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Interoffice Communication To F. Kennedy From W. D. Broddle Oaie March 14, 1980 Subject Meeting of Chemical Manufacturers Association's Vinyl Chloride Project Panel and Research Coordinators As requested, I attended the above meeting held at the CMA offices in Washington, D.C., March 4, 1980. Attachment 1 shows the list of at tendees . The first item discussed concerned the NIH-sponsored conference on VC and PVC to be held March 20-21, 1980 (Attachment 2). Reservations should be made IMMEDIATELY. Unfortunately, I cannot attend this conference but would appreciate any follow-up (handouts, notes, etc). Personnel of CMA member companies will be some of the speakers at the conference. Previously, OSHA had requested additional health and manufacturing data but has extended the deadline to May, 1980. This may allow the EPA and OSHA to use results obtained at the conference for setting a new future exposure standard. OSHA and NIOSH are also developing a CRITERIA DOCU MENT (VC and/or PVC?). Discussion then centered on epidemiological studies completed or pro posed by Environmental Health Associates (Attachments 3 and 4). Deci sions made were as follows: 1. Lines 16-21, page 2, of Attachment 3 will be changed to that in Attachment 4, lines 16-21, page 4, but OMIT the last sentence in either paragraph. 2. Panel Survey Inquiry (Attachment 4): a. Item 4.2: Change to read, "We are interested in financially sponsoring a thorough case-control evaluation and a clinical examination of each brain tumor." b. Item 4.4: It was pointed out that Plan B is an attempt to determine if one can separate the toxicity of VCM vs. PVC, vs. EDC vs. Miscellaneous toxicity. us c. Items 4.4 and 4.5: Omit and consider at a future date. d. Item 5: Omit. CCR 000011271 F. Kennedy Page 2 March 14, 1980 3. Environmental Health Associates (EHA) will be asked to prepare financial estimates for comparing industrial exposure to VCM vs. PVC emulsion-dispersions (excluding latex) vs. all other VCM-PVC workers as to mortality and cancer (cost will hopefully be less than $10,000). Additional discussion involved: 1. EHA will be asked, at no additional cost, to explain the exposure deficiencies for the 3300 employees (Attachment 4). 2. The CMA legal department has not yet prepared a status report of the IBT animal toxicology studies. 3. CMA will re-submit all VC-PVC data and any input provided by the SPI to OSHA as requested recently. 4. SPI would like to publish a review on all VC-PVC studies. Flynt, I enjoyed participating in this meeting, and please inquire as to any questions you may have. W. D. Broddle JJ Enc CC: D. Kuhn CCR 000011272 ATTACHMENT 1 /f77 fAJ P (r S A/ & ' ^ /r?j. ^- - t j At/aSAf x-sJ-tf?7 CONFERENCE TO REEVALUATE THE TOXICITY OF VINYL CHLORIDE, POLYVINYL CHLORIDE AND STRUCTURAL ANALOGUES March 20-21, 1980 National Institutes of Health Masur Auditorium Building 10 Clinical Center Bethesda, Maryland Cosponsors National Institutes of Environmental Health Sciences National Institute for Occupational Safety and Health Occupational Safety and Health Administration CCS 0011273 Thursday, March 20, 1980 8:00 A.M. REGISTRATION 8:30 A.M. INTRODUCTORY REMARKS Dr. David Rail, NIEHS SESSION I - CARCINOGENESIS BIOASSAYS OF VINYL CHLORIDE MONOMER Chairperson: Dr. Umberto Saffiotti, NCI 8:45 A.M. 1. Carcinogenesis Bioassay of Vinyl Chloride Monomer with Particular Reference to Multiple ,Sites and Dosage Review Dr. Caesar Maltoni, Institute of Oncology and Tumor Center, Bologna 9:45 A.M. '2. Experimentally Induced Pulmonary Cancer Dr. Y. Suzuki, Mt. Sinai Medical School 10:00 A.M. Discussion 10:15 A.M. Break - 10:45 A.M. 3. The Role of Aging on Vinyl Chloride Monomer - Induced Cancer Dr- David Groth, NIOSH 11:00 A.M. 4. Carcinogenic Effects of Exposure to Vinyl Chloride Monomer and Ethyl Alcohol on Rats Dr. Martha Radike, University of Cincinnati 11:15 A.M. 5. Cancer Induction Following Single and Multiple Exposures to a Constant Amount of Vinyl Chloride Monomer Dr. Robert Hehir, CPSC SESSION II-- TOXICOLOGY STUDIES OF POLYVINYL CHLORIDE Chairperson: Dr. Peter Infante, OSKA 11:30 A.M. 6. Pneumoconiosis in Animals Exposed to Polyvinyl Chloride Dust Dr. David Groth, NIOSH 11:45 A.M. 7. Results of Carcinogenesis Bioassay of Polyvinyl Chloride Dr. Chris Wagner, BMRC, Penarth, Wales CCR 000011274 Thursday, March 20, 1980 SESSION III-SPUTUM CYTOLOGY OF VINYL CHLORIDE WORKERS Chairperson: Dr. Peter Infante, 0SHA 12:00 P.M. 12:15 P.M. 8. Results of Sputum Cytology Among Vinyl Chloride Polymerization and Polyvinyl Chloride Fabrication Workers Dr. Caesar Maltoni, Institute of Oncology and Tumor Center, Bologna Discussion 12:30 P.M. LUNCH SESSION IV-MORTALITY STUDIES OF WORKERS EXPOSED TO VINYL CHLORIDE Chairperson: Dr. Philip Landrigan, NIOSH 2:00 P.M. 9. Multiple Site Risk Analysis of Vinyl Chloride Related Cancer in Workers - Review Dr. Peter Infante, OSHA 2:15 P.M. 10. Cohort Mortality Study of Vinyl Chloride Workers Dr. H. Weber, Der Staatliche Geverbearzt, Fed. Deutch Republic 2:30 P.M. 11. Epidemiological Study of Vinyl Chloride Workers Dr. Clark Cooper, Consultant 2:45 P.M. 12. Power Considerations in Epidemiologic Studies of Vinyl Chloride Workers Dr. Jay Beaumont, NIOSH 3:00 P.M. Discussion 3:15 P.M. Break SESSION V - LIVER AND BIOCHEMICAL CHANGES ASSOCIATED WITH VINYL CHLORIDE Chairperson: Dr. David Groth, NIOSH 3:45 P.M. 13. Epidemiologic Review of Hepatic Angiosarcoma in the United States Dr. Henry Falk, CDC CCR 000011275 Thursday, March 20, 1980 4:00 P.M. 14. United Kingdom Angiosarcoma Registry Dr. Peter Baxter, CDC 4:15 P.M. 15. Pathology of Vinyl Chloride Induced Liver Lesions Dr. Hans Popper, Mt. Sinai Medical School 4:30 - P.M. 16. Liver Screening Tests for Vinyl Chloride Exposed Workers Dr. Carlo Tambero, University of Louisville SESSION VT - INDUSTRIAL YGIENE MEASUREMENTS OF POLYVINYL CHLORIDE OPERATIONS Chairperson: Mr. James Gideon, NIOSH 4:45 P.M. 17. Polyvinyl Chloride Processes and Products Dr. R. Nick Wheeler, Union Carbide 5:00 P.M. 18. Characterization of Polyvinyl Chloride Homopolymers, Copolymers and-Additives Mr. Jay Jones, NIOSH 5:15 P.M. Discussion CCR 000011276 Friday, March 21, 1980 SESSION VII - MORBIDITY AND MORTALITY STUDIES OF POLYVINYL CHLORIDE EXPOSED WORKERS Chairperson: Dr. R. Greenberg, University of Louisville 8:30 A.M. 19. Mortality Among Polyvinyl Chloride Fabricators Dr. Leonard Chiazze, Georgetown University 8:45 A.M. 20.'Heart Disease in the Swedish Polyvinyl Chloride Fabricating Industry Dr. Gustavo Molina, Colombia 9:00 A.M. -21. An Epidemiological Study of Respiratory Disease in United Kingdom Workers Exposed to Polyvinyl Chloride Dust Dr. Anthony Seaton, University of Edinberg 9:15 A.M. 22. Polyvinyl Chloride Dust Induced Pneumoconiosis Dr. A. Arnaud, Marseille, France 9:30 A.M. 23. An Epidemiologic Study of Pneumoconiosis in the Italian Polyvinyl Chloride Industry 1 Dr. Guiseppe Mastrangelo, Padova, Italy 9:45 A.M. 24. A Case-Control Study of Lung Cancer Among Vinyl Chloride-Polyvinyl Chloride Workers Dr. Richard Waxweiler, NIOSH 10:00 A.M. 25. Review of Pulmonary Effects of Polyvinyl Chloride Exposure Dr. Ruth Lilis, Mt. Sinai Medical School 10:15 A.M. Discussion 10:30 A.M. Break 0000112T7 cc* Friday, March 21, 1980 SESSION VIII - REPRODUCTIVE EFFECTS OF VINYL CHLORIDE Chairperson: Dr. James Wilson, University of Cincinnati 11:00 A.M*. 