bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole‐body autoradiographic disposition, elimination and placental transport of [14C]Tri‐o‐cresyl phosphate in mice
Authors: Ahmed Ahmed E. , Jacob Sam , Soliman Salah , Ahmed Nabila , Osman Khalid , Loh Jiann‐Ping , Romero Natasha
Published: October 2006

Tri‐o‐cresyl phosphate (TOCP) is used commercially as a plasticizer and flame retardant. The disposition, metabolism, elimination and transplacental uptake of [phenyl‐U‐14C]TOCP and/or its metabolites, in pregnant and non‐pregnant mice, were examined. Pregnant (18th‐day gestation) and non‐pregnant, ICR mice were given an i.v. dose of [14C]TOCP (557 μCi kg−1; Specified activity 4.83 μCi μmol−1). At various time intervals (1, 24, 48 and 72 h) the animals were processed for whole‐body autoradiography (WBA). Over 72 h the nonpregnant mice excreted 55% of the 14C in the urine and 9% in the feces, while excretion in the urine and feces by the pregnant mice was 50% and 9% of the total dose, respectively. The WBA and its computerassisted image analysis indicated extensive distribution of the 14C label originally dosed as [14C]TOCP in pregnant mice and their fetuses. The retention of radioactivity in organs such as lung, spleen, gall‐bladder and liver of mother and its fetuses suggest that these are the target sites of TOCP toxicity. The distribution in non‐pregnant and pregnant mice and in the fetal tissues followed a similar pattern in uptake and retention until 72 h. Brain and spinal cord had the least amount of [14C]TOCP. This finding may support reports that explain the insensitivity of the mice towards organophosphate‐induced delayed neurotoxicity (OPIDN) of TOCP.
The diacetylmonoxime assay of urea, its application to the assay of diacetylmonoxime and a comparison with other methods for the analysis of diacetylmonoxime
Authors: Dawson Raymond M.
Published: October 2006

The experiments reported herein were designed to identify the best assay of diacetylmonoxime (DAM) in biological fluids, with particular emphasis on detection limits. Initially, four variations of the assay of urea with excess DAM were compared. The best method, published in 1977, was one that includes thiosemicarbazide, 4‐aminoantipyrine and ceric ammonium sulphate in the acid reagent; it is fast, gives a reasonably stable chromophore and displays good linearity. However, the reaction was two or more times less sensitive when applied to the assay of DAM, with urea in excess, by interchanging the amounts of urea and DAM. Further, the calibration graphs did not pass through the origin, and one of the methods gave a mixture of two chromophores. None approached the sensitivity of a DAM‐urea reaction specifically designed to assay biacetyl (formed from DAM by acid hydrolysis) and published in 1968. This method, using antipyrine and arsenicosulphuric acid, is also fast, with good linearity and a stable chromophore, but is sensitive to interference by plasma and urine. An alternative photometric assay that does not involve urea was equally sensitive. It had the advantage of less interference by plasma and urine but was more time‐consuming. Both of these photometric methods had a limit of detection of ca. 0.2 μg DAM, similar to that of a high‐performance liquid chromatography (HPLC) assay. Sample clean‐up is necessary before application of the HPLC assay.
Evaluation of the genotoxic potential of zinc pyrithione in the Salmonella mutagenicity (Ames) assay, CHO/HGPRT gene mutation assay and mouse micronucleus assay
Authors: Skoulis N. P. , Barbee S. J. , Jacobson‐Kram D. , Putman D. L. , San R. H. C.
Published: October 2006

The mutagenic potential of zinc pyrithione (Znpt) was evaluated in vitro in the Salmonella/mammalian microsome plate incorporation mutagenicity (Ames) assay and the CHO/HGPRT gene mutation assay. The clastogenic potential of Znpt was evaluated in vivo using the mouse micronucleus test. Znpt was negative in the Ames test in five tester strains in the presence and absence of rat liver microsomal enzymes when assayed at concentrations ranging between 10 and 333 μg per plate and between 0.03 and 33 μg per plate, respectively. Znpt also produced negative results in the CHO/HGPRT assay. No significant increases in mutant frequencies were seen in the presence and absence of rat liver microsomal enzymes. In each case, the highest concentrations reduced cellular viability by 83% and 85%, respectively. Znpt also did not induce increased frequencies of micronuclei in mouse bone marrow cells when tested at the maximally tolerated dose (MTD) (44 mg kg−1). These data support the conclusion that Znpt lacks genotoxic activity under the conditions of these tests.
A proposed screen for evaluating low‐molecular‐weight chemicals as potential respiratory allergens
Authors: Gauggel Dorothy L. , Sarlo Katherine , Asquith Thomas N.
Published: October 2006

Allergic asthma can result when reactive low‐molecular‐weight chemicals (LMWCs) haptenate carrier proteins to form immunogenic conjugates, which then induce specific allergic antibodies. As part of an overall assessment process for evaluating the allergenic potential of LMWCs, an in vitro test for detecting the covalent derivatization of proteins by LMWCs was developed. In the assay, globulin‐free serum albumins were incubated with increasing concentrations of a given LMWC and the mixtures separated via reversed‐phase high‐performance liquid chromatography (HPLC). Derivatization was monitored by shifts in the retention time of native versus modified protein. Retention time shifts were seen for most haptens when incubated with human serum albumin at a 50:1 (hapten:protein) starting molar ratio. Some haptens changed the retention time of the protein at a 5:1 initial ratio. Almost all chemicals that non‐covalently bind to proteins did not change the protein retention time, even when incubated at 1500:1 molar ratios. The screen correctly identified 12/14 known human allergenic haptens and 23/24 non‐allergenic LMWCs. It cannot detect sensitizers which must be metabolized into reactive haptens. This screen can be incorporated into an overall risk assessment approach for evaluating chemicals as respiratory allergens.
An attempt to improve the SOS chromotest responses
Authors: Hoflack J. C. , Férard J. F. , Vasseur P. , Blaise C.
Published: October 2006

