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Background: Chlorpyrifos (CPF), a widely used organophosphorus pesticide (OP), is metabolized to CPF-oxon, a potent cholinesterase (ChE) inhibitor, and trichloro-2-pyridinol (TCPy). Urinary TCPy is often used as a biomarker for CPF exposure, whereas blood ChE activity is considered an indicator of CPF toxicity. However, whether these biomarkers are dose related has not been studied extensively in populations with repeated daily OP exposures.oBjective: We sought to determine the relationship between blood ChE and urinary TCPy during repeated occupational exposures to CPF. Methods: Daily urine samples and weekly blood samples were collected from pesticide workers (n = 38) in Menoufia Governorate, Egypt, before, during, and after 9-17consecutive days of CPF application to cotton fields. We compared blood butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) activities with the respective urinary TCPy concentrations in each worker. results: Average TCPy levels during the middle of a 1- to 2-week CPF application period were significantly higher in pesticide applicators (6,437?g/g creatinine) than in technicians (184?g/g) and engineers (157?g/g), both of whom are involved in supervising the application process. We observed a statistically significant inverse correlation between urinary TCPy and blood BuChE and AChE activities. The no-effect level (or inflection point) of the exposure-effect relationships has an average urinary TCPy level of 114?g/g creatinine for BuChE and 3,161?g/g creatinine for AChE. conclusions: Our findings demonstrate a dose-effect relationship between urinary TCPy and both plasma BuChE and red blood cell AChE in humans exposed occupationally to CPF. These findings will contribute to future risk assessment efforts for CPF exposure. [ABSTRACT FROM AUTHOR]

BACKGROUND: Widespread insecticide exposure might be a risk factor for neurodevelopment of our children, but few studies examined the mixture effect of maternal coexposure to organophosphate insecticides (OPPs), pyrethroids (PYRs), and neonicotinoid insecticides (NNIs) during pregnancy on child neurodevelopment, and critical windows of exposure are unknown. OBJECTIVES: We aimed to evaluate the association of prenatal exposure to multiple insecticides with children’s neurodevelopment and to identify critical windows of the exposure. METHODS: Pregnant women were recruited into a prospective birth cohort study in Wuhan, China, from 2014–2017. Eight metabolites of OPPs (mOPPs), three metabolites of PYRs (mPYRs), and nine metabolites of NNIs (mNNIs) were measured in 3,123 urine samples collected at their first, second, and third trimesters. Children’s neurodevelopment [mental development index (MDI) and psychomotor development index (PDI)] was assessed using the Bayley Scales of Infant Development at 2 years of age (푁 = 1,041). Multivariate linear regression models, generalized estimating equation models, and weighted quantile sum (WQS) regression were used to estimate the association between the insecticide metabolites and Bayley scores. Potential sex-specific associations were also examined. RESULTS: Single chemical analysis suggested higher urinary concentrations of some insecticide metabolites at the first trimester were significantly associated with lower MDI and PDI scores, and the associations were more prominent among boys. Each 1-unit increase in ln-transformed urinary concentrations of two mOPPs, 3,5,6-trichloro-2-pyridinol and 4-nitrophenol, was associated with a decrease of 3.16 points [95% confidence interval (CI): -5:59, -0:74] and 3.06 points (95% CI: -5.45, -0.68) respectively in boys’ MDI scores. Each 1-unit increase in that of trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (trans-DCCA; an mPYR) was significantly associated with a decrease of 2.24 points (95% CI: -3.89, -0.58) in boys’ MDI scores and 1.90 points (95% CI: -3.16, -0.64) in boys’ PDI scores, respectively. Significantly positive associations of maternal urinary biomarker concentrations [e.g., dimethyl phosphate (a nonspecific mOPP) and desmethyl-clothianidin (a relatively specific mNNI)] with child neurodevelopment were also observed. Using repeated holdout validation, a 1-quartile increase in the WQS index of the insecticide mixture (in the negative direction) at the first trimester was significantly associated with a decrease of 3.02 points (95% CI: -5.47, -0.57) in MDI scores among the boys, and trans-DCCA contributed the most to the association (18%). CONCLUSIONS: Prenatal exposure to higher levels of certain insecticides and their mixture were associated with lower Bayley scores in children, particularly in boys. Early pregnancy may be a sensitive window for such an effect. Future studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

