Occurrence and potential risks of organophosphate esters in agricultural soils: A case study of Fuzhou City, Southeast China.

Fifty agricultural soil samples collected from Fuzhou, southeast China, were first investigated for the occurrence, distribution, and potential risks of twelve organophosphate esters (OPEs). The total concentration of OPEs (ΣOPEs) in soil ranged from 1.33 to 96.5 ng/g dry weight (dw), with an average value of 17.1 ng/g dw. Especially, halogenated-OPEs were the predominant group with a mean level of 9.75 ng/g dw, and tris(1-chloro-2-propyl) phosphate (TCIPP) was the most abundant OPEs, accounting for 51.1% of ΣOPEs. The concentrations of TCIPP and ∑OPEs were found to be significantly higher (P < 0.05) in soils of urban areas than those in suburban areas. In addition, the use of agricultural plastic films and total organic carbon had a positive effect on the occurrence of OPE in this study. The positive matrix factorization model suggested complex sources of OPEs in agricultural soils from Fuzhou. The ecological risk assessment demonstrated that tricresyl phosphate presented a medium risk to land-based organisms (0.1 ≤ risk quotient < 1.0). Nevertheless, the carcinogenic and non-carcinogenic risks for human exposure to OPEs through soil ingestion and dermal absorption were negligible. These findings would facilitate further investigations into the pollution management and risk control of OPEs.

A High-Throughput Screening Approach for Evaluating the Binding Affinity of Environmental Pollutants to Nuclear Receptors.

Increasing levels of compounds have been detected in the environment, causing widespread pollution and posing risks to human health. However, despite their high environmental occurrence, there is very limited information regarding their toxicological effects. It is urgent to develop high-throughput screening (HTS) methods to guide toxicological studies. In this study, a receptor-ligand binding assay using an HTS system was developed to determine the binding potency of environmental pollutants on nuclear receptors. The test is conducted using a microplate reader (i.e., a 96-well plate containing various chemicals) by measuring the fluorescence polarization (FP) of a specific fluorescent probe. This assay consists of four parts: the construction and transformation of recombinant vectors, the expression and purification of the receptor protein (ligand-binding domain), receptor-probe binding, and competitive binding of chemicals with the receptor. The binding potency of two environmental pollutants, perfluorooctanesulfonic acid (PFOS) and triphenyl phosphate (TPHP), with peroxisome proliferator-activated receptor gamma (PPARγ) was determined to illustrate the assay procedure. Finally, the advantages and disadvantages of this method and its potential applications were also discussed.

Susceptibility to lenacapavir, fostemsavir and broadly neutralizing antibodies in French primary HIV-1 infected patients in 2020-2023.

Surveillance studies of Transmitted Drug Resistance (TDR) are crucial in tracking the evolution of HIV epidemiology. Our aim was to investigate TDR to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), as well as to new drugs: lenacapavir, fostemsavir. Predictive sensitivity was evaluated for maraviroc and broadly neutralizing antibodies (bNAbs) (zinlirvimab and teropavimab). Between 2020 and 2023, 85 people with HIV (PWH) were diagnosed with primary HIV-1 infection (PHI). Pol and env sequences were analyzed and TDR was characterized according to the French ANRS algorithm. The genotypic-based prediction of bNAbs sensitivity was based on HIV env amino acid signatures I108, I201, F353 for teropavimab and N325, N332, H330 for zinlirvimab. TDR to NRTIs, NNRTIs, PIs and INIs was evidenced in 8.2%, 12.9%, 4.7%, and 5.9% strains, respectively. Ten viruses were CXCR4/dual mix. All viruses were susceptible to lenacapavir (100%) and 52% harbored resistance to fostemsavir. The genotypic profile was associated with a predictive positive value (PPV) > 83% of susceptibility to both teropavimab and zinlirvimab for 23 viruses (31%), while 22 (29%) had a PPV between 62% and 75%, suggesting reduced susceptibility to both bNAbs as soon as primary infection. The surveillance of TDR evidenced at the time of PHI is important with regard to new strategies for HIV patients with virological failure and global implementation of PrEP using NRTI, INI such as recently approved injectable cabotegravir, and future long-acting drugs such as lenacapavir and bNAbs.

