Urinary Metabolite Levels Research Articles

Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function.

We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in prostaglandin endoperoxide synthase 1 (PTGS1) (the gene encoding cyclo-oxygenase 1 [COX-1], the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COXderived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 formation by platelets, urinary thromboxane A2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.

Urinary levels of organophosphate pesticides and predictors of exposure in pre-school and school children living in agricultural and urban communities from south Spain

Background. Despite the widespread use of organophosphate (OP) pesticides, information on predictors of children's exposure to such pesticides is scarce.Objective. To assess exposure to OP pesticides in children 3-11 year-old living in agricultural communities and urban areas from Andalusia (Southern Spain), and to identify the main determinants of exposure.Methods. A longitudinal study was conducted in children 3-11-year-old children living in agricultural communities and urban areas from the provinces of Almeria, Granada and Huelva (Andalusia, Spain) between 2010 and 2011. Urinary levels of six dialkylphosphate (DAP) metabolites were measured by UHPLC-QqQ-MS/MS at the periods of low and high pesticide use in the agriculture (LPU and HPU, respectively). Information on sociodemographic characteristics, parental occupation, residential history, lifestyle and diet, among other relevant factors, was obtained from questionnaires administered to the mothers.Results. A total of 559 and 597 children participated in LPU and HPU periods, respectively. The proportion of urine samples below LOD was 67.4% for ΣDMs (sum of dimethyl metabolites), 77% for ΣDEs (sum of diethyl metabolites) and 58.5% for ΣDAPs (sum of total dialkylphosphate metabolites) in LPU period, and 50.4% for ΣDMs, 65.3% for ΣDEs and 43.9% for ΣDAPs in HPU period. Significantly greater urinary ΣDAP, ΣDM and ΣDE levels were observed in HPU relative to LPU period. Maternal schooling years, proximity of the house to crops or greenhouses, use of insecticides at home, spraying the garden with pesticides, storage of pesticides at home, house cleaning frequency, as well as child's frequency of bath/shower, were found to be the major predictors of urinary levels of ΣDAP. Likewise, not washing fruit and vegetables before consumption and banana consumption were also identified as determinants of the exposure levels.Conclusions. Urinary levels of metabolites of OP pesticides found in this study were relatively lower compared to similar studies. DAP levels were significantly increased in HPU period. Maternal schooling years and variables related to residential environment and home exposures were identified as the most relevant determinants of DAP metabolites. Regarding diet, banana consumption and not washing fruit before consumption were also identified as determinants of the exposure levels. This study contributes to improve our knowledge on the main sources and determinants of children exposure to OPS, and given that children are more vulnerable than adults this information is essential to reduce children exposure and protect their health.

Pharmacological Characterization of the Microsomal Prostaglandin E2 Synthase-1 Inhibitor AF3485 In Vitro and In Vivo.

