[Federal Register Volume 79, Number 192 (Friday, October 3, 2014)]
[Page 59768]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-23637]



[EPA-HQ-ORD-2014; FRL-9917-45-ORD]

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 
(202) 564-3393; fax number (202) 564-2070; or email: 

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\ 
    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.
[FR Doc. 2014-23637 Filed 10-2-14; 8:45 am]