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Chlorpyrifos (CPF), an organophosphate insecticide, has been linked to adverse neurodevelopmental effects in animal studies. However, little is known about long-term neurotoxicity of early-life CPF exposure in humans. We aimed to evaluate the associations of both prenatal and early childhood CPF exposure with neurodevelopment of children. In this observational study based on Sheyang Mini Birth Cohort, pregnant women were recruited from an agricultural region between June 2009 and January 2010, and their children were followed up from birth to age three. Urinary 3,5,6-Trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, was quantified using large-volume-injection gas chromatography-tandem mass spectrometry. Developmental quotients (DQs) of children in motor, adaptive, language, and social areas were assessed by trained pediatricians. Data from 377 mother-child pairs were used in the current study. Associations between CPF exposure and neurodevelopmental indicators were estimated using generalized linear models with adjustment for potential confounders. The median concentrations of TCPy in maternal and children's urine were 5.39 μg/L and 5.34 μg/L, respectively. No statistically significant association was found between maternal urinary TCPy concentrations and children neurodevelopment. While for postnatal exposure, we found lower motor area DQ score 0.61 [95% confidence interval (CI): −1.13, −0.09; p = 0.02] and social area DQ score 0.55 (95% CI: −1.07, −0.03; p = 0.04) per one-unit increase in the ln-transformed childhood urinary TCPy concentrations. Further stratification by sex indicated that the inverse associations were only observed in boys, but not in girls. Our findings suggest that adverse neurodevelopmental effects were associated with early childhood CPF exposure, but not prenatal exposure. Additional longitudinal studies are needed to replicate these results and to further understand the toxicological mechanisms of CPF.

Pesticides are an important and high use group of chemicals as they increase crop yield in agricultural activities and help control disease spread in public areas. Globally, over 3 billion kilograms of active pesticide ingredients are used per year. The general population may be exposed to these pesticides through dietary ingestion, inhalation, ingestion of dust and soil, and dermal absorption. Pesticide exposure has been linked to numerous adverse health effects, particularly in children who may have additional exposure pathways and metabolise toxicants more slowly and thus are more sensitive to chemical toxicity. Assessing their pesticide exposure and relevant health impact is therefore particularly important. Human biomonitoring using human body fluids is seen as the “gold standard” approach to assess such exposure and risk. Urine is an ideal matrix to investigate recent exposures for currently used pesticides as the majority of them have short half-lives ( 60%) detected in urine samples from Australian and New Zealand children: dialkylphosphate metabolites (DAPs, except for diethyl dithiophosphate (DEDTP)), 3,5,6-trichloro-2-pyridinol (TCPY), para-nitrophenol (PNP), 3-phenoxybenzoic acid, and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid. Urine samples from Australian children also saw a high detection frequency of atrazine mercapturate (ATZ), metabolite of a chlorotriazine herbicide, atrazine. In contrast, detection of ATZ in urine samples from New Zealand children was rare (≤ 2%) but a phenoxyacetic herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), had a detection frequency of 86%, compared to the Australian study (< 45%). Although comparison between results based on pooled (the Australian study in Chapter 3) and individual (the New Zealand study in Chapter 5) samples should proceed with caution, the above results showed that Australian and New Zealand children share a common exposure of OPs and PYRs but may differ in certain herbicide exposure.Concentrations of DAPs were generally comparable between Australian (0-5 y) and New Zealand children (5-14 y), and were at the lower end compared to other countries. The exception was diethyl thiophosphate (DETP) for Australian pre-schoolers, who had 3 times higher concentration (geometric mean (GM) of 1.8 ng/mL) in urine compared to Japanese peers (~0.6 ng/mL). The other exception was dimethyl phosphate (DMP), for which New Zealand children had a median value of 11 μg/g creatinine, comparable with an existing Australian study on children of the same age but higher than results from other countries such as the US. The profile of DAPs, namely the concentration of ∑DMAP (sum of DMP, dimethyl thiophosphate (DMTP) and dimethyl dithiophosphate (DMDTP)) compared to the one for ∑DEAP (sum of diethyl phosphate (DEP), DETP and DEDTP), were similar between Australia and New Zealand and several other countries such as Canada and Israel. It was however different from some other countries such as Chile and Malaysia, which may reflect the difference in OP use patterns in different countries. The highest level was measured for TCPY, a metabolite for chlorpyrifos, chlorpyrifos-methyl and triclopyr, in both Australian (GM of 9.7 ng/mL urine) and New Zealand (GM of 13 μg/g creatinine) studies. They were generally higher than results from other countries, indicating a prevalent use of and exposure to pesticide products containing the above pesticides in Australia and New Zealand. Although overall exposure risk is low for these pesticides as assessed by calculated daily intake or against Biomonitoring Equivalents, compared to peers in the US, Australian and New Zealand children may have higher exposures to chlorpyrifos/triclopyr and pyrethroids. Biomarker association analysis suggested an important role of permethrin and cypermethrin as sources for pyrethroid exposure for both populations.Age is identified as an important predictor for pesticide exposure but from different directions for children in different ages. Exposure seems to increase following weaning or as a result of increased dietary intake and mobility/activity (0-5 y), and since then, starts decreasing when children are getting older (5-14 y). Girls appear to have elevated concentrations of PNP in urine compared to boys in the 5-14 y group, which may be related to the use of nitrobenzene or PNP itself associated with production of dyes and flavouring agents in cosmetics such as nail polish that girls generally tend to access more than boys.For lifestyle predictors, fruit and vegetable consumptions were found associated with pesticide exposure for children under 3 years but not in the school-age (5-14) group. However, for the school-aged children in New Zealand, urine samples from low spray season had significantly higher concentrations of several biomarkers, which might be associated with consumption of imported fruits and vegetables during this season. Washing fruits and vegetables and hands appear to decrease the exposure to certain pesticides (but not all). Living in rural areas is associated with increased exposure to pyrethroids via pest control practices, whereas children living in urban areas tend to have higher exposure to nitrobenzene or PNP. Having a dog in the home was associated with higher exposure risk to pyrethroids. The exposure risk is further increased for children with a low socioeconomic status.

The aim of this study was to obtain a longitudinal evaluation of the exposure to chlorpyrifos (CP) and chlorpyrifos-methyl (CPM) in agricultural workers in South Tyrol and in a residential group living in the same area. CP and CPM are widely used pesticides in agriculture. Biological monitoring of CP and CPM exposure in humans can be achieved by analyzing urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy). TCPy a metabolite of CP and CPM which is produced by a two-step metabolic transformation. Between May 14th, 2014 and March 16th, 2015 we conducted a longitudinal study on 28 farmers actively working in spray pesticide treatment and 43 non-farmers living in the same agricultural area of South Tyrol (Italy). Urine samples were collected at two time points: during the pesticide treatment period and in a temporally distant season that should guarantee metabolite clearance. We developed and validated a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the determination of urinary TCPy levels. During the treatment season, both farmers and residents showed higher TCPy levels (median = 6.8 and 6.73 ug/g creatinine, respectively) than during the non-treatment season (median = 2.54 and 3.22 ug/g creatinine, respectively), suggesting a similar effect of the pesticide spraying on both groups. However, the observed TCPy levels resulted in a daily CP and CPM intake well below the limits recommended by FAO/WHO. During the non-treatment season, non-farmers showed higher TCPy levels values than farmers, suggesting the existence of TCPy of other unmeasured sources of exposure not considered in this study. This suggests that, for a comprehensive evaluation of the risks associated with TCPy exposure, additional sources should be identified in addition to CP and CPM pesticides.

BACKGROUND The aim of this study was to use an integrated exposure assessment approach, combining spatiotemporal modeling of environmental exposure and fate of the chemical to assess the exposure of vulnerable populations. In this study, chlorpyrifos exposure of pregnant women in Picardy was evaluated at a regional scale during 1 year. This approach provided a mapping of exposure indicators of pregnant women to chlorpyrifos over fine spatial and temporal resolutions using a GIS environment. METHODS Fate and transport models (emission, atmospheric dispersion, multimedia exposure, PBPK) were combined with environmental databases in a GIS environment. Quantities spread over agricultural fields were simulated and integrated into a modeling chain coupling models. The fate and transport of chlorpyrifos was characterized by an atmospheric dispersion statistical metamodel and the dynamiCROP model. Then, the multimedia model Modul'ERS was used to predict chlorpyrifos daily exposure doses which were integrated in a PBPK model to compute biomarker of exposure (TCPy urinary concentrations). For the concentration predictions, two scenarios (lower bound and upper bound) were built. RESULTS At fine spatio-temporal resolutions, the cartography of biomarkers in the lower bound scenario clearly highlights agricultural areas. In these maps, some specific areas and hotspots appear as potentially more exposed specifically during application period. Overall, predictions were close to biomonitoring data and ingestion route was the main contributor to chlorpyrifos exposure. CONCLUSIONS This study demonstrated the feasibility of an integrated approach for the evaluation of chlorpyrifos exposure which allows the comparison between modeled predictions and biomonitoring data.

