On March 29, 2005, EPA issued Guidelines for Carcinogen Risk Assessment (Cancer Guidelines), replacing the 1986 cancer risk assessment guidelines. The revised Cancer Guidelines provide a process to EPA scientists for assessing possible cancer risks and are intended to make greater use of the increasing scientific understanding of the processes of cancer development.
The Cancer Guidelines recommend assessing risks to potentially sensitive people and to people at specific lifestages (for example, children) differently than to the rest of the population. This recommendation led to the development of the Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (Supplemental Guidance), which describes possible approaches that EPA could use in assessing cancer risks to children under age 16. EPA issued the document separately from the Cancer Guidelines so that it can be updated more easily as scientific understanding about the effects of early life exposures develops.
EPA recommends that EPA risk assessors use the new Cancer Guidelines and the Supplemental Guidance when they prepare cancer risk assessments. They are recommended for use:
- in all new cancer risk assessments;
- on a case-by-case basis in current assessments, based on how their use may affect the expected decision and timeline; and
- on a case-by-case basis in assessments that were completed before the Cancer Guidelines were issued, when a new program-specific or site-specific decision that must be supported by an updated cancer risk assessment is required.
You will need the free Adobe Acrobat Reader to view some of the files on this page. See EPA's PDF page to learn more.
Application of Cancer Guidelines and Supplemental Guidance to Risk Assessment
The Cancer Guidelines emphasize the importance of mode of action (MOA) in assessing cancer risk. The MOA determination is used in applying the Supplemental Guidance to characterize risks from early-life exposures to chemicals with a mutagenic MOA for carcinogenesis.
Mutagenic Mode of Action for Carcinogenesis Determination
When conducting cancer assessments, assessors can determine the mode of action by implementing the MOA framework described in the Cancer Guidelines and summarized in the Supplemental Guidance. View a flow chart for early-life risk assessment using mode of action framework (MOA Framework Flow Chart) (PDF) (1 pg, 438K). The Science Policy Council (SPC) Cancer Guidelines Implementation Workgroup described in an October 2005 memo a process for completing a weight of evidence determination for MOA and communicating the results (Communication I) (PDF) (8 pp, 651K). It is important to note that a mode of action determination is something that will typically be done by the IRIS program or the Superfund Technical Support Center as part of a hazard identification and dose-response assessment.
The three possible conclusions from a weight of evidence evaluation regarding a mutagenic MOA for carcinogenesis are:
- a weight of evidence evaluation supports a determination that the chemical is carcinogenic by a mutagenic MOA;
- the weight of 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 a MOA.
Early Lifestage Adjustments
The mutagenic MOA determination is used in applying the Supplemental Guidance to characterize cancer risks from early-life exposures (see Supplemental Guidance MOA Framework Flow Chart (PDF) (1 pg, 438K)):
For chemicals or compounds with a mutagenic MOA for carcinogenesis, the Supplemental Guidance recommends analysis of chemical-specific data to determine if there is evidence that the potency of the chemical is different during early-life exposures than during adult exposures. If chemical-specific data on susceptibility from early-life exposures are available, then the Supplemental Guidance recommends using these data to develop cancer slope factors that specifically address any potential for differential potency in early life stages (Box 5 of MOA Framework Flow Chart (PDF) (1 pg, 438K)). An example is the IRIS assessment of vinyl chloride.
If chemical-specific data are not available on susceptibility from early-life exposures, then risk assessors should apply the default age-dependent adjustment factors (ADAFs) recommended by the Supplemental Guidance (Box 6 of MOA Framework Flow Chart (PDF) (1 pg, 438K)) to calculate or estimate cancer risks associated with exposure during early-life (less than 16 years of age) exposures:
- a 10-fold adjustment for ages 0 – <2 years;
- a 3-fold adjustment for ages 2 – <16 years;
- no adjustment for ages 16 years and older.
For chemicals or compounds with a non-mutagenic MOA for carcinogenesis, the Supplemental Guidance recommends analysis of any chemical-specific data to determine if there is evidence that the cancer potency of the chemical is age-dependent. If such data indicate an age dependency, then the Supplemental Guidance recommends that they be used to develop the dose-response assessment (e.g., if the MOA is linear, the derived cancer slope factors would specifically address any potential for differential potency with age) (Box 4 of MOA Framework Flow Chart (PDF) (1 pg, 438K)).
If data are not available, the Supplemental Guidance recommends no default age-specific adjustment (Boxes 3 and 4 of MOA Framework Flow Chart (PDF) (1 pg, 438K)).
- For chemicals or compounds with indeterminate modes of action for carcinogenesis, the Supplemental Guidance recommends no default age-related adjustment to cancer slope factors (Box 2 of MOA Framework Flow Chart (PDF) (1 pg, 438K)).
For additional information on implementing the MOA framework and Supplemental Guidance into each of the four risk assessment steps (Hazard Characterization, Dose-Response Assessment, Exposure Assessment, Risk Characterization), see the SPC Workgroup memo on a process for completing a weight of evidence determination for MOA and communicating the results (Communication I) (PDF) (8 pp, 651K).