bluuebunny/crossref_metadata_2025 huggingface dataset:
Site of action of grayanotoxins in mad honey in rats
Authors: Onat Filiz , Yegen Berrak C. , Lawrence Roger , Oktay Ahmet , Oktay Sule
Published: October 2006

Grayanotoxins are known to occur in honey produced from the nectar of Rhododendrons of the family Ericaceae. Grayanotoxins extracted from honey sample obtained from a patient who experienced severe bradycardia and hypotension after ingesting two tablespoonfuls corresponded to Rhododendron ponticum tetrades. Anaesthetized albino rats were injected with honey extract intracerebroventricularly or intraperitoneally. The intracerebroventricular dose was equivalent to 50 mg honey and i.p. doses were equivalent to 50 mg, 1 mg kg−1 and 5 g kg−1 honey. Marked bradycardia and respiratory rate depression were observed in rats injected with extract equivalent to 1 and 5 g kg−1 honey i.p. and in rats injected with 50 mg i.c.v., but not in rats given 50 mg i.p. In bilaterally vagotomized animals, grayanotoxin‐contaminated honey extract was not bradycardic. These results suggest that the sites of cardiac and respiratory actions are within the central nervous system, and that the bradycardic effect of grayanotoxin is mediated by vagal stimulation at the periphery.
Biochemical toxicology of argemone oil. I. effect on hepatic cytochrome P‐450 and xenobiotic metabolizing enzymes
Authors: Upreti Kaushal K. , Das Mukul , Khanna Subhash K.
Published: October 2006

The in vivo effect of argemone oil on hepatic xenobiotic metabolizing enzymes was investigated in albino rats following either a single (10 ml kg−1 body wt.) or multiple intraparenteral doses (5 ml kg−1 body wt.) for three days. Animals sacrificed 72 h after a single intraparenteral dose of argemone oil exhibited a significant loss of hepatic cytochrome P‐450 (35%) and cytochrome bs (34%) contents and inhibition of aminopyrine‐N‐demethylase (APD), aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin‐O‐deethylase (ECD) activities (21–39%). Three successive 24‐hourly intraparenteral injections of argemone oil followed by sacrificing the animals after 24 h of the last injection, showed a greater degree of inhibition of the content of cytochrome P‐450 (58%) and its dependent mixed‐function oxidases (35–63%). Also, multiple treatment of argemone oil caused a depletion of endogenous hepatic glutathione (GSH) content (72%) with a concomitant increase in lipid peroxidation (177%) and decrease in glutathione‐S‐transferase (GST) activity (30%). A significant decrease in relative liver weight (39%) was observed in animals treated with multiple treatment of argemone oil. These results suggest that argemone oil can alter both membrane and cytosolic defences and destabilizes the hepatic cytochrome P‐450 dependent mixed‐function oxidase system, so that it tips in the direction of autooxidative peroxidation of lipids.
Early decreases in pulmonary, hepatic and renal glutathione levels in response to cadmium instillation into rat trachea
Authors: Iguchi Hiroshi , Ikeda Masayuki , Kojo Shosuke
Published: October 2006

After instillation of cadmium (Cd) into the rat trachea, reduced and oxidized glutathione (GSH and GSSG) levels in the lung, liver and kidney were studied in relation to Cd concentrations and metallothionein (Mt) contents. Rats instilled with Cd developed haemorrhagic pneumonia, which deteriorated with a marked swelling of the lung throughout the experimental period of 48 h. The total glutathione (GSH + GSSG) level in the organs decreased after 6 h to 60–70% of the control levels. The decreased glutathione level was never restored to the control level within 48 h in the lung, and was possibly due to the pneumonia. Completely recovered glutathione was seen in other organs. The GSSG level did not decrease significantly in the lung or liver but lowered significantly after 12 h and 24 h. The GSSG fraction in the amount of total glutathione was 10% or more in the lung and 5% or less in the liver or kidney. This finding indicated that the total glutathione level was mainly changed by the decrease in the GSH fraction. Cadmium in the lung increased to 7.3 ppm 3 h after Cd instillation and decreased to 2.5 ppm within 48 h. Cadmium in the liver and kidney gradually increased with time, and after 48 h reached 1.1 and 2.3 ppm, respectively. This indicated a transportation of Cd from the lung to these organs. Moreover, the early stage of Cd accumulation coincided with the total glutathione decrease in the organs. After Cd instillation, pulmonary, hepatic and renal Mt started to increase at 3 or 6 h, and markedly increased at 24 h or later. After 48 h, the Mt concentration was similar in both the lung and liver, but was 2.5‐fold higher than in the kidney. These increases appeared to depend on the time that elapsed after Cd instillation, and not on the Cd concentration or glutathione level in each organ. It appears that Cd initially acted to decrease the glutathione level in the organs and then caused Mt synthesis, because the glutathione level was decreased at an early stage of Cd accumulation and preceded an apparent increase in Mt synthesis.
Metabolic aspects of the toxicology of mixtures of parathion, toxaphene and/or 2,4‐D in mice
Authors: Chaturvedi Arvind K. , Kuntz David J. , Rao N. G. S.
Published: October 2006

