bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary biochemical response to slate dust in rats
Authors: Khan M. Firoze , Ali Shahid , Singh Shivendra V. , Rahman Qamar , Viswanathan P. N.
Published: October 2006

The biochemical changes in rat lungs due to intratracheal instillation of 50 mg of slate dust have been studied up to 150 days of dust exposure. The remarkable feature of lung changes was the turnover of collagen in experimental animals after 90 days, reaching substantially higher values at 150 days. A concurrent increase in hexosamine and sialic acid contents was also observed. The phospholipid content in the whole lung tissue, as well as in the mitochondria, was generally higher in the dust‐treated rats, particularly at the later stages. The mitochondrial cytochrome c oxidase and glutamate dehydrogenase activities increased, whereas monoamine oxidase was marginally affected. Mitochondria from experimental animals appeared to be in a swollen state, particularly at 120 days of exposure. The above results suggest that slate dust exerts its toxic effects by causing alterations in the tissue make‐up as well as in the mitochondrial functioning of the lung.
The influence of chemical form of zinc on the effects of toxic intraruminal doses of zinc to sheep
Authors: Smith B. L. , Embling P. P.
Published: October 2006

The EDTA, sulphate and oxide compounds of zinc were administered to sheep as a single intraruminal dose (480, 240 or 120 mg Zn per kg body weight) or as thrice‐weekly doses (240 mg Zn per kg body weight per dose) for 4 weeks. In the single‐dose experiment, serum zinc concentrations rose most rapidly, were highest and fell most rapidly in those animals receiving zinc EDTA. In the sheep receiving the sulphate, serum zinc concentrations were high and stayed high for 2 or 3 days. Zinc oxide caused slight, but prolonged, elevation of serum zinc. High concentrations of zinc were present in urine after administration of zinc EDTA. In the multiple‐dose experiments, the sheep dosed with zinc sulphate showed progressively higher elevations of serum zinc (first dose, 5–10 μg Zn ml−1; day 13, 30–60 μg Zn ml−1) and six of the seven sheep so dosed died before the final dose. At post mortem examination, many of these had lesions of the upper gastrointestinal tract and showed evidence of haemolytic crises. Sheep dosed with zinc oxide also had progressively higher peak serum zinc concentrations. In contrast, the peak serum concentrations for the zinc EDTA‐dosed sheep declined as the experiment progressed. No deaths occurred in the sheep dosed with zinc oxide or EDTA. Major pancreatic injury occurred in sheep dosed with the sulphate or oxide, but was only mild in the sheep dosed with the zinc EDTA. Diarrhea was mild and transitory in the EDTA‐dosed sheep, but more severe and persistent in those dosed with the sulphate. Organ zinc concentrations were very high in the sheep dosed with zinc sulphate or oxide and, although less elevated, were still high in the sheep dosed with the zinc EDTA. Mean pancreatic zinc concentrations were highest, with kidney and liver having slightly lower concentrations, for all the zinc compounds administered.
Alterations of drug‐induced toxicity in the mouse lymphoma assay by a rat hepatic microsomal metabolizing system (S‐9)
Authors: Oldham James W. , Preston Robert F. , Paulson John D. , Pritchard J. Frederick
Published: October 2006

Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver micro‐somal metabolizing system (S‐9) during drug testing in the mouse lymphoma assay. After studying the fate of three drugs in this test system, several mechanisms were demonstrated whereby S‐9 reduced cellular toxicity. For N‐(4‐hydroxyphenyl)retinamide (HPR), fenoctimine sulfate and methyl palmoxirate, the drug concentrations (EC50) in the presence of S‐9 were, respectively, 11.5, 14.3 and 4.1 times the concentrations required to achieve comparable levels of toxicity in the absence of S‐9. HPR was metabolized by the S‐9 and sequestered in the microsomal membranes. This was associated with a marked reduction in the cellular accumulation of the drug. The reduced toxicity of fenoctimine sulfate in the presence of S‐9 was associated with extensive biotransformation to polar metabolites. This was accompanied by a reduction of radioactivity associated with the cells from 5.7% to 0.4% of the administered drug. Methyl palmoxirate was rapidly converted to its acid, palmoxirate, by horse serum enzymes present in the treatment medium. This provides an example of metabolism by a test system component other than the S‐9 or lymphoma cells. The reduced toxicity of this drug in the presence of S‐9 was attributed to further metabolism of palmoxirate and a reduction of the proportion of total radioactivity associated with the cells from 3.1% to 0.4%. These results emphasize the need for pilot toxicity studies, especially when components of the test system are varied, to assess the effect of drug concentration on the toxic response. Moreover, the results illustrate that drug disposition studies may provide explanations for observed changes in drug‐induced toxicity.
Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: Biochemical, functional and ultrastructural studies in the rat
Authors: Szabo S. , Gallagher G. T. , Silver E. H. , Maull E. A. , Horner H. C. , Komanicky P. , Melby J. C. , McComb D. J. , Kovacs K.
Published: October 2006

