Abstract
Human biomonitoring provides information about chemicals measured in biological matrices, but their interpretation remains uncertain because of pharmacokinetic (PK) interactions. This study examined the PKs in blood from Long–Evans rats after a single oral dose of 0.4 mg/kg bw of each pesticide via a mixture of the 17 pesticides most frequently measured in humans. These pesticides are β-endosulfan; β-hexachlorocyclohexane [β-HCH]; γ-hexachlorocyclohexane [γ-HCH]; carbofuran; chlorpyrifos; cyhalothrin; cypermethrin; diazinon; dieldrin; diflufenican; fipronil; oxadiazon; pentachlorophenol [PCP]; permethrin; 1,1-dichloro-2,2bis(4-chlorophenyl)ethylene [p,p′-DDE]; 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane [p,p′-DDT]; and trifluralin. We collected blood at 10 min to 48-h timepoints in addition to one sample before gavage (for a control). We used GS–MS/MS to measure the pesticide (parents and major metabolites) concentrations in plasma, determined the PK parameters from 20 sampling timepoints, and analyzed the food, litter, and cardboard in the rats’ environment for pesticides. We detected many parents and metabolites pesticides in plasma control (e.g., diethyl phosphate [DEP]; PCP; 3-phenoxybenzoic acid [3-PBA]; 3,5,6-trichloro-2-pyridinol [TCPy], suggesting pre-exposure contamination. The PK values post-exposure showed that the AUC0−∞ and Cmax were highest for TCPy and PCP; β-endosulfan, permethrin, and trifluralin presented the lowest values. Terminal T1/2 and MRT for γ-HCH and β-HCH ranged from 74.5 h to 117.1 h; carbofuran phenol presented the shortest values with 4.3 h and 4.8 h. These results present the first PK values obtained through a realistic pattern applied to a mixture of 17 pesticides to assess exposure. This study also highlights the issues of background exposure and the need to work with a relevant mixture found in human matrices.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- 3-PBA:
-
3-Phenoxybenzoic acid
- ADME:
-
Absorption, distribution, metabolism, and excretion
- ATSDR:
-
Agency for Toxic Substances and Disease Registry
- AUC0−∞ :
-
Area under the curve
- C max :
-
Maximum concentration in plasma
- Cl2CA:
-
Cis-/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid
- ClCF3CA:
-
3-(2-Chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid
- DEP:
-
Diethyl phosphate
- DETP:
-
Diethyl thiophosphate
- ED30 :
-
Effective dose
- EDTA:
-
Ethylenediaminetetraacetic acid
- EFSA:
-
European Food Safety Authority
- FNR:
-
Luxembourg National Research Fund (Fonds National de la Recherche)
- GC:
-
Gas chromatography
- GC–MS/MS:
-
Gas chromatography with tandem mass spectrometry
- HCH:
-
Hexachlorocyclohexane (gamma [γ], beta [β])
- LD50:
-
Lethal dose 50%
- MRT:
-
Mean residence time
- PAH:
-
Polycyclic aromatic hydrocarbon
- PCP:
-
Pentachlorophenol
- PK:
-
Pharmacokinetics
- p,p′-DDD:
-
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethane
- p,p′-DDE:
-
1,1-Dichloro-2,2bis(4-chlorophenyl) ethylene
- p,p′-DDT:
-
1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane
- SPME:
-
Solid-phase microextraction
- T 1/2 :
-
Terminal elimination half-life
- TCPy:
-
3,5,6-Trichloro-2-pyridinol
- T max :
-
Time to reach the Cmax
- WHO:
-
World Health Organization
References
Appenzeller BM, Tsatsakis AM (2012) Hair analysis for biomonitoring of environmental and occupational exposure to organic pollutants: state of the art, critical review and future needs. Toxicol Lett 210(2):119–140. https://doi.org/10.1016/j.toxlet.2011.10.021
