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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

Acceptable Risk for Biothreat Agents

Room: Otis   4:00-5:30 PM

Chair(s): Peg Coleman, Lynne Haber

W4-G.1  16:00  Modeling Inhalation Anthrax in Primates to Inform Discussions on “Acceptable Risk”. Diamond G*, Lumpkin M, Rhoades J, Massulik S, Coleman M; Syracuse Reserach Corporation, 7502 Round Pond Road, N Syracuse, NY 13212

Abstract: The practice of microbial risk assessment for biothreat agents is made difficult by limited methodologies available to extrapolate dose-response relationships across species. However, there is great need to quantify internal dosimetry in animals and humans of agents that may be released in bioterrorist attacks. Data to develop predictive internal dosimetry models exist for multiple species of animals, but not humans. We have developed a physiologically based biokinetic/biodynamic (PBBK/BD) model for inhalation anthrax in nonhuman primates (NHPs) and humans that provides estimates of kinetic (spore dose in the deep lung) and dynamic (bacteria levels in lymph and blood) internal dosimeters useful for dose-response analysis. The ICRP human respiratory tract model for radionuclides was allometrically scaled to NHPs and found to predict metal oxide particle lung deposition and clearance in close agreement with observations in monkeys and baboons. Assuming that Bacillus anthracis spores and metal oxide particles of the same size are deposited and taken up by alveolar macrophages similarly, the NHP model was extended to describe B. anthracis spore germination and bacterial growth and clearance in the thoracic lymph and blood. The resulting model is able to predict bacteria levels in monkey lymph and blood quite similar to observations. The PBBK/BD model for NHPs was used to predict internal dosimetry for describing the dose-response of inhaled anthrax spores resulting in mortality or survival in Rhesus and African Green monkeys. From these analyses, the human model was used to extrapolate NHP survival to humans. These exercises are useful for identifying data needs for reducing uncertainty in the model predictions, particularly for humans. They also represent a significant advance in developing a biologically based tool to inform selection of “acceptable risk”.

W4-G.3  16:40  Concerns about release from Biosafety Level 3/4 laboratories. Gronvall GK*; Center for Biosecurity of UPMC

Abstract: This talk will describe the public concerns about high-containment (BSL 3/4) laboratories, what may be done to reduce concerns, and what can be done to reduce the risks these laboratories pose. High-containment laboratories have become increasingly controversial because of highly publicized laboratory errors, especially the missteps of Boston University in handling tularemia infections, and the failure of Texas A&M to report infections to the CDC. These errors have fueled resistance to high-containment laboratory siting proposals. Public resistance was experienced during efforts to build high-containment facilities in Boston, in Davis, California, in Hamilton, Montana, and in Seattle, whereas generally positive support was achieved for the Galveston laboratory administered by the University of Texas Medical Branch. In the end, both the Davis and Seattle facilities were not built, in part due to public opposition. Public protests against the siting of the Boston University National Biocontainment Laboratory eventually led to citywide regulations on research activities and practice, and litigation that is ongoing. Going forward, high-containment laboratories need to actively address these community concerns. Lessons should be learned from laboratories that have been accepted by their communities, which have by and large have procedures that not only encourage active reporting of problems but also keep the community informed about operations.

W4-G.4  17:00  Primate Dose-Response Datasets: Understanding Resistance and Susceptibility to Inhalation Anthrax Set the Stage for Discussing “Acceptable Risk” Levels. Pitt MLM*; United States Army Medical Research Institute of Infectious Diseases

Abstract: Humans appear to be relatively resistant to B. anthracis infection. The most appropriate animal model for extrapolation to humans is uncertain due to the limited information on inhalation anthrax in humans making a comparison with animal data difficult and animal species differ in their natural resistance to the disease. Nonhuman primates are considered the most appropriate for investigations of experimental anthrax. Macaque models, especially the rhesus macaque, have been used extensively since the 1950s to study the pathogenesis of the disease and vaccine efficacy. More recently, the African Green monkey (AGM) model has been established to address disease progression and therapeutic efficacy. Dose-response data is crucial to animal model development. Knowledge of these data sets, generated using well defined methodology, merits scrutiny for risk analysis. Two recent datasets generated in Rhesus and AGM incorporate low doses in the experimental design that influence confidence in empirical dose-response models fit to the data. Empirical techniques were applied for dose-response analysis, including traditional probit modeling, logistic regression, and application of Weibull and other functions encoded in Benchmark Dose software. These analyses include estimation of confidence, including upper and lower limits for mortality. In addition, supplemental studies on the natural history of the disease, expand our understanding beyond variable LD50 estimates. Mechanistic understanding of deposition and clearance of spores in diverse primate species, including humans, is essential to application of new research findings to risk analysis and decision making for inhalation anthrax, as well as other biothreat agents. Future research will address influential gaps in knowledge that will enhance the scientific basis for microbial risk assessment models and expand opportunities for analytic-deliberative process regarding protection of human health and biothreat preparedness.

W4-G.5  17:20  Framework to evaluate child:adult differences in inhalation dosimetry of gases: Application to selected systemically-acting volatile organic chemicals . Haber LT*, Krishnan K, Gentry PR, Patterson J, Parker A, Adamou T; TERA

Abstract: A key issue in considering children’s risk is the relative tissue dosimetry in adults vs. children. To address this question, we developed a framework and analytical approach for evaluating the mean relative tissue dose in adults and children for systemic effects of inhaled gases. Such information can help to focus efforts for obtaining additional data and for more refined analyses on the chemicals where there is the greatest potential of children being at greater risk. The results can be combined with information on variability, to evaluate the adequacy of default UFs for protecting children, or to determine the need for chemical-specific modifications to UFs. We conducted case studies at steady state for systemic effects of VOCs for various combinations of physicochemical and metabolic characteristics. These case studies aim to provide perspective on the potential range of internal dose in children at different ages (3 months, 1 year, 5 years, and 10 years) vs. adults. Calculations were conducted for the parent, reactive metabolite, and stable metabolite for blood:air partition coefficients of 1-50, hepatic extraction ratio of 0-1, and for high or low intrinsic clearance (1000 or 0.1 L/hr). Illustrative analyses were also developed on relative dosimetry for chemicals with flow-limited and enzyme-limited clearance, and those that show significant age-related variability in enzyme capacity. These analyses indicate that in most cases, the ratio of internal dose for children:adults for these chemicals is likely to be within a factor of 2.3 when the toxic moiety is the parent, and within a factor of 1.5 when it is a reactive metabolite. Ratios were generally 1 or less for stable metabolites, but higher ratios were obtained when the toxic moiety is a stable metabolite that is cleared efficiently in adults, but poorly in children. The framework provides a structure for evaluating age-related kinetic differences and to focus future research in this area.

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