bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary excretion of proteins among metal welders
Authors: Bonde JP , Vittinghus E.
Published: December 2008

Joining of metals by welding confer an exposure of dust particulates containing several toxic substances. Chro mium, nickel and manganese is absorbed in the lungs and may adversely affect the renal function. We compared biological markers of glomerular filtration (Kampmann clearance) and tubular function (post-shift urine spot sample concentration of respectively albumin, immuno globulin G, transferrin, orosomucoid and β2-microglobu lin) among 102 ever-welders and 33 never-welders (mostly electricians). The welders were subdivided into groups of stainless steel welders (n=35), mild steel welders (n=46) and ex-welders (n=21). Each group was separately referenced with never-welders. The Kampmann clearance was within normal limits in all workers and not related to welding exposure. However, the urinary concentration of the majority of proteins was 1.5 to 3.0 times higher in both stainless steel and mild steel welders. The number of welding years taken as a measure of cumulative welding exposure was not related to levels of proteins in urine when adjusting for the effect of age. In addition, no alteration of urinary proteins was found among the ex- welders apart from slightly elevated albumin. This indicates that the apparent effect of welding on renal tubular function may at least partially be reversible. In conclusion, this study is in support of the hypothesis that metal welding may adversely affect renal tubular func tion, but it is questionable whether welding exposure has bearings as to occurrence of clinical significant kidney disease.
Cyanide toxicity in mice pretreated with diethylamine nitric oxide complex
Authors: Baskin S.I. , Nealley E.W. , Lempka J.C.
Published: December 2008

1 Since the literature suggested a portion of the overall toxicity of cyanide (CN) may be affected by nitric oxide, we investigated a long acting NO releasing complex (diethy lamine/nitric oxide (DEA/NO)) which may exhibit vasodi latory as well as other nitric oxide effects to determine its ability to modify CN toxicity. Sodium nitrite, a vasodilator commonly used to treat cyanide toxicity thought to act by methemoglobin (MHb) formation, can be rapidly trans formed to nitric oxide (NO).

2 Mice (n=10 per dose) were administered one of five doses of sodium cyanide (NaCN) intraperitoneally (4.28,5.08,6.03,7.17 and 8.52 mg kg-1). DEA/NO was given intravenously (20 mg kg-1) 2 min prior to NaCN. As a control, NG-monomethyl-L-arginine (L-NMMA), which inhibits NO synthesis, was administered intravenously (70 mg kg-1) to mice, 3 min prior to DEA/NO.

3 Before CN toxicity studies, we determined whether DEA/NO was producing MHb by collecting tail vein blood from mice and measuring MHb levels. For example, 4 min after DEA/NO administration (5,10, and 20 mg kg-1), MHb levels were 1.2 7 ± 0.28%, 2.60 ± 0.26% and 6.53 ±0.54% respectively. O2capacity was also decreased in a dose related manner. Carboxyhemoglobin or percent O2satura tion, on the other hand, was not significantly inhibited. The LD50increased from 5.75 ± 0.026 (CN alone) to 7.66 ± 0.021 mg kg-1(CN+DEA/NO) resulting in a protec tive ratio of 1.73.

4 Results suggest the following: (1) L-NMMA, which inhibits the synthesis of endogenous NO, appears to exacerbate the DEA/NO (or exogenous NO) response; (2) DEA/NO appears to reduce the toxicity of CN which suggests that a portion of CN toxicity may be affected by a NO component; and (3) low DEA/NO doses may act via a direct effect while higher doses (40 mg kg-1) may allow for formation of a concentration of MHb which can bind CN to form cyanomethemoglobin and reduce the toxicity of CN.
Cryopreservation of rat hepatocyte monolayer cultures
Authors: Watts P. , Grant MH
Published: December 2008

1 Most previous attempts to cryopreserve hepatocytes have used suspensions stored at either - 70°C or in liquid nitrogen, and the major problem is that these do not, on subsequent thawing, attach well in culture. This limits their use in studies of drug metabolism and xenobiotic- induced toxicity. In this manuscript we demonstrate successful cryopreservation of rat hepatocytes as mono layers attached to a collagen film.

2 Monolayers can be frozen and thawed without significant loss of cells, and although damage to the internal and plasma membranes is evident immediately post-thaw, a remarkable repair process takes place over 24-48 h post-thaw. Immediately post-thaw only 10% of the cells exclude Trypan Blue, but by 48 h 80 - 90% of the thawed cells are viable, indicating that repair of the plasma membranes has taken place.

3 The cells post-thaw retain aspects of liver-specific function including cytochrome P450 content and albumin synthesis. However, cytosolic proteins are lost through the damaged membranes and, probably because of this, urea synthesis from ammonia is retained at only 25% of pre- freeze values.

4 A cryopreservation method based on adherent hepa tocytes on a collagen substrate overcomes the problems encountered with culture of cryopreserved hepatocyte suspensions, and may provide a practical means of establishing a 'bank' of hepatocytes from several donors and species.
Gentamicin nephrotoxicity in the rat: influence of age and diabetes mellitus
Authors: Ali B.H. , Bashir A.K. , El Mugamer I.T. , Tanira M O M
Published: December 2008

1 This work examines the influence of age on some nephrotoxic signs of gentamicin in normal and diabetic rats (aged 1 and 24 months).

