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NCR Workshop: 3rd Review of the IRIS Process Meeting Agenda Now AvailableMarch 27-28, 2013 AgendaThis meeting will include a workshop on weight of evidence on March 27-28th that is open to public. However, there is limited space, and you will need to register in advance to reserve your seat. Please email your contact information to Craig Philip to register. *If you are not able to attend the workshop in person we have secured a teleconference line for guests to listen in (Please note that presentations/slides will not be available for teleconference guests during the workshop). Please contact Craig Philip for teleconference information. FIRST DAY OF WORKSHOP – MARCH 27, 20138:00 ASSEMBLING THE EVIDENCEThis session will address approaches to identifying evidence on agents being considered in IRIS assessments. It will cover methods for searching literature and other data bases. The session will also consider the complicating issues of publication bias, “the grey literature,” selective publication of model results, and access to primary data. A further major set of topics include the use of systematic approaches for characterizing study quality, methods for qualitatively and quantitatively assessing heterogeneity across studies, and use of quantitative synthesis (meta-analysis). An additional topic, potentially relevant to some assessments, is whether all assessments need a comprehensive review of the literature. 8:15 8:25 8:40 8:55 9:10 (1) Do IRIS assessments necessarily require full systematic reviews? (2) How might assessment of risk of bias differ between studies of chemicals and studies of other interventions, such as drugs? (3) What are the implications of heterogeneity of findings for risk relationships? (4) What approaches should be used for assembling different types of evidence, such as epidemiological and toxicological? (5) How can mechanistic information be systematically identified? 10:10 MECHANISM AND MODE OF ACTIONThere is a pressing need to improve efficiency in the risk-assessment process and incorporate high-throughput technology in evaluating the potential health effects of chemicals. Several efforts are underway by EPA to improve chemical risk assessment. For example, EPA’s high-throughput testing program (ToxCast) is designed to identify chemicals with the greatest potential risk to human health. EPA’s IRIS program is charged with evaluating and integrating these and other multiple types of evidence regarding potential adverse effects of environmental contaminants on human health: mechanistic studies, animal bioassays, and human studies. This panel will discuss current and future use of data on mechanism and mode of action in weight-of-evidence considerations. Specific topics of interest are (a) evaluation of strength-of-evidence related to mechanisms, (b) the use and interpretation of high-throughput toxicity screening data, and (c) application of genomic dose-response data to chemical risk assessment. Consideration of application of mechanistic data to cancer and noncancer chemical risk assessment within IRIS assessments is of overarching interest. 10:30 10:40 11:00 Panelists: David Schwartz, Chair of Medicine, Professor of Medicine and Immunology, University of Colorado; George Leikauf, Professor of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh; Rusty Thomas, Director, Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences; Joe Rodricks, Principal, ENVIRON; and Thomas Hartung, Professor and Doerenkamp-Zbinden Chair for Evidence-based Toxicology, Key QuestionsTopic 1: How will findings from new high-throughput assays be used? Can data from high-throughput assays replace more traditional apical end points that are examined in animal toxicity studies? How can dose-dependent changes in mechanisms identified from high-throughput assays be incorporated into chemical risk assessments? How can pharmacokinetic and similar data inform the interpretation of high-throughput screening assays? Topic 2: How should mechanistic information be incorporated into IRIS assessments? How can the science be advanced to improve qualitative and quantitative application of mechanistic information? What are the evidence criteria for concluding that a mechanism is established as relevant to an agent and outcome? 12:00 Break for Lunch INTEGRATION OF DATAEPA’s IRIS program is charged with evaluating and integrating multiple types of evidence regarding potential effects of environmental contaminants on human health: mechanistic studies, animal bioassays, and human studies. Assessments are often challenging due to sparse evidence, the use of relatively high doses in experimental bioassays, unclear toxicological mechanisms of action, and unmeasured co-exposures and other threats to validity in observational designs. This session will address qualitative and quantitative strategies for integrating evidence of different types in human health risk assessments. 1:00 1:10 1:30 Panelists: Steve Goodman, Professor of Medicine and Epidemiology, Stanford University; Kristina Thayer, Director, Office of Health Assessment and Translation, National Toxicology Program; Duncan Thomas, Professor and Verna Richter Chair in Cancer Research, Keck School of Medicine, University of Southern California; Tracey Woodruff, Professor and Director, Program on Reproductive Health and the Environment, University of California, San Francisco; and Lauren Zeise, Deputy Director for Scientific Affairs, Office of Environmental Health Hazard Assessment, California EPA Key QuestionsTopic 1: Hypothetical mechanisms or modes of action have been proposed for some toxicants, largely based on research in animal models. Consequently, it might be difficult to identify or exclude additional mechanisms for toxic effects in humans. Should mechanistic information be used in a qualitative manner, such as in Hill's biological “plausibility” criterion? Can information from observational or clinical studies on intermediate end points related to mechanisms be helpful? How can mechanistic understanding best be reflected in dose-response model selection or parameter estimation? Topic 2: How should evidence of toxicity from high-dose animal studies be weighed against null findings from one or more epidemiologic studies at lower exposures? What level of epidemiologic evidence would be sufficient to dismiss a toxic effect in animals as irrelevant to humans? How can dose-response relationships be combined from different types of research, for example, animal bioassay and epidemiological? Topic 3: Should positive epidemiologic studies with weaker designs (for example, ecological studies, or studies with unmeasured known confounders) or with positive but non-significant associations contribute to the weight of evidence, or should they be considered only as hypothesis generating? 