CYP-Specific PBPK/PD Models to Interpret Biomarkers for Organophosphate Pesticides

EPA Grant Number: R833454
Title: CYP-Specific PBPK/PD Models to Interpret Biomarkers for Organophosphate Pesticides
Investigators: Olson, James , Bonner, Matthew R. , Browne, Richard , Knaak, James B. , Kostyniak, Paul J. , Yu, Aiming
Institution: The State University of New York at Buffalo
EPA Project Officer: Pascual, Pasky
Project Period: September 1, 2007 through August 31, 2010
Project Amount: $749,612
RFA: Interpretation of Biomarkers Using Physiologically Based Pharmacokinetic Modeling (2006) RFA Text |  Recipients Lists
Research Category: Health Effects , Health

Objective:

The primary objective of the proposed studies is to improve existing models to better estimate exposures, target tissue dose and resulting effects in human populations, utilizing the abundance of urinary metabolite / biomarker data for the organophosphate (OP) pesticides, chlorpyrifos, parathion, methyl parathion, and diazinon. Current physiologically based pharmacokinetic /pharmacodynamic (PBPK/PD) models, which utilize single kinetic constants (Km, Vmax) for a given metabolic pathway, using rat liver microsomes, do not accurately reflect human enzymes or the variability in content and activity of key enzymes (cytochrome P450s, CYPs; paraoxonase-1, PON1) which regulate the metabolic activation and detoxification of OPs in human populations exposed to pesticides. It is hypothesized that more accurate measures of exposure, target tissue dose and subsequent effects will come from existing PBPK/PD models, which incorporate human CYP-specific kinetic parameters (Km and Vmax) for OP metabolism, CYP–specific content in the liver, and the function and content of genetic variants in key enzymes (CYP2B6, CYP2C19, PON1) which regulate OP metabolic activation and detoxification.

Approach:

  1. Generate CYP-specific PBPK/PD models, utilizing existing urinary metabolite / biomarker data for chlorpyrifos, parathion, methyl parathion, and diazinon, to better estimate exposure, target tissue dose and effects of these OPs in human populations by incorporating 1) kinetic parameters (Km and Vmax) for OP metabolism by specific human CYPs, 2) hepatic content of specific CYPs, 3) PON1 activity and content, and 4) serum protein binding data for OPs and metabolites into existing PBPK/PD models.
  2. Generate the kinetic parameters for OP metabolism by prevalent polymorphic isoforms of CYP2B6, CYP2C19 and PON1, which are known to exhibit altered enzyme activity and/or expression (biomarkers of susceptibility).
  3. Integrate the altered activity and expression data from the key polymorphic CYPs and PON1 (aim 2) into the CYP-specific PBPK/PD models (aim 1).
  4. Incorporate the data from aims 1-3 into a multiroute, multichemical, PBPK/PD model (ERDEM, Exposure Related Dose Estimating Model) that can convert urine biomarker data for several OP pesticides to measures of exposure, target tissue dose and effect (inhibition of acetylcholinesterase) in populations of interest.
  5. Expected Results:

    Since the hepatic levels of specific CYPs exhibit marked variability across both population and age groups, the proposed CYP-specific PBPK/PD models should prove to be more accurate and more easily modified to address factors such as age, CYP content and genetic polymorphisms in CYPs and PON1 (biomarkers of susceptibility). CYP-Specific PBPK/PK models for OP pesticides, that better estimate population variability in exposure, target tissue dose and effect, will be valuable tools for risk assessment efforts for these OPs in the general population, special exposure groups, susceptible individuals (polymorphisms in CYPs and /or PON1), and 6-11 year old children, which are the age group in the U.S. with the highest levels of urinary metabolites specific for these commonly used OPs (CDC 2005).

    Supplemental Keywords:

    human health, sensitive populations, infants, esterase, oxon, trichloro-2-pyridinol (TCPy), p-nitrophenol (PNP), 2-isopropyl-4-methyl-6-hydroxypyrimidine,, RFA, Health, Scientific Discipline, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, Risk Assessments, endocrine disruptors, Biochemistry, Biology, Endocrine Disruptors - Human Health, neurotoxic, bioindicator, thyroid toxicants, exposure studies, dose response, developmental biology, human growth and development, toxicity, hormone production, ecological risk assessment model