Bibliography Tag: chlorpyrifos

Rauh et al., 2012

Rauh, V. A., Perera, F. P., Horton, M. K., Whyatt, R. M., Bansal, R., Hao, X., Liu, J., Barr, D. B., Slotkin, T. A., & Peterson, B. S.; “Brain anomalies in children exposed prenatally to a common organophosphate pesticide;” Proceedings of the National Academy of Sciences, 2012, 109(20), 7871-7876; DOI: 10.1073/pnas.1203396109.


Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9-11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure x IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose-response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.  FULL TEXT

Rauh et al., 2011

Rauh, Virginia, Arunajadai, Srikesh, Horton, Megan, Perera, Frederica, Hoepner, Lori, Barr, Dana B, & Whyatt, Robin; “Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural pesticide;” Environmental Health Perspectives, 2011, 119(8), 1196-1201; DOI: 10.1289/ehp.1003160.


BACKGROUND: In a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children’s Environmental Health), we have previously reported that prenatal exposure to chlorpyrifos (CPF) was associated with neurodevelopmental problems at 3 years of age.

OBJECTIVE: The goal of the study was to estimate the relationship between prenatal CPF exposure and neurodevelopment among cohort children at 7 years of age.

METHODS: In a sample of 265 children, participants in a prospective study of air pollution, we measured prenatal CPF exposure using umbilical cord blood plasma (picograms/gram plasma) and 7-year neurodevelopment using the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV). Linear regression models were used to estimate associations, with covariate selection based on two alternate approaches.

RESULTS: On average, for each standard deviation increase in CPF exposure (4.61 pg/g), Full-Scale intelligence quotient (IQ) declined by 1.4% and Working Memory declined by 2.8%. Final covariates included maternal educational level, maternal IQ, and quality of the home environment. We found no significant interactions between CPF and any covariates, including the other chemical exposures measured during the prenatal period (environmental tobacco smoke and polycyclic aromatic hydrocarbons).

CONCLUSIONS: We report evidence of deficits in Working Memory Index and Full-Scale IQ as a function of prenatal CPF exposure at 7 years of age. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.


Nolan et al., 1984

Nolan, R. J., Rick, D. L., Freshour, N. L., & Saunders, J. H.; “Chlorpyrifos: Pharmacokinetics in human volunteers;” Toxicology and Applied Pharmacology, 1984, 73(1), 8-15; DOI: 10.1016/0041-008x(84)90046-2.


The kinetics of chlorpyrifos, an organophosphorothioate insecticide, and its principal metabolite, 3,5,6-trichloro-2-pyridinol (3,5,6-TCP), were investigated in six healthy male volunteers given a single 0.5 mg/kg po and, 2 or more weeks later, a 0.5 or 5.0 mg/kg dermal dose of chlorpyrifos. No signs or symptoms of toxicity or changes in erythrocyte cholinesterase were observed. Plasma cholinesterase was depressed to 15% of predose levels by the 0.5 mg/kg po dose but was essentially unchanged following the 5.0 mg/kg dermal dose. Blood chlorpyrifos concentrations were extremely low (less than 30 ng/ml), and no unchanged chlorpyrifos was found in the urine following either route of administration. Mean blood 3,5,6-TCP concentrations peaked at 0.93 micrograms/ml 6 hr after ingestion of the oral dose and at 0.063 micrograms/ml 24 hr after the 5.0 mg/kg dermal dose. 3,5,6-TCP was cleared from the blood and eliminated in the urine with a half-life of 27 hr following both the po and dermal doses. An average of 70% of the po dose but less than 3% of the dermal dose was excreted in the urine as 3,5,6-TCP; thus only a small fraction of the dermally applied chlorpyrifos was absorbed. Chlorpyrifos and its principal metabolite were rapidly eliminated and therefore have a low potential to accumulate in man on repeated exposures. Based on these data, blood and/or urinary 3,5,6-TCP concentrations could be used to quantify the amount of chlorpyrifos absorbed under actual use conditions.

Mesnage et al., 2021B

Mesnage, R., Teixeira, M., Mandrioli, D., Falcioni, L., Ibragim, M., Ducarmon, Q. R., Zwittink, R. D., Amiel, C., Panoff, J. M., Bourne, E., Savage, E., Mein, C. A., Belpoggi, F., & Antoniou, M. N.; “Multi-omics phenotyping of the gut-liver axis reveals metabolic perturbations from a low-dose pesticide mixture in rats;” Communications Biology, 2021, 4(1), 471; DOI: 10.1038/s42003-021-01990-w.


