Analysis of the Sensitivity and Uncertainty in 2-Stage Clonal Growth Models for Formaldehyde with Relevance to Other Biologically-Based Dose Response (BBDR) Models

Abstract

The National Center for Environmental Assessment (NCEA) has conducted and supported research addressing uncertainties in 2-stage clonal growth models for cancer as applied to formaldehyde. In this report, we summarized publications resulting from this research effort, discussed the significance of this work for other biologically-based dose response (BBDR) applications, and provided journal reprints of two of these publications and a Web link to the scientific journal containing the third publication.
As knowledge of the biology of cancer has evolved, researchers have sought to apply biologically motivated models to estimate risks from exposures to carcinogens. In particular, clonal growth models have been fruitful in generating hypotheses, leading to a better understanding of the biology and the implications for human health risk. Clonal growth models have generally not been used in formal chemical risk assessment to predict risk at human exposures from animal toxicological data. However, in a notable exception, scientists have applied a two-stage clonal growth model, referred to in the literature as the CIIT model, for estimating respiratory cancer risk due to inhaled formaldehyde. The conceptual framework of this effort, incorporating substantial mechanistic information at both the toxicokinetic and toxicodynamic levels, combined with advances in computational resources, has made it possible for NCEA to carry out extensive uncertainty analyses on the results obtained with this model.

The publications resulting from the NCEA research indicate that when two-stage modeling assumptions are varied, resulting dose-response estimates can vary by several orders of magnitude. These findings are not supportive of interpreting the CIIT model results as providing a conservative (health protective) estimate on human risk. NCEA research also examined the contribution of the two-stage modeling for formaldehyde towards characterizing the relative weights of key events in the mode-of-action of a carcinogen. For example, the model-based inference in the published CIIT study that formaldehyde’s direct mutagenic action is not relevant to the compound’s tumorigenicity was found not to hold under variations of modeling assumptions.

The analyses presented here emphasize that uncertainty and sensitivity analyses are essential tools when evaluating inferences about fundamental biological processes (e.g., modes of action) that may be drawn from a BBDR model. The approaches used and conclusions drawn in this report also provide insights for investigators looking towards future applications of BBDR models in risk assessment.

Impact/Purpose

In this report, we summarize publications resulting from this research effort, discuss the significance of this work for other biologically-based dose response (BBDR) applications, and provide journal reprints of two of these publications and a Web link to the scientific journal containing the third publication.

Status

Research completed, this is the final report.

Citation

U.S. EPA. Analysis of the Sensitivity and Uncertainty in 2-Stage Clonal Growth Models for Formaldehyde with Relevance to Other Biologically-Based Dose Response (BBDR) Models. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/R-08/103, 2008.

Date	Description
02- 1999	The Chemical Industry Institute of Toxicology (CIIT; now called The Hamner Institutes for Health Sciences) published a Health Risk Assessment Report on Formaldehyde.
03- 2000-2004	Several articles by Drs. Conolly, Kimbell, Overton, Schlosser and co-workers are published in the peer-reviewed literature. These papers detail the dosimetry and clonal growth models utilized in the above CIIT 1999 report for estimating dose-response and cancer risk due to inhaled formaldehyde.
04- 2005-2006	U.S. EPA uses the CIIT modeling results in risk assessment and rule making - represents early example of use of BBDR modeling for decision making needs.
05- 2007-2008	Publications examining uncertainties in the CIIT modeling results appear in the two peer-reviewed journals, Risk Analysis and Annals of Occupational Hygiene.

This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

• Analysis of the Sensitivity and Uncertainty in 2-stage Clonal Growth Models for Formaldehyde with Relevance to Other Biologically Based Dose Response (BBDR) Models (PDF)  (9  pp, 45.9 KB, about PDF)
• Subramaniam, R; Chen, C; Crump, K; .et .al. (2008) Uncertainties in biologically-based modeling of formaldehyde-induced cancer risk: identification of key issues. Risk Anal 28(4):907-923. (PDF)  (17  pp, 405.3 KB, about PDF)
• Subramaniam, R; Chen, C; Crump, K; .et .al. (2007) Uncertainties in the CIIT 2-stage model for formaldehyde-induced nasal cancer in the F344 rat: a limited sensitivity analysis-I. Risk Anal 27:1237 (PDF)  (18  pp, 438.5 KB, about PDF)

Related Link(s)

• Crump, K; Chen, C; Fox, J; .et .al. (2008) Sensitivity analysis of biologically motivated model for formaldehyde-induced respiratory cancer in humans. Ann Occup Hyg 52:481-495.
• Conolly RB, Miller FJ, Kimbell JS, Janszen D 2009. Formaldehyde risk assessment. Ann Occup Hyg 53: 181–184.
• Crump, KS; Chen, C; Fox, JF; et al. (2009) Reply to Conolly et al. (2009) Ann Occup Hyg 53:184–189.