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ST08522U2 PLAINTIFF'S EXHIBIT DOW-1595 TOXICOLOGY AND OCCUPATIONAL MEDICINE Proceedings of the Tenth Inter-American Conference on Toxicology and Occupational Medicine, Key Biscayne (Miami), Florida, October 22-25,1978 Organizer: WILLIAM B. DEICHMANN, PhD, MD (hon) University of Miami School of Medicine, Miami, Florida, USA ELSEVIER/NORTH-HOLLAND NEW YORK AMSTERDAM OXFORD ST 08522U3 01979 by Elsevier North Holland, Inc. with the exception of those articles authored by Kolbye (pp. 9-18), Haas (pp. 31-43), Kraybill (pp. 61-70), Cueto and Chu (pp. 99-108), Cox and Irving (pp. 221-228), Jackson, Frith, West and Stanley (pp. 233-242), Baier (pp. 253-260), L. F. Stickel, W. H. Stickel, R. D. McArthur and 0. L Hughes (pp. 387-396), and William H. Stickel, William L Reichel, and Donald L. Hughes (pp. 397-406) which are works of the United States Government. Published by Elsevier North Holland, Inc. 52 Vanderbilt Avenue. New York. New York 10017 Sole distributors outside the U.S.A. and Canada: Elsevier/North-Holland Biomedical Press 335 Jan van Galenstraat, P. O. Box 211 Amsterdam, The Netherlands Library of Congress Cataloging in Publication Data Inter-American Conference on Toxicology and Occupational Medicine, 10th, Miami, Fla. Toxicology and occupational medicine. (Developments in toxicology and environmental science; 4) Bibliography: p. Includes index. 1. Toxicology--Congresses. 2. Industrial toxicology--Congresses. 3. Carcinogens--Congresses. I. Deichmann, William B. II. Title. III. Series. [DNLM: 1. Industrial medicine--Congresses. 2. Toxicology- Congresses. W1 DE998T v. 4 / WA65 156 1978t] RA1191.157 978 616.9'94'071 78-10198 ISBN 0-444-00288-X Manufactured in the United States of America ST08522U4 Contents - Preface List of Authors HISTORY OF THE INTER-AMERICAN CONFERENCES Rafael Pefialver LEGAL AND SCIENTIFIC CONCERNS RE CARCINOGENS IN FOOD Albert C. Kolbye, Jr. TOXICOLOGY AND ITS ROLE IN REGULATORY PRACTICE Ralph W. Fogleman DESIGN OF EXPERIMENTS TO PROVIDE VALID CONCLUSIONS Alton Butson MERCHANT MARINE INSPECTORS AND CHEMICALS Thomas J. Haas ANIMAL REPRODUCTION AND CARCINOGENICITY STUDIES IN RELATION TO HUMAN SAFETY EVALUATION D.J. Clegg BIOLOGICAL INTERMEDIATES AS RESEARCH PROBES IN CARCINOGENESIS METHODOLOGY H.F. Kraybill THE PREDICTIVE VALUE OF TESTS FOR CARCINOGENIC AND MUTAGENIC ACTIVITY J.D. Jansen SUSPICION AND CONFIDENCE IN TOXICOLOGY AND OCCUPATIONAL MEDICINE H.G.S. Van Raalte THE HIDDEN CARCINOGEN IN THE MANUFACTURE OF ISOPROPYL ALCOHOL Usha Wright CARCINOGENICITY OF DAPSONE AND A,4'-THIODIANILINE Cipriano Cueto, Jr., and Kenneth C. Chu MECHANISM OF ACTION OF DIET AS A CARCINOGEN John H. Weisburger and Howard F. Mower PLANT TANNINS AND ESOPHAGEAL CANCER Julia F. Morton v ix xi 1 9 19 25 31 45 61 71 81 93 99 109 l29 ST0852245 v( SOME QUALITATIVE AND QUANTITATIVE ASPECTS IN THE INTERPRETATION OF CHEMICAL CARCINOGENESIS DATA Frank C. Lu ORGANOCHLORINE PESTICIDES AND LIVER CANCER DEATHS IN THE UNITED STATES, 1930-1972 William B. Deichmann and W.E. MacDonald THE SAFETY OF FOOD ADDITIVES: THE DYNAMICS OF THE ISSUE Frank C. Lu HETEROTOPICALLY TRANSPLANTED RAT URINARY BLADDER AS A MODEL FOR BLADDER CARCINOGENICITY STUDY Ryoichi Oyasu, Takuo Iwaaakl, Yoshihiko Hirao and Kenneth S. Heiferman STRUCTURE-ACTIVITY RELATIONSHIPS AMONGST THE PRIMARY AROMATIC AMINES IN THE INDUCTION OF BLADDER CANCER Jack L. Radomski, William Lee Hearn and Teresa Radomski N-ACETYLTRANSFERASE PHENOTYPE AND RISK IN INDUSTRIAL URINARY BLADDER CANCER: APPROACHES TO HIGH RISK GROUPS Gerald M. Lower, Jr. BIOCHEMICAL LESIONS INDUCED IN THE DNA OF RAT BLADDER EPITHELIUM DURING THE INITIATION OF BLADDER CANCER BY N-METHYL-N-NITROSOUREA Ray Cox and Charles C. Irving BRACKEN FERN (BF), A NATURAL URINARY BLADDER CARCINOGEN George T. Bryan and A.M. Pamukcu EFFECTS OF 4-ETHYLSULFONYLNAPHTHALENE-1-SULFONAMIDE , ACETAZOLAMIDE, AND OXAMIDE ON THE MOUSE URINARY TRACT C.D. Jackson, Charles H. Frith, Robert W. West and James W. Stanley THE EFFECTS OF CIS-RETINOIC ACID ON SCANNING ELECTRON MICROGRAPHS OF BLADDERS FROM RATS FED 0.037. FANFT Sidney Belman and Walter Troll RECENT DEVELOPMENT IN PROTECTING WORKERS FROM CHEMICAL HAZARDS ON THE JOB Edward J. Baler SAFETY EVALUATION OF COSMETIC INGREDIENTS: AN INNOVATIVE PROGRAM Ralph C. Wands 139 147 175 191 201 209 221 229 233 243 253 261 ST0852246 vii TOXICOLOGICAL STUDIES ON SOLVENT REFINED COAL MATERIALS H.N. MacFarland TOXICOLOGIC STUDIES OF 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN (TCDD) IN RATS R.J. Kociba, D.G. Keyes, J.E. Beyer and R.M. Carreon THE METABOLISM/PHARMACOKINETICS OF PENTACHLOROPHENOL IN MAN, AND A COMPARISON WITH THE RAT AND MONKEY Werner H. Braun, Gary E. Blau and Maynard B. Chenoweth PHARMACOKINETICS OF INHALED OR INTRAPERITONEALLY ADMINISTERED STYRENE IN RATS John D. Young, John C. Ramsey, Gary E. Blau, Robert J. Karbowski, Ken D. Nitschke, Richard W. Slauter and Werner H. Braun LEAD CONTENT OF SCALP HAIRS AS AN INDICATOR OF OCCUPATIONAL LEAD EXPOSURE Philippe Grandjean THE EXCRETION OF TRACE METALS IN HUMAN SWEAT James R. Cohn and Edward A. Emmett AN OCCUPATIONAL MEDICAL PROGRAM FOR A "MODEL" URANIUM MILL Henry T. Miller EXCRETION OF CARBARYL INTO SALIVA OF THE RAT AND ITS EFFECT ON CHOLINESTERASE Harry L. Skalsky, Richard W. Lane and Joseph Borzelleca DELAYED NEUROTOXICITY OF PHENYLPHOSPHONOTHIOATE INSECTICIDES . Mohamed B. Abou-Donia PESTICIDE MONITORING STUDIES. THE EPIDEMIOLOGIC AND TOXICOLOGIC POTENTIAL OF URINARY METABOLITES John E. Davies, Henry F. Enos, Ana Barquet, Carmen Morgade and Joseph X. Danauskas ORGANOCHLORINE INSECTICIDES AND POLYCHLORINATED BIPHENYLS IN HUMAN MILK H.J. Miller, Similica Cucos, Dora Wassermann and M. Wassermann 271 281 289 297 311 319. 329 349 359 369 379 ST0852247 vlil CHLORDANE IN BIRDS: A STUDY OF LETHAL RESIDUES AND LOSS RATES L.F. Stickel, W.H. Stickel, R.D. McArthur and D.L. Hughes ENDRIN IN BIRDS: LETHAL RESIDUES AND SECONDARY POISONING William H. Stickel, William L. Reichel and Donald L. Hughes EFFECTS OF CHRONIC ALDRIN FEEDING IN TWO STRAINS OF FEMALE RATS AND A DISCUSSION ON THE RISKS OF CARCINOGENS IN MAN William B. Deichmann, W.E. MacDonald and Frank C. Lu THE CHANGING PROFILE OF FATAL POISONINGS - AN ADDITIONAL 1,676 CASES Joseph H. Davis and Eric Rydland WHAT CAUSES CIGUATERA? Donald P. de Sylva TOXINS IN THE CIGUATERA FOOD CHAIN Donald P. de Sylva and William B. Deichmann PAIN IN JAWBONES AND TEETH IN CIGUATERA INTOXICATIONS William B. Deichmann, W.E. MacDonald, D.A. Cubit, C.E. Wunsch, J.E. Bartels and F.R. Merritt PROGRESS IN POTABLE WATER - USA (1974-1978) Paul J. Schouboe LUMBAR MUSCLE EVALUATION AS A GUIDE TO WEIGHT LIFTING POTENTIAL George D. Alger ESTUDIO IMMUNOTOXICOLOGICO EN PLAGUICIDAS Emilio Astolfi, Waldemar F. Almeida, Armando Maccagno and Rosa Gaeta Subject Index 387 397 407 415 423 433 441 455 465 471 Preface ST0852248 ix The papers la this volume were presented at the 10th Inter-American Conference on Toxicology and Occupational Medicine of the University of Miami, conducted from October 22 to 25, 1978 at the Key Blscayne Hotel, Miami, Florida. This hotel la located on the ocean side of the secluded tropical Island of Key Blscayne, 15 minutes by car from downtown Miami. Each author accepted editorial responsibility for his report. The purpose of the 10th Conference, as in previous conferences, was the presentation by delegates of research reports on subjects In the broad field of Toxicology and Occupational Medicine, followed by free discussions by all participants. The Conference met the specific requirements of the American Medical Association, and of the Florida Medical Association for 16 credit hours: "As an organization accredited for continuing Medical Educa tion, the University of Miami School of Medicine certifies that this continuing Medical Education Activity meets the criteria for sixteen hours In Category One of the Physician's Recognition Award of the American Medical Association. - Florida Medical Association, mandatory hours - sixteen". Delegates attended from the United States, from Buenos Aires (Argentina), Porto Alegre, Salvador - Bahia, Sao Paulo, and Rio de Janiero (Brazil), Ottawa, Montreal and Toronto (Canada), London and Manchester (England), Takoradl (Ghana), and The Hague (Netherlands). S T 0 85224 9 X The Conference honored Florida Congressman Dante Fascell who has "vigorously pursued the Good Neighbor Policy with countries of this hemisphere and who has won the admiration and respect of all of us", and Dr. H.G.S. van Raalte "for his pioneering and outstanding contributions In the field of Toxicology and Occupational Medicine". The Inter-American Conferences on Toxicology and Occupational Medicine would not have been possible without the generous financial contributions of friends In Industry. The 10th Conference was