Distribution of radiolabel in rats after intravenous injection of a toxic dose of 14C-acid-, 14C-alcohol-, or 14C-cyano-labeled deltamethrin

doi:10.1016/0048-3575(81)90074-2

Pesticide Biochemistry and Physiology

Volume 16, Issue 1, August 1981, Pages 79-85

https://doi.org/10.1016/0048-3575(81)90074-2 Get rights and content

Abstract

The tissue distribution of toxic doses of ¹⁴C-acid-, ¹⁴C-alcohol-, and ¹⁴C-cyano-labeled deltamethrin was followed after iv administration to rats. All three radiolabeled preparations were found in every tissue examined within 1 min of injection. Peak central nervous system (CNS) levels were achieved within 1–5 min, but did not correspond to the onset of choreoathetosis. In the majority of the tissues examined the levels of deltamethrin label were similar, proportionately, to those found after administration of alcohol-labeled cismethrin. A major exception was the CNS which contained approximately 20% of the anticipated level of radiolabel suggesting that the CNS threshold for deltamethrin was approximately 0.5–1.0 nmol/g. Progressive accumulation of radioactivity in the erythrocyte fraction of the blood was observed following administration of cyano-labeled deltamethrin. This may contribute to the selective retention of ¹⁴C with this radiolabeled preparation.

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Cited by (12)

Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in the rat
2011, Toxicology
Citation Excerpt :
Several studies suggest that toxicity from pyrethroids occur when central nervous system pyrethroid concentrations exceed threshold quantities. Threshold estimates for deltamethrin from iv exposures in rats range from 100 to 500 ng/g brain tissue (Gray and Rickard, 1981, 1982a,b). Tremors and choreoathetosis were observed in rabbits when brain levels of the Type II pyrethroid cypermethrin reached 0.7 ng/g (Khanna et al., 2002).
The potential for human exposure to pyrethroid pesticides has prompted pharmacodynamic and pharmacokinetic research to better characterize risk. This work tested the hypothesis that blood and brain concentrations of the pyrethroid bifenthrin are predictive of neurotoxic effects. Adult male Long Evans rats received a single oral dose of bifenthrin dissolved in corn oil. Using figure-eight mazes, motor activity was measured for 1 h at 4- and 7-h following exposure to bifenthrin (0–16 mg/kg or 0–9 mg/kg, respectively; n = 4–8/group). Whole blood and brains were collected immediately following motor activity assays. Bifenthrin concentrations in blood and brain were quantified using HPLC/MS/MS. Bifenthrin exposure decreased motor activity from 20% to 70% in a dose-dependent manner at both time points. The relationship between motor activity data and administered dose, and blood and brain bifenthrin concentrations were described using a sigmoidal E_max model. The relationships between motor activity and administered dose or blood concentrations were different between the 4- and 7-h time points. The relationship between motor activity and brain concentration was not significantly different between the two time points. These data suggest that momentary brain concentration of bifenthrin may be a more precise dose metric for predicting behavioral effects because the relationship between brain concentration and locomotor activity is independent of the time of exposure.
Toxicokinetics of lambda-cyhalothrin in rats
2006, Toxicology Letters
The toxicokinetics of lambda-cyhalothrin after single 20 mg kg⁻¹ oral and 3 mg kg⁻¹ intravenous doses were studied in rats. Serial blood samples were obtained after oral and intravenous administration. Liver, brain, spinal cord, sciatic nerve, vas deferens, anococcygeus and myenteric plexus tissue samples were also collected. Plasma, liver, hypothalamus, cerebellum, medulla oblongata, frontal cortex, striatum, hippocampus, midbrain, spinal cord, vas deferens, anococcygeus, myenteric plexus and sciatic nerve concentrations of lambda-cyhalothrin were determined by HPLC. The plasma and tissue concentration–time data for lambda-cyhalothrin were found to fit a two-compartment open model. For lambda-cyhalothrin, the elimination half-life (T_1/2β) and the mean residence time from plasma were 7.55 and 8.55 h after i.v. and 10.27 and 14.43 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.060 l h⁻¹ kg⁻¹. After i.v. administration, the apparent volume of distribution and at steady state were 0.68 and 0.53 l kg⁻¹, suggesting a diffusion of the pyrethroid into tissue. After oral administration, lambda-cyhalothrin was extensively but slowly absorbed (T_max, 2.69 h). The oral bioavailability was found to be 67.37%. Significant differences in the kinetic parameters between nervous tissues and plasma was observed. The maximum concentrations in hypothalamus (C_max, 24.12 μg g⁻¹) and myenteric plexus (C_max, 25.12 μg g⁻¹) were about 1.5 times higher than in plasma (C_max, 15.65 μg ml⁻¹) and 1.3 times higher than in liver (C_max, 18.42 μg ml⁻¹). Nervous tissue accumulation of lambda-cyhalothrin was also reflected by the area under the concentration curve ratios of tissue/plasma (liver). The T_1/2β for lambda-cyhalothrin was significantly greater for the nerve tissues, including neuromuscular fibres, (range 12–26 and 15–34 h, after i.v. and oral doses) than for plasma (7.55 and 10.27 h, respectively).
Toxicokinetics of deltamethrin and its 4'-HO-metabolite in the rat
1996, Toxicology and Applied Pharmacology
The toxicokinetics of deltamethrin and its metabolite 4′-HO-deltamethrinafter single doses of 26 mg of deltamethrin/kg (oral) or 1.2 mg of deltamethrin/kg (intravenous) were studied in male Wistar rats. Serial blood samples were obtained after oral and intravenous administration. Brain, vas deferens, and anococcygeus tissue samples were also obtained after oral administration. Plasma, hypothalamus, cerebellum, frontal cortex, caudate putamen, hippocampus, medulla oblongata, vas deferens, and anococcygeus concentrations of deltamethrin and 4′-HO-deltamethrin were determined by a high-performance liquid chromatographic assay. The deltamethrin and 4′-HO-deltamethrin plasma profiles could be adequately described by a two-compartment open model. For deltamethrin and 4′-HO-deltamethrin, the elimination halflives (t1_2β) from plasma were 33.0 and 25.67 hr after iv and 38.50 and 30.13 hr after po administration of deltamethrin parent compound. The apparent volume of distribution [V_d(area)] and volume of distribution at steady state [V_d(ss) for deltamethrin were 5.33 and 2.04 liters, respectively, after iv administration, suggesting a considerable diffusion of the pyrethroid into tissue. The total plasma clearance of deltamethrin was the saure for both the oral and the iv routes—0.11 liter/hr. After the single oral dose, deltamethrin was rapidly absorbed with a T_max of 1.83 hr. The maximum plasma concentrations of deltamethrin and 4′-HO-deltamethrin were 0.46 and 0.26 μg/ml. The maximum plasma concentration of 4′-HO-deltamethrin was achieved at 3.29 hr. The oral bioavailability of deltamethrin was found to be 14.43%. The