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Initially marketed as a life-saving advancement, flame retardants are now mired in controversy. Some argue that data show the chemicals are unsafe while others continue to support their use. The tactics of each side have far-reaching consequences for how we interpret new scientific discoveries. An experienced environmental sociologist, Alissa Cordner conducts more than a hundred interviews with activists, scientists, regulators, and industry professionals to isolate the social, scientific, economic, and political forces influencing environmental health policy today. Introducing \"strategic science translation,\" she describes how stakeholders use scientific evidence to support nonscientific goals and construct \"conceptual risk formulas\" to shape risk assessment and the interpretation of empirical evidence. A revelatory text for public-health advocates,Toxic Safetydemonstrates that while all parties interested in health issues use science to support their claims, they do not compete on a level playing field and even good intentions can have deleterious effects.

BACKGROUND: Legacy brominated flame retardants have been recognized as risky factors leading to declined sperm quality. The widespread utilization of decabromodiphenyl ethane (DBDPE) as a replacement for decabromodiphenyl ether has given rise to considerable concern over its potential risks to reproductive health. OBJECTIVES: The objectives were to quickly determine whether DBDPE affects sperm quality upon ex vivo exposure, to reveal the reproductive outcomes and underlying molecular mechanisms using an in vivo zebrafish model exposed to DBDPE, and to validate the potential impact on DNA damage and energy metabolism balance in vitro. METHODS: Zebrafish spermatozoa were treated with DBDPE (0.01, 0.1, 1, 10 [micro]M) for 3 h, and the spermatozoa motility and fertilization ability with normal eggs were evaluated. Then adult male zebrafish were treated with DBDPE (0.1, 1, 10, and 100 nM) for 2 months, and their reproductive performance was examined. Four-dimensional label-free proteome and phosphoproteome were performed in zebrafish testes, and the findings were validated by multiple indicators. Finally, mouse spermatogonial GC-1 cells were treated with DBDPE (0.1, 1 [micro]M) for 72 h, and DNA damage was examined, as well as the energy production of glycolysis and oxidative phosphorylation. RESULTS: Ex vivo exposure to DBDPE caused lower motility and fertilization rates of zebrafish spermatozoa. In vivo exposure to DBDPE caused lower sperm motility and abnormal spermatogenesis in male zebrafish testes. Integrated whole-proteome and phosphoproteome analysis revealed DNA damage responses and energy metabolic disorders in zebrafish testes. A dosage window characterized by higher mitochondrial membrane potential (MMP) in combination with unchanged reactive oxygen species and apoptosis rates was observed in both zebrafish testes and GC-1 cells. DISCUSSION: This study suggests that in zebrafish, DBDPE exposure could impair sperm quality and spermatogenesis, and the underlying mechanism could be related to DNA damage and energy metabolic reprogramming in testicular germ cells.

To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides. This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health. Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285.

Organophosphate ester flame retardants and plasticizers (OPEs) have myriad uses in industry and consumer products. Increasing human exposure to OPEs has raised concerns about their potential effects on child neurodevelopment during pregnancy. We investigated whether OPE urinary concentrations during pregnancy were associated with child autism-related outcomes. We included 4159 mother-child pairs from 15 cohorts in the NIH Environmental influences on Child Health Outcomes (ECHO) Consortium, with children born from 2006-2020 (median age [interquartile range]: 6 [4,10] years). Nine OPE biomarkers were measured in urine samples collected mid- to late pregnancy. Dilution-adjusted biomarkers were modeled continuously, categorically (high [> median], moderate [≤ median], non-detect), or as detect/non-detect depending on their detection frequency. We assessed child autism-related traits via a) parent report on the Social Responsiveness Scale (SRS) and b) clinical autism diagnosis. We examined associations of OPEs with child outcomes, including modification by child sex, using generalized estimating equations to account for clustering by ECHO cohort. Compared with non-detectable concentrations, high exposure to bis(butoxyethyl) phosphate (BBOEP) was associated with higher autistic trait scores (adj-β 0.97, 95% confidence interval [CI]: 0.42, 1.52) and greater odds of autism diagnosis (adjusted odds ratio [adj-OR]: 1.27, 95% CI: 1.07, 1.50). Bis(1-chloro-2-propyl) phosphate (BCPP) showed associations with autistic trait scores (BCPP adj-β for high exposure vs. non-detect: 0.34, 95% CI: -0.46, 1.13; BCPP adj-β for moderate exposure vs. non-detect: 0.72, 95% CI: 0.24, 1.20). High exposure to bis(2-chloroethyl) phosphate (BCETP) was associated with lower odds of autism diagnosis (adj-OR: 0.76, 95% CI: 0.60, 0.95). Other OPEs showed no associations in adjusted models. Associations between BBOEP and higher autistic trait scores were stronger in males than females. Prenatal exposure to OPEs, specifically BCPP and BBOEP, may be associated with higher risk of autism diagnosis and related traits in childhood. https://doi.org/10.1289/EHP16177.

