Estimated Dermal Penetration of Tetrachlorvinphos (TCVP) in Humans Based on In Silico Modeling and In Vitro and In Vivo Data

Tetrachlorvinphos (TCVP) is the pesticidal active ingredient in some collars for dogs and cats. The objective of this study was to provide a refined estimate of dermal penetration of TCVP in humans using in silico predictions as well as in vitro and in vivo data. The in vivo dermal absorption of TCVP was previously studied in the rat and shown to be saturable, ranging from 21.7% (10 mu g/cm(2)) down to 3% (1000 mu g/cm(2)) Subsequent in silico predictions were conducted for rats and humans to provide initial evaluations of species and dose-dependent differences in dermal absorption. A definitive comparison of TCVP systemic exposure in rat and human following dermal application was then conducted via a standard in vitro assay. TCVP dose levels of 10, 100, or 1000 mu g/cm(2) were applied to excised rat and human skin mounted in flow-through diffusion cells. The vehicle was 1% hydroxypropylmethylcellulose (HPMC) in water. An additional 5 mu g/cm(2) dose was applied to excised human skin only. The in vitro dermal absorption of TCVP was also assessed from artificial sebum at dose levels of 5, 10, or 100 mu g/cm(2) applied to human skin only. Utilizing the so-called triple pack approach with in vitro and in vivo rat data and in vitro human data, dermal absorption for TCVP was calculated for humans. In silico modeling indicated absorption of TCVP through human skin might be 3- to 4- fold lower than rat skin at all application levels, with a maximum dermal absorption of 9.6% at the lowest exposure of 10 mu g/cm(2), down to 0.1% at 1000 mu g/cm(2). Similar species differences were also found in the definitive in vitro absorption assays. Modeling overestimated TCVP human dermal absorption (9.6%) as compared to excised human skin results (1.7%) for the HPMC vehicle at the lowest exposure (10 mu g/cm(2)), with better agreement at the higher exposures. Conversely, modeling accurately predicted rat dermal absorption (27.9%) as compared to in vivo rat results (21.7%) at the lowest exposure in HPMC, with diminished agreement at the higher exposures. As a first approximation, in silico estimates of dermal absorption are useful; however, these tend to be more variable than in vitro or in vivo measurements. TCVP dermal penetration measured in vitro was lower in 1% HPMC vehicle as compared to artificial sebum. For the 1% HPMC vehicle, in vitro rat dermal absorption was similar to data obtained for in vivo rats, giving confidence in the triple pack approach. In consideration of the triple pack approach, estimated human dermal absorption from 1% HPMC was <= 2%. Based upon excised human skin determinations directly, estimated human dermal absorption of TCVP from artificial sebum was <= 7%.