Acute toxicity of polychlorinated naphthalenes and their effect on cytochrome P450.

Polychlorinated naphthalenes (PCNs) are able to induce cytochrome P-450-dependent microsomal mono-oxygenase activities in vivo and in vitro. The aim of this study was to investigate the toxicity of a PCN mixture, and its effect on the levels of cytochrome P-450 in rats. The animals were intragastrically administered a mixture of PCNs in single doses of 250, 500 and 1000 mg/kg b.w. Dissection of animals was performed 24, 72 and 240 hours after administration. After PCN administration (all doses) the body weight loss (up to 30% in comparison with the control group, 240 hours after administration) and an increase of relative liver mass (about 126-153% of controls, 72 hours after administration) were observed. The exposure to PCN evoked an increase in the level of total cytochrome P-450 as well as the activity of CYP 1A (mediated 7-ethoxyresorufin O-deethylation) at all time points. The maximum activity of CYP 1A (about 12- to 15-fold increase in comparison with the control group) was observed 72 hours after dosing. Malondialdehyde (MDA), determined in the liver, showed a high increase and 240 hours after administration, the level of MDA was about one order of magnitude greater in comparison with control.

Tissue levels of cadmium and trace elements in patients with myoma and uterine cancer.

The aim of this study was to investigate the cadmium (Cd), copper (Cu), zinc (Zn), iron (Fe), magnesium (Mg) and calcium (Ca) concentrations in uterine cancer and uterine myoma. Tissue levels of six elements in 15 uterine cancers and 28 uterine myomas were measured by atomic absorption spectrometry. The samples were collected from women aged 32-79 (uterine myomas, uterine cancer and non-lesion uterine tissues from the same women). The results showed that the tissue Cd concentration was significantly lower in myoma than in non-lesion tissue. In uterine cancer, however, it was statistically significant, but only slightly lower than controls (the non-lesion uterine tissue). In the investigated tissues, the correlation between Cd concentration and age was found, but no effect of menopausal status or smoking habits on Cd level was detected. In uterine cancer tissue, a significant increase in Ca concentration and an insignificant increase in Mg level was observed when compared to normal uterine tissue. In uterine myoma, a significant increase of Mg and Mg/Ca ratio, as well as a decrease in Fe concentration were found. Statistical analysis showed no correlation between smoking habits, age, menopausal status and concentration of Cu, Zn, Fe, Mg and Ca trace metals in myoma or cancer tissue.

The disposition and metabolism of tetrabromobisphenol-A after a single i.p. dose in the rat.

Tetrabromobisphenol-A (TBBP-A) is used as a reactive (primary use) or an additive flame retardant and as an intermediate in the production of other flame retardants. In our study TBBP-A[14C] was administered intraperitoneally (i.p.) in a single dose of 250 or 1000 mg/kg body weight (about 300 kBq per animal). The level of radioactivity in erythrocytes was 10 times higher than in plasma 72 h after the administration. In all examined tissues the peak level of 14C could be observed within the first hour after the administration, and the highest concentrations were detected in the fat tissue, followed by liver, sciatic nerve, muscles and adrenals. Total excretion in faeces 72 h after the administration was about 51-65% of the dose, whereas in urine it was only 0.3%. About 20% was still retained in the rat organism.

The disposition and metabolism of durene (1,2,4,5-tetramethylbenzene) in rats.