The effects of mixtures of parathion (PA; 5 mg kg−1), toxaphene (TOX; 50 mg kg−1) and/or 2,4‐dichlorophenoxyacetic acid (2,4‐D; 50 mg kg−1) on the hepatic mixed‐function oxygenase (MFO) system were studied in ICR male mice (21–24 g) by oral intubation daily for 7 days. In general, TOX and TOX‐containing mixtures were found to induce the metabolism of amidopyrine (21–52%), aniline (58–72%), phenacetin (239–307%), pentobarbital (104–148%) and benzo[a]pyrene (143–304%) in the 9000 g liver supernatants and to increase the hepatic cytochrome P‐450 contents (57–80%). Furthermore, the TOX pretreatemnt was effective in enhancing the biotransformation of PA or paraoxon (PO) in the supernatants. This enhancement was not altered significantly by 5 mM EDTA. Although TOX increased the aliesterase activity in the serum and liver homogenates and supernatants by 31–158%, the activity of paraoxonase was not affected in these preparations. The TOX‐induced increase in the metabolism of PA or PO was, at least in part, associated with the MFO system, and paraoxonase did not have significant involvement in the increase. These findings suggest that the toxicity of the PA + TOX mixture would be lower than that of PA, as TOX has the ability to increase the biotransformation of PA, as well as of PO, and the levels of aliesterase, thereby providing a pool of non‐critical enzymes for the binding of PO. Because of these properties of TOX, it is anticipated that the toxicity of the PA + TOX + 2,4‐D mixture also would be lower than that of PA.
Altered developmental toxicity caused by three carrier solvents
Authors: Rayburn J. R. , Deyoung D. J. , Bantle J. A. , Fort D. J. , McNew R.
Published: October 2006

Many aquatic bioassays rely on chemical solvents to solubilize water‐insoluble test materials. Interactions between solvents and test materials can lead to false positive or negative results. For this reason, tests for interactions between solvents and test materials were performed. The Frog Embryo Teratogenesis Assay–Xenopus (FETAX) was chosen because of its capacity to assess three different endpoints; mortality, malformation and embryo growth. Three solvents–dimethylsulfoxide (DMSO), acetone and triethylene glycol (TG)–were tested with two teratogens–methylmercury chloride (MMC) and trichloroethylene (TCE). DMSO potentiated the lethal effect of both teratogens but did not alter significantly the rate of malformation. Acetone increased the mortality for both teratogens, but only increased the MMC malformation greater than the additive effects. TG only increased the mortality and malformation with TCE. There were additive effects for growth for all solvents with the teratogens. The carrier solvents caused interactions even at their no‐observable‐effect concentration (NOEC). Therefore, the choice of carrier solvent should be made with caution. This study shows that different results can occur depending on the solvent used, and that a difference in one endpoint does not necessarily change the other endpoints.
Possible involvement of 1,2‐diacetylbenzene in diethylbenzene‐induced neuropathy in rats
Authors: Gagnaire F. , Ensminger A. , Marignac B. , de Ceaurriz J.
Published: October 2006

The role of 1,2‐diacetylbenzene (1,2‐DAB) in the peripheral nerve toxicity of 1,2‐diethylbenzene (1,2‐DEB) was investigated in rats. Gas chromatography‐mass spectrometry identified 1,2‐DAB in the urine samples of rats given 165 mg kg−1 1,2‐DEB orally on four consecutive days. 1,2‐DAB shared not only the ability of 1,2‐DEB to cause bluish discoloration of skin, internal organs and urine, but unlike 1,2‐DEB it turned hair blue at the site of intraperitoneal injection.

Intraperitoneal administration of 10 mg kg−1 and 20 mg kg−1 1,2‐DAB to groups of 12 rats, 4 days a week for 11 and 6 weeks, caused a dose‐ and time‐dependent decrease in mean sensory and motor conduction velocities. Recovery in a 5‐week post‐exposure period was gradual but consistent. The effect of 1,2‐DAB on the amplitude of the sensory action potential was ambiguous.

The findings support the hypothesis that the formation of 1,2‐diacetylbenzene derivatives contributes to the neurotoxicity of 1,2‐DEB.
Influence of age and time of administration of dithiocarbamate analogues on cadmium retention in rats
Authors: Kargačin B. , Kostial K. , Arežina R. , Singh P. K. , Jones M. M. , Cikrt M.
Published: October 2006

In the present study the influence of age and time of chelation therapy on cadmium retention in 6‐, 11‐and 14‐day‐old rats and in 6‐week‐old rats has been investigated. Chelating agents N‐benzyl‐dithiocarboxy‐D‐glucamine (BDCG), sodium N‐(metho‐xybenzyl)‐D‐glucamine dithiocarbamate monohydrate (MeOBDCG) and N‐methyl‐N‐dithiocarboxy‐D‐glucamine (MDCG) were administered intraperitoneally to three different groups at a dose of 1 mmol kg−1 body weight on two occasions following 115mCd intraperitoneal administration; immediately and after 24 h; after 24 h and 48 h; or after 48 h and 72 h. The 115mCd retention in the whole body and organs was determined 6 days after cadmium administration. Chelation therapy very effectively reduced cadmium retention in the whole body and organs, MeOBDCG being the most effective. The effects of chelating agents were significantly more pronounced in older than younger animals and in the case of early rather than late administration. The highest fraction of cadmium administered was retained in the liver, where also the strongest effect of chelation therapy was observed. Mobilized cadmium was excreted almost exlusively by the faecal route.
Ni3S2 uptake by lung cells and its interaction with plasma membranes
Authors: Shirali P. , Decaestecker A. M. , Marez T. , Hildebrand H. F. , Bailly C. , Martinez R.
Published: October 2006