A randomized controlled trial of a housing intervention to reduce endocrine disrupting chemical exposures in children.

Few studies have considered household interventions for reducing endocrine disrupting chemical (EDC) exposures. We conducted a secondary analysis of a randomized controlled trial, originally designed to reduce lead exposure, to evaluate if the intervention lowered EDC exposures in young children. Study participants were children from the Cincinnati, Ohio area (n = 250, HOME Study). Prenatally, families received a housing intervention that included paint stabilization and dust mitigation, or as a control, injury prevention measures. At 24-months, we measured organophosphate esters (OPEs) and phthalates or their metabolites in dust and urine. We measured perfluoroalkyl substances (PFAS) in dust and serum at 24- and 36-months, respectively. We assessed associations between dust and biomarker EDCs using Spearman correlations, characterized EDC mixtures via principal components analysis, and investigated treatment effects using linear regression. To mitigate selection bias, we fit statistical models using inverse probability of retention weights. Correlations between dust EDCs and analogous biomarkers were weak-to-moderate (ρ's ≤ 0.3). The intervention was associated with 23 % (95 % CI: -38, -3) lower urinary DEHP metabolites and, in a per-protocol analysis, 34 % lower (95 % CI: -55, -2) urinary MBZP. Additionally, among Black or African American children, the intervention was associated with lower serum concentrations of several PFAS (e.g., -42 %; 95 % CI: -63, -8 for PFNA). Household interventions that include paint stabilization and dust mitigation may reduce childhood exposures to some phthalates and PFAS in Blacks/African Americans. These findings highlight the need for larger studies with tailored and sustained housing interventions.

Biomagnification potential and health risks of organophosphate esters in prey to humpback dolphins based on dietary correction.

Information on the biomagnification of organophosphate esters (OPEs) is limited, and the results are inconclusive, mainly because precise predatorprey relationships have not been determined. Herein, we first evaluated the biomagnification potential and dietary exposure risk of 15 OPEs in 14 prey species (n = 234) to Indo-Pacific humpback dolphins from the northern South China Sea using quantitative fatty acid signature analysis (QFASA). QFASA identified Chinese gizzard shad as the primary prey of dolphins. Among the 15 OPEs, 86.7 % (13/15) had a diet-adjusted biomagnification factor (BMFQFASA) greater than 1, indicating the biomagnification potential between dolphins and their diet. Moreover, BMFQFASA exhibited a considerable positive correlation with the log octanolwater partitioning coefficient of OPEs, indicating that lipophilicity may affect the bioamplification of OPEs. Risk assessments showed that although current OPE levels may not pose substantial health risks to dolphins via diet intake, the nondiet-adjusted hazard quotient/hazard index underestimated the exposure risk of OPEs to this vulnerable dolphin species. This study provides novel evidence regarding the biomagnification and dietary exposure risks of OPEs in cetaceans, emphasizing the importance of estimating the dietary composition of predators in such analyses.

Exposure levels and maternal transfer of emerging organophosphate flame retardants (OPFRs) in pregnant women: Comparison with traditional OPFRs.

