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 it is therefore unlikely that they would experience such high levels of exposure.

Understanding the mechanism by which an exposure causes a health effect adds credence to a causal association. The mechanisms involved in the irritative symptoms of the eyes, skin, and upper respiratory tract associated with CCP exposure have not been established. In fact, it is unclear which of the CCP components might be responsible for these symptoms, although (as mentioned above) chemicals in some types of CCP are known irritants. Few studies have included ordinary bond paper as a control for mechanical abrasion from handling paper or for exposure to chemicals (such as formaldehyde) that are contained in ordinary paper. However, in the few studies that compared CCP with ordinary bond, the irritative effects were clearly greater for CCP (i.e., Nilzen [1975], Norbäck et al. [1983b], Morgan and Camp [1988], and Koenig [1988]). An understanding of the mechanism should not be required for inferring causality. As Hill [1977] suggested, "What is biologically plausible depends upon the biological knowledge of the day." In numerous examples, causal associations have been identified well before the underlying biological mechanisms were understood (e.g., smoking and lung cancer). Overall, reasonably supportive evidence exists for the biological plausibility of the association between CCP exposure and the irritative symptoms of the eyes, skin, and upper respiratory tract observed in the epidemiologic studies.

Coherence requires that the observed association not conflict with what is known about the natural history and biology of the disease. The distinction between this criterion and biological plausibility is a fine one. An example given by Hill [1977] is that the association between lung cancer and smoking is coherent with the temporal rise that has taken place in both variables over the last century. The reports in the literature of an association between exposure to CCP and irritative symptoms of the eyes, skin, and upper respiratory tract are not in conflict with current knowlege of the biology of these health effects. One apparently contradictory fact is that health-related inquiries to CCP manufacturers have reportedly decreased from 1987 to 1996, dropping from approximately 130 to 50 inquiries per year [letter to the NIOSH docket from Robert Tardiff, October 6, 1998]. This decrease has occurred despite increases in the production of CCP from approximately 85,000 to 100,000 tons/year over the same period. However, increases in production would not necessarily lead to increased exposures in offices and other situations where CCP is used.

Thus it is unclear whether the number of people exposed and the level of exposure have dropped or increased during this period. Changes in the formulation of CCP during this period could also explain the decrease in complaints. Therefore, the coherence criterion contributes little to determining causality for the irritative symptoms of the eyes, skin, and upper respiratory tract associated with CCP exposure.

Experiments can provide the strongest evidence for causality, but such information is rarely available for toxic effects in workers. In the case of CCP, a few experimental studies in humans have demonstrated irritative symptoms and signs with exposure to some types or components of CCP. Nilzen [1975] reported weak to moderate signs of skin irritation among atopic persons exposed to CCP with skin-prick testing, but the same reactions were observed with exposure to