2 Gentamicin (80 mg-1kg-1day for 6 days, intramuscu larly) produced the typical pattern of nephrotoxicity; significantly increasing the plasma concentrations of creatinine and urea, and the urinary excretion of protein, copper and zinc and significantly reducing creatinine clearance and cortical alkaline phosphatase activity. The antibiotic produced a marked damage in the proximal renal tubules. Nearly all of these effects were more marked in the old than in the young rats. Cortical gentamicin concentration in the young was about 67% of that in the old.

3 Streptozotocin-induced diabetes significantly amelio rated the signs of nephrotoxicty of gentamicin in young rats. In old rats, diabetes had significantly less protective effect on the gentamicin-induced nephrotoxic signs than in the young rats. Gentamicin nephrotoxicity in diabetic old rats induced mortality in about a third of the animals used, whereas no mortality was seen in young diabetic rats treated with gentamicin.
Comparison of the toxicities of cisplatin and a new cisplatin-procaine complex to rat renal cortical slices
Authors: Zhang J-G. , Esposito M. , Cafaggi S. , Lindup WE
Published: December 2008

1 Procaine has previously been shown to diminish the nephrotoxicity of cisplatin and the nephrotoxic effects of cisplatin and a new cisplatin complex (cis-diammine chloro - [2 - (diethylamino) ethyl - 4 - aminobenzoate, N4]- chlorideplatinum (II) monohydrochloride monohydrate; DPR), that contains procaine hydrochloride were com pared with rat renal cortical slices.

2 Cisplatin at 1 mM caused toxicity to the slices, as shown by an increase in the leakage of aspartate aminotransfer ase and lactate dehydrogenase from the slices into the incubation medium and a decrease in the reduction of a tetrazolium dye (MTT assay). Addition of procaine (1 mM) protected against cisplatin-induced toxicity. DPR either at 1 mM or at 4 mM had no effect either on the enzyme leakage or MTT reduction by the renal slices, but DPR at 10 mM produced a similar magnitude of enzyme leakage to cisplatin (1 mM).

3 DPR lowered the concentration of ATP and glutathione (GSH) in the slices but was less potent than cisplatin. Thiobarbituric acid reactive substances, indicators of lipid peroxidation, released into the medium were increased by the highest concentration of DPR (10 mM), which suggests that DPR has the potential to cause oxidative stress.

4 The results suggest that DPR was far less toxic than either cisplatin alone or a mixture of cisplatin and procaine.
Effects of cyproterone acetate in C57Bl/10J mice
Authors: Tucker Mary J , Jones David V
Published: December 2008

Male and female C57BL/10J mice were fed 0 or 800 ppm cyproterone acetate (CPA) in the diet for 13 weeks.

1 Body weight was reduced (P>0.001 at 13 weeks) by approximately 33%.

2 Seminal vesicle weights were reduced (P>0.001) and showed histological atrophy, changes consistent with the anti-androgenic activity of the compound.

3 Liver weights were increased (P>0.001) by +90% of control mean weights; hepatocyte hypertrophy and increased fat and glycogen were seen by light microscopy, and hyperplasia of smooth endoplasmic reticulin by transmission electron microscopy.

4 Assessment of liver mixed function oxidase activity demonstrated induction of cytochrome P450 enzymes, and increased isozyme 2B1/2 in males and 3A1 in both sexes was confirmed by immunohistochemical staining of liver sections.

5 An increase in bromodeoxyuridine (BrdU) labelling index of the liver was seen in females only.

6 This study is the first in a programme of work with CPA designed to investigate the effects of the compound in mice. It demonstrates that the hepatic effects of the compound which have been described in the rat also occur in mice.
Quantitative risk assessment and the limitations of the linearized multistage model
Authors: Lovell David P , Thomas Gail
Published: December 2008

1 Quantifying carcinogenic risk is an important objec tive for assisting in the assessment and management of risks from chemical exposure. The most widely used ofthe many mathematical models proposed for extrapolation of carcinogenicity data from animal studies to low dose human exposures is the linearized multistage (LMS) model. This has, in effect, become the default approach for much of Quantitative Risk Assessment (QRA). The practical properties of this model have been investigated.

2 Analysis of simulated data using the LMS model showed (i) that the Maximum Likelihood Estimate (MLE) of the low dose slope, q1, was unstable and extremely sensitive to small changes in the data; (ii) the 95% Upper Confidence Limit (UCL) estimate, q1*, preferred by the US Environmental Protection Agency (EPA) was insensitive with only small changes in values being obtained for large changes in the data; (iii) data sets where there was no statistical significance could give risk estimates similar to those obtained from data sets with clear dose-related effects; (iv) the size of the values of the Virtually Safe Dose (VSD) obtained did not necessarily relate to the biological interpretation of the data sets; (v) the value of q1* obtained was closely related to the top dose used in the study.

3 Limitations of the LMS model were illustrated by examples of its use in assessing the carcinogenicity of 2, 3, 7, 8-TCDD leading to the conclusion that the existing models are not suitable for routine use in the estimation of the risk from chemical carcinogens. The use of the LMS model has been justified in part by its original derivation from a mathematical model based upon a multistage model of carcinogenesis. However, estimates of the parameters of the model used to provide estimates of low dose risk to humans have no direct relationship to specific biological event in carcinogenesis. Further developments in mathematical models and increased understanding of the biological events underlying carcinogenesis will lead to more biologically plausible QRA methods which would then justify serious consideration of QRA by regulatory authorities throughout the world.
Liver slice culture for assessing hepatotoxicity of freshwater cyanobacteria
Authors: Bhattacharya R. , Lakshmana Rao PV , Bhaskar Asb , Pant SC , Dube SN
Published: December 2008

1 A modified mouse liver slice culture technique was established and the viability of the system was assessed on the basis of leakage of cytosolic enzymes viz. lactate dehydrogenase (LDH), alkaline phosphatase (ALP), ala nine aminotransferase (ALT), aspartic aminotransferase (AST) and slice histology.

