ToxSci Advance Access originally published online on July 11, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Toxicological Sciences 75, 432-447 (2003)
Copyright © 2003 by the Society of Toxicology
RISK ASSESSMENT |
Biologically Motivated Computational Modeling of Formaldehyde Carcinogenicity in the F344 Rat
CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709
ABSTRACT
Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The human health implications of this effect are of significant interest since human exposure to environmental formaldehyde is widespread, though at lower concentrations than those that cause cancer in rats. In this article, which is part of a larger effort to predict the human cancer risks of inhaled formaldehyde, we describe biologically motivated quantitative modeling of the exposure-tumor response continuum in the rat. An anatomically realistic, three-dimensional fluid dynamics model of the F344 rat nasal airways was used to predict site-specific flux of formaldehyde from inhaled air into tissue, since both SCC and preneoplastic lesions develop in a characteristic site-specific pattern. Flux into tissue was used as a dose metric for two modes of action, direct mutagenicity and cytolethality-regenerative cellular proliferation (CRCP), which in turn were linked to key parameters of a two-stage clonal growth model. The direct mutagenicity mode of action was represented by a low dose linear dose-response model of DNA-protein cross-link (DPX) formation. An empirical J-shaped dose-response model and a threshold model fit to the empirical data were used for CRCP. In the clonal growth model, the probability of mutation per cell generation was a function of the tissue concentration of DPX while the rate of cell division was calculated from the CRCP data. Maximum likelihood methods were used to estimate parameter values. Survivor (a nontumor outcome) and tumor data for controls from the National Toxicology Program database and from two formaldehyde inhalation bioassays were used for likelihood calculations. The J-shaped dose-response for CRCP provided a better description of the SCC data than did the threshold model. Sensitivity analyses indicated that the rodent tumor response is due to the CRCP mode of action, with the directly mutagenic pathway having little, if any, influence. When evaluated in light of modeling and database uncertainties, particularly the specification of the clonal growth model and the dose-response data for CRCP, this work provides suggestive though not definitive evidence for a J-shaped dose-response for formaldehyde-mediated nasal SCC in the F344 rat.
Key Words: formaldehyde; F344 rat; squamous cell carcinoma; dose-response; clonal growth; DNA-protein cross-links; regenerative cellular proliferation; computational modeling; risk assessment.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. B. Conolly, F. J. Miller, J. S. Kimbell, and D. Janszen Formaldehyde Risk Assessment Ann. Hyg., March 1, 2009; 53(2): 181 - 184. [Full Text] [PDF]
|
|
|
|
|
|
K. S. Crump, C. Chen, J. F. Fox, R. Subramaniam, and C. Van Landingham Reply Ann. Hyg., March 1, 2009; 53(2): 184 - 189. [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Andersen, H. J. Clewell III, E. Bermudez, G. A. Willson, and R. S. Thomas Genomic Signatures and Dose-Dependent Transitions in Nasal Epithelial Responses to Inhaled Formaldehyde in the Rat Toxicol. Sci., October 1, 2008; 105(2): 368 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Daston Gene Expression, Dose-Response, and Phenotypic Anchoring: Applications for Toxicogenomics in Risk Assessment Toxicol. Sci., October 1, 2008; 105(2): 233 - 234. [Full Text] [PDF]
|
|
|
|
|
|
K. S. Crump, C. Chen, J. F. Fox, C. Van Landingham, and R. Subramaniam Sensitivity Analysis of Biologically Motivated Model for Formaldehyde-Induced Respiratory Cancer in Humans Ann. Hyg., August 1, 2008; 52(6): 481 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Thomas, B. C. Allen, A. Nong, L. Yang, E. Bermudez, H. J. Clewell III, and M. E. Andersen A Method to Integrate Benchmark Dose Estimates with Genomic Data to Assess the Functional Effects of Chemical Exposure Toxicol. Sci., July 1, 2007; 98(1): 240 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Harkema, S. A. Carey, and J. G. Wagner The Nose Revisited: A Brief Review of the Comparative Structure, Function, and Toxicologic Pathology of the Nasal Epithelium Toxicol Pathol, April 1, 2006; 34(3): 252 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Kimbell Nasal Dosimetry of Inhaled Gases and Particles: Where Do Inhaled Agents Go in the Nose? Toxicol Pathol, April 1, 2006; 34(3): 270 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Hester, W. T. Barry, F. Zou, and D. C. Wolf Transcriptomic Analysis of F344 Rat Nasal Epithelium Suggests That the Lack of Carcinogenic Response to Glutaraldehyde is Due to its Greater Toxicity Compared to Formaldehyde Toxicol Pathol, June 1, 2005; 33(4): 415 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Meek Biologically Motivated Computational Modeling: Contribution to Risk Assessment Toxicol. Sci., November 1, 2004; 82(1): 1 - 2. [Full Text] [PDF]
|
|
|
|
|
|
R. B. Conolly, J. S. Kimbell, D. Janszen, P. M. Schlosser, D. Kalisak, J. Preston, and F. J. Miller 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., November 1, 2004; 82(1): 279 - 296. [Abstract] [Full Text] [PDF]
|
|