The uptake and biological transformation of Ni3S2 was studied on guinea pig alveolar macrophages (GPAM) in primary culture. Two different pathways are observed: (i) phagocytosis of αNi3S2 crystals and subsequent degradation to minute particles, which are recovered bound to the membranes of phagocytic vacuoles and to lysosomal membranes. These degradation products contain sulphur in very reduced quantities, as revealed by energy‐dispersive spectrometry (EDS). (ii) Extracellular degradation to regular round particles (0.1–0.2 μm) and irregular minute particles (10–30 nm). Round particles may enter the cell by pinocytosis and are characterized by the loss of sulphur. Minute particles are bound preferentially to cell membranes, to cytoplasmic organelles, such as endoplasmic reticulum, mitochondria and peroxysomes, to liposomes and to the euchromatinic part of nuclei. EDS analyses in these particles revealed the substitution of sulphur by phosphorus. This observation suggests the formation of an Ni–P complex with the phosphate groups of membranous and liposomal phospholipids and of the euchromatinic part of DNA or RNA. Steady‐state flourescence polarization analysis were carried out on GPAM and, for comparative purposes, on human embryonic pulmonary epithelial cells (L132 cell line). In both cell types they revealed a significant increase of membrane fluidity, induced either by desaturation of aliphatic chains or directly by the cleavage of fatty acid chains.
Carcinogenic effects of Bis(2,3‐dibromopropyl)‐phosphate in wistar rats
Authors: Takada Koichi , Naito Katsushi , Kobayashi Kazuo , Tobe Masuo , Kurokawa Yuji , Fukuoka Masamichi
Published: October 2006

Four groups of 40 Wistar rats of each sex per dose level were fed diets containing 0, 80, 400 or 2000 ppm of the magnesium salt of bis(2,3‐dibromopropyl)phosphate (Bis‐BP) for 24 months. A high incidence of tumours was induced, in both sexes, in the digestive system. Tumours included papillomas and adenocarcinomas of the tongue, oesophagus and forestomach, adenocarcinomas of the intestine and hepatocellular adenomas (neoplastic nodules) and carcinomas. Pre‐terminal mortalities were associated with an increased incidence of forestomach papillomas in both sexes, adenocarcinomas of the small intestine in male rats and increased incidence of hepatocellular carcinomas in females. The data suggest that Bis‐BP is a more potent proximate carcinogen than tris‐(2,3‐dibromopropyl)phosphate (Tris‐BP).
Copper‐induced non‐selective permeability changes in intracellularly perfused snail neurons
Authors: Kiss Tibor , Györi János , Osipenko Oleg N. , Maginyan Silva B.
Published: October 2006

The effect of extracellularly applied Cu2+ was studied on isolated intracellularly perfused Helix pomatia neurons. It was found that the Cu2+‐activated current (ICu) is biphasic and composed of overlapping outward and inward components. The outward component of ICu is the result of a blockade by Cu2+ of the steady‐state outward Cl− current. The inward component is assumed to flow through Ca2+‐activated non‐selective cationic channels. The washing‐out procedure resulted in a large inward current (Iw), which was composed of transient and steady‐state components. It is most likely that the activation of metabolic pumps is responsible for the transient component and the steady‐state component is the result of increased neuronal membrane permeability for Cl−. Moreover, both ICu and Iw were highly Ca2+ ‐ and temperature‐dependent processes. It is concluded that Cu2+ application resulted in complex permeability changes in the Helix pomatia neurons.
Cadmium accumulation in the lung, liver and kidney of mice and rats chronically exposed to cigarette smoke
Authors: Gairola C. Gary , Wagner George J.
Published: October 2006

Cigarette smoking constitutes a major source of cadmium exposure via inhalation in man. To determine how smoke exposure affects the organ distribution and accumulation of cadmium, male C57B1 mice and Sprague‐Dawley rats were exposed daily for 52–60 consecutive weeks to mainstream smoke from the University of Kentucky reference cigarettes (2R1) in a nose‐only exposure system. Exposed mice and rats averaged blood carboxyhemoglobin values of 17.7 and 7.2%, and a daily total particulate matter (TPM) dose of 7.2 and 3.2 mg kg−1 body wt. per exposure, respectively. These results suggested effective inhalation of smoke by the animals. The tissues were acid digested and analyzed for cadmium by atomic absorption spectrometry. Cadmum levels 5–6‐ and 2–3‐fold greater than control levels were detected in the lungs and kidneys, respectively, of exposed animals of both species. In contrast, the liver did not show increased cadmium levels in exposed mice or rats. The data suggest that low‐dose chronic inhalation exposure to cigarette smoke leads to highest cadmium accumulation in the lung, followed by the kidney, with minimal effects on cadmium levels in the liver.
Application of alkaline unwinding to analysis of strand breaks induced by bleomycin in hamster lung DNA in vivo
Authors: Huff Robin A. , Bevan David R.
Published: October 2006

Strand breaks in hamster lung DNA were analyzed following in vivo exposure to bleomycin. An alkaline unwinding procedure involving separation of single‐strand from double‐strand DNA by hydroxylapatite chromatography followed by fluorescence detection of DNA with bisbenzimide was adapted for these studies. Procedures were developed that allowed preparation of DNA from lungs of control animals with a relatively low amount of single‐strand DNA relative to double‐strand DNA. Time dependence of unwinding was demonstrated using samples that were damaged deliberately by brief probe sonication. To verify that residual bleomycin remaining in lungs at the time of sacrifice did not cause strand breaks during sample preparation, bleomycin was added to minced lung in vitro. Under these conditions, the ratio of single‐strand to double‐strand DNA was not increased significantly. Substantial strand breaks were produced in vivo at 15 min and 1 h following intratracheal instillation of bleomycin into hamsters, as evidenced by a 5–6‐fold increase in the ratio of single‐strand to double‐strand DNA relative to controls. The DNA damage appeared to be repaired within 1 day following exposure.
Diurnal exposure profile in rats from dietary administration of a chemical (doxazosin) with a short half‐life: Interplay of age and diurnal feeding pattern
Authors: Charuel C. , Comby P. , Monro A. M.
Published: October 2006

