Chlorotriazine Protein Binding: Biomarkers of Exposure & Susceptibility

EPA Grant Number: R828610
Title: Chlorotriazine Protein Binding: Biomarkers of Exposure & Susceptibility
Investigators: Andersen, Melvin E. , Tessari, John D.
Institution: Colorado State University
EPA Project Officer: Deener, Kacee
Project Period: June 1, 2000 through May 31, 2003 (Extended to May 31, 2006)
Project Amount: $710,617
RFA: Biomarkers for the Assessment of Exposure and Toxicity in Children (2000) RFA Text |  Recipients Lists
Research Category: Economics and Decision Sciences , Children's Health , Health Effects , Human Health , Health

Description:

Atrazine is applied to two thirds of field corn and sorghum and over 90 % of sugarcane in the US. In some rat strains atrazine disrupts ovulation at high daily doses, leading to estrus cycle irregularities and an increased incidence of mammary tumors. Radioactivity from 14C-atrazine accumulates in red blood cells, indicative of covalent binding with hemoglobin. Hemoglobin binding with atrazine occurs with rat and human blood, presumably at cysteine residues. Risk assessments for potential endocrine effects of atrazine in children will require improved measures of exposure, absorption, and tissue reactivity. The main objective of our research is to test the hypothesis that binding of chlorotriazines by hemoglobin and hair proteins can be used to evaluate differences in exposure and in individual susceptibility of children toward these chlorotriazines.

Approach:

This research will measure hemoglobin and hair binding in laboratory animals treated with several triazines, predict differences in chlorotriazine pharmacokinetics for individuals of different acres, and evaluate background binding of triazines to hemoglobin and hair in limited numbers of human samples. Future studies will examine these biomarkers in populations of farm children and children of migrant workers in the Mountain states region. There are four specific aims: (1) further refine GC-MS methods to measure chlorotriazine binding to cysteine residues in hemoglobin; (2) determine the extent of binding of chlorotriazine to cysteine residues in hair proteins; (3) develop PBPK models for juvenile and adults that link chlorotriazine plasma kinetics and protein binding in these two matrices; and (4) use the PBPK models to reconstruct exposure characteristics leading to measured protein binding in hemoglobin and hair in laboratory animals and people. Our studies will develop improved methods for and then measure cysteine residue adducts with GC-MS. Hemoglobin and hair samples from laboratory rats will be studied and second-order rate constants for covalent reactions determined. A PBPK model will link exposure and circulating triazine levels to produce a comprehensive model of triazine binding to hemoglobin/hair proteins to enhance current risk assessment procedures for these compounds. In Phase I here, we will measure background binding in blood and hair samples in a limited number of human samples. The High Plains-Intermountain Center for Agricultural Health and Safety (HI-CAHS) at Colorado State University serves a number of farm and migrant worker populations. In Phase II, we plan to work with these populations to assess exposures to children in these groups.

Expected Results:

These initial studies, improving measurements of binding of chlorotriazines to hemoglobin and hair and the PBPK modeling, will pave the way for use of non-invasive biomarkers for exposure monitoring with these commercially important herbicides. Critical questions about the magnitude of exposures to children and their susceptibility will be more readily and accurately characterized after developing the analytical chemistry and PBPK modeling tools outlined in this proposal.

Publications and Presentations:

Publications have been submitted on this project: View all 28 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 7 journal articles for this project

Supplemental Keywords:

Exposure validation, simazine, cyanazine, chlorinated metabolites,, RFA, Health, Scientific Discipline, Toxics, Environmental Chemistry, Health Risk Assessment, pesticides, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Children's Health, genetic susceptability, Biology, health effects, pesticide exposure, metabolites, hemaglobin binding, tissue reactivity, endocrine disruptors, Human Health Risk Assessment, chlorotriazine protein binding, susceptibility, harmful environmental agents, pharmacokinetc model, triazine herbicides, atrazine, biological markers, growth & development, chlorotriazine, protein binding

Relevant Websites:

Synthesis Report of Research from EPA’s Science to Achieve Results (STAR) Grant Program: Feasibility of Estimating Pesticide Exposure and Dose in Children Using Biological Measurements (PDF) (42 pp, 3.87 MB)

Progress and Final Reports:

2000 Progress Report
2001 Progress Report
2002 Progress Report
2003 Progress Report
2004 Progress Report
Final Report