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CHAPTER 5 APPLICATION OF THE MODEL TO CHEMICAL HAZARDS The Committee on the Scientific Basis of the Nation's Meat and Poultry Inspection Program (NRC, 1985 ~ described the various sources of chemical residues in meat and poultry products and the approach used by FSIS to control them. That committee also made several recommendations for improving the FSIS inspection program and urged the adoption of formal risk-assessment procedures to provide maximum protection of public health. Specifically, the committee recommended that risk assessment play a major role in the establishment of limits for chemical residues in meat and poultry products destined for human consumption, in the prevention and characterization of hazards, in the setting of priorities for controlling residues, and in the design of sampling methods. This chapter contains a discussion of risk assess- ment as a guide to the management of chemical hazards in poultry products, criteria for j udging the safety of poultry products con ~ tanning residues, some approaches to ensuring that safety criteria are met, and the types of data and analysis needed to assess the public health impact of chemical residues in poultry products. It also identifies the necessary elements of a risk-management program and describes the risk-assessment methods needed to establish this program . It does not include cons iteration of current FSIS inspection which is evaluated in subsequent chapters of the report. &; ~ GENERAL METHODS FOR ASSESSING THE PUBLIC HEALTH RISKS OF CHEMICALS There is extensive documentation on deaths and injuries from accidental poisonings by household products, pesticides, and thera- peutic agents. Ordinarily there is little difficulty in estimating the relationship between the extent to which these substances are used and the frequency of poisonings and in documenting the association between a given exposure and a given poisoning when the effect is immediately observable (i.e., acute). It is more difficult to assess risks associated with chemical exposures when no immediately observable effects are produced when the fact or degree of exposure is itself highly uncertain. Since most chemical exposures associated with residues in poultry products are uncertain, the risks must be predicted and those predictions used to set health protection standards. 100

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101 Although the methods used to predict chemical risks are uncertain (e.g., because of incomplete data, the need to extrapolate beyond data, and the lack of knowledge concerning the extent of future human exposure), they are based on a strong scientific foundation (NRC, 1980b, 1983~. The safe use of products, including food ingredients, pesticides, and drugs, depends upon these methods of risk prediction and their use in the establishment of low risk (or safe) exposures (FSC, 1980~. People are exposed to a large number of naturally occurring and man-made chemicals through poultry products and other environmental media. If they are to be protected from the possible adverse effects of these substances, methods to assess the risk assessment of such exposures must be applied. It is a premise of this report that predictive methods developed for and widely used in many areas of public health protection are appropriate for assessing the risks of exposure to chemical residues, establishing appropriate health protection standards for such residues, and guiding the development of programs to manage the risks presented by the residues. Parts or all of the s premise have been adopted by the Food and Drug Administration, the Environmental Protection Agency, and other government agencies charged with protecting consumers from such residues, especially for risk assessment and the establishment of standards. However, there are important limitations in the methods themselves and in their application to specific problems, including those associated with poultry products. THE COMPONENTS OF RISK ASSESSMENT A National Research Council committee described four basic components of risk assessment in the federal government: hazard identification, dose-response assessment, exposure assesment, and risk characterization (NRC, 1983~. Figure 5-1 shows the relationships between these components of risk assessment, research, and risk management. Hazard Identification Toxicity. All chemical substances, whether natural or man-made, can cause some form of biological injury under some conditions of exposure. The purpose of the first phase of risk assessment is to collect and evaluate information on the inherent toxic properties of chemicals of interest. Identifying these properties is not equivalent to identifying possible risk. Thus, it should not be assumed that a substance displaying toxicity presents a risk to human health. All steps of risk assessment must be completed before any statement can be made about risk.

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103 There are two principal sources of information about the toxic properties of chemical substances: investigations of exposed human populations or individuals Epidemiological or clinical investigations and experimental studies in laboratory animals or other biological systems. Knowledge of the molecular structure of some substances may be helpful in predicting toxic properties, but this aspect of toxicological science is still immature (Asher and Zervos, 1977; Klaassen and Doull, 1980; NRC, 1980b; OSTP, 1985) e Data on Humans. Well-conducted Epidemiological and cl inical investigations provide pertinent data for the evaluation of the hazardous properties of environmental agents. Epidemiological studies have provided convincing evidence about the cancer-causing properties of such agents as cigarette smoke, asbestos, vinyl chloride, and diethylstilbestrol (DES) and about the teratogenic effect of thalidomide. Clinical investigations of exposed persons have provided information on the toxicity of consumer and industrial products (MacMahon and Pugh, 1970; OSTP, 1985~. There are, however, the following limitations in the use of both Epidemiological and clinical data for identifying the toxic properties of chemical substances: The deliberate, controlled exposure of human beings to identify toxic effects is, with few exceptions , unethical. Exceptions include short-term exposures to substances (e. g., certain drugs) that produce mild, fully reversible effects. Epidemiological and clinical studies cannot be conducted on newly introduced chemicals or chemicals for which there has been little or no previous human exposure. Accurate data on the chemical nature of the substances to which populations or individuals may have been exposed and on the intensity and duration of their exposure are rarely available, especially when exposures have taken place in the distant past. It is difficult to provide proper controls for Epidemiological studies when the cause-and-effect relationships of a chemical cannot be easily established, as is the case for chemical workers who may be exposed to unknown amounts of other substances in addition to the chemical of immediate interest. In investigations of diseases with long latent periods, such as cancer, it is usually difficult to follow exposed persons for periods long enough for the disease to reach a clinically detectabl e state and thus for firm conclusions to be drawn about the presence or absence of an effect. Epidemiological studies cannot generally detect small but possibly important changes unless the study population is very large (rarely practicable) or the resulting disease is rare (e.g., occurrence of vaginal adenocarcinoma during adolesence in daughters of mothers given DES during pregnancy).