2:30 Break CAUSALITYThe IRIS assessments evaluate hazard, specifically whether the chemical of concern is a cause of one or more adverse outcomes. The goal of the causal criteria session is to consider the best methods available for systematically evaluating the evidence from individual studies with respect to whether, and to what degree, a chemical causes a particular health outcome, and for combining the evidence in individual studies into an overall judgment as to the likelihood of a causal relationship. Specific goals of the session include (1) considering the utility of existing causal criteria outlined in the most recent IRIS documents; (2) comparing causal assessment methods used by other national and international organizations, with the potential goals of elaborating new guidelines for assessing strength of evidence for causation and of achieving some harmonization across agencies; and (3) considering whether the Hill “criteria” are still useful as guides to synthesizing the overall evidence for causation, or whether alternative criteria or guidelines might be an improvement on approaches developed almost half a century ago. 3:00 3:10 3:25 3:40 3:55 Key QuestionsShould the approach to causal inference within EPA guidelines be revised? Are the long-standing causal criteria still useful, given the range of evidence considered in IRIS assessments? How should causal judgments be made in practice? How can they be most useful for practitioners? 4:55 5:30 Adjourn for First Day of Workshop SECOND DAY OF WORKSHOP – MARCH 28, 20138:00 8:15 8:45 METHODS FOR CHARACTERIZING AND COMMUNICATING UNCERTAINTYOne of the primary aims of systematic reviews is to characterize and communicate the state-of-evidence on a specific topic. Absence of evidence and uncertainties may be characterized using different approaches that range from implicit characterization (qualitative discussion, unexplained variance) to explicit and quantitative characterization. In most cases, communicating uncertainty qualitatively or quantitatively should be an intrinsic element of such efforts. Numerical, verbal, and graphical tools are all widely used to characterize and communicate uncertainty, but with varying success. In this session, methods for characterizing and communicating uncertainties in the IRIS assessment will be considered. 9:15 9:25 9:45 10:00 Panelists: Tim Lash, Professor, Rollins School of Public Health, Emory; Chris Frey, Distinguished University Professor, North Carolina State University; David Budescu, The Anne Anastasi Professor of Psychometrics and Quantitative Psychology, Fordham University; Jay Kadane , Leonard J. Savage University Professor of Statistics, Emeritus, Carnegie Mellon University; and Thomas Wallsten, Professor, Department of Psychology, University of Maryland Key QuestionsWhat approaches would enhance the consideration and presentation of uncertainty in IRIS assessment? What attributes of users and uses of IRIS should guide methods for characterizing uncertainties in IRIS assessments? What do we know about tools that are readily available for use in quantifying uncertainty in IRIS? 10:45 Break USE OF EXPERT JUDGMENTExpert judgment is used in systematic review processes and throughout IRIS assessments, as discussed in the earlier sessions at this workshop. Expert judgment is also used in risk analysis to fill gaps when data are unavailable. Although it is an inherent component of IRIS assessments, this has not been explicitly acknowledged. In this session, the use of expert judgment in the IRIS assessment will be considered, identifying those points in the review and assessment process where expert judgment is important. The session will consider processes for using expert judgment as discussed throughout the workshop in previous sessions and in risk assessment, including elicitation and Delphi approaches. 11:00 11:15 Panelists: Tim Lash, Professor, Rollins School of Public Health, Emory; Chris Frey, Distinguished University Professor, North Carolina State University; David Budescu, The Anne Anastasi Professor of Psychometrics and Quantitative Psychology, Fordham University; Jay Kadane , Leonard J. Savage University Professor of Statistics, Emeritus, Carnegie Mellon University; and Thomas Wallsten, Professor, Department of Psychology, University of Maryland [NOTE: All invited workshop participants are urged to participate in this particular discussion.] Suggested topics to address by the panel: (a) elicitation techniques (b) understanding the specificity of expertise and to what extent interdisciplinary expertise is required or possible, (c) opportunities (when and where) for the value of expert judgments in IRIS and (d) limitations (including expert bias) on the value of expert judgments in IRIS. Key QuestionsWhat are best practices for identifying appropriate expertise and eliciting expert judgments, what is the evidence for their effectiveness, and how could they inform the IRIS process? What types of biases in expert judgments might affect IRIS assessments, and how could these be mitigated? 12:15 Opportunity for Public Comment 12:30 Adjourn Workshop See Website for more information. |
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