BACKGROUND: Some pesticides have been shown to interfere with thyroid functions through changes in thyroid hormone (TH) levels. However, few human studies have explored associations between TH levels and environmental exposure to currently used pesticides, including neonicotinoids, phenylpyrazoles, phenoxy acids, and azoles. Moreover, such studies often measure biomarkers of exposure in urine or blood, and thus reveal only recent exposure. In contrast, hair has been demonstrated to be a suitable matrix for assessing chronic exposure to both persistent and nonpersistent organic pollutants. OBJECTIVES: We investigated 54 biomarkers of pollutant exposure in relation to tetraiodothyronine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), and 3,3'-diiodothyronine (T2). METHODS: In a cross-sectional study of 196 healthy Chinese women of reproductive age (25-45 years of age), concentrations of both pollutants and THs were analyzed in the first 12cm (starting from the scalp) of the hair matrix, collected in 2016. Associations between pollutants and TH levels were explored using stability-enhanced least absolute shrinkage and selection operator (lasso) by regressing all exposures against each outcome of interest, adjusted for age, body mass index, and city. RESULTS: Each TH was associated with the mixture of at least eight of the examined pesticides. We found associations of ß-HCH, PCP, DMP, DETP, 3Me4NP, carbofuran, ClCF3CA, imidacloprid, 2,4-D, metolachlor, difenoconazole, and tebuconazole with THs. For example, a 2-standard deviation (SD) increase in log10-transformed hair DMP concentration was associated with lower hair T4 concentration [-15.0% (95% CI: -26.1, -2.21%)] and higher hair T3 concentration [8.16% (95% CI: 1.73, 15.0%)] in the adjusted unpenalized regression models. We also found associations of some pesticides with T3/T4, rT3/T4, and rT3/T3 molar ratios, including PCP, DMP, 2,4-D, metolachlor, difenoconazole, and tebuconazole. DISCUSSION: Our results suggest that exposure to the low levels of pesticides examined here may disrupt thyroid homeostasis in humans. Further studies are needed to confirm our results and to evaluate the long-term consequences of these subtle interferences. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin gene-related peptide (CGRP). OBJECTIVE: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain. METHODS: A calcium imaging–based screen of environmental chemicals was used to investigate activation of migraine pain–associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain. RESULTS: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100 μM. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipid-binding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response (푁total = 144). DISCUSSION: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence of the negative impacts of contemporary use insecticides on sperm concentration has increased over the last few decades; however, meta-analyses on this topic are rare. OBJECTIVES: This investigation assessed the qualitative and quantitative strength of epidemiological evidence regarding adult exposure to two classes of contemporary use insecticides—organophosphates (OPs) and 푁-methyl carbamates (NMCs)—and sperm concentration using robust and reproducible systematic review and meta-analysis methods. METHODS: Three scientific databases (PubMed, Scopus, and Web of Science), two U.S. government databases (NIOSHTIC-2 and Science.gov), and five nongovernmental organization websites were searched for relevant primary epidemiological studies published in any language through 11 August 2022. Risk of bias and strength of evidence were evaluated according to Navigation Guide systematic review methodology. Bias-adjusted standardized mean difference effect sizes were calculated and pooled using a three-level, multivariate random-effect meta-analysis model with cluster-robust variance estimation. RESULTS: Across 20 studies, 21 study populations, 42 effect sizes, and 1,774 adult men, the pooled bias-adjusted standardized mean difference in sperm concentration between adult men more- and less-exposed to OP and NMC insecticides was -0.30 (95% CI: -0.49, -0.10; 푃Satt < 0.01). Sensitivity and subgroup analyses explored statistical heterogeneity and validated the model robustness. Although the pooled