The Risk Assessment Guidelines of 1986

8/10/2019 The Risk Assessment Guidelines of 1986

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United StatesEnvironmental ProtectionAgency

Office of Hea l th andEnvironmental AssessmentWashington 20460

EPA 600 8 87 045August 1987

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EPAResearch and Development

The isl AssessmentGuidelines of 9 8

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SFUN RE OR S TR

997


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T HE R ISK SSESSMENT

GUI ELINES OF 98

u nvironmental Protection AgencyWashington D C

A 600 8 87 045

u ust 98


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DIS L IMER

hi s document ha s been reviewed in accordance with U S Environment al Pl Ot ection Agency policy an dapproved for publication ention o f t ra de n am es o r commercial products does not constitute endorsement orrecommendation for use


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ONT NTS

Preface iv

bs t rac t v

GUIDELINES FOR CARCINOGEN RISK ASSESSMENT 1 1

GUIDELINES FOR MUTAGENICITY RISK ASSESSMENT 2 1

GUIDELINES FOR TH HEALTH RISK ASSESSMENT

OF CIIEMICAL MIXTURES 3 1

GUIDELINES FOR TH HEALTH ASSESSMENT

OF SUSPECT DEVELOPMENTAL TOXICANTS 4 1

GUIDELINES [i OR ESTIMATING EXPOSURES 5 1


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PREF E

On Sep tember 24, 1986 , th e U.S. Environmental Protection Agency (EPA) issued r is k a s se s sm e n tguidelines relating to five areas: carcinogenicity, mutagenicity, chemical mixtures, suspect developmentaltoxicants, and es tima ting exposures 51 FR 33992-34054). Th e guidelines were developed t o p ro mo te h ig htechnical qual ity and Agencywide consistency in th e risk assessment process.

Th e guidel ines were developed partly in response to a 1983 National Academy of Sciences publicationentitled Risk Assessment in the Federal Government: Managing th e Process, which recommended thatFederal regulatory agencies es tab li sh r isk assessment g ui de li ne s. A n EP A task force, convened by thenAdministrator William Ruckelshaus to study ways to improve th e scient i fic foundat ion f or A ge nc yregulatory decisions, accepted th e recommendation, an d work on th e guidelines began early in 1984.

Th e guidelines are products of a two-year Agency development an d review process which included manyscientists from th e larger scientific community. They were developed as part of an interoffice guidelinesdevelopment p ro gr am u nd er t he auspices o f th e Office of Health and Env i ronmenta l Assessment in theAgency s Office of Research an d Development. The scient is ts involved were skilled in each topic, an d earlydraf ts were peer-reviewed by experts from academia, industry, public in te res t groups, and othergovernmental agencies. Subsequently, proposed guidelines were published in th e ederal Register reviewedby special panels of EPA s Science Advisory Board SAB), an d revised to take in to account public and SA Bcomments . Af te r final EP A review an d Office ofManagement an d Budget review, th e guidel ines were s igned

by EP A Administrator Lee M Thomas on August 22 , 1986, an d published in th e ederal egister onSeptember 24,1986.

Each of th e five guidelines provides both technical information an d science policy guidance relating to th econduct of EP A risk assessmen ts and presen ta tion of r isk assessment information. T h e g u id el in e s aresufficiently f lexible to allow skil led scient is ts to make appropr ia te technical judgments on a case-by-casebasis , g iving full consideration to a ll r e levant scientific information. l he guidel ines also stress that riskassessments should include a discussion of th e strengths an d weaknesses of each assessment by describinguncertainties, assumptions, an d limitations, as well as th e scientific basis and rationale for each assessment.They require risk assessors to inform Agency decisionmakers a nd t he public about th e assumptions used inand the implicat ions of individual r isk assessmen t conc lusions , so that a p pr o pr ia te r is k managementdecisions ca n be made an d explained.

While these guidelines are published Agency documents, they should not be interpreted as static, b ut a sth e first step in th e continuing process of identifying th e best methods for assess ing r isk to environmentalpollutants. Consequently, th e r isk assessment guidelines are constantly undergoing Agency scrutiny andwill be revised in l i ne wi th new methods an d information, as appropriate.

This document presents th e five guidelines as they or iginal ly appeared in th e ederal egister but in aformat that is easier to read.

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STR CT

On September 24 1986 th e U.S. Environmental Protection Agency issued risk assessment guidelinesrelating to five areas: carcinogenicity mutagenicity chemical mixtures suspect developmental toxicants

an d estimating exposures 5 FR 33992-34054 . Th e guidelines were developed to promote high technicalq ua li ty a nd Agencywide consistency in th e r is k a ss e ss m en t process This document presents th e fiveguidelines as they originally appeared in th e ederal egister bu t in a format that is easier to read

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51 FR33992

GUIDE L IN E S F OR C AR CIN OG EN RISK

ASSESSMENTSUMMARY:On September 24 , 1986, th e U.S.E n v ir o n m en t al P r o te c ti o n Agency issued thefollowing five guidelines for a ss es si ng t he h ea lt hrisks ofenvironmental pollutants.

Guidelines for Carcinogen Risk Assessment

Guidelines for Estimating Exposures

Guidelines for Mutagenicity Risk Assessment

Guidelines for th e Health Assessment of SuspectDevelopmental Toxicants

Guidelines for t he H ea lt h Risk Assessment ofChemical Mixtures

l his section contains th e Guidelines for CarcinogenRisk Assessment.

Th e Guidelines for Carcinogen Risk Assessment(herea fte r Guide lines ) are intended to guideAgency evaluation of suspect carcinogens in linewith th e policies an d procedures established in th estatutes administered by th e EPA. These Guidelineswere developed as part of an interoffice guidelinesdevelopment pro gr am u nd er t he auspices of theOffice of Health and Envi ronmental Assessment(OHEA) in the Agency s Office of Research an dDevelopment. They reflect Agency consideration ofpublic an d Science Advisory Board (SAB) comments

on th e Proposed Guidel ines for Carcinogen RiskAssessment publ ished November 23, 1984 (49 FR46294).

This publication completes th e first round of riska ss es sm e n t g u id e li ne s d ev el op m en t. T he seGuidelines wil l be revised, an d new guidelines wiIIbe developed, as appropriate.

F O R F U RTH E R INFORMATION CONTACT:

Dr. Robert E. McGaughyCarcinogen Assessment GroupOffice of Health and Envi ronmental Assessment(RD-689)401 M Street, S. WWashington, DC 20460202-382-5898

SUPPLEMENTARY INfl ORMATION: In 1983,the Nat ional Academy of Sciences (NAS) publishedit s book entitled Risk s s es sm e nt i n the FederalGovernment Managing the Process In that book,th e NAS recommended tha t Federal regulatoryagencies establish inference guidelines to ensure

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cons is tency a nd t ec hn ic al qua l i ty in r i sassessments and to ensure that the r i sk assessmentp ro ce ss w as maintained as a s c ie n ti fi c e f fo r tseparate from risk management. A task force withiEPA accepted that recommendation and requestedtha t Agency scient is ts begin to develop sucguidelines.

General

l he guidelines are products of a two-yearAgencywide e ff or t, w hi c h has i nc lu de d m a nyscientists from th e larger scientific community.These guidelines se t forth principles an d proceduresto guide EPA scientists in th e conduct of Agency risassessments , and to inform Agency decision makeran d th e public about these procedures. In particular,th e guidelines emphasize that r isk assessments wbe conducted on a case-by-case basis, giving fuconsideration to a ll r e levan t scientific information.This case-by-case approach means tha t Agencyexperts review th e scientific information on eaca ge nt a nd use th e most scientifically appropriateinterpretation to assess risk. Th e guidelines alsstress that this information will be fully presentedin Agency risk assessment documents, and thaAgency scientists will identify t he s tr en gt hs a ndweaknesses of eac h assessment by describinguncer tainties, assumptions, and limitations, as weas th e scientific basis an d rat ionale fo r eacassessment.

I< inally, the guidelines ar e formulated in partbridge gaps in r is k a s se s sm e nt methodology andata. By identifying these gaps an d th e importanceof th e missing information to th e r i sk assessmentprocess, EP A wishes to encourage research ananalysis that will lead to ne w r is k a s se s sm e n tmethods an d data.

Guidelines fo r Carcinogen Risk Assessment

Work on th e Guidelines fo r Carcinogen RisA ssessm ent began in J a n u a r y 1984. Dra fguidelines were developed by Agency work groupcomposed of expert scient ists from throughout thAgency. T he d ra ft s were peer-reviewed by experscientists. in th e field of carcinogenesis from

universities, environmental groups, industry, labora nd o th er governmental agencies. They were theproposed for public c om men t i n the FE ER LREGISTER (49 FR 46294). On November 9, 19 84the Adminis tra tor directed that Agency offices usthe proposed guidelines in performing r i sassessments until final guidelines become available.


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After th e close of th e public comment periodAgency staff prepared summaries o f the commentsanalyses of th e major i ss u es p r es en t ed by th ecommentors an d proposed changes in th e languageo f the guidelines to deal with th e i ssues rai sed.These analyses were presented to r ev iew panels ofth e SAB o n M ar ch 4 an d April 22-23, 1985, an d toth e Executive Committee of th e SAB on April 25-26,1985. Th e SAB meetings were a nn ou nc ed i n th e

FEDERAL REGISTER as follows: February ] 2,1985 50 FR 5811 an d April 4, 1985 50 FR 13420an d 1342] .

In a letter to th e Administrator dated June 19,1985, th e Executive Committee generally concurredon all five of the guidelines but recommendedcertain revisions an d requested that an y revisedguidelines be submitted to the appropr iate SABreview panel chairman for review an d concurrenceon behal fo f the Executive Committee. As describedi n t he responses to comments see Part B: Responseto the Public and Science Advisory BoardComments each guidel ines document was revised,where appropr ia te cons i s ten t with th e SA Brecommendations an d revised draft guidelines weresubmit ted to th e panel chairmen. Revised draftGuidelines for Carcinogen Risk Assessmen t wereconcurred on in a letter dated February 7, 1986.Copies of th e l et te rs a re available a t th e PublicInformation Reference Unit EPA HeadquartersLibrary as indicated elsewhere in this section.

