On the development of skin models for toxicity testing.

The extrapolation of the results of measurements of skin penetration or skin damage with current in vitro and in vivo animal models to humans is of questionable value. Therefore, the usefulness of two other models is being evaluated: human skin grafts on congenitally athymic mice and cultures of human epidermal cells. The results show that histologically and immunologically the human skin grafts retain their "human" characteristics for at least 6 months. In contrast to animal skin these grafts also form blisters in response to heat and microblisters in response to sulfur mustard. By comparing blood cholinesterase (CHE) activity after epicutaneous, subcutaneous, and intravenous administration of soman in intact and (auto- or homo-) grafted mice it appears that the transplantation process itself does not influence penetration speed, nor does it affect the total amount of soman that ultimately reaches the blood. When applied on the human skin graft, soman penetration is slower and CHE inhibition in blood has not reached a plateau value after 2 1/2 hr. Substantial amounts of soman are metabolized in the skin. With epidermal cell cultures the different mechanisms of action of the mycotoxin T2 and that of tributyltin (TBT) can be demonstrated. In a young growing culture, 10(-8) M T2 completely blocks the increase in the number of epidermal cells, whereas the same concentration of TBT has no effect. In a fullgrown culture, however, 5 X 10(-5) M TBT causes membrane damage, detectable by the leakage of lactate dehydrogenase (LDH) into the medium, whereas the same concentration of T2 has no effect. Moreover the differential effects of TBT on cytoplasmic and lysosomal membranes can be demonstrated by measuring the rates at which the cytoplasmic marker enzyme LDH and the lysosomal marker enzyme N-acetyl-beta-glucosaminidase appear in the medium. From the results obtained so far it is concluded that these two models have quite a number of promising features for dermatotoxicity testing.