Document QXegG5XZDJkE6DBRjQxm35RnE

Marvin A. Schneiderman, Ph.D., of Bethesda, Maryland, is a statistician and epidemiologist who is the former Chief of Statistics and Epidemiology and the former Director for Science Policy of the National Cancer Institute and is currently a consultant. His curriculum vitae is attached. Dr. Schneiderman will testify concerning mathematical models, statistics, and epidemiology in the area of cancer. He will first discuss the epidemiology of dioxins and their contaminants to human cancer insofar as it relates to soft tissue sarcomas, and particularly the EPA peer review group conclusions in regard thereto, stomach cancers and lymphomas. In that regard, he will discuss the relationship of exposure to the time the disease appears, the so-called latency period. He will also discuss the multiplication of base rates in the production of such cancer. Next, Dr. Schneiderman will present a multi-stage model of cancer induction. He will discuss age relationships and the stage of cancer development as they are affected by dioxins and their contaiminants or other materials. He will also present certain pertinent animal data and discuss it as a predictor for human experience. He will also testify that TCDD is more toxic than many other carcinogens, including being more carcinogenic by a factor of 4 or 5 than benzene, for example. He will also explain the concept of risk assessment and how judgments as to such are capable of being made with regard to humans. This will include discussion of a mathematical model for association of the multi-faceted presentation of symptoms and signs in the same 238 veteran to exposure to Agent Orange as a causative factor. He will also discuss the population incidences of these rare cancers, presenting a comparison of the onset ages for them in the general population with the ages of onset for the cancers observed in. the Vietnam veterans. He will also discuss the relationship of cancer induction to immune deficiencies or deficits. He will place special emphasis upon lymphomas and soft tissue sarcomas and explain how the ex perience with transplant patients validates his opinions in this regard. Finally, he will discuss the question of a threshold in the induction of cancer. This will include testimony to the effect that there is no "safe" dose for a carcinogen and that a single exposure may cause cancer. He will also discuss the disease-producing behavior of generalized carcinogens, i.e., the chance of a single carcinogen leading to cancer at multiple sites. \ C^O MARVIN A. SCHNEIDERMAN Dr. Schneiderman is a Clement Associates Senior Science Advisor with principal responsibilities in biostatisticsf epidemiologyr risk assessment, and health surveillance. He has more than 30 years of experience in cancer research and related subjects, and he is the author of more than 130 scientific papers in areas of biostatistics, epidemiology, risk assessment, and science and regulatory policy. During his career with the National Cancer Institute (NCI), he was, successively, Associate Chief of the Biometry Branch, Associate Director for Field Studies (Epidemiology) and Statistics,and Associate Director for Science Policy. In this last position, he was one of the princi pal advisors to the Director of the Institute. Dr. Schneiderraan is a member of the adjunct faculty of the Georgetown University Graduate School, and Professor of Biostatistics at the Uniformed Services University of the Health Sciences. He has held teaching positions at the University of Pittsburgh Graduate School of Public Health and the University of Miami (Florida), as well as at the Georgetown University Medical School. He was also a Rockefeller Public Service Fellow at the London School of Hygiene and Tropical Medicine. He has served on a number of expert advisory committees and is or has been an associate editor of Cancer Research, Blood, Journal of the National Cancer Institute, Biometr ics, Statistics in Medicine, American Journal of Industrial Medicine, and a number of other'scientific journals DEGREES Ph.D., Statistics, American University, Washington, D.C., 1961 M.S., Statistics, American University, Washington, D.C., 1953 B.S., Mathematics and Statistics, City College of New York, 1939 NON-DEGREE EDUCATION Harvard University Graduate School of Business, 1945 Management sciences, economics, statistics Ohio State University Graduate School, 1946-1947 Economics London School of Hygiene and Tropical Medicine, 1959-1960 Epidemiology, medical research involving humans, controlled trials, biostatistics i*> r.-N a X #< 0 4 SCHNEIDERMAN, page 2 1983-present 1981-present 1980-present 1975-present 1980 1978-1980 1970-1978 1967-1978 1966-1975 1960-1970 1960-1965 1959-1960 1955-1959 1948-1955 1939-1948 EMPLOYMENT HISTORY Senior Fellow, Environmental Law Institute, Washington, D.C. Professor (Division of Biometrics), Department of Preventive Medicine, USUHS, Bethesda, Md. Senior Science Advisor, Clement Associates Associate Professor, Graduate Faculty, Georgetown University Expert Consultant, Office of the Director, National Cancer Institute (NCI), National Institutes of Health (NIH) Associate Director for Science Policy, Office of the Director, NCI Associate Director NCI, Field Studies and Statistic Program, Division of Cancer Cause and Prevention, NCI Adjunct Professor, Biostatistics, Graduate School of Public Health, University of Pittsburgh Clinical Associate Professor, Medical Statistics, Georgetown University Medical School Associate Chief, Biometry Branch, NCI Professorial Lecturer, Georgetown University Medical School Rockfeller Public Service Fellow, Statistical Research Unit of the British Medical Research Council, London School of Hygiene and Tropical Medicine Mathematical Statistician and Acting Chief, Therapeutic Trials Section, NCI Mathematical Statistician, Biometrics Section, NCI Private Industry, Military Service (USAF), Other Federal government agencies "1 9n,toK .X i. (*it xj SCHNEIDERMAN, page 3 T T /'W l/'M " * O n u i'iU A D Distinguished Lecturer, Lawrence Livermore Laboratories, Univer sity of California, 1982 American Conference of Government Industrial Hygienists, Symposium Speaker Award, June, 1982 Samuel Wilkes Public Lectureship, Princeton University, 1980 Keynote Lecturer, Society of Occupational and Environmental Health, 1979, North Carolina Public Health Association, 1980 Environmental Defense Fund, Public Interest Science Award, 1977 Distinguished Service Award, Department of Health, Education and Welfare (DHEW), 1974 Superior Service Award, DHEW, 1968 Rockefeller Public Service Fellow, London School of Hygiene and Tropical Medicine, 1959-1960 Phi Beta Kappa, 1939 SELECTED ADVISORY COMMITTEES Committee on Toxicity Data Elements, National Academy of Science 1981-present Subcommittee on the Geochemical Environment in Relation to Health and Disease, NAS/NRC, 1980-present Science Evaluation Board, National Health and Medical Research Council of Australia, 1980-present American Cancer Society, Analysis and Projections Committee, 1976-1978, Institutional Grants Committee, 1980-present Science Advisory Board, Howard University Cancer Center, 1979present (External Review Committee) Center for Science in the Public Interest, Board of Directors, 1983-present Food Safety Council, Board of Directors, 1978-1982 Advisory Committee, Biomedical and Environmental Assessment Division, Brookhaven National Laboratory, 1978-present f', Q f* SCHNEIDERMAN, page 4 Advisory Committee, International Cancer Research Data Bank (CIDAC), Franklin Institute, Philadelphia, 1981-present Task Force on Heart Disease Epidemiology, National Heart, Lung, and Blood Institute, 1979-1980 Science Advisory Board, National Center for Toxicological Research, 1974-1979 Ad Hoc Subcommittee on Asbestos-Related Health Problems, Armed Forces Epidemiology Board, 1978-1979 International (American) Chairman, U.S./U.S.s.R. Working Group on the Epidemiology of Cancer, 1973-1979 Committee on Maritime Hazardous Materials, National Academy of Sciences, 1978 Committee to Coordinate Toxicology and Related Programs, DHEW, 1978 President's Biomedical Panel, 1975-1976 Consultative Panel on Hazards of Chemical Pesticides, National Academy of Sciences, 1974-1976 Chairman and Executive Secretary, Committee of Presidents of Statistical Societies, 1973-1976 Board of Directors, American Statistical Association, 1972-1974 International Council, International Biometric Society, 1971-1973 Immunology-Epidemiology Segment, Special Virus Cancer Program, NCI, 1969-1971 Advisory Panel on Carcinogenicity of Pesticides, Secretary's Commission on Pesticides and Their Relationship to Environmental Health, 1969-1970 Chairman, Subcommittee on Medical Biostatistics, American Thera peutic Society, 1967-1968 Subcommittee on Biologic Effects of Atomic Radiation, NAS/NRC, 1964-1965 SCHNEIDERMAN, page 5 SELECTED SOCIETIES American Association for Cancer Research American Society for Preventive Oncology (Founding Member) American Statistical Association (Fellow) Biometric Society (International) International Epidemiological Association Royal Statistical Society (Fellow) Washington Statistical Society American Association for the Advancement of Science (Fellow) International Statistical Institute (Fellow) Society for Occupational and Environmental Health SELECTED PUBLICATIONS Schneiderman, M.A. Standard setting: Implications of sensitivity and a search for an ethical base. In: Protection of the Sensitive Individual, Annals of the American Conference of Government Industrial Hygienists, 3:133-138 (1932) Schneiderman, M.A. A personal reminiscence (Austin Bradford Hill). Statistics in Medicine 1:307-308 (1982) Schneiderman, M.A. Discussion of "Some Aspects of Cancer Epidemi ology" by Abraham Lilienfeld. Biometrics (Supplement) 38:161-165 (1982) Davis, D.L., Bridbord, K., and Schneiderman, M.A. Cancer preven tion: Assessing cause, exposure, and recent trends in mortality for U.S. males, 1968-1978. Teratogenesis, Carcino genesis and Mutagenesis. Pp. 105-135 (June 1982) Schneiderman, M.A. Trends in cancer mortality and incidence in the United States: Is the future clear or clouded? In Mike, V., e d . Statistics in Medical Research. John Wiley and Sons, New York. Pp. 71-107 (1982) Schneiderman, M.A. Description and reliability of trends in ' cancer incidence. In Magnus, K. Trends in Cancer Incidence. Hemisphere Publishing Corp., Washington, D.C. Pp. 1-2 (1982) Schneiderman, M.A. Cost-benefit, social values and the setting of occupational health standards. In Lee, J.S., and Rom, W.N eds. Legal and Ethical Dilemmas in Occupational Health. Ann Arbor Science, Ann Arbor, Michigan, pp. 191-205 (1982) * <*% r" try SCHNEIDERMAN, page 6 Peto, R. , and Schneiderman, M. , eds. Quantification.of Occupa tional Cancer: Banbury Report No. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1981) . Davis, D.L., Bridbord, K., and Schneiderman, M.A. Estimating cancer risks: Problems in methodology production trends. In Peto, R . , and Schneiderman, M . , eds. Quantification of Occupational Cancer: Banbury Report No. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. Pp. 285315 (1981) Schneiderman, M.A. Summary comments. In Crandall, R.W., and Lave, R . , eds. The Scientific Basis of Health and Safety Regulation. The Brookings Institution, Washington, D.C. Pp. 297-299 (1981) Schneiderman, M.A. Regulation of carcinogens in an imprecise world. Ann. N.Y. Acad. Sci. 363:217-232 (1931) Schneiderman, M.A. Extrapolation from incomplete data to total or lifetime risks at low doses. Environ. Health Perspect. V. 42, Pp. 33-38 (December 1981) Schneiderman, M.A. Toxic Substances in Our Environment-Can we manage them so 'chat they don't manage to harm us? Health Forum 81, The Coalition for Health and the Environ ment, Washington, D.C. (1981) Schneiderman, M.A. Epidemiology: What Can it Tell Us? Pro ceedings of the Conference on Environmental Risk, New Orleans, Louisiana, December 10, 1980. The Electric Power Research Institute, Palo Alto, California, EPRI EA-2064, Project 1316-6. Pp. 369 - 3-89 (October 1981) Schneiderman, M . A . , Nisbet, I., and Brett, S.M. Assessment of Risks Posed by Low Levels of Asbestos in the General Environment. Berichte: Bundesgesundheitsamt. No. 4, 1981. Dietrich Reimer Verlag, Berlin. Pp. 3/1-3/28 (1981) Schneiderman, M . A . , and Levin, D.L. Needs, problems and prospects in cancer epidemiology. In Levin. D.L., ed. Cancer Epidemi ology in the U.S.A. and U.S.S.R. U.S. Department of Health and Human Services, P H S , Bethesda, Maryland. NIH Publication No. 80-2044 (1980) Schneiderman, M.A. The Relationship Between Diet, Occupation, the Environment and Cancer. Proceedings: US/Egypt Symposia", on the Biomedical Effects of Technology Transfer, Cairo, Egypt (February 9-13, 1980) (In Press: Environmental Health Perspectives) 12989 SCHNEIDERMAN, page 7 Schneiderman, M.A. Scientific Issues in a National Cancer Policy. Proceedings of the 4th Toxic Control Conference. Government Institutes, Inc., Washington, D.C. Pp. 95-107 (1980) Schneiderraan, M.A. The uncertain risks we run: Hazardous materials. In Schwin, R.C., and Albers, W . A . , Jr., eds. Societal Risk Assessment. Plenum Press, New York. Pp. 19-41 (1980) Schneiderman, M.A. What's Happening to Cancer in our Advanced Industrial Society? Have the Risks been Overstated? Keynote Address: Society for Occupational and Environmental Health, Washington, D.C. (In Press: Proceedings) (December 3-5, 1979) Blokhin, N.N., and Schneiderman, M.A., eds. Epidemiology of Cancer in the USSR and USA. Meditsina, Moscow (Russian) (1979) Schneiderman, M.A., DeCoufle, P., and Brown, C.C. Thresholds for environmental cancer: Biologic and statistical consider ations. Ann. N.Y. Acad. Sci. 329:92-130 (1979) Schneiderman, M.A. Alpha, beta manitonne-- a new industrial material with unknown benefits and risks. In Carcinogenic Risks/Strategies for Intervention. International Agency for Research on Cancer (IARC), Lyon, France. IARC Sci. Publ, 25:237-239 (1979) Schneiderman, M.A. The Links Between the Environment and Health. Proceedings: National Conference on the Environment and Health Care Costs, .U.S. House of Representatives (August 15, 1978) Biersteker, K. , and Schneiderman, M.A. Epidemiologic Aspects of Drinking Water-Health Relationship. Proceedings of the Health Effects Committee of the NATO committee on challenges of Modern Society. 3onn, W. Germany (April 23- 27, 1978) Schneiderraan, M.A., Mason, T.J., and Hoover, R. Cancer, geography, and geology-- a problem for interdisciplinary cross-fertili zation. In Geochemistry and the Environment. Vol. 3. National Academy of Sciences, Washington, D.C. (1978) Schneiderman, M.A. Legislative possibilities to reduce the impact of cancer. Prev. Med. 7:424-438 (1978) 12390 SCHNEIDERMAN, page 8 Schneiderman, M.A. Water and epidemiology. In Russell, C.S., ed. Safe Drinking Water: Current and Future Problems. Proceedings of the National Conference on Resources for the Future. Pp. 111-1.48 (1978) Schneiderman, M.A. Extrapolating animal and microbiological tests to humans. In Coling, G., e d . Environmental Cancer (Causes, Victims, Solutions). Proceedings of a conference of the Urban Environment Coalition, Inc. Pp. 9-11 (1978) Schneiderman, M.A. Environmental Factors and Cancer Prevention Marcel Dekker, New York (1978). (Third National Symposium on Detection and Prevention of Cancer, New York (April 26-30, 1976) Schneiderman, M.A. Risk assessment of the health effects of water chlorination. In Jolley, R.L., Gorchev, H., and Hamilton, D.H., eds. Water Chlorination-- Environmental Impact and Health Effects. Ann Arbor Science Publications Ann Arbor, Mich. Vol. 2, pp. 509-515 (1978) Schneiderman, M.A., and Brown, C.C. Estimating cancer risks to a population. Environ. Health Perspect. 22:115-124 (1978) Schneiderman, M.A. Eighty percent of cancer is related to the environment. Laryngoscope 88:1-16 (1978) Schneiderman, M.A. Time Trends in Cancer: United States, 1953-1973. Laryngoscope 88, Supp. 8:1-6 (1978) Fears, T.R., Scotto, J., and Schneiderman, M.A. Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. Am. J. Epidemiol. 105:420-427 (1977) DeVesa, S.S., and Schneiderman, M.A. Increase in the number of cancer deaths in the United States. Am. J. Epidemiol. 106:1-5 (1977) Schneiderman, M.A. The numerate sciences-- epidemiology and biometry. JNCI 59:633-644 (1977) Schneiderman, M.A., and Levin, D.L. Epidemiology of cancer and tobacco use: Trends and trend indicators. In Stein- field, J., Griffiths, W . , Ball, K. , and Taylor, R.M., eds. Smoking and Health: II. Health Consequences, Educa tion, Cessation Activities, and Governmental Action. Proceedings of the Third World Conference on Smoking and Health, New York. Pp. 73-84 (1977) j 9 n 91 SCHNEIDERMAN, page 9 Schneiderman, M.A. Health effects-- a scientific and.statistical analysis. In Miller, M.L., ed. Proceedings of the First Toxic Substances Law Seminar. Washington, D.C. .(1977) Levin, D.L., and Schneiderman, M.A. Cancer. In Miller, S.S., ed. Symptoms. Thomas Y. Crowell, New York (1976) Fears, T.R., Scotto, J., and Schneiderman, M.A. Skin cancer, melanoma, and sunlight. Am. J. Public Health 66:461-464 (1976) Schneiderman, M.A. Carcinogenesis as an end point in health impact assessment. In Anderson, E.C., and Sullivan, E.M., eds. Impact of Energy Production on Human Health: An Evaluation of Means of Assessment. National Technical Information Service, Springfield, Va. Pp. 65-74 (1976) Schneiderman, M.A. Sources, resources, and tsouris. In Fraumeni, J.F., ed. Persons at High Risk of Cancer: An Ap proach to Cancer Etiology and Control. Academic Press, New York (1976) Hoel, D.C., Gaylor, D.W., Kirschstein, R.L., Saffiotti, U., and Schneiderman, M.A. Estimation of risks of irreversible, delayed toxicity. J. Toxicol. Environ. Health 1:133-151 (1975) Mantel, N . , and Schneiderman, M.A. Non-parametric interval estimation of relative potency for dilution assays, includ ing the case of non-monotone dosage response curves. Biometrics 31:619-632 (1975) Mantel, N . , and Schneiderman, M.A. Estimating "safe" levels-- a hazardous undertaking. Cancer Res. 35:1379-1386 (1975) Schneiderman, M.A., Mantel, N . , and Brown, C.C. From mouse to man-- or how to get from the laboratory to Park Avenue and 59th Street. Ann. N.Y. Acad. Sci. 246:237-248 (1975) Schneiderman, M.A. How do you know you've done any better? Cancer 35:64-68 (1975) Schneiderman, M.A. Digestive system cancer among persons sub jected to occupational inhalation of asbestos particles: A literature review with emphasis on dose response. Environ. Health Perspect. 9:307-311 (1974) Schneiderman, M.A. Safe dose? The problems of the statistician in the world of trans-science. J. Wash. Acad. Sci. 64:68- 78 (1974) 12392 SCHNEIDERMAN, page 10 Fears, T.R., and Schneiderman, M.A. Pathologic evaluation and the blind technique. Science 183:1144-1145 (1974) Elashoff, R.M., Sobel, M . , and Schneiderman, M.A. A proposal for economical first stage screening for tumorigens with a posssible "joint action" bonus. In Pratt, J.W., ed. Statistical and Mathematical Aspects of Pollution Problems. Marcel Dekker, New York (1974) Van Belle, G., and Schneiderman, M.A. Some statistical aspects of pollution and protection. Int. Stat. Rev. 41:315 (1973) Wynder, E.L., and Schneiderman, M.A. Exogenous hormones-- boon or culprit? JNCI 51:729-731 (1973) Gehan, E.A., and Schneiderman, M.A. Experimental design of clinical trials. In Holland, J.F., and Frei, E., eds. Cancer Medicine. Lea and Febiger, Philadelphia. Po. 499519 (1973) Schneiderman, M.A., and Mantel, N. The Delaney clause and a scheme for rewarding good experimentation. Prev. Med. 2:165-170 (1973) Schneiderman, M.A., and Levin, D.L. Parallels, convergences, and departures in case-control studies and clinical trials. Cancer Res. 33:1498-1503 (1973) Graham, S., and Schneiderman, M.A. Social epidemiology and the prevention of cancer. Prev. Med. 1:371-379 (1972) Scotto, J., and Schneiderman, M.A. Predicting survival in terminal cancer. Br. Med. J. 4:50 (1972) Schneiderman, M.A., and Levin, D.L. Trends in lung cancer: Mortality, incidence, diagnosis, treatment, smoking and urbanization. Cancer 30:1320-1325 (1972) Johnson, R.E., Thomas, L.B., Schneiderman, M.A., Glenn, D.W.., : Faw, F., and Habermann, M.D. Preliminary experience with total nodal irradiation in Hodgkin's disease. Radiology 96:603-608 (1970) Schneiderman, M.A., and Scotto, J. Computer-Investigator Inter actions in Small-Scale Clinical Trials. Proceedings of the Fifth Scientific Meeting of the International Epidemiol ogy Association, Primosten, Yugoslavia. Pp. 449-467 -(1970) SCHNEIDERMAN, page 11 Gold, G .L ., Shnider, B.I., Salvin, L.G., Schneiderman, M . A . , Col sky, J., Owens, A.H., Krant, M.J., Miller, S , Frei, E., Ill, Hall, T.C., Spurr, C.L., McIntyre, O.R., Hopgstraten, B. and Holland, J.F. The use of mechlorethamine, cyclophospha mide, and uracil mustard in neoplastic disease: A coopera tive study. J. Clin. Pharmacol. 10:110-120 (1970) Schneiderman, M.A. How to read the drug literature-- or any other organized collection of numbers from experiments. Mod. Med. 37:92-96 (1969) Malmgren, R.A., Bennett, J . M . , DelVecchio, P.R., DeWhitt, S.H., Feld, M . , Kazam, E., and Schneiderman, M.A. Evaluation studies of peripheral blood leucocyte changes in malignancv. Acta Cytol. 13:149-153 (1969) Schneiderman, M.A. Quantitative thinking in medicine-- biosta tistics. (Using numbers to mark the route from cause to effect and back.) In Cantor, P., e d . Traumatic Medicine and Surgery for the Attorney. Matthew Bender, New York. ?p. 419-477 (1969) Givelber, H., DiPaolo, J.A., and Schneiderman, M.A. The influence of actinomycin D on survival of x-radiated RF mice. Cancer Res. 28:2484-2488 (1968) Pipberger, H.V., Schneiderman, M.A., and Klingeman, J.D. The love-at-first-sight effect in research. Circulation 38:822825 (1968) Carbone, P.P., Spurr, C. , Schneiderman, M.A., Scotto, J., Holland, J.F., and Shnider, B. Management of patients with malignant lymphoma: A comparative study with cyclophosphamide and vinca alkaloids. Cancer Res. 28:811-822 (1963) Hall, T.C., Nevinny, H.B., Holland, J.F., Maldia, G . , Schneiderman M.A., Salvin, L . , Shnider, 3.1. , Gold, G.L., Frei, E., Ill, Carbone, P.P., Colsky, J., Franzino, A., Grob, D., Matiasevic, D., Olson, K.3., Horton, J., Owens, A., Santos, * ^ G.W. , Chalmers, T.C. , and Krant, M.J. Comparison of anti metabolites in the treatment of breast and colon cancer. JAMA 200:770-778 (1967) Schneiderman, M.A. The Shin Tokaido to developing new treatments in medicine: Unbiasedness. In Harris, R.J.C.,ed. Pro ceedings of the 9th International Cancer Congress. SpringerVerlag, Heidelberg. Pp. 194-198 (1967) Bull, B.S., Schneiderman, M.A., and Brecher, G. w? c i u J. a u L u n i a u i u dilution system for the hematology laboratory Clin. Pathol. 47:549-553 (1967) SCHNEIDERMAN, page 12 Schneiderman, M.A. Mouse to man: Statistical problems in bringing a drug to clinical trial. In LeCam, L., and Neyman, J., eds. Biology and Problems of Health. Univer sity of California Press, Berkeley. Vol. 4, pp. 855-866 (1967) Schneiderman, M.A. Non-objective art and objective evaluation of cancer chemotherapy. In Brodsky, I., and Kahn, S.B., eds. Cancer Chemotherapy. New York, Grue and Stratton. Pp. 67-76 (1967) Spurr, C.L., Carbone, P.P., and Schneiderman, M.A. Comparative evaluation of cyclophosphamide and vinca alkaloids in lymphomas. Proceedings of the 57th Annual Meeting of the American Association of Cancer Research 7:67 (1966) Myers, M.H., Schneiderman, M.A., and Armitage, P. Boundaries for closed (wedge) sequential t-test olans. Biometrika 53:431-437 (1966) Schneiderman, M.A. Experimental design considerations in multi clinic trials. In Radouco-Thomas, C., exec, e d . Interna tional Encyclopedia of Pharmacology and Therapeutics. Pergamon Press, Oxford. Vol. 2, pp. 617-636 (1966) Schneiderman, M.A. The value of controlled trials. In Hayward, J.L., and Bulbrook, R.D., eds. Clinical Evaluation in Breast Cancer. London, Academic Press. Pp. 249-259 (1966) Cutler, S.J., Greenhouse, S.W., Cornfield, J., and Schneiderman, M.A. The role of hypothesis testing in clinical trials. J. Chron. Dis. 19:857-882 (1966) Bourgeois, L.D., Hart, L.J., Herman, L.G., Schneiderman, M.A., and Young, V.M. Effect on varying preincubation and diffu sion times and antibiotic disc susceptibility testing. In Day, R.A., e d . Antimicrobial Agents and Chemotherapy-- 1965. Waverly Press, Baltimore. Pp. 283-288 (1966) Schmeiderman, M.A., and Krant, M.J. What shall we measure on whom: Why? Cancer Chemother. Rep. 50:107-112 (1966) Dawson, J.M., Hall, T.C., Schneiderman, M.A., Shnider, B.I., Owens, A.H., Andrews, J.R., Baxter, D.H., Brenner, S., Hunter, C., Levene, M.3., Sheehan, F.R., and White, G. The objective evaluation of change in tumor size in lung cancer patients with non-measurable disease. Cancer 19:415-420 (1966) 12995 SCHNEIDERMAN, page 13 Schneiderman, M.A. Looking backward: Is it worth the crick in the neck? Or: Pitfalls in using retrospective data. AJR 96:230-235 (1966) Bull, B.S., Schneiderman, M.A., and Brecher, G. Platelet counts with the Coulter counter. Am. J. Clin. Pathol. 45:678-688 (1965) Schneiderman, M.A. How can we find an optimal dose? Toxicol. Appl. Pharmacol. 7, Supp. 2:44-53 (1965) Schneiderman, M.A. The optimal dose and the ranking of drugs. J. Oral Ther. Pharmacol. 2:118-119 (1965) Carbone, P.P., Krant, M.J., Miller, S.P., Hall, T.C., Shnider, Colsky, J., Horton, J., Hofley, H., Miller, J.M., Frei, E.J., III, and Schneiderman, M.A. The feasibility of using randomization schemes early in the clinical trials of new chemotherapeutic agents: Hydroxyurea (NSC-32065). Clin. Pharmacol. Ther. 6:17-24 (1965) 3 Schneiderman, M.A. The proper size of a clinical trial: "Grand m a 's strudel" method. J. New Drugs 4:3-11 (1964) Schneiderman, M.A. Defensive design of clinical trials. In Sternberg, T.H., and Newcomer, V.D., eds. The Evaluation of Therapeutic Agents and Cosmetics. McGraw-Hill, New York. Pp. 66-73 (1964) Schneiderman, M.A., Myers, M.H., Sathe, Y.S., and Xoffsky, P. Toxicity, the therapeutic index, and the ranking of drugs. Science 144:1212-1214 (1964) Schneiderman, M.A. Is it really bad? A proposal for the toxi city-testing of drugs. J. Soc. Cosmetic Chem. 14:227232 (1963) Schneiderman, M . A . , and Armitage, P. Closed sequential t-tests. Biometrika 49:359-366 (1962) Brecher, G., Jakobek, E.F., Schneiderman, M.A., Williams, G.Z., and Schmidt, P.J. Size distribution of erythrocytes. Ann. N.Y. Acad. Sci. 99:242-261 (1962) Schneiderman, M . A . , and Armitage, P. A family of closed sequen tial procedures. Biometrika 49:41-56 (1962) Schneiderman, M.A. The clinical excursion into 5-fluorouracil. J. Chron. Dis. 51:283-295 (1962) 12396 SCHNEIDERMAN, page 14 Schneiderman, M.A. Controlled clinical trials: Monday's count down for Tuesday's launching. J. New Drugs 1:250-255 (1961) Schneiderman, M.A. Statistical problems in the screening search for anticancer drugs by the National Cancer Institute of the United States. In Quantitative Methods in Pharmacol ogy. North Holland Publishing Co., Amsterdam. Pp. 232247 (1961) Zubrod, C.G., Schneiderman, M.A., Frei, E . , III, Brindley, G., Gold, G.L., Shnider, B., Oviedo, R . , Gorman, J., Jones, R., Jr., Jonsson, G . , Colsky, J . , Chalmers, T . , Ferguson, B., Dederick, M . , Holland, J., Selawry, 0., Regelson W . , Lasagna, L., and Owens, A.H. Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene, thiophosphoramide. J. Chron. Dis. 11:7-33 (1960) Leiter, J., Wodensky, I., Bourke, A.R., and Schneiderman, M.A. Screening data from the Cancer Chemotherapy National Service Center screening laboratories, III. Cancer Res. 19:438575 (1959) Leiter, J., and Schneiderman, M.A. Screening data from the Cancer Chemotherapy National Service Center screening laboratories. Cancer Res. 19:31-279 (1959) Schneiderman, M.A. Mathematical models in the regulation of granulocyte production. In Stohlman, F., Jr., ed. Kinetics of Cellular Proliferation. Grue and Stratton, New York. Pp. 259-264 (1959) Brindley, C.O., Markoff, E . , and Schneiderman, M.A. Direct observations of lesion size and number as a method of following the growth of human tumors. Cancer 12:139-146 (1959) Freireich, E.J., Schmidt, P.J., Schneiderman, M.A., and Frei, E., III. A comparative study of the effect of transfusion of fresh and preserved whole blood on bleeding in patients with acute leukemia. N. Eng. J. Med. 260:6-11 (1959) Armitage, P., and Schneiderman, M.A. Statistical problems in mass screening program. Ann. N.Y. Acad. Sci. 76:896908 (1958) Frei r E . , III, Holland, J.F., Schneiderman, M.A., Pinkel, D., Selkirk, G. , Freireich, E.J., Silver, R.T., Gold, G.L. , and Regelson, W.A. A comparative study of two regimens of combination chemotherapy in acute leukemia. B l o d d 9 Q Q 7 13:1126-1148 (1958) SCHNEIDERMAN, page 15 Schneiderman, M.A. Epidemiology of carcinoma of the.breast. Med. Ann. Dist. Columbia 27:275-280 (1958) Silver, R . T . , Beal, G.A., Schneiderman, M.A., and McCullough, N.E The role of the mature neutrophil in bacterial infections in acute leukemia. Blood 12:814-821 (1957) Stohlman, F., Jr., Brecher, G., Schneiderman, M.A., and Cronkite, The haemolytic effect of ionizing radiation and its relation ship to the hemorrhagic phase of radiation injury. Blood 12:1061-1085 (1957) Brecher, G . , Schneiderman, M . A . , and Williams, G.Z. Evaluation of an electronic red blood cell counter. Am. J. Clin. Pathol. 26:1439-1449 (1956) Olivier, L . , and Schneiderman, M.A. A method for estimating the density of aquatic snail populations. Exp. Parasitol. 5:109-117 (1956) Stohlman, F., Jr., and Schneiderman, M.A. Application of the cr: technique to the study of experimental hemolysis in the dog. J. Lab. Clin. Med. 47:72-87 (1956). Cutler, S.J., Schneiderman, M.A., and Greenhouse, S.W. Some statistical considerations in the study of cancer in industr Am. J. Public Health 44:1159-1166 (1954) Prehn, R.T., Main, J.M., and Schneiderman, M.A. Factors influ encing tumor distribution among the mammary glands of the mouse. JNCI 14:895-904 (1954) Olivier, L . , and Schneiderman, M.A. Acquired resistance to schistosoma Mansoni infection in laboratory animals. Am. J. Trop. Med. H y g . 2:298-306 (1953) Brecher, G. , Schneiderman, M . A . , and Cronkite, E.P. The reproduc ibility and constancy of platelet counts. Am. J. Clin. Pathol. 23:15-26 (1953) Heston, W.E., and Schneiderman, M.A. Analysis of dose-response in relation to mechanism of pulmonary tumor induction in mice. Science 117:109-111 (1953) Plum, C . M . , Clemmesen, J., and Schneiderman, M.A. In vitro study of bone marrow v. erythropoiesis of bone marrow from cases of pernicious anemia and leukosis. Acta Med. Scand. 143:237-248 (1952) 12S98 Dr. Ellen Silbergeld, Ph.D., is an environmental scientist and toxicologist who is the Chief Toxicologist for the Environmental Defense Fund and a Research Scientist in the Reproductive Toxicology Laboratory of the National Institutes of Health in Bethesda, Maryland. Her curriculum vitae is attached. Dr. Silbergeld will testify as to the scientific models for TCDD toxicity. She will emphasize the receptor model, its role in physiology, how to detect receptors and how to link receptors to function. She will discuss how receptors recognize TCDD by virtue of structural "fine-tuning". She will testify as to the existence of receptors in humans and in their various organs, together with the implications of their presence for TCDD potency. She will also discuss the extrapolations which are possible between animals and humans. She will further testify as to the mechanisms of toxicity including the sensitivity of the reproductive system, both endocrine and gonadal, to the receptor-mediated effects of TCDD. Finally, she will discuss the consequences of receptor inter action with TCDD insofar as that interaction produces results involving RNA-DNA, AHH induction, and heme synthesis regulation, among others. In the field of neurotoxicity, she will discuss the experimental and clinical studies with particular emphasis upon dose-response mechanisms, acute versus chronic exposures and early versus long latency effects. She will also discuss iti@899 SCHNEIDERMAN, page 16 Schneiderraan, M . A . , Mantel, N . , and Brecher, G. The effect of rejection procedures on the accuracy of blood counts. Am. J. Clin. Pathol. 21:973-978 (1951) Schneiderman, M.A., and Brecher, G. The relative frequency of sparse cell elements-- an application to reticulocyte blood counts. Biometrics 6:390-394 (1950) Brecher, G., and Schneiderman, M.A. A time saving device for the counting of reticulocytes. Am. J. Clin. Pathol. 20:1074-1083 (1950) Williamson, C.R., and Schneiderman, M.A. The use of mass x-ray survey films for heart disease case finding. Mass. Health 30:7-14 (1950) 13000 biochemical and morphological effects of TCDD, the electro physiology involved and the effects of TCDD on such things as cognition, mood, and affect. She will also emphasize the basic mechanisms of toxicity on both the central and peripheral nervous systems, specifically dealing with the role of altered porphyrin synthesis on the nervous system. Three aspects of this problem will be discussed: First, the effects of decreased cellular energy supply on neuronal activity and viability; second, the effects of decreased heme systhesis on the integrity of myelin; and third, the neuroactive properties of certain porphyrin precursors. 13001 CURRICULUM VITAE Name: _ -Ellen Kovner Silbergeld Date and Place of Birth: July 29. 1945, Washington. DC Education: 1967 - A.B. 1972 - Ph.D. Vassar College Johns Hopkins University Chronology of Employment: 1967 1968- 1969-71 1972-75 1975 1975-79 1979-81 1982 Instructor. California International Summer Program, Uppsala Sweden 7S0ecretary and Program Officer. National Academy of Sciences. National Research Council. Washington. DC "Nader's Raiders". Center for the Study of Responsive Law. Washington, DC Postdoctoral Fellow in Environmental Medicine and Neurosciences. Johns Hopkins University. Baltimore. Maryland Assistant Professor. Department of Environmental Medicine. School of Hygiene and Public Health. Johns Hopkins University Staff Fellow and Head. Unit on Behavioral Neuropharmacology. Experimental Therapeutics Branch. NINCDS.NIH Chief. Section on Neurotoxicology. NINCDS.NIH Chief Toxics Scientist. Environmental Defense Fund. Washington. DC Guest Scientist. Reproductive Toxicology Section. Pregnancy Research Branch, NICHD.NIH Other Professional Appointments: Consultant. NSF Energy Program. 1974-1975 Member, Nutrition Foundation National Committee on Food Additives and Hyperkinesis. 1975-1980 Member. USDHEW-FDA Committee to Coordinate Toxicology and Related Programs. 1977-1981 Member. US Delegation of the Joint US-USSR Health Agreement on Environmental Health. 1977-78 Member. Society for Neuroscience Committee on Social Issues, 1978 Member. OECD Chemicals Program Ad Hoc Expert Review Committees on Reproductive Toxicity and Neurotoxicity. 1982 - 13002 Member Member. Member. Member. Member. Member. US Delegation to OECD Expert Meetings on Existing Chemicals. 1983 Hazardous Waste Task Force and Hazardous Waste Facilities Siting Board, State of Maryland. 1983 Govenor1s Blue Ribbon Panel on Binghamton. NY, State Office Building. 1982 Executive Committee. Science Advisory Board, US EPA. 1983 Board on Toxicology and Environmental Health Hazards. National Academy of Sciences. 1983 Public Policy Committee. American Society for Neurochemistry. 1983 - Professional Society Memberships: American Public Health Association Society for Occupational and Environmental Health Society for Neuroscience Association of Women in Science American Association for the Advancement of Science International Brain Research Organization American Society for Neurochemistry American Society for Pharmacology and Experimental Therapeutics Engineering Society of Baltimore Other Activities Secretary-Treasurer. Society for Occupational & Environ mental Health. 1983- Editorial Board: Neurobehavioral Toxicology. 1979Aroerican Journal of Industrial Medicine. 1980Neurotoxicology. 1981Environmental Research. 1983Hazardous Waste. 1983 - Participant. NIH Consensus conferences. 1979 and 1982 Expert consultant on lead poisoning. U.S. Secret Service. 1979-81 Chairperson. Society for Occupational and Environmental Health Special Committee on El Paso Lead Poisoning. 1977-1979 Preceptor. NIGMS Pharmacology-Toxicology Research Associateship Program. 1977-1981 Graduate board examiner. University of Pittsburgh and University of Toronto Lecturer, continuing medical education courses in environ mental medicine (Johns Hopkins) and occupational medicine (NIOSH) 2 Elected councillor. NIMH-NINCDS Assembly of Scientists. 1979- 1981 Elected representative. NINCDS EEO Committee. 1977-1980 Co-^organizer. Women in Neuroscience Member, Solovey Lectureship selection committee. NIH. 1980- 1981 Environmental Health Consultant. Oil. Chemical and Atomic Workers Union. AFL-CIO, Washington. D.C.. 1970 Reviewer. EPA documents on lead, manganese. mercury, dioxin, risk assessment, and exposure. 1981Ad Hoc Member. Occupational Safety and Health Study Section. NIOSH. 1983Member. NIMH Committee on Frontiers of Neuroscience. 1983Grants reviewer. National Foundation - March of Dimes; National Science Foundation; Nutrition Foundation; Thrasher Foundation; Hereditary Diseases Foundation. NIH Manuscript reviewer. Life Sciences. Biochemical Pharmacology. Environmental Journal Pharmacology. Science. Neurotoxicology. Neurobehavioral Toxicology Teratology. Pharmacology Biochemical Behavior. Procs. Society Experimental Biological Medicine. Experimental Neurology, etc. Honors and Awards: Graduated sumroa cum laude. 1967 elected to Phi Beta Kappa. 1967 undergraduate academic scholarship. 1963-1965 Woodrow Wilson National Foundation Fellow. 1967-1968 Leverhulme and Fulbright Fellowships to University of London. 1967 National Science Foundation Graduate Traineeship. 1968-1972 Public Health Service Research Fellowship to Woods Hole. 1970 Rockefeller Foundation predoctoral research fellowship. 1971-1972 NIH postdoctoral fellowship in environmental health sciences. 1972-1972 Joseph P. Kennedy, Jr. Fellowship in neurosciences. 1974-1975 Pharmaceutical Manufacturers Association Foundation Research Starter Award. 1974-1975 National Academy of Sciences Exchange Fellow to Yugoslavia. 1976 George Miller lectureship in environmental studies. University of Illinois. 1984 Professional Interests: Neuropharmacology & Toxicology Environmental Risk Assessment 3 13004 BIBLIOGRAPHY ELLEN KOVNER SILBERGELD A. SCIENTIFIC PUBLICATIONS 1. Silbergeld. E.K.: Dieldrin: Effects of chronic sublethal exposure on adaptation to thermal stress in a freshwater fish. Environ. Sci. Technol. 7:846-849. 1973. 2. Silbergeld. E. K.: and Goldberg. A.M.: A lead-induced behavior disorder. Life Sci. 13.(9): 1275-1283. 1973. 3. Silbergeld. E. K.: Blood glucose: A sensitive indicator of environmental stress in fish. Bull. Environ. Contam. Toxicol 11.(1): 20-25. 1974. 4. Silbergeld. E. K.. Fales. J. T. and Goldberg. A.M.: Lead: Evidence for a prejunctional effect on neuromuscular function. Nature 247:49-50. 1974. 5. Silbergeld. E. K.. Fales. J. T. and Goldberg. A.M.: Lead: The effects of inorganic lead on the neuromuscular junction. Neuropharmacology 13.:146-157. 1974 . 6. Silbergeld. E. K. and Goldberg, A.M.: Lead induced behavioral dysfunction: An animal model of hyperactivity. Exp. Neurol. 42.:146-157, 1974. 7. Silbergeld. E. K. and Goldberg, A.M.: Hyperactivity: A lead induced behavior disorder. Environ. Health Persp. 7:227-232. 1974. 8. Silbergeld. E. K. and Goldberg. A.M.: Pharmacological and neurochemical investigations of lead induced hyperactivity. Neuropharmacology 14.:431-444. 1975. 9. Morrison. J. H.. Olton. D. S.. Goldberg. A.M. and Silbergeld. E. K.: Alteractions in consummatory behavior of mice produced by dietary exposure to inorganic lead. Dev. Psychobiol. 8.(5) :389-396. 1975. 10. Silbergeld. E.K.: Neurochemical and pharmacological studies of central nervous system lead toxicology. In Carnov, B.W. (ed.): Health Effects of Occupational Lead and Arsenic Exposure. USDHEW, PHS, CDC, NIOSH. Washington. D.C., pp. 74-85. 1976. 4 --------- 13005 11. Silbergeld. E. K. and Chisolm. J. J.. Jr.: Lead poisoning: Altered urinary catecholamine metabolites as indicators of intoxication in mice and children. Science 192U53-155. 1976. 12. Fitzgerald. R. S.. Garfinkel. F.. Silbergeld. E. K. and Loscutoff. S.C.: Factors in the interpretation of mouth occlusion pressure during measurements of chemosensitivity. Chest 70.(1): 145-149. 1976. 13. Silbergeld. E. K. and Goldberg, A. M. : Hyperactivity. In. Goldberg. A.M. and Hanin. I. (eds): Biology of Cholinergic Function. Raven Press. New York, pp. 619-645. 1976. 14. Silbergeld. E. K. : Interactions of lead and calcium on the synaptosomal uptake of dopamine and choline. Life Sci. 20(2):309-318. 1977. 15. Carroll. P. T.. Silbergeld. E. K. and Goldberg. A. M . : Alteration of central cholinergic function by chronic lead acetate exposure. Biochem. Pharmacol. 26,:397-402. 1977. 16. Silbergeld. E. K. and Pfeiffer. R. F.: Differential effects of three dopamine agonists: Apomorphine. bromocriptine and lergotrile. J. Neurochem. 28:1323-1326. .1977. 17. Silbergeld, E. K.: Na+ regulates release of Ca++ sequestered in synaptosomal mitochondria. Biochem. Biophys. Res. Comm. 77.(2) :464-469. 1977. 18. Silbergeld. E. K.. Adler, H. S. and Costa. J. L.: Subcellular localization of lead in synaptosomes. Res. Comm. Chem. Pathol. Pharmacol. 17:715-725. 1977. 19. Goldberg. A. M. and Silbergeld. E. K.: Animal models of hyperactivity In Hanin. I. and Usdin. E. (eds.): Animal Models of Psychiatry and Neurology. Pergamon Press, New York. pp. 371-384. 1977. 20. Silbergeld. E. K.. Adler. H. S.. Kennedy. S. and Caine. D. B.: the roles of presynaptic function and hepatic drug metabolism in the hypothermic actions of some novel dopaminergic agonists. J. Pharm. Pharmacol. 29:632-635. 1977. 5 1.2008 21. Silbergeld. E. K. : Neuropharmacology of hyperkinesis. iji Valzelli. L. and Essman. W. B. (eds.): Current Developments in Psychopharmacoloqv. vol. 4. pp. 181-214. 1977. 22. Silbergeld, E. K. and Adler. H. S.: Subcellular mechanisms of lead neurotoxicity. Brain Res. 148.(2):451-567. 1978. 23. Silbergeld. E. K.. Carroll. P. T. and Goldberg. A. M . : Neurotoxicity of lead: A review of experimental studies. Proc. International Conference on Heavy Metals in the Environment. University of Toronto Press. Toronto. Canada, pp. 213-228. 1978. 24. Silbergeld, E. K. and Costa, J. L.: synaptosomal calcium metabolism studies by electron microprobe analysis. Exp. Neurol. 61:277-292. 1979. 25. Caine, D. B.. Kebabian. J., Silbergeld, E. K. and Evarts. E.: Advances in the neuropharmacology of Parkinsonism. Ann. Int. Med. 90(2):219-229. 1979. 26. Silbergeld. E.K. and Walters. J.R.: Synaptosomal uptake and release of dopamine in substantia nigra: effects of GABA and substance P. Neurosci. Lett. 12.:119-126, 1979. 27. Walsh. M.J. and Silbergeld. E.K.: Rat rotation monitoring for pharmacology research. Pharmacol. Biochem. a Behavior 10:433-436. 1979. 28. Hruska. R.E., Kennedy. S.. and Silbergeld. E.K.: Quantitative aspects of normal locomotion in rats. Life Sciences 25:171-179. 1979. 29. Hruska, R.E. and Silbergeld. E.K.: Abnormal locomotion in rats after bilaterial intrastriatal injection of kainic acid. Life Sciences 25.:181-193, 1979. 30. Silbergeld. E.K.. Hruska. R.E.. Weir, R.. and Kennedy. S.W.: Dopaminergic and serotonergic effects of ergot drugs. In: Fuxe. K. and Caine. D.B.. eds. Dopaminergic Ergot Derivatives and Motor Function. Pergamon, Oxford, pp. 223-235. 1979. il. Lafferman. J.A.. and Silbergeld. E.K.: Erythrosin B inhibits dopamine transport in rat caudate synaptosomes. Science 205:410-412. 1979. 6 32. Silbergeld. E.K.. Miller. L.P.. Kennedy. S.. and Eng. N . : Lead. GABA and seizures: effects of subencephalopathic lead exposure on seizure sensitivity and GABAergic function. Environ. Res. 19.:371-382. 1979. 33. Silbergeld. E.K. and Hruska, R.E.: Effects of ergot drugs on serotonergic function: behavior and neurochemistry. Eur. J. Pharmacol. 58.:1-10. 1979. 34. Silbergeld. E.K. and Hruslca. R.E.: Effects of kainic acid on behavioral and biochemical aspects of cholinergic function. In: Chase. T.N.. Wexler. N.S., and Barbeau. A., eds.. Advances in Neurology, Vol. 23 (Huntington's Disease). Raven, N.Y.. pp. 633-644, 1979. 35. Silbergeld. E.K. and Hruska, R.E.: Lisuride and LSD: Dopaminergic and serotonergic interactions in the "serotonin syndrome". Psychopharmacology 65.:233-237. 1979. 36. Silbergeld. E.K. and Hruska, R.E.: Tremor: Role of striatal cholinergic neurons and the effect of intrastriatal kainic acid. Neurosci. Letters 15:235-242. 1979. 37. Silbergeld. E.K. and Goldberg. A.M.: Problems in experimental studies of lead poisoning. In Singhal, R.D. and Thomas. J.A. (eds.): Lead Toxicity. Baltimore: Urban and Schwartzenberg.. pp. 19-42. 1980. 38. Hruska. R.E. and Silbergeld. E.K.: Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum. Eur. J. Pharmacol. 62.:397-400, 1980. 39. Silbergeld. E.K., Goldstein. G.W.. and Wolinsky, J.: Electron probe microanalysis of isolated brain capillaries poisoned with lead. Brain Res. 189:369-376. 1980. 40. Silbergeld. E.K.. Hruska. R.E.. Miller. L.P.. and Eng. N . : Effects of lead in vivo and in vitro on GABAergic neurochemistry. J. Neurochem. 14:1712-1718. 1980. 41. Hruska, R.E. and Silbergeld, E.K.: Increased dopamine recepton sensitivity after estrogen treatment using the rat rotation model. Science 208:1466-1468. 1980. 42. Hruska, R.E. and Silbergeld, E.K.: Cortical neurochemical changes after intrastriatal injection of kainic acid. Brain Res. 191:572-576. 1980. 7 13008 43. Hruska. R.E. and Silbergeld, E.K.: Effect of ergot derivatives on post-decapitation convulsions. Conunun. Psychopharm. 4^57-62. 1980. 44. Hruska. R.E.. Ludmer. L.M., and Silbergeld. E.K.: Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment. Eur. J. Pharmacol. 5:455-456 (1980). 45. Silbergeld, E.K. and Hruska. R.E.: Neurochemical investigations of low level lead exposure. In: Needleman. H.L.. ed.. Low Level Lead Exposure: The Clinical Implications of Current Research. Raven. N.Y.. pp. 135-157.1980. 46. Hruska. R.E. and Silbergeld. E.K.: Inhibition of [ H]splroperidol binding by in vitro addition of ethanol. J. Neurochem. ,35:750-752. 1980. 47. Silbergeld. E.K.. and Lamon. J.M.: Role of altered heme synthesis in lead neurotoxicity. J. Occup. Med. 22.:680-684. 1980. 48. Hruska. R. E. . Ludmer. L.M.. and Silbergeld. E. K.: Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats. Neuropharmacol. 19.: 923-926. 1980. 49. Silbergeld. E. K.: Detection of neurotoxicity using neurochemical methods In: R.M. Gryder and V. H. Frankos. (eds.). The Effects of Foods and Drugs on the Development and Function of the Nervous System: Methods for Predicting Toxicity. FDA (No. 80-1076), Washington. D.C.. pp. 99-105. 1980. 50. Silbergeld, E. K.: Erythrosin B is a specific inhibitor of high affinity 3H-ouabain binding and ion transport in rat brain. Neuropharmacol. 20.: 87-90. 1981. 51. Silbergeld. E. K.. and Caine, D. B.: Animal models of parkinsonism. Pharmacol. Ther. 12.: 159-166. 1981. 52. Goudsmit, J.. Rohwer. R. G.. Silbergeld. E. K., and Gadjusek, D. C.: Hypersensitivity of central serotonin receptor activation in scrapie-infected hamsters and the effects of serotonergic drugs on scrapie symptoms. Brain Res. 220: 372-377. 1981. 8 53. Hruska, R. E.. and Silbergeld, E. K.: Inhibition of neurotransmitter binding by ergot derivatives. J. Neurosci. Res. 6.:1-11, 1981. 54. Silbergeld, E. K.. Lamon, J. M . , Bradley. D., Hruska. R.E.. Pitman. K.. Hess. R. A., and Frykholm, B. C.: Heavy metal neurotoxicity: porphyrinopathic mechanisms. Procs. Internat. Symp. on Heavy Metals. WHO-EEC-EPA. Amsterdam, pp. 561-564, 1981. 55. Chisolm, J. J., and Silbergeld, E.K.: Increased excretion of homovanillic acid in children with increased lead absorption. Procs. Internat. Symp. on Heavy Metals. WHO-EEC-EPA. Amsterdam, pp. 565-568. 1981. 56. Weir. R. L., Hruska. R. E.. and Silbergeld. E. K.: Binding of antiparkinsonian ergot derivatives to the dopamine receptor. Psychopharmacol. 7!5: 119-123, 1981. 57. Silbergeld. E.K.: Neurocheraical and ionic mechanisms of lead neurotoxicity. In: (Vernadakis. A., and Prasad. K. N . , (eds.). Mechanisms of Action of neurotoxic Substances. Raven. New York. pp. 1-24. 1982. 58. Hruska. R. E.. Pitman. K. T.. Silbergeld. E. K., and Ludmer. L. M . : Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats. Life Sci. 30: 547-553. 1982. 59. Hruska. R. E.. Ludmer. L. M . , Pitman. K. T.. DeRyck. M . . and Silbergeld. E. K.: Effects of estrogen on striatal dopamine receptor function in male and female rats. Pharmacol. Biochem. Behav. 6.: 285-291. 1982. 60. Silbergeld. E. K.. and Anderson. S. M . : Artificial food colors and childhood behavioral disorders. Bull. N.Y. Acad. Med. 58.: 375-295. 1982. 61. Morris, S. J.. Silbergeld. E. K. . Brown. R. R.. and Haynes, D. N.: Erythrosin B (USFD&C Red 3) inhibits calcium transport and ATPase activity of muscle sarcoplasmic reticulum. Biochem. Biophys. Res. Commun. 104: 1306-1311. 1982. 62. Silbergeld. E.K.: Current status of neurotoxicology, basic and applied. Trends in Neurosci. 8.:291-294, 1982. 9 ----- 12010 63. Silbergeld. E.K.. Anderson. S.M., and Morris. S.J.: Interactions of erythrosin B (U.S. F. D S. C Red 3) with rat cortical membranes. Life Sci. 2 i :957-969. 1982. 64. Sflbergeld. E. K.. Hruska, R. E.. Bradley. D.. Lamon. J. M . . and Frykholm. B. C . : Neurotoxic aspects of porphyrinopathies: lead and succinylacetone. Environ. Res., 29:459-471. 1982. 65. Silbergeld. E. K.: Experimental and environmental neurotoxins: correlation of behavioral and biochemical effects. In Levy. M. and Spiegelstein. A. (eds.) Behavioral Models and the Analysis of Drug Action Elsevier-North Holland. Amsterdam, pp 297-315, 1982. 66. DeRyck. M . . Hruska. R.E.. and Silbergeld. E.K.: Estrogen and haloperidol-induced versus handling-related catalepsy in male rats. Pharmacol. Biochem. Behav. 17:1027-1035. 1982. 67. Silbergeld. E. K.. Lafferman. J., and Finkel. T.: In vitro testing for neurotoxicity. In: Kolber. A.. Wong. T.K. . Grant. L.D.. Dewoskin. R.S.. and Hughes. T.J. (eds). In Vitro Toxicity Testing of Environmental Agents. New York. Plenum, pp 473-486. 1982. 68. Silbergeld. E.K.. and Lamon. J.M.: Effects of altered porphyrin synthesis on brain neurocheraistry. Neurobehav. Toxicol. Teratol. 4,:635-642. 1982. 69. Hruska, R. E., Weir, R. L.. Pitman. K. T., and Silbergeld. E. K . : Ergot derivatives are potent drugs at CNS aminergic receptors: correlationsto behavior and aging. In: Agnoli. A., Trabucchi. M . . and Spano. P. F. (eds). Aging Brain and Ergot Alkaloids. New York. Raven, pp 215-226. 1983 . 70. Silbergeld, E.K.: Experimental studies of lead neurotoxicity: Implications for mechanisms, dose-response, and reversibility. In Rutter. M . . and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 191-216. 1983. . 71. Silbergeld. E.K.: Effects of lead on reproduction: a review of experimental studies. In Rutter. M . , and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 217-227. 1?83. 10 72. Silbergeld. E.K.: Indirectly acting neurotoxins. Acta Psychiat. Scand. 67_ Suppl. 303. 16-25, 1983. 73. Mattison. D.R., Takizawa. K.. Silbergeld. E.K., Nightingale. M.S., Jerina. D.. and Yagi. H . : Genetics of ovarian benzo(a)pyrene. metabolism, oocyte destruction, and impaired fertility. In Rydstrom, J.. Monteluis. J., and Bengtsson, M. (eds) Extrahenatic Drug Metabolism and Chemical Carcinogenesis. Amsterdam. Elsevier, pp 337-350. 74. Silbergeld, E.K.: Localization of lead: implications for mechanisms of neurotoxicity. Neurotoxicol. 4/.193-200, 1983. 11 13012 IN PRESS: Silbergeld. E.K.: Behavioral teratology of lead. In Yanai. J. (ed) Behavioral Teratology. Elsevier/North Holland. Silbergeld. E.K.: Neurotoxicity of lead. In Manzo. L. and Blum. J. (eds) Neurotoxicology. Dekker. Fowler. B.F., and Silbergeld. E.K.: Mechanisms of metal toxicity. In Nriagu. J.. and Hornig. D.F. (eds) Changing Geochemical Cycles of Metals and Implications for Human Health. Berlin. Springer Verlag. Mattison. D.R., and Silbergeld. E.K.: Occupational risks to reproduction. In Osofsky. H. (ed) Advances in Gynecology and Obstetrics. Baltimore, Williams & Wilkins. Silbergeld. E.K.: Mitochondrial mechanisms of lead neurotoxicity. In Narahashi. T. (ed) Cellular and Molecular Mechanisms of Environmental Neurotoxins. Raven Press, NY. in press. Silbergeld. E.K.: Review of occupational health studies on PCBs. In Kuiper. H. (ed) PCBs, Marcel Dekker. in press. Silbergeld. E.K.: Effects of PCBs in Occupational Populations. In Visser. R. (ed) PCBs. Amsterdam. Elsevier. Mattison. D.R., and Silbergeld. E.K.: Reproductive toxicity of TCDD. In Lowrance. W. (ed) Dioxins. Rockefeller University Press. IN PREPARATION: Silbergeld. E.K., and Mattison. D.R.: Effects of three polycyclic aromatic hydrocarbons on fertility in female mice: A lifetime study of the effects of single-dose treatment. Silbergeld. E.K.: A Textbook in Neurotoxicology. 12 12013 B. ABSTRACTS- 1. Silbergeld, E. K.: Effects of lead on neuromuscular functions: In vitro evidence for site of action at the presynaptic level. Fed. Proc. 22.:275, 1973. 2. Silbergeld. E. K. and Goldberg. A. M . : Lead poisoning: an animal model of hyperactivity. Pharmacologist 15.:143 . 1973. 3. Silbergeld. E. K. and Goldberg. A. M . : cholinergic-aminergic interactions in lead induced hyperactivity. Pharmacologist 16.:335. 1974. 4. Goldberg. A. M. and Silbergeld. E. K.: Neurochemical aspects of lead induced hyperactivity. Trans. Amer. Soc. Neurochem. p.185. 1974. 5. Silbergeld. E. K.. Carroll. P. T. and Goldberg. A. M . : Monoamines in lead-induced hyperactivity. Pharmacologist 13:203. 1975. 6. Goldberg, A. M . . Carroll. P. T. and Silbergeld. E. K.: Cholinergic aspects of hyperactivity. Fifth Internatl. Meeting for Soc. Neurochem.. 1975. 7. Pfeiffer. R. . and Silbergeld. E. K.: Differential behavioral and neurochemical effects of three dopaminergic agonists. Neurosci. Abst. ri:720. 1976. 8. Silbergeld, E. K. and Miller. L. P.: Lead intoxication: changes in seizure threshold and gamma-aminobutyric acid function. Neurology 4L(27):405. 1977. 9. Adler. H. S. and Silbergeld. E. K.: Intrasynaptosomal interactions of lead and calcium in dopaminergic neurotransmission. Pharmacologist 19.(2) :40, 1977. 10. Silbergeld. E. K. and Walters. J. R.: Dopamine uptake and release in substantia nigra: Effects of gamma-aminobutyric acid and substance P. Pharmacologist 19.(2} :544. 1977. 11. Silbergeld, E. K., Miller. L. P., Kennedy. S. and Eng. N . : Lead and seizures: Role of gamma-aminobutyric acid. Neurosci. Abst. Ill:1039. 1977. 12. Adler. H. S. Costa. J. L. and Silbergeld. E. K . : X-ray microanalysis in neurochemistry: Localization of an 13 elemental neurotoxin and manipulations of mitochondrial Ca++. Neurosci. Abst. Ill:1235. 1977. 13. Baring. M. D . , Walters. J. R.. Silbergeld. E. K., Eng. N . . and Lakoski. J. M. : Effect of systemic apomorphine on firing rates of dopamine cells in rats with striatal kainic acid lesions. Neurosci. Abst. 4., 267, 1978. 14. Hruska, R. E. and Silbergeld. E. .: Ergot drugs inhibit spiroperidol and serotonin receptor binding. Soc. Neurosci. Abst. 4.: 425, 1978. 15. Silbergeld. E. K., Hruska. R. E.. Walters. J. R.. Kennedy. S.. Eng. N., and deSantis. S.: Effects of intrastriatal kainic acid on motor behavior in rats. Soc. Neurosci. Abst. 4: 49. 1978. 16. Kennedy. S., Hruska, R. E.. and Silbergeld. E. K.: Serotonergic-dopaminergic effects of ergot drugs. Soc. Neurosci. Abst. : 426. 1978. 17. Silbergeld, E. . Hruska, R. E.. Lamon. J. M . . Frykholm, B. F.. and Hess. R. A.: Neurotoxic mechanisms in porphyria and lead intoxication: Possible role of a-aminolevulinic acid. Clin. Res. 22:307A. 1979. 18. Lamon. J. M . , Silbergeld. E. K.. Frykholm. B. F.. and Hruska, R. E.: Extra-erythropoietic heme metabolism in lead intoxication. Clin. Res. 21_: 299A, 1979. 19. Silbergeld. E. K.. Hruska. R. E.. Lamon. J. M . . Frykholm. B. F.. and Hess. R.A.: The effects of lead (Pb) on hepatic heme synthesis and drug metabolism. Pharmacologist 21: 209. 1979. 20. Silbergeld, E. K.. Hruska. R. E.. and Lafferman. J. A.: Actions of lead (Pb) on GABAergic neurotransmission: Discrepancies between in vivo and in vitro effects. Soc. Neurosci. Abst. 5.: 416, 1979. 21. Lafferman, J. and Silbergeld. E. K.: Erythrosin B (Food. Drug and Cosmetic Red No. 3) inhibits dopamine uptake in rat caudate synaptosomes: a kinetic study. Soc. Neurosci. Abst. 5. 562. 1979. 22. Hruska. R. E. and Silbergeld, E. K.: Increased dopamine receptor sensitivity after estrogen treatment. Soc. Neurosci. Abst. 5: 73 (1979). No. 236. 14 J1Lo n \J / 23. Silbergeld. E. K.. Hruska, R. E.. Schwarcz. R.: GABA in the basal ganglia: effects of selective lesions. Brain Res. Bull.. 4: 696. 1979. 24. Weir. R. L., Hruska. R. E. and Silbergeld. E. K.: Effects of dopamine agonists on 3H-spiroperidol receptor binding. Soc. Neurosci. Abst. 5: 81. 1979. 25. Hruska. R. E.. Ludmer. L. M . . and Silbergeld. E. K. : Prolactin increases the number of striatal dopamine receptors. Pharmacologist 22.:220 (1980), No. 338. 26. Silbergeld. E. K.: Erythrosin B: ouabain-like actions of an artificial food dye in rat brain tissue. Pharmacol. 22.:198. 1980. 27. Hruska. R. E.. Ludmer. L. M . . and Silbergeld. E. K.: The striatal dopamine receptor supersensitivity produced by estrogen may be mediated through prolactin. Soc. Neurosci. Abst. 6.: 441. 1980. 28. Chisolm. J. J., and Silbergeld. E. K. : Increased excretion of homovanillic acid (HVA) in urine by young children with increased lead absorption. Neurosci. Abst. vol. 6.:508, 1980. 29. Silbergeld. E. K.. and Anderson. S. M . : Erythrosin B: specific inhibitor of high affinity [3H]-ouabain binding and ion transport in rat brain. Neurosci. Abst. vol. 6.:56, 1980. 30. Silbergeld. E. K.. Anderson. S. M . . DeRyck. M . . Chronwall, B.. and Morris. S. J.: Neurotoxicity of an artificial food color (erythrosin B ) : methods for rapid testing. Abstr. 8th Meeting Internat. Soc. Neurochem.. p. 238, 1981. 31. Ptiman. K. T.. Hruska. R. E.. Ludmer. L. M . . and silbergeld. E. K.: Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats. Soc. Neurosci. Abstr. 1_'. 217, 1981. 32. DeRyck. M . . Hruska. R. E.. and Silbergeld. E. K. : Estrogen potentiates haloperidol-induced catalepsy/akinesia in male rats. Soc. Neurosci. Abstr. 7: 217, 1981. 33. Silbergeld. E.K.: The biochemical basis of lead neurotoxicity. Abstr. Ann. Mtg. AAAS. Toronto. 1981.1 15 1 L o h <J 11-Q0 34. Hruska. R. E., Pitman. K. T., Ludmer. L. M . . DeRyck. M . . and Silbergeld. E. K . : Comparison of the biochemical and behavioral effects of estrogen in male and female rats. Socr Neurosci. Abstr. 7: 218, 1981. 35. Silbergeld, E. K.. Morris. S. J., and Anderson. S. M . : Erythrosin B and Na.K-ATPase: receptor-like interactions with brain synaptic membranes. Soc. Neurosci. Abstr. 7: 105. 1981. 36. Silbergeld. E. K.: Basic and applied neurochemistry of hazards. Abstr. Annual Meet. AAAS, Washington. D.C.. p. 63. 1982. 37. Silbergeld. E. K.: Neurotoxic implications of altered heme synthesis in lead poisoning. Neurotoxicol. 3:119-120. 1983. 38. Silbergeld. E. K., Nightingale. M. S.. and Mattison. D. R.: Effect of oocyte destruction by polycyclic aromatic hydrocarbons (PAH) on fertility of DBA/2N (D2). C57BL/6N (B6). and (D2 x B6) FI mice. Soc. Gynecol. Invest. Abstr.. p. 51. 1983. 39. Silbergeld. E.K.. Nightingale, M.S.. Godlove. K.. Malley. J. . and Mattison. D.R.: Reproductive toxicity of polycyclic aromatic hydrocarbons (PAHs) in female mice. Pharmacol.. 25:655. 1983. 40. Mattison. D.R.. Takizawa. K.. Silbergeld. E.K., Nightingale. M.S.. Jerina. D.. and Yagi, H . : Genetics of ovarian benzo(a)pyrene metabolism, oocyte destruction, and impaired fertility in inbred DBA/2N and C57BL/6N mice and D2xB6 FI heterozygote mice. Abstr. Internat. Conf. Extrahepatic Metabolism of PAHs and Carcinogenesis. 1983. 41. Mattison, D.R.. and Silbergeld. E.K.: Occupational exposures and pregnancy, Abstr. 15th Ann. Cong. Col. Soc. Obstet. Gynecol.. Bucarananja. Columbia. 1983. 42. Mattison. D.R., Nightingale. M.S., Shiromizu. K.. Takizarva K . . Silbergeld, E.K.. Kay. H.H.. and Swartz. W.J.: Ovarian toxicity, Abstr. 15th Ann. Cong. Col. Soc., Obstet. Gynecol. Bucaramanga. Colombia. 1983. 43. Swartz. W . . Silbergeld. E.K.. Malley. K.. and Mattison. D.R.: The effects of benzo(a)pyrene on urine ovarian function and fertility. Abstr. Amer. Assoc. Anat.. in press, 1984. 16 13017 OTHER PUBLICATIONS REVIEWS Silbergeld. E.K.: "Lead in Man and the Environment" for Trends in Pharmacological Sciences, 1981 Silbergeld, E.K.: "Hazardous Waste in American" for Quarterly Review of Biology, in press Silbergeld, E.K.: "Nutrition and Brain Function" for Trends in Neurosciences, in press OTHER Silbergeld, E.K.: "US Lead Program Vital" (editorial) Clin. Chem. News. February. 1983. page 4 Silbergeld, E.K.: "Where do we go from here?", in Legator. M.S. (ed) Community Health STudies: A Guide for Citizens. Johns Hopkins Press. Baltimore. MD. in press Silbergeld. E.K.: "Health Effects" in Environmetal Defense Fund, Dumpsite Cleanups: A Guide to the Superfund Program. Washington. DC. 1983 Silbergeld. E.K.. and Highland, J.: "Ghost Dumps" (letter) Science. 216:462. 1982 Silbergeld, E.K.: "Cancer Policy: Has the Dust Settled?" Environmental Forum. 2 : 25-29. 1983 Hall. K.L., and Silbergeld. E.K.: "Reappraising Epidemiology" Harvard Environmental Law Review. 7:441-448, 1983 17 13018 Dr. Raymond Singer, Ph.D., is a neurotoxicologist and neuropsychologist practicing at Occupational Health Consulting, Inc., of New York, New York. Dr. Singer's curriculum vitae is attached. Dr. Singer will prepare reports concerning each of the veteran plaintiffs. These reports will be based upon personal interviews and review of appropriate test findings performed by himself and/or by others. The personal interview will consist of a thorough account of the veteran's background and current and historic symptoms. It will also detail the educational and occupa tional background of each veteran. Various neuropsychologic tests will be given and discussed with particular reference to whether:; any deficits or changes noted are due to the results of any toxic chemical exposures. Neurophysiologic tests will also be given or reviewed and interpreted, with particular emphasis placed upon nerve conduction velocity findings, and the results will be set out and discussed, with particular reference to whether the findings are related to toxic chemical exposures. To the extent warranted, Dr. Singer will relate any findings to Agent Orange exposure. Dr. Singer will also testify to the effects of toxic chemical exposures as they have been studied in a number of research efforts in both animals and humans. He will discuss the findings reported in various populations exposed to toxic chemicals and particularly to TCDD through the mechanism of industrial ac cidents. He will also discuss the findings concerning demyelination of the fatty sheaths surrounding the nerves and the "dying-back" neuropathy which has been associated with toxic chemical exposures. Dr. Singer will also discuss the results of his own work in relation to occupational exposures to TCDD, and will explain how his results are consistent with those obtained from tests per formed on the veterans here, and how those results are consistent with causation by phenoxy herbicides and their contaminants. 13020 RESOME Name: Raymond M. Singer Born: August 20, 1950; Philadelphia, Pennsylvania Address: 415 East 85th Street, #10H New York, NY 10028 (212) 744-1728 Ph.D. M.S. B.A. EDUCATION AND DEGREES Washington State University Washington State University University of Rochester 1978 1975 1972 Psychology Psychology Psychology PROFESSIONAL ORGANIZATIONS Certified Psychologist, New York State Board of Psychology Member, American Psychological Association Member, National Academy of Neuropsychologists Member, Society for Occupational and Enviromental Health Member, American Public Health Association Associate Member, College of Toxicology 1983 1983 1982 1982 1982 1981 1979 1978 1978 PROFESSIONAL EXPERIENCE 1982 1981 1979 1979 Adjunct Instructor, Mount Sinai School of Medicine Department of Community Medicine, New York City Consultant, New York State Department of Social Services, Office of Disability Determinations President, Occupational Health Consulting, Inc. Clinical Psychologist, Private Practice, New York City Reviewer, The American Journal of Industrial Medicine Fellow, Mount Sinai School of Medicine, Department Community Medicine, Enviromental Sciences Laboratories, New York City NIH Post-Doctoral Fellow in Environmental Epidemiology, Mount Sinai Medical School of Medicine, New York City NIH Post-Doctoral Fellow in Biological Psychiatry, Millhauser Laboratories, New York University Medical Center, Nw York City Clinical Psychology Intern, Park East Psychological Associates, New York City -e 1 u c i Dr. Raymond Singer December 5, 1983 1972 - 1978 Teaching and Research Assistant, Department of Psychology, Washington State University, Pullman, Washington PUBLICATION AND PAPERS Singer, Raymond. Peripheral nervous system assessment in the evaluation of toxic chemical exposure. Paper to be presented at the 12th Annual Meeting of the International Neuropsychological Society, Houston, February, 1984. Singer, Raymond. Neural indicators of phenoxy herbicide exposure. Paper presented at the 1983 Annual Meeting of The Society for Occupational and Environmental Health, Washington (D.C.), December, 1983. Singer, R . , Valciukas, J., and Lilis, R. Lead exposure and nerve conduction velocity: The differential time course of sensory and motor nerve effects. Neurotoxicology, 4, 2, 193-202, 1983. Presented at the XI Triennial World Congress of Pathology, Jerusalem (Israel), September, 1981. Singer, R . , Moses, M., Valciukas, J., Lilis, R., and Selikoff, I.J. Nerve conduction velocity studies of workers employed in the manufacture of phenoxy herbicides. Environmental Research, 29, 297-311, 1982. Presented at the XX International Congress of Occupational Health, Cairo (Egypt), September, 1981. Valciukas, J. and Singer, R. The embedded figures test in epidemiological studies of environmental neurotoxic, agents. Environmental Research, 28:183-198, 1982. Lilis, R . , Valciukas, J., Singer, R., et al. Assessment of Lead Health Hazards in an Autobody Shop at an Automobile Assembly Plant. Report to the National Institute of Environmental Health Sciences, June, 1981. Valciukas, J., Lilis, R., Singer, R . , et al. Lead exposure and behavioral changes: Comparisons of three occupational groups with different levels of lead absorption. American Journal of Industrial Medicine, 1:421-462, 1980. Singer, R. The Neuropsychological Evaluation of Patients Affected by Occupational Neurotoxic Agents. Invited address, New York State Psychological Association Convention, New York City, May, 1980. Dr. Raymond Singer December 5-, 1983 Valciukas, J . , Lilis, R., Singer, R . , et al. Neurobehavioral studies of painters. Presented at the International Symposium on Occupational Health Hazards Encountered in Surface Coating, Handling of Paints in the Construction Industry, Stockholm (Sweden), October, 1979. Manuscript submitted, Archives of Environmental Health. Singer, R. The role of the psychologist in the prevention of myopia. Paper presented at the annual meeting of the American Psychological Association, New York, New York, September, 1979. Singer, R. The Camphill approach to the education of the retarded person. Symposium presented at the annual meeting of the American Psychological Association, New York, New York, September, 1979. Singer, R. The behavioral etiology of myopia. Paper presented at the annual meeting of the Eastern Psychological Association, Philadelphia, Pennsylvania, May, 1979. Singer, R. The relationship between visual refractive error and interests, values, personality, academic performance, and reading. Doctoral dissertation, Washington State University, 1978. Singer, R . , Young, F., and Rokeach, M. Values as predictors of visual refractive error (in Barrow Eskimos). Paper presented at the Western Psychological Association Convention, Seattle, Washington, April, 1977. Singer, R. Can myopia be prevented? Invited address - Presented to the Washington State University Chapter of Sigma XI, February, 1976. Singer, R. The association of personality and myopia. Papers presented at the Western Psychological Association Convention, Sacramento, California, April, 1975. Young, F., Singer, R., and Foster, D. The psychological differentiation of male myopes and non-myopes. American Journal of Optometry, October, 52, 10, 679-686, 1975. 4i r. rs. 9 Q vj THEODOR D. STERLING, Ph.D. Dr. Sterling is Professor in the Facility of Interdisciplinary Studies and Department of Computing Science, Simon Fraser University, Vancouver, British Columbia, Canada. His Curriculum Vitae is attached. Dr. Sterling is a mathematician, statistician, and epidemiologist; as well, Dr. Sterling is intimately familiar with existing data and analyses concerning the effects of phenoxy herbicides and impurities, e.g. 2,3,7,8-TCDD, contained therein. Dr. Sterling has devoted much of his teaching and research to the collection and analysis of data and their use for scientific inference. Dr. Sterling will testify that there exists a considerable body of medical and scientific evidence which demonstrates that the preparations of 2,4,5-T and 2,4-D are toxic, teratogenic, and carcinogenic. Further, there is no credible scientific evidence of a no effect level; said another way, as a carcinogen, there is no safe level and therefore a single exposure years ago may be responsible for human cancer which develops today. In addition, Dr. Sterling will testify that there is ample evidence that exposure to 2,4,5-T is teratogenic in humans when the mother is exposed, and convincing evidence is now extant that the outcome of pregnancy is influenced by exposure to the father alone. Most especially, Dr. Sterling will testify of the incidence of subjective symptoms and/or medical records documenting such symptoms. These symptoms are those which have been compiled by the National Center for Health Statistics, and will be compared, to the extent available, to those symptoms of the Vietnam veterans, particularly those of the representative plaintiffs. The purpose will be to ascertain the incidence of such symptoms in the general population so as to analyze statistically the symptoms of the plaintiffs. The product of such overall incidence will be calculated to examine the possibility or likelihood of such a constellation of Agent Orange/dioxin related symptom complex to occur in a random fashion. The bases or grounds for the facts and opinions of Dr. Sterling's testimony are: educational and professional background; publications regarding the subject phenoxy herbicides; review of the applicable medical and scientific literature; attendance and participation in various symposia dealing with the scientific issues in question; training as a mathematician, statistician, and epidemiologist; and training and experience in the computer sciences. 1 CO CURRICULUM VITAE Theodor D.Sterling EDUCATION B. A. (CUM LAUDE) , 1949, M.A., 1952, University of Chicago; Ph.D., 1955, Tulane University. PROFESSIONAL AFFILIATIONS Present; Professor, The Faculty of Interdisciplinary Studies and Department of Computing Science, Simcn Fraser University. Previous: Visiting Professor, Department of Statistics, Princeton University, (78). Chairman, Department of Computing Science, Simon Fraser University, (72-77). Professor in the Department of Applied Mathematics and Computer Science, Washington University, St. Louis, Missouri (66-72). Also Joint appointment as Professor in the Department of Sociology (66--68) , and Visiting Professor in Computers and Humanities, Hebrew Union College, Cincinnati, Ohio (68-70). Professor of Biostatistics and Director of the Computing Center, College of Medicine, University of Cincinnati, Ohio (58-66). Previously instructed in the Department of Statistics, Michigan State University and Department of Mathematics, University of Alabama. PROFESSICNAL ACTIVITIES ACM Committee on Scientific Freedom and Human Rights; President of the Computer Science Association cf Canada (75-80); Chairman, Ombudsman Committee, Canadian Information Processing Society (73-80); Chairman, President of Biological Information Processing Organization (64-65) ; Chairman, CIPS Special Interest Groups, Humanization of Information Systems (73-80); Chairman, SIGCAS Committee of Information and Public Policy (72- ) ; President of Missouri Chapter, American Association of Workers for the Blind (70-72); Member of the Panel for 3iolcgy, Management, and Social Sciences of the Mathematics Association of America (62-67); Chairman, Committee on Professional Activities of the Blind of the Association for Computing Machinery (63-71) ; Chairman, Ad Hoc Committee on Accreditation, Association for Computing Machinery (66-67); Committee on Radiation Dosimetry, American Association of Physicists in Medicine (66-69) ; National Lecturer for Association for Computing Machinery (72-3, 75-6). EDITORIAL ACTIVITIES: Associate Editor - Canadian Journal of Statistics (73-78); Editorial Board - International Journal of Biomedical Computing (69- ); Computers and Applied Mathematics (73- ), Humanist in Canada (73- )- GOVERNMENT AND OTHER SERVICES: (Consultant/adviser, now and previous): (In Canada) Canadian Standards Board; Environment Canada, The Royal Commission (B.C.) ; Consumers Association of Canada; Society for Professional and Environmental Control. (In U.S.) NIH; PHS; EPA; FTC; SR A; U.S. National Academy of Science, National Research Council; American Lung Association; Natural Resource Hoard (Wisconsin); Environmental Defense Fund, MECCA (Minnesota); Citizens Against Toxic Sprays (Oregon) . (In Kuwait) - Ministry of Health. PROFESSIONAL SOCIETIES: Can. Inf- Proc. See-; Can. Comp. Sci. Assoc-; Assoc. Comp. Machinery; Amer. Math. Assoc.; Math. Soc. ; Inst. Math. Stat.; Amer. Stat. Assoc.; Biometric Soc.; N.. Acad. Sci.; Amer. Assoc. Phys- Med.; Assoc. Res. Opthamology. HONORS AND AWARDS: Fellow, Amer. Assoc- for Advancement of Science; Fellow, Amer. College of Epidemiology; Fellow, Amer- Stat. Assoc.; Fellow, Car. Com. of Scientists and Scholars; Sigma Xi; Pi Nu Epsilon, Morrison Cressy Award in National Science; University Research Professor (1980-1981). X1-*3 0-J? 7* B13 LIOGH APH Y Theodor D. Starling Books A Guide to PL/1 ana Structure! Progranainj. doit, hiuenart ana Kinston, February, 1969. Second edition - 1976. Third Edition 1980. Essentials cf FL/1 . dolt, Ilinenart and 'inston, J.-.nuary, 1973. Visual Prosthesis - The Interaisciplinary Dialogue. (Editor), Academic Press, March, 1971. Computing and Computer Science with PL/1. Macmillan, January, 1970 . Computing and Computer Science with Fortran IV. Macmillan, January, 1970. Introduction to Statistical Data processing. Prentice-Hall, June, 1966. Advances in Biomedical Computing Applications (Suitor), Annals of T.ne New York Academy of science, Vcl 123, 196b. Computers and the Life Sciences. Columbia Press, December, 1965. In preparation: People are Trouble: The Human Side of a Computerized Society. Concepts of Machine Computation. 028 Articles 196U The Economics and Politics of building Illness: The HAS/hHC Report on Indoor Pollutants. International Journal of Health Services 1U(1): U3-53. Second Thoughts: On Filtering Information About Occupation, Smoking and Disease. Journal of Chronic Diseases. (In press) Computers and Society. In Aan ana Davies, (ed.) The Canadian Encyclopedia. (In press) Investigations on the Effect or .-.egulatmg Smoking on Levels or Indoor Pollution and on the Percection cf Health ant Comfort of Office Workers. Proceedings of workshop on Effects and Exposure Levels, Geneva, Switzerland, larch 15-1 7 , 1983. (In press) The Emerging Key Role of White-Collar Computer Workers Vis A Vis Organized Labor. Technology and People. (In press) What is the Most Advanced Technology on Earth Today and for What is it Used? In Gallup, G. and Norbacn, C.T. (t-as.) . America Wants to Know: The Experts' Answer 3ook, New York. A & w Publishers, Inc. (In press) 13029 1 983 The health fleets ot Low-Dose Radiation on Atomic workers: A Case Study of Employer-Directed Research. In Navarro, v., ana Berman, D. (eds.), health and Worn Jnaer Capitalism: An International Perspective. Ea/wood Pubiisners, New York, SY . pp. 55-bw. Concatenation. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia ot Computer Science and Engineering (second edition). Van Nostrand Reinhold Comuany, New York. pp. 395-3S6. t regrarnming. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia of Computer Science and Engineerin'} (s-cond edition). Van Nostrana Reinhold Company, New York. pp. 119U-1 21 7 . Statements. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia of Computer Science and Engineering (second edition). Van Nostrane, heinhold Company, New York. pp. 10d-1d07. Trap. in A. Ralston and E. Reilly, Jr., (ad.) Encyclopedia of Computer science ana Engineering (second edition). Van Nostrand Reinhold Company, sew York. pp. 1534-1535. Corporate Planning and Technological Change. The TWU Transmitter, Special Issue V(6): b. Building Illness in the White-Collar Workplace. International Journal of health Services 13:277-237. Possible Etfects on Occupational Lung Cancer troni Smoking Relatsc Changes in t.-.a Mucus Content of tne Lung. Journal ot Chronic Diseases, 3o (10) :669-b76 . The Impact or Dirferent Ventilation Levels ana fluorescent Lightinq Types on Building Illness: An Experimental Study. Canadian Journal of Public Health. (E. Starlinq, senior author) September/Cetober. Unemployment Follows from the Changes in Telecommunications. Telecommunications workers Union Transmitter IV (8): 9. Air Quality in Public Buildings with Health Related Complaints. ASHRAE Transactions 89(2). Perceived vs Actual Risxs: The Problem of Multiple Confounding. In Covello, V., Flamm, w., RodriCKS, J., and Tardiff, R. (eds.) Th.e Analysis ot Actual Versus Perceived Risks. Plenum Publishing C o r ; i e w York, pp 2C3-212. New Health Hazards in Sealed Buildings. American Institute or Architects Journal, April, 8b :6U-b7. Existing Data Systems: How Useful Are They? la Chiazze, L. Jr., Lundin, F.E. ana Vatkins, W. (eas.) , Methods and issues in Occupational and Environmental Epidemiology. Ann Arcor Science Publisners, Inc., Ar.n Arbor, .Michigan, pp. 51-61. Prevalence of Disease in Wives of Blue-Collar workers: a Comparative Study. In Chiazze, L. Jr., Lunain, F.i;. and Watkins, . (?cs,) , Methods ana Issues in Occupational ana Environmental Lpiaemiclogy. Ann Arncr science Publishers, Inc., Ann Arbor, Michigan, pp. 1b5-176. 1 ysz Unionization of Professionals in Data Processing : An Assessment of Recent Irenes. Communications of the ACM 25(11): 607-816. Health Effects of Chlorophenol Wood Preservatives. International Journal ct Health Services 12(d): 559-571. Job Discrimination Based on Exposure Considerations and Smoking. In Lee, J. ana Rom, w. (eds.) Legal and Ethical Dilemmas in Occupational health. Ann Arbor Science Pualishers, Ann Arbor, Michigan, pp. 379-367. The Case tor Entirely Removing the Gas Range from Indoors. Proceedings of international Symposium on Indoor Air Pollution, Amherst, Mass., Oct. 13-16, 1991. Indoor Byproduct Levels of Tonacco Smoke: A Critical Review or the Literature. JAPCA, March 32: 250-259. What is Ahead for Labour/ManaGement in Data Processing?. Canadian Datasystems 14(5): 90-94. Critique V. The health Effects of 2,U,5-T. In Harnik, P. Voodoo Science, Twisted Consumerism. Center tor Science in the Public In terest. Washington, D.C. 43-49. 1981 Does Smoking Kill workers or working Kill Smokers? Reprinted in Feinberq, R.G . (Chairman) Litigation and Settling Occupational Disease Claims. New fork Law Journal, New York. October. Humanizing Computer Information Systems. Reprinted in Murray Gruber (ed.) Management Systems in the Human Services. Temple University Press. Philadelphia, p a . 287-299. Setting the Stages for Laoour Unrest in the Canadian DP Industry. CI?5 Review, July/Oct. Vol. 5(4): jt>-j7. 13031 What EFT will Mean to the Consumer. CIPS Reviw, nay/June. Vci 5(3) 16-17 Ventilatory Function Changes Over a workshift. Er. J. c Industrial hecicir.e. 38 : 152-lbb. (H. Dinich, senior author.) Unionization anc its Implications. Proceedings of the Sec or. Annual Office Automation Conference, March 23-2b, 1981, Houston Texas. Possible Risks to Human Lungs from nagnetometric Dust Clearanc Experiments. Journal of Applied Physics, Vol. 52 (3, Part II 2575-2577. Use of Gas Hanots tor Cooking me. Heating in groan Dwellings Journal of the Air Pollution Control Association, February, Vo: 31 (2) 162-165. Engineers Threaten Domination or DP Jobs. CIP3 Review, Jan./Fel Vol. 5(1): fc-b. 1980 The Health Effects of Lcw-level of Ionizing Radiation: Dialogue. In Horn, w.N. and Archer, W.E. (ess.) , Heal Implications oi New Energy Technologies. Ann A m o r Sciem Publishers, Inc., Ann Arbor, Hich. Pages 150-164. Stressing Design Rather Than Performance Standards to Ensu: Protection of Information: Comments. In Hoffman, N. (ed . Computers ana Privacy in the Next Decade. Academic Press, Inc 102-107. Smoking, Occupation and Respiratory Disease. Report to ti American Lunc Association, Occupational Health Task fore Meeting, April 5, 1980, Clearwater, Florida. The Social Impacts of Electronic Fund Transfers, The Financi. Post, Special Report, March 8, I960, s11 . The Health Effects cf Low-Dose Radiation on Atomic Workers: Case Study of Employ er -Directed Research. International Journt of Health Services, January, 10(1): 37-46. Cover-up at Hanforu: The Effects of Low-Dose Radiation. Humanii in Canada, Spring (No. 52) XII, No. 1: 5-d. The Computer Ombudsman, A Possible Model of AccountaDil^lty Amo; Professionals, Transactions of Society, 17(2): 31-35. 13032 iy7y Statistical Problems in Eulti-Variate (Etiological) Surveys. Canadian Journal ot Statistics, 7(2): 205-215. The Mutual Relationship Between Smoking, Occupation and Disease. Proceedings of the XIX International Congress on Occupational Health. Supplement to vcl. 30. Consumer Difficulties with Computerized Transactions: An Empirical Investigation. Communications or the ACE, Eay, 22(5): 283-26V. Carbon Monoxide Levels in Kitchens ana Homes witn Gas Cookers. J. Air Pollution Control Association, March, 2L?(J): 239-241. What Consumers Say About Computer Errors, Canacian Datasystems, 11 (12) : b4-b7 . What happens When Major Errors Are Discovered Long Alter An Important Report Has Eeen Published?, Invited talk to the Annual [`eeting of the American Statistic Association, Washington, D.C., August, 1y7y. 197 Computers in Developing Nations: A Cautionary Tale. Reprinted in Personal Computing. February, 27-jl. Smoking Patterns by Occupation, Industry, Sex, and Race. Archives of Environmental Health. Novjiter, 33(b) : 313-317. Processing Errors Among the Pjolic: Their Frequency ina Crigin. Prcceeamgs ot the Session '7d Canadian Computer Conference, CIPS, Edmonton, Alberta. May. Does Smokinc Kill Workers or working Hill Smokers, International Journal of healtn Services, 6(3) : '137-452 . Follow up: New Evidence Concerning Smoking ana health, Med. J. Australia, b5: 364-387* Frequency cf Computer Related Errors Among Holders of Credit, Charge or Bank Accounts, CIPS REVIEW, June, 5: 17. High Level Language Programming. In belzer, J., Holzman, A.G., ana Kent, A. Encyclopedia of Computer Science and Technology, Earcel bekker, y: 57-283. 13033 Humanizing Information Systems. In belter, J., iioizman, A G . and Kent, A. Encyclopedia of Computer Science and Technology, Marcel Dekxer, S : 3 6 1- 57 1 . Natural Language Compilers and Interpreters in hadiation Treatment Planning or Nous radons Anglais Setter Than Jeae Andere Sprache. In V. Rosenow (eo), Computers in Radiation Therapy: Proceedings of the Sixth International Congress on the Use or Computers in Radiation Therapy, University 01 Goettingen, Goettingen, FRG. 19 77 Computers in Developing Nations: A Cautionary Communications of the ACM. December, 20(12): 971-972. Tale. New Evidence Concerning Smoking and Health. Medical Journal of Australia, October, 2: 538-542. Fold, Spindle and Mutilate. Humanist in Canada, March. 40/15-20. Exposure to Pollutants in Enclosed "Living" Spaces. Environmental Research, February, Voi 13: 1-13. I,4,5-T .... Teratogenic Em Droyotoxic, Fetocenic, Mutogenic, ncres U.S.A., 7/7. Smoke Gets m '/our Eyes. Humanist in Canada. '42: 2-5. 197o Humanizing Information Systems. Datamation. Decemcer. Smoking Characteristics by Type of Emoloyment. J. Occup. Medicine, November, 1b (11 ) : 743-754. Do we Neec A Computer Ombudsman? Canadian Datasystems, August, 62-64. Programming. In Ralston, A., ana Meek, C.L. (Editors), Encyclopedia of Computer Science, Petrcce11i-Charter , New /oik, p p . 1127-1156. "Statements, Ralston, A., and Meek, C.L. (Editors), Encyclopedia of Computer Science, Fetrocelli-Charter, New jfork , pp. 326-1329. A Singie-TracK Universal Curriculum for Computing Science. INFOR, February, 14: 1, 40-52. 13034 ran Acainst Himself - Biological Dangers trom the Use ot Herbicices. Humanist in Canada, February, IV (3) : 2-7. Additional Comments on the Critical Assessment of the Evidence Tearing on smoking as the Cause or Lung Cancor. American Journal of Pufciic Health. February, Vol 66(2): 161-164. Relation ot Place or Birth and Migration in Cancer Mortality in the D.S. - A study of Ohio Residents (1959-1967), reprinted in the 1976 Year Booh of Cancer 1y75 Humanizing Computerized Information Systems: Guidelines ana Their Implications. Science, December, Vol 190: 1168-1172. A Critical Reassessment of the Evidence Bearing on Smoking as the Cause ot Lung Cancer. American Journal of Public Health. September, Vol 65(9): 939-953. A Critical Review of Reports on the Effect of Smoking on Sex and Fertility. Journal of Sex Researcn. August, Vol 11(3) 201-217. Lung Cancer Among Black ana -hits Migrants In the U.S. Etiological Considerations. Journal oi the National Medical Association, ilarch, Vol 67(2): 10&-111, 102. (T.F. Mancuso, senior author.) 197L Relation of Place ot Eirth ana Migration in Cancer Mortality in the U.S. - A Study of Ohio Residents (1959-1967). Journal or Chronic Diseases. Vol 27: U59-474. (T. F . Mancuso, senior author.) Guidelines tor Humanizing Computerizes Information Systems: A Report from Stanley House. Communications of the ACM. November, Vol 17 (11): 609-613. (Reprinted in AEDS Journal, Vol 10 (1), Fall 1976: 1-10. Teaching Simulators of Ideal Teaching Machines. S1GSCS Bulletin , ACM. June, Vol & (2): 45-56. X : Proposal for a N'ew Curriculum Approach. Jniversity Affairs. Simon Fraser University, Burnaoy, 3.C. nay, ?p. 6-7. Ideal Teaching Machines -- A Solution- to the Pedagogic Language. Communications of tne ACM. April, vol 1b: 207-208. 12035 The Use or an Information System to "humanize" Procedures in a Rehabilitation Hospital. International Journal of bio-Medical Computing. Vol 5: 51-57. Information for Public Policy. Computers ini Society. Vcl 5(2): 2. (Invited editorial). The Simon Fraser One-Track Universal Curriculum for Computing Science. SIGSCE Bulletin, AC.1. February, vol 6 (1): 28-32 . 19 73 The Statistician vis-a-vis Issues of Public Healtn. The American Statistician. December, Vcl 27(5): 212-217. Extending the General Fieli Equation to fit the Dose Distributions of a Variety of Therapy Units. British Journal of Baoiolcgy. Voi U6: 933-990. (J. einkam, senior author.) Air Pollution and Smoking. Environment. Voi 15(6): 3-5, 25-26. Dynamic Display ot Radiotherapy Plans Using Computer-Produced Films. Radiology. June, Vol 107: 639-691. Humanists ana the Computer Community. Humanist in Canada. Vol 25: 2-6 . Computing and the humanization of Medicine. International Journal ot mioraeaical Computing. Editorial, July, Vol h(3): 159. 1972 Difficulties ot heasurinc the Effects of Air Pollution vs the Effects of Smoking. Presented at the 139th fleeting of the American Association for tne Advancement of Science, December 1972 . a Versatile System for Three-Dimensional Radiation Dose Computation and Display, RTP. Computer Programs m Biomedicine. Vol 2: 178-192. (J. Weinkara, senior author.) Fitting the General Field Equation to the Siemens Gainaatron 3. Technical Report on Research Agreement fio. 1051/CF for the International Atomic Energy Agency, Vienna, Austria. The Incidence of Lung Cancer in the U.S. Since 1955 in relation to the Etiology of the Disease. American Journal ot Public Health. February: 152-158. 1A U do 1y 71 A Critical Assessment of the Evidence on the Cigarette Smoicinq Lung Cancer Relationship. Presented at the 130th fleeting of the American Association for the Advancement of Science, Symposium on Smoking and health Now. Philadelphia, December, 1971. Difficulty or Evaluating tne Toxicity and Teratoqenicity of 2,N,5,-T from Existing Animal Experiments. Science. December, Vol 17n: 1353-13bS. Some Thoughts on Treatment Strategy. Computers in Radiotherapy (proceedings of the uth International Conference on Computers in Radiotherapy, Glasgow, September 1970). Edited by A. S. Glicxsiran, .1. Cohen, and J. H. Cunningham. Published as Special Report No. 5 (1971) by the British Institute of Radiology, London. Three-Dimensional Treatment Plan Display on Computer-Produced Filins. Computers in Radiology, op.12-1d. A Review of the Claim that Excess 'loraidity m u Disability Can Be Ascnb&Q to Smoking. Journal of tna American Statistical Association. Vol to (33d): 251 -257. A Critical Reassessment of the Evidence Bearing on Smoking as the Cause or Lung Cancer. Special Report on the Washington University Project on the Review of Crucial Data Searing on the Snoxinc and Health Issue, St. Louis. Robot Data Screening, An Intelligent (?) Data Search Technique. AGAftD Conference Proceedings No. 9d on Artificial Intelligence, 2-1-2-r, Tecnnical Editing and Reproduction Limited, London. Comment on Smoking Docs. Letter to tne Editor. Archives of Environmental Health, vol. 22: 631-632. 1970 Problems in Determining if a Commonly-Used Herbicide (2,4,5-T) Has an Effect on Human Health. Proceedings of the Sixth Berkeley Symposium on r.atnematical Statistics uni Probability, Held at the Statistical Laboratory, University cf California. University ...ot California Press, pp. u79-49u. Experience with a "Universal" Introductory Course in Computer Science. Proceedings of SIGCSE Technical Symposium on Academic Education m Computer Science, November 16, 1970. Houston, Texas. SIGCSE Bulletin, Vol 2(3), Association for Computing Machinery, hew York. 13037 Robot L'ata Screening, An Autonatic Search Technique. lio-Medical Computing. Voi 1: 61-74. (From the Proceedings ot the Conference on Statistical Computation, University of Wisconsin, April, 1969 .) Report on Progress in the Development of Visual Prosthesis, he New Outlook for the alind. Feoruary, Voi 64: 41-45. 1969 Automatic Data Screening: A Practical Solution to the Multivariate P r o d e m in Clinical Data. Annals of tne New York Academy of Sciences. Vol 161: 632-640. A Comment on "Air Pollution -- The Industrial viewpoint" . Journal of Occupational Medicine. July, Vol 11: 3u1-3d3. Robot Lata Screening -- A Ubiquitous Automatic Search Technique, in nilton, C. h. and Nelder, J. A. (lid.) # Statistical Computation, Academic Press, .New Yor*, pp. 31 9-333 . Measuring tr.e Effect of Air Pollution on Ur can Morbidity. Archives of Environmental Health. April, Vol 13: 485-494. 1968 Computer Interface, Input rietnocs, ana Presentation of Results. Role or Computers in Radiotherapy, International Atomic Energy Agency, Vienna. Paper No. 15, pp. 135-141. Optimization as a Joint Result of Planning and Implementation. Role ot Computers ir. Radiotherapy, International Atomic EnergyAgency, Vienna, pp. 163-167. Display Devices tor Computer Translated Sraille. Proceedings Conference cn New Processes for S m i l e Manufacture, 196c, Center for Sensory Aids Evaluation and Development, Massacnusets Institute ot Technology. February, pp. 14-20. 19 67 Automation of Radiation Treatment Planning, VI: A General Field Equation to Calculate Percent Deptn Dose in the Irradiatea Volume of a Cobalt 60 Beam. British Journal of Radiology. Vol 40: 463-468. Urban hospital Morbidity and Air Pollution: Second Report. Archives ot Environmental Health. Vol 15: 162-374. A New Direction in Pehabi1itaticn Through Advances Instrumentation and Ceraputation. Journal of the American Medical Association'. Vol 200 (7): 625-629. The Use ot Computers in Theraoeutic Radiology, Summary Report of an International Conference held in Camoridge, England, Junt 19tb (Editor). m t i s h Institute of Radiology, London. Final Narrative Report, Traininq of the Blind tor Proiessionai Computer Work. Department of Health, Education, and Welfare, KD-1485-S-b7-C2. 1966 Robot Lata Screening: A Solution to Multivariate Type Proclems in the biological and Social Sciences. Communicatons of the ACM. Vol 9(7): 529-532. A Biologically-Oriented Computer Language. Annals or the hew York Academy ot Sciences. Vol 128(3): 755-765. (S. V. Pollack, senior eaitcr.) Cancer Therapy - Computation ana Visualization of Dose Distributions in External seam Therapy. Journal of Chronic Diseases. Vol 19: 523-539. Use . ct the Computer to Teach Introductory statistics. Coamunicatiens of the ACM. Vol 9: 274-27b. Computers: No Longer a Eig Bargain for 'Jneducated Users. Coraouters ana Automation. Vol 1b: 1-4. (S.V. Pollack, senior author .) The Selection, Training, and Placement of Elind Computer Programmers. Report of the Association for Computing Machinery. Is Medical Diagnosis a General Computer Problem? Journal of the American Medical Association. Vol 196(3): 281-286. Befogging the Issue: California has discovered that laws can't control auto exhaust fumes. Barron's, May 2, pp. 5, 14-15. Urban Borcidity and Air Pollution: A first Report. Archives of Environmental Health. Vol 13: 158-170. The Blind as Computer Programmers. Rehabilitation Record. Vol 7 (1): 7-1 0. Role ot Statistics in the World of Computers. Annals of the New York Academy of Science. Vol 128(3): 1108-1115. 13039 The Role ot the Blind in Data Processing. Presented at Third Annual Conterence on Computer Personnel Research Group, held at Washington University, 1965. Reprinted in Computers ana Automation. Voi lb: 2U-27. Proceedings on tne Braille Research and Development Conference, Sensory Aids, Evaluation and Development. Massachusetts Institute ct Tocnnoicgy, November, 1966. 1965 Automation c t Radiation Treatment Planning, v: Calculation ana Visualisation cf the Total Treatment Volume. British Journal or Radiology. Voi 30: 906-913. Robot Data Processing Techniques for Multivariate Epidemiological Predictions. Annals of the New York /-.cademy ot Science, voi 126 (2): 779-79!. The Role of the Blind in Data Processing. Procedures of Third Annual Computer Personnel Research Conference, June 1u6b. (M. H. Gotterer, ec.) Computers in Personnel Research Group, Silver Spring, Md.; pp. 31-39. Computation of Radiation Dosages. In Stacy, N. ana Nasnan, &., (Ed.), Computers in Biomedical Research. Academic Press, New York,. Vol 1 (Chapter 1if). Toward an Undergraduate Matnematics Program for future Researchers in the Fields of Biology and Medicine. Federation Proceedings. Vol 2U(1): 5-9. Careers for the Blind in Electronic Data Processing. iiectronic Data Processing. Occupational Outlook quarterly. Vol 9(1): 1- U . Employment Potential tor the blina in Computer Related Fields. The International Journal for Education of the blind. October, pp. 1-5. The Blind in EDP. ACM Committee on Professional Activities ot the Blind. 196U Mathematical Analysis of Lead Burdens. Archives of Environmental Health. 8: UU-51. Design ana Operation of a Medical Computing Center. Annals of the New York Academy of Science. vol 115(2): 591-599. (E. Saenger, senior author) . 13040 Planning Radiation Treatment on the Computer. Annals or tne Kew York Academy ot Science. Vol 11b (2): 976-997. Professional Computer Work for the Blind. Communications of the ACM. Ycl 7 (U) : 22b-2 31 . Coaputer Worn as a Profession for the B lmu. Journal of P.ehaDi li ta tion . Vol 3C: 20-21. Epidemiology of Disease Associated with Lead. Archives ot Environmental Health. Vol 8: 333-346. Hatnomatical Analysis of lead Burdens. Archives of Environmental Health. Vol 6: 44-51. Automation of Radiation Treatment Planning, IV: Derivation ot a Hatnematicai Expression ter the Per Cent Depth Dose surface ot Cobalt 60 Beams anc Visualisation of Multiple Field Dose Distrirutions. British Journal of Radiology. Vol 37(439): 54-4--55 0. Locatinc Placenta Praevia. Procedures or the Rochester Conference on Data Acquisition and Processing m Biology and Medicine, New York, 1963. Pergamon Press, New for*, op. 103-111. 19(.3 Do Malignancies Result from Diagnostic and Therapeutic Radiation? Genetics and the Epidemiology of Chronic Disease, U .5. Dept, cf healtn. Education ana Welfare, pp. 3o5-37l. MEDCOMP, Part 1, Statistical Systems. Medical Computing Center, University of Cincinnati, Ohio. Eoron. Cadmium, Chromium, and -licxel in tne iced ana Urine. Archives ot Environmental Health. Vol 6: 236-295. (H Imbus, senior author.) Potential Hazard ot r.xposure to Lead. Archives of environmental Healtn. vol 6: 255: 272 . (R. Kehoe, senior autner.) Carcinogenic Effects of T131 Compared with X-Irraaiation - A Review. Health Physics. Vol 9: 1371-1364. (. Saenger, senior author.) Automation cf Radiation Treatment Planning, 111: A Simplified Tystea of Digitizing Isodoses ana Direct Print-Out of Dose Distribution. British Journal of Radiology, vol 36: 522-527. Intravenous Methotrexate (Amethopterin) Therapy in the Treatment of Acute Leukemia. Pediatrics. Vol 31: e34-339. (J. Perrin, senior author.) 13041 Automation c Radiation Treatment Planning, II: Calculation ot Kon-Convercent Field Dose Distrinutions. British Journal ot Radiology. Vol 36(427): 63-67. Robot ireatr.ent Planning. Procedures ct tne Hocnester Conierence on Data Acquisition ana Processinc in Biology and Medicine, New York, 1bb2. Peraamon Press, New Ycrit, pp. 299-319. Robot Data Screening. Proceedings ot tne Rochester Conference on Data Acquisition and Processing in Biology and Medicine, New York, 1962. Peraamon Tress, New York, pp. 231-242. 1962 Occupational Exposure to Organic Lean Compounds. Archives ot Environmental health. Vol 5: 532-536. (R JeTriviile, senior author .) New Developments in Chronic Disease Epidemiology: Competing Risks ana Eligibility. American industrial hygiene Association Journal. Vci 23: U33-Ua6. Radiation rpideniiolcgy. Cancer. Vol 15: 4d9-5Q3. Comparative Studies of Certain ~ead Alkyls. Archives ot Environmental Health. Vol 5: 525-326, 532-536. (E. Bingham, senior author.) 1 9 r. 1 A Practical Procedure for Automating .aciation Treatment Planning. British Journal of Raaiology. Vol 34: 7^,6-733. Epidemiological Methods and Community Air Pollution. Arcr.ives ot Environmental health. Vol 3: 267-275. (J. Phair, senior author.) Competing Causes ot Deatn in Coal Tar Workers. Kettering Report. 1960 Cesium-137 Retention and Distribution in x - I m o i a t e a Rats. D.S. Army Medical Research Laboratory, fort Knox, Kentucky. Report No 504 . (G. Keriakes, senior author.) Seasonal Variations in the Birth of the Mentally Deficient? American Journal of Public Health. Vol 50: 955-965. 1 ^0 fjhArO The Leaa Content or the Atmosphere. Presented at the 53rd Annual Meeting or AFCA, May 1960, Cincinnati. (J. Cholaic, senior author.) Vhat is z c ie-culiar About Accepting the Null Hypotnesis? Psychological Reports. Vol 7: 363-364. Neoplasia Following Therapeutic Irradiation for B e n i g n Conditions in ChilGhood. Radiology. Vol 74: 389-904. (E. Saencer, senior author.) 1959 Pualic Decisions ana Their PossiDle Effects on Inferences Drawn ircm Tests of Significance - or Vice-Versa. Journal of the Aaerictn statistical Association. Vol 34: jo-3*. Pulmonary Function in Children, I ana II. Journal or Allergy. Vol 30(0) : 51 4-533. (I. L. Bernstein, senior author.) Tables of Pulmonary Function Values in Children Ages 6 to 14. Kreger Printing Co., Cincinnati, Dhio. (I. L. Bernstein, senior aatnor.) The Anorexigenic Action of Dextro-Araphetamine Sulfate upon Feeding Responses ot Differing Strength. Journal v.-r Comparative ana Physiological Psychology. v'ol 52: 179-1 82. (P. Siegel, senior author.) Sources of Contextual Constraint Upon words in sentences. Journal of Experimental Psychology, vol 57: 171-ihO. (ft. Adorn, senior author.) 19 57 Effect or Irrelevant Drive on Extinction of Bar-Pressing. Psychological Reports. Vol 3: 15-613. A Central Surveillance System Measurement Model, Part I, II. Project. Michigan Z345 , Z91U, jniversity of Micnigu. A General Survey of Statistical Decision Theory. Project Michigan Z915, University of Michigan. 13043 Bio-Statistician/MathematicianThis witness will be identified in the near future. At that time a curriculum vitae will be supplied. This witness will describe the mathematical/statistical model which will be used in the presentation of the figures to which the witness will testify. The theory subserving the testi mony is that the multi-faceted presentation of symptoms and signs and test results in the same veteran makes a random compo sition of such an array extremely unlikely in view of the relative in-frequency of each facet of the array. As such, this testimony will be used in the generic and specific proximate causation areas. HENDERSON & GOLDBERG, P.C. 1 6'1 2 F r ic k B u ild in g Pittsburgh, P A 1 5 2 1 9 Thomas W. Henderson Theodore Goldberg Robert L. Jennings, Jr. Joel Persky Antonio D. Pyle Thomas W. White February 27, 1984 l/" Ms. Nancy Petrilla U.S. District Clerk U.S. District Courthouse 225 Cadman Plaza Brooklyn, New York 11201 Re: MDL No. //381, Agent Orange Product Liability Litigation Dear Ms. Petrilla: Please find enclosed for the Court file, Plaintiffs' Compliance with Guideline No. 34 on Plaintiffs' Government Causation witnesses which are to begin being deposed on March 1, 1984 in Washington, D.C. Also Please f-lnd njIngpH an aHrUf.-fon a 1 rnpy nf P1a-Int iff4 ' Expanded I Summaries on the following Plaintiffs' Cansatlnn Fvnp.rts which I promised Magistrate Shindlin she would receive before Wednesday, V February 7Q ...1Qft/i Apparently, the original court copies were missing some pages. I apologize for this inconvenience. Please be advised that by copy of this letter and the enclosed documents I have notified all parties on the attached service list of the filing of said documents with the Court and I have served the U.S. Department of Justice, Ms. Gretched Witt, on or before noon, February 27, 1984, with the enclosed documents as per our agreement. Thank you in advance for your kindness and cooperation in this matter. -Very trul yours, cc: Enclosures Ms. Gretchen Witt See attached Service List Alison Pettiette Hand Delivery 12045 f PIAI IT1FF '3 GOVSRKUEN? CAUSATIOi! WIT !E;:SES Ven.un 13. Kouk A . __ _ Center for T);jsea ce C e n t re! (CD C) A t l a n t a . GA B. Both fact..'-:! ar.d expc-t test iw^ny is s o u g h t . C. G o n e r d Events "vc-1>6i : Any fro v.ai knowledge of the history of lit . s i c J.dc ypr aying in 'J.S. anu ;.l)roai!; faciudin,g ; hut not limited to, (I industrial a p osar ty arc! -a:':pi'.'sions; (2; reg Lstratlon of .':;A-D, 2 . ,5-T v/ith the Department of Agri- r u l t r v e : nti r n y o t h e r g o v e r n m e n a . g c n c i m by riu/a at.. . tLhiec ittt'auLt- i `-y --etna" k::o 1 .?.-1.a r \ : 1- '7 k * `J *-f*-- :dlng , bat r.*t lie .a i*y use of ;r n^e tr.c other phs .ci1 '- in Vi rtu.n.. '2) char.yes . the 'z _J.c*r. rcqti rciccnt of her l .sldc3 wit' tli gov c.rament and it s agencies includin .rdge of 71:TJ>.^/>k3 ^-EPAi and CJIIf ; and (3 l Cr r> ;L\\ \ arjv i a l an-' other hum.-:n 0 / JG,, 2 :,A ,3 -7 in the U 3 . and See ,,?r : ;.sntrl i.'t.srwawcer of Plaintiffs1 to' `<1.OIT"i, *W' CC*l` "nto "-?*u.o%.r*^'*i j Ko. 19 attached v.- ard incor per r.te isreia for all par- re: event S 0 1' c i*r*r-i vitnes ::ec tna; ectu;:1 info rmatioi ab "'r lined : -at cf f: .pest:n s and any f' ua. of . D. Eirpert Taetimciiy roug ht in v;11ncs: 2 ) .uMect. Hr. , 2 ,A >-2'- rCDDDD'!s and diorins; Agent Ora (air r k'hite Ablue, Pink, Greer,.' and 'Furp rz c z i and related chi orophe-uols end human risk aascssnentt rug::..rding enpo cure including butt not limited to, cue or more of the fol loving subje et a r<as : a) Chemistry/E iochetnisttry ) b Manufacture c..id/or I t eduction c } Tt i ,,i1 7 d) Mcdes of I'nac.: Etto cure e Environment (Human0 , i?1-r. Animais) . S..;*.to ci Art/Etut of Medical end Lit eruttare ,e v; V.1"..ne PUy srirIogy /atudies Pii'-:,io logy/Studi:; !L K-.:, Mt- L'p1 .e \ ':y /;ios at i :.j lea 1 .) Piant j animals * huntns :; dancer Epidemiology 1 ; i 2.pre-uct-va Epidomioiogy Ac. ,e-:-c EerltU Ef 3) v.vtrMss vii.. A; r.skid opinions about boti, puIliaUed ar.d/or on-go itt; at ud1 .- 4) .Itattfi vi! 1 b. -..eked opinione about any studi or raccerta. vit nee s has personali;- performed or actually participated in. witness vili be cskod opinions about other governoantal studies . rittnecc is expected to review the following do culi:en !r prier te giving testimony; lite, EIA, Research And Develop m e n t . He alth Ascesmani: Docum ent -on -Pi::: is for th 0-ffi-ce s of Air' ualit 7 ' Pla uni::y 'and Standaie-c , pVepar ed by the Env ir Canetti,cl Criteria and ,1 3 secs C f!:ice , C i .cAanati , Ohio 45148 ( July 12048 A-..,. } r^. ' f. ' r EPA, Research and Development, Health and Environmental Effects Profile f o r ; Tetra Pcnta, and Ilcnaehlarodibenr.o-p-dioxins, for the Office cf Solid Waste and Emer gency Response, by the Env..rcnBental Criteria and Assessment Office, Cineinnat Ohio 45243 (Jen. 1983). ) EPA, Research and Davc._opr.ieat, Ambient Water Quality Criteria for 2,3,7 *8 TCDD , pre pared far Office of Water Regulations and Standards, i. y the Environmental Criteria arc Asses.event Office, Cincinnati Ohio )52-i8 (July 1903). Receiveh a d Dec; lop n e n t , Dio t in .., Indentvial E n v i r o t a e n t a l R e s e a r c h Civ. i.nati -O /(-J.cV*.v'o<y\ . A c o g . ' o.. t h e r e r ' c ; : n . t i : : ,n a t '. eh l . H' i .1. 11 oj?un * aJ c !:. Major Alvin "'cung Dr. Bodnav Eovc-v n. Kenneth V. Themain n. David T. Buzzalii o. D:. Michael Gross 5 ,,. ,j;. Penee Stringimi ir. Dr- Van Miller C<v - rV . y. r `PPLEMEWaL MS3AR TC NO. 13 'Plaintiffs r-vt preliminarily that tbs etrfr-'h Order on product ng fe-t vf.tnsssea states that :f I'lesscs are not lira until Mar 2, 1084. Itvoveu, Plaintiffs irr.* i-.J.l one or nr:.~.of -:lia following poirscris (or these f:car vrviews categories ).istod ]>=:lo*:} at hint: of \. lr.l to testify as to factual knowledge they nr..; have inclutdfng: 1: Kanc& Hand Personnel: there persons will testify tc their knowledge cl: the Stanch Hand Operatic::Hatch Kcndern* exposure to Agent Crane,- '.nc':/or kirvlsdgo relating to the spraying, testing, and effect.:: :f Agent Ovivjo c.:i Inmans. t, Msnbars of lie V. ii. I-rmad Pcrceo: These persons ray testify tc the cirruinstrroe:: aid corro'.tions orcrounding the spraying of Agent Grange, 1. Persons present v. Vietnam d*or'ng the evpc.'ru.re period in question 1031-197?., ir.eludj.nc;. let rot limited ho, military and paramilirrary personnel of 'ho :!., Ife: Zealand and Australia,, v.ho have knewledge of the cpraying oparatiem of !dir herbicides, tho closure of the Plaintiffs* class, the lasar&c acccrripanyr,-.-; any such exposure, the Plaiiitiffs' thsoseives, aid tuie i")efenfant company rerprasentatives present ir. Vietnam to overt'.. the deliveries and spraying ebarations of the I. bioidss the*/ mviufactcred. Persons together with -their drrrristrat; ve and docusasnfcary evidence who gave testiiiiony (which will forra vhe substance of their testimony herein)- at the ETA Cancellation Hearings of 2,4,5-T (1279-1911; ur ss: PITI'', including but not limited Dr. I'oy A.lbr-rtDr. K. Diana Courtney - 'bere Bauchmer .91 I Any current or previous employee, contractor, a;;bcontractrr, in-house >nr private consultant of each cf: the Defendants or any other person who has factual Icrcwj.edge of Ilew dioxins v/ori; uper. plants, animals, ar.d/or humans. Any icaarri.-jat or previous enpioyeo, contra:.tor, subcoivtrae'tr, iu-tteass car private consultant of each of the Defendants or any tidier person who has factual know.'lodge of any statist os concerning `ha effects of dioxins upon plants, animals, at Vor humans. Any crrr'st or previous employe..; ctnt.rr.ctor, subcontactor, in~lKFJEc or private cornu:tent of each of the Defendants or any ttv:... perse including, but ret limited to, msnbers of ErA arti tether gower. .aanta.1 ace c.:.<ng,who has factual :crcn/ledge of 7-is foUtawing incielante: c... O* hove Canai Tiuas lle~::h, Mr.:-.s C Severer, h;* 1'/ v,o1. BAST {1S53f C''-:'./', ^ dieci UOOV:i.--V*t 0. uedvet:.c:;r.i'-hays and,Vr: arpie.cion; r..nee if', :vt.*of the piar.to 0'7 "iv c fro Defer/ .1Vi.1;manti-...luring, l'"'')i 2,i-D, 2,4 j phenol , chlorin '..V:Stic ocid, benzene, nodiutf hydroxide, -.-.fc*---'.J44* '.v/cf:juide.- air1./'or -Igor.'t Orange, 5..r.clu.dir: mishaps ir: the y-rkagdug, an/ ::: ;orcorti.,y U: tho Da::. products f- if:: u. ; V <C-*bases fo:r eventual shipmr..:'. c to Vietnam Sprayii o:r picturr.: f 'O/: .,j//..1 Any ctr ant e:r pro u ras CWCy3C ; . - ^ subcontract. V* i ir.hour... c p:,,ivate .ruealt'cit 'f each w:. ui- n .u*. i .. ; fendant:.: or anv Ohher person 1:<ho has factual fe::f go of ary ;surveys, tests.. epidemiological studies of any k;_.d relating to the effects of roffiosirre to Agent Grange, 2,4~D, 2,0,5-T or any constituent thereof 5jic7.ud.ing the secondary by-product known as dioxins. Any person with factual oiewledgc of how decisions are uade within-the United Gfates government:.. particularly the decision to -ras and to continue to use ohsnray herbicides in Vietnam, particularly Agent Orango; any person with factual lanawledge cf government procurement contracts and the invitation to bidde.es, pa.rticrJ.ariy those pc..-sons who negotiated the government contracts for all phenexy herbicic&g (agents whits, blue, purple, pink, guaen, orange G and with -die individual defendants repre sentatives between 19G7-)f72. -11- f A O f4 001 V Any person with factual knowledge through .any surveys, te-ts, epicerniolocjicaJ studies or ot--horv-i.se undertaken by cay state gover-cuent, any private public or foreign o operation, the U. i. Congress or the government of any ration u m c e m i n g tile chemical ccr.pov-nd'.'., 2,5-D, l,/i,5--Tb dioxins, or related duoronhenoic relating to die creation of dioxins, tiie detection of dioxin:;', the dangers; of dioxins' exposure, and/or the toxicity, carcinogenicity, fetchcxieity, teraferjenicity. scute and/or chronic effects on plants, animals and the hurio.n population Any and all persons listed in '..'he Chemical tcytiie by Alastair May as having factual luiowladge regarding 2,4,5-T, 2 'D, and iri.v: contaminant dioxins. S3L1 worker compensation carriers for the Defendants ar.d dccu- axEita-cior!. 01. all occupat: oral exposures filed since 27S. which Science industrial injuries or diseases at the "TCP, 2,4,5-1, 2,l--tv. Phenol, pacha; li.g, nd.'c;; irur;,y.oration plants c" tho Stefeidknfce. Ary ear' all current a:, prior v.cr'cers c3t>ensaticn claim/..its of the Defendants v;ho -'..sired relevant rcoupaiicnai onposures ana.'or xx event ccorpstiers! injuries and/ :r diseases and/or cymptcms r !iis reievent ylcut listed la Answer to lie. 19 (sub 171 above. Ci...1 1~ -Si .-./t .. . , # q * Hi ^.U'.ew-- o - R e p r e s e n t a t i /o s -n;t*" o' . 1"hr. . r-.itj 1?A a c t i o n s 115c3) :.ind/o: 2T.C.C'a w ith --`ct- ;y :;';/ -J- lineny a l aocaT n;.-:ary an d d e c e n s t r a t i V3 hoar:..up -w hich v / i l l form s u b s ta n3.cC3 CiL 'CliC3J- t o s t : :. ::ny h a r e i n ; o r>. t h e f a i l u r e tlie dia n pr: o p t and ie f f e c live a c t i o n f : ' ban t h e p ro d u c ti.o n o f 2 .4 ,f21 7. f -_1.1 i t s ae:it3ifli:ia:it d ie :u.ns. Any and ail parsons bavinp 1 .crledge o... relevant facts regarding '.-lie financial status of Use Defendants and -their ability to respond in punitivo dast.yer., including, but not limited, to, their past, present, and future pr "its and earnings in th:.. ''sited States and abroad since 1922 through and inciudiny the present frau Hie sale of die products made the basis of this lawsuit, .i.e., 2,4-D, 2,4,5- T, phenoxy herbicides aid the relevant herbicide market. Amy and ail persons, hiring iuiov.iedge of relevant facts regarding the ownership iv/-.erests of t b , Defendants id their ability/- to respou' in punitive car.ages. i.-.eluding, hr . ..at limited to, defend ;.nts: domes tin end foreign subsidiar.-.es, joiit /enturers, licensing :.grc2ser.tr., and/;::: other public or private corporate ons in the rJ, S. and breed, in ..-hioh those defendants cv/n a subst.ru.tial fir/ncial .biterc vt since 1925 t'* .lugh and including the present. -12 -v'4?- .1,, *rb---\'*W 2.:. Any and all persons listed by Plaintiffs1 in both original and ."c.r.idad witness lines, as e::part witness {medical, sciotific o:: causation*, , covcm.3;t witness, gcwernmoat causation witness, dsiendc.'-nts' ei.ployees and/or related personnel and/or any witnesses li.sv.-d by all Defendants, may be called at time of trial to prcsr.t factual : ."o;.T.>:v-.ion as t any issue involved in this c<ise. 23. lay and ail rnstibers of the scientific and/or medical corrsnunihv v:ix> have kr,r.;:.cdg.?. of l\-..levant fasts,, including infe.