An Umbrella Review of Meta-Analyses Evaluating Associations between Human Health and Exposure to Major Classes of Plastic-Associated Chemicals.

Background: Epidemiological research investigating the impact of exposure to plastics, and plastic-associated chemicals, on human health is critical, especially given exponentially increasing plastic production. In parallel with increasing production, academic research has also increased exponentially both in terms of the primary literature and ensuing systematic reviews with meta-analysis. However, there are few overviews that capture a broad range of chemical classes to present a state of play regarding impacts on human health. Methods: We undertook an umbrella review to review the systematic reviews with meta-analyses. Given the complex composition of plastic and the large number of identified plastic-associated chemicals, it was not possible to capture all chemicals that may be present in, and migrate from, plastic materials. We therefore focussed on a defined set of key exposures related to plastics. These were microplastics, due to their ubiquity and potential for human exposure, and the polymers that form the matrix of consumer plastics. We also included plasticisers and flame retardants as the two classes of functional additive with the highest concentration ranges in plastic. In addition, we included bisphenols and per- and polyfluoroalkyl substances (PFAS) as two other major plastic-associated chemicals with significant known exposure through food contact materials. Epistemonikos and PubMed were searched for systematic reviews with meta-analyses, meta-analyses, and pooled analyses evaluating the association of plastic polymers, particles (microplastics) or any of the selected groups of high-volume plastic-associated chemicals above, measured directly in human biospecimens, with human health outcomes. Results: Fifty-two systematic reviews were included, with data contributing 759 meta-analyses. Most meta-analyses (78%) were from reviews of moderate methodological quality. Across all the publications retrieved, only a limited number of plastic-associated chemicals within each of the groups searched had been evaluated in relevant meta-analyses, and there were no meta-analyses evaluating polymers, nor microplastics. Synthesised estimates of the effects of plastic-associated chemical exposure were identified for the following health outcome categories in humans: birth, child and adult reproductive, endocrine, child neurodevelopment, nutritional, circulatory, respiratory, skin-related and cancers. Bisphenol A (BPA) is associated with decreased anoclitoral distance in infants, type 2 diabetes (T2D) in adults, insulin resistance in children and adults, polycystic ovary syndrome, obesity and hypertension in children and adults and cardiovascular disease (CVD); other bisphenols have not been evaluated. Phthalates, the only plasticisers identified, are associated with spontaneous pregnancy loss, decreased anogenital distance in boys, insulin resistance in children and adults, with additional associations between certain phthalates and decreased birth weight, T2D in adults, precocious puberty in girls, reduced sperm quality, endometriosis, adverse cognitive development and intelligence quotient (IQ) loss, adverse fine motor and psychomotor development and elevated blood pressure in children and asthma in children and adults. Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) but not other flame retardants, and some PFAS were identified and are all associated with decreased birth weight. In general populations, PCBs are associated with T2D in adults and endometriosis, bronchitis in infants, CVD, non-Hodgkin's lymphoma (NHL) and breast cancer. In PCB-poisoned populations, exposure is associated with overall mortality, mortality from hepatic disease (men), CVD (men and women) and several cancers. PBDEs are adversely associated with children's cognitive development and IQ loss. PBDEs and certain PFAS are associated with changes in thyroid function. PFAS exposure is associated with increased body mass index (BMI) and overweight in children, attention deficit hyperactive disorder (ADHD) in girls and allergic rhinitis. Potential protective associations were found, namely abnormal pubertal timing in boys being less common with higher phthalate exposure, increased high-density lipoprotein (HDL) with exposure to mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and reduced incidence of chronic lymphocytic lymphoma (a subtype of NHL) with PCB exposure. Conclusions: Exposure to plastic-associated chemicals is associated with adverse outcomes across a wide range of human health domains, and every plastic-associated chemical group is associated with at least one adverse health outcome. Large gaps remain for many plastic-associated chemicals. Recommendations: For research, we recommend that efforts are harmonised globally to pool resources and extend beyond the chemicals included in this umbrella review. Priorities for primary research, with ensuing systematic reviews, could include micro- and nanoplastics as well as emerging plastic-associated chemicals of concern such as bisphenol analogues and replacement plasticisers and flame retardants. With respect to chemical regulation, we propose that safety for plastic-associated chemicals in humans cannot be assumed at market entry. We therefore recommend that improved independent, systematic hazard testing for all plastic-associated chemicals is undertaken before market release of products. In addition because of the limitations of laboratory-based testing for predicting harm from plastic in humans, independent and systematic post-market bio-monitoring and epidemiological studies are essential to detect potential unforeseen harms.

