Characterizing interactions caused by sequential skin exposures to various environmental toxicants can be critical for a meaningful risk assessment. To assess sequential chemical exposure effect on chemical cutaneous disposition and systemic uptake of a toxicant, [(14)C]pentachlorophenol (PCP) was topically administered in three porcine skin models (in vivo, ex vivo, and in vitro) at 40 micro g/cm(2) with or without skin preexposure to benzo[a]pyrene (BaP), a known human carcinogen and cutaneous cytochrome P-450 (CYP450) inducer. In the mass balance studies, BaP skin preexposure was found to enhance (14)C absorption in all three models with detectable in vivo effect during the first several days. Total 8-h absorption was tripled by skin preexposure to BaP in the ex vivo (1.1 to 3.2%) and in vitro (0.20 to 0.66%) systems. As seen in the extended in vivo studies, total absorption was 50-57% regardless of exposure conditions, suggesting the prolonged observation period may conceal existing impact of potentially modified disposition processes, such as cutaneous metabolism, on systemic absorption. Skin preexposure to the skin CYP450 inducer BaP largely changed label penetration depth and distribution pattern in cutaneous tissues and decreased (14)C concentration in skin and fat. Additionally, BaP preexposure altered (14)C systemic tissue disposition, suggesting that altered cutaneous PCP disposition may eventually change the toxicity profile (cutaneous vs. systemic risk). The preliminary tissue distribution and systemic absorption data suggested that skin preexposure to BaP may considerably modify cutaneous biotransformation rate and thus deserves further investigation. The dermal model-dependent impacts of expected skin biotransformation manipulation by preexposure to chemicals such as BaP on cutaneous disposition and systemic uptake of environmental toxicants such as PCP need to be considered in risk assessment.