Building Confidence in New Evidence Streams for Human Health Risk Assessment Lessons Learned from Laboratory Mammalian Toxicity Tests (2023) / Chapter Skim
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Appendix C: Evidence Review: Approach, Methods, and Results
Appendix C: Evidence Review: Approach, Methods, and Results
Pages 126-151
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From page 126... ...
. To identify and evaluate systematic reviews of the scientific evidence of the highest methodological quality relevant to the committee's charge, the committee conducted an overview review.
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From page 127... ...
The literature review will be, as noted in the charge, "comprehensive, workable, objective, and transparent." The primary literature reporting on outcomes in relevant laboratory mammalian toxicity tests and amenable to de novo review and analysis was extensive and broad, and a formal systematic review of this literature was not considered within scope of the committee's effort. However, the committee considered the available literature on this topic that consisted of reviews, wherein information from multiple experiments or databases was compiled and analyzed.
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From page 128... ...
Concordance does not require exact mimicry and can involve a continuum of interrelated biological responses that may act through different or multiple mechanisms, pathways, and organ systems. Adverse health effects in experimental animals and humans can differ from one another in presentation and still be concordant due to a range of reasons including variations that may occur in exposure conditions (e.g., timing and duration of exposure and toxicokinetic differences)
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Objectives, PECO Statements, and Inclusion/Exclusion Criteria Objective 1: To summarize the systematic reviews and authoritative reviews that assess the concordance of adverse health effects between laboratory mammalian models and humans following exposures to environmental agents • Populations: laboratory mammalian models, humans.
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Similar adverse health effects will be based on the preceding definition and include systemic apical endpoints (e.g., observable endpoints such as cancer, birth defects, and organ level effects) , and biolog ical responses (e.g., influences DNA/epigenome, oxidative stress, hormone responses, inflammation, immunosuppression, receptor mediation)
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Include authoritative reviews. • Include systematic reviews comparing results from mammalian model experiments.
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400,004 OR preclinical-drug-evaluation OR drug-evaluation,-preclinical OR drug evaluation-studies,-preclinical OR drug-evaluations,-preclinical OR drug screening OR drug-screenings OR evaluation,-preclinical-drug OR evaluation studies,-drug,-pre-clinical OR evaluation-studies,-drug,-preclinical OR evaluations,-preclinical drug OR medicinal-plants-testing,-preclinical OR preclinical-drug-evaluation OR preclinical-drug-evaluations OR screening,-drug OR screenings,-drug) .ti,ab 2 exp Mice/ or exp Rats/ or exp Guinea Pigs/ or exp Dogs/ or exp Swine, 2,309,138 Miniature/ or exp Primates/ 3 Exp Environmental Pollutants/ OR exp Environmental Exposure/ 537,271 4 1 and 2 300,812 5 Limit 4 to (animals and (meta-analysis or "systematic review")
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.ti,ab 2 Exp drug screening/ OR (antitumor drug screening assays OR antitumour drug 169,435 screening assays OR drug evaluation OR drug scanning OR drug testing OR drug trial OR pharmaceutical screening OR xenograft model antitumor assays OR xenograft model antitumour assays) .ti,ab 3 Exp mouse/ OR exp rat/ OR exp dog/ OR exp guinea pig/ OR exp minipig/ OR 26,014,544 exp ape/ OR exp chimpanzee/ OR exp orangutan/ OR exp halporhini/ or exp pan paniscus/ OR exp gorilla/ OR exp hominid/ OR (mice OR mouse OR rat OR rats OR Cavia OR ginea pig OR guinapig OR dog OR Canis canis OR Canis domesticus OR Canis familiaris OR Canis lupus familiaris OR micro pig OR micropig OR micropigs OR mini pig OR minipig OR mini swine OR miniswine OR miniature pig OR miniature swine OR minipigs OR miniswine OR apes OR hominoid OR Hominoidea OR Haplorrhini OR haplorhini OR monkey OR chimpanzee OR pan paniscus OR gorilla OR orangutan OR hominid OR bonobo)
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and (ape or dog or guinea pig 211 or monkey or mouse or rat or swine) 28 Limit 20 to (animal studies and (meta-analysis or "systematic review")
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73 45 Limited 36 to (meta-analysis or "systematic review") 2,866 Cochrane Database of Systematic Reviews # Query Results 1 Toxicology.mp 53 2 mice OR mouse OR rat OR rats OR Cavia OR ginea pig OR guinapig OR guinea 759 pig OR dog OR Canis canis OR Canis domesticus OR Canis familiaris OR Canis lupus familiaris OR micro pig OR micropig OR micropigs OR mini pig OR minipig OR mini swine OR miniswine OR miniature pig OR miniature swine OR minipigs OR miniswine OR apes OR hominoid OR Hominoidea OR Haplorrhini OR haplorhini OR monkey OR chimpanzee OR pan paniscus OR gorilla OR orangutan OR hominid OR bonobo 3 Pollutant*
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• Critical appraisal of methodologic quality/risk of bias using the AMSTAR 2 (A MeaS urement Tool to Assess systematic Reviews) tool • Accounting of identified studies, those excluded during abstract and full-text review Certainty of Evidence For the evaluation of each of the systematic reviews, an overall judgment will be reached based on the critical elements evaluated (see text description of the AMSTAR 2 approach below)
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, and at most one weakness in the other nine domains Moderate More than one noncritical weaknessa: the systematic review has Cannot have a critical weakness in more than one weakness but no critical flaws. It may provide an any of the seven critical domains accurate summary of the results of the available studies that were (Box C-1)
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From page 138... ...
