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Journal Article 
Chemically induced pheochromocytomas in rats: Mechanisms and relevance for human risk assessment 
Greim, H; Hartwig, A; Reuter, U; Richter-Reichhelm, H; Thielmann, H 
Critical Reviews in Toxicology
ISSN: 1040-8444
EISSN: 1547-6898 
Pheochromocytomas are tumors originating from chromaffin cells of the adrenal medulla, which have been observed in numerous carcinogenicity studies. The authors have evaluated pheochromocytoma concurrence with other effects and the possible mechanisms, in order 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 relatively higher frequency in male rats, especially when the following conditions are involved: hypoxia, uncoupling of oxidative phosphorylation, disturbance in calcium homeostasis, and disturbance of the hypothalamic endocrine axis. The underlying biochemical mechanisms suggest that other substances that interfere 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, and pyruvate dehydrogenase. To date, there is no indication that the substances inducing pheochromocytomas in animal experiments also induce corresponding tumors in humans. Because 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. 
Calcium homeostasis; endocrine disturbances; hepatotoxicity; hypoxia; lung toxicity; nephrotoxicity; pheochromocytomas; uncouplers