Uncertainties in Biologically‐Based Modeling of Formaldehyde‐Induced Respiratory Cancer Risk: Identification of Key Issues

Abstract

In a series of articles and a health-risk assessment report, scientists at the CIIT Hamner Institutes developed a model (CIIT model) for estimating respiratory cancer risk due to inhaled formaldehyde within a conceptual framework incorporating extensive mechanistic information and advanced computational methods at the toxicokinetic and toxicodynamic levels. Several regulatory bodies have utilized predictions from this model; on the other hand, upon detailed evaluation the California EPA has decided against doing so. In this article, we study the CIIT model to identify key biological and statistical uncertainties that need careful evaluation if such two-stage clonal expansion models are to be used for extrapolation of cancer risk from animal bioassays to human exposure. Broadly, these issues pertain to the use and interpretation of experimental labeling index and tumor data, the evaluation and biological interpretation of estimated parameters, and uncertainties in model specification, in particular that of initiated cells. We also identify key uncertainties in the scale-up of the CIIT model to humans, focusing on assumptions underlying model parameters for cell replication rates and formaldehyde-induced mutation. We discuss uncertainties in identifying parameter values in the model used to estimate and extrapolate DNA protein cross-link levels. The authors of the CIIT modeling endeavor characterized their human risk estimates as "conservative in the face of modeling uncertainties." The uncertainties discussed in this article indicate that such a claim is premature.

Sensitivity Analysis of Biologically Motivated Model for Formaldehyde-Induced Respiratory Cancer in Humans

“…As shown in Fig. 6 and discussed further in Subramaniam et al (2008, Fig. 3), these data show roughly an order of magnitude variation in the cell replication rate at a given flux.…”

“…In the Conolly et al modeling, it is further assumed that the formaldehyde flux levels at which cell replication exceeds baseline rates remains essentially unchanged for initiated cells not only for the rodent but also when extrapolated to the human. These assumptions need to be viewed in the context of the uncertainty and variability in the data discussed further in Subramaniam et al (2008). In addition, it may be noted that there are some limited data indicating that exposure to formaldehyde can result in increased cell replication at doses far below those that are considered to be cytotoxic.…”

Proteasome activity is important for replication recovery, CHK1 phosphorylation and prevention of G2 arrest after low-dose formaldehyde

“…DPC are considered to be the main genotoxic lesions for FA and are used in human risk assessment modeling of FA exposures (Subramaniam et al, 2008). Thus, it is important to understand how human cells can cope with FA-induced DPC.…”

“…The most abundant DNA lesions formed by FA in cells are DNA-protein crosslinks (DPC), which have a much greater chemical stability than small DNA adducts (Quievryn and Zhitkovich, 2000). The dose-dependence of DPC formation and nasal cancers in FA-exposed animals showed a close correlation, leading to the use of DPC in modeling of cancer risks associated with human exposures (Subramaniam et al, 2008). Although it is frequently assumed that DPC are major contributors to FA toxicity, their role in specific toxic responses has not yet been assessed experimentally.…”

Ecological and Human Health Risk Assessment

“…Evaluation of biological and statistical uncertainties issues were determined to be necessary by Subramaniam et al (2008) Research was done on laypeople's view of results from a risk assessment study of hazards involved from cell phones and base stations. Siegrist et al (2008) showed how participants in the study were more confident with the outcome when the study indicated a risk and when their prior opinion was proved to be correct.…”