Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.78, #12)
Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data by Robert Hess; Michael J. Bartels; Lynn H. Pottenger (pp. 671-680).
Upon ingestion ethylene glycol (EG, monoethylene glycol) is rapidly absorbed from the gastrointestinal tract, and depending on the severity of exposure signs of toxicity may progress through three stages. Neurological effects characterize the first step consisting of central nervous depression (intoxication, lethargy, seizures, and coma). The second stage, usually 12–24 h after ingestion, is characterized by metabolic acidosis due to the accumulation of acidic metabolites of EG, primarily glycolic acid (GA), contributing to the ensuing osmolal and anion gaps. Stage 3, generally 24–72 h after ingestion, is determined mainly by oxalic acid excretion, nephropathy, and eventual renal failure. Because the toxicity of EG is mediated principally through its metabolites, adequate analytical methods are essential to provide the information necessary for diagnosis and therapeutic management. The severe metabolic acidosis and multiple organ failure caused by ingestion of high doses of EG is a medical emergency that usually requires immediate measures to support respiration, correct the electrolyte imbalance, and initiate hemodialysis. Since metabolic acidosis is not specific to EG, whenever EG intoxication is suspected, every effort should be made to determine EG as well as its major metabolite GA in plasma to confirm the diagnosis and to institute special treatment without delay. A number of specific and sensitive analytical methods (GC, GC-MS, or HPLC) are available for this purpose. Due to the rapid metabolism of EG, the plasma concentration of GA may be higher than that of EG already upon admission. As toxicity is largely a consequence of metabolism of EG to GA and oxalic acid, the simultaneous quantification of EG and GA is important. Formation of calcium oxalate monohydrate in the urine may be a useful indicator of developing oxalate nephrosis although urine crystals can result without renal injury. The pathways involved in the metabolism of EG are qualitatively similar in humans and laboratory animals, although quantitative differences have been reported. Comparison between species is difficult, however, because the information on humans is derived mainly from acute poisoning cases whereas the effects of repeated exposures have been investigated in animal experiments. Based on published data the minimum human lethal dose of EG has been estimated at approx. 100 ml for a 70-kg adult or 1.6 g/kg body weight (calculation of dose in ml/kg to mg/kg based in EG density=1.11 g/l). However, human data from case reports are generally insufficient for the determination of a clear dose-response relationship and quantification of threshold doses for systemic toxicity, in particular renal effects, is limited. As toxicity is largely a consequence of metabolism of EG to GA, it is important to note that no signs of renal injury have developed at initial plasma glycolate concentrations of up to 10.1 mM (76.7 mg/dl). Plasma EG levels of 3.2 mM (20 mg/dl) are considered the threshold of toxicity for systemic exposure, if therapeutic strategy is based on the EG concentration alone.
Keywords: Ethylene glycol; Glycolic acid; Analysis; Toxicokinetics; Nephrotoxicity
Renal effects and erythrocyte oxidative stress in long-term low-level lead-exposed adolescent workers in auto repair workshops by Faruk Öktem; Meltem Koyuncu Arslan; Bumin Dündar; Namık Delibas; Mustafa Gültepe; Inci Ergürhan Ilhan (pp. 681-687).
Lead poisoning is an old but persistent public health problem in developing countries. The present study investigated blood lead levels and its effects on markers of renal function and parameters of erythrocyte oxidative stress in adolescent male auto repair workers in Turkey. Blood Pb level and the ALAD index (logarithm of activated δ-aminolaevulinic acid dehydratase/nonactivated δ-aminolaevulinic acid dehydratase) were measured as indicators of exposure to Pb. Markers of tubular damage urine N-acetyl-β-d-glucosaminidase (NAG), β2-microglobulin (β-2 MG), creatinine (Cr), uric acid (UA), and calcium, markers of glomerular filtration blood urea nitrogen (BUN), serum Cr, UA, and parameters of oxidative damage in erythrocyte were studied in 79 Pb-exposed adolescent and 71 healthy control subjects. Blood lead levels and ALAD index were found significantly higher in the study group than that of normal control group. BUN, UA level, and glomerular filtration rates were detected in normal range in the lead-exposed group. Urinary NAG excretion and calciuria were higher in the study group than in controls. Urinary excretion of NAG was positively correlated with the blood lead levels (r=0.427). There was no relationship between blood lead levels and UA or β-2 MG in urine. Malondialdehyde and glutathione peroxidase levels were significantly elevated in lead-exposed adolescents than controls, but changes in the catalase and superoxide dismutase activities in lead-exposed adolescents did not reach statistical significance. In conclusion, chronic low-dose lead exposure seems as a cause of subtle renal impacts in adolescent workers of auto repair workshops. Lead-induced oxidative stress in erythrocytes probably contributes to these subclinical renal effects.