RationaleThe development of inhibitors of microsomal prostaglandin (PG)E2 synthase-1 (mPGES-1) was driven by the promise of attaining antiinflammatory agents with a safe cardiovascular profile because of the possible diversion of the accumulated substrate, PGH2, towards prostacyclin (PGI2).ObjectivesWe studied the effect of the human mPGES-1 inhibitor, AF3485 (a benzamide derivative) on prostanoid biosynthesis in human whole blood in vitro. To characterize possible off-target effects of the compound, we evaluated: i)the impact of its administration on the systemic biosynthesis of prostanoids in a model of complete Freund's adjuvant (CFA)-induced monoarthritis in rats; ii) the effects on cyclooxygenase (COX)-2 expression and the biosynthesis of prostanoids in human monocytes and human umbilical vein endothelial cells (HUVECs) in vitro.MethodsProstanoids were assessed in different cellular models by immunoassays. The effect of the administration of AF3485 (30 and 100 mg/kg,i.p.) or celecoxib (20mg/kg, i.p.), for 3 days, on the urinary levels of enzymatic metabolites of prostanoids, PGE-M, PGI-M, and TX-M were assessed by LC-MS.ResultsIn LPS-stimulated whole blood, AF3485 inhibited PGE2 biosynthesis, in a concentration-dependent fashion. At 100μM, PGE2 levels were reduced by 66.06 ± 3.30%, associated with a lower extent of TXB2 inhibition (40.56 ± 5.77%). AF3485 administration to CFA-treated rats significantly reduced PGE-M (P < 0.01) and TX-M (P < 0.05) similar to the selective COX-2 inhibitor, celecoxib. In contrast, AF3485 induced a significant (P < 0.05) increase of urinary PGI-M while it was reduced by celecoxib. In LPS-stimulated human monocytes, AF3485 inhibited PGE2 biosynthesis with an IC50 value of 3.03 µM (95% CI:0.5–8.75). At 1μM, AF3485 enhanced TXB2 while at higher concentrations, the drug caused a concentration-dependent inhibition of TXB2. At 100 μM, maximal inhibition of the two prostanoids was associated with the downregulation of COX-2 protein by 86%. These effects did not involve AMPK pathway activation, IkB stabilization, or PPARγ activation. In HUVEC, AF3485 at 100 μM caused a significant (P < 0.05) induction of COX-2 protein associated with enhanced PGI2 production. These effects were reversed by the PPARγ antagonist GW9662.ConclusionsThe inhibitor of human mPGES-1 AF3485 is a novel antiinflammatory compound which can also modulate COX-2 induction by inflammatory stimuli. The compound also induces endothelial COX-2-dependent PGI2 production via PPARγ activation, both in vitro and in vivo, which might translate into a protective effect for the cardiovascular system.

Association between Urinary Metabolite Levels of Organophosphorus Flame Retardants and Serum Sex Hormone Levels Measured in a Reference Sample of the US General Population.

Use of organophosphorus flame retardants (OPFRs) in consumer materials have led to widespread human exposure.Research is needed to examine the health effects attributable to the general population's exposure to OPFRs. Using the data from the National Health and Nutrition Examination Surveys (NHANES) (2013-2014), multiple regression analyses were performed to compare the adjusted geometric means (aGMs) of serum sex hormone by quartiles of urinary metabolites of OPFRs, including diphenyl phosphate (DPhP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), bis(2-chloroethyl) phosphate (BCEP) and dibutyl phosphate(DBuP), in children (6 - 9 years old), adolescents (10 - 19 years old) and adults(≥ 20 years old), while accounting for potential confounding factors. The aGMs of sex hormone-binding globulin increased by 36% (95% CI: 6.1 - 56.7%) in female children (p = 0.03), 44% (95%CI: 16 - 63%) in female adolescents (p = 0.010), and 22% (95%CI: 3.51 - 37%) in female adults (p = 0.025), from the 1st to 4th quartiles of the levels of DPhP, BDCPP, DBUP, respectively. The aGMs of estradiol (EST) decreased by 64% and 77% from the 1st to 4th quartiles of the DBUP levels in female children (p = 0.015) and female adolescent (p = 0.020), respectively. The aGMs of EST increased by 31% (95%CI: 3.8 - 51%) from the 1st to 4th quartiles of the DBUP levels in female adults (p = 0.031). These findings suggest that exposure to certain OPFRs is associated with the altered sex hormone levels in this sample of US population. More studies are needed to examine the mechanisms responsible for these observations.

Non-targeted urinary metabolomics in pregnancy and associations with fetal growth restriction

Our objective was to identify metabolites associated with fetal growth restriction (FGR) by examining early and late pregnancy differences in non-targeted urinary metabolites among FGR cases and non-FGR controls. An exploratory case-control study within LIFECODES birth cohort was performed. FGR cases (N = 30), defined as birthweight below the 10th percentile, were matched with controls (N = 30) based on maternal age, race, pre-pregnancy body mass index, and gestational age at delivery. Gas chromatography/electron-ionization mass spectrometry was performed on urine samples collected at 10 and 26 weeks of gestation. Differences in urinary metabolite levels in cases and controls at each time point and between the two time points were calculated and then changes compared across pregnancy. 137 unique urinary metabolites were annotated, and several identified that were higher in cases compared to controls. For example, urinary concentrations of benzoic acid were higher in cases compared to controls at both study visits (3.01-fold higher in cases at visit 1, p < 0.01; 3.10-fold higher in cases at visit 3, p = 0.05). However, these findings from our exploratory analysis were not robust to false-discovery-rate adjustment. In conclusion, using a high-resolution, non-targeted approach, we found specific urinary organic acids differed over pregnancy by FGR case status.

Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites

IntroductionMetoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension.MethodsWe performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry.ResultsUrinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline.ConclusionIn summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

Exposure to Mono-n-Butyl Phthalate in Women with Endometriosis and Its Association with the Biological Effects on Human Granulosa Cells.

To study the association between urinary phthalate metabolite levels, endometriosis, and their effects on human granulosa cells, we recruited patients who underwent laparoscopy to confirm endometriosis (n = 123) and control patients (n = 78). Liquid chromatography–tandem mass spectrometry was used to measure the following five urinary phthalate metabolites: mono-n-butyl phthalate (MnBP), mono(2-ethylhexyl) phthalate, monobenzyl phthalate, mono(2-ethyl-5-oxo-hexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate. Urinary MnBP levels were higher in patients with endometriosis than in controls after multivariable logistic regression including the number of deliveries, body mass index, and use of medicine as covariables. MnBP correlates with other phthalate metabolites. Previous studies found that endometriosis was a detrimental condition for granulosa cells. In our study, we observed whether MnBP affected granulosa cells. MnBP treatment altered the gene expression of BIRC5, BUB1B, CDC20, cyclin B1, IL-1β, TNF-α, inhibin-B, StAR, and P450ssc and attenuated the ratio of the mitochondrial membrane potential in human granulosa cells. Moreover, MnBP decreased the expression of the anti-Mullerian hormone. These findings suggest that MnBP concentration is associated with endometriosis and may affect the health and steroidogenesis of human granulosa cells.

The Utility of Measuring Urinary Metabolites of Mast Cell Mediators in Systemic Mastocytosis and Mast Cell Activation Syndrome

Mast cells (MCs) leave evidence of their presence and activation. Aside from increased numbers of MCs in tissues, this evidence includes detecting elevated serum levels of tryptase and discovering increased excretion of urinary metabolites of prostaglandin (PG) D2, leukotriene (LT) C4, and/or histamine. The importance of measuring these nontryptase mediator metabolites has largely gone unnoticed. We reviewed the utility of quantitating urinary levels of MC mediator metabolites in systemic mastocytosis (SM) and MC activation disorders and summarized the relative production of these mediators by MCs and other cell types. Quantitation of urinary n-methyl histamine, 2,3-dinor-11βPGF2α, and LTE4 offers a simple, noninvasive avenue to monitor their constitutive release as well as contemporaneous discharge during MC activation as well as supporting a diagnosis of SM. These increases can occur independently of or in addition to raised levels of tryptase. Quantitation of these mediator metabolites potentially offers targets for therapeutic intervention. Synthesis of PGD2, a product nearly exclusively of MCs, can be controlled with aspirin, histamine increase by H1 and H2 receptor blockade, and LTC4 by a 5-LO inhibitor or LT receptor antagonist. Although other sources are reported, the increase in MC numbers in SM supports this cell as the predominant origin of all 3 mediators.

Assessment of the possible association between phthalate exposure and attention deficit hyperactivity disorder in egyptian children

Abstract Background Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood. Phthalates are industrial chemicals often used in personal care products and to soften plastics in toys and household items such as food containers, and medical devices. Animal studies have reported that the phthalate compound might cause hyperactivity and impulsivity in rats. However, the relation between phthalates and ADHD in human is still controversial. Objective The aim of our study is to investigate the possible association between urinary phthalate metabolite levels and attention deficit disorder, learning disability in 6–12-years old children. Methods Urine samples were obtained from 80 children. All children were selected from the attendants of Abu elreesh child psychiatry outpatient clinic, Cairo University. subjects were divided into two main groups Group A consisted of 50 children with Attention-deficit/hyperactivity disorder (ADHD) diagnosed by psychiatric consultant and Group B consisted of 30 normal children. In urine, mono butyl phthalate (MBP) metabolite were measured with high performance liquid chromatography (HPLC). Results The mean concentration of MBP level was (15.539±8.316) for cases (group A) and (8.085 ±2.426) for controls (group B) with significant difference between groups. Also there was significant correlation with processing milk, plastic containers, toys, cosmetics, wall, and floor material containing phthalate exposure and higher level of (MBP) in urine of group A. Conclusion The present study showed association between phthalate metabolites in urine and symptoms of ADHD among school-age children.

