257 research outputs found

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    Unraveling Druggable Key Nodes in Gene Regulatory and Signaling Networks by Integrative Analysis of Multi-omics Data from Head and Neck Cancer

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    Background: Cancer cell plasticity is a fundamental process in the generation of tumor heterogeneity (1). Clonal selection and enrichment of drug-resistant cancer cells are the most common drivers of treatment failure. Identifying underlying molecular principles of tumor heterogeneity remains a major challenge (2). Recently, several studies demonstrated cancer cell plasticity in the pathogenesis and therapy of head and neck cancer. They highlighted SOX2 and SOX9 as key determinants for intrinsic cancer cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related gene regulatory networks with risk factors and genetic or epigenetic alterations in primary head and neck squamous cell carcinoma (HNSCC), and their prognostic value is largely unknown. In the first part of my research project, I identified differentially expressed genes (DEGs) related to inverse SOX2 and SOX9 transcription in TCGA-HNSC, which enabled the clustering of patients into groups with distinct clinical features and survival (3). In the second part, I investigate the cancer-neuron interaction (CNI) as a potential mode of extrinsic regulation of cancer cell plasticity. Early in cancer development, nerve fibers (NF) form and infiltrate tumor tissue, and the density of NF in solid tumors has been associated with a poor prognosis. Though the origin of cancer-related NF and the mode of their mutual interaction with cancer or stromal cells of the tumor microenvironment (TME) are elusive. NF and their associated cells such as Schwann cells (SCs) are emerging as key regulators of cancer initiation, progression, and metastasis. Therefore, SCs might serve as a surrogate marker for the extent of CNI. SCs interact with cancer cells, and the accompanying process of axonal sprouting at the premalignant phase provides the first cancer access to nerves, leading to neural dissemination at an early disease stage (4,5). So, as its crucial role in attracting cancer cells to the perineural niche and enabling adhesion of cancer cells to the nerves, their roles need to be generously addressed in the cancer-nerve cross talk in all solid tumors, including HNSCC. Aims: Various tumor cell-intrinsic and extrinsic factors have been demonstrated to be involved in regulating lineage plasticity. The mechanism of the tumor cell-intrinsic lineage plasticity (e.g., mutational landscape, epigenetic regulation, signaling, and gene regulatory networks), while tumor cell-extrinsic lineage plasticity depends on (e.g., cellular and matrix components of TME). So, in this study, I aimed extensively to examine cancer cell plasticity in the pathogenesis and therapy of HNSCC and other tumors. 1. Focus on cancer cell-intrinsic mechanisms and modulators of plasticity, particularly the role of SOX family members in cancer lineage plasticity, and more precisely the inverse regulation of SOX2- and SOX9-related gene networks in HNSCC and other tumor entities. Clinical relevance of inverse SOX2-SOX9 expression for HNSCC and other tumor entities. Establishment risk models to identify patients with primary HNSCC and other cancers at a higher risk for treatment failure, who might benefit from a therapy targeting SOX2/SOX9-related gene regulatory and signaling networks. Molecular and cellular characterization of the predicted risk models in HNSCC and other tumor entities. 2. Focus on cancer cell-extrinsic mechanisms and modulators of plasticity, particularly the role of molecular mechanisms contributing to the complex crosstalk between cancer cells, neurons, and their associated glial cells such as Schwann cells. Clinical relevance of nerve fibers and associated cells such as Schwann cells for HNSCC and other tumor entities. Molecular characterization of cancer-nerve crosstalk in HNSCC and other tumor types. Establishment and analysis of pre-clinical models as a proof-of-concept for new therapeutic strategies. Results: 1. Differentially expressed genes (DEG) related to SOX2 and SOX9 transcription were identified in TCGA-HNSC, which enables the clustering of patients into groups with distinct clinical features and survival. Moreover, a prognostic risk model was established by LASSO Cox regression based on expression patterns of DEGs in TCGA-HNSC (training cohort) and was confirmed in independent HNSCC validation cohorts as well as other cancer cohorts from TCGA. Additionally, differences in the mutational landscape among risk groups of TCGA-HNSC demonstrated enrichment of truncating NSD1 mutations for the low-risk group and elucidated DNA methylation as a modulator of SOX2 expression. The GSVA revealed differences in several oncogenic pathways among risk groups, including upregulation of gene sets related to oncogenic KRAS signaling for the high-risk group. Finally, in silico drug screen analysis revealed numerous compounds targeting EGFR signaling with significantly lower efficacy for cancer cell lines with a higher risk phenotype, but also indicated potential vulnerabilities. 