Dermatopharmacokinetics and pharmacodynamics: in vivo analysis of common paint product solvents.
NIOSH 2003 Apr; :1-34
Exposure assessment is an important component in estimating health risk for individuals exposed to chemicals. Regulatory agencies have established standards for allowable occupational exposures, primarily via the inhalation pathway. In contrast, very little data is available to provide agencies sufficient guidance to establish permissible dermal exposure levels. Part of this shortfall lies in the fact that measurement of the amount of chemical absorbed through the skin is both experimentally difficult and time-consuming. In the research described here an innovative methodology was utilized to non-invasively evaluate dermal absorption by continually analyzing exhaled breath. Because breath concentrations can be used to reflect blood concentrations, constant analysis of exhaled breath provides an opportunity to evaluate differences in the rapidly changing blood compartment that occurs immediately following peak exposure. Animal studies were conducted to collect time-course data on the dermal absorption of two common solvents toluene and methyl ethyl ketone. Both of these solvents are components of various paint and adhesive products, and may be frequently encountered in the occupational setting and by the consumer. Studies were conducted to expose animals to these compounds to provide an understanding of the impact of exposure matrix on dermal absorption. The exhaled breath kinetic data collected from each exposed animal was subsequently evaluated using an established mathematical model to determine the rate of dermal absorption. The studies indicate that the aqueous compounds are rapidly absorbed through the skin of a rat with a permeability coefficient of 0.074 +/- 0.005 cm/hr for toluene. For methyl ethyl ketone, dermal absorption occurs in an apparent biphasic rate exhaled breath data suggest an initial rapid rate of appearance in systemic 'blood, followed by a slow, sustained rate. The underlying factors driving this observed biphasic dermal absorption remain to be determined. Additionally, the dermal absorption of toluene from an enamel paint matrix is essentially identical to the dermal absorption of toluene from an aqueous matrix when normalized to the toluene exposure concentration. In both cases, a permeability coefficient of 0.07 cm/hr adequately described the data, although toluene concentrations differed significantly (25 mg/ml for enamel paint versus 0.5 mg/ml for the aqueous matrix). To evaluate the impact of paint constituents on the dermal bioavailability, additional dermal exposures were conducted using reformulated enamel paint, wherein the titanium dioxide (particulate) and xylene co-solvent were replaced by toluene. The PBPK model simulations of the exhaled breath data from these exposures required a permeability coefficient roughly half the value from the intact paint (0.032 cm/hr), although the toluene concentration was more than 12 times greater than in the original paint. These data highlight the impacts both concentration and matrix components within the exposure matrix have on dermal permeability. Similar results were observed for dermal exposures to toluene in lacquer thinner-based matrices.
Dermatosis; In-vivo-studies; In-vivo-study; Paints; Solvents; Occupational-exposure; Inhalation-studies; Dermatitis; Toluenes; Methyl-compounds; Mathematical-models; Animal-studies; Animals; Laboratory-animals; Xylenes
Chemical Dosimetry Group, Battelle, Pacific Northwest Division, 902 Battelle Blvd., P.O. Box 999, MS P7-59, Richland, WA 99352
108-88-3; 78-93-3; 13463-67-7; 1330-20-7
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