Dermatopharmacokinetics: in vivo analysis of solvents.
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-003658, 2006 May; :1-24
Dermal exposures and subsequent percutanous absorption of solvents and other chemicals can be a critical exposure route in occupational settings. However, in silico predictive methods do not generally provide an accurate estimate of absorption when compared to dermal studies which have demonstrated that dermal exposures can be a significant contributor to total absorbed dose. Physiologically based pharmacokinetic (PBPK) models allow both the estimation of internal dose from a dermal exposure and the calculation of equivalent dose levels across dosing routes, since many chemicals have more significant oral or IV data sets. Dermal exposures to both lipophilic and hydrophilic chemicals were conducted in F344 rats with uptake measured via exhaled breath to allow detection of rapid concentration changes. Exposures were conducted by placing a set amount of test compound, either neat or in an aqueous formulation, into a sealed chamber secured to the back of the animal and monitoring exhaled breath concentrations from the animal in a gas uptake chamber for approximately three hours. Exposures were conducted for acetone, ethyl benzene, styrene, methyl ethyl ketone, and methyl n-butyl ketone (MnBK). Exposures were conducted with neat test material, in aqueous vehicle, or under both neat and aqueous conditions, depending on the solubility of the individual test compound. Total dermal absorption was found to be greatest for styrene, followed by ethylbenzene > MnBK > MEK > acetone. A PBPK model for MnBK was developed by conducting experimental studies to determine blood and tissue partition coefficient values and by conducting gas uptake studies for derivation of metabolic parameters. Additional exposures (oral and intraperitoneal) were conducted as the basis for constructing a PBPK model for MnBK. The approach of coupling mathematical models with a non-invasive rapidly monitoring methodology is critical for calculating estimates of dermal absorption. However, the dermal patch system utilized here was found to be inadequate for maintaining patch integrity and lacked sufficient volume for solvent vapors. Thus, permeability coefficient values were not possible to calculate.
Models; Solvents; Laboratory-animals; Animals; Animal-studies; Exposure-levels; Exposure-assessment; Quantitative-analysis; Risk-analysis; Skin-sensitivity; Skin-absorption; Skin-exposure; Styrenes; Acetones; Laboratory-animals
Karla D. Thrall, Chemical Dosimetry Group, Battelle, Pacific Northwest Division, 902 Battelle Blvd., P.O. Box 999, MS P7-59 Richland, WA 99352
100-42-5; 67-64-1; 78-93-3
Final Grant Report
NTIS Accession No.
Disease and Injury: Allergic and Irritant Dermatitis
National Institute for Occupational Safety and Health
Battelle Memorial Institute, Richland, Washington