2. A SC-related 43-gene set was elucidated as an accurate surrogate for the presence of peripheral nerves across solid tumor entities. This model is characterized by higher oncogenic pathway activities such as TGF-β signaling in the group with a high SC score with an immunosuppressive phenotype and higher PI3K-AKT-MTOR pathway and cell cycle pathway activity in the group with a lower SC score with an immune active phenotype and more sensitivity to topoisomerase agents as potential treatment vulnerabilities. Finally, the impact of PI3K pathway activity on TME abundance of peripheral neurons is context-dependent and dominated by the TP53 status. References: 1. DOI: 10.1038/nrc3261 2. DOI: 10.1016/j.cell.2017.01.018 3. DOI: 10.1158/1541-7786.MCR-21-0066 4. DOI: 10.1038/nrc.2016.38 5. DOI: 10.1016/0016-5085(94)90080-

    Multi-Omic and Single-cell Characterization of a 3D Skin-Like Tissue Model of Systemic Sclerosis with a Focus on Epigenetics

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    Systemic sclerosis (SSc) is a rare fibrotic autoimmune disease with high mortality and limited FDA approved therapies. Clinical concordance among twins is low; however, a modest familial heritability implicates complex interactions between polygenic risk alleles and the environment as causal – interactions that are mediated by epigenetics. Although mechanisms of tissue fibrosis have been successfully identified and targeted in established in vitro models for SSc, these molecules have ultimately failed in clinical trials. This likely reflects the lack of a reliable in vitro model that faithfully recapitulates the disease. I utilized a 3D skin-like tissue model to study SSc skin fibrosis. I paired this model with epigenomic analysis of Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq). The goal was two-fold: 1) to epigenetically characterize and validate this 3D model and 2) to elucidate epigenetic mechanisms of skin fibrosis at a single-cell level using our 3D tissue model. In Chapter 2, I showed that SSc 3D tissues have patterns of chromatin accessibility that are distinct from monolayer fibroblasts. I also identified a novel region of SSc dysregulation predicted to regulate expression of the gene FER1L6. In Chapter 3, I used a similar experimental strategy to determine if select variants implicated in disease susceptibility impact chromatin accessibility. I identified a region of potential chromatin dysregulation in fibroblasts from an SSc individual with African-Ancestry specific variants of interest. This study demonstrates the potential to determine causality of SSc-associated non-coding variants. In Chapter 4, I applied single-cell ATAC-seq to a 3D tissue model containing increased cellular complexity. I identified several fibroblast subpopulations that correlated with those identified in human skin. Finally, I proposed a model for epigenetic dysregulation in SSc skin fibrosis. These findings establish that 3D tissues are epigenetically distinct from monolayer cultures and closely approximate human skin fibroblast populations. Using this model, I validated previous findings in addition to generating novel insights. Collectively, I believe this body of work contributes to a more accurate understanding of SSc skin fibrosis and establishes a reliable in vitro model for identification of targeted epigenetic therapies that can more effectively translate to clinical improvement

    Proceedings of 14th international symposium Modern trends in livestock production

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    The impact of realistic environmental chemical exposure on male gonadal development and reproductive health

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    Continuing declines in human male reproductive health are of increasing concern. Many believe low-dose exposure to vast numbers of chemicals through the environment, particularly during fetal development, are a contributary factor in this decline. To address limitations with traditional, component-based methodologies of assessing chemical mixtures, this research utilised a unique, ovine based, whole-mixture exposure model. This model was used to investigate the impact of gestational exposure to realistic numbers of chemicals, at appropriately low doses, on male reproductive development. The research detailed herein characterises exposure-induced changes to the testes of neonatal, pre-pubertal, and adult male offspring of mothers exposed to an