Use of PROAST software to assess the influence of decabrominated diphenyl ether and/or cadmium on thyroid hormones homeostasis in rats

Abstract

In relation to commonly used no-observed-adverse-effect-level (NOAEL) point of departure, because of its statistical power and reliability, Benchmark dose (BMD) approach has been proposed as an alternative in dose-response assessment. The aim of this study was to derive BMD (10%) by means of PROAST software to quantify influence of cadmium (Cd) and/or decabrominated diphenyl ether (BDE209) on thyroid hormones homestasis. Study was conducted on male Wistar rats treated orally by gavage for 28 days by either single substances or their combination. Three groups of animals were dosed with Cd at levels of 2.5, 7.5 and 15 mg/kg b.w./day, three groups of animals were dosed with BDE209 at levels of 1000, 2000 or 4000 mg/kg b.w./day, while 9 groups received different dose mixtures of previously given dose levels of Cd and BDE209 (design 3 x 3). Results of the study have indicated that Cd+BDE209 mixtures are likely more potent to disrupt thyroid function than would be expected from the chemicals individually. Derived BMD - lower confidence limits (BMDL), if ratio BMD/BMDL is lt 10, were 9.4 mg Cd/kg b.w./day and 2155 mg BDE209/kg b.w./day for the effect on T3; and 6.22 mg Cd/kg b.w./day in the mixture with BDE209 2000 mg/kg b.w./day for the effect on FT3.

Primena statistički dobijene Benchmark doze (BMD) u proceni rizika predstavlja alternativu najčešće korišćenoj 'dozi bez štetnog efekta' (NOAEL) zbog veće pouzdanosti u analizi odnosa doze i toksičnog efekta. Cilj ovog rada bio je izračunavanje BMD (10%) primenom PROAST softvera radi kvantitativne procene uticaja Cd i/ili BDE209 na homeostazu hormona štitaste žlezde. Ispitivanje je sprovedeno na mužjacima Wistar pacova koji su putem oralne sonde, tokom 28 dana, primali pojedinačne supstance ili njihove kombinacije. Kadmijum je primenjivan u dozama od 2,5, 7,5 i 15 mg Cd/kg t.m./dan, a BDE209 u dozama od 1000, 2000 i 4000 mg BDE209/kg t.m./dan, dok je ostalih devet grupa životinja primalo kombinacije hemikalija (dizajn 3 x 3). Rezultati studije ukazuju da smeša Cd i BDE209 verovatno izaziva intenzivniji poremećaj funkcije štitaste žlezde nego svaka od supstanci pojedinačno. Izračunate Benchmark doze (10%), odnosno odgovarajuće donje granice pouzdanosti (BMDL), uz uslov da je BMD/BMDL lt 10, iznose 9,4 mg Cd/kg t.m./dan i 2155 mg BDE209/kg t.m./dan za efekte na T3 hormon, a za efekat na FT3 hormon 6,22 mg Cd/kg t.m/dan u smeši sa BDE209 od 2000 mg/kg.