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 of the Cancer Guidelines and Accompanying Supplemental 

Guidance - Science Policy Council Cancer Guidelines Implementation 

Workgroup Communication I: Application of the mode of action framework in 

mutagenicity determinations fllr carcino enicily . Q 

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 of March 29, 2005, Administrator Johnson provided general direction on 

implementation of EPA'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 of the
 

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.
 

I have asked the Science Policy Council (SPC) Cancer Guidelines Implementation
 

Workgroup to provide information to facilitate the development of new 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 . S In DIS f sin e dlemictlls such as
 
those in the Agency's Integrated Risk Information System (IRIS). The activities of Agency risk 

assessors are equally diverse, so risk assessors will need to consider their 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 of the topics discussed in this communication. 

The purpose ofthe attached communication is to provide summary information for 

applying the Cancer Guidelines' mode of action (MOA) framework in determining whether a 

chemical has a mutagenic mode of action. This communication also provides information on 

applying the new Supplemental Guidance when assessing risks for carcinogens that have a 

mutagenic mode of action. Specifically, 

• Section 1 summarizes the key steps in the process of determining whether a weight of 

evidence evaluation supports a mutagenic MOA for carcinogenicity. 

• Section 2 outlines how to consider both the Cancer Guidelines' mode of action 

framework and the Supplemental Guidance in each component of a risk assessment 

(hazard characterization, dose-response assessment, exposure assessment, and risk 

characterization). 

It focuses on these particular topics because the new Cancer Guidelines emphasize the 

importance ofMOA in assessing cancer risk, and the MOA determination is critical to the 

application of the new Supplemental Guidance. Additionally, while much of the 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 data to 

estimate cancer risk 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 current practices and activities 

oftheir offices or programs. For example, if a program generally relies on cancer risk 

assessment information contained in IRIS, that program can continue this practice. When IRIS 

states that a weight ofevidence evaluation supports a determination that a chemical is 

cnrcinog nic by a mutagenic mode of action, the program would utilize that determination and 

the appropriate application of recommended age dependent adjustment factors (ADAFs) or 

chemical specific estimates of lifestage susceptibility. In cases where the IRIS assessment on a 

chemical has not addressed application of the Supplemental Guidance, each office or program 

will need to consider application ofthe Cancer Guidelines and Supplemental Guidance. 

2 
Science Policy Council Cancer Guidelines Implementation Workgroup 

Communication I. Application of tbe mode of action 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 of the potential for a mutagenic 

MOA for carcinogenicity, but nothing in this discussion is meant to exclude consideration of 

other carcinogenic MOAs as part ofthe evaluation process. 

An Agency determination regarding a mutagenic mode of action (MOA) for human 

carcinogenicity may be part of a new complete hazard and dose-response assessment. part of an 

updated assessment. or an addition to an existing assessment. The determination should address 

the quality standards described in the Agency's Information Quality Guidelines. The process of 

making each MOA detennination has three essential components, which are discussed below. 

Their description is not intended to imply duplicative analytical steps. 

l.A. Analysis of a 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 CriticalAgency Documents
 

The Cancer Guidelines and Supplemental Guidance
 

(h p. ~cfp .eD .govlnceaJ fmlrecordl play.cfm?del =116283) discuss the 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 of action for certain classes of
 

chemicals may also be relevant.
 

l.A.2. Evaluate Relevant Data 

The EPA Risk As :;sm nt Forum's Mutagenic Mode of Action Working Group is working on 

guidance on the scientific aspects of making mutagenic mode of action determinations, and to 

assist in determinations of mutagenic MOAs for carcinogenicity. Their product will elaborate on 

the essential elements of such determinations which include: 

• reviewing the available mutagenicity data to determine if the chemical is mutagenic; 

• applying the Cancer Guidelines' mode ofaetion framework to ascertain if the weight of 

the evidence supports a determination that a mutagenic mode of action (as described in 

I The phrase, 'determination that a chemical is carcinogenic by a mutagenic mode of action', 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 of evidence narrative "that 

explains an agent's carcinogenic potential and the conditions that characterize its expression"[CG, sec 2.5). The 

slightly short 1 ph is used 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 an Agency 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 ofother plausible modes of action. Ifthere is 

significant biological support for more than one mode of action, each should receive a separate 

analysis (See CO Sec.2.4.3). Infonnation on all modes of action should be integrated to better 

understand which mode(s) may be relevant for different human exposure scenarios, Le., risk 

characterization (See CO Sec. 2.4.3.3). Alternative modes of action for which there is significant 

biological support should, along with their strengths and uncertainties, be part ofthe risk 

characterization (See CO Sec.5.1). When developing an MOA analysis as a companion to an 

existing assessment that may contain a considerable amount of data and analysis, an application 

ofthe mode of action framework may largely rely on citations and analyses from the existing 

assessment. 

l.A.3. Provide the Conclusion ofthe Analysis and Supporting Rationale 

Assessors can make one ofthree major conclusions: 

• a weight of evidence evaluation supports a determination that the chemical is 

carcinogenic by amutagenic MOA; 

• the weight ofthe evidence evaluation does not support a mutagenic MOA; or 

• a weight of evidence evaluation supports the conclusion that a determination of a 

mutagenic MOA for carcinogenicity cannot be made because there are insufficient data 

for determining the mutagenicity, or for defining an MOA. 

Assessors should explain the 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. Peer Review of the MOA Analysis 

The Cancer Guidelines discuss peer review of MOA analyses in section 2.4.2.1. MOA analyses, 

including evaluation of a mutagenic MOA for carcinogenicity, should be peer reviewed 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 of Agency Determinations. 

