Document GK3oOKeyzDXz38Ny2y1NzBL3r

COPIED 5765 - 5785 . J. mmo* lT,,^JG3 1977 NILIIS CONFERENCE NOTES (w.iTUVih4*-j M, Lm S t~ ^ V'L<j ,i ,c. V-U MAY 9 1977 COMPARATIVE METABOLISM AND TOXICITY OF VINYL CHLORIDE RELATED COMPOUNDS Bethesda, Maryland May 2, 1977 AGENDA: See attached Agenda Dr. David P. Rail', Director, NIEHS was Chairman o the morning session. May 2, 1977. After the brea over the Chairmanship. Manuscripts for summaries of the papers were not available at the meeting, und each author was requested to submit their manuscripts to NIEHS for eventual publication in Environmental Health Prospectives. Any request for Dapers 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 vinylidene chloride. The following factors were used as an outline of his discussion: 1. Molecular Structure 2. Concentration 3. Length of Treatment A. Route of Administration 5. Species 6. Strain 7. 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 1 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 Elastomas. ASI 00005765 2- - 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. With 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. Sex - With the Swiss mice the males were much more sensitive than the females, i.e., the ratio of 24 to 1. Maltoni then gave some toxicity values for vinylidene chloride for acute exposure, i.e., exposure four hours daily for two days at concentrations of 200 ppm. He allowed thac rats 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 SURVIVi 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 Wistar rat exposed at 200 ppm. The following is a summary of his results: ASI 00005766 -3- Treatment Sex Numbers Tumor Bearing Tumor of Abdominal Lung Liver Percent Animals Cavity Tumor Tumor 200 ppm 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 ppm 100 ppm 75 ppm 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 Vinylldene 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 vinylidene chloride including any contaminant such as vinyl chloride. There was considerable variation in the vinyl chloride content of the vinylidene 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 Dpra in the drinking water, with 80 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 vinylidene 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. A$1 00005767 * -A- With respect to the inhalation study, this was conducted using the Sprague-Dawley rat with initial concentrations of 10 and AO ppm. 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 mammary 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 Halogenated 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 C3H)F^ 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 dibromide 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, 1,1-dichloroethane, 1,2-trichloroethane, hexachloroethane, 3-chloropropane and tetrr.chloroethylene. All of these compounds provoked tumors in the mouse excepting 3-chloropropane. AS1 00005768 - 5- Dr. B. L. Van Duuren - Chemical Structure, Reactivity and Carcinogenicity of Halohydrocarbons. Dr. Van Duuren discussed possible mechanisms for activation of the halogenated 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 Sanica. 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 epichlorhydrin and elycydaldehyde. Van Duuren also discussed his attempts to trap intermediates, and using mercaptan derivatives. He had been unsuccessful in those attempts. Dr. Kociba - Chronic Toxicity and Reproduction Studies with Rats Given Hexachlorobutadiene. Dr. Kociba reported results of reproduction studies using 0,0.2,2, and 20 mg/kg of Hexachlorobutadiene orally. Using adult animals, lie 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. With respect to the kidney neoplasia the following'was observed: DOSAGE 0 Males Renal Adenomas 1/90 Renal Adenoma Carcinomas 0/90 1/90 Females Renal Adenomas 0/90 Renal Adenoma Carcinomas 0/90 0/90 0.2 0/40 0/40 0/40 0/40 0/40 0/40 2.0 0/40 0/40 0/40 0/40 0/40 0/40 20.0 2/39 7/39 9/39 3/40 3/40 6/40 It was concluded that there was a dosage effect upon tumor incidents of hexachlorobutadiene. 