supported by the Ciba-Geigy Corporation, Dow Chemical U.S.A., Exxon Corporation, International Telephone and Telegraph Corporation, Merck, Sharpe & Dohme Research Laboratories, and Shell Internationale Research MaatschappiJ B.V. The conferences were organized 22 years ago by faculty members of the University of Miami, Miami, Florida, and the University of Havana, Havana, Cuba. The planners visualized that these conferences would be held every two or three years, and that the site would rotate between Miami and Havana. As fate would have it, all conferences have been conducted In Miami -- but whether In Miami or at another site in this hemisphere, long may they continue'. Wm. B. Deichmann November 21, 1978. ST 0852250 MERCHANT MARINE INSPECTORS AND CHEMICALS 31 LT. THOMAS J. HAAS Cargo and Hazardous Materials Division, United States Coast Guard, 400 Seventh Street, S. W., Washington, D. C. 20590 ABSTRACT A major contribution to the uncertainty inherent in toxicologic data stems from the recognition that exposure to a single substance under carefully controlled conditions is generally most unrealistic. The Coast Guard has a group of approximately four hundred officers and warrant officers who are involved with the inspection of merchant vessels. These individuals. Coast Guard Marine Inspectors, are required to enter cargo tanks, void spaces, and cofferdams as well as normally manned spaces, for the purpose of ascertaining the integrity of the hull, machinery and equipment aboard vessels. A certain number of marine inspectors, estimated to be about 150 persons, spend time inside cargo tanks and are likely to be exposed to many chemicals and other stress factors, in varying combinations and sequences, in the course of a normal day. This presents problems of work practice evaluation with an almost infinite number of variables. Consequently, relatively little is known about synergisms, antagonisms, simple additive and simple subtractive phenomena in producing toxic manifestations. BACKGROUND Recently, there has been increasing concern over the effects of chronic exposure to toxic concentrations of chemicals encountered. This concern is not limited only to individual chemical exposure, but to exposure to mixtures. Coast Guard Merchant Marine Inspectors ST085225 I 32 frequently come into contact with chemicals and must be aware of the hazards of low level exposure. In LCDR Pred Halvorsen's article in Proceedings, April 1976, he stated that Merchant Marine Inspectors are voicing concern over chronically toxic concentrations They have had many years of experi ence in the field and understandably desire to know what the ill ef fects may be due to this type of exposure. Kent Savage from the National Fire Protection Association, in Boston, Massachusetts, also finds a growing public awareness of the health hazards of atmospheric contaminants which has brought up the problem of appraising low 2 concentration of potentially toxic gases, vapors, and particles. Outside the Coast Guard, other individuals are raising the same concerns over chronic exposure from hazardous materials and its effect on the human body. For example, medical doctors found that chronic administration of chemical mixtures can induce or inhibit the liver microsomal, drug-metabolizing enzymes. This interaction of chemicals on the liver system can affect the response of the body to drugs.^ Throughout these references the problems adressed are chemical^ chemical interactions, chemical-drug interactions and drug-drug interactions. Very little work has been done in examining the chronic effects of these interactions. In the literature these problems are examined in the acute exposure range with extrapolation necessary to the chronic levels. In most cases this type of approach is speculative, but useful in assessing the type of interaction which might be encountered. This paper will attempt to describe the potential effects of chronic exposure to chemicals on the Coast Guard Marine Inspector. TERMINOLOGY The terminology in the field of chemical interactions can be ST 0852252 33 confusing and misleading. A complete and sound knowledge of the terms is essential to the Merchant Marine Inspector when he performs his duties. In addition he should have some knowledge of the individual interaction of the chemicals to which he will be exposed. The very basic study in this field is the science of poisons. A poison is a substance which can damage biological systems to the extent of serious incapacitation or destruction of body processes and 4 life itself. This way of describing a poison might first appear to be sufficient; however, it fails to establish any guidelines as to concentration or length of exposure in addition to other physical conditions. The toxicity of an agent is more descriptive in assessing the potential of harm from exposure to a chemical substance. Toxicity can be used to set up certain safety limits which can be quantified. This is very important to the Inspector who is concerned whether or not a cargo tank is safe for entry. There are two levels of exposure with which the Inspector must concern himself: acute or chronic. An acute level exposure occurs when a dose is delivered in a single event and absorption into the body is rapid. The concentration level is usually high and effects are immediate. This type of exposure is usually short, but may also lead to long term health effects. Inspectors may be acutely exposed to high levels of chemicals when inspecting a flame screen or when using fresh air blowers to venti late an enclosed space causing vapors to build up in pocket3. Chronic exposures occur when contact with the substance is at some frequency over a period of time, usually at low levels of concentrations. Inspectors seldomly are exposed to acute levels of substances and must be concerned with chronic, low level concentrations found in chemical cargo tanks. The Threshold Limit Values (TLV's), published by the American Conference of Governmental Industrial Hygienists (ACGIH), are limits which represent conditions under which it is ST0852253 34 believed that nearly all workers may be repeatedly exposed day after day without adverse effect. They refer to time-weighted concentrations for a seven or eight hour workday and a forty hour work week. It should be noted that certain hypersensitive individuals, may experi ence discomfort at concentrations at or below the TLV. TLVs should be used as guides in the control of health hazards and should not be 7 used as fine lines between safe and dangerous concentrations. Threshold limits are based on best available information from industrial experience and from experimental human and animal studies. The TLV is usually regarded at the maximum concentration allowed for safety of health, however, the lowest concentration achievable in the work place is desirable. Due to his work practices, the Marine Inspector is exposed to a mixture of chemicals. The exposure of the Inspector is sequential. However, "mixing" takes place creating an exposure to a mixture of chemicals. ACGIH states that special consideration should be given to the application of the TLV's in assessing health hazards which may p be associated with exposure to mixtures of two or more substances. The TLV for mixtures found in the ACGIH Pamphlet "Threshold Limit Values . . . 1977" should be used when the substances have similar toxicological effects. The assumption made here by the ACGIH is that the chemicals are additive in their action, i.e. one chemical will neither enhance o-r inhibit the toxicity of the other chemical or chemicals. The formula used is in the ACGIH TLV pamphlet found on pp. 45-49. This additive or joint toxic action has been examined by Dr. Henry Smyth from the University of Pittsburg using high concentrations. He states that in the occupational, domestic, or ambient environment, encounters with mixtures of chemicals far outnumber encounters with individual chemicals. Judgements of the relative safety or hazards of exposure to these mixtures must often be made, usually in the ST0852254 35 absence of the knowledge of the mode of joint toxic action of the g components. His results showed that in 95 percent of the cases, a model for additive joint toxicity was followed. However, there are no ongoing studies examining joint toxic action for chemical mixtures encountered at chronic levels. When the chemicals do not follow the additive action model, the interaction is synergistic. When you have an effect which is greater than the sum of the two chemicals independent effects, potentiation has occurred. This represents the condition whereby one substance is made more potent in the presence of another amount of another substance.1(^ when the reverse occurs and inhibits the toxicity, antagonism has occurred. These actions have been examined relative to drug-drug interaction and found that both, potentiation and antagonism, occur with regularity in humans.1* One final word must be said concerning concentrations. The most accepted nomenclature for concentrations is the part per million (ppm) volume measurement for low level exposure. The Coast Guard's Vinyl Chloride booklet draws the analogy that one ppm can be illustrated by evaporating an eight ounce cup of liquid vinyl chloride in a room the size of a football field with a sixty foot ceiling. Assuming an equal mixing of air and vinyl chloride, we would have a one ppm concentration. 