The SOS Chromotest was carried out on leachates of ten industrial wastes with the standard procedure and a miniaturized version with microplates. The two methods gave identical results in nine samples (eight negative and one positive). A simple additional manipulation is described for the identification of the false positive response that is frequently observed with complex mixtures. It involves challenging the SOS Chromotest bacteria with samples (having previously shown a positive genotoxic response) just before the enzymatic activities (i.e. β‐galactosidase and alkaline phosphatase) are estimated colorimetrically. This additional step eliminates discrepancies between the results for the standard and the miniaturized procedures.
Induction of chromosomal aberrations and sister chromatid exchange in vivo and in vitro by the insecticide cypermethrin
Authors: Amer Soheir M. , Ibrahim Aziza Abd‐El Samie , El‐Sherbeny Kawser M.
Published: October 2006

The induction of chromosomal aberrations and sister chromatid exchange in vivo in mouse spleen and bone marrow as well as in vitro in cultured mouse spleen cells by the insecticide ‘Cypermethrin’ (cistrans 1:1) was investigated.

The percentage of chromsomal aberrations in the spleen and in the bone marrow as almost the same and reached its maximum 6 h following i.p. injection. The aberrations induced were chromatid and chromosome gaps, fragments and tetraploidy. The insecticide caused a significant and dose‐dependent increase in the frequency of sister chromatid exchanges (SCEs) in mouse bone‐marrow cells: it reached 11.12 ± 0.05 per cell after treatment with Cypermethrin at 300 mg kg−1 body wt. compared with 3.7 ± 0.14 per cell and 4.4 ± 0.26 per cell in the solvent and control, respectively.

The percentage of viable cells in mouse spleen cell cultures reached 87.4% and 99.9% relative to the control after treatment of the cell cultures with 10−3 and 10−7 Cypermethrin, respectively. All the tested concentrations of Cypermethrin (0.25–400 μg ml−1) induced a high percentage of metaphases with chromosomal aberrations after 4 h of treatment. The mean frequency of SCEs per cell reached 15.1 ± 0.05 after treatment with Cypermethrin at 4.00 μg ml−1 compared with 8.6 ± 0.23 and 5.9 ± 0.39 in the solvent and control, respectively.

The results indicate that Cypermethrin is genotoxic in mouse spleen and bone marrow as well as in cultured mouse spleen cells.
Effects of high exposure concentrations of inhaled low‐toxicity dust on pulmonary function in guinea pigs
Authors: Wolff R. K. , Collins M. J. , Carlson K. H. , Allen D. L. , Dorato M. A.
Published: October 2006

The acute pulmonary function response to graded levels of a low toxicity dust was studied in guinea pigs. Four groups of five male guinea pigs each were exposed to mean concentrations of 0, 0.25, 1.01 and 5.39 mg Foundry Hill Clay I−1 air with mass median aerodynamic diameters of 2.6, 4.6 and 6.7 μm, respectively. There was a 15‐min pre‐exposure period to clean air, a 1‐h exposure to the test atmosphere and then a 1‐h recovery period with exposure to clean air. Concentration‐related changes, compared to the pre‐exposure period, occurred with a rapid onset in a number of parameters. Generally, the severity of observed effects increased with exposure time and, therefore, with inhaled dose. Statistically significant changes (P<0.05) were observed in tidal volume, dynamic compliance, dynamic resistance, flow, pressure and minute volume during the last 15 min of exposure. The observed changes were consistent with acute bronchoconstriction. These effects reversed rapidly and there were no significant changes 1 h post‐exposure. These results suggest that adverse physiological responses of short duration can occur when animals are exposed via inhalation to low‐toxicity materials in the concentration range 0.25‐5 mg I−1.
High‐performance liquid chromatography detection of sulfide in tissues from sulfide‐treated mice
Authors: Mitchell Thomas W. , Savage Joseph C. , Gould Daniel H.
Published: October 2006

The biological and forensic use of ion‐interaction reversed‐phase high‐performance liquid chromatography for the determination of hydrogen sulfide‐derived methylene blue is evaluated by measuring the sulfide content in tissues from sulfide‐treated mice. Various preparative conditions were examined. The determinations of background levels of sulfide from brain, liver and kidney were compared to sulfide levels from mice exposed to 60 μg g−1sodium hydrosulfide. At the time of death, significant increases above background sulfide levels were measured for all three biological tissues. To evaluate its forensic potential, we used this sulfide detection methodology to evaluate comparatively the sulfide levels from fresh and frozen samples of brain, liver and kidney. The stability of sulfide levels obtained from frozen brain makes this tissue the most reliable tissue for forensic evaluation. Samples of brain, liver and kidney obtained within 24 h of death by sulfide intoxication had demonstrable elevations in sulfide concentration.
Urinary thiodiglycolic acid and thioether excretion in male rats dosed with 1,2‐dichloroethane
Authors: Payan J. P. , Beydon D. , Fabry J. P. , Brondeau M. T. , Ban M. , de Ceaurriz J.
Published: October 2006