environmental chemical mixture prior to and during pregnancy. A testicular dysgenesis syndrome (TDS)-like phenotype was described in neonatal and prepubertal testes. This TDS-like phenotype was complemented by transcriptomic analyses which showed an extremely high degree of similarity between the testicular transcriptome of the affected pre-pubertal male offspring and those of human TDS patients. While this phenotype was not apparent in the same manner by adulthood, morphological and transcriptomic alterations were still apparent. This both exemplifies the potential for xenobiotic exposure during fetal development to impact reproductive health in later life, despite the cessation of exposure at birth, and indicates periods of post-partum vulnerability to xenobiotic exposure crucial to the persistence of or recovery from the TDS-like phenotype. Further investigations following transcriptomic analyses identified perturbations in the transcription, activation, and/or nuclear localisation of various transcription factors. Of these, there is supporting evidence that one (HIF1α) may have an important role in the pathogenesis of the TDS-like phenotype, while another (CREB1) may facilitate an amount of post-exposure recovery and might also be important in determining susceptibility or resistance to developing the TDS-phenotype. Overall, these findings strengthen the increasing evidence that gestational exposure to realistic levels and mixtures of environmental chemicals can have a negative impact on male reproductive health and provides leads for future investigations into the pathogenesis of TDS

    Investigating the effects of platelet derived growth factor on the microRNA cargo content and function of vascular smooth muscle cell-derived extracellular vesicles

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    Invasive revascularisation procedures such as coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used to treat advanced atherosclerosis. The CABG procedure is the most common type of cardiac surgery performed in the UK and the great saphenous vein (SV) remains the most widely used conduit largely due to availability and length. However, recent reports suggest that approximately 50% of all SV grafts fail at 10 years following CABG and the incidence of arterial restenosis, following drug-eluting stent (DES) implantation remains around 10%. Vascular smooth muscle cells (VSMCs) proliferation- and migration- driven neointimal formation post CABG- and/or PCI- induced vascular injury has been considered a major pathological driver of both vein graft disease (VGD) and in-stent restenosis (ISR) ultimately leading to treatment failure. Accumulating evidence suggests that extracellular vesicles (EVs) play a significant role in intercellular communication in both physiological and pathophysiological conditions, and due to their promising therapeutic potential, EVs are currently being extensively studied as disease mediators and therapeutic delivery vehicles. Understanding the different mechanisms that may be involved in the regulation of VSMC-driven neointimal formation remains an important step towards successfully developing therapeutic strategies that could improve clinical outcomes associated with both CABG and PCI. Therefore, the primary aim of this thesis was to study the effect of VSMC-derived EVs on recipient cell responses with a particular focus on EV-mediated autocrine regulation of VSMC. Since abnormal signalling mediated by platelet-derived growth factor (PDGF), has been implicated in the development of neointimal formation post vascular injury, prolonged PDGF stimulation of human SV smooth muscle cells (HSVSMCs) was used to model the pathological conditions under which neointimal lesions develop in an in vitro setting. Following the optimisation of an EV purification method, EVs were obtained from the conditioned culture media (CCM) of HSVSMCs +/- PDGF stimulation and successfully characterised in terms of size, concentration, protein content and morphological appearance. It was found that while EV size and morphology remained unaltered, PDGF stimulation of HSVSMCs resulted in increased EV secretion. Further studies determined that PDGF was not packaged into EVs after prolonged PDGF treatment of HSVSMCs. Next, following small RNA sequencing (RNAseq) analysis, it was found that PDGF stimulation of HSVSMCs induced significant changes in their EV cargo. Six known differentially expressed miRNAs: miR-24-3p, miR-409-3p, miR-21-5p, let-7A-5p, miR-1-3p and miR-224-5p, were found to be significantly upregulated in PDGF EVs compared to control EVs. Four out of six differentially expressed miRNAs (miR-24-3p, miR-224-5p, miR-409-3p and, let-7A-5p) were also successfully validated by qRT-PCR analysis. Gene set enrichment analysis (GSEA) revealed that miR-24-3p and miR-224-5p miRNAs may be