bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II. Toluene, ethylbenzene and aniline
Authors: Susten Allan S. , Niemeier Richard W. , Simon Stephen D.
Published: October 2006

Percutaneous absorption studies were conducted with three single‐ring, radiolabeled aromatic solvents (benzene derivatives) using a recently described direct method for studying volatile chemicals in hairless mice. Total absorption, determined from the sums of radioactivity found in the excreta, expired breath and carcass, was 2.1%, 3.4% and 4.7% of the nominal dose for toluene, ethylbenzene and aniline, respectively. Breath decay curves indicated that absorption of toluene and ethylbenzene was complete by 15 min after application and that by this time the excretion rate of aniline exceeded the absorption rate. Evaporation rates were used to derive estimated contact times, and these in turn were used in conjunction with the absorbed doses to estimate percutaneous absorption rates. Equivalent dermal exposures (cm2 · min) that would yield body burdens equivalent to those expected following 8‐h inhalations at existing US permissible exposure limits during light work were calculated. The data indicate that dermal absorption of these compounds could approach or exceed that from inhalation under some work conditions. Correlations between absorption and various physical properties were evaluated using Spearman's correlation coefficients. The physical properties evaluated included volatility, solubility, octanol/water partition coefficients and melting points. For this limited series of benzene derivatives, two measures of volatility, i.e. vapor pressure and boiling point, were the only physical properties significantly correlated with percutaneous absorption.
Urinary N‐acetyl‐β‐D‐glucosaminidase activity in lead‐exposed workers
Authors: Endo Ginji , Horiguchi Shun'Ichi , Kiyota Ikuko
Published: October 2006

The adverse effects of long‐term exposure to lead dust on renal tubular functions were studied in 39 male and 7 female workers in a secondary lead refinery. Laboratory examinations showed low or moderate lead absorption levels. The N‐acetyl‐β‐D‐glucosaminidase (NAG) activity in urine showed significant correlation with each of the lead exposure indices. NAG activity increased remarkably in lead workers with blood lead (PbB) above 80 μg 100g−1.

Blood urea nitrogen (BUN) showed significant correlation with PbB and logarithmic urine δ‐amino‐levulinic acid (log(ALAU)), but not with urine lead (PbU) and logarithmic urine coproporphyrin (log(CPU)).

All the other indices of renal function were almost within the normal range and showed no correlation with lead indices.

This study suggests that moderate lead absorption may cause renal tubular impairment, and NAG can be one of the most sensitive indices for estimating renal dysfunction due to lead poisoning.
An evaluation of the epidermal carcinogenic potential of cutting fluids
Authors: McKee R. H. , Scala R. A. , Chauzy C.
Published: October 2006

Epidermal cancer in humans has been associated with industrial exposure to products derived from unrefined petroleum distillates. Because of this association many of these products, including cutting fluids, are now normally produced from highly refined lubricant base oils. Since highly refined oils are not dermally carcinogenic, one would predict that formulated products prepared from these oils would similarly be nontumorigenic. However, there are experimental data that suggest that fresh cutting fluids might be dermally carcinogenic and that industrial usage might increase the carcinogenic hazard. The current studies evaluated solvent‐extracted lubricant base oils and several products, including fresh and used cutting fluids and certain related industrial oils. These materials were all tested for tumorigenic potential in mouse epidermal carcinogenesis bioassays. None of the solvent‐extracted lubricant base oils were dermal carcinogens. Similarly, the cutting fluids and industrial oils formulated from these base oils were not dermally carcinogenic. Finally, there was no evidence that industrial usage influenced the carcinogenic potential of these oils. It was concluded that solvent‐extracted oils and the products derived from these oils pose minimal skin cancer hazards when used under appropriate conditions in industrial settings.
Toxicity of mixtures of parathion, toxaphene and/or 2,4‐D in mice
Authors: Kuntz David J. , Rao N. G. S. , Berg Ivan E. , Khattree Ravindra , Chaturvedi Arvind K.
Published: October 2006

The toxicity of the mixtures of parathion (PA), toxaphene (TOX) and/or 2,4‐dichlorophenoxyacetic acid (2,4‐D) was studied in ICR male mice (21–24 g) by oral intubation, in corn oil, daily for up to 14 days. On Day 15, the exposure was discontinued, and animals were monitored for an additional period of 7 days for the possible reversibility of the toxicity. The body weight gain decreased with the mixtures, as well as with the individual agricultural chemicals (ACs), during the 14‐day period. The cholinesterase (ChE) activity in the serum and brain was inhibited in the animals of the groups of PA (1–10 mg kg−1) and PA (5 mg kg−1)‐containing mixtures. TOX (50–200 mg kg−1) caused initial inhibitory effects of 20–65% on the serum ChE (Day 1) before producing increases of 53–64% in the enzyme activity by Day 15, with little effects on the brain ChE levels. 2,4‐D (50–200 mg kg−1) resulted in significantly elevated levels of the serum ChE, with substantial decreases in the brain ChE activity. The serum glutamic pyruvic transaminase level was up (38–630%) in TOX (50 mg kg−1), 2,4‐D (50 mg kg−1) or their mixture group. No pathological changes at the light microscopic level in the brain and liver were noticed. TOX and TOX‐containing mixtures significantly increased the liver/body weight ratio and decreased the pentobarbital (60 mg kg−1, i.p., in saline)‐induced sleep. When TOX (50 mg kg−1) and PA (5 mg kg−1) + TOX (50 mg kg−1) groups were examined, the dilatation of the hepatic endoplasmic reticulum was distinguished and the decrease in the level of pentobarbital in the serum, brain, liver and kidneys was noted. The effects produced by these chemicals singly, as well as by their mixtures, appeared to be reversible in nature. The toxic effects exhibited by the mixtures of PA (5 mg kg−1), TOX (50 mg kg−1) and/or 2,4‐D (50 mg kg−1) were found to be the resultant of the effects showed by their components individually.
Prevention by silymarin of membrane alterations in acute CCI4 liver damage
Authors: Muriel Pablo , Mourelle Marisabel
Published: October 2006