12 DIFFICULTIES The study of the toxicity of the interaction of two or more chemicals at chronic levels is constantly plagued by lack of data. Throughout the literature, studies have been made on the acute and some of the chronic aspects (tir.a and concentrations) of exposure to individual chemicals; the majority of information generated is at acute levels. A Merchant Marine Inspector can refer to the Chemical Hazards Response Information System (CHRIS CG-446) and Chemical Data ST08S2255 36 Guide for Bulk Shipment by Hater (CG-388) to find information about the acute dangers of exposure to an individual chemical.While there are well-known chronic effects from exposure to chemicals such as benzene causing certain blood diseases or vinyl chloride leading to cancer later in life; the only acute data is well documented for a large number of chemicals. Information can be found concerning drug and drug, drug and chemical, and chemical and chemical inspections. However, the literature reports are deficient with respect to studies done on a chronic level for large numbers of chemicals. The following will give examples of these interactions with an attempt to extrapolate them to chronic levels. 1. Drug-drug interactions are not of primary concern for the Merchant Marine Inspector. However, the number of reports of drug interactions resulting in synergism is increasing rapidly. Drug effects are dependent on concentrations which reach the site of action. Other factors such as metabolism, frequency of admini stration, distribution, and excretion are important in determining the effects of a drug. A classic example of drug interaction was seen in patients hospitalized for myocardial infarction (heart attack) and given an oral anticoagulant such as Warfarin plus a sedative such as phenobarbital. Often the sedative was discontinued when the patients were dismissed from the hospital, and bleeding episodes were noted within a few weeks. The phenobarbital had increased the hepatic (liver) metabolism of the anticoagulant, which necessitated a higher daily maintenance dosage. When the phenobarbital was discontinued, the metabolism returned to its slower rate, resulting in higher anti coagulant levels in the plasma - precipitating bleeding. Therefore, when using various drugs in conjunction, a doctor must be aware of the possible interactions. The chances of drug S T 0852256 37 interactions is diminished by using as few drugs as possible at a single time. 2. Drug-chemical interactions could become a problem for the Merchant Marine Inspector. Phenobarbital, a commonly used barbituate, has been shown to potentiate the toxicity of carbon tetrachloride and chloroform, typical halogenated hydrocarbon solvents.^ It is recognized that in general, barbituates are used by a considerable segment of the working population; thus the increase of solvent toxicity by phenobarbital represents a potential hazard that must be recognized.16 When inspecting tanks, which carried an organic solvent such as tetrachloride, inspectors taking medication such as phenobar bital should take precautions such as consulting a physician. Other studies show that alcohol increases the effects of most tranquilizers, morphine, and barbituates.17 3. Chemical-chemical interactions are of the utmost concern for the Inspector. Many studies have shown that there are effects between some of the chemicals which the Inspector routinely comes into contact.18 Studies have demonstrated the potentiation of carbon tetrachloride by ethanol and isopropanol at various concentrations. '20 This potentiation of toxicity of carbon tetrachloride by ethanol has been known for many years. It was reported in 1925 that the ingestion of alcohol increased the hepatoxic (liver destruction) action of carbon tetrachloride. Later reports described the ethanol potentiation of trichloroethylene toxicity.21 Further studies by Dr. Cornish (University of Michigan) in 1967 showed that various high carbon number aliphatic alcohols potentiated the toxicity of carbon tetra chloride. 22 Carbon tetrachloride, benzene, trichloroethylene, and alcohol are some of the more common types of chemicals to which an Inspector is exposed. The anesthetic effect of alcohol may compound the already ST 0852257 38 narcotic effect of these solvents. Therefore the Inspector may be in trouble if he goes to inspect after a "few". Therefore, not only the individual chemical effects, but the interaction between chemicals, which may be more damaging, must be considered when inspecting various cargo tanks. THE MARINE INSPECTOR The types of chemicals to which a Merchant Marine Inspector may be exposed are listed in Subchapter O and D in Title 46 of CFR. CHRIS and CG-388 have these chemicals listed with some of their common acute exposure effects. However, most Merchant Marine Inspectors feel they are "in the dark" about the effects of chemicals. They are not aware of possible accumulation or interaction effects of chemicals in their bodies. New Orleans and Baton Rouge, in the 8th Coast Guard District, and. along the Ohio River are probably the areas where a Merchant Marine Inspector comes into contact with chemicals more than any other loca tion. One Warrant Officer who has served four years in New Orleans and two years in Baton Rouge stated that an Inspector working in the Eighth Coast Guard District can expect to come in contact with benzene, various nitriles, methanol, caustic soda, carbon tetra chloride, vinyl chloride and anhydrous ammonia. He could possibly be in one tank for up to two hours on one barge or could inspect many tanks in a relatively short period of time. The tanks on the barges may have had different cargoes onboard and the Inspector is exposed to all of the chemicals. While performing his job the Inspector works closely with the Marine Chemists. In LCDR Halvorsen's article "The Marine Chemist and the Marine Inspector", he stated there is a professional respect held between the two parties. 2 3 The Marine Chemist insures that the tank or barge is safe for men and safe for fire. The Marine Chemist ST0852258 39 Certificate Btates, "standard safety designations for men .... means that in the compartment or space so designated: a. The oxygen content of the atmosphere is at least 18.0 percent by volume: b. Toxic materials in the atmosphere are within permissible concentrations; and c. In the judgement of the Marine Chemists, the residues are not capable of producing toxic material under existing atmospheric conditions while maintained as directed on the Marine Chemists' 24 Certificate." (NFPA 306) According to Tom Wolf, a Marine Chemist in Baton Rouge, the per missible levels used are the established TLV's for the material which was in the tank. He went further to attest that when a Coast Guard Inspector enters a tank that he has certified, the atmosphere is at the safest level achievable. In order to have it safe, he must know what the last cargo was, and then take an atmospheric reading for oxygen and toxic atmosphere with an oxygen, carbon monoxide and combustible gas indicator or other suitable device. For particularly hazardous materials such as benzene he will check for the levels of that specific chemical to make his determination. There are problems; a lack of odor does not guarantee safety and a Marine Chemist Certificate is not the last word. The certificate must be current, as conditions at the time of certification may change causing the tank to be unsafe. For many chemicals no TLV's are listed; in addition, there is no reference to the problems of possible inter actions of the chemicals when exposed to different kinds. Each tank must satisfy the TLV for the individual chemical (if TLV is known). No mention is made about the need to achieve a lower TLV due to the subsequent exposure to the Inspector by other chemicals during that day--he must be aware of possible interactions and the possibility of needing a lower exposure limit) The Marine Chemist Certificate is very ST0852259 40 important to the Inspector and he should be aware of all aspects of the gas tests made and the results. Further, appropriate instructions, discrepancies, and dates and times of tests should be examined prior to entry. The Merchant Marine Inspector usually is not exposed to high concen trations of chemicals. When he must check a flame screen he may be subjected to acute concentrations of the chemical which may cause dizziness or nausea, however, most of his exposure will be limited to low concentrations. The problems of interactions or accumulations of chemicals may surface here. In addition, sensitive individuals may have problems working in atmospheres of chemicals at or slightly below TLV levels. For example, one Warrant Officer interviewed had experienced a type of paralysis while working on an inspection in a "safe" atmosphere. He stated that the tank was certified by a Marine Chemist. This after he had been working around chemical carriers for six years. Could he have been accumulating chemicals in his body and the latent response have surfaced with the cargoes encountered during the last inspection? It is impossible to retrace the types of chemicals, exposure concentrations, exposure times and the sequences of exposure, but there seems to be some correlation between the work around chemical carriers and future medical problems. Other Warrant Officers, who after retiring, have been found to have liver dysfunc tions which may be indicative of the kind of work they previously performed. Merchant Marine Inspectors must always be aware of the possibility of harmful effects from their exposure to-chemicals, both acute and chronic. Guidelines (Occupational Safety and Health Administration and Coast Guard regulations) must be followed for safety. Entry into confined spaces should be kept at a minimum and only when necessary. The Inspector must have an awareness and an appreciation of the materials with which he comes in contact. There is a need for ST 0852260 41 "cargo compatibility" of the chemicals within the body. Certain chemicals should not be mixed. This means the Inspector should not drink alcohol before or after (for a specific period of time) working in a chemical atmosphere, any chemical atmosphere. Further examples and safety precautions should be given to the Inspectors in the field. The new Marine Safety Manual to be published soon will be a good up to date reference guide. The Inspectors must not be left "in the dark". The biggest concerns echoed by Inspectors is "what is it?, how does it affect me?, and how can I protect myself?." Medical monitoring is necessary to flag any problems before they surface into disease or impairments. There should not be a blind reliance on the gas free certificate. The time of day, temperature, and other parameters must be taken into account before entry into the tank. The tank might be void of toxic vapors at 0800, but at the temperature increases any liquid could vaporize and concentrations above the TLV could appear in the tanks. The individual Inspector must take each situation as a new one and protect himself from possible injury. Throughout this discussion it has been noted the lack of data exists in the field of interactions of substances on a chronic level of exposure. Information at the acute exposure level may be extrapolated to the chronic levels, making many assumptions; however, this leads to many inaccuracies. Further studies must be made. Personal safety should be the main concern of the Merchant Marine Inspector. Chemical interaction could become an invisible enemy to the health and welfare of the Inspector. Do not fall victim to the psychology, "If I can't see it, it won't hurt me." Treat chemicals with respect. ST08522SI 42 REFERENCES 1. Halvorsen, Fred H., LCDR, USCG. "The Marine Chemist and the Merchant Marine Inspector," Proceedings of the Marine Safety Council, April 1976, p. 72. 2. Savage, Kent M., "Marine Gas Hazards Control," Environmental Research 11, 1976, p. 216. 3. Vessel E. S., "Genetic and Environmental Factors Affecting Drug Response in Man," Federation Proceedings, Federation of American Society for Experimental Biology (Bethesda), July-August 1972, P. 1253. 4. Casarett, Louis J, "Toxicological Evaluation,* Toxicology, Macmillan Publishing Co., Inc., New York, 1975, p. 11. 5. Ibid, p. 13 6. Ibid, p. 13. 7. Cornish, Herbert H., "Solvents and Vapors," Toxicology, Macmillan Publishing Co., Inc., New York, 19?5, p. $03. 8. American Conference of Governmental Industrial Hygienists, "TLVs," Threshold Limit Values for Chemical Substances in in Workroom Air Adopted by ACGIH for 1975, p. 5. 9. Smyth, Henry F., "An Exploration of Joint Toxic Action: Twenty- seven Industrial Chemicals Intubated in Rats in All Possible Pairs," Toxicology and Applied Pharmacology 14, 1969, p. 340. 10. Loomis, Ted A., Essentials of Toxicology, Lea and Febiger, Philadelphia, 1974, p. 101. 11. Ibid, p. 101 12. Department of Transportation, United States Coast Guard, Handling Reguirements for Vinyl Chloride. 13. Department of Transportation, United States Coast Guard, Chemical Hazards Response Information System (CG-446). 14. Hunninghake, Donald B., "Drug Interactions," Postgraduate Medicine (Minn), Jan. 1970, p. 71. 15. Cornish, Herbert H., "Phenobarbital and Organic Solvent Toxicity," American Industrial Hygiene Association Journal, Nov. 1973, p. 487. 16. Ibid 17. Forney, R. B., "Toxicology of Ethanol," Annual Review of Pharmacology, 1969, p. 389. 18. Hallach, H. J., "Interaction of DMSO and Alcohol," Annals New York Academy of Sciences, March 1967, p. 457. 19. Traiger, George J., "Differences in the Potentiation of Carbon Tetrachloride in Rats by Ethanol and Isopropanol Pretreatment," Toxicology and Applied Pharmacology, Sept. 1971 ST0852262 43 20. Cote, Michel G., "Effect of Isopropanol Induced Potentiation of Carbon Tetrachloride on Rat Hepatic Ultrastructure," Toxicology and Applied Pharmacology, March 1974. 21. Cornish Herbert H., "Ethanol Potentiation of Halogenated Aliphatic Solvent Toxicity," American Industrial Hygiene Association Journal, Jan. - Feb., 1966, p. 57. 22. Cornish, Herbert H., "Potentiation of Carbon Tetrachloride Toxicity by Aliphatic Alcohols," Archives of Environmental Health, March, 1967. 23. Halvorsen, loc. cit. 24. Gas Chemist's Certificate, "Standard Safety Designations" OTHER REFERENCES Ast, X, "Acute Toxicity of Drug Combinations," Biological and Medical Research Division, Sandoz Ltd., Basle, Switzerland. Department of Transportation, United States Coast Guard, "When You Enter That Cargo Tank," CG-474. Grosshandler, S. L., "Toxic Reactions Due to Drug Synergism and Antagonism," Anesthesia and Analgesia . . . Current Researchers, July-August, 1968. MEDLINE System, University of Michigan Medical Library, 1968-1976, Synergism and Joint Toxic Action. National Fire Protection Association, "Control of Gas Hazards on Vessels to be Repaired 1975." Smyth, Henry F.f "An Exploration of Joint Toxic Action, (11 Equitoxic Versus Equivolume Mixtures)," Toxicology and Applied Pharmacology, 1970. ST0852263 Ccevrl*' 1979 toy Editor North HoKvtd, Inc. OtfcNnorm: Toxteolonr and Oeo^attonaJ THE PREDICTIVE VALUE OP TESTS FOR CARCINOGENIC AND MUTAGENIC ACTIVITY DR. J.D. JANSEN Shall Internationale Reeearoh Maatsohapplj B.V., P.O. Box 162, The Hague (The Netherlands) ABSTRACT Mutagenio, carolnogenio and epideniologieal data are oonpared between known human carcinogens, probable human carcinogens and compounds which produce tumours in mice but not in other species. It is concluded that tumours of the lung or the liver, produced in the mouse but not in other species, are an unvalidated criterion for prediction of a hazard in man. INTRODUCTION A concerted research effort to identify the main faotors associated with the incidence of human oancer has recently become a real possibility and challenge. This is due mainly to the convergence of three developments. INVESTIGATIVE TOOLS Canoer Registries. Increasing numbers and more comprehensive oanoer regis tries in several countries and close international co-operation between epide miologists has enabled the hypothesis to be derived that perhaps as much as 70 or even 901> of human cancer may be due to extraneous factors and might therefore be preventable. These epidemiological developments have been well presented in reviews by e.g. Higginson 1 , Velaburger et al. 2 , Vynder 1 and 4 Doll . It may be noted that these estimates oruoially depend upon the accuracy of cancer registries in underdeveloped countries. In view of the difficulties involved in running a satisfactory registry, the higher percentage may be un duly optimistic. But even if the real percentage was nearer to, say, 60^, this would fully justify a great effort to lower exposures to identified oaroinogens. Genetlo and ovtogenetlo research. Enormous strides have been made in these fields, largely independent from the main stream of cancer research. This work has led to the development of a number of easily performed short-term methods for testing ohemioals for mutagenio