A single dose of acrylonitrile can produce fatal adrenal apoplexy within approximately 2 h. Our previous studies also indicate that multiple injections of the chemical cause acute hemorrhagic and occasional nonperforating duodenal ulcers. Other authors have reported increase in gut and lung neoplasia after chronic exposure. The present study was designed to elucidate the subacute and chronic actions of acrylonitrile on the adrenals, stomach and duodenum by correlating biochemical, functional and morphologic investigations, as well as to gain insight into the mechanisms of action of acrylonitrile. Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same amount of the chemical given through daily gavage, for 7, 21 or 60 days. Acrylonitrile caused a time‐ and dose‐dependent decrease in plasma corticosterone levels; aldosterone was affected only by the ‘high’ dose and prolonged time of exposure. Young rats were more susceptible than adults to this action of acrylonitrile. The adrenal cortex, especially the zona fasciculata, was atrophic in rats that had ingested the nitrile through drinking water. At 0.05% and 0.2%, it also caused decreased food intake and body weight gain. The adrenals were enlarged with a hyperplastic zona fasciculata after daily doses of a bolus of acrylonitrile. Ingestion of the chemical did not interfere with compensatory enlargement of the adrenal gland following unilateral adrenalectomy. On the other hand, the ACTH‐induced elevation of corticosterone plasma concentration was significantly attenuated by acrylonitrile in drinking water. Electron microscopy of the adrenal glands revealed no consistent changes in the steroid‐producing cells. We thus postulate that accelerated turnover of circulating corticoids and/or interference with the secretion or action of ACTH may primarily be responsible for the decreased plasma levels of corticosterone and aldosterone in rats that ingest acrylonitrile. The mucosa in the stomach at the junction of the forestomach and glandular region of animals that had ingested acrylonitrile was hyperplastic. The corpus also showed regional mucosal hyperplasia with the appearance of ‘cobble‐stoning’. These changes were preceded and associated with an elevated concentration of non‐protein sulfhydryls mostly in the mucosa of the glandular stomach. A similar, less prominent elevation also occurred in the proximal duodenum. These alterations may resemble the preneoplastic combination of elevated glutathione and focal hyperplasia described in the liver with hepatocarcinogens. Acrylonitrile thus serves as a model chemical which affects the adrenal gland and gastrointestinal system.
Subacute oral toxicity of tri‐n‐butyl phosphate in the sprague–dawley rat
Authors: Laham S. , Long G. , Broxup B.
Published: October 2006

Tri‐n‐butyl phosphate was administered by gavage to male and female Sprague‐Dawley rats for 14 consecutive days (low dose: 0.14 ml kg−1; high dose: 0.42 ml kg−1). Effects of this chemical were investigated at the end of the feeding period. Histopathological examination of the testes (high‐dose group) showed the presence of microscopic degenerative changes in the seminiferous tubules. No other abnormal microscopic changes were observed.
Zinc, copper, manganese and iron in rat organs after the administration and withdrawal of aflatoxin B1
Authors: Ikegwuonu Fidelis I.
Published: October 2006

The in vivo levels of zinc, copper, manganese and iron were determined in the testis, kidney and three brain regions (cerebellum, cerebrum and medulla oblongata) from rats intrapertoneally injected with 20 μg per kg body weight of aflatoxin B1 for 6 weeks. Similar investigations were made after a recovery period of 6 weeks. The results obtained were compared with those of pair‐fed control rats. The aflatoxin B1‐induced decrease in testicular zinc was not reversed after the recovery of the rats. On the contrary, the significantly increased zinc concentration in the other organs following aflatoxin B1 exposure, reverted to the control level, as judged by significant levels. Only in the kidney was there accumulation of copper, even after the cessation of aflatoxin B1 administration. The marked increase in the manganese concentration of all the organs following repeated toxin administration, persisted only in the brain regions after the recovery. Aflatoxin B1 treatment significantly decreased the iron concentration in the testis, kidney, cerebellum and cerebrum. Recovery did not alter this trend. Iron concentration in the medulla oblongata was, however, not significantly changed in the presence of aflatoxin B1. The present data suggest that the repeated administration of aflatoxin B1 to rats could result in either a permanent or temporary re‐distribution of these elements in the organs examined.
Quantitative analysis of α, β‐thujone, pulegone, safrole, coumarin and β‐asarone in alcoholic beverages by selected‐ion monitoring
Authors: Galli Corrado L. , Galli Giovanni , Tragni Elena , Caruso Donatella , Fiecchi Alberto
Published: October 2006

Interest in the quantitative analysis of flavouring agents in alcoholic beverages arises from the possible toxicological consequences deriving from their use. The method reported here, based on gas chromatography with selected‐ion monitoring mass spectrometry (SIM), allows the simultaneous measurement of α,β‐thujone, pulegone, safrole, coumarin and β‐asarone at the ppb level in alcoholic beverages.
Sub‐acute versus sub‐chronic oral toxicity study in rats: Comparative study of 82 compounds
Authors: Woutersen Rund A. , Til Heero P. , Feron Victor J.
Published: October 2006

Toxicity data of 82 compounds, tested in both a sub‐acute and a sub‐chronic study, were evaluated to find out whether it is possible to substitute a sub‐acute for a sub‐chronic study without losing quantitative information. The no‐effect level (NEL) and the minimal‐effect level (MEL) were used as the basis for comparison. For each of the compounds, the sub‐acute and sub‐chronic studies were performed under similar conditions, with the same strain of rats and with a comparable range of dietary levels. It appeared that the NEL in the sub‐acute study was equal to the NEL in the sub‐chronic study for 56% of the compounds. For 44% of the compounds reviewed, the NEL in the sub‐chronic test was lower than the NEL in the sub‐acute test, indicating that a sub‐chronic study cannot simply be replaced by a sub‐acute study. However, it may be acceptable to use the NEL obtained in a sub‐acute study as a basis for establishing acceptable daily intakes or permissible exposure levels for humans if an additional safety factor of 10 is applied. Furthermore, it was concluded that the conventional sub‐acute study, including some selected haematological and biochemical parameters, seems extremely useful to obtain quick and reliable information on the toxicity of the numerous non‐regulated chemicals which have to be investigated in the years to come.
Chronic toxicity of S‐(trans‐1,2‐dichlorovinyl)‐L‐cysteine in mice
Authors: Jaffe Deborah R. , Gandolfi A. Jay , Nagle Raymond B.
Published: October 2006

