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Nli-llS CONFERENCE NOTES c<r My S-v Lv S frc. y,,.j^ MAy , 9 19,7 COMPARATIVE METABOLISM AND TOXICITY OF VINYL CHLORIDE RELATED COMPOUNDS Bethesda, Maryland May 2, 1977 AGENDA: See attached Agenda / Dr. Dayid P. Rail', Director, NIEHS was Chairman of the first portion of the morning session, May 2, 1977. After the break. Dr. Hans Falk took over the Chairmanship. Manuscripts for summaries of the papers were not available at the meeting, and each uuthor was requested to submit their manuscripts to NIEHS for eventual publication in Environmental Health Frospectlves. Any request for oapers should be addressed to the Individual office rather than NIEHS. Dr. Caesar Maltoni - Recent Findings on the Carcinogenicity of Chlorinated Olefins. Dr. Maltoni discussed primarily the findings in the labs regarding_ ^ carcinogenicity of vinyl chloride and vlnylidene chloride. The following factors were used as an outline of his discussion: 1. 2i ^3. ... A.' 5. 6. 7. Molecular Structure Concentration Length of Treatment Route of Administration Species Strain Age * Dr. Maltoni then discussed his comparative results of testing of vinyl chloride and vinylidene chloride. With vinyl chloride, Maltoni found multiple tumors in rats, mice and hamsters following inhalation exposure to vinyl chloride. In the case of vinylidene chloride, the only tumor Dr. Maltoni reported was adenocarcinomas of the kidneys. He did not find any tumors in the rats or in hamsters. ' The dosage tested of vinylidene chloride was 25 ppm. With respect to concentration, Maltoni illustrated the vinyl chloride toxicity information using data for inhalation. The following was the table used: Vinyl Chloride Concentration 200 150 100 0 Liver Angiomas 12 5 1 0 Nephure Blastomas 3 7 10 0 Dr. Maltoni used this illustration to show that the incidents of tumors is not always dose related, as illustrated by the Nephur Blastomas. ASI 000012621 I 1 r Maltoni then gave data* again using vinyl chloride Inhalation exposure of 52, 17, 5 and 0 weeks exposure at two different concentrations, showing that the incidents of tumors is reduced with shorter periods of exposure. Ulth respect to routes of administration, Maltoni illustrated data comparing the level of toxicity in air as opposed to toxicity by oral administration. With vinyl chloride, the comparison was 10,000 ppm in air was roughly equivalent to 16 mg/kg body weight oral administration by gavage. Strain*- Maltoni indicated that the Sprague-Dawley strain was much more sensitive than the Wistar strain as it relates to vinyl chloride toxicity carcinogenicity. j Sex - Ulth the Swlas mice the males were much more sensitive than the females, ( l.e., the ratio of 24 to 1. >. .. Maltoni then gave some toxicity values- for vinylidene chloride for acute exposure, i.e., exposure four hours dal,ly for two days at concentrations of 200 ppm. He showed that ratB had no toxic effects of 200 ppm whereby mice there was toxic effects with the males being more sensitive than the females with each strain. Four strains of mice were tested with the following results: STRAIN AND SEX SURVIVORS Swiss Males Swiss Females BALB/C Males BALB/C Females C3H Males C3H Females' C57BL Males C57BL Females 9/60 60/60 6/30 30/30 13/30 19/30 23/30 50/30 Maltoni then discussed comparative toxicity of vinyl chloride at various ages of animals showing how in the newborn there is no difference between sex whereas at a later age there is a development of sex differences. It is probable that the differences has to do with oxidative enzyme development in the females. Dr. P. L. Viola - Carcinogenicity Studies on Vinylidene Chloride Dr. Viola reported his studies of vinylidene chloride using the Uistar rat exposed at 200 ppm. The following is a summary of his results: AST 000012622 Treatment Sex Numbers Tumor Bearing Tumor of Abdominal Lung Liver Percent Animals Cavity Tumor Tumor 200 opm 200 ppm Control Control M F M F 51 23 30 30 8 9 5 10 7 0 1 16 8 1 0 39 5 0 0 17 0 1 0 33 On the Strague-Dawley rats the following was found: `Treatment Sex Numbers of Animals Tumor Bearing Animals Percent 100 opm 100 opm 75 Dpm 75 ppm Control Control M F M F M F 30 30 16 20 , 30 30 3 10 17 57 16 9 43 00 15 50 It would appear that no conclusive results were obtained by Dr. Viola. It was unclear as to exactly What experimental protocol was used. Dr, L, W. Rampy - Toxicity and Carcinogenicity Studies on Vinylideni'Chloride. Dr. Rampy reported the long term studies as sponsored by the Manufacturing Chemists Association at the Dow Chemical Laboratories. These studies include a fwo year drinking water study in rats and a two year inhalation study. The studies are not yet completed with respect to histqpathological examination of all, tissues, however all animals