or cell-transformation activity**. The growing realisation of a dose (but certainly not absolute) correlation between mutagenio and carcinogenic activity'has led to the feasibility of systematically screening the carcinogenicity of the foreign faotors to which we are exposed (the majority of which may be expected in our normal daily ST 0852264 72 food3,4). These methods have also proved of value In identifying active oarci7 nogenlo metabolites of indirect carcinogens'. Animal oarolnogenio studies. The nunber of animal tests for carcinogeni city has been greatly expanded and standardized protocols have enabled an objective comparison to be made of qualitative and quantitative differences in response between epeolee. Consequently, the number of potential tools for soreening has been magni fied over the last few years. Few of these have been developed to the point that they can be relied upon to predict the exietenoe of a human hazard when used on their own. However, confidence in these methods, alone or in combi nation, will grow or diminish when subjected to a continuous and oritical validation process. The difficulty of the validation prooees is illustrated by a recent validation effort of the Ames test and a test on saocharomyces a oerevisiae against the known animal data on several myeotoxins . The authors concluded that exoept for aflatoxin B1 and sterlgmatocystin, "a positive correlation between the other myeotoxins reported to be oarolnogenio and the two in vitro test systems employed was not demonstrated". It is not dear whether the discrepancy was due to a deficiency of the mutagenic test systems or to a deficiency of the animal tests which proved oarolnogenio aotivity in mice but not in rats for those myeotoxins which were found to be non-mutagenic in these tests. VALIDATION This process involves several steps: 1. Most but no all short-term tests assay mutagenio activity. The genetic effects in man are expeoted to be rare events, indistinguishable from the relatively frequent natural background mutations. Consequently, validation of the capacity of mutagenio tests to predict a demonstrable mutational hazard in man is unlikely in the near future. This particular prediction, of course, may be proven wrong by the first comprehensive epidemiological in vestigation10. 2. Due to an observed correlation between mutagenio and carcinogenic aotivity of many (but not all) ohemioals, mutagenio tests are held (often) to predict oarolnogenio aotivity. Indeed, several mutagens havs subsequently been found q to be oarolnogenio in experimental animals , although obvious exoeptions remain. Therefore most mutagenio testing procedures are currently "validated" in terms of correlations with long-term oancer-investigations in animals. 5. The only fully relevant validation of any toxlcologioal test can be ob tained from man. Thus, a continuing oritical effort must be made to cheok ST0852265 73 the validity In Bin of all laboratory data Including animal data. Tor loglatio reasons,it la olear that tha saoond phasa of tha validation prooaaa will prograaa aora rapidly than tha third phaaa. Prograaa In tha firat pbaaa haa still to taka plaoa until tha firat olaarly confirmed apidamlologloal data baooaa available10. As to be expeoted with any toxloologioal teat method, pradietability of eaoh abort-term teat dapenda upon tha claaa of compounds examined11 ' 12 Va ahould not be aisled into thinking that validation will ba easy or quicki There are only a few pure ooapounds which are established carcinogens in man. probably lass than two dosan. In contrast, generally, mixtures are of greater importance in man, auoh as cigarette smoking, nlokel refining or exposure to mixtures suoh as soot, ooaltar or some outtlng oils. If rational action is to be taken in these cases, identification of the responsible carolnogen is neoessary. If not, then it is as likely that suoh faotors are unwittingly introduced into a prooees as they were equally unwittingly removed from e.g. the nlokel refining prooeae in a partioular plant1^. Another example is the Japanese work on faotors in the basio fraotion of oigarette smoke-tar whioh might well be muoh more potent than the polynuolear aromatic fraotions Sinoe the basio fraotion largely stems from the protein oomponent, 2 lowering this fraotion might be quite feasible . Intelligent application of such findings to the development of less dangerous olgarettes might well lead to a greater reduction in the future lung oanoer inoidence than relianoe on educational programmes alone PREDICTABILITY OP ANIMAL TESTS Unfortunately, the soientlflo analysis of the subject of validation of test methods has been postponed beoause initially the dlaouasion was largely limited to the subjeot of occupational oaroinogenesls 17 . Although this subjeot is high ly important in its ovn right, this oiroumstanoe, especially in the USA, trans ferred the necessary critloal disoussion between the many different scientific disciplines involved into the adversary fields or regulatory authorities and pressure groups. The scientific disoussion was distorted out of all recognition by lega^consideratlons , politios, emotions and dogaatio assertions. This situation only delayed the neoessary insight of single scientifio disciplines ^..-into the strength and limitations of related disciplines. Because of this unfortunate intermingling of "political onoology" 19 , emotions and legal constraints, the questions asked have been in terms of l*gal requirements but not in terms whioh are helpful to the aim of identify- S T 0 8 52266 74 ing the Boat important environmental oarolnogena and lowering exposure to eetablished carcinogens. Thus the question has been debated whether aniaal teste are predictive for a human hazard. Of course, they are in certain circumstances the best we have, Also, it is well proven that they can be prediotlve 21 . However, the real queetions should bes (a) do particular animal tests reliably prediot the existence of a human hazard? (b) if so, oan they also prediot that a hazard exists under partioular condi tions of use and exposure of populations? To illustrate the validation process whioh will be necessary, the available data will be reviewed on somet - known human oarolnogens, - probable human oarolnogens, - mouse-speoiflo oarolnogens. Tho above olassifioatlon requires some clarification. The selection of compounds in the second and third class is to some extent arbitrary. In addition, separate problem areas are well-known but will not be discussed here. Some arei oarbontetraohloride, ohloroform, saccharin and many other compounds of whioh the oarcinogenie hazard in man at normally occurring exposures is unknown, and thought by many to be non-existent. Therefore, the classification is certainly neither exhaustive nor final. However, purpose of this division is to illustrate how data from different sources must be combined in order to come to a reasonable estimate of whether a human oarcinogenio hazard is expeoted to exist at any level of exposure. Different (biochemioal and pharmaookinetio) investigations are needed in order to Investigate whether a hazard might exist at low exposure levels. Mutagenio activity of oompounds is not a simple yes or no statement. Chosing plus or minus denotations for inolusion in the Tables is to some extent a subjective effortj in general, the outoome of the Ames-test has been taken as the deolsion point for plus or minus, unless convinolng data were available from other tests. Each such sign in the following Tables has to be confirmed or rejeoted after full quantitative asseesment of each oompound. However, I hope to illustrate that the obvious differences between these olasses should lead to further researoh and more direoted epidemiolo- ST0852267 75 gioal work in order to verify in bow far tba no tad diffaranoas abould be re garded as Important in tha ongoing validation effort. Especially epidemio- logioal investigations ara of tba graataat importance in validation baoauaa tha diraotion of futura oanoar raaaarob nay dapand upon thair outcome22 . DIFFERENCES BETWEEN ANIMAL CARCINOGENS Confirmed huaan carcinogens. Tba firat class (aaa Tabla 1) la a small olaaa of soma ohemically dsfinad known caroinogana in man. TABLE 1 KNOWN HUMAN CARCINOGENS Compound Species tasted Mouse Rat Hamster Rabbit ^-Naphthylamlne2^ Benzidine2^ 4-Amlnobiphenyl 4 Vinylohloride ... monomer'* Bia(chloromethyl) ether 31 Asbestos3' 2 +7 + + + + + +? + + + + + + + + +? + + Arsenic^2 Benzene^ -- Dlethylstllbestrol^ + + + + positive for carcinogenicity or mutagenloity - negative for oaroinogenicity or mutagenicity Monkey + + Mutagenic Aotivity +25,26 +25 +25 +25 +25.31 ohromosome-aberr. ' +20 chromosome.aberr. ' .34 Apart from diethylstilbeatrol all members of this claea are mutagenic. When tested in animals