1. Guidelines for Carcinogen Risk Assessment and Supplemental Guidance for Assessing Cancer Risks from Early-Life Exposures March 29, 2005 Hugh A. Barton, Ph.D., Toxicologist National Center for Computational Toxicology Research & Development U.S. Environmental Protection Agency William H. Farland, Ph.D. Acting Deputy Assistant Administrator for Science Research & Development U.S. Environmental Protection Agency www.epa.gov www.epa.gov/cancerguidelines www.epa.gov/iris www.epa.gov www.epa.gov/cancerguidelines www.epa.gov/iris

2.  History of Risk Assessment at EPA  History of Cancer Guidelines  Key features of the Guidelines Default Options Mode of Action Weight of Evidence Dose-Response Risk Characterization Children’s Risk  Summary  Discussion EPA’s Guidelines for Carcinogen Risk Assessment 2

3. 2000 s 1990s 1970s1970s  Beginnings of the field of risk assessment  Emphasis on oral route per FDA precedent  General acceptance of Safety Factors (10x10)  Beginnings of cancer guidelines 1980s  Adopt NRC RA/RM paradigm  EPA publishes five risk assessment guidelines  First paper on Reference Dose  Data bases (IRIS)  Inhalation RfC methodology  Oral RfD methodology  Applications of PBPK models  BBDR models developed  BMD models developed and applied  Risk Assessment “Staff Paper”  Susceptible populations  Examination of non-cancer methods  Probabilistic approaches  Computational toxicology

4. Guidelines for Carcinogen Risk Assessment # of Pages 140 120 100 80 60 40 20 1976 1986 1996 1999 2005 Draft Draft Final  EPA’s cancer guidelines set forth recommended principles and procedures to guide EPA scientists in assessing the cancer risks from chemicals or other agents in the environment.  They inform EPA decision makers and the public about these procedures.  The guidelines are meant to be dynamic and flexible documents.  EPA continues to revise its risk assessment guidelines and to develop new guidelines as experience and scientific understanding evolve. 4 Guidelines for Cancer Risk Assessment

5. History of EPA’s Cancer Guidelines 5/1976EPA issues “Interim Procedures and Guidelines for Health Risk Assessments of Suspected Carcinogens” 9/1986EPA publishes in Federal Register (FR) final “Guidelines for Carcinogen Risk Assessment” 4/1996EPA issues proposed revised cancer guidelines for public comment and Science Advisory Board (SAB) review 2/1997SAB review meeting 1/1999SAB reviews key sections of proposed guidelines that had been revised to address prior SAB and public comments 7/1999 SAB, with Children’s Health Protection Advisory Committee, begins a third review that focuses on children’s issues 9/2000EPA receives the SAB review report 11/2001EPA publishes FR Notice; Intent to finalize cancer guidelines, provides opportunity to provide additional information and comment; EPA identifies draft guidelines as interim Agency guidance 5

6. 3/2003 EPA released draft final Cancer Guidelines and draft Supplemental Guidance for public comment 5/2003SAB review meeting on draft Supplemental Guidance 3/2004EPA received SAB review comments on draft Supplemental Guidance 11/2004Per SAB recommendation, EPA extended data and analysis used in deriving the adjustments to potency in the draft Supplemental Guidance 1/2005Analysis accepted for publication in National Institute of Environmental Health Sciences’ peer-reviewed journal, Environmental Health Perspectives (EHP) 2/2005Extended analysis subjected to separate expert peer review 2/2005Interagency review 3/2005EPA published updated Cancer Guidelines and Supplemental Guidance 4/2005Extended analysis expected in EHP History (continued) 6

7. Key Features of the Cancer Guidelines  Increased emphasis on analyzing data before invoking default options.  Emphasis on understanding underlying mode of action throughout the guidelines.  Weight-of-evidence narrative replaces the previous “A-B-C-D-E” classification scheme.  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. 7

8. The Guidelines emphasize analysis of all the data before use of default options. 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).” Use of Default Options Analyze the available data