The effect of silymarin on liver lipid peroxidation and membrane lipid alterations induced by an acute dose of CCI4 was studied. Four groups of animals were treated with CCI4, CCI4 + silymarin, silymarin and its vehicles. CCI4 was given orally (0.4 g 100 g−1 body wt.) and silymarin was administered i.p. All animals were sacrificed 24 h after the treatments. Liver lipid peroxidation was measured and plasma membranes were isolated. Alkaline phosphatase (AP) and gamma‐glutamyl transpeptidase (GGTP) were measured in plasma membranes. Membrane lipids were extracted and then analysed by thin‐layer chromatography by measuring the phosphorus of the phospholipids in each spot. Liver lipid peroxidation was increased about three times in the group receiving CCI4 only. Silymarin cotreatment prevented this increase. Phosphatidylethanolamine (PEA) decreased, while phosphatidylinositol (PI) increased in the plasma membranes isolated from the CCI4‐treated group. Animals that received CCI4 + silymarin showed no decrease in PEA content. A partial prevention of the decrease in phosphatidylinositol content was also observed in plasma membranes of animals treated with silymarin in addition to CCI4. CCI4 decreased gamma‐glutamyl transpeptidase (GGTP) and alkaline phosphatase (AP) membrane activities. Silymarin cotreatment prevented the AP (completely) and the GGTP (partially) falls caused by CCI4. Silymarin by itself increased AP membrane activity.

A significant relationship between the membrane content of phosphatidylethanolamine (PEA) and the AP activity was observed in plasma membranes of treated animals and in normal liver membranes enriched with PEA. These results indicate that silymarin can protect against the alterations induced by CCI4 on the liver plasma membrane through its antioxidant properties by modifying the plasma membrane phospholipid content.
Mechanism of testicular atrophy induced by Di‐n‐butyl phthalate in rats. Part 2. The effects on some testicular enzymes
Authors: Fukuoka Masamichi , Zhou Yu , Tanaka Akira , Ikemoto Isao , Machida Toyohei
Published: October 2006

A single oral dose of di‐n‐butyl phthalate (DBF) to male rats caused histologically a sloughing of the germ cells at 6 h. On Days 1 and 2 more severe sloughing was seen, followed by atrophy and the dissociation of the germ cells from the Sertoli cells and the spermatogonia. Biochemically, there was elevation of γ‐glutamyi transferase, a decrease in sorbitol levels at 3 h and a decrease in the activity of aldose reductase at 6 h, in the testes of treated rats. This was followed by decreases in fructose levels and increases in the activity of lactate dehydrogenase (LDH) and in lactate levels at 12 h, and decreases in the activities of sorbitol dehydrogenase and succinate dehydrogenase on Day 2. LDH isoenzymes 4 and 5 increased at 6 h prior to the increase in lactate levels. Increases in the levels of inositol and the activities of alkaline phosphatase and lactate dehydrogenase were also observed. Thus, these data suggest that DBF‐induced testicutar toxichy is caused by, a shortage of energy fuels from glucose metabolism or by an anoxia.
A note on fitting one‐compartment models: Non‐linear least squares versus linear least squares using transformed data
Authors: Bailer A. John , Portier Christopher J.
Published: October 2006

Drug concentrations in one‐compartment systems are frequently modeled using a single exponential function. Two methods of estimation are commonly used for determining the parameters of such a model. In the first method, non‐linear least‐squares regression is used to calculate the parameters. In the second method, the data are first transformed by a logarithmic function, and then the log‐concentration data are fit using linear least‐squares regression. The assumptions for fitting these models are discussed with special emphasis on which data points are most influential in determining parameter values. The similarities between fitting a linear regression model to the log‐concentration data and fitting a weighted regression model to the original data are noted. An example is presented that illustrates the differences in fitting a model to the log‐transformed data versus fitting unweighted and weighted models to the original‐scale data.
The role of iron and glutathione in t‐butyl hydroperoxide‐induced damage towards isolated perfused rat livers
Authors: Younes Maged , Strubeit Otfried
Published: October 2006

The hepatotoxic and lipid peroxidative potentials of t‐butyl hydroperoxide (t‐BuOOH) towards isolated perfused rat livers were investigated at doses of 1 and 3 mmol I−1. t‐BuOOH led to a concentration‐dependent release of cytosolic (glutamate‐pyruvate transaminase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzymes, an accumulation of calcium in the liver, a marked depletion of hepatic glutathione and an enhanced release of it into the perfusate, as well as an enhanced formation and release of malondialdehyde (MDA) by the liver. These effects were blocked in the presence of the potent iron chelator deferrioxamine, and enhanced in livers from iron‐overloaded as well as in livers from glutathione‐depleted rats. Our results indicate that the hepatotoxic and pro‐oxidant actions of organic hydroperoxides depend upon the presence of ionized iron as a catalyst of radical‐forming breakdown reactions, and are potentiated by impairment of glutathione‐dependent detoxification reactions.
Formation of methemoglobin and metmyoglobin using 8‐aminoquinoline derivatives or sodium nitrite and subsequent reaction with cyanide
Authors: Steinhaus Ralph K. , Baskin Steven I. , Clark James H. , Kirby Stephen D.
Published: October 2006

