A Distributed Parameter Physiologically‐Based Pharmacokinetic Model for Dermal and Inhalation Exposure to Volatile Organic Compounds

Abstract

Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady‐state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short‐term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically‐based pharmacokinetic model (DP‐PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP‐PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post‐exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP‐PBPK model predicted a time‐lag in the exhaled breath concentration profile, consistent with the experimental data. The DP‐PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end‐exposure dermal dose predicted by the DP‐PBPK model is similar to that predicted by the EPA recommended method for short‐term exposures, and is significantly greater than the end‐exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP‐PBPK model is substantially less than that predicted by the EPA method, due to the post‐exposure volatilization predicted by the DP‐PBPK model. Moreover, the net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization.