U

WednesdaySeptember 24, 1986

Part II

EnvironmentalProtection AgencyGuidelines for Carcinogen RiskAssessment

33992_____Federal Register / Vol. 51, No. 185 / Wednesday. September 24. 1986 / Notices

ENVIRONMENTAL PROTECTIONAGENCYIFRL-2984-1J

Guidelines for Carcinogen RiskAssessmentAGENCY: U.S. Environmental ProtectionAgency (EPA).ACTION: Final guidelines for carcinogenrisk assessment.SUMMARY: The U.S. EnvironmentalProtection Agency is today issuing fiveguidelines for assessing the health risksof environmental pollutants. These are:Guidelines for Carcinogen Risk

AssessmentGuidelines for Estimating ExposuresGuidelines for Mutagenicity Risk

AssessmentGuidelines for the Health Assessment of

Suspecl Developmental ToxicantsGuidelines for the Health Risk

Assessment of Chemical MixturesThis notice contains the Guidelines forCarcinogen Risk Assessment; the otherguidelines appear elsewhere in today'sFederal Register.

The Guidelines for Carcinogen RiskAssessment (hereafter "Guidelines") areintended to guide Agency evaluation ofsuspect carcinogens in line with thepolicies and procedures established inthe statutes administered by the EPA.These Guidelines were developed aspart of an interoffice guidelinesdevelopment program under theauspices of the Office of Health andEnvironmental Assessment (OHEA) inthe Agency's Office of Research andDevelopment. They reflect Agencyconsideration of public and ScienceAdvisory Board (SAB) comments on theProposed Guidelines for CarcinogenRisk Assessment published November23,1984 (49 FR 46294).

This publication completes the firstround of risk assessment guidelinesdevelopment. These Guidelines will berevised, and new guidelines will bedeveloped, as appropriate.EFFECTIVE DATE: The Guidelines will beeffective September 24,1986.FOR FURTHER INFORMATION CONTACTDr. Robert E. McGaughy, CarcinogenAssessment Group, Office of Health andEnvironmental Assessment (RD-689).U.S. Environmental Protection Agency,401 M Street SW., Washington, DC20460, 202-382-5898.SUPPLEMENTARY INFORMATION: In 1983,the National Academy of Sciences(NAS) published its book entitled RiskAssessment in the Federal Government-Managing the Process. In that book, theNAS recommended that Federalregulatory agencies establish "inference

guidelines" to ensure consistency andtechnical quality in risk assessmentsand to ensure that the risk assessmentprocess was maintained as a scientificeffort separate from risk management. Atask force within EPA accepted thatrecommendation and requested thatAgency scientists begin to develop suchguidelines.General

The guidelines published today areproducts of a two-year Agencywideeffort, which has included manyscientists from the larger scientificcommunity. These guidelines set forthprinciples and procedures to guide EPAscientists in the conduct of Agency riskassessments, and to inform Agencydecision makers and the public aboutthese procedures. In particular, theguidelines emphasize that riskassessments will be conducted on acase-by-case basis, giving fullconsideration to all relevant scientificinformation. This case-by-casie approachmeans that Agency experts review thescientific information on each agent anduse the most scientifically appropriateinterpretation to assess risk. Theguidelines also stress that thisinformation will be fully presented InAgency risk assessment documents, andthat Agency scientists will identify thestrengths and weaknesses of eachassessment by describing uncertainties,assumptions, and limitations, as well asthe scientific basis and rationale foreach assessment

Finally, the guidelines are formulatedin part to bridge gaps in risk assessmentmethodology and data. By identifyingthese gaps and the importance of themissing information to the riskassessment process, EPA wishes toencourage research and analysis thatwill lead to new risk assessmentmethods and data.Guidelines for Carcinogen RinkAssessment

Work on the Guidelines forCarcinogen Risk Assessment began InJanuary 1984. Draft guideline!) weredeveloped by Agency work groupscomposed of expert scientists fromthroughout the Agency. The drafts werepeer-reviewed by expert scientists In thefield of carcinogenesis from universities,environmental groups, industry, labor, 'and other governmental agencies. Theywere then proposed for public commentin the Federal Register (49 FR 46294). OnNovember 9,1984, the Administratordirected that Agency offices use theproposed guidelines in performing riskassessments until final guidelinesbecome available.

After the close of the public commentperiod, Agency staff preparedsummaries of the comments andanalyses of the major issues presentedby the commentors, and proposedchanges in the language of theguidelines to deal with the issues raised,These analyses were presented toreview panels of the SAB on March 4and April 22-23,1985, and to theExecutive Committee of the SAB onApril 25-28,1985. The SAB meetingswere announced in the Federal Registeras follows: February 12,1985 (50 FR5811) and April 4.1985 (50 FR 13420 and13421).

In a letter to the Administrator datedJune 19,1985, the Executive Committeegenerally concurred on all five of theguidelines, but recommended certainrevisions, and requested that anyrevised guidelines be submitted to theappropriate SAB review panel chairmanfor review and concurrence on behalf ofthe Executive Committee. As describedin the responses to comments (see PartB: Response to the Public and ScienceAdvisory Board Comments), eachguidelines document was revised, whereappropriate, consistent with the SABrecommendations, and revised draftguidelines were submitted to the panelchairmen. Revised draft Guidelines forCarcinogen Risk Assessment wereconcurred on in a letter dated February7,1986. Copies of the letters areavailable at the Public InformationReference Unit, EPA HeadquartersLibrary, as indicated elsewhere in thisnotice.

Following this Preamble are two parts:Part A contains the Guidelines and PartB, the Response to the Public andScience Advisory Board Comments (asummary of the major public comments,SAB comments, and Agency responsesto those comments).

The Agency is continuing to study therisk assessment issues raised in theguidelines and will revise theseguidelines in line with new informationas appropriate.

References, supporting documents,and comments received on the proposedguidelines, as well as copies of the finalguidelines, are available for inspectionand copying at the Public InformationReference Unit (202-382-5928), EPAHeadquarters Library, 401 M StreetSW., Washington, DC, between thehours of 8:00 a.m. and 4:30 p.m.

I certify that these Guidelines are notmajor rules as defined by ExecutiveOrder 12291, because they arenonbinding policy statements and haveno direct effect on the regulatedcommunity. Therefore, they will have noeffect on costs or prices, and they will

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have no other s ignif icant adverse effectson the economy. These Guidelines werereviewed by the Office of Managementand Budget under Executive Order12291.

Dated: August 22, 19H6.L«e M. Thomas,Administrator.Contents

Par! A: Guidelines for Carcinogen RiskAssessment

/. Introduction

II. Hazard IdentificationA. OverviewB. Elements of Hazard Identification -

1. Physical-Chemical Properties and Routesand Patterns of Exposure

2. Structure-Activity Relationships3. Metabolic and Pharmacokinetic

Properties4. Toxicologic Effects5. Short-Term Tests6. Long-Term Animal Studies7. Human Studies

C. Weight of EvidenceD. Guidance for Dose-Response AssessmentE. Summary and Conclusion///. Dose-Response Assessment, ExposureAssessment, and Risk CharacterizationA. Dose-Response Assessment

1. Selection of Data2. Choice of Mathematical Extrapolation

Model3. Equivalent Exposure Units Among

Specie*B. Exposure AssessmentC. Risk Characterization

1. Options for Numerical Risk Estimates2. Concurrent Exposure3. Summary of Risk Characterization

IV. EPA Classification System forCategorizing Weight of Evidence forCarcinogentcity From Human and AnimalStudies (Adapted From lAftC)A. Assessment of Weight of Evidence for

Carcinogentcity Prom Studies in HumansB. Assessment of Weight of Evidence for

Carcinogenic)ty From Studies inExperimental Animals

C. Categorization of Overall Weight ofEvidence for Human Carcinogenicity

V. ReferencesPart B: Response to Public and ScienceAdvisory Board Comments/. IntroductionII. Office of Science and Technology Policy

Report on Chemical Carcinogens ___ _.///. Inference Guideline* - '""IV. Evaluation of Benign TumorsV. Transplacental and Muttigenerational

Animal BiaassaysVI. Maximum Tolerated DoseVII. Mouse Liver TvmonVIII. Weight-of-Evidence CategoriesI.. Quantitative Estimates of Risk

Part A; Guidelines for Carcinogen RiskAssessment/. Introduction

This is the first revision of the 1976Interim Procedures and Guidelines forHealth Risk Assessments of SuspectedCarcinogens (U.S. EPA, 1976; Albert etal.. 1977). The impetus for this revision isthe need to incorporate into theseGuidelines the concepts and approachesto carcinogen risk assessment that havebeen developed during the last tenyears. The purpose of these Guidelinesis to promote quality and consistency ofcarcinogen risk assessments within theEPA and to inform those outside the

-fiPA about its approach to carcinogenrisk assessment. These Guidelinesemphasize the broad but essentialaspects of risk assessment that areneeded by experts in the variousdisciplines required (e.g., toxicology,pathology, pharmacology, and statistics)for carcinogen risk assessment.Guidance is given in general terms sincethe science of carcinogenesis is in astate of rapid advancement, and overlyspecific approaches may rapidly becomeobsolete.

