edninistered by severe) routes. It produced bvnign end malignant tumors of the liver, lung, forestomach end ntophogut In nice, of the liver, esophagus ond respiratory systen in rets, end of the upper digestive tract, respiratory system and liver in hemsters; it also produced hepatocellular carcinomas in monkeys. It was carcino genic In nice and hamsters when administered in tingle doses.* 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Muatans. Vol. 17. Lyon, France: IARC, 1978, pp. 287-J01. NPIP belongs to the group of compounds known as nitrosamines. NPIP has been used in the production of epony resin for electrical leads and for cardiovascular implants. NPIP is not manufactured on an Industrial scale but is produced by one company specialising in laboratory chemicals and told in 2S g quantities, because of the small quantities produced, exposure during production Is limited. Nitrosamines are rapidly decomposed by sunlight and therefore do not persist in ambient air or water. The general population way be sporadically exposed to low concentrations of NPIP from cigarette smoke and certain foods. Several scientists have reported trace amounts of NPIP In cigarettes; however, tnese observations hevt not been confirmed in all brands of cigarettes tested. There is evidence that NPIP is present in processed end preserved meats. Concentrations ranging up to (0 vg/kg have been detected in meat and fish products such as bacon, bologna, wieners, and smoked cod. FDA published a regulation on November It, 1973, which requires separate packaging of spices from sodium nitrite 1r dry, premised cures; this dramatically lowered NPIP in dry mixes. The presence of NPIP in meat, cheese, and spices results f:*m the use of the nitrite as a preservative. FDA has estimated that between 10,000 and 100,000 patients mey be exposed to NPIP by medical Implants. The FDA bureau of Medical Devices hat not taken regulatory action at this time. Occupation with the highest probability of exposure to NPIP are cancer researchers, organic chemists, and workers engaged in the menufeeture of pacemakers. 234 HONS 025835 N-nltrosaalnet art frequently produced Airing rubber processing and aay be present at a contaminant *n the final rubber product. Exposure la depen dent on the ability of the nlfosamlne to migrate out of the product and enter the body. CPSC hat a project under way that Is eiamlnlng children's rubber pacifiers. The study will determine the presence of specific nltrosamlnes and the amounts released under normal exposure conditions. RPIP has been Included In the list of chemicals assessed as carcinogens by the CPA Carcinogen Assessment (roup and Is regulated under the Resource Conservation and Recovery Act. The FOA regulates NP1P under the Food. Drug, and Cosmetic Act. KttUtIM i*#totte tea* liber Kligni (ffMttIbitff 9(MM-UM1Imi; lUfMiblwt 1* Nilfttn jei i UMfMifr iMIll w MiUfUf M mdKj if iliwwi# raltiMt trm (9SC) KM. tm-mh bMNtl IU ffrWKlfXillll NKIN. Ml MID MM* M*mlrvtomM*rtoilMl *#1ttIoMimt#iitmo MmM. lIiafimMV #|I|MM N MMflM IMtllMM If ttltoa MV Mttom MtIH IMM to tMMII II to IM MM englMMlI. IfrnlflM I/19/V0. TfCA, *<i)i fmnii fn*rvt| f*i nMriif mill *M im *u. swum* tm/vo. It* Cmlnogeo tiiogpent (roug ititMM tMt* |4tlWRlf)|tRl. IPAI W VvrvM */ UMl. mU. irut (fwlAMftUMMM*f*ifttfnfflwUitMttMi tfNmttd<d(l f(tMii| If**) tllllMb t AtftUUM 10 C9K Ml.11, Hl.U s n is((.H). ism* W*. N)lintl>flN, ll/U/7). CM 11, 191.4# (fMI 235 HONS 0^5836 M-MITROSOPTItROL 101HC There ft sufficient evidence for the carcinogenicity of N-nltrosopyrrolldlne (NPYR) tn experimental animals.1 NPYR wot carcinogenic 4n rots after administration In drinking water. It produced hepatocellular carcinomas. It also Increased the Incidence of lung adenomas In mice when given In drinking water. A study In rats was reported in which a dose-response relationship was established.< International Agency for Research on Cancer. |ARC Monographs on the (valuation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 17. lyon, France: IARC, 1978. pp. 313-26. N-HItrosopyrrolldlne (NPYR) Is a water-soluble llnuld. NPYR belongs to the group of chemicals called N-nitroso compounds, which are widely distributed In the environment and can also be formed In the human body. There Is currently no evidence of coanerclal use of NPYR, although It was reported by one producer for the Topic Substances Control Act (TSCA), Chemical Substance Inventory, *979 (public record). Exposure to NPYR can occur by inhalation and by Ingestion of nitrite-treated nests (e.g.. bacon, sausage, and ham), condiments, tobaccc, curing spices, and animal feed. Heating nitrite-treated foodstuffs may result In formation of NPYR. The recent trend to decrease the concentration of sodium nitrite In food and use ascorbic acid as a substitute preservative hat decreased exposure to NPYR. For example, bacon contained an average of C7 ug/kg of KPYR In 1971-74; but hy 1975-76, it contained only 17 g/ka* When bacon Is fried, an average of SO percent of the NPYR normally present In bacon Is found in the vapor. NPYR has also been found In tobacco smoke In amounts up to 0.113 vg/clgarette. The residue in pipe bowls has been found to contain l.C mg o.' NPYR/kg of residue. In 197t, NPYR production and manufacturing facilities were reported as having 0.09-0.20 ag/1 NPYR In their effluent. Dry premixed cures containing spices and sodium nitrite have been found to contain 40 vg/kg NPYR. In tolces, NPYR Increased to S20 vg/kg during 6 months of storage. NPYR hat been found In SO percent of certain animal feeds at levels of 1-26 ug/kg. There are no available estimates of the extent of human exposure to NPYR; but It should be assumed that exposure Is prohehlc when nitritepreserved foods, especially fatty foods, are heat-prepared and Ingested. 236 fiONS 02583 7 R-nitrosamlnet irt frequently produced during rubber processing end may be present as e contMtnent In the ftnel rubber product, Cxposur, Is depen dent on the ability of the nitrosamine to leigrete out of the product end enter the body. CPSC hes e project under way thet Is examining children's ruSber pacifiers. The study will detenelne the presence of specific nltroSMines and the amounts released under normal exposure conditions. Currently, the CPA regulates WPYR under the Clean Water Act (Cwa), the Resource Conservation and Recovery Act (RCRA), and the TSCA. Under the CWA, the CPA hat published a water qua11t> criteria document for nitrosamlncs; the document addresses NPTR. The RCP.A subjects spill residues in excess of 2200 lb to handling and report/recordRceping requirements. The TSCA reporting rule requires use and process data to be published. UM IlfillllOW mi HMf MtlMI IWMMdll Id MClftw* pMjMt Id lnyiH. IMdfltdfy ItdUtt M* rRoiip* 1M M MNH tf RilPdMdldl fflldM Ifdi pMIMlPt. (OKI CM, Mllli Mp Nl(ly ip1Mp< Ml^lM Id flNl ldd, MdfMWl 1-dltfdNmPinilM. KM, Wl*NN; hdJKU etatf KiMti. faialMOMUtllP'Mimi, Mill PtHMI 1* MUM Ml *f H MMllRf dM Utft/WWMWMH UUtPUMM. Mu MlfNM MIU|WtMHlll M * Mllflddt MNtllMM df MUI, M Wdjectt MW !** (MUM 't Id IN IM niMt<. Mvwlpm 1/19/U. UCA, 1(0): IpgfMM .MMtlaf ut ifi<i niimm ivmnmm. m u mu, tM (dPtldltM UMMMMt (MM dUUMdl NM' l-MPl/lriW/lqdy*<M. dHI MMUTIM Kfdtt df MfvIllldMi IMP CMMII Ctutdw df ItfiUtMR s h nt, p. itM 0 CM m.lt. Ml.u i n d|, $, ijmi IKM) 237 HONS 025038 U-hlTROSOSMCOSlW There Is sufficient evidence for the carcinogenicity of N-nttroiotarcosIne (KSM) In experimental animals.1 NSM wes cerclnooenlc 1* nice end rets. It produced ctrclnonei of the netel cevltles In alee end esophepeel carcinomas In rets efter administration In feed or drinking water, end liver cell cerc1nop.es In newborn alee efter Intreperltoneel Injection.? 1 International Agency for Rtsterch on Cencer. i.'.r.C Monographs on the Evaluation of the Carcinogenic Risk of Chealc.l. to Huruns. Supplement 4. Lyon. France: 1ARC. IPS?. `International Rpency for Research on Cencer. IRRC Monoprephs on the (valuation of the Cerclnopenlc Rick of Chealcals to Munans. Vol. 17. Lyon, France: 1ARC, 1S78, pp. 327-35. ISM Is a pale yellow crystalline solid that Is soluble In water and In polar organic solvents. USM Is neither produced nor used eoaacrclally In the United States. It Is, however, produced by various cheat cal reactions In air, water, soil, food, and antaal systeas. This compound has been d'tected In foodstuffs, particularly meat, In concentrations of 2-56 p/kp of saaple. The pcneral population nay be exposed to NSRR by dietary Intake or throuph Its presence In the environment. IBM has been Included In the list of carcinogens prepared by the (FA Carclnooen Assessment Group. (PA regulates NSAR under the Resource Conservation and Recovery Act. MltlPIHITHlt ItfbWCdM wd MRpF tetfpns Ktt, Mt'NM: lnjw ntt mwti. vtatMcirntm* mumi m win wijm wHi it W> >t % iMHftNMi. him mipmtat m MNtlMrt If Mm, 4 MUMi Mim lam m wm(i It M M Mtrtwmlt. MUim l/tiw. In tawf--w UlMMMt Ifpm iiHnmI mmr lcttylMi--nwmi. ftH| anauTiM IffKt If ImUttdMi MM' tmaaii etuuM If lafulltfM 0 ttt Ml.lt, HUM ftH> 238 HONS 025839 OXYKCTHOUMC Ten cases of liver-cel) turnon hive boon reported In patients with blood dtsorders t'tiled for long periods with oxymetholone llone or In combination with other androgenic drugs; however, t emit relationship cinnot be established. The increased risk of liver-cell tumors could be related to hepatic damage known to be caused hr oxymetholone. Alternatively, patients with conpenltal anemias may he at htjher risk of developing these timers, and this risk nay beeone Manifest during the extended survival resulting from oxymetholone treatment.' This Is considered to provide United evidence of carcinogenicity of oxymetholone In hiaoans. ho data are available concerning the carcinogenicity of oxymetholone In experimental animals.* 1International Agency for hesearch on Cancer. lAhC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 13. lyon, France: 1ARC, 1177, pp. 131-39. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to humans. Supplement t. lyon, France: IAAC, 1982. Oxynetholone Is a synthetic steroid hormone having actions similar to those of the male hormone, testosterone. As a pure substance, oxymetholone Is a crystalline solid that Is practically Insoluble In water. Oxymetholone Is used for adjuvant therapy for senile and postmenopausal osteoporosis. At one time, a major use was for treatment of anemias. In 1972, the FM dropped Its approval of this use pending further Investigation. Oxymetholone Is also used as an anabolic steroid for small animals. Ho evidence has been found that oxymetholone has ever been commercially nroduced In the United States. One U.S. distributor hat boon reported. The U.S. International Trade Coaarittlon reported in 1981 that oxymetholone was Inputted; however, no specific Import data are available. human exposure to oxynetholone can occur principally during its use as a pharmaceutical. FOA's bureau of Drugs estimates that SO,000 to 100,000 patients art treated each year with oxymetholone for postmenopausal osteo porosis. The usual adult dose of $-10 mg/day is administered orally for about 3 weeks, but not exceeding 13 weeks, for a tingle course of thtrapy. FDA reduced the list of approved uses of oxymetholone in 1972. Since 1977, warning labels of possible adverse effects have been required. 239 HONS OiSflhO KhMIim Mi HHr Nttmt M tlTMl KIM. M I4M KtMWI WII1 KMMlI Mi' CISC M'MKtlM. tno Iknw mj>mM*1mi Is < HwwUlil, IN on M*lWl nyiw^ tallftn Hi It. klWN mn It m ntMi 9* smii'i MMlMtM*. *1 Is MlMH? <l IN *f1l lwml|Hl SMNtS Hr NsSNIf flfilltlw. CMIATIM IfNcs ? **MittMi: Mw (mm If NfllltlM NT--ININS Ml WHOM Ml? I|r Mil* M*t f |Nl| UHM M NflClMl N# IlM Mil inNIN Mi MS IMMMi In W Nr MN? Mi ifflCtlMMSI. UNI I?, Ill MH' MNMNN --CMI VMlII?* UNMHr MJmmC MMM? Il MIMMMMMI MSMMlI NM Nm WtM I'm IN UNMN N***** IMINT MmsUmHn f MIS tSS MM iHnUh Mm im. IlM) N 197?, IW MM*Ni I mvIsIM M M9 MlfM MMIIM MCtlM Mt Mill HKNM I lUMill M Ml KtvrrMM * WMmIMm MNlMM Mi MHmII Mm* tHN H MMClIIlM MM MMlHl MMfNH Mtmi/. ISM mtrlltM M Mluirl Mnw cn ti, NKHStir 9 IfMI 240 MOWS 025841 PHMACCTIH There It sufficient evidence that phenacetln It carcinogenic tn experimental animals.1 Rats fed a diet containing phenacetln had an eicesi cf natal and urinary tract tunori. Phenacetln given In the diet to rata enhanced the urinary bladder carcinogenetlt after they had received H-nltroiobuty1-U-l4-hydroxybutyl1amine In drinking water.1-* The evidence for the carcinogenicity of phenacetln In huau.ns It Hail ted.1-* 1 International Agency for Petearch e.i Cancer. IA.tr Monographs on the (valuation of the Carcinogenic Alik of Chemicals to Humant. Supplement 4. lyon, France: IAAC, 1992. `International Agency for Research on Cancer. 1A.1C Monograph* an the (valuation of the Carcinogenic Rltk of (Itealcalt to Humane. Vo). 24. Lyon, France: IARC, I960, pp. 135-61. Phenacetln It a cryttelline nowder that It toluble In water. Phenacetln It uted at an analgetic and antipyretic drug. It It vied alone or In combination with aspirin and caffeine for the relief of nlld to moderate autcle pain. Phenace*ln hat alto been uted at c tub!liter for hydrogen perokIde In heir bleaching preparations. In veterinary nedlclnt, it Is used as an analgesic and antipyretic. Phenacetln hat been produced coeanerclally in the United State! for over SO years, ir. 1979, the (PA indicated an annuel donettk production of approximately 550,000 1b and Import! of 240,000 lb. Human expoture to phenacetln It primarily through Ingestion. The chemical It generally ('emulated with other pharmaceutical agents and used in over-thecounter (OTC) remedies for pain and fever. A high proportion of the population may be exposed to doses ranging up to 1 g per day. The usual dose It 300 mg taken 4-6 timet per day. The CPA regulates phenacetln r.ider the Resource Conservation and Recovery Act. After an advisory panel determined that phenacetln could not be consid ered 'safe' for OTC use, the FOA held hearings to remove it from OTC products. This action ha: been challenged by objections concerning the validity of the carcinogenicity data. 2*1 HONS 015842 KtUUUttS H 9tMP ktlMI tt (***( KtIM, M IM It CttMHMf **4*r {!!( JwrtlttCtlM. Wit) Iffcct f Iffilitltt; 4tlMP (MMItl ClUtitt *f Itftiatitt K4A. Wl'NM. SdiKU |U trtOtcU. fHN(1llcat MKHt, MX l>UI M1Ml It Wfii af 1904 l u MNH( MX It|l 4lltMU| *ttctli M 1 Mtlffwi CMIttbfM tf Mitt, MX IttjKtl Mlttl tw it ctau<* H b tlx u pattlft* tttu. frtaMlfatao l/it/40. tn UitlMM* ItmtMtt Imm iuu. MM ttftf ixtltllltlixnMMM. KM) *o era hi.n. hi.i* in*) IM 3*ptw *f tnrfS. fMC*: ffctatmit Ml MM tHltMl b MM ltl(M IMt M> ITS 1at0P0l OMlpttC. OttlpTfOtH. 0t4 MtlittmUC Ktotcls Ml MtOfOrlM M M MfKtlM fit MXttltb tt4 MM* mil Mt Ml Mil ftp Itc tat. At fM im IMMlM iMalltritlM MtCMflfl M IttttHM MMt> Mt M|tM<m MX Ml* rtliH tttotPtltj MM tallfltr of Mm cirtlMfnttli mu. At ft* it tNX att f t ftltltt tt MU MM tt ttU tXMCM tit # ktttt MM* KtPClttttt. It M* llltl it n at Mt} uftiMfM * ittt Mfttt Mt* MlltMU W IttOtMMU tt IMfMit Mm* upittftticii^rrti*atltt. At >rMtrt actitt Mill rtttv* ttatacatla Ina txr*tM*(M*Vf fratarallata. in*) OtctMMMatlat tf IK itttPtai MMity iniM fatal for atal* ftaita att aMlMati* tU pptatfti. If**) HONS 0258*3 PHEHAZ0PYR1DINE HYDROCHLORIDE There ti sufficient evidence for tK carcinogenicity of phenszopyridine hydrochloride In experimental anlnals.1 Phenazopyrldlne hydrochloride wa> tested in BCFJFl nice and Flscner 344 rats by dietary administration.! In female mice. It sljnlflcantly Increased the Incidence of hepatocellular adenomas and carcinomas. In mole.and female rats. It Induced tumors of the colon and rectum.-.3 ^International Agency fur Research nn Cancer. 1AAC Monographs on the evaluation of the Carcinogenic Risk of Chemlcals'to Humans. Supplement *. Lyon, France: IARC, 153?. `national Cancer Institute. Rloassay of Phenazopyrldlne Hydrochloride for Possible Carcinogenicity. Technical Report Series No. 99, OHCW Publication No. fNIK) 73-1349. Oethesda, Maryland, 1978. ^International Agency for Research on Caxer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 24. I,on, France: IARC, 1980, pp. 163-73. Phenazopyrldlne Is a heterocyclic organic compound thet Is slightly soluble in water. Phenazopyrldlne hydrochloride has been used for 40 years as an analgesic drug either alone or In combination with other drugs to reduce pa<n associated with urinary tract Infections. large-scale production of phenazopyrldlne hydrochloride began In the United States In 1944. In 1972, two companies reported production, but no data were published. The National Disease and Therapeutic Index reported in 1980 that 21 percent of this chemical was used in hospitals. Data from the National Prescription Audit reported that retail ph-'.macles dispensed 4.4 million prescriptions In 1980. The average adult dose rate Is 200 mg three times dally. Exposure to phenazopyrldlne hydrochloride occurs during manufacture and formulation. The 1974 Nitlonal Occupatlmal Hazard Survey estimated a potential occupational exposure for 2800 persons. The FDA has approved the use if phenazopyrldlne hydrochloric; for symptomatic relief of pain and other discomforts arising from Irritation of the lower urinary tract. 243 MOWS 0*5844 ftWMIMjrrttflftC %t*t<h1irHf Mftat1t lirf hk|r a ct"t"t Ktla*. li* f'tflWI I* tMtftr rMKlt ***** CISC ^IKUtlW. IC*C I Htuxwlltll, ft* Ml tMMl tflWllirlli. tfftct tf Rtf*itiai: ttlKf ru Mm tf Hfi, fMCAi tfffMtl far pttitrlfUM tit il|. fl* ft ttlftvrtt tin ftcltlltt tf tUttatiU Mttt CtrcIttfttlCMjr IM tttt tufitlt* l(luiti*i a* IN tatati tf mil arittr? m*t|rtic. IfMl t*Iht thrtttt Utft*Un W`MIU rtlllf tf n<i ttfttMf, irMMi, Ht IlKMfKtl llMlltlt aim iMr 1HM7 tfitt tfactla** ftttff Itttlltf tit) rtfltct CtfTftt tttlttt It *U. ciuilm tf t! (fl, Ittcmttt* IfM) z HONS 025845 PHEWTTOIW The evidence of carcinogenicity of phenytoln In human subjects and In experimental animals it considered ts limited-1 Phenytoln wes shown tu be cerclnopenic in mice efter adminlstretion in liquid diet or by intraperltoneal injection, produci09 lymphomet end leukemias. Studies performed with rtts were considered inadequate.?.3 There ere cate rtpons a..d epidemloloqUal studies of lymphomas occurring In patients that received phenytoln; nowever, nc excess of lymphomas was reported in a lollowjp study of eptlepry patients, many of whom received phenytoln along with other antiepilc^tfc drugs. Thr:e recent papers eport one case of mallanant mesenchymoma and two cases ol neuroblastoma in children with phenytoln-Induced malformations, tn epidemio logical study looted at the frequency ef use of phenytoln end of phenobarbitone in mothers of children with childhood cancers compare!, with mothers of normal children. While more mothers of cancer cases reported a history of epilepsy, no differences were teen in the proportion of epileptic mothers who toot either phenytoln or phenobarbitone. An excess of lymphomas was seen in children of epileptic mothers, but the occurrence of brain tumors was not reported.'>3 ^International Agency for Research on Cancer. IARC monographs on the Evaluation of -he Carcinogenic Risk of Chemicals to Huaans. Stipelament A. lyon, France: IARC, 1982. -International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 1. -yon. France: IARC. 1979. 3lnternatlona1 Agency 'or Research on Cencer. IARC Monographs on the Evaluation of the Cerclnopenic Risk of Chemicals to Man. Vol* 13. Lyon, France: IARC, 1977, pp. 201-25. Phenytoln is e heterocyclic organic compound used in the treatment of grand mal epilepsy and Parkinson's syndrome end in veterinary med<:1- Commercial production of phenytoln was first reported in the United States in 1946. The ERA indicated that phe.iytoln was not reported to the Toxic Substances Chemical Inventory I1975-1977). In 1977, IAkC reported that U.S. sales of phenytoln for use in human medicine were 171,000 IP annually. Inpcrts for 1974 were approximately 15,000 lb. 245 HONS 025846 HunuA esposire to phenytcln occurs prlnctpilly durlnp Its use os Onip. Flpures on the number f | 'ttents ustno phenytoln ore not (volUble, but pnenytoln Is plven to motor secwnt ot l.idirldusls suffer!np from epilepsy. The Orel dose rite. Initial " 'CO np three times per dey, cen produally Increise by 100 mp every 1-1 w-, until the desired the'ipeutlt response Is obtifned. The Intrivenous dose : .'CT-3SO mp/diy. The CPA hoi not reported tny diti Indlcotlnp the presence .1 phenytoln In effluents, emissions, or uestes from phtrneceutlctl mnufutur.;s. TI1.1 FDA repul<tes phenytoln os presr Iptfon drup. The Rureiu of Drops Is eiemtnlnp the tnformtton on potentlil hinen huirds from phenytoln; n Idulsory comnlttee Mill recommend further repulitory action If required. PMiyuia M MMr Actlttt l wmM KtfM. it itM fmm in MiMr ininti attar CttC JirlilfctUi. (CHC) Mmi'. pMirtid m Ha mmiUp tall tit iMuttitwili, (N mi Malta) itfiUunr 1 Haftat la tar. Tut aMcr Ml M IfhtllllM tf IMF trtipnet I* tffttftta, Mtllw, if Mittl Ifi |MMt*mkt< MiMfKtwrtrta *** fact tfttl M aiMMJia: tf putupuli mi rtatrirc ft* 'SCA |t*PM8F7 IMtlltH LJt Vi*' Mjr M MMr tats Wt Mlf M i^vattifaut ftr tatiltla etttra). Ttt mM *f*awtin itltM, cm*rat m kmf Mtlcill (iRClWtl^f UFdMftMl f tWClF*, *dy flill tMlFtlt ftr IM (tniMMli fwtwrc. KM) Ilk Itrtat tf Ml. PMtAi Mtftlattt at a fFittrlftka M- Ym Mrtaa tf trail aaftti ttt Cut aciattlfU Ml* art tat naclniN tt call Mwttit a *imm man canlatft*.* Tat trttlat fcaa Rata mt it at atwlatry iMUm att ttalr raiawiiitito win n cataitM taftrt ttr lUUMit u UatH frtt PM. (PM) KttUTIMS Cfftct tf MmIiUmi; MMf CatataU tt attcHfc t|lit7 aetta* will tatat trftn at atnatfy atitltt taa tat* fatalttr. |f*A) ClUtltt tf MmU'.IM CPA II. McattttP * IPM) 216 tOAIS 025847 POtYBBOMlNAUD BIPHCHTIS (FI rammer FF-1) Flremaster FF-1 (Flremaster BP-6 containing 2 percent of Ctlcltaa trlstllcatel--a *1Hurt of pentabromobtphenyl, hexabromoblphenyl and heptabromoblphenyl with hexabroaroblphenyl being the major component--administered by givijt produced neoplastic nodules tod hepatocellular carcinomas In frmale Sherman strain rati.1 In another btoenay, Flremaster FF-1-- 1*0 adxlnlstared by geve9t--uas carcinogenic to Fltthtr 344 rata and B6C3FI mice of each tea, Inducing neopl.'ttlc nodules, hepatocellular carclnomai, and cholanglocarclnomas In rati and hepatocellular carclnomai in mice-2 ^Kimbrough, B.D., D.F. Groce. H.P. Korver, and V.W. burse. Induction of liver Tucors In Female Sherman St.-aIn katt by Polybromlneted Biphenyls. J. Nat. Cancer Init. Vol. t$, No. ), 1M1, pp. S3S-42. `National Toxicology Program. NTP Technical deport on the Toxlcoloir and Carcinogenesis Bioaitay of Polybromlnated Biphenyl Hlnture (Flremaster FF-1). Technical deport Series No. 244. N1N duplication No. B2-1B00. detearch Triangle Fart, North Carolina. 1BB2. Folybromlnated biphenyls (FBBs) were widely used as flame retardant additives In synthetic fibers and in molded plastics. FCBs art solid at room temperature and practically insoluble In water. They are mixtures of compounds containing, on the average, six bromine atoms per molecule. FBBs have been incorporated Into the plastic housing of many coamerclal products. FBBs have been sold to manufacturers of polycarbonates, polyesters, polyolefins, and polystyrenes. The Consumer Product Safety Commission (CPSC) reported that hexabromobiphenyl (HBB) was the major component In the most widely used PBB mixture, and that FBBs are not presently being used In consiaacr products. The coaaaerclal production of PBB began In 1970. Approximately 11 nil lion lb of HBB were manufactured by a single U.$. company from 1970 to 1974 and marketed under the trade names Flremaster BF-B and Flremaster FF-1. CPSC reported that the sole V.S. manufacturer of HBB ceased production In 1974. The remaining stock of this product held by the sole producer was reportedly exhausted .'n April 197$. Other PBB production ceased 1r. the late 1970s. EFA reported one U.S. producer (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record). The U.S. production of other FBBs (dectbromoblphenyl). at reported to the U.S. International Trade Cowlsslon, was greater than 10,000 lb for I960, according to VC1. 247 HONS 025898 Workers of a cheated company chit manufactured PBR were directly exposed to KB by tkfn contact, tnhilatlon, and unintonttonol Ingottlon. HBI wot detected In worker! ion ot a range of l.l to 1724 epb, end !n thtfr edlpose tissue at a renge cf 0.51-581 ppa. Approximately ynoo 1b of PSBs wore Inad vertently mixed Into '<vestock feed In HI chi gen tn 1471. ThouiarOi ot antaalt died or wort deatroyod. Initially. 8000 to 12.500 Htchtgan resident! were expos'd tn 1471 and 1474 to aeat, allk, and eggs contentnated wttlt PfSs. A general population survey conducted In Htchtgan revealed that only 10 percent Of the population did not have detectable levels of PB8 In their blood. Because the PBBs are biologically stable and slowly eliminated, significant body burdens could persist throughout their Hfitlaes. In 1474, the National Occupational Hattrd Survey estlaated that 4400 workers were potentially exposed to PBBs. The sources of PBBs currently appear to be residues remaining In and around plants that at one time manu factured, processed, or produced products using P88t. FDA stated that a potential for human exposure exists from the Ing-itlon of foods containing residues of these compounds. CPA Is currently proposing a reporting rule for PBBs under the TSCA, 8(a). Under section 40t of the Food, Drvg, and Cosmetic (FDIC) Act, FDA regulates P68 compounds u unavoidable environmental contaminants. In cooperation with COC and the Public Health Department of the State of Michigan, FDA monitors the long-term human health effects from acute exposure to PBBs. khultions M ftNr totlaftt tffMl af ftafHlaram; Otoar (MMBti tfutia* af t*f1atiM M tlffMl KtlM. (CrSC) Bt nfititiwi in firactaa uKlflcaMf at toll toaalcal. Dm (**; citi|wy, ctfttslalaf NUttllllf M IK*M (Mtlll, ll MjKt to * nkUI ISCA, Mat, nU. TSCA, l(i): liu<ri anafactortri to nH<t latant to mm ar <mira wBiita*i if ar fill* towfinn tatiNti ton. l/li/llr iiw tfsUtfa* Bata# a* tiaa Miirlt 1c)aSlat aattttW ea*ciaa*a*ietty mt m fMfiitlan Uut toast (Oarf. cals tra ast Nias insert. 1(H) 40 C' 704.M ((H) fcaairiataC as sMvalSatla snvitoNaaatal toafinit wmr tacitaa 49# af tot fMC tot. totlaa tavals far HI caateat: WH, SalryinSictt* Hast* itfs tansl f*a#s O.K fAf t.SO HA| o.m fA| 9.91 n/'< * (at Baals. tru) 248 HOMS 025849 poltchlorimateo etPHEnus The evidence for carcinogenicity of polychlorinated biphenyls (PC(s) In experimental animalt it tufficient, and the evidence In humans It Inadequate.* Certain mixtures of PCSt (e.o., Ktorch lor SvO, Aroclor 1254 and 12(0) ert carcinogen It in alee xnd rttt after adainittrallon In the diet, producing liver tumors.' A alight Incivtae in the Incidence of cancer, particularly melanoma of the akin, hat been reported In a teiall group of men exposed occupationally to Arocior 1254, a mixture of PC6s.*1 1 International Agency for Aetearch on Cancer. IAAC Monograph! on the Evaluation of the Carcinogenic Alik of Chemtcalt to Humana. Supplement 4. Lyon, Crance: IAAC, 1962. `International Agency for Aeaeerch on Cancer. InAC Monograph! on the Evaluation of the Carcinogenic Alak of Chemlctla to Humana. Vol. 16. Lyon, Prance: IAAC, 1976, pp. 43-103. AC6a vary In appearance from mobile, oily llqutda to white cryatalllne to)Id! to hard noncryttalllne reaint, with all forma Insoluble in water. lefore 1972, PCAs were uaed In tranaformer roollng liquid!, heat tranafer and hydraulic flulda, vacuum pump fluids, lubricants, plasticisers, fillers In Investment catting waxes, surface coatings and sealants, pesticide extenders, and for copy paper. Ay 1974, all domestic uses of PC8s were confined to closed systems. PC(t have been produced In the United States since 1929. Domestic production reached a peak volume of St million lb in 1970 and decreased to approximately 41 million lb by 1974. Annual domestic production prior to 1977 was approximately 35 million 1b. Except for limited research and development applications, the PCI: are no longer produced in the United States, and no import or export of the compounds has been permitted since July 1979. The release of PC6s from prior Industrial uses and the persistence of the compounds In the environment have resulted in widespread contamination of water and soil, with subsequent exposure of the genera) public. Aoutes of eiposure Include skin absorption and ingestion; a major source of exposure is through the diet. A 1976 report Indicated that fish, cheese, eggs, and contaminated animal feed were the major U.S. commodities <n whl'h PC6s were found. The percentage of food samples contaminated with PC6s decreased between 1(73 ,-nd 1(79. Aestdues of PCSs have been detected in human milk and fat samples collected from the general U.S. population. EPA rennrts that approximately 12 million persons within 12 miles of three existing and nine projected coxnercial incinerators could be exposed to ruinates of PCAs. 249 MONS 025850 lit-1*70. tPA Penned PCIs es 4 Wit)cl do Ingredient end cenceled reglstretlon ef product! contilnt nq the PCIi. CPA proaulgeted tonic pollutpnt effluent Ittndprdl in 1777 and nodi fled the aerklng tnd dfsposel rule (n 1*77. Thft lttr reguletlon hot boon effective In Identifying ond ellalnetlng seat lourcot. In 1777, EPA I lived i ben on aenufecturing, processing, end distributing pf PCIs In coanerce; aost aenufecturing bed ceeied volunterlly before these rules were Issued. EPA proposed e weter qutllty crlterle docuaent thet will protect freshweter, scltweter, end epuettc orgenlsas, es well es huaen heelth. Air pollution sources of PCIs were recently Assessed by CPA. end the need for reguletlon of enlssicns frna Inclneretors, the only source for which controls aey be estentlel. Is under consideretfon. Unde' the Sole Drinking Weter Act, CPA Is prepertng e report to the Congress roncernlno the neture end extent of PCI content netton, ts well es retonaendetlons for further reguletory ectlon If necessity. In 1773, FDA estebllshed tolerences for PCBs in severel foods end In feeds for food-producing enfaels. In 1777, four of those toterences were reduced. The current tolerences ere 1.5 ppa Ifet bests) In allk end aenufectured delry products: 3 ppa Ifet bull) In poultry; 0.3 poa In eggs; 0.2 pen In finished entael feed; 2 ppa In entaet feed coaponents of enlael origin; t ppn In fish end shellfish (edible portion); end O.ic ppa In Infent end junior foods. FDA Is currently considering the lowering of PCI stenderds In fish end shellfish froa $ ppn to 2 ppa end hes estebllshed ectlon levels of 3 ppa (fet bests) In red met end 10 ppa in peper food-peckeglng aeterlpl. OSNA hot ndppted on 8-hour ttae-wnighted evereoe (tender! of 1 ag/a? for PCIs conteIninn 42 percent chlorine, end 0.5 ag/aP for PCPs concelnii.g 54 percent chlorine. This stenderd wes Adopted by OSHA for toxic effects other then cencer. 250 "OHS 025851 H\yftltolMto* IlfiltllM Hi 9tMf MllMI mil, li Iihu n mta h iwn HanMt *f mtmt iiw Mir* UllMNIM WrpMftjUI. MiniMttM li^mMU M. lINlltf IKI, It Hi iltHMl Htl. *rtoalfa vwn. TKI, It MM MfrtlflM HIM H<m m im twn iMf ttir im, .|fM. MUM MIMI. |H M *HfKtfH*|( HWfUl*|. M lIlt'MtM * IIMH8 M*clilf (Ht HltflfitHt ll Mf%tM Hi |l|fUl raU). tftowlfato* l/JI/F*. t**f M*lf)i *t*r ***11* crt|*rl rlllMi M fto*l fern. M/M/tt. (M, Itodlt TmM ItMMM. *frta**t HWn. CM! Ml. toiinw n't* totoUim Hto>HlMI| ****rt**li toHUV (* to, .U Ml MM toNltof MMffVaf ItoifMMl. *rtoal|au* KM, Mt*tMti IftoMl Ml* Itolatot It Mtllto WtolMII to Hit *1 Mile *, it/u/n. M(|Mtol KM to MlMNI CIM'.ltoHlI I Ntm, aa* to immm toUMto M wwK/rtoim,| toiiif*. pl|Hii I/IMI. KM, MM: IftotlHIH aa to** ton* taf, M ** f*M. *r HH Mptol *1 DWtolMl itoiHI l|ll|MtM ItHTMI. *r*a*1*a* 9/IVTt. CM: HMIINIt *r Hwnit CWtUtM, I/M. mm iMM> to iiuniM li HH* totlto 1* NffHIM. VM: liwrt to Cnfftti, la *ra**ra> Il*a, *111 WMtai amrt Mi itlMI if Kt ItoWtoUto, toiltoiH, MM M*M toiltotltoM, mm ntolllM mm, if tHtnli Mr to Mini. to* tottoMM Mhunm Vm lUto* Mat MM** I^HtolHiaMlMm*. ItMl atWUHMS IffWt *1 la|*l*ll*ai lltor (mhU (HkiihI; PM**** Mattel*** Mart* If MlilMti Cttollaa al totoWKto ra aatica to.ll iaat to *11 ra*ttrau ffacta*. toMtn a** ton Mhiiiim. /nut Ml tottof llu MM/*r totlftoN. toM MMttl to*** HM allMMIM. Mtotolif lltlM far |H*m> to i/U/ti. lActoallr i/h/n.i toatl *Ma(KlM<*f Mi Hm a\a> twitr itKMttoto* mim to toaaa ftolM (ac**t far unit* til a**llcattaaal. ao era Mi.it, mi.n a ra. *. (ton a* era m a ft m, . mil a era m.m m ***** a* Cucurafti f***wr ca* la a*a.*ifaf aa* Mrt*rtoy to <*Mifall, a* t*a1* ftotoll M rttotltoa *1 *cci*aul to era nr.j. iir.u Vta*> *tot* *1* a*C Mcl* toMM. M IN Itti *1****! i*l aMraata* *C*i a a am lUtoftot litotn vm Ni aaaa taaalacra*. ii ra to, *. mm era mi.it ItoilllllM aa taa* r**'**t t*aclf`.cDr a*rtai* *C*i. W (FI Ml Iac1atrr* ** 9^'y Hm total a* **!** caatsal i# i*a if l|U MM. iimi MTS. *raft rca MtottoMWi. WN 00*, **r*aai taw'. Mill, I.H nrai (Uattto**) 261 HONS 025852 VMU1IM ll|8l(lMI M lu>tf kt<(M (tft ' lifilitlM; Ittir (mmiii FMCA, 999t UtwMCM tt* Kll N iMftlf- Mil (KXMlMMt la N'MlI M ItMi HMtlMH 1/1/7), fmrr MllfMll it* (N l/rt/7). Itll.1 )**! If )|H (fit Mill) ft < U MUIxlM* 1/19/M. 7M MMMM Me l*|f)*lfHtr if MUNd m m Mdiiiniiit lw My'i mU) M MMir to tm*mr M KUPfC M99t 9# tartrtaf f() lUMitll I* fl* M MllflM f IlMMl If*, vm MIN IMl* UNMt * ImU KMtlcHlf w**l. M19I MMA IMIIH 19 lawIt MKlKlIll )**!. (919) Hi) 1 9fJ*3 Mf M IK 99*99*9 99t*H9*K 9.1 9f/*7 Mr IM IM 9*m*t C9l9rlMl. ' flf NO mirtlll* MtH. (IMI*9 9999M9 H* Mil 9f9Ct9 IMr Matt CM***.} (Ml iMliMt llitryi . I9ft> NtlfMMaljr, 1 M/** MlW lIlMlIl wmiMiiw. %tVP\\ MM* Tatam* lt9*9*r*"9**fM IMI arfacttvt. IM) (IWlM 1 *fl8tlW 1) CN 191.39. 199.39 era nu.M 99 n. t. Mill im9 *7 , . 199)9 (fit) 99 Cr 19)9.1999 I9IM) *52 HONS 025853 PROCARBAZINE ANO PROCARBAZINE HYDROCHLORIDE Thera Is sufficient evident* for carcinogenicity In humns of Intensive chesiotherepeutle regimens thet Include alkylating gents, vine* alkaloids, procarbazine hydrochloride, ind prednisone. There Is Inadequate evidence for carcinogenicity of ptocarbazlne hydrochloride alone In lumens. There Is sufficient evidence for the csrclnogenlcfty of procerbazlne In experimental animals.!.* Laboratory exposure of animals to procarbazine was studied by tntraperttoneel Injection. In rats, malignant lymphoma, adenocarcinoma of the mammary gland, and olfactory neuro blastomas were Induced In statistically significant numbers. In mice, malignant lymphoma or leukemia, olfactory neuro blastoma, alveolar/bronchlolar adenoma, and adenocarcinoma of the uterus were Induced In statistical1* significant numbers.* Evidence of carcinogenicity was also found in sice and rats following administration by gavage; in rats following Intra venous adulnlstratloo, and In one In'tance folifwln; trans placental exposure. Two studies In two species of iionhjaan primates suggest that procarbazine hydrochloride may atso produce myelogenous leukemia when administered by multiple routes to the same antral.1 1International Agency for Research on Cancer. 1ARC monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 25. Lyon. France: IARC, 1981, pp. 311-39. National Cancer Institute. Iloassay of Procarbazine for Possible Carcinogenicity. Technical Report Series No. 19, BUMS Publication No. ININ) 79-B19. Bethesda, Maryland, 1979. Procarbazine, ar, organic ccmpov.iu > utuuie uui unstaole in water nr aqueous solutions. Procarbazine hydrochloride Is primarily used as an antlneoplasttc agent In the treatment of advanced Hodgkin's disease and oat-cell carcinoma of the lung. The FDA approved the use of procarbazine hydrochloride In 1969 and Indicated that the drug should be used as an adjunct to standard therapy. Possible exposure occurs during manufacture of the drug, and direct exposure occurs during administration to patients. The National Prescrip tion Audit reported 1.5 million prescriptions dispensed In 1980. Some of the metabolites of procarbazine are bath carclnostatlc and carcinogenic. 