bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of nitrosation on the chemical composition and epidermal carcinogenicity of the nitrogen‐rich fraction of a high‐boiling coal liquid
Authors: Wright C. W. , Chess E. K. , Renne R. A. , Buschbom R. L.
Published: October 2006

An 800–850°F solvent‐refined coal‐II liquid was fractionated into chemical classes to obtain the aliphatic hydrocarbons, polycyclic aromatic hydrocarbons (PAH), nitrogen‐containing polycyclic aromatic compounds (NPAC), and hydroxy‐subsituted PAH (hydroxy‐PAH). The isolated NPAC fraction was refractionated by chemical class both before and after undergoing a nitrosation reaction. The nitrosated and non‐nitrosated refractionated NPAC fractions were further subfractionated into secondary amine (pyrroles), primary amine‐enriched (amino‐PAH), and tertiary amine (azaarene) classes. The PAH and hydroxy‐PAH composition of the NPAC fraction increased upon nitrosation, whereas the amino‐PAH fraction composition decreased upon nitrosation. Nitrosation of standards indicated the amino‐PAH compounds reacted to form parent PAH, chloro‐substituted PAH, and methoxy‐substituted PAH when analyzed by high‐resolution gas chromatography (GC) and GC/mass spectrometry (MS). Some easily oxidized PAH compounds reacted to form ketones and quinones. All other standard reference compounds, chosen to be representative of the major chemical classes of compounds present in coal liquefaction materials, were unchanged by the nitrosation reaction. The amino‐PAH of the nitrosated NPAC fraction reacted to form parent and some chloro‐substituted PAH when analyzed by low‐voltage direct‐probe MS in addition to the methods given above. Epidermal carcinogenesis studies with the PAH, NPAC, nitrosated NPAC, and hydroxy‐PAH fractions isolated from the 800–850°F coal liquid indicated the PAH and NPAC were the most important determiners of skin carcinogenesis, with the PAH giving a higher response than the NPAC. The tumorigenicity of the NPAC was drastically reduced by nitrosation, probably due to the destruction of the amino‐PAH upon nitrosation.
Cellular metabolism of arsenocholine
Authors: Christakopoulos Alexandros , Norin Harald , Sandström Margareta , Thor Hjördis , Moldeus Peter , Ryhage Ragnar
Published: October 2006

The biotransformation of arsenocholine and arsenobetaine, which are organic arsenic compounds present in certain aquatic organisms, has been studied in vitro using synthetic reference substances. Incubation of arsenocholine with different liver cell fractions showed arsenocholine to be biotransformed only in presence of the mitochondrial fraction. The biotransformation products were arsenobetaine aldehyde, arsenobetaine, trimethylarsine oxide and trimethylarsine. Arsenobetaine was the major metabolite and it was formed via arsenobetaine aldehyde. Trimethylarsine oxide was formed via a side reaction from arsenobetaine aldehyde. Further reduction of trimethylarsine oxide, produced trimethylarsine. In vitro studies of arsenobetaine, did not show any formation of trimethylarsine oxide or trimethylarsine. Furthermore, cytotoxicity of arsenobetaine or arsenocholine in isolated hepatocytes was not observed.
In vitro mutagenicity of water contaminants in complex mixtures
Authors: Varma M. M. , Ampy F. R. , Verma K. , Talbot W. W.
Published: October 2006

Trihalomethanes, Carbon tetrachloride and trichloroethylene were tested in single, binary and multi‐complex mixtures using standard tester strains TA1535, TA1537, TA98 and TA100 of Salmonella typhimurium with and without addition of an in vitro metabolizing fraction S‐9. Chloroform (CHCl3) was found to be mutagenic in all strains without S‐9 activation. However, when tested with Bromoform (15%), which was nonmutagenic singly, the combined effect of the mixture was nonmutagenic. CCl4 was a direct mutagen (without S‐9) in all strains except TA 1535. When combined with 85% CHCl3, only strains TA1535 and TA1537 were mutagenic. When tested with mammalian activation (S‐9), CCl4 was mutagenic in all strains. However, when tested with CHCl3 (CHCl3 and CCl4 ‐ 85 : 15), the mutagenic capability was lost.

With or without S‐9 Activation multi‐complex mixture of CHCl3, CCl4 and TCE (85 : 8 : 7) was mutagenic for a narrow range of doses in all strains.
Tris (2,3‐dibromopropyl) phosphate nephrotoxicity in the rat: Histological and biochemical changes in renal components by 13C‐NMR spectra
Authors: Fukuoka Masamichi , Tanaka Akira , Yamaha Tsutomu , Naito Katushi , Takada Koichi , Kobayashi Kazuo , Tobe Masuo
Published: October 2006

Rats receiving a single oral dose of 286.8 μmol/kg tris(2,3‐dibromopropyl)phosphate (Tris‐BP) showed pyknosis of the renal tubular epithelial cells on Day 1, necrosis on Day 2, regeneration from Day 3 and large nuclei formation from Day 4. 13C‐NMR spectra were applied to clarify changes of the renal low‐molecular‐weight components in the kidney injured by Tris‐BP, and sialic acid and inositol were found as the desired marker components. The lesions produced by Tris‐BP were characterized by changes in the renal components and enzyme activities. Increases in sialic acid content of the kidney were observed both on Day 1, suggesting destruction of the epithelial cell membrane, and on Day 5, suggesting regeneration accompanied by an increase of inositol content on Days 7 and 10. Renal activity of cytoplasmic enzyme, alanine aminopeptidase, was decreased on Days 1 and 5 and elevated on Days 7 and 10. Lactate dehydrogenase activity showed a tendency to decrease in the kidneys on Day 1 and to increase significantly on Days 2, 5, 6 and 7.
Evidence that phomopsins A and B are not the only toxic metabolites produced by Phomopsis leptostromiformis
Authors: Allen J. G. , Hancock G. R.
Published: October 2006