known oareinogene were either entirely negative (i.e. up till now* ersenio and benzene) or positive in moat or all apaciea tasted. Probable human oareinogene. The second class (see Table 2) consists of some compounds for which the evidenoe strongly suggests a human carcinogenic hazard under certain conditions of exposure. All are oarcinogenio in all or most species tested and all are mutagenic. In affect, mutagenic teats have been used as a help in identifying the ultimata caroinogana in these classes^. ST0852268 76 3,4-Benzo(a)pyrene has teen put into this category beoause, although the human oaroinogenloity of loot, ooaltar, and aome mineral oil fraotiona ia beyond doubt, the contribution by eaoh member of the large olaaa of polynuolear hydrooarbona is unknown. Some membera of thia olaaa have been found not to be oarcinogenic in animal teata. Aflatoxin has been put into thia oategory beo&uee - although there are good epidemiologieal correlations with the inoidenoe of liver oanoer, aflatoxin la atill not a proven human oaroinogen and aome (very limited) evidence exists that it may not be (strongly) oaroinogenic in man on its own^'^8. The insistence upon scientific proof ia not only of aeademio importance beoause it may help in discovering the real role of aflatoxin in produolng liver oanoer in man (oonoeivably only or mainly in combination with aome other factor^). Such knowledge ia essential if thoae oountriea where aflatoxin oontamination is unavoidable are going to deal effectively with the problem of liver oanoer. TABLE 2 PROBABLE HUMAH CARCINOGENS Compound Aflatoxin^8 Dimethylnitroeamine (and many but not., all nitrosamlnes)3" 3,4-Benzo(a)pyrene (and several but not all polynuolear aromatio HC's)^0 Mouse - (only newborn) + + Speciea tested Bat Hamster Monkey ++ + ++ + ++ + + Poaitive for carcinogenicity or mutagenicity - Negative for carcinogenioity or mutagenioity Activity +25 +2* +25 Mouse-speolflo oarolnogens. Thirdly (see Table 3) there is a steadily in creasing oategory of oompounds whioh after oral or inhalational exposure pro duces tumours of the liver or the lung in mice but not in other speoies. These compounds are not mutagenio or only weakly mutagenio (DDT). On ourrent evidenoe none of these oompounds ia known to present a oaroino genic hazard to man. For some, this merely reflects the absenoe of epldemiologioal data. For phenobarbitone, two epidemiological surveys from different countries were both negative80'81. For isoniazid, the epidemiologioal studies ST0852269 77 are all negative, but may have covered too short a period of exposure62 ' 63 . For DDT and dieldrin, a number of etudles is available whloh are all , , , ^oritioised beoauae of the small populations studied for too short a period 64 65 66 67 However, all of them were negative. For triohloroethylene,' one epldemlologioal study did not find any earolnogenlo effeot in humans68 . On current epldemlologioal evidenoe the data in mioe may all he false positivee and, in view of the reouxrent discussions on the significance of tumours in mioe only, it is gratifying to see that for isoniasid, phenobarbitone and triohloroethylene ongoing epldemlologioal work has been reported69 . Suoh work may olarify a legitimate soientifio controversy vhloh by its nature eannot be settled in the laboratory alone. TABLE 3 MOUSE-SPECIFIC CABCIMOGENS Compound Speoies tasted Mutagenic Mouse Eat Hamster Monkey Aotivity Dieldrin41 + _42 -43 _46,47,48 DDT41 Heptaohlor44 Cblorobensilate41 Phenobarbitone 4^ + +++ -7 weak or -26,25 -48 .48 .25 Tetraohloroethy-.Q lene49 Triohloroethylene^1 Isoniasid^2 Griseofulvin^ Bifampioln9^ + + + + - .50 _51 .53*,54,55 .8,34 .58,59 + Positive for oaroinogeniolty or mutagsniolty - Negative for carcinogenicity or mutagenicity * Positive in host-mediated assay, probably not relevant to human situations Certainly, further research will change the data. Some compounds may be found positive in another or better developed autagenio teat system, suoh as happened in the past with vinylohlorlde monomer2^.Others may be found nonmutagenio after purification of the ooapound as happened with- trichloro ethylene^1. ST0852270 70 Some may be found oaroinogenio In additional epeoiee whan tasted under appropriate oonditions. Finally, one or more may ba found to present a human oaroinogenio hazard under osrtaln oonditions of exposure. But It should be streaeed that all data neoeseary to reSolve the problem can be obtained with ourrently available techniques, i better understanding of this fundamental problem would greatly influenoe the future oourae of canoer researoh and the interpretation of the results of the ourrent validation efforts of short term tests. CONCLUSIONS The following oonoluslons are in aooord with the presently available evideneei a. No chemical, known to be carcinogenic to man, produoe tumours in mice only but not in other epeoiee. There la no evidenoe that the produotion of tumours in mloe only is predlotive of a human hazard*. b. On the basis of the ourrently available evidenoe, the abeenoe of caroinogenio aotivity in rats and of (potent) mutagenio activity of mouseepeoiflo oaroinogens seems more predlotive of the uniformly negative epldemlologioal data than the mouse data. o. Because of the large ongoing programmes to validate mutagenio test systems further epldemlologioal studies of humanB occupationally exposed to mousa-speoifio oaroinogens should be promoted as a matter of urgency. Suoh studiee are essential when a conflict exists between predioitlon of a human hazard based on mouse data and the contrary predlotion from rat and mutagenio data. d. It would seem that the increase of only those tumours whioh commonly occur in the unexposed mouse is an entirely unvalidated criterion for predicting a health hazard in man. RKFBHENCES 1. Eigglnson, J. and Muir, C.S. (1976) Cancer Deteotion and Prevention, 1, 79-105 2. Veisburger, J.H. et al. (1977) in Origins of Human Canoer, Hiatt, Vateon and Vlnsten, ede.. Cold Spring Harbor Lab., pp. 567-602I I 21 This oonolueion does not oontradiot Tomatis et al.'s conclusion of a general correlation between data in mioe and in other species beoause moat oaroinogens in rate and other epeoiee (apart from aflatoxin) will also produoe tumour- in mioe. ST085227 I 79 3. Vynder, E.L. at al. (1977) J. Vat. Caaoar Institute, 58. 623-632. 4. Doll, H. (1977) Nature, 265, 589-596. 5. Anon. (1977) Editorial In tha Lanoat, Maroh 26, 685-687. 6. Bruaiok, D.J. (1978) Chamoaphere, 7, 403-417* 7. Brookes, P. (1977) Mutation Haaaarch, 39, 257-284. 8. Kuezuk, M.H. at al. (1978) Mutation Baaaaroh, 53, 11-20. 9. Suginura, T. at al. (1976) in Soraanlng Taata in Chaaioal Caroinoganaaia, Montaaano, Barta oil and Tomatia ada., IAEC, Soiant. Publ., No. 12, Byron. 10. Vaskell, L. (1978) Mutation Baaaaroh, 57, 141-153* 11. Ashby, J. at al. (1977) Brit. J. Canoar, 36, 564-570. 12. Aahby, J. at al. (1977) Ann. Oooup. Hyg., 20 , 297-301. 13. Doll, fi. at al. (1977) Brit. J. Induatr. Mad., 34, 102-105. 14. Mlauaakl, S. at al. (1977) Mutation Eaaaaroh, 48, 319* 15. Hagao, M. at al. (1977) Proc. Japan. Acad., 53, 95-98. 16. Gorl, S.B. at al. (1978) J. Am. Mad. Aaaoo., 240, 1255-1259. 17. Tomatia, L. (1977) in Origina of Hunan Canoar, Hiatt, Vataon and Vinatan ada., Cold Spring Harbor Lab., pp. 1339-1357* 18. Anon. (1976) Editorial in Tha Lanoat, Maroh 13, 571-573* 19* Higginaon, J. (1977) Am. J. Publ. Haalth, 66, 359-566. 20. Hutt, P.B. (1977) F4. Drug Coaaat. Law J., 32, 275-285* 21. Tomatia, L. at al. (1973) Int. J. Canoar, 12, 1-20. 22. Peto, H. (1977) In Origina of Hunan Canoar, Hiatt, Vataon and Vinatan ada., Cold Spring Harbor Lab., pp. 1403-1428. 23* XARC Monographs on tha Evaluation of Carcinogenic Hiak of Chemical8 to Man (1974) 4, 97-111* 24* IAHC Monographs on the Evaluation of Caroinogenio Risk of Chemicals to Man (1972) 1. 25* McCann, J. at al. (1975) Proo. Nat. Aoad. Sol., 72, 5135-5239. 26. Togal, E. at al. (1976) in Chemical Mutagena, Hollaender ed.. Planum Publ. Corp., New York, vol. 4* 27* Sincock, A.M. (1977) in Origins of Hunan Cancer, Hiatt, Vataon and Vinatan ada., Cold Spring Harbor Lab., pp. 941-954* 28. Kanematsu, K. at al. (1978) Mutation Research, 53, 207-208. 29. Dean, B.J. (1978) Mutation Research, 47, 75-97* 30. Maltoni, C. (1977) In Origins of Hunan Cancer, Hiatt, Vataon and Vinatan ada., Cold Spring Harbor Lab., pp. 119-146. 31. Nelson, N. (1976) Ann. New York Acad, of Sc., 271, 81-90. 32. Tomatia, L. (1978) Canoar Eaaaaroh, 38, 877-885. 33* IAEC Monographs on tha Evaluation of Caroinogenio Risk of Chemicals to Man (1974) 7, 203-221. 34. MoCann, J. at al. (1977) in Origina of Hunan Canoar, Hiatt, Vataon and Vinatan eds., Cold Spring Harbor Lab., pp. I43I-I450. 35* Haiah, D.P.H. at al. (1977) in Origins of Hunan Canoar, Hiatt, Vataon and Vinatan ada., Cold Spring Harbor Lab., pp. 697-707* ST 0852272 80 }6. Wright, 1.3. et al. (1977) Eootox. and Env. Safety, 1, 7-16. 