-snation as any of the previously listed subjects in tils Answer, including,3ast ret limited to : c. David hriebel.. 1'irb. h. Dr. A i m Fclmc Yx. ' .ml * 'jt;. Dr, !.. Depps c. Dr. Cartel, ralF fDi.*. K. `1. 't.Conn g. Dr, h. '.-hi re. h. Alvin Air i. Avrilvu iAuigrrr.ut 21 Arr/ and oil perrons \.hc r.i.v f_.ctv;.'l hnowlocgc ronceming the individr'l representedi.vo L-iaintiffrs dredges, including, but not 11 ; to, the 1 liewing: a. Any and 11 raed' r.l por.cr.ns who have exarairiscl, observed, treated and/';.:: tested the ?1ointiffc: for injuries disersss. and/or related '..ysirai n..d emotional conditions vi. ~h resulted from Plair.fi.-eh. ' ttipesure to Agent Orange, and/or pusnexy herbicides, their conctitr.en.tr, cstaandarv by-products, wastes, residua.'..- end r ~atamiaantn. b. Any and all hospital personnel *.-jhore Plaintiffs have been confined for treatment rolat'eg to their exposure to hefsndants* products in Vietnam. o. Any .end ail p e r m s with knowledge of the economic losses, psychological and/or intangibi' da-r-Bysr: unstained Icy y u r dlaint* .'-f': as - rusu.lf: thei- :i.ne "ierj awl diseases r suiting rect their 'reo.'r.'.re to !.V:fenchants' pu d-.-.cts in Vietnam. h Any a '.d all parser; with madedge of the past, present and/or future ec.r.e sir losses your lie: vtiffn have or will sustain in die fut're os resin '..of tlv.-.:* ;srj of wage eaxsiings rr.h'cr wagc.3 earn:.!.: capacity ros-iting from the injurious and di.sea.ses made the basis cf this ?. /suit vdiich'ere caused by .intiffs e:;posure to Defevdants! p?r.dusts i" Vietnam. 13053 r\ . -f?/-~J'X W'EJ Unitoti :$iaS ::rvMrof'.ni*fv ;i Protection rir; lUifii.-uien-f i.trm r.virtvimwU r\ . i-u*ffcoiv .\nonrwt:OH 45I03 i1.^- ^^ ^U `iS z''"' '/"'N PLAINiF F 'S COVER ilE!:T CAUSATION WITNESSES Jabs M'ikerjeu A. El'A , IJ a hin TV. Eo tb fee ",uu.l and sought. C. General E-,eat s Any factual knowledge of the history of herbicide spraying in U.S. and abroad; including, but not limited to (1 ) industr i. exposures and explosions; (2 ) registration 2,4 ~ D , 2,4.5-T vith the Department of Agricul..ure and any other government agencies b; ary and/c r d l if t::e i:efen clants ; 'll '*`~/ *1 f;tua 1 knewled o f the histsry of ..b !C:i.ie ;pray iug in t7 - U .S . and abroad; inc._n -*< ? but r.ct iimi ted to v (1) D .S . mi ii C. C. Ay u;:e o ' Agent 0 ran ge an< other phsr net:; C2. J -* vletnan ; (2 ) ch r*"rr-a.-5 -?*- ^:;3 , -,3t r-rtf' .or. L*CC" 2 rementk o f he ~1TDj.C1v'l8 3 VJi.tl U .f . government and its agencies includin; u n owl cd of FIERA, F D A ,E P A , and C-SHA; aiu any o*./1 1:dge of indu;`tr,,ija--l! a-nd* other hum. 0X P o 2 ii C_ z: the U.3. and abroa di See ..nsv-er ar.J. Supplr. tentai Answer of Plaintif fs 1 to Dfendants : Int arregato ry No. 19 attache' etc avn.dn i1 1n10co0 rpo0rrated herciti for ail pures rc : events rr ccurrences vhicr. ths satior w icnessc-s y be expectcd to give fact t:a1 informt i thev mav hve reaarr sue Toct c 0 u1 1 ine Human Li. As ses ornant of Exposure to 2,4-0, 2 :4,i;-T and d i<..vins and any ,,actual knowledge in support taereo f . Expert Testimony 1' Te stime -.ay ir sc ;ght in witness' personal and of fini ca p?,u i t y . o bu rO oc.t Matter 2,4- D 2,4,3 --T, TODD s and dioxins ; Ag ont Nr I/._i (also White, Bi u S , Pink, C r e e n . and Pur tf W w* L A-!o D 0 5 and celate' sh ioropheno1 o and h ubian risk assassinar; regi, tding erpes^re , in,- tuding , but not; liritcd to. rue or aore c the a1 low \n g -abject ar tan : a ) Ch erais try /B icch eu._s;ry b / IIaaufacture and /or ?r :duct :<. d ) H od t.c o 2 Human Fnpcsui e) Fate in th e "avii onner. t (Hum,;as, Plants, Animals) f> StGt 1 of Art/State of :dedica" and Scienti! lit arature Plant lays it'op 7 /Studies 7 An... :-l Lhysiolcgy/Studies Hut ,,u Gtuli as n ^ Ep-.da.- ...0 1 ca /2i0 st at is-1.1X C. 3 ? 1ants . untir Is. hunaas Gau-v.-; lpide-..iclogy bap ..:di-c.:.ive Epidemiology n' ''ivr :*S Healtn E :cats J07s' .e r , vr-lin-'i-i/.s r i 1 be ac,kcd opinions ab-'ut both y"ib 1 1 ahed .;.r.J/ov ou -gc.ing studi..s. 4 1 Ya v i m c c ;a vi 1 1 be aslce-d -pinions about any studies or resear ::h uitnees Las personally perf irmed o r ;atu aJ.1y oa rt ici pated in. > J Yas ; wii:nacr. will be asked opinions abc it other go-ornaent.il- studies. 6 ) Yen. vitaass :!.s expected t ~ review the following docu.inn ts .1`.Lor t <iv :i.vp t eo C im-;ny : Sr, E^A, Research and Dev e1 o pme nt , H ea1 th At_ses sp eat ho cun ant, o n -Dioxin n__ or thy 'f:icoe of Air Qua lity,' Planr.inr. 'and I-TcaiTda'rH*s , proparad by the Em* i1,-ouEeD.al Criteria and L-oecstna CC ficf : Cincinnati , Ohio 45148 ( ,Julv 1- ^ 5- i.4y<J Q o EPA ; Rer.aa rci. and Dove lopuant, I' i.tn and Anvi r !iienta 1 Ei fectc Proiile for; Tct Pent.- . and Hexaci. lorodiL er. o-p-d1 oxir.s for .b e Office of Solid VJ.iatc and Emer gene;; Response, by the Environmental Criteria and Assessment Office, Cinein Ohio 45248 (June 1383). E P A research and Development, Ambient. Water Duality Dritc-ria for 2,3 ,7,8 TCDD, pre par od for Office of Wate r Reg 'i.:ti.or.s a i . J S t a n d a r d s , by the Er.v iron i..enta1 r.L?:c:via aa<! As :: er.ament 1 fice , Cine in chit .-5243 (July 1383). E ?-A, T.e sea rch and Dev a lop w e n t , D icxins , industrial Environmental Research Ji..cir.-.ia .i , 0aio (19 78) . copy of tA use fo men to ..3 a otached , .vr StuLCbiH-TOD ANSWER TO ENTSTRCC-ViORY NO. j/J Plaintiffs note preliminarily tiiat the extant Order on producing fart itnesses rvates that fact v/itnecses arc not`duo until March ' 1934.. Kc:wevc;:, Plaintiffs may call one or more of the following persons (or those- from vai/ious categories listed be' :) at time. :f irrial to testify as to factual incwledge they may have, ..neluding: i. Ranch Hard Personr...'.: these persons will testify tc dneir knar-ledge of the Ranch hard Operation, Ranch Handers exposure to Agent Orange, and/or iaicwledge relating to the sp- lying, tenting, and effects of 'gent f range on luruans. M-nmbc2.*s or idi... n. ; ..e . -'ore .j : These per.v^r.s me testify to the circumstance;.- <?na c :r.ditions j-urrounding the . raying of Agent Grange. Persons present :.'.n 7ii::r?trr; curing the e:xc-sure period r.i cuertior; 1351-Lu7?., inciu'vu-g, hut no .limited to, -v if vacy and paramilitary p?..:rscruKi of the U. , ., Low Zealand rid Australia, who have Icncwler;Lge of idle praying operations of the herb:.cider.1, the erprcure of the Plaintiffs' clans the hazards acconpauiying any sue!: exposure, t h e Plaintiff J hhetiselves, and the Defu:n d a n t company representative:: psfcscub ii. Vietnam ..- ov....-rose "he deli/cries .vnd spr 7no operations of the i-arbie.ides they uianufactured. 4, Persons tegocher \dth their demonstrative and documentary evidence who gave testimony (which will form the substance of their testimeny herein) at the EPA Cancellation Hearings of 2,4,5-T (1979-1S30) under FIFRA. including but not limited a. Dr. Roy Alberts fc 'Dr. K. Diane Courtney ...c. Robert K. Baughman, Ph.D. d. Dr. Olav Axeiscn e. Dr. Renate Kimbrough f. Dr. Dawn G. Goodman g. Dr. Kirk rJ.tchin h. Dr. Fona.ld Thomas i. Dr. Rainer Frentzel-Beyme j . Dr. Matthew Msselson, Hs.rva.vd 1 Jo 3 -9- k. Major Alvin Young i. Ur. Rodney Bcvey m. Kenneth V. Th 2rnsin n. David T. Euzzq.lli o. Dr. Michael Gross p. Dr. Renee Stringham r. Dr. Van Miller Any -current or previous employee, centmet or, suLcc in-house or private consultant or each cf the Deix; cr eu:/ other person who has 'mow ledge cf the manufacti m g processes, chemistry, occupational exposure vnd/or jicicity of 2, 4--D and/or 2 r4,-T or related chicrophcno:.s ; inc uding, but not limited to. laborers;. operators? supervisors; ontract administrators? quality control personnel; engineer (process, chemical, mechanic;:JL and/ur safety) . Any current or previous cx p lc y e e .- c o r tractor, subcontractor, in-house u:: private c e n s e l e a n t c f o re :h of the Defendants c~ any ether oerscu who has /::orledge the poocible means : ;;-rcply.~ctic pro testicn fr:..i th e hazoi Is cf dioxvis 1 exposure ; including, but not limited to, labors s, operators , supervisor: contract s.iri.r.irikratorr., quality cone ol personnel , engine-: s (process, dr ...'cal, mechanical and/c:c safetv). Any current or previous c.uployse, cent.ractor, subcon 'tractor, in-house or private consultant r ' aad : of tire Defendants or any other person who has knovtaf- ;e of the means to warn those who might be exported to use f tire he:bicides in question, particularly Agent Orange, including, but not limited to, laborers, operators, supervisors, c.on':ract adrainistrators, quality control personnel, engineers :procss , ch.siu.cal, mechanical and/or safety! . Any current or prev..ov employee, contractor, subcontractor, in-house or private cor ultant of each, of the Defendants or a.v other person who has factual. Icnowiodge of any other manufa ctvring processes which could reduce the risks of exposure to Agent Orange and/or other pheroxy herbicides being contaminated with dioxins end further reduce, the risk ar.d hazard to human health of any such exposure. Any current or previous employee, contractor, sibcontractor, in-house or private consultant of each of the .Defendants or any other perron, who has factual iincwledge of conspiratorial conduct of the D m ndants, individually and/cc duplicative erf -ts (acts which are _.erallel in nature) which tended to or did in fact result in tusleading the public and tiie United States government fron gaining knowledge of die danger:.: attend-:..it fren e:oosure to Agent Orange and ether phrovv herld.ides. x1. c nV xsj a^ ^r <V*N 10. Any current or previous employee, contractor, ou' rontra or, in-house or private consultant of each of the Defendant- or any other person who has factual icucvledge of bar dioxi cork, upon plants, animals, and/or humans. 11. Any current or premiers employee, cc; tractor, suh-c.ontr in-house or private consultant of each of the Defendan any other person who has ..'actual knowledge of any stat concerning the effects of di.oxi.iis upon plants animal's humans. .O S id/or 12. Any current or previous employee, contractor, oubcontac --r t in-house or private consultant of each o f :the Defendant or any other pc...on including, bus rot limited to, members of 7A and other gcr.errsnental agencies, who has factual Jcnowledge c die following incidents; a. Love Canal b. Times Beach, Missouri c. Sevescc, Italy d. BASF (1953, i9ik - 3ad::....;ha in Ccrsnsny) e . Production uinhapa cud/ : cs'p.'ir.icna sir.ta 1925 at ai the plants of any of the Defendants man*afacturing, T2,4-D, 2,4,S-T phenol, chlorine, acetic: acid, benzene hydroxide, potassium hydroxide, and/or Agent Orange, mishaps in the packaging, and transporting of the Dei products to the U. S. Armed Forces bases for eventual to Vietnam. Spraying of Vietnam from 1951-1972. of sodium c oding i-iants1. hipment 13. /buy current or previous employee, contractor, subcontrac r, in-house or private concalteat of each of tlie Defendants r any other person who has factual lincvledgo of any surveys, t; ts, epidemiological studies of any kind relating to the effec z of exposure to Agent Orange, 2.4--D, 2,4,5-T or any constitu -t thereof including the secondary by-produ :*. known as dioxi..is. 14. Any perron with factual knowledge of how decisions are made within the United States government; particularly the decision to use and to continue to use phono:ry herbicides i.n Vietnam, particularly Agent Grange; any tersen with factual knowledge of government procurement contracts ar.d the in Itation to bidders., particularly those persons who negotiated 1 e government contracts for al.l piier.o:o/ herkiciats (agents white, blue, purple, pink, green, orange 1C and II) with the'individuad. defendants' repre sentatives between. '951- 1172. -ii- * ur>'6 0 15. Any person with factual knowledge tlirou-h any sur\ test??, epidemiological studies or otherwise undertaken by -ay state government, any private public or foreign corporat m , the u. Congress or the government c.f any nation ccncarnih- .tire chenacal compounds, 2,5-D, 2,4,5-T, dioxins, or related chii ttphonols relating to the creation of dioxins, the detection )f dioxin;1,, the c-.arpjers of die ,,ins' exposure, and/or the toxicity, arcincgeuicicy, fetotoxicity. teratogenicity, acute and/or cironic ffects on plants, animals and the hunan population. 16. toy and all person., listed in The Chemical Uovche ' Alastair fetevy, as having factual hnov.'le.!.ge regarding 2,4,5-T i,4-D, end its contaminant dioxins. 17. Ai.! 'worker compensation carriers for the Defendant and docu mentation cl all occupational exposures filed sine 1925 which evidence rndustnai injuries or diseases at the TC 2,4,5-T, 2 r4-D, Phenol, paricaging, and/or transpcratic;. pia- s of the Defendants, 1C. Any and all i r.-rant ' : prior workers caroensation <. dinar. :s of tiie Defend?." f who claiif reievant occupational ex eures end/o relevar : oc-nr. :tio^ii irT.trier. and/or disease::; and. : syirntcms a: the xx.l-r.vt- /.inte '...sb. . j.n tr.ov.'or to No. 19 (aid: V, ,,:bcva. 19. Any and all members of ildlC;: .J. I~3 tlOoisc of Represent ives Carenittc a or. Gversinh":; Lcvicw of the T?A actions .983'' and/or any parson her with the:i documenfcarv and done trativo evidence giving testim xy at said hearing (which v/i form th substance of thei.r testimony herein! on the failure .: the EF` to take prompt and effective action to loan the prod: ;icn of 2,/--D- 2,4,5-T, and its contaminant dioxins. 20. Any and all persons having knowledge of relevant fat ; regarding the financial status of the Defendants and their ab: sty to respond in punitive damages, including, but not lira: ed to, their past, present, and future profits and earnings in tl United States a:-d abroad since 192:" through and including the pres nt fran the sale of tiie products made the basis of this lawsuit, i.e., 2,4-D, 2,4.5,--T, phenoxy Iierbicides and: the relevant ' rrbicide market. Any and all persons hiring knowledge of relevant fac. ; regarding the ownership interests -.f the Defendant?-, and their -oility to rescond in punitive damar including, but not limi' d to, defendana s 1 domestic end o.ign subsidiaries, joint nturexs, licansir.j agreements, -nd other public or private >.brporntions in the uf S. and abroad, which theca defendants own a subs:antia! financial intere: since ISIf through and including the orasent. i o U g ft-i 0X - 12-  *v e. Any and ail persons w?i.u knowledge of past, prc and/or future reasonable one necessary coots of doctors, hospitals, nursery care, medical equip drugs, and any other related medical services r or to be rendered in the future to Plaintiffs a: result of their injuries and disease resulting their exposure to Defendants' products in Vietrv .ed f. Any ana all persons with knowledge of tlie physii present!, physical and ; al sent), physical pain (pi an.l doh (past and pres- nt) v jh .d as a result of their f. osura in Vietnam and which in iaintiffs will continue ) .e time into the future i beyond the cate of thi Trie" . Respectfully sub .tted; _ 2 .'_' Themes W. Mender. n, Esqu.i Allison Pettiett' Esquire CERTIFICATE OF SERVICE I hereby certify that a true and correct copy of the aregoing Supplement to Plainti.fi!e Inf nrsrogatories wars mailed Federal Ex ress to Me. William ihrchloy, Valley, Drye Warren. Kr. Gone Locks, Plai .tiffs' ysnagemeno Coned.tv.ee Agent Grange 'Office, with copies to personally servo die remaining Defendant:--;. at the Tuesday depositions and Ms. Nancy Petrilla n.S. District Clerk,-U.S. Courthouse, 225 '(.dman Plaza, Brooklyn, Hsw York 11201 this 20th dry of February, 1301. ' 4 , ! 14..J.J__ ., K- r/'-- Alii ?.on Pettiette - 14- # ** -yj-c Ur;-t>!i'i Slams -nvirtn.Tiem.il Prr.if-.-Ton *lerii'v '`lustrisi tir. 'ifin.nl.. nt:>rv CiiKmn.iti t :ttBS .. ^ /*'" -t 'trj , U O O /T' PLAINTIg? S GOVEIvNlEN'. CAUSAT!'CM WITHES.:FS Janet Springer EPA, Washington, D.C. B . Both Iactual cad e::par: testimony is tough C,, General Events : u :y fa ctual know ledge of the h ry of l r*57 X c iue sprayi ng in .U. and road; 2. 1'.C Iuc!ir.g j .ut not liti;ited to, ) industrial 0 ::poC V1res and e;:closio ns; <' 2 ) : 2 `T - 'h - V 9 /. c o ... ich tk e D coarti r> nr e and cr.y oth .r go vc rnmei istration of t of Agri- agencies by i; V au d/- r til o x the Defendant. s or*v y1 4. 4 .':actual 1-UOW 1 dge o f th uistory of T . n dox>~-. A cprayAng in the . U . 1 abroad; i.clud .'..., bat Uc '.: 1 in it ed to , ) It ili UW --*r' use of Agent: Orange an other pher.r orb I.r i-.as in Vi cinam; (2 ) chan .o in the j 1 st t*,r>tion re _ulrer.cn ts of herb ides w i th th i. j 1 <Tc T amirent and it s .agenda Including Xnow ego of FIT FA.,. FD A, EPA, an JSHA; and (3: & uy kn owled,;, of indus trial and Cher human c. 2 ;su res t o 2 .*4- D , 2 ,AT'-T in t ; U . C . and abroad. See Answer and Suppicnental Answer of Plai: ffs : t... Del andante 1 Interrogatory Nc. 1' ttachcd : eto and x n c c r p o r .od herein ' all pur petes re: events or occurrences, ghi ch these causation witnesses nay be e:cpec ad tc give tty factual itformation they naj lave regardin. ' the subjects outlined in said Ar ;er. ihman Risk Assessment of En posure to 2 ,4- D. ;,4,5-T and ior.inc end any factual kn.iwledg in support thc:veof . h:pert Testimony 1) Testimony is sought in witness' persona' and official cayacit:;/- 2'- Sah je it hatter ^ A-.Vi 9 A t-T "UDETs and dioxii T./II (also White , blue, Pink, Grc Agent Orar.g ai.d Purple 4` t* in f t *! I yoi Cw, and related chloropheu' o and human risk as jcssment regarding exposure, including, but not limited to, one or more of the following s oject areas: a) Chemistry/Biochemistry b) Harraf act ere and/or P; oducti< n c'j 'iOiiicity d) Modes of Human Exposure o) Pate in the Environment (Hr.uans, Animals) 2) State of Art/Stave of Medical and Literatur' Plant fhyriology/Studio n \. Animal Physiology/Studies >j ilv.r.an Studies 5- Ev ida niology/Biost atistAcs 1) Plants, animals, hur :ns 2 ' Cancer Epidemiology o * Repro-ductive Epidemiology Cl y Advcr na r.Ic a1th Effects 3) u vn* cO ) w*.,* .tness will be- asked opinio ns about both published and/or on-going .studies. 4) Tea, witness will be asked opinions about any chuc-ec or roservth witness has personally performed or actually participated in. 5) Yes, witness will be asked opinions about other governmental studies. 6) Yes, witness is expected to review, the following documents prior to giving testimony: See. E?A, Research and Development, Health A s se ssment Document- pit'-Dioxins for the Off Acas- of Air Q u a l i t y . P l a n n i n g 'and '"otart-darcs, pfeplared by the ."nviron :eni.al Criteria and Assessme Off is ^ir. icnati, Ohio 45243 ( July 19 r* r-n ** l C 'J D 0 E'`A, Research and Devalopment, Health and Env J.romaentl Flf:;ectfi Profile for; Te Penta, and Hexach.lorodibenzo-p-dioxin for the Office of Solid Waste ahi Eme gency Responso, by the Environn tal Criteria and Assesaraent Office, Ciuci Ohio 4 5 8 (Juna 1983). EPA, Research and De\reloptnent Ambent Water f'nality Cri te ri a fot 2,3,7,8 TCDD, pr pai: .'.il for Office of 1-Jatar Regalar ions and Stendardo, by the Environmentai Cric cria and Aasescnent Office, Cinti Ohio 452AE (July 2983). EPA, P,crif'n"".l and hovelopment, Dioicirn, ii i .i.l.'il inivirnn>i ini.al al. di . innati, Ohio (l`J78; . docuucnfcs is attnehed. ' jt*. **. 1*2 o d o ( "UPrLSMgra\L ANSWER TO INTERROGATORY NO. 19 Plaintiffs note preliminarily that the extant Grier on producing fact v Ventores etatec that fact witnesses are not due until March 2, 1984. However, Plaintiffs may call one or mere of the following parsons (or these from various categories listed beicrv) at time of trial, to testify as to fac'u.-ul knowledge tft-'-y may have, including: 1. Ranch Hand Personnel: These persons will testify to their knowledge of the Ranch lime. Operation.. Ranch Handers* exposure to Agent Crrngo, ar.d/cr leu .-/ledge relating to the spraying, testing;, and effects of Agent Grange on humane. 2, Maribsrs of the e. 3. Armed .'orcoc: There persons may testify to the circiruchaircef! end condition':: surrounding the spraying of Agent, Ora: :;e. 1. Perse'.is p::rcent in Vietnam during tile exposure period in question 1?6?/ 197/., i.nclt.tr:'ng. !->ut not limited to, military and parmailitaiy peruonr. :! cf the 3:, New Zealand and Austral:.;:, v.ho have hr.r-./j.cdgo of the spraying operations of tile herbicides, the exposure of the Plaintiffs' class, the hazards Ecoanvconying any such exposure, the Plaintiffs' themselves, and the .Defendant company representatives present in Vietnam to oversea the deliveries and spraying ..peratiens of the herbicides they manufactured. 1. Parsons teg '.her void, then:: dmacnntrative and documentary evidence who cave testimony (which v/ill form the substance of their testimony herein) at the VPA Cancailaticn Hearings of 7,4,5-T '1979-1980) under FIFRA, including but not limited to.: a. Dr. Roy Albert: <-b. iv.G K. Diane Courtnc; - c. Rob;art K. Baughman, ] d. Din 01av A:-:elson e.. Or, Renatc I'JLr.'brcur'-'. V Dr. O e m 'o. Gcodr': 3- Dr. dirk T. latch,in h. Dr.. ,.V_n?.id Thome:' U. O r . Rainer Frentcel--! r J' cnbClnv r- - 9- * <7^ ^V 'l l :. Ma or Alvin Young I. Dr. Rodney Povey rr;. Kenneth V. Therein a. David Eutzelii 0 / Dr.. Michael Gross p. Dr. Ranee Stringham r. Dr. van' Miller Any current o:: previous employee, contractor, subcontractor, in-house or private consultant of each of the Defendants or any otrier person who lias knowledgs of the manufacturing grocesoes, chemistry, occupational eccpesure and/or toxicity cf snd/c- 2,4,5-T or related chlcr.,phenols; including, bat rot limited to, laborers;, operators; supervisors; entract administrators? quality control personnel; engineer- {process, dierdcal, reclianiavl and/or safety). fi. Any current or previous employee, contractor, subcontractor in-house cr private cnsultant of each of the Defendants or cry cd'sr perron who Ins Ixowledys of the possible means of ]yrcpliiacfci.c or hecticn from, the Lizards of cUoidns* exposure; inclining, k v net limited to, laborers, operator's, supervisors; contrart cdnvr.irtraters, q-.rlity control personnel, engineers {process, chemical, mscluoiical ond/cr safety';. 7. ?jny current or y.rcivicu..; c. .ployca, contractor, subcontractor, in-house or private consultant cf each of the Defendants or any ether person who has knowledge cf the means to v;am those who might be exposed to use of tiia herbicides in question, particularly -Agent Orange, including, but not limited to, laborers, operators, supervisors, contract administrators, quality control personnel, eng: .,,acts (process, chemical, mechanics;1 and/or safety). i. Any current cr previous employee, ".ltractor, subcontractor, in-house or private consultant of each cf the Defendants cr any other person who has factual laicwledge of any ether manufacturing processes which could reduce the risks of exposure to Agent Grange and/or other phenoxy herbicides being contaminated with dioxins and further reduce the ri sk and hazard to human health cf ar.y such exposure. 9. Any current or previous employee, contractor, subcontractor, inrheizna cr private consultant of each of the Defendants or- any oftier person who has factual jmowledga of conspiratorial conduct of '...he Defendants, individually and/or duplicative efforts (acts which are parallel in nature) which tended to or did in fact result in misleading the public and the United States government from gaining knowledge of the dangers attendant fresa exposure to Agent Orange and ether phenoxy herbicides. -10- .2068 '.jnqzxgty, Any current or previous employee, contractor, subcontractor, in~h::>usa or private consultant of each of the Defendants or any other person who lias factual .cnowledga of hoi// dioxins work upon plants, animals, and/or humans. Any current car previous enploy.ae, contracter, sufccontractor, in-`house or private consultant of each of -the' Defendants or any other parson who lv. a factual knowledge of any statistics ocwoerning the affects of dioxins' upon plants t animal's, and/or unmans. 12. Any current or previous employee., contractor, subcontactor, inr-lioii^e or private consultant of eadi of the Defendant:-: or any ether person i-r ludir.j, but not limited to, members of E2?A and other governmental agencies, who has factual knowledge of the followincr incidents; n. Love Cenar b. Tlares Beach. Kineouri c. Se-vesce, "taiy c. BASF (1951, lidi - Fcvfiisdie in Germany) c. Frcducticn rishapn end/c-r explctiers since 1325 at a. y cf the plants o" any of the afar, "ants lreruifacturing, T. 2,4~D, _2;>i,5-T phenol, cliorina, acetic acid, benzene, sodium hydroxide:, potassium ivciror-lde, ar-d/cr Agent Grange, including Irish',ps in the packaging, and tear-perting of -the Defendants' products f-n the 0 U*. Armed Forcer. bases for eventual shipment t:,,. Vietnam, f. berrying cf Viete .13. Any current or previous ealoyeo, contractor, subcontractor, i-v-house or privata consultant of each of the Defendants or any ether person sin has factual knowledge of any surveys, tests, epidemiological studies of any kind relating to the effects of exposure to Agent Orange, 2,4-D, 2,4,1-0 or any constituent thereof including the secondary by-product known as dioxins. 14. Any psrson with factual kr viledgs of how decisions are made within the United States goverrr.'.ent, particularly trie decision :o use and to continue to use piisnooty herbicides in Vietnam, particularly Agent Grange; any person with factual knowledge of y cmmsiit procurement contracts and the invitation to bidders, . particularly those perrons who negotiated the government contracts far all pbenoxy herbicidfes. (agents white, blue, purple,, pink, green, o/.vnge I and II) with the individual defendants repre sentatives between 1961-1972. -1 15 Any perron with factual knowledge tJurough any surveys, tests,"" epicoi/uological studies or otherwise undertaken fcv any state gover-taent, any 'private public or foreign corpora"-ion, tine U. S. Congress or the government of any nation concerning the chemical compounds, 2,5-D, 2,4,5-?, dioxins, or related chioronhenolc relating to the creation of dioxins, the detection of dioxins, the dangers of dioxins1 exposure, and/or the toxicity, carcinogenicity, fetotoxicity, teratogenicity, acute and/or c.irciit . -feet: on plants, animals and tlie human papulation. 16. Ssrty and nil persons listed in The Chemical Scythe ? Alastair liny, a;., having factual knowledge regarding 2,4,5~'i 2,4-D, and its contaminant dioxins. 17. .'.11 worker cartelisation carriers for .tlie Defendant.; and dccumnitatien of all occupational exposures filed since 1925 which evidence, industrial injuries or diseases at the TCP, 2,4,5-T, 2,-i-D, Phenol, packaging, and/or Ltansporntion pl?*-'r.s -> >' , ryafond.in,'-. 11. Any and all current or prior worker:' oenrpensation claimants cf the Defendants who claim.;../ relevant -.coupational e-eoauren .--.idA rolcvarh "'".'''rC-.vVtCjJ..oC;.nr'.l :;`r -]]vrrnic.e;s and/or diseases c.i syi.yt~.is . . jl-.. t lents _liasut .i iv. . *.w ,w .w w-^~ 1'' v-*- 19r C.j.j. members ;f ;-J-7T ; o -h Oversi.ghtu Devi- :on together with their i givrr.g tes'.:iivcuy at r.. ."'jst-rnce of ::heir test:many herein) on tlie failure cf the E-T. to take, preopt and effective action to can the production of 2,4-D, 2,4,5-T, and its oontraninanl dioxins. 20. Any and all persons havrV.g knowledge of relevant facts regarding the fhiancia?. status cf the Defendants and their ability to respond in pu.ftive damages, including, but not limi-bid to, their pas:-';., present, and future profits and-earnings in the United States and abroad since 1925 through and including 'the presen", from tlie os It of ike products made the basis of this lawsuit, i,,e., 2, -B, i.,4,5-7, phenoxy herbicides and trie relevant herbicide nuu ret. 21. kv.y and all persans having knowledge cf relevant facts regarding the ownership interests o f the Defendants and their ability to r.-pond ;n punitive damages, including, but rot limited to, defendants' domestic and foreign subsidiaries, joint venturers, licensing agreements, and/or other pu b li< :or private corporal:err in the U. n. and abroad, in v.\ ;.l financial ;nto;. ist s uresent1# **3y J T 1- ;U i u,/v. %#' -1 r~ \ e. Pay and all persons with knowledge of past, present and/or future reaccna- ue and necessary costs of doctors,, hospitals, nursery care, medical equipment, drugs, and any other related -medical se: ocas rendered or to be rendered iu the future to Plaintiffs as <_ result of their injuries and disease resulting iron their exposure to Defendants' products in Vietnam. f. hr.y and all parsons with knowledge of the physical disfigurement (past and present), physical and mental rmpairrvsrt (past and present), physical pain (past ana present/ raid mental anguish (past and present) whies Plaintiffs iiave sustained as a result of their eupouure to Defendants' products in Vietnam aid which in reasonable probability Plaintiffs wall continue to sustidr: for an indefinite: time into tire future far beyond tha data of this trial.. idrpectfi:1hy suhnitted, A Jj_f_i_O____ .in:. W. tenctv m, Esquu.ro iUliscn Pettiet isouire o f sfivics . hereby' certify that u Larue and correct- ropy of the foregoing Suprleraer.t to Plaintiff's "nterregat-rres were mailed Federal Express to Mr. f/illiam Krohlcy, Kelley, Drya C- ferrt n> Mr. Gene Leeks, Plaintiffs' Man?c ument Co.rrit.t.ee Agent '"range Office- with copies to personally servo the remaining Defendants at n Ohrestay depositions and Mu. Nancy Petriila, j .:.. icirict l.euk, U.S. Court c u g o , 121 Csd-van: Plaza, Brooklyn, New York 11201 this 20th day of February, l % f . \ h u til Allison Pcttiette 13071 P'.ATNTI FF 'S G O V E R N M E N T C A U S A T I O N W I T N E S S E S Peter Infante / A. National Institu.ce tor Occupational Safety & Health, Wa3 h I>. Both factual and expert testimony is sought. C. .General Events ?re-1961: Any factual knowlod c of the history of herbicide spraying in U.S. and abroad; including, but not limited to, (i) industrial e::pourss and explosions; (2 ) registration o 2,4-0 , 2 , ,5-T with the Department of Agri culture and any other government agencies by any and/or all of the Defendants; il 1961 --presort: : lay 1a....tu-.1 knowledge of the history of herbicide spraying in the U.S. and abroad; including, but net limited to, (1) U.S. n i1itory v.::2 cf Age;t C rar.yn un ?. oth <...r phcr tie-h ` ' ` ; j"> V *et-v-.m: (2 ' changes in t.u gistra _on ;;.:y; romen ta herbici tea v iUli V- .S . g r n m a n t and its agcncie- including knowledge o' FI E R A , FDA,ERA, and OCHA; and (3) ray knowledge of Industrie? and ether human exposures tc 2 , -D , .?,4 ;5~T in the U.S. and abroad See Answer and Supplemental Answer of Plaintiffs1 to Defendruts' Interrogatory No. IS attached hereto a incorporated herein fer all pur poses re.. events or occurrences which these causation: witnesses may be expected to ,lvs any factu.nl information they may have m,garden, the subjects outlined in said Answer. Human Rick Assessment cf Exposure tc 2,4-D, 2,4. 5-T and diox.nr and any factual knowledge in support thereof D. Expert Testimony 1 ) Testimony in sought in. witness' personal and official capacity. ?.) Subject Matter 2,4-D, 2,4,5-T, TCD D'e and dioxins; Agent Oran Z i' l l (also White, Blu.e, Pink, Green, a m ' Furpl V f ? ... '( -------- V and related ch 1 orophe no1 s and human risk assessment regarding exposure, **eluding, but not limited to, one or more of the following subject areas: a) Chemist ry /Bloch ami".::r- b) Manufacture and/or Production c) Toxicity d; Modes of Human Exposure c) Pate in the Environment (Ilutans, Plants, Animals) O State cl Art/State of Medical and Sclent L it ovati: ve 1) Plan-': Physiology/Sti lies :.) Animal Physiology/Studies :; liair. a n Studies orr /`i Er.idrc.:iclogy/Bio.* tatisticc 1) I-lent c , animals , humans ... J Cancer Epidemiology - /> Reproductivo Epidemiology Advcrro Health Elfeats 2} 'res j witness will be ashed opinions about both published and/or on-going studies. 4; Vcs; witi:cso will be asked opinions about any c udie or research witness has personally performed or actually participated in. 5) Jos, witness will be asked opinions about other governmental studies. 6 ) V e s , witness is expected to review the following documents prior to riving testimony: f!ae , PiPA 5 Pc sc r. rc h <m d _ ''ewelopm e n t , : h nnl th Asfjussraent Document c n 'D o_x ns for the Of fi e__o,f. Air' Quality, P la m tln., `and S't~an~3aras , prepared 'by the Environmental Criteria and Aoscssnv Of fice j Cincinnati, Ohio 45143 ( July 74 *ir: /r.li /-N n EPA, Research and Development, I E n v i r o n m e n t a l Effects Prc P e n a , and iiexachlo rodib for Che Office of Solid gency Response, by the E Criteria and Assessment Ohio A 5243 (June 1983). a1th and ile for; Terra zo-p-dioxins, ace and Emerironmental fice, Cine inn,-.t SPA; R e s e a r ch ar. ; D e vel op men t, Quality Criteria for 2,3 pared for Office of Watt and Standard.:, by the En Criteria and Assessment uhio 45148 (July 1933). .blent Water ,3 TCDD, pre- Regulations ronmencal Price, Cincinnati e r nar ch and Devel op men t, '.c.;ins, Industrial Environmental Pesearch cinnaci, Ohio (1378). A copy of trees d o c u n o u t 3 is attar t #**f\ 'J 75 Ir ! !' .'i': j* i i% iu SUPPLEMENTAL ANSWER TO INTEPROGA'L'ORY NO. 19 Plaintiffs note preliminarily that the extant Order on pr educing fact witnesses stages that fact witnesses are not due until ,larch 1 1984. Ecwcvcr, Plaintiffs may call one or more of the following persons r those from arious categories listed below) at tivue of-trial to testify to factual Jxcwledga the -may have, including: 1. Ranch Hand Personnel: These persons will testify to their lusowiedge of the Ranch. Hand Operation,. Ranch Handers' er^osure to Agent Orange,, and/cr Jncv/lcdye relating tc.- the sc;, ying, testing, and effects cf Agent Orange on humans. 2. Members of -cl'.: Aauac! Poroas: Theca parsons may testify tc. the circumstances and ; .ditions surrounding the s.raying of Agent. Grange, Persons present in Vietnam during the exposure peric: in question 136.1-1972,- ir.clu. hug, but rot limited to, military anc. paramoJ.rtary personne.. of the TJ New Zealand :v/h Australia, who have Jen"-.'ledge of th.e spraying operations of the herbicides.- the eiqpccurc cf the Plaintiffs' class, the hazards accompanying air- such exposurer the Plaintiff ; themselves, and the Dofer.dent -ampavy representative present in Vietnam tc oversee tho deliveries and spraying operations cf the herbicides they manufactured. Perse ns together vrih <:heir demonstrative and documentary evidence who gave testimony (which will form the substance of their testimony herein) at the EPA Cancellation Hearings of 2,4,5-T {1979-1380; under Fjj/RA, including but not limited to: a. Or. Roy Albert: b.. Dr. K. Diane Courtney c. Robert K. Baughman, Ph..D. d. Dr. Clav Axclscn 0. Hr. Renate Kiirbrout, , 'Or. Dawn G. Goodman g. Dr. Kirk T. rJLtcbin h. Dr. Ron .old "" cmar 1. Dr. Radnor Frentzel-Eayma j. Dr. Matthew Meselscn, Harveml t*1r\ yy n 0- - . / o  V JT7\ k. Major Alvin Young l. Dr. Rodney Bovey m. i'enneta V. Therein n. David T. Buzzolli o. Dr. Michael Gross p. Dr. Renee Stringham r. Dr. Van Mille.: Any current or previous employee, contractor., subcon actcr, inrhouse or private consultant ; each, of the Defend its or any other parser, who has kncwl a of the it0 r:ufaette m--* processes, chemistry, ocarpatir. ..al --xposure and/or 1 deity of 2,4-D and/or 2,4,5-T or related chiorophenois; inci ting, but not limited to, laborers;. operators; supervisors; c ;tract adairdstraters: quality coritrol personnel; engineer: (process, chemical, msdrmical and/or safety). .Iny current or previous employee, contractor, subcontractor, in-house cr private consultent of each of the Defendants or any oth.r person who has dnowlodgo of the possible ircan . of ---~--0 C.-- - die hazards of dioxins' axcc tuit Includ:.::-but net limited to, ers, operators, nupervir contract administrators. quai .y control rarsonnel, engineer (process, chsnisal, meci.rr. in and/or safety). Any current or previous employee, covrractcr, subcontractor, in-house or private consultant of each cf the Defendants or any other parson v/l.j has knowledge cf the means to wan. throe v;ho might be exposed to use of -the herbicides in question, particularly Agent. Orange, ir.olrding, but not limited to, laborers, operators, supervisors, contract administrators, quality control personnel, engineer:; (process, chemical., mechanical and/or safety). Any current or previous employee, contractor, subcor.uractor, in-house or private consultant of each of the Defendants or any other person who has factual JoicrDledga of any other manufacturing processes which could reduce the risks of exposure to Agent Orange and/or other phenotoy herbicides being contaminated with dioxins and further reduce the risk and hazard to human iiealth of n y such excosure. Any current or previous cnployeo, contractor, subcontractor. in-housc. or private consultant cf each of the Defendants or any other perse: who has factual knowledge of conspiratoria.1 conduct of (due Defendants, indi.vidual.ly and/or duplicative .efforts (acts which are parallel in nature) which tended to or did in fact result in misleading the public and the United States government fran gaining knowledge of the dangers attendant fren exposure to Agent Orange and other phenoxy herbicides.. fi hi JL s) I i .-10- r>N - T V 10. Any currant or previous employee, contractor, subcontractor, in-lTura cr private consultant of each of the '.defendants or any ther perron who has Tactual knowledge of how dioxi: i work upon plr.nts, animals, and/or humans. 11. Any currant or previous employee, contractor, suboontra'-fcor, iii-house or private consultant of each of the Defendant, or any other perron who lias factual knowledge of any stat.i les concerni..g the effects of dioxins upon plants, animals, i/or humans. Any current or previous employee, contractor, subcontac in-heuse or private consultant of each of the Defendant other person including,- but rot limited to, mentors of other governmental agencies, vv.s has- .Tactual itncwledge c following incident:: x, or any ?A and the a. Love Canal. b. Timas '.-each, Missouri c. Sevasco, Italy d. BAS?' (1353 - 19H4 iadi.ooha. in Gerrsir/:e. Prcdu-etion td.shr.ps and/or: explosions since 1315 at aa of the plants of any of tile Defendants manufacturing, if `, 2,4-D, 2,4,5- T phenol, chi. rite, acetic acid, benzene, sodium hydroxide: potassium hydrttide, and/or Agent Orange, including mishaps it:, the packaging, art tv2ispcrfcing of die Defend nits' product.s' to the V. S. Armed Forces bases for eventual shipment to Vietnam.' f- Spraying of Vietnam frtsn ISS1~1.972. Any current or previous employee, contractor, subcontractor, in-house or private consultant of each of the Defendants ir any ether person -who has factual knowledge of any surveys, tests, epidemiological, studies of any kind relating to the effects of exposure to Agent. Orange, 2,4-D, 2,4,5-T or any constituent thereof including the secondary by-product kner.-.n as diox'- is. Any parson with factual Iznovledge of ho; decisions are made -within the inited States government, particularly the decisi . to use ar.d to continue to use phenoxy herbicides in Vietnam, particularly Ago h Orange; any person with factual knowledge of government procurement contracts and the invitation to bidders, particularly those persons who negotiated the government toutracts for all phsncxy herbicicitg (agents white, blue., purple, pink, u.scn: orange 1 and "i; with the individual defendants repre sentatives between 1961-197... . 0 78 -li- Day person with factual knowledge through any surveys, tests, epidemiologies 1 studies or otherwise- undertaken by any state government, any private public or foreign corporation, the U. S. Congress or the government of any nation oonseming the chemical ocaqpounds, 2,5-D, 2,4,5--?, dioxins, or related chic phenols relating to die creation of dioxins, the detection < : dioxins, tiie dangers of dioxins' exposure, and/cr die toxicity, carcinogenicity. fetofcoxicity, teratogenicity, acute and/or chronic <:<r*act on plants, animals and the human -f.cpulc.tion. Any and all -arsons 1:'. ted in the Chemical Scythe by lasta.v. Hay, as having factual knowledge regarding 2,4,5''?. .HD, and its contaminant dioxins. hl3. worker ccinpensafcicr cavrieirs for aha Defendants .arid documentation of alli occupati ..i?.I exposures file-;1 since 1915 which evidence .industrial injur ies diseases at 'the TCP.. 2,4,5~T," 2,4-D, Phenol, puckOjiny. end/c;- t msporation pl-untu of the Defend.--,Vc:. Ar.y and nil cur.cuifc'cr prr.or i.ori. , ccr.r:cnsatictti claimants or the Defender:'-s who claim :: re: v; .occupational exposures and/or relevant occupational injuries. ir.i/civ diseases and/cr symptoms at tin relevant, plaits listed hi carver to No. 19 (sub 17} above. Any and all rr:smbsj's f the '* kC.>. _re Cerai-ittiie an fversichus Re >i'rtt7 any pan..u t. needier ' thei..u dc evideu :--, givi: -j ban. : vjy at said substa. -go fyp 'heir t::r:.;tiray !c.rn to take premp a and cffactive r-\?r ' r Representative:: id denser,strative (which will form the Any and air parser 153T--V*^r knowledge of relevant facts regarding the financial status of the Defendants and their at lity to respond in punitive damages, including, but not. limited to, their past, present, and future profits and earnings in the united States and abroad rinoe 1921 through and including the present fresi the sale of the products inaia the basis of this lawsuit, i.e., 2,4-C, 2,4,5-i'. phc-no::y herbicide:- and the relevant herbicide marker Jury and ail person.1: havii g iciowledge of relevant facto rec.-rdi.ng the ownership interests cf the Defendants and their ability to respond in punitive damages, including, but not limited to, ;:cr.dants: dccactio and foreign subsidiaries, joint venturers, Ircenr'.ng agreements, and/or other publ.-.c or private co.rporations : . fho U. C . and abroad, .in which these defendants our.ni a subp'-ential financial interest since 1925 through and including the present -12TM .11koj nu >/?rai >v Any and ail persens listed by Plaintiffs1 in both original and amended witness lists, as expert v/itness (medical, scientific or causation), gcVermont witness,, covermsnt causation witness, c&iiendants' employees and./cr related personnel and/or any witnesses listed by all Dsfandarhmay be called at time of trial to present factual information as to any issue involved in tins case- T- Sctt rod all msiaberc of the scientific and/or medical oonraanit. wfen have hmowledge of relevant facts, including inforoatian sx..iy of -the previously Listed subjects ii. this Answer, including, 'at :ot Limited `no.' b^.*- Scvid *t;iebsi, bh.e> rv L. A..C.' Polarr .T*)* Det.. vcul Colder 3r. C. Par~t y ..jt*--f.r.'5 G. Dr. Cette1, liitA it Dr. E 3. AzDc-.vaii Dr. U. id &.v..jir.'.i Alvin Aim i. sfarilyn 1ingarhut 1 Anj and all ecu no who hm 'a'.vc.f..;dc.., concer.iing the. irkb'.viduai ierrrnent \"j.i s daoiaces, including, but / rot limiter! fr...lew: a. Any end. i-:e-'i-~.--l penoc:>n why have examined, observed, treated .one..' o: rented the .Avintiffs * fer injuries, diseases and/or related cirri cl and <rxts.r:tl conditions which resulted from Plaintiff-* exposure to Agent C range, and/or phenoxy herbicides, t:i;i...r cor.stitris.nts, oscorrory by-products, wastes, resideal s - t rn:l:s:nine; n . b. Any and til hospital pets;:;:.- -1 where Plaintiffs have been confined for trsatoerA* relating tv< heir exposure to pefsndarts1 products in Vietnam. c. Any end all persons with IcRcwicdc'e of the sconanic losses, psydiologicel and.'':;::; intangible dotages sustained by your Plaintiffs as a result of their injuries and diseases result.!ig frerr. their exposure to bsferdants1 products in Vietnam. d. Any and all persons w i t i k\tv lodge cf the past, preserf. :nd/cu future economic lesser pour Plaintiffs 1. re or will sustain in the future ,-s a result cf their lost of wage comings and/or wages camir.g capacity resulting from th~ injuries and diseases mar'o the Lmsis t thin lawsv t which. were caused !tv '??air._: ffs exDC.:a\re to D efen d an h r ' oreduets in .ietnaro. .3080 U- Ju Un.-tanSutes Envtrormenral Protection A(ancv ' `irtjrcn O(v<ioomo;i{ st i id industrit'l Environment.-.i P.;Ladcratc-i y Cincinnici Oil 40268 I 7P*,P -f ->i- t-A A r^ . I-LAIMTI F" S GCVERUHENT CAUSATION WITf'SSSES D. D ian e Coui'tnoy ^ _ EI-, Washington, D-C. A.. !ih- fastaci m:d oxpert testiaony ia snii; C. Gen c.-Tal 1ventc ? rc - 1 S 61 : Any al knowl- d g cf th Lir..rory of h0 rb i cit!e sprayir.g in U.S. and aaroad; includi n ; , b ut no'- 1 i .'.ad C o , (1) ind ex p0 surna and c x p '. o s io . ; ( 2 ) r e g i ; t r a c 2-,4~D, 1,4,3-T r;i.:h th j D ripartine;: of '.ri- cultura and any othcr gr.vevnmcnt agencies Ir: a n y a n d / r r a l i c : t h De?avida *3 ; ? 981-prcse-. /.cy ^ c r u c l ha a:." ' gr o f t h h r e r e r y o f . . o r b i c i : - r r r r y i r g i n ...he U . 3 . and ...' r e c o ; ir .c i u .; i t b a r not l i m i t a i C o , ( 1 ) "4.7. v:.1 Cary ca 1 A3 eni: Grange ov.d rrrer pii v ; ,:ra1 ;.n iic::n:-u. ; (1) cfcaogaa In th i des V,,t U . S . gC73Vi:. ;cat enei L i' **., i n d diti. hno-rledge cf FI72.A , Fi-A, EPA, aad OSSMHAA;; ando ..1 t'.'.of; c 1 1n c v.s t r i a i a0 d he r 1 urne . c can: 0 ,4 ,5~ Y in i C U .b . and rb or.cT Sa A v . . : r . a n i b u p p lr.-a evitai Ansio Delencnnts intc rr03a >. crete- e: d incorporar rosee re: everr -r causar fon i r:: oz reo t any factus ... -7'- m a ti th sub; ce 01:-line' 1 fi"3 ' tc s . r r a e hed jf c: i. .. cu r- w h i c h th e s n 2d t0 crj_V Q hav c telare Hr.if.anri Hi.sic .h'^erse n t of E mpo0 suera :o 2 ,4--i>, 7-,4,5-T ano i errino and ; factral hciowletige i r s u p p o r t r 1: e r a r f . x p e : L. T e s t ime rsv 1) l ' e 3 i irne n y s c u . '.11 i n wi r." capacity. *\/ ri r ri ile t i s : TCi'D v. / i l ( n i no Uhi f . i *1/, # **\?*)r} 1 4 A 1 and related chloaophenols and i: r,ian riskassessment, regarding exposure, ncluding, but not limited to, one or more of the following subject areas: a) Chemistry/Biochemi3 try b) Manufacture and/or Product!- a c) Tor.icity d) Modes of daman Exposure c) Fat e n the Environment (Hu. cr :, Plants, An '.maIs) r) of Art/State of Medical .end Scientif i L erasure Plant Physiology/Studies .nimal Physiology/3t dies --ni u nudi aa g) id ami ology /Biostatistics 1) Plants, animals, humans 2 ) Cancer Epidemiology 3) Reproductive Epidemiology h` Adverse Health Effects 2) Yes, witness wil. . be asked opinions about both published and/or on-going studies. 4) Ye s, witness will be asked op inions about any studies or research witness has personally performed or actually participated in. 5) Yes, witness will be asked opinions about other governmental studies. 6) Yes, witness is expected to review the. followingd ocumenr. r. prior to giving testimony: See, EPA, Research and_Development ,__Hea 1th Assessment Document on Dioxins for the 0 ffice s_of A ir Quality , Plan ni tip, 'and "Standards, "^nfeparad by the Environment, al Criteria and Assessment Of fine, Cincinnati, Ohio 45243 ( July -'-981: Ja,njv W>--J (( SUlTI M-iBITAL ANSWER T ) INreRROGATORY NO. 19 Plaintiffs note preliminarily that the extant. Older on proiucing fact witnesses states that fact witnesses are not due until March 2. 1984. However, Plaintiffs may call one oi more of the following persons (c those from various categories listed belav) at time of trial to testify a.* to factual knowledge they ray have, including: 1. Ranch Hand Personnel: These persons will testify to t. air iarxtfLedgc of the Ranch Hand Operation., Ranch Handers* :,rposure to Agent Orange, ar.d/or kncw.ledgt relating to the sort : tenting, and iffects of Agent Grange on himsns. tersbers c:. tun IK S. Armed Forces: These persons may .entifv to the circrostanceo and conditions rurrounding the sp aying of Agent Crauge. 3. Perr.ci'is prerant an Vietnam during the exposure period i question 1961-1972, includ-ung, out not limited to, ail'tary and paramilitar1/ personnel of the U. 5., New Zealand a i Australia, who have icr.owledge of the spraying operatic? c of the herbicides, the exposure of the Plaintiffs' class, :he hazards accompanying any such exposure, the Plaintiffs themselvesr and the Defendant ccr.pany representatives present in "ietnam to oversee tlie deliveries and spray ng operations of the herbicides they manufactured. 4. Persons together wi' h their demonstrative and docisaentiry evidence who gave testimony (which will form tlie substance of their testimony herein) at the EPA Cancellation Hearincs of 2,4,5-T (1973-1980) "nde:; 7IFRA, including but not limited to: a. Dr. Rov Albert-b. Dr. K. Diane Courtney C . Robert K. Baughman. Ph.D. d. Dr. 01av Axelsen e. Dr. Renate Kimbrough f Dr. Dawn G. Goodman a . Dr. Kirk T. Kite'in h. Dr. Donald Thomas i. ry*-^ R?iner Krentzei-Boyrne j- Dr. 'rifctl'iew Meselcon, Hnrvax _Q.. i c n $ 4 ( f k. Major Alvin Young l . Dr. Rodney Eovey m. Kenneth V. Themein n. David T. Buzzelli o. Dr. Michael Gross p. Dr. Renee Stringham r. Dr. Van Miller 5_ Any current or previous employee, contractor, subcontr ictor, in-house or private consultant cf each of the Defendaj cs or any cther person who lias knowledge of the manufacturing processes, chemistry, occupational! exposure ant-/or to: icity of 2,/.~D and/or 2,4,5-T or related chlorcphenols; including, but mot liiruted to, laborers?. operators; supervisors; con-jract administrators; .uiality control personnel; engineers process, chemical, mechanical and/or safety). 6. current or previous employee, contractor, subcontractor, iu-bnuse or private consultant of each cf the Defendants or any otivr: perron who lias knowledge of the possible means of prigl-jL. .ic protection frem tho harards of dioxins1' exposure? i&riui but not 1ir.utec. '-o, laborarc, operators, supervisor:;, -rontraet adminirc.rators, quality con.trol personnel, engineers (process, chemical, niechanioal and/or safety) . 7. Any current or previous employee, contractor, subcontractorir>*house or private consultant of each of the Defendants or any other person who bus knowledge cf the means to warn those who might be exposed to use of the herbicides in question, particularly Agent Grange, including, but not limited ;-o, laborers, operators, supervisors, contract administrators, quality control personnel, engineers (process, chasical, mechanical and/or safety). 8. Any current or previous employee, contractor, subcontractor, in-house or private consultant of each of the Defendants or any other person who has factual knowledge of any other manufacturing processes which could reduce the risks of exposure to Agent Orange and/or other phenoxy herbicides being contaminated with dioxins and further reduce the rink and hazard to human health of any such'exposure. 9. Any current or previous snployee, contractor, subcontractor, in-house or private consultant of each of the Defendants or any other person who has factual knowledge of conspiratorial conduct of the Defendants, individually and/-;:; duplicative efforts (acts which are parallel in native) which tended to or did in fact, result in misleading the public and the united States government from gaining knowledge cf the dangers attendant from exposure to Agent Grange and other phenoxy herbicides. -3.0- $ f* l 5*J 10. Any current or previous enployeo, contractor, subcontractor, in-house or private consultant of each of the Defendant:.'; or any oLuar person ulio has factual knowledge of how diox.vs work upon plants, animals, and/or humans. 11. Any current or previous employee, contractor, subcontraccc.:, int-touse or private consultant of each of the Defendants or fiwf other person who has factual knowledge of any statistics concerning the effects of dioxins upon plants, animal's, and/or InfflmaBis- 12. toy current or previous c.nployea, crntrr.otor, subcontactor, irHhcuse or private c r.nsultant of each of the Defendants or any other person ,,nciuding. but net limited to, members of EPA and other governmental agencies, wiio has factual knowledge of the following incidents: a. Love Canal b,, Times Beach, Missouri c. Sevesco, Italv d. BASF (1953, i.,54 - Badisch a in Germany) e. Production mishap:, and/or explosion:; since 1925 at any c.I the plants of any :.f the Defendants manufacturing, TCP, 2,4-D, 24, 5--T phenol., chlorine, acetic acid, benzene, sodium hydroxide- potassium hydroxide, and/or Agent Orange, including mishaps in the packaging, and transporting of the Defendants' product.; to the U. S. Armed Forces bases for eventual shipment to Vietnam. f. Spraying of Vietnam from 196]-1972. 13. Any current or previous employee, contractor, subcontractor,, in-house or private consultant of each of the Defendants or any other person who has factual knowledge of any surveys, tests, epidemiological studies of any kind relating to the effects of exposure to Agent Orange, 2,4-D, 2,4,5-T or any constituent thereof including the :.ccondaxy by-product known as dioxins. 14. Any person with factual knowledge of how decisions are made within the United States government, particularly the decision to use and to continue to use phenoxy herbicides in Vietnam, particularly Agent Orange; any person with factual knowledge c p government prccursn&nt contracts and the invitation to bidders, particularly those persons who negotiated the government contracts for all phenoxy herbicicts (agents white, blue, purple, pink, green, orange I and 11} v;ith the individual, defendants repi.eser.fatives between 1961-1372. - 11- 13038 Anv person win i t'actua knowledge through a m surveys, tests, epidemiological studies or otherwise undertaken by. any stace government, any privy public or foreign corporation, the U. S. Congress or the government of ary nation concerning the chemical cavpcunds, 2,5-D, 2,4,5-T, dioxins, or related chloroyhenols relating to the creation of dioxins, the detection of dioxins, the dangers of dioxins' exposure, ard/cr the toxicity, carcinogenicity fetotoxicity, teratogenicity, acute arc/or chronic effects on plants, animals and the human population. Any and all parsons .listed in The Chemical Scythe by Alastair Siay, as having factual knowledge regarding 2,4,5--T, 2,4-0, and its contaminant dioxins. Ail worker compensation carriers for the Defendants and docu mentation of all occupational exposures filed since 1925 which evidence industrial injuries or diseases at the TCP, 2,4,5-T, 2.4- D, Phenol, packaging, and/or transy.oration plants of the Defendants. Any and all or rent or prior workers compensation claimants of the Defendants who claimed relevant occupational exposures and/or relevant occupational injuries .and/or diseases and/or symptoms the relevant plants listed in Answer to No. 19 (sub 17) above. Any tnd .11 tu'-irfce.vs <. the G. House of Representatives Caixnittee on Oversights Review of the EPA actions (19G3) and/c any person tcgather with flier: dccurrentary and demonstrative evidence giving testimony at said hearing (which will form the substance of their testimony heroin) cn the failure of the EPA to tak .prompt aui effective action to ban the production of 2.4- D , 2,4,5-T, and iis ccntaainant dioxins. Any and ail persons having knowledge of relevant facts regarding the financial status of the Defendants and their ability to respond in punitive damages, including, but not limited to, their past, present, and future profits and earnings in tile United States and abroad since 1925 through and including the present frcr.i die sale of the products made the basis of this lawsuit, i.e., 2.4- D, 2,4,5-T, ;-heroxy herbicides and the relevant herbicide market. Any and all persons having knowledge of relevant facts regarding the ownership interests cf the Defendants and tlseir ability to respond in punitive damages, including,but not limited to, defendants* domestic and foreign subsidiaries, joint venturers, licensing agreements, and/or cuter public or private corporations in the U. C. and abroad, in which these defendants own a subs'-uitial financi.a.l interest since 1925 through and includin.;: the present. \ 15. Any person with factual knowledge through any survc j , tests, epidfcmiological studies or otherwise undertaken by ry state government, any private public or foreign aoi.por.at , the U. S. Congress or the government of any nation concemi n 'the chemical compounds, 2,5-D, 2,4,5-T, dioxins, or related chi ohenols relating to the creation of dioxins, the detect.'tor dioxins, .the dangers of dioxins' exposure, and/or the toxicity, rcinogenicity fetotoxicity, teratogenicity, acute and/or droni. c fects on plants, animals and the human papulation. M. Any and all persons listed in The Chemical Scythe b; Alaetair Heyc as having factual knowledge regarding 2,4,5-T, -,4-0, and its contaminant dioxins. 17- M i worker' compensation carriers for the Defendants and documentation of all occupational exposures filed since 1925 which evidence industrial, injuries or diseases -.t the TCI-. 2,4,5-T, 2.1-D, Phenol, packaging, and/or trensporatien plan of the IDfefe. -'ants. 18. iliy and oil current or refor v;cri:ersconpenration claimants of the Defendants who claimed relevant occupational exposures and/or relevant occupational in1uric:.: and/or diseases er. './ :: symptoms a< the relevant plants listed in i.nswcv to Mo. 19 (sub 1.7) above. 19. Any and ail members of tine U. S. House c': Representatives Committee on Oversights Review of the EPA actions '(1S83) and/or a.ny person together with thoir documentary aid demonstrative evidence giving testimony at said hearing (v-nich will form the substance of their testimony heroin) on the failure of the ETA to take prompt and effective action to ban 'tine production of 2.4- D, 2,4,5-T, and its contaminant dioxins. 20. Any and all persans having knowledge of relevant facts regarding the financial status of the Defendants and their ability to respond is: punitive damages, including, but not limited to, their past, present, and future profits and earnings in the United State and abroad since 1.925 through and including the present fron the sale of the products made the basis of this lawsuit, i.e., 2.4- D, 2.4 ,5~T, pheiioxy herbicides and the relevant herbicide roarxet. 21. Any and all persons having knowledge of relevant facts regarding the ownership interests of the Defendants and thoir ability to respond in punitive damages, including, but not limited to, defendants' domestic and foreign subsidiaries, joint venturers, licensin'" agreements, and/or other public or private corporation in the n, 3. and abroad.. in which these defendants own - sub stantial ncnci.il interest since 1925 through and including the present. -12- :088 !' < 22. Any rid all persons listed by Plaintiffs' in both erf inal and mended! witness lists, as expert witness (medical, sc entific or cauisation) , goverriment witness, government causati witness, defiendamts' lanuloyees and/or related personi.el and/or any witnesses .DiifBSod by all Defendants, may be called it time of trial to jassent factual information as to any issue involved n this ca: 2. 23- fy and all members cf the scientific and/or medical -mnunity whan have knowLedge of relevant facts, including infer .tion cm any of 'due previous;// listed subjects in this Answer, including, bat not limited to: a. David Kriebel, Ph.D. Ib. Dr- AJLan Poland c_ Dr. Paul Goldmann, PAS? di. Dr- C. Kuppe e. Dr. OottuI, BASF f. Dr. E. e . McDonnell g- Dr. K. S. Khiera ir. Alvin Ain: i- Marilyn Fingorhut 24. Any and ill persons who have factual knowledge conce. Ing the individual representative Plaintiff's carnages, inciuc ng, be: not limited to, t! ; fcilc.;ing: a. Any and all medical persons vino have examined, observed, treated and/or tested the Plaintiffs' for injuries. diseases aod/or related physical and emotional conditions vn ch resulted from Plaintiffs1 exposure to Agent Orange, and/or phenoxy herbicides, their constituents.- secondary Ly-products, wastes, residuals and contaminants. b. Any and ail hospital personnel where Plaintiffs have been confined for treatment relating to 'there exposure to Defendant!' products in Vietnam. c. Any and all persons with knowledge of the economic losses, psychological and/or intangible damages sustained by your Plaintiffs as a result of their injuries and .diseases resulting from their exposure to Defendants' products .In Vietnam. d. Any and 11 personr with knowledge of the past, present and/or future economic losses your Plaintiffs have or will sustain in the future as ? result of their loss of wage earnings and/or wages earning capacity resulting from the injuries and disou.ses made the basis of this lawsuit which were caused by Plaintiffs exposure to Defendants' products in Vietnam. -.13- <^ LA Sf N T I F ? ' G O V E R N M E N T G A U G AT IOI? W I T N E L S E o A* Center fo hi sea:e Control ( CDC"> - Nat 1 Inst. 0ecu net S l e t y and Health, Cincinnati, Ohio ii He lib f'.ahi.a1 arc c::pert testimony is sought. c. Genera1 EV 'x: '* id: : Any f a c t u a l k n o j l c d ge c f t he h i s t o ry of herbieide spraying in U.S. i. '.> abr ,;a i in i l a d i n g , h a t n e t d i m i t e d to, \' ni ineu .::cpos-.res and exp lonions; (2) registrar ion 2- --D; .i,5-T with the Department -f Agri .cultura i any cuan" government agencies -.r. y un? / o r a l l c f t h e D e f e n d a n t s j 19 61 y :'r.e n t : ' 1 . ; t u a . '. k n o w l e d g e c f t h e h i s t o r y .. h : r b ' . .da : p r e y i n g i n t-i:- TJ . d . end e l r o a . ' . ; Ircdadi. but net U n i t e d to, (1) U-S . 11 .. . y 2 ' Apart .nngo and other pie .a _ iaide o lv. Ac"tt:' ) .changas in the .is;:ratio a rer.uirfauhs cf herbicides v;ifh 1.3. g -v . -1 ~.tand its agencies _neluding .ns-rdedge of .IPP.A, FIA,EPA, and QSKA; cud f.ay lactic Ipc cf industrial and other Vv.usr 'tpcj-iroc to 1, t-D, h. A, 5-T it the u.L. ;.n;' <?. 1 * S^o .'.aewer and Styplenentr.1 Answer cf Plaintiffs' to Cef end ant r 8 Interrogatory H e . 19 attached hcret' ai:f incorpcrated herein for all vu oses ..a : events o:. occurrences which rh causation witness as nay be expected to give cry factual infernatien they nay have regar f'.u sul'-'octo outlined iu said Answer. .iv.r.n Vi.:!'. Asses f;:.lvl;i: of ^:;:)r;:ro to 2,4-D, 2,t ,5-T an di. ;z M,,li,x..f C_il.-. -r. ti..-,jt... ,1. .-. knowledge in supper the -l r. pert 'lastimn-. t Testirvny it 'ught in witness : personal and offic capac*i'*v * ) Subiccv. Matt C:T A .4--: <n,4 ,5~T, TGDD s and di3 s; A.gent 0 I/11 so White, Dlue, Pink, Greer.: an;- | ftQ -J ,hfc-A*3-1 ".;v: :..1~r c>r1: :e li; tr rirj" Bia.r: r 1 c::pc : a. 3 ..acli;.:;; * r--" C . <>!' . PL0 the .... .te ..ci:.'. I i.,, '3.-.. '.lev. 13; c/\i /3' cir.vt. nr.:. -'-'i!. :d e.'.'.i both '.lb 3 . V.:; .r.. i. w :V .:< .rr... - u'. o .r pc jea !.y "i i . t: . v '__ 0 < . ..' : r :. c:... >; .;rv:r .r .r.'c -h the 3 1.. ; : i: i , v c. i .1::;.r rr :< re.:: o . : : ; : i e c e " t _ / i c , 3 -'. c l i r 7 I-' r t t i r ; ti .0 ; b o n r 0 d 'b ,r .:',i dn' ~'rio:r -.3. Crider: eri A c. j1L Q HU OQ &9 .XW .. > .\i* : if . . -- :. .'..:.:-,,,>i'; ;.ii;'^r ^'\';':..^,'I EPA, Research and Development*^Health and ^ Environmental\EiTiecti^ProEild^for; Te Penta,. f 03 ga C r i t e r i a ; add:;: Ohio 45248 cV * EPA, R e s - a r c h and; 0 ev.dl dpm ent-slfeabi^ Qua1i t y f C r& pei^^ nared- f ot . O f f i c e : o f `hie ie^ kRe gu la iiio n s a n d S t a n d a r d s ^ b j ^ t S d l 'E ^ / C r i t e r i a a n d A esessm entS .O f f I c e ,;, C i n c i Ohio A524S $ Ju ly - EPA, R e s e a r c h a n d D e v e l o p m e n t ^ D i o x i n s In c u s tria l Environmental Researi Ci.acinnat A c o p y o f t h e s e d o c u m e n t s i i; a t t a c \ 1' .jL'?PLMNTA7j ANSWER TO INTERROG ATORY No. 10 Plaintiffi'i notes preliminarily that. the extant Order on yrod icing feet witnesses states that fart witnesses are nc/.due unt-.il March 2, 1984. Towever, Plaintiffc nay call one or more of the following persons (or those freni various categories listed belo'-/) -siine of felci to testify as to JC.* rual kncxdedbe they may have, including: 1. Ranch Hand Personnel: Ttasa persons v.lll testify to their tern-ledge c.: he Rani:!' Hand ' aeration.- Ranch Handers' exposurc- to Agent Orange, ard/cr b*.sr.iici.e-e relating to the spray- .j. testing, and effects of Age:.:L*. Orange on 'vjniar.c. 2. Uzitoaxs of the S. fened f .rrces: These persons may testify to the circjrasfencfi3 and cerrfifeens s-rcroundmig tha spraying of Agent Grange.. 1. Persons present i . V5.at-'am dm..;t.g the eoeposure period in question 19CI-1?'/ i, incluiln-j, hut not liraited to, military and parami:J.tary rsonnel of Lha d., S., New Zealand and Australia,- who ha a icncv/ledge of the rpraying operations of the herb .das, the exposure of ;:-. Plaintiffs' class, the hazards nrpanyir.g ary such 33:00.jure,'the Plaintiffs' thcmsel and the Defend representatives present in Vietnam to oversee .die deliveries and spraying operations of tifa herbicides hav manufactured. bosons t-.c.other --/iti. -'.'sir dsoonstrative and documentary evidence v:hc gave iesiirmvy fehich will form the substance of their testimony herein? a.t ti:e ERA Cancellation Keatings of 2,4,5-Y /1 i960) unde;. EZRA, including but not limit -, to: a. -b. - c. d. e. f. <? ; .. '* hr. Roy Albert: Dr. Ih Piane Conrtnsv Robert K. Eauchman, Fh.h. *ry.- Glav Axelson Dr. Per.Ate Ki-rbrough Dr. Dawn G. Gcodia?1n Kirc T. Kitchin Ujlc Ronald Thecas Or. Reiner F::enf.zel-Eavrae L::. Matthew Merelson. Man; 1 O O 94 0- 3 10. Any current. or previous employee, contractor, subcontra .-tor, in-housc. or private consultant of each of the Defendant ? or any other parson vho lias factual knowledge of hot/ cl"'o:a is work upon plants, animals, and/or humans. 11. Any currant or previous emp. oyee, cortractur, cuboontrc itor, r( Mi I li Hi i Vi ill iM"Ii 1 i I i ii i1 iiH iii m i i | >i 1. i 11., , '.iliiMiMim , i-4lit i 1i<i'M-ii , 1M 'll , |.U ' W i ' l . .11 . .||| I , m i l l cji. lil li.i IItll/liliUuiii M In' iM.y obhM .-n.,>1V'UU;; li. l i UHO-/J I 1, 11 j n, processes, ilicm.'* --,Vr .cuupational otpcsuxe and/or tonicity .jJ ?,4-D ard/cr 2 ,4,f-T ir related ohl/ccphenols? including, but not limits.;! to, :s;, operatore; supervisors? con-tract administratorsr eg1all' -ccutrc-i personnel? engineers (process, chfipical ::zzhzi.ii; al , id/ . safety). liny current or previous ercicyea, contractor, subcontractor, in-horse or private consultant of each of the Defendants or any other parser, vi o has knowledge of the possible means of prcpblaecic protection from the l-.a2 .ards of dioxins' exposure? including, but net limited to, laborers, operators, supervisors, contract adrrnisfcratcrs, quality control personnel, engineers (process, chemical, mechanical and/cr safety). r: current cr previous employee, contractor, subcontractor, in--house or private consultant of each of the Defendants or any other perron -/ho has knowledge of die means to w a m there who. migb-: be expreed to use cf the herbicides in question, nertievlari'*Agent Orange, including, but not limited to, r , o. >s>,.-il,f j r M! , ent|^*r-vi r;n r r , , rv ilv .'tu s li ultvi-i.slJLriI- 1'ilfc m ' , q-'-uliir; control personnel, engin<. jtu (process, chemical, mechr.i-d.cai and/or safety). Any currant cr previous eiployee, contractor, subcontractor, .i.rt-hau.ee or private consultant of each of the Defendants or any other person ho has factual inowiedge of any other manufacturi.' pirocesses which ci-uid reduce the risks of exposure to Agent Orange and/or other phc..ioxy herbicides being contaminated with dioxins end further reduce the- risk and lr.uard to human health of :iy su exoosure. ISC Inv OUTV'+" 0*- ^ 15.. Any p erso n w ith f a c t u a l know ledge idirough a n y c u r e p i le m io lcg ica l stu d io s o r o th erw ise undertaken h governm ent, any p r iv a t e pu.bl.ic o r fo r e ig n cr. p o rt C o n g re ss o r tins governm ent o f .any n a t io n c o u e e m i. compounds, 2 ,5 -D , 2 , 4 , 5 - T , d io x in s , o r r e la t e d civ re la tin g to the c re a tio n o f d io x in s , the cietectio : d a rg e rt o f dioK ir.s* ex p o su re, a n d /cr th e t o x ic it y fe t o t o .;ic ii:y , te rcto g e - i c i l y , a cu te an d /o r chroni* p l a n t s , anima.'.a and t h e human p o p u ..a tio n . ys, t e s t s , any sta te or., th e U i S. t h e c l lent,c a l ro nheno lr o f d i o x in s , tine ca rcin o g e n icity , effe cts .;i 16 A n y and a l l p e r s o n s l i s t e d i n T h e C h e m ic a l S c y t h e y A l a s t a i r . H e r / , 3 h a v in g . f a c t u a l Jcncfr.'l&dcfe r e g a r d i n g 2 , 4 . ! ; ' 2,4-D , did i t s contam inant d ie i n s . V ) . A3; worJ. e - e x : , 'i >--i f v it' c : r ! r r ^ ,>'! t' - r>*,]v-v,xlartf .i'Ciital.j/.,;*. o f ii. - . j . ^.oci.v'V'. - torso.. . .pobi .ccc f l l c a s i n nun p -ctv 1925 w hich e v id e n c e indu;c t r ia r in g .ries o r d is e a s e s a t th e T. : 2 ; 4 , 5 -T , 2 ,4 -D , Phenol , p u ck a g i: y. a n d /cr tra :isg o ra tio n p ic. .cs o f th e D efen d an ts. 1 8 . Ar.y r d a l l o r u r d o r ...ic>: w orJur.'s c c r t o a i s h t i a n ..a r n n n t s .!: ' he b rid a n t:r. who c d :.' cd r e l a v a n t o c c u p a t i o n a l e X ) c u r e s .. i f 1 r e l e v a n t '.c..;.!, ja t io * ,1 : r u r i c r a r c , ' o r d i s e a s e s a ru j f symptoms thr- ; - r y e v e n t '-," - >.,. ' .*,, d .in A n s w - r ) U o . 19 (s*. 1 7 ) a b o v e . 19 Airy an d a l l. mambo.rs o f t h e . S . H-.uea c f For :r e s e n t , t f i v e s u rrm itro e on O v e rs ig h ts R eview o f t i n EFA n o tio n s 11933} an d /o r any person to g e th e r w ith th e: r docum entary and d c .r n s t r a t iv e e v id e n c e g l.v.'n g L e r .t i:;o n y a t s a i d h e a rin g * (w liic h w i l l fo rm t h e s u b s t a n c e ci f t h e i r t e s t im o n y h e r e in ) or. t h e f a i l u r o f t h e r to tak a prompt and a f f e c t iv ^ a c tio n to ban th e prer a ctio n o f 2 ,4 -D , 7 :,4 .5 -T , and i t s contam inant d io x in s . 2 0 . Any and. a l l p e r r o n s h r-.'irj k n o w le d g e o f r e l e v a n t i a c t s r e g a r d i n g th e f in a n c ia l s ta tu s o f th e D efendants and t h e ir a b i l i t y to respond in p u n itiv o damages, in c lu d in g , but n o t lim it e d to , t h e ir p ast., p re s e n t, and fu tu re p r o f it s and e a rn in g s in th e U n ite d S ta te s nd a b ro a d s i n c e 1925 th r o u g h an d i n c l u d i n g t h e p r e s e n t fro m th e s o le o f th e p ro d u cts made th e b a s is o f t h i s la w s u it , i . e . , 2 ,4 -D , 2 , 4 ,5 -T , phenoy* h e rb ic id e s and tiia re le v a n t h e rb ic id e m arket- 2 1 . Any and a l l p e rso n s h a v in g Icnowledge o f r e le v a n t f a c t s re g a rd in g th e o w nersh ip in t e r e s t s o f th e D efen d an ts and t h e i r s'- i i i t y to respond in p u n itiv e damages, in c lu d in g , but not lim it e d to , d e f e n d a n t s 1 d an .-.otic and. f o r e ig n s u b s i d i a r i e s , j o i n t v e n t u r e r : : , lic e n sin g agreem ents, and/or o th e r p u b lic o r p riv a te co rp o ra tio n s .'n t i. s . and .-broad, in 'which t h e s e d e fe n d a n ts own a su b stan t.-..ai f i n a n c i a l i n t e r e s t s in c e 1925. th ro u g h and in c l u d in g th e p re se n t. *3ft t Ui0 y /TV 22. Any and ail persons listed by Plaintiffs' in both original av.d amended witness lists, as escort witness (medical, scientific or causation) , government witness, government causation witness, defendants' employees and/or related personnel and/or any vlhncsses listed by all Defendants, may be called at time of trial to present factual inCotraafcicn as to any issue involved in this case. 23. Any and all members of die scientific and/or medical cartunity oho have knowledge of reliant, facts, including information cn aiy*of /he previously 1.later' subjects but net limited to: David Kriebel, Ph.IJ. b. Dr. Alan Pcrend c.. Dr. Paul Gcldmanr., EAtf d. Dr. C. Rar-po e. Dr. Oettal, FA2? f. Dr. E. E.. MoDc:.nol.l gu- Dr. K. S. Alvin P Khiora j Mar:ilyu Pingerhut At:Y anf3 all persons wiio 1- r> factual irtc individuel representative Plaintiff's -la. r limited to, the folic/,-:Lng: a. Any end all medical persens who have treated and/or tested tee Plaintiffs' for injuries, diseases and./cr related physical arc scestional tiers which resulted freer. Plaintiffs' errpesure to Agent Orange, and/c phenoxy herbicides, their constituents, secondary by-products, wastes,- residuals and. co-:hrnirs.:-::3. b. Any and all hospital personr el where Plaintiffs have been confined for 'treatment relating to their exposure to Defendants' products in Vietnam. c. Any and all persons with knowledge of the eccnanic losses, psychological and/or intangible damages sustained by your Plai-ntiffs as a result of their injuries and diseases resulting from tl.eir exposure to Defendants' products in Vietnam. d. Any and all perrons -with knowledge of the past, present and/or future economic losses your Plaintiffs have or will sustain in the future as r. result of their loss of wage earnings ana or wages earning capacity resulting from the injuries and diseases made the basis of this lawsuit vbich were caused by Plaintiffs exposure to Defendants' product,s in Vietnam. Oi,fUf >7 -13- g . Any end all persons with krewledge of pact, present nd/or future reasonable and necessary costs of doctors, hospitals, nursery care, medical equipment, drugs, and any other related medical services rendered or to he rendered in the future to Plaintiffs as a result of their injuries aid disease resisting from their exposure to Defendants1 products in Vietnam. fey and all persons with knowledge of the physical i'isfinurement (past and present), ph.ysical and mritai rrrpairmint (past and present), physical pain (past and present) art* mental anguish (pest an present) which Plaintiffs have sustained as a result ci their e:qposure to Defendants * products in `'letnam and which in reasonable probability Plaintiffs will continue to oust:'.in for an indefinite time into the future far beyond the date of inis trial. respect!rily submitted, 1r.c.t.to lv. Henderson, Esquire Allison Pettiette. Esquire iEErlFIOVLE 0? SEhvtAi hereby certify that a true or.d correct copy of the foregoing Supylsnert to Plaintiff's interrogatories were mailed Federal Express to hr. Wii.-iun Krohley, Kelley, D::yc & Warner., ifr. Gene Locks, Plaintiffs1 Haragement Ccexr.ittse Agent Orange Office, wuth copies to personally serve the remaining Defendants at the vir.esday depositions and Ms. Nancy Petrillr., j.f. District Clerk, tf.S. Courtitou.ee, 225 Cadmun Plaza, Brooklyn, New York 11201 :iis 2u'di day of February, ISC i. ^) i :Alison Pettiette l.i:> 1 C n CJg A PhAINT ZFF 1S GOVERNMENT CAUSATITI! WITNESSES I Donald Earne3 A . _____ EPA a U n . si h .1ngt on , D . l - . B. Beth factual and expert testimony is sought. C. General Events Fre-lDl: Any factual knowledge of the history herbicidc spraying in U.S . and abroad including, but not limited to, C D indust:-; exposures and explosions; (2) registration 2,4-L, 2,4,5-T with the Department of Agri culture and any other government agencies any and/or all of the Defendants; 13 Si-present: Any factual knowledge of the history o herbicide spraying ir. the U .S . and abr.au; including, but not limited to, (1) U.S. military use of Agent Orange and other pie herbicides i- Vietnam; ( 2 ) changes in f. e gi3traticn requirements of herbicides w t i U.S. government and its agencies including knowledge of FIFEA, FDA.EPA, and 0S1IA; and an}- knowledge industrial and other hum a: exposures to 2,4-h, 2,4,5-T in the U.S. an- a r oae ; See Answer and Supplemental Answer of Plaintiffs' im Tea end ant s ' Interrogatory No. 19 at-fached he-.etc and incorporated herein for all pur poses j o : o v a ::.cs c.r occurrences which ther causation witner ico may be expected to givo any factual information they may have regar the subjects outlined in said Answer. Human disk Assessment of Exposure to 2,4-D, 2,4,5-T at dioxins and any factual knowledge ir supper thereof. Et ' err: T estim o n y 1; Tes t i r any in sough:; in witr.LSs 1 p e r s o n a l and o f f i rap ac i t y . 2) Subject Matter -',4-^, 2 ,',5-T , TCnr,'s nnd dioxins; Agc-c 0 L / 1 7 (a-.ro Whitt, Blue, Pink, Greta, and Pu 1ST - fz y and related chloroplienols and human risk assessment regarding exposure, including, but not limited to, one or more of the following sub set areas: a) Chora .stry, Biochemistry b' l-ieuufactvre and/or 'Production c) Toxicity d) Modes of Human Exposure e) Fate in the Environment (Humans, Plants, Animals) f) .State of Art/State of Medical and Gcienti literature 2} Plant Physiology/Studies 1} Animal Physiology/Studios 20 Er.m.tn Stedies g) Epidemiol"gy/Brostatisties 1 ) rlento, animals, humans 1, Cancer II idemiolog-; 3) Reproductive Epidemiology h) Adverse Health Eff :cts wi tn soc w i11 be aske.d opinions about both published and /o ou- going studies. wi tne: will bo asked opinions about any studie or rosearch w itn es s has personally performs d or r. ctuclly pert 'tip cted in. w i . less will 2' asked opinions about other governmental studies. witness i a expected to review the following documents prior to giving testimony: Coe, ETA, Jleccaroh ad Development , Ur.al*h )iox ir.s for tv: -Lr'IS. r A-ir'0u ..lity , Planning 'and. "Ctanl.ar_?r D f e r e d b the Env i.5. ?.na L r.ces sm Office, 9 > 4524o ( July i 4 X O o 101 EPA, Research and development, il alti; arici Environmental Effects 1' le for; Tot Penta, and Hexaclilorodi je.izo-p-dio/.ins for the Office of Eolio Waste and Emer gency Response, by the En .irontieV tai Criteria and Assessment C .'fice, Cincin Ohio 45248 (June 1983). copy of th EPA, Research and Development, /..'.bient Water Quality Criteria for 2,3 ,3 TODD, pre pared for Office of Watc Regu Ratio-.s and Standards, by the Er .rnnen: to *. Criteria and Assessment Tice, Cincin Ohio 4524C (July 1933) . T7 Ressacch and Development, eicxins, Inclusi ial Environmental Research Cr.sir.ncti , Ohio (19 78). dnenroontr ?.s n t t n ah ad . 1S102 c ^ <A SPPLBMflTAL ANSWER 'Ll. IfJTFJ&.''Utf iVl. y Plaintiffs note preihoinorily that the extant Order on -ing fact witnesses states that fact witnesses are not due until Marcl 984. However, Plaintiffs may call cne or more of the following person; L-nose from vario'as categories listed below) at time of trial to testify :o factual knowledge they may have, including: 1. Ranch Hand Personnel: These persons will testify t newLedge of the Ranch Hand Operation, Ranch Hander to Agent Orange, and/or knowledge relating to the s testing, and effects of ..gent Grange on '-mans. :i.: eposure Lng, Members of the U, 3. Armed 'Force::: These persons m to the circumstances and cj/vdiiious sv.nroundiiig the of Agent Orange. estify eying Persons present in Vietr.en. dr.rrhvg 'the exposure peri' question 1961- 1972, including, but not limited to, rr and paramilitary personnel of the U. 3., New Zealand Australia, who have. Jmcviedce of the spraying eparat. the herbicides, the exposure of the Plaintiffs* clac; hazards accompanying any such exposure, tha Plainti,f hhsinselves, and the Defendant company representative: present in Vietnam to oversee tha deliveries and spr; operation:, of the herbicides they manufactured. i -.ary 1 : of die a 4., Persons t gather wit a their demonstrative and docunsr evidence who gave testimony (which vri.ll f o m the sub; of their testimony herein) at the E?A Cancellation Hr of 2,4,S-T (1979-19C0.' under FIFRA, including but not to: V .r.gs miteel a. Dr. Roy Albert; - b. Dr. R. Diane Courtney _ c. Rober ;K. Baughman, Ph.D. d. Dr. Oiav AxeIson ... br. Renate Kirnt..ough f . Dr. Dorn G. Goodman vu Dr. Kirk T. Kitcbin I*. Dr. Ronald Themas i. Dr, Rairox Frentzel-Rayma j . Dr. Matt haw Meaelr.cn, Harvard 0! -9. \/ \ r k. Major Alvin Young 1. Dr. Rodney Bovoy m. Kenneth V. T'nemein n. David T. Buzzelli o. Dr. Michael Gross P- Dr. Reneo Stringha.1 Dr. Van M i l e r 5. Any current or previous employee, contractor, cut- in-house or private consultant of each of tie Def` any other pe"son who has laicwledge of the manufac processes, chemistry, occupational exposure and/o: 2,4-D and/or 2,4,5-T or related chlorophenols; ii not limited to, Laborers?. operators; supervisors; administrators? quality corrrcl personnel; engine* chemical, mechanical and/or safetv) . rotor, rs or 1 icitv of unci, hut cract process, 6. Any current or previous employee, contractor, sutr in-house or private consultant cf each of 'the Defi any other parse a who lias kjiawied.:.? of the possibl psrep&actic protection froa tie hazards of dioxin: including, hut net limited tc, laborarc, perator: contract: adnmiistratcrs, qualify control parc o m e (process, chemical, mairinical ard/cr safety', . -actor, its or ns cf assure; parvisers, .jsneers 7. Any currant or previous siployee, contractor, subcc in-house or private consultant of each of the Defe: any other parson who has iunowledgc of the means to who might bs exposed to use of the herbicides in qi particularly Agent Orange, including, tut net limit laborers, operators, supervisors, contract adarinisi quality control personnel, engineers (process, chc mechanical and/or safety;. -actor, as or :i those ion, to, ;rs, 8 Any ciorrent or previous employee, contractor, subcc uc or. in-house or private consultant of each of the Defer any ether person who has factual knowledge of any c manufacturing processes which could reduce the risk >f expose; to Agent Orange and/or other phenoxv herbicides bei contaminated with dioxins and further reduce the risk and hazard human health of any such exposure. 9. Any current or previous employee, contractor, subcc. `ciC'COiT; in-house or private consultant of each of the Defer* .ts or any o-iie?- person who has factual Jcncwledge of cent; .-irate ai conduct cf the Defendants, individually and/or drolicatrve : arts (acts whi.ch are parallel in. nature) which tended to or die n fact result in misleading the; public and the United Dtatr Tovemment fre.n gaining knowledge of the dangers' attendant fra. rcosure to Agent Orange and other phenoxy herbicides. <31 A. ^ 0 4 -L0- 'Irs; r Any current or previous employee, contractor, s'abcontractor, in-house or private consultant of each of the Defendants or arty other person who has factual knowledge of how dioxins work upon plants, animals, and/or humans. Any current or previous employee, contractor, subcontract o r , in-house or private consultant of each of the Deft \dants or ear other person who has factoal knowledge of any static ics concerning the effects of dioxins upon plants , animal's, .id/or numans. Any current or previous ernpiovea, contractor, su.bcontactor, in-house or private consultar of each of the Defendant? or any other person including, but . c limited to, ma;ibers of .2PA and other governmental agencies, who has factual knowledge of the following incidents: a. Love Canal b. Times Beach, iMissouii c. Sevesco, Italy BASF {1551, l.) 1 - DadiscliC: in derrnany) o Product.' tn .iisbans and/or explosions since 1925 at ary of tils pLv .to of ary c:i the Defendants manufacturing, TC". 2,4~D, 2,4,5-? phenol, chlorine, acetic acid, benzene, sodium hydroxide, .potassium 1.ydrc3d.de, and/or Agent Orange, including mishaps in the packagilrg, and transporting of the Defendants5 products to the U. S. Armed. Forces bases for eventual, shipment to Vietnam. Spraying of Vietnam frcr.i 1961-1972. Any current or previous employee, contractor, subcontractor, in-home cr private consultant of each of the Defendants or any other person rhc has factual knowledge of any surveys, tests, epidemiological studies of any kind relating to the effects of exposure to Agent Grange, 2,4-D, 2,4,5-T cr any constituent thereof including -the secondary by-prcduct known as dioxins. Ary person with factual knowledge of hew decisions are made within the United States government, particularly the decision to use and to continue to use phenoxy herbicides in Vietnam, particularly agent Grange; any person with, factual knowledge of government procurement co: bracts and tlr. invitation to bidder?:, particularly those persons who negotiated tine government contracts for all phenoxy herbicio'..: {agents white, blue, :uirplr, pin!;, green, orange I and II' with the individual defendants repre sentatives between 1961-1972. -11- fo * Jl^ JL 22 . Any and all persons listed by Plaintiffs' in both original and amended witness lists, as expert witness (metical, scientific or causation) , government witness, government causation witness, defendants; employees and/or related personr l and/or any witnesse listed by all Defendants, may L.e called at time of trial to present factual information as to any issue involved in this care. ;3. toy and all members of the scientific and/or medical conmunity wiio iiave knowledge of relevant facts, including information on any of the previously 1. sted subjects in this Answer, including buiL no't limited to: a. David Kriebsi, Ph.D. b. Dr. Alan Po..me c. Dr. Pau.' Goldnsito., BASF d. Dr. C. huppe e. Dr. Oettel, EfiSF Xc. Dr. B. S. McDonnell g- Dr. K . C . Khiere h. Alv.in Ain i. Marilyn Fingerhut 24. Any and all percent w h h a v e iactu; 1 Icnowledge.concerning the individual representative P.l.\intif: 's damages, including, out ( not limited to, die following: a. Any and oil mditai persons who nave examined, observed, treattd ard/or tasted the Plaintiffs' for injuries, diseases and/or related physical and emotional conditions which resulted from Plaintiffs"' exposure to Agent Orange, and/or phanoxy herbicides, their constituents, secondary by-products, wastes, residuals and cor-tsininants. b. Any and air hospital personnel where Plaintiffs have been confined for treatment relating to their exposure to Defendants products in Vietnam. c. Any and all persons with hxcwledge of the economic losses, psychological and/or intangible damages sustained by your Plaintiffs as : iasu.lt of their injuries and diseases resui from, their e:qposure tc Defendants' products in Vietnam. d. t o y and all persons with, knowledge of the past, present and /-sy- future scenario losses your Plaintiffs have or will sustain in the future m a result of. their loss of wage earnings and./or* wages earning capacity resulting from the injuries and dice, made the basis cf thi:: lawsuit which were caused by Plaint! y.i eoxesura to Defendants' products in Vietnam. 13106 -13- r e. Any and ail persons with iuiowledge of past prand/or future reasonable and necessary cos' s o doctors, hospitals, nursery care, medical 'jui drugs, and any c ther related medical serv. ;s or to La rendered in the future to Plaint: _.is result of their injuries and disease resulting their exposure to Defendants1 products in Viet f. Any and ail persons with knowledge of the pays, disfigurement (past and present), physical and impairment (past and present;, physical p .in ( present) and mental anguish (past and present) Plaintiffs have sustained as a result of their to Defendants' products in Vietnam and which i: reasonable probability Plaintiffs will continue sustain for an indefinite time into the fnoire beyond the date of this trial. red t al and .h jsure Respectfully sv ted, To m a s Vi. Hende:: n, Esquire Allison Pettiett Esquire CERTIFICATE OF SERVICE I hereby certify that a true and correct copy of the re ring Supplement to Plaintiff he Interrogatories were mailed Federal E ess to Mr. William Krchiey, Kell. '/, Drye & Warren, Mr. Gene locks, Pia. :iff.- ' Imagement Ccranittes Agor t Orange Office, with ropiv..3 to persona ,.y serve the remai'ling Defendants at the Tuesday depositions end Ms. Nane PctrilL: TJ.S. District Clerk, U.S. Courthouse, 225 Cabman Plaza, Brooklyn New York 11201 this 20tli day of February, 1904 Allison Pettiette 13107 -14- ' 'v/fcvM: r v?v i*=0'TB8N `:;vtronm. :tii Pm^jcfion iqcncv ?tS-ir:fiA "pee*. a * 10X3J1 usinai rl'V/ironiMenia! r!n ).-.rniorv OH *'5? <* 1 J / N * .<0 , PLAINTIFF'S Gt'VERNMJiK" CAUSATION WITNESSES I Umberto Saffiotti National Cancar Institute, Washington, D.C. B. Both factual and expert testimony is sought. C. General Event.; Pro-1961: Any factual knowledge of the history of herbicide spraying in U.S. and abroad; including, but not United to, (1) industrial exposures and explosions; (2 ) registration oi 2,4-D, 2,4,5"? with the Department of Agri culture end any other government agencies by any and/cr all of the Defendants; 19C1-; .asent: ..my fat tuc?. knowledge of the history of herbicide -ryraying in the U.S. and abro;-. 1; including. Luc tot limited to : (!) U.S. military vis ' of Agent Orange and ether when herbicides in Vietnam; 2*. changes ia the r ._ gist-ration requirements of herbicides with the U.S. government and it a agencies including knowledge of FIFRA, VDA, EPA, and OSHA; and (.3) any knowledge f industrial and other human exposures t ; 2,4-D, 2,4,5-T in the U.S. end abree ; See Answer and Supplemental Answer of Plaintiffs' t o Defendants' Interrogatory No. 19 attached hereto ._nd incorporated herein for all pur poses re: events or occurrences which these causation witnesses may be expected to give any factual information they may have regarding the cub;] secs outlined in said Answer. I nan Risk Assessment of Exposure to 2,4-D, 2,4,5-7 and dioxinr, and any factual knowledge in support thereoi. D. Expert Testimony 1.) Testimony is sought in wit no o s ' personal and official opacity. 2) Subject M a t c.:: , 2,4-D, 2,4,:"-?, TCDD's and dioxins; Agent Crang I/II (also White, Blue, Pink, Green, an. Purple 13109 \v:*- V*. .A., I! .<** t. and related chlorophenole and huaan risk assessment regarding exposure, including, but not Unit ed to, one cr more of the following subject areas: a) Chemistry ''Biochemistry b Manufacture and/or Productitm '/ Toxicity A) Modes of Human Exposure e} i?ace in the Environment (Humans. Plants, Animals) r\ State of Art/State of Medical and Sclent if Literature 1) Plant Physiology/Studies 2) inAn.a! Physiology/Studies 3; Hu an b::abios Epidemiology /Bis atati stics 3.) Plants, ani: sis, humane 2) Cancer Epidemiology 1) Reproductive Epidemiology Adverse Health Affects / 3) "os, witness will be ashed opinions about both published and/or on-going studies. ') Yes, witness will be asked opinions-about any studio; or research witness '.'.as porsrnally pa rformod or actually participated in. 5) Yes, witness will be asked opinions about other go'.'ernmeutcl studi 6) Yes, witness is expected to review the following documents prior to giving testimony^ See, EPA, Research and Development, Health Assessment Document on- 'Dio>rins for the Offices of Air Duality, Planning `and iiandcirdr. ,'*r"pVeparePby the Environmental Criteria and As sensei Office, Cincinnati, Ohio 45248 ( j-.-.lv -- 10 -; V #1 },:-i ~ / T \ v , EPA Research and Development, Health and Environmental Effects Profile for; Tet Renta, and .Ucxacli `orodibenzo-p-dioxins for the Office of Solid Waste and Ever gency Response, by the Environmental Criteria and Assessment Office, Cincin Ohio 45248 (June. 1983). Research and Development, Ambient Water Quality Criteria for 2,3,7,3 TCiiD, are pared for Office of Water Regulations and Standards, by the Environmental Criteria and Assessment Office, Cincir. Ohio A5248 (July 1583). iZPAj Research and Development, Dioxi. s , lad \strial Duvironr-antal Research Cincinnati, Ohio (1573). A copy o f throe documents is attached. ... * >A "-r.-y Wi- .r ;'.Air-Vv, ':-:i i.Z'A ,jt \,:yr: SUPPLEMENTS!- ANSWER TO DTrERTOGATORY KO. IS Plaintiffs note preliminarily th-.t the extant Order cn producing fact witnesses states diet fact witnesses are not due ur.til Ms :ch 2, 1984. However, Plaintiffs may call one or more of the following parsons (or there frou varieus categories listed ixow) at time of trial to testify as to factual -knewiadge they may have, including: 1. Ranch Hand Personnel: Tiieta persons will testify to their knowledge of the Ranch K a m Operation, Rancii Harders* exposure to Agent Orange, and/or knowledge relating to the spraying, testing, and effects of Agent Orange on humane, 2 Marker.' of the G, S. A:med heroes; These persons may testify ho the circumstances and conditions surrounding tiie spraying of Agent Orange. 3. Person:; prenant in Vietnam daring tire exposure period in question 1S61-1D72, including, but rut limited to, military and paramilitary perr rnnel cf t::e U. S., New Zealand and Australia, who have jmowledgo cf the spraying operations of the herbicides, the exposure of tlie Plaintiffs` class, the hazards accompanying any such exposure, the Plaintiffs' themselves, and the tefendant cnmcrr.y representatives present in Vietnam to oversee the deliveries and spraying operations of the herbicides they manufactured. i. ::arsons together wit!-: their demonstrative and docunentary evidence who gave testimony (which will form the substance cf their testimony herein) at the EPA Cancellation Hearings o 2,4,5-T (1979-1980) under F1THA, including but not limited to: a. Dr. Roy Albert; i- 'v. Dr-. K . Diane Courtney _ c. Robert K. Baughman, Fh.D. d. Dr. Oiav Axeleon e. Dr. Reuate Kimbrough f D r . Dawn G. Goodman g. Dr. Kirk T. Kitchi.ii h. Dr. Ronald Thanos i. Dr. Rainer Prentzel-Beyma j. Dr. Matthew Pfccslson, Harvard .3 -9- 1K.- Major iJLvin Young 1. D r . Itocbiev Bcvey in. Kenneth V. Themein n. David T. ifazzelli o. Dr. Michael Gross p. Dr. Renee Stringiiam r. Dr. Van Miller o. Any current cr previous employee, contractor, subcontractor, in-house cr private consultant of each of" the Defendants or any other person who lias knowledge of the manufacturing processes, chem.ic._ry, occupational expo.sure and/or toxi ity of 2,4~D and/or 2,4,5-T or related chlorcphenols; including, but not limited to, laborers?. operators; supervisors; contract administrators; quality control personnel; engineers {process, chemical, nscnanical and/or safety) . G. Any current cr previous employeef contractor, subcontractor, in-house or private consultant of each of the Defendants or any other person who has knowledge cf the possihf means of prephiaciis protection frem the hazards of exposure; includin';, ;.rt not limited to, laborers, operators, supervisor: contract administrators, quality control personnel, engineers (process, chemical, rechanical and/or safety). Any cur;.ant or previous employee, contractor, subcontractor, in-house or private consultant cf each of the Defendants or any other person who has knowledge of'the means to warn those wiio might he e:xo.?cc to use cf the herbicides in question, particularly Agent Orange, 'deluding, but not limited to, laborers, operators, supcrvr.scrs, contract administrators, quality control personnel, engineers (process, chemical, mechanical and/or safety}. 8. Any current or provi.u.s employe.';, contractor, subcontractor, irr-house or private consultant cf each of the Defendants or any other person who has factual Ijxwledge of any other manufacturing processes which could reduce the risks of exposure to Agent Orange and/or othr.r pher.oxy herbicides being contaminated with dioxins and further reduce the risk and hazard to human i valth of any such exposure., 9. Any current or previous employee, contractor, subcontractor, in-heuse or private consultant of each of the Defendants or any other person who has factual knowledge of conspiratorial conduct of the Defendants, individually and/or duplicative efforts (acts which ;-ro parallel in nature) which tended to or did in fact result In misleading the public and the United States government frezn gaining knew)edge of the dangers .attendant frem exposure to Agent Orange and other phenony herbicides. 13113 -10- 'r~^. 15. Any person with factual knowledge through any surveys., ter/ epidemiological studies or otherwise undertaken by any stato government, any private public or foreign oo. poration, the U. 5. Congress or the g. /eminent of any nation concerning the chemical compounds, 2,5-D, 2,4,5-T, dioxins, or related chlorcnhenols relating tc the creation of dioxins, the detection of dioxins, the dangers of dioxins* exposure, and/or tint's toxicity, carcinogenicity, fetctoxicity, teratcgcrdc.ity, acute and/or chronic effect./ on 10. fny current c..: previous erployco, contractor, sufcccntractor, inr-housa or private consultant of each of the Defendants or . any other person who has factual knowledge of how dic:cins work upon plants, animals, nd/or humane. 11. Any current or previous arnplcyea, contractor, subcontractor, in-house or private conruitant of each of the Defendants or any other person cho lias factual knowledge of any statistic/ concerning the effects of dioxins upon plants, animals, and/or humans... 12. Any current or previous cr"-loyea. contractor, suocontactor, in-licuse or private consultant o'- each of the Defendants or any other parser, inaiming, but not .inited tc, members of SPA and ot'or government.?r agencies v/h^ h?.r; factual knowledge of the a. Love tanal . fc. Times Beach, Missouri c. Sevesco, Italy d. BASF {1953, ?.954 Badir-;ha in Genrar. . v . Production rnisbarn ar.d/or explosions since 1925 at any of the plants of any cf the Defendants mam-factiiring, TCP, 2,4-D, 2,4,5-T phenol, chlorine, acetic .cid, ben2ena, sodium hydroxide, potassium hydroxide, and/or Agent Orar.ge, including mishaps ir. the packaging, and trar porting of the Defendants' products to tl:-i U. .c. Armed Faroe; bacon for eventual shipment to Vietnam. f. Spraying o.': Vietnam from 1SQ-1972. 13 Any current or previous onployee, contractor, svboor.tractor, in-hc'.ise cr private consultant of each of the Defendants or any other perron who has factual knowledge of any surveys, tests, epideadolcgical studies of any kind relating to the effects of exposure to Agent Orange, 2,4-D, 2,4,5-T or any constituent thereof including the secc./dary by-product known as dioxins. 14. Any parson with factual Imowlcdge cf how decisions are made id.thin the United States government, particularly the decision to use and to continue to use phenoxv herbicides ir Vietnam: o '<u> . : , ft ` 22. Any and all perse.is listed by Plaintiffs* in both original and amended witness lists, as expert witness (medical, scientific or causation), government witness, government causation witness, defendants1 employees and/or related personam . and/or any witnesses listed by all Defendants, may be called at tuna of trial to present factual information as to any issue involved in tliis case. 23. Any and all members of the scientific and/or medical carenuuity who have Imowledge of relevant facts,, including information on any f t h e previously listed subjects in this Answer, including, but not limited to: a. David Kriebel, Fh.D. b. Dr. Alan Poland c. Dr. Paul Goldmann, BASF d. 'Dr. C. Eappo e. Dr. Gettel, BASF f. Dr. E. E. McDonnell g. Dr. K. S. Khiera h. Alvin Aim i. Marilyn Fingeriet 24. Any and all persorn woo ha i f. ..rtu; 1 knowledge concerning the individual representative Plaintiff's carnages, including, but not limited to, the following: a. Any and all medical persons who have examined, observed, treated and/or tested the Plaintiffs' for injuries, diseases erd/or related physical and ecaticnai 'conditions which recited from Plaintiffs exposure to Agent Grange, and/or phenoxy herbicides, their constituents, secondary by-products, wastes,, residuals and contaminants. b. Any and all hospital personnel where Plaintiffs have been confined for treatment relating to their exposure to Defendants' products in Vietnan. c. Any 'and all terrors with knowledge of -the economic losses, psychological and/or intangible damages sustained by your Plaintiffs as a result of tlieir injuries and diseases resulting from their exposure to Defendants' products in Vietnam. d. Any and all persons with knowledge of the past, present and/or future economic losses your Plaintiffs have or will sustain in the future as a result of their loss of wage earnings ancl'or wages earning capacity resulting from tin injuries and diseases made the basin of this lawsuit which were caused by Plaintiffs exposure to Defendants' products in Vietnam. 'rv^ 1 -1 -13- yTJirp *fa Y Unitoci St.'tfii; Enviromnor.mi Protect: .1 A'jijncv Hccmrch & Doviiinamon; Industrial Environmental i:. Landratruy Cinc.r-n;.:i O H -JE2GS 'A i-Srf'-? S. 'V.^>:'V\^' ; ''ir'- *3*1' X. ""*t*-r1 ./VA. ,,^ /-'v \ j* i 1 /.1 Ji '% * ,V. `i !\ _^ ?^ ^ ' 1^ -* ^ jy * r ->W .>' \ ?\ *,'** V.. T. ''tip* Tf*\ r ;; W 13116 i alat.od c 1 e r api on o 3.s T.ti' yV:;on v in o.-Co.asmer.t ro.j-ar in e;:po :.\ire > i.uclv. JlV. noc 1luiic l o , o b o o Titor e o "-.i i~i i,'J.'.oraizg s a b \ och a r c a r : ; a ? Jlienin ir- /Eiachor.ir,trv liar.:: Jactrurc: a n d / o r t o::ci;-'T on ;cs jr .iv.ir. ati .. y.v c ~ :cc ae ir. iho Ji-.vircnacnC (i'asnar.s . ni.r'.lc) c1 :j .r.i/ .:1 c y,~^/eaj. v.r dlant rV.yciology/3tud:lcs i, jt.r. i. - , ?h*- o*a~ /tu. cs? o - `.Civl.oo iocop ll animis . hit- c 1/ :r.:;;c" :p asiioicgy 1. ..e 1:.- .lv\. 1.>ida1 .o..^C'/ Y :' . ;::*.: .1.1. ...* 'd i i: . h 'd ..h /:! v 1 /*'V OI. -o oa *<"-i';-tk "X y -p ; i ; oprnuons a vout "a ' 'a s e a :.- ,:, v ? neo o har; j a r s o n a . i l ~ j. x.. i. i;i ` -ten ed .va. . r; .ijJ be :pin lorie ; r:e~.".:1 strude-; . f. :ne: ..i r e ::e \-: o t i l a f c l l c v l : : ^ rj?T 77 'ZO ^ -'.I'. *11iJ\J.7tC..l"-- , hcs.'-.c.rch ord _ D a1optaant- 'lertl'd: A .i'r.c .t e i o a i - ic c .u r r . e n t - - o r 7) x o : : z n s o r r C lfrlc-cr;- o:'l__Air' d O -litiy -, T 3.a n .n l n y 'an " S E c . c T r . 'T d o ; p r e p a r a d b y " ...................... nhc Env: '.aerial Crteria and AoS'-.c <-'"icini. -.trO Ohio 4 5 2 id 1117 ? r. '. r y . v : i v . w r . i v :f i c v E : y : " i : n T ..,,n w ::t ; ; s s ^ s C c r.t av f o r D i s *;i. : C o n t r o .'. (CDC) A t l a n t a , Gi .3 . r... -. ot f 1'i y 1 o oou 'ro o cr*n . -11L 1*. 1 c Ar - ,-s * -*. e I: ii3 .0. i 1C r >;; ... j i " " no.i: in 0 .:;. liiuited ar d io , a ; * . .'m.aidl " V ' i o s i o n s ( ! .) r g i r .::: e t i o ; V 5- 11: t'io i;ej..a .: i<: . c Agr vu r . 1 \::y o.:ae:: gcvernr.cnr. 'r-?: icc s3ii ci thn Dfendant s ; '; ' .....)Vjlr g . ;:: r i;.::: y . 1 .b :'o a-d: ---; &: 0' oi .'.laite ; ;; - - y 1 .''l < .'.il V.e-'ir.;.-i ; (2 ) " ,!;:r.j,e s in. ch cl i_ _.OJ._ CS g v e r rnj r r . ; l ; , . ; L - -: l.IT A A , FDA , Z P.;'. , and CSHA ; o u i t r s* 7^ * r \ -* end a c h e r hur.ar.^ ' '*' l"5 ' * v * ^ i - TC ' c l " ir; !;ho U - ano ih::f;u *: .. ;o .r. .en. \fs '>" ..t-*-Tor-*-*-^ H ...V-L1im _ V/TJ 0S3 T ".U; :.ua 'ne - o j . ?.:1Ca. ,z.vi '.O. ..?.C^LJ.4t; i f f : 7 Ce i i0 -> J. . a 11 a c n e c r e i n f . a i l _ .1 r e n n e s o h i Cil Il t) Ct e d CG f; 'L' ny r.;ay iiav a. -c:z id A>.:.a e r . W ! }..:.r:le /. inr*.--.- Cf Er orra flrlcx: *.> < .11 7 .'.atv.a ;V' X*Clf)}T. /. ;. -Y-- U , --i. c/J. e d .9:c; i n c Eroert: Tosti:. . . La ji:' l*.!IXw. car oitr m e s a ' n n en -il and o ff ; ...." .., . . TC. i .:. . h i t n , JM1.il , I r , G r e e n , nn .1 .?a r ? . 13118 iJ '0 H X vf .-4 o X f'J rj rj o sU `i . i T i f ; r -, o r*r r"> 4 ! 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I uJj,''.ra:;} h;i i-3' ? s `'j-i- i!g t!Ei U u ' H z , M fin a a : O ' f.' < --* -* u ) c r.:\ (< (j ,d o-i VJ . r. ..(j. { ,, >s.fi fi . . ri c.' H .r;> r :J ^!'r-ili :-i ilU! VOy r.: -:<\-j! > f J Jrf ' yr (; - ; ! clh: ; J g C-. S, r-:i3>BU.': n*n aM .| a k . i-aj*::x il Lvie ? f o r r g i.- C-r,. ' -jdr.oy i -/v\Sy Iw'oL V. j f i c r e i r il. D e rid T . E t ' r \\ ' j. On L e. Kciiac'' G'-O:;:'. V>- Dr.. Renc: Z:tria ri-c .*# D r. Vax* M i l l e r Any corren!; c r c r o v i etpic g or., r f r a c t e r . 3Ucccntrr.cfcor, :jr,,-i.:ajs or p r v e t e co-ncult/rr-: o f corn o f tir . D fendants c r ci/ '-fcSi-.rr carsou v;c l:s itow led a o f fh e ruerrfacuuriug y v 'c c ir x : -, d ie r f.o tr y . 'ccup^ioru.il expcsrrsa a n /o r t c x i c i t y ri 2 , . - 1 ar..i,c:r ;:. -\, !1 '.: c. relaL ed tloriyjdisrcln; iro.lrdiricj, ?.vit. ivj-t lim ite i! ~ -, 'ri:o . . y y : y c ;e ra fv .r o ; s r o s r tfUsors; cxrotraci a d d id s t r u lc r r , r r l l .y < .d r o i arocnnr 1 ; engin-.:, jr s (prccnrt-;, Civroaical, ms;--i. -al or ".or c a r f y ' . nny cssci :vi. ; : n -;. . roufr-to-Loi-. cvle" i..txacu cr, in ~ b c u se e r r e r ;i: c r. l u l f r i o. ' a a .il c t h e d ife u d a v o c r any otbe.r y i - Los I t... led;:- -.r tu e c c c :d ln ireau.- o f :rrcrL o r f i r c o c i _ l i e r ; . c c e or d i c r r v : expoiure; :'n o ir c i .ry , voi v.-i j.i r.r -, c.- .c.fo r a r r ;, -para ture.. ru p c ry f.o o rr, c o n tra e > - '.ni i ce o r. -u v riity c e .itr e l f.o rev u n o i, originaire p ro c s r c/::- : " r - ;rr .1 r. *.,Vt s a f e ty ) . Any cv-.r r _ . . rr r. , o; cia oint r or ;>:r. oufcorfror..:or i l Xvv.ro: ' o ; :"lrr'-' <: *. c .. vii' * c. ;-ho .1amendants cr rey V/.riel . .r fl i r .<?re c:: rive resivv co war.i tho: . v r c /f- -J - n ] >'foc va qucctior., p e r t ie f r .1 *.. !. -f.'. lir.g, but :.ci: 11" itsd fo , 1: forero 'f- . .V.. ve;orre., conorrct adm inisfrators, q u elite/ c.; . ..2. rl.:::na1 .- gir.sors fococC . '9 O.rrTTljLC"^j. - ;.ief :anj.cri. eriG :,-'.iv< in y cu rt nu cr y . ,,vi e s erg ' o y c r , r: ./.rrr .c r, sabrr/utr* c i c c , in-Loro;a c : r -fo n t v rr'orrltcn': e t r-;icii r i ti a D e fe r a n te or any r ib e r ci-vscr. r'-.; car; fo c f r a i r o e r i r i r e any o tb e r -.vr.v.ufcrc-- \r g or. ;or" ; . . . c i <*o M r o i . :c. ' :r r i vs o f or- ov . i.o ' ~e. f. r ' c c io rr : c i a r ; no .c: Ir-v.b-' .cio-'; io.i.Dg .jontesai"weed `i l i ' :c ' lo : r. '. .'. " . '- : ....i..... tir: :.r rr c.r " Iv o crd t e hron h c o f or-- s ' i v r or . . Any e r r e r r . . - ; re v i eue et: o lc . r i r , c o n t r a - : t e r , s u b c o n tr a c f o r f i n - f o u e e ?>.' .orirrvor r . : r t . i ;yy * e e - f c i f i e D o fe o d a n fr c :: ofl'or : -- -,;h' c o n c n ir a fo r io .f -:ond :r:f. ci the . i'..ipiicahrvo offerfs ',:.rt.: v:." a;: r o r a ii.o i i; .r' - '..:. "'.ici - r r.' t o o r cij.d i n f o r t ro.j/: i ' icicr-f.::./ v Le " r i f e d S i r t e s e o v rm o e u t v,;l ;f,i g fr. . ..ce o f ' ; ' r ; ' :" vffc.i lr c l: frem ;yxcc .r : : :/, (. *r. : C .r.d O..'c .... ' o rb J :1: oc. 13121 tey .nrrcnt or c>" > o-v.pleyeo, oocrircctory subcontrect*: r, in-hcrro or priant:: co eui ;ino of o-rii of ih* bedrrdants or c-ny ocrer persevi v;o io forbo;! h.^iadgc of how L?::ins vrork unc.o plc/ocs, zrJxiC ls, ard/or 'amena.. hivy c m r e n i or prend.',un acployes, cor:Portar, sufcccntraotor, 3iv-V:.ouii3 c.: oriveto rs;:ltr.v:c or eco;', of he Dfendants or ry ofiher oerrcn v;l:o hoc lacerai y.rfo:..ngo of any r.tati.st.ica coRCGming tire offerte of dicrios i:pon niants, aniir-als, r.v:i/or bimano. hny carrent or previe 3;;i viso, contraetor, n-i-acnteotc-r, in-hcuco or privatr c:.r:rtil" .t f cren of dio Dcfoni-uiits or . .7 ether perse.. icruh'V. 'or irvi':v ..or .vcrioLr; of; EFi\ r 1 other gevarnnenfal rjorro,, re ro Y^iix .'.ocvlnch-e .-f tho foilo/i'a rrieten?;:;; a. Leva e m i b, 'fret He:17 birw X e. re. ly ,. '*^.*** *'. 1e-;..;. "-`lC? O** f o r i r r v. .7..morng, ad?, i... r'.f .ri..r, tic Culaco. tediu lvte feto, cnd/or :jrrt Jronge, inci'adirg ring., rei rmrpcriin;; cf tha Dfendants' . .frac ' orco- rare:; f;r eventual nhipssnt ir,e. Mi,~iT.: ilnv .serrar:'*. er previe*.-s arploy-eo, ew;tr..,ctor.. cube ;ntre ter.. ;r irosa rv p;;r;-.fo n ;7':=v.t of croi: cf tre iteferfarvtr or eny ni '7 -'crccv. vivo i ; ferirei irrefeeder of r: y evzvoys, tests.. fole-":'.'I r: udir :eh ;'<? * 7 -1 thr. ''ff ov opr..ro L.j V:;...p, ^ ,b-Jr .r ...i.y re.'.Cline:.:: r'vjsrrcf ::rr.*.ix`:lr..th tei:_ tey-p=rcc"-xt krewr. 03 ficifcis. ory ere. . viith fr-Joro.teerai'.evo f ber dcisions are irai.2 v.din th Urfled irrt ::..:riverii:reni, pr.riicuiarly 'he ccoision .0 rs-o o -continue -o ree -hencr.; Ir;:.-de;',tea .; Vietnam, pr;:l:.;^arly irint nga; ;irre:irr f---.trai '-rroivlvodge oo^eer.:mt procurer-;t t :: 7:r .utk! ''te .irc/i'ntion tc bildere, ;lOrf/rilarly ri o.. - 7 .-...je. '0,.e<.:^' '-':.:-'. f r jrver rn^- ' r e : .Tor cf.l ph ne:?/ !^ ;y 7 . e r'.ji .7 -f.v>. , riur-le. oivi-i, :io: . oraree .. :r"i f ''ho irli- '":*ol *'.ofend:'nt;;rep*--- .....7 ;.7"er 'leteroen.ih .: 7; Any person with factual h..owlcdga thrtu nu surveys.- tests, *pidc.iiioicgical cfco: :vr;v . c i :nr-h :; undertaken by ur.y state govar-.rant, y.u/ gii :topublic or ieroigu v-orpc-iati.cn, ite a. S, ;iangress or the govov eri: or m y nr lien concerning lio clerical eanpeunds, 2,L*-Q, dir:no, or related vhion: yheuoi s relating to tho <taction or io>dr.s> dia detection c. dioxin:.;, the dangers of dlo:<ina; <r occurs, md/or uis toxicity, carcinogenicity, fc.toto. :icity; tarst gcnicity. acute end. or chronic .fleets 00 plants, animala and tie population - Any aid nil parr.0 0 listed in The iignical evthe by Alasfair .7 2 2Key, as having : a cJ'. ]: vrhadge regard ir , V -v, .'D, its untat i-tilt e':.-.-;: Al... wrakc ~irv.v :?.t; 'ri... . ter d:n befendents a....; d su maritatici . a.11 ten. etior;il !;ccraureo filed tinte 1911 elici evic'aii initstri;! nurius or diseases at the ICF, 2,4~D. 1:.:'o ' pod;":' eg, ;viO.<:r ererererst* an ;r.aere cr Ine. dafortiit.io. Any .end .. t a...' c V'** ` :.r.ansai:don cl.-iiivai;te ef '* 3 jj'-'.'' - '<''?* * sT...T.'/c.VI w ?:^epeiiGi.nl expoerres .rii . ;..0.j.evr:;'.i. ; v * ir*. 1 V' O'" -i s ;-id/o'- rync: 'ha i,.-;... . >v; . r* 1 .sub -7; .i.OV. .jcaari '.'.toe c.y ;. ':: ;o y evict...'.: r.4-r- . ' . . .. r. .. -r :; ; !'irasentrrtives it "a . ' ...f 'he h .nhicns (1933' and/or' t tt d n inerii rise, dororstrati 1 : an si unit d 1 .., '.which will .re..: te :td,,in herein' v..n ita failure of die Evi: devivi, a*.tier, ns tiri dia productleu of r; cantarinani ir- .*jr:t id nil rerscss /;:.: inenioisa. or relevant facts rasarring :. iinov: d d.c rirrende*in si r rheir abilitv '0 .urge:.., including, hut nut limited te, 'si: pact. present, end t u t m profits ~:*.d eatai'ncs in the United! tints:, and itread s i m :i,r::".:;h and lard ding the present fn.-m the aals of the arc'rots rarin ;te r"C.is cf this lawsuit, i.c. 2.4-D, 2,4,C-T, th-'.rn ;* !*.:... rei ves end tie relevant herticrir roaricet,, iry ri al", per: ens 'rj 0. i& or relevant factr*. regard'e 'he 'neridiip rnt:.. s/r !: . efor.Vent,s :ivi their obiirtv to respere in puiiifivv: *'l^rrt'yr . ir- -> : 'ri net limited to,. defender!ts: demerit and io*.*'*'' e:hrldio ries, joint vsnrurars, licenr?vy ag'""Gir'*ni:.;. erdt 7 'C 'ut-lic or pv;.:.vate corporatio in th . r.*"% <...m ......._ .'., ; -\; .!h are defendants ever a -sub- stanti :1 li.rsrrial ' .A. il-A ... trough and inni.-ding v... s-rssert. Dry are. rli pero.'ir* 'ioted Ly * *'n r-oth crigi-oal a'";! cii.c:-.dc ' tir:::;.-.; .< no corperC .'.`.no.- ; Unii, :.ori `.tii:u; cr ''ausatisi-;i . gc......:t ..b i.-Ltncsjyovu..r::-v.nfc cuuscv'J. i '.iitnesa, defiridanto: 1r.pI0ye.cs mid/or mlrvi.vi porsor.rjel ;nd/or uny vinr/tses iicted by all icfencoitr, rty be CJ..;o. at fciirt of tr:'il to prcser.t laotiani i; fcrcuatirn as to au.u larve involvcd ~ i chic casa. Any ao 1 all ooobcoo of Ilo sciertifi-. snd/er radicai .umunity wbo ':iov;lacge of relevant facis. iucludirig Infoio otion on m y o vile a \2v :`-o.sly l'.olci r-fbjeotn in tbis Anne :-..i noi . vit:.: 1 t- ixciudi-15, /.... David 1:;:' d., J 0:0 -l . - . . . f . . . c. Do. laui Coll.. .. *--J1 ...t ---,, 6 * Lv.w* ' j;.ww.'. ; ..ni... o. Do. !.. tt 'oliera h. Alvi-... Ab,. L. '71....''.' `.17. A t Any 0.1 rvf o m e r o ccuo.. itrcr.ecrje ceno .ny >io c ni i o l e ' .:...-.co..'::!: n.i t i f i . c:.un incDid- nqr L .1 no l:. - o rhc ; Any oc y'' **V1..' it y.rreiene vbo !rivo e?Kr'TTC- ^ .-.re..7'. C..i ....7 ".vie-; <":.o i.aiil:.info1 f-:r :nj nne;'Vm : -. 7;v'-.-r." .-- r.d e net.lonol conciti: rei. r;Ibll.l'.iV'..'-Ili'* n.-.b....-L'Y.y to ir t Crenee ; or.' '.or `i* ntucrtt, on 'o d?.ry ; *f.l1:.du:io ni or yv; u b. t. ;/ .t.; C-. :..ocp;.''- vr.nour ri viir -a Plantilfs have been confined, : Craaicvni boti,:.;; te .thsir copoturG te Defendants' ero voto : vieti:--:..n aj. pcyrholcci e ..1 arre o r r. ...... -riola cciiaagas orci, n lo in tif f n a s o reru f t e r t b o ir in i u rico 2nd frcr.i tl*. t i r eypoouro to nei r '*'j * ' ~CJ? V '"7 * '.r ' .io.,/ nr.:' ni 1 ' .r: ..t- ; nwloun : on 4-.ie os f o t--.': : - v-7. ' "/ i 'y - . / j '>n P l a i n t i f f . rat.2 will suri v ie futi- ' " ^i?' *i -f tim i;: lo s s o f wage coges e.r-:.ing cooo-'-ity lt:.oy Irrora tiic injuries e-d disse: r rada th boer e cf thic ,,cv/suit \fr.'eh were caused by 'tan-tifir cort'o. to Defemntn' -croi'uofcr; Vietnrr. 3124 vy". es Any and ail parso '.-.dta kv;-- r.e<o.yc of past, present "rd/'or fuhvre oec. .corbie and r ..cosscry east?: of caters.- 1o p t a i s , nrrssry cso-a, metical ccy.rpmsnt, .knags. .id : i\ other related medical eo-ovo cos rendered or to be roidoroo ir. tly futurs to Plaintififa as a result of their :... lories e d ricsasa resulting frcra their erposoro to Defendants' products in Vietnam. ?.. Any ait- all p-r scca with kro'-ziadge of the physical disfit rrir.ro : ;risk ooi present; - physical, and mental in.pain.'ovr:: yaot rod praceuk . physical goon (pool: a rd present) : *5 s'-ooiish 'past aid pot. ant} which llaiutoils ;.r.ve t-tof- .so / ; a result of their cocpocrre to L-ert .dart:..' pot,itch: in Vietnam cod whi di in teasorVrle prolr kill'y Plaintiffs T*ill continue to aunt*it loo an i olefin!to tiie the roture fro; hoy. tin > ho of ik./ trial. Peep ectirtl.r;* ryabr.ittud, `,,..rsnts W. Henderson, Esqui..n VJL'Jnon fettietta- loauire 1C rare ; oo . a `rr-.r; ", :oo ..at aug_ cf the fcreg..irp L.'oplomm... to .l.oh. olff1s .hr. -ator; tore mailed Federal Express to . hr. liic,,a. Krc-hlc/. Kell'"- , t o-; ?. f-tr .ran, *lr. done locks, Plaintiffs*. ifin.o'cr.sr/.Ccavovt .or. hcro-at Irr-rop.; hfoioo, with espies tor personally servo th e re m a in in .; taLuvakor a vie v sdey 1 .T/ccrti-ons red M e tfenuy Ictrilla, r 'st.