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The monitoring and precise determination of pesticides and pharmaceutical drugs and their residues have become increasingly important in the field of food safety and water contamination issues. Herein, a fluorescent aluminium MOF-based sensor (1) was developed for the selective recognition of neonicotinoid insecticide dinotefuran and anti-Parkinson's drug entacapone. Guest-free MOF 1' exhibited ultra-fast response (<5 s) and ultra-low detection limits of 2.3 and 7.6 nM for dinotefuran and entacapone, which are lower than the previously reported MOF-based sensors. In the presence of other competitive analytes, great selectivity was achieved towards both analytes. The probe was recyclable up to five cycles. The sensing ability was explored towards entacapone in human serum, urine and dinotefuran in real soil, rice, honey samples, different fruits, vegetables, real water specimens and a wide range of pH media. A low-cost, handy MOF-based polymer thin-film composite (1'@PVDF-PVP) was developed for the on-site detection of dinotefuran and entacapone. Mechanistic studies involving analytical techniques and theoretical calculations suggested that FRET and PET are the probable reasons for entacapone sensing whereas IFE is responsible for dinotefuran detection. The entire work presents a low cost, multi-use photoluminescent sensor of entacapone and dinotefuran to address the environmental pollution., (© 2024 Wiley-VCH GmbH.)

Background: Organophosphate, pyrethroid, and neonicotinoid insecticides have resulted in adrenal and gonadal hormone disruption in animal and in vitro studies; limited epidemiologic evidence exists in humans. We assessed relationships of urinary insecticide metabolite concentrations with adrenal and gonadal hormones in adolescents living in Ecuadorean agricultural communities., Methods: In 2016, we examined 522 Ecuadorian adolescents (11-17y, 50.7% female, 22% Indigenous; ESPINA study). We measured urinary insecticide metabolites, blood acetylcholinesterase activity (AChE), and salivary testosterone, dehydroepiandrosterone (DHEA), 17β-estradiol, and cortisol. We used general linear models to assess linear (β = % hormone difference per 50% increase of metabolite concentration) and curvilinear relationships (β 2  = hormone difference per unit increase in squared ln-metabolite) between ln-metabolite or AChE and ln-hormone concentrations, stratified by sex, adjusting for anthropometric, demographic, and awakening response variables. Bayesian Kernel Machine Regression was used to assess non-linear associations and interactions., Results: The organophosphate metabolite malathion dicarboxylic acid (MDA) had positive associations with testosterone (β boys  = 5.88% [1.21%, 10.78%], β girls  = 4.10% [-0.02%, 8.39%]), and cortisol (β boys  = 6.06 [-0.23%, 12.75%]. Para-nitrophenol (organophosphate) had negatively-trending curvilinear associations, with testosterone (β 2 boys  = -0.17 (-0.33, -0.003), p = 0.04) and DHEA (β 2 boys  = -0.49 (-0.80, -0.19), p = 0.001) in boys. The neonicotinoid summary score (β boys  = 5.60% [0.14%, 11.36%]) and the neonicotinoid acetamiprid-N-desmethyl (β boys  = 3.90% [1.28%, 6.58%]) were positively associated with 17β-estradiol, measured in boys only. No associations between the pyrethroid 3-phenoxybenzoic acid and hormones were observed. In girls, bivariate response associations identified interactions of MDA, Para-nitrophenol, and 3,5,6-trichloro-2-pyridinol (organophosphates) with testosterone and DHEA concentrations. In boys, we observed an interaction of MDA and Para-nitrophenol with DHEA. No associations were identified for AChE., Conclusions: We observed evidence of endocrine disruption for specific organophosphate and neonicotinoid metabolite exposures in adolescents. Urinary organophosphate metabolites were associated with testosterone and DHEA concentrations, with stronger associations in boys than girls. Urinary neonicotinoids were positively associated with 17β-estradiol. Longitudinal repeat-measures analyses would be beneficial for causal inference., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Chlordecone is an organochlorine that was largely used as an insecticide to control a species of root borers, the Banana weevil (Cosmopolites sordidus), in the French West Indies, Guadeloupe and Martinique. Its molecules have been shown to be very persistent in the environment as pollution in soils leading to contamination of water sources and foodstuff will last for several decades. Our team previously reported associations between prenatal chlordecone exposure and poorer fine motor development at two points in time during infancy., Objective: To document whether effects of prenatal exposure to chlordecone previously reported persists until middle-childhood, and whether deleterious effects are observed in domain of visual processing. Associations with postnatal exposure and sex-specific vulnerabilities were also investigated., Methods: We examined 410 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children's blood at age 7 years. Fine motor function was assessed using the Bruininks Oseretsky Test of Motor Proficiency Second Edition (BOT-2). The Computerized Adaptive Testing System (CATSYS) was used to evaluated postural hand tremor, while non-verbal visuospatial processing was measured using the Stanford Binet copying (S-B copying) test. We used adjusted multiple linear regressions to test the relationship between children's scores and both continuous and categorical blood chlordecone concentrations, adding child sex as a moderator in continuous models., Results: Cord chlordecone concentrations are associated with a regular frequency pattern of subtle hand tremors in both hands, and not related to visual processing and fine motor precision. Chlordecone concentrations in blood sample collected at testing time are associated with poorer visual processing when copying geometric figures, but not significantly related to poorer fine movement precision in tasks requiring pencil, scissors and paper. No sex-specific vulnerability was reported in any of the outcomes., Conclusions: These results at school aged expand those previously reported in the same cohort during infancy at age 7- and 18 months, and corroborate the negative effects of chlordecone exposure on fine motor function in absence of intoxication. Our results support the need to continue public health efforts aimed at reducing exposure especially among women of child bearing age and young children., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This study aims to establish an in vitro monitoring approach to evaluate the pesticide exposures. We studied the in vitro cytotoxicity of three different body fluids of rats to the respective corresponding tissue-derived cells., Methods: Wistar rats were orally administrated daily with three different doses of chlorpyrifos (1.30, 3.26, and 8.15 mg/kg body weight/day, which is equal to the doses of 1/125, 1/50, and 1/20 LD 50 , respectively) for consecutive 90 days. Blood samples as well as 24-hour urine and fecal samples were collected and processed. Then, urine, serum, and feces samples were used to treat the correspondent cell lines, i.e., T24 bladder cancer cells, Jurkat lymphocytes, and HT-29 colon cancer cells respectively, which derived from the correspondent tissues that could interact with the respective corresponding body fluids in organism. Cell viability was determined by using MTT or trypan blue staining., Results: The results showed that urine, serum, and feces extract of the rats exposed to chlorpyrifos displayed concentration- and time-dependent cytotoxicity to the cell lines. Furthermore, we found that the cytotoxicity of body fluids from the exposed animals was mainly due to the presence of 3, 4, 5-trichloropyrindinol, the major toxic metabolite of chlorpyrifos., Conclusions: These findings indicated that urine, serum, and feces extraction, especially urine, combining with the corresponding tissue-derived cell lines as the in vitro cell models could be used to evaluate the animal exposure to pesticides even at the low dose with no apparent toxicological signs in the animals. Thus, this in vitro approach could be served as complementary methodology to the existing toolbox of biological monitoring of long-term and low-dose exposure to environmental pesticide residues in practice., (© 2021. The Author(s).)

To reduce the exposure of the French West Indies population to the organochlorine insecticide chlordecone (Kepone; CLD), the contamination of currently consumed foodstuffs must be reduced. Depuration of contaminated animals before slaughter could be a strategy to obtain safe animal products. The aim of this study was to characterize and quantify CLD elimination in contaminated ewes during depuration process. Experiments A and B consisted in a single intravenous (i.v.) administration of CLD (n = 5) and CLDOH (chlordecol; n = 3) followed by a 84-d and 3-d depuration period respectively with collection of blood, faeces and urine samples. After CLD administration, CLD and conjugated-CLDOH (CLDOH-C) were quantified in serum and urine and CLD and CLDOH were quantified in faeces. Based on calculations of faecal, urinary and body clearances of CLD and CLDOH-C, faeces appeared as the major route of CLD excretion with 86 % of the CLD administered dose eliminated in faeces, either as CLD (51 %) or as CLDOH (35 %)., (Copyright © 2021. Published by Elsevier B.V.)