Human exposure to pesticides is widespread and has received much attention in recent years because of its link to adverse health outcomes. Measurement of urinary concentrations of pesticides and their metabolites is often used in the assessment of body burdens of these chemicals. However, pesticides and their metabolites can be present in blood circulatory system, although little is known on serum levels of pesticides. In this study, we aimed to examine the occurrence and profile of four organophosphate (OP), five pyrethroid (PYR) insecticides, two phenoxy acid (PA) herbicides, 14 neonicotinoid (neonic) insecticides and six dialkylphosphate metabolites in serum from 25 individuals diagnosed with osteoarthritis in Jeddah, Saudi Arabia. 2-Isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), 3,5,6-trichloro-2-pyridinol (TCPY), 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, 3-phenoxybenzoic acid, N-desmethyl acetamiprid, dimethylphosphate (DMP) and dimethylthiophosphate (DMTP) were detected in ≥80% of the serum samples analyzed. Metabolites of OPs, DMTP (median concentration: 2.14 ng/mL), DMP (1.04 ng/mL) and TCPY (0.84 ng/mL), collectively accounted for 67–83% of the total serum pesticide concentrations. Serum concentrations of pesticides were similar to or lower than those reported in urine. Our preliminary evidence suggests that serum can be used as a matrix for the assessment of exposure to OPs, PYRs, PAs and neonics.

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.

Background Variability of short-lived urinary pesticide metabolites during pregnancy raises challenges for exposure assessment. Objectives For urinary metabolite concentrations 3-phenoxybenzoic acid (3-PBA) and 3,5,6-trichloro-2-pyridinol (TCPy), we assessed: (1) temporal variability; (2) variation of two urine specimens within a trimester; (3) reliability for pesticide concentrations from a single urine specimen to classify participants into exposure tertiles; and (4) seasonal or year variations. Methods Pregnant mothers (N = 166) in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) Study provided urine specimens (n = 528). First morning void (FMV), pooled, and 24-h specimens were analyzed for 3-PBA and TCPy. For 9 mothers (n = 88 specimens), each urine specimen was analyzed separately (not pooled) to estimate within- and between-person variance components expressed as intraclass correlation coefficients (ICC). Pesticide concentrations from two specimens within a trimester were also assessed using ICC's. Agreement for exposure classifications was assessed with weighted Cohen's kappa statistics. Longitudinal mixed effect models were used to assess seasonal or year variations. Results Urinary pesticide metabolites were detected in ≥ 93% of specimens analyzed. The highest ICC from repeated individual specimens was from specific gravity-corrected FMV specimens for 3-PBA (ICC=0.13). Despite high within-person variability, the median concentrations did not differ across trimesters. Concentrations from pooled specimens had substantial agreement predicting exposure categories for TCPy (K = 0.67, 95% CI (0.59, 0.76)) and moderate agreement for 3-PBA (K = 0.59, 95% CI (0.49, 0.69)). TCPy concentrations significantly decreased from 2007 to 2014. Conclusions Pooled specimens may improve exposure classification and reduce laboratory costs for compounds with short biological half-lives in epidemiological studies.

Background Exposure to environmental chemicals, including organophosphorus pesticides, is associated with behavioral disorders such as attention deficit hyperactivity disorder (ADHD). However, the impact of occupational pesticide exposure on ADHD development in adolescents has not been examined. Objective We examined the association between exposure to chlorpyrifos and ADHD symptoms among adolescents in Egypt. Methods Adolescent pesticide applicators and non-applicators, 12–21 years old, participated in a 10-month longitudinal study examining health effects from pesticide exposure. Repeated urine and blood samples were collected at various time points during the 10-months to assess biomarkers of chlorpyrifos exposure (urinary trichloro-2-pyridinol or TCPy) and effect (blood acetyl cholinesterase activity and butyryl cholinesterase activity). Parents from a subset of the cohort (N = 64) completed the Short Form of Conners’ Parent Rating Scale – Revised. Poisson regressions were used to examine the associations between the number of ADHD symptoms and occupation and biomarkers. Results Pesticide applicators had significantly more symptoms of ADHD than participants in the non-applicator group. Urinary TCPy levels were associated with increased symptoms, demonstrating a dose-response effect. Applicators with ADHD reported applying pesticides for more hours during the application season and had greater cumulative TCPy levels than participants without ADHD. One fourth of all applicators met the criteria for an ADHD diagnosis (having 6 or more reported symptoms). Conclusions This study provides preliminary evidence of an association between occupational exposure to chlorpyrifos and ADHD symptoms among adolescent pesticide applicators in spite of its limited small sample size. There is a critical need to investigate the susceptibility of children and adolescents to repeated occupational and environmental exposures to pesticides because the developing brain may be uniquely sensitive to the neurotoxic effects of these agents.

Human biomonitoring provides information about chemicals measured in biological matrices, but their interpretation remains uncertain because of pharmacokinetic (PK) interactions. This study examined the PKs in blood from Long–Evans rats after a single oral dose of 0.4 mg/kg bw of each pesticide via a mixture of the 17 pesticides most frequently measured in humans. These pesticides are β-endosulfan; β-hexachlorocyclohexane [β-HCH]; γ-hexachlorocyclohexane [γ-HCH]; carbofuran; chlorpyrifos; cyhalothrin; cypermethrin; diazinon; dieldrin; diflufenican; fipronil; oxadiazon; pentachlorophenol [PCP]; permethrin; 1,1-dichloro-2,2bis(4-chlorophenyl)ethylene [p,p′-DDE]; 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane [p,p′-DDT]; and trifluralin. We collected blood at 10 min to 48-h timepoints in addition to one sample before gavage (for a control). We used GS–MS/MS to measure the pesticide (parents and major metabolites) concentrations in plasma, determined the PK parameters from 20 sampling timepoints, and analyzed the food, litter, and cardboard in the rats’ environment for pesticides. We detected many parents and metabolites pesticides in plasma control (e.g., diethyl phosphate [DEP]; PCP; 3-phenoxybenzoic acid [3-PBA]; 3,5,6-trichloro-2-pyridinol [TCPy], suggesting pre-exposure contamination. The PK values post-exposure showed that the AUC0−∞ and Cmax were highest for TCPy and PCP; β-endosulfan, permethrin, and trifluralin presented the lowest values. Terminal T1/2 and MRT for γ-HCH and β-HCH ranged from 74.5 h to 117.1 h; carbofuran phenol presented the shortest values with 4.3 h and 4.8 h. These results present the first PK values obtained through a realistic pattern applied to a mixture of 17 pesticides to assess exposure. This study also highlights the issues of background exposure and the need to work with a relevant mixture found in human matrices.

Background: There is a paucity of research that tracks changes in liver and kidney function among pesticide applicators. The aim of the current study was to investigate the role of repeated seasonal exposure to the organophosphorus pesticide, chlorpyrifos, on serum measures of liver and kidney function. Methods: Pesticide exposure was assessed by measuring the urinary concentrations of 3,5,6-trichloro-2 pyridinol (TCPy), a specific biomarker for chlorpyrifos. Chlorpyrifos exposure and 8 serum markers of liver and kidney function were measured at 15 timepoints over 3 years prior to, during, and following the end of seasonal pesticide application among adolescent applicators and non-applicators from 4 field stations in Menoufia, Egypt. Results: Urinary TCPy levels showed increases during the application cycles and recovery at the end of each application season. Altered serum markers of liver and kidney function were associated with chlorpyrifos exposure, with some markers recovering 3 months after the end of exposure each year, while other measures demonstrated progressive increase up to 300% the baseline levels at the end of 3 years. Conclusion: The study demonstrated that frequent assessment of liver and kidney function is a sound practice to evaluate cellular injury following chronic repeated occupational and environmental exposure to chlorpyrifos.

Chlorpyrifos is a widely used organophosphorus pesticide that efficiently protects crops against pests. However, recent studies suggest that severe exposure to chlorpyrifos may present adverse health effects in human. To analyze the exposure level and metabolic characteristics of chlorpyrifos pesticide in urban adults and farmers with/without occupation pesticide contact, the occurrence of urinary chlorpyrifos and methyl chlorpyrifos (CP-me), as well as their metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), was determined in farmers of an agricultural village in China, and in urban adults of a nearby town. The geometric mean (GM) concentrations of TCPy, which is the major marker of chlorpyrifos exposure, were 4.29 and 7.57μg/g-creatinine in urban adults and farmers before pesticide application, respectively. Chlorpyrifos spraying significantly increased the concentrations of urinary TCPy. In the first day after spraying, a GM concentration of 43.7μg/g-creatinine was detected in the urine specimens from farmers, which decreased to 38.1 and 22.8μg/g-creatinine in the second and third day after chlorpyrifos spraying. The ratio of TCPy and its parent compounds, i.e. chlorpyrifos and CP-me, was positively associated with the sum concentration of urinary chlorpyrifos, CP-me, and TCPy, suggesting the increasing metabolic efficiency of chlorpyrifos to TCPy at higher chlorpyrifos exposure levels. To estimate the farmers' occupational exposure to chlorpyrifos pesticide, a new model based on the fitted first-order elimination kinetics of TCPy was established. Occupational chlorpyrifos exposure in a farmer was estimated to be 3.70μg/kg-bw/day (GM), which is an exposure level that is higher than the recommended guideline levels. Significant increase of urinary 8-hydroxydeoxyguanosine (8-OHdG) was observed on the first day after chlorpyrifos spraying, which indicates a potential oxidative damage in farmers. However, urinary 8-OHdG returned to its baseline level within two days.

Introduction Chlopyrifos organophosphorous pesticides (OPs) are regularly applied for protection of the cotton crop in Egypt. OP absorption subsequent to dermal exposure has been estimated to be 94%–96% of the total dose. Legs and lower body parts are the most affected during cotton pesticide applications. Pesticides residues on the cotton plants also contaminate clothing and uncovered arms or legs of the applicators as they pass. Protective equipment is not readily available in Egypt. This pilot study was conducted to determine if wearing plastic coverings over pants or changing work practices could reduce pesticide exposure among Egyptian pesticide workers. Methods A controlled intervention study included: protective clothing (plastic pants modelled by the workers and staff who participated in 4 educational focus groups); spray away (instructions were provided to spray away form the workers’ path); control (followed routine work practices). Exposure was assessed measuring pre- and post-application urinary TCPy levels (3,5,6-trichloro-2-pyridinol), the primary chlorpyrifos metabolite used as a biomarker of absorbed dose. Work activities were recorded throughout the three-day study period. Results Twenty-four adult workers (n=8 per group) participated in the study. Time spent applying (range 15–36 min) and mixing (range 10–12 min) pesticides varied between groups and job categories. Other than the pants group, none of the workers had protective clothing. Spraying away did not produce consistent results. Average TCPy levels of the protective clothing group were lower compared to the other two groups, though the differences were not statistically significant (p>0.05). Conclusion Work habits, time spent applying or mixing pesticides and environmental conditions (e.g., wind direction) are important exposure determinants of urinary TCPy levels. However, use of protective clothing covering legs and lower parts of the body would reduce skin contamination, a major route of pesticide exposure. Work was supported by NIEHS grants ES017223 and ES016308.

Few studies have detailed the prenatal pesticide exposure levels of women employed in or residing near large-scale agricultural industries. This study reports pesticide metabolite levels during and shortly after pregnancy in a pilot study of workers in Ecuador. Urine samples were collected for 16 rose workers and 10 nonagricultural workers enrolled into the study in early pregnancy. We measured six nonspecific organophosphatedialkylphosphate (DAP) pesticide metabolites, two alkylenebis-dithiocarbamate pesticide metabolites [ethylene thiourea (ETU) and propylene thiourea (PTU)], 3,5,6-trichloro-2-pyridinol (TCPy), malathion dicarboxylic acid, and two pyrethroid metabolites (2,2-dimethylcyclo propanecarboxylic acid and 3-phenooxybenzoic acid). We collected 141 urine samples (mean: 5.4 per woman). We observed high detection frequencies for five DAP metabolites and ETU, PTU, and TCPy. We report elevated levels of ETU in the entire sample (median 4.24 ng/mL, IQR 2.23, 7.18), suggesting other possible non-occupational pathways of exposure. We found no statistical differences in pesticide levels by current employment status, although the highest pesticide levels were among rose workers. We observed within-woman correlation in TCPy and PTU levels, but not in ETU or DAP levels. The present study is the first to characterize prenatal pesticide exposure levels among working women in Ecuador. Limitations include a small sample size and use of a convenience sample. Strengths include a longitudinal design and multiple urine samples per woman. Results provide an initial characterization of prenatal pesticide exposure levels and how these levels vary over pregnancy in a community impacted by agricultural industry and will inform further studies in the region.

Globally, human exposures to organophosphate (OP) insecticides may pose a significant burden to the health of mothers and their developing fetuses. Unfortunately, relevant data is limited in certain areas of the world concerning sources of exposure to OP insecticides in pregnant populations. To begin to address this gap in information for Puerto Rico, we studied repeated measures of urinary concentrations of 10 OP insecticide metabolites among 54 pregnant women from the northern karst region of the island. We also collected demographic data and self-reported information on the consumption of fruits, vegetables, and legumes in the past 48-hr before urine collection and home pest-related issues. We calculated the distributions of the urinary biomarkers and compared them to women of reproductive age from the general U.S. population. We also used statistical models accounting for correlated data to assess within-subject temporal variability of the urinary biomarkers and to identify predictors of exposure. We found that for all but two metabolites (para-nitrophenol [PNP], diethylthiophosphate [DETP]), 50th or 95th percentile urinary concentrations (the metric that was used for comparison was based on the biomarker’s detection frequency) of the other eight metabolites (3,5,6-trichloro-2-pyridinol [TCPY], 2-isopropyl-4-methyl-6-hydroxy-pyrimidine, malathion dicarboxylic acid, diethylphosphate, diethyldithiophosphate, dimethylphosphate, dimethylthiophosphate [DMTP], dimethyldithiophosphate) were somewhat lower in our cohort compared with similarly aged women from the continental United States. TCPY, PNP, DETP, and DMTP, which were the only urinary metabolites detected in greater than 50% of the samples, had poor reproducibility (intraclass correlation coefficient range: 0.19–0.28) during pregnancy. Positive predictors of OP insecticide exposure included: age; marital or employment status; consumption of cherries, grape juice, peanuts, peanut butter, or raisins; and residential application of pesticides. Further research is needed to understand what aspects of the predictors identified influence OP insecticide exposure during pregnancy.

There are few studies documenting the dust loaded with pesticides as a potential non-dietary exposure source for occupational worker and populations living near agricultural farms and pesticides formulation plants. In present study we have evaluated the pesticide concentration in dust from potential sites and relevant health risk from dust ingestion. Furthermore, the effect of currently used pesticides was investigated on blood and urine parameters of subjects: farmer, factory worker, urban resident and rural resident and controlled subjects with presumably different levels of exposure. The urinary metabolites (TCPY and IMPY) were quantified as biomarkers of exposure to chlorpyrifos and diazinon in relation with biomarkers of effect including BuChE, LH, FSH, testosterone and oxidative stress. Results showed that chlorpyrifos and diazinon were present in higher concentration in dust and posed a high health risk to exposed subjects. The mean SOD value was high among the farmer (3048 U/g Hb) followed by factory worker (1677.6U/g Hb). The urinary biomarkers – TCPY and IMPY- were found higher in exposed subjects as compared to control. Furthermore, testosterone was found in higher concentration in factory worker than control (12.63 ng/ml vs 4.61 ng/ml respectively). A decreased BuChE activity was noticed in occupational group and significant differences were observed in control verses exposed subjects. The PCA analysis evidenced the impact of pesticides on exposure biomarkers and male reproductive hormones. The study suggests that dust contaminated with pesticides engenders significant health risk particularly related to the nervous and endocrine system, not only for occupational workers exposed to direct ingestion but also for nearby residential community. Succinctly putting: Pesticides loaded dust in the city of Lahore, being a high priority concern for the government of Pakistan, demands to be addressed.

Chlorpyrifos (CPF) is an organophosphourus insecticide applied to cotton fields by adolescents employed by the Egyptian Ministry of Agriculture. Urinary 3,5,6-trichloro-2-pyridinol (TCPy) is a biomarker of CPF exposure that has substantial variability among these applicators. In order to identify predictors of CPF exposure, we conducted a longitudinal study of 43 adolescent pesticide applicators in Egypt from April 2010 to January 2011 in Egypt. Urinary TCPy was quantified at 25 time-points, prior to, during, and following application. We used log-linear regression and a best subset selection approach to identify the exposure determinants that were most predictive of cumulative TCPy and participants’ highest TCPy values (peak exposure). Applicators had cumulative urinary TCPy levels ranging from 167 to 49,8208 µg/g creatinine. Total hours applying CPF (semi-partial r2 = 0.32), and total hours in the field applying other pesticides (semi-partial r2=0.08) were the strongest predictors of cumulative TCPy. Applicators had peak urinary TCPy levels ranging from 4 to 5,715 µg/g creatinine. The amount of time applying pesticides prior to blood draw was the strongest predictor of peak TCPy (semipartial r2=0.30). We also observed evidence that wearing clean clothes to work was associated with lower longitudinal TCPy. Our results suggest there is an opportunity for targeted interventions, particularly related to hygiene or implementation of personal protective equipment usage to reduce CPF exposure among adolescent pesticide workers.

In Odense Child Cohort (OCC), concentrations of the pesticide metabolites 3-phenoxybenzoic acid (3-PBA), 3,5,6-trichloro-2-pyridinol (TCPY), 2,4-Dichlorophenoxyacetic acid (2,4-D) and dialkyl phosphates (DAPS) were measured in urine samples collected in gestational week 28 in up to 858 women. Gestational length, birth weight, head and abdominal circumference were obtained from birth records and anogenital distance (AGD) was measured at age three month. We did not find consistent dose-related associations between pesticide metabolite concentrations and birth outcomes or AGD. However, females tended to have shorter abdominal circumference with higher maternal 3-PBA concentrations beta: -0.3 (95% CI: -0.5, -0.003) cm). Further, a non-significant dose-related elongation of AGD in females was seen for 3-PBA (p-trend: 0.14) and diethyl phosphates (p-trend: 0.08). In males, exposure to 2,4-D in the second compared to the first tertile showed a statistically significant shorter AGD (beta: -1.55 (-2.81, -0.28) mm). These findings may suggest a weak disturbance of sex-hormone action. (C) 2018 Elsevier Inc. All rights reserved.

