bluuebunny/crossref_metadata_2025 huggingface dataset:
Early biochemical alterations in liver mitochondria from carbon tetrachloride poisoned rats
Authors: Villarruel M. C. , Fernandez G. , Aguilar E. G. , Castro J. A.
Published: October 2006

Covalent binding of reactive metabolites of 14CCI4 were found 1 or 3 h after treatment with the solvent in the lipid and protein fractions of highly purified liver mitochondrial of rats. Most of the label was found in the phospholipid (PL) fraction, much less in cholesterol esters (ChE), and only minor quantities in other lipids. The reactive metabolites of 14CCI4 activated by isolated mitochondria interact mostly with ChE and far less with PL and other fractions. Both in vivo and in vitro covalent binding to PL is decreasing in the following order: phosphatidylethanolamine > diphosphatidylglycerol > phosphatidylcholine > sphingomyelin > lysophosphatidyl choline. No evidence of lipid peroxidation was found in liver mitochondrial lipids in the first 6 h and only a slight tendency of decrease in arachidonic acid concentration at 24 h. The incorporation of [14C] leucine in mitochondrial, microsomal or cytosolic proteins decreased as early as 1 h after treatment. These results, in agreement with previous reports suggest the existence of multiple sites in liver cells for the activation of CCI4. The transport of altered phospholipids and proteins and the inhibition of protein synthesis might contribute to the propagation of damage from the endoplasmic reticulum to other organelles.
Differential response of NADP‐linked hepatic aldehyde dehydrogenase toward taurine: Implication for behavioural effects of ethanol
Authors: Messiha F. S.
Published: October 2006

The effects of taurine, its initial precursor L‐cysteine, and the major metabolite taurocholic acid on two ethanol‐mediated responses in rodents were studied. Administration of a single dose of taurocholic acid reduced voluntary intake of a 5% ethanol solution by the rat. In the mouse, taurine had no effect on alcohol drinking or on the central depressant action of ethanol, as measured by the duration of ET‐produced loss of the righting reflex. Likewise, taurocholic acid and L‐cysteine did not significantly influence the duration of ethanol‐narcosis time from control mice. Also studied were the effects of acute and short‐term (7 or 10 days) administration of these compounds on hepatic ethanol and acetaldehyde metabolizing enzymes. Short‐term administration of an equimolar concentration of taurine enhanced endogenous NADP‐linked rat liver aldehyde dehydrogenase (L‐ALDH) as contrasted with inhibition of the same enzyme by L‐cysteine. Short‐term (7 days) treatment with L‐cysteine induced rat liver NAD‐linked ALDH, but acute (single dose) treatment did not. Taurocholic acid short‐term administration caused an induction and an inhibition of endogenous mouse liver alcohol dehydrogenase (L‐ADH) and L‐ALDH, respectively. The results suggest that taurine does not directly interact with ethanol. However, its major metabolite, taurocholic acid, may cause rapid metabolic conversion of ethanol to acetaldehyde by induction of L‐ADH, which is then slowly metabolized due to a concomitant inhibition of L‐ALDH. This may cause a build‐up of acetaldehyde and thereby produce adverse reactions similar to those resulting from the combination of disulfiram and ethanol.
Acute effects of isopropyl alcohol exposure on the middle ear mucosa
Authors: Ohashi Yoshihiro , Nakai Yoshiaki , Ikeoka Hiroshi , Koshimo Hiroyuki , Esaki Yusuke , Horiguchi Shun'Ichi , Teramoto Keiko , Nakaseko Hiroyuki
Published: October 2006

Guinea pigs were exposed to 400 ppm or 5500 ppm of isopropyl alcohol (IPA) for 24 successive hours, and then middle ear mucosal samples in both proximal and distal sites to the eustachian tube were obtained for functional and morphological examinations. The ciliary activity was examined according to the photoelectric method of Ohashi and Nakai. The morphology of the middle ear lining was examined by transmission electron microscopy. The results showed that IPA at the allowable level of 400 ppm has an acute effect on the mucociliary system of the middle ear mucosa. Recovery from damage occurs within two weeks. At higher levels of exposure to IPA (more than 10 times the allowable level) moderate deterioration of the ciliary activity and severe damage of epithelial cells were observed and recovery within two weeks was not seen. It is concluded that IPA at the allowable level of 400 ppm does not cause significant middle ear disorders, but workers exposed to higher levels of IPA should be given careful otolaryngological examinations and follow‐up observations.
Effects of in vivo administration of detergents on the hepatic microsomal cytochrome P‐450 system in rat
Authors: Miura Yoshiro
Published: October 2006

The influence of in vivo administration of detergents on the hepatic microsomal cytochrome P‐450 system was studied in rat. Male Wistar rats were administered detergents, Emulgen 913 (50 mg or 100 mg kg−1 of body weight (B.W.)), or sodium dodecylsulfate (SDS, 25 mg or 50 mg kg−1 of B.W.) intraperitoneally once a day for 3 days. Cytochrome P‐450 content in liver microsomes was significantly decreased to 85% and 73% of control by the administration of 50 mg or 100 mg Emulgen, respectively, but the microsomal protein concentration was not changed by these administrations. The content of cytochrome P‐450 was also reduced to 76% and 70% of control by the administration of 25 mg or 50 mg SDS/kg of B.W., respectively. The total hydroxylation activity (the sum of ω‐ and (ω ‐ 1)‐hydroxylase activity) of laurate almost paralleled the decrease in cytochrome P‐450 in detergent‐treated rats. However, the ω/ω‐1‐hydroxylation ratio was not changed. These results suggest that the administration of these detergents lowered the level of cytochrome P‐450 species catalyzing ω‐ and (ω ‐ 1)‐hydroxylation of laurate to a similar extent. On the other hand, aminopyrine N‐ and p‐nitroanisole O‐demethylation activities in Emulgen 913‐treated rats was decreased while those in SDS‐treated rats did not change, though the content of cytochrome P‐450 was decreased by both administrations. Thus, it was demonstrated that the livers of rats responded to exogenous detergents in different manners.
Acute and subchronic toxicity of tetramethylcyclohexanes
Authors: Johannsen Frederick R. , Levinskas George J.
Published: October 2006