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104 Because of these limitations, public health officials must frequently turn to experimental data for information about the toxic properties of chemicals in the environment. Experimental Animal Data. Laboratory animal studies have an advantage over epidemiological and clinical investigations (NRC, 1980b). The experiments can be controlled so that causal relationships between exposure to a substance and toxicity can be established, and the relationship between the intensity and duration of exposure and the magnitude of toxicity can be studied (NRC, 1980b). (See section on Dose-Response Assessment below.) Animals can be studied for functional changes or killed at var' ous times during the experiment and examined for the presence of a variety of biological injuries and pathological changes that are not observable clinically. In rats and mice, the effects of lifetime exposures to an agent can be detected in 2 or 3 years - - the normal lifespan of these species (OSTP, 1985 ~ O These advantages of data from animal studies are partially offset by the obvious fact that animals are not biologically identical to humans. To conclude that some agent can cause a certain form of toxicity in humans because it does so in laboratory animals requires inclusion of some untested assumptions about the biological similarity of various mammalian species. There is evidence that results from animal studies are often applicable to humans. For example, most substances known to be carcinogenic in humans are also carcinogenic in animals. Similar examples could be collected for a variety of other toxic effects (NRC, 1983; OSTP 9 1985 ~ . Exceptions are also common, however . Unless human data are adequate to refute a specific finding of toxicity in animals or there is some other biological reason to do so, it is reasonable to infer a potential for toxicity in humans from observations in experimental studies of animals. Animal experiments are the principal source of toxicity data for assessing the human risks and safety of pesticides, food and color additives, and food and drinking water contaminants, and there is no reason not to rely on such data for similar assessments of chemical residues in poultry products. Manifestations of Toxicity and Tests to Identify Them. Systematic investigation of the toxicity of a chemical substance usual] y begins with a determination of its acute toxicity, which includes a determination of the dose of a substance that in a single exposure (lethal dose) will cause the deaths of the exposed animals within a short time after administration. At successively lower levels of exposure, the percentage of animals that respond decreases correspondingly. The relationship between dose and the percentage of the animal population that dies is called the dose - response relationship for the end point in question- - in this case, death. The range of doses over which deaths are observed and the shape of the dose-response relationship vary from one substance to another, and both are critical to an assessment of a substance's capacity to cause death in an exposed population.

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105 Short-term exposures (i.e., one or several exposures repeated over several days or a few weeks) to chemical substances in amounts lower than the lethal dose may produce toxicity that ranges from mild (e.g., reversible eye or skin irritation or transitory nervous system disorders) to severe (e.g., irreversible blindness or liver damage). The toxic manifestations of a short-term exposure to a chemical depend on the intensity and duration of the exposure and the characteristics of the chemicals (Doull et al., 1980; Loomis, 1978; NRC, 1983~. Studies of short-term exposures are generally followed by studies of long-term exposures to lower doses (chronic toxicity)(NRC, 1980b). These experiments are designed to detect effects that arise after many repeated, sometimes daily, exposures that occur over various periods - - from approximately 10% of an animal ' s lifespan (subchronic toxicity studies) to its ful 1 lifespan (2-3 years for rodents; several times longer for other commonly used animals such as dogs and monkeys) or effects resulting from short- term exposures that do not become clinically detectable until much later (e. g., for DES) . Chronic effects may range from relatively mild conditions to progressive and lethal lesions such as cancer . The form of inj ury or disease and its dose-response characteristics are specific to the chemical, but both these features of chemical toxicity can be altered by characteristics of the exposed animal (e.g. 9 its genetic background, health status, age, or sex) and its environment (e.g., the nature of its diet or the presence of other environmental agents). Such interspecies and intraspecies differences in toxic response and dose-response characteristics for a given substance have strongly influenced the methods used by public health scientists to assess risks. (See section on Risk Characterization below). Subchronic toxicity experiments can reveal much about the potential of a substance to inj ure various organs and systems of the body, including the developing fetus, but they cannot reveal whether a substance can induce cancer (OSTP, 1985), except when it is unusually potent. Determination of carcinogenicity usually requires that test animals be exposed for most of their lifetimes. There are now many well-validated test systems used worldwide by both public health agencies and private concerns to establish the acute, subchronic, and chronic toxicities of chemical substances (EPA, 1982; FDA, 1982b; NRC, 1977~. The most thoroughly tested substances are those that must, by law, be evaluated before they can be introduced into commerce (e.g., food and color additives, drugs, and pesticides)(NRC 9 1985~. Quality and Extent of Data. The quantity and quality of toxicity data available on different substances vary greatly. For a few substances the data base may be extensive and may include results of all the standard toxicity tests as well as data specific to each substance under evaluation, whereas for other substances, the data base