The toxicities of up to four different toxic preparations containing metabolites of Phomopsis leptostromiformis were examined in two experiments with sheep and one with rats. It was shown that the different toxic preparations containing similar amounts of phomopsin A varied substantially in toxicity. Crystalline phomopsin A was the least toxic. It is suggested that the increased toxicity of the other three preparations was due to the presence of toxic metabolites additional to phomopsins A and B. Evidence to support this suggestion is presented.
The histochemical location of three diagnostic enzymes in the marmoset liver
Authors: Davy C. W. , Fulleylove M. , Edmunds J. , Allsop D. , Eichler D. A. , Rushton B. , Walker J. M.
Published: October 2006

The histochemical locations of alkaline phosphate (ALP), leucine aminopeptidase (LAP) and gamma glutamyl‐transferase (GGT) were demonstrated in the liver of the marmoset (Callithrix jacchus). Although all three enzymes were located in cell membranes, the location of LAP was demonstrated by a chromogenic substrate, in the canalicular membrane. GGT was seen in a vascular network, provisionally identified as the peribiliary arterial plexus. Possible diagnostic applications in toxicology are discussed.
Toxicity of aromatic thiols in the human red blood cell
Authors: Amrolia Persis , Sullivan Stephen Gene , Stern Arnold , Munday Rex
Published: October 2006

Thiophenol and 4‐aminothiophenol were used to study levels of toxicity in human red blood cells. Thiophenols caused conversion of oxyhemoglobin to methemoglobin. Reduction of corresponding disulfides by intracelluar glutathione caused cyclic reduction/oxidation reactions, resulting in increased oxidative flux. Three levels of oxidative stress were observed in these experiments: the lowest level resulted from incubation with 0.25 mM thiophenol; the intermediate level with 0.50 mM thiophenol or 0.25 mM 4‐aminothiophenol; the highest levels with 0.50 mM 4‐aminothiophenol. Methemoglobin formation increased with increasing level of oxidative stress. Glycolysis and the hexose monophosphate shunt were inhibited at the intermediate and highest levels of stress, respectively. Above the highest level of stress non‐intact hemoglobin was formed and cell lysis occurred. These metabolic responses were reflected in cellular levels of NADH, NADPH and reduced glutathione. At the lowest level of oxidative stress, both glycolysis and hexose monophosphate shunt were increased such that near‐normal levels of NADH, NADPH and reduced glutathione were maintained and methemoglobin formation was kept to a minimum. The response of red cells to 0.25 mM thiophenol appears to represent a level of oxidative stress to which the cell is capable of adaptive metabolic response. Glycolysis contributes approximately one‐quarter of the total reducing equivalents from glucose metabolism in response to the oxidative challenge by thiophenol. The results suggest that the metabolic response to autoxidation of endogenous thiols is thiol exchange with glutathione and reduction of resulting glutathione disulfide by the hexose monophosphate shunt.
Renal and hepatic toxicity of N‐arylsuccinimides in fischer 344 rats
Authors: Rankin Gary O. , Carl John M. , Hubbard John L. , Teets Vonda J. , Nicoll Derek W. , Brown Patrick I.
Published: October 2006

The role of aromaticity in the nephrotoxic potential of N‐arylsuccinimides was studied in male Fischer 344 rats. Rats were administered a single intraperitoneal (i.p.) injection of an N‐arylsuccinimide derivative (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and the renal function monitored at 24 and 48 h. The parent compound in this series, N‐phenylsuccinimide (NPS), had previously been shown to induce only minimal renal effects, having no effect on urine volume, blood urea nitrogen concentration, kidney weight, p‐aminohippurate accumulation or renal morphology. Only an increase in tetraethylammonium uptake has been observed following NPS administration to rats. These effects were not enhanced by reducing aromaticity (N‐cyclohexylsuccinimide (NCS)). Compounds with increased aromaticity N‐(1‐naphthyl)succinimide (NNS), N‐(1‐anthracenyl)succinimide (1‐NAS) and N‐(9‐anthracenyl)succinimide (9‐NAS) — also only weakly affected renal function. However, NNS (1.0 mmol/kg) and, to a lesser degree, 9‐NAS (1.0 mmol/kg) proved to be hepatotoxins. Liver damage was most pronounced near central vein regions of the lobule and least evident around periportal sites. Damaged liver tissue exhibited unusually large deposits of connective tissue and hypertrophied hepatocytes with numerous vacuoles in their cytoplasm. Therefore, derivatives of NPS with increased or decreased aromaticity relative to the parent compound do not exhibit the ability to induce moderate or marked nephrotoxicity. However, increasing aromaticity did produce the derivatives NNS and 9‐NAS, which are hepatotoxins. These compounds represent the first members in this series of compounds to induce acute hepatotoxicity.
A new method for long‐term inhalation toxicity studies for bronchospasmolytic aerosol formulations in dogs
Authors: Pauluhn Jürgen , Kimmerle Georg
Published: October 2006

In routine inhalation toxicity studies laboratory animals are exposed under dynamic exposure conditions to different steady‐state concentrations of a test compound. The relevant exposure concentration is the analytically determined time‐weighted average concentration in the vicinity of the breathing zone of the animals. If the intended use of a bronchospasmolytic aerosol is taken into account, a non‐steady‐state exposure regimen might be more appropriate. Using this approach local effects of high aerosol concentrations on the respiratory tract were investigated in dogs by daily head/nose‐only exposure for 1 h for 4 weeks. Four groups of four dogs were exposed to 20, 40 and 80 bursts of a bronchodilator formulation using a modified metered dose inhaler. The analytically determined mean concentration of the active ingredient (prostaglandin) in the breathing zone was 43.1, 92.2 and 193.9 μg 𝓁−1 air, respectively. Maximum concentrations were determined by simulation. The aerosol was in the respirable range (mass median aerodynamic diameter ∼ 1.2 μm, geometric standard deviation ∼ 1.4).