26. Transplacental Teratogenic Effects of Vinyl Chloride in Experimental Animals Dr. Jackie John, DOW Midland 11:15 A.M. 27. Transplacental Carcinogenic Effects Dr. Jerry Rice, NCI 11:30 A.M. 28 Mutagenic Effects of Vinyl Chloride Dr. Jill Fabricant, University of Texas, Galveston 11:45' A.M. 29. Power Considerations in Studies- of Reproductive Effects Associated with Vinyl Chloride and Some Structural Analogues Ms. Maureen Hatch, Columbia University 12:00 P.M. Discussion 12:30 P.M. LUNCH SESSION IX - ENVIRONMENTAL EXPOSURE TO VINYL CHLORIDEPOLYVINYL CHLORIDE AND LIVER ANGIOSARCOMA Chairperson: Dr. Pier Bertazzi, Institute of Occupational Health, Milan 2:00 P.M.. 30. Fugitive Emissions of Vinyl ChloridePolyvinyl Chloride Speaker to be Announced 2:15 P.M. 31. Case-Control Study of Liver Angiosarcoma Among Residents in New York Dr. Nicholas Vianna, N.Y.S. Department of Health CCR 000l127g Friday, March 21, 1980 SESSION X - CARCINOGENICITY OF SOME STRUCTURAL ANALOGUES OF VINYL CHLORIDE Chairperson: Dr. Kim Hoooer, University of California, Berkeley 2:30 P.M. 32. Comparative Pathology of Vinyl Chloride and Vinyl Bromide Induced Liver Pathology in Animals Dr. William Busey, Experimental Pathology Laboratories 2:45 P.M. 33. Review of Experimental Carcinogenesis of Vinyl Chloride Related Compounds Dr. Ken Chu, NCI 3:00 P.M. 34. Review of Epidemiologic Study Results of Vinyl Chloride Related Compounds Ms. Rosanne Apfeldorf, OSHA 3:15 P.M. Discussion 3:30 P.M. Break SESSION XI -- RESEARCH NEEDS AND PUBLIC HEALTH INTERVENTION Chairperson: Dr. Anthony Robbins, NIOSH Panel Discussion: 4:00 P.M. 35. Dr. Dale -Haddis, Center for Policy Alternatives, MIT 4:15 P.M. 36. Mr. Steve Wodka, OCAW 4:30 P.M. 37. Dr. Maurice Johnson, B.F. Goodrich 4:45 P.M. 38. Dr. Irving Selikoff, Mt. Sinai Medical School 5:00 P.M. 39. Dr. Joseph Wagoner, EDF 5:15 P.M. Discussion Proceedings from the Conference will be published. CCR 000011279 Program Planning Committee Dr. Richard B. Everson NIEHS, Research Triangle Park, North Carolina Dr. Peter F. Infante OSHA, Washington, D.C. Dr. Philip J. Landrigan NIOSH, Cincinnati, Ohio Dr. Raymond E. Shapiro NIEHS, Research Triangle Park, North Carolina Dr. Richard J. Waxweiler NIOSH, Cincinnati, Ohio CCR 000011280 April 1979 VINYL CHLORIDE REPORTS The Dow Chemical Company 8/19/74 - "Preliminary Report: Vinyl Chl-oride Teratology Study in Mice, Rats and Rabbits"' tx< (Ak f/7 -1/ --'/c/sermro^/Afa3 3vi!I 2/25/75 - "Results of a Vinyl ChLloornidae - Teratology Ssttuuady in Mice- Rats, and Rabbits'-' ? 5/1/75 - "Continued Studies on the Pharmacokinetics/Metabolisra* of Vinyl Chloride in Mammals" /??7 ^ /3/3/76 - "The Effects of Maternally Inhaled Vinyl Chloride on Embryonal and Fetal Development in Mice, Rats and Rabbits' f.zr '--X 5/31/77 - "Summary of the Studies Conducted on the Pharamcokinetics/ Metabolism of Vinyl Chloride in Rats" 7/12/77 - "Resolution of Dose-Response Toxicity Data for Chemicals Requiring Metabolic Activation: Example - Vinyl Chloride" / , j - A Ay )/ cz_ ~ *s 7-1 r / / // CCR 000011281 April 1979 VINYL'CHLORIDE REPORTS Industria1 BIO-TEST Laboratories, Inc*. 6/19/74 - 'Seven-Month Status Summary to Manufacturing Chemists Association, Chronic Vapor Inhalation Toxicity Study with Vinyl Chloride (Ethylene Derived) in Albino Rats, Albino -Mice, and Golden Hamsters" 5/9/75 - 'Gross and Histopathologic Findings, One-Year Interim Sacrifice Chronic Vapor Inhalation Study with Vinyl Chloride (Ethylene Derived) in Albino Rats" 5/13/75 - 'Eighteen Month Status Summary to Manufacturing Chemists Association, Chronic Inhalation Toxicity Study with Vinyl Chloride (Ethylene Derived) in Albino Rats, Albino Mice and Golden Hamsters" 9/23/75 - "23-Month Status Summary to Manufacturing Chemists As sociation, Chronic Vapor Inhalation Toxicity Study with Vinyl Chloride (Ethylene Derived) in Albino Rats, Albino Mice and Golden Hamsters" CC* 01l28z April 1979 Program Teratology Study in Mice, Rats and Rabbits Effects of Maternally Inhaled Vinyl Chloride on Embryonal and Fetal Development in Mice, Rats and Rabbits Summary of Studies Conducted on the Pharmacokinatics/Metabolism of Vinyl Chloride in Rats Resolution of Dose-Response Toxicity Data for Chemicals Requiring Metabolic Activation: e.g., Vinyl Chloride Epidemiological Study of Vinyl Chloride Workers Chronic Vapor Inhalation Study on Vinyl Chloride VINYL CHLORIDE WORK COMPLETED Investigator B. A. Schwetz, et al P. J. Gehring, et al P. G. Watanabe, et al P. J. Gehring, et al Dr. H. Michael Utidjian, et a 1 WORK IN PROGRESS Dr. John W. Goode, et al Organization The Dow Chemical Company The Dow Chemical Company The Dow Chemical Company The Dow Chemical Completion Date 2/25/75 3/3/76 5/31/77 7/12/77 Equitable Environmental Health, Inc. 1/78 Industrial BIO TEST Laboratories, Inc. in progress CCR 0 0 0 0 1 1 2 8 3 April 1979 -2- WORK IN PROGRESS Proqram Investigator Immunological Systems for the Detection of Vinyl Chloride and Other Chemical Injury; Biochemical Enzymatic Systems for Detection of Vinyl Chloride and Other Chemical Injury as a Potential Means of Detection of Cancer in Humans; Biochemical Protein System of Detection? Histological Systems of detection? Chemical Systems of Detection? Assays for the Carcinogenic Potential- of industrial Chemicals Utilizing Prokaryotic and Eukaryotic Systems; Tissue Antigens and Antibodies in the Detection of Vinyl Chloride Injury? Electron Microscopic Evaluation of Liver.Injury from Chemical Workers Dr. C. H. Tamburro et al Organization University of Louisville CO r*-J4 O o o o o o Completion Date 11/30/77 (Completion of First and Second Year of Three Year Research Program _. ."