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if Chemical Contaminants: Safety And Risk Assessment The hazards of ingesting pollutants in drinking water can be assessed in two general ways: with studies of toxicity in the laboratory and with epidemiological studies. Studies in the laboratory may employ a variety of experimental systems, ranging from chemical ejects of pollutants on DNA, through exposure of bacterial or mammalian cells in culture, to lifetime feeding studies on experimental animals. They are prospective studies, in which relatively small numbers of cells or animals are exposed to characterized pollutants at known concentrations. Epidemiological studies deal with human populations. Their design is constrained by external circumstances, and they involve large numbers of people whose exposure to the pollutant in question is commonly uncertain and confounded by exposure to other pollutants. The aim of studies of both types is to allow the risk to man to be estimated. The first can give precise information on relatively high risks related to individual pollutants in this or that animal species to which human exposure and risk may be compared. The second can provide less precise information on the human risk related to one pollutant (isolated, it is hoped, from other pollutants). Toxicity data obtained from laboratory animals will generally have to be relied on for estimating human risk, if we are to control human exposure to carcinogens. Epidemiological studies have discovered causes of disease and can buttress, supplement, or contradict laboratory data. Imaginative comparisons between laboratory and epidemiological data 19

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20 DRINKING WATER AND H"LTH are of the utmost importance, particularly in the area of metabolic pathways and fate of chemicals found to be carcinogens in animals. Efforts to develop rapid assays for mutagenesis and carcinogenesis have recently been greatly expanded. Methods that show promise include tests for mutagenicity that make use of bacterial, cell transformation, and organ culture systems. There appears to be high positive correlation between mutagenicity, as determined by some of these methods, and carcinogenicity in agents already studied (McCann et al., 1975; McCann and Ames, 1976; Ames, 1976~. The utility of these rapid methods will depend on experimental demonstration that their results are well correlated with those obtained from conventional long-term studies of carcinogenicity with well-designed animal systems. High priority should be given this research because it offers a reasonable probability of success in a relatively short time and at lower cost than long-term testing, and there is an urgent need for a primary screen for selecting compounds for long-term assay (DHEW, 19771. The committee is fully conscious of these modern methods for determining genetic and physiological phenomena. Their use, when appropriate, and their further development is strongly encouraged. Pollutants in water have many different effects. At- one extreme, they can impart a disagreeable taste or odor. This is quickly perceived by the community, and the process of characterization and identification of the offending pollutant is generally prompt and fairly straightforward. At the other extreme, the ejects on human health of a carcinogen present in drinking water will probably go undetected, particularly if it produces only a modest in-crease in the incidence of a common cancer. The major toxicological and epidemiological efforts should therefore be directed to characterizing and identifying pollutants whose biological effects include chronic, irreversible, and progressive diseases, such as cancer. It is necessary to develop risk estimates for large human populations of varied susceptibilities that are exposed to small concentra- tions of such toxic pollutants, including carcinogens. The development of safety factors for pollutants whose toxic ejects are reversible and nonprogressive involves empirical calculations based on past history of use and concentrations that appeared safe for the public. These safety factors are usually applied to the highest dose or concentra- tion at which no adverse eject was observed. The chosen dose or concentration is divided by a "safety factor" that varies over a wide range, depending on the adequacy of the data. Whether or not the "safety factor" approach can be used with pollutants that cause chronic, irreversible, and progressive disease in laboratory animals is controversial. Those who argue for safety factors,

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Chemical Contaminants: Safety And Risk Assessment 21 and thereby thresholds, find it inconceivable that very small concentra- tions can cause a cancer to develop, claiming that body defenses can surely protect at doses smaller than the threshold value. Those who argue that safety factors are inadequate and that almost no thresholds can be determined, or theoretically developed, suggest that even one or a very few molecular events have a finite probability of initiating a successful malignant or neoplastic transformation in a cell, and that this can lead to a lethal cancer. Although one malignant cell can lead to death by cancer, many liver or kidney cells can be killed or damaged (but not malignantly transformed), without causing any detectable disease. Furthermore, man is never exposed to one carcinogen at a time, but is exposed to low concentrations of many at the same time. Accordingly, we have adopted a "nonthreshold" approach for estimat- ing risks from pollutants that have been shown to be carcinogenic in laboratory animals. Demonstration that a pollutant is carcinogenic, and application of nonthreshold risk estimates to it, do not imply that its use must be prohibited. Such a proscription might itself give rise to even greater risks to health or other disadvantages. In some cases, a net risk must be estimated, and society must attempt to use the pollutant in such a way as to minimize risk and maximize benefit. Nowhere is this better illustrated than in the use of chlorination to disinfect water. Chlorination controls pathogenic organisms, but introduces chloroform, which is carcinogenic in animal-test systems. Methods must be devised to minimize concentra- tions of chloroform and chlorinated hydrocarbons, from whatever source, in drinking water. But before alternative methods for control of pathogenic organisms are instituted, toxicological studies must show that they are as effective as, and pose no greater risk than, chlorination. We perceive that society is willing to accept some risks to health if the attendant benefits are demonstrably greater. Drinking water contains low concentrations of many chemicals, some of which, if ingested for a long time, could have delayed toxic effects. The insidious eject of chronic exposure to low doses of toxic agents is difficult to recognize, because often there are few early warning signs and, when signs are ultimately observed, the effects may have become irreversible. Subchronic toxicology studies may not offer reliable means for assess- ment of long-term toxic effects in animals, let alone extrapolation to chronic effects in man; hence, different considerations have to be applied in assessing risk. The methods and principles of acute toxicology do not offer any easy, straightforward methods for extrapolation of such experimental data to calculate risks for large human populations. Two important questions must be answered: What assay procedures .. .