253 HONS 025854 IlfllltllN w< MNf IctlM M rnt N kMft KlH*c< In OM<l> prMMIl ttmr VfC J KMC) (ft Mt iMlw*rl 'ii I* r*ri1ti*l rMcMwin 11 MMtfCIVltClIl. IlMt fH, W<i Iwwil fir pnwMM'M M I* I HI. l>M kcuumhs crrwt if f(Mr tiwimi 9m mtrlttM W nIHHIh mmipmi if IMflU'l 41 HIM IM Hr f HMt M ki mniWMUt u IMf fliM #f ((Kir |n<WK. ClMr Cllll^ >lnla| if MCWMif mmI if !)< Iftvr ImteM IM imf< MlW ll |miM Ii MCI*9* ir**i CUitfM f Mfiliilt* (FI tl. (IM) 9 254 "ONS 025155 6-PROPIOLACTONE There 1$ sufficient evidence for the carcinogenicity of (proplolactone In experimental animals.I (-Proplolactone wax carcinogenic In the mouse by skin application or subcutaneous Injection, and In the rat by subcutaneous Injection. Adminis tration by gavage to a small group of female Sprague-Dawley rats pave squamous cell carcinoma of the forestomach.2 international Agency for Research on Cancer. jaAC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement a. Lyon, France: MAC, 1982. `International Agency for Research on Ccneer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals t Man. Vol. 4. Lyon. France: IARC, 1R74, pp. 259-69. (-Proplolactone Is a water-soluble Industrial chemical. More than #5 percent of the l-propiolactone produced In the United States was used In captive consumption for the manufacture of acrylic acid and asters, less than IS percent was used at a sterllant of blood plasma; for vaccines, tissue grafts, surgical Instruments, and ensymes; ano as a vapor-phase disinfectant in enclosed spaces. t-Proplolactone was firs' produced commercially In the United States In 1958. The sole U.S. manufacturer reportedly halted prodiction at the end of 1973. However, for tko period 1S7S-1977, EPA report:d one producer In one region IToxIc Substances Control Act, Chemical Substance Invented, 1979. public record). Exposure to R-proplolactone oecurreJ primarily In the occupational setting, notably through skin absorption and by Inhalation of vatjrs. OSHA estimated that 4SO persons were occupationally exposed to e-oroololaetone. Occupations at greatest risk of exposure Included disinfectant workers and makers of viricidal agents, acrylic plastics, and resins. Potential exposure to waste effluents from production and manufacturing plants was minimal because of R-proplelactone's short half-life In water. OSHA regulates (-proplolactone on the basis of its carcinogenicity In animals. The regulation requires protective clothing, use of respirators, training In hygiene, medical surveillance, engineering controls to limit contamination, sign requirements for posting regulated areas, and labeling requirements fur containers. 255 HONS 0.25856 iHiliMM M MMf Sm CihI>mw Mmwot tn$i immit mmr t`4(itrii*'infiN. MNI NMtitt rmi'itn. lytim M M<(|1 WmlllWM MMti <* NIWl MnillN KW'IttMi n*u*4'iiii nMi iif* MilrwiMI fttr mil! mtimMi Hr ikuiwm. IMM) Mwr Cimihi iifiiMm MiMr bvrymcv Immn liMM- riMtlH m irf'm nin* mu Hr rnirn, ninmuii mfidm fiitrtiM, HnI IMM lUMtlM. IMM) CIUUn 9* ll|UUW i in im.itu (MM) 25$ HONS 025857 RESERPINE Reserplne was tested In 86C3F1 mice by administration in the diet; tt Induced malignant mammary tumors in females end carcinomas ef the seminal vesicles In aules. When given In the diet to FJ44 rots It Incrtosed the Incidence of pheochromocytomas In moles.' This available evidence It considered as limited by an IARC working group,' but In view of another evaluation of NCI results, it can be considered as sufficient.) Thj 14 epidemiological case-control and 2 cohort studies are not consistent in showing an increase in breast cancer associated with the use of reserplne. The available evidence of carcino genicity In humans Is considered Inadequate.' ^National Cancer Institute. Rloassay of Reserplne for Possible Carcinogenicity. Technical Report Series No. 193. OHEW Publication No. (N1H) 80-1749. iethesda, Maryland, 1980. 'International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. tartesemer, R.A., and C. Cueto. Toward a Classification Scheme for Degrees of Experimental Evidence for the Carcino genicity of Chemicals for Animals. In: R. Montesano, H. lartsch, and l. Tomatls, eds. Molecular and Cellular Aspects of Carcinogen Screening Tests, IARC Scientific Publi cations, No. 27. Lyon, France: International Agency for Research on Cancer, 1980, pp. 259-81. Reserplne. a pharmaceutical. Is a naturally occurring substance that Is isolated, from the roots of the plant Rauwolfla serpentina. Tt is marketed under at least ISO trade names. In humans, medicinal preparations are used for treating hypertens'on and at a tranoulllter and sedative. eser5i"e *s slso used In veterinary practice as a trangultlier or sedative. Reserplne preparations are also added to various animal feeds, :uch as turkey feed, to lessen the incidence of aortic rupture. Reserplne was produced by at least six manufacturers. EPA reports one producer In one region (Toxic Substances Control Act, Chemical Substance Inventory, 1979, public record). The annual U.S. sales of reserplne for use In human medicine were reported to be about 440,000 lb In 197$. Approximately 11.7 million prescriptions were dispensed by retail pharmacies during 1979, and an additional 2.) million prescriptions were ordered in hospitals. Sales figures dropped SO percent from 1976-79, Indicating a reduction In reserplne use. 257 RONS 025858 An estimated 1300 to 2700 persons trt occupationally exposed to resorpln*. Exposure of the general population Is unknown but suable, based on the-nunbcr of prescriptions. The average therapeutic dose ranges from 0.1 to 1.0 *g/day. Federal regulations affecting exposure Include CPA's hai-rdous waste rule, which restricts environmental release, and regulations under the Safe Drinking Mater Act and the Aesource Conservation and Recovery Act. C0A regulates reserplne as a prescription drug. FDA also regulates Its use In animal diets, and on February 2b, 1980, FDA revoked the use of reserplne as a component of premised turkey feed. UlRfFlk* MtvUttmt M Mum tot'iw M BPtoN mllm. M tRM pntKt I* toiimr iwmti mmr CMC Jmiiict*m. (CMC) KUUTIW tffm P litoUtlNi: Kmc Ctommti Cttittm f Mf*fnfm KM. 9|.jrt SMJKII tllto ffUrtU. tff.imctffcitfm MtcMi. M iifti ml. mm i* mm if iw 19 u Mmitf me umt/FKPftmiN uwifmm. Mlpuil it MiiMwt emuttvmt if wito. am toljNU NitM tom m cmtit* ft II M MM fM8<fW*ll. tomfyiM I/.MI. Im tmiwm tow'ww tom iutmM Mr l-Kit. lwlRinwim. MI MCFI m.ll. Ifl.M IfMI fM town If totorlim Mflctm, HKAt bfHltof Mr m* f" toWigi to mm MM lacftmc* if Mrtlc mtoto. toimil V41HnMrm. M . tol WUIIt if Wtolir) I4*M, l/lf/M. lam fi(in fv itunii m tu mum* IftN. FM ImN if >nil HiriiiI hr m* rfMfM IN M fnittlW It HWfWMftl M Nr IfllWRt yf MMvIirlt IfHMH* IfMI totoui to mm m rnnw *f i MtoHf to mllwf if fiHryiw i* r*m mfmtt. HtVHlH M WflH im. It Mi MM mMM Mr HM If Mm (Miry CIIKIf VltMVt itftAl lift MUM* If II* M Me Mlwm (MlttM. M Ml WWW IM# IMN IWfHMd Iwf. MU If MMy M MriMl Mill. M l4H RMullUU M0, |Nn Ml MM < UffllltM NMN WH'tfW'l Kl)Kni>fl8M<W Mtlf- ItT M IwMM lactMM* $t mmmry Miff t* fMMtt, HI ft ll IN II ll fuMil ***9 im pm t wnimu mim mil m rmiM u m ii tn M.m flVFV) fat. fM.CM fmmtMf ii. fNinn m h mmK tp rrewlftf SM. IM.M *INflM Me. <m.:m Mmiw (TMI KPflttw *f m mnI uwfNiMiinr tot rvmMt M im amifHmi itniti frw Mm* ulMHtm iMitt. IfMI 258 HONS 025859 SACCHARIN In April 1977, the Commissioner of the Food anti Drug Admini stration proposed to revoke tn Interim fori additive regulation which permitted the use of saccharin and Its salts In prepackaged food (e.g., soft drinks) and as a tahletop nonrutrltlvc sweetener.1 This proposal was based on several V.$. studies2,4 and one Canadian study' showing that saccharin caused bladder cancer In male rats. An analysis'published by the Office of Technology Assessment confirmed this conclusion.* According to an 1ARC working group, there was sufficient evidence that saccharin alone, given In high doses, was carcinogenic In male rats and can proaotc the action of known carcinogens In the bladder of rats of both senes; and that the evidence of carcinogenicity Is limited In mice.4 Another 1ARC working group considered the same evidence as being limited both In rots and mice.4 The available epidemiological data provide no clear evidence that saccharin alone, or In combination with cyclamates, causes urinary bladder cancer, but a small increase In the risk of urinary bladder cancer In the general population or a larger Increese In sore Individuals consuming very high doses of saccharin and cyclamates cannot be excluded.4 The existing human evidence has been classified as Inadequate.4 Jfood and Drug Administration. Saccharin and Its Salts. Proposed Rule Hating. Federal Register, Vol. az, No. 73, 1*77, pp. 19996-20010. `Food and Drug Administration. Histopathologic Evaluation of Tissues from Rats Following Continuous Dietary Intake of Sodium Saccharin and Calcium Cyclamate for a Maximum Period of Two Tears. Final Report. Project P-169-70. Typescript, Oocenter 11, 1971 'Health Protection Branch, National Health and Welfare Department, Canada. Toxv-.lt/ and Carcinogenicity Study of Orthotolvensulfon .vside anu 3ccna> in. rrojvti t-G5/-C5c General Protocol. Typescript, 1977. 'Office of Technology Assessment, Congress of the United States. Cancer Testing Technology and Saccharin. Washington, O.C.: II.S. Covenment Printing Offlcr, 1977. 'International Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 11. Lyon, France; IARC, 1940, pp. 111-85. International Agency for'Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplasmnt 4. Lyon, France: IARC, 1982. 2S9 MOHS 0250*0 Saccharin Is i whit* crystalline powder that Is soluble In water. Saccharin and sodium saccharin have been produced comerclally 'n the United States for over 80 years. Production levels of saccharin In 1977 were esti mated at *.8 million lb. Imports of saccharin were estimated In 1977 at 3 mllllpn lb. and 1.3 million lb In 1980. Sacrharln and Its ammonium and sodium salts were reported for the TSCA Inventory. EPA reported domestic production of 748,000 1b and Imports of 4.Sr million 1b (Tonic Substances Control Act, Chemical Substance Inventory, 1979, public record). There Is only one reported manufac'ur- 19 plant In the United States, and no current production figures are available. Approximately 6-8 million lb of saccharin were used among PDA-regulated products in 197*. *P Saccharin has been used as a nonnutrltive sweetening agent; however. Its use substantially Increased after cyclamates were banned In food In '970. The 1976 V.S. consumption pattern for all forms of saccharin has been estimated as 45 percent In soft drinks; 18 percent In tabletop sweeteners; 14 percent In fruits, juices, sweets, chewing gum, and jellies; 10 percent In cosmetic- and oral hygiene products; 7 percent In drugs such as coating on pills; 2 percent In tobacco; 2 percent In electroplating; and 2 percent for miscellaneous uses. Human exposure to saccharin occurs primarily through Ingestion from Its use In many dietetic foods and drinks and In tome personal hygiene products. Including toothpastes and mouthwashes. The general public is exposed, especially those persons who have to reduce sugar intake. The National Occupational Hazard Survey and OSNA estimated that approximately 28,000 workers are occupationally exposed. In compliance with the Delaney clause, FOA proposed to ben saccharin as a food additive In 1977 on the available evidence of carcinogenicity In animals. However, final regulations are pending because or Congressional action In 1977 requiring further study and labeling of saccharin. A joint FDA/HCI group, the Saccharin Working Group, was formed In 1977. A preliminary report or tho epidemiological findings has been published, but an analysis of all the information gathered is yet to he completed. EPA regulates saccharin under the Resource Conservation and kecovery Act. 260 HONS 0258b! UccMHa tOMftMS IN lMf MHaat Iffact a# iMUUm; iMf (aantl N ttirmt KtlN. ICHC) KM, MJNtl *am |N<Ntl, NttMI. aM 19111 airt m (wHi tindir. (CM) *at<Mt 1* IKNI * IW If M MNII<t N PtlNl VK|rMIN NttlNWWI. MW MllfMtta NIN6NI l6NI<lMt H NIU, Ml ItfINt* Hlltl INMI I* rmuil iKIMfll tl CM IM rMIfNMtl. h'MlfCtM l/ll/tt. hi (lUlliMtl IlMIPfM CfM* ItllPIM Mtf I'KaU-lMINanwa^M. (CM) W lurCM a< 'MU. fclNN If Imt; fM4l ifUf nttN MM INKitIN CMC MCCMH* chin CMCtr 1* NHftaMUl MMailt M IM IMIlN M M* M M If M CMMN. TM CNfMi mnctN Vn ifMv'i MtlM, M IM IWIWl * N* Mum m m 'Nina lam muin ftMti frw itMtat Mi*f imnli; unmm- IfMI M affact Menu tiNNu Mi an'tiiM m. trui Clutiaa af Mfiliitii cn Ml.II. Ml.)) <ll it at imj' IfMI 261 HONS Q25862 SAFROIE There li sufficient evidence for th* carcinogenicity of stfrolt I".*xpr1*ental anisic Is.1 When given In the diet, safroie produced various liver tutors in sovtrsl strolns of mIc tic* tnd mil* and fataIf rats.< international agency for Research on Cancar. I ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement A. Lyon, France: IARC, 1?92. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Han. Vol. 10. Lyon, France: IARC, 1976, pp. 231-44. Safroie Is a colorless liquid that is Insoluble In water and very soluble in alcohol. This co^ound has been used to flavor beverages and foods and as a pesticide Ingredient. It Is reported to be used in soap manufacture, perfumery, sleep aids, and sedatives. CPA Indicated that nine companies produced and imported a total of over t million 1b of the compound in 1977. No production data are available in the trade literature after 1977. However, according to the United States Inter national Trade Commission 11991), approximately 36,000 lb of safroie were Imparted from Rratil during 1990. OSHA estimated that 30 workers were potentially exposed, The FDA Indicated that exposure to safroie of the general public through food consumption was extremely low since the Agency prohibited its use in food. Minimal exposure may occur through the use of edible spices, including .nitmeg and mace, which contain low levels of naturally occurring safroie. The compound does not pose a hatard to the general population through consumption of drinking water because of its insolubility in water. The EPA and the FDA regulate the use v! safroie. During i$77, iPn promul gated standards for voluntary cancellation of safroie in pesticide products. The Agency did, however, pemit one registrant to distribute and sell one lafrole-conteintng product until March 11, 1979. Thereafter, no stocks were available for pesticide use. The FDA banned the use of oil of-safroie and sassafras bark In food. However, edible spices (nutmeg and mace), which contain very email quantities of naturally occurring safroie, were peimitted for use In foods. The Agency has been reviewing the use of safroie in sleeping aids tnd sedatives. 262 HONS 025963 t#fr*l HttUftONS > * Ut1M tffKt if cmIiiimi; ItNr twiltl MW, 1: ftlMMfy CMillKlM if ill ntuintlni, l/H. Iff'IHClfltltlM MtCMk, IN Mill Nil* (Ml In Mill if 100b If II ONlM IN mrtfpariii**t rmiNNiu. *it* MtfMM IN IMIlM II 1 MMNM IMIllMM If Mill, **4 WI)Ktl Mlttl INN M NNII* HUM mn Mln> MU. *WWl*iW4 TtU, Mill frMIII NMNlif nM* NNHlN |*W|M IN * Mil, MlIlM t/n/w. In finiwfM iknnmi Inn iuumn MN iNIIUlWlNflllNN. ItfAl imii if ..itidm * imni f **Mr*. am m Mm if rwM. fNUi hMH fr m ll nm. Ill N UlUfrnt IIIHffll MM M MNI if MtNll ill* MNN. fM Min if fiM. fNU: t1*l IwMff M Mil MM If Ml trMtft*4 *M if iifNti mt *11 if in* UlM <N IIIMfrii MM n wml N IIIvk!* I* fWM. Ill* fM IlfPlII IN UNM MMtff if 1 'fr*l* IMlltlll ! tMlM. Ilfwl**frw if uiufrii MMlttM ** If! .Ml. tlfr*l*frw strict NNHtH If Ntk If!.SI* IN ||NM 1/WNN n mi. MNN M IM.ltt M im/n (41 n IM*M. VM If Him M '*#* MMIIN. (MAI Cltitlw f Ir^tlitlNi rt. i, tmf lim Mtitii MCM Ml.U. HI.)) <1 fl l|. *. 1JM4 (CM] H fl. *. 1)41! m/i/Mi ! n. . HMf (1/ll/fJ. WNNI 4t m.. Mm ut/n/m tmi 263 HONS OZW*4* SELENIUM SULFIft Oerpal application of selenium sulfide to ICR Swiss mice wjs not carcinogenic, but the study was Halted to 88 weeks because of test animal deaths from amyloidosis.! An NCI skin painting study with ICR Swiss alee using Sal sun*, i cowwrclal selenium sulfide formulation, also gave negative results, and >as terminated after 88 weeks tecause of the saae amyloidosis prrblem.* In another chronic skin painting study of alee and rabbits, Sal sunk was also reported negative.' However, selenium sulfide administered by gava,e to F3d4 rats and B6C3F1 alee Induced hepatocellular carcinomas in male and female rats end female alee, and ai'.eolar/brcnciilotar carcinomas and adenomas In female alee, but It was not carcinogenic to male mice.4 These results can be regarded as providing sufficient evidence of carcinogenicity In experimental animals.= National Cancer Institute. Bioassay of Selenium Sulfide for Possible Carcinogenicity (Dermal Study). Technical Report Series No. 197. OHMS Publication No. (NIH) 80-17S3. Nethesda, Maryland, 1980. 'National Cancer Instltuta. Bioassay of Selsun* for Possible Carcinogenicity (Skin Painting Study). DHllS Publi cation No. (NIH) 80-17S3. Bethesfa, Maryland, 1980. 3Stenback, F. Local and Systemic Effects of Commonly Used Cutaneous Agents: Lifetime Studies of 16 Compounds In Mice and Raljlts. Acta Pharmacol. Toxicol. Yol. 41, 1977, ep. 417-31. 'National Cancer Institute. Bioassay of Selenium Sulfide for Possible Carcinogenicity (Savage Study). Technics! Report Series No. 199. WHS Publication No. (NIH) S0-17S0. Bcthesda, Maryland, 1980. PSrtesemer, R.A., and C. Cueto. Toward a Classification Scheme fer Degrees of Experimental Evidence for the Carcino genicity of Chemicals for Animals. In: R. Montesanu, H. oartsen, ana L. Tometls leas.). Molecular and Cellular Aspects or Carcinogen Screening Tests. IARC Scientific Publi cations, No. 27. Lyon, France: International Agency for Research on Cancer, 1980, pp. 259-81. Selenium sulfide, an Inorganic compound. Is Insoluble In water and soluble In alcohol. EPA reports that selenium sulfide Is used for the treataent of seborrhea, especially in shampoos. The chemical Is available over the counter as Seism*, a stabilised buffered suspension. FDA reports that selenlua sulfide Is ar active Ingredient In soae drug products used for the treatment of dandruff 264 HONS 0258*5 and certain types of dermatitis. A dandruff shampoo containing 1 percent selenium sulfide Is available without a prescription and Is reconmended for use once or twice a week, By prescription, selenium sulfldj Is available In a Z.S percent shasFOO or lotion, with the recommended application limited to 10 minutes for 7 days to avoid the pr'.slblllty of acute tosic effects. SeTenlun sulfide Is also used topically In veterinary medicine for eczemas and dermetomycoses. Selenium sulfide was not reported for the Tonic Substances Control Act (TSCA), Chemical Substance Inventory, public record. In 1979, approximately 1000 1b of selenium sulfide were Imported. NCI reports that no separate current data on production or Imports of selanlum sulfide are available. No current U.S. producers were listed In the 1982 Directory of Chemical Producers. NCI estimates that substantial exposure of the population to selenium sulfide Is questionable. Skin absorption has been reported only In patients with open scalp lesions. In 1974, the National Occupational Hazard Survey estimated that 8500 workers were potentially exposed to selenium sulfide. Selenium Is widely distributed throughout the environment, occurring In groundwater, surface water, rocks, and sell. No data on the environmental occurrence of selenium sulfide are available; however, the F*A In 1974 esti mated that about 700 lb of selenium sulfide wastes are generated annually by the medicinal Industry. Selenium sulfide Is currently regulated by EPA under the Resource Conservation and Recovery Act. OSHA has adopted a permissible exposure level of 0.2 mg/m3 time-weighted average for selenium compounds. ItiMtW 1-gfflM hfillllM M4 Ittr M1M KM, WIvWli MJti Kf-iMlftMtlM t#MON. win ififcin. tm will miMf ta wm MM M MMlMf a* wrV *********. aim Mtftui IMMUl M ******** (MltMIt *t otltO. t*mnt*t*** W19/M. IN (MlMM MlNMUt ***** I-MHjlMlMflMTtM. lUUMRt IMUf!m CffMt * liftlitim; (Mf CMMMI MyilltlM lulllM- m CMMlC !fMn fNM uri MMl iRf *t nUNi. I0tl Clllilw *1 llfillllll Nt.ll. HI M (CM) mi l.i MM* TM ItalMHM CMMMI U Ml. (SMI iMium nran': , mii miMMiMir, t.i m*1 MlMm IHtMtntlM. %ninu tmmp j*8M#r*~ C.niml mil Iff|lg. (SMI cm iiw.ioe* (Ml 265 HONS 02586* SOOTS, TARS, ANb MINERAL OILS There It sufficient evidence that foots, tors, and some Mineral oils art carcinogenic both In humans and In experimental anlaals,1 Soots, coal tars, creosote oils, shale oils and cutting oils ire carcinogenic In experimental a.ilmals after skin painting or subcutaneous Injection.1 Occupational exposure lo coal soot, coal tar and pitch, coal tar fumes and some impure mineral oils causes cancer of several sites. Including skin, lung, bladder, and gastrointestinal tract. Recent epidemiological data support those conclusions. This offtct may be due to the presence of ,'Olycy:llc aromatic hydrocarbons tn these materials.1 1International Agency for Restart on Cancer. IARC Monographs on the Evaluation of the Carclnoaenlc Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1S82. Soots, tars, and mineral oils (Including creosote, shale, and cutting oils) are larnely byproducts, contaminants, or wastes. These substances result from fossil fuel processing technology such as coal carbonization and from Incomplete combustion of other carbonaceous materials. Each of these materials Is composed of many Ingredients. Although these substances are largely bypr.ducts, contaminants, or wastes, there are commercial uses of these substances. Coal tart hove been used to treat skin disorders; however, their commercial Importance Is based on their use as chemical Intermediates for a number of products such as creosote, pitch, timber preservatives, pesticide formulations, benzene, toluene, xylene, and naphthalene. Petrolatum and mineral oils are commercially Important because of their utu In pharmaceuticals, In protective coatings on fruits and vegetables, and in bakery products. In I07S, approximately 35 million lb of coal tar and 2 million lb of coal tar neutral oil were manufactured or processed for use. In lg7d, about bat million 1b of creosote were produced In the United States. Human exposu'e to toots, tars, and oils occurs through Inhalation, Ingestion, and skin absorption. H10SH hat estimated that 10,000 coal handlers, cake oven workers, and byproduct plant workers are occupationally exposed to coal tar. OSHA has estimated that 121,000 workers are exposed to tars. The environmental contar.I ration by these substances Is widespread, and it can be assumed that the entire population Is exposed to these substances at tome level. 2S8 HONS 025807 CPA regulates these substances under the Federal Insecticide, Fungicide, ind Rodentlclde Act (FIFRA), which restricts use, <nd under the Resource Coniervitlon and Recovery Act (RCRA), which fosters greater care In handling of chemical wastes. The CPA Carcinogen Assessment Group Included soots, coal tars, and creosote In Its list of carcinogens; and as a result of this listing, theft substances are Included in the hazardous waste disposal rule of the RCRA. FOA regulates the use of petrolatu* and mineral oil in food and the use ef coal tar In drugs. The r'DA Advisory panel on Over the Counter Drug Products has recently determined that coal ter Is not safe when used as a topical antifungal agent. Only petrolatiaa and mineral oil that contain no PAM may be used in coatings for fruits and vegetables and in releasu agents for bakery products. QSHA adopted a permissible exposure limit for coal tar pitch volatiles of 0.2 mg/mJ as an 8-hour time-weighted average. Imu. tin, m4 ftfMral Mil CSMATIMS IlMr CflMt if 4fitM1Mi; (MIIH {fWWlP CM. leUKtl MfU IfNKII. (((MMfKltlM MttMt, MM fit* I IWIMt fa mm ** ;N i| it Maiftaf m# ratar/ fmtfinni. iim iimui cmt H MliflKrt MltHtMM >f mil, Iiied e* chrwlc tteiflty. renin ffgater (in l MMllM NMMl Mut, 0 tn MI.U. til.77 Mil Tf. C-l t Mairil Ml. Mi Craft* HMA, ft (Mlillllw 9t fl|i|f|Yniir tnmu m W4nln fragtlffi MlW. IliHM, 1/1*11. NtlllU fMNtlM ll IN M NNHMM FliKtlM li UftHPI. mil. It IntPldM M Mr WKlflM Ml umimiMM Mll t/MAI. If MM(M OMItllRI # vs*. BNldfl faMatUt It rMNM. IIWU 411. (Ml 4 . f. IMI UHl l fir. MM. i*4 tnw e tMIlHM 4MMM lil| ItltMRt MM t*4tM|(aiMtMf1N- la*l Tar lit fM ftrluo ml m #*r tM CnMif H| NMIl Ml vMinlM Mt Mil Uf If H Mf< M fa MM m Wi*1 Ml* 47 ft. i. ItfIM (7UO Hart fr*ctlM d ataMfti tiiwe u l/t7/7|| MM TUWMf ttM*M"<llffMt IMIt tfftCtltt. 267 HONS 025808 STREPT0Z0T0C1N There t> sufficient evidence that streplotstoeIn (SIR) Is carcinogenic In experimental animals.* Strentoiotocln Is carcinogenic In nice, rats and Chinese .masters following Intravenous or Irt.aperltones! administration. It produced benign and malignant tuaors of the liver and kidney and Isletcel! tumors cf the pancreas- It Is carcinogenic after admin istration In slnglt doses.< Ilnternatlone! Agency for Research on Cancer. IAPC Monographs on the Evaluation of tha Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, Prance: IARC, 1982. 'International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vet. 17. Lyon, France: IARC, 1978, pp. 337-49. STR, a water-soluble H-nltroso compound, was of Interest as a potential antibacterial agent, but the chemical has not been used commercially. STR has been used In studies on diabetes because it has specific toxic action on pancreatic t-celli. Including hyperglycemia. It has been shown to have cytotoxic effects, and it could be used as an antlneoplastlc drug. STR Is produceJ by the roll microorganism Streptomyces achromogenes. STR production was reported by two manufacturers or research oiocnemicals IU.S. Internationa! Trade Commission Publication 804, 1977), but the amounts were not indicated. Human exposure to STR could occur primarily through Ingestion and less likely through skin absorption and Inhalation. Occupational exposure to STR Is limited to pharmaceutical workers and researchers. EPA regulates STR under the Resource Conservation and Recovery Act. The PDA In 1980 reoorted that STR was submitted for approve', as a -*- u<Vy appli cation, but the application was withdrawn before evaluation was completed. 268 MQNS 0258b9 ItntMNtKli teftUttOftl M tlMr ktHM M iiwul KtlK. Ihm tniMf (a NUNir |KM| moo# 9K JortMfrtfO*. umci KM, Im|ku miu r'Mwti, 0#f*tN0tMC0tN MUHt. <"# *OI mtiiu i* torn* ft ION M t M Wltll rNilrWMI. IlM OHlfNUC llmtutwii M 4 niowwi nxtiWM of mi*, on moJocii mw two m r*ui iimm im mu. NmIhM MtM. In (mlMm Hutimt Stn mumt fN MNUW^lHnM. ||M> hfu of Orofi, WU: limit Mr mumoi no <t*orom. tmi atour ios ft Hftiittm; tutor N OffrootO mi lllN. Cttit'm ft llUllt'M *0 CM HI.II, Ht.M ICMI 269 HONS 025870 SUIFAUATE Sulfallate, a chlorinated d(thioc.rb.n.te, *dr1nlstered In the feed, wet carcinogenic te Otbornt-Mtndel rett end te 86C3F1 Ice, Inducing mamiary gland tunort In females of both species, timers ef the forestenech In stale rats, and lung tumors In male Ice.1 National Cancer Institute. Bloastay of Sulfallate for Possible Carcinogenicity. Technical deport Series No. US. OHtV Publication No. (NIH) 78-1370. Bcthesda, Maryland, 1978. Sulfallate It a trade name for dlethyldlthlocarbaalc add 2-chloroellylester; It Is soluble In W.er. The chemical Is formulated Into tmulslflable concentrates, liquids, and granules. The aajor use for sulfallate In the United States Is as a preemergent selective herbicide to control certain annual grasses and broadleaf weeds around vegetable and fruit crops. Sulfallate has also been used for weed control among shrubbery and ornamental plants. Sulfallate was Introduced as a herbicide In 1954. According to NCI. durlnc 1980, the production was greater than 5000 lb. Sulfallate was not reported for the Toxic Substances Control Act (TSCA), Chemical Substance Inventory (public record). The 1974 National Occupational Hazard Survey provided no estimate of the number of'workers potentially exposed to sulfallate. A potential for exposure exists during the manufacture and application of the herbicide. Agricultural workers have the greatest risk of sulfallate exposure, and rural residents of agricultural communities may be exposed te clrborne residues of sulfallate after spraying operations. At commercially reepammnded rates of 4 lb/gal, the average persistence of sulfallate In soil Is 3-6 weexs. The general population may be exposed through Ingestion of residues In food crops. The ERA has established tolerances for sulfallate residues on a variety iaw agricultural commodities. Enforcement Is vested In FDA. IvIfllllW K6UUTI0HS bfilltlM M Other Ittlon tffeet ef lnlitUu; Other tmmnu Ctuttee ef teyelstiee Telcrssees MtMlIikiu ft* MttlcIM ckMlcaU liirMnv Ofrtcettertl mmUMm t/r/ni. (CM) lit** m Mifii effects ef the csMa ul. me Mtteres. sstf Ottectlee Kelts. bferesecAt teste* Is FM. (CPA) o tn soo.icr 270 *ons OiSgJi 2,3,7,8-TETRACHl.OROO IBFNZO-p-OIOXIN (TCCO) Tilt evidence for the carcinogenicity of 2,3.7,8-tetrachlorodlbenzo-p-dloxln (TCDO) tn experimental animali 1$ considered is sufficient.1 An Increased Incidence of hepatocellular carcinomas and squamous-cell carcinomas of the lung, hard palate/nasal turbinates or tongue was observed In rats maintained on diets containing TCDO. In another study, Increased Incidence of tumors In a variety of organs was observed at all dietary levels of TCDO greater than 0.001 ug/kg.1 TCDp administered by gavage to rats and mice Induced follicular-cell thyroid adenomas In males and neoplastic nodules of the liver In females. TCDO also Induced hepatocellular carcinomas In mice of both senes and follicular-cell thyroid edenomes In females.i TCDO applied to the skin wes not carcinogenic to male mice but in females It produced fibrosarcomas In the Integuaentary system.3 There Is no report of htenan exposure to TCP3 alone without the other chemicals such as 2,*.5-tr1chlorophenol or 2,4,4-trlchlorophenoxyacetlc Kid (2,4,5-T) being present. The available evidence from human studies Is considered as Inadequate.1 international Agency for Research on Cancer. {ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: 1ARC, 1882. `National Toxicology Program. Carcinogenesis Bioassay of 2.3.7.8- Tetrachlorodlbenzo-p-dloxln (CAS No. 174C-01-6) In Osborne-Mendel Rats and B6C3F1 Mice (Savage Study). Technical Report Series No. 208. N1H Publication No. B2-176S. Research Triangle Park, N.C., and Bethesda, Maryland: NTP, 1882. ^National Toxicology Program. Carcinogenesis Bioassay of 2.3.7.8- Tetrachlorodlbeflzo-p-dloxln (CAS No. 1744-01-0 In Swtss-Vcbster Mice (Dermal Study). Technical Report Series No. 201. NIK Publication No. 82-17S7. Research Triangle Park, N.C., and Bethesda, Maryland: NTP, 1882. ?,3,7,S-Tetrachlorod1benzo-p-d1ox1n, commonly referred to as TCuu, is a very toxic chemical. TCDO has no reported use other than as a test chemical In basic research. The total estimated release of TCOO Is about BO 1b per year. Sources of potential exposure to TCDO are pestlcldal spraying; cigarette r.oke: and combustion of gasoline, diesel fuel, and wood. Trace concentrations (3-6 ppb) of TCDO have been reported In 3 of 23 samples of beef adipose tissues. 271 MOMS 0258 72 CPA, under the Federal Insecticide, Fungicide, and Fodentlctde act (F1FM), banned detectable TCOO In 2,4.5-T and sllve*. An emergency sus pension order Issued under riFRA.Is (Mil under litigation. Under the Aelource Conservation and Recovery Act, TCOO has been designated as a hazardous constituent of waste, which subjects the chemical to special h.ndling and record, requirements. A health-related water quality criteria document was published under the Clean Water Act. (KMI acourims MnUttlN M ItMf MUlM rtfMti mh r*pi*ibf M rollIH (klKNIlllM U !*, t/M/M. rim. It MM liml far M.f. inCjM*fa*m*1t a/ivrt. km M IWr|MCy MtMlHlfK *fj*r: ca*C*11*tfM HtWRtlW RttUM fir l.l M, l.l.M nun, mm nim, j/it/79. am. SMI*MM: KM II iwtitdHi af mn, m w* Jatta ny nw amtaiMaf nn tmtcil wnnm n m mm/ nuMmlM milnMirti; mi wt nHn unfit. rrmitiM Vtl/M. Cm, 4<*tl MUr mall* *M,Mr14 mum, 16/79. (ffm if im>niwi; OtMr (MMRII Cftatia* if Iffilitlii itoltM ff*tt****ll. IrMMlp |<< matt 1* mm r**ctla* 4a erntmtaattan. lama a# aacayotcitp/fttataafcftr. nail met aim aa #r***t* act*.** -ill cm* ift*r milnlw if (MciMiiit* heariaii m l.a.M am Him. UHtadn Mftfay tmaarary lajaacitm IfllRtt mr|Mq MlMMln oner aimiiM*. Iimmi ia myawi maut caacallatfm mm* j/ia/M, m mil 1* mftn. n mtu* ro-ti, Mat t* 111 I'fKtll ntinniti u r. a. mu m ra, *. IU * era mi.ii rinl criteria m MIA far ucumi raaimi. mat, nfmii t*Ml(a*.iw, 4/li tUi uinmM af mini cm imrnw imIim, i/M. TKA, i CmMUImk far ttawMl *f KM hmmUim mm. udntif mificitm U IN. In (ni*nn nmiimm tnw m<nt mif |.Mnylmnf'nt. (PA) Nitritti rami) *f mm iwnt nu PA awm--l i* eaaaHmea etw ACM rnpiimni. ttMt M'S. <ra**1 cmmbfcitlm. A/M * era r?s (PA) 272 *ONS 025073 thioacetamide There Is sufficient evidence for t** carcinogenicity of thloacetarlde In experimental animals.' Ihioaretamide was carcinogenic In nice and raM forowng admlnlstra'Ion In the diet, the only exposure rv..* W;Ud. It Induced liver-cell tumors in Swiss nice and llwr-cell and bile duct tumors In Wlstar rats. Ho care I nogenu;!' was i.^snrved In nar.sters jtven thloacetamlde dissolved in dlstMled w.ter by stomach tube.2 ^International Anency for Rei*a-clt on Cancer. [ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement t. Lyon, France: lARC, 1982. `International Agency for Research on Cancer. IARC Monor-aphs on the Evaluation of the Carclnoqe.-'v Risk of Chemicals to Man Ynl. 7. Lyon, France: IARC. 197A, pp. 77-83. TMoecetentde (TAA) Is a synthetic ors.ri-. chemical, which Is ;-lnble In water and In ethanol. TAA Is available In the United States as .> laboratory chemical containing SI percent of the active Ingredient. TAA Is used as a replccenent for hydrogen sulfide In quailtatlvr analyses. TAA hat been used as an organic solrerr In the leather, textile, and paper industries; as an accelerator In the volcanliatlon of buna rubber; and at a stablliter of motor fuel. Commercial production of TAA In the United States was flrrt reported in 1921. ERA estimated fix producers and Importers in three regions, with a domestic production of *000 lb and imports of *000 1b (Toxic Sr sCances Control Act (TSCA), Chemical Substances Inventory, 1979, public record). TAA production was not reported to the U.S. International Trade Corxilsslon for 1973-1980. Ho evidence was found that this chemical is now commercially produced or Imported in the United States, according to NCI. H-un exposure to TAA Is prlnclpal'y through Inhalation end skin absorption. Chemists and laboratory technicians are at greatest risk of exposure. In 1974, the waiiunai wccupacionai Hazard Survey estimated that *600 workers were potentially exposed to TAA. TAA it regulated by ERA under the Resource Conservation and Recovery Act. and regulation Is proposed under the TSCA, 8(a), reporting rule that would provide detailed production and marketing data. 273 HONS 02bT* lfelMCU*4 KBUUttONS NttlUlM M KU, MM.MM: Wfrjmi litdM, Mit* iwiitti, m Milt mlMl la IMH1 r INIf If It NNlUf *M rH7l/ Hit (Mllll M CMtllttHl t( Mitt- HwlfllM t/ll/N. 1X1, ft*): ItnoKM ** ***''<* nct M <*M *t. l/lt/M. IM CaftlUfM #me 1-Kiiim<iaf Cm* IUMM M IffKi tf ftf*luaat: IIMf (Mlftl rimiai *t IlfllltlH **f1tm NtH " (****(< Cf Ml.1), MI.JI ^Mitn ftitif cm la ttMiiDf if umhi:iI Him. VWlI HMl M`Ur Mill fir ttla*tl9 Miiiifl afc* mu M ciHllml ilMf m fill tatamlalaf wvM'litiNti f nfilfUfy r Mr cum) Ktlaa. mu il 'l. . ink (MAI 274 HONS 025875 THIOUREA There (t sufficient evidence for the carcinogenicity of thiourea In experimental eninalt.1 Thiourea produced thyroid, liver end lymbsl's gland tumors In several strains of rats after adnlnlstratlon In drinking water or diet. Intraperltoneal Injection followed by adnlnlstratlon In drinking wtter also produced Zywbal's gland tumors In rats. Administration of thiourea 1r the diet or by subcutaneous Injection to mice did not froduce thyroid tumors; however, this experiment was considered Inadequate. An Increased Incidence of liver-cell turners In a feed experiment with trout was reported, but this result cannot be considered as conclusive.2 1 International Agency for Research on Cancer. 