Biomonitoring urinary organophosphorus flame retardant metabolites by liquid-liquid extraction and ultra-high performance liquid chromatography-tandem mass spectrometry and their association with oxidative stress.

Organophosphate flame retardants (OPFRs) are widely used as substitutes for traditional brominated flame retardants, necessitating a reliable and sensitive method for biomonitoring their urinary metabolites to assess human exposure. This study conducted biomonitoring of 10 metabolites of OPFRs in 152 adults and assessed their association with oxidative stress biomarkers 8-hydroxydeoxyguanosine and 8-hydroxyguanosine. Urinary metabolites of OPFRs were released via enzymatic deconjugation. The addition of sodium chloride to the urine samples increases the ionic strength, inducing a salting-out effect that reduces the solubility of these compounds, thereby facilitating their extraction with a mixture of ethyl acetate and acetonitrile. Then, the metabolites of OPFRs were quantified by ultra-high performance liquid chromatography-tandem mass spectrometry, and we validated the method for linear range, precision, matrix effect, and method detection limit. The detection limit of the metabolites of OPFRs ranged from 0.01 to 0.2 µg/L, and these metabolites were detected with high frequencies ranging from 25.0 to 98.68% in the urine samples. The concentration of bis (2-chloroethyl) phosphate was significantly higher in males than in females, with the geometric mean concentration of 0.88 µg/L for males and 0.53 µg/L for females, respectively. Spearman correlation analysis revealed weak but statistically significant positive correlations among the urinary metabolites. Bayesian kernel machine regression analysis showed a significant positive association between elevated urinary concentrations of metabolites of OPFRs and increased oxidative stress levels. Di-n-butyl phosphate was identified as the metabolite that significantly contributed to the elevated level of 8-hydroxyguanosine.

Association between organophosphorus pesticides and obesity among American adults.

OBJECTIVE: To investigate any connections between urinary organophosphorus pesticide (OPP) metabolites and adiposity measures. METHODS: In this study, data from the National Health and Nutrition Examination Survey (NHANES) projects from 2003 to 2008, 2011 to 2012, and 2015 to 2018 were analysed. Obesity was defined as a body mass index (BMI) of 30 kg/m² or higher. Abdominal obesity was defined as a waist circumference (WC) over 102 cm for men and 88 cm for women. Four urinary OPP metabolites (dimethyl phosphate [DMP], diethyl phosphate [DEP], dimethyl phosphorothioate [DMTP], and diethyl phosphorothioate [DETP]) and adiposity measures were examined using multiple linear regression and logistic regression analyses. The correlations between a variety of urinary OPP metabolites and the prevalence of obesity were investigated using weighted quantile sum regression and quantile g-computation regression. RESULTS: In this analysis, a total of 9,505 adults were taken into account. There were 49.81% of male participants, and the average age was 46.00 years old. The median BMI and WC of the subjects were 27.70 kg/m2 and 97.10 cm, respectively. Moreover, 35.60% of the participants were obese, and 54.42% had abdominal obesity. DMP, DMTP, and DETP were discovered to have a negative correlation with WC and BMI in the adjusted models. DMP (OR = 0.93 [95% CI: 0.89-0.98]), DEP (OR = 0.94 [95% CI: 0.90-0.99]), DMTP (OR = 0.91 [95% CI: 0.86-0.95]), and DETP (OR = 0.85 [95% CI: 0.80-0.90]) exhibited negative associations with obesity prevalence. Similar correlations between the prevalence of abdominal obesity and the urine OPP metabolites were discovered. Moreover, the mixture of urinary OPP metabolites showed negative associations with adiposity measures, with DMTP and DETP showing the most significant effects. CONCLUSION: Together, higher levels of urinary OPP metabolites in the urine were linked to a decline in the prevalence of obesity.

Investigating the prevalence of erectile dysfunction among men exposed to organophosphate insecticides.