The influence of demographic and lifestyle factors on urinary levels of PAH metabolites-empirical analyses of Cycle 2 (2009-2011) CHMS data.

Polycyclic aromatic hydrocarbons (PAHs) are a group of compounds formed during the incomplete combustion of organic matter. Several are mutagenic carcinogens; the magnitude of exposure can be assessed by examining urinary levels of PAH metabolites. Data from biomonitoring studies that record urinary PAH metabolite levels, as well as demographic and lifestyle information, can be used to investigate relationships between PAH exposure and variables, such as smoking status, workplace smoking restrictions, age, sex, household income, home age, and occupation. This study analysed creatinine-adjusted urinary PAH metabolite concentrations and questionnaire data from ~1200 individuals aged 16 years and older surveyed in Cycle 2 of the Canadian Health Measures Survey (CHMS). Statistical analyses revealed that smoking status, age, and sex are associated with urinary concentrations of a pyrene metabolite (1-OHP), phenanthrene metabolites (ΣOH-Phen), fluorene metabolites (ΣOH-Flu) and naphthalene metabolites (ΣOH-Nap). More specifically, smoking status, age and sex can collectively account for 30, 24, 52, and 34% of the observed variations in 1-OHP, ΣOH-Phen, ΣOH-Flu and ΣOH-Nap metabolites, respectively (p < 0.001). Analyses of non-smokers revealed weak but significant effects of age, sex, home age, and occupation on urinary levels of selected PAH metabolites (i.e., <7% of observed variation, p < 0.05). The unexplained variation in PAH metabolite levels is most likely related to diet, which was not examined. Although the results revealed significant relationships between urinary PAH metabolite levels and several lifestyle and/or demographic variables, robust examinations of selected effects (e.g., sex, home age, occupation) will require datasets that are balanced with respect to the other highlighted variables. The results can be used to identify remedial measures to reduce exposure and concomitant risk, and/or design follow-up studies to test hypotheses regarding the causes of exposure differences empirically related to sex, age, home age, and occupation.

Liver Fibrosis Associated with Potential Vinyl Chloride and Ethylene Dichloride Exposure from the Petrochemical Industry

Background & Aims: The understanding of the relationship between exposure to carcinogenic vinyl chloride (VCM) and ethylene dichloride (EDC) and liver fibrosis is limited. This study aimed to investigate the associations between the urinary metabolite levels of VCM and EDC and the risk of fibrosis in residents living near a petrochemical complex. Approach & Results: Our study comprised 447 adult residents of two townships with questionnaire survey and health examination near the largest petrochemical complex in Taiwan. The urinary levels of thiodiglycolic acid (TdGA), the metabolite of VCM and EDC, were detected in study subjects. We utilized fibrosis-4 (FIB-4) as the liver fibrosis index. Adjusted generalized linear and logistic regression models were applied to evaluate the associations between those exposure and the risk of fibrosis. The subjects living in the closer township had significantly higher TdGA levels than those living in the more distant (269.6 ±200.7 vs. 199.2±164.7 μg/g creatinine). It showed that TdGA levels were 6.51 μg/g creatinine lower 1 km away from the emission source of the complex after adjusting for confounding factors. It demonstrated that the subjects with the highest TdGA levels (>343.3 μg/g creatinine) had a significantly higher risk of abnormal FIB-4 (OR=2.09; 95% CI: 1.17, 3.77), and those with higher TdGA levels (232.7 to 343.3 μg/g creatinine) had a marginally higher risk of abnormal FIB-4 (OR=1.65; 95% CI: 0.94, 2.90). Conclusion: The residents living closer to the VCM/PVC plant in the complex had higher urinary TdGA levels, which were significantly associated with the risk of fibrosis. This confirmed that the EDC and VCM potentially emitted from the petrochemical industry may have an impact on the liver health of nearby residents. Funding Statement: This research was funded by a grant from the Changhua County Public Health Bureau in Taiwan (grant number 1040723). The study was also funded by the Ministry of Science and Technology in Taiwan (grant number MOST 107-3017-F-002-003, MOST 108-3017-F-002-001) and Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (grant numbers NTU-107L9003, NTU380 108L9003). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Research Ethics Committee of the National Health Research Institutes in Taiwan, and written informed consent forms were signed by each subject.