--'. r.t. . oils rot-1:dry of r'eho;.o..,,lloh I ts iz e , n:-aco?clyn, Nr-; York ,o 111:;:.on :'stti.ette <k> 1 I UNITED STATES DISTRICT C O U R T EASTERN DISTRICT OF NEW Y O R K --- ------------------------------- X In Re "AGENT ORANGE" PRODUCT LIABILITY LITIGATION X MDLNO.381^ /> o. ,, "/* //k DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOVERY ____ i "V r; o kj> BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. 33 Washington Street Newark, New Jersey 07102 (201) 622-7400 I 1. !^ \ UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK ---------------------------------- X In Re "AGENT ORANGE" PRODUCT LIABILITY LITIGATION X MDL NO. 381 DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOVERY BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. 33 Washington Street Newark, New Jersey 07102 (201) 622-7400 DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOVERY On behalf of all defendants, and pursuant to the Scheduling Order For The Completion Of Discovery dated January 10, 1984, counsel for Thompson Chemical Company hereby submits the following list of potential witnesses to be called at trial, attached hereto as Schedule A. These witnesses shall be called to testify as to the issue of the government contract defense. Furthermore, attached hereto as Schedule B, defendants hereby submit a list of witnesses presently scheduled to be deposed at a future date. Therefore, defendants reserve the right, after these witnesses are deposed to determine whether or not these individuals shall be called upon at trial. Each individual defendant also reserves the right to submit an additional list of witnesses on their own behalf which they may choose to call upon to testify . Dated February 29, 1984 Respectfully submitted, BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. Newark, New Jersey 07102 (201)622-7400 Attorneys for Defendant Thompson Chemical Company RIVKIN, LEFF, SHERMAN & RADLER 100 Garden City Plaza Garden City, New York 11530 Attorneys for Defendant The Dow Chemical Company*^? 1 Q>I a TOWNLEY & UPDIKE.. 405 Lexington Avenue New York, New York 10174 (212)682-4567 Attorneys for Defendant Monsanto Company ARTHUR, DRY & KALISH, P.C. 1230 Avenue of the Americas New York, New York 10020 (212) 841-9300 Attorneys for Defendant Uniroyal, Incorporated KELLEY, DRYE & WARREN 101 Park Avenue New York, New York 10178 (212)808-7800 Attorneys for Defendant Hercules Incorporated SHEA & GOULD 330 Madison Avenue New York, New York 10017 Attorneys for Defendant Uniroyal, Incorporated CLARK, GAGLIARDI & MILLER 99 Court Street White Plains, New York 10601 (914) 946-8900 Attorneys for Defendant T H Agriculture & Nutrition Company, Inc. Schedule A Andrew W. Anderson 1311 Thomas Run Road Belaire, Maryland 21014 Gordon A. Anderson 102 Hickory Lane Naugatuck, Connecticut Robert J. Anderson 3624 North 36th Road Arlington, Virginia 22207 Robert L. Andreoli 25 Eighth Avenue Iron River, Michigan John Angel Box 78 Yellville, Arkansas Kenneth Arndt, M.D. 330 Brookline Avenue Boston, Massachusetts Louis B. Arnoldi 512 North Overlook Drive Alexandria, Virginia John C. Atkinson 1222 Merchant Lane McLean, Virginia 22101 Dr. Joseph D. Avellino 2219 South Broad Street Philadelphia, Pennsylvania 19148 Carl Gwin Baker 19408 Charline Manor Road 0 lney, Mary1and John D. Baldeschwieler 619 South Hill Avenue Pasadena, California William F. Barthel Route 2 Mount Vernon, Iowa Richard R. Bates 2810 Pheasant Lane Clarksburg, Maryland Frank L . Bauer 600 Grant Street Pittsburgh, Pennsylvania Russell H. Betts Weldon Bills Peter S. Bing, M.D. 7900 W. Pico Boulevard Los Angeles, California Donald J. Birmingham 19811 Wedgewood Drive Gross Point Woods, Michigan Warren R. Bontoyan 3910 Meeting House Road Perry Hall, Maryland 21228 Rodney William Bovey Dept, of Range Science Texas A&M University College Station, Texas 77343 Lester Boyer Edgewood Church Road Frederick, Maryland Harold Brown 101530 Third Street, N.W. Washington, D. C. Major William Andrew Buckingham,Jr Department of Political Science U. S. Air Force Academy Colorado At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. X ^& ,, 3 jl 9 Schedule A - Page 2 John L. Buckley P. 0. Box 263 Whitnes Point, New York George W. Connell Route 2, Box 626 Warrenton, Virginia Levi T . Burcham 4701 Crestwood Way Sacramento, California Katherine D. Courtney, Ph.D. Environmental Biology Division EPA Environmental Research Center Dr. Edward James Burger, Jr. Research Triangle Park, N.C. 27711 2233 Wisconsin Avenue, Suite 324 Nicholas H. Cox Washington, D. C. 20007 2516 East Cass St. Jack E. Burton Joliet, Illinois 204 Vivian Lane San Antonio, Texas Robert E. Cox 203 East Belerest Rd. Charles E. Bushey Bel Air, Maryland 374 South Peoria Circle Aurora, Colorado 80012 William J. Crawford 524 Margaret Dr. Dohrman H. Byers Fairborn, Ohio 12060 Lawnview Avenue Cincinnati, Ohio William Murlin Creasy 3910 Molly Rd. Theodore Carroll Byerly Pine Bluff, Arkansas 71603 6J Ridge Road . Greenbelt, Maryland Eugene Cutright 1474 Maplewood Dr. John F. Callahan, Sr. Macon, Georgia 31210 2612 Green Road Baldwin, Maryland Roswell G. Daniels 226 West Edgewood St. David M. Cawthorne Morton, Illinois 61550 P. 0. Box 293 Forest Hill, Maryland Robert A. Darrow 7613 Baltimore-National Pike Milton K. Christensen Frederick, Maryland 21701 1089 Clubhouse Boulevard New Smyrna Beach, Florida Thomas R. Dashiell 304 Thomas Ave. Frederick, Maryland 21701 Joseph F. Coates 3738 Kanawaha St., N.W. Delmore, BG Fred J. Washington, D.C. 1600 S. Eads Arlington, Va. *George ^Collins* Joseph Amadeo DiPaolo 6605 Melody Lane Bethesda, Maryland 20034 *At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. iI. C '. OOOx, Schedule A - Page 3 William W. Dorrell 8600 Pine Cliff Drive Frederick, Maryland *Dr. Hans Falk Paul Doty 4 Kirkland Place Cambridge, Mass. Francis Gene Douglas 3101 South 54th St. Kansas City, Kansas Henry N. Doyla 5303 Augusta St. Bethesda, MD. Lee A. DuEridge 1730 Hornet Rd. Pasadena, California Robert H. Duguid 107 South Lyndbrook Rd. Bel Air, Maryland Sigmund R. Eckhaus 4208 Colonial Rd. Pikesville, Maryland Fred I. Edwards 5206 Worthington Drive Bethesda, Maryland William A. Fenner 2713 Roffin Road Hopewell, Virginia 23860 David Firestone HFF 426 200 C. Street S.W. Washington, D.C. 20204 Henry Fischbach. 5627 Bradley Blvd. Alexandria, Virginia Lawrence Fishbein 3203 Misty Lane Littlerock, Arkansas 72207 Oscar G. Fitzhugh 4208 Dresden St. Kensington, Maryland John Stewart Foster 2737 Sinton Place Pepper Pike, 44124 *John Frawley Dr. Kenneth Endicott . 11317 Broad Green Drive Potomac, Maryland Herbert G. Fredericks 2414 Diana Road William B. Ennis, Jr. Baltimore, Maryland 1131 S.W. 74 Terrace Plantation, Fla. 33317 Seymour L. Friess 6522 Lone Oak Court Graydon Casper Essman Bethesda, Maryland 11 Holcomb Drive Williamsburg, Virginia Verne C. Fryklund, Jr. 6805 Broyhill St. Donald W. Falconer McLean, Virginia 22101 115 Kline Blvd. Frederick, Maryland 21701* Donald W.. Fuhlhage Rural Route 1 Tonganoxie, Kansas * At the present time, addresses on these witnesses are unavailable however, they will be supplied as soon as possible. Schedule A - Page 4 James Gardner 1616 Arlington Drive Salt Lake City, Utah 84103 Benjamin Harris 11323 Glenarm Road Glenarm, Maryland ' Major Robert M. Gastineau, M.D. 2381 Rexford Drive Pittsburgh, Pennsylvania 15241 E. Ross Hart 1160 Chain Bridge Road McLean, Virginia 22101 *Perry Gehring Wayland J. Hayes 2317 Gold Club Lane Nashville, Tennesse John H. Gerety, Jr. North Entrance Friendhsip Inn P.0. Box 1885 Klamath Falls, Oregon *Thomas Gervason Harry W. Hays 3900 Watson Place, N.W., Apt. 2G Building A Washington, D.C. 20016 Albert E. Hayward. 5716 Jefferson Blvd. Braddock Heights, Maryland 21714 William Godel 711 Ledo Park Dr. Newport Beach, Ca. 92660 *John Gordon Robert J. Heaston 8231 Stonewall Drive Vienna, Virginia 22180 James A. Hebbeler 821 Park Court Palm Harbor, Florida Nathan Gordon 4990 Sentinel Drive Apartment 301 Bethesda, Maryland 20816 Dr. Herschel E. Griffin 11274 Pabelln Court San Diego, California 92124 *David Henry Groth General Paul Donal Harkins 65104 Northport Drive Dallas, Texas 75230 *Harry Heimann Brunildo Antonio Herrero 616 Lake Hollingsworth Drive Lakeland, Florida Garnett Higginbotham Division of Food and Color Additi FDA 200 C Street, S.W. Washington, D.C. 20204 Donald F. Hornig 16 Longfellow Park Cambridge, Mas s. *At the present time, addresses on these witnesses, are unavailable; however, they will be supplied as soon as possible. 13134 Schedule A - Page 5 Richard G. Horton 208 East Ring Factory Road Bel Air, Maryland 21014 Philip Charles Kearney Building 050 BARC-West Beltsville, Maryland William Horwitz 9830 Cherry Tree Lane Silver Spring, Maryland 20901 Surgeon M. Keeny, Jr. 3600 Albermarle St., N.W., Washington, D.C. Riley D. Housewright 147 Fairview Avenue Frederick, Maryland Dr. Marcus M. Key University of Texas Health Science Center. at Houston Harry Otto Huss Route 1 Box 352 P.O. Box 20186 Houston, Texas 77025 Uhrichsville, Ohio 44683 Dr. Henry A. Kissinger Kent R. Irish 1604 Rock Creek Drive Frederick, Maryland 435 East 52nd St. New York, New York Michael Klein Keith H. Jacobson 740 Beall Avenue Rockville, Maryland 1800 South East St. Lucie Blvd. Building 10-306 Stuart, Florida Dr. Bernard J. Jandorf 6017 Baywood Avenue Baltimore, Maryland 21209 Dayton L. Klingman 2028 Forest Hill Drive Silver Spring, Maryland 20903 Marc Jeffries 2108 Hyden Ct. Fallston, Maryland 21067 Albert Christian Kolbye 4802 Fort Summer Drive Bethesda, Maryland Wesley Rudolph Koster Dr. William Jurgelski 105 Northlake Dr., Apt, 215A Office of Health Hazard Assessment Orange City, Florida 32763 National Institute of Environmental Health Science William George Kratz Research Triangle Park, N.C. 27709 985 North Capitol *Abram Saul Kaplan Many, Louisiana 71449 George M. Lawton 1388 Almond Ave. Ronald Joseph Kassel Livermore, California 222 East Belcrest Road Bel Air, Maryland * At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. 13135 Schedule A - Page 6 John S. Leary, Jr. 2002 Sea Cove Court Nassau Bay, Texas Douglas H.K. Lee 421 Wood DUck Drive Sarasota, Florida Jane Lewis 5125 Temple Hills Road Temple Hills, Maryland 20748 Dr. Douglas Lindsey 1501 North Campbell St. Tuscon, Arizona Gordon J. MacDonald 20 Occom Ridge Hanover, New Hampshire Harold Noble MacFarland 2320 Harrah Manner Drive Pittsburgh, Pennsylvania 15238 Dr. Arthur H. McCreesh 1317 Saratoga Drive Bel Air, Maryland 21014 Harold Joseph Magnuson, M.D. 12305 Fernando Drive San Diego, California 92128 Walter W. Melvin 413 Bobolink Court Fort Collins, Colorado 80526 Edward A. Metcalf 906 Wellington Rd. Baltimore, Maryland 21212 Lester L. Miller 437 Blueridge Drive York, Pennsylvania Charles E. Minarik P.O. Box 682 West Harwich, Mass. Ian Alastair Mitchell, M.D. 110 Parmele Blvd. ( Wrightsville Beach, N.C. Francis W. Morthland 5602 Garrett Rd. Durham, North Carolina Donald W. Norberg 9153 East Stanford Ave. Englewood, Colorado 80111 Dr. Harold T. Magnuson 12305 Fernando Drive San Diego, Cal. 92128 Dr. Arthur H. McCreesh 1317 Saratoga Drive Bel Air, Maryland 21014 William D. McElroy 9651 Black Gold Road LaJolla, Cal. 92037 Robert S. McNamara 2419 Tracy Place Washington, D.C. Vincent McRae 12000 Old Georgetown Rd. Rockville, Maryland John F . O' Leary Route 1, Box 213 Queenstown, Maryland 21658 Peter G. Olenchuk 6801 Baron Rd. McLean, Virginia 22101 Normand E. Olivier 31 Mosher St. South Dartmouth, Mass. Boris J. Osheroff 13102 Camellia Drive Silver Spring, Maryland 20906 Hi J ,. * J J. d o Schedule A - Page 7 Arthur Joseph Pallotta 601 Abbott Lane Falls Church, Virginia Maj. Gen. Jacquard H. Rothschild 2323 N. Central Ave. Phoenix, Az. 85004 Laverne A. Parks 322 E. Garden Green Port Hueneme, Cal. 93041 Dr. Jack Phillip Ruina 28 Hawthorne St. Cambridge, Mass. 02138 *Vernon Perone Umberto Saffiotti 5114 Wissioming Road Bethesda, Maryland Lawrence M. Petrucelli 5600 Cedar Parkway Chevy Chase, Maryland Samuel Sass 17 North Read Street Bel Air, Maryland 21014 Alan P. Poland 2918 Nottingham Way Madison, Wisconsin Paul Aaron Possick 46 Winding Way Woodcliff Lake, N.J. Melvin M. Rabstein 4401 Gulf of Mexico Drive Long Boat Key, Florida Eberhardt Rechtin 1665 Cataluna Palos Verdes Estates, Cal. Kennard A. Reynard 2496 Cedarwood Drive Adrian, Michigan Bernard Schwetz 1101 30th Street, N.W. Suite 205 Washington, D.C. 20007 Robert A. Shade 199 Rooster Drive Eagle, Indiana Warren C. Shaw 1907 Edgewater Parkway Silver Springs, Maryland Carleton G. Shead 1406 Flying W. Trail Helotes, Texas 78023 *John R. Shoemaker Merl Ringenberg 612 Rock Spring Road Bel Air, Maryland Ralph T. Ross Room 330A Administration Building U.S. Department of Agriculture Washington, D.C. Seymour D. Silver 2920 Strathmore Ave. Baltimore, Maryland Dr. Van Murray Sim 1615 Toll Gate Road Bel Air, Maryland *At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. Schedule A - Page 8 Dr. Thomas C. Simmons 2706 Bynum Hill Circle Bel Air, Maryland Charles H. Townes 1988 San AnLonio Ave. Berkeley, California Anthony N. Sinclitico 1800 Willann Road Baltimore, Maryland 21237 John L. Traub 610 West Baker Ave. Abingdon, Maryland Marshall Steinberg 927 Jaysmith Street Great Falls, Virginia Thomas A. Treglia *Dr. Jesse L. Steinfeld John Wilder Tukey 115 Arreton Rd. Princeton, N.J. Herbert E. Stokinger William Martin Upholt 525 East Indian Drive Silver Springs, Maryland William W.. Stone 434 Sanahelena Drive Solana Beach, California Cyrus Robert Vance One Battery Park Plaza New York City Marshall Stubbs 2001 Columbia Turnpike Arlington, Virginia Wayne E . Vandeventer Walter Edward Sultan Filiberto Vargas 1203 Springwoods Terrace 6165 East I Lift Ave. Fallston, Maryland 21047 Apartment 308 B Denver, Colorado 80222 William H. Summerson 5108 Brittany Drive South Henry L. Verhulst Stu Petersburg, Florida 5917 Walton Rd. Bethesda, Maryland Steve S. Szabo 20 Milrose Lane Frank J. Vocci Monsey, New York 6009 Winthrope Ave. Baltimore, Maryland 21206 General Maxwell D. Taylor 2500 Massachusetts Ave. N.W. Dorothy M. Ward Washington, D.C.* 345 Homeland South Way Baltimore, Maryland 21212 *At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. * *; t Schedule A - Page 9 Paul C. Warnke Cummings, Burlington, Rubier, Acheson & Shaw Washington, D .C . John T. Weimer 1500 South View Rd. Bel Air, Maryland 21014 Frank H. Westheimer 3 Berkeley St. Cambridge, Mass. 02138 William Childs Westmoreland Box 1059 Charleston, S.C. 29402 Jerome B. Wiesner 61 Shattuck Rd. Watertown, Mass. Jerome Wilkenfeld 5757 Owensmouth Ave. Woodland Hills, California Donald Whittam 10308 Brookmoor Drive Silver Spring, Maryland 20901 James H. Wills 9706 Bellevue Dr. Bethesda, Maryland Herbert F. York 6110 Camino De LaCosta LaJolla, California Dr. Mitchell Zavon Occidental Chemical Corp. P.0. Box 728 Niagara Falls, New York 14302 Walter Leo Zielinski, Jr. 12705 Darnestown Rd. Gaithersburgh, Maryland 20878 ^ 13139 SCHEDULE B DEPOSITIONS SCHEDULED AFTER FEBRUARY 29, 19-84: 1. Donald Barnes 2. General Stanzwick Hay 3. Julius Johnson 4. Harold Kinney 5. Debdas Mukerjee 6- Elmer Wheeler 140 UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK In Re "AGENT ORANGE" PRODUCT LIABILITY LITIGATION MDL NO. 381 DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOERY BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. 33 Washington Streert Newark, New Jersey 07102 (201)622-7400 Attorneys for Defendant Thompson Chemical Company UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK In re "AGENT ORANGE" Product Liability Litigation x x DEFENDANT DIAMOND SHAMROCK CHEMICALS COMPANY'S PRELIMINARY LISTING OF FACT WITNESSES___ Pursuant to the Special Master's Final Amended Recommended Scheduling Order, approved by the Court on January 10, 1984, defendant Diamond Shamrock Chemicals Company ("Diamond Shamrock") sets forth below its preliminary listing of fact witnesses who may give live testimony at trial in support of Diamond Shamrock's claims and defenses. This listing does not address deposition testimony that may be used at trial, which will be identified as part of preparation of the pretrial order. In accordance with the Scheduling Order and the Magistrate's Pretrial Order No. 9, Diamond Shamrock reserves the right to supplement and amend this preliminary listing. 42 Name and Etegent Address Description of General Nature.of Testimony Dr. Donald J. Birmingham 19811 Wedgewood Drive Gross Point Woods, Michigan Testimony concerning research and investigation of chloracne by U.S. Public Health Service in the 1950's and 1960's, including visits to Diamond Shamrock's former Newark plant. Robert L. Chonoles Diamond Shamrock Chemicals Company Berry Avenue at Route 17 North Carlstadt, New Jersey 07072 Testimony concerning manufacturing operations at Diamond Shamrock's former Newark plant, including: the removal of dioxin from trichlorophenol; and the U.S. Public Health Service study of the Newark workers in 1968-69. Sigmund R. Eckhaus 4208 Colonial Road Pikesville, Maryland Testimony concerning United States' program for the construction of an Agent Orange manufacturing facil ity, and communications with pro ducers of Agent Orange in connec tion with that program. Dr. Marcus M. Key University of Texas Health Science Center P.O. Box 20186 Houston, Texas 77025 Testimony concerning research and investigation of chloracne by U.S. Public Health Service in the 1960's, including visit to Diamond Sham rock's former Newark plant. Jane Lewis 5125 Temple Hills Road Temple Hills, Maryland 20748 Testimony concerning the procure ment and production of Agent Orange pursuant to the Defense Production Act, including directives and priority ratings issued by the United States. Dr. Alan P. Poland 2918 Nottingham Way Madison, Wisconsin Testimony concerning medical study of the workers at Diamond Shamock's former Newark plant in 196869, and research and investigation of trichlorophenol, 2,4,5-T and dioxin at. National Communicable Disease Center in the 1960's. Dr. Paul A. Possick 46 Winding Way Woodcliff Lake, New Jersey Testimony concerning medical study of the workers at Diamond Sham rock's former Newark plant in 196869. 2- - 1 ^>; M - 3 Name and Eresent Address Warren C. Shaw 1907 Edgewater Parkway Silver Spring, Maryland Description of General Nature of Testimony___ Testimony concerning DSDA regula tion of 2,4,5-T under FIFRA in 1950's and 1960's, and USDA research and investigation con cerning health effects and efficacy of 2,4,5-T. F. Gordon Steward Diamond Shamrock Agricul tural Chemicals Inc. P.O. Box H Tuscaloosa, Alabama 35404 Testimony concerning manufacturing operations at Diamond Shamrock's former Newark plant, including: the development, installation and operation of a method for removing dioxin from trichlorophenol; the U.S. Public Health Service study of the Newark workers in 1968-69; and the production and shipment of Agent Orange pursuant to contracts with the United States. Dated: New York, New York February 29, 1984 Respectfully submitted, CADWALADER, WICKERSHAM & TAFT B y J ly A Member of the Firm Attorneys for Defendant Diamond Shamrock Chemicals Company One Wall Street New York, New York 10005 (212) 908-7000 -3- >: - i 1 \ AFFIDAVIT OF SERVICE STATE OF NEW YORK ) SS. : COUNTY OF NEW YORK ) MICHAEL M. GORDON, being duly sworn, deposes and says: 1. I am not a party to this action, am over 18 years of age and reside in New York County, New York. 3. On February 29, 1984, I served the annexed dant Diamond Shamrock Chemicals Company's Preliminary Listing of Fact Witnesses on each of the persons named on the annexed list by depositing a true copy of same enclosed in a postpaid properly addressed wrapper, in an official depository under the exclusive care and custody of the United States Postal Service within the State of New York. The copy to David J. Dean, Esq. was sent by Federal Express. A copy was also sent by Federal Express to the Agent Orange Plaintiffs' Management Committee, 26 Court Street, Suite 905, Brooklyn, New York. Sworn to before me this z r day of February, 1984 No.'391 * CoTMSSSE^rSehx'.S^Jras- avia list roa defendants Leonard L. Rivkin Rivkin, Leff, Sherman 4 Radler (for DOW CHEMICAL) 100 Cardan City Plasa Cardan City Saw York 11530 Morton C. Silbarman Clark, Gagliardi 4 Millar (for T H AGRICULTURE 4 NUTRITION COMPANY, INC.) The Inna of Court 99 Court Street White Plaina, New York 10601 John C. Sabetta Townley & Updike (for MONSANTO) 405 Lexington Avenue New York, New York 10174 William Krohley Xelley Drye 4 Warren (for HERCULES, INC.) 101 Park Avenue New York, New York 10178 John M. Fitzpatrick Dilworth, Paxton, Kalith 4 L e w (for HOOKER PLASTICS 4 CHEMICALS CORP.) 2600 The Fidelity Building Philadelphia, Pennsylvania 19109 Biehard Goldstein Shea 4 Gould 330 Madison Avenue New York, New York 10017 Thomas Beck Arthur, Dry 4 Xalish, P.C. (for UNIROYAL) 1230 Avenue of the Americas New York, New Yozk 10020 David X. Cross Budd, Larner, Kent, Gross, Pieillo 4 Rosenbaum (for THOMPSON CHEMICALS) 33 Washington Street Newark, New Jersey 07102 Arvin Maskin Department of Justice (for THIRD PARTY DEFENDANT USA) Safeway Building 521 12th Street, S.W. Washington, D.C. 20530 L. Kevin Sheridan Executive Assistant U.S. Attorney Eastern District of New York United States Courthouse 225 Cadman Plaza East Brooklyn, New York 11201 COPIES OF ALL DOCUMENTS MUST BE SENT TO:__________________ Clerk of the Panel Judicial Panel on Multidistrict Litigation 1120 Vermont Avenue, N.W. Suite 1002 Washington, D.C. 20005 FOR PLAINTIFFS Victor J. Yannaeone, Jr. Yannaeone 4 Yannaeone Post Office Drawer 4109 Patchogue, New York 11772 Stephen J. Sehlegel Schlegel 4 Trafelet, Ltd. One North LaSalle Street Suite 3900 Chicago, Illinois 60602 Benton Musselwhite Law Offices of Benton Musselwhite, Inc. Suite 517 609 Fannin Houston, Texas 77002 Thomas Henderson Baskin 4 Sears Frick Building - 10th Floor Pittsburgh, Pennsylvania 15219 David J. Dean, Esq. Dean, Falanga 4 Rose 1 Old Country Road Carla Place, New.York 11514' ' ' k' y 'ft-- ';v`' ''" (ftEASTERN -DISTRICT OP NEWC0Y"OR'K! 'ft/; iVi::i;. .. ,. :.r '- .-. `'iw r - - . . .-' ,' R ": *-*''' 1ft\ *<'. '-r'--.ft.M''V'-*y ` !'. : *',"' ftft agent orange ____ .. ........ .' `ft: - ; --v-'.''.'f t ' f t '. -ft .. '-..* -Product Liability Litigation .....,.,..--;..;,..... ''^' ;/ DL ^ .ft .." ft.*-/C ?>;.. :- t /st<**.V>fNrffc'' ;.'-ftftft'ftV/iV'".!''^-t'?.-*;-'.V.,-,.f:>trf't'-rv.--*;'.'.:.<!...~y iftsftf:?-'ft'.ft '.ftft,.-"f'^..K,'.ry-; ..^ ....... . . . . . . . : . ............ _ ....... ...- ,, DEFENDANT DIAMOND SHAMROCK'S OBJECTIONS "'T?/ s'^ic r-..TO PLAINTIFFS` PRELIMINARY.LIST _OFit ri' -'^pss'iiV*- JX- -H.^ POTENTIAL DEPONENTS PRESENTLY OR FORMERLY Vft-ft ^ fti; " -' l f t ' - r, : T r _ - ' ; ^ - _ vvf tV ^ ;. v- : 1* : /-'/'. r f t , : '' - * *" * . , J- . .. + ' ; J - / :.i- " ? * . , M i v - . 4 ' - :\<f.fAffi&yX'f .-ft'-*'-.'*-i\ftV Vy/ftsT'-' .->: `Xft ft-" -''ft- *'L- ;'^t.**' ft1 ; CADWALADER, WICKERSHAM/sfrAPT A PARTNERSHIP INCUOING PROfESSIONAt C O R P 0 M T IO ^ ^ ft/ftft:j;ft^ One Wall Street ' " ^N ew Y o i ^ ^ f t ^ ;. V;. -' N (212) 908-7000-^ - "'''ft::'v;:jf.;.^''if--/;,.' ' UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK ------------------------------------------------------------- - In re "AGENTORANGE" : Product LiabilityLitigation : ----------------------------------x : MDLNo. 381 DEFENDANT DIAMOND SHAMROCK'S OBJECTIONS TO PLAINTIFFS' PRELIMINARY LIST OF POTENTIAL DEPONENTS PRESENTLY OR FORMERLY _____ ___________________________________ Pursuant to the direction of Magistrate Scheindlin at the February 9, 1984 pre-trial conference, defendant Diamond Shamrock Chemicals Company ("Diamond Shamrock") sets forth below its objections to plaintiffs' preliminary list of present or former Diamond Shamrock employees who may be deposed by plain tiffs, served on February 9, 1984 ("Plaintiffs' List"). Diamond Shamrock requests, however, that consideration of its objections by the Magistrate be deferred pending receipt and review of plaintiffs' "priority" deposition list. Since the commencement of deposition discovery in the "Agent Orange" litigation in 1982, plaintiffs have deposed nine present or former Diamond Shamrock employees on substantive rr - AW issues. An additional three employees have been examined pursuant to Pretrial Order No. 57. On December 12, 1983, counsel for plaintiffs confirmed in writing that their deposition discovery of Diamond Shamrock would be completed by the examination of five additional former employees: Richard Marrese, Donald Purdy, Cy Perkins, James King and Stanley Honour. See letter from Edward J. Gorman to Michael M. Gordon dated December 12, 1983 (Exhibit A hereto). Dr. Marrese and Mr. Purdy were examined on December 13, 1983 and January 5, 1984, respectively. The depositions of Mr. Perkins and Mr. King were both tentatively scheduled, and then postponed at plaintiffs' request for various reasons, including ill health of plaintiffs' counsel. The deposition of Mr. Honour remains unscheduled. I jNow, only 12 weeks before trial, plaintiffs have identified ten former Diamond Shamrock employees that they may wish to depose, the three witnesses previously requested and remaining to be scheduled. Thus, if their List is accepted at face value, plaintiffs seek at the last minute to double the number of Diamond Shamrock depositions taken in this litigation. Their List similarly more than triples the number of outstanding depositions to be scheduled, in total repudiation of plaintiffs' most recent assurances to Diamond Shamrock. Plaintiffs' unannounced new "wave" of Diamond Shamrock depositions, in the face of recent representations to the con trary, would seriously and unfairly prejudice Diamond Shamrock's own pre-trial preparations. Instead of the three remaining '2' iZ lid depositions agreed to in December, Diamond Shamrock would now be compelled to locate and prepare for depositions of 13 former employees, most of whom reside far from New York and are unlikely to agree to travel here for their examinations. The strain on the resources of Diamond Shamrock's counsel that would result at i this critical stage of the proceedings is obvious. Absent a compelling explanation for plaintiffs' failure to apprise Diamond . Shamrock of their intentions and to pursue scheduling of Diamond ; Shamrock depositions during the past several months, plaintiffs j should not be permitted to sidetrack Diamond Shamrock's trial preparations in the few precious weeks remaining before jury selection. In fairness to plaintiffs, Diamond Shamrock recognizes that plaintiffs themselves estimate that only a fraction of the deponents they have listed will actually be examined. Plaintiffs have also stated their intention to submit by February 15, 1984 a "priority list" that is expected to contain only one-half to onequarter of the names set forth in their original list, ss tr. at 9214-15. Accordingly, Diamond Shamrock requests that con sideration of its objections to the number of former Diamond Shamrock employees identified as deponents in Plaintiffs' List be deferred to permit receipt and review of plaintiffs' priority -3- pl 1 ^0 U list, and discussion of that list between counsel for Diamond Shamrock and plaintiffs. Dated: New York, New York February 14, 1984 Respectfully submitted, 'T Diamond Shamrock Chemicals Company One Wall Street New York, New York 10005 (212) 908-7000 -4- /l JAM AICA O FFIC E 9 0 -2 4 SU TPH IN BLVD. JAM AICA. N .Y . I 1 4 0 6 (212) 6 6 8 -4 1 1 4 P E T E R M. J . REILLY EDWARD J . OORMAN PE T E R M. J . REILLY. JR . MARK O. SOKO LO FF RICHARD E . CH ESN EY DONALD E . LAMPSON ELIZA B ETH M. O 'N E IL L LAW O FFIC E S O 'H a o a n ,R e i l l y & G o r m a n ,P.G. REILLY BUILDING .444 MAIN S T R E E T P. O. BOX 73 ISL IP, N. Y. 1 I 7 6 1 NEW YORK O FFICE I22 BAST 42ND STREET NEW YORK. NEW YORK 1 0 0 1 7 (212) 6 9 7 -4 2 7 0 OF COUNSEL (616) 6 8 1 -8 6 6 7 H E N R Y J . O 'H A OAN - D E C 'D 1 9 7 8 EDW ARD O . D O U G H E R T Y - D E C 'D 1 9 7 7 OEOROE W. KELLY ALLAN M. KAPLAN RICHARD F . PO H L (ADM. P E N N . BAR) EDWARD F. HAYES. Ill December 12, 1983 Cadwalder, Wickersham Taft, Esqs. One Wall Street New York, New York 10005 Attention of Michael M. Gordon, Esq. RE: In re "Agent Orange" Product Liability Litigation MDL No. 381 Dear Mr. Gordon: This will confirm our telephone conversation of December 8, 1983 wherein you advised that Mr. S. S. Savage is deceased and Mr. S. B. Honour, still shares this earth with us although his exact whereabouts are unknown. Presently scheduled for depositions are Mr. Marrese, Perdy, Perkins and King. As you know Mr. Fiorella has written to Mr. Lex Creamer regarding his deposition but to date we have not heard from this gentleman. What we are looking for is a witness with knowledge of the various South American episodes involving chloracne and the use of 2, 4, 5,T. I doubt if we will hear from Mr. Creamer. If you will be kind enough therefore to arrange to have Mr. Honour presented for deposition, he, in addition to those gentlemen mentioned above,will complete our discovery. Thank you for your cooperation, I remain Very truly yours, CC: Albert Fiorella, Esq. D. Russo, Esq. O'HAGAN , REILLY S GORMAN, P.C. 5< V EDWARD J. GORMAN . M 5 2 AFFIDAVIT OF SERVICE STATE OF NEW. YORK: 1. : ss.: COUNTY OF NEW YORK ) JEFFREY SAPER, being duly sworn, deposes and says: 1. I am not a party to this action, am over 18 years of age and reside in Queens County, New York. 2. On February 14, 1984, I served the annexed De Diamond Shamrock's Objections to Plaintiffs' Preliminary List of Potential Deponents Presently or Formerly Employed by Diamond Shamrock on each of the persons named on the annexed list by depositing a true copy of same enclosed in a postpaid properly addressed wrapper, in an official depository under the exclusive care and custody of the United State Postal Service within the State of New York. The copy to David J. Dean, Esq. was sent by Express Mail. A copy was also sent by hand to the Agent Orange Plaintiffs' Management Committee, 26 Court Street, Suite 905, Brooklyn, New York. Sworn to before me this 1984. MICHAEL MACKIN GORDON W otaiy Public, S tate of New York rv. I*0,-985 C a t i o n E x * ; M*a*r.th aro T tt.& iT SERVICI LIST FOR DEFENDANTS Leonard L. Rivkin Rivkin, Leff, Sherman t Radier (for DOW CHEMICAL) 100 Garden City Plaza Garden City New York 11530 Morton G. Silbernen Clark, Gagliardi t Miller (for T H AGRICULTURE fc NUTRITION COMPANY, INC.) The Inna of Court 99 Court Street White Plains, New York 10601 John C. Sabetta Townley 4 Updike (for MONSANTO) 405 Lexington Avenue New York, New York 10174 William Krohley Xelley Drye 4 Warren (for HERCULES, INC.) 101 Park Avenue New York, New York 10178 John M. Fit2patrick Dilworth, Paxson, Xalish 4 L e w (for HOOXER PLASTICS 4 CHEMICALS CORP.) 2600 The Fidelity Building Philadelphia, Pennsylvania 19109 Richard Goldstein Shea 4 Gould 330 Madison Avenue New York, New York 10017 Thomas Beck Arthur, Dry 4 Xalish, P.C. (for UNIROYAL) 1230 Avenue of the Americas New York, New York 10020 David R. Gross Budd, Larner, Kent, Gross, Picillo 6 Rosenbaum (for THOMPSON CHEMICALS) 33 Washington Street Newark, New Jersey 07102 Arvin Maskin Department of Justice (for THIRD PARTY DEFENDANT USA) Safeway Building 521 12th Street, N.W. Washington, D.C. 20530 L. Xevin Sheridan Executive Assistant U.S. Attorney Eastern District of New York United States Courthouse 225 Cadman Plaza East Brooklyn, New York 11201 COPIES OF ALL DOCUMENTS MUST BE SENT TO:__________________ Clerk of the Panel Judicial Panel on Multidistrict Litigation 1120 Vermont Avenue, N.W. Suite 1002 Washington, D.C. 20005 FOR PLAINTIFFS Victor J. Yannacone, Jr. Yannacone 6 Yannacone Post Office Drawer <109 Patchogue, New York 11772 Stephen J. Schlegel Schlegel 6 Trafelet, Ltd. One North LaSalle Street Suite 3900 Chicago, Illinois 60602 Benton Musselwhite Law Offices of Benton Musselwhite, Inc. Suite 517 609 Fannin Houston, Texas 77002 Thomas Henderson Baskin 6 Sears Frick Building - 10th Floor Pittsburgh, Pennsylvania 15219 David J. Dean, Esq. Dean, Falanga 6 Rose 1 Old Country Road Carle Place, New York 11514' 2f O fr 1 3 3 3 N E W H A M P S H IR E A V E ., N.W . W A SH IN G TO N , O .C. 2 0 0 3 6 (2 0 2 ) 2 9 3 - 6 3 0 0 TW X: 7 1 0 6 2 2 " 193A A P A R TN ER SH IP IN CLU O IN G P R O F E S S IO N A L C O R P O R A TIO N S J fW ./ S (2S2) S O S - 7 O O 0 CA B LE a d d r e s s : la b ellu m T E L E X : 12 9 1 4 6 / B 0 7 4 6 S R A P IP A X : (212) 2 6 9 * 2 3 2 1 X ER O X *. (212) 7 6 5 * 1 6 3 0 2 4 9 R O Y A L P A LM WAY PALM B EA C H , F LA . 3 3 4 6 0 (3 0 9 ) 6 8 8 * 9 8 0 0 TWX! 8 1 0 * 9 8 2 * 7 6 2 8 February 14, 1984 Honorable Shira A. Scheindlin United States Magistrate United States District Court Eastern District of New York United States Courthouse 225 Cadman Plaza East Brooklyn, New York 11201 Re: In re "Agent Orange" Product Liability Litigation, MDL No. 381 Dear Magistrate Scheindlin: Pursuant to your direction at the February 9, 1984 pre-trial conference, I enclose Defendant Diamond Shamrock's Objections to Plaintiffs' Preliminary List of Potential De ponents Presently or Formerly Employed by Diamond Shamrock. Very truly yours MMG/mam Enclosure BY HAND cc(w/encl.): Clerk of the Court1''" Service List il UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK -------------------------------------------------- X In re -r 1. Charles Baron, M.D. 2. Deborah Anne Barsotti, Ph.D. 3. Ronald Codario, M.D. 4. Arthur W. Galston, Ph.D. \ 5. John Garofalo, M.D. 6. Lennart Hardell, M.D. 7. Maureen C. Hatch, Ph.D. 8. Alastair W.M. Hay, Ph.D. 9. Herbert Kay, Ph.D. 10. Ronald H. Kerman, Ph.D. 11. Marvin S. Legator, Ph.D. 12. Alan Scott Levin, M.D. 13. Peter Orris, M.D., M.P.H. 14. Marvin A. Schneiderman, Ph.D. 15. Ellen K. Silbergeld, Ph.D. 16. Raymond Singer, Ph.D. 17. Theodor D. Sterling, Ph.D. 18. Biostatistician/Mathematician (Additional) Exhibit "A" Exhibit "B' Exhibit "Cr Exhibit "D' Exhibit "E" Exhibit "pi Exhibit "G' Exhibit ,,H' Exhibit 'T Exhibit MJ' Exhibit "K* Exhibit ML' Exhibit "M' Exhibit "N' Exhibit "O' Exhibit "pi Exhibit "Q. Exhibit "Rl PLAINTIFFS' MANAGEMENT COMMITTEE Thomas W. Henderson, Esquire IS 15 6 Dr. Charles M. Baron, M.D., is a physiatrist practicing in Philadelphia, Pennsylvania. His curriculum vitae will be supplied. Dr. Baron will testify as to the performance and interpretation of various tests in the veterans. These will include an eltroencephalogram on both sleep and waking states with nasopharyngeal leads. He will also perfrom electromyograms, nerve conduction velocity tests, and somato sensory evoked potentials of the upper and lower extemities. Dr. Baron will then testify as to the mechanisms by which toxins produce the changes noted in the tests and what the various tests are capable of determining as to the medical status of the patient. Then he will relate the results obtained in the testing of each plaintiff examined, give opinions as to the causation of those results where possible from the evidence revealed by the tests, and state the prognosis for the individual plaintiff for further deterioration in test results and/or for the individual's condition as a whole. 13157 Dr. Deborah Anne Barsotti is an Assistant Professor of Toxicology in the Department of Pharmacology and Toxicology of the Philadelphia College of Pharmacy and Science in Phila delphia, Pennsylvania. Her curriculum vitae is attached. Dr. Barsotti is a toxicologist who has done substantial personal investigative work with halogenated aromatic hydrocarbons. This category of chemicals includes various biphenyls and dioxins, and specifically includes tetrachlorodibenzo-prdioxin (TCDD). She will testify as to the relative chemical stability and lipophilicity of these chemicals as well as their resistance to degradation, and will testify that these qualities are what account for the perceived and documented bioaccumulation of the chemicals in the human system. Dr. Barsotti will emphasize the difference in results between chron ic and acute exposures to these chemicals, testifying as to the varying types of responses to acute and chronic exposures. Dr. Barsotti will discuss her own work as well as review the literature in these areas, noting differences in routes of administration, and in the species and genetic strain of the animals involved. She will explain these variations and where they permit extrapolation of results from animals to humans. In particular, Dr. Barsotti will also testify as to the similarities in response to these chemicals by rhesus monkeys and by humans, and will explain how the similarities permit extrapolation in this instance. Dr. Barsotti will also discuss reproductive toxicity, teratology and post-natal toxicity, including instances where no gross or clinical signes of maternal toxicity could be detected. OJ O. CURRICULUM VITAE DEBORAH ANNE BARSOTTI ADDRESS: Home - 4818 T r in it y Place P h il a. , PA 19143 215-724-5387 Business - P h il a. College o f Pharmacy & Science Dept, o f Pharmacology & Toxicology 43rd & Kingsessing Mall P h il a. , PA 19104 215-596-8978 CITIZENSHIP: USA BIRTHDATE: September 14, 1949 MARITAL STATUS: M arried; no ch ild re n EDUCATION: Humboldt S ta te U n iv e rs ity A re a ta , C a lif o r n ia - 1967-1972 Bachelor of A rts Biology-M edical Technology Humboldt S tate U n iv e rs ity A re a ta , C a lif o r n ia - 1972-1973 Graduate School Coursework: Electron microscopy Endocrinology In stru m en tatio n U n iv e rsity o f Wisconsin Madison, Wisconsin - 1973-1980 Doctor o f Philosophy Pathology Thesis T it le : G ross, C lin ic a l & Reproductive E ffe c ts of Polychlorinated Biphenyls (PCBs) in the Rhesus Monkey EXPERIENCE: P h il a. College o f Pharmacy & Science Phi l a . , PA - Ja n u a ry, 1983 to Present A s s t. P ro fe sso r, Dept, of Pharmacology/Toxicology In s tru c t B io lo g ic a l Methods in T o x ic o lo g y , To xico lo g y I I I & Techniques in Electron Microscopy Advise undergraduate students Facu lty ad viso r fo r Tox Club Member, A d viso ry Committe fo r fo u r graduate students Conduct independent research 13160 A s s is ta n t S c ie n t is t - J u ly , 1982 to Ja n u a ry , 1983 P ro je c t A sso cia te - June, 1980 to June, 1982 U n iv e rsity of Wisconsin Dept, of Pathology Madison, Wisconsin Coordinated m u ltifaceted research p ro jects in vo lvin g over 120 rhesus monkeys exposed to low le v e ls o f to x in s (h a lo genated arom atic hydrocarbons) and in te g rate d the c lin ic a l data and o b se rvatio n s w ith the residue analyses o f t is s u e s and f lu id s obtained by gas chromatography (GC) and con firm ed by mass spectrom etry (MS). Supervised the c lin ic a l and reproductive e v a lu a tio n s as w ell as the care o f lab o rato ry anim als. Developed d ata management and word processing systems u t i l iz in g o n - s ite computers and t ie - in s to a Sperry Uni vac 1100 to s o r t , c o lla t e and s t a t i s t i c a l l y e va lu a te d ata. Conducted gross necro psies and m icroscopic e v a lu a tio n s and prepared necropsy rep o rts. Research A s s is t a n t - 1976-1980 U n iv e rsity of Wisconsin Dept, o f Pathology Madison, Wisconsin Conducted radioimmunoassays fo r serum progesterone and e s t r a diol fo r use in evaluating the reproductive parameters in rhesus monkeys. Performed c l i n i c a l assessments on la b . anim als in clu d in g hematology and c lin ic a l ch e m istrie s. Supervised and evaluated data and prepared re p o rts f o r contra c tu ra l work. Separated c e llu la r fra c tio n s of t is s u e homogenates by u l t r a c e n trifu g a tio n and assayed homogenates and re s u lta n t f r a c tio n s fo r content o f vario u s components. Provided animal husbandry fo r rhesus monkey and r a t c o lo n ie s. Supervised u n it members on protocols f o r experim entation and proper methods o f conducting b asic la b o ra to ry a n a ly se s. Pre-D octoral Fello w - 1974-1976 U n iv e rsity o f Wisconsin Dept, of Pathology Madison, Wisconsin Stocked and organized a la b o ra to ry fo r the c l i n i c a l and re p ro ductive analyses of laboratory animals. 2- - 13161 Prepared protocols fo r long-term feeding studies in the laboratory animals including those fo r g ro ss, c lin ic a l and repro d uctive assessments. Developed radioimmunoassay procedures f o r serum proges terone and e s t r a d io l. Conducted metabolism and d is trib u tio n stu d ie s in ra ts and rhesus monkeys using rad io lab e le d isomers o f halogenated arom atic hydrocarbons and other chem icals. Laboratory A s s is ta n t - 1970-1972 Humboldt S tate U n iv e rs ity Student Health Center Areata, C alifo rn ia Duties included a ssistin g in routine c lin ic a l laboratory p ra ctice s involved in u r in a ly s is , gonococcal screen in g , VDRLs, heterophiles fo r mononucleosis, thro at cu ltu re s and pregnancy t e s t s . AWARDS/HONORS: National Sea Grant Graduate Student o f the Year - 1976. PROFESSIONAL SO CIETIES: American So ciety fo r P rim ato lo g ists M id-A tlantic Chapter, Society of Toxicology SEMINARS/MEETINGS: P a rtic ip a n t - Federation o f American S o c ie tie s fo r E x p e ri mental Biology (FA SEB), A tla n t ic C it y , N J, A p r il, 1976. T o p ic : " E ffe c ts o f p o lych lo rin a te d biphenyls on repro duction in the prim ate". P a r tic ip a n t - American A sso cia tio n o f P a th o lo g ists and B a c t e r io lo g is t s , Boston, MA, March, 1976. T o p ic : "The A sso cia tio n o f T ra n sp la ce n ta l and Mammary Movement of PCBs w ith In fa n t M orbidity and M o r ta lit y " . In v ite d Speaker - 9th Annual Sea Grant A ss o c ia tio n M eeting, Los A n g e le s, CA, November, 1976. T o p ic : "Toxico lo g y o f PCBs in the Adult and In fa n t Rhesus Monkey". P a rtic ip a n t - FASEB, Chicago, IL , A p r il, 1977. Topic: " E ffe c t s o f p o lych lo rin a te d biphenyls in nonhuman p rim a te s". P a rtic ip a n t - American Chemical S o c ie ty , 11th Great Lakes Regional Meeting, Stevens P o in t, WI, Ju n e, 1977. To p ic: "Responses o f in fa n t prim ates to in te r u t e r in e and neonatal exposure to polychlorinated biphenyls". In v ite d Speaker - Community Meeting on PCBs, U n iv e r s it y of W isconsin, P arksid e, March, 1977. -3 621 f> * P a rtic ip a n t - In te rn a tio n a l Symposium on Pathobiology of Environmental P o llu ta n ts , S to r rs , CT, June, 1977. T o p ics: "Pathology or rhesus macaques (Macaca m ulatta) exposed to tetrachlorodibenzo-jD -dioxin (TCDD)" and "Exposure o f p o ly ch lo rin a te d biphenyl (PCB) to in fa n t rhesus macaques (Macaca m ulatta)". In v ite d Speaker - Community Meeting on PCBs, Door County, WI, September, 1977. In v ite d Speaker - 45th Annual Convention of A sso cia tio n of Midwest Fish and W ild life A gencies, Milwaukee, W I, J u l y , 1978. To p ic: "Consequences o f d ie ta ry PCB consumption in rhesus monkeys". In v ite d Consultant - Symposium on PBB L it ig a t io n , T ra ve rse C it y , M I, J u ly , 1978. T o p ic: "PBB t o x ic it y in the rhesus monkey". In vite d Speaker - Smerkee's Conservation C lub, Sheboygan, WI, Feb ru ary, 1979. T o p ic: "PCBs and t h e ir e f f e c t s on rhesus monkeys". P a rticip a n t - FASEB, D a lla s , TX, A p r il, 1979. Top ic: "Residual e ffe c t s o f p o lych lo rin ate d biphenyls on ad u lt nonhuman prim ates and t h e ir o ffs p rin g " . Expert Witness - S ta te o f North C a ro lin a , H a lifa x County, testim ony on t o x ic it y o f PCBs, Ju n e , 1979. P a rtic ip a n t - Sea Grant Symposium on T o xic M a te ria ls and t h e ir E ffe c t s on Marine Resources, Madison, W I, J u l y , 1979. PUBLICATIONS: B a r s o t t i, D. A. and Van M ille r , J . P .: Reproductive assessments o f rhesus monkeys housed in clim ate co n tro lle d c o n d itio n s. Amer. J . P r im a t o l., submitted 1983. B a r s o t t i, D. A .: Long term repro d uctive assessment o f rhesus monkeys exposed to ch lo rin a te d biphenyls (A ro clo r 1248). Fd. Cosmet. T o x ic o l., submitted 1983. B a r s o t t i, D. A. and Van M ille r , J . P . : Accumulation o f a commercial p o ly ch lo rin a te d biphenyl m ixture (A ro c lo r 1010) in adult rhesus monkeys and t h e ir n ursin g o ffs p rin g . To xico lo g y. In p re ss. Bowman, R. E. , Heironim us, M. P. and B a r s o t t i, D. A .: Locomotor h yp e ra ct i v i t y in PCB-exposed rhesus monkeys. N e u ro to xico l. 2:251-268, 1981. B a r s o t t i, D. A. , Abrahamson, L. J . , M a rla r, R. J . and A lle n , J . R . : The e ffe c t o f clim ate c o n tro lle d housing on the repro d uctive p o te n tia l o f the rhesus monkey. J . Reprod. F e r t i l . 5 9 :1 5 -2 0 , 1980. . a. - 13163 B a r s o t t i, D. A. and A lle n , J . R . : Health im p lica tio n s o f A ro c lo r 1016 on nursing rhesus monkey infants. T o x ic o l. Appl. Pharmacol. 5 2 :1 3 5 , 1980 (A b stra ct). A lle n , J . R . , B a r s o t t i, D. A. and C a rste n s, L. A .: Residual e f f e c t s o f po ly ch lo rin ated biphenyls on adult nonhuman prim ates and t h e ir o ffs p r in g . J . T o x ic o l. Environ. H lth. 6 :5 5-6 6 , 1980. A lle n , J . R . , B a r s o t t i, D. A. and Van M ille r , J . P . : T o x ic o lo g ic a l e ffe c t s o f A ro c lo r 1016 on nonhuman prim ates. EPA Report #68-02:2464, 1980. B a r s o t t i, D. A . , Abrahamson, L . J . and A lle n , J . R . : Hormonal a lt e ra t io n s in female rhesus monkeys fed d ie ts containing 2 ,3 ,7 ,8 -te tra c h lo ro d ib e n z o - d io x in . B u ll. Enviro n. Contam. T o x ic o l. 21:46 3 -46 9, 1979. B a r s o t t i, D. A . , C a rste n s, L . A. and A lle n , J . R . : Residual e f f e c t s o f poly ch lo rin a te d biphenyls on ad u lt nonhuman prim ates and t h e ir o ffs p r in g . Fed. Proc. 38:1119, 1979 (A b s tra c t). A lle n , J . R . , B a r s o t t i, D. A. and Lambrecht, L . K . : Reproductive e f f e c t s of halogenated arom atic hydrocarbons on nonhuman p rim a te s. New York Academy o f S cie n ce s, 320:419-427, 1979. A lle n , J . R . , B a r s o t t i, D. A. and Van M ille r , J . P . : Pathology o f rhesus macaqques (Macaca m u latta) exposed to te tra ch lo ro d ib e n zo - -d io x in (TCDD). In te rn a tio n a l Symposium on Pathology o f Environm ental P o llu t a n t s , National Research C o u n cil, 346-355, 1979. A lle n , J . R . , Van M ille r , J . P. and B a r s o t t i, D. A . : T o x ic o lo g ic a l responses ( o f nonhuman prim ates to 1 , 2 , 4 , 6 , 7 ,8-h exach lo ro d ib en zo --d io xin (HCDD). T o x ic o l. Appl. Pharmacol. 4 7 :1 7 9 , 1979 (A b s t r a c t). C a rste n s, L . A . , B a r s o t t i, D. A. and A lle n , J . R . : Exposure o f p o ly c h lo rin ated biphenyl (PCB) to in fa n t rhesus macaques (Macaca m u la tta ). In t e r n atio n al Symposium on Pathobiology o f Environm ental P o llu t a n t s , .N ational Research C o u n cil, 339-345, 1979. S ch an tz, S. L . , B a r s o t t i, D. A. and A lle n , J . R . : T o x ic o lo g ic a l e f f e c t s pro duced in nonhuman prim ates c h r o n ic a lly exposed to f i f t y p a rts per t r i l l i o n 2 ,3 ,7 ,8 -te tra ch lo ro d ib e n zo - -d io xin (TCDD). T o x ic o l. Appl. Pharmacol. 4 6 :1 8 0 , 1979 (A b s tra c t). A lle n , J . R. , Lambrecht, L. K. and B a r s o t t i, D. A .: Some general e f f e c t s of polybrominated biphenyls in nonhuman p rim ates. J . Am. V et. Med. Assoc. 173 11 :1485-1489, 1978. Lambrecht, L . K. , B a r s o t t i, D. A. and A lle n , J . R. : Responses of nonhuman primates to a polybrominated m ixture. En viro n. Health Perspec. 23:139147, 1978. A lle n , J . R . , B a r s o t t i, D. A . , Van M ille r , J . P . , Abrahamson, L. J . and L a lic h , J . J . : Morphological changes in monkeys consuming a d ie t co n tain ing low le v e ls of 2 ,3 ,7 ,8 - te tra c h lo ro d ib e n z o - - d io x in . Fd. Cosmet. , T o x ic o l. 15:401 -410, 1977. 5 A lle n , J . R. and B a r s o t t i, D. A .: Responses o f in fa n t primates to in te ru te rin e and neonatal exposure o f p o lych lo rin ate d b ip h e n yls. American Chemical So c ie t y , Proceedings o f 11th Great Lakes Regional Meeting, Jun e, 1977 (Ab s tra c t). A lle n , J . R . , B a r s o t t i, D. A. and Van M ille r , J . P . : Reproductive dysfunc tio n in nonhuman prim ates exposed to d io x in s . T o x ic o l. Appl. Pharmacol. 4 1 :1 7 9 , 1977 (A b s tra c t). Norback, D. H. and B a r s o t t i, D. A .: E ffe c t s o f p o lych lo rin ated biphenyls in nonhuman prim ates. Fed. Proc. 365 :3 9 6, 1977 (A b s tra c t). B a r s o t t i, D. A ., M arla r, R. J . and A lle n , J . R . : Reproductive d ysfu nctio ns in rhesus monkeys exposed to low le v e ls o f p o lych lo rin ate d biphenyls (A ro clo r 1248). Fd. Cosmet. T o x ic o l. 14:99 -1 03 , 1976. B a r s o t t i, D. A. and A lle n , J . R . : The a sso c ia tio n o f tra n sp la ce n ta l and mammary movement o f PCBs w ith in fa n t m o rb id ity and m o rta lity . Amer. J . Path. 8 2 :2 1 a , 1976 (A b s tra c t). A lle n , J . R. and B a r s o t t i, D. A .: The e f f e c t s o f tra n sp la ce n ta l and mammary movement o f PCBs on in fa n t rhesus monkeys. Toxicology 6:331-340, 1976. A lle n , J . R . , B a r s o t t i, D. A. and C a rs te n s , L . A .: Residual e ffe c t s of sh o rt term , low le v e l exposure o f nonhuman prim ates to p o lych lo rin ate d biphenyls. T o x ic o l. Appl. Pharmacol. 30:440-451, 1974. 0- 6 1 Dr. Ronald Corderio, M.D., is an internist practicing in Philadelphia, Pennsylvania. His curriculum vitae will be supplied. Dr. Corderio will testify that he is currently engaged in the private practice of medicine as an internist. He will testify that he personally: has examined and/or treated over five hundred Vietnam veterans for complaints related to Agent Orange. He will testify as to the type of interview he has conducted with each veteran, the type of tests that each veteran should have performed, and the clinical significance of positive or negative findings on each of those tests. He will also discuss how toxins, and specifically Agent Orange, can cause changes in each of the tests and what such changes portend for the individual. Dr. Corderio will next discuss some of the available medical literature in both animals and humans to further validate his own work. Dr. Corderio will then outline in detail the results obtained from his own extensive investigation into Agent Orange toxicity based upon his examination of more than five hundred veterans, and will present those conclusions which he feels are reasonably appropriate based upon an analysis of his investigative work. With this material as background, Dr. Corderio will then proceed to present the test results which have been obtained for each court-approved representative veteran plaintiff. He will interpret each of the test results in terms of those individual plaintiffs. Finally, he will testify on generic causation and specific proximate causation in relation to each representative veteran plaintiff. He will also testify as to prognosis for each representative veteran plaintiff. 13167 ARTHUR W. GALSTON, Ph.D. Dr. Galston is Eaton Professor of Botany, Department of Biology, at Yale University. His Curriculum Vitae will be supplied. Dr. Galston is a plant physiologist and has personally observed the effect of the spraying of Agent Orange on the Vietnam ecosystem, i.e. the devastation of the Vietnamese countryside. Dr. Galston has been in Vietnam on four occasions between 1971 and 1982, and will describe those observations while in Vietnam, with such pictorial evidence as is available. Dr. Galston will testify to the potential and actual effects of phenoxy herbicides and their contaminants, both in Vietnam and elsewhere, including the United States and Sweden, and other places. The testimony will include the chemistry and the mechanisms of action of such chemicals on plant life. In addition, Dr. Galston will testify to the fate of Agent Orange and other phenoxy herbicides and their contaminants, especially TCDD, in the environment generally and in Vietnam in particular. Dr. Galston will testify to the persistence of such chemicals on plants, in water, and in soil, such that exposure to the phenoxy herbicides and their contaminants, especially TCDD, by the veterans in sprayed areas in Vietnam is presumed. The bases or grounds for Dr. Galston's testimony as to any facts and opinions expressed are a review of the scientific literature and his personal research and experience. Dr. John Garofalo is a immunologist practicing in Philadelphia, Pennsylvania. His curriculum vitae will be supplied. Dr. Garofalo will testify to the performance of certain tests on the veteran plaintiffs and their wives and children and to the interpretation of those test results. Specifically, he will be conducting phenotyping assay tests for, among others, B-lymphocytes, K cells, T-lymphocytes, T-helper cells, T-cytotoxic cells, and T-suppressor cells. The purpose of these tests is to determine antigen levels, antibody levels, and the presence of a viral defenses and immune surveillance systems, and to identify various types of cells that may be indicators of and/or precursors of malignancy Not only will the tests determine the presence of such factors, but they will also include functional assays of each. LENNART HARDELL, M.D. Dr. Hardell is employed by the University Hospital in its Department of Oncology in Umea, Sweden, where he specializes in internal medicine and oncology. His work includes diagnosis, treatment, and evaluation of possible causes of cancer, and education of medical students. Dr. Hardell will testify to several epidemiological studies which he and colleagues have conducted in Sweden. This research includes investigations concerning the relationship between the risk for different types of cancer and exposure to phenoxy herbicides and chlorophenols. The research has been published in the medical and scientific literature. These studies utilized the case-control study as the vehicle for investigation. Certain methodological aspects, such as selection of cases, selection of controls, assessment of exposure, and statistical methods, were considered; and then utilization was based upon thoroughly considered aspects of bias, all of which were well controlled. Specifically, these studies, four in number, involved soft tissue sarcomas, malignant lymphomas, and colon cancer. Highly statistically significant risks of soft tissue sarcomas and malignant lymphoma were found, whereas no association was found for colon cancer. In point of fact, the negative finding for colon cancer strongly supports the statistical significance of the increased risk demonstrated for soft tissue sarcomas and malignant lymphomas, i.e. a presumed causal relationship between exposure to phenoxy herbicides and human cancer particularly of soft tissue sarcoma and malignant lymphoma. 1 ? *-- 7 0 Dr. Hardell has also seen in his clinical practice basal cell carcinoma of persons previously exposed to phenoxy herbicides, with no other known confounding variables. With respect to those cases with soft tissue sarcoma, malignant lymphoma, and basal cell carcinomas, Dr. Hardell will testify that the presumed exposure to Agent Orange caused, in significant part, such neoplastic processes. The bases for Dr. Hardell's testimony as to various facts and opinion include: educational background; professional training and experience; review of the applicable medical and scientific literature; personal research; and a review of the pertinent medical data of the relevant representative plaintiffs. <l1' -- 71 2- - MAUREEN C. HATCH, Ph.D. Dr. Hatch is Assistant Professor of Epidemiology at Columbia University, School of Public Health, in New York City. Her Curriculum Vitae will be supplied. The subject matter about which Dr. Hatch will testify is reproductive toxicology and its specific applicability to miscarriages and congenital malformations (birth defects) in the wives and children of Vietnam veterans. Dr. Hatch will testify at length to the data collected in Vietnam regarding untoward pregnancy outcomes. Dr. Hatch is one of two investigators who are to publish that portion of the International Symposium held in Ho Chi Minh City in January, 1983 having to do with reproductive toxicology as a result of exposure to Agent Orange and other phenoxy herbicide spraying in Vietnam. The results of these data demonstrate a statistically significant increase in certain congenital malformations, e.g. cleft palate, limb deformaties, and anencephaly, as a result of paternal mediated reproductive effects. The exposure of the fathers was to the spraying of Agent Orange in Vietnam. The mothers were not exposed. These human data are coupled with positive, consistent animal data. For example, such studies where males were exposed indicate the following; the male gonads, are a target site of 2,3,7,8-TCDD action; at the endocrinological level, there has been demonstrated a major effect, i.e., AHH receptor in male gonads; which very nicely provides a mechanistic linkage; and finally, abnormal biochemical and morphologic characteristics of the sperm have been likewise demonstrated. jt r* * J. ALASTAIR W.M. HAY, Ph.D. Dr. Hay is a lecturer on Chemical Pathology, Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds, England. His partial Curriculum Vitae is attached. Dr. Hay will testify to a broad spectrum of matters related to Agent Orange, phenoxy herbicides, and their contaminants, including dioxins, especially 2,3,7,8-TCDD. Dr. Hay will discuss in detail his knowledge of the various phenoxy herbicides and their contaminants, including but not limited to the various aspects of: chemistry; biochemistry; manufacture and/or production; fate in the environment, animals, and humans; modes of exposure, i.e. absorption, ingestion and inhalation, specifically by the veterans who served in Vietnam; toxicity; and the state of the medical and scientific literature at various times since at least 1957 forward. The medical and scientific literature, attendance and participation in various symposia, review of various documents of certain defendants, personal research, and experience form the bases of whatever facts and opinions to which Dr. Hay will testify. Dr. Hay's testimony regarding the medical and scientific literature will include an exposition of the definitions and explanations, and their applicability to the troops exposed in Vietnam, of the phenoxy herbicides and their contaminants, in the following areas: plant physiology; toxicology; neuro-toxicology, both neurological and psychological; epidemiology; immunology; mutagenicity; teratology; reproductive toxicology; and carcinogenicity. ic *7 3 More specifically, the phenoxy herbicides, including Agent Orange, 2,4-D and 2,4,5-1, and their contaminants, including dioxins, especially TCDD are highly toxic, neuro-toxic, immuno-suppressive, teratogenic, potentially mutagenic, and certainly carcinogenic. As a carcinogen, e.g. TCDD, it has no safe level and indeed any single exposure may prove to result in human cancer many years later; said in another way, there is no "no effect" level that can be established. Dr. Hay will testify to examples of the grounds which support the above, including: knowledge of spraying Agent Orange, especially its effect on the Vietnamese countryside; the purpose and historical tracing of the animal studies; historical tracing of the human data, including the various industrial incidents since 1949; references to specific documents, such as the EPA Dioxin document (presently in Draft form); various cancer epidemiology; pertinent teratology epidemiology; various studies of the Vietnamese, especially in area of reproductive toxicology; and those reports of the symptoms and diagnoses of the U.S. Vietnam veterans. C '* 2- - Name: Alastair Watt Macintyre HAY D.O. B. : 21 April 1947 Marital Status: Married Children: 1 son (Tom) Place of Birth: Glasgow, Scotland Nationality: British Degrees: B.Sc. (Hons), Chemistry IIA - London 1969 Ph.D., Biochemistry, London 1973 Home Address: School House, Arthington Lane, Arthington, Leeds LS21 1PE England. Work Address: Department of Chemical Old Medical School, University of Leeds, Leeds LS2 9NL England. Pathology, Place of Secondary Education: Gifford Technical High School, Bulowayo, Zimbabwe (formerly Rhodesia) Present Appointment: University lecturer in Chemical Pathology since April 1979 (University of Leeds) Leeds, England. Former A p p o i n t m e n t s :: Research Fellow - Zoological Soc. of London September 1972 - November 1977 Research Fellow - University of Leeds, Department of Animal Physiology and Nutrition December 1977 - March 1979 PUBLICATIONS Books "(i) Alastair Hay. The Chemical Scythe: Lessons of 2,4,5-T and Dioxin. Plenum Press. 265pp. August 1982 (ii) Sean Murphy, Alastair Hay and Steven Rose. No Fire: No Thunder. The threat of chemical and biological warfare. Pluto Press. (To be published in January 1984). 135pp. Scientific Papers Some 50 scientific papers including: (i) Hay, A.W.M., Mawer, E.B., Hassan, A.G., Crawford, M.A., & Stevens, P.A. The role of essential fatty acids in vitamin D dependent calcium absorption in -the intestine. Proc. of 5th Vitamin D Workshop. Williamsburg USA now in Vitamin D, Chemical, Biochemical and Clinical Endocrinology of Calcium IS175 . 2 Metabolism. Walter de Gruyter. Berlin. 1982 pp309-311. (ii) Hay, Alastair. Vitamin D: Sunlight and precursors. Nature. 2 9 7 , 364 (1982) (iii) Hay, A. Herbicides, Trichlorophenols and soft tissue sarcomas. Lancet I, 1240, (1982). (iv) Hay, A. It kills weeds, but what about people? New Scientist. 94., N o . 1314. ppl58-161 (1982). (v) Hay,A ., Murphy, S., Robinson, J.P., and S. Rose. The poison cloud hanging over Europe. New Scientist. 9J3, No. 1296 pp630 635 (1982) . (vi) Hay, Alastair. New Pathways for clorinated dioxins. Nature, 294, 514-515 (1981). (vii) Hay, A. Experimental Toxicology and cytogenetics: an overview. In "Herbicides and War" to be published by Stockholm International Peace Research Institute. (1984) A. Westing, Ed. (viii) Hay, A. The Mutagenic properties of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in "Chlorinated Dioxins and Dibenzofurans in the Total Environment. Vol II" Edit, by Keith, L.H. et al to be published in 1984. Other Publications I have written some 90 odd articles for the News, News and Views and books review section of the scientific journal Nature since 1976. o* 1 Dr. Herbert Kaye, P h . D . , is a psychologist in the D e p a r t ment of Psychology at the State University of New York at Stoneybrook, Long Island and a visiting Associate Professor in the De partment of Psychiatry at New York University Medical Center. His curriculum vitae will be supplied. Dr. Kaye will testify concerning the significance of a battery of quantitative neuroph y s i o l o g i c a l tests called n e urometries will which be performed on the veteran, wife and children plaintiffs. The procedures were developed in part by Dr. Kaye in conjunction with medical and psychological researchers from this and other coun tries. He will testify that neurometries, on which he has written extensively, is a sophisticated battery of electrical tests in use for about fifty years, which are highly efficient in determing cortical EEG and evoked responses. Dr. Kay will explain the model used in the computeriza tion against which the test results are compared and will explain . how deviations from normal produce certain effects. Dr. Kaye w ill also discuss the m e c h a n i s m by which toxins produce these altered responses, and what effect those altered re sponses have upon the individual veterans at present, and the prog nosis for any additional changes or deterioration in the future based upon an assumed bioaccumulation of the toxic materials in the system. In doing so, he will rely on his experience in diagnosing many Vietnam veterans exposed to Agent Orange. 1 n<L>'*:7 7 RONALD H. KERMAN, Ph.D. Dr. Kerman is Associate Professor, and Chief, Cellular Immunology, Clinical Immunology Laboratories, the University of Texas Medical School at Houston. His Curriculum Vitae is attached. Dr. Kerman will testify that 2,3,7,8-TCDD in particular causes, among others, immuno-suppressive effects, as reported in the literature regarding the various animal species studies. Specifically, TCDD has been demonstrated to suppress T-cell mediated immunity in such species. This effect likewise has been demonstrated in humans by Bekesi, specifically an alteration of mature T-cells. Dr. Kerman will testify that the special scientific discipline involved is immuno-toxicology which has been defined as "the undesirable effects of an inappropriate response of the immune system". The bases for the facts and opinions to which Dr. Kerman will testify include a review of the applicable medical and scientific literature, his educational and professional background, and his work in connection with the Texas Agent Orange Study. Dr. Kerman will discuss the following in his testimony: the immune system, with its organic, cellular, and humoral components - most especially with regard to the latter, T-helper cells, B-cells, plasma cells and immunoglobulin production; immune response, both beneficial and harmful; the various experimental studies, particularly those demonstrating atrophy of the thymus, weight loss, depletion of lymphoid organs, lymphopenia, cutaneous type delayed hypersensitivity (skin thickness) and altered bacterial immuni ty. 1 o ?7 s Dr . Kerman will testify that on the basis of the above a person exposed to TCDD might have increased predisposition to increased infection and neoplasm (cancer). 131^3 2- - CURRICULUM VITAE Ronald H. Kerman, Ph.D. DATE OF BIRTHr June 10, 1943 PLACE OF BIRTH: Chicago, Illinois NATIONALITY: U.S. Citizen SEX: Male EDUCATION: 1965 1967 1969 University of Illinois, B.S. (with Honors) University of Illinois, M.S. University of Illinois, Ph.D. in Immunology HONORS: 1965 1967-1969 1967 1969-1971 1970 Bachelor of Science with General Honors in the College Recipient of Public Health Service Predoctoral Traineeship Phi Sigma National Biological Honorary Recipient of Public Health Service Postdoctoral Traineeship Society of Sigma Xi RESEARCH AND PROFESSIONAL EXPERIENCE: 19831981- 19771977-1980 1974-1977 1973-1977 1972-1973 1969-1971 Associate Professor Department of Pathology, and Chief, Cellular Im munology, Clinical Immunology Laboratories, The Uni versity of Texas Medical School at Houston Associate Professor Department o f Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division o f Organ Transplantation, The University of Texas Medical School at Houston Member, Program in Immunology, Graduate School o f Bio medical Sciences, The University o f Texas Health Science Center at Houston Assistant Professor Department of Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division o f Organ Transplantation, The University of Texas Medical School at Houston Assistant Professor Department o f Surgery, Loyola University Stritch School o f Medicine, Maywood, Illinois Research Immunologist Chief, Immunobiology Research Laboratory, Research Service, V. A. Hospital, Hines, Illinois Assistant Professor Department of Microbiology, Jefferson Medical College Postdoctoral Fellow, (Immunology) Children's Hospital o f Philadelphia and The University o f Pennsylvania School o f Medicine Curriculum Vitae Ronald H. Kerman, Ph.D. 2 PROFESSIONAL SOCIETIES: RESEARCH INTERESTS: RESEARCH SUPPORT: 1974-1978 1976-1979 1976- 1980 1977- 1978 197719771983-1984 OTHER ACTIVITIES: The Transplantation Society (Editorial Board, Trans plantation and Member, Symposium Committee) American Association of Immunologists American Association for Cancer Research New York Academy of Sciences American Society of Transplant Physicians (Member, and Vice Chairman, Scientific Studies Committee) Society for Experimental Biology and Medicine International Society for Heart Transplantation American Association for the Advancement of Science American Society for Histocompatibility and Immuno- genetics (Chairman, Finance and Audit Com m ittee, and Member, Laboratory Accreditation Committee) Immunologic response to allotransplantation and malignancy Evaluation of immunocompetency Co-principal Investigator: Bronchogenic Carcinoma: Immu nologic Profile, Radio and Immunotherapy - V.A. Medical Research Grant No. MRIS-8121-08. $213,000 Co-principal Investigator: Immunotherapy Adjuvant to Radiotherapy of Head and Neck Cancer - V.A. Medical Research Grant No. MRIS-8121-06. $73,814 Co-principal Investigator: Factors Influencing Immuno com ptence in Human Transplantation - V.A. Medical Research Grant No. MRIS-3068. $68,770 Principal Investigator: Functional and Surface Receptor D ifferences of Human T-lymphocyte Subpopulations General Research Support Funds, The University of Texas Medical School at Houston. $5,000 Principal Investigator: The Role of HLA Typing in Renal Transplantation, ESRD Program, No. 450068. $377,400 (last year) Principal Investigator: Immune Monitoring for the Diagnosis of Renal Allograft Rejection, ESRD Program, No. 450068. $544,800 (last year) Principal Investigator: Immune Evaluation of Veterans Exposed to Agent Orange. Texas Veterans Agent Orange Assistance Program, IAC(83-84)1266. $93,352 Special Consultant in Immunology to the Epidemiology and Disease Control Study Section, NIH Consultant in Immunology and Histocompatibility Testing to the Department of Laboratory Medicine, M.D. Anderson Hospital and Tumor Institute Editorial Board, Transplantation Review of manuscripts for the journal Human Immunology Review of manuscripts for the journal Transplantation Review of manuscripts for the journal Heart Transplantation Book reviewer for Journal of American Medical Association Literature Reviewer for The American Association of Clinical Histocompatibility Testing -- AACHTion News Curriculum Vitae Ronald H. Kerman, Ph.D. 3 Grant Reviewer for the Kidney Foundation of Canada Grant Reviewer in Transplantation Immunology for The March of Dimes - Birth D efects Foundation Outside Reviewer of Research Proposals in Immunology for the Research and Development Committee, The Vet erans Administration Research Service Invited Participant (as a testing laboratory) in The Third American HLA Workshop Invited Participant (as a testing laboratory) in The Eighth International Histocompatibility Workshop "Relevance of DR typing to renal allograft survival" Invited Participant (as a testing laboratory) in The Inter national Transfusion and Transplantation Workshop Invited Participant (as a testing laboratory) for the Ninth International Histocompatibility Workshop Invited Presenter at an NIH Workshop, "The Biological Relevance of Immune Suppression as Induced by Genetic, Therapeutic and Environmental Factors" Invited Participant (as a testing laboratory) in the Inter national Collaborative Transplant Study Laboratory Inspector for Clinical Laboratory Accreditation in Histocompatibility for The American Society for His tocompatibility and Immunogenetics and The C ollege of American Pathologists Chairman, Finance and Audit Committee for The American Society for Histocompatibility and Immunogenetics Member, Symposium and Affiliations Committee, The Transplantation Society Member and Vice-Chairman, Scientific Studies Com m ittee, American Society of Transplant Physicians Member, Acquired Immune Deficiency Syndrome (AIDS) Working Group for the Houston Area Chairman, Organizing Com m ittee and Host for The Fourth International Immune Monitoring Symposium: Im munological Evaluation and Monitoring of the Transplant Recipient (1983) Member, Organizing Committee for the International Sym posium on Relevant Immunological Factors in Clinical Kidney Transplantation, Heidelberg, West Germany, 1985 Member, UTMSH Admissions Interview Committee Member, UTMSH Admissions Committee Member, Medical Review Board, Organ Transplantation Center, UTMSH Member, Committee on Subject Selection for The University of Texas System Agent Orange Study Member, Steering Com m ittee, Program in Immunology, UT-GS3S Chairman, By-Laws Com m ittee, Program in Immunology, UT-GSBS Course Director, "Methods in Cellular Immunology," a Pro gram in Immunology Course, UT-GSBS 82.JL*-' BIBLIOGRAPHY Ronald H. Kerman, Ph.D Publications 1. Kerman, R., Segre, D. and Myers, W.L.: Altered response to pneumococcal polysaccharide in offspring of immunologically paralyzed mice. Science 156:1514, 1967 2. Kerman, R., Segre, D. and Myers, W.L.: The role of immune and natural specific antibodies in immunologic paralysis and immunity of mice to pneumococcal polysac charide Type RI. J. Immunol. 104:655, 1970. 3. Kerman, R. and Segre, D.: Anti-pneumococcal polysaccharide Type III hemolytic plaques in mice: Cellular response in immunity and immunologic paralysis. J. Immunol. 104:1262, 1970. 4. Kerman, R. and Harris, T.N.: Resistance to dnaturation by periodate of a dialyzable histocompatibility antigen. Proc. Soc. Exp. Biol. Med. 141:179-183, 1972. 5. Kerman, R.H., Harris, T.N. and Harris, S.: Preparation of a dialyzable histocompati bility antigen from balb/c mice. Proc. Natl. Acad. Sci. 69:223-227, 1972. 6. Smith, R.A., Kerman, R., Ezdinli, E. and Stfani, S.: A modified assay for the detection of human adult active rosette forming cells. J. Immunol. Meth. 8:175-184, 1975 7. Kerman, R. and Stefani, S.: Immunological evaluation of patients with solid tumors before and after radiotherapy. In Crispen, R.G. (ed.): Neoplasm Immunity: Mecha nisms, pp. 109-120. University of Illinois Press, 1976. 8. Stefani, S., Kerman, R. and Abbate, J.: Immune evaluation of lung cancer patients undergoing radiation therapy. Cancer 37:2792-2796, 1976. 9. Stefani, S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence of patients undergoing radiotherapy for malignancies of the head and neck. Am. J. Roentgenol. 126:880-886, 1976. 10. Kerman, R.H. and Geis, W.P.: Total and active T -cell kinetics in renal allograft recipients. Surgery 79:398-407, 1976. U . Kerman, R., Smith, R., Stefani, S. and Ezdinli, E.: A ctive T-rosette forming cells in the peripheral blood of cancer patients. Cancer Res. 36:3274-3278, 1976. 12. Kerman, R., Smith, R., Ezdinli, E. and Stefani, S.: Unification and technical aspects of total T, active T and B lymphocyte rosette assays. Immunol. Comm. 5(7-3):685694, 1976. 13. Dodson, M.G., Kerman, R.H., Lange, C.F., Stefani, S. and O'Leary, J.A.: T and B cells in pregnancy. Obstet. Gynecol. 49:299-302, 1977. Bibliography Ronald H. Kerman, Ph.D. 2 14. Kerman, R.H. and Stefani, S.: PHA stimulation of lymphocytes from patients with lung cancer. Oncology 34:10-12, 1977. 15. Kerman, R.H. and Stefani, S.: Radio and immunotherapy of lung cancer: A preliminary report. In Crispen, R.G. (ed.): Neoplasm Immunity-Solid Tumor Therapy, pp. 29-35. Franklin Institute Press, 1977. 16. Stefani, S. and Kerman, R.H.: Lymphocyte response to PHA before and after radiation therapy in patients with carcinomas of the head and neck. J. Laryngol. Otol. 91:605-609, 1977. 17. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of the active T-RFC in renal allograft survival. Surgery 2:607-612, 1977. 18. Marshack, M., Toto, P. and Kerman, R.H.: Delayed hypersensitivity in the hamster cheek pouch. J. Immunol. Meth. 15:325-330, 1977. 19. Marshack, M., Toto, P. and Kerman, R.H.: Immunotherapy of chemically-induced tumors in the hamster cheek pouch with dinitrochlorobenezene. J. Dental Res. 57:625-630, 1978. 20. Stefani, S. and Kerman, R.: Prognostic significance of pre-therapy delayed hypersen sitivity and T -cell levels in patients with lung cancer. In Nieburgs, H.E. (ed.): Proceedings of the Third International Symposium on the Detection and Prevention of Cancer, Vol. 1, Part II, pp. 785-797. Marcel Dekker, Inc., 1978. 21. Geis, W.P., Iwatsuki, S., Molnar, Z., Giaechino, J.L., Kerman, R.H., Ing, T.S. and Hano, J.E.: Immunoblastic pseudo-lymphoma in renal allograft recipients. Arch. Surg. 113:461-466, 1978. 22. Dodson, M., Klegerman, M., Kerman, R.H., Lange, C., Tessler, J. and O'Leary, J.: Bechet syndrome: With immunologic evaluation. Obstet. Gynecol. 5_l:621-625, 1978. 23. Dodson, M.G., Klegerman, M.E., Menon, M., Kerman, R.H., Lange, C.F. and O'Leary, J.A.: Establishment and characterization of a squamous cell carcinoma of the vulva in tissue culture and immunological evaluation of the host. Am. J. Obstet. Gynecol. 131:606-619, 1978. 24. Kerman, R.H. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Transpl. Proc. 10(3):633-635, 1978. 25. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Predictive value of active T-RFC in renal allograft survival. Transpl. Proc. 10(3):637-638, 1978. 26. Kerman, R.H. and Stefani, S.S.: E ffect of BCG immunotherapy on the active T and total T-RFC in patients with lung cancer.. Cancer Immunol. Immunother. 4:41-47, 1978. 27. Kahan, B.D., Kerman, R.H. and McConnell, R.: Combination of immunological and radionuclide techniques to diagnose allograft rejection. Surgical Forum. 29:364-366, 1978. tsiDiiography Ronald H. Kerman, Ph.D. 3 28. Stfani, S. and Kerman, R.H.: Prognostic value of the immunologic profile in inoperable lung cancer patients treated by radiation. In Muggia, F. and Rozencweig, M. (eds.): Lung Cancer (Progess in Cancer Research and Therapy), Vol. 11, pp. 465470. Raven Press, Inc., New York, 1979. 29. Kerman, R.H.: Identification of human T and B lymphocytes. In Natelson, S., Pesce, A.J. and D ietz, A.A.: Clinical Immunochemistry: Chemical and Cellular Bases and Applications in D isease, pp. 12-20. American Association for Clinical Chemistry, 1979. 30. Kahan, B.D., Floyd, M., Oka, T., Van Buren, C.T. and Kerman, R.H.: Immunological techniques in clinical renal transplantation. I. Cross-Match Methods, Jap. J. Trans plant. 14:1-13, 1979. 31. Kahan, B.D., Floyd, M., Oka, T., Van Buren, C.T. and Kerman, R.H.: Immunological techniques in clinical renal transplantation. II. Immunological Monitoring Post allografting. Jap. J. Transplant. 14:14-25, 1979. 32. Kerman, R.H., Floyd, M., Conner, W., McConnell, R., McConnell, B.J., Van Buren, C.T. and Kahan, B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Transpi. Proc. Jll:1229-1231, 1979. 33. Geis, W.P., Giacchino, J.L., Buckingham, J.M., Bansal, V.K., Iwatsuki, S., Kerman, R.H., Ing, T.S. and Hano, J.E.: Does suppression of T-RFC determine in vivo immunosuppressive e ffe ct of ATG? Transpl. Proc. JL1:1433-1434, 1979. 34. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant ATG therapy. Transplantation 30:450-454, 1980. 35. Kerman, R. and Kahan, B.D.: Clinical histocompatibility testing in renal transplanta tion: Potential keys to alloimmune specificity and reactivity. In Reisfeld, R. and Ferrone, S. (eds.): Current Trends in Histocompatibility, Vol. 2, pp. 201-226. Plenum Press, 1981. 36. Kerman, R.H. and Kahan, B.D.: Assessment of immune parameters of transplant recipients on immunosuppressive therapy. In Dean, J. and Padarathsingh, M. (eds.): Biological Relevance of Immune Suppression as Induced by Genetic Therapeutic and Environmental Factors, pp. 82-97. Van Nostrand R.einhold Co., New York, 1981. 37. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prolonged allograft survival of strong pretransplant immune responders treated with ATG. Transpl. J?roc. 13:332-335, 1981. 38. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Correlation of non specific immune monitoring with rejection or impaired function of renal allografts. Transplantation 32:16-23, 1981. 39. Kerman, R.H., Floyd, M., Van Buren, C.T., and Kahan, B.D.: Prediction of cadaveric allograft survival based on pretransplant nonspecific immunocomptence. Transpl. Proc. 13:1533-1535, 1981. i 3 8 5 Bibliography Ronald H. Kerman, Ph.D. 4 40. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Serial measurement of nonspecific immune parameters of chronically hemodialyzed renal failure patients. J. Clin. Immunol. 1:163-168, 1981. 41. Kerman, R.H.: New developments in transplantation immunology. The Cancer Bulletin 33(6):281-286, 1981. 42. Kerman, R.H.: E ffect of blood transfusion on renal allograft survival: Immunological considerations. Am. J. Kidney Diseases 2:125-127, 1981. 43. Kerman, R.H. and Kahan, B.D.: Immunological evaluation of transplant rejection: Pre and postoperative indices detecting immune responsiveness. In Hayry, P. (ed.): Present and Future Trends in Clinical Transplantation. Ann. Clin. Res. 13:244-263, 1981. 44. Kerman, R.H., Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan, B.D.: Influence of blood transfusions on immune responsive ness. Transpi. Proc. 14:335--337, 1982. 45. Kahan, B.D., Van Buren, C.T., Lin, S.N., Ono, Y., Agostino, G., LeGrue, S., Boileau, M., Payne, W. and Kerman, R.H.: Immunopharmacologic monitoring of Cyclo sporin A-treated recipients of cadaveric kidney allografts. Transplantation 34:36-45, 1982. 46. Ono, Y., Kerman, R.H. and Kahan, B.D.: Natural cell-m ediated cytotoxicity and suppressor activity for natural cell-m ediated cytotoxicity in long-term renal trans plant patients. Transplantation 34:103-107, 1982. 47. Van Buren, C.T., Kerman, R.H., Agostino, G., Payne, W., Flechner, S. and Kahan, B.D.: The cellular target of Cyclosporin A action in man. Surgery 92:167-174, 1982. 48. Kahan, B.D., Kerman, R.H., Agostino, G., Friedman, A. and LeGrue, S.J.: The action of Cyclosporin A on human lymphocytes. In White, D.J.G. (ed.): Cyclosporin A, pp. 281-293. Elsevier - Biomedical Press, Amsterdam, 1982. 49. Agostino, G.J., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using leucocytes from normal individuals, uremic individuals and allograft recipients. Transplantation 34:367-371, 1982. 50. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, B.D.: CMV and renal allograft survival. In Eisenstein, T. and Friedman, H. (eds.): Host D efenses to Intracellular Pathogens, pp. 517-519. Plenum Press, Inc., New York, 1983. 51. Ettenger, R.B., Kerman, R., Jordan, S.C., Warshaw, B.L., Harris, R. and Fine, R.: Sensitization following donor-specific transfusions for living related renal transplan tation. Transpl. Proc. 15:943-945, 1983. 52. Van Buren, C.T., Kerman, R.H., Agostino, G., Flechner, S., Payne, W., and Kahan, B.D.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Transpl. Proc. 15:527-530, 1983. 83 Bibliography Ronald H. Kerman, Ph.D. 5 53. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S. and Kahan, B.D.: Monitoring T cell subsets and immune events in renal allograft recipients. Transpl. Proc. 15:1170-1172, 1983. 54. Flechner, S., Kerman, R., Van Buren, C.T., Payne, W., and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans plants. Transpl. Proc. 15:442-445, 1983. 55. Agostino, G., Kahan, B.D. and Kerman, R.: D etection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Transpl. Proc. 15:724-728, 1983. 56. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne, W., Flechner, S., Conley, S., Brewer, S. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Transpl. Proc. 15:1022-1025, 1983. 57. Kerman, R.H., Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, 3. and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Trans plantation 36:50-54, 1983. 58. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo sporine improves allograft survival in immunologically high-risk renal allograft recipients. Transpl. Proc. 15:1909-1911, 1983. 59. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Transpl. Proc. 15:1971-1973, 1983. 60. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Detection of host presensitization to donor alloantigens utilizing a comprehensive immune crossmatch. Transpl. Proc. 15:1815-1816, 1983. 61. Flechner, S.M., Payne, W.D., Van Buren, C., Kerman, R., and Kahan, B.D.: The e ffe c t of cyclosporine on early graft function. Transplantation 36:268-272, 1983. 62. Verani, R.R., Bergman, D., and Kerman, R.H.: Glomerulopathy in acute and chronic rejection: Ultrastructural characteristics and relationship to graft survival. Am. J. Nephrol. 3:253-256, 1983. 63. Kerman, R.H.: Editorial: Influence of HLA A, B and DR antigen matching in transfused cadaver renal transplant patients. Cleveland Clinic Quarterly 50:216-217, 1983. 64. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W. and Kahan, B.D.: Immuno logical monitoring of renal allograft recipients treated with cyclosporine. Transpl. Proc. 16:2302-2305, 1983. Bibliography Ronald H. Kerman, Ph.D. 6 65. Van Buren, C., Kerman, R., Agostino, G., Flechner, S., Payne, W.D., and Kahan, B.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Transpi. Proc. 16:2293-2297, 1983. 66. Kahan, B.D., Van Buren, C., Flechner, S., Payne, W.D., and Kerman, R.: Cyclosporine immunosuppression m itigates immunologic risk factors in renal allotransplantation. Transpl. Proc. 16:2469-2478, 1983. 67. Flechner, S.M., Van Buren, C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Transpl. Proc. 16:2689-2694, 1983. 68. Flechner, S.M., Van Buren, C.T., Kerman, R., and Kahan, B.D.: The e ffe c t of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Transpl. Proc., 1983 (In press). 69. Flechner, S.M., Kerman, R.H., Van Buren, C., and Kahan, B.D.: Successful trans plantation of cyclosporine treated haploidentical living related renal recipients without blood transfusions. Transplantation, 1984 (In press). 70. Kerman,_ R.H., Van Buren, C.T., Flechner, S.M., and Kahan, B.D.: Correlation of visual, Slop-release, and flow cytometry crossmatch results to graft survival. Transpl. Proc., 1984 (In press). 71. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Transpl. Proc., 1984 (In press). 72. Van Buren, C.T., Flechner, S.M., Kerman, R.H., Vaughn, W., and Kahan, B.D.: Cyclosporine improves outcome in high risk cadaveric renal allograft recipients. Transpi. Proc. 1984 (In press). 73. Kerman, R.H., Manner, C., Ford, K., and Hoots, K.: Comprehensive immune evaluation of 78 hemophiliacs. Ann. N. Y. Acad. Sc. 1984 (In press). Bibliography Ronald H. Kerman, Ph.D. 7 Abstracts and Presentations 1. Kerman, R., Clark, J. and Wheelock, E.F.: Mononuclear infiltrate into an air pouch: A new in vitro cell mediated immune assay. Fed. Proc. 32:973, Atlantic City, New Jersey, April 1973. 2. Wheelock, E.F., Kerman, R.H., Clark, J. and Toy, S.: Cell mediated immunity in dormant friend virus infections. Proc. Am. Assoc. Cancer Res. 14:68, Atlantic City, New Jersey, April 1973. 3. Stefani, S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence in head and neck cancer patients undergoing radiotherapy. Abstract, American Radium Society Meeting, San Juan, Puerto Rico, May 1975. 4. Kerman, R., Stefani, S. and Geis, W.P.: Total and active T -cell dynamics in renal allograft recipients. Abstracts of the American Society Transplant Surgeons, Chicago, Illinois, May 1976. 5. Kerman, R., Stefani, S., Smith, R., Ezdinli, E. and. Geis, W.P.: Immunological evaluation of patients with solid tumors and hematological malignancies. Presented at the 1975 Cancer Symposium, Neoplasm Immunity: Mechanism, Chicago, Illinois, September 1975. 6. Stefani, S., Kerman, R. and Abbate, J.: Immunological evaluation of patients with bronchogenic carcinoma. Presented at the American Society of Therapeutic Radi ology, San Francisco, California, October 1975. 7. Stefani, S. and Kerman, R.: Determination and prognostic value of immunocompe tence in patients with lung cancer treated by radiotherapy. Abstracts of the Third International Symposium on Detection and Prevention of Cancer, New York, April 1976. 8. Geis, W.P., Vaz, A.L. and Kerman, R.H.: Steroid sparing e ffect of ATG in high risk renal allograft survival. Presented at the American Society of Transplant Surgeons Meeting, Chicago, Illinois, May 1976. 9. Kerman, R.H., and Geis, W.P.: Prognostic significance of the active T -cell in renal allograft survival. Presented at the American Society Transplant Surgeons Meeting, Chicago, Illinois, May 1976. 10. Stefani, S. and Kerman, R.: BCG and radiotherapy in bronchogenic carcinoma: Preliminary report. Presented at the American Society of Therapeutic Radiology, .Atlanta, Georgia, October 1976. 11. Kerman, R. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Presented at the Sixth International Congress of the Transplantation Society Special Session Immunological Monitoring of Transplant Recipient, New York, August 1976. 12. Kerman, R. and Stefani, S.: Radio and immunotherapy of lung cancer: A preliminary report. Presented at the 1977 Chicago Symposium: Immunotherapy of Solid Tumors, Chicago Illinois, February 24-25, 1977. Bibliography Ronald H. Kerman, Ph.D. 8 13. Stefani, S. and Kerman, R.H.: Relevance of immunologic analysis for patients with inoperable lung cancer treated by radiotherapy. Presented at an NCI sponsored Symposium "The Second Conference on Lung Cancer Treatment," at Airlie House, Virginia, May 22-24, 1977. 14. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of active T-RFC in renal allograft survival. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 15. Kerman, R.H. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 16. Ezdinli, E., Simonson, K., Icli, F. and Kerman, R.: E ffects of single vs. multiple agent therapy on cell-m ediated immunity. Proc. Amer. Assoc. Clin. Oncol. 18:355, Denver, Colorado, May 1977. 17. Geis, W.P., Iwatsuki, S., Molnar, Z., Giacchino, J.L., Kerman, R.H., Ing, T.S. and Hano, J.E.: Immunoblastic pseudo-lymphoma in renal allograft recipients. Presented at the Western Surgical Association, Las Vegas, Nevada, November 15, 1977. 18. Kerman, R.H., Roesler, H. and Kahan, B.D.: Specific stimulation of active T -R osette forming cells by 3M KC1 solubilized antigen. Fed. Proc., 1973. Presented at the FASEB-AAI Meeting, Atlanta, Georgia, June 1978. 19. Kerman, R.H., Floyd, M., Conner, W., McConnell, B.J., McConnell, R. and Kahan, B . D.: Correlation of active T-RFC and spontaneous blastogenesis with decreased renal allograft function. Abstracts of the American Association for Clinical Histocompatibility Testing, Boston, Massachusetts, June 1978. 20. Kerman, R.H., Roesler, H. and Kahan, B.D.: Increased active T-RFC with in vitro stimulation by soluble donor antigen. Abstracts of the Amer. Assoc, of Clin. Histocomp.. Testing, Boston, Massachusetts, June 1978. 21. Kerman, R.H., Floyd, M., Conner, W., McConnell, R., McConnell, B .J., Van Buren, C. T. and Kahan, B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Presented at the VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 22. Kerman, R.H.: Invited speaker to a special workshop "Immunological Monitoring of the Transplant Patients", VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 23. Kahan, B.D., Kerman, R. and McConnell, R.: Combination of immunological and radionuclide techniques diagnoses allograft rejection. Presented at the American College of Surgeons, San Francisco, California, October 1978. 24. Michelson, J., McConell, Kerman, R. and Kahan, B.: Association of acute rejection episodes in renal transplant patients with scored results of computer analyzed data. Presented at the Southwest Society of Nuclear Medicine Meeting, March 16, 1979, San Antonio, Texas. 190 Bibliography Ronald H. Kerman, Ph.D. 9 25. Kerman, R.H., Macek, C. and Kahan, B.D.: Increase in 3 different E-rosette markers on human T cells following PHA activation. Fed. Proc. 38 (No. 3, Part n):1282. Presented at the Annual Meeting of The American Association of Immunologists, Dallas, Texas, April 1979. 26. Kerman, R.H.: Immunological considerations in renal transplantation. Clinical Oncology Grand Rounds, M.D. Anderson Hospital and Tumor Institute, September 1979. 27. Kerman, R.H. and Kahan, B.D.: Assessment of immune parameters of transplant recipients on immunosuppressive therapy. Presented at an NIH Workshop on "The Biological Relevance of Immune Suppression as Induced by Genetic Therapy and Environmental Factors," Williamsburg, Virginia, November 1979. 28. Invited participant in a working cadre for the NIH to develop a "Consensus On Immunotoxicology" for the National Toxicology Program, November 1979, Research Triangle Park, N.C., NIEHS, NIH. 29. Kerman, R.H.: Histocompatibility testing in transplantation. Pathology Grand Rounds, St. Luke's Hospital, January 1980. 30. Van Buren, C.T., Kerman, R.H. Van Buren, D. and Kahan, B.D.: Correlation of immune responsiveness with nutritional indices in chronic renal failure patients. Presented at the American Society for Parenteral and Enteral Nutrition, Annual Meeting, Chicago, Illinois, January - February 1980. 31. Kerman, R.H.: Immune monitoring of renal allograft recipients. Surgical Grand Rounds, University of Miami School of Medicine, March 1980. 32. Kerman, R.H.: Pre- and postoperative immune monitoring of allograft recipients. Medical Grand Rounds, Division of Dialysis and Transplantation, Children's Hospital of Los Angeles, April 1980. 33. Kerman, R.H. and Semchuk, R.: Delineation of a radioresistant T cell subpopulation. Fed. Proc. 39(3):945. Presented at the Annual Meeting of The American Association of Immunologists, Anaheim, California, April 1980. 34. Kerman, R.H.: E ffect of heat on the ability of human T cells to express the active T and total T receptors. Fed. Proc. 39(3): 1137. Presented at the Annual M eeting of The American Association of Immunologists, April 1980, Anaheim, California. 3-5. Kerman, R., Peddada, L. and Kahan, B.D.: Correlation of hyperacute rejection with " .LDA and CD A vs. 51cr-labeled donor T and B cell targets. Presented at The American Association for Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 36. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Improved allograft survival of strong responder-high risk cadaver recipients with adjuvant immunosuppressive therapy. Presented at the Annual Meeting of The American Association for Clinical Histocompatibility Testing, April 1980. 12191 Bibliography Ronald H. Kerman, Ph.D. 10 37. Kerman, R., Conklin, R., Cahall, D. and Kahan, B.D.: Association of cytomegalovirus and renal allograft survival. Presented at the meeting of the American Association for Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 38. Kerman, R., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Delineation of donor specific and nonspecific pretransplant immunocomptence as a predictor for LRD allograft survival. Presented at the Meeting of The American Association of Clinical Histocompatibility Testing, St. Louis, ?/lissouri, April 1980. 39. Kerman, R.H., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant immuno suppressive therapy. Presented at the annual meeting of The American Society of Transplant Surgeons, Chicago, Illinois, May 1980. 40. Kerman, R.H., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Correlation of nonspecific immune monitoring of renal allograft recipients with rejection and impaired renal function. Presented at the Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, May 1980. 41. Kerman, R., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Prolonged allograft survival of strong pretransplant immune responders treated with ATG. Presented at the VUIth International Congress of The Transplantation Society, Boston, Massachu setts, June 1980. 42. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prediction of renal allograft survival based on pretransplant non-specific immunocomptence. Presented at The Second International Symposium on Immunological Monitoring of the Trans plant Recipient, Leiden, The Netherlands, September 1980. 43. Kerman, R.H., Floyd, M., Van Buren, C.T., McConnell, B.J., McConnell, R. and Kahan, B.D.: Delineation of renal allograft rejection and impaired renal function by serial measurement of non-specific immune parameters. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 44. Kerman, R.H. and Kahan, B.D.: Increased expression of the active T-RFC receptor as a measure of allosensitization following in vitro stimulation of recipient lympho cytes by soluble donor HLA antigens. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 45. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, 3.D .: Correlation of HLA A,B . and DR typing to cadaveric and living related renal allograft survival. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 46. Floyd, M., Kerman, R., Woo, J., Van Buren, C.T. and Kahan, B.D.: Relationships of beta-2-microglobulin metabolism, immune reactivity and renal allograft rejection. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 92 Bibliography Ronald H. Kerman, Ph.D. 11 47. Kerman, R.H.: Immune monitoring of renal allograft recipients. Surgical Grand Rounds, University of Chicago, June 1981. 48. Kerman, R.H., Van Buren, C.T., LeGrue, S.J. and Kahan, B.D.: Immunopharmacological monitoring of cadaveric renal allograft recipients receiving Cyclosporin A. Presented at the Annual Meeting of the American Society of Transplant Surgeons, Chicago, Illinois, June 1981. 49. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, B.D.: CMV and renal allograft rejection. Presented at a Symposium on Host Defenses to Intra cellular Pathogens, Franklin Plaza Hotel, Philadelphia, Pennsylvania, June 1981. 50. Schoenberg, L.P., Kahan, B.D. and Kerman, R.H.: The use of Cyclosporin A as immunosuppressive medication in renal transplantation. Presented at The National Kidney Foundation, Inc., Washington, D.C., November 1981. Amer. J. Kidney Diseases, Program for Clinical Dialysis and Transplantation Forum, p. 29. 51. Ettenger, R., Kerman, R., Arnett, J., Jordan, S., Warshaw, B., Harris, R., Wassner, S. and Fine, R.: Sensitization following donor-specific transfusions for live-related renal transplantation. American Society of Nephrology, Washington, D.C., November 1981. 52. Flechner, S., Boileau, M., Payne, W., Van Buren, C., Kerman, R. and Kahan, B.: The use of Cyclosporin A in strong immune responder, high risk renal transplant reci pients. American Urological Association, Kansas City, Kansas, 1982. 53. Kerman, R., Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan, B.: Influence of blood transfusions on immune responsiveness. Presented at The Transfusion and Transplantation Conference, Los Angeles, Cali fornia, January - February 1982. 54. Agostino, G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using mononuclear leukocytes from normals, urmies and allograft recipients. Pre sented at the Annual Meeting of The American Association of Immunologists, FASEB, New Orleans, Louisiana, April 1982. 55. Agostino, G.J., Kahan, B.D. and Kerman, R.H.: Measurement of suppressor cell status in potential allograft recipients. Presented at the Annual Meeting of The American Association of Clinical Histocompatibility Testing, San Francisco, Cali fornia, April 1982. 56. Kerman, R.H.: Invited presenter at two workshops on 1) Immune monitoring of allograft recipients and 2) The e ffect of transfused blood and blood products on uremic hosts. Presented at the Annual Meeting of The North American Transplant Coordinators Organization, San Antonio, Texas, May 1982. 57. Kerman, R.H., Van Buren, C., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affectin g cadaveric allograft survival. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, June 1982. 1JLC 93 Bibliography Ronald H. Kerman, Ph.D. 12 58. Agostino, G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using leucocytes from normal individuals, uremic individuals, and allograft recipients. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, June 1982. 59. Kerman, R.H.: Invited presenter at a workshop on "Human T lymphocyte subpopula tions: Their role in rejection and immunosuppression." Presented at the International Congress of The Transplantation Society, Brighton, England, August 1982. 60. Kerman, R.H.: Invited presenter at a workshop on "Mechanisms responsible for blood transfusion effects." Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 61. Ettenger, R.B., Kerman, R., Jordan, S.C., Warshaw, B.L., Harris, R. and Fine, R.: Sensitization after donor-specific transfusions for live-related renal transplantation. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 62. Van Buren, C.T., Kerman, R.H., Agostino, G., Flechner, S. Payne, W. and Kahan, B.D.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 63. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner,.S. and Kahan, B.D.: Monitoring T cell subsets and immune events in renal allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 64. Flechner, S., Kerman, R., Van Buren, C.T., Payne, W. and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans plants. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 65. Agostino, G., Kahan, B.D. and Kerman, R.: D etection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 66. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne, W., Flechner, S., Conley, S., Brewer, E. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 67. Kahan, B.D., Kerman, R., Payne, W.D., Flechner, S. and Van Buren, C.T.: Immunopharmacologic studies of cyclosporine-treated renal allograft recipients. Fifth Tripartite Meeting, Society of University Surgeons, Salzburg, Austria, September 1982. Bibliography Ronald H. Kerman, Ph.D. 13 68. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo sporine improves allograft survival in immunologically high-risk renal allograft recipients. Presented at the Third International Immunological Monitoring Sym posium, Key Biscayne, Florida, November 1982. 69. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: D etection of host presensitization to donor alloantigens utilizing a comprehensive immune crossmatch. Presented at the Third International Immunological Monitoring Sym posium, Key Biscayne, Florida, November 1982. 70. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Presented at the Third International Immunological Monitoring Symposium, Key Biscayne, Florida, November 1982. 71. Kerman, R.H.: Invited plenary speaker at the First Annual Meeting of The American Society of Transplant Physicians, "Optimizing immunosuppression: Mode of action of cyclosporine." Chicago, December 1982. 72. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Cyclo sporine improves allograft survival in immunologically high-risk renal allograft recipients. Presented at The Annual Meeting, National Kidney Foundation, Clinical Dialysis and Transplant Forum, Chicago, December 1982. 73. Kerman, R.H.: Role of immune evaluation in clinical medicine. Clinical Immunology Grand Rounds, The Children's Memorial Hospital, Chicago, Illinois, December 1982. 74. Kerman, R.H.: Immunologic effects of toxic materials. Presented at Toxicology Clinical Update, University of Texas Medical Branch, Galveston, Texas, January 1983. 75. Kerman, R.H.: Cyclosporine improves allograft survival in immunologically high risk renal allograft recipients. Presented at Pathology Grand Rounds, University of Pittsburgh School of Medicine, February 1983. 76. Kerman, R.H.: Immune evaluation of renal failure patients and allograft recipients. Presented at Surgical Grand Rounds, St. Louis University Medical Center, St. Louis, Missouri, March 1983. 77. Kerman, R.H.: Immunological evaluation of hemophiliacs. Presented at a Symposium on Current Problems in the Management of Hemophiliac Complications, Houston, Texas, April 1983. 78. Flechner, S., Kerman, R.H., Van Buren, C.T., Payne, W., and Kahan, B.D.: Successful transplantation of high mixed lymphocyte culture haplo-identical living related donors using cyclosporine and prednisone. Presented at the Annual American Urological Association, Las Vegas, Nevada, April 1983. 79. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Immunolo gical monitoring of renal allograft recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. JL c <u ,,*qJ Bibliography Ronald H. Kerman, Ph.D. 14 80. Van Buren, C., Kerman, R., Agostino, G., Flechner, S., Payne, W.D., and Kahan, B.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 81. Kahan, B.D., Van Buren, C., Flechner, S., Payne, W.D., and Kerman, R.: Improved outcome of 150 renal allografts in immunologically high risk recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 82. Flechner, S.M., Van Buren, C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 83. Flechner, S.M., Van Buren, C.T., Kerman, R., and Kahan, B.D.: The effe ct of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 84. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo sporine immunosuppression overcomes immunologic risk factors for recipients of cadaveric renal allografts. Presented at the Annual Meeting of The American Society of Transplant Physicians, Chicago, Illinois, June 1983. 85. Flechner, S.M., Kerman, R.H., Van Buren, C.T., and Kahan, B.D.: The high risk haploidentical living related recipient: Transplantation without blood transfusions and steroid withdrawal using cyclosporine. Presented at the Annual Meeting of The American Society of Transplant Physicians, Chicago, Illinois, June 1983. 86. Kerman, R.H.: Relationship of immunocomptence of hemophiliac patients and acquired immune deficiency syndrome (AIDS). Presented at the Gulf Coast Hemo philia Chapter Meeting, Houston, Texas, October 1983. 87. Kerman, R., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Correlation of visual, 51-Cr-reiease and flow cytometry crossmatch results to graft survival. Presented at The Fourth International Symposium: Immune Monitoring of The Transplant Re cipient, Houston, Texas, November 1983. 88. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Presented at The Fourth International Symposium: Immune Monitoring of The Transplant Recipient, Houston, Texas, November 1983. 89. Kerman, R.H., Manner, C., Ford, K., and Hoots, K.: Comprehensive immune evaluation of 78 hemophiliacs. Presented at the New York Academy of Sciences Symposium on Acquired Immune D eficiency Syndrome, New York, New York, Novem ber 1983. 90. Kerman, R., Van Buren, C.T., Flechner, S.M., and Kahan, B.D.: DRW6 and DR3 phenotypes correlating with immune response. Presented at the Annual Meeting of The American Association for Clinical Histocompatibility Testing, Chicago, Illinois, November 1983. 3 0^ fr*'* r\ -kv- Ci/' ;; Bibliography Ronald H. Kerman, Ph.D. 15 91. Van Buren, C.T., Flechner, S.M., Kerman, R.H., Vaughn, W., and Kahan, B.D.: Cyclosporine improves outcome in high risk cadaveric renal allograft recipients. Presented at the First Meeting of The European Society for Organ Transplantation, Zurich, Switzerland, November 1983. 92. Kerman, R.H.: Cyclosporine immunosuppression for renal transplantation. Presented toSandoz Pharmaceuticals, Inc., East Hanover, New Jersey, December 1983. 93. Kerman, R.H.: New horizons in transplantation: Influence of cyclosporine on renal transplantation. Invited presenter at the Western Dialysis and Transplantation Society, Park City, Utah, January 1984. 94. Sterling, R.P., Bradley, B.B., Khalil, K.G., Kerman, R.H., and Conklin, R.H.: Compari son of biopsy proven pneumocystis pneumonia in acquired immune deficiency syndrome (AIDS) patients versus renal allograft patients. Presented at The Society for Thoracic Surgeons, San Antonio, Texas, January 1984. 95. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: Correlation of immunopharmacokinetic profiles of cyclosporine-treated allograft recipients and rejection. Presented at The Society for University Surgeons - Residents' Meeting, Chicago, Illinois, February 1984. 174$ if**. JL. - MARVIN S. LEGATOR, Ph.D. Dr. Legator is Professor of Environmental Toxicology, University of Texas Medical School at Galveston. His Curriculum Vitae will be supplied. The subject matter of Dr. Legator's testimony will include: the teratogenic and carcinogenic effects of TCDD, as well as its mutagenic potential; the multi-system effects of TCDD at extremely low concentrations; the demonstrable effects, both gross and more subtle, of TCDD on animals; the extrapolition of the animal studies to humans, that is, the inherent, intended predictive aspects of the animal data to man; and finally to his work as a geneticist with respect to reproductive toxicology, i.e. male (Vietnam Veterans) - mediated birth defects and certain untoward pregnancy outcomes. Dr. Legator will testify to the extreme toxicity of dioxins, particularly 2,3,7,8-TCDD. Specifically, his testimony will indicate that TCDD is a complete carcinogen based upon certain animal studies, and that as a carcinogen, there is no safe level and does not have therefore a so-called no effect level. With respect to that, Dr. Legator will describe the extra ordinary precautions which are taken, and the fears of the researchers, in connection with the laboratory use of TCDD. In addition, Dr. Legator will testify to the reproductive toxicological effects, i.e. birth defects, and miscarriages of the children and wives of the exposed Vietnam veterans. The animal data in this regard are positive and consistent and provide a mechanistic linkage which confirms the Vietnamese epidemiological study of Hatch and others. Specifically, therefore Dr. Legator will testify that the miscarriage of Mrs. Dan G. Jordan and the congenital malformations of the children of Dan G. Jordan, as well as those of Kerry Ryan, daughter of Michael F. Ryan, were caused by the presumed exposure of representative plaintiffs Jordan and Ryan to phenoxy herbicides and dioxins - specifically 2,3,7,8-TCDD -- while serving in Vietnam. The bases or grounds for such facts and opinions include Dr. Legator's: educational and professional experience; personal researches; review of the applicable medical and scientific literature; and a review of the medical records and/or data of the Jordan and Ryan families. -2 - 1 ALAN SCOTT LEVIN, M.D. Dr. Levin is engaged in the practice of medicine in San Francisco, His Curriculum Vitae is attached. Dr. Levin will testify that phenoxy herbicides and their contaminants, including dioxins, most especially 2,3,7,8-TCDD, cause an assortment of immunological responses, i.e. immuno-toxicity, which predispose persons exposed by absorption and/or ingestion and/or inhalation - to such chemicals to a whole host of adverse health effects, such as: chloracne or other skin rashes; various neuro-toxic effects; reproductive effects; and neoplasm. In connection with the carcinogenic effect, Dr. Levin will state there is no safe level for this or any other carcinogen, and that a single exposure several years earlier can result in human cancer many years later. The bases for such facts and opinions expressed herein by Dr. Levin include: review of the medical and scientific literature, including both animal and human data; his personal researches; his clinical experiences; and his personal knowledge of the defoliation of Vietnam by such phenoxy herbicides and dioxins, with such chemicals in the presence of the veterans and their presumed exposure thereby; and review of all pertinent medical data of the representative plaintiffs. Dr. Levin will discuss the following in his testimony: the immune system, with its organic, cellular, and humoral components - most especially with regard to the latter, T-helper cells, B-cells, plasma cells and immuno globulin production; immune response, both beneficial and harmful; the various experimental studies, particularly those demonstrating atrophy of the thymus, weight loss, depletion of lymphoid organs, lymphopenia, cutaneous type delayed hypersensitivity (skin thickness) and altered bacterial immunity. In a d d it io n , D r. L e v in w i l l d is c u s s th e f o llo w in g and t h e ir significance: immunology as molecular biology; chemical-induced immune disregulation; T-cells (lymphocytes from thymus) acting as immune modulators, (for which again there is no "no effect" level); immune surveillance; the similarity of the immune, neurologic, and endocrine systems and their significance in the area of immuno-toxicity; the relationship of immune disregulation caused by chemicals and carcinogenicity. Dr. Levin will then testify to the causal relationship of the various Agent Orange/dioxin related adverse health effects of the representative plaintiffs, including: chloracne; neuro-toxic effects, both neurological and psychological; reproductive toxic effects, both miscarriages and birth defects; and such neoplastic processes as soft tissue sarcoma, as here a rhabdomyosarcoma, lymphocytic lymphoma and basal cell carcinoma. -2 - /" CURRICULUM VITAE - Alan Scott Levin, M.D, Born: High School: College: Graduate School: Masters Thesis: Medical School: Internship: Fellowships: Specialty Board Certifications: Military: Marital Status: January 12, 1938. Chicago, Illinois. Austin, Chicago, Illinois University of Illinois, Champaign-Urbana, Illinois 1956-1960 B.S. Chemistry in L.A. with Honors. University of Illinois (Chicago Medical Center) M.S. in Biochemistry, 1963. Metabolism of Serum Albumin in Rats with Cirrhosis of the Liver, 1963. University of Illinois (Chicago Medical Center) M.D. 1964 Alpha Omega Alpha Honor Medical Society, 1963 Children's Hospital Medical Center, Boston, Mass. Traineeship Grant, Harvard Medical School 1964 Research Assistant, Children's Hospital Boston, 1965. USPHS Hematology Training Grant, University of California San Francisco, Medical Center 1969-1971 (Pediatric and General Immunology). American Cancer Society Faculty Research Award, 1971-1974 1. Certified Diplomnte American Board of Allergy and Immunology, 1975. 2. Certified Diplomate American Board of Pathology-Clinic Pathology, 1977. 3. Fellow in the American College of Emergency Physicians 4. Fellow College of American Pathologists. 5. Fellow American Society -pr Clinical Pathologists. 6 . Member American Academy of Allergy. 