Enhancing global and local decision making for chemical safety assessments through increasing the availability of data.

Toxicity safety assessments are a fundamental part of the lifecycle of products and aim to protect human health and the environment from harmful exposures to chemical substances. To make decisions regarding the suitability of testing strategies, the applicability of individual tests or concluding an assessment for an individual chemical requires data. This review outlines how different forms of data sharing, from enhancing publicly-available data to extracting knowledge from commercially-sensitive data, leads to increased quantity and quality of evidence being available for safety assessors to review. This can result in more confident decisions for different use cases in the context of chemical safety assessments. Although a number of challenges remain with progressing the evolution of toxicity safety assessments, data sharing should be considered as a key approach to accelerating the development and uptake of new best practices.

Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment

The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.

Employing an adverse outcome pathway framework for weight-of-evidence assessment with application to the ICH S1B guidance addendum.

Across industry, there is a paradigm shift occurring for carcinogenicity testing, with the focus moving from long term animal studies to alternative approaches. Based on the explorative work done in recent years, the International Council for Harmonization (ICH) recently published a draft addendum to the S1B guidance, which allows for a weight-of-evidence (WoE) assessment to be conducted based on data gathered throughout the pharmaceutical development process and literature to mitigate some testing in rodents if the body of evidence clearly shows undertaking an animal lifetime study would not add value to the risk assessment. While several alternative approaches already exist, and other new approach methodologies (NAMs) are being explored, all of which can contribute to this WoE, it is important that all the evidence can be combined in a meaningful and consistent way to reach a conclusion. Adverse outcome pathways have been advocated as a framework for organising evidence in an integrated approach to testing and assessment, which gives context to data and can aid reaching a conclusion as to the adverse outcome (AO). This approach can be combined with a reasoning methodology to give a prediction for an AO and applied to the factors which need to be considered for the ICH S1B WoE to predict for carcinogenicity. Using this approach to the WoE assessment, consistent, scientifically robust, and transparent calls can be made as to whether conducting an animal carcinogenicity study would add value to a human risk assessment and mitigate the need to run animal studies unnecessarily.

Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory.

The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-ß expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control.