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4 Risk INTRODUCTION Assessment The purpose of pesticide regulation in this country is to protect the human population, animals, useful vegetation, natural amenities of all sorts, and property from the "unreasonable adverse ejects" of the use of chemical pesticides (P~ 92-516, 19724. All pesticide regulations promul- gated by EPA are intended to serve this purpose. Accordingly, a key component of the preparation of any regulation is an assessment of the dangers presented by the compound under review. If the assessment indicates there are substantial dangers, estimates are required of the extent to which they will be mitigated by various alternative restrictions and regulations that might be imposed. This chapter reviews the methods now employed by oPP in forming the requisite analyses and recommends a number of changes in those procedures. Although in principle the risk assessment of any pesticide entails consideration of all the affected categories listed above, in practice, dangers to human health are currently EPA'S predominant concern. Indeed, within the area of human health, oPP's attention is generally focused on possible oncological and mutagenic effects of suspect pesticides, since these are the most apparent adverse ejects of the chemical pesticides now in widespread use and currently being intro- duced. The discussion in this chapter will therefore concentrate on the assessment of dangers to human health and particularly on the danger of inducing cancers. This narrow focus is dictated by time and resource 65

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66 REGULATING PESTICIDES constraints imposed on the study. It means that a number of important matters, in particular the assessment of environmental risks and eventual indirect elects on humans from long-term environmental effects, have been treated very briefly or not at all. Determination of whether a pesticide poses a serious potential hazard is based on two considerations that are operationally separate. The first is the extent of exposure, that is, the number of people who may be expected to receive dosages of different levels and by different routes if the pesticide is used freely or if it is regulated in various possible ways. The second consideration is the pathological activity or toxicity of the pesticide, including the probability that a person exposed to specified doses by specified routes will super adverse erects of various degrees of severity, sometimes called the dose-response relationship. The analyses of these two aspects employ entirely different data and methods. They are conducted separately and are discussed separately below. Assessment of the dangers to human health caused by the use of a pesticide is treated in the first major section of the chapter. The discussion is divided into three subsections, the first dealing with exposure analysis, the second with pathological activity, and the third with combining the previous two to obtain an overall assessment of risk. In each subsection the procedures currently used are reviewed critically and suggestions for improvement are made. The second major section of the chapter deals, more briefly, with the analysis of risks other than those to human health. HAZARDS TO HUMAN HEALTH EXPOSURE ANALYSIS Current Approach The purpose of oPP's exposure analysis is to determine in as quantitative a manner as possible the number of people exposed to a pesticide by various routes and the doses they receive. The analysis is developed on a use-by-use basis, and a special effort is made to understand how a particular pesticide is used and what human activities are associated with each use. For example, when an analysis is required for a pesticide with multiple uses, estimates are made of exposure by all routes for each use. The analysis includes a brief description of use practices, a summary of available data, and exposure estimates derived from the data. The exposure analysis is used at two stages in the RPAR decision- making process (Severe 1978a):

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Risk Assessment 67 (1) the initial decision to issue an RPAR rests in part on the likelihood of he exposure, so that a preliminary assessment of exposure (i.e., preliminary exposure profile) is needed at this stage; and (2) once an RPAR has been issued, the final nsk/benefit decision generally requires a more thorough analysis of exposure (the degree of completeness required depends In part on the toxic potency, extent of use, and magnitude of benefits to be derived from use of the pesticide In question, and is determined by the Project Manager and/or Working Group during the analysis leading to the final nsk/benefit document Position Document #3~. To date, there are no official agency guidelines for preparation of exposure analyses; however, a draft Procedures Manualfor Preparation of Human Exposure Analyses (Severe 1978a) and other agency documents (e.g., internal memoranda) provide guidance until such guidelines become available. Preliminary Exposure Profile A Preliminary Exposure Profile (PEP) is prepared for use in pre-RPAR activities. Essentially, the PEP is a rough estimate of the number of people exposed to different dose rates (for example, in terms of dose per hour of application) (Severe 1978a). Since few data on pesticide use are likely to be available at the pre-RPAR stage, the project manager maintains a core data base consisting of product label files, information from worldwide literature searches, and agency files of existing exposure information. The rough exposure estimates are determined by tabulating each use listed on the labels and comparing it with model exposure (that is, experimental application) situations, taking the compound's chemical and physical properties into consideration. The PEP thus lists each use indicated on the label along with an estimate of exposure from that use. As a compound proceeds through the RPAR process, additional data are sought to make possible a more detailed evaluation of the exposure situations with which the compound is associated. Data for Exposure Analyses Ideally, a detailed exposure analysis for a pesticide would include estimates of exposure by all routes, both for the entire U.~. population and for particular subgroups that may have different levels of exposure, especially applicators and pickers. Therefore, data on numerous aspects of a particular pesticide are needed for precise estimation of the degree of human exposure associated with its use. oPP has identified several factors critical to the assessment of various exposure situations. The factors include group size; dose from each route of exposure; duration of exposure; statistical reliability of exposure