Doxazosin, an α‐adrenergic blocking agent, has a plasma half‐life in male rats of 1–2 h after i.v. administration. Plasma concentrations of doxazosin were measured in male rats receiving the drug mixed in the diet at dose levels from 5 to 40 mg kg−1. Samples taken at 4‐h intervals during the light (0700–1900) and dark phases revealed peak concentrations at 0400 which were only about three times higher than the trough concentrations observed ca. 12 h later. The 24‐h area under the curve (AUC) values increased disproportionately with dose and with age from 2 months up to 8 months of age; thereafter they were fairly stable to 24 months of age. This age‐related effect may have been due to a reduction in clearance and/or a change in the feeding pattern of the rats. Young rats consumed ca. 84% and old rats only 45% of their daily feed during the nocturnal (active) phase. Given the known diurnal rhythms in absorption, protein binding and enzyme metabolising activity, such a change in feeding pattern with age may have wider toxicokinetic implications.
Review of chemical and uv light‐induced melanomas in experimental animals in relation to human melanoma incidence
Authors: Ingram Andrew John
Published: October 2006

In a few epidemiological studies on oil refinery workers, a slight excess of melanoma incidence has been reported. To see if this might be linked to exposure to polycyclic aromatic hydrocarbons (PAHs) contained in refinery streams, a review of animal data on the relationship between PAH exposure, UV light and melanoma induction has been carried out and compared with human data.

This revealed that the highly carcinogenic PAH 7,12‐dimethylbenz[a]anthracene (DMBA) was capable of inducing melanomas in hamsters, mice and guinea pigs, but only under certain experimental conditions. Evidence suggested that other carcinogenic PAHs were unable to induce melanomas. As high dose levels of DMBA were generally required to produce melanomas, it was not considered that the amounts present in refinery streams would be sufficient to account for an increase in melanoma incidence in exposed workers.

This conclusion was substantiated by the failure of petroleum‐derived complex hydrocarbon mixtures to produce melanomas in animals or man and by drawing attention to the absence of any association between melanoma incidence and the incidence of other skin cancers in man. If PAHs were responsible for an increase in melanoma incidence, an increase in other skin tumours would also be expected.

It was concluded that animal data, taken in conjunction with other information, do not suggest that PAH exposure is likely to be the cause of any elevation in melanoma incidence in refinery workers. More detailed epidemiological findings would be required to establish whether any excess incidence of melanomas was due to sunlight, other risk factors or chance occurrences.
Inhalation exposure of rats to metal aerosol. II. Study of mutagenic effect on alveolar macrophages
Authors: Chorvatovičová Darina , Kováčiková Zuzana
Published: October 2006

The effects of inhalation exposure to metal aerosol derived from nickel refinery waste were studied on the frequency of chromosome aberrations in alveolar macrophages in Wistar rats. A 4‐month exposure period resulted in significant (P < 0.01) increases in chromosome aberrations. Relatively high variability without statistical significance was observed after a 4‐week exposure period. Increase in damaged alveolar macrophages with the length of exposure seems to point to the role of pulmonary metal deposits. Comparison of the results with those found after 6 months of exposure in bone marrow cells confirmed that metal particles in nickel refinery waste are genotoxic. Thus, this study indicates that alveolar macrophages are suitable for monitoring the genotoxic potential of hazardous chemicals administered by inhalation.
Use of hair analysis for evaluating mercury intoxication of the human body: A review
Authors: Katz Sidney A. , Katz Roya B.
Published: October 2006

Relationships have been established between the concentrations of mercury in human scalp hair and environmental or dietary mercury exposures. For chronic exposures, the hair/blood ratio for mercury is in the range 200:1–300:1, and scalp hair mercury concentrations of >5 ppm are indicative of mercury intoxication. These observations, coupled with the ease by which samples may be collected, transported and stored, support the use of hair analysis for evaluating mercury intoxication of the human body.
Efficacy of hydrated sodium calcium aluminosilicate in reducing the toxicity of dietary zearalenone to mink
Authors: Bursian S. J. , Aulerich R. J. , Cameron J. K. , Ames N. K. , Steficek B. A.
Published: October 2006

Ovariectomized mink were fed diets containing zearalenone (ZEN) at concentrations of 0, 10 or 20 ppm with or without 0.5% hydrated sodium calcium aluminosilicate (HSCAS) for 24 days. Zearalenone at 10 and 20 ppm caused a significant increase in uterine weights, while 20 ppm ZEN resulted in significantly higher vulva swelling scores when compared to controls. The presence of HSCAS in the diet did not alter these hyperestrogenic effects of ZEN. In a second experiment, female mink were provided diets containing 20 ppm ZEN, 20 ppm ZEN plus 0.5% HSCAS or a control diet from 1 January 1989 through whelping (25 April to 15 May 1989). The females were given an opportunity to mate with untreated proven breeder males beginning on 1 March (day 59 of exposure). ZEN did not have an effect on the number of females whelping but there was a significant increase in gestation length, a decrease in litter size and an increase in kit mortality from birth to 3 weeks of age when compared to the control group and the group receiving the combination of ZEN and HSCAS. These results suggest that HSCAS can alleviate some of the reproductive effects of ZEN which are not related to its estrogenic action.
Effects of dibutyrylcyclic adenosine monophosphate on bleomycin‐induced lung toxicity in hamsters
Authors: O'Neill Charles A. , Giri Shri N. , Wang Qingjian , Perricone Michael A. , Hyde Dallas M.
Published: October 2006