involved in the regulation of biological processes such as cell proliferation, migration, and apoptosis - all previously implicated in the development of neointimal formation. Next, the effects of miR-24-3p or miR-224-5p EVs on HSVSMC proliferation, migration and cell viability were assessed. It was found that, while neither miR24-3p EVs nor miR-224-5p EVs had any significant effect on PDGF-induced HSVSMC proliferation and cell viability compared to naïve EVs, miR-224-5p EVs significantly inhibited EV-depleted foetal bovine serum (FBS)-induced HSVSMC migration compared to both naïve EVs and miR-24-3p EVs through an unknown mechanism. Finally, it was found that serum EVs from mice with carotid artery ligation induced vascular injury do not significantly differ compared to EVs from control mice in terms of size and concentration. However, qRT-PCR analysis of miR-24- 3p and miR-224-5p suggested that the expression of both miRNAs was significantly upregulated in serum EVs isolated from injured mice at day 14 and day 5 after surgery respectively compared to control mice. Overall, these studies provide evidence that prolonged PDGF signalling in HSVSMCs significantly alters the EV population secreted by those cells in terms of concentration of particles released and miRNA expression profile. Additionally, the demonstrated ability of miR-224-5p EVs to supress HSVSMC migration compared to naïve EVs and miR-24-3p EVs provides valuable insights into an alternative mechanism of EV-mediated regulation of VSMCs with promising potential for future therapeutic studies

    The Minderoo-Monaco Commission on Plastics and Human Health

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    BACKGROUND: Plastics have conveyed great benefits to humanity and made possible some of the most significant advances of modern civilization in fields as diverse as medicine, electronics, aerospace, construction, food packaging, and sports. It is now clear, however, that plastics are also responsible for significant harms to human health, the economy, and the earth's environment. These harms occur at every stage of the plastic life cycle, from extraction of the coal, oil, and gas that are its main feedstocks through to ultimate disposal into the environment. The extent of these harms not been systematically assessed, their magnitude not fully quantified, and their economic costs not comprehensively counted. GOALS: The goals of this Minderoo-Monaco Commission on Plastics and Human Health are to comprehensively examine plastics' impacts across their life cycle on: (1) human health and well-being; (2) the global environment, especially the ocean; (3) the economy; and (4) vulnerable populations-the poor, minorities, and the world's children. On the basis of this examination, the Commission offers science-based recommendations designed to support development of a Global Plastics Treaty, protect human health, and save lives. REPORT STRUCTURE: This Commission report contains seven Sections. Following an Introduction, Section 2 presents a narrative review of the processes involved in plastic production, use, and disposal and notes the hazards to human health and the environment associated with each of these stages. Section 3 describes plastics' impacts on the ocean and notes the potential for plastic in the ocean to enter the marine food web and result in human exposure. Section 4 details plastics' impacts on human health. Section 5 presents a first-order estimate of plastics' health-related economic costs. Section 6 examines the intersection between plastic, social inequity, and environmental injustice. Section 7 presents the Commission's findings and recommendations. PLASTICS: Plastics are complex, highly heterogeneous, synthetic chemical materials. Over 98% of plastics are produced from fossil carbon- coal, oil and gas. Plastics are comprised of a carbon-based polymer backbone and thousands of additional chemicals that are incorporated into polymers to convey specific properties such as color, flexibility, stability, water repellence, flame retardation, and ultraviolet resistance. Many of these added chemicals are highly toxic. They include carcinogens, neurotoxicants and endocrine disruptors such as phthalates, bisphenols, per- and poly-fluoroalkyl substances (PFAS), brominated flame retardants, and organophosphate flame retardants. They are integral components of plastic and are responsible for many of plastics' harms to human health and the environment.Global plastic production has increased almost exponentially since World War II, and in this time more than 8,300 megatons (Mt) of plastic have been manufactured. Annual production volume has grown from under 2 Mt in 1950 to 460 Mt in 2019, a 230-fold increase, and is on track to triple by 2060. More than half of all plastic ever made has been produced since 2002. Single-use plastics