Progress Toward Transforming the Integrated Risk Information System (IRIS) Program A 2018 Evaluation (2018) / Chapter Skim
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Appendix C: Presentations by US Environmental Protection Agency
Appendix C: Presentations by US Environmental Protection Agency
Pages 20-98
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Appendix C Presentations by US Environmental Protection Agency 20
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Speaking] Office of Research and Development NCEA, IRIS 21
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. • IRIS assessments have no direct regulatory impact until they are combined with – Extent of exposure to people, cost of cleanup, available technology, etc.
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– IRIS Program Director: As a recognized leader in systematic review, automation, and chemical evaluations, Kris Thayer brings experience in early partner and stakeholder engagement and input, and demonstrated actions to increase capacity and transparency in assessments. • Improved responsiveness and accountability through Senior Leadership Team.
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• Establishing the SAB Chemical Assessment Advisory Committee (CAAC) – 5 IRIS assessments completed CAAC review since 2014.
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– Systematic review support to chemical assessment teams (e.g., screening, study evaluation, data extraction, use of specialized software, etc. – train the trainer model)
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation GAO 2017 Report • Acknowledged the actions ORD has taken to enable the IRIS Program to produce timely, transparent, and credible assessments in support of EPA's mission. • Discussions with GAO during and after the release of the 2017 High Risk Report have focused on approaches to demonstrate how management and integrity initiatives within IRIS are supporting the transformation of the program Summary of 2015 and 20 17 GAO High Risk Criteria Ratings of the IRIS Program GAO High Risk Criteria 2015 Rating 2017 Rating Leadership Commitment Met Met Monitoring Partially Met Met Action Plan Partially Met Partially Met Demonstrated Progress Not Met Partially Met Capacity Not Met Partially Met • IRIS is engaged in continual ongoing discussion with GAO regarding recommendations from the 2008, 2012, and 2013 reports.
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Learned from the Systematic "The committee discussed at length whether it could provide EPA Review with advice about when a systematic review should be performed but decided it could not be more specific because that decision will depend on the availability of data and resources, the anticipated actions, the time frame for decision making, and other factors." [p.157] "The committee also recognized that it might be advantageous for EPA to build on existing systematic reviews that are published in the peer-reviewed literature." [p.157]
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• Increase transparency and full implementation of systematic review – implement using approaches that foster consistency across the IRIS Program; many active and all new starts address systematic review-related recommendations of 2014 NAS report • Modernize the IRIS Program – through automation and machine learning to expedite systematic review, incorporation of emerging data types • Modularize product lines – implement a portfolio of chemical evaluation products that optimize the application of the best available science and technology. These products will allow IRIS to remain flexible and responsive to clients within the EPA as well the diverse collection of stakeholders beyond EPA, including states, tribal nations, and other federal agencies.
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• Current research efforts and training serve to ensure that methods and staff are able to adapt to changing scientific contexts and sources of evidence, including new and emerging data types 16 SESSION 1: SYSTEMATIC REVIEW IN THE IRIS PROGRAM - EVIDENCE IDENTIFICATION Kris Thayer* , Andrew Kraft*
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2011 18 Systematic Review Elements (NAS 2014) "In the context of IRIS, the committee has defined systematic review as including protocol development, evidence identification, evidence evaluation, and an analytic summary of the evidence" Systematic Reviews NAS 2014, Figure S-1 IRIS also considers these phases as part of its systematic review process 19 30
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• "EPA should include protocols for all systematic reviews conducted for a specific IRIS assessment as appendixes to the assessment." (Chapter 3, Problem Formulation and Protocol Development) IRIS Handbook: Standard operating procedures and considerations Systematic Literature Study Data Evidence Derive Toxicity Scoping Review Protocol Inventory Evaluation Extraction Integration Values Assessment Assessment Initiated Developed Initial Problem Literature Refined Organize Hazard Evidence Analysis and Select and Model Formulation Search, Screen Evaluation Plan Review Synthesis Studies Assessment Plans: Protocols: How the assessment will be conducted What the assessment will cover 21 31
