Analysis of the Sensitivity and Uncertainty in 2-Stage Clonal Growth Models for Formaldehyde with Relevance to Other Biologically-Based Dose Response (BBDR) Models
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.
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.
|1999||The Chemical Industry Institute of Toxicology (CIIT; now called The Hamner Institutes for Health Sciences) published a Health Risk Assessment Report on Formaldehyde.|
|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.|
|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. http://www.epa.gov/ttn/atw/nata1999/99pdfs/healtheffectsinfo.pdf; http://www.epa.gov/ttn/atw/plypart/fr16fe06.pdf.|
|2007-2008||Publications examining uncertainties in the CIIT modeling results appear in the two peer-reviewed journals, Risk Analysis and Annals of Occupational Hygiene.|