1
Introduction

Each of us personalizes values of risk whenever we cross the street, fly in an airplane, or learn of possible threats to our health and well-being. Risks associated with the presence of possible cancer-causing agents in the air we breathe, the water we drink, or the food we eat, evoke a large emotional response—often demanding a full evaluation of the source and immediate correction of the situation. The safety of air, water, and food is considered beyond the average citizen's control; it is regulated, monitored, and evaluated by laws and government agencies. However, a steady flow of articles and reports describes the risks associated with exposure to chemicals that may be present in many situations. These reports have saturated the capacity of most people to differentiate the important from the trivial and to discriminate fact from hypothesis.

In the past 50 or 60 years, our knowledge of nutrition and the role it plays in human health has developed enormously. This same period has seen vast improvements in the safety of the U.S. diet, with technological advances in preservation and shipment of foods and with our ability to identify and reduce risks from various food hazards.

The U.S. diet contains both naturally occurring and synthetic substances that are known or suspected to affect cancer risk. Although many substances present in the food supply have been shown to increase cancer risks under certain conditions—usually not the conditions encountered in consuming food—others may, in fact, decrease risk. The level of risk associated with a carcinogenic



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--> 1 Introduction Each of us personalizes values of risk whenever we cross the street, fly in an airplane, or learn of possible threats to our health and well-being. Risks associated with the presence of possible cancer-causing agents in the air we breathe, the water we drink, or the food we eat, evoke a large emotional response—often demanding a full evaluation of the source and immediate correction of the situation. The safety of air, water, and food is considered beyond the average citizen's control; it is regulated, monitored, and evaluated by laws and government agencies. However, a steady flow of articles and reports describes the risks associated with exposure to chemicals that may be present in many situations. These reports have saturated the capacity of most people to differentiate the important from the trivial and to discriminate fact from hypothesis. In the past 50 or 60 years, our knowledge of nutrition and the role it plays in human health has developed enormously. This same period has seen vast improvements in the safety of the U.S. diet, with technological advances in preservation and shipment of foods and with our ability to identify and reduce risks from various food hazards. The U.S. diet contains both naturally occurring and synthetic substances that are known or suspected to affect cancer risk. Although many substances present in the food supply have been shown to increase cancer risks under certain conditions—usually not the conditions encountered in consuming food—others may, in fact, decrease risk. The level of risk associated with a carcinogenic

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--> agent depends on both the potency of the agent and the level of exposure to it. Carcinogenic potency can be estimated, fairly crudely, using clinical and epidemiologic data on humans or toxicologic data derived from animal cancer tests. Potency of chemical carcinogens varies over a wide range. Ames et al. (1987) introduced a useful measure of carcinogenic potency known as the human exposure/rodent potency (HERP) index. The HERP index reflects the ratio of human exposure to carcinogenic potency determined in rodents; the larger the value of the HERP, the closer the level of human exposure to the dose estimated to cause a 50% excess cancer risk in animals (Gold et al. 1992). Over the past decade, Ames and his colleagues have assembled a Carcinogenic Potency Database (CPDB), which now contains information on the potency of over 1,000 chemicals evaluated in animal cancer tests. However, neither toxicokinetic nor mechanistic considerations are included in this assessment. Exposure to carcinogenic agents present in the diet depends on both food consumption patterns and the concentration of the particular agent in foods consumed. Food-consumption data can be collected by the maintenance of food diaries or by national surveys or questionnaires designed to gauge how often specific foods are consumed or to identify by recall those foods recently consumed. Concentrations of specific, known carcinogenic agents in the food supply can be determined by analytic techniques, such as chemical analyses for pesticide residues present in foods as consumed. Using data from the CPDB, Ames et al. (1990a) compared the potency of naturally occurring compounds with synthetic (chemical) agents found in food that are capable of causing cancer in animals. They argue that the toxicology of synthetic chemicals is similar to that of natural chemicals, which represent the great majority of chemicals present in the human diet. Ames et al. (1990b) note that plants have evolved bioactive compounds to protect themselves from fungi, insects, and predators. Of 50 such natural ''biocides" evaluated in animal cancer tests, about half have demonstrated

