PERCUTANEOUS-ABSORPTION AND DISPOSITION OF [C-14]CHLORDECONE IN YOUNGAND ADULT FEMALE RATS

The objective of this study was to evaluate the effect of age and dosa ge on percutaneous absorption and disposition of [C-14]chlordecone (Ke pone) and to describe results using a physiological based pharmacokine tic (PBPK) model. Female Fischer 344 rats 33 and 82 days old were used as the young and adult animal models, respectively, and were studied over a 10-fold dose range. [C-14]Chlordecone (0.286 mu mol/cm(2)) was applied to dorsal skin (2.3% BSA) and radioactivity was quantified in selected tissues and excreta up to 120 h. Absorption and disposition w ere also determined at three dose levels up to 2.68 mu mol/cm(2); frac tion absorbed decreased as dose increased. In vitro percutaneous absor ption was measured by static and flow-through methods; these yielded s imilar penetration rates, which were lower than those obtainedobtaiend in vivo. In vivo percutaneous absorption over 120 h was 14.4 +/- 0.99 and 14.2 +/-1.5% dose in young and adults, respectively. Organ and ti ssue content increased over time (carcass > liver > kidney), indicatin g prolonged absorption. Statistical differences between young and old were found for liver, skin, and urine, but not for absorption. Excreti on occurred primarily in feces, but also in urine. A biophysically bas ed percutaneous model was fitted to both young and adult in vivo absor ption data. This was embedded in a whole body PBPK model which, upon o ptimization with SAAM II, estimated apparent tissue partition coeffici ents, urinary and fecal excretion rates, and parameters characterizing hepatic nonlinear uptake of bound chlordecone. The model reasonably p redicted tissue chlordecone content at higher doses, when decreased ab sorption was accounted for.