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Page 383

Appendix
D
Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment

Notice

THIS DOCUMENT IS A PRELIMINARY DRAFT. Until formal announcement by the U.S. Environmental Protection Agency is made in the Federal Register, the policies set forth in the 1986 Guidelines for Carcinogen Risk Assessment, as they are now interpreted, remain in effect. This working paper does not represent the policy of the U.S. Environmental Protection Agency with respect to carcinogen risk assessment.

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Page 383 Appendix D Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment Notice THIS DOCUMENT IS A PRELIMINARY DRAFT. Until formal announcement by the U.S. Environmental Protection Agency is made in the Federal Register, the policies set forth in the 1986 Guidelines for Carcinogen Risk Assessment, as they are now interpreted, remain in effect. This working paper does not represent the policy of the U.S. Environmental Protection Agency with respect to carcinogen risk assessment. Office of Health and Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Washington, D.C.

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Page 384 Disclaimer This document is a draft working paper for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsesement or recommendation for use.

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Page 385 Contents List of Figures 387 Authors and Contributors 387 PREAMBLE 388 1. INTRODUCTION 394   1.1. PURPOSE AND SCOPE OF THE GUIDELINES 394   1.2. TYPES OF DATA USED IN CARCINOGENICITY ASSESSMENT 395   1.3. ORGANIZATION OF THE GUIDELINES 396   1.4. APPLICATION OF THE GUIDELINES 396 2. HAZARD ASSESSMENT 397   2.1. INTRODUCTION 397   2.2. INTEGRATING DATA FOR HAZARD ASSESSMENT 398   2.3. ANALYSIS OF HUMAN DATA 398 .   2.3.1 Epidemiologic Studies 398       2.3.1.1 Exposure Focus 399       2.3.1.2 Types of Epidemiology Studies 400     2.3.2. Elements of Critical Analysis 400       2.3.2.1 Exposure 400       2.3.2.2 Population Selection Criteria 401       2.3.2.3 Confounding Factors 402       2.3.2.4 Sensitivity 402       2.3.2.5 Criteria for Causality 403   2.4. SUMMARY OF HUMAN EVIDENCE 404     2.4.1. Category 1 405     2.4.2. Category 2 405       2.4.3. Category 3 405       2.4.4. Category 4 406   2.5. ANALYSIS OF LONG-TERM ANIMAL STUDIES 406     2.5.1. Significance of Response 406     2.5.2. Historical Control Data 407     2.5.3. High Background Tumor Incidence 408     2.5.4. Dose Issues 408     2.5.5. Human Relevance 409   2.6. ANALYSIS OF EVIDENCE RELEVANT TO CARCINOGENICITY 409     2.6.1. Physical-Chemical Properties 409     2.6.2. Structure-Activity Relationships 410     2.6.3. Metabolism and Pharmacokinetics 411

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Page 386     2.6.4. Mechanistic Information 412 .     2.6.4.1 Genetic Toxicity Tests 413 .     2.6.4.2 Other Short-Term Tests 415 .     2.6.4.3 Short Assays for Carcinogenesis 416       2.6.4.4 Evaluation of Mechanistic Studies 416   2.7. SUMMARY OF EXPERIMENTAL EVIDENCE 418     2.7.1. Category 1 419     2.7.2. Category 2 420     2.7.3. Category 3 420     2.7.4. Category 4 421   2.8. HUMAN HAZARD CHARACTERIZATION 421     2.8.1. Purpose and Content of Characterization 421     2.8.2. Weight of Evidence for Human Carcinogenicity 421 .     2.8.2.1 Descriptors 424       2.8.2.2 Examples of Narrative Statements 425 3. DOSE-RESPONSE ASSESSMENT 427   3.1. PURPOSE AND SCOPE OF DOSE-RESPONSE ASSESSMENT 427   3.2. ELEMENTS OF DOSE-RESPONSE ASSESSMENT 428     3.2.1. Response Data 428     3.2.2. Dose Data 429       3.2.2.1 Base Case—Few Data 430       3.2.2.2 Pharmacokinetic Analyses 431       3.2.2.3 Additional Considerations for Dose in Human Studies 431   3.3. SELECTION OF QUANTITATIVE APPROACH 432     3.3.1. Analysis in the Range of Observation 433     3.3.2. Extrapolation 435     3.3.3. Issues for Analysis of Human Studies 436     3.3.4. Use of Toxicity Equivalence Factors (TEF) 436   3.4. DOSE-RESPONSE CHARACTERIZATION 437 4. EXPOSURE ASSESSMENT 438 5. CHARACTERIZATION OF HUMAN RISK 439   5.1. PURPOSE 439   5.2 APPLICATION 439   5.3. CONTENT 439     5.3.1. Presentation and Descriptors 439     5.3.2. Strengths and Weaknesses 440 6. REFERENCES 440

