bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Exercise Training on the Distribution of Metallic Mercury in Mice
Authors: Shimojo Nobuhiro , Arai Yoshihiro
Published: December 2008

1 The purpose of this study was to correlate exercise induced changes of antioxidant enzymes with the distribution of mercury after mercury vapour exposure in mice.

2 Exercise training consisted of swimming (1 h/day for 5 days/week) for 9 weeks. After 9 weeks of training, swim-trained mice showed significantly elevated levels of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSHpx ) in their red blood cells, CAT and GSHpx in their kidneys and SOD in the liver.

3 Exercised mice (Ex) and non-exercised mice (N.Ex) were exposed to mercury vapour (3.5 mg m-3) for 1 h. Mercury concentrations were assayed in the . blood, brain, heart, lungs, liver and kidneys along with the mercury content of the entire body. The whole body mercury content showed no significant difference in any measurement (immediately, 24 h and 48 h after mercury exposure) between the Ex and N.Ex groups. Mercury concentrations in the Ex group were significantly higher than the N.Ex group in the heart, whole blood, red blood cells and the brain at 24 and 48 h; and in the plasma and kidneys at 24 h.

4 It was concluded that exercise training is a factor in distribution changes of mercury after exposure to mercury vapour, though it is not a factor in the total absorption and excretion of mercury.
Occurrence of Autoqntibodies Directed Against Myeloperoxidase and Elastase in Patients Treated with Hydralazine and Presenting with Glomerulonephritis
Authors: Torffvit O. , Thysell H. , Nässberger L.
Published: December 2008

We have undertaken an investigation retrospectively of 21 patients with positive antinuclear antibodies, who had been on hydralazine treatment and developed a glomerulonephritis. Four patients had circulating antimyeloperoxidase (MPO) and two of them were concluded to have a hydralazine-induced glomerulonephritis, corresponding to a frequency of 10%. These two patients had antibodies of IgG and IgM class directed against myeloperoxidase (MPO), and also antibodies against elastase. These two patients had also a biopsy proven extracapillary glomerulonephritis with focal segmental necrosis.

Antibodies against elastase were furthermore seen in three patients with proliferative glomerulonephritis and in one patient with membranoproliferative glomerulonephritis.

This study confirms an association between circulating anti-MPO and a histopathological picture compatible with extracapillary proliferation and focal segmental necrosis. From a clinical, histopathological and serological point of view it can be concluded that in two patients the glomerulonephritis was associated with antibody evidence of an autoimmune side effect.
The adduct and the addict
Authors: Sim Edith
Published: December 2008

The metabolic activation or inactivation of carcinogens varies considerably in human populations and is partly genetically determined. Inter-individual variability in the susceptibility to carcinogens may be particularly important at low degrees of environmental exposure. Examples of probable human carcinogens that present widespread low-dose exposures are environmental tobacco smoke and diesel exhaust. We have determined levels of DNA adducts in bladder cells from 39 people and of 4—aminobiphenyl-haemoglobin adducts in 97 volunteers, together with the N-acetylation non-inducible phenotype, the corresponding genotype and the levels of nicotine-cotinine in the urine. We find that amongst slow acetylators, 4—aminobiphenyl-haemoglobin adducts were higher than in rapid acetylators at low or null cotinine-nicotine levels, whereas the difference between rapid and slow acetylators was less evident at increasing nicotine-cotinine levels. The N-acetyltransferase genotype is highly predictive of the acetylation phenotype. Our results indicate that the clearance of low-dose carcinogens is decreased in the genetically based slow-acetylator phenotype. Such genetic modulation of low-dose environmental risks is relevant to 'risk assessment' procedures.
Of streaming hepatocytes and meandering sinusoids
Authors: Paine Alan J
Published: December 2008

The fate of normal hepatocytes in adult rat liver was studied after genetic labelling using the Escherichia coli β-galactosidase gene coupled to a nuclear localisation signal. The marker gene was introduced by direct in vivo retroviral-mediated gene transfer into hepatocytes 24 h after partial hepatectomy. Analysis of β-galactosidase expression in the liver at various times after gene transfer revealed that labelled hepatocytes were distributed throughout the entire lobule with a predominance in the periportal and mediolobular regions. Long-term experiments demonstrated that division of hepatocytes did occur as was revealed by the increasing number of β-galactosidase-positive cells in isolated clusters. There was no evidence for the participation of stem cells in this process. Moreover, we found that after more than one year, the pattern of distribution of positive cells within the lobule was not modified. This suggests that hepatocytes do not migrate from the portal space to the perivenous region, as has been previously hypothesised.
Elimination Studies of Antipyrine and its Metabolites in Healthy Saudi Arabians
Authors: Ali Hatim A. , El-Yazigi Adnan , Sieck Jens O. , Døssing Martin , Saour Jalal , Raines Dale A. , Ernst Peter
Published: December 2008

1 We measured the antipyrine clearance in 18 healthy Saudi subjects and determined the urinary excretion of three of its metabolites: 4-hydroxyantipyrine (4-OH AP), norantipyrine (NOR AP) and 3 hydroxymethylantipyrine (3-OHM AP) in 21 subjects.

2 The mean ± SD of the antipyrine clearance was 2.4 ± 1.1 h-1 (range 1.0-5.5 l h-1) and the corresponding value per kg body weight was 0.6 ± 0.2 ml min-1 kg-1. Urinary excretion of antipyrine (AP), 4-OH AP, NOR AP and 3-OHM AP expressed as a percentage of the oral dose of antipyrine given was 2.8 ± 2.2, 14.5 ± 6.9, 12.3 ± 5.6 and 7.6 ± 3.2 respectively.