9. Mode of Action  Mode of Action: Key events and processes, starting with the interaction of an agent with a cell, through functional and anatomical changes, resulting in cancer or other health endpoints  EPA’s Framework for Judging Mode of Action: Consistent with similar frameworks under development by the International Programme on Chemical Safety and by the International Life Sciences Institute 9

10. Assess the relevance of laboratory animal results to human environmental exposures Provide insight into whether the dose-response curve is likely to be linear or nonlinear at low doses Identify susceptible populations and lifestages Quantify the relative sensitivity of laboratory animals and human populations Use of Mode of Action Information  An understanding of mode of action can be used in several ways: 10

11. Framework for Evaluating a Hypothesized Mode of Action  Description of the hypothesized mode of action  Discussion of experimental support for the hypothesized mode of action  Consideration of the possibility of other modes of action  Conclusions about the hypothesized mode of action: a.Is the hypothesized mode of action sufficiently supported in the test animals? b.Is the hypothesized mode of action relevant to humans? c.Which populations or lifestages can be particularly susceptible to the hypothesized mode or action? –Question is both qualitative and quantitative –Quantitative differences are used in the dose-response assessment 11

12. Conclusions, including a weight-of-evidence descriptor: –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 Conditions of carcinogenicity: –Route, magnitude, and duration of exposure –Susceptible populations and lifestages Summary of key evidence supporting these conclusions Summary of key default options invoked Summary of potential modes of action Weight-of-Evidence Narrative  Guidelines call for an informative discussion of the scientific evidence: 12

13.  Both linear and nonlinear extrapolation will be considered. Extrapolation Models Linear extrapolation is appropriate: –When the agent has a mutagenic mode of action or acts through another mode of action expected to be linear at low doses, or –Linear extrapolation is also used as default option when the data do not establish the mode of action 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 13

14. STEP 1. Model the observed data down to a point of departure (POD) STEP 2. Extrapolate to lower doses Dose-Response Assessment Dose (mg/kg-d) Tumor incidence ? xx % POD Two-step approach to dose-response will encourage the use of more data. 14

15.  The risk characterization presents an integrated and balanced picture of the analysis of the hazard, dose- response, and exposure. Risk Characterization Summaries of the evidence and results describing the quality of available data and the degree of confidence to be placed in the risk estimates. Choices made about using data or default options in the assessment are explicitly discussed in the course of analysis, and if a choice is a significant issue, it is highlighted in the summary. In situations where there are alternative approaches for a risk assessment that have significant biological support, the decision maker can be informed by the presentation of these alternatives along with their strengths and uncertainties. It is often difficult to know a priori when or how different results of a cancer risk assessment are likely to be used by Agency economists, policy analysts, and decision makers, so it is important that the resulting characterizations include the necessary information for these analyses to the extent practicable. 15

16. Children’s Risk "EPA should assess risks to infants and children whenever it appears that their risks might be greater than those of adults." Science and Judgment in Risk Assessment National Research Council, 1994 11  “Children’s risk” can mean different things to different people: Effects manifested during childhood. Early-life exposures that can contribute to effects at any time later in life.  In the cancer guidelines, EPA is interested in both. 16

17.  Analyzes the data pertinent to cancer risks following early-life exposures  Develops approaches that are consistent with the state of the science  Health-protective when critical information is absent or uncertain  Allows these approaches to be updated when there is new information or new understanding  For chemicals with a mutagenic mode of action, the risk from chemical exposure would be increased by an age-dependent adjustment factor  Constant lifetime exposures result in 1.6-fold adjustment factor Supplemental Guidance for Assessing Cancer Risks from Early-Life Exposures 17

18. Summary EPA’s Guidelines for Carcinogenic Risk Assessment: Emphasis on mode of action Weight-of-evidence narrative and descriptors Two-step approach to dose-response assessment Choice of linear or nonlinear extrapolation Assessment of cancer risks from early-life exposure 18