AEGL values are developed in accordance with the Standing Operating Procedures for Developing Acute Exposure Guidelines Levels (AEGLs) for Hazardous Substances (NRC 2001). At the request of the AEGL/National Advisory Committee (NAC) and the AEGL Subcommittee of the Committee on Toxicology, National Academy of Sciences, this White Paper has been prepared to describe an approach for integrating the use of PBPK modeling into the development of AEGL values.

PBPK modeling serves as a useful adjunct to risk assessment of systemically acting chemicals by improving the basis of, or entirely allowing for, extrapolation of pharmacokinetics between animals and humans, extrapolation between various exposure scenarios (e.g., what exposure concentration for 10 minutes [min] results in the same internal dose produced from a 4-hour [h] exposure), and other types of extrapolation. As internal dose of a chemical agent is more closely associated with toxicity than is external exposure level of chemicals, extrapolating on the basis of internal dose is more reliable. In a sense, the use of PBPK models factors pharmacokinetic differences out of the extrapolation because they are handled by dose calculations instead of on the basis of an assumed equivalency followed by application of an uncertainty factor (UF) that is usually preset because of lack of knowledge about the true difference. As a result of using calculated doses, the overall uncertainty is reduced, and therefore the overall UFs may be reduced, allowing for more realistic exposure guidelines, which is the purpose in the advancement of the risk assessment process.

The risk assessment process includes identifying a point of departure (POD) from toxicity studies. The POD is usually the highest exposure concentration that did not result in the effect under consideration and may be a no-observed-adverse-effect level (NOAEL), a lowest-observed-adverse-effect level (LOAEL) if a NOAEL is not available, a level from a benchmark dose (BMD), or another value. The POD is then divided by UFs composed of estimated uncertainty in interspecies extrapolation, intraspecies variability, and other factors including weakness in the toxicologic database of information on a chemical.

Briefly, PBPK models are a description of the body and processes within the body (animal and human) that affect the disposition of a chemical. Disposition, or pharmacokinetics, includes the processes of absorption, distribution, metabolism, and excretion of chemicals. After development with necessary parameters and equations, the models calculate the concentration of the chemical (and metabolites, if necessary) in various parts of the body using exposure concentrations as the input.

The main function PBPK modeling serves in risk assessments is to provide a computational biology basis for some extrapolations that need to be made in the course of the risk assessment. This process is done by using PBPK models to determine the target tissue dose in humans or the test species (EPA 2006). Historically, in the AEGL program, types of extrapolations have included animal to human, within the human population, and for different periods of expo-

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