INTRODUCTION: Erectile dysfunction (ED) poses a significant disease morbidity and contributor to male infertility, where an estimated 20-40% of men are affected annually. While several risk factors have been identified in the etiology of ED (e.g., aging, heart disease, diabetes, and obesity), the complete pathogenesis remains to be elucidated. Over the last few decades, the contribution of environmental exposures to the pathogenesis of ED has gained some attention, though population studies are limited and results are mixed. Among environmental contaminants, organophosphate (OP) insecticides represent one of the largest chemical classes, and chlorpyrifos is the most commonly used OP in the U.S. OP exposure has been implicated in driving biological processes, including inflammation, reactive oxygen species production, and endocrine and metabolism disruption, which have been demonstrated to adversely affect the hypothalamus and testes and may contribute to ED. Currently, studies evaluating the association between OPs and ED within the U.S. general population are sparse. METHODS: Data were leveraged from the National Health and Nutrition Examination Survey (NHANES), which is an annually conducted, population-based cross-sectional study. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of the most pervasive OP insecticide chlorpyrifos, were quantified as measures of OP exposure. ED was defined by responses to questionnaire data, where individuals who replied "sometimes able" or "never able" to achieve an erection were classified as ED. Chi-square, analysis of variance (ANOVA), and multivariable, weighted linear and logistic regression analyses were used to compare sociodemographic variables between quartiles of TCPy exposure, identify risk factors for TCPy exposure and ED, and to analyze the relationship between TCPy and ED. RESULTS: A total of 671 adult men were included in final analyses, representing 28,949,379 adults after survey weighting. Approximately 37% of our cohort had ED. Smoking, diabetes, aging, Mexican-American self-identification, and physical inactivity were associated with higher ED prevalence. Analysis of TCPy modeled as a continuous variable revealed nonsignificant associations with ED (OR = 1.02 95% CI [0.95, 1.09]). Stratification of total TCPy into quartiles revealed increased odds of ED among adults in the second and fourth quartiles, using the first quartile as the reference (OR = 2.04 95% CI [1.11, 3.72], OR = 1.51 95% CI [0.58, 3.93], OR = 2.62 95% CI [1.18, 5.79], for quartiles 2, 3, and 4, respectively). CONCLUSIONS: The results of our study suggest a potential role for chlorpyrifos and other OPs the pathogenesis of ED. Future studies are warranted to validate these findings, determine clinical significance, and to investigate potential mechanisms underlying these associations.

Association between exposure to organophosphorus pesticide and suicidal ideation among U.S. adults: A population-based study.

OBJECTIVE: This study aims to investigate the potential link between exposure to organophosphorus pesticides (OPPs) and suicidal ideation (SI) among adults. METHODS: This study encompassed four cycles of the National Health and Nutrition Examination Survey (NHANES), involving 5244 participants aged 20 and above. SI was assessed using the Patient Health Questionnaire-9. The levels of exposure to OPPs were estimated by analyzing concentrations of OPP metabolites in urine samples. Multivariate logistic regression models were used to explore the association between exposure to each OPP and SI. Stratified analyses and interaction tests were conducted across various groups, including pairwise combinations of gender and age, as well as body mass index, smoking status, hypertension, and diabetes. Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression (BKMR) models were applied to assess the cumulative impact of exposure to the four OPPs on SI, along with their respective contributions. Additionally, the potential interactions among these four OPPs were evaluated. RESULTS: Multivariate logistic regression revealed that only dimethylthiophosphate (DMTP) among OPPs demonstrated a statistically significant positive association with SI [OR: 1.18; 95 % CI: 1.02-1.37]. Stratified analyses indicated that the influence of OPPs on SI was particularly pronounced in young and older men. The WQS regression analysis revealed a statistically significant association between the mixed metabolites of OPPs and SI [OR = 1.10, 95 % CI: 1.04-1.16], with DMTP (weighted 0.63) contributing the most. Furthermore, the BKMR model supported a positive trend in the overall impact of these OPP metabolites on SI, displaying notable individual exposure-response relationships for DMTP (PIP: 0.77). CONCLUSIONS: Our study suggests an association between exposure to DMTP and an increased risk of SI. Specifically, young adult males and older males appear particularly susceptible to the effects of OPP exposure.

Nephrotoxicity of organophosphate flame retardants in patients with chronic kidney disease: A 2-year longitudinal study.

Humans are extensively exposed to organophosphate flame retardants (OPFRs), an emerging group of organic contaminants with potential nephrotoxicity. Nevertheless, the estimated daily intake (EDI) and prognostic impacts of OPFRs have not been assessed in individuals with chronic kidney disease (CKD). In this 2-year longitudinal study of 169 patients with CKD, we calculated the EDIs of five OPFR triesters from urinary biomonitoring data of their degradation products and analyzed the effects of OPFR exposure on adverse renal outcomes and renal function deterioration. Our analysis demonstrated universal OPFR exposure in the CKD population, with a median EDIΣOPFR of 360.45 ng/kg body weight/day (interquartile range, 198.35-775.94). Additionally, our study revealed that high tris(2-chloroethyl) phosphate (TCEP) exposure independently correlated with composite adverse events and composite renal events (hazard ratio [95 % confidence interval; CI]: 4.616 [1.060-20.096], p = 0.042; 3.053 [1.075-8.674], p = 0.036) and served as an independent predictor for renal function deterioration throughout the study period, with a decline in estimated glomerular filtration rate of 4.127 mL/min/1.73 m2 (95 % CI, -8.127--0.126; p = 0.043) per log ng/kg body weight/day of EDITCEP. Furthermore, the EDITCEP and EDIΣOPFR were positively associated with elevations in urinary 8-hydroxy-2'-deoxyguanosine and kidney injury molecule-1 during the study period, indicating the roles of oxidative damage and renal tubular injury in the nephrotoxicity of OPFR exposure. To conclude, our findings highlight the widespread OPFR exposure and its possible nephrotoxicity in the CKD population.

Associations between prenatal organophosphate pesticide exposure and placental gene networks.

BACKGROUND: Exposure to organophosphate (OP) pesticides during pregnancy has been linked to deficiencies of neurobehavioral development in childhood; however, the molecular mechanisms underlying this association remain elusive. The placenta plays a crucial role in protecting the fetus from environmental insults and safeguarding proper fetal development including neurodevelopment. The aim of our study is to evaluate changes in the placental transcriptome associated with prenatal OP exposure. METHODS: Pregnant farm workers from two agricultural districts in northern Thailand were recruited for the Study of Asian Women and Offspring's Development and Environmental Exposures (SAWASDEE) from 2017 to 2019. For 254 participants, we measured maternal urinary concentrations of six nonspecific dialkyl phosphates (DAP) metabolites in early, middle, and late pregnancy. In parallel, we profiled the term placental transcriptome from the same participants using RNA-Sequencing and performed Weighted Gene co-expression Network Analysis (WGCNA). Generalized linear regression modeling was used to examine associations of urinary OP metabolites and placental co-expression module eigenvalues. RESULTS: We identified 21 gene co-expression modules in the placenta. From the six DAP metabolites assayed, diethylphosphate (DEP) and diethylthiophosphate (DETP) were detected in more than 70% of the urine samples. Significant associations between DEP at multiple time points and two specific placental gene modules were observed. The 'black' module, enriched in genes involved in epithelial-to-mesenchymal transition (EMT) and hypoxia, was negatively associated with DEP in early (p = 0.034), and late pregnancies (p = 0.016). The 'lightgreen' module, enriched in genes involved in myogenesis and EMT, was negatively associated with DEP in late pregnancy (p = 0.010). We observed 2 hub genes (CELSR1 and PYCR1) of the 'black' module to be negatively associated with DEP in early and late pregnancies. CONCLUSIONS: Our results suggest that prenatal OP exposure may disrupt placental gene networks in a time-dependent manner. Such transcriptomic effects may lead to down-stream changes in placental function that ultimately affect the developing fetus.

Residue levels of organophosphate pesticides and dialkylphosphates in agricultural products in Japan.

High urinary levels of dialkylphosphates (DAPs), which are common structures of organophosphate pesticides (OPs), have been associated with several adverse health outcomes in human biomonitoring studies. Previous studies have indicated that dietary OP exposure and ingestion of environmentally degraded DAP, which is inactive with acetylcholinesterase, can lead to an increase in urinary DAP levels in the general population. However, the specific food sources contributing to the intake of OPs and DAPs have not been identified. In this study, we analyzed the levels of OPs and preformed DAPs in various food items. DAP levels were markedly high in certain fruits, such as persimmon, apple juice, kiwi, and mandarin. In contrast, only moderate levels of OPs were detected in these foods. Furthermore, the levels of OPs and DAPs were positively associated with vegetables, whereas no such association was observed in fruits. Increased consumption of certain fruits presumably leads to a marked increase in urinary DAP levels in individuals despite limited exposure to OPs, resulting in reduced reliability of urinary DAPs as a marker of OP exposure. Therefore, the possible effects of dietary habits and the resulting intake of preformed DAPs should be considered when interpreting biomonitoring data of urinary DAPs. Additionally, DAP levels in most organic foods were much lower than those in conventional foods, suggesting that the reduction in urinary DAPs by organic diet intervention may be mainly attributed to the reduced intake of preformed DAPs rather than reduced exposure to OPs. Therefore, urinary DAP levels may not be suitable indicators for evaluating ingested OP exposure.

Influence of exposure to pesticides on telomere length and pregnancy outcome: Diethylphosphates but not Dimethylphosphates are associated with accelerated telomere attrition in a Palestinian cohort.

Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.

Urinary organophosphate metabolite concentrations and birth sizes among women conceiving through in vitro fertilization in Shanghai, China.

BACKGROUND: Few studies have examined the adverse birth sizes of preconception exposure to organophosphate pesticides (OPs) in women undergoing in vitro fertilization (IVF). OBJECTIVES: We investigated the relationship of preconception OP exposure with birth sizes among Chinese women undergoing IVF. METHODS: This study included 302 couples seeking infertility treatment in the China National Birth Cohort Study, from Shanghai, China, who gave birth to singleton infants between 2018 and 2021. Clinical data were collected from medical records. We measured the concentrations of six nonspecific dialkyl phosphates (DAP) metabolites of OPs [diethylthiophosphate (DETP), diethylphosphate (DEP), diethyldithiophosphate (DEDTP), dimethyldithiophosphate (DMTP), dimethylphosphate (DMP), and dimethyldithiophosphate (DMDTP)] in maternal urine. DMDTP and DEDTP were precluded from further analyses due to the low detection rates. Generalized linear models (GLMs) and weighted quantile sum (WQS) regression analyses were performed to examine the individual and joint effects of OP exposures on gestational age, birth weight, body length, and ponderal index. Odder ratio (OR) of preterm birth were estimated using logistic regression models. RESULTS: Women in the highest as compared with lowest quartile of DEP had shorter gestational age (ß = - 0.68; 95% CI = -1.24, -0.11). The association was modified by sex, with boys showing larger decreases in gestational age (ß = - 0.86; 95% CI = -1.60, -0.13). No associations were found between other DAP metabolites and birth sizes. Results from linear models with individual DAP metabolites were corroborated by the WQS regression where DEP had the largest contribution to the overall mixture effect on gestational age (weight = 0.70). Moreover, DEP concentration was associated with an elevated risk of preterm birth (OR = 1.35, 95% CI = 1.11, 2.25). CONCLUSION: Preconception DEP concentration was associated with shortened gestational age and increased risk of preterm birth, and the association was more pronounced among boys than girls.

Prenatal exposure to organophosphate pesticides and autism spectrum disorders in 11-year-old children in the French PELAGIE cohort.

BACKGROUND: Organophosphate (OP) pesticides act by inhibiting acetylcholinesterase activity at synaptic junctions and have already been linked with deleterious effects on neurodevelopment, including autism spectrum disorders (ASD). OBJECTIVES: To investigate the association of prenatal exposure to OP pesticides with traits related to ASD in 11-year-old children. METHODS: The "Childhood Autism Spectrum Test" (CAST) parent questionnaire was used to screen for autistic traits in 792 children from the French PELAGIE cohort. Prenatal maternal urine samples were collected <19 weeks of gestation in which metabolites of organophosphate insecticides were assessed for 185 of them. Negative binomial regression models were performed to explore the association between the CAST score and 8 groups of urine components, adjusted for potential ASD risk factors. RESULTS: In these urine samples, dialkylphosphates (DAP) were detected most often (>80%), terbufos and its metabolites least often (<10%). No association with ASD was found for DAP, terbufos or its metabolites. Incidence rate ratios (IRRs) increased with maternal urinary diazinon concentrations, from 1.11 (95% CI: 0.87-1.42) to 1.17 (95% CI: 0.94-1.46). Higher CAST scores were statistically significantly associated with the maternal urine samples in which chlorpyrifos or two of its metabolites (chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol) were detected. The IRR for exposure to chlorpyrifos or chlorpyrifos-oxon was 1.27 (95%CI: 1.05-1.52) among all children, and 1.39 (95%CI: 1.07-1.82) among boys. CONCLUSION: These findings suggest an increase in autistic traits among 11-year-old children in association with prenatal maternal exposure to chlorpyrifos and possibly diazinon. These associations were previously suspected in the literature, in particular for chlorpyrifos. Further work establishing the causal mechanisms behind these risk association is needed.

Exposure to non-persistent pesticides, BDNF, and behavioral function in adolescent males: Exploring a novel effect biomarker approach.

BACKGROUND: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. OBJECTIVES: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. METHODS: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15-17-year-old boys from the INMA-Granada cohort in Spain. Adolescents' behavior was reported by parents using the Child Behavior Check List (CBCL/6-18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit. RESULTS: IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested. CONCLUSION: BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.

The association between organophosphate insecticides and blood pressure dysregulation: NHANES 2013-2014.

BACKGROUND: Organophosphate (OP) insecticides represent one of the largest classes of sprayed insecticides in the U.S., and their use has been associated with various adverse health outcomes, including disorders of blood pressure regulation such as hypertension (HTN). METHODS: In a study of 935 adults from the NHANES 2013-2014 cycle, we examined the relationship between systolic and diastolic blood pressure changes and urinary concentrations of three OP insecticides metabolites, including 3,5,6-trichloro-2-pyridinol (TCPy), oxypyrimidine, and para-nitrophenol. These metabolites correspond to the parent compounds chlorpyrifos, diazinon, and methyl parathion, respectively. Weighted, multivariable linear regression analysis while adjusting for potential confounders were used to model the relationship between OP metabolites and blood pressure. Weighted, multivariable logistic regression analysis was used to model the odds of HTN for quartile of metabolites. RESULTS: We observed significant, inverse association between TCPy on systolic blood pressure (ß-estimate = -0.16, p < 0.001) and diastolic blood pressure (ß-estimate = -0.15, p < 0.001). Analysis with para-nitrophenol revealed a significant, positive association with systolic blood pressure (ß-estimate = 0.03, p = 0.02), and an inverse association with diastolic blood pressure (ß-estimate = -0.09, p < 0.001). For oxypyrimidine, we observed significant, positive associations between systolic blood pressure (ß-estimate = 0.58, p = 0.03) and diastolic blood pressure (ß-estimate = 0.31, p < 0.001). Furthermore, we observed significant interactions between TCPy and ethnicity on systolic blood pressure (ß-estimate = 1.46, p = 0.0036). Significant interaction terms were observed between oxypyrimidine and ethnicity (ß-estimate = -1.73, p < 0.001), as well as oxypyrimidine and BMI (ß-estimate = 1.51 p < 0.001) on systolic blood pressure, and between oxypyrimidine and age (ß-estimate = 1.96, p = 0.02), race (ß-estimate = -3.81 p = 0.004), and BMI on diastolic blood pressure (ß-estimate = 0.72, p = 0.02). A significant interaction was observed between para-nitrophenol and BMI for systolic blood pressure (ß-estimate = 0.43, p = 0.01), and between para-nitrophenol and ethnicity on diastolic blood pressure (ß-estimate = 2.19, p = 0.006). Lastly, we observed a significant association between the odds of HTN and TCPy quartiles (OR = 0.65, 95% CI [0.43,0.99]). CONCLUSION: Our findings support previous studies suggesting a role for organophosphate insecticides in the etiology of blood pressure dysregulation and HTN. Future studies are warranted to corroborate these findings, evaluate dose-response relationships between organophosphate insecticides and blood pressure, determine clinical significance, and elucidate biological mechanisms underlying this association.

