Pharmacokinetics, safety, and tolerability of sodium phenylacetate and sodium benzoate in healthy Japanese volunteers: A phase I, single-center, open-label study.

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.

Urinary 3-phenoxybenzoic acid (3-PBA) levels and changes in hematological parameters in Korean adult population: A Korean National Environmental Health Survey (KoNEHS) 2012-2014 analysis.

Pyrethroid insecticides have been broadly used as pest control in agriculture and residential spaces, exerting high effectiveness of insecticidal property and relatively low toxicity to humans. Several animal studies suggested that exposure to pyrethroids may induce hematological abnormalities, thereby altering the number of blood cells and resulting in blood disorders. However, no epidemiologic study has reported on the effect of pyrethroid insecticide exposure on hematological changes, except for occupational exposure. This study aimed to investigate the effect of urinary 3-phenoxybenzoic acid (3-PBA) concentrations on hematological parameters in a representative South Korean adult population. We analyzed data from 6296 adults enrolled in the Korean National Environmental Health Survey (2012-2014). We employed multiple linear regression analysis to evaluate the association of urinary 3-PBA levels with eight hematological profiles: white blood cells (WBCs), red blood cells (RBCs), hemoglobin, hematocrit, platelets, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). The urinary 3-PBA levels were negatively associated with WBC, RBC, and hemoglobin levels and positively associated with MCV levels. The direction and magnitude of the association between the 3-PBA and hematological parameters varied according to sex and age. The adverse effects of 3-PBA on hematological parameters were distinctive among males aged 60 years and older. In this age group, 3-PBA levels were negatively associated with the WBC, RBC, hemoglobin, hematocrit, and MCHC levels among males. This study is the first to verify that urinary 3-PBA concentrations at the levels found in a Korean population are associated with blood parameters. This finding merits further investigation to understand the impact of 3-PBA on human blood function and public health.

Multivalent nanobody as capture antibody-based enzyme linked immunosorbent assay for detection of 3-phenoxybenzoic acid in urine.

Nanobodies (Nbs) as capture antibodies in enzyme-linked immunosorbent assays (ELISAs) is greatly hampered by their poor performance after attaching onto polystyrene microplates. Reasons behind those phenomena remain unknown. One of possible explanation is that Nbs with a single domain might lose their accessibility of paratope when adsorbed on the plates. Increasing their binding sites might improve performance in capture Nbs-based ELISA. In this study, anti-3-phenoxybenzoic acid (3-PBA) Nbs was assembled to trivalent form (Nb3) in tandem with flexible linkers (G4S)3. Direct competitive ELISA on the basis of Nb3 and 3-PBA-horseradish peroxidase was developed for detection of 3-PBA in livestock urine. The ELISA had a half-maximum (IC50) inhibition concentration of 0.51 ng/mL, with a limit of detection of 0.02 ng/mL, which was more sensitive than that of the parental Nb with a IC50 of 2.39 ng/mL. The average recoveries of 3-PBA spiked in swine, sheep and dairy cow urine samples by the assay ranged from 89.52% to 114.25% and agreed well with those of liquid chromatography mass spectrometry (LC-MS). The above results indicated that multivalent Nbs could be treated as the capture antibody in ELISA for routine screening analysis of 3-PBA residues in urine.

Characterizing environmental geographic inequalities using an integrated exposure assessment.

