Document kXp7q81469xY1OZzpQDk2xpE

R&S 134505 Founded by Chauncey D. Leake -- 1959 Volume 18 -- Number 2 Fall, 1976 Abstracts of Papers for the Fall Meeting August 15-19, 1976, Tulane University New Orleans, Louisiana American Society for Pharmacology and Experimental Therapeutics o 9650 Rockville Pike, Beihcsd3. Maryland 200H R&S 134506 TOXICOLOGY III THURSDAY, Auguit 19. 1975 - 9,00 A.M. 7ia 719 INHALATION TOXICITY OF VINYL CHLORIDE (VC) OR VINYL 10CiL CHLORIOZ (\DC) IN RATS AND NICE. C. V. B. House,* P. J. PcSfrs.* J. S. 'WqoHs, .-.nH P., L. Oi wr.. Kid'-'tst Rtldreh Institute, ICinssx City, IO 64110, 2.ii Njc I . Inst* of Environ. Health Stl *, NIH, Research Triangle Par*.. HC 27709. Exposure to VC at levels of 250 up to 20,000 ppm lor l. ' months vis reported to cause tumors of the skin, lung, bo- , liver and/or murazsry gland In rats or mice (Cancer Res. ?> . MS, 1971; Lincei-Rcnd. Sc. Fs. hat. enat. 36:1, 1974). In the present study, rats of both sexes exposed to 30, 250, or 1,000 ppa of VC, S hr/day, 5 days/veelc, for up to 6 evanths did not shoo any significant adverse effects including weight gain, various clinical laboratory data, chromosome analysis, or pathologic lesions. In contrast, mice exposed to SC de veloped bronehlolar adenoma in 2 months and osfnaary gland carcinoma with puleunary metastasis in 6 months. The carci nogenic effect appeared to be dose related- The bronehlolar adenoma was also observed in nice exposed to VCC at 55 ppm for 6 months. Hnvcver, the Carcinogenic effect of VDC uas Jquestionable. (Supported by Contract No. NIEHS-N01-ES-2-20S4.) 722 CONTINUOUS INHALATION OF l, l-OICMLOFOSTWYL.*.' (DCS) BY RATS A.\*D MICE DURING CESTAT ION * R. D. Shnce .+ J * L, Minors* U. 3, Hr u + U, Hircy.*, * and C C Lct* Midwest Rea# Ins;. Kansas City* M3 6^110 and .Special Cheolcals Branch, E-?A Washington* 0-C* 204.60* CO rats and CD-I nice exposed Co DCS for 23 hours a day for up to 10 days# In pregnant antral a the LC50 value wa s greater than 460 ppn for rats and 80 (43*119) ppa for nice- No sice survived 130 and 300 ppa of 0CE- 460 ppa 7/13 preg nant and 1/13 nonpregnant rats died# Rats and nice exposed to DCE icon day & to 16 of gestation had both a reduced weight gain and feed consumption during treatment* These effects Ini tially occurred between 15 and 53 ppa of DCE. DCE did not af fect rat fctuics/lUtce at concent rat Iona up to 460 ppa. No litters wre produced in mice at 30 and 55 ppo of DCE. Rat fetal body weights were reduced at 300 and 460 ppa. Sicsllar effects on development occurred in animals pair-fed to these groups* Therefore* these effects couLd not be directly attrib uted to DCE. No gross* soft-tissue* or skeletal malformations*- which could be attributed to DCE* were observed in rats ex posed wo tn 4*0 ppa or ff'.ce exposed to 1J ppa DCE fma gesta tional day 6 to 16. (Supported by EPA Contract No. 63-01-3242.) 7Ii ALDRIN TOXICITY IN HAWAIIAN CEILS, 0. P. OeVore*, H. A. Sheridan*, J. S. Pitman*, and f. 3, Hutson* (SEC.'I: R, i, freudenthjl). Battel le, Columbus Laboratories, Columb'jj, Ohio <3201. Suspension cultures of HeLa cells were used to expand pre vious methodologies (J. Agr. food Chen., 21:362. 1973) fur the measurement of pesticide toxicity based on biochemical responses. Experiments were conducted to measure the tine course of ,1,C-aldrin binding to HeLa cells at a sfnqle pesti cide dose and as a function of filtrate dose as reflected by changes In protein synthesis (!H-amino acid incorporation). Aldrin binding reached a maximum in 15 minutes, approximately 5 minutes later than complete Inhibition of amino acid uptake. ll'C-aldrin binding was dose dependent Over a range of 0 to <00 ug/nl. At a survey dose of 302 ug of aldrin. 