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SCIENTIFIC @ASES FCR ICENTIFYING POTENTIAL CARCINOGENS AVD ESTIMATING THEIR RISKS A report of the` Interagency Regulatory Liaison Group (IRlLG*), Work Group on Risk Assessment ** l 'I~C,uring the preparation nf this ducument, the IRLG consisted of fawi- agencies; the UnilCed States Consumer Product Safety Comaission (CPSC), the 1lnited States Environmental Protection Agency (EPA), the Food and Drug Administration (FDA) of the United States Department of Health, Education and Welfare, and th.e Occupational Safety and Health Administration (OSHA) of the United States Department of Labor. ~1+~lork Grouv Members: Joseph V. Rodricks (Chairman, . Elizabeth L. Anderson (EPA), David W. Gaylor (FDA/National FDA) Center for Toxicolsgical . Research), Richard A. Heller (CPSC), Anson M. KPl ler (OS-tA) , Frank Kover (EPA), Joseph McLaughlin (CPSC). Invited Participants in the klork Grotiv Ray E. Albert (EPA), Richard R. Sates (National Institute of Environmental Health Sciences (NIEHS)), David G. Hoel (NIF}iS), Umberto Saffiotti (National Cancer Institute (NCI)), Marvin A. Schneiderman (NCI). Valuable guidance was received from Arthur C. Upton (Director, NCI) and David P. Rall (Director, NIEHS). The Work Group acknowledges the assistance of Edward Allera (F'CA), Ann Barton (EPA), Steven Bayard (CPSC), Charles C. Brown (NCI), Donald Clay (CPSC), Carl Gerber (Office of Science and Technology Policy), Steven Jellinek (gPA), Richard Hill

(EPA), Nathan J. Karch (Council on Environmental Qualitr), J. William Lloyd (OSr4.A), Ellen Siegler (EPA), James Sontag (NCI), and Raymond Woltman (CPSC). Requests for reprints should be addressed to Executive Assistant, IRLG,'`Room 504, 1111 18th StrQet, N.W., Washington, D.C. 20207. A85lMACT Three types of evidence can be used to identify substances that may pose a carcinogenic hazard: 1), e?idemiological evidence derived from studies of exposed huYnan populations, c) experimental animal evidence dErived from long-term bioassays, and 3) supportive or suggestive evidence derived from studies of chemical structure or from shart-ter4n or other tests that are known to correlate with carcinogenic activity. Part II of the report delineates the scientific bases for •aecepting evidence from these three sources and also •degcribes their relative contributions to the determination that a"substance may pose a carcinogenic hazard. Further, it details those factors that should be considered in the evaluation of experimental and epidemiological data for purposes of ascertaining the reliability and scientific merit of each of these sources of evidence. It also specifies how certain types of limitations in data may require qualification of conclusions drawn. . •• .. Because experimental animal data are currently the major source of info:-mation for assessing carcinogenicity, they receive the .greatest emphasis. Features of experimental design and conduct that influence the evaluation of such studies are discussed, as are the criteria for making evaluations. The report is not intended to specify how such studies should be des=gned and conducted; ratherr it discusses how given types of data, which arise from experimental animal -studies of widely varying content and qualityr should be evaluated for purposes of identifying carcinogens. Although presented in nuch less details epidemiological data and some of their limitations are discussed. Chemical structure and the several kinds of short terta tests that corr elate with carcinogenic activity are briefly described, as are their roles in providing suggestive or, if coupled with positive animal or human data, supportive, evidence of carcinogenicity. CS 04 02l05/T9 -2-

