Blood pharmacokinetic of 17 common pesticides in mixture following a single oral exposure in rats: implications for human biomonitoring and exposure assessment

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.

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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

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Acknowledgements

Caroline Chata benefited from a Ph.D. grant from the Luxembourg National Research Fund (Fonds National de la Recherche [FNR]) (AFR 7009593), Luxembourg.

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Correspondence to Claude Emond.

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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

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Keywords

  • Background exposure
  • Mixture
  • Pesticides
  • Pharmacokinetic
  • Rat