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106 may include, at best, only a determination of acute toxicity or no significant toxicity data at all. For most important industrial chemicals, the quantity and quality of available data fall somewhere between these two extremes, but more toward the lower end of the scale (NRC, 1984~. There is no straightforward way to define the adequacy of a given data base. A data base may be sufficient to determine the safety of a certain use or type of chemical exposure but may be inadequate to determine the risk presented by another use or type of exposure. For example, many agents tested for occupational risk have not been examined for their potential to cause chronic toxicity or birth defects. If such substances show up in the poultry supply because of environmental pollution, the absence of information on chronic effects and their effect on the developing fetus would be of great concern. Similarly, the absence of chronic toxicity data on many chemicals is of concern if the chemicals are found to be present in poultry products to which people could be chronically exposed. The absence of data does not imply that a risk exists, but it does mean that risk (and therefore safety) cannot be ascertained with an adequate degree of confidence. Various methods are used to compensate for such data gaps. These methods are described below in the section on Risk Characterization. Hazard Evaluation. This phase of risk assessment includes a critical review of clinical 9 epidemiological, and experimental toxicity data and identification of the inherent hazardous properties of a substance, the degree to which these hazards are known, and the uncertainties in the data. A critical feature of this process are j udgments about the strength of inferences for human risk from data derived from animal studies . At this stage of risk assessment, no attempt is made to determine the degree of human risk that might be associated with the substance under evaluation. Dose-Response Assessment For an exposure of a given duration, the frequency and severity of toxic effects in an exposed population (the risk) generally increase with increasing dose. Toxic effects may also change as exposure increases. The dose-response relationship is critical to risk assessment and must therefore be well defined. Well-defined dose-response relationships can rarely be obtained from ep~demiological studies because of uncertainty regarding the exposures that produced the toxic responses seen. Therefore, experimental data are the primary sources of dose - response information for risk assessment. The dose of a toxic agent can be expressed in various ways. Most commonly it is presented as the weight (mg) of the agent taken into the body per unit (kg) of body weight (bw) of the human or test animal per unit of time (usually, per day), e.g., mg/kg low/day. Dividing intake by body weight permits comparisons to be made among species with

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107 different average body weights. Other measures of dose, such as mg/kg bw over a lifetime, mg/m of body surface area, parts per million (ppm) in air, water, or diet, are used less often. For most toxic effects, a threshold dose is the amount of exposure that must be exceeded before a specific toxic effect is produced. For other effects such as cancer, however, there appears to be a biological basis for rejecting the threshold hypothesis. As currently practiced, in fact, carcinogenic risk assessment is generally based on the assumption that there is no threshold dose. Rather than entering more fully i nto the complex debate on thresholds, the committee has simply adopted the positions taken by the major regulatory and public health agencies and other NRC committees , i. e., the absence of a threshold for carcinogens . A critical part of dose-response assessment is identification of the dose that produces no adverse response, i.e., the no - observed- effect level (NOEL), in the treated animals. The NOEL is generally taken as the starting point for risk assessment of virtually all effects other than cancer. It may approximate a threshold dose for the animal population under study, but for a variety of reasons the experimentally determined NOEL is probably not identical to the true threshold dose. For carcinogens (even those for which an experimental NOEL for other toxic effects has been determined), the dose-response data are treated differently. The size of the increase in toxic effects at various low doses, where the risk per animal (and by extension, per person exposed) is quite small, is generally of greatest interest but not directly observable because of practical li mits on experi- mentation. Carc~nogenicity data from animal studies generally show that increasingly high doses cause a corresponding increase in the incidence of cancers. However, the doses used in animals are exceedingly high in terms of human risk to compensate for the fact that only small numbers of animals can be used in experimentation of this type (OSTP, 1985~. For example, if 50 animals are exposed to a dose of a carcinogen and 5 develop tumors, the risk is 10% (if no control animals develop a tumor). A cancer risk near 10% would be intolerable in any human setting, but this is about the smallest risk that can be reliably detected in animal experiments of practicable size (OSTP, 1985). The experimentally determined relationship between dose and risk at high doses must therefore be used to assess risk for dose levels corresponding to human exposures. This requires the use of certain mathematical models of the dose-response data (FSC, 1980; NRC, 1980b; OSTP, 1985~. These models generally provide unit risk estimates, i.e., estimates of cancer risk per unit of dose (such as the incidence of cancer at a dose of 1 mg/kg low/day over a lifetime). The models most widely used for low dose carcinogenic risk assessment are based on