A combination experimental and computational approach was developed to predict chemical transport into saliva. A serous-acinar chemical transport assay was established to measure chemical transport with nonphysiological (standard cell culture medium) and physiological (using surrogate plasma and saliva medium) conditions using 3,5,6-trichloro-2-pyridinol (TCPy) a metabolite of the pesticide chlorpyrifos. High levels of TCPy protein binding were observed in cell culture medium and rat plasma resulting in different TCPy transport behaviors in the 2 experimental conditions. In the nonphysiological transport experiment, TCPy reached equilibrium at equivalent concentrations in apical and basolateral chambers. At higher TCPy doses, increased unbound TCPy was observed, and TCPy concentrations in apical and basolateral chambers reached equilibrium faster than lower doses, suggesting only unbound TCPy is able to cross the cellular monolayer. In the physiological experiment, TCPy transport was slower than nonphysiological conditions, and equilibrium was achieved at different concentrations in apical and basolateral chambers at a comparable ratio (0.034) to what was previously measured in rats dosed with TCPy (saliva:blood ratio: 0.049). A cellular transport computational model was developed based on TCPy protein binding kinetics and simulated all transport experiments reasonably well using different permeability coefficients for the 2 experimental conditions (1.14 vs 0.4 cm/h for nonphysiological and physiological experiments, respectively). The computational model was integrated into a physiologically based pharmacokinetic model and accurately predicted TCPy concentrations in saliva of rats dosed with TCPy. Overall, this study demonstrates an approach to predict chemical transport in saliva, potentially increasing the utility of salivary biomonitoring in the future.

Chlorpyrifos (CPF) is a commonly used organophosphate insecticide (OP). In adults, exposure to OPs has been inconsistently associated with reduced lung function. OP exposure and lung function has not been assessed in adolescents. The objective of this study was to assess CPF exposure and lung function among Egyptian adolescents. We conducted a 10-month study of male adolescent pesticide applicators (n = 38) and non-applicators of similar age (n = 24). Urinary 3,5,6-trichloro-2-pyridinol (TPCy), a CPF-specific metabolite, was analyzed in specimens collected throughout the study. Spirometry was performed twice after pesticide application: day 146, when TCPy levels were elevated and day 269, when TCPy levels were near baseline. Applicators had higher levels of TCPy (mean cumulative TCPy day 146 = 33,217.6, standard deviation (SD) = 49,179.3) than non-applicators (mean cumulative TCPy day 146 = 3290.8, SD = 3994.9). Compared with non-applicators, applicators had higher odds of reporting wheeze, odds ratio = 3.41 (95% CI: 0.70, 17.41). Cumulative urinary TCPy was inversely associated with spirometric measurements at day 146, but not at day 269. Although generally non-significant, results were consistent with an inverse association between exposure to CPF and lung function.

Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6 mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6 months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages.

Children and adolescents may have occupational exposure to pesticides. Although previous studies examining prenatal pesticide exposure have identified neurobehavioral deficits in children, there are limited studies examining the impact of occupational exposure in children. The objectives of this study are to estimate exposures to the organophosphorus pesticide, chlorpyrifos (CPF), by measuring urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific CPF metabolite, and blood cholinesterase (ChE) activities and to characterize neurobehavioral performance in adolescents working as seasonal pesticide applicators and non-applicator controls. A neurobehavioral test battery, consisting of 14 tests, was used to assess a broad range of functions. Applicators performed worse than controls on the majority of tests. Principal component analysis was used to reduce the number of outcome variables and two components, focused on reasoning-short-term memory and attention-executive functioning, showed significant deficits in applicators compared to non-applicators. Elevated metabolite levels were found in the applicators compared to the non-applicators, confirming CPF exposure in the applicators. Although this study is limited by a small sample size, it provides preliminary evidence of moderate CPF exposures, decreased blood ChE in some applicators and decreased neurobehavioral performance in an adolescent working population.

The exposure to pesticides amongst school-aged children (6-11 years old) was assessed in this study. One hundred twenty-five volunteer children were selected from two public schools located in an agricultural and in an urban area of Valencia Region, Spain. Twenty pesticide metabolites were analyzed in children's urine as biomarkers of exposure to organophosphate (OP) insecticides, synthetic pyrethroid insecticides, and herbicides. These data were combined with a survey to evaluate the main predictors of pesticide exposure in the children's population. A total of 15 metabolites were present in the urine samples with detection frequencies (DF) ranging from 5% to 86%. The most frequently detected metabolites with DF>53%, were 3,5,6-trichloro-2-pyridinol (TCPy, metabolite of chlorpyrifos), diethyl phosphate (DEP, generic metabolite of OP insecticides), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPY, metabolite of diazinon) and para-nitrophenol (PNP, metabolite of parathion and methyl parathion). The calculated geometric means ranged from 0.47 to 3.36 µg/g creatinine, with TCPy and IMPY showing the higher mean concentrations. Statistical significant differences were found between exposure subgroups (Mann-Whitney test, p

Egyptian adolescents are hired as seasonal workers to apply pesticides to the cotton crop and may perform this occupation for several years. However, few studies examined the effects of repeated pesticide exposure on health outcomes The goal of this study was to determine the impact of repeated pesticide exposure on neurobehavioral (NB) performance and biomarkers of exposure (urinary metabolite) and effect (cholinesterase activity). Eighty-four adolescents from two field stations in Menoufia, Egypt, were examined four times: before and during pesticide application season in 2010 and again before and during application season in 2011. At each of the four time points, participants completed a questionnaire, performed an NB test battery, and were assessed for urinary levels of the chlorpyrifos metabolite TCPy (3,5,6-trichloro-2-pyridinol) and blood cholinesterase activity. Following the study cohort over two consecutive pesticide application seasons revealed that TCPy levels significantly increased following exposure, and returned to baseline levels following the end of the application season. Blood butyryl cholinesterase activity exhibited a similar pattern. Although NB outcomes displayed learning and practice effects over time, deficits in performance were significantly associated with increased TCPy levels with reduction in the number of NB measures showing improvement over time. Biomarkers of exposure and effect demonstrated changes associated with pesticide application and recovery after application ended. Deficits in NB performance were correlated with elevated pesticide exposure. Data demonstrated that repeated pesticide exposure may exert a long-term adverse impact on human health.

Background: Prenatal exposure to organophosphate pesticides (OPs) has been associated with impaired child development. Pesticide exposure determinants need to be studied in order to identify sources and pathways of pesticide exposure. The aim of this paper is to describe prenatal exposure to OPs and evaluate the associated factors in pregnant women. Methods: The study population consisted of pregnant women ( n = 573) who participated in the INMA birth cohort study in Valencia (Spain, 2003 – 2006). OP metabolites were analyzed in maternal urine at the 32nd week of gestation using a liquid chromatography-high resolution mass spectrometry method. The analysis included non-specific (diethyl phosphate [DEP], diethyl thiophosphate [DETP], dimethyl thiophosphate [DMTP], dimethyl dithiophosphate [DMDTP]) and specific metabolites (2-diethylamino-6-methyl-4-pyrimidinol [DEAMPY], 2-isopropyl-4-methyl-6-hydroxypyrimidine [IMPY], para-nitrophenol [PNP], and 3,5,6-trichloro-2-pyridinol [TCPY]). Information about the sociodemographic, environmental, and dietary characteristics was obtained by questionnaire. The association between log-transformed OPs and covariates was analyzed using multivariable interval censored regression. Results: The detection frequencies were low, DMTP and TCPY being the most frequently detected metabolites (53.8% and 39.1%, respectively). All the OP metabolites were positive ly associated with maternal intake of fruits and vegetables. Other maternal characteristics related to the OPs were body mass index (BMI) before pregnancy and smoking habit during pregnancy. Women with lower BMI and those who did not smoke presented higher OP concentrations. Moreover, mothers who had a yard or garden with plants at home or who lived in an urban area were also more exposed to OPs. Conclusions: The OP detection frequencies and the concentrations observed in our study population were low, compared with most of the previously published studies. Given the high vulnerability of the fet us to neurotoxicant exposure, further research on the determinants of the body burdenofOPsduringpregnancywouldbenecessary.The knowledge gained from such studies would enhance the effectiveness of public health control and future recommendations in order to reduce the risk to both the health of pregnant women and the health and development of their children. his study was supported by grants from the Instituto de Salud Carlos III [FIS- FEDER 13/1944, 13/2032, 14/0891, 14/1687, 16/1288 and Miguel Servet-FEDER CP15/0025]; Conselleria de Sanitat, Generalitat Valenciana (FISABIO UGP 15 – 230) and EU (FP7-ENV-2011 DENAMIC cod 282,957)

