Does exposure occur at a reasonable interval before the development of the symptoms or disease of interest? The amount of time between exposure and onset of disease should comply with the underlying biological concept of the disease at hand. For tobacco-induced lung cancer, the latency between exposure and disease often is 25 years or more, although a few cases occur within 10 years of first exposure (Doll and Peto, 1978). Theoretically, higher doses shorten latency. For diseases of shorter latency, periods of hours of acute exposure can be involved. In general, the period of observation should be consistent with the hypothesized relationship, taking into account that variable latencies may be involved. With diseases of long latency, accurate recall or reconstruction of exposures remains a serious problem.

For studies of hazardous-waste sites, the temporality requirements of inferring causation could prove difficult to pin down, given the mobility and the diversity of the study population and the lack of models of many chronic diseases in the human populations. Despite this, studies of diseases with short latencies can sometimes provide useful information. For example, Vianna and Polan (1984) reported that the peak in low birth weight in children born to women who were residents of Love Canal, New York, occurred during the time of greatest estimated exposure to contaminants at that site.

Biologic Gradient or Relationship Between Estimated Exposure and Disease

In general, the greater the exposure, the stronger the effect. The relationship between dose (either estimated or measured) and response should be logical and uniform. The risk of contracting lung cancer increases with the number of cigarettes smoked. Although dose usually equals the concentration integrated over time, there are some important exceptions in which dosing patterns can be more important than overall dose. For instance, early and high exposure to alkylating agents, such as ethylene oxide, could produce a greater response than continual low exposure to the same quantity over a long period of time (Vesselinovitch, 1969).

Also, timing of exposure and host condition can be critical. Exposures to toxic chemicals in infancy and childhood or exposures of persons who are already compromised by some pre-existing chronic disease can produce a stronger effect than that found in healthy adults. It is well known that exposures to some toxic agents during the first trimester of pregnancy are critical for many teratologic and reproductive effects. Thus, there can be long-term and permanent effects

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