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

ABSTRACT

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.

KEYWORDS:

• Dermal exposure and dose
• malathion
• organophosphate pesticides
• PBPK modeling
• percutaneous
• skin surface

Acknowledgment

The authors thank Rick Nelson for editorial assistance.

Disclosure of interest

Preparation of the human PBPK model for malathion used in this manuscript was funded by Cheminova (since purchased by FMC Corp.), a company that manufactures and supplies malathion for agricultural and pharmaceutical applications approved by appropriate regulatory agencies. Exponent, Inc., which funded the rest of this manuscript and employs its authors, is a consulting firm that provides advice on toxicological and risk analysis issues to private and public clients. The authors alone formulated the scientific questions addressed, reviewed literature, synthesized and integrated scientific information, drew the conclusions presented, and decided how and where to submit this paper. Conclusions drawn are not necessarily those of Exponent, Inc., or any of its clients. Exponent, Inc., has been paid consulting fees for regulatory support analysis and related services pertaining to several pesticides that are manufactured and marketed by Cheminova, including malathion.