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--> carcinogenic properties, a number similar to the proportion of synthetic chemicals that test positive. Considering plant biocides as "natural pesticides," Ames concluded that the amount of such naturally occurring compounds in the diet far exceeds that of residues of synthetic pesticides used to enhance agricultural productivity. Inferences about dietary cancer risks are complicated by the fact that the human diet is a highly complex mixture containing a large number of chemical substances that are mostly natural, but also some that are synthetic. Some chemical substances and mixtures, such as pesticide residues, spices and flavoring agents, and indirect food additives, are usually present only in very low concentrations; other macroingredients such as saturated fats comprise a large percentage of the total diet by weight. Dietary cancer risk assessment thus requires study both of the risks associated with individual microcomponents and macrocomponents of the diet and of the manner in which their effects may be modified when consumed as part of the total diet. One's diet is the result of individual choice and depends on many variables: ethnic custom, economic availability, personal likes and dislikes, fads, etc. Although risk assessors state that risk estimates are a statistical expression of probability, the lay public often wants to know the meaning of such a risk to the individual. For example, a risk estimate of 1 in 10,000 means that up to one additional death (or case of cancer) from a designated cause, in a population of 10,000 people, may occur in the next 70 years. The controversial concept of de minimis is generally recognized to represents one additional death (or case of cancer) from a designated cause, in a city of one million people, expected in the next 70 years. One approach used for translating risks into more personalized terms is to rank them by developing a scale of comparative risks. Is the danger of death from a shooting in Washington, DC, greater than the risk associated with smoking a full pack of cigarettes per day for 40 years? Or is the cancer risk from exposure to a chemical by eating a charbroiled

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--> steak greater than the risk of driving from Dallas to Chicago? Some feel that in such a personalized ranking, the statistical probability of risk may be translated into meaningful lay terms. However, individuals perceive risks in different ways, and voluntary risks may be perceived differently from involuntary ones. Estimates of dietary cancer risks are subject to uncertainty. Specifically, uncertainty exists about the potency of carcinogenic substances, about food consumption patterns, and about the concentration of carcinogenic—as well as anticarcinogenic—constituents in foods. When inferences about human risks are based on laboratory studies using animals, several reasons for uncertainty exist: uncertainty about extrapolations from the high-dose levels used in the laboratory to the lower levels of exposure typical of the human diet; about the relative sensitivity of animals and humans to the effects of carcinogenic or anticarcinogenic agents; about the relevance of the animals themselves as suitable surrogates for humans; and the possibility of interindividual variations in susceptibility related to age, body size, and specific inherited or acquired factors. These uncertainties are nearly always addressed by using conservative assumptions or procedures intended to err on the side of overstating the probable risk. Thus, the result is often considered to be a plausible, but a probable upper bound of human risk, accompanied by great uncertainty. In evaluating dietary cancer risks, it is important that this uncertainty be recognized and, if possible, characterized. Epidemiologic studies suggest that a diet with excess fat and caloric intake levels increases risk for some cancers. Studies with rodents have likewise documented the role of excess calories in sensitivity to chemicals that cause cancer. This is a highly important factor to consider in the United States where—although most people recognize that there is a relationship between diet and health and that a life style including a well-balanced, nutritionally adequate diet can have a positive effect on the quality and duration of life—more than 3 in 10 adult Americans weigh at least 20% in excess of their ideal body weight (Kuczmarski et al. 1994).

