The formation and persistence of the DNA adducts 7-(2'-oxoethyl)guanine (OEG) and N2,3-ethenoguanine (EG) were investigated in preweanling Sprague-Dawley rats exposed to vinyl chloride (VC). Lactating female CD rats with 10 day old pups were exposed to 600 p.p.m. VC by inhalation for 5 days, 4 h/day. Groups of rats were killed immediately and 3, 7 and 14 days after exposure. The concentrations of OEG and EG were measured in liver, lung, kidney, brain and spleen. HPLC with fluorescence detection was used for OEG detection, and gas chromatography-negative ion chemical ionization mass spectrometry was used for EG detection. In tissues of neonatal rats, the concentrations of both DNA adducts, expressed as pmol/mumols unmodified guanine, were highest in liver (OEG 162 +/- 36, EG 1.81 +/- 0.25), followed by kidney (OEG 29 +/- 1, EG 0.31 +/- 0.02), and lung (OEG 20 +/- 7, EG 0.21 +/- 0.08). No adducts were found in brain or spleen. DNA adducts were detected only in liver (OEG 43 +/- 7, EG 0.47 +/- 0.14) and lung (OEG 20 +/- 5, EG 0.27 +/- 0.03) of the dams. The ratio between EG and OEG was approximately 1:100 in all tissues immediately after exposure. In the liver of the preweanling rats, this ratio increased to 1:14 1 week after exposure, reflecting a greater persistence of EG. A half-life of 62 h was calculated for OEG, and the estimated half-life for EG was greater than 30 days. In view of the slow loss of EG and its high efficiency for causing base-pair mismatch, these results suggest that EG may be an important DNA adduct in VC-induced carcinogenesis.

Preweanling rats were exposed to 600 p.p.m. (4h/day) of the human carcinogen vinyl chloride for 5 days to determine the molecular dosimetry of DNA adducts in liver, lung and kidney. 7-(2'-Oxoethyl)guanine (7OEG) was the major DNA adduct detected, representing approximately 98% of all adducts. N2,3-Ethenoguanine (epsilon G) and 3,N4-etheno-2'-deoxycytidine (epsilon dC) were present at approximately 1% of the 7OEG concentration, while 1,N6-etheno-2'-deoxyadenosine was present in even lower concentrations. Liver had 3- to 8-fold higher amounts of the DNA adducts than lung and kidney. The persistence of all four adducts was determined at 3, 7 and 14 days post-exposure. Whereas 7OEG had a t 1/2 of -62 h, all three etheno adducts were highly persistent. After accounting for dilution due to growth-related cell proliferation, epsilon G had a t 1/2 of approximately 30 days, while epsilon dC and epsilon dA were not repaired. These data suggest that these cyclic adducts are poorly recognized by liver DNA repair enzymes and have the potential for accumulation upon chronic exposure. This, coupled with the known miscoding properties of the ethenobases, provides a strong rational for examining their role in vinyl chloride-induced cancer and their utility as biomarkers of exposure.

The article contains sections titled: 1. Maleic Acid 2. Maleic Anhydride (MA) 2.1. Properties 2.2. Production 2.2.1. Oxidation of Benzene 2.2.2. Dehydration of Aqueous Maleic Acid Solutions 2.2.3. Oxidation of C 4 Hydrocarbons 2.2.4. Purification 2.2.5. Byproducts, Construction Materials, Effluent, and Discharge Air 2.3. Quality, Storage, and Transportation 2.4. Uses 3. Citraconic and Mesaconic Acids 4. Fumaric Acid 5. Toxicology

A sensitive assay for quantitative determination of the vinyl chloride (VC)-induced cyclic DNA adduct N2,3-ethenoguanine (EG) was developed. The method is based on the detection of EG as its di-pentafluorobenzyl derivative (3,5-PFB2-EG). This compound exhibited good gas chromatographic properties and was detected with high sensitivity by gas chromatography with electron capture detection (limit of detection 300 amol/microliters injected solution) or with negative ion chemical ionization mass spectrometry monitoring the [M-181]-fragment ion at m/z 354 (GC-NICI-MS, limit of detection 190 amol/microliters injected solution). EG, its 13C-labeled analog [13C4]-EG and 3,5-PFB2-EG were synthesized and characterized by UV and fluorescence spectrophotometry, 1H- and 13C-NMR spectroscopy and mass spectrometry. The standards were used to optimize the isolation of EG and its derivatization with pentafluorobenzyl bromide (electrophore labeling) at fmol quantities. DNA solutions were spiked with EG, the DNA was depurinated by mild acid hydrolysis, and EG was isolated from the hydrolysates by low-pressure strong cation exchange chromatography with subsequent C18 solid-phase extraction. The extracted EG was electrophore labeled and 3,5-PFB2-EG was detected using GC-NICI-MS. [13C4]EG served as internal standard. 3,5-PFB2-EG was quantitated relative to its 13C-labeled analog by measuring the ion ratio m/z 354/358. The limit of detection for the complete method was 60 fmol EG/mumols guanine. The method was applied to liver DNA from young Sprague-Dawley rats exposed to 600 p.p.m. VC from day 10 through day 14 after birth. The EG concentration in these samples was 1.8 +/- 0.3 pmol/mumols guanine.

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...