1,2‐dichloroethane (DCE) is extensively metabolized and partially excreted in urine as thioether compounds, which include thiodiglycolic acid (TDGA). In this study, we have compared the urinary excretion of TDGA and thioethers in the rat after administration of increasing doses of DCE. Male Sprague Dawley rats were given a single oral dose of labelled [14C]DCE (0.125 to 8.08 mmol kg−1 body wt.) and 24‐h urine samples were collected. The TDGA and thioethers were determined in urine by a gas chromatography method and by the thioether assay after alkaline hydrolysis, respectively. The percentage of the administered radioactivity that was excreted in urine decreased with increasing dose of DCE and ranged between 63 and 7.4%. The amount of TDGA increased proportionally to the DCE dose up to 1.01 mmol DCE kg−1 body wt. and corresponded to 0.22 mmol TDGA mmol−1 DCE. Up to 0.25 mmol DCE kg−1 body wt., the amount of thioethers recovered in urine was not significantly different as compared to the vehicle control group (11.8 ± 0.6 μmol SH equiv. kg−1 body wt., n = 10). From the 0.25–4.04 mmol DCE kg−1 body wt. dose, the amount of thioethers increased linearly with the dose of DCE and corresponded to 0.028 mmol SH equiv. mmol−1 DCE. The ratio between urinary thioethers and TDGA increased with the DCE dose and reached 0.17 ± 0.01 (n = 5) at a dose of 8.08 mmol DCE kg−1 body wt. Moreover, TDGA contents determined in urine by gas chromatography before and after alkaline hydrolysis were not significantly different.

These results have shown that urinary TDGA was a much better monitor of DCE exposure than total thioethers, not only in specificity but also in sensitivity. Moreover, they point out that TDGA was not hydrolysed under alkaline conditions, making the thioether assay inappropriate for determining TDGA content.
Predicted toxicities of aryl alkanols and related compounds
Authors: Schultz T. Wayne , Lin David T. , Culberson Ronnie W.
Published: October 2006

The relative toxicity of selected aryl and/or alkyl alcohols was evaluated in the batch culture Tetrahymena pyriformis population‐growth impairment assay. Chemicals evaluated included normal and branched primary alcohols with mono‐, bi‐ or diaromatic substituents as well as aryl‐substituted ethers. Log 1‐octanol/water partition coefficients (log Kow) along with previously developed quantitative structure‐activity relationships (QSARs) for both the non‐polar narcosis and polar narcosis mechanism of action were used to predict relative toxicity. Observed and predicted toxicities measured as log IGC50−1 were compared. All phenols and naphthylsubstituted compounds, as well as the biphenyl methanols, benzhydrols and 1,1‐diphenylethanol, model more accurately as polar narcotics. Both monoaromatic‐ and diaromatic‐substituted branched arylalkyl alcohols, as well as monoaromatic ethers, model best as non‐polar narcotics. The C1‐C6 straight‐chain aryl alkanols, as well as 3‐phenyl‐1‐butanol, model intermediately between non‐polar and polar narcosis. The triaromaticsubstituted alcohol was not toxic at saturation. These findings are consistent with the idea that narcosis, the reversible state of arrested bioactivity, is a series of mechanisms.
Testicular lesions by chronic administration of cocaine in rats
Authors: Barroso‐Moguel Rosario , Méndez‐Armenta Marisela , Villeda‐Hernández Juana
Published: October 2006

Although cocaine is a common drug of abuse, its effects on the testicular structure have not been studied in depth. We report here the testicular lesions produced by chronic cocaine administration to rats. Twentyeight male Wistar rats weighing 225–250 g were used throughout. Fourteen of them (controls) were injected i.p. with saline solution and the remaining 14 received 30 mg kg−1 day−1 i.p. of aqueous cocaine hydrochloride solution. Animals from both groups were sacrificed at variable times: 7, 15, 30, 45, 60, 75 and 90 days of treatment. Histopathological examination of the testes showed initial alterations at day 15: capillary dilatation; interstitial oedema with lipoid drops due to incipient necrosis of interstitial cells; and necrosis of the cells of the seminiferous tubules. Lesions progressed until 90 days of treatment, showing atrophic and necrotic cells and terminal tubule fibrosis. At this time, the testes were found to be diminished in size. The seminiferous tubules were shrunken, of small diameter and contained necrotic spermatogenic cells and fibrosis. These lesions may produce testosterone diminution and thus sterility due to the disappearance of spermatogenesis.
Metabolite pharmacokinetics of soman, sarin and GF in rats and biological monitoring of exposure to toxic organophosphorus agents
Authors: Shih Ming L. , McMonagle Joseph D. , Dolzine Theodore W. , Gresham Vincent C.
Published: October 2006

This study reports on the pharmacokinetics of the elimination of the metabolites of three toxic organophosphorus compounds (soman, sarin and GF). Urine, blood and lung tissue were collected from rats dosed subcutaneously at 75 μg kg−1. Urinary excretion of the metabolite was the major elimination route for these three compounds. The major differences among them were primarily the extent and rate of excretion. The hydrolyzed form, alkylmethylphosphonic acid, was the single major metabolite formed and excreted in urine by a non‐saturable mechanism. Nearly total recoveries of the given doses for sarin and GF in metabolite form were obtained from the urine. The terminal elimination half‐lives in urine were 3.7x ± 0.1 and 9.9 ± 0.8 h for sarin and GF, respectively. Soman metabolite showed a biphasic elimination curve with terminal half‐lives of 18.5 ± 2.7 and 3.6 ± 2.2 h. Soman was excreted at a slower rate with a recovery of only 62%. Lung was the major organ of accumulation for soman. In blood the toxic agents were concentrated more in red blood cells than in plasma. The acid metabolites can serve as a better chemical marker for monitoring organophosphorus exposure in humans via their higher concentration and longer half‐life in urine than the parent compounds.
Role of extracellular glutathione and γ‐Glutamyltranspeptidase in the disposition and kidney toxicity of inorganic mercury in rats
Authors: De Ceaurriz J. , Payan J. P. , Morel G. , Brondeau M. T.
Published: October 2006

The role of extracellular glutathione (GSH) and membrane‐bound γ‐glutamyltranspeptidase (γ‐GT) as contributory factors in the disposition and toxicity of inorganic mercury (HgCl2, 1 mg kg−1, i.p.) was investigated in rats pretreated with acivicin (AT‐125, 10 mg kg−1), a γ‐GT inhibitor.

