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 of Action 

FROM:	 

Chief 

William 

Scientist, 

H. Farland, 

Office 

Ph.D. 

of th 

AC@~ 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 of new carcinogenicity 

risk assessments and to promote consistency with Agency policy, guidance, and 

guidelines. 

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 hundreds of chemicals, to comprehensive toxicological 

assessments of single chemicals, such as those in the Agency's Integrated Risk 

Information System (IRIS). The activities ofAgency risk assessors are equally diverse, 

and 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 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 of the topics discussed in this communication. 

The purpose ofthe attached communication is to address how to apply the 

Supplemental Guidance to carcinogens that are described in the Supplemental Guidance 

as having a mutagenic mode of action (MOA). This communication focuses on this topic 

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cancer risk, and the MOA detennination 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 data to 

estimate cancer risk 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
 

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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 of action 

Section 1. Introduction 

The Supplemental Guidance (see Tables 4, 6, and 7) describes the following 12 

chemicals as having a mutagenic mode of action (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 or MNU) 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 Policy Council (SPC) Cancer Guidelines Implementation Workgroup 

(Workgroup) examined these 12 chemicals to determine ifthe analyses in the 

Supplemental Guidance could provide information on or insight into a chemical-specific 

evaluation of cancer potency 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 necessarily represent formal 

MOA analyses. 

Analyses of toxicological data on early-life, adult, or lifetime exposures were the basis 

for the calculation of generic 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 

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in the Supplemental Guidance. The Supplemental Guidance calculates potency ratios 

from early-life to adult or to lifetime exposures. These potency ratios 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 potency ratios in the Supplemental 

Guidance cannot be directly applied to the existing cancer slope factors, they may inform 

development of chemical-specific analyses. Thus, pending any new assessments ofthese 

chemicals, the following recommendations are provided. 

Section 2. Recommendations 

Until a reanalysis ofthe primary data, including the data on early-life exposure, is 

undertaken for the chemicals listed in Section 1, the Workgroup recommends that, with 

the exception of vinyl chloride, ADAFs be used 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 susceptibility will be considered when an Agency assessment 

is undertaken. For vinyl chloride, EPA published a chemical-specific analysis from the 

primary data. This analysis, available on IRIS, should be used when assessing vinyl 

chloride. 

The Workgroup also recognizes that benzo[a]pyrene (SaP) often is used as an index 

chemical when assessing other carcinogenic PAHs. Such a use is described in the' 

"Provisional Guidance for Quantitative Risk Assessment of Polycyclic 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) should be applied to the SaP 

slope factor before using relative potency factors to estimate risk from exposure to other 

PAHs. 

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