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• Chemical-specific documents • IRIS Assessment Plans (IAPs) are problem formulation and scoping documents that include more elements of systematic review • Protocols outline methods, including updates to the IAPs • IAPs and protocols include proposed "modularity," targeted focus and use of existing assessments • Templates created to promote consistency across the IRIS Program, which is 23 implemented across NCEA divisions and geographical locations 32
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criteria which outlines evidence considered most pertinent – Internal review of IAP fosters early and focused Agency engagement • Released for a 30-day public comment period + public science discussion (beginning of IRIS Step 1) 25 – Examples: chloroform, ethylbenzene, nitrate/nitrite (Sept 2017)
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation 26 IRIS Assessment Plan (IAP) Content 27 From draft uranium IAP (2018)
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28 Protocols Systematic Literature Study Data Evidence Derive Toxicity Scoping Review Protocol Inventory Evaluation Extraction Integration Values Assessment Assessment Developed Initiated Initial Problem Literature Refined Organize Hazard Evidence Analysis and Select and Model Formulation Search, Screen Evaluation Plan Review Synthesis Studies Protocols: How the assessment will be conducted (specific) • Assessment specific stand-alone method documents that do not rely on the IRIS Handbook to convey methodology • Comments received on IAP are considered when preparing the protocol (updated IAP text is included in the protocol)
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Protocol Content Updated IAP text and PECO based on public comments 30 From draft chloroform protocol (2018) Protocol Content 31 From draft chloroform protocol (2018)
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Rapid systematic review • EPA response to the Chloroprene Request for Correction (posted January 29, 2018) 32 Literature Searching, Screening, and Inventories*
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Specifically, the protocols should provide a line-by-line description of the search strategy, the date of the search, publication dates searched, and explicitly state the inclusion and exclusion criteria..." Systematic Literature Study Data Evidence Derive Toxicity Scoping Review Protocol Inventory Evaluation Extraction Integration Values Assessment Assessment Initiated Developed Evidence Analysis and Select and Model Initial Problem Literature Refined Organize Formulation Search, Screen Evaluation Plan Hazard Review Synthesis Studies • Protocols outline the specifics of the literature search and screening approaches, including inclusion and exclusion criteria in PECO tables • Dedicated information technologists help formulate searches, and screening decisions are tracked in HERO (tagging) • Manual and semi-automated approaches are being used to identify relevant studies • Inventories of basic study methods organize evidence for refinement and evaluation • Changes and updates are documented in the protocol 34 Routine Evidence Identification Processes Inventories Health Outcome & Screening PBPK Studies Database 1.Title/abstract • Tag studies by line of Searches 2.
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36 Evidence Identification in Protocols special topics would include any specialized software tools 37 39
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation PECO Criteria to Identify Studies Populationsa Example from the draft chloroform protocol 38 Example Literature Screening Form * Forms Independently Entered by 2 Reviewers*
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Assessment-Specific Extraction Details (generic examples) : • Exposure levels tested • Test article details, such as purity or isomeric composition Results are Typically Not Included in Inventories Developing Extraction Forms (all 3 lines of evidence)
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- Organizes the available evidence to allow for pragmatic evaluations of key issues that arise during review of PECO-specific human and animal studies (Session 2) Refinements are tracked and updated in the assessment protocol 42 IRIS has Addressed the Major NAS 2014 Recommendations NAS 2014 Topics IRIS Process Improvements General Process • Draft IRIS Handbook of program SOPs is being reviewed within EPA Issues (Chapter 2)
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Speaking] Office of Research and Development NCEA, IRIS Evaluating Individual Studies: Reporting Quality, Risk of Bias, and Sensitivity Office of Research and Development NCEA, IRIS 43
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– Provides access to the rationale for discipline-specific decisions made during the evaluation process. • Objective of the approach: Identify the most informative and reliable studies for evidence synthesis and integration.
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For details, please see: Model equations are consistent with biochemical and biological understanding • Poster: Well-documented model code is readily available to EPA and public Systematic evaluations of PBPK Set of published parameters clearly identified, including origin/derivation models for human health risk Parameters do not vary unpredictably with dose assessment Initial • e.g., Any dose dependence in absorption constants is predictable across the • EPA website: dose ranges relevant for animal and human modeling technical Sensitivity and uncertainty analysis has been conducted for relevant exposure EPA Response to the Request levels (local sensitivity analysis is sufficient, though global preferred) for Correction of the IRIS e.g., A sound explanation should be provided when sensitivity of the dose Toxicological Review of metric to model parameters differs from what is reasonably expected Chloroprene (2018)
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Evaluation of Individual Health Effect Studies Systematic Literature Study Data Evidence Derive Toxicity Scoping Review Protocol Inventory Evaluation Extraction Integration Values Assessment Assessment Initiated Developed Organize Evidence Analysis and Select and Model Initial Problem Literature Refined Formulation Search, Screen Evaluation Plan Hazard Review Synthesis Studies • General approach same for human and animal studies • Evaluation process focused on: – Internal validity/bias – Sensitivity – Reporting quality 50 Development of Evaluation Strategies • Questions in IRIS Protocol Template highlight general study attributes or elements to consider • Subject-matter knowledge is used to formulate a list of issues to consider in the evaluation • Develop a set of considerations based on exposure and outcome specific knowledge 51 46
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Identified biases or deficiencies interpreted as likely to - Poor have had a notable impact on the results or prevent reliable interpretation of study findings. A judgment that the study conduct relating to the domain introduced a serious flaw that is interpreted to be the Critically -- primary driver of any observed effect or makes the study Deficient uninterpretable.
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makes study results unusable 54 General Considerations to Evaluate Outcomes from Animal Toxicology Studies Domain Metric Reporting Quality Reporting of information necessary for study evaluation Selection or Allocation of animals to experimental groups Performance Bias Blinding of investigators, particularly during outcome assessment Confounding/Variable Control for variables across experimental groups Control Reporting or Attrition Lack of selective data reporting and unaccounted for loss of Bias animals Exposure Methods Characterization of the exposure to the compound of Sensitivity interest Utility of the exposure design for the endpoint of interest Outcome Measures and Sensitivity and specificity of the endpoint evaluations Results Display Usability and transparency of the presented data 55 48
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BMJ 2016; 355:i4919. 56 Epidemiology Evaluation Domains Domain Core Question Exposure Does the exposure measure reliably distinguish between levels measurement of exposure in an appropriate time window?
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• Does the exposure measure reflect a relevant time window? • Was exposure measurement likely to be affected by knowledge of outcome or by presence of the outcome (i.e., reverse causality)
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Appendix C Study Evaluation: Final Review in HAWC Questions, instruction text, and drop down rating options are customizable by user 60 Individual Studies in HAWC Medium confidence Uninformative 61 51
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• Current methods for study evaluation – Chloroform protocol (2018) – EPA Response to Chloroprene Request for Correction (2018)
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• Decisions about the organization of the synthesis made prior to data extraction • Narratives, but not study by study summaries • Highlight information that informs the hazard evaluation Integration: To develop judgments regarding strength of evidence for a health effect across lines of evidence • A two-step process involving transparent and structured approaches for drawing summary conclusions across lines of evidence 65 53
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process...the committee does not offer a preference but suggests that EPA consider which approach best fits..." "EPA should expand its ability to perform quantitative modeling of evidence integration." • The current approach continues to use a guided expert judgment process, but structured sets of categorical criteria for decision-making within that process are more explicitly defined. • The current frameworks, and documentation of decisions within these frameworks, enhance transparency, reproducibility, and comparability across health effects and assessments; these approaches are evolving within NCEA and across the field.
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? 68 Scientific Judgment in Analysis and Synthesis of Evidence Systematic Literature Study Data Evidence Derive Toxicity Scoping Review Protocol Inventory Evaluation Extraction Integration Values Assessment Assessment Initiated Developed Initial Literature Refined Organize Evidence Analysis Select and Model Problem Search, Screen Evaluation Plan Hazard Review and Synthesis Studies Formulation • Synthesis of evidence is more than counting the number of "positive" and "negative" studies • Must systematically consider the influence of bias and sensitivity when describing study results and synthesizing evidence • Synthesis should primarily be based on studies of medium and high confidence (when available)
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outcomes•is assessed during study of Shape presented explanatory factors Other across studies, or • • Results of dose-response curves depend on • Mechanistic evidence is synthesiz edevaluation phase monotonic increasing not alwa ys that outcomes; meta-analysis may mitigate combined in conclusions regarding informs the the human and animal health effect evidence. about chance concerns expected 70 Synthesis Examples: Epidemiology TCE and kidney cancer: stratification by utility Highest exposure level graphed for each study RoC Monograph on Trichloroethylene.