These Guidelines describe the generalframework to be followed1 in developingan analysis of carcinogenic risk andsome salient principles to be used inevaluating the quality of data and informulating judgments concerning thenature and magnitude of the cancerhazard from suspect carcinogens. It isthe intent of these Guidelines to permitsufficient flexibility to accommodatenew knowledge and new assessmentmethods as they emerge. It fa alsorecognized that there i> a need for newmethodology that has not beenaddressed in this document In a numberof areas, e,g., the characterization ofuncertainty. A» this knowledge endassessment methodology arc developed,these Guideline* will be revisedwhenever appropriate.

A summary of the current state ofknowledge in the field of carcinogenesisand a statement of broad scientificprinciples of carcinogen riskassessment, which was developed bythe Office of Science and TechnologyPolicy (OSTP, 1985), forms an importantbasis for these Guidelines; the format ofthese Guidelines it similar to thaiproposed by the National ResearchCouncil (NRC) of the National Academyof Sciences in a book entitled RiskAssessment in the Federal GovernmentManaging the Process (NRC, 1983).

These Guidelines are to be usedwithin the policy framework alreadyprovided by applicable EPA statutesand do not alter such policies. TheseGuidelines provide general directions

for analyzing and organizing availabledata. They do not imply that one kind ofdata or another is prerequisite forregulatory action to control, prohibit, orallow the use of a carcinogen.

Regulatory decision making involvestwo components: risk assessment andrisk management. Risk assessmentdefines the adverse health consequencesof exposure to toxic agents. The riskassessments will be carried outindependently from considerations ofthe consequences of regulatory action.Risk management combines the riskassessment with the directives ofregulatory legislation, together withsocioeconomic, technical, political, andother considerations, to reach a decisionas to whether or how much to controlfuture exposure to the suspected toxicagents.

Risk assessment includes one or moreof the following components: hazardidentification, dose-responseassessment, exposure assessment, andrisk characterisation (NRC, 1983).

Hazard identification is a qualitativerisk assessment, dealing with theprocess of determining whetherexposure to an agent has the potential toincrease the incidence of cancer. Forpurposes of these Guidelines, bothmalignant and benign tumors are used inthe evaluation of the carcinogenichazard. The hazard identificationcomponent qualitatively answers thequestion of how likely en agent to to bea human carcinogen.

Traditionally, quantitative riskassessment has been used as aninclusive term to describe att or parts ofdose-response assessment, exposureassessment, and risk characterbiation.Quantitative risk assessment can be ftuseful general term in somecircumstances, but the more explicitterminology developed by the NRC(1983) is usually preferred. The dot*-.response assessment define* therelationship between the dose of anagent and the probability of induction ofa carcinogenic effect. This componentusually entails an extrapolation from th*>generally high doses administered toexperimental animals or exposures ,. .noted in epidenuolagic studies to theexposure levels expected from humancontact with the agent m theenvironment; it also includesconsiderations of the validity of theseextrapolations.

The exposure assessment Identifiespopulations exposed to the agentdescribes their composition and size.and presents the types, magnitudes;frequencies, and durations of exposureto the agent

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In risk characterization, the results ofthe exposure assessment and the dose-response assessment are combined toestimate quantitatively the carcinogenicrisk. As part of risk characterization, asummary of the strengths andweaknesses in the hazard identification,dose-response assessment, exposureassessment, and the public health riskestimates are presented. Majorassumptions, scientific judgments, and,to the extent possible, estimates of theuncertainties embodied in theassessment are also presented,distinguishing clearly between fact,assumption, and science policy.

The National Research Council (NRC,1983) pointed out that there are manyquestions encountered in the riskassessment process that areunanswerable given current scientificknowledge. To bridge the uncertaintythat exists in these areas where there isno scientific consensus, inferences mustbe made to ensure that progresscontinues in the assessment process.The OSTP (1985) reaffirmed thisposition, and generally left to theregulatory agencies the job ofarticulating these inferences.Accordingly, the Guidelines incorporatejudgmental positions [science policies)based on evaluation of the presentlyavailable information and on theregulatory mission of the Agency. TheGuidelines are consistent with theprinciples developed by the OSTP(1985), although in many instances arenecessarily more specific,//. Hazard IdentificationA. Overview

The qualitative assessment or hazardidentification part of risk assessmentcontains a review of the relevantbiological and chemical informationbearing on whether or not an agent maypose a carcinogenic hazard. Sincechemical agents seldom occur in a purestate and are often transformed in thebody, the review should includeavailable information on contaminants,degradation products, and metabolites.

Studies are evaluated according tosound biological and statisticalconsiderations and procedures. Thesehave been described in severalpublications (Interagency RegulatoryLiaison Group, 1979; OSTP, 1985; Peto etal., 1980; Mantel, 1980; Mantel andHaenszel, 1959; Interdisciplinary Panelon Carcinogenicity, 1984; NationalCenter for Toxicological Research, 1981;National Toxicology Program, 1984; U.S.EPA, 1983a, 1983b, 1983c; Haseman,1984). Results and conclusionsconcerning the agent, derived fromdifferent types of information, whether

indicating positive or negativeresponses, are melded together into aweight-of-evidence determination. Thestrength of the evidence supporting apotential human carcinogenicityjudgment is developed in a weight-of-evidence stratification scheme.B. Elements of Hazard Identification

Hazard identification should include areview of the following information tothe extent that it is available.

1. Physical-Chemical Properties andRoutes and Patterns of Exposure.Parameters relevant to carcinogenesis,including physical state, physical-chemical properties, and exposurepathways in the environment should bedescribed where possible.

2. Structure-Activity Relationships.This section should summarize relevantstructure-activity correlations thatsupport or argue against the predictionof potential carcinogenicity,

3. Metabolic and PharmacokineticProperties. This section shouldsummarize relevant metabolicinformation. Information such aswhether the agent is direct-acting orrequires conversion to a reactivecarcinogenic (e.g., an electrophilic)species, metabolic pathways for suchconversions, macromolecularinteractions, and fate (e.g., transport,storage, and excretion), as well asspecies differences, should be discussedand critically evaluated.Pharmacokinetic properties determinethe biologically effective dose and maybe relevant to hazard identification andother components of risk assessment

4. Toxicologic Effects. Tcxicologiceffects other than carcinogenicity (e.g.,suppression of the immime system,endocrine disturbances, organ damage)that are relevant to the evaluation ofcarcinogenicity should be summarized.Interactions with other chemicals oragents and with lifestyle factors shouldbe discussed. Prechronlc arid chronictoxicity evaluations, as well as othertest results, may yield information ontarget organ effects, pathophysiologicalreactions, and preneoplastic lesions thatbear on the evaluation ofcarcinogenicity. Dose-response andtime-to-response analyses of thesereactions may also be helpiful.

B. Short-Term Testa. Tests for pointmutations, numerical and structuralchromosome aberrations, DNA damage/repair, and in vitro transformationprovide supportive evidence ofcarcinogenicity and may giveInformation on potential carcinogenicmechanisms. A range of teats from eachof the above end points helps tocharacterize an agent's responsespectrum.

Short-term in vivo and in vitro teststhat can give indication of initiation andpromotion activity may also providesupportive evidence for carcinogenicity.Lack of positive results in short-termtests for genetic toxicity does notprovide a basis for discounting positiveresults in long-term animal studies.

6. Long-Term Animal Studies. Criteriafor tue technical adequacy of animalcarcinogenicity studies have beenpublished (e.g., U.S. Food and DrugAdministration, 1982; InteragencyRegulatory Liaison Group, 1979;National Toxicology Program, 1984;OSTP, 1985; U.S. EPA. 1983a, 1983b,1983c; Feron et al., 1980; Mantel 1980)and should be used to judge theacceptability of individual studies.Transplacental and multigeneratlonalcarcinogenesis studies, in addition tomore conventional long-term animalstudies, can yield useful informationabout the carcinogenicity of agents.