3 Compared to Africans, Saudis preferentially metabolize AP to NOR AP and compared to Caucasians to 3-OHM AP, rather than to 4-OH AP. These discrepancies may reflect age differences between the study populations rather than genetic or ethnic variations.
Chronic Nephrotoxicity of Soluble Nickel in Rots
Authors: Vyskočil A. , Viau C. , Čížková M.
Published: December 2008

1 Male and female Wistar rats were given 100 mg L-1 of nickel (as nickel sulfate) in drinking water for 6 months. Lactate dehydrogenase, total proteins, N-acetyl-β-D-glucosaminidase (NAG), albumin and β2-microglobulin were measured in 24 h urine after 3 and 6 months of exposure. Body and kidney weights were also recorded.

2 After 6 months, urinary excretion of albumin in control and exposed rats was 354 and 1319 μg 24 h-1 for female rats (P<0.05) and 989 and 2065 μg 24 h-1 for male rats (P = non significant). Kidney weights were significantly increased in the exposed groups. No significant changes were observed in other parameters.

3 The results suggest that low-level oral exposure to soluble nickel either induces changes of glomerular permeability in female and possibly in male rats, or enhances the normal age-related glomerular nephritis lesions of ageing rats. The intake was probably not high enough to induce significant tubular changes. The female rat seems to be more sensitive to the nephrotoxic effect of nickel than the male rat.
Lead Poisoning from Retained Lead Projectiles. A Critical Review of Case Reports
Authors: Magos L.
Published: December 2008

Case reports demonstrate that embedded lead projectiles (bullets, pellets) have the potential to cause lead poisoning. They also show that the relationship between blood lead concentration and lead poisoning is the same as in lead poisonings of occupational origin and that latent periods between lodgement and the onset of lead poisoning varies from less than a half year to several decades. Nevertheless neither the quantitative relationships between projectiles and blood concentrations nor the number at risk and the number affected are known. The aim of this review is to show the limitations of case studies through the analysis of negative and positive case reports, diagnostic and monitoring methods, differences between bullets and pellets, and factors affecting the disintegration of projectiles and the distribution of released lead.
Thiol Levels in Rat Bronchio-Alveolar Lavage Fluid after Administration of Cysteine Esters
Authors: Lailey Alison F. , Upshall David G.
Published: December 2008

1 The intraperitoneal administration of cysteine, N-acetylcysteine, the methyl, isopropyl, cyclo pentyl, neo pentyl, cyclo hexyl and tertiary butyl esters of cysteine and of cystine dimethyl ester increased the levels of total non-protein sulphydryls and cysteine in the bronchioalveolar lavage fluid and plasma of rats. In all cases the non-protein sulphydryl levels reflected the increased cysteine levels.

2 Cysteine, N-acetylcysteine, the cysteine esters and cystine dimethyl ester raised the levels of non-protein sulphydryls and hence cysteine in the bronchioalveolar lining fluid as follows: CIPE > CCPE > CME > CDME > CneoPE > CCHE > Nac > CySH > CTBE.

3 Plasma levels of NPSH were increased as follows: Nac > CySH > CCPE > CCHE > CneoPE > CIPE > CME > CDME > CTBE.

4 All except CTBE have been shown to protect against the lethal effects of inhaled perfluoroisobutene, a pyrolysis product of polytetrafluoroethene which induces a fulminating pulmonary oedema.

5 This study showed that by raising the levels of thiols in the bronchioalveolar lavage fluid (BALF), the epithelial cells lining the bronchiolar, alveolar regions of the lung could be protected against inhaled toxicants.

6 It is proposed that increased thiol levels in the BALF may contribute to the overall protection induced by these compounds by reacting with inhaled electrophiles to prevent or reduce damage to tissue in close proximity to the airways.
Biotransfiormation and Toxicity of Halogenated Benzenes
Authors: den Besten C. , Brouwer A. , Rietjens I.M.C.M. , van Bladeren P.J.
Published: December 2008

1 Multiple potentially harmful metabolites can be distinguished in the metabolic activation of halogenated benzenes: epoxides, phenols, benzoquinones and benzoquinone-derived glutathione conjugates.

2 The role of these (re-) active metabolites in the toxic effects induced by halogenated benzenes such as hepatotoxicity, nephrotoxicity, porphyria and thyroid toxicity is discussed.

3 Evidence is presented suggesting that the formation of reactive benzoquinone metabolites rather than the traditional epoxides is linked to halogenated benzene-induced hepatotoxicity.

4 A crucial role for the benzoquinone-derived glutathione adducts in halogenated benzene-induced nephrotoxicity is clearly established.

5 Although metabolic activation appears to be involved in porphyria, the nature of the ultimate porphyrinogenic metabolite has not been elucidated yet.

6 Disturbances in thyroid hormone (and retinoid) homeostasis can be (at least partially) explained by the formation of halogenated phenol metabolites.

7 In conclusion, for a relevant prediction of the ultimate fate of a compound in a living organism, one should know the chemical characteristics and reactivity of the parent compound and its metabolites, together with insight into the formation mechanism of each of the suspected metabolites, and an understanding of the interaction between a specific chemical (reactive) structure and its target molecule.
Cellular and molecular aspects of organotin-induced thymus atrophy
Authors: Pieters Raymond H.H. , Bol Marianne , Seinen Willem , Penninks André H.
Published: December 2008

1 Organotin compounds, di-n-butyltin dichloride (DBTC) in particular, have been shown to cause Thymus atrophy in the rat.

2 DBTC-induced thymus atrophy results from a depletion of small CD4+CD8+ thymocytes which is caused by a diminished production of immature CD4-CD8+ and CD4+CD8+ thymoblasts.

