Contribution Of Animal Experimentation To The Interpretation Of Human Epidemiological Data

Estimating the risk of lung cancers for workers in uranium mines and defining the resulting dose equivalent limits have been made possible thanks to work carried out in two scientific fields : physics and epidemiology. Theoretical calculations on the basis of physical models for the former and epidemiological surveys on the mortality of uranium miners from lung cancer for the latter. However, even though considerable work has been done in these two areas, the results obtained still remain controversial on several points. The radioactive and physical instability of the aerosols present in the atmosphere of the mines and the biological complexity of the human lung which even the most sophisticated physical models can reproduce only very schematically have often proved to be insurmountable difficulties for physicists, explaining the uncertainties which subsist concerning the dose delivered to the various parts of the respiratory tract from the air breathed by miners during their work. Epidemiological investigations on the other hand, in spite of the high quality of the surveys carried out, remain open to criticism, essentially because of the very approximative estimation of the individual occupational exposure to radon daughters. This is due to the fact that uncertainties arise from the measurement of radon gas if the state of equilibrium with the daughters is not accurately known or, if the active deposit is measured, to the fact that these measurements are insufficient in number. The controversies and discrepancies which subsist with regard to the evaluation of the level of risk, and in particular for low doses, can thus be understood. In addition, epidemiological surveys cannot dissociate the carcinogenic action of radon from the synergistic or potentiating actions of tabacco and of other pollutants present in uranium mine air. Animal experiments have been largely taken into account for evaluating the toxicity of various radionuclides. This type of experiment is necessary when human data do not exist and has provided us with much information. For instance, the relative biological effectiveness of the various types of radiation, the metabolism of radionuclides and the mechanisms of cancer induction have been approached and satisfactorily resolved in this way. Concerning radon and its daughters, however, animal experiments have been used very little even though it seems apparent that they should complement epidemiological studies. For instance, whereas doubt can be cast on the data obtained from human epidemiology because of the uncertainty concerning the individual exposure of miners, those drawn from experiments are indisputable because in this case the dose is as perfectly known as the effect. In addition, the effects of radon can experimentally be appreciated separately whereas in the surveys, they cannot be dissociated from the effects of the other pollutants in the mine. Finally, there are no other means of dealing with the mechanisms of cancer induction. In order to gain any useful knowledge from this method however, the experimental model must necessarily present certain methodological guarantees and the effects seen in the animals must enable a comparison with those which appear in man. For this reason we will present here the animal model we have been using for 15 years, and will give the results obtained and compare them with human data and made a synthesis. Finally the conclusions which can be drawn will be discussed as well as their limitations with respect to the protection of uranium miners. I - MATERIAL AND METHODS Male SPF Sprague-Dawley rats were used. At the onset of the inhalations they were around 3 months old. Their small size makes it possible to expose a large number of animals at the same time. Their life-span is long enough to be able to follow the evolution of the cancers and to estimate the latency time. Finally, they present the advantage of having a very low rate of spontaneous lung cancers (SANDERS, 1979). I.1 - Three inhalation techniques were used. 1.1.1. – [Inhalation of radon decay products.] The inhalation apparatus has been described previously (CHAMEAUD et al. 1971). The first experiments utilized a room of a half cubic meter linked to a source made up of high grade uranium ore. Later on, a large installation was built with a 10 m3 inhalation chamber making it possible to expose up to 500 rats at one time at radon concentrations ranging from 100 to 10 000 WL for variable lengths of time (1 to 10 hours per day). These concentrations are higher than those to which the miners are generally exposed, but in order for the cumulated doses in man and in animal to be similar and delivered for the same fraction of their respective life-spans, the ratio of the concentrations should be approximately that of the life-spans. The concentrations of radon and its daughters during the experiments were carefully controlled thanks to multiple samplings of radon gas associated with measurements of radon decay products. I.1.2 – [ The dust inhalation chamber] has already been described : it is a dust-loading chamber where the dust content remains constant during the experiment and can hold over 20 - 30 animals (PERRAUD et al, 1970). I.1.3 – [Tobacco inhalations] take place in a smoke box