This study aimed to (i) develop a sensitive method for simultaneous detection and quantification of imidacloprid (IMI) and seven of its metabolites in tissue specimens, and to (ii) determine the biodistribution of the IMI compounds in tissues of C57BL/6J male mice; after exposure to 0.6 mg/kg bw/day of IMI (10% of no observable adverse effect level of IMI) through a powdered diet for 24 weeks. We successfully developed a method which was accurate (recoveries were ≥ 70% for most compounds), sensitive (LODs ≤ 0.47 ng/mL and LOQs ≤ 1.43 ng/mL were recorded for all detected compounds, R 2 ≥ 0.99) and precise (RSDs ≤ 20%) for routine analysis of IMI and seven of its metabolites in blood and various tissue matrices. After bio-distributional analysis, IMI and five of its metabolites were detected in mice. Brain, testis, lung, kidney, inguinal white adipose tissue and gonadal white adipose tissue mainly accumulated IMI, blood and mesenteric white adipose tissue mainly accumulated IMI-olefin; liver mainly accumulated desnitro-IMI; pancreas predominately accumulated 4-hydroxy-IMI. The desnitro-dehydro-IMI and the desnitro-IMI metabolites recorded tissue-blood concentration ratios ≥ 1.0 for testis, brain, lung and kidney. The cumulative levels of the six detected IMI compounds (Σ6 IMI compounds) were found in the decreasing order: blood > testis > brain > kidney > lung > iWAT > gWAT > mWAT > liver > pancreas. Altogether, this study provided essential data needed for effective mechanistic elucidation of compound-specific adverse outcomes associated with chronic exposures to IMI in mammalian species., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in the present study., (Copyright © 2021. Published by Elsevier B.V.)

Pesticide poisoning is a common occurrence due to their widespread use, easy access and high toxicity even in small concentrations. The most common poisoning fatalities have been observed due to exposure to organophosphates, carbamates and neonicotinoids, thus development of a method for the rapid determination of these compounds in blood and urine is of great importance for clinical and toxicology laboratories. A simple, fast and reliable method was developed for the determination of 9 pesticides in blood and urine using HPLC-MS/MS instrumentation. In order to find the most suitable sample pretreatment technique, three different sample preparation procedures: SPE, protein precipitation and QuEChERS were compared. The final optimized analytical method was fully validated with the values of parameters such as calibration linearity, accuracy, precision, recovery, matrix effect and stability being acceptable. The method proved reliable, accurate, robust and sensitive and was successfully applied for the quantitation of pesticides in three postmortem cases of pesticides poisoning., (Copyright © 2021. Published by Elsevier B.V.)

Neonicotinoid insecticides (NEOs) are widely used around the world. The distribution of NEOs in paired saliva and periodontal blood samples was not previously documented in China. In this study, the concentrations of six NEOs and three corresponding metabolites were measured in 188 paired saliva and periodontal blood samples collected from South China. NEOs and their metabolites were frequently detected (68-94%) in paired saliva and periodontal blood, with median levels of 0.01-0.99 ng/mL. 1-Methyl-3-(tetrahydro-3-furylmethyl) urea was the most predominant NEO in paired saliva (39%) and periodontal blood (42%). Gender-related differences in NEOs and their metabolite concentrations were found: males showed lower levels than females. We calculated the concentration ratios between saliva and periodontal blood (S/PB ratios), and found that the median S/PB ratios of NEO and their metabolites were higher than 1, indicating that NEOs and their metabolites were easily excreted via saliva. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) was measured in paired saliva and periodontal blood as a marker of oxidative stress. 8-OHdG concentrations in saliva and periodontal blood were significantly and positively correlated (p < 0.05) with the concentrations of most NEOs and their metabolites in saliva and periodontal blood samples. These findings indicated that exposure to NEOs and their metabolites is associated with oxidative stress. This study is the first to report NEOs and their metabolites in paired saliva and periodontal blood samples collected from South China., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The aims of this study were to evaluate the efficacy of two injectable formulations of doramectin (DRM) against Psoroptes ovis in sheep infested under controlled experimental conditions and to characterize the DRM plasma disposition kinetics in the infested animals. To this end, sheep were experimentally infested with a P. ovis strain from a farm with a history of treatment failure, and then treated either with DRM 1% (traditional preparation) on days 0 and 7 or with DRM 3.15% (long-acting formulation) on day 0. The efficacy of each treatment was calculated by counting live mites in skin scrapings. Plasma samples were obtained from each animal and DRM concentrations were measured by HPLC. After the two doses of DRM 1%, the maximum efficacy (98.8%) was reached on day 28, whereas after the single dose of DRM 3.15%, the maximum efficacy (100%) was reached on day 35 and ratified on day 42. The long-acting formulation allowed obtaining higher exposure and more sustained concentrations of DRM than the traditional preparation. Although both DRM formulations studied were effective according to international protocols, they did not reach 100% effectiveness in the time required for approved pharmaceutical products against sheep scab, according to Argentine regulations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The objective of this study was to obtain data on pathways of absorption of the synthetic pyrethroids deltamethrin (DLM) and cis-permethrin (CPM) following oral administration to rats. Adult male Sprague-Dawley rats with cannulated mesenteric lymph ducts and hepatic portal veins were given single doses of either 5 mg/kg DLM or 60 mg/kg CPM via the duodenum and lymph and portal blood samples collected for up to 300 min. The pyrethroid dosing vehicles (5 mL/kg body weight) were either corn oil or glycerol formal. Levels of DLM and CPM in lymph and portal blood samples were determined by high-performance liquid chromatography-mass spectrometry-mass spectrometry. Over the time period studied, levels of both DLM and CPM following administration in either corn oil or glycerol formal were greater in lymph than in portal blood. Lymphatic uptake of both DLM and CPM was enhanced following dosing in glycerol formal than in corn oil. The results of this study suggest that after oral administration to rats, these two pyrethroids are predominantly absorbed via the lymphatic system rather than via portal blood. The data obtained in this study thus support a recently developed physiologically-based pharmacokinetic (PBPK) model to evaluate age-related differences in pyrethroid pharmacokinetics in the rat, where it was assumed that absorption of pyrethroids was predominantly via lymphatic uptake., (Copyright © 2020. Published by Elsevier B.V.)

Aims: In last few decades, the prevalence of diabetes and vascular diseases has intensified concurrently with increased use of synthetic chemicals in agriculture. This study is aimed to evaluate the association of co-accumulation of arsenic and organophosphate (OP) insecticides with diabetes and atherosclerosis prevalence in a rural Indian population., Methods: This study included observations from KMCH-NNCD-I (2015) cross-sectional study (n = 865) from an Indian farming village. The participants had assessment of clinical parameters including HbA 1c and carotid intima-media thickness and urinary heavy metals. Serum OP residues were extracted and quantified by GC-MS. Statistical analyses were performed to unravel the co-association of arsenic and OPs on prevalence of diabetes and atherosclerosis., Results: On multivariate regression analyses, total organophosphate level and arsenic accumulation showed association with diabetes and atherosclerosis. Higher odds ratio with significant trends were observed for the sub-quartiles formed by the combination of higher quartiles of arsenic and total organophosphates in association with diabetes and atherosclerosis., Conclusions: We observed evidence of possible synergism between arsenic and OPs in association with prevalence of diabetes, pre-diabetes and atherosclerosis in the study population. Our findings highlight the importance of understanding health effects of mixed exposures and raises vital questions on the role of these agrochemicals in the etiology of diabetes and vascular diseases.

