title: Relationship of hepatotoxicity and the target tissue dose of decabrominated diphenyl ether in subacutely exposed Wistar rats.
abstract: OBJECTIVE
  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 x 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 BMDLs 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.
  
  
  CONCLUSIONS
  The results of the present work add up to the issue ofBDE-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 deined than the effect established based on external dose, particularly.
authors.forename: Marijana
authors.initials: M
authors.lastname: Ćurčić
authors.forename: Sladjana
authors.initials: S
authors.lastname: Tanasković
authors.forename: Sanja
authors.initials: S
authors.lastname: Stanković
authors.forename: Saša
authors.initials: S
authors.lastname: Janković
authors.forename: Marko
authors.initials: M
authors.lastname: Antunović
authors.forename: Snežana
authors.initials: S
authors.lastname: Djordjević
authors.forename: Vesna
authors.initials: V
authors.lastname: Kilibarda
authors.forename: Slavica
authors.initials: S
authors.lastname: Vučnić
authors.forename: Biljana
authors.initials: B
authors.lastname: Antonijević
mesh_terms: D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000187:drug effects / Q000378:metabolism
chemical_list: D055768:Halogenated Diphenyl Ethers; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; C010902:decabromobiphenyl ether