The acute oral toxicity in rats was estimated for seven isomers or isomeric ratios of tetramethylcyclohexane (TMCH). Lack of sufficient mortality at the highest dosage test (15.8 g/kg) precluded evaluation of an LD50 for mixed cis, trans‐isomers of 1,2,3,4‐TMCH, 1,2,3,5,‐TMCH, 1,2,4,5‐TMCH and 1,1,2,3‐TMCH, for the separate cis‐ or trans‐forms of 1,1,3,5‐TMCH or a 1:1 mixture of c,t−1,1,3,5‐TMCH and c,t−1,2,3,4‐TMCH. Mixed (c,t‐combined) isomeric TMCH was administered oraiiy to rats (30/group) and dogs (8/group) for 90 days at dietary levels of 0, 3000, 10 000 and 30 000 ppm TMCH and 0, 100, 300 and 1000 ppm TMCH, respectively. Administration of up to 30 000 TMCH to rats produced no discernible effects on survival, behavior, growth, food consumption, clinical blood picture or urine analysis. Absolute kidney weights of male but not female rats were elevated at all test levels. TMCH‐related microscopic lesions were confined to the kidney of male rats in all treated groups. These histopathologic changes were characteristic of tubular nephrosis. No treatment‐related effects were observed in groups of dogs fed up to 1000 ppm TMCH for 90 days.
Maternal toxicity, embryolethality and abnormal fetal development in CD‐1 mice following one oral dose of T‐2 toxin
Authors: Rousseaux C. G. , Schiefer H. B.
Published: October 2006

An experiment was undertaken to determine the teratogenic effect of oral administration of T‐2 toxin, a trichothecene mycotoxin. Firstly, a dose response study using 0,0.5, 1.0, 2.0, 3.0, 3.5 and 4.0 mg/kg T‐2 toxin in propylene glycol, on day 9 of pregnancy, was undertaken. Maternal deaths and toxicity was noted in the 4.0 and 3.5 mg/kg groups post‐toxin administration. These groups gained less weight throughout gestation than the rest of the groups, because no fetuses were found in the 4.0 mg/kg group and the 3.5 mg/kg group had significantly fewer fetuses than the remaining groups. The total fetal weight was similar among all groups with fetuses, and normal sex ratio of offspring was seen. More major and minor defects were seen in the 3.0 mg/kg T‐2 toxin treated group than any other group. Secondly, a day response trial using a single dose of 3.0 mg/kg T‐2 toxin given on either days 6, 7, 8, 10, 11 or 12 of gestation was undertaken. Maternal mortality, with placental hemorrhage, was observed. Fetal loss was greater in the T‐2 toxin treated groups than in the starved controls. The greatest number of dead term fetuses was seen in mice treated on day 9 of gestation. Normal sex ratios were present in the offspring. Major skeletal defects were more numerous in mice treated on day 7 of gestation, whereas minor defects, retardations and variants were more common in mice treated on day 8. It was concluded that a single oral dose of T‐2 toxin in propylene glycol is primarily maternotoxic and embryolethal, and that defective development was possibly secondary to maternal toxicity.
Evaluation of the nephrotoxic potential of styrene in man and in rat
Authors: Viau C. , Bernard A. , de Russis R. , Ouled A. , Maldague P. , Lauwerys R.
Published: October 2006

The urinary excretion of β2‐microglobulin, retinol‐binding protein and albumin was measured in 65 workers exposed to styrene at levels averaging 50 percent of the current threshold limit value (215 mg/m2) for 1–13 years (mean: 6 years). By comparison with a control group matched for age and socioeconomic status, no significant difference was observed in the urinary excretion of proteins. In rats, styrene was weakly nephrotoxic. No functional or morphological renal change could be disclosed in rats exposed to 565 mg of styrene/m3, 5 days/week for 13 weeks. The repeated i.p. injection of 1 g styrene/kg (1/5 of oral LD50) for 10 days induced only a slight tubular dysfunction as evidenced by a 5‐fold increase in β2‐microglobulinuria. Altogether, these epidemiological and experimental data suggest that the current threshold limit value for styrene (215 mg/m3) proposed by the American Conference of Governmental and Industrial Hygienists does not entail any risk of renal toxicity.
Inhalation toxicity of ribavirin in suckling ferrets
Authors: Hoffmann Saroita H. , Staffa Jeffrey A. , Smith Roberts A. , Craig Douglas K. , Parker George
Published: October 2006

Ribavirin is a broad‐spectrum antiviral agent useful for treatment of infants. To study the effects in developing mammalian lungs, four groups of jill ferrets and their litters were given whole body inhalation exposures for 6 h a day for 10 or 30 consecutive days to concentrations of 0 (vehicle control), 162, 355 or 620 mg/m3. The effects, including special lung observations in suckling kits, were evaluated after exposures at weaning and at puberty. First the high dose, then the mid dose jills developed lactation failure. Probably due to nutritional deficiency, approximately half of the mid dose and three quarters of the high dose kits were found dead or killed whilst moribund. There were no test compound‐related deaths in the control or low dose level groups. Reductions in body weight gain were observed in both 10 and 30 day exposed kits, and high dose kits actually lost weight as exposure continued. Some recovery was apparent in survivors. Some discoloration of the liver was seen in malnourished kits at necropsy. There were no gross or histopathologic lesions in the lungs or tracheas of suckling ferrets attributable to the test material. Ribavirin exposure had no effect on the lavageable cell pool, while lung DNA to protein ratios showed a mild, reversible, proliferative response in smaller kits. There were no differences in lung function between controls and low dose kits of either group. Effects seen in the higher dose groups are due to differences in size. While there may have been a real dose‐related enlargement of alveolar diameters at 40 days of age, this disappeared in males by puberty and did not seem toxicologically significant in females. The low dose, which corresponds to an exposure dose 4 to 6 times that used clinically, appeared to be a no‐effect level.
A rapid method for determining soot content of lungs in diesel‐exposed rodents
Authors: Henderson Rogene F , Waide James J. , Mauderly Joe L. , McClellan Roger O.
Published: October 2006