Prenatal exposure to organophosphorus flame retardants (OPFRs) has been linked with adverse effects on reproductive health, and new OPFRs are continually emerging. In this study, emerging OPFRs, such as bis(2-ethylhexyl) phenyl phosphate (BEHPP), triamyl phosphate (TAP), tris(4-tert-butylphenyl) phosphate (T4tBPPP), oxydi-2,1-ethanediyl phosphoric acid tetrakis(2 chloro-1-methylethyl) ester (RDT905), cresyl diphenyl phosphate (CDP), and 2-isopropylphenyl diphenyl phosphate (2IPPDPP), were detected in 84 %, 100 %, 100 %, 52 %, 40 %, and 40 % of 25 decidua samples with average concentrations of 2.36, 6.21, 1.5, 2.6, 1.07, and 0.09 ng/g of dry weight (dw), respectively. Six of the aforementioned emerging OPFRs (BEHPP, T4tBPPP, RDT905, 2IPPDPP, CDP, and TAP) were simultaneously detected in paired chorionic villus samples, and their average concentrations were 11.3, 1.77, 3.64, 0.11, 0.58, and 3.34 ng/g, which were significantly higher than and positively correlated with those in decidua samples. The geometric mean concentration ratios between chorionic villus and decidua samples for BEHPP, T4tBPPP, RDT905, 2IPPDPP, CDP, and TAP were 4.02, 1.61, 1.73, 1.48, 0.82, and 0.69, respectively, consistent with transthyretin binding-dependent behavior. Prenatal exposure to such emerging OPFRs, especially for BEHPP with relatively high concentration and maternal transfer, is of high concern from the view of women's reproductive health.

[Distribution of 21 organic ophospesters and their metabolites in drinking water in Dongcheng District of Beijing and their health hazard assessment in 2023].

OBJECTIVE: To investigate the pollution of organophosphate esters(OPEs) and their metabolites in drinking water in Dongcheng District of Beijing, and to assess the exposure risk of adults in drinking water. METHODS: The contents of 14 OPEs and 7 metabolites in drinking water were determined by automatic solid phase extraction, isotope dilution and liquid chromatography tandem mass spectrometry. The average daily potential dose(ADD) were calculated based on the recommended intake of drinking water. RESULTS: Seventeen pieces of tap water and 30 pieces of packaged drinking water collected by supermarket were measured. OPEs and di-OPEs were widely detected in drinking water(11 kinds of OPEs and 6 kinds of di-OPEs with the detection rate of more than 50%). The ΣOPEs range was 16.8 to 177ng/L, and the Σdi-OPEs range was 0.328 to 16.3 ng/L. The average daily dose of adult population was calculated: the ADD of 14 kinds of ΣOPEs in male and female were 3.15 and 3.10 ng/(kg·BW·d), and the P95 exposure was 6.95 and 7.00 ng/(kg·BW·d), respectively. The ADD of the seven Σdi-OPEs in male and female were 0.150 and 0.147 ng/(kg·BW·d), and the P95 exposure was 0.330 and 0.332 ng/(kg·BW·d), respectively. The hazard quotient(HQ) of exposure to OPEs through drinking water, calculated using the EPA's oral reference dose assessment, was much less than 1. CONCLUSION: The current exposure of OPEs via drinking water poses a low health risk to adult residents in Dongcheng District. However, due to the lack of Health-based guidance values for the metabolites of OPEs, the exposure risk may be underestimated.

Combining QSAR and SSD to predict aquatic toxicity and species sensitivity of pyrethroid and organophosphate pesticides.

The widespread use of pyrethroid and organophosphate pesticides necessitates accurate toxicity predictions for regulatory compliance. In this study QSAR and SSD models for six pyrethroid and four organophosphate compounds using QSAR Toolbox and SSD Toolbox have been developed. The QSAR models, described by the formula 48 h-EC50 or 96 h-LC50 = x + y * log Kow, were validated for predicting 48 h-EC50 values for acute Daphnia toxicity and 96 h-LC50 values for acute fish toxicity, meeting criteria of n ≥10, r2 ≥0.7, and Q2 >0.5. Predicted 48 h-EC50 values for pyrethroids ranged from 3.95 × 10-5 mg/L (permethrin) to 8.21 × 10-3 mg/L (fenpropathrin), and 96 h-LC50 values from 3.89 × 10-5 mg/L (permethrin) to 1.68 × 10-2 mg/L (metofluthrin). For organophosphates, 48 h-EC50 values ranged from 2.00 × 10-5 mg/L (carbophenothion) to 3.76 × 10-2 mg/L (crufomate) and 96 h-LC50 values from 3.81 × 10-3 mg/L (carbophenothion) to 12.3 mg/L (crufomate). These values show a good agreement with experimental data, though some, like Carbophenothion, overestimated toxicity. HC05 values, indicating hazardous concentrations for 5% of species, range from 0.029 to 0.061 µg/L for pyrethroids and 0.030 to 0.072 µg/L for organophosphates. These values aid in establishing environmental quality standards (EQS). Compared to existing EQS, HC05 values for pyrethroids were less conservative, while those for organophosphates were comparable.

Potential mechanisms and modifications of dietary antioxidants on the associations between co-exposure to plastic additives and diabetes.

BACKGROUND: The association of plastic additive mixture exposure with diabetes and the modifying effects of dietary antioxidants are unclear. METHODS: The data from the NHANES 2011-2018 were retrieved, and phthalates and organophosphate esters (OPEs) were selected as exposures. The coexposure effect was analyzed by the environmental risk score (ERS) and quantile g-computation. To mitigate any potential bias caused by using the internal weights, another version of ERS was constructed using the cross-validation approach. The level of dietary antioxidant intake was measured by the composite dietary antioxidant index (CDAI). The biological mechanism underlying the association was studied by the adverse outcome pathway (AOP) framework. RESULTS: Fifteen chemicals (ten phthalates and five OPEs) were measured in 2824 adult participants. A higher ERS was significantly associated with an increased risk of diabetes (OR per 1-SD increment of ERS: 1.25, 95% CI: 1.13-1.39). This association apparently interacted with the CDAI level (ORlow: 1.83, 95% CI: 1.37-2.55; ORhigh: 1.28, 95% CI: 1.15-1.45; Pinteraction = 0.038). Moreover, quantile g-computation also revealed higher level of combined exposure was positively associated with diabetes (OR: 1.27, 95% CI: 1.05-2.87), and the addition of dietary antioxidants showed a null association (OR: 1.09, 95% CI: 0.85-2.34). The AOP study identified TCPP and TCEP as key chemicals that cause aberrant glucose metabolism and insulin signaling pathways and result in diabetes. CONCLUSIONS: Coexposure to phthalates and OPEs is positively associated with diabetes, where an antioxidative diet plays a modifying role. Several potential mechanisms have been proposed by AOP framework.

Identification of Primary Organophosphate Esters Contributing to Enhanced Risk of Gestational Diabetes Mellitus Based on a Case-Control Study.

Epidemiological studies on associations of organophosphate ester (OPE) exposure and gestational diabetes mellitus (GDM) risk, which remain rare and inconclusive, were carried out with a case-control population comprising 287 GDM and 313 non-GDM pregnant women recruited from Tianjin. The GDM group suffered distinctly higher serum concentrations of tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP), tri-iso-propyl phosphate (TIPP), and tri(1-chloro-2-propyl) phosphate (TCIPP) than the healthy control group (p < 0.001). Traditional analysis methods employed for either individual or mixture effects found positive correlations (p < 0.05) between the concentrations of five OPEs (i.e., TNBP, TBOEP, TPHP, TIPP, and TCIPP) and the incidence of GDM, while 2-ethylhexyl diphenyl phosphate, tri(1-chloro-2-propyl) phosphate, and bis(2-ethylhexyl) phosphate exhibited opposite effects. Three machine learning methods considering the concurrence of OPE mixture exposure and population characteristics were applied to clarify their relative importance to GDM risk, among which random forest performed the best. Several OPEs, particularly TNBP and TBOEP ranking at the top, made greater contributions than some demographical characteristics, such as prepregnancy body mass index and family history of diabetes, to the occurrence of GDM. This was further validated by another independent case-control population obtained from Hangzhou.

Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.

Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.

Structure-Dependent Distribution, Metabolism, and Toxicity Effects of Alkyl Organophosphate Esters in Lettuce (Lactuca sativa L.).