account for 35-40% of current plastic production and represent the most rapidly growing segment of plastic manufacture.Explosive recent growth in plastics production reflects a deliberate pivot by the integrated multinational fossil-carbon corporations that produce coal, oil and gas and that also manufacture plastics. These corporations are reducing their production of fossil fuels and increasing plastics manufacture. The two principal factors responsible for this pivot are decreasing global demand for carbon-based fuels due to increases in 'green' energy, and massive expansion of oil and gas production due to fracking.Plastic manufacture is energy-intensive and contributes significantly to climate change. At present, plastic production is responsible for an estimated 3.7% of global greenhouse gas emissions, more than the contribution of Brazil. This fraction is projected to increase to 4.5% by 2060 if current trends continue unchecked. PLASTIC LIFE CYCLE: The plastic life cycle has three phases: production, use, and disposal. In production, carbon feedstocks-coal, gas, and oil-are transformed through energy-intensive, catalytic processes into a vast array of products. Plastic use occurs in every aspect of modern life and results in widespread human exposure to the chemicals contained in plastic. Single-use plastics constitute the largest portion of current use, followed by synthetic fibers and construction.Plastic disposal is highly inefficient, with recovery and recycling rates below 10% globally. The result is that an estimated 22 Mt of plastic waste enters the environment each year, much of it single-use plastic and are added to the more than 6 gigatons of plastic waste that have accumulated since 1950. Strategies for disposal of plastic waste include controlled and uncontrolled landfilling, open burning, thermal conversion, and export. Vast quantities of plastic waste are exported each year from high-income to low-income countries, where it accumulates in landfills, pollutes air and water, degrades vital ecosystems, befouls beaches and estuaries, and harms human health-environmental injustice on a global scale. Plastic-laden e-waste is particularly problematic. ENVIRONMENTAL FINDINGS: Plastics and plastic-associated chemicals are responsible for widespread pollution. They contaminate aquatic (marine and freshwater), terrestrial, and atmospheric environments globally. The ocean is the ultimate destination for much plastic, and plastics are found throughout the ocean, including coastal regions, the sea surface, the deep sea, and polar sea ice. Many plastics appear to resist breakdown in the ocean and could persist in the global environment for decades. Macro- and micro-plastic particles have been identified in hundreds of marine species in all major taxa, including species consumed by humans. Trophic transfer of microplastic particles and the chemicals within them has been demonstrated. Although microplastic particles themselves (>10 µm) appear not to undergo biomagnification, hydrophobic plastic-associated chemicals bioaccumulate in marine animals and biomagnify in marine food webs. The amounts and fates of smaller microplastic and nanoplastic particles (MNPs <10 µm) in aquatic environments are poorly understood, but the potential for harm is worrying given their mobility in biological systems. Adverse environmental impacts of plastic pollution occur at multiple levels from molecular and biochemical to population and ecosystem. MNP contamination of seafood results in direct, though not well quantified, human exposure to plastics and plastic-associated chemicals. Marine plastic pollution endangers the ocean ecosystems upon which all humanity depends for food, oxygen, livelihood, and well-being. HUMAN HEALTH FINDINGS: Coal miners, oil workers and gas field workers who extract fossil carbon feedstocks for plastic production suffer increased mortality from traumatic injury, coal workers' pneumoconiosis, silicosis, cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer. Plastic production workers are at increased risk of leukemia, lymphoma, hepatic angiosarcoma, brain cancer, breast cancer, mesothelioma, neurotoxic injury, and decreased fertility. Workers producing plastic textiles die of bladder cancer, lung cancer, mesothelioma, and interstitial lung disease at increased rates. Plastic recycling workers have increased rates of cardiovascular disease, toxic metal poisoning, neuropathy, and lung cancer. Residents of "fenceline" communities adjacent to plastic production and waste disposal sites experience increased risks of premature birth, low birth weight, asthma, childhood leukemia, cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer.During use and also in disposal, plastics release toxic chemicals including additives and residual monomers into the environment and into people. National