bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity of adenosine triphosphatases in different brain regions to polychlorinated biphenyl congeners
Authors: Maier William E. , Kodavanti Prasada Rao S. , Harry G. Jean , Tilson Hugh A.
Published: October 2006

Polychlorinated biphenyl (PCBs) mixtures contain a number of different congeners, some of which have been proposed to be neuroactive. Recent studies have suggested that ortho‐substituted PCBs may be neuroactive, while ‘dioxin‐like’ non‐ortho‐substituted congeners are not. This study compared the in vitro effects of a putative neuroactive ortho‐biphenyl (2,2′‐dichlorobiphenyl; DCBP) with that of a putative non‐neuroactive congener lacking ortho‐chlorine substitutions (3,3′,4,4′,5‐pentachlorobiphenyl; PCBP) on Mg2+‐ATPase activity in mitochondrial and synaptosomal preparations from striatum, hypothalamus, cerebellum and hippocampus. In these studies, DCBP significantly inhibited oligomycin‐sensitive (OS) Mg2+‐ATPase activity in all four brain regions in a concentration‐dependent manner; PCBP, on the other hand, had no effect on OS Mg2+‐ATPase activity in any brain region examined at concentrations up to 100 μM. The striatum, a dopamine‐rich region, was not preferentially sensitive to the effects of DCBP. Furthermore, DCBP did not inhibit synaptosomal Na+/K+‐ATPase activity, suggesting a specificity of action on OS Mg2+‐ATPase. These data support previous structure‐activity relationships, suggesting that ortho‐substituted PCB congeners are neuroactive while non‐ortho‐substituted congeners are not. Disruption of mitochondrial oxidative energy production may play a role in the neuroactivity of ortho‐chlorinated PCBs.
Carcinogenic evaluation of 2,3‐dimethyl‐2,3‐dinitrobutane via the mouse skin bioassay
Authors: Reddy Tirumuru V. , Daniel F. Bernard , Robinson Merrel , Olson Greg R.
Published: October 2006

Female SENCAR mice initiated with 2,3‐dimethyl‐2,3‐dinitrobutane (DMDNB) and promoted with 12‐Otetradecanoylphorol‐13‐acetate (TPA) via the SENCAR mouse skin bioassay did not exhibit a significant increase in skin tumors. The mice received 20 mg kg−1 DMDNB divided into six intragastric doses over 2 weeks and were promoted three times per week for 20 weeks.
28‐day inhalation study of a cross‐linked polyacrylate superabsorbent in the Hamster
Authors: McGrath James J. , Purkiss Laquetta , Eberle Mary , McGrath W. R.
Published: October 2006

Male and female Syrian Golden hamsters (20 of each sex) breathed respirable cross‐linked polyacrylate dust (0.3, 1.0 or 10 mg m−3) for 6 h a day, 5 days a week for 28 exposures. More than 99% of the particles were 3–4 μm or smaller. No differences in overall health or body weight were observed among the groups, nor were there deaths during exposure or during the post‐exposure period.

In animals killed within 24 h after the final exposure, foreign material was detected in the lungs in a doserelated manner. In animals examined 4 weeks post‐exposure, much of this material had been cleared from the lungs. There was a significant alveolar macrophage and a non‐significant inflammatory cell response following exposure; both responses appeared to decrease during the post‐exposure period. There was no evidence of fibrosis in the low‐ or medium‐exposure groups after the exposure or post‐exposure periods. In the high‐exposure group there was equivocal evidence of fibrosis in one set of lungs at the end of the exposure and in another set after the post‐exposure period.

These results indicate that subacute exposure of Syrian Golden hamsters to low concentrations of cross‐linked polyacrylate dust in particle sizes capable of reaching deep lung structures does not cause pulmonary fibrosis in the hamsters and that resolution of the cellular response induced by these particles occurs. These results also indicate that the test material was cleared from the lung following termination of exposure.
The local lymph node assay: An interlaboratory evaluation of Interleukin 6 (IL‐6) production by draining lymph node cells
Authors: Dearman R. J. , Ramdin L. S. P. , Kimber I. , Scholes E. W. , Basketter D. A.
Published: October 2006

The murine local lymph node assay is a predictive method for the identification of skin‐sensitizing chemicals in which activity is measured as a function of proliferative activity induced in lymph nodes draining the site of exposure. In the present study, the induction by topically applied chemicals of draining lymph node cell (LNC) production of the cytokine interleukin 6 (IL‐6) has been evaluated as an alternative endpoint for the local lymph node assay. In addition, results derived from studies of IL‐6 production by LNC performed independently in two separate collaborating laboratories have been compared. Of the nine skin sensitizing chemicals examined, six provoked detectable levels (>150 pg ml−1) of IL‐6 production by draining LNCs (as measured by enzyme‐linked immunosorbent assay) following exposure of mice to at least one test concentration of the material in both of the laboratories. Three other sensitizing chemicals failed to induce measurable IL‐6 production at any test concentration in either one or both of the participating laboratories. Both of the non‐sensitizing chemicals evaluated (sodium lauryl sulphate and methyl salicylate) also failed to result in detectable IL‐6 synthesis. There was a high level of agreement between the two laboratories. The rank order of chemicals with respect to IL‐6 production by LNCs was identical in both cases, as was the dose‐response relationship observed with each test material.