Following t hi s Preamble ar e two parts: Part Acontains the Guidelines an d Part B, th e Response toth e Public an d Science Advisory Board Comments summary of th e m aj or p ub li c c om me nt s SABcomments a nd Agency responses to thosecomments .

The Agency is continuing to study th e riskassessment issues raised in th e guidelines an d willrevise these Guidelines in l i ne wi th new informationas appropriate.

References suppor t ing documents andcomment.s received on th e proposed guidelines aswell as copies o f th e final guidelines are availablefor inspection an d copying a t th e Public InformationReference Unit 202-382-5926 , EP A HeadquartersLibrary 401 M Street S.W. Washingt.on DC,between th e hours of8:00 a.m. an d 4:30 p.m.

certify that these Guidelines are n ot m aj orrules as defined by Executive Order 12291, becausethey are nonbinding policy statements an d have nodirect effect on th e regulated community. Thereforethey will have no effect on costs or prices, an d theywill

[51 FR 33993Jhave no other

significant adverse effects on th e economy. TheseGuide l ines were rev iewed b y th e Office of

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Management. a nd B ud ge t under Executive Order12291.

August 22, 1986

Le e M. Thomas

Administrator

CONTENTS

Par t A: Guidelines fo r Carcinogen Risk AssessmentI. Introduction

ll.Hazard Identification

A.OverviewB. Elements of f lazard Identification

1. Physical-Chemical Pruperties an d Routes an dPat ternsof Exposure

2. Structure-Activity Relationships3. Metabolic and Pharmacokinetic Properties4. Toxicologic Eflects5. Short-Term Tests6. Long-Term Animal Studies7. Hwnan Studies

C. Weightof EvidenceD. Guidance for Dose-Response AssessmentE. Summary an d Conclusion

III.Dose ResponseAssessment Exposure ssessment an d RiskCharacterization

A_DoseResponse Assessment1.Selection ofOata2. Choice of Mathematical Extrapolation

Model3. Equivalent Exposure UnitsAmongSpecies

B. Exposure AssessmentC. Risk Characterization

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

IV.EPA Classification System for Catagorizing Weight o fEvidence for Carcinogenicity from Human an d AnimalStudies Adapted from IARC

A. AssessmentofWeight of Evidence for Carcinogenicity fromStudies in Humans

B. Assessment of Weight of Evidence for Carcinogenicity fromStudies in Experimental Animals

C. Categorization of Overal l Weight of Evidence for HumanCarcinogenicity

V.References

Par t B: Response to Public an d Science Advisory BoardComments

Introduction

II. Office of Science an d Technology Policy Report onChemical Carcinogens

Ill. Inference Guidelines

IV. Evaluation o f Benign Tumors

V. Transplacental an d M ultigenerationol Animal BioassaY3VI. Maximum Tolerated Dose

VII. Mouse Liver Tumors

VIII. Weight or Evidence Categories

Xl . Quantitative Estimates ofRis1c


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P a r t A: G u i d e l i n e s for a r c i n o g e n R i s kAssessment

Introduction

This is th e f ir st r ev is io n of th e 1976 InterimProcedures and Guide l ines fo r Heal th RiskAssessments of Suspected Carcinogens U.S. EPA,

1976; Albert e t aI., 1977). r he impetus for thisr ev isi on is the need to incorporate into theseG ui de lin es th e concepts a nd a pp ro ac he s tocarc inogen r is k a ss es sm e nt t h a t h a v e beendeveloped during th e last te n years. Th e purpose ofthese Guide l ines is to promote qual i ty andconsistency of carcinogen r i sk assessment s withinth e EPA a nd to i nform those out side th e EPA aboutit s approach to carcinogen r is k a ss es sm en t. T he seG ui de li ne s e mp ha si ze t he broad b u t e ss en ti ala sp ects of r isk assessment tha t are needed byexperts in th e various disciplines required e.g.,toxicology, pathology, pharmacology, an d statistics)for carcinogen risk assessment . Guidance is given ingeneral terms since th e science of carcinogenesis isin a state of rapid advancement, an d overly specificapproaches ma y rapidly become obsolete.

T he se G ui de li ne s d esc rib e th e g e n e r a lframework to be followed in developing an analysisof carcinogenic r is k a nd some salient principles to beused in eva lua t ing the quali ty of data and informulating judgments concerning th e nature andmagnitude of th e c an ce r h az ar d from suspectcarcinogens. is th e intent of these Guidelines topermit suffic ient f lexibi li ty to accommodate ne wknowledge an d ne w assessment methods as theyemerge. i s a ls o recognized that there is a need fornew methodology that h as n ot been addressed in thisd o c u m e n t in a nu mb e r of a r ea s , e.g. , th echaracterization of uncertainty. As this knowledgeand assessment methodology ar e developed, theseGuidelines will be revised whenever appropriate.

A summary o f t he cur ren t s t at e of knowledge inth e field of carcinogenesis an d a statement of broadscientific principles of carcinogen r i sk assessmen t ,w hi ch w as developed by th e Office of Science an d rechnology Policy OSTP, 1985), forms an impor tan tbasis fo r these Guidelines; the lo rmat of t he seG ui de li ne s i s s imi la r to tha t proposed by theNationa l Resea rch Council NRC) of th e NationalAcademy o f S ci en ce s in a book ent i t l ed Risk s sessment in the ederal Government anagingthe Process NRC, 1983).

These Guidelines are to be used within thepolicy framework already provided by applicableEPA statutes an d do no t al ter such policies. TheseGuidelines provide general directions for analyzingan d organ iz ing avai lab le da ta . They do n ot i mp lythat o ne k in d of data o r a no th er is prerequisite forr egu lato ry act ion t o con trol , prohibit, or allow th eus e of a carcinogen.

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R e gu l at o ry d e c is i on m a k i n g invo lves tw ocomponents: risk assessment and risk management .Risk a s s e s s m e n t def ines th e a dv ers e heal thconsequences of exposure to toxic agents. The riskassessments will be ca rr i ed ou t independenUy fromconsiderations of the consequences o f r e gu l at o rya ct io n. R is k m a n a g e m e n t combines the r i skassessment with the direct ives of regula torylegislation, t oge the r with socioeconomic, technical,political, and other considerat ions, to reach adecision as to whether or how much to control futureexposure to th e suspected toxic agents.

Risk a ss es sm en t i nc lu de s o ne or more of th efollowing components: haza rd iden t if i ca t ion , doseresponse assessment, exposure assessment , and riskcharacterization NRC, 1983).

H a z a rd i d en t if i ca t io n is a qual i ta t ive r iskassessment, dealing with th e process of determiningwhether exposure to an agent ha s th e p o te nt ia l t oi nc re as e t he incidence of cancer. I or purposes ofthese Guidel ines, both m alig na nt a nd b en ig n

tumors a re used in th e eva lua t i on of th ecarcinogenic h az ar d. T he h a z ar d i d en t if i ca t io ncomponent qualitatively answers th e question ofhow likely an agen t is to be a human carcinogen.

Traditionally, quantitative risk assessment hasbeen used as an inclusive term to describe al l o rpar t s of dose-rcsponse assessment , exposureassessment , and risk characterization. Quantitativerisk assessment can be a useful general te rm insome c i rcumstances , bu t th e more exp l i c i tterminology developed by th e NRC 1983) is usuallypreferred. Th e dose-response assessment defines th er el at ionsh ip bc twecn the dose of an agent and theprobability of induction of a carcinogenic effect. Thiscomponent usually en ta i ls an extrapolation from th egenerally h igh doses administered to experimentalanimals or exposures noted in epidemiologic studiesto th e exposure levels expected from human contactwith th e agent i n t he e nv ir on me nt ; i t a lso inc ludescons idera t ions of th e v a l i d i t y o f t h e s eextrapolations.

Th e exposure assessment ident i fies populat ionsexposed to t he a g en t, d es cr ib es their compositionan d size, and presents the types, magni tudes ,frequencies, and dura t ionsof exposure to the agen t .

[51 FR 33994)In risk c h ar a ct e ri z at io n , t h e resu l t s o f the

exposure a s s e s s m e n t and t he d os e- re sp on seassessment are combined to est imate quant i tat ivelyth e carc inogenic r i s k As p a r t o f r i s kcharacterization, a summary of th e strengths an dweaknesses in the h a za r d i d en t if i ca t io n , doseresponse, assessment , exposure assessment, a nd t hepublic health r i sk es timates are p re se nt ed . M a jo rassumptions, scientific judgments, and, to th e extentpossible, est ima tes of the uncer ta int i es embodied inth e assessment are also presented, dist inguishingclearly between fact, assumption, an d science policy.


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Th e National Research Counc il NRC, 1983)pointed out t ha t there are many ques t ionsencountered in the r isk assessment process t h at a reunanswerable given current scientific knowledge.To bridge th e uncertainty that exists in these areaswhere there is no scientific consensus, inferencesmust be made to ensure that progress continues inth e assessment process. Th e OSTP 1985) reaffirmedthis position, an d generally left to th e regulatoryagencies th e job of articulating these inferences.Accordingly, th e Guidelines incorporate judgmentalpositions science policies) based on evaluation of thep r es e nt l y a v ai la b le i nf or m at io n a n d on theregulatory mission o f t he Agency. The Guidelinesar e consistent with th e principles developed by th eOSTP 1985), al though in many instances arenecessari Iy more specific.II Hazard Identification Overview

The q u al it at iv e a s se s sm e n t o r haza rdidentification part o f r is k a ss es sm en t contains ar ev ie w o f th e relevant biological a nd c he mi ca linformation bearing on whether or no t an agent ma ypose a carcinogenic hazard. Since chemical agentsseldom occur in a pure s ta te and are oftent ransformed in th e body, th e review should includeavailable information on contaminants, degradationproducts, an d metabolites.

Studies are evaluated according to soundbiological and s ta t i s t ica l considerat ions andprocedures. These h av e b ee n d es cr ib ed in severalp u bl ic at io n s I n te ra g en cy R e g ul a to r y LiaisonGroup, 1979; OSTP, 1985; Peto et aI., 1980; Mantel,1980; Mantel an d lIaenszel, 1959; InterdisciplinaryPanel on Carcinogenicity, 1984; National Center forToxicological Research, 1981; National roxicologyProgram, 1984; U.S. EPA, 1983a, 1983b, 1983c;Haseman , 1984). R esu lts an d conclus ionsconcerning the agent , derived from different types ofinformation, whether indicating positive or negativeresponses, are melded together into a weight-ofevidence determination. The s t rength of th eevidence suppor t ing a po ten t i a l humancarcinogenicity judgment is developed in a weightof-evidence stratification scheme. Elements of Hazard Identification

Hazard identification should inc lude a review of.the following information to th e extent that it isavailable.

Physical Chemical Properties an d Routes an d

Patterns o f Exposure P a ra m e te r s r e le v an t tocarcinogenesis, including physical state, physicalchemical properties, an d exposure pathways in th eenvironment should be described where possible.

2 Structure Activity Relationships This sections h ou ld s u m ma r iz e r e le v an t s t r uc t u r e- a c t iv i ty

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correlations that s up po rt o r argue agains t th eprediction of potential carcinogenicity.

3 Metabolic an d Pharmacokinetic PropertiesThis section should summarize relevant metabolicinformation. Information such as whether th e agentis direct-acting or requires conversion to a reactivecarcinogenic e.g., a n e le c tr o ph il ic ) species,metabol ic pa t hways fo r such conve r s ions ,

macromolecular in te rac t ions , and fate e.g.,transport, storage, an d excretion), as well as speciesdifferences, should be discussed a nd c ri ti ca ll yevaluated. Pharmacokinctic properties determineth e biologically effective dose an d may be relevant tohazard identification a nd o th er components o f r is kassessment.

4 Toxicologic Effects roxicologic effects otherthan carcinogenicity e.g., suppression of theimmune system, endocrine d is t ur b an c es , o rga ndamage) t.hat are relevant t o th e evaluat.ion ofcarcinogenicity should be summarized. Interactionswith other chemicals o r a ge nt s an d w it h l if es ty lefactors should be discussed. Prechronic an d chronictoxicity evaluations, as well as o th er t es t results,ma y yield i nf or ma ti on o n t-arget organ effects,pathophysiological reactions, a nd p r en e op l as t iclesions t h a t b ea r on th e e v a l u a t i o n o fcarcinogenicity. Dose-response an d time-to-responseanalyses of these reactions may also be helpful.

5 Short Term Tests Tests for point mutat ions,numerical and structl l ra l chromosome aberrations,DNA damage/repair, an d in vitro transformationprovide supportive evidence of carcinogenicity an dmay give information on poten tia l ca rc inogen icmechanisms. A range oftests from each of the aboveen d points helps to characterize an agent s responsespectrum.

Short-term in vivo an d in vitro tests tha t ca ngive indication of initiation an d promotion activitymay a ls o p ro vi de s up po rt iv e e vi de nc e forcarcinogenicity. Lack of positive results in shortterm tests for genet ic toxic ity does no t provide abasis for discounting positive results in long-termanimal studies.

6 Long Term Animal Studies Criteria for th et e ch n ic a l a de q ua cy of a n im a l c a r ci n o ge n i ci t ys tudies have been published e .g., U.S. Food an dDrug Administration, 1982; Interagency RegulatoryLiaison Group, 1979; National Toxicology Program,1984; OSTP, 1985; U.S. EPA, 1983a, 1983b, 1983c;Feron et al. , 1980; Mantel, 1980) an d should be usedto judge th e accep tab il ity of individual studies. r r ansp l acen t a l and m u l t i g e n e r a t i o n a lcarcinogenesis s tudies , in addit ion to moreconventional long-term a n im a l s tu di es , ca n yielduseful information ab ou t t he carcinogenicity ofagents.

i s r ecognized that chemicals that. inducebenign t um or s f re qu en tl y al so i nd uc e malignant


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tumors, an d that, benign tumors often progress tomalignant t um o rs ( In te rd is ci pl in ar y P a ne l onCarcinogenicity, 1984). Th e incidence of benign an dm a l i g n a n t t u m o r s wil l be c om bin ed w he nscientifically defensible (OS rp, 1985; Principle 8).For example, th e Agency will, in general, considerth e combination of benign and malignan t tumors tobe scientifically defensible unless the benign tumors

are no t considered to have th e potential to progressto t he a ss oc ia te d m al ig na nc ie s o f the s amehistogenic origin. If an increased incidence ofbenigntumors is observed in th e absence o f m a li gn an ttumors , in m o s t cases the e vi de nc e w il l beconsidered as limited evidence of carcinogenicity.

The weight o f e vi de nc e t ha t a n ag en t ispotentially carcinogenic for humans increases 1w it h t he i nc re as e i n n um b er o f t is sue s it e s affectedby th e agent; 2) with t he i nc re as e in number ofa n im a l s pe ci es , s t ra ins , sexes, an d n um be r ofe xp er im en ts a nd doses showing a carcinogenicresponse; 3) with th e occurrence of clear-cut doseresponse relationships as well as a high level of

stat is t ical signif icance of th e i nc re as ed t um orincidence in treated compared to control groups; 4)when there is a dose-:related shortening of th e timeto-tumor occurrence or time to d eat h w it h t um or ;an d 5) when there is a dose-related increase in th eproportion oftumors that are malignant.

Long-term a ni ma l s tu di es t or nea r themaximum tolerated dose level MTD) are used toensure an adequate power fo r th e detect ion ofcarcinogenic

{5 FR 33995)ac t i v i t y ( N T P,

1 98 4; I AR C, 1982). N e ga t iv e l o ng - te r m animalstudies a t exposure levels above th e MTD m ay n ot be

acceptable i f animal survival is so impaired that th es en sit iv it y o f the stu dy is significantly reducedbelow that of a conventional chronic animal study a tth e MTD. Th e OSTP 1985; Principle 4) h as s ta te dthat,

The carcinogenic effects of agents ma y be influenced by nonphysiological responses such as extensive organ damage, radicald is ru pt io n o f hormonal function, saturat ion of metabolicpathways, formation of stones in the urinary tract , saturation ofDNA repair with a functional loss of the system) induced in themodel systems. Testing regimes inducing these responses shouldbe evaluated for their relevance to t he h um an response to anagent an d evidence from such a s tudy, whether positive ornegative, mustbe carefully reviewed.

Positive studies a t levels above th e MTD should becarefully reviewed to ensure that th e responses areno t du e to factors which do not opera te a t exposurelevels below th e MTD. Evidence indicating that highexposures a l t e r t u m o r responses by ind i rec tmechanisms tha t ma y be unrelated to effects a tlower exposures should be dea l t with on ani nd i vi du a l b as is . As noted by th e O ST P ( 19 85 ), Normal metabol ic act ivat ion of ca rc inogens ma ypossibly also b e altered an d carcinogenic potentialreduced as a consequence [of high-dose testing).

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Carcinogenic responses under conditions of th eexperiment should b e r ev ie we d carefully as theyrelate to th e relevance of the e vi de nc e t o humancarcinogenic risks e.g., th e occurrence of bladdertu mo rs in th e presence o f b la dd er s to ne s andimplantat ion si te sarcomas) . In te rpre ta t ion ofanimal studies is a ided by th e review of target organtoxicity an d other e ff ec ts ( e. g. , c ha ng es in the

immune and endocrine systems) that may be notedin prechronic o r o th er toxicological s tu d ie s. T im eand dose-related ch an ge s in th e inc idence ofpreneoplast ic lesions may also be helpfu l ininterpreting animal studies.

Agents that are positive in long-term animalexperiments and also show evidence of promoting orcocarcinogenic act ivi ty in specialized tests shou ld beconsidered as complete carcinogens unless there isevidence to th e contrary because it is , a t present ,d iffi cu lt t o determine whether an agent is only ap ro mo ti ng o r cocarcinogenic a ge nt . A ge nt s t h tshow positive results in special tests for initiation,promotion, or cocarcinogenicity an d no indication of

tumor response in well-conducted an d well-designedlong-term animal studies should be deal t with on anindividual basis.

1 0 evaluate carc inogenic i ty, th e p r im ar ycomparison is tumor response in dosed a ni ma ls a scompared with tha t in c on te m po ra ry m a tc h edcontrol an ima ls . His to ri ca l cont ro l da ta a re oftenvaluable, however, and could be used a lo ng w it hconcurrent control da t a in th e eva lu a t i on ofcarcinogenic responses (Haseman e t aI. , 1984) . [< orth e evaluat ion of rare tumors, even small tumorresponses may be significant compared to historicaldata. Th e review o f t um or data a t sites with highspo n t a neous background r q u i r s spec i a l

considerat ion ( OS TP, 1 98 5; Pr inc ip le 9) . F orinstance, a response that is s ignif icant with respectto t h e e xp e ri me n ta l control g ro up may becomequestionable if t he h is to r ica l control data indicatet h a t th e exper imenta l control group h ad anunusually low background incidence (NTP, 1984).

Fo r a number of reasons, there a re widelydiverging scientific views (OSTP, 1985; Ward et aI.,1979a, b; Tomatis, 1977; Nutri t ion {< oundation.1983) abou t the validity of mouse liver tumors as anindication of po tent ia l carcinogenicity in humanswhen such tumors occur in s t ra ins w ith h ig hspontaneous background incidence an d when theyconstitute th e only tumor response to an agent .These Guidelines take th e position that when theonly tumor r es po ns e i s i n th e mouse liver an d whenother conditions for a classification of su ffi c ien tevidence in animal studies are me t e.g., replicatestudies, malignancy; see sect ion IV), th e data shouldbe cons idered as su ff i c i en t e v i d e n c e o fcarc inogenic i ty. is unde r s t o od t h t t h i sclass i f ica t ion could be c ha ng ed o n a case-by-casebasis to limited, if warranted, when factors such asth e following, ar e observed: an increased incidence


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of tumors only in t h highest dose group and/or onlyat. t.he en d o f t he s tudy; no substantial dose-relatedi nc re as e i n th e p ro po rt io n o f tumors t.hat. aremalignant; th e o cc ur re nc e o f tumors that arepredominantly benign; no dose-related shortening ofth e time t o t.he appearance of t.umors; negative orinconclusive results from a spectrum of short-termtests for mutagenic activity; th e occurrence of excesstumors only in a single sex.