biomonitoring surveys in the USA document population-wide exposures to these chemicals. Plastic additives disrupt endocrine function and increase risk for premature births, neurodevelopmental disorders, male reproductive birth defects, infertility, obesity, cardiovascular disease, renal disease, and cancers. Chemical-laden MNPs formed through the environmental degradation of plastic waste can enter living organisms, including humans. Emerging, albeit still incomplete evidence indicates that MNPs may cause toxicity due to their physical and toxicological effects as well as by acting as vectors that transport toxic chemicals and bacterial pathogens into tissues and cells.Infants in the womb and young children are two populations at particularly high risk of plastic-related health effects. Because of the exquisite sensitivity of early development to hazardous chemicals and children's unique patterns of exposure, plastic-associated exposures are linked to increased risks of prematurity, stillbirth, low birth weight, birth defects of the reproductive organs, neurodevelopmental impairment, impaired lung growth, and childhood cancer. Early-life exposures to plastic-associated chemicals also increase the risk of multiple non-communicable diseases later in life. ECONOMIC FINDINGS: Plastic's harms to human health result in significant economic costs. We estimate that in 2015 the health-related costs of plastic production exceeded 250billion(2015Int250 billion (2015 Int) globally, and that in the USA alone the health costs of disease and disability caused by the plastic-associated chemicals PBDE, BPA and DEHP exceeded 920billion(2015Int920 billion (2015 Int). Plastic production results in greenhouse gas (GHG) emissions equivalent to 1.96 gigatons of carbon dioxide (CO2e) annually. Using the US Environmental Protection Agency's (EPA) social cost of carbon metric, we estimate the annual costs of these GHG emissions to be 341billion(2015Int341 billion (2015 Int).These costs, large as they are, almost certainly underestimate the full economic losses resulting from plastics' negative impacts on human health and the global environment. All of plastics' economic costs-and also its social costs-are externalized by the petrochemical and plastic manufacturing industry and are borne by citizens, taxpayers, and governments in countries around the world without compensation. SOCIAL JUSTICE FINDINGS: The adverse effects of plastics and plastic pollution on human health, the economy and the environment are not evenly distributed. They disproportionately affect poor, disempowered, and marginalized populations such as workers, racial and ethnic minorities, "fenceline" communities, Indigenous groups, women, and children, all of whom had little to do with creating the current plastics crisis and lack the political influence or the resources to address it. Plastics' harmful impacts across its life cycle are most keenly felt in the Global South, in small island states, and in disenfranchised areas in the Global North. Social and environmental justice (SEJ) principles require reversal of these inequitable burdens to ensure that no group bears a disproportionate share of plastics' negative impacts and that those who benefit economically from plastic bear their fair share of its currently externalized costs. CONCLUSIONS: It is now clear that current patterns of plastic production, use, and disposal are not sustainable and are responsible for significant harms to human health, the environment, and the economy as well as for deep societal injustices.The main driver of these worsening harms is an almost exponential and still accelerating increase in global plastic production. Plastics' harms are further magnified by low rates of recovery and recycling and by the long persistence of plastic waste in the environment.The thousands of chemicals in plastics-monomers, additives, processing agents, and non-intentionally added substances-include amongst their number known human carcinogens, endocrine disruptors, neurotoxicants, and persistent organic pollutants. These chemicals are responsible for many of plastics' known harms to human and planetary health. The chemicals leach out of plastics, enter the environment, cause pollution, and result in human exposure and disease. All efforts to reduce plastics' hazards must address the hazards of plastic-associated chemicals. RECOMMENDATIONS: To protect human and planetary health, especially the health of vulnerable and at-risk populations, and put the world on track to end plastic pollution by 2040, this Commission supports urgent adoption by the world's nations of a strong and comprehensive Global Plastics Treaty in accord with the mandate set forth in the March 2022 resolution of the United Nations Environment Assembly (UNEA).International measures such as a Global Plastics Treaty are needed