The kinetics of the oxidation of hemoglobin (Hb) and myoglobin (Mb) by sodium nitrite, 8‐[(4‐amino‐1‐methylbutyl)amino]‐6‐methoxy‐quinoline diphosphate (primaquine), 6‐methoxy‐8‐(6‐diethvlaminohexylamino)‐4‐meihyl‐quinoline dihydrochloride (WR6026) and 8‐[(4‐amino‐1‐methylbutyl)amino]‐2,6‐diniethoxy‐4‐methyl‐5‐[(3‐trifluoromethyl)phenoxy]quinoline succinate (WR238,605) were studied at pH values ranging from 7.4 to 7.6 and at 37 ± 1°C. The reaction between Hb and primaquine, WR6026 and WR238,605 resulted in precipitation, as did the reaction between Mb and WR238,605. The reaction between nitrite ion (NO2−) and Hb showed a lag period followed by an autocatalytic phase. The data in this study are consistent with and substantiate the proposed mechanism for the Hb–NO2− oxidation reaction. The reaction between Mb and NO2− at higher NO2− concentrations also showed a lag period followed by an autocatalytic period, while at lower NO2− concentrations no lag period was seen. The data suggest a shift in rate constant at these lower NO2− concentrations. The reaction between Mb and both WR6026 and primaquine followed a two‐term rate law with oxidant‐dependent and ‐independent terms. Concentration–effect curve data, along with these results, suggest the presence of a catalytic pathway. The rates of formation of cyanomethemoglobin and cyanometinyoglobin complexes from cyanide ion and methemoglobin (MHb) and metmyoglobin (MMb), respectively, were followed in the presence of the heme oxidants. The rate constants were all within a narrow range and suggest that complexation of cyanide by MHb and MMb is not affected by the presence of oxidants.
Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice 1. Hydrochlorothiazide
Authors: Bucher John R. , Huff James , Haseman Joseph K. , Eustis Scot L. , Elwell M. R. , Davis William E. , Meierhenry Earl F.
Published: October 2006

Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15‐day, 13‐week and 2‐year studies. No rats died during the 15‐day or 13‐week studies at dietary concentrations of up to 50 000 ppm. Deaths of male mice in the top dose group in the 13‐week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical‐related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2‐year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non‐neoplastic lesions in mice were associated with hydrochlorothiazide. In high‐dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.
Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice 2. Furosemide
Authors: Bucher John R. , Huff James , Haseman Joseph K. , Eustis Scot L. , Davis William E. , Meierhenry Earl F.
Published: October 2006

Toxicology and carcinogenesis studies of furosemide, a widely used diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 14‐day, 13‐week and 2‐year studies. Deaths occurred among rats and mice receiving diets containing 46 000 ppm furosemide in 14‐day studies, and animals given diets containing lower concentrations lost weight. No deaths were seen in 13‐week studies using top concentrations ranging from 10 000 to 20 000 ppm, but animals at higher concentrations had lower weight gains than controls. Nephrosis in rats and mice was the only significant compound‐related lesion observed in the prechronic studies. In 2‐year studies, rats received diets containing 0, 350 or 700 ppm furosemide and mice received diets containing 0, 700 or 1400 ppm furosemide. Survival of dosed and control rats of both sexes and male mice was similar; survival of high‐dose female mice was lower than controls. Nephropathy was increased in male rats and in male and female mice. In female mice, increased malignant tumors of the mammary gland were associated with furosemide administration. In male rats, marginal increases in tubular cell neoplasms of the kidney and in meningiomas of the brain were observed in dosed animals, but these were not considered to be related clearly to exposure to furosemide.
The effect of sodium tetrathionate on cyanide conversion to thiocyanate by enzymatic and non‐enzymatic mechanisms
Authors: Baskin Steven I. , Kirby Stephen D.
Published: October 2006

Sodium tetrathionate has been proposed as a cyanide antidote despite its reported toxicology and inhibitory effect on rhodanese. We investigated the effectof tetrathionate and an analog, dithionite, on rhodanese activity because of their structural similarily to thiosulfate, a known sulfane sulfur donor for this enzyme. Rhodanese activity of guinea pig liver homogenate was assayed by measuring the formation of ferric thicyanate complex at 460 nm. With thiosulfate as a substrate, the Km for rhodanese was 6.7 mM and the Vmax was 0.67 μmol thiocyanate min−1 mg−1 protein. The conversion of cyanide to thiocyanate by rhodanese was inhibited in the presence of terathionate at the millimolar concentration (e.g. 1 mM) range. Dithionite had a negligible effect on rhodanese activity. Netiher thiosulfate (1–100 mM) nor dithionite produced significant amounts of thiocyanate from cyanide spontaneously (i.e. non‐enzymatically). However, in the absence of rhodanese, tetrathionate (1.0, 10.0 and 100.0 mM) produced a dose‐dependent increase in thiocyanate. These data suggest that tetrathionate detoxifies cyanide non‐enzymatically, which may, in part, account for its antidotal effects.
Biochemical and histopathological changes following dermal exposure to paraphenylene diamine in guinea pigs
Authors: Mathur A. K. , Gupta B. N. , Narang S. , Singh S. , Mathur N. , Singh A. , Shukla L. J. , Shanker Ravi
Published: October 2006

The guinea pigs were dermally exposed to paraphenylene diamine (PPI) at a dose level of 0.1 ml day−1 of a 1.0% (w/v) solution of PPD for 1, 3, 5 and 7 days. The absorption of PPD and its effects on lipid peroxidation, glutathione, histamine and several enzymes were assessed in skin and serum. Histopathological changes in liver, kidney and skin were examined also. The findings of the study indicated that PPD exposure resulted in significantly increased levels of lipid peroxidation and histamine contents in skin. The activity of enzymes increased significantly in skin and serum. PPD exposure also showed degenerative changes in liver and hyperkeratosis together with infiltration of cells in the dermis. Biochemical defects and histopathological changes in skin and serum correlated with the duration of exposure.
Antidotal effects of dimercaptosuccinic acid
Authors: Ding Guang‐Sheng , Liang You‐Yi
Published: October 2006

Dimercaptosuccinic acid (DMS), HOOC‐CH(SH)‐CH(SH)‐COOH, was first developed in China as an effective antidote for poisoning from many heavy metals, such as Pb, Hg, As, Cd, Sb, TI, Au, Zn, Ni, Pt, Ag, Co and Sn. DMS increases the excretion of Ce, Pm, Sr and Po from the body. Hundreds of patients suffering from hepatolenticular degeneration (Wilson's disease) have been treated successfully with DMS. Recently, DMS was found to be effective also in treating certain non‐metallic intoxications, like some of the new non‐phosphate pesticides and mushroom poisonings.
Changes in urinary proximal tubule parameters in neonatal rats exposed to cadmium chloride during pregnancy
Authors: Saillenfait A. M. , Payan J. P. , Brondeau M. T. , Zissu D. , de Ceaurriz J.
Published: October 2006

Pregnant Sprague‐Dawley rats were injected intraperitoneally with physiological saline solution (vehicle) or cadmium chloride (CdCI2) at 2.0 or 2.5 mg kg−1 on days 8, 10, 12 and 14 of gestation. On postnatal day (PND) 3, 12 or 49, the offspring were examined for 8‐ or 24‐h urinary excretion of β2‐microglobulin (β2‐m), metallothionein (MT) and urinary activity of three proximal tubular enzymes: gammaglutamyl transferase (GGT), alkaline phosphatase (ALP) and N‐acetyl‐β‐glucosaminidase (NAG).

Treatment with CdCI2 did not affect growth or survival of offspring. Significant decreases in the urinary excretion of GGT, ALP and NAG were observed on PND 3, at both doses. Exposure to 4 × 2.5 mg kg−1 resulted in functional deficit of the proximal tubule on PND 3, as evidenced by the significant increase in β2‐m. Except for a slight but significant increase of β2‐m in 49‐day‐old males, all the other urinary parameters returned to control values on PND 12. There was no effect on MT.

Results from this study show that prenatal exposure to CdCI2 can induce significant changes in the kidney biochemistry of rats in the early postnatal period.
Evidence for behavioral teratogenicity in humans
Authors: Nelson B. K.
Published: October 2006

Central to both the scientific development of behavioral teratology and the attention paid to this field as an important area of study is establishing that prenatal exposure of pregnant females to exogenous agents leads to neurobehavioral disorders in their offspring. This tenet may not be questioned by the majority of toxicologists, but others may not be convinced. This paper serves as a brief review of the accumulated evidence that prenatal exposure to a number of drugs and environmental/industrial agents produces behavioral disorders in human infants.
Effects of short‐term oral dosing of polychlorotrifluoroethylene (polyCTFE) on the rhesus monkey
Authors: Jones Christopher E. , Ballinger Michael B. , Mattie David R. , Delraso Nicholas J. , Seckel Constance , Vinegar Allen
Published: October 2006

Polychlorotrifluoroethylene (polyCTFE—primarily oligomers with 3–4 monomer units), a non‐flammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg−1. The administered dose was at a level that had caused toxicity in rats. Steady‐state blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co‐A beta‐oxidation rates or by electron microscopy, showed no significant indication of peroxisomal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion.
Neurotoxic esterase activity in brain, spinal cord and platelets of certain birds and mammals
Authors: Husain K. , Mirza M. A. , Matin M. A.
Published: October 2006

The level of neurotoxic esterase in brain, spinal cord and platelets of certain birds and mammals has been determined. The enzyme activity for the birds was maximal in hens and for the mammals was maximal in rats. The activity decreased progressively in the cerebral cortex, corpus striatum, spinal cord and blood platelets of the birds as well as the mammals. The difference in the susceptibility of birds and mammals to organophosphate‐induced delayed neurotoxicity may be related to differences in the relative concentrations of the enzyme in the different species.
Evaluation of potential chemoprotectants against microcystin‐LR hepatotoxicity in mice
Authors: Hermansky S. J. , Stohs S. J. , Eldeen Z. M. , Roche V. F. , Mereish K. A.
Published: October 2006

