Long ago and far away: a retrospective on the implications of Minamata

Minamata claimed entry into the lexicon of toxicology 40 years ago as a definition of methylmercury poisoning, but deposited a legacy of unsolved puzzles that still endures. In fact, they scatter ramifications across the entire domain of neurotoxicology. One puzzle is how the earliest clinical index of adult toxicity, paresthesia, can remain stable, even with continued exposure. Does damage, like body burden, reach a plateau? A second enigma is the question of silent damage to nerve cell populations even more vulnerable than those whose loss of function results in minimal symptoms such as paresthesia. Is there a population of unidentified humans exposed to methylmercury whose deficits might be uncloaked by neurobehavioral test methods that have succeeded in revealing silent toxicity in populations exposed to lead, manganese, and elemental mercury? A third puzzle arises in the context of aging. Attrition of nerve cells occurs naturally as the brain ages, but is also accompanied by dendritic sprouting in those that remain. Damage incurred earlier in life, as in mild polio infections that seemed to fade, may emerge late in life in the form of the post-polio syndrome. Most explanations ascribe the syndrome to compensatory dendritic sprouting by surviving neurons and the consequent metabolic overload imposed on them. Could parallel processes be induced by neurotoxicants such as methylmercury? Or, alternatively, might the compensatory sprouting accompanying aging be inhibited by neurotoxic agents? All such questions have a bearing on how the risks of low-level exposures are evaluated.