Keywords: Lead exposure; Adolescent; Oxidative stress; KidneyN-Acetyl-β-d-glucosaminidase
Analysis of gene expression profiles of forestomach tumors in rasH2 mice initiated with N-ethyl-N-nitrosourea by Miwa Okamura; Kayo Sumida; Tomoko Muto; Yoko Kashida; Noboru Machida; Tomoyuki Watanabe; Kunitoshi Mitsumori (pp. 688-696).
To clarify the mechanisms underlying enhancement of carcinogenesis in transgenic mice carrying a human prototype c-Ha-ras gene (rasH2 mouse), animals received a single intraperitoneal injection of 120 mg/kg N-ethyl-N-nitrosourea (ENU) and at 20 weeks thereafter expression profiles in three induced forestomach squamous cell carcinomas were assessed using high-density oligonucleotide microarrays. In addition, the reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess mRNA expression of human c-Ha-ras gene and some molecules involved in the Ras-regulated mitogen-activated protein kinase (MAPK) pathway. Compared with normal forestomach tissue from control mice, 416 and 368 genes, respectively, were found to be commonly up- and down-regulated by 2-fold or more in the three tumors. Many genes involved in tumor invasion and metastasis such as transforming growth factor β1 and matrix metalloproteinases were up-regulated, reflecting tumor progression. RT-PCR analysis confirmed up-regulation of transgene, mouse endogenous Ha-ras, N-ras, raf, Mekk2, c-fos, junB, c-myc and cyclin D1. These results suggest that activation of the Ras–MAPK cascade following up-regulation of both human and mouse endogenous ras genes is involved in the enhanced tumorigenesis of ENU-induced forestomach squamous cell carcinomas in rasH2 mice.
Keywords: rasH2 MouseN-Ethyl-N-nitrosourea; Gene expression; Forestomachras Gene
Hepatotoxic effects of polidocanol in a model of autologously perfused porcine livers by Christian Grosse-Siestrup; Volker Unger; Jeanette Pfeffer; Q. Thai Dinh; Stefan Nagel; Jochen Springer; Christian Witt; Anke Wussow; David A. Groneberg (pp. 697-705).
Polidocanol is an effective sclerosing agent that consists of 95% hydroxypolyethoxydodecane and 5% ethyl alcohol and is known to have a low risk of complications. However, since the compound has been proposed for the local treatment of liver diseases, the potential for topical hepatic side effects should be examined. Therefore, the new model of normothermic-hemoperfused isolated porcine slaughterhouse livers was used to examine polidocanol-hepatotoxicity encompassing the advantages of slaughterhouse organs to reduce animal experiments and autologous blood as an optimal perfusate. Polidocanol was administered via the hepatic artery and portal vein and the effects of the sclerosant on organ function parameters were compared with those in an untreated control group. In contrast to the untreated control organs, significant differences were found in the polidocanol group for parameters such as alanine aminotransferase or organ weight after perfusion. The most striking differences were found for hepatic bile flow, which dropped in the polidocanol group to 0.24±0.02 ml/min per 1000 g after administration of the compound compared with 3.80±1.08 ml/min per 1000 g in the control group. In summary, the present observations indicate a risk of hepatotoxic effects of polidocanol. Clinicians should be aware of this problem and the use of polidocanol for intrahepatic sclerosing should be restricted to specialized centers.
Keywords: Liver; Toxicology; Polidocanol; In vitro; Alternative testing
Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives by Carina Carlsson; Mikael Harju; Fariba Bahrami; Tatiana Cantillana; Mats Tysklind; Ingvar Brandt (pp. 706-715).
