Concordance of Noncarcinogenic Endpoints in Rodent Chemical Bioassays

Summary The European Chemicals Agency, ECHA, made available a total of 13,832 oral toxicity studies for 8,568 substances up to December 2014. 75% of studies were from the retired OECD Test Guideline 401 (11% TG 420, 11% TG 423 and 1.5% TG 425). Concordance across guidelines, evaluated by comparing LD50 values ≥ 2,000 or < 2,000 mg/ kg bodyweight from chemicals tested multiple times between different guidelines, was at least 75% and for their own repetition more than 90%. In 2009, Bulgheroni et al. created a simple model for predicting acute oral toxicity using no observed adverse effect levels (NOAEL) from 28-day repeated dose toxicity studies in rats. This was reproduced here for 1,625 substances. In 2014, Taylor et al. suggested no added value of the 90-day repeated dose oral toxicity test given the availability of a low 28-day study with some constraints. We confirm that the 28-day NOAEL is predictive (albeit imperfectly) of 90-day NOAELs, however, the suggested constraints did not affect predictivity. 1,059 substances with acute oral toxicity data (268 positives, 791 negatives, all Klimisch score 1) were used for modeling: The Chemical Development Kit was used to generate 27 molecular descriptors and a similarity-informed multilayer perceptron showing 71% sensitivity and 72% specificity. Additionally, the k-nearest neighbors (KNN) algorithm indicated that similarity-based approaches alone may be poor predictors of acute oral toxicity, but can be used to inform the multilayer perceptron model, where this was the feature with the highest information value.

Section: Resultsmentioning

confidence: 59%

Analysis of public oral toxicity data from REACH registrations 2008-2014

Luechtefeld

2016

“…Only 11 chemicals had NOAEL below one third of the 28-day NOAEL, while 122 (91.7%) were within this limit. Given the reproducibility issues of repeated dose studies (Wang and Gray, 2015), this is strong confirmation of this pragmatic approach. The approach has not been evaluated for food additives though.…”

Section: Subchronic Toxicity Studies With Rodentsmentioning

confidence: 62%

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

Hartung

2018

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.

“…The OECD guidelines do not make randomization and blinding mandatory, and the guideline statistics do not control for multiple testing, despite the fact that about 60 endpoints are assessed. The cancer bioassay might be a difficult case as some colleagues argue, but when looking at the non-cancer endpoints for 37 substances, very little of the earlier chronic studies was reproduced and consistency between genders and rodent species was low (Wang and Gray, 2015).…”

Section: Evidence Vs Opinion As To Reporting Qualitymentioning

confidence: 99%

“…Guinea pigs and mice predict skin sensitization of each other in 77% of cases (Luechtefeld et al, 2016b). Mouse and rat have little prediction for each other's chronic toxicities (Wang and Gray, 2015).…”

Section: Animal Experiments Do Not Even Predict Other Animal Speciesmentioning

confidence: 99%

Opinion versus evidence for the need to move away from animal testing

Hartung

2017

toxicology, animal models are as much misleading as they are helpful. Half of the results are wrong (Ioannidis, 2005) -we only don't know which half… But the statement "half are wrong" is probably rather optimistic. Evidence versus opinion in toxicologyI am a strong advocate of evidence-based approaches, not least because I was one of the initiators of Evidence-based Toxicology (EBT) and the respective Collaboration and hold the first IntroductionFor the 10 th anniversary of Food for Thought … in ALTEX, it seemed appropriate to summarize what we have learned on this journey with respect to the core subject of this journal: the need for alternatives to animal experimentation. The series has mostly focused on toxicology, but here the aspects that apply also to drug development and basic research shall be considered.Sure, we need animal models -when we want to study animals. For example, we have to test drugs for animals in animals. However, when studying human physiology, pharmacology and Food for Thought ... Opinion Versus Evidence for the Need to Move Away from Animal Testing Thomas HartungJohns Hopkins University, Bloomberg School of Public Health, Center for Alternatives to Animal Testing (CAAT), Baltimore, MD, USA, and University of Konstanz, CAAT-Europe, Konstanz, Germany SummaryScience is based on facts and their discourse. Willingly or unwillingly, facts are mixed with opinion, i.e., views or judgments formed, not necessarily based on fact or knowledge. This is often necessary, where we have controversial facts or no definitive evidence yet, because we need to take decisions or have to prioritize. Evidence-based approaches aim at identifying the facts and their quality objectively and transparently; they are now increasingly embraced in toxicology, especially by employing systematic reviews, meta-analyses, quality scoring, risk-of-bias tools, etc. These are core to Evidence-based Toxicology. Such approaches aim at minimizing opinion, the "eminence-based" part of science. Animal experiments are the basis of a lot of our textbook knowledge in the life sciences, have helped to develop desperately needed therapies, and have made this world a safer place. However, they represent only one of the many possible approaches to accomplish all these things. Like all approaches, they come with shortcomings, and their true contribution is often overrated. This article aims to summarize their limitations and challenges beside the ethical and economical concerns (i.e., costs and duration as well as costs following wrong decisions in product development): they include reproducibility, inadequate reporting, statistical under-powering, lack of inter-species predictivity, lack of reflection of human diversity and of real-life exposure. Each and every one of these increasingly discussed aspects of animal experiments can be amended, but this would require enormous additional resources. Together, they prompt a need to engineer a new paradigm to ensure the safety of patients and consumers, new products and therapies.