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--> Animals maintained on a calorie-restricted diet have shown significant reduction in the rate of onset of tumor formation and adverse toxicity to chemicals recognized to initiate cancer or cell death. The specific relevance to humans of this caloric restriction is, as yet, undetermined. However, the inclusion in the human diet of vegetables and fruits is associated with a decreased risk of cancer. This association may be due to one or more of several causes: the antioxidant or other biological effects of specific vitamins or polyphenols; the protective effect of fiber; the inhibition of those enzymes functioning in the enzymatic conversion of pro-carcinogenic chemicals to carcinogens; the enhanced synthesis of enzymes (often the conjugating enzymes) that combine with reactive metabolites to form inactive derivatives; the stimulation of enzymes participating in the repair of modified DNA; or other mechanisms yet to be discovered. Other dietary components induce the synthesis of detoxifying enzymes, thereby reducing the formation of toxic oxygen products, such as the superoxide anion, formed by redox reactions of quinones. This report focuses on the presence of naturally occurring chemicals that might be carcinogenic ("naturally occurring carcinogens") in the diet of the average U.S. citizen and compares the risk from these chemicals with synthetic chemicals that may also be present in the food we eat. Although much of the current concern about the risks of naturally occurring carcinogens is motivated by concern about the potential effects of bioactive natural chemicals, the committee addressed the broader comparison between naturally occurring chemicals that may possess carcinogenic potential and other naturally occurring dietary carcinogens, such as aflatoxin and other mycotoxins. Naturally occurring agents suspected of carcinogenic activity are frequently normal chemical constituents of foods, or they may be chemicals formed during the processing, cooking, or storage of foods. They range from those chemicals that function as part of the plant's normal physiology (e.g., plant hormones, such as auxins, gibberellins, cytokinins, ethylene, and abscisic acid required

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--> for growth and development); or naturally occurring protective chemicals that make up the defense system against diseases or predators (phytoalexins); or color and aroma chemicals (anthocyanins and monoterpenes) that serve as pollinator attractants, repellants, or feeding inhibitors to limit the predation of herbivorous pests; to those chemicals that are formed as breakdown products of naturally occurring chemicals during the preparation of a food (e.g., pyrolysis products of amino acids generated during the charbroiling of meat and fish). For the chemist, there is no distinction between a naturally occurring chemical and its equivalent counterpart, a manmade (synthetic) chemical. One significant operational difference, however, is that naturally occurring chemicals in the food supply are not subject to the same government regulations as manmade chemicals, a fact that raises questions about their safety and role as a possible threat to the health and well-being of an individual. In 1938, the U.S. Congress passed the Food, Drug, and Cosmetic Act, which contained food-related provisions, such as tolerances for unavoidable toxic substances, and prohibited the marketing of any food containing such substances. In 1948, the Miller Pesticide Amendment was passed by Congress to streamline procedures for setting safety limits for pesticide residues in raw agricultural commodities. The Food Additive Amendment, which contains the "Delaney Clause," was passed on September 6, 1958. That clause states that no additive (either natural or manmade chemical) is to be permitted in any amount if it has been shown to produce cancer in animal studies or in other appropriate tests. This amendment also provides that an additive may be permitted at not more than the amount necessary to produce the intended effect. The amendment does not apply to all food ingredients, because it excludes substances classified as "generally recognized as safe" (NRC 1984), as well as several other categories of food components. The Color Additive Amendment, enacted in 1960, allowed the Food and Drug Administration (FDA) to regulate the

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--> conditions of safe use for color additives in foods, drugs, and cosmetics, and to require manufacturers to perform tests to establish safety. The Food, Drug, and Cosmetic Act and its various amendments are administered by the FDA. These regulations affect approximately 60% of the food produced in the United States. (The remaining 40% is under state regulations, which in many cases are tailored after federal legislation [NRC 1989]). These highly compartmentalized laws are concerned in part with what humans put into food, rather than with what occurs naturally. In addition, at the time each part of the legislation was drafted, many of the questions being asked today—particularly involving quantification—were not (and could not be) envisioned, much less answered. Furthermore, increasingly sensitive, sophisticated technologies have been developed that can detect minuscule amounts of chemicals, unimaginable when these legislative initiatives were enacted, and when "not detectable" meant "safe." But what of the naturally occurring carcinogens? How many of them are there? What is the burden of exposure for the average person? Is there a difference in the ability of natural and synthetic chemicals to cause or prevent cancer? The report presented here attempts to address these questions. Plants are the major source of naturally occurring chemicals. Historically, in addition to serving as a major food source, they have served as a source of medicines, potions, amulets, poisons, and panaceas to alleviate pain and cure illnesses, enhance physical and sexual performance, or terminate a rival. A vast history of folk medicine exists based on the cumulative experience of observations and trials through centuries. Even today there remains a constant search for chemicals in plants (phytochemicals) that can serve as therapeutic agents. The plant kingdom is a vast reservoir of chemical variety. It is estimated that millions of chemicals are synthesized by plants as a result of the diversity of products that biochemical processes have produced over millions of years. Many chemicals present in the growing plant are modified during