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2011. Toxicological Review of Trichloroethylene 72 Synthesis Examples:Animal Toxicology Hormone Level Pathology Incidence Behavioral Function All Rodents All Rats All Rats Gestational By Species Medium/ High Confidence Low Juvenile/Adult Confidence 73 57
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To narrow the scope of the analyses of mechanistic information, IRIS applies an iterative approach to identifying key mechanistic questions at various stages of the systematic review • Problem formulation identifies predefined analyses (e.g., when a mutagenic MOA is indicated) • Literature inventory allows identification of studies on an organ system that human and animal studies meeting the PECO criteria have not examined • Human and animal evidence syntheses may flag impactful qualitative and quantitative analyses 75 58
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across sets of potentially related endpoints/outcomes to inform the consideration of coherence during evidence integration – Aid extrapolation (high-to-low dose; short-to-long duration; route-to-route) – Improve dose-response modeling and quantification of uncertainties 76 Mechanistic Analysis Focused on Specific Questions Examples of when these analyses have been triggered in recent IRIS Assessments: • Benzo[a]
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are useful for organizing and documenting these analyses transparently to convey conclusions for evidence integration 78 Moving from Synthesis to Integration Systematic Literature Study Data Evidence Derive Toxicity Scoping Review Protocol Inventory Evaluation Extraction Integration Values Assessment Assessment Initiated Developed Initial Literature Refined Organize Evidence Analysis Select and Model Problem Search, Screen Evaluation Plan Hazard Review and Synthesis Studies Formulation Outputs of Evidence Synthesis Results of Human Health Evidence Integration Effect Study Synthesis Transparent and Structured Results of Animal Health Processes for Drawing Effect Study Synthesis Summary Conclusions Across Lines of Evidence Results of Synthesis of Mechanistic Evidence Informing the Human and Animal Syntheses 79 60
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Animal health effect study synthesis conclusions for each consideration are integrated in light of mechanistic evidence in exposed animals or animal cells (or other relevant models) 80 Within-Stream (Human; Animal Stream)
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of interest 82 Step 2: Framework for Overall Evidence Integration Conclusions Judgments regarding the strength of the human and animal evidence streams are combined to draw a conclusion for a given human health effect A veery hig igh lev el of f ceertainttainty thahat expxposuree caauses thehe healthealth eff ffect t in v r h h leve o c r y t t e o r c u t h e e c in humans umans, e. .g.,: .,: h , e g • Thehe st trongeest t evidenc vidence judg T sr g s e e judgmen ent fo r thehe humanuman evidenc vidence st treeam m t for t h e e s r a Strongest Conclusion for a Humanand thehe sttrongeestt animalanimal • A moder derately ly st trong humanuman evidenc vidence judg m o a e sr h e e judgmen ent and m t Health Effect s t sr g evidenc vidence judg e e judgmen ent alonglongside strong mechanis echanisticic evidenc vidence thahat MO OAs s andnd m t a s ide st r m t e e t t M A a kk d id fifi dd i l i l i i d i h h Reasonable certainty that exposure causes the health effect in humans, although some outstanding questions may remain, e.g.,: STRONGER CONCLUSION The strongest evidence judgment for the animal evidence stream, but not meeting the criterion above A moderately strong human or animal evidence stream judgment, or the weaker judgments when evidence from the opposite stream (e.g., mechanistic evidence of precursors supporting coherence)
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Studies and Factors that increase Factors that Within stream Inference across Summary of findings Overall conclusion interpretation strength decrease strength evidence judgments evidence streams [Health Effect or Outcome Grouping] Human relevance of Describe conclusion(s)
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sensitivity • Decisions and supporting rationale are clearly documented • Study evaluations impact subsequent assessment decisions Evidence Integration • Structured frameworks provide transparency in expert judgments for Hazard across human, animal, and mechanistic studies (based on Hill) Identification • Standardized templates documenting key evidence integration (Chapter 6)
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For example, such a strategic plan should address: – Applying advances in data retrieval and text-mining "The committee also found that the proposed format for the assessments should enhance "user friendliness" and transparency. The evidence tables and data displays in the new documents are moving to the standard practice for systematic reviews." [p.