00005769 ASI Dr. C. C. Lee - Toxicity and Carcinogenicity of Vinyl Chloride Compared to Vinylidene Chloride Dr. Lee conducted his work at the Mid-West Research Institute, Kansas City, MO- under the contract from N1EHS, The protocol used was inhalation exposure, with rats and mice, with 36 animals per sex per group. With vinyl chloride the concentrations were 50, 250 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 chloride, Dr. Lee found 7 mice exposed to 55 Dpm vinylidene chloride had bronchial alveolar adenomas, as compared to one mouse in the control group. Dr. Lee also reported Hepatic angiosacoma in females exposed to the 55 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. Maltoni 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 angiosacoma 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 vinylidene chloride in the inhalution chambers, and the possibility of c;n r;-iver 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 00005770 - . -4. A. AGENDA MAY Confercncp On COMPARATIVE METABOLISM AND TOXICITY OF VINYL CHLORIDE RELATED COMPOUNDS May 2-4, 1977 9 19?r Monday, May T. SESSION 1 Carcinogenicity of Halogenated Olefins Chair.v.ar.: Or. David P. Rail, NlEHS 8:30 a.m. 8:40 a.m. 9:00 a.m. 9:20 a.m. 9:40 a.m. 10:10 a.n. 10:30 a.m. 10:50 a.m. 11:10 a.m. 11:30 a.n. 11:50 a.m. 12:30 p.m. Welcome ar.d Introduction - Dr. Rail Recent Findings cn the Carcinogenicity of Chlorinated Olefins Dr. C. Maltoni Carcinogenicity Studies on Vinylidene Chloride Dr. P. L. Viola Toxicity and Carcinogenicity Studies on Vinylidene Chloride Dr. L. W. Rampy DISCUSSION COFFEE BREAK _ Carcinogenicity Studies of Halooenatc-d Hydrocarhms Dr. Elizabeth K. Weisburger Chemical Structure, Reactivity and Carcinogenicity of Halchydrocarbons Dr. B. L. Van Duuren Ct.rcjiic Toxicity and Reproduction Studies v:ith Pets Given Haxach lorobutedier.e Dr. R. J. Kocibi Toxicity and Carcincgo-icity Of Vinyl Chlorine Compared to Vinylidene Chloride Dr. C.-C. Lee DISCUSSION LUNCH BREA^ (Special Line in Cafeteria, Building 10) SESSION II Mutagenicity and Teratogenicity Of Halogenated Olefins Chairman: Dr. Raymond Shapiro, NlEHS 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 Vinylidene and Vinyl Chlorides in Relation to Outstanding Oncogenic Potential TrensDlacental Toxicity of Placidyl (Ethchlorvynol) in Rats DISCUSSION Dr. A. J. Garro Dr. D. Henschler Dr. H. S. Rosenkranz Dr. Nicola Loprieno Dr. S. Laham Dr. D. E. Hathway Dr. William Jurgelski AS1 00005771 . r'`.M Tuesday, May :3 SESSION III Halothane Chairman: Dr. Terri Damstra, NIEHS oo o 8:3C a.m. 8:50 a.m. 9:10 a,ni. 9:30 a.m. a.m. 10:30 a.m. a.n. 11:10 a.m. 11:30 a.n. 11:50 a.m. 11:55 a .m. 12:30 p.ru Absorption, Biotransformation and Storage of Halothane The Relationship of Enzyme Induction to Wephrppothy Due to Halothane and Related Compounds Bioactivation and Covalent Binding of Halothane to Liver Kacrcrolecules DISCUSSION COfFEE BREAK Metabolism of Halothane and Toxicity of 1,1 ,l-trifluoro-2-chlorcethane Behavioral and Neurcpatholcgical Effects of Prenatal Halothane The Effects of Halothane on Fetal Brain Metabolism Trace-Level tnflurance Exposure in Pregnant Rats Mutagenic Activity Detected in the Urines of Anesthesiologists DISCUSSION LUNCH CREAK Dr. D. A. Holaday Dr. B. A. Hitt Dr. 1. G. Sipes Dr. B. R. Brown Robert E. Bowman Dr. R. C. Vannucci Dr. M. L. Nahrwold Dr. H. S. Rosenkranz o <jOn SESSION IV Absorption, Metabolism, and Interaction oP Haloeenated Olefins Chairman: Dr. V. B. Vouk, WHO, Geneva 1:30 p.rn. 1:50 p.m. 2:10 p.m. 2:20 p.m. 2:40 p.rn. 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. Leibm.an The PharmCvOkinetics of Vinylide.oe 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 Halcgenated Olefins to Macro-molecules Dr, H. M. Bolt DISCUSSION COFFEE BREAK Damage to Cellular Membranes by Chlorinated Olefins with Emphasis on Synergism and Antagonism Dr. E. 5. 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 Hepatotoxic Response to Halogenated Olefins Dr. H. Cornish DISCUSSION ASI 00005772 V'rdnesdav, May < 3 5E5SI0N V Toxicity of Hilcgenated Olefins Chairman: Dr. 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. 11:3D a.m. 11:50 e.m. 12:30 p.m. session vi Toxicology oo Chlcrcprere, 1,3-Dichloro2-butene, end 1,4-Dicnlpro-2-butene Mechanism of Action, Tissue Distribution, and Covalent Dinting cf Vinylidene Chloride Dr. J. J. Clary Dr. R. J, Jaeger Acute Hepatetoxicity cf Ethylene and Rory Conolly Halogrnated Ethylenes After PCS Pretreatrents DISCUSSION COFFEE SPEAK Quantitative relationship Between Halogcnated Or. M. lkeda Olefins in Locking Environment and Urinary Elimination of Metabolites in Man Human Exposure to Tetrachloroethylene -Inhalation end Shin Contact Dr. Carl l. Hake Pulmonary Edc-ma cn Human Exposure to Tetrechloresthylone Dr. R, Patel Pathologic Chances end Behavioral Deviations Dr. L, W. Chang