/"V. ; . -` r'K '*"' CROUPS aid XIUlaTlCENT I vo o pf=. n VC 10 ppm. ni VC 5 ppo. IV vc 1 ppm. V No treatment Octal AHTHAL3 (SPRAGUE-DaWLEY RATS) Total Survivors ire 120 120 120 120 EOO 110 m H3 112 97 543 Zyiebal gland carcinomas No. . ANIMALS WITH TUMOURS Nephrobls5t Angio sarcomas Liver Other si Kb, 1!0. ilo. _ __ . __ . .. ._ . - - -- Other type and/or si xe No, Total Ho. -- Experiment BT17 s Exnogurc by inhalation to VO In ait- at l ppm., 4 hrs, Aaily, 5 bays weekly, far 52 weeks, ReBults after iC weeks. URCUP3 AND TREATMENT I VC 1 ppm. II No treatment Total ANIMALS V'WZSTAR RATS) Total Survivors Cymbal gliu-.d earciuoauis llo. ANIMALS WITH TUMOURS Na nhroblastomas Anslo9aroonaa Liver Other sites No. Ho, No, Other type and/or ait* No. Total No. 120 9fi - - -- - - 130 89 _ __ _. 25C 165 - - -- - - M i..;Hli. ' '$ .ill!! B*- 1: W, u CCR 0000U2B5 .7^ W*-.' 143 Experiment BT8 ! Expo sure by Inhalation to VC in air at 10,000, 5,000, 2,500, 500, 25O, 50 ppm., 4 hrs. daily, 5 dayB weekly, for 30 weeks. Reeulta after '05 weeks. GROUTS AND TREATMENT ANIMALS (BOLDEN HAMSTERS) Total Survivors I VC 10.000 cum. 11 VC 6,000 ppm. III VC 2.500 cum. VC 500 rpm. V VC 250 ppm. VI VC 6C Dto. VII !7o treatment 35 3? 33 33 32 33 70 1 Skin triLiver choepithe ar.gioear- liomaa and coffifto bassliomae fa) no. Ho. -6 12 -' 23 -3 _6 -2 ABDULS WITH TUMOURS Mel&nofflas lyraphomaB Forestomach epithelial tumours (b) Ho. Ho. Ho. 1 _4 227 _ 1 10 -1 7 -12 l4 Other type and/or si t* Bo. 2 (c) 7 (d> 3 (e) 2 (f) _ Total ig) Ho, 4 1C 12 12 6 '0 5 Total 266 1 23 A 34 14 59 a) Several cases with acanth09la and some undergoing malignant trasformatlcm. b) Papillomas, acanthomas, Borne of which undergoing malignant trasformatioji. c) 1 oubeuteneoUB angiomaj 1 gall-bladder adenocarcinoma. d) 2 hepatomas! ? liver fibroar.giomasj 2 liver angiomas* 1 tiliduets adenocarcinoma, e} 1 hepatoma; 1 liver fibrcengiomaj I liver angioma, f) 1 subcutaneous angioma* 1 bronchial carcinoma, g) Several tu-iiir-als with 2 or more tumours. Experiment BTll : Exposure by ingestiop (stomach tube) *0 vc in olive oil, at 50.00, '6.65, 3.33 og/Kg body weight, once daily, 4-5 days weekly, for 52 weeks. Rae-ulta after 64 veeke. CROUPS abd TREATMENT AJJIMALS (3TRACCE-DAWLEY RATS) Total Survivors I VC 50.00 mg/Kg 80 25 II VC 16.65 mgAs 30 33 III VC J.33 TgAg TV Controls olive Oi.1 80 80 39 37 Zymbal gland carcinomas Bo. ANIMALS WITH TUMOURS Hephroblae toitas Anfin0 sarcowas Liver Other Bites 110 No. NO* Other type and/or site ib) No. - - 8 1 (a) 3 (0) 1 1 5_ _ l_ _ - - -- - Total No. 11 (d> 7 _ - Total 320 134 1 1 1J 1 3 13 a) 1 thymuo angiosarcoma. n) Several canon of breast fibroadanomaaj arlrenal and pituitary tumours (generally adenomas) have oat b"an "Tnid nrod, nines theii distribution in the different groups dote not vary, a 3 1 mmroiry "i--ircmo; ? i -,rnn 1 -,nih popl 11-jnviii. 1) I rmtrvil "'l.h 0 tuiroiro. VC 10. Off a) 1 hi 1 d) 1 0) 1 f) 1 CCR 000011286 0-\ ABSTRACTS: SEVENTEENTH ANNUAL MEETING 13 15. Resolutign-nf-Dose--Response Toxicity Datafor Chemicals Requiring Metabolic Activation Using' Vinyl ChlqdSe^fif an Example. P. J. Gehrino, P. G. Watanabe, and C. N. Park. Toxicology-Research Laboratory. The Dow Chemical Company. Midland, Michigan. The toxicity of many chemicals results from biotransformation products formed from the chemical rather than from the chemical per se. In such cases, the incremental response may become diminishingly smaller with increasing dose or exposure because activation of the chemical to the toxic form follows apparent Michaelis-Menten rather than apparent fiTst-order kinetics. To illustrate this concept, rats were exposed to concentrations ranging from 1.4 to 4600 ppm of vinyl chloride for 6 hr and the total amount metabolized was determined. The amount metabolized followed apparent Michaelis-Menten kinetics. For rats, the logarithmic probability incidence of angiosarcoma versus the amount of vinyl chloride metabolized (rather than the exposure concentration of vinyl chloride) is linear. Assuming no threshold (in spite of evidence to the contrary), extrapolation of the data below the range of doses causing experimentally observable responses predicted an incidence of 0.01% hepatic angiosarcoma in rats exposed to 4.6 ppm of vinyl chloride. Theoretical extension of the extrapolation to humans exposed daily for 8 hr to I ppm suggests an incidence of 1.5 per 100,000,000. This theoretical incidence is less than that expected to occur spontaneously. It is concluded that pharmacokinetic parameters must be elucidated before designing toxicological experiments or before interpreting the results therefrom. 16. Studies of the in Vitro Metabolism of Thioaceiamide and Thioacetamide Sulfine. William R. Porter and Robert A. Neal, Center in Toxicology, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee. Quantitative radiotracer methods, utilizing either thin-layer or high-pressure liquid chromatography, have been developed for the study of the metabolism of thioacetamide and its sulfine metabolite, thioacetamide-S-oxide. Thioacetamide is oxidized to thioacetamide-.S'-oxide by rat liver microsomes and by a reconstituted mixed-function oxidase system comprised of purified cytochrome P-450, purified NADPH--cytochrome c reductase, and phospholipid. The reaction requires NADPH (which requirement can be only partially met by NADH) and is inhibited by carbon monoxide. SK.F 525A. and an antibody to rat cytochrome P-450. Thioacetamide-S-oxide is oxidized by rat liver microsomes to acetamide and unidentified polar products: some of the substrate becomes irreversibly bound to the microsomes during the course of the reaction. The reaction has the same cofactor requirements and generally responds to inhibitors in a manner similar to that observed for thioacetamide. Michaelis-Menten kinetic parameters were determined for the metabolism of thioacetamide and thioacetamide-S-oxide by microsomes from untreated and from both phenobarbital- and 3-methylcholanthrene-pretreated rats. The Kfs for formation of thioacetamide-S-oxide from thioacetamide were 0.06, 0,11, and 0,09 mM. respectively. The Km for the formation of acetamide from thioacetamide-S-oxide and for irreversible binding to microsomes did not diiTer significantly; a value of about 0.4 mM was obtained in all cases. Phenobarbital pretreatment increased metabolism of both thioacetamide und thioacetamide-S-oxide. The results indicate that thioacetamide-S-oxide is an obligatory intermediate in the two-step metabolic conversion of thioacetamide to acetamide, polar products, and microsome-bound material and that both steps require, at least in part, the cytochrome p.450 mixed function oxidase system. 