A kinetic model was developed to simulate the mean and maximum non‐steady‐state concentration for an exposure regimen of 20, 40 and 80 bursts per hour under dynamic exposure conditions. The model was based on first‐order inhalation chamber kinetics. The kinetic model was validated experimentally by comparing measured mean and simulated mean concentrations. In all exposure groups the simulated maximum concentrations were ca. 80 mg of test compound (formulation) per litre of air. Plasma levels were elevated in a dose‐dependent manner as evidence of the validity of the test model employed.
The dermal carcinogenic potential of unrefined and hydrotreated lubricating oils
Authors: McKee R. H. , Daughtrey W. C. , Freeman J. J. , Federici T. M. , Phillips R. D. , Plutnick R. T.
Published: October 2006

Unrefined lubricating oils contain relatively high levels of polycyclic aromatic hydrocarbons (PAH) and have been shown to induce tumors in mouse skin. Exxon has developed a new method of refining these materials, a severe hydrotreatment process that is optimized for PAH removal. The specific objectives of the current study were to assess PAH reduction and then to evaluate directly the dermal carcinogenic potential of the materials that spanned the range of products produced by this method.

The test samples included unrefined light and heavy vacuum distillates from a naphthenic crude oil, as well as the corresponding severely hydrotreated products. Two sets of samples were prepared to assess the effects of various operating parameters in the reactor. Additionally, positive (benzo[a]pyree), negative (white mineral oil) and vehicle (toluene) control groups were included to assess the sensitivity and specificity of the bioassay. Each sample was applied in twice‐weekly aliquots to the backs of 40 male C3H mice.

In the analytical studies, significant reductions in the levels of several specific PAH were demonstrated. In the dermal carcinogenesis studies, the unrefined oils and the positive control induced tumors and also significantly reduced survival. None of the mice treated with severely hydrotreated oils or with the negative or vehicle controls developed skin tumors, and survival of these mice was not significantly different from the control. Thus, the data demonstrated that this new, severe hydrotreatment process was an effective means of converting carcinogenic feedstocks to non‐carcinogenic products.
Effects of aflatoxin on the immune system of the chick
Authors: Virdi J. S. , Tiwari R. P. , Saxena M. , Khanna V. , Singh G. , Saini S. S. , Vadehra D. V.
Published: October 2006

A decreased antibody response to injected sheep red blood cells and weight losses to the extent of 25–38% were observed in the bursa Fabricii and thymus in chicks fed an aflatoxin diet (10% w/w) for 3 weeks. The immune organs did not show any significant histopathological changes. The antibody titre decreased from day 6 of treatment onward until the 15th day, when the antibody titre had disappeared completely in the test chicks. The body weight gain was also less in test chicks (9.7–37.3%) given test feed or test feed along with Salmonella pullorum in water (108cfu ml−1) in comparison to chicks given toxin‐free diet and water after 3 weeks of feeding trials. The disappearing component in the test chicks' liver homogenate was found to be antigenic by immunoelectrophoretic studies.
Predicting toxicokinetic parameters in humans from toxicokinetic data acquired from three small mammalian species
Authors: Bachmann Kenneth
Published: October 2006

Values for the indepedent kinetic variables, clearance (CL) and volume of distribution (V), for six xenobioticsantipyrine, ethosuximide, phencyclidine, theophylline, valproic acid and warfarin—were culled from the literature for each of three small subhuman species and for humans, and then allometrically scaled. Scaling was performed in two ways. First, using kinetic data acquired for three small subhuman species and for man, scaled parameters were observed for goodness of fit to a standard allometrie expression. Second, scaled parameters were averaged for three subhuman species. Mean scaled kinetic parameters from only three species were used to predict half‐life values of the xenobiotics in humans. Finally, predicted percentages of the xenobiotic burdens remainig in humans at the end of four allometrically‐predicted half‐lives were compared with the expected percentages of remainig xenobiotic based upon four actual half‐lives in humans. The results suggest that it may be feasible to estimate, using three small subhuman specie, allometrically‐derived toxicokinetic parameters of some substances in man with sufficient accuracy to be of practical value.
Lipid peroxidation in acrylonitrile‐treated rats, evidenced by elevated ethane production
Authors: Ivanov V. , Rahier J. , Lauwerys R.
Published: October 2006

The intraperitoneal administration of acrylonitrile (> 25 mg kg−1) to rats is associated with an increased production of ethane and a rise of the serum activity of the cytosolic enzyme, sorbitol dehydrogenase. These effects are prevented by pretreatment with vitamin E and the microsomal enzyme inhibitor SKF 525A, but are exacerbated by pretreatment with the microsomal enzyme inducer, phenobarbital.

Repeated intraperitoneal administration of acrylonitrile (40 mg kg−1) for four weeks also increases ethane production and serum SDH activity, and produces various morphological changes in liver parenchymal cells (necrosis, increased mitotic activity, increased nucleolar size and myelinic figures in mitochondria) and inhibits the growth of the animals. All these effects are prevented by the administration of vitamin E (190 mg kg−1 i.p., daily) during the last two weeks of treatment.

A dose of sodium cyanide (2.5 mg kg−1 i.p.) which leads to a urinary excretion of thiocyanate similar to that found after the intraperitoneal administration of 25 mg kg−1 acrylonitrile, does not stimulate ethane production.