These data reveal that, although inducible IL‐6 production by draining LNCs provides a robust approach to the measurement of strong sensitizing activity, as performed here the method is of insufficient sensitivity for the routine identification of skin allergens.
Woodworkers' exposure to tannins
Authors: Bianco M.‐A. , Savolainen H.
Published: October 2006

The tannin concentration of hard‐ and soft‐wood dust was determined in dust powder and in samples on filters. It varied from 1.6 ± 0.3 mg g−1(± SD) for fir, which is a soft wood, to 80 ± 30 mg g−1(± SD) for oak, which is a hard wood. The low detection limit of the spectrophotometric method (1.5 μg per sample) made the analysis possible with no interference from cellulose ester filters. In five woodworking shops the concentrations of the total dust varied from 0.2 to 20 mg m−3, while those of tannins varied from 2 to 341 μg m−3. As hard woods like oak or mahogany have a higher tannin concentration than soft woods, tannin concentration analysis in wood dust can be used as an indicator of exposure to hard‐wood dust.
Early hepatic changes induced by nuarimol in rats
Authors: Kostka Grazyna , Palut Danuta , Kopeć‐Szlȩzak Joanna
Published: October 2006

It is commonly believed that in short‐term tests hepatic cytochrome P‐450b inducers stimulate liver enlargement and mitogenesis in the absence of overt hepatotoxic effects. In this investigation male Wistar rats received naurimol (an organochlorine pesticide) in one, three and five oral doses of 31.5, 62.5 and 125 mg kg−body wt. day−, whereupon the effects on liver were determined. The early effects were dose‐dependent increases in p‐nitroanisole metabolism, hepatocyte proliferation (DNA synthesis and mitotic activity) and liver weight. Five administrations of the lowest does (31.5 mg kg−1body wt. day−1) did not change liver weight, despite increased p‐nitroanisole metabolism and hepatocyte proliferation. In contrast to p‐nitroanisole metabolism and hepatomegaly, proliferation was only transient and disappeared even when treatment continued. The increase in binuclear hepatocytes and signs of necrosis suggested that the hepatomitogenic effect of nuarimol reflected a regenerative response, which may simulate the proliferation caused by partial hepatectomy.
Effects of lead loads on branchial osmoregulatory mechanisms in the rainbow trout Oncorhynchus mykiss
Authors: Sola François , Masoni Armand , Isaia Jacques
Published: October 2006

Exposure of rainbow trout to lead chloride (PbCl2, 1 ppm) in fresh water killed all animals within 16 days. Exposure to this lethal dose for 6 days only showed a significant increase in the haematocrit. Calcium, sodium and chloride concentrations in plasma were not notably modified. Both the influx and the net flux of sodium fluctuated much less than the diffusional water fluxes through secondary lamellae in gills. Branchial Na,K‐ATPase, Ca‐ATPase and HCO3‐ATPase activities were not sensitive to lead toxicity. Lead caused a cellular ‘wave‐shaped’ degeneration and renewal with modification in the number and morphology of chloride cells. Results are discussed in relation to the hydromineral balance of the trout.
Effect of protein malnutrition on the neurobehavioural toxicity of styrene in young rats
Authors: Khanna Vinay K. , Husain Raushan , Seth Prahlad K.
Published: October 2006

Neurotoxic effects of styrene on certain biochemical and behavioural indices were studied in young rats kept deficient in protein during the weaning period. Young rats fed a low‐protein diet showed a significant decrease in the level of dopamine and an increase in frontocortical [3H]serotonin binding in comparison to the group of rats fed a normal protein diet. These rats also showed a significant increase in foot shock‐induced aggressive behaviour, while no changes in amphetamine‐induced locomotor activity, levels of norepinephrine and serotonin and binding of [3H]spiperone to striatal membrane were observed. On exposure to styrene, rats fed a normal protein diet showed a decrease in dopamine level and an increase in foot shock‐induced aggressive behaviour only, with no significant change in other parameters, in comparison to the respective controls. It was, however, interesting to note that when rats fed a low‐protein diet were exposed to styrene they showed a significant decrease in the levels of norepinephrine, dopamine and serotonin and an increase in the binding of [3H]spiperone and [3H]5‐HT to striatal and frontocortical membranes, respectively. A significant increase in foot shock‐induced aggressive behaviour and amphetamine‐induced locomotor activity was also observed in this group of animals in comparison to those fed a low‐protein diet. The biochemical and behavioural data indicate that protein deficiency makes young animals more vulnerable and it is an important predisposing factor in the neurobehavioural toxicity of styrene.
Nickel hydroxy carbonate increases tumour necrosis factor alpha and interleukin 6 secretion by alveolar macrophages
Authors: Arsalane Karim , Gosset Philippe , Hildebrand Harmut F. , Voisin Cyr , Tonnel André‐Bernard , Wallaert Benoit
Published: October 2006

The aim of the current study was to assess the in vitro effects of nickel hydroxy carbonate (NiHC) at noncytotoxic concentrations on the production of cytokines such as tumour necrosis factor alpha (TNF‐α) and interleukin 6 (IL‐6) in alveolar macrophages (AMs). The effect of NiHC was evaluated in both unstimulated AMs and cells activated by lipopolysaccharide (LPS). Cytotoxicity was related to lactate dehydrogenase release and ATP cell content. The results confirm that NiHC at concentrations of 0.125, 1.25 and 3.125 μg NiHC 10−6 cells was not cytotoxic. The NiHC exposure of unstimulated AMs significantly increased the release of TNF‐α at all concentrations and that of IL‐6 at 1.25 μg NiHC 10−6 cells. LPS addition significantly increased the secretion of both cytokines. However, NiHC did not cause a significant increase in the release of TNF‐α and IL‐6 in LPS‐stimulated cells. In conclusion, the ability of NiHC to activate AMs and to release increased amounts of pro‐inflammatory mediators may be responsible, at least partly, for inflammation and pneumotoxicity associated with nickel exposure.
Two‐generation reproduction study on commercial hexane solvent
Authors: Daughtrey Wayne C. , Neeper‐Bradley Teresa , Duffy Jeffrey , Haddock Linda , Keenan Thomas , Kirwin Carroll , Soiefer Andrew
Published: October 2006

