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Russell S. Thomas,¹ Raymond S.H. Yang,¹ Daniel G. Morgan,² Michael P. Moorman,³ Hamid R.S. Kermani,³ Richard A. Sloane,³ Robert W. O'Connor,⁴ Bernard Adkins, Jr.,⁴ Michael L. Gargas,⁵ Melvin E. Andersen⁶

¹Center for Environmental Toxicology and Technology, Department of Environmental Health, Colorado State University, Fort Collins, CO 80523-1680; ²Glaxo, Inc., Research Triangle Park, NC 27709; ³National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; ⁴ManTech Environmental, Research Triangle Park, NC 27709; ⁵McLaren/Hart/ChemRisk, 29225 Chagrin Blvd., Cleveland, OH 44122-4629; ⁶ICF Kaiser, K.S. Crump Division, Morrisville, NC 27560 USA

Abstract

During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm ; 6 hr/day, 5 days/week) , gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F₁ mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (V_maxc) was observed at the 1-day and 1-month exposure points when compared to concurrent control mice, while decreases in glutathione S-transferase (GST) rate constant (K_fc) were observed in the 1-day and 1-month exposed mice. Within exposure groups, the apparent V_maxc maintained significant increases in the 1-month and 2-year control groups. Although the same initial increase exists in the exposed group, the 2-year V_maxc is significantly smaller than the 1-month group (p < 0.001) . Within-group differences in median K_fc values show a significant decrease in both 1-month and 2-year groups among control and exposed mice (p < 0.001) . Although no changes in methylene chloride solubility as a result of prior exposure were observed in blood, muscle, liver, or lung, a marginal decrease in the fat:air partition coefficient was found in the exposed mice at p = 0.053. Age related solubility differences were found in muscle:air, liver:air, lung:air, and fat:air partition coefficients at p < 0.001, while the solubility of methylene chloride in blood was not affected by age (p = 0.461) . As a result of this study, we conclude that age and prior exposure to methylene chloride can produce notable changes in disposition and metabolism and may represent important factors in the interpretation of toxicologic data and its application to risk assessment. Key words: bootstrap resampling, glutathione S-transferase, methylene chloride, Monte Carlo simulation, physiologically based pharmacokinetic modeling, risk assessment. Environ Health Perspect 104:858-865 (1996)

Address correspondence to R.S. Thomas, Center for Environmental Toxicology and Technology, Colorado State University, Fort Collins, CO 80523-1680 USA.

The experimental work on this study was conducted at the National Institute of Environmental Health Sciences (NIEHS) and the efforts of many NIEHS collegues are gratefully acknowledged. We thank Richard Reitz for allowing investigators to conduct interlaboratory enzyme assays in his laboratory at Dow Chemical Company, Midland, MI, and for donating samples of radiolabeled methylene chloride. Computer analyses and preparation of the final manuscript were carried out at Colorado State University. Thus, the work was supported in part by a Research Contract (F33615-91-C-0538) from the Toxicology Division, Armstrong Laboratory, U.S. Air Force and an NIEHS Superfund Basic Research Program Project Grant (P42 ES05949) . We also thank Sean Hays for his input on mammalian physiology.

Received 13 December 1995 ; accepted 12 April 1996.