Data from al l long-term animal studies ar e to beconsidered in the evaluation of carcinogenicity. Ap osit iv e c arc in og en ic resp onse in onespecies/strain/sex is not general ly negated bynegative resul t s in other species/strain/sex.Repl ica te nega t ive studies tha t are essent.iallyidentical in al l other respects to a positive study mayindicate that th e posit.ive results ar e spurious.

Evidence for carcinogenic action should be basedon th e observation of statistically significant tumorresponses in specific organs or tissues. Appropriatestatistical analysis should be performed on datafrom long-term studies to help determine whether

th e effects are t reatment-related or possibly du e tochance. Tnese should a t least inc lude a statisticaltest for trend, including appropriate correction fordifferences in survival. Th e weight to be g iven to th elevel of statistical significance the p-value an d toother available pieces of informa tion i s a matter ofo v er a ll s c ie n ti fi c judgment . A s t a t i s t i ca l lysignificant excess o f t um or s of all types in th eaggregate , in the absence of a s ta t i s t ica l lysignificant increase of an y individual tumor type,should be regarded as minimal evidence ofcarcinogenic a ct io n u nl es s t he re a re p er su as i vereasons to th e contrary.

H u ma n S tu di es Epidemiologic studiesprovide unique information about th e r es po ns e o fhumans wh o have been exposed t o suspec tcarcinogens. Descriptive epidemiologic studies ar euseful in generating h yp ot he se s a nd p ro vi di ngsupport ing data , bu t c an r ar el y be used to make acausal inference. Analytical epidemiologic studies ofth e case-control or cohort var ie ty, on the other hand,ar e especially useful in assessing r isks to exposedhumans.

Criteria fo r th e adequacy of epidemiologicstudies ar e well recognized. T he y i nc lu de f ac to rssuch a s the proper selection an d characterization ofexposed an d control groups, the ad eq uac y o fdurat ion and quality of follow-up, the prop eridentification and characterizat ion of confounding

factors an d bias, t he a pp ro pr ia te c on si de ra ti on o flatency effects, th e valid ascertainment of th e causesof morbidity an d death, a nd t he a bility to detectspecific effects. Where i t ca n be calculated, th estatistical power to detect an appropriate outcomeshould be included in th e assessment.

Th e strength o f th e epidemiologic evidence forcarcinogenicity depends, among other things, on th e

6

1

type of analysis and on the m a gn it ud e a ndspecificity of the response. f he weight of evidenceincreases r ap id ly w it h th e number o f a de q ua testudies that show comparable results on populationsexposed to the same agent u n d e r d i f f e r en tconditions.

t should be recognized tha t epidemiologicstudies are inherently capable of de tec ting only

comparatively large increases in th e relat ive r isk of FR 99 ]cancer. Negative

results f rom such studies cannot prove th e absenceof carcinogenic action; however, negative resultsfrom a well-designed a nd w e ll -c on du ct edepidemiologic study that contains usable exposured at a c an serve to define upper l im it s o f risk; thesear e useful i f animal evidence indicates that th eagent is potentially carcinogenic in humans.

C. Weight of Evidence

Evidence of possible carcinogenicity in humanscomes primarily from two sources: long-term animaltests and epidemiologic investigations. Results fromt he se s tu di es a r e s up p le m en te d with availableinformation from short-term tests, pharmacokineticstudies, comparative metabolism studies, struct.ureactivity relationships, and o the r re levan t toxicologicstudies. Th e question of how likely an agent is to bea human carcinogen should be answered in theframework of a weight-of-evidence judgment.Judgments a bo ut t he weight of evidence invo lveconsiderations of th e q ua li ty a nd a de qu ac y of thedata and th e kinds an d consistency of responsesinduced by a suspect carcinogen. There are threemajor steps to characterizing the weight of evidencefor carcinogenicity in humans: I) characterizationofthe evidence from human studies and from animals tud ies individually, 2 combination of thecharacterizations of these two types of data into anindication of th e overall weight of evidence fo rhuman carcinogenicity, and 3 evaluation of al lsupporting information to determine i th e overallweight of evidence should be modified.

EPA ha s developed a system for stratifying th eweight o f e vi de nc e see section IV). T h i sclassification is not meant to be applied rigidly orm e ch an ic al ly. A t v a ri ou s p oi nt s in the abovediscussion, EPA has emphas ized th e need fo r anoverall, balanced j ud gm en t o f t he t ot al it y of th eavailable evidence. Particularly for well-studiedsubstances , the scientific data base will have acomplexity tha t cannot be captured by anyc lass if i ca t ion scheme. Therefore, the hazardidentification s ec ti on s ho ul d i nc lu de a narrat ivesummary o f t he s tr en gt hs a nd w ea kn es se s of th eevidence as well as it s categorization in th e EP Ascheme.

Th e EPA classification system is, in general, anadaptation of the Internat ional Agency for Researchon Cancer lARC, 1982 approach for classifying th e


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j

weight of e v i e n ~for human data and an ima l data. fhe EPA class i f ica t ion sys tem fo r thecharacterization of the overall weight of evidence forcarcinogenici ty ( an im a l, h um an , and othersupportive data) includes: Group A -- Carcinogenicto Humans; Group B -- Probably Carcinogenic toH um an s; G r ou p C -- Poss ibly Carc inogenic toHumans; Group D No t Classifiable as to Human

Carcinogenicity; an d Group E Evidence of NonCarcinogenicity for Humans.

T he f ol lo wi ng modificat ions of the [ARCapproach have been made for classifying human andanimal studies.

For human studies:(1) Th e observat ion of a statistically significant

association between an agen t and l i fe - th rea ten ingbenign tumors in humans i s in cl ud ed in th eevaluation of risks to humans.

2 A no data available classification is added. 3 A n o ev id en ce o f carc inogenic i ty

classification i s added. This classificaton indicatesthat no association was found between exposure an d

increased risk of cancer in well-conducted, welldesigned, independent analyt ical epidemiologicstudies.

For animal studies: 1 An increased incidence of combined benign

an d malignant tumors will be considered to providesuffi ci en t evidence of carcinogenicity if the oth ercriteria defining th e suffic ient c lass i fication ofev idence a re m et (e.g., rep l ica te s tud i e s ,malignancy; see sect ion IV). Benign and mal ignan ttumors will be c om bi ne d w he n scient if ical lydefensible.

2 An increased i nc id en ce o f b en ig n tumorsalone generally const itutes l imited evidence ofcarcinogenicity.

3 An inc reased incidence o f n eo pl as ms thatoccur wi th h igh spontaneous background incidence(e.g., mouse l iver tumors and ra t pituitary tumors incertain strains) general ly const i tutes sufficientevidence of carcinogenicity, bu t may be changed to l imi ted when w ar ran t e d by th e spec i f icinformation available on the agent.

4 A no data available classification ha s beenadded.

5 A n o e vid en ce o f carc inogenic i tyclassif icat ion is a ls o a dd ed . T h is o p er at io n alclassification would include substances for whichth er e is no increased incidence of neoplasms in atleast two well-designed an d well-conducted animals tu di es o f a de qu at e power an d dose in different

species.D Guidance for Dose-Response Assessment

The qualitative e vi de nc e f or carcinogenesisshould be discussed for purposes of guiding th e doseresponse assessment . The guidance should be givenin terms o f t he a pp ro pr ia te ne ss a nd limitations ofspecif ic s tud ies as well a s p h ar m ac ok in et icconsiderations that should be factored into th e dose-

1-7

response assessment. T h e a pp r op r ia te method o fextrapolat ion should be factored in w he n theexper imental route of exposure d if fe rs f ro m tha toccurring in humans.

Agents that ar e judged to be in t.he EP A weightof-evidence stratification Groups A an d B would beregarded as su i tab le for q u n t i t t i v r i skassessments. Agents t ha t a re judged to be in GroupC will general ly be r eg ard ed a s suitable fo rquanti ta tive r isk assessment , bu t judgments in thisregard may be made on a case-by-case basis. Agentsthat ar e judged to be in Groups D an d E would no thave quantitative risk assessments.

Summary and Conclusion

T he s um m ar y should present al l of the ke yfindings in al l of the sections of the qual i ta t ivea ss ess me nt an d th e interpret ive ra t iona le t h a tforms th e basis for th e conclusion. Assumptions,uncertainties in th e evidence, and o the r factors tha tma y affect th e relevance o f t he evidence to humansshould be discussed. Th e conclusion should present

both t h e w e ig h t- o f- e vi d en c e r ank ing and adescription that brings ou t th e more subt le aspects ofth e evidence tha t may not be evident from theranking alone.

III. Dose Response Asses smen t Exp os u re ssessment an d Risk Characterization

After da t a c on ce rn in g t he carc inogenicp ro pe rt ie s o f a substance have b e en c o ll e ct e d.evaluated, an d categorized, it is frequently desirableto estimate the l ikely ra ng e o f excess cancer riskassociated w ith given levels and conditions ofhuman exposure. T he f ir st step of the ana lys i sneeded to make such estimations is th e developmento f the likely relationship between dose an d response

(cancer incidence) in th e region of human exposure.This informat ion on dose-response relationships iscoupled with in format ion on th e na tu re a ndmagni tude of human exposure to y ie ld an estimateo f h um an risk. The r isk-cha rac te ri za tion s tep a l soincludes an in terpreta t ion ofthese estimates in l ightof the biological , s t a t i s t i ca l , a nd exposureassumptions an d uncertainties tha t have e.risenthroughout the process ofassess ing r isk.

T he e le me nts o f dose-response assessment aredescribed in section III.A. Guidance on h u m a nexposure assessment is provided in another I


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require that an agent be carcinogenic in humans.The likelihood that an agent. is a human carcinogenis a function o f t he weight of evidence, as this hasbeen descr ibed in th e hazard identification section ofthese Guidelines. t is nevertheless important topresent quanti tat ive es t imates , appropr ia te lyqualified and interp re ted, in those circumstances inwhich there is a r easonab le poss ib i li t y, based onh u m a n and an imal data , t t the ag e n t is

carcinogenic in humans.I t should be emphasi zed in every quantitative

r isk estimation tha t th e r es ul ts a re u nc er ta in .U n c e r t a i n t i e s due to e x p e r i m e n t a l a n depidemiologic variability as well as uncertainty inth e exposure assessment can be important. Thereare major unce r ta int ie s in extrapolating both fromanimals to h um an s a nd from high to low doses.There ar e important species differences i n u pt ak e,metabolism, an d organ dist.ribution of carcinogens,as well as species an d strain differences in targetsite susceptibility. Human populations are variablewith r e s p e c t to genet ic co ns t i t u t i on , die t ,o cc up at io na l a nd home env i ronment , act ivi typatterns, a n d o th e r cultural factors. Risk estimatess ho ul d b e p re se nt ed t og et he r w it h th e associatedhaza rd assessment section Ute 3 to ensure thatthere is an apprecia tion of th e weight of evidence forcarcinogenicity that underlies t he quan t it a tive r iskestimates.

