2014-23637. Notice of Availability of Guidance for Applying Quantitative Data To Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation

AGENCY:

Environmental Protection Agency.

ACTION:

Notice of availability.

SUMMARY:

This notice announces the availability of Guidance for Applying Quantitative Data to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation (DDEF Guidance). This document lays out methods for calculation of factors compensating for the application of animal toxicity data to humans (interspecies) and for compensating for sensitive populations (intraspecies). The use of data to conduct these extrapolations rather than rely on default values advances EPA's policy of considering relevant data first when conducting its chemical assessments.

DATES:

The document will be available October 3, 2014.

ADDRESSES:

The Guidance for Applying Quantitative Data to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation is available at the EPA Web site http://www.epa.gov/​raf/​DDEF/​index.htm.

FOR FURTHER INFORMATION CONTACT:

Dr. Michael Broder, Office of the Science Advisor, Mail Code 8105R, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460; telephone number [phone]; fax number [phone]; or email: [e-mail].

SUPPLEMENTARY INFORMATION:

Historically, EPA has employed default uncertainty factors in its computation of toxicity values (e.g., reference concentrations [RfC] and reference doses [RfD]) to compensate for an absence of data. Default uncertainty factors have historically been based on policy or regulatory positions rather than on empirical data applicable to the chemical of interest. Among the uncertainty factors used in EPA assessments are those compensating for a lack of information on how well animal models used in toxicity studies mimic humans (interspecies) and differences in response between the majority of the population (central tendency) compared with the sensitive individual (intraspecies). With the publication of An Examination of EPA Risk Assessment Principles and Practices “Staff Paper” published in 2004, and EPA's Guidelines for Carcinogen Risk Assessment, published in 2005, the Agency announced its policy of considering all relevant data before applying default values.

In 2011 EPA published Recommended Use of Body Weight^3/4 as the Default Method in Derivation of the Oral Reference Dose. In that guidance EPA listed the optimal approach as using a physiologically-based pharmacokinetic or other biologically-based model with the default approach using the ratio of body weights raised to the 3/4 power.

The DDEF Guidance lays out a computational process for using chemical-specific data on toxicokinetics (adsorption, metabolism, distribution and excretion) and toxicodynamics (response of the tissue to the active form of the agent).

It should be noted that the DDEF Guidance is the first EPA product to provide a method both for quantitative determination of relative sensitivity of the pharmacodynamic response in an assessment and for empirical determination of intraspecies sensitivity. As such, this method provides a valuable tool for identifying and quantifying sensitive populations and lifestages.

Dated: August 21, 2014.

Robert Kavlock,

Interim EPA Science Advisor.