bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of paraquat on the mutagenicity of benzo(a)pyrene
Authors: Wei C. I. , Allen K. , Misra H. P.
Published: October 2006

Elevated activities of superoxide dismutase (SOD) were detected in histidine‐requiring strains of Salmonella typhimurium after the bacteria were preincubated for 1 h at 37°C with S‐9 mix and paraquat (methylviologen, PQ2+) at 10−4M. A fivefold increase in SOD level was found for strains TA 98 and TA 100. These elevated levels of SOD activity were correlated with a significant reduction of the mutagenicity of metabolically activated benzo(a)pyrene (B(a)P) in these tester bacteria when evaluated in a preincubation assay system. A 69.0–92.5% and 23.5–66.9% reduction was noticed when 0.5–4.0 μg per plate of B(a)P was used in TA 98 and TA 100, respectively. However, exogenous superoxide dismutase at 10–100 μg ml−1 added to top agar had no significant effect on the number of revertants produced by activated B(a)P. These data indicate a major role of intracellular superoxide anion in promoting mutagenicity of B(a)P.
Toxicity study of uracil in dogs
Authors: Spicer E. J. F. , Richter W. R. , Morita K.
Published: October 2006

Uracil was administered to male and female dogs for 3 months and to male dogs for 12 months at dose levels of 0, 210, 420, 840 and 1680 mg uracil per kg body weight per day by gavage. While there were minor differences seen in food consumption, water consumption and erythroid parameters between the 3‐month and the 12‐month studies, it was concluded that there were no adverse effects seen on these parameters nor on body weight, EKG, clinical laboratory studies and organ weights. Pathological observations did not show treatment‐related effects.
Oxidation state analysis of mercury: Evidence of the formation of mercurous ion in the oxidation of mercury by peracetic acid
Authors: Wigfield Donald C. , Perkins Sherry L.
Published: October 2006

Both elemental mercury and the mercurous ion give rise to a signal in Cold‐Vapor Atomic Absorption Analysis under non‐reducing conditions. Distinction between these species based on the greater solubility of the mercurous ion in water is possible, and the potential of this analytical distinction is illustrated with the finding that oxidation of mercury by peracetic acid involves the mercurous state.
The effect of chronic exposure to 3.5 ppm NO2 on hormone levels and organ weights in rats
Authors: Vyskočil Adolf , Tušl Miloslav , Zaydlar Karel
Published: October 2006

Male Wistar rats were exposed continuously for 1 or 2 months to 3.5 ppm NO2. Levels of histamine and serotonin in lung, noradrenaline in hypothalamus, corticosterone and thyroxine in serum and catecholamines in the adrenals were estimated. No significant changes were observed in lung histamine and serotonin, serum corticosterone, or adrenal catecholamine levels; or in the weights of lung, spleen, adrenal glands, hypothalamus, liver and the whole body. The only significant change was a decrease in the concentration of hypothalamic noradrenaline after 2 months of exposure. The results suggest that prolonged exposure to 3.5 ppm NO2 does not result in changes in hormone levels, organ and body weights, and therefore does not precipitate pulmonary defensive reactions or non‐specific stress response.
Biogenic amines and some metals in brain of cadmium‐exposed diabetic rats
Authors: Chandra Satya V. , Kalia Kiran , Hussain Tahir
Published: October 2006

Diabetic rats (alloxan diabetes) were exposed to cadmium (2 mg kg−1 i.p.) daily for 21 days to investigate the levels of blood glucose, biogenic amines and iron, copper, zinc and cadmium in the brain. Cadmium exposure to diabetic rats produced a significant exacerbation in the hyperglycemic effect and accumulation of cadmium in the blood compared with that observed after diabetes or cadmium exposure alone. The elevation in the levels of brain dopamine and 5‐hydroxytryptamine were also more pronounced in cadmiumexposed diabetic rats compared with either cadmium exposure or diabetes alone. Cadmium exposure to diabetic rats also produced significant changes in the concentrations of copper in the blood. These results indicated enhanced cadmium toxicity in diabetic rats.
Effects of intravenous infusion of doxorubicin on blood chemistry, blood pressure and heart rate in rabbits
Authors: Robison Timothy W. , Giri Shri N. , Schiedt Mary , Parker Harold R. , Ishizaki Goro , Curry Donald L.
Published: October 2006

The effects of a 1h continuous infusion of doxorubicin (12.5 mg kg−1, 200 mg M−2) on blood chemistry was examined in rabbits over a 6‐h period. Plasma glucose levels remained unchanged while insulin levels were significantly decreased to 39, 45 and 61% of the zero time value (12.8 ± 2.9 ng ml−1) at 30, 60 and 120 min, respectively, after starting the drug infusion. Plasma cortisol levels were increased to 141, 140 and 131% of the initial zero time value (12.3 ± 2.2 ng ml−1) at 120, 240 and 360 min, respectively. Doxorubicin had no effect on plasma electrolytes, osmolality and urea nitrogen but significantly increased plasma creatinine over the corresponding control value (2.2 ± 0.8 μg ml−1 to 4.9 ± 0.7 μg ml−1) at 120 min and the level remained elevated for the remaining period of the study. Systolic and diastolic pressure, and heart rate were also depressed at 240 and 360 min. The data collected in the present study indicate that the doxorubicin infusion might have a direct effect on beta cells in the pancreas as well as muscle tissue. Changes in cortisol, blood pressure and heart rate appear to be secondary to other effects produced by doxorubicin.
The inhibitory effect of alcide®, an antimicrobial drug, on protein synthesis in Escherichia coli
Authors: Scatina Joann , Abdel‐Rahman Mohamed S. , Goldman Emanuel
Published: October 2006

Alcide®, a broad‐spectrum antimicrobial drug, has been shown to kill a wide range of common pathogenic bacteria as well as fungi, in vitro. This agent consists of Part A and Part B which contain sodium chlorite and lactic acid as the active ingredients, respectively. The mixing of these two parts immediately prior to use results in the formation of chlorine dioxide (ClO2), a potent germicidal compound.