S‐(trans‐1,2‐Dichlorovinyl)‐L‐cysteine (DCVC) exposure causes acute renal tubular cytotoxicity. To further characterize the effects of DCVC, a chronic study was undertaken. Male Swiss–Webster mice received DCVC dissolved in their drinking water at 0.01, 0.05 and 0.1 mg ml−1. At 4, 8, 21 and 37 weeks, animals were terminated. Bladders, spleens, livers, kidneys and eyes were removed for histopathological examination. At 0.05 and 0.1 mg ml−1 DCVC, growth retardation was evident by 21 weeks. By 26 weeks, all animals in the 0.1 mg ml−1 group had developed cortical cataracts. Cytomegaly, nuclear hyperchromatism and multiple nucleoli were noted in the cells of the pars recta region of the kidney by 4 weeks and correlated to time and dose. At later time points, renal tubular atrophy and early interstitial fibrosis were evident. The epithelial cytological cellular abnormalities appear to be dose‐related. Minor pathological changes were noted in the spleen, while there was no effect on the liver or bladder. Chronic ingestion of DCVC results in severe kidney injury.
The effects of fasting on the acute oral toxicity of nine chemicals in the rat
Authors: Dashiell O. L. , Kennedy Gerald L.
Published: October 2006

Nine chemicals, with a range from extremely to slightly toxic, were used to measure the oral LD50 in both fasted (24‐h) and non‐fasted rats. Each chemical was tested as a solution or suspension in corn oil, responses within 14 days post‐treatment were evaluated, and LD50s were calculated. Hexachlorophene was more toxic in non‐fasted rats. The LD50 values for tetraethyl lead, methomyl and hexamethylenediamine were essentially the same in both fasted and non‐fasted rats. Adiponitrile, bromobenzene, caffeine, carbon tetrachloride and N‐butyl‐1,6‐hexamediamine yielded lower LD50 values in fasted rats. The use of non‐fasted rats in acute oral toxicity determinations allows both the establishment of relative potency and the estimation of dosage levels for further repeated dose oral studies. The LD50 values obtained were generally (7 of 9) higher in non‐fasted rats, but the magnitude of the differences was not great enough to suggest routine use of both fasted and non‐fasted rats in oral toxicity studies.
Screening for ochratoxin A in blood by flow injection analysis
Authors: Hult Karl , Fuchs Radovan , Peraica Maja , Pleština Radovan , Čeović Stjepan
Published: October 2006

A micromethod for ochratoxin A detection in human sera by flow injection technique is described. The method requires 50 μl of sera, and it is designed to distinguish samples containing less than 10 ng ochratoxin A per ml. The method is based on fluorescence measurement following a simple extraction procedure for which very small amounts of chemicals are needed. Since the method is not confirmatory, all samples showing fluorescence above a certain intensity have to be reanalysed with some other method where a confirmation step in included. Because of the small amount of serum needed and the rapid procedure (less than 15 min), a large number of samples can be analysed very quickly. The method may therefore be applicable for large screening campaigns conducted to determine the presence of ochratoxin A in blood. This conclusion is based on 1675 samples and 147 standards analysed concurrently by the flow injection technique and an earlier published enzymic method. The method is also suitable for monitoring ochratoxin A levels in the blood of experimental animals.
The effects of disulfiram on the experimental C3H mouse embryo
Authors: Thompson P. A. C. , Folb P. I.
Published: October 2006

Disulfiram, in 1 mg and 10 mg oral doses, was given to inbred C3H mice prior to and for the duration of pregnancy. The effects on the fetus have been assessed at 18 days gestation by means of fetal and placental weights, number of resorptions, skeletal preparations and Wilson's sections. Disulfiram dissolved in diethyl ether was administered to 8‐ and 9‐day embryos in vitro in concentrations of 0.1, 10 and 100 μgml−1 of culture medium, and the effects of ether alone and ether plus disulfiram assessed by evaluation of morphological development over a 28‐h period, and inhibition of DNA synthesis using tritiated thymidine labelling over a 4‐h period. Disulfiram (1 mg) in vivo caused no adverse effects on the fetus, but disulfiram (10 mg) was toxic, in that it caused a significant increase in early resorptions. Disulfiram in vitro, in the 10 and 100 μg ml−1 concentrations, proved to be very toxic to the embryos, affecting both morphological development and DNA synthesis in 9‐day embryos and morphological development in 8‐day embryos. DNA synthesis was only inhibited at the 100 μg ml−1 concentration in 8‐day embryos. The 0.1 μg ml−1 concentration of disulfiram caused abnormal central nervous system development in 8‐day embryos, but was otherwise non‐toxic to 8‐ and 9‐day embryos. Apart from a reduction in somite counts, ether in concentrations of 0.285 mg ml−1 and 2.85 mg ml−1 caused no adverse effects on morphological development in 8‐ or 9‐day embryos. DNA synthesis was inhibited by ether in a concentration of 2.85 mg ml−1 in 9‐day embryos.
Lethality in mice and rats exposed to 2450 mhz circularly polarized microwaves as a function of exposure duration and environmental factors
Authors: Berman E. , Kinn J. B. , Ali J. , Carter H. B. , Rehnberg B. , Stead A. G.
Published: October 2006