Socioeconomic adversity, maternal nutrition, and the prenatal programming of offspring cognition and language at two years of age through maternal inflammation.

Increasing rates of child neurodevelopmental vulnerability are a significant public health challenge. The adverse effect of socioeconomic adversity on offspring cognition may be mediated through elevated prenatal maternal systemic inflammation, but the role of modifiable antecedents such as maternal nutrition has not yet been clarified. This study aimed to examine (1) whether prenatal factors, with an emphasis on maternal nutrition, were associated with prenatal maternal systemic inflammation at 28 weeks' gestation, including the metabolomic marker glycoprotein acetyls (GlycA); (2) the extent to which the association between prenatal maternal nutrition and child cognition and language at age two years was mediated by elevated maternal inflammation in pregnancy; (3) the extent to which the associations between prenatal socioeconomic adversity and child neurodevelopment were mediated through prenatal maternal nutrition and GlycA levels. We used a prospective population-derived pre-birth longitudinal cohort study, the Barwon Infant Study (Barwon region of Victoria, Australia), where 1074 mother-child pairs were recruited by 28 weeks' gestation using an unselected sampling frame. Exposures included prenatal factors such as maternal diet measured by a validated food frequency questionnaire at 28 weeks' gestation and dietary patterns determined by principal component analysis. The main outcome measures were maternal inflammatory biomarkers (GlycA and hsCRP levels) at 28 weeks' gestation, and offspring Bayley-III cognition and language scores at age two years. Results showed that the 'modern wholefoods' and 'processed' maternal dietary patterns were independently associated with reduced and elevated maternal inflammation respectively (GlycA or hsCRP p < 0.001), and also with higher and reduced offspring Bayley-III scores respectively (cognition p ≤ 0.004, language p ≤ 0.009). Associations between dietary patterns and offspring cognition and language were partially mediated by higher maternal GlycA (indirect effect: cognition p ≤ 0.036, language p ≤ 0.05), but were less evident for hsCRP. The maternal dietary patterns mediated 22 % of the association between socioeconomic adversity (lower maternal education and/or lower household income vs otherwise) and poorer offspring cognition (indirect effect p = 0.001). Variation in prenatal GlycA levels that were independent of these dietary measures appeared less important. In conclusion, modifiable prenatal maternal dietary patterns were associated with adverse child neurocognitive outcomes through their effect on maternal inflammation (GlycA). Maternal diet may partially explain the association between socioeconomic adversity and child neurocognitive vulnerability. Maternal diet-by-inflammation pathways are an attractive target for future intervention studies.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Impacts associated with the plastic polymers polycarbonate, polystyrene, polyvinyl chloride, and polybutadiene across their life cycle: A review.