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108 assumptions that there is no threshold and that risk at very low doses increases in direct proportion to dose. Several models meet this criterion. EPA uses the linearized multistage model, which incorporates an upper 95% confidence limit on the estimated linear term. Table 5-l presents risks per unit of low dose exposure predicted by this model for substances that are potential contaminants of poultry products. Models used by FDA and the National Research Council's Safe Drinking Ilater Committee (NEt.C5 1980a) would yield unit cancer risks close to those shown in Table 5-1. It Is not possible to demonstrate that any mathematical models are fully in accord with biological reality. Because this subject has been discussed elsewhere (NRC, 1980a; OSTP, 1985), the committee simply notes in this report that certain models are widely used in risk prediction and that they are generally interpreted on the basis of little direct evidence as providing upper limits on low dose risk, although recent data suggest that this may sometimes be wrong (J. C. Bailar, Harvard School of Public Health, personal communication, 1987~. Policy choices needed in the face of scientific uncertainty have also been discussed in another National Research Council report (NRC, 1980b). The dose-response assessment phase of risk assessment thus generally concludes with a determination of NOELs (for noncarcinogenic effects) and of estimates of risk per unit dose (unit risks) for cancers. In both determinations there are important uncertainties that need to be specified in the report of the risk assessment. Since many of these uncertainties concern the data on which these dose-response estimates are based and are therefore chemical- specific, they must be defined by experts who have studied a specific substance. Other uncertainties are generic (e.g., some are inherent in models for extrapolating from high to low doses) and therefore apply to all chemicals. Exposure Assessment Exposure assessment is a highly complex subject, and is reviewed here only to the extent necessary to prepare for the later discussion of chemical residues in poultry products. In this phase of risk assessment, knowledge of the magnitude and duration of human exposure to environmental agents and, most importantly, the dose that results from this exposure, is essential As used herein, the term exposure describes a person's contact with a medium (e.g., poultry) containing a chemical. The magnitude of the dose that results from the exposure depends on several factors, which are described in the following paragraphs O To estimate dose, the possible routes of chemi cat ~ ntake must first be identified. For residues in poultry, ingestion is the only route of concern. Occupational exposures might include inhalation, derma] contact, or other routes of exposure, but these routes are not germane

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109 TABLE 5-1 Unit Cancer Risks and Strength-of-Evidence Categories for 47 Chemicals, as Evaluated by the EPA Carcinogen Assessment Groupa Level of Evidenceb Unit Cancer Risk . . . Compound Humans Animal s per mg/kg bw/dayC Acrylonitrile L S 0. 24(W) Aflatoxin B1 L S 2, 900 Aldrin I L 11.4 Allyl chloride -- -- 1.19 x 10 2 Arsenic S I 15 (H) Benzo ~ a ~ pyrene I S 11 . 5 Benzene S S 2.9 x 10-2(W) Benz idene S S 2 34 (W) Beryllillm L S 2 .6 (W) Cadmium L S 6 . 1 (W) Carbon tetrachloride I S 1. 30 x 10~ Chlordane I L 1.61 Chlorinated ethanes: 1,2-Dichloroethane I S 9.1 x 10-22 Hexachloroethane I L 1.42 x 10- 1,1,2,2-Tetrachloroethane I L 0.20 2 1,1,2-Trichloroethane I L 5.73 x 10- Chloroform I S 8.1 x 10-2 Chromium VI S S 41(W) Dichlorodiphenyltrichloroethane (DDT) I S 0 34 Dichlorobenzidine I S 1.69

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110 TABLE 5-1 (continued) Level of Evidenceb Unit Cancer Risk Compound Humans Animals per mg/kg bw/dayC Dieldrin ~ S 30.4 Ep~chlorohydrin I S 9.9 x 10-3 Bis(2chloroethyl~ether I S 1.14 Bis~chloromethyl~ether S S 9,300(In) Ethylene dibromide I S 41 Ethylene oxide L S 3.5 x lO~l(In) Heptachlor I S 3 . 37 Hexachlorobenzene I S 1. 67 Hexachlorobutadiene I L 7.75 x 10-2 Hexachlorocyclohexane: Technical grade ~ 4.75 Alpha isomer I S 11.12 Beta isomer I L 1.84 Gamma isomer I L 1.33 Nickel refinery dust S S 1.05(W) Nitrosamines: Dimethylnitrosamine I S 25.9(not by q )~ Diethylnitrosamine I S 43.5(not by q Dibutylnitrosamine I S 5.43 N-Nitrosopy~rol~dine I S 2.13 N-Nitroso-N-ethylurea I S 32.9 N-Nitroso-E-methylurea I S 302.6 Polychlorinated biphenyls (PCBs) I S 4.34 Phenols: 2, 4,6-Trichlorophenol I S 1.99 x 10-2 Tetrachlorodibenzo-~-dioxin (TCCD) I S 1.56 x 10+5