Exposure of exponentially growing E. coli cells to Alcide® resulted in a rapid inhibition of growth as well as loss of viability. Alcide® inhibited DNA, RNA, and protein synthesis; however, RNA and protein synthesis were affected at much lower concentrations. The accumulation of the amino acid analog aminoisobutyric acid into growing cultures of E. coli was only partially impaired by Alcide®. Cell‐free protein synthesis using an RNA directed system was inhibited by Alcide® and this effect was lessened in the presence of mercaptoethanol. Higher concentrations of Alcide® (1 mM) oxidized 25% of the methionine to methionine sulfoxide. Aminoacylation of E. coli bulk tRNA was decreased in vitro and the amino‐acylation of tRNAfMet was particularly sensitive to Alcide®.
Cimetidine enhances and phenobarbital decreases parathion toxicity
Authors: Mourelle Marisabel , Girón E. , Amezcua J. L. , Martinez‐Tabche L.
Published: October 2006

Parathion toxicity has been attributed to its metabolic product paraoxon which is formed in the mammal liver through the multiple oxidase enzymes. These are induced by barbiturates and inhibited by SKF 525 A and cimetidine. We assessed the effects of these drugs on the acute toxicity of parathion in rats by measuring the rate of survival at 24 h after the administration of the oral LD50 of parathion to four groups of rats: control and pretreated with the aforementioned drugs. Additional rats of these groups were used to measure the capability of liver isolated microsomes to transform p‐nitroanisole to p‐nitrophenol. In the control and cimetidine groups we also measured the transformation of parathion to paraoxon and p‐nitrophenol by the liver microsomes. Phenobarbital increased the survival 100% whereas cimetidine and SKF 525 A dramatically potentiated parathion toxicity. Phenobarbital increased the formation of p‐nitrophenol but cimetidine and SKF‐525 A produced the opposite effect. Paraoxon and p‐nitrophenol from parathion were decreased by cimetidine. Our results strongly suggest that parathion itself is largely responsible of its toxicity and the inhibition of its metabolism is harmful rather than beneficial.
Imipramine prevention of carbon tetrachloride‐induced liver necrosis at late states of the intoxication process
Authors: Fernández G. , Villarruel M. C. , de Ferreyra E. C. , de Fenos O. M. , Castro J. A.
Published: October 2006

Impiramine administration (50 mg kg−1, i.p.) to Sprague–Dawley male rats (240–290 g) 6 or 10 h after CCl4 (1 ml kg−1, i.p.) partially prevents liver necrosis induced by the hepatotoxin. When imipramine is given 30 min before CCl4, it inhibits in part the CCl4‐inhibits in part the CCl4‐induced lipid peroxidation and the covalent interactions of reactive metabolites with microsomal lipids or proteins and partially prevents CCl4‐induced cytochrome P‐450 destruction, but not glucose 6 phosphatase activity depression.

Impiramine administration prior to CCl4 does not modify levels of the hepatotoxin reaching the liver or the body temperature of CCl4 treated animals. Early preventive effects of imipramine on cytochrome P‐450, might be attributed to inhibition of covalent interactions of reactive metabolites.

The hypothesis that imipramine exerted late preventive effects by interfering with calcium deleterious effects or by modulation of protein and phospholipid synthesis or degradation is analyzed.
Evidence of differential hematopoietic compensation to lead intoxication in blood, liver and kidney
Authors: Hollebone B. R. , Johnson P. M. , Chakrabarti C. L. , Karwowska R.
Published: October 2006

The dependence of fluorescent porphyrin levels on the concentration of lead in blood, liver and kidney has been examined as functions of both the level and duration of dosing. Individually housed male Wistar COBS rats of 200 g were randomly selected for 3, 7, 21 and 35 day dosing periods in groups of: control, 50, 100 and 1000 ppm dosing in drinking water. The plot of all data points for porphyrin concentration against measured lead burden covers the same range of levels and closely resembles the scatter of data observed in humans. However, subsets of this plot defined by individual dose levels and durations yield well‐defined linear relationships. At all dose levels at 7 days the correlation of porphyrin concentration to lead tissue burden is negative in all tissues, showing a direct inhibition of hemopoiesis with lead burden. Depending on the tissue the slope becomes less negative, or, as in blood, positive at 21 and 35 days at all doses. This compensation is most rapid in blood, then liver and is least evident in kidney. The time at which compensation is observed is the same for all doses in each tissue and seems therefore, to depend on the rate of protein turnover in different tissue types.

These results suggest that a direct correlation of porphyrin concentration to lead burden is not valid without knowledge of the dosing history. As well, evidence of compensation in one tissue does not imply successful compensation in other affected tissues where regeneration rates are slower. However, these observations do suggest that a correlation could be made between the extent of compensation in blood and that implicit for less accessible systems. Since blood compensation is most rapid, caution will be necessary in establishing tolerable lead levels for tissues at higher risk.
The effect of cadmium on chemical‐ and viral‐induced tumor production in mice
Authors: Blakley Barry R.
Published: October 2006