A. Dose-Response Assessment

1. Selection Data As indicated in section II.D.,guidance needs to b e g iv en by th e individuals doingth e qua l i t a t i ve a s se s sm e n t t o xi co l og i st s ,pathologists, pharmacologists, ele. to t ho se d oi ngth e quant i ta t ive assessment as to t he appropr i at edata to be used in th e dose-response assessment.This is determined by th e quality o f th e d at a, i tsrelevance to human modes of exposure, an d othertechnical details.

If available, estimates based on adequate humanepidemiologic da ta are preferred over est imatesb as ed on a nim al d ata . I f adequate exposure dat.aex is t in a well-designed an d well-conducted negativeepidemiologic study, it ma y be possible to obtain anupper-bound e st im at e o f r isk from tha t study.Animal-based estimates, if avai lable , a lso should bepresented.

In th e absence of appropri a te human studies,data from a species that responds mos t l ike humanss hou ld be us ed, i information to this effect. exists.Where, fo r a given agen t , s ev e ra l s tu d ie s are

available, w hic h m ay involve d if fe re n t a n im a lspecies, s tr ai ns , a nd sexes a t several doses an d bydifferent rou tes o f exposure, th e following approachto selec ting the d at a s et s is used: 1 The tumorincidence d at a a re separated according to organ sitean d tumor type. 2 Al l biologically an d statisticallyacceptable data sets ar e presented. 3 Th e range ofthe risk estimates is presented with due regard t

1-8

biological relevance particularly in th e case ofanimal studies an d appropriateness of route ofexposure. 4 Because i t is possible tha t humansensi t ivi ty is as high as the most sens i t iveresponding an imal s pe ci es , i n th e absence ofevidence to th e contrary, th e biologically acceptabledata se t from long-term animal studies showing th egreatest sensi t ivi ty should g en er al ly b e g iv en th egrea tes t emphasis , ag ain with due regard to

biological and statistical considerations.When th e exposure route in th e species from

which th e dose-response information is obtaineddiffers from th e route occurring in environmentalexposures, th e considerations used in m ak in g t heroute-to-route extrapolat ion must be careful lydescribed. Al l assumptions shou ld be presenteda long with a discussion of th e uncert.ainties in theextrapolation. Whatever procedure i s adopted in ag iven case, it m ust be consistent with th e existing~ e t o l i can d pharmacokinet ic information on th echemical e.g., absorption efficiency vi a t.he gut an dlung, target organ doses, a nd ch ang es in placentaltransport throughout gestation for. tram;placentalcarcinogens .

Where two or more significantly elevated tumorsi tes or types are o ~ e r v e din the s am e s tu dy ,extrapolations may be conducted on selected s it es o rtypes. These selections will be made on b io logicalgrounds. To obtain a total e st im a te o f carcinogenicrisk, animals with one or more t umor s i te s or typesshowing signif icant ly elevated tumor incidenceshould be pooled an d used for ex trapo lat ion . Thepooled estimates will generally be used in preferenceto risk estimates based on single si tes or types.Quant i ta t ive r isk extrapolations will general ly no tbe done on the basi s oftotals that include tumor siteswithout statistically significant elevations.

Benign tumors should generally be combinedwith malignant tumors for risk estimates unless th ebenign tumors are not considered to have thepotential to progress to th e associa ted mal ignanciesof t he s am e histogenic origin. Th e contribution ofth e benign tumors, however, to th e total risk shouldbe indicated.

hoice Mathematical Extrapolation ModelSince r isks a t low exposure levels c a n n o t bemeasured directly either by animal experiments orby epidemiologic studies, a number of mathematicalmodels have been d ev el op ed t o extrapolate fromhigh to low dose. Different extrapolation models,however, m ay f it th e observed data reasonably wellbu t ma y lead to large differences in th e projectedrisk a t low doses.

As was point ed ou t by OSTP 1985; Principle26 ,

single mathematical procedure is recognized as th e mostappropriate for low-dose extrapola tion in carcinogenesis. Whenrelevant biological evidence on mechanism of action exis ts e.g pharmacokinetics, target organ dose , the models or procedures


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employed should be consistentwith the evidence. When data andinformation are limited, however, an d when much uncertaintyexists regarding th e mechanism of carcinogenicaction, models orprocedures which incorporate low-dose linearity ar e preferredwhen compatible with the l imi ted information.

At p r es e nt , m e ch an is m s of th e carcinogenesisprocess ar e largely unknown and d at a a re generallylimited. If a carcinogenic agent acts by acceleratingth e same carcinogenic process that leads to th ebackground occurrence of cancer, th e added effect ofth e carcinogen a t low doses is expected to bevirtually linear (Crump et a t , 1976).

Th e Agency wil l review each assessment as tot he e vi de nc e o n c ar ci no ge ne si s m ec ha ni sm s a ndother biological or statistical evidence that indicatesth e suitability of a particular extrapolation model.Goodness-of-fit to th e experimental observations isnot an effective m ea ns o f d is cr im in at in g amongmodels (OSTP, 1985). A rationale wil l be included tojustify th e use of th e chosen model. In th e absence ofadequate information to th e contrary, th e linearizedmultistage p ro ce dur e w ill b e em plo yed . Whereappropr ia te , the resul t s of u sin g v ar io us

extrapolation models ma y be useful for comparisonwith t he l in ea ri ze d multistage procedure. Whenlongitudinal da ta on tumor development areavailable, time-to-tumor models ma y be used.

should be emphasized that th e linearizedmultistage procedure leads to

[51 33998]a plausible upper

l imit to th e risk that is consistent with someproposed mechani sms of ca rc inogenes is . Such anestimate, however, does n ot n e ce ss a ri ly give arealistic prediction of th e risk. Th e true value of th eris k is unknown, and may be as low as zero. Th er an ge o f risks, def ined by th e upper l imit g iven byth e chosen model an d th e lower limit which ma y beas low as zero, should be explicitly stated. Anestablished procedure does no t ye t exi st for making most l ikely or best es timates o f r isk within therange of uncer tainty defined by th e upper and lowerl im it e st im at es . I f data an d procedures becomeavailable, th e Agency will also provide most likelyor best estimates of risk. This will be most feasiblewhen human d a ta a re available and when exposuresar e i n t he dose r ange of the data.

I n c er ta in c as es , th e linearized multistageprocedure cannot be used with th e observed data as ,for example , when th e data ar e nonmonotonic orflatten ou t a t high doses. In these cases, it ma y benecessary to make adjustments to achieve low-doselinearity.

When pharmacokinetic or metabolism dataar e available, or when other substantial evidence onth e m ec ha nis ti c a sp ec ts o f th e c arc in og en es isprocess exists, a low-dose extrapolation model otherthan th e linearized multistage procedure might beconsidered more appropriate on biological grounds.When a different model is c hose n, the r isk

1-9

assessment should clear ly discuss the na tu re andweight o f e vi de nc e t t le d to th e choice.Considerable uncertainty will remain concerningresponse at low doses; therefore, in most cases anupper-limit risk est imate using th e l inearizedmultistage procedure should also be presented.

quivalent xposure nits mong SpeciesLow-dose risk es tima tes derived from laboratorya n i m a l data ex t r apo l a t ed to h u m an s a recomplicated by a varie ty offactors that differ amongs pe ci es a nd potentially affect the response tocarcinogens. Included a mon g t he se f ac to rs a redifferences between humans an d experimental testanimals with respect to l ife span, body size, geneticvariability, population homogeneity, existence ofconcurrent disease, pharmacokinetic effects such asmetabolism and excret ion pat te rns , an d th eexposure regimen.

Th e usual approach fo r making interspeciescomparisons ha s been to use standardized scalingfactors. Commonly employed standardized dosagescales include mg pe r kg body weight pe r day, pp m

in the diet orw t ~ r

m g p er m2

body surface a re a p e rday, an d mg p er k g body weight pe r lifetime. In th eabsence of comparative toxicological, physiological,metabolic, an d pharmacokinetic data fo r a givensuspect carcinogen, th e Agency t ak es t he positionthat th e extrapolation on th e basis of surface area isconsidered to be a pp ro p ri at e b e ca u se cer ta inpharmacological effects commonly scale according tosurface area (Dedrick, 1973; [


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th e potential for exposure via ingestion, inhalation,an d dermal pene tra tion from relevant sources ofexposures including multiple avenues of intake fromth e same source.

S pe ci al p ro bl em s arise when the humanexposure situation of concern suggests exposureregimens, e.g., route an d dosing schedule that ar esubs tan t ia lly d i ffe ren t from tho se u se d in th ere levant animal s tudies . Unless there is evidence toth e contrary in a particular case, th e cumulativedose received over a lifetime, expressed as averagedai ly exposure prorated over a l i fe t ime, isrecommended as a n a pp ro pr ia te measure ofexposure to a carcinogen. That. is, t.he assumpt.ion ismade that a high dose of a carcinogen received over ashort period oft ime i s equivalent to a correspondinglow dose spread over a lifet .ime. This approachbecomes more problematical as the exposures inquestion become more i nt en se b ut less frequent,especially when t.here is evidence that th e agent ha sshown dose-rat.e effects.

An attempt should be made to assess th e level ofunce r t a in ty assoc ia ted with the exposureassessment. which is to be used in a c an ce r r is kassessment . This measure of uncertainty should beincluded in th e r isk character izat ion (section IILC.)i n o rd er t o p rovide th e decision-maker with a clearunderst.anding of th e i mp ac t o f this uncertainty onan y final quantitative risk estimate. Subpopulat.ionswit.h heightened susceptibility (either because ofexposure or predisposition) should, when possible, beidentified.

