An updated analysis of respiratory tract cells at risk for formaldehyde carcinogenesis

Abstract

Study of the mode of action (MOA) relating exposure to a given chemical with an associated adverse outcome is an iterative process with each iteration driven by new understandings of the relevant biology. Here, we revisit a previously described, MOA-based clonal growth model of the human respiratory tract cancer risk associated with formaldehyde inhalation. Changes reflect a better understanding of populations of cells at risk of carcinogenic transformation in the pharynx, larynx and respiratory bronchiolar portions of the human respiratory tract and inclusion of basal cells in the pool of cells at risk. The focus of this report is not on cancer risk per se, but rather on the sensitivity of model parameters and predicted risks to alternative descriptions of the fraction of cells at risk for carcinogenic transformation. For a population of formaldehyde-exposed nonsmokers, revised specification of cells at risk resulted in changes in both parameter estimates and in predicted risks. Compared to our previous assessment, predicted additional risks were up to 87% greater at exposure levels ≤1 ppm, but up to about 130% lower at high exposure levels (2–5 ppm). While this work should not be considered an update to MOA-based risk assessments for formaldehyde described previously, it illustrates the sensitivity of parameter estimates and risk predictions to the quantitative specification of cells at risk of carcinogenic transformation and, therefore, the motivation for describing the relevant biology as accurately as possible.

Keywords:

• Formaldehyde carcinogenesis
• humans
• dosimetry
• progenitor cells

Acknowledgments

The authors wish to acknowledge Dr. James Crapo and Dr. Jack Harkema for helpful discussions on some of the topics covered in this article.

Disclosure statement

Rory Conolly is an employee of the U.S. EPA (EPA). However, his contribution to the work described in this manuscript was not conducted as part of his official duties as an EPA employee. Rather, Dr. Conolly’s work on this manuscript was conducted as an “Outside Activity” that was formally approved by his EPA management. Thus, this work does not represent official policies or positions of the EPA. No potential conflict of interest was reported by the authors.