Female Swiss mice were exposed to cadmium in the drinking water at concentrations ranging from 0 to 50 ppm for 105 or 280 day time periods. In the 105 day study, the effect of cadmium on urethan‐induced pulmonary adenoma formation was evaluated. Urethan‐induced sleeping times observed following i.p. injection of urethan after 3 weeks of cadmium exposure were not affected by cadmium indicating that chronic cadmium exposure did not alter the eliminaton of urethan. Pulmonary adenoma formation which was evaluated 84 days later was not affected by cadmium. The size and number of tumors remained unchanged. This suggests that the immunosuppressive actions of cadmium do not influence urethan‐induced adenoma formation. In the 280‐day study, the effects of cadmium on the incidence of spontaneous murine lymphocytic leukemia was evaluated. Mortality from the leukemia virus was greater in the cadmium‐exposed mice. Mice exposed to 10 or 50 ppm cadmium experienced 33% more deaths from the virus. The average time till death was unaffected. It appears that the immunosuppressive effects of cadmium impair immunosurveillance mechanisms that control expression of the murine lymphocytic leukemia virus.
Effects of some monocyclic aromatic solvents and their metabolites on brain dopamine in rabbits
Authors: Romanelli Alessandro , Fatzol Maurizio , Mutti Anomio , Bergamaschi Enrico , Franchini Innocente
Published: October 2006

Adult male rabbits were exposed to high concentrations (750 ppm, 12 hours daily for 7 days) of toluene, xylenes, styrene, ethylbenzene, vinyltoluene (3‐methylstyrene), and 7‐methyl‐styrene vapours or were dosed with 4 mM/kg/day i.p. of hippuric, methylhippuric, mandelic, phenylglyoxylic, and 7‐methyl‐mandelic acids. Styrene, vinyltoluene and ethylbenzene caused a marked depletion of striatal and tuberoinfundibular dopamine. Such an effect was also caused by treatment with phenylglyoxylic and mandelic acids. Dopamine depletion was associated with an increase in homovanillic acid concentration in the same regions. These results indicate that dopamine metabolism is a target for the neurotoxic effects of some monocyclic aromatic hydrocarbons and their metabolites, a lateral vinyl‐ or ethyl‐chain being crucial for the structure/activity relationship of such compounds.
The effect of carbon monoxide on hormone levels and organ weights in rats
Authors: Vyskočil Adolf , Tušl Miloslav , Zaydlar Karel
Published: October 2006

Male Wistar rats were exposed continuously for 1 or 2 months to 25 or 100 ppm CO. The concentrations of noradrenaline in the hypothalamus, corticosterone and thyroxine in serum and of adrenal catecholamines were estimated. After exposure to 25 ppm CO no significant changes were observed in the serum corticosterone and thyroxine, hypothalamic noradrenaline, adrenal catecholamines levels, or in the weights of lung, spleen adrenal glands, liver and the whole body. Exposure to 100 ppm CO induced a decrease in hypothalamic noradrenaline and serum thyroxine and an increase in adrenal catecholamines and serum corticosterone. Whole‐body and organ weights were unchanged except for a slight decrease in liver weight. The results suggest a non‐specific stress response in the rat to 100 ppm CO whilst concentration of 25 ppm CO was without any stress effect.
Pyrethroid inhibition of basal and calmodulin stimulated Ca2+ ATPase and adenylate cyclase in rat brain
Authors: Kabeer Sahib I. Ahammad , Rao K. S. Prasada , Desaiah D.
Published: October 2006

Effects of two classes of pyrethroids, permethrin and resmethrin (type I), cypermethrin and deltamethrin (type II), on basal (calmodulin‐deficient) and calmodulin stimulated activities of Ca2+ ATPase and adenylate cyclase from rat brain were studied in vitro. None of the pyrethroids inhibited synaptosomal basal Ca2+ ATPase, but permethrin and deltamethrin inhibited basal adenylate cyclase in the nuclear fraction of a brain homogenate. Both groups of pyrethroids decreased the calmodulin activated Ca2+ ATPase and adenylate cyclase from brain synaptosomes and nuclear fraction. The results indicate that calmodulin‐stimulated Ca2+ ATPase is more sensitive to type II pyrethroids and pyrethroids are more effective on calmodulin stimulated enzymes than basal enzyme activities. Since calmodulin, adenylate cyclase and Ca2+ ATPase are known to participate in various brain processes, it is possible that pyrethroids alter neural transmission, however, additional in vivo work would be needed to confirm this possibility.
Interrelationship between hemolysis and lipid peroxidation of human erythrocytes induced by silicic acid and silicate dusts
Authors: Singh Shivendra V. , Rahman Q.
Published: October 2006

Silicic acid and silicate dusts (slate dust and chrysotile asbestos) cause hemolysis of erythrocytes in vitro. The peroxidation of polyunsaturated fatty acids (PUFA) of erythrocyte membrane lipids is also enhanced by incubating the erythrocytes with silicic acid and silicate dusts in in vitro. Hemolysis of erythrocytes elicited by silicic acid and silicate dusts is inhibited significantly by polyvinyl‐pyrrolidone and dipalmitoyl lecithin (DPL). These agents, however, have no effect on silicic acid and silicate dust induced peroxidation of erythrocyte membrane lipids. On the other hand, peroxidation of erythrocyte membrane lipids, induced by silicic acid and silicate dusts, is inhibited almost completely by adding superoxide dismutase and catalase to the incubation system, whilst the hemolysis of erythrocytes induced by silicic acid and silicate dusts is unaffected by these agents. Similarly the lysis of erythrocytes, induced by silicic acid and silicate dusts, proceeds at a much faster rate than silicic acid and silicate dust induced lipid peroxidation. These results indicate that silicic acid and silicate dust induced hemolysis and lipid peroxidation represent two independent processes.
Halothane hepatotoxicity in glutathione depleted rats
Authors: Wilhelm Klaus‐Peter , Younes Maged , Sellin Dieter , Siegers Claus‐Peter
Published: October 2006

Experimental models for halothane hepatotoxicity require microsomal enzyme induction by phenobarbital or triiodo‐thyronine pretreatment and hypoxic conditions. The role of GSH in the metabolism of halothane, however, is still unclear. We therefore pretreated male rats with phorone to deplete hepatic GSH, phenobarbital as a microsomal enzyme inducer and exposed them to halothane 1 % for 4 h under hypoxia (10% O2). Increases in serum enzyme activities of alanine aminotransferase (GPT) and sorbitol dehydrogenase (SDH) were observed 24 and 48 h later. Histomorphological examinations showed centrilobular hepatic necrosis. In GSH‐depleted rats the increments of serum enzyme activities and histomrphological alterations were significantly aggravated as compared with controls.