BACKGROUND: At a regional or continental scale, the characterization of environmental health inequities (EHI) expresses the idea that populations are not equal in the face of pollution. It implies an analysis be conducted in order to identify and manage the areas at risk of overexposure where an increasing risk to human health is suspected. The development of methods is a prerequisite for implementing public health activities aimed at protecting populations. METHODS: This paper presents the methodological framework developed by INERIS (French National Institute for Industrial Environment and Risks) to identify a common framework for a structured and operationalized assessment of human exposure. An integrated exposure assessment approach has been developed to integrate the multiplicity of exposure pathways from various sources, through a series of models enabling the final exposure of a population to be defined. RESULTS: Measured data from environmental networks reflecting the actual contamination of the environment are used to gauge the population's exposure. Sophisticated methods of spatial analysis are applied to include additional information and take benefit of spatial and inter-variable correlation to improve data representativeness and characterize the associated uncertainty. Integrated approaches bring together all the information available for assessing the source-to-human-dose continuum using a Geographic Information System, multimedia exposure and toxicokinetic model. DISCUSSION: One of the objectives of the integrated approach was to demonstrate the feasibility of building complex realistic exposure scenarios satisfying the needs of stakeholders and the accuracy of the modelling predictions at a fine spatial-temporal resolution. A case study is presented to provide a specific application of the proposed framework and how the results could be used to identify an overexposed population. CONCLUSION: This framework could be used for many purposes, such as mapping EHI, identifying vulnerable populations and providing determinants of exposure to manage and plan remedial actions and to assess the spatial relationships between health and the environment to identify factors that influence the variability of disease patterns.

Sensitive monitoring of the main metabolites of tri-(2-ethylhexyl) trimellitate (TOTM) in urine by coupling of on-line SPE, UHPLC and tandem mass spectrometry.

Tri-(2-ethylhexyl) trimellitate (TOTM or TEHTM) is a substitute for the plasticizer di-(2-ethylhexyl) phthalate (DEHP). Here, a fast and sensitive UHPLC-MS/MS method is presented enabling the simultaneous quantification of the six main TOTM metabolites in urine. These include the primary metabolites 1-MEHTM and 2-MEHTM (1-/2-mono-(2-ethylhexyl) trimellitate) and two oxidized metabolites of each to ensure a precise determination and comparison of the regioselective pathways. The method is based on online enrichment of the analytes after enzymatic hydrolysis with subsequent UHPLC separation and tandem mass spectrometry using isotopically labeled internal standards. The method is distinguished by its high sensitivity with detection limits ranging from 0.01 to 0.04 µg/l and a proficient precision with relative standard deviations well below 10% for each analyte. The application of UHPLC-MS/MS analysis proved to significantly enhance the sensitivity of the method due to the efficient separation of the regioisomeric structures of the TOTM metabolites considered. Additionally, a proficient repeatability and recovery was achieved by the use of structurally identical isotopically labeled internal standard substances. The method was successfully applied to urine samples of infant patients indicating urinary levels of the TOTM metabolites examined in a very low concentration range.

Pyrethroid Insecticides in Households from Urban Areas: An Association of the 3-PBA Metabolite and Hand Wipes.

Background: Pyrethroid exposure in the household environment affects children directly via inhalation or dermal exposure. Hand wipes can effectively predict pyrethroid exposure to young children along with the children's activities. The main purpose of this study is to identify the relationship between 3-PBA metabolites, hand wipe sample concentrations and multiple exposure factors, within the population of households with young children in urban Bangkok, Thailand. Methods: Interviews were conducted with the parents of 80 children (aged 2-3 years). Urine was collected to analyze for 3-PBA metabolites and hand wipe samples were collected to analyze for cypermethrin. Both were analyzed by gas chromatography (GC/MS). Results: A Spearmen's correlation test of the increase of 3-PBA metabolites was significantly associated with an increase in hand wipe samples (cypermethrin) in children (rs = 0.226-0.274, p-value < 0.05). The binary logistic regression test presented an association between exposure factors with 3-PBA metabolite concentration. Gender presented a significant association with 3-PBA metabolites (p-value = 0.035, OR = 0.326, 95% CI 0.115-0.926), and frequency of bare feet inside the household presented a significant association with 3-PBA metabolites (p-value < 0.01, OR = 7.072, 95% CI 1.707-29.291). In addition, exposure factors were not significantly associated with wipe sample concentration (cypermethrin) but showed high risk of exposure to young children. Conclusions: Suggestions to reduce the risk from long-term pyrethroid insecticide exposure to children living in households include increased education, awareness, and management.