Effect of severe renal impairment on the pharmacokinetics of brigatinib.

Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non-small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.

Organophosphate metabolite concentrations in maternal urine during pregnancy.

The burden of organophosphate (OP) pesticides in pregnant women from Tarragona (n = 157), a Mediterranean area of intense agricultural activity, has been assessed from the study of hydroxylated organic metabolites in urine samples in the three trimesters of pregnancy. 2-Diethylamino-6-methylpyrimidin-4-ol (DEAMPY), a metabolite of pirimiphos, was the compound found in higher concentration, medians 0.66-2.8 µg/g creatinine. 4-Nitrophenol (PNP), a metabolite of parathion, medians 0.24-0.41 µg/g creatinine, was the second most abundant compound. 2-Isopropyl-6-methyl-4-pyrimidol (IMPY), a metabolite of diazinon, was also present but in lower concentrations. Except for DEAMPY, the concentrations found in this cohort were lower than those reported in studies from other countries. Intraclass correlation coefficients (ICCs) were calculated for the compounds found in more than the 35% of the samples, the reliability between trimesters was poor (<0.40) to fair (0.40-0.60). Statistically significant differences were observed for the creatinine adjusted concentrations of the most abundant OP metabolites in these trimesters when examined with the Wilcoxon signed rank test for paired data. In general, no association was found between urinary OP metabolites and most demographic and lifestyle predictors. However, a positive significant association was observed for women with vegetarian diet and for women of higher economic status and eventual consumption of organic food which showed higher PNP concentrations. These results suggest that higher fruit and vegetable consumption may involve higher OP pesticide ingestion but the overall association was weak.

Highly sensitive retrospective determination of organophosphorous nerve agent biomarkers in human urine implemented in vivo in rabbit.

Highly toxic organophosphorous nerve agents (OPAs) have been used in several armed conflicts and terror attacks in the last few decades. A new method for retrospective determination of alkyl methylphosphonic acid (AMPA) metabolites in urine after exposure to VX, GB and GF nerve agents was developed. This method enables a rapid, sensitive and selective determination of trace levels of the nerve agent biomarkers ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA) in urine. The new technique involves a unique combination of two solid phase extraction (SPE) cartridges: a Ba/Ag/H cartridge for urine interference removal, and a ZrO2 cartridge for selective reconstitution and enrichment of the AMPAs. Extraction of AMPAs from the ZrO2 cartridge was accomplished with a 1% ammonium hydroxide (NH4OH) solution and was followed by analysis via liquid chromatography-mass spectrometry (LC-MS). The limits of quantitation (LOQs) were in the range of 10-100 pg/mL with recoveries of 64-71% (± 5-19%) after fast sample preparation and a total LC-MS analysis cycle time of 15 min and 13 min, respectively. This method was successfully applied in vivo in a rabbit that was exposed to 0.5 LD50 (7.5 µg/kg, i.v.) sarin for retrospective monitoring of the IMPA metabolite in urine. For the first time, IMPA was determined in rabbit urine samples for 15 days post-exposure, which is longer than any reported post-exposure method for AMPAs. To the best of our knowledge, this new method is the most sensitive and rapid for AMPA determination in urine by LC-MS/MS analysis.

An educational intervention on the risk perception of pesticides exposure and organophosphate metabolites urinary concentrations in rural school children in Maule Region, Chile.