The reproductive effects of inhalation exposure to commercial hexane vapors were evaluated in Sprague‐Dawley rats. Males and females were exposed to commercial hexane vapor at target concentrations of 0, 900, 3000 or 9000 ppm for 6 h a day, 5 or 7 days a week, over two generations. In addition to pre‐breed exposures of 10 weeks' duration, exposures continued through mating, gestation and lactation. At both the F0 breed to produce F1 litters and the F1 breed to produce F2 litters, reproductive parameters were unaffected by commercial hexane exposure. The mating, fertility and gestational indices, as well as litter size and postnatal survival, were not significantly different between exposure groups. However, reductions in body weight and body weight gain were observed in both F1 and F2 litters exposed to 9000 ppm. Effects on body weight were not observed in offspring exposed to the two lower concentrations of commercial hexane. Histopathological examination of selected tissues revealed hyaline droplet nephropathy in adult F0 and F1 males exposed to 9000 ppm. This finding was anticipated and is not believed to be relevant for the assessment of human health effects. No other treatment‐related histopathological lesions were observed. Thus, exposure of rats to commercial hexane for two generations resulted in reduced body weight gains at 9000 ppm but no adverse effects on reproduction. These findings suggest that occupational exposure to commercial hexane vapors at currently recommended threshold limit value concentrations (i.e. TLV for n‐hexane is 50 ppm and TLV for other hexane isomers is 500 ppm) should not pose a reproductive hazard.
Retention of inhaled hexafluorocyclobutene in the rat
Authors: Maidment M. P. , Rice P. , Upshall D. G.
Published: October 2006

Hexafluorocyclobutene (HFCB), a cyclic analogue of perfluoroisobutene (PFIB), is a reactive gas that induces a fulminating pulmonary oedema in rats from which animals may die after an apparently asymptomatic period between 24 and 30 h, depending on the dose. To determine the dose of inhaled gas to the respiratory tract, the retention of HFCB has been determined in the rat at three inhaled concentrations with simultaneous measurement of respiratory parameters.

Rats exposed continuously to HFCB retained 25%, 19% and 16% of the inhaled dose after exposure to 1.2, 6 and 30 ppm, respectively, which fell to 24%, 17% and 9% at 30 min and 21%, 16% and 6.5% after 1 h. The rate of uptake of HFCB decreased markedly at the highest concentration from 200 to 112 nmol min−1 kg−1 after 30 min and to 90 nmol min−1 kg−1 after a further 30 min. Ventilatory parameters were unchanged throughout the experiment and there was no evidence of pathological or histopathological damage at the end of the exposure.

On renewal of exposure to gas after a 15‐min pause, the percentage of gas retained was unchanged from that determined previously.

The results indicate that there is a saturable component within the respiratory tract that is both time and concentration dependent. Hexafluorocyclobutene does not produce direct pathological damage outside the lung, which indicates that it may react rapidly with tissue components within the lung.
Comparison of the sensory irritation response in mice to chlorine and nitrogen trichloride
Authors: Gagnaire F. , Azim S. , Bonnet P. , Hecht G. , Hery M.
Published: October 2006

The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 60‐min oronasal exposure to increasing concentrations of chlorine and nitrogen trichloride. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each chemical. Chlorine and nitrogen trichloride showed dissimilar concentration‐response curves. While the maximal response of nitrogen trichloride was reached in 10 min, the maximal response of chlorine was reached between 45 and 60 min of exposure. The results showed both chemicals to have an irritant potency of the same order of magnitude. The RD50 values of chlorine and nitrogen trichloride were 3.5 and 2.5 ppm, respectively. On the basis of a TLV‐STEL (threshold limit value for short‐term exposure limit) equal to 0.1 RD50 and a TLV‐TWA (time‐weighted average) equal to 0.03 RD50, the current TLVs for chlorine seem too high (1 and 0.5 ppm, respectively) and should be reduced to 0.5 and 0.1 ppm, respectively. For nitrogen trichloride, 0.3 ppm and 0.1 ppm are proposed as TLV‐STEL and TLV‐TWA, respectively.
Toxicological evaluation of 1‐chloroacetophenone and dibenz[b,f]‐1,4‐oxazepine after repeated inhalation exposure in mice
Authors: Kumar Pravin , Flora S. J. S. , Pant S. C. , Sachan A. S. , Saxena S. P. , Gupta S. Das
Published: October 2006