Followin' Exposure to llalothane DISCUSSION LUNCH BREAK Halogenated Olefin Groups in Other lrportant iChemicals Chairman: Dr, Hans L. Falk, MEHS 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. Dchalogenaticn*and Degradation of Hera toe ides -- The Nature of the Active Metaholites ''rtaholism arid Toxicity of Pyrcthroids with Dihalovinyi 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 Trif1uorcethyl Vinyl Ether Dechlorination Mechanisms of Chlorinated Olefins DISCUSSION Overview and Surmary - Dr. Sheldon Murphy Dr. C. E. Castro Dr. Luis 0. Ruzo Dr. H, M. Mehendale Dr. Herbert S. Posr.tr Dr. P. F. Infante Dr. V. Fiserova-Bergerova Dr. R. A. Van Dyke i 11 / lse i r- V'SSS'V-* AS I 00005773^ r?V  4 * rt* MAY 9 1977 COMPARATIVE METABOLISM AND TOXICITY OF VINYL CHLORIDE RELATED COMPOUNDS LIST OF ATTENDEES Dr. T. R. Aalto Tenneco Chemicals P 0 Box 365 Piscataway, NJ 08854 ----- . -*?'? a 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 Wright Patterson AFB Dayton, OH 45433 Dr. Raymond E. Bahor National Cancer Institute Pharmacology - Toxicology 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 Commission Washington, DC 20207 Dr. Eula Bingham Assistant Secretary for Occupational Safety and Health Department of Labor Room S 2315 200 Constitution Avenue, N.W. Washington, DC 20210 Dr. Marvin J Bleiberg Division of Toxicology 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 00005774 2 . --* 4 - -i wS t .< Dr. 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 Drug Administration 8757 Georgia Avenue HFK-400 Silver Springs, MD 20910 Mr. Richard C. Brooke Approvals Manager Borg-Warner Chemicals P 0 Box 68 Washington, WV 26181 Dr. Burnell R. Brown, Jr. Department of Anesthesiology The University of Arizona Arizona Medical Center Tucson, AZ 85724 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 4 Mr. Joseph Cirvello Environmental Protection Agency Mail Drop 12 Research Triangle Park, NC 27711 Dr. 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 0000577S 3 M l .. Dr. Herbert H. Cornish Department of Industrial Health University of Michigan 3550 School of Public Health Dr. J. Fielding Douglas National Institutes of Health National Cancer Institute Bethesda, MD 20014 Ann Arbor, MI 48104 Dr. Julie Du Ms. Madge Crouch 8ureau of Biologies Building 29 Cancer Center University of Louisville Louisville, KY 40201 National Institutes of Health Bethesda, MD 20014 Dr. George D. Duda Division of Biomedical and Ms. Terry L. Crutcher National Institutes of Health Building 13, Room 3K07 Environmental Research Biomedical Programs Washington, DC 20545 Bethesda, MD 20014 Dr. Virginia Dunkel Dr. Cipriano Cueto Acting Chief, Carcinogen Bioassay and Program Resources Branch National Institutes of Health National Cancer Institute Bethesda, MD 20014 Division of Cancer Cause and Prevention National Cancer Institute Bethesda, MD 20014 Mr. William Edwards National Institutes of Health Bureau of Biologies Dr. Terri Damstra National Institute of Environmental Building 29 Bethesda, MD 20014 Health Sciences P 0 Box 12233 4 Research Triangle Park, NC 27709 Mr. A. J. Eschenbach W. R. Grace and Company 62 Whittenmore Avenue Dr. P. R. Datta Cambridge, MA 02140 Environmental Protection Agency WH 568 0BB 401 M Street, S.W. Washington, DC 20460 Dr. Hans Falk National Institute of Environmental Health Sciences P 0 Box 12233 Dr. Robert L. Dedrick Research Triangle Park, NC 27709 National Institutes of Health Building 13, Room 3W13 Bethesda, MD 20014 Dr. Henry Falk Center for Disease Control Building 1, Room 5127 Mr. A1 Del Grosso Bureau of Biologies ; 1600 Clifton Road Atlanta, GA 30333 Food and Drug Administration Building 29A, Room 1D10 8800 Rockville Pike Bethesda, MD 20014 Dr. Vera Fiserova-Bergerova ' Department of Anesthesiology University of Miami (Medicine) P 0 Box 520875 Biscayne Annex . Miami, FL 33152 ASI 00005776 r 4 --**i Dr. Lawrence Fishbein 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 ; r-j r*.. <7 SS2 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 , ____ :\Sgj ------1 j Ms. Helga Gerstner TIRC Oak Ridge National Laboratory Building 7509 P 0 Box X Oak Ridge, 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 Go!berg 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 Ms. Betsy Grim Bureau of Biologies Food and Drug Administration Building 29A, Room 1D10 8800 Rockville Pike Bethesda, MD 20014 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 Dr. Carl L. Hake Department of Environmental Medicine The Medical College of Wisconsin 8700 West Wisconsin Avenue Milwaukee, WI 53226 ASX 00005777 m i ittsikfcfcy \ V* ' '* i Dr. Elliott Harris National Institute of Occupational Safety and Health Taft Laboratory 4676 Columbia Parkway Cincinnati, OH 45226 Dr. Robert Harris Environmental Defense Fund 1525 18th Street, N.H. 