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22 DRINKING WATER AND H"LTH are required for a valid assessment of chronic toxicity of chemicals in experimental animals? How can the data from such procedures be extrapolated to estimate risks in humans? In dealing with these questions, we use the specific risk of cancer as our major example, although other toxicities are considered. This report seeks to summarize the state of the art in extrapolating to man the results of experiments on animals, chiefly in relation to carcinogenesis. EFFECTS ON HEALTH The purpose of drinking-water standards is to ensure protection from acute poisoning and from long-term, or "chronic," effects. In recent years, numerous short-duration, presumptive tests in vitro have been developed that may help to predict carcinogenesis. Nonetheless, studies of chronic toxicity continue to be required for safety evaluations. These are necessary because there is no general way to predict carcinogenic elects on the basis of the observed short-term elects of chemical- biological interactions. [The significance to health of the finding that a pollutant is mutagenic in the new test systems is unknown (See Drake, 1975; DHEW, 1977~. But, because evidence of the correlation between mutagenicity and carcinogenicity continues to accumulate, we suggest that a conservative safety factor be provisionally applied to the mutagenicity data and that, if new information (such as the results of a reliable carcinogenicity study) is lacking 4 yr from the time a mutagenici- ty study is completed, nonthreshold methods be used to establish risk.] Chronic exposures and chronic effects are different (Casarett, 1975~. The former means frequent ingestion over a long period of time. The latter implies injury that persists, either because the injury is irreversible or progressive, or because the exposure is prolonged and the rate of new injury exceeds the rate of repair. Chronic exposure in animals is generally considered to be at least half the life span. In man, it can be much less. Injury from chronic exposure may occur in at least three ways: by accumulation of the chemical to a critical concentration at sites of action sufficient to induce detectable injury; by accumulation of injury until physiological reserves can no longer compensate (i.e., repair is never complete); or after a long, latent period beginning with an exposure that has an unrecognized biological elect, and precipitates the eventual appearance of injury. In the first case, knowledge of the kinetics of chemical absorption, metabolism, and excretion obtained in short-term studies may allow computation of the amount of the toxic chemical that will accumulate in long-term use. Such investigations will improve the

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Chemical Contaminants: Safety And Risk Assessment 23 usefulness of long-term, low-dose, chronic-exposure studies. To predict chronic accumulation, or latent development, of injury from the results of short-term tests requires knowledge of the kinetics of injury and repair. There are few, if any, substances for which such understanding is at hand. Reversibility of Chemical Injury Reversible elects disappear after exposure ends. The time required for return to normal should be a small fraction of the remaining lifetime of an organism. During the period of return to normal, the organism must be at no greater risk (than one that was never exposed) of further or other damage from other sources. For some elects, reversibility may be qualified by the normal lifetime of a specific cell or macromolecule that serves as the end point of the elect. A nonreversible effect is one in which the damage does not regress completely, or may progress after exposure ceases. Some erects of toxic chemicals are unmistakably irreversible. They include terata, malignant tumors, mutations in offspring of exposed animals, and some neurological changes. These are gross manifestations of specific chemical-cell interactions, and it is possible, or probable, that there are early reversible effects, either in the cellular process first affected or at intervening stages. Prediction of adverse effects from short-term studies is possible if the critical dose and the rate-limiting factors that determine reversibility are known. Without this knowledge, evaluation of toxicity will generally deal more with the possibility of irreversible effects than with speculatively reversible elects. Net reversibility varies from one tissue, species, strain, or individual to another. It is generally impossible to measure the specific processes involved in injury and repair in the standard toxicity-evaluation study. However, measurements of reversibility in short-term studies should provide useful information that may allow extrapolation to the longer term. The predictive value of such tests does not necessarily depend on the persistence of the chemical in the test organism. If the chemical produces a reversible erect and then is rapidly detoxified or excreted, it may be possible to compute the doses or schedules of exposure that would not produce cumulative and ultimately nonreversible or irreversible effects (see definitions below). But other factors might be overriding. For example, rapid reversibility after a single dose might not indicate the rate of reversal after repeated doses, if the first dose, in addition to the measured erect, altered the repair process or processes responsible for detoxification (Murphy, 1967~. To evaluate repeated-dose effects, sub