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68 REGULATING PESTICIDES estimates; and exposure to metabolites, by-products, impurities, and contaminants (Severe 1977a). The worldwide computer literature survey made for each RPAR candidate pesticide identifies studies relevant to various aspects of the principal compound and its metabolites or degradation products (Severe 1977a). The studies serve as a primary source for many of the data needed to prepare a detailed exposure analysis of a given pesticide. Additional data sources include, among others, agency files, the USDA, the FDA, industry, user groups, the open literature, and universities. Information on patterns and practices associated with the use of a pesticide serves as a basis for ranking use patterns according to potential for human exposure. Each use practice is thoroughly described, including all sites of application; formulations used at each site; application rates and dilutions; representative labels and packaging information; methods of mixing and loading; application techniques and schedules, including a description of apparatus and common practices during application, and the times and numbers of applications per year; number of applicators involved and their identity (farmers, commercial applicators, industrial users, and so on); extent of use (total acres treated and pounds used annually by crop and state); number of associated personnel involved in application (such as mixers, loaders, and flaggers); estimate of total hours of application activity; extent of use and kind of protective clothing; and percentage of each crop treated annually (Severe 1977a). Data regarding patterns of exposure serve as a basis for estimating the amounts of a pesticide received through ingestion, inhalation, and dermal routes. Relevant information for exposure through ingestion includes data on food tolerances, residues, food consumption patterns, food processing and distribution practices, and drinking water surveys (Severe 1977a). The data come primarily from the open literature and Registration Division files of oPP. Estimates of food consumption patterns are based largely on nationwide averages (usually provided by USDA) and allow for variations in both geography and age (Severe 1977a). In addition, background data on food processing and distribu- tion practices allow estimation of the extent to which foods consumed may be contaminated by residues of the pesticide. Estimation of inhalation and dermal exposures is based on data from air monitoring, applicator practices, dynamics of application, and absorption of the compound (Severe 1977a). EPA surveys and the open literature are primary sources of available air monitoring data. Requisite data on applicators include numbers, extent of training, work schedules and practices, and protective clothing used. Information concerning the

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Risk Assessment TABLE 4. ~ Sources of Data Used In Exposure Analyses of Selected Pesticides 69 Data EPA Source Treflana Air concentrations Registrant Inhalation rate Bioastronautics Data Book (1964) Duration of exposure Doane Agriculture Station (1975) (applicators); USDA (field workers) Number of field workers USDA Dermal exposure estimates Wolfe et al. (1967); Hayes (1975) Chlorobenzilateb Number of applicators USDA Inhalation/dermal Wolfe et al. (1967) exposure estimates Average adult food USDA consumption rates Residue data Florida; USDA; EPA (limited) LindaneC Duration of exposure EPA Inhalationldermal Wolfe et al. (1967) exposure estimates Food tolerances EPA Food factors (commodity EPA distribution) Extent of pesticide use EPA a Source: Severn (1977b). b Source: Severn(1978b). c Source: Donoso and Collier (1978). dynamics of the application of a pesticide is based primarily on data concerning drift and transport near adjacent populations, Canon, persistence and reentry, and presence of particulates (Severe 1977a). Human monitoring data come primarily from the open literature and EPA projects (e.g., the Human Monitoring Program). Relevant data include surveys of blood, urine, adipose tissue, and mother's milk (Severe 1977a). Also data from household surveys indicate the potential for exposure via pesticide-contaminated dust and home-use practices (Severe 1977a). Data used in selected exposure analyses for several pesticides are summarized with respect to type and source in Table 4.1. Inhalation Exposure Estimates of respiratory exposure (i.e., via inhala- tion) are presented in terms of ambient air concentrations of the pesticide in the breathing zone of exposed persons (Severe 1978a).

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70 REGULATING PESTICIDES Because air concentrations may vary widely, estimates of the likely range and mean of the concentrations are desirable. The physical state (vapor, aerosol, or particulate) of the pesticide is also noted. If sufficient data are available, time-weighted average concentrations are computed. Esti- mates of inhalation exposure for a given population are a function of estimates of ambient concentrations, duration of exposure, and number of people exposed. The Toxicology Branch of HED determines the rate of inhalation and the extent to which the pesticide penetrates and is absorbed into the lungs. Estimates of individual inhalation exposures are commonly derived either by measuring the concentration of the pesticide in samples of ambient air or by determining the amount of the pesticide actually trapped by the filter system of a respirator worn by a worker for a specified period of time (Hayes 1975~. The first method requires calculation of breathing rates before actual inhalation doses can be determined. However, use of either approach appears to be determined more by the nature of available data (i.e., its quality and quantity) than by predetermined Agency guidelines. Dermal Exposure Estimates of dermal exposure are presented in terms of milligrams of pesticide per hour that come into contact with the skin of exposed persons. The clothing worn by agricultural workers plays a critical role in the determination of dermal exposures (Severe 1978a). The extent to which pesticides that are deposited on skin are absorbed is determined by HED'S Toxicology Branch. An important dermal exposure situation arises from reentry into areas previously treated with pesticides (Severe 1978a). It is difficult to predict quantitatively the actual dermal (and respiratory) exposure of, for example, orchard fruit pickers. Such exposure depends on the amount of residues remaining at the site, which relates directly to persistence and degradation characteristics of the pesticide in question. The Environmental Fate Branch of HED maintains a file of data on dislodgeable residues (mostly organophosphates) and other information on reentry. When an analysis requires an estimate of exposure during reentry, experts in particular geographical areas are usually consulted. Ingestion Exposure The general approach to determining the amount of a pesticide ingested by humans in their diets is to multiply an estimate of the number of micrograms of the pesticide per kilogram of food in the various foodstuffs that may contain it by estimates of the amounts of those foods in a normal daily diet. The estimate of the amount of the pesticide per unit of a food is obtained in either of two ways. If there are actual measurements of pesticide residues in foods, those measurements