A rapid optical method for determining the quantity of soot in the lungs of rodents exposed to diluted diesel exhaust has been developed. The method is nondestructive to enzymatic components of the lung, allowing dose and biochemical assays to be done on the same sample. The lung burdens of soot were determined by comparing the extinction of light at 620 nm of lung homogenates from exposed animals to that of lung homogenates containing spiked standards.
Hepatotoxicity induced by the herbicide atrazine in the rat
Authors: Maria C. Santa , Moreno J. , Lopez‐Campos J. L.
Published: October 2006

The hepatotoxicity of atrazine was investigated by studying clinical parameters related to hepatic function and by electron microscopy. Three groups to male albino rats (Wistar strain) received 100, 209 and 400 mg of atrazine/per kg of body weight/per day, for 14 days. One group received 600 mg atrazine/per kg of body weight/per day, for 7 days. At termination of dosing, the animals were sacrificed and blood was drawn for the determination of serum total lipids, glucose, alanine aminotransferase (ALT) and alkaline phosphatase (SAP). A dose dependent decrease in serum glucose concentration was observed in all the groups. In contrast, a dose relate increase in total serum lipids, was apparent at all dose levels studied. Activity of serum ALT and SAP increased approximately 60% and 200% respectively in rats given 600 mg atrazine/kg bw for 7 days. The liver was examined grossly and microscopically. Electron microscopy disclosed no changes in the hepatocytes of rats treated with the low dose (100 mg/kg bw). At high doses, electron microscopy revealed hepatocytic proliferation and degeneration of smooth endoplasmic reticulum, lipid accumulation and alteration of bile canaliculi proportional to dose and duration of treatment.
Respiratory and non‐respiratory lung function indices during the development and resolution of O,S,S‐trimethyl phosphorodithioate‐induced lung damage in the rat. A chemical model of adult respiratory distress syndrome
Authors: Nemery Benoít
Published: October 2006

Arterial blood gases and the pulmonary uptake of putrescine and 5‐hydroxytryptamine (5‐HT) were studied between 6 h and 18 days after the administration to rats of an oral LD50‐dose of the pneumotoxin, O,S,S‐trimethyl phophorodithioate (OSSMe), a potential impurity in several organophosphorus insecticides.

Aortic blood was sampled under pentobarbitone anaesthesia for measurements of arterial pH, and partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2). PaO2 was significantly decreased 4 days after OSSMe administration, i.e. at the time of maximum lethality and increases in wet lung weight. This was accompanied by a significant increase in PaCO2 and acidosis. These results are compatible with an impairment of gas exchange due to diffuse lung damage. For reasons that are unclear, PaCO2 was slightly increased 2, 6 and 12 days after dosing.

The uptake of putrescine (1,4‐diaminobutane) and of 5‐HT was measured by incubating lung slices with several concentrations of [3H]‐putrescine and [14C]−5‐HT, so as to estimate the apparent kinetic parameters of uptake, Vmax and Km. The Vmax for putrescine‐uptake was significantly decreased 1,2,4,6 and 12 days after the administration of OSSMe. The Vmax for 5‐HT‐uptake was significantly increased 1 day and significantly decreased 4 days after OSSMe administration.

The uptake of 5‐HT is an endothelial function, and the decrease in 5‐HT‐uptake at 4 days may reflect injury to the pulmonary vascular endothelium at this time. The uptake of putrescine probably reflects the function of the pulmonary (mainly alveolar) epithelium. Alveolar type I cells are the cellular targets for the toxic action of OSSMe, and their destruction is followed by type II cell proliferation. The early and prolonged decrease in putrescine‐uptake, therefore, suggests that this function is different in proliferating type II cells as opposed to quiescent type II cells.
Effects of altered exposure chamber pressure on the breathing pattern of conscious rats in nose‐only exposure tubes
Authors: de Madron E. , Mauderly J. L.
Published: October 2006

Rats exposed to inhaled toxicants while in plethysmographs having nose or neck seals may breathe against a negative pressure gradient during exposure. Breathing against negative pressure might affect the respiratory pattern and thus, the uptake or deposition of toxicant. The respiration of 10 conscious rats restrained in plethysmographic nose‐only inhalation exposure tubes having a neck seal, was measured during breathing against ambient, negative and positive pressures (0 to ± 7.5 cm H2O). Negative pressure increased respiratory frequency and reduced tidal volume, but minute volume was little changed. The estimated fraction of inspirate reaching the alveoli was reduced and inspiratory flow was increased. The magnitudes of these changes were small at typical exposure pressures, and the magnitudes of their effects on uptake and deposition would be expected to fall within the range of normal intersubject variability. Positive pressure tended to have effects opposite those of negative pressure.
Mutagenicity and cytotoxicity of n‐methyl‐2‐pyrrolidinone and 4‐(methylamino)butanoic acid in the Salmonella/microsome assay
Authors: Wells David A. , Thomas Harvey F. , Digenis George A.
Published: October 2006