2 This system was employed for toxicity screening of five algal species of Indian origin on the basis of the EC50 for LDH leakage (dose of cyanobacteria resulting in leakage of 50% of enzyme) of a known toxic cyano bacterial strain Microcystis aeruginosa (PCC 7820). On the basis of both in vitro and in vivo toxicity none of the five species screened exhibited toxicity.

3 The toxicity of PCC 7820 was compared with a purified cyanobacterial hepatotoxin, Microcystin-LR. Various biochemical indices and histological changes confirm the hepatotoxic nature of the toxins.

4 The toxins did not induce glutathione-mediated lipid peroxidation but they did cause significant mitochondrial damage based on an MTT assay.

5 The study illustrates the utility of this in vitro system in identifying naturally occurring toxic cyanobacteria, particularly hepatotoxic species.
Nasal lavage as tool for health effect assessment of photochemical air pollution
Authors: Steerenberg PA , Fischer PH , Gmelig Meyling F. , Willighagen J. , Geerse E. , van de Vliet H. , Ameling C. , Boink Abtj , Dormans Jama , van Bree L. , Van Loveren H.
Published: December 2008

It is widely accepted that humans exposed to known concentrations of ozone under controlled conditions exhibit reversible changes that affect the large and small airways as well as the alveolar region of the lung. Among the reversible changes, the induction of inflammatory responses in the lung are of major concern.

Many of the cell types found in the lining of the nasopharyngeal region are similar to cells of the tracheal and bronchial lining. Therefore, it has been suggested that the cellular responses in the nose to toxicants are likely to be similar to the lower airway at the same dose of the agent. If these pollutants are respiratory irritants, capable of causing cellular damage, effects may therefore be detected in the nasal passage. Experimental studies have shown that the inflammatory response in the nose may be predictive for the situation in the lung.

In this paper we described the results of a feasibility study on the use of nasal lavage for epidemiological studies. Nasal lavages were performed in 12 volunteers, 5-7 times per volunteer during 2 months. Polymorph nuclear leukocytes (PMN's), immune mediators and markers for exudation were monitored in the nasal lavage (NAL). It was found that the procedure of the nasal lavage technique was minimally invasive, very well tolerated and no adverse side effects were observed. The leukocytes, the proteins myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8) were detectable in NAL of most volunteers, while tryptase IgE and IL-6 were not detectable. Exudation markers albumin, urea and uric acid were also detectable. The coefficient of variance (CV) values of the various cells and mediators varied between 13% and 137%. It was calculated that, except for the number of leukocytes and the concentration of ECP, it should be possible to detect ozone effects with a study- protocol of 6 repeated measurements among 35 children and an assumed 26% increase in cells or mediators per 100 μg O3 per m3. To measure increase in leukocytes number or in ECP concentration more children are needed.

In conclusion, this pilot study has shown that it is possible to measure relevant biomarkers in NAL, and that these assays can be easily incorporated in epidemiological studies
Continuous deep intravenous infusion in rabbit embryotoxicity studies
Authors: Barrow Paul C , Guyot Jean-Yves
Published: December 2008

1 This investigation was undertaken to evaluate the suitability of an intravenous infusion technique in the pregnant rabbit.

2 18 New Zealand White rabbits were anaesthetised on day 1 of gestation and an indwelling catheter was implanted into the superior vena cava by introduction into the jugular vein. The catheter was attached by a tether system to a remote infusion pump.

3 The pregnant rabbits were infused with physiological saline at a rate of 4 ml kg-1 day-1 until day 19 of gestation. A caesarean examination was performed on day 29 of gestation. The results obtained were compared with historical control data from 150 mated rabbits.

4 Anaesthesia and catheter implantation caused a slight transient reduction in maternal food consumption and weight gain. Pregnancy rate, pre-implantation loss and early resorption incidence were not affected.

5 Late resorption incidence and post-implantation loss were higher in the infused group by comparison with the historical controls but the individual data did not suggest an effect of treatment. Foetal weight was not adversely influenced. Three of the infused dams each contained one malformed foetus: a possible influence of infusion in the aetiology of these abnormalities cannot be excluded nor confirmed within the limitations of this experiment.
Assessment of the biochemical effects of percutaneous exposure of sulphur mustard in an in vitro human skin system
Authors: Lindsay CD , Rice P.
Published: December 2008

1 Sulphur mustard (HD) is a potent chemical warfare agent which causes incapacitating blisters on human skin. There is no specific pretreatment nor therapy against this agent and the mechanism of dermo-epidermal cleavage is unclear. The aim of this study was to use a human skin explant system to determine the consequences of percuta neous exposure to HD.

2 Increased activities of serine proteases associated with blistering disorders in humans were detected from human skin explants after exposure to HD. The most consistent response and the highest protease activities measured were found for trypsin. This class of enzyme is therefore implicated in the dermo-epidermal separation which is associated with blistering in humans following exposure to HD.

3 An inflammatory response was observed in the skin explants exposed to HD. At low doses of HD it was characterised by the presence of neutrophils in the papillary dermis, culminating in the infiltration of the epidermis by these inflammatory cells at higher concen trations of HD. A variety of other histopathological changes in the explants was found such as focal dermo- epidermal separation, nuclear pyknosis and perinuclear vacuolation.

