# Presentation: 025311

## EPA Risk Assessment Practice:

*February 2-3, 2005*

***EPA Risk Assessment Practice:***
***Extrapolation Between Species***

***Kerry L. Dearfield, Ph.D.***
***Senior Scientist for Science Policy***
***Office of the Science Advisor***
***United States Environmental Protection Agency***

##                                        Staff Paper

-  EPA Publication # EPA/100/B-04/001
-  Found on Office of the Science Advisor web site: www.epa.gov/osa
-  Published March 2004

## Document as Staff Paper

- Document is an EPA Staff Paper
- Presents the perspectives of EPA risk assessors on how they understand risk assessment is conducted at the Agency
- Also presents staff recommendations for EPA and interested stakeholders to consider for how EPA can move forward to strengthen and improve its risk assessment practices
- Staff paper as it stands does not represent EPA policy

## Use Data Before Invoke 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).”***

## Outline of Presentation 

- Relevance of animal data to humans and issues
- Interspecies extrapolation and issues
- Target organ concordance
- Route to route extrapolation

## Relevance of Animal Data to Humans

- Positive adverse effects in animal studies indicate the agent under study can have toxicological potential in humans unless there are data to indicate otherwise
- Based on assumption there are important similarities between animal models and humans (e.g., most known human carcinogens are positive in animal models)
- Prefer information from animals that are as similar to people as possible

## Relevance of Animal Data to Humans

- The most sensitive responding species (given several data sets to choose from) are selected
- Mode of action information is becoming more useful to help determine relevance

## Relevance of Animal Data to Humans: Issues

- Contrast adverse with beneficial or adaptive changes that may be observed; also, if and when does adaptive become adverse
- Severity of effect – how relate qualitatively and quantitatively to the toxicity
- Reversibility of effect
- Paucity of comparative data on metabolism for specific chemicals and other interspecies differences that can affect toxicity

## Interspecies Extrapolation

- Use of PBPK models can enhance the calculation of internal dose for systemic toxicants and help refine the interspecies extrapolation
- For RfD derivation, the UF of 10 is divided into PK and PD components
- For RfC derivation, PK methods help derive the PK component of the UF; the PD component is a default of 3 (unless data are available)
- Most physiological endpoints scale by body weight to the 3⁄4 power

## Interspecies Extrapolation: Issues

- Do all PBPK parameters scale to the same 3⁄4 power?
- Uncertainty around the extent of interspecies variability
- Species specific sensitivity
- Does the most sensitive animal estimate an average human, or most sensitive human?

## Target Organ Concordance

- No evidence that a mechanism(s) in one specie is necessarily target organ concordant in another
- Site concordance is not assumed *a priori*
- However, if mode of action is established, there is an expectation for site concordance when making the mode of action case – this is a case by case circumstance

## Route to Route Extrapolation

- If an agent causes an internal effect by one route of exposure, it will cause the effect by a different route if it is absorbed by the other route to give an internal dose unless data are available to indicate otherwise
- Assumes that the internal dose to the tissue of interest is the ultimate determinant of toxicity

##  3 Examples

- Alpha-2u-globulin: specific to male rat kidney tumors
- Thyroid tumors: animal model demonstrates mode of action to indicate non-linear extrapolation for humans
- Concordance of endpoint may not be the best predictor of developmental effects in people

## The End 

-       Thank you very much

## Extra Slides 

-       	  Extra slides

## Risk Assessment at EPA 

- EPA conducts risk assessment in order to provide the best possible scientific characterization of the risk in question, based on a scientifically sound, rigorous analysis of available information and knowledge.
- Risk assessment informs decision makers about the science implications of the risk in question.

## EPA Risk Assessment Approach 

- Confidence in our risk assessments is critical.
- Approach is to use to fullest extent site- and chemical-specific data relevant to the decision needed.
- Without such information, we use defaults to ensure we cover the uncertainty of the remaining data or lack of data.

## EPA Risk Assessment Approach (cont.) 

- The data and information we use in developing risk assessments has inherent uncertainty and variability.
- Due to the general uncertainty and variability of the data, information, and methodologies EPA assesses, we tend to take a more health and environmentally protective stance to ensure we do not underestimate risk.

## General Nature of Comments 

- EPA is being criticized for its risk assessment practices
- Generally, the nature of these criticisms are:
- EPA must not intermingle policy judgments within the scientific assessment of risk
- Risk assessments should not rely on conservative (“worst case”) assumptions that distort outcomes and yield estimates that grossly overstate risk
- Risk assessments should acknowledge the presence of considerable uncertainty