An Innovative Nanobody-Based Electrochemical Immunosensor Using Decorated Nylon Nanofibers for Point-of-Care Monitoring of Human Exposure to Pyrethroid Insecticides.

A novel ultrasensitive nanobody-based electrochemical immunoassay was prepared for assessing human exposure to pyrethroid insecticides. 3-Phenoxybenzoic acid (3-PBA) is a common human urinary metabolite for numerous pyrethroids, which broadly served as a biomarker for following the human exposure to this pesticide group. The 3-PBA detection was via a direct competition for binding to alkaline phosphatase-embedded nanobodies between free 3-PBA and a 3-PBA-bovine serum albumin conjugate covalently immobilized onto citric acid-decorated nylon nanofibers, which were incorporated on a screen-printed electrode (SPE). Electrochemical impedance spectroscopy (EIS) was utilized to support the advantage of the employment of nanofibrous membranes and the success of the immunosensor assembly. The coupling between the nanofiber and nanobody technologies provided an ultrasensitive and selective immunosensor for 3-PBA detection in the range of 0.8 to 1000 pg mL-1 with a detection limit of 0.64 pg mL-1. Moreover, when the test for 3-PBA was applied to real samples, the established immunosensor proved to be a viable alternative to the conventional methods for 3-PBA detection in human urine even without sample cleanup. It showed excellent properties and stability over time.

Investigation of the Small Size of Nanobodies for a Sensitive Fluorescence Polarization Immunoassay for Small Molecules: 3-Phenoxybenzoic Acid, an Exposure Biomarker of Pyrethroid Insecticides as a Model.

Limited reports on the use of nanobodies (Nbs) in fluorescence polarization immunoassay (FPIA) aroused us to explore if the small size of Nbs is a drawback for the development of sensitive FPIA to small molecular compounds, particularly since FPIA is a technology strongly dependent on molecular weight. In the present work, three different molecular weight Nbs against 3-phenoxybenzoic acid (3-PBA), an exposure biomarker of pyrethroid insecticides, including bare Nbs (15 kDa), Nbs-Avidin (Nbs-AV, 60 kDa), and Nbs-Alkaline phosphatase (Nbs-AP, 130 kDa) were specifically generated to cover distinct regions on the polarization and molecular weight relationship curve for a fluorescein tracer. In competitive FPIA, similar half-maximal inhibitory concentrations (IC50) of 3-PBA of 16.4, 12.2, and 14.8 ng mL-1 were obtained for Nbs, Nbs-AV, and Nbs-AP, respectively, indicating that the size of Nbs in the range tested had no significant effect on the sensitivity of the resulting competitive FPIA. An IC50 of 20.2 ng mL-1 for an anti-3-PBA polyconal antibody based FPIA further demonstrated the performance of Nbs, which was comparable to that of traditional antibodies in FPIA. Spike-recovery studies showed good and reproducible recovery of 3-PBA in urine samples, demonstrating the applicability of Nb-based FPIA. Overall, our results show that Nb-based FPIA achieves sensitivity levels of FPIA based on conventional antibodies and further indicate that Nb absolutely meets the sensitivity requirement of FPIA.

Effect of a 24-week randomized trial of an organic produce intervention on pyrethroid and organophosphate pesticide exposure among pregnant women.

