2011-4250. Notice of Availability; Recommended Use of Body Weight3∕4 as the Default Method in Derivation of the Oral Reference Dose

AGENCY: Environmental Protection Agency (EPA).

ACTION:

Notice of availability.

SUMMARY:

This notice announces the availability of “Recommended Use of Body Weight^3/4 as the Default Method in Derivation of the Oral Reference Dose” (referred to hereafter as BW^3/4). This document was developed as part of an Agency-wide guidance development program by a technical panel of the U.S. EPA's Risk Assessment Forum, composed of scientists from across the Agency. Selected drafts were peer reviewed internally by EPA scientists and externally by experts from academia, industry, environmental groups and other government agencies.

DATES:

The document will be available for use by EPA risk assessors on February 25, 2011.

ADDRESSES:

The Guidelines are available electronically through the EPA Web site at http://www.epa.gov/​raf/​publications/​interspecies-extrapolation.htm. A limited number of paper copies will be available from EPA's National Service Center for Environmental Publications (NSCEP), P.O. Box 42419, Cincinnati, OH 45242; telephone [phone] or [phone]; facsimile: [phone]. Please provide your name, mailing address and the title and number of the requested publication. Additionally, copies of the document will be available for inspection at EPA headquarters and regional libraries, through the U.S. Government Depository Library program.

FOR FURTHER INFORMATION CONTACT:

Dr. Michael W. Broder, Risk Assessment Forum, Office of the Science Advisor (8105R), U.S. Environmental Protection Agency, Washington, DC 20460; telephone [phone] or e-mail: [e-mail].

SUPPLEMENTARY INFORMATION:

In order to assess the toxicity of a particular chemical in the absence of human data, EPA relies on the use of animal models as surrogates. EPA endorses a hierarchy of approaches to derive human equivalent oral exposures from data from laboratory animal species, with the preferred approach being physiologically based toxicokinetic modeling. As a default method to account for differences in dosimetry between the animal models and humans, EPA previously applied a direct body-weight conversion from the model to humans (i.e., BW^1/1) for non-cancer endpoints, in the absence of chemical-specific data. In contrast, EPA applies a dosimetric adjustment factor (DAF) based on body weight raised to the three-quarter power (BW^3/4) for cancer assessments. By adopting the adjustment, this document moves in the direction of harmonizing the approach for assessing cancer and noncancer endpoints.

In addition to laying out the computational method for interspecies extrapolation, the document also addresses the issue of changes to the interspecies uncertainty factor (UF_A). The document recommends a reduced interspecies UF_A (with a default value of 3) in lieu of a default of 10 for the reference dose (RfD) calculation. The quantitative significance of this procedure with regard to the magnitude of an RfD will depend on the body weight of the species (as well as the value assigned to the UF_A) and may be more or less than the current procedure of dividing by the default composite UF_A of 10.

BW^3/4 scaling for derivation of the human equivalent dose is recommended as the default approach for RfDs for remote, as well as portal-of-entry effects. It is noted that this scaling is not inclusive of lethal or frank effects for which maximum concentration (C_max) may be the most appropriate dose metric and that such effects are not among those effects recommended for use in deriving RfDs (USEPA, 2002). This default approach generally applies to different durations of exposure. The reader is encouraged to read the document carefully, however, in order to fully understand how to apply the policy appropriately. Additionally, although non-oral RfDs can be estimated (e.g., a dermal RfD), this document focuses only on oral RfDs and for this document the acronym refers only to RfDs for oral exposure.

It is recognized that this procedure, as with all default procedures, may not always predict oral exposures associated with precise toxicologically-equivalent doses for specific chemicals. It should be emphasized that other biological information not discussed in this document may inform interspecies adjustments. As a general default procedure, however, it may be anticipated to provide a reasonable description of average behavior of many chemicals much of the time.

Even though this document is not a binding rule, EPA is issuing it in a manner consistent with the procedures in the Administrative Procedure Act that are generally applicable to rulemaking, including providing opportunity for public comment. EPA considered and responded to all significant public comments as it prepared the document.

Dated: February 16, 2011.

Paul T. Anastas,

EPA Science Advisor.