Few population studies have measured urinary levels of pesticides in individuals with vegan, vegetarian, or organic diets. The objectives of this study were to evaluate whether a vegan/vegetarian diet was associated with increased exposure to organophosphate and carbamate pesticides, and to evaluate the impact of organic consumption on pesticide exposure in vegans and vegetarians. In the current pilot study conducted in 2013–2014, we collected spot urine samples and detailed 24 h recall dietary data in 42 adult residents of Amirim, a vegetarian community in Northern Israel. We measured urinary levels of non-specific organophosphate pesticide metabolites (dialkylphosphates, (DAPs)) and specific metabolites of the current-use pesticides chlorpyrifos (3,5,6-trichloro-2-pyridinol (TCPy)), propoxur (-isopropoxyphenol (IPPX)), and carbaryl (1-naphthol). Six DAP metabolites were detected in between 67 and 100% of urine samples, with highest geometric mean concentrations for dimethylphosphate (19.2 μg/g). Creatinine-adjusted median concentrations of total DAPs and of TCPy were significantly higher in Amirim residents compared to the general Jewish population in Israel (0.29 μmol/g compared to 0.16, p 25% of the produce they consume is organic (0.065 μmol/L compared to 0.22, p

Organophosphorus (OP) and pyrethroid (PYR) compounds are the most widely used insecticides. OPs and PYRs are developmental neurotoxicants. Understanding the extent of exposure in the general population and especially in young children is important for the development of public health policy on regulation and use of these chemicals. Presented here are the results of the first investigation into the extent of environmental exposure to neurotoxic insecticides in preschool children in South Australia (SA).Children were enrolled from different areas of SA and assigned into urban, periurban and rural groups according to their residential address. Residential proximity to agricultural activity, parental occupational contact to insecticides and use of insecticides within the household were investigated as potential indirect measures of exposure. We used liquid chromatography/tandem mass spectrometry to measure the following metabolites of OPs and PYRs in urine samples as direct indicators of exposure: dialkylphosphates, p-nitrophenol, 3-methyl-4-nitrophenol, 3,5,6-trichloro-2-pyridinol, cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid, cis-3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid, 2-methyl-3phenylbenzoic acid and 3-phenoxybenzoic acid. Results were analysed to assess factors affecting the risk and level of exposure. Results were also compared to the published data in similar age groups from US and German studies.The results of this study demonstrate that there was widespread chronic exposure to OPs and and PYRs in SA children. OP metabolites were detected more commonly than PYR. Exposure to more than one chemical and contemporaneous exposure to chemicals from both OP and PYR groups was common in the study population. There were some differences in risks and levels of exposure between the study groups. Exposure to some restricted use of chemicals, for example, fenitrothion, was higher in periurban and rural children. There was no difference among the study groups in exposure to chlorpyrifos, used commonly in agriculture and in domestic settings and most frequently found OP pesticide in food in Australia. South Australian children appear to have higher levels of exposure compared their peers in US and Germany. Keywords: Environmental exposure, Organophosphate, Pyrethroid, Neurotoxic insecticides, Children, South Australia

The developing fetus is particularly vulnerable to adverse effects from pharmaceutical and exogenous chemical exposure. Deciduous teeth primarily form over specific periods from the second trimester in utero through the months after birth. We hypothesized that organic chemicals or their metabolites circulating in the bloodstream may sorb into forming dental tissues and remain stored in the tooth thereafter. Our aims were to devise analytical and preparation methods for potentially toxic or beneficial organic chemicals or metabolites in deciduous teeth and to estimate their detection frequencies. The analgesic acetaminophen was stored at greater concentration in a child's second molar than a first molar, consistent with intake, suggesting that acetaminophen concentration in molars may be a biomarker of acetaminophen exposure during molar formation. Chemicals detected by liquid chromatography/tandem mass spectrometry in molars of 21 typically developing children include the endocannabinoid anandamide (86% of children), acetaminophen (43%), and specific metabolites mono-2-ethylhexyl phthalate (MEHP, of plasticizer di-2-ethylhexyl phthalate, 29%), 3,5,6-trichloro-2-pyridinol (TCPy, of organophosphate (OP) insecticide chlorpyrifos, 10%), and 2-isopropyl-6-methyl-4-pyrimidinol (IMPy, of OP insecticide diazinon, 10%). None of these chemicals has previously been detected in human teeth. Molars from the two oldest subjects contained the largest concentrations of MEHP, TCPy, and IMPy. Potentially protective fatty acids detected by gas chromatography/mass spectrometry after derivatization include docosahexaenoic (19%), arachidonic (100%), and linoleic (100%). Validation studies are necessary to verify that each detected chemical in molars provides a biomarker of perinatal exposure.

Chlorpyrifos (CPF) is a widely used organophosphorus (OP) pesticide. CPF is bioactivated by cytochrome P450s (CYPs) to the potent cholinesterase inhibitor chlorpyrifos oxon (CPF-O) or detoxified to 3,5,6-trichloro-2-pyridinol (TCPy). Human CYP2B6 has the highest reported Vmax)/Km (intrinsic clearance--CL(int)) for bioactivation while CYP2C19 has the highest reported CL(int) for detoxification of CPF. In this study, 22 human liver microsomes (HLMs) genotyped for common variants of these enzymes (CYP2B6*6 and CYP2C19*2) were incubated with 10 μM and 0.5 μM CPF and assayed for metabolite production. While no differences in metabolite production were observed in homozygous CYP2C19*2 HLMs, homozygous CYP2B6*6 specimens produced significantly less CPF-O than wild-type specimens at 10 μM (mean 144 and 446 pmol/min/mg, respectively). This correlated with reduced expression of CYP2B6 protein (mean 4.86 and 30.1 pmol/mg, for CYP2B6*6 and *1, respectively). Additionally, CYP2B6*1 and CYP2B6*6 were over-expressed in mammalian COS-1 cells to assess for the first time the impact of the CYP2B6*6 variant on the kinetic parameters of CPF bioactivation. The Vmax for CYP2B6*6 (1.05×10⁵ pmol/min/nmol CYP2B6) was significantly higher than that of CYP2B6*1 (4.13×10⁴ pmol/min/nmol CYP2B6) but the K(m) values did not differ (1.97 μM for CYP2B6*6 and 1.84 μM for CYP2B6*1) resulting in CL(int) rates of 53.5 and 22.5 nL/min/nmol CYP2B6 for *6 and *1, respectively. These data suggest that CYP2B6*6 has increased specific activity but reduced capacity to bioactivate CPF in HLMs compared to wild-type due to reduced hepatic protein expression, indicating that individuals with this genotype may be less susceptible to CPF toxicity.

Chlorpyrifos exposures were assessed in 12 Egyptian cotton field workers.3,5,6-trichloro-2-pyridinol (TCPy) was measured in 24-hour urine samples to estimate absorbed dose. Workshift air samples were used to calculate chlorpyrifos inhalation dose.Patches on legs had the highest chlorpyrifos loading rates among body regions sampled. Geometric mean chlorpyrifos air concentrations were 5·1, 8·2, and 45·0 μg/m(3) for engineers, technicians, and applicators, respectively; peak TCPy urinary concentrations were 75-129, 78-261, and 487-1659 μg/l, respectively; geometric mean doses were 5·2-5·4, 8·6-9·7, and 50-57 μg/kg, respectively, considering TCPy excretion half-life values of 27 and 41 hours. All worker doses exceeded the acceptable operator exposure level of 1·5 μg/kg/day. An estimated 94-96% of the dose was attributed to dermal exposure, calculated as the difference between total dose and inhalation dose.Interventions to reduce dermal exposure are warranted in this population, particularly for the hands, feet, and legs.

The paper presents a case study of the application of a “source-to-outcome” model for the evaluation of the health outcomes from dietary exposures to an insecticide, chlorpyrifos, in populations of adults (age 30) and children (age 3). The model is based on publically-available software programs that characterize the longitudinal dietary exposure and anthropometry of exposed individuals. These predictions are applied to a validated PBPK/PD model to estimate interindividual and longitudinal variation in brain and RBC AChE inhibition (key events) and chlorpyrifos concentrations in blood and TCPy in urine (biomarkers of exposure). The predicted levels of chlorpyrifos and TCPy are compared to published measurements of the biomarkers. Predictions of RBC AChE are compared to levels of inhibition associated with reported exposure-related effects in humans to determine the potential for the occurrence of adverse cholinergic effects. The predicted distributions of chlorpyrifos in blood and TCPy in urine were found to be reasonably consistent with published values, supporting the predictive value of the exposure and PBPK portions of the source-to-outcome model. Key sources of uncertainty in predictions of dietary exposures were investigated and found to have a modest impact on the model predictions. Future versions of this source-to-outcome model can be developed that consider advances in our understanding of metabolism, to extend the approach to other age groups (infants), and address intakes from other routes of exposure.