Neurobehavioral performance of PAH exposure in male coal miners in Shanxi, China: a cross-sectional study.

Coal miners are exposed to polycyclic aromatic hydrocarbons (PAHs), a group of neurotoxicants formed and released during incomplete combustion of coal. High levels of anxiety and depression have been reported in coal miners, but little is known about neurobehavioral functions in populations that are occupationally exposed to PAHs. We tested neurobehavioral performance in coal miners and correlated it with levels of urinary markers of PAH exposure. Levels of urinary PAH metabolites were measured in 652 male coal miners as an indicator of exposure. Subjects were divided into a high-exposure group and a low-exposure group based on the median level of total PAH metabolites. A neurobehavioral core test battery and a questionnaire were used to assess neurobehavioral performance and collect demographic information, respectively. The median level of total PAH metabolites in urine was 4.88μmol/mol creatinine. Highly exposed workers exhibited more fatigue-inertia than less-exposed workers (p < 0.05), and had lower scores in forward digit span, digit symbol, and Benton visual retention tests (p < 0.05). Multiple linear regression indicated that age, education, and shift work were significantly correlated with test scores. PAH exposure may be associated with neurobehavioral alterations, which should be monitored in coal miners to prevent neurobehavioral disorders.

What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review.

SummaryBackgroundEpidemiological studies indicate that gene–environment interactions play a role in atopic dermatitis (AD).ObjectivesTo review the evidence for gene–environment interactions in AD aetiology, focusing on filaggrin (FLG) loss‐of‐function mutations.MethodsA systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS‐I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta‐analysis.ResultsOf 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG–environment interactions in six of the studies (P‐value for interaction ≤ 0·05), including early‐life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss‐of‐function mutations and exposure to specific environmental factors, and variation in exposure definitions.ConclusionsEvidence on FLG–environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.

Time course of phthalate cumulative risks to male developmental health over a 27-year period: Biomonitoring samples of the German Environmental Specimen Bank

In several human biomonitoring surveys, changes in the usage patterns of phthalates have come to light, but their influence on the risks associated with combined exposures is insufficiently understood. Based on the largest study to date, the 27-year survey of urinary phthalate metabolite levels in 24-hour urine samples from the German Environmental Specimen Bank, we present a deep analysis of changing phthalate exposures on mixture risks. This analysis adopts the Hazard Index (HI) approach based on the five phthalates DBP, DIBP, BBP, DEHP and DINP. Calculations of the hazard index for each study participant included updated phthalate reference doses for anti-androgenicity (RfDAAs) that take account of new evidence of phthalates’ developmental toxicity.The Maximum Cumulative Ratio (MCR) approach was used to establish whether a subject’s combined exposure was dominated by one phthalate or was influenced by several phthalates simultaneously. Generally, over the years there was a shift towards lower HIs and higher MCRs, reflecting an increased complexity of the combined exposures. The decade from 1988 to about 1999 was characterised by rather high HIs of between 3 and 7 (95th percentile) which were driven by exposure to DBP and DEHP, often exceeding their single acceptable exposures. Traditional single phthalate risk assessments would have underestimated these risks by up to 50%. From 2006 onwards, no study participant experienced exposures above acceptable levels for a single phthalate, but combined exposures were still in excess of HI = 1. From 2011 onwards most individuals stayed below HI = 1. In interpreting these results, we caution against the use of HI = 1 as an acceptable limit and develop proposals for improved and more realistic mixture risk assessments that take account of co-exposures to other anti-androgenic substances also capable of disrupting the male reproductive system. From this perspective, we regard HIs between 0.1 and 0.2 as more appropriate for evaluating combined phthalate exposures. Assessed against lowered HIs of 0.1 – 0.2, the combined phthalate exposures of most study participants exceeded acceptable levels in all study years, including 2015. Continued monitoring efforts for phthalate combinations are required to provide the basis for appropriate risk management measures.

