Utility of real time breath analysis and physiologically based pharmacokinetic modeling to determine the percutaneous absorption of methyl chloroformin rats and humans

Due to the large surface area of the skin, percutaneous absorption has the potential to contribute significantly to the total bioavailability of some compounds. Breath elimination data, acquired in real-time using a novel MS/ MS system, was assessed using a PBPK model with a dermal compartment to det ermine the percutaneous absorption of methyl chloroform (MC) in rats and hu mans from exposures to MC in non-occluded soil or occluded water matrices. Rats were exposed to MC using a dermal exposure cell attached to a clipper- shaved area on their back. The soil exposure cell was covered with a charco al patch to capture volatilized MC and prevent contamination of exhaled bre ath. This technique allowed the determination of MC dermal absorption kinet ics under realistic, non-occluded conditions. Human exposures were conducte d by immersing one hand in 0.1% MC in water, or 0.751 MC in soil. The derma l PBPK model was used to estimate skin permeability (K-P) based on the fit of the exhaled breath data. Rat skin K(P)s were estimated to be 0.25 and 0. 15 cm/h for MC in water and soil matrices, respectively. In comparison, hum an permeability coefficients for water matrix exposures were 40-fold lower at 0.006 cm/h. Due to evaporation and differences in apparent K-P, nearly t wice as much MC was absorbed from the occluded water (61.3%) compared to th e non-occluded soil (32.5%) system in the rat. The PBPK model was used to s imulate dermal exposures to MC-contaminated water and soil in children and adults using worst-case EPA default assumptions. The simulations indicate t hat neither children nor adults will absorb significant amounts of MC from non-occluded exposures, independent of the length of exposure. The results from these simulations reiterate the importance of conducting dermal exposu res under realistic conditions.