This study suggests that the hepatoxicity of acrylonitrile may, at least partly, result from a lipoperoxidation process and is linked with its microsomal oxidative biotransformation.
Effects of intrauterine exposure to parathion on the activity of renal ATPases in offspring
Authors: Jaramillo‐Juárez Fernando , Del Rio Francisco A. Posadas , Reyes José L. , Rodríguez Maria Luisa , Irene Sánchez Elsa , Cuellar Luis Humberto
Published: October 2006

The effects of ethyl parathion on the activities of various renal enzymes were studied in the offspring from dams treated with this insecticide during pregnancy. The enzymes tested were the (Na+‐K+)‐ and the Mg2+‐dependent ATPases, the glutathione S‐transferases and carboxylesterases. The postnatal effects of parathion on kidney ATPases from undernourished rats were also assessed. The organophosphate was administered per os to pregnant rats at a dose of 1 mg kg−1 body weight per day throughout gestation, and suspended after delivery. The offspring were divided in groups of normally‐fed and undernourished rats. In the undernourished group, food restriction produced a decrease of 43% in body weight as compared to the normally‐fed group. Offspring were sacrificed 6 weeks after birth and the enzymatic activities were determined in kidney homogenates. We found a decrease in the enzymatic activity of total ATPases, at the expense of the Mg2+‐dependent ATPase. However, the activities of the (Na+‐K+)‐dependent ATPase, the glutathione S‐transferases and the carboxylesterases did not show significant changes. On the other hand, undernutrition did not potentiate the effects of parathion on the ATPases. Thus, this organophosphate administered during pregnancy produced a selective inhibition on the renal Mg2+ ‐dependent ATPase from offspring, which was not potentiated by our undernutritional model.
Effects of short‐term and long‐term administration of amiodarone on hepatobiliary function in male rats
Authors: Young Robert A. , Mehendale Harihara M.
Published: October 2006

Functional, biochemical and histological parameters of hepatotoxicity were assessed in male Sprague‐Dawley rats receiving amiodarone (Am) short‐term by gavage (5, 50, 150 and 500 mg Am kg−1day−1, 10 days) or dietary exposure (50 ppm, 1500 ppm, 4‐week duration), or by long‐term dietary exposure (50 ppm, 8‐month duration). Serum enzyme (ALT, AST, ICD) levels and histopathological examination indicated no observable evidence of toxicity among rats of any of the treatment groups. Reduced food intake and reduction in weight gain was observed for rats exposed short‐term to 1500 ppm dietary Am. Assessment of hepatobiliary function in treated rats indicated that short‐term and long‐term dietary exposure to Am resulted in a compromised excretion of readily excretable phenolphthalein glucuronide (PG), although inanition may account for this effect in the 1500 ppm group. Rats receiving Am by gavage exhibited a reduction in biliary excretion of PG, which was not dose‐dependent. Distribution of Am and its major metabolite, desethylamiodarone, was similar to previous reports wherein both compounds accumulated in adipose, lung and liver tissue. These data suggest that minor alterations of hepatobiliary function occur in the absence of histological alterations and may preceed biochemical changes, as assessed in this study.
Structure–activity relationships for osteolathyrism. III. Substituted thiosemicarbazides
Authors: Dawson Douglas A. , Schuitz T. Wayne , Baker Leslie L. , Mannar Anuradha
Published: October 2006

Eight substituted thiosemicarbazides were assayed for their toxicity and teratogenicity using early embryos of Xenopus laevis. Results of the 96‐h static tests on seven 4‐position alkyl substituents were used for quantitative structure–activity relationship (QSAR) analyses, with thiosemicarbazide as the parent compound. The compounds induced malformations via the connective tissue defect osteolathyrism. Teratogenicity (log EC50) was negatively correlated with molar refractivity, suggesting that steric inhibitions were important in explaining the variations in biological activity due to changes in the 4‐position substituent. It appeared that there were two separate modes of lethal action, one associated with the ring‐containing substituents and the other with straight‐chain substituents. However, QSARs were not developed for embryolethality (log LC50) or for the mortality/malformation index (LC50/EC50) due to the limited number of chemicals eliciting each lethal mode of action.
Triiodothyronine (T3) increases cisplatin nephrotoxicity in young and adult rats
Authors: Appenroth Dorothea , Gambaryan Stephan , Bakhteeva Vera , Winnefeld Klaus , Schröter Heinz , Gerhardt Steffen , Bräunlich Helmut
Published: October 2006

The influence of pretreatment with triiodothyronine (T3) on cisplatin (CP)‐induced nephrotoxicity was investigated in 10‐ and 55‐day‐old rats. Triiodothyronine pretreatment enhanced CP proteinuria in young and adult rats, and increased blood urea nitrogen concentration in 55‐day‐old rats. As T3 decreased Pt concentrations in renal tisssue, the enhanced nephrotoxicity of CP by T3 must have another mechanism. Enhanced CP nephrotoxicity is discussed in connection with an increase of glutathione concentration obtained in renal tissue as a consequence of T3 pretreatment.
A teratological assessment of coal liquefaction products in the rat
Authors: Chu I. , Villeneuve D. C. , Valli V. E. , Black W. D. , Robinson K. , Beyrouty P.
Published: October 2006

Teratogenicity of coal liquefaction products (CLP) was assessed in the pregnant rat. Three product streams of CLP (medium, hydrotreated medium and heavy fractions) were each administered dermally on Sprague‐Dawley rats at doses of 125, 250 or 500 mg kg−1day−1 from Day 6 through to Day 15 of gestation. Depressed maternal weight gain and reduced number of fetuses resulting from an increased resorption rate, decreased fetal weight and retarded ossification were observed in the group treated with the heavy fraction at a dose of 500 mg kg−1day−1. The heavy fraction at 500 mg kg−1 day−1 also caused anaemia and increased liver and spleen weights in dams. The dams exposed to the highest dose of three CLP fractions had mild and adaptative hepatic changes consisting of increased cytoplasmic eosinophilia and nuclear anisokaryosis. No treatment‐related histological changes were observed in fetuses. None of the fractions demonstrated any teratological effects.
Acute toxicity and mutagenicity of the copper complex of pyruvaldehyde‐bis (N‐4‐methylthiosemicarbazone), Cu‐PTSM
Authors: Kostyniak Paul J. , Nakeeb Shaheen M. , Schopp Ellen M. , Maccubbin Alexander E. , John Elizabeth K. , Green Mark A. , Kung Hank F.
Published: October 2006