In this model (+)‐catechin protected against halothane‐induced hepatotoxicity as evidenced by reduced serum enzyme elevations and morphological alterations whereas diethyldithiocarbamate faiied to exert any protective effects. Free fluoride concentrations in plasma was used as an index of the non‐oxidative defluorination of halothane. Increased plasma fluoride levels were observed under conditions which evoked hepatotoxicity but did not correlate with the protective effect of (+)‐catechin. Our experimental data indicate that glutathione might be involved in the non‐oxidative metabolic pathways of halothane. Furthermore, (+)‐catechin seems capable of protecting against the direct toxic effect of halothane metabolites resulting from the reductive pathways.
Studies of the in vitro effect of methylmercury chloride on rat brain neurotransmitter enzymes
Authors: Kung Mei‐Ping , Kostyniak Paul , Olson James , Malone Maureen , Roth Jerome A.
Published: October 2006

The in vitro effect of methylmercury (MM) on the enzymatic activities of brain cell specific marker enzymes, choline acetyltransferase (CAT), glutamic acid decarboxylase (GAD), 2′, 3′‐cyclic nucleotide phosphohydrolase (CNP), glutamine synthetase (GS) and enolase was examined. The results demonstrate that at 100 μM MM, GS activity was not affected whereas a small decrease in the activity of both GAD (20%) and enolase (10%) was observed. CNP and CAT activity appeared to be more sensitive toward MM with 100 μM MM producing inhibition of 50% and 30%, respectively. The addition of sulfhydryl protecting reagents such as DTT or sodium thioglycolate can restore the enzyme activities to normal control levels despite prior exposure of the enzymes to MM.
Mechanisms of toxicity of 2‐ and 5‐hydroxy‐1,4‐naphthoquinone; absence of a role for redox cycling in the toxicity of 2‐hydroxy‐1,4‐naphthoquinone to isolated hepatocytes
Authors: Doherty Mary D'Arcy , Rodgers Adrian , Cohen Gerald M.
Published: October 2006

The mechanisms of toxicity to isolated rat hepatocytes of two structurally related naphthoquinones have been studied. Both 5‐OH‐1,4‐naphthoquinone (5‐OH‐1,4‐NQ; juglone) and 2‐OH‐1,4‐naphthoquinone (2‐OH‐1,4‐NQ; lawsone) caused a concentration‐dependent cytotoxicity to hepatocytes which was preceded by a depletion of intracellular glutathione. 5‐OH‐1,4‐NQ caused a depletion of intracellular glutathione when incubated either at 4°C or 37°C whereas 2‐OH‐1,4‐NQ caused a depletion of intracellular glutathione when the hepatocytes were incubated at 37°C but not at 4°C. 5‐OH‐1,4‐NQ but not 2‐OH‐1,4‐NQ reacted with glutathione in buffered solution. These results suggested that the depletion of intracellular glutathione by 2‐OH‐1,4‐NQ is enzyme mediated whereas in the case of 5‐OH‐1,4‐NQ the direct chemical reaction with glutathione may be largely responsible for the depletion. A critical role for depletion of protein thiols in menadione‐induced cytotoxicity has been proposed. In agreement with earlier work, menadione caused a decrease in protein sulphydryls prior to cell death, however, at cytotoxic concentrations of both 2‐OH‐1,4‐NQ and 5‐OH‐1,4‐NQ this decrease only accompanied rather than preceeded cell death.

The mechanism of toxicity of 5‐OH‐1,4‐NQ is similar to that of other naphthoquinones and involves formation of its corresponding naphthosemiquinone, active oxygen species and redox cycling as it stimulated a disproportionate increase in both microsomal NADPH oxidation and oxygen consumption. No evidence for redox cycling of 2‐OH‐1,4‐NQ was obtained either with microsomes or hepatocytes and thus its cytotoxicity must involve a different mechanism to that currently proposed for other naphthoquinones. This inability of 2‐OH‐1,4‐NQ to redox cycle may be due to its very low one‐electron reduction potential (E1/7‐415 mV). Thus, it is a very poor substrate for reduction to a semiquinone by cellular reductases.
A 13‐week vapor inhalation study of 3,3‐dimethyl‐2‐butanol in sprague‐dawley rats
Authors: James John T. , Armstrong Robert D. , Leach Glenn , Farrand Richard L. , Burnett David , Englee Mae Jean , Hall William C.
Published: October 2006

Four groups of male and female Sprague‐Dawley rats were exposed for 13 weeks to 3,3‐dimethyl‐2‐butanol (PA) at concentrations of 0.00, 0.20, 1.00 or 5.00 mg/l (1 mg/l = 240 ppm). Exposures were for 6 hr per day, 5 days per week with sacrifices at 7 and 13 weeks of exposure, and at 4 weeks after exposure. The test animals were evaluated for abnormalities in physiology, behaviour, clinical laboratory parameters, and gross and microscopic morphology. No abnormalities were detected in electrocardiograms, respiratory indices, spontaneous activity, passive avoidance activity and open‐field behaviour. Clinical signs related to PA exposure included alopecia, ataxia and lacrimation. There were no biologically significant between‐group differences in body‐weights during the study. The clinical laboratory data demonstrated a 30% increase in serum cholesterol and bilirubin at 7 weeks in high‐dose males and an increase in urea nitrogen in intermediate and high‐dose males at 13 weeks. There were no abnormalities in hematologic or coagulation parameters. At necropsy there were no significant gross abnormalities; however, examination of organ weights revealed enlarged kidneys in high‐dose male rats at 13 weeks, enlarged ovaries in high‐dose female rats at 13 weeks, and microscopic study of tissue sections revealed minimal to mild renal tubular injury in high and possibly intermediate dose males at several sacrifices.

