L.-J. Chen

Metabolism and disposition of 2,2',4,4',5-pentabromodiphenyl ether (BDE99) following a single or repeated administration to rats or mice

The metabolism and disposition of 14C-labelled 2,2′,4,4′,5-pentabromodiphenyl ether (BDE99) were studied in F344 rats and B6C3F1 mice. Approximately 85% of a 1 µmol kg−1 oral dose was absorbed by male rats and mice. Within 24 h following oral doses ranging from 0.1 to 1000 µmol kg−1 to rats, 39–47% of the dose was excreted in the faeces (including 16% unabsorbed), up to 2% was excreted in the urine, and 34–38% remained in the tissues, mostly in adipose tissue. Mice excreted more in the urine and less in the faeces than rats. Tissue accumulation was observed following repeated dosing to rats. Two dihydrohydroxy-S-glutathionyl and two S-glutathionyl conjugates of BDE99, 2,4,5-tribromophenol glucuronide, two mono-hydroxylated BDE99 glucuronides, and three mono-hydroxylated tetrabromodiphenyl ether glucuronides were identified in male rat bile. 2,4,5-Tribromophenol and its glucuronide and sulfate conjugates, were identified in male rat urine. 2,4,5-Tribromophenol, one mono-hydroxylated tetrabromodiphenyl ether, and two mono-hydroxylated BDE99 were characterized in male rat faeces. BDE99 undergoes more extensive metabolism than does BDE47. Half of the absorbed oral dose in male rats was excreted in 10 days mostly as metabolites derived from arene oxide intermediates.

DISTRIBUTION AND METABOLISM OF (5-HYDROXYMETHYL)FURFURAL IN MALE F344 RATS AND B6C3F1 MICE AFTER ORAL ADMINISTRATION

(5-Hydroxymethyl)furfural (HMF), a heat-induced decomposition product of hexoses, is present in food and drink. Recent reports have shown HMF to be an in vitro mutagen after sulfate conjugation and to be a promoter as well as a weak initiator of colonic aberrant foci in rats. In order to investigate the metabolic activation further and to provide information for HMF toxicology studies, the disposition of [14C]-HMF has been investigated in male F344 rats and B6C3F1 mice following po administration of either 5, 10, 100, or 500 mg/kg. Tissue distribution results indicated that absorption of HMF was rapid in male rats and mice and that tissue concentrations in male mice at the earliest time point are not linearly proportional to dose. Excretion was primarily via the urine in both, with 60-80% of the administered dose excreted by this route in 48 h. Tissue/blood ratios of HMF-derived radioactivity were greater than 1 for liver and kidney. Three metabolites were identified and quantitated in urine. Formation of one of the metabolites, N-(5-hydroxymethyl-2-furoyl)glycine, was inversely proportional to dose in rats but not mice. None of the metabolites were sulfate conjugates nor likely to be formed from sulfate conjugates. There were relatively low levels of nonextractable radioactivity in liver, kidney, and intestines, indicating that some reactive intermediate(s) may be formed.

Metabolism and disposition of 2,2′,4,4′- tetrabromodiphenyl ether following administration of single or multiple doses to rats and mice

The metabolism and disposition of 14C-labelled 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) were investigated in F344 rats and B6C3F1 mice. Approximately 75–85% of 1 µmol BDE47 kg−1 was absorbed following oral administration to either rats or mice. Sex and species differences were observed in tissue distribution and excretion of BDE47-derived radioactivity. Absorption and distribution of 14C to major tissues were dose-proportional in male rats from 0.1 to 1000 µmol kg−1. BDE47-derived radioactivity increased in all rat and mouse tissues examined following repeated daily doses of 1 µmol kg−1. Accumulation of 14C in tissues of mice was less than in corresponding rat tissues. Glutathione conjugates of BDE47 were excreted in rat bile. A glucuronide and a sulfate conjugate of 2,4-dibromophenol were detected in the urine of BDE47-treated rats. BDE47 appears to induce its own metabolism. Increased formation of reactive metabolites over time may correlate with toxicological effects in BDE47-treated rodents.

Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents

The disposition of the 14C-labelled polybrominated diphenyl ether (PBDE) 2,2′,4,4′,5,5′-hexaBDE (BDE153) was investigated in rodents following single and multiple doses and in a mixture with radiolabelled 2,2′,4,4′-tetraBDE (BDE47) and 2,2′,4,4′,5-pentaBDE (BDE99). In single exposure studies there was little or no effect of dose on BDE153 disposition in male rats in the range 1–100 µmol kg−1. No major sex or species differences in the in vivo fate of BDE153 were detected. BDE153 was absorbed in rats or mice following gavage by approximately 70%; retained in tissues; and poorly metabolized and slowly excreted. Mixture studies indicated that, relative to each other, more BDE47 was distributed to adipose tissue, more BDE153 accumulated in the liver, and BDE99 was metabolized to the greatest extent. BDE153 was probably retained in the liver due to minimal metabolism and elimination after ‘first-pass’ distribution to the tissue following gavage.

Formation of o-nitrosobenzaldehyde from hydrolysis of o-nitrobenzyl tosylate. Evidence of intramolecular nucleophilic interaction

Abstract Hydrolysis of o -nitrobenzyl tosylate in CH 3 CN:H 2 O (1:1, v/v) gave o -nitrobenzyl alcohol and o -nitrosobenzaldehyde in 1.8:1 ratio. Formation of o -nitrosobenzaldehyde indicates that the nitro group participates in the leaving of the tosylate group. o -Nitrosobenzaldehyde was reduced by biological thiols to give o -aminobenzaldehyde. Reaction of o -nitrosobenzaldehyde with 1 mol of benzylamine afforded 3-(N-benzylamino)anthranil (or its tautomer) as a major product.

Disposition of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in B6C3F1 mice and F344 rats

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone (MX) is a mutagenic by-product of chlorination of drinking water, particularly where the water contains humic matter. MX has been estimated to account for 50% of the mutagenic activity in some drinking water. A bioassay in rats demonstrated an increased tumor incidence, primarily in liver and thyroid glands. This study was designed to provide disposition/metabolism information in mice to evaluate the necessity of a National Toxicology Program chronic bioassay and to provide data for female rats. Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 h following oral administration of 14 C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 h postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid. Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.

Metabolism and disposition of juglone in male F344 rats

The metabolism and disposition of 14C-labelled juglone in male F344 rats following oral, intravenous and dermal administration were studied. Approximately 40–50% of an oral dose (0.1 to 10 mg kg−1) and less than 20% of the dermal dose (4 mg kg−1) were absorbed within 24 h. Most of the oral dose was excreted in faeces and urine within 24 h and only 1–3% remained in the tissues. High concentrations of juglone-derived radioactivity were found in kidney for all three dosing routes. The accumulation in kidney can be attributed to covalent binding of juglone and/or metabolites to cytosolic protein. Five metabolites were identified in the urine of rats treated with an oral dose: 1,4,5-trihydroxynaphthalene di-glucuronide, 1,4,5-trihydroxynaphthalene mono-glucuronide mono-sulfate, 2-sulfo-2,3-dihydrojuglone, 4,8-dihydroxy-1-tetralone mono-glucuronide and 1,4,5-trihydroxynaphthalene mono-glucuronide. Liver microsomal incubations of juglone in the presence of NAD(P)H and UDP-glucuronic acid gave rise to two 1,4,5-trihydroxynaphthalene mono-glucuronides.

Metabolism and Disposition of n-Butyl Glycidyl Ether in F344 Rats and B6C3F1 Mice

The disposition of [14C]-labeled n-butyl glycidyl ether (BGE, 3-butoxy-1,2-epoxypropane) was studied in rats and mice. The majority of a single p.o. dose (2–200 mg/kg) was excreted in urine (rats, 84–92%; mice, 64–73%) within 24 h. The rest of the dose was excreted in feces (rats, 2.6–7.7%; mice, 5.3–12%) and in expired air as 14CO2 (rats, 1.5%; mice, 10–18%), or remained in the tissues (rats, 2.7–4.4%; mice, 1.5–1.7%). No parent BGE was detected in rat or mouse urine. Fifteen urinary metabolites were identified, including 3-butoxy-2-hydroxy-1-propanol and its monosulfate or monoglucuronide conjugates, 3-butoxy-2-hydroxypropionic acid, O-butyl-N-acetylserine, butoxyacetic acid, 2-butoxyethanol, and 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol, the mercapturic acid metabolite derived from conjugation of glutathione (GSH) with BGE at the C-1 position. Some of these metabolites underwent further ω-1 oxidation to form a 3′-hydroxybutoxy substitution. One urinary metabolite was from ω-oxidation of 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol to yield the corresponding carboxylic acid. Oxidative deamination of 3-butoxy-1-(cystein-S-yl)-2-propanol gave the corresponding α-keto acid and α-hydroxy acid metabolites that were present in mouse urine but not in rat urine. An in vitro incubation of BGE with GSH showed that the conjugation occurred only at the C-1 position with or without the addition of GSH S-transferase.