A primer on systematic reviews in toxicology

Hoffmann, Sebastian; Vries, Rob B. M. de; Stephens, Martin L.; Beck, Nancy B.; Dirven, Hubert; Fowle, John R.; Goodman, Julie E.; Hartung, Thomas; Kimber, Ian; Lalu, Manoj M.; Thayer, Kristina A.; Whaley, Paul; Wikoff, Daniele; Tsaioun, Katya

doi:10.1007/s00204-017-1980-3

Cited by 76 publications

(61 citation statements)

References 60 publications

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“…The large impact of such a formal process has been demonstrated in the field of medicine by the Cochrane collaboration and their 'systematic reviews and protocols' on health care. This concept has been adopted for toxicology by the Evidence-Based Toxicology Collaboration (Hoffmann and Hartung 2006), which addresses the quality scoring of existing studies (Samuel et al 2016) and systematic reviews (Stephens et al 2016;Hoffmann et al 2017). The AOP guidelines have particularly optimized this procedure for toxicity pathways.…”

Section: Systematic Collection Of Weight Of Evidencementioning

confidence: 99%

Adverse outcome pathways: opportunities, limitations and open questions

et al. 2017

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Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

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Section: Systematic Collection Of Weight Of Evidencementioning

confidence: 99%

Adverse outcome pathways: opportunities, limitations and open questions

et al. 2017

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“…A systematic review of the literature (Rooney et al, 2014;Stephens et al, 2016;Hoffmann et al, 2017) represents the most appropriate tool here.…”

Section: Limiting Testing Needsmentioning

confidence: 99%

Rebooting the generally recognized as safe (GRAS) approach for food additive safety in the US

Hartung

2018

ALTEX

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SummaryThe US Food and Drug Administration (FDA) has premarket review authority over food additives, but a food manufacturer may, according to the legislation, intentionally add a substance to human food or animal food without their premarket review or approval if the substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use. Generally recognized as safe (GRAS) implies that the current scientific community agrees on the adequacy of how data is generated. This system has come under public pressure because of doubts as to its efficiency and the FDA's recent GRAS rule is part of the response. The FDA guidance for testing food additives, known as the "Redbook", is about two decades old. Work toward a new "Redbook" is on the way, but the US Grocery Manufacturer Association (GMA) also has initiated the development of an independent standard on how to perform GRAS determinations. This review of the current guidance shows a very rigorous system for higher concern levels, but also many waiving options. Opportunities and challenges for safety evaluations of food additives are discussed. Where scientific progress has allowed improving existing and adapting new methods, these should be adopted to improve product safety and animal welfare. The continuous adaptation of such improved methods is therefore needed. Especially, there are opportunities to embrace developments within the toxicity testing for the 21 st century movement and evidence-based toxicology approaches. Also, the growing understanding of the limitations of traditional tests needs to be considered.

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“…As the environmental health community is beginning to utilise systematic review frameworks and integration techniques (such as GRADE), questions have been raised on how these concepts are considered within GRADE and whether they may be 'missing' or in need of refinement relative to their application in toxicology and risk assessment (Durrheim and Reingold, 2010;Hoffmann et al, 2017). As the environmental health community is beginning to utilise systematic review frameworks and integration techniques (such as GRADE), questions have been raised on how these concepts are considered within GRADE and whether they may be 'missing' or in need of refinement relative to their application in toxicology and risk assessment (Durrheim and Reingold, 2010;Hoffmann et al, 2017).…”

Section: )mentioning

confidence: 99%

EFSA Scientific Colloquium 23 – Joint European Food Safety Authority and Evidence‐Based Toxicology Collaboration Colloquium Evidence integration in risk assessment: the science of combining apples and oranges 25–26 October 2017 Lisbon, Portugal

2018

EFSA Supporting Publications

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In evidence-based scientific assessments, evidence synthesis is the step that occurs after collecting the data relevant to a clearly formulated research question and appraising the validity of the studies selected for the assessment, according to structured and pre-defined approaches. When studies are readily comparable, evidence synthesis is usually carried out through meta-analysis. In hazard assessment in chemical risk assessment (CRA), the process for combining evidence, 'evidence integration', is a recognised challenge as the underlying evidence bases are very diverse and not readily comparable (owing e.g. to varying degrees of validity and precision, diverse data types, different populations and species, models, end-points, routes of exposure, and evidence streamshuman observational studies, experimental animal studies, in vitro and computational models data). The European Food Safety Authority (EFSA) and the Evidence-Based Toxicology Collaboration (EBTC) organised a Colloquium to develop a multistakeholder understanding of the best practices, challenges and research needs for evidence integration in CRA, with a focus on hazard identification and on combining multiple studies and end-points for dose-response modelling. The methods discussed included: qualitative methods for integrating evidence within-and across evidence streams; biasadjusted meta-analysis; quantitative approaches to combine evidence across evidence streams; and quantitative approaches for combining multiple end-points and multiple studies for dose-response modelling. All these methods showed advantages and needs for further development, testing, validation and effective implementation. Support to this could be provided by: more published primary toxicological and epidemiological data; optimisation of study design; a shared primary data repository; the establishment of a community of knowledge of toxicologists, epidemiologists and statisticians. Equally, to be conducted soundly, evidence integration in CRA should be undertaken by multidisciplinary groups (toxicologists and methodologists knowledgeable of the various integration techniques). EFSA and EBTC will continue the collaboration towards the development, testing and validation of best practices for evidence-based CRA.

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A primer on systematic reviews in toxicology

Cited by 76 publications

References 60 publications

Adverse outcome pathways: opportunities, limitations and open questions

Adverse outcome pathways: opportunities, limitations and open questions

Rebooting the generally recognized as safe (GRAS) approach for food additive safety in the US

EFSA Scientific Colloquium 23 – Joint European Food Safety Authority and Evidence‐Based Toxicology Collaboration Colloquium Evidence integration in risk assessment: the science of combining apples and oranges 25–26 October 2017 Lisbon, Portugal

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