The industrial solvent N‐methyl‐2‐pyrrolidinone (NMP) and its hydrolysis product, 4‐(methylamino)butanoic acid (N‐MeGABA), were examined for mutagenicity and cytotoxicity in the Ames Salmonella/microsome assay. In order to detect a broad range of possible mutagenic endpoints, the following strains were used in the assay: base‐pair substitution strains TA100, TA102 and TA104; frameshift strains TA97 and TA98; and repair proficient strains TA2638, UTH8413 and UTH8414. In the standard plate incorporation assay, six log‐linear doses of each compound were tested; doses ranged from 0.01 to 1000 μmol/plate for NMP, and 0.01 to 316 μmol/plate for N‐MeGABA. Neither compound was detectably mutagenic when tested in the presence and absence of metabolic activation by Aroclor‐induced rat liver S9. NMP did show significant responses with strains TA102 and TA104 that were less than two‐fold over background, but no clear dose–response relationships were evident. A preincubation modification of the assay was also performed, using strains TA98 and TA104. Mutagenic activity was not observed for NMP, while N‐MeGABA showed significant responses with TA104 but dose‐related mutagenicity was not established. Preincubation testing revealed both NMP and N‐MeGABA to be cytotoxic to the test population of Salmonella at the highest treatment doses.
A simplified protocol for the mouse bone marrow micronucleus assay
Authors: Garriott Michael L. , Piper Charles E. , Kokkino Andrew J.
Published: October 2006

Complex and expensive protocols involving multiple sampling times have been proposed and recommended for the in vivo mouse bone marrow micronucleus assay. The purpose of this study was to determine whether a simplified procedure employing two identical exposures and a single sampling time would be equally effective at detecting chemical clastogens. Furthermore, the utility of the protocol was investigated for both intraperitoneal and oral routes of administration. The results obtained from a group of chemicals spanning the known time range for maximum frequency of micronucleus induction prove the effectiveness of this simplified protocol.
A subchronic inhalation study with unleaded petrol in rats
Authors: Vyskočil Adolf , Tušl Miloslav , Obršál Jindřich , Zaydlar Karel
Published: October 2006

The effect of intermittent 2 months' exposure to 2 g/m3 unleaded petrol on the hypothalamo‐pituitary‐thyroid‐adrenal system was evaluated by measuring hypothalamic noradrenaline (NA), serum corticosterone (CS), thyroxine (T4) and adrenal catecholamine (CA) levels in male rats. Serum CS and adrenal CA were increased and hypothalamic NA was decreased by exposure. No changes were observed in serum T4. Exposure induced an increase in spleen, kidney, liver and lung weights; weights of adrenals and hypothalamus were not changed. All the petrol‐induced effects depended on the length of exposure. Rats exposed to petrol gained less weight than controls. The results suggest a non‐specific stress response in the rat.
Effect of deferrioxamine and diethyldithiocarbamate on paracetamol‐induced hepato‐ and nephrotoxicity. The role of lipid peroxidation
Authors: Younes Maged , Sause Christiane , Siegers Claus‐Peter , Lemoine Robert
Published: October 2006

In mice subjected to glutathione depletion by pretreatment with phorone (diisopropylidene acetone, 200 mg/kg i.p. in 10 ml/kg olive oil) paracetamol (acetaminophen, 300 mg/kg p.o. in 10 ml/kg tylose 2 h later) led to a marked hepatotoxicity as evidenced by increased plasma activities of the liver‐specific enzymes sorbitol dehydrogenase (SDH) and glutamate‐pyruvate‐transaminase (GPT) 3 and 24 h after treatment. Nephrotoxicity was also indicated at both timepoints by an increased creatinine concentration in plasma, while neither the urine volume nor its content in γ‐glutamyl transpeptitase over 20 h were affected. Hepato‐ and nephrotoxicity were also assessed histomorphologically. In vivo lipid peroxidation (LPO), as measured by ethane exhalation over 3 h, was clearly enhanced by paracetamol. Malondialdehyde content was increased and glutathione concentration diminished in the liver, but not in the kidney. Diethyldithiocarbamate (DTC, 200 mg/kg i.p.) or deferrioxamine (DFO, 500 mg/kg i.p.) both given 30 min before PA, inhibited in vivo LPO. However, only DTC was capable of antagonizing the hepato‐ and nephrotoxic effects of paracetamol, while DFO only delayed the onset of nephrotoxicity but left the hepatotoxicity unaffected. Both agents inhibited the rise in hepatic malondialdehyde‐content, but only DTC prevented paracetamol‐induced glutathione depletion. These results indicate that LPO is not mainly responsible for paracetamol toxicity towards liver or kidney.
Do cage effects influence tumor incidence? An examination of laboratory animal carcinogenicity studies utilizing fischer 344 rats
Authors: Haseman Joseph K.
Published: October 2006

Approximately 125 carcinogenicity studies in Fischer 344 rats conducted by the National Toxicology Program (NTP) were examined to determine the frequency with which cage effects were associated with observed carcinogenic responses. All studies involving groups of 50 rats housed five per cage and showing evidence of chemically‐related carcinogenicity were considered. For each of these experiments, two statistical analyses were carried out for each dosed and control group: (i) a test to determine whether or not the occurrence of tumors clustered within cages; and (ii) an evaluation to determine whether or not tumor incidences differed significantly between differing cage shelf levels. These analyses showed that the numbers of statistically significant (P < 0.05 or P < 0.01) effects were consistent with the number expected by chance alone. Thus, cage‐related factors appeared to have little or no impact upon tumor incidence in these particular studies. Experimental design protocols now used by the NTP (which include random assignment of animals to cages; random assignment of columns of cages to dosed and control groups; and periodic rotation of cage location) further reduce the likelihood that factors associated with the housing of the animals could influence tumor incidence in current studies.
Three‐generation reproduction study with caprolactam in rats
Authors: Serota David G. , Hoberman Alan M. , Friedman Marvin A. , Gad Shayne C.
Published: October 2006

