The mission of EPA is to protect human health and the environment. In support of its regulatory actions, the Agency relies on toxicological data often generated with animal models. To relate animal toxicological data to humans, assessors extrapolate animal response data to the central tendency of humans (interspecies) followed by further extrapolation of the central tendency value to sensitive groups and lifestages (intraspecies). In the absence of data, the Agency has employed standard default values to complete these extrapolations.
This guidance outlines approaches for developing factors for inter- and intraspecies extrapolation based on data describing toxicokinetic and/or toxicodynamic properties of a particular agent. The guidance document was primarily developed to instruct EPA toxicologists and risk assessors on this methodology and in doing so promote consistency to the way that this method is used but also to provide transparency to stakeholders and other interested parties.
This guidance extends several principles contained in US and International guidance. The explicit addressing of toxicokinetics as one half of the default factor for interspecies extrapolation was established in the EPA's Reference Concentration Methodology (1994). The subdivision of both inter- and intraspecies uncertainty factors was established by the World Health Organization's International Programme on Chemical Safety in 2005. In 2011 EPA established body weight scaling as the default method for the interspecies toxicokinetic extrapolation for orally encountered contaminants. The Develop Data-Derived Extrapolation Factors (DDEF) approach is consistent with that recommended in the 2005 Cancer Guidelines and by the National Academies of Science, in that it guides an assessment of potentially reliable data before default values for uncertainty factors are invoked.
Recognizing that toxicokinetic extrapolation involves characterizing the relationship between applied dose and target tissue concentration, this document uses target tissue concentrations to link the evaluation of toxicokinetics and toxicodynamics. It provides the Agency’s initial guidance on quantification of toxicodynamic events, and does so in a manner consistent with policies and practices established for toxicokinetic evaluations. In doing so, this document employs the International Program on Chemical Safety (IPCS) framework of subdividing the factors for interspecies and intraspecies extrapolation into toxicokinetic and toxicodynamic components and guides the identification, evaluation, computation and application of non-default extrapolation factor values for application in health risk assessment.
An appendix to this document contains case study examples taken from the Integrated Risk information System (IRIS) and from Program Office records. The case studies present the application of principles contained in this document to data and modeling studies for actual chemicals and should serve as instructional aides.
This guidance has undergone public comment and independent peer review that was organized, convened and conducted by an EPA contractor in 2011. The peer review report and response to peer review comments are attached below.
The Charge Questions were developed for the External Reviewers of the document.