37. Linaell, C.l. et al. (1977) in Origins of Human Canoer, Hiatt, Watson and Winsten eds.. Cold Spring Harbor Lab., pp. 549-956. 38. I1BC Monographs on the Evaluation of Caroinogenio Bisk of Chemloals to Kan (1976) 10, 51. 39. I1HC Monographs on the Evaluation of Caroinogenio Risk of Chemicals to Man (1972) 1, 95-106. 40. IIRC Monographs on the Evaluation of Caroinogenio Bisk of Chemioals to Man (1973) 3. 91-136. 41. IARC Monographs on the Evaluation of Caroinogenio Bisk of Chemioals to Man (1974) 5. 42. Cabral, J.B.P. et al. (1977) Proo. 68th Inn. Mtg. AiCR, p. 28. 43. Wright, 1.3. at al. (1972) Pd. Cosmet. Tor., 10, 311. 44. Bobens, J.F. (1978) Tor. and Ippl. Pharmacol., 45, 236. 45. Butler, W.H. et al. (1976) Eootoz. and Env. Safety, 1, 503-509. 46. Bean, B.J. et al. (1975) Pd. Cosmet. Tor., 15, 317-323* 47. Bidwell, K. et al. (1975) Environ. Mutag. Soo.,Proo. 6th inn.Mtg., 32. 48. Shirasu, 7. (1977) in Origins of Human Canoer, Hiatt, Watson euid Winsten eds., Cold Spring Harbor Lab., pp. 267-285. 49* HX03H Intelligence Bull. (1978) Im.Induatr. Hyg. Issoo. J., 39, 123-129. 50. Greim, H. et al. (1975) Sioohem. Pharmacol., 24, 2013-2017. 51. Hensohler, D. (1977) Arohiv. Torikol., 37, 233-236. 52. IARC Monographs on the Evaluation of Caroinogenio Bisk of Chemicals to Man (1973) 4, 159-172. 53 Braun, B. et al. (1976) Biol. Zbl., 95, 423-436. 54. Chaubey, B.C. et al. (1978) Mutation Research, 53, 164. 55 BShrborn, G. et al. (1978) Human Genetlos, 42, 1-60. 56. IARC Monographs on the Evaluation of Caroinogenio Risk of Chemicals to Man (1976) 10, 153-161. 57* Bella Porta, C. et al. (1978) Tor. ippl. Pharmaool., 43, 293-302. 58. Vogel, E. et al. (1973) Experientia, 29, 124-125. 59. Srb, V. et al. (1974) Experientia, 30, 484-486. 60. Clemmesen, J. et al. (1978) Eootox. and Env. Safety, 1, 457-470. 61. Sutherland (1976) in Antioonvulsant Drugs and Enzyme Induction, Richens, and Woodford eds., Elsevier Excerpta Medioa, Horth-Holland,pp. 128-130. 62. Goldman, P. et al. (1977) in Origins of Human Canoer, Hiatt, Watson and Winsten eds.. Cold Spring Harbor Lab., pp. 465-474* 63. Stott, H. et al. (1976) Tubercle, 57, 1-15. 64. Lavs, E.R. et al. (1973) Aroh. Env. Health, 27, 318-321. 65. Delahmann, Vm.B. et al. (1977) Eootox. and Env. Safety, 1, 89-110. 66. Jager, K.W. (1970) Thesis, Elsevier Publ. Co., Amsterdam. 67. Van Baalte, H.G.S. (1977) Eootox and Env. Safety, 1, 203-210. 68. Axelson, 0. et al. (1978) J. Oooup. Med., 20, 194-196. 69. IABC Soientifio Publications (1977) Bo. 17, Lyon. 70. Be Serres, P.J. (1977) Env. Health Perepect., 20, 190-192. 71. Announcement (1978) Mutation Besearch, 54, 203-206. S T 0 8 52273 Copyright 1979 by Sbaviar North Holland, Ine. OtMunann: Toxicology and Occupational Madklna SUSPICION AND CONFIDENCE IN TOXICOLOGY AND OCCUPATIONAL MEDICINE DR. H.G.S. VAN RAALTE, M.D. Shell Internationale Research Keatschapplj B.V., P.O. Box 162, The Hague (The Netherlands) ABSTRACT With the possible exception of one or two compounds all known human industrial chemical carcinogens have been detected by an alert physician who suspected the chemical. In certain cases of reduced exposure, the Industrial physician may have confidence that the risk of the exposed may not be greater than that of the non-exposed. It is a historical fact that, with one or perhaps two exceptions, all indus trial chemical or occupational carcinogens which are recognised today, have been identified in workers in the workplace. This has been accomplished through the suspicion of an observant physician, more often than not in association with an industry. It is a lesson of history - even as recent as a decade ago - that in the industrial setting cheailcal or industrial process carcinogens can be identified in small populations after a relatively short latency period and at a comparatively early age of onset. These compounds Include: - radon and radium compounds - certain polynuclear aromatic hydrocarbons (PAH) in soot, pitch, shale oil, paraffin, cutting oils - arsenic - chromates - certain aromatic amines and related compounds (auramine, benzidine, alpha- and beta-naphthylaminea, 4-aminodiphenyl) ST0852274 82 - asbestos _ benzene - phenacetin - BCME 1 Theophrastus von Hohenhelm (1567) , the famous Paracelsus, a Junior contem porary of Columbus described as "malum metallorum" a disease In his Saxon Schneeberg miners an Invariably fatal disease caused by exposure to something in the mines Three hundred years later this disease was diagnosed as lung 2= cancer by HMrtlng and Hesse . At that time the group numbered 262 miners and could not have been much greater at the time of Paracelsus. In 1932 Pirchan 3 and Sikl described similar cases In miners from Joachimsthal. They reported 9 cases from 13 autopsies in 19 miners, dying from the disease, out of a group of 323 miners and 83 retired miners. The carcinogenic effect of other radium derivatives vas also Identified In a relatively small occupational population 4 in New Jersey. In 1929 Blum , a dentist detected the cause of the "radium jaw" which led to osteosarcomas In radium watch-dial painters. A few years later 5,6 Martland (1929 and 1931) found nine cases occurring between 1914 and 1924 in a group of 800 "girls" of whom no more than 500 were working In the luminous dial palntshop at any one time. 7 In 1775 Perclvall Pott detected cancer of the scrotum In chimney sweeps as an occupational disease and noted that the disease was probably due to soot. It is estimated that at the time Pott identified the carcinogen, the popula tion at risk in London would not have numbered more than 200 boys, since during the 15 year period, 1911-1935, the exposed population In the whole United 8 Kingdom numbered 5274 (Goldblatt and Goldblatt,1956) . Twenty years later, 9 Benjamin Bell (1794) agreed with Pott that soot obviously was the cause of scrotal cancer and we now know that soot may contain a considerable amount of ST0852275 83 benzo (a) pyrene and ocher polynuclear aromatic hydrocarbons (PAH). About a 10,10a cenCury after Pott's discovery, Volkmann described scrotal cancer In workers employed in the separation of paraffin from the destlllates of German 11 brown coal. The year thereafter another Bell (1876) also from Edinburgh first described scrotal cancer in a Scottish shale-oil worker also producing 12 paraffin. Wilson (1927) reported the carcinogenic action of shale-oil and some mineral oils. The case of cutting oil cancer provides a similar story (Cruickshank and Squire, 1950; Mastromatteo, 1955; Rivoire et al. . 1965; Thony 13,14,15,16,16a et al., 1970, 1970a) 17 In 1820 Ayrton Paris who for a few years practised in Penzance, a small town in the Cornwall (England) mine district reported scrotal cancer in copper 18 smelters which he ascribed to arsenic. In 1887, Sir Jonathan Hutchinson in London described five cases of skin cancer following prolonged administration 19 of arsenlcals. Robson and Jellffe (1963) described six similar cases of yatrogenic arsenic skin cancer, all of whom developed cancer of the lung. Again, a specific cancer, identified in a comparatively small group (Middlesex Hospital). One of the patients was a female only 31 years old. Liver and lung cancers from occupational exposure to arsenic-containing pesticides used by small groups of applicators in small areas of wine-growing, 20 in Germany and France, were reported by Llebegott (1952) and Galy et al. , 21 (1963) . Thus in the case of arsenic, like with the PAH's, the carcinogeni city for man was detected by observant physicians in relatively small groups of exposed people without the co-operation of predicting laboratory rodents and epidemiologists with computers. It is interesting to notice that in later - Some people now believe that some or even many of these latter cases were rather caused by arsenic. S T 0 8 52276 84 years, scientists have never succeeded In eliciting cancer in laboratory rodents by arsenic which suggests the occurrence of a species specificity. 