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The aim of the study was to evaluate the association between environmental exposure to nonpersistent insecticides and semen quality (concentration, motility, morphology, computer-aided semen analysis [CASA] parameters, and sperm DNA damage). Urine samples ( n = 315) collected from men who attended the infertility clinic with normal semen concentration of 15 to 300 mln/ml and age under 45 years were analyzed for two metabolites (1-naphthol [1N] and 3,5,6-trichloro-2-pyridinol [TCPY]) of nonpersistent insecticides. Participants provided semen, blood, and saliva samples; additionally, men filled a detailed questionnaire. The results identified that urinary TCPY concentration was significantly associated with a decrease in motility; also there was a positive association between TCPY and DNA fragmentation index (DFI). 1N concentration was negatively associated with a percentage of sperm with normal morphology and positively with one of the CASA parameters (curvilinear velocity [VCL]). The results suggest that environmental exposure to nonpersistent insecticides may have an impact on semen quality parameters and sperm DNA damage.

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. [ABSTRACT FROM PUBLISHER]

3,5,6-trichloropyridinol (TCPY) is a metabolite of chlorpyrifos and chlorpyrifos-methyl, whose presence in the environment is of potential toxicity to human. So, it is need to monitor and regualte TCPY levels to protect human health. However, it is not known whether TCPY is associated with all-cause and cancer mortality and to which degree its levels contributed to hazard risk. The study enrolled 3951 participants from the National Health and Nutrition Examination Surveys (NHANES). Ultra-high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry was used to measure urinary TCPY. Cox proportional hazards regression analysis was performed to explore the associations between TCPY and all-cause and cancer mortality. The study found that the average level of TCPY in the cohort was 1.79 μg/L and was higher in those who had passed away. Individuals in the highest quartile had a 1.56-fold independent increase in rate for all-cause mortality compared to those in the lowest quartile (hazard ratio [HR] 1.56, 95% confidence interval 1.09–2.24, p = 0.002). However, while the univariate model showed a hazard ratio of 2.37 (1.19–4.71) for the highest quartile in regards to cancer mortality, this association disappeared after adjusting for demographics, lifestyles, and comorbidities. Exposure to urinary 3,5,6-trichloropyridinol, as a result of insecticide exposure, increased the rate of all-cause mortality but was not independently associated with cancer mortality. [ABSTRACT FROM AUTHOR]

The compound 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of the broad-spectrum organophosphorus insecticide chlorpyrifos, is both more persistent and more water soluble than its parent compound. This difference, which allows TCPy to more readily leach into surface water and groundwater, has led to widespread contamination of TCPy in soils and aquatic environments. In this study, the degradation of TCPy by sulfate radicals was evaluated using zero valent iron activated persulfate in aqueous media. Response surface methodology coupled with Box-Behnken design was applied to evaluate the effects of the independent variables (concentration of zero valent iron, concentration of persulfate, and pH) on the mineralization of TCPy by zero valent iron activated persulfate system. The interactions, coefficients, and residuals of these variables were statically evaluated by analysis of variance. Based on the model, the optimum conditions for maximum TCPy mineralization were determined as 10.4mM of persulfate, 1.2 g/L of zero valent iron and an initial pH of 3.2. The reaction kinetics of the degradation process were examined as functions of persulfate concentration, zero valent iron concentration, and pH. Results show that zero valent iron activated persulfate can effectively remove TCPy in water with a high mineralization rate of up to 81.1%. The degradation pathways of TCPy were proposed based on the products identified by GC-MS. Calculated ΔG values using density functional theory agreed with the proposed experimental pathway. [ABSTRACT FROM AUTHOR]

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 salivamedium) conditions using 3,5,6-trichloro-2-pyridinol (TCPy) ametabolite 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 cellularmonolayer. In the physiological experiment, TCPy transport was slower than nonphysiological conditions, and equilibriumwas achieved at different concentrations in apical and basolateral chambers at a comparable ratio (0.034) to what was previouslymeasured in rats dosed with TCPy (saliva:blood ratio: 0.049). A cellular transport computationalmodel 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 computationalmodel 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. [ABSTRACT FROM AUTHOR]