Toxicological evaluation was made on the effects of two peripheral sensory irritants (tear gases): 1‐chloroacetophenone (CN) and dibenz[b,f]‐1,4‐oxazepine (CR). Animals had a 15‐min daily inhalation exposure to average vapour concentrations of 87.6 mg CN m−3 or 1008 mg CR m−3 (both equal to 0.05 LC50) for 5 or 10 days and were sacrificed 24 h after the last exposure, when biochemical and histopathological observations were made. Both chemicals caused a significant decrease in body weight gain. Histological changes in lung, liver and kidneys were more severe after 10 than after 5 days of exposure and were more severe in CN‐exposed than in CR‐exposed mice. Organ weight to body weight ratios remained normal except for the spleen to body weight ratio, which decreased in CN‐exposed mice after both 5 and 10 days of exposure. Biochemical indicators showed a toxic response only in CN‐exposed mice, but the only consistent change was an increase in blood glucose. Hepatic alkaline phosphatase was not influenced, malondialdehyde concentration and acid phosphatase activity were increased only after 5 days of exposure and liver GSH concentration decreased after 10 days of exposure. Results indicate that CN is not only more toxic than CR in absolute terms but is also more toxic at the 5% level of their LC50.
Effect of chemical form, route of administration and vehicle on 3,5‐dichloroaniline‐induced nephrotoxicity in the fischer 344 rat
Authors: Lo Herng‐Hsiang , Valentovic Monica A. , Rankin Gary O. , Brown Patrick I.
Published: October 2006

Chloroanilines are widely used chemical intermediates for the manufacture of dyes, agricultural chemicals and industrial compounds. Nephrotoxicity occurs as one toxicity following intraperitoneal (i.p.) administration of chloroaniline hydrochlorides to rats. The purpose of this study was to examine the effect of chemical form, route of administration and vehicle on 3,5‐dichloroaniline‐induced nephrotoxicity. In one set of studies, male Fischer 344 rats (four to eight per group) were administered a single i.p. injection of 3,5‐dichloroaniline free base or hydrochloride salt, cysteine hydrochloride or ornithine hydrochloride (0.8, 1.0 or 1.5 mmol kg−1) or an appropriate vehicle and renal function monitored for 48 h. Only 3,5‐dichloroaniline hydrochloride induced nephrotoxicity that was characterized as acute renal failure. When 3,5‐dichloroaniline free base (0.8 mmol kg−1) was administered in dimethyl sulfoxide (DMSO), all rats died within 24 h. In a second experiment, the free base or hydrochloride form of 3,5‐dichloroaniline (1.5 mmol kg−1) or vehicle (0.9% saline or sesame oil, respectively) were administered orally and renal function monitored for 48 h. No evidence of nephrotoxicity was observed following either treatment. However, when the hydrochloride salt was given in 25% DMSO in 0.9% saline, all rats died within 24 h, with two rats demonstrating increased proteinuria, glucosuria and hematuria within the first 6 h after treatment. These results demonstrate that 3,5‐dichloraniline nephrotoxicity is potentiated by the administration of systemic acid, but that acid alone has no effect on renal function at the dose tested. Also, 3,5‐dichloroaniline (hydrochloride or free base form) is less toxic orally than when administered i.p. In addition, when DMSO is used as part of the vehicle, 3,5‐dichloroaniline toxicity is potentiated. Thus, chemical form, route of administration and vehicle are all important factors in 3,5‐dichloroaniline‐induced toxicity.
Role of lipid peroxidation in biliary obstruction in the rat
Authors: Muriel Pablo , Suarez Oscar R.
Published: October 2006

There is poor evidence about the participation of lipoperoxidative processes in liver damage induced by biliary obstruction, thus the aim of this work was to study the role of lipid peroxidation in this model of liver injury. Biliary obstruction was induced in male Wistar rats by ligation of the common bile duct; control animals were sham operated. Rats were sacrificed at different times after surgery. Liver sections were used for glycogen and lipoperoxidation quantification. Markers of liver damage were determined in serum. All serum markers of liver damage increased after 1 day of biliary obstruction. Liver glycogen content decreased 1 day after surgery. On the other hand, lipoperoxidation increased later than markers of liver damage, suggesting that it is a consequence rather than the cause of liver injury. Moreover, administration of colchiceine (a good free‐radical scavenger) or vitamin E prevented lipoperoxidation but not liver damage, confirming that lipoperoxidation does not play an important role in liver damage induced by biliary obstruction. This model of liver injury seems to be useful for testing hepatoprotective drugs that do not act as free‐radical scavengers.
Toxicological evaluation of μ‐agonists part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo‐alpha‐acetylmethadol HCl (LAAM)
Authors: Borzelleca Joseph F. , Egle John L. , Harris Louis S. , Johnson David N. , Terrill James B. , Belleville Jo Ann Nuite
Published: October 2006

This study evaluated levo‐alpha‐acetylmethadol hydrochloride (LAAM), a long‐acting morphine‐like (μ) agonist approved in 1993 to treat opiate dependence. Sprague‐Dawley rate (20/sex/group) were gavaged with doses of 3.0–33.5 mg kg−1 for 30 days followed by a 14‐day drug‐free recovery period. Treatment‐related effects included dose‐dependent CNS depression, decreased food consumption and body weight gain, reddish urine and abdominal staining. Tolerance developed by day 7. Mortality was dose‐dependent; deaths occurred predominantly during the first week. Increased alanine aminotransferase (SGOT, AST) and lactate dehydrogenase (LDH), observed only in high‐dose males, were associated with findings in liver. Decreases in spleen/brain weight and increases in brain/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for high‐dose groups. Kidneys of mid‐ and high‐dose groups displayed intertubular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high‐dose males and mid‐ and high‐dose females. Following the recovery period, decreased body weights and increased brain/body weight ratios occurred in mid‐dose males and low‐dose females. Weights of liver and kidney and organ/brain weight ratios were decreased in mid‐dose males. Histopathological findings observed in kidneys and livers had abated.