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Risk Assessment 71 are used. More frequently, the residue concentrations are too small to be measured by available analytical methods. In such cases, it is assumed that the foods contain the maximum amount of pesticide residue permitted by EPA (i.e., the tolerance level). The amounts of the foods contained in normal diets are derived from food consumption surveys conducted primarily by USDA, which are often adjusted for both geographic and age variations in consumption patterns. Assumptions Data on many of the factors that are critical to the preparation of a detailed exposure analysis for a particular pesticide often are unavailable. In such cases, oPP either makes assumptions that it feels are necessary under the circumstances or, alternatively, derives estimates of exposure from data on other compounds that are used in similar patterns. Assumptions made in preparing exposure analyses for the three pesticides displayed in Table 4.1 are summarized in Table 4.2. oPP's approach to estimating exposure of spray applicators to chlorobenzilate, for example, was based largely on the assumption that inhalation and dermal exposures vary the same way under different application conditions. The same assumption was used in the exposure analyses of Treflan (Severe 1977b) and Lindane (Donoso and Collier 1978~. In the absence of data on actual applicator exposure to chlorobenzilate, probable estimates of both dermal and respiratory exposure were based on data for other pesticides used under conditions similar to those associated with chlorobenzilate (Severe 1978b). The data, as reported by Wolfe et al. (1967), consist of measured dermal and respiratory doses received by spray applicators while applying azinphosmethyl, DDT, dieldrin, malathion, and parathion. However, since the data reported by Wolfe et al. are based only on orchard spray conditions, oPP is initiating the development of models for other application situations (D. Severn, OPP, EPA, Washington, D.C., personal communication, 1978~. The assumption that 10 percent of the amount of a pesticide (in solution) that comes into contact with the skin is absorbed plays an important role in evaluation of dermal exposures. Although pesticides may be absorbed through the skin with varying efficiencies (Hayes 1975), the absorption rate of 10 percent has been used in several exposure analyses prepared by oPP (e.g., chlorobenzilate and Treflan; see Table 4.2~. When, for example, information on protective clothing worn by agricultural workers is lacking, it is assumed that exposed workers wore short-sleeved shirts and long trousers but no hats or gloves (Severe 1978a). In this situation, estimates of dermal exposure are derived from existing data on measured skin deposition from a known spray

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72 TABLE 4.2 Exposure Analysis Assumptions REGULATING PESTICIDES Treflan Air sampling data follow log-normal distribution All inhaled NDPAa is retained, not exhaled Ten percent of the amount of pesticide that comes into contact with the skin is absorbed Field workers wear no protective clothing Inhalation and derrnal exposures vary the same way under different application conditions Treflan will continue to be used indefinitely at about the current rate(s) of application Chlorobenzilate Occupational exposure of citrus pickers is less than that of spray applicators Ten percent of the amount of pesticide that comes into contact with the skin is absorbed Inhalation and dermal exposures vary the same way under different application conditions Residues in treated commodities approach established tolerance levels Inhalation per applicator-hour is the same as for other pesticides used in similar situations Chlorobenzilate will continue to be used indefinitely at about the current rate(s) of application Lindane Residues in treated commodities approach established tolerance levels Inhalation and dermal exposures vary the same way under different application conditions Lindane will continue to be used indefinitely at about the current rate(s) of application a Nitroso dipropylamine. concentration of another pesticide (Severe 197Ba). The dermal dose of other pesticides with similar spray characteristics can then be calculated from the spray concentration used. Since patterns of pesticide use are difficult to observe and enforce, there is, in many cases, a total absence of data on dermal and inhalation exposures during application. A1- though estimation of dermal ejects attempts to incorporate both chemical and toxicological aspects of a particular compound, the 10 percent skin-absorption rate may be inaccurate by an order of magni- tude. Studies are now under way to evaluate the roles played by skin and protective clothing as physical barriers in determining occupational exposures (D. Severn, oPP' EPA, Washington, D.C., personal communica- tion, 1978~. For dietary exposures worst-case estimates are usually based on the assumption that residues exist in or on commodities at the limit of established tolerances. This assumption was used in both the Lindane and chlorobenzilate exposure analyses (see Table 4.2), but the availabili- ty of actual residue-monitoring data may permit more reliable estimates. When estimates of daily exposure are converted to lifetime equiva- lents, oPP assumes that a pesticide will remain on the market and in use indefinitely. For respiratory and dermal exposures, which are usually