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Page 387 List Of Figures Figure 1   423 Authors And Contributors This draft working paper was prepared by an intra-Agency EPA working group chaired by Jeanette Wiltse of the Office of Health and Environmental Assessment. Working Paper For Considering Draft Revisions To The U.S. Epa Guidelines For Cancer Risk Assessment This working paper identifies cancer risk assessment issues that some Agency scientists have been discussing as a basis for possible proposed revisions to EPA's 1986 Guidelines for Carcinogen Risk Assessment. The working paper is being given to other scientists to obtain early comment on the many issues that remain undeveloped or are still under discussion. The working paper is not a proposal. It has not been reviewed or approved by any EPA official, and the proposal that is eventually approved is likely to be very different in many respects from this working paper. When proposed revisions are ready, EPA will publish them in the Federal Register for public comment. Until formal announcement by the U.S. Environmental Protection Agency is made in the Federal Register, the policies set forth in the 1986 Guidelines for Carcinogen Risk Assessment, as they are now interpreted, remain in effect. This working paper does not represent the policy of the U.S. Environmental Protection Agency with respect to carcinogen risk assessment.

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Page 388 Preamble The United States Environmental Protection Agency (EPA) 1986 guidelines on carcinogenic risk assessment (51 FR 33992, September 24, 1986)) stated that, ''… [a]t present, mechanisms of the carcinogenesis process are largely unknown …". This is no longer true. The last several years have brought research results at an explosive pace to elucidate the molecular biology of cancer. This new knowledge is only beginning to be applied in generating data about environmental agents. Guideline revisions are intended to be flexible and open to the use of such new kinds of data even though the guidelines cannot fully anticipate the future forms that carcinogenicity testing and research may take. At the same time, the guidelines address assessment of the kinds of data that are the current basis of carcinogenicity assessment as a result of the past two decades of development of the science of risk assessment. Because methods and knowledge are expected to change more rapidly than guidelines can practicably be revised, most of the Agency's development of procedures for cancer risk assessment will henceforth be accomplished through publication of technical work performed under the aegis of the Agency's Risk Assessment Forum. The technical documents of the Forum are developed by a process that engages the general scientific community with EPA scientists. The documents are made available for public examination as well as for scientific peer review through the EPA Science Advisory Board and other groups. The Forum sponsored two workshops in which areas of potential revision to the guidelines were discussed by scientists from public and private groups. (USEPA, 1989a; USEPA, 1991a). Major Changes from 1986 Guidelines Revisions in this working paper differ in many respects from the Agency's 1986 guidelines. The reasons for change arise from new research results, particularly about the molecular biology of cancer, and from experience using the 1986 guidelines. One area of change is increased emphasis on providing characterization discussions for each part of a risk assessment (hazard, dose-response, exposure, and risk assessments). These serve to summarize the assessments with emphasis on explaining the extent and weight of evidence, major points of interpretation and rationale, strengths and weaknesses of the evidence and analysis, and alternative conclusions that deserve serious consideration. Two other areas of major change are in: (1) the way the weight of evidence about an agent's1 hazard potential is expressed; and 1The term "agent" is used throughout (unless otherwise noted) for a chemical substance, mixture, or physical or biological entity that is being assessed.