30.2 ug was bound to 2 x 10s cells. Below 50 ug/ml little to no effect On amino acid incorporation was observed. Preliminary studies to examine mechanisms of pesticide toxicity were conducted by determining the effect of aldrin on A1P-and cyclic Ah? (cAhP) levels in exposed cells. ATP levels were grossly affected and decreased following aldrin incubation. Experiments to measure effects on CAN? levels are still in progress. These results provide basic information required for the development of an accurate-predictive cell culture screen for pesticides. (Sup ported by USPHS, N1EHS Grant ES00365). D( FTERTMTIAL- PROTECTS* BY CERTAIN AGENTS AGAINST CAR30M tetrachloride-wouced increase in bile cuct-pamcfeatic fluid FLOW. T. Lra-sura*. J, M, FuiLnoto, A, Klccker*, R. Z, Peter son* and C. P. Crwir.^s Sed. Col. Wis., Milwaukee* u, 5323J. Since the svc.hanisa by which CClu (1 tilAg L.p. in com oil* 7m hr pretrcatrenc) increases bile duct-pancreatic fluid flow (BDPF) is not known, the purpose w** to see whether agents which protect against certain CClu effects also protect against the increase in BDPf. Change in BDPF was assessed against increased C?T, hepatic necrosis (KN), hepatic rrigiyceride (HTG), and decreased hepatic bile flow (H3f). Cys teine (1.3 gAg, p.o.) administered 30 sin before CClu sigfti/Tcantly protected against the increased 30PT. SC?T* HTG and KN but not the decreased HBF. Py ra to le (300 ng/kg, i.p.) adnunistered 30 ain before CClu protected against the increased Hff, KTC but net against the increased BDPF a.nd SG?T. No pro tection against the decreased H3F was afforded. A snail dose of CClu (0.2 eiiAg. i,p.) 2* hr before the usual pretreat.etnt with CClu protected against all the effects including that on BDPF increase. Thus* with the combination of results, it is 'concluded that the increase in BOPf produced by CClu is not correlated with the extent of iiv-r necrosis, hepatic tri glyceride accureulaticn cr effects on hepatic bile flow. The source of the Increased BDPF regains unknown. (Supported by USPHS Grant Grt-165Q3e) 722 HEYACHLnSOBF.NTr.NE (HCS) PORPHYRIA IN RATS: DirmCNCE BETVTFN SEXT3. C.D. Sweeney end K.C. Jonei*, "c"u(,r L'niverilty. Kullton, Ontario. PCS, PCS'e and t etrechiorod Iber.to-(p) -dox ` r. tauie hrpaiie porphyria in laboratory anto.xli. rha rat t er 1 .c te ftaturea of thie porphyria Include a long latent ptrlod. excretion of porphyrins with 8. 7. 6. 5 and < carhoxvl groups, and of SIsocoproporphyrins I -aminolevulinic acid svnthaae Is elevated and there is Induction of hepatic drug-eetabnlI a In* eoxyne eyotews. An earlier report emph-ae land the greater susceptibility of female rsts to develop porphvrta; this study examined the phenomenon further. 0,2,. practical arade BCR was added to th.e diet o( ferv,lr. castrated male and sale Wtstar rata. Porphvrla appeared after 5. 7 and 10 week* respectively In Che three groups. Feeales excreted 2o; of porphvrln as porphvr Inogrn. males 15-401. C-tnchro-e Ptjn was highest ^.SOn'I/eiR prot.) In the rs, 1 e group. Intermediate (1.31) in the tascreced and Invest (1.03) In the (males. Pthyl isocyantde binding spectra with nlcrosores frnn the 3 groups st pH 7.4 were the eaise* Tfir Increased suae ept lb 11 11 y of feesle rats to porphyria Is associated with decreaaed induction of drug neta^ol11 log entyme svstera: Intact teatra confer some protection. The srs dependence of the porphvrln/ porphyrinogen ratio is of Intc.cst. (Supported by the H.R.C. o( C-nada) 723 ` PERTURBATION BY ORCANOOT.ORINZ PESTICIDES OF 3H-TEST0STER0HI METABOLISM IN RODENT HEMATIC MICR05OME5 AND PROSTATE CLAN0 IN VITRO. K. P. Donovan*. J,A, Thomas, L,G. Schetn* and P.A. klase*. Vj . Cnlv. "ed. Ctr., Morgan town, kV 265C6. ' ' ' ' Foraaclon of 3H-dIhydrote*tosterone (^-OKT) fron 3H-cestoi- terone by rodent prostate gland Jin vtt ro was inhibited by organochlorlne pesticides. Kcpcachlor was east potent, inhibiting 3H-0HT format inn in rat tissue at 10"^M and In oouse t 10 Chlofdjne Inhibited In tissue froa souse but not froo rat. Tissue from either species was refractory to fLcthovychlor. roraatlon of ,H-hydruxy tes tosce rone tso<ner* by both mouse and rat hepatic nicrosones was reduced by all three coepounds at 10" M. In addition, rouse enzy^o w^re Inhibited by |0"*M and hrpc.achlor. Incer.ictlon of these orgono- Chlorines with cytorhroaw: P-450 produced Typ* I spectral chances In souse liver nlcro.ioaea. Spectral titrations Indicated the presence of more than one type of binding sits. (Supported by LPA 68-01-1926.) The Pharmacologist 245 iajL*-M. ."is ---------- - KVlWW,.'' "^r Manufacturing Chemists Association Minutes of Meeting MEDICAL SURVEILLANCE AND RECORDS SUBCOMMITTEE FOR VINYLIDENE CHLORIDE TECHNICAL PANEL MCA Conference Room Washington, D.C. August 11,. 1976 R&S 134507 Dr. McDonough presided and convened the meeting at 12:00 p.m. The record of attendance is: MEMBERS PRESENT: J. R. McDonoughs W. A. FishbeckV H. B. Lovejoy M. Freifeld Chairman Tennessee Eastman Company The Dow Chemical Company PPG Industries, Inc. MCA Staff MEMBERS ABSENT: Z* G. Bell, Jr. M. N. Johnson PPG Industries, Inc. The B. F. Goodrich Company ****** * * * * * The purpose of the meeting was stated by Dr'. McDonough as the preparation of the medical section of a document being pre pared by the Work Practices Subcommittee. It was decided to start fresh rather than attempt to modify an earlier draft de veloped under the chairmanship of Dr. Ronayne, who is no longer on the Subcommittee. It was noted the finished work practices document would be distributed to supporting companies and possibly to customers using VDC as well as appropriate govern ment agencies. Dr.' Fishbeck reviewed the favorable results of a Dow study of their employees exposed to VDC. It has been submitted for publication in the Journal of Occupational Medicine. VUUVtoW - ^ In the MCA-administered animal studies at Dow, Dr. Fishbeck said that both hepatic and kidney damage were noted. A draft was then written for the medical section of the work practices document. The meeting was adjourned at 3:00 p.m. Minutes Subject to Approval MF: ec August 13, 1976 Milton Freifeld Project Manager Vinylidene Chloride Research R&S 134508 R&S 134509 s t i ! i i EVALUATION OF THEENVIRONMENTAL TOXICANTS VINYL CHLORIDE (VC) AND VINYLIDENE CHLORIDE (VDC) by Cheng-Chun Lee Joseph M. Winston Paul J. Peters Jagdish C. Bhandari John R. Hodgson Jack H. Hagensen Thomas W. Reddig Ellen R. Ellis PROGRESS REPORT NO. 9 1 January through 31 March 1976 Contract No. N01-ES-2-2084 (Continuation of NIH-NIEHS-72-2-2084) MRI Project No. 3612-B '\ 'j For National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Attn: James S. Woods r f . n * *< 1 . j .?'.h rr MIDWEST RESEAnCH IMSflfUlE J2f> VOl.KEH UOULCVARD, KANSAS OUT. MISSOURI G4 1 10 '816 5GI-02O2 <. I '^l*1***^ ,.4*\ - J'J- ' L!  