BACKGROUND: Organophosphate (OP) pesticides can be hazardous to human health if not applied with appropriate precautions. There is evidence in the Maule region of Chile that rural schoolchildren are exposed to OP pesticides. OBJECTIVE: To evaluate the effectiveness of an educational intervention on OP exposure and understanding of pesticides and their hazards (risk perception) in two school communities in the Maule Region of Chile during 2016. METHOD: We conducted a quasi-experimental study about the effects on OP pesticide exposure of a community outreach and education program (COEP) administered in four 2-h sessions that's included hands-on activities among 48 schoolchildren from two rural schools. The intervention was directed to groups of parents and school-children separately, and aimed to educate them about the risks of exposure to pesticides and their effects on health. We measured 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), malathion dicarboxylic acid (MDA), p-nitrophenol (PNP), specific urinary metabolites of the OP pesticides chlorpyrifos, diazinon, malathion and parathion, respectively, as well as the non-specific diethylakylphosphates (DEAPs) and dimethylalkylphosphates (DMAPs) in 192 urine samples of schoolchildren collected before and after the intervention. The risk perception of school children and their parents was also assessed through a questionnaire before and after the intervention. Generalized Estimated Equations were used to account for each child's repeated measures during four sessions, two in September 2016 (pre-intervention) and two in November 2016 (post-intervention). RESULTS: The intervention level had significant effect on the risk perception of adults and children, which increased after the intervention. However, the intervention was not associated with reduced of urinary metabolites levels, with no significant differences between the pre and post measures. The detection frequencies were 1.1% (MDA), 71.4% (TCPy), 43.3% (IMPY), 98.96% (PNP), and 100% (DEAPs and DMAPs). Higher DEAPs urine concentrations were associated with eating more fruit at school (p = 0.03), a younger age (p = 0.03), and being male (p = 0.01). DMAPs showed no associations with potential predictor variables (e.g. OPs applied at home, fruit consumption at school, among others). Higher TCPy was associated with attending a school closer to farms (p = 0.04) and living in a home closer to farm fields (p = 0.01); higher PNP was marginally associated with children younger age (p = 0.035). CONCLUSION: Environmental exposure to OP pesticides was unchanged even after behavior changes. It is possible that a longer time period is needed to observe changes in both behavior and urinary metabolites. The levels of DEP and DMP metabolites found here are above the reference population of the US, and our findings indicate exposure to a wide variety of OP pesticides. Given that individual-level interventions were not associated with lower exposures, efforts to reduce exposure must occur upstream and require stricter regulation and control of pesticide use by government agencies.

Determination of Picomolar Concentrations of Paraoxon in Human Urine by Fluorescence-Based Enzymatic Assay.

Organophosphate (OP) pesticides are widely used in the agricultural field and in the prevention of pest infestation in private and public areas of cities. Despite their unquestionable utility, several of these compounds demonstrate toxic effects to the environment and human health. In particular, the occurrence of some organophosphate pesticides is correlated to the incidence of nervous system disorders, especially in children. The detection of pesticide residues in the human body represents an important task to preserve human health. In our work we propose the use of esterase-based biosensors as a viable alternative to the expensive and time-consuming systems currently used for their detection in human fluids. Using the esterase-2 activity, coupled with a fluorescence inhibition assay, we are able to detect very low concentration levels of diethyl (4-nitrophenyl) phosphate (paraoxon) in the range of the femtomole (fmol). Method robustness tests indicate the stability of esterase-2 in a diluted solution of 4% human urine, and we are able to accurately determine concentration levels of paraoxon in the range from 0.1 to 2 picomoles (pmol). The system sensitivity for OP detection is calculated at 524 ± 14.15 fmol of paraoxon recognized at 10% of inhibition, with an estimated limit of quantification of 262 ± 8.12 pmol mL-1. These values are comparable with the most recent analysis methods based on mass spectrometry carried out on human samples for pesticide detection. This research represents a starting point to develop cheap and fast testing methods for a rapid screening of toxic substances in human samples.

Assessment of spray polyurethane foam worker exposure to organophosphate flame retardants through measures in air, hand wipes, and urine.