Cu‐PTSM is a potential imaging agent for the heart and brain when labeled with either 64Cu or 62Cu. Unlabeled Cu‐PTSM was evaluated for its acute toxicity and mutagenicity. Cu‐PTSM had an i.v. LD50 of 26 mg kg−1 in the rat and 2 mg kg−1 in the rabbit. At necropsy, rats exhibited severely hemorrhagic lungs, histological findings of acute pulmonary congestion, hemorrhage and edema, and mild congestion in kidney, liver and brain. The rabbit displayed marked polymorphonuclear infiltration in alveoli, peribronchial and periarterial areas with marked macrophage hyperplasia, congestion and mild hemorrhage into alveolar spaces. No effects were found in kidney, liver, testes or brain. Administration of 2.16 μg kg−1 day−1 for 5 days per week for 2 weeks resulted in no changes in histopathology, hematology or clinical chemistry parameters. This daily dose is at least 300 times the diagnostic dose intended for use in man. Cu‐PTSM was not mutagenic when tested in the absence of S9 supernatant, but elicited a weakly mutagenic response in the presence of S9. Since acute effects in the lung occur at doses approaching 300000 times the diagnostic dose, it is highly unlikely that the clinical use of Cu‐PTSM would result in any acute adverse effects.
Plasma clearance of 51Cr‐EDTA as an estimator of glomerular filtration rate in conscious rats
Authors: Seefeldt Torben , Houghton Donald C.
Published: October 2006

A method is described whereby the plasma clearance of 51Cr‐EDTA is used to estimate the glomerular filtration rate (GFR) in conscious rats. EDTA clearance rates were calculated based on one and two exponential disappearance curves and compared in groups of animals studied under conditions of normal, high and low GFR. Like previously described related methodologies, this technique obviates the need for urine collections and marker infusions for GFR estimates. An important added advantage is that it provides the opportunity to study animals free of the effects of anesthetic, supine position and surgical stress.
Proposal and application of an ecotoxicity biotest based on escherichia coli
Authors: Espigares M. , Roman I. , Alonso J. M. Gonzalez , de Luis B. , Yeste F. , Galvez R.
Published: October 2006

The authors propose the use of an ecotoxicity biotest based on Escherichia coli for the sanitary control of water. The sensitivity of the proposed model was evaluated using a group of representative toxicants, and its response (synergism, additive or antagonism) to toxicants was observed. Finally, the biotest was applied to 124 water samples from rivers, underground sources, drinking water and wastewater.

The results of the biotest were compared with the sanitary classification of the waters.
Mechanisms of testicular atrophy induced by Di‐n‐butyl phthalate in rats. Part 3. Changes in the activity of some enzymes in the sertoli and germ cells, and in the levels of metal ions
Authors: Zhou Yu , Fukuoka Masamichi , Tanaka Akira
Published: October 2006

A single oral dose of di‐n‐butyl phthalate (DBP) to male rats caused a sloughing of the germ cells at 6 h, with more severe sloughing at 24 and 48 h. DBP is metabolized to mono‐n‐butyl phthalate (MBP), which is transported through the blood‐tubular barrier into the seminiferous lumen. MBP is incorporated into the lumen at a maximum rate between 1 and 3 h after dosing with DBP. MBP caused decreases in the activities of succinate dehydrogenase in the Sertoli cells and sorbitol dehydrogenase in the germ cells, an increase in the activity of lactate dehydrogenase (LDH) in the germ cells and in the seminiferous lumen and a decrease in testicular iron levels.
Changes in lipid peroxidation levels and lipid composition in the lungs, livers, kidneys and brains of mice treated with paraquat
Authors: Sato Nobuyoshi , Fujii Kohyu , Yuge Osafumi , Morio Michio
Published: October 2006

We examined lipid peroxide levels and the lipid composition of homogenates prepared from the lungs, livers, kidneys and brains of 48 male ICR mice treated with 30 mg kg−1 paraquat (1,1′‐dimethyl‐4,4′‐bipyridylium dichloride). The mice were divided into eight groups, in which they were killed 0, 1.5, 3, 6, 12, 24, 48 and 120 h after the administration of paraquat. A significant increase in the lipid peroxide level was identified only in the liver. Change in lipid composition was identified in all the examined organs. However, the change was not a characteristic one in which there is a selective decrease of polyunsaturated fatty acids which become degraded in a lipid peroxidation reaction. It is possible that the mechanism of paraquat toxicity may differ in different organs.
ATP‐mgcl2increases cisplatin toxicity in the dog and rat
Authors: Hardie Elizabeth M. , Page Rodney L. , Hoopes P. Jack
Published: October 2006