It is recognized that chemicals thatinduce benign tumors frequently alsoinduce malignant tumors, and thatbenign tumors often progress tomalignant tumors (InterdisciplinaryPanel on Carcinogenicity, 1984). Theincidence of benign and malignanttumors will be combined whenscientifically defensible (OSTP. 1985;Principle 8). For example, the Agencywill, in general, consider thecombination of benign and malignanttumors to be scientifically defensibleunless the benign tumors are notconsidered to have the potential toprogress to the associated malignanciesof the same histogenic origin. If anincreased incidence of benign tumors Isobserved in the absence of malignanttumors, in most cases the evidence willbe considered as limited evidence ofcarcinogenicity,

The weight of evidence that an agentis potentially carcinogenic for humansincreases (1) with the increase Innumber of tissue sites affected by theagent; (2) with the increase in number ofanimal species, strains, sexes, andnumber of experiments and dosesshowing a carcinogenic response; (3)with the occurrence of clear-cut dose-response relationships as well as a highlevel of statistical significance of theincreased tumor incidence in treatedcompared to control groups; (4) whenthere is a dose-related shortening of thetime-to-tumor occurrence or time todeath with tumor; and (5) when there isa dose-related increase In the proportionof tumors that are malignant

Long-term animal studies at or nearthe maximum tolerated dose level(MTD) are used to ensure an adequatepower for the detection of carcinogenic

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activity (NTP, 1984; IARC, 1982).Negative long-term animal studies atexposure levels above the MTD may notbe acceptable if animal survival is soimpaired that the sensitivity of the studyis significantly reduced below that of aconventional chronic animal study atthe MTD. The OSTP (1985; Principle 4)has slated that.

The carcinogenic effects of agents may beinfluenced by non-physiological responses(such as extensive organ damage, radicaldisruption of hormonal function, saturation ofmetabolic pathways, formation of stones inthe urinary tract, saturation of DNA repairwith a functional loss of the system] inducedin the model systems. Testing regimesinducing these responses should be evaluatedfor their relevance to the human response toan agent and evidence from such a study,whether positive or negative, must becarefully reviewed.

Positive studies at levels above the MTDshould be carefully reviewed to ensurethat the responses are not due to factorswhich do not operate at exposure levelsbelow the MTD. Evidence indicatingthat high exposures alter tumorresponses by indirect mechanisms thatmay be unrelated to effects at lowerexposures should be dealt with on anindividual basis. As noted by the OSTP(1985). "Normal metabolic activation ofcarcinogens may possibly also bealtered and carcinogenic potentialreduced as a consequence [of high-dosetesting]."

Carcinogenic responses underconditions of the experiment should bereviewed carefully as they relate to therelevance of the evidence to humancarcinogenic risks (e.g., the occurrenceof bladder tumors in the presence ofbladder stones and implantation sitesarcomas). Interpretation of animalstudies is aided by the review of targetorgan toxicity and other effects (e.g.,changes in the immune and endocrinesystems) that may be noted inprechronic or other lexicological studies.Time and dose-related changes in theincidence of preneoplastic lesions mayalso be helpful in interpreting animalstudies.

Agents that are positive in long-termanimal experiments and also showevidence of promoting or cocarcinogenicactivity in specialized tests should beconsidered as complete carcinogensunless there is evidence to the contrarybecause it is, at present, difficult todetermine whether an agent is only apromoting or cocarcinogenic agent.Agents that show positive results inspecial tests for initiation, promotion, orcocarcinogenicity and no indication oftumor response in well-conducted andwell-designed long-term animal studies

should be dealt wilh on an individualbasis.

To evaluate carcinogenicity. theprimary comparison is tumor responsein dosed animals as compared with thatin contemporary matched controlanimals. Historical control data areoften valuable, however, and could beused along with concurrent control datain the evaluation of carcinogenicresponses (Haseman et al., 1984). For theevaluation of rare tumors, even smalltumor responses may be significantcompared to historical data. The reviewof tumor data at sites with highspontaneous background requiresspecial consideration (OSTP. 1985;Principle 9). For instance, a responsethat is significant with respect to theexperimental control group may becomequestionable if the historical controldata indicate that the experimentalcontrol group had an unusually lowbackground incidence (NTP, 1984).

For a number of reasons, there arewidely diverging scientific views (OSTP,1985; Ward et al., 1979a, b; Tomatis.1977; Nutrition Foundation, 1983) aboutthe validity of mouse liver tumors as anindication of potential carcinogenicity inhumans when such tumors occur instrains with high spontaneousbackground incidence and when theyconstitute the only tumor response to anagent. These Guidelines take theposition that when the only tumorresponse it In the mouse liver and whenother conditions for a classification of"sufficient" evidence in animal studiesare met (e.g., replicate studies,malignancy; see section IV), the datashould be considered as "sufficient"evidence of carcinogenicity. It isunderstood that this classification couldbe changed on a case-by-case basis to"limited," if warranted, when factor*such as the following, are observed: anincreased incidence of tumors only inthe highest dose group and/or only atthe end of the study; no substantialdose-related increase in the proportionof tumors that are malignant; theoccurrence of tumors that arepredominantly benign; no dose-relatedshortening of the time to the appearanceof tumors; negative or inconclusiveresults from a spectrum of short-termtests for mutagenic activity; theoccurrence of excess tumors only in asingle sex.

Data from all long-term animal studiesare to be considered in the evaluation ofcarcinogenicity. A positive carcinogenicresponse in one species/strain/sex isnot generally negated by negativeresults in other species/strain/sex.Replicate negative studies that areessentially identical in all other respects

to a positive study may indicate that thepositive results are spurious.

Evidence for carcinogenic actionshould be based on the observation ofstatistically significant tumor responsesin specific organs or tissues.Appropriate statistical analysis shouldbe performed on data from long-termstudies to help determine whether theeffects are treatment-related or possiblydue to chance. These should at leastinclude a statistical test for trend,including appropriate correction fordifferences in survival. The weight to begiven to the level of statisticalsignificance (the p-value) and to otheravailable pieces of information is amatter of overall scientific judgment. Astatistically significant excess of tumorsof all types in the aggregate, in theabsence of a statistically significantincrease of any individual tumor type,should be regarded as minimal evidenceof carcinogenic action unless there arepersuasive reasons to the contrary.

7. Human Studies. Epidemiologicstudies provide unique informationabout the response of humans who havebeen exposed to suspect carcinogens.Descriptive epidemiologic studies areuseful in generating hypotheses andproviding supporting data, but canrarely be used to make a causalinference. Analytical epidemiologicstudies of the case-control or cohortvariety, on the other hand, areespecially useful in assessing risks toexposed humans.

Criteria for the adequacy ofepidemiologic studies are wellrecognized. They include factors such asthe proper selection andcharacterization of exposed and controlgroups, the adequacy of duration andquality of follow-up, the properidentification and characterization ofconfounding factors and biae, theappropriate consideration of latencyeffects, the valid ascertainment of thecauses of morbidity and death, and theability to detect specific effects. Whereit can be calculated, the statisticalpower to detect an appropriate outcomeshould be included in the assessment.

The strength of the epidemiologicevidence for carcinogenicity depends,among other things, on the type ofanalysis and on the magnitude andspecificity of the response. The weightof evidence increases rapidly with thenumber of adequate studies that showcomparable results on populationsexposed to the same agent underdifferent conditions. • -

It should be recognized thatepidemiologic studies are inherentlycapable of detecting only comparativelylarge increases in the relative risk of

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cancer. Negative results from suchstudies cannot prove the absence ofcarcinogenic action; however, negativeresults from a well-designed and well-conducted epidemiologic study thatcontains usable exposure data can serveto define upper limits of risk; these areuseful if animal evidence indicates thatthe agent is potentially carcinogenic inhumans.C. Weight of Evidence

Evidence of possible carcinogenicityin humans comes primarily from twosources: long-term animal tests andepidemiologic investigations. Resultsfrom these studies are supplementedwith available information from short-term tests, pharmacokinetic studies,comparative metabolism studies,structure-activity relationships, andother relevant toxicologic studies. Thequestion of how likely an agent is to bea human carcinogen should be answeredin the framework of a weight-of-evidence judgment. Judgments about theweight of evidence involveconsiderations of the quality andadequacy of the data and the kinds andconsistency of responses induced by asuspect carcinogen. There are threemajor steps to characterizing the weightof evidence for carcinogenicity inhumans: (1) Characterization of theevidence from human studies and fromanimal studies individually, (2)combination of the characterizations ofthese two types of data into anindication of the overall weight ofevidence for human carcinogenicity, and(3) evaluation of all supportinginformation to determine if the overallweight of evidence should be modified.

EPA has developed a system forstratifying the weight of evidence (seesection IV). TSiis classification is notmeant to be applied rigidly ormechanically. At various points In theabove discussion, EPA has emphasizedthe need for an overall, balancedjudgment of the totality of the availableevidence. Particularly for well-studiedsubstances, the scientific data base willhave a complexity that cannot becaptured by any classification scheme.Therefore, the hazard identificationsection should include a narrativesummary of the strengths andweaknesses of the evidence as well asits categorization in the EPA scheme.

