# Presentation: 393770

## BOSC Risk Assessment WorkshopFeb 2-3, 2005, Wash. DC

- Extrapolation Between Species:  Issues and Opportunities for the Future
- James S. Bus, Ph.D DABT
- The Dow Chemical Company

## Cross-Species Extrapolation: Refining Default Assumptions

- The value of mechanisms
- Defining relevance of animal species responses
- Study design and interpretation
- Applications of new technologies, e.g. toxicogenomics, transgenic animals
- Pharmacokinetics: linking exposure to dose
- The context of natural dietary chemicals: implications for current cross-species assumptions

## The Value of Mechanisms

- Defining relevance of animal species responses
- Pharmacodynamic
- male rate α-2u-globulin nephropathy
- rodent thyroid tumors
- rodent peroxisome proliferation
- cytotoxicity driven cell proliferation
- Pharmacokinetic
- High-dose dependent nonlinear pharmacokinetics
- Species-specific pharmacokinetics and metabolism
- Relevance of dose in animal studies to human exposure

## The Value of Mechanisms

- Impact on study design and interpretation
*a priori* inclusion of mechanism data in standard bioassays
- enzyme induction
- cell proliferation
- hormonal measurements
- etc.

## The Value of Mechanisms

- Applications of new technologies
- toxicogenomics and systems biology
- mechanistic insights into vexing cross-species response differences, e.g., dioxin-like chemicals
- transgenic animals and genetically-modified cells
- evaluation of susceptible subpopulations, e.g., genetic polymorphisms, disease states, etc.

## Susceptible subpopulations:  Importance of Dose-response

**From:  C. Kent, “The Basics of Toxicology”, J.Wiley & Sons, New York, 1998**

## Pharmacokinetics: Defining relevance of animal models to humans

- Example of 2,4-D
- Overall NOEL in rodents = 5 mg/kg/day
- Overall NOEL in dogs = 1 mg/kg/day
**What model to regulate on?**

## 2,4-D Renal Excretion

- Timchalk, Toxicol. 200: 1-19 (2004)

## 2,4-D: Relevance of Dog for Human Risk Assessment

- Timchalk, Toxicol. 200: 1-19 (2004)

## 2,4-D: Relevance of Dog for Human Risk Assessment

- Timchalk, Toxicol. 200: 1-19 (2004)

## Pharmacokinetics:  Improving links of human exposure data to dose in animal toxicology studies

- Emergence of human biomonitoring programs, e.g., CDC
- Extensive toxicology data, often in diet or drinking water
- Test guidelines encourage oral gavage dosing for pharmacokinetic studies
- Improvements in analytical science and technology make plasma/tissue parent and metabolite analyses easier
**Assess plasma/tissue concentrations under conditions in which toxicology data is generated**

## 2,4-D:  Plasma Equilibrium after 28-Day Dietary Administration 

## The Context of Natural Dietary Chemicals: Implications for Defaults

- The Baseline assumption:
- basic food supply, e.g., fruits, vegetables, etc., is “safe”, despite containing many chemical substances
- The Opportunity (or challenge):
- work traditional chemical risk problem “backward”, i.e., start with standard that food is safe, and test risk performance of natural food components using current chemical risk paradigm against this standard

## Acrylamide:  The Issue

- Industrial chemical:  large toxicology database, e.g., cancer, genotox, repro, etc.
- Conventional risk assessment available
- Discovered as natural constituent in foods
- food concentrations predict potential cancer risk of  6/10,000 (Dybing and Sanner, ToxSci 2003)
- FDA action plan includes: new cancer bioassays, genotoxicity evaluations, PBPK modeling, metabolism, and neurotoxicity

## Acrylamide:  The Conundrum

- By initiating research program to characterize risk, *de facto* affirmation of need to include natural food chemicals in balance of risk
- What should FDA do with data when done?
- risk <<< 6/10,000?
- risk >>>/= 6/10,000?
- Acrylamide represents *only one* of many chemicals present in food (fried potatoes)

## Slide 16

## Slide 17

## Slide 18

## Slide 19

## Implications of Dietary Chemicals for Default Assumptions

- Charles et.al., Fd.Chem.Toxicol. 40: 1391-1402 (2002)