The purpose of this study was to examine if ATP‐MgCl2, an agent that protects against acute cisplatin toxicityin vitro, protected against cisplatin toxicityin vivo. Baseline renal function measurements were obtained on dogs (n= 12) and rats (n= 20) on day –1. Dogs were given 90 mg m−2cisplatin (n= 5), 90 mg m−2cisplatin and 50 μmol kg−1ATP‐MgCl2(n= 5), or 90 mg m−2cisplatin and 150 μmol kg−1ATP‐MgCl2(n= 2), in a slow bolus i.v. injection on day 0, Rats were given 4 mg kg−1cispiatin i.p. (n= 6) and 25 μmol kg ATP‐MgCl2(n= 8) i.v. or 4 mg kg−1cisplatin i.p. and 25 μmol kg−1ATP‐MgCl2(n= 6) i.v. on day 0. Renal function was assessed on a routine basis for 14 days. All dogs had significantly decreased creatinine ciearance following cisplatin administration. There were no significant differences in renal function tests between groups of dogs. One dog given 50 μmol kg−1ATP‐MgCl2and both dogs given 150 μmol kg−1ATP‐MgCl2in addition to cisplatin developed acute anuric renal failure and were euthanatized prior to completion of the study. Rats given 4 mg kg−1cisplatin and 25 μmol kg−1ATP‐MgCl2had significantly increased blood urea nitrogen and serum creatinine after drug administration, compared to rats given cisplatin alone. The results indicated that ATP‐MgCl2worsenedin vivocisplatin renal toxicity in the dog and rat.
Mutagenicity evaluation of riot control agent o‐chlorobenzylidene malononitrile (cs) in the ames salmonella/microsome test
Authors: Meshram Ghansham P. , Malini R. Padma , Rao Kola M.
Published: October 2006

o‐Chlorobenzylidene malononitrile (CS), a riot control agent, was evaluated for its possible mutagenic activity in the Ames Salmonella/mammalian microsome mutagenicity test. Five histidine‐deficient (His−) mutant tester strains of Salmonella typhimurium—TA97a, TA98, TA100, TA102 and TA104—were used. The liquid preincubation procedure was used with metabolic activation (presence of S9 mixture) and without metabolic activation (absence of S9 mixture). For the experiments with metabolic activation, three different concentrations of S9 fraction (supernatant of Aroclor 1254‐induced rat liver homogenate at 9000 g)—5%, 15% and 30% in S9 mixture—were used. Along with mutagenic activity, CS was also evaluated for cytotoxic activity in all the five tester strains of Salmonella typhimurium, both in the presence and absence of S9 mixture. The mutagenic and cytotoxic activities of CS were assessed by counting the His+ revertant colonies and by counting the microcolonies (His−, auxotrophs in the background lawn), respectively, and the respective mean values were compared with the relative negative (solvent) control. A dose range of 12.5–800 μg plate−1 for CS did not induce a mutagenic response either in the presence or absence of S9 mix. No change in the negative mutagenic response of CS has been observed even in the presence of an elevated level of S9 fraction in the S9 mix. A dose of 200 μg plate−1 for CS was found to be cytotoxic by decreasing the surviving cells as well as His+ revertant colonies; however, the effect was reduced in the presence of an elevated level of S9 fraction in the S9 mix.
Pulmonary reactivity to vanadium pentoxide following subchronic inhalation exposure in a non‐human primate animal model
Authors: Knecht Edwin A. , Moorman William J. , Clark John C. , Hull R. Delon , Biagini Raymond E. , Lynch Dennis W. , Boyle Terrence J. , Simon Stephen D.
Published: October 2006

An experimental study was conducted to evaluate changes in pulmonary reactivity resulting from repeated vanadium pentoxide (V2O5) dust inhalation. The study assessed pulmonary reactivity to V2O5 through the use of provocation challenges, and compared V2O5 reactivity before and after subchronic V2O5 exposure. A total of 24 adult, male cynomolgus monkeys (Macaca fascicularis) were exposed by inhalation for 6 h per day, 5 days per week, for 26 weeks. Two V2O5‐exposed groups (n=8 each) received equal weekly V2O5 exposures (concentration x time) with different exposure profiles. One V2O5‐exposed group received 0.1 mg V2O5 m−3 on Mondays, Wednesdays and Fridays, with a twice‐weekly peak exposure of 1.1 mg V2O5 m−3 on Tuesdays and Thursdays, and was included to investigate the influence of an exposure regimen with peaks on the development of pulmonary hyper‐reactivity. The other V2O5‐exposed group received a constant daily concentration of 0.5 mg V2O5 m−3. A control group (n‐8) received filtered, conditioned air. Pre‐exposure challenges with V2O5 produced a concentration‐dependent impairment in pulmonary function, characterized by airway obstructive changes (increased resistance and decreased flow). Analysis of respiratory cells recovered from the lung by bronchoalveolar lavage demonstrated that airway obstruction was accompanied by a significant influx of inflammatory cells into the lung. Subchronic V2O5 inhalation did not produce an increase in V2O5 reactivity in comparison to the control group, and cytological, immunological and skin test results indicate the absence of allergic sensitization. Instead, a trend toward decreased pulmonary reactivity was found following subchronic V2O5 inhalation. Pulmonary reactivity to V2O5 (both functional and cellular responses) was affected, as well as non‐specific reactivity to methacholine. This finding suggests that the absence of increased pulmonary reactivity to V2O5 following subchronic inhalation may be related to the induction of tolerance under the exposure conditions used in the study.
Silymarin protects against paracetamol‐induced lipid peroxidation and liver damage
Authors: Muriel Pablo , Garciapiña Tania , Perez‐Alvarez Victor , Mourelle Marisabel
Published: October 2006