Neonicotinoids (NNs), a widely used class of systemic pesticides, are regarded as exhibiting selective toxicity in insects. However, NNs are suspected of exerting adverse effects on mammals as well, including humans. To date, only adult male animal models have been subjected to general toxicity studies of NNs; fetuses have yet to be considered in this context. Here, we focused on the NN clothianidin (CLO) for the first quantitative LC-MS/MS analysis of maternal-to-fetal transfer and residual property of once-daily (single or multiple days), orally administered CLO and its metabolites in mice. The results revealed the presence of CLO and its five metabolites at approximately the same respective blood levels in both dams and fetuses. In the dams, CLO showed a peak value 1 h after administration, after which levels rapidly decreased at 3 and 6 h. In the fetuses of each group, levels of CLO were almost the same as those observed in the corresponding dams. The present results clearly demonstrated rapid passage of CLO through the placental barrier. However, metabolite-dependent differences observed in blood pharmacokinetics and residual levels. This is the first quantitative demonstration of the presence of CLO and its metabolites in fetal mouse blood., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Permethrin exposure of children and adults is widespread in many populations, but knowledge of its relative toxicokinetics (TK) and health risks in immature age groups is lacking. Studies were conducted in rats to determine the influence of immaturity and sex (on plasma and target organ dosimetry of each of the insecticide's 2 isomers, cis- and trans-permethrin [CIS and TRANS]). Postnatal day 15, 21, and 90 (adult), Sprague Dawley rats were orally administered a graduated series of doses of CIS and TRANS in corn oil. Serial sacrifices were conducted over 24 h to obtain plasma, brain, liver, skeletal muscle, and fat profiles of CIS and TRANS. Levels of TRANS decreased relatively rapidly, despite administration of relatively high doses. Concentrations of each isomer in plasma, brain, and other tissues monitored were inversely proportional to the animals' age. The youngest pups exhibited 4-fold higher plasma and brain area under the curves than did adults. Little difference was observed in the TK of CIS or TRANS between adult male and female rats, other than higher initial plasma and liver CIS levels in females. Elevated exposure of the immature brain appears to be instrumental in increased susceptibility to the acute neurotoxicity of high-dose permethrin (Cantalamessa [1993]), but it remains to be established whether age-dependent TK is relevant to long-term, low-level risks., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies have suggested that exposure to environmental chemicals with hormonal properties, also called endocrine disrupting chemicals, may be involved in the occurrence of prostate cancer (PCa). Such exposure may also influence the treatment outcome as it is still present at the time of diagnosis, the beginning of therapy, and beyond. We followed 326 men in Guadeloupe (French West Indies) who underwent radical prostatectomy as primary treatment of localized PCa. We analyzed the relationship between exposure to the estrogenic chlordecone, the antiandrogenic dichlorodiphenyldichloroethylene (DDE, the main metabolite of the insecticide DDT), and the nondioxin-like polychlorinated biphenyl congener 153 (PCB-153) with mixed estrogenic/antiestrogenic properties and the risk of biochemical recurrence (BCR) after surgery. After a median follow-up of 6.1 years after surgery, we found a significant increase in the risk of BCR, with increasing plasma chlordecone concentration (adjusted hazard ratio = 2.51; 95% confidence interval: 1.39-4.56 for the highest vs. lowest quartile of exposure; p trend = 0.002). We found no associations for DDE or PCB-135. These results shown that exposure to environmental estrogens may negatively influence the outcome of PCa treatment., (© 2019 UICC.)

The aim of the study was to assess temporal trends in health risks related to most common persistent contaminants, including polychlorinated biphenyls (PCBs), dichloro-diphenyl-trichloroethanes (DDTs), lead (Pb), as well as mercury (Hg) among indigenous peoples living in coastal areas of Chukotka in Arctic Russia. This is examined in relation to exposure pathways and a range of social and behavioral factors capable of modifying the exposure to these contaminants, including place of residence, income, traditional subsistence, alcohol consumption, and awareness of risk prevention. The primary exposure pathway for PCBs is shown to be the intake of traditional foods, which explained as much as 90% of the total health risk calculated employing established risk guidelines. Nearly 50% of past DDT-related health risks also appear to have been contributed by contaminated indoor surfaces involving commonly used DDT-containing insecticides. Individuals who practiced traditional activities are shown to have experienced a 4.4-fold higher risk of exposure to PCBs and a 1.3-fold higher risk for DDTs, Pb, and Hg. Low income, high consumption of marine mammal fat, alcohol consumption, and lack of awareness of health risk prevention are attributed to a further 2- to 6-fold increase in the risk of PCBs exposure. Low socioeconomic status enhances the health risks associated with exposure to the persistent contaminants examined.

Developmental neurotoxicity (DNT) studies via dietary method of administration have been conducted for zeta-cypermethrin, a pyrethroid insecticide. The objectives of the current study were to determine the toxicokinetics (TK) of zeta-cypermethrin in postnatal day (PND) 11, 21 and 90 rats after gavage doses and use the internal exposure data from the DNT and TK studies to calculate an offspring NOAEL in mg/kg/day during lactation. The DNT studies showed that zeta-cypermethrin is not a developmental neurotoxicant. The NOAEL for maternal and offspring was determined to be 125 ppm (9.0 and 21.4 mg/kg/day for dams during gestation and lactation, respectively), based on systemic toxicity of reductions in maternal body weight, body weight gains and food consumption and offspring body weight at 300 ppm (LOAEL). The TK data from the gavage study showed that dose normalized C max and AUC is approximately 3-fold and 2-fold higher in PND 11 and 21 than those in PND 90 rats. By using the mean maternal/offspring plasma concentrations (535/245 ng/mL) during lactation day LD/PND 5-21 from the range-finding DNT studies, a conservative 3.1X relative TK factor (exposure ratio from the gavage study) and equation 3.1 × 535/21.4 = 245/x, the offspring NOAEL of 125 ppm was calculated to be 3.2 mg/kg/day during lactation. The offspring NOAEL based on internal exposure data from DNT studies and TK data after gavage doses is considered conservative for risk assessment for all human populations including infants and children for zeta-cypermethrin., (Copyright © 2019. Published by Elsevier Inc.)

Although experimental evidence indicates that certain organochlorine insecticides are hepatocarcinogens, epidemiologic evidence for most of these chemicals is very limited. We estimated associations, using prospectively collected sera, between organochlorine insecticide concentrations and cancer registry-identified primary liver cancer in two cohorts, one from the United States and one from Norway. In nested case-control studies, we used sera collected in the 1960s-1980s from 136 cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the population-based Norwegian Janus cohort. We measured concentrations of nine organochlorine insecticides/metabolites and markers of hepatitis B and C in sera. Adjusted odds ratios (OR) and 95% confidence intervals (CI) for tertiles of lipid-corrected organochlorines were calculated for each cohort using conditional logistic regression. Among MHC participants with sera from the 1960s, there was a suggestive exposure-response trend for trans-nonachlor (second and third tertile of analyte ORs = 1.63 and 1.95, respectively; p-trend = 0.08) and a nonsignificantly elevated risk for the highest tertile of oxychlordane (OR = 1.87). Among Janus participants with sera from the 1970s, we observed an apparent trend for p,p'-DDT (second and third tertile ORs = 1.70 and 2.14, respectively; p-trend = 0.15). We observed little consistency in patterns of association between the cohorts. We found limited evidence that exposure to p,p'-DDT and chlordane-related oxychlordane and trans-nonachlor may be associated with increased risk of primary liver cancer. However, the modest strength of these associations and their lack of concordance between cohorts necessitate caution in their interpretation., (© 2019 UICC.)