3 DBTC inhibits the activation, but not the differentiation of immature CD4-CD8+ thymocytes in vitro and in vivo suggesting a selective anti-proliferative activity of DBTC.

4 DBTC inhibits the adhesion molecule-mediated binding of thymocytes to thymic epithelial cells.

5 DBTC enhances the Ca2+ release elicited by cross-linking of the T cell receptor complex (TcRαβ-CD3) on thymocytes and moreover delays cap formation of the TcRαβ-CD3 receptor.

6 It is concluded that DBTC possibly interferes with the functioning of the cytoskeleton. The relation of the in vitro findings to the inhibition of immature CD4-CD8+ thymocyte activation and the induction of thymus atrophy is unknown as yet.
Inhibition of aflatoxin B1-induced cell injury by selenium: an in vitro study
Authors: Shi Chen-Yang , Hew Yin-Chin , Ong Choon-Nam
Published: December 2008

Dietary selenium is an essential trace element in human nutrition. Selenium has been shown in animal studies to inhibit aflatoxin hepatocarcinogenesis. However, the cellu lar mechanism responsible for the inhibition has not been thoroughly studied. This study examines the effect of two selenium compounds, namely, sodium selenite and selenium- enriched yeast extract (SeY), on the cytotoxicity, DNA- binding and mutagenicity of aflatoxin B1 (AFB1) in cul tured Chinese hamster ovary (CHO) cells. CHO cells, after treatment with 2 μg ml-1 selenite or 80 μg ml-1 SeY, exhibit ed increased resistance to AFB1-induced cell killing. At a concentration of 50 μg ml-1 AFB1, cell survival, measured by the clonogenicity assay, was increased by 21- and 10- fold in selenite- and SeY-treated cells, respectively. However, selenium treatment did not appear to affect AFB1-DNA binding. Similarly, no effect was observed on AFB1 mutagenicity, as determined by the hypoxanthine- guanine phosphoribosyl transferase (HPRT) gene mutation assay. The results showed that selenium could effectively protect cells from AFB1 cytotoxicity in cultured cells but had no effect on AFB1-DNA adduct formation or mutagen esis. It is suggested that there are multiple pathways of AFB1 toxicity and that selenium can modulate AFB1- induced cell killing independent of its genotoxicity.
Protection against inhalation toxicity of ricin and abrin by immunisation
Authors: Griffiths G.D. , Lindsay C.D. , Allenby A.C. , Bailey S.C. , Scawin J.W. , Rice P. , Upshall D.G.
Published: December 2008

1 Abrin and ricin are highly toxic plant proteins which are very similar in structure and function and inhibit protein synthesis in eukaryotes.

2 Rats have been immunised against either toxin using formaldehyde-toxoids by three subcutaneous injections at intervals of 3 weeks. For abrin, serum titres in 14 out of 15 rats were raised to between 1 : 12800 and 1 : 51200 after two injections, 6 weeks from the start of the experiment. Titres of between 1 : 256 and 1 : 1024 were also measured in lung washes after challenge with active abrin toxin.

3 The three major antibody classes, IgG, IgM and IgA were present in the immune sera but IgG and IgA only were detected in lung washes. The proportion of IgA to IgG was higher in the lung fluid than in sera. Rats immunised by abrin toxoid were protected against 5 LCt50's of abrin by inhalation but others exposed to ricin were not.

4 For ricin, serum titres ranged from 1 : 800 to 1 : 25600 after two injections and after a third injection the titre range was the same but population samples were weighted towards the higher titres. All rats immunised with ricin toxoid survived the challenge of 5 LCt50's of ricin toxin by inhalation over the observation period of 28 days post-challenge.

5 Representative immunised rats (abrin toxoid) were taken at various times post-exposure, humanely killed and tissues were examined for pathological changes. It was concluded that an apparently severe lung lesion occurred at a later time than in non-immunised, toxin challenged rats. This damage was not lethal over the experimental observation periods.

6 Immunisation by the sub-cutaneous route therefore protects against lethality from challenge by inhalation of ricin or abrin toxins but does not prevent significant lung damage.
Human metabolism of aluminium-26 and gallium-67 injected as citrates
Authors: Priest ND , Newton D. , Day JP , Talbot RJ , Warner AJ
Published: December 2008

126Al and67Ga were given as citrates to a healthy male volunteer by intravenous injection. The retention of both tracers was studied by body radioactivity measurement. Levels in blood and excreta were determined by y-ray spectrometry and/or accelerator mass spectrometry.

2 More than half of the26Al had left the blood after 15 min and the decline continued, leaving <1% in blood after 2 d; the losses occurred both to renal excretion and through uptake by other compartments. Estimated excre tion up to 13 d was 83% (urine) and 1.8% (faeces). Whole-body retention of 15% at 13 d declined to ∼4% at 1178 d, when the daily reduction corresponded to a bio logical half-life of 7 y, suggesting that sustained intake of dietary aluminium may lead to a progressively increas ing internal deposit.

3 The metabolism of67Ga differed markedly from that of26Al in all aspects studied.
Cimetidine as adjunctive treatment for acetaminophen overdose
Authors: Burkhart Keith K , Janco Nancy , Kulig Kenneth W , Rumack Barry H
Published: December 2008

The aim of this study was to determine if cimetidine in addition to N-acetylcysteine and standard supportive care provide additional hepatoprotection following acute acetaminophen poisoning.

It was designed as a prospective study with alternate month treatment protocol, and the work was carried out at a regional certified poison information centre.