Adult male CD‐1 mice and CD rats were used to determine LD50/24 h lethality rates from exposure to 2450‐MHz circularly polarized microwaves. Groups of 16 mice or six rats were exposed in each of 32 combinations of nominal power density (10, 25, 50 or 75 mW cm−2), exposure duration (1 or 4 h), and environmental temperature (20 or 30 °C) and relative humidity (35 or 80%). An analysis of variance probit model was used to determine the influence each variable had on the probability of death. Significant factors in lethality were nominal power density, exposure duration and environmental temperature, but not environmental relative humidity. The estimated power density (mW cm−2) required to kill 50% of the animals in 24 h is halved when the environmental temperature is increased from 20 to 30 °C. Similarly, only 20–25% of the power density is required when the exposure duration is increased from 1 to 4 h. The use of nominal power density as a predictor of the probability of death was more efficient than specific absorption rate estimated experimentally by twin‐well calorimetry. The exposure of one mouse at a time, instead of 16, did not alter the predicted death rate.
Adenosine triphosphatase activities in plasma liver membranes of rats treated with DDT and toxaphene
Authors: Mourelle Marisabel , Garcia Martha , Aguilar Carolina
Published: October 2006

The effect of exposure to chlorinated insecticides (DDT and toxaphene) on Na+, K+‐ATPase, Mg2+‐ATPase and Ca2+‐ATPase activities of the plasma membrane of hepatocytes was determined. Acute treatment with DDT (200 mg per kg body weight) or toxaphene (110 mg per kg body weight) produced a significant decrease in Na+, K+‐ATPase activity (80% and 85%, respectively) 24 h after treatment. DDT also produced a 30% decrease in Mg2+‐ATPase and Ca2+‐ATPase activity, but toxaphene treatment did not modify these enzymes. The effect of exposure to daily doses of DDT (30 mg per kg body weight) or toxaphene (16.5 mg per kg body weight) for a period of 3.5 months was also studied. Animals were sacrificed at 15‐day intervals and results showed that Na+, K+‐ATPase activity decreased 80% from the beginning of each treatment and the activity remained low throughout the treatment period. DDT, but not toxaphene, also led to a decrease in Mg2+‐ATPase (20%) and Ca2+‐ATPase (35%) activity. The low values observed from the beginning remained low throughout the treatment period. We believe that the general mechanism of ATPase inhibition by organochloride compounds could be the result of its interaction with membrane lipid components, although some differences could arise from differences in their spatial structure.
Effects of bleomycin on 14C‐proline uptake, its incorporation into proteins and hydroxylation in collagenous proteins of hamster lung slices
Authors: Giri Shri N. , Younker Wanda R. , Schiedt Mary J.
Published: October 2006

The uptake of 14C‐proline by lung slices and its incorporation into trichloroacetic‐acid (TCA)‐insoluble proteins and hydroxylation in collagenous proteins were studied. They were found to be linearly increased with the incubation time for as long as 8 h. The effects of different concentrations of bleomycin on these parameters were subsequently investigated. Bleomycin at 10−3M significantly reduced the uptake of 14C‐proline to 75% of the control value. The incorporation of 14C‐proline into TCA‐insoluble proteins was reduced to 84%, 78% and 75% of the control at 2.5 × 10−4M, 5 × 10−4M and 10−3M concentrations of bleomycin, respectively. Bleomycin failed to alter the proline pool size of the lung slices at any of these concentrations. In addition, bleomycin also inhibited the hydroxylation of 14C‐proline into collagen to 72% and 69% of the control at 5 × 10−4M and 10−3M, respectively. These findings show that bleomycin‐induced increases in collagen synthesis in vivo is probably secondary to inflammatory reactions of the lung and bleomycin per se has little effect on increased collagen synthesis responsible for lung fibrosis.
Neuropathy target esterase in human lymphocytes and platelets
Authors: Maroni M. , Bleecker M. L.
Published: October 2006

The target enzyme in organophosphorous‐induced delayed neuropathy (OPIDN) has been designated neuropathy target esterase or neurotoxic esterase (NTE). NTE activity can be measured in blood lymphocytes and platelets, which could be of use as biomonitors in man at risk for the development of OPIDN. Separation of lymphocytes and platelets from whole blood, recovery, purity, storage and expression of data were examined. A substantial amount of the NTE activity of a human lymphocyte preparation made using Ficoll/Pacque was due to contamination by platelets; further purification was achieved by sucrose‐gradient centrifugation. In an easily prepared sample of human platelets less than 10% of NTE was associated with contaminating white cells. We were unable to preserve NTE activity of platelets or lymphocytes at −80°C either ‘dry’ or with added buffer and glycerol. In 68 male subjects, NTE activity in platelets averaged 8.36±1.54 nmol min−1 mg protein−1 and NTE activity in lymphocytes, obtained from blood after removal of platelets, 13.34±2.42 nmol min−1 mg protein−1. A good correlation was found between platelet and lymphocyte NTE activity. NTE activity in platelets may be a preferable method for measuring exposure to axonopathic organophosphorous compounds because of the ease and purity of separation. No correlation with other neuropathic risk factors such as age, smoking and alcohol intake was noted.
Effect of ascorbic acid on humoral and other factors of immunity in coal‐tar exposed workers
Authors: Dobiáš Lubomír , Lochman Ivo , Machálek Jan , Šrám Radim
Published: October 2006