Organophosphates are chemical pollutants that are existed widely in the environment, but the reactions of these agents with blood proteins are still not fully clarified. The current story was to analyze the static and dynamic interactions between human serum albumin (HSA) and phenthoate and then uncover the impact of the conjugations on the acetylcholinesterase (AChE) activity at the microscopic scale. Experimental results revealed clearly that the bioconjugate of the HSA-phenthoate was yielded and the conformation of HSA can produce autoregulation during the reaction. Dynamic reaction processes suggested that the conformational flexibility of the specific protein domain was changed significantly in equilibrium, and the electrostatic interaction energy played a major role in total energy of the biosystems, which matches the results of wet experiment and molecular docking. We also found that the modes of homologous proteins-phenthoate have obvious distinctions, and this point is related closely to the local dynamic flexibility of biomolecular structures. Additionally, the degree of bioconjugation of the HSA-phenthoate is positively associated with the enzymatic activity of target AChE, which may be attributed to the competitive reactions between HSA and AChE. Evidently, this scenario could provide useful molecular information for the systematic exploration of the toxicokinetics of organophosphorus compounds., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Indoor Residual Spraying (IRS), the application of insecticides on the inside walls of dwellings, is used by 84 countries for malaria control. Although effective in preventing malaria, this practice results in elevated insecticide exposure to >100 million people, most of whom are Africans. Pyrethroid insecticides and dichlorodiphenyl trichloroethane (DDT) are currently used for IRS. Animal and in vitro studies suggest that pyrethroids and DDT interfere with thyroid hormone homeostasis but human studies are inconsistent and no prior study has investigated this question in a population residing in an area where IRS is conducted. Our objective was thus to evaluate whether prenatal exposure to pyrethroids, DDT or DDT's breakdown product dichlorodiphenyl dichloroethylene (DDE) is associated with altered thyroid hormone levels among neonates from Limpopo, South Africa, where pyrethroids and DDT are used annually to control malaria. We measured serum DDT/E and urinary pyrethroid metabolite concentrations in maternal peripartum samples from 717 women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study conducted in Limpopo's Vhembe district. We measured total thyroxine (T4) and thyroid-stimulating hormone (TSH) in dried blood spots collected via heel stick. We found that all pyrethroid metabolites were positively associated with TSH; trans-DCCA and 3-PBA showed the strongest associations with a 12.3% (95%CI = 3.0, 22.3) and 14.0% (95%CI = 0.5, 30.2) change for each 10-fold increase in biomarker concentration, respectively. These associations were substantially stronger among children from households below the South African food poverty line. DDT and DDE were associated with lower total T4 among boys only (β = -0.27 μg/dL per 10-fold increase; 95%CI = -0.47, -0.04). Results suggest that prenatal exposure to DDT, DDE and pyrethroid insecticides is associated with changes in neonatal thyroid hormones consistent with hypothyroidism/hypothyroxinemia and that sex and poverty modify associations. Further research is needed to confirm these findings and examine whether they have implications for child development., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pyrethroids, organic compounds similar to natural pyrethrums, constitute the majority of insecticides. Pyrethroids are widely used around the world owing to their excellent selective toxicity to certain insects. In addition, they are easily found in daily life, accounting for most household pesticides. Owing to the easy access to pyrethroid insecticides, pyrethroid-related accidents and suicides have occurred yearly. For the first time, nine pyrethroids commonly used in South Korea and their seven major metabolites were simultaneously analyzed and validated in human plasma using liquid chromatography triple quadrupole mass spectrometry. Plasmas spiked with these pyrethroids and their metabolites were prepared and deproteinized via the addition of acetonitrile. This deproteinized supernatant was filtered and directly injected to ascertain the liquid chromatography-tandem mass spectrometry. For a sensitive and reproducible analysis, all the pyrethroid and metabolite analysis conditions for the multiple reaction monitoring mode were optimized in advance and employed. The validation parameters of the method, including the specificity, linearity, limit of detection, limit of quantification, accuracy, precision, recovery, matrix effect, and stability were also evaluated. The R 2 value of linearity was greater than 0.997 for all the analytes, the accuracy ranged from 81.8% to 112.3%, the precision from 0% to 10.1%, and the recovery from 90.9% to 112.4%, depending on the analyte. The stability was 97.0% to 107.0% in fresh plasma and 97.6% to 107.7% in corrupt plasma. The results were satisfactory for all the validation parameters. Furthermore, authentic pyrethroid-poisoned samples were analyzed using this validation method, to determine the suitability; deltamethrin and its metabolites, cis-DBCA and 3-PBA, were successfully analyzed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Permethrin use has been associated with an increased risk of multiple myeloma (MM) among pesticide applicators. However, the biological plausibility and mechanisms underlying this association are not fully understood. The aim of this study was to assess whether exposure to permethrin is related to haematological alterations among occupationally exposed pesticide applicators., Methods: We conducted a longitudinal study among 33 pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture study comparing haematological parameters in the offseason with the day after permethrin exposure and, for 27 participants, approximately 3 weeks postexposure. Complete blood counts with white blood cell differential and lymphocyte subsets were measured at each visit. Multivariate linear mixed effects models were used to assess the relationship between natural log-transformed haematological parameters and exposure to permethrin., Results: The adjusted geometric mean immature granulocyte count was elevated among pesticide applicators following permethrin exposure compared with their offseason levels (37% increase, 95% CI 6% to 76%). Modest but statistically significant (p<0.05) alterations in red blood cell (RBC) parameters (eg, decreased RBC count and haemoglobin and increased mean corpuscular volume and RBC distribution width-SD) were also observed the day after permethrin use compared with offseason levels; decreases in RBC count and haemoglobin and increases in RBC distribution width-SD persisted approximately 3 weeks after permethrin use., Conclusions: Altered haematological parameters could be indicative of disrupted haematopoiesis, providing insights into the biological plausibility of the observed association between permethrin use and MM risk among pesticide applicators., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Fipronil is a highly effective insecticide with extensive usages; however, its distribution and toxic/health effects in the human population after chronic exposure have not yet been clearly identified. Our objectives were to determine the levels of serum fipronil and fipronil sulfone, a primary fipronil metabolite, in a general and sensitive human population using a birth cohort of parent-infant triads in Korea. We further investigated whether in utero exposure to fipronil and fipronil sulfone can affect health outcomes in newborn infants. Blood and umbilical cord blood from 169 participants, 59 mother-neonate pairs and 51 matching biological fathers, were collected; serum fipronil and fipronil sulfone (both blood and cord blood) and serum thyroid hormones (cord blood) were measured. Demographic, physiological, behavioral, clinical, and socioeconomic data for each participant were collected via a one-on-one interview and a questionnaire survey. Fipronil sulfone was detected in the serum of mothers, fathers, and infantile cord blood, while fipronil itself was not. Maternal fipronil sulfone levels were correlated to those of matched biological fathers and newborn infants. Adjusted analyses identified significant associations between parental fipronil sulfone levels and household income. Infantile fipronil sulfone levels were significantly associated with both maternal and paternal levels as well as maternal pre-pregnant BMI. Furthermore, infantile fipronil sulfone levels were inversely associated with cord blood T3 and free T3 levels as well as 5-min Apgar scores of newborn infants. Serum fipronil sulfone was detected in a specific population of mother-neonate pairs and their matched biological fathers in a manner suggestive of regular exposure to fipronil among urban residents. The findings also suggest that serum fipronil sulfone placentally transfers to the fetus and affects infantile adverse health outcomes. This is a first of its kind study; therefore, future studies are warranted., (Copyright © 2019. Published by Elsevier GmbH.)

Background: Outdoor, early-biting, zoophagic behaviours by Anopheles farauti (s.s.) can compromise the effectiveness of bed nets for malaria control. In the Western Pacific region, pigs and dogs represent significant alternative blood sources for mosquitoes. Treating these animals with endectocides may impact mosquito survival and complement control measures. This hypothesis was explored using membrane feeding assays (MFAs), direct feeds on treated pigs, pharmacokinetic analyses and a transmission model., Results: Ivermectin was 375-fold more mosquitocidal than moxidectin (24 h LC 50  = 17.8 ng/ml vs 6.7 µg/ml) in MFAs, and reduced mosquito fecundity by > 50% at ≥ 5 ng/ml. Treatment of pigs with subcutaneous doses of 0.6 mg/kg ivermectin caused 100% mosquito mortality 8 days after administration. Lethal effects persisted for up to 15 days after administration (75% death within 10 days)., Conclusion: The application of these empirical data to a unique malaria transmission model that used a three-host system (humans, pigs and dogs) predicts that the application of ivermectin will cause a significant reduction in the entomological inoculation rate (EIR = 100 to 0.35). However, this is contingent on local malaria vectors sourcing a significant proportion of their blood meals from pigs. This provides significant insights on the benefits of deploying endectocides alongside long-lasting insecticide-treated nets (LLINs) to address residual malaria transmission.

Biomonitoring of people exposed to hazardous materials provides opportunities for early identification of several diseases, particularly in those individuals who are constantly exposed to pesticides, such as pesticide operators and workers in pesticide manufacturing industry. However, data on this hot topic are limited in Pakistan. In this study, insecticide toxic effects and biochemical alterations (i.e., damage in DNA and enzyme activity) were studied in blood samples of occupationally exposed individuals from Punjab, Pakistan. Eight out of twenty-seven blood samples (29.6%) of the pesticide operators were found positive in five insecticides, with the maximum concentration found for chlorpyrifos-methyl (0.039 μg/mL). Eleven out of twenty-seven blood samples (40.7%) of the pesticide industry workers were found positive in eight insecticides, with the maximum concentration found for endosulfan (0.051 μg/mL). Comet tail length was 16.88 ± 4.57 μm in pesticide industry workers and 16.33 ± 3.78 μm in pesticide operators, which were significantly higher (P < 0.01) than that recorded in the control group (4.84 ± 2.21 μm). Values of serum cholinesterase (SChE) concentration were slightly lower (P > 0.05) in exposed individuals, whereas values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) concentration were significantly higher (P < 0.01) in exposed individuals compared with control group. Exposure duration and total insecticide concentration in blood samples were positively associated with comet tail length, ALT activity, AST activity, and ALP activity, but negatively with SChE. DNA damage was higher in smokers vs. non-smokers. Also, a positive association was found between comet tail length and number of cigarettes per day. Overall, occupational exposure to insecticides can pose serious health risks to pesticide operators and workers in pesticide manufacturing industry, highlighting the necessity of personal protection in those groups for preventing exposure and resultant health disorders., (Copyright © 2018. Published by Elsevier B.V.)