This study provides a comprehensive investigation into the structure-dependent uptake, distribution, biotransformation, and potential toxicity effects of alkyl organophosphate esters (OPEs) in hydroponic lettuce (Lactuca sativa L.). Trimethyl, triethyl, and tripropyl phosphates were readily absorbed and acropetally translocated, while tributyl, tripentyl, and trihexyl phosphates accumulated mainly in lateral roots. The acropetal translocation potential was negatively associated with log Kow values. Trimethyl and triethyl phosphates are less prone to biotransformation, while a total of 14 novel hydrolysis, hydroxylated, and conjugated metabolites were identified for other OPEs using nontarget analysis. The extent of hydroxylation decreases from tripropyl phosphate to trihexyl phosphate, but multiple hydroxylations occurred more frequently on longer chain OPEs. Further comparative toxicity test revealed that hydrolyzed and hydroxylated metabolites have stronger toxic effects on Ca2+-dependent protein kinases (CDPK) than their parent OPEs. Dibutyl 3-hydroxybutyl phosphate particularly induces upregulation of CDPK in lateral roots of lettuce, probably associated with adenine reduction that may play an important role in the self-defense and detoxification processes. This study contributes to understanding the uptake and transformation behaviors of alkyl OPEs as well as their associations with a toxic effect on lettuce. This emphasizes the necessary evaluation of the environmental risk of the use of OPEs, particularly focusing on their hydroxylated metabolites.

Comprehensive dietary exposure assessment of the Chinese population to organophosphate esters (OPEs): Results of the sixth China total diet study.

Organophosphate esters (OPEs) are emerging pollutants, while data on their occurrence in foods and human dietary intake are limited. Based on the 6th China total diet study conducted in 2016-2019, this study implemented a comprehensive survey of OPEs in plant-derived foods of cereals, potatoes, legumes, fruits, vegetables, and further assessed dietary exposure from both plant- and animal-derived food. The sum concentrations of 15 OPEs in the plant-derived samples ranged from 0.567 to 106 ng/g ww. 2-Ethylhexyl diphenyl phosphate (EHDPP) (median: 1.14 ng/g ww) had the highest level in plant-derived foods, with a proportion of 35.6% in the total median OPEs. Regional distribution analysis showed a higher contamination of OPEs in plant-derived food from northern area of China. Estimated dietary intakes (EDIs) of ∑OPEs for Chinese population were from 109 ng/kg bw/day in Beijing to 1164 ng/kg bw/day in Gansu province, with mean and median of 296 and 222 ng/kg bw/day, respectively. Although animal-derived foods had higher levels of OPEs, plant-derived foods, specifically cereals, was the major source of dietary OPE intake. The EDIs were much lower than reference doses, which suggested the intakes of OPEs via food consumption could not cause significant health risks to the Chinese population at present.

From e-waste to living space: Flame retardants contaminating household items add to concern about plastic recycling.

Brominated flame retardants (BFRs) and organophosphate flame retardants (OPFRs) are commonly used in electric and electronic products in high concentrations to prevent or retard fire. Health concerns related to flame retardants (FRs) include carcinogenicity, endocrine disruption, neurotoxicity, and reproductive and developmental toxicity. Globally, a lack of transparency related to chemicals in products and limited restrictions on use of FRs in electronics have led to widespread use and dissemination of harmful FRs. Despite the lack of transparency and restrictions, plastics from electronics are often recycled and can be incorporated in household items that do not require flame retardancy, resulting in potentially high and unnecessary exposure. This study sought to determine whether black plastic household products sold on the U.S. market contained emerging and phased-out FRs and whether polymer type was predictive of contamination. A total of 203 products were screened for bromine (Br), and products containing >50 ppm Br were analyzed for BFRs, OPFRs, and plastic polymers (e.g. acrylonitrile butadiene styrene, high impact polystyrene, polypropylene). FRs were found in 85% of analyzed products, with total FR concentrations ranging up to 22,800 mg/kg. FRs detected include the restricted compound deca-BDE, which was used widely in electronics casings, as well as its replacements decabromodiphenyl ethane (DBDPE) and 2,4,6-Tris(2,4,6-tribromophenoxy)-1,3,5-triazine (TBPP-TAZ) along with associated compound 2,4,6-tribromophenol (2,4,6-TBP), recently detected in breast milk. Plastic typically used in electronics (styrene-based) contained significantly higher levels of ∑FRs than plastics less typically used for electronics (polypropylene and nylon). Estimation of exposure to BDE-209 from contaminated kitchen utensils indicated users would have a median intake of 34,700 ng/day, exceeding estimates for intake from dust and diet. The detection of FRs in collected household products indicates that recycling, without the necessary transparency and restrictions to ensure safety, is resulting in unexpected exposure to toxic flame retardants in household items.