These findings suggest that the primary target organ of PA, when given by inhalation, is the kidney in male rats and possibly the ovary in female rats. The renal changes in the high‐dose males were not fully reversible during the recovery period. Because abnormalities were also observed in the intermediate‐dose males, the no‐observed‐effect level is 0.2 mg/I. The renal lesions were morphologically similar to those reported in male rats exposed to hydrocarbons and may be unique to male rats. It must be emphasized that PA, like most alcohols, is not highly toxic by the inhalation route.
Sensory irritation of methylisocyanate vapor
Authors: James John T. , Buettner Leonard C. , Hsu Sam S.
Published: October 2006

The respiratory‐depression (RD) profile in mice exposed to methylisocyanate (MIC) vapor is reported. The RD50 value calculated from this profile was 2.9 (2.7–3.2) ppm. Concentrations of MIC that have been reported to be unbearable in humans were of approximately the same magnitude as RD50 concentrations in mice for brief exposures.
Comparative studies on nephrotoxic effects of Tris (2,3‐dibromopropyl) phosphate and Bis (2,3‐dibromopropyl) phosphate on rat urinary metabolites
Authors: Fukuoka Masamichi , Takahashi Terue , Naito Katsushi , Takada Koichi
Published: October 2006

The mechanism of Tris‐BP or Bis‐BP (a metabolite of Tris‐BP) induced nephrotoxicity was investigated by determining urinary excretion of enzymes and selected metabolites. Rats received single oral doses of 0, 71.7, 143.4 and 286.8 μmol/kg tris (2,3‐dibromopropyl) phosphate (Tris‐BP) or bis (2,3‐dibromopropyl) phosphate (Bis‐BP). Urine was collected over a 24 h period and subjected to biochemical examinations. Comparative studies on Tris‐BP‐ and Bis‐BP‐induced nephrotoxicities were carried out for abnormal patterns of urinary excretion. The urinary excretion of glucose was higher in Bis‐BP than Tris‐BP at a dose of 143.4 μmol/kg, but this pattern reversed at a dose of 286.8 μmol/kg. Peak lactate excretion occurred later than peak glucose excretion with 143.4 and 286.8 μmol/kg Tris BP and 143.4 μmol/kg Bis‐BP. Bis‐BP 286.8 μmol/kg caused a transient urinary elevation of lactate on Day 2. Uric acid was excreted at higher levels for Bis‐BP than Tris‐BP on day 2 of urine collection. Activities of urinary enzymes including alkaline phosphatase, aspartate aminotransferase and γ‐glutamyltransferase, were different on the first day of post‐treatment for Tris‐BP and Bis‐BP. Leucine aminopeptidase and lactate dehydrogenase levels differed on the second day. Activities of the former enzymes on the day 2 urine suggested a transformation of Tris‐BP to Bis‐BP. Urinary patterns of lactate dehydrogenase isoenzymes (LDH‐1‐LDH‐5) were different between Tris‐BP and Bis‐BP when rats were treated with the dose of 286.8 μmol/kg: Tris‐BP caused a higher excretion of LDH‐4 and LDH‐5 in urine on day 1 and all five isoenzymes into the day 2 urine. Bis‐BP caused slightly higher excretion of LDH‐5 and LDH‐4 into the day 1 and 3 urine, respectively. Bis‐BP but not Tris‐BP caused abnormally urinary excretion of sodium ion. Histopathologically, the nephrotoxic effect of Tris‐BP appeared one day later and was more obvious than that of Bis‐BP in rats after single oral administration.
Comparative sensitivity of histo‐pathology and specific lung parameters in the detection of lung injury
Authors: Hooftman R. N. , Kuper C. F. , Appelman L. M.
Published: October 2006

The sensitivity of different parameters for the determination of lung injury caused by nitrogen dioxide (NO2) was investigated. Male rats were exposed to concentrations of 0, 4, 10 or 25 ppm NO2 for 6 h/day, for 7, 14 or 21 days. Histopathology of the nasal cavity, larynx, trachea and lungs was compared with the changes in macrophage function and morphology. In addition several biochemical parameters were determined in lung lavages. Cytotoxic effects were investigated in primary cultures of rat and bovine alveolar macrophages, exposed to the same NO2‐levels as in the in vivo exposure. Treatment‐related histopathological changes were observed in the lungs. No differences between exposed and control animals were observed in the nasal cavity, larynx or trachea. The morphology of the lavaged alveolar macrophages was changed at all exposure concentrations on day 7, 14 and 21. An increase in the number of macrophages was found after exposure to 10 and 25 ppm NO2 on days 7, 14 and 21. The phagocytic capacity was diminished after 14 and 21 days exposure to 25 ppm and at both times exposure to 10 and 25 ppm increased the level of gamma‐glutamyl transferase (GGT) in lavage fluids. Morphology of the macrophages and levels of GGT were found to be sensitive parameters of nitrogen dioxide toxicity. In vitro exposure of rat and bovine alveolar macrophages to comparable NO2‐concentrations induced effects on phagocytosis similar to those observed for macrophages from exposed rats.
Nuclear aberrations and micronuclei induction in the digestive tract of mice treated with different iron salts
Authors: Bianchini F. , Caderni G. , Dolara P. , Tanganelli E.
Published: October 2006