Deltamethrin (DLM) is a commonly used pesticide that helps to control crop destruction, disease, and nuisance insects. In rodents DLM can produce choreoathetosis, salivation, and decreased acoustic startle responses (ASR). Herein, adult Sprague Dawley rats were assessed for ASR 2 h after DLM delivered in 5 ml/kg corn oil, however no decrease was observed. Therefore, a test-retest protocol was used to reduce variability, and the effects on ASR on postnatal day 15 (P15) and adult rats were assessed 2, 4, 6, and 8 h after DLM administration (0, 1, 2, or 4 mg/kg for P15 rats and 0, 2, 8, or 25 mg/kg for adults). In a separate set of rats identically treated, DLM levels were determined in blood and brain. DLM (8 or 25 mg/kg) in adult rats decreased ASR up to 4 h, whereas in P15 rats decreases were observed between 2 and 8 h. The adult 25 mg/kg group showed consistent signs of salivation and tremor, whereas in P15 rats salivation was observed in the 2 and 4 mg/kg groups and tremor was observed at all doses over the 8-h period. Mortality was observed in all P15 dose groups but not in adults. Dose-dependent increases of DLM in blood and brain regardless of age were observed. At approximately equivalent whole brain concentrations, effects were more pronounced in P15 rats than in adult rats. Comparable brain levels of DLM do not explain differences in ASR and tremor between the P15 and adult rats. These data indicate age-dependent differences in sensitivity to DLM., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The insecticide fipronil can be metabolized to its sulfone in mammalian species. Two camel single-domain antibodies (VHHs) F1 and F6, selective to fipronil and fipronil-sulfone, respectively, were generated and used to develop enzyme linked immunosorbent assays (ELISAs) for the detection of the two compounds in the sera of black-tailed prairie dogs and rats. The limits of detection of fipronil and fipronil-sulfone in the rodent sera by the corresponding ELISAs were 10 and 30 ng mL -1 , and the linear ranges were 30-1000 and 75-2200 ng mL -1 . ELISAs showed a good recovery for fipronil and fipronil-sulfone cospiked in the control sera of the black-tailed prairie dogs (90-109%) and rats (93-106%). The VHH-based ELISAs detected fipronil and fipronil-sulfone in the sera of the rodents that received a repeated oral administration of fipronil. The average concentration of fipronil-sulfone was approximately 3.2-fold higher than fipronil in the prairie dog sera (1.15 vs 0.36 μg mL -1 ) and rat sera (1.77 vs 0.53 μg mL -1 ). ELISAs agreed well with a liquid chromatography-mass spectrometry method for the quantification of both fipronil and fipronil-sulfone in real serum samples. Fipronil-sulfone was identified as the predominant metabolite of fipronil in the black-tailed prairie dog and rat sera.

Endosulfan is one of the most prevalent organochlorine pesticides used in the agricultural sector in the developing countries including India. It affects the physiological functioning of different organ systems including nervous, immune, hepatic, and reproductive system. Realizing the safety and health concern, restrictions have been imposed at various levels, but the usage has still continued in the plantation crops. Owing to pesticide beneficiary of north India, the cotton belt commonly called the Malwa region of Punjab was evaluated for identifying the levels of Endosulfan in the blood samples of women working in agricultural fields. Gas chromatograph with electron capture detector was used for detecting the levels of endosulfan metabolites among twenty active female workers. The mean level of endosulfan recorded in the tested population was observed to be 2.22 ppb. It is difficult to draw a certain conclusion based on these findings because the subjects were less in number. However, detection of even very low concentrations of endosulfan residues signifies its continued accessibility to the women population. Encouragement of more such population-based research needs to be adopted to determine the body burden of such pesticides in humans. The effective implementation of the ban on Endosulfan could be checked by a combined retrospective and prospective study to infer a justifiable impact., Competing Interests: None

Although effective in controlling malaria, indoor residual spraying results in elevated exposure to insecticides such as dichlorodiphenyltrichloroethane (DDT) and pyrethroids. These chemicals cross the placenta, but no studies have examined their associations with birth outcomes in populations residing in indoor residual spraying areas. We investigated this question in the Venda Health Examination of Mothers, Babies and Their Environment (VHEMBE), a birth cohort study of 751 South African children born between 2012 and 2013. We measured maternal peripartum serum DDT and urine pyrethroid metabolite concentrations and collected data on birth weight, length, head circumference, and duration of gestation. We analyzed the data using marginal structural models with inverse-probability-of-treatment weights, generalized propensity scores, and standard conditional linear regression. Using all 3 analytical methods, p,p'-DDT, o,p'-DDT, and to a lesser extent p,p'-dichlorodiphenyldichloroethylene were related to elevated birth weight, birth length, and head circumference among girls. Changes in gestational duration did not mediate this relationship, suggesting that these exposures accelerate fetal growth, which is consistent with the known estrogenic properties of o,p'-DDT and p,p'-DDT. No associations with pyrethroid metabolites were found. Results suggest that prenatal exposure to DDT is related to elevated birth size. Further studies are needed to elucidate the implications of these findings.

This work describes the optimization of a new method for the determination of five organophosphorus insecticides in whole blood. The analytes were extracted from the matrix (50 μL) using the dried blood spot (DBS) approach and were analyzed by gas chromatography (GC) coupled to tandem mass spectrometry (MS/MS). The studied compounds (diazinon, chlorpyrifos, parathion-ethyl, chlorfenvinphos and quinalphos) were chosen based on the statistics of intoxications in Portugal, and ethion was used as internal standard. The method was fully validated, taking into account international guidelines for bioanalytical method validation, such as those of the Food and Drug Administration (FDA), International Conference on Harmonization (ICH) and Scientific Working Group for Forensic Toxicology (SWGTOX). A linear range of 0.1-25 μg/mL was obtained for all compounds, except for diazinon and quinalphos (0.05-25 μg/mL and 0.25-25 μg/mL, respectively), presenting determination coefficients above 0.99. Concerning precision, the coefficients of variation (CVs) were lower than 14% for all compounds. Those compounds were found to be stable in the samples. Although the values obtained for recovery were low (between 1 and 12%), the method proved to be sensitive, since detection limits between 0.05 and 0.1 μg/mL were obtained. The novelty is the use of the DBS approach in the extraction of these compounds, and this is the first paper reporting it: DBS is a recent technique of bioanalysis in the field of toxicology, and in addition to its simplicity and sensitivity, it is applicable routinely in both clinical and forensic toxicology situations. Graphical abstract ᅟ.

Background: Concentrations of persistent organic pollutants (POPs) in humans are influenced by a large number of factors including birth year, reproductive history and diet. Accordingly, information on dietary habits and socio-demographic variables may predict plasma concentrations of POPs, thus enabling studies on health effects in large epidemiological studies, without performing time consuming and expensive chemical analyses on entire cohorts., Aims: To develop and evaluate statistical models for predicting concentrations of POPs in participants of the Norwegian Women and Cancer (NOWAC) study, using questionnaire information and measured plasma POP concentrations., Materials and Methods: Information on estimated dietary intakes and socio-demographic variables from four different questionnaires (in 1991, 1994, 2004 and 2005) were obtained from participants in the NOWAC study. We measured POP concentrations in a total of 367 blood samples from 2005 and built multivariable linear regression models for p,p'-DDE, PCB-118, -138, -153, -180 and summed PCB concentrations in one subsample (N = 259) and evaluated the models in another subsample (N = 108). Measured and predicted values were compared using correlation coefficients and inter-method agreement was evaluated using weighted Cohen's κ for tertile categorization., Results: Median POP concentrations in the population ranged from 13 ng/g lipid to 162 ng/g lipid (lowest for PCB-118 and highest for p,p'-DDE). Common predictors for all POPs were birth year, breastfeeding and the weight-related variables (BMI or weight change), whereas influential dietary variables differed and were of varying importance. The predicted plasma concentrations were significantly correlated with the measured values (r s  = 0.24, 0.33, 0.41, 0.50, 0.56, and 0.54 for p,p'-DDE, PCB-118, -138, 153, -180 and summed PCBs, respectively). Tertiles of predicted plasma concentrations displayed significant, but varying agreement with measured concentrations (Weighted Cohen's κ = 0.19, 0.22, 0.33, 0.42, 0.45, and 0.50 respectively)., Conclusion: Predicted plasma concentrations of certain PCBs showed good precision (Kw > 0.4) when compared to measured concentrations. Thus, the models can be used to classify NOWAC participants into high, medium and low PCB exposure groups., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Insecticides, essential for crop protection measures, leave behind several toxic residues that can result in a series of human health disorders. Therefore, this study was planned for the determination of residues and adverse effects of insecticides in blood samples of sprayers, pesticide-industry workers and controls by using blood parameters of these individuals as biomarkers. Optimized analytical methods using GC-MS and HPLC for the simultaneous detection of 22 currently used insecticides were adopted. Eight of twenty-seven (22.22%) sprayers' blood samples were found positive for five different insecticides. Eleven of twenty-seven (40.74%) pesticide-industry workers were found positive for eight different insecticides. The blood samples of both the exposed groups, sprayers and industry workers had significantly (P < 0.001; Mann-Whitney U-tests) low hemoglobin-Hb concentrations (12.17 ± 2.13 and 12.22 ± 2.37 g/dl respectively) than the average value of the control group with 14.23 ± 2.37 g/dl. The erythrocyte sedimentation rates (ESRs) in sprayers and insecticide industry workers (28.78 ± 20.72 and 28.17 ± 25.14 mm/1st h respectively) were greater significantly (P < 0.001; Mann-Whitney U test) than the control blood samples (9.53 ± 3.34 mm/1st h). These results indicate that the exposed individuals have experienced significant hemotoxic effects during insecticide exposure. The study also predicts the risk to exposed individuals in developing countries like Pakistan and demands realization of safety measures to prevent such dangerous effects of pesticide exposures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Autism is a complex neurodevelopmental disorder with a largely unknown etiology. To date, few studies have investigated prenatal exposure to toxins and risk of autism by using maternal biomarkers of exposure. Persistent organic pollutants are lipophilic halogenated organic compounds and include the insecticide dichlorodiphenyltrichloroethane (DDT), as well as its metabolite p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE), and polychlorinated biphenyls (PCBs). The objective of this study was to test whether elevated maternal levels of persistent organic pollutants are associated with autism among offspring., Method: The investigation was derived from the Finnish Prenatal Study of Autism, a national birth cohort study based on a nested case-control design. Cases of autism among children born between 1987 and 2005 were ascertained by national registry linkages. In cases of childhood autism and matched control subjects (778 matched case-control pairs), maternal serum specimens from early pregnancy were assayed for levels of p,p'-DDE and total levels of PCBs., Results: The odds of autism among offspring were significantly increased with maternal p,p'-DDE levels that were in the highest 75th percentile, with adjustment for maternal age, parity, and history of psychiatric disorders (odds ratio=1.32, 95% CI=1.02, 1.71). The odds of autism with intellectual disability were increased by greater than twofold with maternal p,p'-DDE levels above this threshold (odds ratio=2.21, 95% CI=1.32, 3.69). There was no association between total levels of maternal PCBs and autism., Conclusions: These findings provide the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring. Although further research is necessary to replicate this finding, this study has implications for the prevention of autism and may provide a better understanding of its pathogenesis.