1ARC Monographs on the Evaluation nr the Carcinogenic Risk of Chemicals to limans. Supplement 4. Lyon, France: 1ARC, 1982. `International Agency fur Research on Cancer. IARC Monographs on the Evaluation or the Carcinogenic Risk of Chemicals to Man. Yol. 7. Lyon, France: IAP.C, 1974, pp. 95-109. Thiourea Is an almost colorless crystalline solid that Is soluble In water and In alcohol. Thiourea was used In a variety of consumer applications Including fire retardants, photographic chemicals, rust removers, animal glue llquetlers, and silver tarnlsn removers, but a recent evaluation has Indicated that It Is now used only 1h animal gluv Ifgueflers and silver tarnish removers. Liquid animal glues may contain 10-20 percent thiourea as a liquefying agent. Ever these uses are diminishing. Thiourea Is renoited to be used commercially In the production of flame retardant resins and as a vulcanization accelerator. Two companies began commercial production of thiourea In the United States In 1938. One company transferred tl,* production vu Cn*uo in aiii, uo the ether discontinued production 1r 1954. In their Initial inventory of chemical manufacturers and Importers, ERA reported that in 1977 there were 21 producers and Importers In six regions, with a domestic production of 4.4 million lb and Imports of 2 million 1b (Toxic Substances Control Act, Chmaical Substance Inventory, 1979, public record). Production of thiourea was nnt reported to the U.S. International Trade Comission In 1979-1980. There are now no manufacturers In the U.S. that produce either thiourea or Its 275 HONS 025876 nilor derivltive. thlourei dioxide. The U.S. consumption depends it present on imports. About 70 ccapinics hive been reported by ERA is distributors of thlourei. The chcmlcil is imported mainly from Jenin, with smell quantities coming from the Federil Aepublic o' Gemeny. According to CRSC, there his been i recent upsurge in the mirket for thiouret. leciuse liquid iiiimel glues conttining thtourei hive been ltrgely renltced by better woodworking glues, the chemicil Is probtbly t minor source of consumer exposure. In silver tirnlsh-remover dtps, thlourei is used to dissolve silver sulfide ternfsh. Thus, Mibstlnttil skin contict Is possible, tnd smell Mounts of thlourei mey be Ingested if newly cleened utensils ire not wished thoroughly before use. Two tirnlsh-remover dips hove been identi fied. tnd one Is widely distributed (CRSC). In 1974, the Nitlone! Occcpitionil Hilird Survey estlM'id thtt 213,COO workers were potent!illy exposed to thlourei. ERA regulites thlourei under the Resource Conservition ind Recovery Act. The FDA prohibits the use of thlourei in hutiin food. Tklmwi llfflltlm M (Mr ktioet M MffRt Nlle| MMK II M4U * rw, (OX) PnjKt KM. Mtl-MMi tofoWcmtlto <** M *#tl Rtiltol ll NUII to MM If M NMtdf M HMrV rmfNNf'if rmiriMRU. aim *niMm IMHul II NlNNH (NUtlMM if NIU. towlf*ta l/lf/M. to* Cmftof** Iihimm In* (UImmI Mtr tlU|lNlffMf*U. fCtoi ItMUntl N*kN(W lw to <R **M fM. IfMI IMUTUMS Ifftot to UfililfNi; >**!' C--IH* CfMtfto to tofaiaiiM NftUtiw Mato m Ufi< toatstty, fMttrt ffNtir urg I* iiMll* of itoitti n*u. IfM) 40 tot Ml.II. Ml.it (toll noun irMi 276 HONS 02577 THORIUM 01OXIDE Thorotrast (thorium dioxide) has received welt attention since 1947 when MacMahon et al.* reported the first death due to Its use. Their patient developed an endothelial cell carcinoma of the liver 12 years after the Intravascular use of Thorotrast. Since that tine, there have been over SO cases of neoplasms attributed to Us use.' Additional evidence for the carcinogenicity of thorium dioxide (administered diagnostically at "Thorotrast") Is given by a study In Portugal.3 One-thousand one-hundred and seven (46.S percent of the exposed Thorotrast population) had been traced uo to December 31, 1963; of these 609 had died and 408 were still living. Twenty-two cases of a special sarcoma of the liver, hcnanoloendothelloma, have occurred. This tumor Is virtually Thorotrast-speclflc In the liver. The latent period between Thorotrast administration and onset of the fatal Illness was 20 years or more with only one exception. IftacMahon, H.E., a.S. Murphy, and M.t. Sates. Endothelial Cell Sarcoma of Liver Following Thorotrast Injection. American Journal of Pathology. Vol. 23, 1947, pp. 585-613. `Barry, U.J., and C.J. Romlnger. Thorotrast Sranulomas. American Journal of Roentgenology. Vol. 92(3), 1954, op. 584-90. 30ai Horta, J., J.O. Abbatt, l.C. Da Motto, and M.l. Rorlt, Malignancy and Other Late Effects Following Administration of Thorotrast. Lancet: 19S5, pp. 201-05. The chemical thorium dioxide Is a crystalline powder that Is Insoluble In water, acids, and alkalies. This chemical was used In the development of nuclear reactors. Because of Its long-life Incandescent properties, however, thorium dioxide was primarily used In gat mantles. The chemical was also used In electrodes for arc welding and In Thorotrast, a radlopague medium for X-ray Imaging In medical diagnostic procedures. EPA reported for 1977 five producers and importers In fuur regions, with domestic production as 373,000 lb and imports of 4200 lb (Toxic Substances Control Act, Chemical Substance Inventory, 1979, public record). Exposure to the compound may occur through Inhalation of dust or gas. Intravenous Injection, Ingestion of llguld thorium dioxide, and skin absorp tion. Occupations at greatest risk of exposure were ceramic makers. Incan descent lamp makers, magnesium alloy makers, metal refiners, nuclear reactor workers, chemists, and vacuum tube makers. OSHA estimated that 128,500 workers were potentially exposed to the compound during production and use. A number of patients were exposed to Thorotrast when It was administered for X-ray procedures. 277 MOHS 025678 leciuse of the reported citclnogenlc effects of Thorotrest In hununs, sever!) Governuent Agencies hoot restricted the use of this MtorUl. The FDA hot opprovtd thorium dloilde for us* is < redlopiqu* medium for X-ry Inigin) where there It limited lift espeetincy. In Htrch 1980, the Mucletr Aegulttorv Commission (HRCi withdrew luthorljitloni for use ind tnnsfer of the wteriel' for lnteri*1 or extern*) medic I nil ute In humtns. Authorljitloni were Issued, however, for reietrch, development, eduetlonl, coomerclil, or operttlonil purposes under conditions specified by the NRC. The Agency further st*ted thit ute *>>d trinsfer of the miter111 for these purposes m*y not ciceed 15 lb t *ny one time tnd no more then * tote) of ISO lb In tny on* cilender yeer. tkr*n Kial M Ktouriw) ItfdUtlMI 8M ItlHf ktlKH Iffwt / a*p'*ttmi: ItMr ClMitl UlNdf) ftpdftM ftr M .IKI iMAMfy, tMfitf nt<4i intintt u %t MM 1* M(IN. Ill KMXtfM 11 MrfftCfMlI? >M M *IC IPtmil II 1 >* Kltfltf. IPA) fU IgfNg t |ftl, HKIt %lt Wt *M tot* ImMuIIM M ffMtfMAIh JHWr nIefNirrliMf f)MfH. ( PMIMMM IMl IMU t* <M Wfl ttm it HwiM ttr MHttinqi UiMiii. if*1' IflMlltl M* l fM-KMMt*f MMlIl. (f8l tl'ItlM 9* IlfilltlM n tn, VMNtur i, n era im.iw IfMI m HONS 025879 0-TOLUIDINE AND O-TSIUIDINE HY0R0CH10R1DE There (t sufficient evidence for *.he carcinogenicity of orthotoluldlne hydrochloride In experimuntal animals.* Orthotoluldlne hydrochloride was tested In several axperlments, Out only two experiments In ale* and two experiment! In rats In which tk* compound was adulnlstcrad In the diet wore adequate. It was carclnopenlc In alee, producing hepatocellular carcinoma* or adenomas In feaales and heaan|losarcoaas at all sites In aales of one strain and heaanglesarcoaas and hemangiomas of the abdominal *1 seera In anfaals of both sexes of another strain. It was carcinogenic In rats: In anlaalt of one strain It produced sarcoaas of aultlple organs In anlaals of both saxes, fibromas of the subcutaneous tissue and aesotheltomas In aales, and sarcoma of the spleen, transitional-cell papillomas, and carcinomas of the urinary bladder, and mammary gland fibro adenomas and adenomas In females. In male rats of another strain, It prodjced subcutaneous fibromas and fibrosarcomas as well as a slight Increase In the Incidence of aultlple tuaors, Including transttlonal-cell carcinomas of the urinary bladder.?,3 In epidemiological studies, an Increased Incidence of bladder cancer has been observed in workers exposed to ortho-tolu1dine, but as all were exposed to other possibly carcinogenic chemicals, ortho-toluldtne cannot be Identified specifically as the responsible agent.1 The evidence is considered inadequate In huaans. international Agency for Research on Cancer. IARC Mcncrraphs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. .Supplement 4. Lyon, France: IARC, ISM. `International Agency for Research on Cancer. IARC Monographs on the evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 27. Lyon, France: IARC, 1982, pp. 1SS-7S. ^National Cancer Institute, iloestay of o-Tololdlne Hydro chloride for Possible Carcinogenicity. Technical Report Series No. 1SS. DIMS Publication No. (N1H) 79-1709. lethesda. Maryland. 1979. o-Toluldlnc hydrochloride is a salt of an aromatic amine, and It Is used primarily In the manufacture of a large amber of coamercisl dyes Including aio plpaent Ryes, ti<aryImethane dyes, sulfv Ryes, and Indigo cot rounds. o-Toluidtne hydrochloride has been used commercially in the United States for over SO years. Commercial production was first reported In ISIS, in 1977, 1000 lb of o-toluldlne hydrochloride were manufactured. In 197S, 2S.OOS 1b of o-toluldlne hydrochloride were Imported. 279 NONS 025880 Th principal route of human exposure to o-toluidfne hydrochloride Is the respiratory system, although the compound may also he adsorbed through the thin. OSHA has reported that an estimated 13,900 workers were exposed to o-tolutdine. Occupations with the greatest potential for exposure Include dyemakers and pigment leakers. Consular exposure to o-tcluldlne hyo-ochlorlde nay occur from residues present In commercial dyes used on textiles. The presence of o-tolufdlne hydrochloride even as a trace contaminant would be a cause for concern. However, In September 1980, the Consumer Product Safety Commission (CPSC) staff preliminarily determined that o-toluldln* hydrochloride was not present In consumer products under CPSC jurisdiction. Th Comission subsequently requested (45 Fit 61344) public couMunt to verify the accuracy of Its Information, but no consents were received. Pending the receipt of new Information, the Commlsslcn plans no action on o-toluldlne hydrochloride. CPA regulates o-toluldlne hydrochloride under the Resource Conservation and Recovery Act and Is proposing regulation under the TSCA, G(a), reporting rule. FOA reports that exposure Is limited to trace amounts In any products under Its Jurisdiction. OSHA adopted a permissible exposure limit of 5 ppm <22 mg/*!) as an 8-hour time-weighted average for occupational exposure to b-tblultflne. 0S!IA adopted this standard for toxic effects other than cancer. Mi DflPKUltflM iMdltlni Mi ttMT ACtlMft t Mrrtfil MttM. (CMC) KM, MM-MM: bUmi Mlt tnii, Mtmt. Mt *11) Milo Ml M MtM f MM If M MNlldl MC MrlMMU. IfMlr mm i/m. Mm MlfuM liUrtil* MmMMii II I MUfMI tMllMM If MU. Mi 8MjWtt uditot tnton tfdtlle ItM Uv MM MMtranMtl. IfMlfdUi l/ll/M. IK*. Mill IfNPtlPd nil rmlrlmf gn. <888 Mi IN MU, IfWMN l/lf/M UedliUlN Mljrl. lM CdWtlMfM liNIMU UW IttlMUt MV UNI vnutiM (IfM U ttu'll'Mi INN (Mint CtUtlM H Ufilit'w Men ui.u M cr wr.si il U It. . IMN UN) jmmti^ /mu. min. HU S ip 111 ***) !.))<>. liUMIll Hr ill MtvitlN MU. (lUMiri MMtoi Hr Ma iffstts ttK Dm iMtiPi) (MM) MUM MMilHf CMilltlM f CM> unImnu M>i<r. IfM) 1/27/7)s MM Tinetf StMHri mtnI INII iffNtlW. 4MNA) ifcn tfii.iMo IMM) 280 HOMS 025881 TOXAPHENE There Is sufficient evidence for the carcinogenicity of toxaphene In experimental animals.1.` Technical grads toxaphene administered In feed Increased the Incidence of hepatocellular ctrclnonas In nale end female BBC3F1 alee. An Increased Incidence of thyroid tumors was observed In Osborne-Mendel rats.*.' 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Cheatcals to Humans. Supplement 4. Lyon, France: IARC, 1IU. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Maans. Vol. 20. Lyon, France: IARC, 1979, pp. 327-498. 'National Cancer Institute, (toassay of Toxaphene for Possible Carcinogenicity. CAS No. 8001-35-2-NC1-CG. Technical Report Scries No. 37. WHS Publfcatlon No. (NIH) 79-837. Bethesda, Maryland, 1979. Toxaphert Is a mixture of chlorinated camphenet that appears as a waxy amber solid. The exact eompositlo- of the mixture is not known. (hiring the last 10 years, toxaphene has been used In larger quantities In the United States then In previous years. Its use Increased, due In part to the phasing out of DOT. Toxaphene was first eonmerelal ly produced In the United States In 1947. It Is available as uettehle powder, emulslflable concentrate, dust, granule, bait, oil, and emulsion. During 1976-7B, a reported 39-12 million 1b of the compound were produced. Etghty-ftve percent of the toxaphene used In this country was for the control of cotton Insect pests, and the remaining IS percent was used for the control of Insect pests on livestock, poultry, and for a few field crops other then cotton. In 1978, fa.-mers used 3*1 million lb of toxaphene on cotton crops, 2.2 million lb on soybeans, 1 million 1b on sorohun. and 400.000 1b on oeanuts. The Southeast and Delta States cs.tsusod most of the toxaphene produced. Manufacturers of toxaphene, cotton forme's, and pesticide applicators were among the persons at highest risk of exposure. OSHA estimated that only 100 Industrial workers were potentially exposed. This figure very likely Included only workers Involved In the manufacture of the insecticide. No rstlmotes are available on the number of people potentially exposed th'ough agricultural use and handling. This number may be significant because toxaphene represented 41 percent of the total Insecticide used on cotton crops In 1976. 281 HONS In Ui National Soils Monitoring Program, few toxaphena residues wort found (4.2 percent of 1729 sltas sampled). The ranga of toxaphana residues detected was 0.1 to 11.72 ppn In positive samples. Howavar, tha material can ba extremely parslstant In soil reviving direct application (l.e., cropland). In one stud*. 45 percent of tha toxipnene applied to a sandy loam soil In 19S1 was detectable 20 years later. In some Instances, agricultural runoff has polluted local lakes and stream,. In 1960, CPA published a water quality criteria document for tha protec tion of human health. In 1977, under tha Clean Mater Act, CPA promulgated a toxic pollutant effluent standard and a hazardous spill regulation requiring stringent reporting of spills Involving quantities of 1 lb or more. A Rebuttable Presumption Against Registration hod been Issued under the Federal Insecticide, Fungicide, and nodontlclde Act. In October 1982, the CPA published a notice of ir.tent to cancel or restrict registrations for products containing toxaphena. Under the Safa Drinking Water Act, a maximum contami nant level of 0.005 mg/1 was established. The OSHA standard for toxaphene Is O.OS ng/mJ as an l-nour time-weighted average. This standard was adopted by OSHA for toxic effects other than cancel'. 282 ACNs 025883 VtM8*a*a CCUL8TI0N* Mftuim ito *tMar ktlm Iffact to lafiiiiiMii Ctoar Ctotnt Chatta* to lattoatlaa h awrraat kii#< it imm muiti It (MMMf in*cti Mir CMC jtriMUKM. ICMCI CM. Mtftl: ttltr aathty ffMarta pwitM** in mmi tf, u/at/M. mini.CM, With TmK aallaurt ifflmi tta*. ttto janfil taatclt/. MM. CM, >Ut Hatartaaa #HH nl H- lllt'M rwrutlt aatatltr II h, 1,114 i|| M wwiti npHtiM >tai.>tn>. !?> tita* 9/tf/n. at him a* (itiN(a iictir; Mat itniian ltaitt". * to 1)1, 9. I|)l| to CM it*.4, lrt.it* to CM ill.). iiM) ICU. M)tcu mu rMatti. tof*M*Cthtto kite***. DM llll rail- CM* It Mill to IM If to toftjtav jrt itunlnttrAmiti rttotottu. Uh mtoMil toutMtt at t totarfltvt ca*tti MU to Mitt, M MlU Hill! MM to ttototo It to to* tto* MUlriMMI. If*> l*tiM l/lt/M. to CM Ml.11. Mi l) M, mil ftavltto *r"*!rv totor taiMMi immikhi Infi KtotolM tor Ptototl, C/U. rvM. <> toa ifMto, tntm. HIM, t to*H* to tittat to (Mil ar mirkt MfmrMttn tor iimmii cwtotatoy toatotoM. ll/IC/Ct. Otottay tottoto tMtttttm tmt *f .Ml */ II -4/U 'Will to tore*. Ototll ttaMIti, (trtlMftoldtir, It katof MMlttnt. (Ml to CM iai.lt MW, ntnto, l.-.i to M. . HIM to m m. 9. Ill*# <|M| Cm CtrttoNM iwint traa* lUtant mm Mmriiito1mit. ItH) fUt M a*/*1 l*fer 7M. HttMlil f*r tola *|W. ilU-M,, *Ma tar t*ic artacta atotr via* *aactr.) (M| mlittir Mittnf! C/fr/Hi MM Tataarar UMtto--vrrwt Itolt tofactl**. ?WH It CM Ifto.MM IMMI 283 MOHS 025884 2.4,6-TRICHLOROPHCNOL 2,4,6-Trlchlorophensl was tested In on* experiment In two strains of nice treat'd Initially by gavage and then given the mbitance In the oiet, but this experiment was not considered at adequate.1 The National Cancer Institute also tested this compound, and under the conditions of this bioassay 2,4,6-trlchlorophennl administered In the diet was carcinogenic In male F344 rats, inducing mononuclear cell leukemias or lymphomas. The test chemical was also carcinogenic In both sexes of B6C3F1 mice, Inducing hepatocellular carcinomas and adenomas.* The available data are regarded as providing sufficient evidence for the carcinogenicity of this substance In experimental animals.3 'international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to .Humans. Vel. 20. Lyon, France: IACC, 1979, pp. 349-67. `National Cancer Institute. Blots say of 2,4,0-Trlehlorophenol for Fustible Carcinogenicity. Technical Report Series No. 1SS. OHEH Publication No. (NIH) 79-1711. Bethesda, Maryland, 1979. ^International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. 2.4.6- Trlchlorophenol, an organic aromatic compound, Is soluble In water, acetone, alcohol, and ether. 2.4.6- Trlchlorophenol has been used as a wood preservative, a glue preservative, and an antlmlldew treatment for textiles. The chemical has also been used as a bactericide, a herbicide, and a defoliant. Commercial production of 2,4,6-trlchlorophenol in the United States was first reported In 19S0. Production of this compound was limited In 1976, due to tne high cost of removing toxic chlorinated dlbeuo-p-dioxlns, which have keen found in samples of 2,4,6^tr1chlorophenol as Impurities. The U.S. International Trade Commission (USITC) reported In 1976 that 2240 1b were Imported. In their Initial Inventory of commercial chemicals, the EPA estimated four producers and Importers, with a domestic production of 37,000 lb and imports of 37,500 1b (Toxic Substances Control Act (TSCA), Chemical Substance Inventory, 1979, public record). The production of 2,4,6-trlchlorophenol was not reported to the USITC In 1979-1990, but 198C Imports through principal U.S. customs districts were 560 lb. The 1982 Directory of Cheerical Producers lists two U.S. companies currently producing this chemical. HONS 025885 2.4.4- Tr1chlorophei:ol 1* < strong dermal Irritant. Hunan exposure to 2,4,4-trichlorophenol can occur through skin absorption or ingestion. In th* 1474 National Occupational Hazard Survey, NIOSN estimated that 110 workers were exposed to 2,4,4-trichlorophenol. Substantial exposure of the population Is questionable, according to NCI. 2.4.4- Trlchlorophenol can be produced when Industrial waste water con taining phenol or certain aromatic acids Is treated with hypochlorite. Trtchloropheno! (unspecified Isomers) has been detected In river water samples, landfill leachate samples (40 >'g/l), and tapweter samples (2-4 ng/1). Pro duction emissions have been estimated at 1.0 lb/ton. 2,4,4-Trlchlorophenol Is currently under evaluation by CPSC. CPA regulates 2,4,1-trlchlorophenol under the Clean Water Act (CWA, 304 and 311) and under the Resource Conservation and Recovery Act (RCRA. 3001-3004). ERA has published a water quality criteria document (11/28/40) on 2,4,4-trtchloropheno) for the protection of human health. 1,4 .4-tHlil<n--M--l MCMriM MfiUtffM t*4 MMr ftctlww IffRl If MfllltllRti Mar C--mu (lUtlM If IlftllMH Ml* mlMtlM. (CMC) (M, M4i MlIf (Httrll fMftllaftM U riMl fM M ll/M/M. Otf, Jit* HllirMvt 411 Ptfilillw NMlllNI r**8TU*1# Mftltty HI 11. i.H i|l m iiwm nwrtiaf fmifMii. ProHiptM mm. KM, MMH tfMMdflcMM NKWIi ! IMMIU. M Wilt MUMt In Mltll 1M If M MMMaf M MMM/ W1|H|IM fMlMHU. IlH mlpNIH CMftUll M IIUPMH IMtlMdt if o4Ra. PrenulHUd t/tl/M. IIMI 4$ ft, *. run MfaUifM Mm4 w untie ttt*<Ur. 'lltPft <-- w. Rf MHNlif tf CMItltl. MfaUtll* HiR m omit tttttflp. fnun trait* can i* MMiitf f OWtUl m#ll*l. ICMl cm nr.), 'if.i) cn hi.a. ni.h ((Ml 285 HONS 025886 TR1SI1-AZIR101NYL)PHOSPHINE SULFIDE (THIOTEPA) Th*r* It lufftclent evidence for the carcinogenicity of trls(1-ailrltilnyl Iphosohlne sulfide (thlotepa) In evperlnental animals.! Thlotepa wat carcinogenic In mice and rats after admints- ration by.various routes, prcduclng a variety of malignant tunors.`>7 There are several reports and epidemiological studies suggesting the developeient of acute non-lynphocytlc leukemia In patients treated with thlotepa for ovarian and other malignant tumors,2 but the evidence is considered as Inadequate In humans. international Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 9. Lyon, France: IARC, 1975, pp. 85-94. ^National Cancer Institute. Bioastay of Thlotepa for Possible Carcinogenicity. Technical Report Series No. S8. OHEV Publication No. (NIH) 78-1308. Bethesda, Maryland, 1978. Thlotepa, a white crystalline solid, is a polyfunctional alkylating agent used in the chemotherapy of some neoplastic diseases. Thlotepa has been prescribed for a wide variety ef neuplastlc diseases (adenocarcinomas of the breast and the ovary, superficial carcinoma of the urinary madder, controlling intracavitary or localised neoplastic disease, lymphomas such as lymphosarcoma and Hodgkin's disease, as well as bronchogenic carcinoma). It It new largely superseded by other treatments. There Is only one known producer of thlotepa In the United States, end production data are not reported. The National Prescription Audit reported that 30,000 prescriptions wore dispensed by retail pharmacies In 1900. An unknown quantity was ordered by hospitals. The EPA designates thlotepa as a haiardous constituent of wastes and regulates It under the Resource Conservation and Recovery Act. The FDA approved thlotepa on February 19, 195y, with the warning that dosing must be carefully Indlviduallied. 2SS HONS 0258*7 lllilltlHl Wifi* to*Utt* m4 Ottor Acttwn M Mmt KtU*. h IM> pmhc ( mmnnf kmku iMir CfK Jwrtomtf**. iwo ICM. MOMttot <* tot** H 1 tUtrftM (MltltDHl *f Ntttl, M M|Ntt MIUI MW H (WttU Wmiim Mf itfirt/miPiiNrii PWtflrmftti. l/ll/M. Im tiniMft* Mhimm Vwf iuu*nt Nff (IM) INC*: tofrtrH f*r pr*tcrMlto M to lift. KttUTlttS Cfftct *f l*1tlM>; fUMT ilalM to totorH iih to tmtoftt If CMCCP. Ill* *11 llllldllf f*MS. ttlitm to cImpIjt totoito w i urtlMMf Hto tot* imm ik *1tot tot*. IllrtiN tot w* tot* liffilf Mfirntoi to ittof mtoMi. etutt** f 40 Itl.U (IM) 287 MGNS 025888 TRISI2, 3-0 IBROMOPROPTl) PHOSPHATE There It sufficient evidence for the carcinogenicity of this substance In experimental animals.1-3 Trls(2,j-dlbromopropyl)phosphate (IRIS) administered In the diet wes carcinogenic to MC3F1 mice, causing Increased Incidence of tumors In livers. Tunes, and stomachs of female mice and In Sidneys, lungs, and stomachs of male nice. TRIS was also carcinogenic In Fischer 344 rats, causing an Increased Incidence of kidney tumors In both sexes.? After skin application to ICR'Ka Swiss female mice, It produced tumors of the skin, lung, forestomach and oral cavity.3 'international Agency for Research on Cancer. 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chenlcslt to Humans. Supplement 4. Lyon, France: IARC, 1982. ^National Canter Institute. Bioassay of Tr1s(2,3-d1bromopropyl)phosphate for Possible Carcinogenicity. Technical Report Series No. 76. OHHS Publication No. (NIP) 78-1326. Bethesda, Maryland, 3973. 'International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 20. Lyon, France: IARC, 1979, pp. 575-88. Tr1s(2,3-dltronooropyl)phosphate, commonly known as TRIS, Is no longer used In the Ur.lted States. Major uses of tr1s(2,3-dlbromopiopy1)phosphate were In plastics, and as a flame-retardant additive lor synthetic textiles used In ch11<'-en's nightwear. Other applications were for tne tryet--nt of poiyuretnane focus useo in cushions for aircraft and automotive Interiors, home Insulating foam, uphol stered furniture, packaqlnq, draperies. Institutional bedding, toys, doll dotting, and wigs. All domestic production of TRIS wa: banned In 1978. Commercial produc tion In the United States was first reported In 1959. In 1975 production was estimated to range between 9 and 11 million lb. During 1972-76, a significant number of Infants and children were exposed to TRIS, primarily through skin absorption and occasionally through Ingestion from oral contact with TRIS-treated garments. The Consumer Product Safety Commission (CRSC) stated that over a 6-year period a child wearing TRIS-treated clothing could absorb a total of 2-77 9/kg TRIS. More recent data Indicated this estimate may be even higher. The National Occupational Hazard Survey In 1974 estimated that 29,000 workers were exposed to TRIS through skin absorption, :s8 MOMS 025889 Is HU. CP$C acted under the Federel Hazard SubsUnee Act to remove ell TRIS-treated eMldren'i clothing end other consumer products contelnlng THIS from the market, end In 1*73, It prohibited the expert of such products. As A result. In 1*77, approximately 20 million germents were recelted end some destroyed; however, some mey still be In wsrehouses. Some rRIS-treated children s sleepwoer, manufactured prior to 1978 and stored In warehouses, may reaopear Illegally In the marketplace. . Consumers wro suspect they may be purchasing pre-l*78 TRIS-treated sleepwear are advised to contact the manufacturer or call the CPSC Hotline at 800/638-8320. CPA regulates THIS under the Resource Conservation and Recovery Act and under the Toxic Sutitances Cont.-ol Act, 8(a), which reoulres that EPA be notified of Intent to resume manufacture or Importation. tHi|>.i.<I*wPl< llWl**i(* Kstunws irtoct to ifvtitiMit toto Cl--it* V*#%MnlmU, lctHncMnImnHUKHrtmollu 9PMM lli cMItoto'l <HMf Hi IM mpI--< wall f II IPtHlbl to M Mwli to UltPlv Mil* Mil M WMI finHtl Hi M HHI *1 HMWH Ml Iflml. irt/n, cm whwinnvupi> Mill M MMirWrMM IHHCH. tend U tot tofInf ll If??, Mtof.lMto'l M-n tllllM ftoMIto MM MCtll*. lM to to* flMMto MM MtMDH; NM MV ttlll ! to MPtotoMI' TRI1 li M Itofpr MMftomtoto to HH toMiKlMltyv icmi aw, m>Mt hljHtl Hiu HHKtl. tff>0l(IHlllil MHMl, M Mill f|tl*H to MHI M IM If M MMtlaf M toin/pwip|ini**i puMMim. MM fMtfMtot HIS M HHHHI NMdMM M mill, im Mllacti ,* HM 18 M*UM 1. to IM MM rM*m Ml. HwlfHM l/lf/M. TKA, Mill Ikh*i MMtocton if MMI MM MM MWMtlMtf. M MM* bpy Nttoi Hf MCA Ml Wail WHUffl MCAwM toll Ml tola M Mil tot M MJfCM to MMlMtoPlH MllflUlto MM to* MMtla AMMflMly. 1 Mil MMlPto# tott IM M MtiiiM if :mm to HIM MMftotoM J HtoMmlM Ml tofMlfttof, W/H.'Mv tot CtoftMfN iHMMit Mu ItoMMM >MMlMMllMMM. KMI Mil HMfiiy Halt m tottoiiii ito ^rtor iMMMctito to Vilf Hu to* SWlfWMOt. (IM! dun** to tofMii*i 41 fl. . WM itriet a era aii.u, ni.m a n ica. i. raw KM| 28* HONS 025890 URETHANE Thtrt It sufficient evidence of the carcinogenicity of urethene In experimental animals.1 Urethene was carcinogenic In (rice, rats and haunters following oral adailnlStratton (In drinking water or by stoaiach tube). Inhalation, and subcutaneous or Intraperitonesl Injection producing lymphomas, hepatomas, mrlanciaes, and vascular, lung and other tumors. It was an Initiator of skin carcinogenesis In Mice when given either orally or topically. Urethane also enhanced the leikenogenlc effect of X-Irradlation In mice. It was carcinogenic In single dose aperlmerits ard following prenatal exposure. Neonatal and Infant mice were more susceptible to cancer Induction by urethane than were adult mice.* ^International Agency for Research cn Cancer. 1ARC Monographs on tl.e Evaluation cf the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, 1982. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol. 7. Lyon, France: IARC, 1974, pp. 111-40. Urethane (ethyl carbamate) Is a colorless, odorless organic compound that Is soluble In water. Urethane Is available In the United States In crystal fens er as a fused solid. The primary use ef urethane Is as a chemical Intermediate In the prepa ration of amino resins. Urethane Is also used as an Intermediate In the production of pnarmaccutlcals, Insecticides, and fungiciots, in uiir:niait.*l research; and In human and veterinary medicine. In the past, urethane was used as an active Ingredient in drugs prescribed for tl a treatment of neo plastic diseases, as a hypnotic, at a component of a sclerosing solution for varicose veins, and as a topical bactericide. In 1970, approval of new drug applications for products containing urethane at an active Ingredient was withdrawn after It had been found that urethane was Ineffective. Umth>ne hat alto beat used at an Inactive component er solubilizer In liquid prepara tions far Injections. FCA withdrew the new drug application approval for nil drug products containing urethane as an Inactive Ingredient (Federal Register, 41 FA OS*!, 4, E/E7/7S). Two anticonvulsant drugs, trlnethedlone and paranetbadlene, cat be contaminated by urethane. The allowable limit has been set at 1 ppm. These anticonvulsant drugs may be useo only to treat epilepsy that Is refractory to other available drugs. 290 HONS 025891 Urethane ha* been commercially produced In the United States ilnce IMS. Between 1975 end 1977, there were five producer* In four CPA regions manu facturing ebout 4 nil Hon 1b (Tonic Substencet Control Act (TSCA), Chemical Subitence Inventory, 1979, public record). Several companies now produce urethane solely for research. No estimate was available to NCI on the volume of urethane currently used In the United States, but the use Is believed tc be small. heports of huaan enpesure are not available. In 1974, the National Occupational Hazard Survey made no estimate on the potential worker exposure to urethane. Urethane Is volatile at room temperaturu, and expoture can occur through Inhalation and skin absorption during manufacture and processing. Urethane may also be Ingested by humans. Urethane has been found In diethylpyrocarbonate-treated beverages. Urethane was also found In wine, beer, orange Juice, and some soft drinks. Currently, urethane Is regulated by CPA under the Resource conservation and Becovery Act (RCIIA), and regulation proposed under TSCA, 8(a), would provide detailed production and marketing data. CPA hat also designated urethane as a huardous constituent of waste and will determine the appro priateness of additional regulatory or other control actions. The use of urethane In drugs Is prohibited, and approval has been withdrawn of all drugs containing urethane as an Inactive Ingredient (2/27/76) (FDA). MnUtlM M tun AcitMf MU. MVImMOCt lUMCti tffwfMrlflCitlM MMf. Mill kmku. mt Will WHOll la if IM l iai rwr 7 HMM6M lay PBt*tPUMI> Mm UtlfNIlt (MMMl M Wllf<M CMMtNDt if MIU. )r)|itrt l/'./M. TfU, Mill Maartlaf mil mulrlii fvmctti a IN MU. MMW t/m. (KMI NMIM M* M tf Bflttlll M M KIM tr IniIM tafriilaat la Mfa. niMiw WWII af ll mm taatalafaf iM.w ii m laaetlvi fafrailMt. IfMl ItUUflM tffict if IttiUtlaai; Mmr CaaMu layulatiaa mmi m dmale muitr- ftitin futav cm* l* kM|1 la# if IMIlttl MIIH. tiUttm f Mfalttfaa cr* :i.u. m.jj Mali amlM MtUr Mill far tilt* Mttaf Miwm MMatlil, mkd pat M COMldeeud ilaag olih eoi la imumiumh if nfiliiri tr mmt mmi miM. UMI ! ft. . MMI IPU 41 ft, f*. HIM 41 , ii. H04t Mf/H IfMl P.91 MOIUS 0^589d VINYL CHLORIDE There It sufficient evidence that vinyl c.ilortde (VC) Is < human carcinogen.) Its target organs are the liver (angio sarcomas), brain, lung and hemo- and lymphopoietic systems. Although evidence of a carcinogenic effect of VC In humans hat cone from groups occupationally exposed to high doses of VC, there It no evidence that there Is an exposure level below which no Increased risk of cancer would occur In humans.2 VC was tested In rats by oral, subcutaneous and Intraperltoneal administration, and In mice, rats and hamsters by Inhalation exposure. Following gastric Intubation of a solution In olive oil, VC was carcinogenic In rats: inhalation exposure produced tutors at different sites In all three species, Including angiosarcomas of the liver. VC w>s carcinogenic In rats following prenatal exposure. A nse response has been demon strated.< There Is sufficient evidence of the carcino genicity of this compound In experimental animals.2 1International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 4. Lyon, France: IARC, IRK. `International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 19. Lyon, France: IARC, 1979, pp. 377-437. VC Is a colorless gas that Is slightly soluble In water. The principal use of VC Is In the production of plastics. VC Is also used In the synthesis of other chemicals, and It was formerly a component of aerosol propellants. The vinyl chloride-vinyl acetate copolymers ure used extensively In the production of vinyl asbestos floor tiles. Annual production of VC In the United States Is approximately 7 billion 1b. Domestic production of the VC homopolymer is reported as 5 billion lb. and Imports amount to SS million lb. The estimated domestic production of the VC acetate copolymer Is 279 million 1b. Human exposure to VC occurs primarily through Inhalation and less frequently through skin absorption. More than 3.S million workers are potentially exposed to this chemical. In addition, there Is a potential exposure for 4.4 million people who live within S miles of Industrial sites at which environmental emissions occur. Air emissions measured near several production facilities contained 3.1-12.5 pph of VC. Very low exposure may occur if unreacted VC remaining In polyvinyl chloride packaging materials leaches Into food and beverages (O.OS-2S ng/kg). or medical products. 292 HONS 025893 The Consumer Product Safety Comxtsslon, the EPA, end the FDA etch binned the me of VC is in aerosol propellant, eliminating exposure of 1-S million people annually, 'inder the Clean Water Act, EPA has published a water quality criteria document for the protection of human health. The document addresses VC. The Clean Air Act. National Emission Standards for Hazardous Air Pollutants, addresses VC emissions from production and manufizturlng facilities. The Resource Conservation and Recovery Act I NCSA) subjects VC waste products, off-speclf(cation batches, and spill residues In excess of 2PC0 ib to handling and report/recordkeeping requirements. RCRA also designates VC as a hazardous constituent of waste, and subjects wastes known to contain It to the same requirements. FDA has eliminated the use of VC In drug products and has alerted food manufacturers to the need for monitoring packaging materials for VL. The Sureau of Foods Is presently reevaluattng Its position on the September 3, 1975, proposal and may withdraw it. The OSHA standard of 1 ppm as an 8-hour time-weighted average, and a S ppm celling for any 15-minute period, was adopted In October 1974. Medical surveillance, training for workers, use of protective clothing and respirators, warning signs, product labeling, and periodic monitoring are required by OSHA. 293 MOMS 025894 ffliqrl Ul*rl MGIUTIM Itlilltlwl M IVHf ktlMf it* *f iminu mum Ml CNNUla t1*l <l*Mr 81 8* iMrMim if ii m KtHiim. ICMCt CM, 1U: iw tUrtiw M( cniariM iiiini rm *yi chimi* mmmr inMni* an# nlfMfiiHM, an# (trull itlylMi IIOliHM mn fNtoftll fKlIlllft. frmllMM ic/*i/h. u/j/ji.4/j/n. CM. JMIah mir gMlIty cHUpU MIIMI In final Im, U/W/M. PtPM. It Canetllattaa/MMaMtan / II ilifl cnlaria* Kwr-oaUiKif tnwtNt nfinrN far m in MHI, fail MMlUg HUHIlMHtl, MflUll. IN KKIIIN 48848, yr%. ICM, Mi'Mls VNjttti Hitt inf. NCU, Nff.tmlfKatlNN MUM, Mf tm mim i mm if ICM if H MNlltf NM PNNtfVrNCNPMNMINf MUlfMIU. Ala# MtlfMWf iyf Mliriai m uiimih (t*n)M*i If Hilt, 0f MNJNCtl atlttt NM k cantata hum mm nnifttit. Prannlgavaa l/ttftt. la* tinMfW IimiuM Intt itaium nMtr y*acttrla#tanf1nartat< (IM* (ffacl af Imalattai.t; Otnar Ctaufll at a rtw'l af Ut k CMC. lit, l'a. 1*1 atlllaa pantti at lanpar tipattt. ICfSCI intm nfiNtril twtnh urn m* Man mawt ta mki aaimaaa tt H parcaat atar precentral la**ii. a.l ailHaa paapia lira rfcim 1 aflat af facilitlaa tmjact ta taata iunini. Matt *lpl saiartna in aaitfelaat i ataa at an mratal la praaallaati. IVA) fU knit tf >n|i. Cmn tf Mini avMft' ta trn kmm^i n*uii*i **' tmtritt Ml N mmwpa Ut NM rnfl 4tl<CI* tm mnii. m bm # ittai NNMtMn tttkt u itkUN rltfl Nlm NNNNiM In paataging NaMptai. t f Mia ami. M nln ttn nh fiMliMC. (PMI let tlklMItf MtMtf vlNfl ttltrlfi in crag pmcacta ana at a prapallaat nMflt In aatvMl praaactt. ?Mt Ni ala.