22 In 1890 Newman detected the carcinogenicity of chromates, later confirmed 23 in Germany by Ffell (1935) who detected seven lung cancers in chromate workers in a comparatively small plant. Chromates have not been shown to be inhalation carcinogens in animals, although tumors have been produced by Intra24,25 pleural administration (Hueper and Payne, 1959; Payne, 1960) One of the most striking examples of the identification of a chemical human carcinogen by an observant physician associated with industry is the 26 famous case of the aromatic amines, 83 years ago. In 1895 Rehn detected Che carcinogenic action of aniline derivatives in a worker population of only 45 men in the "Puchsine (Magenta) room" of a coaltar plant. Once he had been 27 alerted, Rehn reported 10 years later twenty further cases in one factory. Even at that time he mentioned naphthylamlne as the possible culprit among the 28 aromatic amines. Leuenberger (1912) reported 18 cases in dye-workers in Basle in a total population of only 840 workers over one decade. Much later, the carcinogenicity was confirmed by animal experimentation, and some other aromatic amines and allied compounds were also shown to have carcinogenic activity. Another good example is the well-known case of asbestos. Excellent epide miological studies in large populations have been carried out in England and 29,30,31 in the United States (e.g. Doll, 1955; Sellkoff et al., 1972,1973) 32 Later (i.e. Gross et al. , 1967) positive experiments with animals were reported. However, twenty years before the first epidemiological study, Gloyne 33 34 (1935) in England, together with Wood (1934) reported two lung cancers and one pleura malignancy in a relatively small group of asbestos workers. ST0852Z77 85 35 A similar situation axiata with benzane. In 1928, Dalora and Borgooano first reportad on tha occurrence of leukemia in relation to exposure to benzene. - 3 A confirmation followed four years later (Zmile-Weil, 1932) Penatl and 37 Vigliani (1938) demonstrated that it is not always so difficult to detect in industry - with the necessary alertness - a carcinogenic agent. Laboratory studies in mice with benzene were initiated after the first clinical report had appeared but it has not been possible to demonstrate a leukemogenic activity of benzene in laboratory rodents. The first clinical observations were confirmed 38 25 years later by an epidemiological study (Rfvol et si., 1954) An additional example, showing that it is- possible to Identify a human chemical carcinogen in a small Industrial population is the case of bischioromethylether. In 1962, the suspicion arose that an excessive number of workers with lung cancer were being reported in one area of one plant (Figueroa et al., 39 1973) : three cases among 50 operators in one building. 40 A similar early suspicion arose In Germany (Thless et_ al., 1973) who eventually found eight cases among 68 workers. One of them was a young man of 31 years old with 12 years between onset of exposure and death. Again, sus picion and identification occurred earlier than could be shown by animal experimentation and epidemiological studies. Interesting for several reasons is the case of phenacetin and renal pelvis tumors. The observant physician who identified the causative chemical was 41 Grlmlund (1963) . He was a medical officer at a small-arms factory in the small Swedish town of Huakvarna employing 1800 workers, many of whom regularly 42 took phenacetln-containlng "HJorton's powder". Hultengren et al., (1965) and 43 Bengston et al.. (1968) confirmed Grimlund's findings. ST0852278 86 Studying the original reports. It appears quite often In these Industrial settings that the latency period was not always long, at tines even as short as a few years, and the age at onset was by no means always as late In life as Is usually purported; young people were often afflicted. 5,6 Thus In Martland's series of exposure to radium a derivative, a latency period of one year was seen, and the patients were "girls". Sir James Earle 44 (1808} editing Perdvall Pott's publications remarked that the Interval between first exposure of chimney sweeps and the appearance of scrotal cancer (at puberty) was often 8-10 years. He himself observed a case In a child, 16,16a eight years old. Patients among Thony's cutting oil workers sometimes 45 had a latency period of only 4 years (Graves and Flo, 1940 observed a latency of 3- ^/2 years); some patients were in their forties. 46 In the case of the chromate workers, Gross and Kglsch (1943) reported a 47 latency of 7 years, one case was In a man of 32. In Hanusco's (1951) study the geometric mean of the latency was 10.6 years. As regards the aromatic 48 1/ amines, Hueper (1966) found in 11- '2 per cent of the bladder tumors a latency 49 period of 1-5 years and Goldblatt (1949) mentioned a case of papilloma after only six months of exposure. Even with asbestos, the classic example of a carcinogen with long latency periods, cases occur even in small populations, where exposure times and latent periods are only Intermediate (Hood and Gloyne, 1934: 8 years in 35 year old man; Selikoff, 1972: 10 years; Nordmann, 1938: patients of 25-41 years old) 33,31,50 . In the case of benzene, the latency may be as short as 2 years or 51 52 less (Girard e al., 1970) , and Hallory (1939) described a case in a boy age 12. ST0852279 87 Today, to the alert physician in Indue try, some substances should come under suspicion of carcinogenesis. The cancer death rate in the U.S. is now 170 per 100,000 population, l.e. 53 54 18.6 per cent of total deaths (Anon., 1977) . Yet, Higginson (1976) stated that cancers identified as due to occupational factors form a relatively small proportion of all cancers (less than one per cent). That is, of course, one per cent too many and everything possible should be done to reduce the number of cases of occupational cancer. Efforts in this respect Include technical refinements to reduce exposure. It is well known that the law of diminishing returns applies here and works in both directions. More and more technical refinements Involve ever higher costs and ever lesser effects. Since eventua lly it is society, the public, and not the manufacturer who has to realize the extra cost and effort, the question will be raised of whether or not, at a certain moment, the extra coat and effort raised for considerations of health should not rather be used in a different area of health promotion. And this raises the question of whether or not an absolute no-effect level of exposure to a carcinogen, an absolute "safe dose" exists. In the context and limita tion of thlB article it la not possible to go further into the philosophy and intricacies of this question. It is.however, suggested that today, in the occupational setting, the question of the existence or not of an absolute no effect level, an absolute safe level may not be relevant. It is suggested that absolute safety or zero-risks are not obtainable. Every human activity carries a risk, and inactivity carries perhaps, a greater risk. The specious concept of "socially acceptable risk" is not more than a siren song. It is usually not possible to predict the incidence of occupational cancer associated with a certain defined level of exposure. For many reasons extrapolation from animals to man quantitatively is unjustified. Among these reasons are the great variations in susceptibility within and between species ST 0852280 88 and Che differences between species In response. It Is simply not possible, baaed on an Incidence of cancer occurring in groups of rodents at certain levels of exposure, to arrive at the prediction of a risk of Incidence in man at a much lower level of exposure. Therefore, It Is equally Impossible to philosophize or to consider whether such a risk is "socially acceptable". It Is impossible, however, for existing compounds already in use, to compare incidence in a group at low level exposure to incidence in an unexposed group. Sometimes, one will find that the incidence in the low-level exposed group is no greater than it is in the unexposed group. At these low levels of exposure one cannot guarantee that nobody will get cancer, but the risk is not greater than in those not so exposed. A similar situation exists with radiation. Not withstanding predictions based on assumptions and mathematics, the cancer Incidence in mile-high Denver is not greater and is, on the contrary, lower 55 than elsewhere in the United States (Fraumeni, 1975) . Cancer of che scrotum in wax pressmen has disappeared and it does not occur in machinists with low-level exposure to cutting oils in the United States and 56 the Netherlands (Pruyn, 1972) . No hemanglosarcomas have occurred in vinyl- 57 chloride workers who had a comparatively low-level exposure (De Boer, 1978) The incidence of renal pyelum carcinoma in occasional users of phenacetincontaining painkillers is not Increased, and lead workers have no higher cancer risk than other workers (Dingwall et^ ^1., 1963; Robinson, 1974; 58,59,60 Hernberg, 1977) The reason that no excess cancer appears in these low-exposure groups may well be that at these low levels of exposure the latency period exceeds the lifespan. In cases such as phenacetln, the necessary antecedent tissue injury, the papillary necrobiosis, does not occur. This tissue injury itself has a no effect level. :ST085228I 89 After having reviewed the above historical facts we may conclude that, today, the Industrial physician must not ever lay aside the good habit of a healthy suspicion. 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