Research focus: Chlorpyrifos is an organophosphate insecticide used primarily to control pests on a variety of food and feed crops. Humans are directly or indirectly exposed to this pesticide through food, air, and occupation. The ill effects of chlorpyrifos on various organ systems of human has been widely documented, but less is known about its influence on human bones. Aim: To analyze the effect of chlorpyrifos and its metabolites 3,5,6‐trichloro‐2‐pyridinol (TCPy) on the skeletal system of the chick embryo. Materials and Methods: Fertilized chick eggs were exposed to different concentrations of chlorpyrifos and its metabolite 3,5,6‐TCPy on 1.5 days of incubation. The proximal phalanx of 18‐day‐old embryos was analyzed for defects in growth and ossification through histopathology, immunohistochemistry, angiogenesis assay, and gene expression study. Results: Dose‐dependent variations in developing bone of chick embryo were observed. Histochemical and histomorphometry studies of proximal phalanx showed increased in the growth plate length (F(9, 59) = 228.9509, p =.00001) with a reduction in the total length of the phalanx (F(9, 59) = 109.9905, p =.00001), decreased mineralization (F(9, 59) = 224.6872, p =.00001), decreased blood islands in the bone marrow (F(9, 59) = 7.7083, p =.0001) of chlorpyrifos, and 3,5,6‐TCPy‐exposed group. Significant downregulations in the expression patterns of the transcription factors, such as SOX9, RUNX2, and ALP, were also observed. Conclusion: Chlorpyrifos and its metabolite 3,5,6‐TCPy exposure alters the chondrogenesis in the growth plate cartilage of long bone in chick embryo. The pesticide and its metabolite also interfere in ossification. [ABSTRACT FROM AUTHOR]

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

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

A series of regioisomeric monoaryl‐substituted pyridines containing a tricyanobutadiene fragment were prepared using modified known and novel developed synthetic approaches. Advantages and limitations of the used methods were discussed. Dependence of the optical absorption and emission characteristics on the position of aromatic substituent was studied. An unusual intramolecular charge transfer from malononitrile fragment to the pyridine ring was found, which was consistent with observed experimental and theoretical data. [ABSTRACT FROM AUTHOR]

In order to investigate the effect of diazinon and chlorpyrifos on agricultural workers exposed to pesticides, urinary metabolites 2-Isopropyl-6-methyl-4-pyrimidinol (IMPy) and 3,5,6-Trichloro-2-pyridinol (TPCy) in farm workers, sprayer operators, and non-exposed people as a control group were measured. The modified QuEChERS method was applied to extract samples and was measured using a gas chromatograph/nitrogen-phosphorus detector. The obtained results showed that the median concentrations of TCPy were 36.92–547.7 and 7.7–49.58 ng/mL for sprayer operators and farm workers, respectively. Moreover, the median concentrations of IMPy were 81.66–593.1 ng/mL for sprayer operators and 40.6–66.1 ng/mL for farm workers. The control group had no measurable metabolites. The IMPy level of 60% of sprayer operators was significantly higher (P ˂ 0.05) than the TCPy level. The analysis of variance highlighted the significant relationship (P ˂ 0.05) between the levels of each metabolite and the use of safety gloves, respiratory masks, safety goggles, working time per week, and type of insecticide exposure. Our findings revealed the need to measure the urinary metabolites of these insecticides in other exposed workers. Also, workers should be taught the impact of using personal protective equipment. [ABSTRACT FROM AUTHOR]