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24 DRINKING WATER AND H"LTH chronic- and chronic-exposure studies should include groups of animals that are removed from exposure at selected intervals during the experiment. The rate of reversal of elects in these animals can be measured at intervals, or at some critical time after exposure ceases. If the chemical persists in the organism, quantification of rates of reversal is more complicated. Data are needed on absorption and disposition to correspond with data on rates and reversal of elects. Perspectives and Perceptions of Effects Whether an elect is reversible, nonreversible, or irreversible might be shown by experiments (or epidemiological studies) that include observa- tions during exposure-free "recovery"periods similar to those made at the end of the exposure period. Nonreversible and irreversible injuries are of greater concern than reversible injuries in evaluating human health elects. However, frequently recurring reversible injury may lead to greater morbidity than a nonreversible or irreversible injury that appears only late in life. Characterization of an effect as reversible implies that there is a dose below which health will not be compromised. This assumes, of course, that any subliminal cellular injury that is responsible for the manifest elect is also reversible. Full understanding of thresholds, margins of safety or safety factors, and extrapolations of estimated risk requires understanding the underlying cellular mechanisms of injury. An alternative to the safety-factor approach for reversible toxicity may be considered. The nonthreshold approach is attractive partly because of the idea that one transformed cell could lead to fatal neoplastic disease. What number of damaged (but not transformed) or killed kidney, liver, or lung cells is compatible with a healthy life? If these numbers, or fractions of total organs, could be estimated for a number of species, including man, and if experimental dose-response curves for fractional damage to all vital organs could be obtained, the numbers of damaged cells that are compatible with health could be estimated. This might constitute an initial approach to the development of rational risk estimates for toxic effects other than cancer. Clearly, a major research effort is needed. Where it was once common to refer to "no-effect doses" of chemicals and "safe" doses, it is now more appropriate to speak of"no-observed- adverse-e~ect" doses and "acceptable risk" when describing permissible use or exposure to chemicals. This change has been accompanied by an increasing concern for the health of the most susceptible individuals in

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Chemical Contaminants: Safety And Risk Assessment 25 the population, besides that of the average individual. Many scientists now distinguish between injuries produced by chemicals for which there is likely to be a threshold dose and elects (e.g., carcinogenesis and mutagenesis) for which there is likely to be either no threshold dose or no way presently known to estimate one for large, heterogeneous popula- tions. [A report of another committee of the National Academy of Sciences expresses some doubt about the validity of the threshold concept for any type of biological erect (NAS, 1975~; see also Drake et al., 1975, and Hoel et al., 1975.] From another point of view, Well (1972), considering statistics and judgment in safety evaluation, wrote: "No matter what the biological erect, at some concentrations under some sets of conditions, a dose level must exist below which no biological damage will occur during the life-span of the great majority of men. No matter how small the dose, however, one, or a few, of millions of subjects may exhibit the critical response." It is more prudent to treat some kinds of toxic elects that may be self- propagating or strictly cumulative, or both, as if there were no threshold and to estimate the upper limits of risk for any given exposure. Included among these are elects that result from an initial, chemically induced alteration in cellular genetics that is transmitted by cell propagation. Carcinogenesis and mutagenesis are examples in which a single cell transformation has the theoretical potential for irreversibility, which might involve self-propagation, even in the absence of further exposure. Other injuries may become self-propagating-e.g., advanced stages of cirrhosis but they are usually preceded by detectable injury that is reversible. The initial erects should have a dose-response threshold, inasmuch as the nature of cellular injury that precedes them can be detected while the injury is still reversible. Some forms of injury may be strictly cumulative, because the cells in which they occur are not repaired or replaced. (For example, destruction of enough neurons leads to a decrease in central nervous system function.) Congenital malformations appear to be irreversible. In this case, injury occurs from exposure during only a brief period. In addition, it is probable that a threshold dose could be estimated from adequate experimental or epidemiological data. Current knowledge of the proper principles for extrapolating toxicolog- ical data from high dose to low dose, and from one species to another, is inadequate. Nonetheless, standards for drinking water must be devel- oped. Whenever possible, a maximal no-observed-adverse-effect dosage should be identified. Three major categories of erects should be