EVALUATION OF TOE ENVIRONMENTAL TOXICANTS VINYL CHLORIDE (VC) AMD VltfYLIDENE CHLORIDE (VDC) (Progress Report No. 9) ' ABSTRACT _>- * R&S 134510 We have continued to study the inhalation toxicity of various levels of vinyl chloride (VC) and one level of vinylidene chloride (VDC) in rats and mice. At the end of 6 months, rats of both sexes exposed to 50, 250, or 1,000 ppm of VC or 55 ppm of VDC, 6 hours a day, 5 days a week, did not show any significant adverse effects on various clinical laboratory data or cause any apparent gross or microscopic lesions. The weight gains of rats exposed to VDC were less than those of the controls. Exposure to 50, 250, or 1,000 ppm of VC- caused a number of deaths or early terminations in mice during the 21st to 26th week. The clinical signs in these mice included rough hair coat, lethargy, anorexia,' and sudden weight loss. The high level caused changes in the peripheral blood elements including decreased hematocrit, hemoglobin concentration and/or erythrocyte count, and neutrophilia wi-th a corresponding lymphopenia. The macrophage count in the lung washings was also elevated. All three levels caused acinar proliferation and/or bronchiolar adenoma; the middle and high level also caused angiosarcoma in the liver and/or mammary gland, ductular adenocarci noma, and squamous cell and anaplastic carcinoma' in the mammary gland. The squamous cell and anaplastic carcinomas metastasized to the lung. The in cidence and severity of these tumors were' in direct proportion to the levels of VC. In addition, malignant lymphoma occurred in the heart, lung, liver, spleen and kidney of one mouse exposed to the low level, and infiltrated the cervical tissue surrounding the trachea, blood vessels and esophagus of one mouse exposed to the high level. There was also a hemangioma' in the connec tive tissue attached to the salivary gland of one mouse exposed to the high level. The tumors were responsible for deaths or early terminations of some . mice. At 250 or 1,000 ppm of VC, nearly all mice that died or were terminated during the 21st to 26th weeks had tumors in one or more ' tissuesJ Exposure to the high level of VC also caused other lesions In the liver of some mice which were probably associated with angiosarcoma; these included infiltration of nucleated erythrocytes, focal degeneration with necrosis, and infiltration of inflammatory cells in the sinusoids and parenchyma. Exposure to 55 ppm of VDC for up to.6 months in mice did not cause any adverse signs, including changes in laboratory data or macrophage counts in the lung washings. At the end of 6 months, one male of the eight mice which were terminated had a mild bronchiolar adenoma and two other males had nild acinar proliferation in the lung. iv R&S 134511 IV. DISCUSSION AND CONCLUSIONS A. Rats Exposure of rats of both sexes at .6 hours/day and 5 days/week for up to 6 months to 50, 250, or 1,000 ppm of VC or 55 ppm of VDC did not cause *ny serious adverse effects. The weight gains of the female rats exposed to 55 ppm of VDC were less than those of the controls during the 6th month. The laboratory results, including hematology, clinical blood chemistry, serum imounoglobins, serum proteins, and macrophage counts in lung washings were not apparently affected. The cytogenetic effects as measured by chromosomal chan ges in bone marrow cultures are under evaluation. Collagen content in the liver and lung of these rats was not apparently altered. Exposure to VC or VDC did not cause any apparent changes in organ weights nor cause any lesions. B. Mice 1, Vinyl Chloride Exposure to various levels of VC caused a number of deaths in mice between the 21st and 26th weeks. There were two deaths in the group exposed to 50 ppm, three early terminations in the group exposed to 250 ppm, and four deaths in the group exposed to 1,000 ppm. .Clinical signs in these mice in cluded rough hair