Document X74LnEN9x6mm9O2DMLgjYLN2d

!'H\ tr`>ntn>nt<i! Ilrulth ft r \fut riv r\ i,.i .'/ (>f y *: /vt; Inhalation Toxicity of Vinyl Chloride and Vinylidene Chloride* by C. C. Lee,* J. C. Bhandari,* J. M. Winston,* W. B. House,* P. J. Peters,* R. L. Dixon,* and J. S. Woods* I of miii` tn MMMf ppm f viuvl rhlorith* t VO, ft hr <lu>* * duvs. week* caused some mute deaths with toxic hepatitis and marked tubular necrosis of the renal torivx. Starting the sixth month* mite e\poM*tl to MMM)* 250, or 5b ppm of V(` became lethargic* lost weight quick)* * and died. Onlv a few mice exposed to 50 ppm Mirvivcd for 12 months, Pulmouarv macrophage count was elevated in some mice. I hen "as a high incidence of tnonchiolo-aheolar adenoma, matnmarv gland tumors including ductular adenocarcinoma* squamous and anaplastic celt carcinomas with metastasis to the lung, and htmangiuxurconta in the liver, and, to a levser extent, in some other organs. The Incidence of these tumors quit Ms increased, and the seserits w us in direct proportion to the levels of VC and the length of exposure. Malignant Jvmphonni involving various organs was observed in a few mice. Kats were more resistant to the toxic effects of Vt . Kxposurt* to HKHJ ppm slighdv depressed the bods weight of the females, exposures of 250 or H>00 ppm caused a numt>er of deaths and hemanginsarcomu in the liver star ting the ninth month. Most rats with ht-puik hemangmsurcomu also dcvetojx`d hemuugiosarcoma in the lung* Memangiosarcoina <xcasionall> occurred in other tissues of one or two rats exposed to 50 ppm or higher level of V(\ l.xposure of mice to 55 ppm of vinvlidcne chloride iMM'i also caused a few acute deaths and a few hepatic hemangiosarcoums. Inflamimitorv, degenerative, and mitotic changes occurred in the liver. No mouse exposed to VlH` developed mtv rnarumarv gland tumors. Several mice had hronclnoloalveolar adenoma. Kxposure of rats to 55 pptn of VtK' stightK depressed the bodv weight. Hemangiosarcoma occurred in the mesenteric hrnph node or subcutaneous tissue in two rats. Introduction \ ins I cltioi ale i VC t was first prepared more Hum a cnuii \ ago, and jis fire and explosion hazards me v.oil known. Acute toxicity of VC was first re ported m guinea pit!'. (/I. Ax a possible anesthetic agent in dogs. \ ( wax iomul to cauxc incoordinated mu-ctilar actixity of the extremities. cardiac ar- tt-stilK were pri.-seiUi.-ii to lhi- !9"h )-a)l mL-i-lnip >! the Auii-rti'an Sisn-ty !'oi t'kiinuiioloL-y .uni I-\piniui-iit.tl I hi-rapi-iia.-s. \ucuxt I?-I9, 1976. I nlanc University. New Or leans, | inusi.ru.t, puMtshixl in the I'tuiruiucployist. IN: Nil, 2. 745 i! pi'i-i ,nul p' ihe t'nsi Intelmitioniil ( enitress on towei'l- I'tw , M.ttih Ul-April 2. 1*477. I oionl". < Abstiusts. 1977. P 'Oi. *l'ti:um.uo!i'i:> .mil I osteology. Midwest Research Institute. 42? Votker Houles.ml. Kansas City. Missouri 64110. :t nsiri antcntal Ie\ici'luj:v Branch. National Institute of l-n- *iionment;! Health Sciences. F*. O. Box Research 111,mule Park. North t aiolma 77709. ihwhmiax (7), and sensitization of the myocardium i/i. Relatively high concentrations of \'(' (lO-itf / in at: 1 foi 5(1 min produced narcosis and/or death in mice. rats, and guinea piyix (4). The guinea pigx weic found to he more resistant. The main lesions were congestion of the lung with pulmonary edema and hemorrhages in some animals, and congestion of the liver and kidney. Failure of the Flood to clo: was also observed. Detectable injury of the liver and or kidney occurred in rats exposed to 100, 250. or s(H) ppm bui not 50 ppm of VC'. T hr/day and 5 dayx/week. for up to 6 months O). Changes in liver and spleen weights, a decrease in leukocytes, and an increase in erythrocytes were observed in rats exposed to 257 VC, VS hr,day for 5 months (6). Carcinogenic action of VC was first reported in I9'M, Male rats (Ar/IRF.) exposed to 50.000 ppm of VC. 4 hr/dav and 5 davs/week for 12 months, de* veloped tumors