BACKGROUND: Introduction of an organic diet can significantly reduce exposure to some classes of pesticides in children and adults, but no long-term trials have been conducted. OBJECTIVES: To assess the effect of a long-term (24-week) organic produce intervention on pesticide exposure among pregnant women. METHODS: We recruited 20 women from the Idaho Women, Infants, and Children (WIC) program during their first trimester of pregnancy. Eligible women were nonsmokers aged 18-35 years who reported eating exclusively conventionally grown food. We randomly assigned participants to receive weekly deliveries of either organic or conventional fruits and vegetables throughout their second or third trimesters and collected weekly spot urine samples. Urine samples, which were pooled to represent monthly exposures, were analyzed for biomarkers of organophosphate (OP) and pyrethroid insecticides. RESULTS: Food diary data demonstrated that 66% of all servings of fruits and vegetables consumed by participants in the "organic produce" group were organic, compared to <3% in the "conventional produce" group. We collected an average of 23 spot samples per participant (461 samples total), which were combined to yield 116 monthly composites. 3-Phenoxybenzoic acid (3-PBA, a non-specific biomarker of several pyrethroids) was detected in 75% of the composite samples, and 3-PBA concentrations were significantly higher in samples collected from women in the conventional produce group compared to the organic produce group (0.95 vs 0.27 µg/L, p = 0.03). Another pyrethroid biomarker, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, was detected more frequently in women in the conventional compared to the organic produce groups (16% vs 4%, p = 0.05). In contrast, we observed no statistically significant differences in detection frequency or concentrations for any of the four biomarkers of OP exposure quantified in this trial. DISCUSSION: To our knowledge, this is the first long-term organic diet intervention study, and the first to include pregnant women. These results suggest that addition of organic produce to an individual's diet, as compared to conventional produce, significantly reduces exposure to pyrethroid insecticides.

Environmental pyrethroid exposure and thyroid hormones of pregnant women in Shandong, China.

BACKGROUND: Pyrethroid insecticides have been extensively used in China and worldwide, while their effects on thyroid functions are rarely explored, especially in susceptible pregnant women. OBJECTIVE: To assess the association between 3-phenoxybenzoic acid (3PBA), a major urinary metabolite of pyrethroids, and thyroid hormone levels in pregnant women in China. METHODS: Three hundred and seventy-four pregnant women were recruited during the admission for delivery (third trimester of pregnancy) in a local hospital in Shandong, China during December 2011 to December 2013. Pyrethoids exposure was assessed by examining urinary metabolite of 3PBA levels. Thyroid hormones were detected by measuring serum concentrations of thyroid stimulating hormones (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4) and free thyroxine (FT4). Multiple linear regression models were used to investigate the associations between 3PBA concentrations and thyroid hormones levels. RESULTS: The detection frequency of 3PBA was 90.4%, with a median concentration of 1.14 µg/g creatinine. After adjusted for potential confounders, we found a significant negative relationship between 3PBA and serum FT3 (ß = -0.06, 95% CI = -0.11 to -0.01) as well as an inverse dose dependent association (p for trend = 0.023). No significant association was found between 3PBA concentrations and other thyroid hormones. CONCLUSIONS: Our findings indicated that pyrethroid exposure was widespread and negatively associated with serum FT3 concentrations in pregnant women in northern China. Given to the widespread of pyrethroid exposure and critical role thyroid homeostasis plays during pregnancy, more studies are warranted to explore their relationships as well as underlying mechanisms.

The relationship of urinary 3-phenoxybenzoic acid concentrations in utero and during childhood with adiposity in 4-year-old children.

