Local proinflammatory effects of repeated skin exposure to warfarin, an anticoagulant rodenticide in rats.

OBJECTIVE To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. METHODS Rats were exposed to warfarin by applying 10 μg of warfarin-sodium to 10-12 cm(2) skin (range 0.8-1 μg per 1 cm(2)) for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. RESULTS Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury (increased malondialdehyde, MDA, production, evident histo-morphological changes in epidermis and dermis depicting cell injury and death). Increased numbers of proliferating cell nuclear antigen (PCNA(+)) cells indicated reparative processes in injured skin. Infiltration of CD3(+) cells (T lymphocytes) along with the increased production of tumor necrosis factor-a (TNF-a) by epidermal cells from warfarin-treated skin and their co-stimulatory effect in an in vitro T-cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. CONCLUSION Presented data have documented tissue damage associated with immune/inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.