Tris(1-chloro-2-propyl) phosphate (TCPP, also referenced as TCIPP), a flame retardant used in spray polyurethane foam insulation, increases cell toxicity and affects fetal development. Spray polyurethane foam workers have the potential to be exposed to TCPP during application. In this study, we determined exposure to TCPP and concentrations of the urinary biomarker bis(1-chloro-2-propyl) phosphate (BCPP) among 29 spray polyurethane foam workers over 2 work days. Work was conducted at residential or commercial facilities using both open-cell (low density) and closed-cell (high density) foam. Study participants provided two personal air samples (Day 1 and Day 2), two hand wipe samples (Pre-shift Day 2 and Post-shift Day 2), and two spot urine samples (Pre-shift Day 1 and Post-shift Day 2). Bulk samples of cured spray foam were also analyzed. Sprayers were found to have significantly higher TCPP geometric mean (GM) concentration in personal air samples (87.1 µg/m3), compared to helpers (30.2 µg/m3; p = 0.025). A statistically significant difference was observed between TCPP pre- and post-shift hand wipe GM concentrations (p = 0.004). Specifically, TCPP GM concentration in post-shift hand wipe samples of helpers (106,000 ng/sample) was significantly greater than pre-shift (27,300 ng/sample; p < 0.001). The GM concentration of the urinary biomarker BCPP (23.8 µg/g creatinine) was notably higher than the adult male general population (0.159 µg/g creatinine, p < 0.001). Urinary BCPP GM concentration increased significantly from Pre-shift Day 1 to Post-shift Day 2 for sprayers (p = 0.013) and helpers (p = 0.009). Among bulk samples, cured open-cell foam had a TCPP GM concentration of 9.23% by weight while closed-cell foam was 1.68%. Overall, post-shift BCPP urine concentrations were observed to be associated with TCPP air and hand wipe concentrations, as well as job position (sprayer vs. helper). Spray polyurethane foam workers should wear personal protective equipment including air-supplied respirators, coveralls, and gloves during application.

Characterization of organophosphate pesticides in urine and home environment dust in an agricultural community.

CONTEXT: Organophosphorus insecticides (OPs) have been used to control agricultural pests found in Washington state. Farmworkers (FW) have higher exposure to OP pesticides than non-farmworkers (NFW), and FW children may in turn have higher exposure than NFW children. OBJECTIVE: To examine the association between the concentration in house dust of five OPs used commonly in pome fruit orchards and the concentration in urine of dialkylphosphate metabolites (DAP), in a cohort of Hispanic FW and NFW and their children. METHODS: Parents and children participated in three data collection periods over the course of one year. Urine samples were evaluated for the DAPs characteristic of OP exposure, and dust from homes and vehicles was evaluated for intact OP residues. RESULTS: Geometric mean (GM) concentrations of OPs in house and vehicle dust were higher in FW households than NFW households in all agricultural seasons. GM concentration of urinary DAPs was higher for children in FW households than NFW households. DISCUSSION: Regression analysis found a positive association between OP residues in house dust and the children's urinary DAPs. CONCLUSIONS: To our knowledge, this study is the first to report an association between pesticides in house dust and their biological metabolites in urine.

Correlation of pesticide exposure from dietary intake and bio-monitoring: The different sex and socio-economic study of children.

Exposure to organophosphorus pesticides was assessed though bio-monitoring of urinary dialkyl phosphate metabolites to characterize children's exposure to pesticides. No reports have been found which evaluate exposure of pesticides among adolescents of different sexes. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine the metabolite concentrations. Related objective was to determine any significant changes of pesticide exposure among the adolescents of different sexes. The primary objective was to develop a coupled exposure-dose modeling approach to determine the metabolites concentrations to keep children's urine metabolites levels below specified values considering exposures from water, and the food related objective was to determine any significant changes of pesticide exposure among the adolescents of different sexes. We recruited a sample of 377 children (188 boys, 189 girls) ages 6-10 and 11-15 years from Hyderabad, India for urine collection. Results showed that the mean concentrations of dialkyl phosphate metabolites in first morning first urine samples (3.05 µmol L-1) were strongly correlated with concentrations of the same-day 24-h samples (1.7 µmol L-1) ( r = 0.997, model R2 ≈ 0.994, p < 0.00) with 99.4% accuracy. Irrespective of similar amounts of conventional food consumption, girls showed 87.5% of detection frequency of DAP metabolites which was higher than the 74% detection frequency of DAP metabolites among boys. The female group showed (87%) higher pesticide metabolite levels than boys. This report may help to focus on new studies of the connection between adolescents of different sex and organophosphorus metabolite exposure and to develop an exposure database to facilitate health risk assessment in our day-to-day environment.