Riley's classic 1970 experiment showing a specific cytotoxic effect of 4-hydroxyanisole (4-OHA) on tissue-cultured melanocytes of black guinea pig ear skin was repeated on normal human melanocytes, and the results were examined by electron microscopy. In dispersed tissue culture, no specific toxic effect on human melanocytes was observed following equally timed exposures to similar (10(-3) M) or even higher (10(-2) M) concentrations of the drug; plasma membrane, nucleus, and cytoplasmic organelles, including melanosomes were unaffected. The same applied to melanocytes of whole epidermis exposed for 5 hr to the same concentrations of 4-OHA in culture medium. Melanocytes of PUVA treated skin similarly exposed for up to 24 hr to 10(-2) and 10(-3) M 4-OHA, likewise exhibited no evident morphological damage at the ultrastructural level. The discrepancy of results between guinea pig and man could have a variety of explanations, one of which could be due to a possible relatively low level of active tyrosinase in the human melanocytes (Riley believes the cytotoxic effect of 4-OHA to be due to the fact that it acts as a substrate for tyrosinase, toxic intermediates being liberated as a result). However, the lack of effect on the PUVA-activated melanocytes indicates that this cannot be the entire explanation.