Human respiratory tract cancer risks of inhaled formaldehyde: Dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) analyzed the rat tumor dose-response assuming that both DNA-reactive and cytotoxic effects of formaldehyde contribute to SCC development. The key elements of their approach were: (1) use of a three-dimensional computer reconstruction of the rat nasal passages and computational fluid dynamics (CFD) modeling to predict regional 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 was 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. In the present work the modeling approach used by Conolly et al. (ibid.) was extended to humans. Regional dosimetry predictions for the entire respiratory tract were obtained by merging a three-dimensional CFD model for 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. Three sets of baseline parameter values for the human clonal growth model were obtained through separate calibrations against respiratory tract cancer incidence data for nonsmokers, smokers, and a mixed population of nonsmokers and smokers, respectively. Additional risks of respiratory tract cancer were predicted to be negative up to about one ppm for all three cases 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 maximum likelihood estimates (MLE) of additional risk were obtained. These MLE estimates were lower, for some comparisons by as much as 1,000-fold, than MLE estimates from previous cancer dose-response assessments for formaldehyde. Breathing rate variations associated with different physical activity levels did not make large changes in predicted additional risks. In summary, this analysis of the human implications of the rat SCC data indicates that (1) cancer risks associated with inhaled formaldehyde are de minimis (10(-6) or less) at relevant human exposure levels, and (2) protection from the noncancer effects of formaldehyde should be sufficient to protect from its potential carcinogenic effects.