For a 2-year period, consultations received by the Rocky Mountain Poison Center involving acute aceta minophen overdose patients with a serum level above the nomogram line, but who would not receive N-acetylcys tine therapy until at least 8 h postingestion, were prospec tively evaluated for adjunctive treatment with cimetidine. All patients received standard supportive therapy and N- acetylcysteine treatment. During odd numbered months, cimetidine 300 mg was administered intravenously every 6 h for the duration of N-acetylcysteine therapy.

Forty-one cimetidine treated patients were compared to 66 patients in the control group. The peak measured AST levels (+/- s.e.) were 1259+/-330 and 1301+/-451 for the control and cimetidine treatment groups, respectively (P = 0.94). Fourteen of 64 patients (21%) in the control group and 8/41 patients (20%) in the cimetidine group developed an AST > 1000 IUL-1. There were no statistical differences between the cimetidine-treated and control groups when classified by AST<100IUL-1, 100- 1000IUL-1, or >1000IUL-1.

The addition of cimetidine therapy to standard N- acetylcysteine treatment did not provide additional hepatoprotection in acutely acetaminophen poisoned patients when treatment was started later than 8 h post overdose. Larger doses of cimetidine along with more fre quent or continuous intravenous administration may war rant further study.
The effect of chronic and acute ethanol treatment on morphology, lipid peroxidation, enzyme activities and Na+ transport systems on WRL-68 cells
Authors: Gutiérrez-Ruiz MC , Bucio L. , Souza V. , Cárabez A.
Published: December 2008

In this study we measured some parameters that are asso ciated with ethanol damage to the liver. The method allowed us to determine the injury that chronic and acute ethanol treatments produce at the cellular level without interference from homeostatic or compensatory mecha nisms. The system used is a hepatic fetal human cell line, WRL-68, which retains, in culture, many of the liver-spe cific functions. WRL-68 cells do not metabolise ethanol, and consequently we could evaluate the effect of ethanol alone. We explored two different conditions: 30 days with 0.1 M ethanol (chronic treatment) and 24 h in the presence of 0.5 M ethanol (acute treatment).

1 The transmission electron microscopy studies revealed, in both treatments, the presence of granules not usually present in the cytoplasm of control cells and morphologi cal mitochondrial alterations in chronically treated cells.

2 Lipid peroxidation, measured as the rate of malondi aldehyde production, increased three and a half times in acutely treated cells and about twofold in chronically treated cells.

3 The percentage of total activity (activity in the medi um/(activity in the medium + activity of the cells). 100) and the enzymatic activity in the culture medium of gamma glutamyl transpeptidase (GGT), alanine amino transferase (ALAT), aspartate amino transferase (ASAT) and alkaline phosphatase (AI-P), increased.

4 We measured some parameters related to the transport of sodium across the membrane. Cells chronically treated with ethanol had higher rate constants and effluxes than control cells. There was no difference between the total and passive efflux. Ethanol treated cells apparently lacked the ouabain sensitive pathway. In acutely treated cells, the total sodium efflux and the rate constant were enhanced. Sodium pools in the acutely treated cells were diminished and active sodium pumping was seven times higher than in control cells.

5 We determined the number of high affinity ouabain binding sites per cell. Ethanol did not alter the number of pumps, rather it seems to induce a functional alteration. Our results indicate that ethanol per se induces lipid per oxidation, alters enzymatic activities, sodium transport systems, sodium pools and cellular morphology, and that all these changes may be partly responsible for ethanol- induced hepatotoxicity. The data compare favourably with those reported in the literature for many different systems. Therefore our model for studying the mechanism of alco hol effects appears to be valid, with the advantage of being able to compare experiments that can be done in the same system and under the same conditions.
Investigation of immunotoxicity of supercypermethrin forte in the Wistar rat
Authors: Tulinská J. , Kubová J. , Janota S. , Nyulassy Š.
Published: December 2008

The study was done to find out whether subacute exposure to supercypermethrin forte (SCM) affected cellular and humoral immunity.

Groups of 10 male Wistar rats were given SCM by gav age for 28 days at 12.5 mg kg-1 day-1 (1/14 LD50), 8.75 mg kg-1 day-1 (1/20 LD50) and 4.38 mg kg-1 day-1 (1/40 LD50) and the response of splenocytes to mitogens, natural killer cell activity, plaque forming cell assay and phagocytosis were examined.

The response of splenocytes to the mitogens phyto haemagglutin and concanavalin A, and to a T-dependent antigen (sheep red blood cells), was enhanced at 1/40 LD50 SCM, and at 1/20 and 1/14 LD50 these variables were sup pressed. In the group exposed to 1/14 LD40 SCM the sup pression was statistically significant. A non significant but dose-related increase in NK-cell activity was observed. The phagocytic activity of polymorphes was not signifi cantly affected. Thus, SCM at 1/14 LD50 had significant adverse effects on a number of immunological functions in rats, but lower doses had no effect on these activities.
Effect of inhaled aerosol of 1-Chloroacetophenone (CN) and Dibenz (b,f)-1,4 oxazepine (CR) on lung mechanics and pulmonary surfactants in rats
Authors: Kumar Pravin , Vijayaraghavan R. , Pant SC , Sachan AS , Malhotra RC
Published: December 2008

