Malathion dermal permeability in relation to dermal load: Assessment by physiologically based pharmacokinetic modeling of in vivo human data.
Estimates of dermal permeability (Kp), 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 Kpand 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 Kpapproach 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 Kpand L are independent typically applied for dermally administered liquids or solutions, the 29 PBPK-based estimates of Kpobtained 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 Kpestimates obtained by fitting this model to human experimental urinary-excretion data correlate well with L2/3, 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.
a Exponent Health Sciences , Oakland , California , USA.
Kenneth T
KT
Bogen
a Exponent Health Sciences , Oakland , California , USA.
Ankur
A
Singhal
D002250:Carbon Radioisotopes / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D006801:Humans; D007700:Kinetics; D008294:Malathion / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D010539:Permeability; D010575:Pesticides / Q000493:pharmacokinetics; D012869:Skin Absorption
D002250:Carbon Radioisotopes; D010575:Pesticides; D008294:Malathion
Dermal exposure and dose; PBPK modeling; malathion; organophosphate pesticides; percutaneous; skin surface