7. Member American Association of Clinical Chemists. USN attached to USMC as Flight Surgeon 1966-1968 Viet Nam Campaign ribbons and unit citation, Navy and Marine Corps Commendation, First through Fourth Air Medals Bronze Star Medal with Combat "V", Silver Star Medal, Honorable Discharge November 1969. Married to Vera S. B v e r s , P h . D . , M.D. Mo chi 1dren. man i. C & U Academic Appointments : Adjunct Instructor in Pediatrics University of California San Francisco Medical Center 1971 - 1972 Assistant Professor of Immunology in Dermatology University of California San Francisco Medical Center 1972 - 1978 Adjunct Associate Professor of Immunology University of California San Francisco Medical Center 1978 - Director of Laboratory of Immunology University of California and Kaiser Foundation Research Institute Joint Program Project San Francisco, California 1971 - 1974 Director of Division of Immunology Western Laboratories 2945 Webster Street Oakland, California 1974 - 1977 Medical Director MML/Solano Laboratories 2920 Telegraph Avenue Berkeley, California 1977 - 1979 Medical Director A Levin Clinical Laboratories, Inc. 326 6th Stree-t San Francisco, California 1979-1981 / . Private Practice of Medicine 450 Sutter, Suite 1138 San Francisco, California, 9410S 1981 - Member, Medical Quality Rev i Committee, #4 Board of Medical Quality Assurance State of California 1932 - i ALAN SCOTT LEVIN, M.D. BIBLIOGRAPHY (Abstracts not included) 1. Levin, A.S., and Jeffay, H.: Metabolism of serum albumin in rats with cirrhosis of the liver. J. Lab & Clin. Med. 63: 776-783, 1964. 2. Klemperer, M.R., Gotoff, S.P., Alper, C.A., Levin, A.S., and Rosen, F.S.: Estimation of serum beta 1-C globulin concentration: Its relation to the serum hemolytic complement titre. Pediatrics 36: 766-769, 1965. 3. Alper, C.A., Levin, A.S., and Rosen, F.S.: Beta-IC-globulin: Metabolism in Glomerulonephritis. Science 153 (3732): 180-182, 1966. 4. Vyas, G.N., Levin, A.S., Fudenberg, H.H.: Intrauterine isoimmunization caused by transplacental passage of maternal IGA. Nature 225: 275-276, 1970 5. Levin, A.S., Pipkins, M.O., and Fudenberg, H.H.: A rapid.radioimmunoassay for measuring nanogram levels of antigens. Vox. Sane. 13:459-466, 1970. 6. Levin, A.S., Spitler, L.E., Stites, D.P., and Fudenberg, H.H.: A gene tically determined cellular immunologic deficiency: Clinical and laboratory responses to therapy with transfer factor. Proc. Natl. Acad. Sci.USA 67: 321-323, October, 1970. 7. Stites, D.P., Levin, A.S., Austin, K.E., and Fudenberg, H.H.: Immuno biology of Human Lymphoid Ceil Lines. Immunoglobulin biosyntheseis in cultures from Hypogamma-globulinemias and Paraproteinemia. J. Immunol. 107: 1376-1381, November, 1971 8. Levin, A.S., Fudenberg, H.H., Hopper, J.E., Nisonoff, A., and Wilson, S.K.: Immunofluorescent evidence for control of synthesis of variable regions of light and heavy chains of IgG and IgM by^the same gene. Proc. Natl. Acad. Sci. USA 63: 169-171, 1971 9. Fudenberg, H.H., Wang, A.C., Pink, J.R.L., and Levin, A.S.: Studies of an Unusual Biclonal Gammopnthy. Ann. N.Y. Acad. Sci. 190:501-506, 1971. 10. -.Levin, A.S., Fudenberg, H.H., Pete, L.D., and Sharp, G.C.: IgG levels in Cerebrospinal Fluid of Patients with Central Nervous System Lupus. Clin. Immunol, and J. Immuncnath. 1: 1-5, 1972 11. Spitler, L.E., Levin, A.S., Huber, H., and Fudenberg, H.H.: Prediction of Resulcs of Transfer Factor Therapy in the Wiskott-Aldrich Syndrome by Monocyte IgG Receptors. In Proceedings of the Sixth Leukocyte Culture Conference. Academic Press, Inc., New York and London, P.795-803, 1972. 04 % ,W ( 12. SpiLler, L.E., Levin, A.S., Stites, D.P., Fudenberg, H.H., Pirofsky, C.S., August, E.R., Stiehm, W.K., Hitzig, H., and Gatti, R.A.: The WiskottAldrich Syndrome Results of Transfer Factor Therapy. J. Clin. Invest. 51: 3216- 3224, 1972 13. Spath, P., Garraty, G., Levin, A.S., Petz, L.D., Fudenberg, H.H.: Immunhematologisc'ne Vernderungen bei Cephalosporin-therapie. Verhandlungen der Duetschen Gesselschaft fr innere Medizin, Vol. 78, 914-916, 1972. 14. Fudenberg, H.H., Spitler, L.E., and Levin, A.S.: Treatment of Immune Deficiency Disorders. Amer. J. Pathol. 69:529-536, 1972 15. Stites, D.P., Levin, A.S., Lauer, B., Costom, B.H., Fudenberg, H.H.: Selective "Dysgammaglobulinemia" with elevated serum IgA and chronic salmonellosis. Amer. J. Med. 54:260, 1973 16. Spitler, L.E., Levin, A.S., and Fudenberg, H.H.: Agammaglobulinemia and Lymphopenia without infection: A demonstration of immunologic unknowns. Amer. J. Med. 54: 371-377, 1973. 17. Raubitschek, A.S., Levin, A.S., Stites, D.P., Shaw, E.B., and Fudenberg, H.H.: Normal Granulocyte Infusion Therapy for Aspergillosis in a Patient with Chronic Granulomatous Disease. Pediatrics 51-230-233, February 1973. 18. Wybran,J., Levin, A.S., Spitler, L.E., and Fudenberg, H.H.: Rosette Forming Cells, Immunological Diseases and Transfer Factor. New Eneland Journal of Med. 228:710-713, 1973. 19. Spitler, L.E., Levin, A.S., and Fudenberg, H.H.: Human Lymphocyte Transfer Factor in "Methods in Cancer Research", H. Busch (ed.) Acad. Press. Ill 5th Ave., New York, N.Y., 59-106, 1973. 20. Levin, A.S., Spitler, L.E., and Fudenberg, H.H.: Transfer Factor Therapy in Immune Deficiency States. Ann. Rev. Med, (invited Review) 1973 21. Levin, A.S., Spitler, L.E., and Fudenberg, H.H.: Immune Deficiency States. Introduction to Clinical Allergy (ed.: B. Feingold) Charles Thomas, Springfield, Illinois, Chapter 19, 346-359, 1973. 22. Spitler, L.E., Levin, A.S., and Fudenberg, H.H.: The Wiskott-Aldrich Syndrome. In the Science and Practice of Clinical Medicine. J.M. Dietschy, L.E. Early, H.H. Fudenberg, A. Renold, C.A. Sanders, and J.P. Sanford (ed.) New York, 1974. 23. Spitler, L.E., Levin, A.S., Fudenberg, H.H.: Transfer Factor. Clinical Immunology Volume M. (cd. R.A. Good & Each), 2: 153-175, Academic Press, N.Y. 1974. 24. Fudenberg, H.H., Levin, A.S., Spitler, L.E., Wybran, J.E., and Byers, V.S.: Therapeutic Uses of Transfer Factor. Hosnical Practice 9:95-104, 1974 * \,ia R-w,`I.>) \ 25. Levin, A.S., Transfer Factor Therapy: Current Status. So. Med. Journal (invited editorial) _6^3, 1465-1466, 1975 26. Fudenberg, H.H., Byers, V.S., Levin, A.S., and Hackett, A.J.: Additional evidence for viral etiology of certain human tumors in A.A. Gottlieb, M.D., Fundamental Aspects of Neoplasia. New York: SpringerVerlag, 1974 27. Fudenberg, H.H., Byers, V.S., and Levin, A.S., : Immunologic Evidence for a Viral Etiology of Certain Malignant Tumors, in Perspectives in Virology (Gustav Stern Symposium), New York, February 4-5, 1974. 28. Levin, A.S., Byers, V.S., Fudenberg, H.H., and Wybran, J.: Immunologic Parameters for monitoring immunotherapy with tumor-specific transfer factor. Trans. Assoc. Amer, Phys.,_87, 153-158, 1974 29. -Fudenberg, H.H., Byers, V.S., Levin, A.S., and Hackett, A.J.: Immunologic Evidence for a Viral Etiology of Certain Human Malignant Tumors. Ann. N.Y. Acad. Sci. (In Press, 1975) 30. Wybran, J., Levin, A.S., Fudenberg, H.H., and Goldstein, A.L.: Thymosin: Effects on Normal Human Blood T Cells. Ann. N.Y. Acad. Sci. 249:301-307, 1975 31. Carter, J.B., Ponce, B., Byers, V.S., Barr, G.D., Fudenberg, H.H. and Levin, A.S.: Standardization of tissue culture conditions for spontan eous thynidine-2l4c incorporation by unstimulated lymphocytes: Circadian rhythm in Human Lymphocytes. J. of Allergy and Clinical Immunology 56, 191-196, 1975. 32. Byers, V.S., Levin, A.S., Hackett, A.J., and Fudenberg, H.H.: Tumor specific cell mediated immunity in household contacts of cancer patients. J. of Clin. Invest. 55-500-517, 1975. 33. Levin, A.S., Byers, V.S., Fudenberg, H.H., Hacketc.^ A.J., Johnston, J.O., and J.E. Wybran: Osteogenic sarcoma: Immunologic parameters before and during therapy with tumor specific transfer factor. J. Clin. Invest _55: 487-499, 1975. 34. Levin, A.S., Spitler, L.E., and Fudenberg, H.H.,:' Transfer Factor 1. -Methods of Therapy, (end Int. Conf. on Immunodeficiency in Man. St. Petersburg, Fla. 1973), in BIRTH DEFECTS: Original Article Series (Editors: D. Bergsma and R.A. Good), Sinauer, Assoc., Inc., N.Y., 1975. 35. Spitler, L.E., Levin, A.S., and Fudenberg, H.H.: Transfer Factor II. Results of Therapy. (2nd Int. Conf. on Immunodeficiency Disease in Man, St. Petersburg, Fla., 1973), in BIRTH DEFECTS:. Original Article Series (Editors: D. Bergsma and R.A. Good), Sinauer Assoc., Inc., N.Y., 1975. ' 034 " > I 36. Fisher, J., Byers, V.S., Shafrin, M., and Levin, A.S.: Relationship of Cu and Zn levels to metastatic events in human bone sarcomas. Cancer, 37, 356-364, 1976. 37. Spitler, L.E., Levin, A.S., and Fudenberg, H.K.: The Wiskott-Aldrich Syndrome: Immunological Studies in Patients and Family Members Cellular Immunology, 19, 201-218, 1975. 38. Byers, V.S., Levin, A.S., Hackett, A.J., and Johnston, J.W.: Quantitativ Iramunofluorescent Studies on the Tumor Antigen Bearing Cell in Giant Cell Tumor of Bone and Osteogenic Sarcoma, Cancer Research, 35:2520 2531, 1975. 39. Jones, L.W., Levin, A.S., and Fudenberg, H.K.: Glomerular Antigen Comple Associated with Transitional Cell Carcinoma. Surgery, Gynecology and Obstetrics 140:896-898, 1975 40. Kaplan, M.A., Byers, V.S., Levin, A.S., German, D., Fudenberg, H.H., and LeCam, L.: Circadian Rhythm in Human Lymphocyte Function. J. Allergy and Clinical Immunology: 58 I, 180-189, 1976. 41. Spitler, L.E., Levin, A.S., and Wybran, J.: Adjuvant Immunotherapy for Malignant Melanoma with BCG and Transfer Factor. Cellular Immunology 21, 1 - 19, 1976. 42. Levin, A.S., Byers, V.S., Hackett, A.J., Johnston, J.O., and LeCam, L.M. Tumor Specific Transfer Factor Therapy in Osteogenic Sarcoma, Immunotherapy in Cancer, Proceedings of ITR-C'nicago, 1975. 43. Byers, V.S., Levin, A.S., Hackett, A.J., Johnston, J.O., and LeCam, L.M. Tumor Specific Transfer Factor Therapy in Osteogenic Sarcoma, A Two-Year Followup Study, Annals of New York Academy of Science, 277, 621-627, 1976. 44. Byers, V.S. and Levin, A.S., Tumor Immunology, in Basic and Clinical Immunology: Eds. Caldwell, J. , Fudenberg, H.H., .-^tites, D.P. and Wang, A.S., Lange Books, 1976. 45. 'Levin, A.S., Byers, V.S., LeCam, L.M., and Johnston, J.O., An Unusual Metastasis in an Osteogenic Sarcoma Patient on Tumor Specific Transfer Factor Therapy, Transfer Factor, 537-542, Academic Press, 1976. 46. Byers, V.S., LeCam, L.M., Hackett, A.J., Johnston, J.0. and Levin, A.S.: Familial Incidence of Breast Carcinoma Immunity - A Statistical Survey. Cancer Immunology and Immunotherapy. 2, 163-172, 1977 47. Byers, .S., and Levin, A.S.: Tumor Antigen Density on Osteogenic Sarcoma Cells in Vitro. Cancer Research. 37, 3173-3183, 1977. #^ ^'3;\***? 1-V J 5 L i Chun. Shi --i-.i, :rco:L, C.R., Giblett, E .R ., Levin, A.S.: Adenosine Deaminase Dei iciency: Another Family with a "Silent" Ada Allele and Normal Ada Activity in Two Ketcrozygotes. American Journal of Human Genetics. Vol. 29, 642-644, 1977. 49. Mamor, M.D., Nelson, J.W., Levin, A.S.,: Copper Metabolism in American Retinitis Pigmentosa Patients: British Journal of Opthalmologv. Vol. 6_2. 163-171, 1978. 50. Byers, V.S.,. LeCam, L., Levin, A.S., Johnston, J.O., and Hackett, A.J.: Osteogenic Sarcoma: Immunotherapy of Clinically Disease Free Patients with Transfer Factor: Long-Term Follow-up. Cancer Immunology and Immunotherapy - 6_. 243-251, 1979. 51. Byers, V.S., Levin, A.S.: Poison Oak III: Genetic Restriction in T Cell Mediated reactivity-Journal of Clinical Investigation.-Submit ted. 52. Newman, B.R., Byers, V.S., German, D., and Levin, A.S.: Variability of Lymphocyte Function by Serum Factors. Journal of Clinical Laboratory Immunology 2, 151-154, 1979. 53. McGovern, J.J.,Jr., Lazaror.i, J.L., Saifer, Phyllis, Levin, A.S., Rapp, D.J., Gardner, R.W.: Clinical Evaluation of the Major Plasma and Cellular Measures of Immunity. Journal of Orthomolecular Psychiatry. Vol. 12, No. 1. , 1933. 54 . Lev in, A. s., Emb le ton, M .J ., and Price, M.R .r Use in the Diagnosis and Treatment of :1s ar.d Ca nee'r, PP- 15-3d . L. LeCam and nd, 1932 . ao. Binder, R.L., Callaway, E. Lev in, A. s., S ti tes, D P Relationship between Creatine Phosp'nokj ise and I-mu n<og.lobu lins in Unmedicated Caucasian Schizophrenics. iioloui cal Psvchiat rv. In Press. 1983. 56 McGovern, J.J.,Jr., Rapp, D.J., Levin, A.S.: Phenol Provokes Abnormal Immune Response During Double-Blind Testing. J.'A.M.A. Submitted 1983. I ALAN SCOTT LEVIN, M.D. BIBLIOGRAPHY (Abstracts Only) I. Alper, C.A., Levin, A.S., and Rosen, F.S.: Turnover of an I complement component. J. Clin. Invest. May 1965. labeled 4 2 Levin, A.S., Pete, L.D., Fudenberg, H.H.: Immunoglobulins and C Levels in Normal and CNS-SLE -Cerebrospinal fluids using new micro radio immuno assays. Abstract presented ASCR Western Regional Meetings. 3. Levin, A.S., Stites, D.P. , Spitler, L.E., Sa'nud, M.A. and Fudenberg, H.H.: Induction of "delayed hypersensitivity" in Wiskott-Aldrich patient by transfer factor. Clin. Res. 18:426, April, 1970. 4. Vyas, G.N., Levin, A.S., and Fudenberg, H.H.: Isoimmunization to human IgA in pregnancy. Clin. Res. 18:157, April 1970. 4 5. Levin, A.S., Petz, L., and Fudenberg, H.H.: IgG and C levels in CSF of patients with active CNS-SLE. Clin. Res. 19:137, June 1971 6. Levin, A.S., Fudenberg, H.H. , Hopper, J.., and Nisonoff, A.: Immunohistologic investigations of a Biclonal Camopathy: Detection of identical antigen in variable regions of IgG and IgM producing cells. Presented at ASH Meeting, San Juan, P.R. Blood XXXVI (6), 831, 1970. 7. Spitler, L.W., Levin, A.S., Stites, D.P., and Fudenberg, H.H.: Current status of transfer factor therapy in Wiskott-Aldrich Syndrome. Presented at ASCI Western Regional Meetings, Carmel, Jan. 1971 Clin. Res. XIX (j) 162, 1971 8. Levin, A.S., Weiner, R.S., Fudenberg, H.H., Spath, and Petz, L.: Granulocytopenia caused by anticephalothin antibdViies. Clin. Res. XIX (2) 424, 1971 9. Levin, A.S,Spitler, L.E., Stites, D.P., and Fudenberg, H.H.: Molecular intervention in genetically determined cellular immune deficiency disorder J. Clin. Invest^ 50:59a, 1971 /. 10. Spitler, L.E., Levin, A.S., Fudenberg, H.H., Huber, H.: Abnormal monocyte IgG receptors in the Wiskott-Aldrich Syndrome. Sixth Annual Leukocyte Culture Conference. Academic Press, 1972. II. Spitler, L.E., Levin, A.S., Stites, D.P., Pirofsky, Fudenberg, H.H.: Transfer Factor Therapy in Mucocutaneous Candidiasis. Sixth Annual Leukocyte Culture Conference. Academic Press, 1972 12. Wybran, J., Spitler, L.E., Levin, A.S., and Fudenberg, H.H..: The Rosette Forming Cell as an Indicator of Successful Transfer Factor Therapy in Tmmuno Deficiencies. Clin, Res. XX (3), 1972 1 13. Levin, A.S., Spicier, L.E., Wybran, J., and Fudenberg, H.H.: Treatment of Osteogenic Sarcoma with Tumor Specific Transfer Factor. Clin. Res. XX (3), 56S, 1972. 14. Spicier, L.E., Levin, A.S., and Fudenberg, H.H.: Immunologic Evaluation of Patiencs wich MicocuCaneous Candidiasis and Results of Transfer Factor Therapy. Clin. Res. XX (3), 519, .1972. 15. Spider, L.E., Levin, A.S., Blois, M.S., Epstein, W. , Fudenberg, H.H., Hellstrom, I., and Hellstrom, K.E.: Lymphocyte Responses to Tumor Specific Antigens in Patients with Malignant Melanoma and Results of Transfer Factor Therapy. J. Clin. Invest. 16. Wybran, J., Levin, A.S., Spider, L.E., and Fudenberg, H.H.: Tne Human Rosette Forming Cell, Transfer Factor and Prognosis of Cancer. Clin. Res XX, (3) 635, 1972. 17. Fcnes, D.W. , Mogerman, S.N., Spider, L.E., Stites, D.P., Shinefield, H.R., Fudenberg, H.H., and Levin, A.S.: Graft Versus Host (GVK) in A Di George Patient: Probable Accelerated Induction of T Cell Competence. Clin. Res. XXI (2) 309. 18. Mogerman, S.N., Levin, A.S., Spider, L.W., Stites, D.P., Fudenberg, H.H and Shinefield, H.R.: Transfer Factor Therapy in X-Linked Recessive Severe Combined Dual System Immune Deficiency Disorder (SCID). Clin. Res. XXI (2) 310. 19. Carter, J.8., Pence, 3.E., Stites, D.?., Levin, A.S., German, D.F., and Fudenberg, H.H.: Spontaneous Thymidine' - l--"4 C Incorporation by Unstimulated Normal Human Peripheral Lymphocytes _In Vitro: Tissue Culture Conditions and Quantitative Measurements. 2 0 . Carter, J.B., Ponce, B.E., Stites, D.P., Levin, A.S., German, D.E., and Fudenberg, H.H.: Circadian Cycle of Spontaneous Thymidine-2-^ C Incorporation by Unstimulated Normal Human Peripheral Lymphocytes In Vitro. ----------------------- *.V.X 2 1 . Fones, D.W. , Levin, A.S., Mogerman, S.M., Spider, L. E. , Stites, D.P., Shinefield, H.R., and Fudenberg, H.H.: Graft Versus Host Followed by Host Versus Graft: Evidence for Accelerated Induction of T-Cell Competence. /y 22: Levin, A.S', ySpider, L.F.'. , Wybran, J., Byers, V.5., and. Fudenberg, H.H. Treatment of Osteogenic Sarcoma (OS) with Tumor Specific Dialysablo Transfer Factor (TF). Clinical Research. 1973 23. Levin, A.S., Byers, V.S., Fudenberg, H.H., and Wybran, J.E.: Immunologic Parameters for Monitoring Immunotherapy with Tumor Specific Transfer Factor. Clin. Res. 1974. 2i,, Gardner, R.D., Byers, V.S., Levin, A.S., and Fudenberg, H.H.: Frozen Human Lymphocytes: Dissociation between Tumor Specific Cytotoxicity and Mixed Leukocvte Renctivitv (MLC Reactivitv). Clin. Res. 197b. \ 25. Byers, V.S., Levin, A.S., and Fudenberg, H.H.: Detection of Tumor Specific Immunity in Normal Household Contacts of Tumor Bearing Patients. Clin. Res. 1974. 26. Levin, A.S., Byers, V.S., Johnston, J.O., Hackett, A.J.,and Fudenberg, H.H.: Host-Tumor Relationships in Giant Cell Sarcoma of Bone (GCS): Measurement by Quantitative Immunofluorescence. Clin. Res. 1974 27. Fudenberg, H.H., Byers, V.S., Levin, A.S., and Hackett, A.J.: Evidence for Viral Etiology of Human Hypernophroma and Osteosarcoma. Perspectives in Virology. In Press, 1974 28. Levin, A.S., Byers, V.S., LeCam, L., and Johnston, J.O.: Evidence for Regression in Osteogenic Sarcoma Induced by Tumor Specific Transfer Factor. 2nd International Workshop on Transfer Factor. Frederick, MD., 1975. 29. Hackett, A., Springer, L., Levin, A.S., and Fink, M.: Transmission and Scanning Electron Microscopic Studies on Osteo Sarcoma Before and After Transfer Factor Therapy. Cancer Research 16:193, 1975 30. Levin, A.S., LeCam, L.M., Hackett, A.J. and Johnston, J.O.: Osteosarcoma (O.S.): 5 Year Followup of Epidemiology and Tumor Specific Transfer Factor Therapy (TSTF). Clin. Res. 1976 31. Levin, A.S., LeCam, L,,M., and Agraz, J.M.: Dip-Stick Method of Quanti tative Immunofluorescence. Clin. Res. 1976, 32. Newman, B.R., Byers, V.S., Levin, A.S., and Jerman, D.: Circadian Influences on T. Lymphocyte Function Mediated by Serum Factors. Clin. Res. 1976 33. Levin, A.S., Kassel, S.D., and Flam, M., A New Diagnostic Index: Collagen Disease vs. Malignancy vs. Infectious Disease. J.A.M.A. 237, 1916, 1977. \ 34. Levin, A.S., and Baldwin, R.W.: Solid Phase Fluoroimmunoassay to Detect Serum Immune Complexes. 6th International Congress on Immunofluorescence, Vienna, Austria. 1973 3-5, Levin, A.S., McGovern, J.J.,Jr., Miller, J.B., LeCam, L.L., and Lazaroni, J.: Non-Anaphylactic Food Allergies Mediated by Immune Complexes: Ann. Allergy, Abstract in Press. 1981 -f- j* Dr. Peter Orris is an internist practicing in Chicago, Illinois. His curriculum vitae will be supplied. Dr. Orris will testify as to the clinical aspects of the diseases in the representative plaintiff veterans. His testimony will be based upon a medical records review and an analysis of various test results that will have been performed upon the repre sentative plaintiffs. Dr. Orris will also testify on generic causation and specific proximate causation in relation to each representative veteran, plaintiff. He will also testify as to prognosis for each representative veteran plaintiff t J- q 9 1 2^ Marvin A. Schneiderman, Ph.D., of Bethesda, Maryland, is a statistician and epidemiologist who is the former Chief of Statistics and Epidemiology and the former Director for Science Policy of the National Cancer Institute and is currently a consultant. His curriculum vitae is attached. Dr. Schneiderman will testify concerning mathematical models, statistics, and epidemiology in the area of cancer. He will first discuss the epidemiology of dioxins and their contaminants to human cancer insofar as it relates to soft tissue sarcomas, and particularly the EPA pe'er review.group conclusions in regard thereto, stomach cancers and lymphomas. In that regard he will discuss the relationship of exposure to the time the disease appears, the so-called latency period. He will also discuss the multiplication of base rates in the production of such cancer. Next, Dr. Schneiderman will present a multi-stage model of cancer induction. He will discuss age relationships and the stage of cancer development as they are affected by dioxins and their cohtaiminants or other materials. He will also present certain pertinent animal data and discuss it as a predictor for human experience. He will also testify that TCDD is more toxic than many other carcinogens, including being more carcinogenic by a factor of 4 or 5 than benzene, for example. He will also explain the concept of risk assessment and how judgments as to such are capable of being made with regard to humans. This will include discussion of a mathematical model for association of the multi-faceted presentation of symptoms and signs in the same 1 39 veteran to exposure to Agent Orange as a causative factor. - He will also discuss the population incidences of these rare cancers, presenting a comparison of the onset ages for them in the general population with the ages of onset for the cancers observed in the Vietnam veterans. He will also discuss the relationship of cancer induction to immune deficiencies or deficits. He will place special emphasis upon lymphomas and soft tissue sarcomas and explain how the ex perience with transplant patients validates his opinions in this regard. Finally, he will discuss the question of a threshold in the induction of cancer. This will include testimony to the effect that there is no "safe" dose for a carcinogen and that a single exposure may cause cancer. He will also discuss the disease-producing behavior of generalized carcinogens, i.e., the chance of a single carcinogen leading to cancer at multiple sites. 13214 MARVIN A. SCHNEIDERMAN Dr. Schneiderman is a Clement Associates Senior Science Advisor with principal responsibilities in biostatistics, epidemiology, risk assessment, and health surveillance. He has more than 30 years of experience in cancer research and related subjects, and he is the author of more than 130 scientific papers in areas of biostatistics, epidemiology, risk assessment, and science and regulatory policy. During his career with the National Cancer Institute (NCI), he was, successively, Associate Chief of the Biometry Branch, Associate Director for Field Studies (Epidemiology) and Statistics, and Associate Director for Science Policy. In this last position, he was one of the princi pal advisors to the Director of the Institute. Dr. Schneiderman is a member of the adjunct faculty of the Georgetown University Graduate School, and Professor of Biostatistics at the Uniformed Services University of the Health Sciences. He has held teaching positions at the University of Pittsburgh Graduate School of Public Health and the University of Miami (Florida), as well as at the Georgetown University Medical School. He was also a Rockefeller Public Service Fellow at the London School of Hygiene and Tropical Medicine. He has served on a number of expert advisory committees and is or has been an associate editor of Cancer Research, Blood, Journal of the National Cancer Institute, Biometrics, Statistics Tn Medicine, American Journal of Industrial Medicine, and a number of other scientific journals. DEGREES Ph.D., Statistics, American University, Washington, D.C., 1961 M.S., Statistics, American University, Washington, D.C., 1953 B.S., Mathematics and Statistics, City College of New York, 1939 NON-DEGREE EDUCATION Harvard University Graduate School of Business, 1945 Management sciences, economics, statistics Ohio State University Graduate School, 1946-1947 Economics London School of Hygiene and Tropical Medicine, 1959-1960 Epidemiology, medical research involving humans, controlled trials, biostatistics 13215 SCHNEIDERMAN, page 2 1983-present 1981-present 1980-present 1975-present 1980 1978-1980 1970-1978 1967-1978 1966-1975 1960-1970 1960-1965 1959-1960 1955-1959 1948-1955 1939-1948 EMPLOYMENT HISTORY Senior Fellow, Environmental Law Institute, Washington, D.C. Professor (Division of Biometrics), Department of Preventive Medicine, USUHS, Bethesda, Md. Senior Science Advisor, Clement Associates Associate Professor, Graduate Faculty, Georgetowr University Expert Consultant, Office of the Director, Natior Cancer Institute (NCI), National Institutes of Health (NIH) Associate Director for Science Policy, Office of the Director, NCI Associate Director NCI, Field Studies and Statist Program, Division of Cancer Cause and Prevention. NCI Adjunct Professor, Biostatistics, Graduate School of Public Health, University of Pittsburgh Clinical Associate Professor, Medical Statistics, Georgetown University Medical School Associate Chief, Biometry Branch, NCI Professorial Lecturer, Georgetown University Medical School Rockfeller Public Service Fellow, Statistical Research Unit of the British Medical Research Council, London School of Hygiene and Tropical Medicine Mathematical Statistician and Acting Chief, Therapeutic Trials Section, NCI Mathematical Statistician, Biometrics Section, NCI Private Industry, Military Service (USAF), Other Federal government agencies -1. ' n t) SCHNEIDERMAN, page 3 HONORS Distinguished Lecturer, Lawrence Livermore Laboratories, Univer sity of California, 1982 American Conference of Government Industrial Hygienists, Symposium Speaker Award, June, 1982 Samuel Wilkes Public Lectureship, Princeton University, 1980 Keynote Lecturer, Society of Occupational and Environmental Health, 1979, North Carolina Public Health Association, 1980 Environmental Defense Fund, Public Interest Science Award, 1977 Distinguished Service Award, Department of Health, Education and Welfare (DHEW), 1974 Superior Service Award, DHEW, 1968 Rockefeller Public Service Fellow, London School of Hygiene and Tropical Medicine, 1959-1960 Phi Beta Kappa, 1939 SELECTED ADVISORY COMMITTEES Committee on Toxicity Data Elements, National Academy of Sciences, 1981-present S u b c o m m i t t e e on the Ge o c h e m i c a l E n v i r o n m e n t in R e l a t i o n to Health and Disease, NAS/NRC, 1980-present Science Evaluation Board, National Health and Medical Research Council of Australia, 1980-present .American Cancer Society, Analysis and Projections Committee, 19-76-1978, Institutional Grants Committee, 1980-present Science Advisory Board, Howard University Cancer Center, 1979present (External Review Committee) Ce nte r for Sc i e n c e in the Pu blic Interest, Board of Directors, 1983-present Food Safety Council, Board of Directors, 1978-1982 Advisory Committee, Biomedical and Environmental Assessment Division, Brookhaven National Laboratory, 1978-present SCHNEIDERMAN, page 4 Advisory Committee, International Cancer Research Data Bank (CIDAC), Franklin Institute, Philadelphia, 1981-present Task For ce on- He ar t Dise as e E p i d em io lo gy , Na ti o n a l Heart, Lung, and Blood Institute, 1979-1980 Science Advisory Board, National Center for Toxicological Research, 1974-1979 Ad Hoc Subcommittee on Asbestos-Related Health Problems, Armed Forces Epidemiology Board, 1978-1979 I nt er n at io n al (American) Chairman, U . S . / U . S . S .R. W o r ki ng Gro up on the Epidemiology of Cancer, 1973-1979 Committee on Maritime Hazardous Materials, National Academy of Sciences, 1978 C o m m i t t e e to C o o rd ina t e T o x i c o l o g y and Related Programs, DHEW, 1978 President's Biomedical Panel, 1975-1976 Consultative Panel on Hazards of Chemical Pesticides, National Academy of Sciences, 1974-1976 Chairman and Executive Secretary, Committee of Presidents of Statistical Societies, 1973-1976 Board of Directors, American Statistical Association, 1972-1974 International Council, International Biometric Society, 1971-1973 Immunology-Epidemiology Segment, Special Virus Cancer Program, NCI, 1969-1971 Advisory Panel on Carcinogenicity of Pesticides, Secretary's Commission on Pesticides and Their Relationship to Environmental Health, 1969-1970 Chairman, Subcommittee on Medical Biostatistics, American Thera peutic Society, 1967-1968 Subcommittee on Biologic Effects of Atomic Radiation, NAS/NRC, 1964-1965 1 SCHNEIDERMAN, page 5 SELECTED SOCIETIES American Association for Cancer Research American Society for Preventive Oncology (Founding Member) American Statistical Association (Fellow) Biometric Society (International) International Epidemiological Association Royal Statistical Society (Fellow) Washington Statistical Society American Association for the Advancement of Science (Fellow) International Statistical Institute (Fellow) Society for Occupational and Environmental Health SELECTED PUBLICATIONS Schne i d e r m a n , M.A. Standard setting: Implications of sensitivity, and a search for an ethical base. In: P r o t e c t i o n of the Sensitive Individual, Annals of the American Conference of Go v e r n m e n t I n d u s t r i a l Hy gienists, 3:133-138 (1982) Schneiderman, M.A. A personal reminiscence (Austin Bradford Hill). St at is ti cs in M e d i c i n e 1:307-308 (1982) Schneiderman, M.A. Discussion of "Some Aspects of Cancer Epidemi ology" by Abraham Lilienfeld. Biometrics (Supplement) 38:161-165 (1982) Davis, D.L., Bridbord, K . , and Schneiderman, M.A. Cancer preven tion: Ass es si n g cause, exposure, and recent trends in mortality for U.S. males, 1968-1978. Teratogenesis, Carcino genesis and Mutagenesis. Pp. 105-135 (June 1982) Sch ne id er man , M.A. Tr ends in cancer mortality and incidence in the United States: Is the future clear or clouded? In Mike, V. , ed. S t a t i s t i c s in M e d ic al Research. John W i l e y and Sons, New York. Pp. 71-107 (1982) S c h n e i d e r m a n , M.A. D e s c r i p t i o n and re liability of trends in c an cer incidence. In Magnus, K. Tr ends in C a n c e r Incidence. H e m i s p h e r e P u b l i sh i n g C o r p . , Washington, D.C. Pp. 1-2 (1982) Schneiderman, M.A. Cost-benefit, social values and the setting of o c c u p a t i o n a l h e a l t h standards. In Lee, J.S., and Rom, W.N., eds. Legal and E t h i c a l Di lemmas in O c c u p a t i o n a l Health. Ann Arb or Science, Ann Arbor, Michigan, pp. 191-205 (1982) r\ Q 1 9 SCHNEIDERMAN, page 6 Peto, R. , and Sc hn eid er ma n, M. , eds. Quanti f ication.. of O c c u p a tional Cancer: B a n b u r y R ep or t No. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1981) . Davis, D.L., Bridbord, K . , and Schneiderman, M.A. Estimating cancer risks: Pr o b l e m s in m e t h o d o l o g y pr o d u c t i o n trends. In Peto, R . , and Schneiderman, M . , eds. Quantification of O c c u p a t i o n a l Cancer: B a n b u r y R ep or t No. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. Pp. 285315 (1981) Schneiderman, M.A. Summary comments. In Crandall, R . W . , and Lave, R . , eds. The Scientific Basis of Health and Safety Regulation. The Brookings Institution, Washington, D.C. Pp. 297-299 (1981) Schneiderman, M.A. Regulation of carcinogens m an imprecise world. Ann. N Y. Acad. Sci. 363:217-232 (1981) Schneiderman, M.A. E x trapolation from incomplete data to total or lifetime risks at low doses. Environ. Health Perspect. V. 42, Pp. 33-38 (December 1981) Sch neiderman, M.A. To x i c Substances in Our E n v i r o n m e n t - C a n we manage them so that they don't manage to harm us? Health Fo rum 81, The Coalition for Health and the Environment, Was hin gto n, D.C. (1981) S c h n e i d e r m a n , M.A. Epidemiology: What Can it Tell Us? P r o ceedings of the Conference on Environmental Risk, New Orleans, Louisiana, Decemb er 10, 1980. The E l e c t r i c Power Research Institute, Palo Alto, California, EPRI EA-2064, Pr oj ect 1316-6. Pp. 369 - 3-89 (October 1981) Sc hn eid erm an, M . A . , Nisbet, I., and Brett, S.M. Ass e s s m e n t of Risks Pose d by L ow Levels of As be s t o s in the General En vir onm en t. Berichte: B u n d e s g e s u n d h e i t s a m t . No. 4, 1981. Di e t r i c h Reimer Verlag, Berlin. Pp. 3/1-3/28 (1981) Schneiderman, M . A . , and Levin, D.L. Needs, problems and prospects in cancer epidemiology. In Levin. D.L., ed. Cancer E p i d e m i ology in the U.S.A. and U.S.S.R. U.S. Department of Health and Human Services, P H S , Bethesda, Maryland. NIH Publication No. 80-2044 (1980) Schneiderman, M.A. The Relationship Between Diet, Occupation, the Environment and Cancer. Proceedings: US/Egypt Symposium on the Biomedical Effects of Technology Transfer, Cairo, Eg yp t (February 9-13, 1980) (In Press: E n v i r onment al Health Perspectives) a n223 SCHNEIDERMAN, page 7 S c h n e i d e r m a n , M.A. S c i e n t i f i c Issues in a Na ti on al Cancer Policy. Proceedings of the 4th Toxic Control Conference. Government Institutes, Inc., Washington, D.C. Pp. 95-107 (1980) Schneiderman, M.A. The uncertain risks we run: Hazardous materials. In Schwin, R.C., and Albers, W . A . , Jr., eds. Socie ta l Risk Assessment. Plenum Press, New York. Pp. 19-41 (1980) Schneiderman, M.A. Wh at 's H a p p e n i n g to C an ce r in our Ad va nc e d Industrial Society? Have the Risks been Overstated? Keynote Address: Society for Occupational and Environmental Health, Wa sh in gt on, D.C. (In Press: Proceedings) (December 3-5, 1979) Blokhin, N.N., and S c h n e i d e r m a n , M .A ., eds . Epidemiology of Ca n c e r in the USSR and USA. Med i ts i n a , Moscow (Russian) (1979) Schneiderman, M.A., DeCoufle, P., and Brown, C.C. Thresholds for environmental cancer: Biologic and statistical consider ations. Ann. N.Y. Acad. Sci. 32 9: 92-130 (1979) Schneiderman, M.A. Alpha, beta manitonne-- a new industrial material with unknown'benefits and risks. In Carcinogenic Risks/Strategies for Intervention. International Agency for Research on Cancer (IARC), Lyon, France. IARC Sci. Publ. 25:237-239 (1979) Schneiderman, M.A. The Links Between the Environment and Health. Proceedings: National Conference on the Environment and He alt h Ca r e Costs, U.S. House of R e p r e s e n t a t i v e s (August 15, 1978) Biersteker, K., and Schneiderman, M.A. Epidemiologic Aspects of Drinking Water-Health Relationship. Proceedings of the Health Effects Committee of the NATO committee on ch a l l e n g e s of Mo d e r n Society. Bonn, W. G e r m a n y (April 23- , 27, 1978) Schneide rm an, M . A . , Mason, T.J., and Hoover, R. Cancer, geography, and geology-- a problem for interdisciplinary cross-fertili zation. In G e o c h e m i s t r y and the Envir on me nt . V o l . 3. N a t i o n a l A c a d e m y of Sciences, Wa sh in gt on , D.C. (1978) Sc hn eide rman, M.A. Le g i s la ti ve p o s s i b i l i t i e s to reduce the impact of cancer. Prev. Med. 7:424 -4 38 (1973) 1_L 0 0 2 1J* iw w -*** SCHNEIDERMAN, page 8 Schneiderman, M.A. Water and epidemiology. In Russell, C.S., ed. Safe Drinking Water: Current and Future Problems. Proceedings of the National Conference on Resources for the Future. Pp. 111-148 (1978) Schneiderman, M.A. Extrapolating animal and microbiological tests to humans. In Coling, G., ed. Environmental Cancer (Causes, Victims, Solutions). Proceedings of a conference of the Urban Environment Coalition, Inc. Pp. 9-11 (1978) Schneiderman, M.A. Environmental Factors and Cancer Prevention. Marcel Dekker, New York (1978). (Third National Symposium on Detection and Prevention of Cancer, New York (April 26-30, 1976) Schneiderman, M.A. Risk assessment of the health effects of water chlorination. In Jolley, R.L., Gorchev, H., and Hamilton, D.H., eds. Water Chlorination-- Environmental Impact and Health Effects. Ann Arbor Science Publications, Ann Arbor, Mich. V o l . 2, pp. 509-515 (1978) Schneiderman, M.A., and Brown, C.C. Estimating cancer risks to a population. Environ. H ea lt h Perspect. 22:115-124 (1978) Schneiderman, M.A. Eighty percent of cancer is related to the environment. Laryngoscope 88:1-16 (1978) Schneiderman, M.A. Time Trends in Cancer: United States, 1953-1973. Laryngoscope 88, Supp. 8:1-6 (1978) Fears, T.R., Scotto, J., and Schneiderman, M.A. Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. Am. J. Epidemiol. 105:420-427 (1977) DeVesa, S.S., and Schneiderman, M.A. Increase in the number of cancer deaths in the United States. Am. J. Epidemiol. 106:1-5 (1977) Schneiderman, M.A. The numerate sciences-- epidemiology and biometry. JNCI 59:633-644 (1977) Schneiderman, M.A., and Levin, D.L. Epidemiology of cancer and tobacco use: Trends and trend indicators. In Steinfield, J., Griffiths, W . , Ball, K., and Taylor, R.M., eds. Smoking and Health: II. Health Consequences, Educa tion, Cessation Activities, and Governmental Action. Proceedings of the Third World Conference on Smoking and Health, New York. Pp. 73-84 (1977) Jtt 'j & SCHNEIDERMAN, page 9 Schneiderman, M.A. Health effects-- a scientific and.statistical analysis. In Miller, M.L., ed. Proceedings of the First Toxic Substances Law Seminar. Washington, D.C. .(1977) Levin, D.L., and Schneiderman, M.A. Cancer. In Miller, S.S., ed. Symptoms. Thomas Y. Crowell, New York (1976) Fears, T.R., Scotto, J., and Schneiderman, M.A. Skin cancer, melanoma, and sunlight. Am. J. Public Health 66:461-464 (1976) Schneiderman, M.A. Carcinogenesis as an end point in health impact assessment. In Anderson, E.C., and Sullivan, E.M., eds. Impact of Energy Production on Human Health: An Evaluation of Means of Assessment. N ational Technical Information Service, Springfield, Va. Pp. 65-74 (1976) Schneiderman, M.A. Sources, resources, and tsouris. In Fraumeni, J.F., ed. Persons at High Risk of Cancer: An Ap proach to Cancer Etiology and Control. Academic Press, New York (1976) Hoel, D.C., Gaylor, D.W., Kirschstein, R.L., Saffiotti, U., and Schneiderman, M.A. Estimation of risks of irreversible, delayed toxicity. J. Toxicol. Environ. Health 1:133-151 (1975) Mantel, N . , and Schneiderman, M.A. Non-parametric interval estimation of relative potency for dilution assays, includ ing the case of non-monotone dosage response curves. Biometrics 31:619-632 (1975) Mantel, N . , and Schneiderman, M.A. Estimating "safe" levels-- a hazardous undertaking. Cancer Res. 35:1379-1386 (1975) Schneiderman, M.A., Mantel, N., and Brown, C.C. From mouse to man-- or how to get from the laboratory to Park Avenue and 59th Street. Ann. N.Y. Acad. Sci. 246:237-248 (1975) Schneiderman, M.A. How do you know you've done any better? Cancer 35:64-68 (1975) Schneiderman, M.A. Digestive system cancer among persons sub jected to occupational inhalation of asbestos particles: A literature review with emphasis on dose response. Environ. Health Perspect. 9:307-311 (1974) Schneiderman, M.A. Safe dose? The problems of the statistician in the world of trans-science. J. Wash. Acad. Sci. 64:6878 (1974) J<L c o ,v &o *1 SCHNEIDERMAN, page 10 Fears, T.R., and Schneiderman, M.A. Pathologic evaluation and the blind technique. Science 183:1144-1145 (1974) Elashoff, R.M. , Sobel, M. , and Schneiderman, M.A. A proposal for economical first stage screening for tumorigens with a posssible "joint action" bonus. In Pratt, J.W., ed. Statistical and Mathematical Aspects of Pollution Problems. Marcel Dekker, New York (1974) Van Belle, G., and Schneiderman, M.A. Some statistical aspects of pollution and protection. Int. Stat. Rev. 41:315 (1973) Wynder, E.L., and Schneiderman, M.A. Exogenous hormones-- boon or culprit? JNCI 51:729-731 (1973) Gehan, E.A., and Schneiderman, M.A. Experimental design of clinical trials. In Holland, J.F., and Frei, E., eds. Cancer Medicine. Lea and Febiger, Philadelphia. Pp. 499519 (1973) Schneiderman, M.A., and Mantel, N. The Delaney clause and a scheme for rewarding good experimentation. Prev. Med. 2:165-170 (1973) Schneiderman, M.A., and Levin, D.L. Parallels, convergences, and departures in case-control studies and clinical trials. Cancer Res. 33:1498-1503 (1973) Graham, S., and Schneiderman, M.A. Social epidemiology and the prevention of cancer. Prev. Med. 1:371-379 (1972) Scotto, J., and Schneiderman, M.A. Predicting survival in terminal cancer. Br. Med. J. 4:50 (1972) Schneiderman, M.A., and Levin, D.L. Trends in lung cancer: Mortality, incidence, diagnosis, treatment, smoking and urbanization. Cancer 30:1320-1325 (1972) Johnson, R.E., Thomas, L.B., Schneiderman, M.A., Glenn, D.W.., Faw, F., and Habermann, M.D. Preliminary experience with total nodal irradiation in Hodgkin's disease. Radiology 96:603-608 (1970) Schneiderman, M.A., and Scotto, J. Computer-Investigator Inter actions in Small-Scale Clinical Trials. Proceedings of the Fifth Scientific Meeting of the International Epidemiol ogy Association, Primosten, Yugoslavia. Pp. 449-467 (1970) < r f%A jL .v w * SCHNEIDERMAN, page 11 Gold, G.L., Shnider, B.I., Salvin, L.G., Schneiderman, M.A., Colsky, J . , Owens, A.H., Krant, M.J., Miller, S.P., Frei, E., Ill, Hall, T.C., Spurr, C.L., McIntyre, O.R., Hoogstraten, B . , and Holland, J.F. The use of mechlorethamine, cyclophospha mide, and uracil mustard in neoplastic disease: A coopera tive study. J. Clin. Pharmacol. 10:110-120 (1970) Schneiderman, M.A. How to read the drug literature-- or any other organized collection of numbers from experiments. Mod. Med. 37:92-96 (1969) Malmgren, R.A., Bennett, J.M., DelVecchio, P.R., DeWhitt, S.H., Feld, M . , Kazam, E . , and Schneiderman, M.A. Evaluation studies of peripheral blood leucocyte changes in malignancy. Acta Cytol. 13:149-153 (1969) Schneiderman, M.A. Quantitative thinking in medicine-- biosta tistics. (Using numbers to mark the route from cause to effect and back.) In Cantor, P., e d . Traumatic Medicine and Surgery for the Attorney. Matthew Bender, New York. ?p. 419-477 (1969) Givelber, H., DiPaolo, J.A., and Schneiderman, M.A. The influence of' ac t i n o m y c i n D on survival of x-r ad ia te d RF mice. C anc er Res. 28:2484-2488 (1968) Pipberger, H.V., Schneiderman, M.A., and Klingeman, J.D. The love-at-first-sight effect in research. Circulation 33:822825 (1968) Carbone, P.P., Spurr, C., Schneiderman, M.A., Scotto, J., Holland, J.F., and Shnider, B. Management of patients with malignant lymphoma: A comparative study with cyclophosphamide and vinca alkaloids. Cancer Res. 28:811-822 (1968) Hall, T.C., Nevinny, H.B., Holland, J.F., Maldia, G . , Schneiderman, M.A., Salvin, L . , Shnider, B.I., Gold, G.L., Frei, E . , III, Carbone, P.P., Colsky, J., Franzino, A., Grob, D., Matiasevic, D . , Olson, K.3., Horton, J., Owens, A., Santos, G.W. , Chalmers, T.C. , and Krant, M.J. Comparison of antimetabolites in the treatment of breast and colon cancer. JAMA 200:770-778 (1967) Schneiderman, M.A. The Shin Tokaido to developing new treatments in medicine: Unbiasedness. In Harris, R.J.C., ed. Pro ceedings of the 9th International Cancer Congress. SpringerVerlag, Heidelberg. Pp. 194-198 (1967) Bull, B.S., Schneiderman, M.A., and Brecher, G. Semi-automatic dilution system for the hematology laboratory. Am. J. Clin. Pathol. 47:549-553 (1967) j? jr* SCHNEIDERMAN, page 12 Schneiderman, M.A. Mouse to man: statistical problems in bringing a drug to clinical trial. In LeCam, L., and Neyman, J., eds. Biology and Problems of Health. Univer sity of California Press, Berkeley. Vol. 4, pp. 855-866 (1967) Schneiderman, M.A. Non-objective art and objective evaluation of cancer chemotherapy. In Brodsky, I., and Kahn, S.3., eds. Cancer Chemotherapy. New York, Grue and Stratton. Pp. 67-76 (1967) Spurr, C.L., Carbone, P.P., and Schneiderman, M.A. Comparative evaluation of cyclophosphamide and vinca alkaloids in lymphomas. Proceedings of the 57th Annual Meeting of the American Association of Cancer Research 7:67 (1966) Myers, M.H., Schneiderman, M.A., and Armitage, P. Boundaries for closed (wedge) sequential t-test plans. Biometrika 53:431-437 (1966) Schneiderman, M.A. Experimental design considerations in multi clinic trials. In Radouco-Thomas, C., exec, ed. Interna tional Encyclopedia of Pharmacology and Therapeutics. Pergamon Press, Oxford. Vol. 2, pp. 617-636 (1966) Schneiderman, M.A. The value of controlled trials. In Hayward, J.L., and Bulbrook, R.D., eds. Clinical Evaluation in Breast Cancer. London, Academic Press. Pp. 249-259 (1966) Cutler, S.J., Greenhouse, S.W., Cornfield, J ., and Schneiderman, M.A. The role of hypothesis testing in clinical trials. J. Chron. Dis. 19:857-882 (1966) Bourgeois, L.D., Hart, L.J., Herman, L.G., Schneiderman, M.A. , and Young, V.M. Effect on varying preincubation and diffu sion times and antibiotic disc susceptibility testing. In Day, R.A., ed. Antimicrobial Agents and Chemotherapy-- 1965. Waverly Press, Baltimore. Pp. 283-288 (1966) Schmeiderman, M.A., and Krant, M.J. What shall we measure on whom: Why? Cancer Chemother. Rep. 50:107-112 (1966) Dawson, J.M., Hall, T.C., Schneiderman, M.A., Shnider, B.I., Owens, A.H., Andrews, J.R., Baxter, D.H., Brenner, S., Hunter, C., Levene, M.B., Sheehan, F.R., and White, G. The objective evaluation of change in tumor size in lung cancer patients with non-measurable disease. Cancer 19:415-420 (1966) 12228 SCHNEIDERMAN, page 13 Schneiderman, M.A. Looking backward: Is it worth the crick in the neck? Or: Pitfalls in using retrospective data. AJR 96:230-235 (1966) Bull, B.S., Schneiderman, M.A., and Brecher, G. Platelet counts with the Coulter counter. Am. J. Clin. Pathol. 45:678-688 (1965) Schneiderman, M.A. How can we find an optimal dose? Toxicol. Appl. Pharmacol. 7, Supp. 2:44-53 (1965) Schneiderman, M.A. The optimal dose and the ranking of drugs. J. Oral Ther. Pharmacol. 2:118-119 (1965) Carbone, P.P., Krant, M.J., Miller, S.P., Hall, T.C., Shnider, 3 Colsky, J., Horton, J., Hofley, H . , Miller, J.M., Frei, E.J., III, and Schneiderman, M.A. The feasibility of using randomization schemes early in the clinical trials of new chemotherapeutic agents: Hydroxyurea (NSC-32065). Clin. Pharmacol. Ther. 6:17-24 (1965) Schneiderman, M.A. The proper size of a clinical trial: "Grand ma's strudel" method. J. New Drugs 4:3-11 (1964) Schneiderman, M.A. Defensive design of clinical trials. In Sternberg, T.H., and Newcomer, V.D., eds. The Evaluation of Therapeutic Agents and Cosmetics. McGraw-Hill, New York. Pp. 66-73 (1964) Schneiderman, M.A., Myers, M.H., Sathe, Y.S., and Xoffsky, P. Toxicity, the therapeutic index, and the ranking of drugs. Science 144:1212-1214 (1964) Schneiderman, M.A. Is it really bad? A proposal for the toxi city-testing of drugs. J. Soc. Cosmetic Chem. 14:227232 (1963) Schneiderman, M.A., and Armitage, P. Closed sequential t-tests. Biometrika 49:359-366 (1962) Brecher, G., Jakobek, E.F., Schneiderman, M.A., Williams, G.Z., and Schmidt, P.J. Size distribution of erythrocytes. Ann. N.Y. Acad. Sci. 99:242-261 (1962) Schneiderman, M.A., and Armitage, P. A family of closed sequen tial procedures. Biometrika 49:41-56 (1962) Schneiderman, M.A. The clinical excursion into 5-fluorouracil. J. Chron. Dis, 51:283-295 (1962) SCHNEIDERMAN, page 14 Schneiderman, M.A. Controlled clinical trials: Monday's count down for Tuesday's launching. J. New Drugs 1:250-255 (1961) Schneiderman, M.A. Statistical problems in the screening search for anticancer drugs by the National Cancer Institute of the United States. In Quantitative Methods in Pharmacol ogy. North Holland Publishing Co., Amsterdam. Pp. 232247 (1961) Zubrod, C.G., Schneiderman, M.A., Frei, E . , III, Brindley, G., Gold, G.L., Shnider, B., Oviedo, R . , Gorman, J., Jones, R . , Jr., Jonsson, G . , Colsky, J., Chalmers, T., Ferguson, B., Dderick, M . , Holland, J., Selawry, O., Regelson W . , Lasagna, L . , and Owens, A.H. Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J. Chron. Dis. 11:7-33 (1960) Leiter, J., Wodensky, I., Bourke, A.R., and Schneiderman, M.A. Screening data from the Cancer Chemotherapy National Service Center screening laboratories, III. Cancer Res. 19:438575 (1959) Leiter, J., and Schneiderman, M.A. Screening data from the Cancer Chemotherapy National Service Center screening laboratories. Cancer Res. 19:31-279 (1959) Schneiderman, M.A. Mathematical models in the regulation of granulocyte production. In Stohlman, F., Jr., ed. Kinetics of Cellular Proliferation. Grue and Stratton, New York. Pp. 259-264 (1959) Brindley, C.O., Markoff, E . , and Schneiderman, M.A. Direct observations of lesion size and number as a method of following the growth of human tumors. Cancer 12:139-146 (1959) Freireich, E.J., Schmidt, P.J., Schneiderman, M.A., and Frei, E . , III. A comparative study of the effect of transfusion of fresh and preserved whole blood on bleeding in patients with acute leukemia. N. Eng. J. Med. 260:6-11 (1959) Armitage, P., and Schneiderman, M.A. Statistical problems in mass screening program. Ann. N.Y. Acad. Sci. 76:896908 (1958) Frei, E . , III, Holland, J.F., Schneiderman, M.A., Pinkel, D., Selkirk, G. , Freireich, E.J., Silver, R.T., Gold, G.L., and Regelson, W.A. A comparative study of two regimens of combination chemotherapy .in acute leukemia. Blood 13: 1126-1148 (1958) SCHNEIDERMAN, page 15 r Schneiderman, M .A . Epidemiology of carcinoma of the..breast. Med. Ann. Dist. Columbia 27:275-280 (1958) Silver, R.T., Beal, G.A., Schneiderman, M.A., and McCullough, N.B. The role of the mature neutrophil in bacterial infections in acute leukemia. Blood 12:814-821 (1957) Stohlman, F., Jr., Brecher, G., Schneiderman, M.A., and Cronkite, : The haemolytic effect of ionizing radiation and its relation ship to the hemorrhagic phase of radiation injury. Blood 12:1061-1085 (1957) Brecher, G . , Schneiderman, M.A. , and Williams, G.Z. Evaluation of an electronic red blood cell counter. Am. J. Clin. Pathol. 26:1439-1449 (1956) Olivier, L . , and Schneiderman, M.A. A method for estimating the density of aquatic snail populations. Exp. Parasitol. 5:109-117 (1956) Stohlman, F., Jr., and Schneiderman, M.A. Application of the c r ^ technique to the study of experimental hemolysis in the dog. J. Lab. Clin. Med. 47:72-37 (1956) Cutler, S.J., Schneiderman, M.A., and Greenhouse, S.W. Some statistical considerations in the study of cancer in industry. Am. J. Public Health 44:1159-1166 (1954) Prehn, R.T., Main, J.M., and Schneiderman, M.A. Factors influ encing tumor distribution among the mammary glands of the mouse. JNCI 14:895-904 (1954) Olivier, L., and Schneiderman, M.A. Acquired resistance to schistosoma Mansoni infection in laboratory animals. Am. J. Trop. Med. Hyg . 2:298-306 (1953) Brecher, G., Schneiderman, M.A., and Cronkite, E.P. The reproduc ibility and constancy of platelet counts. Am. J. Clin. Pathol. 23:15-26 (1953) Heston, W.E., and Schneiderman, M.A. Analysis of dose-response in relation to mechanism of pulmonary tumor induction in mice. Science 117:109-111 (1953) Plum, C.M., Clemmesen, J., and Schneiderman, M.A. In vitro study of bone marrow v. erythropoiesis of bone marrow from cases of pernicious anemia and leukosis. Acta Med. Scand. 143:237-248 (1952) 1 ^tj n 9 it' SCHNEIDERMAN, page 16 Schneiderman, M.A., Mantel, N . , and Brecher, G. The .effect of rejection procedures on the accuracy of blood counts. Am. J. Clin. Pathol. 21:973-978 (1951) Schneiderman, M.A., and Brecher, G. The relative frequency of sparse cell elements-- an application to reticulocyte blood counts. Biometrics 6:390-394 (1950) Brecher, G., and Schneiderman, M.A. A time saving device for the counting of reticulocytes. Am. J. Clin. Pathol. 20:1074-1083 (1950) Williamson, C.R., and Schneiderman, M.A. The use of mass x-ray survey films for heart disease case finding. Mass. Health J. 30:7-14 (1950) 13230 Dr. Ellen Silbergeld, Ph.D., is an environmental scientist and toxicologist who is the Chief Toxicologist for the Environmental Defense Fund and a Research Scientist in the Reproductive Toxicology Laboratory of the National Institutes of Health in Bethesda, Maryland. Her curriculum vitae is attached. Dr. Silbergeld will testify as to the scientific models for TCDD toxicity. She will emphasize the receptor model, its role in physiology, how to detect receptors and how to link receptors to function. She will discuss how receptors recognize TCDD by virtue of structural "fine-tuning". She will testify as to the existence of receptors in humans and in their various organs, together with the implications of their presence for TCDD potency. She will also discuss the extrapolations which are possible between animals and humans. She will further testify as to the mechanisms of toxicity including the sensitivity of the reproductive system, both endocrine and gonadal, to the receptor-mediated effects of TCDD Finally, she will discuss the consequences of receptor inter action with TCDD insofar as that interaction produces results involving RNA-DNA, AHH induction, and heme synthesis regulation, among others. In the field of neurotoxicity, she will discuss the experimental and clinical studies with particular emphasis upon dose-response mechanisms, acute versus chronic exposures and early versus long latency effects. She will also discuss the, _ _ biochemical and morphological effects of TCDD, the electro physiology involved and the effects of TCDD on such things as cognition, mood, and affect. She will also emphasize the basic mechanisms of toxicity on both the central and peripheral nervous systems, specifically dealing with the role of altered porphyrin synthesis on the nervous system. Three aspects of this problem will be discussed: First, the effects of decreased cellular energy supply on neuronal activity and viability; second, the effects of decreased heme systhesis on the integrity of myelin; and third, the neuroactive properties of certain porphyrin precursors. C' Q O LC/.C&& CURRICULUM VITAE Name: _ -Ellen Kovner Silbergeld Date and Place of Birth: July 29, 1945, Washington. DC Education: 1967 - A.B. 1972 - Ph.D. Vassar College Johns Hopkins University Chronology of Employment: 1967 1968-70 1969-71 1972-75 1975 1975-79 1979-81 1982 Instructor, California International Summer Program, Uppsala Sweden Secretary and Program Officer, National Academy of Sciences. National Research Council. Washington. DC "Nader's Raiders", Center for the Study of Responsive Law. Washington. DC Postdoctoral Fellow in Environmental Medicine and Neurosciences. Johns Hopkins University, Baltimore. Maryland Assistant Professor. Department of Environmental Medicine, School of Hygiene and Public Health, Johns Hopkins University Staff Fellow and Head. Unit on Behavioral Neuropharmacology. Experimental Therapeutics Branch. NINCDS.NIH Chief. Section on Neurotoxicology. NINCDS.NIH Chief Toxics Scientist, Environmental Defense Fund. Washington. DC Guest Scientist. Reproductive Toxicology Section, Pregnancy Research Branch. NICHD.NIH Other Professional Appointments: Consultant . NSF Energy Program. 1974-1975 Member. Nutrition Foundation National Committee on Food Additives and Hyperkinesis, 1975-1980 Member. USDHEW-FDA Committee to Coordinate Toxicology and Related Programs, 1977-1981 Member, US Delegation of the Joint US-USSR Health Agreement on Environmental Health. 1977-78 Member, Society for Neuroscience Committee on Social Issues. 1978 Member, OECD Chemicals Program Ad Hoc Expert Review Committees on Reproductive Toxicity and Neurotoxicity. 1982 - 13233 Member, Member. Member. Member. Member. Member, US Delegation to OECD Expert Meetings on Existing Chemicals, 1983 Hazardous Waste Task Force and Hazardous Waste Facilities Siting Board, State of Maryland. 1983 Govenor's Blue Ribbon Panel on Binghamton. NY. State Office Building. 1982 Executive Committee. Science Advisory Board. US EPA. 1983 Board on Toxicology and Environmental Health Hazards. National Academy of Sciences, 1983 Public Policy Committee. American Society for Neurochemistry, 1983 - Professional Society Memberships: American Public Health Association Society for Occupational and Environmental Health Society for Neuroscience Association of Women in Science American Association for the Advancement of Science International Brain Research Organization American Society for Neurochemistry American Society for Pharmacology and Experimental Therapeutics Engineering Society of Baltimore Other Activities Secretary-Treasurer. Society for Occupational & Environ mental Health. 1983- Editorial Board: Neurobehavioral Toxicology, 1979American Journal of Industrial Medicine. 1980Neurotoxicology. 1981Environmental Research, 1983Hazardous Waste. 1983 - Participant. NIH Consensus conferences, 1979 and 1982 Expert consultant on lead poisoning. U.S. Secret Service, 1979-81 Chairperson, Society for Occupational and Environmental Health Special Committee on El Paso Lead Poisoning, 1977-1979 Preceptor. NIGMS Pharmacology-Toxicology Research Associateship Program. 1977-1981 Graduate board examiner. University of Pittsburgh and University of Toronto Lecturer, continuing medical education courses in environ mental medicine (Johns Hopkins) and occupational medicine (NIOSH) 2 S234 Elected councillor. NIMH-NINCDS Assembly of Scientists. 1979- 1981 Elected representative. NINCDS EEO Committee. 1977-1980 Co-^organizer. Women in Neuroscience Member, Solowey Lectureship selection committee. NIH, 1980- 1981 Environmental Health Consultant. Oil. Chemical and Atomic Workers Union. AFL-CIO. Washington. D.C.. 1970 Reviewer. EPA documents on lead, manganese. mercury, dioxin, risk assessment, and exposure. 1981Ad Hoc Member, Occupational Safety and Health Study Section. NIOSH. 1983Member. NIMH Committee on Frontiers of Neuroscience, 1983Grants reviewer. National Foundation - March of Dimes; National Science Foundation: Nutrition Foundation: Thrasher Foundation; Hereditary Diseases Foundation. NIH Manuscript reviewer. Life Sciences. Biochemical Pharmacology. Environmental Journal Pharmacology. Science. Neurotoxicology. Neurobehavioral Toxicology Teratology. Pharmacology Biochemical Behavior. Procs. Society Experimental Biological Medicine. Experimental Neurology, etc. Honors and Awards: Graduated summa cum laude, 1967 elected to Phi Beta Kappa. 1967 undergraduate academic scholarship. 1963-1965 Woodrow Wilson National Foundation Fellow, 1967-1968 Leverhulme and Fulbright Fellowships to University of London. 1967 National Science Foundation Graduate Traineeship. 1968-1972 Public Health Service Research Fellowship to Woods Hole, 1970 Rockefeller Foundation predoctoral research fellowship. 1971-1972 NIH postdoctoral fellowship in environmental health sciences, 1972-1972 Joseph P. Kennedy. Jr. Fellowship in neurosciences. 1974-1975 Pharmaceutical Manufacturers Association Foundation Research Starter Award. 1974-1975 National Academy of Sciences Exchange Fellow to Yugoslavia, 1976 George Miller lectureship in environmental studies. University of Illinois. 1984 Professional Interests: Neuropharmacology & Toxicology Environmental Risk Assessment 3 f ?a j ,P--v-`JJ-j BIBLIOGRAPHY ELLEN KOVNER SILBERGELD A. SCIENTIFIC PUBLICATIONS 1. Silbergeld. E.K.: Dieldrin: Effects of chronic sublethal exposure on adaptation to thermal stress in a freshwater fish. Environ. Sci. Technol. 7:846-849, 1973. 2. Silbergeld. E. K.: and Goldberg. A.M.: A lead-induced behavior disorder. Life Sci. 13_(9): 1275-1283 . 1973. 3. Silbergeld. E. K.: Blood glucose: A sensitive indicator of environmental stress in fish. Bull. Environ. Contain. Toxicol ll(l):20-25. 1974. 4. Silbergeld, E. K., Fales, J. T. and Goldberg. A.M.: Lead: Evidence for a prejunctional effect on neuromuscular function. Nature 247 :49-50. 1974. 5. Silbergeld. E. K., Fales. J. T. and Goldberg, A.M.: Lead: The effects of inorganic lead on the neuromuscular junction. Neuropharmacology 13_:146-157. 1974. 6. Silbergeld. E. K. and Goldberg, A.M.: Lead induced behavioral dysfunction: An animal model of hyperactivity. Exp. Neurol. 42_:146-157. 1974. 7. Silbergeld, E. K. and Goldberg. A.M.: Hyperactivity: A lead induced behavior disorder. Environ. Health Persp. 7:227-232. 1974. 8. Silbergeld, E. K. and Goldberg. A.M.: Pharmacological and neurochemical investigations of lead induced hyperactivity. Neuropharmacology 14.:431-444 , 1975. 9. Morrison. J. H., Olton. D. S.. Goldberg. A.M. and Silbergeld. E. K.: Alteractions in consummatory behavior of mice produced by dietary exposure to inorganic lead. Dev. Psychobiol. 8.(5):389-396 . 1975. 10. Silbergeld, E.K.: Neurochemical and pharmacological studies of central nervous system lead toxicology. In. Carnow, B.W. (ed.): Health Effects of Occupational Lead and Arsenic Exposure. USDHEW. PHS. CDC, NIOSH. Washington. D.C.. pp. 74-85. 1976. 4 11. Silbergeld. E. K. and Chisolm. J. J.. Jr.: Lead poisoning: Altered urinary catecholamine metabolites as indicators of intoxication in mice and children. Science 192:153-155. 1976. 12. Fitzgerald, R. S.t Garfinkel, F.. Silbergeld, E. K. and Loscutoff, S.C.: Factors in the interpretation of mouth occlusion pressure during measurements of chemosensitivity. Chest 70(1):145-149. 1976. 13. Silbergeld, E. K. and Goldberg. A. M . : Hyperactivity, in Goldberg. A.M. and Hanin. I. (eds): Biology of Cholinergic Function. Raven Press, New York. pp. 619-645. 1976. 14. Silbergeld. E. K.: Interactions of lead and calcium on the synaptosomal uptake of dopamine and choline. Life Sci. 20(2) :309-318. 1977. 15. Carroll, P. T.. Silbergeld. E. K. and Goldberg. A. M. : Alteration of central cholinergic function by chronic lead acetate exposure. Biochem. Pharmacol. 2j6:397-402. 1977. 16. Silbergeld. E. K. and Pfeiffer. R. F.: Differential effects of three dopamine agonists: Apomorphine, bromocriptine and lergotrile. J. Neurochem. 28:1323-1326. 1977. 17. Silbergeld. E. K.: Na+ regulates release of Ca++ sequestered in synaptosomal mitochondria. Biochem. Biophys. Res. Comm. 77(2):464-469. 1977. 18. Silbergeld. E. K.. Adler, H. S. and Costa. J. L.: Subcellular localization of lead in synaptosomes. Res. Comm. Chem. Pathol. Pharmacol. 17:715-725, 1977. 19. Goldberg. A. M. and Silbergeld. E. K.: Animal models of hyperactivity In. Hanin. I. and Usdin, E. (eds.): Animal Models of Psychiatry and Neurology. Pergamon Press, New York. pp. 371-384, 1977. 20. Silbergeld. E. K.. Adler. H. S.. Kennedy. S. and Caine, D. B.: the roles of presynaptic function and hepatic drug metabolism in the hypothermic actions of some novel dopaminergic agonists. J. Pharm. Pharmacol. 29:632-635. 1977. 5 3,3337 21. Silbergeld. E. K.: Neuropharmacology of hyperkinesis. In Valzelli. L. and Essraan. W. B. (eds.): Current Developments in Psychopharmacology. vol. 4, pp. 181-214, 1977. 22. Silbergeld, E. K. and Adler. H. S.: Subcellular mechanisms of lead neurotoxicity. Brain Res. 148(2):451-567. 1978. 23. Silbergeld, E. K.. Carroll. P. T. and Goldberg. A. M . : Neurotoxicity of lead: A review of experimental studies. Proc. International Conference on Heavy Metals in the Environment. University of Toronto Press, Toronto, Canada, pp. 213-228. 1978. 24. Silbergeld. E. K. and Costa, J. L.: synaptosomal calcium metabolism studies by electron microprobe analysis. Exp. Neurol. 63_:277-292. 1979. 25. Caine. D. B.. Kebabian. J.. Silbergeld. E. K. and Evarts. E.: Advances in the neuropharmacology of Parkinsonism. Ann. Int. Med. 90(2):219-229. 1979. 26. Silbergeld. E.K. and Walters. J.R.: Synaptosomal uptake and release of dopamine in substantia nigra: effects of GABA and substance P. Neurosci. Lett. 12.:119-126, 1979. 27. Walsh, M.J. and Silbergeld, E.K.: Rat rotation monitoring for pharmacology research. Pharmacol. Biochem. a Behavior 10:433-436. 1979. 28. Hruska, R.E.. Kennedy. S., and Silbergeld. E.K.: Quantitative aspects of normal locomotion in rats. Life Sciences 25.:171-179, 1979. 29. Hruska. R.E. and Silbergeld. E.K.: Abnormal locomotion in rats after bilaterial intrastriatal injection of kainic acid. Life Sciences 2.5:181-193. 1979. 30. Silbergeld. E.K., Hruska. R.E.. Weir. R., and Kennedy. S.W.: Dopaminergic and serotonergic effects of ergot drugs. In: Fuxe, K. and Caine. D.B.. eds. Dopaminergic Ergot Derivatives and Motor Function. Pergamon, Oxford, pp. 223-235. 1979. 31. Lafferman, J.A.. and Silbergeld. E.K.: Erythrosin B inhibits dopamine transport in rat caudate synaptosomes. Science 205.:410-412 . 1979. 6 I <T. {'*> 32. Silbergeld. E.K., Miller. L.P., Kennedy. S., and Eng. N . : Lead. GABA and seizures: effects of subencephalopathic S' lead exposure on seizure sensitivity and GABAergic function. Environ. Res. 19.:371-382. 1979. 33. Silbergeld, E.K. and Hruska. R.E.: Effects of ergot drugs on serotonergic function: behavior and neurochemistry. Eur. J. Pharmacol. 58.:1-10. 1979. 34. Silbergeld, E.K. and Hruska. R.E.: Effects of kainic acid on behavioral and biochemical aspects of cholinergic function. In: Chase. T.N.. Wexler, N.S.. and Barbeau, A., eds.. Advances in Neurology, Vol. 23 (Huntington's Disease). Raven. N.Y.. pp. 633-644, 1979. 35. Silbergeld. E.K. and Hruska. R.E.: Lisuride and LSD: Dopaminergic and serotonergic interactions in the "serotonin syndrome". Psychopharmacology 65.:233-237, 1979. 36. Silbergeld. E.K. and Hruska. R.E.: Tremor: Role of striatal cholinergic neurons and the effect of intrastriatal kainic acid. Neurosci. Letters 15:235-242. 1979. 37. Silbergeld, E.K. and Goldberg. A.M.: Problems in experimental studies of lead poisoning. In. Singhal, R.D. and Thomas, J.A. (eds.): Lead Toxicity. Baltimore: Urban ( and Schwartzenberg. pp. 19-42. 1980. 38. Hruska, R.E. and Silbergeld, E.K.: Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum. Eur. J. Pharmacol. 62_:397-400, 1980. 39. Silbergeld, E.K.. Goldstein. G.W., and Wolinsky, J.: Electron probe microanalysis of isolated brain capillaries poisoned with lead. Brain Res. 189 :369-376. 1980. 40. Silbergeld. E.K., Hruska, R.E.. Miller, L.P., and Eng, N.: Effects of lead in vivo and iji vitro on GABAergic neurochemistry. J. Neurochem. 14:1712-1718. 1980. 41. Hruska, R.E. and Silbergeld. E.K.: Increased dopamine recepton sensitivity after estrogen treatment using the rat rotation model. Science 208:1466-1468, 1980. 42. Hruska, R.E. and Silbergeld. E.K.: Cortical neurochemical changes after intrastriatal injection of kainic acid. Brain Res. 191:572-576. 1980. 7 v T9 239 43. Hruska, R.E. and Silbergeld, E.K.: Effect of ergot derivatives on post-decapitation convulsions. Commun. Psychopharm. 4.:57-62, 1980. 44. Hruska. R.E.. Ludmer. L.M., and Silbergeld, E.K.: Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment. Eur. J. Pharmacol. 65.:455-456 (1980). 45. Silbergeld. E.K. and Hruska. R.E.: Neurochemical investigations of low level lead exposure. In: Needleman. H.L.. ed.. Low Level Lead Exposure: The Clinical Implications of Current Research. Raven, N.Y.. pp. 135-157,1980. 46. Hruska. R.E. and Silbergeld. E.K.: Inhibition of [ H]sp? roperidol binding by in, vitro addition of ethanol. J. Neurochem. 3j>.:750-752. 1980. 47. Silbergeld. E.K., and Lamon. J.M.: Role of altered heme synthesis in lead neurotoxicity. J. Occup. Med. 22^:680-684, 1980. 48. Hruska. R. E. , Ludmer, L.M.. and Silbergeld. E. K.: Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats. Neuropharmacol. 19.: 923-926. 1980. 49. Silbergeld. E. K.: Detection of neurotoxicity using neurochemical methods In: R.M. Gryder and V. H. Frankos, (eds.). The Effects of Foods and Drugs on the Development and Function of the Nervous System: Methods for Predicting Toxicity. FDA (No. 80-1076). Washington. D.C., pp. 99-105. 1980. 50. Silbergeld. E. K.: Erythrosin B is a specific inhibitor of high affinity 3H-ouabain binding and ion transport in rat brain. Neuropharmacol. 20: 87-90. 1981. 51. Silbergeld, E. K., and Caine. D. B.: Animal models of parkinsonism. Pharmacol. Ther. 12.: 159-166, 1981. 52. Goudsmit. J.. Rohwer, R. G.. Silbergeld. E. K., and Gadjusek. D. C.: Hypersensitivity of central serotonin receptor activation in scrapie-infected hamsters and the effects of serotonergic drugs on scrapie symptoms. Brain Res. 220: 372-377. 1981. 8 13240 53. Hruska, R. E., and Silbergeld, E. K.: Inhibition of neurotransmitter binding by ergot derivatives. J. Neurosci. Res. 6.:1-11. 1981. 54. Silbergeld, E. K., Lamon, J. M.. Bradley, D., Hruska. R.E., Pitman, K.. Hess. R. A., and Frykholm. B. C.: Heavy metal neurotoxicity; porphyrinopathic mechanisms. Procs. Internat. Symp. on Heavy Metals, WHO-EEC-EPA. Amsterdam, pp. 561-564, 1981. 55. Chisolm. J. J.. and Silbergeld. E.K.: Increased excretion of homovanillic acid in children with increased lead absorption. Procs. Internat. Symp. on Heavy Metals. WHO-EEC-EPA. Amsterdam, pp. 565-568. 1981. 56. Weir, R. L.. Hruska, R. E.. and Silbergeld. E. K.: Binding of antiparkinsonian ergot derivatives to the dopamine receptor. Psychopharmacol. 75.: 119-123, 1981. 57. Silbergeld. E.K.: Neurochemical and ionic mechanisms of lead neurotoxicity. In: (Vernadakis. A., and Prasad. K. N., (eds.). Mechanisms of Action of neurotoxic Substances. Raven. New York. pp. 1-24. 1982. 58. Hruska, R. E.. Pitman. K. T.. Silbergeld. E. K.. and Ludmer, L. M. : Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats. Life Sci. 30.: 547-553, 1982. 59. Hruska, R. E., Ludmer. L. M.. Pitman, K. T., DeRyck. M . . and Silbergeld. E. K. : Effects of estrogen on striatal dopamine receptor function in male and female rats. Pharmacol. Biochem. Behav. 16.: 285-291, 1982. 60. Silbergeld. E. K., and Anderson, S. M . : Artificial food colors and childhood behavioral disorders. Bull. N.Y. Acad. Med. 5: 375-295, 1982. 61. Morris. S. J.. Silbergeld. E. K.. Brown. R. R., and Haynes. D. N.: Erythrosin B (USFD&C Red 3) inhibits calcium transport and ATPase activity of muscle sarcoplasmic reticulum. Biochem. Biophys. Res. Commun. 104: 1306-1311, 1982. 62. Silbergeld, E.K.: Current status of neurotoxicology, basic and applied. Trends in Neurosci. 8.-.291-294, 1982. 9 11 0 9 63. Silbergeld, E.K.. Anderson. S.M., and Morris, S.J.: Interactions of erythrosin B (U.S. F. D & C Red 3) with rat cortical membranes. Life Sci. 3.1:957-969. 1982. 64. Silbergeld. E. K.. Hruska, R. E., Bradley. D.. Lamon. J. M . , and Frykholm. B. C.: Neurotoxic aspects of porphyrinopathies: lead and succinylacetone. Environ. Res., 29:459-471. 1982. 65. Silbergeld. E. K.: Experimental and environmental neurotoxins: correlation of behavioral and biochemical effects. In Levy. M. and Spiegelstein. A. (eds.) Behavioral Models and the Analysis of Drug Action Elsevier-North Holland. Amsterdam, pp 297-315, 1982. 66. DeRyck. M . . Hruska. R.E., and Silbergeld, E.K.: Estrogen and haloperidol-induced versus handling-related catalepsy in male rats. Pharmacol. Biochem. Behav. 17:1027-1035. 1982. 67. Silbergeld. E. K.. Lafferman, J.. and Finkel. T.: In vitro testing for neurotoxicity. In: Kolber, A.. Wong. T.K., Grant, L.D.. Dewoskin, R.S.. and Hughes. T.J. (eds). In Vitro Toxicity Testing of Environmental Agents. New York. Plenum, pp 473-486, 1982. 68. Silbergeld, E.K.. and Lamon. J.M.: Effects of altered porphyrin synthesis on brain neurochemistry. Neurobehav. Toxicol. Teratol. 4/.635-642. 1982. 69. Hruska, R. E.. Weir. R. L.. Pitman. K. T.. and Silbergeld, E. K.: Ergot derivatives are potent drugs at CNS aminergic receptors: correlations to behavior and aging. In: Agnoli. A.. Trabucchi. M.. and Spano. P. F. (eds). Aging Brain and Ergot Alkaloids. New York, Raven, pp 215-226. 1983 . 70. Silbergeld, E.K.: Experimental studies of lead neurotoxicity: Implications for mechanisms, dose-response, and reversibility. In Rutter, M.. and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 191-216. 1983 . 71. Silbergeld. E.K.: Effects of lead on reproduction: a review of experimental studies. In Rutter. M.. and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 217-227. 1983. 10 13242 72. Silbergeld. E.K.: Indirectly acting neurotoxins. Acta Psychiat. Scand. 67. Suppl. 303, 16-25, 1983. 73. Mattison. D.R., Takizawa, K.. Silbergeld. E.K., Nightingale. M.S.. Jerina. D.. and Yagi. H.: Genetics of ovarian benzo(a)pyrene, metabolism, oocyte destruction, and impaired fertility. In Rydstrom, J.. Monteluis. J.. and Bengtsson, M. (eds) Extrahepatic Drug Metabolism and Chemical Carcinogenesis. Amsterdam. Elsevier, pp 337-350. 74. Silbergeld. E.K.: Localization of lead: implications for mechanisms of neurotoxicity. Neurotoxicol. 4/.193-200, 1983. 11 - 13243 IN PRESS: Silbergeld. E.K.: Behavioral teratology of lead. In Yanai. J. (ed) Behavioral Teratology. Elsevier/North Holland. Silbergeld, E.K.: Neurotoxicity of lead. In Manzo, L. and Blum, J. (eds) Neurotoxicology. Dekker. Fowler, B.F., and Silbergeld, E.K.: Mechanisms of metal toxicity. In Nriagu, J.. and Hornig. D.F. (eds) Changing Geochemical Cycles of Metals and Implications for Human Health. Berlin, Springer Verlag. Mattison, D.R.. and Silbergeld. E.K.: Occupational risks to reproduction. In Osofsky, H. (ed) Advances in Gynecology and Obstetrics. Baltimore. Williams & Wilkins. Silbergeld. E.K.: Mitochondrial mechanisms of lead neurotoxicity. In Narahashi, T. (ed) Cellular and Molecular Mechanisms of Environmental Neurotoxins. Raven Press, NY. in press. Silbergeld, E.K.: Review of occupational health studies on PCBs. In Kuiper. H. (ed) PCBs. Marcel Dekker. in press. Silbergeld. E.K.: Effects of PCBs in Occupational Populations. In Visser. R. (ed) PCBs. Amsterdam. Elsevier. Mattison, D.R., and Silbergeld, E.K.: Reproductive toxicity of TCDD. In Lowrance, W. (ed) Dioxins. Rockefeller University Press. IN PREPARATION: Silbergeld, E.K., and Mattison, D.R.: Effects of three polycyclic aromatic hydrocarbons on fertility in female mice: A lifetime study of the effects of single-dose treatment. Silbergeld. E.K.: A Textbook in Neurotoxicology. 12 13244 B. ABSTRACTS 1. Silbergeld, E. K.: Effects of lead on neuromuscular funetions: In vitro evidence for site of action at the presynaptic level. Fed. Proc. 32.:275, 1973. 2. Silbergeld, E. K. and Goldberg. A. M . : Lead poisoning: an animal model of hyperactivity. Pharmacologist 5:143. 1973. 3. Silbergeld. E. K. and Goldberg, A. M. : cholinergic-aminergic interactions in lead induced hyperactivity. Pharmacologist 6:335, 1974. 4. Goldberg. A. M. and Silbergeld, E. K.: Neurochemical aspects of lead induced hyperactivity. Trans. Amer. Soc. Neurochem. p.185. 1974. 5. Silbergeld. E. K., Carroll, P. T. and Goldberg, A. M . : Monoamines in lead-induced hyperactivity. Pharmacologist 3:203. 1975. 6. Goldberg. A. M.. Carroll. P. T. and Silbergeld. E. K.: Cholinergic aspects of hyperactivity. Fifth Internatl. Meeting for Soc. Neurochem., 1975. 7. Pfeiffer. R. . and Silbergeld. E. K.: Differential behavioral and neurochemical effects of. three dopaminergic agonists. Neurosci. Abst. 1:720, 1976. 8. Silbergeld, E. K. and Miller. L. P.: Lead intoxication: changes in seizure threshold and gamma-aminobutyric acid function. Neurology (27):405, 1977. 9. Adler. H. S. and Silbergeld, E. K.: Intrasynaptosomal interactions of lead and calcium in dopaminergic neurotransmission. Pharmacologist (2):40, 1977. 10. Silbergeld. E. K. and Walters, J. R.: Dopamine uptake and release in substantia nigra: Effects of gamma-aminobutyric acid and substance P. Pharmacologist 9.(2) :544, 1977. 11. Silbergeld. E. K.. Miller, L. P., Kennedy, S. and.Eng. N.: Lead and seizures: Role of gamma-aminobutyric acid. Neurosci. Abst. Ill:1039. 1977. 12. Adler. H. S. Costa, J. L. and Silbergeld. E. K.: X-ray microanalysis in neurochemistry: Localization of an 13 KCjf O 'rZ elemental neurotoxin and manipulations of mitochondrial Ca++. Neurosci. Abst. Ill:1235. 1977. 13. Baring. M. D., Walters. J. R.. Silbergeld. E. K.. Eng. N.. and Lakoski. J. M.: Effect of systemic apomorphine on firing rates of dopamine cells in rats with striatal kainic acid lesions. Neurosci. Abst. 4.. 267. 1978. 14. Hruska. R. E. and Silbergeld. E. .: Ergot drugs inhibit spiroperidol and serotonin receptor binding. Soc. Neurosci. Abst. 4.: 425, 1978. 15. Silbergeld. E. K., Hruska, R. E.. Walters. J. R.. Kennedy. S.. Eng, N., and deSantis. S.: Effects of intrastriatal kainic acid on motor behavior in rats. Soc. Neurosci. Abst. 4: 49. 1978. 16. Kennedy, S., Hruska, R. E.. and Silbergeld. E. K.: Serotonergic-dopaminergic effects of ergot drugs. Soc. Neurosci. Abst. 4.: 426, 1978. 17. Silbergeld. E. . Hruska. R. E., Lamon. J. M . . Frykholm. B. F., and Hess, R. A.: Neurotoxic mechanisms in porphyria and lead intoxication: Possible role of a-aminolevulinic acid. Clin. Res. 27.:307A, 1979. 18. Lamon. J. M. , Silbergeld. E. K.. Frykholm. B. F., and Hruska. R. E.: Extra-erythropoietic heme metabolism in lead intoxication. Clin. Res. 27_: 299A, 1979. 19. Silbergeld. E. K.. Hruska. R. E.. Lamon. J. M . . Frykholm. B. F., and Hess. R.A.: The effects of lead (Pb) on hepatic heme synthesis and drug metabolism. Pharmacologist 21: 209. 1979. 20. Silbergeld. E. K., Hruska. R. E., and Lafferman. J. A.: Actions of lead (Pb) on GABAergic neurotransmission: Discrepancies between in vivo and in vitro effects. Soc. Neurosci. Abst. 5.: 416, 1979. 21. Lafferman. J. and Silbergeld. E. K.: Erythrosin B (Food. Drug and Cosmetic Red No. 3) inhibits dopamine uptake in rat caudate synaptosomes: a kinetic study. Soc. Neurosci. Abst. 5. 562. 1979. 22. Hruska, R. E. and Silbergeld, E. K.: Increased dopamine receptor sensitivity after estrogen treatment. Soc. Neurosci. Abst. 5.: 73 (1979). No. 236. 14 :a 23. Silbergeld. E. K., Hruska. R. E.. Schwarcz. R.: GABA in the basal ganglia: effects of selective lesions. Brain Res. Bull., 4: 696, 1979. 24. Weir, R. L., Hruska. R. E. and Silbergeld, E. K.: Effects of dopamine agonists on 3H-spiroperidol receptor binding. Soc. Neurosci. Abst. 5: 81, 1979. 25. Hruska, R. E.. Ludmer. L. M . , and Silbergeld, E. K.: Prolactin increases the number of striatal dopamine receptors. Pharmacologist 22.:220 (1980). No. 338 . 26. Silbergeld. E. K.: Erythrosin B: ouabain-like actions of an artificial food dye in rat brain tissue. Pharmacol. 21:198. 1980. 27. Hruska, R. E., Ludmer. L. M . . and Silbergeld. E. K.: The striatal dopamine receptor supersensitivity produced by estrogen may be mediated through prolactin. Soc. Neurosci. Abst. 6.: 441, 1980. 28. Chisolm, J. J., and Silbergeld. E. K.: Increased excretion of homovanillic acid (HVA) in urine by young children with increased lead absorption. Neurosci. Abst. vol. 6_:508. 1980. 29. Silbergeld. E. K., and Anderson, S. M . : Erythrosin B: specific inhibitor of high affinity [3H]-ouabain binding and ion transport in rat brain. Neurosci. Abst. vol. 1:56, 1980. 30. Silbergeld, E. K., Anderson. S. M.. DeRyck. M . . Chronwall, B.. and Morris, S. J.: Neurotoxicity of an artificial food color (erythrosin B): methods for rapid testing. Abstr. 8th Meeting Internat. Soc. Neurochem.. p. 238. 1981. 31. Ptiman, K. T.. Hruska, R. E.. Ludmer. L. M.. and silbergeld. E. K.: Prolactin increases the density of striatal dopamine receptors in normal and hypophyse.ctomized male rats. Soc. Neurosci. Abstr. 7: 217. 1981. 32. DeRyck. M.. Hruska. R. E.. and Silbergeld, E. K.: Estrogen potentiates haloperidol-induced catalepsy/akinesia in male rats. Soc. Neurosci. Abstr. 7: 217, 1981. 33. Silbergeld, E.K.: The biochemical basis of lead neurotoxicity. Abstr. Ann. Mtg. AAAS. Toronto. 1981. 15 13247 34. Hruska. R. E.. Pitman. K. T., Ludmer. L. M . , DeRyck. M . . and Silbergeld. E. K.: Comparison of the biochemical and behavioral effects of estrogen in male and female rats. So-Cr Neurosci. Abstr. 7: 218, 1981. 35. Silbergeld, E. K., Morris, S. J., and Anderson, S. M . : Erythrosin B and Na,K-ATPase: receptor-like interactions with brain synaptic membranes. Soc. Neurosci. Abstr. 7: 105. 1981. 36. Silbergeld, E. K.: Basic and applied neurochemistry of hazards. Abstr. Annual Meet. AAAS. Washington, D.C.. p. 63. 1982. 37. Silbergeld. E. K.: Neurotoxic implications of altered heme synthesis in lead poisoning. Neurotoxicol. 3_:119-120, 1983. 38. Silbergeld, E. K., Nightingale. M. S., and Mattison, D. R.: Effect of oocyte destruction by polycyclic aromatic hydrocarbons (PAH) on fertility of DBA/2N (D2). C57BL/6N (B6). and (D2 x B6) FI mice. Soc. Gynecol. Invest. Abstr., p. 51. 1983. 39. Silbergeld, E.K., Nightingale, M.S., Godlove. K.. Malley, J. , and Mattison, D.R.: Reproductive toxicity of polycyclic aromatic hydrocarbons (PAHs) in female mice. Pharmacol., 25_*.655, 1983 . 40. Mattison, D.R., Takizawa, K.. Silbergeld, E.K.. Nightingale. M.S., Jerina. D.. and Yagi. H.: Genetics of ovarian benzo(a)pyrene metabolism, oocyte destruction, and impaired fertility in inbred DBA/2N and C57BL/6N mice and D2xB6 FI heterozygote mice. Abstr. Internat. Conf. Extrahepatic Metabolism of PAHs and Carcinogenesis, 1983. 41. Mattison, D.R., and Silbergeld. E.K.: Occupational exposures and pregnancy, Abstr. 15th Ann. Cong. Col. Soc. Obstet. Gynecol., Bucarananja, Columbia, 1983. 42. Mattison, D.R., Nightingale, M.S.. Shiromizu, K.. Takizarva K. . Silbergeld. E.K.. Kay, H.H.. and Swartz. W.J.: Ovarian toxicity, Abstr. 15th Ann. Cong. Col. Soc.. Obstet. Gynecol. Bucaramanga, Colombia. 1983. 43. Swartz, W.. Silbergeld. E.K., Malley. K.. and Mattison. D.R.: The effects of benzo(a)pyrene on urine ovarian function and fertility. Abstr. Amer. Assoc. Anat.. in press, 1984. 16 1C OTHER PUBLICATIONS REVIEWS Silbergeld. E.K.: "Lead in Man and the Environment" for Trends in Pharmacological Sciences. 1981 Silbergeld. E.K.: "Hazardous Waste in American" for Quarterly Review of Biology, in press Silbergeld. E.K.: "Nutrition and Brain Function" for Trends in Neurosciences, in press OTHER Silbergeld, E.K.: "US Lead Program Vital" (editorial) Clin. Chem. News. February. 1983, page 4 Silbergeld, E.K.: "Where do we go from here?", in Legator, M.S. (ed) Community Health STudies: A Guide for Citizens. Johns Hopkins Press. Baltimore. MD. in press Silbergeld. E.K.: "Health Effects" in Environmetal Defense Fund. Dumpsite Cleanups: A Guide to the Superfund Program. Washington. DC. 1983 Silbergeld. E.K.. and Highland, J.: "Ghost Dumps" (letter) Science. 216:462. 1982 Silbergeld, E.K.: "Cancer Policy: Has the Dust Settled?" Environmental Forum. 2.:25-29, 1983 Hall. K.L.. and Silbergeld, E.K.: "Reappraising Epidemiology" Harvard Environmental Law Review. 7:441-44.8, 1983 17 1 3249 Dr. Raymond Singer, Ph.D., is a neurotoxicologist and neuropsychologist practicing at Occupational Health Consulting, Inc., of New York, New York. Dr. Singer's curriculum vitae is attached. Dr. Singer will prepare reports concerning each of the veteran plaintiffs. These reports will be based upon personal interviews and review of appropriate test findings performed by himself and/or by others. The personal interview will consist of a thorough account of the veteran's background and current and historic symptoms. It will also detail the educational and occupa tional background of each veteran. Various neuropsychologic tests will be given and discussed with particular reference to whether:: any deficits or changes noted are due to the results of any toxic chemical exposures. Neurophysiologic tests will also be given or reviewed and interpreted, with particular emphasis placed upon nerve conduction velocity findings, and the results will be set out and discussed, with particular reference to whether the findings are related to toxic chemical exposures. To the extent warranted, Dr. Singer will relate any findings to Agent Orange exposure. Dr. Singer will also testify to the effects of toxic chemical exposures as they have been studied in a number of research efforts in both animals and humans. He will discuss the findings reported in various populations exposed to toxic chemicals 13250 and particularly to TCDD through the mechanism of industrial ac cidents. He will also discuss the findings concerning demyelination of the fatty sheaths surrounding the nerves and the "dying-hack" neuropathy which has been associated with toxic chemical exposures. Dr. Singer will also discuss the results of his own work in relation to occupational exposures to TCDD, and will, explain how his results are consistent with those obtained from tests per formed on the veterans here, and how those results are consistent with causation by phenoxy herbicides and their contaminants. 13251 RESUME Name: Raymond M. Singer Born: August 20, 1950; Philadelphia, Pennsylvania Address: 415 East 85th Street, #10H New York, NY 10028 (212) 744-1728 Ph.D. M.S. B.A. EDUCATION AND DEGREES Washington State University Washington State University University of Rochester 1978 1975 1972 Psychology Psychology Psychology PROFESSIONAL ORGANIZATIONS Certified Psychologist, New York State Board of Psychology Member, American Psychological Association Member, National Academy of Neuropsychologists Member, Society for Occupational and Enviromental Health Member, American Public Health Association Associate Member, College of Toxicology 1983 1983 1982 1982 1982 1981 1979 1978 1978 PROFESSIONAL EXPERIENCE 1982 1981 1979 1979 Adjunct Instructor, Mount Sinai School of Medicine Department of Community Medicine, New York City Consultant, New York State Department of Social Services, Office of Disability Determinations President, Occupational Health Consulting, Inc. Clinical Psychologist, Private Practice, New York City Reviewer, The American Journal of Industrial Medicine Fellow, Mount Sinai School of Medicine, Department Community Medicine, Enviromental Sciences Laboratories, New York City NIH Post-Doctoral Fellow in Environmental Epidemiology, Mount Sinai Medical School of Medicine, New York City NIH Post-Doctoral Fellow in Biological Psychiatry, Millhauser Laboratories, New York University Medical Center, New York City Clinical Psychology Intern, Park East Psychological Associates, New York City 1 ^ 0 52 Dr. Raymond Singer December 5, 1983 1972 - 1978 Teaching and Research Assistant/ Department of Psychology, Washington State University, Pullman, Washington PUBLICATION AND PAPERS. Singer, Raymond. Peripheral nervous system assessment in the evaluation of toxic chemical exposure. Paper to be presented at the 12th Annual Meeting of the International Neuropsychological Society, Houston, February, 1984. Singer, Raymond. Neural indicators of phenoxy herbicide exposure. Paper presented at the 1983 Annual Meeting of The Society for Occupational and Environmental Health, Washington (D.C.), December, 1983. Singer, R., Valciukas, J., and Lilis, R. Lead exposure and nerve conduction velocity: The differential time course of sensory and motor nerve effects. Neurotoxicology, 4, 2, 193-202, 1983. Presented at the' XI Triennial World Congress of Pathology, Jerusalem (Israel), September, 1981. Singer, R., Moses, M., Valciukas, J., Lilis, R., and Selikoff, I.J. Nerve conduction velocity studies of workers employed in the manufacture of phenoxy herbicides. Environmental Research, 29, 297-311, 1982. Presented at the XX International Congress of Occupational Health, Cairo (Egypt), September, 1981. Valciukas, J. and Singer, R. The embedded figures test in epidemiological studies of environmental neurotoxic agents. Environmental Research, 28:183-198, 1982. Lilis, R., Valciukas, J., Singer, R., et al. Assessment of Lead Health Hazards in an Autobody Shop at an Automobile Assembly Plant. Report to the National Institute of Environmental Health Sciences, June, 1981. Valciukas, J., Lilis, R., Singer, R., et al. Lead exposure and behavioral changes: Comparisons of three occupational groups with different levels of lead absorption. American Journal of Industrial Medicine, 1:421-462, 1980. Singer, R. The Neuropsychological Evaluation of Patients Affected by Occupational Neurotoxic Agents. Invited address, New York State Psychological Association Convention, New York City, May, 1980. Dr. Raymond Singer December 5, 1983 Valciukas, J., Lilis, R., Singer, R., et al. Neurobehavioral studies of painters. Presented at the International Symposium on Occupational Health Hazards Encountered in Surface Coating, Handling of Paints in the Construction Industry, Stockholm (Sweden), October, 1979. Manuscript submitted, Archives of Environmental Health. Singer, R. The role of the psychologist in the prevention of myopia. Paper presented at the annual meeting of the American Psychological Association, New York, New York, September, 1979. Singer, R. The Camphill approach to the education of the retarded person. Symposium presented at the annual meeting of the American Psychological Association, New York, New York, September, 1979. Singer, R. The behavioral etiology of myopia. Paper presented at the annual meeting of the Eastern Psychological Association, Philadelphia, Pennsylvania, May, 1979. Singer, R. The relationship between visual refractive error and interests, values, personality, academic performance, and reading. Doctoral dissertation, Washington State University, 1978. Singer, R . , Young, F., and Rokeach, M. Values as predictors of visual refractive error (in Barrow Eskimos). Paper presented at the Western Psychological Association Convention, Seattle, Washington, April, 1977. Singer, R. Can myopia be prevented? Invited address - Presented to the Washington State University Chapter of Sigma XI, February, 1976. Singer, R. The association of personality and myopia. Papers presented at the Western Psychological Association Convention, Sacramento, California, April, 1975. Young, F., Singer, R., and Foster, D. The psychological differentiation of male myopes and non-myopes. American Journal of Optometry, October, 52, 10, 679-686, 1975. 1 r' / r~i-)' *-i THEODO R D . S T E R L IN G , P h .D . Dr. Sterling is Professor in the Facility of Interdisciplinary Studies and Department of Computing Science, Simon Fraser University, Vancouver, British Columbia, Canada. His Curriculum Vitae is attached. Dr. Sterling is a mathematician, statistician, and epidemiologist; as well, Dr. Sterling is intimately familiar with existing data and analyses concerning the effects of phenoxy herbicides and impurities, e.g. 2,3,7,8-TCDD, contained therein. Dr. Sterling has devoted much of his teaching and research to the collection and analysis of data and their use for scientific inference. Dr. Sterling will testify that there exists a considerable body of medical and scientific evidence which demonstrates that the preparations of 2,4,5-T and 2,4-D are toxic, teratogenic, and carcinogenic. Further, there is no credible scientific evidence of a no effect level; said another way, as a carcinogen, there is no safe level and therefore a single exposure years ago may be responsible for human cancer which develops today. In addition, Dr. Sterling will testify that there is ample evidence that exposure to 2,4,5-T is teratogenic in humans when the mother is exposed, and convincing evidence is now extant that the outcome of pregnancy is influenced by exposure to the father alone. Most especially, Dr. Sterling will testify of the incidence of subjective symptoms and/or medical records documenting such symptoms. These symptoms are those which have been compiled by the National Center for Health Statistics, and will be compared, to the extent available, to those symptoms of the Vietnam veterans, particularly those of the representative plaintiffs. 9* 1 O - DO The purpose will be to ascertain the incidence of such symptoms in the general population so as to analyze statistically the symptoms of the plaintiffs. The product of such overall incidence will be calculated to examine the possibility or likelihood of such a constellation of Agent Orange/dioxin related symptom complex to occur in a random fashion. The bases or grounds for the facts and opinions of Dr. Sterling's testimony are: educational and professional background; publications regarding the subject phenoxy herbicides; review of the applicable medical and scientific literature; attendance and participation in various symposia dealing with the scientific issues in question; training as a mathematician, statistician, and epidemiologist; and training and experience in the computer sciences. i -2- VJ C U R R IC U L U M V IT A E Theodor D.Sterling EDUCATION B. A. (CUM LAUDE) , 1949, M.A., 1952, University of Chicago; Ph.D., 1955, Tulane University. PROFESSIONAL AFFILIATIONS Present: Professor, The Faculty of Interdisciplinary Studies and Department of Computing Science, Simcn Fraser University. Previous: Visiting Professor, Department of Statistics, Princeton University, (78). Chairman, Department of Computing Science, Simon Fraser University, (72-77). Professor in the Department of Applied Mathematics and Computer Science, Washington University, St. Louis, Missouri (66-72). Also Joint appointment as Professor in the Department of Sociology (66-68) , and Visiting Professor in Computers and Humanities, Hebrew Union College, Cincinnati, Ohio (68-70). Professor of Biostatistics and Director of the Computing Center, College of Medicine, University of Cincinnati, Ohio (58-66). Previously instructed in the Department of Statistics, Michigan State University and Department of Mathematics, University of Alabama. PROFESSIONAL ACTIVITIES ACM Committee on Scientific Freedom and Human Rights; President of the Computer Science Association cf Canada (75-80) ; Chairman, Ombudsman Committee, Canadian Information Processing Society (73-80); Chairman, President of Biological Information Processing Organization (64-65); Chairman, CIPS Special Interest Groups, Humanization of Information Systems (73-80) ; Chairman, SIGCAS Committee of Information and Public Policy (72- ) ; President of Missouri Chapter, American Association of Workers for the Blind (70-72) ; Member of the Panel for Biology, Management, and Social Sciences of the Mathematics Association of America (62-67) ; Chairman, Committee on Professional Activities of the Blind of the Association for Computing Machinery (63-71); Chairman, Ad Hoc Committee on Accreditation, Association for Computing Machinery (66-67); Committee on Radiation Dosimetry, American Association of Physicists in ' Medicine (66-69); National Lecturer for Association for Computing Machinery (72-3, 75-6). EDITORIAL ACTIVITIES: Associate Editor - Canadian Journal of Statistics (73-78); Editorial Board - International Journal of Biomedical Computing (69- ); Computers and Applied Mathematics (73- ), Humanist in Canada (73- ). < rr GOVERNMENT AND OTHER SERVICES: (Consultant/adviser, now and previous): (In Canada) Canadian Standards Board; Environment Canada, The Royal Commission (B.C.); Consumers Association of Canada; Society for Professional and Environmental Control. (In U.S.) NIH; PHS; EPA; FTC; SR A; U.S. National Academy of Science, National Research Council; American Lung Association; Natural Resource Board (Wisconsin); Environmental Defense Fund, MECCA (Minnesota); Citizens. Against Toxic Sprays (Oregon) . (In Kuwait) - Ministry of Health. PROFESSIONAL SOCIETIES: Can. Inf. Pxoc. See. ; Can. Comp. Sci. Assoc. ; Assoc. Comp. Machinery; Amer. Math. Assoc.; Math. Soc. ; Inst. Math. Stat.; Amer. Stat. Assoc.; Biometric Soc-; N.Y. Acad. Sci.; Amer. Assoc. Phys. Med.; Assoc. Res. Opthamology. HONORS AND AWARDS: Fellow, Amer. Assoc. for Advancement of Science; Fellow, Amer. College of Epidemiology; Fellow, Amer- Stat. Assoc.; Fellow, Car. Com. of Scientists and Scholars; Sigma Xi; Pi Nu Epsilon, Morrison Cressy Award in National Science; University Research Professor (1980-1981). 5I3LIOGRPHY Theodor D. Sterling Sook s A Guide to PL/1 and Structured rrog ramm in g . doit, iinenart and Winston, February, 1969. Second edition - 1976. Third Eaition 1900. Essentials cf PL/1. Molt, Rinenart and Winston, January, 1S73. Visual Prosthesis - The Interdisciplinary Dialogue. (Editor), Academic Press, March, 1971. Computing and Computer Science with PL/1. Macmillan, January, 1970 . Computing ana Computer Science with Fortran IV. Macmillan, J a n u a r y , 1970. Introduction to Statistical Data Processing. Prentice-Hall, June, I9 6 0 . Advances in Biomedical Computing Applications (Editor), Annals of The New York Academy of Science, Vol 1 2 3 , 1966. Computers and the Life Sciences. Columbia Press, December, 1965. In preparation: People are Trouble: The Human Side of a Computerized Society. Concepts of Machine Computation. s2259 Articles 1984 The Economics and Politics of building Illness: The NAS/NRC Report on Indoor Pollutants. International Journal of Health Services 14(1): 43-53. Second Thoughts: On Filtering Information About Occupation, Smoking and Disease. Journal of Chronic Diseases. (In press) Computers and Society. In Adriana Davies, (ed.) The Canadian Encyclopedia. (In press) Investigations on the Effect of Regulating Smoking on Levels of Indoor Pollution and on the Perceotion of Health ana Comfort of Office Workers. Proceedings of workshop on Effects and Exposure Levels, Geneva, Switzerland, larch 15-1 7 , 1983. (In press) The Emerging Key Role of White-Collar Computer Workers Vis A Vis Organized Labor. Technology and People. (In press) What is the Host Advanced Technology on Earth Today and for What is it Used? In Gallup, G. and Ncrtack, C.T. (oas.). America Wants to Know: Ihe Experts' Answer H o o k , New York. A 6 w Publishers, Inc. (In .ress) 198 3 The Health Effects of Low-Dose Radiation on Atomic workers: A Case Study of Employer-Directec Research. In Navarro, V., and Berman, d . (eas.), Health and Work Jnder Capitalism: An International Perspective. Eaywood Publishers, New York, NY. pp. 55-bd. Concatenation. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia of Computer Science and Engineering (second edition). Van Nostranci Reinhold Company, New York. pp. 395-396. Programming. In A. Ralston and E. Reilly, Jr., (ed.) encyclopedic: of Computer Science and Engineer ir.q (second edition). Van Nostrand Rainhold Company, New York. pp. 119U-1217. Statements. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia ot Computer Science and Engineering (seccna edition). Van Kostrana. keinhold Company, New York, pp. 1d04-iu07. Trap. In A. Ralston ana . Reilly, Jr., (ad.) Encyclopedia of Computer science ana Engineering (second edition) . Van Nostrand Reinnolc Company, ew York, pp . 1 53a-1 b35 . Corporate Planning and Technological Change. The TV U Transmitter, Special Issue V ( b ): S. Buildinu Illness jn the White-Collar Workplace. I;iter nat iona i Journal cf health Servises 13:277-287. Possible Erfects on Occupational Lung Cancer from Smoking Relatec Changes in the Mucus Content of the Lung. Journal ot Chronic Diseases. Jo (10) :6 fc?-b76 . The Impact or Different Ventilation Levels and fluorescent Lighting Types on Building Illness: An Experimental Study. Canadian Journal ot Public Health. (E. Sterlinq, senior author) Sep ternter/October. Unemployment Follows from the Changes in Telecommunications. Telecommunications workers Union Transmitter 17(3): 9. Air Quality in Puolic Buildings with Health Related Complaints. ASHRAE Transactions 89(2). Perceived vs Actual 7<isks: The Problem of Multiple Confounding. In Covello, V., Flamm, w., Rodricks, J., and Tardiff, R. (eds.) The Analysis ot'Actual Versus Perceived Risks. Plenum Publishing Ccrp., ;iew York. p 203 -21 2. New Healtn Hazaras in Scaled Buildings. American Institute or Architects Journal, April, 86:bU-b7. Existing Data Systems: flow Useful Are They? In Chiazze, L. Jr., Lundin, F.E. ana Watkins, H. (eds.), Methods and Issues in Occupational and Environmental Epidemiology. Ann Arbor Science Publishers, Inc., Ann Arbor, Michigan, pp. 51-61. Prevalence of Disease in Wives of Blue-Collar workers: A Comparative study. In Chiazze, L. Jr., Lundin, F.E. and Watkins, W. (90s.) , Methods and Issues in Occupational and Environmental Epidemiology. Ann Arbor science Publishers, Inc., Ann Arbor, Michigan, pp. 165-176. 1 982 Unionization of Professionals in Data Processing: An Assessment of Recent Irenes. Communications of the ACM 25(11): 807-816. Health Effects of Chlorophenol Wood Preservatives. International Journal ot Health Services 12(4): 559-571 . Job Discrimination Based on Exposure Considerations and Smoking. In Lee, J. and Horn, w. (eds.) Legal and Ethical Dilemmas in Occupational Health. Ann Arbor Science Publishers, Ann Arbor, Michigan, pp. 379-367. The Case tor Entirely Removing the Gas Range from Indoors. Proceedings of international Symposium on Indoor Air Pollution, Amherst, Mass., Oct. 13-16, 1931. Indoor byproduct Levels of Tobacco Smoke: A Critical Review of the Literature. JAPCA, -:arch 32 : 250-259. What is Ahead tor Labour/Management in Data Processing?. Canadian Datasystems 14(5): 90-94. Critique V. The Health Effects of 2,4,5-T. In Harnik, P. Voodoo Science, Twisted Consumerism. Center tor Science in the Public Interest. Washington, D.C. 43-49. 1981 Does Smoking Kill Workers or Working Kill Smokers? Reprinted in Feinberq, H.G. (Chairman) Litigation and Settling Occupational Disease Claims. New York Lau Journal, New York. October. Humanizing Computer Information Systems. Reprinted in Murray Gruber (ea.) Management Systems in the Human Services. Temple University Press. Philadelphia, PA. 287-299. Setting the stages for Lanour Unrest in the Canadian DP Industry. CIPS Review, July/Oct. Vol. 5(4): 36-37. What EFT Will Mean to the Consumer. CIPS Reviw, aay/June. Vol. 5(3) 1b-1 7 . Ventilatory Function Changes Over a workshift. Br. j. oi Inoustrial Medicine. 38 : 152-155. (;-!. DimLch, senior author.) Unionization and its Implications. Proceedings of the Second Annual Cflice Automation Conference, March 23-25, 1981, Houston, Texas. Possible Risks to Human Lunas from Magnetometric Dust Clearance Experiments. Journal of Applied Physics, Vol. 52 (3, Part II) 2575-2577. Use of Gas Ranges ror Cookinc and Heating in Uroan Dwellings. Journal of the Air Pollution Control Association, February, Vol. 31 (2) 162 -165. Engineers Throe ter; L'o.Ti na ti:n or OP Jobs. TIPS Review, Jan./Feb. Vol. 3(1): fc-6. 19 60 The Health Et facts o f Low -level of Ionizing Paciation: A Dialogue. In Rom , W.!1 . and Archer, W.E. (eds.) , Health Implications of Sew Energy Te ch nologies. Ann Aroor Science Publishers, In c ., Ann Arbor, Mien. Pages 150-164. Stressing Design Rather Than Performance ita ncards to Ens \ire Protection of Information: Comments. In Hoffman, U . (cd.) , Computers ana Privacy in the Wext Decade. Academic P ress, IDC . 102-1C7. Smoking, Occupation and Respiratory Disease. Report to the American Lung Association, Occupational Health Task Force Meeting, April 9, 1960, Clearwater, Florida. The Social Impacts of Electronic Fund Transfers, The Financial Post, Special Report, March 6, 1980, s11. The Health Effects of Low-Dose Radiation on Atomic Workers: A Case Study of Employer--Directed Research. International Journal of Health Services, January, 10(1): 37-46. Cover-up at Hanfora: The Effects of Low-Dose Radiation. Humanist in Canada, Spring (No. 52) XII, ilo. 1: 5-8. The Comoutet Ombudsman, A Possible Model of Accountauility Among Professionals, Transactions of Society, 17(2): 31-35. 263 1979 Statistical Problems in Multi-Variate (Etiological) Surveys. Canadian Journal ot Statistics, 7(2): 205-215. The Mutual Relationship Between Smoking , Occupation and Disease. Proceedings of the XIX International Congress on Occupational Health. Supplement to vol. 30. Consumer Difficulties with Computerized Transactions: An Empirical Investigation. Communications of the ACM, Ray, 22 (S) : 283-289. Carbon Monoxide Levels in Xitchens and Homes witn Gas Cookers. J. Air Pollution Control Association, bared, 29(3): 238-241. Khat Consumers Say About Computer Errors, Canacian Datasystems, 11 (12) : 64 -b7 . What Happens When Ragor Errors Are Discovered Long After An Important Report Has Eeen Published?, Invited talk to the Annual Meeting of the American Statistic Association, Washington, D.C., August, 1979. 197b Computers in Developing Nations: A Cautionary Tale. Reprinted in Personal Computing. February, 27-jl. Smoking Patterns by Occupation, Industry, Sex, and Race. Archives ot Environmental Health. November, 33(6) : 313-317. Processing Errors Among the Public: Their Frequency and Crigin. Proceedings of the Session '78 Canadian Computer Conference, CIFS, Edmonton, Alberta. May. Does Smoking Kill Workers or working Kill Smokers, International Journal ot healtn Services, 6(3): 437-452. Follow up: New Evidence Concerning Smoking ana Health, Med. J. Australia, 65: 384-387. Frequency of Computer Related Errors Among Holders of Credit, Charge or Dank Accounts, CIPS REVIEW, June, 5: 17. High Level Language Programming. In Belzer, J., Holzman, A.G., ana Kent, A. Encyclopedia of Computer Science and Technology, Marcel uekker, 9: 257-283. Humanizing Information Systems. In aelzer, J., riolzman, A.G. ana Kent, A. Encyclopedia of Computer Science and Technology, Marcel Cekker , 9 : 361-37 1. Natural Language Compilers and Interpreters in hadiation Treatment Planning or Nous Parlons Anglais better Than Jede Anaere Sprache. In v. hosenou (?.a) , Computers in Radiation Therapy: Proceedings of the Sixth International Congress on the Use ot Computers in Hadiation Therapy, University oi Goettingen, Goettingen, FRG. 1977 Computers in developing Nations: a Cautionary Communications of the ACM. December, 20 (12): 971 -972. Tale. New Evidence Concerning Smoking and Health. Medical Journal of Australia, October, 2: 53B-SU2. Fold, Spinole and Mutilate. Humanist in Canada, March. 40/1b-20. Exposure to Pollutants in Enclosed "Living'1 Spaces. Environmental Research, February, Voi 13: 1-13. 2,U,o-T .... T er at og en ic Emoroyotoxic, F o t o g e n i e , M u t o g e n i c , Acres U.S.A., 7/7. Smoke Gets in our Eyes . Humanist in Canada.- a2: 2-b. 1 97o Humanizing Information Systems. Datamation. Decerncer. Smoking Characteristics by Type of Employment. J. Occup. Medicine, November, 1b (11): 743-754. Do we Neec. A Computer Ombudsman? Canadian Datasystems, August, 62-64. . Programming. In Fialston, A., and Meek, C.L. (Editors), Encyclopedia of Computer Science, Petrccelli-Charter, New York, pp. 1127-1156. Statements, Ralston, A., and Meek, C.L. (Editors), Encyclopedia ot Computer Science, Petrocelii-Charter, New York, pp. 326-1329. A Single-Track Universal Curriculum for Computing Science. INFOK,'February, 14: 1, 40-52. f.O wt Kan Against Himself - Biological Dangers from the Use of Herbicides. Humanist in Canada, February, IV(3): 2-7. Additional Comments on the Critical Assessment of the Evidence Bearing on smoking as the Cause or Lung Cancer. American Journal of Public Health. February, Vol 66(2): 161-164. Relation of Place of Birth and Migration in Cancer Mortality in the U.S. - A study of Ohio Residents (1959-1967), reprinted in the 1976 Year Book of Cancer. 1y7b Humanizing Computerized Information Systems: Guidelines ana Their Implications. Science, December, Vol 190: 1168-1172. A Critical Reassessment of the Evidence Bearing on Smoking as the ^ause of Lung Cancer. American Journal of Public health. Septem her, Vol 65 (9): 9 39-953 . A Critical Review of Reports on the Effect of Smoking on Sex and Fertility. Journal of Sex Rosearea. August, 7cl 11(3) 201-217. Lung Cancer Among black an a white Migrants In the U.S. !:tio 1o c-1 ca i Co nsi de r at i o n s . Journal u t the National Medical Association, .Jarcn , Vol 6 7(2) : 1j - 1 11 , 102. (T f ancuso, senior author.) 19 74 Relation of Place of birth ana Migration in Cancer Mortality in the U . gtub) or Ohio Reel tents ;!9b 3-1 9b 7) . Journal or Chronic Diseases. Vol 27: abg-u7 u. (T. F. Mancuso, senior author.) Guidelines tor Human izi na Ccmr-ur-r izer. In ferna ticn Systems : Report from Stanley House. C o mm u n i c a t i o n s or the ACM. November, Vol 17 (11) : 609-61 3 . (Reprinted in AEDS Journal, Vol 10 (1) , Fall 1976: 1-10. Teaching Simulators of Ideal Teaching Machines. SIGSCc Bulletin, ACM. June, Vol 6(2): 45-56. a Proposal tor a New Curriculum Approach. Jniversity Ait,.its. Simon Fraser University, Eurnacy, 3.C. May, pp. 6-7. Ideal Teaching Machines -- A Solution to the Pedagogic Language. Communications of tne ACM. April, Vol 16: 207-208. * r-ft >-r* i,it)0 The lise- of an Information System to "iluinanizo" Procedures in a rehabilitation Hospital. International Journal or -io-tfedical Computing. Voi 5: 51-57. Information for Public Policy. Computers m i Society. Vcl 1(1 ): 2. (Invited editorial). The Simon Fraset One-Track Universal Curriculum for Computing Science.. 5 1GSCL Bulletin, ACM. February, Vo 1 6(1): 28-12. 1171 The Statistician vis-a-vis Issues of Public Health. The American Statistician. December, Vcl 27(5): 12-217. Extending the General Fiell Equation to lit the Dose Distributions of a Variety of Therapy Units. British Journal cf Radiology. Vol 46: 535-990. (J . e inxam , senior author.) Air Pollution and 5mo k i ng . Environ ment. Vol 15(b): J-b, 25-26. Dynamic bls;1ay o i nac ict hera .jy Plans U s in Co ir.put*-r-Proa ucea Films. Radiology. June, voi 107: o ?9-b9 1 . Human!s ts a rid tne Ccni.u ter Ccvru:.i ty . humanist in Lan2 j d * voi 2b: f- . Computing and the nu ma ni sa ti or. of ?. ed lei no . Interr.ationai Journal ot riomedical Ccnputin ;. Editorial, July, Voi 4(1): 159. 19 7s Difficulties ci Measuring tne effects of Air Pollution v s the-. Effects of Smoking. Presented at the 135th Meeting of the American Association tor tne Advancement or Science, EacemLer 1972 . A Versatile System for Three-Dimensional Radiation Dose Computation and Display , HTP. Computer Programs in biomedicine. Vol 2: 178-192. (J. weinkam, senior author.) Fitting the General Field Egu 1 i on to tne Siemens 5amatron J. Te chnical Report on Research Ag reement do. 1051/CF for the In ternaticnal Atomic Energy A .money , Vienna, Austria. The In cidence of Lung Cancer in the U.S. Since 1955 in Relation tc the Etiology or the Disease. Am erican Journal or Public Health. February: 152-158. 1y71 A Critical Assessment of the Evidence on the Cigarette Snoxinq Lung Cancer Relationship. Presented at the 13i31h Meeting of the American Association for the Advancement of Science, Symposium on Smoking and Health Now. Philadelphia, December, 1971. Difficulty of tvaiuatinc t.i" Toxicity and Teratogenicity of 2,h,5,-T from Existing Animal Experiments. Science. December, Vol 17U: 1358-1359. Some Thoughts on Treatment Strategy. Computers in Hadiotherapy (proceedings of the nth International Conference on Computers in Radiotherapy, Glasgow, September 1970). Edited by A. S. Glicksman, ;1. Cohen, and J. R. Cunningham. Published as Special Report No. 5 (1971) by the British Institute of Radiology, London. Three-Dimensional Treatment Plan Display on Computer-Produced Films. Computers in Radiology, op. 12-1 d . A Review of the Claim that Excess Morbidity and Disability Can Be Ascribed to Smoking. Journal of the American statistical Association. Vol to (33d): 251-257. A Critical Reassessment of the Evidence Bearing on Smoking as the Cause or Lung Cancer. Special Report on the Washington university Project on the Review of Crucial Data Rearing on the Cmokint! and Health Issue, St. Louis. Robot Data Screening, An Intelligent (?) Data Search Technique. AOARD Conference Proceedings No. 9d on Artificial Intelligence, 2-1- - r , Technical e d i t inc and Reproduction Limited, Loncon. Comment on Smoking Dogs. Letter to the Editor. Archives of Environmental health, vol. 22: b31-632. 1970 Problems in Determmina if a Commonly-Used Herbicide (2,d,5-T) lias an Effect on Human Health. Proceedings or the Sixth Berkeley Symposium on Mathematical Statistics and Probability, Reid at the Statistical Laboratory, University cf California. University of California Press, pp. U79-H9U. Experience with a "Universal" Introductory Course in Computer Science. Proceedings of SIGCSE Technical Symposium on Academic Education in Computer Science, Noveuner 16, 1970. Houston, Texas. SIGCSE Bulletin, Vol 2(3), Association tor Computing Machinery, New York. 38 Robot Lata Screening, An Automatic Search Technique, i:io-flea ical Computing. Voi 1: 61-7a. (from the Proceedings of tha Conference on Statistical Computation, University of Wisconsin, April, 1y69 .) Report on Progress in the Development of visual Prosthesis. The New OutiooK for the blind. Feoruary, vol 54: ul-up. ivss Automatic Data Screening: A Practical Solution to the Multivariate Pro M e m in Clinical Data. Annals oi tne hew York Academy or Sciences. Vol 151: bji-ouQ. A Comment on "Air Pollution -- The Industrial viewpoint". Journal of Occupational Medicine. July, Vol 11: j<il-jc3. Robot Lata screening -- A Ubiquitous Automatic Search Technique, in nilton, C. a. and .`elder, J. A. l-'i.) , statistical Computation, Academic Press, Mew Yonc. pp. 319-333 . Measuring 1 1: e Z iiac t of .Mr 'c l i o u c r. :n vr can do riiui ty . Archives or Environment al Health. April, vol 13: -.ob-uga. 1'J r>b Computer Interlace, Incut Metnocs, 1res en tat ion of Results. Ao 1 e o i c ompu 1 1 rs in } a nctherapy , In t rna trinai .-.to aic Ene rc y Agency, Vienna. Paper ho. 15, pp. lab-141. Opti mi ration as a Joint Result of Piar.ninu m u Implementation. Role or Computers i .-..idiotno rapy , international Atomic Energy Agency, Vienna, pp. 153-157. Display Devices ror Computer Translatai araille. Proceedings Conference cn New Processes tor :raii1 a .Mnurac tu re , 196c, Center tor sensory hies Evaluation ana Development, ii=ssacn us t ts Institute ot Technology. February, pp. 14-20. 1M / Automation cf Radiation Treatment Pia nni r.g, vi: A Generai Fie la liquation to Calclate Percent Deptr; Dose m th Ir rao.latea Volume of a Cobalt 50 Beam. Britisn Journal or Kauiolocy. Voi 4 0 : 'i6 3-4 bb . rcan hospital Korbiaity and Air Pollution: Second Report. Archives or Envxrcr.rsental Health. Vol 1 b : 35 2 - 3 7u . A New Direction in Rehabilit ation Through Advanced Instrumentation and Computation. Journal of the American Medical As soc iation. Vol 200 (7): 625-629 . The Use of Comp ute rs in T h e ra p e u ti c Radiology, Summary Report of an Intern ati on al C o n f e r e n c e held in Camoridge, England, June 19tb (iaitor) . m t i s h Institute of Radiology, London. final Narrative Report, Training of the Blina tor Professional Co mpu te r Work. D epartment of Health, Education, and Welfare, SD-1 a* b-S-67-C,. . 1966 Robot Data Screening: A Solution to Multivariate Type Proclems in the biological and Social Sciences. Communicatons of the ACM. Vol 9(7): 529-522 . A B io lo g ic a l l y - O r i e n t e d Computer Language. Annals of the hew York Academy of Sciences. Vol 128(3): 755-765. (S. V. Pollack, senior eaitcr.) Cancer Therapy - Computation ana Visualization Distribu ti ons in External seam Therapy. Journal Diseases. Voi 19: 523- 5 39 . of Dose or Chronic Use of the Com pu ter to Teach Introductory stat is ti c s . Communications ot the ACM. vol 9: 274 - 27b . Computers : No Longer a Eig H a rga in Comouters IUi Automation. Vol 15: 1-4 . author.) tor Uneducated (3 .V . Pollack, U se r.s . senior The Selection, Training, and Pl acement of Blind Computer Programmers, report or the Association tor Computing Machinery . Is Medical Diagnosis a General Co mputer ProDlem? Journal of the American Medical Association. Vol 196(3): 281-266. [efogging the Issue: California has discoverec that laws can't control auto exhaust fumes. B a r r o n 's, May 2, pp. b, 14-15. Urban norcidity and Air Pollution: A first Report. Arc hives of Invironmental Health. Vol 13: 150-170. The Blind as Computer Programmers. Rehabilitation Record. Vol 7(1): 7-10. Role of S ta ti sti cs in the World of Computers. Annals of the New York Academy ot Science. Vol 128(3): 1108-1115. o f' The Role et tne 3lina in Data Annual Conle re nce on Computer Washington University, 1965. Automation. Voi It: 2b - 27 . Processing. Presented at Third Personnel Research Group, held at Reprinted in Computers and Pro cee di ngs on the i-raille Research ana Development Conference, Sensory Aids, Evaluation ana Development. Massachusetts Institute c t T(cn no ic a y , November, 19 66 . 19 65 Automation of Radiation Treatment Planning, v : Calculation una Visualisation of the Total Treatment Volane, dr itis n Journal or. Radiology . Voi 58 : 9 0b- 91 1 . Robot Data Processing Tecnniques tor ilu11 ivaria te Epidemiolceical Predictions. Anriols ot the New York ncacemy ot Science. Vox 116(2): 779-79'. The Role of the Blind in Data Processing. Procedures oi Third Annual Co a pu ter Pur son r,oi Research Conference, June 1 b5 . (11. H . Gctterer, ?:. ; Computers in Personnel Research Group, Silver Spring, Do.; pp . u1 - i 9. Computation or Radiation D.osa-jes. In Stacy, R. and 9asman, B ., (Ed.), Computers in :,i o.-sedica i Research. Academic Press, ..ew York, Vol 1 (Chapter Id). ( Toward a Under:: redd ato a tnem aticr Proof ,n u t.u t F.e se ar cn e rs in the iuJ'is o i io lo ay m e dea ici;,e. Fe aeration Proceedings. Vci 2 d (1) : 5-9. Careers tor the: Elina in Elec renie Data Processing. ai ec tro nc Data Processing. Occu pa tio na l Outlook ,,uarterly. Voi , (1 ) : 1- . Employment Potential ter the Elina in Computer Hc-Iat<-a Fields. The International Journal for Education of tne Blind. October, p c . 1--5 The timo. in the Blind. D P . ACM Co mm i ttee on Professional Activities ot 19(>u Mathematical Analysis of Lead Burdens. Archives of Environmental Health. 6: dd-51. Design ano Operation of a Medical Co mputing Center t h e e w York Academy of Science. Voi 1 1 5 (2 ): 3ae n gsr , senior author) Annals ct 91-599. (E. A 1co i Planning F.aaiation Treatment or. the Computer. Annals or the hew York Academy of Science. Vol 115(2): 976-997. Professional Computer Work for the Blind. Communications of the ACM. Vcl 7 (4) : 226-211 . Computer vcr;; as a Profession for the Blind. Journal of Rehabilitation. Vol 1C: 20-21. Epidemiology of Disease Associated with Lead. Archives of Environmental health. Vol 8 : 133-148. '!atnom at ica 1 Analysis or Lead Burdens. Archives of Environmental Health. Vol 8 : 44-51. Automation of Radiation Treatment Planning, IV: Derivation of a Mathematical Expression for the Per Cent Depth Dose Surface of Cobalt 60 Beams and Visualisation of Multiple Field Dose Distributions. British Journal of Radiology. Vol 37(439) : 544-550. Locating Placenta Praevia. Procedures or the Rochester Conference on Data Acquisition ana Processing in biology ana Medicine, Hew York, 1963. Pergamon Press, New York, pp. 103-111. 196 3 Do Malignancies Result rron Diagnostic and radiation? Genetics ana the .ipiueiiioiogy of 2 U.S. Dept, of health, Education and Welfare, pp. Therapeutic MEDCOMP, Part 1, Statistical Systems. Medical Computing Center, University of Cincinnati, Ohio. Boron, Cadmium, Chromium, and riicxel in the Blood ana Urine. Arcnives of fcnvironrental health. Vol 6 : 236-295. (H. Imbus, senior author.) Potential Hazard of Exposure to Leaa. Archives of Environmental Health. Vol 6 : 255: 272 . (R. Kehoe, senior autnor.) Carcinogenic Effects of Till Compared with X- Irraoietion - k Review. Health Physics. Vol 9: 1371-1 j;4 . (2 . Saer.ger, senior author.) Automation of Radiation Treatment Planning, 111: A Simplified System of Digitizing Isodoses ana Direct Print-Gut of Dose Distribution. British Journal of Haaiclogy. vol 36: 522-527. Intravenous Methotrexate (Amethopterin) Thirapy in the Treatment of Acute Leukemia. Pediatrics. Vol 31: 834-339 . (J . Perrin, senior author.) Autonation cf Radiation Treatment Planning, II: Calculation or lion-Convergent Fiala Dose Distributions. British Journal ot Radiology. Voi 36(427): 63-67. Roto t Treatment Planning, i'roceduies ut t n a i-ioc tester Cor. ierence on Data Ac qui sition ana Processine in a i o l o cy and medicine, ie Yorx, 1962. Peraason Press, New Yorh, pp. 294-319. Robot Lata Screening. Proceedings ot m e Hocnes tei Conference on Data Acquisition ana Processing in Biology and Medicine, New Yorh , 1462. Per can.on Press, New Yor't , p p . 31 -2^2 . 19 6 2 Occupational Exposure to Organic Leac Compounds. Archives oi Environmental health. Vol 6: 532 -336. (h . DeTriviiie, senior a u t h o r .) New Developments in Chronic .'.'isease Epidemic log y : Competing Risks ana Eligibility. American industrial hygiene Association Journal. Vc i so: u 3 j-1g 6. !:.aa iatiot: ruoic :v . Ca nce n1 5. Comparative Studies enviro n m e n t a l t-t-ai th . senior author.) Certain Lead Alxyls Archives ot (E . Hinqham. 19 61 A Practical Procedure for Automating Radiation Treatment Planning, ciitish Journal ot iat,ioiogy. Vox i-i: 76-7 33. Epidemiological Methods ana Community Air Pollution, .ircnives or Environmental health. Vol 3: 267-275. (J. ah air, senior author.) Competing Causes ct Deatn in Coal Tar or/ters. .-lettering Report. 1 9 60 Cesium-137 Retention and Distribution in x-Irraaiateu Rats. U.S. Army Medical Research Laboratory, Fort Knox, Ken tucity. Report N o . 504. (G. Keri altes, senior author.) Seasonal Variations in the Birth 0 1 the dentally Deficient? American Journal ei public e a11n V0 1 50 : 33-^6 3 . 1 The Leaa Content o the Atmosphere. Presented at the 63rd Annual Meeting of a p c a , Hay 1960, Cincinnati. (J . Ch olaK , senior a u t h o r .) V.hat is so Ee c u liar About Accepting the hull hypothesis? Psycnolccica1 htports. Vol 7: 363-36u. Neoplasia following Therapeutic Irradiation tor Benign Conditions m C hiiahood. Radiology. Vol 7 4 : o39-904 . (L. Ssender, senior author.) 19 59 Public Decisions ana Their PossiDle Effects Inferences Drawn from Tests of Sigr.it icanee - or Vic e-ve rsa. Journc of the A m e n c e n S tatisticai Association. Vol 54 : 3-J*. Pulmonary function l n Children, I and LI . Journal or Aile ru y Voi 3 ( z ) : f1u-baJ . (I. L. -trnste. in , seni or au thci .) Tables of Pulmonary function Values in Children Ages o to 19. Kreaer Printing Co., Cincinnati, Ohio. (I. L. Eernsttin, senior author.) The Anor xi4 er.ic Action of Feeding ne s ^o ns-s or .:-itiering ana Physiclogicai Psychology senior author.) Doxtro-iop n at a i r.e Sulfate upon o 11ena tn . Journal of Comparative Vol 5 2 : 1 79-1 8 2. (P . S i e g e l , Sources o 1 Contextual Co ns tralnt pc :i .-.oris in Sen tenets . Journal of Experimental Psychology, Voi 5 7 : 171 - n. c . (1. Adorn, senior author.) 19 L 7 Effect or Irrelevant Drive on Extinction or Bar-Pressing. Fsyc no loci cal Reports. Vol 1: 61 5- 1n . A Central surveillance System dessurement Model, Part I, II. Pro I'-'Ct M ;o!. : pin Z34 o , Z71'!, :tive rs1 1y or nicnig^n. A General Survey of Statistical Decision Theory. Project Michigan Z915, University of t i c m q a n . 132 Bio-Statistician/MathematicianThis witness will be identified in the near future. At that time a curriculum vitae will be supplied. This witness will describe the mathematical/statistical model which will be used in the presentation of the figures to which the witness will testify. The theory subserving the testi mony is that the m u l ti-faceted presentation of symptoms and signs and test results in the same veteran makes a random compo sition of such an array extremely unlikely in view of the relative in-frequency of each facet of the array. As such, this testimony will be used in the generic and specific proximate causation areas. 1 3275' S tephen J. Schlegel M.D e a n T ra pelk t Ivar R. A zr aih S teven P. P oliok J ames A. Romanyak S c h l e g e l & T r f e l e t . Lt d . A t t o r n e y s at L aw O n e N orth La Salle S t r e e t C h ic a g o , Il l in o is G 0G 02 February 13, 1984 S u ite oooo (312) 782-1001 Honorable Shira Schneindlin Magistrate & Special Master United States District Court Eastern District of New York 225 Cadman Plaza East Brooklyn, New York 11201 Re: In re "Agent Orange" Product Liability Litigation - MDL No. 381 Dear Magistrate Scheindlin: In conformity with the representation made by the Plaintiffs to you at the hearing he d on February 9, 1984, we are tendering the following as our preliminary list of our priority witnesses. Plaintiffs wish to depose: Debdas Mukerjee, EPA - D.C. Philip J. Landrigan, CDC, NIOSH Janet Springer, EPA - D.C. Vemon N. Eouk, CDC - Atl. James Mason, CDC - Atl. Dr. Diane Courtney, EPA - D.C. Peter Infante, NIOSH, D.C. Umberto Saffiotti, NCI - D.C. Donald Bames, EPA - D.C. 1327? DIAMOND-SHAMROCK WITNESSES I. Diamond-Shamrock employees: David J. Porter S . B . Honour J. 0. King Melvin Hochberg Howard E. Edison Lex Creamer (Would like to depose, but unable to locate) II. Government witnesses: M. Isele, DCAS - Contracting officer J. K. Murphy, Chief - Contracts branch E. R. Sabala, DCAS - Contracihg officer I. Wolin, DCAS - Cleveland, Ohio DCASR - Commander Contracting officer 1367 E. 6th Cleveland, Ohio -2- 13278 DOW CHEMICAL COMPANY Employees: George E. Lynn Julius Johnson H. R. Hoyle Ross Mulholland Larry G. Siiverstein Ray Holmes R. D. Wilcox V. K. Rowe G. Goergen Paul Orrefice Sam Birkman John Barber Joseph G. Temple, Jr. Etcyl H. Blair David L. Rooke 13279 HERCULES' WITNESSES I. First priority list : C . L . Dunn T. Eagon A. E. Sidwell A. L. Triesback H. E. Wilder II. Second priority list : J. G. Copeland Rafael H. Huston Charles E. Minarick, U.S. Army - Biochemical Custodian of Records of NACA - National Agriculture Chemicals Association, Washington, D.C. Custodian of Records of Bionetics Research Laboratories, Bethesda, Maryland III. Third priority list : Otis Fancher, Industrial Biotests Laboratories Custodian of Records of Industrial Biotests Laboratories, Illinois R. T. Yates Custodian of Records of Hazleton Laboratories, Falls Church, Virginia 13280 HERCULES' WITNESSES - cont. IV. Defense Personnel Supple Center - Contracting officers: Government witnesses Donald Elmore Thomas P. Dalby Jacob L. Bolton Ellis Cash 1328 4i -5- MONSANTO WITNESSES Charles Luecke John Mullendore Carl Bohl Phillip Balderson Homer Payton Frederick L. Rupel Ronald R. Smith R. L. Payne Tom K. Smith Richard Wallace, M.D. Nel Putzel Louis Schwartz Robert R. Rumer (Recall) U . L . Sims R. L. Null Toby White Howard Minkler E. Weger Nick Machacrola Paul Ekberg Jim Starrett Bruce Ely MONSANTO WITNESSES cont. II. Contracting; officers - Richmond, Virginia : John Blish George Collins Jesse Gershberg III. Monsanto inspectors - St. Louis region : Ten Eyck R. D. Fisher M. McCalley Roy Meyers N. Wirz R. Wright 1328 -7- THOMPSON CHEMICAL COMPANY WITNESSES I. Employees : John Mayer Leo Crivello D. Halleck Cecil McGill James Reagan F. Vargas II. Government witnesses : DCSR, Director Commander - St. Louis, Missouri III. Miscellaneous witnesses: Dr. Earnest Velasco Kosciusko Medical Clinic St. Louis, Missouri American Mutual Liability Insurance Company St. Louis, Missouri 13284 -8- UNIROYAL, INC. WITNESSES Defense Contract Administration Service Office : F. H. Placet (Process inspector) A. Matasauage - Industrial Specialist M. Dojny - Quality Assurance Rep. (Chemical inspector) A. W. Glenn - Preservation Packing Specialist Harold A. Lloy - Administration Contracting officer Wayne Vandervendor - Specialist for Technical Orange Herbicides T-H AGRICULTURE & NUTRITION CO. WITNESSES I. II. T-H Agriculture & Nutrition Co. employees: L. S. DeAtley Bill Sulzen Art Wilson Dr. Charles Lewis Bob Mayer Jack Hallen Government witnesses: Edward E. Adams - St. Louis, Missouri A. A. Block - Kansis City, Missouri James E. Bowers - St. Louis, Missouri Charles Dilley - Kansas City, Missouri Frank W. Kleman - St. Louis, Missouri Joseph W. Fowler - Kansis City, Missouri Respectfully submitted, Management Committee 132-86 -10- AGENT ORANGE SERVICE LIST Judge Jack B. Weinstein ** United States District Court Eastern District of New York 225 Cadman Plaza East Brooklyn, New York 11201 Honorable Shira Schneidlin ** Magistrate - Special Master United States District Court 225 Cadman Plaza East, Rm. 285 Brooklyn, New York 11201 Honorable Sol Schreiber Milberg, Weiss, Bershad & Specthrie One Penn Plaza New York, New York 10019 Stephen J. Schlegel, Esq. Schlegel & Trafelet, Ltd. One N. LaSalle St., Ste. 3900 Chicago, Illinois 60602 Thomas W. Henderson, Esq. ** Henderson & Goldberg Frick Building, Rm- 1601 Pittsburgh, Pa. 15219 David J. Dean, Esq. ** Dean, Falanga & Rose 1 Old Country Road Carle Place, New York 11514 Benton Musslewhite, Esq. ** 609 Fannin - Suite 517 Houston, Texas 77002 Newton B. Schwartz, P.C. Houston Bar Center Bldg. 723 Main, Suite 325 Houston, Texas 77002 Stanley M. Chesley, Esq. Waite, Schneider, Bayless & Chesley Co., L.P.A. 1318 Central Trust Tower Fourth & Vine Streets Cincinnati, Ohio 45202 Neil Peterson, Esq. ** Gene Lo'cks, Esq. Greitzer & Locks 1500 Walnut St., 21st FI. Philadelphia, Pa. 19102 Phillip E. Brown, Esq. Hoberg, Finger, Brown, Cox & Molligan, P.C. Central Tower 703 Market Street San Francisco, Calif. 9410 John O'Quinn, Esq. O'Quinn, Hagans & Wettman 3200 Texas Commerce Tower Houston, Texas 77002 Plaintiffs' Management Commi c/o Jan Levien, Esq. ** 26 Court St., Suite 905 Brooklyn, New York 11242 Irving Like, Esq. ** Reilly, Like & Schneider 200 West Main Street Babylon, New York 11702 Clerk of the Panel ** Judicial Panel on Multi district Litigation 1120 Vermont Avenue, N.W. Suite 1002 Washington, D.C. 20005 Arvin Maskin, Esq. ** United States Attorney United States Dept, of Justic Safeway Bldg. - Room 904D Washington, D.C. 20530 Leonard Rivkin, Esq. ** Rivkin, Leff, Sherman & Radle 100 Garden City Plaza Garden City, New York 11530 John C. Sabetta, Esq. ** Townley & Updike 405 Lexington Avenue New York, New York 10017 Wendall B. Alcorn, Jr., Esq. ** Cadwalader, Wickersham & Taft One Wall Street New York, New York 10005 Thomas Beck, Esq. ** Arthur. Dry & Kalish, P.C. 1230 Avenue of the Americas New York, New York 10020 Judith L. Spanier, Esq. ** Shea & Gould 330 Madison Avenue New York, New York 10017 Morton B. Silberman, Esq. ** Clark, Gagliardi & Miller 99 Court Street White Plains, New York 10601 William A. Krohley, Esq. ** Kelley, Drye & Warren 101 Park Avenue New York, New York 10178 David R. Gross, Esq. ** Budd, Lamer, Kent, Gross, Picillo & Rosenthal 33 Washington Street Newark, New Jersey 17102 Herbert L. Fenster, Esq. McKenna, Conner & Cunes 1575 Eye Street, N.W. Washington, D.C. 20005 ** John M. Fitzpatrick, Esq. Stillworth, Paxson, Kalish & Levy 2600 Fidelity Building Philadelphia, Pa. 19109 ** Paul V. Esposito, Esq. Lewis, Overbeck & Furman 135 S. LaSalle Street Suite 1060 Chicago, Illinois 60603 *** Howard Lester, Esq. ** Lester, Schwab, Katz & Dwyer 120 Broadway New York, New York 10271 Michael V. Corrigan, Esq. ** Simpson, Thatcher & Bartlett One Battery Park Plaza New York, New York 10004 Mr. Robert Heinemann ** Clerk of the United States District Court 225 Cadman Plaza East Brooklyn, New York 11201 *** _ Hand Delivered ** - Delivery by Federal Express Delivered regular mail to everyone else. 132B& -2- UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK In re: "AGENT ORANGE" Product Liability Litigation X X MDL #381 PRESENT LIST OF PLAINTIFFS' CAUSATION WITNESSES WITH ATTACHED EXPANDED SUMMARIES IN ACCORDANCE WITH FRCP 26(b)(4)(A)(i) AND GENERAL STATEMENT OF SCIENTIFIC' PRINCIPLES AND ASSUMED FACTS PLAINTIFFS' MANAGEMENT COMMITTEE ---Thomas W. Henderson, Esquire / Id GENERAL STATEMENT OF SCIENTIFIC PRINCIPLES AND ASSUMED FACTS A. BACKGROUND The Plaintiffs' experts represent a cross-section of the scientific and medical community who have individualized areas of specialization, but, who, because of their training and expertise, have a common nucleus of scientific principles and assumed facts, which would be virtually unknown to the lay person and the jury without some explanation. This will serve to inform the Court and the Defendants of those areas which any one or more of the Plaintiffs' individual experts may testify to and which represent a "common consensus" of scientific principles and assumed scientific facts which the credible medical and scientific community, including all plaintiffs' experts, share. The complexity of the instant litigation from the perspective of a layman necessitates a rather comprehensive overview of the basis scientific and medical disciplines. See Plaintiffs' Supplemental Answer to Interrogatory No. 2(d) which lists the basic scientific medical disciplines involved. Plaintiffs have attempted to select causation experts who have unique areas of specialization which will in large part form the bases of thueir testimony, but, more importantly, these particular experts, because of1*-3 2 3 0 their broad based experiences and qualifications, will hopefully be able to synthesize for the jury the broad scope of issues which are at the crux of : / this lawsuit including: (1 ) The chemistry, biochemistry of the defendants' products, including Agent Orange and its dioxins; (2) The manufacturing and industrial processes used by the defendants to formulate Agent Orange and as a by-product the formation of dioxins; (3) The extreme toxicity of one particular dioxin, 2,3,7,8-TCDD, which is the most toxic chemical ever synthesized by man. Specifically, the toxic effects of Agent Orange and 2,3,7,8-TCDD and its other dioxins, on our entire ecosystem and the balance of life that nature tries to maintain, including TCDD's threat to plant life, animal life, and human life, and more specifically, to the Veteran class of plaintiffs who were exposed to this most toxic of all poisons while serving their country in Vietnam. Plaintiffs have exerted their best efforts to avoid repetition and unnecessary overlap of testimony. While the plaintiffs' experts testimony may in some instances overlap, each individual expert will be able to enlighten the Court and jury within their own specialty areas. *> 132^ -2- B. DEFINITIONS AND SHORT EXPLANATIONS OF EACH DISCIPLINE (Tabors' Cyclopedic Medical Dictionary, lLth Ed., F.A. Davis CoTT (1915 Arch St., Phil) 1970) I. Chemistry/Botany 1. Botany/Plant Physiology - Science of cells, tissue and organs of plants 2. Biochemistry - The chemistry of living things; the science of the chemical changes accompanying the vital function of plants and animals 3. Bio-Assay - Greek bios - life French essayer - to try Estimation of strength of a drug by noting its effect in test animals and comparing such with effect of a standard preparation 4. Chemistry The science that treats the molecular and atomic structure of matter and composition of substances, their formation, decomposition, and various transformations which they may undergo. 5. Biological Chemistry The chemistry of living things involving all chemical processes which take place within an organism, such as, digestion of food, anabolism and catabolism. 6 . Inorganic Chemistry The chemistry of compounds not containing carbon. 7. Organic Chemistry The chemistry of carbon compounds. 8 . Pathological Chemistry 13293 The study of chemical change by disease processes; changes in -3- Chemistry or organs and tissues, blood, secretions, excretions, etc. 9. Physiological Chemistry Study of chemical nature of living matter and the changes occurring in the metabolic activities of plants and animals . Animal Toxicology 10. Animal Toxicology The study or science of poisons, their nature, effects and antidotes in animals 11. Toxic Greek: poison/poisonous To, resembling or caused by poison 12. Toxicity The extent, quantity and degree of being poisonous 13. Toxicide A chemical antidote for poisons 14. Toxicology The study or science of poisons, their nature, effects and antidotes. 15. Toxigenic/Toxigenicity Producing toxins or poisons; the virulence of a toxin - producing pathogenic organism. 16. Toxins A poisonous substance of animal or plant origin 17. Bacterial Toxin A.. Exotoxins (extracellular) Toxin produced by bacteria, which diffuse from bacterial cells into surrounding medium B. Endotoxins (intracellular) Toxin produced by bacteria, which are liberated only when bacterial cell is destroyed III. Neuro-Behavorial 18. Neurotoxicity Study of the behavior of poisons on the neurological system (nervous tissues) of animals and humans, particularly TCDD 19. Neurology The branch of medicine that deals with the nervous system and its diseases 20. Neurolysin A substance which destroys nerve cells 21. Neuron A nerve cell, the structural and functional unit of nervous system consisting of a cell body (perikaryon) and its processes (on axon and one or more dendrites) initiators and/or conductors of messages from the terminal branches of cell to the cell body or receptor 22. Peripheral Nervous System Whose processes (messages) constitute the nerves conducting messages from the brain and the spinal cord throughout the body of animals and humans into the body's extremities 23. Central Nervous System The brain and spinal column nervous of an animal and human which send messages to all other parts of body via peripheral nerves. 24. Porphyrin Levels One group of cells forming basis of animal and plant respiratory pigments, obtained from hemoglobin (blood - human/animals) and chlorophyll (plants) -5- 25. P o r p h y r ia (P C T ) Porphyrin in the blood; a rare metabolic disease characterized by excessive excretion of porphyrins, acute abdominal pain and neurologic disturbances, sensitivity to light is characteristic 26. Myelin Sheath A fat-like substance or protective covering for nerve fibers; Greek word: myelos = marrow) A complex lipoid (fatty) substance present in the brain in small quantities, but predominantly a protective shield for the nerves conducting messages throughout the bodies of animals and humans IV. Immunology 27. Immunology Study of how body responds to foreign (antigenic) stimulation and tries to protect itself 28. T - Lymphocytes; B - Lymphocytes Immunoregulatory cells of immune system - regulates a number of responses which destroy host cells bearing foreign substances; and regulates cell - mediated resistance to infectious agents 29. Immune Bodies Substances in those afflicted with an infectious disease or toxic foreign substance formed by the tissue and possessing power to destroy or injure the disease producing or poison producing agent or to neutralize the toxins. These substances are formed in serium of coagulated blood, in blood plasma and in lymph glands - called antibodies; each is result of specific antigen (foreign substance) or disease producing factor which acts only upon the same antigen. They are determined by the effect they cause. If the antigen is poisonous it is called toxin and its antibody, is called an Antitoxin. 29a. Immuno-Toxicology The undesirable effects of an inappropriate response of the immune system. -6- V. Oncology 30. Oncology The diagnosis, treatment and care of cancer victims with emphasis upon the cause of the cancer so that preventive medicine may prevent the occurrence of cancer in others. 31. Carcinogen Any substance that has been shown to cause tumors in animals or man. As a matter of principle all chemical carcinogens which are shown to be active in men are also active in animals. Scientifically, there is no way to determine a "safe" level for substances (chemical) known to produce cancer in animals or man. A malignant tumor or neoplasm; a sarcoma or carcinoma. VI. Reproductive Toxicology 32. Reproductive Toxicology Study of poisons which affect the process by which plants, animals and humans give rise to offspring or create a similar structures or living bein^ (the act of duplicating oneself). VII. Other Definitions 33. Internal Medicine The study of the human body as a whole with emphasis on the internal body structure and organs, their functions and interrelationships of the various body systems. 34. Psychology The study of medicine dealing with mental processes, both normal and abnormal and their effects upon behavior, including four primary methods: (1) experimental; (2) comparative; (3) genetic; and (4) pathological. 35. Physiologic; Psychology The study of the structure and function of nervous system and other bodily organs and their relationship to behavior. 7- 36. F e t o t o x ic it y / T e r a t o t e n ic it y Fetotoxicity is a general term used to describe all abnormalities (both transient and permanent) originating in an embryo or fetus regardless of the timing of any such action. A special fetotoxic effect is called teratotenicity which is an abnormality from impairment of an event which occurs at a specific time in an embryo's or fetus' development in the mother. 37. Mutagenicity/Cytotoxicity Sudden, permanent variation with offspring differing from the parents in a marked characteristic as differntiated from gradual variation through many generations; a dramatic change in genes and/or chromosomes potentially capable of being transmitted to offspring. 38. Epidemiological and Biostatistics The methods by which cause and effect relationships are determined in the medical and scientific community. The study of medicine concerned with explaining the interrelationships of the host, agent and environment in causing or contributing to cause a disease or physical condition. 39. Gonadotoxicitv The study of substances which poison the gonads; "Gonad" refers to both the female sex glands or ovaries, and the male sex gland or testes. The embryonic sex gland before differentiation into testes or ovary. 40. Genetics The science that accounts for natural differences and resemblances among organisms related by descent; the study of heredity and its variation 41. Dermatology The study of the skin and the diseases of the skin. 132S7 c. CHEMISTRY/BIOCHEMISTRY I. Chemical Formulation of 2,4-D, 2,4,5-T and 2,3,7,8-TCDD Plaintiffs as a class represent the veterans who served in Vietnam between 1961 and 1972 and were exposed to the spraying of a herbicide known as Agent Orange which was composed of 2,4-D (Dichlorophenoxyacetic acid) and 2,4,5-T (trichlorophenoxyacetic acid), which chemical compounds are known to be neuro toxins by the credible scientific and medical community. It has further been established that a family of chemical compounds, commonly known as dioxins (dibenzo-p-dioxins), are produced in the manufacturing processes utilized by the Defendants in the instant lawsuit since the date production of these herbi cides began in approximately 1925 through the last days of spraying operations in Vietnam in approximately 1972. The Defendants comprise almost 99% of the relevant herbicide production market between 1961-1972 which was sold to the U. S. Government for spraying operations in Vietnam. The World Health Organiza tion in 1971 found "no acceptable daily intake for man" for 2,4,5-T. Because of the extreme toxicity of all dioxins, and particularly of 2,3,7,8-TCDD, a known contaminant of 2,4,5-T and hence of Agent Orange, it is important to understand the chemical formation of dioxin 2,3,7,8-TCDD, the "most toxic chemical synthe sized by man." II. Chemistry of Dioxin Formation The basic chemical composition of the family of compounds known as "dioxin" consists of two double-bonded benzene rings interconnected with a pair of oxygen atoms which close a third center ring. The nucleus of a "dioxin" is clearly shown in the diagram below, and represents a triple ring structure. Each of the numbered positions as shown in the diagram can hold a chlorine or 13288 , -9- other halogenated or organic radical. Or, if there are no other substituents in the formula in the manufacturing or process formula, a hydrogen will be attached at one or more of the numbered positions. 91 | rS^2 i y j ^3 1 04 The only difference in the "dioxin" family is the nature and positions of the substituents which are attached to the benzene rings at the numbered positions above. Most of the environmental interest in the dioxin group is centered in chlorinated dioxins where chlorine atoms are attached to one or more of the eight positions on the two benzene rings. There are theoretically seventy-five (75) positions available for chlorine atoms to attach in various formations. These represent differences in the number of chlorine atoms which attach to the eight positions available and to the relative positioning of chlorine atoms in the "dioxin" nuclues itself. See list of all seventy-five theoretical Chlorinated Dioxins on the Table which follows. For example, there are two possible isomers of monochlorodibenzo-p- dioxin (MCDD). Therefore, there are two places on the two benzene rings which allow only one chlorine atom to attach and those are at positions no. 1 or no. 4. Also important is that the particular type of dioxin, tetrachlorodibenzo- p-dioxin (TCDD's) which has been classified as most toxic, has twenty-two (22) isomeric possibilities. On page 4 of the EPA Chart which follows is the diagram of the 2,3,7,8-TCDD nuclues, the most toxic contaminant of Agent Orange and of all dioxins. 132S9 -10- Table I lists the 75 possible chlorinated dioxins, an d also notes the 40 that have been prepared and tdenimed and whose analvttcal characteristics have been punlished tlluser, Bosshardt. and Rappe I97X; Huser ISJ" 5: Pohlanu and Yana 1972: Bolton I97X|. Five others, as noted in the table, have been identified as distinct compounds but have not been clearlv differentiated from each other I Baser. Bosshardt. and Rappe I97X: Buser 1975: R ap p e 1978). TABLE 1. CHLORINATED DIOXINS 1 cnloro 2-cnloro 1,2-dicnloro 1 3-dichloro 1,4-dicnioro ) ,6-dicnloro 1.7 aicnloro 1 8-dichloro 1,9-dicnloro 2 .3-dicn laro 2.7 -dicnloro 2.8-dicnloro 1,2,3-tricnloro 1,2.4-trichloro 1 2.6-tricnloro 1.2.7-tricnloro 1,2.8-trtcnioro 1,2.9-tricnloro 1,3.5-tncnioro 1,3.7-tncntoro 1,3.8-tncnloro 1,3 .9 -tn c n lo ro 1.4 6-tricnioro 1.4.7-tricnioro 2.3.6-tricnloro 2.3.7-tricnloro a 3 a a a a a a a a a a a 1,2.3.4-tetrachloro a.d 1.2.3.4.6-oentacn loro 1, 2 . 3 . 6 - t e t r a c n l o r o 1.2.3.4.7-oentacnloro 1,2.3.7-tetrachloro 1,2.3.6.7-pentachloro 1,2.3.8-tetracnloro a 1,2.3.6.8-oentacnioro 1,2.3.9-tetracnloro 1.2.3.6.9-pentacnloro 1.2.4.6-terrachloro 1 2.3.7.8-oentacnloro 1, 2 . 4 . 7 - t e t r a c h l o r o 1,2.3.7.9-pentacnloro 1 2.4.8-tetrachloro 1.2.3.8.9-pentacnloro 1 2.4.9-tetracnloro ' .2.4.6.7-pentacnloro 1.2.S.7->9tracnioro a 1.2.4.6.8-pemacnloro 1,2.6.8-tetracnloro 1,2.4.6.9-oentachloro 1 2.6.9-tetracnloro a 1.2.4,7 8-pentacnioro 1.2.7.3-tetracnloro a 1,2.4.7.9-pentachloro 1.2.7.9-tetracnioro 1.2.4 8.9-pentachloro 1,2.3.9-tetracnloro a 1.2.3.4 6.7-hexacnioro 1 3.6.8-tetracnloro a 1.2.3.4 6.8-hexaemoro 1.3.6 9-tetracnioro a 1.2.3.4.6.9-hexacnioro 1.3. 7.3-tetracnloro a 1.2.3.4.7.8-hexacnloro 1 3.7.9-tetracnloro a 1.2.3.6.7.8-hexacnioro 1,4.6.9-tetracnloro a 1,2.3.6.7.9-hexacnloro f 4.7.3-tetracnloro 1,2.3.6.8.9-hexachloro 2.3.7.8-retracnloro a 1,2.3.7.8.9-hexacbloro 1,2.4.6.7,9-hexachloro 1,2.46.8.9-hexacnioro 1, 2 . 3 . 4 . 6 . 7 . 3 - h e p t a c h l o r o 1 2.3.4.6.7.9-heptacnioro Octacnloro a a c a c a c a a a a a a b a a b a a 3 a--identified comoounas. b--One or tne otner of these comoounas has been oreoared. c--A mixture of these three comoounas has oeen oreoareo. 0--The Oow Chemical Comoanv has recently reoortea the synthesis of ail 22 TCDO isomers The interest oi health and environmental researchers in dioxins arose principally because of the toxicity and distribution of one of th e s e c o tn p o u n d s. 2..C7.X-1 CD D. whose structural fo rmula is as tollows: 13300 - li- The nucleus of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is unusual in its symmetry on the horizontal and vertical axes and represents a chemically stable and non-reactive molecule. It is not soluble, in water and most organic liquids. It is extremely lipophilic molecule and colorless crystaline solid at room temperature. The only other formation of dioxin which is similar to the TCDD's is the OCDD's which has the same two-fold symmetry. III. Precursors/Predioxins Dioxins apparently are not constituents of a normal growing environ ment. They are not formed biosynthetically by living organisms. In order to cosntitute a dioxin precursor, a chemical compound used in industry has to meet two conditions: (1 ) the precursor compound must be an ortho-substituted benzene ring in which one of the substituents includes an oxygen atom directly attached to the right. It should be noted that a singe oxygen atom is very unstable and does not occur by itself; therefore, usually a phenol group (OH) is used in order to detach the oxygen atom from the hydrogen in a process known as hydrolosis. (2) it must be possible for the two substituents excluding the oxygen atom to react with each other to form an independent compound. The most common manufacturing for this two step reaction is the hydroxal group of phenols, which supplies the ring attached oxygen and the hydrogen of the hydroxal atom is capable of reacting with chlorine. The most common predioxins are trichlorophenol potasium salt and trichlorophenol sodium salt. The condensation of 2,4,5-trichlorophenol (TCP), the first step in the 13301 process, results in the formation of a dibenzo-p-furran (two benzene rings with -12- four symmetrical chlorine atoms (2 ,3,7,8) and one oxygen atom connected at the top of the two benzene rings, and also produces industrial salt NACL or KCL, sodium chloride or potassium chloride. The second step then substitutes the second oxygen which closes the benzene ring or which has the potential for closing the benzene ring with the second oxygen connecting it and allows the sodium or potassium to react with chlorine to make industrial salt used primarily in fertilizers. All of these reactions occur under heat and pressure and over and in the presence of metal catalysts. The importance of the manufacturing process itself is emphasized because process engineers choose various chemical compounds to create an end product, not based on its safety, but simply based on the ability of the manufacturer to produce the maximum amount of the product at the lowest possible cost; hence, various manufacturing processes themselves yield differing amounts of the 2,3,7,8-TCDD contaminant based on factors such as (1) heat, (2) pressure, (3) photostimulation, (4) precursor chemical compounds used and (5) the catalysts, reagents and solvents which are used to encourage the reaction from the clorinated precursors to the predioxins and into dioxins themselves. The importance of chemical structure of the compounds of 2,4-D, 2,4,5-T emphasize their close similarity with polychlorinated biphenols and other chlorinated napthalenes which have similar chemical structures although somewhat less complex than the triple bonded ring structure of dioxin and have a long history of toxic effects and hazards to humans. The following quotations from the EPA Dioxin Report, 1978 are relevant: I OQdo> Un . o/ "On a molecular basis, 2,3,7,8-TCDD is perhaps the most poisonous, synthetic chemical . . . only bacterial exotoxins are more potent poisons." "It is reasonable to presume, therefore, that the slightest trace of 2,3,7,8-TCDD in the environment may have adverse effects on the health of both human and animal populations." Toxicity of 2,3,7,8-TCDD "Because of the remarkable stability of this substance (2,3,7,8-TCDD) in biological systems and its extreme toxicity, cumulative effects of extremely small doses are a major concern." EPA Dioxin Report, 1978, p.l -1 4 - D . E X P O S U R E TO D IO X IN S I. Modes Because of the extreme toxicity of all dioxins, but particularly of 2,3,7,8-TCDD, it is important to carefully scrutinize the probable avenues of contamination of the environment. It is known that 2,3,7,8-TCDD can be produced in the manufacture of 2,4,5-Trichlorophenol and other chlorophenols. The amounts of dioxin may vary in each commercial product with temperature and pressure. Since dioxin contaminants are present in the manufacturing process, the amounts of dioxins varying with different process controls by each individual manufacturer, they are present in chemical waste and sludges remaining from these processes. If these waste products are indiscriminately discharged into the environment or not properly disposed of, contamination of water, air, or food stuff results in widespread exposure of the population to TCDD's and other dioxins. Humans can absorb these chemicals by absorption through the skin; by inhalation while breathing; by ingestion through food and water; and exposure from the use, of proximity to and/or spraying of herbicides. Occupational exposure has occurred in the following situations; (1 ) in manufacturing plants when TCDD was formed in excessive amounts because the reaction temperature and pressure were high enough to favor dioxin formation, but not high enough to produce an explosion; (2) in explosions at manufacturing plants where the re action temperature and pressure levels reached exothermic proportions; and (3) from contaminated waste products of these same manufacturers which were released into the environment and/or handled by scientists testing these products. See attached charts on documented human exposures (VA Review of Literature, Exhibit A1-A3). Military exposure to TCDD resulted from the spraying of enormous quanti ties of 2,4,5-T in South Vietnam which was contaminated with TCDD. 13304 -1 5 - IN D U S T R IA L E X P L O S IO N S References on Industrial Explosions That Involved TCDD LOCATION REFERENCES Monsanto Nitro, WV Suskind (1973); VA (1980). Zack and Suskind (1980) BASF Ludwigshafen, W. Germany Goldmann (1972); Goldraann (1973) Thiess and Frentzel-Beyme (1977) Rhone Poulenc Grenoble, France Dugois et al. (1958) Italy Joint NIESH/IARC Working Group (1978) Young et al. (1978) Philips-Duphar Amsterdam, Netherlands Dalderup (1974); Berlin et al. (1976) Rawls and Sullivan (1976); Hay (1977) Rhone Poulenc Grenoble, France Dugois et al. (1963) Rawls and Sullivan (1976) Coalite & Chemicals Products Jensen and Walker (1972) Boisover, Derbyshire, U.K. Jensen et al. (1972; May (1973) ICMESA Seveso, Italy Commoner and Scott (1976; Hay (1976) Rawls and Sullivan (1976); Fara (1977) Gianotti (1977); Walsh (1977) Bonaccorsi, et al. (1978); Greim (1978) Laporte (1973); Reggiani (1978) Hornberger, et al. (1979) Malizia, et al. (1979) Pocchiari, et al. (1979) Reggiani (1979); Strik (1979) Reggiani (1980); VA (1980); VA (1981) References Which Review Industrial Exposures to TCDD Forth (1977) IARC (1977) IARC (Joint NIESH/IARC-1978) Hay (1979) Moses and Moore (1979) Esposito et al. (1980) Hay (1977) Firestone (1978) Young et al. (1978) Malizia et al. (1979) Crow (1980) Suskind (1980) 13305 -1 6 - IN D U S T R IA L EXPO SURES References on Industrial Exposures to TCDD YEAR LOCATION REFERENCES 1949 Nordheim, WestfalLen, Wesc Germany Baader & Bauer (1951) 1951-52 2 factories in Middle Rhein, W. Germany Bauer et al. (1961) 1954 Boehringer, Ingelheim Hamburg, West Germany Kimmig & Schulz (1957) Kimmig & Schulz (1957) Schulz (1957); Bauer ec al. (1961) 1956 Diamond Alkali Newark, N.J. Bleiberg et al. (1964) Poland et al. (1971) 1964 U.S.S.R. LARC (1977) 1964 Dow Chemical (2,4,5-crichloropheno 1 production) Midland, Michigan Firescone (1978) Cook et al. (1980) Rowe (1980) 1965-9 Spoiana Czechoslovakia Jirasek et al. (1973) Jirasek et al. (1974) Pazderova et al. (1974) Jirasek et al. (1976) Pazderova-Vejlupkova et al. (1980) 1970 Japan Miura ec al. (1974) 1972 U.S.S.R. Zelikov and.Danilov (1974) 1950-1975 Dow Chemical (2,4,5-T production) Midland, Michigan Kramer (1974)* Ott et al. (1980) Townsend ec al. (1980)* 1955 - 1977 Monsanto Nitro, West Virginia VA (1980) *unpublished reports 13306 -1 7 - . R EFER EN CES ON O TH ER HUM AN EXPO SU RES TO TCD D YEAR LOCATION POPULATION DESCRIBED REFERENCES 1971 Missouri Farm residents Carter et al. (1975) Case (1976) Beale et al. (1977) Kimbrough et al. (1977) Crow (1980) 1970 England 3 laboratory workers 01 iver (197 5) 1967-1970 Vietnam Vietnamese residents Vietnamese refugees Vietnam veterans Vietnam military NRC (1974) Tung et al. (1971) Rose and Rose (1972) Tung et al. (1980) Bogen (1979) Halprin (1980) Stellraan & Stellman (1980) VA (1980) Harmon (1971) Allen .(1980) -18Exhibit A3 133G II. T h e F a te o f 2 ,4 ,5 - T and Its D io x in I m p u r it ie s Conclusions about the environmental fate of 2,4,5-T vary somewhat with the exosystem being considered. There is general agreement, however, that it is (a) rapidly degrated microbiologically in soil (Norris 1966) ; (b) not readily leached from soil into the water table (Wiese and Davis 1964) ; (c) immobilized by soil organic matter (Helling, et al. 1973); and (3) photodecomposed on the soil surface by ultraviolet light (Crosby and Wong 1973). In animals, 2,4,5-T is known to be hydroxylated, degraded to the halogenated phenol, detoxified by coupling to glycine and taurine, and rapidly excreted in the urine (Grunow and Bohme 1974; Shafik, et al. 1971). Where massive doses are given, some residues are detectable in the milk (Leng 1972) and bodily organs (Clark, et al. 1975). In microbes and plants, 2,4,5-T is degraded to the phenol (Fitzgerald, et al. 1967; Sharpee 1973) and subsequently to carbon dioxide in water. TCDD, by contrast is relatively immobile in soil and not photodecomposed'*' when attached to soil (Helling, et al. 1973; Kearney, et al. 1972). TCDD is not readily removed from soil to plant, and in the plant does not accumulate in the edible seeds or fruits of soybean or oats (Isensee and Jones 1971). However, in aquatic systems, soil containing 0.1 parts per billion (ppb) TCDD (a concentration that could occur under normal field use of 2,4,5-T) caused appreciable TCDD accumulation in algea, crustaceans, snails,, and fish (Isensee and Jones 1975). In order to decompose this molecule, Crummet of Dow Chemical Co. has done studies that indicate that dioxin survives burning up to 1150 C. Recently, evidence has been presented that TCDD breaks down in ultraviolet light (Wong and Crosby 1978) . 13308 -19- Further, although certain higher chlorinated dioxins may lose chlorine atoms on exposure to sunlight or to some types of gammaradiation, the basic dioxin structure is largely unaffected and TCDD is highly stable (Crosby, et al. 1971; Buser, Bosshardt, and Rappe 1978). "In comparison to any other organic compound, the biological degradation rate of chlorinated dioxins is slow, although measured rates differ widely." It has been further established that . . . 2,3,7,8-TCDD can enter the human body from a 2,4,5-T - treated food chain and can accumulate in the fatty tissues and secretions including milk (Galston 1979). "Because of the remarkable stability of this substance (2,3,7,8-TCDD) in biological systems and its extreme toxicity, cumulative effects of extremely small doses are a major concern." (EPA at p. 1) 1. Metabolism A large portion of guinea pigs administered 2,3,7,8-TCDD show that this chemical persists in unmetabolized form in the liver and is responsible for its toxic effects in animals and men. There is some indication that persons with high dietary iron intake are more susceptible to 2,3,7,8-TCDD liver toxicity than persons with marginal iron intake. (a) Pharmacokinetics & Tissue Distribution Pharmacokinetics is the study of the rate of elimination and retention of any chemical in animals or humans. Tests performed on tissue distribution of ingested 2,3,7,8-TCDD on rats, guinea pigs, monkeys and chick embryos, as well as the tests performed on humans show accumulation of this toxin in animals as well as humans. (b) Enzyme Effects Several investigations show that 2,3,7,8-TCDD has a dramatic influence upon various enzyme systems in many species including man. Several J3309 -20- studies show that 2,3,7,8-TCDD induces many enzyme systems and suppresses others. The mechanism of AHH induction of 2,3,7,8-TCDD and possible the mechanism by which the substance produces other toxic effects had been advanced; 2,3,7,8-TCDD moves into a cell and binds to a specific receptor. The receptor-dioxin complex then moves into a cell's nucleus where it "turns on" the synthesis of a specific messenger RNAs which direct the synthesis of cytochrome Pl/450 and related enzymes. This enzyme induction increases the metabolism of TCDD itself as well as other compounds; as a consequence, reactive and cytotoxic and carcinogenic compounds are formed. (c) Effect on Lipids 2.3.7.8- TCDD has dramatically altered the lipid profiles in laboratory animals and man. Studies of workers occupationally exposed to 2,3,7,8-TCDD have shown lipid abnormalities, elevated serum cholesterol levels, abnormalities in lipid metabolism and liver function. Further, these lipid abnormalities resulting from 2,3,7,8-TCDD exposure may be a significant risk factor to ischemic vascular disease. (d) Gross and Histopathologies The macroscopic-gross pathology and histopathology-microscopic of tissues of dioxin-exposed chickens, rats and monkeys have been examined extensively. At post-mortem examination, the most striking findings in dioxin-exposed animals are usually: (1 ) substantial loss of body fat; (2) involution lesions of thymus; (3) testicular alterations, including atrophy, necrosis, and abnormal spermatocyte development; and (4) liver cell pathology. (e) Acute Toxicity 2.3.7.8- TCDD is a highly toxic material, several orders of magnit more potent than many pesticides or herbicides. Some consider it to be the most toxic small molecule made by man (Poland & Kende, 1976). 13310 -21- E. AD VERSE H EA LTH EFFEC T S Plaintiffs will testify to their individual exposures to Agent Orange in Vietnam and all experts will base their testimony upon the presumed fact of exposure. Experts will testify that there is no "safe" level of any carcinogen to humans. Agent Orange is a chemical caricnogen and/or carcinogen. There is no "safe" level for any human exposure to 2,3,7,8-TCDD and other dioxins. Human exposure to 2,3,7,8-TCDD has induced chloracne, and often disfiguring and persistent dermatologic disorders, polyneuropathy (multiple lesions of peripheral nerves), mystagmus (involuntary rapid movement of the eye ball), and liver dysfunction as manifested by hepatomegaly (increase in liver size), and enzyme elevations. In animals and man, this compound has been shown to be teratogenic, mutagenetic, immunotoxic, embryotoxic, carcinogenic, and co-carcinogenic, and caused untoward pregnancy outcomes and birth defects in the wives and children of the veteran plaintiffs. For further explanation of all adverse effects of Agent Orange in the Plaintiffs and the human population, see Plaintiffs' Answers and Supplemental Answers to Defendants' Interrogatories Nos. 1, 2(d), 3(a), 4(a), and 4(c). 13311 -22- ERN EST M . BAR AN , M .D . I. Qualifications (See Curriculum Vitae) II. Subject Matter Dr. Baran will testify as to the performance and interpretation of various tests in the veterans. These will include an electroencephalogram on both sleep and waking states with nasopharyngeal leads. He will also perform electromyograms, nerve conduction velocity tests, and somato sensory evoked potentials of the upper and lower extremities. Dr. Baran will then testify as to the mechanisms by which toxins produce the changes noted in the tests and what the various tests are capable of determining as to the medical status of the patient. Then he will relate the results obtained in the testing of each plaintiff examined, give opinions as to the causation of those results where possible from the evidence revealed by the .tests, and state the prognosis for the individual plaintiff for further deterioration in test results and/or for the individual's condition as a whole. III. General Scientific Principles Various substances cause sensory conduction deficits. Among them are neurotoxins. Agent Orange is a neurocoxin capable of causing a sensory conduction deficit. The mechanisms by which such deficits are caused are either by a demyelinating process in which the sheath of the nerve itself is gradually erroded or by an axonal degeneration in which the nerve itself is broken. ' The result of the demyelinating process is that nerve impulses are slowed and, on a functional basis, cause lack of sensation in coordination. 13312 The result of axonal degeneration is that the impulse stops where the break has occurred. If enough of the nerve fibers themselves are caught, there is no response whatsoever. If a lesser number of fibers are caught, there is a smaller response. Functionally, a severence of the nerve chain results in impairments dealing with feeling, touch, and discriminative sensation (i.e. telling rough from smooth surfaces, etc.). Additional tests may help to specify the particular causative agent for the sensory conduction deficit. Tests would include those which show which fibers had degenerated, tissue assays and a study of antibody deposits on the nerves. IV. Substance of Opinion 1. Agent Orange could cause sensory conduction deficit. V. Grounds for Opinion Dr. Baran has been out of town and has not been able to prepare the grounds for his opinion as yet. He must do some library work in preparation for it, and he indicates that he will forward the grounds for his opinion as soon as he has done his library work. Dr. Baran will also rely, in addition to medical and scientific articles, on testing on which he has done on 10 to 15 Vietnam Veterans. Additionally, Dr. Baran served as an Army medical officer in Vietnam from August, 1969 to July, 1970. During that time, he was an orthopedic and general surgeon. For approximately six months, he operated in the fields in various Vietnamese villages. He has personally observed defoliation in Vietnam, especially on the perimeters of the compounds in which he was stationed as a surgeon. -2- DEBORAH A. BARSOTTI, Ph.D . I. QUALIFICATIONS Dr. Barsotti is an Assistant Professor of Tocicology in the Department of Pharmacology and Toxicology of the Philadelphia College of Pharmacy and Science in Philadelphia, Pennsylvania. Her curriculum vitae is attached. II. SUBJECT MATTER Dr. Barsotti is a toxicologist who has done substantial personal investigative work with halogenated aromatic hydrocarbons. This category of. chemicals includes various biphenyls and dioxins, and specifically includes tetrachlorodibenzo-p-dioxin (TCDD). She will testify as to the relative chemical stability and lipophilicity of these chemicals as well as their resistance to degradation, and will testify that these qualities are what account for the perceived and documented bioaccumulation of the chemicals in the human system. Dr. Barsotti will emphasize the difference in results between chronic and acute exposures to these chemicals, testifying as to the varying types of responses to acute and chronic exposures. Dr. Barsotti will discuss her own work as well as review the literature in these areas, noting differences in routes of 13314 D. That TCDD accumulates and persists in the lipid stores. E. That TCDD, in chronic doses, is toxic, is parti cularly toxic to reproductive system, is teratogenic, and is fetotoxic. F. There are ample scientific bases, for extrapolat ing animal experimental data to man, in the case of TCDD, for example, as demonstrated by Dr. Barsotti's work on rhesus monkeys. V. GROUNDS FOR EACH OPINION A. General Review of applicable medical and scientific litera ture; education and training; personal research. The work on the chronic toxicity of HAHs in rhesus monkeys has culminated in numerous publications as p resented in Dr. Barsotti's curriculum vitae. In addition, she has been invited to speak or present her work in various atmospheres including community meetings and scientific symposia. B. Specific 1. With respect to opinion IV A, see generally references attached. 2. With respect to Opinion IV B, note the following: 13315 Dr. Barsotti will contrast the acute toxicity that one observes in accidental or intentional ingestion of toxic or lethal doses of chemicals with the effects of chronic or lower levels of exposure to chemicals such as HAHs. 4. With respect to Opinion IV D, note the following: Dr. Barsotti will comment on the state of the literature on the fate of TCDD once in the body, i.e. TCDD metabolism (Vinopal and Cassida, 1973; Ramsey et a l ., 1979; Schlatter, 1979). Efforts to identify metabolites in tissues and excreta from various studies have been unsuccessful. Recent advances in detection methodology indicate elevated levels of TCDD in Vietnam veterans and other exposed persons. Generally, however, the data indicate that if metabolism does occur the rate is slow (Guenthner et a l ., 1979) The ramification of this finding is that the body would be incapable of or slow in ridding itself of TCDD and TCDD would accumulate and persist in the lipid stores. In Dr. Barsotti's work, as well as others', this appears to be the case with rhesus monkeys and man (Montagna et al^. , 1979; Van Miller, 1981; McNulty et a l ., 1983) . 5. With respect to opinion IV E, note the following: Not only did the rhesus monkey appear a good model for HAH toxicity but established, as had been in other animal species, that the reproductive system was extremely sensitive to PCBs at intake levels below that required for the manifestation of toxic signs in the adult (Barsotti et a_l., 1976) . In addition to PCB induced reproductive toxicity, PCBs were found to be fetotoxic 13316 three months in animals receiving TCDD in the diets at levels of 500 parts per trillion (ppt) and in animals consuming diets contain ing 50 ppt TCDD these same symptoms occurred after consuming the diets for 30 months (Allen et a l ^ , 1977; Schantz t al,, 1979). This indicates cumulative toxicity associated with ingestion of TCDD. Thus, there is evidence for bioaccumulation and associated chronic toxicity at lower doses than that required for acute toxi city in rhesus monkeys and presumably man (Pazderova ^t l, 1981; Ideo et al., 1982.) 6. With respect to Opinion IV F, see ge references attached and V A above. 13317 REFERENCES P.W. Albro, J.T. Corbett, M. Harris and L.D. Lawson, Chem-Bio. Interact., 25, 515, 1979 J.R. Allen, D.A. Barsotti and L.A. Carstens, Toxicol. Appl. Pharmacol., 50, 440, 1974* J.R. Allen, D.A. Barsotti and L.K. Lambrecht, New York Academy of Sciences, 521, 419,1979* J.R. Allen, D.A. Barsotti, J.P. Van Miller, L.J. Abrahamson and J.J. Lalich, Fd. Cosmet. Toxciol., 15, 401, 1977. J.R. Allen and D.A. Barsotti, Toxicol., 6, 551, 1976. D.A. Barsotti, R.J. Marlar and J.R. Allen, Fd. Cosmet. Toxicol., 14, 99 1976. D.A. Barsotti, Doctoral Thesis, University of Wisconsin, 1980. 13318 D. A. Barsotti, L.J. Abrahamson and J.R. Allen, Bull. Environ. Contain. Toxicol., 21, 463, 1979- R.E. Bowman, M.P. Heironimus and D.A. Barsotti, Neurotoxicol,m 2, 251, 1981. K.D. Courtney and J.A. Moore, Toxicol. Appl. Pharmacol., 20, 396, 1971 T.M. Guenthner, J.M. Pysh and D.W. Nebert, Pharmacol., 19 12, 1979. G. Ideo, G. Bellati, Al Bellobuono, P. Mocarelli, A. Marochhi and P. Brambilla, Clinica Chimica Acta, 120,.273, 1982. A.R. Isensee and G.E. Jones, Environ. Sei. Technol., 9, 668, 1975 E. E. McConnell, J.A. Moore, J.K. Haseman and M.W. Harris, Toxicol Appl. Pharmacol., 44, 335, 1978 a. E.E. McConnell, J.A. Moore, and D.W. Dalgard, Toxicol. Appl. Pharmacol., 175, 1978 b. W.P. McNulty,K.A. Nielsen-Smith, J.O. Lay, D.L. Lippstreu, N.L. Kangas, P.A. Lyon and M.L. Gross, Pd. Chem. Toxic., 20, 371, 1982. I. Manara, P. Coccia and T. Croci, Drug Met. Rev., 13, 423, 1982. A.C. Marinucci and R. Bartha, Bull. Environm. Contam. Toxicol., 29, 326, 1982. J. Mes, D.J. Davies and D. Turton, Bull. Environm. Contam. Toxicol., 28 97, 1982. M. Meselson, P. O'Keefe and R. Baughman, In: Symposium on the use of herbicides in forestry, 91, February 21-22, 1978. M. Montagna, A. Fornari and S. Facchetti, In: Forensic Toxicology, 78, 1979- J.R. Olson, M.A. Holscher, and R.A. Neal, Toxicol., Appl. Pharmacol., 55, 67, 1980. J. Pazderova, M. Nemcova, J. Pickova, 1. Jirasek and E. Lucas, Arch. Environ. Health, 36, 5, 1981. A. Poland and E. Glover, Molec. Pharmacol., 17, 86, 1980. A. Poland and J.C. Knutson, Ann. Rev. Pharmacol. Toxicol.,22, 517, 1982. H. Poger, H. Buser, H. Weber, U. Zweifel and C. Schlatter, Experimentia, 4 484, 1982. 1332-0 R. C. Ramsey, J.G. Hefner, R.J. Karbowski, W.H. Braun and P.J. Gehring, Toxicol. Appl. Pharmacol., 47, A162, 1979 - S. L. Schantz, D.A. Barsotti and J.R. Allen, Toxicol. Appl. Pharmacol., 46, 180. 1979- S.L. Schantz and R.E. Bowman, The Toxicologist, Vol. 4, Abstract number 333, March, 1984- J.P. Van Miller, Doctoral Thesis, University of Wisconsin, 1981. J.H. Vinopal and J.E. Cassida, Arch. Environ. Contam. Toxicol. 1, 122, 1973- 13321 DR. RONALD CODARIO I. QUALIFICATIONS See the attached curriculum vitae. II. SUBJECT MATTER Dr. Codario will testify concerning acute and chronic toxicity of herbicides and TCDD in animals and humans. He will also testify concerning the metabolism of TCDD in body fat, and its mechanism of action, and its persistance in the environment, including both the surrounding environment and the body itself. He will also testify concerning exposures and the amounts of herbicides sprayed, the particular types, and the component elements of TCDD therein. III. GENERAL SCIENTIFIC PRINCIPLES Dr. Codario will testify that an organism can have varying types of exposures to toxins, including acute and chronic exposures. An acute exposure, according to the literature, is that which is used to define all the effects of a single exposure on an organism. A chronic exposure is a continuous exposure for up to thirty days or more. A chronic exposure can be an exposure to an exterior toxin, or an exposure to a toxin contained in some manner within the body itself after an exterior exposure. Toxins can have effects upon the following systems: a. Teratogenicity b. Mutagenicity c. Carcinogenicity d. Neurotoxic affects e. Gastro-intestinal disturbances, including porphyrins. f. Immunologic and hematologic g. Renal h. Cardiovascular i. Endocrine and metabolic j. Pulmonary The metabolism of herbicides, including Agent Orange, and TCDD is known for animals, but not directly known for humans. It is located in all body tissues in animals, but the herbicides are eliminated through the renal system because they are water soluble. The elimination period in humans appears to be between twelve and twenty-four hours. However, TCDD is not water soluble but is fat soluble. Therefore, it is not eliminated by the kidneys unless it is converted to a water soluble substance, which does not appear to occur in humans. In animals, TCDD is metabolized in the following manners: a. It is broken down to a water soluble substance and eliminated in the urine. b. It is eliminated in bile fluid. c. It is sequestered in fat. d. It is converted to a different toxic substance. The mechanism of action of herbicides and TCDD in particular is determined at the micromolecular level. At that level, TCDD changes the body chemistry and initiates enzyme induction. TCDD is persistent, especially in the human environment, both externally and internally. In the external environment, it was thought that the half-life of TCDD in the soil after being sprayed in Agent Orange was approximately three years (900 days). However, the measurements were done in the top soil and it appears that the under-soil has both five to seven times higher concentrations than the top-soil does and that its half-life is longer at the sub-soil level. At least one of the herbicides sprayed in Viet Nam has been determined to exist in soil, ten years after spraying, and recent reports indicate concentrations both longer and deeper than previously thought. The amount of exposure any individual had in Viet Nam may be determinable in part through use of H E R B S T A P E S ,which record the spraying missions flown by aircraft in Viet Nam. However, the HERBSTAPES do not cover nearly all of the spray missions flown there by various aircraft. The doctor will testify as to the totals of each type of herbicide sprayed per year and in total, how much TCDD was was in each type of herbicide, and the acreage sprayed each year for each herbicide. IV. SUBSTANCE OF OPINIONS Dr. Codario will testify to the following opinions: 1. Agent Orange, and in particular, TCDD is a chemical toxin. 2. Animal research experience is relevant to humans. 3. Agent Orange and its constituents and its contaminant TCDD effect all of the systems listed above in both man and animals. 13324 4. The doctor will furnish conclusions as to individual plaintiffs in his reports on those individual plaintiffs. 5. TCDD, the particularly harmful toxin, is stored in body fat and furnishes a constant source of exposure to all body systems. 6. The literature and his research documents that chronic exposure to TCDD exhibits many more deleterious effects than single or acute exposures. 7. TCDD binds to a cytosol receptor, which is a gene product of the Ah locus on the chromosomes. 8. TCDD drifts. 9. The Ah locus of the chromosome determines whether the organism will demonstrate toxic effects and whether the liver will go about breaking the substance down. This is what accounts for individual susceptability and the fact that different people exposed to the same toxin do not necessarily get any effects or the same effects. 10. TCDD persisted in the soil of Viet Nam for the duration of the war. 11. The individuals serving in Viet Nam were exposed to TCDD by spraying operations, by drinking contaminated water, by eating wild animals, and by clearing underbrush and digging in the soil. 12. Substantial amounts of TCDD were sprayed throughout Viet Nam to the point that the presence of any veteran in Viet Nam, in any location, means that he was exposed to TCDD through one mechanism or another, which exposure was sufficient to give him some form of disease depending upon the genetic predetermination of the Ah locus of his chromosomes. V. GROUNDS FOR OPINIONS The grounds for Dr. Codario's opinions include: 1. See the attached bibliography. 2. Young, Toxicity And Persistance Of Agent Orange And TCDD In The Environment. 3. Herbicides And Related Dioxins - A Review Of The Literature, J.R.B. Associates. 4. The doctor's own clinical and research work on approximately 500 veterans whom he has personally examined. This work is currently being translated into computer language, and will be computerized for analysis and comparison purposes. The computer data will be furnished as soon as it is completed. 13326  OARO CIKTiriXO IN TK R N A L M IO IC IN K R O N A L D A. C O D A R IO. M. D. 1427 SOUTH BROAD STREET P H IL A D E L P H IA . P A 1 0 1 4 7 CURRICULUM VITAE 2 IB.467*3083 ADDRESS: Home - 205 Porter Street Philadelphia, Pennsylvania 19148 215-46 5-9476 DATE OF BIRTH: 12-9-47 (Pennsylvania Hospital) PERSONAL: Married Celeste DiSabatino Children: Ronald Anthony (6-16-81) (Pennsylvania Hospital) Maria Celeste (6-14-83) (Pennsylvania Hospital) EDUCATION : LaSalle High School (1961-1965) LaSalle College (1965-1969 B.A. Biology) Hahnemann Medical College (1969-1973 M.D.) St. Agnes Hospital (1973-1974 Medical Internship) University of Pennsylvania.Division of Philadelphia Hospital (Medical Residency 1974-1976) Genera PROFESSIONAL SOCIETIES: American Medical Society Philadelphia County Medical Society Pennsylvania Medical Society AWARDS: WHO'S WHO OF MEDICAL SPECIALISTS 1977-1978 MARCONI RECOGNITION AWARD - June 1980 (Outstanding contributio in the efforts to build Marconi Plaza) DISTINGUISHED ACHIEVEMENTAWARD - St. Agnes Hospital, Dept, of Medicine - February, 1980 FREEDOM'S FOUNDATION AT VALLEY FORGE GOLD MEDAL - April, 1981 - (Outstanding achievement and humanitarian efforts in treating Vietnam veterans and their families free of charge) E GUBERNATORIAL CITATION: -.April 1981 - (Special achievement in working with Vietnam veterans exnosed to herbicides) PENNSYLVANIA HOUSE OF REPRESENTAT!VES CITATION - December 7. 1 (special citation-sponsored by Rep. Paul Clymer and Rep. George Sauerman in recognition of work done to aid Vietnam veterans) AGENT ORANGE NATIONAL HOTLINE CERTIFICATE OF APPRECIATION December 10, 1981 (Volunteer work with Vietnam veter CHAFEL OF FOUR CHAPLAINS LEGION OF HONOR AWARD - February 28, UNITED STATES CONGRESSIONAL.CERTIFICATE OF MERIT - June 24, 19 SPECIAL CITATION -DISABLED. AMERICAN VETS - July, 1982 (Outstandingrseiad.ce to Vietnam veterans) CHAPEL OF FOUR CHAPLAINSCEGION OF HONOR - September 12, 1982 UNITED STATES CONGRESSifl^RTIFICATE OF MERIT - September 19, 19 (Outstanding '.setyice tfo Vietnam Vets) VIETNAM VETERANS OF AMEEqSf^WARD OF MERIT - November, 1982 (Outstandingv^p^tiS'teer service to Vietnam vets) HONARARY MEMBER OF THElOffijpEARY BOARD OF THE UNITED VIETNAM VETERANS 0RGANIZATI0N~-fflal982- (honorary position due to "your positionnas a leader of the community") SIGNUM FIDEI MEDAL - NoT|y. 18, 1983 - (Awarded annually to trie individual^wno'has manifested the highest tradi tions of Christianity and humanitarianism)LaSalle 13327 ColleE  O A flO C C R T t F II O IN TK ftN A U M K 0 IC IN S R O N A L D A. C O D A f tlO , M. D. 1427 SOUTH BROAO STREET P H IL A D E L P H IA PA. IS 147 \ 213 . 4 0 7 . 3 8 8 3 LECTURES/TEACHING: Administrative Head - Division of Internal Medicine 1978 (St. Agnes Hospital) Director of Clinical Pathological Conferences 1977-1978 (St. Agnes Hospital) Lecture - Clinical Pathological Conference (January 1977 - Pseudomonas septicemia in a burn patient) Lecture - Medical Grand Rounds - St. Agnes Hospital December 1981 - "Human Manifestations of Herbicide Poisoning" Lecture - Medical Grand Rounds - Methodist Hospital, February, 1982 - "Medical .Effects of Agent Orange Exposure" Lecture - Medical Grand Rounds - Albert Einstein Hospital, August 1982 - "Medical Effects of Herbi cide Poisoning Lecture - Clinical Pathological Conference "Sudden Death in a Patient with Lung Carcinoma" January, 1984 Lectures - 1983 - Lecture tour of senior citizen homes and meetings to promote health care and Albert Einstein Medical Center Lectures - 1981 to present - series of 36 lectures on the East coast tConnecticutt to Alabama) on Agent Orange toxicity along with special lec:ures to the Pennsylvania, New York, West Virginia, Illinois Agent Orange Commissions Lectures - October 1 9 , 1983 and November 1 6 , 1933 "Agent Orange Toxicity" - sponsored by the Pennsylvania Medical Society Lecture - April 28, 1983 - "Agent Orange Effects on Vietnam veterans" - sponsored by the Pennsylvani Health Department P-VV. ''lTminaLt *ODOT '''TTMM.ENTS: Internship - St. Agnes Hospital 19 7 3 - '971Medical Residency - University of Pennsylvania Division - P h iladelphia General Hospital l97l-:9 Assistant Chief Admitting Physician - Emergency Room of Philadelphia General Hospital, 1976-1977 St. Agnes Medical*Center - Attending Physician 19 7 6 - p r e s e n t Methodist Hospital - Attending Physician - 19 8 0 - p r e s e n t Albert Einstein Daroff Medical Center - 1982-ores Attending Physician Police Surgeon, City of Philadelphia, 1978-presen MEDICAL EXECUTIVE COMMITTEE - St*. Agnes Hospital 1983 UTILISATION REVIEW COMMITTEE - St. Agnes Hospital 1984 and Albert Einstein Hospital (1985-presen PUBLICATIONS: September 1976 - "Stroke" - G o l d b e r g , H. , Codario., R. et ai REGIONAL CEREBRAL BLOOD FLOW IN PATIENTS WITH SEVERE HYPERTENSION FOLLOWING THE ADMINISTRATION OF DIAZOXIDE 13328 R O N A L D A . C O D A p t O , M. D. 142.7 S O U T H . B R O A D S T R E E T P H IL A D E L P H IA P A 19 147 BO ARO C X R T lP IK O IN T IR N A L M C O IC IN K PUBLICATIONS (cont): Januar" , 1? 8 l Agent O r a n g c - 1'y ths and leali tics, t:f ' vt.t""a X P %'CT ? .y .'"r , , J a n . / 7 ec. page 12 April,. 1982 - REVERSE PHASE HPLC PROFILES OF URINARY PORPHYRINS IN PATIENTS EXPOSED (19 6 L - 197l TO AGENT. ORANGE AS COMPARED TO HPLC PORPHYRIN PROFILES IN PORPHYRIA, Petryka, Z.J., C o d a r i o , R. April, 1982 - OMENS - "THE CURSE THAT LINGERS" Codario, R. January, 1983 - Agent Orange Controversy - OMN I . page 16 November, 1982 - STARS AND STRIPES 106(50:7-10. Point of*View: Agent Orange - The Curse That Ling Codario, R. RELATED ARTICLES/EOOKS/TELEViSION/RADiO PHI LA DELPHIA INQUIRER: O c t o b e r 25, 1981 -Ihvestigat Agent Orange: a d o c t o r 's personal project. Darryl Sifford PHIL AD EL PH IA JOURNAL: No ve mb er 20, 1981 - Agent Orange Makes South Philly Doc See Red. Bruce Bee CAMDEN COURIER-POST: May 1?, 1982 - Doctor treats Vets but has no answers, Julie Buscy ALUMNI - feature article of the Hahnemann Medical College - Soring, 1982 OMNI - August* 1982 - THE AGENT ORANGE MYSTERY Pamela Weintraub PH IL AD EL PH IA DAILY NEWS, N o v e m b e r 10, 1932 Battleground - Viet Vets Still Fignting the War Maria Gallagher Television October, 1981 - K Y W - T V Special Report on Agent Or October 9, 1982 - PRI ME TIME - feature on my work with Vietnam veterans (WFVI-TV) September 20, 1932 - PEOPLE A R E TALKING - discuss. group on Agent Orange (KYAV-TV) Nov ember 11, 1982 -(Channel 29) - DLL VAL discussion groun on Agent Orange January L, 1985 - EVENING *M AG AZ IN E - (KT.7-T7) feature presentation on Agent Orange June 16 , 1983 - WCAU-TV - discussion on herbicace toxicity with Herb Dennenberg June 1S , 1983 - Niag ar a School of Applied Arts Documentary on Agent Orange Radio July 28, 1983 - WIP People Talk with Michele Iaia featured discussant on Agent Orange September, 1983KSTP News Talk (Minnesota) - The Dick Pomerantz Program - discussion on Agent Orange BOOKS WATTING FOR AN ARMY TO D I E , the tragedy of Agent Ora nge by Fred Wilcox, pp. 11L - 125 1332S BO ARO C E R T IF IC O IN TER N A I. M E D IC IN E RONALD A. CODARIO. M. D. A.\ A Z 7 S O U T H B R O A D S T R E E T - P H IL A D E L P H IA . f>A. 1 8 1 4 7 *^<**' KP'-t. ' ' I 2 tD .4 8 7 .3 a a 3 ARTICLES PENDING: \ ' Review of the Signs and Symptoms of ^00 Vietnam Veterans with Special A t te nt io n to Porph yr in Analysis Case Report: Dying Back Ne ur opathy Due to Dioxin Exposure Case Reports: Review of 10 Liver Biopsies in Vietnam Veterans (exposed to herbicide s) wi th porphyrin disturbances Instructive Manual : Toxic Herbicide Poisoning-Diagnosis and Management (Sponsored by the Pennsylvania Health Dept, anc the Pennsylvania Medical Society) LITIGATION EXPERIENCE As a Pollen Surgeon for the City of Philadelphia for the past seven years i have been called to testify as an expert witness 5 0 -- 50 times in matters related to drivers under the influence of drugs, illness, alcohol; as well as the health ana physical state of police officers injured in the line of duty. 'DC-'NAL I have testified in the disability hearings of 18 patient, as the expert witness (treating pr.ysician) I ''.ave recently finished testi fyi. case. This case dealt with the n to the plaintiff by his exposure (This case was recently won by th nausea the 5 - :- develoner. "ri I 'nave testified at the Veterans several patients (!'leenam vets an to obtain service ccnnec tea disabCllltv vets; i: ^ c::.e - --,, *-1, 1^ _ --I.y,- I have ex," " . .n, p 1/ veterans free cf cr.arge and have conducte^dr* tne largest independent survey of their health problems ever recorded. This survey is presently being computeris~eo d and stattiisstical!,v anal .".ted. 13330 A R T H U R W . G A L S T O N , P h .D . I. QUALIFICATIONS Dr. Arthur W. Galston is Eaton Professor of Botany in the Department of Biology, Yale University, New Haven, Connecticut. See attached curriculum vitae. II. SUMMARY OF TESTIMONY Dr. Galston is a plant physiologist and has personally observed the effect of the spraying of Agent Orange on the Vietnam ecosystem, i.e. the devastation of the Vietnamese countryside. Dr. Galston has been in Vietnam on four occasions between 1971 and 1982, and will describe those observations while in Vietnam, with such pictorial evidence as is available Dr. Galston will testify to the potential and actual effects of phenoxy herbicides and their contaminants, both in Vietnam and elsewhere, including the United States and Sweden, and other places. The testimony will include the chemistry and the mechanisms of action of such chemicals on plant life. In addition, Dr. Galston will testify to the fate of Agent Orange and other phenoxy herbicides and their contaminants, especially TCDD, in the environment generally and in Vietnam in particular. Dr. Galston will testify to the persistence of such chemicals on plants, in water, and in soil, such that exposure to the phenoxy herbicides and their contaminants, especially TCDD, by the veterans in sprayed areas in Vietnam is presumed. 13331 III. S C IE N T IF IC P R IN C IP L E S AND ASSU M ED FA C T S See General Summary of Scientific Principles and Assumed Facts. IV SUBSTANCE OF OPINION Dr. Galston will testify to the following opinions: 1. Agent Orange, phenoxy herbicides and their contaminants have had a long-term catastropic effect upon the environ ment in Vietnam. 2. 2,3,7,8-TCDD, one contaminant of Agent Orange, persists in the ecosystem for long periods of time. 3. The level of use of Agent Orange in Vietnam exposed servicemen there to significant levels of TCDD. 4. 2,3,7,8-TCDD can enter the human body from a 2,4,5-T treated food chain and can accumulate in the fatty tissues and secretions including milk. 5. The level of use of phenoxy herbicides and the persistence of the herbicides and their contaminants in the environment means that all veterans in sprayed areas in Vietnam can be presumed to have been exposed to the phenoxy herbicides and their contaminants, including TCDD. V. FACTUAL BASIS OF OPINION Dr. Galston's opinion is based upon his personal observations regarding the long-term effects of the use in Vietnam, his knowledge of the persistence of TCDD in the environment, his knowledge as to how TCDD can be transmitted to humans through the food chain and all or part of the following references: 13332 REFERENCES CITED Alien. J. R., D. A. Busotti. J. P. Van Miller. L. J. Abrahamson. and J. J. Lalich. 1977. Morphological changes in monkeys con 2su.3m,7i.n8g-teairadciehtlocroodnitbaeinnzino-gp-ldoiwoxilne.v eFl so oodf Cosmet. Toxicol. 15: 401-410. Allen. J. R., and L. A. Carstens. 1967. Light and electron microscopic investigations in Macaca mulatta monkeys fed toxic fat. Am. J. Vet. Res. 28: 1513-1526. Baughman. R.. and M. Meselson. 1973. Ana lytical method for detecting TCDD (dioxin): levels of TCDD in samples from Vietnam. Environ. Health Perspect. 5: 27-35. Blair. E. H.. ed. 1973. Chlorodioxins --Origin and Fate. Advances in Chemistrv Series 120, American Chemical Society. Washing ton. DC. Clark. D. E.. i. S. Palmer. R. D. Radeleff. H. R. Crookshank. and F. M. Farr. 1975. Residues of chlorophenoxy acid herbicides and their phenolic metabolites in tissues of sheep and cattle. J. Agric. Food Chem. 23(3): 571-578. Crosby, D. G.. and A. S. Wong. 1973. Pho- FtaocodeoetdiccoCmahpceiomds.it(i22o1,n4(6.5o):-fT21).045,i52n--1tnw0c5ah4t.elorr. oJp.heAngorxiyc.- Davis. war. BDi.oSEc.ie1n9c7e9. Herbicides 29:84. 91-94. in peace and Dougherty, R. C.. and K. Piotrowska. 1976. Screening by negative chemical ionization mass spectrometry for environmental con tamination to human uwnitnhest.oxPicrorce. siHduaeils.: Aapcpaldic. aSticoin. USA 75(6): 1777-1781. Environmental Health Perspectives. 1973. Experimental Issue No. 5. 1-313. U.S. De partment of Health. Education and Wel fare. NIEHS. Research Triangle Park. NC. Environmental Protection Agency (EPA). 1978. Rebuttable presumption against regis- tration and continued registration of pesti- cide products containing 2.4.5-T. Fed. Reg. 43(78): 17116-17157. Epstein. S. 1970. A family likeness. Environ ment 12(6): 16-25. Fahmy, O. G.. and M. J. Fahmy. 1954. Cyto glaaennndoegttiaucsmtaeonrua. rlyIIsi.insThohibfeitthmoeresacinchtaiDonnirsomosfoocpafhriicnlaidnuocgteimonnes- oenfedimominion)a-ln:3t:5le-ttrhiaazlsineb.yJ.2G:4e:6n-e<t.ri(5e2t:h6y0l3- - 619. ; j i ! i i i | 13333 .----------1955. Cytogenetic analysis of the ac tion of carcinogens and tumour inhibitors in Drosophila melanotfaster. III. Chromo some structural changes induced by 2:4:6- 5tr3i:(e1t8h1y-l1e9n9e.imino)-I:3:5-triazine. J. Genet. Fitzgerald. C. H.. C. L. Brown, and E. G. BecV. 1967. Degradation chlorophenoxyacetic acid in of 2. woody 4p.l5a-n1trsi-. Plant Physiol. 42: 459-460. Gentile. J. J.. and J. Plewa. 1976. Mutagenici ty of airazine: a maize-microbe bioassay. Mutt. Res. 38: 287-292. Gentile, J. M., E. D. Wagner, and M. J. Plewa. 1977. The detection of weak recom- binogcnic activities in the herbicides ala- chlor and propachlor using a plant activa tion bioassav. Mutt. Res. 48: 113-116. Grunow. W,, and C. Bohme. 1974. Metabo lism of 2.4.5-T and 2.4-D in rats and mice. i(cTorla. n3s2la:t2ed17f-r2o2m5. the German.) Arch. Tox Helling. C. S.. A. R. Isensee. E. A. Wool- son. P.- D. J. Ensor. G. E. Jones. J. R. Plimmer. and P. C. Kearney. 1973. Chlo- rodioxins in pesticides, soils, and plants. J. Environ. Qual. 2(2): 171-178. Herskowitz, I. H. 1956. Mutagenesis in ma ture Drosophila spermatozoa by ``tnazine" applied in vaginal douches. Genetics 41: 605-609. Isensee. A. R., and G. E. Jones. 1971. Ab sorption and translocation of root and foli age applied 2.4-Jichlorophenol. 2.7-dichlo- rodibenzo-p-dioxin and tetrachlorodibenzo-p-dioxin. J.2 .A3.u7r,i3c.- Food Chem. ________ 1975. D19is1t6r)i:bu12ti1o0n-12o1f4.2.3.7.8-tet- rachlorodibenzo-p-dioxin tTCDD) in aquat ic model ecosystem. Environ. Sci. Technol. 9(7): 668-672. Johnson. J. E. 1971. The public health impli cations of widespread use of the phenoxy herbicides and pictoram. BioScience 21(17): 899-905. Kearney, P. C.. E. A. Woolson. and C. P. El lington. Jr. 1972. Persistence and metabo lism of chlorodioxins in soils. Environ. Sci. Technol. 6(12): 1017-1019. Kearney. P. C.. E. A. W oolson. A. R. Isensee. and C. S. Helling. 1973. Tetra- cshoulorrcoedsi,befantzeo,daionxdindecinontthaemiennavtiiornon. mEennvti: ron. Health Perspect. 5: 273-277. Lang, A., ed. 1974. Effects of Herbicides in South Vietnam. Summary and Con clusions. National Academy of Sciences. Washington, DC. Leng, M. L. 1972. Residues in milk and meat and safety to livestock from the use of phe noxy herbicides in pasture and rangeland. Down Earth 23(1): 12-20. Liang, G. H.. and Y. T. S. Liang. 1972. Ef fects of atrazine on chromosomal behavior in sorghum. Can. J. Genet. Cytol. 14: 423- 427. Meselson. M.. P. O'Keefe. ami R. Baugh man. 1978. The Evaluation of Possible Health Hazards from TCDD in the Envi ronment. Symposium on the use of herbi cides in forestry, Arlington, VA. 21 -22 February. Meselson. M. S.. A. H. Westing, and J. D. Constable. 1972. Background material rele tvhaentAtoApArSe.seUnt.aSt.ioCnsonagt rt.heR1e9c7.0 meeting of 118: 6807- Mr6a8k1.3.E. 1969. Report of the secretary's com mtoisesniovniroonnmpeensttaiclidheesalatnhd. Cthhe.ir8reinlatTioenrashtoip genicity Health. oEfdPuceasttiiocnideasn.dUW.Se.lfDareep.arWtmaeshnitnogf ton. DC. Muranvi-Kovacs, I.. G. Rudali. and J. Im- bert. 1976. Bioassay of 2.4,3-tri- chlorophenoxyacetic acid for carcinogenic ity in mice. Sr. J. Cancer 33: 626-633. Mumik. M.. and C. L. Nash. 1977. Mutage cnyicaintyazoinfe.thaendtrsiiamzianzeinheeirnbDicridoessopahtirlaazminee-, lanogaster. J. Toxicol. Environ. Health 3: 691-697. NiCckhcelml.. LE.nGg.. N19e7w8s. Plant growth regulators. 36(41): 18-34. No2r.r4i.s3.-TL.inAf.or1e9s6t6.litDteerg.rJa.dFatoiroensto. f624.(47-)D: 4a7n3d- 476. O'Keefe. P. W., M. Meselson. and R. W. Baughman. 1978. A neutral cleanup proce dure for 2.3.7.3-tetrachlorodibenzo-y>-diox in residues in bovine fat and milk. J. Assoc. Off. Anal. Chem.. in press. Shadotf. L. A.. R. A. Hummel. L. Lamparsni. and J. H. Davidson. 1979. A search f(oTrCD2D.3).7in.8a-nteetnrvaicrro.nlomreondtibexenpzoose-pd-adnionxuianl ly to 2.4.3-tnchlorophenoxyacetic acid es ter (2.4,3-T) herbicides. Bull. Environ. Cuntarn. Toxicol., in press. Shank. M. T.. H. C. Sullivan, and H. ! Enos. 1971. A method for determination i Ilonwt. Jle.vEeinsvoirfoenx.pAonsuarl.e Ctoh2em.4.-01:an2d3-23.34..3-T Sharpee. K. 1973. 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Cytol. 8: 481-501. ______ 1967. Chromosomal aberrations in dleuyc.eCdybtoylopigeisatic3i2d:e3s1i-n41m. eiotic cells of bar 126-12-7122 BIOGRAPHICAL SKETCHES ARTHUR . GALSTUN. Ph.D., Eaton Professor of Botany, Department of Biology, Tale University Born April 21, 1920, New York City. Married, 2 children. B;S. Cornell University 1940; M.S. University of Illinois 1942; Ph.D. University of Illinois 1943. U.S. Navy, 1944-46; Agriculture Officer, U.S.N. Military Government, Okinawa, 1945-46. Elected to Phi Beta Kappa, Phi Kappa Phi, Sigma li, American Academy of Arts and Sciences; National Sigma Ii Lecturer, 1966; National Phi Beta Kappa Visiting Scholar, 1972-3. Award of the New York Academy of Sciences, 1979. Honorary LL.D., 1980, Iona. Plant Physiologist, Emergency Rubber Project, California Institute of Technology 1943-44; Instructor in Botany, Yale University, 1946-47; Senior Research Fellow, California Institute of Technology, 1947-50; Associate Professor of Biology, California Institute of Technology, 1951-1955. Professor of Plant Physiology, Department of Botany, Yale 1961--62;University 1955--61; Chairman, Department of Botany, Director, Division of Biological Sciences, Yale University, 1965-66; Professor of Biology, 1962-73; Eaton Professor of Botany, 1973- Fellow of the John Simon Gngenheim Memorial Foundation, Stockholm and Sheffield, 1950-- 51; Fulbright Fellow, Canberra, Australia, 1960-61; National Science Foundation Faculty Fellow, London, 1967-68; Albert Einstein Fellow and Visiting Professor, Hebrew University of Jerusalem, 1980. Visiting Fellow, Yolfson College, Cambridge, England, 1983. Secretary, American Society of Plant Physiologists, -1955-57; Vice President, 1957-58:.President, 1962-63. Secretary-Treasurer, International Association for Plant Physiology, 1962-67. VicePresident, Botanical Society of America, 1967-68; President, 1968-69; Merit Award, 1970. Formerly Council, Federation of American Scientists; President, Society for Social Responsibility in Science; Board Member, Scientists' Institute for Public Information. Member, Committee on Space Biology and Medicine, National Research Council. Editorial Board Member: Journal of Plant Growth Regulation. Pesticide Phvs iology and Biochemistry. Environment. Formerly Chemical and Engineering News. Science Year. Plant Physiology, Phytochemistry. American Journal of Botany. Llovdia. Formerly regular columnist, Natnral History magazine. Former member: Metabolic and Regulatory Biology Panels, Nation Science Foundation; Executive Committee, Growth Society; and Governing Boards, Biological Sciences Curriculum Study, Commission on Undergraduate Eduation in the Biological Sciences and American Institute of Biological Sciences. First American scientist to visit the People's Republic of China, 1971. Metnrn visits to Far East, 1972, 1975, 1977. 1980. Books: 'Principles of Plant Physiology' (with J. Bonner). Freeman, 1952. 'Life of the Green Plant'. Prentice-Hall, 1961, 2nd Edn., 1964, 3rd Page 26 a oO S a l ton. A r thur T. 126-12-7122 Edn. . 1980 (with. P.J. Davies and B.L. Setter). 'Control Mechanisms in Plant Development', (with P.J. Paries), Prentice Hall. 1970. 'Daily Life in People' China', Crowell, 1973; Simon and Schuster, 1975. 'Green Visdom' Basic Books, Inc. NT, 1981. Arthur f. Galston Publications (1979-1983) A. In Press Eaur-- Sawhney, R. and A.V. Galston. 1983. The culture of oat protoplasts and tissues. In: Evans, D.A., T.R. Sharp, P.V. Aoairato and 7. Tamada (eds.) 'Protoplast and Tissue Culture Methods for Crop Iaproveaent,' MacMillan Publications on Plant Tissue Culture, Morristown, New Jersey. Shekhavat, N.S. and A.V. Galston. 1983. Isolation, culture and regeneration of noth bean Vigna aconitifolia leaf protoplasts. Plant Sci. Lett. Slocum, R.D., J.J. Gaynor and A.f. Galston. 1984. Experiments on plants grown in space: Cytological and ultrastrnctural studies on root tissues. Ann. Bot. 1 9 8 3 .Young, N.D. and A.V. Galston. Are polyaaines transported in etiolated peas? Plant Physiol. B. Published Britz, S.J. and A.V. Galston. 1983. Physiology of movements in the stems of seedlings Pisua sat ivum L. cv. Alaska. III. Phototropism in relation to gravitropism, nutation, and growth. Plant Physiol. 71: 313-318. Duraortier, F.M., H.E. Flores, N.S. Shekhawat and A.V. Galston. 1983. rGoraodt sienotfs Pof polyaaines corn. Plant haynsdi o tl .he7i2r: bi9os1y5n- 9t1he8t. ic enzymes in coleoptiles and Galston, A.V. 1983 . Polyaaines as modulators of plant development. Bio Science 33: 382-388. Gaynor, J.J. and A.V. Galston. 1983. Purification and characterization of amyloplasts from etiolated epicotyls of Pisua sativum. Plant and Cell Physiol. 24: 411-421. Goballe, G.T. and A.V. Galston. 1983. Vound-induced lignin formation and resistance to cellulase in oat leaves. Phytopathology 73: 619-623. ( Racusen, R.H. and A.V. Galston. 1983. Developmental significance of light' ----mediated electrical responses in plant tissue. JLn Photomorphogenesis. Edited by V. Shropshire, Jr. and H. Mohr. Encyclopedia of Plant Physiology 16: 687-703. Springer-Verlag, Berlin, Heidelberg, New York, Tokyo. Shekhavat, N.S. and A.V. Galston. 1983. Kesophyll protoplasts of Fenugreek (Trigonella foenuagraecum) : Isolation, cultnre and shoot regeneration. Plant Cell Report 2: 119-121. 13238 Young, N.D. and A.V. Galston. 1983. Pntrescine and acid stress. Induction of arginine decarboxyl ate activity and pntrescine accnlation by lev pH. Page 27 12.6-12-7122 Plant Physiol. 71: 767-771. 1983. Britz, S.J. and A.V. Galston. 1982. Physiology of movements in items of seedling Pisnm sativnm L. cv. Alaska. I. Plant Physiol. 70: 264-271. Britz, S.J. and A.?. Gal ton. 1982. Physiology of movements interns of seedling Pisnm sativnm L. cv. Alaska. II. The role of the ajfcal hook and of auxin in nntation. Plant Physiol. 70: 1401-1404. Britz, S.J. and A.V. Galston. 1982. Light-enhanced perception of gravity in stems of intact pea seedlings. Planta 134: 189-192. Dai, Y . , R. ranr-Savhney and A.V. Galston. 1982. Promotion by giSberellic acid of polyamine biosynthesis in internodes of light-grown dnrf peas. Plant Physiol. 69: 103-106. Flores, H.E. and A.V. Galston. 1982. Analysis of polyamines in Mgher plants by high performance liquid performance. Plant Physiol. 69: 701-706. Flores, H.E. and A.V. Galston. 1982. Polyamines and plant stress; Activation of pntrescine biosynthesis by osmotic shock. Scieace 217: 1259-1261. Flores, H.E., A. Thier and A.V. Galston. 1982. In vitro cnltnreif grain and vegetable amaranths (Amaranthns Spp.) Amer. J. Bot. 69: 109-1054. Fhrer, J. , R. Raur-- Sawhney, L.M. Shih and A.V. Galston. 1982. BXects of exogenous 1 ,3-diaminopropane and spermidine on senescence of sat leaves. II. Inhibition of ethylene biosynthesis and possible mode of iction. PI. Physiol. 70: 1597-1600. Galston, A.V. and R. Raur-Sawhney. 1982. Polyamines: Are they anew class of plant growth regulators? Plant Growth Substances 1982. Aademic Press, pp. 451-461. Galston, A.V., H.E. Flores and R. laur-Sawhney. 1982. Polyamine formation by arginine decarboxylase as a transducer of hormonal, environmental and stress stimuli in higher plants. The Physiologist 25 (6): SS7-138. Geballe, G.T. and A.V. Galston. 1982. Vound-indnced resistance taeellulase in oat leaves. Plant Physiol. 70: 781-787. Geballe, G.T. and A.V. Galston. 1982. Ethylene as an effector oiseundinduced resistance to cellulose in oat leaves. Plant Physiol..70: 788-790. Goren, R . , N. Palavan and A.V. Galston. 1982. Seperating phytochasae effects on arginine decarboxylase activity from its effect on growth. J. Plant Growth Regnl. 1: 61-73. Goren, R . , N. Palavan, H. Flores and A.V. Galston. 1982. ChangesS> polyamine titer in etiolated pea seedlings following red light treatment. Plant and Cell Physiol. 23: 19-26. Raur-Sawhney, R . , L.X. Shih and A.V. Galston. 1982. Relation of jqiyamine biosynthesis to the initiation of sprooting in potato tubers, ant Physiol. 69: 411-415. Page 28 a o C'Q *' Eaur-Sawhney, R. , L.X. Shih, T. Cegielska and A.F. Galston. 1982. Inhibition of protease activity by polyamines. Relevance for control of leaf senescence. FEBS Lett. 145: 345-349. Raur-Savhney, R. , L.X. Shih, H.E. Flores and A.F. Galston. 1982. Relation of polyamine synthesis and titer to aging and senescence in oat leaves. Plant Physiol. 69: 405-410. Palavan, N. and A.F. Galston. 1982. Polyamine biosynthesis and titer during various developmental stages of Phaseolns vulgaris. Physiol. Plant 55: 438-444. Shih, L.X. , 2. Ranr-Savhney, J. Fhrer, S. Samanta and A.F. Gals to*. 1982. Effects of exogenous 1 ,3-diaminopropane and spermidine on senescence of oat leaves. I. Inhibition of protease activity, ethylene production, and chlorophyll loss as related to polyamine content. Plant Zhysiol. 70; 1592- 1596. Slocum, R.D. and A.F. Galston. 1982. A comparative study of monocat and dicot root development in normal (earth) and hypogravity (space) environments. The Physiologist 25(6): S131-132. Racusen, E.H. and A.F. Galston. 1981. Phytochrome modifies blue-lightinduced electrical changes in corn coleoptiles. Plant Physiol. 66: 534-535 Dai, Y. and A.F. Galston. 1981. Simultaneous phytochrome-- controlled promotion and inhibition of arginine decarboxylase activity in buds and epicotyls of etiolated pea*. Plant Physiol. 67: 266-269. Flores, H.E., R. Ranr-- Sawhnoy and A.F. Galston. 1981. Protoplasts as vehicles for plant propagation and improvement. in R. Maramorosch (ed). Advances in Cell Culture 1: 241-279. Academic Press, N.Y. Raur-- Sawhney, R. and A.F. Galston. 1981. On the physiological sipdficance of polyamines in higher plants. Recent Developments in Plant Sciences, pp. 129-144. Raur-- Savhney, R. , H.E. Flores and A.F. Galston. 1981. Polyamine cxidase in oat leaves: A cell vall-localized enzyme. Plant Physiol. 63: 494-498. Satter, R.L. and A.F. Galston. 1981. Xechanisms of control of leaf movements. Ann. Rev. Plant Physiol. 32: 83-110. Satter, R.L., S.E. Guggino, T.A. Lonergan and A.F. Galston. 1981. The effoct* of blue and far red light on rhythmic leaflet movements in Sananea and Albixxia. Plant Physiol. 67: 965-968. Flores, H.E. and A.F. Galston. 1980. Tissue culture of Amarsnth: Initial results and prospects. JLn Proceedings of the Second Amsrsnth inference, 1979. Rodale Press, Inc., pp. 105-108. " Galston, A.F. 1980. Circumnntstion. rhythms and light-regulated scfeaents in plants. JLn Plant Grovth Substances 1979. Ed. by F. Shoog. Proceedings of the 10th International Conference on Plant Grovth Substances, Xadison, Tisconsin. July 22-26. Springor-Verlag, Berlin Heidelberg, Nv York pp. Page 29 13340 437-443. Galston, A.f. 1980. Herbicides. _in Academic American Encyclopedia. Arete Pnbliahin* Co., Inc., Princeton Forrestal Center., Princeton. N.J. Galston, A.f. and R. tanr-Sawhney. 1980. Polyaaines and plant cells. That's New in Plant Physiology 11: 5-8. Kaur-Sawhney, R., H.E. Flores and A.f. Galston. 1980. Polyamine-indnced DNA synthesis and mitosis in oat leaf protoplasts. Plant Physiol.* 65: 368-371. Galston, A.f. 1979. Herbicides: A mixed blessing. Bio.Science 29: 85-90. Galston, A.f. and C.L. Slayman. 1979. The not-so secret life of plants. American Scientist 67: 337-344. Galston, A.f., R. lanr-Sawhney, A. Altman and H. Flores. 1979. Polyamines, l amacromolecular syntheses and the problem of cereal protoplast regeneration. Advances in Protoplast Research. Proceedings of the 5th International Protoplast Symposinm, Szeged, Hungary, July 9-14. Aiademiai Hi ado pp. 485-497. Kaur-Savhney, R. and A.f. Galston. 1979. Interaction of polyamines and light on biochemical processes involved in leaf senescence. Plant, Cell and Environment 2: 189-196. 1979 Galston, A. W. Herbicides: A mixed blessing. 3I0SCIEJCE Vol. 20 (3): 85-90, 1979. Page 30 CONTINUED BIBLIOGRAPHY OF ARTHUR W. GALSTON 1977 Racusen, R. H. and A. W. Galston. Electrical evidence for rhythmic changes in the cotransport of sucrose and hydrogen ions in Samanea pulvini. PLANTA (BERL) 134(1): 57-62. 1977. Satter, Ruth L., Martin Schrempf, Javade Chaudhri and Arthur W. Galston. (Dep. Biol., Yale Univ., New Haven, Conn. 06520, USA.) Phytochrome and circadian clocks in Samanea: Rhythmic redistribution of potassium and potassium and chloride within the pulvinus during long dark periods. PLANT PHYSIOL (BETHESDA) 59(2): 231-235. 1977. Rancillac, Michael, Ravindar Kaur-Sawhney, Brian Staskawicz and and Arthur W. Galston. Effects of cycloheximide and kinetin pretreatments on responses of susceptible and resistant Avena leaf protoplasts to the phytotoxin victorin. PLANT CELL PHYSIOL 17(5): 987-995. 1976. Simon, Satter, and Arthur W. Galston. Circadian rhythmicity in excised Samanea pulvini: II. Resetting the clock by phytochrome conversion. PLANT PHYSIOL (BETHESDA) 58(3): 421-425. 1976. Fuchs and Arthur W. Galston. Macromolecular synthesis in oat leaf protoplasts. PLANT CELL PHYSIOL 17(3): 475-482. 1976. Schrempf, Satter and Arthur W. Galston. Potassium-linked chloride fluxes during rhythmic leaf movement of Albizzia julibrissin. PLANT PHYSIOL (BETHESDA) 58(2): 190-192. 1976. 1976 Kaur-Sawhney, Rancillac, Staskawicz, Adams and Arthur W. Galston. Effect of cycloheximide and kinetin on yield, integrity and metabolic activity of oat leaf protoplasts. PLANT SCI LETT 7(1): 57-67. 1976. Satter, Applewhite, Chaudhri and Arthur W. Galston. Pfr phytochrome and sucrose requirement for rhythmic leaflet movement in Albizzia. PHOTOCHEM PH0T0BI0L 23(2) : 107-112. 1976. Reid and Arthur W. Galston. Experiments on the isolation and cultivation of protop Lasts and calli from agriculturally important plants: II. Soybean(Glycine max L.) BIOCHEM PHYSIOL PFLANZ (BPP) 168(5.6): 473-482. 1975[recd. 1976.] Brenneman and Arthur W. Galston. Experiments on the cultivation of protoplasts and calli of agriculturally important plants: I. Oat (Avena sativa L.) Biochem Physiol Pflanz (BPP) 1968(5/6): 453-457. 1975[reed. 1976]. 4 AO A 1975 Lisansky and Arthur W. Galston. Phytochrome stability in vitro: II. A low molecular weight protective factor. PLANT PHYSIOL 57(2): 188-191. Ulus. 1976. Novak and Arthur W. Galston. Control of in vivo protein synthesis and peroxidase formation by DNA-containing extracts of noraal and crown gall tissues. PHYTOCHEMISTRY (OXF) 14(1): 49-56. Ulus. 1975. Satter, Gebalie, Applewhite and A. W. Galston. Potassium flux and leaf movement in Samanea Saman: I. Rhythmic movement. J GEN PHYSIOL 64(4): 413-430. Ulus. 1974. Satter, Gebalie and A. W. Galston. Potassium flux and leaf movement in Samanea Saman: II. Phytochrome controlled movement. J GEN PHYSIOL 64(4): 431-442. Ulus. 1974. Satter, Applewhite and Arthur W. Galston. Rhythmic potassium flux in Albizia: Effect of animophylline, cations, and inhibitors of respiration. PLANT PHYSIOL 54(3): 280-285, Illus. 1974. 1974 Whitney R., Jr. and Arthur W. Galston. Differential effects of ethylene on pith peroxidase of intact tobacco plants aari excised tissue. PLANT PHYSIOL 53(6): 1931-933. Illus. 1974. Lisansky and A. W. Galston. Phytochrome stability in vitro: I. Effect of metal ions. PLANT PHYSIOL 53(3): 352-359. Illus. 1974. Applewhite, Satter and A. W. Galston. Protein synthesis doting endogenous rhythmic leaflet movement in Albizia. J GEN PKESIOL 62(6): 707-713. Illus. 1973. Satter, Applewhite, Kreis and A. W. Galston. Rhythmic lealet movement in Albizia julibrissin: Effect of electrolytes aed temperature alteration. PLANT PHYSIOL 52(3): 202-207. Illas. 1973. 1973 Satter, A. W. Galston. Leaf movements: Rosetta stone of plant behavior? BIOSCIENCE 23(7): 407-417. Illus. 1973. Satter, Applewhite and A. W. Galston. Phytochrome-controDed nyctinasty in Albizzi julibrissin: V. Evidence against acetycholine participation. PLANT PHYSIOL 50(4): 523-525. 1972. JOHN A. GAROFALO, M.D. I. QUALIFICATIONS See attached curriculum vitae. II. SUBJECT MATTER The subject matter of Dr. Garofalo's testimony will per tain to the field of immunology. He will elaborate on the effect that Agent Orange (dioxin) can have on the immune system. III. GENERAL SCIENTIFIC PRINCIPLES The field of immunology involves the study of how the body responds to antigenic (foreign) stimulation. Peripheral blood lymphocytes are made up of B-cells; T-cells; and T cell subsets (also referred to as the immunoregulatory cells of the immune system). During the past two decades, the field of immunology has recorded a number of dramatic advances. The most significant of which have been the recognition of the various classes of T and B lymphocytes, hybridoma technology (provides a reliable and consis tent method for providing large quantities of monoclonal antibodies directed against specific cell surface antigens) and the technological advances in flow cytometry. T lymphocytes (65-85% of lymphocytes) are responsible for a spectrum of immune responses referred to as cell-mediated immunity which in clude delayed hypersensitivity; allograph rejection; tumor cyto toxicity, whereby they destroy host cells bearing foreign anti gens; and cell-mediated resistance to infectious agents (fungi, viruses, and intracellular faculative bacteria). Two functionally 133 distinct subsets of T cells have been defined with monoclonal antibodies. T 4 + cells represent the helper/inducer population 38-53%) whereas T8+ cells represent the suppressor/cytotoxic pop ulation (18-30%) (cytotoxic refers to the major effector functions of T cells, the capacity to kill specific cells to which they are sensitized). T4+ (helper/inducer) cells regulate the immune re sponse by means of cell-cell interactions as well as by producing biologically potent regulatory molecules. T4 + cells provide indu cer function in T-T cell (required for optimal development of cy totoxicity by the T8+ c e l l s ) ; T-B cell (induces B cells to pro liferate and differentiateinto immunoglobulin containing plasma); and T-macrophage interactions. T4+ cells produce humoral factors such as lymphocyte mitogenic factor, which induces proliferation of all major lymphocyte subclasses. Antigen stimulated T4+ cells produce helper factors that modulate erythroid stem-cell production and are important in hematopietic differentiation. T8+ cells con tain cells with suppressor/cytotoxic functions. This subset suppresses B cell immunoglobulin synthesis and has the capacity to kill cells to which they are sensitized. B lymphocytes are cells coded to product immunoglobulins, which are proteins found in blood and various secretions. B cells product Ig which belong to four major g o r u p s : IgG - responsible for defense against bacterial infections i.e. pneumonia and strep throat; IgM - responsible for the defense against anerobic bacterial infections i.e. bowel pathogens; IgA - defends us against viral infections and is found in large quantities in our secretions; IgE - responsible for our defense against allergens. 2- - HYBRIDOMA TECHNOLOGY -- The advent of hybridome technology has pro vided a new approach to immunology research. With its application monoclonal antibodies capable of recognizing with precision the functional components of the immune system provide the medical community with highly specific reagents for the study of T lympho cyte maturation and for the identification of T lymphocyte syb- populations. ORTHO SPECTRUM III utilizes the observation that human lymphocytes, monocytes and granulocytes posses different light scattering characteristics. Cells undergoing analysis travel in single file through a quartz cuvette where they intersect a nar rowly focused 488nm wavelength beam of light from an argon-ion laser. The illuminated cells scatter the light in all directions. A so 1 i d-stintn sen so r m l le e r s low .irujln forward s c a t t e r to d is c r im inate size of cells, and a photomultiplier tube (PMT) set at 90. These signals produce a histogram of cells counted based on in tensity of green fluorescence. Analysis of peripheral blood samples is performed using whole blood. The cells are labeled by direct immunofluorescence, in which the monoclonal antibody directed against the desired cell surface antigen is conjugated with a flourescent dye, or by indirect immunofluorescence, in which the monoclonal antibody, having been found to the cell surface, is visualized with a second fluoresceinated antibody directed against the monoclonal immunoglobulin. i Q q *.C J V Xj In the evaluation of lymphocyte populations both per centages and absolute values are taken into consideration. The mechanism of how abnormal lymphocyte populations affects the im- mune response will be set out. The basic theorem is that changes in lymphocyte populations are suggestive of disease processer and often but not universally relate to dysfunction. For the purposes of this litigation, it is important to distinguish between immune deficiencies and immuno-suppression. Suppression referring to an acquired immune deficiency that can be the result of exposure to chemical toxins. Dr. Garofalo has had particular clinical experience rele vant to this litigation. He has, since December, 1983, examined about thirty-five (35) Vietnam veterans for Agent Orange-related immune abberations. To the best of his knowledge, the published literature does not contain any reports of data comparable to that which he has acquired. A general review of his date indicates that the Vietnam veterans exposed to Agent Orange have slightly elevated levels of lymphocytes, with particular reference to T helper cells. There is even some elevation of suppressor T cells. IV. SUBSTANCE OF OPINIONS 1. Agent Orange can affect the immune system by produ cing changes in the numbers and distribution of T cells, T helper cells, and T suppressors cells, though it is much more likely that it has its effect through changes in the latter two types of cells. 2. The effect on helper T cells may result in a h e i g h tened immune response, leading to the formation of auto-immune diseases. These in turn may lead to excess cancer formation, arthritis, and nerve damage, the latter including both central .1XSw'0-'* -4- nerve damage and peripheral neuropathy, of which the "dying back" variant is typical. 3. Agent Orange can cause an excess of T8+ cells (suppressor/ c y t o t o x i c ) . This may represent an increase in either the suppressor population which in turn can interfere with helper T cell and B cell function or the cytotoxic cell population which have the capacity to kill specific cells to which they are sensi tized . 4. Agent Orange may act as an antigen bound to body tissues resulting in the formation of autoantibodies and cytotoxic cells directed against the sensitized tissue. Auto Antibody: "Auto" refers to self; "Antibody" refers to a protein formed by the immune system in a response to antigen exposure. An autoantibody is thus an antibody that is formed within a person against their own tissues, i.e., red blood cells, platelers, nerve tissue, skin). 5. Individual opinions concerning the representative plaintiffs are contained in their individual reports. V. GROUNDS FOR OPINIONS Dr. Garofalo will rely upon his own experience in the evaluation of other veterans he has evaluated in the past or whom he will evaluate in the future, and upon the attached list of articles. -5- ARTICLES UPON WHICH DR. GAROFALO MAY RELY IN WHOLE, OR IN PART, ARE: J. Hopkins Dioxin: Carcinogenicity FD. COSMET. TOXICOL. 1980 Voi. 18, pp. 739-741 J. Hopkins, P. Cooper Dioxin Dangers to Man FD. COSMET. TOXICOL. 1980 Vol. 18, pp. 541-546 J. E. Huff, J. A. Moore, R. Caracci and L. Tomatis Long-Term Hazards of Polychlorinated Dibenzodioxins inated Dibenzofurans ENVIRONMENTAL HEALTH PERSPECTIVES 1980 Vol. 36, pp. 221-240 and Polychlor David Paen & Edward Glover Our Promotion by O in Skin of MACMILLAN JOURNAL November 18, 1982 Vol. 300, pp. 271-273 HRS/J Hairless Mice G. Reggiani, F. Hoffmann Acute Human Exposure to TCDD in Seveso Italy JOURNALOF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1980 Vol. 6, pp. 27-43 Michael I. Luster, Gary A. Boorman, Jack H. Dean, Martha W. Harris, Robert W. Luebke, M a rtin L. Padarathsingh and John A. Moore Examination of Bone Marrow, Immunologic Parameters and Host Susceptibility Following Pre- and Postnatal Exposure to 2,3,7,8Tetrachlorodibenzo-p-Diox in (TCDD) INT. J. IMMUNOPHARMACY 1980 Vol. 2, pp. 301-310 Willi a m G. Dunagin, M.D. Dioxin Effects on Human Health MISSOURI MEDICINE March, 1983 Vol. 80, No. 3, pp. 127-131 -6 - 19348 R. P. Sharma, P. J. Gehring Effects of 2,3, 7 , 8-Tetrachlorodibenzo-p-Dioxin (TCDD) On Splenic Lymphocyte Transformation in Mice After Single Repeated Exposures ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 487-497 and S. J. Stohs, M.Q. Hassan and W. J. Murray Lipid Peroxidation as a Possible Cause of TCDD Toxicity BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS March 29, 1983 Volume 111, No. 3, 1984, pp. 854-859 David A. Clark, Jack Gauldie, Myron R. Szewczuk and George Sweeney Enhanced Supressor Cell Activity as a Mechanism of Immunosuppres sion by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (41275) PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 19 81 pp. 290-299 Graziella Filippini, M.D., Bianca Bordo, M.D., Paolo Crenna, M.D., Nicoletta Massetto, M.D., Massimo Musicco, M.D., Renato Boeri, M.D. Relationship Between Clinical and Electrophysiological Findings and Indicators of Heavy Exposure to 2,3,7,8-Tetrachlorodibenxodioxin SCAND J WORK ENVIRON HEALTH 1981 Voi. 7, pp. 257-262 C. M. Bishop, A. H. Jones Non-Hodgkin's Lymphoma of the Scalp in Workers Exposed to Dioxins THE LANCET August 15, 1981 p . 369 Jana Pazderova-Vejlupkova, M.D., Marcela Nemcova, Ph.D., Jane Pickova, Ph.D., Lubor Jirasek, Ph.D., Edgar Lukas, Ph.D. The Development and Prognosis of Chronic Intoxication by Tetrachlordibenzo-p-dioxin in Men ARCHIVES OF ENVIRONMENTAL HEALTH January/February, 1981 Vol. 36, No. 1, pp. 5-11 -7- Henry C. Pitot, Thomas Goldsworthy, H. A. Campbell, and Alan Poland Quantitative Evaluation of the Promotion by 2,3,7,8,-Tetrachlorodibenzo-p-dioxin of Hepatocarcinogenesis from Diethylnitrosamine CANCER RESEARCH October, 1980 Vol. 40, p p . 3316-3620 J. G. Vos, J. G. K r e e f t e n b e r g , H. W. B. Engle, A. Minderhoud and L. M. Van Noorle Jansen Studies on 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Induced Immune Suppression and Decreased Resistance to Infection: Endotoxin Hypersensitivity, Serum Zinc Concentrations and Effect of Thymosin Treatment TOXICOLOGY 1978 V o l . 9, pp. 75-86 Michael I. Luster, Robert E. Faith and George Clark Laboratory Studies on the Immune Effects of Halogenated Aromatics ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 473-483 Ralph R. Cook Dioxin, Chloracne, THE LANCET March 14, 1981 and Soft Tissue Sarcoma A. Mantovani, A. Vecchi, W. L u i n i , M. sironi, G. P. C a n d i a n i , F. Spreafico and S. Farattini Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on Macrophage and Natural Killer Cell-Mediated Cytotoxicity in Mice BIOMEDICINE 1980 Vol. 32, pp. 200-204 Michael I. Luster and Robert E. Faith Assessment of Immunologic Alterations Caused by Halogenated Aromatic Hydrocarbons ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 572-577 i 1 3 3 ru x-i 8- - John A. Garofalo, M.D. 847 Old Lancaster Road Bryn Mawr, PA 19010 Date of Birth: August 15, 1946 SPECIALTY: Hematology - Oncology - Immunology AFFILIATIONS : Assistant Professor of Medicine Thomas Jefferson University Hospital Philadelphia, Pennsylvania Assistant Attending Department of Medicine Bryn Mawr Hospital Bryn Mawr, Pennsylvania EDUCATION: 1977-1980 1977-1980 1976-1977 1975-1976 1974-1975 1969-1974 1964-1969 Clinical Fellow - Immunology - Oncology Memorial Sloan Kettering Cancer Center New York, New York. Research Fellow - Immunobiology Memorial Sloan Kettering Cancer Center New York, New York. Medical Resident - Pennsylvania Hospital, Philadelphia, Pennsylvania. Medical Intern, Philadelphia General Hospital Philadelphia, Pennsylvania. Research Fellow - Immunobiology, Memorial Sloan Kettering Cancer Center New York, New York. University of Rome, Faculty of Medicine. Oklahoma State University, Stillwater, Oklahoma - Bachelor of Science in Physiology. 1983 1983 Medical Director - Home Cancer Care, INC. Home Health Care Agency Medical Director - Immunodiagnostics Clinical Laboratories, INC., Reference Immunology Laboratory. BIBLIOGRAPHY John A. G arofalo I . L it e r s to the E d ito r 1. AHJTI, F . , GAROFALO, J . A . : Rectal irr.n'.ur.og1obul in syn th esis in u lc e ra tive c o l i t i s . To The E d ito r: New Ennland Journal of Medicine vol 287, Na. 22, 1151 , 1972. ------------------------------------------- 2. GSvQFALO, J . A . , STRONG, ., GOOD, R. A. : Zinc and in te s tin a l bypass procedures. To the E d ito r: Annals of In te rn a l M edicine, June 1979. I I . Abstracts li G/at-AL, iA,, CiiNrli^Nufii'.i,i-K!jfjwLi-.A, S ih viir-iffnets nf zinc chloride on lymphocyte transform ation Fed. Proc. 37( 6) , 31 54, 1978. 2 . GSSFALO, J . A . , STRONG, E . , CUNNINGMAM-RUNDLES, S . , ERLANDSON, E . , KESENDEZ-BOTET, C ., SCHWARTZ, M ., GOOD, R . A . : Serum zinc ir, p a tien ts with epidermoid cancer of the head and ~eck. Fed. Proc. 38( 3) , 2561. 3. CUHINGHAM-RUNDLES, C ., CUN.NINGKAM-RUNDL ES, $ ., GAROFALO, J . , IWATA, T ., INCEFY, G ., TWOMEY, J . , GOOD, R. A. : Increased T lymphocyte func tion and thymonoietin fo llo w in g zin c replacement in man. Fed. P ro c. 38(3), 5259, 1979. 4. CUKINGHAM-RUNDLES, S . , CUNNINGHAM-RUNDLES , C . , GAROFALO, J., DUPONT, B ., GOOD, R . A . : E f f e c t of zin c on human B c e ll a c tiv a tio n . Fed. Pro c. 33(2), 3735, 1979. 5 . ' GAJSfALO, J . A . _et a_l_.: Serum zinc and copper and the Cu/Zu r a t io in patients w ith can cer. AACR/ASCG, 733, 1980. 11. Publications 1. AUm , F . , LACAVA, V ., GAROFALO, J . A . , 0 *AMELIO, R . , D`ASERO, C .: Surface markers on human lymphocytes: Studies of normal su b je cts and of patients w ith primary im m unodeficiencies. C l i n . Ex p . Immunol. 15: 43-52, 1973. 2. AILTI, F . , CIARLA, K . V . , D1ASERO, C ., 0 'AMELIO, R ., GAROFALO, J . A . : Surface markers on lymphocytes of p a tie n ts w ith in fe c tio u s d ise a se s. Infection and Immunity 8(1 ) , 110-117 , 1973. 3 . A lim , F . , PAPA, G ., LACAVA, V ., CIARLA, M. V. , D*AMELIO, R ., GAROFALO, J . : Lymphocyte membrane markers in acute lym phoblastic leukem ia. B r i t . J . Baem, 27, 635, 1974. 4 CUHINGHAM-RUNDLES, S., DE SOUSA, M ., GAROFALO, J.A., BOGNACKI, J.J., LEE, 5.J., DUPONT, B., GOOD, R.A.: D iff e r e n t ia l a n a ly sis of spontaneous uptake of thymidine and t r a n s fe r r in by mononuclear c e lls in v it r o in Hodkin's d ise a s e . 13th In te rn a tio n a l Leukocyte Con;erence, 1979. 13353 5. SCHLOEN, L.H., FERNANDES, G., GAROFALO, J.A., GOOD, R.A.: Nutrition, Immunity and Cancer - A Review, Part II. Clinical Bulletin, 9, #2, 1979. 6. GAROFALO, J.A., CUNNINGHAM-RUNDLES, S., BRAUN, D.W., GOOD, R.A. : In Vitro Effect, of Zn'r"r on Peripheral Blood Lymphocytes in Patients with Cancer. Inter. J. of Immunopharmacology, 2, 37-44, 1980. 7. GAROFALO, J.A., ASHIKARI, K., LESSER, M., MENENDEZ-BOTET, C., CUNNINGKAM-RUNDLES, S., SCHWARTZ, M.K., GOOD, R.A.: Serum Zinc, Copper and the Cu/Zn Ratio in Patients with Benign and Malignant Breast Lesions. Cancer, 46, 2, 26S2-2685, 1980. 8. GAROFALO, J.A., ERLANDSON, E ., STRONG, E., LESSER, M ., GEROLD, F., SPIRO, R., SCHWARTZ, M . , GOOD, R.A.: SErum Zinc, Serum Copper and the Cu/Zn Ratio in Patients with Epidermoid Cancer of the Head and Neck. J. of Surgical Oncology, Vol. 15, issue 4, 381-386, 1980. 9. SCKULOF, R.S., GAROFALO, J.A., GOOD, R.A., GUPTA, S.: Concanavalin A Induced Suppressor Ceil Activity for T Cell Proliferative Responses: Autologous and Allogenic Suppression in Aging Humans. Cellular Immunoloqv, 56, 80-88, 1980. 10. GOOD, R.A., FERNANDES, G., CUNNINGHAM-RUNDLES, C., C'JNNINGHAM-RUNDLES, S., GAROFALO, J.A., RAO, K., INCEFY, G.S., IWATA, T.: The Relation of Zinc Deficiency to Immunologic Function in Animals and Man. In Pr imary Immunodeficiencies, Inserm Symposium No. 16, 223-234, Editors: M. Seiigmann and W.K. Hitzig, Biomedical Press, 1980 . 11. GOOD, R.A., FERNANDES, G., GARCFAL^, ...A., CUNNINGHAMRUNDLES, C., IWATA, T., WEST, A.: Zinc ana Immunity. In: International Conference on Cxi icai and Public Health Significance of Trace Minerals in tr.e World Population, Detroit, 1980; Proceedings (A.S. Prasad, ed.), New York, Alan R. Liss. 13354 LEN N ART H AR D ELL, M .D ., Ph.D . I. QUALIFICATIONS Dr. Hardell is employed by the University Hospital in its Department of Oncology in Umea, Sweden, where he specializes in intern medicine and oncology. His work includes diagnosis, treatment, and evaluation of possible causes of cancer, and education of medical students. His Curriculum Vitae is attached. A list of seminars is also attached. II. Subject Matter Dr. Hardell will testify to several epidemiological studies which he and his colleagues have conducted in Sweden. This research includes investigations concerning the relationship between the risk for different types of cancer and exposure to phenoxy herbicides and chlorophenols. The research has been published in the medical and scientific literature. These studies utilized the case-control study as th e vehicle for investigation. Certain methodological aspects, such as selection of cases, selection of controls, assessment of exposure, and statistical methods, were considered; and then utilizatioa was based upon thoroughly considered aspects of bias, all of which sere well controlled. 