In vitro and in vivo evaluation of tedizolid nanoparticle incorporated buccal films for oromucosal infections.

A novel tedizolid phosphate (TZP) nanoparticle (NP)-loaded buccal film formulation was developed for the treatment of buccal wounds infected with S. aureus. TZP-loaded chitosan NPs were produced and characterized to prepare this composite system. The optimum NP formulation was then loaded into mucoadhesive buccal films. The antibacterial effects of the obtained buccal films were evaluated by in vitro and in vivo studies. The optimum TZP-NP formulation (F8) had a particle size of 177.40 ± 2.97 nm and PDI and ZP values were 0.437 ± 0.002 and 33.9 ± 0.5, respectively. In antibacterial efficacy tests, the optimum NP containing buccal film formulation was used, which released approximately 90 % of TZP within 5 h. TZP-NP-loaded buccal films achieved a 3 log10 reduction in S. aureus within just 3 h. It was also administered to Wistar albino rats with S. aureus-infected buccal wounds. As a result of in vivo studies, a significant decrease in the number of S. aureus was detected in wound samples treated with TZP-NP-loaded buccal films. In addition, a complete inhibition of growth was observed on the fifth day of the film application. The current work suggested that the TZP-NP-loaded composite films could be promising candidates for effective and long-acting antibacterial treatment of buccal wounds.

Comparison of the presence of high production volume chemicals in farmed and wild fish highly consumed in catalonia and their risk assessment.

The decline in fish populations and the depletion of marine resources have sparked concerns about sustainable fish production, driving the innovation of new aquaculture methods. While some argue that wild fish are healthier than farmed fish due to less exposure to contaminants and pathogens, wild fish can accumulate contaminants from more contaminated water sources. The slower growth of wild fish and their longer exposure to the environment may contribute to higher pollutant levels in fish tissues. In this study, we focus on 25 contaminants considered as high production volume chemicals (HPVCs), such as organophosphate esters (OPEs), benzothiazoles (BTs), benzosulfonamides (BSAs) and phthalates (PAEs). The compounds were extracted from the edible part of the fish using the QuEChERS method and analysed by gas chromatography-tandem mass spectrometry. A total of 74 samples were analysed from three of the most commonly consumed species in Catalonia, Spain (turbot, sea bass and sea bream). Two samples of each species were collected each month, one form farmed and one from wild origin. In general, the compounds were found in all the samples in a wide concentrations range, although no significant differences were observed between the mean concentration of wild and farmed samples. Although similar mean concentrations for the OPEs, BTs and BSAs were found between farmed and wild origin samples, PAEs were more frequently detected in farmed samples. Di-n-octyl phthalate and diethyl phthalate showed the highest concentrations in all fish samples, with values up to 19505 and 17605 ng g-1 (d.w.), in sea bass and sea bream, respectively. Di-(2-ethylexyl)-adipate proved to be the most relevant carcinogenic compound, with no associated health risk. Despite the detection of the studied HPVCs, no health risk was associated with the consumption of these three fish species.

Urinary Concentrations of Organophosphate Flame-Retardant Metabolites in the US Population.