Polymers are the main building blocks of plastic, with the annual global production volume of fossil carbon-based polymers reaching over 457 million metric tons in 2019 and this figure is anticipated to triple by 2060. There is potential for environmental harm and adverse human health impacts associated with plastic, its constituent polymers and the chemicals therein, at all stages of the plastic life cycle, from extraction of raw materials, production and manufacturing, consumption, through to ultimate disposal and waste management. While there have been considerable research and policy efforts in identifying and mitigating the impacts associated with problematic plastic products such as single-use plastics and hazardous chemicals in plastics, with national and/or international regulations to phase out their use, plastic polymers are often overlooked. In this review, the polymer dimension of the current knowledge on environmental release, human exposure and health impacts of plastic is discussed across the plastic life cycle, including chemicals used in production and additives commonly used to achieve the properties needed for applications for which the polymers are generally used. This review focuses on polycarbonate, polystyrene, polyvinyl chloride, and polybutadiene, four common plastic polymers made from the hazardous monomers, bisphenol, styrene, vinyl chloride and 1,3-butadiene, respectively. Potential alternative polymers, chemicals, and products are considered. Our findings emphasise the need for a whole system approach to be undertaken for effective regulation of plastics whereby the impacts of plastics are assessed with respect to their constituent polymers, chemicals, and applications and across their entire life cycle.

Blueprint for the design, construction, and validation of a plastic and phthalate-minimised laboratory.

Micro and nanosized plastics (MNPs), and a range of associated additive chemicals, have become pervasive contaminants that humans and the environment are exposed to everyday. However, one of the principal challenges in their analysis is adequate strategies to minimise background contamination. Here a blueprint for a specialised plastics and additive-minimised clean room laboratory built for this purpose is presented. Common laboratory construction materials (n = 23) were tested, including acoustic baffles, ceiling materials, floor materials, glazing rubber, and silicone sealant. The % polymer content ranged from 2-76% w/w while the sum concentration of six phthalates ranged from 0.81 (0.73-0.86) to 21000 (15000-27000) mg/kg, assigning many of these materials as inappropriate for use in a clean room environment. The final design of the laboratory consisted of three interconnected rooms, operated under positive pressure with the inner rooms constructed almost entirely of stainless steel. Background concentrations of MNPs and phthalates in the new laboratory were compared to two Physical Containment Level 2 (PC2) laboratory environments, with concentrations of MNPs reduced by > 100 times and phthalates reduced by up to 120 times. This study reports the first known clean room of its kind and provides a blueprint for reference and use by future plastics research.

Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits.

BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months), and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism-based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models. RESULTS: Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08-0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = -0.74), highlighting developmental heterogeneity. CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.

The plastic health map: A systematic evidence map of human health studies on plastic-associated chemicals.

BACKGROUND: The global production and use of plastic materials has increased dramatically since the 1960s and there is increasing evidence of human health impacts related to exposure to plastic-associated chemicals. There is, however, no comprehensive, regulatory, post-market monitoring for human health effects of plastic-associated chemicals or particles and it is unclear how many of these have been investigated for effects in humans, and therefore what the knowledge gaps are. OBJECTIVE: To create a systematic evidence map of peer-reviewed human studies investigating the potential effects of exposure to plastic-associated particles/chemicals on health to identify research gaps and provide recommendations for future research and regulation policy. METHODS: Medline and Embase databases were used to identify peer-reviewed primary human studies published in English from Jan 1960 - Jan 2022 that investigated relationships between exposures to included plastic-associated particles/chemicals measured and detected in bio-samples and human health outcomes. Plastic-associated particles/chemicals included are: micro and nanoplastics, due to their widespread occurrence and potential for human exposure; polymers, the main building blocks of plastic; plasticizers and flame retardants, the two most common types of plastic additives with the highest concentration ranges in plastic materials; and bisphenols and per- or polyfluoroalkyl substances, two chemical classes of known health concern that are common in plastics. We extracted metadata on the population and study characteristics (country, intergenerational, sex, age, general/special exposure risk status, study design), exposure (plastic-associated particle/chemical, multiple exposures), and health outcome measures (biochemical, physiological, and/or clinical), from which we produced the interactive database 'Plastic Health Map' and a narrative summary. RESULTS: We identified 100,949 unique articles, of which 3,587 met our inclusion criteria and were used to create a systematic evidence map. The Plastic Health Map with extracted metadata from included studies are freely available at https://osf.io/fhw7d/ and summary tables, plots and overall observations are included in this report. CONCLUSIONS: We present the first evidence map compiling human health research on a wide range of plastic-associated chemicals from several different chemical classes, in order to provide stakeholders, including researchers, regulators, and concerned individuals, with an efficient way to access published literature on the matter and determine knowledge gaps. We also provide examples of data clusters to facilitate systematic reviews and research gaps to help direct future research efforts. Extensive gaps are identified in the breadth of populations, exposures and outcomes addressed in studies of potential human health effects of plastic-associated chemicals. No studies of the human health effects of micro and/or nanoplastics were found, and no studies were found for 26/1,202 additives included in our search that are of known hazard concern and confirmed to be in active production. Few studies have addressed recent "substitution" chemicals for restricted additives such as organophosphate flame retardants, phthalate substitutes, and bisphenol analogues. We call for a paradigm shift in chemical regulation whereby new plastic chemicals are rigorously tested for safety before being introduced in consumer products, with ongoing post-introduction biomonitoring of their levels in humans and health effects throughout individuals' life span, including in old age and across generations.

