Malathion dermal permeability in relation to dermal load: Assessment by physiologically based pharmacokinetic modeling of in vivo human data

Estimates of dermal permeability (K_p), obtained by fitting an updated human PBPK model for malathion to previously reported data on excreted urinary metabolites after 29 volunteers were dermally exposed to measured values of [¹⁴C]malathion dermal load (L), were used to examine the empirical relationship between K_p and L. The PBPK model was adapted from previously reported human biokinetic and PBPK models for malathion, fit to previously reported urinary excretion data after oral [¹⁴C]malathion intake by volunteers, and then augmented to incorporate a standard K_p approach to modeling dermal-uptake kinetics. Good to excellent PBPK-model fits were obtained to all of 29 sets of cumulative urinary metabolite-excretion data (ave. [±1 SD] R² = 0.953 [±0.064]). Contrary to the assumption that K_p and L are independent typically applied for dermally administered liquids or solutions, the 29 PBPK-based estimates of K_p obtained for malathion exhibit a strong positive association with the 2/3rds power of L (log-log Pearson correlation = 0.925, p = ∼0). Possible explanations of this observation involving physico-chemical characteristics and/or in vivo cutaneous effects of malathion are discussed. The PBPK model presented, and our observation that K_p estimates obtained by fitting this model to human experimental urinary-excretion data correlate well with L^2/3, allow more realistic assessments of absorbed and metabolized dose during or after a variety of scenarios involving actual or potential dermal or multi-route malathion exposures, including for pesticide workers or farmers who apply malathion to crops.