Data from National Health and Nutrition Examination Survey for the years 2007-2008 were used to evaluate the association between serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3), total thyroxine (TT4), and thyroglobulin (TGN) with the urinary levels of 3,5,6-trichloro-2-pyridinol (TCPY). Gender-stratified regression models with log10-transformed values of thyroid hormones as dependent variables and TCPY tertiles, age, race/ethnicity, smoking and iodine sufficiency statuses, fasting time, body mass index, and poverty income ratio as independent variables were fitted. TCPY levels were not found to be associated with the levels of TSH, FT3, FT4, and TT3 for either males or females. TCPY levels in the third tertile as compared to first tertile were found to be negatively associated ( p ≤ 0.01) with TT4 levels for both males and females. TGN levels for those males who were in third tertile of TCPY were statistically significantly lower ( p < 0.01) than for those who had their TCPY levels in first or second tertile. Irrespective of age, gender, race/ethnicity, and smoking status, unadjusted TCPY levels for the period 2009-2010 were statistically significantly lower ( p < 0.01) than TCPY levels during the period 2001-2002. TCPY levels for 2009-2010 were as low as 35.8% of what they were in 2001-2002 for adolescents and not more than 56.9% of what they were for 2001-2002 for males. [ABSTRACT FROM AUTHOR]

Pesticide handlers and pet owners who use products such as shampoos and dips and insecticide-impregnated collars to treat and control fleas on companion animals are exposed to a variety of active ingredients. Chlorpyrifos exposures of adults and children were measured using urine biomonitoring following use of over-the-counter products on dogs. Age and gender-specific measurements of urinary 3, 5, 6-trichloro-2-pyridinol (TCPy) revealed modest elevations of biomarker excretion following shampoo/dips. Smaller TCPy increments were measured following application of impregnated dog collars. The extent of indoor activity and potential pet contact were important determinants of urine biomarker level. Children without direct pet contact excreted more TCPy following collar application. Pet collars may be a source of indoor surface contamination and human exposure. Children excreted up to 4 times more TCPy than adults when urine volumes were adjusted using age-specific creatinine excretion levels. Although chlorpyrifos is no longer used in the United States in pet care products, results of this research provide perspective on the extent of human exposure from similar pet care products. These pilot studies demonstrated that pet care products such as insecticidal shampoos and dips and impregnated collars may expose family members to low levels of insecticide relative to toxic levels of concern. [ABSTRACT FROM AUTHOR]

The tcpRXABCYD operon of Cupriavidus necator JMP134 is involved in the degradation of 2,4,6-trichlorophenol (TCP). All of the gene products except TcpY have assigned functions in TCP metabolism. Sequence comparison identified TcpY as a member of COG4313, a group of hypothetical proteins. TcpY has a signal peptide, indicating it is a membrane or secreted protein. Secondary structure and topology analysis indicated TcpY as a β-barrel outer membrane protein, similar to the Escherichia coli outer membrane protein FadL that transports hydrophobic long-chain fatty acids. Constitutive expression of tcpY in two C. necator strains rendered the cells more sensitive to TCP and other polychlorophenols. Further, C. necator JMP134 expressing cloned tcpY transported more TCP into the cell than a control with the cloning vector. Thus, TcpY is an outer membrane protein that facilitates the passing of polychlorophenols across the outer membrane of C. necator. Similarly, other COG4313 proteins are possibly outer membrane transporters of hydrophobic aromatic compounds. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorpyrifos (CPF), and previous studies have suggested consistent partitioning of 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of CPF, into saliva after exposure to TCPy. The objective of this study was to quantitatively evaluate in vivo pharmacokinetics and pharmacodynamics of CPF and TCPy in saliva after CPF administration. Rats were coadministered CPF (0.5–5mg/kg) and pilocarpine (~13mg/kg) iv. Saliva and blood were collected, and levels of CPF, TCPy, and cholinesterase (ChE) activity were quantified. Experimental results suggest that CPF is rapidly metabolized after iv administration. Formation of TCPy from administered CPF at the low dose (0.5mg/kg) was slower than from higher CPF doses, potentially due to differences in plasma protein binding to CPF. CPF was measured in saliva only at the first time point sampled (0–15min), indicating low partitioning and rapid metabolism. After formation, TCPy pharmacokinetics were very similar in blood and saliva. Saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood, saliva flow rate, or salivary pH and were consistent with previous studies. ChE activity in plasma demonstrated a dose-dependent decrease, and ChE activity in saliva was extremely variable and demonstrated no dose relationship. A physiologically based pharmacokinetic and pharmacodynamic model for CPF was modified and predicted the data reasonably well. It is envisioned that a combination of biomonitoring compounds like TCPy in saliva coupled with computational modeling will form an approach to measure pesticide exposure to susceptible human populations such as agricultural workers. [ABSTRACT FROM PUBLISHER]