Correction: The Minderoo-Monaco Commission on Plastics and Human Health.

[This corrects the article DOI: 10.5334/aogh.4056.].

The Minderoo-Monaco Commission on Plastics and Human Health.

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 $250 billion (2015 Int$) 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 $920 billion (2015 Int$). 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 $341 billion (2015 Int$).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.

Increased maternal non-oxidative energy metabolism mediates association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and offspring autism spectrum disorder symptoms in early life: A birth cohort study.

Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as part of the Barwon Infant Study (BIS), a population-based birth cohort of 1,074 Australian children. We estimated phthalate daily intakes using third-trimester urinary phthalate metabolite concentrations and other relevant indices. The metabolome of maternal serum in the third trimester, cord serum at birth and child plasma at 1 year were measured by nuclear magnetic resonance. We used the Small Molecule Pathway Database and principal component analysis to construct composite metabolite scores reflecting metabolic pathways. ASD symptoms at 2 and 4 years were measured in 596 and 674 children by subscales of the Child Behavior Checklist and the Strengths and Difficulties Questionnaire, respectively. Multivariable linear regression analyses demonstrated (i) prospective associations between higher prenatal di-(2-ethylhexyl) phthalate (DEHP) levels and upregulation of maternal non-oxidative energy metabolism pathways, and (ii) prospective associations between upregulation of these pathways and increased offspring ASD symptoms at 2 and 4 years of age. Counterfactual mediation analyses indicated that part of the mechanism by which higher prenatal DEHP exposure influences the development of ASD symptoms in early childhood is through a maternal metabolic shift in pregnancy towards non-oxidative energy pathways, which are inefficient compared to oxidative metabolism. These results highlight the importance of the prenatal period and suggest that further investigation of maternal energy metabolism as a molecular mediator of the adverse impact of prenatal environmental exposures such as phthalates is warranted.

Cord blood immune profile: Associations with higher prenatal plastic chemical levels.

Prenatal exposure to plastic chemicals has been associated with alterations to early-life immune function in children. However, previous studies have generally been small and focused on limited repertoires of immune indices. In a large population-based pre-birth cohort (n = 1074), third-trimester measurements of eight phthalate metabolites and three analogues of bisphenols were used to estimate prenatal exposure to phthalate and bisphenol compounds. In cord blood, immune cell populations were measured by flow cytometry and an extensive panel of cytokines and chemokines were measured by multiplex immunoassay. We used these cord blood analytes to estimate "early life" immune profiles. The full study sample comprises data from 774 infants with prenatal plastic metabolite measurements and any cord blood immune data. Multiple linear regression analysis was used to evaluate whether prenatal phthalate and bisphenol exposure was prospectively associated with cord blood immune cell populations and cytokine and chemokine levels. Generally, inverse associations were observed between prenatal phthalate exposure and cord blood immune indices. Higher exposure to di-n-butyl phthalate was associated with lower cord blood levels of platelet-derived growth factor (PDGF) and interferon gamma-induced protein 10 (IP-10); higher exposure to the sum of dibutyl phthalates was associated with lower cord blood levels of IP-10; and higher exposure to benzyl butyl phthalate was associated with lower cord blood levels of interleukin 1 beta (IL-1ß). There was less evidence of associations between bisphenols and cord blood immune indices. These results extend previous work examining prenatal plastic chemical exposure and early-life immune development and highlight the importance of further examination of potential associations with health-related outcomes.