Toxic effects of ferrous sulfate and of ferric chloride were determined in the gastrointestinal tract by measuring the induction of nuclear aberrations and micronuclei. In fasting animals ferric chloride induced a dose‐related increase of nuclear aberrations in the stomach, whereas ferrous sulfate was not active. In normally feeding animals no increase of nuclear aberrations was observed. The effects of the iron compounds on the duodenum were minimal. In fasting animals a dose‐related increase of nuclear aberrations was observed at the level of the colon, with no clear difference between ferrous and ferric compounds. A modest increase of nuclear aberrations of the colon was seen in feeding animals only with ferrous sulphate. By intrarectal administration, nuclear aberrations were induced especially by ferric chloride.

An increase of the frequency of micronuclei was not observed at the level of the stomach, duodenum and colon, with the exception of ferric chloride, that induces a significant, although small increase of colon micronuclei when administered intra‐rectally. The data demonstrate that iron compounds have an intrinsic cellular toxicity when not administered with food, but do not seem to carry any genotoxic potential for the gastrointestinal tract.
An illustration of dangers of ignoring survival differences in carcinogenic data
Authors: Bailer A. John , Portier Christopher J.
Published: October 2006

This paper illustrates the effects of survival differences on the routine analysis of 2‐year animal carcinogenesis experiments using quantal response. Not adjusting for decreased survival in the higher dosed groups results in a decrease in the actual significance level for the quantal response trend test, and a corresponding decrease in sensitivity for detecting a true treatment effect. Similar results hold for estimation of carcinogenic risk. Tables of the range of survival differences found in recent National Toxicology Program carcinogenesis studies are presented.
Oxmetidine (H2 receptor antagonist) induced cytotoxicity in isolated rat hepatocytes
Authors: Willson R. A. , Hall T. , Hart J.
Published: October 2006

Oxmetidine, a new and more potent analogue of the H2 receptor antagonist, cimetidine, was recently withdrawn from clinical trials because of associated hepatotoxicity. We investigated the potential hepatotoxicity of the drug in vitro and in vivo in the rat. In addition, we investigated, in in vitro experiments, the potential hepatoxicity of other gastric acid inhibitory drugs (cimetidine, ranitidine, omeprazole and nolinium bromide). In in vitro experiments, oxmetidine, at various concentrations, was added to isolated hepatocyte incubations and cytoxicity was assayed by trypan blue exclusion. In in vivo experiments, oxmetidine was administered both i.p. and orally, and hepatotoxicity was assessed by serum biochemical measures (transaminases, alkaline phosphatase, 5′nucleotidase, gamma glutamyl transpeptidase) and liver histopathology. In the in vitro studies, the addition of oxmetidine to the hepatocyte incubations was associated with significant (P<0.001) dose and time dependent cytotoxicity. However, the in vivo experiments revealed no significant changes in serum biochemistry and no significant alterations in liver histopathology up to 72 h following the administration three different dosages of oxmetidine. Of the other gastric acid inhibitory drugs, only nolinium bromide was associated with significant (P<0.001) in vitro cytotoxicity. Our in vitro observations establish that oxmetidine is cytotoxic to isolated rat hepatocytes and suggest that nolinium bromide be further evaluated for potential hepatotoxicity.
Uptake of inert particles by dog alveolar macrophages in vitro — a comparison of monolayer and suspension techniques
Authors: Mueller Heinz‐Leonhard , Guilmette Raymond A. , Muggenburg Bruce A.
Published: October 2006

This study was conducted to determine if significant differences in phagocytosis occurred in pulmonary alveolar macrophages in suspension or monolayer cultures. Dog alveolar macrophages were incubated with different numbers of fluorescent polystyrene latex microspheres, both in suspension and in monolayer cultures. The particle uptake by cells was linear for 10–100 min and the fraction of cells that contained particles was similar for both incubation techniques. Differences between carboxylated and non‐carboxylated microspheres were statistically not significant. The overall particle numbers associated with cells were 2–5 times higher for cells incubated in suspension compared to adherent cells. Many more cells were found with low particle numbers at all incubation times using the monolayer technique compared to the suspension technique. When cells were treated with xylene for 1 h after different times of incubation in vitro, a higher decrease in particle numbers in cells was found in suspension cultures than in monolayer cultures. This finding suggests higher particle binding when cells were incubated in suspension, but particle numbers after xylene treatment were still higher in cells incubated in suspension than in monolayers. A comparison with the uptake of similar particles by dog alveolar macrophages in vivo suggests that the suspension cultures were more similar to the events in the dog lung, but uptake rates were about a factor of two lower with suspended cells than those seen in vivo.
Role of activated oxygen species on the mutagenicity of benzo[a]pyrene
Authors: Wei C. E. , Allen K. , Misra H. P.
Published: October 2006

Different scavengers of active oxygen species (superoxide dismutase, catalase, mannitol and dimethylfuran) were tested in the Ames Salmonella assay to determine the role of the reactive oxygen species in the benzo[a]pyrene (B[a]P) mutagenesis process. Exogenously added superoxide dismutase or catalase at 10–100 μg ml−1 top agar, or 3–12 mM mannitol showed no effect on B[a]P mutagenicity in the presence of S9 mix. However, dimethylfuran (DMF), a singlet oxygen scavenger, inhibited in a dose‐related manner the mutagenic response of B[a]P in the presence of the microsomal fraction. DMF at 3 and 6 mM inhibited the number of revertants by 69 and 93% for strain TA 100, and 76 and 78% for TA 98, respectively. DMF at these levels was neither toxic nor mutagenic to the bacteria. The result indicates that singlet oxygen may play an important role in promoting B[a]P mutagenicity.
Further evidence that dichloromethane does not induce chromosome damage
Authors: Westbrook‐Collins Barbara , Allen James W. , Sharief Yousuf , Campbell James
Published: October 2006