4 The study indicates that full thickness human skin explants can be used to investigate various aspects of the possible pathogenesis of HD-induced skin damage, in cluding the associated inflammatory response.
A biological index to predict patient outcome in paraquat poisoning
Authors: Ragoucy-Sengler C. , Pileire B.
Published: December 2008

1 In humans, the accidental or voluntary ingestion of paraquat, a non selective contact herbicide, is often lethal. Paraquat induces renal failure amongst other effects.

2 In this study we test the value of an index of the rate of increase in plasma creatinine over a 5 h period (dCreat/dt) to predict the outcome in intoxicated patients. These results are compared to previously published indices of severity of the paraquat poisoning. The proposed index is reliable, within the capability of any laboratory and will indicate the prognosis for poisoned patients within 6 h of admission to hospital.
Histopathological effects of Illudin S, a toxic substance of poisonous mushroom, in rat
Authors: Tanaka K. , Miyasaka S. , Inoue T.
Published: December 2008

1 Rats were dosed orally with illudin S, a toxic substance derived from the poisonous mushroom Lampteromyces japonicus. The digestive tract showed severe damage, whereas the liver, kidney and lung did not show any significant changes.

2 The effects observed became more pronounced with increasing illudin S dose (5, 10 or 20 mg kg -1 body weight).

3 Severe inflammation and oedema were observed in the stomach and moderate changes in the proximal part of the small intestine.

4 Histopathological examination revealed haemorrha gic erosions and marked inflammatory oedema in the gastric mucosa.
Lead exposure in a population of Mexican children
Authors: Calderón-Salinas JV , Valdéz-Anaya B. , Mazúñiga-Charles  , Albores-Medina A.
Published: December 2008

The effects of low lead exposure were investigated in 98 children (7-12 years old) living and studying within a 1 km radius of a lead smelter (exposed population) located in Torreón, Coahuila, México, and compared with 30 children living and studying 4.5 km from the same smelter (control population). Both populations had similar socio- economic conditions. The exposed population showed higher blood lead (PbB) and free erythrocyte protopor phyrin (FEP) concentrations (17.3 ± 5.6 μg dl-1 and 53.9 ± 46.1 μg μl-1, respectively) than controls (PbB, 6.4 ± 3.1 μg dl-1 and FEP,13.9 ± 7.3 μg di-1). PbB concen trations were inversely correlated to distance from the smelter ( r2 = 0.494). However, in the exposed population, wind direction also had a significant effect on the PbB and urinary lead (PbU) concentrations. The exposed popula tion was divided according to PbB into a high level lead group (PbB > 15 μg dl-1), which also showed high FEP concentrations and a low lead group (PbB < 15 μg dl-1). Clinically, the high lead group showed a greater incidence of general symptoms (colic, headache, paresthesia, myalgia and dizziness), impairment of some neuromus cular functions (neuromuscular conduction velocity and motor coordination) and a decrease of intelligence quotient (IQ), which was not related with sex or socio- economic status. These results are an evidence of morbidity in children with high PbB concentrations.
Bacterial reduction of N-oxides of tobacco- specific nitrosamines (TSNA)
Authors: Atawodi SE , Richter E.
Published: December 2008

1 Contrary to established metabolic pattern, a recent investigation of NNK metabolism produced in rat urine higher levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyri dyl)-1-butanol (NNAL) than their N-oxides, suggesting that reconversion of N-oxides could occur after urine formation.

2 To verify the possible role of bacteria in the reduction of NNK-N-oxide and NNAL- N-oxide to their respective parent compounds, NNK and NNAL, in smokers with urinary tract infection (UTI), the N-oxides were isolated from the urine of rats treated with [5-3H]NNK and individually incubated at 37°C with ten bacterial species in sterile human urine under different pH regimens. After incubation with the bacteria, aliquots of culture media were analyzed by high pressure liquid chromatography (HPLC) with radiochemical detection.

3 Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae and Proteus mirabilis possessed varying capacity to regenerate NNK and NNAL from their N- oxides while others showed no detectable reductive capability within 24 h.

4 This result constitutes the first experimental evidence that in tobacco users with concomitant UTI, bacterial regeneration of the procarcinogenic NNK and NNAL from their N-oxides could occur in the bladder leading to increased carcinogen burden in these individuals.
Octadentate catecholamide ligands for Pu(IV) based on linear or preorganized molecular backbones
Authors: Durbin PW , Kullgren B. , Jeung N. , Xu J. , Rodgers SJ , Raymond KN
Published: December 2008