-tM Mfi(trtrt ta i*t maa if mhut uttr NciiftN aattrult far riajrl e-:lartia aaiiaaii1. Nrtw af itcaaal, Taaacea. an finam mi tawtf NlftlDfl illtrlft (MUlwrl far iltlhitn tavarapa*. aataa n *U -art. tm Itmt af fttn it amantir raaralaadag ttc aatuta* an (** t/l/lt pmaatal aaa mtf ilttfri* it. tf Ml Kit 1 pp C-kr TM, 1 a#n/li-l TM MtllNp: N flfHt (l*U(t !!* 11<rtf. Inuittn Onmm, im<*i*i> 8N Mul MPvniiInnm rmlrMili fan Mrtarci ntlUfitf nntrmi; ngn wuiiwttu ft* rttvltua irttti laatling NfiiMtiiti far inuiiin. (MM| aawlatarr nuar tfifr ftiiMtiif, wa a** imin allaaaata tancantrcnan. P/lT/Ti: OSM facaarar itlManSUpm (UM ag/*J) calling. afl/1i: latrttnf Tauparanr Itancara.. M tan calling. PVTCt Pinal )unin-<ttm*i Malt affactfra. fMM) :iutt* af Mgalatiaa 1M0 CP* iMo.uumai (CMC) a eta it.M, at.n m pi t. p. nui M PI. a. MM 40 CPI Ml.lt. M1.J3 l(P) M PI. p. KPM Itftai it PI. j. Mil* |P#a tt cpi tm.titT tasM) 294 HONS 025895 IV. REQUESTS TO WINS FOR RESEARCH AND TESTING. AND TO PROVIDE INFORMATION Tab!* 1 lists chemicals nominated to the NTP for carcinogenicity testing (n calendar year 1981. Table 2 contains status changes of compounds previously listed In Table 2, Section IV of the Second Annual Reports on Carcinogens. Table 3 lists the chemicals acted upon by the NCI Chemical Selection Work Inn Group (CSWG) but not submitted to NTP for Chemical Evaluation Committee (CEC) review. Table 4 contains Information related to the National Center for Toxicological Research's (NCTR) restirch and testing relevant to the car cinogenicity of substances. Table 5 contains Information requests received by NIOSH pertaining to the chemicals In the Annual Reports. Table 8 lists the requests for chemical Information received by the National Library of Medicine during 1980-1982. 295 HONS 025896 CMiMta M. |<4 IMMM umm K>*f N. MI NM-M4 NtM mm i* *"* mi ittiww W M i> m omiigmin mnt > (mimmi Km mi snmmw MiCI miiiwu m wwtif mm* Lt *l I4MM4.allr iMMftftlMl Mtamif ttrtrata MfMlM Myflt MMrMi lww CrMifi h41m 1 lyiwtiM * 1 ,MttMww>wtM hk MlM NCI mft wimHIm; MylrMi `1lrt->.Ml*t.N**aIKltMlt iKUrMtUi UrtrMai MOMMf act nci f*C|IM fall* lf Mm Nulllt ClftlMHI 1 ftltrM.Mkyl.r. ijiSKimv- ItflWMl MK (HlUy tertral Mr IIIMKMl mm HIMmI Mi flMt M4i|M tatpryrl HNi Kl CUM MMy| ccry.tc taMiit; mMM MrUiM *( >kim|mUIi> hiyylX Kl (Minty*** Kl t-CfcliratfMClrtfliwM* Kl Um<: wwiy<nt rn My ftMMM IHItMt KWH Kl Kl (miMMU mhiwii IMPKill (MllMIH CwiMtrtMt Mp(M M(M|m HMIimIIi rtlcIN II l** WilMIM Ittlllll (MflaVfM iMMIMl UNI mt IMMII IfttMi ImiIII rtmlll act Mfk * MI* HMUil riMliMlIi 14 Mm iinlMfii Mwmm ( yiitiMilkiilii, Mfltltof taliltf IM Urate NM Im Mnl Mlty h uc Mmm In iHilMyntdly MtMti tar iiiiM IMMIH lr MI. fltp, iwi'm. MhMr *M MMI> ImIIm iIImIi iMlMf m IMtlBf IVIMiwm m uc . Mm rmOt lr Miy. l MKil M*Mi< far nr. llMIMlOly IMIlM MIMM far IM. OMtMUttf Itrttai MIMM tar or* iImMUIIi uum MUilM far car. tUnraUlly latltot tuMMMi far Mi. ImMIIi. I.M , Mt ayitai | Kiiil. taOaa riyiaMIlM lIlMHt fW|U)Mt. il'y !**) ly UC IwlMIM Iw lr. ilmiililiy lattM# hons a**897 oi mn ftMUHS HMMM min-im M-M-l mna ini'M'i W4M m~.\ JIMI-f i. cmrims minus w m fit m '`wimbbkitt ihtik w cm mu no itaj i<m<ima) CtfNK* IM ws.t atftSIM M1NMU IN NWII mjtn ai|* /MMIll IK MM HMTI mycit M|K /MMlil lar km M/KOII ATl/CM lfh iMKIil far Mm l*un rml< kM UmIiIiIIM KM ftMrtlM H(lllW/MK) M%l lnM MUfl hl%l luMfl lMN MvlIrlllwiKtliiN NllINU ! iI Kl lr.MllriM,lllil< nM Kl H< DflMNIrMuMi Kl M.l< BKk|l Calif. feat, ikilu in. K1/CMa Nt.Mt toikfl l/lflm Kl Kl lUNtirill/ rtlilM I* urn nnlm; Uf /Krllll lar MM KfMKI Mm IlftMTIj m/km iwilnyi Mi* Htmtiii nr Mm /MKIj W<m UMltll UIKtKI lilt af tid. m iMiiiiitfi |I|K KNMIIm KhM FataMlal ctrlMtm: Ml t miylMIti ifrnt Mi mtmtui ik mm nfMtrt M8 tl HUfllll*! MMt KIM If IMS Mi >(H Ik |mrtl tmuitf. Mm MmmtN illMl IMltliMltHy liilkK MINIM Ik fmarat u>iiii|t >> riKiMItN trim* lKllW|lMtM/ tttttof MliilM Ik K*kiI INltll|t MU MKtMiiN trims 1 iKtliniMlUf imitf MInIM Ik ik. ttupiHHi tmtaf MwlM Ik IK. ItUMf MliilM Nr |Kcl*. KNIIi 11111*1 (titmMM Ik in. lIlMtllll/ |l-t*t llm) taut CSC liiawMl far tmtt llrala A lt taaaam MH/ to cic Mftatm Ik nr. ciaaamUHf mit*a totammtoa iw K|. mmllt Mitr NM. Tim cttl Mtftmra ma ttiit a m*m Im mm<m nit/ to tie HONS 025898 IM9*VI f**.| Mt*M mt-v) iimi-i llt-IM m*.** M.N.I rm.N.1 util i. cKMut mmuu$ it mm m MicitKitKm mint u cmimii km mi MUM MM MtflCT M4MSIM MIMMlt tm Utfff TI if IMS | 1 1 Melt! m(4 KlWtlMf (wiNfrruM 1Nrw (uttfii) Nll.flMM NffrWlN PnM# lllMMflMI It*rtffimKa llt) MtaattMavlt Kit! MMltt Jltrt'trtal Ktlftri ,.lwiatttrt. JM**tt taaaMrafyrlitM m tu unak Mlf Mkm! Ml Kt Jft/CM hUI dm Matyt (lUtlttl) larft HKHfii Mflltlt IMttt IdtlKUt (MNwl M fflfkltl ftf MM ttttrt: lUMMKl ftll* lltMM# It MM M|ft HIMMil Ik 1 NHMI (amtrtlt Mm! Mlf Mtllly Caatral Ink Kt Kl CaW. MNtl iittr fMllty (MMliirl InN I* tHaklaa attar IIMIHH ittl lM IIIU| IMfett tt MKMtltM illMti I* Wtrl hrwMil nlMlMM* tt Mm (wcImms M|t NtMilll far MM MftHM MM at it talvaa*, kt.aaa. l. imm tiulftl, ratktr MlIM IMMIIMM a# Mil artaa MMimhI u a Minn Kl tryl nIImmIM (Imi lIMfl la* tattUlaa h tMtltla nr(lafN! M|t mm* m* Kt M|k lall'll*a af INtta*. taaKHfi |rit tattatl*! far tMMMlj rtflaatilt<t alatla MraiM V! IMf Kl Mrjrl mIImmI'i etui Haty; 1iMNlil tarclaaftaj mH t Mtjar Hi rt IkmmM far tar* ttatfaaKHr UtlWtf ttaaataOaal tv ar MlulM far arla^tMltliv tti'.tat MilHat far immiI laataalatr. rta-atM* Hit tffttlt I ttrtl* MfMllXl IlIlN Mlnitf far ftaaraf laatrafatr. mriMi. flat Iffan ctrtU taftaltflf laMMf Miami In laar r--attr atafftt Nimrt m It ImI tf MfMiM tf tar* tlatfiaKKy MliiM far MifMKttv, aaniat. ttalcHi M ra#rt* Mill fffM taittaf Kini.tlt far Klaaatt tKrattatl twrija**!# lluMlI M*IMW rkU| ty CM tir--iiiMt far ar. MMatatM far tot. Matlla Mirwatr HOMS 0*5*99 tl.MI IMM N-N-i IIMM HW44 (M>4 mu ii t i! ua <OWHUT ujanafs) MttlKttBICIlT TIITIW H CMlWH lt IMI (eaatl*.**) Mfacr MMSftK urwMii m kmh Kim t% mu M MhuitnU r -tlktaia)yltulfi-> t* WfxMaawWM ImUIM 1; 1(1 IttfKlIirifWMlMI M|4rU< IttrNM 1 i),M4urNlWfrrN iMtfNM tMiUt urn* VtoUkflMMla U4KMITI. maiu act aci Kt C*H. Mtlf Mill* (Mini lufi Cl i/c Cl Cl Kt/CwlM IMI fa* W|l UllMMitit; lr mm MM*I IuwmIii tar IllMlIH !* WyH Aryl MllMMlM flat! M*y; IMltMlIll MM MMMli 1M M#UlM M pMMtkl* (MlMfM taratlaratly ntilN U Wmm iMClMtM fw*tf it aitiiti mh, l*a aatttara MMIM alatl tt*Mi Uliui# HlMIll MmmmMM lr l*NMl *Mf, piliini iimm BmImIH f*r (if. iMpiidif iniif MmM Im mi> **lHy. iMilt*. fMUIty rtKMM* Um tlfMtt miiif Ml--MM* lr | tit-- nmnwiwt WilMll NMMt | fPimptalty Mffc MMIIil la* Mm HHMI MlMtil iirtlttfM Umtinl Mtmit immUI MMlil <mlM|M<lly; H4 II MIAflMtH |M MINIM f* ftaaral iMlidf*. (ifraM* ll* aflactt C car. M'lllf Matte* MlirtH lr tir. aai^tiy Mat > IwartMl fa* M Mid i*a*t ia MHaaktii taut. rifMMilM atfattt I iwimnuui M CK teiaamaia far mifaaMIty M lr*M 1 iIMmti il*Mm a-- a mv h ue MONS 025900 M Mil Ifl-IM rotMM iMit i, t*tcm wmiMf n m m m tmtmtuittii ilium m tmwi uu mi <cn--> CWMC* MW STMrTWU M4UCSHM IAII0MIC M HWW Kim H *mt I.MTH4IM ttf < ,<-f'MtVIMamlaa KX.ltl wittwtM i^iwv, ttrwciaratlj ratal** la laaxa urctaafaa i/cm MM MtMtlil far mid fiMlwi KI/MliMr|tr MMftlH'M KMMl af flautaa; itrwiari u'lvttj nliilmiif kMMH tar jaaara) i*i#lttr. rtfraaxlln iftam. car. (tMMMi; < *<*!** imM| MMNIM tar ftaaril laatialafir. rtf****. IN arfact. 1 car. ilaattJtnty lama* BrtanMM tar n MMIlMl latttaf at IMt Itat a/ ((( at m ttaatwl tulMtla* (MlUN InciIIw |-wrl irttlM Ml aa Klim fty CKC. MUmM far ra*m KtaWa* If CtC. Ih%IIi Mr IfMN CtC mi fc--mill-- far tnitaf ttaaa. HONS 025901 m mmt IMM U.*M WMMM INN..| m-U't MI4M M.U4 n<4 IMM MM tMii t. mm wkh * tmmtci tur.**t u;i w mu i m t* utm mm. umi m tm.mttn CMRU1 MM tiMMTMfl) ncki MIMSIIM MflttMK ft (Mtf >1- Kim tf Mart Actittoakjrfa fcatanltrlla lwt dtirMi Iwml iMltlAMl Mnikul* cftlartta hNMlUiU MMrUMirIM Nti*r> dlirlM C MwUm: Mitfl Ir1l*t M1NM IhM Ifttlt HtKfl CTMlK ft lft>l {rMMU C) IM>I>IUI fi MfMlMfiM IM iiHKMfrrXlN tMarl* itlAVA net dm Staty; fMXHttl ftr MniIi M Ml M| ityaiart; Mifltl** *1 ctrcto*ftal< Mtlttlf MlKlM IMlMM MU ki Nlntlil far Mfft hh^i NMi Hit to 1 fa**# 1* M<(> *>*frm ki ki Kl Kl Kl Kl Mr MlMfn NH, Cfcatlt* Map, M Kl UM It toll fMMUl lr (MllArMlt MM dm kdri kmiii r*f iiriHod (iwvii ikiiiif ll IMM #>< MhImi M ll'lllll IfllMI M C*rM* MMl iMNlltlli to Ml Urattat mi ijaiaa* hlmtlil far al^i Mm* MflMI (tm tttori ky (M MMII MfUto f (MtllMHlllly Ml Kill l< M IlM fniMt to aatar la*ltot: MU** IMflClM #f IMM> fMldtyi Mf-llyl yra*Mlt** Ctm MMft fMiMlil f*r llflM.'l| MlMM #1 Mlllllf 1* *w| htoMltn nartirHHtflTitniKnvuiiMi MMlIt MMUfttl MiMltl far Im| umm to MtocIlM aartara l**alH it* (to May MtodlM iicimut I* N # . Ctm tttoyi Mtolil tor l>*irtl*| MM HMWi *# M Mfllltol IfK, IMrtlin taiatoto* *1 caratoataaitHy far tartto* IMhlif tattto MmM tor M*> Mltlty tatttof Cr**t Mat to *arm MMH far Miaif at nan tar* awtattotclly tom, rayraawtto* aftoctt 1 tarttaaantitla t*> tolutaf far ur> aliaaMtoity itath* ImImM* tor cartlM|iliH| laHlat totolat tor car. ctoaaa*Mif itMtof |VM IMMlat far to atira cyt*fr*lfta IrataaMla iitota*. Hilar wmM HCMaya 1 trrcto***to*ta Ivttl HONS 025902 ttl KM! MOtM-t WN>) w^n-t N>-n- IM'IM IMtM (Mill, tutu comwi m tirnu mwem iimi n wm i <r m Htm tmm amt m oacwm itmiwa CtfMJC* M MW+t m KfHSf Klim ti iwi h*i;l tftlarlat IntlK IMNIWUH (( mIM Ca#i win#* tklnfHM| butlfkt* | (IIM.II4N Ixyl Ufiltll fllllMU uiMir IM Mr MMIm NtM. CMttl- n Kl Kt Kl Kl MMtlll fa* lf (Mir 1* Miin iMiirt *\\% %H M*T MlMttta* iKltlllat la let a.I. CVaalt tall la warm Halt tta*r; affft |MMI|I far Wii nHwri lilactM far ititla* / aia. aiMfaaa u ta*lr*4tar Cim *.: aaMt Uit (IMIlM llmlr||l| INllfM la im wtri i'. iriracaM win carciaafia MtMln aataataa *ar iinla * la| Mim iiny M atMr taart ur ut (lltl Ra#rt WHU1 far iwilwnaii Mw hwmi; M'M at IKIIN. iwliliy (till IM)t MtHlil iU Hfililiiii Mm* nwiwi Mlirtif far MiafM.HU, aaraal aturwh* tiMy IVM> Inlnltf far nr. tla#fa!Mr taitlaf tMft ftrutM (trM n lrl|Mi C Kt r.aatjr) |<H| Cl*l WNlM Kl. Kl Kl l;r <u at ynwilil lir Wii iMuri dm uwri Miutw a# ti'tlaataaltfijr: ilf*lll**t WtHl'ii far Mm nwimi auwrwii la wtir data Nf|| riwrlM tartiaaWihHi af atMr (Wlw(MllM*| iMIMUlj ll*tficnw iMaiitii lar iw ai#atra (tm RWii raaartaf (aiM* faauitt if Mur nMw. caata*alaf laaraaal<i; ilftl* lltaai immIiI lar a.aaa Mlaita# far aattarjr af Mart im mi. aalcMf lattt, nratitlUi affatu 1 tariNttfMtaltjr IVM| mmaura ta ata far 'wtlat MiiMtaa m aat Mifiif (Mirrif Mil Mian#4 M m Mlacta# (MfarrN IW| *qns 01S903 mawa IMM im-iM NM-H-I IIMM m$ n > **.*- 5 W*IM MM kumm mu i. uiw tutu m i--i rrniwn mm n tot turn turn urn* mm: uaciawn immi WMW MM KMUtUft tAUMU f **!( Kltaa m tan Caffalaa (mtok atM Mitmm MnM CMaraalaa (OtMOaUHrMtinn CftalaMtral MtMirit 1 4 C.I. Nile M It c.i. mi* C.I. Mini M t FM Kl MCI K| VI Kl Kl t.ilttra.t.Mlaratlttoat (.i. MihIi Mm Ca*pM 1, *M Kl Px-lHttrl# FM/KI ... FM/KI c.i. iim M< Kill M ft Kl HI ft Imh( kl<VMl| UU | CUM SIWf | kk* ilfMffi lillMlil far M tacMtaatl (MatM f u HI (milk aclf < iim *# ulwtoi frUOpta) mart Mm (KkdNin far* lirta ftUMltl far ItfMHI kwi U MH{ MMrtltf far Mmm iifaimi MtfM iiwtl KMhIIm VtfM prKIIi Ml afttBam fMMlil tarclaapaa Ctaaa HMn lift MtflcfM af |miM urtiiNMklifi MlMtlil far imImiMi jama aapaura data HHit ri^riNMitlH aaaaaraaail nwi'.ft 4ftatftM4 Mat Pataatlal far imu tafttMrai taiplataa a# fftMlil <ar. (laafMlcHr CUM lMf| MMllI Mr bMaa iimarai ttractaralir aaiiaptaa w wtmm mum imrMlf ti carttaapaafc aft MriHMk. aft m a-tolrUtaIMM MUM riHUftk It a nil tarclaapaa la rata M*Kft far car. ataaftaHItf taatMf Prtcaraalt tail la Kar* fracaratla tail ta prapraM FrataraaU tail la prapraaa --laatal far Mattarp af Mart .tar* aftt. fk*iHp anti, rapraftMtia affma M tarttaafMiatif iWfl) apart aaatlaMla Salactaft 1 aiilfM far trtl*ftltli M afp m ittiMf nu*nm (ii/ai) a laMtap IMMMN (It/tl) Mliiitf far tirafa Mt ht| aftaaMt aaaap aft aaaar Mart tar* taati HONS 025904 fttatiM MMII MI-M4 W-M-l IM>IM Mfl-IM MMM-I mill, mm mmat cwww wwmi imif it tin mw uta-- nww m tucimun UM'faartt MKW HN sn4hiN(i) M9*s;:a unimi raa mqmi? KIMn M (1. MfKl Hat 1 (.1. Mract II aa 1 t.|. Mract llaa II (.1. Mract Mae III C.I. Mract a 1 C.I. Mract M M 1.1. mmm m n C.I. MfatM Vallaa M t.i. nm Ml t.t. ICCIfi CtUaalaa ft? tlfM Mac MI; /a*tala ff Mat Vi Mlaaclc Mi Maa C.I. tftofi Mtia Meet Mi ftatala fan Mac l| Mate Hack M IM* I'MMfTftf flaa Ml atfM/otc Ml i. m 'Mteewrpwrta M imwK ..1. (MM .'(attic Scarlet N kinvmc i.IMPity.I.II-anltv. '..MirataiiiiMwj* {l.eftrefMtf1 ).|4ta#f MlWMIfttUtUa Kl pNty))i|).C.(lattt> ti|fka|l|*t4M Mtteaataa Cl Clan tca*i fctaatlat ate f> l*act latar *ratl*f iKMIfM tlfiMl fraa I#** ctrtlta. ft) aa tact Ml*; M*t*lil alia two araacara Mrltaa Iren tee* carclteftai (acaatitl far caaiiatrtaia mm ataatara: m taaattta tan an* MM MtMClal far Mm ttpatart; ai#lcte* tf (Mtatitl tcrciaaftaUltv at m M Mata MM; aacaactal far caatiatraala mu* tftc<ri| iif aatfi:iM a# famial <arttaaaal(*r Kfairttm aaiaalfal far bmm ataaMrai Mtliit* af pMHIlil ca'tHMftatcttf It t* teltMea.aeaea fa Slfatflcaet faCtatlal far Mm ataattrat Mfida* af petmtlal carctaaftafcltf at m a-(allafaa*aat4 a;a Cltu ttci; Ilf wtfidM f yaitltH <arctaaat*f mtfllr: rafactla* alt:tfC af aia llattfa wtlc !* INftw( rtlMti la Mao* itrtlaafrat; aataattal far CMalftraala immi atfert Clan Ite*; patrMUl far iat|tftraal MM naati'f; l* lattUlaa af ftnitlt ctrcteefeatc tclMtf Ctfteaa rtCMtlw claaaaM af ata lltiift Male yitit tMtt.nt ralatrt ia ttrilMfi tftrraa (!,)) MMM M m NtMlM iHtHM M fM MlMtM Ikwmmm Par h mmcm: mu 0/911 blKM far IHM*| f Ml. attlrH It laN/KNr iNtMuM far * iMHIaMl lataa liml (tCMttata far aa IfmMtitlaatl tract Macvtatc (ttt It pr kltttM far litlltt, atttfaa* far .aarclaa* |NHII| CaHlav HONS 025905 cm mil m IHM MN-I R44.9 m-w.i Ml-w-l IMM IMM W('l iam11. mit gums tfjfiHu*) MCHjmt iism it iami m M new mnn. *nai m taaciMuti iumimh) oamt* am STRM1M(S) miiimu m uchii KINkll MH C.l. 1M 11 * 1 l.l-TUta'a MIN (lltklllN (IPIfll Cwiwta (in latarlc) UruiM C|tMM NNraaMltaa Mr*. talarMl c.l. mm C.l. NinM IIm M 1 C IfN N. Ml|i (ifMIMli) iMtllMM aiaiM/CMC 1M Kl Ml m NI|A UMIMt; |*MM M a 4m Ip 4taU Jaaai Wa Mima i<mipi 4. i-**`-J* data Moft; filwUil far ImiMhMI. Wm* ItHMM AIM M1|UlM 9* |n<( actimr (lait M4i| mini III In (MtlAtfMlf MM nfMPtl riMIHMilIrt *1 IN IrifiiM MMM *f IN UltlllM NIMH far Ma. ataUllf! rtpraAM* (lit HlMtl, MM aaiarNNa, | Mtirl. MM IkOn< tMiotr (i.p.i mia 0/411 Pmpmi: mu la papm firi jmImIN fr rtaraMIN affaafi 1 MfdaafaalitiB laUa IW9II MhMH far Ml4a. alrhtkil HUM A Minaalaliy laUi MfMiPi niMlMMi; IHilll IPN*HI* Pradraatf Ml la pnr* wmt CytNtM rlM* |. a.ItWnPMMfl* C/INtM nyici tM Clan UM; aalaallal far IlfllklM til|IMll HfllMt I|N MUlltH a MMapt* MM| Clan ftNl nfriMUMlN mMUm Mica, |IIM l4ala Utratla* u aalaali la larpa taaat. alaat laN la in auMalalfaa at MN'Ii mV r hMiIIi praAKtf HtaaOai im<mi * * 4#vf Np natMari. Itaa if llf at taattof raiawiai own tfr.aa* taal4ara* IIM If Kf HONS 025906 MMMI (wt*n-i I4NMM ltl4M [ HM>I U>I mi ^ | tl*4 mmm M>H*t u*t i. mnw tmmt% or tw>mn mcihikt umi it rmi i m m utam mm tmi w t**nwf Ht-vmt* Ml(H KM MllWlW ` MMrl WOillK M>*yrtctwMrU |H|>ilM I'MkIi') tUflMnrii MMIIria ktrluiN iMtto* kHTMlWlil 4lM)fl> MnrtlirMi KfMItlM |4a(M.t,MUktn* MlMIIINll (M act ttt IP* Ndiwl(Nrili| Mi *M; #**! MMtllmMl OlMJjMlIlKIWtlt SCI Kl Kl r. im m PM/KI PM/MCI tMMMM ft* HqMH *CV|* to pmi . ----------------- ------------- -------- 1-- lpf* prKKilM- U Mtwti (Ml 9t 4\ tM M4i P*tMIl f*P IfftlflCMt MM* tvtpUtt* *t fMlMHI r> lapfMKIp MHW r iu llrtt*rl mlv m tmMMMm cun it*?; ui$utm *t CMUI MmUIIM l OPlMlaf MtP mwmU um ta ktlMM far tfitMMf mimih rp M'tii * -IM M|I>M IIM| M MM JMt !# (Mil IIIMM 'lar (p. (HMmU imW| MM MfXUI If Ilf* MM MHMTI MlMllI (W(li4(M NlMM U Mlf) MMIll iw Mm mmmi ClMI fttopi lM/MMrMl MfHlM IMiUmmIOII ftov* m MiH'ri m * tUl'flMMi HtlltUI ft# Mm imimI Mf* MMM N NMMill M * MM ItPtltfM k tiitlii mmUI *if* imhmi: *14 arvf MW ittotto ly IlMkrli IMI # kU| KllM Mtotafftl Hill iTMipfili Ml la pp*r* PpmwmHc Ini li PPlfPNI kMM Im laMtaf Ip Ml, IMl|Ml ll UMMltM PpMftPMl* lilt to **PM kP MMlIfl* IM Of IIP MtMptll l*l I* *PPfP|t kkt MMikfi* IlM |p IIP ppttfepwU um to ppifPtoi HONS 023907 MM nmm #>im HMt-l M-*l IMM *. n-n-i MWM im-iM mi i. mm cmmi * carum wiwm iun w unt i ar ik wccr mm wm m oxuoat ctuM-ni (MK1CM. m iwrruil SRwIim wiwmi m kmii kiim n pm I.MH'fMMt trfaauta* IlM toaal* Illy1#a JlMlM tliylM |ljrttl llkflm mM (IHvIMiMil tort* nIMi Miwrtww trtHnxP Mttottoto' altaM C*BM**I (rm ilttlll tra ||f) tolfrta rt. *f( t SttWMC*r lM Itf KwiltfHtl fMW l< toMlatfaa ./ ittktfMl ^Miiu Mt iMIMl* iim u nr (M/tMV cnc/Ki ar.i t'm Mwto; Mwllil lac (WtMirMii mm mhimi riMVMlI (Ml to KlfllM BtotoittB M Ml lull ll/BI) Kl On fMMiUI Im Mmih Im MiKr imiiihmIi mm Hffiifii af mwi iim ihii Im tol it toclUtof to (|ff|| MtHl'M M Ilf 18 MtWft HrMHlw UM/NC1 9SMTCI tn RMliriltr riMM to lM CaiitafM M|k IMMI CMaUat ftliM It MriItoat, RM IMitalH IMM TIM*VMI ttototo litl la Ririti (utmIi mu to Rtolll MttoM Iim tar. Umbmui (auto* to*M tumt My* r*rMtlM 1 paimiil liMimii mu to IMfltl M/irVKI r. ImM flfft) HI** RMRIIM tMlWt, fMMIll WtlMRI MIlMlli ! 4l(HllflNafl|. MMIMt (MW) HIM Ml Im fM m to iwiImimIi Ik fill Ml alta (armtc MU la RMHl tolillrt to im> ctopiMir Mttla FM/KI n. Mr l KMlUlf e) cum M4n mum ii far MM hynvit MOfMilr MM MMmIIm; rtM to M l/MI< m if IrM-AltilMl mmIi Mill MMUmI toffttotot Saattolaa af carctoafaatoltfi IMllWi to fit* a tut lai maaMM (li/Bt) tonMitoh HOMS 025908 CM MM *MM IM-IM i IMM IJCMM MMH IWM M-fM M>II4 iMii i. ihui tumcii of (wwit witwhh mm n nxi I 9 m tm mui kwh m tMciMuas icwiimmi CNIC4 Mtf !MMVN(S| Mine M CM SUM MrtWMU FM M<Ml! KMM rm mu fairU Mil lUMl CalltM irwMl Clfttl (mlN M) IMIM flaltt tlHMllMMl Mil tlkaata lt f t'lKlalt If*11 iifir mM ( I. M#n Mila I lialMilWIMMw iKaril Narl Iihmi (MlfMl r*ywi IWVOK/ RJCM/RCI rw1r. A. Cl r. 1. Him (0 (nc^iWM cm/mi im/rimr fM/KI (lilt Hrt iMirni la t*a MaiMpmiiif HMr: Ik kimImIm lllar ta|liuiUM la wllt l l*f*a anal laitlat rit. |U/d) W|1 IdlKllw 1 * atiMria ittK nr. (taaaaaaiM latllaf fet|a dm Hair: 'ikiuimi<i HUM (111 MOMIll far KcmlillM a III MaRall* MfK CUrttlM hK*fa*allai IMf HiMlll'ittM la MlMlt la Ikm aaiat dm Haty; fata laiaf. aaaiata l* tka irUarbaiylU Ida unit Ml aataatlil far liaaciMatatiaa af tit wwiu aa/af caiMalk laianaalalat Mtf Mataltiratlaa la iilNtl la laf|a aaitl Mir <aitatra* iim kr iti iMaMaaaN Sal* Malta amnit/M! MiMltl canlaaan MtaaraM alia* ik> ilaafaaaati tmtaf Prajattal ata *a Ifca italiaa. laclar laaailff Ik |MIiaalialt nit*; Hraalafil tatarm laa laaaairlat Hiwai aaalk Mia lafMtlaa data Ba4y; mkikIHIi Rarlaa; ll|nm IMHM MMM far aallallta Mattaa mftraalt utl la Rftfrata a laatlaa raw* awM |IMl| faitatlal care laato? taamrla! aaaat*.*t Maailal lar* imimti tkraata mm mtaai} Ik fi|iliiaf| ik|iiii atari mtlaaia H Hit Ckraatt tail to KtoMI HONS 025909 Ut WN(t IH-M-4 Mill n-H-i KMM H4M m-*M TMii i. itmw amn * eg99m rwiwmi uin n wtigw mw mum ami m tmmun Kan-ai MNKM MM >rMMTN(t) mmi MfHSriM MIMNU fto KMf ttim it Mt (,1-tlMtNllMlN km IfMlMtc km UfttM dmmti hliiu MkrufMiMiMMtHlt i*IMMlyl MUvl litm tortarU iMirMi MnwH IK i.MlM-l'Mthrl' K*M**I| kM ItaMaalaft km (MM.il-tota* h<mim*u km .(mIhM kM ktMKMrMMU KM M'MmInMimU uM; liltn IM (M rwKi 1M/NCI r. (NM (tr*)/Ki WMi Kl NCI Ml. NtM-MMm-l* IMNl>l) MMMM Kl c.i. mm ItllM mmvM nMi KMfto Kl kWIIMNl W4 IIWlI UHlKt kNMM far Nliftalilt) lam Wit tltlKt; NM I# KtilM NitKtll Clan ftMfi MKIMMUli* NMI MlN KM ClMI Stairs 'MMIMtHti* KlUKIIM fact* kM| |a'fl**| MIHMM HHtKI altar tar. tlaayaaatlt lattMf N|M IMk ttiarallaa |y It) to itriltf maa* f.aa (iiyci) Clati KM|r; pataaiial far UmicimIiiiw a# lit Muaaltc M/K HlINMlllM ftr Malai If11 la* la aataalt M tarn Natal to tttlla rrtaaNMM (!/ Clm NMyi rMMMKMlM lull mIm aflat inaailal Ik miMii taaatafi Clata kMri tl^lfitaof tMMlal far Niat laaaiartt ai* mania* af cartiaa* af awaaaata mIkIn IMaMlal KH aaaatft; (aaiftaat wHIat tatM* Hti fiMtr tiaaaa* <aalalataf caaraaai) toiar CNHlatrftlaa >/ Mr (atlai tar NMitt to atr. HiitNf u mraciar Ktytu Clan Hairs lat#llaa al /Naattal tartlaayaalcl> Mima af im ralatlaaiMf la tt|iMiiaM t*a tataKnaaiaa Mteft art factlaafaaH la rata toalailai far tlrato $ aaaaa ln| aia*aaa mar #ai Miar KWI INI IIMI total clan ta#* toaeNraak lM la CUtt KM}} pataHlat far ttptftfaal KM ufUKii raaraaaatatlva aarcar/ (II) talc to Malta* >KtMM IVIII li & MOMS 025910 M imi WIIM H-W-l mwi IW-M-t MM MM IMM RMM NM>N*I imi i. ;uie owm or c--oenn wnm inwi w im i nr im mo* mu* mm m umimcw iteeiiwaci CK*Kft MM kMnn(i| M(MT MM HIM MtICMM lK HMS> KfIM (I Ml NalNffrlldH RMkMit nil* MkUir>MMn(M>nl. MtM (Mtttfl-Meht*. weteiytV-*--!-- Ntihpl hrmICe MlrlM (lltrMt Nrtl)l IWJiMtl )Ntthrl*Mt*tMi. nlulN MIn IMnIMm. Wllmk I-Mm. IIIIH|> ImMIUnIi M%(krq.Ma<H> MllUllllIl NMrMDlH* uiiMiw lwcinniiii NIC IMM-IiMuilf IM im Ml Ml Ml Met. el Health, MMi UtlferaU IM/MI Ml Ml a Uilloi Pie ptilllft <wtrel IrNNIf IlfMIKM MM MHiWIt preateettp Irilll dll IrtNiNU UU retelli Matt KM: wwUIm # MlnKlil iirduMMhli} MWM M tit Mllvlti #t l aateffa la U| Met URtril| eaeleeai ( |* aephthyleelM, I ttrhetytHl rMtl< aalae u*tlaeeea cun hm; niiMiM tiai. fHiM M***1'1 lv *M* tMMwit iir>eirtllf Mill, wet M the ci'tlaefaelt llpMaylaalaei fee meet to litre teilt iMel wtifSeir^?tl*llr lilettie ler tettlef hp it*. Iitlfaee te <M>eM *r*rM letette# ter mi- r^!" Malaetie lie #rlllltoy Mltwel ler ter. ttor aaMieara. IM Ip IN Mfh 1 ItoMRI Mnilil frr etpeterts r*lM el he*tali ereMcee ! the lerttl MWthtet U the Wile# Metet l 1*1* Ctiit Keps pettatlel fer eaea eifeterei nehiM el peteetlet tertlaaeaaltllp tectele el lit reletleatht# *.e tlaele.rt*| carhecptllc ereeatlc aaleet we !>* Mltetee thliielet leva* te he <arilee**lt 1* the Iteereterp (y#l< leel la er*rtt Mr.feette ler Miaeettltp tattle* H/wi reelaetee ler ttrele 1 leaf Hikwi ettep KM Mart ler* teeti MOMS 02S9U cm mn IMt-l WMM rt.n-i iM.m IMU.M.I IMII'I NMM M-IM imu i. mm cmmi c--ownj wnnw uma i im t m m tM mwc mmi m (muxiw iimiimk* CMHIM MM SVHM|S) mcmi ICfftlTIM MINNU ft* MQUCH Kit** H MM lljtkyl Mil U.VHirmtftmyl-IaIw-nmllrMtMi .*. MitlyMMrrlMN* NaMVlpktaliaft MaacMaraacttU MIC IMMMl Mtlll IlMvl drtfpirta y.Mlraaatttaa (KUMlwIl HaiilP MIUm-MtUfM. sialyl Ml IvvlMlkrt* ItntwMi 1-flMrMlN'MMU KM Mtyl Mttr MUrNmit Miff fMMtatk r. Mil ttH) Matt Mm M)mu U I Will>M>lf<HllM Ml MlHirHIi mm*MI Mm tfiari Ml cardM* f**lt MtlHIf ffcraalt ini ta frapm MilMltl ii a iitwrik <mm|. Ml fcrilwtt ti li imiImmI la kt ilractaralli lMfttof| aafyattlf mIMmi af tarilaayaalaliy fra* yravlaaa uir Mmih far ttrifa a mm Im mix may (Will Clata X4f| tifirMi Mfl> ctaa litH an tirrtlartl rdatiattMp la hm* card. Mfta; pMMilal tar aUrata. |l*t UMlIifiMi arttHUI far iifaiai ItmMmIi tail la fnyin Claat *<. jyilMimi tarda tatattta far taMtaf af MilMltl afiMa: (Mate *a aIf mlyMf it ata la (illfriai lad af Mi aaaIradar Mf laiicllv ta mImIi lad* fvadraatt late la cafti fMHtlll kauri la MM a*tariff MaylldMMIala aMeft M raaartaf la aa kaNta* IMtlMtMll MmIHI mm carclaataa Vtrf (a faraatla atticlaa ky Htrylaat Uhi tallta IHMMH Clatt ttafyi da watWIaa af pallida rtftaaafaldtyi Mtadtl far caatliwaalt MN MfMWI imi UMU'i far iMiiMa- lalattai far tartfay ky rtf, aiilfd la taalrwtar laladai far farttoy ky Bff. aulyal ta taairaatar HOMS 025912 c*awu K-n-i in-w-i IIM444 im*M4 |M4M mi-w-i wn*M *114 iam.1 i. miri tnrnii m c--ki nmtut umi it tmh i ir in Mtw umm <twt m tmmu*% KmUm MNIC* NK JINK*!) mkt MlKIflM UIIMIIMNMU KIMMM MtrilMiM mifOwuil Ckltflft f-Mlrakaatayl cMtrlft f-Mlraykaaal -Jlraaatiatkaaalaalaa HrMllNM nuMfni| til if alrtaaa MlirAiiiHl cklarlta 4>Mlraka*tayl iktartta |> ^MrttUtt klrilU A NIMta (I) illwl* Sfe"' tH4tl'lk||l.4|.NlN(U> MKftllTMlllIt hdti|VUtl fitmltrili ttM/KI Cl Kl ItM/KI TM NM Kl tm/ki K1 Clan Maty; M'lll rniklM fridruli tall la If ctrcJatftalctty; M(*lfll 1'trail far (MiltrrMU Im i>|Miri Ctltl Maty) klyk yrHMIlMl M*ll4 far call Hllllil llftUllll IMMII IruMfarMtla* 1 III HfMtwi m aryl Mattel lira tmiiM Ml k|I Cklarlta Clm Slaty; ll| tayartls flllllll carclaafta ttctatt M In itractara ti a* try! lira (*f| iat acyl ctlartta taalM tar call lrMlta<la* Itatlll leaf.* yrt*acttaa/t*t*i*rai MMUI carclttfat MiliyM*lCr la yrafrtit ttfi 1 illfli Mta MirfMd/nMiati yaltalllt carctaafta atari aeatlakla Clm k-ti: aattafiai far mmIIiiiUi Imii atyatara; if iMKiit at aa aacicatltat flit li aal caatrallat Miaul far art*. family lam NlMIll rMi iiMiwii KMltl UMIHfM ctan *ays mt> ftimiii far rum 11 fIt (iFUHtillrt *1 lft m> araiat Iklacalat yrtaaraali frafratt mhki tar iw. ataafralcMy taillay Mwllil t*lraa**Mal lack t( lailta* a* MU Mnllil Mft M|*ifi It Im itrtii ir nm ni ftalikat tlir NIlMlil la^Mri ti Irif frMlrwU Call I* frackraau Ini It #rifiii Mwlrwl ttrill HONS 025913 CM MU Ml.) M-H-l IMM mm-n-i MM.II4 U>NI N>|M WM*t HU:) imli *. turn mww> m tmnm rauiantt mm rati mum mo* mm. MMII -- CMCIIMHI KaattaaMt tmm*. s summo) acmcr nqmsvim MtMMII IM IIW11 Ktm M Mt HwWlUM MImMIviIIw I'UmtI'I.MMi tMcJP O.MmmMmwUmw MUmnl< UH|W NlfilaytafrratMaaa fal|*art fraMMiU trcaatMilaa fraraathaltM WaUM fiafrlM dlaraMriaa %ata.MNafrafy1iN*> Mlfl lawikM-Ntr* tasarmm Iatari RCI Ir. Rvrji KlMM (Milftl tatlltatl) Kt imnvki IN CHC/fIVtWI mi/KI IM rinMi (tilt Huir; paitattal far mm* unnrti MlfM lUMUra h a thaiffcarMlaa Mmtaral'v lcritl*t Mcaati It iiMiIn U UriffM I* CM IMdMlMM Mllirl IwliHtl Nr car. CtMfMlCttJ IH|t*| IwlMtil far killtr^ af MHiiltlir ima (vat) cm luff; iNI aa lit mu af lit iiractaral Miltf* it itMt fdlt araMlIc Mlaa urciaafiai MttlH far aifal* A l*| ifama mif a him iaar tar* mu Iirfa rMKllt*/taitn; NactraaH MU N Mifaitaii (nlMfa*l|llf arafrt'.l aatai aH aa a* aatl-caavaltaal Ncart N wlr--aU; Ma aa iitraaaly lav taaal la*a- liltaa MiMiim Niartlal Ua aaaatvra vttMrt** till! Na*i al alfllf itif fan a* mim aa a MrltlMl ta*>laaaM| rtfrcaaacaclta laftMcaatalalaf laarfaalc M IiiiIh racaa. *M fllNO aaaara if arvf N caritaaaalcl| lailla fiMVaiU laat la irarrai frwMraalc laat la papm (lata lif|i; draft aaa a* larfa aitNatatf Iaval af ataaavrat lad af tmlaa. faaldi/ aaia MtaUaf Nr tnilaa ty f, mifaafl ta caMractar Clan Matyi aatiatlal far aipllliiU Mw aatvraj MflilM af muii)< CKiiaaaalclt/ auacll <! dart data utirlMtif alcaavlt Mar taaalNrallaa N Uf HONS 025914 CM MU MM MMM IIMM MM UMI>I Uf*l IMM '.If. tutw UMM> r tmmmi mmmi um w mli cr w wet- m utw wcaacmoccn iCMHaui MNK1 M< |VMilN(S) MK1 KMSTM UIMMif / MMIf MINk tt M Mnu* Mafia* ta ItatMofM tHMlftflllM Wa Kutllm toi !< htflMMlM l4ManfM>* mU m raa/aci rn Cl iMtiflNla IUMi 1, titMia r Urmia# rtAMi Kl re* m IM M4taUit.|* MiraallMliBMrl. dUMi MlMlaUlM Kl k Mttl*a cim ir MtlMlKlW *1 III W<kll( M/tT (MMtIU ImitmUhii Mar HitaliirMlaa la aatotli U Urf* km Wk MHM Mkllil (irtlMfM llkM Miri| ktHtlll liiH kkkn (Ini Hmii itaamcMt Htiklil lr m|iki tlpMKt Clata Miki fkkilil fk tkMltaril.t Mm tiMMfii imiuim a pukiw nwlk|lh| Mktlll ilk nyiwri; HUMlil *rctaaaa PMMIIil tarf* MMri ki II ktWMI 1* uk Ml miriMiM; (Midi lm I WIMlI It IlMMI MllMj M| (IIMM Mill iIIkU Mmiii ilk MHMk/ ifMij mk rMiu'H Clan ***; Ik* wtpHIki f (mtaattalifijn pmailil Ik IMlUkWlI MM a^aMrai Miklil Him riilkt b nlM 1I i! KhMmU ihi m kH* IlM If all kllfH ll IMIlM. tar kkkMli ini t K*raa ratraaa IMIIM MM* a*am (il/til ailailta Ik rik** kiilw iHaU ak lkllil)liUlly IlMI (V9t> Mlkkk* kMkkli |M M K*r OkkMC tail Ik K*trm 025915 HONS CM MMMI IIHM IN-M-I WN-N-I KMM m-M-t g M-M-V IN-it-l N4I4 M-IM imu . ium cwcit or ciwmh mutut imti ia rau t r tw mw mm. xroii m tmimuti k--ii--ni it. CHINK*. *NC fK KCII* MIlWIM r tfCMil **** tf Mtl MfN Mm t, >, f fttrtcMsrMINftN. <iii VtlrtflsSTMlHflfS* hlrNflrilirM iHrMlUmtMM IkwrMtMN IftMfHylllM kiwis l|4rMrHl w CM tstrftsrsstMss NfOtoNUirlMl IM tiMNMfwyltwfy*tMHil*m; *ill Kl mi. mrt i fcMnW KI/MM IM Kl NhIk^ * 1# Kl tewlH HHrKMwt* IMmIm Iffridlirl* Vttwl* l| MwMnMi rMfKI * Mm#I |4hlMtMml Kl NMfMflt r| llf M *rrM rifliimMi MpUlM sf rclMfMtilly kwi t mlrMtili UK inN Ml Il'tlN* (MUIlf (( mtlMK Ml* pMMlil 1st IMM *f*wr4 M **! (rclssfislclir mu Mm (kImmi MMlil f*r Mriliflul iMIfl 1/ IMtlMlM l MllftMl prUNlI HfiMii (Ini Us* WhIIiI lir iifMi D4r lasilSa. Hm *t aif mmI I* KIM MlillH f*r Mt* iMh*. |Nll|p lllll * Mir twillifi. tlM *f Slf fPMMMH IM IS prsfraM NmvmIi mi Is Rl carc Issftsl<lly laillsy ClitI ItMi; mmIIiI lr (Mtkrilli mm* MM WlflllW If |MMUI uril**i*l(llf Clm tlMpi pMMtlil lr Nm tMWi; M*m M|UIh sf iwtliMiiUlIf Niw*U Ini Is MfMI IsliHH Nr MrtN M*M Nss MMM MM IVtlJ Clan flsM; ff**stl*l fr NIMlllll* #f IM IMlMk yrNMti il UImIs ill* MslaliumIm is astsali Is Iw* Hill CMlaMn IIStMIIrS; fIMI MiMMlil I* Ill* if III |Ml*llil <miM|i*tilif * irMlIsssa ratttmes. IlfiMI W* MMNhHIm IfUl HONS 0i5916 NMM N-IM m-N-s RMI4 mn*4 nm> im Ml*? IW-N.I m-114 MU t. wwi * tmrnm mnwwo un> n imu > m m mcmp mum, mwi m MlWU M IWWIlHS) MCtlCI MfVtlllll UIM(rNH(!l ic-it--o Klip N MH i-cnut) (IM** IrlMirwi M.I-VrkkHrtf*Ml IiIwhiI pN>m trlittmlHlN (MlHAUf Rajr"'-` IMC1M t jlrl(MniiU|l)> IlMMI VHlityt MM**! fkMptrU kII irii MvIpkNiMtilir ha HI Cl (fV*l fiA/nci Kl MW Ml irvNti r. |. Mil. Mpr (Ml) tllli Slwfjr; wUm t linhifnUlti; iMI Cm*<m4 fr tMinltl iImi Clm ft My; pMwliil far Hi* ItHUft) M>MI MtflclM if MiMUl lr ur. MHIIr iMtlaf MImIM Im mi* 'MM- 1**1 lllMII, MM i miiiMiM, ur* Mill (i/ii) MilNUI M M dm ft4y; Iff! MIlHiM ll if (Mttlf ii 'mi *1 urtmiNiiiir Mil; Wlldm ltrwlartl iMiriM l IM dm MM; ilfillltMl mmiii tr mm imw'ii NMuti MflllM *1 IMClM|Ml(lt| htmlil tctin*i MUMUI MlllMl IM MlarUMIH id-Mtl dm ft*#yi Mimiii itr (IptllUM MM UMMII Mmiii ii imiiiIi unM. fMi< mifiir *iii **r w IHClMH *W MW Mill klM<M fir IntlH r in, <** ii (Mruiw Minn* M Mt MlHIM MIllM In tiwlt r aw, miMi ii cmmur Mlrilrl fir ur* CtMfMltlir liMH CIHI ft**r: nm<ll*i irmtu iMirMit rmiutMT MMlil far umiiiui il| iMlMMI *1 MllfHNl IM> mi riftriH I* Milwunr KM; mUi IwIi i<ii klMM h HUM Mr ini ittifM w iMnmr MlmtH Mr lMUr If MM MM Ml* fMllllr MUM. t.MilIt*. VMMM* U*l llfltu M tiMMldu (I/III HONS 025917 W*f him MMM t*M IHM l(N4 MM II4M IMIMM iii t. w>m owm f wwm wmw&t uw> w unt mn mtw mm mh w ornwaw icmmhi MMC* mm MINCV HMtim aAnMM ra tenant acnca w to* Irla'IHlIc My*Mi trlytlfaaialaa iMfilH urtUt tanfttta HMUrtMl IH m act laratrU Vhfl IImIA ftayt|*a flaart* *tayt Mh IttaMa % f/ratlaa .iMIfNflt aci IM/nci MSI Ml ravaci flat nrriuloM IlM W(lN Cl Ml MMtlll (VClMfM hllfN U mi/K. tar a tiniimwuiii uM*f flat* K4f', far fewM riprtiMHIlit lHn rill 44 MtMU Mfk MMtlll ft iifMiKi frwinaaU 'lit U KHMH aaUiUt In UitlM If Bit fcilHIH In Ul- nppH it TVU imiim. In Om U4ft alfMtl fMMtil ft l>W41 HHMfl tf tM tKMIMf KMlU laa Mill a lm*| ritaaaa*4 hMrtlil cmUtfMi MUflUwl H*JWI Wa |inr<| farm m naliaM far liMtet Mfh I (HWM| rUMltl IIMhlfN Caraalc Ini la Clut Kafr; >|Nit i.t. irMtllM if lit iIImIm uMiMHl *1ft *r Hf| lw|| HIM ti M IMlftH ataai*ai far aa Mtaar taniaa samp NtwUil t CUu ttw*yi HMil far Mail liflliri WlNno ilm *r. ClHlMm Ini lay toyaa Mn iaaIJar. llaa ay atf hohs Tiki# ). Cfcmlcil kcUd kko* kr MCI ICSUG`1 tut ' kub-IttM to lk far CIC kfftrw US Ml MS-1 cmmcal nm. Anthretelnone SVMMUMS) 9. )9-MtftrKim9lM AnthraOlone NCQtfSTiNG NCI MUON*If FOR RIQUCST Air Pollutants Class Study; mi of two raerosMtattves of t*> polycyclic rMttc l>|i4rKirbM iMtliu; Interest In testinf oereftt roefound if class tf car((MfMlc Mint- nltrosetstltuted Mdiri^vlNNNI ACTION IT OMIS C$ut*Rejectedno niiM fl*to m-u-i mi(k)Krl*lM f.Asohcnt ( lenthracme NCI I.MtlllKfUlN Air fnllitMti Clm Study; ttnflt imImiIm fro* N- hoterocycles iwklifi; sus picion of (irdMtnlt rltl, envlroMoental occurrence ant nilrmwitul file CSUC-Short Ter# Tests MMOM I.MMlImkltnl lS-kM l.MtAilwtlilmlMi NCI Aroatl IIkIAi Clou Study; ilitfli CSue-Aejoctte. r^rniMiUvi tf ottrefon Nefatlvo auta- kliricjitlU il|nl* tonicity tosts; fitMt fir km* tel led cord* exposure frw Id use as a sWnlclde m4 fMflclM oofrnlcUy SMIei p.Cfcl#ro>*flf*)4!ty4* 9 -ClitiriltimKirkoi altetijrfe NCI Chemicals found 1* dunps; kl|k ^MMtlil for Nona exposure; MkMM suspl- cion of carclnofonlcltf CM* Short tern tests Only J,l-0lhj4re*jrtenaU1nt pfttnyl).3,)*.0lel CPSC/NCI No ^nloM edetuete carctnofenlclty tests; conftre srifftstlv* evidence that It Is carcinogenic In rodents CSUA*Rejected. Aeoltlnf resells of lente-tyei short tem tests K1 Owlckl SklKtlw ktrklH In* tt HONS 025919 llkll 1. CHg.ltill clH Ukon b He I (CSH6) tut Ml SutwIUM to Hit for etc l< UIMI CHCHKAL MM IN-tO-l fmethylamlm. syngnums) N-HelNylmetheoealne MQUtSTIM NCI RATIOMU rot ICQUCST Air PiUvtwti Cliu ItvPy; mutapentc In tact test; klph potential for huoao eipetwra KTtw It MU CS'**MJoctfO. CIS! tostlnp. IIMJ-I In* mm(l,t,)(*) fluoranthene l,*.:S,S-Mhenio- nfricyltM o-Phepyleneflooranthent .S-<1,1-Pheny!ene)flueroftthcoe NCI Air Pollutant! Clatl StoOy; one of two representative! of the PAN iwhclat!; structural Intereit In PAN CSUN*Hutafomlcity tosts omly imj-j HethOhOtMel Mercaotomethono talhyl MrciftiA NCI Air Pollutants Class StuPy; sole nomination Iron the alkane sulfur canpaonPs suhclass whose potential cardnopenlclty Is unknown; environmental occurrence CSNC*Shert term tests only itt-n-s Methyl vinyl ether fcthosythylemo Vinyl nethyl itktr NCI (thers Class StuPy; repre sentative of staple aliphatic ethers; aoOeeate suspicion of carclnopenlclty; commercial inportanc* as a monomer ano comonomer CSNtNeJectoP. teaPtly OyProlyreO; Unite* aposurt tlSPt-lf-t t(TMocynonothylthfo)- lvt>i JO? MMMinli lesa-i IV ICMP NCI Ihlraolei Class Stopy; poten CSMI-SeJtcieP. tial carctnoyenlcHy an# low tipaiari. tlpnlflcamt patentlal for tasean tiposuro JMM TrIchloroft ooremethene 11 NCI Air Palletants Clast StoOy; tta'liJattoS. solo nomlnatlao from alkyl AlreaPy repela. helloes suhclass; wIPttprtaP loP; low ops* presence In atoesphere; sort structural ralatlonshlp to chloroform 11N carhen tetrachlarlPe HONS 025920 Uf MMfft U>H-I ISM-11* HMW HNIM MfCMM IMM NIM IMMM 8:J mu MMM H>N>( m*u . womtw mu n kii`> mwmci * uhmc mum n tMtiwwicm m pm\*mn MMM IM inWHMfl) *UK1 UMHItt MIIMI f Ktl KIIM M mu MkMylMImOmtim MfNt IIMl M MrMt MmI ll< MrMl ItM IS Mmi Hm N (MMIMM MU Mm Ml MrMt Mm Ml MWI III I MrMt M M MIm MlM UM*M (.*; a.|.