In a three‐generation reproduction study, rats were given caprolactam in the diet of 0, 1000, 5000 and 10,000 ppm. No treatment‐related effects were observed in the parental animals with respect to mortality, clinical signs, reproductive performance or gross pathology findings. Consistently lower body weights were noted in the P2 and P3 mid‐ and high‐dose males and females. Consistently lower mean food consumption values were noted in the P2 and P3 mid‐ and high‐dose males and the high‐dose females. These differences were generally significant (P ≤ 0.05) in the high‐dose group of both sexes. Compound‐related histopathologic findings noted in the high‐dose P1 males consisted of a slight increase in the severity of spontaneous nephropathies, occasionally accompanied by granular casts. The offspring data revealed no treatment‐related effect with respect to gross appearance, gross pathology, survival, number of pups, percentage of male pups or kidney weight. Analysis of the offspring body weights on Days 1, 7 and 21 of lactation revealed consistently and generally significant lower mean values in the high‐dose male and female animals of all filial generations. The mean body weights of both sexes in the mid‐dose group were generally lower than those of the controls. The effects on mean body weight, mean food consumption and the group increases in the severity of nephropathy, accompanied by the presence of granular casts in some animals, are considered to be related to the administration of caprolactam.
Effectiveness of chelation therapy with time after acute vanadium intoxication
Authors: Gómez M. , Domingo J. L. , Llobet J. M. , Paternain J. L.
Published: October 2006

The effect of increasing the time interval between vanadium exposure and chelation therapy was studied in male Swiss mice. The following chelating or reducing agents were administered i.p. at 0, 0.5, 2 and 8 h after i.p. administration of 0.16 mmol kg−1 sodium metavanadate: ascorbic acid, deferoxamine mesylate (DFOA) and 4,5‐dihydroxy‐1,3‐benzene‐disulphonic acid (Tiron). These agents were given at doses equal to one‐quarter of their respective LD50 values. Daily elimination of vanadium into urine and faeces was determined for four days. The excretion of vanadium was especially rapid in the first 24 h. Treatment with Tiron increased significantly the urinary elimination of vanadium in all four groups during Day 1, whereas DFOA significantly increased the faecal excretion during the same period. Treatment with DFOA or Tiron resulted in a significant decrease in the concentration of vanadium in the kidney four days after sodium metavanadate administration. The magnitude of the increased elimination of vanadium, as well as the decreased tissue concentration of the metal, was remarkably attenuated by increasing the time interval between vanadium injection and administration of the chelators.
Effect of iron overload on spontaneous and xenobiotic‐induced lipid peroxidation in vivo
Authors: Younes M. , Eberhardt I. , Lemoine R.
Published: October 2006

To study the effect of iron‐overload on hepatic lipid peroxidation, two rat models of haemochromatosis were employed: in the first model resembling secondary haemochromatosis, repeated i.p. injections with Fe‐dextran led to an accumulation of Fe in Kupffer cells, while in the second model resembling hereditary haemochromatosis, iron was located mainly in periportal hepatocytes after feeding on a diet containing 3.5% Fe‐fumarate for 3 weeks. In both models, total hepatic iron content was elevated four‐ to fivefold over controls. In vivo lipid peroxidation (ethane exhalation) was enhanced only in the second model, indicating that the hepatocytes are the main targets of Fe‐induced lipid peroxidation. Low hepatotoxicity was observed in the second model. Additional treatment of the rats with hepatotoxic agents led to different results: with ethanol and bromobenzene, lipid peroxidation was only evident in both models of iron‐overload, while paracetamol‐induced lipid peroxidation was seen only in Fe‐fumarate‐fed rats. CCl4‐induced lipid peroxidation was strongly enhanced in both models of haemochromatosis. Hepatotoxicity was enhanced by iron overload only in the case of CCl4 treated, Fe‐fumarate‐fed rats. The activities of phase I and phase II enzymes of xenobiotic metabolism were not markedly altered in livers of iron‐overloaded rats. This implies that neither the bioactivation nor the detoxification of the agents studied were affected in experimental haemochromatosis.
Specific determination of bromobenzene metabolites by high‐performance liquid chromatography
Authors: Truchon G. , Brodeur J. , Gérin M.
Published: October 2006

A chromatographic method for the quantitative and simultaneous determination of phenolic and mercapturic acid type metabolites of bromobenzene is presented. Acid hydrolysis (1.5 N HCI, 100°C, 10 min) yielded unconjugated bromophenols. After extraction (ethyl acetate, pH 2), evaporation to dry ness and dissolution in methanol, samples were analysed by high‐performance liquid chromatography (HPLC) with a c18 reverse‐phase column and a phosphate buffer (0.1 M,pH 9 + 5 mM tetrabutylammonium dihydrogen phosphate) — acetonitrile gradient with ultraviolet detection (225 nm). Benzylmercapturic acid and o‐chlorophenol were used as internal standards. Using this method, it was possible to determine simultaneously o, m‐ and p‐bromophenols together with o‐, m‐ and p‐bromophenylmercapturic acids. Additional validation data were obtained by analysis of urine samples from rats treated with bromobenzene. This new method was compared to existing procedures.
Effects of vinyl chloride on liver function of exposed workers, evaluated by measurements of plasma clearance of the 99Tc–N‐2,4‐dimethylacetanilido‐iminodiacetate complex
Authors: Studniarek Michał , Durski Krzysztof , Liniecki Julian , Brykalski Dariusz , Poznańska Anna , Głuszcz Maria
Published: October 2006

In 77 males exposed occupationally to vinyl chloride (VC), the plasma clearance (Cl) of 99Tc–N(2,4‐dimethylacetanilido)iminodiacetate (‘HEPIDA’ complex) was determined. The results were juxtaposed with a scaled assessment of liver parenchyma performance based upon clinical examination and a series of biochemical tests. Detection of the diagnosable damage of liver parenchyma by means of the reduced clearance was sensitive (90%) at the reasonable specificity of 74%. Probability of exclusion of liver damage in patients with the clearance above 240 ml min−1 1.73 m−2 amounted to 92%.