Cyclic nucleotides play an important role in the regulation of fibroblast proliferation and collagen metabolism. In the present study, the antifibrotic potential of dibutyrylcAMP (Bt2cAMP) was evaluated in the bleomycin (BLM)‐hamster model of pulmonary fibrosis. Bt2cAMP (10 mg kg−1, s.c.) or saline (SA, s.c.) was given daily two days prior to the first intratracheal (i.t.) dose of BLM or SA and thereafter throughout the study. BLM or SA was instilled i.t. in three consecutive doses (2.5, 2.0 and 1.5 U 5ml−1 kg−1) at weekly intervals. Hamsters were killed at 7, 14 and 20 days after the third i.t. instillation. Bt2cAMP significantly reduced the contents of lung hydroxyproline and lung thiobarbituric acid reactive substance equivalents in BLM‐treated animals at 7 and 14 days. Bt2cAMP significantly elevated lung superoxide dismutase activity in BLM‐treated animals at 7 days. Lung prolyl hydroxylase activity was significantly elevated at 14 and 20 days in SABLM‐ and Bt2cAMPBLM‐treated animals. The ratio of cAMP/cGMP was significantly reduced at all tone points in SABLM‐treated animals but only at 7 and 14 days in Bt2cAMPBLM‐treated animals. Bt2cAMP caused no significant changes in lung calcium and calmodulin levels and protein content of the bronchoalveolar lavage. BLM significantly increased various inflammatory cell counts in the lavage at all three time points. The cell counts in the Bt2cAMPBLM groups were generally lower at 7 days and higher at 20 days than those of the SABLM groups. Histological evaluation showed that the lungs of Bt2cAMPBLM‐treated hamsters progressed from an inflammatory cell lesion to a fibrotic lesion at a slower rate than the SABLM groups. It was concluded that Bt2cAMP attenuated BLM‐induced pulmonary fibrosis in hamsters in part by delaying the acute phase of the inflammatory reaction.
Two‐year toxicity and carcinogenicity study of acrolein in rats
Authors: Parent Richard A. , Caravello Halina E. , Long James E.
Published: October 2006

Five‐hundred and sixty Sprague‐Dawley rats were randomized into one control and three treatment groups (70 of each sex per group). Animals were treated by daiiy gavage with 0.0, 0.05, 0.5 and 2.5 mg kg−1 acrokin in water (10 ml kg−1). These dosing levels were selected as a result ofa 6‐week range‐finding study. Ten rats of each sex per group were sacrificed at 1 year, and the remainder of the animals were treated for 102 weeks. Daily observations were made, and various clinical, hematological and urine parameters were measured after 3, 6, 12 and 18 months of treatment and immediately prior to termination. All animals, whether found dead or sacrificed, were subject to necropsy and both absolute and relative organ weights were recorded. An extensive array of tissues were examined microscopically for all test animals.

The only effects noted for treated rats that were statistically different from controls were consistent depression of creatinine phosphokinase levels, which was difficult to explain, and consistent increases in early cumulative mortalities in both males and females. There was no significantly increased incidence of microscopic lesions in treated rats, whether neoplastic or non‐neoplastic. This study clearly demonstrates the lack of neoplastic response in Sprague‐Dawley rats as a result of being treated with acrolein by gavage.
Failure of N‐Acetylcysteine to reduce alpha amanitin toxicity
Authors: Schneider Sandra M. , Michelson Edward A. , Vanscoy Gordon
Published: October 2006

Acetaminophen undergoes toxic conversion in the liver to a free‐radical intermediary which binds to glutathione. N‐Acetylcysteine acts as a glutathione precursor when natural stores are depleted, and is an effective antidote for acetaminophen overdose. Mushrooms containing amatoxins (such as Amanita phalloides) may undergo similar toxic conversion. However, in our amatoxin‐poisoned mouse model, N‐acetylcysteine (1.2 g kg−1) produced no change in survival or hepatic enzyme elevation compared to control animals. We conclude that N‐acetylcysteine has no clinical role in the treatment of Amanita phalloides ingestion.
Promotional activities of the non‐genotoxic carcinogen bemitradine (SC‐33643)
Authors: Gad Shayne C. , Burton Earl , Chengelis Christopher P. , Levin Stuart , Piper Charles E. , Oshiro Yuki , Semler David E.
Published: October 2006

Bemitradine (SC‐33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2‐year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg−1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5–15% in the female and 10–12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg−1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms.

The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC‐36741; desethylbemitradine) were tested and found to be non‐genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/− (bemitradine only) assays.

Finally, in an altered hepatic foci (Y‐glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital.

We concluded that bemitradine (which has been dropped from development) is a non‐genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.
Effects of palytoxin on porcine coronary artery rings
Authors: Robinson Casey P. , Franz David R. , Bondura Maria E.
Published: October 2006

Palytoxin, in concentrations as low as 100 fM, caused contractions of porcine coronary artery rings. Palytoxin concentrations of < 1 nM caused slowly developing contractions which were not maximal even after 2 h. Rings contracted by 100 nM palytoxin achieved maximal tension by 10 min and relaxed to 53% of that maximum after 2 h. Verapamil (1 μM) reduced the rate of contractions induced by 10 nM palytoxin. Exposure of rings to > 10 nM palytoxin for 1–2 h reduced contractions to potassium 18 h later to 61% of the expected contraction and abolished those to palytoxin administered later. Both 10 and 100 nM palytoxin depleted potassium from coronary artery rings. Verapamil (10 μM) prevented potassium depletion by 10 nM palytoxin, but neither 10 μM verapamil nor 1 μM nifedipine prevented potassium depletion in rings exposed to 100 nM palytoxin. Thus, the contractile action and the potassium depleting action of palytoxin on the porcine coronary artery involve mobilization of nifedipine‐ and verapamil‐sensitive calcium. Verapamil‐ and nifedipine‐sensitive calcium was not required for depletion of potassium by the highest PTX concentration (100 nM), however.
Cytogenetic analysis of pulmonary lavage and bone marrow cells of rats after repeated formaldehyde inhalation
Authors: Dallas Cham E. , Scott Michael J. , Ward Jonathan B. , Theiss Jeffrey C.
Published: October 2006

