Biomathematics Seminar
Tuesday 3/13/07

Speaker:Rory B. Conolly
National Center for Computational Toxicology, Office of Research and Development
U.S. EPA., Research Triangle Park, NC 27711, USA


Title: The different roles of cytolethality and DNA reactivity in the carcinogenicity of 
formaldehyde:  Implications for risk assessment.  


Abstract:

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma 
(SCC) in F344 rats.  Here I describe an analysis of the rat tumor dose-response and its scale-up 
to predict human cancer risk.  The analysis assumed that both direct DNA reactivity and 
cytolethality of formaldehyde contribute to SCC development.  The key elements of analysis are: 
(1) use of a three-dimensional computer reconstruction of the rat nasal passages and 
computational fluid dynamics (CFD) modeling to predict the regional nasal dosimetry of 
formaldehyde; (2) association of the flux of formaldehyde into the nasal mucosa, as predicted by 
the CFD model, with formation of DNA-protein cross-links (DPX) and with 
cytolethality/regenerative cellular proliferation (CRCP) and (3) use of a two-stage clonal growth 
model to link DPX and CRCP with tumor formation.  With this structure, the prediction of the 
tumor dose-response is extremely sensitive to cell kinetics.  The raw dose-response data for 
CRCP are J-shaped and use of these data led to a predicted J-shaped dose-response for tumors, 
notwithstanding a concurrent low-dose linear, directly mutagenic effect of formaldehyde 
mediated by DPX.  For extension of this work to humans, regional dosimetry predictions for the 
entire respiratory tract were obtained by merging a three-dimensional CFD model of the human 
nose with a one-dimensional typical path model for the lower respiratory tract.  In other respects, 
the human model was structurally identical to the rat model.  The predicted human dose-response 
for DPX was obtained by scale-up of a computational model for DPX calibrated against rat and 
rhesus monkey data.  The rat dose-response for CRCP was used "as is" for the human model 
since no preferable alternative was identified.  Maximum likelihood estimates (MLE) of 
additional risks of respiratory tract cancer were predicted to be negative up to about one ppm 
when the raw CRCP data from the rat were used.  When a hockey stick-shaped model was fit to 
the rat CRCP data and used in place of the raw data, positive though de minimus MLE of 
additional risk were obtained for relevant exposure concentrations.  This analysis thus indicates 
that little or no cancer risk due to formaldehyde inhalation is expected for environmentally-
relevant exposure levels that are below the level eliciting cytolethal effects.  This work was 
reviewed by the U.S. EPA and approved for publication but does not necessarily reflect Agency 
policy

References:

Conolly, R.B., Kimbell, J.S., Janszen, D., Schlosser, P.M., Kalisak, D., Preston, J., and Miller, 
F.J. (2003).  Biologically motivated computational modeling of formaldehyde carcinogenicity in 
the F344 rat. Toxicol. Sci. 75:432-447.

Conolly, R.B., Kimbell, J.S., Janszen, D.J., Schlosser, P.M., Kalisak, D., Preston, J., and Miller, 
F.J. (2004). Human respiratory tract cancer risks of inhaled formaldehyde: Dose-response 
predictions derived from biologically-motivated computational modeling of a combined rodent 
and human dataset. Toxicol. Sci. 82:279-296.