of the skin, lungs, and bones |7>. December 1977 R&S 025875 Ffm thcnnore. /vmhal gland carcinomas. nephro blastoma. hepatic and cxtrahepatic angiosarcomas noio observed in mi' .iiui pulnion.ity tumors. mammal y carcinomas. .tiul loci aneio^aicomas weie ohseixed in mice exposed to as lou as 50 ppm ill V( , 4 hr day. 5 daxsweek. .t!or ,-12 months t-V>. Angiosarcoma of :ho Met and othei hepatic diseases. notably portal fibrosis, weie identified among \'( poly nierizu! ion woiker's An epidemiological study I IS) indicated [lint cancers nt multiple sites might be developed in VC and poly(vinyl chloride) workers. I ho pre-'Cn; stiuK w;is undertaken to deienmne the tosic and carcinogenic effects ot 50, 2?!). or 1000 ppm of Y( in rats and mice and to define any possi- bie biochemical change-' relating to anv histological and neoplastic lesions. In addition, one extra chamber was available and used to compare the ol ivets of 55 ppm of vinylidene chlotide (VIX'I. Material and Methods Inhalation Chambers and Monitoring I he inhalation chambers are cubical type and made of stainless steel, with a volume of a.5 m'. I hree chambers weie user! for 50. 250, or 1000 ppm of YC: imc chamber was used for 55 ppm of VDC, ami one chambei was user) for uncontnminnied air as control, V(` gas (99pure, Matheson Pioductsi was metered with rotameters into the ehambet air supply. \'IX' <99(7 pure. Aldrich ( ompain i was heated to 37C to generate the vapor. "I he VDC lines and lotameier were heated to 90 ( to prevent condensation. Chamber air was initially sampled w ith a syringe and monitored using a gas chromatograph (Varian-2700) with a flume ioni/ation detector. An automatic sampling system was later used. Periodically, a sample was directed to the gas chromatograph and the readout was pro cessed by a Varian CDS 111 electronic integratoi. t he integrator was programmed to measure peak area and to calculate chanihcr concentrations by external standards. Experimental Design Albino CD-I mice and CD rats (Charles RivetBreeding Lab) about 2 months old were used at the start in these studies. For each species. 360 animals were divided into five groups, each consisting of 36 males and 36 females. Each group of both species w as exposed to 50. 250. or 1000 pprr. of VC. 55 ppm of VDC. or uncontaminatcd air ibr 6 hr/dav and 5 days/week. All animals lived in the same stainless steel cages with wire bottoms during exposure and outside ot the ehambets. Mice weie housed tour in six pet cage and rats two per cage. Pulverized or Mock laboiatoiy chow (Wayne Manufacturing ( ouipanx was provided at all times except during expostite. \\ atei was available ui/ hhilttfn. A 12-hr liehi cvcle was maintained at all tunes. I he temporatme in the chambei and in the room averaged 24 rc, l.t ( |he relative humidity, ranged 25,-60'd at the stait of the exper iment anil was later regulated at 50 - 10',/. l our animals ot each species, sex. and ex posure level were terminated for various laboratory tests, cross and histopathologic examinations at the end of I. 2. 3. 6. and 9 months: the surviving ani mals were terminated at the end ol 12 months. Laboratory Evaluations All animals were observed throughout the study for adverse signs. Feed consumption was recorded weekly and body weight biweekly at a uniform lime of day. Heart (mouse) or aortic (rat) blood from foni males and four females o| each group ol each species was collected under anesthesia (other foi mice and sodium pentobarbital for rats) at in terim and final terminations. I lematologv (RIK . re ticulocyte. platelet. VVBC and Jiffcicniial counts, nucleated RHC. hematocrit, hemoglobin, incthcmoglohin. and Heinz bodies) and clinical blood chemistry (SCiPT and BUN) were performed on all samples. For rats, prothrombin time, SCiOT. alkaline phosphatase, bilirubin, creatinine. I.DH. (i-Hlll)H. immunoglobin IgA, IgB-A. IgB-B. and Ig.M (//), total protein (A5). albumin 116). globulin (by difference), and collagen contents in liver and lung (17, 18) were also measured. Macrophage counts of pulmonary washings and eytogemc analysis of bone marrow cultures t/9) were per formed on the control, and animals receiving 1000 ppm YC and 55 ppm VDC animals. Limbs from the longest exposed animal'' were examined for ostcopoiosis or malacia rising a monograph x-ray machine. They were examined for the presence of any bone tumors, any changes in bone density, cor tical thickness or striations within the bone cortex, any loss of hone cortex, or any unusually trabecular pattein ol the hone. Other specific studies including "('-thymidine incorporation into DNA (2(0. he patic aminolevulinic acid (ALA) synthetase (2/). urinary ALA assays (22) and n-fctoprotein (2a I were performed in mice and or rats. When moribund or at termination, all animals weie euthanized for necropsy after the collection of blood, dross examination, especially for any ap pearance of abnormal growth or other lesions, was carefully perlormed on till tissues including the brain, pituitary, thyroids, respiratory tract, alimen- R&S 025876 26 Environmcntal Health Perspectives Inr> canal. in ogcniial oigans, linmus. heait. Iivei. p.iik'KMv. spleen. me'cnteiic I1, mp!i nodes, and !''inl> e.o ities. I he ht am. i o oi. h idne\ s, spleen .uul Connds weio !emo\ed and weighed Illinois with adjacent iii it m.11 t issues and tho w hole oi poi turns o' tlio i.moiiv iiwiic' weie fixed. ptocessed. sec tioned. ,iih! 'l.unoil loi nuctoscopic examination. All extetna! .uul iiUcin.il iiiiimi' were catefulb ex amiikd ;iiui ivioniil'ioO histologicalh . Results Mice ('.corral Observations. I here were live early deaths, appaientlx due to the acute effect of the test compounds, I wo males and one female exposed to the hi.ehest lexel of VC were found dead between the thiiil and ninth daxs tf exposure: two males exposed to VDC died on the l.'th dax. They were replacevl w ith healths mice from the same shipment for the remainder of the experiment. Thereafter, all mice appealed in good health. Dunne the sixth month, a few mice exposed to VC died oi were terminated before their imminent death. The clinical signs included rough hair coat, lethargx. anorexia and rapid weight loss. No death occulted m the control group or the group exposed to YDC. During the seventh through the ninth months, the general health of the mice exposer) to VC deteriorated. Additional clinical signs were ab dominal distention and/or the appearance of exter nal tumor masses, especially mammary gland mmois m the females. As shown in Table I. there were numerous deaths or unscheduled tormina- tions, proportional to exposure levels of V( , Ify the end of the ninth month, all males and temales in the gioup exposed to ItlMO ppm and all lemales exposed t*i 2s() ppm died or weie terminated. Additional mice exposed to 25l> or 50 ppm died or were termi nated ilnring the 10th through 12th months. In the eontiol group, two males died during the eighth and ninth mouths. One death was due to injury from lighting, the other mouse was found dead with aatoKsis and the cause of death was unknow n. Of the mice exposed to 55 ppm of V[)C. two males were terminated during the ninth month and one female during the Uith month, l hex till hail tumors in the livet. lindtj Wright. I he weight gains of the male and female tniee exposed to 1000 ppm of VC or 55 ppm of VDC were comparable to those of the respective controls during the first s months ( big. I). Although not shown, the body weights of the mice exposed to 50 oi 250 ppm of VC were also not significantly iliffcicn! from the contioK During the ninth month, the body weights of both the males and the females exposed to 1000 ppm began to decline, followed by sudden death. Tithle I. Number ol dentils unit iiiisehedttled terminations of mile exposed lii VC or Vllf. t teatment ( Otlttol V( . <0 ppm XT. 2'0 rpm \T, moo ppm XT. 55 ppm Sc\ XI h xt I- M I M I- M l December 