A high degree of γ‐GT inhibition (75%) and of protection (90%) against HgCl2‐induced nephrotoxicity was obtained in γ‐GT‐inhibited rats 24 h post‐treatment. Pretreatment with acivicin affected the fractional distribution profile of 203Hg, resulting in a twofold decrease in the renal incorporation of mercury 4 h posttreatment and a threefold increase in the 24‐h urinary excretion of mercury. Plasma radioactivity remained constant over 24 h in rats dosed with 203Hg alone, whereas it decreased by 60% between 4 h and 24 h in γ‐GT‐inhibited rats. In γ‐GT‐inhibited rats treated with HgCl2 the renal and plasma reduced glutathione (GSH) content increased by 68% and 330% respectively, as compared to controls. The γ‐GT inhibition affected the distribution profile of mercury within urinary proteins, shifting the binding of mercury from the inghmolecular‐weight fraction (3% against 80%) to the low‐molecular‐weight fraction (72% against 10%). A significant but less impressive shift of mercury from the ingh‐ to the low‐molecular‐weight fraction also arose in the plasma.

These results taken together support the pivotal role of extracellular GSH and membrane‐bound γ‐GT in the renal incorporation, toxicity and excretion of inorganic mercury in rats.
Mechanism of antifoaming action of simethicone
Authors: Brečević Ljerka , Bošan‐Kilibarda Ingrid , Strajnar Franjo
Published: October 2006

The mechanism of the foam‐inhibiting action of simethicone, mainly used against flatulence, has been studied. Its effect on foaming systems containing synthetic gastric juice and a surface‐active substance (anionic surfactant, cationic surfactant, soap solution) was quantitated by measuring the surface tension, foam stability and initial foam density. The effect of simethicone on each of the examined systems was the result of the combination of two actions: the drainage of liquid from foam films and the rupture of relatively thick liquid films. The mechanism of these actions may be described as the liquid drainage followed by bridging of the liquid film by polydimethylsiloxane droplets, helped by hydrophobic silica particles also present in the antifoaming agent, leading to the rupture of the film surface and air escape.
Beryllium‐induced biochemical alterations and their prevention following Co‐administration of Meso‐2,3‐dimercaptosuccinic acid or 2,3‐dimercaptopropane sulphonate in rats
Authors: Mathur Seema , Mathur R. , Flora S. J. S. , Kannan G. M. , Gupta S. Das
Published: October 2006

The effects of meso‐2,3‐dimercaptosuccinic acid (DMSA) and 2,3‐dimercaptopropane sulphonate (DMPS) on body beryllium burden, hepatic lipid peroxidation, glutathione, alkaline and acid phosphatase and some biochemical variables of porphyrin metabolism were studied in beryllium‐poisoned rats. It was observed that beryllium poisoning is associated with a slight increase in lipid peroxidation, significant depletion of alkaline phosphatase and elevation of acid phosphatase activities in the liver and increased beryllium concentration in blood and other soft organs. Evidence is presented that both DMSA and DMPS during concomitant administration prevented most of the above beryllium‐induced biochemical alterations. Tissue beryllium concentration and histopathological lesions in liver and kidneys were also significantly less marked following simultaneous administration of DMPS compared to beryllium‐exposed controls; DMSA was comparatively less effective.
Autometallographic detection of silver in hypothalamic neurons of rats exposed to silver nitrate
Authors: Stoltenberg Meredin , Juhl Søren , Poulsen Elin Hyldgaard , Ernst Erik
Published: October 2006

The silver amplification technique, autometallography, has been used to reveal silver accumulation in neurons in the hypothalamus of male Wistar–Kyoto rats. Silver penetrated the blood‐brain barrier after exposure to silver nitrate, and differences in staining intensity were found between the hypothalamic nuclei. When using light microscopy, the silver staining of the hypothalamic neurons was highly heterogeneous. Silver was detected exclusively in lysosomes of the loaded neurons. Aspects of this heterogeneous localization are discussed in relation to the distribution of autometallographically developed gold and mercury.
Urinary enzyme excretion as a parameter for detection of acute renal damage mediated by N‐(3,5‐dichlorophenyl)succinimide (NDPS) in fischer 344 rats
Authors: Valentovic Monica , Williams Pamela , Iii John Carl , Rankin Gary O.
Published: October 2006

The kidney has been identified as the specific target organ for in vivo exposure to an agricultural fungicide, N‐(3,5‐dichlorophenyl)succinimide (NDPS). The goal of this study was to determine if urinary protein and enzyme excretion were sensitive, non‐invasive markers for NDPS‐induced renal damage. The proximal tubular enzymes that were monitored were the brush‐border enzyme alkaline phosphatase (ALP) and the lysosomal enzyme N‐acetyl‐β‐D‐glucosaminidase (NAG). Male Fischer 344 (F344) rats were injected intraperitoneally (i.p.) with 0.2 or 1.0 mmol kg1 NDPS. Control animals were injected i.p. with sesame oil (2.5 ml kg−1). Urine was collected on ice 0–3, 3–6 and 6–24 h after NDPS or vehicle injection. Urinary protein and urinary NAG excretion levels were elevated (P < 0.05) above the control levels 0–3 h after treatment with 0.2 mmol kg−1 NDPS. Urinary protein and enzyme excretion was comparable between 0.2 mmol kg−1 NDPS‐treated and control groups for all other time periods. Administration of a marked nephrotoxicant dose (1.0 mmol kg−1) was associated with elevated levels of urinary protein, NAG and ALP beginning 0–3 h after treatment when compared to the control group or to respective baseline values. It was concluded from these studies that measurement of urinary protein as well as the release of ALP and NAG were sensitive markers of renal damage produced by NDPS.
Liver lipid peroxidation and glutathione‐related defence enzyme systems in mice treated with paracetamol
Authors: Özdemirler Gül , Aykaç Gülçin , Uysal Müjdat , Öz Hikmet
Published: October 2006