Health effects of pesticides are not always accurately detected using the current battery of regulatory toxicity tests. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in a subchronic toxicity test of a mixture of six pesticides frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole) in Sprague-Dawley rats. Analysis of water and feed consumption, body weight, histopathology and serum biochemistry showed little effect. Contrastingly, serum and caecum metabolomics revealed that nicotinamide and tryptophan metabolism were affected, which suggested activation of an oxidative stress response. This was not reflected by gut microbial community composition changes evaluated by shotgun metagenomics. Transcriptomics of the liver showed that 257 genes had their expression changed. Gene functions affected included the regulation of response to steroid hormones and the activation of stress response pathways. Genome-wide DNA methylation analysis of the same liver samples showed that 4,255 CpG sites were differentially methylated. Overall, we demonstrated that in-depth molecular profiling in laboratory animals exposed to low concentrations of pesticides allows the detection of metabolic perturbations that would remain undetected by standard regulatory biochemical measures and which could thus improve the predictability of health risks from exposure to chemical pollutants. FULL TEXT

Moore et al., 2014

Moore, C. A., Wilkinson, S. C., Blain, P. G., Dunn, M., Aust, G. A., & Williams, F. M.; “Percutaneous absorption and distribution of organophosphates (chlorpyrifos and dichlorvos) following dermal exposure and decontamination scenarios using in vitro human skin model;” Toxicology Letters, 2014, 229(1), 66-72; DOI: 10.1016/j.toxlet.2014.06.008.


To date, there has been little research investigating low-level human exposure to chemicals, and so the aim of this study was to examine the percutaneous penetration of organophosphates (dichlorvos and chlorpyrifos) using low-level exposure scenarios in vitro. Dermal absorption of chlorpyrifos applied in different vehicles was measured at 0, 4, 8 and 24 h, after dose application for 4 and 24 h exposure (finite dose, 500 ng/cm(2)) in isopropanol (IPA), isopropyl myristate (IPM) and propylene glycol (PG). Dichlorvos was applied to the skin for 24 h (infinite dose, 1 mg/cm(2) and 10 mg/cm(2); finite dose, 5 mug/cm(2)) using the same vehicles. Human skin was mounted in flow through diffusion cells with minimum essential medium eagle pH 7.4 (supplemented with 2% BSA) as receptor fluid. Following exposure, the skin surface dose was removed by tissue swabbing, the stratum corneum removed by sequential tape stripping, and the skin digested prior to scintillation counting (chlorpyrifos), or GC/MS analysis (dichlorvos). The dermal absorption of chlorpyrifos was the greatest following application in PG (19.5% of dose), when compared with absorption from the IPA and IPM vehicles (10.3% and 1.9% absorbed respectively). However, dichlorvos showed greater dermal absorption than chlorpyrifos from all vehicles used, with greatest absorption from the IPA vehicle (38.6% absorbed). Although dichlorvos exhibited a short lag time (0.6 h from IPA and IP vehicles, and 0.4 h from PG), chlorpyrifos displayed greater propensity to accumulate in the stratum corneum and epidermis/dermis. These results demonstrate that prompt skin surface decontamination would be required for both dichlorvos and chlorpyrifos (and chemicals with similar properties) in the event of skin contact. The magnitude of the skin reservoir formed with chlorpyrifos was time dependent, therefore, prompt decontamination of this and similar chemicals would be required to reduce delayed systemic absorption.

Geer et al., 2004

Geer, L. A., Cardello, N., Dellarco, M. J., Leighton, T. J., Zendzian, R. P., Roberts, J. D., & Buckley, T. J.; “Comparative analysis of passive dosimetry and biomonitoring for assessing chlorpyrifos exposure in pesticide workers;” Annals of Occupational Hygeine, 2004, 48(8), 683-695; DOI: 10.1093/annhyg/meh056.


Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the US Environmental Protection Agency (EPA) has the authority to regulate the use of pesticides to prevent unreasonable adverse human health effects associated with pesticide exposure. Accordingly, the EPA requires pesticide registrants to perform studies evaluating the potential for pesticide handler exposure. Data from five such studies that included exposure measurements based on both external measurements and biological monitoring were used to examine methods of assessment, routes and determinants of exposure and dose to the pesticide chlorpyrifos. Eighty workers across four job classes were included: mixer/loaders (M/L, n = 24), mixer/loader/applicators (M/L/A, n = 37), applicators (A, n = 9) and re-entry scouts (RS, n = 10). Results showed that doses were highly variable and differed by job class (P < 0.05) with median total (inhalation and dermal combined) exposure-derived absorbed doses (EDADtot) of 129, 88, 85 and 45 microg/application for A, M/L/A, M/L and RS, respectively. Doses derived from the measurement of 3,5,6-trichloro- 2-pyridinol (3,5,6-TCP) in urine were similar in magnitude but differed in rank with median values of 275, 189, 122 and 97 microg/application for A, M/L, RS, and M/L/A, respectively. The relative contribution of dermal to inhalation exposure was examined by their ratio. The median ratios of exposure-derived absorbed dermal dose (EDADderm) (assuming 3% absorption) to exposure-derived absorbed inhalation dose (EDADinh) (assuming 100% absorption) across job classes were 1.7, 1.5, 0.44 and 0.18 for RS, M/L, A and M/L/A, respectively, with an overall median of 0.6. For 34 of 77 workers (44%), this ratio exceeded 1.0, indicating the significance of the dermal exposure pathway. Different dermal absorption factor (DAF) assumptions were examined by comparing EDADtot to the biomarker-derived absorbed dose (BDAD) as a ratio where EDADtot was calculated assuming a DAF of 1, 3 and 10%. Median ratios of 0.45, 0.71 and 1.28, respectively, were determined suggesting the DAF is within the range of 3-10%. A simple linear regression of urinary 3,5,6-TCP against EDADtot indicates a positive association explaining 29% of the variability in the 3,5,6-TCP derived estimate of dose. A multiple linear regression model including the variables EDADderm, EDADinh and application type explained 46% of the variability (R2 = 0.46) in the urinary dose estimate. EDADderm was marginally significant (P = 0.066) while EDADinh was not (P = 0.57). The EDADderm regression coefficient (0.0007) exceeded the coefficient for EDADinh (0.00002) by a factor of 35. This study demonstrates the value of the pesticide registrant database for the purpose of evaluating pesticide worker exposure. It highlights the significance of the dermal exposure pathway, and identifies the need for methods and research to close the gap between external and internal exposure measures. FULL TEXT

Meuling et al., 2005

Meuling, W. J., Ravensberg, L. C., Roza, L., & van Hemmen, J. J.; “Dermal absorption of chlorpyrifos in human volunteers;” International Archives of Occupational and Environmental Health, 2005, 78(1), 44-50; DOI: 10.1007/s00420-004-0558-6.


OBJECTIVE: The methods and results are described of a study on the dermal absorption of chlorpyrifos (CPF) in humans established via urinary excretion of the metabolite 3,5,6-trichloro-2-pyridinol (TCP).

METHODS: Two dermal, single, doses of CPF were applied in two study groups (A and B) each comprising three apparently healthy male volunteers who gave their written informed consent. The clinical part of the study was conducted in compliance with the ICH Guideline and the EC principles of good clinical practice (GCP). An approximately 0.5 ml dilution of CPF in ethanol was applied to an area of approximately 100 cm(2) of the volar aspect of the forearm, resulting in doses of either 5 mg (A) or 15 mg (B) of CPF per study subject. Duration of dermal exposure was 4 h, after which the non-absorbed fraction was washed off. The following samples were collected at pre-determined intervals for the determination of either CPF or its metabolite TCP: dosing solutions, wash-off fractions and urine samples collected up to 120 h after dosing.

RESULTS: A relatively large fraction of CPF (42%-67% of the applied dose) was washed off from the exposed skin area. Application of either 5 mg (A) or 15 mg CPF (B) resulted in the total urinary excretion of 131.8 microg (A) or 115.6 microg (B) of TCP 120 h after dosing. This indicated that 4.3% of the applied dose has been absorbed (A), while in group (B) no significant increase in urinary TCP (115.6 microg) was established. The latter indicates that an increase in the dermal dose at a fixed area does not increase absorption, which suggests that the percutaneous penetration rate was constant. Further, it was observed that the clearance of CPF by the body was not completed within 120 h, suggesting that CPF or TCP was retained by the skin and/or accumulated in the body. A mean elimination half-life of 41 h was established.

CONCLUSION: The results show that daily occupational exposure to CPF may result in accumulation of CPF and/or its metabolites, possibly resulting in adverse effects. FULL TEXT


Linhart et al., 2021

Linhart, Caroline, Panzacchi, Simona, Belpoggi, Fiorella, Clausing, Peter, Zaller, Johann G., & Hertoge, Koen; “Year-round pesticide contamination of public sites near intensively managed agricultural areas in South Tyrol;” Environmental Sciences Europe, 2021, 33(1); DOI: 10.1186/s12302-020-00446-y.


BACKGROUND: In a previous study, we found that 45% of public playgrounds near intensively managed agricultural areas were contaminated with mainly endocrine active pesticide residues in spring. Here, we investigated potential contamination over the course of a year.

METHODS: Residue data were analyzed from 96 grass samples collected in spring, summer, autumn, and winter by the South Tyrolean Medical Service in 19 public playgrounds, four schoolyards, and one marketplace located within intensively managed agricultural landscapes. Samples were analyzed for 281 substances using gas-chromatography and mass-spectrometry.