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26 DRINKING WATER AND H"LTH considered, and different ways of arriving at standards can be proposed for each. Irreversible (SeIf-Propagating) Effects (These are likely to become life-threatening even after exposure has ceased) 1. Genetically self-propagating ejects, e.g., somatic or germ-cell mutation that culminates in a malignant neoplasm or is transmitted to later generations: Assume no threshold, assume a linear dose-response at low doses, and estimate risk. Set standard at something other than zero only if exposure cannot be eliminated by reasonable means, or if material has no safer substitute, and if it has great utility or social value. An acceptable degree of risk arrived at by a case-by-case consideration involving numerous scientific, technological, economic, and societal issues and values should determine the permitted dose. Nonreversible Effects 1. Ejects that are sequels to probably detectable, reversible injury, but that may become self-propagating (such as cirrhosis): If a threshold can be demonstrated, use it as an upper limit, with application of an appropriate safety factor. If not, proceed as in "Irreversible Ejects." 2. Death of irreplacable cells, cumulative with continued exposure, e.g., central nervous system disease, as in exposure to methyl mercury. If a threshold can be demonstrated, use it as an upper limit, with application of an appropriate safety factor. If not, proceed as in "Irreversible Effects." Reversible Effects 1. Life-threatening or major morbidity, e.g., inhibition of a vital enzyme system. If a threshold can be demonstrated, use it as an upper limit. If not, proceed as in "Irreversible Ejects." 2. Minor morbidity, e.g., sensory irritation without histological change. Determine the range of sensitivities and choose an upper limit low enough to minimize occurrence in the population. 3. No detectable functional or sensory decrement, but possibly predictive precursor of more serious effect, e.g., plasma cholinesterase inhibition, or small increase in liver enzymes in plasma. Proceed as in 2.

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Chemical Contaminants: Safety And Risk Assessment 27 IRREVERSIBLE TOXICITY Many factors make the assessment of long-term health risks to human populations difficult for example: 1. The sensitivity of the test systems used to detect carcinogenic ejects depends on the number of animals used in each test and on the duration of their survival. 2. Any series of experiments will yield false-positive and false-negative results. 3. Detection of neoplastic changes in treated animals requires exten- sive gross and microscopic examination of many tissues by trained people. 4. Time, resources, and money required to conduct an adequate test are all substantial. Controversies have arisen because of the above problems and because of inadequate testing for long-term effects. False-positive results can cause unnecessary public concern and the removal of useful materials from the market, and false-negative results can endanger the health of large groups of people. Long-term ejects are particularly difficult to detect and treat because they are discovered only after many years, by which time they are often irreversible. The main question to be answered is: "Within the limitations of present-day capabilities, what are the minimal requirements for an adequate test (on experimental animals) of the long-term effects of potentially toxic agents, and how can these results be used to estimate possible risk to the human population?" Summary of Principles for Extrapolating Animal Toxicity To Humans Despite wide gaps in our knowledge of the metabolism and ultimate fate of chemicals in man, properly conducted experiments will yield results that can improve our estimates of the risk to human populations from long-term exposures. Many mechanisms for chemical carcinogenesis have been postulated. If the mechanism involves somatic mutation or alteration, there is no threshold dose for long-term exposure; if the mechanism is unknown, it is prudent to assume that DNA damage is involved. The idea that there is a "safe" dose of such chemicals may be conceptually valid, but "safety" cannot be established by any experimental method now available. Every dose

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28 DRINKING WATER AND H"LTH should be regarded- as carrying some risk. A "most probable risk" can be estimated by appropriate statistical treatment of the results of experi- ments on animals, and once the benefits of use of a chemical have been defined and estimated, it is possible to weigh the health risks against the health benefits. The balance between them should then be the overriding consideration in regulating the amounts of such substances in the environment. The method used in classical toxicology for determining safe doses for short-term exposure of humans to drugs is to estimate a maximum exposure that is tolerated without adverse ejects in a group of animals, and to apply a safety factor. This procedure is valid only for estimating the risk of reversible toxic effects. "No-observed-adverse-effect dose" is a better term, because it makes clear that the exposure can often be a function of the size of the experiment the larger the experiment, the lower this dose can be. Studies in laboratory animals must be used to predict the safety of environmental chemicals. Human epidemiological studies cannot be used to predict nor assure safety, for several reasons: 1. Epidemiology cannot tell what effects a material will have until after humans have been exposed. One must not conduct what might be hazardous experiments on man. 2. If exposure has been ubiquitous, it may be impossible to assess the ejects of a material, because there is no unexposed control group. Statistics of morbidity obtained before use of a new material can sometimes be useful, but when latent periods are variable and times of introduction and removal of materials overlap, historical data on chronic ejects are usually unsatisfactory. 3. It is usually difficult to determine doses in human exposures. 4. Usually, it is hard to identify small changes in common ejects, which may nonetheless be important if the population is large. 5. Interactions in a "nature-designed" experiment usually cannot be controlled. With the possible exception of arsenic and benzene, the known human carcinogens are carcinogenic in some laboratory species. Therefore, animal studies of carcinogenesis in laboratory animals are useful for predicting effects in man. Thus, for ethical and practical reasons, data derived by using animals for toxicity testing are essential for protecting the public from harmful effects of new chemicals in the environment and probably also necessary for evaluating the potential harm of "old" chemicals. By the same token,

