1. EPA’s cancer risk assessment guidelines: General overview Jim Cogliano, Ph.D. United States Environmental Protection Agency* Office of Research and Development National Center for Environmental Assessment Washington, D.C. * The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.

2. Topics to be covered Key features of the new guidelines. –Use of defaults. –Emphasis on mode of action. –Weight-of-evidence narrative and descriptors. –Dose-response assessment: two-step approach and choice of linear or nonlinear extrapolation. –Cancer risks from early-life exposure. Anticipated schedule and opportunities for interaction.

3. Risk assessment HAZARD ASSESSMENT Can the agent cause cancer? Is this relevant to humans? Who may be more sensitive? DOSE-RESPONSE ASSESSMENT Estimate a dose-response curve Account for high-to-low-dose, animal-to-human, route-to- route, and other differences EXPOSURE ASSESSMENT How do people come in contact with the agent? How much are they exposed to? RISK CHARACTERIZATION Integrate HAZARD, DOSE- RESPONSE, and EXPOSURE Describe the assessment’s strengths, limitations, and research needs

4. Why change the guidelines? New kinds of studies (mechanistic studies) are giving insight into how a chemical causes cancer The 1986 guidelines do not discuss how to evaluate mechanistic studies For some carcinogens, the mechanistic studies indicate that the dose-response curve is likely to be nonlinear at low doses The 1986 guidelines do not discuss how to evaluate nonlinear dose-response relationships

5. Key features of the new guidelines Emphasis on analyzing data before invoking defaults. Emphasis on mode of action throughout the guidelines. Weight-of-evidence narrative replaces the “A-B-C-D-E” classification scheme; descriptors can be route-specific. Two-step dose-response process separates (1) modeling the observed data from (2) extrapolation to lower doses. Linear and nonlinear extrapolations are considered. Differential risks to children are addressed.

6. The 2002 draft emphasizes analysis of data before use of defaults Analyze the available data Is there too much uncertainty or is critical information lacking? Invoke a default option* N Y * “The primary goal of EPA actions is public health protection, accordingly, as an agency policy, the defaults used in the absence of scientific data to the contrary should be health protective (SAB 1999).”

7. Uses of mode of action in the 2002 draft guidelines Assess the relevance of laboratory animal results to human environmental exposures Identify sensitive populations and lifestages Provide insight into whether the dose-response curve is likely to be linear or nonlinear at low doses Quantify the relative sensitivity of laboratory animals and human populations

8. Framework for evaluating support for an hypothesized mode of action a.Is the hypothesized mode of action sufficiently supported in the test animals? –Examination loosely patterned after the “Hill criteria.” b.Is the hypothesized mode of action relevant to humans? –Considers all populations and lifestages. –Anticipated low human exposure levels are not used to conclude that a mode of action is not relevant. c.Which populations or lifestages can be particularly susceptible to the hypothesized mode of action? –Question is both qualitative and quantitative. –Quantitative differences are flagged for use in the dose-response assessment.

9. The “Hill criteria” Used by epidemiologists to infer whether an observed association may be a causal association. a.Consistency of the observed association. b.Strength of the observed association. c.Specificity of the observed association. d.Temporal relationship of the observed association. e.Biological gradient (exposure-response relationship). f.Biologic plausibility. g.Coherence. h.Experimental evidence. i.Analogy.

10. Weight-of-evidence narrative in the 2002 draft guidelines Conclusions about human carcinogenic potential, including a weight-of-evidence descriptor. Conditions of carcinogenicity: –Route, magnitude, and duration of exposure. –Susceptible populations and lifestages. Summary of key evidence supporting these conclusions. Summary of key default assumptions. Summary of potential modes of action.

11. Weight-of-evidence descriptors “Carcinogenic to humans.” “Likely to be carcinogenic to humans.” “Suggestive evidence of carcinogenic potential.” “Inadequate information to assess carcinogenic potential.” “Not likely to be carcinogenic to humans.”