(lMnivl KllMNii HwrtM'l KitHttt; |.RM|t<l iriwllwmi Kt/MT/ IM CM in C.l. MIS lHfMll W*kj MU C.l. ISMC NrpMt ItM X IM CMC/fM CTSC/CM C.l. C.I. DM (RfURdll RUM M WC/IM p ruulHir ItlRtR MMmcIImMmmm CM/I//CM IM (WWlt URU |NM HftllWIWUUl RlfMMMj. UlMllI iMlfWKlI (MUaltRlM (MMI IRMRI CNIMf HRX" klRtlMI hrim kCRMMI RRM Icrkmi HRWI kRl>Rrl RfMM hRlMRri mlRu U Rllll MM* ImImIIri tf INr Ikmm hriH # I MnS (Mil IMWlf MMjr n*tt! moil whImim InlM it ftetl HIKtl INMt p*Mt) miriHtl HUM KkIriiM ( tf IM (IHM ImUMIIm) MR M ItMl MfRl (olMllR) CMe* # IM MRM (MlMtlR) |R|R M flMl mmm Mr m riMi (M*rt (uliRMn) ktlw | Ihxl MRM (mIiRHn) R IlNl ORRrtt URr INN PwriH UM fNii HONS 02592X CM XU* IM-IM WM MM MMtol 1MU 4. (tflMIM MUin M i.fi'i actCMO i runic mnw r# cmtmtMttirr m MMM MM Miner nciiiiM UtNMU FM HMCIf IMMBtfrlMlM I BiyMnyl--lx MMM iMctori* IdlmtkiitM u-tim>yt hIm NWIN NifMMM nt/w revm in ** revtr/rai fMlIClt MrclMtMUUi fHilltt urdMfMUlif kfvlmry. yvtMttal cmtMto-.lctiy hfniitwr, nfimi*i rnlMI U *{! Mitt 4CIHMI m* to till to Utl *! ftl tlMl riftrt CVMll M4/ pMM toMlt HM F**tl B 02^iZ *0*5 iMit I. mi acwtis it mast it rrMMit wroMuioi kcmjik m tiw tr cMcuoattcm m It lirttttt It CKNtMl tISHt N IM NCtML ftoll M tMCMUKI . Cto'IlM l/l/W (CtocttoHI MM-M-S tkrl( ku im-tf-t CtrlM ?l IIJMM Hiltl mm iNtil knl<i l.i. bitw ir* tx/lim MVMI Hrll ito* ! trtfrHt *f iiHtvi to MUItf rt> Rtillb ktirl InlMilM nrt 4 rmwmbllw ki'NH. l*U iit 1* ^t|mi it m****** to Iwvl. fltll ilit form I* I'ttl liillt fftcti f cm! riHIdUt* Ifito. iww timii(t fniitiiM|i 9t im4ki* 1*1 NrtitMy IM| W urtrt itwrt to >t (ktoul lr Ito l*N AmmI ltt t< HONS 025'2<* TAIL! I. ftCQUCSH to* INTOMATION (INCLUDING CAJtCINOCCNtSIS) ADOUf 111 CHCHICAIS; IMO-1 Mi Search ItcwKtd it contlt A. MCI (IMO) Cheolcal Cedatu* SulMdt Sources >eircN4* TOI/MCO 0IA10C LIT III 1INC Lll No. of Refereocet LocaleO ISO Dl-U-ethylbeiyt) phthelate as above 093 CadolMi Oilde Nickel SwHair at above at above 301 404 Tfcluvrtl TU/HCD DIALOG TlftC Lll OK TMoecetaartde at above ooo Dlcthjrlsllbettrel at above et Cyctephospbaafdc at above 1IW 9eni(a)enthracerte at above 2132 Lead Acetate hanlilnriii as above it ibvf 400 i<l forMldehjrde TOK/fCD DIALOG 293 (COMttlN^) HONS 025925 TAKE S. REQUESTS FOR IRTORHATIOH (INCLUOINT. (AT.irKCNCSIS) AOOVT US CHEMICALS; 1900-1942 Swell ReovettN A. NCI (INI) __ * ' (INI) *. IMS (INO) c. fewl Mmi Sullen (IN#) .- 1. #H- < iMrigr (INI) (. ln#mtr/ (ISM) r. AltHHJI (ISM) (INO) CH*1ct1 CldhliM Sv'MOe Carfatlwn Ihlll CHmIwm Nitrite Rtserplne Chrole OclOftte UrtlfiiM Arsenic In coel Nickel Nitrite FerawMefcyde CtOMlWR Nickel ferMte RfelNjrltUHoitrtl (review ertlclet enly) eniene Soorces Searched* TOI/^ED 0IA106 efceve MOLARS RIAIW I0X/HCD IQJ/HtO (01/HE0 RECON I0I/HE0 o;ko6 (01 101/W# (01 HEO TOX/MCO Ro. if (firnKit tKiUE 0 It 570 253 <49 294 IS ISOS 4 JO 1 35 JJ7 (ConllrntO) HONS 0*59*6 TMU I. KOUCSIS m mrOWWTIlM (NCIWIM CAKIHOCCWSIS) MOOT III CMHICAlSl IMO-IM1 Soerdi OeooesteO tor !*le): F. MIKMfl (INI) * Chenlcat formaUthjrde (fas) * In Koblle Hums Soorccs Searched* NCO rox/KO No, of leftrnKtt located ill 3 * (IN*) ' ON*) 1. Llkrirltt (INO) ** feraalletiylo In Nobile Hones enzene NlycMortnotcl Itthcnyls (ttretofeolcftjr tf) Ciailun (leraOftolcIty *0 CMorofora (UritOftNldljf of) Carbon tetrocMorllt (leralOfenlcHy of) Oeniene (teratogenicity () oiaioc 1CCON HCDiMS TQX/KO IOX/KO 1OI/K0 TOX/ICO iox/hio 15 540 *0 IF* 104 93 229 Oovonwenl tenlceoler (INI) m* * 2'iapfcthjrltfRine, N-fbenyl; N-NItro*.o41boty1 ainlnt; IMHUosohM N*9rooy1 mint; leniofb) rioorantbene 0o4e<tee;beniene; lnit(i )tyreoe {fomeUebyle {reviews only test ret) nW CyefoMMtmlOo KO T01/MC0 TOO _ 4 390 t (CortlnwN) HONS tNi! i. Requests for mroRmHo* (irciuoi* caacinohksis) amut hi cmchicais; \m-im (cmci^) Start** Kttwiltl to Uml: N. lovtrmtnl Contractor (1WD (INI) (1991) (I9M) (IWJ) * Ckwltal Otrylllwi TbloacttlftUc, *ctttIO, A IdlfMllMlIt LtaO Actlttt ImiUlM Cbroo'oai .'llcktl SMKlflOt FtntUthyft 9<io(a)Pjrrm Sources Searched* MtDLARS TOX/tM fOX/ttO OIAIU NCU/DIAl CMCIRlir M9/PIAI CAJICCRtIT tt above Am <i Mon of Rtftrtnttt lee tuo t m u 1*7 74 MS *3 47) 412 1. Prim, MIvIJmI (1 WO) CM orofor* oyOatt TOX/Wt 49 J. Rrlvtlt MKMU1 (1091) I. Jorol,* hixitir fetrattbyl itttf Md Cidnlw Carbon ttlracMoi'Uo TOI/HCO line III TOX/KD 370 4t$ l. V.S. (mnuttl Asbestos NCM.ARS 707 m tonim tnO back flits wi - mount tnO bock Mitt mums aii out Ootobosts IIAIOC CAS on! IICSIS flits, ptos olhtrs as ooorofrUtt III 111 StioOorO library Rtftrtncts like III library rtsoorcts available In Toatcolooy InfiriwtlM Itsponit Ctnltr MOMS 025920  WEHOIMS AJt HONS 025929 *. AlpMxtlMd Synonym and Trad* Hta, in*.. *1* Subitancm l(,"d* cporooptaartoaMtlowflallooapt1tRfdoCnIHtaa0oo0lIatutftnohcmto tPaa<(i tatvro of soptral cimlcali. pbitdoaacrwatoaoaoof fathy 3*1 HONS 025930 MMHfllt# lo| l**l| <** |b#f| IM IMIIWM llltlt IH I0*(I9*HHI It* I*** NIIIM IH 9MI to IK* M IH WIHMI Hi I.MtllHIlHIW ID to MM In |*tfMviMIMtlVMIM Mllrt** ilHMI Ht t*M* MMMHKKIMlim IIMMf IH In M*IHMlMH**iWH HUH to HMIMM 4HM til HMMIH MMMIM In MMIII KII>'N|N|IM In NI1-MHNHIW t* MMmim* .t*|it***Moti- *<i iHiHctM* MltMMM* IMII In hiimim. i*cm in |H|lnm*MtNl|lH MltMIM. Ill< IKtl III nilHIIMIH MIHMIlt NNi lll> In OtMtft*iMM lMtlMtMttMMtlMtM 1i MN(|t|* MlIMIM*r*f*tM to M(lmM|n|ifi|H NIIMM IHH HMI * III >.r-IIHtiHifHllllo| MMMNI Hill *** *# * I. r >tlMittaf MdlMHHINIW to (MllilllilHIIM |H MIIWIIIM. t**M*M*- In *MM* MM MMMI Ml MHU to I I**|HMM**VM1M MIM Kl. MIIHMII- ltd* |i| Hlt*|||*|(|MC MINIIIIMW to nNMIUMM M|l>NI|>l*tHlK( Im N|H(ll|* HIIMin>ntHII|IH In ***III* MUM HIMIIMM * IH*HII MmmiHiiM in HiMdin MllimiMliliM mu to mudii* MIIMMlIINI* * HIMCIIII MINIMMUIIM to NfMiili* MIIIINNHMM to i*|*l(l'l* HIHHtMUK to IMM|i|> IIMMIMM IM*I MiHI ft In t.*nt*>l-M*|M**OMlMM 'IHMMINM In iWHttll* II'NMIW* to Ntwtlll* i.iimmuimim ** ti . MIHIMIMMINMM III l**t11 v| ****** UMIM >N|in>l'iaMltll*|i< III l-HIHlHIHflHHM Hllil-l (l**l?MltlM to KHnilll* imiiii>mhiiim*i in ni*mi'i 8IH.NIMIIII* to IMMIIIH mmim* to mcmcmim MM IIM MHMM In mi<MC i*l !<( CMHIHI Mtt III! MMHUIMII to Mtllll M (IIIIIR MIMIC IMMHI mmihm in niMftimMiim MMiinnim* ninninihinimiimi iii MmtMttlll IM*I In MIllHnllll MtiUtlHIll IMII In KHUOIIIII KinMiiiui mini I,* *c*tMiMitt Cf|*-.ft| HIIIHI MIIMIHI MllHIMIIHIIII ti Itlllltt Hum to Mt**M ti **(* im* mini* iii niimai iMi*l-IIIHIM ! 11111*111 MMIII* In HnlliHM * I** him im* mi Ml In MlllHIM MI`JM IIHIM M| Hull MlMHItMmHIIIM IMMM MUIHI* I III Hli'HI*! *!I** *1 HiilHiM riMtM* II |,, HIIIHHI l|fM tl ildlHIN int'HM it miiiiiM *U*HIM *i|i * mmhiii* in HMnimiiiiiM HMMl*M I*W**HI IIUUMIIIHlf|M* imiH*HnMcilHN'IIMIMt hmm ** nMm im cm* miimimmmimhm ihmh Jj f " IWMM M* cm* HMIMMItMMMtM INMH ; ]. W mimhhmmumim HMMI 2*] * ' `*M*M ' MM* HIIOIHMHIIHIIM IMMH **M'i; IIMMI im HMI H'HlIHMHlMliM INMH Ml* HHC* M*t* In MMCI M*f* I* I MMII In lll|M*MII|tl*m*IMMIM WHIM MIMH mil It | !!(* IIMI M IMMII MM IM In limt 11(1 IIM MMC* MM IM In #1*1*1 MM < `IM* #1*11* Ml* MM* I* #l#lf* t|*C* It IIM MMII Ml* |m MM* HIM I* IIH* MMCI Ml* * * HMII M HIH. H*'ll|lM*|MM*M*IMl*MM*m>. . IMII Hi mMM (*#> In I***! mtMt HfHMM | In :i#M#**l lUHtl IMtH* to **|*ll||4 lIMtn In *-llli|-(Miii|i)i|i-f-uiainiiiiiaf Hinni* In nmni* *IMM*I IMlr* IMHiHi *(*** In *|||**|r| |OlO IfUMIM IIHIH S* M(l*|l* tltl* In *Mi*MM llltll to ttnfMM t-Min.|.MMCM**M* In lillMI MlfttatlMM MttMM IIMI lo HMHI m MnilnlUt>II(I`*Mltn*lnMiMimiiiiiMtNI*IiMi**i In IH*ImHIi ** t **! (M*Olt*lM IIIIM*MM In t*MI *tt*t***MMtt*M MMMIM MM* In l**Ml| 'IUH*MMil|(l| iHtiiHnN MM*I to IWHtf llt***M*lMt MtnllM MM* In * M(**l.l*tll-HM- *I>M**##**!*******IM!*#*** (MU to H'M'MIM In HTMMOM HONS 025931 <*> taa Mil N'lllMI M* II taa I I"ttNt M#a|t**tlUM MUM NNt n taa timi ||< MMHt IIMI W Ih #ttf<l hid MMH IIM m hi ItllM IVH I Mt| fat l|IMIIIIIMMI*l MMUIHW In IHHMMIII MMHHII | mMWMHI MIMMIM 1m IMHH l MUtHWMMII duii HIKHIlKmiMllll IIMIt at imw m |MI NiilhlM(*tll<:iiai !||*1M MIMIHI III imm * IIMI !UIXHKmiMlIM 'Mam IMHI MIMKI wUati'M |h IIMIIII H(NM-Mtai.MlMHIitmllliilllllHHta .aa|||NMMtiM |a*|rtMlt ItHMlHIII In IMII'IMIIIIII afMMCMMIM ItlM-MlatMlNM MHHMHIII r:a-imill artMiHIlIM I>m|i|>i.I|-m|*IIIIIMM taa Mai*tMMUHaM MMMMlHi|a| taa |.MHt<aiatin|iM |.--tm i.n-iaa-- m--i in |.wiaaMMiwiM NIi-MMlMMIIlaiaM l-iMalMIMMaiatal MaMtaMtnimM i|t a* Mainiwian laa l-MlaaillMail MtnaiaaiMi at t>a*t.a^Hm Mian lihi taa a-caititmt MtONINlMt faa *MHN|h|'H| MnaaiMNi i -MiiiaiiNii tt<.ftmMt>i><MlHM>t la* uctltittm l.ftm MmaW*-l-timhHh taa MIIN>l*ia|IIIW }>MM>l<aimii--a|IHMa|m taa t.Mttt*-t*aM1lllt WN HmawHNHWa| taa ! itt-l-Mlllfli* |.tm--fmmmamtwwf # imiiN iam#--aitwnMat imi aa Mitmtm >MKia-i-Mia*iMiMtHah at (MMI-MIMhMhth laa M<*-IMMtM* MMi|*l>a|ianillll< taa HMf'lHlIliai t>tm*i>MNtuiiliM aittaumiN laa imwuim mmcMtvtiM amachHlh laa l-mamal aimmiilH HMWtaIM||it laa l-a<Nln|i*|H i<M|ia-fhHaMnait taa t*m-*>miHi I.MIWIMM aa M'*l-mtiatN Hut winniaih iiM ihamh Mamwilh aaMMhwim ftaa muitim miKH*lil |>MNniMal iumwwm laa a ttaaMih *th(XMIM |.ata*-#-itltm ftaa i,i.||iaialitia| l-MM-l-MlttllM laa l.*<|IM|a|tMM MMINiHItN Ml* laa l**it*auiut WMIMNil taa tfllHH |.aMMHItm laa MIHH Mihl<l,|,iiailM|| laa MIMMI >.iaaanaifia i* Miiiau I Mn-hNMNM taa M|iai I-mam i.i.Hinim laa Miithi Itltmi taa Mitmi i.ann-iMitnnn u* tamati ahamillMI Ihial Nltli'Hl taa MltHll MM MIIMI MIMIIItt M laa M|MM tiniiiiiii*inmii>ii laa MtMl MM laa "(Mail lailllt Saa taiUMI Mill M. laa tMiaMl mmn laa mmimI HIM N taa M|lMI atmai-i laa aamatl mill in* ta amIM litMl aim laa |t<tll MIIM M N| laa M|riMI HUM I laa MlltMl "MI* util tu**i iaiMwiiiaan at Mtlali atMaia*. aMMI.IIMiia aitaat Tl--mill M*M|H mil ftn'tfl IIMI ssrir a Hictu Hiiain. itm.miat* uait iMtam MNMI itHItll |aa i|tlit|| MMHMI taa itNiin MMM taa MMt'aatwl Milam laa HthlifM awn laa ntahllia aaatMW* laa HiaitNIM tMlflMH laa aaat*aMM Miinawil taa hihiaaim MtlUMM laa HihllMM natl laa tta*raa| MflM Ml laa MIHM-HHIWaMhl^MMUl "'m'l'MlIiaiNIIMIIt Mil laa IMtailla MniK.i.t'-hianiMiiiii *. taaii taa nianiai iiummmmii MIM, .`MIM|tMMM.a*IMIMI> Mill taa l,t'-|l<niM mi.a.||*tto*lMIM<ttM MltlM. a-M|t- lea i-MiaNUMMl M| M'WIMtM taa MlaailfhMI tMltl*IM laa ml*ia|lltiN HiaHMIinMiai taa MM'iMIIIM a HltlHt "MMHtllM t -MHtmtNf. t-fl*t- Utn MNItllH t-Mttumt. f-ana*- utn aa t>MM->t> itltta| talMH.M>IIM|H.laaatMia MMM taa .iMMMMIMt tMtat* MMMI.M'ltMM-. maatl laa f.a-MMMMMtmftmaatt " zr~&rz'zrmm ^*11 watll taa IlliaaiM MU ttMl taa hlllfM WMWtftlll laa alMIIM ----------mm taa MMtIM iwihhwi iaa MnaMtMMiMth M. i-Min. mn taa t-MiTumi--1 MiMiNtna|.i-Mtn-l-hMf|> fMM taa `- -y-- mnimiMi mi ittail taa *lM4miMllll !" a MIlMtUl taa fitmalttitMlttM amIIIMIH laa Ninitia HOMS 025932 U* **|**f|N Mffftm IMMI Mt #' idWnHNXIMlM IMM*t ** i||.| ** iNM mf WWlURHIMI MItNIUM*|Wti|lMM1*11(111H' KI > MMMtinlMt U* MIIM'M HIJIH HM1II Ml*|l MllifMt M*|l| MM|l|>it 'h **Mllt IMM*t limn i wwiitiMin nmmi * tIM * HIWlMIMIIt timMII l IM In NnmMIMni lim*nl i ihi M n tmUMii iiNtni I l|*f * *t* IIN4"I I l|M >H MMOmiM'll IlfMMit i tm * mnnH'Mi'i n44*nt iI ||m| kIltl mMMtMUlMimIMtIiHii tiwllilm'nil i mt k* nttmuhtiti iituMit I tlM, tf* HttMItlMli* IINIMII H m, MM lit MMK Ml (*! *MHI tlMlWI MM MM, M*HtlM MU itMMt Ml t*'*l MM*If * IHfMtI 4MW * MMtt Ml tlMIM MN*II MMIWM | MW IHWtM It* MtCN M# IIIKM MM*M IMNMM I *W IIMtn UIHM wmw ** M I NMMIM lit Mtnlt Mt (tilt* MMM( IMMNM i imimiii hmm kt mini mm limn *i*it nnwmi I km k mmmi m limn miMi immmii I HIM tH MtMII Mf irillM Mtlm MIWII I hi: tiiwt* i*Mi mi mini m*i chum iiimic cwwmmi t mil HIW kl MM*Mt MM lltltk miMI IMMMtl I l| NM t** MNH MM HUH* MM*N (HHfllH t n*mnw in mm*h mi hh*i* * tMtmt | |f*H*M kt MNI( MM tl'*l* *MMt IMWII I kUtik. mn inm in mmh * nun" mtm imuhi i HtMtMiN *i Mtint i*m wmt twnwn I. wiw twit t* hnui m {it'll* mh*-*. crnmi | tttHIM kl MM*K MM <** *m(( IMMMII MtHWti WIW mil MM (* MlNH'l. k mW* Minn mm Him* mm*h ii'Mmii k* imm mm mm* ******* .r**t hwiww MW ki mm*ii mm (Mit* i:mM IMMMII WIW MW IIHWII (Hill* Ml* Ifl mil to* MH*N Mt (HIM* mull IMMMH mww MW HHWII wtilllt* Ml* IMII Ml m*M *W tllltl* MH*H IMM'MI MMWIM Nil, N*IM Mil kl MN"H *W Ill'll* MWI* ( ********* MNI * **M*H mm |*i*l ''* IMMim mwikl HWHW kl MM*IC W HIM .*M*I( (MWkl HM**I k* Mll*lt MM Ill'll* **M*H CMHMH **** MMtllW In **!( tm% |liH> .. ... *M*WI HIM kl **** in ((( MtOH n*kHI ******** kin mm*hih in **h*< <*** miMi n--mm MIIMMI kl mull m (*>* (*< nmrni ------- *1111 ***! 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Ullll|a Ml* mu kl M*l( MM Ufttl* iflUII tfffffl M IHMfM I** WMIIIII IHIIH ** * **1 *lflHfl I** HMIIfl fffllH *IHt Ml IlfltlH Mtltfl *!* IIMI'M IMIIHI ! *Mtl*M MINIM Ml MtllflM M!Hfff*imimMwf Mn*M*MMnIMi MM I k* <MIHWM*fMM I In Nl'Mtf (Ilf Mf Ml****** If Iff mihmi ******l| MM* H ** IIIH* KM* M IIIMIII UNI I In Mfttf MMI M Himlll HM I M *!** f*M* M ****( mn in nmi mmi if I1MMI* mm* IM III NNI MM* M if*MMIt HHt N ** HHt* MMI M IIUMM NMI IM* kl ItMt* MMI M MltNItt MMI UN kl imil MM* H ****HM MM* If k< mill f**ff H HimtM MW II Iff imtl MW tut m mwii *t nn*n mim wiwmi M* flfltl riNi I III ftfltt MN* M IM HHtf MM |l I** MU' MM I IM Mt* HUM Mf l,*HNmt*INi|NI*l*N affMInf am**M*M * * ***m||* Ml m*"*M MNI MUM Ml M*IH mf Hflflf <M*II* l|MNf miffffW kf IHIIMM Mil* INNNli MifNM *M|M Iff IWflUl *!(** MIMt* t kl *M*f*M M||IMMIMI**IHNII * IIN"II*.*HI*IIIN MUItH*lli.lM*MMI*l kl MNNIM'NIIMN l|M|M Mi M*W*I l|mW|i*lM* NMI kl *111*11 Mwtim m Mini HIM Ml* MM* If I** mill MM* M MI1MM. *,tii"*WI**lw>*<WlW*M*! sm mnumtmt*hpimn tf**t:< MMMIM Mmi* kl !** H-M'tlllN m*IH HN||I kl flffM-mfflf|M HHtMlif. *-IIMIfM**!** t** -t*M m;miM*4ff**HM MUNI MMI If kl IIMtt MMI If HOMS 025933 < I'M it * imti if < INMM taa MwlWHIItil MtlKitWIH HIIWK taa M|<i||Tt||M KnlVM IM*M * -MINI * HintoiM IIMM lilt MM UK ! 1.1' *t!M lattiMattMM MUM mi Mat ihi i. 1.1* -ttMlatntjaittiM nan Mat t tut Mt :.|'-im'mi'H'iiii*i mi iiMiitw t MwianntM MMtminM Matt Ml U Mt MMIIIIM Id IHIMM Ma MNIM'IIIIM WMMINMIM INI* MMIMn a In t.-tl*"t"ait4tM hum r*ti mm t iii i.r iih*mmihin imin mu Mat imi Mi i.i'-atMHMi<M*miai Itt.atatt*--It In NIMN*<IIIIIII a*atMt*IM unit tint tat in attiti tt< it Mtatat Mat It |*i IINIi Mat i MMM Ml Mllttll MMI In MlttMl Mftita*ta in *ata*ta**iaiM aiatatMtaiM Mt-ini Mi a*tiatMt><ta*iMiiM MM*tl Ml MtMNIIIIIIM nllMMMIM I It l*MI Mi t*t* Him* t Ht Ml IMtmtMWMM inn Mi MMtnnHiM t* Mi MMniwiMMm laaatll Mi HMMM #WIM Ml IINMM tMIttta t* mnlMimiM nHMMMIM tt* MWI Mt Nt M*MlintMllMI tawm t*tit *mmi untMn , M* *|<||| MWatat. attMt CMMIMI M n m i.t*tttaaMt<i><Ma*a*t**at ft* In tatft tat Matt at mnMK'lintnol ittMtt Milt M* WtHiHttttMWtat M*t Mi IIMMMtMWni |l*tl MttMl Mt tawttt>at MHaaaaa ttttttit t* ttait. i*at. *a aiat*n am ttlMMMT MNI tt M tltttt NK> It KIMHM MM tt H. IIW MM I MMIM M* HMMM MMIttt MNI I Ma tttftl MM M MMttM MM It Mt Matt* MM i MatttM Ma ttMtatM ' MI-MI M |IMM Wt t*at* M'HMMMMIMtMH IMMM Matt* It Ma IMMM Mt tlatt MiKMtttCMtMtlM* I Matl*tMMttM tata li 1.1- ttatO`MmatlM Ma ttamiMfatattat tfltat* taa mtiat aat ttata itMnutlHiMfiMt nmn tf|flM `U-atlaatiiMni-i-iil-atr*natai||at>at! iall Ma Mttt#t*ttM ta* MtCittailM aittttatttlM MaftMM MNI | Ma Mtttl MN< M Mataatt MM It Ma Matt* MM MNWWtNMN Ma MNnHMMMIM 1.1- ttataataaattat Ma ttatt*aaaaatat Jif.l-ttatMMaaattat Ma tltaa(i*.aiMtM.|at Mtaaiaatat M* MNidimmmM l.|.*fiMlattat Mi MafitiMlataciaf MNniiilM Ma MMtiMMaaat t.i-atatitirafi i hmiiiimi|i I,Mattf M<t*MaafMn|af |,, Ma(Wti*lttaM'atM aaftaaatat. .a-tl*tmi>i>ita|it||tn IKII tlMMiuilMlNMNIN ttaitaaaMt. l-NWinJ'"titi-, t.i.atMamnitii-MiaitilntlMn in *>*aiiittM HailMaiM. l-*tati.|.a|lan- INI) Ma a.mtltlM *atiaa-t-aiiat- ittli In l>attta-t<aa|tiatM MallaaaiBt. f-NIH- Ma taiat**Mfltlat MattM lift ** tlaitat. K-i.i.inwtMtntii. inn ,, (mi Matl-t. 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MMIWMI to* IMWlMINlll MNMtl lUMM. t.*-#!to*- to* N*lltl** MMI MMM* MMI I Mi MMU MMI to ill* w. immiiiii* to* mmiMHHii iimutni NMMM Ml NMM MMMIMtM*ll*|M Mi I If<*** limniiMM to* i-MNNIMlin *>*t*M*HMMM to* MMHIMHH hflWHMMHMIM Mi NMUIMMMIM MimwtMim imii * i.i*i*hwi*i MMII*i**Hl `HllimHHHIiilf (Mil III Ml'lll'1 IIIM MMM|MMM Ml MMKIIHIM .'MMMttMMtM to* MMIIM l.l'>MM*MIMMMM to* H*tl*l*t |.*MMM*toM IUMMHII * NiNIHiiMM l-IIIMm HMM to* M|*Wlto**| MMUMMIM Ml MHIHHIHH MMI'HnMMtN Mi INIHIW MMMMNIMM Im MHHH MMIWMMN to* to**-M1* HMNWMMN to* M'.MM IM MIM to* MMVtfM MMHMIIMIIIMI IMIMMIM NMMMIlmiMIIM to* MmtIM MIlMMIIMtMl 1*4*1 *<M**T*nI MHHM to* MMIM Ml .i-ihmm mmMn Mt nm mnhm MMnillll * MIMUMmiM MMMHHMM to* MtliilM MMMNMMM to* MtlMlW I.MIUHMMIMMIHIM*1 Ml* * MIM I-MMIWMIHM to* MIMW HIMM MUMM to* IMIMIM M-Mimil-WMMIWl*.HIWMIWHUMMMIH 1(11 IMII MM HHIMI miMMM to* IMHHM t.|-to*|ll|lliwnn<| to* NMlllimtMM .MMmtM to* NMMIMMIM I**M** IIMH1**1 *l*M*lm Ml***II Mil to* MNNWH I litM * -MlMMHHHWHM to* *** HHMIl-milHIWniUHWI* to* MIIIIMIH--11--tM MMMMMMIM to* NMMIIMMM *.*-llll(MMI*M**N IMMIM I** M**flMII*||*K MIH tof to* MtollMMl M* tll*a HmilM IHHIIH 8m imii hm * MintH* m iiiut* Minim mmmmi mta to* Min' to* w iiium Nimm itoiu IiIiI!li-mf*IiMM>-i-*ti*l*nMi*IMfi*nN-Mi-nl*n**M***to--*Mi.*.*i*.i|-|*toff*i**1*.IM^HHMinil*lU*-iMl .l.t*IIMI*t **M*llto* onto--to--HIM NMIM IM mill* H*nito* IMMMM * * > IIHM*MIMM|| .Mil Im 1 8mum* m*h*M* imhh M> nimm im iii*i* hihui* CMmuM III l-tolMM**** I Ml*IM to* MU** III unto hmwimnim to* Mtinn* w iinito H*n;n* imihm lllt>(*IMMMNI>M*******l*N**IM MINIM MMMM 1111(111 ! 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I**MM***MN l*1IMMMI**|Mt Mil MtlMM * **M**I to* tNIMMKMIM **1M 1*1*1MM***| !*.#**(*****lto*M I* Mil HIM M*MM MINIM* MIMN IMM* I to* MINIM* 1*1 <|l*l!* MINIIM tMllllH to* INUNMIiaiM HONS 025935 *t,llf'fBiMtll*fMMMt-l>B|a*iitiB|M liMWM Htll|hllltMi*lf'W'ltMB%MMMtttlMBt|t*lWaBM|B|MMi<ki'*-H|'i.i.MHf'Nltitlri1'uN-i IN>#O(ta(i *>*( lit MiriMii* MNM.'-miNtll|lM|ll'i|in|i|'ll>Ml<(|a| |,i HHVIMII i-wi-htiiimwww-- mwnmm>imi i`mMftM-i-iUimHn-iwiMii<tv anitM> iwnM.lw..WMHWHWiHtWMMWMimMi-wl-wmHwiWi HmMu|m| mi i mNuMn HII|mWWtM|Haftr-MMIM (Mil* IWWHHHM (Hit Wm-tMUmumniMmiM (** inmmmn nm mmn iiiiHmWMwiutwww im aniin mi .M|MI WIMlwmIM.>1 I'MM W4MMIII Ml IKtmMNMIM HI M M MHHIlMlwni imi M'lltHIliHIlllillilllHIWMHiiH M* l.rMMMM ilM*.MMMUl||MM*M .* mUMM'IMMUIMUM Iimi |* |,i' MMHM MII,MIMnuiltMMM nm-iimi*iniMiMnHMi lM l.l'MMMM IIMMMI MlMHMMI IHHIM M* l,l'>|IM||i| mM.Mm'IIMMIMill>| In i,i,'iMnM Min<i-ii*iMniii>itu*Mi ||||t.M,MNM|MMIMn|MIMi| Ml t,l''|M|M |||n.i-IH|MllMllMM mnmiiiiiiinmww< Ml l,l'MMIM |||W,MMMt|||INIM*M M'iHMIMIMlMI|MMMM Mi IHMII'I IHM I,I'MMIII|WHHMI|I*MMMW It* IIIH-I HIM llllHIiMWIMIIMMIMMI IIIM Ml *lllll'l l|IM Hm|iiMi*i*iiIiMi,li<nmMMMMMmll ^IIi-InMMIcn*MHMII't HIM Ml iM'lt WMMi MIIMIHUM BUMl I--II Ml MMIHIMMMiwlMMiimni ilM>|Mi||itiIiMMIKi iimilM.|ii|Mli|MMni iiiiMii i.i4hii.i'Mmiii'I-ni; hiiwxkiihhim IMHH M Ml IIIMtNUliniNWHMI MMlH II III MIMIN||inMMNil| MIMIl MI MMMNIIM nNHMHN HIM Mi NNMiMHMNMiN MHI IMM It* IMII MKI M Mil 4M Ml IMII MHI M MM HMHM In Mlltin UN Ml IN* I In .f.|IH"tl*M"tfaia| ItM Mil H In 1.1**#IM*#*!!>* MM M MM Mi I.IMIMutiaitllM IlN M Ml* Mi I.l'tlNf* *M*MPIM IlM Ml* M t t.|*IIH*B|afllBfl|ta| tilt II lM !(* MM I M*Mm MiIlnMMi IMIM|II|MIINHIUI l| Ml.i'MMi HMHNlminiitlilHlNMN HMI Im NMIIIIHINI Ml Ml MM MMIIIMtMC HIwW Mil MM MM In l.>'.MittlM**tmiM MINMNl *MI MM Mil l.r-IIM'NItMallllN MMItMHWi HHI M M* IIMII HMI H MHIIIMN MM M Mi IIMII MM MMI 111 Mi mil. IHI. Mai aiNiit Ittl IHIHM* mNI lliiall MMI lima MHI M Ml.IlM* MM Ml MUM Mi MINNNiaialinWIIN MIUIIB* ** Mlllf HUM Mi 1 IHTiri-liMiiMIMlBlIM IIIIMI *Ht MUM Ml *INHHwiialtMilMIMIM MIHHI* Mi MilMiat MlMIIM Ml MIIMIM MUM Ml I.HHinilMIIMI HMH * IMlM Ml IMI:l.lMMIMMMn iNNlaill MMI MlHIl Ml KliMllli UMMMl Mi *,l*ltllMMIMM MMIHIM Ml MMMIM NfM-IIW Im MtlMUHa MM Ml IIIIWMIlMItll*M imiibim Mi lull nimh. itiUifiaiini tttiai immi MtMIIM MIMlIM lai MMIMIMaM atiaiHM IINIM III IIINIIHIMI HIM fftmiM III MIIMTMIIM HIM. *aiaiWI'iMII M* IHfHiHIM MIIMMitlM'll Mi UMaatM MHMMlIIM'll Hi tlllMlM MtlllMlM M* NI'IIIH MUM MUM H'MINttnwMIllliaiW NINMIM. MIMHfl* Mi l-alllMH|.i.||lnMN .NfNHMIHM'i'NIMM Ml I<i|II|HIIn.HIui*M l*ii>tM**lM(Mifi-iHiaiaailMit |.|HMaim iiim M l HHMIHH Ml*M| In MMI| |..t.MinMiMaiMiNiiHaniHin mimim m mummhmi HlMtllinHiainHttatHnini fmMNMi MMH Mi NNI'I Hi.HiHMmimuiHi i.mhmw*i Hum mi mmim l-*>MM>Mt*|iMaMllIMMin l*CNIHI't lM>m Mi NWHI *at<M*naMMivtiMiaMii rHUMMim MINIM >,> lllHln*|a|tlllHfHtHalHNI*N HHIH Mi MMIM MMlaniMf|Ma*iIl.IMflMlNHn lUCU-IMHMHtMWn MlmUiIiMHalIiamalaItIMu.IIim:< UMl Ml OHlaa MM (111*11 |mbIII --MMt mmh im iiiiih caaaiBi hmmii * n HONS 025936 OttlH attt | Ht OMO It( It im>M* IM Mi*tP IWIW <WII>| HIONt IKHI H li (tt*W m Otttia ItMM ttawtt OWIW |(K tlUW III l iMilit tat (I'MM |N*ltl OarWatt tattw mum Ht ttata* i(i**ttatiH }'2! Itttw lit into tt Ht Maltm c**ia imihiumh (aim* nMMiitl ! |ihii tat tiatoa titrw cmrwit t ttatta *|it*tatttlM iim * *** atmm W Ui dtMi* w*t IllMW lamtw <t**t*att (aWita awWIM tat UMli* !** MM* llatral ftWWt Hiatt taa (twit* *at Cttiaia (ttM littWt tttatta HraIfMttt*taItItItHttttaOtaW% iatl*ttatat#*(<t*M<w* ifatttantytaatti tltfW lOtatHHlM ItOI , oatw ( mHHIH Wt ... . Mltat Ht fattW 'IIMtilMIH Mnait tut. aitti ho mmi IHtllt WO*H Im fwaiw tat Ott|a OWIW ctr'W'Wt OWIW WOW tfoW ta* OHM" *t tlttifa owtw twatwtt ftfIf tatta**t tat MHIta IM !** t*iaaa i(a*n fttatta WtratM lit tttaita tat (ititia uaia ctarwwt k'ssj.sj--........... ..... .... laatlitta Ht miaaiw Vtfattt mtw III MMa tat tltlila Matt* <amt< toann ta mttam tUMIt *1ttw CM. t: tt OWN' H (ttltia otaiW <alwtl ottitt m ittttiat liana ttitw tat. mio iiana at ottti# riaia laiwai latttn Ht ntt'itii nant huh im. n*a Ht twow tat ctoti* naw irtwm t> IHt Itt l<HHMHKtl iin now ita(, rtiMttt tt Maia tat com i nan* ttarwttt O tai Itt a.tll(MtatOa*t IiHtfi tltW ttata Itt OWIW H oa'tia MHIK ttinwatt nwt now M Htt Itt (twin an (|IU|< tttatta twnatt tl iHI Ht ("iMiatMIt tt ItO Ha Wtaattaa tttMta now Hatiw Itt data t-l oora (ttaita (Hawaii (Mill Ha (HttawtaaMiH IWant nilW MIOTHI imiii It* Maia tat liotia cataiaa taattwatt Hit t.t. Ht nimtit uata nttw Mt tat naw tat utm* tma (await tot Ht l*lm*ia t*ww mtw im tat it rata t#t tt**t" Mata tiaaat maati Ht liawat m tl>l* iltlMtlHMtiaMat natM tnaa now HI ta* MCla aw (Mtia uata taaww (man MtNa now t Itt (Mata* tat tiata -- (whh now Ht Man* mi eimn nata trnati twin* a (Waif Ht Mitnt IN tttota aattatt oaataatt llltafl ItMM Ht iWttat tat OWt Htnnatl'timiMt IM mitlHH I Ht HI,*H"OaitMaMtiaf IIOHam W Ht I. l'MHafttWHiaf CtialM Ht .tIHHtOataf (MOW atMtan MINI .H'lt Ht HU'K tat (ItUta tttWIf taiwnt MOW tt'Han. Ht It ttw'1 I** ttttatt w| ittitta tatiatl f"--** Mtuw a*tl a Ht i*-1*at** tataatWtawt ((ttllaf now M Ht t-OWIatuaiWtmta/IW tat:n HlMN tat HM*H it t(Mtla MttaK tawmit fit ttt attain aowt Mtwin* win inm m* hhik w ot*ta imhn Mont Ht H*t tain* (attain tat oiwna a*l nna mam ataataut: WO Ht Ht HfttlH IlfOtt (attnt lataatn KKIIII tat *twitt art tlMil* (aacitt IWWM taftl nil f Ht atilait tat (ftltia attlait ta*WW cattM* main ini ttt wwitt m iimhi t*taia taawtt fatHWfat ttt ittaaatat inih catwt now to tatwiH Ht ifotn maia twmi loom oiHnt MtH ttnwi t*t maia in touta mala iwatwti H Ht Milan tat lOHia atMatt ta*wtt 5Mint MiiKiuhiM itt mata m tttt*ia taata taitatt tint MwMttfMt tat Mwnt *h oaoia ttMaii taaa tMOHOHHI Ht Uttm an IMtilt MtMIt ttaawtt CMWit Ht atttfatwtatm #ia*taa (Mlttm tint taa MHO HKI It manm tiittnttnmniitiii Ht hmiiii'i fiiwiM ant im Ht mho nit n l-ctHtaon MOatitmitoaHaati |M wtmtait iat(win rn it Ha Main mh HtuniMM t.ai||MitNM|MMlMii| Ha Wtaatotf (Mini* H 'M la atMini fOMtaWfH att tl tHItna n Ml t*a atytott mm" at ih Ht atftom (atHMtaf owt If Ht MHO 0*0 w (HlHIt I IM* Ht MOfttl mwmti ont ttt h- toio mkiu fattttataa ai.tt h h* attt nw w tunana i** iaiam IMHiain Mail lat Ht IIMO HiM M INMKiH Ht naawfH COHWWf MH W Ht *01(1 Matt W fwmW WOW* Ha tti*HM mam on it itt mho oh i faaat* mat now ta-im Ht maw taa cmmi* mww tmtaw oatnw taa twnw m oooa nam cwtt.att WtttMinf (MtW OKI t H. MHO OMl W toHn ftttw ont ti Ht imit ont h fawnlat Ha nhtaMMti ftwwif nw. NfioiMntt*. tatMtoot o*it ihh h mrttiot mtwwaiaamawtaaattwtoinntaatnHhit mho ont n intfl l WtHIM* MH*atf IKM Itt Mnnt(t*l*Ni( mam maaawm a* woa*awoi taatMM WIHIM. a.a*tiattan* Ht tH'ittMHmn otatlM cbumio ont f Ht otto om n MOWS 025937 (MHm hid it in umi nu it tiHumiditMH mumie*i* *mmmiidiki*it< ii fl***l*t lllMt* mil I III Hill' hid II (MHIIH lid Idd mid IlMi II ihihh hh in min hh HIONH .* Hi mid hll I ihHHT ! IhdWhKii IHHIWI IMCMIOll 1*11111*1 IhHMCM hi II**"! (HHIH*I Hi llHi*l HU mil *tii(t|liMHii*di*( ltmi| IMHIMN In IIMI 1*1*11*1 l*lHd*idl lit {> `IIHIII ihhihh i* iHimmdii mfni KtHIMMI llhlw `I* IHK'lM(*ll| t"tl* Hil|| |IMI( U'**t1 MIMNIII |II*|*'( 'Mi(*tHI*dll l*IMNMI |tN*l(*t Hi I'.ItthHIMlII IHHmi |H|I"IM * ,l-miH*1HMI .MI'l'*ll> '*MH|I |IHM(M|| Hi .|||IM*HMI*t|I-I *iMi*iii*I* IHIMHIIM .ll(Ml|Mld*fd*l-*d*lnillll hi IIHM*iHMinu*i>*m*uMi*l INIHIdHvn Hi N('(IIHI*MI iimhu l*1HI Hi ini(hHlii|| HI*I1I CHHiimMi)intMiidiMi iiiimiHHinu imi ..MIHHH11H1 In (11111*1' llIHlm**l HIH*HHIi-tniMllli-i'l'ii*l "MU'* m I-1(|H.|,|.HH1iHM|Im III l.t.llM'J"*- l.(*tMHIHi4 IHHHHH IHHiKHdl IHIHIMNIll Hi IH.IHH iHHMIMHil d*d Hi IHHMIWI Hn IWI WHlitHU Hi Him (ilHIH I'lHMIHn MINII1 *f 1>lft.|lldWimtt-l>MI#Ml*l I * IIMItl HMNiHn t>i|Hin-i*iHi>Mdd*i>ii'i(>ii in maut NlMHMNII'l'MIH I.I.HI1IM*ll'l'l'.lll-HI*l|l>n HIHII III 111*111 MH>niHH)*n>Nii'i t*imivimityi-iMi'>iHi*idn Midi Hi MWMI IIMMHHHHHW*'tH II IIWI (WHIM IMMfllM IIHI Ml IMtlHH* mn i/i ihhhii* WHHII1H Hit IIHtmilltl 111 H"|l*MClltia*| IhHIII mHHHWHHWni** lit IHHIH 1**1 Mini INI I**mjm** imi iiiimtHHiini iwi IHHtHIIII HMH imi d|l *1 imhihmim ."ti-t*t*MiMti-i--u*uniiM WUIiii-hhw hi *>a-m<l-t>mi*'\i-l iMiiii,i*l WHHllilHH Hi l.MlllMtHMIfll>Miiii|i*l*| MHIH l-MHim ||||iilii|Mllirilldl *hii| imih uiHfi umi i hi m;d iiM ii lM '.(IIHI Mill 1C Hi mid Idd II immi iiiiH* iimi i" in mid im ii im*h Mm iii mid it mi m immi Hum mm ii in mid mm |HH IldHI NIUIMI Idd II III mid MM* II (HIM Him III tMMm IM (1*1*1" <M|*|| tHIHHI imih itiia* I r*Hin * ilium c*Mt** imiuhi umi iuM i* i*> iii*ii i*i ciiitm ii* imi*i iii*" ii in (*n*mi*i iimm mi"" cm i"Mm mm mat * ihi* *h tum* uuaiH* * lMM HUM* III"* IIU ! MI rn*m (a* aia (| (**( mm *dl* * | dH*IM m (tl*la IMHIl* c c*i*i mm aitia >ii cuaaiaa m iimii (Mt*m limim M*1 mm "III** id* l* |*H*|I*I a* (ituia 'MMtia tl~~l" II (mi mum Miiaa ** * (i**n* i* tuuu - ------------ - idM mum niNHi mi (Hi*.** mi (( (Ml mm HIMMI I|I1 Hi dHall* (IIIIH* |**VM mia II |a*aai*a mi f|*| (***)* imiiHI C"iirt( di. mil i*ii*ita mi mini imhii* t*-~*u u I*I:i Mil. Mil* IMIl III <ai*"la m* (till!* tM|aia ( I* mm **i*.m in c*mi*b mi iimi" (mdihi danm *HM1l HIM1*1 IMI * Hi l*l|*ll* **> ttlllN t*N*M l i**ta * min* mihim imhmh >iu N <M*aiH miilll III ("IMI"a *a* ((ll*m {iN*m Tfljull limidlM UIMIM Hi ("HaMa in Clitim immim fM (*atvai|t iiimim hi ("alia iH (litila |aa.|a um l*l** mH <**l"l*a Ml IMUIa IMHIM (HIMull (**1111 IMItIM i"l*M*tll IMI* l***l ii. IIMUM <al*MM1l IBami|ltM Hi KHUII (Mditid iiifiiri in iiiiih CIM l|i* Hi imar IIMIII IIMI * *l* I* 1** t.)' l|a*?M**M<*tlltM (Itli IHHI I * ia|a*-| adiiui'iHHDM fim.lMf l* laiciua IIIIHIMM Hi tlu*ilMM ! HdMH* i.i. mu mil ihimh it t>idn.i-MiiniH (.1. !! Mill miHtil l If M'>IHItHiiNamiH .l. IKK tM*HHf H, I1| ||H I ** m .(> I. !* MU* mia'H III III MaftlfH t. l. mu MiM * .*1 ii; Im I.Mali*l* u. mm mm ii ( min hmi ii 1.1. HHd mmi m. miiiva hu imii iimh iimi m 1.1. IIHM MM I. ltM*l*l I*I (Mil Hi *11(1* MM I 1.1. IIIMIVI MMI I * l.l>.||HN|im*tlllH 1.1 .*IMI**V mail II *. l-MIX I-XI*l|MI*imt>M I.I. Himm HU ill l.dflMHMIMMai I.I. HIM'm 1*11 |.*.yiia|*|alMil *M*ift I.I. *tllH`M 1*11 |t Hi I,i.*' IMWHH 1.1. NIH'IH IMI II Hi M.||ii|XI||MH 1.1. iilliim Mil II* Hi |..*|a|a*iM"la| 1.1. HWW MUM II |a*fa|*a # tfiliia |M*IM icmmi 1.1. I|M|I* MUM II Hi laiMIM Ml (litila |M*MI IMNHI 1.1. HM. HUM H Hi i**aia w tHl* WMI* HMHH1 1.1. m.|"f MUM |l l*l |IMI*a Ml (HUM IIMM.I I----- - (.1. MiMM MUM I lit da* ia*lIMlallM 1.1. MiMat **UM I HIM |* miBda*M|a*m<BtfM i.t, hi in HiHwimi Cl-ill In M--1 *M1 Ml I.t. Min *-iia*ma(a*| (.1. Mill :iu**ni*|aMIMiMt I.t. IMI* In muI MM I 1.1. dll* Hi tiatM*im:f:M I.t. HMI ! I.> *|a|i"M*(*->lital HONS 025938  HIM t* 'IMKlHItl l.l. HIM It* (IIN'I'WimiM t.l Milt t** MM MMI It t.l. HIM tt t.l. I'm Ml .(`I t.t. mu ta* ** ***i,*i 1.1. wm mi i>ii(|'l'i(i*ni*iMiMirM 1.1. inn t* t.*.t<*ai.ttta(i<M t.l. Mill ***l la* l.t.tll'MIMlMtl HK'I I 1.1. him i imid ii citt*i immm unnii imi ih imii* mi iiiiii* mii 1.1. imi in (nii* in ii*iia imunwi nwM'ii 1.1. imi iNM ut mi.iit* m ttin. tmnni C.|. Him Ih IWMIV" m M**l* **!" (IHRHI 1.1. Hill Ih III! KIMIt Ml illl nWMill l.l. Illll *ltH l|l||l. MKIi.tllMl* aiiaft |(M|fN|| l.l. mu in miiii iinun. it*n.chmim inn imammi l.l. Illll It* 11*11 IJI|IM. llt .filial* aiCltl (**!** iimi i* mumwiMiii i.miM in mil *m*m*iii IIMMIHI Ml *ll*tl Ml IHM llIC IMIMII IIMMtlll t* M1l*lf Ml 11*1 I* Hate IMMiatl itmmwi t* innmmiH>M ||IH*<ia Ih NIMIIII* !! M |Ia*||a* tilit-f*lt**ll MM tlt*t* III HHtumnill IIMIM.I im m* i-m in iihmii limilMI Mi IIMM IIHMIIIM Ih .IH#-"ll* |ia*t*-|.aaia*i*aia* Mm *a* lHMH.l r|ia* li.H IM MMIM In M*tlM IM IM taa Mill. . Ml M'M Hit (Mi IM IVMI It* util. IM*. M| Hum till IM im t*iataa mi tM'i. ***. am mm in CfM IM Ml Ml mil. lift. in *|I|IH Ml IM iii mi imii in mil. **. mu *t*t**t mi mmm imm m imi it*nt IMMM it* IWNllll Mtt Mil MM* C ta* tiller MMI It IM Mil IIHIIIM lifi IMMMI MtHMt Ml HHIMH In Male tn <fti|a aMa| IMM HIM * (#!* mi luma caimva (iwhlt ft*t*tH MM* I* Hi tlHCI MM* I* Hni'MMItl t* IIIMMM ll(M IMIIM t** tllMMIIHimilM tMNHtm IHtWHM * tl|l*tVlimn*l tMHtM %** mnllll (ailtlaa ih MMIIH IMMINMI ta* IMMI|t| hmhm ii MittMtf*i*ciiit IMtWI Mft laa MiHH IMtMMII ta* ||MM| *a* mil af*CBta*tC*ia*r*aaf itMM*. IMlWt tt* ta* tltl`IMMal*fii**imiai| (MUM lit* taa iHtat iimhh 1*1* in imma (M*l`*ttl taa MMIItll IMtMINItM la* mmiim It mn taa M*aati <*-**-afIt In atiataitMMatiai Mil tlMCI 11*1* I t* laic* < i| ;t*ictti taa MiMtnn CHirHff taa |ai(|ti (tl'IM.1 laa aalaaclrm ca taa Hlttaattaaaatif } | J!J2 !>!- am emu- IMMIM ltt*Ht '!' taa (ai|a||a ** tltttla II.IMI* ttaafi M tta.*.*HMIHtaaia*Willtlaaaliaiital lii |i (MlatM mb* t M *a I* in* Im *tMH-a*aM*-*M9 I* .*( laa titaaitan JIIIJ*!! HI|. tM|. m |afHi till CMtltH liM. In ttt'l. Ia*. ant a*4*t *||| tllllt'l *11****** ta* I9*f|, fa*t. * a||t| f||a l*lttt*l MMI tta. aaa i,t la**, aa* *|*tl*l ||i| ** tit taa MM. laa*. .a* aiitat #,,| MIMIII til ITtfl taa !**. It*t. IH *|a**a| tit* `ll'JIU: *?n !"'M" mil. **t. Ml *HH*ti an* CMtltlM (Mtltia* In**t(-t<**tllttl*t HtltflM tltt It taa tl*t(t Hat (> in i*aaa|a 1111*1 It CHftttt taa tMH. *. am *|aiM tilt (l|*la*a la* l*i*a*|a| Ctlttmt ft ta* llHNiai tttcitatiil la* *tatiat oat IMt IH i*tai in .(Him IMtltMtm I** aatt*tt l*MI *|a|t M| (MHHII It* a**|aic ta* t|ata| ||1|M|------------- (Ml t*t IM ta* MtH. alt. ant *IMM aitt (MHIIMM ta* MIIMIM Cll In MIINMMmIh ******** ***r It* **!< JW* ttafai* niiait it -*ini CMMiil* *** Wall* taa MlanlM lltl|<t*|iMlttHI IMM at* ta* MianiM lti)|.(Hi*MiiMi (HINMI a lit It* tl<Ht*ttfttt"t < t* HtllHtt*W*lt| <*IMtf t** MIMIM tltlt-Mtt*a*lllla l*a*ll*UM ta* M**l*H*ttl c(*a**l !N MI*M* t|*tM| ttIM ta* (***! <*(** ltell ** catatl* cntie ****. HIM IHIi aa a.antii-fit*aaataa--*aM*aHMHtK Mia iMMiMi'l It* (MtatMIHMlM IHtMIMf, Ml**.I..|.al*<tt*t- * HHM *M *; *|t *tt faat*t i**t**( IMMII imiMIMt. Mtl.i.l.l,i.|.|.*|lM*lf|. * llHM MJ |laf* atfa(*i***ca*t#!a**a ItMllt tttIMIHM. i.M.t.',.*tMt*||*|.. **.. taa IIMM| aaa l*Ml af*<*i***C*tta|***l tMm IMItMllM. *.t. l.l. I. (***. ***. *!# ik:, laa ll**** am |i*|i B|**c*i*afC*<t*at*** imhh ihimihm. i.f..a..a.*ttacMta*a<. ** la* llNaao* *M HMI Mni.iHM KirHitH 11tall* C*l*a|l*M. i..l..t.l-aft*<B|t*t-> *** mil ta* I ia|M>f 1*1 aaa<* a>*tit**a*Ct**l>a* HONS 025939 KltMllM. t.|.|.*.l.l>Mll(*lto*'. **i*.i*#*H m iiwh * tmi MumiwmMnn ( In (!*( H>* IIMI HMatHNttlM**I*W ikIHiiHH l*<Mm*tu**mM.m .mf.l,t,h.hIHi **ittH*t"*tit*iM*-.n*i*m**tM immii MKNHHIM to* HUM IMKflnillHNttlM-n.ll'MIirO-iililIKItntM-l.ii-IH, In nuiltl** IHimillKIlWNIM'n.li'WtiM'iMliMaKMHi-i.n-llM, |.|iliNIN.lM|IN*triin|i*.|-*|ia*i. In iMMHIH miHtMMIMi HIKiim>. Ik |lll l.l'tMlto . *. l.I.M.l.t-dlumN*-, inn in n In *1 ( (KlkNMMMII m (UlINMIMIII IH#*IMWtll ** |4| IHlUXHmim* In INil'HinMlN ihiiwiww vinimiNi>iii IKHMMMM In IXimiinnlH nun in immw Inn u mnniuiMitw inn * m iRnniiiiMiim mnwH `niiw m nimumiiin iniiMiN inwnn wnmuinin nmcmnn IHHMI In MMintllllM I'HKKWIN iiiywinii m ikiinmmmih iiiiiM m iwinnimim iinw in wi*i ntn wttMii't m miiwi in.wtoi*i mhiinMi in*ni .toiM***tou ** m in im. wi wunuiunin M uni hi i>iiiiMiwiwi*M*rn MM In nwnlH llllMhllMIlMl mum mm mn* * in mnin m umn imww iwnnni * --------rnnnnMin jt rm* in mn'in iwilini In MMi*l< |IMi*MNIMMI tniw***I*lf**M n in nnitn **. wwim HIM* In MIHhlin Ml* M MMItli inn n to* MMMttt* mil MtIMI M HInMHMMM WMM tn iMKii.niinlilin t*n<MK In MM*t**.*M*** Nn<nl In IIMNM'itniM Mill* to* MNWM-IIMM l,|,|.Mh M W|ihi.*imnlM Ml* In *.|.tMMMlIM>MMMM Ml to* t.HIIWWWM, w innn m* imi mni m*mimm*i nntn M* nm hi IMM ** urn nwiMittiMiM (Will IW to* 'ItniNI-l'NniMIM h*i in *.i|iinni--NiMMin m ** iMniii*MM nwm M* fit fMtl to* (Mil. till, m* i*(*t mi mi * i<t*nimmm l.l.l,I.i-M*<**M**l l.l.llt*H *..* I,II. *:** ****** in him MOMINtltM In lHM mi*im**** M>Ntnn>n-(niNi<n(iiM>ii|i* i-w * ** a I*. * I* < III *(!t'*t(W****Mt *II**M-.** ni*t**> !* t*tlMMII*l*t*l*M*'l>to* to* HIM N<KM*IN(l*n|lM,l.i'l i*M*l*-tmNlillhinilllnll * l|W ******.**MH*!**M*ll>11.1.1.!**** I.n.nl'l I.M.Hto* I.IHNIWalaM Mi**M*MM*t*lMi*i...ill.*i.*ii.**.*!.iti**ei*-*-** i*. nnn Miitnnnii'MHiiM.M.nin *.<*.<** *.*.** i.inni*>Mn to* iM l|KMto*t|i**|totMltMto to* HIM H(HM**nin>iH'.'-HMnin)nm *. inn* MIM'HHMWnniHHlC* to* l*l* NinMH In HHi M<MW*M Hl to* MM* (HiiriM mi <t to* mu HMIHH hi to* *1*1* MtMMMt * to* *1*1* H<* in iiii-nnHini**niuH M* * *-HIIMNI|Mni*M MM to* **IIHH*llwni*M M**i to* M*H|II !**** (MtM***t*IIMt*MtMl<M*M*t|M*l-*'Wll**'JH*to i iiiimniNn i-W*MMnnmi-l-*IHHWMttoftoltoto*to*tol to* iMH**M*MI<* MhMM*Mi itl*ot*MnlMmIiftttootlot** mi*II*|M|mnl*tm*om|l*M*mtMl Mt****iMHNnnnHMHi him * fimnhHMiMi Mtotot to* llinitiiiHnw MIIMMt MH-WI to* I.MKHhKTMH Nim*ii*Mi * r**M n* *m* himhnkhimim ihhh Mm II to* HIM H* ***** HMHMimMMn NMN M*IIM* | to* l.-*l#n**W**-! MHiM* M to* M-imnim. . M*!*** Mi to* .>MMtMI*tMM Mviltol* * to* M-*ll*intMHH MHIMI M ** I.HIMMHIMH MHIM* II to* l.nilMlWIIHM HHIhtl Mm to* l.*-*l**|*t*toMM NHihii ** * I mimurmhh MHIMt I to* l.*ll*IM*MMt-| NHihH i* to* l.-*i**n**MHM MUM to* !i*toW *M l*|* NHMMIHlMliH I**** MttM i*f* innll to* l*to M***M MUM*** if to* IH* Mill** iihhiim mi ** in i.i'.nnmnnHiiiH Milt HH M to* l.i'**IMI*toM*miM NHillM MM M to* l*<lt MM HONS 025940 9IM9IIM Ml* N*U IM<(| ttM M **"* Ml* ** J lltltl NHI M tsK^jussr M*W |h HMUM IMM H% N MMt hn flWIM MM N t ****** MM |g}*JifgJg2g.SgglgLg?rJJLM?!_'. *M!>,MwM'llHUKK|*MM Ritasass: sa::, RAaissais:, In MMIIIM ..*,M*l*l*n Ml MMIMM f*fT*T**Mri;IM<H*MNtUMN**m t* M**||m HliHiiMwiiMi ```.T1***1* *'* IHWMIIUm IIIMMM******** wssbsku*-- :;,;r.:rMw-i M<r|HIN IMMUtmH In I M *.. aM,a-Msa*MaaNssWassKc*NsMss.*"mMJ2M..aM.5MsNI.M^,,,,"**,,,,, ???*--M'j'HlM Im V-llw|a|*Mlla| M>HWIHIMN Ml I.-*IWU|IMNN lt NNKM fljMMMM Mt .|.MMIMMMIMM MMM'IMMNIMIrMMN*l.lI. M* M'HMNU*ttHH*WIIMWMUlU mmmnmm mm* * ..............< mmTm MM M ! tlMd MM ?!?*****< M **!# J* **M1|< *M (*M HM*t( (IMMHI mtta!mif 2MMLmMMu? In 1. I*<IMM*MMMIM*Mint MM9MM Ml* M t.l'-tlMtMMMMIMM iww MM* * * MM* M MUM Mr M In IINII MM I MMM M* 'll MM* I MH<I MM* M HUM Mllll NHI $ l* |*tl MKI M U* UNHIWNINW WWNl I*m *** MM In > I'**IM'***<*)*IIM MM* MM* M h* mill MM* M MMN MM M * ***** I MM *l*m MM Ml**** In III* MlUlf Ml (f** MNNIII ;;; ajaras::.. < . ....... ... U! S." 3SS!.JS.SXS,"* "" < aaaaaaa a: asaRasaaa **I'I'I*MMMM*IIM In Si"him!h !S l imit IimiSIIIT^ N; NN*|tl.HI||,H mmm ! !!;! ! !! wii.iM**#M 3S3.':::.'S!i!!3 . Ks:s:::i!23aM-.rrJ . sa:5asaaaa::a:sa:Raar,a-5.rI:-;,.""Si.sasass. NNHNl.lMitiH III '! *mm*.**m*i*im iaitrarrasaa". *|,m aaassarassa;:! XT;:;"*" ""* i^Visara3'ctsssksssn. ttR-aarasaa a: aasaaraas l.***.(*MttMM*MM * IN**HU.IIN*| NH*NN.I*NIH mmmm*.i*****m I S! !*} ,J IU*" * miiiiimMiitN . arraarra:ai,aR 'arR.gffgf!*1 **flt M* *M*itit|iMt**M **?***!!?**M ** *. HIIIMII l**|H . rraasaaa:MN*.MI-*>MM*!*M U, .i iihmii.ih INII * I.MHmi***H .;Ji|a82aRar,a'2!a*`!..a:,:::r:f;.'aisr""~ > aTRSsSj^^iwR-aiaaa;'IimIIi1---` "**!!!**' ** 'I'HIMM.MNlMt*, J''`*****'IMMM-*INI-mNIN It. NUN* IN * *. f*llfMMM *<* l*Vft**MItiiM In I.MHIHNIINM HONS 025941 ' MWH-4MI1* iitnimiMnni In mt.ri>ittl*<*l**M'*M t.|*.Mt**MI--1*4*4 to* irniMMll"l i, 1` IHWIWItWHII In IlHMMNlllM to* --till 4|f|*|--. *11411.fflftl* MMII I IllwW-tll I-- n|l*| ' ' ii4*4*Mii-- *-- nt M.I.*.*l|4|ni4fMI to* |M*tito*f-- MM * *t< 1HHI*IIIMI 1.1*4.