have been sacrificed and gross observations made. Dr. Rampy gave the purity of vlnylidene chloride including any contaminant such as vinyl chloride. There Was considerable variation in the vinyl chloride content of the vlnylidene chloride with some values being in excess of 1,000 ppm. The protocol for the study includes`a companion 90 day study and a three generation reproduction study. The dosage concentration was 0, 60, 100 and 200 Dpm in the drinking water, with 8-0 animals per sex in the control and 48 animals per sex in each of the treated groups. All drinking water was assayed, with an 8 to 10% overage of vlnylidene chloride determined. There was no effect on body weight or food intake due to the dietary treatment, excepting that at some intervals there was variation which may or may not be due to the experimental treatment. Mortality - there was little difference in mortality incidents at various intervals, however it was somewhat higher at ome intervals in the treatment groups as opposed to the controls. Throughout the study there did-not appear to be a significant decrease in body weight due to experimental treatment. Dr. Rampy gave values on the tumor incidents, with no apparent increase due to experimental treatment of the tumors which were discussed. Overall there was no increase in tumor numbers or number of animals with tumors. The final report has not yet been prepared. ASI 000012623 With respect to the Inhalation study, this was conducted using the Sprague-Davley rat with initial concentrations of 10 and 40 pptu. After completion of the subacute phase, the dosage was increased to 25 and 75 ppm. There was little effect on erowth and mortality was slightly higher in the treated group. The toxic effects were questionable reduction in testicular weight following 30 days of treatment, however this was not observed at later times. No other observation in the Inhalation study was consistent. Following the presentation of Dr. Rampy, there was a question and answer program. The first question had to do with the lowest concentration of vinyl chloride which would produce maunary tumors, the question was addressed to Dr. Maltoni. Dr. Maltoni said that he would not have the completion of his ongoing studies until mid-June, and at that time could report the results of low level Inhalation exposure. Dr. Rudolph Jaeger - from Harvard, then discussed Circadian Rhythms as it relates to possible detoxification mechanisms and Influence of treatment timing upon detoxification. Dr. Jaeger said there was a ten to one hundred fold differences in the glutathion concentration in blood and liver, which was related to eating patterns. The lowest concentration being in the evening, where the animals would not be exposed to the inhalation work. There also was discussion of mixed function oxidase, with the differences between the sexes probably being due to the concentration of these enzymes, i.e., the female .has higher level than the male. Dr. E. K. Weisburger - Carcinogenicity Studies of tfalogenated Hydrocarbons Dr. Weisburger discussed the contract with Hazleton Laboratories in which several halogenated hydrocarbons were evaluated in a carcinogenic bioassay program using the Osborne-Mendel rat and (C57BL X CSHJF^ mice. She outlined the program from the standpoint of the acute dose ranging, using 10 small groups of animals, and determining the levels to be used in subacute studies. 8 week pilot programs were initiated using five males and 5 female rats in each group. All exposures were done by oral gavage using cottonseed or other edible oil as the carrier. Carbon tetrachloride was used as a positive control in these studies. The duration of exposure was 78 weeks, followed by a 12 week post-treatment period in the mice and a 32 week post-treatment period in rats, for a total of 90 weeks mouse study and 110 weeks rat study. Dr. Weisburger Indicated that reports had been written on trichloroethylene chloroform and 1,1,1 trichloroethylene. She also said that a paper by Olson, et al regarding Ethylene dibromlde and l,2-dibromo-3-chloropropane has been published (J NCI 51 1993, 1973). Dr. Weisburger reported the carcinogenicity of the TCE and Chloroform, and the fact that 1,1,1 Trichloroethylene had no effect on the rats or mice. Dr. Weisburger also discussed the results of 1,2-dichloroethane, l.l^dichloroethane, 1,2-trichloroethane, hexachloroethane, 3-chloropropane and tetrr.chloroethylen.3. All of these compounds provoked tumors in the mouse excepting 3-chloropropane. ASI 000012624 5 Dr. B. L. Van Duuren - Chemical Structure, Reactivity and Carcin genldty of Halohydrocarbona. Dr. Van Duuren discussed possible mechanisms for activation of the hal genated hydrocarbons* using Trichloroethylene as an example. He discussed the formation of peroxides or