Hexachlorobenzene-induced hypothyroidism. Involvement of different mechanisms by parent compound and metabolite

Rats received repeated oral treatment with different doses of hexachlorobenzene (HCB) (0-3.5 mmol/kg) for 2 or 4 weeks. Measurements of thyroid hormone status after 2 weeks showed a dose-dependent decrease of total thyroxine (TT4) levels, decreased free thyroxine (FT4) levels and little change of total triiodothyronine (TT3) levels. The effects on thyroid hormone status were more pronounced after 4 weeks and also included increased thyroid stimulating hormone (TSH) levels. These conditions suggest that HCB had induced hypothyroidism in these animals. Indications for occupation of thyroid hormone binding proteins were found in serum of exposed animals. The major metabolite pentachlorophenol (PCP) also caused, by competitive interactions with thyroid hormone binding proteins in serum, a rapid and dose-dependent decrease of TT4 and FT4 levels, but not of TT3 levels in serum. The decrease of serum TT4 levels by repeated dosing with 3.5 mmol HCB/kg for 4 weeks could be attributed to competitive interactions of PCP with hormone serum binding proteins and to increased metabolism induced by HCB to an equal degree. At lower dose levels or with shorter dosing periods, increased metabolism of T4 is the main cause of decreased TT4 serum levels. This is the first indication that a similar effect is caused simultaneously by the parent compound and its metabolite through different and independent mechanisms.