1977 OiMih* i>i tcnnuMtimiN dunnu cvpi'Miic month 7 to n i: -- -- 1 t -- -- -- ti 1i t--i i *\ 4 4 -- : t t A ** t -- i 4 10 ----" > % *i M 5 ___ ___ (i 4 -- -- -- -- -- -- ^ _____ -- -- -- --- -- 1 'Els Pii.i m 1, Body weights of male and female mice exposed to VC or VDC: () eontiol; (A) 1000 ppm VC: (a) 55 ppm VDC. Laboratory Taxis. No persistent change was found in the following laboratory results of the male and female mice exposed to VC or VDC as com pared with those of the respective controls; hematology, clinical blood chemistry, cytogenic 27 analxsis ol bone m.niow enllntt,'. x-i.;\ exa-mn.ilions ol' extiemitic- .mi! scnim o-lcloptoiem llmu`H'1. 'he pniinon.ii> m.icioph.ivv count in the mule mice esposcvl to imxi ppm ol \ ( . bn; no; .0 Imu'i levels. wu- gteulei th.iU th.il o' the conltol mice .U llie etui ot the ninth month I he onk tvm.de mouse in ihe oi luuoppmot Vf eiovip that w.iexamined ;ii liie end oi the ninth month ,iKo h.iel .m elevation ol pulmonun maciophage couni. At the 12th month, one of two males exposed to 50 ppm also had an elevated macrophage count. I heie vs as no survival in the group exposed to 250 ot 1000 ppm. I he mice with elevated macrophage count aNo had bronchiolo-alveolar adenoma. A study of DNA synthesis was undertaken to determine if the observation of an increased number of mitotic figures in the liver of a few mice exposed to VC or VIX could !v contained at the biochemi cal level. DNA synthesis, as measured by 1 `C-thymid"ie incorpoiation inis' DNA. vxas sigmficanllv increased in the livers of male mice ex posed to 50 ppm of VC lot II months l iable 2l. However, the livers of these mice did not show any incieasc in the number of mitotic figures or am evidence of neo- or preneoplastic lesions. `I!!.* 2. **( * Miwtutfine IfK'<tr{Htr;tfiwi into Hepatic l)\A f mult* mice exposed to VC for 11 months. \ A loci. ppm 0 14( ` itvti^ 11v, dpm imij I)NA" 2SSf * 2-l0(Si miti'tw tiguic- to (>!>!> pbodv mic: I'b'L i mononuclear cell"', local dcgcnctation and necio-. I he mci>tenee and -events ol these le-ions p; c:e-'cd w ith the length- ot exposure Some ol if. mice also had hemangiosuicom.t. 7 ninois. Neaih all the mice tli.it -tied ot vv;tetmutated ahead ol schedule and m.inv mite In. weie terminated on schedule at v.uious time- !v 'eloped one or more types ol tunnus, Htonshioh alvcolat adenoma first occurred tn mice exposed U 10<Xt or 25*1 ppm of V( during the second month I he adenoma wa- chatacteii/ed b> papillaiv pi oh. elation of alvcofu epithelium forming small and w ell-demarcated, but not capsulated, lound nodules. "I he incidence if ig. 2) .md sevefity ol thilumoi increased in direct proportion to the level o! V( ami to the length of exposuie. Onlx one control male mouse had ;i bronehiolo-alveolai adenoma dining the ninth month. A few- small nodules o! bronchiolo-alveolar adenoma occurred in six mice exposed to 55 ppm of VDC. 4-. i /I tt i I "Mean * SI* UUhmKt of obseiNatiotisl. ^Siumlkstntlv diltoiem horn the conifot (luo-samplc tank leM c-nj, /.r.viou.v in r.ttrhj Deaths. Microscopic exami nation of the five unscheduled deaths (two males and one female exposed to 1000 ppm of VC for 5 to *> slavs. and two males exposed to 55 ppm of VDC for 15 days) revealed a number of lesions. These included an acme toxic hepatitis, characterized by focal to marked congestion, and marked diffused coagulation type necrosis of hepatocytes beginning in the centrilohular area. Marked tubular necrosis chancteri/ed by pvknosis and eosinophilic granula tion of the cytoplasma in the renal cortex was also observed. Lesions in J.ate Death, During the eighth to ninth months of exposure, several mitotic figures w ere observed in the liver of a number of mice ex posed to 50 or 1000 ppm of VC- This observation was not apparent in mice terminated at other times. Mice exposed to VDC for <5 to 12 months had sev eral changes in the liver. There were enlarged and basophilic hepatoevtes with enlarged nuclei, many of which had large round eosinophilic inclusions; rcpcntm; m-s in months bii-i ki 2. tncsIciK.