free radicals as potential mechanisms. Dr. Van Duuren discussed nossible substitutes for trichloroethylene* Indicating that methalene chloride had been substituted for trichloroethylene In the manufacture of Sanies. He was concerned about the possibility of carcinogenicity of methylene chloride and said It "should be looked at". Dr. Van Duuren then discussed metabolic studies on several compounds, Including perchlcroethylene and tetrachloroethylene* including potential metabolites such as epichlorhydrln and elycydaldehyde. Van Duuren also discussed his attempts to trap intermediates* and using mercaptan derivatives. He had been unsuccessful In those attempts. Dr. Koclba - Chronic Toxicity and Reproduction Studies with Rats Clven Hexachlorobutadiene. Dr. Koclba reported results of reproduction studies using 0,0.2,2, and 20 mg/kg of Hexachlorobutadiene orally. _ Using adult animals, he found toxicity at 20 mg/kg, lesser effects at"2 mg/kg, and no effect at the 0.2 mg/kg. In the long term toxicity studies he observed at 20 mg/kg kidney nodules, kidney neoplasia and kidney hyperplasia. At 2 mg/kg kidney hyperplasia and 0.2 mg/kg there was no effects. WithI* respect to the kidney neoplasia the following'was observed: DOSAGE Males Renal Adenomas 0 1/90 0.2 0/40 2.0 i 0/40 20.0 2/39 Renal Adenoma Carcinomas 0/90 1/90 0/40 0/40 0/40 0/40 7/39 9/39' Females Renal Adenomas 0/90 . 0/40 0/40 3/40 Renal Adenoma Carcinomas 0/90 0/90 0/40 0/40 0/40 0/40 3/40 6/40 It was concluded that there was a dosage effect upon tumor incidents of hexachlorobutadiene. * ASI 000012625 t Dr. C. C. Lee - Toxicity and Carcinogenicity of Vinyl Chloride Compared to Vinylidene Chloride Or. Lee conducted hie work at the Mid-West Research Institute, Kansas City, MO. under the contract from MIEHS. The protocol used was inhalation exposure, with rats and mice, with 36 animals per sex per group. With vinyl chloride the concentrations were 50, 25Q and 1.000 ppm with vinylidene chloride the concentrations were 55 ppm. Inhalation exposure was 6 hours per day, 5 days per week. There were Intermediate terminations of animals at 1, 2, 3, 6 and 9 months, and the study was terminated at 12 months. With respect to the vinylidene chloridep^r. Lee found 7 mice exposed to 55 opm vinylidene chloride had bronchial alveolar adenomas, as compared to one mouse in the control group. Dr., Lee also reported Hepatic anglosacoma in females exposed to the 5 ppm vinylidene chloride. With respect to malignant lymphoma he found it in the vinyl chloride but not in vinylidene chloride. Lee found the rats more sensitive to vinyl chloride than mice. Dr. Maltonl questioned Dr. Lee as to the strain of mice. The answer was CD1. Dr. Maltoni said that the dosages used by Lee is much higher than could be tolerated in the four strains of rats tested in Italy. Maltoni also pointed out that there was no anglosacoma reported in the Italian studies. There was a good deal of discussion as it relates to the method of administration of the vinyl chloride and vlnyli&ene chloride in the inhulation chambers, and the possibility of cairy-tver in that the same chambers were used for both compounds. The measurement of the gases in the chamber was by gas chromatograph using a carbontetrachloride standard. Dr. Lee was not certain as to whether the same columns were used for both gases, and whether the separation between the vinyl chloride and vinylidene chloride was such that there could be a determination of cross contamination. Dr. Lee also reported the results of acute studies of vinyl chloride and in vinylidene chloride found acute hepatitis in 5 days after exposure to vinylidene chloride at sublethal doses. WAO/lr ASI 000012626 AGENDA MAY Conference On COMPARATIVE METABOLISM AMD TOXICITY OF VINYL CHLORIDE RELATED COMPOUNDS Hay 2-4, 1977 9197? Monday. Mav 2 SESSION I Carcinogenicity of Halogenated Olefins Chairman: Or. David P. Rail, NIEHS 8:30 a.m. 8:40 a .m. 9:00 a.m. 9:20 a .m. 9:40 a.m. 10:10 e.n. 10:30 a.m. 10:50 a.m. 11:10 a.m. ir 11:30 a.m. 11:50 a.m. 12:30 p.m. Welcome and Introduction - Dr. Rail Recent Findings on the Carcinogenicity of Chlorinated Olefins Dr. C. Maitoni Carcinogenicity Studies on VlTfyJIdene Chloride Dr. P. L. Viola Toxicity and Carcinogenicity Studies on Vinylidene Chloride Dr. L. U. Rampy Discussion COFFEE BREAK Carcinogenicity Studies of Halogenated Hydrocarhcns Dr. Elizabeth K. Weisburger Chemical Structure, Reactivity and Carcinogenicity of Halchydrocarbons Dr. B. L. Van Duuren Chromic Toxicity and Reproduction Studies with Rets Given Hexachlorobutadisr.e Dr. R. J. Kocibs Toxicity and Carcinogenicity ef Vinyl , Dr. C.