Methods for assessing uncertainty in fundamental assumptions and associated models for cancer risk assessment.
The distributional approach for uncertainty analysis in cancer risk assessment is reviewed and extended. The method considers a combination of bioassay study results, targeted experiments, and expert judgment regarding biological mechanisms to predict a probability distribution for uncertain cancer risks. Probabilities are assigned to alternative model components, including the determination of human carcinogenicity, mode of action, the dosimetry measure for exposure, the mathematical form of the dose-response relationship, the experimental data set(s) used to fit the relationship, and the formula used for interspecies extrapolation. Alternative software platforms for implementing the method are considered, including Bayesian belief networks (BBNs) that facilitate assignment of prior probabilities, specification of relationships among model components, and identification of all output nodes on the probability tree. The method is demonstrated using the application of Evans, Sielken, and co-workers for predicting cancer risk from formaldehyde inhalation exposure. Uncertainty distributions are derived for maximum likelihood estimate (MLE) and 95th percentile upper confidence limit (UCL) unit cancer risk estimates, and the effects of resolving selected model uncertainties on these distributions are demonstrated, considering both perfect and partial information for these model components. A method for synthesizing the results of multiple mechanistic studies is introduced, considering the assessed sensitivities and selectivities of the studies for their targeted effects. A highly simplified example is presented illustrating assessment of genotoxicity based on studies of DNA damage response caused by naphthalene and its metabolites. The approach can provide a formal mechanism for synthesizing multiple sources of information using a transparent and replicable weight-of-evidence procedure.
Civil & Environmental Engineering and Engineering & Public Policy, Carnegie Mellon University, Pittsburgh, PA 15213, USA. ms35@andrew.cmu.edu
Mitchell J
MJ
Small
D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D016013:Likelihood Functions; D008962:Models, Theoretical; D009281:Naphthalenes / Q000506:poisoning; D009369:Neoplasms / Q000209:etiology*; D018570:Risk Assessment / Q000379:methods; D035501:Uncertainty
D009281:Naphthalenes; D005557:Formaldehyde; C031721:naphthalene