A scoping review protocol on in vivo human plastic exposure and health impacts.

BACKGROUND: Global plastic production has increased exponentially since the 1960s, with more than 6300 million metric tons of plastic waste generated to date. Studies have found a range of human health outcomes associated with exposure to plastic chemicals. However, only a fraction of plastic chemicals used have been studied in vivo, and then often in animals, for acute toxicological effects. With many questions still unanswered about how long-term exposure to plastic impacts human health, there is an urgent need to map human in vivo research conducted to date, casting a broad net by searching terms for a comprehensive suite of plastic chemical exposures and the widest range of health domains. METHODS: This protocol describes a scoping review that will follow the recommended framework outlined in the 2017 Guidance for the Conduct of Joanna Briggs Institute (JBI) Scoping Reviews, to be reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. A literature search of primary clinical studies in English from 1960 onwards will be conducted in MEDLINE (Ovid) and EMBASE (Ovid) databases. References eligible for inclusion will be identified through a quality-controlled, multi-level screening process. Extracted data will be presented in diagrammatic and tabular form, with a narrative summary addressing the review questions. DISCUSSION: This scoping review will comprehensively map the primary research undertaken to date on plastic exposure and human health. Secondary outputs will include extensive databases on plastic chemicals and human health outcomes/impacts. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (OSF)-Standard Pre-Data Collection Registration, https://archive.org/details/osf-registrations-gbxps-v1 , https://doi.org/10.17605/OSF.IO/GBXPS.

Infant inflammation predicts childhood emotional and behavioral problems and partially mediates socioeconomic disadvantage.

BACKGROUND: Emotional and behavioral problems (EBP) are common in children. Environmental factors like socioeconomic disadvantage influence EBP pathogenesis and can trigger inflammation. However, the link between early inflammation-EBP in children is unclear. We investigated the associations between i) infant inflammatory biomarkers and subsequent EBP and ii) early life environmental factors and EBP and assessed whether infant inflammation mediated these associations. METHODS: Inflammatory biomarkers glycoprotein acetyls (GlycA) and high-sensitivity C-reactive protein (hsCRP) were quantified at birth and 12 months in a population-derived birth cohort, the Barwon Infant Study. Early life factors including demographic, prenatal, and perinatal factors were collected from antenatal to the two-year period. Internalizing and externalizing problems at age two were measured by the Child Behavior Checklist. Prospective associations were examined by multivariable regression analyses adjusted for potential confounders. Indirect effects of early life factors on EBP through inflammation were identified using mediation analyses. RESULTS: Elevated GlycA levels at birth (GlycAbirth) were associated with greater internalizing problems at age two (ß = 1.32 per SD increase in GlycA; P = 0.001). Inflammation at birth had a stronger magnitude of effect with later EBP than at 12 months. GlycAbirth partially mediated the associations between lower household income (6%), multiparity (12%) and greater number of older siblings (13%) and EBP. Patterns were less evident for hsCRP or externalizing problems. CONCLUSIONS: GlycAbirth was positively associated with EBP at age two and partially mediated the association between several indicators of socioeconomic disadvantage and EBP. Prenatal and perinatal inflammation may be relevant to early neurodevelopment and emotional health.

Shortened Infant Telomere Length Is Associated with Attention Deficit/Hyperactivity Disorder Symptoms in Children at Age Two Years: A Birth Cohort Study.

Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between infant TL and ADHD symptoms in children and assessed environmental factors as potential confounders and/or mediators of this association. Relative TL was measured by quantitative polymerase chain reaction in cord and 12-month blood in the birth cohort study, the Barwon Infant Study. Early life environmental factors collected antenatally to two years were used to measure confounding. ADHD symptoms at age two years were evaluated by the Child Behavior Checklist Attention Problems (AP) and the Attention Deficit/Hyperactivity Problems (ADHP). Associations between early life environmental factors on TL or ADHD symptoms were assessed using multivariable regression models adjusted for relevant factors. Telomere length at 12 months (TL12), but not at birth, was inversely associated with AP (ß = -0.56; 95% CI (-1.13, 0.006); p = 0.05) and ADHP (ß = -0.66; 95% CI (-1.11, -0.21); p = 0.004). Infant secondhand smoke exposure at one month was independently associated with shorter TL12 and also higher ADHD symptoms. Further work is needed to elucidate the mechanisms that influence TL attrition and early neurodevelopment.

A Pathway-Based Genetic Score for Oxidative Stress: An Indicator of Host Vulnerability to Phthalate-Associated Adverse Neurodevelopment.

The developing brain is highly sensitive to environmental disturbances, and adverse exposures can act through oxidative stress. Given that oxidative stress susceptibility is determined partly by genetics, multiple studies have employed genetic scores to explore the role of oxidative stress in human disease. However, traditional approaches to genetic score construction face a range of challenges, including a lack of interpretability, bias towards the disease outcome, and often overfitting to the study they were derived on. Here, we develop an alternative strategy by first generating a genetic pathway function score for oxidative stress (gPFSox) based on the transcriptional activity levels of the oxidative stress response pathway in brain and other tissue types. Then, in the Barwon Infant Study (BIS), a population-based birth cohort (n = 1074), we show that a high gPFSox, indicating reduced ability to counter oxidative stress, is linked to higher autism spectrum disorder risk and higher parent-reported autistic traits at age 4 years, with AOR values (per 2 additional pro-oxidant alleles) of 2.10 (95% CI (1.12, 4.11); p = 0.024) and 1.42 (95% CI (1.02, 2.01); p = 0.041), respectively. Past work in BIS has reported higher prenatal phthalate exposure at 36 weeks of gestation associated with offspring autism spectrum disorder. In this study, we examine combined effects and show a consistent pattern of increased neurodevelopmental problems for individuals with both a high gPFSox and high prenatal phthalate exposure across a range of outcomes, including high gPFSox and high DEHP levels against autism spectrum disorder (attributable proportion due to interaction 0.89; 95% CI (0.62, 1.16); p < 0.0001). The results highlight the utility of this novel functional genetic score and add to the growing evidence implicating gestational phthalate exposure in adverse neurodevelopment.

Early life environmental factors associated with autism spectrum disorder symptoms in children at age 2 years: A birth cohort study.

LAY ABSTRACT: Mounting evidence indicates the contribution of early life environmental factors in autism spectrum disorder. We aim to report the prospective associations between early life environmental factors and autism spectrum disorder symptoms in children at the age of 2 years in a population-derived birth cohort, the Barwon Infant Study. Autism spectrum disorder symptoms at the age of 2 years strongly predicted autism spectrum disorder diagnosis by the age of 4 years (area under curve = 0.93; 95% CI (0.82, 1.00)). After adjusting for child's sex and age at the time of behavioural assessment, markers of socioeconomic disadvantage, such as lower household income and lone parental status; maternal health factors, including younger maternal age, maternal pre-pregnancy body mass index, higher gestational weight gain and prenatal maternal stress; maternal lifestyle factors, such as prenatal alcohol and environmental air pollutant exposures, including particulate matter < 2.5 µm at birth, child secondhand tobacco smoke at 12 months, dampness/mould and home heating with oil, kerosene or diesel heaters at 2 years postnatal. Lower socioeconomic indexes for area, later birth order, higher maternal prenatal depression and maternal smoking frequency had a dose-response relationship with autism spectrum disorder symptoms. Future studies on environmental factors and autism spectrum disorder should consider the reasons for the socioeconomic disparity and the combined impact of multiple environmental factors through common mechanistic pathways.