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Chemical Contaminants: Safety And Risk Assessment 29 epidemiological surveillance studies are necessary for detecting the errors that will surely arise from use of the animal studies alone. Thus, epidemiological studies are both a last line of defense and a means for verifying and adjusting the conclusions from animal studies. The General Problem Of Extrapolation The knowledge and insight that provide a basis for more successful extrapolation are rapidly increasing. The value of tests on laboratory animals is most easily estimated when the chemical agents tested are ultimately administered to, or confront man in a manner similar to the animal exposure, as in the drug-development process. The sequence of animal tests of a new chemical agent, after toxicological studies, continues with studies conducted in order to determine: the mechanism through which the laboratory animals respond to the agent, the nature of its metabolism in tissues and organs, and the rates and routes of elimination of the agent and its derivatives. Thus, damage observed in an organ of an animal provides clues that lead to an understanding of the metabolism and organ involvement of the substance in humans. Similarities and differences between humans and animals can be noted, and the validity of the laboratory-animal test systems can be better estimated. This approach is most useful for observing early elects that occur soon after the substance is administered. The use of such data for assessing long-term effects in humans has many difficulties. When a mouse or man is exposed to a chemical, a number of events can occur that can greatly influence the final reaction, which may appear as the observed toxic elect. These events include: absorption; distribu- tion and storage; metabolism, excretion, and reabsorption; arrival at the site of action; reaction with the biological receptor; and interaction with other constituents of the environment. They can be compared among various animal species and among strains and individuals. Anatomical, biochemical, physiological, pharmacological, and pathological differ- ences and similarities can and have been identified, and there have been efforts to characterize systematically the differences and similarities between species for some compounds and classes of compounds. These are appropriate subjects for research. Chemicals to which man is exposed can be divided into two classes: those deliberately administered for therapeutic, diagnostic, or nutritive purposes, which contribute to health, and those with uses that do not directly benefit health, but reach man through a variety of routes. To some extent, the acute toxicity of the first class can be observed directly in man. If the chemicals are already in use, the laboratory-animal

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52 DRINKING WATER AND H"LTH background." This kind of interaction phenomenon has important implications for the models used in extrapolation. It implies that these models may not assume any threshold for a new material in a world already populated by many carcinogens. It also leads to the conclusion by Crump et al. (1976) that "all models of carcinogenesis thus far proposed will be linear at low doses." The discovery of interactions will require more sophisticated experi- mental techniques than are now being used. Testing combinations of materials multiplies the number of tests that must be done (100 materials, tested two at a time, will require 100X 99/2! tests; tested three at a time will require 100 x 99 x 98/3! tests). New techniques for multiple testing will have to be developed. Uncovering deficiency interactions will require entirely new and different approaches. SUMMARY Chemical Contaminants: Safety and Risk Assessment Large populations are repeatedly exposed to potentially toxic contami- nants in the drinking water in minute amounts over many months or years, or over whole lifetimes. Delayed, essentially irreversible, ejects can occur. Methods and criteria of classical, conventional toxicology do not offer reliable means for assessing long-term toxic ejects such as carcinogenesis in man by extrapolation from animal data; hence, novel considerations have to be applied in assessing risk. The insidious ejects of chronic exposure to low doses of toxic agents is difficult to recognize, because there are few, if any, early warning signs and, when signs are ultimately observed, they often imply irreversible ejects. For example, cancer induction in experimental animals, even with the most potent carcinogenic chemicals, requires at least several months and in many instances a whole lifetime. There are as yet no easy, straightforward methods for extrapolating even chronic-exposure experi- ~nental data to calculate risks to large human populations. Teratogenic ejects are easier to establish by animal experimentation, but there are similar uncertainties in extrapolating to human populations. Mutagenic ejects are difficult to assess experimentally in mammals, and such ejects are particularly insidious, in that they appear only in later generations. Various measures used in assessing acute toxicity such as LD~o, LD50, and maximal tolerated dose are generally found to be quantita- tively similar among most animals. On the basis of dose-per-unit of body surface, toxic ejects in man are in the same range as those in experimental animals, such as mouse, rat, hamster, dog, and monkey. On a body-weight basis, man is generally more vulnerable than the