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129 If poultry feed and water limits are properly set and enforced, there may still be occasional failures to keep residues within tolerance levels. These failures may have only limited health consequences, however, because tolerance limits for chronic exposure include large safety factors. Although there is no precise definition of an occasional failure, it should be assumed to mean rare occurrence in the life of an individual. When such excursions above tolerance levels are detected, it should be determined whether they present any reason for concern about larger, longer, or more frequent violations of standards. Each such finding should trigger an effort to learn the cause of the problem and to find a remedy. In the context of adequate feed and water controls, it is not possible to predict how long such tolerance violations should be allowed to continue before poultry or poultry products are condemned. However, once a tolerance violation occurs, a risk assessment is needed at times to identify the seriousness of the potential risk. A decision could then be made on the need for condemnation as well as the need to change the feed and water tolerances, alter the production process, or intensify inspection. Activity 7. Enforcement Monitoring programs to manage risks are not effective unless they can ensure that excessively contaminated poultry feed or water is not used and that excessively contaminated poultry products do not reach consumers. Regulatory agencies have long had programs of enforcement to ensure that these objectives are met. The need for such programs is obvious, and no additional justification need be given here. Activity 8. Establishing Priorities Any program based on Activities 1 through 7 will require establishment of priorities. Two monitoring efforts (Activity 5, for feed and water, and Activity 6, for poultry products) require the development of sampling plans that can ensure, with some predetermined degree of confidence, that risk-management objectives are being achieved. As stated above, risk-management priorities and the frequency and intensity of monitoring should be based on risk assessment. For much risk-management planning, only the relative risks of various substances are of concern. A methodology for assessing relative risks is proposed in the following paragraphs. Assessing Relative Risks A scheme for assessing relative risks need not include estimation of the absolute risk of any of the substances to be ranked. It is necessary only that it incorporate in a systematic way some measures of both toxicity and exposure that are as accurate as possible; risk assessment cannot proceed without them. The exposure and toxicity data

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130 on Class 1, 2, and 3 chemicals vary widely in quality and content. These differences should be taken into account in a systematic way. The primary purpose of a relative risk assessment is to ensure that the two major risk-management activities (monitoring of feed and water and monitoring of poultry products, including whole birds) achieve the intended objectives. That is, the degree of risk-management attention accorded a substance is directly related to the probability that it will be found in food intended for human consumption and to the risk it may pose if it escapes detection Two useful measures for ranking relative toxicity are the ADI ~ for noncarcinogens ~ and the UCR. These measures have the following desirable characteristics. They are derived from toxicity data in ways that are now rather well standardized and accepted. Different types of toxicity data gaps are treated in a relatively uniform way for different substances, e.g., by the application of standardized risk- assessment procedures. These measures are based on chronic exposure. They should be estimated for all substances monitored. (Recall that surveillance i s used to identify substances for which risk assessment and tolerances need to be established, whereas monitoring is restricted to substances for which tolerances have been established. ~ These two measures are adequate to rank the chronic toxicities of Class 1 and 2 substances. The committee knows of no other measures that have all the above characteristics. To provide a systematic way of comparing carcinogens and noncarcinogens, it may be necessary to develop a single toxicity scale that integrates both categories of substances. It is possible to derive an ADI equivalent for a carcinogen from its UCR by using certain assumptions about the level of risk considered to be negligible and the level of risk associated with an ADI for a threshold agent. Under the assumptions used to derive UCRs, carcinogens present a nonzero risk at all exposure levels above zero. Nevertheless, it is commonly accepted that for all carcinogens there is an exposure ra5ge that6presents only a small risk, e.g., lifetime risks less than 10- or 10- , which reflect highly unlikely events O It is not possible to demonstrate that an ADI carries absolutely no risk for the human population. At best, all that can be claimed for an ADI is that any potential risk is not likely to exceed some very small but quantified risk In the absence of evidence to the contrary, and to provide two different toxicity scales for carcinogens and noncarcinogens, it may be assumed that the range of risk associated with an ADI is the same as that as that considered to be very small carcinogens ~ i . e ., 10 ~ 5 to 10 ~ 6 ~ . This assumption is presented here only in the context of this specific risk-ranking obj ective to