Inhalation toxicity following exposure to 1-Chloroace tophenone (CN) and Dihenz(b,f)-1,4 oxazepine (CR) aerosols for 60 min at sublethal concentrations were stud ied in rats. The dynamic surface tension (γ max and stabil ity ratio) of lung homogenate increased significantly on CN exposure. The lung mechanics studies revealed a sig nificant increase in compliance in CN exposed rats. CR, on the other hand did not influence any of the above vari ables except for a decrease in compliance. Total lung phos pholipids and sphingomyelin contents decreased signifi cantly following exposure to CN, while CR exposure pro duced an increase in sphingomyelin, reduction in phos phatidylcholine and ethanolamine, with no change in total phospholipid contents. Histomorphological observations indicated cellular degeneration in the epithelium of the bronchiole and alveolar septal-wall thickening due to the presence of an increased number of mononuclear cells in CN exposed rats. However, CR induced inflammatory reaction and enlargement of respiratory air spaces. It is concluded that of the two sensory irritants (tear gases) examined, CN is potentially more toxic compared to CR in rats.
Poisoning due to Chinese proprietary medicines
Authors: Chan Thomas YK , Lee Kenneth KC , Chan Albert YW , Critchley Julian AJH
Published: December 2008

1 To determine the toxic potentials of those Chinese pro prietary medicines (CPM) which are commonly used for self-poisoning by adults in Hong Kong, all patients admit ted to four of the eight general medical wards at the Prince of Wales Hospital between January 1988 and December 1993 were retrospectively studied.

2 There were 54 women and 17 men with their age rang ing from 15 to 86 years. Twenty-three subjects (32%) also took alcohol, chemicals or drugs. Of the 51 subjects (72%) who had taken topical medicaments, 22 had no symptoms while 28 had minor features of gastrointestinal irritation ( n = 26), mild ( n = 2) or severe ( n = 1) salicylate poisoning. Of the 17 subjects (24%) who had taken CPM tablets/cap sules, nine had mild symptoms including nausea/vomiting and drowsiness. The three remaining patients (4%) who had ingested liquid CPM preparations were asymptomatic. Elevated plasma salicylate or paracetamol concentrations (> 0.1 mmol l-1l) were found in some patients who had taken topical medicaments and CPM tablets/capsules, respectively. All the 71 patients completely recovered. 3 Most of the CPM used for self-poisoning in Hong Kong were of low to moderate toxicity except for those contain ing wintergreen oil (methyl salicylate).
Potential neurotoxicity of a novel aminoacridine analogue
Authors: Walker TM , Starr B. , Dewhurst BB , Atterwill C.
Published: December 2008

1 A class of compounds, 9-aminoacridines, have long been known to be reversible inhibitors of acetyl cholinesterase (AChE - EC 3.1.1.7), the most familiar of which is 9-amino-1,2,3,4-tetrahydroacridine (Tacrine).

2 A novel aminoacridine was synthesised: - 2-tertiary butyl-9-amino-1,2,3,4-tetrahydroacridine (2tBuTHA).

3 In vitro comparisons of the acetylcholinesterase inhibitory potential and neurotoxicity compared to Tacrine were performed using a chemically differentiated neuroblastoma cell line (Neuro 2A). 2tBuTHA, but not Tacrine, was cytotoxic to the neural cell following 20 h exposure, despite being the least potent AChE inhibitor (IC80 AChE 12.53 μM +/- 1.14 s.e.m., Neutral Red Uptake IC50 9.53 μM +/- 0.98 s.e.m., MTT Reduction IC80 14.6 μM +/- 1.43 s.e.m.).

4 In vivo studies used a novel application of a five arm radial maze to assess neuropharmacological effects on working memory in control and Scopolamine (1 mg kg-1 i.p.) treated mice. There was an impairment of short term cognitive function with 2tBuTHA (15 mg kg -1 i.p.), but not Tacrine (10 mg kg-1 i.p.) which improved the Scopolamine deficit as expected.

5 This combined in vitro and in vivo data infers a neuro toxic property for the novel compound 2tBuTHA, a close structural analogue of Tacrine.
Effect of dermal application of hexachlorocyclohexane (HCH) on male reproductive system of rat
Authors: Prasad AK , Pant N. , Srivastava SC , Kumar R. , Srivastava SP
Published: December 2008

1 The toxic manifestations of dermally applied hexa chlorocyclohexane (50 mg or 100 mg kg-1 body weight day -1, 5 days in a week for 120 days) on testes and sperm of rat have been investigated.

2 The results indicate that exposure of HCH through the dermal route could lead to an alteration in the activities of marker testicular enzymes viz. sorbitol dehydrogenase (SDH), glucose-6-P-dehydrogenase (G6PDH), γ-glutamyl transpeptidase (γ-GT) and β-glucuronidase (βGluc.) associ ated with specific cell types.

3 Significant quantities of HCH and its isomers accumu lated in testes as well as sperm of treated rats.

4 HCH exposure also led to a decrease in serum testos terone levels, epididymal sperm count, sperm motility and an increase in the percentage of abnormal sperm. 5 These observations indicate the possibility of adverse effects of HCH on the male reproductive functions of men exposed dermally to this pesticide in industry or during spraying in the field.
Polycyclic aromatic hydrocarbons in placenta, maternal blood, umbilical cord blood and milk of Indian women
Authors: Madhavan ND , Naidu KA
Published: December 2008

Human placenta, umbilical cord blood, maternal blood and breast milk samples from mothers were analysed for the presence of selected polycyclic aromatic hydrocarbons (PAHs). Benzo(a) pyrene (B(a)P), dibenzo(a,c)anthracene (DBA) and chrysene (Chy) were detected in all the four types of sample. Levels of dibenzo(a,c)anthracene were higher in the above samples compared with the other two PAHs. Umbilical cord blood and breast milk samples showed relatively high concentrations of all the three PAHs and thus demonstrated that the developing foetus/new born were exposed to these carcinogenic envi ronmental contaminants. The possible implications of PAHs in relation to human health are discussed.
Concentration-response relationships for three nonsteroidal anti-inflammatory drugs in the rat intestine
Authors: Ford J. , Houston JB
Published: December 2008

1. The effect of diclofenac, piroxicam and (S+)-ibuprofen upon the rat intestine has been measured at constant drug plasma concentrations in the rat, using (51Cr)-EDTA intestinal permeation as a measure of damage. Initially disposition studies after sc administration of the three NSAIDs were carried out. From these studies it was found that constant-rate iv infusions were necessary to maintain plasma concentrations of diclofenac and (S+)-ibuprofen. Administration of piroxicam by sc bolus gave relatively constant plasma concentrations, thus iv infusions were not necessary to obtain concentration-response data for this drug. Relative potency was found by comparing the con centration-response profiles of the three NSAIDs and the rank order of potency obtained was: diclofenac > piroxi cam > (S+)-ibuprofen.