BACKGROUND: Environmental chemical exposures have been associated with metabolic outcomes, and typically, their binding to nuclear hormone receptors is considered the molecular initiating event (MIE) for a number of outcomes. However, more studies are needed to understand the influence of such exposures on cell membrane-bound adiponectin receptors (AdipoRs), which are critical metabolic regulators. OBJECTIVE: We aimed to clarify the potential interactions between AdipoRs and environmental chemicals, specifically organophosphorus flame retardants (OPFRs), and the resultant effects. METHODS: Employing in silico simulation, cell thermal shift, and noncompetitive binding assays, we screened eight OPFRs for interactions with AdipoR1 and AdipoR2. We tested two key events underlying AdipoR modulation upon OPFR exposure in a liver cell model. The Toxicological Prioritization Index (ToxPi)scoring scheme was used to rank OPFRs according to their potential to disrupt AdipoR-associated metabolism. We further examined the inhibitory effect of OPFRs on AdipoR signaling activation in mouse models. RESULTS: Analyses identified pi-pi stacking and pi-sulfur interactions between the aryl-OPFRs 2-ethylhexyl diphenyl phosphate (EHDPP), triphenyl phosphate (TPhP), and tricresyl phosphate (TCP) and the transmembrane cavities of AdipoR1 and AdipoR2. Cell thermal shift assays showed a >3[degrees]C rightward shift in the AdipoR proteins' melting curves upon exposure to these three compounds. Although the binding sites differed from adiponectin, results suggest that aryl-OPFRs noncompetitively inhibited the binding of the endogenous peptide ligand ADP355 to the receptors. Analyses of key events underlying AdipoR modulation revealed that glucose uptake was notably lower, whereas lipid content was higher in cells exposed to aryl-OPFRs. EHDPP, TCP, and TPhP were ranked as the top three disruptors according to the ToxPi scores. A noncompetitive binding between these aryl-OPFRs and AdipoRs was also observed in wild-type (WT) mice. In db/db mice, the finding of lower blood glucose levels after ADP355 injection was diminished in the presence of a typical aryl-OPFR (TCP). WT mice exposed to TCP demonstrated lower AdipoR1 signaling, which was marked by lower phosphorylated AMP-activated protein kinase (pAMPK) and a higher expression of gluconeogenesis-related genes. Moreover, WT mice exposed to ADP355 demonstrated higher levels of pAMPK protein and peroxisome proliferator-activated receptor-a messenger RNA. This was accompanied by higher glucose disposal and by lower levels of long-chain fatty acids and hepatic triglycerides; these metabolic improvements were negated upon TCP co-treatment. CONCLUSIONS: In silico, in vitro, and in vivo assays suggest that aryl-OPFRs act as noncompetitive inhibitors of AdipoRs, preventing their activation by adiponectin, and thus function as antagonists to these receptors. Our study describes a novel MIE for chemical-induced metabolic disturbances and highlights a new pathway for environmental impact on metabolic health.

Tris (2-chloroethyl) phosphate (TCEP), a widely used flame retardant, is widespread in the environment and potentially harmful to organisms. However, the specific mechanisms of TCEP-induced neurological and reproductive toxicity in fish are largely unknown. Turbot (Scophthalmus maximus) is cultivated on a large scale, and the emergence of pollutants with endocrine disrupting effects seriously affects its economic benefits. This study aimed to investigate the toxic effects of TCEP on turbot by integrating physio-biochemical and transcriptomic analyses. TCEP exposure induced severe neuroendocrine disrupting effects in turbot. Firstly, the hormone levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and 11-ketotestosterone (11-KT) were significantly decreased under prolonged TCEP stress, which may have a negative impact on normal reproductive function. We identified and summarized representative differentially expressed genes (DEGs) and their functions, such as endocrine system and oxidative stress. Pathway enrichment showed that the toxicological characteristics of TCEP on turbot were neuroendocrine regulation disorders, including oxidative phosphorylation, apoptosis, steroid biosynthesis, GnRH signaling pathway and so on. Weighted gene co-expression network analysis (WGCNA) also revealed key genes involved in these pathways. Among these genes, those encoding the components of the electron transport chain presented an initial increase in expression followed by a decrease, indicating that TCEP stress might affect mitochondrial function and lead to cell damage. This finding was also supported by the upregulation of apoptosis-related gene expression. Moreover, acute exposure to TCEP regulated MAPK-mediated transduction and regulation of GnRH signaling, thereby altering the expression of hypothalamic-pituitary-gonadal (HPG) axis-related genes. These findings revealed the endocrine disrupting effects of TCEP on turbot and identified biomarkers related to reproductive toxicity, providing early warning for the monitoring of healthy aquaculture.

In the United States, one in six children are affected by neurodevelopmental disorders, and polybrominated diphenyl ethers (PBDEs) in flame-retardant chemicals are measured ubiquitously in children. We conducted a systematic a systematic review regarding developmental exposure to PBDEs and intelligence or Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans. We searched articles published up to 26 September 2016, and included original studies that quantified exposures to PBDEs incurred any time in proximity to conception or during , perinatal, or childhood time periods. We evaluated the risk of bias of individual studies and the overall quality and strength of the evidence according to the Navigation Guide systematic review methodology. We established criteria in advance to identify studies that could be combined using random effects meta-analyses (DerSimonian-Laird method). Fifteen studies met the inclusion criteria; 10 studies met the criteria for intelligence and nine for attention-related problems. We rated studies generally with \"low\" to \"probably low\" risk of bias and rated the overall body of evidence as \"moderate\" quality with \"sufficient\" evidence for an association between Intelligence Quotient (IQ) and PBDEs. Our meta-analysis of four studies estimated a 10-fold increase (in other words, times 10) in PBDE exposure associated with a decrement of 3.70 IQ points (95% confidence interval: 0.83, 6.56). We concluded the body of evidence was of \"moderate\" quality for ADHD with \"limited\" evidence for an association with PBDEs, based on the heterogeneity of association estimates reported by a small number of studies and the fact that chance, bias, and confounding could not be ruled out with reasonable confidence. We concluded there was sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ. Preventing developmental exposure to PBDEs could help prevent loss of human intelligence. https://doi.org/10.1289/EHP1632.

Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes. We evaluated associations between urinary concentrations of PFR metabolites and outcomes of fertilization (IVF) treatment among couples recruited from an academic fertility clinic. This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman. Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of ΣPFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%). Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021.

Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results. We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex. We included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as -transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex. Three OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per ; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. ; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age -scores ( for detect vs. ); other chemicals showed null associations. In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.