A group of 30 coal‐tar workers was treated with 1 g of ascorbic acid (AA) orally five times a week for 3 months. The effect of this treatment was assessed on serum IgG, IgM, IgA, α1‐antitrypsin, prealburmin, orosomucoid, transferrin, α2‐macroglobulin, C‐reactive protein, ceruloplasmin, the latex fixation test and cancer serum index (CSI). After 3 months treatment the concentration of AA in the blood increased from 9.52 to 60.75 μmol 1−1 (i.e. from 0.15 to 1.07 mg 100 ml−1), prealbumin increased from 0.37±0.08 g 1−1 to 0.48±0.08 g 1−1 (P < 0.01), CSI decreased from 2.28±0.88 to 1.76±0.50 (P <0.01) and α2‐macroglobulin decreased from 3.40±0.95 to 2.06±0.39 g 1−1 (P <0.01). These findings, together with reports that AA is a strong stimulator of xenobiotic biotransformatin in the liver, support the use of AA as a prophylactic agent for coal‐tar exposed workers.
Deposition of ultrafine aggregate particles in exercising rats
Authors: Hesseltine Gregg R. , Wolff Ronald K. , Mauderly Joe L. , Cheng Yung‐Sung
Published: October 2006

The effect of exercise on particle deposition in rats was investigated. Twenty male rats were trained to run on a treadmill and were exposed to gallium‐67 oxide (67Ga2O3) particles (0.1 μm activity median diffusion diameter) for 30 min while running at 30m min−1. Twenty resting controls were exposed in the same system while confined in wire mesh cages. Ten exercising and 10 resting rats were killed 2 h and 12 days after exposure. Tissue radioactivity levels of 67Ga2O3 were measured and normalized for differences in exposure concentration and body weight. Significantly (P<0.05) more 67Ga was deposited in the nasal passages (20 vs 5 nCi) and in the trachea and mainstem bronchi (0.5 vs 0.03 nCi) of exercising rats than in resting rats. There were no significant differences between the exercising and resting rats in amounts of 67Ga in the lung lobes at 2 h after exposure. Using assumed minute volumes, exercising rats had a significantly (P<0.05) lower lung deposition effeciency, expressed as percentage of estimated inhaled material, than did resting rats (3 vs 10%). The results suggest that exercising rats inhale more ultrafine particles, but deposit a smaller fraction of them in their lungs. The result is a similar lung burden of 0.1 μm particles in resting and exercising animals.
Effects of methyl mercuric chloride and sulfhydryl inhibitors on phospholipid synthetic activity of lymphocytes
Authors: Kageyama Katsuhiro , Onoyama Yasuto , Kano Eiichi
Published: October 2006

The effect of methyl mercuric chloride on the activity of phospholipid synthesis of rat lymph node lymphocytes was compared with that of sulfhydryl inhibitors. Measurement of the radioactivity of [14C]oleic acid and [14C]acetate incorporated into lecithin of cells during short‐term incubation showed that all the inhibitors tested similarly reduced the incorporation. However, methyl mercuric chloride (MMC) was the strongest inhibitor, being effective at 4 μM, and causing more than 80% decrease at 20 μM. Inhibition by the sulfhydryl inhibitors, at less than 40 μM, ranked as follows: N‐ethylmaleimide > α‐chloroacetophenone > hydroquinone > iodoacetamide. MMC also obstructed the enhancement by phytohemagglutinin of [14C]oleic acid incorporation into lecithin. MMC was effective at 2 μM, while the other agents had little or no effect at this concentration. Further investigation suggested that inhibition of phospholipid synthesis did no depend on reduced incorporation of oleic acid into the cellular membrane but on decreased turnover of the fatty acid into phospholipids after the incorporation. The viability of lymphocytes incubated with the agents was measured by trypan blue dye‐exclusion test. More than 90% of the cells treated with MMC at a concentration as low as 20–40 μM died, but the SH inhibitors, including NEM which greatly inhibited the phospholipid synthesis, produced few cell deaths at these concentrations. These observations show that the SH inhibitors affect enzymes in phospholipid synthesis, whereas MMC not only inhibits the enzymes but kills cells.
The teratogenic effect of phenobarbital on the embryonic chick heart
Authors: Nishikawa Toshio , Bruyere Harold J. , Takagi Yasuo , Gilbert Enid F. , Matsuoka Rumiko
Published: October 2006

Phenobarbital was observed to produce cardiovascular malformations in embryonic chicks. Malformations included simple ventricular septal defects, ventricular septal defect associated with dextroposition of the aorta, double outlet right ventricle, and several types of aortic arch anomalies. Embryos were exposed to phenobarbital at doses of 1–25 μmol on day 4 of incubation (Hamburger‐Hamilton development stage 24). Doses equal to and greater than 5 μmol phenobarbital (26 mg/kg egg) significantly increased the frequency of embroys with cardiovascular malformations compared with lesser doses and with saline. A significant reduction in heart rate and abnormal rhythm of the heart were observed in embryros treated with teratogenic doses of phenobarbital. No arrhythmia nor significant changes in heart rate were observed in embryos exposed to subteratogenic doses of phenobarbital or to saline.
The effect of composite oral treatment for internal contamination with several radionuclides on 131I thyroid uptake in humans
Authors: Šimonović I. , Kargačin B. , Kostial K.
Published: October 2006

The efficiency of a composite oral treatment on 131I thyroid uptake was investigated in three adult volunteers. The treatment consisted of 10 g of calcium alginate, 3 g ferrihexacyanoferrate(II), 130 mg of potassium iodide and 5 g of Zn‐DTPA. This mixture when administered 30 min before 131 I almost completely blocked the 131 I thyroid uptake. This indicates that simultaneous administration of other antidotal agents do not cancel or decrease the effect of potassium iodide on 131 I thyroid uptake. The finding deserves attention since composite oral treatment is the recommended therapy in cases of accidental environmental exposure to several radionuclides.
Lung development and postnatal survival for rats exposed in utero to a high‐boiling coal liquid
Authors: Springer D. L. , Hackett P. L. , Miller R. A. , Buschbom R. L.
Published: October 2006

