Chemically induced pheochromocytomas in rats: mechanisms and relevance for human risk assessment

Abstract

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.

Keywords::

• Calcium homeostasis
• endocrine disturbances
• hepatotoxicity
• hypoxia
• lung toxicity
• nephrotoxicity
• pheochromocytomas
• uncouplers

Acknowledgement

This work was done in the course of the authors’ regular employment at the institutions indicated on the first page, in conjunction with the Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, supported by the Deutsche Forschungsgemeinschaft.

The authors gratefully acknowledge Patricia Brozena for her competent assistance in reviewing and editing this document.

Declaration of interest: The authors alone are responsible for the content and writing of the paper.