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131 provide a systematic means for comparing the toxicities of carcinogens and noncarcinogens. It does not imply that the actual risk at an ADI is in the range assumed here. It is further assumed that an ADI for a noncarcinogen will ensure that there is not more than a 10-6 (1 in a million) risk of a toxic effect occurring. An ADI equivalent derived for carcinogens will be taken as the dose estimated to give rise to the same maximum lifetime risk (10-6~. The ADI equivalents for carcinogens can then be directly compared to ADIs for noncarcinogens, because both will have been adjusted for potency and represent the same estimated risk level. Figure 5-2 presents the linear low-dose response of several carcinogens with different UCRs. For each 6f these carcinogens, a dose providing an estimated lifetime risk of 10- can be identified. These ADI equivalents are represented by points for carcinogens A, B. C, And D along the dose scale. Thus, a carcinogen (B) with a OCR of 10- per unit of dose measured in mg/kg low/day would have an ADI equivalent of 0.001 mg/kg/day. A UCR of 10-7 (carcinogen D) would correspond to an ADI equivalent of 10 mg/kg/day. These ADI equivalents can be calculated for the entire range of published UCRs. A representative range of ADIs and ADI equivalents and some possible toxicity ranking scores are presented in Table 5-3. Unfortunately, there appears to be no single, direct measure of potential exposure. Thus , in constructing a ranking system for exposures, many factors must be considered. For example, the following factors all contri bute to potential exposure for Class 1 and 2 substances: 1. The portion of the ADI or other tolerable limit to which people are ordinarily exposed. Frequent exposures to large fractions of the ADI (through poultry products only or through several environmental media) present higher potential risks than occasional exposures to only a small fraction of the ADI. A tolerance violation may have much greater significance for the former than for the latter exposure . 2. The frequency with which the chemical is or is likely to be detected in feed, water, or poultry products. 3. The volume of use for Class 1 substances and the volume of production, industrial use, or natural occurrence for Class 2 substances . 4. The number of birds treated or otherwise exposed. 5. The propensity for bioacc~mulation.

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132 l o _ l in o or C: Sit v o 7 o _ I\ to ; ~ lo lo 70 To lo lo lo, _ _ _, _ _ ~ _ o ASIA - C,9 a oo , _ o En ~-! ~ o .> o c) o sit H ,,4 ~ o F=, ~ - o Cal 1 Us

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133 Table 5-3. Chronic Toxicity Scoringa ADI Range (mg/kg/day) Toxicity Score <10-7 210-7 <10~6 21o~6 <1o~5 210-5-<10-4 210-4-<10-3 210-3 <10~2 >1o-2-< 210~1 <1 2 1 9 8 7 6 5 4 3 2 1 aFrom Environ Corporation, 1985. For non- carcinogens, use ADI; for carcinogens, use an ADI equivalent, than 10-6. assuming a lifetime risk no greater 6. The frequency and magnitude of consumption of the mayor tissues in which residues occur. (Substances accumulating in skin and muscle are of greater concern than those present only in the lung or kidney.) ~ , FSIS should use these six factors to establish a ranking scheme for chemical exposures. Generally, the range of possible scores for potential exposure should approximately equal the range of toxicity scores (i.e., toxicity and exposure should be given approximately equal weight). One such scheme would be to assign a numeric score to each of the six items: for example, a score of 1 or 2 for factors 1 and 5; a score of 0, 1, or 2 for factor 3; and a score of 0, 2, or 4 for factors 2, 4, and 6. The total of these scores divided by 2 would yield exposure scores ranging from 1 through 9. The overall priority ranking system would then be based on a combination of this exposure score with the toxicity score. for examcle. a score of 1 or 2 for factors 1 and 5; a Use of Relative Risk Scores. ranking procedure, one should By systematic application of this able to establish priorities for

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134 monitoring feed, water, and poultry products and to develop sampling plans that are matched to the potential risks . The procedure shou1 d also be useful in establishing ADIs and tolerances for residue levels in poultry products. Use of a single monitoring strategy for all chemicals would be inappropriate, since adequate attention would not be given to potentially high risk substances and too large a share of resources would be devoted to low risk substances. A more appropriate scheme would be based on first ranking the risk (e.g., high, medium, and low risk) and then categorizing the chemicals according to the type of risk they present (e.g., carcinogens, teratogens, liver toxicants). Intensive monitoring programs should be devised for potentially high-risk substances, less-intensive programs for those posing medium risks, and minimal monitoring activity for low-risk substances. Of course, ranking should be continually updated as new data emerge to determine the need for regrouping. Of particular importance for the two - stage monitoring strategy described above is the choice of sampling rate. Statistical sampling strategies can be devised to ensure, with a specified degree of confidence, that products containing excessive levels of chemical res idues are identified for removal from the food supply . The desirable degree of confidence for a potentially high-risk substance should be greater than for other substances. In Chapter 7, the committee recommends criteria for sampling chemical res idues pos ing different levels of potential public health risk. Finall y, all eight essential activities of a risk-management program for chemical residues are based on applying, with varying degrees of rigor, the elements of a risk- assessment scheme based on specific types of data. Although an effective risk-management scheme will require all eight activities, not all of them need be under the direct control of FSIS. Indeed, some activities are already established at FDA and EPAo Nevertheless, to the extent possible, PSIS should ensure that all eight activities are under way and are adequately pursued. SPECIAL PROBLEMS As noted above, two aspects of chemical hazards in poultry require special treatment: Class 4 substances (those formed during processing, storing, and heating) and metabolites and degradation products of chemicals . Class 4 Substances The information needed to perform risk-assessment activities 1 through 3 for Clas s 4 subs tances is the same as that required for Classes 1, 2, and 3, but there are few data on the potential public