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Chemical Contaminants: Safety And Risk Assessment 53 experimental animal, probably by a factor of ~12. Comparative studies have shown generally that absorption, metabolism, and excretion of various drugs are slower, dose-for-dose, in man; that there is greater retention of such drugs; and that higher concentrations occur in body fluids and tissues in man than in small mammals. With an awareness of these quantitative differences, appropriate safety factors can be applied to calculate relatively safe therapeutic dosages for man. These methods and principles of classical toxicology are useful for assessing toxic effects that are reversible and nonprogressive. They are much less useful in dealing with the problems of chronic irreversible toxicity or the effects of long- term exposure. This subject has not been considered widely in the past. From the review of available information, two major questions emerge: "What types of experimental-assay procedures are required for a valid assessment of chronic toxicity of chemicals in experimental animals?" "How can such data be extrapolated to estimate risks in humans?" In dealing with these questions, our recommendations are restricted to a specific risk namely, cancer with the understanding that the same considerations will apply at least partially to the problems of mutagenesis and teratogenesis. Furthermore, we consider only carcinogens whose mechanisms involve somatic mutations. Some principles that underlie efforts to assess the irreversible effects of long-continued exposure to carcinogenic substances at low dose rates are outlined below. Principle 1 EFFECTS IN WAS, PROPERLY QUALIFIED, ~ ITALIC - LE TO ~ This premise underlies all of experimental biology and medicine, but because it is continually questioned with regard to human cancer, it is desirable to point out that cancer in men and animals is strikingly similar. Virtually every form of human cancer has an experimental counterpart, and every form of multicellular organism is subject to cancer, including insects, fish, and plants. Although there are differences in susceptibility between different animal species, between different strains of the same species, and between individuals of the same strain, carcinogenic chemicals will affect most test species; and there are large bodies of experimental data that indicate that exposures that are carcinogenic to animals are likely to be carcinogenic to man, and vice versa. Evidence that circumstances leading to cancer induction in humans are also applicable to experimental animals stems from the very first observation of chemical carcinogenesis the appearance of cancer of the

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54 DRINKING WATER AND H"LTH scrotum in chimney sweeps, observed by the British surgeon, Percival Pott, in 1775. It was not until modern times that a substance implicated in human cancer was found to be carcinogenic in animals, when the Japanese scientists, K. Yamagiwa and K. Ichikawa, found in l91S that extracts from coal tar cause cancer when applied to the skin of experimental animals. Many pure carcinogenic chemicals have since been isolated from a wide variety of"tars" derived from incomplete combustion of organic matter, such as coal, wood, and tobacco. There is little doubt that these and other chemicals, alone or in combination, are responsible for the greatly increased incidence of lung cancer among smokers. With the possible exception of arsenic and benzene, all known carcinogens in man are also carcinogenic in some species, although not in all that have been tested. Principle 2 METHODS DO NOT NOW EXIST TO ESTABLISH A THRESHOLD FOR LONG TERM EFFECTS OF TOXIC AGENTS With respect to carcinogenesis, it seems plausible at first thought, and it has often been argued, that a threshold must exist below which even the most toxic substance would be harmless. Unfortunately, a threshold cannot be established experimentally that is applicable to a total population. A time-honored practice of classical toxicology is the establishment of maximal tolerated (no-e~ect) doses in humans based on finding a no-observed-adverse-e~ect dose in chronic experiments in animals, and to divide this dose by a "safety factor" of, say, 100, to designate a "safe" dose in humans. There is no scientific basis for such estimations of safe doses in connection with carcinogenesis. For example, even if no tumors are obtained in an assay of 100 animals, this means only that at a 95% confidence level, the true incidence of cancer in this group of animals is less than 3%. Even if we were to carry out the formidable task of using 1,000 animals for assay and no tumors appeared, we could only be 95% sure that the true incidence were less than 0~3%. Obviously, 0.3% is a very high risk for a large human population. In fact, there are no valid reasons to assume that false-negative results of carcinogenicity tests are much less frequent than false-positive ones. To dismiss all compounds that did not induce tumors in one or two mouse and rat experiments as noncarcinogenic is wrong. Labeling as "carcinogens" all substances that gave rise to increased incidence of tumors is justified only if there is conclusive evidence of a causal relationship. The "relative risk" of compounds that are not found to

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Chemical Contaminants: Safety And Risk Assessment 55 induce tumors in animal experiments must also be considered. But this requires evaluation of data other than those collected in chronic toxicity studies on rodents. Experimental procedures of bioassay in which even relatively large numbers of animals are used are likely to detect only strong carcinogens. Even when negative results are obtained in such bioassays, it is not certain that the agent tested is unequivocally safe for man. Therefore, we must accept and use possibly fallible measures of estimating hazard to man. This reasoning leads us to the statement of Principles 3 and 4. Principle 3 THE EXPOSURE OF EXPERIMENTAL ANIMALS TO TOXIC AGENTS IN HIGH DOSES IS A NECESSARY AND VALID METHOD OF DISCOVERING POSSIBLE CARCINOGENIC HAZARDS IN MAN The most commonly expressed objection to regulatory decisions based on carcinogenesis observed in animal experiments is that the high dosages to which animals are exposed have no relevance in assessment of human risks. It is therefore important to clarify this crucial issue. Practical considerations in the design of experimental model systems require that the number of animals used in experiments on long-term exposure to toxic materials will always be small, compared with the size of the human populations similarly at risk. To obtain statistically valid results from such small groups of animals requires the use of relatively large doses so that effects will occur frequently enough to be detected. For example, an incidence as low as 0.01% would represent 20,000 people in a total population of 200 million and would be considered unacceptably high, even if benefits were sizable. To detect such a low incidence in experimental animals directly would require hundreds of thousands of animals. For this reason, we have no choice but to give large doses to relatively small experimental groups and then to use biologically reasonable models in extrapolating the results to estimate risk at low doses. Several methods of making such calculations have been considered and used, but we think that the best method available to us today is to assume that there is no threshold, and that the incidence of tumors is directly proportional to dose. However, it is important to recognize that such calculations may give either too small or too large an estimate risk. The actual risk to humans might be even greater over a human lifetime, because it is about 35 times that of a mouse; and there is evidence that the risk of cancer increases rapidly with the length of exposure. Moreover, experimental assays are conducted under controlled dietary and environ