Glutathione levels were found to be decreased while lipid peroxide levels were increased in total liver homogenates 6 h following paracetamol treatment (500 mg kg−1 i.p.). Furthermore, it has been determined that cytosolic glutathione S‐transferase (GST) activity was decreased and glutathione peroxidase (GSH‐Px) activity remained unchanged. On the other hand, a decrease in liver microsomal lipid peroxide levels and an increase in GST and GSH‐Px activity has been observed. We concluded that decreased lipid peroxide levels in microsomes could be a consequence of increased GSH‐Px and GST enzyme activities. In this way, these glutathione‐related defence enzyme systems may play an important role in protecting microsomes from lipid peroxidation.
Review of oximes available for treatment of nerve agent poisoning
Authors: Dawson R. M.
Published: October 2006

A review was conducted of papers describing the use of N‐methyl‐2‐pyridinealdoxime (PAM), toxogonin or HI‐6 as antidotes to the nerve agents tabun, sarin, soman and VX. The review included use of the oxime alone, oxime plus atropine and oxime plus atropine plus diazepam, given therapeutically, i.e. after nerve agent, in all cases. Experiments with any of these compounds given prophylactically were not considered. The review also included protocols of pyridostigmine prophylaxis and oxime‐atropine therapy (with or without diazepam). It was difficult to draw conclusions as to the best oxime to use, because of lack of data in many cases. The identity of the oxime did not appear to be important when pyridostigmine prophylaxis was combined with atropine‐oxime‐diazepam therapy; in these cases, very good protection was observed in guinea pigs against all four nerve agents. The choice of oxime based on the data presently available may well depend on factors other than protection against lethality, such as cost and availability of the oxime and human toxicity of the oxime. This last factor was also reviewed, and the results showed that toxogonin is likely to cause more side‐effects than PAM or HI‐6. The efficacy of the oximes against the emerging threat agent GF was also reviewed.
Chromium‐induced micronuclei in fish
Authors: Al‐Sabti K. , Franko M. , Andrijanič B. , Knez S. , Stegnar P.
Published: October 2006

An investigation of the cytogenetic effects of chromium (Cr(VI) and Cr(III)) in Prussian carp (Carassius auratus gibelio) was made. For detecting cytogenetic damage, micronuclei induction in fish erythrocyte cells was employed. Fish were investigated 100 m above and 400 m below the discharge of leather waste products into the river Ljubljanica, and by exposing fish to three doses of chromium (Cr(VI) and Cr(III)) in the laboratory. The exposure of fish to various concentration levels (sub‐lethal) of chromium under laboratory and field conditions caused an increase in the frequency of micronuclei compared with the control groups.
Teratological assessment of stobadine after single and repeated administration in mice
Authors: Ujházy E. , Dubovický M. , Balonová T. , Janšák J. , Zeljenková D.
Published: October 2006

Teratological studies were performed with stobadine, a compound with antiarrhythmic and antihypoxic activity. Single i.v. injections of stobadine in the form of dihydrochloride (DH 1011) to ICR mice on days 3, 6, 9 or 12 of gestation at doses of 1 and 3 mg kg−1 had no teratogenic effect. Slight fetal toxicity was manifested by decreased fetal weight after treatment on days 3 and 6, increased incidence of rudimentary ribs after treatment on days 9 and 12 of gestation and non‐significantly increased postimplantation loss after injection on day 6 of gestation. The effect of repeated oral administration in the form of dipalmitate salt (DP 1031) was studied in doses of 12.2, 61.0 and 122.0 mg kg−1 on days 4–16 of gestation. Oral exposure to 61.0 mg kg−1 DP 1031 resulted in significant reduction of implantations, live fetuses and litter weight, and after 122.0 mg kg−1 DP 1031 the fetal weight was significantly decreased. External and skeletal examinations of the fetuses revealed no evidence of teratogenesis. The relevance of the two routes of stobadine administration for risk involvement is discussed.
Method for preserving erythrocytic δ‐aminolevulinic acid dehydratase activity that facilitates population studies on lead intoxication
Authors: Burns C. B. , Sriprakash K. S. , Powers J. R. , Currie B. J.
Published: October 2006

A method preserving the activity of the erythrocytic enzyme α‐aminolevulinic acid dehydratase (EC 4.2.1.24) was developed using a vehicle of 50% aqueous glycerol containing dithiothreitol (80 μM). Whole heparinized blood (0.5 ml) was added to 0.75 ml of this mixture in a cryovial tube (capacity 1.3 ml), mixed well and stored in a freezer at −20°C for 21 days. Statistical comparison of the enzyme activity when freshly assayed and after storage indicated excellent agreement for quantitation of the non‐activated enzyme (intraclass correlation coefficient = 0.99) and the activated enzyme (intraclass correlation coefficient = 0.98). This storage method will facilitate future population studies on lead intoxication, particularly those in remote locations.
Ex vivo technique for evaluating the effect of chemical vapours on mucociliary activity
Authors: Bonnet P. , Nunge H. , Gagnaire F. , Zahm J. M.
Published: October 2006

An experimental protocol has been developed for the use of rat tracheal explant to evaluate the effects of inhaled chemicals on the mucociliary function. Rats were exposed for 4 h or 7 days (24 h per day) to different concentrations of toluene diisocyanate (TDI). Each rat trachea was subsequently removed rapidly and placed in a humid chamber maintained at 37°C. Mucociliary function was evaluated by video measurements of the two following parameters: mucociliary beating frequency (MCBF) and number of active (A+), partially active (A−) and inactive areas (A−).