Previous studies performed in this laboratory indicated that exposure of rat fetuses to high‐boiling coal liquids from 12–14 days of gestation (dg) induced a number of major malformations, including cleft palate, diaphragmatic hernia and small lungs. The study reported here was designed to determine postnatal viability and development of survivors following in utero exposure to Harmarville process solvent (HPS), a wideboiling‐range (150 to > 455°C) coal liquid. For this study, 0.74 g kg−1 of the coal liquid was administered (by intragastric intubation) to rats from 12 to 14 dg. Offspring were evaluated for postnatal survival, growth and lung and thymus weights. Randomly selected pups from control and treated liters were killed and necropsied at 1, 3, 7 and 21 days postpartum. In addition, data for control pups were obtained at 0.25 and 0.5 days postpartum for comparison with body, lung and thymus weights of pups that died during this interval. Fifty‐four per cent of the exposed pups and 9% of the control pups died between birth and 3 days postpartum. Of the treated pups that died, 10% (6/5; pups/litters) had cleft palate, 27% (17/9) had small lungs and 33% (21/8) had both cleft palate and small lungs. No gross malformations were observed in the remaining 30% of the dead pups. Microscopic examination of lungs from HPS‐treated pups revealed no evident histological abnormalities. Body, lung and thymus weights for treated animals that died were significantly less than those of controls. Surviving exposed pups weighed significantly less than control pups from 0.25 to 21 days postpartum and their thymus weights were also depressed through 21 days postpartum. These data suggest that retarded lung growth during prenatal life as a result of in utero exposure to the coal liquid contributes to a significant portion of the observed neonatal mortality. Furthermore, lung weights of survivors, although significantly lower than control values through 7 days postpartum, appeared to have recovered by 21 days postpartum.
Neurotoxicity assessment of O‐ethyl‐O'‐(2‐diisopropylaminoethyl) methylphosphonite (QL) in hens
Authors: Olajo E. J. , Bergmann J. , Weimer J. T. , Wall H.
Published: October 2006

O‐ethyl‐O'‐(2‐diisopropylaminoethyl) methylphosphonite (QL), an intermediate in the formation of ethyl S‐2‐diisopropylaminoethyl methylphosphonothiolate, was evaluated for neurotoxicity in the adult hen. Birds were given a single oral dose of QL ranging from 635 to 6080 mg kg−1. The QL‐treated hens were observed for up to 24 h after dosing for acute toxicologic effects and over a 24 d post‐dose period for evaluation of delayed neurotoxicity. The oral LD50 in hens is 1186 mg kg−1. Neurologic dysfunction, as evidenced by motor incapacitation, was observed at 6 days and thereafter after treatment with QL. Neurotoxic esterase (NTE) activity was not inhibited at 24 h after exposure to compound. Neural damage, multifocal in nature, was noted in the peripheral nervous system of QL‐treated hens at dose levels ≥ 635 mg kg−1, oral dose. These findings indicate neural damage tendencies following QL exposure.
Estimation of acute oral toxicity in rates by determination of the approximate lethal dose rather than the LD50
Authors: Kennedy Gerald L. , Ferenz Rayanne L. , Burgess Bruce A.
Published: October 2006

The approximiate lethal dose (ALD) to rats following oral administration of nine chemicals was determined. The ALD (lowest dose at which death was produced) for each chemical was used to define the general order of toxicity as being either extremely, highly, moderately, slightly, or practically non‐toxic. For each of the nine chemicals tested, the category indicated by the ALD was identical with the category determined in the more extensive LD50 studies. In this study, an average of 6.8 rats was needed to determine the ALD while an average of 56.3 rats was needed to determine the LD50.
Reproductive and teratological effects of continuous low‐level dietary T‐2 toxin in female CD‐1 mice for two generations
Authors: Rousseaux C. G. , Schiefer H. B. , Hancock D. S.
Published: October 2006

A two‐generation female reproduction and teratology study was undertaken using 0, 1.5 and 3.0 ppm of T‐2 toxin in a semisynthetic diet. Conception rate was lowest at the first breeding and lowest in the control group at this time, but in later breedings the conception rates of each group were very similar. No significant differences were noted in litter size, death of fetuses, sex of fetuses and gestational length. Feed consumption was similar in all groups, as were the non‐pregnant or pregnant female weight gains. Although the second‐generation offspring grew faster than the first‐generation offspring, and significantly lower body weights were seen in the 3.0 ppm T‐2 toxin group at 2, 5 and 6 weeks of age, all offspring reached the normal weight for CD‐1 mice at 6 weeks of age. Gross and histological evaluation of all animals at postmortem examination did not reveal any significant results, nor were there significant differences in major and minor or retardation defects among the treatment groups. Relative spleen weights of the second‐generation offspring were significantly higher in control females compared with the treated groups but treated males had significantly increased relative spleen weights compared with control males of this generation. It was concluded that no long‐term reproductive and teratological effects of low‐dose dietary T‐2 toxin were found in this study.
1984 survey of genetic toxicology testing in industry, government and academic laboratories
Authors: Farrow M. G. , McCarroll N. E. , Auletta A. E.
Published: October 2006

Complied results of the 1984 Genetic Toxicology Association's survey representing a total of 72 responses from governmental, contract, industrial, or academic institutions regarding the status of 32 recognized genetic toxicology assays, were as follows:

Most frequently performed on a routine or occasional basis: Ames (76% of all respondents routinely or occasionally perform the assay); in vitro cytogenetics (59%); in vivo Bone Marrow Cytogenetics (56%); in vitro Sister Chromatid Exchange (56%); in vitro Unschedled DNA Synthesis (43%); Mutation in CHO HGPRT (42%); Micronucleus test (41%); Mutation in L5178Y (36%).

