US EPA

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.

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.

Research completed, this is the final report.

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.