Relationship of hepatotoxicity and the target tissue dose of decabrominated diphenyl ether in subacutely exposed Wistar rats

Marijana Ćurčić; Sladjana Tanasković; Sanja Stanković; Saša Janković; Marko Antunović; Snežana Djordjević; Vesna Kilibarda; Slavica Vučinić; Biljana Antonijević

doi:10.2298/5479

Marijana Ćurčić Department of Toxicology “Akademik Danilo Soldatović”, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
Sladjana Tanasković Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
Sanja Stanković Center for Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia
Saša Janković Institute of Meat Hygiene and Technology, Belgrade, Serbia
Marko Antunović National Poison Control Center, Military Medical Academy, Belgrade, Serbia
Snežana Djordjević National Poison Control Center, Military Medical Academy, Belgrade, Serbia; Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
Vesna Kilibarda National Poison Control Center, Military Medical Academy, Belgrade, Serbia; Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
Slavica Vučinić National Poison Control Center, Military Medical Academy, Belgrade, Serbia; Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
Biljana Antonijević Department of Toxicology “Akademik Danilo Soldatović”, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

DOI: https://doi.org/10.2298/5479

Keywords: halogenated diphenyl ethers, liver, toxicity test, rats,

Abstract

Background/Aim. Based on numerous studies in animals, the most prominent toxic effects of decabrominated diphenyl ether (BDE-209) are observed in the liver, thyroid hormone homeostasis, reproductive and nervous systems. BDE-209 exhibits its toxic effects partly through the aryl hydrocarbon (Ah) receptor and consequent induction of hepatic microsomal enzymes. The aim of this study was to assess the hepatotoxic effect vs target tissue dose of BDE-209 in the subacutely orally exposed Wistar rats. Methods. Effects were examined on male Wistar rats, weighing 200–240 g, exposed to doses of 1,000, 2,000 or 4,000 mg BDE-209/kg body weight (bw)/day by gavage during 28 days. Animals were treated according to the decision of the Ethics Committee of the Military Medical Academy, No 9667-1/2011. Evaluation of the hepatotoxic effect was based on: relative liver weight water and food intake, biochemical parameters of liver function [aspartate amino transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gama glutamyl transferase (γ-GT)], and oxidative stress parameters in liver homogenates [malondialdehiyde (MDA), superoxide dismutase (SOD), -SH] and morphological and pathohistological changes in the liver. For the assessment of internal dose – response relationship, lower confidence limit of Benchmark dose (BMDL) of 5% or 10% i.e. BMDL₅ or BMDL₁₀, were calculated using PROAST software. Results. After the application of 1,000, 2,000 or 4,000 mg BDE-209/kg bw/day, the concentrations of BDE-209 measured in liver were 0.269, 0.569 and 0.859 mg/kg of liver wet weight, (ww) respectively. Internal doses correlated with external (r = 0.972; p < 0.05) according to equation: internal dose (mg BDE-209/kg of liver ww) = 0.0002 ´ external dose (mg/kg bw/day) + 0.0622. Hepatotoxicity was demonstrated based on significant increase in AST and γ-GT activities and the degree of histopathological changes. The lowest BMDL₅ of 0.07228 mg BDE-209/kg of liver ww, correlating to external dose of 39 mg/kg/day, indicated the increase of AST activity as the most sensitive biomarker of BDE-209 hepatotoxicity in subacutely exposed rats. Conclusion. The results of the present work add up to the issue of BDE-209 toxicity profile with a focus on relationship between internal dose and hepatotoxicity. Critical internal dose for the effect on AST of 0.07 mg/kg of liver ww, corresponding to external dose of 39 mg/kg/day, is the lowest dose ever observed among the studies on BDE-209 hepatotoxicity. For the persistent substances with low absorption rate such as BDE-209, critical effect based on internal dose in majority of cases is considered as more precisely defined than the effect established based on external dose, particularly.

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