Reviewing the thoroughness of human safety testing for succinate dehydrogenase inhibitors: fluopyram as a case study.

It has been suggested that fungicides which are succinate dehydrogenase inhibitors also inhibit this enzyme in humans, with potentially serious health consequences. It has also been suggested that regulatory studies conducted on these fungicides have missed succinate dehydrogenase inhibition and its effects. Using fluopyram as a case study, this paper addresses these suggestions by critically examining all the studies related to human safety. The mechanism causing each toxicity is considered, including the possibility that inhibition of succinate dehydrogenase might be the root cause. If fluopyram were to inhibit succinate dehydrogenase, then the consequent effects and their likelihood of detection are evaluated. Many fluopyram toxicity studies are completely untargeted, with a huge number of endpoints examined, any one of which might reveal an important toxic effect. Rat and mouse studies from a single dose to near lifetime exposure are included, whilst dog studies add biological coverage. The consistent pattern seen is that the primary toxicities caused by fluopyram are effects on the liver and thyroid, plus a kidney effect in ageing male rats. The mechanisms causing these effects have been proven in bespoke mechanistic studies-they are not relevant to humans and do not involve the inhibition of succinate dehydrogenase. If fluopyram were to inhibit succinate dehydrogenase then this would be apparent, as the tissues most likely to be affected-the nervous system, heart and muscle-were examined microscopically in numerous studies with no effects seen. The low affinity of fluopyram for mammalian succinate dehydrogenase and its rapid metabolism explain the results.