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Uncertainties in the CIIT Model for Formaldehyde‐Induced Carcinogenicity in the Rat: A Limited Sensitivity Analysis–I

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  • Ravi P. Subramaniam
  • Kenny S. Crump
  • Cynthia Van Landingham
  • Paul White
  • Chao Chen
  • Paul M. Schlosser

Abstract

Scientists at the CIIT Centers for Health Research (Conolly et al., 2000, 2003; Kimbell et al., 2001a, 2001b) developed a two‐stage clonal expansion model of formaldehyde‐induced nasal cancers in the F344 rat that made extensive use of mechanistic information. An inference of their modeling approach was that formaldehyde‐induced tumorigenicity could be optimally explained without the role of formaldehyde's mutagenic action. In this article, we examine the strength of this result and modify select features to examine the sensitivity of the predicted dose response to select assumptions. We implement solutions to the two‐stage cancer model that are valid for nonhomogeneous models (i.e., models with time‐dependent parameters), thus accounting for time dependence in variables. In this reimplementation, we examine the sensitivity of model predictions to pooling historical and concurrent control data, and to lumping sacrificed animals in which tumors were discovered incidentally with those in which death was caused by the tumors. We found the CIIT model results were not significantly altered with the nonhomogeneous solutions. Dose‐response predictions below the range of exposures where tumors occurred in the bioassays were highly sensitive to the choice of control data. In the range of exposures where tumors were observed, the model attributed up to 74% of the added tumor probability to formaldehyde's mutagenic action when our reanalysis restricted the use of the National Toxicology Program (NTP) historical control data to only those obtained from inhalation exposures. Model results were insensitive to hourly or daily temporal variations in DNA protein cross‐link (DPX) concentration, a surrogate for the dose‐metric linked to formaldehyde‐induced mutations, prompting us to utilize weekly averages for this quantity. Various other biological and mathematical uncertainties in the model have been retained unmodified in this analysis. These include model specification of initiated cell division and death rates, and uncertainty and variability in the dose response for cell replication rates, issues that will be considered in a future paper.

Suggested Citation

  • Ravi P. Subramaniam & Kenny S. Crump & Cynthia Van Landingham & Paul White & Chao Chen & Paul M. Schlosser, 2007. "Uncertainties in the CIIT Model for Formaldehyde‐Induced Carcinogenicity in the Rat: A Limited Sensitivity Analysis–I," Risk Analysis, John Wiley & Sons, vol. 27(5), pages 1237-1254, October.
  • Handle: RePEc:wly:riskan:v:27:y:2007:i:5:p:1237-1254
    DOI: 10.1111/j.1539-6924.2007.00968.x
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    References listed on IDEAS

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    1. Kenny S. Crump & Ravi P. Subramaniam & Cynthia B. Van Landingham, 2006. "Acknowledgment of Prior Solution to MVK Cancer Model," Risk Analysis, John Wiley & Sons, vol. 26(1), pages 3-4, February.
    2. Rudolf T. Hoogenveen & Harvey J. Clewell & Melvin E. Andemen & Wout Slob, 1999. "An Alternative Exact Solution of the Two‐Stage Clonal Growth Model of Cancer," Risk Analysis, John Wiley & Sons, vol. 19(1), pages 9-14, February.
    3. Peddada, Shyamal D. & Dinse, Gregg E. & Kissling, Grace E., 2007. "Incorporating Historical Control Data When Comparing Tumor Incidence Rates," Journal of the American Statistical Association, American Statistical Association, vol. 102, pages 1212-1220, December.
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    Cited by:

    1. Ravi P. Subramaniam & Chao Chen & Kenny S. Crump & Danielle DeVoney & John F. Fox & Christopher J. Portier & Paul M. Schlosser & Chad M. Thompson & Paul White, 2008. "Uncertainties in Biologically‐Based Modeling of Formaldehyde‐Induced Respiratory Cancer Risk: Identification of Key Issues," Risk Analysis, John Wiley & Sons, vol. 28(4), pages 907-923, August.

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