The olfactory mucosa (OM) is an important target for metabolism-dependent toxicity of drugs and chemicals. Several OM toxicants share a 2,6-dichlorinated benzene structure. The herbicides dichlobenil (2,6-dichlorobenzonitrile) and chlorthiamide (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide all induce toxicity in the OM following covalent binding in the Bowman’s glands. In addition, we have shown that 2,6-dichlorophenyl methylsulfone targets the Bowman’s glands and is probably the most potent OM toxicant so far described. These findings suggest that the 2,6-positioning of chlorines in combination with an electron-withdrawing group in the primary position of the benzene ring is an arrangement that facilitates OM toxicity. This study examined the physicochemical characteristics of the 2,6-dichlorinated OM toxicants. A number of 2,6-dichlorinated benzene derivatives with various types of substituents in primary position were tested for OM toxicity in mice. In addition, some other 2,6- and 2,5-substituted benzene derivatives were examined. Two novel OM toxicants, 2,6-dichlorobenzaldehyde oxime and 2,6-dichloronitrobenzene, were identified. By the use of partial least squares projection to latent structures with discriminant analysis (PLS-DA) a preliminary quantitative structure-activity relationship (QSAR) model was built also using reported OM toxicity data. Physicochemical properties positively correlated with olfactory mucosal toxicity were identified as molecular dipolar momentum and the electronic properties of the substituent. Inversely correlated descriptors were variables describing the hydrophobicity, electronic properties of the molecule such as electron affinity and the electronic charge on the primary carbon. In conclusion, this preliminary PLS-DA model shows that a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron-withdrawing substituent in the primary position has the potential of being a potent OM toxicant in mice.
Keywords: Olfactory mucosa; Quantitative structure-activity relationship; Nasal toxicity; Chlorinated benzenes; Substituents
Nephrotoxicity of 4-cycloocten-1-carbaldehyde by Horst Messinger; Marcus Kleber; Walter Aulmann (pp. 716-722).
Natural and synthetic chemicals are often used in the fragrance industry. A toxicological profile of the synthetic fragrance booster, 4-cycloocten-1-carbaldehyde, was generated using a test program including the following methods: acute oral toxicity, acute dermal toxicity, acute skin and eye irritation, skin sensitization, subchronic toxicity, and mutagenicity. The substance was strongly irritating to the skin but only weakly irritating to the eye. It gave a clear indication of having skin-sensitizing properties. Based on the comprehensive data from a mutagenicity test battery, 4-cycloocten-1-carbaldehyde was assessed to be nonmutagenic. Although its acute toxicological profile shows no toxicity after oral or dermal application, 4-cycloocten-1-carbaldehyde displays a complex toxicological response after repeated dosing over 13 weeks. 4-Cycloocten-1-carbaldehyde or its metabolites show clear nephrotoxic properties focusing on tubular cells of the kidney. In view of these data no no-effect level can be derived from this study with 4-cycloocten-1-carbaldehyde. A broad interaction of the test substance with various tissue types and cell parameters together with severe and irreversible organic defects even at low doses leads to the conclusion that 4-cycloocten-1-carbaldehyde is unsuitable for the intended use in industrial fragrance formulations.
Keywords: 4-Cycloocten-1-carbaldehyde; Risk assessment; Subchronic toxicity tests; Nephrotoxicity; Metabolism; Genetic toxicity tests; Acute toxicity tests; Sensitization tests
Failure of ethanol and acetaldehyde to alter in vivo norepinephrine release in the striatum and hippocampus of rats by Mostofa Jamal; Kiyoshi Ameno; Mitsuru Kumihashi; Weihuan Wang; Setsuko Ameno; Takako Kubota; Iwao Ijiri (pp. 723-727).
The effect of ethanol (EtOH) and acetaldehyde (AcH) on norepinephrine (NE) release was examined in the striatum and hippocampus of freely moving rats by means of in vivo microdialysis coupled with high-performance liquid chromatography and an electrochemical detector. Rats were treated intraperitoneally with EtOH (1 g/kg) or cyanamide (CY, 50 mg/kg, a potent aldehyde dehydrogenase inhibitor) plus EtOH (1 g/kg). No significant difference in NE levels in the dialysates was observed in the striatum and hippocampus in either the EtOH or CY+EtOH groups. NE levels in the hippocampal dialysates were about fivefolds higher than those in the striatum. The concentration of EtOH and AcH in the striatal dialysate reached a peak at 30 min after EtOH dosing and then gradually decreased in the CY+EtOH group. In the EtOH group the striatal concentration of EtOH also reached a peak at 30 min after EtOH dosing, and then gradually decreased while AcH was not detected. The present study suggests that there is no in vivo effect of brain EtOH or AcH on NE release in the striatum and hippocampus of awake rats.
Keywords: Norepinephrine; Acetaldehyde; Ethanol; Striatum; Hippocampus