*MfMM*-- to* *M*t*to**l M'lllMHiMINwi-l.l'-ttWI I |.i >f<Mtotl*tl*l-- iitxiNiimi* n limn m* mu in limn m itium omm ii*m M`<IHIH(`I>''*IIMMIII'>IM' M Ilf**.MMt4III** nM'm`>I:Hii>'*mIM'il.ii>`w'lili*iM'iNhN>|m>mi| *! lU:MN HMlIKI MMKMWmilHl WlflM mini Ml lll>|MMItl*,l I'MI M* miWN'il'iMl I'fll HM.NMHiniHMiimin mu t* iuii*m<i Nimt mmi -IM**MM'I'*>( lM* Iff IIIIIMmNXH' MM* t**.Mtntot>*tt***t nm iiinnii'i'*iii mu m HmMIMMI Iff I.MInIWM.(MMWoMttoI M'**-- i.i-m*imiiMi fh* hi MMI|>(IIINIniMlMM`lll*<>ltl'l-M<mi|i(IKI'i>|.HllN iiiii * mimuMnui l>IMIMl|IMNf||||MI|.|ll|| In immnnMiiH fMM**mmimmi>n*iiitmm iff fimnw HtH|imiwiwi.i'WiMui>M iff mMii lMNII(l|IMIUH|l|lN(MlNM| Iff *llNtln I.MlINnMMM to* *M*l*totia* III*--tM*MM|-- In ll*f*t*IM--l**;-- .>*114--*4t*Mfl-- In *.***--41 **-- **-- *.I-M.4*Ml.|*.I>|H|4IM**fN*.l't1l--*4 *-l**lt*--*ll-f!*4l----t 4tMot**%l|t**l|l||M|4*t iTt(M*M----l...M*fi.fr*<--1M,iMi>.t*|--.|*nl*.t*o|.i*nt.*i**..i!|.lti|fll--MltMMttilMMnhtluttoo*ml--imto*nlilt'I*mI--Ni4*l*ti<*ilittMl*itmmi*--i IIIIMIMM, -IIIMt- IMM -ll**MUi*4|MM*t tl *--. M,.|i**ii*if*.*it**i4. to* --intmimr' iiiwiii'Miunnii m* i-minni'i intt * im**u*i MIIMUM *I**M to* *..lt**-- I.*.*4MII<M totol-l to* M'llMMI HtttllM |MMI to* i.i-tlt**-- ItllitllM M**t to* 1.*!#** Mtt*lH**t*IM to* |ttt*MI|i**IM*t-- tl*****f**M*t*l to* tt*MtoM*****t-- I. MIMniMIHMtlM ** lltM*ll**Mf-- t4ttflP|4tMMW*M to* *-*MmMII*IHll-- If-- .*--*.*lll*tttttHM*lt to* IIItf*llM'Mt**M ttti#MtmMtttt*t to* iiitimMMNi OM.MlIltimiHlMi-l'MififflfflHINK Mil Iff CMMmirtn |MMi|l*lllHmH|M*l MfW|N|*l I***--If Ml* If* (fUffWNII .*..1inMl.|MIMI'*iUl>'><>l M*f*l< *! t** MtUliMII MI,.|l*HHmiMf|MMMMf| ***!( Ml* to* I'ltn'MIl lfMtt.*ltt**|ll|ttllM*ti to* *lt*M4l*ll*llltM 1 IINMIIIINMIII * II* t*it----n.iltm*at*o*ttMuImM4t**M** itiom* *n!*i*M**tM4*4ii*HH*i**M .lltomMMtoniMIM .*.ffffntM fto--tit CI> lint tlt*t --***! to* iml--minH HIMMM ltf| ****--I--MUM to! IIMft-l|4*IIM*Mm4M-.*'-*M*MMIMtontMlM-- to* MIntltlMttt*l tlll'tl--lfttniMI--tMII't I** llf-l**M--**l >*--** iiimitifini *** * *ii|.t*nMi*i>--*M4t: NII.NH'*INf|N|M<l Ml MM * --tiff* Ml |.l'>tot*t--Mt**t to*M*C to* --!>** Ml tl.lMMtotolt'l WtMM to* --lift* Ml *IU-t***t--4****ffl** * It* MII.imfntlltMtt fltMf **lttt*o4* ltll.ltl-Mtlt*1***M-- HUMIMnW If* l.`*l*tM*f -- HIM* to* *-- III'IK>IMI>M,>l|M>|f|*l--*1)*-- to* MitolfM l|i*>(tMMUMMI I --HMMtotfMI * MM* If* IIICfttototoMHI 11*11 HurIi*i--M* ttoo*f **--*--*i*m! l*|.--MM to*|.M '***'*---- to* .Mm-WMM<**t l l.wNIftlniM l-MI*.--***!--*-- I** *|*4tolMMMl*| if I--.** *ltl'f*IMMl--t MNto4**t-- I** >>MIMHfi(Mli^U-I MMi*nMM IKI M4* toto**f--Niitilif |l**M*4tl to* 4MMHI4 ,MiM|ttiMtiiu*Mi*i*Mitoi to* :ni*i i*i*mu *.*-ii--*--.|.*Mtf*Mi*mM*i*itof---tomnittM**-- h|.*l.*MWtM--tHlo'iIM1*Mto--n**IM*IMM* I'f*to***m*4*lH *<.-*--MMCtol4Mto*M-- * HMM* l.**MtMMMMMt *---4**to|**| |--t to* *|4***ll> |.-M**MMHMI M4IMMM4 I4M* In I**M* .t4*f`IMMM***t4**>t*MIIM**!***It Ml* (I'll tlH* 1*4 tHtto--toMMM M>t*iM'to%llto to* MtM*t to* **|4**tt4MMI*--4 MtMlMtMto*l*l*ftm .*#!--M**lfl**l--IIMC**tlf*tf Mi totl--*! ||nt*Hf*iMtt* to* f--*** l.l-*|tota*tt*'tia to* to|*4#t* MNMnnmm* mi * --#**m* ||N|ttnMM|l NIIM to* *----*! I.MII--tfIMMMtl* Mill* l* W"'4I* *ltotn**t*l*--! to* nii*itl* *tltotat*TM*f-- to* **t**rtM*riM lI.}-<t.lt|IoM|--*%t|n*>*l**|I|IMM toto**--*M--i*M**M---t---- t*4 MtMl MI|*tM. INMUIIUI4 Mttll I *4>M-tHI*to**M**l*Ktti 4.|.|to|M|MMlIM IMM ** **M*IMt--l-- l,|.*|M(illll*lltlllll-l.l<MI*t to* *--*. HONS 0259*2  i(i*hi #a tiKMii* * < piMim txiNfii MMtt * laa U|ltil<4 NHWIUmMH ll U|lt|>M IliiHIMliniN II III aaiaifaiM tinNNUMti |. IIMMI I M'-IIIWNMHIl lolltl NM|>.i'<Mn|iii*iki,*illlii-llli*ntMtl|ii| t* >ll<nitM\nillll ,I*.III HlliniillllltHI i,*tiiMiiinwiwmnmi i. him* IIIHII Il'tM Ntnlll* Mlttlffl* m*(m imi im *m'ii ItlHtti lo HIMUM mall* miwa t mmnn NIHIIN Ma *** INlMiw Ma niMiin l.|ltl|lllNfllll liu Ill i,i'<iiiimM.i'-iiwiMtiMMi i i.f MMUimiHiiim imwwwiw. .|IIMHItn*IM|a| HHHfummimmii t-iiMiii'iaiiiiii laa MMIlfl Mm^wWiiIiW- iHw.Wim|I|mIH1HnIN l-IIM ll|M|Nt|fMlt<il in Mimi*nMmi*iii*ni iwuMuminfiN iwn wnwwnmiN 1*1 i>niMiMiMiifmiM*tiM I'lmnuMM hn'Iim >wWu.rMn --I1i--lift:m--mimuiiNNfm-i*iIumnM'>|IiMiHIi*mi|M>iil>|it|tini|IM >MM MtflWtwnmw l INlil*IIM''ltH IlmmiWWIHHUMI WIMM % INMniMINU litltlM lIWIWMl|liltimHHW Im **Mta*tMiaMmiaftat M'|l|ll|l*tHIINn|iiMl laa i.i'NItniM HMa.i-imilH|illilfiN laa *-IHHWIMIHlll< M>HHnmNalllia ll l.l'-INIMlIlimiai il,,ilmll<tli|til(l,iliailitimm*nlll>mli>l| l.l,lMlMlllllll .*!Im IN imiMKHIMHI Ml* IMMIM Im MM MmcaMaaMi (-MMIM INIWUMIMII ll '.MIN la# lNiiiu<i|i|iri l*IHIII MMNifiiMiMiNti mum * aiMimaaaMi iwwiii .MmnniMiMiNfi wihh hihiumim cwmih liwfntHHwn mmM im .>MMIMIIMIIMH IMHItl MMIl(MIMt| mHIII la# INWI|(IIIM|)| |MtM (.IIMIWIIMKMI laiHIII Im MIWlllliMI'l (mi|I IMIMIONMH Mi IHrnrn litMl :m*i|IM*Mla(l Mi IlilllMian Mini INI INNl*l>i'*IM<i|IIMNI laa IIIKMINMlMii INI i* i**aiaain *a#i* MaaniaaiM mi !*!<him 1.1'-MW*t*aoi*ManMi . I'-ttrl fWMaiiai"l INNI MMNMtl laa INI**! IMUII MMInIIIMMN Ml -IIIHIMI1IMIMHK .>11 iwiaitHIMN Im nn IHIMM mi mM naiiaaiaiiamaataf t i-iniiiiHiitii?iMii .a>MMta*w>tMiitaamt Iminwihiiihmii .N-tiRivni*a>miiiiiaiMiitat Mi iN<nii^mnim .-taitaat.a.itMiiatatMMalaaiM l-ll|iMHntil1llIIM tfa*i*4*lf*|a*tittiM*llaMial laa I-INHIIMMMMIM1<|< timiMt imiiiI ftf* in IHIMM IMUII mu INKII llinil l|t*l IMIMII iHln; Milan mini *iii* i.*i*nni*iiiaMiiai NU UllN Mail* laa tMta*iMiMalM<ltM MMtatt villi* .IIMl*la||IM Mi HmianiiHUHIIIN l!MMatMItiliHt |a llliatii.aiatiiiM M,l,MIMNiaMI||l*l laa liMM^a, jixtlMM I'alll* lit M|iMiai INIIM l NIlMIII %mm MIMUII IV4I * ||||ll|l4M|r|tM|l| Itaan m i iMlitM i.i*H*i*t0iaiaiHi . >'*111*1 m*inhiib*hi l.!!ai*tifa|***l laa i.a-i*aa4 IHM laa la*MIM I.MIIMM Ma I.MIIMMl MMM laa M-IIMM 1 M-IIMM trt* M IIMMI (NH laa t..|IM*M -(#1 mil Ma i.Mll*M IIMaM'M laa (.IIMaM MN MMIIIM IwiuiMall laa |.l.f.l-l|MMinMMIM*l l-l|Ma MWtt. II1IMIMI* laa M<IIMM I.MItllN, IIIIMIMM la. 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H**M *H*M IM In I MtelMM IIM tn mmuii In* <**,: In iteitai* HCMIt tn tllMIMM Hi Ml'llli IIMMI tn *ttt**'M Until tn MIHMI IIIIHMI tn iltmtM IHtM tn iteltlMI tattm * * mikmi taitM Hi MIHMI mmi hi *Maitii 1* millte CMfMM In *|teMIII* HONS 025944 IMtllli lt NMIMM INMMNHIMMm IfMl tMiKt imtiHMiM >nin im NHNtiHwiM IMIMv.itH Mt Ktimi'niiM Mt tww* l* HM Itili N Mt IMMII MHt (I |tt mill ||t M * MM tm Mt I1HII MM mmim im hiimih IMItM IM NIWNI'* NIIMI Ml NlnHt' |M M Mt KIHMmit N* MM Im MIOIMMIM'I W II.HI Im titltMtNMtttM Ml IMtl Im MlllMI Ml **.!* Im MMt'l IM M>MI Im MM! |M ,IM Mt ItMM MHMMMIM |M l.m M< IMM Mt IMII NMMMiniMlM ||Mn im mm Im imm *m tmti MiinwiniiMiM iinn jm i.jij gt jjMiiijji mu mimumhmimmm immm IMl<|lt IM iihm |M>MIM Ml MMMIM IMWm im ,m*m mt mmi mmmmiwn IM Im MHMU'i'IMWIi HUM Im NtMtm (HMII* In MIM MMMl `r fMMHIl PMMMM IfMtl Mt MtMIIK mil* IM N|M|H I'MOn |m IMMIlia l immnii imm>l Nnmi (mMmmltMi WIMmtImmNmnNHhnHkHIt immi Mt mmuit _______ _______ I NHI M ltd MHt t Mt MMtt MNl II HI! 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MfiCl.filial* mcmc Tl--II II ICIIICttaC tat Cl|lMCMlMCIMC ------- MaiM Caa ClimtCUlMClMC ac*il* Caa ti**t a** mu HaaiNNMMiMUM * ImmimmCC fata im wpwhimim ICCMH &3SR!: m1'SrtJSSX,'"" rHlllimw CM*i|*w Caa MM4<MHf J2IJ1H MMf : Caa MMCI MMI M iCMati* Caa *mmi*i**M IWaail.a |a *c**aM*iH *M*IC aiMMCf Caa HHHimN IMNIf Mac* C Caa WIMfl M#f M JHiJJfCMIC MKl I* l.a CMICI Clift M MKl la Caa Ctaact M*fl I* - *y?e MKl IC Cat ciailt HKI M *M*M Caa HINIMa*a SS!"!.i SIM*M MUMMIM Ca* CwcMMCt* 5 "*w ltatIK t.a.CtawiMIMMK C* Caa l.a.fia*l*ca*tCMC CMMM I Caa l.t.ClawiMIMMM ?!!2 I. .*-Cia*l**iMMM * Hi .-cia*|**aw|Mif WMII 2M2MIM2 w' MC-al I*..a#*(i.aa*iiManaH*tCMMHI Cmmi MONS 02594* HtvtifM in nuit limit mittc ntmn mil II k< IMNt tflMt*!! . tllMH IIHI*I H tflWt m | w.i|t-mw>,.>,ti,HmtM-tmikMiiMiwtwufi- hl.MI|NI.MHHNl-i>lmtM-l-<i|ni> tHI'MItl hNmNIit*H*inkHiI.MMt uiinnimi wmM tltft tf M ft* mill.MlWIMIIMniMWtil MMIM Ml IMMM Ml MMI MMtWMtfHIMIMM IIMMI fMHIf Ml IIMMI Mf MMI NIIIMUMMIMIIM IIMMI --------- Ml IMM Mf c----- ------------------------------* ----------- Ml IIMMI MW MMI HIHHHMHIMMIMM IWtlM MMMMM Ilf IMMM MW MM' I'lMtlMMUMIHM IMMM MMMNM Mf lltMM Mf tint M'MnMMWMIMM IMMM IMMM If Ml IMMM Mf MMI iOHUMMIUMiwI IIMM intuit If In limn MM l't|l MiMHMMMtltlMM IIMIII f-t-M---M---f--f-f-f-f-t-W-- - M- -l--N---M--IMMIWM ftt|f MlMUmmiMIUf ItMlII I MMM ft iffI fra MMI DIMM Ml fMMMMM IM limn |ffWt# IMffMI MlfMt* In MMHlilt MMM MMIMMIiMI Mf* tt MtfM MiilMM tot MMNi M...i I.t ... . 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KC*ll .tltltta *ICI|| irriiti tttMM Hill l I** ttt*t. tott. **t *l*ftot till tint to* fw**ft**MtlK a*ttM*ia*`M lltm to* M|Mfto*tltlK *HKKttltt iiihmhi h.ih to* timitmK*nmt` .m ninm I** tatit. *. **t iihih tut rtitiitm ft to* KHtitt toiMttau to* ttmiatim to a*ttat Klitft I** itit Kimi t*t tin nn**ni MIMHI IMIMII to* Hum* Mt 11*1*1* irrlflti CBM totattat wtHH t* it*t Ktittt **t tttt mum mtwtwiatttt rinHt tM* IMHHtHKtolH to* ItllMM mvcattaiatiit ttma*t t* iHKnmamt tim**it mnatniatitt timant tt* tttKKtttatitt ctatKKt to* m*mt tMKKtttatmm ihhhhimiii timant mnattmiatatat I** NuiMH itl.Mi ** lit* Mil*** mitIH HK t to* tIMII till* M IHIHHI MKI It* to* tintl flKt M ttatoam MKItm ta to* l.i-tlinmitlMK milM Ktt ttttatit h* MH*ti m tititfa mh>ii i Kitttiaa Mttattl to* itttait at mitt* mint uri* .. nititm Mia*M iwtMtti to* **K*K m tint's mm cm rtititna uMMit atattnit t** *m*K m cttttia hwh m m*ttwa miihii, mil tan to* **mk m unm mmi ttmtltH MNll| to* Mtiait tat ttttota m*ll H ttotl atimita MMalit. ttut IMII to* MaK taf tltltla mtaM nnttiaa awaaii inimi t* nt*t< m tm*i* nnm ttiattiaa ttamttta uhmii i*tut*i t** atttatt m ;tt*ia mia.% imm tmtlta avtmia titt*nt l* !*( m (inna t Pttmita avtmia *t||*it l|*tt* tot ttttatt tat Cttttia ttt*K Itattftt mttttaa Kittttiain t* tniait tat tltitia ui*ic MKtlttma to* fttlatat HONS 025956 MHtWKIH to* KftMOf MINIHHl to! IIMMIW m# i* twmm hnmi Ml IMP* IMMIflt HHHt i **#C*##*|M Ml NMMIlim MMtnMIM >111 ril MNllMIW MM) to* MKMIiriM *M MMHMIIM ITMMMHtM hm*m> im miiMitMtiM mwuii|> mimic *>% immii nunc ixmmi Mwmiwii mmiI im mint m titut* miiii im'hmi MWPIM kt HP HMIM MPJKI-H tot lUMMll IIIMII l-MPM<|> lM liyipll IUPII MpHMfM. M|IIM|.|.MP'(- Im IIMIMI-a MCHMMM HPlMi <*tM#*t.l'#ltoP*' ! I.MIHPI-HMNIMIMM mWW Ml#. MtHpe. Nh iM'PI * Ml* MPiMMtPI l-MPMIt to* IHMPn H(P HIPWII. MI.|.NHtMfPlM>. | .CH| MM **l ff|f| MPMPIM kl Ml* MPIMMIPI MMItl |.fi#M--IIM to* Ml* IPIIMH'PI NPIPMHIU Pi KluPIHIII HUHPnilM to* i;ii\pmui |-H*MMllltt IpMH IIN M-H/HIH IM# |t*|*ntl*.l<MUII pi NlitPItllU I'MMIM'I'IMIM. (<*!#*#*. IKIIIIIIIilKlllillll <t HUmill |.*MIM**l>l.|MM#MI#*#lt tot HMPI 1-lHiPiniH.l.NMiiinpi Pi iimm* |.iMwnwiM,|.MmiPwi i* mMi *.MVM I M*VtolWH#*MMCW to* lidltl MfMMMItMVM toMMIM |IM* Itt t*tll NW1NKIM to* Ml* *C#MMClp*t > mi* HPINKIM |i ,* t,i.npiwmpi iii MPWKipi I'MMIMMWM |* Ml* *#*IMMI#M MPIPK MW. |-f#*#C*-. IIIMMIPI lit H** HPiniCM MII.HPIPlimpI to* MM MVMMMMPt NPM to* IIPIPM *<toto Mli-niNPNIM Pi Ml* HPIMKIPI Mf*###M HIPM * IM**#*U m#*M M#HI**|M. M|im#`M *l* -I'HMI l MPfUIIII MUm i.hNiWIIHlI to* **M .1 M##n*l.l*MMM|IMl#**MMIM to* |iM<H1 MttHt to* MM*M Ml |lt*|M *.! iprtfii ****!<** to* IIIMtMllMl*M *M*##imi#mm* I*mi * I*m*l ft mipmi *i*ii cimmm. M*c*fi .if* iim mum iMiptii to* *HMl M*PMM **.Cl*l !<* #M*to"l IMHIPIt WIPIW MPMIM !* IMPM* M# <t'li|* IMPIW IMMPM MMIMM to* MIMMM ***** IM to* *MftMV*IM*'l* l**`IM*l HMp to* WPMNIMIII m<MM*|| HlMII to* *MM(lt| PH1.M to* MIMlimillM aiNMPHIH #V**#MM to* HIMIPIIIIIM *#*MMC|M IMIPI to* *MM*H**I*IM ' HMM|l*fM MHPOt to* MMIP'IIIIM **MM*1*1*1 .*** Ml to* *M*MV*tC*MM *******iC*t*C hump ** PiMjp.tmw itmcuMiii 1**111*11 I** MMI****I*IM MmPIII CMIttM. I.*#!**!*#|*t*M#w*|*f*|.. MMHHM'I :*! IMM to* *M**l#***tIM MWKMPIH l..*f*W|M#IMIM. -#M*nf#*. --I'HMUM--IM to* *MM4|****|*IM **VMCMMIM IHIIP to* *MM*#**MI#IM PINIPNN l**l#|*|lt to* NtWIPHIHH *#*MM#*IM **t***|*|a MMIpmilM ***MMWIM *! tot MMIPnIIM ntlMMPM ''tHMVt tot H*tlM HIVMMMC to* MMttM I***%IIMMIM. I'llHtlP M*t#lia ft* *MMIII to* -*HHIPlllpltlM NIHPII p *MMIIIM Wlllft#* lit ItMiM M* PUMP * IIMMIM MI*CM#*toMIPM**M IMMII MIPMI It* MMIIIll IIIIMMIIMniMt Ml Itt ***|t| I# !* It* I**##* HIIMMHIN I* to* IMPPP* || iMMIIIlwll Pi (********* I# ** tot |MI*#*M* # to* .Mim-t*iPNi*ni'i-ippni*iP Mipi i% in hiiimi IMIIP to* MIM#II M|1 ftltl* to* MCMI II*l*IM. ptill.lHPpptin IPM *M MCtll IlfPIP. MCMI.CIMMw MCMI IPHPH to* (Kill IIMMIM. MCMI.tM'ftM MCMft IIPMII PHI la* MtHMM HMM to* HltMIM HlfPI to* *|ft|*iM C**#|C|a to* MlttolM *#i*#i# * iiimm *n*| to* MII*MM lNI to* Mill*IM WI9MIV Itt Hiimm MH#*#IM to* *111 IMM HPPIP to* HIIHM HPHHI to* *%||**|*| l*PH IM to* MW*I||| P"*PM #! to* M*I**IM PP* MIMMM a***m it* CCIMMM Ml# to* Mll**IM M*IM to* HIIHIP *|*P ft* MtHMM civil .* tot mitoiM WUIII to* MlltolM MM*n to* MH**|M MHIMl-MI It* Mil IMM IPIIMP It* iril*M l*ICM*Mt lit MIIIMM MIIIMM It* MtHMM *% to* MIIIMM MIMaIC to** *MiiiIIMi*tIM M*UI# to* MIIMIM -* HONS 025957 Mmn * miMM IIWINII* In HHWM (MMIIN Ml HMMN IMMIMI Mi HMMm H* Hill'll WO<* In NHI'IH NMH Ml HIIHIH HNMIH Ml IlNWIH iimni'iM' ih mii'w Mm* Im HHMN K ll| Im *1(111 IHKIM. t<ll.<ll*N *llilt I H niviiini m* in MiMiiMMiuiMiwuii mini.. KtiHm HUI*H 1m HMH* Im N I* 1*1*1 **! |M 4,i-|t*|*iilN*l HH K* t (Mull IINH I Ml HWHIN Mi MHMIM NMIII Mi NUHIH MMHM Im HUHIH HMtli Mi HMHIH HHMII Mi NHHI1 NNHIl |* HIIHIH IIIIMI Mi MUHIH HII'IH Im Huhih HUKHI Mi mMHIN MMHM Im HMHIH NMNIM IM NHHIH NNHIl Im NIIHW NN*N Im HIIHM Mint* Im HIIHIH NNH Im HMHIH IINH Mi IIMH-H NH*N| Ml MM**IH NMHHI M* HHHIH NMHHi M* HMHIH HNHIH Ml HMHIH MMMtl M HMHIH MH**N NIINMI Hill I* 1.1* HIMMttll Mi HMHIH MMHHHI Mi HMHIH NNH|| M* HMHIH NNHIMM M HMHH HIIHtl Ml HMHIH MMHM Ml HMHIH NNWM M* HMHIH NMHHI Mi HMHIH HMHIH Mi HMHIH NlliltM Ml HMHIH MMtMM Im HMHIH NMH M HMl'tH NHHI NIIH M M* -llllM*IN*HHtlH HKtHi HMHIH NMIMN NIIH WO Ml -IIMHM(lIHIHIMlH MMM** In IIIHIM IIMIII* In IIHH IIMIIIM HMHIH MMim Ml MMIH NlHM HMHIH HIIHHl Ml l|l|l*IH ill Ml IIMIIII WMM* IN Mi l|t||r| litMIU Him ? Mi |IK||*I lalMUl MlH III Ml MMHI IIMHI Mi HMHIH |l|l Mi Millll* Mi HMHIH lIHlil Ml MMHIH ,>;:t:yMHIH H lUHMMIH HNCiH*IN miiiM>*i mi miini IINM Ml MHtHH MMH Ml HMHIH It Mi HMHIH MINI* M HMHIH t|t*NII Mi HMHIH Nl t Ml l'>lIH*||l*IH NIHIM I Ml HNI|I||M**IM MM* M* HI|i*M HIM Ml H*M III Ii*Mt*UiMi ! MMi i:te*%t;*u!iiiIll minitMM Ml mt-MH* IMIMIII tt> III MMHIH Nil Ml WIMIN im**W MMHM Mi IMWI! MtlNIMl Mi INIMIII MlHHIH Mi MUHIN HI MINIM Mi MfHHtt UHHMH Mi MUii. I* IKIMIH Ml IMHMtl MINI Ml Nt*lN M*HH Mi M*Hlt MMH Mi M*H*I MMHI *ft m MMHI. IN*Ml* Mi IMIHI MMHI N Mi M*Hll IHI'IU Ml HMIIMi Mil * lll|M Mi HU Mlfltl Hi ||N HHMII MlHHI Mi HIIHIH ININNH Mi HMHIH IMMiltU Mi IHHCIHI IMN*U NHI |t Mi IIU> MW II MNI| Mi HMHIH lilUlll Ml HMHIH MiffII Ml IHMHIN MM (MM Mi IIH*H HI 1**11 HiKHHHHlMHMH |MNI| HONS 025958 |M* *#tf MM |t|| I to l.l'-atfM*tMM|ttl*l ctomm* to *nr*ui* to NtNilM HHtinM to KimtM l-IHIMttl^ to ** tOtttlO. HOO- tHM (MIMI I** HIMCIH* vtuimN to tttMn.t ltMMttM to M.NMH OHO** |H MMMIM tO**M* to IIMtPIM Mill to MMIMM MMtli to MMiKIIH to MIIHI Mt IMIlll Ot|M|< to. twit MMIIHMI ( a*tl**t tit tt imi to (ttoot-i-ototritPiH tM to MMNM MCMtt* to OM*l< of (M'lll MIINIt miMMt MM'HtMM to MMMIM MM-MtMMM to MMI'IM MMMtril to 001*10 ItMIlMIN to MMMIM MNIMMI to MtlHIO mniiim m tiiummiiiHM 8toit to hmmim MtH to MMOCOtllllM OtttCMMttf MIMMI MMMIMM to tttIMMM MdlM Hit*It* IMIIM ** Hi MUim wmim ko tiuo** mutt MMMM to IMlMMMlMIN 8 S=------------ to IMIWtMnnM ------------ to IMIMHtflMIH MWtat to wtiot Mt MIMMI to MMMIM MUM! Hi *0*0111* MMM tit MMMIM MtlMIt to MMMIM MIMM MMM u to MHO-1-0 1*0**10*010*1 HitttM HMI t to tint* tlttv M IIIMMt ti MMMIM MM to MMMIM l<MM o MMMIM MIMlt Ml MMMIM M*fHt to MMMIM MMMtll to MMMIM IIMMHMM to MMMIM MttMtM to MMI'IM MMMIt to MMMIM MOItll MMWIM t MMMIM MMMIMMINI to It MMM tttt'ttlHtltttt I to liftIt MM MMMIHIIMII It. I to IIMMIll MMIIMMtIMI H. to MMMIM ttoim mill to iniMm MMMM to MMMIM MMMI to MMMIM ttooot to ttimiM MMM to MMMIM tttPMtt t* inmin ItiMItt to MlltllM tltPttl* to ottoto MINI to HMMIM HIM** to OIH'IO tt**t*m to tmiiiM OOtMl|* Im oiioio |M'**HM HIIHIM tlOtftflO to OMOtt mimiiim wmim to tttttiM 1101*110 MiMII' to MMMIM liri'M to Otl*IO MOIt to MMMIM tomtit to M'.flHM 01*110 t* MMMM 001*1 to tCOMtat IIHIM iMMM((tl|fMI 001*0 tl Kill*III IIOIIOI to Otll.t iiMimi to ooi*i*t MMIII to 1101*10 MMMI* to MMMIM tiitatt to atootM ttt**t to tttiMm o.oio* mooio 01*011 to 00**10 to MMMIM mho to tiiontoiHttm MMMI to 00**10 omit to tttiHto OtllOl* to MMMIM ttOIM to OttMIO XM!N!?H!t!l.M!!*1!to"*t!O' 1laotOItt'tlO'-ttl*M* IMltNMIlIM MIIIMII to IMNM MIMMI ! 10*01 HMt to llllHIIIHMtIMI tHilMMlmI* toto*0ti<*1i-*0to*noiHi*o**i*tt .*:::sr . . -tl*l**t out* Itt to nMM'iwmmitMHIM smsst ItOtO Hi *0-m*l* IIMIMM 0**101 It* to 010*10 IMttttH to tltl*ntlUHtttO tHMlI* to 0**ttll* tlMHI to 01*01 H* llllit II H* *0*0111* 11*11111 Hi mii-om toot to otto* lit t**-t* to OIMMtMH'IIO WllltMl to MIMOMMINM Mtum to *0*0*1* MUM Nil *OtlMt|. 0*f***V*lft to to*i o ttotM mmmi irrmii SnStiStS* !ooo!Zm!i'ii mh*iiHtt*tif*o**ti(mu* *mmilo*oomn**my H* mmmii iMtmwo O*toroot MOHS 025959 to* MHMt M4 *( lllimi CMMMtl mw IH'MM tfta> to* '< u ctt'tl* IIMNIC I________ imw HhMIl MMnrHI'1 to* MM*II Clllim ***' HWWMt WIW lNMI| to* * IIMlIt IIMMOtt MtlW IttoMt. 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(im |*a t*(*N* **t 11*1*1* IMHiM tMH*It HWaltW IM*M*1t*ta * tMWna aw tiltat* (***)* 1" -- -* tt*t hh* HUH to* (mwiw a*t tiatat* " " I to* |IM*f*tt*M 1* totaini * i*icm*i* *M* M to* *>* 1**1*4*l**IM<*tl*1 hh* *%* * *-*wnMi*in*in*< W*` ItliN M to* 'tlWlMM|*HINti|*t tWM II1IH M* to* l-ll*(la4IM|HinMl'IH IM** H * #* !* *:i** MW lit* MM**(| Mtiauatt Im* im Mt**M. til**(tHMt**(l *1111 to. wt'HI to! HWtNI*ll*IM to* toCCMIt* HtltWHIIII Mil IHtM to* IMIMII* H4IH wiiatl to* WllHI Ml WHIM MIMI |*| to* WltUI * Ml*H HI*IH to* ** IMilH MIMIC MIC, f*aMll* to** li* to* Wmwa Ml liaiaH* UliilN* tWMi II miHu mt MCtiid** ** to* <t(iit *t*t*fM, Mitii.cimt* Mian itomiiia MVIMH Ml*. Mlmtld toll ! ** Mian hmmm. *ic*t%.*** * r MIMII mi;. ica|td*itat to* M*lt M*I*IW. *.(f**l* *** 4.............. witMwt mi*. H.Mtt.winN(wi<i*i-Ni*niMn mhhwim MtHH to* MMIMMIIM iVMMMHIN tot Mat* wtwHia MWNWtalllt IIIM to* toC***M toirwta HMtaa* to* waitaw * Nt*M Wlt*t tot to* aMd** tot wihwm mi*, lawn* i* mu to* (WNW *M lltllia lawn* IH*H*M W`ll M*M*tto |m N(Mt*M toftNan * illfMtM VM*W|t MIMI to* *I*HW-*!****MM*Mt*MV MflHIM to* MlMdlll mim**i MM-i* ** tiMit mw mt*ia mt** itomm MM to# M(*Mia *iaHt*| |* MHIIla HONS 025960 i*tmt MNitn I'MtlM-N Itt l>M(NN X* ImtNW X* MtHMMM i.acmia tiiNmnutixM *! IX* Xt (WtaMIMH * MIWtllmflltHt X* **fa*xx x* iiiiiiniiuNiiw IX Xl ft* X WlfNflMilN IKM X> IHHH X* Nfttlfit Mum* x* ntxi Mtxx 'MW Xt tflltM ut Cft| ttm ,1 IWWIM Itliwn IX Xt MIIMlimMIHM " Xt llXItt Ml IWI MtmiMimMtitf lltatll IX X* Will IMI. Ml Manx *111 XI IM x Cat*!* tw. tat XXIX till Matt X* I.MiHllti(M|t|ltM*fl't*l|i| MW Xt t..>.l>tllXXtttmlt->M'l| M.'.t-ttat Xt M.I.|*t|MM(IMIINff>t>llli|l *M Xt |,t4fMIMlHM im xt wiM.miiitinimiNMMttf JJIXIM W Xt IIX X *f IWI XtXXXWfUXItaX ll-atH sinisiurv'i.ums " --o' HIM IW NX* I Xt 9IHCI IIXt >| fMMXXMtHM Xt MMMKI HMWMIM Xt MMIfltf MattCCMMfafC. Xt MMIIIM HWn Xt MIIHN ijtiwn xt nniiim WWWIX 'ttllt* Itt IIHIMM IMWltll Xt MMWIM HMIMM Xt MIIHIM MXIMMMM Xt HHttlN niMIflM Xt MIIWIM tmtna x* NMirm HMxttw xt wimnit tltftX t Xt I MMIMltlMtl titttwcwc* xxt i xt ime xx it imattctwr xx hi x* titm xxt m WWMMI MM ft Xt tIMfl XX I M*Hf NX XXt t Xt tttlCf Xtrt It IMWII MM ft Xt Intel UBC t IfWt X* Mllll.tf|t|l rn IIMVIIM tttfix HHmW Xt tlltl**tfmtltttitMWHat Mt'lll IIWMIM Xt ttlfi i tt|t||iat| tatataatac tat'iat Httt.XX Xt t.lM|iniM t*fa.*-l*cnm tixt:xtMtn aicwi Mimti. aiccii.ccitiia aittu mmwmi Xt <*M111 MIMIM. Ktm.lltliM tlttll CMMtail HfXCMMMMffM Itt ttttti HIIHt MIM MlMCXWWtMMt Xt Cliff* ftffXttVtttt ti)fifl|fMCN%ttttlMaft*f>1 M t >t Itftftt Xt f.)'M*tftXXWttlXMt-t-tltt| * I.U.HIIIMMWflMMt-f'llllIl t*t (ft 1.1. t.t<*ft*xttttlMBft*i ta X* f.l-fIfttfatttMIttttttla t|tintii<**iitaXitt Iittt*M'Nf<fttnllitMattltx llfttattit-i.t-tltt| X* '.tltllM l.|fl.ttn.Mtt.lt.>MNti.<.tl7*wl|i|(.ittl^-M^llXx^X:*ftXmtlJtaTt*M-----x--^---,-*- a JVtSlillStU'**"* fitl.flatfa*tttCMCwiMM t.l*l|ttX M*t||MHttlN|Mt*|MX t.a -'*ttat*t*IMMfa>t?ltvat.at-*ttMw|tfatM*tHwmmti _ *:! "?!'** *x l|IM,-HMItt|WMMIM Xt ^I.I.Mt^I^tWXIMIIItiI^II.l'..UtMlBfNtait*liMittawttiMiHtHtt^ttl .a.a*.*.ICfCMflt|>i.l-.f|txattlf*Xttattaiac fllllMHI Xat nHtXll'l'mMVit.Mlt|lNM|MfilMi||NMM fcfitm Xt umm icttxxttm IMMtMa i*C x *|a#*|t|* tJwJUf2t2MJSiJX? !X!'.t t*c;tnilt*a*tat IfataiinMmrfnMNtilitMaitcemThi tafftiati !* Xi MUKhMImiii iiwntl xitcfiMttc xt mtMiiMrt ItllMHMt Xt WifllM Xilttacatt Xt NtMlIM a MftMflMItf t*t Ml IttlIXMUIIMtfat(X| ti,,flftMalMiaMtfIt ' '"JJ'JJJ, * ';jil-M:iflMniWVi| XMIM n*tw hmiuf'ftHftc?*1?XtWHMHMtlHfHMlWlllliHXtiHaitifMlMHt ltaWt lflM I-Xixtuixixifit Xt iMtiMTxitatct ^ m .........................*nfUx. tf|M Wlt*atMt*taiH< .`***lfl*.>CIMMtlf _ lM MillMlltlliiti WitMiH MMN MtttattattttniM. .' ,r.it||intl- m' M Xf*fittciaaxiit x Mitttc* 2IK! !M!**i 'i*iiixiii*w*mii#w#iNtxi..ittt*a*ntitatciwiw faia'Ml Xt I*. .4>lllt|t|ant**t*|af WMIM t **' 'W,*U,,,#*wMMMtWW NtMM l**afat;a t* ttiaatn Mittwtt. a.a-.it.f.naixfini- x Maniac faitaxt *"*! Itt MMM MlifM ratamm ntaiac t* hi fattica taitc imii m taicita titaiM fatttfftfi Xt lataiar ttcnw tataicaci xt fattiaa titaiM atutat. -aaaa*ata- *. IIC'ftiN'MC HONS 025961 * ki tiiNHi tM!*W**t to*** imifMMitianifMnitii mkIMm INMkMHI k imiMH<ltwUN*ini'* kNM*l k.UIH IIWNN kl WtllM m ** >I-*>kmt MmiNUnwI'ItInHiiInMI *1 Ilk III Ml'tlM'IMI l| N Im imiMtdllikkl tMtol*l m ki NutlN urn uMiim ** mmim Ik in kttkw l I iiiiimi Ik !* to* WINM* lk-| W l|lkl l.klUMII tto#l*IMI4ttl*t*4 klklM* N ).l*>l|l|l*nMMIM< mum * MMiHikikkiiitk (IUNMI |H I* >9*14 ***|H*4ttm M'>tMINK Im I**|#t*4l*l*l 1`Wllkl to* l.l'-IINlkikklliN I, '** I*k4 to* M'>IMNnM*imN ItlMMIM. IHII to* HkMIHW M* MNIMIIM MkkMkIN ***"* I *! *M*4 Ito 11 ** M'*II<4IMM>I MMMilMklN to* .M*(**itototo HI.MH---kk-lM-M--Mk- NIMM*. Mto--* tIo*v*l*ik>ktt*omli> Hiiitoto nwuikik -to*i*ii *>*tmitom kwinikw mtoito to* HMimn mkknkiM l-NUnmilMW to* M-IIWlikMkM M'lMkltllllMM to* |,>IIMlkkMk IkHNIIMHH to* M-*IMI*kkkk kMt-mnki to* kii>'kini*i mnkitoc nkkikiii i* -*to*iii*< *t*ti**tM ikillk-I.Mlwik to* i.>|nkkkM*i IknMtIWIto to* M>UM<4IM*MI M'WHmMMtH to* M IIMIKkMMir *>iwnitoto**i*l M-MkiNikkk iktok to* ikiikk WHIt to* Ikiklk *Mtot*mMkHK*l mliitl* it*o* I*****!*' Mmini*Ii*I ttoo** Mi*iU**M*f*Ht HiMN IHt I to* ikiniMiwinMink l*MNkn to* NIIHIM NitiWmMmII ittoo*ilHM**I'Mk Miiit IiikiUfHHItioit*iowi*MiiMnmVmMtmlnlk*to*tMMimm* i*Hikiii*i limit IlliWMM to* M|t*to M'l,l.l-It*m* t*M|*! to* MIHMI wmn MIIMW. . ... llllkfHWMH M,HIKKIHN|*M lf* to* l*tlMilk .................... HlMIH ntlll-MHIlinMIkkvm milll to* imi|.i|ltlllkill*i|ii|i| MUIN .*>l*l t**||f**|tol**MMM *.to.** i'miiiMiwnmiiiimimikkiHi kMkMikiMknnw to* ttttt **MIM9t4*t>*t*t**lM tolllM to* tlMl|lll*|:*tor*l milk .i'.V.MHIMUHNIklMikMIlklk to* *M<i>ilM*i*ti*toi*rk toiiiM 'lllmklMM *tl* *|l*lltt*t*4|fIt *ito*ci* imi M*n*i*i**t: toiiiw immii * im Hum m m wiwim i*iib t nf*ti**iKm ni i;*.ii.n'iNw<i'mnw*M'..irimmin*wiii i*yimn*n*nuMuinimw SmSwmto* kmimiNMmit nil to* im.l-H**ki**tol IMMMilt IM* Him Ml**fI to* IM**|.I>*|*H ' * Him. l.ltHIMMUti im lt||lt.l||l|||M|llll4 milk H* IN !!** to* !Mtol.lltMf*to*to**M>***t ** Mim.i MHkiMmnNk--# iMtot.toi***M*MMti *******11 * .......... ........r~r~~-ir nruii i*i*l.l*toM*to*n* imimii xii tm* '^^^****^*** * HIHI.MHIkkUmilNkMIl i*itol.toM*tokM*ti*MrMi* iim t* *tt*t to* HIININ il!l|,|,nmlmkl^'H,,'*`,, '*mi*i*i*** ********t mim **tl** to* *|H ***! tolls w* ** IIM*lk**t*m**tto*i| llll* M to* miMli Ikl to* **IVtt *f l*l*l*ft INMNM milk INMkll to* HIININ nwittot ** iiiMttiiitikiim kk*i*M** kto*I***.!Mkiw*m*m Nllkl to* IIIIHI4 klk HMI f to* Mini 1,41 II WIHNN to* HH*I4 NIHN to* IMIk HltMtklk WMWN to* NkkMlltk NHkHklk . *-l*n-*.*|tto#- IWII to* mnkkkMMUHi ** I.HI**IM*I**|*. * rmik KlkHi kl*. *tm*t-MMt*w I** *Hn:*m--4wnk kl*. **!*.*.|t*MW IMI* to* !*---tornHH*IM ki*. m> mi im*f* tolMM* miMM NINWI 1*9* |H klM*M l* NlklkHIIIN kkiciklk HIHH * INMWMIIIIN hiiwinw HONS 025962 m*ivm>tt im MmotniM IHM *4* N|M||*ltlllM D(MI If* MMKlMIII wtim m *f* *vMtnmivt nMMMMIH IHM Ml Iff I.fllfM*Vi"il1VtI WlM'l <! Iff IVIfNI'iilM (I'M Iff .V*#*M*M|ilf ni ii'ti m MMm mi m-4i mi ntn*iH vim mi t>ttn"'iMii(miin W !** Ml HIMlMi WH *11 * n|lil imtM Ml NMfUMIlin tlK>IMIN 1MM Mi MMMIM IIMIIMl Ml IlflMItmilltlM <H Ml *! IMMIII mi * ( tninit m Mi HinniiiHi itMMi * mMiim mmi wm t* mi'mhii MM>W Ml ll<M<(ll* HKMI ** MINIMI mm im NinMitmi miiin mi mimmm hmmimicii Mi mm mic*iMM HIMM KM iimumKIIII Him Hi Mi 'MiM M hiiii m mwiMHiiin hunmiim HMHM M Ml |H.*i*fM*f * tHH mi imm mv Mini i (m:w mwmmi iimi Im mmitw IIIIIMI Mi It !!* INf|Ml iMlMtlll .... i i nnw nn innm iiwt ihmim miimi * *i*n ihnim *mn iimhh Mi Minmi'mi *tmiMiii> *>iHMiM iiiNti' ikii i* Hiiimumn iihimm: MI-NIhM Ml HHIIN film Mi limn in mu M>KiiHmiiiiiH i*m<* hmhii nm s* *1*1:1 *< m HIM Ml WIIHtl * MUHlI *HI II In M|l*|| MiHii f'C if* *i*mm Mtimm 1*11 Ml imtlMHIIN IMCHIIHI *M(vN I Mi IWUIH lMv*t* wti mi in mu. mi. m m**m * WWM HUM * ** *.H*ltHi*|i|i|*MillH MINIM llllll HI Iff -*IHllM*Vt|VV*HM M*M IM Ml mtllll MIM* *1 Ml MUHlI VIIMim Mi M|l*M< MIMIIV WIMII III MUmi mum it* M**ir IfM)l Ml * MMI*t MIMIN HMI !* HHMlI MMIM t If* lMI**tl MtMIM i Iff HIHMI MINI i*HIU Iff IIIIIMI MlMCtW Iff MMII VMM Mll H IMIMMI If* 4*WI m llllllf UMfll |i IIIHIM Ml lf|H(|l|l mini in mi HiHtinHin-Nifiiiri MN IMMIH Iff . INI, MV nnm *m m iivvt* if* iimimi mil * MiMtfti* imiinn if i.iiiMiioiin MHilMIH If* I-WHIIIIHIM iiim um iimi* *t mmi m mm * imimi m mmii in iiitiHi*i'MiiimiH mm nttniiiu in ifiMiif * tiiiii* :*** " ?M|HII-I|.(illiml< *CI* NllfUIH l> NHHl'HnlfM.il HIHIIIIH Hill'll* Mi:i.nii'ii.iiiiMii.<miMiiH>nii *. iinii.ihhm.ii. itm.|l*liHaM<iiH l**l* l.i.HilHIHiniHMlI HI'lli Iff *l|M|<f| mtn tf m'i: m |.miii * mtm mi muni cmiMt mi mimiiiii iMiim * mmm HM'.flll If- M HIHUfl nnmi * *** hm*vmi * Nimiii itit* m* tvn. mi. m *i*m*i vtu imimi m * iimi.|.|iMMMiMniM*i'fiii IIIMII I* Mf llim.MIIHH'Mmi'HHflll IHI f*l M* I.MIMIHIMIH im* in t.'*<i*vfvnv * m*m mm MfllMtf |,i.||i*IHiMMH IVfV* Mf MV *I**M MMMf 'MHlHI HONS 025963 . Slotsary, Aerotqns, tod Units of fessurownt 0-* MOMS 025964 GLOSSARY adenocarcinoma--I malignant epithelial tumor (rising from the glandular epithelial tissue ttfcnome--t benign neoplasm of glandvlar epithelial tissue adrenal gland--t honaonc-serretlng organ located near each kidney albino--an organism cahtbttlng deficient pigmentation in skin, eyes, and/or hair alkylating agent--a substance that produces a reaction product containing an alkyl group alveolar--small saclike pouches that may be located In the Jaws where the teeth arise, the air cells of the lungs, or in glands amines--any member of a group uf chemical compounds formed from ammonia ay replacement of one or more hydrogen atoms by organic radicals aaiyloldosls--the accumulation of amyloid (an abnormal complex material most probably a protein compound with a carbohydrate) In various body tissues analgesic--pain relieving analytical grade--the highest available purity of a chemical anemia--a condition In which the number of red blood cells or the amount of hemoglobin In a given volume of blood Is less than normal antibiotic--a chemical substance produced by a microorganism that has the capacity to Inhibit the growth of or kill other microorpanlsms entlconvulsant--relieving convulsions antiepileptic--preventing epileptic set lures ant1>1nflaa*atory--counteracting or suppressing Inflammation antimicrobial--destroying microorganisms or arresting their growth antlneoplastlc--inhibiting the survival and proliferation of malignant cells B-l HONS 025965 antioxidant--synthetic or natural substance added to t product to prevent or delay It* deterioration by the action of oxygen antipyretic--relieving or reducing fever adrtc--the wain trjnk of the arterial system, conveying blood from .he left ventricle of the heart to ell of the body except the lungs aplastic aneaila--a for* of anemia characterized by greatly decreased formation pf red blood cells and hemoglobin o'ometlc amine--an organic base characterised by a benzene-type ring system containing one or mure amino groups aromatic hydrocarbon--an organic base characterized by the pretence of at least one benzene ring and containing only carbon and hydrogen atoms arsenical--a compound containing arsenic auditory sebaceous gland--gland of the skin, secreting an oily substance, sebum, and situated In the cerium basal diet--the ordinary adeouate diet fed to animals during experiments and to uhlch special Ingredients to be tested may be added benign tumor--a tumorous growth that Is not malignant and usually Is not life threatening bile duct--a tube for the passage of bile from the liver Into the Intestine bloacciznulntlon--the process by which the amount of an environmental contami nant present In a living organism Increases with tine breakdown product--a chemical derived from a parent compound that has been altered, usually by heat, light, or enzymes bronchogenic--originating In one of the larger air passages In the lung caucer--a general term used to Indicate any of various types of malignant neoplasms carbonization--the process of converting carbcn or a carbonic residue carcinogen--a cancer-producing agent carcinogenesis--forMtlon of cancer carcinogenic--producing carcinoma, a malignant neoplasm of epithelial tissue (-2 HONS 025966 carcinogenicity--the power, ability, or tendency to produce cere Inane, < malignant neoplasm or eplthellsl tissue carcinoma--a malignant neoplasm of eplthellcl tissue cerdnostltlc--tending to check the truth of carcinoma ctrdlovesculer--of, relettnt tr. or Involving the heert end blood vessels centrel nervous system (CHS)--the division of the nervous system comprising the breln end spinel cord cervix--the neck of the uterus Cheaosterllant--a chemical compound thet ceuses sterility of en orgeniso uhen Infested chemotherapeutic--pertaining to tht treetment of dlseese by chemlcel agents chelanglocirclnona--adenocirclnoma of the bile ducts choltnglocellular--of or pertelnlng to the gallbladder or bile ducts chronic--continuing for a tong time clltorel--pertaining to a sma'.l, elongated, erectile body situated at the anterior or ventral part of the vulva col on--the part of the large Intestine extending from the cecum (blind gut) to the roctua (terminal portion of the digestive tube) conjunctiva--the mtmbra.nd that lines the eyelid and covers part of the eyeball connective tissue--t tissue that connects, supports, or surrounds other tissues or organs COnUalnent--an Impurity; In the environment, a chemical that Is not usually present and that may have deleterious effects eopolyner--a polymer conttlnlng more than one kind of monomer corpus uteri--the main pert of the uterus cystitis--Inflammation of the urinary bladder cytology--study of cells, their origin, structure, function, and pathology cytotoxic--having a toxic action to tells denscl--pertaining to thin 6-J hgais desiccator--* heavy glass container froai which Moisture Is removed by vacuum or chemicals diabetes--* disease In which the ability of the body to use sugar Is impaired and sugar appears abnormally In the urine and Is characterised by excessive urination diamine--a compound that contains two amino groups distant tiMior--a tumor that is located far from the point of attachment or origin distillation--a process that consists of driving gas or vapor from llgutds or solids by heating and condensing to liquid products D,l--refers to mirror Images of compounds that rotate polarised light to the right ID) or left CL) dose-response relationship--a relationship between dose I amount) of a chemical oAalnlstcred, or taken Into the body, and the effects dyscrtslas--a pathological condition resulting from the presence of abnormal material In the blood effluont--waste material discharged Into the environment endometrlimi--the mucous membrane that lines the uterus enzyme--a complex organic compound (protein) produced In the organism that can accelerate a particular biochemical reaction; a biological catalyst epidemiology--a science concerned with the occurrence and distribution of disease In human populations epilepsy--a nervous disease usually characterized by seizures with convulsions and loss of consciousness epithelium--tissue covering Internal and external surfaces of the body esophagus--the passage that carries food from the throat to th* stomach estrogen--any of a group of female sex hormones estrus--the female sexual cycle fibroadenoma--a benign neoplasm that contains fibrous tissue fibrocarcinoma--carcinoma with a hard structure owing to the formation of dense connective tissue M HONS 025968 fibrosarcoma--a aaltgnant neoplasu derived fro* fibrous connective tissue folltculir cell--modified epithelial cells that surround the ovum In various follicles and iicrete follicular 'luld forestoaiacb--a nonglandular section of the stomach that Is lacking In the human organism fungi.