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135 health risks presented by these chemicals. For example, it appears that there has been no comprehensive risk assessment for any of these substances found in table-ready broiler chickens. Because Class 4 substances contaminate poultry products by mechanisms different from those for Classes 1, 2, and 3, it is not clear whether the risk- management strategies described for those classes are appropriate for Class 4. The committee believes it would be premature to devise a comprehensive risk-management strategy for them and recommends that FSIS initiate efforts to assess their risks in a comprehensive manner. Metabolites and Degradation Products In the regulation of residues in poultry, most attention has been given to the parent compounds administered to or ingested by the bird rather than to the' r metabolites or degradation products. EPA and FDA have given some consideration to those products, but it is not clear to the committee that the two agencies have treated the subject adequately or consistently. There are no data indicating that metabolites or degradation products pose significant risks that are unregulated or that the risks of these products, to the extent they are considered, are under- or overestimated by the agencies. It nevertheless seems important to examine this issue carefully and to evaluate its present status. ASSESSING PUBLIC HEALTH RISKS OF CHEMICAL RESIDUES IN POULTRY PRODUCTS The magnitude of the public health risk from chemical residues in poultry products has not yet been examined, but the committee believes it important that such risk assessments be undertaken routinely. The chemical residue data developed by FSIS (Table 5-2) are not by themselves adequate for risk assessment, because the following information is lacking: the quantitative relationship between the levels of residues found in specific tissues examined by FSIS and the levels present in all other edible tissues; the amounts of different poultry products consumed by different segments of the population; the capability of the analytical methods used to detect residues below a certain level of contamination; toxicity data, ADIs, and UCRs for each residue; the level of human exposure resulting from other environmental media in which residues of the same chemicals may be present; and time trends in contamination patterns. The information necessary to perform residue-specific risk assessments is available for many substances, especially those in Class 1. Access to FDA and EPA data files will be necessary to acquire

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136 the necessary toxicity and tissue distribution data and to estimate background levels. FSIS residue data should be analyzed statistically to determine the extent to which they are representative of the poultry product supply as a whole. These are tasks that can be completed with varying degrees of thoroughness for different residues. They should nevertheless be undertaken for all commonly found residues, but extreme care must be taken to ensure that the limitations in the data base and in the risk-assessment methodologies used are clearly set forth. Qualitative risk assessments should always be accompanied by descriptions of their limitations. Because compliance with current tolerances for Class 1 chemicals is relatively high, it is likely that risk assessments undertaken for them will result in very low risk estimates. However, compliance with prescribed tolerances does not necessarily ensure low risk 9 since the adequacy of the data base for Class 1 substances has not been reviewed and there may be significant data gaps or limitations. Many substances in Class 1 were approved or registered by FDA and EPA many years ago; however, the committee knows of no routine federal effort to ensure that the data base for these substances meets current standards, except for limited EPA efforts with regard to some pesticides. It would thus be necessary to review the toxicity data base for Class 1 substances before accurate risk assessments can be completed. The data base for Class 2 substances is certain to be less adequate than that for Class 1 substances It is not even clear that all important chemicals in Class 2 have been identified. Nevertheless, risk assessment for Class 2 substances should be undertaken and limitations in data and methodology described to the extent possible with current ;nfo'=ation. It is particularly important to include information on other environmental sources of exposure to these chemicals, such as PCBs and some of the widely dispersed chlorinated hydrocarbon pesticides, so that the contribution of poultry products to total risk can be understood and the information can be used to estate ish special control programs where high risks exist and to reduce or eliminate programs now focusing on trivial problems. Although the committee examined the data and found no evidence of significant public health risks attributable to chemical residues in broilers, risk assessments and data are needed before definitive conclusions can be reached. REFERENCES Asher, I. M., and C. Zervos, eds. 1977. Structural Correlates of Carcinogenesis and Mutagenesis. A Guide to Testing Priorities? Proceedings of the Second FDA Office of Science Sumner Symposium held at the U.SO Naval Academy, August 31-September 2, 1977. DREW Publ. No. (FDA) 78-1046 O The Office of Science, U.S. Food and Drug Administration, Rockville, Md. 241 pp.