BACKGROUND: Pyrethroid pesticides are reported to be the most commonly used residential insecticides worldwide. We aimed to investigate the relationship between prenatal and postnatal 3-phenoxybenzoic acid (3-PBA) concentrations, and growth and adiposity parameters in 4-year-old children. METHOD: We obtained data from 578 children who participated in the prospective Environment and Development of Children (EDC) study at around 4 years of age (45-55 months) between August 2008 and July 2011. Anthropometric measurements were obtained at age 4 years. Prenatal and postnatal urinary 3-PBA concentration was measured in maternal urine samples at around 20 weeks of gestation, and in the 4-year-old children, respectively. RESULT: The detection frequency of urinary 3-PBA (geometric mean concentration) was 98-99% (0.98 µg/g Cr) in maternal urine, and almost 99-100% (1.34 µg/g Cr) in 4-year-old children. Prenatal urinary3-PBA concentration was not associated with height, weight, or body mass index (BMI) z-scores at 4 years of age, regardless of sex. Postnatal urinary3-PBA concentration was not related to height z-scores, but was positively associated with weight z-scores with marginal significance among only girls (p = 0.058). Analyzed by sex, there was a significant relationship between postnatal urinary 3-PBA concentration and BMI z-scores (p = 0.015) among girls, after adjusting for covariates. CONCLUSION: Childhood urinary 3-PBA concentration measured at 4 years of age was positively associated with BMI z-scores in 4-year-old girls, but prenatal urinary 3-PBA concentration at midterm pregnancy exhibited no association.

Association of urinary 3-phenoxybenzoic acid level with pulmonary function reduction in an urban elderly population with repeated measures data.

Pyrethroids are a class of man-made insecticides associated with various adverse health outcomes including respiratory problems. However, there were limited evidences on the relation between 3-phenoxybenzoic acid (3-PBA) as a metabolite of pyrethroids and pulmonary function, particularly among elderly population who have declining pulmonary function. Therefore, we collected urine samples and performed pulmonary function test (PFT) repeatedly in a total of 559 Korean elderly living in Seoul as an urban area. After measurement of urinary 3-PBA levels, cross-sectional relations of visit-to-visit variation in 3-PBA level on visit-to-visit variation in PFT parameters were evaluated using linear mixed effect models and generalized additive mixed models after adjustment for age, sex, body mass index, smoking status, education, visit episode, and phthalate metabolite levels. The Korean elderly were highly exposed to pyrethroids with 30.2% of elderly people with 3-PBA level over reference value derived on the 95th percentile of representative samples (2 ng/mL). Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of FVC (FEF25-75) as PFT parameters showed significant reductions by an increase of 3-PBA level (FEV1, ß = -1.48, p-value < 0.01; FVC, ß = -1.14, p-value < 0.01; and FEF25-75, ß = -1.11, p-value = 0.03). The negative associations of 3-PBA level with FEV1, FVC, and FEF25-75 were found only for females (FEV1, ß = -1.64, p-value < 0.01; FVC, ß = -1.47, p-value < 0.01; and FEF25-75, ß = -1.06, p-value = 0.07), but not for males. However, the longitudinal effect of 3-PBA level on the trajectory of FEV1, FVC, and FEF25-75 declines in females was not found. Community-level exposure to pyrethroids was associated with pulmonary function reduction in elderly population, indicating that more stringent control of pyrethroids is necessary to protect the elderly who have declining pulmonary function.

Development of a Highly Sensitive Direct Competitive Fluorescence Enzyme Immunoassay Based on a Nanobody-Alkaline Phosphatase Fusion Protein for Detection of 3-Phenoxybenzoic Acid in Urine.

3-Phenoxybenzoic acid (3-PBA) is a human urinary metabolite of many pyrethroid insecticides and can be used as a biomarker to monitor human exposure to these pesticides. A rapid and sensitive direct competitive fluorescence enzyme immunoassay (dc-FEIA) for detecting 3-PBA on the basis of a nanobody (Nb)-alkaline phosphatase (AP) fusion protein was developed. The anti-3-PBA Nb-AP fusion protein was expressed and purified. The 50% inhibitory concentration (IC50) and linear range of dc-FEIA were 0.082 and 0.015-0.447 ng/mL, respectively, with a detection limit of 0.011 ng/mL. The IC50 of dc-FEIA was improved by nearly ten times compared with those of one-step and three-step direct competitive enzyme-linked immunosorbent assay (dc-ELISA). Spiked urine samples were detected by both dc-FEIA and liquid chromatography-mass spectrometry (LC-MS), and the results showed good consistency between the two analysis methods, indicating the reliability of dc-FEIA based on the Nb-AP fusion protein for detecting 3-PBA in urine.

