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Potential Health Effecta in tha Hunan From Expoaura to PolyAlorinated Elphenyla (PCBa) and Ralatad lapurltlai January 25 > 19E2 Praparad byt Drill. Frlaaa. Haya, Looaiia t Shaffer, Inc. Conaultanta In Toxicology 1901 I. Port Myer Dr., Suita 204 Arlington, VA 22209 HONS 016218 larry w Hy, tjfb. ^Vrvm.<____________ Tad A. Loomis, H.D., Ph.D. C. Boyd Shaffar, Ph.D. t" HONS 01.6219 TABLE Or CONTENTS lucutlvt Sumary .................................................................. X. Introduction ................................................................. XX. Yuaho Eplaodo ............................................. ,.............. XXI. Body Burdans, Hataboliaa andEinatics ................... XV. Ganaral Toxicity................................................... V. Skin and Othar CutanaouaTlaauaa ............................. VI. Liver Effect a.............................................................. VIX. Gaatrlc Laa Iona ........................................................... VIXI. Cardnogeneelai Exparlaantaland Clinical ........... XX. Reproductive tffecta .................................................. X. Hutamentala ......................... XX. Othar Health Effecta ................................................. XXI. Epldealology................................................................ XXXX. Referancea ..................................................................... xxv. Gioaaary of Taras ....................................................... 1 9 25 31 33 (1 (3 95 99 11? 131 137 159 203 223 HONS 01622 _ -1EXECUTIVE SUMMARY The present study on the potent lei health effects In huaan populations from exposure to coanerclal polychlorinated biphenyl (KB) Mixtures under occupational or other envlroiuaental conditions was conducted by a tea* of specialists in the aedical, toxicological and epldeaiologlcal sciences designated as the Category I teaa. Draft Material for the study report was reviewed by a second group of specialists designated as the Category XI teaa, and other scientists, leading to coaaents and suggestions for laproveaent which were incorporated into the dreft report. The available body of scientific literature on health effects of KBs in huaans and in test snlaal systeas was revlswed and analysed with eaphasis on the relationships linking exposure, dosage to the biological target, and occurrence of specific health effects in the anlaal or huasn. Both the toxicological and epldeaiologlcal data froa acute and chronic anlaal and huaan exposures were considered in generating assessaents of tha prob ability of occurrence of any specific health effect in huaans. The results of these assessaents are suaaarlxed below, separately itealsed under each aajor health effect. It should be noted that each assessaent applies to the potential for developaent of that effect under the type and level of huaan exposures actually encountered in the 0.8. during the past decades, with the aost intensive integrated exposures having occurred in manufacturing operations that were terminated in this country in 1*71. MQNS 016221 Yusho Disease Separate consideration was devoted to tha Yusho episode recognising tha apaeial Character of tha human exposuree to high concantratlona of mixtures of PCla and thalr thermal degradation products, polychlorinated dlbensofurans (PCDFa) and polychlorinated quaterphenyle (PCQs). Several conclusions reached by tha Category Z taan are of importancei (a) it is iaposslbla to stipulate whether any of the health effects observed is causally related to PCS exposure, since the other halogenated compounds are also biologi cally active! (b) the dosage patterns experienced by YUsho patients and U.S, industrial workers (PCI-exposed) are not at all coaiparsbla; the latter group experienced low level, long tine period expoeuree primarily via inhalation and skin contact, with only minimal oral inqestloni (c) the eiailar health effects seen in Tusho patients from the Japanese and Taiwanese episodes of exposure to contaadnated cooking oils point to the sane type of toxle mixtures resulting from thermal heat exchanger action in tha two events; (d) because of points (a)-(e) above, and the fact that at least the PCOPs in the Yusho oils are potentially more toxle than the PCSs on the basis of animal data, it is not possible to extrapo late the Yusho