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Page 389 (2) approaches to dose-response assessment. 1. To express the weight of evidence for carcinogenic hazard potential, the 1986 guidelines provided tiered summary rankings for human studies and for animal bioassays. These summary rankings of evidence were integrated to place the overall evidence in alphanumerically designated classification groups A through E, Group A being associated with the greatest probability of carcinogenicity. Other experimental evidence played a modulating role for ranking. Considerations such as route of exposure (e.g., oral versus inhalation) and mechanism of action were not explicitly captured in a characterization. These working revisions take a different approach. The idea of summary ranking of individual kinds of evidence is retained and expanded, but these are integrated differently and expressed in a narrative weight of evidence characterization statement. {Whether an alphanumerical rating will be a part of this statement is an unresolved issue still under discussion at EPA.} The narrative statement is preceded by summary rankings of human observational evidence and of all experimental evidence. The summary ranking for experimental evidence is composed of long-term animal bioassay evidence and all other experimental evidence on biological and chemical attributes relevant to carcinogenicity. This stepwise approach anticipates marshalling evidence and organizing conclusions as analysis proceeds, for convenience of consideration. It also gives explicit weight to certain kinds of experimental evidence that previously were considered in a "modulating" role. The narrative statement provides a place to describe evidence by route of exposure and to describe the hazard assessment and dose-response implications of mechanism of action data in characterizing the overall weight of evidence about human carcinogenicity. 2. The approach to dose-response assessment is another area of major change. It calls for a stepwise analysis that follows the conclusions reached in the hazard assessment as to potential mechanism of action. Two steps divide the analysis into modeling in the range of observed data and analysis of dose-response below the range of observed data. {The process for combining all the findings relevant to human carcinogenic potential is a matter of continuing discussion at EPA. This working paper presents one of a number of suggested approaches. The objective is to be integrative and holistic in judging while at the same time giving guidance to junior scientists in various disciplines about how to marshal and present findings.} {How to use mechanistic information in dose-response assessment is incom-

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Page 390 pletely developed in these working paper. Specific issues are pointed out in later sections.} Perspectives for Carcinogenicity Assessment The following paragraphs summarize part of the current picture of the events in the process of carcinogenesis. Most of the research cited was conducted with experimental approaches not commonly used to study environmental agents. Nevertheless, as this picture is elaborated, more experimental approaches will become available for testing specific mechanisms of action of environmental agents. Even before this happens as a general forward step, information currently available for some agents can be interpreted in light of this picture to make informed inferences about the role the agent may play at the molecular level. Normally, cell growth in tissues is controlled by a complex and incompletely understood process governing the occurrence and frequency of mitosis (cell division) and cellular differentiation. Adult tissues, even those composed of rapidly replicating cells, maintain a constant size and cell number (Nunez et al., 1991). This appears to involve a balance among three cell fates: (1) continued replication or loss of ability to replicate, followed by (2) differentiation to take on a specialized function or (3) programmed cell death (Raff, 1992; Maller, 1991; Naeve et al., 1991; Schneider et al., 1991; Harris, 1990). As a consequence of either the inactivation of processes that lead to differentiation or cell death, replicating cells may have a competitive growth advantage over other cells, and neoplastic growth clonal expansion can result (Sidransky et al., 1992; Nowell, 1976). The path a cell takes is determined by a timed sequence of biochemical signals. Signal transduction pathways, or "circuits" in the cell, involve chemical signals that bind to receptors, generating further signals in a pathway whose target in many cases is control of transcription of a specific set of genes (Hunter, 1991; Cantley et al., 1991; Collum and Alt, 1990). A cell produces its own constituent receptors, signal transducers, and signals, and is subject to signals produced by other cells, either neighboring ones or distant ones, for instance, in endocrine tissues (Schuller, 1991). In addition to hormones produced by endocrine tissues, numerous soluble polypeptide growth factors have been identified that control normal growth and differentiation (Cross and Dexter, 1991; Wellstein et al., 1990). The cells responsive to a particular growth factor are those that express transmembrane receptors that specifically bind the growth factor. One can postulate many ways to disrupt this kind of growth control circuit, including increasing or decreasing the number of signals, receptors, or transducers, or increasing or decreasing their individual efficiencies. In fact, human genetic diseases that make individuals cancer-prone involve mutations that appear to have some of these effects (Hsu et al., 1991; Srivastava, 1990; Kakizuka et al., 1991). Tumor cells found in individuals who do not have genetic disease