There was a significant correlation between degree of exposure to VC and the frequency of low clearance values.

It appears that the periodic determination of the 99Tc–HEPIDA clearance in workers exposed to VC allows the assessment of incipient liver damage and signals the need for prophylactic measures.
A rapid digestion method for analysis of nickel compounds in tissue by electrothermal atomic absorption spectrometry
Authors: Benson Janet M. , Eidson Arthur F. , Hanson Ray L. , Henderson Rogene F. , Hobbs Charles H.
Published: October 2006

Quantification of nickel in animal soft tissue is of toxicological interest. A digestion method applying the use of microwave ovens for irradiating samples in Teflon digesters was developed. An acid mixture containing nitric acid (16 M, 1.0 ml g−1 tissue), hydrochloric acid (6 M, 0.5 ml g−1 tissue) and H2O2 (30%, 1.0 ml g−1 tissue) and irradiation at 600 W for 5 min were required for complete dissolution of tissue matrices and nickel compounds. Analyses of Ni in National Bureau of Standards Reference Material 1566 oyster tissue gave 0.87 ± 0.24 μg g−1 (mean ± SD, n = 5), which was in agreement with the NBS certified value of 1.03 ± 0.19 μg g−1. Recoveries of 1–300 μg Ni added as nickel sulfate (highly soluble), nickel subsulfide (moderately soluble in biological fluids and acid) or nickel oxide (green high‐temperature oxide, low solubility in biological fluids and acid) to lung, liver, lymph node and kidney were quantitative, except in the case of nickel sulfate added to kidney, where recovery was less than quantitative for 1–10 μg Ni. The method appears effective for digestion of a variety of tissues requiring Ni analyses.
3‐Hydroxypropylmercapturic acid: A biologic marker of exposure to allylic and related compounds
Authors: Sanduja Radhika , Ansari G. A. S. , Boor Paul J.
Published: October 2006

3‐Hydroxypropylmercapturic acid [3‐OHPrMCA, S‐(3‐hydroxypropyl)‐N‐acetyl‐‐l‐‐cysteine] was quantitatively measured by high‐performance liquid chromatography (HPLC) in the urine of rats given allylamine‐HCl (5, 25, 50, 100 and 150 mg kg−1), acrolein (13 mg kg−1), allylalcohol (64 mg kg−1), allylchloride (76 mg kg−1), allylbromide (120 mg kg−1), allylcyanide (115 mg) and cyclophosphamide (160 mg kg−1) by gavage in water. 3‐OHPrMCA was measured by HPLC in 24‐h urine collections; the lower detection limit was 1.25 μg or 5.6 nmol ml−1. Various doses of allylamine resulted in 3‐OHPrMCA excretion at a fairly constant percentage of the dose, ca. 44–48% at 0–24 h and 3% at 24–48 h, indicating rapid metabolism through glutathione conjugation in the first 24h. Similarly, 3‐OHPrMCA was recovered in the urine of rats given acrolein (78.5%), allylalcohol (28.3%), allylchloride (21.5%), allylbromide (3.0%), allylcyanide (3.7%) and cyclophosphamide (2.6%). These data indicate that 3‐OHPrMCA can be used as a marker of exposure to allylic and other compounds that lead to the metabolic formation of acrolein.
Complex mixture effects on the dermal absorption of benzo[a]pyrene and other polycyclic aromatic hydrocarbons from mouse skin
Authors: Dankovic David A. , Wright Cherylyn W. , Zangar Richard C. , Springer David L.
Published: October 2006

To study the dermal penetration of benzo[a]pyrene (BAP) in relation to other polycyclic aromatic hydrocarbons (PAHs), a complex mixture of PAHs was applied to the backs of CD‐1 mice, and the dermal residence times of BAP and eleven other PAHs were determined using gas chromatography. The dermal penetration of BAP was found to be representative of the other PAHs studied, with a dermal half‐life of 6.7 h. Half‐lives of the other eleven PAHs ranged from 5.0 to 8.8 h. The dermal half‐life of BAP applied in a volatile organic solvent, rather than a PAH mixture, was 3.0 h. The effects of five complex organic mixtures, with boiling points ranging from 300–700°F to >850°F, on the dermal residence time of BAP was studied by adding radiolabeled BAP to the mixtures, and applying them to the backs of mice. All of the mixtures studied increased the dermal residence time of BAP by amounts ranging from 1.8‐fold to 6.9‐fold.
Sebaceous gland suppression as a short‐term test of the cutaneous carcinogenic activity of mineral oils
Authors: Peristianis G. C.
Published: October 2006

Forty‐seven mineral oils were tested for their ability to induce sebaceous gland suppression in female C3H/HeN or CF1 mice. Six groups of five mice were treated with zero, one, two, three, four or six epidermal applications of one or more of three volumes (0.2, 0.1 or 0.05 ml) of the test substance. The sebaceous gland suppression indices were calculated from the total numbers of sebaceous glands and hair follicles in nine sections of treated skin from each mouse. Suppression curves were drawn by plotting the mean suppression indices against the number of applications of each oil sample.