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• Any progress on semi-automation could result in large time and cost savings • In 2017, NCEA created an interagency agreement with NTP to leverage resources – Current activities focus on creating test/training sets and model development for basic content of animal studies (e.g., test chemical, species, dose levels, randomization, etc.)
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Appendix C Suite of Systematic Review Software Tools – Upcoming Demonstrations ARE TOOLS INTEROPERABLE 92 SWIFT Review: Scoping and Problem Formulation e https://www.sciome.com/swift-review/ 93 67
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For Queries and Filters: It category "Health Outcomes" includes example, the tag incorporates several pre-defined search filters.These filterstags:"Cancer," "Cardiovascular," and scientists the following have been prepared by information or various topics of relevance to with the Tag Browser or "Neurological." When used environmental health scientists. f Search functionalities, tags facilitate increased efficiency Details on these filters are documented (click Help > Search during scoping and problem formulation by quickly finding Strategies)
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Appendix C 96 Built-in and User-Defined Search Strategies 97 69
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Tag Browser Search by Health Outcome 98 Tag Browser Search by Health Outcome 99 70
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Appendix C Searching Additional Tag Categories Tox21 Chemicals Keyword Text Highlighting 100 Interactive Displays Reveal Patterns of Available Evidence 101 71
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Publication Year by Health Outcome 102 Priority Ranking Reduces Screening Burden 103 72
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Appendix C Automated Priority Ranking Reduces Screening Burden Topic modeling is a statistical methodology (Latent Dirichlet Allocation or LDA) that automatically computes then categorizes documents according to pre-defined topics.
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Priority Ranking Improves Literature Screening Efficiency Increase screening efficiency Reduce screening burden on average 50% 106 Automated Priority Ranking 107 74
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Appendix C SWIFT Active Screener Capabilities Improved Ranking Model • Web-based, real-time, collaborative, systematic review software application • State-of-the-art statistical models prioritize articles as they are being reviewed • Experience suggests screening burden is reduced by at least 50% (likely more) • Algorithm improves from screener-input without training "seeds" further increasing efficiency (more efficient than implementing a "seed studies" only model)
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation User Input Improves the Algorithm to Priority Rank While Screening 110 "Seed" studies when Relevant On/Off Topic Literature is Identified 111 76
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Appendix C Manage References with Conflict Resolution – Track and Archive Changes 112 113 77
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation SWIFT Active: Data Integration • Active Screener integrates with systematic review tools already in use: – Accepts imports from bibliographic databases and reference curation platforms including SWIFT Review, EndNote, Mendeley, Zotaro, and PubMed – Results from screening in Active Screener can be exported in standard data formats compatible with applications including HAWC and Excel, EndNote, Mendeley, and Zotaro Current Users 114 HAWC: Study Evaluation, Extraction, Visualization and Data Sharing e https://hawcproject.org/ 115 78
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Appendix C HAWC Capabilities • Free and open source • Developed at UNC by Andy Shapiro* with Ivan Rusyn • Literature search and initial screening • Animal bioassay, epidemiological, and in vitro structured study methods/data extraction and visualization • Interactive "click to see more" graphics • Risk of bias and sensitivity evaluation • Modular to work with other tools and maximize flexibility for users • Works best in Google Chrome (preferred)
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Epidemiology: Click to See More Display Example from Chloroform 118 Visualizing Epidemiology Evidence Example from Chloroform 119 80
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Appendix C Visualizing Animal Evidence Chloroform Fetal Survival 120 Visualizing Animal Evidence Chloroform Fetal Survival 121 81
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation Multiple Formats to Present Results Chloroform Fetal Survival Animal data can be expressed as effect size, e.g., percent control 122 HAWC: Dose-Response Displays 123 82
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Appendix C HAWC: Dose-Response Displays 124 HAWC: Download Reports • Entire database for an assessment can be downloaded in Microsoft Excel exports 125 83
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Progress Toward Transforming the Integrated Risk Information System Program: A 2018 Evaluation HAWC Benchmark Dose Modeling 126 Advantages • Structured extraction to promote consistency and completeness • Free, open source and customizable • Enhance opportunities for database interpretability • Integration with automated data-extraction tools • Web-based to promote team collaboration • Ability to export data files promotes further analysis of findings and quantification (in assessments or for methods development) • Creates possibilities for web-based, interactive reports 127 84
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Office of Research and Development NCEA, IRIS 85
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– New approach methods and assays are increasingly being evaluated quantitatively. 130 Evidence Integration Conclusions Inform when to Develop Toxicity Values Evidence integration conclusion Quantitative toxicity value provided?