Dichloromethane (DCM) is a widely used industrial solvent that has been determined to be a carcinogen in rats and mice. In vitro and in vivo analyses of chromosome damage induced by this agent have provided conflicting results. In order to further investigate the clastogenic potential of DCM in vivo, we analyzed sister chromatid exchanges (SCEs) and chromosome aberrations (CAs) in mouse bone marrow cells following intraperitoneal exposures of 100–2000 mg kg−1 DCM. Dichloromethane failed to increase the frequencies of either SCEs or CAs.
Comparative flow cytometric analysis of bleomycin toxicity on normal and tumour sheep cell kinetics in vitro
Authors: Shrivastava Ravi , Ratinaud Marie Helene , Julien Raymond
Published: October 2006

The cytotoxic effects of bleomycin on cell proliferation, morphology and cycle progression were compared in a sheep tumour cell line and in normal sheep sinus cells. They were concentration and time dependent, irreversible, and were accompanied by increased cell diameter and cytosolic synthetic activity. Cell accumulation in the G2M phase, without much change in the cell cycle progression through the S phase, was observed using flow cytometry.

Although the tumour cells showed a greater sensitivity to low bleomycin concentrations compared to the normal cells, both cell types exhibited equal sensitivity to higher drug concentrations.

Provided that tumour cells are also preferentially affected by bleomycin in vivo, these findings raise the possibility that bleomycin cytotoxicity can be reduced or avoided in normal tissue.
Diethylbenzene‐induced sensorimotor neuropathy in rats
Authors: Gagnaire F. , Marignac B. , de Ceaurriz J.
Published: October 2006

The commercial isomer mixture of diethylbenzene (DEB mixture), 1,2‐diethylbenzene (1,2‐DEB), 1,3‐diethylbenzene (1,3‐DEB) and 1,4‐diethylbenzene (1,4‐DEB) were administered orally to male Sprague‐Dawley rats. The experimental rats and the appropriate controls were examined electrophysiologically for motor and sensory conduction velocities (MCV and SCV), and for the amplitude of the sensory action potential (ASAP) of the tail nerve, at weekly or bi‐weekly intervals. Oral administration of DEB mixture (750 or 500 mg kg−1, once daily, 5 days per week for 10 weeks) and 1,2‐DEB (100 mg kg−1, once daily, 4 days per week for 8 weeks) produced a time‐dependent decrease in MCV, SCV and ASAP. Rats treated with DEB mixture and 1,2‐DEB exhibited a blue discoloration of tissues and urine.

No changes in MCV, SCV and ASAP developed in rats administered orally with 1,3‐DEP and 1,4‐DEB (500 mg kg−1, once daily, 5 days per week for 8 weeks).

The results indicate that 1,2‐DEB is the isomer responsible for neurotoxicity and suggest that a metabolic pathway giving rise to coloured compounds is involved in the neurotoxicity of DEB.
Carcinogenic oil fractionation and nuclear enlargement in mouse skin
Authors: Ingram A. J.
Published: October 2006

SUMMARY A non‐solvent‐refined oil, previously shown to produce tumours in a long‐term skin painting assay and a positive result in the mouse skin nuclear enlargement test, was separated using silica gel elution techniques into eight fractions. Fraction 1, which contained saturated and 1–2 ring aromatic hydrocarbons, was used to dilute the other fractions to produce solutions equivalent to and twice their original concentration in the intact oil. Fraction 1, diluted fractions 2–8, the reconstituted oil, the original oil and a negative control oil were examined for their ability to produce nuclear enlargement.

The degree of nuclear enlargement observed with fraction 1 was considered to indicate marginal or no carcinogenic activity. With the fraction that contained 2–3 ring aromatic compounds, weak carcinogenic activity could not be ruled out but it is unlikely that these components played a major role in the carcinogenicity of the oil. The greatest activity was identified in the fraction containing the total 3/4–6 ring polycyclic aromatic hydrocarbons (PAHs) and further fractionation of this suggested that the parent 4–6 ring PAHs were responsible for more than half the activity of the intact oil, despite being present at only 0.06%. The fraction that contained polar compounds showed no activity. The reconstituted oil showed slightly less activity than the original oil. Other fractions, which contained alkylated PAHs, did not seem to have much activity. These findings, which are in close agreement with published evidence on tumour induction by fractions of oils and coal liquids, suggest that the components responsible for inducing nuclear enlargement are the same as those responsible for skin tumour induction. The results also suggest that estimates of carcinogenic activity made from analytical findings, such as the weight of DMSO extractable material, or even from the total 3–6 ring PAHs may be misleading as the main active components form such a small proportion of the material measured.
Alterations in xenobiotic metabolizing enzymes in brain and liver of rats coexposed to endosulfan and malathion
Authors: Srikanth Nadadur S. , Seth Prahlad K.
Published: October 2006