-C. Lee Chlorine Compared to Vinylidene Chloride Discussion LUNCH BREAr (Special Line in Cafeteria, Building 10) SESSION II Mutagenicity and Teratogenicity of Halogenated Olefins Chairman: Dr. Raymond Shapiro, NIEHS 1:30 p.m. 1:50 p.m. 2;10 p.m. 2:30 p.m. 3:00 p.m. 3:30 p.m. 3:50 p.m. 4:10 p.m. 4:30 p.m. 4:40 p.m. Mutagenicity of Halogenated Olefins Metabolism and Mutagenicity of Halogenated Olefins -- A Comparison of Structure and Activity Toxicity and Mutagenicity of Dibromoethane and Related Compounds DISCUSSION COFFEE BREAK Mutagenicity of Halogenated Olefins Placental Transfer of Trichloroethylene Comparative Mammalian Metabolism of Vinylider.e and Vinyl Chlorides in Relation to Outstanding Oncogenic Potential Transplacental Toxicity of Placidyl (Ethchlorvynol) in Rats DISCUSSION Dr. A. J. Garro Dr. 0. Henschler Dr. H. S. Rosenkranz Or. Nicola Loprieno Dr. S. Laham Or. D. E. Hathway Or. William Jurgelski ASI 000012627 Tuesday. May 3 2 SESSION III Halothane Chairman: Dr. Terri Damstra, NIEHS 8:30 a.m. 8:SO a.m. v 9:10 a.m. 9:30 a.m. 10:00 a.m. 10:30 a.m. 10:50 a.m. 11:10 a.m. 11:30 a.m. 11:50 a.m. 11:55 a.m. 12:30 p.n. Absorption, Blotransformatton and Storage Of Halothane The Relationship of Enzyme Induction to Neptirppathy Duo to Halothane and Related Compounds Bioactivation and Covalent Binding of Halothane to Liver Macromolecules DISCUSSION COFFEE BREAK Metabolism of Halothane and Toxicity of 1,1 tl-tr1f1uoro>2-chlorcethant. Behavioral and Neuropathological Effects of Prenatal Halothane The Effects of Halothane on Fetal Brain Metabolism Trace-Level Enflurance Exposure In Pregnant Rats Mutagenic Activity Detected in the Urines of Anesthesiologists DISCUSSION LUNCH CREAK Dr. 0. A. Holiday Dr. B. A. Hitt Dr. 1. G. Sipes Dr. B. R. Brown Robert E. Bowman Dr. R. C. Vannuccl Dr. M. L. Nahrwold- * Dr. H. S. Rosenkranz / SESSION IV Absorption, Metabolism, and Interaction of Halogenated Olefins Chairman: Dr. V. B. Vouk, WHO, Geneva 1:30 p.m. 1:50 p.m. 2:10 p.m. 2:20 p.m. 2:40 p.m. 3:10 p.m. 3:40 p.m. 4:00 p.m. 4:20 p.m. 4:40 p.m. Metabolism of Halcger.ated Olefins Dr. K. C. Loibman The Pharmacokinetics of VinylIdene Chloride Dr. M. J. McKenna in the Rat -- Comparison with Vinyl Chloride The Effect of Various Pretreatments on the Acute Lethality of Inhaled Vinylidene Chloride ,R. D. Short Binding of Halogenated Olefins to Macromolecules Dr. H. M. Bolt OISCUSSION COFFEE BREAK Damage to Cellular Membranes by Chlorinated Olefins with Emphasis on Synergism and Antagonism Dr. E. S. Reynolds The Oral Toxicity of Vinylidene Chloride in Dr. M. E. Andersen the Rat: Effects of Sex, Age and Fasting influence of Aliphatic Alcohols on the Dr. H. Cornish Hepatotoxic Response to Halogenated Olefins DISCUSSION ASI 000012628 1?TOT 3 Wednesday. Mav 4 SESSION V Toxicity of Halogenated Olefins Chairman: Or. Sheldon Murphy, Harvard School of Public Health 8:30 a.m. 8:50 a.m. 9:10 a.m. 9:30 a.m, 10:00 a.m. 10:30 a.m. 10:50 a.m. 11:10 a.m. 11:30 a.m. 11:50 a.m. 12:30 p.m. Toxicology of Chloroprene. 1,3-D1ch1oro2-butene, and 1,4-01chloro-2-butene Or. J. J. Clary Mechanism of Action; Tissue Distribution, Dr. R. J. Jaeger and Cov'alent Binding cf Vinyl!dene Chloride Acute Hepatotoxlclty of Ethylene and Rory Conolly Halogenated Ethylenes After PCB Pretreatments DISCUSSION COFFEE BREAK Quantitative Relationship Between Halogenated Dr. M. Ikeda Olefins In Working Environment and Urinary Elimination of Metabolites In Man Human Exposure to Tetrachloroethylene -- Inhalation and Skin Contact . Dr. Carl L. Hake Pulmonary Edcr* on Hunwn Exposure to Tetrachloroethylene Dr. R. Patel Pathologic Chances and Behavioral Deviations Dr. L. W. Chang Followin'. Exposure to Halothane .. DISCUSSION * LUNCH BREAK SESSION VI 'T 1:30 p.m., 1:50 .p.m.; 2:10 p.m. 2:30 p.m. 3:00 p.m. 3:30 p.m. 3:50 p.m. 4:10 p.m. 4:30 p.m. 4:50 p.m. 5:20 p.m. Halogenated Olefin Groups in Other Important Chemicals Chairman: Dr. Hans L. Falk, hlEHS Dehalogenatlon and Degradation of Nomatoeides -- The Nature of the Active Mctaholltes Metabolism and Toxicity of Pyrcthroids with Dinalovinyi Substituents The Chemical Reactivity -- Absorption, Retention, Metabolism, and Elimination of Hexachlorocyelopentadiene DISCUSSION COFFEE BREAK The Presence of the Halo Olefin Group In Chemicals of Industrial, Environmental and Medicinal Significance Health Risks Associated with Halogenated Olefins Besides Vinyl Chloride Species Differences In Metabolism and Toxicity of Trifluoroethyl Vinyl Ether Dechlorination Mechanisms of Chlorinated Olefins DISCUSSION Overview and Summary - Dr. Sheldon Murphy Dr. C. E. Castro Dr. Luis 0. Ruzo Dr. H. M. Mehendale Dr. Herbert S. Posner Dr. P. F. Infante Dr. V. Flserova-Bergerova Dr. R. A. Van Dyke / I im ran iro n ASI 000012629 * LIST OF ATTENDEES Dr. T. R. Aalto Tenneco Chemicals P 0 Box 365 Piscataway, NJ 08854 Dr. Roy E. Albert Institute of Environmental Medicine New York University Medical Center 550 1st Avenue New York, NY 10016 Dr. Elizabeth Anderson