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73519 2 EVALUATION OF PUBLIC HEALTH ASPECTS OF CARCINOGENIC/MUTAGENIC BIOREFRACTORIES IN DRINKING WATER PREV MED 9(2): 212-218; 1980 KRAYBILL, HF// WYNDER, EL~ SCHEEL, M, FRAUMENI~ J, HAMMOND~ EC; HIGGINSON, J, SHUBIK' P; STELLMAN' S; WEISBURGER; JH, BULL, BAILAR, JC REVIEW:. AS PART OF ACONFERENCE ON PRIMARY PREVENTION OF CANCER THAT DEALS WITH BOTH PREVENTIVE MEASURES AND THE RELATIVE IMPORTANCE OF ENVIRONMENTAL RISK FACTORS, THIS ARTICLE EVALUATES THE PUBLIC HEALTH ASPECTS OF CARCINOGENS AND MUTAGENS IN DRINKING WATER, (16 REFS,) DISCUSSION: "CARCINOGENS AND MUTAGENS HAVE BEEN IDENTIFIED IN DRINKING WATER, DATA COLLECTED OVER THE PAST FEW YEARS HAVE DEMONSTRATED THAT MATERIAL OBTAINED BY CONCENTRATING DRINKING WATER WAS MUTAGENIC IN ~AND BALB 3T3 CELLS, MINIMALLY ~ONCENTRATED DRINKING WATER SAMPLES (100- TO 200-FOLD) TREATED WITH DISINFECTANTS,,, HAVE BEEN SHOWN TO PRODUCE MOUSE SKIN PAPILLOMAS IN TWO-STAGE INITIATION PROMOTION STUDIES,,,, ADDITIVE EFFECTS OF CARCINOGENS CANNOT BE OVERLOOKED AND THE FACT THAT SINGLE CHEMICAL ANALYSIS IN RODENTS INDICATES CARCINOGENICITY RAISES SUSPICIONS THAT THE MULTIPLE STRESS FROM CARCINOGENS IN WATER COULD CONTRIBUTE TO THE CANCER LOAD IN MAN, HOWEVER, THE FACT THAT SOME CARCINOGENS FROM DRINKING WATER MAY PERSIST IN BODY TISSUES MAKES QUANTIFICATION DIFFICULT, THE EXPERIMENTAL INVESTIGATIONS THUS FAR PROVIDE ONLY PRESUMPTIVE EVIDENCE AND THIS SITUATION MAY REMAIN UNTIL BETTER PROCEDURES ARE DEVELOPED TO MEASURE THE TOTAL CARCINOGENIC INSULT OF MULTIPLE COMPONENTS IN WATER BY ORAL ADMINISTRATION IN RODENTS OR FISH AS ANIMAL MODELS,,,, "WHILE THE CONCENTRATION OF A SINGLE CHEMICAL CARCINOGEN IN DRINKING WATER WILL OCCUR AT MICROGRAM LEVELS, THE CONCENTRATION OF A COMPOSITE

73519 OF ALL CARCINOGENS HAS BEEN CALCULATED TO BE AT THE MILLIGRAM LEVEL, A DOSE CAPABLE OR ACHIEVING A POSITIVE RESPONSE IN EITHER ANIMAL MODELS OR IN MAN,,,, "WHILE THESE EXPERIMENTAL AND EPIDEMIOLOGIC STUDIES PROVIDE SOME SUGGESTIVE EVIDENCE ON THE POTENTIAL.HAZARD OF THESE CARCINOGENIC BIOREFRACTORIES, ONE CANNOT DESCRIBE, WITH ASSURANCE~ ANY CAUSALITY FOR CANCER BUT THE PROBABILITY REMAINS THAT THESE INGESTED WATER CONTAMINANTS MAY CONTRIBUTE TO THE TOTAL CANCER BURDEN, WITH THIS IN MIND IT SEEMS PRUDENT TO CONTROL AND/OR REDUCE THE EXPOSURE TO CARCINOGENIC/MUTAGENIC CONTAMINANTS IN DRINKING WATER," /JP/ (PRESENTED AT AN AMERICAN HEALTH FOUNDATION/GERMAN CANCER CARE CONFERENCE ON THE PRIMARY PREVENTION OF CANCER, NEW YORK~ NY~ JUNE 7-8, 1979,) (PART OF A SERIES: SEE DOCUMENT Nos, 73510-73536,) NAT CANC I~ BETHESDA, MD REVIEW, CANCER PREVENTION, DRINKING WATER, WATER CARCINOGENS, WATER MUTAGENS, WATER INGESTION, WATER SUPPLY, CANCER RISK FACTORS, CHEMICAL CARCINOGENS, CHEMICAL MUTAGENS, WATER POLLUTION CARCINOGENICITY/ WATER POLLUTION HEALTH EFFECTS, GOVERNMENT ORGANIZATIONS,WATER PURIFICATION, WATER CONTAMINATION, DISINFECTANTS, INDUSTRIAL CHEMICALS, ORGANIC CHEMICALS, INORGANIC COMPOUNDS, INDUSTRIAL POLLUTION, NATURAL CARCINOGENS, INDUSTRIAL CARCINOGENS, ENVIRONMENTAL CARCINOGENS, CARCINOGENS CONTAMINATION, TRIHALOMETHANE CARCINOGENICITY, CHLORINE, WATER ARSENIC~ WATER TRACE ELEMENTS, WATER MINERALS~ TRACE ELEMENTS CARCINOGENICITY, SKIN CANCER, LIVER CANCER RISK FACTORS, LUNG CANCER RISK FACTORS, LUNG CANCER TRACE ELEMENTS CAUSATION 1~ LUNG CANCER ARSENIC CAUSATION 1, LUNG CANCER ARSENIC CAUSATION 2, ARSENIC CARCINOGENICITY, ARSENIC INGESTION, METHodoLoGY ANALYSIS, 2

