Dose-rate effects on lung cancers induced by exposure to radon progeny in rats

Epidemiological studies in uranium miners and other underground miners showed an association between an excess risk of lung cancer and exposure to radon and its progeny, but the evidence of an excess risk of lung cancer from residential radon indoor exposure is less certain. Animal studies were used in addition to epidemiological studies to investigate the effects of exposure, exposure rate and other factors in predicting risks resulting from human exposures both in the home and in the workplace. The advantage of animal data is that animal experiments are generally conducted under well controlled conditions and that exposure and exposure rate can be estimated more accurately. Radon animal data, obtained primarily in adult rats, were provided mainly by the Pacific Northwest Laboratory (PNL) in USA and our group in France. Despite the fact that significant cumulative exposures at typical residential exposure rates of about 1.810-5 Jhm-3 per week, approximately 0.005 WLM per week, cannot be tested in a short-lived species like the rat, the rat model is valuable for reducing the uncertainties that exist in human data, particularly in regard to the exposure-rate effect. In PNL lifespan animal experiments, a trend towards increasing tumour risk with decreased exposure rate has been reported in Wistar rats exposed at 2.1 mJm-3 (100 WL) and 21 mJm-3 (1,000 WL) and cumulative exposures varying from 2.3 Jhm-3 (640 WLM) up to 18.4 Jhm-3 (5,120 WLM). A trend towards increasing tumour risk with decreased exposure rate was observed in our Sprague-Dawley rats exposed at cumulative exposure varying from about 0.72 Jhm-3 (200 WLM) up to 10.8 Jhm-3 (3,000 WLM) and high exposure rates varying from 0.09 Jhm-3 (25 WLM per week) to 1.8 Jm-3 (500 WLM per week). In contrast, the results obtained at low cumulative exposure, comparable to domestic indoor exposures showed no evidence of an inverse exposure-rate effect. Chronic radon exposure at 0.09 Jhm-3 (25 WLM), protracted over a 18 months period, at a potential alpha energy concentration (PAEC) of 0.042 mJm-3 (2 WL), resulted in fewer lung carcinoma in rats than a similar cumulative exposure protracted over 4 to 6 months at a PAEC of 2.1 mJm-3 (100 WL). Moreover, the lung cancer incidence in rats exposed at low exposure rate (0.60%) was slightly lower than that in control animals (0.63%). The results of a new series of experiments carried out to investigate the influence of exposure-rate on lung cancer induction in rats at relatively low cumulative exposures of 0.36 Jhm-3 (100 WLM), and PAEC varying from 0.22 mJm-3 (13 WL) to 3.15 mJm-3 (150 WL) indicate that at relatively low cumulative exposures comparable to lifetime exposures in high-radon houses or current underground mining exposures, the risk of lung cancer in rats decreases with decreasing PAEC, i.e., exposure rates. These data suggest that in terms of risk of induction of lung cancer, there is a complex interplay between cumulative exposure and exposure rate, resulting in an optimal exposure rate at a given exposure level. The significance of exposure rates in assessing the hazards of domestic radon exposure was addressed on biophysical grounds by Brenner, who concluded that, when cumulative exposures are sufficiently low that multiple traversals of target cells by alpha particles are rare - that is the case for typical domestic radon exposures -, all exposure-rate enhancement effects disappear. The results of recent experiments of the same group showed that traversal of cell nuclei by a single alpha particle induced significantly lower oncogenic transformation in the C3H10T1/2 mouse fibroblast system than does a Poisson-distributed mean of one alpha particle, suggesting that cells traversed by multiple alpha particles contribute most to the risk. In this respect, based on dose-rate effect considerations, extrapolation of lower exposure-rate miner data to residential exposures - where no target cell is traversed by more than a single alpha particle - may overestimate risks associated with typical residential expos ures and exposure rates. Our recent data in rats appear to follow the same trend and to support the hypothesis that, at low doses, the risk of lung cancer is governed by the rate at which the dose is delivered, and not by the total cumulative dose alone. (author)