Nine new octadentate ligands based on cyclic, spermine (3,4,3-LI), desferrioxamine (DFO), or H-shaped tetrakis amine (penten) molecular backbones were prepared containing catecholamide (CAM), carboxycatecholamide (CAM(C)), or terephthalamide (TAM) chelating units. Mice were injected intravenously with 238Pu(IV) citrate, treated with 30 μmol kg-1 of a ligand by intraperitoneal injection at 1 h or by gastric intubation at 3 min, and Pu retention in tissues and Pu transfer to excreta were measured at 24 h. Given by injection, three soluble ligands composed of MeTAM (3,4,3-LIMeTAM, DFO-MeTAM, H(2,2)-MeTAM) reduced Pu retention in the body to 27- 28% of control compared with 32 and 37% of control obtained in mice similarly treated with 3,4,3-LICAM(C) or CaNa3-DTPA, respectively. The MeTAM ligands reduced Pu retention in the skeleton as much as an equimolar amount of CaNa 3-DTPA, while Pu retention in the liver (on average, 16% of control) was significantly less than was obtained with CaNa3-DTPA (35% of control). Given orally, H(2,2)-MeTAM reduced Pu retention in the whole body to 58% of control compared with reductions to 62 and 94% of control achieved with 3,4,3-LICAM(C) or CaNa3-DTPA, respectively. Penten is both partially preorganized for metal binding and spatially suitable for encapsulation of actinide(IV), and ligands with the penten backbone are easier and less costly to prepare than those based on spermine or DFO. The biological results confirmed that penten is a suitable as well as practical structural backbone for new octadentate ligands. In agreement with the great stability of the ferric complex with MeTAM, as determined in vitro, the small, simple, soluble penten- based octadentate ligand, H(2,2)-MeTAM, was shown to be, overall, the most effective catecholamide ligand for enhancing Pu excretion. Either combined in H(2,2)- MeTAM or separately, the penten backbone and the MeTAM chelating unit are potentially useful additions to the set of backbones and binding units of multidentate ligands identified as effective for in vivo chelation of the actinides.
A systemic reaction following exposure to a pyrethroid insecticide
Authors: Box SA , Lee MR
Published: December 2008

The pyrethroids are a group of pesticides in wide use around the world. They are felt to be safer than the organophosphates. We report a case of an acute systemic reaction in a farmer following exposure to the synthetic pyrethroid flumethrine.
Influence of cimetidine on the toxicity and toxicokinetics of diazinon in the rat
Authors: Wu HX , Evreux-Gros CI , Descotes J.
Published: December 2008

1 The influence of cimetidine on diazinon toxicity and toxicokinetics was investigated in male Wistar rats.

2 The acute toxicity of diazinon, as well as brain acetylcholinesterase and carboxylesterase inhibition, were potentiated by pretreating rats with cimetidine (80 mg kg-1, ip) 1 and 24 h prior to diazinon applica tion (50 mg kg-1, i.p.).

3 Comparison of toxicokinetic parameters between control and cimetidine-treated animals, showed a significant decrease in diazinon total body clearance and a marked increase in the area under the plasma concentration-time curve following cimetidine.

4 These results indicate that a major cause of the potentiation of diazinon may be related to the increase in the amount of diazinon in the systemic circulation as well as in the brain.
Reproductive toxicity and tissue concentrations of lindane in adult male rats
Authors: Dalsenter PR , Faqi AS , Webb J. , Merker H-J. , Chahoud I.
Published: December 2008

1 The effects of lindane on the reproductive system and its concentration in different tissues were investigated. Groups were dosed orally with 6 mg lindane/kg for 5 days or with a single dose of 30 mg/kg body weight.

2 The results indicate that the number (mio) of sperma tids counted in the testes of both treated groups 2 weeks after treatment were significantly reduced compared to the control rats. Effects on the number of sperms were observed in both treated groups, but significant differences were only revealed on those with 30 mg/kg.

3 The concentration (μg/g tissue) of lindane in adipose tissue, liver, brain and testis was determined 24 h and 2 weeks after the last treatment. Lindane was detected in the testis of both groups 24 h and 2 weeks after the last treatment.

4 Histological investigation by electron microscopy revealed a pronounced ballooning of Sertoli cells accompanied by fragmentation or complete loss of organelles.

5 According to the result obtained, it is evident that lindane passes through the testis and exerts its toxic effect.
Presentation of poisoned patients to accident and emergency departments in the North of England
Authors: Thomas Shl , Bevan L. , Bhattacharyya S. , Bramble MG , Chew K. , Connolly J. , Dorani B. , Han KH , Horner JE , Rodgers A. , Sen B. , Tesfayohannes B. , Wynne H. , Bateman DN
Published: December 2008

1 A 12 week prospective survey of all patients of any age with confirmed or suspected poisoning presenting to six accident and emergency departments in the North East of England was performed to establish the local incidence and patterns of presentation of poisoning.

2 945 episodes of poisoning involving 852 patients were recorded representing approximately 1.2% of all A&E presentations and suggesting an annual attendance rate of 2.7 per 1000 persons per year.

3 Attendance rates varied threefold between hospitals and were similar in males and females overall; between the ages of five and 14 attendances were more common in females (1.9 vs 0.6/103/y) while between 0 and 4 y (3.1 vs 2.4) and 25 and 34 y (3.9 vs 2.9/103/y) they were more common in males.

4 The median interval between poisoning and presenta tion was 2 h (mean 4.1 h) and only 19% of cases presented within 1 h. Presentation was most common between Friday evening and Tuesday morning and in the late afternoon and evening.

5 6% of the patients presented more than once with poisoning during the study period and 37% had a past history of deliberate self-harm. The most common poisons involved were paracetamol (43%), opioids (15%) and benzodiazepines (15%).