experience to prediction of acute and sub-chronic effects of eosuserelal PCI mixtures in the human* (e) finally, with respect to predictions of human carcinogenesis from the Yusho type of exposure the data are so incomplete that conclu sions regarding any types and amounts of excess cancers attrlbottable to those exposures have to await further definitive study. HONS 016222 -I- , loiv lariBi, Mtb8llw. and Klnatlca Son* general observations derive from consider- tion of the data on the storage, distribution, aataboliaa and excretion of coeinercial FC1 nixturee (with aaaoclatad impurities such aa tha FCSFs) in isajusalisn ayataan. Tha dynanics of tha pathwaya by Which thaaa procaaaaa occur in taat animal models have baan arplorad lntanaivaly and hava baan fairly wall workad out. Tha variability of FCB affacta with apaciaa of taat aninal nodal haa baan investigated for a aunbar of inportant affacta, and aona ganaral structure va. activity rulaa hava amargad fron thaaa atudlaa. Thar* thua exists a concaptual franawork, but not axparinantal data, for daacrlbing such phenomena in hunaaa. Furthar, Inportant data on tha bioChanical lntaractlons of FCBa, FCDFa and notabolltas with tisauaa hava baan obtainad that baar diractly on intarpratatlon of toxic affacts in thaaa tisauaa. Oanaral Toxicity Fron acuta, subchronic and chronic atudlaa of FCB affacts in taat aninal nodala, a ganaral sunnary of haalth offsets ancountorad includaa (a) a low ordar of acuta toxicity* (b) akin lesions* (e) offsets on llvar tissue that are generally reversible at lower doses but that trand toward irravarslbllity with lncraasad dosing* (d) affacts on tha gastric nucosa* (a) affects on tha nenstrual cycle and on reproduction* ' HONS 016223 <f> porphyrin (g) effecta on the hldneyi and (h) miscelleneoua changaa Including hematologic altaratione, thyaic atrophy and lymphatic changaa. ' Thara ia a conaidarabla ranga of apaciaa aueceptibllity to biological activity of tha PCBa, with ona rapraaantativa comparlaon of order of dacraaaing activity being mink, monkey, rat. It ia concluded that there ia no baele for determining which apeelaa moat accurately eervea aa a model for prediction of general eubchronie/chronic toxicity ia nanr rather, the judg ment of Che moat iuitable aurrogate for man muet be made indepen dently for each major health effect. Finally, it ia notad that although there la tone aimilarlty between acute health effect phenomena produced by PCI expoeure in the monkey and human Yuaho dlaeaae, it would be incorrect to equate Yuaho dlaeaae with PCS intoxication becauaa of the much more complex mixture of ccmpouada encountered in Yuaho oil than In a commercial PC> mixture. kln and Other Cutaneoua Tlaauee ' Commercial PCBa ara capable of producing akin leelone in the monkey model and la expoaed humane. Chronic adminlatration of PCBa to the monkey prodpcea ehloracne. In humane occu pationally expoaed to PCBa akin diaordere including ehloracne have occaalonally been obaerved. Thaee akin dlaordera have been ahown to be reveraible in acme of the animal and human atndlee. HONS 01622* -5- Liver Kfwtl PCI mixturea are capable of generating important affacta on liver tlaaue in aniaml nodala. Thaaa affaeta include, (a) incraaaa in livar weighta; (b) biatopathologie changaa in liver including enlarged hepetocytee, dapoeition of fat dropiate in tiaauai and tlaaue naeroaia and call deathi (c) enlargement of the liveri (d) the occurrence of adenofibroaia, a benign leelont and (a) an Incraaaa in proliferative laaiona of the liver, including increaaea in hyperplaetie foci and nodular tayperplaaia. Thaaa increaaea in proliferative laaiona appear to lneraaae in aeverity with inereaelng degree of chlorination of the PCI mixture,' aa aeen in the greater potency of Aroclor 1210 over Aroclor 12S4, The effecta on liver tlaaue are gen erally revereible at lower doeea but trend toward irrevereibllity with lncreaaed doeing. However, in contract with the poeitiva flndinge of PCI effecta on liver tlaaue in animal modela, no aigniflcant affaeta on liver function taata have been obaerved from clinical data on human pcpuletiona expoeed to PCIa in the occupational eettlng. Further, there haa been no epidemiological finding of liver diaeaae la 0,1. oecupationally-axpoaed peraonnel. Alao, aa noted in the Yuaho diacuaalon about peraona expoaed to contaadnated cooking oil with a PCI content of 1000 