2. The effect of mode of administration upon intestinal damage was also investigated using diclofenac. Intestinal permeability was measured in rats given diclofenac either by sc bolus or iv infusion and dose-response data com pared. It was found that for the same dose, administration by sc bolus gave a higher degree of damage than by iv infusion.
Further evidence that the blood/brain barrier impedes paraquat entry into the brain
Authors: Naylor JL , Widdowson PS , Simpson MG , Farnworth M. , Ellis MK , Lock EA
Published: December 2008

The distribution of the non-selective herbicide paraquat was examined in the brain following subcutaneous admin istration of 20 mg kg-1paraquat ion containing [14C]paraquat to male adult rats in order to determine whether paraquat crosses the blood/brain barrier. Following administration, [14C]paraquat reached a maxi mal concentration in the brain (0.05% of administered dose) within the first hour and then rapidly disappeared from the brain. However, 24 h after administration of the herbicide, about 13% of the maximal recorded concentra tion of paraquat remained in the brain (1.6 nmol g-1wet weight) and could not be removed by intracardiac perfu sion. Using measurements of [14C]paraquat in dissected brain regions and using quantitative autoradiography we demonstrated an asymmetrical distribution in and around the brain at 30 min (maximal concentration) and 24 h after administration. Most of the paraquat was associated with five structures, two of which, the pineal gland and linings of the cerebral ventricles lie outside the blood/brain barrier whilst the remaining three brain areas, the anterior portion of the olfactory bulb, hypothalamus and area postrema do not have a blood/brain barrier. Overall, the distribution of [14C]paraquat in the brain 24 h after systemic administration was highly correlated to the blood volume. These data indicate that any remaining paraquat in the brain 24 h after systemic administration is associated with elements of the cerebro-circulatory sys tem, such as the endothelial cells that make up the capil lary network and that there is a limited entry of paraquat into brain regions without a blood/brain barrier. No [14C]paraquat was detected in regions where there has been demonstrated pathology in brains from humans with Parkinson's disease. Finally, we could find no evidence for paraquat-induced neuronal cell necrosis 24 or 48 h after systemic administration. Overall it may be concluded that systemically administered paraquat does not pose a direct major neurotoxicological risk in the majority of brain regions which have a functional blood/brain barrier since paraquat can be excluded from the brain by this barrier.
Effect of pyridostigmine pretreatment on cardiorespiratory function in tabun poisoning
Authors: Worek F. , Kleine A. , Szinicz L.
Published: December 2008

1 The effect of pyridostigmine on cardiorespiratory func tion after oxime+atropine injection was investigated in tabun poisoned guinea-pigs and without tabun poisoning.

2 The trachea, a carotid artery and jugular vein were can nulated in female urethane-anaesthetised Pirbright white guinea-pigs. After baseline measurements the ani mals received pyridostigmine (0.05 μmol kg-1) and 30 min later atropine (29.5 μmol kg-1) plus obidoxime, HI 6 or HL6 7 (30 or 100 μmol kg-1) or tabun (1.85 μmol kg-1= 5 x LD50) followed by oxime+atropine treatment (all i.v.). Erythrocyte, brain and diaphragm acetyl cholinesterase (AChE) activity were determined. Similar groups without pretreatment were included for compar ison.

3 Pyridostigmine aggravated the oxime+atropine induced hypotension and prevented the increase in heart rate but not the respiratory stimulation. The pyridostigmine inhibited AChE recovered only in the 100 μmol kg-1kg oxime groups at the end of the experiment.

4 In tabun poisoning, pyridostigmine reduced the oxime+atropine induced circulatory recovery and decreased the survival time and rate. It did not affect the therapeutic oxime+atropine effect on respiratory function.

5 These results suggest that pyridostigmine enhances oxime+atropine related circulatory depression which may be the reason for the reduced efficacy of oxime+atropine treatment in tabun poisoning. The pos sible mechanisms are discussed.
Intrapleural administration of vitreous high duty ceramic fibres and heated devitrified ceramic fibres does not give rise to pleural mesothelioma in rats
Authors: Carthew P. , Edwards RE , Dorman BM , Brown RC , Young J. , Laskowski JJ , Wagner JC
Published: December 2008

In order to determine whether they are potentially car cinogenic to the pleural mesothelium, three samples of ceramic fibre have been administered to rats by the intrapleural route. These samples were a high-duty grade refractory ceramic fibre (manufactured by Thermal Ceramics Ltd) in the as-manufactured vitreous state and two devitrified samples produced by heating the same fibre for 2 weeks at 1200°C and for two weeks at 1400°C. The mean lifespans of the groups of rats treated with vitri fied and devitrified ceramic fibres were not significantly different from that of the control rats. In these studies none of the treated or control rats developed pleural mesothelioma, making it unlikely that ceramic fibres of this type, whether vitreous or devitrified, are potentially carcinogenic to the pleural mesothelium.
Effect of intraventricular injection of 1-methyl-4-phenylpyridinium: protection by acetyl-L-carnitine
Authors: Steffen V. , Santiago M. , de la Cruz CP , Revilla E. , Machado A. , Cano J.
Published: December 2008