RESULTS: A total of 32 pesticide residues and one preservative agent were found. Almost all of the sites (96%) were contaminated with at least one residue during the year; in 79% of the sites, more than one residue was found. Among the detected residues, 76% are classified as endocrine active substances, with the highest concentrations of the insecticide chlorpyrifos-methyl (0.71 mg kg−1), the herbicide oxadiazon (0.64 mg kg−1), and the fungicides captan (0.46 mg kg−1) and fluazinam (0.23 mg kg−1). The number of residues, their concentrations, and the proportion of contaminated sites varied across seasons (p < 0.001). Twenty-five residues were found in 83% of the sites in spring (median concentration 0.240 mg kg−1), nine in 79% of the sites in summer (0.092 mg kg−1), three in 50% of the sites in autumn (0.076 mg kg−1), and four in 17% of the sites in winter (0.155 mg kg−1). Playgrounds already examined in 2017 in the previous study, were more often contaminated with multiple pesticide residues in 2018 (p = 0.045).

CONCLUSION: This study confirms previous findings of widespread pesticide contamination of public sites within intensively managed agricultural areas. Moreover, pesticide residues were also found in periods with little or no pesticide application in the field (autumn and winter). It is worrisome that many of the detected residues are endocrine active substances and that some of them (thiacloprid, bupirimate, captan, folpet) are “suspected human carcinogens”, according to EU authorities. Thus, we call for more effective controls of pesticide applications to minimize pesticide drift into public places. FULL TEXT

Sheppard et al., 2020

Sheppard, L., McGrew, S., & Fenske, R. A.; “Flawed analysis of an intentional human dosing study and its impact on chlorpyrifos risk assessments;” Environment International, 2020, 143, 105905; DOI: 10.1016/j.envint.2020.105905.


In March 1972, Frederick Coulston and colleagues at the Albany Medical College reported results of an intentional chlorpyrifos dosing study to the study’s sponsor, Dow Chemical Company. Their report concluded that 0.03 mg/kg-day was the chronic no-observed-adverse-effect-level (NOAEL) for chlorpyrifos in humans. We demonstrate here that a proper analysis by the original statistical method should have found a lower NOAEL (0.014 mg/kg-day), and that use of statistical methods first available in 1982 would have shown that even the lowest dose in the study had a significant treatment effect. The original analysis, conducted by Dow-employed statisticians, did not undergo formal peer review; nevertheless, EPA cited the Coulston study as credible research and kept its reported NOAEL as a point of departure for risk assessments throughout much of the 1980’s and 1990’s. During that period, EPA allowed chlorpyrifos to be registered for multiple residential uses that were later cancelled to reduce potential health impacts to children and infants. Had appropriate analyses been employed in the evaluation of this study, it is likely that many of those registered uses of chlorpyrifos would not have been authorized by EPA. This work demonstrates that reliance by pesticide regulators on research results that have not been properly peer-reviewed may needlessly endanger the public. FULL TEXT

Alavanja et al., 2004

Alavanja, M. C., Dosemeci, M., Samanic, C., Lubin, J., Lynch, C. F., Knott, C., Barker, J., Hoppin, J. A., Sandler, D. P., Coble, J., Thomas, K., & Blair, A.; “Pesticides and lung cancer risk in the agricultural health study cohort;” American Journal of Epidemiology, 2004, 160(9), 876-885; DOI: 10.1093/aje/kwh290.


The authors examined the relation between 50 widely used agricultural pesticides and lung cancer incidence in the Agricultural Health Study, a prospective cohort study of 57,284 pesticide applicators and 32,333 spouses of farmer applicators with no prior history of lung cancer. Self-administered questionnaires were completed at enrollment (1993-1997). Cancer incidence was determined through population-based cancer registries from enrollment through December 31, 2001. A lung cancer standardized incidence ratio of 0.44 (95% confidence interval: 0.39, 0.49) was observed overall, due in large part to a low cigarette smoking prevalence. Two widely used herbicides, metolachlor and pendimethalin (for low-exposed groups to four higher exposure categories: odds ratio (OR) = 1.0, 1.6, 1.2, 5.0; p(trend) = 0.0002; and OR = 1.0, 1.6, 2.1, 4.4; p(trend) = 0.003, respectively), and two widely used insecticides, chlorpyrifos and diazinon (OR = 1.0, 1.1, 1.7, 1.9; p(trend) = 0.03; and OR = 1.0, 1.6, 2.7, 3.7; p(trend) = 0.04, respectively), showed some evidence of exposure response for lung cancer. These excesses could not be explained by previously identified lung cancer risk factors. The usage levels in this cohort are considerably higher than those typically experienced by the general population. An excess risk among spouses directly exposed to pesticides could not be evaluated at this time. FULL TEXT