SYSTEMIC UPTAKE AND CLEARANCE OF CHLOROFORM BY HAIRLESS RATS FOLLOWING DERMAL EXPOSURE .1. BRIEF EXPOSURE TO AQUEOUS-SOLUTIONS

The systemic uptake of chloroform from dilute aqueous solutions into l ive hairless rats under conditions simulating dermal environmental exp osure was studied. Whole blood was sampled during a 30-min immersion o f an animal within water containing a known concentration of chlorofor m and then for 5.5 h following its removal from the bath. The amount o f chloroform systemically absorbed was determined by comparing the AUC s of the blood concentration vs. time plots from dermal exposure to th at obtained after IV infusion (for a period of 30 min) of an aqueous s olution containing a known amount of chloroform (positive control). Al though 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 percutane ous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings sugge st that about 10.2 mg of chloroform was systemically absorbed after de rmal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amou nt is substantially higher than the predictions of mathematical risk-m odels put forth by some investigators. However, when expressed as the ''effective'' permeability coefficient (K-p(eff)), close agreement was noticed between our value and those estimated by others using physiol ogically based pharmacokinetic (PBPK) models. Also, in terms of K-p(ef f), reasonable agreement existed between our and another investigator' s past estimates of uptake based on depletion of bath level of chlorof orm and the actual uptake measured in our current experiments. The est imated onset of systemic entry seen here is entirely consistent with o ur estimate of how long it takes to establish the diffusion gradient a cross the stratum corneum based on tape stripping.