73519 METHODOLOGY VALIDITY, CARCINOGENS DETECTION, ENVIRONMENTAL EXPOSURE, TUMOR PROMOTERS~ CANCER PROMOTERS~ CANCER INITIATORS~ PUBLIC HEALTH~ CARCINOGENS BIOASSAY~ NICKEL CARCINOGENICITY, WATER CHLORINATION~ LEAD INGESTION, LEAD CARCINOGENICITY~ WATER LEAD, EPIDEMIOLOGICAL DATA EXTRAPOLATION~ BERYLLIUM CARCINOGENICITY~ LUNG CANCER ENVIRONMENTAL FACTORS CAUSATION 1, ANIMAL EXPERIMENTS, RIVER WATER, SURFACE WATER~ UNDERGROUND WATER, CANCER DRINKING WATER CAUSATION 1, CANCER DRINKING WATER CAUSATION 2] CARCINOGENS POTENCY, GOVERNMENT LEGISLATION~ GOVERNMENT REGULATIONS~ WATER POLLUTION LEGISLATION, WATER POLLUTIONCONTROL, WATER COMPOSITION, DATA VALIDITY~ EXPERIMENTAL METHODS VALIDITY~ ACTIVATED CHARCOAL, CANCER ENVIRONMENTAL FACTORS CAUSATION 1, BLADDER CANCER RISK FACTORS, BLADDER CANCER ENVIRONMENTAL FACTORS CAUSATION 1, CAUSAL VARIABLES, EPIDEMIOLOGICAL STUDY VALIDITY, EPIDEMIOLOGICAL METHODS, POPULATION SAMp~E. VALIDI.TY, .......... POPULATION MOBILITY~ POPULATION STRUCTURE CHANGES~.HEALTH STATISTICS~ INTERPRETATION VALIDITY~ POPULATION SAMPLE SIZE VALIDITY, STATISTICAL ASSOC, EXPERIMENTAL ACCURACY, EPIDEMIOLOGICAL STUDY HI, ADDITIVE EFFECTS, MULTIPLE FACTORS INTERACTION, DNA BINDING~ CARCINOGENS BINDING, ORGAN SUSCEPTIBILITY, TISSUE SUSCEPTIBILITY, CARCINOGENS SUSCEPTIBILITY~ RISK ESTIMATION, MATHEMATICAL MODEL~ SPECIES DIFFERENCES A~ SPECIES DIFFERENCES, SPECIES SUSCEPTIBILITY SPECIES SUSCEPTIBILITY, SPECIES SPECIFICITY A, SPECIEs SPECIFICITY, CARCINOGENS SPECIFICITY, SYNERGISM, CARCINOGENS INGESTION, ANIMAL MODEL EXTRAPOLATION~ CARCINOGENS DOSE, FISH/ VIRUS CONTAMINATIDN~ BACTERIAL CONTAMINATION, PARASITES~ WATER FILTRATION, CHLOROFORM CARCINOGENICITY~ WATER NITRITE, NITRITE CARCINOGENICITY~ DIGESTIVE CANCER RISK FACTORS, GAS LIQUID CHROMATOGRAPHY~ MASS SPECTROMETRY, ANALYTICAL METHODS~ WATER CHEMICAL ANALYSIS~ THRESHOLD VALUE, DNA REPAIR~ CELL CULTURE TECHNIQUES A, BACTERIA~ CELL TRANSFORMATIONS MALIGNANT TRANSFORMATION, CIGARETTE SMOKING, BLADDER CANCER SMOKING CAUSATION 1~ CORRELATION COEFFICIENTS~ REGRESSION COEFFICIENTS, MICE~ 0ZONE~ SKIN TUMOR A, SKIN PAPILLOMA A~ CARCINOGENS DOSE A~.DRINKING WATER A~ WATER CARCINOGENICITY A, CHEMICAL REACTION, CHEMICAL REACTIVITY, CARCINOGENS BIOASSAY A, CARCINOGENS DETECTION A, 3