6 The study illustrates the frequency of presentations of poisoning to A&E departments. The high rate of poisoning in young men and the increasing use of paracetamol are particular causes for concern.
Evaluating clinical case report data for SAR modeling of allergic contact dermatitis
Authors: Gealy Robert , Graham Cynthia , Sussman Nancy B , Macina Orest T , Rosenkranz Herbert S , Karol Meryl H
Published: December 2008

Clinical case reports can be important sources of information for alerting health professionals to the existence of possible health hazards. Isolated case reports, however, are weak evidence of causal relationships between exposure and disease because they do not provide an indication of the frequency of a particular exposure leading to a disease event. A database of chemicals causing allergic contact dermatitis (ACD) was compiled to discern structure-activity relationships. Clinical reports repre sented a considerable fraction of the data. Multiple Computer Automated Structure Evaluation (MultiCASE) was used to create a structure-activity model to be used in predicting the ACD activity of untested chemicals. We examined how the predictive ability of the model was influenced by including the case report data in the model. In addition, the model was used to predict the activity of chemicals identified from clinical case reports. The following results were obtained:

• When chemicals which were identified as dermal sensitizers by only one or two case reports were included in the model, the specificity of the model was reduced.

• Less than one half of these chemicals were predicted to be active by the most highly evidenced model.

• These chemicals possessed substructures not pre viously encountered by any of the models.

We conclude that chemicals classified as sensitizers based on isolated clinical case reports be excluded from our model of ACD. The approach described here for evaluating activity of chemicals based on sparse evidence should be considered for use with other endpoints of toxicity when data are correspondingly limited.
4-Methylpyrazole (4-MP) is effectively removed by haemodialysis in the pig model
Authors: Jacobsen D. , Østensen J. , Bredesen L. , Ullstein E. , McMartin K.
Published: December 2008

The safety and pharmacokinetics of the alcohol dehydro genase inhibitor 4-MP have recently been evaluated and its clinical use in ethylene glycol poisoning in France is promising. The dialysability of 4-MP is not known. This is important as hemodialysis is one of the cornerstones in the treatment of (late) ethylene glycol and methanol poison ings. We therefore studied the dialysability of 4-MP in the pig model. Anesthesized pigs (maintained on respirator) given 4-MP, 10 mg/kg, served as controls (n=3) to the pigs (n=3) given 15 mg/kg and hemodialyzed for 4 h. 4-MP plasma elimination curves for both groups were compared for 12 h and dialysance data calculated. 4-MP (MW 82) was removed by the same rate as urea (MW 60) by the 0.3 m2 dialysator, thus indicating no significant protein binding of 4-MP. The mean dialysance of 4-MP (and urea) in the three pigs were 61 (63), 51 (53) and 56 (48) ml/min, at a blood flow of 75 ml/min. The amount of 4-MP removed by hemodialysis in 4 h was 57-76 mg compared to a urinary excretion of 1-3 mg over 12 h. We conclude that the dialysablity of 4-MP is significant and this must be taken into account when these two treatment procedures are combined.
A search for possible cytogenetic effects of low frequency vibrations in cultured human lymphocytes
Authors: Khalil Ahmad M , Qassem W.
Published: December 2008

1 Acute cytogenetic effects expressed as sister-chroma tid exchanges (SCE) in peripheral blood lymphocytes were investigated after in vitro exposure to low vibration regimes (5 - 30 Hz, at 0.1 cm amplitude) for 20 min intervals and compared to non-vibrated control cultures.

2 There was no significant (P<0.05) increase in the range of SCE incidence at any vibration frequency compared to the mean value of control; 6.88 ± 0.11 to 7.97±0.22 versus 6.83±0.86, respectively.

3 When cultures were incubated for 1 h in the presence of 0.5 μg ml-1 mitomycin C (MMC; the positive control) significant elevations in the SCE frequency were observed (19.81 ± 0.67), indicating the sensitivity of the system to in vitro SCE induction.

4 Other cell parameters, such as mitotic index and cell proliferation index were statistically similar in the experimental cultures and the negative control.

5 The observed differences in the investigated end points are considered within those typically found in vitro. This suggests no relation between low frequency vibrations and cytogenetic effects.
HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats
Authors: Alexander DJ , Libretto SE , Adams MJ , Hughes EW , Bannerman M.
Published: December 2008

1 HFA-134a was administered to AHA rats by snout-only inhalation for 1 h daily to assess the effects of treatment on reproduction and development.

2 In a fertility study, rats were exposed to atmospheres of 2500, 10000 or 50000 p.p.m. HFA-134a throughout gametogenesis, mating, pregnancy and lactation.

3 In a peri- and post-natal study, rats were exposed to HFA-134a from days 17 to 20 of pregnancy and days 1 to 21 post partum to atmospheres of 1800, 9900 or 64 400 p.p.m.

4 The only treatment-related effect was a slight reduc tion in body weight gain of males of the treated parental generation at 50 000 p.p.m. (fertility study).

5 In neither study were there any adverse effects of HFA- 134a on the reproductive performance of treated animals or on the development, maturation or reproductive performance of up to two successive generations.
Metabolites and DNA-binding of carbamazepine and oxcarbazepine in vitro by rat liver microsomes
Authors: Castrén Katariina , Pienimäki Päivi , Arvela Pentti , Vähäkangas Kirsi
Published: December 2008

DNA-binding of carbamazepine (CBZ) and oxcarbazepine (OCBZ) catalysed by non-induced, phenobarbital-induced or methylcholanthrene-induced rat liver microsomes in vitro was studied.14C-CBZ 200 nmol incubated with DNA, liver microsomes and cofactors led to the formation of a significant amount of CBZ-epoxide, which has been suspected as the cause of teratogenesis and other side- effects of CBZ,1,2but has not been reactive in any test systems for genotoxicity, including the Ames test.3No enzyme-dependent DNA-binding of CBZ was found. Using the same conditions, however, OCBZ was bound to DNA. This binding was dependent on the presence of NADPH. 10-hydroxy-10,11-dihydro-carbamazepine, which is known to be the major metabolite of OCBZ, and an unknown peak were demonstrated by HPLC. These results are the first indication of a higher level of covalent DNA binding of OCBZ than of CBZ. The nature of the unknown metabolite and the pathway leading to covalent binding remain to be studied.
The effect of sulphur mustard on glutathione levels in rat lung slices and the influence of treatment with arylthiols and cysteine esters
Authors: Langford AM , Hobbs MJ , Upshall DG , Blain PG , Williams Faith M
Published: December 2008

1 Sulphur mustard reacts directly with benzenethiols and cysteine esters in aqueous medium.

2 Benzenethiols diffuse into lung slices in short term culture.

3 Treatment of lung slices in short term culture with benzenethiols does not protect cellular glutathione from conjugation with sulphur mustard.