Microcystin‐LR (MCLR) is a potent cyclic heptapeptide hepatotoxin produced by the blue‐green algae, Microcystis aeruginosa. Toxic blooms of this cyanobacteria have been reported throughout the temperate world. In spite of the potential economic loss and health hazard posed by this toxin, few studies on the development of an antidote have been conducted. Thus, a number of biologically active compounds were tested in mice for effectiveness in preventing the toxicity of a lethal dose of MCLR (100 μg kg−1). Efficacy was evaluated based upon the percentage of surviving mice, time to death and serum lactate dehydrogenase activity 45 min after treatment with the toxin. The biologically active compounds were separated into groups based upon proposed mechanisms of action. Enzyme induction by phenobarbital but not by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) resulted in partial protection against toxicity. Calcium channel blockers, free‐radical scavengers and water‐soluble antioxidants produced little protection against toxicity. The membrane‐active antioxidants vitamin E and silymarin, as well as glutathione and the monoethyl ester of glutathione, produced significant protection from lethality. Rifampin and cyclosporin‐A, both immunosuppressive and membrane‐active agents, which also block the bile acid uptake system of hepatocytes, produced complete protection from the toxicity of MCLR. Thus, lipophilic antioxidants provide partial protection against MCLR toxicity while cyclosporin‐A and rifampin are highly effective and potentially useful antidotes. The toxicity of MCLR may depend upon stimulation of the immune system and may be mediated by membrane alterations.
Interactions between verapamil and metoprolol in the developing chick embryo heart
Authors: Nishikawa Toshio , Kasajima Takeshi , Kanai Takao
Published: October 2006

A calcium blocking agent, verapamil, and a β1‐adrenoreceptor blocking agent, metoprolol, were administered alone or in combination to 4‐day‐old chick embryos (Hamburger‐Hamilton developmental stage 24). Embryos co‐administered with verapamil (0.05 nmol) and metoprolol (0.1 or 1.0 nmol), neither of which alone caused significant teratogenicity, showed cardiovascular malformations, including ventricular septal defects associated with or without dextroposition of the aorta (overriding aorta). The alteration of calcium movement into the myocyte and/or the haemodynamic change following impaired calcium transport are suggested to be possible causative factors.
Cardiotonic drugs inhibit purified mammalian acetylcholinesterase
Authors: Hanke D. W. , Nelson M. E. , Baskin S. I.
Published: October 2006

Oxime‐ and non‐oxime‐related drugs, as well as cardiotonic drugs (CDs), have been used to treat the effects of organophosphorus (OP) poisoning. We conducted our experiments to determine what effects CDs may have on acetylcholinesterase (AChE), and how CDs interact with other treatment drugs as well as with OP‐inhibited AChE. True AChE (EC 3.1.1.7) was purified from fetal bovine serum, and enzyme activity was measured according to Ellman et al. The CDs coumingine, cassaine, proscillaridin and convallatoxin were incubated with AChE at 550 μM at pH 7.6 and 25°C. The CD ouabain was incubated with AChE at 500 μM. The CDs inhibited AChE by 97%, 89%, 10%, 7% and 6%, respectively. The mean AChE activities for these experiments, except for ouabain, were significantly different (P = 0.05) from their controls, as determined by the two‐tailed Student's t‐test. In a separate experiment, the oxime TMB‐4·2Br (100 μM), which did not inhibit AChE, increased the inhibitory effect of proscillaridin from 4% to 11% (a 3.7‐fold increase). When AChE was inhibited 39% with 37 nM VX, the addition of proscillaridin increased the inhibition to 51% (a 1.3‐fold increase). When TMB‐4 was added to the proscillaridin‐ and VX‐inhibited AChE mixture, the inhibition decreased from 50% to 32% (a 0.37‐fold decrease), whereas TMB‐4 alone added to VX‐inhibited AChE decreased the inhibition from 39% to 24% (a 0.38‐fold decrease). The results show that TMB‐4 increases the inhibition of AChE by proscillaridin. However, TMB‐4 decreases the inhibition of AChE by VX and proscillaridin combined. The inhibition of AChE by the CDs alone may help in part to account for the cardiac parasympathetic response of CDs.
Urinary cyclophosphamide excretion in rats after intratracheal, dermal, oral and intravenous administration of cyclophosphamide
Authors: Sessink P. J. M. , van den Broek P. H. H. , Bos R. P.
Published: October 2006

The urinary excretion of unmetabolized cyclophosphamide was studied in rats after intratracheal, dermal, oral and intravenous administration. Rats were given two doses of 1 mg kg−1 cyclophosphamide 48 h apart and urine was collected for 96 h after the first treatment.

With the help of a phosphor‐specific filter in a flame photometer attached to a gas chromatograph, low levels of cyclophosphamide were determined after derivatization with trifluoroacetic anhydride.

Cumulative excretion as a percentage of dose ranged from 4.0 to 6.9 after the first dose and 2.7 to 5.5 after the second dose. The highest rate of excretion after the second administration was observed in rats treated intratracheally, while cumulative excretion was higher (6.9%) after the first than after the second (2.7%) intravenous treatment. The most prolonged excretion was observed after dermal application.
Anamnestic responses to contact allergens: Application in the murine local lymph node assay
Authors: Kimber I. , Weisenberger C.
Published: October 2006

The murine local lymph node assay, an alternative predictive test for the identification of contact sensitizing chemicals, is based upon the fact that skin allergens induce proliferation in lymph nodes draining the site of application. In the present study we have examined whether pre‐exposure to the test chemical at a distant site enhances subsequent draining lymph node cell proliferation and, thereby, the sensitivity of the assay. Experiments were performed using both in vitro and in situ measurement of induced lymph node cell proliferation. It was found that, with the exception of potent skin sensitizers such as picryl chloride and oxazolone, which impair subsequent proliferative activity as a consequence of induced immunoregulatory processes, pre‐treatment with the test allergen resulted in enhanced proliferation. Evidence is presented that the local lymph node assay response to a variety of skin allergens (including eugenol, isoeugenol, dihydrocoumarin, 4‐vinylpyridine, cinnamic aldehyde and 2,4,5‐trichlorophenol) was augmented when mice received a single exposure to the same chemical 5 days earlier.

