concentration within the cell exceeds a certain level, the toxic agent is unlikely to reach its intracellular target.29 Second, although the target is hit, recovery is likely to occur unless the toxic dose is high enough to saturate the cell’s recovery system.30 Third, if a cancer cell is produced, that cell must override the resisting host to produce a tumor. And fourth, the toxic substance may not always be toxic. Selenium, for example, becomes progressively more toxic and eventually lethal at levels of 5–10 ppm (and above) in the diet, but it is an essential element for the good health of many domestic animals at a minimum level of 0.1 ppm.31 Such factors will affect the shape of the dose-effect curve (the toxic effect of selenium has a threshold) and may complicate its interpretation, especially in the low-dose region.
In the case of man, the epidemiological study of smoking provides the major chemical example of the knowledge that can be gained when large numbers of exposed and cooperative individuals are available and when the level of exposure is relatively high.32 As with all exposures continuing over a period of years, assessment at one particular time (e.g., at the time of the study inquiry, as is often the case in pollution studies) may have little to do with health at that time or in the future. Thus, in the case of smoking, even after termination of the habit, significant though diminished increments in death rate occur 10 or more years afterward from chronic bronchitis and emphysema, and from pulmonary heart disease.33
A cancer dose-effect equation for cigarette smoking has been obtained using data drawn from a 20-yr prospective study of some 34,000 British physicians.34 The equation was based on the age-standardized incidence of bronchial carcinoma in those physicians who began smoking at 16–25 years of age and who had each reported the number of cigarettes smoked per day at a relatively constant rate (but not more than 40/day) from that age onward. No cancers were observed prior to 40 years of age. For the age range 40–79 years, the fitted equation for annual risk of bronchial cancer (per person) was the following.
Cancer therefore was a nonlinear function of exposure, and its incidence rate depended on intensity of exposure and years of exposure.
Other types of dose-effect curves induced by irritating particulates are seen in asbestosis, byssinosis, and silicosis.35
Adequate dose-effect curves are rarely available for the very low ranges of exposure that are now at issue in the regulatory process, especially when