In control tracheas, all areas were active and the MCBF showed hardly any variation around 15.3 Hz. In rats exposed to ca. 0.27 or 0.54 ppm of TDI for 4 h, tracheas showed a significant decrease in the number of active areas and a significant decrease in the MCBF. The same changes were observed in tracheas from rats exposed to approximately 0.05 and 0.10 ppm of TDI for 7 days. After a 7 day recovery period the number of active areas and the MCBF were similar in exposed and control rats except in the group exposed for 7 days to the highest concentration; these showed only partial recovery. The results of this study showed that this ex vivo method is useful for detecting mucociliary dysfunction.
Oxidant radical release by alveolar macrophages after cadmium chloride exposure in vitro
Authors: Leduc D. , Gressier B. , Gosset Ph. , Lheureux Ph. , De Vuyst P. , Wallaert B. , Yernault J. C.
Published: October 2006

Chronic exposure to cadmium can cause lung emphysema, the mechanism of which is unknown. Current concepts on the pathogenesis of emphysema largely emphasize the role of a protease‐antiprotease imbalance. The aim of this work was to study the effects of cadmium on the regulation of antiprotease activity and the release of oxidant radicals from alveolar macrophages.

Guinea pig alveolar macrophages (AM) were exposed overnight to cadmium chloride (CdCl2) in vitro. To define the cytolytic threshold dose, cell lysis was evaluated by trypan blue exclusion and lactate dehydrogenase release. Non‐cytolytic concentrations were then used (0.1, 0.4 and 0.8 ppm) to simulate chronic exposure conditions. Overnight exposure to 0.1, 0.4 and 0.8 ppm CdCl2 decreased intracellular ATP (mean ± SD: 91 ± 8%, 72 ± 7%, 50 ± 8% of control cells, respectively), suggesting that even at non‐cytolytic doses, Cd2+ can cause cell injury. The assessment of oxygen radical release from AM after overnight exposure to CdCl2 showed a dose‐dependent decrease to 54.3 ± 8.2%, 32.2 ± 4.3% and 25 ± 3% of control after exposure to 0.1, 0.4 and 0.8 ppm Cd2+, respectively. At non‐cytolytic concentrations (0.1, 0.4 and 0.8 ppm) CdCl2 did not decrease α1‐proteinase inhibitor activity either in the absence of AM or in the presence of AM and myeloperoxidase.

In conclusion, our in vitro results do not suggest that a protease‐antiprotease imbalance is involved in the pathogenesis of cadmium‐induced emphysema. However, these data should be considered in the context of an eventual increase of protease burden in the lung caused by the migration of neutrophils and macrophages into the alveolar space after CdCl2 exposure in vivo. Cadmium, by impairing the release of oxidant radicals from AM, may increase susceptibility to respiratory infections.
Time‐dependent effects of lead on rat reproductive functions
Authors: Kempinas W. G. , Favaretto A. L. V. , Melo V. R. , Carvalho T. L. Lamano , Petenusci S. O. , Oliveira‐Filho R. M.
Published: October 2006

The effects of exposure to lead on endocrine function and the reproductive parameters were studied in pubertal rats treated with 1.0 g l−1 lead acetate in drinking water for 20 days (subacute group) or 9 months (chronic group) in addition to i.v. injections of lead acetate (0.1 mg 100 g−1 body wt.) every 10 (subacute group) or 15 days (chronic group). Although basal levels of testosterone were higher both in plasma and in testes of acutely intoxicated animals, the circulating levels of luteinizing hormone (LH) were not affected in either group, nor was the LH‐releasing hormone content of the median eminence. The density of [125I]LH/human chorionic gonadotrophin (hCG) binding sites in testicular homogenates was reduced by saturnism in both groups, concomitant with a significantly increased apparent affinity constant of the hormone‐receptor complex. These data can be viewed as the result of a mixture of specific lead toxicity (e.g. at the enzyme level) with other more general actions (e.g. at the level of the hypothalamus‐pituitary‐testicular axis).
Pathological mechanisms of hepatic tumour formation in rats exposed chronically to dietary hexachlorobenzene
Authors: Carthew P. , Smith A. G.
Published: October 2006

The chronic dietary administration of hexachlorobenzene (HCB) to rats for a year or more results in the formation of liver tumours described as hepatocellular carcinomas, hepatomas or haemangiomas. The hepatotoxicity of HCB, which is greatest in hamsters and rats, gives rise to peliosis and necrosis with haemosiderosis. This pattern of hepatotoxicity indicates vascular damage, which through haemosiderosis could increase not only the toxic effect of HCB to hepatocytes but also its tumourogenic potential. The present study confirmed vascular damage by the identification of widespread fibrin deposits in the livers of rats chronically exposed to HCB, using an antibody to rat fibrin. Based on our study we suggest that the formation of hepatomas and haemangiomas with elements of peliosis (cystic blood‐filled cavities) could be explained by the compensatory hyperplastic responses to hepatocellular necrosis and by the simultaneous loss of hepatocellular cords. The accumulation of iron in the liver would strongly potentiate the development of hepatic tumours, as has been found in HCB and polychlorinated biphenyl‐treated mice with iron overload. The implications of this non‐genotoxic mechanism of hepatoma formation for the assessment of human health risk are discussed.
Analysis of feed blends containing microencapsulated 2‐ethyl‐1‐hexanol: Verification of homogeneity and stability
Authors: Arneson Dora W. , Kuhn Gustav O. , Jameson C. W.
Published: October 2006