- ot bronchiolo-;i!veolaradenoma in male and female mice e.xpo-ed in VC or VDC: (> I(XX) ppm \'C; (2.) 250ppm VC:(0)50ppm VC:(V)S5 ppm VDCudcontrols. Hemangiosareoma occurred in the livers of mice exposed to 1000 or 250 ppm of VC starling the sixth month. The hemangiosareoma was characterized by moderate to severe proliferation of endothelial cells lining the sinusoids, dilation of the sinusoids, focal hemorrhage forming small to large cavernous blood spaces, invasion of the hepatic parenchyma w'iih neoplastic cells, and mild to severe necrosis. In addition, hemangiosareoma was occasionally found in other tissues including mammary gland. 28 Environmental Health Perspectives 30 CD O ro cn oo ~-i oo sf 1 JS * 'i 1 i' ',J .i i \ I )ii i .ii i i lic;u!. east nMiUc'tinal Ir.iCl, pancteas. kidney, epididymis, lestis, mesenteric lymph nodes and skeletal rmisclc. The incidence and severity of the hem.mgios.ucomn in the loci ,md the ovciull mcideuce in other tissues were related to the lose! of V( anti the length ot exposure fl ig. D Hepatic hcmangios.uvoma occurred in thtee nuee exposed to 55 ppm of VD( , 1 hi-* tnmot was not found in any control mice. 1 here were also hemangiomas in the mediastinum of one female exposed to 50 ppm of \ C and in the connective tissue adjacent to the salivary eland ot one male exposer! to I (KM) ppm. found in any control mice or mice exposed to 55 ppm of VDC. Three mice exposed to VDC de veloped hepatoma. Hepatic cell carcinoma, renal adenoma, or skin ktuatoacanthoma. was observed in one or two mice exposed to 50 or KMX) ppm of VC or 55 ppm of VDC. - t'j R&s 025879 ht.i ki }. Incidence *>! hcm.<ni:tON.irvinn:t in malt* and female mice e\posed lo V(' oi V D( ; <*! 1000 ppm V('. () *50 ppm V(`;(o) ^OppmN'f ;i i 5* ppm YOti-------Miser; i-*i othei oilmans The third major type of tumor was found m the mammary gland of the females. Mammary gland tumors started to occur during the sixth or seventh month. The incidence incteased with increases in VC levels and or length of exposure d ig. 4). 4 hese tumors were composed of ducttihi! adenocar cinoma, squamous cell carcinoma, and/or anaplas tic cell carcinoma: The severity of these tumors in creased in mice exposed to higher levels of VC' and in mice that died or terminated at later dates. In addition, the squamous and/or anaplastic cell car cinomas metastasized to the lungs of a number of mice. This type of tumor was not seen in tiny con trol mice or mice exposed to 55 ppm of VDC. Malignant lymphoma was seen in one female ex posed to 50 ppm and one male exposed to 1000 ppm timing the sixth month, in two females exposed to 250 ppm tinring the ninth month, and in one male and three females exposed to 1000 ppm during the ninth month. The malignant lymphomas involved the spleen, liver, lung, kidney, heart, subcutaneous tissue, and/or mammary gland. This tumor was not I'if.i hi J. Incidence of mamnidid *m* mui mcUM;i>es in the hin^ :n tcm.ile muo e\p vd '* V< 'n ICHHippm.fAt ppm; ( M 50 ppm. ( -- ---i in.nnm.tr} cl.tnd [inoc. t -- i moUtMitsi's to June. Rats CGeneral Obxerratinns. No remarkable ad verse signs were seen in any rats during the first 7 months. Thereafter, a number of rats died or were terminated before their imminent death. In the group exposed to l(X>0 ppm of VC. eight males and 15 females died or were terminated during the eighth through the 12th months. In the giotip ex posed to 250 ppm. four males and 10 females died or were terminated during the s.mte period. Two females exposed to 50 ppm died. No death occurred in the control group. One female rat exposed to 55 ppm of VDC was terminated. Before death, these rats had rough hair coat, lost muscular tone, were lethargic and lost weight. Jinfhj Weight. The body weights of the female rats exposed to ItXlO ppm of VC or 55 ppm of VDC were generally less than that of the female controls after the 4th week and those of the males exposed to 55 ppm of VDC were generally less than that of the male controls after the 24th week t big. 5>. The body weights of the male and female nits exposed to 50 or 250 ppm of VC. although not shown in bigure 5. were comparable to the controls. December 1977 29 I K>i u) ' U<\h uciiih's o! ic.cv v MX . I.