bluuebunny/crossref_metadata_2025_split huggingface dataset:
The fixed-dose procedure and the acute-toxic-class method: a mathematical comparison
Authors: Stallard N. , Whitehead A. 
Published: December 2008

The fixed-dose procedure (FDP), proposed by the British Toxicology Society, and the acute-toxic-class (ATC) method, proposed by the German Federal Health Authority, provide alternatives to the LD50 test for classify ing substances by their acute oral toxicity. This paper pre sents a mathematical model that is used to compare the two procedures in terms of their classification properties and the required numbers of animals. It is found that the classification properties of the proce dures depend on the dose levels used, the number of ani mals tested per dose and the criteria that are used to decide whether testing should continue at a higher or lower dose. For substances with steep dose-response curves, the most likely classification is determined chiefly by the choice of the dose levels whilst the number of ani mals and continuation criteria used are increasingly important for substances with dose-response curves with a smaller slope. The use of toxicity as a possible endpoint as in the FDP and the use of a two-stage testing procedure at each dose as in the ATC method are both found to reduce the expect ed numbers of animals required with little effect on the classification properties. On the strength of these findings it is indicated that a new procedure combining the dose levels and testing approach of the ATC method with the inclusion of toxicity as an endpoint as in the FDP would be more efficient than either the FDP or the ATC method.
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.
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.
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.