17. uC-Labeled Ethylenethiourea Metabolism in the Cat: Blood Decay Profile and Urinary Metabolites. F. Iverson and K. Khera, Food Directorate, Health Protection Branch, Ottawa. Canada. Ethylenethiourea (ETU) is a teratogen in the rat, producing a range of deformities. The cat is currently under investigation to determine the response of this species to teratogenic agents. In ihu* present study, two female cats were dosed iv with 4 mk/kg of l4C-labeled ETU, a known S' OCR 000011287 lv -if.. f y TOXICOLOGY AND APPLIED PHAHMACOLOGY 44, 581-591 <1978) Resolution of Dose-Response Toxicity Data^crrChemicals Requiring Metabolic Activation: Example^--Vinvl Chl~":j~1 P. J. Gehring,2 P, G. Watanabe,2 and C. N. Park3 Toxicology Research Laboratory. Health and Environmental Research, and Physical Research Laboratory. Math Applications. Dow Chemical USA.. Midland. Michigan 48640 Received August 30, 1977; accepted November 4, 1977 Resolution of Dose-Response Toxicity Data for Chemicals Requiring Metabolic Activation: Example--Vinyl Chloride. Gehring, P. J., Watanabe. P. G.. and Park. C. N. (1978). Toxicol. Appl. Pharmacol. 44, 581-591, The toxicity of many 'chemicals results from biocransformation products formed from the chemical rather than from the chemical per se. In such cases, the incremental response may become diminishingly smaller with increasing dose or exposure because activation of the chemical to the toxic form follows apparent MichuelisMenten rather than apparent first-order kinetics. To illustrate this concept, rats were exposed to concentrations ranging from 1.4 to 46o;i ppm of vinyl chloride for 6 hr, and the total amount metabolized was determined. T5ie amount metabolized followed apparent Michaelis--Menten kinetics. For rats, the logarithmic probability incidence of angiosarcoma versus the amount of vinyl chloride metabolized rather than the exposure concentration of vinyl chloride is linear. Assuming no threshold in spite of evidence to the contrary, extrapolation of the data below the range of doses causing experimentally observable responses predicted an incidence of 0.01% hepatic angiosarcoma in rats exposed to 4.6 ppm of vinyl chloride. Theoretical extension of the extrapolation to humans after adjusting for metabolic and body mass differences was under taken. The theoretical extrapolation for man exposed daily for 8 hr to I ppm suggests an incidence of 1.5 per 100,000,000. This theoretical incidence, although a likely overestimate because of a less than predicted incidence in men exposed to 200 ppm and greater, as well as evidence for a threshold in rats, is less than that expected to occur spontaneously. The concepts evolved from this analysis reveals why pharmacokinetics must be considered in designing toxicology experiments as well as in interpretation of the resulting data. There exists a great deal : uncertainty in predicting the potential response of exposure to chemicals at concentrations below those producing an experimentally discernible response. This is particularly true when the response to the chemical in question is oncogenesis. Statistical projections recommended for assessing the risk of exposure to doses of oncogenic chemicals lower than those producing an observable response include those based on logarithm probability curves (probit curves), logistic curves, or linear curves (one-hit curves) (FDA Advisory Committee on Protocols for Safety Evaluation, 1971). One of the most commonly used statistical projections for risk assessment has been that promoted by Mantel and Bryan (1961) in which a logarithm probability pro- 1 This study wrs funded by the companies supporting the vinyl chloride projects being administered by the Manufacturing Chemists Association. Washington. D.C. 1 Health and Environmental Research, Dow Chemical U.S.A., Midland. Michigan -t:W>40, manuscript No. B 600-176 77. j Physical Research Laboratory, Dow Chemical U S.A., Midland, Michigan 48640. 581 IXMl -(lXX/78/(M43-0<RIS02.00'0 Copyright C' I 77H by Academic Press. Inc. Ail rights of reproduction in any term reserved. Printed in Great Britain p * CCR 000011288 582 GEHRING. WATANABE, AND PARK jection with a slope of l is utilized. A flaw innate to all of these methods is that the doseresponse information used to make the projection is based on the dose of chemical administered to the animal rather than the quantity of the administered dose giving rise to the response: the latter may either increase or decrease disproportionately as the administered dose is increased. The use of high doses to reveal the chronic toxicity incurred with exposure to a chemical is a common, scientifically defensible practice if judgment and scientific rationale are used in designing the experiments and in assessing the resulting data. However, such doses frequently overwhelm the enzymatic processes for activation of the chemical to the toxic form or for deactivation of the toxic form to an innocuous form. In this paper, it is demonstrated how the dose-dependent activation of vinyl chloride to an oncogenic product must be considered in resolving the dose-response of rats exposed via inhalation to vinyl chloride. methods Material. Vinyl chloride (l4C-1abeled) was synthesized from 1,2-dichloroi 1,214Clethane (New England Nuclear, Lots, No. 819-221 and 819-292, 5.0 and 4.8 mCi/mmol. respectively) directly prior to use (Wagner et al.. 1975). Nonlabeled VC (Matheson Gas Products) of 99.9% purity was mixed with the IJC-labeied material to obtain the desired specific activity. Animals. Male Sprague-Dawley rats (Spartan Research Laboratory) weighing 200250 g were used throughout the study. Food and water were provided ad libitum except during the exposure. Exposures were conducted between 9:00 am and 3 :00 pm (EST). Groups of three to six rats were exposed to various concentrations of ,4C-VC for 6 hr. Exposure and procedure. The rats were exposed by inhalation under dynamic conditions in a 30 liter glass inhalation chamber. The mean analytical concentrations of VC measured by gas chromatography were 1.4 0.3 (+-SD). 9.3 + 0.2. 24.7 * \. 51 2. 109 23. 250 2, 511 11. 