ppm, there waa no finding of liver diaeaae in the catcgorlee of either Jaundice or hepatocellular injury. - M0NS 016225 Qaatrlc LeaIona when taated In aonkaya and rodanta. PCX* ahow aped** padfldty with raapact to a toxic effect on tha gaatrlc aplthalluia, or atoawch lining. In tha aonkay, with Aroclor 1242, thara la a nucoua convaraion of tha gaatrlo aplthalla that can boat bo daaerlbad aa a dyaplaatle growth pattarn. Thla growth pattarn doaa not conatltuta a naoplaatle tranafonatloa. In rodanta. PCX* do not avoka thla affaet on tha gaatrlo noeoaa. In hunana occupationally axpoaad to PCXa thara ara no clinical findinga to data of gaatrlo laalona. and no evidence of atonaoh eaneer due to thla aapoaoro. Carelnooanaalu Exnarlnantal and Clinical ' A alaaabla volune of aainal axparlnantal work haa boon directed toward chronic etudlec in aavaral apaelaai tha nocaa, tha rat and tha deg. There ara aone araaa of Interpretation that ara atlll undaf debate by tha invaatigatera concerned, hot in tha opinion of tha Category X taaa the following rapraaanta cooolualona that can be drawn fron praaantly available datat (a) tha evidence on carcinogenicity la negative for gaatrolntaa- tlnal carcinoM and bladder earelnocM in rata and hapatocallclar cardaeaa la tha dogt (b) aoaa atudlea have reported aa lacraaaa In hepatocellular cardnena la ailca and rata axpoaad to Conner- dal PCX* chronically, where** other atudlea have afforded nega tive raaulta. HONS 016*2* _ -7- With respect to the possibility of eanear linked to exposure of huaan* to Ki, epidemiological atudlaa ahow to data aaaantlally negative rtaulta for hapatocallular carcinoma, gastrolntaatinal carclnoaa and all othar forna of eanear. Thara is a alngla preliminary atady that purport* to show an inertaaa in melanoma (akin eanear) la occupationally axpoaad paopla, but tha full data dlaplay and analyal* have not baan aado for thla atody. In contrast, In two larger and aort datallad atudlaa, thla finding haa not baan confirmed! no axcaaa Incldanea of aalanaaa in axpoaad paraonnal ha* baan observed. Retrospective oortallty atudlaa of PCS-exposed huoan population* hava not daaonatratad a eonalatant ralatlonahlp batwaan extant of axpoaura and tha davalopaant of any par ticular typo of cancer. The buaan atudlaa In hapatocallular carelnotM ar* not comprehensive, but to tha extant that they hava baan davalopad tha raaulta do not confine tha projection of a riak for liver eanear baaed on tha anlaal atudlaa. Soon finding* of ineraaaa* la lymphatic and haaatopoiatlc aallgnanelaa ware below tha level of statistical significance, and wars refuted by observations of changes in the opposite direction in othar epidemiological atudlaa. Evan findings of statistically signi ficant differences batwaan exposed and control populations with raspact to tha lncideace of rectal cancer In woman at one plant hava not baan confirmed by observation* In othar studies. The variance In thasa findings pointa up tha important principle that tha Standard Mortality latlo (SMX) aay vary widely In different HONS 016227 -*- studies, and that undue eaphasla should not bo plaead on the SMR found In one atudy unloaa It has boon confirmed by similar findings in repeat or parallel studies. Reproductive Effects Experimental work with commercial PCI mixtures and animal models has been directed to the reproductive process itself, to teratogenesls in the offspring, and to possible fetotoxlclty. In swat teat species PCBs produce deleterious effects on reproduction at high dosages. In the female aonkay at relatively high dosages, difficulties are encountered in con ception, in implantation of the fertilised ovum, and in carrying the fetua to term. Similarly dosed, the male monkey does not transmit these difficulties to the reproductive process. In the human, exposed occupationally or otherwise to Kts, there is in general no evidence for adverse effects on the reproductive process, although there are little data from which to draw con clusions. In the very special case of Tusho exposure to high levels of PCBs and other polychlorinated hydrocarbons, the new born in significant proportion were pigmented, small, and showed a retarded rate of growth. Sowever, this pigmentation disap peared and the infants caught up with control population Infants in total growth. the potential for PCS-Induced teratogenesls, or produc tion of defects in the embryo or fetus, has