1-methyl-4-phenylpyridinium (MPP+) is the bioactivated product of 1-methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyri dine (MPTP). The neurotoxic action of MPP+ injected intracerebroventricularly (ICV) in the rat has been stud ied, using dopaminergic systems in the substantia nigra, striatum, olfactory bulb, median eminence and hypoph ysis. The following results were obtained: (1) Rats with ICV administration of 1 μl MPP+ solution (62.5 μg of MPP+ rat) showed 50% mortality; (2) The ICV administration of MPP+ produced a decrease in dopamine (DA) concentra tion in different areas of rat CNS studied: striatum (83%), hypophysis (95%) and median eminence (70%). However, olfactory bulb and substantia nigra were not affected; (3) MPP+ by ICV administration produced neurotoxic effect on the dopaminergic system. We also studied the possible protective action of acetyl-L-carnitine (ALC) against the neurotoxic action of MPP+. Rats were intraperitoneally injected daily for 8 days with 100 mg kg-1 of ALC and 3 days from the beginning of the MPP+ treatment; (4) We found that the ALC treatment significantly protected against mortality produced by the ICV injection of MPP+. Rats treated with ALC showed no mortality; (5) We did not find a protective effect on the dopaminergic system study ing either catecholamine concentration or measuring tyro sine hydroxylase, neurofilament or glial fibrillary acid protein; (6) The results suggest that the ALC protective action could be related to energy metabolism.
Effect of oral administration of carbofuran on male reproductive system of rat
Authors: Pant N. , Prasad AK , Srivastava SC , Shankar R. , Srivastava SP
Published: December 2008

1 Carbofuran was administered orally to adult male rats at dose levels of 0.1, 0.2, 0.4 or 0.8 mg kg -1 body weight, 5 d wk-1 for 60 days. A dose dependent decrease was observed in body weight of rats treated with 0.2-0.8 mg carbofuran kg -1 body weight

2 A significant decrease in the weight of epididymides, seminal vesicles, ventral prostate and coagulating glands was observed at various test doses of carbofuran except at the lowest dose.

3 Decreased sperm motility, reduced epididymal sperm count along with increased morphological abnormali ties in head, neck and tail regions of spermatozoa were observed in rats exposed to 0.2, 0.4, or 0.8 mg carbo furan kg-1 body weight.

4 In addition, significant alterations were observed in the activities of marker testicular enzymes viz. sorbitol dehydrogenase (SDH), glucose-6-P-dehydrogenase (G6PDH) (decreased), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GT) (increased) depending on dose.

5 Histologically, the results indicated the toxicity of carbo furan on testes depending on dose. The changes pre dominantly consisted of moderate oedema, congestion, damage to Sertoli cells and germ cells, along with the accumulation of cellular debris and presence of giant cells in the lumen of a few seminiferous tubules which showed disturbed spermatogenesis with the higher doses of carbofuran.

6 These observations determined a no effect level dose of 0.1 mg kg-1 body weight of carbofuran on the biochemi cal and morphological indices studied for male repro ductive toxicity assessment in the rat model. The results of the present study provide first hand information on the reproductive toxicity of carbofuran in male rats.
Small-intestinal transfer mechanism of prunasin, the primary metabolite of the cyanogenic glycoside amygdalin
Authors: Strugala GJ , Stahl R. , Elsenhans B. , Rauws AG , Forth W.
Published: December 2008

1 The small-intestinal transfer of prunasin (D-mandelo nitrile-β-D-glucoside), the primary metabolite of amyg dalin which is not absorbed in the small intestine as such, was studied in rat jejunum and ileum in vitro.

2 As shown by high pressure liquid chromatography, prunasin is transferred essentially intact across the intesti nal wall, without cleavage of the glycosidic bond and thus no formation of benzaldehyde or cyanide during the mucosal passage.

3 Only the jejunal transfer of prunasin followed satura tion kinetics (vmax = 1.6 μmol cm-1 min-1; KT = 460 μmol l-1) and exhibited a clearsodium-ion dependence. As indicated by the temperature dependence, only the jejunal mucosa- to-serosa transfer and the corresponding tissue uptake of prunasin required apparently high activation energies. Transfer in the terminal ileum showed diffusion character istics.

4 Jejunal methyl α-D-glucoside transfer was inhibited by the presence of prunasin. Furthermore, the tissue uptake of methyl α-D-glucoside in rat jejunum was competitively inhibited by prunasin.

5 The results indicate that prunasin is absorbed unmetabolised in the jejunum of the rat via the transport system of glucose.
Gastrointestinal iron and cobalt absorption and iron status in young rats and guinea pigs
Authors: Naylor Gpl , Harrison JD
Published: December 2008

The gastrointestinal absorption of Fe and Co by rats and guinea pigs of different ages was measured by comparing the whole-body retention of 59Fe and 57Co after oral and intraperitoneal administrations. The age-groups studied included newborn, weanlings and adults. The absorption of both Fe and Co decreased markedly with age in both rats and guinea pigs. In the rat, absorption remained ele vated during the suckling period, while in the guinea pig absorption decreased markedly during suckling. In both species, Fe and Co absorption were similar, and remained elevated above adult values for some time after weaning. The generally greater absorption of Fe and Co by rats than by guinea pigs and the longer duration of maximal absorp tion in the rats may have involved differences in Fe status in the two species and differences in the timing of gut mat uration.
Accelerating ADME studies
Authors: Chasseaud L.F.
Published: December 2008