1020 13, and 4600 311 ppm. Details of this exposure and the method of analytical determinations have been reported previously (Watanabe et al.. '1976a). Immediately following the 6-hr exposure to various concentrations of ,4C-VC (1.4--4600 ppm), the rats were killed by a blow to the head, and the carcass was analyzed for total radioactivity (Watanabe et al.. 1976b). Previous studies have shown that only a small percentage of radioactivity (< 12%) is excreted as metabolites other than MC-VC per se during 72 hr following a 6-hr inhalation exposure (Watanabe et al.. 1976a). A large proportion of the 12% is comprised of l4C02 excretion 72 hr after exposure. Furthermore, very little urine is excreted during the exposure period. Thus, the nonvolatile radioactivity determined immediately after exposure in the tissue and carcass is a good estimate of the total amount of metabolized VC. RESULTS Consistent with the results of previous studies (Watanabe et al.. 1976a,b), the metabolism of VC by rats does not increase proportionately with increasing concentrations of VC being inhaled (Table 1). The nonlinearity of the amount of VC cc* 0000112s9 metab accor In thi biotrr hr. S expre para- l cor "1: `M Tt were form U cn verif by ti fittin estir of \ resp' O func VC VC uosemical g rise s the to a ntific data. the :brm. de to iosed ,| I 71 4.8 ial to 200ceept :CT'I hr. ic ... of 1.4. fthis >usly rious lead. -lOUS :d as isure CO, : the after lized the ising VC DOSE response: vinyl chloride 583 metabolized during 6 hr of exposure to various concentrations of VC appeared to be in accordance with Michaeiis-Menten kinetics as described by the equation: (1) In this equation, r and T,,,, are the velocity and maximum velocity, respectively, for the biotransformation of VC expressed as microgram equivalents of VC metabolized per 6 hr. 5 and K,,y are the concentration of VC being inhaled and the Michaelis constant expressed as micrograms of VC per liter of air, respectively. TABLEl Parameters for Descrihing the Metahoi ism oi Inhaled Vinyl Chloride (VC) Using Michaelis--Men ten Kinetics Exposure concentration 5 (ppm of VC) 1.4 9 25 51 109 250 511 1020 4600 S'(,ug of VC/liter of air)" 3.6 23.0 64.0 130.6 279.0 640.0 1308.2 2611.2 11776.0 of VC metabolized^ hr) 30 y 242 + 26 557 + 42 1181 i 93 2406 + 173 3826 + 345 6263 355 4257 + 765 9255 + 1467 v/S 8.33 10.52 8.70 9.04 8.62 5.98 4.79 1,63 0.79 1 I ppm of VC -- 2.5ft ug of VC/liter of air. 1 Determined from the total radioactivity in the carcass. Mean SD. To ascertain whether Michaeiis-Menten kinetics were applicable, the data in Table 1 were analyzed in accordance with the linear Woolf-Augustinson--Hofstee trans formation of the Michaeiis-Menten equation (Segel, 1976), +^ (2) It can be seen from the plot (Fig. 1) that the data appear to lie along a straight line thus verifying, at least visually, the Michaeiis-Menten model. Vm and A'in can be estimated by the ordinate intercept and the slope of the line or they can be estimated directly by fitting the nonlinear Michaeiis-Menten model. Both procedures yield similar parameter estimates. The estimates derived by fitting the mode! directly are 8558 i 1147 (SD) of VC metabolized and 860 159 (SD) fig of VC/liter of air for Vm and Km respectively. Once a means is obtained to calculate the amount of VC metabolized by rats as a function of exposure, it is then possible to relate the untoward effects associated with VC exposure to the amount biotransformed rather than the exposure concentration of VC per se incurred by rats exposed to VC. CCR 000011290 584 GEHHING, WATANABE. AND PARK mu vei air in I-'ic. 1. Metabolism of vinyl chloride analyzed in accordance with the Wonlf-Augusiinson-Hol'stce linearized fnrrr. of the Michaclis-Mcnten equation. Values of r and r/S were taken from Table I. The line was fit by linear regression analysis. The correlation coefficient. R. was 0.88. Maltoni and Lefenjine (1975) reported the incidence of hepatic angiosarcoma in rats exposed to different concentrations of VC. 4 hr/day, 5 days/week for 12 months and subsequently held for observation until death (Table 2). Before attempting to relate these data to the amount of VC biotransformed in accordance with the MichaclisMenten equation using the previously determined values of Vm and AT,,,, the value for Vm CORRI TABLE 2 \HON BETWEEN EXPOSURE CONCENTRATION OK VlNYL CHLORIDE. METABOLISM AND 1 nouciion or Hkpaiic Angiosarcoma in Rats Exposure concentration Stppm of VC) S(;/g of VC/ liter of air)" i'0/g of VC metabolized7/^ hr) log r Percentage incidence of hepatic angiosarcoma' 10.000 6.000 2.500 500 250 50 25.600 15.360 6.400 1.280 640 128 5.521 5.403 5.030 3.413 2.435 739 3.742 3.733 3.702 3.533 3.386 2.869 15 22 22 12 7 2 >g of VC) I ppm of VC 2.56 liter of air J pg of VC metabol ized'j * Cni corrected for 4 hr exposure. 8558 4/6 -- 5706 6 hr of VC inclaboli/ed : r = ^5706 4 hr 5(/ig/liter)j ^ |860(/ig/iiler) + 5(^g/liter)i. ` From Maltoni and Lefcmine (1975). CCR 0001i29l T1 he ar n lo a ai U e> t l III 11 nnson- Molstee able 1. Tlie line coma in rats months and ing to relate e Michaelisvalue for Vm "'l.ISM AND Percentage incidence of hepatic igtosarcoma1' 15 22 22 dose response: vinyl chloride 585 must be adjusted for the shorter exposure duration used by Maltoni and Lefemine, 4 versus 6 hr. This adjustment is accomplished by multiplying Vin by 4/6. Thus, the amount of VC biotransformed daily by rats exposed to the various concentrations used in the experiment of Maltoni and Lefemine can be calculated from the equation: J5706 Pg of VC\ 4 hr v Ug\ \ liter) 860 rn + S (2 liter/ \ titer (3) The resulting values for are given in Table 2. Figure 2A, depicts a logarithm probability plot (probit plot) of the incidence of hepatic angiosarcoma observed in rats by Maltoni and Lefemine (1975) versus the amount of VC biotransformed for 4 hr of exposure, v, or the exposure concentration, S. The incidence of hepatic tu giosarcoma in rats is linear with respect to log v but not log 5. The line drawn for log v versus tumor incidence (Fig..2) was determined by using a probit regression analysis program, and the equation relating the incidence of tv patio angiosarcoma to log v was: probit response = --t.625 + 1.543 log v (4) Using the foregoing equation, a projection below the levels of exposure producing an experimentally discernible response has been made (dashed line). Assuming no iter) I. Fig. 2. (A) Metabolism of vinyl chloride expressed as log r (Micrograms of VC metabolized/4 hr> versus percentage incidence of hepatic angiosarcoma (probability scale). (B) Exposure concentration expressed as log S (parts per million) versus the percentage incidence of hepatic angiosarcoma. The probit equivalents of the percentage incidence are shown on the right hand ordinate. The solid line is the best fit for experimentally observed responses while the dashed line represents extrapolation below those doses producing an observable response assuming no threshold. CCR 000011292 586 GEHR1NG, WATANABE, AND PARK threshold for the induction of angiosarcoma in rats exposed to VC, the exposure concentration producing one angiosarcoma in 10.000 rats can be calculated. The probit percentage representing an incidence of 0.01% is 1.28. Substitution of this value into the Eq. (4) yields: Log v = 1.8827, v = 76.33 ug of VC metabolized/4 hr Using Eq. (3), the concentration of exposure to VC needed to give this value for v is 11.66 ^/g/liter or 4.6 ppm (approximate 95% confidence limits obtained by substituting the upper and lower 95% confidence limits for v in Eq. (3) and solving for S are 0.038.7 ppm]. Hence, exposure of rats to 4.6 ppm of VC for 4 hr daily. 