tissue concentration time data for deltamethrin and its metabolite 4′-HO-deltamethrin were found to fit a one-compartment open model. Considerable concentrations of deltamethrin and 4'-HO-deltamethrin were found in the hypothalamus, cerebellum, frontal cortex, caudate putamen, hippocampus, medulla oblongata, vas deferens, and anococcygeus tissues. The elimination half-lives (t1_2e1) for both deltamethrin and 4′-HO-deltamethrin were somewhat smaller for the cerebellum, frontal cortex, caudate putamen, medulla oblongata, vas deferens, and anococcygeus tissues (range, 18-33 hr for deltamethrin and 15-28 hr for 4′-HO-deltamethrin) than for plasma (t1_2e1, 38.50 and 30.13 hr, respectively). Exceptions were seen for the hypothalamus and hippocampus in which the t1_2e1's for deltamethrin were 40.76 and 38.50 hr, respectively. Nervous tissue accumulation of deltamethrin and its metabolite 4′-HO-deltamethrin was evidenced by the tissue/plasma area under the concentration (AUC) versus time curve ratios. The ratios of AUC_tissue/AUC_plasma for deltamethrin were 2.32 in medulla oblongata, 295.30 in hypothalamus, and intermediate in other tissues.
The effects of two types of pyrethroid on rat skeletal muscle
1987, European Journal of Pharmacology
The mechanical and electrophysiological effects of two synthetic pyrethroids, cismethrin (Type I) and deltamethrin (Type II) have been studied in whole rat gastrocnemius muscle and in isolated perfused rat diaphragm. In both directly or indirectly stimulated preparations deltamethrin but not cismethrin had a positive inotropic effect which in the case of the whole animal could be reversed by increasing the stimulation frequency. In the isolated diaphragm the deltamethrin effect could be prevented by TTX suggesting it is primarily the result of an increased sodium conductance. Deltamethrin also reversed a partial curare blockade in the diaphragm. Electrophysiological studies showed that the inotropic effect of deltamethrin is accompanied by repetitive muscle action potentials. In addition deltamethrin significantly increased muscle fibre input resistance, a novel finding which may underlie the curare reversal effect. It is concluded that the effectiveness of deltamethrin compared with cismethrin in causing repetitive firing in the muscle membrane is attributable to the greater duration of the after-depolarization produced by deltamethrin.
Effect of pyrethroid insecticides on EEG activity in conscious, immobilized rats
1985, Pesticide Biochemistry and Physiology
Preseizure and seizure EEG patterns elicited by the pyrethroid insecticides, deltamethrin and cis-permethrin, were compared in immobilized Sprague-Dawley rats. Deltamethrin (1–3 mg/kg, iv) produced a preseizure EEG pattern of high-amplitude, slow, 2- to 5-Hz synchronized cortical waves or spike-wave complexes. cis-Permethrin (20–40 mg/kg, iv) elicited an immediate EEG change characterized by 6- to 12-Hz high-amplitude waves with intermingled high-voltage spikes. DDT (50–70 mg/kg, iv) produced a sustained EEG activation similar to that seen after cis-permethrin, but of higher frequency. All three insecticides produced generalized EEG seizure activity, but this was more prominently associated with poisoning due to deltamethrin. cis-Permethrin and DDT gave rise to EEG seizures only at lethal doses. Electrodes stereotaxically positioned in ventral hippocampus, caudate, putamen, thalamus, septum, red nucleus, and cerebellum detected no preferential activation of any of these subcortical sites in either preconvulsive or convulsive phases of poisoning. These results indicate that both deltamethrin and cis-permethrin can have marked effects on mammalian EEG activity. This does not support the hypothesis of differing sites of action, i.e., peripheral vs. central, for the two types of compound. The more pronounced seizure-inducing action of deltamethrin may instead reflect a greater efficacy of cyanopyrethroids at target sites within the central nervous system.
Correlation of blood and brain levels of the neurotoxic pyrethroid deltamethrin with the onset of symptoms in rats
1985, Pesticide Biochemistry and Physiology
Rats were injected intraperitoneally with ¹⁴C-labelled deltamethrin at the threshold doses required to produce the motor symptoms of toxicity of tremor and choreoathetosis. Blood and brain samples were analysed for their total radiolabel content, and were also extracted with ethyl acetate to determine the levels of extractable parent deltamethrin and 3-phenoxybenzyl-derived acid (the final radiolabelled metabolite after oxidative cleavage) and the residual radiolabel after this extraction. There was a clear correlation between symptom onset and blood and brain levels of deltamethrin. It was found that certain threshold levels of parent deltamethrin in the blood and brain were required for symptom development, and that the symptom persisted for as long as this threshold was maintained. The distribution of the radiolabel in various tissues was also followed over the time course of the blood and brain studies.

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Distribution of radiolabel in rats after intravenous injection of a toxic dose of 14C-acid-, 14C-alcohol-, or 14C-cyano-labeled deltamethrin

Abstract

Pestic. Biochem. Physiol

Pestic. Biochem. Physiol

Pestic. Biochem. Physiol

Pestic. Biochem. Physiol

Structure-activity relationships of some pyrethroids in rats

Arch. Toxicol

Toxicity of new pyrethroid insecticide

Nature (London)

An EEG investigation of decamethrin-induced choreoathetosis in the rat

Exp. Brain Res

Distribution of radiolabel in rats after intravenous injection of a toxic dose of ¹⁴C-acid-, ¹⁴C-alcohol-, or ¹⁴C-cyano-labeled deltamethrin