Magnitude of behavioral deficits varies with job-related chlorpyrifos exposure levels among Egyptian pesticide workers

Chronic occupational exposure to organophosphorus pesticides (OPs) is consistently associated with deficits on behavioral tests when compared to unexposed comparison groups. However, a dose-response relationship has yet to be established, leading some to doubt an association between occupational OP exposure and behavioral deficits. Pesticide application teams in Egypt who are primarily exposed to one OP, chlorpyrifos (CPF), were recruited into a field assessment. Trail Making A and the more challenging Trail Making B tests were administered to 54 engineers (who supervise the pesticide application process, usually from the side of the field), 59 technicians (who guide the pesticide applicators in the field), 31 applicators (who mix and apply pesticides using knapsack sprayers), and 150 controls (who did not work in the fields) at two different times during the OP application season as well as immediately after applications had ended and 1.5 months later. All participants were males since only males work on pesticide application teams in Egypt. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, confirmed the pattern of lower to higher CPF exposures from engineers to technicians to applicators, and these were all greater than urinary metabolite levels in controls. A consistent relationship between job title and performance speed on the behavioral task was observed: Controls had the best (fastest) performance on Trail Making A and B tests throughout the application season, and applicators had significantly slower performance than engineers on Trail Making A (p = 0.015) and B (p = 0.003). However, individual urinary TCPy, blood acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) levels did not predict individual performance. This study identifies a dose-related effect based on job title, which serves as a surrogate for chronic exposure in that differing job titles exhibit varying group exposure levels. The results establish that chronic occupational exposure to chlorpyrifos is neurotoxic and suggest that the classic biomarkers of recent CPF exposure are not predictive of chronic exposure effects.

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers

Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3′-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p = 0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p = 0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p = 0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.

Investigation of phthalate metabolites in urine and daily phthalate intakes among three age groups in Beijing, China

Phthalates are widely used as binders and plasticizers in industrial and consumer products but show diverse toxicity. We investigated the level of human exposure to phthalates in Beijing, one of the most densely populated cities in the world. In this study, 12 metabolites of phthalates were measured in 70 spot urine samples collected from Beijing residents from August 2017 to April 2018 using ultra high-performance liquid chromatography tandem mass spectrometry. We found that metabolites of phthalates were ubiquitous in all urine samples. Total concentrations of phthalate metabolites ranged from 39.6 to 1931 ng mL−1, with median concentrations were in decreasing order of children (371 ng mL−1)> younger adults (332 ng mL−1)> older adults (276 ng mL−1). Mono-n-butyl phthalate (MnBP) was the predominant compound, and occurred at concentrations greater than those reported for people in other countries. The mean values of estimated daily intakes (EDIs) of ∑phthalate were 35.2, 10.3 and 10.9 ng (kg-bm)−1 d−1 for children, younger adults and older adults, respectively. EDIs of di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP) and di-(2-ethylhexyl) phthalate (DEHP) exceeded reference values suggested by the US Environmental Protection Agency and the European Food Safety Authority. When concentrations were normalized to volume or creatinine-adjusted, hazard quotients (HQs) for 40 of 70 participants exhibited larger HQs >1 for individual phthalates, which was indicative of potential for adverse effects. Thus, exposure to phthalates might be a critical factor contributing to adverse health effects in Beijing residents. To the best of our knowledge, this is the first study to establish a pre-baseline level of urinary phthalate metabolites among residents in Beijing.

Pyrethroid pesticide exposure during early pregnancy and birth outcomes in southwest China: a birth cohort study.