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Risk Assessment 73 occupational, exposure is assumed to occur over a typical number of work years for the number of days per year that a pesticide is used. For example, it was estimated that spray applicators were exposed to chlorobenzilate for 10~0 days per year (depending upon the number of applicators), over a 40-year work life (U.S. EPA 1978a). Dietary exposure was assumed to occur daily over a full 70-year lifetime. Occasionally, there may be too few data available to permit a quantitative estimate of exposure. The 25,000 30,000 citrus pickers who may be exposed to chlorobenzilate represent a case in point. Here, oPP assumed that the pickers were less frequently exposed than the spray applicators (Severe 1978b), but no quantitative estimates were made. In considering enforcement, oPP assumes that label restrictions will limit occupational exposure to some extent, and in this context, develops various regulatory options that may result in reduced levels of exposure. For example, the recommended regulatory option for chlorobenzilate includes requirements for specific types of clothing and respirators to be worn during application (U.S. EPA 1978a). A more detailed review of the chlorobenzilate exposure analysis is presented in Chapter 7. Comments and Recommendations In the Committee's judgment, oPP makes sensible and competent use of the often incomplete information available in performing its exposure analyses. The Committee does not recommend any far-reaching changes in oPP's general approach to exposure estimation, but there are a number of important changes that ought to be made in some of the detailed procedures followed and in the methods of presenting results. Data Gathering and Use Exposure to a pesticide is not a simple mechanical matter. It depends on such properties of the pesticide as persistence, solubility, vapor pressure, adsorbability, partition coefficient, and thermodynamic characteristics. These properties influence the extent of vapor contamination, water contamination, biological availability, and persistence of residues. Estimates of exposure require information about all these chemical and physical properties of the pesticide and careful evaluation of their influence on the doses received through various routes by exposed populations. Estimates of exposure should take these considerations into account more extensively than now appears to be the case. In estimating exposures, as in other phases of its work, oPP is constantly hampered by lack of adequate data, and is forced to resort to indirect and inaccurate methods in its effort to make plausible estimates.

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74 REGULATING PESTICIDES A typical example is the use of the dermal and respiratory doses received by spray applicators while applying DDT, dieldrin, and several other compounds to estimate the doses received by chlorobenzilate applicators for whom no data exist. The valid use of such indirect evidence requires close and subtle familiarity with the pesticide under consideration, including its chemical, physical, and pathological properties, and details of the methods by which it is applied. Such familiarity can seldom be gleaned from the literature. The Committee therefore makes the following recommendation. · It should be routine practice for the members of the EPA stay team reviewing a pesticide to visit sites where it is applied, facilities where it is formulated and handled, and laboratories where it is studied, and on these visits to hold informal discussions with the people involved in day-to-day manufacture, handling, and use of the pesticide. Not only is there no substitute for this firsthand contact as a basis for informed judgment, but it has the further advantage of demonstrating to the people who will be affected by any future decision that their knowledge and views have been taken into account in the course of arriving at the decision. Agricultural experiment stations are particularly important sites for these visits and have the added advantage of often directing attention to useful publications of the stations or other sources that the usual literature indexes do not include. Economic Life of a Pesticide For many pesticides, particularly those likely to induce cancers, the likelihood that an effect will eventualize is cumulative, so that estimates of lifetime exposures, rather than of rates of dosage during short periods, are relevant to risk assessments. As noted earlier in this chapter, the usual practice for making such estimates at present is to assume that if a pesticide is reregistered, it will continue to be used indefinitely at about current levels of application. In fact, the economic life of a pesticide or the length of time that it is expected to be bought and used is -limited by (1) the rate of development of resistance or tolerance to it in the target pest, and (2) the introduction of more elective or economical alternative pesticides into the market. Thus, as do most tools, pesticides have a limited useful life. Information on the economic life of pesticides should be included in all risk (and benefit) analyses of pesticides. Exposure, and hence risk, would generally be expected to drop to near zero as soon as a pesticide's economic life is spent and the pesticide is no longer used. Of course, there are always exceptions. For example, an environmentally persistent pesticide such as DDT may continue to present a potential for low-level

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Risk Assessment 75 exposure for a period ranging from a few months to more than 10 years beyond its economic life. In order for oPP to make well-founded estimates of lifetime exposures to pesticides (as well as accurate benefit estimates), the Committee makes the following recommendation: · oPP should undertake or sponsor a study of the economic lives of pesticides and the factors that influence them. Estimates of both lifetime exposures and economic benefits should be based on periods of use consistent with thefindings of the study. The Committee's best estimate on the basis of available information is that the use of a pesticide for specific pests has averaged about 10 years in a range of 2 to more than 34 years. (It should be recognized that the total economic lifetime of a pesticide encompasses all uses and therefore may be longer than the lifetime for a particular use.) When regulatory options are considered on a use-by-use basis, as they are in this report and in the oPP evaluations, the 10-year average figure, with its accompanying range, appears appropriate for estimating anticipated economic lifetimes until more reliable estimates become available. This figure, however, is rough and purely provisional and should be quickly superceded. Factors such as increasing testing costs and their eject on innovation in the pesticide industry may substantially alter estimates of the economic lives of pesticides in the future. For pesticides that have already been on the market for a number of years, an educated guess based on expert opinion will have to suffice for the time being for estimating the additional average number of years those pesticides can be expected to remain on the market. For example, in Chapter 7, the Committee estimates that if reregistered, chlorobenzi- late would continue in use for another 10 years beyond the more than 20 years it has already been used on citrus. In cases of this type, it should be assumed that, should registration of the pesticide be continued, addition- al exposure of the population and the resulting biological effects will not, on average, exceed the effects attributable to the additional years of use (unless persistence is known to be a problem). Presenting Probable-Case Estimates and Confidence Limits There is a general tendency when estimates are uncertain, which is almost always the case, to adopt "conservative" estimates. If"conservative" means tending to err on the safe side, it must be pointed out that neither side is safe. On the one side, if a regulator decision is predicated on erroneously low estimates of the number of people who would be exposed to injurious doses of a pesticide whose use is unrestricted, the decision will be biased toward inadequate restriction, with possible