The effect of silymarin on liver damage induced by acetaminophen (APAP) intoxication was studied. Wistar male rats pretreated (72 h) with 3‐methylcholantrene (3‐MC) (20 mg kg−1 body wt. i.p.) were divided into three groups: animals in group 1 were treated with acetaminophen (APAP) (500 mg kg−1 body wt. p.o.), group 2 consisted of animals that received APAP plus silymarin (200 mg kg−1 body wt. p.o.) 24 h before APAP, and rats in group 3 (control) received the equivalent amount of the vehicles. Animals were sacrificed at different times after APAP administration. Reduced glutathione (GSH), lipid peroxidation and glycogen were measured in liver and alkaline phosphatase (AP), gamma‐glutamyl transpeptidase (GGTP) and glutamic pyruvic transaminase (GPT) activities were measured in serum. After APAP intoxication, GSH and glycogen decreased very fast (1 h) and remained low for 6 h. Lipid peroxidation increased three times over the control 4 and 6 h after APAP treatment. Enzyme activities increased 18 h after intoxication. In the group receiving APAP plus silymarin, levels of lipid peroxidation and serum enzyme activities remained within the control values at any time studied. The fall in GSH was not prevented by silymarin, but glycogen was restored at 18 h. It was concluded that silymarin can protect against APAP intoxication through its antioxidant properties, possibly acting as a free‐radical scavenger.
Body distribution and endocrine toxicity of hexachlorobenzene (HCB) in the female rat
Authors: Foster Warren G. , Pentick Julie A. , McMahon Avril , Lecavalier Pierre R.
Published: October 2006

Hexachlorobenzene (HCB) residue levels in dosed rats (50.0 mg kg−1 body wt. day−1, n = 9) were significantly (P<0.05) greater in the periovarian fat compared to the thyroid gland. Hexachlorobenzene residue levels were significantly (P<0.05) greater in the thyroid versus the adrenal and ovary. Ovarian HCB residue levels were greater than those found in the thymus, liver and lung. Serum thyroxin (T4) and the free T4 index (FTI) were significantly (P<0.05) suppressed in HCB‐treated rats compared to the control group (n = 8). In contrast, no significant differences in serum concentrations of oestradiol (E2), progesterone (P4) or percentage triiodothyronine uptake (%T3) were observed, thus suggesting an HCB‐induced hypothyroid‐like state. In a second experiment, adult female Sprague Dawley rats (n = 16) were dosed as above and superovulated with pregnant mare serum gonadotrophin (PMSG, 10 IU s.c.) and human chorionic gonadotrophin (hCG, 20 IU s.c.). Circulating levels of P4 were significantly (P<0.05) elevated compared to the control group (n = 8). The %T3 uptake and serum T4 levels were significantly (P = 0.05) suppressed compared to controls. Hexachlorobenzene treatment had no effect on circulating levels of E2 or on the FTI. These results suggest that HCB‐induced changes found in the spontaneously cycling rat are augmented by ovulation induction strategies. We also conclude that HCB concentrates in the endocrine tissues in addition to the fat.
Pharmacology of organophosphates
Authors: Koelle George B.
Published: October 2006

The cholinergic nerve fibers, which employ acetylcholine (ACh) as a neurohumoral transmitter, and the results of their activation are listed. The reactions between the enzyme acetylcholinesterase (AChE), its natural substrate, ACh, and the various types of inhibitors are described. The limited therapeutic uses of the anticholinesterase (anti‐ChE) agents are considered. The toxicological effects encountered when the anti‐ChE agents are employed as insecticides or as chemical warfare (CW) agents are discussed. Certain anti‐ChE agents produce also a delayed neurotoxic effect which is apparently unrelated to the inhibition of AChE.
Vision and ocular changes following accidental exposure to organophosphates
Authors: Rengstorff Roy H.
Published: October 2006

The most conspicuous short‐term effects of exposure to organophosphates are miotic pupils and a reduced visual field. Two men accidentally exposed to vapors of sarin, a cholinesterase inhibitor and extremely toxic nerve gas, showed these effects but no adverse effects on near‐ or far‐visual acuities, oculomotor functions, intraocular pressure or color vision. However, reports of other accidental exposures to organophosphorus compounds suggest that there are visual and ocular changes, including myopia and decreased visual acuity.
Ocular effects of organophosphates: A historical perspective of saku disease
Authors: Dementi Brian
Published: October 2006

Many publications, primarily of work performed in Japan, report findings in human populations of an increased incidence of myopia and of a more advanced visual disease syndrome (Saku disease), which reportedly correlated with increasing use of organophosphate pesticides in agriculture. Follow‐up studies in animals performed in Japan using such agents as ethylthiometon, fenthion and fenitrothion demonstrate adverse effects of organophosphates on the visual system. The several ocular effects in question are dose dependent, ranging in severity from lenticular and electro‐retinographic changes to the seemingly more serious histophysiological changes in such tissues as the ciliary body and retina. An important question arising from this work is that of the role of cholinesterase inhibition in the etiology of the effects.

Studies currently in progress on particular organophosphates being conducted at EPA's research facility and by certain registrants of pesticides, which are in various stages of completion, appear to be substantiating much that has been reported in Japan. While animal studies clearly show that some organophosphates elicit ocular toxicity, there are many knowledge gaps with regard to effects in humans and the ocular toxicity in general, e.g. time and dose dependency, cholinesterase inhibition vs ocular effects and effects of routes of exposure. Consequently, the office is unable at this time to incorporate hazard assessment data with exposure assessment data or to perform risk assessments on organophosphates based on the ocular toxicity potential of this class of chemicals.
In vivo performance of antibiotic embedded electrospun PCL membranes for prevention of abdominal adhesions
Authors: Bölgen N. , Vargel İ. , Korkusuz P. , Menceloğlu Y. Z. , Pişkin E.
Published: October 2006

The aim of this study was to prepare nonwoven materials from poly(ε‐caprolactone) (PCL) and their antibiotic containing forms by electrospinning, so as to prevent postsurgery induced abdominal adhesions in rats. ε‐Caprolactone was first polymerized by ring‐opening polymerization, and then it was processed into matrices composed of nanofibers by electrospinning. A model antibiotic (Biteral®) was embedded within a group of PCL membranes. In the rat model, defects on the abdominal walls in the peritoneum were made to induce adhesion. The plain or antibiotic embedded PCL membranes were implanted on the right side of the abdominal wall. No membrane implantation was made on the left side of the abdominal wall that served as control. Macroscopical and histological evaluations showed that using these barriers reduces the extent, type, and tenacity of adhesion. The antibiotic embedded membranes significantly eliminated postsurgery abdominal adhesions, and also improved healing. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Neurotrophin‐eluting hydrogel coatings for neural stimulating electrodes
Authors: Winter Jessica O. , Cogan Stuart F. , Rizzo Joseph F.
Published: October 2006