Throughout Part II of the document are presented the criteria used to ascertain the adequacy of evidence purporting to show that a substance does not pose a risk of cancer. Also included in Part IY are__ discussions of some of the types of experimental evidence that,,,if of adequate extent and quality, may be used to show that certain carcinogenic responses observed in experimental animals may not be predictive of human response. P4rt III of the report sets ,forth current methodologies for quantification of risk. Included aro discussions of mathematical models available for extrapolation, within a biological system, of cancer incidence data observed at eiperimental dose levels to estimate risks at the (usually Fruch loyier ) levels of concern for humans. Also presented are the factors that shduld be considered when attempting to identify the human population(s.) at risk and to define their conditions and levels of carcinogen exposure. Part III also deals with the problem of correlating the magnitude of effects observed in one human population group or in experimental animals, under their conditions and level of expnsure, with the magnitude of effects in the human population for which the estimate of risk is being made. Limitations in current risk estimation methodologies are described as are the problems of ensuring that human risk is not underestimated: The issue of thresholds for carcinogens is discussed the final section of Part III. ;

t INCEX Page Par t I -- INTRCI7L:CTIOiV 7 Par t 11 A. s -- ?h'E GUALITATIVE CE?ERMINATION THAT A 5U8STAMCE PDSES A CARCINOM4IC ' HAZARD Definition and extent of the problem. 9 1. Nature of carcinogenesis and ~ carcinogenic responses. 2. Estimating the numbar of caresnogenic 12 substances. 3. Enhancing factors. 13 4. Variability of effects of carcinogens. 15 8. Epidemiologic evidence. ' 16 . . 1. Types of epideraiologic evidence. 18 2. Oisease ascertainment. 21 C. Experimental animal evidence. 22 1. Criteria for evaluating experimental design and conduct. a. Experimental design. 23 b. The choice of the animal model. 24 c. The number of animals. d.' The route of administration. 29 . e. The identity of the substance 31 tested. I 02106/T9 -4-

S` f. The dose levels. .~ g. The age at treatment. h. The conduct and duration of animal 37 bioassays. . 2. Criteria for evaluating pathology. a. The pathology examination. b. The evaluation of pathologieal results. ( i) Internal consistency of the data. (ii) Reproducibility of test. results. (iii) ,-Evidence of a positive dose-response relationship. (iv) Concordance of results. .. (vY Evaluation of tumor incidenze. (vi) Evaluation of tumor morphology. (vii) General evaluation of neoplastic pathology for carcinogenesis bicassays. Pag e 33 35 39 39 43 53 3. Statistical analysis of results. 57 D. Short-term tests for sarcinogens. 61. 1. Methods based on genetic 4lterations: 61 2. Methods based on neopl,astic cell f63 transformation. . 02J06/79 -5-

C Page 3. Evaluation of short-term test results. 6-S K E. Molecular structure as supporting evidence 67 in the identification of carcinogens. F. Qualitative 3udgmental factors in the 69 evaluation of the total.evidence. Part III - THE QUAS4TZTATI41E ESTIMATIfl1V CP RySH . 72 A. Mathematical models for high-to-low dose 77 extrapolation within a single biological system. 1. The models. 78 2. Discussion of procedures. •84 8. Characterization of Population Exposure. 86 1. Sources of human exposure. 2. Analytical methods for detecting and measuring exposures. 3. Routes and conditions.of exposure. 4. Duration, frequency and intensity of exposure. 5. Size and characteristics of the 41 exposed populations. C. Extrapolation from observed'effects to estimates of risk for the exposed population. 1. Correlations from observed human populatisn groups to others. 87 92 93 95 2. Animal to htiman correlations. 96 D. Lack of predictable thresholds for 100 an exposed population. E. Sumnary of risk estimation. REFERENCES 101 103

