The significance of in vitro rat skin absorption studies to human risk assessment

The present paper reviews the comparative rates of skin penetration between rat and man for a total of 14 chemicals in in vitro absorption studies. The results showed that in vitro absorption assays are capable of demonstrating large differences in the rate of skin penetration. Saturation of absorption was also frequently observed at higher exposure levels. The highest absorption rates through rat and human epidermis were observed with compounds with a molecular weight of approximately 300, an aqueous solubility of approximately 1-6 mg/l, and a log(10) (P-OCTANOL/WATER) of approximately 3-4. When the absorption data for 3 compounds with a log(10) (P-OCTANOL/WATER) of 2.9-3.0 were compared, there appeared to be an inverse relationship between molecular weight/aqueous solubility and the rate of dermal absorption. Lipophilic compounds with low aqueous solubility ( < 4 mg/l) showed the highest penetration rates through rat skin, but this was not always the case for human skin. The human skin was invariably less permeable to all tested substances than rat skin, though no constant factor of difference could be identified. The factor of difference would not appear to be determined by molecular weight, lipophilicity, or aqueous solubility. The actual systemic exposure of humans may be significantly overestimated if risk assessment is based only on the results of an in vivo rat study. It would appear that dermal penetration through human skin should be based on the combined use of in vivo and in vitro data, using the following equation: %Human dermal penetration = [% dermal penetration rat (in vivo)]x[rate dermal penetration human (in vitro)]/[rate dermal penetration rat (in vitro)] (C) 2003 Elsevier Ltd. All rights reserved.