A toxicokinetic model has been optimized to describe the time profiles of common biomarkers of exposure to permethrin and cypermethrin: trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acids (trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). The model then served to reproduce urinary time courses in exposed agricultural workers and predict corresponding absorbed doses. It allowed for the prediction of the main routes of exposure in workers during the study period. Modeling showed that simulating exposure mostly by the oral route, during the 3-day biomonitoring period, provided best-fits to the urinary time courses of most workers. This is compatible with an inadvertent oral exposure during work. According to best-fit scenarios, absorbed doses in workers reconstructed with the model reached a maximum of 2.4 µg/kg bw/day and were below the absorbed dose limits associated with an exposure to the reference dose values established by the U.S. Environmental Protection Agency (0.06 and 0.25 mg/kg bw/day for cypermethrin and permethrin, respectively) and the Acceptable Operator Exposure Level set by the European Commission (0.06 mg/kg bw/day for cypermethrin). Modeling was further used to derive biological reference values for cypermethrin and permethrin exposure. Respective values of 7 and 29 nmol/kg bw/day of trans-DCCA, and 3 and 13 nmol/kg bw/day of 3-PBA were obtained. None of the workers presented values above these biological reference values.

A controlled kinetic study was conducted in volunteers dermally exposed to the widely used lambda-cyhalothrin pyrethroid pesticide to document the time courses of relevant biomarkers of exposure, in order to better assess biomonitoring data in workers. Matador ® EC120 formulation (120 g/l) was applied on 40 cm 2 of the forearm at a 0.25 mg/kg dose of lambda-cyhalothrin and left without occlusion or washing for 6 h. The application site was then washed thoroughly with soap and water. The kinetic time courses of cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were determined in plasma and urine up to 84 h post-application. Results show that the fraction of lambda-cyhalothrin absorbed in the body was rapidly cleared following dermal contact. According to CFMP and 3-PBA plasma profiles, calculated mean apparent absorption half-lives (t 1/2 ) were 3 and 7.3 h, respectively, and corresponding mean apparent elimination t 1/2 were 11.2 and 7.6 h. These differences suggest some metabolism at the site-of-entry and storage of metabolites by the dermal route. Toxicokinetic parameters calculated from urinary profiles confirm the values of absorption and elimination rates. Metabolites were almost completely excreted over the 84-h period post-application and, on average, 0.12 and 0.08% of the applied lambda-cyhalothrin dose was recovered in the urine as CFMP and 3-PBA, respectively, indicating a low dermal absorption fraction of this pyrethroid. This study showed the potential use of CFMP and 3-PBA biomarkers for the assessment of dermal exposure to lambda-cyhalothrin pyrethroid., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The World Health Organization recommends indoor residual spraying (IRS) of insecticides (including dichlorodiphenyltrichloroethane [DDT]) to fight malaria vectors in endemic countries. There is limited information on children's exposure to DDT in sprayed areas, and tools to estimate early-life exposure have not been thoroughly evaluated in this context., Objectives: To document serum p,p'-DDT/E levels in 47 mothers and children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a study conducted in an area where IRS insecticides are used annually, and to evaluate the precision and accuracy of a published pharmacokinetic model for the estimation of children's p,p'-DDT/E levels., Methods: p,p'-DDT/E levels were measured in maternal serum at delivery, and in children's serum at 12 and 24 months of age. A pharmacokinetic model of gestational and lactational exposure was used to estimate children's p,p'-DDT/E levels during pregnancy and the first two years of life, and estimated levels were compared to measured levels., Results: The geometric means of children's serum p,p'-DDT/E levels at 12 and 24 months were higher than those of maternal serum levels. Regression models of measured children's p,p'-DDT/E levels vs. levels estimated with the pharmacokinetic model (which only accounted for children's exposure through placental transfer and breastfeeding) had coefficients of determination (R 2 ) ranging from 0.75 to 0.82. Estimated p,p'-DDE levels were not significantly different from measured levels, whereas p,p'-DDT levels were overestimated by 36% at 12 months, and 51% at 24 months., Conclusion: Results indicate that children living in a sprayed area have serum p,p'-DDT/E levels exceeding their mothers' during the first two years of life. The pharmacokinetic model may be useful to estimate children's levels in the VHEMBE population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Permethrin is a type I (noncyano) pyrethroid that induces tremors at high concentrations and increases acoustic startle responses (ASRs) in adult rodents, however its effects in young rats have been investigated to a limited extent. ASR and tremor were assessed in adult and postnatal day (P)15 Sprague-Dawley rats at oral doses of 60, 90, or 120 mg/kg over an 8 h period. Permethrin increased ASR in adults, regardless of dose, and 20% of the high-dose rats showed tremor at later time points. For the P15 rats all doses induced tremor at all time points, and ASR was increased at 2 h in the 90 and 120 mg/kg groups with a trend in the 60 mg/kg group compared with controls. The 60 mg/kg group showed increased ASR at 4 and 6 h, whereas the 90 mg/kg group showed no differences from the controls at these times. The 120 mg/kg group showed decreased ASR from 4- to 8-h posttreatment. P15 and adult rats both showed plasma and brain cis- and trans-permethrin increases after dosing. After the same dose of permethrin, P15 rats had greater cis- and trans-permethrin in brain and plasma compared with adults. P15 rats had an increased tremor response compared with adults even at comparable brain permethrin concentrations. For ASR, P15 rats responded sooner and showed a biphasic pattern ranging from increased to decreased response as a function of dose and time, unlike adults that only showed increases. Overall, young rats showed greater effects from permethrin compared with adults.

