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.

Uncovering global-scale risks from commercial chemicals in air.

Commercial chemicals are used extensively across urban centres worldwide1, posing a potential exposure risk to 4.2 billion people2. Harmful chemicals are often assessed on the basis of their environmental persistence, accumulation in biological organisms and toxic properties, under international and national initiatives such as the Stockholm Convention3. However, existing regulatory frameworks rely largely upon knowledge of the properties of the parent chemicals, with minimal consideration given to the products of their transformation in the atmosphere. This is mainly due to a dearth of experimental data, as identifying transformation products in complex mixtures of airborne chemicals is an immense analytical challenge4. Here we develop a new framework-combining laboratory and field experiments, advanced techniques for screening suspect chemicals, and in silico modelling-to assess the risks of airborne chemicals, while accounting for atmospheric chemical reactions. By applying this framework to organophosphate flame retardants, as representative chemicals of emerging concern5, we find that their transformation products are globally distributed across 18 megacities, representing a previously unrecognized exposure risk for the world's urban populations. More importantly, individual transformation products can be more toxic and up to an order-of-magnitude more persistent than the parent chemicals, such that the overall risks associated with the mixture of transformation products are also higher than those of the parent flame retardants. Together our results highlight the need to consider atmospheric transformations when assessing the risks of commercial chemicals.

Do flame retardant chemicals increase the risk for thyroid dysregulation and cancer?

PURPOSE OF REVIEW: Flame retardant chemicals are added to consumer products to reduce fire incidence and severity; approximately 1.5 million tons of these chemicals are used annually. However, their widespread use has led to their ubiquitous presence in the environment and chronic accumulation in human tissues. We summarize current trends in human flame retardant chemical exposure, and review recent data highlighting concerns for thyroid dysregulation and cancer risk in human populations. RECENT FINDINGS: Polybrominated diphenyl ethers were once commonly used as flame retardant chemicals, but recently were phased out. Exposure is associated with thyroid dysregulation (mainly T4 reductions) in animals, with new work focusing on specific mechanisms of action. Polybrominated diphenyl ethers also impact human thyroid regulation and are related to clinical thyroid disease, but associations appear both dose and life-stage dependent. Emerging data suggest that common alternate flame retardant chemicals may be more potent thyroid disruptors than their predecessors, which is particularly concerning given increasing levels of exposure. SUMMARY: Potential health impacts of flame retardant chemicals are only beginning to be understood for 'legacy flame retardant chemicals' (i.e., polybrominated diphenyl ethers), and are largely unevaluated for newer-use chemicals. Cumulatively, current data suggest impact on thyroid regulation is likely, potentially implicating flame retardant chemicals in thyroid disease and cancers for which thyroid dysregulation impacts risk or prognosis.

Health consequences of exposure to brominated flame retardants: a systematic review.

BACKGROUND: Brominated flame retardants (BFRs), are chemicals widely used in consumer products including electronics, vehicles, plastics and textiles to reduce flammability. Experimental animal studies have confirmed that these compounds may interfere with thyroid hormone homeostasis and neurodevelopment but to date health effects in humans have not been systematically examined. OBJECTIVES: To conduct a systematic review of studies on the health impacts of exposure to BFRs in humans, with a particular focus on children. METHODS: A systematic review was conducted using the MEDLINE and EMBASE electronic databases up to 1 February 2012. Published cohort, cross-sectional, and case-control studies exploring the relationship between BFR exposure and various health outcomes were included. RESULTS: In total, 36 epidemiological studies meeting the pre-determined inclusion criteria were included. Plausible outcomes associated with BFR exposure include diabetes, neurobehavioral and developmental disorders, cancer, reproductive health effects and alteration in thyroid function. Evidence for a causal relationship between exposure to BFRs and health outcomes was evaluated within the Bradford Hill framework. CONCLUSION: Although there is suggestive evidence that exposure to BFRs is harmful to health, further epidemiological investigations particularly among children, and long-term monitoring and surveillance of chemical impacts on humans are required to confirm these relationships.

Organophosphate ester flame retardant-induced acute intoxications in dogs.

INTRODUCTION: Flame retardants have wide industrial applications and are incorporated into articles found in automobiles and home environments, including seat cushions. These compounds differ widely chemically and in their toxic potential. We report here two cases involving dogs following ingestion of car seat cushions impregnated with organophosphate ester fire retardants. CASE REPORTS: Two case reports are presented. Two adult American Pit Bull dogs were presented at an emergency clinic with acute signs of central nervous system excitation including seizures. The most severely affected dog died 15 min after presentation, while the less affected dog fully recovered following treatment. In the second case, both a German Shepherd and a Rottweiler were found dead in the morning after they were left in a car overnight. A comprehensive toxicological analysis of samples from both cases revealed the presence of significant amounts (>2 ppm) of tris(2-chloroethyl)phosphate (TCEP) in stomach contents. This compound is a known inducer of epileptic seizures. Some other structurally related organophosphate ester compounds were found, and their role in the acute intoxications reported here is not known and remains to be determined. CONCLUSION: This is the first report linking acute deaths in dogs to the ingestion of car seat cushions found to contain large amounts of TCEP, an organophosphate ester compound. It is highly likely that this compound caused death through its known seizure-inducing activity.