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88 2,000 1 ,000 <: 1 00 REGULATING PESTICIDES 10 0.001 \ 0.01 0.1 LIFETIME DOSE (m moles/kg body weight) 1.0 FIGURE 4.1 Relationship between CAT and dose for vinyl chloride. Source: Denved from Table 4.3. that on the average for mice administered test compounds orally and demonstrating comparable tumor response levels, heptachlor is approxi- mately 30 times as active a carcinogen as dicofol. This is because under similar experimental conditions a given number of moles of heptachlor per unit of body weight will have approximately 30 times as great an ~ . , .. . . ~ .. . . . i` .. . . .... ~ . . . enect (on the nasls of the data reviewed) on the pronaulllty ot developing excess tumors as the same number of moles of dicofol. Similarly, using data from Innes et al. (1969), chlorobenzilate, when administered orally, is about one third as active as dicofol in inducing tumors in certain laboratory mice. The table therefore can serve as a scale against which the pathological activity of any compound under review can be measured if experimental conditions are comparable (see Appendix B). If CAPS are to be useful for policy purposes, however, they must provide information on the dangers to humans of exposures to potential carcinogens such as certain pesticides. More precisely, the CAPS would have to allow for assertions and comparisons such as, "ingestion of x m

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Risk Assessment 89 moles of endrin has about the same probability of inducing a cancer as ingestion of 10x m moles of chloroform." A number of assumptions must be made before such assertions based on experimentally observed CAYS can be justified. One set of assumptions that permits useful inferences to be drawn about the erect of specific pesticides on human health is suggested and discussed in Appendix B. The reader is urged to read and consider those assumptions. One will see that they are not innocuous and that, though intuitively appealing, they have little experimental support. The reason for preferring the evaluation of risks by means of CAN'S to the current procedures is that the current procedures require substantially stronger and less plausible assumptions and produce an end product that is much more liable to misinterpretation. In spite of the limitations that have been noted, the Committee feels that potency indexes, such as the CAN'S, are the best indicators available of the relative danger of different pesticides. Responsible officials and the general public should be informed of such indicators (together with the ranges of experimental error and uncertainty to which they are subject), and regulatory decisions should take them into account. The Committee recognizes that it would be more convenient if regulatory decisions could be based on reliable estimates of the probable elects of different regulatory options on human morbidity and mortality. But such estimates cannot be justified given the current state of scientific knowledge. Accordingly: · The Committee recommends that when laboratory data are used to estimate pathological activity, potency indexes, such as the cods defined above, be used to indicate the pathological virulence of the pesticide under consideration and that no numerical estimates of elects on human morbidity or mortality be extrapolated from laboratory data. The estimated potency indexes should be presented as most probable values accompanied by indications of ranges of uncertainty. How the CAPS can be taken into account will be discussed further below and again in Chapter 6, and illustrated in Chapter 7. COMBINING EXPOSURE AND PATHOLOGICAL ACTIVITY Estimates of exposure and pathological activity must be combined in appraising the hazard to human health posed by the use of a pesticide. The current procedure, to be discussed more fully below, is to make the combination by calculating, for each relevant segment of the population, an estimate of the probability that an individual will contract a disease

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go REGULATING PESTICIDES (such as cancer) as a consequence of the use of the pesticide. The preceding discussion indicated that available estimates of the effects of pesticide use on incidence of disease in humans do not merit scientific credence. Therefore, the Committee recommends that the practice of making such estimates be abandoned. At the same time, the procedures for appraising pathological activity recommended by the Committee do not, in principle, lend themselves to similar, quantitative estimates of ejects on human morbidity or mortality. Thus, different methods must be used to combine exposure and pathological information. The current methods and a recommended alternative are discussed in the following two subsections. Current Practice The risks incurred by the use of any pesticide vary. They include carcinogenicity, mutagenicity, other chronic health impairments, and acute reactions. There are also risks to natural biota and to agriculture and livestock. The overall assessment of risks must take all these possibilities into account. For this reason, and perhaps others, the risk assessments in available oPP position documents have not followed a standard format. The risks associated with a pesticide have been appraised by various methods, talking account of the nature of the predominant risks of concern as well as characteristics of the available data. The appraisals share certain fundamental features, however. For example, as noted previously, the risks associated with cancer are estimated by the CAG primarily on the basis of animal bioassay data and evaluations of the metabolic and toxicological characteristics of the compound. Other hazards to human health are appraised by oPP's HED, using similar types of data and epidemiological evidence when available. Hazards to wildlife or biota and potential crop or livestock damage are evaluated by HED also, through searches of the relevant literature. The USDA/EPA benefit assessment teams play an important role in acquiring information about the use of pesticides that may generate such hazards. Potential and actual exposures are estimated, as described above, by well-standardized methods. In the end, these diverse kinds of informa- tion must be pulled together, and it is at this point that standardization ceases. Two examples will suffice. In the appraisal of chlorobenzilate (U.S. EPA 1978a), the induction of cancers was judged to be the primary type of risk with which to be concerned. Accordingly, factors provided by CAG were used to infer the increase in the lifetime probability of contracting cancer that would