The organ and tissue distribution, excretion and metabolism of [3H]1,2,4,5-tetramethylbenzene ([3H]durene) in male Wistar albino rats were investigated following a single i.p. administration (40 mg/kg) and within 9 days after five daily repeated administrations. Urine proved to be the main route of tritium excretion. Within the first 24 h after a single administration 69% of the radioactivity was excreted in the urine and only 9% in the feces. The highest level of tritium binding was found in the fat tissue, liver, kidneys and adrenal glands. The accumulation of tritium in the plasma proceeded with a kinetic constant of 0.49 h(-1), whereas the half-life of radioactivity decay amounted to about 6.3 h. In erythrocytes, the tritium level was found to be about three times lower than in blood plasma. The total amount eliminated during the 9 days following repeated administration was about 94% of the five doses given. The highest level of tritium was found in fat tissue and adrenal glands, followed by the liver, kidneys, sciatic nerve and muscle. A gradual decline in tritium levels was observed during the following 4 days in most tissues to reach about 2% of the dose given. The main urinary metabolites resulting from the administration of durene were 2,4,5-trimethylbenzyl alcohol (about 22%), 4,5-dimethyl-1,2-benzdialdehyde (about 19%), 2,4,5-trimethylbenzaldehyde (about 19%) and 2,4,5-trimethylbenzoic acid (about 16%). The oxygen-containing metabolites accounted for almost 80%, whereas sulphur-containing metabolites accounted for approximately 10% of the products of biotransformation. In conclusion, most of the durene administered has a relatively rapid turnover rate, with minor levels retained in the tissues for longer time periods.

Disposition and metabolism of 1,4-dimethylnaphthalene in rat.

The distribution, excretion and metabolism of 1,4-dimethylnaphthalene following i.p. administration of a single dose of 28 mg/kg to rats, was investigated using radiotracer [3H] and gas chromatography-mass spectrometry technique (GC-MS). After 72 h, about 97% of the given dose was excreted in urine and faeces. Maximum level of tritium in plasma was observed during the 4th h. after the compound administration. In organs and tissues, the highest concentration during the first hours after administration was detected in the fat, liver, spleen and kidneys. Then gradual decline in tritium was noticed in all examined tissues. In urine the following substances were identified and quantified by GC peak areas: unchanged 1,4-dimethylnaphthalene, 1-hydroxymethyl-4-methylnaphthalene, 4-methyl-1-naphthoic acid, 1,4-dimethylnaphthol, 4-methyl-1-naphthoic aldehyde and 1,4-dimethyl-methylthionaphthalene.

The disposition and metabolism of naphthalene in rats.

The aim of this study was to investigate the distribution, excretion and metabolism of naphthalene-[ring-U-3H] in rats. The experiments were performed on 54 male outbred IMP: Wist rats with body weight of 200-220 g. The compound was administered intraperitoneally in olive oil in a single dose of 20 mg/kg (about 540 kBq per animal). 3H radioactivity was traced in selected organs and tissues, blood, urine and faeces, 1-72 h following the administration. The main metabolites were isolated from urine and identified by the GC-MS method. Urine and faeces proved to be the main route of tritium elimination. Over 88% of the compound was excreted during the first 72 hours. Maximum level of tritium in plasma was observed at the 2nd h after administration following a biphasic decline. Half-lifes for phases I and II were 0.8 and 99 h, respectively. In erythrocytes 3H-decline was monophasic with the half-life of about 9 h. In organs and tissues, the highest concentrations during the first hours after administration were detected in the fat, liver and kidneys. Then, gradual decline of tritium was noticed in all examined tissues. In urine of rats the following substances were identified: (1) naphthalene, (2) 1-naphthol, (3) 2-naphthol, (4) 1,2-naphthalenediol-1,2-dihydro, (5) methylthionaphthalenes (two isomers). In conclusion, naphthalene has a relatively rapid turnover rate in the rat organism and does not form considerable deposits in the tissue. The metabolism encompasses ring hydroxylation, hydration and glutathione conjugation.

The disposition and metabolism of 1,3-dibromobenzene in the rat.

