The EU Green Deal's ambition for a toxic-free environment: filling the gap for science-based policy making

Around the world, many ambitious environmental conventions and regulations have been implemented over recent decades. Despite this, the environment is still deteriorating. An increase in the volume and diversity of chemicals is one of the main drivers of this deterioration, of which biodiversity loss is a telling indicator. In response to this situation, in October 2020, a chemicals strategy for sustainability (CSS) was published in the EU. The CSS is the first regional framework aiming to address chemical pollution in a holistic manner. The CSS covers the complete lifecycle of a chemical, including the design of better substances and remediation options, to remove chemicals from the environment. The strategy contains terms, such as a “toxic-free environment,” for which no clear definition exists, potentially hampering the implementation of the CSS. In this paper, a definition for a “toxic-free environment” is proposed on the basis of a survey and a discussion held at the 2020 SETAC Europe Annual Meeting. In addition, key issues that are absent from the CSS but are considered to be key for the realization of a toxic-free environment are identified. To achieve the policy goals, it is recommended to align the definition of risk across the different chemical legislations, to establish a platform for open data and data sharing, and to increase the utility and use of novel scientific findings in policymaking, through the development of a strong science to regulation feedback mechanism and vice versa. The paper concludes that environmental scientists have the tools to address the key challenges presented in the CSS. However, an extra step is needed by both policymakers and scientists to develop methods, processes and tools, to increase the robustness and transparency of deliberation processes, and the utility of science. Integr Environ Assess Manag 2021;17:1105–1113

The EU Green Deal's ambition for a toxic-free environment:Filling the gap for science-based policymaking

Around the world, many ambitious environmental conventions and regulations have been implemented over recent decades. Despite this, the environment is still deteriorating. An increase in the volume and diversity of chemicals is one of the main drivers of this deterioration, of which biodiversity loss is a telling indicator. In response to this situation, in October 2020, a chemicals strategy for sustainability (CSS) was published in the EU. The CSS is the first regional framework aiming to address chemical pollution in a holistic manner. The CSS covers the complete lifecycle of a chemical, including the design of better substances and remediation options, to remove chemicals from the environment. The strategy contains terms, such as a “toxic-free environment,” for which no clear definition exists, potentially hampering the implementation of the CSS. In this paper, a definition for a “toxic-free environment” is proposed on the basis of a survey and a discussion held at the 2020 SETAC Europe Annual Meeting. In addition, key issues that are absent from the CSS but are considered to be key for the realization of a toxic-free environment are identified. To achieve the policy goals, it is recommended to align the definition of risk across the different chemical legislations, to establish a platform for open data and data sharing, and to increase the utility and use of novel scientific findings in policymaking, through the development of a strong science to regulation feedback mechanism and vice versa. The paper concludes that environmental scientists have the tools to address the key challenges presented in the CSS. However, an extra step is needed by both policymakers and scientists to develop methods, processes and tools, to increase the robustness and transparency of deliberation processes, and the utility of science

Diagnosing Childhood-onset Inborn Errors of Metabolism by Next Generation Sequencing

BACKGROUND : Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches. METHODS : We designed and validated a Next Generation Sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based sub-panels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs. RESULTS : In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0·0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0·0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause. CONCLUSIONS : NGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis.The Manchester Biomedical Research Centre, the British Inherited Metabolic Disease Group 2015 Studentship scheme and the Central Manchester NHS Foundation Trust Newly Appointed Consultants Leadership Programme 2014.http://adc.bmj.comhb2017Paediatrics and Child Healt

Structure of the MutLα\alpha C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site.

International audienceMismatch-repair factors have a prominent role in surveying eukaryotic DNA-replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutLα (Mlh1-Pms1 heterodimer) C-terminal domain (CTD) from $Saccharomyces\ cerevisiae$, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutLα as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutLα(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs