Toxicokinetics of p -tert-octylphenol in male Wistar rats

Abstract

Only weak oestrogenic activity has been reported for p-alkylphenols compared with the physiological hormone 17 beta-estradiol. Despite the low potency, there is concern that due to bioaccumulation oestrogenically efficient blood levels could be reached in humans exposed to trace levels of p-alkylphenols. To address these concerns, toxicokinetic studies with p-tert-octylphenol [OP; p-(1,1,3,3-tetramethylbutyl)-phenol] as a model compound have been conducted in male Wistar rats. OP blood concentrations were determined by GC-MS in rats receiving either single oral (gavage) applications of 50 or 200 mg OP/kg body wt or a single intravenous injection of 5 mg/kg body wt. The OP blood concentration was approximately 1970 ng/ml immediately after a single intravenous application, decreased rapidly within 30 min, and was no longer detectable 6-8 h after application. The curve of blood concentration vs time was used to calculate an elimination half-life of 310 min. OP was detected in blood as early as 10 min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract; maximal blood levels reached 40 and 130 ng/ml after applications of 50 and 200 mg/kg, respectively. Using the area under the curve (AUC) of blood concentration vs time, low oral bioavailabilities of 2 and 10% were calculated for the 50 and 200 mg/kg groups, respectively. OP toxicokinetics after repeated administration was investigated in male Wistar rats receiving daily gavage administrations of 50 or 200 mg OP/kg body wt for 14 consecutive days. Profiles of OP blood concentration vs time determined on day 1 and day 14 were similar, indicating that repeated oral gavage administration did not lead to increased blood concentrations. Another group of rats received OP via drinking water saturated with OP (approximately 8 mg/l, corresponding to a mean daily dose of approximately 800 micrograms/kg) over a period of up to 28 days. OP was not detected in any blood sample from animals treated via drinking water (detection limit was 1-5 ng/ml blood). OP concentrations were also analysed in tissues obtained from the repeated gavage (14 days) and drinking water groups (14 and 28 days). In the 50 mg/kg group, low OP concentrations were detected in fat and liver from some animals at average concentrations of 10 and 7 ng/g tissue, respectively. OP was not detected in the other tissues analysed from this group. In the 200 mg/kg group, OP was found in all tissues analysed except testes (fat, liver, kidney, muscle, brain and lung had average concentrations of 1285, 87, 71, 43, 9 and 7 ng/g tissue, respectively). OP was not detected in tissues of animals receiving OP via drinking water for 14 or 28 days, except in muscle and kidney tissue of one single animal receiving OP for 14 days. Using rat liver fractions it was demonstrated that OP was conjugated via glucuronidation and sulphation in vitro. A Vmax of 11.24 nmol/(min * mg microsomal protein) and a Km of 8.77 mumol/l were calculated for enzyme-catalysed OP glucuronidation. For enzyme-catalyse...

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

“…Estrogenic hormones are excreted from the body following metabolic conversion to biologically less active water-soluble metabolites via cytochrome P450-mediated hydroxylation, glucuronidation, Omethylation, or sulfation (22), and many of these pathways are also utilized for the metabolism of alkylphenols in fish and mammals (23)(24)(25)(26)(27). Exposure of the invertebrate Daphnia magna to either nonylphenol polyethoxylate or nonylphenol has been shown to disrupt endocrine function by decreasing both the glucuronidation and sulfation of testosterone (28), but it was not demonstrated whether the alkylphenols were substrates for the D. magna testosterone sulfotransferase in this study.…”

Effect of maternal exposure to octylphenol (4-tert-octylphenol) on the growth of the adrenal gland in male albino rats

“…Actually, one study suggested that OP is directly toxic to spermatogonia and Sertoli cells in culture, exerting its effects through a calcium-independent apoptotic pathway [28]. In male rats, oral ingestion of high concentrations of OP can lead to an increased accumulation of the chemical in various tissues [4], suggesting that these alkylphenolic compounds are capable of bioaccumulation in mammalian cells, and thus, they contribute substantially to the environmental estrogen pool. Sharpe et al [29] suggesting that also the proliferation of germ cells in the pre-spermatogenic wave is dependent on a certain concentration of testosterone.…”

“…The previous studies, which indicated that 4-tertoctylphenol has impact estrogenic action and anti-androgen, causing an adverse impact on the reproductive system of living organisms [14,4,15]. …”

“…Because of large quantities of alkylphenols are manufactured every year to provide substrate for the production of APEOs, they continue to contaminate the environment along with their respective alkylphenols. OP shows marked similarities to that of natural estrogens [2,3] and has been known to have a higher estrogenic potency compared with other alkylphenols of the same class of chemicals [4].…”

Effects of Stilbene and Related Compounds on Reproductive Organs in B6C3F1/Crj Mouse

“…However, these metabolites would be rapidly conjugated in vivo to inactive forms, as reported in bisphenol A and p-tert-octylphenol. [28][29][30] This may be the reason why trans-stilbene exhibited estrogenic activity in vivo only at a high dose. Other potentially proestrogenic aromatic compounds that may be activated to estrogens by hydroxylation in vivo include methoxychlor, benzophenone, benzo[a]pyrene, diphenyl, 2-nitrofluorene and styrene oligomers.…”