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DEVELOPMENT OF PHYSIOLOGICAL-BASED PHARMACOKINETIC MODEL FOR DERMAL ABSORPTION NAD PENETRATION OF METHYL TERTIARY BUTYL ETHER IN HUMANS
KIM, D., L. NYLANDER, J. PIEIL, AND J. D. PRAH. DEVELOPMENT OF PHYSIOLOGICAL-BASED PHARMACOKINETIC MODEL FOR DERMAL ABSORPTION NAD PENETRATION OF METHYL TERTIARY BUTYL ETHER IN HUMANS. Presented at Occupational and Environmental Exposures of Skin to Chemicals, Stockholm, SWEDEN, June 12 - 15, 2005.
Background: Methyl tertiary butyl ether (MTBE) is a volatile organic chemical that is added to gasoline as an octane booster and to reduce vehicular emissions of carbon monoxide. MTBE is introduced into the environment through fuel spills, leakage of storage tanks, and evaporation during auto refueling, leading to contamination of ambient air and water supplies. MTBE has been linked to toxicity and cancer in animals. The main route of human exposure to MTBE is from inhalation of gasoline vapors; however, dermal exposures may also be significant. The objective of this study is to construct a skin model that adequately describes dermal absorption of MTBE in humans. Methods: Physiologically-based pharmacokinetic (PBPK) models developed previously were modified to include a two-compartment model for the skin. The initial model contained compartments for skin (stratum corneum and viable epidermis), blood (arterial and venous), brain, kidney, fat, liver, gastrointestinal tract, rapidly perfused tissues, and slowly perfused tissues. The parameters describing the skin compartment were estimated using blood data collected from humans following 1-h exposure to MTBE in water. Sensitivity analysis was implemented to identify parameters that could be adjusted. Results: The following skin parameters were estimated: permeability coefficients across the stratum corneum (PERM1) and the viable epidermis (PERM2), partition coefficients for vehicle to stratum corneum (PD), stratum corneum to viable epidermis (PE), and viable epidermis to venous blood (PEB), and cardiac output (QE) to the skin. The estimated values are PERM1=0.015 cm/hr, PERM2=0.0044 cm/hr, PD=2.4, PE=0.5, PEB=15.4, and QE=10 L/hr. Conclusions: The model demonstrates that the process of dermal absorption and penetration by MTBE can be described and quantified using a two-compartment model of the skin. Estimation of the skin parameters suggests that the diffusion of MTBE across the stratum corneum is more rapid than across the viable epidermis.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
HUMAN STUDIES DIVISION
CLINICAL RESEARCH BRANCH