The EPA classification system is, ingeneral, an adaptation of theInternational Agency for Research onCancer (IARC, 1982) approach forclassifying the weight of evidence forhuman data and animal data. The EPAclassification system for thecharacterization of the overall weight ofevidence for carcinogenicity (animal,

human, and other supportive data)includes: Group A—Carcinogenic loHumans; Group B—ProbablyCarcinogenic to Humans; Group C—Possibly Carcinogenic to Humans;Group D—Not Classifiable as to HumanCarcinogenicity; and Group 13—Evidence of Non-Carcinogenicity forHumans.

The following modifications of theIARC approach have been made forclassifying human and animal studies.

For human studies:(1) The observation of a statistically

significant association between an agentand life-threatening benign tumors inhumans is included in the evaluation ofrisks to humans.

(2) A "no data available"classification is added.

(3) A "no evidence of carcinogenicity"classification is added. Thisclassificaton indicates that noassociation was found betweenexposure and increased risk of cancer inwell-conducted, well-designed,independent analytical epidemiologicstudies.

For animal studies:(1) An increased incidence of

combined benign and malignant tumorswill be considered to provide sufficientevidence of carcinogenicity if the othercriteria defining the "sufficient"classification of evidence ana met (e.g.,replicate studies, malignancy; seesection IV). Benign and malignanttumors will be combined whenscientifically defensible.

(2) An increased incidence of benigntumors alone generally constitutes"limited" evidence of carcinogenicity.

(3) An increased incidencit ofneoplasms that occur with highspontaneous background incidence (e.g.,mouse liver tumors and rat pituitarytumors in certain strains) generallyconstitutes "sufficient" evidence ofcarcinogenicity, but may be changed to"limited" when warranted by thespecific information available on theagent.

(4) A "no data available"classification has been added.

(5) A "no evidence of carcinogenicity"classification is also added. Thisoperational classification would includesubstances for which there is noincreased incidence of neoplasms in atleast two well-designed and well-conducted animal studies of adequatepower and dose in different species.D. Guidance for Dose-ResponseAssessment

The qualitative evidence forcarcinogenesis should be discussed forpurposes of guiding the dose-responseassessment. The guidance should be

given in terms of the appropriatenessand limitations of specific studies aswell as pharmacokinetic considerationsthat should be factored into the dose-response assessment. The appropriatemethod of extrapolation should befactored in when the experimental routeof exposure differs from that occurringin humans.

Agents that are judged to be in theEPA weight-of-evidence stratificationGroups A and B would be regarded assuitable for quantitative riskassessments. Agents that are judged tobe in Group C will generally be regardedas suitable for quantitative riskassessment, but judgments in this regardmay be made on a case-by-case basis.Agents that are judged to be in GroupsD and E would not have quantitativerisk assessments.E. Summary and Conclusion

The summary should present all of thekey findings in all of the sections of thequalitative assessment and theinterpretive rationale that forms thebasis for the conclusion. Assumptions,uncertainties in the evidence, and otherfactors that may affect the relevance ofthe evidence to humans should bediscussed. The conclusion shouldpresent both the weight-of-evidenceranking and a description that brings outthe more subtle aspects of the evidencethat may not be evident from theranking alone.///. Dose-Response Assessment,Exposure Assessment, and RiskCharacterization

After data concerning thecarcinogenic properties of a substancehave been collected, evaluated, andcategorized, It is frequently desirable toestimate the likely range of excesscancer risk associated with given levelsand conditions of human exposure. Thefirst step of the analysis needed to makesuch estimations is the development ofthe likely relationship between dose andresponse (cancer incidence) in theregion of human exposure. Thisinformation on dose-responserelationships is coupled withinformation on the nature andmagnitude of human exposure to yieldan estimate of human risk. The risk-characterization step also includes aninterpretation of these estimates In lightof the biological, statistical, andexposure assumptions and uncertaintiesthat have arisen throughout the processof assessing risk.

The elements of dose-responseassessment are described in sectionII1.A. Guidance on human exposureassessment Is provided in another EPA

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document (U.S. EPA, 1986); however,section III.B. of these Guidelinesincludes a brief description of thespecific type of exposure informationthat is useful for carcinogen riskassessment. Finally, in section III.C. onrisk characterization, there is adescription of the manner in which riskestimates should be presented so as tobe most informative.

It should be emphasized thatcalculation of quant i ta t ive estimates ofcancer risk does not require that anagent be carcinogenic in humans. Thelikelihood that an agent is a humancarcinogen is a function of the weight ofevidence, as this has been described inthe hazard identification section of theseGuidelines. It is nevertheless importantto present quantitative estimates,appropriately qualified and interpreted,in those circumstances in which there isa reasonable possibility, based onhuman and animal data, that the agentis carcinogenic in humans.

It should be emphasized in everyquantitative risk estimation that theresults are uncertain. Uncertainties dueto experimental and epidemiologicvariability as well as uncertainty in theexposure assessment can be important.There are major uncertainties inextrapolating both from animals tohumans and from high to low doses.There are important species differencesin uptake, metabolism, and organdistribution of carcinogens, as well aaspecies and strain differences in target-site susceptibility. Human populationsare variable with respect to geneticconstitution, diet, occupational andhome environment, activity patterns,and other cultural factors. Riskestimates should be presented togetherwith the associated hazard assessment(section III.C.3.J to ensure that there isan appreciation of the weight ofevidence for carcinogenic! ty thatunderlies the quantitative risk estimates.A. Dose-Response Assessment

1. Selection of Data. As indicated insection H.O., guidance needs to be givenby the individuals doing the qualitativeassessment (toxicologists, pathologists,pharmacologists, etc.} to those doing thequantitative assessment as to theappropriate data to be used in the dose-response assessment. This is determinedby the quality of the data, its relevanceto human modes of exposure, and othertechnical details.

If available, estimates based onadequate human epidemiologic data arepreferred over estimates based onanimal data. If adequate exposure dataexist in a well-designed and well-conducted negative epidemiologic study,it may be possible to obtain an upper-

bound estimate of risk from that study.Animal-based estimates, if available,also should be presented.

In the absence of appropriate humanstudies, data from a species thatresponds most like humans should beused, if information to this effect exists.Where, for a given agent, several studiesare available, which may involvedifferent animal species, strains, andsexes at several doses and by differentroutes of exposure, the followingapproach to selecting the data sets isused: (1) The tumor incidence data areseparated according to organ site andtumor type. {2} All biologically andstatistically acceptable data sets arepresented. (3) The range of the riskestimates is presented with due regardto biological relevance [particularly inthe case of animal studies) andappropriateness of route of exposure. (4)Because it IB possible that humansensitivity is as high as the mostsensitive responding animal species, inthe absence of evidence to the contrary,the biologically acceptable data set fromlong-term animal studies showing thegreatest sensitivity should generally begiven the greatest emphasis, again withdue regard to biological and statisticalconsiderations.

When the exposure route in thespecies from which the dose-responseinformation is obtained differs from theroute occurring in environmentalexposures, the considerations used inmaking the route-to-route extrapolationmust be carefully described. Allassumptions should be presented alongwith a discussion of the uncertainties inthe extrapolation. Whatever procedureis adopted in a given case, it must beconsistent with the existing metabolicand pharmacokinetic information on thechemical (e.g., absorption efficiency viathe gut and lung, target organ doses, andchanges in placental transportthroughout gestation for transplacentalcarcinogens).

Where two or more significantlyelevated tumor sites or types areobserved in the same study,extrapolations may be conducted onselected sites or types. These selectionswill be made on biological grounds. Toobtain a total estimate of carcinogenicrisk, animals with one or more tumorsites or types showing significantlyelevated tumor incidence should bepooled and used for extrapolation. Thepooled estimates will generally be usedin preference to risk estimates based onsingle sites or types. Quantitative riskextrapolations will generally not bedone on the basis of totals that includetumor sites without statisticallysignificant elevations.

Benign tumors should generally becombined with malignant tumors for riskestimates unless the benign tumors arenot considered to have the potential toprogress to the associated malignanciesof the same histogenic origin. Thecontribution of the benign tumors,however, to the total risk should beindicated.

2. Choice of MathematicalExtrapolation Model. Since risks at lowexposure levels cannot be measureddirectly either by animal experiments orby epidemiologic studies, a number ofmathematical models have beendeveloped to extrapolate from high tolow dose. Different extrapolationmodels, however, may fit the observeddata reasonably well but may lead tolarge differences in the projected risk atlow doses.

As was pointed out by OSTP (1985;Principle 26).