Introduction The impact of environmental exposure to pesticides from agricultural drift on human health is a major public health concern. The International Agency for Research on Cancer (IARC) has classified several pesticides as carcinogenic or probable carcinogenic to humans. Residential proximity to treated farmland is a source of environmental pesticide exposure and has been associated with increased concentrations of pesticides in residential dust and urine samples. Little is known on the seasonal variations of pesticide concentrations. The SIGEXPOSOME project aims to investigate seasonal variations of the exposure to multiple agricultural pesticides of residents proximate to vineyards and of pesticide applicators in the Beaujolais area of the Auvergne-Rhone-Alpes Region, France. The study is based on a longitudinal study involving overall 185 subjects, with repeated sampling of multiple matrices (residential dust, urine, blood and hair). We report here preliminary results on 19 residents. Methods We sampled morning urine and household dust in 19 non-smoking, men, aged 18 to 65 years, without professional pesticides use, residing in the study area. Sampling was performed in July and October 2015. House dust: We used the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method for extraction and analytical multi-residue methods based on gas chromatography coupled to mass spectrometry (GC–MS) and liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). After analyses of the efficiency and repeatability of the analytical methods for 62 compounds, 53 pesticides were retained for analyses [recovery rate 70–120%; relative standard error (RSD) Results House dust: 40 pesticides out of 53 were quantified, including 11 compounds of high public health priority. Among pesticides with a detection frequency > 70% for at least one of the two sampling periods, we observed significant seasonal variations in prevalence for 10 pesticides (out of 18) and significant differences in concentrations for 14 pesticides: Chlorpyriphos, Cyprodinil, Difenoconazole, DimetomorpheI, DimetomorpheII, Fludioxynil, Indoxacarbe, Kresoxim-methyl, Myclobutanil, SpiroxamineI, SpiroxamineII, Tebuconazole, Trifloxystrobin and Zoxamide with an average concentration higher in July than in October. Urine samples: The LC-HRMS analyses showed the presence of three pesticides metabolites: 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of the organophosphate insecticides chlorpyrifos and chlorpyrifos-methyl; 3-phenoxybenzoic acid (3-PBA), a nonspecific metabolite of the pyrethroid insecticides permethrin, cypermethrin or cyhalothrin; hydroxy- and carboxy-metabolites of tebuconazole. The identity of TCPy and 3-BPA was confirmed by comparison with authentic standards. Conclusion This study, analyzing the seasonal variations of multiple pesticides, is unique in France. House dust of non-professional residents proximate to vineyards showed seasonal variations with higher prevalence and concentrations of agricultural pesticides during the application period. Also, results show the capacity of our screening approach based on LC-HRMS to detect agricultural compounds present at low concentrations in urine. Correlation between residential dust and urine contamination will be further explored as well as association between concentrations of pesticides in house dust and urine, and proximity to treated vineyards, a surrogate for pesticides drift. Funding Auvergne-Rhone-Alpes Region; Metropole Lyon; Canceropole CLARA.

Neurobehavioral deficits have been reported in Egyptian pesticide application teams using organophosphorus (OP) pesticides, but whether these effects are related to OP pesticide exposures has yet to be established. In preparation for a comprehensive study of the relationship between OP pesticide dose and neurobehavioral deficits, we assessed exposure within this population. We conducted occupational surveys and workplace observations, and collected air, dermal patch and biological samples from applicators, technicians and engineers involved in chlorpyrifos applications during cotton production to test the hypotheses that: (1) dermal exposure was an important contributor to internal dose and varied across body regions; and (2) substantial differences would be seen across the three job categories. Applicators were substantially younger and had shorter exposure histories than did technicians and engineers. Applicators and technicians were observed to have relatively high levels of skin or clothing contact with pesticide-treated foliage as they walked through the fields. Both dermal patch loadings of chlorpyrifos and measurements of a chlorpyrifos-specific metabolite (TCPy) in urine confirmed substantial exposure to and skin absorption of chlorpyrifos that varied according to job category; and dermal patch loading was significantly higher on the thighs than on the forearms. These findings support our hypotheses and support the need for research to examine neurobehavioral performance and exposures in this population. More importantly, the exposures reported here are sufficiently high to recommend urgent changes in work practices amongst these workers.

Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of both in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual's contact with both the parent pesticide and exposure to these metabolites in the environment. In the current study, simultaneous dosing of 13C- or 2H-isotopically labeled CPF (13C-labeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare the pharmacokinetics and metabolism of CPF with TCPy, and DETP. The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 micromol/kg; approximately 5 mg/kg CPF). Major differences in the pharmacokinetics between CPF and metabolite doses were observed within the first 3h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (> or =3h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or (2)H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact their pharmacokinetics.

Biological monitoring (biomonitoring) to quantify systemic exposure to the organophosphorus insecticide chlorpyrifos (CPF) has historically focused on the quantitation of major CPF metabolites in urine. Noninvasive techniques are being advocated as novel means of biomonitoring for a variety of potential toxicants, including pesticides (like CPF), and saliva has been suggested as an ideal body fluid. However, in order to be acceptable, there is a need to understand salivary pharmacokinetics of CPF metabolites in order to extrapolate saliva measurements to whole-body exposures. In this context, in vivo pharmacokinetics of 3,5,6-trichloro-2-pyridinol (TCPy), the major chemical-specific metabolite of CPF, was quantitatively evaluated in rat saliva. Experimental results suggest that TCPy partitioning from plasma to saliva in rats is relatively constant over a range of varying physiological conditions. TCPy pharmacokinetics was very similar in blood and saliva (area under the curve values were proportional and elimination rates ranged from 0.007 to 0.019 per hour), and saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood (p = 0.35) or saliva flow rate (p = 0.26). The TCPy concentration in saliva was highly correlated to the amount of unbound TCPy in plasma (r = 0.96), and the amount of TCPy protein binding in plasma was substantial (98.5%). The median saliva/blood concentration ratio (0.049) was integrated as a saliva/blood TCPy partitioning coefficient within an existing physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF. The model was capable of accurately predicting TCPy concentrations in saliva over a range of blood concentrations. These studies suggest that saliva TCPy concentration can be utilized to ascertain CPF exposure. It is envisioned that the PBPK/PD can likewise be used to estimate CPF dosimetry based on the quantitation of TCPy in spot saliva samples obtained from biomonitoring studies.

Concerns about reproductive and developmental health risks of exposure to organophosphate (OP) pesticides, phthalates, and bisphenol A (BPA) among the general population are increasing. Six dialkyl phosphate (DAP) metabolites, 3,5,6-trichloro-2-pyridinol (TCPy), BPA, and fourteen phthalate metabolites were measured in 10 pooled urine samples representing 110 pregnant women who participated in the Norwegian Mother and Child Birth Cohort (MoBa) study in 2004. Daily intakes were estimated from urinary data and compared with reference doses (RfDs) and daily tolerable intakes (TDIs). The MoBa women had a higher mean BPA concentration (4.50 mu g/L) than the pregnant women in the Generation R Study (Generation R) in the Netherlands and the National Health and Nutrition Examination Survey (NHANES) in the United States. The mean concentration of total DAP metabolites (24.20 mu g/L) in MoBa women was higher than that in NHANES women but lower than that in Generation R women. The diethyl phthalate metabolite mono-ethyl phthalate (MEP) was the dominant phthalate metabolite in all three studies, with the mean concentrations of greater than 300 mu g/L. The MoBa and Generation R women had higher mean concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) than the NHANES women. The estimated average daily intakes of BPA, chlorpyrifos/chlorpyrifos-methyl and phthalates in MoBa (and the other two studies) were below the RfDs and TDIs. The higher levels of metabolites in the MoBa participants may have been from intake via pesticide residues in food (organophosphates), consumption of canned food, especially fish/seafood (BPA), and use of personal care products (selected phthalates). Published by Elsevier GmbH.

Nearly 40% of the Egyptian workforce is employed in agriculture. The cotton industry relies on children and adolescents, who work seasonally, to apply pesticides to the cotton crops. Although previous research has examined adult pesticide exposures in this workforce in Egypt, no research has examined the health effects in adolescents. This study attempts to systematically replicate findings examining the impact of organophosphate pesticide (OP) exposure in adults on Arabic speaking children working as applicators. The aim of this study was to examine the impact of pesticide exposure on children and adolescents spraying cotton fields. Male children currently applying pesticides between the ages of 9 and 15 (Younger, n=30) and 16 and 19 (Older, n=20) were recruited for the study. They completed a neurobehavioral test battery; personality inventory; work, health, and exposure questionnaires; and medical and neurological screening exams. Blood samples were collected to measure acetylcholinesterase. Children not working in agriculture, matched on age and education, served as controls. Both Younger and Older applicator groups, performed significantly worse than the controls on the majority of neurobehavioral tests controlling for age and years of education. The applicators reported significantly more neurological symptoms than the controls and had lower acetylcholinesterase activity. A dose-effect relationship demonstrated that increased years of exposure to organophosphate pesticides is associated with cognitive deficits. This is one of the several studies demonstrating that functional cognitive effects are positively correlated with increased years of exposure to OP pesticides, though primarily in adult populations, building confidence in the association. Since children around the world are exposed to OP pesticides, these studies suggest that the need to evaluate this potential problem is urgent.

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply. Current "background" (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase. However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association. Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms. Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized.

Direct measurements of exposure represent the most accurate assessment of a subject's true exposure. The clearance of many drugs and chemicals, including pesticides such as chlorpyrifos (CPF), can be detected non-invasively in saliva. Here we have developed a serous-acinar transwell model system as an in vitro screening platform to prioritize chemicals for non-invasive biomonitoring through salivary clearance mechanisms. Rat primary serous-acinar cells express both α-amylase and aquaporin-5 proteins and develop significant tight junctions at postconfluence - a feature necessary for chemical transport studies in vitro. CPF exhibited bidirectional passage across the serous-acinar barrier that was disproportional to the passage of a cell impermeable chemical (lucifer yellow), consistent with a hypothesized passive diffusion process. CPF was metabolized to trichlorpyridinol (TCPy) by serous-acinar cells, and TCPy also displayed bidirectional diffusion in the transwell assay. This model system should prove useful as an in vitro screening platform to support the non-invasive monitoring of toxicons and pharmacons in human saliva and provide guidance for development of advanced in vitro screening platforms utilizing primary human salivary gland epithelial cells.