It is concluded that the use of a modified protocol, incorporating pre‐exposure to the test material, can enhance local lymph node assay responses to all but the most potent skin allergens, and may be of particular value when increased sensitivity is required.
Methylthiazolidine‐4‐carboxylate for treatment of acute T‐2 toxin exposure
Authors: Frick Robert F. , Jorge Juan
Published: October 2006

The effect of T‐2 toxin on hepatic glutathione content and the protective effect of 2‐methyl‐thiazolidine‐4‐carboxylate (MTCA), an L‐cysteine prodrug, were studied in mice. Acute exposure to T‐2 toxin (4 mg kg−1, s.c.) resulted in a progressive decrease in glutathione content, reaching a minimum 6–8 h after toxin administration. Because T‐2 toxin caused decreased food consumption, a condition known to deplete hepatic glutathione, glutathione was measured in both fed and fasted control and toxin‐treated mice. Glutathione content (μmol g−1 tissue) was 9.01 ± 0.66 (control) and 4.26 ± 0.41 (toxin) for fed mice, 4.45 ± 0.39 (control) and 2.45 ± 0.26 (toxin) for 16‐h fasted mice, and 7.18 ± 0.26 (control) and 3.76 ± 0.65 (toxin) for mice fed before, but fasted after exposure to toxin. In all cases, toxin treatment resulted in significant decreases in glutathione content compared to controls. Treatment of T‐2‐intoxicated mice with MTCA (750 mg kg−1, i.p.) not only maintained glutathione content at control levels or higher but significantly improved survival as well. Therefore, the toxicity and lethality of T‐2 toxin may be associated with decreased hepatic glutathione content, since MTCA maintained glutathione content and improved survival.
Nephrotoxicity of paracetamol in the rat—mechanistic and therapeutic aspects
Authors: Möller‐Hartmann W. , Siegers C.‐P.
Published: October 2006

Besides hepatotoxicity, paracetamol may exert nephrotoxic effects in experimental animals and patients. The present study in rats shows that antidotes known to protect against hepatotoxicity, such as methionine or N‐acetylcysteine, are not effective in preventing paracetamol‐induced kidney damage. Only diethyldithiocarbamate, an inhibitor of microsomal monooxygenases, provided complete protection against both hepato‐ and nephrotoxicity. While a marked depletion of glutathione was observed in the liver, no such effect was seen in the kidney. These data suggest that the mechanism of paracetamol nephrotoxicity seems to be quite different from that responsible for the hepatotoxicity. The hypothesis that a C–S‐Iyase‐mediated final metabolism of paracetamol–S conjugates in the kidney might be responsible for nephrotoxicity needs support by further experimental investigations.
Inhalation toxicity of methyl isocyanate: Biochemical and cytological profile of bronchoalveolar lavage fluid in rats
Authors: Gupta G. S. D. , Kaw J. L. , Naqvi Syed H. N. , Dixit Renu , Ray P. K.
Published: October 2006

Acute pulmonary injury in rats following a single inhalation exposure to methyl isocyanate (3.2 mg I−1) was reflected by alterations in the biochemical and cytological constituents of bronchoalveolar lavage fluid (BALF) over a period of 30 days. Total protein, sialic acid and lactic acid contents of BALF were increased followed by a gradual decline to normalcy between day 3 and day 30 post‐exposure. The activity of lactic dehydrogenase also increased progressively with time. The cellularity of BALF was increased significantly and primarily comprised of polymorphonuclear neutrophils at 8 days. The adherence of macrophages was unchanged but their viability was lowered at 30 days post‐exposure. The results indicate the significance of bronchoalveolar lavage analysis in monitoring pulmonary toxicity by methyl isocyanate, which is characterized by the hypoxic condition and reduced cellular defence. Some toxic manifestations are potentially reversible with time after cessation of exposure.
Assessment of cadmium‐induced osteopenia by measurement of serum bone gla protein, parathyroid hormone, and 1α,25‐dihydroxyvitamin D
Authors: Kido Teruhiko , Honda Ryumon , Tsuritani Ikiko , Ishizaki Masao , Yamada Yuichi , Nogawa Koji , Nakagawa Hideaki , Dohi Yoshiko
Published: October 2006

To assess the osteopenia induced by environmental cadmium (Cd) exposure by measurement of serum bone Gla protein (BGP), parathyroid hormone ((PTH) and 1α,25‐dihydroxyvitamin D (1α, 25(OH)2D), 29 men and 41 women who lived in a Cd‐polluted area and showed renal tubular dysfunction were selected. To evaluate the degree of osteopenia, microdensitometry (MD) was used. Compared with the non‐exposed subjects, the levels of serum creatinine and BGP, urinary Cd and β2‐microglobulin and blood Cd were higher, while the levels of serum inorganic phosphorus and MD indicators were lower in the Cd‐exposed group. In simple correlation matrix, BGP showed significant correlations with serum alkaline phosphatase (S‐Al‐p) and MD indicators in the Cd‐exposed men, and also correlations with S‐Al‐p and 1α‐25(OH)2D in the Cd‐exposed women.