No single mathematical procedure isrecognized as the most appropriate for low-dose extrapolation in carcinogenesis. Whenrelevant biological evidence on mechanism ofaction exists {e.g.. pharmacokinetics, targetorgan dose), the models or proceduresemployed should be consistent with theevidence. When data and information arelimited, however, and when much uncertaintyexists regarding the mechanism ofcarcinogenic action, models or procedureswhich incorporate low-dose linearity arepreferred when compatible with the limitedinformation.

At present, mechanisms of thecarcinogenesis process are largelyunknown and data are generally limited.If a carcinogenic agent acts byaccelerating the same carcinogenicprocess that leads to the backgroundoccurrence of cancer, the added effect ofthe carcinogen at low doses Is expectedto be virtually linear (Crump et at, 1976).

The Agency will review each ,assessment as 10 the evidence oncarcinogenesiu mechanisms and otherbiological or statistical evidence thatindicates the suitability of a particularextrapolation model. Goodness-of-fit tothe experimental observations is not aneffective means of discriminating amongmodels (OSTP, 1985}. A rationale will beincluded to justify the use of the chosenmodel. In the absence of adequateinformation to the contrary, thelinearized multistage procedure will beemployed. Where appropriate, theresults of using various extrapolationmodels may be useful for comparisonwith the linearized multistageprocedure. When longitudinal data ontumor development are available, time-to-tumor models may be used.

It should be emphasized that thelinearized multistage procedure leads to

33998 Federal Regisler / Vol. 51, No. 185 / Wednesday, September 24, 1986 / Notices

a plausible upper limit to the risk that iaconsistent with some proposedmechanisms of carcinogenesis. Such anestimate, however, does not necessarilygive a realistic prediction of the risk.The true value of the risk is unknown,and may be as low as zero. The range ofrisks, defined by the upper limit givenby the chosen model and the lower limitwhich may be as low as zero, should beexplicitly stated. An establishedprocedure does not yet exist for making"most likely" or "best" estimates of riskwithin the range of uncertainty definedby the upper and lower limit estimates.If data and procedures becomeavailable, the Agency will also provide"most likely" or "best" estimates of risk.This will be most feasible when humandata are available and when exposuresare in the dose range of the data.

In certain cases, the linearizedmultistage procedure cannot be usedwith the observed data as, for example,when the data are nonmonotonic orflatten out at high doses. In these cases,it may be necessary to makeadjustments to achieve low-doselinearity.

When pharmacokinetic or metabolismdata are available, or when othersubstantial evidence on the mechanisticaspects of the carcinogenesis processexists, a low-dose extrapolation modelother than the linearized multistageprocedure might be considered moreappropriate on biological grounds.When a different model is chosen, therisk assessment should clearly discussthe nature and weight of evidence thatled to the choice. Considerableuncertainty will remain concerningresponse at low doses; therefore, inmost cases an upper-limit risk estimateusing the linearized multistageprocedure should also be presented.

3. Equivalent Exposure Units AmongSpecies. Low-dose risk estimatesderived from laboratory animal dataextrapolated to humans are complicatedby a variety of factors that differ amongspecies and potentially affect theresponse to carcinogens. Includedamong these factors are differencesbetween humans and experimental testanimals with respect to life span, bodysize, genetic variability, populationhomogeneity, existence of concurrentdisease, pharmacokinetic effects such asmetabolism and excretion patterns, andthe exposure regimen.

The usual approach for makingInterspecies comparisons has been touse standardized scaling factors.Commonly employed standardizeddosage scales include mg per kg bodyweight per day, ppm in the diet or water,mg per m* body surface area per day,

and mg per kg body weight per lifetime.In the absence of comparativelexicological, physiological, metabolic,and pharmacokinetic data for a givensuspect carcinogen, the Agency takesthe position that the extrapolation onthe basis of surface area is consideredto be appropriate because certainpharmacological effects commonly scaleaccording to surface area (Dedrick, 1973;Freireich et a!., 1966; Pinkel, 1958).

B. Exposure AssessmentIn order to obtain a quantitative

estimate of the risk, the results of thedose-response assessment must becombined with an estimate of theexposures to which the populations ofinterest are likely to be subject. Whilethe reader is referred to the Guidelinesfor Estimating Exposures (U.S. EPA,1988) for specific details, it in importantto convey an appreciation of the impactof the strengths and weaknesses ofexposure assessment on the overallcancer risk assessment process.

At present there is no single approachto exposure assessment that isappropriate for all cases. On a case-by-case basis, appropriate methods areselected to match the data on hand andthe level of sophistication required. Theassumptions, approximations, anduncertainties need to be clearly statedbecause, in some instances, these willhave a major effect on the riskassessment

In general, the magnitude, duration,and frequency of exposure providefundamental information for estimatingthe concentration of the carcinogen towhich the organism Is exposed. Thesedata are generated from monitoringinformation, modeling results, and/orreasoned estimates. An appropriatetreatment of exposure should considerthe potential for exposure via tngestion,inhalation, and dermal penetration fromrelevant sources of exposures includingmultiple avenues of intake from thesame source.

Special problems arise when thehuman exposure situation of concernsuggests exposure regimens, e.g., routeand dosing schedule, that aresubstantially different from 'those usedin the relevant animal studies. Unlessthere is evidence to the contrary in aparticular case, the cumulative dosereceived over a lifetime, expressed asaverage daily exposure prorated over alifetime, is recommended as anappropriate measure of exposure to acarcinogen. That is, the assumption Itmade that a high dose of a carcinogenreceived over a short period of time IBequivalent to a corresponding low-dose

spread over a lifetime. This approachbecomes more problematical as theexposures in question become moreintense but less frequent, especiallywhen there is evidence that the agenthas shown dose-rate effects.

An attempt should be made to assessthe level of uncertainty associated withthe exposure assessment which is to beused in a cancer risk assessment. Thismeasure of uncertainty should beincluded in the risk characterization[section III.C.) in order to provide thedecision-maker with a clearunderstanding of the impact of thisuncertainty on any final quantitativerisk estimate. Subpopulatlons withheightened susceptibility (either becauseof exposure or predisposition) should,when possible, be identified.C. Risk Characterization

Risk characterization is composed oftwo parts. One is a presentation of thenumerical estimates of risk; the other isa framework to help judge thesignificance of the risk. Riskcharacterization includes the exposureassessment and dose-responseassessment; these are used in theestimation of carcinogenic risk. It mayalso consist of a unit-risk estimatewhich can be combined elsewhere withthe exposure assessment for thepurposes of estimating cancer risk.

Hazard identification and dose-response assessment are covered insections II and I1I.A., and a detaileddiscussion of exposure assessment iscontained in EPA's Guidelines forEstimating Exposures (U.S. EPA. 1986).This section deals with the numericalrisk estimates and the approach tosummarizing risk characterization.

1. Options for Numerical RiskEstimates. Depending on the needs ofthe individual program offices,numerical estimates can be presented inone or more of the following three ways.

a. Unit Risk—Under an assumption oflow-dose linearity, the unit cancer risk isthe excess lifetime risk due to acontinuous constant lifetime exposure ofone unit of carcinogen concentration.Typical exposure units include ppm orppb in food or water, mg/kg/day byingestion, or ppm or fig/m9 in air.

b. Dose Corresponding to a GivenLevel of Risk—This approach can beuseful, particularly when usingnonlinear extrapolation models wherethe unit risk would differ at differentdose levels,

c. Individual and Population Risks—Risks may be characterized either Interms of the excess individual lifetimerisks, the excess number af cancers

Federal Register / Vol. 51, No. 185 / Wednesday, September 24, 1986 / Notices 33999

produced per year in the exposedpopulation, or both.

Irrespective of the options chosen, thedegree of precision and accuracy In thenumerical risk estimates currently donot permit more than one significantfigure to be presented.

2. Concurrent Exposure. Incharacterizing the risk due to concurrentexposure to several carcinogens, therisks are combined on the basis ofadditivity unless there is specificinformation to the contrary. Interactionsof cocarcinogens. promoters, andinitiators with known carcinogensshould be considered on a case-by-casebasis.

3. Summary of Risk Characterization.Whichever method of presentation ischosen, it is cr i t ica l that the numericalestimales not be allowed to stand alone,separated from the various assumptionsand uncertainties upon which they arebased. The risk characterization shouldcontain a discussion and interpretationof the numerical estimates that affordsthe risk manager some insight into thedegree to which the quantitativeestimates are likely to reflect the truemagnitude of human risk, whichgenerally cannot be known with thedegree of quantitative accuracyreflected in the numerical estimates. Thefinal risk estimate will be generallyrounded to one significant figure andwill be coupled with the EPAclassification of the qualitative weight ofevidence. For example, a lifetimeindividual risk of 2xlO~4 resulting fromexposure to a "probable humancarcinogen" (Group B2) should bedesignated as: 2xlCT4 [B2]. Thisbracketed designation of the qualitativeweight of evidence should be includedwith all numerical risk estimates (I.e.,unit risks, which are risks at a specifiedconcentration or concentrationscorresponding to a given risk). Agencystatements, such as Federal Registernotices, briefings, and actionmemoranda, frequently includenumerical estimates of carcinogenic risk.It is recommended that whenever thesenumerical estimates are used, thequalitative weight-of-evidenceclassification should also be included.