The suppression curves were compared with the cutaneous carcinogenic potentials of these mineral oils, assessed by long‐term skin bioassays. All the carcinogenic oil samples induced suppression of sebaceous glands. The non‐carcinogenic samples had no significant suppressant activity. There was a correlation between cutaneous carcinogenic activity and suppressant potential for all tested samples. Results of the suppression tests considered, together with the kinematic viscosities of the test substances, enabled accurate prediction of their cutaneous carcinogenic potential.
Renal handling of 2‐methyl‐4‐chlorophenoxyacetic acid (MCPA) in rats
Authors: Bräunlich Helmut , Bernhardt Heike , Bernhardt Ingo
Published: October 2006

Following i.p. administration of various doses of 2‐methyl‐4‐chlorophenoxyacetic acid (MCPA), ca. 50% is excreted during a 5‐h diuresis experiment. After i.p. administration of MCPA, virtually no distribution occurs (Vrel = 18% of the body weight). Renal excretion of MCPA can be accelerated by inhibition of its renal tubular reabsorption. The distinct inhibition of renal excretion of MCPA by simultaneous administration of probenecid or p‐aminohippurate (PAH) indicates the active tubular transport of MCPA; this transport process can be stimulated by treatment of rats with triiodothyronine. Active tubular transport of MCPA was confirmed by measurement of MCPA accumulation in renal cortical slices, both under aerobic and anaerobic conditions. Accumulation of MCPA under anaerobic conditions indicates an additional passive uptake and binding of MCPA in kidney tissue in accordance with the high degree of binding to plasma albumin (85%).
Metal inhibition of calmodulin activity in monkey brain
Authors: Vig P. J. S. , Nath R. , Desaiah D.
Published: October 2006

Studies were conducted to investigate the effect of vanadium (V5+), cadmium (Cd2+), mercury (Hg2+), aluminium (Al3+), lead (Pb2+) and manganese (Mn2+) ions on calmodulin (CaM)‐related Ca2+‐ATPase activity in rhesus monkey (Macaca mulatta) brain (RMB). The cerebral cortex of RMB was dissected and homogenized in 10% sucrose buffer, and synaptic plasma membranes (SPM) were prepared. Ca2+‐ATPase activity was determined by the inorganic phosphate method. Different concentrations of metal ions were incubated with RMB fractions containing endogenous CaM and RMB fractions without CaM. The results show that no metal ion inhibited the basal enzyme but that they showed a profound inhibition of total Ca2+‐ATPase containing CaM. The order of potency of metals was Hg>Cd>Pb>Mn>Al>V. Exogenous addition of CaM restored the metal‐inhibited enzyme activity to near the normal level. The basal enzyme, when reconstituted with CaM, showed sensitivity to metal ions. These data, presented for the first time in non‐human primate brain, indicate that the metal ions inhibit CaM activity in RMB.
A comparison of the effects of dietary cadmium on heart and kidney antioxidant enzymes: Evidence for the greater vulnerability of the heart to cadmium toxicity
Authors: Jamall I. Siraj , Naik Malini , Sprowls J. J. , Trombetta L. D.
Published: October 2006

This study demonstrates the greater susceptibility of the heart as compared to the kidney to cadmium in the presence of high dietary selenium. Male weanling rats were fed an adequate‐copper low‐selenium feed supplemented with 0, 10 or 50 ppm copper with or without 50 ppm dietary cadmium for 7 weeks. All rats received 0.5 ppm selenium in their drinking water. Cadmium treatment resulted in histopathological lesions in the heart, but not in the kidney. Although cadmium treatment resulted in more extensive effects on glutathione peroxidase and superoxide dismutase in the heart as compared to the kidney, no increase in peroxidation was noted in either organ, suggesting that cadmium cardiotoxicity can be dissociated from tissue peroxidation. Mean cadmium concentrations in the heart ranged from 0.55 to 1.22 μg cadmium g−1 tissue, wet weight, and in the kidney from 11.53 to 21.04 μg cadmium g−1 tissue, wet weight, and in the kidney from 11.53 to 21.04 μg cadmium g−1 tissue, wet weight. In both tissues examined, cadmium levels were influenced by dietary copper and heart cadmium concentrations did not correlate with either the biochemical or histological lesions observed. Thus, tissue cadmium levels alone may not be adequate for predicting cadmium toxicity.
Dose and time effects of combined exposure to lead and ethanol on lead body burden and some neuronal, hepatic and haematopoietic biochemical indices in the rat
Authors: Tandon Sushil K. , Flora Swaran J. S.
Published: October 2006

Ethanol (1, 2 or 5 g kg−1) and lead (0.55 g I−1 in drinking water) were given either alone or in combination for 4 months to rats. The uptake of lead in tissues, some lead‐sensitive variables, the levels of biogenic amines in different brain regions, hepatic lipid peroxidation, glycogen and blood glucose concentrations were measured.

Ethanol or lead when given alone inhibited the activity of blood δ‐aminolevulinic acid dehydratase (ALAD). The co‐administration of 5 g kg−1 but not 1 or 2 g kg−1 ethanol significantly enhanced the lead‐induced inhibition of blood δ‐ALAD activity and the elevation of δ‐aminolevulinic acid (ALA) excretion. Co‐exposure to lead and ethanol (5 g kg−1) produced a more pronounced increase in hepatic lipid peroxidation and blood glucose level than either ethanol or lead alone. This combination also caused a significant increase in the dopamine (DA) contents of striatum, midbrain and pons medulla, norepinephrine (NE) contents in midbrain and 5‐hydroxytryptamine (5‐HT) contents of hypothalamus, striatum, midbrain and pons medulla over levels produced by lead alone. However, the level of NE in hypothalamus decreased upon co‐administration. The uptake and retention of lead was significantly higher in blood, liver, kidney and brain in animals co‐exposed to lead and 5 g kg−1 ethanol. Blood and kidney lead was also increased by 2 g kg−1 ethanol. The results suggest that prolonged and heavy consumption of alcohol may increase the toxicity of lead.
Evaluation of the teratogenic potential of the rubber accelerator dibenzthiazyl disulphide in rats
Authors: Ema Makoto , Sakamoto Jun , Murai Toshimi , Kawasaki Hironoshin
Published: October 2006