Cytogenetic analyses were conducted on bone marrow and pulmonary lavage cells from rats that received repeated inhalation exposures to formaldehyde. Male Sprague‐Dawley rats were exposed to 0, 0.5, 3, or 15 ppm formaldehyde for 6 h per day, 5 days per week, for 1 and 8 weeks. There was no significant increase in chromosomal abnormalities in the bone marrow cells of formaldehyde‐exposed rats relative to controls. There was a statistically significant increase in chromosomal aberrations in the pulmonary lavage cells from rats that inhaled 15 ppm. There were 7.6 and 9.2% of the scored pulmonary lavage cells that had aberrations following 1 and 8 weeks, respectively, of 15 ppm formaldehyde exposure (with control levels of 3.5 and 4.8%, respectively). The predominant damage seen was chromatid breaks. These findings indicate that marginal but statistically significant genotoxic effects could be detected locally in lung alveolar macrophages, but not distally in bone marrow, following repeated formaldehyde exposures only at a high concentration that is carcinogenic to rats. The biological significance of this effect is uncertain since formaldehyde is not considered to be a lung carcinogen in rats.
Renal effects of N‐(3,5‐disubstitutedphenyl)‐succinimides in the fischer 344 rat
Authors: Rankin Gary O. , Teets Vonda J. , Shih Hsiencheng , Beers Kelly W. , Nicoll Derek W. , Anestis Dianne K. , Brown Patrick I. , Hubbard John L.
Published: October 2006

Previous studies have demonstrated the importance of substitution at the 3‐ and 5‐positions of the phenyl ring in N‐phenylsuccinimides for the production of nephrotoxicarrts in this series of compounds. The purpose of this study was to determine if the electronic nature of the 3,5‐substituents is an important determinant for nephrotoxic potential. Male Fischer 344 rats (four rats per group) were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol kg−1) or vehicle, and the renal function was monitored for 48 h. Only N‐(3,5‐dichlorophenyl)succinimide (0.4 or 1.0 mmol kg−1) induced marked changes in renal function. Urine volume, BUN concentration and proteinuria were increased following N‐(3,5‐dinitrophenyl)succinimide (1.0 mmol kg−1) treatment but other renal parameters and renal morphology were unchanged in this treatment group. These results indicate that the presence of halogen atoms atthe 3‐ and 5‐positioiis of the phenyl nag in N‐phenylsuccinimides is more important for nephrotoxic potential than the presence of non‐halogen substituents. The reason why halogen substitution is an important determinant for N‐phenylsuccinimide nephrotoxicity is unknown.
Distribution to the fetus and major organs of the rat following inhalation exposure to pyrene
Authors: Withey J. R. , Shedden J. , Law F. P. C. , Abedini S.
Published: October 2006

Concentrations of pyrene and total metabolites were determined for individual fetuses and selected maternal organs and tissues immediately and 6 h followinga 95‐min head‐only exposure of pregnant Wistar rats, on gestation day 17, to five levels of pyrene over therange 200–800 mg m3 as a microcondensation aerosol. The influence of uterine horn, side and position, on distribution to the fetus was assessed. The concentration of both pyrene and its metabolites increased more over the exposure range (eightfold) than did those in the fetus. Concentrations of pyrene or its metabolites in fetal tissues were not found to be related to its position on the uterine horn. There was an unexplained and significant (P < 0.01) higher concentration of pyrene in fetuses on the right side relative to the left side of the uterine horn for the animals killed immediately following exposure.

A comparison of the levels in maternal tissues measured immediately following the exposure and 6 h later showed that there was some redistribution of pyrene and its metabolites to the fat tissues, i.e. levels in the fat increased over the 6 h period following the exposure. Levels in the other tissues diminished dmmg this period. In general, concentrations of pyrene and its metabolites were lowest in the fetal tissues relative to those in the sampled maternal organs and tissues.
In vivo evaluation of airway and pulmonary tissue response to inhaled methacholine in the rat
Authors: Sakae R. S. , Martins M. A. , Criado P. M. P. , Zin W. A. , Saldiva P. H. N.
Published: October 2006

The current study was designed to assess the methacholine dose‐response behaviour of the airways and pulmonary parenchyma with the aid of alveolar capsules. The experiments were performed in eight adult female Wistar rats (155–250 g). The animals were anaesthetized with sodium pentobarbital (30 mg kg−1 i.p.) and mechanically ventilated. Measurements of tracheal (ptr) and alveolar (pA) pressures and the pressure change across the airway (paw) were performed prior to and after exposing rats to aerosols generated from sequentially increasing concentrations of methacholine chloride solution (2, 4, 8, 16, 32, 64 and 128 mg ml−1) through the breathing circuit. Baseline paw and pA mean (± SD) values (6.44 ± 2.06 and 8.25 ± 3.44 cmH2O, respectively) were not statistically different (P = 0.220). The increases in ptr and pA were significant during the dose‐response study (P = 0.001), whereas paw was not increased. The increase in pA was significantly higher than that of paw (P < 0.001). The relationship between the mean (± SE) values of ptr and pA could be well described by a straight line (r = 0.990, P < 0.001). There were also significant correlations based on regression equations between ptr and paw (r = 0.947, P < 0.001) and pA and paw (r = 0.913, P = 0.004). These findings suggest that the pulmonary tissue of rats is a major component responsible for the increase in lung impedance observed after methacholine challenge. In addition, airway and pulmonary parenchyma pressure changes were correlated, suggesting that both lung regions have a similar sensitivity to the agonist. Our results indicate that the response of peripheral tissues should be considered during bronchial challenge protocols in rats.
Toxicology of carbaryl and aldicarb on brain and limb cultures of chick embryos
Authors: Farage‐Elawar M. , Rowles T. K.
Published: October 2006