Environmental Protection Agency 401 M Street, S.W. Room 415, West Tower PM 223 Washington, DC 20460 Dr. Melvin E. Andersen NMRI/TD * , Building 433, Area B Wright Patterson AFB Dayton, OH 45433 Dr. Kenneth C. Back 6570 AMRL/THT. Wriqht Patterson AFB Dayton, OH 45433 Dr. Raymond E. Bahor National Cancer Institute Pharmacology - Toxicoloqy Program Bethesda, MD 20014 Miss Doris Baldwin Department of Labor OSHA, Room N3641 3rd and Constitution Avenue, N.W. Washington, DC 20210 Dr. Erwin Baumel National Institute of Occupational Safety and Health Rockville, MD 20857 Dr. Bernard Becker Abbott Laboratories Department 468 Abbott Park North Chicago, IL 60064 Dr. George Bierbower Bureau of Biomedical Science Consumer Product Safety Comnisslon Washington, DC 20207 Dr. Eula Bingham I Assistant Secretary for Occupational | Safety and Health 1 Department of Labor Room S 2315 200 Constitution Avenue, N.W. Washington, DC 20210 Dr. Marvin J Bleiberg Division of Tbxicology HFF-152 Bureau of Foods, Food and Drug Administration Washington, DC 20204 Dr. Herbert Blumenthal Division of Toxicology Food and Drug Administration 200 C Street, S.W. Washington, DC 20204 Dr. H. M. Bolt Institute of Toxicology University Tubingen - D-74 Tubingen Wilhelm strasse 56 WEST GERMANY Mr. J. J. Bonin Regulatory Affairs Representative Shell Oil Company, Suite 200 1025 Connecticut Avenue, N.W. Washington, DC 20036 ASI 000012630 1 2 Or. Robert E. Bowman Department of Psychology The University of Wisconsin 22 N. Charter Street - Primate Lab Madison, WS 53706 Dr. Louis W. Chang Department of Pathology The University of Wisconsin 470 North Charter Street Madison, WI 53706 Dr. Carl Breech Food and Di^ug Administration 8757 Georgia Avenue HFK-400 Silver Springs, MD 20910 Mr. Richard C. Brooke Approvals Manager Borg-Warner Chemicals P 0 Box 68 Washin*gton, WV 26181 Dr. Burnell R. Brown, Jr. Department of Anesthesiology The University of Arizona Arizona Medical Center Tucson, AZ 85724 i Dr. Thomas Cameron National/Institutes of Health National Cancer Institute Bethesda, MD 20014 Mr. Pheophilus R. Carson Food and Drug Administration HFF-152 200 C Street, S.W. Washington, DC 20204 Dr. C. E. Castro Department of Nematology University of California, Riverside Riverside, CA 92502 Dr. Ke-Chang Chen Head, Biomedical Science General Motors Corporation REB, Room 106 12 Mile and Mound Roads Warren, MI 48090 Dr. I.^Chu Environmental Toxicology Division Environmental Health Center Tunneys Pasture Ottawa KIA 0L ' CANADA Dr. Ken Chu National Institutes of Health National Cancer Institute Bethesda, MD 20014 a Mr. Joseph Cirvello Environmental Protection Agency Mall Drop 12 Research Triangle Park, NC 27711 Dri Margaret Clark ,11921 Goya Drive Potomac, MD 20854 Dr. John J. Clary Haskell Laboratory for Toxicology and Industrial Medicine E. I. Du Pont de Nemours Company Wilmington, DE 19898 Dr. Jerry Chandler National Institute of Occupational Safety and Health 5600 Fishers Lane Criteria Development Branch Rockville, MD 20857 Mr. Joe Colony National Aeronautics and Space Administration, 313 Goddard Space Flight Center Greenbelt, MD 20771 Dr. Rory Conolly Department of Physiology Harvard School of Public Health 665 Huntington Avenue Boston, MA 02115 ASI 000012631 T Dr. Herbert H. Cornish Department of Industrial Health University of Michigan 3550 School of Public Health Ann Arbor, MI 48104 Ms. Madge Crouch Bureau of Biologies Building 29 National Institutes of Health Bethesda, MD 20014 Ms. Terry L. Crutcher National Institutes of Health Building 13, Room 3K07 Bethesda, MD 20014 I Dr. Cipriano Cueto Acting Chief, Carcinogen Bioassay and Program Resources Branch Division of Cancer Cause and Prevention National Cancer Institute Bethesda, MD 20014 Dr. Terri* D^mstra National'Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 Dr. P. R. Datta Environmental Protection Agency WH 568 0BB 401 M Street, S.W. Washington, DC 20460 Dr. Robert L. Dedrick National Institutes of Health Building 13, Room 3W13 Bethesda, MD 20014 Mr. A1 Del Grosso Bureau of Biologies Food and Drug Administration Building 29A, Room 1 DIO 8800 Rockville Pike Bethesda, MD 20014 Dr. J. Fielding Douglas National Institutes of Health National Cancer Institute Bethesda, MD 20014 Dr. Julie Du Cancer Center University of Louisville Louisville, KY 40201 Dr. George D. Duda Division of Biomedical and Environmental Research Biomedical Programs . Washington, DC 20545 Dr. Virginia Dunkel National Institutes of Health National Cancer Institute Bethesda, MD 20014 Mr. William Edwards National Institutes of Health Bureau of Biologies Building 29 Bethesda, MD 20014 Mr. A. J. Eschenbach W. R. Grace and Company . 