UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



## JUN I 

## A 2006

OFACE OF E SCIENCE ADVlSOR

MEMORANDUM
SUBJECT: Implementation ofthe Cancer Guidelines and Accompanying Supplemental Guidance

- Science Policy Council Cancer Guidelines Implementation Workgroup Communication II: Performing Risk Assessments that include Carcinogens Described in the Supplemental Guidance as having a Mutagenic Mode ofAction
FROM: William H. Farland, Ph.D.

# AC@~ ChiefScientist, Office ofth Sin Advisor

--­ TO: Science Policy Council Science Policy Council Steering Committee
The Science Policy Council (SPC) Cancer Guidelines Implementation Workgroup (Workgroup) provides information to facilitate the development ofnew carcinogenicity risk assessments and to promote consistencywith Agency policy, guidance, and guidelines.
The information in the attached communication is intended for Agency risk
assessors who are involved in conducting orreviewingrisk assessments for carcinogens. The scope ofAgency assessments varies widely, from screening level exposure and risk assessments involvinghundreds ofchemicals, to comprehensive toxicological assessments ofsingle chemicals, such as those in the Agency's Integrated Risk Information System (IRIS). The activities ofAgencyrisk assessors are equally diverse, and 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 2005 Guidelines for Carcinogen Risk Assessment (Cancer Guidelines) and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (Supplemental Guidance) that are relevant to their particular activities, and to consult these documents for a more complete description ofthe topics discussed in this communication.
Thepurpose ofthe attached communication is to address how to applythe Supplemental Guidance to carcinogens that are described in the Supplemental Guidance
as having a mutagenic mode ofaction (MOA). This communication focuses on this topic 

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Inlomel Mdross (UI'\L) of hllp:JJwv,w.o.pa.gov**~ecylll.dfReoyeI8bl** •• Pnntnd wUh egelable on Based Inks on 1oem PostconlllJmer, Process Chlorine Free RecyeleCl Papercancerrisk, and the MOA detennination is critical to the application ofthe new Supplemental Guidance. Additionally, whilemuch 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.

For additional information, contact the workgroup co-chairs: Lee Hofmann, 202 566 1928; hofmann.lee@epa.gov Bill Sette, 2025640693; sette.wiUiam@epa.gov



### 2Science Policy Council Cancer Guidelines Implementation Workgroup
Communication II. Performing risk assessments that include carcinogens described in theSupplemental Guidance as having a mutagenic mode ofaction
Section 1. Introduction
The Supplemental Guidance (see Tables 4, 6, and 7) describes the following 12 chemicals as having a mutagenic mode ofaction (MOA) for carcinogenicity\:
Chemical CASRN benzidine 92-87-5 benzo[a]pyrene (BaP) 50-32-8 dibenz[a,h]anthracene (DBA) 53-70-3 diethylnitrosamine (DEN) 55-18-5 {aka diethylnitrosamine (DENA), n-nitrosodiethylamine (NDEA), n-ethyl-n-nitrosoethanamine} dimethylbenz[a]anthracene (DMBA) 57-97-6 dimethylnitrosamine (DMN) 62-75-9 {aka dimethylnitrosoamine (DMNA), nitrosodimethylamine (NDMA), n-methyl-n-nitrosomethanamine} ethylnitrosourea (ENU) 759-73-9 {aka n-nitroso-ethylurea} 3-methylcholanthrene (3-MC) 56-49-5 methylnitrosourea (NMU orMNU) 684-93-5 {aka n-nitroso-n-methylurea (NMU)} safrole 94-59-7 urethane 51-79-6 {aka ethyl carbamate} vinyl chloride 75-01-4
The Science PolicyCouncil (SPC) CancerGuidelines Implementation Workgroup (Workgroup) examined these 12 chemicals to determine ifthe analyses in the Supplemental Guidance could provide information on orinsight into a chemical-specific evaluation ofcancerpotency for early-life exposure. The available data cited in the Supplemental Guidance and Barton et al. (2005)\ provide answers to some ofthe questions posed in a MOA analysis, although they do not necessarilyrepresent formal MOA analyses. Analyses of toxicological data on early-life, adult, orlifetime exposures were thebasis for the calculation ofgeneric age-dependent adjustment factors (ADAFs) recommended

I Barton et al

.. 2005. "Assessing Susceptibility from Early-Life Exposure to Carcinogens." Environmental Health Perspectives 113(9): 1125-1133, available at www.epa.gov/cancerguidelines

3in the Supplemental Guidance. The Supplemental Guidance calculates potencyratios from early-life to adult orto lifetime exposures. These potencyratios were used for the analyses in the Supplemental Guidance to derive the generic ADAFs, but they were not designed to be applied to the chemical-specific cancer slope factors previously calculated for the chemicals named above. Although the potencyratios in the Supplemental Guidance cannotbe directly applied to the existing cancer slope factors, theymayinform development ofchemical-specific analyses. Thus, pending anynew assessments ofthese chemicals, the following recommendations are provided.
Section 2. Recommendations
Until a reanalysis ofthe primary data, includingthe data on early-life exposure, is undertaken for the chemicals listed in Section 1, the Workgroup recommends that, with the exception ofvinyl chloride, ADAFs beused for the chemicals with existing IRIS slope factors (benzidine, SaP, DEN, and DMN). No recommendation is made for chemicals for which there are no existing IRIS dose-response assessments. Rather, the available data on early-life susceptibilitywill beconsidered when an Agency assessment is undertaken. Forvinyl chloride, EPA published a chemical-specific analysis from the primary data. This analysis, available on IRIS, should beused when assessing vinyl chloride.
TheWorkgroup also recognizes that benzo[a]pyrene (SaP) often is used as an index chemical when assessing othercarcinogenic PAHs. Such a use is described in the' "Provisional Guidance for Quantitative Risk Assessment ofPolycyclic Aromatic Hydrocarbons" (U.S. EPA 1993. EPA/600/R-93/089). When assessing early-life exposure for PAHs using such an approach, the ADAF(s) shouldbe applied to the SaP slope factor before using relative potency factors to estimate risk from exposure to other PAHs.

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