A Tiered Approach to Systemic Toxicity Testing for Agricultural Chemical Safety Assessment

Doe, John; Boobis, Alan R.; Blacker, Ann M.; Dellarco, Vicki L.; Doerrer, Nancy G.; Franklin, Claire A.; Goodman, Jay I.; Kronenberg, Joel M.; Lewis, Richard; McConnell, Ernest E.; Mercier, Thierry Le; Moretto, Angelo; Nolan, Canice; Padilla, Stephanie; Phang, Whang; Solecki, Roland; Tilbury, Lorraine; Ravenzwaay, Bennard van; Wolf, Douglas C.

doi:10.1080/10408440500534370

Cited by 97 publications

(28 citation statements)

References 29 publications

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“…Those factors are used to refine testing priorities to focus first on areas of greatest concern in early tiers and then to move judiciously to advanced testing in later tiers as needed. In addition, an emphasis on pharmacokinetic studies in tiered approaches has been considered in recent discussions of improving toxicity testing of pesticides (Carmichael et al, 2006; Doe et al, 2006). …”

Section: Visionmentioning

confidence: 99%

Toxicity Testing in the 21st Century: A Vision and a Strategy

Krewski

Acosta

Andersen

et al. 2010

Journal of Toxicology and Environmental Health, Part B

787

475

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With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

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Section: Visionmentioning

confidence: 99%

Toxicity Testing in the 21st Century: A Vision and a Strategy

Krewski

Acosta

Andersen

et al. 2010

Journal of Toxicology and Environmental Health, Part B

787

475

View full text Add to dashboard Cite

show abstract

“…A number of analyses showed very convincingly that the test does not add to the 90-day-study in dogs (Appleman and Feron, 1986;Contrera et al, 1993;Gerbracht and Spielmann, 1998;Spielmann and Gerbracht, 2001;Box and Spielmann, 2005;Doe et al, 2006;Dellarco et al, 2010;Kobel et al, 2010Kobel et al, , 2014Linke et al, 2017). While this challenges the value of this animal test also for food additives, there is no similar analysis.…”

Section: One-year Toxicity Studies With Non-rodentsmentioning

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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“…In 2000, this organization redesigned safety testing schemes for agricultural chemicals. The resulting multifaceted approach was adopted by the International Commission on Harmonisation (ICH) and the US FDA.In these harmonized study guidelines traditional toxicology tests were redesigned to integrate several sciences, such as metabolism/kinetics and life stages, in a single study to eliminate the requirement for separate studies to evaluate each parameter and reduce the number of animals used [52][53][54][55]. Further, the metabolism/kinetics component of the strategy can be particularly relevant to the alleviation of pain in laboratory animals: based on the metabolism of a test substance in the animal model.…”

Section: Sd Defines Humane Endpoints In Toxicology Studiesmentioning

confidence: 99%