effect estimate was modified by risk of bias, insecticide class, exposure setting, and recruitment setting, it remained negative in direction across all meta-analyses. The body of evidence was rated to be of moderate quality, with sufficient evidence of an association between higher adult OP and NMC insecticide exposure and lower sperm concentration. DISCUSSION: This comprehensive investigation found sufficient evidence of an association between higher OP and NMC insecticide exposure and lower sperm concentration in adults. Although additional cohort studies can be beneficial to fill data gaps, the strength of evidence warrants reducing exposure to OP and NMC insecticides now to prevent continued male reproductive harm. [ABSTRACT FROM AUTHOR]

BACKGROUND: Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents. METHODS: We assessed 519 participants (11-17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl) benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, 17β-estradiol, and testosterone was assessed using structural equation modeling. RESULTS: The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0-2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration (β)= -0.19 95% confidence interval (CI): -0.31, -0.07], language [β= -0.12 (95% CI: -0.23, -0.01)], and memory/learning [β= -0.11 (95% CI: -0.22, 0.01)]. Glyphosate had a statistically significant negative association only with social perception [β= -0.08 (95% CI: -0.14, -0.01)]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed. CONCLUSION: This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. [ABSTRACT FROM AUTHOR]

Background: Although pesticide use is widespread, the possible effect of early-life exposure to organophosphate (OP) on pediatric respiratory health is not well described. Objectives: We investigated the relationship between early-life exposure to OPs and respiratory outcomes. Methods: Participants included 359 mothers and children from the CHAMACOS birth cohort. Dialkyl phosphate (DAP) metabolites of OP pesticides, specifically diethyl (DE) and dimethyl (DM) phosphate metabolites, were measured in urine from mothers twice during pregnancy (mean = 13 and 26 weeks gestation) and from children five times during childhood (0.5–5 years). Childhood DAP concentrations were estimated by the area under curve (AUC). Mothers reported their child’s respiratory symptoms at 5 and 7 years of age. We used generalized estimating equations (GEE) to examine associations of prenatal and childhood DAP concentrations with repeated measures of respiratory symptoms and exercise-induced coughing at 5 and 7 years of age, adjusting for child’s sex and age, maternal smoking during pregnancy, secondhand tobacco smoke, season of birth, PM2.5, breastfeeding, mold and cockroaches in home, and distance from highway. Results: Higher prenatal DAP concentrations, particularly DE, were nonsignificantly associated with respiratory symptoms in the previous 12 months at 5 or 7 years of age [adjusted odds ratio (aOR) per 10-fold increase = 1.44; 95% CI: 0.98, 2.12]. This association was strongest with total DAP and DE from the second half of pregnancy (aOR per 10-fold increase = 1.77; 95% CI: 1.06, 2.95; and 1.61; 95% CI: 1.08, 2.39, respectively). Childhood DAP, DE, and DM concentrations were associated with respiratory symptoms and exercise-induced coughing in the previous 12 months at 5 or 7 years of age (total DAPs: aOR per 10-fold increase = 2.53; 95% CI: 1.32, 4.86; and aOR = 5.40; 95% CI: 2.10, 13.91, respectively). Conclusions: Early-life exposure to OP pesticides was associated with respiratory symptoms consistent with possible asthma in childhood. [ABSTRACT FROM AUTHOR]

Background: A reduction in the use of polybrominated diphenyl ethers (PBDEs) because of human health concerns may result in an increased use of and human exposure to organophosphate flame retardants (OPFRs). Human exposure and health studies of OPFRs are lacking. Objectives: We sought to define the degree of temporal variability in urinary OPFR metabolites in order to inform epidemiologic study design, and to explore a potential primary source of exposure by examining the relationship between OPFRs in house dust and their metabolites in urine. Methods: Nine repeated urine samples were collected from 7 men over the course of 3 months and analyzed for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPP), metabolites of the OPFRs tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phos­phate (TPP), respectively. Intraclass correlation coefficients (ICCs) were calculated to characterize