62 Whlttenmore Avenue Cambridge, MA 02140 Dr. Hans Falk National Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 Dr. Henry Falk Center for Disease Control Building 1, Room 5127 1600 Clifton Road Atlanta, GA 30333 Dr. Vera Fiserova-Bergerova ' Department of Anesthesiology University of Miami (Medicine) P 0 Box 520875 Biscayne Annex . Miami, FL 33152 ASI 000012632 aSgd . stga ------ - 3) Dr. Lawrence Fishbeln National Center for Toxicological Research Jefferson, AR Dr. Jean French National Institute of Occupational Safety and*Health Office of Extramural Coordination and Special Projects Parklawn Building 5600 Fishers Lane Rockville, MD Dr. A. J. Garro Associate Professor Mt. Sinai School of Medicine of the City University of New York Fifth Avenue and 100th Street New York, NY 10029 Ms. Helga Gerstner TIRC Oak Ridge National Laboratory Building 7509 P 0 Box X , Oak Ridqe, TN 37830 Dr. Jack Giacin Food Science Department Cook College Box 231 Rutgers Unversity New Brunswick, NJ 08903 Dr. Seymour Gilbert Food Science Department Cook College Box 231 Rutgers University New Brunswick, NJ 08903 Mr. Richard H. Glover National Institutes of Health Building 13, Room 3K07 Bethesda, MD 20014 Dr. Leon Golberg Chemical Industries Institute of Toxicology, P 0 Box 12137 Research Triangle Park, NC 27709 Dr. B. M. Goldschmidt New York University Medical Center New York, NY Dr. John Goode Industrial Biotest Laboratory 1800 East Pershing Road Decatur, IL 62526 Dr. Richard Griesemer National Institutes of Health National Cancer Institute Bethesda, MD 20014 MsBetsy Grim Bureau of Biologies Food and Drug Administration Building 29A, Room 1010 8800 RockvilH Pike Bethesda, MD 20014 - ^ j ; Mr. Fred Gross National Aeronautics and Space Administration Goddard Spac Flight Center, 313 Greenbelt, MD 20771 Dr. F. Peter Guengerich Assistant Professor of Biochemistry Vanderbilt University Center in Toxicology, School of Medicine Station 17 Nashville, TN 37232 Dr. Rizwanul Hague Environmental Protection Agency Office of Water Supply WH 550 401 M Street, S.W. Washington, DC 20460 Or. Carl ,L. Hake Department of Environmental Medicine The Medical College of Wisconsin 8700 West Wisconsin Avenue Milwaukee, WI 53226 ASI 000012633 1 Or. Elliott Harris National Institute of Occupational -1 Safety and Health Taft Laboratory 4676 Columbia Parkway Cincinnati, OH 45226 Dr. Robert Harris Environmental Defense Fund 1525 18th Street, N.W. Washington, DC 20036 ! Dr. D. E. Hathway Central Toxicology Laboratory Imperial Chemical Industries LTD Nr. Macclesfield Cheshire SK 10 4TJ UNITED KINGDOM Dr. D. Henschler Institute of Toxicology Universitat of Wurzburg D-8700 Wurzburg - Versbacher LandstraBe 9, WEST GERMANY Dr. Joseph Highland Environmental Defense Fund 1525 18th Street, N.W. Washington, DC 20036 Dr. Steve Hilbert National Institutes of Health Bureau of Biologies Building 29 Bethesda, MD 20014 Dr. R. K. Hlnderer n Ethyl Corporation Toxicology and Industrial Hygiene Department Ethyl Tower, 451 Florida Baton Rouge, LA 70801 Dr. Ben A. Hitt Research Biochemist Palo Alto Veterans Administration Hospital 1 Palo Alto, CA 94304 Dr. D. A. Holaday Department of Anesthesiology University of Miami School of Medicine P 0 Box 520875 - Blscayne Annex Miami, FL 33152 Dr. David Holbrook University of North Carolina Division of Biochemistry Chapel Hill, NC 27514 Ms. liana Howarth National Institute of Occupational . Sifety and Health Room 340, 5600 Fishers Lane Rockville, MD 20857 Miss Judith Hushon Mitre Corporation Westgate Research Park McLean, VA 22101 Dr. George Ikeda Food and Drug Administration Route 2, Box 277 Laurel, MD 20811 Dr. Masayukl Ikeda Department of Hygiene Tohoku University School of Medicine Selryocho 2-1 . Sendai, 980, JAPAN Dr. Peter F. Infante National Institute of Occupational Safety and Health 4676 Columbia Parkway Cincinnati, OH 45226 Dr. Joseph K. Inscoe Bureau of Drugs, BD, 160 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20852 Dr. Rudolph J. Jaeger Assistant Professor of Toxicology Harvard School of Public Health 665 Huntington Avenue Boston, MA 02115 ASI 000012634 6.:- / * zj* i Dr. M. N. Johnson Administrator Environmental Health Products The B. F. Goodrich Company 500 South Main Street Akron, OH 44318 Mr. Roderick B. Judge Hatco Chemical Divison U. R. Grace & Company King George Post Road Fords, NJ 08863 Mr. Bob Jungers Environmental Protection Agency National Environmental Research Center Mall Drop 78 Research Triangle Park, NC 2771] Dr. Myra Karstadt U. S. General Accounting Office Room N1649 New Department of Labor Building 200 Constitution Avenue, NW Washington, DC Dr. E. J* Kerfoot BASF Wyandotte Corporation 1609 Biddle Avenue Wyandotte, MI 48192 Dr. R. J. Koclba Toxicology Research Laboratory Health and Environmental Research Dow Chemical Company, USA Midland, MI 48640 Dr. Charles Kokoskl Division of Toxicology Food and Drug Administration HFF-152 200 C Street, S.W. Washington, DC 20204 Dr. Mary