-a major group of saprophytic and parasitic lower plants, that lack chlorophyll and the tissue differentiation of higher plants fungicide--an agent that destroys fungi gallbladder--a reservoir for the bile located near the liver gastric (stomach) Intubation--Insertion of a tube Into the stomach gastric tube--t tube passed through the moutn and Into the stomach gastrointestinal--pertaining to or communicating with the stomach and Intestine gavage--feeding through a tube passed through the mouth Into the stomach genitourinary--pertaining to the genital and urinary organs geothermal--of e> relating to the heat of the earth's Interior gestation--pregnancy; In maanals, the period of the development of the yourg from the time of fertilization of the ovum (egg) gland--an aggregation of cells specialized to secrete certain substances of biological importance glomerulonephritis--a renal disease characterized by Inflammation of the capillary loops In the glomeruli of the kidney gonad--the sex gland of the male or female gonadal dysgenesis--impaired development of the gnnads grand mal seizure--major epileptic convulsion hamaagloendothelloma--a neoplasm derived from blood vessels In which the endothelial cells are the most prominent component half-life--the time In which a substance will be reduced to onn-half of its present value through degradation or elimination from the organism HONS 025969 R-5 hsrdertio e'ind--secessory licrlmsl glsnds it the (nn*r corr.jr of the eye In nlmels referred to is th `third milt' or tht semllunir conjunctlvil fold htrd ptlite--the interior, rigid portion of tht partition sepintlng tht nisi) end ort) eivltlts heoenglotircome--t rirt nillgntnt neoplism of tndothtllil cells derived from blood vessels hemttopoletlc--pertiln'ng to or iffeeting tht fometfon of blood cells hepstlc--pertilnlng to tht liver hepstltls--Inflianiitlon rf tht liver hepotocellolir--ptrtelnlng to llvtr cells hepetemt--t ttssor of the llvtr htrblddt--on tgtnt thet Is dtstroctlvt to Mttds Mstologleel--pertilnlng to tht study of tht Icroseoplc structure end ccaposttfon of tlstuts histology--the study of enstosy thet dtils with tht minute structure, composition, ind function of tissues Hodgkins dinette-- t Mllgrant condition chertcttrlzed by painless, progres sive tnlergtintnt of tnt lymph nodes, spleen, tnd gentrsl lymphoid tissues hormone--chemical substinees produced by the endocrine glinds thet have specific regulttory effects on the ectlvlty of certain orgsns hyperglycemia--an (bnomtlly tncreised content of sugtr In the blood hyperpltslt--sn Increose In the size of e tissue or orgtn due to in Incraise In the number of cells hypnotic--sleep-inducing; a sleep-Inducing drug hypotensive--ciuslng diminished blood pressure Impurity--e contemlnent; en unnecestery pert of t mixture or compound Inhalation--the drewlng of sir or other substances Into the lungs n-e HONS 0*5970 tnttlatcr--i chemical that permanently alters cH or group of cell* and In the cos* of carcinogens Is tumor producing Integumentary system--an enveloping layer las a skin, membrane) of an organism or on* of itt parts Intrabronchlal--situated or occurring within a bronchus, a division of the trachea that leads Into the lung Intragastrtc--within the stomach Intramuscular (In) Injection--Injection Into muscle tissue Intraperltoneal (Ip) Injection--Injection Into the abdooitnal cavity that It lined by a serous sac (peritoneum) Intrapleural--within the pleura, a serous membrane enveloping the lungs and lining the walls of the pleural cavity Intratracheal--within the trachea (windpipe) Intravenous (iv) Injection--Injection Into a vein In otero--within the uterus Invasive--spreading beyond specific body tissues labile--unstable; tending to dissociate into component parts lactation--the secretion of milk larynx--the upper end of the trachea (windpipe) latency period--a seemingly inactive period, as that between the exposure of tissue to an Injurious agent and the menlfestatlcn of response, or that between the Instant of stimulation and the beginning of a response leaching--a process by tdtlch a substance or ccntamlnant In the soil is displaced, usually by water, to another location lesion--a wound or Injury leukemia--a cancer of the blooi-forming tissues characterised by a marked Increase In the number of abnormal white blood cells leukemogenlc--causing leukemia, an acute or chronic disease characterised by an abnormal Increase In the number or' leukocytes lymph--a clear liquid that Is collected from the tissues throughout the body and flows In lymphatic vessels 6-7 HONS 025971 lymphatic--pertaining to vascular channels that transport lymph or to a lymph lymphoid--resembling lymph or lymphatic tissue lymphoma--* ncop'asm of th lymphatic tissue lymphoretlcular--proliferation of tha reticuloendothelial cells of the lymph (1 ends lymphosarcoma--malignant neoplastic disorders of lymphoid tissue, but not Including Hodgkin's disease malignant--tending to become progressively worse; life-threatening mamnary--pertaining to the breast marmoset--a toft furred, clawed monkey found In South and Central America melanoma--a neoplasm derived from cells that are capable of forming aielantn menopause--the cessation of menstruation mesentery--a fold of peritoneum that attaches the small Intestine to the posterior abdominal wall by tdilsk the viscera are supported mtso--a compound whose molecules are superlmposable on their mirror images mesothelioma--a neoplasm derived from cells lining the pleural and peritoneal cavities metabolism--the transformation of chemicals by which energy is made available for the uses of t!.e organism ard by which contaminants ry be converted to different compounds for easier elimination metabolite--any substance produced by metabolism or by a metabolic process metasttsls--In cancer, the appearance of a reoplasm In parts of the body remote from tha site of Its origin miscible--capable of being mined w'thout separation Into phases mononuclear--a cell having a tingle nucleus, especially a monocyte of the blood or tissues multiple myeloma--* malignant neoplasm derived from plasma cells and found at several foci In the body 8-8 HONS 025972 mutagenicity--the property of being oble to induce on Inherfteble chonge myasthenia gravis--a disease of the muscular system characterized by frogres- ilve weak nett of muscles myeloma--a malignant neoplasm derived from platma cells myeloproliferative dltorder--a disorder characterized by proliferation of one or more bone marrow elements nasal turbinates--the convolutlng supportive structure of the nose necropsy--the examination of a dead body by dissection for detailing the effects of disease neonatal--relating to or effecting the first four weeks after birth neoplasia--the process that results In the formation end growth of a tiaaor neoplasm--any new and abnormal growth; neoplasms may be either benign or malignant neoplastic--pertaining to or like any new or abnormal growth neural--pertaining to tho nerves neuroblastoma--a malignant tumor of the nervous system neurogenic--originating In the nervous tissue; forming nervous tissue nodule--a swelling or protuberance oat cell carcinoma--a type of lung cancer olfactory--pertaining to the sense of smell oropharynx--a dlvls'or within the tube connecting the mouth and nasal passages to the esophagus osteoporosis--an abnormal thinning of the bone ovarian--pertaining to an ovary or ovaries, the female reproductive organ In which eggs develop ovary--the female reproductive organ in which eggs develop palate--the partition separating the nasal and oral cavities pancreas--a large gland behind the sumach that secretes both hormones and enzymes Involved In digestion and me'ahollsm B-S HONS 025973 papilloma--a benign tumor derived from epithelial tissue parathyroid--any on* of four smell glands situated beside the thyroid blind perenteral--not through the alimentary (fojd) cinil, but by subcutaneous, intramuscular, or intravenous Injection Parkinson's syndrome--a disease chiricterlied by muscular rigidity, tremor, md sillvitlon particulates--composed of lopinte particles luring cherrcterlsttc properttn end itructuret pothoiogiil--in expert in the study of the neture of dlseiset pelvis-.the lower (ciudel) portion of the trunk of the body, bounded interiorly end leterelly by the two hip bones end posteriorly by the sacrimi end coccyx percutmeous ebsorption--ebsorption through the skin perI toneten--the lining surrounding the ebdominel cevity end contetning the viscere pesticide--e poison used to destroy pests of eny kind pH--the negetlve logerttha of the hydrogen ion concentretion used in expressing both ecidtty end alkalinity. On e scele of 0-14, 7 represents neutrelity pituitery--e smell glind nt the bese of the brein that secretes sevcrel tmportent hormones pleural--pertaining to the membrene surrounding the lungs and lining the thoracic cevity polycyclic--containing more then one benzene ring polycythemia vere--a disease characterized by an absolute Increase in red cell mass and total blood volume, associated freguently with Splenomegaly, leukocytosis, and thrombocythemia postpertin--occurring after childbirth prenatal--existing or occurring before birth with reference to the fetut primary cancer--the original cancer developed in an organism J-10 HONS 025974 promoter--a chemical that. though not Itself carcinogenic, serves to potentiate, sometimes quite dramatically, th effect of carcinogen prostate--a (lend tn na'es that surrounds the neck of the orfnery bladder and the urethra, ar.d secretes a milky field that Is discharged at the tine of emission of semen protastatltls--Inflammation of the prostate gland pulmonary--pertaining to the lungs pyelonephritis--Inflammation of thu kidney and Its pelvis pyrolysis--decomposition of a substance by heat qoorternary--containing four chemical elements or groups racemate--the rotation of an (toner that Is esactly cancelled by an equal and opposite rotation radioactive--laving the property ef emitting radiation (such as alpha, beta, or gamno rays) from an atomic nucleus remission--a diminution or abatement of the signs or symptoms of a disease renal--pertaining to the kidney respiratory--pertaining to the act of breathing retlculi* cell--a netuort, especially a protoplasmic nctuork In cells, such as the flattened double membrane sheets of the endoplasmic retlculma retrospective study--a study (epidemiological) that collects Information about past events that nay be related to the present distribution of disease rheumatoid arthritis--a chronic disease of the Joints, marked &y inflam matory changes of Joint structures ' rodentlcide--any agent used for destroying rodents salivary--pertaining to the saliva, or the glands that secrete saliva sarcoma--a malignant neoplasm derived from connective tissue scrotwn--the pouch that contains the testes and their accessory organs secondary cancer--a cancer arising through metastases of primary cancer B-U MOMS 025975 stdc'Iva--an agent that rtlevel axcltament or anxiety and Induce! sleep maU Intestine--th small tube of the Inteittna, about 20 foot long, extending from the opening of the steaech to the large Inteitlne tael ter--an ettabllihaent uied to icperata or refine a aetel often with accompanying cheated change iplacn--a large vascular lymphatic organ that llat In the unper abdoalnal cavity; It ttorea blood edit and produces lymphocytes aguameus cells--thin, flat cells ttoaach tuba--a tube passed through the aouth down Into the stoaach, used saaatlaes as a means of dosing anlaalt subcutaneous (sc)--beneath the skin systaaic--pertaining ti or affecting the body av whole target organ--the organ affected by a specific chealcol In a specific soectcs technical grade chemical--a chemical that has not bean purified after pro duction and may contain multiple lapurltles tastes--the male gonads situated In the scrotum that produen sperm thorax--the part of the body between the neck end the resptretory diaphragm encaeed by ribs; the chest topically--pertaining to a particular surface aree and affecting only that area toxic--poisonous trtthosl--pertaining to the trachea, the mein trunk of the systom of tubes by which elr posses Into the lungs transitional coll--a call that Is changing, auch as In movement, development, or (volution from ona form, stage, or style to another transplacental--through the placenta (the organ uniting mother and fetus) thraafeephltbltls--Inflammation of a vein with secondary clot (thrombus) formation thymus--t gland that Is located In tlw lower nect thyroid gland--i gland that produces, stores, snd secretes hormones thot regulltv the rote of metabolism B-12 HOMS 025976 tubular cell--pertaining to t cell, with t tubule er small tube-like structure ti*.----* neoplasm; a him of new tissue that persists end (rows Independently of It* surrounding structures end that Ml no physiological nit; ft My be benign or Mllgnent twOf1<)en1c--cuttng or producing tianort urlnery tract--pertaining to the organs and passageways concerned with the formation and dfscMrge of the urlnn uteruv--the hollow muscular organ <n female anlmsH that Is the abode and place of nourishment of the fetus vagina--the passage leading from the uterus to the outside of the fcMle body valency--the electrical charge of a chemical atom vascular-pertaining to blood vessels or Indicative of a copious blood supply vector control--control of Insect; and other organisms transmitting Infec tious agents of disease vehicle--the substance In which a compound Is dissolved or mixed prior to dosing an anlMl with that compound vesicant--causing blisters; a small round hollow outgrowth of tlie skin volatile--readily changes to a vapor X-Irradlatlon--X-ray exposure Zymbal's glands--sebaceous glands surrounding the external jr canal In rodents 6-13 *QHS 0*597? Aft/CIO AbFb SATF 1C W IF |M0 DTb CAA CAS CAS COC CF.C CFb Cl CUT Cbb CFSA CFSC CSW CWA DHCW IRWS DHCF DOC DOC CDF EEC CFA FAO FDA FDACA rHSA F1FDA FI FT WAS HCH HfOf hr ACDONfflS ANO AMbCTlATlIKS American Federation of Labor/Congrest of Industrial Organisations Advinct Notico of Propoied A1tookInf bureau of Alcohol,Tobseeo, ondFirearms burton of Census lorm of Oruyt. FPA bureau of Foods, FDA burton of bedlcal Dotlcdl, FDA burton of Veterinary Medicine, FDA Clton Air Act Carcinogen Assessment Sroup, CFA Chemical Abstract Strvlct Ctntors for Dlstast Control Chemical Evaluation Comnlttee, NTF Cod* of Ftdtrol Rofolattons C#1ovr Iwln Chemical Industry Institute of Toxicology Chemical Marketing Deflator Consoter freduct Safety Act Conswer Froduet Safety Cameltssen Cboalcal Selection Harking Croup, HTF Clean Water Act II.S. Oepartaent of Health, Education, and W*1f*rt U.S. Department of Health and Hunan Services Diet, Hutrltlor, and Cancer Profrtas, NCI U.S. Department rf Conatrc* II. S. Oepartaent of Energy Environmental Defense Fond European Cconoalc Cotauntty U.S. Environmental Protection Agency Food and Agriculture Organisation Food and Drug AdalnlStratton Food, Drug, and Cosmetic Act Federal Hasard Substances Act Federal Insecticide,Fungicide, and bodentlclda Act Federal baft star Fiscal Tear Sanerally becofnlted As Safe Hydrogen Cyanide Hydrogen Feroaldt hour d-i HONS 025978 iarclM0l 1 iris iv Ml mcl In MSHA MCI IKSHA? NICKS NIK NIOSH HIM NOKS NONS NOS rrocs NNC WTP OAONS OCW OPP OATS OSNA osw OTC 0TS OWN' N\H TCL PHS PL PPPA PR NCR* RAO RPAR RTECS 'OWA sec sol SPNO SVS International Agency fcr Research on Cancer Insoluble Intrape'ltoneal Interagency Regulatory Hilton Group Intravenous maximum Maxlmmi Contrmlnant L*1 Inute Min* Sifcty and Health Administration National Cancer Institute National Enlisluns Standards for Kaiardous Air Pollutar.tt National Institute of Environmental Health Sciences National Institutes uf Health National Institute for Occupational Safety and Health National library of Medicine Natlcr.al Occupational Hsiard Survey National Orpanic Reconnaissance Survey Hot Otherwise Specified Rational Pollutant Discharp* Climlnation System Nuclear Regulatory tomtsslon National Toxicology Prograa Office of Air Quality Planning and Standards, CPA Office of Drinking Water, CPA Office of Postldoe Prograns, CPA Office of Pesticides and Toxic Subvtances, CPA Occupational Safety and Health Administration Office of Solid Waste, CPA Gv-r The Counter Office of Tor.le Substances, CPA Office cf water Regulations and Standards, CPA Polycyclic Aromatic Hydrocarbon Permissible Exposure Limit Public Health Service Public law Poison Prevention Packaging Act Pistlcide Registration Resource Conservation and Recovery Ac* Research and Development Rebuttable Presumption Against Registration Registry of Toxic Effects of Chemical Substances Safe Orlnklng Water Act section soluble Special Pesticide Review Division Saybolt Universal Seconds >-15 HONS 025979 n xee TW W'Jk TWA UwSiPrAe USA voi. WHO ToborColotS* Toxicology Pit* Unk Tkruhold Halt Tilue Toxic Substance* Control Act 11n-Wn*tittd Ararat* United St'trs Department of Ajrtcul ture United Stltct International Trod* Concussion Unltld Stitif Abaraacoptta rolixa* World Hoiltli Orjanlaatlor B-16 HONS 025980 'JUSTS or hiASUUWKT Welphts f l( lb t pAp I ppb ppm Pgt >1 I'M 1 p 0.03$ oz kilogram 1 bp 2.1 lb pountf(s) 1 lb 0.45 kg MMlIfriM 1 mg - 10-1 j when referrlnj to doslnp. It mpent ag of chemlcel amalnl stored per bp body uelpht of tne dosed enlmtl Mnogrcft 1 *9 10-* g ounce 1 01 28.3 p parts per billion 1 ppb ugAg parts per million 1 ppm mgAp parts per trillion 1 PPt ngAp alcropran 1 up 1 X 1' p Volumes cc *1 1 m Ml cubic centimeter pallon (li.S.) liter cubic meter milliliter 1 CC 1 gal 11 m* 1 ml . 1 ml 3.8 1 0.9$ Ifqultf quirt 35 cubic feet 10-3 j it Lengths CM km centimeter kilometer meter nllllaeters million parts per cubic foot 100 cm 1 km ter 1 am 1 0.6 mile 3.3 feet 1/1000 a Temperature *C r degree Centigrade degree Fahrenheit 1* c C F-121 r f C C * 9/4) 32 exponentialS 10*. 10J. 10*. tic.: superscripts refer to the number of tines "10" It multiplied by Itself, e.j., 10* 10 x 10 100; 10* 10 x 10 x 10 1000. B-17 HONS 025981 C. Lift of SuHtoKii and Their Synonyes and Trad* heats* Tkd ld* alto Includts th* trad* naawt of "'> btcuil they cental* th* listed sutttanc* as a part of a later* of several chaalcals. 6-4 MONS 025982 lilt M tMI lNMnMINf|l|IH III! H-'l-l MlMIM. IM|| miiimm. -M>ftnia.|-n. mu IMIlMHNtlNMM Ml Ml Ml IVMI VIHMIMItNIIMIN l-HN*lUItMIN MmtanttMtaa nmMimii mm ttf-ii-i MKMtiIiMmititi tttu MMIMIMtl IMIt KltMIIIII MMMI (NMtin M*ItHHMIIWI l>M1MVMNHI It lit HUM lan mmhn MIIIMMHMII IIM ttll-fl l MMIIItl | MINIM M iflllMII M WMIUIIMMMM *I*I WUNiM M M.aiMMINlM II IIIIWMMMIIM M IlfNNWMNIMI || |-taiM.t,i.4iatMMa mi>MiiiwiHiimia I'MIN- uni Nl-ll|l| .MMMIMHM t 'MiaMaaiiiMNtiainti MHIMi MllltM MlI IMMItl*t 11111*1, MIIIM* InM IiImN,iiINIIItMIMl* > IlIMl|Mln|imMMtl|I|l M,l,*IIM|1ll|*MI>|N iini*mmiih mu l.lI.IMIllilnlMl MMI IIMlWIMMf i*ifiiMi mu Ml I tMI M Will MM MMMIMMM M|NMIIMI I'MMtltDtllHI NlitllMIMtlil NMII II IM'lainnimiminiai HRMI<MfWnMIHI|t*|*| Ulf ||.l|.| tciltfl Mil HUM MMiM|<Mt.MMlwiai.ni*M*IMMi>imtMtMn mi mMtiIiIcUwMnIaNnI III m.iimihi ami it It ei.t;naantmwii IIMtMt MNII Iviat MI1IM-MaiMi|ii*niiaiM aaciat'aUMittaiiiti awn u attaaaiaai mi*m m M HONS 025983 MMI Uil M-M-t HtH'mtMMnn--wlM'Nm.MIliiniximi HMN.|,|,4.miNU HMtHtlMMI m* NNUIM MW ttUNtl NIHflUl H MMMMMMIITNttIMIIHt ,%. mm t*w *a awiiwt MUM mhiw a mmaw at aw MWM MMtM aawi iw w IIMW1UI a ||H tian ttiaw witawi`1 mmw taw mmw aawtw H IIM|| MtW HHawHimWm*aMi* MrawtMiMH wm waaimi naaa.aa IMtIW ttKItmi .III ii*it'initunaiw. i-mw- .Mu It ifti ia-ia mim ai M(mllUantl miMti w<a*m caaaaw aai MiattM MM* MI*tW I MINIM n waatt aiMMM Mtaactta i>h( tiaaia HWMIIIIW ||| U.M*t a*aiIMW-wMiMIIWiMIWU (i.MMHwaia*tiwwnfiiaiiiiai aa*aa*MkftiMMM IaMawIMiaCwmtMaI.llinamMiWmiv* aa*-- m wiumnumm mw*miiiw aaaattwaaiai <* ii4.|t.| I'MIMMlaMI MNMMNIH aHi.aMMMiatM-mM>iaMi*iMMmfic*aintwMHi niatNitMaiaMwmatiaaawiaLttHiH aitMMiinMM avaawwaaiaa na.iii.himmimt . |.MWif*. waaawaataa twit tut mi aa mm iwwiMMawatiim tatnaaiaa aar--wt--aaii iw aaaawatNiw aintwwnniniMW aaaawwwtaa Mi*aaa i mi na-at-a waaiitat tawiat MMU aaa*iftta aa*aN HI<MmNINIH>MriU|IIM lUMNHlan mill* aa MOMS 025984 H*Ntl>WnNMIIMHNWH lCMM*mt*M*fttiitIiiKi nIIHunn chmmimvi WnMN'WWmMWIWIutlMonUMMyn !(<u--iMtINi | lr(MM * hi ii.m IIHMMIM HIN'IIK I IWiah. H>MinMIMIil*l nmhi m iimn Minn inmni MHHwImHIn HM-M-I mu MMMI MMI MMMHI MWMIl mil INM tminH mwM *mmcmihmiicimmimmii imi-h-i MUM Ml* WHIItM hm*h mmiM wayi*t iiwi NMIM HIM IHNII 1 VMM !**! * HIM mini f*wmiw MMMI MrMIN MWN KMIHNi Mill INK MMMMI MMI|M HMHMMMIIWMHMMMNIM. mil * MMMMI Ml* MMMI MIN IIMMMI ttlNIM MMI I* HIMMMI MM Kit miimm mm mmummm umififi HM IM"U |l*MMIC ttIMttf Mill IMMII min* minii mi t'at<*j-i *!* Ml* |<!*!| , nmw Mil ||.|| (KII limn itimii IHCtMM MIMtl ICMIlHItfl MUM miMIM. Mil* IMII IHIIM MIMMtlMII UKlfMlllMl nti'iii c*t*CM *% liHMia Nit HUH lltl III* HIM* INCH IMMH Mli'llt !!!HCIMM ItSIMM IMIIW IISINlia nil IHII'ltl (Kill ta*a initi MMMi*i urn iiaaMt *aia. iittiwi mu imi imii mu ihcimm aattaifi mum lamni. mta min MMOitna iiimti MMMI IIMIIM MIMlI UMMH (III <* ia*tii imim miimii t*Mt MUM Mlllll.lMllilMNIII *im*mm ki laitMic, Mriuitaiii imumm. mm*i UVUTt, **tMfHIII iimim n*HM miimm hmmmii miimmiii II1MIM MMMtMMI IIMN'I NHMiMlII mmmu NiMiai itaiMti iniii'mi mmmiimii IMIM MN Mil. mhmmiiii Mian laiiNirt. i*tu, |iti**ai(a mum aaaiNifi MMiatviiii MMM MIMItll in* tnntii mi.i.i <i* in* MMMti Cl* in* *atM*iaaiMfi iiMtt *a in* MIIMtll male in* iau m >MI*I in* act* imii Hi* mumh III* MMMMI mi* IMII M*n* II* Ml HUMMil|lll* Mil HONS 025985 o millMIIfMMWMUMHNIIHMUUllll(u?'l* -*i # iiiwh mm. iiihiiw mr vnvrIttfliMf MMRi*Mwmii MWiHin iimmw < WHIM Hll aniHH HVMMM MMMII IWIItMl ifllHW IHMH. WWIII WHIII* WHMH, mil IH" MlMtIWI IHIMIIIW HMM'I MV MUM IMIMIM HHnil IUIIWI HUHIW MHWIi MHMU M*miH IlKHf HUMIf IUItil1 MlHUM HNMIf MM M*,-ll*l IMtUttV MM IlMMII . W<IIIW Mil IMII MMMi Hlli MIHMM IUI IHMI M**** MIIIIIM HU IHII WU`t NUtlN m mm MMMIM MMM|1 MMMM MMM'I. INI INM MIUUM MIXIMDII MIM MMMIt Mil MMI-I MfNlP MUM MMMM INtl MtIM MMMM IM|M*t*l MMNIIMII MUM MMMM IIHI MtIM MMMM MtUM IM*Mt*.fMMt MtIM MVMtMMM MIHii MIM tm MMMIM Ml MH-M-I HIM * MM Ml* V IM*N II tM* MMMt tll'Ml hum MMMMMl N>MI MUM MMMM MtIM MMMIM I***) I VMIM MMMIM UVMIt mu MtIM MIMIMNIf IMIIW INI nil'll'* IMVIIIM IIH*l MIIMIM miMHIl* IMI*IMIM*I mu *; WMMtllHI Ml iittim IIMIIM Mil* IMIIII *IM< IMIIIII MUIMMiIiIi Ciimin IN l|Mltt until* N IN MIHII > HI until* M emu* ii IMVMVtl I luniiiii mn iihi (Mvttfltl |MM*HllltM| Mllltllll UHltM CltCItCUH utiittniv iiMi UMIMtlllt II I HINMINWIl1II MtMl M.l IMnillll IMIIW I Ml IIIIIIMII nttu IMMIIM IMMilM IHII m*h;m nwwwI m ** |*I**MW**CIM MV* M-M-l 1.1'MMMMafMMVM MMMIMMIM I.MIMmMIMIM I.MINMIMIH f!*!*KIM ||(|*U<WINIII<lt i,MI*lfHW,IIM MN|*Mmil l! lt* l.mmiiilH I.- MttM**MItlM I. *M*MIM MWVIMHNI*! MIUIMM HONS 0^59*6 Ml NXIH <N1I iMminmt* Mm M*M<I NaNIIH ihmwh M itinrw IMM Ml ItN NNIIM imMIIIIHN H4NIM MMtM mm imm NMIMN iNII wmm. *.'*MM4r UNM iI.fIN. MMHmINmMiiMMmmm Mli*.IiN''^IiMmjii9nWInNDiiHmmiimin M'.imww MUMIHmuMNDC IMI IIHI-I Hilt yiHlllllWW NMHIKtNMMM* HMmil*ilfMHMMIM 11 HHtMMatMM MitHl.iMuaiMnni M-MMVINMHMI ' if ii.M'NMminMtMiii IMatM I.MIMMI || MAI* MMt*MM Mintl.I.IKMtHX 1.4-MWMtMM I.VNWN 11*11l**4l*l Ii..MMIfIiIimKtilMlM Mimiw Ml (HliM llimira uw NiiMMin cm uiii*iM Nimmic <*1*11114*1 iiimm Miifict mti n mi cm iNHi'i Ml** 'toHimilOII can iMtt imi Mlainnttitmn mitmmMmiMmimiiimitart Minn** mmn titii*t Mann** cm *-*<- HmicmmiMn .f MTMI** MIM Minit** MK1IM MMHM III Mtnii** mimti iimcih Nirnna **M*M* NMNITI mwi n mil mniMi mi ii*i MmitJ* mtlll *M lltll-M'l MIKH MII. Mmil** MU #* Mimii* aim at*ita cm* * Minn** lllltlH aik iiimiN mtciti .*-Mt<t*mMMta*ii-i**M*nmufM mi* *mmi iH.MIMm!i*ciiMNnm-i-uMnmtfMi Mows 0^598 (HM'ftMmntw HMNWIMM MflHI m mi mWMIfffWilttlMI Mil HHW MlllMIlMIIMIMUHmm* hmSSSnSm ni mu MV% * VM. r.MM_W____m_i MlMMn (Mil m* wimmuhi unn mu iMMn mHUuM *mi Mnn I*mi IMMM Ml MltiM IIMIM linn--II -------MM.m.mmNw*#***t MM MIMN *M MW umim iimnim NM IMIIII MM II1M-H-* IMMMM MMWM'I nwi-- mm* IIMIM miMlf miM mm. MMiwini mu WHIM MM IIIHM MMl MUM l.l. nmn Mini II t.i. iiim*i mm it I t. IftW UMIM WIN* IM MMMI IlW MUM lit UMIM MMIWMM UMIM mitlM UMIM tUIW IMK. lift MMIM MUM MM. MtMl UMIM Hllll IM. IMM MMIM miM IM. IIIMMI umim mm um UMIM HUM M MM MMIM MUM MMMMt MMIM NIIM MIMM IMIII UMN miM M UMIM MUM IM IM MMIM MUM Ml UMIMI HIM* HUM mnui hum MINIM Mill U*M MUM Milt MMII MUM HIM MUM NIIMIIItl m iiiimhiiiii mii m-ii-i NMIINMI IMM* MMIM MMM MMIM ICtMl UHM Mt IIMIIMIM IMM t*IM~ ------------------------------ MIM ihm in MIMM ntUIMMIM MMMl, IIIMMiMt* MMMMMIMM It l*MI IIIIMMMMUM . IIUIMMMMIM iiiumMMMMi MmriMt IIIUIIM lUtiiM* mai 0259*8 HO NS wwwww mi Mimi'MMIMlI IMtWIlWMHTMH Kl MM><MNlhmHMMniH(MN(anNlf(IN Ml# uitim wnMmnwwiwnttt>it hii IMI fI>MiWHMaimiMmMiM)rtwnN|,tnit mu u mi imhwiw Miwii*i*iiminiiwnM*wwmmMmtiiffllmMil i*m*it*iMU*MiHi>MiHHHin nmn kii M4timHHHWI`IIIMMIWN|IWUWIH Mil IllItIMMHti tMIIM IIMMRMMRIIMM rci-OMM Ml-MM MWIIHMH Mil MKRII MirMl IMI *! IHHI'MI IMtl f >RR|W IMtl INI M RMWIt MMHMMIM ... J. lllfMIM* MMMU NNMMIM MMn NKMMIM MMIIIH IM if iMrmnaNfi KtllM IIIWIM HIM ttiimi l*IIIN nMMW HIM MUIM HMWIMtf C MI.MMt IMHHHHWUMINII1*1111 (.1* Mill I.* Mill < Min MUM NtMMini HtMlM MIHIM * flll*M*| INRII Mil ninu IMI Mil mnn mi. mu RMII Mil* Mill IMI I IimmMunMmiiI hwhiii nHMmamiMiii nut CIMMMMIlnMMIMIMIMIM (Mil mumh i*i (inm mumj'alliMinMnIiHMIMMiitiM Mil WIMMI cm# im*v*| Il.lI.. HlltINMH MUM H *! IMMI MUM UMt l.l. HIM MUM MUM l.l. IMMI MUM MIMM IMIM MUM MMI MUM I MUM MUM II MUM MUM If HUM MUM IMI till MUM MUM MMI MUM MUM MIMM |f IMM MUM MUM IMI MMM MUM MUM mi HM MUM MUM IMI IMMI MUM HIMHI Mil IMMI MUM MIMIM llll MM MUM M MIMIM MUM IMMI MUM 11*1(11 IMMI MUM I IMM MUM IIM MMII till MIMIM m*HI IMI laIMMI lM| till wmimi IIIIIM MUM IIM* HUM ntll MUM HONS 025989 I'NMNnMRwHfirwitpIiNwinIu*<wItK ** NINiNl UIIMN*NmM9wMII mIINnmItNn** mIMmMUtt iIIN'IM innim iIiInINmMinN mNmNmmMiiIiiI Ii*'lnitt*l* IIINNIMMNIWM <N*ltNl| l|HI am ml.tu.mHNuIWh tilhUnN>iIhI im Hum mi him mitiM m mi M*cnttm iii-n-i HHM--mm nmi imi |.WNH>NNn>tHNI*UMtlM Hm'l*NNNIINMN MMmUti'iMi-Nt uanrnwttimn-i ikii HHIMMINIimIH. /' n ININM ININII INININ . tHmw* t-m mum im (NINN'I'NINI lUNMIH *.NNNINNIMim it<NiNN*iimN<HNi mtmim mi NMIMN *-*i!iiiHiMW**m>wmMMiw**wNutMmMinmi--mimimiwmmt i MiiNiM*mwiMiNinwm ummim mt mm*mmMNmIIumHH*M*'-KmNiIkiNumiiIN*ilNinliitlllMNNNIliuHNI 1NNlllNNNWMN NIWUlN"ir"" M.M....N....I.I.I.Nt.t.MttIM niimi'iN'iiiNimini-Nii'MmiNtimiN immMHl*MUNM iN ut* ii-u-i IIHIH mwiinHwMiNmiwwNt)iit'.HWNUMiMnmin acts i iM.mlmIHuINmIIi|uMM|lln*NMli>i-iMolmlli>*nuttu**iNuNrmiIIiMn*i*MHK<mN*mlullnnNia>| tH.MNN,mNuIIiiH* it t->.HtaHMmimitiiiiIHiitI-i-iIwMNImNmiiNiItNIiN--i*nnnn>!>*i*-N!-i'fli*iiln-l*n*mt-ii-infm**haiin-n.fcimwwnmitmohnn.mniMiuHn UUMiNM*wIWNmtNHmNII*nMi*Hl|*l-I.MNlMI*WtN imiM t-ljlll mNN**ntM|N>t>IN'l-N-MNNMNNI>m *IIHHIM.WmMuIli-ImMIImIN*wllIitNM-.uiHwiNmiiNiNiNiiiMNMNNRNNiwtiImNNnlnnNlliuMNinuNwiwiMiiuiIuNiHm. m-nwii-Nlil,im.HMI-Nii.iHiw.HIuNMmNWiUiNNii-NI H I(III HIM IM-NNIIHI UNI N .*IHMl*INIiU nUNNNWuNmIUwltWi tH HU *M**Nill mmHiuut*------------------ (iiinmmu l.-HIH*llNUmi-*.MHmiN-lN**HH (HII|.|NHNNniWIIM-'MI-> MNWiWNltH.NH'I*|.IU|iH|Ml*li.iif|INMIMHNHIfNWlN*UI**iMUmUnfmlNM*miUlt*l-IN*.lINNNWIN HIIMMII Hit III! m|NifIMiuIi M HOHS 0259*0 IKIIM NWIU MflU MHMIH HNilM Hmwmnl IHMII U lM * MlfII....MWttl-..MIMMMMWIMtMMfIM* I4MMtNMB*UMIMIOMMWliWt''l l I.VMMMMIHNNHfMVItM iK.tm.MmUMMJHUmmnci IMHM MB MMMM N MNMMMIMM M*M t MMtf-l.l-NWMtlMIM MKf! 1 WW1WMMW 2J^ . h m M|MM* MINIIM MM MB n IM M MUM MM MIMM (Ml M Hi MM MM HUM M( m-mmimihmm Ml* ( INK***BMH*IMta > MMIIM* MM C.l. 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IWUMtlW lt> IIHHH HWWOWHW mm * MwiMlHuwmMmnMwHii.i.MuI'MINmuIMmufnlWwtmM IVMfQW *w!B m rVMIMt Ml HHNM imuil IMt fWtMttl NMtM n i|tr in m , l-mw-M.iiHM- MiaiM Mf lMn*MIIIfH.NHHN'IIIUHNMI t*M| t.HtMMIfUlf Nfl mwih m IN-II --HI IINtwVIlINN MIIMNNIMIM itaniai iinnin ini* tvctt Horn NnUniNtiMiim*mim NNNKf>itH|| III nnnw NIIIIN HIIINHI HIIIMN-II HIl'Nt NtltN NNIflN. IKMN- INII milllN. I.I'-IIIHIN- mn mt.ii.nuiamr it* l.l<-IIM(l>WIII||IIN HONS 025992 m....m...m...w...t..w..m.....h|n..i<.*|--fl i. r.imM*M.i>.itiiuMMir*Mn mummiwn IMHMrWNM I.IM IMMI MtNNIN IlmiN MlilN wmum mmim MMM IIIWIM N'MI. MiM*IHi|il'IMII I.I.M-UHlIfNIMI . m.**MMM*MMM . .MMMVWfMJ iiJNtfIMIM IHMUMI MININ MIlMli 1,1*1.*-*#- m.ti*M*tM<lm-iNMniMiinMiiiii.im'Mi* imM*.iiiiiH> Niniii miMNmatnii Mniiui HMltt IN IINMII l im*lf*nMMm****** III NimniKiHi NiMiitt MiwiHmtwMMUmtliiflwItiMntun I'llf-Mm NHHUM IMIfUH 'H mn*in Niiniri l.lianaKvi Niaid'i nmni m ii MIIIMl MINI IN INNIII IN KI.IIHII MUM Mill HtUUII |*M IIUIIIM M NIHIII Mil. 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MM MKI II tiiMii mki ra tan mki a |*|| mki M Mil MKI IK Mil MK MM *11 MKI HI MU Ml till mki mi till IIIIIMM MKI I Mil riMI MKI if MMII* MKI Mill MKI H IIUMI MKI I IHWMIM lull 1 HMM MKI | IMIII MKI If IMMI MKI I* MMII MKI Ml IMItl MKI fl IMMM* MKI M ihimm* met riei t met mm mki VIM 111111 MM MKI II mil Mill MM MKI IHHI IHII ItlfMI MKI II HIM lltllt MMIK MKI Ml tlllftt MKI II Mil MKI mu tmet MKI II MtMl IMMI MKI II MHMIH MffM MM MKI WIN MM MKI me mki m mil iim * VMM MM MKI I IIIIHM MKI I lUMIM MK* I NIMIM MKI I KIIMUM MKI MM MffHM MKI IIMf IMN*M MKI M IflMIIM Mid | miUlH MKI I IM VMM MKI IV VMM MKI Ml ffiiniM MKI I VfMMMM *IKI |M HMflt MKI IIIIHH MKI lilM Mil MKI I ONS 025997 niinihki * MMMMNMMIt*toHto m IH* NKM MM iw MM* MW ** (Wit MW ft M MMI* MM WMMt MW M f#4W MW ft Miwm mw w miM MM It MfMf| MW ft Mft MW *** t*M# MM H*-l MW* tow tt MW ft ttw ft tu< NMIIWM MW ft UUIMM l(W ft IMM--*M MW It tWM.fM MM t tWt--tM MM to WWM IMfWt MM ft t.l. .. MMft M(t MM t. ft! 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MUBlNS>SHTHiw MmwMiiiiImww.MiimNii'Nimli,iNMi(iN*wIi.MiItIiH.MI-H-Mnt*W^imti(iNiNlHliir4wtWitimmWiwnli,4K.Mnl 1.Hi4I(NWn-Wt-H e mmnwiw*mwimmui.i.i.im..i....m....m.....i..n....t.....m......i....m.MwIMI-6*KN m ommimmm.M.iiw* mmmwiMiMmImIMHUMIMM mmiw i.mmin* mi NtnnmHiiwiiN*<MinwiiaMim m im mm mikhi mi mHmIM'I-Mi MIHKHIKIMlIHNHHIII um mi t.l- i*ii IIIMII IM* Mint* itu Klim UK K*mi mtMiii UK MUII IWIINMill UK NIHII IVMM UKiili Mitra iiihi*i Klim UK VIHIUII UK limit MIUII mm uk mini Ml W KIM* IMM W UK uii Miiinii ut* mi.|M (III lINHNitl lml*ti HmWiHfNiiHi mil (III ININitl IHIHHMI tUiKll NNHNNMI1lIII iHiilt| IIKlIO MUMIII NIMI till NMMHNIII flKMM Mttlll hMM taiimti tllllK MKKull IIMMK* lMt|n !**r*KMIMMIWM M| |TVM MlHlllMtmMIMI IVMM II nr*-MiiinMMi(irin*i un ii|-#6* um<imi>i MmmMiii NIIW HuniMIN>lllW>ltlMI um>M miMiHt. unm.i.M.i i-HumiHlllimiMI. hlM.M-NHInm-. M**ttitlMim. 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M**t*IMt- lil'MlIHMillM *.!,.*.. NIHIHH-. Mutt mi MM .HNHMHMHflll- m ________I.Hu>H* NIMNM Ml III HHIKHHMHWHH.I.Hm.M-IMmiWUHIIHHmH MHIIWWIMIHIWIIHIM m *.m HMtMKM M IH NMHIIMmMMWIlN IIMI M>M>MMMMH-l,t'Hlll/lilllltN IIMI mi im Ml-Mtll* ItHMIMMIHHIMIIM . HNMNMMMHIHl.I.MIMMlI'tMIMHMIM .m. IHiwMMMMMMMHt-ml mnH HHMHMHini m#IM IIHI-miMMnrtMNIN HH.HiMimii'ittn*MniM lMlf,.>HiMtra'*rMMtnMiwW>Mi IHIIti*iiNMIIN ll-MHIMtltt MUM MUM lilMMMIMMn MlMM M l*M iwMWr mi* mWIiIlH M MUM*. M*N MMII VMM _ Ii<*HmHtMi*iTMi KMIHUlM* MMMI ItlMH IIHMMnMMnt II MM MIMI MM MUM Ml MMI MMI MUM MMI i.t' im ii*imiiMMMii I'MraimMiM t*i tt-tt-i mmiimmmhm l.|. Illll MM Mini* Ml tt*nu*fM IMII iIt'HnM*n>ilWM MIIH mil HIIHN, *11*11 M IIIIIM IIIIK IIM MMl MM MMM t.i. *m *1 IVMI I IM I HIM I HIM IIIIMMI M-MMf IIMI Ilium. Ml IMII IIMI MM MIMI It! mP-ml IVimMI miiii MM* HIM MI*M*ltM/| IMI MIMI Hllill III! Itl-IIM MIIII Ml*, *11111 IUI mimi mi *tim IIMI UMMIV* MNIt MM IIIIMM i--MIM MIMI MMII IMMMiatMMM HWHIH *|IM1 MIMM IVMI *11 M*niM HtM'l <atla*IMV*lt IIMI MIMM1I MM IIIHM Mill *11111 MM*I* MIMI (illHUI It'll HONS 026003 Mttlt IUNMII tauttl WIMIIII MMMtl MtHMI'l WMHN IHMIN INWMfl tatttlt WtMM UNMK NjNwm uh tmioM mm iMMMt ittn mm lUNMt mat atttH tmaij iimtin tttit WmIuINiml VimIIMnMmUimVt It mWN UM SSSil"! SSS8 sanis'. HUM ItH llll-lt-t MMlINMtMlHMdli MMI MN1MHMIIHII HNMUWtMlkt.iNHNmW4IHiMINHMIlHINM.MMlintmMiMn*mIKnII .i.nt(Wl, IIM **------1 IIH (HI M-l Itt MM INM fl-l man hihmwimim it mNaMIt MMfHMItI |MMI mm mam itm wwmi mam itMit*i MMttt IIHIMI'I Wfllt IIMI IMMMt M'l'l ivtawit act* aiMMilM mi mmit Mil. aMMtllM ||(| ||M imitfitKtm mit mu iiimm Mint Kit. IIMttllM IMII MIMIIiMIIII Mlt M.M>IitiltiiMiMiMiiniiiniM itmim i iKIM. .MtiMMtavaiiafti- inii aMa|tt 111 Kit MMtltll fifiwn i IMMKtUWIt Kit MMUIUMKIRt <M it'itM* mm itifit-t I. -ilMtttl MMMM* IMMtK M'MlNHtMin iiiiMnun inii t.wimmmtm Hutttatan ttata *"*tMMtMtf MlflMfattat I.HUMWIlm MIIHWMIt IKII uiMiMa -aittt*l'.*'tlattM'at*n li*M Vtntt>I.MNMIMIIIMin IIMt tllttMM ItHI IM | Itt 1*11 IK-1 MOMS 026004 MtMtai H*nn INMM MMMt u MIHIHIW. IMHMm-l-aim- 11(11 WMI ilM# HMMm *1 t.l. HIM Ml-MilUNMMI-tl-llMIM-l-WW--1M I'MMMVHflllMMHIlfft >*1*--tw Miiw-wimiwnni lMIMlMtMfMllla t-wnm* MM MIMMMMtn Mim MHINNINtHMM NNMinwMHMM mi m-i< liliMiMimni KyiciuM-- MMMMNtIMMM MMNIKIHIlI.Mr M itMNi, i,r><HiNimMi` (l it MU* alNNUMIHMMM MMMMIMMMI WW Mil m mmmmimmmm MltlMNHMflNM fill ll-ll-l MIWnMNM( HMM- (MU Vt* nmmiiHUMiiK litnuiH, a-aitinHiNIIWNIIIWt MIM IfHM-IMlUMlirt a-aifaau-a.a MltitiMlM nKiHimintMiia ** m-u.* tlMtuviMtafi i-hiihi- imii IfNNnillNIMIX .IIHiniMIMIMIN IIMMniltllMMtN t*a|1MM-.<tM1aiUtMt NHIIIM ('ItlMMIMniMM (IlHH-i-NIKUHlIMiim MNHIMMlillMNlDIM lit lirMnuani. miinh- inii IlfWUMtlMMM I.MHNHUIHIMWI M(MNimiimniinn -n(iMinnwin I* l-llltM-a-IIMIHI innitniNNit ctan->aiiM-t|4 a-tan-a>altMtaaM HONS 026005 >mii MIINIIHi-IMHimi (If* t(*ll-f WIWWIMIWUM Mi HWIHMIIMHIH*I miHW'l wiwiiuiwim Mniwiwnwn HIHW'MI MilMl IHMfJM* I MMt HMI* MM|iI.WI'MI wn.i.amm- NO. imii MttMMMnniiMumM iw ni*nMM. mnn*miMw mikihmitw.i mawmm MMIWI MHII. --I.Wf MIM MMItIWtMIIMMlIM MM l'f|IMMM>M1IM*IMIM MWI IMMI*|, fHKIfl-l-MIMII if(|l NIM IHI MHHMNWHMM (*( HHMM MINIM. I*Ml**!! -wlIIMI- IHII -----*-- ' --ItM-l'-MM'lHiiM*BMiim HiMM___ _____. IMMNN-HIMIflltUlMMlIIIHl HIMIMM'IMWIWlnMIXimfl i niiMMUmmm i im-ii- M|IIMMflM(l*ltl mi 114-H-t Il-tH'fKIlflIlHlrilMlllil *11IMMOtllIM III! Ilt|-|.f WWIM. `imi*fllllltl. -*M|tMin*-M.|-(MIIMIIIIHM*.I( tfltUIMMIII*lliM< 11M*M| IHMMfUtMIM UMiitin. (tail*- itc 1 II* MMM(|M IMIIHM MHfIMM twti *.l. Ml |!U|<| MM i-fiiniwiMniM.iMiikminwifniiTiiiMtiM HtMtiMIMMHr*MNnllnM|f||ll|MIM iuhhiikmiumi miium M'HIN HIHtMH IHMIMIM MfM*MMM| lifllMI Nnwiui IM* *-*% HONS 026006 Mt.MtlMmiMrA, 'I.IIMiMlatliil MIIHIIHI. 'MM* 1M11IwM>'iIMHiX>mIItliMiniM mhunhuih KMUMMIUW (Mil muiniiiiiiin l>HINH|l|imi| MINHMIIM Ml * tit it *MUC H IMHMtfHttWIII* lII4HNIMMI ICC -ItaWfMCtMHIlM IMWMM1IMIMM hiiiwiiww iiiimi Me HMnwiwmimni rtuMiliM fl*M 'Ml M IICIIMl Miitin M*lMCI t' IWtll KlMlC men I Ml CCfl MMItIC IIMII* '*% XNIWMIIN IHKIIIMIIIIIII* MIMIIII IMIIMM MIIHill tlKNu IIIIINI mMii CCUtt| niMiitiM NIMIItM* Ml Mlltli niMNti nee IMMIItll NIMIfttM IMNIIN MNMfICMtf. Cliff llN*l IMHI IIWIII IIIMMItMll II INI llllIKU CMC IMlill IfNltlll ixHtm-M ItMINIt HONS OZbOOl IKK tIMNIIN nOMMIN l-l MIHIH IN* *<UIW *14 MIIM IHNM NMIWHIIIK IWMitHH imttIliftlHll.lMt MIMMtK*HM (ItMIt MiKMmmWI#IiIwhmMmuMwtl MMIIWiiillmMmIt MnNHIlIlMMllftMU MMMNI IMIM4 MIMUM MIMir MIMIfltl Inilni l*IMWMl>i 'Mil IIMIW MIIIMtl OIMlil Vlltltt till Cltt ||.H uiMta MHI4III llflilll IMIM MMlIMI* HMMMtaImllll <UWU<1* (IIMMIMW* IMII*| IMIIMM I*m IMIl MMMt *MM IMIIIMI um IMIIIM UMt *# ll<IM IHa Umi (nlllN KIMIWI-IN'II* IIMMM mniN IIMMII M himhim IIUMIIR HOMS 026008 MMIMI IIKNt MMIHII IIMIItl IIMNMW iintmniNtMt (HIWmiHItMIK iiMdnn*4Mti mim j.Mi>wMinw>ii* imih HMMwtwma mm' iHHmmMWIIWMM. UI HHMI lnmii mm VHHIMM-I MM' MW W |M*'M* MWtinM MMIItX MIM MMIMI VIIMI4 itlMiMia NIMaiai atNaiii IMIIII I.MINMI* HI> NMaiMM, |,|.|iman., IMIM Mir M"**>n' *** kiiui iimi tlai|| IIMI'K limiiRM IMM*l IIMItM IIMIa MIMM MHitm m*MMIM*l NIMIMriM m IWRIIIM IIWLI OHn'MiitM VIM NiMaiu IRIMIIM nimiik MIMI'M MNMIMN-I*4M mwiwi imin 'NINfftlM MtMHINI IMIM IiMMaimfMi liani, IMa IMMMN MHiiia IMMM liwwimwilia IMIM flfNIMI NIMIIItin IMIM im'MtMMattlMM miM i.!(Nn>i.>iaiamiaiM*iM IMIM MNiMINMMMM MM l.l'll <*l*i|in|Mllini| IMIM latainia IM MH in IIIMIII* IMwm MlMil KKattllk HMlftlC * *QNS 026009 hllHMWl mi* mituii IKfWMI MkliWII HKHWMNI fmNlltl IN MnHtlll w* UM HIIMI'l NttHM-MNINm MINN mvmwiMtit MM*m ui< hm-m-i MMIN mmim mm mmim mi MMIM MM MMm MM MMIM mmim MmMi MMIM MM MMIM MM MMIM IHI MMIM MU IWHII. IWNIMHI IHIM .(MM tUlwWMMNI MMMIM MMIM MINN MMVHM MMVMM IN **M ( Ilf MIHMI ftl MlKMNhNIII IIMWl Ml KMMWINMI MMMIIMIMt IHlMltN lnltmlHHM M txfMIMl M-i *|i ! nMiMiim mi ... HiMlM `11-Mlavittom-l'IM-HMTXviWVMMIM'Mlani'IMII IIINMNUIN MMMMI'llMl*I I'Ml**l#*M2IM*l'fM*M|M M>MM*IMMimMMIMW>TI>lM IWWMIIIM >ll*ll*M*?M*ll*Mtt**l l*-IMMMUMf**MI -Mian M*r| nrNUMI Ml !*MI MMMNIM lll IMIMNtilHtMMiNM>W*`iMi`MWiNwuIInIn* i*lll--niii->liwnitMiMfi' IU IMMIMHIUUN IIIMNIVIIa nMNUNIM UttMMllM HMWMMIM Ml MMNMMnuHiNmiMniu-mwwwmM xihmmim HI||NNtlmMMIM*l|M-NWMMIIUMI mim.iwih Mwniin>i-ii-MinMMimMwmiiMiM mhnmnin mmmnwiMMiiiinnMUiN>`i-mMiHi mmwmmim lllRIMI MI*>MIV|*tNillMMMni**'INMNUMIMIN MMMMMIH i>Mwn-H-mMMiniiiiiiio iunmniiim itnnhnin 1'MfMlMMf*tlM*MfV%CMtMf4M*MlIHINJIN IIMWMWIM I* MlMM MIMWl NNIMINI >** flNNMMIM NMMHIIIIMIII N -* MU MMWKIM III* It'll'! MtlMM HMWNMMt* l -!- * hons 026010 MIIM iMUm MINI! N4IH *M1 tIHWKtMH MMMHtw NttlWIM IMWII MIU<M NMM*W WnnMuItI*HMIim'H INMMWN itMmi NNW'K NlOllhl MNMaHI IMWM HlWIil IHHMM tlMMtf HNm IMHIIIH IM-HMI IHWIM IH'IIH IIMMHW IWMI I M MW( I* MHIMI Ilf fMtl nrililHw INIIII lltMII* IMIM,t HMUt'CMlMIM III . uiftiir il*lilta IHItlll ui*li|*llli ! MltllMt* ItMIMIM MMHIWI* NlUlatll Mllll IIHMifl |.i iltmi |t*U * i.<,i1.H-ltIf|Ma|IIMMMiililtWim||i|imMl* HIM It-HtltlM Mimi UNItll CI>NI MM'UWIl MI-MIIIIMH N**lM!tlllllM WIIOMf MIHIMII MKII NIWUWIU millllM NIUllHW NllltMX MKU*I* KMW HIWOIIIIIIIIII mIMMl* Miinn HMHIM KMiim l>MH IIH*M!It HlHIH I HUM MHIIH IMIIIU HIM' HONS 026011 c-ao MtMHt tMiMWlWfMMhHI WNttW * NMHI NN'IM MMMtl HMNIi NNlrt* MUM NNM HIM* NNt> HHMM NHWMN hnhui MIMMM NNMl MMMM Ml* Mm Mill M.t limn MMMIMM NMMli MNI* IiiIHNHIIInMw HMHUWI-JI.I HMHMt IIHifIM Mlll< NIIMN HIM IIINm NIMIN MIMin IIINIIM nirim MtllM (IIIIMI IIIIMI mut inciw tnm NtfMH III! IMIMtl tmitMK tMMIl IIIUMIIM IIIMIIWH#IIIMMI uIIIM'oIlMiuiimII imiiH IIIIWHMINIHMM mmii ram iNiuiM IIIMIIHIMIl I MliMmaitmH.fMtMUMM aM*.. I MM*M#*MaIti atlMI Haul lMIiIaWM**MiaIat t <imm lilMMU HONS 0260 U MMtMIM UMMIM 'Mllllt' NNim N<*n HHIllll HIMIM NWM HMM tM****tm*il IM'lftW Htnn UtlWIi UtMII HHM NHtllM Himit HlltH M*tM M*M*IH mim imM#Mt niwi iiwk mitiw ImIIMHHMMK Mill* WIIIlKM MHMIW** IMMII MMMI* *-- mhM*I'MMMMMMM Ml* M>MMIM'IMM*MII>M l.l>*IMIM l<l'IMIIMi|l|llll-l`W' M<IIUIM (Mil 1.1-MMItMMUmiM-l-M l.l-MMIM I. IMIM llHH MIMIM l-MMIK l<HIMIN fattl* NINWIN < MMIMM IINIMINN MMI.WMMIM I'MMIHl M l*|M 1-tot mmmm HMlin tMIMtll Mlltin MMMIM I'lMnifk'ltIMIMIMtMMMmi M-lllMH-MIIMIllltMMMIMlM I. >-*lT**-l-IMI|im<MI*MIMI t. HMiMt-1 HMMIIIMM NIMNi I IImIMutMl *$ IMIIII BMW *** l*-t-> 'Uin>i.HMi(iiiMiiiMiMint i-Hm*.t-Mtnta<*ttomatfto I* Min I. MMMIIMI mniMMm unnw mm* IUMIMHMIM MIlfllM IMII -mTtr***Cttttaia Mniilal imi 1`mtlMMOItllM IMMlMMN miih mninNimw mimiim imo Witn-l.l-lMtamtotlM*!