The section on risk characterizationshould summarize the hazardidentification, dose-responseassessment, exposure assessment, andthe public health risk estimates. Majorassumptions, scientific judgments, and,to the extent possible, estimates of theuncertainties embodied in theassessment are presented.

IV. EPA Classification System forCategorizing Weight of Evidence forCarcinogenicity From Human andAnimal Studies (Adapted From IARC)A. Assessment of Weight of Evidencefor Carcinogenicity From Studies inHumans

Evidence of Carcinogenicity fromhuman studies comes from three mainsources:

1. Case reports of individual cancerpatients who were exposed to theagent(s).

2. Descriptive epidemiologic studies inwhich the incidence of cancer in humanpopulations was found to vary in spaceor time with exposure to the agent(s).

3. Analytical epidemiologic [case-control and cohort) studies in whichindividual exposure to the agent(s) wasfound to be associated with anincreased risk of cancer.

Three criteria must be met before acausal association can be inferredbetween exposure and cancer inhumans:

1. There is no identified bias thatcould explain the association.

2. The possibility of confounding hasbeen considered and ruled out asexplaining the association.

3. The association is unlikely to bedue to chance.

In general, although a single studymay be indicative of a cause-effectrelationship, confidence in inferring acausal association is increased whenseveral independent studies areconcordant in showing the association,when the association Is strong, whenthere is a dose-response relationship, orwhen a reduction in exposure iafollowed by a reduction in the incidenceof cancer

The weight of evidence forCarcinogenicity 1 from studies in humansis classified as:

1. Sufficient evidence ofCarcinogenicity, which indicates thatthere ifl a causal relationship betweenthe agent and human cancer.

2. Limited evidence of Carcinogenicity,which indicates that a causalinterpretation is credible, but thatalternative explanations, such aschance, bias, or confounding, could notadequately be excluded.

3. Inadequate evidence, whichindicates that one of two conditionsprevailed: (a) there were few pertinentdata, or (b) the available studies, whileshowing evidence of association, did notexclude chance, bias, or confounding

and therefore a causal interpretation isnot credible.

4. No data, which indicates that dataare not available.

5. No evidence, which indicates thatno association was found betweenexposure and an increased risk ofcancer in well-designed and well-conducted independent analyticalepidemiologic studies.B. Assessment of Weight of Evidence forCarcinogenicity From Studies inExperimental Animals

These assessments are classified intofive groups:

1. Sufficient evidence * ofCarcinogenicity, which indicates thatthere is an increased incidence ofmalignant tumors or combinedmalignant and benign tumors: 8 (a) inmultiple species or strains; or (b) inmultiple experiments (e.g., with differentroutes of administration or usingdifferent dose levels); or (c) to anunusual degree in a single experimentwith regard to high incidence, unusualsite or type of tumor, or early age atonset.

Additional evidence may be providedby data on dose-response effects, aswell as information from short-termtests or on chemical structure.

2. Limited evidence of Carcinogenicity,which means that the data suggest acarcinogenic effect but are limitedbecause: (a) the studies involve a singlespecies, strain, or experiment and do notmeet criteria for sufficient evidence (seesection IV. B.l.c); (b) the experimentsare restricted by inadequate dosagelevels, inadequate duration of exposureto the agent, inadequate period offollow-up, poor survival, too fewanimals, or inadequate reporting; or (c)an increase in the incidence of benigntumors only.

3. Inadequate evidence, whichindicates that because of majorqualitative or quantitative limitations,the studies cannot be interpreted asshowing either the presence or absenceof a carcinogenic effect.

4. No data, which indicates that dataare not available.

5. No evidence, which indicates thatthere is no increased incidence ofneoplasms in at least two well-designed

1 For purposes of public health protection, agentsassociated with life-threatening benign tumors inhumans are included In the evaluation.

1 An increased incidence of neoplasms that occurwith high spontaneous background incidence (e.g.,mouse liver tumors and rat pituitary tumor* tncertain strains) generally constitutes "sufficient"evidence of Carcinogenicity. but may be changed to"limited" when warranted by the specificInformation available on the agent

* Bentgn and malignant tumors will be combinedunless the benign tumor* are not considered to have,the potential to progress to the associatedmalignancies of the same histogenic origin.

34000 Federal Register / Vol. 51, No. 185 / Wednesday. September 24. 1966 / Notices

and well-conducted animal studies indifferent species.

The classifications "sufficientevidence" and "limited evidence" referonly to the weight of the experimentalevidence that these agents arecarcinogenic and not to the potency oftheir carcinogenic action.C. Categorization of Overall Weight ofEvidence for Human Carcinogenicity

The overall scheme for categorizationof the weight of evidence ofcarcinogenicity of a chemical forhumans uses a three-step process. (1)The weight of evidence in humanstudies or animal studies is summarized;(2) these lines of information are

combined to yield a tentativeassignment to a category (see Table 1);and {3J all relevant supportiveinformation Is evaluated to see if thedesignation of the overall weight ofevidence needs to be modified. Relevantfactors to be included along with thetumor information from human andanimal studies include structure-activityrelationships; short-term test findings;results of appropriate physiological,biochemical, and lexicologicalobservations; and comparativemetabolism and pharrnacokineticstudies. The nature of these findingsmay cause one to adjust the overallcategorization of the weight of evidence.

TABLE 1 .—ILLUSTRATIVE CATEGORIZATION OF EVIDENCE BASED ON ANIMALAND HUMAN DATA l

Human evidence

Limited...................................................Inadequate............................................No data .................................................No evidence .........................................

Animal evidence

Sufficient

AB1B2B2B2

Limited

AB1CCC

Indequate

AB1DDD

Nodal*

A61DDD

No.Evidence

AB1DEE

1 The above assignments are presented for flkistrativ* purposes. There may be nuances In theclassification of both animal and human data indicating thai different categorizations than tfiosa given hi tftetabto should be assigned. Furthermore, these assignments are tentative and may be modified by ancillaryevidence. In (his regard all relevant information should be evaluated to determine if the d

Federal Register / Vol. 51, No. 185 / Wednesday, September 24, 1986 / Notices 34001

Evaluation of the Carcinogenic Risk ofChemicals to Humans. Supplement 4. Lyon,France: International Agency for Researchon Cancer.

Mantel, N. 1980. Assessing laboratoryevidence for neoplastic activity. Biometrics36:381-399.

Mantel. N.. and Haenszel, W. 1959. Statisticalaspects of the analysis of data fromretrospective studies of disease. J. Natl .Cancer Inst. 22:719-748.

Nat iona l Center for Toxicological Research(NCTR). 1981. Guidelines for statisticaltests for carcinogenicily in chronicbioassays. NCTR Biometry TechnicalReport 81-001. Available from: NationalCenter for Toxicological Research.

National Research Council (NRC). 1983. Riskassessment in the Federal governmenl:managing (he process. Washington. D.C.:National Academy Press.

Nat iona l Toxicology Program. 1984. Report ofthe Ad Hoc Panul on ChemicalCarcinogenesis Testing and Evaluation ofthe National Toxicology Program. Board ofScientific Counselors. Available from: U.S.Government Printing Office. Washington.D,C. 1984--*21-132:4726.

Nutr i t ion Foundation. 1983. The relevance ofmouse liver hepatoma to humancarcinogenic risk: a report of theInternational Expert Advisory Committeelo the Nulril ion Foundalion. Availablefrom: Nutr i t ion Foundalion. ISBN 0-935368-37-x.

Office of Science and Technology Policy(OSTP). 1985. Chemical carcinogens:review of the science and its associatedprinciples. Federal Register 50:10372-10442.

Peto, R.. Pike. M.. Day. N., Gray, R.. Lee. P.,Parish, S-, Peto, ].. Richard. S., andWahrendorf, J. 1980. Guidelines for simple,sensitive, significant tests for carcinogeniceffects in long-term animal experiments. In:Monographs on the long-term and short-term screening assays for carcinogens: acritical appraisal. 1ARC Monographs.Supplement 2. Lyon. France: InternationalAgency for Research on Cancer, pp. 311-426.

Pinkel. D. 1958. The use of body surface areaas a criterion of drug dosage in cancerchemotherapy. Cancer Res. 18:853-856.

Tomatis, L 1977. The value of long-termtesting for (he implementation of primaryprevention. In: Origins of human cancer.Hiatt. H.H.. Watson. J.D., and Winstein,J.A., eds. Cold Spring Harbor Laboratory.pp. 1339-1357.

