Systemic Uptake and Clearance of Chloroform by Hairless Rats Following Dermal Exposure. I. Brief Exposure to Aqueous Solutions

The systemic uptake of chloroform from dilute aqueous solutions into live hairless rats under conditions simulating dermal environmental exposure was studied. Whole blood was sampled during a 30‐min immersion of an animal within water containing a known concentration of chloroform and then for 5.5 h following its removal from the bath. The amount of chloroform systemically absorbed was determined by comparing the AUCs of the blood concentration vs. time plots from dermal exposure to that obtained after IV infusion (for a period of 30 min) of an aqueous solution containing a known amount of chloroform (positive control). Although dermal data implied two‐compartment disposition characteristics, IV infusion data fit best to a three‐compartment disposition. Linear pharmacokinetics was observed both by IV administration and percutaneous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings suggest that about 10.2 mg of chloroform was systemically absorbed after dermal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amount is substantially higher than the predictions of mathematical risk‐models put forth by some investigators. However, when expressed as the “effective” permeability coefficient (Kpeff), close agreement was noticed between our value and those estimated by others using physiologically based pharmacokinetic (PBPK) models. Also, in terms of Kpeff, reasonable agreement existed between our and another investigator's past estimates of uptake based on depletion of bath level of chloroform and the actual uptake measured in our current experiments. The estimated onset of systemic entry seen here is entirely consistent with our estimate of how long it takes to establish the diffusion gradient across the stratum comeum based on tape stripping.