Chemically Induced Pheochromocytomas in Rats: Mechanisms and Relevance for Human Risk Assessment [MAK Value Documentation, 2010]

Abstract

Pheochromocytomas are tumors originating from chromaffin cells of the adrenal medulla, which have been observed in numerous carcinogenicity studies. We have evaluated their concurrence with other effects and the possible mechanisms to assess the relevance of such data for the classification of carcinogenic effects and their relevance to humans. The evaluation revealed that pheochromocytomas occur with relative frequency in male rats, especially when the following conditions are involved: hypoxia, uncoupling of oxidative phosphorylation, disturbance in calcium homeostasis, disturbance of the hypothalamic endocrine axis. The underlying biochemical mechanisms suggest that other substances that interfer with these biochemical endpoints also produce pheochromocytomas. Such endpoints include enzymes involved in catecholamine synthesis, receptor tyrosine kinase (RET), hypoxia‐inducible factor (HIF), succinate dehydrogenase, fumarate hydratase, pyruvate dehydrogenase. To date there is no indication that the substances inducing pheochromocytomas in animal experiments also induce corresponding tumors in humans. Since the mechanisms of action identified in rats are to be expected in humans, pheochromocytomas may be induced after exposure conditions similar to those used in the animal studies. Whether hereditary mutations represent a risk factor in humans is not clear. Pheochromocytomas that occur in animal experiments currently appear to have little relevance for conditions at the work place. When sufficiently documented and evaluated, such secondary pheochromocytomas are not relevant for classification and human risk assessment.