A novel method is described for quantitative whole- body autoradioluminography using [14C]-radioactive standards prepared from rat red blood cells. MicroComputer Imaging Device model 2 (MCID) and ImageQuant (IQ) imaging systems were evaluat ed for imaging performance and autoradioluminog raphy quantitation. Weighted linear regression analysis resulted in linearity over five orders of magnitude with a lower limit of quantitation of 2.7 nCi g-1. Using IQ, 16 days were necessary for image analysis and data processing of 30 whole-body cryosections and 1080 standards. MCID reduced the image and data processing of the same cryosections and standards to only 4 days. Embedding a series of radioactive standards with each specimen in the same carboxymethyl cellulose block provided an effective method of assessing intrasection and inter section variations in thickness of whole-body cryosections. These results demonstrated that autoradioluminography provided a sensitive, accu rate, precise and reproducible method for the quan titative measurement of the tissue distribution of [14C]-radiolabelled xenobiotics in whole-body cryosections. Evaluating the biodistribution of [14C]- xenobiotics by autoradioluminography, not only provides pharmacokinetic data required for predict ing the potential tissue deposition of an absorbed dose of radioactivity in man, but also allows for visual and quantitative evaluation of radioactivity in small anatomical structures that otherwise could not be detected or measured by conventional tissue combustion technology.
More on genetic predisposition
Authors: Strange Richard C
Published: December 2008

The individual genotoxic response of cultured human lymphocytes to diepoxybutane (DEB), an epoxide metabolite of 1,3-butadiene, shows a bimodal distribution. Blood donors can be classi fied as either DEB-sensitive or DEB-resistant on the basis of the frequency of sister chromatid exchanges (SCEs) induced by DEB in whole-blood lymphocyte cultures. The genetic basis of this phenomenon has thus far been unknown. To investigate if differences in the ability of individuals to detoxify DEB could explain the bimodal response, sister chromatid exchanges (SCEs) induced by a 48-h treatment with DEB (2 and 5 μM were analysed in whole-blood lymphocyte cultures of 20 human donors with known genotypes of two polymorphic glutathione S-transferases (GSTs). GSTT1 and GSTM1. Both polymorphisms include a homozygous null geno type lacking the respective GST gene and isozyme. The mean frequency of SCEs/cell was 1.6 times higher among GSTT1 null donors (n = 8) than GSTT1 positive donors (n = 12) at both 2 μM DEB (mean 67.3 versus 40.9) and 5 μM DEB (mean 123.2 versus 77.5), with no overlapping in DEB-induced individual SCE frequencies between the two geno types. Thus, all DEB-sensitive individuals were of the GSTT1 null genotype, while all DEB-resistant persons had a detectable GSTT1 gene. A significant (P < 0.05) negative correlation (r = -0.65 at 5 μM, r = 0.56 at 2 μM) was obtained in the GSTT1 positive donors between DEB-induced individual SCE fre quency and RBC GSTT1 activity, measured by formaldehyde formation from dichloromethane; the GSTT1 null individuals showed no GSTT1 activity. At 5 μM DEB, the lymphocyte cultures of the GSTT1 null donors also had a significantly decreased repli cation index, indicating an impact of GSTT1 geno type on the cytotoxicity of DEB. No influence on DEB-induced SCEs or cytotoxic effects was observed for GSTM1 genotype. It is concluded that sensitivity to in vitro SCE induction by DEB is explained by the lack of GSTT1.
Gender bender
Authors: Schwarz Leslie R. , Wolff Thomas
Published: December 2008

Cyproterone acetate (CPA), a synthetic steroid used in human therapy, has recently been shown to cause DNA damage in cultured rat hepatocytes and in rat liver. In the present study we have investigat ed whether CPA also induces genotoxic effects in human hepatocytes. Genotoxicity of CPA was deter mined by measuring the capability of the com pound for inducing DNA repair synthesis and for causing the formation of DNA single-strand breaks. Autoradiography and alkaline elution were used to quantitate DNA repair and DNA fragmentation, respectively. Exposure of hepatocytes to CPA for 20 h induced DNA repair synthesis in two hepatocyte preparations derived from males and in four of the five preparations derived from females. In cultures from some donors, induction of repair was detected at 1 μM CPA, the lowest concentration tested. The maximum effect generally occurred at 10-20 μM. Only a very slight increase in the frequency of DNA single-strand breaks was found following exposure of the hepatocytes to 50 μM CPA for 20 h. For com parative purposes, the effects of CPA on DNA repair and DNA fragmentation were also determined in cultured rat hepatocytes. A strong induction of DNA repair synthesis, but only a slight enhancement in DNA fragmentation was observed in CPA- treated hepatocytes derived from female rats. These results indicate that the measurement of repair is a more sensitive indicator for the genotoxicity of CPA than the measurement of DNA fragmentation. No genotoxic effects of CPA were detectable in hepatocyte cultures derived from male rats. The present findings show that CPA is genotoxic in human hepatocytes and that the striking sex difference in the genotoxicity of CPA in rat cells is not observed with human cells.
Usage and adverse effects of Chinese herbal medicines
Authors: Chan Thomas Y K , Critchley Julian A J H
Published: December 2008

The great majority of Chinese herbal preparations are safe, and in the past, some useful Western drugs have been derived from these herbs.

Nearly all serious poisonings are due to the few preparations containing aconitine, podophyllin or anti cholinergics or else proprietary preparations containing dangerous Western drugs or heavy metals. Both medical professionals and the general public should be alerted to the potential toxicity of herbal remedies. There should be frequent monitoring of Chinese herbal medicines or their derivatives, such as some Chinese proprietary medicines, for undeclared Western drugs and heavy metals. Mothers should be discouraged from treating their children with herbal or proprietary medicines. There should be con tinuing efforts to collect safety information on these widely used products.