73519 1 1 1 TRICHLOROETHANE~ POLYCYCLIC AROMATIC HYDROCARBONS CARCINOGENICITYj CARCINOGENS ADMINISTRATION ROUTE A, BLADDER CANCER OCCUPATIONAL FACTORS CAUSATION 1~ BLADDER CANCER ALCOHOL CAUSATION 1, BLADDER CANCER DRUGS CAUSATION 1] BLADDER CANCER COFFEE CAUSATION 1, BLADDER CANCER ETHNIC FACTORS CAUSATION 1, BLADDER CANCER SOCIOECONOMIC FACTORS CAUSATION 2,BLADDER CANCER DIETARY FACTORS CAUSATION 1, COFFEE INeESTION, ALCOHOL INGESTION, DRUG INGESTION, WATER BENZO A PYRENE, WATER POLYCYCLIC HYDROCARBONS~. BENZO.A PYRENE CARCINOGENICITY, POLYCYCLIC HYDROCARBONS CARCINOGENICITY)CARBON TETRACHLORIDE CARCINOGENICITY, VINYL CHLORIDE CARCINOGENICITY~ DIOXANE, METHYL IODIDE, DDT, CHLORDANE~ LINDANE, DIELDRIN, BENZENE CARCINOGENICITY, VINYLIDENE CHLORIDE, TRICHLoROETHYLENE CARCINOGENICITY, TETRACHLOROETHYLENE, HEPTACHLOR EPOXIDE, ~IETHYL BROMIDE, !~ETHYL CHLORIDE, ALDRIN CARCINOGENICITY, 0CTADECANE, TETRADECANE, PESTICIDES CARCINO~ENICITY~ ~ETHYLENE CHLORIDE, 1 2 DICHLOROPROPANE, DICHLOROETHANE~ ACRYLONITRILE .. CARCINOGENICITY~ 1 3 BUTADIENE~ PYRENE CARCINOGENICITY, 0 CRESOL, 2 q DIMETHYLPHENOL, PHENOL CARCINOGENICITY, DODECANE, DECANE, LIMONENE/ ENGLISH LANGUAGE, BETHESDA MD RESIDENCE~ USA RESIDENCE, CONFERENCE~ GRANTOR AMER HEALTH FOUND, GRANTOR GERMANY CANCER CARE~ NEW YORK ARGENTINA, USA USPHS NATL CANCER INST, US NATL ACAD ScI, NEW YORK ACAD SCI~ MISSISSIPPI RIVER, AMER CANCER SOC, INTERNATL AGENCY RES CANCER, US ENVIRONMENTAL PROTECTION AG£NCY~ TAIWAN~" EPPLEY INST RES CANCER 4

PREVENTIVE MEDICINE 9, 163- 164 (1980) Conference on the Primary Prevention of Cancer: Assessment of Risk Factors and Future Directionst American Health Foundation, 320 East 43rd Street, New York, New York 10017, June 7-8, 1979 Forward Ernst L. Wynder Introduction Mildred Scheel Assessment of Risk Factors Panel 1, Chairman: Johannes Clemmesen Tobacco E. Cuyler Hammond and Herbert E. Seidman Alcohol Kenneth J. Rothman Occupations John Higginson Panel 2, Chairman: Charles B. Arnold Nutrition Food Additives Drugs Anthony B. Miller Philippe Shubik Paul D. Stolley Panel 3, Chairman: John C. Bailar Air Pollution Water Pollution Radiation Ultraviolet Light E. Cuyler Hammond and Lawrence Garfinkel Herman F. Kraybill Seymour Jablon, John C. Bailar, and Arthur C. Upton Frederick Urbach Panel 4, Chairman: Gregory T. O'Conor Genetics Henry T. Lynch Virology Fred Rapp Immunology Alexandra H. Filipovich, Beatrice I). Spector, and John Kersey Assessment td' Risk Factors for Cancer Legislative Medicine European Viewpoint U.S. Viewpoint Heahh Education Chairman: Walter G. James Peter Greenwald Dietrich Schmahl Albert C. Kolbye, Jr. Sponsored by the American Health Foundation, Dr. E. L. Wynder, President; and the Deutsche Krebshilfe, Bonn, F.I).R.. Dr. Mildred Scheel. President. 163 0091-7435/80/020163-02502.00/0 Copyright (~ 1980 by Academic Press, Inc. All rights of reproduclion in any form reserved.

164 Health Education for Children Health Education for Adults Product Mod~/~cation Chairman: Harry Demopoulos The Less Harmful Cigarette CONFERENCE~ PRIMARY PREVENTION OF CANCER Christine L. Williams Walter G..lames Extending the Prudent Diet Priorities in Cam'er Prevention: A Conference Al~praisal Future Directions in Cancer Prevention Future Directions in Cancer Prevention The Deutsche Krebshilfe: A Catalytic Mode of Action Future Directions of Primary Cancer Prevention in the Federal Republic of Germany Cancer Research Programs of the American Cancer Society Dietrich Hoffmann, T. C. Tso, and Gio B. Gori John H. Weisburger, D.Mark Hegsted, Gio B. Gori, and Barry Lewis Gio B. Gori Arthur C. Upton P. H. Hofschneider Georges Fulgraff LaSalle D. Leffall, Jr.