13355 Dr. Hardell has also seen in his clinical practice basal cell carcinoma of persons previously exposed to phenoxy herbicides, with no other known confounding variables. III. Scientific Principles See General Statement of Scientific Principles and Assumed Facts attached. Dr. Hardell will use as a factual base for his testimony his hands-on diagnoses and treatment of various cancer victims as well as his review of the medical records and examinations of cases involved in his epidemiological studies. His additional clinical experiences also form a factual basis for his testimony, especially those patients with basal cell carcinoma. Dr. Hardell will also review the medical records of George Ewalt, Danny Ford, and David Lambiotte for the opinions which he will express regarding the causation (in the legal sense) and their exposure to Agent Orange and basal cell carcinoma, rhabdomyo sarcoma (form of soft tissue sarcoma) and malignant lymphocytic lymphoma. 13358 IV. Substance of Opinions A. Specifically, Dr. Hardell's studies, four in number, involved soft tissue sarcomas, malignant lymphomas, and colon cancer. Highly statistically significant risks of soft tissue sarcomas and malignant lymphoma were found, whereas no association was found for colon cancer. In point of fact, the negative finding for colon cancer strongly supports the statistical significance of the increased risk demonstrated for soft tissue sarcomas and malignant lymphomas, and that there exists a presumed causal relationship between exposure to phenoxy herbicides and human cancer, particularly of soft tissue sarcoma and malignant lymphoma. B. With respect to those cases with soft tissue sarcoma, malignant lymphoma, and basal cell carcinomas, Dr. Hardell will testify that the presumed exposure to Agent Orange caused, in significant part, such neoplastic processes. V. Grounds for Each Opinion A. General The bases for Dr. Hardell's testimony as to various facts and opinions include: educational background, professional training, and experience; diagnosis and treatment of patients, review of the applicable medical and scientific literature; personal research; and a review of the pertinent medical data of the relevant representative plaintiffs. B. S p e c i f i c 1. Soft tissue sarcomas and malignant lymphoma References : Cook RR (1981): Dioxin, chloracne, and soft-tissue sarcoma. Lancet i. 618-619. Eriksson M, Hardell L, Berg NO, Moller T, Axelson 0 (1981): Soft-tissue sarcomas and exposure to chemical substances; a case-reference study. Br J Ind Med 38: 27-33. Hardell L (1979): Malignant lymphoma of histiocytic type and exposure to phenoxyacetic acids or chloropheno1s . Lancet i: 55-56. Hardell L (1981): Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chloropheno1s and other agents. Scand J Work Environ Health 7: 119-130. Hardell, L, Sandstrom A (1979): Case-control study; softtissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer 39: 711-717. Hardell L, Eriksson J, Lenner P, Lundgren E (1981): Malignant lymphom.' and exposure to chemicals, especially organic solvents, chlorophenols and phenoxy acids; a case-control study. Br J Cancer 43: 169-176 Honchar PA, Kalperin WE (1981): 2,4,5-T trichlorophenol, and soft tissue sarcoma. Lancet i: 268-269. Johnson F E , Kugler M A , Brown SM (1981): soft-tissue sarcomas and chlorinated phenols. Lancet I: 1370. Moses M, Selikoff IJ (1981): soft-tissue sarcomas, phenoxy herbicides and chlorinated phenols. Lancet i: 1370 Pitot HC, Golds worthyT, Poland H (1980): Promotion by 2,3, 7 ,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. Cancer Res 40: 3616-3620. Poland A, Palen D, Glover E (1982): Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300: 271-273. Sarma PR, Jacobs J (1982) Thoracic soft-tissue sarcoma, in Vietnam veterans exposed to agent orange. N. Engl J. Med 306: 1109 13358 2. Basal Cell Carcinoma Case history: Woman born in 1946. In 1964 operated for a cyst on one of her ovaries. No other diseases. In the end of the 1960's she developed a blister on her left shoulder and in the 1970's several ones on her back. In June 1977, two basal cell carcinomas were surgically removed from her back. In September 1977 nine more and in December 1977, two more basal cell carcinomas were excised from her back. In January 1983 one basal cell carcinoma on her shoulder and another on her back were cured by radiotherapy. In October 1983 five tumors were removed from her back; two basal cell carcinomas and three basal cell carcinomas in situ. During summertime in 1959, 1960, and 1961 the patient afforested for one month each summer. The seedlings were treated with DDT. Moreover, she carried water for the dilution of phenoxy acids used by back pack sprayers. She walker in newly sprayed areas. In 1960 she used to basal bark spray for six weeks and in 1961 for two weeks. The chemical used was a combination of 2,4,5-T and 2,4,-D. She was thereby stripped to her waist but for a brassiere. She used no gloves . The patient reported no heredity for basal cell carcinoma. She had not used any special drugs or been exposed to arsenic. i Xw00 0 Curriculum Vitae Lennart Hardell M. D. , Ph. D. Department of Oncology, U n iv e rs ity Hospi t al , S-901 85 UMEA, Sweden Born in October 18, 1944. Medical degree from U n iv e rs ity of Upsala, Sweden October 27, 1971. A utho rizatio n to p ra c tic e the. medical p ro fe ssio n , National Board of Health and W eifar^ S^ cirhoTnvflkJvem ber 5, 1971. S p ecialized in in te rn a l medicine October 18, 1976. S p ecialized in oncology, June 20, 1979. Medical d is s e rta tio n U n iv e rs ity of Ume, May 15, 1981. D ire c t testimony before the United S ta te s Environmental Pro tectio n Agency in the matter of the hearing of 2 , 4 , 5 - T and S i l v e x , Washington DC, September 29-30 1980 and February 9, 1981. R eceiver of the Fernstrom Award, U n iv e rs ity of Ume, October 9, 1982. D elivered by the King Carl XVI G ustaf of Sweden. Member of "Expert Panel on Dioxin Documents", United S ta te s Environmental P ro te ctio n Agency, C in c in n a ti, Ohio, J u ly 27-29, 1983. Q u a lifie d fo r A sso ciate P ro fe sso r of oncology, U n iv e rs ity of Ume, December 9, 1983. Member of the Swedish Medical A sso cia tio n . Member of Nordic Radiotherapy Club Member of Swedish A sso ciatio n of Radiotherapy Member of Swedish A sso ciatio n of Oncology Member of Swedish Epidem iological A sso ciatio n 123P.Q Appointments by Or Lennart H ardell A fte r au th o rizatio n worked a s: General p r a c t it io n e r , Prim ary Health Centre, Haparanda, November 1 1971 - August 31 1972. Ju n io r r e g is t r a r , Department of P s y c h ia try , County H o sp ita l, K ristineh am n , September 1-30, 1972. Ju n io r r e g is t r a r , Department of P s y c h ia try , County H o sp ita l, Boden, October 1 - December 31 1972. From January 1 1973 to August 31 1976 vario us appointments as Ju n io r r e g is t r a r , Senior r e g is t r a r and co nsu ltant at the Department of In te rn a l Medicine, County H o sp ita l, Boden. From September 1 1976 vario us appointments as a Ju n io r r e g is t r a r , Senior r e g is t r a r and co nsu ltant at the Department of Oncology, U n iv e rs ity H o sp ita l, Umea. September 1 - December 31 1983 Head and co n su lta n t, Centre of Oncology, U n iv e rs ity H o sp ita l, Umea. For the moment appointed as co nsu ltant at the Department of Oncology, U n iv e rs ity H o sp ita l, Umea, Sweden. 13361 COURSES tN WHICH DR LENNART HARDELL HAS PARTICIPATED Cardiology Hypertonia, hypotonia and blood vessel diseases Lung d ise a se s, e s p e c ia lly astma, autoimmune and work re la te d lung diseases Gastroenterology and liv e r diseases Acute medicine Hematology, nephrology Course in endocrinology In tra th o ra c a l tumours In fe c tio u s d iseases and a n tib io tic therapy Cancer epidemiology, cancer s t a t i s t ic s and e a rly diagnoses of cancer Postgraduate course in c lin ic a l oncology, so ft tissu e sarcomas, plasma c e ll tumours, cancer of the esophagus and stomach B io lo g ic a l and medical e ffe c ts of irra d ia tio n , course for oncologists B io s ta tic s in epidemiology, methods and a p p lic a b i1it y Therapy with c y t o s ta t ic drugs and hormones of malignant tumours and o rie n ta tio n about progress in tumour immunology Cancer epidemiology Radiation physics for oncologists U n iv e rs ity of Lund Regional H ospital of Malmo U n iv e rsity of Upsala U n iv e rs ity of Gothenburg Regional H ospital of rebro U n iv e rsity of Linkping Karolinska In stitu te , Stockholm Regional H ospital Huddinge U n iv e rs ity of Gothenburg Karolinska In s titu te , Stockholm Royal Marsden H o sp ita l, The Chester B eatty Research I n s t it u t e , London Karolinska In stitu te , Stockholm U n iv e rs ity of Umea Karolinska In stitu te , Stockholm IARC, Lyon, France Karolinska In s titu te , Stockholm A p ril 2-6 1973 November 5-9 19/ March 11-15 197^ May 13-17 1974 November 18-22 1 A p ril 7-11 1975 November 3-7 197 February 23-27 11 February 15-19 1: October 11-15 19. November 14-18 19- May 2-6 1977 March 11-18 1978 May 8-12 1978 J u ly 31-August 11 October 2-6 1978 0, o ^ 1 Clinical oncology II and radiation therapy Cl in ic a l oncology I Course on epidem iological approach to occupational cancer Methods of epidemiology University of Lund U n iv e rs ity of Ume IARC, Lyon, France U n iv e rs ity of Umea October 16-20 1 March 19-23 197! March 17-21 198' Course fo r threr weeks June 1980. P u b iicatio n s 1. H ardell L . Maligna mesenkymala mjukdelstumrer och expo sitio n fo r fe n o xisyro r - en k l i n i s k o b servatio n . Lkartidningen 71 ( 1977 ) 2753-2754. (In Swedish, English summary) 2. H ardell L . Kemiska substanser och maligna mesenkymala tumorer. Svensk f re n in g f r medicinsk ra d io lo g i. Fdrhandlingar nr 9 (1978) 18-21. (In Swedish). 3. Hardell L , Sandstrm A. Case-control S tu d ie : Maligna mesenkymala m jukdels tumrer och exp o sitio n f r fe n o x is y ro r e l l e r k lo rfe n o le r. Lkartidningen 75 (1978) 3535-3536. (In Swedish). 4. Hardell L , Sandstrm A. Case-control stud y: S o ft- tis s u e sarcomas and exposure to phenoxyacetic acid s or chlo ro pheno ls. Paper presented at the conference on p e stic id e s and human h e a lth . S o cie ty fo r Occupational and Environmental H ealth , Washington O. C. , USA December 10-13, 1978. 5. H ardell L . Malignant lymphoma of h is t io c y t ic type and exposure to phenoxy a ce tic acids or chlorophenols. Lancet i (1979) 55-56. 6. Hardell L , Sandstrm A. Case-control stud y: S o ft- tis s u e sarcomas and exposure to phenoxy acid s or chloro pheno ls. B r. J . Cancer 39 (1979) 711-717. 7. Eriksso n M, H ardell L , Berg NO, M ljer T , Axelson 0. Case-control Studie over maligna mesenkymala mjukdelstumrer och e xp o sitio n fo r kemiska su b stan se r. Lkartidningen 76 (1979) 3872-3875. (In Sw edish). 8. Hardell L . Cancer epidemiology in northern Sweden. Nordic Council A rc t . Med. Res. Rep. No. 26 (1980) 94-97. 9. H ardell L . The c lo fib r a t e problem: A d iffe re n c t view po int. Lancet i i (1980) 1081-1082. 10. H ardell L . Case-control s tu d ie s : S o ft- tis s u e sarcomas and m alignant lympho mas and exposure to phenoxy a cid s o r chlo ro pheno ls. In : Progress in Mutation Research, Vol. 2, d. Koppas. Elsevier/N o rth -H o llan d . Biomedical P re ss, pp. 105-108, 1981. 11. Hardell L . D ire ct testim ony before the United States Environmental Protection Agency. Washington DC. E x ih ib it No. 762, September 29-30, 1980. 12. Hardell L, Eriksson M, tenner P. En f a ll- k o n t r o ll stu d ie : Maligna lymfom och exposition fo r kemiska substanser, s a r s k ilt organiska losningsmedel, k io rfe n o le r och fe n o x is y ro r. Lakartidningen 77 (1980) 208-210. (In Swedish). 13. H ardell L , Eriksson M, Lenner P. (Hodgkins sjukdom - en ko m p letterin g ). Rep 1ik Lakartidningen 77 (1980) 983. (In Swedish). 14. H ardell L . R elatio n of s o ft - t is s u e sarcoma, malignant lymphoma and colon cancer to phenoxy a c id s , chlorophenols and other agents. Scand. J . Work. Environ. Health 7 (1981) 119-130. 15. H ardell L , Eriksso n M. S o ft- tis s u e sarcomas, phenoxy h e rb icid e s and c h lo rinated phenols. Lancet i i (1981) 250. 16. H ardell L . Epidem iological stu d ie s on s o ft- tis s u e sarcoma and malignant lymphoma and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. Umea U n iv e rs ity Medical D is s e r ta tio n s . New S e rie s No 65 - ISSN 0346-6612. 1981. 17. Hardell L . D ire ct testimony before the United States Environmental Pro te ctio n Agency. Washington D.C. E x ih ib it No 956, February 9, 1981. 18. H ardell L , Eriksso n M, Lenner P, Lundgren E. Malignant lymphoma and expo sure to chem icals, e s p e c ia lly organic so lv e n ts, chlorophenols and phenoxy a c id s : A case-con trol stu d y. B r. J . Cancer 43 (1981) 169-176. 19. H ardell L , Eriksso n M. F e n o x isy ro r, k io rfe n o le r och ca n ce r. Lakartidningen 78 (1981) 2862-2863. (In Sw edish). 20. Axelson 0, Flodin U, H ardell L. A comment on the re fe re n ce s e rie s with regard to m u ltip le exposure evalu atio n in a c a se -re fe re n t study. Scand. J . Work. En viro n. Health 8 (1982) suppl. 1, 15t 19. ci 1 21. Eriksson M, H ardell L, Berg NO, M ller T, Axelson 0. S o ft- tis s u e sarcomas and exposure to chemical substances: a c a se -re fe re n t study. B r. J . Ind. Med. 38 (1981) 27-33. 22. Hardell L . F a ll- k o n t r o ll s t u d ie r : Maligna mesenkymala mjukdelstumrer, maligna lymfom och exponering fo r fe n o xisyro r e l l e r k lo rfe n o le r. N JF-serm inar 12-13 november 1980. Nordisk jo rd b ru ksfo rskn ing 1 (1981) 58-59. (In Sw edish). 23. Osterman B, H ardell L , Holm J , Lenner P, Lindholm C, Wahl in A. E rfa re n h e te r av in te n siv cyto statikab ehan d ling vid akut myeloisk leukem i. Lkartidningen 79 (1982) 2107-2109. (In Swedish). 24. Sandahl C, H ardell L . K o ststu d ie vid onkologisk k l i n i k . D e lstu d ie . Maten p sju kh u set. I . P a tie n t- och I I . personalsynpunkter. N ringsforskning 27 (1983) 14-21. (In Swedish, En g lish summary). 25. Hardell L . Cancer. Kap itel i lrobok i invrtesm edicin f r sju kskb 'tersko r. (1982), 263-268. (In Swedish). 26. Hardell L , Axelson 0. S o ft- tis s u e sarcoma, malignant lymphoma and exposure to phenoxy acids or chlorophenols. Lancet i (1982) 1408-1409. 27. H ardell L , Johansson B, Axelson 0 . Epidem iological study on nasal cancer and nasopharyngeal cancer and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. Am. J . Ind. Med. 3 (1982) 247-257. 28. H ardell L . Exposure to chlorophenols and phenoxy h e rb icid e s in the working environment. A b stract before the 13th In te rn a tio n a l Cancer Congress. September 8-15, 1982. S e a tt le , Washington USA. 29. H ardell L . Exposure to p o lychlo rin ated dibenzo-p-dioxins and dibenzofurans in the environment. In : 13th In te rn a tio n a l Cancer Congress, Part E . Cancer Management. Eds. Mirand, Hutchinson, M ihich. Alan R L is s , New York, pp. 357-369, 1983. 30. H ardell L , Eriksso n M, Lenner P, Lundgren E. Malignant lymphoma and ex posure to chem icals, e s p e c ia lly organic s o lv e n ts , chlorophenols, and phenoxy a c id s : A case-co n tro l study. Poster at the 13th In te rn a tio n a l Cancer Congress, September 8-15, 1982. S e a tt le , Washington USA. 31. H ardell L . Epidem iological stu d ie s on s o ft - tis s u e sarcoma, malignant lymphoma, n a s a l, and nasopharyngeal cancer and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. In : C h lo rinated D ioxins and Dibenzofurans in the Total Environment. Eds. Choudhary, K e ith , Rappe. Butterworth P u b lish e rs, Boston, pp. 367-374, 1983. 32. Bengtsson NO, H ardell L , E riksso n M. Asbestos exposure and malignant lymphoma. Lancet i i (1982) 1463. 33. H ardell L , Bengtsson NO. Ep idem iological study o f socioeconomic fa c to rs and c lin ic a l fin d in g s in Hodgkin's d ise a s e , and re a n a ly s is of previous data regarding chemical exposure. B r . J . Cancer 48 (1983) 217-225. 34. Sandahl, Ronnlund U, H ardell L . K o ststu d ie vid onkologisk k l i n i k . N u tritio n s s ta tu s hos radioterapibehandlade head- och n e ck p a tie n te r. Ume U n iv e rs ite t 1983. (In Swedish). 35. H ardell L . Epidem iological stu d ie s on s o f t - t is s u e sarcoma, m alignant lym phoma, n a s a l, and nasopharyngeal cancer and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. A bstract before D ividsion of Environmental Chem istry, American Chemical S o c ie ty , Kansas C it y , M iss o u ri, September 15-16, 1982. 36. D ire c t testimony of Dr. Lennart H a rd e ll, "The Herbicide Court Case", Nova S c o tia , Canada, May 1983 (presented by Dr. M. E rik s s o n ). 37. H ardell L . Axelson 0, Rappe C. Nasal cancer and chlorophenols. Lancet i (1983) 1167. 38. Sandahl C, Ronnlund U, H ardell L . B a ttre n arin g sstatu s hos ca n ce rp a tie n te r med h ja lp av n utritio n sg ru p p och kostombud? Lakartidningen 80 (1983) 2234-2235. (In Swedish). JL 39. Domellof L . Hansson M. H ardell L . Nygren M. Rappe C. Le ve ls of p o lych lo rin ate d dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) in f a t tis s u e from ca n cerp atien ts and c o n tro ls . A b stract before the AACR annual meeting May 9-12, 1984, Toronto, O n tario , Canada. H A R D ELL, L e n n a rt 1. Conference organized by the Swedish Society of Medical Radiology (Invited speaker) 2. Conference by the Finnish Medical Association; Duodecim and Medical Faculty 3. Malignant Tumors and Chemical Risk Sectors in the Environment (Invited speaker) A. Meeting on Phenoxy Acids; The Committee on Agriculture of Swedish Parliment (Invited speaker) 5. Soft-tissue Sarcoma and Exposure to Phenoxy Acids or Chlorophenols; Meeting by the Swedish Pharmaceptical Association in UmeS (Invited speaker) 6 . Conference on Pesticides and Human Health - Society for Occupational and Environmental Health (Invited speaker) 7. Symposium by Nordic Counsel on Arctic Medical Research (Invited speaker) 8 . Seminar by Ume University Before The Swedish Work Environmental Fund; Chemical Substances in the Environment (Invited speaker) V Ume, Sweden Oulu, Finland Oulu, Finland September 23-24, 1977 February 22-23, 1978 Stockholm, Sweden October 17, 1978 Ume, Sweden November 9, 1978 Washington, D.C. December 10-13, 1978 Leykgavik, Iceland June 29-30, 1979 Ume, Sweden September 11-12, 1979 9. Seminar on the Work with Pesticides and Associated Risk; The National Swedish Environmental Protection Board (Invited to participate) 10. Seminar on the Use of Phenoxy Acids in the Agriculture; Swedish National Board of Occupational Safety and Health (Invited to participate) 11. Conference on the Use of Pesticides in Forestries - Swedish Association of Churches (Invited speaker) 12. Conference by the Swedish Association of Pesticide Manufacturers; Phenoxy Acids and Cancer (Invited speaker) 13. Committee on the Use of Pesticides in Forestry and Agriculture The Swedish Parliment (Invited speaker) 14. Conference on Use and Regulation of Pesticides - Nordic Counsel of Workers in Agriculture and Horticulture; Health Effects of Phenoxy Acids (Invited speaker) 15. Tenth Annual Meeting of European Environmental Mutagen; Society on Environmental Mutagenisis (Invited speaker) 16. Seminar on Demands Made by the Society for Registration and Use of PesticidesAssociation of Nordic Agricultural Research (Invited speaker) Stockholm, Sweden September 20, 1979 Stockholm, Sweden October 3, 1979 Sodrahoka, Sweden November 6, 1979 Stockholm, Sweden November 27, 1979 Stockholm, Sweden February 20, ]980 Istab, Sweden September 1-5, 1980 Athens, Greece September 14-19, 1980 Helleiud, Norway November 3.2--13, 1980 4 17. Seminar on Phenoxy Adics and Cancer; Institute of Occupational Health (Invited speaker) 18. international Symposium on Prevention of Occupational Cancer; Institute of Occupational Health, Helsinki, Finland;: and International Labor Office and World Health Organization 19. Staff Meeting - University Hospital, Linkping, Sweden; Phenoxy Acids or Soft-tissue sarcoma and Malignant Lymphoma (Invited speaker) 20. Thirteenth International Cancer Congress; The Environment and Cancer; Recent Epidemiologic Developments (Invited speaker) 21. Symposium on Chlorinated Dioxins and Dibenzo Phurons in the Total Environment; The 184th American Chemical Society Meeting (Invited speaker) 22. Seminar on Pesticides - of Benefit or Environmental Pollutant; County Hospital at Karlshamn (Invited speaker) 23. Expert Panel on Dioxon Documents; United States Environmental Protection Agency (Invited member) 24. Symposium on the Swedish Cancer Registry; Yesterday, Today and Tomorrow (Invited speaker) H e ls in k i, F in la n d D ecem ber 12, 1980 Helsinki, Finland April 21-24, 1981 Linkping, Sweden October 22, 1981 Seattle, Washington September 8-15, 1982 Kansas City, Missouri September 12-17, 1982 Karlshamn, Sweden March 11, 1983 Cincinnati, Ohio July 27-29, 1983 Liding, Sweden November 11, 1983 25. Seminar on Drugs and Pesticides; The Swedish Branch of Friends of Earth International ((nvited speaker) Conference on Biological Mechanisms of Dioxin Action Symposium on Toxicology; Swedish and Finnish Association of Toxicology (Invited speaker - unable to attend) Symposium on Leukemia and Related Diseases; International Association for Comparative Research (Invited speaker - unable to attend) Internation Symposium on Herbicides and Defoliants in War; The Long-Term Effects on Man and Nature (Invited speaker - unable to attend) Symposium on Public Health and Risks of Chlorinated Dioxins (Invited speaker - unable to attend) Congress on the Scientific and Social Response from Exposure to Dioxins and Related Material; Association of Occupational and Environmental Health (Invited speaker - unable to attend) v Biskopnarno, Sweden November 26-27, 1983 Banbury Center, NY April 1-4, 1984 Stockholm, Sweden May 16, 1981 Los Angeles, CA August 31-September 4, 1981 Ho Chi Minh City, Vietnam January 13-20, 1983 Rockefeller University October 19-20, 1983 New York Arlington, Virginia December 6-7, 1983 M AU REEN C. H A TCH , P h .D . I. Qualifications Dr. Hatch is Assistant Professor Of Epidemiology at Columbia University, School of Public Health, in New York City. Her Curriculum Vitae and an Addendum listing non-scientific work experience and scientific meetings attended are attached. II. Subject Matter The subject matter about which Dr. Hatch will testify is reproductive epidemiology and toxicology, and theirspecific applicability to miscarriages and congenital malformations (birth defects) in the wives and children of Vietnam veterans. Dr. Hatch will testify at length to the data collected in Vietnam regarding untoward pregnancy outcomes. Dr. Hatch is one of two investigators who are to publish that portion of the International Symposium held in Ho Chi Minh City in January, 1983 having to do with reproductive problems as a result of exposure to Agent Orange and other phenoxy herbicide spraying in Vietnam. I ll. S c ie n tific P r in c ip le s See General Statement of Scientific Principles and Assumed Facts attached. IV. Substance of Opinions A. That exposure to Agent Orange in Vietnam has resulted in certain epidemiological data showing a statistically significant increase in certain congenital malformations, e.g. cleft palate, limb deformaties, and anencephaly, as a result of paternal mediated reproductive effects where only the fathers were exposed to Agent Orange. B. That animal experiments confirm the epidemiological data in that TCDD exposure of the male has shown reproductive toxicity. V. Grounds for each Opinion A. General Review of applicable medical and scientific literature; personal research; attendance and/or participation at various seminars; education and training. 13373 R EFER EN CES C IT E D Allen JR, Carstons LA. Light and electron microscopic observations in Macaca mulatta monkeys fed toxic fat. Am J Vet Res 28:1513-1526, 1967. Constable J, Hatch M. Herbicide exposure and reproductive outcome. In: Herbicides in War: The Long-term Effects of Man and Nature, AW Westing, ed. New York: Taylor & Francis, 1984 (in press). Khera KS, Ruddick JA. Polychlorodibenzoistar-p-dioxins: Perinatal effects and the dominant lethal test in Wistar rata. In: Chlorodioxins - Origin and Fate, EH Blaire, ed. Washington DC: American Chemical Society, 1973, pp 70-84. Kociba RJ, Keeler PA< Park CN, Gehring PJ. 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD): Results of a 13-week oral toxicity study in rats. Toxicol Appl Pharmacol 35:553-575, 1976. McConnell EE< Moore JA< Haseman JK, Harris MW> The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Toxicol Appl Pharmacol 44:335-356, 1978. Mattison DR, Thorgeirsson SS. Gonadal aryl hydrocarbon hydroxylase in rats and mice. Cancer Res 38:1368-1373, 1978. Norback DH, Allen JR. Biological responses of the nonhuinan primate, chicken and rat to chlorinated dibenzo-p-dioxin ingestion. Environ Health Perspect 5:233-240, 1973. Peterson, R. Hormonal changes and "wasting" observed in moderately-high-dose animal experiments. Presented at the Symposium on Public Health Risks of the Dioxins, The Rockefeller University, October 19-20, 1983. (Proceedings in press, Alan R. Liss Inc.) Poland A, Knutson JC. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related aromatic hydrocarbons: Examination of the mechnanism of toxicity. Ann Rev Pharmacol Toxicol 22:517-554, 1982. Tofilon PJ, Piper WN. 2,3,7,8-tetrachlorodibenzo-p-dioxinmediated depression of rat testicular heme synthesis and microsomal cytochrome P-450. Biochem Pharmacol 31:3663-3666, 1982. 1 M a u re e n C . H a tc h RELEVANT EMPLOYMENT: 2 Curriculum Vitae MAUREEN C. HATCH 412 Mountain View Road Englewood, New Jersey 07631 Home: (201) 569-4139 Business: (212) 694-3944 Born: 26 March, 1942 SS # 054-34-6077 EDUCATION: B.A., 1963: Manhattanville College, Purchase, N.Y. Graduate studies in urban planning, 1965-67: Hunter College, N.Y.C. M.P.H., Epidemiology, 1979: Columbia Unversity School of Public Health, N.Y.C. Ph.D., Epidemiology, 1983: Columbia University Graduate School of Arts and Sciences, N.Y.C. Thesis Topic: Paternal Risk Factors for Spontaneous Abortion. HONORS: 1977-79: N.I.C.H.D. Fellowship, Epidemiology of Mental Retardation and Other Developmental Disorders 1978: Selected for the Society for Epidemiologic Research Student Workshop PROFESSIONAL SOCIETIES: Society for Epidemiologic Research, Occupational Reproductive Hazards Committee COMPUTER SKILLS: Computer languages: Wylbur, UC360 Statistical software: SAS, SPSS, CROSSTABS M a u re e n C . H a tc h 3 Hatch, M., Kline, J. Epidemiology Studies: Spontaneous Abortion and Exposure to the Herbicide 2,4,5-T. U.S. Environmental Protection Agency, Washington, D.C., 1981 (EPA 560/6-81-006). Stein, Z., Hatch, M., Kline, J., Shrout, P., Warburton, D. Epidemiologic Considerations in Assessing Health Effects at Toxic Waste Sites. In: Assessment of Health Effects at Chemical Disposal Sites, William W. Lowrance, Ed. The Rockefeller University, New York City, 1981. Edmonds, L., Hatch, M., Holmes, L., Kline, J., Letz, G., Levin, B., Miller, R., Shrout, P., Stein, Z., Warburton, D., Weinstock, M., Whorton, D., Wyrobek, A. Report of Panel II: Guidelines for Reproductive Studies in Exposed Human Populations. In: Guidelines for Studies of Human Populations Exposed to Mutagenic and Repro ductive Hazards, Arthur D. Bloom, Ed. March of Dimes Birth Defects Foundation, 1981. Kline, J., Stein, Z., Hatch, M., Strobino, B. The Role of Spontaneous Abortion Studies in Environmental Research. EPA Technical Report, 1983 (in press). Kline, J., Stein, Z., Hatch, M., Hutzler, M., Lai, A., Pantel-Silverman, J. Surveillance of Parental Occupational and Spontaneous Abortion. NIOSH Technical Report, 1983 (in press). Hatch, M. Occupational and environmental hazards to human reproduc tion. In: Double Exposure: Women's Health Hazards on the Job and at Home, Wendy Chavkin, Ed., Monthly Review Press, 1984 (in press). Stein, Z., Hatch, M. Outcomes of occupational exposures: Antenatal and postnatal impairment. In: Review of Occupational Ha zards to Reproductive Health, World Health Organization, Geneva, Switzerland, 1983, pp 79-91. Constable, J., Hatch, M. Herbicide exposure and reproductive outcome- an overview. In: Herbicides in War: The Long-term Effects on Man and Nature, A.W. Westing, Ed., New York: Taylor & Francis, Pubs., 1983 (in press). Hatch, M. Parental occupation and cytogenetic findings in abortuses. In: Reproduction: The New Frontier in Occupational Health, James Lockey, Grace Lemasters, William Keye, Eds., New York: Alan R. Liss, Inc., 1984 (in press). Hatch, M. Reproductive effects of the chlorinated dioxins. In: Public Health Risks of the Dioxins, William W. Lowrance, Ed., The Rockefeller University, New York City, 1984 (in press). -T> 1 ii ;/ M a u re e n C . H a tc h A PRESENTATIONS: Hatch, M. Testing Clusters of Reproductive Anomalies to Screen for New Teratogens. Presented at the Society for Epidemiologic Research, Student Workshop on Epidemiologic Methods, Iowa City, Iowa, June 1978. Hatch, M. Environmental Hazards to Human Reproduction. Presented at the March of Dimes Nursing Symposium, New York City, March 1981. Hatch, M. Social Context, Concepts of Safety, and Occupational Epidemiology. Presented at the Conference on Work and Health, Case Western Reserve University, Cleveland, Ohio, April 1981. Hatch, M. Spontaneous Abortion as an Endpoint in Environmental Research. Presented at the Latin American Course on Genetic Toxicology, Mexico City, August 1981. Hatch, M. Reproductive Hazards in the Workplace: Research Findings, Research Issues. Presented at the New Jersey Family Planning League Symposium on Occupational Hazards and Reproductive Health, Clark, New Jersey, October 1981. Hatch, M., Kline, J., Stein, Z., Hutzler, M., Silverman, J . , Lai, A. Parental Employment and Spontaneous Abortion. Presented at the American Public Health Association Meetings, Montreal, November 1982. Hatch, M., Kline, J., Stein, Z., Hutzler, M., Lai, A., PantelSilverman, J., Parental Employment and Spontaneous Abortion. Presented at the Conference on Reproductive Health Studies in Industry, East Millstone, New Jersey, December 1982. Hatch, M. Reproductive Effects of Herbicide Exposure in Humans. Presented at the International Symposium on Herbicides and Defoliants in War: The Long-term Effects on Man and Nature, Ho Chi Minh City, Vietnam, January 1983. Hatch, M. Agent Orange and the Herbicide 2,4,5-T. Presented at the American Chemical Society Conference on Dioxins, Old Westbury, May 1983. Hatch, M. Environmental Influences on Reproduction. Medical Department Seminar, Brookhaven National Laboratory, Upton, Long Island, September 1983. Hatch, M. Environmental Agents and Aneuploidy in Human Spontaneous Abortions. Presented at the Environmental Protection Agency Workshop on Approaches for Assessing the Risk of Aneuploidy Induction by Chemicals, Washington, D.C., October 1983. Hatch, M. Reproductive Epidemiology. Presented as part of the University of Ottawa refresher course, Recent Advances in Occupational and Environmental Health, Ottawa, Ontario, October 1983. M a u re e n C . H a tc h 5 CONSULTING EXPERIENCE: Council on Environmental Quality: Scientific advisory panel for report entitled "Chemical Hazards to Reproduction." Environmental Protection Agency: Reviewer for study by Dow Chemical Co. on the reproductive effects of occupational exposure to chlorinated dioxins. National Opinion Research Center: Reviewer for reproductive portion of survey instrument developed for the Air Force study of herbicide-exposed personnel. TEACHING EXPERIENCE: Coordinator for Columbia core course in epidemiology for public health students. Teaching Assistant and section leader for courses in epidemiology and cancer epidemiology for public health and medical students. AD D EN D U M Nonscientific Work Experience: 1963-64 Harper & Row Publishers: designed promotional brochures , wrote jacket copy. 1964-68 Architects' Renewal Committee in Harlem, Inc.: administrative assistant, junior planner. 1968-69 Model Cities Program, Hoboken, NJ: Planner. 1970-73 C. Richard Hatch Associates, Inc.: conceived and wrote educational materials on urban planning and ecology. 1973-76 Parttime freelance editing for such firms as Harry Abrams, Inc. and World Publishing Co. Scientific Meetings Attended in Addition to Those on CV: . Society for Epidemiologic Research, Iowa City, 6/78 . Society for Epidemiologic Research, New Haven, 6/79 or 6/80 . Birth Defects Symposium X: Human Embryonic and Fetal Death, Albany, 9/79 . Birth Defects Symposium XI: Human Mutation, Albany, 9/80 . American Public Health Association Meetings, New York City 1980 (?) . First Annual Symposium on Environmental Epidemiology, Pittsburgh, 4/80 . Changing Risk of Disease in Women, Johns Hopkins University, 10/81 Please note also that the last two papers mentioned on p.3 of the attached CV were originally presented at scientific meetings whose proceedings are currently in press; Reproduction: The New Frontier..., a symposium at the Rocky Mountain Center for Occupational and Environmental Health of the University of Utah, Park City, 4/83, and Public Health Risks of the Dioxins, a symposium at The Rockefeller University, 10/83.I I also attended an allegedly impartial scientific meeting on 2,4,5-T convened in June, 1980 (?) by Dr. Frederick Coulston, at which there were many Dow scientists whose names had not appeared on t original list of conferees. ALASTAIR W. M. HAY, Ph.D. I . QUALIFICATIONS Dr. Hay is a lecturer on Chemical Pathology, Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds, England. His Curriculum Vitae is attached. A list of seminars, meetings and awards is also attached. II. SUBJECT MATTER Dr. Hay will provide background testimony on a broad range of matters relating to Agent Orange, phenoxy herbicides, and their contaminants, including 2, 3, 7, 8-TCDD. Dr. Hay will discuss in detail his knowledge of the various phenoxy herbicides and their contaminants, including but not limited to the various aspects of: chemistry; biochemistry; manufacture and/or production; fate in the environment, animals, and humans; modes of exposure, i.e. absorption, ingestion and in halation, specifically by the veterans who served in Vietnam; toxicity; and the state of the medical and scientific literature at various times since at least 1957 forward. Dr. Hay's testimony regarding the medical and scientific literature will include an exposition of the definitions and explanations, and their applicability to the troops exposed in Vietnam, of the phenoxy herbicides and their contaminants, in the following areas: plant physiology; toxicology; neuro-toxicology, both neurological and psychological; epidemiology; immunology; mutagenicity; teratology; embryotoxicity; reproductive toxicology; and carcinogenicity. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. IV. SUBSTANCE OF OPINION*1 Dr. Hay will testify to the following opinions: A. That phenoxy herbicides, including Agent Orange, and 2, 4, 5-T, and their contaminants, especially TCDD, are: 1. Highly toxic 2. Neurotoxic 3. Immunosuppressive 4. Teratogenic and Embryotoxic 5. Potentially Mutagenic 6. Carcinogenic. B. That there is no "minimum effect" level for 2, 3, 7, 8-TCDD and all other dioxins or, in other words, there is no known "safe level" for any human intake of 2, 3, 7, 8-TCDD and all other dioxins. V. GROUNDS FOR EACH OPINION A. General The medical and scientific literature, attendance and participation in various symposia, review of various documents of certain defendants, personal research, and experience form the bases of whatever facts and opinions to which Dr. Hay will testify. B. More specifically, the phenoxy herbicides, including Agent Orange, 2,4,-D and 2,4,5-T and their contaminants, including dioxin, especially TCDD, are: 1. Highly toxic McConnell, E.E., et al. Toxicology & Applied Pharmacology 44, 355-356 (1978); Schwetz, B.A., et al. Advances in Chemistry Series, ed. E. H. Blair, 120 55-69 (1973); Greig, J.B., et al. Food & Cosmetics Toxicology, 11,585-595 (1973); 2. Neurotoxic Kimmig, J. & Schultz, K. H. Dermatologica 115, 540-546 (1957); Bauer, et al. Archiv. Fuer Gewerbepathology un Gewerbehygin, 18,538-55 (1961) 3. Immunosuppressive Vos, J.G., & Moore, J.A. Internal Archives of Allergy and Applied Immunology 47,777-794 (1974); Faith, R.E., and Luster, M.I. Annals o5f64T-5h7e1N.(Y1.979A)cad, of Sciences, 320, 13383 4. Teratogenic and Embryotoxic 5. Potentially Mutagenic 6. Carcinogenic Neubert, D., and Dillmann, I. Naunym Schmiedebergs Archives and Pharmacology (Berlin) 272 (3), 243-264 (1972) Neubert, D. Environmental Health Perspectives 5, 67-79 (1973); Courtney, K.D., and Moore, J.A. Toxicology and Applied Pharmacology, 20, 396-403 (1971); Courtney, K.D. Bulletin of Environmental Contamination and Toxicology, 16, 674-681 (1976); Smith, F.A., et al. Toxicology and Applied Pharmacology 38, 517-523 (1976) ; Moore, J.A., et a l . E n v iron mental Health Perspectives 5, 81-85 (1973); Sparschu, G.L., et a l . Food and Cosmetic Toxicology, 9, 405-412 (1971); Roll, R. Food and Cosmetic Toxicology, 9,671-676 (1971) Rogers, A . M . , et a l ., Mutation Research 105, 445-449 (1982); Bronzetti, G., et a l . in Chlorinated Dioxins and Related Compounds: Impact on the Environment (pergamon Press, Oxford, NY (1982) pp 429-436; Hay, A. in The Chemical Scythe (Plenum Press, 1982) pp. 43 Allen, et al., Chemosphere, 9,537-544 (1977) ; Kociba, R.J., et a l . T o x i cology and Applied Pharmacology. 46, 279-303 (1978); Anonymous. Bioassay of 2,3,7,8-tetrachlorodi- benzo-p-dioxin for possible carcino genicity (gavage study), National Cancer Institute DHHS Publication No. (NIH) 80-1757 (1980); Toth, K.S., et al. Nature (London) 278,548-549 (1979); Anonymous. National Cancer Institute Technical Report Series No. 123 (1979); Anonymous. Bioassay of a mixture of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p- dioxin for possible carcinogenicity (gavage study), National Cancer Institute, Technical Report Series No. 198 (1980); Anonymous. Bioassay of a mixture of 1/2/3/6/7/8- and 1/2/3/7/8/9hexachlorodibenzo-p-dioxin for 1338 possible carcinogenicity (dermal study), National Cancer Institute, Technical Report Series No. 202 (1980) Dr. Hay will testify to examples of the grounds which support the above, including: knowledge of spraying Agent Orange, especially its effect on the Vietnamese countryside; the purpose and historical tracing of the animal studies; historical tracing of the human data, including the various industrial incidents since 1949 (Hay, A. The Chemical Scythe, Plenum, N.Y. (1982) pp 95-146); references to specific documents such as the EPA Dioxin document (presently in draft form); various cancer epidemiology; (Hardell, L. & Sandstrom, A. British Journal of Cancer, _39/ 711-717 (1979) ; Hardell, et al. British Journal of Cancer, 4_3, 169-176 (1981); Honchor, P.A. and Halperin, W.E. Lancet, I. 268-269 (1981); and Cook, R.R., Lancet, I. 618-619 (1981); pertinent teratology epidemiology (Hanity, J.A., et al., Science, 212, 349-351 (1981); Field, B., and Kerr, C. Lancet I. 1341-1342 (1979)); various studies of the Vietnamese (Tung, T.T., LaRevue de Medicine, 1_4, 653-657 (1977)); especially reproduction toxicology (Constable, J. Report of the Workshop on Reproductive epidemiology. International Sym posium on Herbicides and Defoliants in War: The long term effects on Man and Nature. Ho Chi Minh City 13-20 January 1983; to be published in Herbicides in War. Ed. A.H. Westing, SIPRI); and those reports of the symptoms and diagnoses of the U. S. Vietnam veterans. C. The above will be relied upon to show that the is no "minimum effect" level for 2,3,7,8-TCDD or other dioxins. I33B5 Name: Alastair Watt Macir.tyre HAY D.Q.B.: 21 Apr:1 19 47 A Marital Status: Married Chi 1crer.: 1 son (Tom) Place of Birth: Glasgow, Scotland. Nationality: British Degrees: B.Sc.(Hons), Chemistry IIA - London 1969 Ph.D.. Biochemistry, London 1973 Home Address: School House, Arthington Lane, Arthington, Leeds LS21 1PE England. Work Address: Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds LS2 9NL England. Place of Secondary Education: Gifford Technical High School, Bulowavo, Zimbabwe (formerly Rhodesia) Present Appointment: University lecturer in Chemical Pathology since April 1979 (University of Leeds) Leeds, England. Former Appointments: Research Fellow - Zoological Soc. of London September 1972 - November 1977 Research Fellow - University of Leeds, Department of Animal Physiology and Nutrition December 1977 - March 1979 Societies: Biochemical Society Nutrition Society Expert Committees: PUBLICATIONS : Books 1983 EPA Review Panel on Dioxins for Environmental Criteria and Assessment Office. 4r 1. Alastair Hay. The Chemical Scythe: Lessons of 2,4,5-T and Dioxin. Plenum Press. 265 pp. August 1982. 2- Sean Murphy, Alastair Hay and Steven Rose. No Fire:- No Thunder. The threat of chemical and biological warfare. Pluto Press. (To be published in January 1984). 135pp. 1I> V.. 1. Sjr.cioir, A. J., Fiennes. R.N.T.W., Hay, A.W.M., Watson. G., Crawford, M.A.. & Hart, M.G. Linolenic acic deprivation in Capuchin monkeys. Proc. Nutr. Soc., _33, 49A (1974). 2. Hay.A.W.M., Sinclair, A.J., & Ray, W.G. Some useful techmaues in thin laver chromatoaraphy. J. Lab. Pract. 73 483-484 (1974). ' ' 3. Hay, A.W.M. & Ray, W.G. A simple macrotome. J. Lab. Pract. 24. 35 (1975). 4. Hay, A.W.M. Comparative aspects of vitamin D transport. In: Calcium Regulating Hormones (Excerpta Medica, Amsterdam). The Proc. of the 5th Parathyroid Conference, Oxford. pp 405407 (1975). 5. Hay, A.W.M. & Watson, G. Binding of 25-hydroxyvitamin to plasma protein in New World monkeys. Nature, 256, 150 (1975). 6. Hay, A.W.M. The transport of 25-hydroxycholecalciferol in a New World monkey. Biochem. J. 151, 193-196 (1975). 7. Hay, A.W.M. & Watson-, G. The plasma transport proteins of 25-hydroxycholecalciferol in mammals. Comp. Biochem. Bhysiol. 53B, 163-166 (1976). 8. Hay, A.W.M. & Watson, G. The plasma transportprotein of 25-hydroxychclecalciferol in fish, amphibia, reptiles and birds. Comp. Biochem. Physiol. 53B, 167-172 (1976). 9. Hay, A.W.M. The transport of vitamin D in the Giant Panda. Trans. Zool. Soc. Lone., _33_, 139-140. (1976). 10. Hay,A.W.M. Vitamin D transport in vertebrates. Proc. Anat. Soc. J. Anat. 121, 195 (1976). 11. Hay, A.W.M. A possible role for vitamin D. in vertebrate evolution. Proc. of the 2nd Internation Workshop on Calcified Tissues. (Abstract) . Isr. J. Med. Sci. _1_2, 31-32 (1976) . 12. Hay, A.W.M. & Watson, G. The binding of 25-hydroxycholecalcifer and 25-hydroxyergocalciferol to tissue binding proteins in a New World and an Old World primate. Comp. Biochem. Physiol. 56B, 131-134 (1977). 13. Hay, A.W.M., & Watson, G. Vitamin D~ in vertebrate evolution. Comp . Biochem. Physiol. 56 B, 375-380 (1977). 14. Hay, A.W.M. & Watson, G. Binding properties of serum vitamin D transport proteins in vertebrates for 24R, 2 5 -hydroxycholecalcif and 24S, 25-hydroxycholecalciferol in vitro. Comp. Biochem. Physiol. 58B, 42-48 (1977).. 13387 00 r-- 4 15. Hay, A.K..'-:. ' Viatson, G. Evolution o /itamir D serum transport pi-teins in vitamin D; Biochemical, Chemical and Clinical Aspects related to Calcium Metabolism (Ec. by Norman, A.W. et al) Walter de Gruvter," Berlin & New York (1977) pp 483-4S9. 16 . Hay , A..W.M. Vitamin D at Asi lomar. Report of 3rd Workshop on Vitamin D. Nature 266, 17- 18 (1977). 17. Hay , A.W.M. Combatting rickets. Nature 270, 289 (1977) Hay , A.W.M. Vitamin D^ metabolism in New World prima tes. Proc. of the 3rd International Workshop on Calcified Tissues, Israel 6-9th March 1978 (in press). 19. Hay, A.W.M., Darling, M. & Watson, G. Rickets and vitamin D metabolism in primates. Proc. Nutr. Soc. .37., 42A. (1978) . 20. Hay, A.W.M. Tetrachlorodibenzo-p-dioxin release at Seveso. Disasters 1(4) 289-308 (1977). 21. Hay, A.W.M. Identifying carcinogens. Nature, 269, 468-470 (1977) . 22. Hay, A.W.M. Seveso: No answers yet. Disasters 2., 163-168 (1978) . 23. Hay, A.W.M. Vitamin D transport (Review). C.R.C. Handbook series in Nutrition and Food (in press) . 24. Hay, A.W.M. Resurgence of Vitamin D. Nature, 273, 426-427 (1978). 25. Hay, A.W.M. Halogenated Hydrocarbon Effects. Nature, 274, 533-534. (1978). 26. Hay, A.W.M. & Jones, G. The elution profile of vitamin D 2 metabolites on Sephadex LH20. Clin. Chem. 25, 473-475 (1979) . 27. Hay, A.W.M. Accidents in trichlorophenol plants: a need for realistic surveys to ascertain risk to health. Proc. of N.Y. Acad. of Sci. 320, 321-324 (1979). 28. Rivers, J.P.W., Frankel, T.L., Juttla, S-, & Hay, A.W.M. Vitamin D in the Nutrition of the Cat. Proc. Nutr. Soc. 38., 36A (1979) . 29. Hay, A.W.M., Hassam, A.G., Crawford, M.A., Stevens, P.A., Mawer, E.B. & Case, L. The ability of la,25-dihydroxycholecalciferol to alter the fatty acid composition of phosphoglyceric in rat intestinal mucosa and smooth muscle in Vitamin D Basic Research and its Clinical Application (Ed. by Norman, A.W., et al). Walter de Gruyter, Berlin, & N.Y. (1979). 13388 - *1 - 30. Care. A.D., lckard, D.W., Ross, R.. I. A.W.M., Garel, j .m . & Reoel, J. A comparison of the effects of 25, 26-dihyd roxychclecalciferol (25,26-DHCC) and 24.25-DHCC on calcitonin secretion rate m vitamin D depleted pics. J. Endocrinology 85.. (2), 54p-55p (1980). 31. Fleming , J. Cooper, E.H., Hay, A.W.M., Morgan, D.B., and Tarapia, L. Tubul oprotei n u n a in Cancer Chemotherapy. La Ricerca Clin Lab. j_0, 135-141 (1980). 32. Hay. A. Complecation of vitamin D metabolism still increasino Nature, 27s`. 509-510 (1979). 33. Hay, A.W.M. Essential fatty acid restriction inhibits vitamin D dependent Calcium absorption. Lipids. 15, 251-4 (1980). 34. Intestinal, la. 25-dihydroxycholecaleiferol-dependent calcium absorption inhibited by essential fatty acid restriction. Proceedings of Nutri. Soc. .39., 89A (1980). 35. Halogenated hydrocarbon. Hay, A.W.M. in 1981 EST Yearbook of Science & Technology. McGraw-Hill ppl98-200. 36. Hay, A.W.M. Exposure to TCDD: the health risks. Chlorinated dioxins and related compounds. Impact on the Environment. O. Hutzinger, et al. Pergamon Press, Oxford, N.Y. (1982) . 37. Fleming, J.J., Child, J.A., Cooper, E.H., Hay, A.M., Morgan, D.B. & Parapia, L. Renal tubular damage without glomeular damage after cytotoxic drugs and aminoglycoside Biomedicine J3_3, 251-254 (1980). 38. Hay, Alastair. New pathways for chlorinated dioxins. Nature. 294. 514-515 (1981). 39. Hay, A.W.M., Mawer, E.B., Hassan, A.G., Crawford, M.A. & Stevens, P.A. The Role of essential fatty acids in vitamin D dependent calcium absorption in the intestine. Proc. of 5th vitamin D workshop. Williamsburg, U.S.A. New in Vitamin D, chemical biochemical and clinical endocrinology of calcium metabolism. Walter de Guyter. Berlin, N.Y. (1982) pp309-311. 40. Hay, Alastair. Vitamin D: sunlight and precursors. Nature. 297, 364 (1982) . 41. Sheltawy, M., Hay, A.W.M., Hullin, R.P., and Morgan, D.B. Vitamin D2 and D 3 in the nutrition of elderly. Clin. Sci. 6 2, 15-16 (1982) (abstract). 42. Hay, A. Herbicides, trichlorophenols and soft tissue sarcomas. Lancet I, 1240 (1982). 133C '07 ) , - 5- 4 i. hay, A. It kills weeds, but what, about people? hew Scientist. j?4_, No. 1314 pplSS-161 (1982) 44. Hay, A., Murphy, S., Robinson, J.P. Sr Rose, S. The poison cloud hanging over Europe. New Scientist 93, No. 1296 ppe 30-6 25 (1982) 45. Hay, A. Experimental Toxicology and cytogenetics: an overview. Ir. "Herbicides and War" to be published by Stockholm International Peace Research Institute 1984 A. Viesting. Edit. 46. Hay, A. The Mutagenic Properties of 23,7,8 -Tetrachlorodiben p-dioxin in "Chlorinated Dioxins and Dibenzofurans in the Total Environment. Vol II. Edit, by Keith, L.H. et al to be published in 1984. 47. Jones, C., Hay, A.W.M., Morgan, D.B., and Hullin, R.P. Response of the serum 25-hvdroxy vitamin D to minimal exposure to sunshin in patients in a long stay mental hospital. (abstract) To be published in November 1983 Proceedings of the UK Bone and Tooth Society. 48. Sheltawy, M., Newton, H., Hay, A., and Morgan, D.B. and Hull, R.P. The contribution of diet and sunlight to the plasma 25-hydroxy vitamin D. (abstract) to be published in November 1983. Proceedings of UK Bone and Tooth Society. 49. Feely, M., Hay, A., Clarke, N., Price, D., and Cooke, J. "mini-Dose" Phenobarbitone : A useful marker of compliance submitted to IUPH.AR 9th International Congress of Pharmacology 50. Sheltawy, M., Newton, H., Hay, A., Morgan, D.B., and Hullin, The contribution of dietary vitamin D and sunlight to the plasma 25-hvdroxy vitamin D in the elderly. Submitted to Clin:Leal Nutri Other Scientific Ar 1 . Hay, Alastair. (1976) . 2 . Hay, Alastair. 270 (1976) 3. Hay, Alastair. (1976) 4 . Hay, Alas tair. 310 (1976) . 5. Hay, Alastair. (1976) 13390 6 . Hay, Alastair. Seven months on. 265, Nature, 490 (1977). 1 . Ala s t a i r Hay, S e v e s c : D i o x i n d a m a g e . Nature 2 6 6 .7-8 (1977) . 8 . Hay, Alastair. Zoo story. Nature 267, 94-95 (1977). r 9. Hay, A l a s t a i r . Italy: Distant d r u m s . Natur e 267, 30 1 (1977) 10 . Hay, Alastair. Seves o solicit u d e . Nature. 26 7, 384-385 (1977) 11 . Hay, Alastair. An aid to deve l o p m e n t ? Natu re, 267, 571- 572 (1977) 12 . Hay, Alastair. Roche's reply. Nature, 267, 74 9 (1977) 13. Hay, A l a s t a i r . Twelve months after Seveso. Na ture, 268 90 (1977) . 14 . Hay, Alastair. Seveso Row. Nature, 268, 395 (1977) 15. Hay, Alastair. Timely delay. Nature, 269, 279 (1977). 16. Hay, Alastair. Informing on 2,4,5-T. Nature, 26 9, 749-^-750 (1977). 17. Hay, Alastair. Health and safety 3 years on. Nature, 270, 91-93(1977). 18 . Hay, Alastair. Combatting rickets. Nature, 270, 289 (1977) . \ 19. Hay, Alastair. Science Key to Vietnams Recovery, Nature 271, 101-2 (1978) . 2 0 . Hay, Alastair. Science helps to rebuild Vietnam. Nature, 271, 101-102 (1978). 2 1 . Kay, Alastair. Dioxin meeting recommends cancer study. Nature. 271, 202 (1978) . 22 . Hay Alastair. Vietnams Dioxin Problem. Nature, 271, 597-598 (1978) . 23. Hay, Alastair. Vietnam calls its scientists to arms. 273, 94-95 (1978). 24 . Hay, Alastair. Israel's Scientist-President Resigns. Nature, 273, 93 (1978) . 25. Hay, Alastair. Vietnam extends scientific links. Nature. 273, 419 (1978) . 26 . Hay, Alastair. Commonwealth Science Council Coordinates approach to UNCSTD. Nature, 273, 697-698 (1978). 27. Hay, Alastair. Company's claim sparks fresh controversy over Seveso. Nature, 274, 108 (1978). 13391 i Hay. Alastair. Neurotcxins ir.av go unrecoonised. Nature. 274, 206 (1978). 29. Hay, Alastair. Dioxin source is 'safe'. Nature, 274, 526 (1578) . 30. Hay, Alastair. Vietnam still looking for foreign aid. Nature, 275, 6-7 (1978) 31. Hay, Alastair. Vietnam's scientists wait for books and equipment. Nature, 276, 203 (1978). 32. Hay, Alastair. Dioxin workshop. Nature, 276, 304 (1978). 33. Hay Alastair. Health and safety research gets underway. Nature, 226, 435-437 (1978). 34. Hay, Alastair. Switzerland to consider revised guidelines. Nature, 277, 341-342 (1979). 35. Hay, Alastair. Italian Commission covered up Seveso delays. Nature, 277, 588-589 (1979), 36. Hay, Alastair. Dioxin: the 10 year battle that began with Agent Orange. Nature, 278, 108-110 (1979) . 37. Hay, Alastair. UK ministry gives green light to 2,4,5-T. Nature, 278, 388 (1979). 38. Hay, Alastair. Complexities of vitamin D metabolism still increasing. Nature, 278, 509-510 (1979). 39. Hay, Alastair. Critics challenge data that led to 2,4,5-T ban. Nature, 279, 3 (1979). 40. Hay, Alastair. Skin toxicology. Nature, 279, 375 (1979). 41. Hay, Alastair. US Defense Department destroys evidence of Vietnam devastation. Nature, 279, 662 (1979). 42. Hay, Alastair. What caused the Seveso explosion? Nature, 273, 582-583 (1979). 43. Hay, Alastair. US scientists to join Italians in dioxin study. Nature, 221 338 (1979). 44. Hay, Alastair. Rickets under control again in UK. Nature, 279. 749 (1979). 45. Hay, Alastair. Vietnam veterans studied for herbicide exposure. Nature, 279. 667. (1979). 46. Hay, Alastair. Handle us with care. Nature, 280, 8-9 (1979) . 13392 8 47 . Hay, Alastair. M a l f or ma ti on s at birth increased in Seveso last year. . Nature, 2 8 0 , 184 (1979). 48 . Hay, Alastair. Press banned from conference. Nature, 2S0, 623 (1979), 49 . Hay, Alastair. Asbestos: killer dust, says book. Nature, 28 1. 172 (1979) . 50 .Hav, Alastair. Seveso: the crucial questi on of reactor safety Nature. 28JL* 521 (1979). 51. Hay, Alastair. D i s pu te over Dow Chemicals theory of dioxin traces. Nature, 2 8 1 , 619-620 (1979). 52. Hay, Alastair. UK to tighten asbestos controls. Nature, 282, 5 (1979) . 53. Hay, Alastair. EPA panel recommends p o s t p o n e m e n t of 2,4,5-T hearings. Nature. 282, 124 (1979). 54. Hay, Alastair. Short term tests can p r e di ct potential carcinogens, says study. Nature, 282, 664 (1979). 55. Hay, Alastair. Dioxin as a health hazard. Book Review. Nature, 283, 229-230 (1980). 56. Hay, Alastair. Health m o n i to ri ng enda ng er ed at Seveso. Nature, 2 8 3 , 237 (1980). 57. Hay, Alastair. Dioxin detection. Nature, 2 8 3 , 426 (1980). 58. Hay, Alastair. Study finds m a l nu tr it io n in 7% of elderly. Nature, 2 8 3 , 612 (1980) . 59 Hay, Alastair. Chemical company study shows no dioxin hazard. Nature, 2 3 3 , 613 (1980). 60. Hay, Alastair. Ch emical company suppresses dioxin report. Nature, 2 8 4 , 2 (1980) . 61. Hay, Alastair. Dioxin and 2,4,5-T: what are the risks? Nature, 2 8 4 . Ill (1980). 62. Hay, Alastair. The CIA's toxic agents. Nature, 2 8 4 , 296 (1980) . 63 . Hay, Alastair. Coalite health su rvey talks. Nature, 2 8 4 , (1980) . 64 . Hay, Alastair. Red faces (and hot tempers) on 2,4,5-T. Nature, 2 8 6 , 97 (1980). 65 . Hay, Alastair. A plea for 2,4,5-T. Nature, 2 8 7 , 659-570 (1980) . 13393 66 . H a y , A l a s f r . H e r b i c i d e safety: B i . of Health. Na tcuurree,, "'D C 4-5 (1931) . 67. Hay, Alas tai r . Rickets at bay. Nature. 289, 113 (193 1) - 68 . Hay, Alastai r . C h l o r i n a t e d diox in s and the environment. Nature. 289, 351-352, (1981). 69 . Hay, Alastair. Seveso: the intrigue and the infighting. Book Review. Nature, 2 9 0 , 71-72 (1981). 70'. Hay, Alastair. D i s p o s i n g of dioxins by oxidation. Nature, 290, 294, (1981). 71 . Hay, Alastair. S e c re cy at Coalite. Nature, 2 9 0 , 729, (1981) . 72. Hay, A., Murphy, S., Robinson, J.P. On Chemical War. Nature, 94, 204 (1981) . 73. Hay, Alastair. Spot the potential carcinogen. Nature, 296 , 100, (1982) . 74. Hay, Alastair. R e l a t i n g to halen at ed hydrocarbons. Nature, 296, 688 (1982). 75 . Hay, Alastair. Ch e m i s t r y at War. Nature, 2 9 8 , 205-206 (1982) . 76 . Hay, Alastair. The official's book of risky business. Book Review. Nature, 301, 640 (1983). 77. Hay, Alastair. De f o l i a n t s in Vietnam: the long term effects. Nature, 02, 208-209 (1983). 78 . Hay, Alastair. Empow er ed to set standards. Book review. Nature, 305. 77 (1983) . 79 . Hay, A l a s t a i r . . .and its control. Journal Review. Nature. 305, 486 (1983) . 80 . Hay, Alastair. Fresh support for apian origin. Nature. 3 0 6 . 8 (1983).1 1 OOotfaS i H AY, A la s t a ir W .M . Additional Papers 1. Paper: "Relationship between Sex Hormones and Fructose Metabolisms in Rat Liver"; Presented at Nutrition Society, London, December 7, 1972. 2. Participant: International Agency for Research on Cancer, NIEHS/IARC Working Group on the Coordination of Epidemiological Studies on the Long-Term Hazards of Chlorinated Dibenzo Dioxins-Chlorinated Dibenzo Phurons; Lyon, Lyon, France, January 10-11, 1978. 3. Member: Panel on Human Observation of the Consequences of Dioxon Exposure; Meeting: International Symposium on Chlorinated Dioxins and Related Compounds, Arlington, Virginia, October, 1981. 4. Paper: "The Role of Membrane Lipids in the Expression of Vitamin D Function in the Intestinal Nucosal Cell"; Presented at the Biochemical Society, London, December, 1981. 5. Paper: "The Manufacture of 2,4,5-Trichlorophenol and its Social Consequences"; Presented at the Royal Society of Chemistry, Education Division Meeting, Leeds, England, September, 1981. 6 . Presentation: "Renal Toxicity to the Yorkshire Regional Health Authority Meeting on Aspects of Pathology:; Harigat, January, 1980. 7. Paper: "TCDD Mutagenic Property"; Presented at the International Symposium on Herbicides and Defoliants in War; Long-Term Effects on Man and Nature; held in Ho Chi Minh City, Vietnam; Also, repertoire of working group on experimental toxicology and cytogentics at this Conference. H ERBERT KAYE, P h .D . I. QUALIFICATIONS Dr. Herbert Kaye, Ph.D., is a psychologist in the Department of Psychology at the State University of New York at Stoneybrook, Long Island and a visiting Associate Professor in the Department of Psychiatry at New York University Medical Center. See attached curriculum vitae. II. SUBJECT MATTER OF TESTIMONY Dr. Kaye will testify concerning the significance of a battery of quantitative neurophysiological tests called neurometries which will be performed on various plaintiffs. The procedures were developed in part by Dr. Kaye in conjunction with medical and psychological researchers from this and other countries. He will testify that neurometries, on which he has written extensively, is a sophisticated battery of electrical tests in use for about fifty years, which are highly efficient in the determining cortical EEG and evoked responses. Dr. Kaye will explain the model used in the computerization against which the test results are compared and will explain how deviations from normal produce certain effects. Dr. Kaye will also discuss the mechanism by which toxins produce these altered responses, and what effect those altered responses have upon the individual veterans at present, and the prognosis for any additional changes or deterioration in the future based upon an assumed bioaccumulation of the toxic materials in the system. In doing so, he will rely on his experience in diagnosing many Vietnam veterans exposed to Agent Orange. III. GEN ERAL S C IE N T IF IC P R IN C IP L E S R E LE V A N T TO A R EA : The scientific principles arise from three general disciplines: neurophysiology, mathematics, and neuropsychology. The area of neurophysiology includes the work on neuro-anatomy, neurochemistry, neuropharmacology, and applied or clinical electrophysiology. The work in mathematics represents multivariate statistics. The work in neuropsychology includes direct and indirect brain-behavior research and clinical diagnostics. The neurophysiological basis of the development of neurometries is presented in Volumes I and II of Functional Neurosciences, published in 1977 by Lawrence Erlbaum Associates, publishers, Hillside, New Jersey. However, this work represents an integration of research and applications in the neurosciences over a period four decades, initiated with the seminal EEG work of Gibbs (see, for example, Atlas of Electroencephalography, Cambridge, Massachusetts, Addison-Wesley) W. Gray Walter (see, for example, Electronic Engineering, 1943, 16, pp. 9-13) and going through the specific and extensive quantitative work of Matousek and Peterson (Automation of Clinical Electroencephalography, New York, Raven Press, 1973, pp. 75-102) and current work by quantitative electrophysiologists such as A. S. Gevins, C. Shagass, Theodore Gasser, Enoch Calloway, T. M. Itil, L. Goldstein, and others. (See, for example, Neuro-psychopharmacology, Proceedings of the Tenth Congress of the Collegium Internationale Neuro-psycho-psychopharmacologicum, eighth relevant norm. (See John, et al., Science, Volume 210, 1980). Neuropsychological literature represents the third strand. This represents the melding of brain electrophysiology and other neurophysiological techniques with those of psychology, or the study of mental and behavioral processes. There is a huge literature in the area, and recent work by such researchers as Gevins, Galin, Tucker, Thatcher, Needleman, and others, as well as those studies of Dr. Kaye and his students and colleagues indicate that quantitative electrophysiology is valuable in diagnosing underlying cortical processes serving certain behaviors. IV. SUBSTANCE OF OPINION 1. Agent Orange represents a neurotoxic agent that works indirectly by affecting liver function and the liver's production of heme; and in doing so makes an individual, so affected, vulne^ible to neurohvpoxia. 2. Agent Orange may also work at a local level on enzymes relevant to the production and mobilizations of neurotransmitters. 3. Agent Orange, which is lipid, soluable, is likely to be stored in myelin and other fatty material and is collectively "time released" under "stress". 4. Storage is likely to be greater in the long fiber tracts, such as the major pathways from spinal cord to peripheral cutaneous receptors, pathways from frontal cortical regions to the thalimus and in spinal cortical motor pathways. 5. Changes in cortical functioning, represented by each EEG's slowing, represent breakdown of neural metabolic function occurring as a result of progressive neurotoxic assault. 6 . Changes in cortical functioning represented by inter-hemispheric asymmetries and wave-shape incoherence represent the disruption of neural -4- timing either through the breakdown of cortical pacers, or through the failure of transcortical communication via the corpus collosum. 7. The occurrence of sharp-wave activity is caused by disruption of inhibitory neurotransmicters and represents a mechanism that can partially account for mood lability, which along with selective suppression of frontal lobe function would provide the basis for behavioral discontrol. V. GROUNDS FOR MY OPINION' A recent study by Needleman (Acta Psychiatrica-Scandinavica, 1983, Supplement No. 303, pp. 26-37) indicates the ability to utilize simple quantitative EEC spectral measures along with the pa chological measures to classify children from the "normal" population to have high and low lead levels (using Jentvne lead levels). The disreiminating variables for the EEC were the variables associated in our and inconventional EEG work with abnormalities; that is, excessive slow wave energy. Recent work in our evaluation unit has examined the abnormality profiles of thirty-two Vietnam veterans. In summary, approximately fifty percent showed spectral abnormalities, fifty percent showed power asymmetries, fifty percent showed wave-shape incoherence, and fifty percent showed sharp wave activity. In all, eighty-four percent showed some significant degree of abnormality. Correlation of these patients' neurometries profiles with other behavioral and physiological data is progressing. Specific correlation of neurometries profiles and behavioral reports of individual patients who were exposed to herbicides while engaged in non-military activities is also proceeding. Finally, there is a growing body of data relating research with people who were exposed to low levels of toxic material and who show the range of effects present in the Vietnam veterans exposed to Agent Orange. In particular, research on the mechanisms underlying heavy metal toxicity (such as with lead and wiih methyl mercury) suggests possible mechanisms for both neurotoxic and genetic effects. (See, for example, Chang, L.W. "Pathogenetic Mechanisms of the Neurotoxicity of Methyl Mercury" in Mechanism of Actions of Neurotoxic Substances, edited by K.N. Prasad and A. Vernagakis, Raven Press, New York, 1982; and, Egan, et al., "Experimental Design for Animal Toxicity Studies" in Experimental and Clinical Neurotoxicology, edited by P.S. Spenser and H.H. Schaumberg, Williams and Wilkins, Baltimore, 1980. 13400 -6- 1` Cinnicuhm l'Ita - HeA.be/iZ: Kaye. Vote Binth and Binthplace: Hay 23, 193 5, Hew Hon.li City Manital Status Hannled, one child Fuslness Addness: Psychology Vepantment S.U.H.V. at. Stony Bnook Stony Snook, Hew Yank 1179C Phone.: (516) 246-7632 Clinic Addness: Heunometnlcs Evaluation Unit Hauppaugc Pno Sessional Puilding 111 Smithtown Bypass Hauppauge, Hew Honk 11717 Education: Rennslean Po.tytech. Institute., finom 9/53 to 1/56, faield: englneenlng Hunten College, nom 1/56 to 6/56 Columbia Uni.ventity, {nom 7/56 to 7/60 B.S.C. (1/60), psychology Bnown University, 9/60 to 6/62, M.S.C. (6/ 62) , psychology Bnown Univensity, 9/62 to 6/64, Ph.V. [6/64], psychology Pnofaessionai Expe/Uence: Bnown Univensity, 7/64 to 1/66 Reseanch Associate, Vepantment Oq Psychology Emony Univensity, 9/66 to 6/67 Assistant PnoWesson, (joint position) Gnaduate School cft Psychology and In the Medical School, the Vepantment o Cbstetnlcs and Gynecology Emony Univensity, 7/67 to 3/71 Associate Pno^esson, (joint appointment] Gnaduate School o/ Psychology and In the Medical School, the Vepantments o^ Cbstetnlcs and Gynecology State Univensity o$ Hew Yank at Stony Pnook., 4/71 to pnesent Associate PnoWesson o$ Psychology Hew Yank Univensity Medical Centen, Vept. o P s y c h i a t n y Bnain Reseanch Labonatonles, 1977 to pnesent Visiting Associate PnoWesson 13401 -1- ' * ' p A c f e i s i o n a l S qa.va. c c . (7) Llyiivensity: ".iAeetoA Institute for ReseoAch in Learning and Instruction: (i?77-7974) ViieetoA Vevelcpmaital Psychology pA.cgAam: f 797 7- 7976/ 7977;7 97g*;1 9%1-pAesent) Pe.paAtme.yit Executive Committee IS of 12 years th A o u g h 19S3-4 Academic year) VepaAim.ent Graduate Committee 12years) , department Undergraduate Committee [Z years) ViA.eci.oA. of Undergraduate Psychology PAcgAam (775-6} University Special Committees: (a) Peh.avioA.al M e d icin e (b) Chair Tenure Committee: Kenneth Code (c) Chair Special Education Committee Id) Pay Care (e.J Undergraduate Studies ( fj University Awards .Program of SJ'.M.V. ( 192?-S3) Vepaatment Special Committees: la) Applied Child and Family Concentration (hj Setting of S.C.V.C. on South Campus (c) Vay Care Vissentations and Theses: la) Ph.v's: 5 Students (6) Master's: 12 Stud eats (cj T huve been on about 15 disseAtaticn committees of students other than my own. ( Z} Outside University: Consulting EditCA: (a) Journal of ExpeAimertal Child Tsyeholugij {1967-1974) lb) Vevelopment Psychology 11969-1974) (c) J o u A n a l cf I n f a n t Behavior and Vevelopment ( 1976- fonward. ] Id) JouAnal o(J LeaAning Visabilities 11977-forward) (e) Child Vevelofoment 11977-1910; 19S5-forivard) Associate EditoA: JouAnal of LeaAning disabilities; Game's Application: Guest EditoA la) Science ( b) JouAnal Ayiim.al P.ehavicA (cj Psychological Review (d) S.R.C.V. Monograph ( G] Human. Vevelopment ( f ) P eh avicA P.eseaAch. Methods and 1n stn u m en ta ticn (g) JouAnal exp. Child Psychology M. l.H. Member of, Clinical and. VcAScnality Fellowship Review-Committee ( 1970-75) N. S.F. Curst Reviewer of Research Grants 11S2) A.C.I..P. /N.l.N.C.V.S 5 year SuppoAt Priorities Subcommittee 11971) (3) Outside Consultant Activities: Uacted. Motions VeveiopvienCTrogr.om (7 976-fcAwaAd) WoAid. Health Organization, Pan American Health. Organization (7 7 l-l 910) Jamaica Ministry of Education and Mitrestry of Social Security 11979-1910) 14) Outside Committee Activities: 13402' Committee for Research' in Infancy lone of the founding members, 163) The VAazelton Infant PehavicA Seale (committee on use for pAematuAe infants, 1977.) Committee fcA Research in Infancy iRccoAd.ing secActary 1967; coorganizer of meet. -7- & B.O.C.E.S., I T I , Committee on Student Adjustment. CentcA, (Jhave seAved cu an occasional irembe.t $ca szvzaoX s e k e d dlstAlats in Suffolk County in helping tc develop S p e d a i Fdetention f a c i l i t i e s . ! (I (ave s zaved as an ou tside evaluation fcA tenute and/on /yiomction d z d s io r s qoa. pxcfessiorals a t 7 univzAsi.ti.es: Einstein. UnivcAsitu; C.H.d.Y.; PatgeAS Univttsily; UniveAslty of Connecticut; University of Ala Fama; University cf Illinois; and University cf Chicago.) dembzAship in PAofessiona l Asse dations: ' Sigma XI American Psychology A,i>soda.tien did Atlantic Asioc.ia.tLon cf Vevzlcpmzrtal Psychologists SLtffolk County Psychological Assentation JtitzA.nati.onal Conference fea Truant Studies Committee {OA PzseoAch in Infancy S c d c X y for Peseatch in Child Development d m Yo a Ii dento pi iJeliological GAoup Infancy Ga o up of Mew YeAt d m Yca !z Academy cf Sdeners InteAnalicnal deuAcpsycholcgical S o d c i y S o d z t y fen the Kennesciences (pending) dationcJ. Academy of deuAopsychology (pending) JnteAnaiional S o d z t y fon the Study o Infant Peh.avicA Hcucas .P.A. Fellov:,V.Lv.csion 7, 1914 A.P.A. division 1 Candidate fen CAedentials Committee dZ/tAltl-PalmzA Annual Heeling: Keynote SpeakzA, 1972 Association of Childten with Lcanning Pisa b-il!ties : Special Pazs entallo n: (1916-1c Association of ChlidAcn with Leatning disabilities dolio nal Institute of d cunoloe and. Communicable Piscases and StAcke Special Ccmmltte.c on PeseoAch PKionitizu fOA Gov eAnment SuppcAt (1972) Pan American Health CAganizatlcn JnteAnaiional Workshop Participant.: Ejects of U.ateAnal dulAiticn on Jurants Health, Pandjachel, Guatemala, (1979) GAants on ('.'kick J Was P d n d p l e Juvestigatoa qa Co-pAlndple Investigatea : d. J.CJT.D. nfant VehavscA (1966-1 970) McCandless Fund: Early Language development (1967-1969) d.J.E. Hale/Female Differences In F.tee WoAd Associations (Ia69-70) S.U.H.Y. Biomedical Fund: Jnfant BehavloA (1972-1973] d.S.F./P.A.d.d. : Erain-Eekavion Pelalio ns hips (1971 -73; 73-76; 76-79) d.J.C.H.P. Jn^ant BehavlcA (197F-7S) Office of Education, E.E.H. (d.V.U. Hed. Centzn.) Brain function and Pemcdlatlon c Leatning P-Lsabltitles (1976-21) A^llllatlcn to Other GAants: U.d.P.P. datx.bbean~J!utJiiticnot. and. Jurant. High Pis!- Longitudinal Study H.ajcn Jnvited LectuAes (last 2 years) : &J"."17lAgsrja~Clfe SpdrTVevetejment Cenfietence: Pialectic AppAoach.es to Development Hethods (1976) S.P.C.V. CcnveAsaticn Holla, on Physiology Heosllaement (1922) A.P.A. Conversation Holla with H. Kaye (1976) S.P.C.V. JntAoductoAy Speo.ker at Symposium: Ju ra n t Conditioning and Pevelop. (197 Hinnesota Sumpcsium en Development: Baci: Funatlcn in J dfancy (1 976) J.d.S. (Etiropean Division) CcmputzA Applicatiom in Heure psycholeg y (Jtaly, 1920] Hid-A.H. Pevel.opmcndtal Psychological Heelings (1921) A.C.L.V./d.J.d.C.P.S. ( 797S] 13403.  Joint U.S.S.P-.-'.'.S.A. Ccn ca enee.: TheoAetlcal. Conceptuallzatloni o{) ExpeAlmental Methodology; U.P.: H.t (enfasi, (1QEC) S a c e l l i Boa. d n c d a l l e r , ( s t a n i m i r i d i l o n; J 911 V ietn am VetcAanH Su a v I vcah S y m p o n lu r, 198? V ie tn a m Ve.teAa.iu Acj e r i charge Victim Annoe . (In v it e d V o A t l d p a n t , 1952) ( I have given about 30 leduAeA to local chcol gaoupn, S p e d a i Education PaAent- Tea.ch.eAH Anne elation*,, and local. lnt.eA.eHt gA.oup In the lant 5 yeoAH. ) 13404 -4- TuXUaticns: "Developmental changes in the olfactony threshold of the. neonate" . Child. Vevetpm., 1965, 34_, 571-376. [with Lips-itt, L.P. and Engen, T.) "Two alter:]otS tc demonstnate tonal suppnession of non-nutnit.ive suck-uig in neonates." Pencep-t. Hot. Stull*, 1963, 1J_, 521-522. (with Levin, G.P.j "Conditioned sucLing in the. human newboAH." Psyehon. S e c . , 1963, 1, 29-3C, (with Lipsitt, L.P. J "Clfaetcny nespenses and adaptation in ike. human neonate.." J. ccmp. physiol. Psychol., 56_, 1964, 73-77. (with Engen, T. and Lipsitt, L.PT1 "Skin Conduc-tance in ike Human Slecnate." Child. Vevelpm., 1964, 35, 1297-1305 "The relation of eteetxono.etu.al thAcs hold to basal skin conductance in the human neonate, Child Develpn., 1964, 35, 1307-1312. (with Lipsitt, L.P. "Hcn-nuinitive sucking by human neoiiate." Child V evetpn., 1964, 35_, 4 79-755. (with Levin, G.R.) "rnimany and seccndany punishment of toe sue king in the infant nhesus monkey." Psychol. Sei., 1965, 3_, 73-74. (with Cox, J., Eosack, P., and Andenson, K.) "Change in neonatat Acsponse to optimizing and non-optimizing ueking timiiation." Psyeh.cn. Sii..,1965, l, 221-222. [with Lipsitt, L.P.) "The eaiditioned Pafcfc.cn response in human newhenns." Psyehon.Sci., 1965, 2, 287-228 "Qpenant Avoidance, in an infant nhesus within the finst month of life." Psyehon. Sei., 1965, 3, 371-372 "Reacting cf M. S'ulatta fnom binth." Labonatoni' Animat Cane Panel, 1966, 16, 176-486. "Enhancemetut cf neonatat ueking through. Aeinfcncemcut." J. Exp. Child Psychol. 1966, 163-168. (with Lipsitt, L.P. and Eosaek, T . ) "Sucking behavicA in the kun:an infant: An evaluation of tie pAoeess aid its modification." Advances in_Child Development and Eeluivion, 1967, Til, 1-50. "The effects of feeding and tonal s-timu.lati.on on non-nu.tA.ltive su.ck.ing in the human nCwbonn." J. Exp. Child Psychol., 1966, 5, 146-154. (with Levin, G.P..) "Wonk decAemcnt and nest ncccveny cuning ncn-nutniti.ve sucking in the human neonate." J. Exp. Child Psychol., 1966, 3_, 146-154. (with Levin, G.P.) "Sensony Pnocesses in Infancy." In Reese, H. and Lipsitt., L.P. (eds.) Expenimeivtal. Child Psychology, Slew Vonk- Academic nness, 1969, l/cl. 3 "Agneemovt among Subjects in choosing .tAigAa.m. labels fon nandom shapes." Amen, J c u a . of Psychol., Dot. 83, Mo. 1, Stanch, 1970. "Effects of vaniatlcn of anal expedience upon suckle." In Posma, J. Qnal 13405 Publication!: (Coni'd.) Semotion and PcAcc.pid.cn, I'cl. 3, C. C. Thomas, H. V., 1973. "Feedback <Acm the lucking envlAnment and lubiequent modification Oq lucking behavicA in ike. human neoriate." J. Exp. Child Piychol., 1974 ^ [with. PhJxiieLi, ( i Ja .) "Some l u g g e i i i o n i fcA a. e c l a i l i f i c a t i c n o n io g cn e iJ.ca .Z iy A e l.e v c n t eaAi.tj piych.omoi.oA b e h a v ic A ." In S c h c p le A , F. and P .e i c lic A , P . FiA l t ly iic A n a iic n a i Lee ^anneA Sym poiium , (PeAgemann Pa c u , London, 1976). "Eanly ExpeAicncc ai ike Faiii foA Unity and. CoopcAoZicn cf ''^iffeAencm", licit Virginia Sympoiiiun in Life Span Vevelopment, Pol. 5, 7?75. "UeuAcmeiAici: Humeaical iaxonemy identifier diffeAent pA.cfil.ei of baai.n function! uithin gAcupi cf bchavioAolly lim-Lia* people." Science, 1977, Uolime 196, UumbeA 4297 (with John, E. Pay and. oiheAl) Kamel, P.Z., Kaye, H. 8 John, E.P. developmental neuAomeiAici: ike uie cf quantitative analyiii cf tAain el.cctAicai. activity to pAobe mental function tliAougkoui life-ipan. In hdnneiota. 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Petersen (Eds.), Automation of clinical electroencephalography. New York: Raven Press, 1973, 217-234. Chang, L.W. Pathogenetic mechanisms of the neurotoxicity of methylmercury. In K.N. Prosad and A. Vernadakis (Eds.), Mechanisms of Actions of Neurotoxic Substances. New York: Raven Press, 1982. Cohen, R., and Nardini, J. The correlation of bilateral occipital slow activity in the human EEG with certain disorders of behavior. Am. J. Psychiat., 1958, 115, 44-54. Duffy, T.E., and Plum, F. Hepatic encephalopathy. In I. Arias, H. Popper, D. Schachter, and D.A. Shafritz (Eds.), The Liver: Biology and pathobiology. New York: Raven Press, 1982. Dwyer, J.H., Karoly, Toth, and Epstein, S.S. Cancer clinical epidemiology in Viet Nam: Phenoxy Herbicides, primary hepatic carcinoma, and toxic neurasthenia. In A.H. Westing (Ed.), Herbicides in War: The long-term effects on man and nature. Stockholm: in press, 1984. Flor-Henry, P., Koles, L.J., Bo-Lassen, P., and Yendall, L.T. 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EEG and Clinical Neurophysiol., 1969, 27_, 480-486. Girgis, M., and Kiloh, L.G. Limbic epilepsy and the dyscontrol syndrome. Amsterdam: Elsevier, 1980. Hecaen, H., and Albert, M.L. Human neuropsychology. New York: Wiley, 1978. Heifel, J., and Bohman, M. Benign epilepsy in children with centrotemporal EEG foci: Intelligence, behavioral, and school adjustment. Epilepsia (Vol. 6 ). New York: Raven Press, 1975, 679-687. Hodgson, E., Bend, J.R., and Philpot, R.M. Reviews in biochemical toxicology. New York: Elsevier Biomedical, 1982. Hoyumpa, A.M., Jr., and Schenker, S. Perspectives in hepatic encephalopathy. J. Lab. Clin. Med., V.100, 1982, 477-487. Ingemar Petersen, K.G., and Sellden, N. On the need to collect EEG data from so-called normal individuals. Clinical Neuropsychology. John, E.R. Functional Neuroscience, Vol. II, Neurometries: Clinical applications of quantitative electrophysiology. Hillsdale, NJ: L.E.A. Publishers, 1977. John, E.R., Easton, P., Prichep. L, Ahn, H., and Baird, H. Neurometric features of children with various cognitive functions or neurological disorders. In A. Rothenberger (Ed.), Developments in Neurology, Vol. 6 , 1983, 389-403. John, E.R., Kaye, H., Friedman, J., Prichep, L., and Ahn, H. Validity, utility and limitations of neurometries evaluations of children. In A. Rothenberger (Ed.), Developments in Neurology, Vol. 6 , 1983, 11-33. John, E.R. Prichep, L., Ahn, H., Easton, P., Friedman, J., and Kaye, H. Neurometric evaluation of cognitive dysfunctions and neurological disorders in children. Prog, in Neurobiology, Vol. 21, 1983, 239-290. Kamp, A., Schrijer, C.F.M., and Storm Van Leeuwen, W. Occurrence of "Beta bursts" in human frontal cortex related to psychological parameters. Electroenceph. Clin. Neurophysiol., 1972, 33_, 257-267. Kellaway, P., and Petersen, I. 'Quantitative analytic.studies in epilepsy. New York: Raven Press, 1976. Kiloh, L.G., McComas, A.J., and Osselton, J.W. Epilepsy. Clinical Electro encephalography (3rd Edition). London: Butterworths, 1977, 71-108. Koshino, Y., and Niedermeyer, E. The clinical significance of small sharp spikes in the electroencephalogram. Clinical Electroencephalography, 1975, 6^, 131-140. IS4C9 -2- Kulig, B.M., Meinardi, H., and Stores, G. (Eds.), Epilepsy and behavior '79. Proceedings of WOPSASSEPY I The first workshop on the Psychological Assess ment of Persons with Epilepsy, 1980, 132-139, 30-35, 90-97. Lockhard, J.S., and Ward, A.A. (Eds.), Epilepsy; A window to brain mechanisms. New York: Raven Press, 1980. Lopes De Silva, F.H., Van Hulten, K., Lommen, J.G., Storm Vein Leeeuwen, W. , Van Veelen, C.W.M., and Vlieganthart, W. Automatic detection and localization of epileptic foci. Electroencephalography and Clinical Neurophysiology, 1977, 43, 1-13. Luria, A.R. Higher cortical functions in man. New York: Basic Books, 1980. Mailman, R.B. Biochemical toxicology of the central nervous system. In E. Hodgson and F.E. Guthrie (Eds.), Introduction to biochemical toxicology. New York: Elsevier, 1980. Manzo, L. , Liery, N., LaCasse, Y., and Roche, L. Advances in neurotoxicology. New York: Pergamon Press, 1980. Matthis, P., Schiffner, D., and Benninger, C. Spectral analysis of the EEG: comparison of various spectral parameters. Electroencephalography and Clinical Neurophysiology, 1981, 52_, 218-221. Milner, B. Hemispheric specialization: Scope and limits. In F.O. Schmitt and F.G. Warden (Eds.), The Neurosciences: Third study program. Cambridge, Mass.: MIT Press, 1974, 75-89. Mirsky, A.F. Epilepsy, attentiveness and consciousness: Recent contributions from behavioral and physiological investigations. A summary and commentary. Contemporary Clinical Neurophysiology (EEG Suppl.), 1978, 34[, 269-275. New York State Department of Health. Dioxin Exposure: Report to the Governer and Legislature, April 1982. Article 24-B, Public Health Law. Nicholson, W.J., and Moore, J.A. Health effects of halogenated aromatic hydro carbons. Annals of the New York Academy of Sciences, Vol. 320, 1979. Nowak, S.M., and Marczynski, T.J. Trait anxiety is reflected in EEG alpha response to stress. Electroencephalography and Clinical Neurophysiology, 1981, 52, 175-191. Penry, J.K., and Daly, D.D. (Eds.), Complex partial seizures and their treatment. Advances in Neurology, Vol. II. New York: Raven Press, 1975. Perry, N.W., Jr., McCoy, J.G., Cunningham, J.C., Falgout, J.C., and Street, W.J. Multivariate visual evoked response correlates of.intelligence. Psycho physiology , 1976, 13, 323-329. Poland, A., and Knutson, J.C. 2, 3, 7, 8-Tetrachlorodibenzo p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annual Review of Pharmacology and Toxicology, 1982, Vol. 22, 517-554. -3- Prasad, K.N., and Vernadakis, A. Mechanisms of action of neurotoxic substances. New York: Raven Press, 1982. Read, A.E. The EEG in liver disease. In A.E. Read (Ed.), The Liver. London: Butterworth, 1967. Rhodes, L.E., Dustman, R.E., and Beck, E.C. The visual evoked response: A comparison of bright and dull children. Electroencephalography and Neuro physiology, 1969, 3_, 364-372. Riley, T.L., and Massey, E.W. The syndrome of aphasia, headaches, and left temporal spikes. Headache, 1980, 20_(2) , 90-92. Riley, T., and Niedermeyer, E. Rage attacks and episodic violent behavior: Electroencephalographic findings and general considerations. Clinical Electroencephalography, 1978, , 131-139. Shagans, C., Gershen, S., and Friedhoff, A.J. Psychopathology and brain dysfunctic New York: Raven Press, 1977. Shukla, G.D., Srivastava, O.N., Katiyor, B.C., Joshi, V. , and Mohan, P.K. Psychiatric manifestations in temporal lobe epilepsy: A controlled study. British Journal of Psychiatry, 1979, 135, 411-417. Simon, 0., Mullner, E., and Heinemann, U. Relationship between background activity and subclinical seizure pattern. Electroencephalography and Clinical Neuro physiology, 1976, 40, 449-455. v Sittenfeld, P., Budzynski, T., and Stoyva, J. Differential shaping of EEG theta rhythms. Biofeedback and Self-Regulation, 1976, 1_, 31-46. Survillo, W.W. Interhemispheric EEG differences in relation to short term memory. Percept, and Motor Skills, Vol. 31, 1971, 246-253. Sutton, S., Tueting, P., Zubin, J., and John, E.R. Information delivery and the sensory evoked potential. Science, 1966, 155, 1436-1439. Thatcher, R.W. Electrophysiological correlates of animal and human memory. In R.D. Terry and S. Gershon (Eds.), Neurobiology of Aging. New York: Raven Press, 1976. Thatcher, R.W., and John, E.R. Functional neurosciences: Vol. I, Foundations of cognitive processes. Hillsdale, NJ: L.E.A. Publishers, 1977. Thatcher, R.W. , McAlaster, R. , Lester, M.L. , Horst, R.L., and Cantor,. D.S. Hemispheric EEG asymmetries related to cognitive functioning in children. Publications of the Applied Neurosciences Laboratories, University of Maryland Medical School, 1983. Towe, A.L. Electrophysiology of the cerebral cortex: Consciousness in neuro physiology. J.C. Ruth, H.D. Patton, J.W. Woodbury, and A.L. Towe, Eds. W.B. Saunders Co., 1968, 455-464. 13411 -4 - Tucker, D.M., Stenlie, C.E., Roth, R.S., and Shearer, S.L.. Right frontal lobe activation and right hemisphere performance decrement during a depressed mood. Archives General Psychiatry, in press, 1983, 1-35. Wagner, S.L. Clinical toxicology of agricultural chemicals. Park Ridge, New Jersey: Noyes Data Corp., 1983. Walsh, K.W. Neuropsychology. Edinburgh: Churchill Livingstone, 1978. Walter, G. Intrinsic rhythms of the brain. In J. Field, H.W. Magoun and V.E. Hall (Eds.), Handbook of physiology, Vol. I. Washington; Am. Physiol. Soc. , 1959, 279-298. Ward, A.A., Penry, J.K., and Purpura, D.P. Epilepsy: Research publications: A.R.N.M.D., Vol. 61. New York: Raven Press, 1983. Waxman, S.G., and Geschivind, N. The interictal behavior syndrome of temporal lobe epilepsy. Archives General Psychiatry, 1975, 32./ 1580-1586. Wexler, B.E. Cerebral laterality and psychiatry: A review of literature. American Journal of Psychiatry, 1980, 137:3, 279-291. 13412 R O N A LD H. K E R M A N , P h .D . I. Qualifications Dr. Kerman is Associate Professor, and Chief, Cellular Immunology, Clinical Immunology Laboratories, the University of Texas Medical School at Houston. His Curriculum Vitae is attached. 11. Subject Matter Dr. Kerman will testify that the special scientific discipline involved is immuno-toxicology which has been defined as "the undesirable effects of an inappropriate response of the immune system". Dr. Kerman will discuss the following in his testimony: the immune system, with its organic, cellular, and hesroral components - most especially with regard to the latter, T-helper cells, 3-cells, plasma cells and immunoglobulin prodaition; immune response, both beneficial and harmful; the various experimental studies, particularly those demonstratin'.!! atrophy of the thymus, weight loss, depletion of lymphoid orpns, lymphopenia, cutaneous type delayed hypersensitivity jskin thickness) and altered bacterial immunity. III. S c ie n tific P rin c ip le s See General Statement of Scientific Principles and Assumed Facts attached. IV . Substance of Opinions A. That TCDD is immunosuppressiveB. That a person exposed to TCDD might have increased predisposition to increased infection, neoplasm (cancer), and other diseases. V . Grounds for each opinion A. General The bases for the facts and opinions to which Dr. Kerman will testify include a review of the applicable medical and scientific literature, his educational and professional background, and his work in connection with the Texas Agent Orange Study. 13414 B . Specif ic As indicated above, Dr. Kerman will testify that 2,3, 7,8-TCDD in particular causes, among others, immuno-suppressive effects, as reported in the literature regarding the various animal species studies. Specifically, TCDD has been demonstrated to suppress T-cell mediated immunity in such species. This effect likewise has been demonstrated in humans by Bekesi, specifically an alteration of mature T-cells. A mort complete exposition of the substance and grounds for Dr. Kerman's opinions is set forth below. B etw een 1961 and 1971, th e U n ite d S ta te s A ir F o rc e dropped more than 100 million pounds of herbicides is Vietnam to defoliate certain forest regions. Chief among the herbicidal agents used was "Agent Orange" which is a mixture of equal parts of 2,4-dichlorophenol (2,4-D) and 2,4,5 trichloropheno 1 (2,4,5-T). Agent Orange contains a toxic contaminant, 2 ,3 ,7 ,8-1 et rach lo rod ib en zo-p-d iox in (variously referred to as TCDD or dioxin), which has been called by some authorities "the most potent small-molecule toxin known" (1 - 2 ). TCDD produces toxic effects in various mammalian species; the toxic manifestations often depend on the species. Guinea pigs are very sensitive to the toxic effects pf TCDD, the single LD50 dose for this chemical being less thaa 1 ug/kg body weight. The LD50 value for mice and rabits is about 100 ug/kg. The toxic effects of the chemical include hepatic damages, thymic atrophy, hematological alterations and teratological effects in various species (3-7). A consistent toxic effect of TCDD in various test animals is damage to the thymus gland. A dose-related depletion of hymocytes from this organ leading to cortical atrophy and hymic involution has been described in various species. Buu-Hoi et al (4) were first to suggest that sublethal doses of TCDD produced thymus atrophy and proposed that the thymus, liver and heart were the target organs of dioxin toxicity. Single or repeated toxic doses of TCDD caused a decrease in bo H $ Q "7 s weight and several vital organs and often reduced organ: body weight ratios. TCDD has been reported to cause a reduction of body weight in guinea pigs, rats, mice, rabbits and monkeys (as reviewed in 8 ). In all species, a consistent reduction in thymus weight was seen. This is often associated with atrophy of the thymic cortex subse quent to the gradual depletion of lymphocytes in this area at low doses of TCDD. Vos and co-workers (6 ) reported the effects of TCDD on the immune system of guinea pigs, rats and mice. Several tests were employed in these three species and the authors con cluded that the Effect of TCDD was primarily on cell mediated immune mechanisms of these animals. Guinea pigs treated with 1 ug/kg of TCDD per week either died or were moribund after 4 doses. At this dose and also at smaller doses (0.008, 0.04 and 0.2 ug/kg), guinea pigs showed severe loss of body weight, depleting of lymphoid organs, particularly the thymus and lymphopenia. At sublethal doses the effects were primarily on the thymus. In selected experiments, the treated and control animals were challenged with a subcutaneous dose of tetanus toxoid or an oil suspension of killed mycobacterium tuberculosis. One and two weeks after a second challenge 7 dose, the TCDD animals had significantly lower tetanus antitoxin titers. Similarly, TCDD animals displayed deceased skin thickness reactions when tested for delayed type hypersensitivity to intradermal tuberculin injections. Female albino rats treated orally with TCDD once a week for 6 weeks displayed reduced body and thumus weights (The relative thymus weight of TCDD treated vas about half of the controls). On the basis of these experiments Vos et al (6 ) concluded that TCDD suppressed the ce11-mediated immunity in guinea pigs, mice and rats. The humoral immunity (antibody response) in guinea pigs Vas also slightly suppressed. Thigpen et al (9) challenged groups of mice treated orally with TCDD to either Salmonella born or Herpesvirus suis. Treatment of mice with TCDD reduced the time of death, after bacterial challenge and also increased the mortality to S.bern. The influence of challenge to similar animals with H. suis influenced neither the period of death nor mortality rate. The conclusion was that treatment with TCDD had i differential effect on bacterial vs. viral challenge. The possibility of alterations in phagocytic ce11 -juact ion or in the interaction of T-cells with phagocytic cells vas suggested. In similar experiments Dean et al (10) reported that mice treated pre and post natally with TCDD displayed decreased host resistance and increased susceptibility to bacterial challenge (listeria monocytogenes). Additionally, these mice were more susceptible to tusor for mation following challenge with PYBG tumor cells froa syngeneic transplantable tumors. Finally, these mice displayed depressed lymphoproliferative responses to PHA which correlated with the decreased host resistance. Sharma et al (11) reported that rabbits orally exposed to TCDD for 8 weeks and then innoculated with tetanus toxoid displayed depressed thymus and popliteal lymph node eights. Serumantitetanus titers showed a decrease at treatmist levels starting from 0.1 ug/kg. Similarly, a significant decrease in the number of plasma cells in popliteal nodes was observed. Skin reactivity to tuberculin was depressed at all TCDD levels. These results were somehwat comparable to those reported in mice by Sharma and Gehring (12) using a similar protocol. It may be concluded that treatment of animals with TCDD produced effects on cell-mediated immune reactions at very low doses, whereas the effect on humoral immunity was observed at high dose levels. The effect on humoral immune responses may be an in direct one, produced by an initial suppression of T cells involved in such mechanisms. Recently, Clark et al (13) reported on the chronic immunocoxic effects of TCDD in mice. Total doses of 1 00 ug/kg or greater produced cellular depletion in thymus, spleen and lymph nodes and the animals appeared sick. The antibody response to sheep red blood cells was impaired following 40 ug/kg TCDD, the delayed hypersensitivity response to oxazolone was impaired by 4 ug/kg and the generation of allo-antieen specific cytotoxid T-cells (CTL) was sensitive to as little .004 ug/kg TCDD. In vitro analysis of the mechan ism of suppression indicated generation of cells capable of suppressing CTL generation in vitro following TCDD. Several studies have been reported where exposure of animals to TCDD has been shown to decrease the responsiveness of lymphocytes to various mitogens in culture. Exposure of rats to various doses of TCDD, pre and postnatally through maternal treatments decreased the synthesis of DNA by splenic and thymic lymphocytes when cultured in the presence of PHA (14). The decreased responsiveness of thymus cells to mitogens, together with the fact that there was depletion of cells in the thymus, suggest a strong immunosuppressive effect of TCDD. A similar effect to that described above for rats was observed in mice and rabbits when these animals were challenged with an appropriate antigen (tetanus toxoid). The effects of a single dose of TCDD in suppressing mitogen responsiveness was most marked in younger animals (1 0 ). The influence of direct addition of TCDD to mouse splenic cultures was reported by Sharma and Gehring (12). TCDD decreased the unstimulated DNA synthesis in lymphocytes at concentrations as low as 10 -9 M. The relative effect of mitogens such as PHA and PWM was also reduced. Luster and co workers exposed spleen cells to TCDD and reported DNA, RNA and protein synthesis in spleens were inhibited. In man several episodes of accidental or purposeful exposure to TCDD have occurred including 1) Sevese, Italy, 1976 where a transient decrease in lymphocytes was reported (15); 2) Monsanto incident, 1949 (Bekesi, personal communications) reporting alterations in mature T cells and 3) the United Kingdom incident at Coalite (reported out in a Transcript from EPA Cancellation Hearings on 2,4,5-T and Silvex (November 14, 1980) wherein the highly exposed group was observed to display depressed PHA response and IgM and IgD immunoglobulin levels. This brief review (as cited above) indicates that TCDD is a potent immunosuppressive. What is most distressing and of greatest concern is the data reflecting decreased immunocomptence following TCDD exposure leading to increased susceptibility to infection and/or possible tumor challenge in experimental animals. It indicates a fundamental inbalance in immunoregu1 ation. R EFER EN C ES 1. Poland, A. and Glover, E.: 2 ,3,7 ,8 -Tetrachlorodibenzo-p-dioxin; a potent inducer of aminolevulinic acid synthetase. Science, 179: A76 , 1973 . 2. McConnell, EE, and McKinney, J.D.: Exquisite toxicity in the guinea pig to structurally similar halogenated dioxins, furans, biphenyls and naphthalenes. Toxicol. Appl. Pharmacol. 45: 298, 1978. 3. Gupta, B.N., Vos, J.G., Moore, J.A., Zinkl, J.G., and Bullock, B.C.: Pathologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals. Environ. Health Perspect. 5:125, 1973 4. Buu-Hoi, N.P., Chanh, P.H., Sesque, G., Azum-Gelade, M.C., and Saint-Ruf, G.: Organs as targets of dioxin intoxication. Naturwissenschaften. 59: 174, 1972 5. Vos, J.G., Moore, J.A., and Zinkl, J.G.: Effect of TCDD on the Immune System of Laboratory Animals. Environ. Health Perspect. 5:149, 1973. 6 . Zinkl, J.G., Vos, J.G., Moore, J.A. and Gupta, B.N.: Hematological and clinical chemistry effects of TCDD. Environ. Health Perspect. 5, 111, 1973 7. Courtney, K.D. and Moore, J.A.: Teratology studies with 2,4,5-T and TCDD. Toxicol. Appl. Pharmacol. 20: 396, 1971 8 . Sharma , R.P.: Effects of TCDD on immunologic systems, in Immunologic Considerations in Toxicology (R.P. Sharma, ed) pg. 89, CRC Press, Inc., Boca Raton, Florida 9. Thigpen, J.E., Farth, R.E., McConnell, E.E. and Moore, J.A.: Increased susceptibility to bacterial infection as a sequela of exposure to an environmental contaminant TCDD. Infect. Immun. 12: 1319, 1975. 10. Dean, J.H., Luster, M.I., Boorman, G.A., Padarathsingh , M.L., Luebke, R.W. and Clements, M.E.: Host resistance models as endpoints for assessing immune alterations following chemical exposure: Studies with Diethy1stilbestjo 1, cyclophosphamide and 2,3,7 ,8- 1 etrachlorodibenzo-p-dioxin in Biological Relevance of Immune Suppression as induced by genetic, therapeutic and environmental factors, (Dean, J.H. and Padarasthingh, M.D., eds), Pg. 233, Van Nostrand Reinhold Co., New York Sharma, R.P., Kociba, R.J. and Gehring, P.J.: Immunotoxicologica1 effects of TCDD in mice and rabbits. J. Environ Pathol. Toxicol. (In Press). Sharma, R.P. and Gehring, P.J.: Effects of TCDD on Splenic Lymphocyte transformation in Mice after Single and Repeated Exposures. Ann N.Y. Acad. Sci. 320: 487, 1979 Clark, D., Gauldie, J., Szewczuk, M.R. and Sweeney, G.: Enhanced suppressor cell activity as a mechanism of Immuno suppression by TCDD. Proc. Soc. Expt.l. Biol. Med. 168: 290, 1981. V o o , J.G. and Moore, J.D. : Suppression of cellular immunity in rats and mice by maternal treatment with TCDD. Int. Arch. Allergy 47: 777, 1974 Reggiani, G.: Medical problems raised by TCDD contamination in Seveso, Italy. Arch. Toxicol. 40: 161, 1978. CURRICULUM VITAE Ronald H. Kerman, Ph.D. DATE OF BIRTH: June 10, 1943 PLACE OF BERTH: Chicago, Illinois NATIONALITY: U.S. Citizen SEX: Male EDUCATION: 1965 1967 1969 University of Illinois, B.S. (with Honors) University of Illinois, M.S. University of Illinois, Ph.D. in Immunology HONORS: 1965 1967-1969 1967 1969-1971 1970 Bachelor of Science with General Honors in the College Recipient of Public Health Service Predoctoral Traineeship Phi Sigma National Biological Honorary Recipient of Public Health Service Postdoctoral Traineeship Society of Sigma Xi RESEARCH AND PROFESSIONAL EXPERIENCE: 19831981- 1977-1980 1974-1977 1973-1977 1972-1973 1969-1971 Associate Professor Department of Pathology, and Chief, Cellular Im munology, Clinical Immunology Laboratories, The Uni versity of Texas Medical School at Houston Associate Professor Department of Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division of Organ Transplantation, The University of Texas Medical School at Houston Member, Program in Immunology, Graduate School of Bio medical Sciences, The University of Texas Health Science Center at Houston Assistant Professor Department of Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division of Organ Transplantation, The University of Texas Medical School at Houston Assistant Professor Department of Surgery, Loyola University Sritch School of Medicine, Maywood, Illinois Research Immunologist Chief, Immunobiology Research Laboratory, Research Service, V. A. Hospital, Hines, Illinois Assistant Professor Department of Microbiology, Jefferson Merfeal College Postdoctoral Fellow, (Immunology) Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine Curriculum Vit.ie Ronald H. 1\ormati. Ph.D. 2 PROFESSIONAL SOCIETIES: RESEARCH INTERESTS: RESEARCH SUPPORT: 1974-1978 1976-1979 1976- 1980 1977- 1973 197719771983-1984 OTHER ACTIVITIES: The Transplantation Society (Editorial Board, Trans plantation and Member, Symposium Committee) American Association of Immunologists American Association for Cancer Research New York Academy of Sciences American Society of Transplant Physicians (Kember, and Vice Chairman, Scientific Studies Committee) Society for Experimental Biology and Medicine International Society for Heart Transplantation American Association for the Advancement of Science American Society for Histocompatibility and Immuno- genetics (Chairman, Finance and Audit Committee, and Member, Laboratory Accreditation Committee) Immunologic response to allotransplantation and malignancy Evaluation of immunocompetency Co-principal Investigator: Bronchogenic Carcinoma: Immu nologic Profile, Radio and Immunotherapy - V.A. Medical Research Grant No. MRIS-8121-08. $213,009 Co-principal Investigator: Immunotherapy Adjuvant to Radiotheraoy of Head and Neck Cancer - VTA. Medical Research Grant No. MRIS-8121-06. $78,814 Co-principal Investigator: Factors Influencing Immuno comptence in Human Transplantation - V,,A. .Medical Research Grant No. MRIS-3068. $68,770 Principal Investigator: Functional and Surface Receptor Differences of Human T-lymphocyte Subocpulations General Research Support Funds, The Diversity of Texas Medical School at Houston. $5,000 Principal Investigator: The Role of HLA Typing in Renal Transplantation, ESRD Program, No. 4500S& $377,400 (last year) Principal Investigator: Immune Monitoring for tbe Diagnosis of Renal Allograft Rejection, ESRD Program, No. 450068. $544,800 (last year) Principal Investigator: Immune Evaluation d Veterans Exposed to Agent Orange. Texas Veterans Agent Orange Assistance Program, IAC(83-84)1266. $93,3$ Special Consultant in Immunology to the Epideaiology and Disease Control Study Section, NIH Consultant in Immunology and Histocompatibility Testing to the Department of Laboratory Medicine, .'O . Anderson Hospital and Tumor Institute Consulting Immunologist to the Upjohn and Sebz Pharma ceutical Companies Editorial Board, Transplantation Review of manuscripts for the journal Human fcnmunology Review of manuscripts for the journal Transpiration Review of manuscripts for the journal Heart Transplantation Book reviewer for Journal of American MedicaSJssociation Literature Reviewer for The American Ansjciation of Clinical Histocompatibility Testing -- AACBSion News Curriculum Vitae Ronuld 11. Kerman, Ph.D. 3 Grant Reviewer for the Kidney Foundation of Canada Grant Reviewer in Transplantation Immundbgy for The March of Dimes - Birth Defects Foundation Outside Reviewer of Research Proposals in Iramunology for the Research and Development Committee, The Vet erans Administration Research Service Invited Participant (as a testing laboratory) in The Third American HLA Workshop Invited Participant (as a testing laboratory) in The Eighth International Histocompatibility Workshop "Relevance of DR typing to renal allograft survival" Invited Participant (as a testing laboratory) The Inter national Transfusion and Transplantation Wsekshop Invited Participant (as a testing laboratory) i>r the Ninth International Histocompatibility Workshop Invited Presenter at an Nil! Workshop, "716 Biological Relevance of Immune Suppression as induced by Genetic, Therapeutic and Environmental Factors" Invited Participant (as a testing laboratory) in the Inter national Collaborative Transplant Study Laboratory Inspector for Clinical Laboratory Accreditation in Histocompatibility for The American Soeiety for His tocompatibility and Immunogenetics and Tbe College of American Pathologists Chairman, Finance and Audit Committee for "Rte American Society for Histocompatibility and Immunofsnetics Member, Symposium and Affiliations C osaittee, The Transplantation Society Member and Vice-Chairman, Scientific StudiesCommittee, American Society of Transplant Physiciuns Member, Acquired Immune Deficiency Synskome (AIDS) Working Group for the Houston Area Chairman, Organizing Committee and Host for The Fourth International Immune Monitoring Symposium: Im munological Evaluation and Monitoring of Transplant Recipient (1983) Member, Organizing Committee for the International Sym posium on Relevant Immunological Factors in Clinical Kidney Transplantation, Heidelberg, West Germany, 1985 Member, UTMSH Admissions Interview Committee Member, UTMSH Admissions Committee Member, Medical Review Board, Organ TrasDlantation Center, UTMSH Member. Committee on Subject Selection for T> University of Texas System Agent Orange Study Member, Steering Committee, Program in Immunology, UT-GSBS Chairman. Bv-Laws Committee, Program in feimunolojy, UT-GSBS" Course Director, "Methods in Cellular Immuiwkgy," a Pro gram in Immunology Course, UT-GSBS BIBLIOGRAPHY Ronald II. Kerman, Ph.D. Publications 1. Kerman. R., Segre, D. and Myers, W.L.: Altered response to pneumococcal polysaccharide in offspring of immunologically paralyzed mice. Science 156:1514, 1967. 2. Kerman. R., Segre, D. and Myers, W.L.: The role of immune and natural specific antibodies in immunologic paralysis and immunity of mice to pneumococcal polysac charide Type III. J. Immunol. 104:655, 1970. 3. Kerman, R. and Segre, D.: Anti-pneumococcal polysaccharide Type III hemolytic plaques in mice: Cellular response in immunity and immunologic paralysis. J. Immunol. _104:1262, 1970. 4. Kerman. R. and Harris, T.N.: Resistance to dnaturation by periodate of a diaiyzable histocompatibility antigen. Proc. Soc. Exp. Biol. Med. 141:175-183, 1972. 5. Kerman. R.H., Harris, T.N. and Harris. S.: Preparation of a diaiyzable histocompati bility antigen from balb/c mice. Proc. Natl. Acad. Sci. 69:223-227, 1972. 6. Smith, R.A., Kerman, R., Ezdinii, E. and Stfani. S.: A modified assay for the detection of human adult active rosette forming ceils. J. Immunol. Meth. 8:175-184. 1975. 7. Kerman. R. and Stefani. S.: Immunological evaluation of patients with solid tumors before ar.d after radiotherapy. In Crispen, R.G. (od.): Neoplasm Immunity. Mecha nisms, pp. 109-120. University of Illinois Press, 1976. 8. Stefani, S., Kerman, R. and Abbate, J.: Immune evaluation of lung cancer patients undergoing radiation therapy. Cancer 37:2792-2796, 1976. 9. Stefani. S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence of patients undergoing radiotherapy for malignancies of the head and neck. Am. J. Roentgenol. 126:880-886, 1976. 10. Kerman, R.H. and Geis, W.P.: Total and active T-cell kinetics in renal allograft recipients. Surgery 79:398-407, 1976. 11. Kerman. R., Smith, R., Stefani, S. and Ezdinii. E.: Active T-rosette forming cells in the peripheral blood of cancer patients. Cancer Res. 3^:3274-3278, 1976. 12. Kerman, R., Smith, R., Ezdinii, E. and Stefani, S.: Unification and technical aspects of total T, active T and B lymphocyte rosette assays. Immunol. Comm. 5(7-8):685694,1976. 13. Dodson, M.G., Kerman, R.H., Lange, C.F., Stefani. S. and O'Leary, J..A.: T and B cells in pregnancy. Obstet. Gynecol. 49:299-302, 1977. Bibliogmony Ronald 11. Kerman. Ph.D. * 14. Korman. R.H. and Stefani. S.: PHA stimulation of lymphocytes from patients with lung cancer. Oncology 34:10-12, 1977. 15. Kerman. R.H. and Stefani, S.: Radio and immunotherapy of lung cancer: A preliminary rcoort. In Crispen, R.G. (ed.): Neoplasm Immunity-Solid Tumor Therapy, pp. 29-35. Franklin Institute Press, 1977. 16. Stefani, S. and Kerman, R.H.: Lymphocyte response to PHA before and after radiation therapy in patients with carcinomas of the head and neck. J. Laryngol. Otol. 91:605-6091 1977. 17. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of the active T-RFC in renal allograft survival. Surgery 8_2:607--612, 1977. 18. Marshack, M., Toto, P. and Kerman, R.H.: Delayed hypersensitivity in the hamster cheek pouch. J. Immunol. Meth. _15:325-330. 1977. 19. Marshack. M., Toto. P. and Kerman. R.H.: Immunotherapy of chemically-induced tumors in the hamster cheek pouch with dinitrochlorobenezene. J. Dental Res. 57:625-630, 1973. 20. Stefani. S. and Kerman. R.: Prognostic significance of pre-therapy delayed hypersen sitivity and T-celi levels in patients with lung cancer. In Nieburgs, H.E. (cd.k Proceedings of the Third International Symposium on the Detection and Prevention of Cancer. Voi. 1, Part U, pp. 785-797. Marcei Dekker, inc., 1978. 21. Geis. W.P.. Iwatsuki. S., Molnar, Z., Giacchino, J.L., Kerman, R.H., Ing, T.S. ana Hano, J.E.: Immunoblastic pseudo-lymphoma in renal allogratt recipients. Arch. Surg. H3:461-466, 1978. 22. Dodson, M., Klegerman. M., Kerman, R.H.. Lange, C., Tessler. J. and O'Leary, J.: Bechet syndrome: With immunologic evaluation. Obstet. Gynecol. 5_l:621-625, 1978. 23. Dodson, M.G., Klegerman, M.E., Menon. M., Kerman. R.H., Lange, C.F. and O'Leary, J.A.: Establishment and characterization of a squamous ceil carcinoma of the vuiva in tissue culture and immunological evaluation of the host. Am. J. Obstet. Gvnecoi. 1_31_:606-519, 1978. 24. Kerman, R.H. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Transpl. Proc. _H)(3):633-635, 197S. 25. Kerman, R.H., Ing, T.S., Hano. J.E. and Geis. W.P.: Predictive value of active T-RFC in renal allograft survival. Transpl. Proc. ]_0(3):637-638, 1978. 26. Kerman, R.H. and Stefani, S.S.: Effect of BCG immunotherapy on the active T and total T-RFC in patients with lung cancer. Cancer Immunol. Immunothcr. 4:41-47, 1978. 27. Kahan, B.D.. Kerman, R.H. and McConnell. R.: Combination of immunological and radionuclide techniques to diagnose allograft rejection. Surgical Forum. 29:364-366, 1973. ` '_ 13429 Bibliography Ronald II. Kerman. Pli.D. 3 `23. Stefani. S. and Kerman. R.H.: Prognostic value of the immunologic profile in inoperable lung cancer patients treated by radiation. In Muggia. F. and Rozencweig, M. (eos.): Lung Cancer (Progess in Cancer Research and Therapy), Vol. 11, pp. 465470. Raven Press. Inc., New York. 1979. 29. Kerman. R.H.: Identification of human T and B lymphocytes. In Natelson, S., Pesce, A.J. and Dietz, A.A.: Clinical Immunochemistry: Chemical and Cellidar Bases and Applications in Disease, pp. 12-20. American Association for Clinical Chemistry, 1979. 30. Kahan, B.D., Floyd, M., Oka, T., Van Buren, C.T. and Kerman, R.H.: Immunological techniques in clinical renal transplantation. I. Cross-Match Methods, Jap. J. Trans plant. 14:1-13, 1979. 31. Kahan. B.D., Floyd, M., Oka. T., Van Buren, C.T. and Kerman. R.H.: bnmunological techniques in clinical renal transplantation. II. Immunological Monitoring Postallografting. Jap. J. Transplant. J_4:14-25, 1979. 32. Kerman, R.H.. Floyd, M., Conner, \V., McConnell, R., McConnell. B.J.. Van Buren. C.T. and Kahan. B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Transpi. Proc. 1_1:1229-1231, 1979. 53. Geis. W.P., Giacchino, J.L., Buckingham, J.M., Bansal. V.K.. Iwatsuki.. S,, Kerman, R.H.. Ing, T.S. and Hano. J.E.: Does suppression of T-RFC determine in vivo immunosuppressive effe ct of ATG? Transpl. Proc. _U: 1433-1434, 1979. 34. Kerman. R.H.. Floyd, M., Van Buren. C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant ArG therapy. Transplantation 30:450-454, 1980. 35. Kerman, R. and Kahan, B.D.: Clinical histocompatibility testing in renal transplanta tion: Potential keys to alloimmune specificity and reactivity. In Reisdd, R. and Ferrone, S. (eds.): Current Trends in Histocompatibility, Vol. 2, pp. 20I-26. Plenum Press, 1981. 36. Kerman, R.H. and Kahan, B.D.: Assessment of immune parameters transplant recipients on immunosuppressive therapy. In Dean. J. and Padarathsingh, M. (eas.): Biological Relevance of Immune Suppression as Induced bv Genetic Theaneutic ann Envi mil inentai Factors, pp. 32-97. Van Nostrana Keinhold Co., New Yort, 19,31. 37 Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prolon^d allograft survival of strong pretransplant immune responders treated with ATG. Transpl. Proc. 13:332-335, 1981. 38. Kerman, R.II., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Correlation of non specific immune monitoring with rejection or impaired function of renal allografts. Transplantation 32:16-23, 1981. 3 9 . Kerman, R.H., Floyd, M., Van Buren, C.T., and Kuhan. B.D.: Predictiona cadaveric allograft survival based on pretransplant nonspecific immunocompetents. Transpl. Proc. 13:1533-1535, 1981. Bibliograohy Ronald il. Kerman, Ph.D. 4 40. Kerman. R.H.. Floyd, ?>!., Van Buren, C.T. and Kahnn, 3.D.: Serial measurement of nonsDecific immune parameters of chronically hemodialvzed renal failure patients. J. Clin. Immunol. 1:163-108, 1981. 41. Kerman, R.H.: New developments in transplantation immunology. The Cancer Bulletin 33(6):231--236, 1981. 42. Kerman, R.H.: Effect of blood transfusion on renal allograft survival:Immunological considerations. Am. J. Kidney Diseases 2:125-127, 1981. 43. Kerman, R.H. and Kahan. B.D.: Immunological evaluation of transplant rejection: Pre and postoperative indices detecting immune responsiveness. In Hayry, P. (ed.): Present and Future Trends in Clinical Transplantation. Ann. Clin. Res. 13:244-263, 1981. 44. Kerman. R.H., Van Buren. C., Payne, W., Flechner, S.. Agostino, (L. Conley, S.. Brewer, E. and Kahan, B.D.: Influence of blood transfusions on immcsse resDonsiveness. Transpi. Proc. 14:335-337, 1982. 45. Kahan. B.D., Van Buren, C.T., Lin, S.N., Ono, Y., Agostino, G., LeGr. S., Boileau, M., Payne. W. and Kerman, R.H.: Immunopharmacologic monitorng of Cyclo sporin A-treated recipients of cadaveric kidnev allografts. Transolantation 34:36-45. 1982. 46. Ono, Y., Kerman, R.H. and Kahan, B.D.: Natural cell-mediated cytotoxicity and suppressor activity for natural cell-mediated cytotoxicity in long-tens renal trans plant patients. Transplantation 34:103-107, 1982. 47. Van Buren. C.T., Kerman, R.H., Agostino, G., Payne, W., Flechner. S. and Kahan, B.D.: The cellular target of Cyclosporin A action in man. Surgery 92:lfT-174, 1982. 48. Kahan, B.D., Kerman, R.H., Agostino, G., Friedman. A. and LeGrue, SJ,; The action of Cyclosporin A on human lymphocytes. In White, D.J.G. (ed.): Cyclosporin A. pp. 281-293. Elsevier - Biomedical Press, Amsterdam, 1982. 49. Agostino, G.J., Kahan. B.D. and Kerman, R.H.: Suppression of rnised leucocyte culture using leucocytes from normal individuals, uremic individuals and allograft recipients. Transplantation 34:367-371, 1982. 50. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, 3J3.: CMV and renal allograft survival. In Eisenstein, T. and Friedman, H. (eds.): Hog Defenses to Intracellular Pathogens, pp. 517-519. Plenum Press, Inc., New York, 12SI. 51. Ettenger, R.B., Kerman, R.. Jordan, S.C., Warshaw, B.L., Harris, R. and Fine, R.: Sensitization following donor-specific transfusions for living related raal transplan tation. Transpl. Proc. 15:943-945, 1983. 52. Van Buren, C.T., Kerman, R.H., Agostino, G., Flechner, S., Payne, W,, and Kahan, B.D.: Effect of cyclosporine on immunoregulatory cells of renal allograft recipients. Transpl. Proc. 15:527-530, 1983. 13431 Biblio.mony Ronaid '.I. Kerman, Ph.D. 53. Kerman. R.H., Van Buren, C.T., Payne, W,, Flechner, S. and Kahan, B.D.: Monitoring T eeii subsets and immune events in renal allograft recipients. Transpl. Proc. 15:1170-1172, 19S3. 54. Flechner, S., Kerman, R., Van 3uren, C.T., Payne, W., and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans plants. Transpl. Proc. 15:442-445, 1983. 55. Agostino. G., Kahan, B.D. and Kerman, R.: Detection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Transpl. Proc. 15:72 4--72S, 1983. 56. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne, W., Flechner, S., Conley, S., Brewer, S. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Transpl. Proc. 15:1022-1025, 1983. 57. Kerman, R.H., Van Buren, C.. Payne, W., Flechner, S., Agostino, G., Conley, S.. Brewer. . and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Trans plantation 3(5:50-54, 1983. 58. Kerman, R.H.. Flechner, S., Van Buren, C.T., Payne, IV., and Kahan, 3.D.: Cyclo sporine improves allograft survival in immunologicaily high-risk renal allograft recipients. Transpl. Proc. 15:1909-1911, 1983. 59. Kerman, R.H., Van Buren. C.T., Payne, W., Flechner, S., and Kahan, 3.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Transpl. Proc. 15:1971-1973, 1983. 60. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Detection of host presensitization to donor alloantigens utilizing a. comprehensive immune crossmatch. Transpl. Proc. 15:1815-1816, 1983. 61. Flechner, S.M., Payne. W.D., Van Buren, C., Kerman. R., and Kahan. B.D.: The effect of cyclosporine on early graft function. Transplantation 36:268-272, 1983. 62. Verani, R.R.. Bergman, D., and Kerman, R.H.: Glomerulopathy in acute and chronic rejection: Ultrastructural characteristics and relationship to graft survival. Am. J. Nephrol. 3:253-256, 1983. 63. Kerman, R.H.: Editorial: Influence of IILA A. B and DR antigen matching in transfused cadaver renal transplant patients. Cleveland Clinic Quarterly 50:216-217, 1983. 64. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, '.V. and Kahan. B.D.: Immuno logical monitoring of renal allograft recipients treated with cyclosporine. Transpl. Proc. 16:2302-2305, 1983. Bibliograohy Ronald 'I. Kerman. Ph.D. 6 65. Van Buren. C., Kerman. R.. Agostino, G., Flechner, S., Payne, W.D., and Kahan, 3.: Effect of cvclosDorine on immunoregulatorv cells of renal allograft reciients. Transpi. Proc. _Pt2293-2297. 1933. 65. Kahan, 3.D.. Van Buren, C., Flechner, S.. Payne, W.D., and Kerman, R.: Cyclosporine immunosuppression mitigates immunologic risk factors in renal allotransplantation. Transpi. Proc. T_5:2469-2478, 1983. 67. Flechner, S.M., Van Buren. C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Transpi. Proc. _16:2G89-2694, 1983. 68. Flechner, S.M., Van Buren, C.T., Kerman, R., and Kahan, B.D.: The effe ct of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Transpi. Proc., 1983 (In press). 69. Flechner. 3.M., Kerman, R.H.. Van Buren, C., and Kahan. B.D.: Successful trans plantation of cyclosporine treated haploidenticai living related renal recipients without blood transfusions. Transplantation, 1984 (In press). 70. Kerman. R.H.. Van Buren, C.T.. Flechner, S.M.. and Kahan, B.D.: Correlation of visual, 3 ^-Cr-release, and flow cytometry crossmatch results to graft survival. Trunspl. Proc., 1984 (In press). 71. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Transpi. Proc., 1984 (In press). 72. Van Buren, C.T., Flechner, S.M., Kerman, R.H., Vaughn, W., and Kahan. 3.D.: Cyclosporine improves outcome in high risk cadaveric renal allograft reem ents. Transpi. Proc. 1984 (In press). 73. Kerman, R.H., Manner, C., Ford, K., and Hoots, K.: Comprehensive immune evaluation of 78 hemophiliacs. Ann. N. Y. Acad. Sc. 1984 (In press). 13433 Bibliography Ronald 11. Kerman. Ph.D. Abstracts and Presentations 1. Kerman, R.. Clark, J. and '.Vbeelock, E.F.: Mononuclear infiltrate into an air pouch: A new in vitro cell mediated immune assay. Fed. Proc, 32:973, Atlastic City, New Jersey, April 1973. 2. Wheelock, E.F., Kerman, R.H., Clark, J. and Toy, S.: Cell mediated immunity in dormant friend virus infections. Proc. Am. Assoc. Cancer Res. _H:68, Atlantic City, New Jersey, April 1973. 3. Stefani, S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence in head and neck cancer patients undergoing radiotherapy. Abstract, American Radium Society Meeting, San Juan, Puerto Rico, May 1975. 4. Kerman. R., Stefani, S. and Geis, W.P.: Total and active T-cell dynamics in renal allograft recipients. Abstracts of the American Society Transplant Surgeons. Chicago. Illinois, May 1976. 5. Kerman, R., Stefani, S., Smith, R., Ezdinli, E. and Geis, W.P.: Immunological evaluation of patients with solid tumors and hematological malignancies. Presented at the 1975 Cancer Symposium, Neoplasm Immunity: Mechanism, Chicago, Illinois. September 1975. 6. Stefani, S., Kerman. R. and Abbate, J.: Immunological evaluation of patients with bronchogenic carcinoma. Presented at the American Society of Therapeutic Radi ology, San Francisco, California, October 1975. 7. Stefani, S. and Kerman, R.: Determination and prognostic value of aimunocompetence in patients with lung cancer treated by radiotherapy. Abstracts of the Third International Symposium on Detection and Prevention of Cancer, New York, April 1976. 8. Geis, W.P., Vaz, A.L. and Kerman, R.H.: Steroid sparing effe ct of ATG in high risk renal allograft survival. Presented at the American Society of Transplant Surgeons Meeting, Chicago, Illinois, May 1976. 9. Kerman, R.H., and Geis, W.P.: Prognostic significance of the active T-cell in renal allograft survival. Presented at the American Society Transplant Surpons Meeting, Chicago, Illinois, May 1976. 10. Stefani, S. and Kerman, R.: BCG and radiotherapy in bronchogesw carcinoma: Preliminary report. Presented at the American Society of Therapeu&k Radiology, Atlanta, Georgia, October 1976. 11. Kerman, R. and Geis, W.P.: T-RFC monitoring of CMI events in rsial allograft recipients. Presented at the Sixth International Congress of the Transplantation Society Special Session Immunological Monitoring of Transplant Recipia, New York, August 1976. 12. Kerman, R. and Stefani. S.: Radio and immunotherapy of lung cancest Apreliminary report. Presented at the 1977 Chicago Symposium: Immunotherapy ofSalid Tumors, Chicago Illinois, February 24-25, 1977. 13434' Bibliorrrnohy Roruild !I. Kerman, Ph.D. 8 13. Stefani. S. and Kerman, R.H.: Relevance of immunologic analysis for patients with inoperable lung cancer treated by radiotherapy. Presented at an NCI sponsored Symposium "The Second Conference on Lung Cancer Treatment," at Airlie House, Virginia. May 22-24, 1977. 14. Kerman. R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of active T-RFC in renal allograft survival. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 15. Kerman. R.H. and Geis, IV.P.: T-RFC monitoring of CMI events in renal allograft recipients. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 16. Ezdinli, E.. Simonson, K.. Icli, F. and Kerman, R.: Effects of single vs. multiple agent therapy on cell-mediated immunity. Proc. Amer. Assoc. Clin. Oncol. J_3:355. Denver. Colorado. May 1977. 17. Geis. W.P., Iwntsuki. S.. Molnar. Z.. Giacchino. J.L., Kerman, R.H.. Ing. T.S. and Hano. J.E.: Immunoblastic pseudo-lymphoma in renal allograft recipients. Presented at the Western Surgical Association, Las Vegas, Nevada, November 15. 1977. 18. Kerman. R.H.. Roesler, H. and Kahan.B.D.: Specific stimulation of active T-Rosette forming cells by 3M KC1 solubilized antigen. Fed. Proc., 1978. Presented at the FASEB-AAI Meeting, Atlanta, Georgia, June 1978. 19. Kerman, R.H., Floyd, M., Conner. IV., McConnell, B.J.. McConnell, R. and Kahan. B . D.: Correlation of active T-RFC and spontaneous blastogenesis with decreased renal allograft function. Abstracts of the American Association for Clinical Histocompatibility Testing, Boston, Massachusetts, June 1978. 20. Kerman, R.II., Roesler, H. and Kahan, B.D.: Increased active T-RFC with in vitro stimulation by soluble donor antigen. Abstracts of the Amer. Assoc, of Clin. Histocomp. Testing, Boston, Massachusetts, June 1978. 21. Kerman, R.H., Floyd, M., Conner, IV., McConnell, R., McConnell, B.J., Van Buren, C. T. and Kahan, B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Presented at the VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 22. Kerman, R.H.: Invited speaker to a special workshop "Immunological Monitoring of the Transplant Patients", VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 23. Kahan, B.D., Kerman, R. and McConnell, R.: Combination of immunological and radionuclide techniques diagnoses allograft rejection. Presented at the American College of Surgeons, San Francisco, California, October 1973. 24. Michelson, J., McConell, Kerman, R. and Kaaan, B.: Association of acute rejection episodes in renal transplant patients with scored results of computer anulyzed data. Presented at the Southwest Society of Nuclear Medicine Meeting, March 16, 1979, San Antonio, Texas. B ibliorrriJDliy Ronald H. Kerman, Ph.D. 9 25. Kerman. R.II., Macek. C. and Kahan, B.D.: Increase in 3 different E-wsette markers on human T cells following pHA activation. Fed. Proc. 38 (No. 3. Part II): 1282. Presented at the Annual Meeting of The American Association of Immunologists, Dallas, Texas. April 1979. 26. Kerman. R.H.: Immunological considerations in renal transplantation. Clinical Oncology Grand Rounds, M.D. Anderson Hospital and Tumor Institute, September 1979. 27. Kerman. R.H. and Kahan, B.D.: Assessment of immune parameters of transplant recipients on immunosuppressive therapy. Presented at an NIH Woctshop on "The Biological Relevance of Immune Suppression as Induced by Genetie Therapy and Environmental Factors," Williamsburg, Virginia, November 1979. 28. Invited participant in a working cadre for the NIH to develop a Consensus On Immunotoxicology" for the National Toxicology Program, November 1379, Research Triangle Park, N.C., NIEHS, NIH. 29. Kerman. R.H.: Histocompatibility testing in transplantation. Pa&ology Grand Rounds, St. Luke's Hospital, January 1980. 30. Van 3uren, C.T., Kerman, R.H. VanBuren, D. and Kahan, B.D.: Correlation of immune resDonsiveness with nutritional indices in chronic renal faiiire patients. Presented at the American Society for Parenteral and Enteral Nutrition, Annual Meeting, Chicago, Illinois, January - February 1980. 31. Kerman. R.H.: Immune monitoring of renal allograft recipients. Sjrgical Grand Rounds, University of Miami School of Medicine, March 1980. 32. Kerman, R.H.: Pre- and postoperative immune monitoring of allograft recipients. Medical Grand Rounds, Division of Dialysis and Transplantation, C'nilEen's Hospital of Los Angeles, April 1980. 33. Kerman, R.H. and Semchuk, R.: Delineation of a radioresistant T celltubpopulation. Fed. Proc. 39(3):945. Presented at the Annual Meeting of The Americsn Association of Immunologists, Anaheim, California, April 1980. 34. Kerman, R.H.: Effect of heat on the ability of human T cells to expres the active T and total T receptors. Fed. Proc. 39(3): 1137. Presented at the Anreal Meeting of The American Association of Immunologists, April 1980, Anaheim, California. 35. Kerman, R., Peddada. L. and Kahan, B.D.: Correlation of hyperacute rejection with LDA and CDA vs. ^ICr-labeled donor T and B cell targets. Presented at The American Association for Clinical Histocompatibility Testing, St. Lons, Missouri, April 1980. 36. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Improved afiagraft survival of strong responder-high risk cadaver recipients with adjuvant imrenaosuppressive therapy. Presented at the Annual Meeting of The American Associa&n for Clinical Histocompatibility Testing, April 1980. Bibliography Ronuld H. Kerman, Ph.D. 10 37. Kerman. R., Conklin, R.. Cahail, D. and Kahan, B.D.: Association of cytomegalovirus and renal allograft survival. Presented at the meeting of the American Association for Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 3S. Kerman. R., Floyd, M., VanBuren, C.T. and Kahan. B.D.: Delineation of donor specific and nonspecific pretransplant immunocomptence as a predictor for LRD allograft survival. Presented at the Meeting of The American Association of Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 39. Kerman, R.H., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant immuno suppressive therapy. Presented at the annual meeting of The American Society of Transplant Surgeons, Chicago, Illinois, May 1980. 40. Kerman, R.H., Floyd, M., VanBuren. C.T. and Kahan, B.D.: Correlation of nonsoecific immune monitoring of renal allograft recipients with rejection and impaired renal function. Presented at the Annual Meeting of The American Society of Transplant Surgeons, Chicago. Illinois, May 1980. 41. Kerman. R.. Floyd, M., VanBuren, C.T. and Kahan, B.D.: Prolonged allograft survival of strong pretransplant immune resDonders treated with ATG. Presented at the VIIIth International Congress of The Transplantation Society, Boston, Massacnusetts, June 1980. 42. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prediction of renal allograft survival based on pretransplant non-specific immunocomptence. Presented at The Second International Symposium on Immunological Monitoring of the Trans plant Recipient, Leiden, The Netherlands, September 1980. 43. Kerman, R.H., Floyd, M., Van Buren, C.T,, McConnell, B.J., McConnell. R. and Kahan, B.D.: Delineation of renal allograft rejection and impaired renal function byserial measurement of non-specific immune parameters. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 44. Kerman, R.H. and Kahan, B.D.: Increased expression of the active T-RFC receptor as a measure of allosensitization following in vitro stimulation of recipient lympho cytes by soluble donor HLA antigens. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 45. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, 3.D.: Correlation of HLA A,B and DR typing to cadaveric and living related renal allograft survival. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 46. Floyd, M., Kerman, R., Woo, J., Van Buren, C.T. and Kahan, B.D.: Relationships of beta-2-microglobulin metabolism, immune reactivity and renal allograft rejection. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 13437 Bibliogrnohv Ronald II. Kerman. Ph.D. 11 47. Kerman. R.H.: Immune monitoring of renal allograft recipients. Surgical Grand Rounds, University of Chicago, June L981. 48. Kerman, R.H., Van Buren, C.T., LeGrue, S.J. and Kahan, B.D.: Immunopharmacological monitoring of cadaveric renal allograft recipients receiving Cyclosporin A. Presented at the Annual Meeting of the American Society of Transplant Surgeons, Chicago, Illinois. June 1981. 49. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, B.D.: CMV and renal allograft rejection. Presented at a Symposium on Host Defenses to Intra cellular Pathogens, Franklin Plaza Hotel, Philadelphia, Pennsylvania, June 1981. 50. Schoenberg, L.P., Kahan, B.D. and Kerman, R.H.: The use of Cyclosporin A as immunosuppressive medication in renal transplantation. Presented at The National Kidney Foundation, Inc., Washington, D.C., November 1981. Amer. J. Kidney Diseases, Program for Clinical Dialysis and Transplantation Forum, p. 29. 51. Ettenger. R., Kerman, R., Arnett, J., Jordan, S., Warshavv, B., Harris, R., Wassner, S. and Fine. R.: Sensitization following donor-specific transfusions for live-related renal transolantation. American Society of Neohrology, Washington, D.C., November 1981. 52. Flechner, S.. Boileau, M., Payne, W., Van Buren, C., Kerman, R. and Kahan, B.: The use of Cyclosporin A in strong immune responder, high risk renal transplant reci pients. American Urological Association, Kansas City, Kansas, 1982. 53. Kerman, R.. Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan. B.: Influence of blood transfusions on immune responsiveness. Presented at The Transfusion and Transplantation Conference, Los Angeles, Cali fornia, January - February 1982. 54. Agostino, G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using mononuclear leukocytes from normals, uremics and allograft recipients. Pre sented at the Annual Meeting of The American Association of Immunologists, FASEB, New Orleans, Louisiana, April 1982. 55. Agostino, G.J., Kahan, B.D. and Kerman, R.H.: Measurement of suppressor cell status in potential allograft recipients. Presented at the Annual Meeting of The American Association of Clinical Histocompatibility Testing, San Francisco, Cali fornia, April 1982. 56. Kerman, R.H.: Invited presenter at two workshops on 1) Immune monitoring of allograft recipients and 2) The effect of transfused blood and blood products on uremic hosts. Presented at the Annual Meeting of The North American Transplant Coordinators Organization, San Antonio, Texas, May 1982. 57. Kerman, R.H., Van Buren. C., Flechner, S., Agostino, G., Conley, S., Brewer, E, and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, June 1982. *2; O' Bibliography Ronuld IL Kerman, Ph.D. 12 58. Agostino. G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using leucocytes from normal individuals, uremic individuals, and allograft recipients. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago. Illinois, June 1982. 59. Kerman. R.H.: Invited presenter at a workshop on "Human T lymphocyte subpopula tions: Their role in rejection and immunosuppression." Presented at the International Congress of The Transplantation Society, Brighton, England, August 1982. 60. Kerman. R.H.: Invited presenter at a workshop on "Mechanisms responsible for blood transfusion effects." Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 61. Ettenger. R.B., Kerman. R., Jordan, S.C., Warshaw, B.L., Harris, R. and Fine. R.: Sensitization after donor-specific transfusions for live-related renal transplantation. Presented at The International Congress of The Transplantation Society, Brighton. England. August 1982. 62. Van Buren. C.T., Kerman. R.H.. Agostino, G.. Flechner. S. Payne. W. and Kahan. B.D.: Effect of cyclosporine on immunoregulatory cells of renal allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton. England, August 1982. 63. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S. and Kahan. B.D.: Monitoring T cell subsets and immune events in renal allograft recipients. Presented at The International Congress of The Transplantation Societv, Brighton, England. August 1982. 64. Flechner. S., Kerman, R., Van Buren, C.T., Payne. VV. and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans plants. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 65. Agostino, G., Kahan, B.D. and Kerman, R.: Detection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 66. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne. IV., Flechner, S., Conley, S., Brewer, E. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 67. Kahan, B.D., Kerman, R., Payne, W.D., Flechner, S. and Van Buren, C.T.: Itnmunopharmacologic studies of cyclosporine-treated renal allograft recipients. Fifth Tripartite Meeting, Society of University Surgeons, Salzburg, Austria, September 1982. /a UibliograDnv Ronald !I. Kerman. Ph.D. 13 r 63. Kerman, R.H., Flectiner, S.. Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo sporine improves allograft survival in immunologicallv high-risk renal allograft recipients. Presented at the Third International Immunological Monitoring Sym posium, Key Biscayne, Florida, November 1982. 69. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Detection of host presensitization to donor alloantigens utilizing a comprehensive immune crossmatch. Presented at the Third International Immunological Monitoring Sym posium, Key Biscayne, Florida, November 1982. 70. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Presented at the Third International Immunological Monitoring Symposium, Key Biscayne, Florida, November 1982. 71. Kerman, R.H.: Invited plenary speaker at the First Annual Meeting of The American Society of Transplant Physicians, "Optimizing immunosuppression: Mode of action of cyclosporine." Chicago, December 1982. 72. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Cyclo sporine improves allograft survival in immunologicallv high-risk renal allograft recipients. Presented at The Annual Meeting, National Kidney Foundation, Clinical Dialysis and Transplant Forum, Chicago, December 1982. 73. Kerman, R.H.: Role of immune evaluation in clinical medicine. Clinical Immunology Grand Rounds, The Children's Memorial Hospital, Chicago, Illinois, December 1932. 74. Kerman, R.H.: Immunologic effects of toxic materials. Presented at Toxicology Clinical Update, University of Texas Medical Branch, Galveston, Texas, January 1983. 75. Kerman, R.H.: Cyclosporine improves allograft survival in immunologicallv high risk renal allograft recipients. Presented at Pathology Grand Rounds, University of Pittsburgh School of Medicine, February 1983. 76. Kerman, R.H.: Immune evaluation of renal failure patients and allograft recipients. Presented at Surgical Grand Rounds, St. Louis University Medical Center, St. Louis, Missouri, March 1983. 77. Kerman, R.H.: Immunological evaluation of hemophiliacs. Presented at a Symposium on Current Problems in the Management of Hemophiliac Complications, Houston, Texas, April 1983. 78. Flechner, S., Kerman, R.H., Van Buren, C.T., Payne, 'V., and Kahan, B.D.: Successful transplantation of high mixed lymphocyte culture haplo-identicul living related donors using cyclosporine and prednisone. Presented at the Annual American Urological Association, Las Vegas, Nevada, April 1983. 79. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, 3.D.: Immunolo gical monitoring of renal allograft recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. *$lk Bibliography Ronaid IL Kerman. Ph.D. 14 80. Van Buren. C., Kerman. R., Agostino, G., Flechner, S., Payne, W.D.. and Kahan. B.: Effect of cyclosporine on immunorcgulatory cells of renal allograft recipients. Presented at The First International Congress on Cyclosporine, Houston, Texas, Mav 1983. 81. Kahan, 3.D.. Van Buren, C., Flechner, S., Payne, W.D., and Kerman, R.: Improved outcome of 150 renal allografts in immunologically high risk recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 82. Flechner, S.M., Van Buren, C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 83. Flechner, S.M., Van Buren. C.T., Kerman, R., and Kahan, B.D.: The effect of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 84. Kerman, R.H., Flechner, S.. Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo sporine immunosuDpression overcomes immunologic risk factors for recipients of cadaveric renal allografts. Presented at the Annual Meeting of The American Society of Transplant Physicians, Chicago, Illinois, June 1983. 35. Flechner. 5.M., Kerman, R.H., Van Buren, C.T., and Kahan, B.D.: The high risk hapioidenticai living related recipient: Transplantation without blood transfusions and steroid withdrawal using cyclosporine. Presented at the Annual "Meeting of The American Society of Transplant Physicians, Chicago, Illinois, June 1983. 86. Kerman, R.H.: Relationship of immunocomptence of hemophiliac patients and acquired immune deficiency syndrome (AIDS). Presented at the Gulf Coast Hemo philia Chapter Meeting, Houston, Texas, October 1983. 87. Kerman, R., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Correlation of visual, 51-Cr-release and flow cytometry crossmatch results to graft survival. Presented at The Fourth International Symposium: Immune Monitoring of The Transplant Re cipient, Houston, Texas, November 1983. 88. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Presented at The Fourth International Symposium: Immune Monitoring of The Transplant Recipient, Houston, Texas, November 1983. 89. Kerman, R.H., Manner, C., Ford, K., and Hoots. K.: Comprehensive immune evaluation of 78 hemophiliacs. Presented at the New York Academy of Sciences Symposium on Acquired Immune Deficiency Svndrome, New York, Now York, Novem ber 1983. 90. Kerman, R., Van Buren, C.T., Flechner, S.M., and Kahan, 3.D.: DRU'6 and DR3 phenotypes correlating with immune response. Presented at the Annual Meeting of The American Association for Clinical Histocompatibility Testing, Chicago, Illinois, November 1983. Bibliography Ronald H. Kerman. Ph.D. 15 01. Van Buren. C.T., Flechner, S.M., Kerman, R.H.. Vaughn, W., and Kahan, B.D.: CyciosDorine improves outcome in high risk cadaveric renal allograft recipients. Presented at the First Meeting of The European Society for Organ Transplantation, Zurich, Switzerland, November 1983. 92. Kerman. R.H.: Cyclosporine immunosuppression for renal transplantation. Presented to Sandoz Pharmaceuticals, Inc., East Hanover, New Jersey, December 1983. 93. Kerman. R.H.: New horizons in transplantation: Influence of cyclosporine on renal transplantation. Invited presenter at the Western Dialysis and Transplantation Society, Park City, Utah, January 1984. 94. Sterling, R.P., Bradley, B.B., Khalil, K.G., Kerman, R.H., and Conklin, R.H.: Compari son of biopsy proven pneumocystis pneumonia in acquired immune deficiency syndrome (AIDS) patients versus renal allograft patients. Presented at The Society for Thoracic Surgeons, San Antonio, Texas. January 1984. 95. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: Correlation of immunopharmacokinetic profiles of cyclosporine-treated allograft recipients and rejection. Presented at The Society for University Surgeons - Residents' Meeting, Chicago, Illinois, February 1984. M A R V IN S. LEG ATO R , P h .D . I. QUALIFICATIONS Dr. Legator is Professor of Environmental Toxicology, University of Texas Medical School at Galveston. His Curriculum Vitae is attached. Dr. Legator has been associated with many committes investigating various toxins, including TCDD, and most especially the recent EPA committee involved with dioxin exposure. II. SUBJECT MATTER The subject matter of Dr. Legator's testimony will include: the teratogenic and carcinogenic effects of TCDD, as well as its mutagenic potential; the multi-system effects of TCDD at extremely low concentrations the demonstrable effects, both gross and more subtle, of TCDD on animals; the extrapolation of the animal studies to humans, that is, the inherent, intended predictive aspects of the animal data to man. Dr. Legator will testify that the animal data are positive and consistent and provide a mechanistic linkage which confirms the Vietnamese epidemiological study of Hatch and others. Further he will testify to his work as a geneticist with respect to reproductive toxicology, i.e. male (Vietnam Veterans) mediated birth defects and certain untoward pregnancy outcomes. Further, insofar as the reproductive toxicological effects, i.e. birth defects and miscarriages, of Agent Orange and/or TCDD, et al. Dr. Legator will testify that such can occur through one or more of the following bio logical mechanisms: (1 )decreased quality of sperm resulting from gonadal lesion during spermatogenesis, altered hormonal regulation, or transmittable defects in heritable characteristics of sperm; (2) potentiation of xenobiotic metabolism in gonadal tissue; (3) secretion of chemicals in Agent Orange or their metabolites into seminal fluid and subsequent transfer to the womb. These mechanisms can result from either the long term effects of past exposure to Agent Orange or from the continuing presence of biologically active concentration of Agent Orange and metabolites of its constituent chemicals within the bodies of exposed persons. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. Dr. Legator will describe the extraordinary precautions which are taken, and the fears of the researchers, in connection with the laboratory use of TCDD.IV. IV. SUBSTANCE OF OPINIONS A. That dioxins are extremely toxic, particularly 2,3,7,3-TCDD. B. That TCDD is exceptionally toxic at extremely low levels; C. That TCDD is a complete carcinogen; D. That, as a carcinogen, there is no safe level of exposure. E. That there is therefore no "no-effect" level of TCDD : F. That TCDD is the most toxic substance ever synthesized by man; G. That TCDD is acnegenic; H. That TCDD is immunosuppressive; I. That TCDD is teratogenic; J. That TCDD is fetotoxic; K. That TCDD is gonadotoxic; L. That TCDD is capable of transmitting genetic damage; M. That the miscarriage of Mrs. Dan G. Jordan and the congenital malformations of the children of Mr. and Mrs. Dan G. Jordan, as well as those congenital malformations and birth defects of Kerry Ryan, daughter of Mr. and Mrs. Michael F. Ryan, are consistent with the presumed exposure of representative plaintiffs Jordan and Ryan to phenoxy herbicides and dioxins - specifically 2,3,7,8-TCCD -- while serving in Vietnam. GROUNDS FOR OPINIONS A. General The bases or grounds for such facts and opinions include Dr. Legator's: educational and professional experience; personal research; review of the appli cable medical and scientific literature; and a review of the medical record and/or data of the Jordan and Ryan familes. B. Specific The additional grounds for Dr. Legator's opinions can be found in:1 1. Dioxins are extremely toxic: the EPA Criteria Documents, Publications and associated references. 2. TCDD toxic at low levels: the EPA Criteria Documents, Publications and associated references. 3. TCDD complete carcinogen: National Cancer Institute 1980a. Bio assay of 2 ,3,7,8 - tetrachloro-dibenzo-pdioxin for possible carcinogenicity (dermal study) U. S. Department of Health and Human Services Pub. No. 80-1757. National Cancer Institute 1980B. Bio assay of 2 ,3,7,8-tetrachloro-dibenzo-pdioxin for possible carcinogenicity (gavage study) U. S. Department of Health and Human Services Pub. No. 80-1765. 4. No safe level: IARC: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 5. No "no effect" level: IARC: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 6 . TCDD most toxic substance: EPA (cited above) IARC (cited above) 7. TCDD - acnegenic : Kearney, D.C., et al. 1973 Environmental Significance of chlorodioxins. Adv. Chem. Ser. 120:105 8 . TCDD - immunosuppressive: - Harris, M.W., J.A. Moore, J.G. Vos and B. N. Gupta. 1973. General biological effects of TCDD in laborator animals. Environ. Health Perspect. 5: 101. - Kearney, D.C. et al. 1973. Environmental significance of chlorodioxins. Adv. Chem. Ser. 120: 105. 9. TCDD - teratogenic: - Courney, K.D., D. W. Gaylor, M.D. Hogan and H. L. Falk. 1979. Teratogenic evaluation of 2,4,5-T. Science 1968: 864. - Kociba, R. J., P. A. Kesler, C. N. Park and P. J. Gehring. 1976. 2 ,3,7 ,8-Tetrachlorodibenzop-dioxin results of a 13-week oral toxicity study in rats. Toxicol. Appl. Pharmacol. 35: 553. - Kociba, R. J., D. G. Keyes, J. E. Beyer, R. M. Carreon, C. E. Wade, D. A. Dittenberg, R. P. Kalnins, L. E. Frauson, C. N. Park, S. D. Barnard, R. A. Hummel and C. G. Humiston. 1978. Results of a two-year chronic toxicity and oncogenicity study of 2 ,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46: 279. - Kociba, R. J., D. G. Keyes, J. E. Beyer, R. M. Carreon and P. J. Gehring. 1979. Long term toxicologic studies of 2 ,3,7,8-tetrachlorodibenzop-dioxin in laboratory animals. Ann. N.Y. Acad. Sci. 320: 397-404. 10. TCDD - fetotoxic: - McConnell, E.E., J. A. Moore and D. W. Dalgard. 1978a. Toxicity of TCDD in Rhesus monkeys (Macaca mulatta) following a single oral dose. Toxic. Appl. Pharmacol. 43: 175. ' TCDD - gonndotoxic: - Neuoert, D., P. Zens, A. Rothenwallner and H. J. Merker. 1,973. A survey of the embryotoxic effects of 1CDD in mammalian species. Environ. Health Perspect. 5: 67. i2. TCDD can cause genetic damages: - Murray, F. J., F. A. Smith, K. D. Nitschke, C. G. Humiston, R. J. Kocibe and B. A. Schwutz. 1979. Three-generation reproduction study .f rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol. Appl. Pharmacol. 50: 241. - Seiler, J. P. 1977. Inhibition of testicular DNA synthesis by chemical mutagens and carcinogens. Preliminary results in the validation of a novel sh. rt-term test. Mutat. Res. 4t: 335. - Green, S. et al. 1977. Cytogenetic effect of 2 ,3,7,8-tetrachlorodibenzo-p-dioxin on rat bone marrow cells. U . S. Food and Drug Admin., Washington. D.C. FDA By-Lines 7: 292. Allen JR, Carstons LA. Lignt and electron microscopi. observations in Mncac ; mulatto monxeys ted toxic rat. Am J Vet Res 2o :1513-i_<20, - Jons table J, Hatch M. Herbicide exposure and rcoroduc *v outcome. In- Herbicides :n W ;r: The Lone-term Ef:rcts ni and 'of.ire, AW nesting, ec. New- iorx: tayior A rrancis, SJoi* yin press). _ Khera ".S, Ruddick JA. Pciychlorodibenzoistar-p-dioxins: Perinatal effects and the dominant iotnal test in Wistar rata. In: Chiorcuioxms - Origin and Fate, l.:: Blairc, ed. Washington DC: American Chemical Society, 1973, pc 70-Sa . ~ Kociba F.J, Peeler PA< Pork CM, Gehr :ng PJ. 2,3,",Stctrachlorodibonao-p-aioxin (TCDD): Results of a 13-week oral toxicitv study m rats. Toxicol Appl Pharmacol 33:553-575, 1976. - McConnell PC'. Moore JA-.' Haseman JK, Harris MV?> The comparative toxicif of .:.lormated ci ber.co-;>-d: oxins m mice and guinea pigs. Toxicol Appl Pharmacol -*:335-356, 1973. - Mattison DR, Thorgeirsson SS. Gonadal arvl hvdrocarncn hvdroxvlase m rats and mice. Cancer Res 33:1jo8-i3~3, 17S. 13447 - N'orback DH, Allen JR. Biological responses of the nonhuman primate, chicken and rat to chlorinated dibenzo-p-dioxin ingestion. Environ Health Perspect 5:233-240, 1973. -Peterson, R. Hormonal changes and "wasting" observed in moderatelv-h:gh-u'se animal experiments. Presented at the Symposium or Putilic Health Risks of the Dioxins, The RocKeieller Lmversit y , October 19-20, 1933. (Proceedings in press, Alan R. Liss Inc.) -Poland A, Knutson JC. 2,3,7,S-tetrachlorodibenzo-p-dioxin and related aromatic hydrocarbons: Examination of the mechnanism of toxicity. Ann Rev Pharmacol Toxicol 22:517-554, 1982. -Tofilon PJ, Piper W'N. 2,3,7,8-tetrachlorodibenzo-p-dioxinmediated depression of rat testicular heme synthesis and microsomal cytochrome P-450. Biochem Pharmacol 31:3663-3666, 1982. In addition, Dr. Legator may rely on some of the following reference for his specific opinions REFERENCES A l l e n , J . R . , D.A. B a r s o t t i , J . P . Van M i l l e r , L . J . Abrahamson and J . J . Lauch. J 977 . Morphological cnanges in monkeys consuming a d ie t containing low l e v e l s of TCDD. Food Cosmet. To xic ol. 15: 401. B erry , D.L. et a l . 1976. Transplacental induction of carcinogen hy d rnx iy lc ti ng systems with 2 ,3 , 7 , 8 - tetrachlorodibenzo-p-dioxin. T o xic o l. Appl. Pharmacol. 36: 569. Be rry , D.L. et a l . 1972. Studies with chlor inated dibenzo-po io x in s , polybron.'inated biphenyls, and polychlorinated biphenyls in a two-stage system of mouse skin tumorinenes i s : potent an t ic arc in o qenic e f f e c t s . Am. N.Y. Acad. S c i. 320: 405. Chliabra, R .S. et a l . 1974. Selection of inducers as an importance factor in characterizing genetic differences to induction or aryl hydrocarbon hydroxylase in s t r a i n s of mice. L i f e S c i . 15: 123. DiGiovanni, J . , A. V i a j e , D.L. Be rry , T . J . Slaga and M.R. Juchau. 1977. Tu m or- in it ia ti n g a b i l i t y of 2.3,7,8-Letrachlorodibenzo-pdioxin (TCDD) and Arochlor 1254 in the two-stage system of mouse skin carcinogenesis. B u l l . Environ. Contain. T o x ic o l. 18: 552. DiGiovanni, J . , D.L. B e r ry , M.R. Juchau and T . J . Slaga. 1979b. 2 ,3 .7, 8-T etr ach lor odi t; cr.zo -p- di ox in: po:.ent anticarcinogenic a c t i v i t y in CD-I mice. Biomem. Biophys. Res. Comm. 86: 577. DiGiovanni. J . , D.L, Be rry , T . J . Slaga, A.H. Jones and M.R. Juchau. 1979a. E f f e c t s of pretreatment with 1CDD on the capacity of hepatic and ext raheoatic mouse t is s u e s to convert procarcinogens to mutagens f o r S t yphirn:;;-; cm auxotrophs. To x ic o l. Apr'. Pharmacol. 50: 229. (i re c r, 5. arid F . S . Moreland. 29 75. Cytogenetic evaluation of several dioxins in the r a t . To x ic o l. A r p l . Pharmacol. 32: 161. Grieg, J . B . ano F. DoMatteis. 1973. E f f e c t s of 2 , 3 , 7 ,8 -t e tr a ch lo r o dahc-n:::j- p-oioxir. on dre'" metabolism and heoatic microsomes of ra t s and mice. Environ. Health Aersoect. 5: 211. Guenther, T.M ., J.M. Fysh and G.W. Nebert. 1979. 2 ,3 , 7 , 8 - Te t r a - ch 1orodibenzo-p-ciioxin: covalent binding of r e a c t iv e metailb o lic intermediates p r i n c i p a l l y to protein in v i t r o . Pharmacology (19) 12- 22. 1; Hussain. S. , L. Ehrenberg, G. Lofroth and T. G e j v a l l . 3972 . Muta genic e f f e c t s of TCDD on b a c te r ia l systems. Ambio. 1: 32. Jones, G. and J . E . G; iec*. 1575. Pathological changes in the l i v e r of mice given ? , 3 , 7 , 8 - Letrachlorodibenzo-p-dioxin. Exp erien tia 31(12): 1315-1317. Khera, K.S. and J . A . Roddick. 1973. Pcl.ychlorodibenzo-p-dioxins: prenatal e f f e c t s and inn dominant let hal test in Wistar r a t s . I n : E.D. B l a i r ( e d . ) , Chi orodi oxi ns - o r i g i n s end f a t e . Adv. Clism. S e r . , No. 120. Am. Chem. Soc. , Washington, D.C. o. 70. K o u r i , R. 1976. . .ationship between le v e ls of aryi hydrocarbon hydroxylase a c t i v i t y and s u s c e p t i b i l i t y to 3-methyicholanthrene and benzo(a)-pyrene-induced cancers in inbred s t r a i n s of mice. j_n: R . J . Freudr-' thal and P.W. Jones ( e d s . ) , Polynuclear aromatic hydrocarbons: chemistry, metabolism and carcinogenesis. V o l. 1. Raven Pr es s, N.Y. p. 139. K o u r i , R .E . and [).W. Nebert. 1977. Genetic regulation of suscep t i b i l i t y to p o l y c y c l i c hydrocarbon-induced tumors in the mouse. I n : Proc. Symp. Origins of human Cancer. Cold Spring Harbor, N.Y. L u c i e r , G.W. et a l . 1973. TCDD-induced changes in r a t l i v e r microsomal enzymes. Environ. Health Perspect. 5: 199. Matsumura, F. and H . J . Benezet. 1973. Studies on the bioaccumula tion and microbial degeneration of 2,3 ,7 ,8 -t et ra c hl oro di be nz o-p d io xin. Environ. Health Perspect. 5: 253. McConnell, E . E . , J . A . Moore, J . K . Haseman and M.W. H a r r i s . _ 1978b. The comparative t o x i c i t y of chlor inated dibenzo-p-dioxins in mice and ouinea pigs. To x ic o l. Appl. Pharmacol. 44: 335. Moore, J . A . , B.fl. Gupta, J . G . Z i n k l , J . G . Vos. 1973. Postnatal e f f e c t s of maternal .-oosure to 2 ,3 , 7 , 8- te tra ch lo ro di benzo-p-di ox in (TCDD). Environ, lie ch Perspect. 5: 81. Neal, R . A . , P.W. Beatty and T.A. Gasiewicz. 1979. Studies of the mechanisms of t o x i c i t y of 2 ,3 ,7 ,8 -te tra c hl oro di be nz o-p- d io xin (TC;'T). Ann. N.Y. Acad. S c i . 320: 204. P i t o t , H. C. , T. Goldsworthy, H.A. Campoell and A.` Poland. 1980. Quan titative evaluation of the promotion by 2 , 3 , 7 , 8 - t e t r a c h l o r o dibenz -p-dioxin o? hepatocarcinoaenesis from d i e t 1, initrosamine. Can. Res. 40: 3516-3620. Poland, A.P. and E. Glover. 1973a. Chlorinated dibenzo-p-dioxins: potent inducers of u-Aminoievulinic acid synthetase and aryl hvdrocarbon hyoroxylase. I I . A study of the structure- a c t i v i t y r e l a t i o n s h i p . Molecular Pharmacol. 9: 736. Poland, A.P. and E. Glover. 1973b. 2,3 ,7, 8-T etrachlorodibenzo-pdioxin: a potent inducer of u-Aminolevulinic acid synthetase. Science 179: 476. Poland, A.P. and E. Glover. 1974. Comparison of 2 , 3 , 7 , 8 - t e t r a chlorodibenzo-p-dioxin a potent inducer of ary l hydrocarbon hydroxylase with 3-methylcholanthrene. Mol. Pharmacol. 10: 349. Poland, A.P. and E. Glover. 1979. An estimate of the maximum in vivo covalent binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rat l i v e r p r o t e i n , ribosomal RNA, and DNA. Cancer Res. 39: 3341. Poland, A.P. and A. Kende. 1976. 2 ,3 ,7 ,8 -te tra c hl oro di be nz o-pd i o x i n : environmental contaminant and molecular probe. Fed. Proc 35: 2 m - Poland, A . P . , D. Smith, G. Metier and P. P o ' s i c k . 1971. A health survey of workers in a 2,4-D and 2 , 4 , 5 - T p i j t. Arch. Environ. Health 22: 316. 13450 Poland', A.P. et a l . 1974. Genetic expression of aryl hydrocarbon hydroxvlase a c t i v i t y induction of mono-oxygenase a c t i v i t i e s and cvtochrome P-1-450 formation by 2,3,7,8-TCDD in mice g e n e t i c a l l y . Jour. B i o l . Chem. 249: 5599. S e i l e r , J . P . 1973. A survey on the mutagenicity of various p e s t i c ide s. Experientia 20: 622. Smith, F . A . , B.A. Schwetz and K.D. Nitschke. 1976. Te ra tog eni cit y of TCDD in CF-1 mice. T o x i c o l . Appl. Pharmacol. 38: 517. Sparschu, G . L . , F . L . Dunn and V. K. Rowe. 1971. Study of the t e r a to g e n ic i ty of TCDD in the r a t . Food Cosmet. T o xic o l. 9: 405. Toth, K. , S. Somfai-Relle, J . Sugar and J . Bence. 1979. Carcino genicity of herbicide 2,4,5-trichloro-phenoxyethanol-containing dioxin and of pure dioxin in Swiss mice. Nature 278: 548. CURRICULUM VITAR NATE: Marvin Seymour Legator, Ph.D. DATS: November, 1983 PRESENT POSITION AND ADDRESS: Professor and Director Division of Environmental Toxicology Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston, Texas 7755*0 Office phone: 409/761-1803 BIOGRAPHICAL: Date of Birth: Place of birth: Marital Status: Children: Home Address: Socia.1 Security Number: June 27, 1926 Chicago, Illinois Married Three 70 Colony Park Galveston, Texas 77951 348-16-3682 EDUCATION : 1948 Microbiology-Biochemistry 3.A. University of Illinois Urbuna, Illinois 1948 Biochemistry M.S. University of Illinois Urbana, Illinois 1981 Microbial Genetics-Biochemistry Ph.D. University of Illinois Urbana, Illinois PROFESSIONAL AND TEACHING EXPERIENCE: 1976-present Professor aid Director Division of Environmental Toxicology Depiirtment of Preventive Medicine and Community Health University of Texas Medical Branch Curriculum Vi rae - Ilarviti oeymour Legator Paye 2 1972-1976 Professor of Genetics 1965-1972 Professor (part-time) General and Medical Genetics 1962 - 1972 Chief, Branch Genetic Toxicity Branch 1952-952 Head, Animal Healtli Program 1951-1952 Senior Microbiologist 19^-1550 instructor Galveston, Texas Brown University Providence, Rhode island George Washington University Washington, D.C. Food and Drug Administration Washington, D.C. Shell Development Company Modesto, California Julius Hyman Company Denver, Colorado University of Illinois Urbana, Illinois COMMITTEE RESPONSIBILITIES: UT!3 Committees : University Cancer Center Committee (through 1952) University Appointment, Promotion and Tenure Committee (through I960) University Fellows Grants Committee Department of Preventive Medicine and Community Health Executive Committee Department of Preventive Medicine and Community Health Steering Committee Department of Preventive Medicine and Community Health Application, Promotion and Tenure Corsmittee Outside Committees: 1953 Environmental Protection Agency Science Review Panel, for Health Research 1953 Subject Selection Committee of the Texas Veterans Agent Orange Assistance Program 195U March of Dimes Committee on Reproductive Hazards (Chiirrnan) 1950 19oU Environmental Protection Agency Research Grant Review Panel Environmental Protection Agency Criteria Document Panel 13153 Curriculum Vitae - Marvin Seymour1 Legator Page 3 190 190 1975 1975 1973 1972 1971 1971 1971 1970 1970 Environmental Protection Agency Committee Chairman, Gene-Tox Program (HHA) Science Committee of Food Safety Council Oversight Committee for Proctor and Gamble to determine adequacies of toxicological procedures Committee 17, Analysis of Methodology of Mutagenicity Testing National Academy of Science Cocmittee on Biological Hazards of Low Levels of Radiation Member of Swedish Government Sponsored Corrmittee on Mutagenicity Testing Japanese and United States Government Committee on Toxicology Member of World Health Organization Committee on Use of Hycanthone Chairman of Government Hearing on Safety of Lmmunological Preparations Member Steering Committee on Industry-Academic, Committee on Toxicology National Institute of Mental Health - Committee on Genetics Effects of Drug Abuse MEMBERSHIP IN SCIENTIFIC SOCIETIES: American College of Toxicology Environmental Mutagen Society New York Academy of Sciences Society of Occupational and Environmental Health HONORS: Honorary Health Advocate Award - "... awarded in recognition of outstanding contributions in health advocacy and promotion of the public's health to Marvin S. Legator." Health Policy Advisory Center, New York, New York, November lb, 193- Food Safety Council 1976-1932 - "With deep appreciation for the tireless effort that Marvin Legator devoted to help the Food Safety Council achieve its goals. Ibis experiment in concensus building ins s h o w that representatives from industry and non-industry with different viewpoints can work together toward a better way for mailing food safety decisions." 45 Curriculum Vi cue - Marvin eymour Legator Page 4 U.S. Environmental Protection Agency Certificate of Award - Presented to Marvin S. Legator in recognition of noteworthy contribution and special achievement for the U.S. Environmental Protection Agency, Cincinnati, Ohio Visiting Scholar Award at Western Michigan University 1980 Nominated for I98O Distinguished Faculty Research Award F.D.A. Award of Merit - Presented to the Genetic Toxicology Branch (M. Legator, Chief), 1971 Key Lecture Award by the American Genetics Association for Outstanding Contributions on the Implementation of Genetics for Hunan Welfare and Improvement, 1970 U.S. Government Award - Technique Advance in Cell Culture, 1985 ADDITIONAL INFORMATION: Areas of Teaching and Research Competency: Mutagenicity Cytogenetics Reproductive Studies Biochemistry Molecular Biology Tissue Culture (Post Doctorate Course, University of Wisconsin, Madison, Wisconsin) Consulting Activities: Panel Member, Toxicology Panel on Psychochemicals, Commission on Life Sciences, National Research Council, National Academy of Sciences, 1983 Expert Witness, Texas Senate Subcommittee on Consumer Affairs, 1982 Expert Witness, U.S. House Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, 1982 Consultant, Hooker Chemical Company, 198U Consultant, JRB Associates, 198U Consultant, Toxi-Genics (Fabrizio), 1980 Consultant for Environmental Protection Agency, 197b-l980 Consultant for Lady Clairol, 1978-1978 Expert Witness, Committee on Science and Teclinology, 1979 Dow Chemical Company, 197^--1979 National Institute of Drug Abuse, 1973-1980 Consultant, Senate Committee on Public works, 1970 Other Activities: Elected Member, Collegium Ramazzimi, 1983 Member of the Board of Directors, Committee for Responsible Genetics, 1983. 13455 Curriculum Vitae - Marvin ,,ymour Legator Page 5 Member, Critical Issues Committee on Accreditation, Certification and Standardization, Environmental Mutagen Society, 1983-84. Co-chairperson, Workshops and Training Committee, Environmental Mutagen Society, 1983-84. Member of the Board, Texas Center for Rural Studies, Inc. The corporation is organized to provide research and educational services rcgaruing the quality of life in Texas, including, but not limited to, the health, economic and environmental effects of pesticides and other chemicals; public policies effecting the rural economy; and the enhancement of the role of family farmers, farm laborers and rural residents in Texas agriculture, 1983, Austin, Texas. Co-Director of Workshop, Environmental Influences on Fertility, Pregnancy, and Development: Directions for Future Research, May 24-25, 1982, Cincinnati, Oiiio Director of CME Workshop for Practicing Physicians, Recognizing, Diagnosing, and Treating Chronic Toxic Chemical Effects, July 16-18, 1981, Galveston, Texas Director of Annual Genetic Toxicology Course, Galveston Director of Annual Genetic Toxicology Course, Hunt Valley Co-Director of Annual Toxicology and Law Course, Houston Director of Annual Workshop on Carcinogenicity, Mutagenicity and Teratogenesis sponsored by the March of Dimes Birth Defects Foundation Faculty member of short course on Toxicology at Wayne State University, 1976-1979 Coordinator of Workshop on Occupational Monitoring for Genetic Hazards, March 27-29, 1975 Visiting lecturer to Heidleburg University, Germany, 1971 iessensibilities: Editor, Journal of Teratogenesis, Carcinogenesis, and Mutagenesis Editorial Board of Environmental Mutagenesis Journal (through 1981) BIBLIOGRAPHY: Journal Articles: Legator, M.S., and Gottlied, D. 1954. The Biosynthesis of Chloramphenicol 1 Precursors Stimulating the Synthesis. J. Bacteriol. 2. Legator, M.S., and Racussen, D. 1959- Mechanism of Ally Alcohol Toxicity. J. Bacteriol. 2. Legator, M.S., and Withrow, A. 1964. Aflatoxin: Effects on Mitotic Division in Cultured Embryonic Lung Cells. J. Assn. Official Agricultural Chemists 47:1007-1009. Cliilds, V.A. , and Legator, M.S. 1965- Lactic Detiydrogenase. Isozymes in Diploid and Heterploid Cells. Life Sciences 4: 1p 43-1650. Legator, M.S., Zuffante, S.M., Harp, A.R. 1965- .Aflatoxin: Effect on Cultured Heteroploid Human Embryonic Lung Cells. Mature (London) 208:345-347- Curriculum Vitae - Marvin Seymour Legator Page 6 Childs, V.A., and Legator, M.S. 1966. Induction of Thymidine Kinase by Aflatoxin. Life Sciences 5:1053-lU56. Legator, M.S., Jacobson, C.B., Perry, M., and DolLmpio, D. 1966. Tlie l/ooly Opossum -- A New Research Tool for Cytogenetic Studies. Life Sciences 9:397-402. Legator, M.S. 1966. Biological Effects of Aflatoxin in Cell Culture. Bacteriological Reviews 30:471-477- Wragg, J., Ross, V.C., and Legator, M.S. 1967* Effect of Aflatoxin B1 on Deoxyribonucleic Acid Polymerase of Escherichia Coli. Proceedings of the Society for Experimental Biology and Medicine 125:1052-1055- Kolbye, S., and Legator, M.S. 1966. Mutagenic Activity of Streptozotocin. Mutation Research 6:367-369- DolLmpio, D., Jacobson, C., and Legator, M.S. 1966. Effect of Aflatoxin on Human Leukocytes. Proceedings of the Society for Experimental Biology and Medicine 127:559-562. Legator, M.S., and Jacobson, C.B. 1966. Chemical Mutagens as a Genetic Hazard. Clinical Proceedings 24:164-169- Gubridge, M.D., DeNunzlo, A., and Legator, M.S. 1969- Cycasin: In Vivo Detection of Associated Mutagenic Activity. Science 163:669-691- Gabridge, M.G., DeNunzio, A., and Legator, il.S. 1969- Microbial Mutagenicity of Streptozotocin in Animal-Mediated Assays. Nature 221:66-70. Gabridge, M.G., Oswald, E.J., and Legator, M.S. 1969- The Role of Selection in the Host-Mediated Assay for Mutagenicity. Mutation Research 7-117--119- Gabridge, M.G., and Legator, M.S. 1969- A Host-Mediated Microbial Assay for the Detection of Mutagenic Compounds. Proceedings of the Society for Experimental Biology and Medicine 130:631-634. Mayer, V.U. and Legator, M.S. 1969- Production of Petite Mutants of Saccharomyces Cerevisiae by Putulin. J Agric Food Chern 17:454-456. Legator, M.S. and Mailing, H.V. 1969. Concepts in Mammalian Testing for Chemical Mutagens. EMS Newsletter 1:12-15- Legator, M.S., Palmer, K.A., Green, S., and Petersen, K.W. 1969- Cytogenetic Studies in Rats of Cyclohexylanine, a Metabolite of Cyclamate. Science 165:1139-1140. Legator, M.S., Kelly, F.J., Green, S., and Oswald, E.J. 1969- Mutagenic Effects of Captan. New York Academy of Sciences 160: 344-351- Mayer, V.W., and Legator, M. 1970. induction of N-Metiiyl-N'-Nitrosoguanidine and IT/ Light of Petite Mutants in Aerobically and Anaerobically Cultivated Saccharomyces Cerevisiae. Mutation Research 9:193-196. IM S Curriculum Vitae - Marvin ..--yrnour Leacot' Page 7 Green, 3., Palmer, K.A., and Legator, M.S. 1970. In Vitro Cytogenetic Investigation of Calcium Cyclamate, Cyciohexylamine and Trifluoropromazlne. Food and Cosmetics Toxicology 6:617-623. legator, M.S. 1970. Chemical Mutagenesis Comes of Age: Environmental Implications. Journal of Heredity 61: 269-292. Legator, M.S. 1970. Mutagenic Effects of Aflatoxin. Journal of the American Veterinary Medical Association 159:2060-2(163. Legator, M.S. 1970. Host-Mediated Assay. E1S Newsletter 3:39. Legator, M.S. 1970. Chemical Mutagens in Man's Environment-- Book Review. H-1S Newsletter 3'-33-39. Palmer, K.A., Green, S., and Legator, M.S. 1970. Cytogentic Effects of DDT and Derivatives of DDT in a Cultured Mammalian Cell Line. Toxicology and Applied Pharmacology 17:276. Kelly, F., and Legator, M.S. 1970. Effect of N-Methyl-N'-Nitro-NNitrosoguanidine on Cell Cycle and Chromosomes of Human Embryonic Lung Cells. Mutation Research 10:237-296. Zeiger, E., and Legator, M.S. 1971- Mutagenicity of N-Nitroso-Morpholine in the Host-Mediated Assay. Mutation Researcli 12:969-971 Kelly, F., ana Legator, M.S. 1971. Tne Effects of N-Methyl-N'-Nitro-NNitrosoguanidine and Strepzotocin on Mammalian Cell Cultures. Mutation Research 12:163-190. Legator, M.S. 1971 Method for Detecting Chemically-Induced Mutations in Food Additives. Journal American Oil and Chemical Society 96:333A. Brusick, D., and Legator, M.S. 1971 Utilization of Saccharomyces Cerevisiae in the Host-Mediated Assay. EMS Newsletter 9:31-32. Legator, M.S. 1971. Deficiencies in our Present Protocol for Chemical Evaluation and Possible Remedies. Annals of the New York Academy of Sciences 179: 508-513 Zeiger, E., Legator, M.S., and Lljinsky, W. 1972. The Mutagenicity of N-Nltroso-Piperazines for Salmonella typhimurium in the Host-Mediated Assay. Cancer Research 32:1598-1599- Legator, M.S. 1972. Genetic Effects of Environmental Contaminants. Population and Pollution. Proceedings of the Annual Symposium of the Mutagen Society, 6th (1971), pages 95-99 Legator, M.S. 1972. Chemical Mutagens. Annual Review of Medicine 23:913-926. Legator, M.S. 1972. Hie Need to Detect Chemically Induced Mutations in Experimental Animals. Mutagenic Effects of Environmental Contaminants, pp. 67-79 13458 Curriculum Vitae - Marvin Seymour Legator Page 8 Legator, M.3. 1972. Indirect Indicators for Mutagenicity Testing-- An Overview. ElIS Newsletter b:10. Green, S., Palmer, K.A., and Legator, M-S. 1972. Effects of Cyclohexylamine on the Fertility of Male Rats. Food and Cosmetic Toxicology 10:29-34. Peterson, K., Legator, M.S., and Figge, F.H. 1972. Dominant Lethal Effects of Cyclohexylamine in C57 B1 Fe Mice. Mutation Research 14:126-129. Palmer, K.A., Green, S., and Legator, M.S. 1972. Cytogenetic Effects of DDT in a Cultured Mammalian Cell Line. Toxicology and Applied Pharmacology 22:355-364. Palmer, K. A., Kelly-Gavert, F., and Legator, M.S. 1972. Methods for Preparing Anaphase Figures from Rat Bone Marrow. Mutation Research 16:111-112. Kelly, F., and Legator, M.S. 1970. Effects of Cyclohexylamine on the Fertility of Male Rats. Food and Cosmetics Toxicology 10:29-34. Petersen, K., and Legator, M.S. 1973- The Dominant Lethal Results of Trlfluoropromazine in Hybrid C3D2F1/J Mice. Mutation Research 17'-87-92. PaLmer, K.A., Green, S., and Legator, M.S. 1973- Dominant Lethal Study of p,p'-DDT in fiats. Food and Cosmetics Toxicology 11:53-62. Kelly-Gavert, F., and Legator, M.S. 1973* Photoactivation of Ciilorpromazine: Cytogenetic and Mutagenic Effects. Mutation Research 21:101-105- Kelly-Gavert, F., and Legator, M.S. 1973- Cytogenetic and Mutagenic Effects of DDT and DDE in a Chinese Hamster CellLine. Mutation Research 17:223-229* Green, S., Carr, J.V., Sauro, F., and Legator, M.S. 1973* Effects of Hycanthone on Spermatogonial Cells (Cytogenetics) DNA Synthesis and Dominant Lethality in Rats. Journal of Pharmacology and Experimental Therapeutics 187:437-443. Green, S., Sauro, F.M., and Legator, M.S. 1973* Cytogenetic Effects of Hycanthone in the Rat. Mutation Research 17:239-244. Carr, J.V., and Legator, M.S. 1973* Hexachlorophene-Induced Alterations in a Metabolism of Cultured Human Lung Cells. Proceedings of the Society for Experimental Biology and Medicine 142:564-566. Kelly-Gavert, F., and Legator, M.S. 1973* Cytogenetic and Mutagenic Effects of DDT and DDE in a Chinese Hamster CellLine. Mutation Research 17:223-229- Legator, M.S., PaLmer, K.A., and Adler, I.D. 1973- In Vivo Cytogenetic Analysis - A Collaborative Study. Toxicology and Applied Pharmacology 24:337-350. Legator, M.S., and Flamm, W.G. 1973- Environmental Mutagenesis and Repair. Annual Review of Biochemistry 42: 683-7U8. Legator, M.S. 1973. Procedure for Conducting the Host-Mediated Assay Utilizing Bacteria (Salmonella typhimurium). Agents and Actions - Svriss Journal of Pharmacology, 3irkiiauser Verlag, Switzerland 3:111-115. Curriculum Vitae - Marvin Seymour Legator Page 9 Connor, T., Stoeckel, M., and Legator, M.S. 1974. Niridazole, A Direct Acting Frameshift Mutagen, Not Affected by Microcoral Enzyme Preparation Wliich can be Detected in the Host-Mediated Assay. Mutation Research 26:456-457- Legator, M.S. 1974. Mutagenesis and Its Environmental Implications. Journal of Occupational Medicine 16(10):672-675- Legator, M.S. 1974. Relevance of Mutagenesis to Carcinogenesis. Proceedings of the Annual Conference on Environmental Toxicology 5th, pp. 293-306. Legator, M.S., and Williams, R. 1974. The Inadequacies of Submammalian Tests for Mutagenicity. Molecular and Environmental Aspects of Mutagenesis, Proceedings Publ Rochester International Conference on Environmental Toxicology 6th (1973), pp. 266-262. Legator, M.S., Stoeckel, M., and Connor, T. 1974. Techniques for Isolating Mutagenic Substances from Urine and Blood of Treated Mammals Using Histidine Auxotropns of S. typhimurium as the Indicator Organism. Mutation Research 26:456. Michel, T.M., and Legator, M.S. 1974. Chromosomal Aberrations Induced In Vivo by DNA Repair Synthesis and Triethyieneneiamlne. Mutation Research 24:41-45- Weber, E., Bidwell, K., and Legator, M.S. 1974. An Evaluation of the Micronuclei Test for Routine Cytogenetic Analysis. Mutation Research 26(5):461. Michel, T.M., and Legator, M.S. 1974. Comparative Study of Mutagens. Mutation Research 26(5):460. Legator, M.S., Connor, T., and Stoeckel, M. 1975- Detection of Mutagenic Activity of Metronidazole and Niridazole in Body Fluids of Humans and Mice With Salmonella typhimurium. Science 166:1116-1119- Legator, M.S., and Ziirmering, S. 1975. Genetic Toxicology. Annual Review of Fnarmacoiogy 15:367-406. Committee 17 of the Environmental Mutagen Society. 1975- Environmental Mutagenic Hazards. Science 167:503-514. Legator, M.S., and Zimmering, S. 1975- Integration of Marrmaiian, Microbial and Drosophila Procedures for Evaluating Chemical Mutagens. Mutation Research 31. Legator, M.S., Connor, T.H., and Stoeckel, M. 1975- The Detection of Mutagenic Substances in the Urine and Blood of Man. Annals of the New York Academy of Sciences. M.S. Legator and A. Hollaenaer, ed., 269:16-20. Bidwell, K., Weber, E., Nienhold, I., Connor, T., and Legator, M.S. 1975Comprehensive Evaluation for Mutagenic Activity of Dieldrin. Mutation Research 31:314. Gupta, A.K., and Legator1, M.S. 1975. Chromosome Aberrations in Cultured Human Leucocytes After Treatment with the Fungicide Benlate. Proceedings of . Symposium on Mutagenicity, Carcinogenicity and Teratogenicity. Chemistry, Curriculum Vitae - Marvin Seymour Legator Page 10 PP- 95-103* Stoeckel, M., Weber, E., Connor, T., and Legator, M.S. 1975- Failure to Detect Mutagenic Effects of Delta-9-Tetrahydrocannabinol in In Vitro and In Vivo Studies with Mice. Mutation Research 31:313-314. Weber, E., Bidwell, K., and Legator, M.S. 1975* Evaluation of the Micronuclei Test using Triethyleneanine, Trimethylphoshate, Hycanthone and Niridazole. Mutation Research 28:101-106. Zimmering, P.K., Legator, M.S., and Weber, E. 1975- Effect of Pyrogen Treatment on Cytogenetic ResDonse with Chemical Mutagens in Mice. Mutation Research 31:339-340. Green, S., Zeiger, E., Palmer, K.A., Springer, J.A., and Legator, M.S. 1976. Protocols for the Dominant Lethal Test, Host-Mediated Assay and In Vivo Cytogenetic Test Used in the Food and Drug Administration's Review of Substances in the GRAS (Generally Recognized As Safe) List. Journal of Toxicology and Environmental Health 1:921-928. Nienhold, I., Kaplan, S., and Legator, M.S. 1976. Decrease in 3H-Tiiymidine Incorporation in Cells Derived from Systemic Lupus Erythematosus Patients Following Exposure to 4-Nitroquinoline 1-oxide. Mammalian Chromosomes Newsletter 217(1/2):3. Connor, T.H., Stoeckel, M., Evrard, J., and Legator, M.S. 19*77. The Contribution of Metrinidazole and Two Metabolites to trie Mutagenic Activity Detected in Urine of Treated Humans and Mice. Cancer Research 37:629-633- Kilian, D.J., Moreland, F.M., Benge, M.C., Legator, M.S., and Whorton, E.B., Jr. 1977. Collaborative Cytogenetics Study to Measure and Minimize Interlaboratory Variation. Mutation Research 44:97-104. Connor, T., and Legator, M.S. 1978- Method for Separation and Analysis of Body Fluids in Rodents and Humans for Mutagenic Components Using Salmonella typhimurium as the Indicator of Mutagenicity. Mutation Research 33:71-72. Coutino, R., Meyne, J., and Legator, M.S. 1978. Cytogenetic Studies in Chinese Hamster Ovary Cells With the Narcotic Antagonistic Naltrexone. Mutation Research 53:80. Kilian, D.J., Pullin, T.G., Connor, T., Legator, M.S., and Edwards, H.N. 1978. Mutagenicity of Epichlorohydrin in the Bacterial Assay System: Evaluation by Direct In Vitro Activity and In Vivo Activity of Urine from Exposed Humans and Mice. Mutation Research 53:72. Kilian, D.J., Whorton, E.B., Jr., and Legator, M.S. 1978. Response to Critique of Paper 'A Collaborative Study to Measure and Minimize Interlaboratory Variation'. Mutation Research 50:293-294. Meyne, J., Rinkus, S., and Legator, M.S. 1978. Distribution of Chromosomal Breaks Induced by Three Chemicals. Mutation Research 53:80. Molina, L., Rinkus, S., and Legator, M.S. 1978. Evaluation of the Micronucleus Curriculum Vitae - Marvin Seymour Legator Page 11 Procedure Over a 2-Year Period. Mutation Research 53:125- Rinkus, S., and Legator, M.S. 1978. Deficiencies in the Microbial Activation System for l'lutagenic-Oarcinogenic Screening. Clinical Genetics 13:133-134. Troung, L., and Legator, M.S. 1978. In Vivo Determination of Alkylation of Amino Acids in Hemoglobin and Urine to Detect Potential Mutagenic-Carcinogenic Effects. Mutation Research 33:121. Nienhold, 1. and Legator, H.S. 1978. Assessment of Unscheduled DNA-Syntnesis in Lupus-Erythematosus (SLE) Patients. Clinical Genetics 13(1):130. Biles, R.W., Connor, T.H., Trieff, N.M., and Legator, M.S. 1978. The Influence of Contaminants on the Mutagenic Activity of Dibromochloropropane (DBCP). Journal of Environmental Pathology and Toxicology 2:301-312. Truong, L., Ward, J.B., Jr., and Legator, M.S. 1978. Detection of Alkylating Agents by the Analysis of Amino Acid Residues in Hemoglobin and Urine. 1. Tne In Vivo and In Vitro Effects of Etnyl Methanesulfonate, Methyl Methanesulfonate, Hycanthcne Methanesulfonate, and Naltrexone. Mutation Research 54:271-281. Rinkus, S.J., and Legator, M.S. 1979* Chemical Characterization of 465 Known or Suspected Carcinogens and Their Correlation with Mutagenic Activity in the Salmonella typhimurium System. Cancer Research 39:3289-3318. Legator, M.S., Kouri, R.E., Parmar, A.S., Zimmering, S., Putman, C., Latt, R., Heicklen, J., Meagher, J.F., weaver, J., and Kelly, N. 1979* Mutagenic Testing of Diethylhydroxylamine, Nitroethane and Diethyfamine Hydrogen Sulfite. Environmental Research 20:99-124. Connor, T.H., Meyne, J., Molina, L., and Legator, M.S. 1979* A Combined Testing Protocol Approach for Mutagenicity Testing. Mutation Research 64:19-26. Legator, M.S. and Zimmering, S. 1979* Review of the Genetic Effects of Caffeine. Journal of Environmental Science and Health, Part C-Environmental Health Sciences 13(2):135-188. Moreland, F.M., Kiiian, D.J., Palmer, K.A., Springer, J.A., Green, S. and Legator, M.S. 1979- A Collaborative Dominant Lethal Study of Triethylenemelamine in the Rat. Toxicology and Applied Pharmacology 49(1):161--170- Trieff. N.M., Walker, R.D., Connor, T.H., Mackenzie, K. and Legator, M.S. 1979Mutagenic Assessment of Air Particulate Samples of Houston, Texas USA. Fed. Proc. 38(Vol. 3, part 1):535- Infante, P.F. and Legator, M.S. 1979* Workshop on Methodology for Assessing Reproductive Hazards in the Workplace - Recommendations for Future Research - April 19-22. Environmental Research 20(1):217-223- Connor, T.H., Cantelli-Forti, G., Sitra, P. and Legator, M.S. 1979* Bile As a Source of Mutagenic Metabolites Produced in vivo and Detected By Salmonella typhimurium. Environmental Mutagenesis 1(2):269-276. Curriculum Vitae - Marvin Seymour Legator Page 12 Legator, M.S. iy79- Chronology of Studies Regarding Toxicity of 1-2-Dibromo- j-CliloroproDane. Annals of the New York Academy of Sciences 329:331-338. Connor, T.H., Pullin, T.G., Meyne, J., Frost, A.F. and Legator, M.S. 1980. Evaluation of the Mutagenicity of Normal-BGE in a Battery of Short-Term Assays. Environmental Mutagenesis 2(2):284. Connor, T.H., Meyne, J. and Legator, M.S. 1980. Hie Mutagenic Evaluation of Tetraids (Hydroxymethyl) Phosphonium Sulfate Using a Combined Testing Protocol Approach. Journal of Environmental Pathology and Toxicology 4(1):145-158. Meyne, J. and Legator, M.S. 1980. Sex-Related Differences in Cytogenetic Effects of Benzene in the Bone Marrow of Swiss Mice. Environmental Mutagenesis 2:43-50. Connor, T.H., Ward, J.B. Jr., Meyne, J., Pullin, T.C-. and Legator, M.S. 1980. The Evaluation of the Epoxide Diluent, n-Butylglycidyl Ether, in a Series of Mutagenicity Assays. Environmental Mutagenesis 2:521-530. Kapp, R.W., Jr., Benge, M.C., Picclano, D.J., Kilian, D.J., Legator, M.S., and Jacobson, C.B. I98O. Monitoring Y Chromosomal Nondisjunction in Humans with the YFF Sperm Test. In: Proceedings of a Workshop on Methodology for Assessing Reproductive Hazards in the Workplace. DHHS (NI0SH) Publication No. 81-100. U.S. Government Printing Office, Washington, D.C. Legator, M.S. 1980. Human Exposure to Formaldeliyde Monitored by Several Assays for Mutagenesis in Man. Toxicology Research Projects Directory 5(H)- Made Gowda, N.M., Sadagopa Ramanujam, V.M., Trieff, N. M., and Legator, M.S. 1980. Assay of Thioacetamlde and Thiobenzanide 'with Chlorumine-T. Analytical Chemistry 52:209-211. Rinkus, S.J. and Legator, M.S., 1980. An Evaluation of In Vitro Testing for Mutagens. DHHS (NIOSH) Publ. (U.S.):81-100, Proc. Workshop Methoaol Assessing Reprod. Hazards Workplace, pp. 117-33* Albrecht, T., Speelman D.J., Sadagopa Ramanujam, V.M., Lund, H.W., Legator, M.S. and Trieff, N.M. 1980. Correlation of the Chemical Structure of 4-Nitroquinolines Inactivating Human Cytomegalovirus and established In Vivo Carcinogenicity Tests. Teratogenesis, Carcinogenesis, and Mutagenesis 1(2):161-169- Legator, M.S. I960. Radiation Equivalents for Chemical Mutagens: A Critique. International Atomic Energy Agency, Vienna, pp. 87-90. Adams, P.M., Fabricant, J.D., and Legator, M.S. 1981. Cyclophosphamide Induced Sperrnatogenic Effects as Detected in the FI Generation by Bellavioral Testing. Science 211:80-82. Ramanujam, V.M.S., Connor, T.H. and Legator, M.S. 1981. High Performance Liquid-Chromatographic Determination of Normal 3utylgiycidyl Ether. Microchemical Journal 26(2):217-220. 13463 Curriculum Vicue - Marvin Seymour Legator Page 13 Trieff, N.M., Ramanujam, V.M.S., Connor, T.K., ilade Gowda, N.I1. and Legator, M.S. 1981- Mutagenicity Studies of Aromatic Amines. Environmental Mutagenesis 3(3):322-j2o. Legator, M.S. 1981. Mutagenicity of Captan. Mutation Research 85(4):220. Speelman, D., Li, J.L.H., Ramanujam, V.M.S., Legator, M.S. and Albrecht, T. 1981. Herpes-Viruses Inactivation by Chemical Carcinogens - Differential Inactivation of Herpes-Simplex Viruses By 4-Nitroquinoline 1-Oxide and Related Compounds. Environmental Mutagenesis 3(4):467-476. Rinkus, S.J. and Legator, M.S. 1931. Salmonella Revisited: A Reply to Ames and McCann. Cancer Research 41:4196-4203- Fabricant, J.D. and Legator, M.S. 1981. The Mutagenicity of Vinyl Cliloride. Environmental Health Perspectives 41:189- Legator, M.S. 1931. Mutagenesis Test Systems - Development. Toxicology Research Projects Directory 6(10). Fabricant, J.D. and Legator, M.S. 1931. Etiology, Role and Detection of Chromosome Aberrations. Journal of Occupational Medicine 23(9):617-625- Frost, A.F. and Legator, M.S. 1932. Unscneduled DMA synthesis induced In Human Lymphocytes Ey Butyl Glycdyl Ethers. Mutation Research 102:193-200. Legator, M.S., Bueding, E., Batzinger, R., Connor, T.H., Eisenstadt, E., Farrow, M. G., Fiscor, G., Ksle, A., Seed, J., and Stafford, R.S. 1982. An Evaluation of the Host-Mediated Assay and Body Fluid Analysis. A Report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Research 93(3):319-374. Walker, R.D., Connor, T.H., MacDonald, E.J., Trieff, N.M., Legator, M.S., Mackenzie, K.W., Jr., and Dobbins, J.G. 1982. Correlation of Mutagenic Assessment of Houston Air Particulate Extracts in Relation to Lung Cancer Mortality Rates. Env. Research 28:303-312. Adams, P.M., Fabricant, J.D., and Legator, M.S. 1982. Active-Avoidance Behavior in the FI Progeny of Male Rats Exposed to Cyclophosphamide Prior to Fertilization. N'eurob. Tox. 4(5):53I-534. Fabricant, J.D., Legator, M.S., and Adams, P.M. 1983- Post-Meiotic Cell Mediation of Beriavlor in Progeny of Male Rats Treated with Cyclophospliamide. Mutation Research 119(2):185-190. Meyne, J., and Legator, M.S. 1983- Clastogenic Effects of Transplacental Exposure of Mouse Embryos to Nitrogen Mustard or Cyclophospnomide. Teratog. Carcinog. Mutagen 3(3):281-287. Connor, T.H., V.M. Sadagopa Ramanujam, Rinkus, S.J., Legator, M.S., and Trieff, N. M. 1983- The evaluation of mutagenicities of 19 structurally related aromatic amines and acetamides in Salmonella typhimurium TA98 and TA100. Mutation Research 118:49-59. Curriculum Vi cae - Marvin Seymour Legator Page 14 used for immunotherapy desensitization. Lancet ii, p. 915- Books/Book Chapters: Ledley, R.S., Legator, M.S., and Wilson, J.B. I96B- Automatic Determination of Mitotic Index. Pictorial Pattern Recognition. B.C. Cheng, R.S. Ledley, D.K. Pollock, and A. Roseru'eld, eas. , Thompson Book Company, Wasiilngton, D.C. Legator, M.S. 1969- Biological Assay for Aflatoxin. Aflatoxin - Scientific Background, Control, and Implications. I. Goldblatt, ed., pp. 107-149, Academic Press. Legator, M.S., and Sperling, D. 1970. Selective Toxicity: Genetic Implications. Laboratory Diagnosis of Diseases Caused by Toxic Agents. F.W. Sunderman ana F.W. Burroeman, Jr., eas., pp. 7-22, Warren~H. Green, Inc., St. Louis, Missouri. Legator, M.S., and Jacobson, C.V. 1970. Detection of Cytogenetic Effects of Toxic Agents in Mammalian Systems. Laboratory Diagnosis of Diseases Caused By Toxic Agents. F.W. Sunderman and F.W. Sunderman, Jr., eds., pp. b-c-L, Warren h. Green, Lnc., St. Louis, Missouri. Legator, M.S. 1970. The Host-Mediuated Assay: A Practical Procedure for Evaluating Potential Mutagenic Agents. Chemical Mutagenesis In Animals and Man. F. Vogel and G. Rohrborn, eds., pp. 260-270, Springer-Verlag, New York and Germany. Legator, M.S. and Mailing, H.V. 1971- The Host-Mediated Assay: A Practical Procedure for Evaluating Potential Mutagenic Agents in Mammals. Chemical Mutagens. A. Hollaender, ed., Vol. 2, pp. 569-909, Plenum Press, New York and London. Epstein, S.S., and Legator, M.S. 1971. The Mutagenicity of Pesticides. Massachusetts institute of Technology Press, Camcriage, Massachusetts. Legator, M.S. 1972. The Use of Indirect Indicators for Mutagenicity Testing.. Non-Psychiatric Effect of Drugs of Abuse. S.S. Epstein, ed., pp. 171-176, Government Printing Office, Washington, D.C. Legator, M.S. 1972- Drugs as Potential Mutagens. Mutagenic Effects of Environmental Contaminants. E. Sutton and II.I. Harris, eas., Academic Press, New York. Legator, M.S., and Epstein, S. 1974. Environmental Mutations in Man. Environmental Problems in Medicine. M.S. Legator and S.S. Epstein, eas., Criarles C. Thomas, Springfield. Legator, M.S., and Simmering, S. 1975- Genetic Toxicology. Annual Review of Pharmacology. .Annual Reviews Inc., Palo Alto, California. Curriculum Vitae - Marvin Seymour' Legator Page 15 Legator, M.S., and Nichols, W. 1975- Mutagenicity Testing. Laboratory Manual, Plenum Press. Legator, M.S. 1975* Environmental Problems in Medicine, Mutagenic rffects of Environmental Agents, diaries C. Thomas Publishing Company, Springfield, Ohio. Legator, M.S., Zinmering, S., and Connor, T. 1976. Use of Indirect Indicator Systems to Detect Mutagenic Activity in Human Subjects and Experimental Animals. Chemical Mutagens and Principal Methods for Their Detection. A. Hollaender, ed., Vol. A, pp. 171-191', Plenum Press, New York and London. Kilbey, B.J., Legator, M.S., Nichols, W. and Ramel, C. 1977- Handbook of Mutagenicity Test Procedures. Elsevier/North Holland Biomedical rress, Amsterdam. Legator, M.S., Rinlcus, S.J. 1977. Tlie Chemical Environment and Mutagenesis. Women and the Workplace. J. Wagoner and E. Bingham, eds., Government Printing Office, Washington, D.C. Legator, M.S., Pullin, T.G., and Connor, T.H. 1977. The Isolation of liutagenic Substances in Body Fluid and Tissues of Animals and Body Fluid of Human Subjects. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M.S. Legator, W. Nichols, and 0. Hamel, eds., pp. 149-159, Elsevier/Iiorth Holland Biomedical Press, Amsterdam. Lilian, D.J., Moreland, F.M., Benge, M.S., Legator, M.S., and Whorton,E-B., Jr. 1977- Collaborative Study to Measure Interlaboratory Variation Widi the In Vivo Bone Marrow Metaphase Procedure. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M.S. Legator, W. Nichols, and C. Hasel, eds., pp. 2AP-LU, Elsevier/North Holland Biomedical Press, Amsterdam. Butterworth, B.E., Longstaff, E., Clive, D., Plenta, R.J., Kuna, R., Legator, M.S., Tliilly, U.G., Ray, V.A., Sheridan, W., Williams, G.M., and Efenkel, V. 1979* II. Practical Guidelines for the Use and Interpretation of Short-Term Testing for Hutagens/Carcinogens. Strategies for Short-Term Testing for Mutagens/Carcinogens. B.E. Butterworth, ed., CRC Press, Inc., West Palm Beacn, Florida. Rinlcus, S.J., and Legator, M.S. 1979- An Evaluation of In Vitro Testing for Mutagens. Genetic Damage in Man Caused by Environmental Agents. L Berg, ed., pp. 34p-po2, Academic Press, New York. Legator, M.S. 191. A Holistic Approach to Monitoring High-Risk Populations by Short-Term Procedures. Banbury Report 9: Chantifleafion of Occupational Cancer, pp"! 3j5-3^5, Cold Spring harbor Laboratory. Legator, M.S., and Rinlcus, S.J. 191. Mutagenicity Testing: Problems 22 Application. Short-Term Tests for Chemical Carcinogens. H.F. Stich and R-H.C. San, eds., pp. 4j>-54, Springer-Verlag, New York. Ward, J.B., Jr., Rinlcus, S.J., and Legator, M.S. 19ol. Strategies for r3rerooming the Deficiencies of Microbial Activation Systems for Detecting Cheical Mutagens. Microbial Testors for Chemical Carcinogens. I. Cecil iellcner, Curriculum Vitae - Marvin Seymour Legator Page 16 ed., pp. 107-166, Marcel Dekker Inc., New York. Legator, M.S. and Harper, B.L. 1962. Animal-Human Studies: An Integrated Approach to Identifying Hazardous Chemicals in the Workplace. Mutagens In ur Environment. M. Sorsa and H. Vainio, eds., pp. 161-2U2, Alan R. Liss, Inc., New York. Harper, B.L., Rinlcus, S.J., Scott, M.J., Anmenheuser, M., Bang, K.M., Lowery, M., and Legator, M.S. 1962. Correlation of NCI and IARC carcinogens with their mutagenicity in Salmonella, in: Use of Human Cells for the Evaluation of Risk from Physical arid Chemical Agents. a NAIL) Publication. Plenum Press pp. 656-424. Legator, M.S. and Harper, B.L. 1962. Prom Bacteria to Man, The Evolution of Mutagenicity Testing, in: Use of Human Cells for Evaluation of Risk From Physical and Chemical Agents. A NATO Publication. Plenum Press pp. 467-496-' SUBMITTED: Legator, M.S. and Ward, J.B., Jr. Genetic Toxicology - Relevant Studies with Animal and Humans. Anglo-American Conference on Pregnant Women at Work, The Royal Society of Medicine, June 16-15, 1966- Ward, J.3., Jr., Hokanson, J.A., Smith, E.R., Chang, L.W., Pereira, M.A., Whorton, E.B., Jr., and Legator, M.S. Sperm Count, Morphology and Fluorescent Body Frequency (YFF) In Autopsy Service Workers Exposed to Formaldehyde. Mutation Research. IN PRESS: Sadagopa Ramanujam, V.M., Made Gowda, N.M., Trieff, N.H., and Legator, M.S. Ultraviolet Spectrophotometric Assay of p-Aminobenzenesulfonamides. Microchemical Journal (in press). Legator, M.S. The Successful Experiment That Failed. Bulletin of Hastings Institute. Hastings, New York (in press). Adams, P.M., Siiabrawy, 0. and Legator, M.S. Male-Transmitted Developmental and Neurobehaviorul Deficits. Environmental Influences on Fertility, Pregnancy, and Development: Directions for Future Research. May 24-26, 1962, Vernon Manor Hotel, Cincinnati, Ohio (Meeting Proceedings in press). Legator, M.S. and Ward, J.B., Jr. Personnel Monitoring with Cytogenetic and Other Short Term Bioassays. Ann Arbor Science Publishers (in press). OTHER: Oswald, E.J., Harp, A.R., and Legator, M.S. 1966. Survival of PPLO aid "L" Forms in Antibiotics. Bacterial Proceedings _lb- 13467 Curriculum Vitae - Marvin Seymour Legator Page 17 Childs, V.A., and Legator, M.S. 1966. Lactic Deliydrogenase Activity and Isozyme Pattern as a Function of Age in Diploid Cultures. Proceedings of the 16th Annual Meeting of Tissue Culture Association 77. Legator, M.S., and Reedy, R.J. 1966. The Use of Semisynthetic Pennicillians in Tissue Culture. Conference on Antibiotics and Chemotherapy. Legator, M.S. 1970. Drug Risks. Symposium, National Academy of Science National Academy of Engineering. Legator, M.S. 1970. Mutagenic Effects of Environmental Intrusions. Association of Food and Drug Officials of the U.S. 34 (1). Brusick, D., and Legator, M.S. 1971. Utilization of Saccharomyces Cerevisiae in the Host-Mediated Assay. EEM3 NEWSL; 4:31-32. Legator, M.S. and Hollaender, A. 1975* Occupational Monitoring for Genetic Hazards. Annals of the New York Academy of Sciences. 269:1-45. PATENTS: Legator, M.S. 1961. Initibiting Growth of Bacteria in Water Flooding Process. U.S. Pat. 2,967,475- Legator, M.S. 1961. Slimicide. U.S. Pat. 3,006,607. Rader, Legator. 1962. Preservation of Foods. U.S. Pat. 3,044,864. Racusen, Legator. 1962. Soil Fumigant. U.S. Pat. 3,052,596. Legator, Kreutzer, Soloway. 1963- Soil Fungicide. U.S. Pat. 3,060,274. Legator, M.S. 1964. Synergistic Antibiotic Compositions and Preparation. U.S. Pat. 3,126,316. Legator, M.S. 1964. Growth Promotant Substances. U.S. Pat. 3,146,968. Tieman, Legator. 1965- Trihalo-substituted Esters. U.S. Pat. 3,169,969* Fan, Rader, Legator, Dowding. 1965- Polyhydronaphtiialene Biepoxides. U.S. Pat. 3,215,708. Haynes, Legator. 1966. Coccidiosis Control Compositions and Methods of Using Same. U.S. Pat. 3,234,087. Legator, M.S. 1966. Growth Promotant Substances. U.S. Pat. 3,240,605. Legator, M.S. 1966. Control of Microorganisms with Acrolein. U.S. Pat. 3,250,667 Legator, Page. 1971. Use of Certain Polyamines as Antimicrobial Agents. U.S. Pat. 3,567,420. 13468 J ALAN SCOTT LEVIN, M.D. I. QUALIFICATIONS Dr. Levin is engaged in Che practice of medicine in San Franciso. His Curriculum Vitae and Addendum, listing Professional Societies and Awards, are attached. II. SUBJECT MATTER Dr. Levin will discuss the following in his testimony: the immune system, with its organic, cellular, and humoral components - most especially with regard to the latter, T-helper cells, B-cells, plasma cells and immuno globulin production; immune response, both beneficial and harmful; the various experimental studies, particularly those demonstrating atrophy of the thymus, weight loss, depletion of lymphoid organs, lymphopenia, cutaneous type delayed hypersensitivity (skin thickness) and altered bacterial immunity. In addition, Dr. Levin will discuss the following and their significance: immunology as molecular biology; chemical-induced immune disregulation; T-cells (lymphocytes from thymus) acting as immune modulators (for which there is "no effect" level); immune surveillance; the similarity of the immune, neurologic, and endocrine systems and their significance in the area of immuno-toxicity; the relationship of immune disregulation caused by chemicals and carcinogenicity, including cancer and the oncogene theory. Also, Dr. Levin will discuss clinical uses of the epidemologic approach, i.e., clinical epidemiology. And, D r. L e v in w ill d is c u s s th e p r o b le m s o f d ia g n o s in g " p s y c h ia tr ic disease" and the misdiagnosis which frequently occurs. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. IV. SUBSTANCE OF OPINIONS A. That phenoxy herbicides and their contaminants, specifically dioxin, most especially 2,3,7,8-TCDD, cause, an assortment of immunological responses, i.e. immuno-toxicity, which predispose persons exposed, by absorption and/or ingestion and/or inhalation, to such chemicals to a whole host of adverse health effects, such as: chloracne or other skin rashes; liver and other organ damage; various neuro-toxic effects; reproductive effects; and neoplasm. B. That, in connection with the carcinogenic effect, there is no safe level for TCDD or any other carcinogen, and that a single exposure several years earlier can result in human cancer many years later. C. Dr. Levin will then testify to the causal relationship of the various Agent Orange/dioxin related adverse health effects of the representative plaintiffs, including: chloracne; liver damage; neuro-toxic effects, both neurologi cal and psychological; reproductive toxic effects, both miscarriages and birth 13470 defects; and such neoplastic processes as soft tissue sarcoma, as here a A LA N SCO TT L E V IN , M .D . ADDENDUM Professional Societies1 1. Alpha Omega Alpha Honor Medical Society 2. Certified Diplomate-American Board of Allergy and Immunology 3. Certified Diplomate-American Board of Pathology-Clinical Pathology 4. Member-Medical Quality Review Committee if4, Board of Medical Quality Assurance, State of California 5. Fellow-American College of Emergency Physicians 6. Fellow-College of American Pathologists 7. Fellow-American Society of Clinical Pathologists 8. Member-American Academy of Allergy 9. Member-American Association of Clinical Chemists 10. Member-Americal Medical Association 11. Member-California Medical Association 12. Member-San Francisco Medical Society L3. Member-Society for Clinical Ecology Awards 1. American Cancer Society Faculty Research Award D r. L e v in w ill a ls o r e ly on th e fo llo w in g a r t ic le s : Gallo, R.C. The Virus-Cancer Story: Hospital Practice pp. 79-89, June 1983. Leder, P. Genetic Control of Immunoglobulin Production: Hospital Practice pp 73-82, February 1983. Bishop, J.M. Oncogenes and Proto-Oncogenes: Hospital Practice pp. 67-74, August 1983. Biological Relevance of Immune Suppression as Induced by Genetic, Therapeutic and Environmental Factors: J. H. Dean and M. L. Padarathsingh Editors, Litton Bionetics, Van Nostrand Reinhold Co. New York, Cincinanti, London, 1981. Inadvertent Modification of the Immune Response: The Effects of Foods, Drugs and Environmental Contaminantsl Proceedings of the 4th FDA Science Symposium August 28-30, 1978. Immunologic Considerations in Toxicology Vol 1 & 2, Raghubir P. Sharma, CRC Press, Inc. Boca Raton, Fla. 1981. Pathology of Drug-Induced and Toxic Diseases: R.H. Riddell editor. Churchill Livingstone, New York and London, 1983. Goldberg, R.J. Clinical Uses of the Epidemiologic Approach: Hospital Practice pp. 177-188, August 1983. C. With respect to Opinion IV B, note the following IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. EPA Criteria Documents, Publications and Assorted References Re: TCDD 13472 A PLEA FOR THOUGHTFUL CONSIDERATION Submitted to THE BOARD OF MEDICAL QUALITY ASSURANCE By THE SOCIETY FOR CLINICAL ECOLOGY (Northern California Chapter) Alan S. Levin. M.D. 450 Sutter Street. Suite 1138 San Francisco. California 94108 Richard B. Spohn. Esq. NOS SAMAN, GUTHNER. KNOX & ELLIOTT 100 The Embarcadero. Third Floor San Francisco. California 94105 TABLE OF CONTENTS I. II. III. V. Introduction Clinical and Scientific Demonstration of the Efficacy and Safety of Provocation Testing and Neutralization Therapy. Flaws In The Opponents' Case Against Provocation/Neutralization References I . INTRODUCTION The members of the Society for Clinical Ecology. Northern California Chapter ("Petitioners") are most anxious that this presentation be given the closest, most thoughtful attention by the Board of Medical Quality Assurance. They are acutely aware of' the attacks on their techniques that have emanated from certain quarters for some time. The Petitioners understand that medical break-throughs and innovations are often resisted by those who have become comfortable with accustomed techniques. The Petitioners have each made the extremely modest intellectual and clinical journey represented in testing and treating their allergy patients with the subject techniques, which are but precise refinements, albeit important refinements, of the more traditional techniques. The Petitioners have been dismayed by the virulence of the attacks on their techniques and upon themselves. They have been dismayed at the refusal of their antagonists to engage in a good faith, collaborative scientific dialogue in which an exchange could take place. Indeed. Petitioners have been amazed as much at the refusal of their antagonists to observe patients or to examine carefully the statistical and -1 - t" -? r' immunological research as they have been embarrassed for their antagonists over the seriously flawed analyses upon which they have been forced to rely in rejecting the provocation/neutralization modalities. The Board of Medical Quality Assurance should at once acknowledge this internecine conflict and yet avoid getting drawn into it. It should acknowledge it. for what it is -- the manifestation of pains of scientific growth and advance ment. New clinical and research findings, which are explained by corroborative evidence in basic immunology, have led a large number of allergy practitioners to modify the classical techniques of testing and treatment. The results have been dramatic. Many individual allergy sufferers who have each typically been treated by several classical practitioners without success have had their symptoms relieved. The newer techniques of testing are quicker, and the treatment far less burdensome to the patient. The newer techniques rely far less on drug therapy. The newer techniques in the entirety of their application are demonstrably less costly. -2- I O .<' if ?5 3 Si t O- These various indices of effectiveness can be threatening to those who do not use the techniques and who are not knowl edgeable about the literature or the immunological bases of the techniques. In the end. however, the controversy is a classic of innovation and change. In the past it has been viewed also as a clinical vs. academic conflict, but the immunological discourse presented below should erase that false dichotomy. The Petitioners appreciated the opportunity to meet with officers of the Board of Medical Quality Assurance some months ago. Petitioners in this Presentation bring to BMQA's attention a number of rigorously scientific studies that document and explain the safety and efficacy of the sublingual, intracutaneous and subcutaneous provocative and neutralization testing and neutralization therapy tech niques. They detail the immunological framework and mechanisms which explain not only why these techniques are sound, but also why they are more consonant with modern medical knowledge than parallel testing and therapeutic techniques of certain other allergists. An extensive methodological and statistical critique is also -313477 made of the reports critical of the provocative neutraliza tion techniques. Finally, the scientific soundness of the alternative allergy testing and treatment are placed in perspective'. Petitioners request the Board to review these comments care fully, and stand ready to assist the Board and its staff in securing further clarification. (These Comments were originally prepared for submission to the Health Care Financing Administration of the U. S. Department of Health and Human Services for its enlighten ment and assistance in evaluating the Petitioners' tech niques as eligible for Medicare coverage. Hence the odd section numbering and pagination.) -4- I I . CLINICAL AND SC IEN TIFIC DEMONSTRATION OF THE EFFICACY AND SAFETY OF PROVOCATION TESTING AND NEUTRALIZATION THERAPY L h (Prepared by Alan S. Levin, M.D. with the assistance of Joseph D. Miller, M.D. and Sidney Weinstein, B.A.) INTRODUCTION Opponents brand the provocation and neutralization techniques of allergy testing and treatment as "experimental" and unreliable. Yet. this technique has proven safe and effective in thousands of clinical trials. Furthermore, it has afforded relief to patients whose allergies have proven unresponsive to less precise methods of allergy testing and treatment, either because of the type of sensitivity (for example, poison oak-ivy)^" or because the extent of sensitivities ("chemical hypersensitivity" or "immune dysrgulation" ) have seriously compromised their immune system's ability to respond appropriately to antigens. It is a method whereby permanent relief from food, inhalant, and chemical allergies and other antigen-related illnesses can be obtained without the use of harmful alternatives such as psychotropic drugs, artificial prostaglandin inhibitors, or r -21- 13479 synthetic adrenal corticosteroids. Provocation and neutralization also obviate the need for antihistamine, bronchodilator, or steroid therapy, the long-term side effects of which have never been tested. The efficacy of this approach is well-supported by well-known immunological mechanisms. Three recent rigidly controlled, double-blind placebo-controlled studies3'-4.' 5 have demonstrated the scientific validity of this approach and have substantiated the immunological mechanisms of action as well. A number of earlier studies also statistically validate the efficacy of provocation/neutralization'. In support of the safety, reliability, efficacy, and scientific soundness of provocation and neutralization techniques, this section will describe: II. CLINICAL AND SCIENTIFIC DEMONSTRATION OF THE EFFICACY AND SAFETY OF PROVOCATION TESTING AND NEUTRALIZATION THERAPY A. What is provocation testing and neutralization treatment? 3. The clinical observations which initiated the development of the provocation/neutralization techniques C. How does provocation/neutralization differ from conventional allergy techniques? D. Which kinds of medical illnesses are best treated with provocation/neutralization? E. The controlled double-blind clinical trials which establish the efficacy of provocation/neutralization F. Modern concepts of the immune response and how they relate to provocation/neutralization 1. The highly regulated and controlled immune system 2. The phasic phenomenon of immune response 3. How provocation/neutralization works k. The immune -response is often mediated by factors other than IgE 5. Two interacting immune mechanisms explain non-IgE mediated allergic reactions 6 . Cellular and humoral effectors of the phasic immune response a- Role of macrophages b. Basophils and mast cells: role of histamine c. Role of lymphocytes -23- d. Role of neutrophils G. Why do intradermal and sublingual administration of antigen provoke and neutralize symptoms? -24- A. WHAT IS PROVOCATION TESTING AND NEUTRALIZATION THERAPY? The provocation and neutralization method of testing and treating allergies is a technique by which the clinician can quickly ascertain the doses of allergen that will induce ("provoke") symptoms of allergy, then relieve ("neutralize") the induced symptoms. To determine the precise beneficial.concentration of each antigen to be tested, a concentration of an inhalant extract designed to induce ("provoke") mild symptoms is injected intradermally. The wheal size is measured initially 10 minutes later. Wheal growth of greater than 2x2 mm is considered "positive". Less than 2x2 mm growth or reduction in wheal size is considered "negative". Consecutively stronger or weaker concentrations, depending on whether the initial wheal is negative or positive, are then.injected at 10-minute intervals until the strongest concentration is found which relieves ("neutralizes") the induced symptoms in 10 minutes and produces a negative wheal. This is the therapeutic or neutralizing dose. To use this technique correctly, the practitioner must systematically evaluate the effects of a series of different dose levels in each individual. Provoked signs and symptoms are sometimes strikingly intensified rather than relieved by -25- vOf subsequent administration of a much less concentrated dilution of extract than the provoking dose. Therapy is begun with intradermal injections of a solution containing the full individually determined neutralizing dose of each antigen. In some cases, relief can be achieved during the first testing session. __ Most patients beginning immunotherapy with this technique note marked improvement or complete clearing of symptoms within two to three weeks. Thereafter, marked relief usually begins within 30 minutes after each injection and lasts a week. Scientific evidence has shown that sublingual drops are generally as effective as intradermal injections and provide relief in less than 10 minutes. When indicated, practitioners conduct oral and inhalation challenges with allergens or placebo in a single-blind manner to verify the validity of their patients' responses. As will be seen later in this section, provocation and neutralization techniques initiate a biochemical process that alters the ratio of suppressor to helper|inducer T-cell subsets, thereby changing the phase of immune response and resulting in immune unresponsiveness to challenge with additional specific antigen. -2 6 - 13 B.THE CLINICAL OBSERVATIONS WHICH INITIATED THE ' DEVELOPMENT OF PROVOCATION/NEUTRALIZATION TECHNIQUES Virtually every practicing allergist has noted a strange phenomenon in some patients receiving build-up immunotherapy. When these patients reach a particular dosage level, they report that each injection provides marked relief which begins in minutes or hours and lasts 'about a week. Some return once a week requesting another "relieving injection". This immediate response is unanticipated. It does not fit the doctors' accepted concepts of immunotherapy, yet many allergists have wished they could duplicate this phenomenon in all of their patients. This relieving phenomena is duplicatable in most cases. For most patients, a specific symptom-relieving therapeutic concentration for each antigen extract exists and can be determined individually by skin testing. This is the clinical principle behind provocation/neutralization. In "the case of multiple allergies, the relieving concentrationfor each antigen may differ considerably. However, all of the relieving doses can be combined into a single vial to provide response to all the allergens at once. -27- 134-85 C. HOW DOES PROVOCATION/NEUTRALIZATION DIFFER FROM TRADITIONAL ALLERGY TECHNIQUES? Provocation/neutralization has been in use for close to 40 years, and represents a refinement of older techniques. Both use the same allergy extracts supplied by the same supply houses. Both skin test intradermally with stock solutions of extracts. Practitioners of the newer techniques, however, use certain crucial refinements of the traditional methods. (1) They test one item at a time., in 1:5 concentrations, rather than 20-40 allergens at one time in 1:10 dilutions. (2) They carefully observe the patients during the 10 minutes between tests. The wheal size is always monitored, but they also observe every nuance of the patient's affect behavior. When indicated, they measure: nasal passageway patency; pulse; blood pressure; pulmonary function (using a peak flow meter); handwriting changes; and picture-drawing abilities. On the basis of the above monitored criteria, a decision is made concerning the correct treatment dose for therapy for the individual item which is being tested on that particular patient. The most radical difference between traditional and newer techniques is the determination of the therapeutic dose. Traditional allergists start therapy with a dose that 13486 p r o d u c e s a "safe" wheal, t hat is, w h e r e the increase in wheal size is not excessive within 10 minutes. In contrast, the refined approach determines the correct dilution that will neutralize symptoms for that particular patient for the items tested. The traditional therapy requires injections by the physician 1-3 times a week for up to 30 weeks, and then once a month for many years. With the refined approach, once the correct therapeutic dilution is determined, it is combined with the correct dilutions of the other tested items. The patient can then self-treat safely, using sublingual therapy 3 times a week to once every two weeks, or injection therapy once daily and in time once every week or two, as indicated. \ D. WHAT KINDS OF MEDICAL ILLNESSES ARE BEST TREATED WITH PROVOCATION/NEUTRALIZATION ? Provocation and neutralization techniques can be used to test and treat a wider variety of allergic disorders than can those employed by conventional allergists. The patient's response is often most gratifying. Most physicians using provocation/neutralization report that use of specific neutralizing doses of specific stock allergy extracts results in improved "tolerance" to offending antigens when compared to conventional hyposensitization techniques. Traditional allergists are often perplexed by patients who have classical year-round or seasonal asthma or hayfever without having positive skin reactions. The newer techniques of provocation testing and neutralization therapy enable these patients to be effectively treated with stock allergy extracts once it is realized that their illnesses are not caused by an IgE mechanism. Conventional allergists are somewhat successful in treating traditional allergic reactions to pollen, dust, and mold for traditional nasal symptoms, asthma, post-nasal drip, conjunctivitis, urticaria, and at times atopic dermatitis. Most of these reactions are mediated by IgE mechanisms. Practitioners using provocation/neutralization modalities have successfully treated these and other symptoms that have 13488 -30- Finally, these techniques have proven useful for treating various syndromes and infectious diseases10,167-171 such, as resistant vaginal candidiasis12 , dysmenorrhea12 , and active viral infections1 0 as well as certain autoimmune disaeses such as lupus erythematosus.12 '13 -32- 13489 been linked for the past 0 years to a wide variety of environmental factors, including foods, pets, toxic chemicals, and infectious diseases. These immune reactions are mediated by factors other than IgE (including IgG, IgA, 7 etc.) and frequently involve diverse parts of the body. A surprising number of patient complaints include both the typical and less well-recognized signs and symptoms of allergy. Both types of illnesses respond equally well to neutralizing immunotherapy once the appropriate specific antigenic material has been determined and injected in appropriate symptom-relieving doses. Examples of such illnesses include: aphthous stomatitis; chronic diarrhea; chronic ulcerative colitis; atopic dermatitis; chronic urticaria; hyperkinesis; migraine; and some resistant respiratory inhalant syndromes including perennial allergic g gg rhinitis, asthma, and recurrent laryngeal edema. ' ' Some patients sensitive to foods, inhalants, and|or chemicals have multi-system disease with symptoms referable to many organs. In these patients, immune complexes or other # vascular perturbation factors affect almost the entire vasculature. Formerly, these patients were often considered neurotic because of- the multiplicity of their complaints and intractable because no adequate therapy was available. Many of these patients have multiple sensitivities that are readily relieved by neutralization therapy. -31- 1348 o E. THE CONTROLLED DOUBLE-BLIND CLINICAL TRIALS WHICH ESTABLISH THE EFFICACY OF PROVOCATION/NEUTRALIZATION Three rigidly controlled, double-blind placebo studies on allergy testing and treatment clearly demonstrate the efficacy of provocation/neutralization techniques. In addition, several earlier studies also illustrate their efficacy. Boris et al (1983) . These researchers have recently reported a double-blind controlled study on the effect of neutralization therapy on asthma. They evaluated 19 subjects with a history of wheezing to animal dander. The subjects were challenged with inhaled animal antigen to determine the dose causing a 20% decrease of FEV^. The neutralizing dose was determined by the five-fold serial dilution skin technique. On two subsequent days, one week apart, the specific antigen neutralizing dose of placebo was injected and bronchoprovocation was performed with the dose previously ascertained by the provocation test. FEV'1 decreased 31.8% from baseline in the controls, 27.4.% post-placebo, and 10.7% post-neutralization injection (p less than 0.01). FVC and FEF 25-75, and PEF had similar responses. These results demonstrate that neutralisation therapy. when properly performed, produces a statistically significant improvement in bronchospasm in asthma patients sensitive to animal dander. 13491 -33- Rea et al (1983)^. This group performed a similar study using food-sensitive patients. In this study, 22 subjects were selected who had a documented adverse reaction to certain foods. A neutralizing dose was obtained by intradermally titrating the subjects to the sensitizing foods. The patients were then given oral food challenge and injected with neutralizing dose or placebo in a double-blind controlled experiment. Signs and symptoms, Visual Analogue Discomfort Rating, heart rate, Aaron Smith Symbol Digit Modalities Test, Symbol Digit Modalities Subtest, and patient signature were evaluated. The neutralizing dose, compared to placebo, produced a 'protective effect on all parameters measured. Statistical analysis showed the difference between neutralizing dose and placebo to be highly significant (p less than 0.001-0.05) in all parameters with the exception of the Symbol Digit Modalities Subtest. These results demonstrate that neutralization therapy, when properly performed, produces a statistically significant improvement in the symptoms of food intolerance. McGovern et al (1983)5. McGovern et al studied the reliability of the provocative challenge test in six patients and controls. This study used a double-blind, randomized, placebo-controlled protocol. In addition to clinical parameters, it measurea cellular and humoral immune factors in the blood of these subjects. The investigators measured IgG, IgA, IgM, IgD, Co, C^, IgE, immune complexes (by the -3 4 - 13492 polyethylene glycol technique which detects both complement-associated and non-complement-associated immune complexes), total white blood cell count, absolute lymphocytes, total T cells, T-helper cells, T-suppressor cells, and helper/suppressor ratios. The injection of specific doses of allergenic extracts and haptens ' induced objective physical abnormalities with statistically significant frequency in patients, when compared with placebo injections. In ten additional patients and controls, the authors showed that the neutralization, but not the placebo injection, brought about a reversal of the patients1 induced clinical reaction with .statistically significant frequency. Blood samples taken before and after provocation and neutralization injections in allergic subjects showed' markedly fluctuating levels of parameters of inflammation when compared with- controls. These levels directly correlated with the onset of systemic reactions after provocative injection and with the disappearence of systemic reaction after neutralization. This study is unique. Not only does it demonstrate that provocation/neutralization testing techniques, when performed correctly, produce statistically significant clinical responses when compared to placebo, but it also objectively demonstrates the marked instability of allergy patients' immune systems. -35- In addition to these 3 most recent double-blind placebo controlled studies, there are 9 other controlled studieswhich establish the efficacy of provocation/neutralization testing and treatment techniques. Of these nine studies, three8 '17 'X8 stand out as well-controlled scientific studies which when considered alone, clearly demonstrate the efficacy of the provocation/neutralization technique. Two19 '20 of the remaining reports are well-controlled, very convincing studies performed in double-blind . crossover-controlled fashion on single patients. The remaining four21 '6'2 2 '23 studies, when viewed with-the others, further corroborate the efficacy of provocation/neutralization. Q Miller, J. (1977) . This is a well-designed, double-blind, crossover-controlled study which was the first in a series .of confirmatory studies on the provocation/neutralization technique. The major attribute of this study was that it was carefully performed in a double-blind fashion by the recognized leader in the development and clinical use of the technique. Patients were selected who presented with symptoms found from extensive clinical experience to be caused frequently by food sensitivities. Prior to the double-blind phase, subjects underwent a trial treatment J period with neutralization therapy. For the double-blind phase, eight subjects were treated during four separate 2 0 -day periods either with the putative neutralizing antigens or phenolated saline colored with mushroom extract to -36- t O / 'O simulate the neutralizing vaccine. A careful symptom survey was made during the first office visit and symptom changes were recorded during and at the end of each of the four 20-day courses of therapy. Each subject received two courses of antigen and two of placebo in a crossover fashion. During neutralization dose therapy the average improvement score was 3.68 while that for the placebo was 2.25. The difference is stasitically significant (p less than .0 0 2 ). This study clearly demonstrates that provocation/neutralization therapy produces statistically significant improvement when compared to controls. King, D. (1982)17. This is one of the most definitive studies ever performed to test the efficacy of sublingual provocation/neutralization testing. The author evaluated allergy patients who had also had at least one psychological symptoms such as anxiety, depression, confusion, or difficulty concentrating. The major question was whether sublingual provocation with antigen or placebo would induce psychological symptoms more frequently. Selection of the antigens for challenge was based on the patient's individual history. Thirty patients were challenged with four selected foods and with triple distilled water as placebo. There were four kinds of trials: 1 ) allergen trials (four antigens, each given three times), 2 ) placebo trials (two tests, each give three times), 3) base-rate trials in which the subjects -37 received nothing sublingually but for which the dependent end points were measured (three trials), and 4) open placebo trials to assess the biological reactivity to the placebo (three trials). Two blinded judges independently assessed symptoms. Symptom severity was reported quantitatively. The integrity of the double-blind was evaluated, and data points in which the double blind might have been jeopardized were excluded. Average symptom scores for psychological symptoms were four times higher after antigen than after placebo provocation. This difference was statistically significant (p=0.001). Severe, reactions were also more frequent after antigen challenge (p=0.'006). Mixed psychological-somatic symptoms were more frequent after antigen provocation (p=0.02). Somatic symptoms were significantly more.frequent after antigen provocation according to one method of analysis, but this difference was not statistically significant using a different analysis. This comprehensive study demonstrates that psychological symptoms can be provoked with statistically significant frequency using active antigen administered sublingually when compared to placebo controls. 1a Lee, L.K. (1982) This controlled study measured the relative efficacy of skin endpoint therapy as compared to conventional treatment and finds the titration technique superior. -38- 1 Q O 1 Q Rapp,___ D_.____(1978) 19 This is a double-blind, placebo-controlled study of milk sensitivity in one 9-year-old boy. The patient was treated with neutralization therapy after the study and improved dramatically. A study of one patient does not prove the case when considered alone, However, when considered in conjunction with other confirmatory studies, this well-designed double-blind, placebo-controlled study further corroborates the efficacy of provocation/neutralization therapy. Rapp, D. (1982) 20 This is another double-blind, placebo-controlled study performed on one patient with documented wheat allergy. This patient was diagnosed by two opthalmologists as having moderately severe chronic allergic blepharo-conjunctivitis. These symptoms improved markedly on a wheat-elimination diet. The patient was then tested intradermally with wheat antigen and opthalmologic symptoms returned. A neutralizing dose of wheat antigen was then determined. The patient was then asked to avoid wheatin all forms and to ingest 24. capsules (six teaspoons) each day for a period of 12 days. The capsules for each three-day period contained either wheat germ or similarly colored group peanut which had been coded in a double-blind manner. The patient remained asymptomatic throughout the entire 1 2 -day period. She was then told to eat large quantities of wheat. Shortly after reintroducing wheat into her diet, her opthalmologic -39- Xt - Q*$ t::O' t symptoms recurred. During the next 12 weeks, she limited her wheat ingestion to 1 slice of bread per day while she was treated sublingually with the neutralizing dose of wheat antigen. Her eyes returned to the asymptomatic condition and remained in that condition throughout the 12-week test period. Three bottles, identical in color and taste were then prepared and double-blinded. Two contained phenolated saline while the third contained phenolated saline and her neutralizing dose of wheat antigen. While ingesting large quantities of wheat each day, the patient found that 'her eyes began to tear for the first time in three months after she had used a placebo solution for five' days. Her eyes continued to tear for the next three days while she tried the second`placebo solution. Her symptoms cleared within 1 1/2 days of using the bottle containing the active neutralizing dose. This study constitutes a brilliant investigative effort for a busy practicing clinican and a cooperative patient. Although this study involved only one patient, every busy practitioner will appreciate that this patient was definitely responding favorably to the active treatment dose and was not benefitting from a placebo response. Mandell, M. and Conte, A. (1982)21. In the Mandell study, the investigators studied 30 volunteers with documented arthritic pain. Each received a sublingual challenge of 19 food -40- 4S 8 antigens, 9 inhalants, and 4 placebos of distilled water. The positive symptomatic response was 61% for the foods, 38% for the inhalants, and 6.6% for placebos. Eachdifference is highly significant statistically. The data and structure of this study are somewhat difficult to assess and the method of assuring the double-blind are not clearly outlined. Despite these flaws, this report adds further corroborative evidence to the efficacy of sublingual provocation/neutralization techniques when it is considered in conjunction with the other positive double-blind controlled studies. Miller, J .(1972)^ . This book represents a comprehensive text on the "how to" of provocation/neutralization techniques. O'Shea, J., and Porter, S. (1981) 22 . In this study, fifteen children were chosen who met the clinical criteria of hyperkinetic syndrome. The mean score by both parents and teachers was 20 on the Abbott's Hyperkinetic Index (an adaptation of Conner's hyperkinesis scale). A detailed history and physical examination confirmed the diagnosis of hyperkinetic syndrome. Food and inhalant extracts were serially diluted in multiples of five for intradermal testing. .The food dyes were commercial food colors sold in most food stores. Placebo was preservative-free chlorophyll. The study lasted for seven weeks and consisted of two 3-week -41- 13499 periods separated by one weeks's vacation. During each 3-week period, every child was randomly given either the allergy extract or the placebo. The same Hyperkinetic Index was used as in the Connor study. However, in contrast to that study, the children were monitored daily. The allergy extract could be differentiated from the placebo solution by 11 of 14. (78%) of the parents and 7 of "13 (54%) of the teachers because of improved activity and behavior patterns in the children studied. This study indicates that allergy extract therapy can produce significant symptomatic improvement in documented hyperkinetic children, often obviating the need for the dangerous practice of treating these children with amphetamine-like drugs. Rapp, D. (1979) 23 In this study, eleven children were treated with a food extract after titration food allergy testing. ` Extract was administered sublingually or subcutaneously. These patients remained improved, as measured by the Abbot Hyperkinesis Index Scale, for one to three months while ingesting the foods to which they were sensitive. Five of eight patients then completed a double-blind evaluation of the food extract and successfully differentiated the latter solution from two placebo ones. All solutions were dispensed in opaque bottles to avoid patient recognition of color. Two of the three children who -42- 13500 failed to correctly identify the food extract relapsed when food therapy was discontinued. They responded favorably when the therapy was reinstituted. This study, like the O'Shea one, further corroborates the efficacy of sublingual provocation/neutralization therapy for food allergy treatment. -43- 13501 F. MODERN CONCEPTS OF THE IMMUNE RESPONSE AND HOW IT RELATES TO PROVOCATIVE/NEUTRALIZATION Although the efficacy of provocation/neutralization has been firmly established clinically and by placebo-controlled double-blind studies, controversy still surrounds the techniques. This is based, in part, on the critics' assumptions that the treatable allergic reactions are mediated by IgE, and that no immunologic mechanisms exist which can explain the provocation/neutralization phenomenon. The past decade has brought major changes in the concepts underlying the mechanisms of allergy. We originally thought that the immune response was a specific reaction to challenge from a specific antigen, mediated by IgE antibody. The immune response was seen as a linear function of ever-increasing doses of specific antigen producing ever-increasing amounts of antibodies, until the immunologically reactive cells were exhausted and immunologic unresponsiveness ("tolerance") resulted. 