ITED ATES ENV RO E T L P oreCTlO AGENCY ASHI GTO • D. . 2 0

October 4, 2005 C1ENCE PO\.lC'i COU Cll
MEMORANDUM SUBJECT: Implementation ofthe Cancer Guidelines and Accompanying Supplemental Guidance

- Science Policy Council Cancer Guidelines Implementation Workgroup Communication I: Application ofthe mode ofaction framework in mutagenicity determinations fllr carcino enicily

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FROM: William H. Farland, Ph.D. 

# A.A--:-**(Z7~** Chair, Science Policy Council

--­ TO: Science Policy Council Science Policy Council Steering Committee In his memo ofMarch 29, 2005, Administrator Johnson provided general direction on implementation ofEPA's 2005 Guidelines for Carcinogen Risk Assessment (Cancer Guidelines, CG) and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (Supplemental Guidance, SG). The Administrator's memo says that the Cancer Guidelines and the Supplemental Guidance should be used:

• for all carcinogenicity risk assessments that are newly**initiated~** • on a case-by-case basis for assessments that currently are being performed, based on consideration ofthe potential effects oftheir use on the expected decision and**timeline~** and • on a case-by-case basis for assessments that were completed before issuance ofthe Cancer Guidelines, when a new prog mn-specific or site-specific decision is required that needs to be supported by an updated carcinogenicity risk assessment. Ihave asked the Science Policy Council (SPC) Cancer Guidelines Implementation Workgroup to provide information to facilitate the development ofnew carcinogenicity risk assessments and to promote consistency with Agency policy, guidance, and guidelines. I anticipate providing additional information on these topics in the future as the Agency gains experience with the new Cancer Guidelines and Supplemental Guidance and as new questions and issues arise. The information in the attached communication is intended for Agency risk assessors who are involved in conducting or reviewing risk assessments for carcinogens. The scope of Agency assessments varies widely, from screening level exposure and risk assessments involving hun r 5 of ht'l it. 1 ,l cu 

### rd,**n~j'** to. 'ieologjcal

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### f sin e dlemictlls such as

### those in the Agency's Integrated Risk Information System (IRIS). The activities ofAgency risk assessors are equally diverse, so risk assessors will need to considertheir specific roles and responsibilities when deciding how best to use the information provided here. Agency risk assessors are strongly urged to become familiar with the sections ofthe Cancer Guidelines 

### and Supplemental Guidance 

### that are relevant to their particular activities, and to consult these documents for a fuller description ofthe topics discussed in this communication. The purpose ofthe attached communication is to provide summary information for applying the Cancer Guidelines' 

### mode ofaction (MOA) framework in determining whether a chemical has 

### a mutagenic mode ofaction. This communication also provides information on applying the new Supplemental Guidance 

### when assessing risks for carcinogens that have a mutagenic mode ofaction. Specifically,

• Section 1summarizes the key steps in the process ofdetermining whether a weight of evidence evaluation supports a mutagenic MOA for carcinogenicity. • Section 2 outlines how to considerboththe Cancer Guidelines'

### mode ofaction framework and the Supplemental Guidance 

### in each component ofa risk assessment (hazard characterization, dose-response assessment, exposure assessment, and risk characterization). It focuses on these particulartopics because the new Cancer Guidelines 

### emphasize the importance ofMOA in assessing cancerrisk, and the MOA determination is critical to the application ofthe new Supplemental Guidance. 

### Additionally, while much ofthe Cancer Guidelines 

### focus on hazard characterization and dose-response assessment, the Supplemental Guidance 

### includes guidance for risk assessors who are using slope factors and exposure datato estimate cancerrisk for early-life exposures in risk characterization. This communication clarifies how risk assessors should apply the Cancer Guidelines 

### and accompanying Supplemental Guidance 

### within the context ofthe currentpractices and activities oftheir offices or programs. For example, ifa program generally relies on cancerrisk assessment information contained in IRIS, thatprogram can continue this practice. When IRIS states that a weight ofevidence evaluation supports adetermination that a chemical is cnrcinog nic by a mutagenic mode ofaction, the program would utilize that determination and the appropriate application ofrecommended age dependent adjustment factors (ADAFs) or chemical specific estimates oflifestage susceptibility. In cases where the IRIS assessment on a chemical has 

### not addressed application ofthe Supplemental Guidance, 

### each office orprogram will need to considerapplication ofthe Cancer Guidelines 

### and Supplemental Guidance.

2Science Policy Council CancerGuidelines ImplementationWorkgroup Communication I. Application oftbe mode ofaction framework in mutagenicity determinations for carcinogenicity Section 1. Essential Components in tbe Process for Determining a Mutagenic Mode of Action for Carcinogenicity!

