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.
Results obtained in long-term carcinogenicity studies with animals should be evaluated, first and foremost, by statistical comparisons of the data obtained from the treated group with that from the concurrent control group. Often the results are compared with data from so-called historical control groups in order to take variations in the incidences of spontaneous tumours into account. Because historical control data change in the course of time and for a variety of reasons, certain requirements must be met before they may be used in the evaluation of the results of long-term studies. The present paper discusses potential sources of variability of tumour incidences in untreated animals, presents databanks for historical control data, mentions the factors that affect tumour incidences in untreated animals and describes biostatistical data evaluation. Finally, details are given of the criteria used by the DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area to decide whether historical control data may be applied. These include the requirement that the historical control data were obtained with animals of the same species and strain and from the same breeder. The data were obtained in the same laboratory, the study design, experimental methods and assessment criteria were the same, and the studies used for the comparison were carried out within a limited time window. Historical control data that have not been published may be used provided they fulfil the above criteria and have been made available in sufficient detail to be comprehensible.
Carcinogenic chemicals in the work area were previously classified into three categories in section III of the German List of MAK and BAT values (the list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification was based on qualitative criteria and reflected essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. In the new classification scheme the former sections IIIA1, IIIA2, and IIIB are retained as categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to the risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by non-genotoxic mechanisms, and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose/response relationships and toxicokinetics and for which risk at low doses can be assessed are classified in category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for category 4 (1,4-dioxane) and category 5 (styrene) are presented.
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