12. Some remarks about the descriptors Multiple descriptors can be used if the cancer hazard is route-dependent or dose-dependent. When an agent has not been tested in a cancer bioassay, conclusions can still be drawn by scientific inference from toxicokinetic or mode-of-action data, for example: –The agent operates through a mode of action for which cancer data are available. –The agent’s effects are caused by a human metabolite for which cancer data are available.

13. Two-step dose-response assessment in the 2002 draft guidelines Dose (mg/kg-d) Tumor incidence STEP 1. Model the observed data down to a point of departure STEP 2. Extrapolate to lower doses ? xx % POD

14. Characterizing the point of departure: the POD narrative a.Nature of the response. b.Level of the response. c.Nature of the study population. d.Slope of the dose-response curve at the POD. e.Relationship of the POD with other cancers. f.Extent of the overall cancer database.

15. Choosing linear or nonlinear extrapolation Linear extrapolation is appropriate: –When the agent is mutagenic or acts through another mode of action expected to be linear at low doses, or –Human exposure or body burden is high and near doses associated with key precursor events. Linear extrapolation is also used as a default when the data do not establish the mode of action. A slope factor is developed in these cases. Nonlinear extrapolation is appropriate –When there is no evidence of linearity, and –There is sufficient information to support a mode of action that is nonlinear at low doses.

16. Linear extrapolation under the 2002 draft guidelines Dose (mg/kg-d) Tumor incidence STEP 1. Model the observed data down to a point of departure STEP 2. Extrapolate to lower doses xx % POD

17. Nonlinear extrapolation under the 2002 draft guidelines Dose (mg/kg-d) Tumor incidence STEP 1. Model the observed data down to a point of departure STEP 2. Extrapolate to lower doses xx % POD exposures of interest

18. Dose-response characterization in the 2002 draft guidelines Recommended estimates (for example, slope factors). Summary of the data supporting these estimates. Summary of the modeling approaches used. The POD narrative. Identification of susceptible populations or lifestages and quantification of their differential susceptibility. Strengths and limitations of the dose-response assessment, highlighting: –Significant issues –Alternative approaches considered equally plausible. –How these issues were resolved.

19. Children’s risk in the 2002 draft guidelines “Children’s risk” can mean different things to different people: –Effects manifest during childhood. –Early-life exposures that can contribute to effects at any time later in life. In the cancer guidelines, we are interested in both.

20. Some reasons why cancer risks can differ following early-life exposure Differences in capacity to metabolize and clear chemicals. More frequent cell division during development: –Enhanced expression of mutations due to reduced time for repair of DNA lesions. –Clonal expansion of cells with unrepaired DNA damage. Immune system that is not fully functional. Hormonal systems that operate at different levels. Potential for developmental abnormalities to result in a predisposition to carcinogenic effects later in life.

21. Review of the data pertinent to cancer risks from early-life exposure Comparison of cancer bioassays using mature animals with those using developing animals. EPA’s vinyl chloride assessment on IRIS. Other chemicals with studies of cancer following early-life exposure. Site-specific human cancer risks following exposure to radiation at different ages.

22. EPA is developing new approaches for assessing children’s cancer risks Examine the data pertinent to cancer risks following early-life exposures. Develop approaches that are: –Consistent with the state of the science. –Health-protective when critical information is absent or uncertain. Allow these approaches to be updated when there is new information or new understanding.

23. Anticipated schedule and opportunities for interaction By end of 2002: EPA expects to release two new drafts: –Guidelines for carcinogen risk assessment. –Supplemental guidance on assessing risks to children. At this time, EPA will ask for: –Executive-branch agency review. –Public comment (60 days). –One-on-one outreach meetings with stakeholders. Early in 2002: EPA expects to begin addressing the comments received. EPA will obtain peer review of the scientific basis of the supplemental guidance on assessing risks to children.

24. Thank you.