Appenzeller BM, Hardy EM, Grova N et al (2017a) Hair analysis for the biomonitoring of pesticide exposure: comparison with blood and urine in a rat model. Arch Toxicol 91(8):12. https://doi.org/10.1007/s00204-016-1910-9
Appenzeller BMR, Hardy EM, Grova N et al (2017b) Hair analysis for the biomonitoring of pesticide exposure: comparison with blood and urine in a rat model. Arch Toxicol 91(8):2813–2825. https://doi.org/10.1007/s00204-016-1910-9
ATSDR (2002) Toxicological profile for DDT, DDE, and DDD. Agency for Toxic Substances and Disease Registry, Atlanta, p 497
Barr DB (2008) Biomonitoring of exposure to pesticides. J Chem Health Saf 15(6):9
Bastias-Candia S, Zolezzi JM, Inestrosa NC (2019) Revisiting the paraquat-induced sporadic Parkinson’s disease-like model. Mol Neurobiol 56(2):11. https://doi.org/10.1007/s12035-018-1148-z
Beranger R, Hardy EM, Dexet C et al (2018) Multiple pesticide analysis in hair samples of pregnant French women: results from the ELFE national birth cohort. Environ Int 120:43–53. https://doi.org/10.1016/j.envint.2018.07.023
Chata C, Grova MH, Appenzeller BM (2016) Influence of pesticide physicochemical properties on the association between plasma and hair concentration. Anal Bioanal Chem 408(13):3601–3612. https://doi.org/10.1007/s00216-016-9442-y
Curl CL, Beresford SA, Fenske RA et al (2015) Estimating pesticide exposure from dietary intake and organic food choices: the Multi-Ethnic Study of Atherosclerosis (MESA). Environ Health Perspect 123(5):475–483. https://doi.org/10.1289/ehp.1408197
Dereumeaux C, Saoudi A, Pecheux M et al (2016) Biomarkers of exposure to environmental contaminants in French pregnant women from the Elfe cohort in 2011. Environ Int 97:56–67. https://doi.org/10.1016/j.envint.2016.10.013
EFSA (2017) The 2015 European union report on pesticides in food, p 134
Grova N, Salquebre G, Schroeder H, Appenzeller BM (2011) Determination of PAHs and OH-PAHs in rat brain by gas chromatography tandem (triple quadrupole) mass spectrometry. Chem Res Toxicol 24(10):1653–1667. https://doi.org/10.1021/tx2003596
Gupta RC (1994) Carbofuran toxicity. J Toxicol Environ Health 43(4):383–418. https://doi.org/10.1080/15287399409531931
Haines DA, Saravanabhavan G, Werry K, Khoury C (2017) An overview of human biomonitoring of environmental chemicals in the Canadian Health Measures Survey: 2007–2019. Int J Hyg Environ Health 220(2 Pt A):13–28. https://doi.org/10.1016/j.ijheh.2016.08.002
He CT, Yan X, Wang MH et al (2017) Dichloro-diphenyl-trichloroethanes (DDTs) in human hair and serum in rural and urban areas in South China. Environ Res 155:279–286. https://doi.org/10.1016/j.envres.2017.02.011
Hernandez AF, Gil F, Lacasana M et al (2013) Pesticide exposure and genetic variation in xenobiotic-metabolizing enzymes interact to induce biochemical liver damage. Food Chem Toxicol 61:144–151. https://doi.org/10.1016/j.fct.2013.05.012
Jaga K, Dharmani C (2005) The epidemiology of pesticide exposure and cancer: a review. Rev Environ Health 20(1):15–38
Khemiri R, Cote J, Fetoui H, Bouchard M (2017) Documenting the kinetic time course of lambda-cyhalothrin metabolites in orally exposed volunteers for the interpretation of biomonitoring data. Toxicol Lett 276:115–121. https://doi.org/10.1016/j.toxlet.2017.05.022
Kumar A, Sharma B, Pandey RS (2009) Cypermethrin and lambda-cyhalothrin induced in vivo alterations in nucleic acids and protein contents in a freshwater catfish, Clarias batrachus (Linnaeus; Family-Clariidae). J Environ Sci Health B 44(6):564–570. https://doi.org/10.1080/03601230903000537
LaKind JS, Sobus JR, Goodman M et al (2014) A proposal for assessing study quality: biomonitoring, environmental epidemiology, and short-lived chemicals (BEES-C) instrument. Environ Int 73:195–207. https://doi.org/10.1016/j.envint.2014.07.011
Lebov JF, Engel LS, Richardson D, Hogan SL, Sandler DP, Hoppin JA (2015) Pesticide exposure and end-stage renal disease risk among wives of pesticide applicators in the Agricultural Health Study. Environ Res 143(Pt A):198–210. https://doi.org/10.1016/j.envres.2015.10.002
Lehmann E, Oltramare C, Nfon Dibie JJ, Konate Y, de Alencastro LF (2018) Assessment of human exposure to pesticides by hair analysis: the case of vegetable-producing areas in Burkina Faso. Environ Int 111:14. https://doi.org/10.1016/j.envint.2017.10.025
Luo D, Pu Y, Tian H et al (2016) Concentrations of organochlorine pesticides in umbilical cord blood and related lifestyle and dietary intake factors among pregnant women of the Huaihe River Basin in China. Environ Int 92–93:276–283. https://doi.org/10.1016/j.envint.2016.04.017
Ma Q, Lu AY (2003) Origins of individual variability in P4501A induction. Chem Res Toxicol 16(3):249–260. https://doi.org/10.1021/tx0200919
Mansouri A, Cregut M, Abbes C, Durand MJ, Landoulsi A, Thouand G (2017) The environmental issues of DDT pollution and bioremediation: a multidisciplinary review. Appl Biochem Biotechnol 181(1):309–339. https://doi.org/10.1007/s12010-016-2214-5
Mucke W, Alt KO, Esser HO (1970) Degradation of 14 C-labeled diazinon in the rat. J Agric Food Chem 18(2):208–212
Mühlebach S, Moor MJ, Wyss PA, Bickel MH (1991) Kinetics of distribution and elimination of DDE in rats. Xenobiotica 21(1):111–120. https://doi.org/10.3109/00498259109039455
NRC/NAS (2006) Human biomonitoring for environmental chemicals. The National Academies Press, Washington, DC
Palazzi P, Mezzache S, Bourokba N et al (2018) Exposure to polycyclic aromatic hydrocarbons in women living in the Chinese cities of BaoDing and Dalian revealed by hair analysis. Environ Int. https://doi.org/10.1016/j.envint.2018.10.056
Ratelle M, Cote J, Bouchard M (2015) Time profiles and toxicokinetic parameters of key biomarkers of exposure to cypermethrin in orally exposed volunteers compared with previously available kinetic data following permethrin exposure. J Appl Toxicol 35(12):1586–1593. https://doi.org/10.1002/jat.3124
Reigner BG, Gungon RA, Bois FY, Zeise L, Tozer TN (1992) Pharmacokinetic concepts in assessing intake of pentachlorophenol by rats after exposure through drinking water. J Pharm Sci 81(11):1113–1118
Rodriguez-Gomez R, Martin J, Zafra-Gomez A, Alonso E, Vilchez JL, Navalon A (2017) Biomonitoring of 21 endocrine disrupting chemicals in human hair samples using ultra-high performance liquid chromatography-tandem mass spectrometry. Chemosphere 168:676–684. https://doi.org/10.1016/j.chemosphere.2016.11.008
Saeed MF, Shaheen M, Ahmad I et al (2017) Pesticide exposure in the local community of Vehari District in Pakistan: an assessment of knowledge and residues in human blood. Sci Total Environ 587–588:137–144. https://doi.org/10.1016/j.scitotenv.2017.02.086
Salquebre G, Schummer C, Millet M, Briand O, Appenzeller BM (2012) Multi-class pesticide analysis in human hair by gas chromatography tandem (triple quadrupole) mass spectrometry with solid phase microextraction and liquid injection. Anal Chim Acta 710:65–74. https://doi.org/10.1016/j.aca.2011.10.029
Schulz C, Angerer J, Ewers U, Heudorf U, Wilhelm M, Human Biomonitoring Commission of the German Federal Environment A (2009) Revised and new reference values for environmental pollutants in urine or blood of children in Germany derived from the German environmental survey on children 2003-2006 (GerES IV). Int J Hyg Environ Health 212(6):637–647. https://doi.org/10.1016/j.ijheh.2009.05.003
Sheldon LS, Berry Jr. MR (1999) Bioaccumulation of POPs in fish and estimation of human dietary exposure and dose ISEE/ISEA ‘99 Athens, Greece
Smith JN, Campbell JA, Busby-Hjerpe AL et al (2009) Comparative chlorpyrifos pharmacokinetics via multiple routes of exposure and vehicles of administration in the adult rat. Toxicology 261(1–2):47–58. https://doi.org/10.1016/j.tox.2009.04.041
Song G, Wu H, Yoshino K, Zamboni WC (2012) Factors affecting the pharmacokinetics and pharmacodynamics of liposomal drugs. J Liposome Res 22(3):177–192. https://doi.org/10.3109/08982104.2012.655285
Srinivasan K, Radhakrishnamurty R (1983) Studies on the distribution of beta- and gamma-isomers of hexachlorocyclohexane in rat tissues. J Environ Sci Health B 18(3):401–418. https://doi.org/10.1080/03601238309372378
Starr JM, Graham SE, Ross DG et al (2014) Environmentally relevant mixing ratios in cumulative assessments: a study of the kinetics of pyrethroids and their ester cleavage metabolites in blood and brain; and the effect of a pyrethroid mixture on the motor activity of rats. Toxicology 320:15–24. https://doi.org/10.1016/j.tox.2014.02.016
Storm JE, Rozman KK, Doull J (2000) Occupational exposure limits for 30 organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase. Toxicology 150(1–3):1–29
Tang C, Lin JH, Lu AY (2005) Metabolism-based drug-drug interactions: what determines individual variability in cytochrome P450 induction? Drug Metab Dispos 33(5):603–613. https://doi.org/10.1124/dmd.104.003236
Timchalk C, Busby A, Campbell JA, Needham LL, Barr DB (2007) Comparative pharmacokinetics of the organophosphorus insecticide chlorpyrifos and its major metabolites diethylphosphate, diethylthiophosphate and 3,5,6-trichloro-2-pyridinol in the rat. Toxicology 237(1–3):145–157. https://doi.org/10.1016/j.tox.2007.05.007
Tornero-Velez R, Davis J, Scollon EJ et al (2012) A pharmacokinetic model of cis- and trans-permethrin disposition in rats and humans with aggregate exposure application. Toxicol Sci 130(1):33–47. https://doi.org/10.1093/toxsci/kfs236
Tsaboula A, Papadakis EN, Vryzas Z, Kotopoulou A, Kintzikoglou K, Papadopoulou-Mourkidou E (2016) Environmental and human risk hierarchy of pesticides: a prioritization method, based on monitoring, hazard assessment and environmental fate. Environ Int 91:78–93
van der Mark M, Vermeulen R, Nijssen PC et al (2014) Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands. Occup Environ Med 71(11):757–764. https://doi.org/10.1136/oemed-2014-102170
WHO (2018) Pesticide residues in food. http://www.who.int/en/news-room/fact-sheets/detail/pesticide-residues-in-food
Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 99(3):306–314. https://doi.org/10.1016/j.cmpb.2010.01.007
Acknowledgements
Caroline Chata benefited from a Ph.D. grant from the Luxembourg National Research Fund (Fonds National de la Recherche [FNR]) (AFR 7009593), Luxembourg.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors do not have any conflicts of interest to disclose.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Chata, C., Palazzi, P., Grova, N. et al. Blood pharmacokinetic of 17 common pesticides in mixture following a single oral exposure in rats: implications for human biomonitoring and exposure assessment. Arch Toxicol 93, 2849–2862 (2019). https://doi.org/10.1007/s00204-019-02546-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-019-02546-y