< vt*n<D! i ` i tOH* < \t \ 1 #{ e',,. Litbimihiri/ I'rst*. No peisistcni was Ay fotirul in the lollowmi: laboiatoi \ lesults ot the male -m^^tnd lemale rats exposed to \( ot \ DC as com- 5V-^Hpared with those of the ; e spes 11 \ c conttols- ? ' hematolouy. clinietil hli'in! shemistiy. pulmonaiy b; macrophage count. cyto.ecmc an.ilv "iv of bone m.u- 43f ^-'ro\v culture. x-rav o\:imin:itioi, of cxticnuties. col- lagen content'' in 11 \ e i ami lime, serum AI A on- ?- :bf..s theiase. urinary AI \ level, and set urn -fetoproioin. Tumors. Hepatic anil or pulmonary hemaneio- sarcoma oeemred in rate exposed to Z^u ot ld<>l> ppm of VC iluriny the ninth tluouyh the 12th months: the incidence increased with increases m VC levels and length of exposure (big. Co. Most ot these rats died or vveie terminated ahead ol schedule. The rats with hepatic hemangiosareoma usually developed pulmonurv hemangiosareoma. In addition, hemangiosareoma occasionally occurred in other tissues including omentum, mesentery. ot subcutaneous tissue of iats exposed to 5<i, 25<'. or 1000 ppm of \'C. two rats exposed to 5s ppm of VDC developeil hemangiosareoma in the mesen teric lymph node or subcutaneous tissue. Ileman- giosarcoma was not found in the liver, lime or any other organs of any control rats. A few other tumors occasionally occurred in one or several rats. The tumors included a small nodule of bronchiolo-alveolar adenoma: rcliculo-cn- ilothelial cell catcinoma oi hepatoma in the livei: litctular tidenoeareinoma or fibroadenoma in the nummary "land of the female: malignant lymphoma m the spleen or other organs; adenoma in the hid30 'i \ ( in himippii, t i ? ; ; rn t - - - *; I; v: ()lln r \/ii msrnj>it ( luni"r\. \ mdd to m.irkedlx sevete focal, disseminated vacuolization, p.'obuhh. tatty chance, vias obseiveil m liveis of most ot the rats treated with VIX . A lew controls and a lew iats iteatcd with VC showed this chance but to a milder deciee. Discussion and Conclusions Mice 1 xposuic >o VC or VDC caused some early deaths, \mong a total of Mi mice of each sex. two males and one female exposed to HWtO ppm of VC died between the third and ninth days, and two males exposed to 55 ppm of VDC died on the 15th day. Histopatholocy revealed acute toxic hepatitis and marked tubular necrosis of the renal cortex. I hcreaftet. all mice appealed in good health. Dur um the sixth month, a few mice exposed to various concentrations of VC had rough hair coat, became lethareic. and lost weight quickly. They died or wetc terminated before their imminent death. After the seventh month, the general health of the mice exposed to VC deteriorated. A large number of mice had abdominal distention and external tumor masses, especially mammary gland tumors in the females. |U the ninth month, both the male and Knvironmental Health Perspectives R&S 025880 y:j '-fi 1 ;'\f 'o ;)in \{ ,-w` .i: !cl<: tic- \['.'M.\f 'o 7't> ,,:,v<i ,> w e;e V;m; lev e s p" -, 1 ' 1 . . eb ''11 ::: i. ' i' i t - I wo m.-Ie v-'-';; H 'lie mb. !t!..'Cs .mb ''Mi' !C`,.;,e Cvt'V,':\ vi' ^ ppm i'! \ I )( dunne the expe: nnein I'llimon.U v m.U lOpll.i'Je Count w,;s ilexmed Hi m'iir1 mice exposed to \ ( . I he n).;C(i'ph..ec count w.is eiex..ted e.iihei m mice esiV'-ic! to lUtOut 2'tt pptn ih.in m mice expo-mo to '<* pp;::. I tie mice w ith elex.Hed m,ic; oph.me count ,'.i'o hmt hronchioio- .iKeohi! .ulenomn. Howexct. noi .dl mice with i'ioiiehio!o-.i!