Despite the developmental toxicity reported in animals, few epidemiologic studies have investigated the potential effects of prenatal exposure to pyrethroid pesticides (PYRs) on fetal growth. A birth cohort study was conducted to examine the association between prenatal exposure to PYRs and birth outcomes, and a nested case-control study was conducted in this cohort to evaluate the effects of PYR on congenital defects. The assessment of PYR exposure was based on self-reported household pesticide use and urinary PYR metabolite levels. We found that pregnant women in this region were ubiquitously exposed to low-level PYRs, although few reported household pesticide use. Women who often ate bananas or cantaloupes had a higher level of urinary 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the number of fruit types consumed by pregnant women was positively related to the concentrations of 3-phenoxybenzoic acid (3PBA) and total PYR metabolites (P < 0.05). Increased urinary 4-fluoro-3-phenoxybenzoic acid (4F3PBA), DBCA, and total PYR metabolites were associated with increased birth weight, length, and gestational age, and with decreased risk of small for gestational age (SGA) and/or premature birth. However, maternal household pesticides use was related to congenital anomalies. Thus, although prenatal exposure to low-dose PYRs promoted the fetal growth, the beneficial effects of fruit intake may outweigh the adverse effects of pesticide exposure. This study provided us an insight into the biological mechanisms for the effect of prenatal PYR exposure on fetal development, and suggested that further investigations in a larger study population with low-dose PYR exposure is needed.

The safety and applicability of synthetic pyrethroid insecticides for aircraft disinsection: A systematic review.

Air travel contributes to the global spread of vectors and vector-borne infections. Although WHO provides guidance on methods for disinsection of aircraft, there is currently no harmonized or standardized decision-making process to decide when disinsection of an aircraft should be conducted. It is however compulsory for flights arriving in certain countries. Concerns have been expressed about the usefulness of disinsection for preventing the international spread of vectors and vector-borne diseases via air travel and possible toxicity for passengers and flight crew. We performed a systematic literature review using the databases PubMed, Embase, Medline, Scopus and CINAHL to evaluate all research findings about the applicability and safety of chemical-based, aircraft disinsection. Official reports from the WHO were also screened. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and meta-analysis (PRISMA) statement. The literature search strategy included "disinsection, airplane/plane/aviation/aircraft" and several other search items including d-phenothrin, permethrin, insecticide. Papers in English, French and German were reviewed. Reports of adverse events attributed to the disinsection of aircraft were also searched. AMP and PS screened all papers of relevance and agreed on a final selection. Our search resulted in 440 papers of possible relevance. After screening, we included a total of 25 papers in this systematic review. Ten papers reported possible human toxicity and 17 papers addressed the applicability of disinsection and 2 papers addressed both topics. Chemical disinsection at recommended insecticide concentrations was found to be highly effective against a broad range of arthropods. Three papers reported passenger or crew illness possibly associated with insecticide spraying in passenger cabins - one describing a single passenger, the other two papers describing occupational illness of 12 and 33 aircrew members respectively, possibly due to aircraft disinsection. Another paper evaluating exposure of flight attendants to permethrin found higher levels of urinary metabolites in those working in planes that had recently been sprayed but this could not be linked to adverse health outcomes. Our analysis confirmed that disease vectors are carried on international flights and can pose a threat particularly to island populations and certain airport hub areas. Disinsection with permethrin or d-phenothrin was shown to be highly effective against vectors. Despite several hundred million passenger and crew exposures to chemical disinsection, very few proven cases of toxicity have been reported. There is limited evidence linking exposure to insecticide spraying with negative health impact.

Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose

Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107−164 μg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (FUE): 10–40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an FUE of 0.20% (range: 0.17–0.24%). FUEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03–0.10%) and 0.05% (0.01–0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (tmax1 = 1.5–2.3 h, tmax2 = 3.8–6.4 h). Elimination half-lives (t1/2, calculated after the second tmax) for 5cx-MEPA were calculated between 2.1–3.8 h. The majority (98–100%) of metabolites was excreted within 24 h. The FUE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 μg/kg bw/day). The highest daily intake (114 μg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.