U.S. Environmental Protection Agency (U.S.EPA). 1976. Interim procedures andguidelines for health risk and economicimpact assessments of suspectedcarcinogens. Federal Register 41:21402-21405.

U.S. Environmental Protection Agency (U.S.EPA). 1980. Water quality criteriadocuments: availability. Federal Register45:79318-79379.

U.S. Environmental Protection Agency [U.S.EPA). 1983a. Good laboratory practicesstandards—toxicology testing. FederalRegister 48:53922.

U.S. Environmental Protection Agency (U.S.EPA). 1983b. Hazard evaluations: humansand domestic animals. Subdivision P.

Available from: NT1S. Springfield, VA. PB83-153916.

U.S. Environmental Protection Agency (U.S.EPA). 1983c. Health effects test guidelines.Available from: NTIS, Springfield. VA. PB83-232984.

U.S. Environmental Protection Agency (U.S.EPA). 1988. Guidelines for estimatingexposures.

U.S. Food and Drug Administraiion (U.S.PDA). 1982. Toxicological principles for thesafety assessment of direct food additivesand color additives used in food. Availablefrom: Bureau of Foods. U.S. Food and DrugAdministration.

Ward. J.M., Gritrsemer, R.A., and Weisburger,E.K. 1979a. The mouse liver tumor as anendpoint in carcinogenesis teats. Toxicol.Appl. Pharmacol. 51:389-397.

Ward. J.M., Goodman, D.G,. Squire. R.A.,Chu. K.C.. and Linhart, M.S. 1979b.Neoplastic and nonneoplastic lesions maging (C57BL/6N x C3H/HeN)F, (B6C3F.)mice. J. Natl. Cancer Insl. 63:849-854.

Part B: Response to Public and ScienceAdvisory Board Comments/. Introduction

This section summarizes the majorissues raised during both the publiccomment period on the ProposedGuidelines for Carcinogen RiskAssessment published on November 23,1984 (49 FR 46294). and also during theApril 22-23; 1985, meeting of theCarcinogen Risk Assessment GuidelinesPanel of the Science Advisory Board(SAB).

In order to respond to these issues theAgency modified the proposedguidelines in two stages. First, changesresulting from consideration of thepublic comments were made in a draftsent to the SAB review panel prior totheir April meeting. Secondly, theguidelines were further modified inresponse to the panel'srecommendations.

The Agency received 62 sets ofcomments during the public commentperiod, including 28 from corporations, 0from professional or trade associations,and 4 from academic institutions. Ingeneral, the comments were favorable.The commentors welcomed the updateof the 1976 guidelines and felt that theproposed guidelines of 1985 reflectedsome of the progress that has occurredin understanding the mechanisms ofcarcinogenesis. Many commentors,however, felt that additional changeswere warranted.

The SAB concluded that theguidelines are "reasonably complete intheir conceptual framework and aresound in their overall interpretation ofthe scientific issues" (Report by the SABCarcinogenicity Guidelines ReviewGroup, June 19,1985). The SABsuggested various editorial changes andraised some issues regarding the content

of the proposed guidelines, which arediscussed below. Based on theserecommendations, the Agency hasmodified the draft guidelines,//. Office of Science and TechnologyPolicy Report on Chemical Carcinogens

Many commentors requested that thefinal guidelines not be issued until afterpublication of the report of the Office ofTechnology and Science Policy (OSTP)on chemical carcinogens. They furtherrequested that this report beincorporated into the final Guidelinesfor Carcinogen Risk Assessment.

The final OSTP report was publishedin 1985 (50 FR 10372). In itsdeliberations, the Agency reviewed thefinal OSTP report and feels that theAgency's guidelines are consistent withthe principles established by the OSTP.In its review, the SAB agreed that theAgency guidelines are generallyconsistent with the OSTP report. Toemphasize this consistency, the OSTPprinciples have been incorporated intothe guidelines when controversial issuesare discussed.///. Inference Guidelines

Many commentors felt that theproposed guidelines did not provide asufficient distinction between scientificfact and policy decisions. Others feltthat EPA should not attempt to proposefirm guidelines in the absence ofscientific consensus. The SAB reportalso indicated the need to "distinguishrecommendations based on scientificevidence from those based on sciencepolicy decisions."

The Agency agrees with therecommendation that policy,judgmental, or inferential decisionsshould be clearly Identified. In itsrevision of the proposed guidelines, theAgency has included phrases (e.g., "theAgency takes the position that") to moreclearly distinguish policy decisions.

The Agency also recognizes the needto establish procedures for action onimportant issues in the absence ofcomplete scientific knowledge orconsensus. This need wasacknowledged in both the NationalAcademy of Sciences book entitled RiskManagement in the FederalGovernment: Managing the Process andthe OSTP report on chemicalcarcinogens. As the NAS report states,"Risk assessment is an analytic processthat is firmly based on scientificconsiderations, but it also requiresjudgments to be made when theavailable information is incomplete.These judgments inevitably draw onboth scientific and policyconsiderations."

34002 Federal Register / Vol. 51, No. 185 / Wednesday, September 24, 1986 / Notices

The judgments of the Agency havebeen based on current availablescientific information and on thecombined experience of Agency experts.These judgments, and the resultingguidance, rely on inference; however,the positions taken in these inferenceguidelines are felt to be reasonable andscientifically defensible. While all of theguidance is, to some degree, based oninference the guidelines have attemptedto distinguish those issues thatdepended more on judgment. In thesecases, the Agency has stated a positionbut has also retained flexibility toaccommodate new data or specificcircumstances that demonstrate that theproposed position is inaccurate. TheAgency recognizes that scientificopinion wilt be divided on these issues.

Knowledge about carcinogens andcarcinogenesid is progressing at a rapidrate. While these guidelines areconsidered a best effort at the presenttime, the Agency has attempted toincorporate flexibility into the currentguidelines and also recommends thatthe guidelines be revised as often aswarranted by advances in the field.IV, Evaluation of Benign Tumors

Several commentors discussed theappropriate interpretation of anincreased incidence of benign tumorsalone or with an increased incidence ofmalignant tumors as part of theevaluation of the carcinogenicity of anagent. Some comments were supportiveof the position in the proposedguidelines, i.e., under certaincircumstances, the incidence of benignand malignant tumors would becombined, and an increased incidenceof benign tumors alone would beconsidered an indication, albeit limited,of carcinogenic potential. Othercommentors raised concerns about thecriteria that would be used to decidewhich tumors should be combined. Onlya few commentors felt that benigntumors should never be considered inevaluating carcinogenic potential.

The Agency believes that currentinformation supports the use of benigntumors. The guidelines have beenmodified to incorporate the language ofthe OSTP report, i.e., benign tumors willbe combined with malignant tumorswhen scientifically defensible. Thisposition allows flexibility in evaluatingthe data base for each agent. Theguidelines have also been modified toindicate that, whenever benign andmalignant tumors have been combined,and the agent is considered a candidatefor quantitative risk extrapolation, thecontribution of benign tumors to theestimation of risk will be indicated.

V. Transphcental andMultigenerationa! Animal Bioossays

As one of its two proposals foradditions to the guidelines, the SABrecommended a discussion oftransplacental and multigenerationalanimal bloassays for carcinogenicity.

The Agency agrees that such data,when available, can provide usefulinformation in the evaluation of achemical's potential carcinogenicity andhas stated this in the final guidelines.The Agency has also revised theguidelines to indicate that such studiesmay provide additional information onthe metabolic and pharmacokineticproperties of the chemical. Moreguidance on the specific use of thesestudies will be considered in futurerevisions of these guidelines.VI. Maximum Tolerated Dose

The proposed guidelines discussed theimplications of using a maximumtolerated dose (MTD) in bioassays forcarcinogenicity. Many commentorsrequested that EPA define MTD. Thetone of the comments suggested that thecommentors were concerned about theusea and interpretations of high-dosetesting.

The Agency recognizes thaicontroversy currently surrounds theseissues. The appropriate text from theOSTP report has been incorporated intothe final guidelines which tiuggests thatthe consequences of high-dose testing beevahiated on a case-by-ca»e basis.Vll Mouse Liver Tumors

A large number of commentonexpressed opinions about theassessment of bioassaya in which theonly increase in tumor incidence wasliver tumors in the mouse. Many felt thatmouse Uver tumors were afforded toomuch credence, especially jjpven existinginformation that indicates that theymight arise by a different mechanism,e.g., tissue damage followed byregeneration. Others felt that mouseliver tumors were tut one case of a highbackground incidence of one particulartype of tumor and that all such tumorsshould be treated in the same fashion.

