# Presentation: 464556

## William H. Farland, Ph.D.
Acting Deputy Assistant Administrator for Science
Office of Research and Development
U.S. ENVIRONMENTAL PROTECTION AGENCY

**Acting Deputy Assistant Administrator for Science**
***Office of Research and Development***
**U.S. ENVIRONMENTAL PROTECTION AGENCY**

*Biomarkers: Taking Stock****~ Biomarkers in Risk Assessment ~*****Current Use and Future Directions**

**STAR Regional Science Seminar**
**Chicago, IL**
**July 14, 2004 **

##  Research         Assessment        Management

*** ******Research         Assessment        Management***

**Risk Assessment**

- Dose-Response
- Characterization

-  Animal Toxicology
-  Clinical Studies
-  Epidemiology
-  Cell/Tissue
-       Experiments
-  Computational
-      Methods
-  Monitoring/
-      Surveillance

***Research***
***Needs***

- Hazard
- Characterization

- Exposure
- Characterization

***Risk***
***Characteri-***
***zation***

- Control
- Options

- Non-risk
- Analyses

**Risk Management**

**Collaboration**

**Collaboration**

**External Input**
**into Research/ Assessment  **

-  Other Federal Agencies
-  States/Local Agencies
-  Academia
-  Industry
-  Public Interest/Environmental Groups

**Decisions**

**EPA Scientific Research/**
**Data Collection**

## Recent Emphasis Focuses on the Use of Mode-of-Action Data 

**Recent Emphasis Focuses on the Use of *****Mode-of-Action***** Data **

- “The quality of risk analysis will improve as the quality of input improves.  As we learn more about biology, chemistry, physics, and demography, we can make progressively better assessments of the risks involved.  Risk assessment evolves continually, with
- reevaluation as new models and data become available.”
**	****	**
**	****	****“****Science and Judgment in Risk ****	****	****	****Assessment” (National Research ****	****	****	****Council, ****1994****)**

## Revision Directions for Risk Assessment Guidelines --

- Emphasize full **characterization**
- Expand role of **mode-of-action  **information** **(and, therefore, ***biomarkers****!*)
- Use **all information **to design dose response approach
**Two step **dose response assessment

## BIOMARKERS --

*Three types:** *
***	***Exposure
- 	Effect
- 	Susceptibility

*Definition:** *
*	*Biologic markers are indicators 		signaling events in biologic systems 	or samples.

## Systematic Characterization of Comprehensive

**Exposure-Dose-Response Continuum and the Evolution of Protective to Predictive Dose-Response Estimates**

## Mechanism vs. Mode-of-Action

**Mechanism of action:**
*	**Detailed molecular description of a key event in the induction of cancer or other health endpoints*
**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*

## Mode-of-Action --

- How does the chemical   produce its effect?
- Are there mechanistic data      to support this hypothesis?
- Have other mechanistic hypotheses been considered  and rejected?

## MODE-OF-ACTION:Species- and Chemical-Specific Influenceson Exposure-Dose-Response Relationships

**MODE-OF-ACTION:*****Species- and Chemical-Specific Influences******on Exposure-Dose-Response Relationships***

- Jarabek et al. (In preparation)

## How is mode-of-action information used?

- Comparative Structure Activity Relationships (SAR)
- Relevance of animal data for extrapolation
- Shape of dose-response curve
- Range of Observation
- Range of Inference
- Susceptibility of individuals/ subpopulations

***Address Uncertainty in Risk ***
***Assessment:***

## Uncertainty and the Continuum

**                ****Human ****Susceptibility**

**                 ****Human Variability**

**Internal**
**Dose**

**Early**
**Biological**
**Effect**

**Exposure**

**Altered**
**Structure/**
**Function**

**Disease**

**Target**
**Organ**
**Dose**

**Biologically**
**Effective**
**Dose**

**Uncertainty and the Continuum**
** ****Between Exposure and Disease**

- UNCERTAINTY

## Demonstrating a Mode-of-Action --

- To show that a postulated ***mode-of-action*** is operative, it is generally necessary to:
- 		**outline** the sequence of events leading 			to effects;
- 		**identify** key events that can be 						measured; and
- 		**weigh** information to determine 						whether there is a causal relationship 				between events and cancer formation.

## Framework --

- Summary Description of Postulated               Mode-of-Action
- Topics:
*1."Identify key events”  (**** BIOMARKERS****?****)*
*2."Strength, consistency, specificity                         of association” *
*3. “Dose-response relationship”*
*4. “Temporal relationship”*
*5. “Biological plausibility and coherence”*
- Conclusion

## Key Event--

**Key Event--**

*   **DEFINITION:*
- 	An empirically observable, precursor step that is a necessary element of the mode-of-action, or is a marker for such an element

## Key Event --

- Metabolism
- Receptor-ligand changes
- DNA or chromosome effects
- Increased cell growth and organ weight
- Hormone or other physiological perturbations
- Hyperplasia, cellular proliferation

***Examples:***

## Use of Mode-of-Action Information: Examples

**Formaldehyde****	****	****DNA crosslinks                                              ****	****	****Cell proliferation**
**Methylene ****	****	****Pharmacokinetics**
**Chloride****	****	****Genetic polymorphisms**
**d-Limonene****	****	********-2-u-globulin, etc.**
**Chloroform****	****	****Cytotoxicity**
**Dioxin****	****	****Receptor-mediated ****	****	****  responses**

## Use of Mode-of-Action Information: More Examples

**Amitrole ****	****Increased Thyroid ****	****	****  Stimulating Hormone (TSH)****	****Cell proliferation**
**Melamine ****	****Increased urinary pH                  ****	****Irritation**
***Perchlorate******	******Altered thyroid homeostasis***
***Vinyl Acetate******	******Cytotoxicity                  ******	******	******Cell proliferation***

**Use of Mode-of-Action Information: *****More Examples***

## Where do we go from here?

- Development/validation of sensitive tools 		aimed at understanding mode-of-	action
- Incorporation of “Framework” Concept
- More Attention to Route-Specific/  					Situation-Specific Characterizations
- Addressing Sensitive Subpopulations

***“******Biologically-Based Risk Assessments...”***

- and

## Biologically-Based Risk 	Assessment

- Refine estimates of dose to relevant targets through use of biomarkers of exposure
- Improve hazard characterization through   use of biomarkers of response with mechanistic linkage to endpoints of concern
- Strengthen inferences regarding the shape   of dose/response curves outside the range   of observation
- Identify targets of opportunity for further  study in potentially sensitive human populations