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Page 391 have also been shown to have mutations with these consequences (Salomon et al., 1990; Bottaro et al., 1991; Kaplan et al., 1991; Sidransky et al., 1991). For example, neoplastic cells of individuals with acute promyelocytic leukemia (APL) have a mutation that blocks cell differentiation in myeloblasts that normally give rise to certain white cells in blood. The mutation apparently alters a receptor that normally responds positively to a differentiation signal. Patients with APL involving this mutation have been successfully treated by oral administration of retinoic acid, which functions as a chemical signal that apparently overrides the effect of the mutation, and drives the neoplastic cells to stop replicating and differentiate. This "differentiation therapy" demonstrates the power conveyed by understanding the growth control signals of these cells (Kakizuka et al., 1991; de The et al., 1991). Several kinds of gene mutations2 have been found in human and animal cancers. Among these are mutations in genes termed tumor susceptibility genes. One kind, mutations that amplify positive signals to replicate or avert differentiation, are termed oncogenes (proto-oncogenes in their normal state). Another kind are mutations in genes involved in generating negative growth signals, termed tumor suppressor genes (Sager, 1989). Damage to these two kinds of genes has been found in cells of tumors in many animal and human tissues including the sites of the most frequent human cancers (Bishop, 1991; Malken et al., 1990; Srivastava et al., 1990; Hunter, 1991). The functions and deoxyribonucleic acid (DNA) base sequences of the genes are highly conserved across species in evolution (Auger et al., 1989a, b; Kaplan, 1991; Hollstein et al., 1991; Herschman, 1991; Strausfeld et al., 1991; Forsburg and Nurse, 1991). Some 100 oncogenes and several tumor suppressor genes have thus far been identified; specific functions are known for only a few. The growth control circuit can also be altered without permanent genetic change by, for example, affecting the responsiveness of signal receptors, the concentration of signals, or the level of gene transcription (Holliday, 1991; Cross and Dexter, 1991; Lewin, 1991). These can come about through mimicry or inhibition of a signal or through physiological changes such as alteration of hormone levels that influence cell growth generally in some tissues. Current reasoning holds that cell proliferation which results from changes at the levels of DNA sequence or DNA transcription, from changes at the level of growth control signal transduction, or from cell replication to compensate for toxic injury to tissue can begin a process of neoplastic change by increasing the number of cells that are susceptible to further events that may lead to uncontrolled growth. Such further events may include, for instance, errors in DNA replication that occur normally at a low background rate or effects of exposure to 2The term "mutations" includes the following permanent structural changes to DNA: single base-pair changes, deletions, insertions, transversions, translocations, amplifications, and duplications.

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Page 392 mutagenic agents. Effects on elements of the growth control circuit, both permanent and transient, probably occur continuously in virtually all animals due to endogenous causes. Exogenous agents (e.g., radiation, chemicals, viruses) also are known to influence this process in a variety of ways. Endogenous events and exogenous causes such as chemical exposure appear to increase the probability of occurrence of cancer by increasing the probability of occurrence of effects on one or more parts of the growth control circuit. The specific effect of one exogenous chemical, aflatoxin B1, on a tumor suppressor gene has been postulated on the basis of molecular epidemiology. Mutations in the tumor suppressor gene p53 are commonly found in the more prevalent human cancers, e.g., colon carcinomas, lung cancer, brain and breast tumors (Levine et al., 1991; Malkin et al., 1990). Populations with high exposure to aflatoxin B1 have a high incidence of hepatocellular carcinoma showing a base change at a specific codon in the p53 gene (Hollstein et al., 1991). However, the patterns of base changes in this gene that are found in virus-associated hepatocellular carcinomas and at other sites of sporadic tumors showing p53 gene mutation are different from the pattern found in aflatoxin B1-exposed populations, supporting the postulate that the specific codon change is a marker of the effect of aflatoxin B1 (Hayward et al., 1991). Research continues to reveal more and more details about the cell growth cycle and to shed light on the events in carcinogenesis at the molecular level. As molecular biology research progresses, it will become possible to better understand the potential mechanisms of action of environmental carcinogens. It has long been known that many agents that are carcinogenic are also mutagenic. Recognition of the role of oncogenes and mutations of tumor suppressor genes has provided specific ideas about the linkage of chemical mutagenesis to the cell growth cycle. Other agents that are not mutagenic, such as hormones and other chemicals that are stimulants to cell replication (mitogens), can be postulated to play their role by acting directly on signal pathways, for example as growth signals or by disrupting signal transduction (Raff, 1992; McCormick and Campisi, 1991; Schuller, 1991). While much has been revealed about likely mechanisms of action at the molecular level, much remains to be understood about tumorigenesis. A cell that has been transformed, acquiring the potential to establish a line of cells that grow to a tumor, will probably realize that potential only rarely. The process of tumorigenesis in animals and humans is a multistep one (Bouk, 1990; Fearon and Vogelstein, 1990; Hunter, 1991; Kumar et al., 1990; Sukumar, 1989; Sukumar, 1990), and normal physiological processes appear to be heavily arrayed against uncontrolled growth of a transformed cell (Weinberg, 1989). Powerful inhibition by signals from contact with neighboring normal cells is one known barrier (Zhang et al., 1992). Another is the immune system (at least for viral infection). How a cell with tumorigenic potential acquires additional properties that are necessary to enable it to overcome these and other inhibitory processes is