Kornreich Mitre Corporation Westgate Research Park McLean, VA 22101 Dr. Steven Krop Food and Drug Administration BD HFD 413 200 C Street, S.W. Washington, DC 20204 Dr. Robert Kuna Box 45 Exxon Linden, NJ 07036 Dr. Souheil Laham . Senior Research Scientist Inhalation Toxicology Section Environmental Health Centre Tunney's Pasture Ontario K1A 0L2, CANADA Dr. Cheng-Chun Lee Biological Science Division Mtdwest Research Institute Kansas City, MO 64110 Dr. Kenneth C. Lelbman Professor of .Pharmacology University of Florida J. Hill Is Miller Health CenterGainesville, FL 32610 Mr. Frank Letklewicz Environmental Protection Agency Office of Toxic Substances Mail Drop WH 557 401 M Street, S.W. Washington, D*C. 20460 Dr. Trent Lewis National Institute of Occupational Safety and Health 4676 Columbia Parkway Cincinnati, OH 45226 Dr. William C. Mackrodt ICI Corporate Laboratory Runcorn, Cheshire ENGLAND Dr. Yuji Maeda Kreaha 1 5528 South Hyde Park Boulevard , Chicago, IL 60637 Dr. Harry Mahar Mitre Corporation Westgate Research Park McLean, VA 22101 ASI 000012635 T 8 Dr. Roscoe Moore, Jr. National Institute of Occupational Safety and Health Room 3-40, Park Building 5600 Fishers Lane Rockville, MD 20857 Ms. Mary Moslen Department of Pathology University of Texas, Medical Branch Galveston, TX 77550 Dr. Sheldon D. Murphy Harvard School of Public Health 665 Huntington Avenue Boston, MA 02115 Ms. Anne Mustafa Bureau of Biologies Food and Drug Administration Building 29A, Room 1D10 8800 Rockville Pike Bethesda, MD 20014 ' Dr. Michael L. Nahrwold Assistant Professor of Anesthesiology The Milton S. Hershey Medical Center The Pennsylvania State University Hershey, PA 17033 Dr. Jessie Norris Dow Chemical Company, USA P 0 Box 1706 Midland, MI 48640 Dr. William Olson Consultant 2347 Paddock Lane Reston, VA 22091 Dr. Thomas Orme National Institutes of Health National Cancer Institute Bethesda, MD 20014 Dr. Rita Orzel Consumer Product Safety Comnlsslon 5401 Westbard Avenue, Room 100 Bethesda, MD 20207 Mr. Boris Osheroff Principal Environmental Officer Parklawn Building Room 17A46 5600 Fishers Lane Rockville, MD 20857 Mr. Clyde Overlander Bureau of Drugs, BD 160 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20852 Mi% William B. Papageorge Monsanto Company 800 Lindbergh St. Louis, MO 63166 Dr. Ramesh Patel . Division of Adult Cardiology Cook County Hospital 1825 West Harrison Street Chicago, IL 60612 Dr. W. A. Patterson W. R. Grace & Company P 0 Box 464 Duncan, SC 29334 Mr. Robert Philips Department of Microbiology Mt. Sinai School of Medicine 5th Avenue and 100th Street New York, NY 10029 Dr. Warren Piver National Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 Dr. Herbert Posner National Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 Mr. James H. Price, Jr. Air Quality Evaluation Division Texas Air Control Board 8520 Shoal Creek Boulevard Austin, TX 78758 ASI 000012637 Mr. Edward Raden National Institutes of Health Building 13, Room 3K04 Bethesda, MD 20014 Dr. Martha J. Radike Department of Environmental Health University of Cincinnati Medical Center 3223 Eden Avenue Cincinnati, OH 45267 Dr. David P. Rail Director National Institute of Environmental, Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 4 Dr. Larry Rampy Toxicology Research Laboratory Health and Environmental Research Dow Chemical Company Midland, MI 48640 Mr. Robert Rauch Environmental Defense Fund 1525 18th Street, N.W. Washington, DC 20036 Dr. Edward S. Reynolds Department of Pathology The University of Texas Medical Branch Galveston, TX 77550 Mr. Charles Rigg Occupational Safety and Health Administration Department of Labor Washington, DC 21210 Dr. H. S. Rosenkranz Department of Microbiology New York Medical College Basic Science Building Valhalla, NY 10595 Dr. Larry Rosenstein Biology Division Environmental Protection Agency National Environmental Research Center Mail Drop 74 Research Triangle Park, NC 27711 Dr. Robert Rubin Department of Environmental Health Sciences Johrs Hopkins School of Hygiene and Public Health 615 North Wolfe Street Baltimore, MD 21205 Dr. Luis 0. Ruzo Division Entomology and Parasitology University of California, Berkeley Berkeley, CA 94720 Mr.