PXEVI~NI IVI~ MIiDICiNF. 9, 212-218 {1980) Evaluation of Public Health Aspects of Carcinogenic/Mutagenic Biorefractories in Drinking Water1 HERMAN F. KRAYBII.L N.lio#tol ('¢t~tcer II~.~litttlc Room 3C37, La#tdo.' B.ihlin,~. I'h'the.~'da, Moryhtltd 211205 COMMITTEE MEMBERS E. CI~Yt I.r IIAMMONI), JIHIN HI(;(;INSON, M.D. htl('rottfiotlal A.t, ettc)'.Ji~r Re.search World Health PIIII IPPE StlUBIK. M.D. IQ~ph,y In.~titttte,lbr Research in Cancer, Utdrersit.v o.]" Nebraska Medical Center SlE'¢EN SIf:l 1 MAN. American Ih'alth JollN H. WI!iSIIt~R(;I!R. PIt.D. American th, alth t'ottndaliott AI the turn of the century, concern over conl:lmination of drinking water was focused on that caused by viruses, bacteria, and parasites. However, in the developed countries allen- lion is currenlly focused on organic chemical contaminants and, to a lesser exlent, the inorganic chemicals. Of the wide spectrum of organic biorefractories in potable water, an identification and classification of a list of 309 in 1977 revealed 23 carcinogens and 30 mutagens. A current list updating such information may reveal a larger number, While some chemicals in drinking waler, such as arsenic and nitrite, were incriminated in studies some years ago with regard to cancer, current studies on organic biorefractories are inconclnsiv¢. Some experimental studies in systems, in ritro and in fifo. would indicate some mulagenic and carcim'~genic aclivity, however, more comprehensive sludies are needed to provide more convincing evidence on cause and effecl. Similarly. there have been 12 reported epidemiological studies of various types, some of which suggest interesting statistical as- sociations. The studies, however, are limited with some uncontrolled variants, Future studies will have to correct for certain deficiencies. While the experimental and epidemiologic studies provide some presumptive evidence, one cannot establish, with any degree of asst.rance as yet, any causality relevant to cancer from these micropollutants. There is serious concern, however, about those contaminants with the realization that the ingested curcinogenic-mutugeni¢ biorefractories may contribute to the total cancer burden. Thus, control and reduction technologies in water treatment are recommended. INTRODUCTION According to the U.S. Environmental Protection Agency (EPA) there are 40,000 municipal water systems providing drinking water, as well as 200.000 water supply systems for nonresidential locations (15). Many of these systems are not equipped to treat water from contaminated sources but are designed to disinfect ' Presented at th'e American Health Foundation/I)culsche Krebshilfe Conference on the Primary Prevention of C,'mcer: Assessmenl of Risk Factors and Future Directions. N.Y., N.Y.. June 7-8, 1979. 212 0091-7435/80/020212-07502.1)0/0 Copyr~h! ~ |gHo by Academic Prc~, Inc. All ri|hts of reproduction in any form reserved.

