An approach to mechanism-based cancer risk assessment for formaldehyde.
The established carcinogenicity of formaldehyde in the rat and suggestive epidemiological evidence that formaldehyde may be a human carcinogen have led to its regulation by U.S. Federal agencies as a probable human carcinogen. These risk assessments have typically been based on tumor data in F344 rats exposed chronically to formaldehyde by inhalation and used the inhaled concentration as a measure of dose and the linearized 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 manuscript, 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-based risk assessment for formaldehyde is then described. This risk assessment uses data on target tissue dosimetry, size of the target cell population in the rat nasal epithelium, number and size of putative preneoplastic lesions, and tumor incidence. These data establish parameter values for a biologically based, multistage cancer model that is then used to predict cancer risk at low exposure levels. Such work provides insights into the relative roles of formaldehyde-stimulated cell replication and procarcinogenic mutation in tumor formation. Finally, future directions are outlined for research on tissue dosimetry and scaling of the mechanism-based formaldehyde risk model from rats to people.
Conolly
R B
RB
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Andersen
M E
ME
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000633:toxicity*; D006801:Humans; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D012307:Risk Factors
D005557:Formaldehyde