The teratogenic potential of dibenzthiazyl disulphide (MBTS) was studied in Wistar rats. Pregnant rats were given MBTS at a dosage of 0, 0.04, 0.2 or 1% in the diet from day 0 to day 20 of pregnancy. Daily intakes of MBTS were 26 mg kg−1 for the 0.04% group, 127 mg kg−1 for the 0.2% group and 596 mg kg−1 for the 1% group. Maternal body weight gain during day 0 to day 14 of pregnancy in the 1% group was significantly lowered, but no significant changes induced by MBTS were observed in any other maternal parameters, such as food consumption and clinical sign of toxicity. There were no significant compound‐related effects on the incidences of pre‐ and postimplantation losses and the number, sex ratio and body weight of live fetuses. Morphological examinations of the fetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from the dams given MBTS, a high survival rate and good growth of the offspring were seen. It could be concluded that MBTS possesses no adverse effects on the pre‐ and postnatal development of the offspring in rats at the doses employed in the present study.
A rapid bioassay for chemicals that induce pro‐oxidant states
Authors: Knobeloch L. M. , Blondin G. A. , Lyford S. B. , Harkin J. M.
Published: October 2006

A new bioassay has been developed that allows rapid, sensitive detection of chemicals such as paraquat and adriamycin, which manifest their acute toxicity, mutagenicity or carcinogenicity by inducing a pro‐oxidant statein vivo.Submitochondrial particles isolated from bovine myocardium are used to catalyze NADH‐dependent enzymatic reduction of these chemicals to free radicals. The highly reactive species generated in this system reduce molecular dioxygen to the superoxide anion radical, which is detected spectrophotometrically using the adrenochrome reaction. The anticancer drug adriamycin, the herbicides paraquat and diquat, the analytical dye sulfonazo III, and the experimental carcinogen 4‐nitroquinoline‐N‐oxide have been used to test the sensitivity of this new method. This assay can be used to screen fresh water samples for the presence of pollutants that can generate oxygen‐centered free radicalsin vivo, or to test newly synthesized chemicals for this activity, and may therefore be valuable for environmental monitoring and preliminary toxicity evaluation of industrial or pharmaceutical products.
Delayed neuropathy and acute toxicity studies with pirimiphos‐methyl in the hen
Authors: Lock Edward A. , Johnson Martin K.
Published: October 2006

This paper describes studies aimed at determining the acute anticholinergic and delayed neurotoxic potential of the organophosphate insecticide pirimiphos‐methyl (O‐2‐diethylamino‐6‐methylpyrimidin‐4‐yl O,O‐dimethyl phosphorothioate) in the hen. Delayed neuropathy was assessed by biochemical measurement of neuropathy target esterase (NTE) activities in the brain and spinal cord, clinical signs of neuropathy over two 21‐day periods and histological assessment of nervous tissue. Acetylcholinesterase (AChE) activity was also determined in the brain and spinal cord. Hens were given a single oral dose of 100 mg kg−1 pirimiphos‐methyl, which was followed by a repeated dose after 21 days. Tri‐o‐cresyl phosphate (TOCP), 500 mg kg−1, was used as a positive control. All pirimiphos‐methyl‐treated hens received prophylactic doses of N‐methylpyridinium‐2‐aldoxime methanesulphonate (P2S) and atropine sulphate.

Hens dosed with pirimiphos‐methyl had very low AChE activities (<20% of control) in both the brain and spinal cord, 24 and 48 h after dosing. In the TOCP‐treated hens, the activities were about 90% of control. NTE activities in the brain and spinal cord of pirimiphos‐methyl‐treated hens were identical to those in the controls, while they were profoundly inhibited (<80%) in the TOCP‐treated hens. All hens dosed with pirimiphos‐methyl showed the expected signs of AChE inhibition and, following recovery, usually by Day 5, no clinical signs of delayed neuropathy were seen. The TOCP‐treated hens developed clinical signs of neuropathy. No histological evidence of axonal degeneration in the spinal cord or peripheral nerves was seen in pirimiphos‐methyl‐treated hens, while significant axonal degeneration occurred in the TOCP‐treated hens. Thus biochemical, clinical and neuropathological evidence indicates that pirimiphos‐methyl has no capacity, at a dose that produces severe AChE inhibition, to cause delayed neuropathy in the adult hen.
CCl4‐induced lipoperoxidation triggers a lethal defect in the liver plasma membranes
Authors: Mourelle Marisable , Meza Miguel Angel
Published: October 2006

Loss of calcium regulation across the plasma membrane of hepatocytes is responsible for irreversible cell damage by CCl4. The mode of action of colchicine in CCl4 acute liver damage is not completely understood. We followed the time courses of the changes in lipoperoxidation, the activities of liver plasma membrane Ca2+‐ATPase, γ‐glutamyl transpeptidase and alkaline phosphatase, as well as the time courses of serum markers of liver damage in rats acutely intoxicated with CCl4. We assessed the effects of colchicine in this model and evaluated the effect of this drug on liver cytochrome P‐450. Increased lipoperoxidation is the earliest and shortest lasting effect of CCl4 in the liver and is followed by a decrease in the activities of plasma membranebound enzymes. The alterations in serum enzymes showed a slower onset and were more protracted. Colchicine pretreatment produced a small decrease in cytochrome P‐450 in the liver but completely prevented most of the changes produced by CCl4 in lipoperoxidation, liver plasma membrane enzyme activities and serum enzyme activities. We conclude that CCl4 metabolites trigger lipoperoxidation and then produce a longer lasting change in the plasma membrane, which thus allows calcium accumulation. Colchicine prevents the early mechanisms of CCl4 damage, and its effect on cytochrome P‐450 perhaps plays only a contributory role.