Applying multivariate analysis to the Cd‐exposed subjects, BGP, %TRP and base excess were found to show significant associations with the MD indicators in the men. In the women, PTH, age, blood Cd and BGP were associated significantly with the MD indicators.

Only serum BGP showed a significant correlation in both sexes of the Cd‐exposed subjects, and a sex difference was found in the relationship between bone metabolic markers and osteopenia.

These results suggest that serum BGP has a close independent association with the osteopenia induced by Cd exposure and that BGP, which has a different biological function from that of PTH or 1α,25(OH)2D, may be a useful indicator to detect bone damage in Cd‐exposed subjects.
Trichloroethylene interactions with muscle cells
Authors: Kössler F.
Published: October 2006

The toxic effect of trichloroethylene (TCE) was investigated on isolated muscles prepared from frog and rats. Twitch and tetanic contractions as well as caffeine‐induced contractures, were recorded. Trichloroethylene at a concentration of 0.25–4.0 mM depressed the force development of both twitch and tetanic tension in a dose‐dependent manner. This effect was not influenced by the type of muscle. As TCE shortened the time to peak of twitch contractions, it may alter the Ca2+ binding kinetics.

Subthreshold caffeine concentrations applied after pre‐exposure to TCE (1 or 2mM) induced contractures. The same TCE exposure enhanced regular caffeine contractures through increasing the speed of tension development and the absolute force. Exposure to 5 or 10 mM TCE did not affect the first caffeine‐induced contracture but enhanced the potency of the second caffeine dose given 15 min after the first. The results suggest that the interaction of TCE with membrane sites is responsible for Ca2+ release for contractile processes.
Effectiveness of some chelating agents on distribution and excretion of vanadium in rats after prolonged oral administration
Authors: Gómez M. , Domingo J. L. , Llobet J. M. , Corbella J.
Published: October 2006

Vanadium has been shown to have a number of insulin‐like effects and has been demonstrated to be beneficial in the treatment of streptozotocin‐diabetic rats when included in the drinking water. However, some signs of toxicity and vanadium accumulation in all analysed tissues were reported in vanadium‐treated animals. In the present study, the effect of repeated intraperitoneal administration of sodium 4,5‐dihydroxybenzene‐1,3‐disulfonate (Tiron), ascorbic acid and deferoxamine mesylate (DFOA) or 2‐mercaptosuccinic acid on the distribution and excretion of vanadium was determined in male Sprague‐Dawley rats. Rats received sodium metavanadate (NaVO3) or vanadyl sulphate pentahydrate (VOSO4·5H2O) in the drinking water at concentrations of 0.15 mg ml−1 (NaVO3) and 0.31 mg ml−1 (VOSO4·5H2O) for 6 weeks. After the end of this exposure period, chelating agents were administered for 2 weeks (3 days per week) at doses approximately equal to one‐tenth of their respective LD50. Urine was collected on days 1, 7 and 14 of treatment. Twenty‐four hours after the final chelator injection, rats were killed and vanadium concentrations were determined in various tissues. Tiron and DFOA were effective compounds in mobilizing vanadium after NaVO3 administration, whereas Tiron was the most effective chelator after vanadyl sulphate administration. Ascorbic acid neither increased urinary elimination nor decreased tissue vanadium concentrations.
Kelthane residues in tissues of the tropical penaeid prawn, Metapenaeus monoceros (fabricius), under sublethal chronic exposure—a monitoring study
Authors: Surendranath P. , Rao K. V. Ramana
Published: October 2006

Monitoring the biodegradation and bioaccumulation of kelthane residues were undertaken during reclamation through oxygen consumption (respiration) and target enzyme activity assays. Even after 30 days of reclamation, non‐recovery in respiration and target enzyme assays revealed the accumulation of kelthane as a residue in tissues. Thin‐layer chromatography demonstrated the presence of kelthane residues as spots in tissue extracts of midgut gland and muscle after a 30‐day recovery period. This confirms that kelthane is a persistent insecticide of low biodegradability and capable of accumulating in tissues as residues even at sublethal concentration under chronic exposure.
Comparative studies of the covalent binding of [14C]‐2‐chloro‐4‐acetotoluidide by liver and kidney slices of the starling
Authors: Giri Shri N. , Siegel David M.
Published: October 2006

In tissue slices of female starlings, binding of [14C]‐2‐chloro‐4‐acetotoluidide (CAT) radioactivity to liver proteins was almost five times greater than binding to kidney proteins after 2 h of incubation. Binding to protein of liver slices increased in a log linear fashion with increasing CAT concentrations. Binding to protein of kidney slices also increased with increasing concentrations but not in a log linear fashion. Mixed‐function oxidase inhibitors, SKF 525‐A and α‐naphthoflavone, decreased binding to liver slices but did not affect binding to kidney slices. Anaerobic incubation conditions inhibited binding to both tissues. P‐Hydroxymercuribenzoate and sodium cyanide did not affect the binding of radioactivity associated with [14C]‐CAT to proteins of either liver or kidney slices. Diethyl maleate increased binding of the radioactivity to proteins of the kidney slices but not to liver slices. Cysteine also increased binding in kidney slices. Binding in liver slices did not increase significantly with cysteine. The cysteine‐induced increase in protein binding in kidney slices did not appear to depend on the formation of sulfate from the metabolism of cysteine. There was no sex‐dependent difference in starlings as to the binding of radioactivity in either liver or kidney slices. Male chicken kidney slices bound a much higher amount of radioactivity associated with [14C]‐CAT than male starling kidney slices, while the liver slices bound comparable amounts. Male hamster liver slices bound much more radioactivity than did male starling liver slices. However, hamster kidney slices bound much less than did starling kidney slices. Male mouse liver and kidney slices bound much less radioactivity than the comparable tissue slices of male starlings. It was concluded that in vivo metabolism of CAT in starlings plays an important role in covalent binding of [14C]‐CAT radioactivity to kidney proteins and this may be responsible for nephrotoxicity.
The production of hepatic cirrhosis in rats
Authors: Tomaszewski Konrad E. , Harries Gina C. , Jeffrey Phillip
Published: October 2006