Background: This cross-sectional study aimed to investigate the relationship between urinary pesticide residue levels and neurotoxic symptoms amongst women working on Western Cape farms in South Africa. Method: A total of 211 women were recruited from farms (n = 121) and neighbouring towns (n = 90). Participant assessment was via a Q16 questionnaire, reporting on pesticide exposures and measurement of urinary OP metabolite concentrations of dialkyl phosphates (DAP) and chlorpyriphos, 3,5,6-trichloropyridinol (TCPY) and of pyrethroid (PYR) metabolite concentrations (3- phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the cis- and trans isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid. Results: Median urinary pesticide metabolites were slightly (6%–49%) elevated in the farm group compared to the town group, with 2 metabolites significantly higher and some lower in the farm group. The prevalence of all Q16 symptoms was higher amongst farm women compared to town women. Three Q16 symptoms (problems with buttoning, reading and notes) were significantly positively associated with three pyrethroid metabolites (cis- and trans-DCCA and DBCA), although associations may due to chance as multiple comparisons were made. The strongest association for a pyrethroid metabolite was between problems with buttoning and DBCA (odds ratio (OR) = 8.93, 95% confidence interval (CI):1.71–46.5. There was no association between Q16 symptoms and OP metabolites. Conclusions: Women farm residents and rural women from neighbouring towns in the Western Cape are exposed to OP and PYR pesticides. The study did not provide strong evidence that pesticides are associated with neurotoxic symptoms but associations found could be explored further.

Exposure to organophosphate (OP) insecticides may alter reproductive hormone levels in men and increase the risk for poor reductive health and other adverse health outcomes. However, relevant epidemiology studies in men are limited. We evaluated urinary concentrations of OP metabolites (3,5,6-trichloro-2-pyridinol and six dialkyl phosphates) in relation to serum concentrations of testosterone (T) and estradiol among 356 men aged 20–55 years old from the U.S. National Health and Nutrition Examination Survey. Biomarkers were detected in greater than 50% of the samples, except for diethyldithiophosphate, dimethylphosphate, and dimethyldithiophosphate. In adjusted regression models, we observed a statistically significant inverse relationship between diethyl phosphate (DEP) and T when DEP was modeled as either a continuous or categorical variable. These findings add to the limited evidence that exposure to certain OP insecticides is linked to altered T in men, which may have important implications for male health.

We report population-based concentrations (stratified by age, sex, and composite race/ethnicity variables) of selective metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol; TCPY), chlorpyrifos methyl (TCPY), malathion (malathion dicarboxylic acid; MDA), diazinon (2-isopropyl-4-methyl-6-hydroxypyrimidine; IMPY), methyl parathion (para-nitrophenol; PNP), and parathion (PNP). We measured the concentrations of TCPY, MDA, IMPY, and PNP in 1997 urine samples from participants, aged 6-59 years, of the National Health and Nutrition Examination Survey, 1999-2000. We detected TCPY in more than 96% of the samples tested. Other organophosphorus pesticide metabolites were detected less frequently: MDA, 52%; IMPY, 29%; and PNP, 22%. The geometric means for TCPY were 1.77 microg/L and 1.58 microg/g creatinine. The 95th percentiles for TCPY were 9.9 microg/L and 8.42 microg/g creatinine. The 95th percentiles for MDA were 1.6 microg/L and 1.8 microg/g creatinine. The 95th percentiles for IMPY and PNP were 3.7 microg/L (3.4 microg/g creatinine) and 5.0 microg/L (4.2 microg/g creatinine), respectively. Multivariate analyses showed that children aged 6-11 years had significantly higher concentrations of TCPY than adults and adolescents. Similarly, adolescents had significantly higher TCPY concentrations than adults. Although the concentrations between sexes and among composite racial/ethnic groups varied, no significant differences were observed.

The importance of “judicious use of language in regard to public communication of pesticide health risks” (Lu et al. 2006b) is clearly recognized and acknowledged in recent letters from Avery (2006) and Lu et al. (2006b). Their correspondence concerned perceptions of risk conveyed by the article “Organic Diets Significantly Lower Children’s Dietary Exposure to Organophosphorous Pesticides,” published by Lu et al. (2006a). My concern is more fundamental than the need for effective communication and the stated “public misunderstanding of this important issue” (Lu et al. 2006b). I believe the primary issue concerns science and how we accumulate knowledge. There is no guarantee that judicious use of language can prevent misunderstanding of even the most rigorous and carefully performed studies. It is important, however, to put the results into the existing scientific and regulatory contexts. Lu et al. (2006a) noted that “the paucity of exposure data renders the debate over pesticide-related health risks in children controversial.” Curl et al. (2003) stated that “reduction of children’s risk from pesticides requires an understanding of the pathways by which exposure occurs.” The primary objective of the longitudinal study by Lu et al. (2006a) was determination of “overall pesticide exposure in a group of elementary school-age children.” The authors reported that children who consumed organic diets eliminated (via urine) nondetectable amounts of organophosphorous (OP) insecticide metabolites. The finding supports the consensus that the diet is the predominant source of OP compounds and OP metabolites excreted in urine (Barr et al. 2004; Duggan et al. 2003; Krieger et al. 2003). Lu et al. (2006a) claimed “a convincing demonstration of the ability of organic diets to reduce children’s OP pesticide exposure and the health risks that may be associated with these exposures.” When the study was developed and throughout the period of data collection, analysis, and publication by the University of Washington investigators, there could be no doubt that dietary exposures were very low or miniscule relative to acute toxicity (Curl et al. 2003). Indeed, it is intuitive that the change in diet reduced OP metabolite elimination in urine. If this were not the case, one might expect parked cars to get speeding tickets. Specific health risks have never been associated with such miniscule insecticide exposures. If risk is defined as the likelihood of an adverse effect in an exposed population, the risk of neurotoxicity caused by these dietary OP exposure(s) is zero; that is, disease has not been observed in the population who consumes food that sometimes contains OP pesticides or OP metabolite residues (Krieger et al. 2003). Back-calculated OP exposures are well below the experimental lowest observed adverse effect level (LOAEL), the estimated no observed adverse effect level (NOAEL), and the regulatory reference dose (RfD) for neurotoxicity of any OP insecticide used in crop protection (Barr et al. 2004; Duggan et al. 2003; Fenske et al. 2000). The research is misrepresented with respect to its relevance to risk reduction (that is the point of the fundamental “observed” in the LOAEL and the NOAEL upon which RfDs are based). With zero cases of disease in the population exposed to dietary OP pesticide, the numerator of measurements of risk such as odds ratios or relative risk is also zero. As a result, measured risk of acute neurotoxicity is zero. The axiomatic truth that “dose determines a poison” and its corollary that “there is a safe level of everything” must both be considered in responsible risk communication. Careful choice of words may sometimes prevent misunderstanding of health research reports, but more importantly our common understanding and well-being require that we clearly distinguish chemical exposure and health risk. Lu et al. (2006a) wrote, We were able to demonstrate that an organic diet provides a dramatic and immediate protective effect against exposure to organophosphorus pesticides that are commonly used in agricultural production. Their findings are expected rather than dramatic, and the term “protective” in reference to a no observed effect exposure is misleading at best. Effective communication requires awareness that potential impacts of conjecture about matters of health and pesticides likely include heightened anxiety and fear, and may prompt misallocation of resources as some persons pursue something less than zero risk—a point where scientific evidence and mystical, supernatural beliefs must be distinguished.

Most of the general population is exposed to carbaryl and other contemporary-use insecticides at low levels. Studies of laboratory animals, in addition to limited human data, show an association between carbaryl exposure and decreased semen quality. In the present study we explored whether environmental exposures to 1-naphthol (1N), a metabolite of carbaryl and naphthalene, and 3,5,6-trichloro-2-pyridinol (TCPY), a metabolite of chlorpyrifos and chlorpyrifos-methyl, are associated with decreased semen quality in humans. Subjects (n=272) were recruited through a Massachusetts infertility clinic. Individual exposures were measured as spot urinary concentrations of 1N and TCPY adjusted using specific gravity. Semen quality was assessed as sperm concentration, percent motile sperm, and percent sperm with normal morphology, along with sperm motion parameters (straight-line velocity, curvilinear velocity, and linearity). Median TCPY and 1N concentrations were 3.22 and 3.19microg/L, respectively. For increasing 1N tertiles, adjusted odds ratios (ORs) were significantly elevated for below-reference sperm concentration (OR for low, medium, and high tertiles = 1.0, 4.2, 4.2, respectively; p-value for trend =0.01) and percent motile sperm (1.0, 2.5, 2.4; p-value for trend = 0.01). The sperm motion parameter most strongly associated with 1N was straight-line velocity. There were suggestive, borderline-significant associations for TCPY with sperm concentration and motility, whereas sperm morphology was weakly and nonsignificantly associated with both TCPY and 1N. The observed associations between altered semen quality and 1N are consistent with previous studies of carbaryl exposure, although suggestive associations with TCPY are difficult to interpret because human and animal data are currently limited.