Pseudo-outbreak of antimony toxicity in firefighters - Florida, 2009.

Antimony oxides, in combination with halogens, have been used as flame retardants in textiles since the 1960s. Uniforms made from fabric containing antimony are common among the estimated 1.1 million firefighters in the United States. In October 2008, CDC received a report from the fire chief of a fire department in Florida (fire department A) regarding an outbreak of antimony toxicity among 30 firefighters who had elevated antimony levels detected in hair samples. This report summarizes the ensuing health hazard evaluation conducted by CDC to determine the source of antimony exposure. In February 2009, CDC administered questionnaires to and collected urine samples from two groups of firefighters: 20 firefighters from fire department A who did not wear pants made from antimony-containing fabric, and 42 firefighters from fire department B (also located in Florida) who did. All 20 firefighters from fire department A and 41 (98%) from fire department B had urine antimony concentrations below or within the laboratory reference range. CDC concluded that wearing pants made from antimony-containing fabric was not associated with elevated levels of urinary antimony. Only validated methods (e.g., urine testing) should be used for the determination of antimony toxicity. Accurate and timely risk communication during suspected workplace exposures should underscore the importance of using validated tests, thereby refuting an unproven hypothesis, allaying unsubstantiated concerns, and enhancing public trust.

Risk assessment for children exposed to decabromodiphenyl (oxide) ether (Deca) in the United States.

Decabromodiphenyl (oxide) ether (Deca) is a widely used brominated flame retardant in the United States predominantly in the hard-plastic housings of consumer electronics and in flame-retarded backing on textiles used in furniture. A child-specific exposure assessment of Deca was performed for the US Environmental Protection Agency's Voluntary Children's Chemical Evaluation Program (VCCEP). The VCCEP guidance for a tier 1 exposure assessment requires that a screening-level assessment be conducted using currently available data and conservative assumptions. For Deca, relevant exposure pathways considered were general environmental exposures (e.g., exposures to contaminated soil, dust, air, and food), breast milk exposures, inhalation of Deca-containing particulates in air, and mouthing Deca-containing consumer products. For each of these scenarios, a mid-range and upper estimate of age-appropriate intakes were calculated. The calculated intakes indicate that, despite the uncertainties, children appear to be exposed to Deca at levels at least 1 order of magnitude, with most being several orders of magnitude, below the National Academy of Sciences reference dose for Deca of 4 mg/kg/d. This analysis indicates that, using the available data, current levels of Deca in the United States are unlikely to represent an adverse health risk for children.

Reactive airways dysfunction syndrome caused by bromochlorodifluoromethane from fire extinguishers.

Although the neurological and cardiovascular effects of Freons have been extensively described, the respiratory effects have been less well documented. We report four cases of occupational asthma following accidental exposure to bromochlorodifluoromethane (Halon 1211) due to release of the contents of a fire extinguisher. All subjects developed an irritative reaction of the upper airways and lower respiratory symptoms immediately after exposure. Non-specific bronchial hyperreactivity was present for at least two months in all subjects and was still present more than two years after exposure in one case. The diagnosis of reactive airways dysfunction syndrome can be adopted in at least three of these four cases.

[Determination of bromochlorodifluoromethane (Halon 1211) in biological material by gas chromatography with mass detector]. / Oznaczanie bromochlorodifluorometanu (Halon 1211) w materiale biologicznym metoda chromatografii gazowej z detektorem masowym (GC/MS).

A gas chromatographic method with mass spectrometry has been developed for the determination of bromochlorodifluoromethane (Halon 1211) in biological material (whole blood, organ samples). After incubation of the sample (temp. 65 degrees C, 15 min), 10 microliters of the headspace is analysed using a capillary column DB-5 ms (30 m x 0.25 mm x 0.25 micron). Quantitative analysis was made with the use of a single ion monitoring option--m/z 85 and m/z 87. This developed method was used to determine the concentration of bromochlorodifluoromethane in biological material collected from the body of the man whose death was due to intoxication of Halon 1211--fire-extinguisher contents.

Sudden infant death syndrome: a possible primary cause.