Kinetic time courses of lambda-cyhalothrin metabolites after dermal application of Matador EC 120 in volunteers.

A controlled kinetic study was conducted in volunteers dermally exposed to the widely used lambda-cyhalothrin pyrethroid pesticide to document the time courses of relevant biomarkers of exposure, in order to better assess biomonitoring data in workers. Matador® EC120 formulation (120 g/l) was applied on 40 cm2 of the forearm at a 0.25 mg/kg dose of lambda-cyhalothrin and left without occlusion or washing for 6 h. The application site was then washed thoroughly with soap and water. The kinetic time courses of cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were determined in plasma and urine up to 84 h post-application. Results show that the fraction of lambda-cyhalothrin absorbed in the body was rapidly cleared following dermal contact. According to CFMP and 3-PBA plasma profiles, calculated mean apparent absorption half-lives (t1/2) were 3 and 7.3 h, respectively, and corresponding mean apparent elimination t1/2 were 11.2 and 7.6 h. These differences suggest some metabolism at the site-of-entry and storage of metabolites by the dermal route. Toxicokinetic parameters calculated from urinary profiles confirm the values of absorption and elimination rates. Metabolites were almost completely excreted over the 84-h period post-application and, on average, 0.12 and 0.08% of the applied lambda-cyhalothrin dose was recovered in the urine as CFMP and 3-PBA, respectively, indicating a low dermal absorption fraction of this pyrethroid. This study showed the potential use of CFMP and 3-PBA biomarkers for the assessment of dermal exposure to lambda-cyhalothrin pyrethroid.

Human metabolism and kinetics of tri-(2-ethylhexyl) trimellitate (TEHTM) after oral administration.

Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for PVC material and is used for medical devices as an alternative to di-(2-ethylhexyl) phthalate. As plasticizers are known to migrate easily into contact liquids, exposure of patients to TEHTM is highly probable. In the present study, human metabolism pathways of TEHTM and its elimination kinetics were investigated. For that purpose, four healthy volunteers were orally exposed to a single dose of TEHTM. TEHTM and its postulated primary metabolites were investigated in blood samples (up to 48 h after exposure), and in urine samples (collected until 72 h after exposure) using liquid chromatography tandem mass spectrometry (LC-MS/MS). TEHTM was found to be regioselectively hydrolyzed to its diesters di-2-(ethylhexyl) trimellitates (1,2-DEHTM, 2,4-DEHTM) with maximum blood concentrations at 3-h post-exposure, and to its monoester isomers mono-2-(ethylhexyl) trimellitates (1-MEHTM, 2-MEHTM) with peak blood concentrations 5-h post-exposure. For the elimination of investigated urinary metabolites, biphasic elimination kinetics was observed. The most dominant urinary biomarker was found to be 2-MEHTM (2-mono-(2-ethylhexyl) trimellitate), followed by several specific secondary metabolites. All in all, approximately 5.8% of the orally administered dose was recovered in urine over a period of 72 h, indicating a comparatively low resorption rate of TEHTM in humans in combination with an apparently rather slow metabolism and excretion rate. In fact, TEHTM and selected metabolites were still detectable in blood and urine 48-h and 72-h post-exposure, respectively. This study is the first to elucidate TEHTM metabolism pathways in humans and to identify metabolites of TEHTM in blood and urine by usage of especially designed human biomonitoring methods. Powerful tools for exposure monitoring and risk assessment of TEHTM are therewith available for future research.

Urinary levels of pyrethroid pesticides and determinants in pregnant French women from the Elfe cohort.