. Carcinogenesis is a complex process requiring that assessors sometimes consider more than one MOA for carcinogenicity. This memo addresses the evaluation ofthe potential for a mutagenic MOA for carcinogenicity, but nothing in this discussion is meant to exclude consideration of othercarcinogenic MOAs as part ofthe evaluationprocess. An Agency determination regarding a mutagenic mode ofaction (MOA) for human carcinogenicity may be part ofa new complete hazard and dose-response assessment. part ofan updated assessment. or an addition to an existing assessment. The determination should address the quality standards described inthe Agency's Information Quality Guidelines. The process of makingeachMOAdetenninationhasthree essential components, which are discussed below. Their description is not intended to imply duplicative analytical steps. l.A. Analysis ofa mutagenic MOA for carcinogenicity. Risk assessors should implement the following steps when determining whether a chemical is considered carcinogenic by a mutagenic MOA. 

### 1.A.I. 

### Consult CriticalAgencyDocuments The Cancer Guidelines and 

### Supplemental Guidance (h p.**~cfp** .eD .govlnceaJ fmlrecordl play.cfm?del =116283) discussthe MOA analysis and considerations for mutagenicity as a 

### MOA for carcinogenicity (See CG Sec. 

### 2.4; SO Sees. 

### 3.2.1­ 2). Other documents, such as EPA publications on modes ofaction for certain classes of chemicals may also be relevant. 

### l.A.2. 

### EvaluateRelevantData TheEPA Risk As :;sm nt Forum'sMutagenic Mode ofAction WorkingGroup is workingon guidance onthe scientific aspects ofmaking mutagenic mode ofaction determinations, and to assist in determinations ofmutagenic MOAs for carcinogenicity. Theirproduct will elaborate on the essential elements ofsuch determinations which include:

• reviewing the available mutagenicity datato determine ifthe chemical is mutagenic; • applying the Cancer Guidelines' mode ofaetionframework to ascertain ifthe weight of the evidence supports a determination that a mutagenic mode ofaction (as described in

IThe phrase, 'determination that a chemical is carcinogenic by a mutagenic mode ofaction', and similar phrases, are intended to indicate a weight ofthe evidence detennination that includes an evaluation ofthe mode of action in animals as well as its relevance for humans, as part ofthe broader weight ofevidence narrative "that explains an agent's carcinogenic potential and the conditions that characterize its expression"[CG, sec 2.5). The slightly short 1ph isused to imp ve Ih flow ofthe text.the 

### Cancer Guidelines and 

### Supplemental Guidance) is (l) applicable to animals and (2) relevant to humans; and • reaching anAgency conclusion for a mutagenic MOA for carcinogenicity when a mutagenic MOA is determined, and applying the 

### Supplemental Guidance. (For further infonnation, contact Resha Putzrath, 202564-3229; putzrath.resha@epa.gov>. In addition to evaluating mutagenicity as a MOA for carcinogenicity, the MOA analysis should also evaluate the strengths and weaknesses ofotherplausible modes ofaction. Ifthere is significant biological support for more than one mode ofaction, each should receive a separate analysis (See CO Sec.2.4.3). Infonnation on all modes ofaction should be integrated to better understand which mode(s) maybe relevant for different human exposure scenarios, Le., risk characterization (See CO Sec. 2.4.3.3). Alternative modes ofaction for which there is significant biological support should, along with their strengths and uncertainties, be partoftherisk characterization (See CO Sec.5.1). When developing an MOA analysis as a companion to an existing assessment that may contain a considerable amount ofdata and analysis, an application ofthe mode ofaction framework may largely rely on citations and analyses from the existing assessment. l.A.3. Provide the Conclusion of theAnalysis andSupporting Rationale Assessors can make one ofthree majorconclusions: • a weight ofevidence evaluation supports a determination that the chemical is carcinogenicby amutagenic MOA; • the weight ofthe evidence evaluation does not support a mutagenic MOA; or • a weight ofevidence evaluation supports the conclusion that a determination ofa mutagenic MOA for carcinogenicity cannot be made because there are insufficient data for determining the mutagenicity, orfor defining an MOA. Assessors should explainthe rationale for their conclusion clearly and in appropriate detail. In some cases, where there are few data and where the data are insufficient to support a mutagenic MOA detennination, this rationale may be quite brief. I.B. PeerReview ofthe MOA Analysis The 