Toxicokinetics of cyfluthrin after single oral [20 mg/kg body weight (bw)] and intravenous (IV) (3 mg/kg bw) doses were studied in rats. Serial blood samples were obtained after oral and IV administration. Brain tissue samples were also collected after oral administration. Cyfluthrin concentrations in plasma and brain tissues (hypothalamus, striatum, hippocampus and frontal cortex) were quantified using liquid chromatography tandem mass spectrometry (LC/MS). Cyfluthrin disposition was best described by the use of a two-compartment open model. When given orally, plasma kinetics showed an extensive oral absorption of cyfluthrin and a slow elimination. The area under the concentration-time curve [AUC (0-24h) ] and maximal plasma concentration (Cmax) were 6.11 ± 1.06 mg h/L and 0.385 ± 0.051 μg/mL, respectively; β phase elimination half-life (T 1/2 β) was (17.15 ± 1.67 h). Oral bioavailability was found to be 71.60 ± 12.36%. After oral administration, cyfluthrin was widely distributed to brain tissues. AUC (0-24h) was significant higher in all tested brain tissues than in plasma. The largest discrepancy was found for hypothalamus. AUC (0-24h) , Cmax and T 1/2 β in hypothalamus were 19.36 ± 2.56 mg h/L, 1.21 ± 0.11 μg/g and 22.73 ± 1.60 h, respectively. Assuming the identified toxicokinetics parameters, this study serves to better understand mammalian toxicity of pyrethroid cyfluthrin and to design further studies to characterize its neurotoxicity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Indoor residual spraying (IRS) of insecticides, conducted in low- and middle-income countries to control malaria, may result in high exposure to dichlorodiphenyltrichloroethane (DDT), its breakdown product dichlorodiphenyldichloroethylene (DDE), or pyrethroids. Animal studies suggest in utero exposure to these chemicals may increase childhood infection frequency., Objectives: We investigated associations between maternal DDT/E and pyrethroid metabolite concentration and child infection associations in an IRS setting in which susceptibility factors are common and infections are leading causes of child morbidity and mortality., Methods: Using gas chromatography-mass spectrometry, we measured serum DDT/E and urinary pyrethroid metabolite concentrations in peripartum samples from 674 women participating in the Venda Health Examination of Mother, Babies and their Environment (VHEMBE) study. Counts of persistent child fevers, otitis media, and severe sore throat between 1 and 2 y of age were ascertained from maternal interviews. Associations between DDT/E and pyrethroid metabolite concentrations and infections were estimated using zero-inflated Poisson regression. We estimated relative excess risks due to interaction (RERI) with poverty, maternal energy intake, and maternal HIV status., Results: Concentrations of DDT/E, particularly p,p' -DDE, were associated with higher rates of persistent fevers [IRR=1.21 (95% CI: 1.01, 1.46)], for a 10-fold increase in p,p' -DDE). This association was stronger among children from households below versus above the South African food poverty line [IRR=1.31 (95% CI: 1.08, 1.59) vs. IRR=0.93 (95% CI: 0.69, 1.25), respectively] and for children whose mothers had insufficient versus sufficient caloric intake during pregnancy [IRR=1.30 (95% CI: 1.07, 1.58) vs. IRR=0.96 (95% CI: 0.72, 1.28), respectively]., Conclusions: In utero IRS insecticide exposure may increase childhood infection rates. This was particularly apparent among children from poorer households or whose mothers had low energy intake during pregnancy. https://doi.org/10.1289/EHP2657.

Background: Zoonotic visceral leishmaniasis (ZVL) caused by Leishmania (Leishmania) infantum is an important disease in humans and dogs. Different mammal species are reservoirs but dogs are considered to be the main one. Phlebotomine sand flies are the proven vector. Four systemic insecticides approved for their use in dogs were previously selected based on their potential to be used in endemic countries as part of the control programs of ZVL. These insecticides are proved to be safe and effective against the on-label insects and parasites, but there is no information about their activity against phlebotomine sand flies., Methods: The phlebotomine mortality of four systemic insecticides in dogs was evaluated using two randomized clinical trials. For the first trial, thirty dogs were randomly allocated into five groups: four treatments and one control, of equal size. The treatments evaluated were: Guardian®SR, Elanco (moxidectin); Comfortis®, Elanco (spinosad); Bravecto®, Merck Animal Health (fluralaner); and NexGard®, Merial (afoxolaner). Blood from dogs was taken at days 2, 4, 21 and 31 post-treatment (trial 1). The compound that showed the highest efficacy was selected for a second trial (trial 2) with 20 dogs sampled at days 0, 2, 4, 7, 14, 18, 32, 39, 51 and 84 post-treatment. Membrane feeding bioassays with Phlebotomus papatasi were used to evaluate the phlebotomine mortality efficacy of the different treatments. Phlebotomine mortality was observed every 24 h following the membrane feeding during 5 days. A mixed model for a negative binomial logistic regression, and a Cox proportional hazard mixed model were used to estimate phlebotomine mortality due to different treatments., Results: Fluralaner was the only compound that showed significant phlebotomine mortality. Fluralaner maintained the phlebotomine mortality between 60-80% for 30 days after treatment. In trial 1 we found that fluralaner increased the risk of death by 1.9 times (95% CI: 1.02-3.6) and 1.7 times (95% CI: 1.09-2.6) at days 2 and 4 after treatment. The Cox model resulted in an increase of 1.47 (95% CI: 1.1-1.96) times in hazard risk at day 2 and 1.89 (95% CI: 1.35-2.45) at day 4 after treatment. In trial 2 we found that fluralaner increased the risk of death by 1.64 times (95% CI: 1.16-2.54) and 1.97 times (95% CI: 1.23-3.17) at days 14 and 32. The hazard risk was also increased by 1.92 (95% CI: 1.4-2.64) times at day 14 after treatment. Phlebotomine survival including all experimental days was significantly lower in the fluralaner group in both trials., Conclusions: A single oral treatment of fluralaner in dogs induces phlebotomine mortality. Systemic insecticides in dogs should be considered as a potential preventive measure of ZVL.

Background: Occupational studies suggest that exposure to organophosphate insecticides (OPs) can lead to vision or hearing loss. Yet the effects of early-life exposure on visual and auditory function are unknown. Here we examined associations between prenatal OP exposure and grating visual acuity (VA) and auditory brainstem response (ABR) during infancy., Methods: 30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Grating visual acuity (VA) (n = 179-200) and auditory brainstem response (ABR) (n = 139-183) were assessed at 6 weeks, 9 months, and 18 months. Outcomes included VA score, ABR wave V latency and central conduction time, and head circumference (HC). Associations between sensory outcomes during infancy and cord OPs were examined using linear mixed models., Results: Prenatal chlorpyrifos exposure was associated with lower 9-month grating VA scores; scores were 0.64 (95% CI: -1.22, -0.06) points lower for exposed versus unexposed infants (p = 0.03). The OPs examined were not associated with infant ABR latencies, but chlorpyrifos and phorate were both significantly inversely associated with HC at 9 months; HCs were 0.41 (95% CI: 0.75, 0.6) cm and 0.44 (95% CI: 0.88, 0.1) cm smaller for chlorpyrifos (p = 0.02) and phorate (p = 0.04), respectively., Conclusions: We found deficits in grating VA and HC in 9-month-old infants with prenatal exposure to chlorpyrifos. The clinical significance of these small but statistically significant deficits is unclear. However, the disruption of visual or auditory pathway maturation in infancy could potentially negatively affect downstream cognitive development., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Studies were conducted to determine the distribution and elimination of imidacloprid (IMI) in rainbow trout. Animals were injected with a low (47.6 μg/kg), medium (117.5 μg/kg) or high (232.7 μg/kg) dose directly into the bloodstream and allowed to depurate. The fish were then sampled to characterize the loss of IMI from plasma and its appearance in expired water (all dose groups) and urine (medium dose only). In vitro biotransformation of IMI was evaluated using trout liver S9 fractions. Mean total clearance (CL T ) values determined by non-compartmental analysis of plasma time-course data were 21.8, 27.0 and 19.5 mL/h/kg for the low, medium and high dose groups, respectively. Estimated half-lives for the same groups were 67.0, 68.4 and 68.1 h, while fitted values for the steady-state volume of distribution (V SS ) were 1.72, 2.23 and 1.81 L/kg. Branchial elimination rates were much lower than expected, suggesting that IMI is highly bound in blood. Renal clearance rates were greater than measured rates of branchial clearance (60% of CL T in the medium dose group), possibly indicating a role for renal membrane transporters. There was no evidence for hepatic biotransformation of IMI. Collectively, these findings suggest that IMI would accumulate in trout in continuous waterborne exposures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lotilaner is a new oral ectoparasiticide from the isoxazoline class developed for the treatment of flea and tick infestations in dogs. It is formulated as pure S-enantiomer in flavoured chewable tablets (Credelio™). The pharmacokinetics of lotilaner were thoroughly determined after intravenous and oral administration and under different feeding regimens in dogs., Methods: Twenty-six adult beagle dogs were enrolled in a pharmacokinetic study evaluating either intravenous or oral administration of lotilaner. Following the oral administration of 20 mg/kg, under fed or fasted conditions, or intravenous administration of 3 mg/kg, blood samples were collected up to 35 days after treatment. The effects of timing of offering food and the amount of food consumed prior or after dosing on bioavailability were assessed in a separate study in 25 adult dogs. Lotilaner blood concentrations were measured using a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated by non-compartmental analysis. In addition, in vivo enantiomer stability was evaluated in an analytical study., Results: Following oral administration in fed animals, lotilaner was readily absorbed and peak blood concentrations reached within 2 hours. The terminal half-life was 30.7 days. Food enhanced the absorption, providing an oral bioavailability above 80% and reduced the inter-individual variability. Moreover, the time of feeding with respect to dosing (fed 30 min prior, fed at dosing or fed 30 min post-dosing) or the reduction of the food ration to one-third of the normal daily ration did not impact bioavailability. Following intravenous administration, lotilaner had a low clearance of 0.18 l/kg/day, large volumes of distribution V z and V ss of 6.35 and 6.45 l/kg, respectively and a terminal half-life of 24.6 days. In addition, there was no in vivo racemization of lotilaner., Conclusions: The pharmacokinetic properties of lotilaner administered orally as a flavoured chewable tablet (Credelio™) were studied in detail. With a T max of 2 h and a terminal half-life of 30.7 days under fed conditions, lotilaner provides a rapid onset of flea and tick killing activity with consistent and sustained efficacy for at least 1 month.

