# Presentation: 120343

## Guidelines for 

- 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

## EPA’s Guidelines for 

- 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

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## 1990s

**1990s**

**1970s**

- 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

- Risk Assessment at EPA

## Guidelines for Cancer Risk Assessment

- <date/time>

- <footer>

***Guidelines for Carcinogen Risk Assessment***

**# of Pages**

**140**
**120**
**100**
**  ****80**
**  ****60**
**  ****40**
**  ****20**

**   ****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.

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## History of EPA’s Cancer Guidelines

- <date/time>

- <footer>

**5/1976****	**EPA issues “Interim Procedures and Guidelines for 	Health Risk Assessments of Suspected Carcinogens”
**9/1986**	EPA publishes in *Federal Register* (FR) final “Guidelines for 	Carcinogen Risk Assessment”
**4/1996**	EPA issues proposed revised cancer guidelines for 	public comment and Science Advisory Board (SAB) review
**2/1997**	SAB review meeting
**1/1999****	**SAB 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
**9/2000**	EPA receives the SAB review report
**11/2001**	EPA publishes FR Notice; Intent to finalize cancer 	guidelines, provides opportunity to provide additional 	information and comment; EPA identifies draft guidelines as 	interim Agency guidance

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## History (continued)

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

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## 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.

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## 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

## 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* *

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## 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

- 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:

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## 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:
Is the hypothesized mode of action sufficiently supported in the test animals?
Is the hypothesized mode of action relevant to humans?
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

- 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:
- Is the hypothesized mode of action sufficiently supported in the test animals?
- Is the hypothesized mode of action relevant to humans?
- 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*

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## 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

- 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:

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## 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*

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## ?

**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**

## 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.

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## Children’s Risk

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- “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_.

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## Supplemental Guidance for Assessing Cancer Risks from Early-Life Exposures

- 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

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## 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

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