AN APPROACH TO MECHANISM-BASED CANCER RISK ASSESSMENT FOR FORMALDEHYDE

The established carcinogenicity of formaldehyde in the rat and suggest ive epidemiological evidence that formaldehyde may be a human carcinog en have led to its regulation by U.S. Federal agencies as a probable h uman carcinogen. These risk assessments have typically been based on t umor data in F344 rats exposed chronically to formaldehyde by inhalati on and used the inhaled concentration as a measure of dose and the lin earized multistage model (LMS) for dose-response characterization. Low -dose risks estimated with the LMS are thought to be conservative but are also generally acknowledged to be highly uncertain. In this manusc ript, we first consider in generic terms how use of chemical-specific data on mechanisms of target tissue dosimetry and the series of tissue responses to the chemical that culminate in tumor formation can lead to more accurate dose-response characterization. A planned mechanism-b ased risk assessment for formaldehyde is then described. This risk ass essment uses data on target tissue dosimetry, size of the target cell population in the rat nasal epithelium, number and size of putative pr eneoplastic lesions, and tumor incidence. These data establish paramet er values for a biologically based, multistage cancer model that is th en used to predict cancer risk at low exposure levels. Such work provi des insights into the relative roles of formaldehyde-stimulated cell r eplication and procarcinogenic mutation in tumor formation. Finally, f uture directions are outlined for research on tissue dosimetry and sca ling of the mechanism-based formaldehyde risk model from rats to peopl e.