EPA Science Inventory

Impact of In Vitro System, Chemical Mistures, and Stereochemistry on the Intrinsic Clearance of 1,2,4-Triazole Fungicides in Human and Rat

Citation:

Kenneke, J., S. Marchitti, S. Rawat, Chris Mazur, Q. Cheng, M. Goldsmith, D. Chang, AND C. Grulke. Impact of In Vitro System, Chemical Mistures, and Stereochemistry on the Intrinsic Clearance of 1,2,4-Triazole Fungicides in Human and Rat. Presented at The 19th International Symposium on Microsomes and Drug Oxidations and 12th European ISSX Meeting, Noordwijk aan Zee, NETHERLANDS, June 17 - 21, 2012.

Description:

The exposure of humans and ecologically important species to environmental chemicals typically occurs at unknown concentrations and for uncertain durations. Exposure becomes an internal dose when the chemical crosses the body barrier. Characterizing internal dose is important for reconstructing exposure events and predicting undesirable effects. Chemical clearance, which depends on the intrinsic ability of organs to metabolize or eliminate the chemical from the body, can significantly affect internal dose. Clearance provides an understanding of a chemical’s metabolic stability and the contribution of metabolism to total clearance in vivo. In vitro methods are frequently used to measure intrinsic clearance and can be used to rank chemicals based on their metabolic stability. In conjunction with toxicity information, this rank-order approach can be used to prioritize the testing of chemicals for which there is little exposure or effects data. As a first step in evaluating this prioritization process, we examined the clearance of twenty, 1,2,4-triazole agricultural fungicides in purified human CYP3A4 and rat and human cryopreserved hepatocytes and hepatic microsomes. Agricultural and pharmaceutical 1,2,4-triazole fungicides are potent cytochrome P450 modulators that can disrupt mammalian steroid biosynthesis and promote tumor formation in rodents. Michaelis-Menten kinetics (Vmax and KM) and the in vitro substrate depletion T1/2 method were used to measure intrinsic clearance. We observed good agreement between the two approaches; clearance values spanned several orders of magnitude for each system, and the relative order of fungicide clearance was similar between the in vitro systems and between the species. In general, fungicides containing straight alkyl chains were cleared quickly while fluorine-containing compounds exhibited very slow clearance or were unreactive. Least-squares linear regression models were developed to extrapolate clearance between the

Purpose/Objective:

Presented at the 19th European ISSX Meeting. June 17-21, 2012. Noordwijk aan Zee, the Netherlands

URLs/Downloads:

19th European ISSX Meeting   Exit

Record Details:

Record Type: DOCUMENT (PRESENTATION/SLIDE)
Start Date: 06/21/2013
Completion Date: 06/21/2013
Record Last Revised: 12/17/2013
Record Created: 10/16/2012
Record Released: 10/16/2012
OMB Category: Other
Record ID: 246933

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL EXPOSURE RESEARCH LAB

ECOSYSTEMS RESEARCH DIVISION