### Cancer Guidelines discuss peerreview ofMOA analyses in section 2.4.2.1. MOA analyses, including evaluation ofa mutagenic MOA for carcinogenicity, should be peerreviewed in accordance with EPA's Peer Review Policy, and c\)ndoct fthe eTT \ "\ 'h 

### '0 be in accordance with EPA's Peer Review Handbook (hap: www.epa.guv/uscu'sp<.:**pcr~(rev.bcml.** I.C. Communication ofAgency Determinations. For infonnational purposes, chemical-specific mutagenic MOA analyses for carcinogenicity should be shared acrossthe Agency priorto any public release. Communication with the public should beconducted in r AIle with th Ag n ..'s Info lall n Quality Cui eli and th 4practices ofthe specific program office or region making the determination. These analyses should make clear, across the Agency (and to the public, when appropriate): • whether a detennination ofa mutagenic MOA has been made; and • whether age-dependent adjustment factors (ADAFs) should be applied; or • ifchemical- specific data incorporating lifestage susceptibility were available for derivation ofcancer slope factors. For IRIS assessments, communication ofthe MOA determination across the Agency occurs during the IRIS Agency Review. Communication with the public occurs when the toxicological assessment is released for external peer review, and when 

### the 

### fmal assessment is posted on IRIS. When the IRIS program makes a mutagenic MOA determination for a chemical, the IRIS assessment for the chemical will containthe MOA determination. When a mutagenic MOA determination for a chemical has been made outside ofthe IRIS assessment process, the analysis and determination, while not necessarily partofthe IRIS assessment for the chemical, generally will be accessible from the IRIS assessment (e.g., via hyperlinks). 

### Section 2. ImplementingtheMOA Framework and

### Supplenuntal Guidance in Risk Assessment Implementing the MOA framework described in 

### the Cancer Guidelines requires particular considerations in each component ofa risk assessment: hazard characterization, dose-response assessment, exposure assessment, and risk characterization. The purpose ofthis section is to describe how to use the MOA framework and consider the Supplemental Guidance in each component. Figure I (adapted from Figure 3 ofthe Supplemental GUidance) provides a flow chart ofthe MOA framework. Reference to a "box" in the following text means one ofthe boxes in Figure 1. 

### 2.A. Hazard Characterization In this step, the assessor weighs the evidence for carcinogenicity and makes a conclusion regarding carcinogenicity to humans. In addition, the assessor analyzes information on possible MOAsfor carcinogenicity, including a mutagenic MOA in animals, to detennine whether there is sufficient infonnation to support a MOA determination and ifany proposed MOAs are relevantto humans (Box 1ofFigure 1). Section I, "Essential Components in the Process ofa Determination ofa Mutagenic Mode ofAction for Carcinogenicity," provides additional guidance**o~** the key steps in determining a mutagenic MOA. Ifplausible mutagenic MOAs for carcinogenicity have been considered and rejected, and no other MOA can be determined, the Cancer Guidelines recommend assessing cancerrisk for exposures ofinterest using slope factors derived via the default linearextrapolation, without further adjustment (Box 2). Ifa mutagenic MOA for carcinogenicity is supported by the database and is relevant to humans, then the assessor flags susceptible lifestages and populations for application ofchemical specific quantification inthe dose-response step or application ofADAFs in the risk characterization step.2.B. Dose-Response Assessment In the dose-response step ofa risk assessment, the conclusions ofthe MOA analysis influence the method 

### used to extrapolate from the range ofexposures in the available studies to environmental exposure levels. Generally, the 

### Cancer Guidelines recognize various implications for low-dose extrapolation. The decision to use a particular extrapolation approach is 

### based on the analysis ofthe entire database and the conclusion onthe MOA. A non-linear approach is used for agents having a carcinogenic MOA sufficient to conclude that it is non-linear at low doses; the RfCIRfD method is the default approach. A linearapproach is used either as a default in the absence ofsufficient toxicological infonnation to detennine a MOA or when the MOA is consistent with low-dose linearity, such as may be the case with a mutagenic MOA. Ifa weight ofevidence analysis supports a mutagenic MOA for carcinogenicity and the extrapolation approach is linear, then as described in the 

### Supplemental Guidance, it is necessary to analyze the available data on potential susceptibility ofearly lifestages (lower box in Figure 1) to detennine whether chemical-specific slope factors incorporating lifestage susceptibility are to be developed orADAFs should be applied in the risk assessment. Specifically:

• Ifappropriate chemical-specific data on susceptibility from early life exposures are available, then these data are used to develop cancer slope factors that specifically address any potential for differential potency in early lifestages. Anexample is the IRIS assessment ofvinyl chloride (http://www.epagov/iris/subst/1001.htm).