where available. Charge question 2: Given What does the literature Review the scientific Scoping Question 2: the results of the literature review indicate about literature pertaining to What do systematic review and workshops, qualitative and the qualitative and reviews conclude about what are the implications quantitative variability quantitative variability in variability in of the qualitative and of laboratory laboratory mammalian laboratory quantitative variability of mammalian toxicity toxicity tests.
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From page 139... ...
Further information, including the detailed evaluation criteria, can be accessed for these studies via the evidence map dashboard.1 Of the 25 studies of higher methodological quality (i.e., with an overall judgment of low, moderate, or high) , 6 are described in the text of Chapters 3 and 4 (Andersen et al., 2020; Soliman et al., 2021; the two systematic reviews in the 2017 NASEM report [NASEM, 2017]
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The report focused on temporal aspects of animal test guidelines for endocrine disruption and found many gaps and limitations in design that compromised concordance. FIGURE C-1 PRISMA diagram for variability studies.
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Appendix C FIGURE C-2 PRISMA diagram for concordance studies.
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They should be considered inconclusive and used for hypothesis-generation only." An analysis of variability (qualitative or quantitative) across multiple laboratory mammalian toxicity studies was not included.
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One limitation of this systematic review is that the researchers only evaluated rat studies and did not include studies of other mammals. Although they noted there were studies in mice and hamsters, no method or data were reported to demonstrate a systematic search and evaluation of mouse and hamster studies.
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From page 144... ...
Introduction The goal of the supplemental literature review is to assemble material presented to the committee during the workshops and by the EPA to inform the committee's answers to the charge questions regarding variability and concordance. Specifically, the objective is as follows: to compile and assess studies presented to the committee by the EPA or at the workshops that assess variability or concordance of outcomes in laboratory mammalian studies following exposures to environmental agents (drugs, chemicals, radiation)
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From page 145... ...
• Include studies that evaluate any adverse health outcomes (observable systemic apical endpoints such as pathology, cancer, birth defects, and biological responses such as hor mone responses, mutagenicity, inflammation markers, immunological markers and other key characteristics as needed)
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From page 146... ...
Evaluation of Internal Validity The NIEHS DTT IHAB method (https://ntp.niehs.nih.gov/ntp/ohat/pubs/riskofbiastool_ 508.pdf) , with a question on funding bias, will be used for primary literature (i.e., presents primary data)
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Appendix C RESULTS Figure C-4 and Figure C-5 show the PRISMA diagrams for the supplemental literature review on variability and concordance, respectively. FIGURE C-4 PRISMA diagram for the supplemental literature on variability.
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The remaining studies on variability and concordance are further detailed in Table 3-3 and Table 4-2, respectively. FIGURE C-5 PRISMA diagram for the supplemental literature on concordance.
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From page 149... ...
2021. "Draft Systematic Review Protocol Support ing TSCA Risk Evaluations for Chemical Substances Version 1.0" https://www.epa.
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2020. "Perinatal Selective Serotonin Reuptake Inhibitor Exposure and Behavioral Out comes: A Systematic Review and Meta-Analyses of Animal Studies." Neuroscience and Bi obehavioral Reviews 114 (July)
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2016. "ROBIS: A New Tool to Assess Risk of Bias in Systematic Reviews Was Developed." Journal of Clinical Epidemiology 69, 225-234.
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