In summary, acute and repeated administration of LAAM produced a spectrum of activity consistent with its profile as a long‐acting pure μ‐agonist which stimulates microsomal enzymes in rodents. Renal and hepatic effects seen in initially drug‐naive rats treated with morphine‐type agonists are not observed in tolerant individuals stabilized on μ‐agonists to treat opiate dependence.
Determination of free malonaldehyde formed in liver microsomes upon CCl4 oxidation
Authors: Ichinose T. , Miller M. G. , Shibamoto T.
Published: October 2006

Free malonaldehyde formed in the microsomes prepared from livers of monkey, rat, rabbit, mouse, cow, pig, dog, sheep and horse upon CCl4 oxidation was derivatized by reaction with N‐methylhydrazine to form 1‐methylpyrazole which was subsequently analyzed by capillary gas chromatography. Among the livers from animals tested, the monkey and rat livers produced the most malonaldehyde upon CCl4 treatment. Horse liver showed the greatest resistance to CCl4 oxidation. The gas chromatography method used in the present study exhibited an accurate and specific measurement of free malonaldehyde that might provide an understanding of the biochemical process of in vitro lipid peroxidation.
Effect of palytoxin on endothelium‐dependent and ‐independent relaxation in rat aortic rings
Authors: Taylor Thomas J. , Smith Neil C. , Langford Michael J. , Parker Gerald W.
Published: October 2006

Endothelium‐intact rat aortic rings were incubated with palytoxin (PTX, 10−11–10−9M, 10 min) in oxygenated (O2 95%, CO2 5%) baths. Phenylephrine (PE)‐contracted vascular rings demonstrated decreasing relaxation to acetylcholine (ACh), depending upon PTX incubation in a dose‐dependent manner; however, sodium nitroprusside (NaNP) persisted in returning the ring to its pre‐PE tension. After incubation with PTX, relaxation to the receptor‐independent, endothelium‐dependent relaxant A23187 was also attenuated. Thus, endothelium‐dependent mechanism(s) normally responsive to both ACh and A23187, stimulators of nitric oxide (NO) release, were disrupted. Following incubation with PTX, endothelium‐independent relaxation to NaNP remained intact but relaxation to atriopeptin II (APII) decreased. Electron microscopy demonstrated microvesiculation of endothelial cell cytoplasm and an irregular luminal surface following incubation with PTX. The intact response to NaNP, despite the loss of relaxation to ACh, indicated that soluble guanylate cyclase was not affected by PTX. However, loss of relaxation to AP‐II, involving particulate guanylate cyclase of vascular smooth muscle (VSM), was inhibited by PTX pre‐incubation. Determination of the site(s) of action of PTX requires further study.
Use of a head dome system to compare i.v. methacholine‐induced bronchoconstriction in conscious vs anesthetized rhesus monkeys
Authors: Allen D. L. , Pollard K. R. , Hughes B. L. , Dorato M. A. , Wolff R. K.
Published: October 2006

The use of a newly developed head dome system has allowed measurement of pulmonary function in conscious monkeys. Such information is often desired, so that pharmacological or toxicological effects of administered compounds can be measured in the absence of effects from anesthetic agents. The current study was conducted to gain experience with this method and to allow the determination of the effects of sodium pentobarbital anesthesia (30 mg kg−1 i.v.) on the bronchoconstriction seen during i.v. infusion of methacholine in rhesus monkeys. Bronchoconstriction was measured as changes in respiratory resistance using a Buxco LS20 pulmonary mechanics computer. Four male rhesus monkeys (4.2–5.1 kg) were used. For the anesthetized exposures, the animals were intubated with a 4.0‐mm cuffed endotracheal tube attached to a size ‘O’ Fleisch pneumotachograph. For the conscious exposures, the animals sat in restraining chairs with a custom‐built head dome attached to the same pneumotachograph. In both cases, transthoracic pressure was monitored with an intrapleural catheter. Each monkey was infused with methacholine in stepwise doses, while anesthetized and conscious, until a 75% increase in respiratory resistance was seen. The ed50 values of 0.134 and 0.180 mg ml−1 methacholine were not significantly different in anesthetized vs conscious monkeys, respectively.
Red blood cell damage by wollastonite: in vitro study
Authors: Aslam M. , Arif M. J. , Rahman Q.
Published: October 2006

Asbestos is known to cause lung diseases in occupationally exposed workers. These properties have restricted its use. Industries have been exploring the possibility of other mineral fibres to replace the asbestos. In this direction, wollastonite has gained great attention owing to its high thermal resistance. In the present paper, the toxicity of three samples of Indian wollastonite was compared to that of chrysotile. Dust suspensions were added to the red blood cell suspensions to obtain a final dust concentration of 1.0–5.0 mg ml−1 in the system. The wollastonite varieties were found to have smaller haemolytic potential in human red blood cells than that of chrysotile in vitro. Chrysotile also was more effective in inducting peroxidative damage of polyunsaturated fatty acid (PUFA) than wollastonites in the present system. The peroxidative damage of PUFA and the haemolysis were both time and dose dependent. A higher value of malonaldehyde (a lipid peroxidation product) formation in low‐speed supernatant of haemolysate was observed than in the intact cells. As the free‐radical scavengers vitamin E and reduced glutathione prevent haemolysis and lipid peroxidation, these data are consistent with the involvement of lipid peroxidation in the haemolytic process.
Role of cellulose in wood dust‐induced fibrosing alveo‐bronchiolitis in rat
Authors: Tátrai Frzsébet , Adamis Zoltán , Böhm Ute , Merétey Katalin , Ungváry György
Published: October 2006