C. Risk Characterization

Risk characterization is composed of two parts.One is a presentation of the numerical estimates ofrisk; th e other is a framework t o help judge th e

significance of the risk. Risk character izat ionincludes th e exposure assessment and dose-responseassessment ; these ar e used in t he e st im at io n o fcarcinogenic risk. ma y also consist of a unit-riskestimate which ca n be combined elsewhere with theexposure assessment for th e purposes of est imat ingcancer risk.

H a z ar d i d en t if ic a ti o n and dose- responseassessment are covered in sections an d lILA., an da detailed discussion of exposure assessment isc on ta in ed i n EPA s Guidelines fo r EstimatingExposures (U.S. EPA, 1986). This section deals withth e numer ica l r i sk estimates an d th e approach tosummarizing risk characterization.

Options for Numerical Risk EstimatesDepending on th e n ee ds o f th e individual programoffices, numerical est imates can be presented in oneor more of the following three ways.

a. U nit Risk -- Under an assumption of low-doselinearity, t he u ni t cancer r isk is th e excess lifetimer is k d ue to a continuous constant lifetime exposureof on e uni t of carcinogen concentrat ion. Typical

l

exposure units include ppm or pph in food or water,mg/kg/day by ingestion, or ppm or ll m in a i r.

b. Dose Corresponding to a Given Level of Risk -This a pp ro ac h c an h e u se fu l, p a rt ic u la r ly w he nusing nonlinear extrapolation models w her e t heunit risk would differ a t different dose levels.

c Individual an d Population Risks -- R is ks m aybe characterized either in terms of th e excessindividua l l if e time r i sks, th e e xc es s number of

cancers5 FR 33999]

produced peryear in th e exposed population, or both.

Irrespective of the l t , lions chosen, th e degreeof precision an d accuracy in t he n um e ri ca l riskestimates current ly do no t permit more than on esignificant figure to be present.ed.

Concurrent Exposure In characterizing th er isk due to c o nc u rr e nt e x po su re to severa lcarcinogens, t he risks are combined on t he b as is ofadditivity unless there is specific information to th econtrary. Interactions of cocarcinogens, promoters,an d inititators with known carcinogens should be

considered on a case-by-case hasis. Summar y o f R i sk C h ar a ct er iz at io n

Whichever met.hod of presen ta tion i s chosen , i t iscritical that th e numerical est imates not be allowedto stand alone, separa ted from the var iousassumptions and uncertainties upon which they arebased. Th e r isk charac te r iza tion shou ld contain adiscussion an d i n te r pr e ta t io n o f th e numericalestimates that affords t.he risk manager someinsight into the degree to which t.he quantitativeestimates ar e l ikely to reflect t he t ru e magnitude ofhuman risk, which generally cannot be known wit.hth e degree of quant.itative accuracy reflected in th enumerical estimates. 1 he final risk estimat.e will begenerally rounded t o one significant. figure an d willbe coupled with th e EP A classification of th equalitative weight of evidence. For example, alifel.ime individual risk of 2 X l 0. 4 resulting fromexposure to a probable human carcinogen (GroupB2) should be designated as 2 X 10. 4 [B21 . Thisbracketed designation o f t he q ua li ta ti ve w ei gh t ofevidence should be included with al l numerical r iskest.imates (Le., unit risks, which are r isks a t aspecif ied c on ce nt ra ti on o r concen t r a t ionscorresponding t o a given risk). Agency statements,such as FEDERAL REGISTER notices, briefings,and a ction m e m o r a n d a , f re q ue n tl y i nc lu denumerical estimates of carcinogenic r isk. isrecommended tha t whenever these numer ica l

estimates a re used, th e quali tat ive weight-ofevidence classification should also be included.

1 he section on risk characterization shouldsummarize th e hazard identification, dose-responseassessment, exposure assessment, and the publichealth risk estimates. Major assumptions, scientificjudgments , and, to the ex ten t possible, estimates of

1-10


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the uncertainties embodied in the assessment arepresented.

IV. EP lassification System for ategorizingWeight of Evidence for Carcinogenicity from Humanan d nimal Studies Adapted from IARC

A. Assessment of Weig ht of Evidence fo rCarcinogenicity from Studies in Humans

Evidence of carcinogenicity from human studiescomes from three main sources:

1. Case reports of individual cancer patients whowere exposed to th e agent s).

2. Descriptive epidemiologic studies in which theincidence of cancer in human populations was foundto vary in space or time w it h e xp os ur e to th eagent s).

3. Analytical epidemiologic case-control an dcohort) studies in which individual exposure to th ea ge nt s) w as found to be associated with anincreased risk of cancer.

Three criteria must be met before a causalassociation ca n be inferred between exposure an dcancer in humans:

I . T he re is no identified bias that could explainth e association.

2. Th e possibility of confounding has beenc on sid ere d a nd ru le d out as e xp la in in g t heassociation.

3. The assoc ia t ion is unlikely to be du e tochance.

In general , a l though a single study may beindicative of a cause-effect relationship, confidencein infer r ing a causal association is increased whenseveral independent s tu di es a re c on co rd an t i nshowing th e association, when th e association iss t rong, when there is a dose-response relationship,or when a reduction in exposure is followed by areduction in th e incidence of cancer.

Th e weight of evidence for carcinogenicityl fromstudies in humans is classified as:

I. Sufficient evidence of carcinogenicity, whichindicates that there is a causal relationship betweenth e agen t and human cancer.

2. Limited evidence of carcinogenici ty, whichindicates that a causal interpretation is credible, bu tthat alternative explanations, such as chance, bias,or confounding, could not adequately be excluded.

1 For purposes of public health protection, agentsassociated with life-threatening benign tumors in humans ar e

included in the evaluation.2 An increased incidence of neoplasms that occur with highspontaneous background incidence e.g., mouse liver tumorsan d ra t pituitary tumors in certainstrains) generallyconstitutes sufficient evidence of carcinogenicity, bu t may bechanged to limited when warranted by th e specificinformation available on the agent .

3 Benign an d malignant tumors will be combined unlessth e benign tumors ar e not considered to have th e potential toprogress to th e associated malignancies ofthe same histogenicorigin.

3. Inadequate evidence, which indicates that on eof two condition::; prevailed: a) there were fe wpertinent dat a, or b) the ava i lable s tu di es , w hi leshowing evidence of association, di d no t excludechance, bias, or confounding, an d therefore a causalinterpretation is not credible.

4. No data, which indicates that da ta are no tavailable.

5. No e vi de nc e, w hi ch indicates t h a t noassociat ion was found be tween exposure an d anincreased ri sk of c an ce r i n well-designed an d wellconducted independent ana ly t ica l ep idemio log icstudies.

B. Assessment of Weight of Evidence forCarcinogenicity from Studies in ExperimentalAnimals

These assessments are c la ss if i ed i n to fivegroups:

I. Sufficient evidence 2 of carcinogenicity, whichindicates that there is an increased incidence ofm ali gn an t tu mo rs o r combined m a li gn an t a ndbenign t u ~ o r s a) in mult iple species or strains; or b) i n m ul ti pl e e xp e ri m en ts e.g., with differentroutes of administ rat ion or us ing d i ffe ren t doselevels); or c) to an unusual degree in a singleexperiment with regard to high incidence, unusualsi te or type of tumor, or early ag e a t onset.

Additional evidence may be provided by data ondose-response effects, as well as in fo rmation f romshort-term tests or on chemical structure.

2. Limited evidence of carc inogenici ty, whichmeans that th e data suggest a carcinogenic effectbut a re limited because: a) t he s tu di es involve asingle species, strain, or experiment an d do no t meetcriteria for sufficient evidence see section IV. B.I.c); b) the experiments are restricted by inadequate

dosage levels, inadequate duration of exposure to th eagent, inadequate period of follow-up, poor survival,too few animals, -or inadequate reporting; or c anincrease in th e incidence of benign tumors only.

3. Inadequa te evidence, which indicates tha tbec ause of m ajor q u al it at iv e o r quan t i t a t i velimitations, t he s tu di es c an no t be interpreted asshowing either t he p re se nc e or absence of acarcinogenic effect.

4. No data, which indicates t ha t d at a are notavailable.

5. No evidence, which indicates that there is noincreased incidence of neoplasms in at least tw owell-designed

[51 FR 34000J

and wel l -conducted animal studies in different species.

Th e classifications sufficient evidence and limited evidence r efe r only to th e w ei gh t of theexperimental evidence t h a t these agents a recarcinogenic and not to th e potency of t he i rcarcinogenic action.

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C. Categorization of Overall Weight of Evidence forHuman Carcinogenicity

T he o ve ra ll s ch em e for categorization of th eweight of evidence of carcinogenicity of a chemicalfor humans uses a three-step process. (1 ) Th e weightof evidence in human studies o r a ni ma l studies issummarized; (2) t he se l in es of information arec om bi ne d t o y iel d a t e nt a ti v e a s si g nm e nt to a

category (see Table 1); and (3 ) a ll r ele van tsupport ive in fo rmation i s evaluated to see i f th edesignation o f t he overall weight of evidence needsto be modified. Relevant factors to be included alongwith the tumor information from human an d animalstudies include structure-activity relationships;short-term test findings; results of appropriatephysiological, biochemical , and toxicologicalobservations; a nd c om pa ra ti ve m et ab ol is m a ndpharmacokinetic studies. The nature of thesefindings ma y cause one to adjust t he o ve ral lcategorization ofthe weight of evidence.

Th e agents ar e categor ized into five groups asfollows:

Group A -- II uman CarcinogenThis group is used on ly when there is sufficient

evidence from epidemiologic studies to support acausal associa tion between exposure to t he a ge nt san d cancer.

Group -- Probable Human Carcinogen

This group includes agents for which th e weighto f e vi de nc e o f h um an c ar ci no ge ni ci ty based onepidemiologic studies is limited an d also includesagents for w hich the w eig ht of e vid en ce ofcarcinogenici ty based on animal s tudies is sufficient . The group is divided in to tw osubgroups. Usually, Group B is reserved for agentsfor which there is l imited evidence of carcinogenicityfrom epidemiologic studies. It is reasonable, forpract ical purposes, to regard an agent for whichthere is sufficient evidence of carcinogenicity inanimals as i it presented a carcinogenic risk tohumans. Therefore, agents fo r which there is sufficient evidence from a ni ma l s tu di es a nd forwhich t he re i s inadequate evidence or no dataf ro m e p id e mi o lo g ic s tudies would usually becategorized under Group B2.