The distribution, excretion and metabolism of 1,3-dibromobenzene following a single i.p. administration to rats 100 or 300 mg/kg was investigated using radiotracer [3H] and GC-MS technique. After 72 hours about 74 to 90% were excreted in urine. The highest radioactivity was observed in the liver, kidneys and fat tissue. Later on a steady decline of radioactivity was apparent in all investigated tissues except for blood cells and the sciatic nerve, where constant levels were noted. In urine the following substances were identified and quantified by GC peak areas: unchanged 1,3-DBB (18%), dibromophenols (34%), dibromothiophenols (28%), dibromothioanisole (1.8%), bromophenol (5.5%), bromohydroxythiophenols (5%), and bromohydroxythioanisole (7.5%).

The disposition and metabolism of 1,3,5-[U-14C]trioxane in male Wistar albino rats.

The present study was designed to investigate 1,3,5-[U-14C]trioxane (TOX) distribution, excretion and metabolism. The experiments were performed on male Wistar albino rats after a single administration of TOX at doses of 40 mg/kg and 400 mg/kg. The exhaled air proved to be the main route of 14C elimination, mainly as 14CO2. During the first 12 h following the administration of 40 mg/kg of TOX the exhalation of 14CO2 was monophasic, with a half-life of 3.5 h. After the administration of 400 mg/kg, TOX was eliminated mainly as 14CO2 with the exhaled air (77%) and unchanged TOX (8%). About 3% of 14C was excreted in the urine as unchanged 1,3,5-trioxane. With regards to TOX elimination from blood plasma for the lower dose, a biphasic process was observed, with half-lives of 4.5 and 72 h. The amount of 14C bound by the erythrocytes was minute compared with the amount in blood plasma. When the higher dose of TOX was administered the efficiency of 14C binding to the erythrocytes was found to be 10 times higher than the respective value for blood plasma. Among the examined tissues the highest concentration of TOX-derived radioactivity was detected in the liver while the lowest was in fat tissue and brain. A subsequent decay of radioactivity occurred in the tissues. The results of the present study indicate that TOX belongs to the group of compounds, which are rapidly eliminated from the organism; hence TOX should not be expected to accumulate within the tissues. The data obtained confirm the assumed pattern of metabolic transformation, according to which 1,3,5-trioxane undergoes enzymatic transformation to formaldehyde, with carbon dioxide and water being the final products.

Disposition and metabolism of 1,2-dimethylnaphthalene in rats.

The aim of this study was to investigate the distribution, excretion and metabolism of 1,2-dimethylnaphthalene-[ring-U-3H] in rats. The experiments were performed on 54 male outbred IMP:Wist rats with body weight of 200 g +/- 20%. The compound was given i.p. in olive oil in a single dose of 28 mg/kg (about 6.2 MBq per animal). 3H radioactivity was traced in selected organs and tissues, blood, urine and faeces, 1-72 h following the administration. The main metabolites were isolated from urine and identified by the GC-MS method. Faeces and urine proved to be the main route of tritium elimination. Over 93% of the given compound was excreted during the first 72 h. Maximum level of tritium in plasma was observed during the 4th h after the compound administration. The accretion of 3H proceeded with kinetic constant of 0.7 h, followed by monophasic decline with the half-life of about 19h. In organs and tissue, the highest concentration during the first hours after administration were detected in the fat, adrenals, liver, spleen and kidneys. Then gradual decline of tritium was noticed in all examined tissues. The following urinary metabolites were identified: 1. 1,2-dimethylthionaphthalene, 2. 1,2-dimethylnaphthol, 3. 1-methylnaphthalene-2-methanol, 4. 1-methyl-2-naphthoic acid and 5. 1,2-dimethylmethylthionaphthalene. In conclusion, 1,2-dimethylnaphthalene has a relatively rapid turnover rate in the rat organism and does not form deposits in the tissue. The metabolism encompasses ring hydroxylation and glutathione conjugation leading to thionaphthol and oxygenation, and then to naphthoic acid.

The distribution and excretion of hexabromobenzene after a single administration in rat.