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Risk Assessment 91 result from the continued use of chlorobenzilate. Separate factors were computed for different segments of the population to allow for the different lifetime doses to which people would be exposed. For example, the general U.S. population is exposed to very low doses by eating foods on or in which residues of the chemical remain, while applicators receive much higher doses through dermal and inhalation exposure (see Chapter 7~. The risk analysis data were therefore summarized by displaying the increase in the maximum, or worst-case, lifetime probability of contract- ing cancer for members of each of seven population groups and for seven possible regulatory options (see Table 6.1~. In the analysis of the risk associated with endrin (U.S. EPA 1978b), not cancer but the likelihood of teratogenesis was the primary concern. Three groups of women may be exposed to significant doses of endrin: female pilots of endrin-spraying aircraft (probably a very small number of women), downwind neighbors exposed during the spraying operation, and women who eat fish from water contaminated by runoff and drainage from fields treated by endrin. For each of these groups a plausible daily dose (in milligrams per kilogram) was estimated and a margin of safety was computed according to the formula: Margin of Safety = Largest dose for which no effects were Ibsen n experimental animals Dose to which some (perhaps few) members of the population may be exposed A margin of safety of 300 or less was judged to indicate a significant risk. In general, as suggested by these illustrations, there is no attempt to be uniform in assessing the potentials of different pesticides for harming public health, wildlife, materials, and crops. Each analysis is adapted to particular circumstances. Comments and Recommendations The practices described above, representing current attempts to quantify the risks of using different pesticides, super from at least two serious deficiencies. The first is the noncomparability of the risks estimated for one pesticide with those of another estimated in a different form. The second, which was discussed at length above, is the unreliability inherent in estimates of change in human morbidity or mortality extrapolated from experiments with animals.

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92 REGULATING PESTICIDES The lack of comparability is a consequence of the wide variety of ways in which a pesticide may inflict harm. There is no defensible formula for reducing all varieties of damage to human health to a common index of seriousness. Nevertheless, it is important that when similar consequences are at issue, they be estimated and reported in comparable ways. If this can be done, serious inconsistencies among decisions relating to different compounds will be minimized and the accumulation of useful experience in appraising risks, on the part of both the Administrator and the staff, will be facilitated. The appraisal of risks to human health can be systematized by applying the concept of the CAI together with analogous concepts. We have already discussed at length problems of measuring and expressing the potential carcinogenicity of a compound, and we concluded that the best method, generally, is to indicate carcinogenic activity relative to that of other compounds using a CAT. The indicator must then be combined with estimates of the numbers of people exposed to different doses of the compound to yield an overall assessment of the cancer risk that is posed. The question is how to do this. It is not meaningful to combine the CA' with estimates of exposure by multiplying them or by any other simple arithmetic formula. Some people like pesticide applicators are exposed to doses several orders of magnitude greater than others are exposed to. In the absence of a dose-response curve applicable to humans, it is not possible to aggregate the different population segments receiving widely different doses into an overall estimate of the eject of the use of a pesticide on public health. In terms of eject on public health, 1,000 N people each receiving a dose of D is not equivalent to N people each receiving a dose of 1,000 D, nor do we know of any reliable way to compare the effects of the two exposures. The results must be presented as a table or graph that shows the numbers of people exposed to different doses. Furthermore, the dose to which each population segment is exposed may be different under different regulatory options, the ejects of which can be indicated by a compara- tive exposure graph as illustrated in Figure 4.2. The illustration compares the doses to which three population segments are exposed under four regulatory options of increasing stringency. The CAP'S must be used in preparing such a comparison. To illustrate, let us suppose that Option A in Figure 4.2 is the unrestricted use of pesticide X while Option B involves banning its use in certain areas. The farmers in the prohibited areas can then be expected to resort to other expedients: some might use pesticide Y. others pesticide Z. others biological controls, and so on. The eject of these changes on exposure to pesticides X, Y. and Z cannot be foreseen with

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Risk Assessment x LU cat o LL In o - 93 AnoIicators (1,000)~ Local Inhabitants (50,000) Consumers (220 million) - - - A R EG U LATO RY OPTI ON FIGURE 4.2 Comparative exposure graph (schematic). D precision, but it can be approximated with the help of the CAN'T. Suppose, for example, that under Option B when pesticide X is banned, Py percent of the crop will be treated with the substitute pesticide Y. Pz with pesticide Z. and so on. Using the assumptions described in Appendix B. it can be shown that if doses Do and Dy are not very dissimilar, the applicator population, for example, is consequently exposed to pesticide Y at a dose equivalent to Dye units of pesticide X where Dy = CA~y CAix Dy. That is, Dyeis the dose of pesticide X that produces the equivalent pathological eject of the dose of pesticide Y that applicators might be expected to receive under regulatory Option B. The same will pertain for

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94 REGULATING PESTICIDES pesticide Z. In toto, the average exposure of applicators under Option B in terms of pesticide X equivalents will be PxDx + P'Dy + PzDz This is the number to be plotted on the chart. The approximating assumption used in making the comparison is that pathological response is proportional to dose for moderate ranges of doses, though not for large variations. Where better approximations are known (e.g., linearity instead of proportionality), they should be used. To this point, the risks associated with different options have been expressed in units of exposure to the pesticide under consideration. A final step in the presentation is to note, again using the CAN'T, how the carcinogenic activity of the pesticide compares with the activities of other pesticides currently in use or previously regulated. These compari- sons are discussed in Chapter 6, where benefits of the different regulatory options are compared with their risks, and later illustrated in Chapter 7. Again, the Committee has not studied other risks to public health as carefully as it has studied carcinogenicity. Nevertheless, it believes that many of the problems of appraising risks of mutagenicity, teratogenicity, and acute and chronic toxicity in humans are closely analogous to those encountered in the analysis of cancer risks to the extent that reliance is placed on extrapolations from bioassays using laboratory animals. The same methods of risk assessment should therefore apply. Indicators must be constructed showing the comparative potencies of different com- pounds in inducing mutations, abnormal offspring, and toxic effects. Consequences of different regulatory options can then be compared by the methods just described, using the appropriate activity indicators and, when available, human data. ANALYSIS OF ENVIRONMENTAL RISKS In addition to considering the risks to human health posed by an RPAR compound, the Agency is also obligated under 40 CFR 162.11 to identify and weigh any environmental risks associated with the chemical. Specifically, the environmental risk triggers are (1) acute toxicity to nontarget species, (2) chronic toxicity to members of endangered species, and (3) chronic toxicity to nontarget species (see Note to Chapter 2~. The environmental risk analyses performed by oPP's HED are some- what analogous to the human health risk analyses. In particular, the