5 days/week for 1 year can be expected to produce one angiosarcoma per 10.000 rats if the dose-response curve remains valid at exposures, less man those producing a discernible experimental response. DISCUSSION For many chemicals, toxicity may not be a function of exposure to the chemical per se. but rather to a biotransform." non product of the chemical. Frequently, production of a toxic metabolite is' dependent upon enyzmatically mediated reactions which are classically described by Michaelis-Menten kinetics. Since enzymatically mediated reactions are concentration dependent and saturable, toxicity resulting from exposures to chemicals requiring activation to a toxic form cannot be related directly to the magnitude of exposure or dose. In such a case, it is necessary to determine the amount of the chemical undergoing biotransformation as a function of dose or exposure before a meaningful dose-response relationship can be established. There is considerable evidence that vinyl chloride requires bioactivation to produce tumors. Metabolic activation is required to induce mutations in bacteria exposed to VC (Bartsch et ai. 1975: Malavichc'er ai. 1975: Rannug et ai. 1974). Covalent binding of UC to hepatic macromoleculcs in rats (Watanabe et ai, 1978) exposed to MC-VC also requires bioactivation. Covalent binding of electrophiles to DNA has been associated with tumorigenesis. For vinyl chloride-induced hepatic angiosarcoma in rats, a logarithmic probability plot (probit plot) of the incidence versus the amount of vinyl chloride metabolized. t\ over a range of exposures from 50 to 10,000 ppm of VC gives a classical straight line (Fig. 2A). The dose-response relationship is not a straight line when plotted as a function of the exposure concentration. 5 (Fig. 2B). These results support further the conclusion: that VC requires biotransformation to an active metabolite for tumorigencsis. Furthermore, a more reasonable evaluation of the dose-response data for vinyl chloride-induced tumorigenesis requires knowledge of the amount of VC activated as a function of exposure. After arbitrarily excluding data acquired from rats exposed to concentrations of VC exceeding 500 ppm in the experiment of Maltoni and Lefemine (1975). Schneiderman et al. (1975) extrapolated the remaining data to predict an incidence of 0.01% hepatic angiosarcoma in rats exposed to 1 ppm of VC. This number is reasonably close to our prediction of 4.6 ppm of VC for the same incidence. If Schneiderman et al. (1975) had used all of the data, a dose-response curve with an unrea hepati The Lefen Assui the e produ Asi form, desigi chenv will r respo Since to del parar There three expos expos than > well . logic: Un resoh value Thus, fracti toxic lion * dose incre large In sarcr polat the n of V( ppm and 1 quern of he expo1 result excee other CCR 0011293 exposure ed. The probit value into the value for v is iy substituting >r 5 are 0.03ys/week for 1 dose-response . experimental : chemical per production of ns which are illy mediated om exposures irectly to the te the amount posure before i produce xposed to VC *nt binding of > UC-VC also en associated ic probability etabolized, i\ .1 straight line plotted as a rt further the * for tumoriJata for vinyl ictivated as a s exposed to md Lefemine o predict an of VC. This .ne incidence, urve with an dose-response: vinyl chloride 587 unrealistically shallow slope would have resulted and the predicted level causing 0.01% hepatic angiosarcoma would have been much smaller, on the order of 0.00001 ppm. The concepts developed herein allow use of all of the data presented by Maltoni and Lefemine (1975) to construct a dose-response curve on a scientifically defensible basis. Assuming that the resulting J.>se-response curve can be projected beyond the range of the experimentally discernible responses, the exposure concentration required to produce an incidence of 0.01% hepatic angiosarcoma in rats is 4.6 ppm. Aside from interpreting toxicity data for chemicals requiring activation to a toxic form, there are some practical implications of the concepts presented herein for designing experiments to assess the toxocity, including carcinogenicity, of such chemicals. For these chemicals, increasing the concentration above the apparent will produce diminishingly smaller increments in the response; no increase in the response is to be expected when the exposure concentration is two or three times Km. Since total dose is a function of exposure time as well as concentration, it is important to determine the effect of exposure time on the response. As shown in Eq. (3), the only parameter influenced by exposure time is Vm) which is iqqreased linearly with time. Therefore, after the concentration to which the animals are exposed becomes two to three times Am, the amount metabolized, v, will increase linearly with increasing exposure time. For this reason, the gradation of incidence of amvosarcoma in rats exposed to high concentrations of VC will become a function of exposure time rather than concentration. This reasoning makes it imperative that the duration of exposure as well as exposure concentration be considered in evaluating the results of epidemio logical studies of people exposed to high concentrations of VC in the work environment. Unless the dose-dependent, Michaelis--Menten type pharmacokinetic parameters are resolved prior to designing the experiment, the results may be robbed of much of their value for characterizing the dose-response function for the untoward effects observed. Thus, the current approach using the maximum tolerated dose as defined presently and fractions thereof may be scientifically unsound if the objective is to assess the potential toxicity of exposure to much lower doses or exposures. For some chemicals detoxifica tion of the chemical per se or reactive r tabolites formed from the chemical may also be dose-dependent and saturable leading to a build-up of toxic materials. In such cases, the incremental responses to increasing doses or exposures will become disproportionately larger rather than smaller (Gehring and Blau, 1977). In the foregoing analysis of the dose-response data for the induction of angio sarcoma in the rat, no threshold for the response was assumed. As indicated, extra polation below the range of doses resulting in an observable response may overestimate the response in rats because there is evidence that detoxification of reactive metabolites of VC may occur more efficiently in rats exposed to concentrations of VC below 50 ppm (Watanabe et at., 1976c). Indeed, further analysis of the data reported by Maltoni and Lefemine (1975) also provides an indication of a practical threshold. In a subse quent presentation of these data, it was revealed that the latencies for the development of hepatic angiosarcoma were, respectively, 64, 70, 78, 81, 79, and 135 weeks for rats exposed to 10,000. 