The effects of benzo[a]pyrene-induced skin cytochrome P450 elevation on 3,3',4,4'-tetrachlorobiphenyl percutaneous absorption and tissue disposition.
American Industrial Hygiene Conference and Exposition, May 20-25, 2000, Orlando, Florida. Fairfax, VA: American Industrial Hygiene Association, 2000 May; :56
Skin metabolism has considerable impact on cutaneous and systemic risk of a topically exposed toxicant by changing its disposition and activity. Workers could be exposed to both 3,3´,4,4´-tetrachlorobiphenyl (TCB) and benzo[a]pyrene via the dermal route. To quantify skin cytochrome (Cyt) P450 induction effects on dermal absorption and local disposition, [14C]TCB was topically applied in vivo (n = 3), ex vivo (isolated perfused porcine skin flap, n = 4), and in vitro (flow-through diffusion cells, n = 6 to approximately 9) to porcine models at 40 mg/cm2 skin surface with or without Cyt P450 inducer benzo[a]pyrene pretreatment. It was found that skin Cyt P450 induction enhanced 14C absorption in all models tested. Total 8-hour ex vivo (0.11%-0.46%) and in vitro (0.21%-0.48%) 14C absorption was increased 2 to approximately 4 fold by skin P450 induction. The in vivo excretion via renal and fecal routes accounted for 5% and 9% of the doses. However, if the observation time was prolonged to 11 days as in the in vivo studies, the total absorption was 23%-30% regardless of skin Cyt P450 status, suggesting that the extended observation period may conceal the impact of modified skin metabolism on dermal absorption. Skin Cyt P450 induction also changed label penetration depth and distribution pattern in local cutaneous tissues, suggesting that the enhanced cutaneous TCB metabolism may change the toxicity profile (cutaneous vs. systemic). On average, 82% of the topical doses were recovered. It was concluded that the effects of cutaneous metabolism manipulation by pre-exposed or co-administered enzyme inducer(s) such as benzo[a]pyrene need to be taken into account for occupational and environmental dermal risk assessment. The mechanisms for such cutaneous Cyt P450 induction effects on total dermal absorption and disposition need to be further elucidated.
Skin-exposure; Skin-absorption; In-vivo-study; In-vitro-study; Metabolism; Benzopyrenes; Pyrenes; Biphenyls
American Industrial Hygiene Conference and Exposition, May 20-25, 2000, Orlando, Florida