Biomarkers of Human Exposure to Pesticides Utilizing a New PBPK/PD Model and Kinetic Data on Pesticide Metabolism in HumansEPA Grant Number: R830683
Title: Biomarkers of Human Exposure to Pesticides Utilizing a New PBPK/PD Model and Kinetic Data on Pesticide Metabolism in Humans
Investigators: Olson, James , Knaak, James B. , Kostyniak, Paul J.
Institution: The State University of New York at Buffalo
EPA Project Officer: Fields, Nigel
Project Period: December 18, 2002 through December 17, 2005
Project Amount: $747,704
RFA: Issues in Human Health Risk Assessment (2001) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health Risk Assessment , Health
Biomarkers can be utilized to assess exposure to a chemical agent, the individual susceptibility to that agent and ultimately biological effects which the chemical elicits in the organism. Assessing age and gender related differences in key metabolic enzymes can assist in fine tuning parameters which are utilized in physiologically based pharmacokinetic (PBPK) models to improve the scientific basis for human health risk assessment. Regardless of rigor, the ultimate utility of PBPK models is limited by the availability of accurate parameters which reflect the rate of biotransformation of xenobiotics in the population of interest. It is hypothesized that the ontogeny of drug metabolizing enzymes in humans will result in significant age-dependent differences in the metabolism and toxicity of xenobiotics. Therefore, a primary objective of the proposed studies is to obtain kinetic parameters (Vmax, Km values) for the metabolism of model pesticides (parathion and chlorpyrifos) in liver from humans of various ages. Age- and gender-specific kinetic parameters (Vmax, Km) for selected pesticides will then be utilized in a very recently developed multi-route, multi-chemical PBPK/ pharmacodynamic (PD) model (ERDEM, Exposure Related Dose Estimating Model) (Blancato et al., 2000; Knaak et al., 2001) to estimate the sensitivity of individuals within each age group based on biomarkers of susceptibility, exposure and effects.
Specific Experimental Aims are as follows: 1) Characterize the levels and activities of specific cytochrome P450s and phase II enzymes and paraoxonase genotype in liver specimens from humans of five age groups (0-2, 3-10, 11-20, 21-40, and >40 years). 2) Measure the kinetics (Km, Vmax) for the metabolism of parathion and chlorpyrifos in hepatic microsomal and S-9 fractions from humans of five age groups. 3a) Utilize selected experimental exposure levels, age- and gender-specific metabolic parameters (Vmax, Km) obtained for parathion and chlorpyrifos in the ERDEM to determine the sensitivity of individuals within each age group to these pesticides based on biomarkers of susceptibility (i.e., paraoxonase and CYP2D6 phenotypes), exposure (i.e., urinary metabolites), and effects (i.e., blood acetylcholinesterase AChE/BChE inhibition). 3b) Utilize human exposure estimates from available monitoring studies in the ERDEM to estimate biomarkers of exposure and effects. Finally, the ERDEM will be validated by comparing model biomarker estimates with values from available human monitoring studies.
The proposed studies will improve health risk assessment for various human age groups to these model chemicals using biomarkers of susceptibility, exposure and effects. Aim 1 will establish a bank of liver specimens, from humans, 0 to >40 years of age, that have been characterized for the levels and activities of phase I and phase II drug metabolizing enzymes. While the proposed studies focus on prototypical organophosphate insecticides, this approach and the characterized bank of human liver specimens will provide an optimal approach for future studies on the metabolism and PBPK modeling of other classes of xenobiotics in humans.