This study investigated the conditions necessary to produce a predictable yield of cirrhosis in rats. A previously published method, using carbon tetrachloride, was used as a basis for the study. Histopathology was used in a semi‐quantitative manner to examine which observations could be used for the prediction of progression and final yield of cirrhosis. A comparison of different vehicles for oral carbon tetrachloride administration showed no effect of vehicle on the final yield of cirrhosis. Also, there were no observations during the study that could be used for prediction. Variability in the severity of hepatic impairment is an inherent feature of this model, and supporting histopathology is essential. We recommend a simple protocol for the initiation of cirrhosis in rats using carbon tetrachloride.
Poisoning by Gyromitra esculenta–a review
Authors: Michelot Didier , Toth Bela
Published: October 2006

Gyromitra esculenta (Pers.: Fr.) Fr. and a few other mushrooms have caused severe poisonings and even deaths in humans. Clinical data are characterized primarily by vomiting and diarrhea, followed by jaundice, convulsions and coma. Gastrointestinal disorders distinguish this poisoning. Frequent consumption can cause hepatitis and neurological diseases.

The species of concern are mainly G. esculenta and G. gigas (Kromb.) Cooke (non Phill.). Nevertheless, recent advances in chromatography, biochemistry and toxicology have established that other Ascomycetes species also may prove toxic.

Gyromitrin (acetaldehyde methylformylhydrazone, G) and its homologues are toxic compounds that convert in vivo into N‐methyl‐N‐formylhydrazine (MFH), and then into N‐methylhydrazine (MH). The toxicity of these chemicals, which are chiefly hepatotoxic and even carcinogenic, has been established through in vivo and in vitro experiments using animals, cell cultures and biochemical systems. When we consider the chemical nature and the reactivity of these natural compounds, we suggest that chemical and biochemical mechanisms may explain their intrinsic biological activity.
Organophosphate poisoning in Urban Zimbabwe
Authors: Kasilo O. J. , Hobane T. , Nhachi C. F. B.
Published: October 2006

A total of 606 organophosphate poisoning admission incidents were recorded and analysed retrospectively at the six central hospitals of Zimbabwe. The incidents covered a period of 10 years, i.e. from 1980 to 1989, inclusively. This accounted for 12% of all poisoning admission cases recorded at these hospitals and 84% of all pesticide poisoning cases. Of these organophosphate poisoning cases, 75% (450) were suicides and or parasuicides, 21% (126) were accidental, 2% (12) were homicides and 5% (30) were cases of an undetermined nature. The mortality rate was established at 8% (48). The study revealed that the 21–30‐year‐old age group is significantly more prone to poisoning (42% of the total) than other age groups.

The mean period of hospitalization of an organophosphate‐poisoned patient was found to be 8 days (the range was 1–29 days). The mean cost of keeping a poisoned patient in hospital during that period was calculated at Z$450.00 (i.e. US$225), excluding the cost of treatment. The total number of hospitalization days was 1599 and the total cost of keeping the patients in hospital was therefore Z$89,943,75, i.e. Z$11, 242,96 per year. The most popular (utilized) first‐line treatment (22% of all patients) was a combination of ipecacuanha syrup plus atropine, with atropine alone a poor second (10% of treated patients).
Interaction of ethanol and xylene in their effects on erythrocytes and other haematological parameters in the rat
Authors: Wrońska‐Noferδ Teresa , Rosin Janusz , Bartosz Grzegorz
Published: October 2006

Rats were given ethanol in drinking water for 8 months, followed by inhalation exposure (5 h daily) to 12.000 mg m−3 xylene for 9 days. Combined exposure to xylene and ethanol induced the same changes in the haematological, biochemical and biophysical parameters of the erythrocyte membrane as those found previously in our experiment with toluene–ethanol. Macrocytosis, a decrease in sedimentation rate and erthrocyte packing difference, as well as decreased fluidity of the erythrocytes membrane in the middle zone of the lipid bilayer, were the most significant changes of exposure to ethanol and xylene.
Effects of soman on calcium uptake in microsomes and mitochondria from rabbit aorta
Authors: Hu Chao‐Yu , Hsu Chia‐Hsuh , Robinson Casey P.
Published: October 2006

Daily administration of soman for several days results in several alterations in the vascular neuroeffector system. To determine whether or not soman alters intracellular Ca2+ uptake, the effects of acute exposure to soman or 7‐day administration of 5μg kg−1 of soman on the capacity of microsomes and mitochondria from rabbit aortic vascular smooth muscle to take up 45Ca2+ were determined. Acute exposure to soman concentrations of 1–100 μM did not alter significantly (P>0.05) 45Ca2+ uptake by either microsomes or mitochondria. On the other hand, 7‐day soman administration markedly reduced (P<0.05) 45Ca2+ uptake by both microsomes and mitochondria. Thus, calcium uptake and intracellular calcium uptake‐dependent responses will be affected by repeated soman administration.