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--> harvesting, storage, processing, and cooking, making the listing of all the chemicals present in the diet a gargantuan task. Very few of them have been tested to determine if they are carcinogens. Do naturally occurring and synthetic chemicals, considered as general classes, differ in their chemical and physical properties? Can the principles and techniques used for the evaluation of the carcinogenic and toxic properties of synthetic chemicals be used in the evaluation of naturally occurring chemicals? As examples for comparing the characteristics of naturally occurring and synthetic carcinogens, the committee used peroxisome proliferators, nitrosamines, hydrazines, phenolic antioxidants, methylenedioxyphenyl (benzodioxole) compounds, sodium salts (e.g., saccharin and ascorbate), aromatic amines, and naturally occurring versus synthetic 2u-globulin binding compounds. Each of these was considered as a single chemical species (not present as mixtures), evaluated using the rodent carcinogen bioassay system currently employed to assess the cancer-causing properties of a chemical. The committee considered whether the same principles governing toxicity and carcinogenicity apply to a naturally occurring chemical and a manmade chemical. Unexplored were questions evaluating the importance of so-called "organic foods" and claims that they protect an individual by reducing the level of exposure to a potentially deleterious synthetic chemical in the food supply. Statement of Task and Deliberations of the Committee The Committee on Comparative Toxicity of Naturally Occurring Carcinogens was convened in 1993 by the National Research Council of the National Academy of Sciences on the recommendation of the Board on Environmental Studies and Toxicology. The committee was charged to "examine the occurrence, toxicologic data, mechanisms of action, and potential role of natural carcinogens

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--> in the causation of cancer (in humans), including relative risk comparisons with synthetic carcinogens and a consideration of anticarcinogens." In addition, the committee was charged to "include the assessment of the impact of these materials (natural carcinogens) on initiation, promotion, and progression of tumors." It was also charged to "focus on the toxicologic information available for natural substances" and to "develop a strategy for selecting additional natural substances for toxicological testing." The committee met frequently during its 2 years. A number of distinguished individuals presented their views to the committee, and a public forum was scheduled for the presentation of comments by interested individuals and organizations. The committee was burdened by the complexity of the issues involved and the paucity of data available for analysis. Extensive discussion of key issues resulted in consensus—based many times on the best professional judgment of the committee members. Readers seeking rigorous scientific evidence on the issues will need to review the many references included in the report. Considerably more research will be required to identify the comparative risks for cancer of naturally occurring chemicals ranked against manmade chemicals. The committee has identified the directions for this research that it considers most promising to resolve scientifically testable hypotheses. Factoring in the elements of life style as contributors to any calculation of risk must be considered as unresolved, except for the oft-repeated admonition to reduce calories as a risk factor for cancer as well as heart disease. It should be noted that although the committee was charged to assess the impact of naturally occurring carcinogens on initiation, promotion, and progression of tumors, it is difficult to define precisely these stages in most animal model systems and especially in human carcinogenesis. It is particularly difficult to classify chemicals or other agents as initiators, promoters, or progressors. It was decided to use more contemporary and accurate terminology. This report addresses the impact of agents in carcinogenesis in