Group C -- Possible Human Carcinogen

This group is used fo r agents w it h l im it edevidence of c ar ci no g en ic it y i n animals in th eabsence of human data. includes a wide variety ofevidence, e .g. , (a) a malignant tumor response in asingle well-conducted experiment that does not mee tconditions fo r sufficient evidence, (b) tumorresponses of margina l s tat i st i ca l significance ins tud ies having inadequate design or reporting, (c)benign but not malignant tumors with an agentshowing no response in a variety of short-term testsfo r mutagenicity, an d (d) responses of marginal

statistical significance in a tissue known to have ahigh or variable background rate.

roup D -- N ot l as s if ia bl e as to HumanCarcinogenicity

This group is generally used for agents withinadequate human and an ima l evidence ofcarcinogenicity or for which no data are available.

Group E -- Evidence of Non Carcinogenicity forHumans

T hi s g ro up is used for agents tha t show noevidence for carcinogenicity in a t least two adequateanimal tests in different species or in both adequateepidemiologic an d animal studies.

Th e designation of a n a ge nt a s b ei ng in Group gis based on th e available evidence an d should not interpreted as a definitive conclusion that th e agentwill not be a carcinogen under any circumstances.V. References

Albert, R.E., Train, R.E., an d Anderson, E. 1977. Rationaledeveloped by the Environmental Protection Agency for the

assessment' of carcinogenic risks. J . Nat . Cance r lnst .58:1537-1541.Crump, K.S., Hoel, D.G., Langley,C.H., Peto R 1976.

Fundamental carcinogenic processes an d their implicationsfor low dose risk assessment.Cancer Res.36:29732979.

Dedrick, R.L. 1973. Animal Scale Up. J . Pharmacokinet.Biopharm.l :435-461.

(I eron, V.J., Grice, H.C., Griesemer, R., Peto R., Agthe, C., Althoff,J. , Arnold, D.L., Blumenthal, H., Cabral, J.R.P., Della Porta,G., I to , N., Kimmerle, G., Kr oe s, R., Moh r, U ., Napalkov,N.P., Odashima, S., Page, N.P., Schramm, T., Steinhoff, D.,Sugar,J., Tomatis, L., Uehleke, II., an d Vouk, V 1980. Basicrequirements for longterm assays for carcinogenicity. In :Long-term an d short-term screening assays for carcinogens:a critical appraisal. IARC Monographs, Supplement 2. Lyon,France: International Agency for Research on Cancer, pp 2183.

Freireich, E.J.,Gehan, E.A., Rail, D.P., Schmidt, L.H., an d

Skipper, H.E. 1966. Quantitative comparison of toxicity ofanticancer agents in mouse, r a t, hams ter, dog, monkey an dman. Cancer Chemother. Rep.50:219-244.

Haseman, J .K. 1984. Statistical issues in th e design, analysis andinterpretation o f an ima l carcinogenicity s tudies . Environ.lIealthPerspect.58:385-392.

Haseman,J.K., HutT,J.,and Boot man,G.A.1984. Use ofhistorical control data in carcinogenicity studies in rodents.Toxicol. Pathol.I2:126-135.

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TABLE l I L L U ~ T R A T I V ECATEGORIZATION OF EVIDENCE SED ON ANIMAL AND HUMAN DATAl

Animal evidence

Human evidence

Sufficient Limited Inadequate No data No evidence

Sufficient A A A A A

Limited Bl

Inadequate B2 C D D D

No data B2 C D D E

No evidence B2 C D D E

1 The above assignments are presented fo r i llustrative purposes. There may be nuances in the classification of bothanimal and human data indicating t h at d i ff er e nt categorizations than those given in t he t ab le should be assigned.Furthermore these assignments are tentative and may be modified by ancillary eVidence. In t hi s r egard all relevantinformation should be evaluated to determine if the designation of the overall weight of eVidence needs to be modifiedRelevant factors to be included along with t he tumor data from human and animal studies include structure activityrelationships short term test findings results of appropriate physiological. biochemical and toxicological observations andcomparative metabolism and pharmacokinetic studies. The nature of these findings may cause an adjustment of the overallcategorization of theweight of evidence.

National Research Council NRC). 1983. Risk assessment in theFederal government: manag ing the process. WashingtonD.C.: National Academy Press.

National Toxicology Program. 1984. Reportofthe Ad Hoc Panelon Chemical Carcinogenesis Testing an d Eva luat ion o f theNational Toxicology Program Board of Scient if icCounselors. Avai lable f rom: U.S. Government PrintingOffice, Washington D.C. 1984-421-132:4726.

Nutrition Foundation. 1983. The relevance of mouse liverhepatoma to human carcinogenic r isk: a report of theInternational Exper t Advisory Committee to t h e Nu tr it ionFowldation. Available from: Nutrition Foundation. ISBN 0935368-37-x.

Office of Science an d Technology Policy OSTP). 1985. Chemicalca rc inogens : r evi ew of th e science an d it s associatedprin cipl es. I< ederal Register 50:10372-10442.

Peto, R., Pike M., Day N Gray R., Lee, P., Parish S., Peto, J.

Richard S., an d Wahrendorf, J. 1980. Guidelines for simple,sensitive significant tests for carcinogenic effects in longt e rm an ima l experiments. In: Monographs on the long-terman d short-term screening assays for carcinogens: a criticalappraisal. IARC Monographs, Supplement 2. Lyon, France:International Agencyfor Researchon Cancer, pp. 311-426.

Pinkel D. 1958. The use of bodysurface area as a criterion ofdrugdosage in cancerchemotherapy.Cancer Res.18:853-856.

Tomatis L. 1977. The value oflong-term testing for th eimplementation of primary prevention. In: Origins of humancancer. Hiatt H.H., Watson J.D. an d Winstein, J.A., eds.Cold Spring Harbor Laboratory pp. 1339-1357.

U.S. Environmental Protection Agency U.S. EPA). 1976. Interimprocedures an d guidelines fo r h ea lth r is k a nd economicimpact a s ses smen ts o f suspected carcinogens. FederalRegister41:21402-21405.

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1985 reflected some ofthe progress that has occurredin understanding the mechanisms of carcinogenesis.Many commentors, however, felt tha t additionalchanges were warranted.

The SA B concluded that th e guidelines are reasonably complete in their conceptual frameworkan d are sound i n t he ir overall interpretation of th esc ient i f ic i s sues (Repor t by the SA BCarcinogenicity Guidelines Review Group, June 19,1985). Th e SAB suggested various editorial changesan d r ai sed some issues regarding the con tent of th eproposed guidelines, which are discussed below.B as ed o n these recommendations, th e Agency ha smodified the dra ft guidelines.

II Office of Science an d Technology Policy Report onChemical Carcinogens

M an y c om me n to rs requested tha t th e finalguidelines no t be issued until after publication ofthereport of th e Office of Technology an d Science Policy(OSTP) o n c he mi ca l c ar ci n og e ns . They furtherrequested that this report be incorporated into th efinal Guidelines for Carcinogen Risk Assessment.

Th e final OSTP report was published in 1985 (50It R 10372). In it s deliberations, th e Agency reviewedth e final OSTP report an d feels that th e Agency sguidel ines are c o ns is t en t w i th the principlesestablished by th e OSTP. In it s review, th e SABagreed that th e Agency guidelines ar e ger:lerall yconsistent with th e OSTP report. To emphaSIze thIsconsistency, the OSTP p r in c ip le s h av e beenincorporated into th e guidelines when controversialissues ar e discussed.

Ill Inference Guidelines

Many c om m en to rs f e lt tha t the proposedguidelines did no t provide a sufficient distinctionbetween scientific fact an d policy decisions. Othersfelt that EP A should no t attempt to propose firmguidelines i n t he absence of scientific consensus. Th eSAB report also indicated th e ne ed to distinguishrecommendations based on scientific evidence fromthose based on science policy decisions.

Th e Agency agrees wit h t he recommendationtha t policy, judgmental, or inferential decisionsshould be c lear ly identified. In it s revision of th eproposed g ui de li ne s, t he Agency has includedphrases (e.g., t he Agency t ak es t he position that )to more clearly distinguish policy decisions.

Th e Agency also recognizes th e need to establishprocedures for action on important issues in th e

a bs en ce o f c om pl et e s ci en ti fi c knowledge orconsensus. This need was acknowledged in both th eNational Academy of Sciences book entitled RiskManagement in the Federal Government Managingt he P ro ce ss and the OSTP report on chemicalcarcinogens. As th e NA S r ep or t s ta t es , Riska ss es sm en t i s an analytic process that is f ir mlybased on sc ien t if i c considera tions, but i t also

requires judgments to be made when th e availableinformation is incomplete. These judgmentsinevitably draw on both scientific and policyconsiderations.

L FR34002JThejudgments ofthe Agency have been based on

current available scientific information and on th ecombined experience of Agency experts. Thesej ud gm en ts , a nd th e resulting g ui da nc e, r el y on

inference; however, th e positions taken in theseinference guidelines ar e felt to be reasonable andscientifically defensible. While all ofthe guidance is,to some degree, based on inference, th e guidelineshave attempted to distinguish t ho se i ss ue s thatdepended more on judgment. In these c as es , t heAgency ha s stated a position bu t ha s also r e t a i f lexibi li ty to accommoda te ne w data or speCIfICcircumstances that demonstrate that th e proposedposition is inaccurate. Th e Agency r e c o ~ i z e sthatscientific opinion will be divided on these Issues.