Our experiments suggest that in the development of plant dust‐induced fibrosing alveobronchiolitis—Scadding's fibrosing alveolitis—the cellulose content of plant dusts has a decisive aetiological role. Namely, the wood dust (pine) and the cellulose induced morphologically identical granulomatous inflammation and fibrosis, whereas the fibre‐free extract of wood dust did not cause pathological changes in the lungs. The induction of H2O2 and superoxide anion production, shown in vitro in leucocytes, probably has an important role in the development of fibrosis.
Relationship between oxygen‐induced alveolar macrophage injury and cell antioxidant defence
Authors: Aerts Colette , Wallaert Benoit , Gosset Philippe , Voisin Cyr
Published: October 2006

Exposure to hyperoxia causes alveolar macrophage (AM) injury. The present study investigates the roles of intracellular antioxidant enzymes and of glutathione in the protection of AMs against hyperoxia in a biphasic cell culture system in aerobiosis. The effect of normoxia or hyperoxia on the integrity of AMs was related to indices of cell injury (ATP cell content and lactate dehydrogenase release into culture medium) and cell mass (protein content of AMs). Antioxidant activities were measured in guinea‐pig AMs exposed to 95% O2 or to normoxia (control cells) for 3 days. A 3‐day AM culture in normoxia showed a significant decrease in protein and catalase, whereas ATP cell content, superoxide dismutase (SOD) (both Cu, Zn‐SOD and Mn‐SOD) and glutathione peroxidase (GPx) activities significantly increased. The content of reduced glutathione (GSH) did not change. Using the ATP content in AMs expressed as a cell injury index (CII), AM injury increased with increasing O2 exposure time (1 day: 13 ± 4.4%; 2 days: 34 ± 3.8%; 3 days: 40 ± 4.1%; 4 days: 55 ± 7.3%; 6 days: 87.5 ± 5.4%). Exposure to 95% O2 for 3 days was associated with a significant decrease in ATP cell content, protein, catalase and GSH to the total glutathione ratio, whereas SOD, GSH and total glutathione did not change significantly. The GPx activities increased significantly. There was no significant correlation between the AM CII and SOD or GPx content. In contrast, a significant correlation was observed between hyperoxia‐induced AM CII and catalase content (r = 0.71) and glutathione content (r = 0.71). Incubation of AMs with buthionine sulphoximine, a specific inhibitor of glutathione synthesis, significantly decreased the GSH content, whereas the ATP content and antioxidant enzyme activities in the AMs did not change. Reduction of intracellular GSH increased hyperoxia (50% O2)‐induced AM injury from 2.2 ± 6% to 53 ± 10.2%. Our results support the concept that regulation of cell GSH is an important mechanism of protection against hyperoxic injury.
Long‐term effects of a cross‐linked polyacrylate superabsorbent in the hamster
Authors: McGrath James J. , Purkiss Laquetta , Eberle Mary , McGrath W. R.
Published: October 2006

Male and female Syrian Golden hamsters breathed respirable (<10 μm) cross‐linked polyacrylate dust (0.3, 1.0 or 10 mg m−3) for 6 h a day, 5 days per week for 28 exposures and were then held for 42 and 46 weeks. The animals appeared healthy during and immediately following the exposure; there were no differences in body weight at any dose, nor were there any deaths.

Foreign material was detected in the lungs 42 and 46 weeks post‐exposure. There was a slight increase in alveolar macrophages, which appeared to be dose related, and there was a slight increase in inflammatory cells at the highest dose. There was no evidence of fibrosis in any group either 42 or 46 weeks post‐exposure.

The first animal (male, control) died 12 weeks post‐exposure and mortality increased from 21 weeks post‐exposure. The deaths were not dose related but were distributed equally across all groups and appeared to be part of the normal mortality patterns for hamsters.

These results indicate that repeated exposure of Syrian Golden hamsters to low concentrations of cross‐linked polyacrylate dust in particle sizes capable of reaching deep lung structures does not cause pulmonary fibrosis at a later time in the life‐cycle. When combined with our earlier results, these data indicate that the test material is continuously cleared from the lung following termination of the exposure.
Dose‐response relationship between total cadmium intake and prevalence of renal dysfunction using general linear models
Authors: Hochi Yasushi , Kido Teruhiko , Nogawa Koji , Kito Hideaki , Kito Hideaki , Shaikh Zahir A.
Published: October 2006

To determine the maximum allowable intake limits for chronic dietary exposure to cadmium (Cd), the dose‐response relationship between total Cd intake and prevalence of renal dysfunction was examined using general linear models considering the effect of age as a confounder. The target population comprised 1850 Cd‐exposed and 294 non‐exposed inhabitants of Ishikawa, Japan. They were divided into 96 subgroups by sex, age (four categories) cadmium concentrations in rice (three categories) and length of residence (four categories). As indicators of the cadmium‐induced renal dysfunction, glucose, total protein, amino nitrogen, β2‐microglobulin and metallothionein in urine were employed. General linear models were fitted statistically to the relationship among prevalence of renal dysfunction, sex, age and total Cd intake. Prevalence of abnormal urinary findings other than glucosuria had significant associations with total Cd intake. When total Cd intake corresponding to the mean prevalence of each abnormal urinary finding in the non‐exposed subjects was calculated using general linear models, total Cd intakes corresponding to glucosuria, proteinuria, aminoaciduria (men only) and proteinuria with glucosuria were determined to be ca. 2.2–3.8 g and those corresponding to prevalence of metallothioneinuria were calculated as ca. 1.5–2.6 g. The low‐molecular‐weight protein in urine was confirmed to be a more sensitive indicator of renal dysfunction, and these total Cd intake values were close to those calculated previously by simple regression analysis, suggesting them to be reasonable values as the maximum allowable intake of Cd.
Two‐generation reproduction toxicity study with isopropanol in rats
Authors: Bevan C. , Tyler T. R. , Gardiner T. H. , Kapp R. W. , Andrews L. , Beyer B. K.
Published: October 2006