^Sheldon Samuels Industrial Union Department AFLCIO 815 16th Street, N.W. Washington, DC _20006 Mr. Robelan Sboloyi Stanford Research Institute 1611 North Kent Street Rossalyn Plaza Arlington, VA #22209 Dr. M. Schulman Division of Biomedical and Environmental Research U.S. Energy Research Development and Administration Washington, DC 20545 Dr. Alberta M. Schumacher National Cancer Institute Bleir Building, 523 Bethesda, MD 20014 Dr. Irving J. Selikoff Mt. Sinai School of Medicine 5th Avenue and 100th Street New York, NY 10029 Dr. Raymond Shapiro National Institute of Environmental Health Sciences Room 17A46, Park!awn Building 56000 Fishers Lane Rockville, MD 20857 Dr. Samuel I. Shibko Division of Toxicology HFF-150 Food and Drug Administration 200 C Street, S.W. Washington, DC 20204 ASi 000012636 Dr. Robert D. Short Midwest Research Institute 425 Voelker Boulevard Kansas City, MO 64110 Dr. Sidney Siegel National Institutes of Health National Cancer Institute Bethesda, MD 20014 Ms. Jenny Sih Bureau of Biologies Food and Drug Administration Building 29A, Room 1D10 8800 Rockville Pike Bethesda, MD 20014 Dr. I. Glenn Sipes Department of Anesthesiology The University of Arizona Arizona Medical Center Tucson, AZ 85724 Dr. Brian Smith National Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 Dr. Robert C. Sonders Abbott Laboratories D-463, AP-9 North Chicago, IL 60064 Dr. Jerry Stara Environmental Protection Agency 26 West St. Clair Street Cincinnati, OH 45268 Dr. Harvey Stein National Institute of Occupational Safety and Health Room 3-40, Park Building 5600 Fishers Lane Rockville, MD 20857 Dr. Klaus Steamer College of Medicine University of Cincinnati 3223 Eden Avenue Cincinnati, OH 45267 Dr. Joe Strasser Dow Chemical Company, USA Saran and Converted Products 1603 Building Midland, MI 48640 Mr. Wade Talbot Environmental Protection Agency Health Effects Division RD 683 401 M Street, S.W. Washington, DC 20460 Dr. Carlo H. Tamburo Department of Medicine University of Louisville School of Medicine Preston and Walnut Streets Louisville, ICY 45201 Dr. Alam Sundaram Department of National Health & Welfare Environmental Health Center Tunney's Pasture Ottawa K1A 0L2 CANADA Dr. Richard Thomas Stanford Research Institute 1611 North Kent Street Rossalyn Plaza Arlington, VA 22209 Captain Joseph Thomaslno Occupational and Environmental Medicine Division U.S. Army Environmental Hygiene Agency AGG, MD 21010 Mr. Lad Thomka Dow Chemical Company, USA 2040 Dow Center Midland, MI 48640 Dr. George Thompson Epidemiology Unit Food and Drug Administration HFF-108 200 C Street, S.W. Washington, DC 20204 ASI 000012639 Mr. T. R. Torkelson Corporate Medical Department The Dow Chemical Company, USA Bennett Building 2030 Dow Center Midland, MI 48640 Dr. Frode UJvedal Environmental Protection Agency Health Effects Division RD 683 401 M Street, S.W. Washington, DC 20460 Dr. Kris Vadlamudi Food and Drug Administration HFK-400 8757 Georgia Avenue Silver Springs, MD 20910 Dr. Lawrence Valcovic National Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 Dr. B. L, Van Duuren New York University Medical Center Institute Environmental Medicine 550 First Avenue New York, NY 10016 Dr. Russell A. Van Dyke Department of Anesthesiology Mayo Clinic Rochester, MN 55901 Dr. R. C. Vannucci Pediatric Neurology The Milton S. Hershey Medical Center The Pennsylvania State University Hershey, PA 17033 Dr. Pier Luigi Viola Isituto Regina Eleno Per lo Studio e la Cura dei Tumori Viale Regina Eleno, 291 ROME, ITALY u Dr. V. B. Vouk Chief, Control of Environmental Pollution and Hazards World Health Organizations 1211 Geneva 27 SWITZERLAND Mr. R. Walcott Stanford Research Institute Rosslyn Plaza Rosslyn, VA Ms. Helen Warren Toxicology Information Response Center ORNL, Building 2509 P 0 Box X Oak Ridge, TN 37830 Dr. David Warshawsky University of Cincinnati MedicaT-Center Department EH 3223 Eden Avenue Cincinnati, OH 45267 Mr. J. Coleman Weber Manager, Product Acceptability Monsanto Industrial Chemicals Company 800 North Lindbergh Boulevard St. Louis, MO 63166 Dr. Elizabeth Weisburger National Cancer Institute Building 37, Room 3B27 Bethesda, MD 20014 Dr. Kathaleen Weston Stanford Research Institute 1611 North Kent Street Rosslyn Plaza Arlington, VA 22209 Mr. Roscoe Wheeler Bureau of Biologies Food and Drug Administration Building 29 A, Room 1D10 8800 Rockville Pike Bethesda, MD 20014 i ASI 000012640 Or. Virgil Whitehurst Bureau of Drugs, BD 160 Food and Drug Administration 5600 Fishers Lane Rockville,vMD 20852 Dr. Jack Winstead Advisory Center on Toxicology National Academy of Science 2101 Constitution Avenue Washington, DC 20418 Dr. Constantine Zervos Food and Drug Administration 783-HFS-50 Parklawn Building 5600 Fishers Lane Rockville, MD 20857 Professor John Wong Department of Chemistry University of Louisville Louisville, KY 40208 ; Dr. James Woods National Institute of Environmental Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 i Ms. Barbara Woolf National Institute of Occupational Safety and Health Room 3-40, Park Building 5600 Fishers Lane Rockville, MD 20857 Mr. Douglas Worf Environmental Protection Agency National Environmental Research Center Research Triangle Park, NC 27711 Dr. Lillian Yin Food and Drug Administration HFK-400 8757 Georgia Avenue Silver Springs, MD 20910 Dr. Mitchell Zavon Hooker Chemical and Plastic Corporation P 0 Box 728 Niagara Falls, NY 14302 12 ASI 000012641