Derivation of a Time Dependent Dose Response Model for Inhaled Hydrazine Using the Combined Information from Animal Cancer Bioassays, Human Epidemiology Studies and the Mutations Observed in Human Tumors. T. W. Thorslund and S. P. Bayard, US Department of Labor, DC
Ideally a mathematical exposure-cancer model should be based upon a plausible hypothesis of the mode of action of the agent on tumor development. Numerous sources of information can be used to define the required elements in such models. To illustrate consider the case of inhaled hydrazine an agent to which humans are often exposure during rocket fueling operations. A human epidemiology study strongly suggest hydrazineis a lung carcinogen. However, the available industrial hygiene information is insufficient to obtain even crude estimates of worker exposure levels. A number of inhalation bioassay have been conducted showing hydrazine induces tumors in multiple species of rodents. Also under the hypothesis that hydrazine is a lung carcinogen it is plausible that hydrazines carcinogenic effects are highly dependent upon an individuals smoking habits. One of many possible mathematical models that are consistent with the preceding information is derived and its parameters estimated. It assumes cigarettes and hydrazine cause mutations in a suppressor gene (perhaps p53) and when both alleles are deactivated a clone of pre-neoplastic cells develop. Cigarette smoke has the additional effect of promoting clone growth. Finally a spontaneous mutation in a oncogene (perhaps K-ras) in one of the clone cells results in a malignant cell that develops into a malignant tumor. Extrapolation from rodents to humans is achieved by assuming a common relative mutation rate per unit of hydrazine exposure.
The views expressed in this abstract are those of the authors and do not necessarily reflect the official position of OSHA.
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