Relationship Between the Dose Administered, Target Tissue Dose, and Toxicity Level After Acute Oral Exposure to Bifenthrin and Tefluthrin in Young Adult Rats.

Most pyrethroid insecticides (PYRs) share a similar primary target site in mammals. However, the potency estimates of the lethal and sublethal effects of these compounds differ up to 103-fold. The aim of this study was to evaluate the relationship between the dose administered, the target tissue dose, and the effect of 2 highly toxic PYRs, tefluthrin (TEF; 0.1-9 mg/kg) and bifenthrin (BIF; 0.5-12 mg/kg), by using the oral route, a corn oil vehicle (1 ml/kg) and subcutaneous temperature (Tsc) monitoring assays in adult rats. The Tsc was determined at 30-min intervals for 5 h (TEF) or 4.5 h (BIF) after dosing. Rats were sacrificed at 6 h after dosing, and BIF and TEF concentrations were determined in blood (Bd), liver (Lv), and cerebellum (Cb) by using a GC-ECD system. The minimal effective dose of BIF (3 mg/kg) affecting Tsc was similar to that found in prior studies using other testing paradigms. Regarding TEF, a very steep relationship between the dose administered and toxicity was observed, with a near-threshold to low-effective range for Tsc at 0.1-6 mg/kg, and a near lethal syndrome at ≥ 7.5 mg/kg. At 6-7.5 mg/kg TEF, the Cb/Bd and Cb/Lv concentration ratios were both > 1. Conversely, for BIF, the Cb concentration was barely over the Bd concentration and the Cb/Lv concentration ratio remained < 1. Our results and previous findings call for more comprehensive consideration to establish the relevance of the distribution into target tissues and the tissue dosimetry for health risks through the exposure to PYRs in humans.

Relationship between exposure, body burden and target tissue concentration after oral administration of a low-dose mixture of pyrethroid insecticides in young adult rats.

Pyrethroids (PYRs) are synthetic insecticides increasingly used in agricultural and household pest control. Little is known on how the toxicity of highly effective bolus doses of single compounds compares to more realistic scenarios of low-level exposure to PYR mixtures. In this study, we examined a quaternary mixture of two noncyano (tefluthrin, TEF; bifenthrin, BIF) and two cyano (α-cypermethrin, α-CPM; deltamethrin, DTM) PYRs in young adult rats. These compounds are mostly composed of PYR isomers ranking top ten in acute lethality in rats. Concurrently, we administered near-threshold levels of the four PYRs dissolved in corn oil by oral route. Six hours later blood was collected and the liver and cerebellum were dissected out to determine PYR concentrations in these tissues using Gas Chromatography with Electron Capture Detector (GC-ECD). The mixture caused mild-to-moderate changes in non-locomotor behaviors and subcutaneous body temperature (up to +1.2-1.5 °C increase at 2-4 h after dosing, respectively, compared to pre-dosing records). The most toxic PYRs BIF and TEF reached higher concentrations in the cerebellum than the cyano-compounds α-CPM and DTM. In addition, PYR concentrations in the cerebellum were correlated to single compound proportions in the dosing solution and changes in body temperature. Our results suggest that aggregate exposures resulting in a target tissue burden of ∼10-1 nmoles PYR/g may be toxicologically relevant, expanding the evidence on exposure-dose-effect relationships for PYRs, and serving to design convenient pharmacokinetic models for environmentally relevant exposures to PYR mixtures.

Evidence for effects on thermoregulation after acute oral exposure to type I and type II pyrethroids in infant rats.

Most pyrethroid (PYR) insecticides may be classified either as type-I compounds, which produce whole body tremors and hyperthermia, or type-II compounds, which produce salivation, choreoathetosis, and hypothermia (i.e., producing T and CS neurobehavioral syndromes, respectively). This classification is based on clinical observations in adult rats and mice after intracerebroventricular or intravascular administration of highly effective acute (bolus) doses. PYR neurotoxicity in infant animals is not characterized as much as in adult animals. Endpoints informing on vital determinants of mammal's maturation, such as body temperature may help recognizing age-related differences in susceptibility to PYRs. In this work, body temperature (Tb) was monitored at 30-min intervals after acute oral exposure to T-syndrome PYR bifenthrin (BIF), CS-syndrome PYR cypermethrin (CYPM), and a BIF­CYPM mixture in weanling rats by using a subcutaneous temperature monitoring system. In both single-compound assays, a time- and dose-related decline of Tb was the most evident impact on thermoregulation observed starting at ~2­3 h after dosing.Moreover, 15­18 mg/kg BIF induced a mild increase in Tb before the hypothermic action was apparent. The lowest effective dose for temperature perturbation was 15mg/kg for BIF and 10mg/kg for CYPM, and moderate neurobehavioral alterations were evident at 12 and 10mg/kg, respectively. When low effective doses of BIF and CYPM were co-administered mild behavioral effects and a transient increase in Tb (p=0.02) were observed at 1­2 h, and no Tb decline was apparent afterwards compared to control animals. Noteworthy, the hypothermic action of BIF in infant rats was quite different from the hyperthermia consistently reported in studies using mature animals. Our results suggest that body temperature monitoring may be useful as a complementary assessment to reveal qualitative age-specific pesticide effects in rats.