We measured two diethyl organophosphorus (OP) pesticides--chlorpyrifos and parathion--in residences, and their metabolic by-products, in the urine of children 6 years old or younger in a central Washington State agricultural community. Exposures to two dimethyl OP pesticides (azinphos-methyl and phosmet) in this same population have been reported previously. We categorized children by parental occupation and by household proximity to pesticide-treated farmland. Median chlorpyrifos house dust concentrations were highest for the 49 applicator homes (0.4 microg/g), followed by the 12 farm-worker homes (0.3 microg/g) and the 14 nonagricultural reference homes (0.1 microg/g), and were statistically different (p < 0.001); we observed a similar pattern for parathion in house dust. Chlorpyrifos was measurable in the house dust of all homes, whereas we found parathion in only 41% of the homes. Twenty-four percent of the urine samples from study children had measurable 3,5,6-trichloro-2-pyridinol (TCPy) concentrations [limits of quantitation (LOQ) = 8 microg/L], and 7% had measurable 4-nitrophenol concentrations (LOQ = 9 microg/L). Child urinary metabolite concentrations did not differ across parental occupational classifications. Homes in close proximity (200 ft/60 m) to pesticide-treated farmland had higher chlorpyrifos (p = 0.01) and parathion (p = 0.014) house dust concentrations than did homes farther away, but this effect was not reflected in the urinary metabolite data. Use of OP pesticides in the garden was associated with an increase in TCPy concentrations in children's urine. Parathion concentrations in house dust decreased 10-fold from 1992 to 1995, consistent with the discontinued use of this product in the region in the early 1990s.

The use of pesticides for crop production has grown rapidly in Thailand during the last decade, resulting in significantly greater potential for exposure among children living on farms. Although some previous studies assessed exposures to pesticides in this population, no studies have been conducted to evaluate corresponding health effects. Twenty-four children from a rice farming community (exposed) and 29 from an aquaculture (shrimp) community (control) completed the study. Participants completed a neurobehavioral test battery three times at 6 month intervals: Session I: preliminary orientation; Session II: high pesticide use season; Session III: low pesticide-use season. Only sessions II and III were used in the analyses. High and low pesticide use seasons were determined by pesticide use on rice farms. Urinary metabolites of organophosphates (OPs) and pyrethroids (PYR) were analyzed from first morning void samples collected the day of neurobehavioral testing. Rice farm participants had significantly higher concentrations of dialkylphosphates (DAPs) (common metabolites of OPs) and TCPy (a specific metabolite of chlorpyrifos) than aquaculture farm children during both seasons. But, TCPy was significantly higher during the low rather than the high pesticide use season for both participant groups. Rice farm children had significantly higher DCCA, a metabolite of PYR, than aquaculture participants only during the high exposure season. Otherwise, no significant differences in PYR metabolites were noted between the participant groups or seasons. No significant adverse neurobehavioral effects were observed between participant groups during either the high or low pesticide use season. After controlling for differences in age and the Home Observation for Measurement of the Environment (HOME) scores, DAPs, TCPy, and PYR were not significant predictors of adverse neurobehavioral performance during either season. Increasing DAP and PYR metabolites predicted some relatively small improvement in latency of response. However, due to the small sample size and inability to characterize chronic exposure, any significant differences observed should be regarded with caution. Moreover although not statistically significant, confidence intervals suggest that small to moderate adverse effects of pesticide exposure cannot be ruled out for some indicators of neurobehavioral performance.

Chlorpyrifos (CPF) and profenofos (PFF) are organophosphorus (OP) insecticides that are applied seasonally in Egypt to cotton fields. Urinary trichloro-2-pyridinol (TCPy), a specific CPF metabolite, and 4-bromo-2-chlorophenol (BCP), a specific PFF metabolite, are biomarkers of exposure, while inhibition of blood butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities are effect biomarkers that may be associated with neurotoxicity. Urinary TCPy and BCP and blood BChE and AChE activities were measured in 37 adult Egyptian Ministry of Agriculture workers during and after 9-17 consecutive days of CPF application followed by an application of PFF (9-11 days), and a second CPF application (5 days) in 2008. During the OP applications, urinary TCPy and BCP levels were significantly higher than baseline levels, remained elevated following the application periods, and were associated with an exposure related inhibition of blood BChE and AChE. Analysis of blood AChE levels before and after the PFF application period suggests that individual workers with peak BCP levels greater than 1000 μg/g creatinine exhibited further inhibition of blood AChE with PFF application, demonstrating that PFF exposure had a negative impact on AChE activity in this highly exposed worker population. While large interindividual differences in exposure were observed throughout this longitudinal study (peak urinary BCP and peak TCPy levels for individuals ranging from 13.4 to 8052 and 16.4 to 30,107 μg/g creatinine, respectively), these urinary biomarkers were highly correlated within workers (r=0.75, p

Chlorpyrifos is a common agricultural insecticide and has been used residentially in the United States until the year 2000 when this use was restricted by the U.S. Environmental Protection Agency (U.S. EPA). A chlorpyrifos metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) has been found in urine samples collected during exposure field studies. In this work, we use urinary biomarker data and the inverse solution of a simple pharmacokinetic (PK) model for chlorpyrifos to estimate the magnitude and timing of doses. Three urine samples were collected on separate days from each of 15 children (ages 3-12) who were participants in the Minnesota Children's Pesticide Exposure Study (MNCPES). The total volume of urine was noted and samples analyzed for TCPY: The urinary data was used along with constraints imposed on dose timing, based on responses of the individuals to pesticide-use surveys. We predicted the time and magnitude of multiple "event" exposures characterized by short-term, relatively high doses superimposed over a continuous background exposure. The average dose of chlorpyrifos predicted by the model was 1.61 microg/kg per reported event. Average background dose rate for these children that reported exposure events was 0.0062 microg/kg/h, or 0.15 microg/kg/day. In addition to predicting the total dose of chlorpyrifos received by an individual from urinary biomarker measurements, the model can then be run in a forward manner once the exposure regime is determined. This will allow the prediction of the total amount of TCPy eliminated in the urine over any time period of interest.

The Minnesota Children's Pesticide Exposure Study is a probability-based sample of 102 children 3-13 years old who were monitored for commonly used pesticides. During the summer of 1997, first-morning-void urine samples (1-3 per child) were obtained for 88% of study children and analyzed for metabolites of insecticides and herbicides: carbamates and related compounds (1-NAP), atrazine (AM), malathion (MDA), and chlorpyrifos and related compounds (TCPy). TCPy was present in 93% of the samples, whereas 1-NAP, MDA, and AM were detected in 45%, 37%, and 2% of samples, respectively. Measured intrachild means ranged from 1.4 microg/L for MDA to 9.2 microg/L for TCPy, and there was considerable intrachild variability. For children providing three urine samples, geometric mean TCPy levels were greater than the detection limit in 98% of the samples, and nearly half the children had geometric mean 1-NAP and MDA levels greater than the detection limit. Interchild variability was significantly greater than intrachild variability for 1-NAP (p = 0.0037) and TCPy (p < 0.0001). The four metabolites measured were not correlated within urine samples, and children's metabolite levels did not vary systematically by sex, age, race, household income, or putative household pesticide use. On a log scale, mean TCPy levels were significantly higher in urban than in nonurban children (7.2 vs. 4.7 microg/L; p = 0.036). Weighted population mean concentrations were 3.9 [standard error (SE) = 0.7; 95% confidence interval (CI), 2.5, 5.3] microg/L for 1-NAP, 1.7 (SE = 0.3; 95% CI, 1.1, 2.3) microg/L for MDA, and 9.6 (SE = 0.9; 95% CI, 7.8, 11) microg/L for TCPy. The weighted population results estimate the overall mean and variability of metabolite levels for more than 84,000 children in the census tracts sampled. Levels of 1-NAP were lower than reported adult reference range concentrations, whereas TCPy concentrations were substantially higher. Concentrations of MDA were detected more frequently and found at higher levels in children than in a recent nonprobability-based sample of adults. Overall, Minnesota children's TCPy and MDA levels were higher than in recent population-based studies of adults in the United States, but the relative magnitude of intraindividual variability was similar for adults and children.

As part of a longitudinal investigation of environmental exposures to selected chemical contaminants, concentrations of the pesticide metabolites 1-naphthol (INAP), 3,5,6-trichloro-2-pyridinol (TCPY), malathion dicarboxylic acid (MDA), and atrazine mercapturate (AM) were measured in repeated samples obtained from 80 individuals in Maryland during 1995-1996. Up to six urine samples were collected from each individual at intervals of approximately 8 weeks over a 1-year period (i.e., one sample per participant in each of six cycles). INAP (median=4.2 microg/l and 3.3 microg/g creatinine) and TCPY (median=5.3 microg/l and 4.6. microg/g creatinine) were present in over 80% of the samples, while MDA and AM were detected infrequently (6.6% and