A variety of carbamates have been developed since the 1960s for use as broad‐spectrum insecticides. An easy and inexpensive in vitro assay using chick‐embryo derived cells was examined for its capability to screen and test the toxicity of these compounds. Chick embryo brain and limb bud cultures were treated with different concentrations of either carbaryl or aldicarb with or without activation (± S‐9) for 5 days. Viability and cytotoxicity using the neutral red assay, and carbamate effects on cell migration and colony spread were measured. S‐9 decreased the effects of carbaryl and aldicarb on brain cell cytotoxicity at exposures of 15–60 ppm and 40–200 ppm, respectively, as indicated by increased concentrations of neutral red. Viability of brain cell cultures was not altered by aldicarb, but was decreased by carbaryl plus S‐9 in concentrations of > 40 ppm. In limb cultures, carbaryl without S‐9 was significantly toxic at 8–25 ppm, but only concentrations of > 25 ppm of carbaryl plus S‐9 significantly affected cytotoxicity. In contrast, aldicarb without S‐9 caused no effect on limb cell cytotoxicity at concentrations of 40–200 ppm, but aldicarb plus S‐9 significantly reduced cellular cytotoxicity at concentrations of > 160 ppm. Carbaryl ± S‐9 decreased the spread of both brain and limb colonies; aldicarb ± S‐9 caused a significant increase in the spread of the brain but not limb colonies. These results suggest that toxicities of carbaryl and aldicarb can be detected in vitro, but that these two carbamates have a selective toxicity, with carbaryl toxic to both brain and limb buds and aldicarb more toxic to brain than limb cells. S‐9 was more likely to decrease the toxicity of carbaryl than the toxicity of aldicarb.
Incidence of residual levels of organophosphorus insecticides in farm produce in the region of murcia, spain. comparison of intake in the 1985–86 and 1989 campaigns
Authors: García S. Navarro , Cámara M. A. , Barba A. , Toledano R. , Luna A.
Published: October 2006

We calculated the effective dietary exposure to 20 organophosphorus insecticides in a sample of residents of the Region of Murcia (Spain). Calculations were based on the contamination of 2310 specimens of citrus fruits, pitted and seedy fruits and vegetables collected in the 1985–86 and 1989 campaigns. A comparison of the results from the two campaigns showed that the mean annual insecticide ingestion determined from the mean consumption of each type of farm produce fell from 7.82 mg to 5.55 mg over the 4‐year period studied. The total annual ingestion of insecticides during the 1985–86 and 1989 campaigns was ca. 0.133 and 0.1 mg kg−1 body weight; these values are well below the admissible annual ingestion of 29.565 mg kg−1 body weight.
Relationship between eye and skin irritation in rabbits using a series of textile fiber finishes
Authors: Kennedy Gerald L. , Banerjee Asit K.
Published: October 2006

A series of 76 fiber finishes, typically composed of blends of lubricants, emulsifiers, antistatic agents and fatty acid soaps, were tested in rabbits to determine both the eye and the skin irritation potential. Each finish was classified as being either non‐, slightly, mildly, moderately or severely irritating to the target tissue during a 48‐h post‐treatment period. Seven (9.2%) of the finishes tested were severely irritating to both the skin and the eye; two (2.6%) were determined to be non‐irritating to both tissues. While occasionally finishes produced equal degrees of damage resulting in similar irritancy classifications, seven (9.2%) finishes were found to be severely irritating to the skin without producing any irritation in the eye. Conversely, one finish was found to be a severe eye irritant without producing any skin irritation. The suggested use of the skin irritation data to predict the ocular reaction needs to be carefully examined, particularly with materials such as these fiber finishes. The prediction that a severe skin irritant is also a severe eye irritant was demonstrated to be in error with 8 of 75 (10.5%) of the finishes studied. Further, there is little predictive association between the skin and eye irritation for these compounds.
Attempted use of zinc in vivo to protect against nitrogen mustard toxicity in tumor‐free and in l1210 leukemia‐bearing female b6d2f1 mice
Authors: Shackelford Mary E. , Tobey Robert A.
Published: October 2006

The use of alkylating agents in treating cancer is limited by their toxicity to both normal and tumor tissue. Early in vitro studies indicated that zinc might be effective in mitigating this toxicity to normal tissue. The present studies were done to determine the capability of zinc to induce in vivo a protective response to an alkylating agent without also contributing to mortality. Tumor‐free and L1210 leukemia‐bearing female B6D2F1 mice were treated with zinc before administration of the alkylating agent nitrogen mustard. Protocols for administration route and frequency as well as the chemical formulation of the zinc were varied. The effect of a phytate‐free diet was studied. Two parameters were used to determine the effectiveness of zinc in protecting animals from the toxicity of nitrogen mustard: the number of tumor‐free mice that survived and an increase in the median life span of the tumor‐bearing mice. The zinc‐induction protocols used in these studies provided a limited degree of protection against nitrogen mustard toxicity in tumor‐free female mice, but in tumor‐bearing animals the protective response elicited with the protocols examined did not provide an appreciable therapeutic benefit.
Acute hepatic and renal toxicity of dichlorobenzene isomers in fischer 344 rats
Authors: Valentovic Monica A. , Ball John G. , Anestis Dianne , Madan Elio
Published: October 2006