Knowledge about ca rc inogen s andcarcinogenesis is progressing a t a rapid rate. Whilethese guidelines ar e considered a best effort at the

present t ime, the Agency hasa t t e m t e ~

toincorporate flexibility into th e current gUIdelInesan d also recommends that th e guidelines be revisedas often as warranted by advances in th e field. Evaluation of Benign Tumors

Several commentors discussed th e appropriateinterpretat ion of an increased incidence of benigntumors alone or with an i nc re as ed i nc id en ce o fmalignant tumors as part o f t he evaluation of thecarcinogenicity of an agent. Some comments weresupportive ofthe position in th e proposed guidelines,Le., under cer t ain circumstances, th e i n c i d e n ~ofbenign and malignant tumors would be combmed,an d an increased incidence of ben ign tumors alone

would be considered an indication, albeit limited, ofcarcinogenic potential. Other commentors raisedconcerns a bo ut t he criteria that would be used todecide which tumors should be combined. Only a fewcommentors felt that benign tumors should never beconsidered in evaluating carcinogenic potential.

The Agency believes that current informationsupports th e use of benign tumors. Th e guidelineshave been modified to incorporate th e l anguage ofth e OSTP report, Le., benign tumors will becombined with m a l i g n a n t t umors whenscientifically defensible. This posi t ion allowsflexibility in e va lu at in g t he d ata b as e for eachagent. Th e guidelines have also been modified to

indicate that whenever benign a nd m al ig na nttumors have b ee n c om b in e d, an d th e ag en t isconsidered a candida te fo r quant i ta t ive r iskextrapolation, the contribution of benign tumors toth e estimation ofrisk will be indicated.

V. Transplacental an d ultigenerational nimalBioassays

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As one of it s two proposals for additions to th eguidelines, th e SAB recommended a discussion oft ra n sp la c en t al a nd mu l ti gene r a ti onal an im a lbioassays for carcinogenicity.

Th e Agency agrees t ha t such data, whenavailable, ca n prov ide use fu l information in th eevaluation of a chemical s potential carcinogenicity

an d ha s s ta te d t hi s in th e f ina l guidel ines. Th eAgency ha s also revised the guidelines to indicatet ha t such s tudies may provide add i t i ona linformation on the metabolic an d pharmacokineticproperties of th e chemical. More g ui da nc e o n th especific use of these s tudies will be conside red infuture revisions of these guidelines.

VI aximum Tolerated Dose

T he p ro po se d g u id e li ne s d is cu s se d th eimplications o f u si ng a maximum tolera ted dose(MTD) in bioassays fo r carcinogenicity. Manycommentors requested that EPA define MTD. Th etone of the comments sugges ted t h t th ecommentors were concerned a bo ut the uses an dinterpretations of high-dose testing.

The Agency recognizes t ha t cont roversycurrently su rrounds these issues. Th e appropriatetext from the OSTP report ha s been incorporatedinto th e final guidelines which suggests that th econsequences of high-dose testing be evaluated on acase-by-case basis.

VII Mouse Liver umors

A l arg e nu mbe r of commentors expr essedopinions about. the assessment of bioassays in whichth e only increa se in tu mor incidence wa s livertumors in th e mouse. Many felt that mouse livertumors were afforded too much credence, especiallygiven existing information that indicates that theym ig ht a ri se by a different mechanism, e.g., tissuedamage followed by regeneration. Others felt thatmouse liver tumors were but on e case of a highbackground incidence of one par t icu la r type oftumor and that a ll s uc h t um or s should be t r ea ted inthe same fashion.

l he Agency ha s reviewed these comments andth e OSTP principle regarding this issue. Th e OSTPreport does not reach conclusions as to the treatmentof tumors with a high spontaneous background rate,b u t s ta te s, as is now included in th e tex t of theguidelines, t ha t these da ta requi re speci alconsideration. Although ques tions have been raised

regarding th e validity of mouse live r tu mor s ingeneral, th e Agency feels that mouse l iver tumorscannot be ignored as an indicator of carcinogenicity.Thus, th e position i n t he proposed guidelines ha s no tbeen changed: an increased incidence of only mousel iver tumors will be regarded a s s uf fi ci en tevidence of carcinogenicity al l other criteria, e.g.,replication and malignancy, are met with th eunderstanding that th i s c lass if i ca t ion could bechanged to limited if warranted. The factors that

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m ay c au se this re-evaluation ar e indicated in th eguidelines.

VIII Weight ofEvidence Catagories

Th e Agency was praised by both th e public an dth e SAB for incorporating a weight-of-evidences ch em e i nt o it s eva lua tion of carc inogen ic r isk.Certain specific a sp ec ts o f th e scheme. however.were criticized.

1. Several com mentors noted that while th e textof the proposed guidelines clearly states tha t EP Awill use all available data in it s categorization of theweight of t he e vi de nc e t ha t a chemical is acarcinogen, th e classification system in Par t A.section IV did not indicate the manner in which EP Awill use information other than data from humansan d long-term animal studies in assigning a weightof-evidence classification.

Th e Agency ha s added a d iscuss ion to Par t A.section IV.C. dealing with the characterization ofoverall evidence for human carcinogenicity. Thisdiscussion clarif ies EPA s use o f s u pp o rt iv einformation to adjust, as warranted . th e designationthat would h ave be en made solely on th e basis ofhuman an d long-term animal studies.

2. Th e Agency agr ee s with the SAB and thosecommentors who felt that a simple classification ofth e weight of evidence, e,g., a single letter or even adescriptive tit le, is inadequate to describe fully th eweight of evidence for each individual chemical. Th ef inal guidel ines propose t ha t a pa rag raphsu mm ariz in g t he d at a s ho uld a cc om pa ny thenumer ica l es t imate and weight -of -ev idenceclassification whenever possible.

3. Severa l co m mentors ob jected to t h e

descriptive title E (No Evidence of Carcinogenicityfor Humans) because t hey f el t th e title would beconfusing to people i ne xp er ie nc ed w it h theclassif icat ion system, Th e title for Group E. NoEvidence of Carcinogenicity fo r Humans , wa sthought by these commentors to suggest the absenceof data. This group, h ow ev er, i s intended to bereserved for agents for which there exists credibled a ta d em o ns tr at in g t h t the a g e n t is no tcarcinogenic.

Based on these commen t s an d f u r t h rdiscussion, the Agency ha s changed th e

[51 FR 34003)t it le of Group E

to Evidence of Non-Carcinogenicity for Humans.

4. Several commentors fel t tha t th e title fo rGroup C, Possible Human Carcinogen, wa s notsufficiently distinctive from Group B, ProbableHuman Carcinogen. Other commentors fe lt tha tthose agents that minimally qualified for Group Cwould lack sufficient data for such a label .

Th e Agency recognizes that Group C covers ar an ge o f chemicals an d ha s considered whether tosubdivide Group C. The consensus of th e Agency s


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Carcinogen Risk Assessment Committee, however,is that th e u ~ r n tgroups, which are based on th eIARC categories, ar e a reasonable stratification andshould be re ta ined at present. Th e s tructure o f thegroups will be reconsidered when th e guidelines arereviewed in th e future. Th e Agency also feels thatt he desc rip tive title i t originally selected bestconveys th e meaning of th e classification within thecontext of EPA s past an d current activities.

5. Some com mentors indicated a concern aboutthe distinction between and 132 on th e basis ofepidemiologic evidence only. T hi s i ss ue ha s beenunder discussion in t he Agency and may be revisedin future versions of th e guidelines.

6. C om me nt s w ere a ls o r ec eiv ed about th epossibility of k ee pi ng t he g ro up s for a nim al a ndhuman data separate without reaching a combinedclassification. Th e Agency feels that a combinedc la ss if ic at io n i s useful; thus, the combinedclassification was retained in th e final guidelines.

Th e SAB suggested that a table be added to PartA, section IV to indicate th e manner in whichhum an and anim al data would be combined to

obtain an overall weight-of-evidence category. Th eAgency realizes that a table that would present a l lpermutations of potentially available data would becomplex an d possibly impossible to construct sincenumerous combinations o f a nc ill ar y d at a (e.g.,genetic toxicity, pharmacokinetics) could be used toraise or lower th e weight-of-evidence classification.Nevertheless, th e Agency decided to include a tableto illustrate the most probable weight-of-evidenceclassification that would be assigned on th e bas is o fs tandard a n i m a l and h u m a n d a t a withoutconsideration ofthe ancillary data. While it is hopedthat this table will clarify th e weight-of-evidenceclassifications, it is a lso important to recognize thatan agent may be assigned to a f inal categor izat ion

different from t he c at eg or y which would appearappropriate from th e t ab le a nd still conform to th eguidelines.

IX u ntit tive stimates of Risk

The method fo r q u a n ti ta t iv e e s ti m a t es ofcarcinogenic r is k i n th e proposed guidelines receivedsubstantial comments from th e public. Five issueswere discussed by th e Agency an d have resul ted inmodifications ofthe guidelines.

1. Th e major c ri ti ci sm was th e perception thatEPA would use only one method fo r theextrapolation of ca rc inogen ic r isk and would,therefore , obtain on e es t imate o f ris k. Evencommentors who concur with th e procedure usuallyfollowed by EP A felt that some indica tion of th euncertainty of t he r is k e st im at e should be includedwith th e risk estimate.

Th e Agency feels that th e proposed guidelineswere no t intended to suggest tha t EP A wouldperform quant i ta t ive r i sk estimates in a rote or

mechanical fashion. As indicated by th e OSTPreport an d paraphrased in th e proposed guidelinesno single mathematical p ro ce du re h as ~determined to be the most appropriate method forrisk extrapolation. Th e final guidelines quote ratherthan paraphrase th e OSTP principle. Th e guidelineshave been revised to stress th e importance ofconsidering all available data i n t he risk assessmentan d now state , T he A ge nc y w il l review eacha ss es sm e nt a s to th e evidence on carcinogenicmechani sms and other biological o r s ta t is ti c alevidence that indicates the suitability of a particularextrapolation model. Two issues ar e emphasized:First, th e text now indicates th e potential forpharmacokinetic information to contribute to theassessment of carcinogenic risk. Second, th e finalguide l ines s t a t e t t t ime - to - t u m or r iskext rapola t ion models m ay be used whenlongitudinal data on t um o r d ev elo pm en t a reavailable.

2. A number of c o mm e nt or s n o te d tha t th eproposed guidelines did not indicate how th euncertainties of risk character izat ion would bepresented. Th e Agency has revised th e proposed

guidelines to indicate tha t major assumpt ions ,scientific j udgments , and, to th e extent possible,estimates of

The Risk Assessment Guidelines of 1986

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