A two‐generation reproduction toxicity study was conducted in rats with isopropanol. Thirty rats of each sex per group (P1) were dosed once daily by oral gavage with 0, 100, 500 or 1000 mg isopropanol kg−1 for at least 10 weeks prior to mating. Parental animals were mated within groups for up to 3 weeks. Parental females were dosed during mating, gestation and lactation; parental males were dosed during mating through delivery of their last litter sired. The P2 adults were selected from the F1 litters and were dosed for 10–13 weeks before mating to produce a single litter. Findings in the parental animals included increased lactation body weight gain in the mid‐ and high‐dose females, increased liver and kidney weights in the mid‐ and high‐dose groups of both sexes and centrilobular hepatocyte hypertrophy in some P2 males. There was also accumulation of hyaline droplets and other microscopic findings in the kidneys from the mid‐ and high‐dose P1 males and from all treated groups of the P2 males. Increased mortality was observed in the high‐dose F1 offspring during the early postnatal period, although no other clinical signs of toxicity were observed in the offspring of either generation. In addition, offspring body weight was reduced during the early postnatal period in the high‐dose F1 males and in the high‐dose F2 pups of both sexes. Eighteen out of 70 F1 weanlings in the 1000 mg kg−1 group died or were euthanized prior to P2 selection. No treatment‐related post‐mortem findings were observed in the offspring from either generation. A statistically significant reduction was observed in the male mating index of the high‐dose P2 males compared with that of the controls. However, no treatment‐related microscopic changes in reproductive tissues or biologically meaningful differences in other reproductive parameters were observed in adults of either generation. The no‐observed‐effect‐level (NOEL) for reproductive effects in this study, based on the reduced male mating index of the high‐dose P2 males, is 500 mg kg−1 day−1.
High fat diet and liver damage induced by biliary obstruction in the rat
Authors: Muriel Pablo
Published: October 2006

There is a great body of evidence linking a high fat diet with the formation of gallstones. However, the effect of fat per se on obstructive liver damage (not involving gallstone formation) has not been assessed. The aim of this work was to study the effect of a high fat diet on liver damage induced by bile duct ligation in rats. Male 21‐day‐old Wistar rats were divided into two groups: group 1 received standard Purina chow diet 5001 containing 4.5% fat, group 2 received Purina chow diet 5001 enriched with 33% pork fat. Animals were allowed food and water ad libitum for 5 weeks. Obstructive jaundice was induced by double ligation and division of the common bile duct. The animals were sacrificed 1 week after biliary obstruction. Control animals were sham operated. Serum bilirubins and alkaline phosphatase, γ‐glutamyl transpeptidase and glutamic pyruvic transaminase enzyme activities increased by biliary obstruction. Glycogen content decreased in the bile duct‐ligated rats. These effects were more important in the group fed a 33% fat diet. Our results show that a high animal fat diet increases liver damage in experimental biliary obstruction in rats. Owing to our experimental design (bile duct ligation), the effect of a high fat diet cannot be attributed to an increase in the formation of gallstones but a direct effect must be considered. The mechanism by which fat augmented liver damage can be associated with an increase of total bile content and its toxicity.
Decrease in hepatotoxicity by lead exposure is not explained by its mitogenic response
Authors: Calabrese Edward J. , Baldwin Linda A. , Leonard Denise A. , Zhao Xiao Qiang
Published: October 2006

The present research was conducted to evaluate the effect of mitogen pre‐exposure on CCl4‐induced hepatotoxicity. Male Wistar rats were administered a single i.p. injection of CCl4 (0.3 ml kg−1 in corn oil) 48 h following either a single dose of lead nitrate (0.33 mg kg−1) or distilled water via i.v. injection. Hepatotoxicity, as measured by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was monitored 6, 24, 48, 72 and 120 h after CCl4 exposure. The lead nitrate‐pretreated rats displayed markedly lower serum ALT and AST levels at 24, 48 and 72 h than rats pretreated with distilled water. However, treatment with the antimitotic agent colchicine did not alter the lead‐induced protection. These findings suggest that the lead‐induced protection is not associated with the major mitogenic response of lead, despite its strong temporal association. A critical review of the available toxicological data also argues against the lead protection being a function of its capacity to inhibit cytochrome P‐450.
Acute renal and hepatic effects induced by 3‐haloanilines in the fischer 344 rat
Authors: Rankin Gary O. , Valentovic Monica A. , Nicoll Derek W. , Ball J. G. , Anestis Dianne K. , Brown Patrick I. , Hubbard John L.
Published: October 2006