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56 DRINKING WATER AND H"LTH mental conditions with genetically homogeneous animals, whereas humans live under diverse conditions, are genetically heterogeneous, and are likely to include subpopulations of unusual susceptibility. It should be emphasized that these general considerations give only a minimal estimate of human risk; moreover, they do not take into consideration differences in susceptibility between species. For example, beta-naphthylam~ne is well established as a human carcinogen on the basis of epidemiologic studies of occupationally exposed workers, whereas experiments have not shown it to be carcinogenic in the hamster, which is relatively resistant. Not all substances that cause a given incidence of cancer in the rat are equally carcinogenic for man. This means that chronic-toxicity studies, which are imperfect assay systems for carcinogenicity testing, should not be used as the sole criterion in the assessment of risk. Principle 4 MATERIAL SHOULD BE ASSESSED IN TERMS OF HUMAN RISK, RATHER THAN AS SAFE OR UNSAFE The limitations of the current experimental techniques do not allow us to establish safe doses, but with the help of statistical methods we may be able to estimate an upper limit of the risk to human populations. To calculate such a risk, we need data to estimate population exposure; a valid, accurate, precise, and reproducible assay procedure in animals; and appropriate statistical methods. Several general guidelines may be presented. First, no rigid, generally applicable procedure can be recommended for testing all toxic agents. Substances diner too much in their overall effects, and the design of appropriate assays will ultimately have to be left to the well-informed judgment of expert investigators. If substances that affect large populations are found to be carcinogenic, experiments of much wider scope may have to be conducted to obtain more detailed information on their possible ejects in humans. As a pragmatic guideline, it would be desirable to test a compound for carcinogenicity in at least two species, such as the mouse and the rat, and the strains of animals used should have a rather low incidence of spontaneous tumors under the conditions of the test. It is important to include "positive" controls, with known carcinogens, under the same conditions used for the test animals. This has been a point of considerable controversy. Experiments should be conducted over as much of the lifetime of the experimental animal as possible. The highest dose should be the

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Chemical Contaminants: Safety And Risk Assessment 57 maximum that is tolerated without shortening the lifespan through causes Other than cancer. Every animal, whether it dies during the exposure period or is sacrificed at the end of the experiment, should be examined grossly and microscopically, and all toxic effects (not only cancer) should be noted. Risk constitutes but half the essential comparison that should be made in the assessments of human hazard; the other half is benefit to the exposed population of the agent for which hazard has been identified. Decisions cannot involve merely the risk. Statements of benefits should include the nature, extent, and recipient of the benefit. Technology has always been associated with some risk. But the acceptability of risk should depend on the specific benefits derived, the nature of the population exposed, and the availability of practical alternatives. It is not possible to guarantee a risk-free society; nor is a risk-free society necessarily the best society. It is often necessary to accept the risks of chemicals such as drugs and pesticides when the benefits warrant their use. Risks imposed on persons who gain no benefits are generally not acceptable. Personal choice and personal values enter into the risk- benefit comparison. For major benefits- for example, in the treatment of otherwise incurable or incapacitating diseases much higher risks are allowable than otherwise. An important principle in risk-benefit assess- ment is that each person must be allowed the widest possible choice supported by full information on risks, as well as benefits so that intelligent choices may be made. The benefit portion of the equation should be well defined by knowledgeable experts, and based on data at least as good as the risk data. It is important, therefore, that the benefit-risk comparisons be established with the active cooperation of people who are qualified to assess the usefulness of a substance and the consequences to those in need of it, as well as to the population at large. Finally, mankind is already exposed to many carcinogens whose presence in the environment cannot be easily controlled. In view of the nature of cancer, the long latent period of its development, and the irreversibility of chemical carcinogenesis, it would be highly improper to expose the general population to an increased risk if the benefits were small, questionable, or restricted to limited segments of the population. Principles To Be Used for Noncarcinogens and Nonmutagens The nature and reversibility of the toxic eject must be considered. For carcinogens that are not shown to be mutagens, some sort of extrapolation must be postulated.