Importance: Organophosphate flame retardants (OPFRs) are an important group of pollutants associated with endocrine disorders, cancer, and nephrotoxicity. However, temporal trends in OPFR metabolite concentrations remain understudied. Objectives: To examine changes in urinary concentrations of OPFR metabolites among US children, youths, and adults from 2011 to 2020, and to evaluate whether sociodemographic factors were associated with variations in temporal trends. Design, Setting, and Participants: This population-based cross-sectional study used data from 4 US National Health and Nutrition Examination Survey (NHANES) cycles (2011-2012, 2013-2014, 2015-2016, and 2017-2020 [to March 2020 before the COVID-19 pandemic]). The study included children and youths (aged 6-19 years) and adults (aged ≥20 years) with valid urinary concentrations of the following OPFR metabolites: bis(2-chloroethyl) phosphate (BCEtP), bis(1-chloro-2-propyl) phosphate (BCPP), diphenyl phosphate (DPhP), and dibutyl phosphate (DBuP). Data analysis was performed between February and May 2024. Exposures: Calendar year and key sociodemographic subgroups (age, race and ethnicity, sex, educational attainment, and poverty-to-income ratio). Main Outcomes and Measures: The main outcome was urinary concentrations of OPFR metabolites among children, youths, and adults. Survey-weighted linear regression models were applied to estimate trends. Results: The study population of 10 549 NHANES participants included 3154 children and youths (mean [SE] age, 12.5 [0.1] years; 51.2% were male) and 7395 adults (mean [SE] age, 47.8 [0.4] years; 52.0% were women). Among children and youths, mean (95% CI) BCEtP concentrations decreased from 0.68 (0.60-0.77) µg/L in 2011-2012 to 0.41 (0.37-0.45) µg/L in 2017-2020 (P for trend < .001). Among adults, mean (95% CI) BCEtP concentrations decreased from 0.43 (0.37-0.50) µg/L in 2011-2012 to 0.29 (0.27-0.33) µg/L in 2017-2020 (P for trend < .001), and mean BCPP concentrations decreased from 0.15 (0.14-0.17) µg/L to 0.13 (0.12-0.14) µg/L (P for trend = .002). Parent level of educational attainment was associated with concentrations of BCPP and BCEtP among children and youths; however, no significant differences among adults were observed. Conclusions and Relevance: This study identified variations in temporal trends in urinary concentrations of OPFR metabolites among the US population from 2011 to 2020. In addition, substantial disparities in exposure levels persisted among children with different levels of parent educational attainment. These findings suggest that policy makers should consider socioeconomic factors to further reduce OPFR exposure and promote equity, ensuring a safe living environment for all individuals.

US cost-utility model of lenacapavir plus optimized background regimen (OBR) vs fostemsavir plus OBR and ibalizumab plus OBR for people with HIV with multidrug resistance.

BACKGROUND: Heavily treatment-experienced (HTE) people with HIV (PWH) have limited treatment options owing to multidrug resistance (MDR). Lenacapavir (LEN) is indicated, in combination with other antiretrovirals, for the treatment of adults with MDR HIV-1 experiencing failure of their current antiretroviral regimen because of resistance, intolerance, or safety considerations. OBJECTIVE: To evaluate the cost-utility of LEN in combination with an optimized background regimen (OBR) vs alternative recently approved treatments for HTE PWH, fostemsavir (FTR)+OBR and ibalizumab (IBA)+OBR, for the treatment of PWH with MDR, from a mixed US health care payer perspective. METHODS: A Markov state-transition model with a lifetime time horizon was developed. Transition probabilities between viral load categories were based on individual participant data from the CAPELLA trial for LEN+OBR and on relative efficacy parameters obtained from indirect treatment comparisons for comparators. Health state utilities were sourced from the literature. Costs included drug acquisition costs, drug administration costs, disease management costs, adverse event costs, AIDS-related event costs, and treatment switching costs and were sourced from red book costs, Medicare and Medicaid fees, and the literature. Costs and outcomes were discounted at 3% annually. The model was used to estimate total and incremental costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. A deterministic and a probabilistic sensitivity analysis, as well as scenario analyses, were performed to address elements of uncertainty in the model and to explore the robustness of the results. RESULTS: Over a lifetime time horizon, LEN+OBR was associated with the highest absolute QALYs (9.41) and the greatest number of LYs (12.09) compared with FTR+OBR (QALYs: 8.75; LYs: 11.26) and IBA+OBR (QALYs: 8.36; LYs: 10.78). LEN+OBR was also associated with the lowest total lifetime costs of the 3 interventions (LEN+OBR: $1,441,122 [US dollars]; FTR+OBR: $1,504,986; IBA+OBR: $1,524,396) and therefore was dominant over both comparators in the base case. LEN+OBR remained dominant vs FTR+OBR and IBA+OBR across the range of scenarios tested and LEN+OBR had a 99% probability of being cost-effective compared with FTR+OBR and IBA+OBR in the probabilistic sensitivity analysis at a willingness-to-pay threshold of $50,000/QALY. CONCLUSIONS: This economic evaluation demonstrated that LEN+OBR provides meaningful increases in QALYs and LYs, and is dominant over a lifetime time horizon, compared with FTR+OBR and IBA+OBR for the treatment of PWH with MDR in the United States.