The aim of this study was to investigate the disposition of [1-14C]-hexabromobenzene (HBB) in rats. The experiments were performed on 76 female Outbred IMP: Wist rats with body weight of 200 g +/- 20%. The compound was given orally in a single dose of 600 mg/kg and 4500 mg/kg. 14C radioactivity was traced in selected tissues, blood, urine and faeces, 0-72 hours following the administration. Maximum concentration of the 14C in blood was observed during the 2nd hour after the compound administration. The accretion of 14C in plasma proceeded with kinetic constant of 1.35/hour, whereas 14C-decline was biphasic. Half-lives for phase I and II were 1.2- and 440 hours, respectively. No substantial differences were noted in relation to the HBB dose. In tissues the highest radioactivity was observed in the fat tissue, adrenals and sciatic nerve. About 16 to 24% of the administered radioactivity was still retained in the rat body, 72 hours after administration of the compound. Faeces turned out to be the main route of excretion (about 75% of the given dose); only 1% was excreted in urine. Following on the literature data and our total balance of 14C elimination with faeces, we concluded, that almost 70% of 14C found in the faeces were composed of other metabolites than HBB and its lower-brominated derivatives. The above data indicate that HBB, especially in the case of chronic exposure, might accumulate in the body.

Chemical toxicity and reactive oxygen species.

Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.

The disposition and metabolism of methyl acrylate in male Wistar albino rats.

The present study was designed to investigate methyl-[2,3-14C]acrylate (MA) distribution, excretion, and metabolism. Data presented here show that the radioactivity derived from MA is rapidly absorbed after i.p. and p.o. administration and distributed into all major tissues of rats. The highest concentration of MA-derived radioactivity was detected mainly in the liver and kidneys at 1 (i.p.) or 2 (p.o.) hours after dosing. There were only slight differences observed in the dynamics of tissue distribution and excretion in relation to the route of administration. The major route of MA excretion was CO2 exhalation (approximately 54% of the administered dose in 48 h) followed by urinary excretion. Two metabolites were identified in the urine, namely, N-acetyl-S-(2-methylcarboxyethyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine, and ratio between those was about 1:1.

The dynamics of distribution and excretion of butyl-(2,3-14C)-acrylate in male Wistar albino rats.

The disposition of butyl-(2,3-14C)-acrylate has been studied following intraperitoneal and oral administration to rats. Most of the administrated acrylate underwent rapid metabolism and excretion with expired air (more than 70% of the dose) and urine (15-22%). Most of 14C found in tissues was associated with the liver and kidneys. The level of 14C associated with most of the examined tissues remained unchanged, at least, for the first 8-10 hours, followed by its fairly rapid loss. The only exception was erythrocytes, fat and the sciatic nerve. Significant differences in the rate of 14C loss from tissues were found in relation to the route of its administration.

Distribution and binding of 1, 3, 5 [U14C]-trioxane in maternal and fetal rats.

The tissue distribution and binding of 14C activity were studied at different time intervals following a single oral administration of 1,3,5[U14C]-trioxane (14C-TOX) (40 mg/kg: 1.6 MBq/kg) to pregnant rats. Animals were killed on the 21st day of gestation 3, 24, or 48 hours after administration of TOX. In maternal rats, 3 hours after administration, the highest levels of total radioactivity were found in the liver and plasma, followed by a slow, gradual decline with time. The level of 14C-activity in the whole fetus was comparable to that of the maternal kidney through the study. The radioactivity in the fetal kidney and liver at the end of 48 hours after single administration was higher than at 3 hours after administration. Slow decline in radioactivity was observed with time in the fetal brain, skin and carcass. However, after 48 hours the level of total radioactivity in the fetal kidney and brain was more than twice as high as in the corresponding maternal organs. Three hours following 14C-TOX administration 35-41% of the respective total 14C radioactivity in maternal liver and kidney was firmly bound to the macromolecules, while the fetal liver and kidney showed 100-72% binding with respect to their total radioactivity.