to curb plastic production and pollution, because the harms to human health and the environment caused by plastics, plastic-associated chemicals and plastic waste transcend national boundaries, are planetary in their scale, and have disproportionate impacts on the health and well-being of people in the world's poorest nations. Effective implementation of the Global Plastics Treaty will require that international action be coordinated and complemented by interventions at the national, regional, and local levels.This Commission urges that a cap on global plastic production with targets, timetables, and national contributions be a central provision of the Global Plastics Treaty. We recommend inclusion of the following additional provisions:The Treaty needs to extend beyond microplastics and marine litter to include all of the many thousands of chemicals incorporated into plastics.The Treaty needs to include a provision banning or severely restricting manufacture and use of unnecessary, avoidable, and problematic plastic items, especially single-use items such as manufactured plastic microbeads.The Treaty needs to include requirements on extended producer responsibility (EPR) that make fossil carbon producers, plastic producers, and the manufacturers of plastic products legally and financially responsible for the safety and end-of-life management of all the materials they produce and sell.The Treaty needs to mandate reductions in the chemical complexity of plastic products; health-protective standards for plastics and plastic additives; a requirement for use of sustainable non-toxic materials; full disclosure of all components; and traceability of components. International cooperation will be essential to implementing and enforcing these standards.The Treaty needs to include SEJ remedies at each stage of the plastic life cycle designed to fill gaps in community knowledge and advance both distributional and procedural equity.This Commission encourages inclusion in the Global Plastic Treaty of a provision calling for exploration of listing at least some plastic polymers as persistent organic pollutants (POPs) under the Stockholm Convention.This Commission encourages a strong interface between the Global Plastics Treaty and the Basel and London Conventions to enhance management of hazardous plastic waste and slow current massive exports of plastic waste into the world's least-developed countries.This Commission recommends the creation of a Permanent Science Policy Advisory Body to guide the Treaty's implementation. The main priorities of this Body would be to guide Member States and other stakeholders in evaluating which solutions are most effective in reducing plastic consumption, enhancing plastic waste recovery and recycling, and curbing the generation of plastic waste. This Body could also assess trade-offs among these solutions and evaluate safer alternatives to current plastics. It could monitor the transnational export of plastic waste. It could coordinate robust oceanic-, land-, and air-based MNP monitoring programs.This Commission recommends urgent investment by national governments in research into solutions to the global plastic crisis. This research will need to determine which solutions are most effective and cost-effective in the context of particular countries and assess the risks and benefits of proposed solutions. Oceanographic and environmental research is needed to better measure concentrations and impacts of plastics <10 µm and understand their distribution and fate in the global environment. Biomedical research is needed to elucidate the human health impacts of plastics, especially MNPs. SUMMARY: This Commission finds that plastics are both a boon to humanity and a stealth threat to human and planetary health. Plastics convey enormous benefits, but current linear patterns of plastic production, use, and disposal that pay little attention to sustainable design or safe materials and a near absence of recovery, reuse, and recycling are responsible for grave harms to health, widespread environmental damage, great economic costs, and deep societal injustices. These harms are rapidly worsening.While there remain gaps in knowledge about plastics' harms and uncertainties about their full magnitude, the evidence available today demonstrates unequivocally that these impacts are great and that they will increase in severity in the absence of urgent and effective intervention at global scale. Manufacture and use of essential plastics may continue. However, reckless increases in plastic production, and especially increases in the manufacture of an ever-increasing array of unnecessary single-use plastic products, need to be curbed.Global intervention against the plastic crisis is needed now because the costs of failure to act will be immense
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