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58 DRINKING WATER AND H"LTH For noncarcinogens for which it seems likely that there are thresholds for toxic ejects, the acceptable dose should be below the threshold. If a threshold cannot be shown, the acceptable dose must be related to the data from animal experimentation and consideration of the seriousness of the toxic effects, as well as the likelihood and ease of reversibility, the variability of the sensitivity of the exposed population, and the economic and health-related importance of the material. RESEARCH RECOMMENDATIONS Research must be supported to develop an understanding of the mechanisms by which water pollutants produce toxic effects. This includes pharmacokinetics, tox~cation-detoxication mechanisms, and biochemical and pathological mechanisms of action. Estimates of margin of safety can be made more precisely and rationally as more is known about what happens to a chemical in the body and what the chemical or its metabolites do to the body. The results of such research also are necessary to develop rapid, inexpensive, accurate screening tests for various critical forms of toxicity. It is recognized that much of this research is going on, but the Committee is convinced that more must be done. In protecting the population of the United States from environmental pollution there is no more important or potentially- productive effort than the support of this kind of research. Since these studies are long-term in nature and must be closely coupled to basic biomedical research, they should be supported primarily by research rather than regulatory agencies. There are many research needs in the field of chronic disease epidemiology. Manpower is in critically short supply. There are critical problems of data resources. Research on statistical methods and mathematical models for estimat- ing low dose ejects should be encouraged. Statistical work is pratically nonexistent for effects other than carcinogenesis. Although a consider- able effort has been expended on dose-response estimation for carcino- genesis, very little has been done on species variability and susceptible subgroups. This area could at least be studied from an empirical standpoint so that there would be a better understanding of the precision of low-dose risk estimates. These recommendations are summarized below: 1. Studies of the physiological and biochemical mechanisms by which the toxic substances in water produce their ejects.

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Chemical Contaminants: Safety And Risk Assessment 59 2. Development of rapid, inexpensive, and precise tests to identify substances that may produce important toxic ejects at low doses and dose rates. 3. Epidemiological studies of chronic disease. 4. Research on statistical methods and analytical models for describ ing and estimating the ejects of long exposure to low doses of toxic substances. Studies should not be limited to carcinogenesis and should consider, also, differences between species, and particularly sensitive subgroups in the population. REFERENCES Ames, B.N. 1976. Carcinogenicity tests. (Letters) Science 191 :241-245. Arley, N., and S. Iversen. 1952. On the mechanism ofexperimentalcarcinogenesis.VI. Hit theory interpretation of some experiments of Berenblum and Shubiko Acta Path. Microbial. Scand.31: 164 171. Armitage, P., and R. Doll. 1954. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer 8: 1-12. Armitage, P., and R. Doll. 1957. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br. J. Cancer 11: 161-169. Armitage, P., and R. Doll. 1961. Stochastic models for carcinogenesis. In Proceedings of the Fourth Berkeley Symposium on Mathematical Statistics and Probability, vol. 4, pp. 19- 38. University of California Press, Berkeley and Los Angeles. Barendsen, G.W. 1975. The effectiveness of small doses of ionizing radiations for the induction of cell reproductive death, chromosomal changes and malignant transforma- tion. Presented at 5th Symposium on Microdosimetry, Verbania Pallanza, Italy, Sept. 22. Berenblum, I., and P. Shubik. 1947. A new quantitative approach to the study of the stages of chemical carcinogenesis in the mouse's skin. Br. J. Cancer 1:383-391. Berenblum, I. 1974. Carcinogenesis as a Biological Problem. North Holland Publ. Co., Amsterdam/Oxford. 376 pp. Brown, C.C. 1975. Personal Communications. Brown, J.M. 1976. Linearity versus nonlinearity of dose-response for radiation carcinogen- esis. Health Physics 31:231-245. Burch, P.R.J. 1960. Radiation carcinogenesis: A new hypothesis. Nature 185:135-142. Bush, M.T., G. Berry, and A. Hume. 1966. Ultra-short-acting barbiturates as oral hypnotic agents in man. Clin. Pharmacol. Ther. 7:373-378. Casarett, L.J., and J. Doull, eds. 1975. Toxicology: The Basic Science of Poisons, pp. 11-25. Macmillan Publ. Co., New York. Cleaver, J.E. 1968. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652~56. Conney, A.H., and J.J. Burns. 1972. Metabolic interactions among environmental chemicals and drugs. Science 178:576-586. Cattier, H., M.W. Hess, H.U. Keller, P. Luscieti, and B. Sordat. 1974. Immunological deficiency states and malignancy. In Interaction of Radiation and Host Immune Defense Mechanisms in Malignancy. Proceedings of a Conference at Greenbrier, West Virginia, March, pp. 3(~4.

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62 DRINKING HER MID H"~H ail, C.S. 1972. S~1ishcs vs. s^V racers and sdent~c ju_nt ~ He eviction of =~ far man. l~col. Pal. Sol. 21:45~3. Witty, A., and J.B. KeDer. inactive ~eodes of Crests. in press. Yummy, K., a~ K. Iffy. 1915. ~h~n~De Stumble Oar die Pa~o~nese tier Epi~elial~s~ste. Mitt. red. Fat. go 15: 295~.