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Risk Assessment 95 environmental risk analyses attempt to determine the extent to which current use and exposure patterns, and the use-exposure patterns likely to arise under the various regulatory options, may prove lethal to nontarget organisms. oPP's environmental analyses are based upon either theoretical considerations or empirical evidence. For instance, oPP's presumption that endrin is acutely toxic to rabbits and pheasants was based on theoretical calculations of the endrin residues likely to be found on items consumed by these animals (U.S. EPA 1978b: 13~. The theoretical arguments were eventually modified to reflect the findings of actual residue studies submitted by an endrin registrant (U.S. EPA 1978b: 14~. In contrast to the acute toxicity presumption, the presumption that endrin is responsible for significant reductions in nontarget populations was based upon actual data on fish kills derived from the Pesticide Episode Reporting System (U.S. EPA 1978b: 181. Unfortunately, the data available on environmental hazards are often too incomplete to allow for the development of accurate, quantitative risk estimates. Realistically, there is currently no way of developing reliable estimates of, for example, the number of rabbits or pheasants that die each year from ingesting endrin residue on forage or seeds. Even in cases involving significant local population reductions, such as large fish kills, oPP may have little or no quantitative (or even qualitative) evidence. Position Document 2/3 for endrin notes, for example, that the Pesticide Episode Reporting System (which depends on voluntary reporting) is so unreliable that it missed at least 20 endrin-related fish kills over a 5-year period in Mississippi. As a result of these data shortages, the environmental risk analyses tend to rely heavily upon sketchy, perhaps even qualitative, information. The Committee has focused its attention in this report on health effects. This is not to say that it felt the assessment of environmental risks is not significant, but only to confess that the Committee chose not to study it in depth itself. Nevertheless, it is clear to the Committee that an improved data base is necessary. To this end, and on the basis of the Committee's observations and review of selected oPP position docu- ments, we suggest that EPA (1) devote more resources to environmental monitoring and (2) initiate more studies of environmental toxicology of selected pesticides. When quantitative environmental risk analyses are made, we further recommend that estimates be reported as ranges. As for human exposure analyses, the ranges should be presented as a pair of numbers, one showing the most-probable environmental risk and the other showing the maximum-plausible estimate.

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96 REGULATING PESTICIDES RISKS TO STRUCTURES, MATERIALS, AND CROPS Generally speaking, risks to structures and materials entailed by the use of pesticides are negligible. On the other hand, pesticides may be harmful to crops grown In nearby fields, to livestock, or to commercial fisheries. In the latter instances, current practice is to estimate the monetary value of the decreases in yield or increases in cost of maintenance estimated to result from use of the pesticide. In the Comm~ttee's judgment, the methods currently used for making these estimates are straightforward and sound, although we recommend that such estimates be derived and reported for both the most-probable and max~mum-plausible cases. OVERALL ASSESSMENT OF RISKS The use of any pesticide entails a complex bundle of risks: risks to the health of different segments of the population, to wildlife, to vegetation, to crops and livestock, and to buildings and materials. Each of these risks is a result of several factors: the number of vulnerable elements exposed to the pesticide, the dose to which each element is exposed, and the potency or harmfulness of the pesticide. At some stage in the evaluation of regulatory options, appraisals of the different kinds of risks must be combined and compared with the costs of different options. How to consolidate appraisals of the individual types of risks and the extent to which they can be consolidated are among the principal concerns of Chapter 6. The assessments of the several types of risk reviewed in this chapter are necessary ingredients in that final appraisal. REFERENCES Crump, K.S., D.G. Hoel, C.H. Langley, and R. Peto (1976) Fundamental carcinogenic processes and their implications for low dose risk assessment. Cancer Research 36:2973- 2979. Donoso, J. and C.W. Collier (1978) Exposure Analyses for Lindane. Hazard Evaluation Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D.C. (Unpublished) Epstein, S.S. (1976) Carcinogenicity of heptachlor and chlordane. The Science of the Total Environment 6: 103-154. Hayes, J., Jr. (1975) Toxicology of Pesticides. Baltimore: The Williams and Wilkins Company. Hoel, D.G., D.W. Gaylor, R.L. Kirschstein, U. Saffiotti, and M.A. Schneiderman (1975) Estimation of risks of irreversible, delayed toxicity. Journal of Toxicology and Environmental Health 1: 133-151.