been investigated in several species of test animals. Host animal testa have yielded negative reeults when PCBs were administered to pregnant females during the critical periods for organogenesis. HONS 016228 Several possible exceptions to this statement might ba notad. In aiea, a single congener, 3,4,3',4'-tetrachloroblphenyl, tnduead a bahavloral defect fwaltilng syndrome*) that aay ba ralatad to an anatomical dafact In tha lnnar aar. PCBs In alca aay produce aoaa deley in iaplantation. In rata, no groaa taratologlcal changes wars obaarvad, but aoaa alterations in thyroid structure or function produced by PCB adalnistratlon sight fall under the definition of tarata. In dogs and in swine, no taratologlcal effects were noted at lower PCB doses; however at the highest doses of PCB in the feed, at which the dam suffers aarked reduction in food consumption and' is therefore nutritionally deficient, there ara dose-related taratologlcal effects in the offspring. In monkeys dosed with PCBs, there are no dose-related abnoraalitles in the offspring, but they are smaller in site. Based on those observations, it is the Cate gory I team's conclusion that commercial PCBs present no appreci able risk of teratogenicity in offspring of human females exposed under occupational conditions. In test animals, l.e. rats, dogs and rabbits, PCBs are fetotoxie when administered at relatively high doses to the pregnant female. In the human, the only reported epidemiological evidence for fetotoxldty in exposed populations stems from the unique Yusho event, In which causation may not be linked to PCBS. HONS 016229 Mutagenesis Investigation* of possible autaganaeis froa acuta or chronic exposure* to ca--urelal CBs hsvs shown negative results in % aarias of in vitro and in vivo taat aystarns. Isolated baetarlal tost system* (Anas taat) and human lymphocytes la eul- tura ahewod no avidanea for rcs-induead nutation or transforaatlon. With in vivo systana In Intact anlnalsi (a) cytogenetic tasts for alterations of call structures or for Induction of ehronosoan abnormalities ylaldad negative results and (b) both the mouse nicronuclaus test and the doninant lethal taat danonatratad negative roaults. Incubation of humn lymphocyte* In oultura with Kls caused an alteration la glucose transport through the call aonbraaes. - * Thara la no significant avidanea that PCI* are nutaganic In test systana. and no reports of such activity In human populations. It la quits unlikely that comnsrcial PCS mixtures would start nutaganic activity in huaans. This conclu sion la consistent with the lack of axcass cancer incidanca observed in PCS-axposed human populations. Other Health Iffecte This grouping includes ensyn# induction, innuno competence and porphyria. PCSs induce nixed function oxidasos (MPO) in the liver of taat animals. The Important lasua la whether or not thla process lacXudea the specific induction of cytochrome P-44S as a general property of the PCBa, with the added implication that some oxidate system is being induced that HONS 01S130 11 could be involved In chemical carcinogenesis. Several conclu sions wars reached with respect to this issuei (a) the pre dominant effect of commercial PCBs is cytochrome P-450 induction, not F-44S| (b) commercial PCBs in the U.S. can contain up to about 2 ppm of PCOPsi and (e) the PCDFs can Induce cytochrome P-441. From these observation* in animal model systems and our judgment, it is concluded that under conditions of U.S. occu pational exposure to PCBs, non* of the MFO inducing actions of the commercial mixtures will be of toxicological significance over the lifetime of a PCB-exposed person. With respect to potential PCB effects on immunocompetence in test animal systems, soaw observations are pertinent to the assessment of probable hatard in the human. It has been ob served in chicks that if the KB dosages are high enough, atrophy of the splenic pulp and necrosis of the lymphoid system can be demonstrated. Similar indicators of change in lmmunocompetence can also be produced in ducklings, alee, and monkeys as a conse quence of sever* change in nutritional etatus. High doses of KBS loading to marksd reduction of food intake and utilisation can lead to such changes in nutritional status. These conslderstlons lead to two general conclusions relative to the KB-exposed humansi (a) as projected from animal studies, if the PCB dosage is