24- Although immunologic tolerance is the'goal of build-up immunotherapy modalities, these conventional allergy methods have been unsuccessful in treating non-IgE-mediated allergies (Type 1, immediate response) as well as some classical IgE-mediated illnesses. We now know that many types of allergies, e.g., those cue to -44- 13502 foods and environmental chemicals, cause other-than-IgE mediated reactions. The immune response is a complex series of well-programmed interactions and counteractions between various cellular and humoral components of the immune system. These interactions follow a biphasic or multiphasic curve if plotted out. Because the immune system is part of a larger interactive network involving the lymphoreticular, nervous, 2 5 '2 5 and endocrine systems, 2 5 '2 5 an immune response may involve multiple systems and organs and result in such diverse clinical signs and symptoms as migraine, 27 food addiction, 7 behavior or mood changes, 23 '29 '30 hyperkinesis, 22 '23 heart problems, 31 or joint diseases. 21 Provocation/neutralization is the clinical correlate of the phasic immune response, where one dose of antigen provokes an immune response, a lower dose cancels ("neutralizes") it, and a still lower dose again provokes it. This pattern occurs because the various components of the immune system involved in an immune reaction are dynamically interacting to return the organism to homeostasis or nonreactivity. Physicians using these modalities can safely and effectively treat antigen-related allergies in most cases because administration of a neutralizing dose of specific antigen alters the body's phase of immune response, thereby enabling it to return to homeostasis. 1. THE HIGHLY REGULATED AND CONTROLLED IMMUNE SYSTEM The immune system is a highly regulated system which monitors and responds to changes in the chemical composition of the body. These changes trigger signals from cellular and molecular elements of the immune system which distinguish between harmless and harmful agents. The signals switch various cellular and humoral effectors "on" or "off" to control and modulate growth and development within the organism. They interact not only with elements of the lyimphoreticular system but with those of the neuroendocrine system as well. Immunologic regulation is effected _bj a tightly controlled interactive balance between inducer and suppressor T-cell subsets, idiotypic and anti-idiotypic antibodies, and a multitude of other immunomodulatory molecules and cells Once the immune system has distinguished between harmful and harmless agents, it must induce the appropriate molecular and cellular reactors to ignore (suppress active inflammatory reactions) or challenge (induce active inflammation). Many of the factors secreted by immune-reactive cells are soluble peptides and lipids which circulate to remote sites of the body and cause effector functions. 135 '4.1-4.4. Objective changes in brain chemistry, 25 joint metabolism, and endocrine glands result from remote immunologic reactions. The immune system's tightly controlled interaction of 13504 antibodies and cells are directed against specific antigens and are called idiotypes. Production of these idiotypes is modulated by specific antibodies .(anti-idiotypes) against the antigen-combining site of these antibodies and cells. The production of these anti-idiotypes are in turn controlled by anti-anti-idiotypes and these by anti-anti-anti-idiotypes. The presence of the family of anti-idiotypic antibodies lends smoothness to the immune response, much like extra cylinders provide smooth function to a gasoline engine. -47- 13505 2. THE PHASIC PHENOMENON OF IMMUNE RESPONSE Specific immunologic unresponsiveness ("tolerance") occurs when responsive cell clones have been eliminated by prior contact with antigen, with the result that no immune response against that antigen occurs on re-administration. One of the original workers to note the phasic nature of immunological responsiveness and unresponsiveness was Mitchison.51 In his study, newborn rats were injected daily for 2 weeks with a wide range of doses of bacterial flagellin antigen. Control rats received no antigen. All animals, including controls, were then given a stimulatory dose (10 meg) of flagellin twice a week for 4 more weeks, and their antibody responses measured. The results are shown in figure 1 at the end of this subsection. As can be seen in the figure, the response to varying doses of antigen in the tolerized animals produced a biphasic distribution. At very low tolerizing doses of antigen (less than 10 pg of flagellin antigen/gr body weight) the animals responded to the immunizing dose with near-normal (control) levels. As the tolerizing doses approached 10-3 pg, the animals developed specific immunologic unresponsiveness (low-dose tolerance). As the tolerizing dose increased to around 10-1 pg, the animals responded with a supernormal ("overshoot") immune response. When the tolerizing dose -48- IS approached 100 pg and above, the animals again exhibited specific unresponsiveness. This phenomenon has been shown to be due to the modulatory effects of suppressor T cells which respond to various concentrations of antigen. These suppressor cells can be categorized as non-antigen-specific and specific. Most react through soluble factors which can circulate throughout the body. "Tolerance" occurs when the specific suppressor T-cell factors are dominant over specific helper/inducer T-cell f-act,ors. 60-74. Biphasic and multiphasic responses to antigen and other mediators of the inflamatory process are not' unusual. Although not specifically discussed, they have been found by a number of investigators in their studies. For example, in experiments using spin label probes to detect the release of myelin-basic protein from lipid vesicles in an artificial membrane, Boggs et a l .52 showed a reciprocal and essentially biphasic response between specific antibody-dependent and antibody-independent release as a function of increased antigen concentration. Eichmann^ found that 50% of the antibodies to a specific bacterial carbohydrate produced by a strain of mice had cross-reacting idiotypes. When these animals were pretreated with anti-idiotypic antibody, their idiotype response was -49- s suppressed. The amount of suppression followed a biphasic curve. Small amounts of anti-idiotype produced little idiotypic suppression, intermediate doses produced maximum suppression, and larger doses produced less suppression. 3 y I A similar phenomenon was demonstrated by Szewczk et al5'14' when they measured the affinity distribution of the IgG anti-TNP plaque-forming cells in the spleen of animals ci ri 1 treated with various doses of histamine which is a suppressor cell inducer. Sullivan et al^5 found that modulation of cyclic AMP in purified rat mast cells by pharmacologic stimuli follows a biphasic mode. They demonstrated a biphasic response of purified rat mast cell cAMP to carbamycholine, exogenous adenine, and diazoxide. A biphasic response develped in rats1 capacity to respond to :1 sensitization with a supraoptimal dose of oxazolone when they were pre-treated with various doses of oral cyclophosphamide.5 S ri vj J Serial assessment of antibody concentrations weeks after immunization with antigen often shows a multiphasic curve. 57 These biphasic and multiphasic responses to varying concentrations of antigen are due to the phasic nature of the immune network which is a complex interaction of idiotypes 1350 -5 0 - and anti -i.dio.types.58 When the helper/inducer cells are dominant in function, idiotypes are synthesized. This provokes a reciprocal synthesis of anti-idiotypes which enhance the activity of the suppressor cells. The suppressor cells then suppress the action of the idiotype-producing B cells. This cycle continues with ever-decreasing intensity until the base line is re-established. 75-77 The Phasic figure 1: Nature of the Immune Response 51 -51- 3 . HOW PROVOCATION/NEUTRALIZATION WORKS Many types of allergic reactions are mediated through the formation of immune complexes. Provocation/neutralization works because it alters the ratio of antibody to antigen by addition of a small amount of antigen. The combination of antibody with antigen is one of the fundamental life-preserving processes of immunology. Yet these complexes,once formed, must be completely removed from the circulation quickly, for their persistence is itself a threat to survival of the organism. This is because such persistence can call complement and polymorphonuclear leucocytes into action to destroy the remaining complexes. Since these destructive effects are nonspecific, cells in the vicinity of the complexes may be damaged or destroyed, possibly resulting in lethal immune-complex-mediated disease. The existence and potential pathogenicity of immune complexes were first suggested in 1905 by von Pirquet and Schick. 7 8 Immune complexes are formed daily in everyone from foods, inhalants, micro-organisms, and many other antigens, 7 9 -8 1 but their size, level, and rate of removal from- the circulation are such that clinical immune complex disease does not normally occur. Very small complexes which are formed in antigen excess are less likely to be pathogenic than somewhat larger ones.82 - 5 2 - 13510 This is because they may contain only one IgG antibody which is incapable of activating complement. They are small enough to pass completely out of the circulation through inter-endothelial cell pores in vascular basement membranes. These very small complexes do very little harm since they activate complement and do not deposit in vessels. Very large'complexes (over 19S) formed in antibody excess are efficiently cleared from the circulation by macrophages of go the reticulo-endothelial system. They are also relatively harmless. Intermediate-sized complexes formed at approximate equivalence (ag:ab ratio of approximately 3:2) with a molecular weight of about one million, are the potentially toxic ones. They are too small to be efficiently phagocytosed by macrophages, and are too large to completely traverse the pores of vascular basement membranes. They tend to persist in the circulation and become lodged in these pores. This automatically activates the complement cascade which in turn .attracts polymorphonuclear leukocytes. The destruction of neighboring endothelial and tissue cells flows from two mechanisms, destruction by complement cascade proceeding to C8 and C9, and neutrophil enzymatic digestion. 82 -53- JLO j l . A If complement activation proceeds only to the point of liberating anaphylatoxins, particularly if only to C3a, there is much less likelihood of inducing irreversible cell injury by either mechanism. Anaphylatoxins can cause release of histamine and other mediators from mast cells and basophils, inducing reversible enlargement of inter-endothelial cell pores resulting in increased capillary permeability and local edema. It is chiefly by way of such edema that allergic symptoms can be initiated without the involvement of IgE'and without the cellular destruction associated with full complement activation and neutrophil participation. Antigen-antibody interaction in immune complex formation is a highly dynamic process. Antigens and antibodies in complexes can quickly dissociate and recombine in other ratios. Complement activation and inactivation and anaphylatoxin-induced mediator release can occur in seconds or minutes. 83 Adding a small amount of antigen or antibody can shift the reaction rapidly and markedly. This shift results in smaller or larger- complexes, thereby altering the potential for complement activation.. If the right amount of antigen is added to shift the curve from pathogenic to a nonpathogenic mode, rapid symptom-relief occurs. This is what happens in neutralization. Repeatedly adding this dose of antigen keeps equilibrium reactions stable and symptoms controlled. If the amount of antigen added is too small or too large, symptoms are induced. The induction and relief of symptoms in this manner are consistent with the "turn-on"/"turn-off" phenomena noted during provocation and neutralization testing and with the long-term relief provided by regularly administered neutralization injections. See figure 2 (next two pages) for a diagram of how provocation/neutralization works, and an explanation of the diagram. 13513 -55- figure X: How Provocation/Neutralization Works AMFRTIOGMEN G I TRACT AWFRTOI MGEN SKIM -56- AWRPHVLA- 1/A5CUL AR --------------- PERMEABILITY TXIUS EDEMA) 1- Legend to figure 1 How Provocation/Neutralization Works 1. Antigen from G-I tract (A) enters circulation, is bound byantibody to from ag-ab complexes. 2. If complexes persist in circulation, complement is activated, anaphylatoxin released. 3. Anaphylatoxin triggers mast cells and basophils to release mediators, resulting in vascular permeability, edema, and allergic symptoms. 4. Antigen injected into skin (B) in appropriate doses takes three pathways a. Enters circulation to alter circulating antigen-antibody ration and affect immune complex formation. b. Combines with IgE antibody on surfaces of mast cells in skin, and also possibly with basophils in circulation, or arriving in tissue at site of antigen injection. This stimulates local release of mast cell mediators, including histamine. Histamine stimulates mast cells and basophils to stop mediator release, and stimulates T-suppressor cells to secrete HSF. HSF suppresses T-helper cells, which turns of B-cell release of IgE, reducing vascular permeability, edema, and allergic symptoms. c. Stimulates skin macrophages to transmit signals to T. cells to turn on increased B-cell formation of fgG, which enter circulation and favorably affect' antigen-IgG ration, reducing formation of toxic complexes. -57- 4. THE IMMUNE RESPONSE IS OFTEN MEDIATED BY FACTORS OTHER THAN IgE The past 10 years have changed many of our concepts of allergy and immune response. For example, the common consideration of IgG only as a blocking ("good") antibody in allergy, and IgE only as a symptoms-inducing ("bad") antibody is obsolete. Such a simplistic scenario is too incomplete to explain recently accumulated data concerning complicated interactions among humoral and cellular reactants and the two cell types (helpers and suppressors) that can effect opposite reactions. 46 '84 For example, IgG can form immune complexes to. produce harmful allergic .syndromes as well as lethal diseases. 80 . Co_n.versely, IgE can induce local histamine release which itself can quickly turn off allergic symptoms and stimulate expansion of clones of protective suppressor liympuhocy*t.es.85-99 Allergy symptoms are mediated by the formation of specific antigen-induced immune complexes rather than by specific antibodies. As demonstration of this, symptoms of non-IgE mediated allergy may be produced in some patients by antigen-induced immune complexes, and relieved by antigen injection which induces rapid clearing of these complexes. It is well-recognized that immune complex-mediated disease can be associated with symptoms in virtually any organ. A classic example is systemic lupus erythematosus. Lupus - 5 8 - 13516 patients with central nervous system involvement may experience headache, hyperactivity, visual changes, disorientation, aggressiveness, -and frank psychosis. These symptoms have been shown to be related to the presence of immune complexes in the peripheral circulation and to changes in complement components in the cerebrospinal fluid.30 ' They are caused by anaphylatoxin-induced histamine release from mast cells and basophils leading to increased capillary permeability in the brain or adjacent structures. Similar symptoms occur after the ingestion of al,,lergenic food.s. 102-104 In lupus, the immune complexes are generally made up of double-stranded DNA . antigen and a complement-fixing IgG anti-DNA antibody. In allergic patients, antigens complexed with circulating and cell-fixed antibodies activate complement to produce anaphylatoxin-mediated histamine release resulting in the increased capillary permeability which causes the observed allergic symptoms. A recent series of -papers by Brostoff et al80 '81 and Paganelli 7g et al confirm the existence in food allergic patients of circulating immune complexes composed of food antigen and a variety of immunoglobulins including IgG, IgA, and IgE. Matthews and Soothill^09 and Atherton et a l ^ have demonstrated complement activation secondary to immune complex mediation in food allergic patients undergoing food -59- 5. challenges with their allergenic foods. Minor, Tolber, and Frick^^ also found that immune complexes participate in delayed food allergy. May112 has similarly demonstrated chronic high background blood levels of histamine in food-allergic patients. 135 5. TWO INTERACTING IMMUNE MECHANISMS EXPLAIN NON-IgE MEDIATED ALLERGIC RESPONSES Two interacting immune mechanisms explain non-IgE mediated allergic reactions. The first mechanism concerns allergic symptoms caused by increased capillary permeability due to antigen-induced, immune complex-mediated phenomena, and relief of such symptoms by injecting precisely determined doses of antigen to beneficially .alter antigen-antibody ratios and allow for more efficient clearing of these complexes. This is accomplished through interactions of immune complex-clearing systemic macrophages, antigen-stimulated skin macrophages, T cells, B cells, and various humoral products. Injected antigen interacting with macrophages, T cells, and B cells also stimulates B cells to produce specific IgG, thus increasing specific IgG levels to favorably alter the ratio of antigen to antibody in immune complex formation. Secondly, injected antigens interacting with mast cell-bound IgE in the skin cause the release of histamine which can produce, two opposing effects. Histamine causes symptoms by stimulating effector cells to "turn on" allergic symptoms. However, at known concentrations, histamine also quickly "turns off" further histamine release by mast cells and basophils, "turns off" IgE-forming B cells by stimulating T-cell secretion of histamine-induced suppressor factor, and stimulates and expands T suppressor populations. 35 '36 -61- fi Injected antigen interacting with macrophages, T cells, and B cells also stimulates B cells to produce specific IgG, thus increasing specific IgG levels to favorably alter the ratio of antigen and antibody in immune complex formation. These two mechanisms are interdependent facets of a single system. Their operation is reflected in experimental evid ence and clinical experiences from many laboratories and clinics. Resulting predictions can be tested by available laboratory and clinical techniques, and correlations can be made that place hitherto puzzling observations of responses to allergy and immunotherapy in the mainstream of current immunological understanding. -61a- 13 on VN> r~. r-: L 6 . CELLULAR AND HUMORAL EFFECTORS OF THE PHASIC IMMUNE RESPONSE The cellular systems (macrophages, mast cell-basophils, neutrophils, platelets, and lymphocytes) are inextricably interwoven with the humoral system to produce allergic responses. The humoral elements, including antibodies, endocrine and non-endocrine hormones, eicosanoids, plasma kinins and coagulation cascades as well as many other humoral participants, including neurotransmitters, are also integral parts of the same system. The sequence of biochemical events that produce symptoms of allergy, for example food allergy, is: 1) food antigens combine with food antibodies to form immune complexes, 2) which trigger complement activation to produce anaphylatoxins, 3) which induce release of histamine and other mediators from mast cells and basophils, 4.) which result in increased capillary permeability, edema, and allergic symptoms. It is chiefly by way of such edema that allergic symptoms can be initiated without the involvement of IgE and without the cellular destruction associated with full complement activation and"neutrophil-participation. a . R ole o f M acrophages Macrophages serve two functions in this process: clearing of immune complexes, and secretion of suppressor and -helper factors. 13521 -62- It is well-known that the rapidity with which immune complexes can be cleared from the circulation depends upon the integrity of the phagocytic cells of the blood and tissues. The macrophages of intact animals clear complexes rapidly. Animals with reticulo-endothelial blockade, caused by injection of bentonite or carbon particles are unable to clear their circulation of immune complexes. The same is true of animals whose reticulo-endothelial cells are engorged with viruses or bacteria from overwhelming infection. Chronic or repeated showers of immune complexes in the circulation of humans also produce varying degrees of reticulo-endothelial blockade. The slower or more limited clearing of symptoms seen in some patients with multiple sensitivities indicates a temporary or prolonged overload on the phagogytic system. Macrophages also participate in the initiation and regulation of immune responses4'^ by secreting humoral factors, including some with helper and some with suppressor functions.^6 '4-7 These substances are antigen-specific and genetically restricted. 4.7--49 Thus, for example, macrophages can secrete specific suppressor and helper factors for ovalbumin just as can ovalbumin-sensitive suppressor and helper T cells. The symptoms seen in some patients with non-IgE mediated allergy are caused by: 1) transient showers of 13522 -63- r antigen-antibody complexes initiating partial complement activation, 2) which induce anaphylatoxin formation, 3) which leads to release of histamine and other mediators from mast cells and basophils, and ) which results in allergic edema. The presence, severity, and duration of symptoms is, in part, a function of the c o m p l e x e s .8 2 level, size, and persistence of such Provocation and neutralization of symptoms result from alterations in blood and tissue levels of pathogenic complexes. 2 '5 Circulating monocytes and _fixed macrophages are important participants in these reactions through removal of immune complexes. When antigen is introduced into the skin, antigen-stimulated l skin macrophages are the cells most intimately involved in secretion of antigen-specific helper and suppressor factors which can affect antibody formation and in turn alter circul.a.t.ing ant.i.gen-ant.i..bod.y rat.i.os. 115-119 When T 0 suppressor lymphocyte function becomes inadequate to control ills IgE-forming B cells, allergy results. Injecting precisely chosen doses of specific antigens into the skin cam stimulate and "train" skin macrophages to assume a greater portion of the needed suppressor function.^20 r. b. Basophils and Mast Cells: Role of Histamine 13523 released from mast cells and basophils by IgE and non-IgE mechanisms can turn on immediate allergic symptoms by binding to HI receptors on target cells such as bronchial smooth muscle (a proflammatory effect). At higher concentrations, histamine can also quickly turn off symptoms through a feedback loop to the H2 receptors on mast cells and basophils, stopping further histamine release (an anti-inflammatory effect).86,86 In addition, histamine has a delayed and prolonged effect on other cellular interactions. By binding to H2 receptors on T lymphocytes, neutrophils, and eosinophils, histamine modulates the function of these cells involved in delayed as well as immediate reactions. 87--92 After antigen injection into the skin, mast cell-released histamine in the skin can stimulate local T supresssor cells to release their Histamine-induced Suppressor Factor (HSF). HSF traverses the circulation and suppresses distant helper T cells, thus turning off antibody synthesis by B cells, and altering circulating and cell-fixed antigen-antibody ratios. 91 '94.'95 Histamine levels are themselves modulated by histamine released from complement-stimulated . neutrophils,96 and histamine levels are regulated by a product of histamine degradation, imidazole acetic acid. 13k Specific local concentrations of histamine are critical in determining which mode is operative. Histamine release from mast cells and from basophils recruited to the skin in 13524 -65- cutaneous basophil hypersensitivity is inhibited in vivo by locally released histamine in the concentration range of lo-6 _ 4 , 92 1. to 10 M. High levels of histamine are found in the blood of persons with food allergies. 97 Significant elevations in blood histamine levels occur with subcutaneous injection of an allergenic food extract. These patterns reflect the high local histamine concentrations T: occuring transiently in the micro-environment around degranulating mast cells and basophils. 92 12 In neutralization therapy, a dual therapeutic response occurs consisting of rapid relief in minutes o r hours after each" subcutaneous treatment injection, and increasing ability to (r* tolerate exposures ("hyposensitization") to the antigen over l ; weeks, months, and years. Rocklin et al 99 and Evans et al 131 have demonstrated that antigen-specific suppressor cells are induced by repeated injections of antigen. Decreased <. suppressor activity leads to clinical allergic sensitivity. Stimulation of increased suppressor activity and increased suppressor T cell populations account for much of the n long-term improvement in allergic patients on immunotherapy. 0 Thus, it is well established that symptoms of allergy can be caused by histamine released from mast cells and basophils by both IgE and non-IgE mediated mechanisms. These symptoms can be quickly relieved by injecting a quantity of antigen which induces the release of the precise amount of histamine r\ -66-- 13525 required to turn off further histamine release. Maintenance treatment with these extracts repeatedly stimulates suppressor T cells to release HSF, further suppressing specific IgE antibody production. This effect of antigen on suppressor T cells can be direct or mediated by histamine or by stimulated macrophages. As discussed earlier, suppressor T cell populations are increased by repeated antigen injections. Finally, repeated antigen injections acting through macrophages, T cells, and B .cells also stimulate increased specific IgG antibody production, favorably altering antigen-antibody ratios in immune complex interactions and diminishing the potential for complement activation and symptom induction. c. Role of Lymphocytes Minor, Tolber, and Frick109 have reported that leucocyte migration inhibition factor (LIF) was frequently elevated, in patients with delayed type food allergy. The presence of this lymphocyte-secreted product supports the fact that lymphocytes take part in delayed allergic reactions. They postulate that LIF release is a result of antigen-antibody complexes on the surface of lytmphocytes or neutrophils (Type III response). May97 reported a high nonspecific background leucocyte histamine release in food-sensitive patients. He suggested that these chronically high histamine blood levels can be 13526 -67- L_, n * L, explained by immune complexes on the surface of basophils. Circulating food antigen complexed with antibodies and attached to basophils induce a constant discharge of histamine from the basophils. It is evident from such observations that food antigen-induced, immune complex-mediated phenomena cause commonly encountered food allergy symptoms by several pathways, and that further study of these interacting pathways might well illuminate puzzling clinical observations. The phenomena of intradermal provocation and neutralization is thus tied- into the interactions of: 1)intradermally injected antigen, 2)antigen-processing macrophages, in the skin, 3)T and B lymphocytes which come in contact with the antigen-stimulated macrophages or soluble factors to participate in signal transmissions, and k)the subsequent T cell action responses. 132 of suppressing or stimulating B cell Langerhans cells themselves can be damaged by immune complex-activated complement and destroyed by killer T lymphocytes. 61 '33 Thus, the regulators are themselves regulated. Mast cell histamine release can participate in this series of interactions by increasing local capillary permeability to facilitate the movement of antibodies and cells into the site of the reaction. As local histamine levels rise, histamine can then terminate increased capillary permeability by ...... - 68- _ 13527 turning off further histamine release through H2 receptors on mast cells and basophils. Histamine can also act by stimulting local T cells to release HSF and turn off IgE-forming B cells. Injected antigen can also act by increasing specific IgG levels to favorably alter the ratio of antigen and antibody in immune complex formation, and by stimulating and expanding T cell populations. If additional histamine release is required by the mast cells to accomplish i .their ends, these cells can recruit basophils to enter the reacting site and provide the additional histamine. All the individual facets of these multiple interactions are well documented and conform to the clinical phenomena observed in intradermal provocation and neutralization. c. Role of Neutrophils A major factor in food allergy disease process is the generation of an immune complex complement-consuming process j which precipitates intravascular inflammatory events. These .. > inflammatory events produce endothelial damage in various target organs. Inflammatory events can be the result of the action of one or a few cells. Complement activation by immune complexes can cause the aggregation of leukocytes I through the action of the chemotactic factors of C3a and C5a.^3 Granulocytes are capable of causing both endothelial and interstitial injury. Neutrophils liberate superoxide radicals and other highly reactive oxidant byproducts of phagocytosis. The superoxide radical has- been shown in 13528 - -69- tissue culture to injure endothelial cells. 1 3 7 In addition, neutrophils produce neutral and ' acid proteases 138 that destroy structural proteins such as collagen elastin and the adhesive glycoprotein fibronectin, 139 a necessity for ordering the interstitial topography of cells and connective 14,0 tissue. These proteases also cleave fibrinogen, the Hageman factor, complement, and other plasma proteins. Thus, neutrophil proteases can both destroy intersitial t;V architecture and permit local amplification of tissue injury K. U by activating plasma precursors that ultimately result in further leukocyte aggregation and intravascular coagulation. E Using the lung as a model target organ for immune tissue P3 damage, it has been demonstrated that the tissues' natural defense against damage induced by superoxide radicals, alpha 1 antitrypsin from plasma, can be inactivated by the ni'-.l superoxide radical or by oxygen leaking into damaged tissue. The sequence of events is as follows: 1)circulating immune complexes lodge in a target organ, 2) which results in local fi activation of complement, 3) which generates C5a and C3a, and Id 4.) which cause leukocyte aggregation in the target organ. As B L in the case of the heart or brain, very small numbers of leukocytes could produce wide-ranging symptoms. Aggregated 13529 r u -70- neutrophils injure endothelial cells by the generation of toxic oxygen radicals. The neutrophil liberates proteases that destroy structural proteins such as collagen, elastin, ib1.l31 and fibronectin as well as promote further local inflammatory changes by proteolysis of circulating plasma proteins such as the Hageman factor, fibrinogen, and complement. At the same i'i time, protective antiproteases are inactivated by oxygen radicals released from immune effector cells. J Endothelial damage caused by' small numbers of inflammation cells can cause wide-ranging symptoms with little or no histologically definable target organ damage. For example, microscopic inflammatory events in the heart can cause fatal arrythmias with little or no detectable histologic changes. Microscopic inflammatory events in the brain can cause wide-spread symptoms of behavioral changes and epilepsy with little or no detectable histologic changes. 144 Thus, reversible microvascular inflamatory events caused by small numbers of neutrophils are most probably the basis of many antigen-associated allergies, for example to foods. -71- (no page 72) 13531 G. WHY DO INTRADERMAL AND SUBLINGUAL ADMINISTRATION OF ANTIGEN PROVOKE AND NEUTRALIZE SYMPTOMS? The epidermis (and sublingual tissue) is one of the most immunologically active organs in the body. It contains most if not all of the cells known to be functional in immune response. ' The epidermis is the first line of defense in bacterial, fungal, and parasitic infestation. Complement-consuming dermatopathologic processes induced by immune complex formation have been documented as being caused by the inhalation of aerosolized petrochemicals from copying machines, various petrochemicals used in plastics, and 145 foods. Mediators originating from immunologic reactions in the skin can quickly become systemic due to the skin's vascular structure, making the skin the ideal organ for testing overall immune reactivity. The epidermis (and sublingual tissue) contains a meshwork of fixed macrophages, the Langerhans cells, with long contracting cytoplasmic extensions. These cells contain la antigens and are very active antigen-processing cells. Just below the basement membrane of the epidermis is a rich capillary network. Materials injected intradermally reach this network' and absorb very rapidly by comparison with materials injected into subcutaneous fat or muscle tissue^0 where macrophages and capillaries are less concentrated. -73- Fixed macrophages in the skin are therefore well-equipped and well-situated to quickly detect and process specific antigens injected intradermally and to secrete specific modulating humoral factors which can quickly find their way to the systemic circulation. Once in the circulation, they can traverse the entire body in approximately 15 seconds. These factors thus can quickly suppress or stimulate specific antibody secreting B cells in the gastrointestinal tract, central nervous system, and other distant regions. Langerhans cells in the epidermis can migrate to the dermis and also through lymphatic channels to regional n o d e s .^'4'8 ' In nodes they are capable of transmitting signals to many T and B cells. They are known to function in contact dermatitis 117 as well as in herpes simplex virus infections, responses to intradermally injected P P D , ^ 8 D N F B , ^ 3 various haptens, and other allergens. 119 While macrophages in the subcutaneous tissues perform similar functions, those in the epidermis do so more rapidly and vigorously. This fits observed clinical- phenomena, including more rapid and vigorous symptom provocation and neutralization with intradermal as compared to subcutaneous antigen administration. Intradermal injection of antigen characteristically induces marked symptom provocation or neutralization beginning within three to four minutes and reaching peak effect in ten minutes. Sublingual -74- 13533 administration works as fast as and by the same mechanisms as intradermal injections. Subcutaneous administration usually induces such changes more gradually over a period of thirty minutes. -75- O o III. FLAWS IN THE OPPONENTS' CASE AGAINST PROVOCATION/NEUTRALIZATION The opponents' case against provocation/neutralization techniques is flawed and scientifically unsound. In addition, the studies supporting the efficacy of traditional techniques are also flawed and fail to demonstrate their efficacy as an alternative to provocation/neutralization. This section will contain: A. Critique of the opponents' case against provocation/neutralization B. Representative flaws in the science supporting the clinical techniques of conventional allergists 1353 A. CRITIQUE OF THE OPPONENTS' CASE AGAINST PROVOCATION/NEUTRALIZATION The careful reviewer of these comments may note an information gap between the NCHCT 1981 Evaluations, upon ' which the proposed HCFA action is based, and the empirical and scientific justification for the. efficacy and safety of provocation/neutralization outlined in the preceeding sections of these Comments. The gap is real. The NCHCT Evaluations cite only one of the 12 laboratory studies supporting provocation/neutralization. They do not even attempt to examine the immunological mechanisms behind these techniques. The latest critical bibliographic entry for the intradermal/subcutaneous NCHCT report is dated 1976, and the latest citation in support of provocation/neutralization is dated 1978. For the sublingual report, the latest critical citation is 1980, and the latest supportive one is 1980. Finally, both NCHCT reports were issued in 1981, before 3 of 3 4. 5 the strongest double-blind studies ' ' in support of provocation/neutralization had been published. Yet no attempt has been made to incorporate the new data into HCFA's rule-making. NCHTC references criticizing provocation/neutralization techniques lack scientific credibility. In support of its 13536 -77- criticisms of the intradermal/subcutaneous modalities, NCHTC offers: 2 abstracted reports (one 7 years old, the other 12 years old, and neither have been followed up by full-length scientific articles); one letter to the editor ( 1 2 years old and never followed up by a full-length scientific article); and one uncontrolled study which appeared as a 1 -page article in the Archives of Otolaryngology. The other references . cited are favorable. For the sublingual modalities, the report cites: the same 1 2 -year-old abstract; a seriously flawed 9-year-old committee report; and a more recent study c whose author has acknowledged " many inadequacies in the study". The other references cited were favorable. u. Kailen and Collier (1971) . This study is a 12-year-old, 3-paragraph letter to the editor. The authors are still alive yet the letter has never been followed up by a full-length article in a refereed journal. The only possible r cJ reason for this is that the study was not good enough. Nothing more need be said about it. B i' ' * Hirsch et al(198l) This study has been roundly G criticized by pediatric, internal. medicine, and otolaryngologic allergists as well as by immunologists familiar with provocation/neutralization techniques. Among the more obvious errors in this study is its poor structure. The individuals administering the test had less than 4. hours of didactic training in the technique (physicians practicing i. i_j ir." -78- this method are usually trained through graduate or continuing education courses). In addition, the observers' objectivity has been questioned by a variety of investigators. The only parameter identified by critics as significant is the so-called "Symptoms Medication Index". Symptoms are very subjective and difficult to assess. Most practitioners using provocation/neutralization techniques use far fewer prescription medications than practitioners of conventional build-up immunotherapy. Therefore, the information derived through this index must be considered unreliable. The worst aspect of this study is that although the investigators measured certain biochemical parameters in an attempt to correlate them with the clinical findings, they never measured any of the immunological factors known to effect neutralization in immunotherapy. Any allergist who is current with the immunology literature Of the last decade knows that effective immunotherapy is characterized by the generation of antigen-specific suppressor cells. The investigators in this study never bothered to examine suppressor cell activity. In summary, this study was conducted by people who were unfamiliar with the technique being evaluated. The provocation/neutralization techniques were performed in a 13538 -79- manner inconsistent with current cliriical practice. The only statistically significant finding is based solely on unreliable subjective observations. Finally, the investigators never attempted to measure obvious objective immunological parameters which would have truly established the efficacy or inefficacy of the techniques. The remaining studies attempt to assess provocation testing. The critiques of these critiques are expanded in Appendix A, excerpted from a paper prepared by Dr. David S. King, M.D. of the Department of Psychiatry, University of California, San Fransico Medical Center. Dr. King examines the concepts of reliability and validity as well as the proper statistical techniques by which to assess them. He then reviews the research purporting to evaluate provocation testing methods. In reviewing this critical literature, Dr. King includes the A studies upon which the American Academy of Allergy based its position statement (issued May 1981) branding subcutaneous and sublingual testing as ineffective. These same studies also form the basis for the 1980 American Academy of Allergy communication to the NCHCT declaring provocation techniques to be unproven and therefore "experimental". Since NCHCT and HCFA, by adoption of NCHCT's positions, rely so heavily on the American Academy of Allergy's conclusions, reviewers should give their very deliberate and detailed attention to these critiques. 1315S9' -80- Dr. King's review finds that serious flaws in study design and analysis are common in the critical literature. These shortcomings include: 1) comparison of subjects' responses to antigen and placebo without verification of their having specific sensitivities to the antigens administered, 2) failure to incorporate double-blind procedures with placebo controls in the study design or execution, 3) failure to analyze study results statistically, k) improper statistical analysis, and 5) in some cases, re-analysis of the original dataseriously affecting the conclusions of the study. Bronsky et al(1971)153. This is a 12-year-old abstract, the authors of which are still alive. .The data was never presented in a full-length report which could be ahalyzed by unbiased observers. Since no placebo was given, double blinding seems unlikely. The design of the study does not rule out the possibility that the children were not sensitive to some or all of the foods tested. It is also not known whether the children were medicated. Caplin, I.(1973) 15k This report describes a study in which subjects were challenged sublingually with five standard foods and also placebo. Each antigen was challenged on two separate occasions. Although the results are reported as statistically insignificant, the committee's statistical consultant stated, "because of the design of this study one 81 must be careful of drawing any conclusions". Despite this warning, the committee reached the conclusion that the "test doesn't discriminate between control and food extracts". The protocol called for substantially more patients than were actually tested and even fewer received feeding tests. Additionally, the data on 17 of the patients was rejected without explanation. It is not stated whether this attrition occurred before or after the double-blind code was broken. Fifty percent of the remaining data was rejected for analysis because of "faulty protocol". An additional confounding factor in data analysis is the fact that most of the investigators were unfamiliar with the techniques used. Of the 10 physicians participating, only 3 had had previous experience with sublingual provocation. In stammary, this study is seriously flawed by its poor design and irregular handling of the data. The investigators were inexperienced, and the data was manipulated in an unexplained fashion. Despite the- warning by its statistician, the committee chose to form a conclusion based on this study. (Surprisingly, this data was used in the 1974. follow-up report discussed below.) The numerous methodological and analytical flaws in this study have been extensively noted and critiqued. Crawford et al(1976)^55. This is a 7-year-old abstract which was never followed up by a full-length article. Since this -32- O P / ^ study has only been published in abstract form, it is impossible to evaluate the materials, methods, or data analysis. It is curious that the scientists who were charged with assessing a technique which has been in continuous use for close to 40 years chose to cite studies whose data is unavailable for critical analysis by unbiased observers. I Draper, L.W. (1972) . This is a 1-page article which reports the findings of a study for which lack of proper i controls renders clear interpretation of the data impossible. 4 No statistical tests were reported. The absence of blinding and the failure to incorporate placebos in the design both seriously detract from the study. Since the intradermal tests were given only once, nothing can be said regarding their reliability. Breneman et al(1974)158. This report contains the 1973 data, 7* i mentioned above, as well as information on additional patients. The placebo response rate as calculated from the data was 50%. This is inordinately high and leaves the objectivity of this study in serious doubt. In addition, as in the 1973 report, there is unexplained attrition of patients in this study. The protocol called for 30 patients, but the data on only 2 0 patients are included in this analysis. No mention is made of precautions taken to insure blind conditions. The data are presented in summary form in tables, with no statistical analysis provided. -83- CO' In summary, this report relies on seriously questionable data to form the conclusion that the technique evaluated was not effective. apparently It is curious that the investigators were \ oblivious to the obvious flaws in their experimental design and data analysis. V' u Lehman, C.(1980) 157 This study claims to assess the 0 efficacy of sublingual food allergy provocation. The investigator attempts to quantitate changes in the edema and L; swelling of the nasal mucosa as induced by specific food antigens and placebo. The major design error in this study is cited by the author himself, "the nasalmucosal edema is r- constantly changing from one 10-minute interval to another, independently of placing food antigens under the tongue" . n i This choice of an inherently non-stable endpoint compromises U any assessment based on that endpoint. Another design error V; LJ is that patients were not required to' be sensitive to SP specific antigens to be tested. Subjects were supposed to have a "history of food allergy or other demonstration of food allergy". However, according to the reported data, e clinical sensitivity was suspected for only li of the 6C antigens which were challenged. There is no reason to expect L'< to provoke symptoms with an antigen to which the subject is not sensitive. No statistical analysis was reported. i. In summary, this study used an unreliable endpoint to test L i -84- the reaction of poorly selected patients against antigens to which they were not sensitive. In fairness to the author, it should be noted that he acknowledged "many inadequacies in the study". 13544 -85- B. REPRESENTATIVE FLAWS IN THE SCIENCE SUPPORTING THE CLINICAL TECHNIQUES OF CONVENTIONAL ALLERGISTS Although some good science is being performed byimmunologists associated with classical allergists, most of the double-blind, placebo-controlled clinical trials by which they attempt to establish the efficacy of their treatment modalities are seriously flawed. The data from these studies is questionable, and the conclusions drawn by the authors are consequently unsound. An analysis of some representative studies follows. Conners et al (1976)^^. This article is one of the major studies frequently cited by- the conventional allergists in support of their methods. This Nutrition Foundation-supported study purports to be a controlled double-blind experiment although its conclusions have been severely criticized. The "control" conditions of the challenge diet and "placebo-controlled" challenge trials are invalid and misleading. In this study of allergic children, milk, corn, wheat, eggs, chocolate (all common allergy-producing foods) were used as inert placebo. In addition, the challenge dose of food coloring constituted as little as 1/12 of the real-world exposure of children to food coloring additives. The children were evaluated weekly for evidence of allergic responses, a schedule that completely ignored the wide diversity of reaction times among allergic children. It is doubtful that the aberrant behavior of even a single child would become apparent on such an observation schedule. This study clearly demonstrates the lack of scientific training and bias of the investigators. That it was published as the lead article in Pediatrics is a telling commentary on the peer reviewers. Norman and Lichtenstein (1978)^63. This study purported to show clinical and immunological specificity of therapy in..a group of patients with rhinitis caused by ragweed and grass pollen. The investigators used ragweed antigen only. They showed an increase in IgG "blocking antibodies" and significantly reduced symptom response scores to ragweed without a corresponding reduction in the symptom response to grass pollen or production of IgG in these patients. This paper is widely cited as establishing the efficacy of conventional build-up immunotherapy for pollen sensitivity. The major flaw is that the investigators were measuring parameters which had nothing to do with clinical efficacy. The concept that IgG "blocking antibodies" effect clinical responses in patients treated with specific antigen immunotherapy had been obsolete for at least 3 years at the time of publication. Worse yet, this concept is still cited in text books used by conventional allergist today as the 13546 reason for symptomatic improvement, even though it has been proven unsound for more than a decade. In addition to this parameter, the authors used a "Symptom Medication Index", which is highly subjective and vulnerable to investigator and patient bias. Of interest, too, is the investigators' failure to consider whether foods were a major factor in their subjects' symptoms. Conventional allergists, in the main, lack sufficient scientific understanding of basic immunological principles and practices to perform credible clinical trials. In addition, the safety of conventional allergy treatment has been questioned. In one report,^55 5 of 19 patients who developed polyarteritis nodosa received conventional immunotherapy. No such finding has ever been reported in patients receiving provocation/neutralization therapy. Thus, based on the design and performance of the "classical studies" cited by conventional allergists as proof, it is far from clear that conventional allergy testing and treatment is either safe or effective. 88 3 V. REFERENCES 1. Miller JB, Personal Communication. 2. McGovern JJ Jr., Lazaroni JL, Saifer P, Levin AS, Rapp DJ, Gardner RW: Clinical evaluation of the major plasma and cellular measures of immunity. Journal of Orthomolecular Psychiatry; 1983; 12(1): 12. 3. Boris M, Schiff M, Weindorf S, and Inselman L: Bronchoprovocation blocked by neutralization therapy. Journal of Allergy and Clinical Immunology 1983; 71:92. 4. Rea WJ, Podell RN, Williams ML, Fenyves E, Sprague DE, and Johnson AR: Intracutaneous neutralization of food sensitivity: a double-blind evaluation. Archives of Otolaryngology 1983 (in press). 5. McGovern JJ, Rapp DJ, Gardner RW, 0 1Bannon DR, Peters P, Painter K, Percia S: Double-blind studies support reliability of provocative-neutralization test. Archives of Otolaryngology 1983 (in press). 6 . Miller JB: Food Allergy: Provocative Testing and Injection Therapy. Springfield, Illinois, Charles C. Thomas, 1972. 7. Dickey L (ed): Clinical Ecology. Springfield, Illinois, Charles C. Thomas, 1976. 8 . 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D; SHARP J G DEP. ANATOMY, UNIV. NEBR. MED. CENT., 42ND DEWEY, OMAHA, NE 68105. INT J IMMUNOPHARMACOL 4 (4). 1982. 323- CODEN: IJIMD TOXICOLOGICAL EVALUATION OF URBAN WASTE INCINERATOR EMISSIONS. RIZZARDINI M; ROMANO M; TURSI F; SALMONA M; VECCHI A; SIRONI M; GI BENFENATI E; GARATTINI S; FANELLI R ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI, VIA ERITREA 62, MILAN, ITALY. 3RD INTERNATIONAL SYMPOSIUM ON CHLORINATED DIOXINS AND RELATED COMF SALZBURG, AUSTRIA, OCT. 12-14, 1982. CHEMOSPHERE 12 (4-5). 559-564. CODEN: CMSHA DIFFERENTIAL INDUCTION OF 2 DIFFERENT FORMS OF CYTOCHROME PEXTRAHEPATIC TISSUES OF THE RAT BY 2 3 7 8 TETRA CHLORO DI BENZO-P-DI GOLDSTEIN J A; LINKO P NIEHS, RES. TRIANGLE PARK, N.C. 2770967TH ANNUAL MEETING OF THE FEDERATION OF AMERICAN SOCIETIES EXPERIMENTAL BIOLOGY, CHICAGO, ILL., USA, APRIL 10-15, 1983- FED PRO (4). 1983. ABSTRACT 3007- CODEN: FEPRA ASSESSMENT OF MYELO TOXICITY CAUSED BY ENVIRONMENTAL CHEMICALS. BOORMAN G A; LUSTER M I; DEAN J H; CAMPBELL M L NATIONAL TOXICOL. PROGRAM, NATIONAL INSTS. OF HEALTH, P.O. BOX RESEARCH TRIANGLE PARK, N.C. 27709SYMPOSIUM ON TARGET ORGAN TOXICITY: IMMUNE SYSTEM, ARLINGTON, VA., OCT. 20-21, 1980. ENVIRON HEALTH PERSPECT 43 (0). 1982. 12 CODEN: EVHPA 1 1356 ALTERED IMMUNE FUNCTIONS IN RODENTS TREATED WITH 2 3 7 8 TETRA CHLO BENZO-P-DIOXIN PHORBOL 12 MYRISTATE 13 ACETATE AND BENZO A PYRENE. LUSTER M I; DEAN J H; BOORMAN G A NATIONAL TOXICITY PROGRAM, NATIONAL INST. ENVIORN. HEALTH SCI., RES; TRIANGLE PARK, NC 27709. HUNT, V. R., M. K. SMITH AND D. WORTH (ED.). BANBURY REPORT, VOL. ENVIRONMENTAL FACTORS IN HUMAN GROWTH AND DEVELOPMENT; SYMPOSIUM, NOV. 1981. XX+570P. COLD SPRING HARBOR LABORATORY: COLD SPRING HARBOR, N USA. ILLUS. ISBN 0-87969-210-3- 0 (0). 1982. PI99-216. CODEN: BANF THE EFFECTS OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN ON CELL MED" IMMUNE FUNCTION IN THE MOUSE. JACKSON J D; SHARP J G DEP. OF ANATOMY, UNIV. NEBR. MED. CENTER, OMAHA, NEBRASKA 68105. 92ND ANNUAL MEETING OF THE NEBRASKA ACADEMY OF SCIENCES AND AFFILI SOCIETIES, LINCOLN, NEBR., USA, APR. 16-17, 1982. PROC NEBR ACAD SCI A SOC 92 (0). 1982. 25. CODEN: PNBAA ESTIMATION OF ISOZYMES OF MICROSOMAL CYTOCHROME P-450 IN RATS RABBIT: HUMANS USING IMMUNOCHEMICAL STAINING COUPLED WITH SODIUM DODECYL SUL POLY ACRYLAMIDE GEL ELECTROPHORESIS. GUENGERICH F P; WANG P; DAVIDSON N K DEP. BIOCHEM., VANDERBILT UNIV. SCH. MED., NASHVILLE, TENN. 37232, US BIOCHEMISTRY 21 (7). 1982. 1698-1706. CODEN: BICHA EFFECT OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN AND PHENO BARBITA THE OCCURRENCE AND DISTRIBUTION OF 4 CYTOCHROME P-450 ISOZYMES IN RA KIDNEY LUNG AND LIVER. DEES J H; MASTERS B S S; MULLER-EBERHARD U; JOHNSON E F DEP. BIOCHEM., UNIV. TEXAS HEALTH SCI. CENT., DALLAS, TEX. 75235. CANCER RES 42 (4). 1982. 1423-1432. CODEN: CNREA ENHANCED SUPPRESSOR CELL ACTIVITY AS A MECHANISM OF IMMUNO SUPPRESSIC 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN. CLARK D A; GAULDIE J; SZEWCZUK M R; SWEENEY G DEP. MED., HOST RESISTANCE PROGRAM, MCMASTER UNIV., 1200 MAIN ST. W HAMILTON, ONT. L8N 3Z5, CAN. PROC SOC EXP BIOL MED 168 (2). 1981. 290-299- CODEN: PSEBA SCREENING AND FUNCTION STUDIES IN IMMUNO TOXICITY TESTING. VOS J G LAB. OF PATHOL., NATIONAL INST. OF PUBLIC HEALTH, P.O. BOX 1, BILTHOVEN, THE NETHERLANDS. VET Q 3 (4). 1981. 190-195. CODEN: VEQUD 3720 STRUCTURAL GENE PRODUCT OF THE AH COMPLEX EVIDENCE FOR TRANSCRIPTI CONTROL OF CYTOCHROME P-1-450 INDUCTION BY USE OF A CLONED DNA SEQUENCE TUKEY R H; NEBERT D W; NEGISHI M DEV. PHARMACOL. BRANCH, NATL. INST. CHILD HEALTH HUM. DEV., BETHESDA, 20205 J BIOL CHEM 256 (13). 1981. 6969-6974. CODEN: JBCHA 2 13563 STRUCTURAL GENE PRODUCTS OF THE MURINE AH COMPLEX DIFFERENCES I ONTOGENESIS AND GLUCOSAMINE INCORPORATION BETWEEN LIVER MICROSOMi'CYTOCHROME P-1-450 AND CYTOCHROME P-448 INDUCED BY POLY CYCLIC AROMATI COMPOUNDS NEGISHI M; JENSEN N M; GARCIA G S; NEBERT D W DEVELOPMENTAL PHARMACOL. BRANCH, NATL. INST. CHILD HEALTH DEVELOPMENT 9000 ROCKVILLE PIKE, BETHESDA, MARYLAND USA 20205EUR J BIOCHEM 115 (3)- 1981. 585-594. CODEN: EJBCA IDENTIFICATION OF THE FORM OF CYTOCHROME P-450 INDUCED IN NEO NAT.- RABBIT LIVER MICROSOMES BY PHENO BARBITAL SCHWAB G E; NORMAN R L; MULLER-EBERHARD U; JOHNSON E F DEP. BIOCHEM., SCRIPPS CLIN. RES. FOUND., 10666 N. TORREY PINES RD., L JOLLA, CALIF. 92037, USA. MOL PHARMACOL 17 (2). 1980. 218-224. CODEN: MOPMA EFFECT OF POLY CHLORINATED BI PHENYL DI BENZO FURAN AND DI BENZ0-P-DI0X1 ON THE SUSCEPTIBILITY OF MALE MICE TO ENDO TOXIN OISHI S; HIRAGA K DEP. TOXICOL., TOKYO METROP. RES. LAB. PUBLIC HEALTH, HYAKUNIN 3-24- SHINJUKU, TOKYO 160, JPN. J ENVIRON SCI HEALTH PART B PESTIC FOOD CONTAM AGRIC WASTES BI5 (1 1980. 77-86. CODEN: JPFCD ISOLATION AND CHARACTERIZATION OF A CONSTITUTIVE FORM OF RABBIT LIV MICROSOMAL CYTOCHROME P-450 JOHNSON E F DEP. BIOCHEM., SCRIPPS CLIN. RES. FOUND., LA JOLLA, CALIF. 92037, USA. J BIOL CHEM 255 (1). 1980. 304-309- CODEN: JBCHA STRUCTURAL GENE PRODUCTS OF THE AH LOCUS GENETIC AND IMMUNOCHEMIC EVIDENCE FOR 2 FORMS OF MOUSE LIVER CYTOCHROME P-450 INDUCED BY 3 METH CHOLANTHRENE NEGISHI M; NEBERT D W DEV. PHARMACOL. BRANCH, NATL. INST. CHILD HEALTH HUM. DEV., BETHESDA, M 20205, USA. J BIOL CHEM 254 (21). 1979- 11015-11023- CODEN: JBCHA THE EFFECT OF PERI NATAL EXPOSURE TO TETRA CHLORO DI BENZO-P-DIOXIN THE IMMUNE RESPONSE OF YOUNG MICE THOMAS P T; HINSDILL R D DEP. BACTERIOL., UNIV. WIS., MADISON., WIS. 53706, USA. DRUG CHEM TOXICOL 2 (1-2). 1979- 77-98. CODEN: DCTOD A RADIO IMMUNOASSAY FOR CHLORINATED DI BENZO-P-DIOXINS ALBRO P W; LUSTER M I; CHAE K; CHAUDHARY S K; CLARK G; LAWSON L CORBETT J T; MCKINNEY J D ENVIRON. BIOL. CHEM. BRANCH, NATL. INST. ENVIRON. HEALTH SCI., RESEAR TRIANGLE PARK, N.C. 27709, USA. TOXICOL APPL PHARMACOL 50 (1). 1979- 137-146. CODEN: TXAPA 3 HUMAN HEALTH EFFECTS FROM ACCIDENTAL RELEASE OF TETRA CHLORO BENZO-P-DIOXIN AT SEVESO ITALY POCCHIARI F; SILANO V; ZAMPIERI A IST. SUPER. SANIT., ROME, ITALY. NICHOLSON, W. J. AND J. A. MOORE (ED.). ANNALS OF THE NEW YORK ACADEMY SCIENCES, VOL. 320. HEALTH EFFECTS OF HALOGENATED AROMATIC HYDROCARBC INTERNATIONAL SYMPOSIUM, NEW YORK, N.Y., USA, JUNE 24-27, 1978. X+730P. YORK ACADEMY OF SCIENCES: NEW YORK, N.Y., USA. ILLUS. MAPS. PAPER. I 0-89766-008-0. 0 (0). 1979 (R E C D . 1980). P311-320. CODEN: ANYAA INDUCTION OF CYTOCHROME P-450 FORM 6 IN RABBIT KIDNEY AND LUNG BY 2 3 TETRA CHLORO DI BENZO-P-DIOXIN LIEM H; MULLER-EBERHARD U; JOHNSON E F DEP. BIOCHEM., SCRIPPS CLIN. RES. FOUND., 10666 N. TORREY PINES RD., JOLLA, CALIF. 92037, USA. 64TH ANNUAL MEETING OF THE FED. AM. SO C . EXP. BIOL., ANAHEIM, CALI USA, APR. 13-18, 1980. FED PROC 39 (3). 1980. ABSTRACT 3931. COD FEPRA INDUCTION OF ALDEHYDE DEHYDROGENASES EC-1.2.1.3 DEITRICH R A; BLUDEAU P; ROPER M; SCHMUCK J DEP. PHARMACOL., UNIV. COLO. SCH. MED., DENVER, BIOCHEM PHARMACOL 27 (19). 1978. 2343-2348. COLO. 80262, USA. CODEN: BCPCA RAT LIVER ALDEHYDE DEHYDROGENASE EC-1.2.1.3 EC-1.2.1.4 EC-1.2. IMMUNOCHEMICAL IDENTITY OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN INDUC NORMAL LIVER AND 2 ACETYLAMINO FLUORENE INDUCIBLE HEPATOMA ISOZYMES LINDAHL R; ROPER M; DEITRICH R A DEV. BIOL. SECT., DEP. BIOL., UNIV. ALA., UNIVERSITY, ALA. 35486, USA. BIOCHEM PHARMACOL 27 (20). 1978. 2463-2465. CODEN: BCPCA IDENTIFICATION OF THE MAJOR CYTOCHROME P-450 FORM TRANS PLACENTA INDUCED IN NEO NATAL RABBITS BY 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN NORMAN R L; JOHNSON E F; MULLER-EBERHARD U DEP. BIOCHEM., SCRIPPS CLIN. RES. FOUND., LA JOLLA, CALIF. 92037, USA. J BIOL CHEM 253 (23). 1978. 8640-8647. CODEN: JBCHA CHEMICAL SEPARATION OF HELPER CELL FUNCTION AND DELAYED HYPER SENSITIV RESPONSES FAITH R E; LUSTER M I ; MOORE J A BIOMED. RES. CENT., ORAL ROBERTS UNIV., 7777 S. LEWIS, TULSA, OK 74171 U S A . CELL IMMUNOL 40 (2). 1978 275-284. CODEN: CLIMB ANALYSIS OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN IN ENVIRONMEN SAMPLES MCKINNEY J D RAMEL, C. (ED.). ECOLOGICAL BULLETINS NRF (NATURVETENSKAPL FORSKNINGSRADET), NO. 27. CHLORINATED PHENOXY ACIDS AND THEIR DIOXINS. M OF ACTION HEALTH RISKS AND ENVIRONMENTAL EFFECTS. CONFERENCE. STOCKHO SWEDEN, FEB. 7-9, 1977. 302P. ILLUS. SWEDISH NATURAL SCIENCE RESEA COUNCIL: STOCKHOLM, SWEDEN. ISBN 91-546-0234-3. 1978 53-66 CODEN: 06 4 1 Q K JKu IMMUNO TOXICOLOGIC EFFECTS OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN LABORATORY ANIMALS SHARMA R P; KOCIBA R J; GEHRING P J TOXICOL APPL PHARMACOL 45 (1). 1978 333 CODEN: TXAPA STUDIES ON 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN INDUCED IMMU) SUPPRESSION AND DECREASED RESISTANCE TO INFECTION ENDO TOXIN HYP' SENSITIVITY SERUM ZINC CONCENTRATIONS AND EFFECT OF THYMOSIN TREATMENT VOS J G; KREEFTENBERG J G; ENGEL H W B; MINDERHOUD A; VAN NORRLE JANSEN M NATL. INST. PUBLIC HEALTH, P.O. BOX 1, BILTHOVEN, N E T H . TOXICOLOGY 9 (1-2). 1978 75-86. CODEN: TXCYA SYNTHESIS OF 1 AMINO-3 7 8-TRICHLORO DI BENZO-P-DIOXIN AND 8-TETRACHLORO DI BENZO-P-DIOXIN AS HAPTENIC COMPOUNDS CHAE K; CHO L K; MCKINNEY J D AGENCY DEF. DEV., SEOUL, S. KOREA. J AGRIC FOOD CHEM 25 (5). 1977 1207-1209- CODEN: JAFCA 1 AMINO-2 3 RADIO IMMUNOASSAY FOR 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN ALBRO P W; CHAE K; LUSTER M; MCKINNEY J D; CHAUDHARY S; CLARK G; FAWKES ; CORBETT J ENVIRON HEALTH PERSPECT 20. 1977 (RECD 1978) 247 CODEN: EVHPA IMMUNOLOGIC RESPONSE AND FACTORS AFFECTING ITS ASSESSMENT MOORE J A; FAITH R E ENVIRON HEALTH PERSPECT 18. 1976 (RECD 1977) 125-131 CODEN: EVHPA MULTIPLE FORMS OF CYTOCHROME P-450 FROM LIVER MICROSOMES OF RABBI TREATED WITH 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN JOHNSON E F; MULLER-EBERHARD U FED PROC 36 (3). 1977 833 CODEN: FEPRA Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin strains of mice with different susceptibility to induction of ar hydrocarbon hydroxylase Vecchi A.; Sironi M.; Canegrati M.A.; et a l . 1st. R i c . Farmacol. 'Mario Negri', 20157 Milan ITALY TOXICOL. APPL. PHARMACOL. (U.S.A.) ,1983, 68/3 (434-441), Code TXAPA Lectin-mediated attachment assay for teratogens: Results pesticides Braun A.G.; Horowicz P.B. D e p . Radiat. Ther., Harvard Med. S c h ., Boston, MA 02115 U.S.A. J. TOXICOL. ENVIRON. HEALTH (U.S.A.) ,1983, 11/2 (275-286), JTEHD with Code 5 135613 Biochemical aspects of action mechanisms of 2,3,7,8-tetrachlorodibenzo-dioxin (TCDD) and related chemicals in animals Matsumura F. Pestic. Res. Cent., Michigan State Univ., East Lansing, MI 48824 U.S.A. PHARMACOL. THER. (ENGLAND) ,1982, 19/2 (195-209), Coden: PHTHD Immunochemical comparison and quantitation of microsom flavin-containing monooxygenases in various hog, mouse, rat, rabbit, do and human tissues Dannan G.A.; Guengerich F.P. Dep. Biochem., Vanderbilt Univ. Sc h . Med., Nashville, TN 37232 U.S.A. MOL. PHARMACOL. (U.S.A.) ,1982, 22/3 (787-794), Coden: MOPMA Quantitation of hepatic cytochrome Psub 1-450 mRNA with the use of cloned DNA probe. Effects of various P-450 inducers in C57BL/6N and DBA/ mice Tukey R.H.; Negishi M.; Nebert D.W. Dev. Pharmacol. Branch, Natl. Inst. Child Health Hum. Dev., Natl. Ins Health, Bethesda, MD 20205 U.S.A. MOL. PHARMACOL. (U.S.A.) ,1982, 22/3 (779-786), Coden: MOPMA Functional and quantitative effects of 2,3,7,8-tetrachlorodibenzo-p-dic in (TCDD) exposure on the cell-mediated immune system in mice Jackson J.D.; Sharp J.G. Dep. Anat., Univ. Nebraska Med. Cent., Omaha, NE 68105 U.S.A. INT. J. IMMUNOPHARM. (ENGLAND) ,1982, 4/4 (323), Coden: IJIMD Epidemiological problems with TCDD (A critical view) Tognoni G.; Bonaccorsi A. Ist. Ric. Farmacol. 'Mario Negri', 62-20157 Milan ITALY DRUG METAB. REV. (U.S.A.) ,1982, 13/3 (447-469), Coden: DMTRA Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Kociba R.J.; Schwetz B.A. Toxicol. Res. Lab., Dow Chem. USA, Midland, MI 48640 U.S.A. DRUG METAB. REV. (U.S.A.) ,1982, 13/3 (387-406), Coden: DMTRA Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on serum concentratic and the uterotrophic action of exogenous estrone in rats Shiverick K.T.; Muther T.F. Dep. Pharmacol. T h e r ., Univ. Florida, Gainesville, FL 32610 U.S.A. TOXICOL. APPL. PHARMACOL. (U.S.A.) ,1982, 65/1 (170-176), Code TXAPA 6 Differential effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on nuclear Rt\ polymerase activity in the rat liver and thymus Kurl R.N.; Lund J.; Poellinger L.; Gustafsson J.A. Dep. Med. Nutr., Karolinska Inst., S-104 01 Stockholm SWEDEN BIOCHEM. PHARMACOL. (ENGLAND) ,1982, 31/15 (2459-2462), Coden: BCPC Tetrachlorodibenzodioxin : A survey of subjects ten years after exposure May G. UNITED KINGDOM BR. J. IND. MED. (ENGLAND) ,1982, 39/2 (128-135), Coden: BJIMA Assessment of myelotoxicity caused by environmental chemicals Boorman G.A.; Luster M.I.; Dean J.H.; Campbell M.L. Natl. Toxicol. Program, Natl. Inst. Environ. Health Sci., NIH, Triangle Park, NC 27709 U.S.A. ENVIRON. HEALTH PERSPECT. (U.S.A.) ,1982, V o l . 43 (129-135), EVHPA Researc Coder Approaches to assessing host resistance Bradley S.G.; Morahan P.S. Dep. Microbiol., Virginia Commonw. U n i v ., Richmond, VA 23298 U.S.A. ENVIRON. HEALTH PERSPECT. (U.S.A.) ,1982, Vol. 43 (61-69), EVHPA Coder Cell-mediated immunity and its application in toxicology Luster M.I.; Dean J.H.; Boorman G.A. Lab. Environ. Chem., Natl. Inst. Environ. Health Sci., Research Triang: Park, NC 27709 U.S.A. ENVIRON. HEALTH PERSPECT. (U.S.A.) ,1982, Vol. 43 (31-36), Coder EVHPA Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phnobarbital occurrence and distribution of four cytochrome P-450 isozymes in kidney, lung, and liver Dees J.H.; Masters B.S.S.; Muller-Eberhard U.; Johnson E.F. Dep. Biochem., Univ. Texas Health Sci..Cent., Dallas, TX 75235 U.S.A. CANCER RES. (U.S.A.) ,1982, 42/4 (1423-1432), Coden: CNREA on tl rabb: Immunoteratology of chlordane: Cell-mediated and humoral immune response in adult mice exposed in utero Spyker-Cranmer J.M.; Barnett J.B.; Avery D.L.; Cranmer M.F. Dep. Pharmacol., Univ. Arkansas Med. Sci., Little Rock, AR 72205 U.S.A. TOXICOL. APPL. PHARMACOL. (U.S.A.) ,1982, 62/3 (402-408), Coder TXAPA 7 Toxicology of the immune Davies G.E. Cent. Toxicol. Lab., Macclesfield, Cheshire UNITED KINGDOM HISTOCHEM. J. (ENGLAND) system Imp. ,1981, Chem. Industr. 13/5 (879-884), Ltd, Alderley Pa Coden: HISJA Enhanced suppressor cell activity as a mechanism of immunosuppression 2.3.7.8- tetrachlorodibenzo-p-dioxin Clark D.A.; Gauldie J.; Szewczuk M.R.; Sweeney G. Dept. Med., McMaster Univ., Hamilton, Ontario L8N 3Z5 CANADA PROC. SOC. EXP. BIOL. MED. (U.S.A.) ,1981, 168/2 (290-299), Cod PSEBA Studies on the mechanisms of action of modifiers of skin Slaga T.J. Biol. D i v ., Oak Ridge Nat. Lab., Oak Ridge, TN 37830 U.S.A. POSTEPY MIKROBIOL. (POLAND) ,1981, 20/1-2 (113-129), carcinogenesis Coden: PMKMA Influence of inducers of monooxygenases on cytotoxic efficiency ellipticine on leukemia L1210 cells Lesca P.; Monsarrat B.; Cros S.; Paoletti C. Lab. Pharmacol. Toxicol. Fond., Toulouse Cedex 31078 FRANCE J. NAT. CANCER INST. (U.S.A.) ,1981, 67/4 (871-876), Coden: JNCIA Pentachlorophenol and liver function: A pilot study on occupationa exposed collectives PENTACHLOROPHENOL UND LEBERFUNKTION: EINE UNTERSUCHUNG AN BERUFL BELASTETEN KOLLEKTIVEN Zober A.; Schaller K.H.; Gossler K.; Krekeler H.J. Inst. Arbeits- Soz. Med., Univ. Erlangen-Nurnberg, D-8520 Erlangen GERMANY, WEST INT. ARCH. OCCUP. ENVIRON. HEALTH (GERMANY, WEST) ,1981, 48 (347-356), Coden: IA0HD Ultrastructural alterations in the liver of rats (8 - m o n o h y d r o m i r e x ) Singh A.; Valli V.E.O.; Ritter L.; Villeneuve D.C. Dept. Biomed. Sci., Univ. Guelph, Ontario CANADA PATHOLOGY (AUSTRALIA) ,1981, 13/3 (487-496), Coden: fed photomir PTLGA Rapid vertical tube rotor gradient assay for binding 2.3.7.8- tetrachlorodibenzo-p-dioxin to the Ah receptor Hing Wo Tsui; Okey A.B. Div. Clin. Pharmacol., Dept. P aed., Hosp. Sick Child., Toronto M5G 1X8 CANADA CAN. J. PHYSIOL. PHARMACOL. (CANADA) ,1981, 59/9 (927-931), Code CJPPA 8 135GB Selective suppression of cytotoxic T cell (CTL) generation by halogenat aromatic hydrocarbons Clark D.A.; Gauldie J.; Sweeney G.; Szewczuk M.R. Host Resistance Program, McMaster Univ., Hamilton, Ontario L8N 325 CANADA FED. PROC. (U.S.A.) ,1981, 40/311 (No. 4918), Coden: FEPRA Immunosuppression in mice induced by dioxin (TCDD) in feed Hinsdill R.D.; Couch D.L.; Speirs R.S. Dept. Bacteriol., Univ. Wisconsin, Madison, W i s . 53706 U.S.A. J. ENVIRON. PATH. TOXICOL. (U.S.A.) ,1980, 4/2-3 (401-425), JEPTD Code Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on macrophage and natur killer cell-mediated cytotoxicity in mice Mantovani A.; Vecchi A.; Luini W . ; et al. 1st. Ricerche Farmacol. Mario Negri, 20157 Milan ITALY BIOMEDICINE (FRANCE) ,1980, 32/4 (200-204), Coden: BIMDB Examination of bone marrow, immunologic parameters and he susceptibility following pre- and postnatal exposure 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Luster M.I.; Boorman G.A.; Dean J.H.; et al. Nat. Inst. Environm. Hlth S c i ., Research Triangle Park, N.C. 27709 U.S.A. INT. J. IMMUNOPHARM. (ENGLAND) ,1980, 2/4 (301-310), Coden: IJIMD The effect of acute administration of 2,3,7,8-tetrachlorodibenzo-p-dio> (TCDD) on humoral antibody production and cell-mediated activities in mic Vecchi A.; Mantovani A.; Sironi M.; et al. 1st. Ric. Farmacol. Mario Negri, 20157-Milan ITALY ARCH. TOXICOL. (GERMANY, WEST) ,1980, 45/SUPPL.4 (163-165), Code ARTOD Immunotoxicity assessment: Screening and Vos J.G. Nat. Inst. Publ. Hlth, Bilthoven NETHERLANDS ARCH. TOXICOL. (GERMANY, WEST) ,1980, ARTOD function studies 45/SUPPL.4 (95-108), Code Identification of the form of cytochrome P-450 induced in neonatal liver microsomes by phnobarbital Schwab G.E.; Norman R.L.; Muller-Eberhard U.; Johnson E.F. Dept. Biochem., Scripps Clin. Res. Found., La Jolla, Calif. 92037 U.S.A. MOL. PHARMACOL. (U.S.A.) ,1980, 17/2 (218-224), Coden: MOPMA rabfc 9 13570 Effect of acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin humoral antibody production in mice Vecchi A.; Mantovani A.; Sironi M.; et al. 1st. Ri c . Farmacol. 'Mario Negri', 62-20157 Milan ITALY CHEM.-BIOL. INTERACT. (NETHERLANDS) ,1980, 30/3 (337-342), Code CBINA Role of the endocrine system in the action 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the thymus Van Logten M.J.; Gupta B.N.; McConnell E.E.; Moore J.A. Nat. Inst. Environm. Hlth Scis, Research Triangle Park, N.C. 27709 U.S.A. TOXICOLOGY (NETHERLANDS) ,1980, 15/2 (135-144), Coden: TXCYA Acute human Reggiani G. Hoffmann-La SWITZERLAND J. TOXICOL. JTEHD exposure to TCDD in Seveso, Roche Ltd., Basel ENVIRON. HEALTH (U.S.A.) Italy ,1980, 6/1 (27-43), Cod Effect of polychlorinated biphenyl, dibenzofuran and dibenzo-p-dioxin the susceptibility of male mice to endotoxin Oishi S . ; Hiraga K . Dept. Toxicol., Tokyo Metropol. Res. Lab. Pub l . Hlth, Tokyo JAPAN J. ENVIRON. SCI. HEALTH (U.S.A.) ,1980, 15/1 (77-85), Coden: JPFC Series: PART B PESTIC. FOOD CONTAMIN. Extrapolating carcinogenesis data from animals to humans Falk H.L. Office Hlth Hazard Assessment, Nat. Inst. Environm. Hlth S c i ., Triangle Park, N.C. 27709 U.S.A. FED. PROC. (U.S.A.) ,1980, 39/1 (76-80), Coden: FEPRA Resea Comparative toxicology of chlorinated compounds on mammalian species Allen J.R.; Hargraves W.A.; Hsia M.T.S.; Lin F.S.D. Dept. Pathol., Univ. Wisconsin Med. Sch., Madison, W i s . 53706 U.S.A. PHARMACOL. THER. (ENGLAND) ,1979, 7/3 (513-547), Coden: PHTHD The Seveso accident: Its nature, extent and consequences Homberger E.; Reggiani G.; Sambeth J.; Wipf H.K. ANN. 0CCUP. HYG. (ENGLAND) ,1979, 22/4 (327-367), Coden: A0HYA Structural gene products of the Ah locus: Genetic and immunochemi evidence for two forms of mouse liver cytochrome P-450 induced 3-methylcholanthrene Negishi M.; Nebert D.W. Developm. Pharmacol. Branch, Nat. Inst. Child Hlth Hum. Developm., N Bethesda, M d . 20205 U.S.A. J. BIOL. CHEM. (U.S.A.) ,1979, 254/21 (11015-11023), Coden: JBCHA1 10 1 *3?ITU's  Symptoms in Bogen G. U.S.A. J. AM. MED. Vietnam veterans ASSOC. (U.S.A.) exposed ,1979, to Agent 242/22 Orange ( 2 3 9 D :, Coden: JAMAA Induction , inhibition, and some enzymological properties of hydrocarbon hydroxylase in fresh mitogen-activated human lymphocytes Gurtoo H.L.; Parker N.B.; Paigen B . ; et al. Dept. Exp. Therapeut., Roswell Park Mem. Inst., New York State H l t h , Buffalo, N.Y. 14263 U.S.A. CANCER RES. (U.S.A.) ,1979, 39/11 (4620-4629), Coden: CNREA D Induction, inhibition, and biological properties of aryl hydroca hydroxylase in a stable human B-lymphocyte cell line, RPMI-1788 Freedman H.J.; Parker N.B.; Marinello A.J.; et a l . Dept. Exp. Therapeut., Roswell Park Mem. Inst., New York State C Hlth, Buffalo, N.Y. 14263 U.S.A. CANCER RES. (U.S.A.) ,1979, 39/11 (4612-4619), Coden: CNREA1 11 1 O VJ i 73058434 A-' RECURRENT ENVIRONMENTALLY TRIGGERED THROMBO PHLEBITIS A 5 YEAR FOLLOW-UP. REA W J; PETERS D W; SMILEY R E; EDGAR R; GREENBERG M; FENYVES E 8345 WALNUT HILL LANE, SUITE 205, DALLAS, TEX. 75231. ANN ALLERGY 47 (5 PART 1). 1981. 338-344. CODEN: ANAEA 1/3/2 23017587 CONTROLLED STUDIES ON FOOD SENSITIVITY USING INJECTION THERAPY. REA W J; WILLIAMS M L; SPRAGUE D E DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 139. CODEN: ANAEA 1/3/3 23017576 CHEMICAL SENSITIVITY AMD THROMBO PHLEBITIS. REA W J; EDGAR R T; FENYVES E J DALLAS, TEX. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY CODEN: ANAEA SCIENTIFIC CONGRESS, 47 (2). 1981. 132. 1/3/4 23017569 CHEMICAL SENSITIVITY IN PHYSICIANS. JOHNSON A R; REA W J; SMILEY R E; SPRAGUE D E; FENYVES E J; EDGAR R T DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 129CODEN: ANAEA 1/3/5 23011227 CHEMICAL SENSITIVITY RELATED TO PESTICIDE OVER EXPOSURE. REA W J; KAHN A A; JOHNSON A R; FENYVES E J; SMILEY R E; SPRAGUE D E; EDGAR R T DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 124. CODEN: ANAEA 1/3/6 23011226 THE EFFECTS OF ENVIRONMENTAL CONTROL AND FASTING ON HEAD ACHES. GREENBERG M R; REA W J; STROUD R M DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 124. CODEN: ANAEA 1/3/7 23005903. ACUTE LARYNGEAL EDEMA. REA W J DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, 13573 W SHINGTON, D.C CODEN: ANAEA 1/3/8 20055067 COMPREHENSIVE ARTHRITIS USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 119p?'*'?v ENVIRONMENTAL CONTROL AND ITS EFFECT ON RHEUMATOID O i H U U u A ri j ;\ A \J rv i l i\ u A i l n *i u j o n x i_ i *v un it nauw BULLOCK T M; MARSHALL R i; RANDOLPH T G UNIV. ALA. MEETING OF THE AMERICAN RHEUMATISM ASSOCIATION, CENTRAL REGION, CHICAGO, ILL., USA, NOV. 7, 1980. CLIN RES 28 (4). 1980. 791A . CODEN: CLREA ? B55 $1.65 $0.20 $1.12 $2.97 20feb84 20:49:11 User55273 0.025 Hrs File5 1 Descriptor Tymnet 8 Types Estimated Total Cost File55:BIOSIS Previews - 1977 thru 1980 (Copr. BIOSIS 1980) See Files 5,255 Set Items Description ? E AU=REA W J Ref Items Index-term E1 28 AU=REA T H E2 1 AU=REA W A E3 7 *AU=REA W J E4 8 AU=REACH G E5 1 AU=REACH I E6 1 AUrREACH R C E7 1 AU=READ A D E8 30 AU=READ A E E9 2 AU=READ A P E10 1 AU=READ A R E 11 1 AU=READ B C E12 3 AU=READ B D ? TSSE3 1 0 SE3 -more- 2 7 AU=REA W J ? T2/3/1-7 2/3/1 68025129 AIR POLLUTION ANALYSIS USED IN OPERATING AN ENVIRONMENTAL CONTROL UNIT EDGAR R T; FENYVES E J; REA W J SUITE E 305, 12110 WEBB CHAPEL RD., DALLAS, TEX. 75234, USA. ANN ALLERGY 42 (3)- 1979- 166-173- CODEN: ANAEA 2/3/2 67031938 FOOD AND CHEMICAL SUSCEPTIBILITY AFTER ENVIRONMENTAL CHEMICAL OVER EXPOSURE CASE HISTORIES REA W J; BELL I R; SUITS C W; SMILEY R E SUITE E305, 12110 WEBB CHAPEL RD., DALLAS, TEX. 75234, USA. ANN ALLERGY 41 (2). 1978 101-1 10. CODEN: ANAEA 135^^ 2/3/7 ENVIRONMENTALLY TRIG. .RED CARDIAC DISEASE REA W J 8345 WALNUT HILL LANE, SUITE 240, DALLAS, TEX. 75231, USA. ANN ALLERGY 40 (4). 1978 243-251. CODEN: ANAEA 2/3/4 64024295 ENVIRONMENTALLY TRIGGERED SMALL VESSEL VASCULITIS REA W J ANN ALLERGY 38 (4). 1977 245-251. CODEN: ANAEA 2/3/5 63005822 ENVIRONMENTALLY TRIGGERED THROMBO PHLEBITIS REA W J ANN ALLERGY 37 (2). 1976 101-109- CODEN: ANAEA 2/ 3/6 77075477 ECOLOGIC ORIENTATION IN THORACIC AND CARDIO VASCULAR SURGERY REA W J DICKEY, LAWRENCE D. (ED.). CLINICAL ECOLOGY. XVI+807P- ILLUS. CHARLES C THOMAS PUBLISHER: SPRINGFIELD, ILL., USA. ISBN 0-398-03409-5- 1976 650-661 CODEN: 05358 2/3/7 77075423 RELATIONSHIP OF FOOD AND CHEMICAL SENSITIVITIES TO ACUTE RESPIRATORY FAILURE REA W J DICKEY, LAWRENCE D. (ED.). CLINICAL ECOLOGY. XVI+807P- ILLUS. CHARLES C THOMAS PUBLISHER: SPRINGFIELD, ILL., USA. ISBN 0-398-03409-5. 1976 180-183 CODEN: 05358 ? B255 $1.58 $0.19 $0.98 $2.75 20feb84 20:50:31 User55273 0.024 Hrs File55 1 Descriptor Tymnet 7 Types Estimated Total Cost File255:BIOSIS Previews - 1969 thru 1976 (Copr. BIOSIS 1976) See Files 5,55) Set Items Description ? E AU=REA W J Ref Items Index-term E1 1 AU=REA V E E2 2 AU=REA W E3 12 *AU=REA W J E4 1 AUrREACTIVITY OF TYROSIN E RESIDUES IN THE E5 1 AU=READ A E6 1 AU=READ A D E7 35 AU=READ A E E9 1 AU=READ A J E10 1 AU=READ A T Ell 3 AU=READ B A N ? SS E3 1 12 AU=REA W J ? T1/3/1-12 1/3/1 57047351 CROSS LINKED HEPARIN BINDING OF A MEMBRANE OXYGENATOR SYSTEM EBERLE J W; MANTON J R; MEALS C R; WHITLEY D E; REA W J J BIOMED MATER RES 7 (2). 1973 145-153- CODEN: JBMRB 1/3/2 56017058 HYPER ALIMENTATION IN PULMONARY SURGERY REA W J; ECKER R R; EBERLE J W; SUGG W L CHEST 62 ((5 PT 1)). 1972 577-580. CODEN: CHETB 1/3/3 55029919 ZINC IN CARDIAC SURGERY REA W J; ECKER R R; SUGG W L J SURG RES 12 (3)- 1972 164-167- CODEN: JSGRA 1/3/4 55021777 DIAZEPAM AS AN ADJUNCT TO BRONCHOSCOPY ECKER R R; SUGG W L; REA W J CHEST 62 (3)- 1972 259-262. CODEN: CHETB 1/3/5 73015673 MANAGEMENT OF INJURIES OF THE INNOMINATE AND PROXIMAL LEFT COMMON CAROTID ARTERIES ECKER R R; DICKINSON W E; SUGG W L; REA W J J THORAC CARDIOVASC SURG 64 (4). 1972 618-624 CODEN: JTCSA 1/3/6 73009410 LONG-TERM MEMBRANE OXYGENATION WITHOUT SYSTEMIC HEPARINIZATION REA W J; WHITLEY D; EBERLE J W AM SOC ARTIF INTERN ORGANS. TRANSACTIONS AMERICAN SOCIETY FOR ARTIFICIAL INTERNAL ORGANS, VOL. 18. SEATTLE, WASHINGTON, APRIL 17-18, 1972. XII+634P. ILLUS. AMERICAN SOCIETY FOR ARTIFICIAL INTERNAL ORGANS: WASHINGTON, D.C., U.S.A. 1972 316-320 CODEN: 02735 1/3/7 53059137 CONTROL OF INTRACTABLE VENTRICULAR TACHY CARDIA BY CORONARY RE VASCULARIZATION ECKER R R; MULLINS C B; GRAMMER J C; REA W J; ATKINS J M CIRCULATION 44 (4). 1971 666-670. CODEN: CIRCA loo ** 1/3/8 72096498 IMPORTANCE OF VENTRICULAR FUNCTION IN PREDICTING OPERATIVE M O R T A L I T Y t m  w 11 iJ X C ,itr 1 o REA W J; ECKER R R; ..JLLINS C B; SHAPIRO W; POMBO J F; SUGG W L CIRC SUPPL 44 (4). 1971 11-215 CODEN: CISUA 1/3/9 72084252 HYPER ALIMENTATION IN CHEST SURGERY REA W J COWAN, GEORGE S. M. JR. AND WALTER L. SCHEETZ (ED.). INTRAVENOUS HYPERALIMENTATION. XXIII+225P. ILLUS. LEA & FEBIGER: PHILADELPHIA, PA., U.S.A. 1972 176-184 CODEN: 02504 1/ 3/10 72060043 GAS TRANSFER IN A HEPARINIZED MEMBRANE OXYGENATOR REA W J; EBERLE J W; WATSON J T; ECKER R R; SUGG W L SURG FORUM 22. 1971 188-190 CODEN: SUFOA 1/3/11 71073996 INTRA VENOUS HYPER OSMOLAR ALIMENTATION REA W J; WYRICK W J JR; MCCLELLAND R N; WEBB W R ARCH SURG 100 (4). 1970 393-398 CODEN: ARSUA 1/ 3 / 1 2 71051715 NECROTIZING FASCIITIS WYRICK W J JR; REA W J REV SURG 28 (2). 1971 143 CODEN: RESUA ? LOGOFF $1.45 $0.18 $1.68 $3*31 20feb84 20:51:46 User55273 0.022 Hrs File255 1 Descriptor Tymnet 12 Types Estimated Total Cost LOGOFF 20:51:49 TYMNET: call cleared by request please log in: 13578 PETER O R R IS , M .D . I. QUALIFICATIONS Dr. Orris is a practicing physician, specializing in internal medicine. His practice is based in Chicago, Illinois where he is a member of the Division of Occupational Medicine at Cook County Hospital, Southwest Physicians Limited in Chicago, and part of NIOSH Region V. His curriculum vitae is attached. He is currently involved in a research study of truck drivers in the St. Louis, Missouri area through the Teamsters Central States Fund for potential exposure to dioxin at Times Beach and a study through the Veterans Administration of Wisconsin in surveying approximately 61 veterans twin pairs wherein one of the twins served in Vietnam and the other did not. He is participating in these separate studies of potential dioxin-related health effects from the clinician's point of view in preparing an initial survey questionaire to be followed by examinations. His clinical practice has involved the hands-on diagnosis and treatment of veterans who had served in Vietnam. II. SUBJECT MATTER The subject matter of Dr. Orris' testimony will include his clinical evaluation of Vietnam veterans in his own practice, a methodology for the assessment of TCDD intoxication and the diagnosis of symptoms and/or syndromes of TCDD intoxication. He will testify that the diagnosis of TCDD intoxication rests upon three categories of evidence, i.e. a history of exposure, a clinical syndrome consistent with that exposure history and chronologically appropriate, and laboratory evidence consistent with the exposure history and clinical syndrome. His testimony will finally include a review of the representative plaintiffs' medical records and clinical evaluations. 13579 III. S C IE N T IF IC P R IN C IP L E S See General Statement of Scientific Principles and Assumed Facts Attached. IV SUBSTANCE OF OPINIONS A. Dioxins are extremely toxic particularly 2,3,7,8-TCDD. B. That TCDD is extremely toxic at extremely low levels. C. That TCDD is acneogenic. D. That TCDD is teratogenic. E. That TCDD is fetotoxic. F. That TCDD is capable of transmitting genetic damage. G. That TCDD is capable of causing liver dysfunction. H. That TCDD can cause peripheral neuropathy. I. That TCDD is carcinogenic, specifically causing soft tissue sarcomas and lymphomas. J. That TCDD as a carcinegen does not affect one organ, but many. K. That additional sites of cancer may be caused by exposure to TCDD. L. That TCDD may cause neuropsychiatric disorders. V. GROUNDS FOR OPINIONS*1 A. General The bases or grounds for such facts and opinions include Dr. Orris' educational and professional experience; personal research; review of the applicable medical and scientific literature; and a review of the medical records and/or data of the representative plaintiffs. B. Specific For several of the opinions articulated above, Dr. Orris will rely in part on the following references: 1. Van Miller, J. T., Lalich and Allen, 1977, Increased incidence of Neoplasm in Rats Exposed to Low Levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin, Chemosphere 6(9, 10), 537-544 and 625-632. Kociban, R. M., Keyes, and Beyer, 1978, Results of a twoyear Chronic Toxicity and Oncogenicity of 2,3,7,8-tetrachlorodibenzop-dioxin in Rats, Toxicology and Applied Pharmacology, 46 (2): 279-303. -2- J Esposito, M. P., Tiernan and Dryden. 1980. Dioxins. Prepared for industrial pollution control division, U.S. EPA, Cincinnati, Ohio Contract Nos. 68-03-2577, 68-03-2659, and 68-03-2579. EPA 600/2-80-197. The EPA Advisory Committee and Criteria Documents. The additional specific references for the specific opinions articulated are being compiled by Dr. Orris but as of this submission, because of the require ments of his clinical practice, has been unable to compile the entire list of references but he shall forward those references within two weeks. -3- i'i/u.c ADDRESS niMwn.vr; B7 r,T:: educati 1-uv.u: rrj .ua ce rra Poso C (Aiate Addi LI1 aI CP.'ir.: Tr -c t.''.i.M'ber 13, 1983 Peter Orri Resi donee: bil.'-y South Kenwood C!i i ..;tc;o, I l l i n o i s 6Ob.15 O i l : ) 7G2-76S0 Business: Ili vi si en o f Occupati oral Ted ici ne Coo!: County Hospital 720 S. Wolcott Chicago, 111. 60512 (312) 633-5310 HI OSH Regien V. 300 S. Wacker, Chicago, 111. 60606 (312)885-3651 October 7, 1945 l .o'- Angeles, C a li forni a Southwest Physicians Ltd . 3214 I/. 63 S tre e t Chicago, I l l i n o i s 60629 (312) 434-0556 June, 1967 J u r r , 1970 K1jlin 1975 1975-19 1977-1979 J u l y , 1965 Bachelor of Arts (B .A .) harvard College Cambridge, Massachusetts Master of Public Health (M.P.M.) Yale University New Haven, Connecticut Doctor of Medicine (H .D .) Chicago Medical School Chicago, I l l i n o i s Intern al Medicine Resi do,icy Cook County Hospital Chicago, I llin o is Occupational Medicine Residency Cook County Hospital Chicago, I l l i n o i s Bio-medical Cl a c t r o n ics He.r v r-d U;li v e r s i ty Cambridge, Massachusetts 1i !v7 - 1 9 ci3 Ja n u a ry , 1979 Advanced E l e c t r i c a l C i r c u i t Thoor" Depart: t of Engineering and Applied Thysics Harvard U n iversity Cambridge, Massachusetts UICC/ILO System of Radiographic Evaluation o f Ptieumocconiosi s NIOSH approved American College Chest Physicians Continuing Medical Education Course. CERTIFICATION AMD LICENSES 1979 1976 Diplomat, American Board of Preventive Medicine in Occupational Medicine State of I llin o is , Physician and Surgeon, #36-52014 CURRENT EMPLOYMENT J u l y , 1979- Attending Physician, D iv is io n s o f General and Occupational Medicine Department of Medicine Cook County Hospital Chicago, I l l i n o i s Responsibilities include: 1) In te rn a l Medicine H ousestaff su pervisio n and d i r e c t p a tie n t care in. the o u t- p a tie n t c l i n i c and on a general medicine ward s e r v i c e . 2) Occupational Medicine h o u sestaff supervision and d ir e c t p a tie n t care on the in p a t ie n t c o n su lta tio n s e rv ic e and in the o utpatien t clin ic. 3) D id a c tic sessions with the h o u se s ta ff on both In te rn a l and Occupational Medicine t o p ic s . 4) C lin ica l research in Occupational Medicine. 51 Supervision of the Epidemiologic Research of the Occupational Medicine Housestaff. 1358 o1%-7 Ji Region . Nations n stitu te For Occupational Safety and Health U.S. Public Health Service Chicago, I llin o is Responsibilities include: 1) Conducting epidemiologic stu d ies to evaluate in d u strial health hazards in the States of Ohio, Ind iana, I l l i n o i s , Michigan, W isconsin, and Minnesota. 2) Providing Occupational Medical co nsu ltative s e r v ic e s to the medical community. 3) Le ctu rin g management, la b o r, and medical groups on Occupational Health to p ics as requested. ACADEMIC APPOINTMENTS 1975-1550 1930- 1379-1381 19811933- Department of Preventive Kedi ci ne Abraham Linco ln School of Medici ne University of Illin o is Chicago, Illin o is Instructor Lecturer Department o f Community Heal tri and P reven tive Medici ne School of Medicine North.western U n ive rsity Chicago, Illin o is Associ ate Assistant Professor, Clinical School o f Public health University of Illin o is Chicago, Illin o is Lecturer HOSPITAL STAFF APPOINTMENTS 1979- Dept, o f Internal Medicine Cook County Hospital Chicago, Illin o is 19821983OCCUPATIONAL MFD ICAL CONSULTANT TO: TEACHING OF UNDERGRADUATE MEDICAL COURSES 1977 1978 PAST LI'PLOYMENT 1930-1983 1931,1982 1966-19G7 1967-1968 Dn pt . c 'nternal Modi cine Mount Sinai Hospital Chicago, Illinois Dept, of Internal Medicine Mercy Hospital and Medical Con tor Chicago, Illinois Occupational Health Program of Mercy Hospital and Medical Center Miles Laboratories, Inc. H. Kramer and Company Industrial Medical Program of Mt. Sinai Hospital The Epidemiology of Cardiovascular Di sea se University of II 1inois , Abraham Lincoln School of Medicine. International Health Care Systems University of Illinois, Abraham Lincoln School of Medici ne. International Comparison of HeFftirCare Systems HorfcTi\stern Uni versfty Medical School Occupational Health northwestern University Medical School. Research Assistant to Dr. David T. Donhardt Dept, of Biology Harvard University Cambridge, Massachusetts Research Assistant to Dr. J. A. Hobson Dept, of Psychiatry Harvard Medical School Boston, Massachusetts 19/0 1970-1982 1971-1972 1372-1975 1979-1900 1979-1960 Ad rn i:;tr:.ti vc inter !i111 He a 'th Carter He\/ H.iv . Cr,nn.ee tic Edi torial Ccr.sol tant Ac adoray Professional Servioes licw York, N.Y. Nurse Technician Trau.na Unit Cook County Hospital Research Assistant Division of Emergency Medical Services Illinois Dept, of Health Chicago, Illinois Attending Physician Div. of Emergency Medicine Cook County Hospital Chicago, Illincis Medical Director Hi'10 Fe asib i1ity Study Southeast Health Plan Chicago, Illinois. Orris, !'., Daniels, Health Hazard Report 30-201 Health Effects of 1,1_,1 , Trichloroethan^ on So"; av can AssemoTy" i'pToyocs U.S. oparcrout of Health 'T7d fijtV"Seryices, *Publie ileal ch Service, Center for Disease Control, national Institute for Occupational Safety and Health, Cincinnati, Feb. 1900 Orris, P.: Unjustified Conclusion?(Letter) Journal of Occupational '!TedTcTrTc, VoT7~?j , lio. 1, Jan. 1931, p.7. Edmonds, L., McQuilkin, S., Orris, P., Daniels, U. Health Hazard Report 80-053-874, An Evaluation of Potential Abortifactants At A PlaTit ProcuTcTTT;" Mac!-in c To6fs T)enartTTarTc"o7 1 fiTtfi"aiid Uun n Serv c o s , Pu -ic TTsaTv.n Service, Canter for Disease Control, Ration 1 Institute for Occupational Safety and Health, Cincinnati, May, 1981. Orris, P., Daniels, W., Health Hazard Report C.l-0'.8-9o9 An Evaluation of Possible Garrir,0 'r'nir Effect:', of TTroTcftic Iiyiii-oco-;bio^"ljTo"7"lJJpir :ent of TieaTuf f'7nrF^in7^vr7'~ P i |Udc U-al th Service, Center for Disoc.-.e Control , National Institute f; Occupational Safety and Health, Cincinnati, October 1931 135B6 Orris, P. , Daniels, Heal tl~ Hazard Report 80-244-992 Heal th Hazards of .. atomacious Earth and Phosphoric Acid at a Hanufacturinn Plant in ChT.r.~pn" U T S . Department or lieaich and Human SeFv :~es~7 fuo fic Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, November, 1931 Orris, P., Daniels, W., Health Hazard Report 80- 025-989 Health Effects of Low Dose Sulfuric Acid U.S. Department or neTTYh and Human services, FUTITc Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, November, 1981 Orris, P., Almaguer, 0., Health Hazard 81-185-1C07 Health Effects of a Spray Paint and Shot Blast Process U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnalti, Ohio, November, 1981 Orris, P. Daniels, W., Health Hazard Report 81- 054-1035, Polychlorinated Biohenyl Exposure to Electrical V/orkers in a Steel !h iTT'U'."S'. Department otnieaftn and Human services, PuoTic Health Service, Center for Disease Control , National Institute for Occupational Safety and Health, Cincinnati, Ohio, January 1982 Orris, P. Haalth Hazard Report 80-235-1055, Cpcer Mortal ity of Electrical Workers in a Steel Ro Ii~~ T H tH 1, u."S. Department of Health and Human Services, "Puoi ic Haalth Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, March 1982 Orris, P. Almaguer, D. Kramkcwski, R. Health Hazard Report 81-123-1107, Low Dose TDI Exposure in a Fcam Seat Mannf acturing Process, U. S. D e pa r' an r. c f He il11li "and Human Services, PubVicf Health Service, Canter for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, May 1932 Kahn, H.S., Orris, P., The Emerging P.olo of Salaried Physicians: An Organizational proposal Journal of PuCl ic Tiea~l th Po 11 cy, ToT. 3, m o . 3, 1982 Orris, P. Kennedy, M.J. Guerriero, J. Hess!, S.M. Hryhorczuk, D.O. and Hoffman, D. Activi ties O f An Emp 1o.vr Indcpen ant Occupati onal iladici ne Li inic America:! Journal of Public Health, Voi. 72, No. 10, October, 1982 i 35 o Q IOt ti.1 i*.10:. :tp;1 , m0,.Uti.y t'CL#I_*5 10'-.1 liiiv\ :.>v<>.iu>i Her vie*,. Irc7-New York, N .Y . 982 Orris, P. Alme.guer, 0. Kra.aikowski, R. Hc*a1 Lh Hazard Report S2-05`T-1194, Lew Lazo Solvent Exposure In A S'.1.::,11 Lngi no ?:am;fac Lurfn;)~'1an t, IJ. S. Department of TleaTth ai;i71Ti7.iiar73orvi'ces,' PTibnc Meal th Service, Center for Disease Control, national Institute for Occupational Safety and Health, Cincinnati, Ohio, Sept. 1002 Fagan, K. Orris, P. & Daniels, V/. Health Hazard Report Cl-239-1201 , Low Dose Carbon Monoxide Expo sura in a Steel Mill , U. S. Department oTlleaPcn ifnd'l.uinan Services, Public Health Service, Center for Disease Control, national Institute for Occupational Safety and Health, Cincinnati, Ohio, Oct. 1932 Orris, P. Daniels, W. Health Hazard Report 81-317-1202, Health Effects of Oil Mist Exposure In A Machine Shop,- U. S. Department of Heal th and Human 'Services,' Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Oct. 19C2 Orris, P. Baron, S. Occupational Medicine: A Role for the Primary Care Phy sTc inn, Hospi ta~~^ra~ctTc'eVuT. 13,1,0. J7"Tiarciij TlTa. Orris, P. Danir4s, W. Health Hazard Report 0U-112-12G1, Health Effects of Iron Oxide Exposure in A Steel Tubin~~ ITTl , U DeparH-rit oTTlTi crT anu ~ Human Service:., PuDlic Health. Service, Center for Disease Control, National I n st i t u t e for Occupational Safety and Health, Cincinnati, Ohio, Feb. 1933 Orris, P. Cone, ,1, Dozier, E ., McQuilkin, S. Health Hazard Report 80-096-1359, Health Effects of Va.nad:fo Pentoxide In Thermal Patt e r Tliaimfactare , U. S. Department orlleai th and Henan Services- Publ ic ilea ith Service, Cenf:r for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Aug. 1963 Orris, P. Health Hazard Report 82-239-1355, Evajua f 'an of a Suspect:*'! Cancer Excess in an ElectricaTToiT '" llanorac iwri tujliop,ir iTuuit, U. S. [)eparti'ife;:c""oT M l fth and Huine.ii Services, PunTic Health Service,' Center for Di sons o Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Aug. 1933 13588 PRESENTED PAPERS Lv'iin, J. Idris, A. Narcynski,Ji. Sherer, R. L'i\v.;.i;r, D. Fateli, 0. McCulley, D. and 'is, P. Uipaire-I In:,1/,;noi oc ic Function In Hospitalized Intravedi':~s Drug Abusers, Archives of Interna i Modici n e , Accop~d~forr publication November, 1983. OCTOBER, 1975 OCTOBER, 1976 Orris, P., Sheaf, L. , Boyd, D., Freeland, J., & yellow, S. Mobile Intensive Care Units, Cests~ `TT~ ITfectiveness: An Assessinent ~c Two PlTot Projf'Ci' in 11!inoi :V~ 7wTerlcajT T T cTT -.aTcTi Association Annual Convention Orris , P., Carl son, C . , & Conibear, S. Occupational Health Education of T n d u s t n a T T'order's : A New Approach Am.erican~P'ubl ic Health Association Annual Convention Kientz, R., Orris, P. The Economic Fe a s i b i l i t y of a National Health Service /..-.encan Puohc Health Association Annual Convention. OCTOBER, 1979 Orris, P. Occupational Medicine in a Public General Hospital American Pud ilc Heal th Association Annual Convention. JULY 8, 1981 NOVEMBER 3, 1931 NOVEMBER 4, 1-9P.1 Orris, P. The Cook County Hospital Occupational i-Teciicine Clinic NIOSH Conference on Occupational Health and Safety of Miir.ority Workers Orris, P., Kahn, H.S., Sayres, B.B., Physicians Forum Task Force Report: The Salaried Physi:ian A~merican Public Health Association Annual Convention Orris, P., Kennedy, M.J. Guerriero, J. Nessi, S.M. Hryhorczuk, D.O. and U Tf: an, D. Activities of An Employer Tritiep oncint ccup T a T id FT 'edic ine Cl inic Alfierican Pubi .:c He;, en Association Annual Convention MAY L'5, lPr-3 June, 2, 1903 Snxena, K ., Johnson, 8., Ilryhorozu' D., and Orri:., F. Intitial r.. dice1 Hanaccmoot uf a Mi ni -Uiso s tor w izh a Tra nsTerriiTr' FTrenTi.-.TtTfnq PolychlorinTr.-.l ~Ei piiuny ia iTiird World iTigresc on Emergency and Disaster Medicine, Rome, Italy. Orris, P. Hryhorezuk, D. Piagnosis of TCDD Intoxication, American Public Hea1th Association, Occupational ;_*alth Section Midwest Regional Meeting AUGUST 1, 1983 Orris, P. Socioeconomic Determinants of AdlilTUiseaco, national Medical /ssociation, 88th Annual Convention, Chicago, Illinois LECTURES Graduate? Modica! Education : Moal th Effects of 2,3,7,8 TtraciT! cro'd lb"c;'i:-:o-7T~uipxl n . Case Western Reserve University School of Medicine, University of Tennessee Medical School , Wayne State University School of Medicine, Mt. Sinai Hospital, Chicago. Epidemioloqy as a Tool of tho Ce cup or.al 1laa itli ProressTnaT Wisconsin Association of Occupational Health Professionals, Milwaukee, Wi sconsi n . Occupational Disoase in Pr ima ry Caro Trac ti co Anal g tod Clothing 2 Textile Workers Union, AFL-CIO, Hew York City., Grant Hospital, Chicago., Alexian Brothers Medical Center, Chicago., University of Tennessee School of Medicine . Occupational Renai Disense University of Illinois Great Lakes Educational Resource Center, United States Uavy, Virginia Beach, VA. Occupational Lead Ucphropatliy Respiratory Hazards of Workers in ch.1 kTTFc of IIo'.TT.TrTTTns Case Western Reserve University School of Medicine, Cleveland, Ohio Hew Orleans General Hospital , Mew Orleans, La. Agent P:*ance: .rr;?nt Know lede a Can Ikimanisn Survive Medicai Sai-.oo ? Is Competition Heal tliy For FioTc"iT Occupational Medicine: ArTOvervi ew The American .dical Student Association 31st Annual Conventic--, State University of Maw York Medical School, Syracuse, Maw York Dept, of Preventive Medicine, Wayne State University School of Medicine, Detroit, Michigan. Dept, of Preventive Medicine, St. Louis University, St. Louis, Mo. Continuing Education in Occupational Health: Medical Surve il lance For "Foundry Workers Allied Industrial Workers, AFL-CIO, National Foundry Conference, Milwaukee, Wise. Health Hazards of Women in tTie~l ec tri cal Industry Health Services Seminar, Motorola, Inc., Chicago, Illinois. Infectious Disease Risks o f Fiospltal Workers American Federation of Government Employees, AFL-CIO, Chicago, Illinois. PCBs: Current Knowledge International Brotherhood of Electrical Workers, North Chicago, Il 1inoi s. TESTIMONY BEFORE GOVERNMENTAL AND CITIZENS COMMITTEES 0CT03ER, 1975 Sub Committee on Health, U. S. House of Representatives Re: National Health Insurance APRIL, 1976 Democratic National Committee Re: Housestaff Trade Unions NOVEMBER, 1976 U. S. Congressional Hearings Re: Black Lung Compensation SEPT. 25, 1981 NOVEMBER 6, 1982 Illinois Commission on the Status of Women. Re: Reproductive Hazards in Industry Illinois Legislative Study Commission on Agent Orange. Re: Health Effects of Dioxin (TODD) MARCH 21, 1983 Citizens Commission On Justice At Hanes, Chicago, Illinois. Re: Carpal Tunnel Syndrome J U; Ici 3, 1j 8 3 m i n o i s ..'iiuTco Pubi ic l'aol th, Welfare, and Corroctitns Committee. Re: Repentine! of Parental 0ccui at"TonlTtTr7^g7b'rs~u?pc i c l i 7cZcU?*s September 25, 1903 Illinois Legislative Siuciy Commission on Agent Grange. Re: Di agno r.i s of TCDD Intrigati on AWARDS AND HONORS 1973 1900- Ciba Community Affairs Award Fcllcv/, American Colics of Preventive Medicina PROFESSIONAL SOCIETY KEM3ERSHIPS 19691974- 1975 19751970- 19701970- 1579197913791531- American Public Heal th Association American Trauma Socio/. Physicians Forum American Occupational Sdical Association. Illinois Public Heal Association American Academy of Occupational Medici ne Chicago Medical Society Illinois State Medical Society American Medical Association American College of Preventive Medici ne COMMITT.I MEMBERSHIPS 1972-1975 1975-1979 Executive Committee, Gricaqo Area Committee on Occupational Safety and Health. Executive Medical Staff, Cook County Hospital 19/ /-ivb 1978-1980 19731979-1982 1980-1932 193219321983- , '1U'JC un i.c;.ui;.1i ; il:i Propose 1s Modicol Care Section, The Amer n Public Heal cli Associ ati un Resolutions Committee, Illinois Public Health Association Occupational Health Committee, Cook County Hospital. Program Committee, Medical Care Section, American Public Health Association Chairman, Sub Committee on Public Hospitals Illinois Public Health Associ ati on. Action Board, American Public Health Association. Joint Policy Committee, American Public Health Association. Member, Scientific Review Panel of the American Occunational Medical Association's Self Assessment Examination. 13593 MARVIN A. SCHNEIDERMAN, Ph.D. I. QUALIFICATIONS Marvin A. Schneiderman of Bethesda, Maryland is a statistician and epidemiologist who is the former Chief of Statistics and Epidemiology and the former Director for Science Policy of the National Cancer Institute. He is currently a consultant. His curriculum vitae is attached. II. SUBJECT MATTER Dr. Schneiderman will testify in areas concerning mathematical models, statistics, and epidemiology particularly in the area of the determination of cancer causation. He will also discuss the epidemiology of dioxins and their contaminants specifically as that relates to cancer in humans specifically soft tissue sarcoma, stomach cancers and lymphcaas. He will further testify to the relationship of exposure to the cime of manifestation of disease, i.e. the "latency period" for the development of neoplsns. Included within his testimony will be a discussion of the aultiplication of base rates in the production of cancers; the presentation sf a multi-stage model for cancer induction; the age relationships and the role age plays in the various stages of cancer development as they are effected by dioxins and/or their contaminates. He will also discuss and present the pertinent animal data and the fact that the animal data in the reputable and respected medical and scientific literature is consistent with the epidemiological studies pertaining to dioxin effects in humans and that the animal data is an accurate and appropriate method for the extrapolation and prediction of disease in humans. His presentation will include a discussion of a mathematical model for the association of the multi-faceted presentation of signs and symptoms in the veteran who was exposed to Agent Orange and the correlation between those signs and symptoms and said exposure and the causal relations between those two elements. Dr. Schneiderman will, of necessity, discuss the incidence of these rare cancers in the general population for a comparison of the onset ages in the general population as compared to the ages of onset for these cancers observed in the Vietnam veterans. His testimony shall also include a discussion of the relationship of cancer induction to immune deficiencies or deficits as brought about by the immuno-suppressive effects of exposure to dioxin and will rely upon the experience with organ transplant patients and the development of lymphomas and soft tissue sarcomas which he will testify validates his opinions as to the cancer induction in the representative veterans. Finally, his testimony shall include a discussion of the question of a threshold exposure to a known carcinogen for the induction of cancer. This will include testimony to the effect that there is no "safe" level for exposure to a carcinogen, that a single exposure may cause cancer, and that there is no "no effect" level to a known carcinogen. In his testimony he will present his opinion that TCDD is the most toxic and potent carcinogen ever synthesized by man. And, finally, his testimony shall cover the widely held belief in the respected medical and scientific community that an sarcomas, lymphomas and skin cancers. 12. A carcinogen capable of causing cancer in one organ or system is more probably than not capable of causing cancer in a variety of organs or systems. 13. The cancers present in representative plaintiffs Lambiotte and / Ford are consistent with TCDD exposure. 14. It is more probable than not that the cancers present in Plaintiffs Ford and Lambiotte were caused by their exposure to Agent Orange. V. BASES FOR OPINIONS A. General Dr. Schneiderman's opinion will be based upon his education, training, experiences, participation in on-going scientific research and investigations, a review of the medical and scientific research, and a review of the zedical records of the plaintiffs. B. Specific 1. Epidemiology of Cancer 1. Hardell, L., 1981, Epidemiological Studies of Soft-tissue Sarcoma and Malignant Lymphoma and Their Relation to Phenoxy Acid or Chlorophenol Exposure, UmeS University Medical Dissertations, U Series, No. 65-ISSN 0346-6612, Ume3, Sweden, 1981. 2. Axelson, 0. and L. Sundell, K. Anderson, C. Edling, C.Hogstedt and H. Kling, 1980, Herbicide Exposure and Tumor Mortality. An Updated Epidemiologic Investigation on Swedish Railroad Workers, Scandinavian Journal of Work, Environment and Health, Volume 6:73-75. 3. Young, A.L., M.R. Flicker, H.K. Kang, 3.M. Shepard, 1583, Health Surveillance of Vietnam Veterans Claiming Agent Orange Exposure presented at American Chemical Society National Meeting, Washington, D.C., August 30, 1983 for publication in Proceedings of the Symposium "Chlorinated Dioxins and Dibenzofurans in the Total Emrironment-Il", Ann Arbor Science, 1984. 4. Back, J.A. and R.R. Suskind, 1930, The Mortality Experience of Workers Exposed to Tecrachlorodibenzo Dioxin in a Trichlorophenol Process Accident, Journal of Occupational Medicine, 22, No. 1, 11-14. 5. Cook, R.R., J.C. Townsend, M.C. Ott, L.G. Silverstein, 1980, Mortality Experience of Employees Exposed to 2,3,7,8-cetrachlorodibenzo-p-dioxin, Journal of Occupational Medicine 22 (8): 530-32. 6. Ott, M.G., D.B. Holder and R.D. Olson, 1980, Mortality Analysis of Employees Engaged in the Manufacture of 2,4,5-crichloroplienoxyaceticacid, Journal of Occupational Medicine 22 (i): 47-50. 7. Olsson, H. and L. Brandt, 1981, Non-Hodckins Lymphoma of the Skin and Occupational Exposure to Herbicides, Lancet, 12 September 19S1, p. 579 . 8. Honchar, P.A. and W.E. Halperin, 1981, 2,4,5-trichlorophenol and Softtissue Sarcoma, Lancet, No. 8214: 269-269. 9. Cook, R.R., 1981, Dioxin, Chlorncne and Sort-tissue Sarcoma, Lancet: 618-619. 10. Cook, R.R., 1981, Mortalitv Experience of Employees Exposed co 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Journal of Occupational Medicine, 23 (1): 8. 11. Hardell, L., and Eriksson, M., 1981, Soft-tissue Sarcomas, Phenoxv Herbicides and Chlorinated Phenols, Lancer: S240, 1 August 1981. 12. Barthel, E., 1981, Increased Risk of Lung Cancer in Pesticide Exposed Male Agricultural Workers, Journal of Tox. and Environmental Health, 8:1027-1040. 13. Bishop, C.M. and A.H. Jones, 1981, Non-Hodgkins Lymphoma of the Scalp in Workers Exposed to Dioxin, Lancet (2), 369. 14. Coulston, F. and F. Pocchiari, 1983, Editors, Accidental Exposure to Dioxins, Human Health Aspects, Academic Press, New York, New York. 15. Hardell, L., B. Johansson, and 0. Axelsson, 1982, Epidemiologic Study of Nasal and Nasal Pharyngeal Cancer and Their Relation to Phenoxy Acid or Chlorophenol Exposure, Am. Journal of Ind. Medicine, 3: 247-257. 16. Maclennan, R., J. Ford and M. Coates, 1982, Cancer in the Blue Mountains of New South Wales, Medical Journal of Australia, 2:319-323. 17. Moses, M . , and I.J. Selikoff, 1981, Soft-tissue Sarcoma, Phenoxy Herbicides and Chlorinated Phenols, Lancet (1): 1370. 18. Riihimaki, Z., S. Asp, and S. Hernberg, 1982, Mortality of 2,4-D and 2,4,5-T Herbicide Applicators in Finland: First Report of an Ongoing Prospective Cohort Study, Scan. J. of Work, Env. and Health, 8:37-42. 19. Riihimaki, Z., S. Asp, E. Pukkala, and S. Hernberg, 1983, Mortality and 1 3 n Cancer Morbidity Among Chlorinated Phenoxy Acid Applicators in Finland, Chemosphere 12: 779-784. ro 20. Sara:, P.R. and J. Jacops, L9S2, Thoracic Soft-tissue Sarcoma in Veterans Exposed to Agenc Orange, New England Journal of Medicine, 300:1109. 1. Smith, A.H., D.O. Fisher, H.J. Giles ana Pearce, 1983, The New Zealand Soft-tissue Sarcoma Case Control Study; Interview Findings Concerning Phenoxy Acetic Acid Exposure, Chemosphere 12: 565-571. 22. Thiess, A.M. and R. Frentzei-Bevme, and R. Link, 1982, Mortality of Persons Exposed to Dioxin in a Trichlorophenol Process Accident That Occurred at the BASF AG on November 17, 1953, American Journal of Industrial Medicine, 3:179-- L89. 23. Neal, M.W., and D.K. Basu (for the Svacruse Research Corporation), 1983, Working Document prepared for Environmental Criteria and Assessment Office, EPA, Cincinnati, Ohio "Hazardous Air Pollutant Document on 2,3,7,S-TCDD" , 23 United States Department of Health, Education and Welfare, 196a, Smoking and Health.; Report of the Advisory Committee to the Surgeon General of the Public Health Service, PHS Publication 1103. 24. United States Department of Health, Education and Welfare, 1979, Smoking and Health: The Report of the Surgeon General Office on Smoking and Health, DHEW Publication No. (PHS) 79-50066. 25. U.S. Department of Health and Human Services, 19S2, The Health Consequences of Smoking: Cancer, a Report of the Surgeon General Oft ice on Smoking and Health. 2. Multi-Stage Theory of Carcinogenesis Sans concepts of latency, concepts of thresholds, extrapolation, and risk assessment. 1. Armitage, P. and R. Doll, 1954, The Age Distribution of Cancer and a Multi-stage Theory of Carcinogenesis, British Journal of Cancer, 8: 1- 1 2 . 2. Armitage, ?. and R. Doll, 1961, Stochastic Models of Carcinogenesis in Neyman, J., Editor, Proceedings of the Fourth Berkley Symposium on Mathematical Statistics and Probability, Volume 4, University of California Press, Berkley, CA, pp. 19-38. 3. Brown, C.C., 1976, Mathematical Aspects of Dose Response Studies in Carcinogenesis-The Concept of Threshold in Oncology, 33:62-65. * Brown, C.C., 1983, Approaches to Intraspecies Dose Extrapolation in R. Tardiff, and J.V. Roaricks, Editors, Principles for the Evaluation of Toxic Hazards to Human Health, Chapter 13. 5, Brown, C.C. and K.C. Chu, Approaches to Epidemiologic Analysis of Prospective and Retrospectivie Studies: Example of Lung Cancer and Exposure to Arsenic in Environmental Epidemiology, in Environmental Epidemiology: Risk Assessment, Proceeding of a SIMS Conference, Altar, Utah, June, 1982, SIAM institute for Mathematics in Society. 13588 6. Day, N.E. and C.C. ! vn, 1980, Multi-stage Models a. Primary Prevencin of Cancer, Journal or the Nacional Cancer Institute, 04:977-989. 7. Crump, K.S., D. Hoel, C. Langley and R. Peto, 1976, Fundamental Carcinogenic Processes and Their Implications for Low Dose Risk Assessment, Cancer Research 36:2973-2979. 8. Falk, H.L., 1978, Biological Evidence for the Existence of Threshold Chemical Carcinogenesis, Environmental Health Prospective, 22: 167-170. 9. Gaylor, D.W., and R.L. Kodell, 1980, Linear Interpolation Algorithm for Low Dose Risk Assessment of Toxic Substances, Journal of Environmental Pathology and Toxicology, 4: 305-312. 10. Cornfield, J., 1977, Carcinogenic Risk Assessment, Science 198: 693-699. 11. Gehring, P.J., P.G. Watanabe, and J.D. Young, 1977, The Relevance of Dose Dependent Pharmacokinetics in the Assessment of Carcinogenic Hazard of Chemicals in Origins of Human Cancer, Editors, H.H. Hiatt, -- J.D. Watson, and J.A. Winston, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, Book A, pp. 187-203. 12. Guess, H.A., and D.G. Hoel, The Effect of Dose on Cancer Latency. Journal of Environmental Pathology and Toxicology, 1: 279-286. 13. Hoel, D.G., 1980, Incorporation of Background Response in Dose Response Models, Federation Proceedings, 39: 67-69. 14. Hoel, D.G., D.W. Gaylor, R. Kirschstein, U. Saffiotti, and M. Sc'nneiderman, 1975, Estimation of Risk of Irreversible Delaved Toxicity, Journal of Toxicology and Environmental Health, 1: 133-151. 15. Brown, C.C., T.R. Fears, M.H. Gail, M.A. Schneiaerman, R.E. Tarone, and N. Mantel, 1978, Models for Carcinogenic Risk Assessment, Science 202: 1105. 16. Food Safety Council, 1980, Quantitative Risk Assessment, Food and Cosmetic Toxicology, 18: 711. 17. Gori, G.B., 1980, The Regulations to Carcinogenic Hazard, Science 208: 256. 18. Haseman, J.K., D.G. Hoel and R.I. Jennrich, 1981, Some Practical Problems Arising from the Use of the Gamma Multi-hit Model for Risk Estimation, Journal of Toxicology and Environmental Health. 19. Krewski, D.R. and C.C. Brown, 1981, Carcinogenic Risk Assessment: A Guide to the Literature, Biometrics, 37: 353. 20. Mantel, N. and D.W. Bryan, 1961, "Safety", Testing of Carcinogenic Agents, Journal of the National Cancer Institute, 27: 455-470. 21. Mantel, N., W. Heston and J. Gurian, 1961, Threshold in Linear Dose Response Models for Carcinogenesis, Journal of the National Cancer Institute, 27: 203-215. 22. Mantel, N. and M.A. Schneiderman, 1977, Estimating "Safe" Levels: A Hazardous Undertaking, Cancer Research, 35: 1379-1386. Monro , I .C . and D .R . Krewski , :9s:. olSit Asjtiijsniu.'it -- r'.o Ab s 'j j c o ry Decs ion-Making,i F>. and Cosmetic./ lexicology, 19: ,a_3o0. Peco, R. , 1973 , Care inogenic Effect of Chronic Exposure to Very Low Level s of Toxic Subs tances, Envircnm entai Health ?raspee tive, 22: loo. 25. National Academy Science/Nacionai Research Co u n c i l S a t e Drinking Wacar Committee, 1980, Drinking Wacer and Health, Volume 5, National Acaaemy Press, Washington, D.C. 26. Rai, 'C. and J. Van F.yzon, A Generalized Mulit-Hit Dose Response Model for Low Dose Extrapolation, Biometrics 37: 2-11. 27. Rail, D.P., 1973 , Threshold, Envircr.Tnencai Healer. Prospective, 22: 163-165. 23. Schr.eideman, M..A. , ?. Deccusle, and C.C. 3rcwn, 1979, Thresholds for Environmental Cancers: Biological ar.d Statistical Considerations, Annals New York Academy of Science 329: 92-120. 29. Truhaut, R . , 1979, An Overview of the Problem of Threshold ror Chemical Carcinogens in Carcinogenic Risk/Serategies for Intervention, Editors, W*. Davis, C. Rosen: eld, IAF.C Publication No. 25, p. 191. International Agency for Research on Cancer, Lyon, France. Weil, C.S., 1972, Statistics Versus Safety Factors and Scientific Judgment in the Evaluation of Safety for Man, Toxicology and Applied Pharmacology 21: 54. 31 Vhittancre, A.S. ar.d J.3. Relier, 1973 , Quantitative Theories of Carcinogenesis, SIAM Review 20: 1-30. Peto, R. , 1977, Epidemiology Mult i-stzage Models and Short-Term Mutageni zity Teszs in Origins of Humar. C.nr.cer, Bock C, pp. 14,j3-14 27, Editors, J.r.. .:iact, a .D . i:jon inc J.D . Wins con, iCold Spring Haroor Lacera eery, Cole Spring Harbor, New York. 33. Schneiderman, M.-*n. N. 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