6000, 2500, 500. 250, and 50 ppm of VC (Maltoni. 1975). These results indicate that at some low levels of exposure the time required for induction may exceed considerably the life expectancy for rats. This is consistent with the work of others suggesting that multiples of a lifetime may be required for expression of cancer in CCR 000011294 i. 588 GEHR1NG, WATANABE, AND PARK response to low doses of a carcinogen (Druckrey, 1967; Albert and Altshuler, 1973). Thus, extrapolation of the data obtained for rats below the range of exposures causing a discernible response may be expected to overestimate the projected incidence. The ultimate objective of a toxicological study is to develop data which can be used to assess the potential risk for man. It is worthwhile to utilize the concepts presented herein to achieve this objective realizing fully that such extrapolation is fraught with uncertainties. The basic assumptions made are: (i) Induction of angiosarcoma is related to the amount of reactive metabolite of VC per unit of mass. (ii) Exposure of rats for 12 months approximates exposure of workers for their working life. (iii) There is no threshold for the induction of angiosarcoma in cither rats or man which likely overestimates the assumption of ris* as discussed above. (iv) The efficiency of the metabolic processes involved in the conversion of VC to the reactive form is proportional to the body surface area. Since data for the bio transformation of VC by man are not available, the most logical basis for translation of the animal data to man would seem to be on the basis of body surface area. The last assumption deserves comment. There are considerable data in the literature showing that metabolism in general and other physiological parameters as well are relatable directly to the surface area of the body (Schmidt-Nielsen, 1970: Pinkel, 1958). For this reason, administration of biologically active chemicals to various species frequently gives an equivalent response when the dose is administered in proportion to the surface area of the body, that is dose per square meter of body surface (Pinkel. 1958). This relationship is gaining recognition in estimating the risk incurred by man from exposure to che nicals in the environment (Committee on Safe Drinking Water. National Research Council, 1977). In utilizing this relationship it must, however, be recognized that the original relationship was developed for biologically active agents. Since metabolism and othe'r physiological processes involved in detoxification are more active in smaller animals, the dose of a biologically active chemical per unit of mass required to produce a given effect increases as the body decreases, while the dose per unit surface area remains relatively constant. However, for a chemical requiring activation to the biologically active toxic form, the total amount transformed will be roughly proportional to the body surface area. Since toxicity is a function of the concentration of the active form in tissue, this total amount transformed must then be normalized for mass to estimate an equivalent response. Using aforementioned rationale, the maximum velocity, Vm, for a 70 kg man can be estimated by calculation using the Vm value obtained for a 0.250-kg rat. The Km of man for VC will be: or 1.85 m2 Vm (man) = (8558 /ig/6 hr) = 351829 <ug/6 hr. 0.045 m2 cca oooou*95 ;r, 1973). es causing a e. can be used ts presented fraught with te of VC per neir working r man which if VC to the for the biot translation area. fhe literature as well are h'nkel. 1958). 'ious species proportion to face (Pinkel. rred by man ng Water, owever, be ictive agents, lion are more unit of mass the dose per cal requiring irmed will be nction of the must then be g man can be he Vm of man DOSE RESPONSE: VINYL chloride 589 where the values 1.85 and 0.045 m2 are the body surface areas of a 70 kg man and a 0.250-kg rat. respectively (Pinkel, 1958). For an 8-hr exposure, the value is 469,105 j/g/8 hr. In order to use this number to theoretically estimate the response in man using data collected in rats, the Vm for man must be adjusted to a mass equivalent to that of rats since toxicity is a function of concentration in tissue. To do this the number is divided by 70 kg/0.25 kg or 280. The resulting Vm for man on a mass equivalent basis to that of rats is 1675 //g/8 hr. Using this value, the amount of VC transformed to a reactive form by man on a mass equivalent basis to rat is given by the equation: 1675 //g/8 hr S'Cug/liter) v(ju%/8 hr) = 860 ^g/liier + SOig/liter) (5) Using this equation, the amount of VC transformed by man on a mass equivalent basis to rats was calculated as a function of exposure concentration and the expected incidence of angiosarcoma estimated from r:q, (4) (Table 3). For men exposed to greater than 200 ppm of VC, the incidence of angiosarcoma has been reported to be 0.02% (Fox and Collier. 1977).( Hence, the theoretical calculated incidence using data from rats exceeds that currently detected by approximately 50 fold. This may indicate that people are less sensitive than rats to the induction of angiosarcoma, or it may indicate that a practical threshold for the induction of angiosarcoma had been attained. Consistent win. this latter possibility is that i' on a mass equivalent basis to rats for men exposed to 200 ppm is 625. This number lies below that for rats exposed to 50 ppm. As indicated previously, angio sarcoma observed in rats exposed to 50 ppm occurred only in a rat that lived 135 weeks (Maltoni, 1975), Further, this rat did not die as a result of the angiosarcoma but was killed. Thus, as indicated previously, projection of the data collected in rats below the range of exposures producing an observable response may overestimate the incidence. TABLE 3 Theoretical Amounts of Reactive Product Formed from VC by a 70 kg Man Exposed Continuously for 8 hr and the Corresponding Expec ted Incidence of Angiosarcoma as Predicted from Data Collected in Rats Assuming no Threshold Exposure concentration H/jgofVC mctabolitedV8 hr) log V Probit response1' Theoretical percentage incidence of angiosarcoma1 (ppm) 200 50 5 1 Cug/liter)" 512 128 12.8 2.56 625 217 24.6 4.97 2.79 2.34 1,39 0.70 2.68 1.98 0,52 -0.54 1.02 0.11 3.74 x I0-4 1.5 x 10-6 J I ppm = 2.56 //g/tner. i> v