The Agency has reviewed thesecomments and the OSTP principleregarding this issue. The OSTP reportdoes not reach conclusions as to thetreatment of tumors with a highspontaneous background rate, butstates, as ia now included in the text ofthe guidelines, that these data requirespecial consideration^ Althoughquestions have been raised regardingthe validity of mouse liver tumors ingeneral, the Agency feels that mouseliver tumors cannot be ignored as an

indicator of carcinogenicity. Thus, theposition in the proposed guidelines hasnot been changed: an increasedincidence of only mouse liver tumorswill be regarded as "sufficient" evidenceof carcinogenicity if all other criteria,e.g., replication and malignancy, are metwith the understanding that thisclassification could be changed to"limited" if warranted. The factors thatmay cause this re-evaluation areindicated in the guidelines.Vttl. Weight-of-Evidence Categories

The Agency was praised by both thepublic and the SAB for incorporating aweight-of-evidence scheme into itsevaluation of carcinogenic risk. Certainspecific aspects of the scheme, however,were criticized.

1. Several commentors noted thatwhile the text of the proposed guidelinesclearly states that EPA will use allavailable data in its categorization ofthe weight of the evidence that achemical is a carcinogen, theclassification system in Part A, sectionIV did not indicate the manner in whichEPA will use information other thandata from humans and long-term animalstudies in assigning a weight-of-evidence classification.

The Agency has added a discussion toPart A, section IV .C. dealing with thecharacterization of overall evidence forhuman carcinogenicity. This discussionclarifies EPA's use of supportiveinformation to adjust, as warranted, thedesignation tnat would have been madesolely on the basis of human and long-term animal studies*

2. The Agency agrees with the SABand those commenton who felt that asimple classification of the weight ofevidence, e.g., a single letter or even adescriptive title, Is inadequate todescribe fully the weight of evidence foreach individual chemical. The finalguidelines propose that a paragraphsummarizing the data shouldaccompany the numerical estimate andweight-of-evidence classificationwhenever possible.

3. Several commentors objected to thedescriptive title E (No Evidence ofCarcinogenicity for Humans) becausethey felt the title would be confusing topeople inexperienced with theclassification system. The title for GroupE, No Evidence of Carcinogenicity forHumans, was thought by thesecommentors to suggest the absence ofdata. This group, however, is intendedto be reserved for agents for whlchthereexists credible data demonstrtftUJgMnatthe agent is not carcinogenic.

Based on these comments and furtherdiscussion, the Agency has changed the

Federal Register / Vol. 51. No. 185 / Wednesday. September 24. 1986 / Notices 34003

title of Group E to "Evidence of Non-Carcinogenicity for Humans."

4. Several commentors felt that thetitle for Group C, Possible HumanCarcinogen, was not sufficientlydistinctive from Group B, ProbableHuman Carcinogen. Other commentorsfelt that those agents that minimallyqualified for Group C would lacksufficient data for such a label.

The Agency recognizes that Group Ccovers a range of chemicals and hasconsidered whether to subdivide GroupC. The consensus of the Agency'sCarcinogen Risk AssessmentCommittee, however, is that the currentgroups, which are based on the IARCcategories, are a reasonablestrat if icat ion and should be retained atpresent. The structure of the groups willbe reconsidered when the guidelines arereviewed in the future. The Agency alsofeels that the descriptive title itor iginal ly selected best conveys themeaning of the classification within thecontext of EPA's past and currentactivities.

5. Some commentors indicated aconcern about the distinction betweenBl and B2 on the basis of epidemiologicevidence only. This issue has beenunder discussion in the Agency and maybe revised in future versions of theguidelines.

6. Comments were also received aboutthe possibility of keeping the groups foranimal and human data separatewithout reaching a combinedclassification. The Agency feels that acombined classification is useful; thus,the combined classification wasretained in the final guidelines.

The SAB suggested that a table beadded to Part A, section IV to indicatethe manner in which human and animaldata would be combined to obtain anoverall weigh t-of-evidence category. TheAgency realizes that a table that wouldpresent all permutations of potentiallyavailable data would be complex andpossibly impossible to construct sincenumerous combinations of ancillarydata (e.g., genetic toxicity,pharmacokinetics) could be used toraise or lower the weight-of-evidenceclassification. Nevertheless, the Agencydecided to include a table to illustratethe most probable weight-of-evidenceclassification that would be assigned onthe basis of standard animal and humandata without consideration of theancillary data. While it is hoped thatthis table wilt clarify the weight-of-evidence classifications, it is alsoimportance recognize that an agentmay be assigned to a finalcategorization different from thecategory which would appearappropriate from the table and stillconform to the guidelines.

IX. Quantitative Estimates of RiskThe method for quant i ta t ive estimates

of carcinogenic risk in the proposedguidelines received substantialcomments from the public. Five issueswere discussed by the Agency and haveresulted in modifications of theguidelines.

1. The major criticism was theperception that EPA would use only onemethod for the extrapolation ofcarcinogenic risk and would, therefore,obtain one estimate of risk. Evencommentors who concur with theprocedure usually followed by EPA feltthat some indication of the uncertaintyof the risk estimate should be includedwith the risk estimate.

The Agency feels that the proposedguidelines were not intended to suggestthat EPA would perform quanti tat iverisk estimates in a rote or mechanicalfashion. As indicated by the OSTPreport and paraphrased in the proposedguidelines, no single mathematicalprocedure has been determined to bethe most appropriate method for riskextrapolation. The final guidelines quoterather than paraphrase the OSTPprinciple. The guidelines have beenrevised to stress the importance ofconsidering all available data in the riskassessment and now state, "The Agencywill review each assessment as to theevidence on carcinogenic mechanismsand other biological or statisticalevidence that indicates the suitability ofa particular extrapolation model." Twoissues are emphasized: First, the textnow indicates the potential forpharmacokinetic information tocontribute to the assessment ofcarcinogenic risk. Second, the finalguidelines state that time-to-tumor riskextrapolation models may be used whenlongitudinal data on tumor developmentare available.

2. A number of commentors noted thatthe proposed guidelines did not indicatehow the uncertainties of riskcharacterization would be presented.The Agency has revised the proposedguidelines to indicate that majorassumptions, scientific judgments, and,to the extent possible, estimates of theuncertainties embodied in the riskassessment will be presented along withthe estimation of risk.

3. The proposed guidelines stated thatthe appropriateness of quantifying risksfor chemicals in Group C (PossibleHuman Carcinogen), specifically thoseagents that were on the boundary ofGroups C and D (Not Classifiable as toHuman Carcinogenicity), would befudged on a case-by-case basis. Somecommentors felt that quantitative riskassessment should not be performed onany agent in Group C.

Group C includes a wide range ofagents, including some for which thereare positive results in one species in onegood bioassay. Thus, the Agency feelsthat many agents in Group C will besuitable for quantitative riskassessment, but that Judgments in thisregard will be made on a case-by-casebasis.

4. A few commentors felt that EPAintended to perform quanti tat ive riskestimates on aggregate tumor incidence.While EPA will consider an increase intotal aggregate tumors as suggestive ofpotential carcinogenicity, EPA does notgenerally intend to make quant i ta t iveestimates of carcinogenic risk based ontotal aggregate tumor incidence.

5. The proposed choice of bodysurface area as an interspecies scalingfactor was criticized by severalcommentors who felt that body weightwas also appropriate and that bothmethods should be used. The OSTPreport recognizes that both scalingfactors are in common use. The Agencyfeels that the choice of the body surfacearea scaling factor can be justified fromthe data on effects of drugs in variousspecies. Thus, EPA will continue to usethis scaling factor unless data on aspecific agent suggest that a differentscaling factor is justified. Theuncertainty engendered by choice of -scaling factor will be included in thesummary of uncertainties associatedwith the assessment of risk mentionedin point 1, above.

In the second of its two proposals foradditions to the proposed guidelines, theSAB suggested that a sensitivityanalysis be included in EPA'squantitative estimate of a chemical'scarcinogenic potency. The Agencyagrees that en analysis of theassumptions and uncertainties inherentIn an assessment of carcinogenic riskmust be accurately portrayed. Sectionsof the final guidelines that deal with thisissue have been strengthened to reflectthe concerns of the SAB and theAgency. In particular, the last paragraphof the guidelines states that "majorassumptions, scientific judgments, and,to the extent possible, estimates of theuncertainties embodied in theassessment" should be presented in thesummary characterizing the risk. Sincethe assumptions and uncertainties willvary for each assessment, the Agencyfeels that a formal requirement for aparticular type of sensitivity analysiswould be less useful than a case-by-caseevaluation of the particular assumptionsand uncertainties most significant for a.particular risk assessment.(FR Doc. 86-19601 Filed »-23-88; fc45 am]MLUNQ CODE B5M-50-M

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