4 Following uptake of cysteine ester into lung slices cysteine is elevated but this does not protect cellular glutathione from sulphur mustard.
Respiratory toxicity of direct lytic factor in the venom of the southern Chinese cobra (N. naja atra) in dogs
Authors: Huang Shou-Jian , Jian Fu , Sun Jia-Jun
Published: December 2008

The effects of direct lytic factor (DLF) on respiratory ventilation, gas exchange as well as hemodynamics were studied in anesthetized dogs. After an intravenous DLF dose of 1 mg/kg, the initial manifestation of intoxication was observed as follows: (1) Increase in airway impedance characterized by slowed air flow rate and increased negative transpulmonary pressure. (2) Decrease in dy namic compliance. (3) Progressive increase in venoarter ial shunt (Qs/Qt) and decrease in PaO 2. (4) Elevation of pulmonary artery blood pressure and fall of mean systemic blood pressure and maximal left ventricular pressure. Above actions reached the peak values at 15 min and thereafter all respiratory functional parameters, except Qs/Qt and hypoxemia, returned gradually to approach the normal levels at 50 min. The tidal volume, PaCO2 and LVEDP remained unchanged until another DLF dose of 1.5 mg/kg was given. After a second dose of DLF (total 2.5 mg/kg), the respiratory functions and the cardiac performance deteriorated as follows: (1) Further increase in Qs/Qt and hypoxemia. (2) Appearance of hypercapnea and acidosis. (3) Fall of dP/dt max and elevation of LVEDP, widening of QRS complex of ECG. (4) Blood pressure run a downhill course. From above experimental evidence, we came to the conclusion that as well as the basic cardiotoxicity, respiratory toxicity of DLF must be considered as the primary, because of broad spectrum of action of DLF and early effect on respiratory function.
Carcinogens in food: priorities for regulatory action
Authors: McDonald AL , Fielder RJ , Diggle GE , Tennant DR , Fisher CE
Published: December 2008

A pragmatic possible approach to the prioritization of chemical carcinogens occurring as food contaminants is described, based on the carcinogenic risk to the popula tion. This should be of value in ensuring that resources for assessment and management of carcinogens in food are directed to the most important areas with regard to carcinogenic risk to the population. Key components of this approach are an assessment of the carcinogenic hazard to humans combined with estimations of intakes per person and of the proportion of the population exposed. These are used to derive an index referred to as the Population Carcinogenic Index. Concerning the hazard assessment expert judgement is used to place the chemical in one of five categories. The highest category is for chemical carcinogens that are believed to act by a genotoxic mechanism. It is recognised that such com pounds may vary enormously with respect to their potency and various approaches to ranking carcinogens on the basis of potency are reviewed. The approach adopted is to subdivide the genotoxic carcinogens category into high, medium and low potency based on the TD 50 value. Methods of estimating intakes and exposed populations are considered and an approach which groups these into broad categories is developed. The hazard and exposure assessments are then combined to derive the Population Carcinogenicity Index.
Protein-energy malnutrition and oxidative injury in growing rats
Authors: Rana Satyawati , Pal Sodhi Chhinder , Mehta Saroj , Vaiphei Kim , Katyal Ranjan , Thakur Sarita , Satish Kumar Mehta
Published: December 2008

1 Weaning rats were fed ad libitum isocaloric diets containing 5% and 20% casein based proteins. 5% protein diet was protein deficient diet. Pair fed rats with the 5% protein group were maintained simulta neously on 20% protein diet but the amount restricted to the amount taken up by PEM group.

2 Glutathione, antioxidative enzymes, lipid peroxida tion and histopathological studies in liver and only glutathione and antioxidative enzymes in blood were carried out.

3 Rats fed the 5% protein diet developed a severe protein energy malnutrition (PEM) whereas those on pair-fed diet developed mild to moderate PEM.

4 Glutathione related thiols, superoxide dismutase, glutathione peroxidase, catalase and glutathione-S- transferase with (1 Chloro 2,4-dinitro benzene (CDNB) substrate) were decreased in liver with concomitant increase of lipid peroxidation in severe PEM. In blood glutathione, glutathione peroxidase and catalase were decreased while superoxide dismutase was increased in severe PEM group.

5 Mild to moderate PEM (pair-fed group) also resulted in similar changes in liver except glutathione peroxidase, lipid peroxidation in liver and superoxide dismutase in blood.