Pyrethroids are insecticides which are widely used for agricultural and domestic purposes. The general population can be exposed to them. Given the suspected effects of pesticides on the development of the foetus, exposure to pyrethroids during pregnancy is a major public health concern. The objective of this paper is to describe the urinary levels of the following five pyrethroid metabolites and their associated determinants among pregnant French women in 2011 enrolled in the Elfe cohort (n = 1077): a) 3-phenoxy benzoic (3-PBA), b) 4­fluoro­3­phenoxy benzoic acid (4-F-3-PBA), c) Cis­3­(2,2dibromovinyl)­2,2­dimethyl cyclopropane-carboxylic acid (Cis-DBCA); d) Cis­3­(2,2dichlorovinyl)­2,2­dimethyl cyclopropane-carboxylic acid (Cis-DCCA) and e) Trans-3­(2,2dichlorovinyl)­2,2­dimethyl cyclopropane-carboxylic acid (Trans-DCCA). The distribution levels were estimated for each pyrethroid metabolite. Multivariable analyses helped determine the predictors of these levels. All metabolites except 4-F-3-PBA were detected in all the urine samples. The mean urinary concentration of the sum of the metabolites (3-PBA, Cis-DBCA, Cis-DCCA, Trans-DCCA) was 1.18 µg/L, with the highest concentrations observed for 3-PBA. A comparison of these levels with other studies showed that pregnant French women tend to be more exposed to pyrethroids than their American counterparts, less exposed than Chinese and Caribbean mothers, and have similar exposure to Japanese mothers. In our study, urinary levels of pyrethroid metabolites were positively related to smoking during pregnancy, consuming fish and alcohol, domestic pesticide use and living in the vicinity of crops during pregnancy. These findings highlight the importance of non-dietary pathways when evaluating exposure to pyrethroids.

Comprehensive monitoring of specific metabolites of tri-(2-ethylhexyl) trimellitate (TEHTM) in urine by column-switching liquid chromatography-tandem mass spectrometry.

Tri-(2-ethylhexyl) trimellitate (TOTM or TEHTM) is a substitute for the plasticizer di-(2-ethylhexyl) phthalate (DEHP). Here, a fast and robust HPLC method is presented for the first time enabling the simultaneous quantification of several TEHTM metabolites in urine. These are the three TEHTM monoester isomers 1-mono-(2-ethylhexyl) trimellitate (1-MEHTM), 2-mono-(2-ethylhexyl) trimellitate (2-MEHTM), and 4-mono-(2-ethylhexyl) trimellitate (4-MEHTM) as well as several selected side chain oxidized monoesters of TEHTM, namely, 1-mono-(2-ethyl-5-hydroxyhexyl) trimellitate (5OH-1-MEHTM), 2-mono-(2-ethyl-5-hydroxyhexyl) trimellitate (5OH-2-MEHTM), 1-mono-(2-ethyl-5-oxohexyl) trimellitate (5oxo-1-MEHTM), 2-mono-(2-ethyl-5-oxohexyl) trimellitate (5oxo-2-MEHTM), 1-mono-(2-ethyl-5-carboxypentyl) trimellitate (5cx-1-MEPTM), 2-mono-(2-ethyl-5-carboxypentyl) trimellitate (5cx-2-MEPTM), 2-mono-(2-carboxymethylhexyl) trimellitate (2cx-2-MMHTM), and 1-mono-(2-carboxymethylhexyl) trimellitate (2cx-1-MMHTM). The method is characterized by a short sample preparation, for which the urine samples are enzymatically hydrolyzed and cleaned up by an online column arrangement. Separation of the analytes is enabled using liquid chromatography coupled with tandem mass spectrometry. Thus, in less than 30 min, 11 postulated metabolites of TEHTM can be selectively and sensitively quantified. The method is distinguished by its wide linear working range of up to 1800 µg/L with detection limits ranging from 0.3 µg/L (for 5oxo-1-MEHTM) to 1.5 µg/L (for 1-MEHTM). Precision and repeatability of the method were proven with determined relative standard deviations between 2.5 and 11.3%. The selection of the analytes of this method was based on a pilot study, by which several potential TEHTM metabolites were investigated in human urine of an orally exposed volunteer. Thus, the here presented method is a perfect tool for human biomonitoring of TEHTM exposure. Graphical abstract Analysis of several postulated TEHTM metabolites in human urine using LC-MS/MS.