For infonnational purposes, chemical-specific mutagenic MOA analyses for carcinogenicity 

should be shared across the Agency prior to any public release. Communication with the public 

should be conducted in r AIle with th Ag n ..'s Info lall n Quality Cui eli and th 

4 
practices 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 of a mutagenic MOA has been made; and 

•	 whether age-dependent adjustment factors (ADAFs) should be applied; or 

•	 if chemical- specific data incorporating lifestage susceptibility were available for 

derivation of cancer slope factors. 

For IRIS assessments, communication of the 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 contain the MOA determination. When a mutagenic MOA 

determination for a chemical has been made outside of the IRIS assessment process, the analysis 

and determination, while not necessarily part of the IRIS assessment for the chemical, generally 

will be accessible from the IRIS assessment (e.g., via hyperlinks). 

Section 2. Implementing the MOA Framework and Supplenuntal Guidance in Risk 

Assessment 

Implementing the MOA framework described in the Cancer Guidelines requires particular 

considerations in each component of a risk assessment: hazard characterization, dose-response 

assessment, exposure assessment, and risk characterization. The purpose of this section is to 

describe how to use the MOA framework and consider the Supplemental Guidance in each 

component. Figure I (adapted from Figure 3 of the Supplemental GUidance) provides a flow 

chart ofthe MOA framework. Reference to a "box" in the following text means one of the 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 

MOAs for carcinogenicity, including a mutagenic MOA in animals, to detennine whether there 

is sufficient infonnation to support a MOA determination and if any proposed MOAs are 

relevant to humans (Box 1 of Figure 1). Section I, "Essential Components in the Process of a 

Determination of a Mutagenic Mode of Action for Carcinogenicity," provides additional 

guidance o~ the key steps in determining a mutagenic MOA. If plausible mutagenic MOAs for 

carcinogenicity have been considered and rejected, and no other MOA can be determined, the 

Cancer Guidelines recommend assessing cancer risk for exposures of interest using slope factors 

derived via the default linear extrapolation, without further adjustment (Box 2). If a mutagenic 

MOA for carcinogenicity is supported by the database and is relevant to humans, then the 

assessor flags susceptible lifestages and populations for application of chemical specific 

quantification in the dose-response step or application of ADAFs in the risk characterization 

step. 
2.B. Dose-Response Assessment 

In the dose-response step of a risk assessment, the conclusions ofthe MOA analysis influence 

the method used to extrapolate from the range of exposures 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 of the entire 

database and the conclusion on the 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 linear approach is used either as a default in the absence of sufficient 

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. 

If a weight of evidence 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 of early lifestages (lower box in Figure 1) 

to detennine whether chemical-specific slope factors incorporating lifestage susceptibility are to 

be developed or ADAFs should be applied in the risk assessment. Specifically: 

•	 If appropriate 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. An example is the IRIS
 

assessment of vinyl chloride (http://www.epagov/iris/subst/1001.htm).
 

•	 If appropriate 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 of exposure in the development 

of risk 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 of cancer 

risk the Agency recommends int~gration ofag~.sp~ciflCva/flUfor both exposur~ and 

toxicity/potency wh~,.e such data are avaiJllb/e and appropriate," since "children, in general, are 

expected to have some exposures that differ from those of adults (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 consider the 

potential for higher cancer risks from early-life exposure." 

6 
Section 6 ofthe Supplemental Guidance provides several examples of how to integrate age­


dependent estimates of exposure and potency. to estimate risks from lifetime and less-than­


lifetime oral exposures. EPA's Risk Assessment Forum is also nearing completion of guidance
 

for selecting age groups for monitoring and/or assessing childhood exposures.
 

(hap:II' hu . p.g In .iJ '. fin; or see
 

btlp:Jl fpu . p. In ratfr rd' pI y. em. d = - - 7). The Supplemental 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 of ages in 

the exposure assessment will need to be integrated with the ADAF age groupings to derive age 

group-specific risk estimates. For example, an assessor may determine that an exposure is agedependent, necessitating the use of age-specific exposure factors in the risk assessment (for 

example, age-specific body weights). In this case, the assessor may find that age groups for 

which exposure factors are available do not match the ADAF age groupings, such that the 

assessor will need to sub-divide an exposure age group to 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 should explicitly 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 extrapolation performed, one ofthe following pertains: 

• If chemical-specific data on susceptibility from early-life exposures were available for 

derivation of cancer slope factors, those slope factors are used for risk characterization, 

and the ADAFs are !l2! applied. 

• If chemical-specific data on susceptibility from early life exposures were not available, 

the ADAFs are applied in calculating or estimating risks associated with early-life 

exposures (see SO, Sec.6). 

In $.Orne EPA P,.o~d\fferent people are involv d in the different steps ofthe risk 

assessment In those cases, there will need to be clear communication concerning the decisions 

made in the various steps ofrisk assessment and there will need to be a clear understanding of 

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 of hazard and 

dose-response assessments are responsible for assuring that ADAFs or chemical specific data are 

appropriately used given the exposure scenario. 

For additional information, contact the workgroup co-chairs: 

Lee Hofmann, 202 566 1928; hofmann.lee@epa.gov 

Bill Sette, 202 564 0693; sene.william@epa.gov 

7 
Figure 1. Flow Chart for Early-Life Risk Assessment Using Mode of Action Framework 

(Source: Figure 3. Supplemental Guidance for Assessing Susceptibilityfrom Early-Life Exposure to 

Carcinogens) 

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