Evaluating the Relationship Between Variance in Enzyme Expression and Toxicant Concentration in Health Risk Assessment

The replacement of default uncertainty factors with those based on chemical-specific data is a topic of interest to a growing number of government-based organizations and those in affiliated professional societies. The division of the uncertainty factors for animal-to-human extrapolation and human interindividual variance (UF_A and UF_H, respectively) into their pharmacodynamic (PD) and pharmacokinetic (PK) components invites additional and specific considerations. Where data are available, or substantiated PK models have been developed, the animal-to-human chemical-specific differences have been quantified and utilized to replace the PK component of the uncertainty factor. The increasing degree to which the genome is being characterized has stimulated additional interest in describing the impact of genetic polymorphisms on susceptibility. Frequently, proteins for which the genes are being evaluated are the group of xenobiotic metabolizing enzymes. In-depth understanding of the genetic polymorphisms of genes coding for Aldehyde dehydrogenase, glucuronyl transferase and cytochrome P450 enzyme forms has been combined with information on the bioactivation or detoxication of environmental contaminants. The preliminary conclusion of some of these considerations is that alterations in enzyme content or enzyme activity result in a de facto alteration of risk. While this may be true of the “all-or-none” genetic alterations, the impact of more subtle changes in enzyme content and/or activity are more difficult to predict. The hepatotoxicity of trichloroethylene (TCE) is dependent upon an initial, cytochrome P450 2E1 (CYP2E1)-mediated oxidative step. Variance of CYP2E1 content of human liver has been characterized from a bank of tissues from human organ donors and combined with data describing the in vitro Michaelis-Menten kinetic parameters in order to extrapolate the metabolic capacity (and variance thereof) from in vitro to in vivo and assess its impact on PK through incorporation in a physiologically based pharmacokinetic (PBPK) model. This presentation summarizes that work, and demonstrates and discusses why extremes of CYP2E1-mediated metabolic capacity in adult humans has virtually no impact on the PK metric most closely related to hepatotoxic injury from TCE exposure.