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--> terms of DNA reactivity or DNA and chromosome damage (genotoxicity) and DNA replication and possible other nongenotoxic effects. This subject is covered in detail in Chapter 3 of the report. The committee also viewed its charge to address toxicologic issues as limited to cancer. Definitions For the purpose of this report, the term diet refers to the foods and beverages one consumes intentionally and customarily, not as a result of accident or deprivation. The diet will vary depending on age, customs, preferences, and availability of foods. It is not possible to describe a diet that will be common for all humans, not even when restricted to the confines of a single country, particularly not in such a country as the United States, with its population of multiethnic origins. Most significant are differences in the diets of infants and young people (NRC 1994). Diets often include at least low levels of potentially hazardous substances associated with some common foods and beverages. Estimates of exposure to these hazardous substances may be determined from knowledge of the aggregate amount of food consumed—but data permitting the further identification of food consumed by subgroups of the population are largely lacking. The term naturally occurring chemicals comprises those that are constitutive, derived, acquired, pass-through, or added (see Table 1-1). In addition to these naturally occurring chemicals, food often contains a number of synthetic chemicals, although at a far lower level and in less variety. An additive is any minor ingredient added to food to produce a specific effect. Direct additives include natural and synthetic noncaloric sweeteners, antioxidants, colorants, flavor ingredients, and preservatives. Indirect additives are those chemicals present in the food because of their use in raw or packaging materials but no longer effective in the food as sold

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--> Table 1-1 Definitions Term Definition Examples Constitutive naturally occurring substances Substances synthesized by physiological and biochemical processes present in food organisms themselves Furano coumarins, isoflavanoids, phytoalexins, cutins, alkaloids Derived naturally occurring chemicals Substances formed as a result of the breakdown of constitutive chemical during stress, storage, processing, and preparation of foods Polycyclic hydrocarbons, pyrazines, and heterocyclic amines that provide characteristic flavor of roasted and cooked foods—coffee, chocolate, nuts, meats, and browning products that add color and flavor to foods, such as toast and tawny port wine Acquired naturally occurring chemicals Substances present by infection or spoilage caused by bacteria or fungi or passively acquired from the environment Aflatoxin B1 or botulism toxin, as well as chemicals such as the residues of persistent pesticides no longer used but remaining in the soil Pass-through naturally occurring chemicals Materials present in animal products consumed by humans that are derived from food eaten by an animal Any seafood toxins sometimes present in shellfish, toxol in snakeroot, or aflatoxin, which can appear in cows milk, or arsenic (a carcinogenic, toxic metal found naturally in seawater and marine microorganisms), assimilated by shrimp from consumed zooplankton

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--> Term Definition Examples Added naturally occurring chemicals Constitutive or derived naturally occurring substances that are isolated from raw or traditionally processed plant or animal sources then added to the same or other foods Sucrose, glucose, isolated soy protein used in infant formulas, flavors extracted or distilled from spices, numerous gums and starches (e.g., corn or tapioca starch) that, because of specific functional characteristics, are used in other food and consumed. Examples are pesticides, solvents, and chemicals derived from packaging. The definition of carcinogen proposed by IARC is used in this report: a carcinogen denotes any agent, exposure to which is capable of increasing the incidence of malignant neoplasia (IARC 1993). The term exposure is restricted to mean the amount of a naturally occurring substance ingested orally in the human diet. The substance may be a solid or liquid. The presence of a specific chemical in a food may vary greatly for the reasons discussed in the report. Of greater relevance to safety, however, is the amount of a chemical determined as the form absorbed, distributed, and metabolized in the body for presentation at a target organ. A carcinogenic risk factor is a contributor to the process of tumor formation and growth. For example, the diet is a source of calories (dietary energy, now often expressed as joules) derived from fats, carbohydrates, and proteins. Calories in excess of body needs can serve as an important contributor to cancer (Kritchevsky 1995). Likewise, smoking or alcohol consumption may serve as confounding life-style risk factors when considering the statistics associated with the frequency of occurrence of neoplasia in relation to diet. The committee recognized that the diet consists of a complex mixture of natural and synthetic chemicals and