CONFERENCE: PRIMARY PREVENTION OF CANCER 213 relatively pure water from selected sources. At the turn of the century most concern was centered upon processes which removed viruses, bacteria, and cer- lain parasites. Sedimentation filtration and disinfection have virtually eliminated these potential disease vectors. However, inorganic and organic chemicals have appeared as new contaminants as a result of industrial activities and, to a lesser extent, as recognizable contaminants in natural water supplies. Some of the or- ganic contaminants such as the trihalomethanes (chlor.oform, bromoform, di- bromochloromethane, dichlorobromomethane) are the result of attempts to reduce bacterial contamination by using the disinfectant chlorine. Most attention is fo- cused on the more significant qualitative and quantitative aspects of organics over the inorganics. More studies need to be conducted on inorganic contaminants in water. In a study conducted on nitrite in drinking water, there appeared to be an association between levels of nitrite and incidence of gastric cancer. Levels of nitrite in drinking water were 80 ppm (4). Arsenic in drinking water in Taiwan and Argen- tina was associated with cancers of the skin, lung, liver, and other organs (6, 16). While these inorganic elements could be the etiologic agents, it is conceivable that on the basis of current sophisticated analytical methodology (gas-liquid chroma- tography and mass spectrometry), other contaminants might have been identified as the primary water contaminants in these statistically associated cancers. It is possible to estimate the levels of some volatile organic chemicals in water but the nonvolatile organics are much harder to identify and it is estimated that one can only account for 10% of the total organic chemicals (TOC) present as biorefractories in drinking water. Thus, if the larger component includes some carcinogenic organics, the total levels of carcinogenic contaminants could be un- derestimated. The EPA monitoring systems now have identified 699 biorefrac- tories in the USA water supplies. Of an original list of 309 biorefractories in 1977, the National Cancer Institute (NCI) has identified and classified 23 carcinogens, 30 mutagens, and il promoters in drinking water (9) (Tables 1-3). This list is currently being updated. An excellent report entitled "Safe Drinking Water," prepared by the National Academy of Sciences (NAS) in 1977 at the request of the EPA, considers the public health aspects of viruses, solid particles, inorganic solutes, pesticides, radioactivity, and the major component of interest, the organic biorefractories (12). The report is quite detailed on safety and risk assessment and includes most of the current issues on carcinogenesis such as animal-to-man extrapolations, thresh- olds, dose-response, repair mechanisms, and potential interaction of chemicals. A conference on Biological Effects of Aquatic Pollutants with Emphasis on Neoplasia was held by the New York Academy of Sciences in 1976 (14). ASSESSMENT OF THE PROBLEM As early as 1950, the National Cancer Institute studied the carcinogenicity of water pollutants (?). These studies employed bioassays on industrially polluted water as did some later studies (5). These studies, despite the crudity of experi- • mental approaches, showed some suggestive evidence but the findings were not too convincing. Other NCI epidemiologic studies followed in an attempt to relate inorganic materials in river basins to cancer mortality. They raised some suspi- cions about nickel, arsenic, beryllium, and lead (1).