2‐ethyl‐1‐hexanol (2‐EH) was nominated for carcinogenicity testing by the National Toxicology Program because it is a high‐volume chemical and a major metabolite of di(2‐ethylhexyl)phthalate, a known hepatocarcinogen and a known contaminant in blood storage bags. In addition to uses as an intermediate in the manufacture of plasticizers, 2‐EH is also used as a solvent, a lubricant and as a finishing compound for paper and textiles. The preferred route of administration for the carcinogenicity studies was oral via the diet. However, feed blends containing neat 2‐EH were not sufficiently stable for feed studies. Dosed feed blends prepared with neat 2EH retained only 86% of the theoretical concentration after blending, and 46% of theoretical after storage for 2 days in a rat cage environment. Feed blends containing microencapsulated 2‐EH were sufficiently stable for toxicity studies: no losses of 2‐EH were observed after blending, feed blends stored for 7 days in a rat cage retained 99% of the theoretical concentration and blends stored in sealed containers at room temperature for 21 days retained 97% of the theoretical concentration. These studies demonstrate the potential for microencapsulation technology to eliminate dose formulation problems associated with volatile chemicals.
Preclinical safety studies with recombinant human interleukin 6 (rhil‐6) in the primate callithrix jacchus (marmoset): Comparison with studies in rats
Authors: Ryffel B. , Weber M.
Published: October 2006

The haemopoietic and immunostimulatory properties of recombinant human interleukin 6 (rhIL‐6) might be used clinically in cancer patients. For the preclinical assessment of the safety of such a therapy, we chose the primate marmoset (Callithrix jacchus) and Wistar rats.

Recombinant hIL‐6 given to marmosets at doses of up to 1000 μg kg−1 day−1 over 4 and 9 weeks did not induce fever and was very well tolerated. Haematological alterations included a sustained two‐ to threefold increase of thrombocyte counts, peaking at 4 weeks, as well as an increase in neutrophils and basophils. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased, but the ploidy grade was augmented. An acute‐phase protein response was observed within 24 h after the first IL‐6 administration, which reached a maximum after 1 week. The acute‐phase protein response was not accompanied by functional or morphological signs of hepatocellular damage. Increased immunoglobulin and soluble IL‐2 receptor in the serum levels reflected systemic immunostimulation.

Recombinant hIL‐6 was also given to rats at 500 μg kg−1 day−1 s.c. for 4 weeks, where it induced a stimulation of thrombopoiesis associated with increased platelet counts within 1 week. Furthermore, rhIL‐6‐treated rats had signs of immunostimulation and increased acute‐phase reactants in serum, as in marmosets. There was no evidence of renal glomerular or hepatic pathology.

In conclusion, despite the pleiotrophic effects of IL‐6 observed in vitro, prolonged administration of rhIL‐6 induced quite a selective stimulation of thrombopoiesis and the immune system, which were not associated with any major adverse effect in the two animal species. Since neutralizing antibodies developed against rhIL‐6 in both species within 2–4 weeks, which abolished the biological effect of IL‐6, the conductance of long‐term studies with rhIL‐6—especially on possible tumour‐promoting effects—are not warranted.
Effects of ricin on the ability of rabbit arteries to contract and relax
Authors: Christiansen Victoria J. , Hsu Chia‐Hsuh , Zhang Lin , Robinson Casey P.
Published: October 2006

Ricin, a toxic lectin from castor beans, reduces blood pressure. The current studies determined the effect of ricin on contractions in response to norepinephrine (NE) of rabbit central ear artery, endothelium‐dependent relaxations to methacholine and ATP of aorta rings and endothelium‐independent relaxations to papaverine in central ear artery and aorta rings. Rabbits were given 0.11 or 0.22 μg kg−1 ricin i.v. and 18 h, 4 days, or 7 days later the arteries were removed and tested. Maximal contractions to NE were increased by 8–23% (P > 0.05) with ricin treatment. The EC50 was increased in five of six ricin‐treated groups, although only significantly so at 18 h after a minimum lethal dose of ricin. Maximum relaxations to methacholine were increased by 20–57% (P > 0.05) at 18 h following both ricin doses but returned to control values at later time points. Relaxations in response to ATP were significantly enhanced in all ricin‐treated groups (95–205%) except in the 18 h and 4‐day 0.11 μg kg−1 dose groups where the increase was 0–46%. Relaxations in response to papaverine were not altered in either artery. Thus, ricin decreases the sensitivity of the rabbit central ear artery to NE and increases endothelial‐dependent relaxations of the rabbit aorta. Therefore, decreased blood pressure following ricin administration may be due to vasodilation caused by decreased vascular contractions and increased endothelial‐dependent vascular relaxation.
Protective effect of colchicine on acute liver damage induced by CCL4. Role of cytochrome p‐450
Authors: Martínez Martín , Mourelle Marisabel , Muriel Pablo
Published: October 2006

The aim of this work was to study if colchicine protects against CCl4 ‐induced changes in hepatic biochemical parameters by reducing cytochrome P‐450, by comparing the effects of colchicine and SKF 525‐A, a well‐known inhibitor of cytochrome P‐450. Our results show that both drugs reduced the cytochrome P‐450 content and p‐nitroanisole o‐demethylase activity to the same extent. However, colchicine afforded a total protection from markers of liver injury, while SKF 525‐A protected only partially. The difference in the hepatoprotective activity of both drugs indicates that the beneficial effect of colchicine cannot be attributed solely to the inhibition of the activation of CCl4. Other actions, perhaps at the level of the propagation of lipid peroxidation or a ‘membrane‐stabilizing’ effect cannot be ruled out.
Epidermal carcinogenesis studies of eds liquids
Authors: McKee R. H. , Plutnick R. T.
Published: October 2006

A series of liquids representing different potential design options or operating configurations for the EDS direct coal liquefaction process* were evaluated for skin cancer potential. All of the samples that contained substantial amounts of material boiling above 370°C were active dermal carcinogens; tumor yields were near 100% and median times to tumor development generally ranged from 30 to 40 weeks. Two liquids that boiled below ca. 200°C were tested and each produced one squamous cell tumor. These data suggested that high‐boiling‐point, coal‐derived liquids are likely to be relatively potent dermal carcinogens; whereas low‐boiling‐point liquids do not possess significant carcinogenic potential. Based on a comparison of the carcinogenic potency data, liquids produced by the EDS process apparently do not present a significantly greater dermal carcinogenic hazard than other coal‐derived materials of similar boiling range.
Mechanism of citrinin‐induced dysfunction of mitochondria iii. Effects on renal cortical and liver mitochondrial swelling
Authors: Chagas Generoso M. , Oliveira Ma. Benigna M. , Campello Annibal P. , Klüppel Ma. Lúcia W.
Published: October 2006

