A developmental neurotoxicity adverse outcome pathway (DNT-AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE).

The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion.

Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals.

Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available for only a small percentage of manufactured compounds. Test methods with a higher throughput than current regulatory guideline methods, and with improved human relevance are urgently needed.

Current status and future directions for a neurotoxicity hazard assessment framework that integrates approaches.

Neurotoxicology is the study of adverse effects on the structure or function of the developing or mature adult nervous system following exposure to chemical, biological, or physical agents. The development of more informative alternative methods to assess developmental (DNT) and adult (NT) neurotoxicity induced by xenobiotics is critically needed. The use of such alternative methods including approaches that predict DNT or NT from chemical structure (e.

Evaluating Confidence in Toxicity Assessments Based on Experimental Data and Predictions.

Understanding the reliability and relevance of a toxicological assessment is important for gauging the overall confidence and communicating the degree of uncertainty related to it. The process involved in assessing reliability and relevance is well defined for experimental data. Similar criteria need to be established for predictions, as they become increasingly more important to fill data gaps and need to be reasonably integrated as additional lines of evidence.

The Tox21 10K Compound Library: Collaborative Chemistry Advancing Toxicology.

Since 2009, the Tox21 project has screened ∼8500 chemicals in more than 70 high-throughput assays, generating upward of 100 million data points, with all data publicly available through partner websites at the United States Environmental Protection Agency (EPA), National Center for Advancing Translational Sciences (NCATS), and National Toxicology Program (NTP). Underpinning this public effort is the largest compound library ever constructed specifically for improving understanding of the chemical basis of toxicity across research and regulatory domains. Each Tox21 federal partner brought specialized resources and capabilities to the partnership, including three approximately equal-sized compound libraries.

Harmonized Cross-Species Assessment of Endocrine and Metabolic Disruptors by Ecotox FACTORIAL Assay.

Environmental pollution is a threat to humans and wildlife species. Of particular concern are endocrine disrupting chemicals (EDCs). An important target of EDCs is nuclear receptors (NRs) that control endocrine and metabolic responses through transcriptional regulation.

Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library.

Background: Thyroid hormone receptors (TRs) are critical endocrine receptors that regulate a multitude of processes in adult and developing organisms, and thyroid hormone disruption is of high concern for neurodevelopmental and reproductive toxicities in particular. To date, only a small number of chemical classes have been identified as possible TR modulators, and the receptors appear highly selective with respect to the ligand structural diversity. Thus, the question of whether TRs are an important screening target for protection of human and wildlife health remains.

Evaluating Chemicals for Thyroid Disruption: Opportunities and Challenges with in Vitro Testing and Adverse Outcome Pathway Approaches.

Background: Extensive clinical and experimental research documents the potential for chemical disruption of thyroid hormone (TH) signaling through multiple molecular targets. Perturbation of TH signaling can lead to abnormal brain development, cognitive impairments, and other adverse outcomes in humans and wildlife. To increase chemical safety screening efficiency and reduce vertebrate animal testing, in vitro assays that identify chemical interactions with molecular targets of the thyroid system have been developed and implemented.

Corrigendum to Recommendation on test readiness criteria for new approach methods in toxicology: exemplified for developmental neurotoxicity.

In this manuscript, which appeared in ALTEX 35 , 306-352 ( doi:10.14573/altex.1712081 ), the Acknowledgements should read: This work was supported by the Doerenkamp-Zbinden Foundation, EFSA, the BMBF, JPI-NutriCog-Selenius, and it has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No.

International Regulatory and Scientific Effort for Improved Developmental Neurotoxicity Testing.

The Organisation for Economic Co-Operation and Development (OECD) coordinates international efforts to enhance developmental neurotoxicity (DNT) testing. In most regulatory sectors, including the ones dealing with pesticides and industrial chemicals registration, historical use of the in vivo DNT test guideline has been limited. Current challenges include a lack of DNT data and mechanistic information for thousands of chemicals, and difficulty in interpreting results.

The US Federal Tox21 Program: A strategic and operational plan for continued leadership.

The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be tested, time and resource intensive nature of traditional toxicity tests, and unexpected adverse effects that occur in pharmaceutical clinical trials despite the extensive toxicological testing.Over a decade ago, the U.

Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity.

Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria.

Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes.

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential.

Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations.

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and non-governmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathways-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research.

The Next Generation of Risk Assessment Multi-Year Study-Highlights of Findings, Applications to Risk Assessment, and Future Directions.

Background: The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.

Objective: Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.

FutureTox III: Bridges for Translation.

Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making.

ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology.

The U.S. Environmental Protection Agency's (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches to support the development of improved toxicity prediction models.

Environmentally relevant pyrethroid mixtures: A study on the correlation of blood and brain concentrations of a mixture of pyrethroid insecticides to motor activity in the rat.

Human exposure to multiple pyrethroid insecticides may occur because of their broad use on crops and for residential pest control. To address the potential health risk from co-exposure to pyrethroids, it is important to understand their disposition and toxicity in target organs such as the brain, and surrogates such as the blood when administered as a mixture. The objective of this study was to assess the correlation between blood and brain concentrations of pyrethroids and neurobehavioral effects in the rat following an acute oral administration of the pyrethroids as a mixture.

Editor's Highlight: Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space.

Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, responses of 1060 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a battery of 815 in vitro assay endpoints from 7 high-throughput assay technology platforms were analyzed in order to distinguish between these types of activities. Both cell-based and cell-free assays showed a rapid increase in the frequency of responses at concentrations where cell stress/cytotoxicity responses were observed in cell-based assays.

Effects of an environmentally-relevant mixture of pyrethroid insecticides on spontaneous activity in primary cortical networks on microelectrode arrays.

Pyrethroid insecticides exert their insecticidal and toxicological effects primarily by disrupting voltage-gated sodium channel (VGSC) function, resulting in altered neuronal excitability. Numerous studies of individual pyrethroids have characterized effects on mammalian VGSC function and neuronal excitability, yet studies examining effects of complex pyrethroid mixtures in mammalian neurons, especially in environmentally relevant mixture ratios, are limited. In the present study, concentration-response functions were characterized for five pyrethroids (permethrin, deltamethrin, cypermethrin, β-cyfluthrin and esfenvalerate) in an in vitro preparation containing cortical neurons and glia.

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries.

High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the U.S.

Expanding the test set: Chemicals with potential to disrupt mammalian brain development.

High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery.