Bioavailability and nervous tissue distribution of pyrethroid insecticide cyfluthrin in rats

Highlights

• Toxicokinetics of cyfluthrin after single oral and intravenous (IV) doses were determined in male Wistar rats.

• Serial plasma and brain tissue samples were collected and analysed to quantify cyfluthrin concentrations by LC/MS.

• Cyfluthrin kinetic disposition after IV and oral doses was best described by the use of a two-compartment open model.

• When administered orally, cyfluthrin was extensively absorbed, distributed to brain tissues and slowly eliminated.

• Cyfluthrin brain accumulation, mainly in hypothalamus, was observed; Cmax in hypothalamus was 3.3 times higher than in plasma.

Abstract

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_1/2β) 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_1/2β 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.

Introduction

Pyrethroid insecticides are synthetic analogues of the natural pyrethrins, which are components of extracts from the flowers of Chrysanthemum spp. Pyrethrins are potent insecticides with relatively low mammalian toxicity but are very sensitive to air and light. Hence, the use of pyrethrins for crop protection and to control disease-carrying insects is limited. With an altered structure, the pyrethroids are more photostable, and generally more toxic to insects than natural pyrethrins. Pyrethroids have replaced other pesticides (e.g. organophosphates) that are considered to have higher mammalian toxicity (Williams et al., 2008). From the many uses of pyrethroids including agricultural, commercial and residential pest control, and veterinary and medical practices (Anadón et al., 2009, 2013a; Wei et al., 2012), humans can be exposed to multiple pyrethroids (Amweg et al., 2005; Bradberry et al., 2005; Stout et al., 2009). Exposure to pyrethroids in the general population may occur by dietary intake of pesticide residues on fruits, vegetables, cereals but also by dermal contact and respiratory uptake (Schettgen et al., 2002; Ferland et al., 2015). Although clinical features resulting from acute accidental exposure to pyrethroids are well described in humans (e.g. paraesthesia, and respiratory, eye and skin irritation), several recent epidemiological studies have raised concerns about potentially adverse effects on sperm quality and sperm DNA, reproductive hormones, and pregnancy outcomes (Saillenfait et al., 2015).

The basic mechanism of pyrethroid action in both insects and mammals involves interference with the nerve membrane sodium channels, leading to prolonged depolarization and induction of repetitive activity (Vijverberg and van den Bercken, 1982; Narahashi, 1985). Pyrethroids are commonly divided into Type I compounds (or T-syndrome pyrethroids), which lack an α-cyano substituent and Type II compounds (or CS-syndrome pyrethroids), which contain an α-cyanophenoxybenzyl substituent (Gammon et al., 1981; Verschoyle and Aldridge, 1980; Soderlund et al., 2002; Wolansky et al., 2005). The main symptom of exposure to the former is tremor, whereas choreoathetosis and salivation are the main symptoms of the latter. Some pyrethroids produced tremors and salivation, classified as the intermediate TS-syndrome. The nervous system is the primary target tissue for the neurotoxicity produced soon after acute exposure to pyrethroids in laboratory animals (Scollon et al., 2011).

The international regulatory agencies are currently evaluating health risks of pyrethroids. Toxicokinetics studies (absorption, tissue disposition, metabolism and elimination) are playing an increasingly important role in reducing uncertainties inherent in risk assessments. Chemical toxicity is a dynamic process, in which the degree and duration of adverse effect are dependent on the amount of toxic compound reaching and remaining at the target tissue. In the publications and reports, four characteristics have been mentioned which are allegedly typical of pyrethroids and responsible for the health risks involved: (a) synthetic pyrethroids such as Type I pyrethroids are easily cleaved at the ester linkage followed by oxidation and conjugation, the derived metabolites are rapidly excreted as glucuronide, glycine and sulfate conjugates, however the rate of ester cleavage is lower for the Type II pyrethroids (Kaneko, 2011); (b) due to their lipophilic and metabolic properties, pyrethroids can accumulate in nerve tissue; nervous tissue accumulation of Type II pyrethroids was evidenced by nervous tissue/plasma area under the concentration vs time curve ratios (Anadón et al., 1996, 2006); (c) the neurotoxicity of pyrethroids appears to be due to parent compound; brain concentrations of the Type II pyrethroid deltamethrin correlate with neurotoxic endpoints (Rickard and Brodie, 1985; Anand et al., 2006; Kim et al., 2010) and (d) there is no evidence indicating if the nervous system is reversibly or irreversibly damaged (Appel et al., 1994; Shafer et al., 2005).

Although some aspects of persistence and metabolism of pyrethroids have been reported in the scientific literature, only few studies have been conducted to analyse with detail the toxicokinetics properties in laboratory animals. Pyrethroids studied in rats include the Type I pyrethroids permethrin (Anadón et al., 1991) and bifenthrin (Gammon et al., 2015; Hughes et al., 2016) and the Type II pyrethroids deltamethrin (Gray and Rickard, 1982; Anadón et al., 1996; Godin et al., 2010; Mirfazaelian et al., 2006; Kim et al., 2007, 2008; 2010; Gammon et al., 2015; Hughes et al., 2016) and lambda-cyhalothrin (Anadón et al., 2006). Because human population is exposed to pyrethroids, and since the toxic properties of pyrethroids are directly related to the parent compound, a characterization of the kinetic profile of these insecticides is required. With this type of data, more informative physiologically based pharmacokinetics and pharmacodynamics models can be developed and decrease uncertainties in risk assessments of pyrethroids.

Cyfluthrin is a Type II pyrethroid, it was first registered for use in the United States in 1987 (US EPA, 1987), frequently it is used in veterinary medicine, agriculture against grasshoppers and pests, industrial and residential settings, and public health and, in some countries for the protection of stored products (Ritter and Chappel, 1997; FAO, 1999). To date, toxicokinetics data have not been reported for cyfluthrin in mammals, the objective of this study was to define the toxicokinetics of the Type II pyrethroid cyfluthrin (Fig. 1) including oral bioavailability and brain tissue disposition in the Wistar rat.