Assay associated with in vivo and in vitro chromosomal end points (aberrations, SCE, micronucleus) constituted the major area of increased use since the 1982 survey.

Assays of developmental interest included DNAS binding both in vitro and in vivo and UDS in vivo.

Quantitative analysis of the data indicated:

Industrial and contract laboratories processed the largest volumes of chemicals over the broadest spectrum of assays.

Industrtial laboratories showed a marked increased since 1982 in testing compounds in‐house.

The number of assays sponsored by governmental laboratories, both in‐house or subcontracted, increased from 1982.

Academic institutions ranked lowest in number of compounds examined.
Pulmonary toxicity of the insecticide fenitrothion in the rat following a single field exposure
Authors: Coulombe P. A. , Lortie S. , Cčte M. G. , Chevalier G.
Published: October 2006

The pulmonary toxicity of the organophosphorus insecticide fenitrothion was evaluated following a single exposure of rats to the field formulation, at the site of an aerial spraying. Four groups of 40 Sprague‐Dawley rats (including a control), set in wood enclosures, were placed under the aerial lines of the spraying aircraft. The degree of exposure was monitored at the ground level by air sampling and visual evidence of droplet activity deposition. Plasma pseudocholinesterase activity and pulmonary alveoli ultrastructure were used as indices to the fenitrothion exposure. Rat lungs were examined under light and electron microscopy at days 3, 7, 21, 60 and 180 after the exposure. Although a few signs of toxic lung injury were observed at days 3 and 7 there was no cholinergic crisis nor an effect on the pseudocholinesterase activity within 12 h in the exposed animals, when compared with controls. The alveolar toxic reaction was limited to small and discrete foci, and was entirely reversible within a period of 2 months. On a morphological basis it is thus concluded that a single field exposure to fenitrothion did not induce any permanent change in the alveolar area of the rat lung.
Influence of chelating agents on the toxicity, distribution and excretion of vanadium in mice
Authors: Domingo J. L. , Llobet J. M. , Tomas J. M. , Corbella J.
Published: October 2006

The effects of the chelating agents Na2Ca‐ethylendiaminetetraacetate (EDTA), Na3Ca‐diethylentriaminepentaacetate (DTPA), L‐cysteine, 4,5‐dihydroxy‐1,3‐benzene‐disulfonic acid (Tiron) and deferoxamine mesylate and the reducing agent ascorbic acid on the toxicity, excretion and distribution of i.p. injected vanadium were studied in male Swiss mice. Chelating and reducing agents were administered intraperitoneally at doses equal to one‐forth of their respective LD50. To determine the effects of the various chelators on the mortality of vanadium, various doses of NaVO3 (0.30–1.20 mmol kg−1 i.p.) were given, followed immediately by one of the chelating or reducing agents. Survival was recorded at the end of 14 days. Significant increases in survival were noted with ascorbic acid, Tiron and deferoxamine, with ascorbic acid being the most effective. Deferoxamine and Tiron were the most effective in increasing the excretion of vanadium and reducing the concentration of vanadium found in various tissues. However, ascorbic acid appears to be the most effective agent in the prevention of vanadium intoxication.
Inhibition of tributyltin mediated hemolysis by mercapto compounds
Authors: Gray Bryan H. , Porvaznik Martin , Lee Lanfong H. , Flemming Carlyle
Published: October 2006

Hydrophobic tributylin (TBT) compounds at concentrations greater than 10 μM used hemolysis of human erythrocytes and formed structures in plasma membranes. The mercapto compounds, β‐mercaptoethanol (β MER), 2,3‐dimercaptopropanol (BAL), 2,3‐dimercapto‐1‐propane sulfonate (DMPS), DL‐dithiothreitol (DTT), and meso‐2,3‐dimercaptosuccinic acid (DMSA) were examined for their ability to inhibit TBT mediated hemolysis. The relative order of effectiveness for inhibition of TBT mediated hemolysis was BAL>DTT>DMSA>DMPS>β MER. A four‐fold excess of BAL over TBT prevented hemolysis for 4 hrs and addition of BAL 0.5 hr after TBT reduced the rate of hemolysis. The number of membrane associated TBT aggregates observed per cell profile decreased as the BAL concentration increased from 0 to 100 μM. However, the mean diameter of TBT aggregates nearly doubled in erythrocyte suspensions at 100 μM BAL. Reactions of dimercapto compounds with lipophilic TBT aggregates may depend on their relative lipid solubilities. Also, conversion of the weak Lewis acid, TBT, from a four to a five or six‐coordinate tin adduct by the dimercapto Lewis bases used could also be a factor slowing hemolysis rates.
Subacute (4‐week) inhalation toxicity study of formaldehyde in male rats: 8‐hour intermittent versus 8‐hour continuous exposures
Authors: Wilmer J. W. G. M. , Woutersen R. A. , Appelman L. M. , Leeman W. R. , Feron V. J.
Published: October 2006

Male Wistar rats were exposed for 4 weeks, 5 days a week, to 0 (controls), 5 or 10 ppm formaldehyde continuously (8 hours a day), or to 10 or 20 ppm formaldehyde interruptedly (eight 30 min exposure periods separated by 30 min non‐exposure periods). Histopathology and cell proliferation studies indicated that under the conditions of exposure used, concentration rather than the total dose of formaldehyde determined the severity of the cytotoxic effects on the nasal epithelium.
Discovery of multiple organofluorophosphate hydrolyzing activities in the protozoan Tetrahymena thermophila
Authors: Landis Wayne G. , Haley Donna M. , Haley Mark V. , Johnson Dennis W. , Durst H. Dupont , Savage Russell E.
Published: October 2006