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--> that additive, synergistic, or inhibitory interactions may occur between chemicals, influencing one or several steps in the multistage mechanisms associated with the formation and development of cancers. Toxicity is defined by the dose at which adverse effects are produced by chemicals. Many chemicals, either natural or manmade, that induce cancer require metabolic activation for conversion from a procarcinogen to a carcinogen. For the purpose of this report, the terms procarcinogen and carcinogen will be used interchangeably, except where identified. Other terms used in this report include anticarcinogens known to inhibit the formation of cancers or the growth of tumors. (Carcinogens and anticarcinogens are not mutually exclusive, as discussed in detail in Chapter 2.) More than 600 chemicals are claimed to be anticancer agents. These range from natural chemical constituents present in garlic, broccoli, cabbage, and green tea, to manmade antioxidants, such as butylated hydroxyanisole (BHA) and derivatives of retinoic acid. Much about how anticarcinogens act remains to be explained before they can be considered and employed as an effective part of any anticancer strategy. Structure of the Report The results of the committee's deliberations are found in the chapters that follow. Chapter 2 provides an analysis and assessment of naturally occurring chemicals that may be carcinogenic in the diet, as well as anticarcinogenic chemicals. The chapter discusses exposure, the effects of processing and contamination on the formation of carcinogens, and the effects of macronutrients and micronutrients in carcinogenesis. Chapter 3 presents an overview of direct and indirect synthetic food additives that might be carcinogenic and provides comparisons with naturally occurring chemicals. Chapter 4 discusses methods for evaluating potential carcinogens

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--> and anticarcinogens, from studies in human populations to rodent bioassays and various short-term tests, and provides criteria for selecting and testing of carcinogens and anticarcinogens. Chapter 5 addresses the following critical questions: Does dietary exposure to naturally occurring carcinogens differ from dietary exposure to synthetic carcinogens? Do the potencies of naturally occurring and synthetic carcinogens differ (also addressed in Chapter 3)? Does cancer risk due to naturally occurring substances in the diet exceed that due to synthetic substances? Do naturally occurring and synthetic substances cause cancer by similar mechanisms (also addressed in Chapter 3)? Does diet contribute to an appreciable proportion of human cancer? Are there significant interactions between either synthetic or naturally occurring carcinogens and anticarcinogens in the diet? Chapter 6, the final chapter, provides the committee's conclusions and recommendations for future directions. References Ames, B.N., R. Magaw, and L.S. Gold. 1987. Ranking possible carcinogenic hazards. Science 236:271-279. Ames, B.N., M. Profet, and L.S. Gold. 1990a. Nature's chemicals and synthetic chemicals: comparative toxicology. Proc. Natl. Sci. U.S.A. 87:7782-7786. Ames, B.N., M. Profet, and L.S. Gold. 1990b. Dietary pesticides (99.99% all natural). Proc. Natl. Acad. Sci. U.S.A. 87:7777-7781. Gold, L.S., T.H. Slone, B.R. Stern, N.B. Manley, and B.N. Ames. 1992. Rodent carcinogens: Setting priorities. Science 258:261-265. IARC (International Agency for Research on Cancer). 1993. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.

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--> Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins. Volume 56. Lyon, France: IARC. IOM (Institute of Medicine). 1984. Cancer Today: Origins, Prevention, and Treatment. Washington, D.C.: National Academy Press. 132 p. Kritchevsky, D. 1995. Fat, calories and cancer. Pp. 155-165 in Dietary Restriction: Implications for the Design and Interpretation of Toxicity and Carcinogenicity Studies. R.W. Hart, D.A. Neumann, and R.T. Robertson, eds. Washington, D.C.: ILSI Press. Kuczmarski, R.J., K.M. Flegal, S.M. Campbell, and C.L. Johnson. 1994. Increasing prevalence of overweight among US adults: The National Health and Nutrition Examination Surveys, 1960-1991. JAMA 272(3):205-211. NRC (National Research Council). 1989a. Diet and Health: Implications for Reducing Chronic Disease Risk. Food and Nutrition Board, Committee on Diet and Health. Washington, DC.: National Academy Press. NRC (National Research Council). 1989b. Drinking Water and Health. Vol. 9. Selected Issues in Risk Assessment. Washington, DC: National Academy Press. NRC (National Research Council). 1994. Science and Judgment in Risk Assessment. Washington, DC: National Academy Press.

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