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137 Calabrese, E. J. 1983. Principles of Animal Extrapolation. Wiley, New York. 603 pp. CFR (Code of Federal Regulations). 1986. Title 21, Food and Drugs; Section 520.2240a, Sulfaethoxypyridazine drinking water. U.S. Government Printing Office, Washington, D.C. Doull, J., C. D. Klaassen, and M. O. Amdur, eds. 1980. Casarett and Doull's Toxicology--The Basic Science of Poisons, 2nd ed. Macmillan, New York. 778 pp. Environ Corporation. 1985. Documentation for the Development of Toxicity and Volume Scores for the Purpose of Scheduling Hazardous Wastes. Prepared for the Office of Solid Waste, U.S. Environmental Protection Agency. EPA Contract No. 68-01-6861, Subcontract No. 38-9. Environ Corporation, Washington, D.C. 130 pp. EPA (Environmental Protection Agency). 1980. Water quality criteria documents; availability. Notice cuff water quality criteria doc~ents . Fed. Regist. 45: 79317-79379 . EPA (Environmental Protection Agency). 1982. Pesticide Assessment Guidelines, Subdivision F , Hazard Evaluation: Human and Domestic Animals . Publ . No . EPA 540/9 - 82 -025 . Office of Pesticide Programs, Office of Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, D.C. 163 pp. Available from the National Technical Information Service in Springfield, Va ., as PB83 -153916 . EPA (Environmental Protection Agency). 1985. Health Assessment Document for Chloroform: Final Report. Publ. No. EPA/600/8-84/004F. Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Washington, D.C. [415 pp.] Available from the National Technical Information Service in Springfield, Va., as PB86-105004. FDA (Food and Drug Administration). 1979. Polychlorinated biphenyls (PCB's); reduction of tolerances. Final rule. Docket No. 77N-0080. Fed. Regist. 44:38330-38340. FDA (Food and Drug Administrations. 1982a. D&C Green No. 6; li sting as a color additive in externally applied drugs and cosmetics . Final rule . Docket No . BIN- 0301 . Fed. Regist O 47: 14138 - 14147 . FDA (Food and Drug Administration). 1982b. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Bureau of Foods, U. S . Food and Drug Administration, Washington, D. C. ~ 248 pp . ~

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138 FDA (Food and Drug Administration). 1985. Sponsored compounds in food producing animals; criteria and procedures for evaluating the safety of carcinogenic residues. Proposed rule. Docket No. 77N-0026O Fed. Regist. 50:45530-45555 FSC (Food Safety Council). 1980. Proposed System for Food Safety Assessment. Final Report of the Scientific Committee of the Food Safety Council. Food Safety Council, Washington, D.C. 160 pp. Klaassen, C. D., and J. Doull. 1980. Evaluation of safety: Toxicologic evaluation. PpO 11-27 in J. Doull, C. D. Klaassen, and M. 0. Amdur, eds. Casarett and Doull's Taxicology--The Basic Science of Poisons, 2nd ed. Macmillan, New York. Lehman, A. J., and 0. G. Fitzhugh. 1954. lOO 'ford margin of safety. Assoc. Food Drug Off., Q. Bull. 18: 33-35. Loomis, T. A. 1978. Essentials of Toxicology, 3rd ed. Lea & Febiger, Philadelphia. 245 pp. MacMahon, B., and T. F. Pugh. 1970. Epidemiology: Principles and Methods. Little, Brown, Boston. 376 pp. Nisbet, I. C. T. 1981. The role of exposure assessment in risk evaluation: Research needs. Pp. 419-429 in C. R. Richmond 9 P. J. Walsh, and E. D. Copenhaver, eds. Health Risk Analysis, Proceedings of the Third Life Sciences Symposium. Franklin Institute Press, Philadelphia. NRC (National Research Council). 1977. Drinking Water and Health. Report of the Safe Drinking Water Committee, Advisory Center on '[oxicology. National Academy of Sciences, Washington, D. C. 939 pp. NRC (National Research Council). 1980a. Drinking Water and Health, Vol. 3. Report of the Safe Drinking Water Committee, Board on Toxicology and Environmental Health Hazards. National Academy Press, Washington, D.C. 415 pp. NRC (National Research Council). 1980b. Risk Assessment/Safety Evaluation of Food Chemicals. Report of the Subcommittee on Food Toxicology, Committee on Food Protection, Food and Nutrition Board. National Academy Press, Washington, D. C. 36 pp. NRC (National Research Council). 1983. Risk Assessement in the Federal Government: Managing the Process. Report of the Committee on the Institutional Means for Assessment of Risks to Public Heat th, Commission on Life Sciences. National Academy Press, Washington, D-C- 203 ppO

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139 NRC (National Research Council). 1984. Toxicity Testing, Strategies to Determine Needs and Priorities. Report of the Steering Committee on Identification of Toxic and Potentially Toxic Chemicals for Consideration by the National Toxicology Program, Board on Toxicology and Environmental Health Hazards. National Academy Press, Washington, D.C. 395 pp. NRC (National Research Council). 1985. Meat and Poultry Inspection: The Scientific Basis of the Nation's Program. Report of the Committee on the Scientific Basis of the Nation's Meat and Poultry Inspection Program, Food and Nutrition Board. Press, Washington, D.C. 209 pp. National Academy NRC (National Research Council). 1986. Drinking Water and Health, Vol. 6. Report of the Safe Drinking Water Committee, Board on Toxicology and Environmental Health Hazards. National Academy Press, Washington, D.C. 457 pp. OSTP (Office of Science and Technology Policy). 1985. Chemical carcinogens; a review of the science and its associated principles, February 1985. Final document. Ped. Regist . 50 : 10372 - 10442 . Rodricks, J., and M. R. Taylor. 1983. Application of risk assessment to food safety decision making. Regul. Toxicol. Pharmacol. 3:275-307.