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Citation
Tags
HERO ID
699830
Reference Type
Journal Article
Subtype
Review
Title
Chemically induced pheochromocytomas in rats: Mechanisms and relevance for human risk assessment
Author(s)
Greim, H; Hartwig, A; Reuter, U; Richter-Reichhelm, H; Thielmann, H
Year
2009
Is Peer Reviewed?
Yes
Journal
Critical Reviews in Toxicology
ISSN:
1040-8444
EISSN:
1547-6898
Volume
39
Issue
8
Page Numbers
695-718
Language
English
PMID
19743946
DOI
10.1080/10408440903190861
Web of Science Id
WOS:000270810500004
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
Tags
IRIS
•
Hexachloroethane (HCE) (Final, 2011)
OPPT REs
•
OPPT_Carbon Tetrachloride_F. Human Health
Total – title/abstract screening
On topic
Peer review
Secondary source/ Review
Cited in IRIS document or IRIS HERO page
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