# Presentation: 464554

##   Use of Data in Assessing Human Health Effects                  

**Vanessa T. Vu, Ph.D.**
***Endocrine Disruptor Methods               Validation Subcommittee Meeting***
***                      *****March 26, 2002**
**                                ****Washington, D.C.**

## Objectives

**Describe ongoing activities addressing human relevancy **
**Overview of EPA’s current approach to human health risk assessment**
**Focus on data used in Hazard and Dose-Response Assessment**
**Discuss the need for further work**

## EPA Risk Assessment Guidelines

**Provide guidance to the Agency and inform outside parties how risk assessments are to be conducted to foster sound science, consistency, and transparency**
**Lay out scientific principles, approaches, processes, and procedures for conducting human health and ecological hazards and risks**
**Guidance for data interpretation, and use of data**

## EPA Human Health Risk Assessment Guidelines 

**Specific Health Effects**
***Carcinogenicity (1986, 1999) ***
***Neurotoxicity (1998) ***
***Reproductive toxicity (1996) ***
***Developmental toxicity (1991)***
***Mutagenicity (1986)***
**Others**
***RfC (1994), Benchmark Dose (2000), ***
***Chemical Mixtures (1986, 2001)***
***Risk Characterization (2000)***
***Exposure Assessment (1996)***

## Risk Assessment ProcessHuman Health

**Risk Assessment Process*****Human Health***

**HAZARD****ASSESSMENT**

**Integrative**
**Analysis**

**Hazard**
**Characterization**

**Risk**
**Characterization**
**Summary**

**DOSE RESPONSE**
**ASSESSMENT**

**Dose-Response**
**Characterization**

**EXPOSURE**
**ASESSMENT**

**Exposure**
**Characterization**

**Risk Characterization Process**

## Current Approach

**Emphasize full characterization and integration**
**Maximum use of all relevant information**
**Expand role of mode of action information **
**Harmonized approaches for all “toxicities”  **
**Two-step dose response assessment **
**Evaluate data in range of observation **
**Evaluate in range of human exposure (extrapolation)**

## Data Used in Hazard and Dose Response Assessment 

**Studies of humans**
**Data from other species**
**Standard screening and toxicity studies **
**Toxicokinetic and metabolic studies**
**Mode of action information**
**Other relevant information, e.g., chemical and physical properties, SAR**

## Major Default Assumptions

**In the absence of adequate human data**
**An agent that produce an adverse effect in experimental animal studies is assumed to pose a hazard to humans; and **
**Data from the most appropriate or sensitive species should be used**
**In the absence of mode of action information**** **
**A linear dose response curve is assumed for  carcinogenic effects**
**A nonlinear dose response (or threshold) is assumed for other effects**

## Mode of Action 

**How does the agent produce its effect?**
**Are there data to support a postulated mode of action?**
**Have other modes of action been considered and rejected?**

## Mode of Action vs.Mechanism 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 toxicity*
**Mechanism of Action**
*	**Detailed molecular description of a key event in the induction of toxicity*

## Use of Mode of Action Information

**Use of Mode of Action Information**

**Evaluate relevance of animal models **
**Determine relative sensitivity of animal models compared to humans  **
**Identify susceptible subpopulations and estimate variability in response**
**Refine measures of “dose” and “response”**

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

## Use of Mode of Action Information (continued)

**Strengthen inferences regarding the shape of dose response curves outside the range of observation**
**Provide the basis for an integrated approach for all health endpoints**
**Extrapolate within chemical classes with common mode(s) of action**

## 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 **
**Weigh information to determine whether there is a causal relationship between events and toxic effects**

## Key Event-- Examples 

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

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

**Formaldehyde****	****DNA crosslinks                                              ****	****Cell proliferation**
**d-Limonene****	********2u-globulin**
**Chloroform****	****Cytotoxicity**
**Dioxin****	****Receptor-mediated ****	****	****responses**
**Perchlorate****	****Altered thyroid homeostasis**
**Vinyl acetate****	**** Cytotoxicity                  ****	****	**** Cell proliferation**

## Current ActivitiesCarcinogenicity

**Framework for evaluating mode of action has been developed for carcinogenic effect ***(IPCS, 2000)*
**Several activities are underway to provide additional guidance for evaluating the relevance of the animal mode of action to humans**
**EPA-- **Finalize*** ****EPA’s Carcinogen Risk Assessment Guidelines*
** ****ILSI-RSI, WHO/IPCS**

## Current Activities (continued)

**Review of available data for pharmaceuticals to determine similarities and differences between animals and humans**
**Concordance of toxicity (ILSI-HESI)**
**Pharmacokinetics (EPA)**

## Endocrine DisruptionEPA Interim Policy

**“*****Based on the current state of science, ***_***the Agency does not consider endocrine disruption to be an adverse endpoint per se, but rather a mode or mechanism of action***_*** potentially leading to other outcomes, for example, carcinogenic, reproductive or developmental effects, routinely considered in reaching regulatory decisions. Evidence of endocrine disruption alone can influence priority setting for further testing and the assessment of the results of this testing could lead to regulatory action if adverse effects are shown to occur. This position could change as additional data become available on the mechanisms and role of endocrine disruptors.”***
**Special Report on Environmental Endocrine Disruption: An Effects Assessment and Analysis (1997)**

## Planned Activities on Endocrine Disruptors

**Case studies demonstrating an integrated approach for using all available data to assess effects in humans and wildlife species (EPA)**
**Framework for Risk Assessment of EDCs (EPA)**
**Review of pesticides with common modes of action- anti-thyroid, anti-androgen compounds (EPA)**

## Future Needs

**Continued research and evaluation of the modes of toxic action in animals and human relevancy**
**Endocrine disruption modes of action**
**Demonstrate the usefulness of  a framework to evaluate modes of action for non-cancer toxicities and human relevancy **