Developmental toxicity of an emerging organophosphate ester Bis-(2-ethylhexyl)-phenyl phosphate on embryonic zebrafish: Comparison to 2-ethylhexyl diphenyl phosphate.

Bis-(2-ethylhexyl)-phenyl phosphate (BEHPP) and its structural analog, 2-ethylhexyl diphenyl phosphate (EHDPP), are widely present in the environment. However, their toxic effects, particularly developmental toxicity, remain poorly understood. In this study, we evaluated the impacts of BEHPP and EHDPP on multiple developmental endpoints in zebrafish. BEHPP did not lead to mortality and malformations of embryos within the test concentration range (0.5-4.0 µM). In contrast, EHDPP had significant lethal effects, with an LC50 of 2.44 µM, and induced malformations, notably pericardial edema (PE), with an EC50 of 1.77 µM. In addition, BEHPP induced cardiac dysfunctions in embryos to a similar degree as EHDPP. Both stroke volume and cardiac output were significantly increased at BEHPP concentrations of 1.8 nM and above and at EHDPP concentrations of 4.3 nM and above. Transcriptomic analysis further corroborated the similar disturbance at the molecular level for both substances and revealed the Key Events (KEs) in the cardiac toxic regulation, including the focal adhesions, ECM-receptor interaction, cardiac muscle contraction, and the adrenergic signaling in cardiomyocytes. Taken together, the present study provided novel insights into the adverse effects of these emerging organophosphate esters and highlighted their potential risks to embryonic development in both ecosystems and humans.

Kinetics of uptake, translocation, and metabolism of organophosphate esters in japonica rice (Oryza sativa L.): Hydroponic experiment combined with model.

Hydroponics combined with fugacity model was employed to investigate the kinetics of uptake, accumulation, and metabolism of organophosphate esters (OPEs) by japonica rice. The time-dependent process for uptake and accumulation of 5 OPEs and their diester-metabolites in both rice root and shoot fitted well with the pseudo-first-order kinetic model. The peak OPE accumulations in rice root and shoot were significantly positively or negatively correlated with their octanol-water partition coefficient (logKow) respectively, but not for their apparent accumulation rates. Root concentration factors (RCFs) and root-to-shoot translocation factors (TFs) of OPEs were found to be positively and negatively correlated with their logKow, respectively. Triphenyl phosphate with benzene ring substituents showed the highest RCF, but the lowest TF, because of its high potential for root adsorption due to the π electron-rich structures. Sterilized root exudates can hinder the root adsorption and absorption of OPEs from solution probably through competitive adsorption of OPEs with root surface. The first-hand transport and metabolism rates were also obtained by generating these rates to fit the dynamic fugacity model with the measurement values. The simulation indicated that the kinetics of OPE accumulation in rice plants may be controlled by multiple processes and physicochemical properties besides Kow.