temporal reliability. Paired house dust and urine samples were collected from 45 men. Results: BDCPP was detected in 91% of urine samples, and DPP in 96%. Urinary BDCPP showed moderate-to-strong temporal reliability (ICC range, 0.55-0.72). ICCs for DPP were lower, but moderately reliable (range, 0.35-0.51). There was a weak [Spearman r ( rS) = 0.31] but significant (p = 0.03) correlation between urinary BDCPP and TDCPP concentrations in house dust that strengthened when nondetects (rS = 0.47) were excluded. There was no correlation between uncorrected DPP and TPP measured in house dust ( rS < 0.1). Conclusions: Household dust may be an important source of exposure to TDCPP but not TPP. Urinary concentrations of BDCPP and DPP were moderately to highly reliable within individuals over 3 months. [ABSTRACT FROM AUTHOR]

Objectives: We conducted a systematic review and meta-analysis of childhood leukemia and parental occupational pesticide exposure. Data sources: Searches of MEDLINE (1950-2009) and other electronic databases yielded 31 included studies. Data extraction: Two authors independently abstracted data and assessed the quality of each study. Data synthesis: Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs). There was no overall association between childhood leukemia and any paternal occupational pesticide exposure (OR = 1.09; 95% CI, 0.88-1.34); there were slightly elevated risks in subgroups of studies with low total-quality scores (OR = 1.39; 95% CI, 0.99-1.95), ill-defined exposure time windows (OR = 1.36; 95% CI, 1.00-1.85), and exposure information collected after offspring leukemia diagnosis (OR = 1.34; 95% CI, 1.05-1.70). Childhood leukemia was associated with prenatal maternal occupational pesticide exposure (OR = 2.09; 95% CI, 1.51-2.88); this association was slightly stronger for studies with high exposure-measurementquality scores (OR = 2.45; 95% CI, 1.68-3.58), higher confounder control scores (OR = 2.38; 95% CI, 1.56-3.62), and farm-related exposures (OR = 2.44; 95% CI, 1.53-3.89). Childhood leukemia risk was also elevated for prenatal maternal occupational exposure to insecticides (OR = 2.72; 95% CI, 1.47-5.04) and herbicides (OR = 3.62; 95% CI, 1.28-10.3). Conclusions: Childhood leukemia was associated with prenatal maternal occupational pesticide exposure in analyses of all studies combined and in several subgroups. Associations with paternal occupational pesticide exposure were weaker and less consistent. Research needs include improved pesticide exposure indices, continued follow-up of existing cohorts, genetic susceptibility assessment, and basic research on childhood leukemia initiation and progression. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Agricultural Health Study (AHS) is a prospective cohort study of licensed pesticide applicators from Iowa and North Carolina enrolled between 1993 and 1997. EPTC (S-ethyl-N,N-dipropylthiocarbamate) is a thiocarbamate herbicide used in every region of the United States. The U.S. Environmental Protection Agency reports that EPTC is most likely not a human carcinogen; however, the previous epidemiologic data on EPTC exposure and cancer risk were limited. OBJECTIVES: The purpose of this study was to examine cancer incidence and EPTC use in 48,378 male pesticide applicators enrolled in the AHS. METHODS: We estimated the rate ratio (RR) and 95% confidence intervals (CIs) for all cancers and selected cancer sites using Poisson regression. We assessed EPTC exposure using two quantitative metrics: lifetime exposure days and intensity-weighted lifetime exposure days, a measure that accounts for application factors that modify personal exposure likelihood. RESULTS: Among the 9,878 applicators exposed to EPTC, 470 incident cancer cases were diagnosed during the follow-up period ending December 2004 compared with the 1,824 cases among individuals reporting no use. Although EPTC was associated with colon cancer in the highest tertile of both lifetime exposure days and intensity-weighted lifetime days (RR = 2.09; 95% CI, 1.26--3.47 and RR = 2.05; 95% CI, 1.34--3.14, respectively) and the trend test was < 0.01 for both, the pattern of RR was not monotonic with increasing use. There was a suggestion of an association with leukemia. No other associations were observed. CONCLUSION: In this analysis, EPTC use appeared to be associated with colon cancer and leukemia. However, given the relatively small number of cases in the highest exposure tertile, results should be interpreted with caution, and further investigations are needed. [ABSTRACT FROM AUTHOR]