Studies were conducted to examine acute hepatic and renal toxicity of dichlorobenzene (DCB) structural isomers. Male Fischer 344 (F344) rats were injected with 2, 3 or 4 mmol kg−1 of 1,2‐DCB, 1,3‐DCB or 1,4‐DCB (o−, m−, p−). Pair‐fed control (PFC) animals were injected (i.p.) with corn oil (1 ml kg−1). Hepatic and renal toxicity was quantitated 24 h after injection of DCB or vehicle. Plasma transaminase (ALT/GPT) activity was increased (P<0.05) by 1,2‐DCB as a function of dose administered. Centrilobular necrosis was observed in rats treated with 1,2‐DCB while morphology was relatively normal in rats treated with m‐ or p‐DCB. Administration of (2 or 4 mmol kg−1) 1,3‐DCB or 1,4‐DCB did not alter kidney weight or blood urea nitrogen (BUN) levels. Renal cortical slice accumulation of p‐aminohippurate (PAH) was decreased (P<0.05) by (2 and 4 mmol kg−1) 1,3‐DCB and (3 and 4 mmol kg−1) 1,2‐DCB while accumulation of the cation tetraethylammonium (TEA) was decreased by 4 mmol kg−1 1,4‐DCB. (TEA). The results of these studies demonstrated that ortho substitution enhanced hepatic and renal toxicity. The results also would suggest that the liver was more sensitive than the kidney for DCB toxicity.
Influence of methylamine and N,N'‐dimethylurea, the hydrolysis products of methyl isocyanate, on its systemic toxicity
Authors: Jeevaratnam K. , Sugendran K. , Vaidyanathan C. S.
Published: October 2006

Subcutaneous administration of the LD50 dose of methyl isocyanate (MIC) to rats induced severe hyperglycaemia, lactic acidosis and uraemia in rats. Neither methylamine (MA) nor N,N′‐dimethylurea (DMU), the hydrolysis products of MIC, administered in equimolar doses had any influence on these parameters except for a marginal transient increase in plasma urea by DMU. Methyl isocyanate administration led to haemoconcentration, resulting in an increase in the plasma concentration of total proteins and a decrease in both the plasma concentration of albumin and the plasma cholinesterase activity. The hydrolysis products of MIC had no influence on any of these parameters. Thus, it seems reasonable to suggest that the systemic effects of MIC are caused by MIC per se, in spite of its high hydrolytic instability.
Partial contribution of biliary metabolites to nephrotoxicity, renal content and excretion of [14C]hexachloro‐1,3‐butadiene in rats
Authors: Payan J. P. , Beydon D. , Fabry J. P. , Morei G. , Brondeau M. T. , Ban M. , de Ceaurriz J.
Published: October 2006

Male Sprague Dawley rats with cannulated bile duct (BDC rats) received 100 or 200 mg kg−1 labelled hexachloro‐1,3‐butadiene ([14C]HCBD) by gavage 1 h (BDC1, rats) or 24 h (BDC24 rats) after surgical cannula implantation. Twenty‐four hours after treatment with HCBD, rats were examined histochemically and biochemically for kidney damage. Urine, faeces, liver and kidney radioactivities were also measured in 24‐h samples. Results were compared with those obtained from non‐cannulated (NC) rats. Bile‐duct cannulation did not completely protect against HCBD‐induced kidney damage. The 24‐h [14C] urinary excretion and tissue content was 30–50% lower in BDC rats compared to NC rats and correlated well with the toxicity findings.

BDC1 rats appeared to be much more resistant to HCBD treatment than BDC24 rats. Since faecal [14C] radioactivity extractible by diethyl ether at neutral pH in BDC1, rats was twice that measured in BDC24 rats, the greater resistance was attributed to a higher deficiency in the gastrointestinal absorption of unchanged HCBD.

The present results reveal that the biliary metabolites of HCBD are not solely responsible for kidney toxicity as previously assumed. They suggest a sinusoidal efflux of the HCBD conjugates from the liver.
The dermal bioavailability of radiolabelled benzo[a]pyrene from acetone or from oils of differing viscosity, assessed by DNA and protein binding
Authors: Ingram A. J. , Phillips J. C.
Published: October 2006

Tritium‐labelled benzo[a]pyrene ([3H]BaP) was applied to mouse skin in acetone or mineral oils of differing viscosity. Epidermal DNA and protein were extracted after 24 or 48 h and the degree of adduct formation determined by the radioactivity present.

When [3H]BaP was applied in acetone, the degree of DNA and protein binding was around 15–20 times greater than that observed when a low‐viscosity oil was used as a vehicle. When applied in oils of differing viscosity, however, only a twofold difference was seen across the whole viscosity range (13.5 cSt

St = stokes, a unit of kinematic viscosity (10−4 m2 s−1)

at 40°C to 1665 cSt at 60°C). From measurements made of urine and fecal radioactivity and from small‐scale investigations using other routes of administration, it was clear that the grooming activity of the animals had a marked effect on skin absorption and macromolecular binding. It is possible that greater grooming activity with low‐viscosity oils may explain why oil viscosity did not have a greater effect on binding levels, but further studies are needed to investigate this.

These findings may have important implications in the interpretation of long‐term skin painting studies and may assist in the interpretation of analytical data and short‐term biological assays.