Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is ...not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential.
We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential.
•Current in vivo developmental neurotoxicity (DNT) testing is not efficient and coverage is sparse.•In vitro mechanistic data could support various regulatory applications.•Human induced pluripotent stem cell-derived neuronal models are recommended for DNT testing.•Further development of adverse outcome pathways relevant to DNT is urgently needed.•In vitro approaches should be included in regulatory DNT testing
The EU Directive 2010/63/EU on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way ...toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.
This Guidance describes how to perform hazard identification for endocrine‐disrupting properties by following the scientific criteria which are outlined in Commission Delegated Regulation (EU) ...2017/2100 and Commission Regulation (EU) 2018/605 for biocidal products and plant protection products, respectively.
This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2018.EN-1447/full
Structured frameworks are extremely useful in promoting transparent, harmonized approaches to the risk assessment of chemicals. One area where this has been particularly successful is in the analysis ...of modes of action (MOAs) for chemical carcinogens in experimental animals and their relevance to humans. The International Programme on Chemical Safety (IPCS) recently published an updated version of its MOA framework in animals to address human relevance (cancer human relevance framework, or HRF). This work has now been extended to noncancer effects, with the eventual objective of harmonizing framework approaches to both cancer and noncancer endpoints. As in the cancer HRF, the first step is to determine whether the weight of evidence based on experimental observations is sufficient to establish a hypothesized MOA. This comprises a series of key events causally related to the toxic effect, identified using an approach based on the Bradford Hill criteria. These events are then compared qualitatively and, next, quantitatively between experimental animals and humans. The output of the analysis is a clear statement of conclusions, together with the confidence, analysis, and implications of the findings. This framework provides a means of ensuring a transparent evaluation of the data, identification of key data gaps and of information that would be of value in the further risk assessment of the compound, such as on dose-response relationships, and recognition of potentially susceptible subgroups, for example, based on life-stage considerations.
The rising prevalence of adolescent mental health problems has created a need for increased public health programming in schools. Globalization and the expansion of the International Baccalaureate ...programs have led to higher numbers of Third Culture Kids (TCKs) attending international schools worldwide. Our review highlights unique characteristics of TCKs and presents a tactical blueprint to meet mental health needs. The first step was to develop an overview of existing mental health promotion practices implemented in national schools across the globe and the research that influenced their development. A second step was to provide suggestions for the application of these blueprints and resultant programs within international schools.
•Endocrine disruption is a complex and important toxicological problem to consider.•The retinoid system is evolutionary conserved and central for endocrine regulation.•Regulatory tests are missing ...for assessing the retinoid system at any life-stage.•Ongoing work by OECD member states will identify knowledge gaps and testing needs.
Endocrine disruption continues to be a matter of high concern, and a subject of intensive activities at the public, political, regulatory and academic levels. Currently, available regulatory test guidelines (TGs) relevant to the identification of endocrine disrupters are largely limited to estrogen, androgen, thyroid and steroidogenesis (EATS) pathways. Thus, there is an increasing interest and need to develop test methods, biomarkers, and Adverse Outcome Pathways (AOPs), for identification and evaluation of endocrine disrupters in addition to the EATS pathways. An activity focusing on the retinoid system has been jointly initiated by the Swedish Chemicals Agency and the European Commission. The retinoid system is involved in fundamental life processes and has been described, in previous work at the OECD, as a system susceptible to environmental endocrine disruption, the disruption of which could contribute to the increasing incidence of certain disorders in humans and wildlife populations.
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