\eoi.e .tdenom.i hud -lie elevutton o! m.tcioph.iec coum I tie iclmionship of macioplr.iec count .wiii iln-. piilmon.ii > Mimoi need' timber in'.ectieation. A modeiate nnmtvr ot mitotic fieutes were oh- sc' x ed in the loet ot'miee eNpo'erl to \ C dunne the ninth month I)\A '\uthcs>s ,i' mcustircd h\ '( dumidme meoi po; ,-t ion into [)S \. w.ts Me mlv.mth mcic.t'cd m the hxeis ot m.ile mice ex- I'oh'J to "-ii ppm ot \( foi 11 month'.. Howexei. :he 'inn>M' t lenn s w e:e not ohsci \ ed m the liu'n ol these min', no; w.is theie mix evidence ot neopliis. tie mni p: eneophiMie lesions. 1 tit ther studies me niv.ietw,i\ to determine it'the histop:itlu'lo$:icd oh- 'eii.itioii eonhl he tcl.iled to ch.mites tit the hiochcmicui level A nnmbei of lesions oventied in the liver ol mice exposed to 5' ppm of V PC i he lesions included enl.need ,md h.isophilv hep.itocx tec. enj.ueed nti eiei w i;!i eosinophilic ineiiisions. mitotic fietites or poh ploids . uiietotoei ol mononueleai cells. foeul deeene:.ition. mid neeio'is. I In; 'leniltemiee of the'C lesions .is lelnted to ihe hem,ineios.neom;i oi otln.-i !tvei Illinois m.o he ot' ,i "pteneopl:isiie" n;t- ti.ie Since onlv ,i few mice .is compared to the numlv: "t those with these , :eneopi.istic lesions, desclopeit tile delmite neopinsms. Inrthei Miidx w itii nnee exposed to liieh levels ol \ PC is needed to estni'hsh mu delmite .oneltisions I xposiire to 'it. 2^0 oi mutt ppm ot' \ ( . u In d.iv mid s (!.,\s week, etuised bronchiolo-ulveolut .idenomus. m.immmv "land Illinois, mid hem.ineiosntconins. Ihe squamous and anaplastic cell e.nemomas of the nianimarx nlmu) metastasi/ed 1c' the lime. ! lemaneiosaieorn.is fust oeetirred in the IKcr and then in othet oreans. Ihe meidenee of these tumors c|uickl\ inereased. espeeitillx in mice exposed to loon or 250 ppm. 1 he severity was in dnec! proportion to the lexeK of \(' anti the ieneih ot evposme. In atltlition. a few mice exposed to V( also dexeh'petl malignant Ixmphomas. Hronehioloahei'lat adenomas and hepatie hemtmtiiosai- c'omas also occurred in some mice e.xpdsed to 55 ppm ot \ DC. "Ihe pathoeenesis^'of these uimor> was tie'snhed elsewhere <25t. December 1^77 Rats ( ' s | I, i!V O' 1} t C h\iv ii nd cmo! \ < * ; \ 1 X 1 \pnvii,` e O' '(). ..I \ 1 ; > ' '' IT ol \ 1H did not e Oils. Ot III'. PcMvi^t.inl ch: mees m me.d ! .hi i;.Hoi . f ostdI %, Mi iwevei. ppm u! \ ( i. i ppm ( 1 \ D( slight's depiessed the Pott\ weielit ot the IcmalCs or t'otfi sexes. In- addition, a mmihci of deaths oc elli ted m the la!' exposed to 2so or loop ppm of VC oi '' ppm t'f V|)( staitine the Vlh month. I xpostue to 251* ot MIOO ppm of \'C eatiseti hemaneiosareoma m the loei staitini; the ninth month In contrast to the mice, main of the rats with hepatic hematic.>snrcomas also developed liemanen"aicom.is in the lime. I wo rats exposed to '' ppm ol 5 DC dexelopetl heniaiieiosaietmias in the mesentciie (x mpfs node oi sul'iciitaneous tissue, I In1 Io- e; - ol most ia;. exposed to VI)( had a mild o: mat fedh sexete !o..,d. disseminated xaciioli/a- Oou pioixihh. t at t \ '! ia nee. (he siem! icanee ol this chaiiee as jelated to 'he expositie o! \ D( is not i Uldei stood . 1 ,.c .C i. ! Ai AS -A -pp* ted ' Hie X tlll'Il.ll 1 t'tute ! f`nM" . *' ` H-a'th s IfflA ' nil Ic: ( . nti.tct Ko \o] is;. is.; W ** a;*1 irn ehied 1): p.ibcn I) shorx. ,Ir s. .* ii- A'l.c-! Mu!a. si kc v.l'Al M't'llstf iit his '.ope? - c Ash tt .*! O idlC-.M! < P<*. 'ir-'.tl.i `n'iCiili \ 1, A miie- \,SV Uii M ?' v \f \ .-.A t >, Ini ii K It. deso'2 1 lead. Mu*. flvniiCa l and |)cvc'a,P`i eit! ti I'h.mn M.duesi Ke- 'C h Ins. . (f tat Stv st;M C1 * : vt .11 M i*l:cs `in s t 'ilageu Cv'U- \ and s toecilK t'1 *,v. s 1 to 11. N, 1 Mailm. \s' Sl 1. J t*c Pi.. tC'S4*i o* I ). t4jrt .s-S Ci.lli'ti* Hie 1 iiuomK \d K A!1 as Mo i!-. ! < cntc? Ka .s.,s ( Me . K.ms is tor las .is^i-xTance ,;; 111 : ' i'i'*!' on > -*,t\ % .;,'R M?! *1? i>! oIk'iiiiiii'-. to D;. Mf, art Sc i Iholcsva v . ho< ol Mv dicme. iim-MR i>t aJ tt: hi.i s a n I) i c e o < -O'lo r hfs a ssfstafK'e on j.'lctoptorctn as'-as: Io Msv JtulMh () M I i -\SC P f*i ho MipcrM^ion ur> tht* hcnvto{oi:> :ind clinical am*: \'sh .iiui l'1 M> I I!ctt K \ !i:v, s'lrc: 5 c'l the "icp.it.tl'or v*1-* - t` t hvi HVA l.KK\< T.sS Palls. I \ . v\ .d. \xiiU1 KKpv'ti'sc d! k'liiiKM !