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 to an irritant and thus should probably be viewed as a single effect and consistent with the specificity criterion.

Temporality requires that the exposure precede the disease and that the effects follow a course in time that is physiologically plausible in relation to the exposure. In the epidemiologic studies, it can be reasonably assumed that the CCP exposures preceded the observed symptoms or signs. Furthermore, several of the case reports describe symptoms or signs of disease that subsided or disappeared after the subject left work or after the CCP exposure was removed. Thus these human studies meet the temporality criterion for the irritative symptoms of the eyes, skin, and upper respiratory tract associated with CCP exposure.

Biological gradient refers to evidence for a dose-response (or exposure-response) relationship. A dose-response relationship is viewed by most epidemiologists to be strong evidence for causality. A dose-response relationship is less likely to be explained by reporting bias or confounding than is an overall measure of association (i.e., a yes/no exposure). However, it is possible that such a dose-response relationship could be produced by confounding.

A positive dose-response relationship between the frequency of handling CCP and the prevalence of irritative symptoms of the eyes, skin, and upper respiratory tract was reported in the nine studies that examined this relationship (Table 5–1). Recall bias might explain these relationships in some studies. However, it is unlikely to explain the relationships observed in the study by Skov et al. [1989], which was one of the indoor air quality studies that was not conducted at a building with previous complaints related to CCP. Overall, these studies demonstrate a biological gradient by providing consistent evidence for an exposure-response relationship for irritative symptoms of the eyes, skin, and upper respiratory tract associated with exposure to CCP.

Biological plausibility exists when an association is consistent with what is known about the biology of the disease. The biological plausibility of the symptoms associated with CCP exposure is supported by the presence of several well-known irritants in some formulations of CCP (e.g., formaldehyde, isocyanates, phthalates, acrylates, glutaraldehyde, amines, and kerosene). For example, in seven studies of CCP and formaldehyde, nearly all exposure measurements exceeded the NIOSH REL (but not the OSHA PEL) for formaldehyde [Chrostek and Moshell 1982; Gockel et al. 1981; Hazelton Laboratories 1985; Apol and Thoburn 1986; Chovil et al. 1986; Omland et al. 1993; Zimmer and Hadwen 1993]. The biological plausibility of the irritative effects is further supported by the similar effects observed in animal studies. Irritation of the skin or respiratory tract has been demonstrated in several studies of animals exposed to CCP or its components (e.g., see Certin and Zissu [1983]; Wolkoff et al. [1988]; Anderson [1992]). Irritation of the skin was reported in a number of the industry-sponsored toxicologic studies reported to the NIOSH docket, although these reactions did not indicate primary skin irritation according to the regulatory criteria established by FDA. In addition, the positive reactions observed in these studies were generally due to exposures to CCP components in liquid form. Users of CCP are not exposed to these substances in liquid form, and