6 Hepatic injury was detectable only in the severe PEM group.

7 Oxidative-stress and hepatic injury occurred in severe PEM and to a lesser degree in mild to moderate PEM.
Trichloroethylene metabolism in vitro: an EPR/SPIN trapping study
Authors: Steel-Goodwin Linda , Pravecek Tasha L , Carmichael Alasdair J
Published: December 2008

Trichloroethylene (TCE) was hypothesized to produce free radicals which could be detected using electron para magnetic resonance spectroscopy with the spin trap, PBN (α-phenyl tert-butyl nitrone). The free radicals detected following incubation of precision cut liver slices in media containing 10 mM PBN had hyperfine coupling constants aN=1.61 mT and aH=0.325 mT. There was a linear increase in free radicals detected in the bathing media when the headspace TCE concentration was increased from 2500- 10 000 p.p.m. The levels of conjugated dienes measured in the slices incubated in PBN supplemented media were less than slices exposed to TCE in incubation media without PBN. The PBN trap may act as a scavenger preventing the propagation of free radicals and inhibiting lipid peroxida tion. The experiments suggest that free radical formation by TCE leads to a concomitant increase in conjugated dienes in liver slices which may contribute to the pathological changes which occur in liver following TCE exposure.
Effects of mode of inhalation of carbon monoxide and of normobaric oxygen administration on carbon monoxide elimination from the blood
Authors: Levasseur L. , Galliot-Guilley M. , Richter F. , Scherrmann JM , Baud FJ
Published: December 2008

1 The half-life of carbon monoxide (CO) in blood was studied retrospectively in 26 fire victims and in 19 cases of CO poisoning. Normobaric oxygen therapy was administered via mechanical ventilation in 19 fire victims, and by facial mask to the rest of the casualties.

2 Arterial pH was significantly lower (P < 0.05) and PaO2 significantly greater (P<0.01) in the mechanically ventilated fire victims compared to the spontaneously breathing fire victims.

3 The blood CO half-lives were 91 ± 38 min for the 26 fire victims and 87±40 min for the 19 pure CO intoxica tions.

4 The blood CO half-lives were 92 ± 40 min for the 19 mechanically ventilated fire victims and 87 ± 37 min for the 26 spontaneously breathing subjects.

5 We conclude that the elimination of CO from blood was a slow process with no significant effects on the blood CO half-life of either the cause of the CO poisoning or the mode of normobaric oxygen therapy. These data suggest that enhancement of the elimination of carbon monoxide by normobaric oxygen in both pure CO poisoning and fire victims is more difficult to achieve and more complex than has previously been reported.
Assessment of aspects of the toxicity of Clostridium perfringens E-toxin using the MDCK cell line
Authors: Lindsay Christopher D
Published: December 2008

1 The epithelial Madin Darby Canine Kidney (MDCK) cell line was used to study the toxicity of ∈-toxin from Clostridium perfringens. The epithelial MDCK cell line is known to be sensitive to ∈-toxin of Clostridium perfringens and to investigate its mechanism of action, the neutral red assay has been used to determine the viability of cultures of this cell line.

2 Comparison of the LC 50s obtained at 34°C and 0°C showed that the lethality of ∈-toxin was reduced by 18- fold at the lower temperature. The effect of tempera ture on ∈-toxin lethality is unlikely to be due to reductions in membrane fluidity for the addition of Ca2+ or Mg2+ (2 mM) to buffer containing toxin was without effect. Varying the pH of the toxin-containing buffer from 6.9 to 8.7 did not increase the lethality of the toxin, though the most acidic pH used (5.8) was found to potentiate its action on MDCK cells.

3 The effect of inhibiting endocytosis on the lethality ofe toxin was also investigated by incubating cultures of MDCK cells with and without sodium azide over a range of concentrations of toxin. The co-administra tion of sodium azide did not reduce the toxicity of ∈ toxin, suggesting that energy-dependent uptake pro cesses such as endocytosis were unlikely to be involved in its mechanism of action. The results are, however, consistent with known receptor-based me chanisms of uptake and with other mechanisms of internalisation across the plasma membrane. ∈-toxin thus interacts with cell surfaces by a temperature sensitive mechanism potentiated by low pH.
Effects of catecholamines and diazepam in chloroquine poisoning in barbiturate anaesthetised rats
Authors: Buckley Nicholas A , Smith Anthony J , Dosen Peter , O'Connell Dianne L
Published: December 2008

The recommended treatment of human chloroquine poisoning is diazepam and adrenaline but neither has been evaluated in controlled clinical trials. We investi gated whether diazepam provided any added benefit over barbiturate anaesthesia and whether the protective effect of catecholamines in chloroquine poisoning was mediated through alpha or beta receptor stimulation.

Rats, anaesthetised with thiobutobarbitone had a continuous intravenous infusion of 3 mg/kg/min of chlor oquine. This caused a steady decline in pulse rate and blood pressure. When diazepam (3 mg/kg iv) was admi nistered 5 -10 min later, heart rates decreased at a faster rate (P=0.005), blood pressure was consistently lower (P=0.01) and there was a shorter time to arrhythmias and death (P < 0.05). Adrenergic agents were given by titration to attempt to maintain mean blood pressure > 75 mmHg. Compared with the phenylephrine (selective alpha agonist) group, the group treated with isoprenaline (selective beta agonist) had faster heart rates which decreased more slowly (P < 0.0001), higher blood pressure (P=0.005) and longer time to arrhythmias and death (P=0.005). Adrenaline and noradrenaline had intermedi ate effects. Thus beta agonist effect appears to explain the beneficial effects of adrenaline but alpha agonist activity may be harmful. This animal work suggests that a combination of barbiturate anaesthesia and isoprenaline may be better than the diazepam and adrenaline in combatting the effects of chloroquine.