C I TNTRC3QUCTZ QN .- This document describes the best judgments of the IRLG agencies on the scientific concepts and metNods currently in use,to identify and evaluate substances that may pose a risk of cancer to humans. These are fitndameMtal steps in any program regtslafang carcinogens. The document was prepared by the Risk Assessr»ent Work Group of the IRLG agencies and senior scientists from the National Cancer Institute and the National Institute of Environmental Health Sciences. The document describes: (1) the basis for makin9 a qualitative evaluation of whether , a particular substance presents a carcinogenic hazard and- how the results of epidemological studies and animal bioassays, along with other types of -inform,ation, are used in making that evaluation; and (2) the methQds that are used in making quantitative estimates of the carcinogenic risk posed by the substance, if such risk estimates are appropriate or required. This document will provide a valuable scientific tool, to be considered in association with other information, in the evaluation of risk and as a means of ascertaining- the adequacy of experimental and epidemiological methods used in that

c C evaluation. It 'is an important step in ensuring that the regulatory agencies evaluate carcinogenic risks consistently. The four IRLG agencies caution, however, that this document has no regulatory status at the present time. Its use will, of '~ tourse, depend upon the statutory requirements of the individual agencies. The Agencies are subjecting this document to scientific peer review through the submission of the dccument to the Journ I Qf the Natie_nal ,__Carcer Yr,s±itu-,8gx for refereed publication. In addition, a public notice and comment procedure will be initiated. Since QSH4 has already' received extensive public camrr~ent on these and other.-issues in its cancer policy rule;riaking, and will soon promulgate its policy, only CPSC, EPA, and FDA will participate in the public notice - , . . and comment procedure on this document. At the canclusion of the notice and comment procedure an this document, OSHA will consider whether revisions to its final cancer policy are appropriate. The four agencies emphasize that the goal of this process is to articulate a consistent policy on the scientific principles applicable to the-identification and evaluation of substances that may pase a carcinogenic risk to humans. Part II discusses the qualitative determination that substance poses a eartinagenit hazard. - Part III discusses quantitative estimation of risk. a I C21C6/T4 -s- 4

P II TI-iE (3tJAt. ITATI VE DETEF~M I NATI ON THAT A SLEST~tC,E POSES A CARCINOG~ IC HAZARD ~ . The methods used for regulatory purposes in making a qualitative determination that a substance poses a carcinogenic hazard to humans are based on a substantial scientific consensus, which has emerged from experience, research, debate e"d review. While some points need further clarification and definition, substantial agreement exists among the fgder.al regulatory agencies on criteria f or evaluating the carcinogenicity of a substance. In addition to determining that a substance may pose a hazard of cancer, regulatory agencies must consider other possible health hazards and, in some cases, are required to balance considerations of risk with other factors (such as 0 possible health benefits, or economic costs and benefits) in reaching regulatory decisions. A. QefinitiQr and EYtent o* the Prohlem 1. Nature of carcinoaene5is and carcinaaenic re5vanges. . The characteristic toxicologic event in carcinogenesis is a change in . the regulatory mechanism of the target cells resulting in sslf-replicating cell lesions. The carcinogenic event so modifies the genome and/or other molecular control mechanisms in the target cells that these are enabled to give i

C C rise to a progeny of permanently altered cells. It is this progeny of cells that constitutes the basis of the neoplastic disease. The e-xpression of the toxic injury therefore does not derive from the same cells that were originally hit by the. toxic agent nor from their functional products but rather from the proliferation of a new populatiorn of altered cells. The critical molecular injury caused by specific carcinogenic agents may be quantitatively extremely limited even to a few cells - and may therefore not be detectab2e. What will make it manifest, through the subsequent growth of a clinically detectable neoplasia, is the proliferation of.the altered cell population. The intensity of the pathological response in a subject, (i.e. the growth rate and spread of a cancer), is dependent.on conditions of the host subsequent to V the initial carcinogenic event and can be modified by other factors, such as enhancing agents and -dietary factors. Th continued progression of clinical manifestations of the carcinogenic process can occur in the absence of continued exposure to the carcinogen. Carcinogenic effects are therefore self-replicating tox3.c eff ects, different from the common terminal toxic effects, in which the manifestations of toxicity are due to altered functional products, degenerative changes or death o¢ the target cells themselves(1).