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132 More Explicitly Defining the Attributes IRIS Uses to Evaluate Studies for Derivation of Toxicity Values In addition to qualitative study evaluation judgments (i.e., medium or high confidence studies are preferred) , studies are assessed across several study attributes Example Primary Considerations for Selection of Studies for Derivation of Toxicity Values Study attribute Human studies Animal studies Test species Human data are generally preferred to Animals that respond most like humans are eliminate interspecies extrapolation preferred.
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(EPA, 2016) https://cfpub.epa.gov/ncea/iris/iris_documents/docum ents/toxreviews/1025tr.pdf 134 IRIS is also Presenting Arrays of Candidate Toxicity Values Benzo[a]
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• A probabilistic approach to adjustments from animal to human; a framework for refining toxicity values.
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138 Use of Quantitative Modeling to Inform Evidence Integration Meta-Analysis: Increasingly Being Used to Interpret Sets of Results across Similar Populations • Formal tools continue to be used to combine similar human epidemiology studies to improve decisions about hazard and about slope of dose-response. • These approaches have also been used to better understand animal data that differ between studies of similar species and endpoints.
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. – Bayesian Analysis is compatible with the WHO/IPCS Approach for characterizing uncertainty • Model Averaging – Bayesian approaches are being applied to individual BMD models, and then model averaging is used to characterize uncertainty • Meta-Analysis – Bayesian meta-analysis is currently being used to evaluate arsenic epidemiology studies • Bayesian Networks (exploratory research is currently underway)
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have been published regarding the use of New Approach Methods (NAM) across the human health risk assessment paradigm (i.e., shifting the paradigm)
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? Will need to optimize metabolism protocols; integrate IVIVE Data-poor chemicals • Evidence base for hazard • Empirical dose-response based on pathway perturbations • Reduce need for longer-term animal studies IRIS-type chemicals • Augment WOE (e.g., MOA/AOP)
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one of the stronger evidence integration conclusions, as well more specific criteria for the evaluation of individual studies • Providing MLE estimates of BMDs, along with BMDLs • Applying and exploring quantitative approaches to better characterize uncertainty, including probabilistic and Bayesian approaches Future Directions • Quantitative assessment methods will be updated in a continuing, (Chapter 8 "Lessons strategic fashion, including capacity building (e.g., training; evolving best Learned" and practices) for current approaches including meta-analysis, probabilistic "Looking Forward")
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Speaking] Office of Research and Development NCEA, IRIS Training and Collaboration • Held multiple training sessions for IRIS Program staff in 2017, ranging from demos, seminars, to retreats.
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• Frequent opportunities for stakeholder engagement • Draft IRIS Handbook of program SOPs is being reviewed within EPA • Re-occurring staff training and template IAPs and protocols promote consistency and quality control Problem • IAPs allow early comment on problem formulation Formulation and • More frequent Agency engagement facilitates scope refinement Protocol • Assessment protocols describe methods and allow for iteration Development (Chapter 3) Evidence • Consultation with information technologists and subject experts Identification • Adopts current systematic review best practices, including use of (Chapter 4)
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• Developing and applying quantitative tools in support of evidence synthesis and integration, including meta-analytical approaches • Expanded development and use of more advanced quantitative methods in software tools, such as BMDS 152 IRIS has Addressed the Major NAS 2014 Recommendations NAS 2014 Topics IRIS Process Improvements Derivation of • Developed more explicit criteria for deriving toxicity values, Toxicity Values including the intent to derive quantitative toxicity values when IRIS (Chapter 7) reaches one of the stronger evidence integration conclusions, as well more specific criteria for the evaluation of individual studies • Providing MLE estimates of BMDs, along with BMDLs • Applying and exploring quantitative approaches to better characterize uncertainty, including probabilistic and Bayesian approaches 153 97
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for current approaches including meta-analysis, probabilistic analyses, and Bayesian methods 154 98
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