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Page 393 unknown. For known human carcinogens studied thus far, there is an often decades-long latency between exposure to carcinogenic agents and development of tumors, which may suggest a process of evolution (Fidler and Radinsky, 1990; Tanaka et al., 1991; Thompson et al., 1989). The events in experimental tumorigenesis have been described as involving three stages: initiation, promotion, and progression. The initiation stage has been used to describe a point at which a cell has acquired tumorigenic potential. Promotion is a stage of further changes, including cell proliferation, and progression is the final stage of further events in the evolution of malignancy (Pitot and Dragan, 1991). The entire process involves a combination of endogenous and exogenous causes and influences. The individual human's susceptibility is likely to be determined by a combination of genetic factors and medical history (Harris, 1989; Nebreda et al., 1991), lifestyle, diet, and exposure to chemical and physical agents in the environment. A number of key questions about carcinogenesis have no generic answers—questions such as: How many events are required? Is there a necessary sequence of events? The answers to these questions may vary for different tissues and species even though the nature of the overall process appears to be the same. The fact that the nature of the process appears empirically to be the same across species is the basis for using assumptions that come from general knowledge about the process to fill gaps in empirical data on a particular chemical. Knowledge of the mechanisms that may be operating in a particular case must be inferred from the whole of the data and from principles on which there is some consensus in the scientific community. Information from studies that support inferences about mechanism of action can have several applications in risk assessment. For human studies, analysis of DNA lesions in tumor cells taken from humans, together with information about the lesions that a putative tumorigenic agent causes in experimental systems, can provide support for or contradict a causal inference about the agent and the human effect (Vahakangas et al., 1992; Hollstein et al., 1991; Hayward et al., 1991). An agent that is observed to cause mutations experimentally may be inferred to have potential for carcinogenic activity (U.S. EPA, 1991a). If such an agent is shown to be carcinogenic in animals the inference that its mechanism of action is through mutagenicity is strong. A carcinogenic agent that is not mutagenic in experimental systems, but is mitogenic or affects hormonal levels or causes toxic injury followed by compensatory growth may be inferred to have effects on growth signal transduction or to have secondary carcinogenic effects. The strength of these inferences depends in each case on the nature and extent of all the available data. These differing mechanisms of action at the molecular level have different dose-response implications for the activity of agents. The carcinogenic activity of a direct-acting mutagen should be a function of the probability of its reaching

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Page 438 In cases, where a mechanism has been identified that has special implications for early-life exposure, differential effects by sex, or other concerns for sensitive subpopulations, these are explained. Similarly, any expectations that high dose-rate exposures may alter the risk picture for some portion of the population are described. These and other perspectives are recorded to guide exposure assessment and risk characterization. 4. Exposure Assessment Guidelines for exposure assessment of carcinogenic and other agents are published in USEPA, 1992a. The exposure characterization is a key part of the exposure assessment; it is the summary explanation of the exposure assessment. The exposure characterization a. provides a statement of purpose, scope, level of detail, and approach used in the assessment; b. presents the estimates of exposure and dose by pathway and route for individuals, population segments, and populations in a manner appropriate for the intended risk characterization; c. provides an evaluation of the overall quality of the assessment and the degree of confidence the authors have in the estimates of exposure and dose and the conclusions drawn; and d. communicates the results of exposure assessment to the risk assessor, who can then use the exposure characterization, along with the characterization of the other risk assessment elements, to develop a risk characterization. In general, the magnitude, duration, and frequency of exposure provide fundamental information for estimating the concentration of the carcinogen to which the organism is exposed. These data are generated from monitoring information, modeling results, and or reasoned estimates. An appropriate treatment of exposure should consider the potential for exposure via ingestion, inhalation, and dermal penetration from relevant sources of exposures, including multiple avenues of intake from the same source. Special problems arise when the human exposure situation of concern suggests exposure regimens, e.g., route and dosing schedule that are substantially different from those used in the relevant animal studies. The cumulative dose received over a lifetime, expressed as average daily exposure prorated over a lifetime, is an appropriate measure of exposure to a carcinogen particularly for an agent that acts by damaging DNA. The assumption is made that a high dose of a carcinogen received over a short period of time is equivalent to a corresponding low dose spread over a lifetime. This approach becomes more prob-

