Development of a Method to Quantify the Impact of Human Biochemical Individuality in the Production of Risk-Relevant Pharmacokinetic Outcomes in Adults and Children

This project has the following objectives:

  • To develop and apply a method to refine estimates of pharmacokinetic variance among humans by characterizing the distribution of enzyme content in actual human liver tissues and developing physiologically-based pharmacokinetic (PBPK) models which incorporate these distributions of enzyme content to predict the variance risk relevant pharmacokinetic outcomes.
  • To develop age-specific PBPK models for environmentally-important contaminants and to apply these models to ascertain the magnitude of age-related differences in risk relevant PK outcomes in humans.
  • To demonstrate the value of in vitro derived measures of variance in the process of developing more realistic values for inter- and intraspecies extrapolation of risk.

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Advances in human health risk assessment, especially for contaminants encountered by the inhalation route, have evolved so that the uncertainty factors (UF) used in the extrapolation of non-cancer effects across species (UFA) have been split into the respective pharmacodynamic (PD) and pharmacokinetic (PK) components. Present EPA default values for these components are divided into two half-logs (e.g., 10 to the 0.5 power or 3.16), so that their multiplication yields the 10-fold UF customarily seen in Agency risk assessments as UFA.

The state of the science at present does not support a detailed evaluation of species-dependent and human interindividual variance of PD, but more data exist by which PK variance can be examined and quantified both across species and within the human species. Because metabolism accounts for much of the PK variance, we sought to examine the impact that differences in hepatic enzyme content exerts upon risk-relevant PK outcomes among humans. Because of the age and ethnic diversity expressed in the human organ donor population and the wide availability of tissues from these human organ donors, a program was developed to include information from those tissues in characterizing human interindividual PK variance. An Interagency Agreement with CDC/NIOSH Taft Laboratory, a Cooperative Agreement with CIIT Centers for Health Research, and a collaborative agreement with NHEERL/ETD were established to successfully complete the project.

The distribution of seven important cytochrome P450 enzymes within adult human liver has been successfully characterized, and age dependent variance in key PBPK model inputs (blood flows, tissue compartment volumes, etc.) have been collected and child and adult model templates were are being constructed. NHEERL has characterized the in vitro rates and kinetic constants governing chloroform oxidation in human liver tissue and in rat liver tissue preparations; age-dependent PBPK models will be applied to determine the variance in the formation of biologically reactive (oxidative) metabolites of chloroform among adults based on data describing the hepatic enzyme content of adults and children.

The separate PBPK models will be exercised to simulate age-specific and adult interindividual variability in hepatic metabolism of inhaled chloroform. The extent to which the enzymes are responsible for the metabolism of many environmental contaminants (PAHs, pesticides, additional DBPs and some CCL chemicals) enables the generalization of the approach to include other environmental contaminants for which some data on chemical metabolism exist or can be readily generated. The development of these model structures and their successful application will demonstrate the usefulness of collection of specific biochemical information, thus allowing ORD components to optimize and expand data collection; the development and dissemination of advanced pharmacokinetic methods will allow risk assessors to produce and include precise data on human biochemical individuality in order to better quantify the magnitude of variance of chemical-specific, risk-relevant pharmacokinetic outcomes among humans, thus reducing uncertainty in the extrapolation of risk.

In addition to enzyme content, other physiologic and anatomic factors vary with age and with disease status; these factors can also influence susceptibility to the toxicities associated with exposure to environmental contaminants. Because of the relationship between physiology/disease and susceptibility, this project will also collect and organize information linking the toxicities of key environmental contaminants with physiologic processes which determine, regulate or are themselves altered by the chemicals toxicity.

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Future Products

  • The Impact of Cytochrome P450 2e1-Dependent Metabolic Variance on a Risk Relevant Pharmacokinetic Outcome in Humans
  • How Differences in Enzyme Expression Can Translate Into Pharmacokinetic Variance and Susceptibility
  • Interindividual Variance of Cytochrome P450 Forms in Human Hepatic Microsomes: Correlation of Individual Forms with Xenobiotic Metabolism and Implications in Risk Assessment.