The hypothesis that poisoning by phosphines, arsines and stibines might be the primary cause of sudden infant death syndrome (SIDS) was investigated. Most mattress materials contain phosphorus or antimony compounds as fire retardant additives. Mattress materials in areas affected by the warmth and perspiration of the sleeping infant were found to be naturally infected by the fungus Scopulariopsis brevicaulis which is thought to be capable of generating phosphines, arsines and stibines from materials containing phosphorus, arsenic or antimony compounds. These gases may cause anticholinesterase poisoning and cardiac failure in infants, but contributory factors include the prone sleeping position and overwrapping. In England and Wales, the progressive increase in SIDS between 1951 and 1988 seems to be related to increasing use of phosphorus and antimony compounds as fire retardents in cot mattresses.

Fatal accidental inhalation of bromochlorodifluoromethane (Halon 1211).

Bromochlorodifluoromethane (Halon 1211) is a widely used fire extinguishing agent. Several cases of sudden death in teenagers associated with BCF abuse have been reported. BCF is used as a fire extinguisher in battle tanks. Two young previously healthy male soldiers were accidentally exposed to BCF in a battle tank. The tank driver died, but the gunner survived the event with no medial complications. It is concluded that BCF should be used in confined chambers only after the evacuation of all personnel.

Effects of polybrominated biphenyls on the concentration and clearance of steroids from blood.

Hepatic microsomal mixed-function oxidases have been stimulated when cattle were experimentally fed polybrominated biphenyls (PBB; fireMaster BP-6). These changes provide mechanisms for alteration of the metabolism and clearance of steroid hormones that might then affect reproductive function. This study was conducted to examine the effects of PBB on the clearance of radiolabel from injected estradiol-17 beta and progesterone along with daily determinations of concentrations of endogenous estradiol-17 beta and progestins in blood plasma. Toxicity was induced by dosing two Holstein cows with 25 g of fireMaster BP-6/d for 39 or 50 d. Single iv injections of 35 microCi [4-14C] progesterone and 400 microCi [2,4,6,7-3H] estradiol-17 beta were given on d -5, 10, 30 and 38 or 48 relative to dosing. Last injections were given when severe toxic symptoms were observed in each animal. Clinical signs, blood constituents, and necropsy findings confirmed the toxic syndrome. Clearance of 14C from progesterone was described by a biexponential function of time, while 3H from estradiol was cleared more slowly with a triexponential function. The total clearance rate for radiolabel from progesterone was approximately four times greater than estradiol throughout the experiments. The total clearance rates were similar for both steroids before and 10 d after dosing with PBB. A toxic syndrome was well developed by d 30 of PBB dosing and the total clearance rate of both steroids decreased approximately 50% with precipitous decreases when animals were terminally toxic. Despite the developing toxic syndrome, plasma concentrations of estradiol-17 beta and total progestins were normal and the periodicity of estrous cycles was maintained.

Effects of polybrominated biphenyls on the excretion of steroids.

When polybrominated biphenyls (fireMaster BP-6, PBB) are ingested by cattle, they have been shown to alter hepatic enzyme systems, and produce renal lesions with chronic high exposure. These changes provide mechanisms for alteration of the metabolism and clearance of steroid hormones that might then affect reproductive function. This study was conducted to examine the effects of PBB on the excretion of radiolabel from injected estradiol-17 beta and progesterone. Toxicity was induced by dosing two Holstein cows with 25 g of fireMaster BP-6/d for 39 or 50 d. Single iv injections of 35 microCi [4-14C] progesterone and 400 microCi [2,4,6,7-3H] estradiol-17 beta were given on d -5, 10, 30 and 38 or 48 relative to dosing. Last injections were given when animals were terminally toxic. Clinical signs and necropsy findings confirmed the typical toxic syndrome and renal lesions. Excretion of 14C was primarily in feces, while 3H appeared in both urine and feces. As toxicosis developed, the excretion of steroids in feces was delayed as anorexia reduced mass and rate of passage of feces. This had little effect on the amount of steroid excreted and the rate of urinary excretion was affected only minimally. Recovery of both radiolabels declined 10 to 20% by d 30 of dosing as excretion rate was reduced from pre-PBB dosing. Excretion declined sharply when animals were moribund. Despite developing toxicosis, both animals continued to have estrous cycles with normal periodicity.

Investigation of the health status of Michigan chemical corporation employees.

Clinical findings are reported for a group of 55 employees of the Michigan Chemical Corporation which manufactured FireMaster BP-6 from 1970 to 1974, in addition to a variety of other halogenated fire retardant chemicals. The results are compared with those from a group of male farm residents and consumers from Michigan examined at the same time. An increased prevalence of chest and skin symptoms was observed, compared with farmers. Skin symptoms were more prevalent among former PBB production personnel. Musculosketal symptoms were less prevalent among these workers than among farmers. Serum PBB concentrations are signicantly higher than among farmers. Blood chemistry results were similar for workers and farmers. However, both groups exhibited a significantly higher prevalence of elevated liver function tests (SGOT, SPGT) than a control population of nonexposed farmers. Both farmers and chemical workers showed an association of elevated CEA with serum PBB greater than 10 ppb.