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Society For Risk Analysis Annual Meeting 2008
Risk Analysis: the Science and the Art
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
W2-C |
| Chair(s): Elizabeth Julien |
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W2-C.1 10:30 An introduction to the Key Events Analytical Framework and application to environmental chemicals . Daston G*, Boobis A, Preston J, Julien E, Olin S; 1-Procter & Gamble Company; 2-Imperial College London; 3-US Environmental Protection Agency; 4-ILSI/RF; 5-ILSI/RF daston.gp@pg.com Abstract: Risk assessment for chemicals, nutrients, allergens or microbes makes assumptions about the existence of biological thresholds, assumptions based on theoretical considerations about the underlying processes leading to toxicity or disease. These assumptions were developed several decades ago and need to be revisited given the huge volume of information that has been generated about the molecular pathogenesis that leads to disease. A reductionist approach that evaluates the potential for the existence of a threshold for each key event from exposure to frank toxicity or disease is now technically feasible, given advances in molecular biology and biotechnology. For chemical agents, there is empirical evidence available to challenge assumptions about thresholds; e.g., we now know that cancer can only occur after several mutations in key cellular control genes, contradicting the assumption that a single mutation is sufficient for tumor formation. We also know that chemically-induced mutational spectra frequently differ from spontaneous spectra and are therefore not additive, contradicting the assumption that chemically-induced cancers are adding to a pre-existing background of molecular lesions. There is evidence for non-genotoxic mechanisms of carcinogenicity for which persistent inflammation, cell proliferation or other events involving large numbers of cells are necessary to drive the response. It has been assumed that non-cancer responses exhibit a threshold because of the requirement that numerous cells must be affected in order to produce an adverse effect. However, particularly for receptor-mediated effects (e.g., endocrine or neurotoxicity), consideration needs to be given to the possibility that the exogenous substance adds to the endogenous background. Case studies for genotoxic and non-genotoxic carcinogens and for receptor-mediated toxicity will be discussed. |
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W2-C.2 10:50 The Key Events Analytical Framework: Application to food allergens. Gendel SM*, Houben GF, Taylor SL; USFDA steven.gendel@fda.hhs.gov Abstract: Food allergies are caused by immunological reactions to normal protein components of foods. True food allergies may affect 2-3% of adults and 6-8% of children. Food allergies can manifest in a wide variety of signs and symptoms, ranging from mild itching or nausea to extensive urticaria or anaphylactic shock. For any given allergic individual, the severity of a reaction is generally assumed to be proportional to the level of exposure to the allergenic protein. Current regulatory approaches for food allergens are largely qualitative – i.e., a product either does, or does not, contain allergens. In order for manufacturers to provide more accurate and informative labels, it would be valuable to understand whether thresholds for eliciting allergic reactions exist – and if they do exist, to understand how such thresholds are distributed within the food-allergic population. Government agencies could also benefit from this understanding when establishing regulatory thresholds or providing GMP guidance. Unlike other biological stressors, information on individual sensitivities can be obtained through direct clinical testing using double blind placebo controlled studies. However, use of the “key events” approach will help generate a coherent picture of the various ‘drivers’ of the allergic response and identify which events in the overall elicitation process appear to control the nature or severity of response. This approach might also make it possible to identify the sources of interindividual and intraindividual variability. |
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W2-C.3 11:10 The Key Events Analytical Framework: A case study with Listeria monocytogenes. Havelaar AH*, Smith MA, Whiting RC, Buchanan RL; National Institute of Public Health and the Environment Arie.Havelaar@rivm.nl Abstract: There are three main categories of foodborne microbial pathogens, based on their general biological mechanisms. One group, toxigenic (e.g., C. botulinum, S. aureus), releases toxin into food products prior to food ingestion. A second group, toxicoinfectious (e.g., V. cholerae, enterohemorrhagic E. coli), colonizes the GI tract and then releases toxin that is absorbed into the body. A third group, infectious (e.g., Listeria monocytogenes Salmonella enterica), is capable of invading the intestinal epithelium and often internal tissue. For each of these mechanistic categories, current approaches to characterizing the dose-response relationship at low dose rely heavily on assumptions regarding thresholds. This presentation describes our working group’s application of the Key Events Analytical Framework to a case study of L. monocytogenes, for which (based on single hit and independent action assumptions), it is widely assumed that intake of a single bacterium has a non-zero probability of causing infection and illness. Our Key Events analysis systematically considers each major biological step in the pathway from ingestion to the endpoint of concern with regard to: i) the interplay between the pathogen and host response mechanisms (e.g., innate and adaptive immune response); and ii) modifying factors (e.g., life stage, disease state, prior exposure) that may modify the effectiveness of host response and thereby affect the ultimate dose-response relationship. The dynamic and probabilistic nature of individual key events and their integration into a multiple step pathway will be discussed, along with the potential influence of inter- and intraindividual variability at specific key events. Finally, the potential value of this Key Events approach for advancing the scientific basis of dose-response evaluation of foodborne pathogens will be noted. |
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W2-C.4 11:30 The Key Events Analytical Framework: A case study with retinol (Vitamin A). Russell RM*, Ross AC, Miller SA, Munro I, Yetley EA, Rodricks JV; Tufts University rob.russell@tufts.edu Abstract: Methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify the intake levels associated with adverse effects, and uncertainty factor (UFs) are applied to establish ULs. An underlying assumption in setting ULs has been that of a threshold dose – an intake level that must be exceeded before any adverse effect occurs. With nutrients there is also a second type of threshold – an intake level required to prevent adverse effects associated with deficient or inadequate intakes. In each case, however, the assumption of a threshold intake has been fundamental to establishing reference intake levels for public health purposes. Typically, the threshold intake values calculated for a given nutrient are estimates, due to inadequate understanding of the relationship between the biologically relevant intake(s) and the causative biological effect(s) that ultimately lead to the observed adverse effect. The ILSI Key Events Analytical Framework can be used to systematically examine the main biological events that occur between initial intake and the ultimate effect of interest with regard to the influence of each event on the overall intake-response relationship. This presentation will discuss application of the Key Events Analytical Framework to a case study of retinol (Vitamin A) where the effect of concern is caused by excess intake. The connection between homeostatic controls and threshold intakes at various pharmacokinetic and pharmacodynamic steps will be discussed, along with intake levels and processes that may disrupt such controls. Also, the role of modifying factors (e.g., life stage, exposure patterns) on the efficacy of homeostatic controls will be considered. Information useful for focusing future research and for public health applications will be discussed. |
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