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. Hinderer 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 Palo Alto, CA 94304 >C*3 5 Dr. D. A. Holaday Department of Anesthesiology University of Miami School of Medicine P 0 Box 520875 - Biscayne 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 Safety 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. Masayuki Ikeda Department of Hygiene Tohoku University School of Medicine Seiryocho 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 ASX 00005778 SSeSS&ag&&Zs. 6 **& *Sc 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 W. R. Grace & Company King George Post Road Fords, NJ 08863 Mr. Bob Jungers Environmental Protection Agency National Environmental Research Center Mail Drop 78 Research Triangle Park, NC 27711 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. Kociba Toxicology Research Laboratory Health and Environmental Research Dow Chemical Company, USA Midland, MI 48640 Dr. Charles Kokoski 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 Midwest Research Institute Kansas City, M0 64110 Dr. Kenneth C. Leibman Professor of Pharmacology University of Florida J. Hill is Miller Health Center Gainesville, FL 32610 Mr. Frank Letkiewicz EnvironmentaJ 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 5528 South Hyde Park Boulevard , Chicago, IL 60637 Dr. Harry Mahar Mitre Corporation Westgate Research Park McLean, VA 22101 ASI 00005779 1 7 Dr. C. Mai torn Istituto di Qncologia "F. Addarii" and Centro Tumori Bologna, ITALY Dr. William L. Marcus Supervisor of Testing Office of Toxic Substances WH-557 Environmental Protection Agency Washington, DC 20460 Dr. H. Marico Medical University of South Carolina Department of Medicine 80 Barre Street Charleston, SC 29401 Dr. Patricia Marlow Department of Labor Room S2315 200 Constitution Avenue, N.W. Washington, DC 20210 Dr. Thomas J. Mason National Institutes of Health Environmental Epidemiology Branch Room A521, Landow Building Bethesda, MD 20014 Dr. Joan May Bureau of Biologies Food and Drug Administration Building 29A, Room 1D10 8800 Rockville Pike Bethesda, MD 20014 Dr. John May *j National Institute of Occupational Safety and Health Rockville, MD 20857 Dr. Arthur McCreesh Toxicology Division U.S. Army Environmental Hygiene Agency AGG, MD 21010 Mr. James McCullough Congressional Research Service Library of Congress Washington, DC 20540 Dr. Michael J. McKenna Toxicology Research Laboratory Health and Environmental Research 1803 Building Dow Chemical Company, USA Midland, MI 48640 Dr. Joseph McLaughlin Bureau of Biomedical Science Consumer Product Safety Commission Washington, DC 20207 Ms. Jo-Ann McNally Congressional Research Service Library of Congress Washington, DC 20540 Dr. H. M. 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Rail Director v..jf National Institute of Environmental 53 Health Sciences P 0 Box 12233 Research Triangle Park, NC 27709 sS 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 y* -h Dr. Edward S. Reynolds Department of Pathology The University of Texas Medical Branch Galveston, TX 77550 -- Mr. Charles Rigg ~ Occupational Safety and Health S Administration 3; Department of Labor ^ Washington, DC 21210 Dr. H. S. 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Walcott Stanford Research Institute Rosslyn Plaza Rosslyn, VA Ms. Helen Warren Toxicology Information Response Center 0RNL, Building 2509 P 0 Box X Oak Ridge, TN 37830 Dr. David Warshawsky University of Cincinnati Medical 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, M0 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 1010 8800 Rockville Pike Bethesda, MD 20014 ASI 00005784 ` r*v' S-W> rfXjiS*.*'* * 5$$ i Dr. Virgil Whitehurst Bureau of Drugs, BD 160 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20852 Dr. Jack Winstead Advisory Center on Toxicology National Academy of Science 2101 Constitution Avenue Washington, DC 20418 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 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 Dr. Constantine Zervos Food and Drug Administration 783-HFS-50 Parklawn Building 5600 Fishers Lane Rockville, MD 20857 12 ASI 00005785 1