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Page 439 lematic as the exposures in question become more intense but less frequent, especially when there is evidence that the agent acts by a mechanism involving dose-rate effects. 5. Characterization Of Human Risk 5.1. Purpose The risk characterization is prepared for the purpose of communicating results of the risk assessment to the risk manager. Its objective is to be an appraisal of the science that the risk manager can use, along with other decisionmaking resources, to make public health decisions. A complete characterization presents the risk assessment as an integrated picture of the analysis of the hazard, dose response, and exposure. It is the risk analyst's obligation to communicate not only summaries of the evidence and results, but also perspectives on the quality of available data and the degree of confidence to be placed in the risk estimates. These perspectives include explaining the constraints of available data and the state of knowledge about the phenomena studied. 5.2. Application A risk characterization is a necessary part of any Agency report on risk, whether the report is a preliminary one prepared to support allocation of resources toward further study or a comprehensive one prepared to support regulatory decisions. Even if only parts of a risk assessment (hazard and dose-response analyses for instance) are covered in a document, the risk characterization will carry the characterization to the limits of the document's coverage. 5.3. Content Each of the following subjects should be covered in the risk characterization. 5.3.1. Presentation and Descriptors The presentation of the results of the assessment should fulfill the aims as outlined in the purpose section above. The summary draws from the key points of the individual characterizations of hazard, dose response, and exposure analysis performed separately under these guidelines. The summary integrates these characterizations into an overall risk characterization (AIHC, 1989). The presentation of results clearly explains the descriptors of risk selected to

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Page 440 portray the numerical estimates. For example, when estimates of individual risk are used or population risk (incidence) is estimated, there are several features of such estimates that risk managers need to understand. They include, for instance, whether the numbers represent average exposure circumstances or maximum potential exposure. The size of the population considered to be at risk and the distribution of individuals' risks within the population should be given. When risks to a sensitive subpopulation have been identified and characterized, the explanation covers the special characterization of this population. 5.3.2. Strengths and Weaknesses The risk characterization summarizes the kinds of data brought together in the analysis and the reasoning upon which the assessment rests. The description conveys the major strengths and weaknesses of the assessment that arise from availability of data and the current limits of understanding of the process of cancer causation. Health risk is a function of the three elements of hazard, dose response, and exposure. Confidence in the results of a risk assessment is, thus, a function of confidence in the results of the analyses of each element. The important issues and interpretations of data are explained, and the risk manager is given a clear picture of consensus or lack of consensus that exists about significant aspects of the assessment. Whenever more than one view of the weight of evidence or dose-response characterization is supported by the data and the policies of these guidelines, and when choosing between them is difficult, the views are presented together. If one has been selected over another, the rationale is given; if not, both are presented as plausible alternative results. If a quantitative uncertainty analysis of data is appropriate, it is presented in the risk characterization; in any case, qualitative discussion of important uncertainties is appropriate. 6. References Allen, B. C.; Crump, K. S.; Shipp, A. M. (1988) Correlation between carcinogenic potency of chemicals in animals and humans. Risk Anal. 8: 531-544. American Industrial Health Council, (1989) Presentation of risk assessment of carcinogens. Report of an Washington, D.C. ad hoc study group on risk assessment presentation. Ames, B. N.; Gold, L. S. (1990) Too many rodent carcinogens: mitogenesis increases mutagenesis. Science 249: 970-971. Ashby, J.; DeSerres, F. J.; Shelby, M. D.; Margolin, B. H.; Isihidate, M. et al., eds. (1988) Evaluation of short-term tests for carcinogens: report of the International Programme on Chemical Safety's collaborative study on in vivo assays. Cambridge, United Kingdom: Cambridge University. v. 1,2; 431 pp., 372 pp. Ashby, J.; Tennant, R. W. (1991) Definitive relationship among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res. 257: 229-306. Auger, K. R.; Carpenter, C. L.; Cantley, L. C.; Varticovski, L. (1989a) Phosphatidylinositol 3-kinase

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