* x.tpors -M Mime new cormiUMCRil oijianic compounJ4*. V: Vitivl cnlorufc. Pith, HtMllh Kepi. I Wo 2. (Ktcr, H,, t-t ;tl. AncNihc^ta. X\VI1. NarcoMs with vinyl chioritk* AncMhcMi'lojjv ' Cart, J.. cl ul. AncNthcMii. XXIV. C'htrmioal constiUmon of hvvlri'carlvns and cardiac automaiiciiv. J. Pharmacol. V?; I (PU^t ^ Masiionuittvo. I . cl al A^ntc inhalation chhnixlc lahoi.itoM atvm.iN \incr Ind. M>c. 'omw 2\: i p*fah ^ Io?kciMn, I. K,. ct al. ! he !OMCt\ ot \m\l chloride as dctctmincd *\v rcpw'atcd c\p`Kurc of lah*M,iior\ animals. Amcr Ind, Hyp \ssov h 72. '/*- I cmci . D.. ex al. I .tlect'' ot single and repeated exposures ol , humans and rais to \inyl chionde. Amcr, Irtd. Hyg' \ssoe. - J 24: 2h5 'ilWO), ' r . 'v 7. \ iola. P I . et a! Oncoecnic response ol rat v^irs, hm^s. M M -HI 4 - Z1 'S& ' 1' vi 'lA; 2S A 33 (/> '<t>y bones i<> vinyl ,h|oisde < .meet Res '! 5 m 'tVlt. M.:!t,nu, ( , .md I demine. t> ( .iivinoi.-envu\ hioa"ays of v u^^Mlotide. ( uiient lesuhs. Ann, N S . Acad Net. 2-H*`. < reoeh. ,l. I . and Johnson, M. N, Anciosnrcoma of liver in the manufacture ft pole vine! chloride I Ovcnp Mol. |f> 150 i t->~4i ) ilk, II , cl al Hepatic disease'unsone workers at vine! , hlonde poly men/ation pi.ml. ,1. Amci, Mo!. A'W. 250: 5o 11 u'-i i. Makk. I ot ,tl. I i\i*i damage .iiitl live! aneio'urcoma in viml chloride worker. .1. Amet, Med. Assoc. 250 M i I'iM i. -. , ... fee, I-. I . and Harry. IX S. Angiosarcoma of the hverm a vinyl chloride worker, l ancet-1; 15lb(lV74t. labetshaw, 1. R., and Galley. \V. K. .Mortality study of workeic m the mnnulacturc ot vinyl chloride and it' poly-- mers. J. Occupy Med.'16; '00 I|V74l - ., Mancini. ( .. et;(!. Immunochemical quantiiution of antigens ' by single radial immunodiffusion. Immunochemistry 2; 2*5 i i'omi' ' v ' Kinjrchy. (i. R. The direct biuret method for the determina tion of \crum protein ac applied to photoelectric and visual colorimetry. .J. lab. Clin. .Med. 27: S40 < I9l2>. \ ! Dountas, H. T,, el all Albumin standards and the measure-, ment of setum allntmiu with Hmmcrcsol Green, Clin, f hem. Acta 51. 87 (10711. ' Houck, .1 and Jacob. R. A. Chemical dissection of rat ,`SSC' skin I'roc So. f'vpO lud Mol loV '24 fJOriOt, Is Martin, C J,; and AvctroJ, A, I A muddied method !q;: *,-Aaiji'i S"J' stetetniination ol hydiuvyptolim,- 'r.-s.Soc I'.'P'I Mrti.-M, 4M it'bb ......... IV ,1 jio. J I I., and Many. J. Direct chroiriosrime preparafw>rt^J?!;-'7?.;f^%3 o? boric marrow cell' In: Human f hromersome'Mcthi:doi7 oev J J y unis, | ,d \,aderun. I'ie,' Nr* 'link, 1V05, Hoi ton. K, A-study ol the condi'ion- ami mechanism* of trie dtpheliylattune reaction !i the (.oionnetric estimation of t'od dc**vy tibonusteic acid, Miochcm .1 '>2, 515 (IVfht- . .l v Woods, .1, S, Studies oit the role til lions' m fhc regulation of V fi-nrm'hotevulimc acid sy nthetase durine fetal hepatic de` V'elopment. Mol, I'harmueo!. Hi: W' 11074/. - 5, ,1'i 'DayikV. ,;J, R. and Andeirimn. S L, dcltti-aminofcvtiiimc aetd t A I, At level' in lead it modified ntethod for the. rapid determination of urinttiryb;^,ai.^|| delta-aminolevulinic acid usine disposable roh-exchange-'.^'o^^^s^ chrOmatouraphv columns. Arch. I nvinm, Health j/:-*" j ivftT). v -. ........ Sell.S.. and Grad, D. Rat n-fetoprotcin--111 lennemcrr taUioimnii.noassay .for detection of i ne rat V<,F.- munochemi'iTy 10; 4Ju i |V75. . ' 2a, . Matin; H.-H.. and Whitney J, H. On a test of whether or two random variables is statistically' lariter than.'he other Aam.,,....Mvia-.tthi,. CSil-a.,t. IISV 5sn') ,(IiVti4c7"), 1 "1e - -t. , -1-TM,! 25. I.ec.' C- C., ot ;il. C'arcinoeenicity of vinyl chfonde and ... , '-'c..V vinvlidene chloride. J. To.mcoJ. Hnviron. HeaJlh. in press. . , -5'' - o t- " - . -. - V 9! "* ; ' '.`'.uPt v ^ 'v'-' -''I