• Ifappropriate chemical-specific data are not available on susceptibility from early life exposures, the dose-response assessment should indicate that the ADAFs should be used with the cancer slope factors and age specific estimates ofexposure in the development ofrisk estimates. See Section 

### 2.0, Risk Characterization, below. The Agency is currently considering how this infonnation will be presented and fonnatted in IRIS ass $ment&. and 

### win provid further infonnation on this. 2.C. Exposure Assessment According to the 

### Supplemental Guidance, "when developing quantitative estimates ofcancer risk the Agency recommends**int~gration** of**ag~.sp~ciflC** va/flU for both**exposur~** and toxicity/potency**wh~,.e** such data are avaiJllb/e andappropriate," since "children, in general, are expected to have some exposures that differ from thoseofadults (either higher or lower), due to differences in size, physiology, and behavior." Further, "this approach is adopted because risk estimates based on an average daily exposure pro-rated over a lifetime do not considerthe potential for higher cancer risks from early-life exposure."

6Section 6 oftheSupplemental Guidance provides several examples ofhow to integrate age­ dependent estimates ofexposure andpotency.to estimate risks from lifetime and less-than­ lifetime oral exposures. EPA's Risk Assessment Forum is also nearing completion ofguidance for selecting age groups for monitoring and/or assessing childhood exposures. (hap:II'

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## em. d = - - 7). TheSupplemental Guidance establishes ADAFs for three specific age groups 

## « 2 years, 2 to < 16 years, 16 years and above). Ifthe dose-response assessment indicates that ADAFs should be applied, any grouping ofages in the exposure assessment will need to be integrated with the ADAF age groupings to derive age group-specific risk estimates. Forexample, anassessor may determine that anexposure is agedependent, necessitating the use ofage-specific exposure factors inthe risk assessment (for example, age-specific bodyweights). Inthis case, the assessor may find that age groups for whichexposure factors are available do not match the ADAF age groupings, suchthatthe assessor will need to sub-divide anexposure age groupto accommodate the age groupings for the ADAFs. In the risk characterization, cancer risk is derived for each age group, as appropriate, and summed across age groups, to obtain the total risk for the exposure period of interest (See SO Sec.6). 

### 2.0. 

### Risk Characterization
The risk characterization shouldexplicitly discuss the MOA conclusion, the low-dose extrapolation approach, and consideration ofthe potential for early lifestage susceptibility. In assessments for chemicals for which a mutagenic MOA for carcinogenicity has been determined and a linear low-dose extrapolationperformed, one ofthe following pertains: • Ifchemical-specific data on susceptibilityfrom early-life exposures were available for derivation ofcancer slope factors, those slope factors are used for risk characterization, and the ADAFs are 

### !l2! applied. • Ifchemical-specific data on susceptibility from early life exposures were not available, the ADAFs are applied in calculating orestimating risks associated with early-life exposures (see SO, Sec.6).
In $.Orne EPA**P,.o~** d\fferent peopleare involv d in the different steps ofthe risk assessment In thosecases, there will need to be clearcommunicationconcerningthe decisions made inthe various steps ofrisk assessment and there will need to be a clear understandingof who is responsible for implementing each ofthe various elements ofthe Supplemental Guidance. For example, risk assessors who use slope factors from IRIS or any other source ofhazard and dose-response assessments are responsible for assuring that ADAFs orchemical specific data are appropriately used giventhe exposure scenario.
For additional information, contactthe workgroup co-chairs: Lee Hofmann, 202 566 1928; hofmann.lee@epa.gov Bill Sette, 202 564 0693; sene.william@epa.gov

7Figure 1. Flow Chartfor Early-Life RiskAssessment Using Mode ofAction Framework (Source: Figure 3. Supplemental GuidanceforAssessingSusceptibility from Early-Life Exposure to Carcinogens)

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