The effects of the mycotoxin citrinin on renal cortical and liver mitochondrial swelling were studied. Citrinin decreases the rate of swelling induced by the valinomycin–K+ complex, suggesting that the mycotoxin interferes with the mitochondrial membrane fluidity. Citrinin promotes reduction of the amplitude of swelling in the presence of Na+ ions. This alteration reflects interference with complex I of the respiratory chain and ATP synthase complex activity without disarranging the inner mitochondrial membrane, in view of the fact that the shrinkage was not affected. The effect increases with citrinin concentration. Renal tissue is more susceptible than hepatic tissue.
Pharmacokinetics of benzophenone‐3 after oral exposure in male rats
Authors: Kadry Abdelrazak M. , Okereke Chukwuemeka S. , Abdel‐Rahman Mohamed S. , Friedman Marvin A. , Davis Richard A.
Published: October 2006

Benzophenone‐3 (BZ‐3) is one of the UV‐absorbing agents that has been used in industry and medicine for more than 30 years. Millions of consumers are exposed to benzophenones on a daily basis owing to the widespread use of these compounds in many of the products on the market, such as lipsticks, hair sprays, hair dyes, shampoo and detergent bars and sunscreen lotions. This study was performed to investigate the pharmacokinetics of BZ‐3 after oral administration at 100 mg kg−1 body weight in male Sprague‐Dawley rats. Absorption from the gastronintestinal tract was rapid because BZ‐3 was detected in blood 5 min after administration. The peak plasma concentration (Cmax) was 25.6 ± 4.6 μg ml−1 and the time of occurrence (tmax) was 3.0 ± 0.4 h. The half‐life of absorption of BZ‐3 was 0.71 h. The elimination pattern was biphasic with α and β half‐lives of elimination of 0.88 and 15.90 h, respectively. The results of this study indicate the presence of strong binding between the plasma protein and BZ‐3.

Tissue distribution studies at 6 h indicate that the liver contained the highest concentration of free (58.9 ± 23.8 μg) and total (free + bound or conjugated) BZ‐3 (2087 ± 60.1 μg), followed by kidney and testes, respectively.

Urine and feces analysis indicate that urine was the major route of excretion, followed by feces. Further analysis of urine samples also indicates that conjugation of BZ‐3 with glucuronic acid was the major systemic elimination route for the compound.
Evaluation of the toxicity of several heavy metals by a fluorescent bacterial bioassay
Authors: Mariscal Alberto , García Antonio , Carnero Manuel , Gómez Jorge , Pinedo Alfonso , Fernández‐Crehuet Joaquín
Published: October 2006

This new bioassay determined the toxicity of chemical compounds dissolved in water by measuring the degree of inhibition of the ultraviolet light‐stimulated fluorescence of Escherichia coli in a culture medium in which 4‐methylumbelliferyl β‐D‐glucuronide was the only carbon source. Inhibition produced by one of five heavy‐metal salts (Cd2+, Cr6+, Hg2+, Pb2+ or Zn2+) was the end‐point and comparison standard to determine the EC50 and minimum effective concentration (MEC) that produced a decrease of E. coli growth rate, increased doubling time and percentage inhibition and reduced numbers of generations; all these values were derived from the fluorescence signals. Only Cr6+ and Hg2+ at two concentrations (0.25 and 0.5 mg I−1) almost completely inhibited this E. coli strain. All toxicant concentrations tested produced at least partial inhibitions of growth; Cr6+, Hg2+ and Cd2+, in that order, were most toxic, and Pb2+ the least. Zn2+ gave higher EC50 values at 3 h of incubation than at 4 h. The method was simple, rapid and inexpensive and would permit a large number of samples to be tested quickly.
Reduction of erythema in hairless guinea pigs after cutaneous sulfur mustard vapor exposure by pretreatment with niacinamide, promethazine and indomethacin
Authors: Yourick Jeffrey J. , Dawson Jeffrey S. , Mitcheltree Larry W.
Published: October 2006

Erythema is the initial symptom that occurs after sulfur mustard (HD) cutaneous exposure. The time course of HD‐induced erythema is similar to that observed after UV irradiation, which can be reduced by indomethacin. Sulfur mustard lethality is decreased by using promethazine, which is an antihistamine. Niacinamide can reduce microvesication after HD vapor exposure in hairless guinea pig (HGP) skin. The present study examines the effect of the combined administration of niacinamide, indomethacin and promethazine used alone or in all possible combinations on the degree of erythema and histopathologic skin damage after HD exposure in HGP. Niacinamide (750 mg kg−1, i.p.), promethazine (12.5 mg kg−1, i.m.) or indomethacin (4 mg kg−1, p.o.) used singly or in combination was given as a 30‐min pretreatment before an 8‐min HD vapor cup skin exposure. Using a combination pretreatment of niacinamide, promethazine and indomethacin, erythema was reduced at 4 (91%) and 6 (55%) h, but not 24 h after HD. The incidence of histopathological skin changes (microvesicles, follicular involvement, epidermal necrosis, intracellular edema and pustular epidermatitis) 24 h after HD was not reduced. This study indicates that HD‐induced erythema may result from several different mechanisms, including inflammation, histamine release and DNA damage. It is suggested that two phases of inflammation may occur: an early phase sensitive to antihistamines and non‐steroidal antiinflammatory drugs and a late phase of extensive cell damage that was not sensitive to these drug pretreatments.