high enough to lead to general toxicity in the human (e.g., decreased food Intake, fall in body uelght, tall in weight gain). HONS 016231 ~ - 12 - laaunoeupprasalon say ba daaonatrable aecondary to aalnutrltiont and (b) at lower dose level*, there la no likelihood of algnlfleant laaunoauppreeaion. Porphyria, or dapoaitlon of porphyrln-darlwed plgaents in liver and urine, haa baan observed In experiaental anlaala sueh an tha rat and rabbit doaad with PCBa. Tha affaet haa a dalayad onaat, and aapaelally In tha rat, saaaa to taka plaea by aechanlsaa dlffarant frea thoaa aaployad by known ehaaieal porphyrla-produeara in tha huaan. it la concluded that, aalda frea tha unique caaa of Tuaho dlaaaaa, no evidence haa aceroad for tha oecurranea of porphyria In populations aapoaad to PCBa even under high lawal occupational axpoaura condltlona. BPldeaiology Thla aaetlon (XII) of tha atudy praaanta a aaparata. Independent aaaaaaaant of the recorded epidemiological literature and data baaea on huaan expoaurea to eoaaerdal PCBa, and on tha significance of tha health affacta attributed to thaaa expoaurea. SuaaMry polnta In thla aaaaaaaant Include tha following! (a) aortality data, baaed on wary aaall nuabera of daatha, do not confirm a carcinogenic affect of PCBa in nani (b> data on huaan akin laalona in relation to FCB expoaurea hawa abown warlablllty In incidence of thla affect with geographical locua and with incraaalng blood lawal indicators of axpoaura; (e) data frea atudiaa of llwer anxyaaa and llwer function auggaat changaa in one or aora anxyaaa related to PC* axpoaura that ara not aaaoclated MONS 01623i 13 with liver di* and that occur levels bolow those at which chloracne occurs; (d) there is frequently a positive cor* relation between PCI levels and triglyceride levels in blood; end (e) epidemiological data on reproductive effects, heaatology and isssunology in huieans exposed to PCls do not suggest sbnoralities in these systems or processes. Human Occupational Exposure Levels . Of the various effects noted in animal test systems, only dermatological affects. Including ease chloracne, have bean elearly demonstrated in human populations at the dosage levels associated with occupational exposures. Table 10 susasarlses 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 PCI content in blood and adipose tissue. Since the risk to human health from even high level occu pational exposures has been shown by the studies evalleble to be low, it My be concluded that much lower hnimn exposure levels do not present significant risks. HONS 016233 HONS 016234 jocinalll (1954) (1972) xtvra ami itiaM M !*>--In arm um> 11*79) Plant alff torn aith (1901) I1N1I (1901a) BBHII1H I________ capioMor punT KB OowtoUan In Air ^ *naa isi*r *700 6012) KS Uwl in Blood Rmo Contact Farts par hilllon** Itotad? Ho. OutxiscE? X--n mma KJ Lswal in Mlfor Tissue Perts per nUlion Ha. Bi0>.* Man ween i A (KSMg5.)0- 200 B 10O- 500 D 500- 700 1 200-1700 r 99 370 60- 920 < 1000 * lo mxpom. 320-2220 70- 410 Med. * 410- COO Hi COO-UOO As Above ms 24- 393 170-1260 M.D.- 264 tins 12 13 34 ISO 62 43 26 14 12 SS 440 110-1900 020 320-2100 400 nr.-1300 L- 73 B- 41 L-171 H- 25 Ir-266 B- 02 tr- 03 2-1412 H- 19 1-60 3 360 160-635 26 Ir24 2-271 B- 6 .2-19 lr-502 210-3330 B- 44 20- 150 le>237 34-2400 B- 51 10- 250 U1--6 tareioa ith (1901b) utility wrint nailnrwr rapair ynft) KB Concentration la Air . . Kama va/m 37- US >n KB bawl la Blood rlMM Porta par billion** Wo. Wdrtac&~Haan mu 14 V- 23 B- 24 S- S2 7- 74 If 1C H- 7 1- 52 4- 19 4 If 36 23- 59 H- 10 7- 17 13 If 24 12- 35 B- 6 . 1- 18 7 If 11 H- 6 1- 30 4- 10 15 If 22 TIT B- 31 11--140 RB Iaoel 1,. Mipauc Tinuo Porta par aillion** tto. M>. Naan fcana HONS 0 1 6 2 3 5 10 b- 22 12- a H* 26 7-250 13 If 23 13- 52 B- a 5- 25 If 19 12- 42 H- 6 3- 11 rau amj 55 IWIJ Mapths rapsir) OnllHIwg 48-275 Taa Tas.. 46 12 K is 377 <8-1319 200 41-470 TTT~--------- -UPH5----------X 5.C V.IV-I1.6-------- 14.2 10- 30 5 1.4 1.0- 1.0 Wotai pcb plaat analyaaa ara apmal in parts par MIlian (Including aana a^l), uhlla adlpoaa tiaaua analyaaa ara aagptaaaad in parts par adlllon. "L* KBs (loasr braeInga) and *11" KBa Oii^ar hnanloga) ara dafinad aa apadaa having, raapactivaly, atortsr and longar gw chccwtograghie ratantlon tlsauw than ths DOT natafaollts p,p -aw. "V KBa Includa 2-KBs through 4-KBa, plua aoan 5-KBai *B* KBa Ineluda S-Kha and highar. plus swan 4-KBa. **4