Distribution and elimination of (14C)-2-ethylhexyl acrylate radioactivity in rats.

The fate of (14C)-2-ethylhexyl acrylate was studied in adult male Wistar rats given an intravenous (i.v.) or intraperitoneal (i.p.) injection of 10 mg/kg (0.054 mmol/kg). The elimination of radioactivity from blood was bi-exponential, irrespective of the route of (14C)-2-EHA administration or the age (weight) of the rats. The first phase half-lives after i.v. and i.p. administration in 4-month-old rats were 30 and 60 min, in 7-month-old rats 115 and 130 min, respectively. The corresponding values for the slow-phase were 5 and 6 h, and 14 and 14 h. Elimination of the radioactivity from tissues followed a pattern similar to that seen for blood. More than half of the administered radioactivity was exhaled as carbon dioxide. Exhalation of unchanged (14C)-2-EHA accounted for only 0.05% (i.v.) or 0.3% (i.p.) of the initial dose of radioactivity. The radioactivity excreted in the urine within the first 24 h post-treatment accounted for 7% (i.p.) or 14% (i.v.) of the initial dose, and only 2% was excreted as thioethers.

The disposition of [2,3-14C]-methyl and [2,3-14C]-2-ethylhexyl acrylate in male Wistar albino rats.

The disposition of methyl [2,3-14C]-acrylate (MA) and 2-ethylhexyl [2,3-14C]-acrylate (EHA) following intraperitoneal and oral administration to rats has been studied. The 14C found in the tissues was mainly associated with liver, kidneys and lungs. Loss of 14C from these tissues occurred fairly rapidly, excluding the rats given EHA intraperitoneally. Most of the administered acrylates underwent rapid metabolism and excretion with expired air (more than 50% of the dose and urine (10-50% of the dose). Significant differences in the rates of 14C loss from tissues and excretion occurred after intrapritoneal administration of MA and EHA. A possible cumulation of EHA in the organism was suggested.

Biliary excretion and organ distribution of 14C radioactivity after 14C-2-ethylhexyl acrylate administration in rats.

Rats were intravenously administered (14C)-2-ethylhexyl acrylate at the dose 10 mg/kg or 50 mg/kg b. w. Biliary excretion of 14C-radioactivity was followed in 1-3 hour intervals within the first 24 hours after administration. The rats were then sacrificed and distribution of 14C-radioactivity was followed in some organs. Highest radioactivity was found in liver, less in the kidneys and the least in the brain. A significant increase of bile flow was observed. In the 24-hour intervals 2.2% of the dose was eliminated via bile at both dosages, most of it (83%) during the first 3 hours.

The disposition of [14C]acrylonitrile in rats.

1. The disposition of [1,2-14C]acrylonitrile and acrylo[14C]nitrile has been studied following intraperitoneal and oral administration to rats. 2. Most of the 14C found in the tissues was associated with erythrocytes, liver and kidneys. Loss of 14C from liver and kidneys occurred fairly rapidly, but the 14C in the erythrocytes was still mostly retained 48 h after administration. Significant differences in the rates of 14C loss from tissues occurred with [1,2-14C]acrylonitrile and acrylo[14C]nitrile given orally. 3. The 14C from both labelled forms of acrylonitrile was excreted mostly in the urine (82-93% dose) with a smaller amount exhaled unchanged in the breath (3-7% dose) in 24 h.

[Toxicity and metabolism of acrylonitrile]. / Toksycznosc i metabolizm akrylonitrylu.

The paper presents the problem of occupational exposure to acrylonitrile vapours and toxic properties of this compound, as well as its metabolism in experimental animals, including its administration route. In addition, it deals with the mechanism of its toxic effects depending on the reactivity of the functional group of acrylonitrile particle. The authors discuss also the latest views on the capacity of acrylonitrile metabolites [S-(2-cyanoethyl)-mercapturic acid and rhodanates], depending on the route of acrylonitrile administration to rats.