Society For Risk Analysis Annual Meeting 2012

Advancing Analysis

Session Schedule & Abstracts


* Disclaimer: All presentations represent the views of the authors, and not the organizations that support their research. Please apply the standard disclaimer that any opinions, findings, and conclusions or recommendations in abstracts, posters, and presentations at the meeting are those of the authors and do not necessarily reflect the views of any other organization or agency. Meeting attendees and authors should be aware that this disclaimer is intended to apply to all abstracts contained in this document. Authors who wish to emphasize this disclaimer should do so in their presentation or poster. In an effort to make the abstracts as concise as possible and easy for meeting participants to read, the abstracts have been formatted such that they exclude references to papers, affiliations, and/or funding sources. Authors who wish to provide attendees with this information should do so in their presentation or poster.

Common abbreviations

M3-H
Low-Dose, MOH and Cancer Methods

Room: Pacific Concourse L   1:30 - 3 PM

Chair(s): Julie Fitzpatrick, Bette Meek



M3-H.1  13:30  Efficient Stress-Dependent Tumorigenesis: A New Cancer Theory and Implications for Chemical Carcinogen Risk Extrapolation . Bogen KT*; Exponent, Inc. - Health Sciences   kbogen@exponent.com

Abstract: The most efficient tumorigenic pathways are particularly important to understand, because they likely account for most spontaneous tumors observed in mammals, as well as for most exposure-induced tumors observed epidemiologically and in animal bioassay experiments. Since 1976, the multistage oncogene-mutation/clonal-expansion (MMC) theory of cancer has been the basis used by U.S. regulatory agencies for default, linear no-threshold (LNT) extrapolation of increased cancer risk posed by exposures to (at least genotoxic) chemical carcinogens. However, there are six other current contending theories of carcinogenesis: chronic oxidative stress (COS), chronic inflammation and its microenvironment (CIM), defective wound healing (DWH), aberrant DNA methylation (ADM), aneuploidy and consequent genomic instability (AGI), and microRNA dysregulation (MRD). All seven theories have overlapping attributes, empirical strengths, and empirical weaknesses, but only the MMC theory generally implies plausibility of LNT low-dose risk extrapolation for all genotoxic chemical carcinogens (as the AGI theory does for LNT aneuploidogens). The MRD theory provides a mechanistic basis to combine elements of all seven theories into a new theory of benign and malignant tumorigenesis. The new theory predicts that: (i) tumors arise most efficiently under stress conditions that induce and sustain either of two specific states of adaptive hyperplasia (AH), protective or regenerative; and (ii) if mutagenically dysregulated, these AH states may yield benign or malignant tumors, respectively. By this theory, most genotoxic chemical carcinogens are predicted to increase cancer risk with a profoundly nonlinear low-dose dose response.

M3-H.2  13:50  Using Model Averaging and SemiParametric methods in low dose extrapolations. . Wheeler MW*, Bailer AJ; National Institute for Occupational Safety and Health   mwheeler@cdc.gov

Abstract: Experiments with relatively high dose conditions are often used to predict risks at appreciably lower doses. A point of departure (PoD) can be calculated as the dose associated with a specified response level that is often in the range of experimental doses considered, e.g., benchmark dose associated with a benchmark response of 5% or 10%. A linear extrapolation to lower doses, such as those doses associated with a 1 in 1000 extra risk, can then follow. An alternative to the PoD method defined from a single model is to develop a model that accounts for the model uncertainty in the dose-response relationship and to use this model to estimate the risk at low doses. Two such approaches that account for model uncertainty are model averaging (MA) and semi-parametric methods. We use these methods, along with the PoD approach in the context of a large animal (40,000+ animal) bioassay that exhibited low-dose non-linearity. When the low dose data are omitted from analysis the methods that account for model uncertainty procedures produce dose estimates associated with a particular excess risk that are closer to the observed risk than the PoD method, which produced risk estimates several orders of magnitude smaller than the observed dose. When smaller bioassays are considered (such as NTP long term bioassays) these model uncertainty extrapolations produce estimates similar to the PoD method for linear-dose response data. For non-linear dose response data estimates can be different by an order of magnitude. In all cases, the model uncertainty methods are very similar in their estimation of risk suggesting that they are accounting for the same dose-response uncertainty.

M3-H.3  14:10  Elicitation of Expert Judgment on the form of the Dose-response Curve for Genotoxic Carcinogens at Low Exposures – more questions than answers! Flari V*, Boobis A, Gosling JP, Hart A, Craig P, Rushton L; Government; Academia   villie.flari@fera.gsi.gov.uk

Abstract: The general approach to genotoxic carcinogens has been to reduce exposure to levels that are "as low as reasonably achievable/practicable" (ALARA/P), although it does not provide a clear basis for deciding on the urgency or extent of risk management actions. The "Margin of Exposure" (MOE) approach was recommended to address this, but its interpretation requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. A rather large (theoretically infinite) number of low dose response models for genotoxic carcinogens exist and different countries and organisations support different assumptions. The models may be based on different physiological considerations regarding possible effects of genotoxic carcinogens, although they all lack a detailed, transparent, rigorous scientific rationale to justify their employment in interpreting the risks from exposure to genotoxic carcinogens.In a structured expert elicitation exercise, which included experts from both the EU and the US, we captured expert opinion on possible low dose-response relationships for genotoxic carcinogens. The exercise allowed us to elicit (a) individual judgments about dose-response relationships at low levels of exposure that can be made for genotoxic carcinogens in general and the uncertainties affecting expert judgments on, and (b) whether the nature of dose-response relationships for genotoxic carcinogens at low levels of exposure should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts’ views on the form of the dose-response curve for low dose exposure and major sources of uncertainty and most importantly, query the vigour of the assumption of a linear relationship.

M3-H.4  14:30  Mode of Action Human Relevance (MOA/HR) Framework– Comparative Analysis of Weight of Evidence. Meek ME, Bachman A, North C, Palermo C*, Lewis RJ; McLauglin Center for Population Health Risk Assessment, University of Ottawa, ExxonMobil Biomedical Sciences, Inc   r.jeffrey.lewis@exxonmobil.com

Abstract: The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for critical effects and their relevance to humans. This framework continues to evolve, as experience increases in its application. Though the MOA/HR framework is not designed to address the question of “how much information is enough” to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE), amongst different cases and hypothesized modes of action. The potential utility of the MOA/HR framework is explored in this context, based on a comparative WOE evaluation as a basis to increase understanding of the relative extent of supporting data and their implications for dose-response analysis. This involved comparisons for two existing chemical assessments (i.e. 1,2,3 trichloropropane [TCP] and carbon tetrachloride) with differing hypothesized MOAs for cancer. For TCP, possible MOAs related to cytotoxicity with tissue repair, mutagenicity, and cell signalling disruption were considered; cytotoxicity with tissue repair and mutagenicity were evaluated for carbon tetrachloride. Evidence summarized in narrative tables for each hypothesized MOA was classified as supporting, inconsistent or missing , based on considerations incorporated in framework analyses (namely temporal and dose-response concordance, strength, consistency and specificity and biological plausibility). Questions were posed to guide thinking on evaluating the relative WOE to support a hypothesized MOA, as a basis to consider its qualitative characterization (e.g., as probable, possible, inadequate, insufficient). Comparative analysis of this nature facilitates assessment of the adequacy of data on MOA in animals as a basis to increase transparency in delineating science judgment vs. science policy, as well as identifying key data needs to evaluate hypothesized MOAs.



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