The effects of endosulfan (3 mg kg−1 body wt., i.p.) and malathion (30 mg kg−1 body wt.) and their coexposure on rat hepatic and brain xenobiotic metabolizing enzymes were investigated. Endosulfan was found to induce aminopyrine‐n‐demethylase (81%) and aniline hydroxylase (59%) activities significantly in liver and to a lesser extent in brain. Malathion treatment induced malathion carboxylesterase activity in both liver (50%) and brain (22%), significantly depleted liver glutathione (35%) content with stimulation of glutathione‐S‐transferase (50%) and inhibited the activity of mixed‐function oxidases. In the coexposed animals, malathion's inhibitory influence on mixed‐function oxidases and endosulfan's inhibitory effect on malathion carboxylesterase were found to dominate, while endosulfan potentiated the activity of glutathione‐S‐transferase significantly in liver (69%) and brain. A similar trend of alteration in coexposed brain was found, but to a lesser extent. A significant inhibition in brain acetylcholine esterase activity (42%) in the coexposed animals suggests that endosulfan may potentiate the toxicity of malathion by interfering with glutathione and carboxylesterase routes of malathion detoxification.
Identification of contact allergens using the murine local lymph node assay: Comparisons with the buehler occluded patch test in guinea pigs
Authors: Kimber I. , Hilton J. , Botham P. A.
Published: October 2006

A murine local lymph node assay has been developed for the identification of contact sensitizing chemicals. In the present study, the performance of the local lymph node assay has been evaluated with twenty‐four coded chemicals of previously unknown skin sensitizing potential and the results compared with predictions made from concurrent occluded patch tests (Buehler tests) in guinea pigs. The data presented demonstrate that the local lymph node assay successfully identified those chemicals that were classified'as moderate or strong skin sensitizers in the Buehler test. In the present series of experiments, chemicals predicted to be mild sensitizers in the Buehler test were classified as not strong sensitizers' in the local lymph node assay. In the majority of instances, the Buehler test and local lymph node assay were in agreement with regard to the identification of non‐sensitizing chemicals. However, two chemicals that were classified as non‐sensitizers in the guinea pig test exhibited positive responses in the local lymph node assay and were predicted to be sensitizers. Some coloured chemicals resulted in obscured Buehler readings and, here, assessment was based upon histological examination of the challenge site. These compounds were examined also in the local lymph node assay and similar predictions of sensitizing potential were made.

Taken together, the data reveal close, but not absolute, concordance between the local lymph node assay and the Buehler test. The relative merits of these predictive test methods are discussed.
Developmental toxicity of vanadium in mice after oral administration
Authors: Paternain J. L. , Domingo J. L. , Gómez M. , Ortega A. , Corbella J.
Published: October 2006

Vanadium, as vanadyl sulphate pentahydrate, was evaluated for its embryotoxic, fetotoxic and teratogenic potential in Swiss mice. The compound was administered by gavage to pregnant mice at doses of 0, 37.5, 75 or 150 mg kg−1 day−1 on days 6–15 of pregnancy. On gestation day 18, all live fetuses were examined for external, visceral and skeletal malformations and variations. Maternal toxicity was observed in the vanadium‐treated animals, as evidenced by reduced weight gain, reduced body weight on gestation day 18 (corrected for gravid uterine weight) and decreased absolute liver and kidney weights at 75 and 150 mg kg−1 day−1. The number of total implants, live and dead fetuses, late resorptions, the sex ratio and the post‐implantation losses were not significantly different between the vanadium‐treated mice arid the controls. However, there was a significant increase in the number of early resorptions per litter at all dose levels. Fetotoxicity was evidenced by lower fetal weights and fetal lengths, and the presence of developmental variations. Malformation incidence also was increased by the administration of vanadium. Thus, the no observable effect level' (NOEL) for maternal toxicity, embryofetotoxicity and teratogenicity for vanadyl sulphate pentahydrate under these test conditions was below 37.5 mg kg−1 day−1 for Swiss mice.
Haematological and hepatotoxic effects of isoprocarb in chicken
Authors: Rahman M. F. , Siddiqui M. K. J. , Mahboob M. , Mustafa M.
Published: October 2006

The haematological and hepatotoxic effects were studied after oral administration of Isoprocarb at 75, 112.5 and 150 mg kg−1 daily for 21 days in male and female chicken Gallus gallus domesticus (White Leghorns). The toxic effects as observed 10 or 21 days after medication include a statistically significant reduction in haemoglobin (Hb) content, haematocrit (Ht), protein and serum glutamate pyruvate transaminase (SGPT), and an increase in glucose, serum glutamate oxaloacetate transaminase (SOOT) and serum acid phosphatase (SAP) activities of male and female chicken. The changes in other haematological parameters were generally insignificant, except for one or two doses in RBC, WBC, mean corpuscular haemoglobin concentration (MCHC) and chloride. A significant inhibition of RBC acetylcholinesterase was noticed after 21 days of dosing only at the high dose (150 mg kg−1) in hens. The decrease in food intake and body weights of males and females indicated the overt signs of toxicity. In addition to haematological alterations, the results suggest both hepatotoxic and stress effects and pinpoint that these early biochemical changes induced by Isoprocarb may be predictive of pesticide toxicity.
Comparative study of toxic lead effect on gill and haemoglobin of tilapia fish
Authors: Tabche L. M. , Martinez C. M. , Sanchez‐Hidalgo E.
Published: October 2006

This study was designed to determine the 72‐h LC50 of lead for tilapia fish (Oreochromis hornorum), as well as the effect of exposure to sublethal lead concentrations (15, 23, 31, 39 and 47% of the LC50) on gill tissue lysosomal membranes of the fish and the haemoglobin concentration in blood. The LC50 value was found to be 202 mg Pb2+ l−1. Exposure to sublethal lead concentrations for 72 h showed significant increases in the lability of gill lysosomal membranes, measured by the release of acid phosphatase. Changes in membrane lability and in haemoglobin concentration were dependent on the amount of lead used during the exposure. We considered that the membrane lability is an adequate parameter to assay for monitoring lead contamination in water, because it is more sensitive than the haemoglobin concentration in blood.