Improved sensory and motor prostheses for the central nervous system will require large numbers of electrodes with low electrical thresholds for neural excitation. With the eventual goal of reducing stimulation thresholds, we have investigated the use of biodegradable, neurotrophin‐eluting hydrogels (i.e., poly(ethylene glycol)‐poly(lactic acid), PEGPLA) as a means of attracting neurites to the surface of stimulating electrodes. PEGPLA hydrogels with release rates ranging from 1.5 to 3 weeks were synthesized. These hydrogels were applied to multielectrode arrays with sputtered iridium oxide charge‐injection sites. The coatings had little impact on the iridium oxide electrochemical properties, including charge storage capacity, impedance, and voltage transients during current pulsing. Additionally, we quantitatively examined the ability of neurotrophin‐eluting, PEGPLA hydrogels to promote neurite extensionin vitrousing a PC12 cell culture model. Hydrogels released neurotrophin (nerve growth factor, NGF) for at least 1 week, with neurite extension near that of an NGF positive control and much higher than extension seen from sham, bovine serum albumin‐releasing boluses, and a negative control. These results show that neurotrophin‐eluting hydrogels can be applied to multielectrode arrays, and suggest a method to improve neuron‐electrode proximity, which could result in lowered electrical stimulation thresholds. Reduced thresholds support the creation of smaller electrode structures and high density electrode prostheses, greatly enhancing prosthesis control and function. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Protective effects of antioxidants on micronuclei induced by camphorquinone/N,N‐dimethyl‐p‐toluidine employing in vitro mammalian test system
Authors: Li Yi‐Ching , Huang Fu‐Mei , Lee Shiaun‐Shinn , Lin Ruey‐Hseng , Chang Yu‐Chao
Published: October 2006

Camphorquinone (CQ) is widely used as an initiator in modern visible‐light (VL) cured resin systems. CQ is also characterized as a potential allergenic compound. To date, there is growing concern that CQ may produce genetic damage by inducing mutation. In this study, CQ in the presence of reducing agent N,N‐dimethyl‐p‐toluidine (DMT) with or without VL irradiation was analyzed for the induction of chromosomal aberrations indicated by micronuclei (MN) induced in CHO cells. Our data demonstrated that an increase in the numbers of MN was observed with CQ/DMT with or without VL irradiation (p < 0.05). Significant prolongation of cell cycles was observed by the treatment with CQ/DMT with or without VL irradiation (p < 0.05). In addition, VL irradiated CQ/DMT was found to exhibit significantly genotoxic and cytotoxic effects as compared with CQ/DMT alone (p < 0.05). Furthermore, to determine whether oxidative stress could modulate the MN induced by CQ/DMT with or without VL irradiation in CHO cells, cells were pre‐treated with various antioxidants 10 mM N‐acetyl‐L‐cysteine (NAC), 2 mM ascorbic acid, and 2 mM α‐tocopherol. The pre‐treatment with antioxidants could antagonize not only the increased MN cells but also the prolonged cell cycle induced by CQ/DMT with or without VL irradiation in CHO cells (p < 0.05). Our findings provide the evidences for the induction of MN by CQ/DMT employing mammalian test system, indicating clastogenic activity of CQ/DMT with or without VL irradiation in vitro. In addition, VL irradiated CQ/DMT exhibits higher genotoxic and cytotoxic effects than CQ/DMT alone. Moreover, NAC, ascorbic acid, and α‐tocopherol act as the antagonists against the genotoxicity and cytotoxicity of CQ/DMT with or without VL irradiation. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
The synthesis of 2,2′,5′,2″– [2′,5′ –14C2] terthienyl and 1,4–bis (2–thienyl) [1,4–14C2] butadiyne
Authors: Beny Jean‐Pierre , Kagan Jacques
Published: October 2006

2,2′,5′,2″– [2′,5′ –14C2] Terthienyl and 1,4–Bis (2–Thienl) [1,4–14C2] butadiyne were synthesized from [14C] formic acid.
Synthesis of singly 2H‐, 3H‐, and 14C‐ and doubly labeled acetaminophen, phenacetin, and p‐acetanisidine
Authors: Chan Kenneth K. , Pang K. Sandy
Published: October 2006

Several efficient procedures for the synthesis of deuterium, tritium, and 14C–labeled acetaminophen, phenacetin, and p‐acetanisidine are described. p‐Aminophenol was acylated by the appropriate acetic anhydride under mild conditions yielding labeled acetaminophen. With 0‐alkylation using NaCH2SOCH3 and appropriate labeled and unlabeled alkyl halides, labeled phenacetin and p‐acetanisidine were also obtained. Phenacetin labeled both with 14C on the acyl group and deuterium on the ethoxy group was synthesized in high yield by acylation of p‐phenetidine‐d5. The last compound was obtained by acid hydrolysis of phenacetin‐d5 synthesized previously.
Synthesis of phenyl [1‐14C]acetylene and 1,4–diphenyl[1,4‐14C2] butadiyne
Authors: Dhawan Som N. , Kagan Jacques
Published: October 2006

Phenyl [1‐14C] acetylene (0.012mCi/mmole) was synthesized in 12.5% yield from [1‐14C] acetic acid through [1‐14C] acetophenone, its semicarbazone, and 4‐phenyl‐[4‐14C] 1,2,3‐selenadiazole obtained by selenium dioxide oxidation. Oxidative coupling gave 1,4‐diphenyl [1,4‐14C2] butadiyne in 80% yield.