Purpose: Chlorpyrifos (CPF) is one of the most widely used organophosphorous pesticides in China. However, few reports on CPF pesticide exposure and body burden of infants at 2 years of age in China are available. The aim of this study was to assess the exposure level and the absorbed daily dose (ADD) of CPF among infants from an agricultural area of Jiangsu, China, and determine whether the infants' estimated dose exceeds the recommended reference dose (RfD) and the population adjusted dose (PAD) set by U.S. Environmental Protection Agency (EPA). Methods: In our study, 364 infants at 2 years of age who lived in the agricultural area of Jiangsu Province (China) were enrolled into the biomonitoring study from June 2011 to January 2012. CPF exposure was estimated based on both questionnaire survey and measured results of urinary metabolite 3,5,6-trichloro-2-pyridinol (TCPy) of CPF by high-performance liquid chromatography. Furthermore, the ADD of CPF among infants was also evaluated and compared with the RfD and the PAD values issued by EPA. Results: Urinary TCPy was detected in more than 70 % of the urine samples among 364 infants. The unadjusted and creatinine-adjusted geometric means in these subjects for TCPy were 1.33 μg/L and 6.73 μg/g Cre., respectively. Infants lived nearby (100 m distance) plantations or green parks present significantly higher levels of urinary TCPy than those lived far away ( p = 0.045). Urinary TCPy levels were also significantly higher in infants who had frequent hand-to-mouth activities than those with less frequency ( p = 0.037). Urinary TCPy concentrations in the infants at 2 years of age in Jiangsu were lower than those in the children at 2-6 years of age in the USA. The median estimated ADD of CPF in this study (0.07 μg/kg/day) was much lower than the acute and chronic RfDs (5 and 0.3 μg/kg/day, respectively) announced by EPA, but higher than the chronic PAD (cPAD) (0.03 μg/kg/day) for children. Additionally, the 75th percentile of the estimated ADD in our study was 2.5 times as much as the cPAD from EPA, even assuming only half of the TCPy amount from CPF exposure. Conclusions: Our findings revealed that infants at 2 years of age in Jiangsu of China were widely exposed to CPF pesticide. The estimated ADD probably suggested that about 25 % of the enrolled infants were at potential risk of pesticide exposure, which warned of urgency to eliminate the potential exposure risk to infants living in agricultural areas of China. [ABSTRACT FROM AUTHOR]

Pesticides are products developed to prevent, destroy, repel or control certain forms of plant or animal life that are considered to be pests. However, now they are one of the critical risk factors threatening the environment, and they create a significant threat to the health of children. Organophosphate (OP) and pyrethroid (PYR) pesticides are widely used in Turkey as well as all over the world. The main focus of this presented study was to analyze the OP and PYR exposure levels in urine samples obtained from 3- to 6-year-old Turkish preschool children who live in the Ankara (n:132) and Mersin (n:54) provinces. In order to measure the concentrations of three nonspecific metabolites of PYR insecticides and four nonspecific and one specific metabolite of OPs, liquid chromatography–tandem mass spectrometry (LC–MS/MS) analyses were performed. The nonspecific PYR metabolite 3-phenoxybenzoic acid (3-PBA) found in 87.1% of samples (n = 162) and the specific OP metabolite 3,5,6-trichloro-2-pyridinol (TCPY) found in 60.2% of samples (n = 112) were the most frequently detected metabolites in all urine samples. The mean concentrations of 3-PBA and TCPY were 0.38 ± 0.8 and 0.11 ± 0.43 ng/g creatinine, respectively. Although due to the large individual variation no statistically significant differences were found between 3-PBA (p = 0.9969) and TCPY (p = 0.6558) urine levels in the two provinces, significant exposure differences were determined both between provinces and within the province in terms of gender. Risk assessment strategies performed in light of our findings do not disclose any proof of a possible health problems related to analyzed pesticide exposure in Turkish children. [ABSTRACT FROM AUTHOR]