coat, lethargy, anorexia, and.sudden weight loss. One fe~ nale exposed to the middle level and three females exposed to the high level had tumors in the mammary gland which were from white to gray to dark red in color. Exposure to the high level of VC caused some changes in the peri pheral blood elements. There were decreases in hematocrit, hemoglobin con centration and/or erythrocyte count. Neutrophilia with a corresponding lympho penia occurred. These changes were not seen in the control mice or in mice exposed to 1,000 ppm of VC for 1, 2, or 3 months.U The macrophage count in the lung washings of mice of both sexes exposed to the high level was elevated. Since macrophage counts were not performed in mice exposed to the low or mid dle level, the possibility of a dose response relationship cannot be assessed. Exposure to various levels of VC did not cause any other apparent changes in peripheral blood elements or clinical blood chemistry tests.' As for rats, the cytogenetic effects as measured by chromosmal changes in the bone marrow cultures are under evaluation. Gross and microscopic examinations revealed chat 50, 250, or 1,000 ppa of VC caused acinar proliferation and/or bronchiolar adenoma in the lung. The middle and high level also caused angiosarcoma in the liver and various tumors in the mammary gland. The angiosarcoma was also found in the mammary 9 gland of two females and hemangioma in the connective tissue adjacent to the salivary gland of one male exposed to the high level. The pathogenesis or sequence of changes for the various tumors in the mammary gland is -complex. Whether the tumors started at first as ductular adenocarcinoma and then un derwent a metaplastic change to squamous cell and anaplastic carcinomas, or all tumors started simultaneously is questionable. However, the squamous cell and anaplastic carcinomas did metastasize to the lung, suggesting a strong malignancy of the neoplasms. In1addition, a marked, diffuse malignant lym phoma was found in the heart, lung, liver, spleen and kidney of one mouse exposed to the low level of VC and a malignant lymphoma infiltrated the cervical tissue surrounding the trachea, blood vessels and esophagus of one mouse exposed to the high level. Between the 5th and 6th months the var ious tumors occurred in five of 10 mice necropsied at 50 ppm, 10 of 11 mice necropsied at 250 ppm, and all 12 mice necropsied at 1,000 ppm. The severity of these tumors in the lung, liver, and mammary gland was also in direct proportion to the exposure level of VC. These tumors were responsible for the various deaths and early terminations of some mice. Exposure to the high level of VC also caused other lesions, probably associated with angiosarcoma, in the liver of some mice. These lesions were infiltration of nucleated erythrocytes, focal degeneration and necrosis, and infiltration of inflammatory cells in the sinusoids and parenchyma. Intra nuclear inclusions increased in the hepatic cells of two mice exposed to the .high level of VC. The significance of this increase as related to the treat ment is questionable. ' ' 2. Vinylidene Chloride Mice exposed to 55 ppm of VDC for up to 6 months did not show any adverse signs, any changes in laboratory data or macrophage counts in the lung washings. Cytogenetic effects are under evaluation. One male of eight nice terminated at the end of 6 months had a mild bronchiolar adenoma. Two other males had mild acinar proliferation in the lung. These three and another male also had increased intranuclear inclusions in the hepatic cells. The clinical significance of this increase is not understood. : 10 R&S 134512