Impact/Purpose:

1) To develop a physiologically-based pharmacokinetic (PBPK) model for As;
2) To elucidate two related and critical aspects of the dynamic behavior of arsenic - the enzymatically-catalyzed production of methylated arsenicals and the modulation of NAD(P)H oxidoreductases by arsenicals and their complexes with thiols.
3) To develop a biologically-based dose response (BBDR) model that describes the relation between tissue levels of arsenicals and the effects of arsenic on biomarkers of oxidative stress.

Description:

This project integrates research on aspects of the kinetic and dynamic behavior of arsenic. A PBPK model for arsenic will be developed using metabolism and disposition data from studies in mice. Retention of arsenic in the tissues following exposure to arsenic will be investigated, providing tissue profiles for several arsenic species. Rates of metabolism in tissues will be determined for incorporation into the PBPK model. This refined model will allow more accurate assessment of the tissue dosimetry of arsenic during chronic exposure to this metalloid. The BBDR model will focus primarily on the effects of arsenic as an inducer of oxidative stress. Potential biomarkers of exposure and effect will be evaluated during the course of these studies.

Regulatory Relevance: This research addresses fundamental questions that underlie uncertainties about the health effects of arsenic in humans. The development of a BBDR model will permit description of the quantitative relationship between tissue dose and early biological responses, the systematic examination of the impact of different exposure scenarios, and of host and environmental factors (e.g. methylation capacity and nutritional status ) that may modify response. BBDR model development also aids in the identification of susceptible sub-populations, allows evaluation of the impact of co-exposures to chemicals that operate via a similar mechanism and may suggest productive lines of research for development of biomarkers of exposure and effect. Identification of appropriate biomarkers of exposure and effect will aid in the design of new epidemiological studies of the effects of chronic exposure to arsenic.

Record Details:

Record Type:PROJECT

Start Date:04/01/1996

Completion Date:04/01/1999

OMB Category:Other

Record ID: 66012

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Project Information:

Status : Peer-reviewed publications for FY 98, 99, and 00:

Hughes MF, Kenyon EM. Dose-dependent effects on the disposition of monomethylarsonic acid and dimethylarsinic acid in the mouse after intravenous administration. J Toxicol Environ Health A. 1998 53:95-112.

Styblo, M., Vega, L., Germolec, D.R., Luster, M.I., Del Razo, L.M., Wang, C., Cullen, W.R., and Thomas, D.J.: Metabolism and toxicity of arsenicals in cultured cells. In Arsenic Exposure and Health Effects, ed. by W.R. Chappell, C.O. Abernathy, and R.L. Calderon, pp. 311-323, Elsevier, Amsterdam, 1999.

Styblo, M., Del Razo, L.M., LeCluyse, E.L., Hamilton, G.A., Wang, C., Cullen, W.R., and Thomas, D.J.: Metabolism of arsenic in primary cultures of human and rat hepatocytes. Chem. Res. Toxicol. 12:560-565, 1999.

Lin, S., Cullen, W.R., and Thomas, D.J.: Methylarsenicals and arsinothiols are potent inhibitors of mouse liver thioredoxin reductase. Chem. Res. Toxicol.12:924-930, 1999.

Hughes, M.F., Kenyon, E.M., Edwards, B.C., Mitchell, C.T., and Thomas, D.J.: Strain-dependent disposition of inorganic arsenic in the mouse. Toxicology 137:95-108, 1999.

Kenyon E.M., Hughes M.F., Del Razo L.M., Edwards B.C., Mitchell C.T., and Levander O.A. (1999). Influence of dietary selenium on the disposition of arsenite and arsenate in the female B6C3F1 mouse. Nutr. Environ. Interact. 3, 95-113.

Kitchin KT, Del Razo LM, Brown JL, Anderson WL, Kenyon EM. An integrated pharmacokinetic and pharmacodynamic study of arsenite action. 1. Heme oxygenase induction in rats. Teratog Carcinog Mutagen. 1999;19(6):385-402.

Styblo, M., Del Razo, L.M., Vega, L., Germolec, D.R., LeCluyse, E.L., Hamilton, G.A., Wang, C., Cullen, W.R., and Thomas, D.J.: Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in human cells. Arch. Toxicol. 74:289-299, 2000.

Hughes, M.F., Del Razo, L.M., Kenyon, E.M. (2000). Dose-dependent effects on tissue distribution and metabolism of dimethylarsinic acid in the mouse after intravenous administration. Toxicology 143, 155-166.



Research Component :ARSENIC

Risk Paradigm :EFFECTS