Background: Lotilaner (Credelio™) is the newest member of the novel isoxazoline chemical class to be developed to treat canine ectoparasitism. Administered orally, lotilaner is rapidly absorbed with peak blood levels occurring within 2 h post-treatment. A study was undertaken to determine the earliest onset of lotilaner's efficacy against existing flea infestations., Methods: From 72 Beagles, 64 qualifying dogs were ranked in descending order of flea counts from a Day -8 infestation and placed into eight blocks. Within blocks, eight dogs were randomly allocated among eight groups: Groups 1 to 4 were treated orally with lotilaner, at as close as possible to the minimum dose rate of 20 mg/kg within 30 (± 5) minutes after feeding; Groups 5 to 8 were untreated controls. All dogs were infested with 100 ± 5 fleas on Day -2, and whole-body flea counts were completed at 30 min and one, two and 8 h after treatment. Efficacy calculations were based on arithmetic and geometric means if an adequate infestation (at least six of eight untreated dogs with a flea retention of ≥ 50%) was demonstrated in the equivalent control group., Results: Adequate infestations were established in all control groups. At 30 min and 1 h post-treatment, relative to the matching untreated control group, there were no significant reductions in mean flea counts in lotilaner-treated dogs, although moribund fleas were evident at 1 h post-treatment. At 2 h after treatment, compared with the equivalent control group, the geometric mean flea count reduction in the lotilaner group was 64.0% (t (7)  = 2.86, P = 0.0242). At 8 h after treatment, lotilaner efficacy was 99.6%. There were no treatment-related adverse events., Conclusion: This study demonstrates that lotilaner flavored chewable tablets are well tolerated and begin to kill fleas within 2 h of treatment, achieving 99.6% efficacy within 8 h. Lotilaner can therefore be used to quickly alleviate the flea irritation that arises from existing infestations.

Rationale: Transfluthrin is a relatively non-toxic rapid-acting synthetic pyrethroid insecticide. It is widely used in household and hygiene products. A sensitive and accurate bioanalytical method is required for quantification of its concentration in plasma and its potential target organ, the brain for studies to assess its health effects and toxicokinetics in mammals., Methods: The samples were prepared by liquid-liquid extraction. Gas chromatography mass spectrometry (GC/MS) analysis was performed for the determination of transfluthrin in biological samples with an overall method run time of 15 min. Transfluthrin was quantified using selected-ion monitoring (SIM) in the negative chemical ionization (NCI) mode. Chromatographic separation was achieved using a Zebron® ZB5-MS GC column operating with 1 mL/min constant flow helium. Cis-Permethrin was used as the internal standard., Results: The method was validated to be precise and accurate within the linear range of 1.0-400.0 ng/mL in plasma and 4.0-400.0 ng/mL in brain homogenate, based on a 100 μL sample volume for both matrices. This method was applied to samples following administration of a 10 mg/kg oral dose to male adult rats. The plasma concentrations were observed to be 11.70 ± 5.69 ng/mL and brain concentrations 12.09 ± 3.15 ng/g when measured 2 h post-dose., Conclusions: A rapid GC/NCI-MS method was demonstrated to be sensitive, specific, precise and accurate for the quantification of transfluthrin in rat plasma and brain. The optimized method was successfully used to quantify the rat plasma and brain concentrations of transfluthrin 2 h after the oral dosing of Sprague-Dawley rats., (Copyright © 2017 John Wiley & Sons, Ltd.)

Permethrin, the most widely used household insecticide in the United States, is marketed as a mixture of its cis (CIS) and trans (TRANS) isomers. The major objective of this investigation is to develop and utilize a reliable approach to determine in vivo partition coefficients (PCs) for CIS and TRANS in immature and adult Sprague-Dawley rats. Adult, postnatal day (PND) 21, and PND 15 rats were infused with environmentally relevant concentrations of CIS or TRANS via a subcutaneous osmotic pump for 48 or 72 h. The adult and PND 21 rats also received an oral loading dose. Systemic steady-state or equilibrium was attained in each age group within 72 h of the protocol. CIS and TRANS were both distributed to tissues according to their neutral lipid content, with adipose tissue exhibiting much higher tissue:plasma PCs than skeletal muscle, liver, or brain. Liver:plasma and brain:plasma PCs were consistently at or lower than unity. Tissue:plasma PCs were generally higher for CIS than for TRANS, although the isomers are of comparable lipophilicity. Significantly higher blood levels of CIS apparently saturate plasma binding, resulting in greater tissue deposition of the isomer. CIS and TRANS tissue:plasma PCs were found to be inversely related to the rats' age, although TRANS brain:plasma PCs were comparable in immature and mature animals. These data support the conclusion that age-dependent partitioning is an important determinant of the pharmacokinetics of permethrin. Such partitioning could influence the risk assessment of these insecticides in infants and children when incorporated into physiologically based pharmacokinetic models., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Although indoor residual spraying (IRS) is an effective tool for malaria control, its use contributes to high insecticide exposure in sprayed communities and raises concerns about possible unintended health effects., Objective: The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort study initiated in 2012 to characterize prenatal exposure to IRS insecticides and exposures' impacts on child health and development in rural South Africa., Methods: In this report, we describe the VHEMBE cohort and dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) serum concentrations measured in VHEMBE mothers when they presented for delivery. In addition, we applied a causal inference framework to estimate the potential reduction in population-level p , p' -DDT and p , p' -DDE serum concentrations under five hypothetical interventions. A total of 751 mothers were enrolled., Results: Serum concentrations of p , p' isomers of DDT and DDE were above the limit of detection (LOD) in ≥98% of the samples, whereas the o , p' isomers were above the LOD in at least 80% of the samples. Median (interquartile range) p , p' -DDT and p , p' -DDE serum concentrations for VHEMBE cohort participants were 55.3 (19.0-259.3) and 242.2 (91.8-878.7) ng/g-lipid, respectively. Mothers reporting to have lived in a home sprayed with DDT for malaria control had ~5-7 times higher p , p' -DDT and p , p' -DDE serum concentrations than those who never lived in a home sprayed with DDT. Of the five potential interventions tested, we found increasing access to water significantly reduced p , p' -DDT exposure and increasing the frequency of household wet mopping significantly reduced p , p' -DDT and p , p' -DDE exposure., Conclusion: Our findings suggest that several intervention approaches may reduce DDT/DDE exposure in pregnant women living in IRS communities. https://doi.org/10.1289/EHP353.

Lambda-cyhalothrin is a pyrethroid pesticide largely used in agriculture. Exposure assessment can be performed by measuring key urinary metabolites. For a proper use of biomonitoring data, it is however important to gain information on the toxicokinetics of these key biomarkers of exposure. A human volunteer study was performed to document the plasma and urinary time courses of major lambda-cyhalothrin metabolites. Seven volunteers ingested 0.025mgkg -1 body weight of lambda-cyhalothrin. Blood samples were withdrawn prior to dosing and at fixed time periods over the 72 h-period following ingestion and complete urine voids were collected pre-exposure and at pre-established intervals over 84h post-dosing. The cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were quantified in these samples. Plasma concentrations of CFMP and 3-PBA increased rapidly after ingestion, with average peak values at 3.1 and 4.0h post-dosing, respectively; subsequent elimination phase showed a rapid decay with a mean half-life (t ½ ) of ≈5.3 and 6.4h for CFMP and 3-PBA, respectively. Urinary rate time courses displayed a profile similar to the plasma concentration-time curves with corresponding mean t ½ of ≈4.2 and 5.9h. In the 84-h period post-treatment, on average 21% of lambda-cyhalothrin dose were excreted in urine as CFMP as compared to 30% as 3-PBA. Overall, CFMP and 3-PBA metabolites were confirmed to be major metabolites of lambda-cyhalothrin and exhibited similar kinetics with short half-lives; they thus both appear as useful biomarkers of exposure to lambda-cyhalothrin in humans., (Copyright © 2017 Elsevier B.V. All rights reserved.)