has been calculated using the Michaelis-Mentcn equation after calculating the I'm for man from the l'm determined for rats. This calculation was made by assuming C(1 is proportional to body surface area and subsequently adjusting it to a mass equivalent to that of rats. See text. ' The expected probu response was calculated from probit Eq. (3) (see text). Subsequently the theoretical percentage incidence of angiosarcoma was determined from the respective probit. CCR 000011296 590 GEHRING, WATANABE, AND PARK In spite of the likelihood of overestimating the incidence of angiosarcoma in rats or man. the incidence predicted for people exposed to 1 ppm. the current OSHA (Occupational Safety and Health Act) standard, is very'small (1.5 per 100 million). This value which is likely an overestimate is below the expected incidence of spontaneous angiosarcoma reported to be 20 to 25 cases in the U.S. annually (Makk et aU 1976). In summary, it has been demonstrated that the incidence of VC induced angio sarcoma in rats is related not to the concentration of exposure but rather to the amount of VC biotransformed. Biotransformation of VC by rats is a dose-dependent process characterized by Michaelis-Menten type kinetics. The concepts evolved from this analysis reveal why pharmacokinetics must be considered in designing toxicology experiments as well as in interpretation of the resulting data. Having characterized the dose-response for induction of angiosarcoma in rats as a function of the amount of VC biotransformed, a theoretical estimate of the incidence expected to occur in exposed men was undertaken using the data collected in rats. For daily 8-hr exposures to 1 ppm, the predicted incidence is 1.5 in 100.000,000 which is less than that expected to occur spontaneously. This predicted incidence is likely an onverestimate of that which will occur as a result of exposure to 1 ppm because there is some evidence fo< at least a practical threshold in both rats and man. There are no illusions that this estimate by extrapolation of data outside the range of doses causing experimentally observable responses and subsequently to man is without flaws. However, the rationale used represents a new approach which utilizes more logic than methods employed currently for such extrapolation. REFERENCES Albert. R. E.. and Altschuler. B. (1973). Considerations relating to the formulation of limits for unavailable population exposures to environmental carcinogens. In Radionuclide Carcinogenesis, Proceedings of the 12th Annual Hartford Biology Symposium at Richland, Washington, pp. 234--253. Barisch, H,, Malavielle. C.. and Montesano, R. (1975). Human, rat and mouse liver mediated mutagenicity of vinyl chloride in Salmonella tvphimurium strains. Int, J. Cancer 15.429-437. Committee on Safe Drinking Water (1977). Summary Report: Drinking Water and Health. Advisory Center on Toxicology, Assembly of Life Sciences. Washington. D.C. Druckrfy, H. (1967). Quantitative aspects in chemical carcinogenesis. In Potential Carcinogenic Hazards From Drugs. Evaluation of Risks (R, Trubant. ed.), U1CC Monograph Series. Vol. 7, pp. 60-78. Springer-Verlag, Berlin. Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation (1971). Panel on Carcinogenesis Report on Cancer Testing in Safety Evaluation of Food Additives and Pesticides. Toxicol. Appl. Pharmacol. 20,419-438. Fox. A. J.. and Collier, P. F. (1977). Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Bril. J. Ind. Med. 34. 1-10. Gehring, P. J.. and Blau. G. (1977). Mechanisms of carcinogenesis: Dose-response. J. Environ. Pathol. Toxicol., in press. Mark. L.. Delmore. F.. Creech. J. L.. Ogden. L. L.. Fadell. F,. H.. Songster. C. L.. Clanton. J.. Johnson, M. N., and Christopherson. W. H. (1976). Clinical and morphologic effects of hepatic angiosarcoma in vinyl chloride workers. Cancer 37. 149-163. Malavif.lle, C.. Bartsch, H., Barbin. A.. Camus, A. M,, and Montesano. R. (1975). Mutagenicity of vinyl chloride, chloroethyleneoxide, chloroacetaldehyde and chloroethanol. Biochem. Biophys. Res. Commun. 63, 363-370. CCR 000 oil*97 Mal ex; Mal re' Man in Pink tht Ran: oT Sens Pi SCHC to 24 Segi Wac G ch Wat. Wat at Wai di Cl' Wat m P' its or t OSHA i million), dence of (Makk et id angioe amount it process from this jxicology irized the mt of VC i exposed to 1 ppm, I to occur vhich will at least a cimate by bservable nale used currently in of limits dionuclide hlund, louse liver J. Cancer nd Health. Potential J.), U1CC .r Safety Evaluation :d to vinyl . hul. Med. .sponse. J. ifr, C. L.. .inical and 149-163. R. (1975). .xoeihanol. DOSE-RESPONSE: VINYL CHLORIDE 591 Maltoni, C. (1975). The values of predictive experimental environmental carcinogenesis. An example: Vinyl chloride. Ambio 4, IS--23. Maltoni. C,. and Lkhemine, G. (1975). Carcinogenicity assays of vinyl chloride: Current results. Ann. /V. Y. Acad. Sci. 246, 195-224. Mantel, N.. and Bryan, W. R. (1961). "Safety" testing of carcinogenic agents. J. Nat. Cancer Inst. 27. 455-470. Pinkel, D. (1958). The use of body surface area as a criterion of drug dosage in cancer chemo therapy. Cancer Res. 18, 853-856. Ranniju, U.. Johansson, A., Ramel, C., and Wachtmeister, C. A. (1974). The mutagenicity of vinyl chloride after metabolic activation. Ambio 3. 194--197. ScHMinr-Nu i SEN. K. (1970). Energy metabolism body size, and problems of scaling. Fed. Proc. Fed. Attier. Soc. Exp Biol. 29, 1524-1532. St'HNKiDi-RMAN, M. A.. Maniel, N.. and Brown, C. C. (1975). From mouse to man--or how to get from the laboratory to Park Avenue ami 59th Street. Ann. N. Y. Acad. Sci. 246, 237248. Seoel, I. H. (1976) Biochemical Calculations, 2nd Ed., pp. 236- 237. Wiley, New York. Wagner, E. R.. Moulder, W. W., Watanabe. P. G., Hefner, R. E., Jr.. Braun, W. H.. and Gehring, P. J, (1975). Gas chromatographic method for the preparation of ,4C labelled vinyl chloride. J. Labeled Compounds 11, 535-542. Watanabe, P. G.. McGowan, G. R.. Madrid. E. O., and Gehring, P. J. (1976a). Fate of l4C-vinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol. 37, 49-59. Watanabe, P. G., McGowan, G. R., and Gehring, P. J. (1976b). Fate of 14C vinyl chloride after single ora! administration in rats. Toxicol. Appl. Pharmacol. 36, 339-352. Watanabe, P. G., Hefner. R. E., Jr,, and Gehring, P. J. (1976c). Vinyl chloride induced depression of hepatic nonprotein sulfhydryl content and effects on bromosulpluhalein (BSP) clearance in rats. Toxicology 6, 1-8. Watanabe, P. G., Zempel, J. H., Pegg, D. G., and Gehring, P. J., (1978). Hepatic macromolecular binding following exposure to vinyl chloride. Toxicol. Appl. Pharmacol., in press. t t CCR 00002 1*98 CCR 000011299 w*f~ Jk. OOQii 300