214 HERMAN F. KRAYBIi.I. TABLE I CARCINO(IENS ANI) ~USI'I'.('I |il) CAR('INO(IENS IN DRINKIN(I WA I~ER (U.S.A.) I. Benzolu)pyrene 2. Carbon telrachloride 3. Chloroform 4. Vinyl chloride 5. 1,4-Dioxane 6. Methyl iodide 7. DI)E 8. DDT 9. Chlordane I0. Lindane II. Dieldrin 12. Benzene 13. Vinylidene chloride 14. fleplachlor 15. I, 1,2-Trichloroethane 16. I, 1,2-Trichloroelhylene" 17. l~i~( 2-chhu'oelhyl)ether 18. Simazine 19, Telraehloroelhylene 20. Heplachlor epoxide 23. Bulyl bromide " Recent reports attribute NCI reported carcinogenicily of TCE to epichlorhydrin as stabilizer addi- tive in technical grade TCE and not to pure TCE. As indicated, a spectrum of the organic chemicals identified in drinking water has been shown to be carcinogenic in bioassays (Table I). There is some evidence that marine animals in polluted waters show a fourfold increase in tumor incidence compared with those from less-polluted waters (2). There are two approaches to assessment of the carcinogenic hazard of drinking water contaminants. The first would be toxicity studies or carcinogenic bioassays on a mixture or composite of these micropollutants in water using various experi- mental systems such as whole animal bioassays on concentrates of drinking water samples, synthetic formulation of water samples with identified contaminants at determined levels added to relatively uncontaminated water, bioassay of water samples using the fish as the animal model, and bioassay of water samples on cell cultures and bacterial systems (Ames' procedure) for determination of mutagenicity and cell transformations. The second approach entails epidemiologic and statistical studies on various human populations. Some of these studies relate to investigation of relationships between the levels of trihalomethanes in water and possible increases in cancer. Other studies have focused on effects of chlori- nation on surface waters versus ground water, probably not chlorinated, in terms of comparative incidences and possible increases in human cancer. SYNOPSIS OF STUDIES CONDUCTED Some preliminary reports from experimental i, vitro studies indicate that con- centrates of municipal water supplies and fractions of these concentrates have mutagenic and carcinogenic activities (i I). The EPA, however, has proposed

CONFERENCE: PRIMARY PREVENTION OF CANCER 'I'A I~II.E 2 Mut A(iliNS ANI) SUSI'I ('II.I) MtilA(il NS IN I)RINKIN(; WA l liR I. I,l,I-Trichlt~roclhanc 2. I|romtm~¢llu~i~c (methyl hronlidcl 3. Methyl cldoride 4. Bromochloromclhane " 5. Methylene chloride 6. Bromtfform 7. Brtm~odichloromet bane 8. 2-Chltlropropane 9. 1,2-1)ichloropropane Ill. I-Chloropropcne I1. 1,2-1)ichlorocthane 12. Bis(2-¢hloroisopropyl)et her 13. Chlorodibromomelhane 14. 1,3-1)ichloropropcne 15. 2.6-1)initroloh~cnc 16. I)i¢ hloroa¢clonilrile 17. Melhylcne bromide 18. Chlordane 19. Vinylidcne chloride 21L n-Btltylbromidc 21. Bisl2-chloroct hyl)cther 215 24. Methyl iodide 25. Vinyl chloride 26. 1,3-Butadicne 27. 1,2-Bistchloroethyoxy~ethane 28. Pyrene 29. I, 1.2-Trichloroe~hylene .t0. Tetrachloroethylene (perchloroethylene) various approaches, augmented by those of the NCI previously mentioned, to determine the carcinogenic potency, if any, of contaminated drinking water in order to establish whether low concentrations of these organic trihalomethanes at the proposed regulation of 100 ppb ( 100 ~g/liter) really afford a measure of safety. TABLE 3 PROMOIER~i IN DRINKING WAIER (U.S.A.) I. Ortho-cresol 2. 204-Dimethylphenol 3. Phenol 4. n-Dod¢cane 5. Eicosane 6. 2,4-Dichlorophenol 7. n-I)¢cane 8. Limonene 9. Octadec.',ne 10. n-Telradecan¢ II. n-Unde~ane