Screening-level Biomonitoring Equivalents for tiered interpretation of urinary 3-phenoxybenzoic acid (3-PBA) in a risk assessment context.

3-Phenoxybenzoic acid (3-PBA) is a common metabolite of several pyrethroid pesticides of differing potency and also occurs as a residue in foods resulting from environmental degradation of parent pyrethroid compounds. Thus, 3-PBA in urine is not a specific biomarker of exposure to a particular pyrethroid. However, an approach derived from the use of Biomonitoring Equivalents (BEs) can be used to estimate a conservative initial screening value for a tiered assessment of population data on 3-PBA in urine. A conservative generic urinary excretion fraction for 3-PBA was estimated from data for five pyrethroid compounds with human data. Estimated steady-state urinary 3-PBA concentrations associated with reference doses and acceptable daily intakes for each of the nine compounds ranged from 1.7 µg/L for cyhalothrin and deltamethrin to 520 µg/L for permethrin. The lower value can be used as a highly conservative Tier 1 screening value for assessment of population urinary 3-PBA data. A second tier screening value of 87 µg/L was derived based on weighting by relative exposure estimates for the different pyrethroid compounds, to be applied as part of the data evaluation process if biomonitoring data exceed the Tier 1 value. These BE values are most appropriately used to evaluate the central tendency of population biomarker concentration data in a risk assessment context. The provisional BEs were compared to available national biomonitoring data from the US and Canada.

Pyrethroid pesticide residues in the global environment: An overview.

Pyrethroids are synthetic organic insecticides with low mammalian toxicity that are widely used in both rural and urban areas worldwide. After entering the natural environment, pyrethroids circulate among the three phases of solid, liquid, and gas and enter organisms through food chains, resulting in substantial health risks. This review summarized the available studies on pyrethroid residues since 1986 in different media at the global scale and indicated that pyrethroids have been widely detected in a range of environments (including soils, water, sediments, and indoors) and in organisms. The concentrations and detection rates of agricultural pyrethroids, which always contain α-cyanogroup (α-CN), such as cypermethrin and fenvalerate, decline in the order of crops > sediments > soils > water. Urban pyrethroids (not contain α-CN), such as permethrin, have been detected at high levels in the indoor environment, and 3-phenoxybenzoic acid, a common pyrethroid metabolite in human urine, is frequently detected in the human body. Pyrethroid pesticides accumulate in sediments, which are a source of pyrethroid residues in aquatic products.

Maternal Exposure to Pyrethroid Insecticides during Pregnancy and Infant Development at 18 Months of Age.

The possible association between maternal exposure to pyrethroid insecticides (PYRs) during pregnancy and infant development was explored. Levels of exposure to PYRs was assessed by metabolite (3-phenoybenzoic acid, 3-PBA) concentration in maternal spot urine sampled in the first trimester of index pregnancy, and infant development was assessed at 18 months of age using the Kinder Infants Development Scale (KIDS), which is based on a questionnaire to the caretaker. The relationship between KIDS score and maternal urinary 3-PBA levels was examined by a stepwise multiple regression analysis using biological attributes of the mother and infant, breast feeding, and nursing environment as covariates. The analysis extracted 3-PBA and the nursing environment as significant to explain the KIDS score at 18 months of age with positive partial regression coefficients. Inclusion of fish consumption frequency of the mother during pregnancy as an independent variable resulted in the selection of fish consumption as significant, while the two variables were marginally insignificant but still with a positive coefficient with the KIDS score. The result suggested a positive effect of maternal PYR exposure on infant development, the reason for which is not clear, but an unknown confounding factor is suspected.