Recently it has been found that homogenates of Tetrahymena thermophila can hydrolyze the potent acetylcholinesterase inhibitors O,O‐diisopropylphosphofluoridate (DFP) and O‐1,2,2‐trimethylpropylmethylphosphonofluoridate (soman). Upon purification of the DFP hydrolyzing activity 10‐fold it had been noted that the soman hydrolyzing activity increased only 2–3 fold. Treatment with manganous ion and comparison of the soman and DFP hydrolysis rates of the homogenate indicated that a mixture of the squid‐type and Mazur‐type DFPases may be present. Subsequent purification of the enzymatic activities within the Tetrahymena‐homogenate demostrated that there are at least five functioning proteins of molecular weights 67 000 to 96 000. None are directly homologous to the DFPases found in hog kidney or squid. The enzymatic activities are designated DFPase‐1 through DFPase‐5. A hypothesis is presented that the functions of DFPases are in the normal metabolism of organophosphates naturally synthesized by T. thermophila.
Subchronic (13‐week) inhalation toxicity study of formaldehyde in rats
Authors: Woutersen R. A. , Appelman L. M. , Wilmer J. W. G. M. , Falke H. E. , Feron V. J.
Published: October 2006

Male and female albino Wistar rats were exposed to concentrations of 0, 1, 10 or 20 ppm formaldehyde vapour during 6 h/day, 5 days/wk for 13 weeks. Treatment‐related changes observed at 20 ppm included in both sexes: stared coats, uncoordinated locomotion and excitation during the first 30 minutes of each exposure, yellowing of the fur, growth retardation, a decreased level of plasma protein, severe and extensive karatinized stratified squamous metaplasia of the nasal respiratory epithelium, and focal degeneration and squamous metaplasia occasionally accompanied by keratinization of the olfactory epithelium; in males only; increased activities of plasma aspartate amino transferase (ASAT), alanine amino transferase (ALAT) and alkaline phosphatase (ALP) and squamous metaplasia of the laryngeal epithelium.

Lesions seen at 10 ppm included yellowing of the fur and moderate squamous metaplasia of the nasal respiratory epithelium. The only change observed in three out of twenty 1 ppm exposed animals that might or might not be treatment‐related was minimal focal epithelial hyperplasia and squamous metaplasia of the respiratory epithelium lining the nasal septum and maxillary turbinates.

No histopathological evidence of hepatotoxicity was detected in any of the formaldehyde‐treated groups.

An in vivo/in vitro cell proliferation study showed an increase in [3H]‐thymiding labeling index of the respiratory epithelium lining the nasoturbinates of rats exposed to 10 or 20 ppm formaldehyde on three successive days, whereas at the 1 ppm level the labeling index was similar to that of controls. It was concluded that under the conditions of the present 13‐week inhalation study, formaldehyde at concentrations up to 10 ppm was not hepatotoxic to rats. At the 20 ppm formaldehyde level, a slight effect on the fiver of mate rats cannot be completely excluded. The study was inconclusive with respect to 1 ppm formaldehyde being a cytotoxic or a no‐cytotoxic effect level for the nasal epithelium.
Hearing loss in rats caused by inhalation of mixed xylenes and styrene
Authors: Pryor Gordon T. , Rebert Charles S. , Howd Robert A.
Published: October 2006

We have reported that inhalation exposure of rats to toluene causes permanent hearing loss, e.g. Pryor et al. Neurobehav. Toxicol. Teratol. 5, 53–62 (1983). Therefore, it was of considerable interest to examine the ototoxic potential of two structurally related solvents—mixed xylenes and styrene—compared with that of toluene. Male, weanling Fischer‐344 rats were exposed to clean air or solvents in four identical 62.5 I Pfexiglas chambers. Exposures to 800, 1000, and 1200 ppm were daily for 14 hours/day and lasted 6 weeks for mixed xylenes, 3 weeks for styrene. An additional experiment with xylenes examined the effect of exposure for only 4 (1700 ppm) or 8 (1450 ppm) hours or for 8 (1450 ppm) hours on three consecutive days to compare the results with those obtained with toluene under comparable exposure schedules. Both xylenes and styrene caused marked hearing loss as assessed by behavioral (conditioned avoidance) and electrophysiologic (brainstem auditory‐evoked response) methods. Moreover, both solvents appeared to be more potent ototoxicants than toluene, as indicated by effective concentration, effective durations of exposure, and the range of frequencies affected.
The potentiation of the non‐behavioural effects of amphetamine by carbon disulphide
Authors: Caroldi Stefano , Magos Laszlo , Jarvis Jack , Forshaw Philip , Snowden Roger T.
Published: October 2006

In agreement with the inhibition of dopamine‐β‐hydroxylase by exposure to CS2, the extension of exposure time from 4 to 16 h increased dopamine concentrations in the hypothalmus and adrenals, and decreased noradrenaline concentration in the hypothalmus. The extension of exposure time also increased the toxicity of amphetamine. In conscious animals the stereotypic activity produced by 6.0 mg/kg and even that of 3.0 mg/kg amphetamine sulphate was suppressed by severe hyperthermia resulting in exhaustion, prostration and eventually death. A 16h exposure to CS2 did not increase the lethal or hyperthermic effects of amphetamine in rats anaesthetized with 60 mg/kg sodium pentobarbitone. In fact the CS2 exposed rats became more hypothermic than non‐exposed rats.