Haloanilines are commonly used as chemical intermediates in the manufacture of a wide range of products. The purpose of this study was to examine the in vivo nephrotoxic and hepatotoxic potentials of the 3‐haloanilines. The in vitro effects of the 3‐haloanilines on renal function were also examined. In the in vivo experiments, male Fischer 344 rats (four rats/group) were administered a single intraperitoneal (i.p.) injection of an aniline hydrochloride (1.0 or 1.25 mmol kg−1) or vehicle. Renal and hepatic function were monitored at 24 and/or 48 h post‐treatment. None of the 3‐haloanilines were potent nephrotoxicants at either dose level. The greatest effects on renal function were observed following administration of 3‐chloroaniline at a dose of 1.25 mmol kg−1 (oliguria, glucosuria, hematuria, decreased p‐aminohippurate accumulation by renal cortical slices and increased blood urea nitrogen concentration). 3‐Chloroaniline also was the only aniline compound to increase plasma ALT/GPT activity at 48 h. In the in vitro experiments, the ability of an aniline (10−5–10−3M) to decrease organic ion accumulation in renal cortical slices from untreated rats was examined. The decreasing order of in vitro nephrotoxic potential was 3‐iodoaniline > 3‐bromoaniline > 3‐chloroaniline > aniline > 3‐fluoroaniline. These results indicate that the 3‐haloanilines are not potent nephrotoxicants or hepatotoxicants at sublethal doses. In addition, the reasons why the 3‐haloanilines have different orders of nephrotoxic potential in vivo and in vitro are not clear at this time.
Potency ranking of methemoglobin‐forming agents
Authors: French C. L. , Yaun S.‐S. , Baldwin L. A. , Leonard D. A. , Zhao X. Q. , Calabrese E. J.
Published: October 2006

This study represents the first systematic attempt to rank methemoglobin‐forming agents. It is a quantitative potency ranking study utilizing linear regression analysis of dose‐response data for comparative purposes. Six agents that are direct‐acting and eight that require bioactivation were tested for their ability to induce methemoglobin formation in Dorset sheep erythrocytes under defined in vitro conditions. The agents were then ranked according to three complementary methods based on the slope of the linear regression, the calculated dose expected to induce a given amount of methemoglobin formation and the calculated percentage methemoglobin response induced by 1 mmol 1−1 of the agent. The direct‐acting agents, ranked from most to least potent inducers of methemoglobin formation, are: p‐dinitrobenzene > o‐dinitrobenzene > copper = nitrite > chlorite > chlorate. The ranking from most to least potent inducers of the bioactivated agents are: α‐naphthol > p‐nitroaniline > m‐nitroaniline, o‐nitroaniline > p‐nitrotoluene = aniline > m‐nitrotoluene = o‐nitrotoluene. The ranking procedures are discussed and issues of interindividual variation and agent‐specific sensitivities are addressed.
Monoisoamyl and mono‐n‐hexyl meso‐2,3‐dimercaptosuccinate in mobilizing 203hg retention in relation to age of rats and route of administration
Authors: Kostial K. , Blanuša M. , Piasek M. , Prester Lj. , Jones M. M. , Singh P. K.
Published: October 2006

Monoisoamyl (Mi‐ADMS) and mono‐n‐hexyl (Mn‐HDMS) monoesters of meso‐2,3‐dimercaptosuccinic acid (DMSA) were given orally or parenterally for the mobilization of inorganic mercury in suckling and older rats. Chelators were administered at a dose of 2 × 0.5 mmol kg−1 on two consecutive days 2 weeks after a single 203Hg injection. Six days later, whole‐body, kidney, liver and brain radioactivities were determined in gamma scintillation counters.

Both Mi‐ADMS and Mn‐HDMS were found to be superior to DMSA in mobilizing mercury from body and organs. The results were similar after oral or parenteral treatment. The efficiency of both monoesters was even higher in younger than in older rats. This is the first report on the mobilization of mercury from the body of sucklings under conditions of late oral treatment.
Histopathological changes in the respiratory tract of mice exposed to ten families of airborne chemicals
Authors: Zissu D.
Published: October 2006

The objective of this experimental work was to identify and compare the histopathological changes induced in the respiratory tract of Swiss mice exposed to repeated inhalation (4, 9 or 14 days) at typical concentrations of RD50, 0.3 × RD50 and 3 × RD50 of airborne chemicals. These substances were selected from ten chemical families: aldehydes, organic acids, alcohols, ketones, ethers, aromatic hydrocarbons, halogenated aromatic hydrocarbons, inorganic bases, amines and isocyanates.

These experiments showed that the lesion intensity observed in the nasal passages varied with exposure duration and type of airborne chemical, but did not depend on the concentration of the substance. Results did not allow us to establish a relationship between the histopathological changes and the type of chemical family. No injuries were observed in trachea and lungs.
Effects of zearalenone and/or tamoxifen on swine and mink reproduction
Authors: Yang H.‐H. , Aulerich R. J. , Helferich W. , Yamini B. , Chou K. C. , Miller E. R. , Bursian S. J.
Published: October 2006

Tamoxifen (TAM), which binds to estrogen receptors and can act as an estrogen antagonist, was incorporated into the diets of swine and mink to determine if it would ameliorate the effects of the estrogenic mycotoxin zearalenone (ZEN). Sows and female mink were fed diets containing 2 ppm (swine) or 20 ppm (mink) ZEN and/or 10 ppm TAM from day 30 of gestation through weaning (swine) or from 2 months prior to breeding through weaning (mink). The diets containing ZEN and/or TAM did not adversely affect reproduction in the sows. Although some hyperestrogenic effects on testes, uterine and ovarian weights were observed in the F1 piglets at 21 days of age, subsequent breeding performance was not affected. All the female mink exposed to ZEN mated, but only 25% whelped. No mink fed TAM (singly or in combination with ZEN) mated. Necropsy of these unmated females fed TAM revealed consistent severe pyometra. Histological examination of the reproductive tracts of the ZEN, TAM and ZEN + TAM‐treated mink showed similar alterations, including ovarian follicular atrophy and degeneration, and mild to severe uterine atrophy, pyometra and endometritis. The results of these studies indicate that TAM was not effective in ameliorating the hyperestrogenic effects of ZEN in swine and mink, but rather it acted as an estrogen agonist.