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Risk Assessment 97 Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein, E.R. Hart, AJ. Pallotta, R.R. Bates, H.L. Falk, J.J. Gart, M. Klein, I. Mitchell, and J. Peters (1969) Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: A preliminary note. Journal of the National Cancer Institute 42(6): 1101-1114. Interagency Regulatory Liaison Group (1979) Scientific Bases for Identifying Potential Carcinogens and Estimating Their Risks. Work Group on Risk Assessment, Em, Washington, D.C. (Unpublished. Available from Executive Assistant, HAG, Room 500, 1111 18th St., N.W., 20207) International Research and Development Corporation (1973) Report to the Velsicol Chemical Corporation. (Unpublished. Data with critique are also presented in Epstein 1976) Mantel, N. and W.R. Bryan (1961) 'Safety' testing of carcinogenic agents. Journal of the National Cancer Institute 27:455-470. Meselson, M.S. and K. Russell (1977) Comparison of carcinogenesis and mutagenesis potency. Pages 1473-1481, Book C, Origin of Human Cancer, edited by H.H. Hiatt, J.D. Watson, and J.A. Winsten. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. National Cancer Institute (1976) Bioassay of Chloroform for Possible Carcinogenicity. CAS No. 67-66-3. Washington, D.C.: U.S. Government Printing Office; Springfield, Va.: National Technical Information Service. National Cancer Institute (1977a) Bioassay of Chlordane for Possible Carcinogenicity. cats No. 57-749, NCI-CG-TR-8. Washington, D.C.: U.S. Department of Health, Education and Welfare. National Cancer Institute (1977b) Bioassay of Heptachlor for Possible Carcinogenicity. cats No. 76 41 8, NCI-CG-TR-9. DHEW Publication No. (NOSH) 77-809. Washington, D.C.: U.S. Department of Health, Education and Welfare. National Cancer Institute (1977c) Bioassay of Lindane for Possible Carcinogenicity. CAS No. 58-89-9, NCI-CG-TR-14. DHEW Publication No. (NOSH) 77-814. Washington, D.C.: U.S. Department of Health, Education and Welfare. National Cancer Institute (1978a) Bioassay of Aldrin and Dieldrin for Possible Carcinoge- nicity. CAS No. 309~2, NCI-CG-TR-21. DHEW Publication No. (em) 78-821. Washington, D.C.: U.S. Department of Health, Education and Welfare. National Cancer Institute (1978b) Bioassay of Chlorobenzilate for Possible Carcinogenici- ty. CAS No. 510-15-6, NCI-CG-TR-75. DHEW Publication No. (NOSH) 78-1325. Washing- ton, D.C.: U.S. Department of Health, Education and Welfare. National Cancer Institute (1978c) Bioassay of Dieldrin for Possible Carcinogenicity. CAS No. 60-57-1, NCI No. 22. CHEW Publication No. (NOSH) 78-882. Washington, D.C.: U.S. Department of Health, Education and Welfare. National Cancer Institute (1979) Bioassay of Endrin for Possible Carcinogenicity. CAS No. 72-2~8, NCI-CG-TR-12. DHEW Publication No. (NOSH) 79-812. Washington, D.C.: U.S. Department of Health, Education and Welfare. Olson, W.A., R.T. Habermann, E.K. Weisburger, J.M. Ward, and J.H. Weisburger (1973) Induction of stomach cancer in rats and mice by halogenated aliphatic fumigants. Journal of the National Cancer Institute 51: 199~1995. Pesticide and Toxic Chemical News (1978) Dr. Dubin resigns from CAG with stunning charges leveled at Dr. Albert. November 22: 2~26. Pesticide and Toxic Chemical News (1979) 'Weakly positive' evidence shows BAAM a likely carcinogen, CAL says. January 10:7~. Public Law 92-516 (1972) Federal Environmental Pesticide Control Act of 1972. 7 usc 135 (1972).

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98 REGULATING PESTICIDES Severn, D.J. (1977a) Data Requirements for Exposure Analyses. (Note: This unpublished memorandum was prepared by D.J. Severn and is available from the Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D.C. 20460) Severn, D.J. (1977b) Estimates of Human Exposure to Nitrosamines from the Use of Trifluralin and Trichlorobenzoic Acid Herbicides. Hazard Evaluation Divison, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D.C. (Un- published) Severn, D.J. (1978a) Draft Procedures Manual for Preparation of Human Exposure Analyses. Hazard Evaluation Division, Office of Pesticide Programs, U.S. Environn~en- tal Protection Agency, Washington, D.C. (Unpublished) Severn, D.J. (1978b) Exposure Analysis for Chlorobenzilate. Hazard Evaluation Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D.C. (Unpublished) U.S. Environmental Protection Agency (1975) Scientific and Technical Assessment Report on Vinyl Chloride and Polyvinyl Chloride. STAR Series, CAS No. 75-014, EPA-600/~75- 004. Washington, D.C.: U.S. Environmental Protection Agency. U.S. Environmental Protection Agency (1976) Health Risk and Economic Impact Assessments of Suspected Carcinogens: Interim Procedures and Guidelines. 41 Federal Register (102)21402-21405. U.S. Environmental Protection Agency (1978a) Chlorobenzilate: Position Document 3. Special Pesticide Review Division, Office of Pesticide Programs, U.S. EPA. (Note: This unpublished report was prepared under the general direction of J.B. Boyd, Project Manager, and is available from oPP' Washington, D.C. 20460) U.S. Environmental Protection Agency (1978b) Endrin: Position Document 2/3. Special Pesticide Review Division, Office of Pesticide Programs, U.S. EPA. Mote: Us unpublished report was prepared under the general direction of K. Barbehenn, Project Manager, and is available from oPP, Washington, D.C. 20460) Wolfe, H.R., W.F. Durham, and J.F. Armstrong (1967) Exposure of workers to pesticides. Archives of Environmental Health 14:622~33.