Annals of Occupational Hygiene Advance Access originally published online on July 14, 2008
Annals of Occupational Hygiene 2008 52(6):481-495; doi:10.1093/annhyg/men038
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Sensitivity Analysis of Biologically Motivated Model for Formaldehyde-Induced Respiratory Cancer in Humans
1 ENVIRON International Corporation, 1900 North, 18th Street, Suite 804, Monroe, LA 71201, USA
2 National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Mail Code 8623D, 1200 Pennsylvania Avenue, NW, Washington, DC 20460, USA
* Author to whom correspondence should be addressed. Tel: +318-257-4051; fax: +318-257-3182; e-mail: kennycrump{at}email.com
Conolly et al. (2003, 2004) developed biologically motivated models of formaldehyde carcinogenicity in F344 rats and humans based on a two-stage clonal expansion model of cancer. Based on the human model, Conolly et al. (2004) claimed that cancer risks associated with inhaled formaldehyde are deminimis at relevant human exposure levels. However, they did not conduct a sensitivity analysis to evaluate the robustness of this conclusion. Here, we present a limited sensitivity analysis of the formaldehyde human model. We show that when the control animals from the National Toxicology Program (NTP) studies are replaced with control animals only from NTP inhalation studies, estimates of human risk are increased by 50-fold. When only concurrent control rats are used, the model does not provide any upper bound (UB) to human risk. No data went into the model on the effect of formaldehyde on the division rates and death rates of initiated cells. We show that slight numerical perturbations to the Conolly et al. assumptions regarding these rates can be made that are equally consistent with the underlying data used to construct the model, but produce estimates of human risk ranging anywhere from negative up to 10 000 times higher than those deemed by Conolly et al. to be ‘conservative’. Thus, we conclude that estimates of human risk by Conolly et al. (2004) are extremely sensitive to modeling assumptions. This calls into question the basis for the Conolly et al. claim of de minimis human risk and suggests caution in using the model to derive human exposure standards for formaldehyde.
Keywords: formaldehyde • nasal cancer • quantitative risk assessment • respiratory cancer • sensitivity analysis • two-stage clonal expansion model
3 Present address: Department of Mathematics and Statistics, Louisiana Tech University, Railroad Avenue, George T. Madison Hall, Room 330, PO Box 10348, Ruston, LA 71272-0046, USA.
The original version was incorrect. A few errors had not been corrected.
Received April 2, 2008; in final form May 30, 2008
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