* IMII MltM. l.l-IMMntlM***tf>--m**t|. Mil IIMMI. iM|i l.t-Mmi***lt. HI-MMlml- M'Nmiiiumi. i-mnIMItMItMIII IIM*. t|o>M-*|MaIftoM*tMtf IIMIIIM l.t-MItTIIMIIIIMIItMXIM l.*atfniM*l*a*<Mn*f*ll*f I HMlnilMIIMII'>MI'|M|M*MM M'MIt||Mimi`*'MINlUI*MM I.HMKniMIIMII-^'WnMMBM M-MIni*IIIMf>l<MMMn MMMI 1*11 l-l.|*fMMIMMI -MMaatl**. I-*I**!*! I MMMI I -1. |-*I*;31M*MI MMil*i.l>rlWMIi4linMMIM HONS 026013 MHniniiiMm Mimxi mu ------ IMWI N WNIiIMMII NIlvNNiHWIMMHN M* MM-H-I wnm WWIIIMM Mtnn* MNNIII Mm MllMIM tmti. *m n* iiwm tut niNri iimii * mi>ih wni Ml tM IM MNNII CM* IM tit rill IM Mt IMI IMtMtt MM t*i lit (nhhi nt tMttttr ill ittn IHtttll MH IM IMl I rnmn iiimn MM Mi tttll Mill Ml llitIt MM* *H ... ...Ml IHI MIHI;( ICHIIIH IMtMII INMMI IMMMI l*MII IMHHI NIIMM MM IM (Ml MH'M'I MM *M ItMl HimIMiuIVMM MIHMi IMMMHMM I Ml IHIHI'l |-MM9>MH-l*H0*HM'Hnm)>rl-inVIiInMiHMiHnIMHi> MMCI'I'HlllIllII IIIIMiniM iliin| iuiuin Mil mimm im* ii-m-i iniiiK mi*, iiinininii.. mi* imii cm*imim tiiiMtitviM*iniiM Hnntmii iiiiBHttict*ia*B*tt HIIMIIIIH .B>*lttBnV<lIMMt*Bll H* *<iiMtt i-l-'iirini *tiiNf(*t*MMiti*Mi 1.1*1 IMI**l*|MI*(MtiMM Ml* I Mtmmu tin* MI'IMMI t-lt*VIM*l-l*IM. I-Cium- , minilinntMiiMii !vttMt*n IIIIHI lllllll 1114 1 i. *.i-uuMttMtitiit-*-*t#iiv m**i mi .H *l*il taiMlcttl MHiim immimmi 'l*H MMM.M-IIH MiniitMiM t#*i MlfMItt. IM' IMII MltlBItM Mila HIM* mi*ii*mi:m IMMttVIHBIM IMl CM! Il-ll-l iHMiwin iimi MIIMNIMII IIMI MniiNMtMn*iMH t|l*tBttMIVMM IB IMl* IBV Hill M Ml*. MU' IMII HU IMII MQNS 02601* m mtiM mi uM-iiMtll MNtvr HIM I1MI NM*NtlllM (III IMI-* |>HM* HUMlHMIM MMIH-Mlinil'MX (MmmHH H* IMMM MttimM. HtMtl' i..i.mintn-(MiaeM'iHM HH|.aUnnHmmmiHiIm*lNHMMHiiwii* H(M*tMi||MlliiMIM l*-1M*l III t-waitiM (HW-IMIIMM hNumn amaan* cm i i- Hum-immimim mmnwiM |.<m.|.HWIIIWIM nMM*lNIN HIMIIIMII HNWItHHl i-mwiumm mmuMW i.MiiH.i-mimnw rhohHkcw*iiiiHn MtnrnNM wmmgrn -nimimum iimmHiM MHMINIIHMIH mMMMMHI (MMmMMiMiMm nmiimi" atlNtllH |MmilM WHMNMWmMMIHIM mWMM tt Mil 11*1 MdllM MUI mill I MHIiNmI HIM IMNHMM IHWWII seas innimiii imumh IHINIIHMI till t(mmmitt*t cmiai* ai(ic(amtti imiiiiimm IlMKlI mmumi on MhlHHI NlllniilKHHItl Nliuiia IMIinHI>MMI| HdUtHinlll IMNItll HUillMKHlHlPl IIINUI'I inlHIII MM IdIMII If (Mil unmi i*di ; iMfi iiih taa HI IM I IIIIIM MI-IIK Minn 1(111 IIHMM IlfMIMMI lalMlt IIHMMMIIIN (MIMaWdNIiaiM. a.a*.a*1 III-* .MIMHimlaiarmmaiiaiM. .* -NtifaiiCM* HONS 026015 tiMMM NHHIH aMwHIsf r* rawls^S--1... " nililiMtMiMaiiitiwiMHiti ' mi * ir-M* IMII *. II# MHmiiii I IK MNMIIII nuiMi ftMl I It# tlMNl II nmn i-t n# nItMmHMiIwSnn. H||# nUuI Nil tMifll ImIUuN MJIIMMMMM. n INM#NI| lnniin in mi (>( ll#UM|f*| IINIInuH iiwtraiat U Ml nkimwim mkmimi* mum '* mMIM on >!-*- ((MMMMMMUHnMm (rrMavNtiNMn. imilkml . ixn IIMM MMCatMIM MjJMMMMfaiat #r ffl *% IMIIIN INI) *** MININ I 1MNI ' MINIM |ii|| HONS 026016 0. List of Rortlclptnts HONS 026017 LIST OF PARTICIPANTS Centers for Oiseis* Control/National Institute for Occupational Safety and Health Hr. Richard Lemen* Hr. Roger Nelson Consumer Product Safety Commission Or. Marilyn Wind* U.S. Environmental Protection Agency Ms. Eleinor Merrick* Office of Tonics Integration Food end Drug Administration Or. Allen Helm* Office of Science Coordination Dr. Herbert Schumacher National Center for Toxicological Research National Institutes of Health/Netlonal Cancer Institute Or. Richard Adamson* Director, Division of Cancer Cause and Prevention Dr. Elizabeth Weisburger Assistant Director for Jiemlce! Carcinogenesis National Institutes of Health/National Institute of Environmental Health Sciences Dr. Raymond E. Shapiro* Assistant Director for Toxicology Coordinitlon (Executive Secretary HTP/W6 ARC) * Member, NTP Working Croup for the Annual Reports on Carcinogens (NTP/Wi ARC) 0-1 MOMS 0^60X0 National Institutes of Heatth/Natlonal Institute nf Environmentjl Health Sciences (continued) Office of Heilth Kmrd Assessment National Institutes of Health/Natlonal library of Medicine Or. Paul Craig Or. Henry Kinsman* U.S. Oeprtmer,t of labor/Occupational Safety and Health Administration Dr. Patricia Breslln* National Toxicology Program Or. David P. Rail* Director. National Toxicology Program (Chairperson, NTP/UO ARC) Or. Dorothy Canter* Or. Jemes Huff Nr. Steve d'Aratien Support to the National Toxicology Program for the preparation of the Third Annual Report on Carcinogens as provided by 6E0HET Technologies, Inc., through NCI Contract Number HOI 'CP-056 L8, * Member, nTR Working Group for the Annual Reports on Carcinogens (NTP/NG ARC) 0-R MOMS 0^6019 E. Cumulative Index to the Annual Reports on Carcinogens B-j. 0260ZO HONS CUMULATIVE INDEX TO THE ANNUAL REPORTS Oil CARCINOGENS First Annuli Report on Carcinogens, 1980 Substances Page Aflat'ains............................................................................................................. 4-Aminobiphenyl .................................................................................................. 'Arsenic and Inorganic Arsenic Compounds .................................................. Asbestos................................................................................................................. Auremlne......................................... . ................................................................ Bentene................................................................................................................. Bentidine............................................................................................................. M,H-Bts(2-chloroethyl )-2*naphthyl imine...................................................... Bislchloronethyllether ...................................................................................... Cadmium and Cadmium Compounds...................................................................... Chloramphenicol .................................................................................................. 'Chloramethyl Methyl Jther .............................................................................. Chromium................................................................................................................. Cyclophosphamide.................................................................................................. Diethylstilbestrol .............................................................................................. Hematite and Iran Oride.................................................................................. Isopropyl Oils............................. ., , .......................................................... Helphalan..................................... -.................................................................... Mustard ................................................................................................................... 2-HaphthyIamine.................................................................................................. Nickel and Nickel Compounds .......................................................................... Oxynetholone.......................................................................................................... Phenacetin............................................................................................................. phenytoln and Phenytoin Sodium ............................ . ................................... Soots, Tars, and 0*1s .............................................................................................. Mnyl Chloride...................................................................................................... II, 37 12, 37 12, 31 13, 42 11, 44 IS, 45 16, 46 2S, 65 17, 47 21, 48 25, $1 17, 52 72, 53 26, SB 26, 59 23, 60 24. 60 27, 61 '7, 61 so, or 23, 63 27, 65 28. 66 29, 67 18, 67 20.69 Asterisks mark those substances whose nomenclature was revised for the Second Annual Report. -1 MOWS 026021. Second Annual Report on Carcinogens, 19<U Substances Fife E-Acetylamlnofluorene ............................................................................................. 17 Acrylonitrile............................................................................................................. 19 Aflatoxln*................................................................................................................. 73 4-Anlnoblpheny'......................................................................................................... 75 Ami trol t..................................................................................................................... 77 Arealte ........................................ ..... ....................................................... 79 Arsenic and Certain Arsenic Compounds .............................................................. 31 Asbestos..................................................................................................................... 37 Aureailne and the Manufacture of Auramlne...................................................... 42 Senile)anthracene ..................................................................................................... 44 Seniene........................................................................................... `tentidl.te..................................................................................................................... 51 tentolb)fluoranthene and Borto(J)fluoranthene .......................................... 53 8en*o(s)pyrene................................................................ lerylllun and Certain terylllun Compounds...................................................... 56 *W,U'lis(?-chloroethyl)-2-napbtby1an1ne.......................................................... 6t *lls(chlorcnethy1!ether and Technical Grade Chloronethyl Methyl ether *3 *Cada1us and Certain Cadmliaa Compounds.............................................................. 58 Carbon Tetrachloride............................................................. 1 Chlorambucil ............................................................................................................. 76 Chloroform................................................................................................................. 76 Chromlnn end Certain Shromliae Compounds.......................................................... 81 Coke Oven Emissions ................................................................................................. 66 P-Cresldtne....................................................................................... Cycasln ........... ............................................................................. 97 `Cyclophosphamide ..................................................................................................... 93 (Continuedl 47 55 73 90 * Asterisks nark these substances that appeared In the First Annual. Report ar.d that Mere updated In the Second Annual Report. Substances without asterisks appear for the first time In the Second Annual Report. E-2 HONS 026022 Second Annual Report on Carcinogen!, 1981 (Continued) Substance! _aje 2.4- Dlamlnotoljene ............................................................................................... 95 Dlberj(a,h)acr1d1ne ................................................................................................ 97 D1bent(a,J)acrid1ne................................................................................................ 99 Dlbenzta.Mantm-acene ......................................................................................... 101 7H-01benzo(r,g)carbazole ................................................................................. 103 01benzo(a,h)pyr*ne ............................................................................................. 10S Dlbe(.zo(a,1)pyrene............................................................................................. ..... 1.2- D1bronio-3-ehloropropine.................................................................................109 1.2- Dtbromocthane..................................... . . . ....................................... 112 IDIchlorobenzIdlne.......................................... 115 1.2- Dlchloroethaue ........................................................................................... 118 Dlethylstllbestrol ............................................................................................. 121 (Dimathylamfnoazobenzene .................................................................................. 124 Dimethyl carbamoyl Chloride.................................................................................. 127 Dimethyl Sulfite......................................................................................................129 1.4- Olnxenc............................................................................................................... 131 Formaldehyde.............................................................. 134 Hematite: Underground Hematite Mining ...................................................... 137 Hydrtzobenzene..........................................................................................................139 1ndenol1.2,3-cd)pyrene ..................................................................................... 141 tlron Dextran..............................................................................................................143 Isooronyl Alcohol Mcnufactur'ng (Strong Acid Process) ........................... 145 Kepone...................................................................... 1(7 Lead Acetate and Lead Phosphate...........................................................................143 lindane and Other Heaachlcrocydohesane Isomers........................................... 152 Melphalan ............................... 1SS (Continued) * Asterisks mark those substances that appeared In the First Annual Report and that were updated In the Second Annual Report. Substances without asterisks appear for the first time In the Second Annua) Report. t Daggers mark those substances whose nomenclature was revised for the Third Annual Report. C-3 moms 0^60*3 Second Annuel Report on Carcinogens, 1981 (Continued) Substances Pape HI rex . Mustard Gas ............................................................................................................................. 159 2-Naphthyl amine.......................................................................................................... 161 Nickel, Certain NickelCompounds, and Nickel Refining .................................. 163 N-N1trosod1-n-buty)an1ne .............................................................................................. 169 N-N1trosodlethano)am1ne .................................................................................................. 171 N-N1tro$cdtethy1 amine............................................................................................. 1/3 N-NItrosodlmethylanine .................................................................................................. 17S N-Nltroiodl-n-propylaailne.............................................................................................. 178 N-Nltroso-N-ethylurea............................................................................................. 183 N-MItroso-N-nethylurea .................................................................................................. 182 N-Mtrosomethylvfnylamine.............................................................................................. 184 N-NItrosomorphollne ........................................................................................................... 188 H-Nttrosonornlcotine ....................................................................................................... 189 N-N.trosoplperldlne ........................................................................................................... 191 N-HItrosopyrrolldlne ....................................................................................................... 194 N-Nltrososarcoslne ........................................................................................................... 196 OxysMitholone ........................................................................................................................ 198 Phenecetln................................................................................................................. 200 Phenazopyrldlne Hydrochloride ..................................................................................... 202 'henytoln................................................................................................................................. 204 Polychlorinated Biphenyls .............................................................................................. 206 Procarbazine and Procarbazine Hydrochloride .................................................. 210 8-Proptolactone .................................................................................................................... 212 Reserplne..................................................................................................................... 214 Saccharin................................................................................................................................. 217 (Continued)* * Asterisks stark chose substances that appeared In the First Annual Report and that uere updated In the Second Annual Report. Substances without asterisks appear for the first tine In the Second Annual Report. C-4 hONS 026024 Second Annual Report on Carcinogens, 1981 (Concluded) Substances Paae Safrole........................................................................................................................ 219 Soots, Tars, and Mineral Oils .......................................................................... 221 Streptoaotocln ..................................................................................................... 224 2,3,7,8-Tetrachlorodlbenjo-p-dlonin (TCDO) ............................................... ;?6 Thorium DtonlJc......................................................................... o-Tclvidfne Hydrochloride..................................................................................... 2J0 Tokaphene..................................................................................................................... 232 Tris!l-ai1r1d1nyl(phosphine Sulfide.................................................................. 234 Trts(?,3-d1broaiopropyl!phosphate..................................................................... 234 Vinyl Chloride..................................................................................................... 238* 2 * Asterisks mark those substances that appeared In the first Annual Report and that ware updated In the Second Annual Report. Substances without asterisks appear for the first tine In the Second Annual Report. E-5 MONS 026025 Third Annual Report on Carcinogens, 1982 Substances Page 2-Acetylamlnofluorene ............................................................................................. 21 Acrylonitrile ........................................................................................................................ 23 Aflatoilns............................................................................................................................ 2V 12-Anlnoanthroqulnone ....................................................................................................... 29 4 >Ainl nobiphenyl.................................................................................................................... 31 tl-Amlno-2-nethylsnthraqulnone..................................................................................... 33 Anltrole................................................................................................................................. 35 to-AnlsIdlne and o-Ants<dtnc Hydrochloride ............................................................ 37 Araait ta..................................................................................................................................... 39 'Arsenic and Certain Arsenic Conpojnds ..................................................................... 41 'Asbestos.......................................................................................... Auranlne and the Manufacture of Aureal ne............................................................ 52 *8enz(a)anthracene ................................................................................................................ 54 ........................................................................................................................................................ 52 Beni I dine............................................................................................................... (enzo(b)fluoranthene . . .............................................................................................. 62 Senxo(a)pyrrnc .................................................................................................................... *4 Beryllium and Certain Berylllga Compounds ............................................................ 66 N,N-Bts(2-ch1oroethyl )-2-nephthylantne(Chlomaphailne)................................. 69 Sltfchloroaethyllether and Technical Grade Chloromethyl Methyl Ether 71 Cadalua and Certain Cadnlua Compounds .................................................................... 75 "Carbon Tetrachloride ....................................................................................................... 80 Chlorambucil ........................................................................................................................ 83 Chloroform................................................................................................................. 85 (Continued)* 60 * Asterisks nark those substances that appeared In the First and Second Annua) Reports and that were updated for the Third Annual Report. t Daggers nark those substances that appear for the first tine In the Third Annual Report. Substances without an asterisk or a daggr are repeated fro* the First and Second Annual Reports and contain no updated data In the Third Annua) Report. C-6 MONS 0^6026 Third Annul1 Report on Carcinogens, 1982 (Continued) Substances Pape 'Chromium and Certain Chromium Compounds ...................................................... lg Coke Dven emissions............................................................................................. 95 p-Crestdlne............................................................................................................. 97 ICupferron................................................................................................................. 99 Cycasln................................... 101 Cyclophosphamide....................... 102 12,4-OUmlnoanlsole Sulfate..................................................................................10A *2,4'Dlam1notnlt:cne.................................................................................................. ICC *01benz(a,h)acr(d1n* ............................................................................................. ICO 01benz(a,j)acr1dlne ............................................................................................. 110 'Dlbenzfa.hlenthracene ......................................................................................... 112 *7H-Dlbenzo(c,p)cart,azole...................................................................................... 114 `Dlbnnzoll.hlpyrene .................................................................................. ... 116 'Dlbenzola.Kpyrene..................................................................................................118 *l,2-Dlbromo-3-citloropropane.................................................................................. 120 *1,2-Dlbromoethene............................................ 12} 3.3'-0lchlorobenzld1ne ................... 126 1,2-Dlchloroethane ............................................................................................. 129 tOlepoaybutane ........................ ........ ............................................... 132 fDi(2-ethylhexyl)phthalate .................................................................................. 134 Dltthylstllbestrol ............................................................................................. 137 t3,3'-OIethoxybentldlne ........................ 139 '4-Dtrethylamtnoazobenzene ...................................................................................... id 13,3'-Dliethylbenild1ne.......................................................................................... 143 (Continued) * Asterisks mark those substances that appeared <n the First and Second Annual Reports and that were updated for the Third Annual Report. t Dappers mark those substances that appear for the first time In the Third Annuli Report. Substances wUheut an asterisk or a dapper are repeated from the First and Second Annual Reports anti contain no updated Cata In the Third Annual Report. -7 HONS 02602? Third Annual Deport on Carcinogens, 1982 (continued) Substances Pape Dimethylczrbamiyl Chloride .............................................................................. 14S DlnelJ.yl Sulfate..................................................................................................147 1,4-Dlcxane..............................................................................................................149 tOlrect Clack 38......................................................................................................1S1 (Direct Blue <..........................................................................................................154 (Ethylene T.ilourea .................................................................................................. 156 "Formaldehyde ..........................................................................................................158 Hematite Underground Mining .............................................................................. 161 IHexachlorobenzene .................................................................................................. 162 (Hydrazine and Hydrazine Sulfate ...................................................................... 165 "Hydrazobenzene...................................................................................................... 106 "Indero(l,2,3-cd)pyrene ...................................................................................... 170 ' Iron Dextran Complex .......................................................................................... 172 Isopropyl Alcohol Manufacturing (Strong-Acid Process) ............................ 174 Kepcne* (Chlordccone) .......................................................................................... 176 "Lead Acetate and Lead Phosphate ...................................................................... 178 "Lindane and Other Hexachlorocyclohexane Isomers ....................................... 181 Helphalan..................................................................................................................184 t4,41-MethylenebIs(2-chloroontline) (MOCA) ................................................... 186 t4,4'-Methylenefe1s(N,N-d1nethy1)benzenan1ne............................................... ISP tMIchler's Ketone .................................................................................................. 191 Ml rex......................................................................................................................... 1C3 Mustard Gas..............................................................................................................195 *2-Napht.!iy1 amine . . ...........................................................................................197 (Continued) * Asterisks mark those substances that appeared In the First and Second Annual Reports and that were updated for the Third Annual Report. t Daggers mark those substances that appear for the first tine In the Third Anneal Report. Substances without an asterisk or a dagger are repeatud from the First and Second Annual Reports and conirli. no updated data In the Third Annual Report. E-8 HONS 026028 Ultra Annual Report an Carcinogens, 1982 (Continued) Substinces Pace 'Nickel Refining, Nickel, and Certain Nickel Comoounds .............................. 199 tNitrtlotrlactetic Add.................................................................................................. 205 tS-Nitra-o-iniitdlne ...................................................................................................... 208 INitrofen................................................................................................................................ 210 N-Nitrosodl-n-butylamine.............................................................................................. 212 N-Nttrosodtethanol amine ............................................................................................. 21b N-NItrosodiethyl amine.......................................................................................................217 N-Kitrosodtnethyl amine.................................................................................................. 219 tp-Mitrosodlphenylamine.................................................................................................. 222 N-Nttrosodl-n-propylamln*.............................................................................................. 224 N-Nitroso-N-ethylurea ........................................... ..... ............................... 228 N-Nttroso-H-nethylurca .............................................................................................. 228 N-Nttrosomethylvinylamine.............................................................................................. 230 R-Kitrosomorpholine ...................................................................................................... 231 *N-N1trosonornicottne .................................................................................................. 233 M-Nitrosopiperidlne ....................................................................................................... 234 N-Nitmtopyrrolidine...................................................................................................... 236 il-Nitrososarcosioe...........................................................................................................238 Oaymetholone ..... ............................................................................................. 239 Phenacettn............................................................................................................................ 241 'Phenazopyrtdlne Hydrochloride ................................................................................. 243 Phenytotn................................................................................................................................ 24S tPolyhrominated iiphenyls..............................................................................................247 'Polychlorinated Biphenyls ......................................................................................... 249 (Continued) * Asterisks mark those substances that appeared in the First and Second Annual Reports and that ware updated for the Third Annual Report. t Daggers mark those substances that appear for the first time in the Third Annual Report. Substances without an asterisk or a dagger are repeated from the First and Second Annual Reports and contain no updated data In the Third Annual Report. E-9 HONS 026029 Third Annuil Alport on Carcinogens, 1982 (Concluded) Substances Pipe Procarbazine ind Procirbtzlne Hydrochloride .............................................. 253 B*Rroplolictone ...................................................................................................... 255 Reserplne................................................................................................................. 2S? Saccharin................................................................................................................. 259 Safrole.............................................................................. ... .................................. 262 ISelenlum Sulfide .................................................................................................. 264 Soots, Tirt, ind Miner*) Otic .......................................................................... 266 Streptozotocfn ..................................................................................................... 268 tSulfellite............................................................................................................. 270 2,3,7,8-Tetrechlorodlbenzo-p-dloxln (TCOO) ............................................... 271 IThloacetanlde .......................................................................................................... 273 fThiourea........................................................... ......................................................275 Thorium Dioxide............................................................... ... ............................ , 27? o-Toluldlne Hydrochloride............................................... ... .............................. 279 Toxaphene..................................................................................................................281 12,6,6-Trtchlorophenol .......................................................................................... 284 Trlsll-azlrldlnyl(phosphine Sulfide...............................................................286 Tr1x(2,3-d1bromopropy1)phosphate.................................................................. 288 turethane................................................................................................................. 290 Vinyl Chloride............................................................... ... .................................. 292 * Asterisks hark those substance; that appeared In the First and Second Annual Reports and that were updated for the Third Annual Report. t Daggers mark those substances that appear for the first time In the Third Annual Report. Substances without an asterisk or 4 dagger are repeated from the First and Second Annual Reports and contain no updated data In the Third Annual Report. .*. 'Tiiiii.it r.irriM unn. mMnrnniM E-10 HONS 026030 DISCLAIMER D! SCRIM RATIO;: PROHIBITED: Under provisions of applicable Public lows enacted by Congress sine* IMA, no person In ttie United States shall, on the grounds of race, color, national origin, handicap, or age, t excluded fro* participation In, be denied the benefits of, or be sub* Jetted to discrimination under any program or activity (or, on the basis of sex, with respect to any education program or activity) receiving Federal financial assistance. In addition. Executive Order 11141 prohibits discrimination on the basis of age by con tractors and subcontractors In the performance of Federal contracts, and Executive Order 11246 states that no federally funded contractor my discriminate against any employee or pplleant for employment because of me, color, religion, sex, or national origin. Therefore, the Hatlona) Toxicology Fiogram must be operated in compliance with these laws and Executive Orders. e- IRONS 026031