bluuebunny/crossref_metadata_2025 huggingface dataset:
Do the Hydrolysis Products, Methylamine and N,N'-Dimethylurea, Play any Role in the Methyl Isocyanate-Induced Haematological and Biochemical Changes in Rabbits?
Authors: Jeevaratnam K. , Sugendran K. , Vaidyanathan C.S.
Published: December 2008

The subcutaneous administration of methyl isocyanate (MIC) to female rabbits, resulted in significant increases in haemoglobin concentration, erythrocyte volume fraction and leucocyte number in blood, as well as plasma total proteins, and urea. The present study was designed to investigate whether the hydrolytic products of MIC, methylamine (MA) and N,N'-dimethylurea (DMU) play any role in eliciting these changes. Both MA and DMU administered subcutaneously in an equimolar dose to that of 1.0 LD50 MIC, 2.2 mmol kg-1, had no influence on these parameters, although there was a marginal increase in the plasma urea level shortly after the administration of DMU. This study establishes that the observed haematological and biochemical changes induced by MIC intoxication in rabbits are mostly due to MIC.
Modelling Dermal Pharmacokinetics Using in vitro Data Part I. Fluazifop-butyl in the Rat
Authors: Auton T.R. , Ramsey J.D. , Woollen B.H.
Published: December 2008

The pharmacokinetics of the herbicide fluazifop-butyl have been determined in female rats following oral and intravenous dosing, and described by a mathematical model. Penetration of fluazifop-butyl through epidermal membranes has been determined using three different receptor fluids. It is demonstrated how this in vitro absorption data can be used with a pharmacokinetic model derived from oral and i.v. dosing studies to predict plasma concentrations and urinary excretion profiles following dermal dosing. Model predictions are compared with experimental measurements and found to be in good agreement.
Effect of Methanol or Modifications of the Hepatic Glutathione Concentration on the Metabolism of Dichloromethane to Carbon Monoxide in Rats
Authors: Pankow D. , Jagielki S.
Published: December 2008

1 The metabolism of dichloromethane (DCM) to carbon monoxide as measured by the carboxyhaemoglobin (COHb) level in the blood is stimulated by pretreatment with methanol (MET). After simultaneous administration of both DCM, 6.2 mmol kg-1p.o., and MET, > 148 mmol kg-1p.o., the COHb formation is inhibited.

2 MET ingestion results in a transient decrease of the glutathione (GSH) content of the liver. In rats treated with GSH-depleting chemicals such as diethylmaleate (DEM), phorone (PHO), or buthionine sulphoximine (BSO) there were no enhancements of the carboxyhaemoglobinaemia caused by DCM. The COHb formation was not influenced by an increase of the hepatic GSH concentration due to repeated administration of butylated hydroxyanisole (BHA).

3 It is concluded that cytochrome P450 IIEl (CYP 2E1) is responsible for the metabolic interaction of both DCM and MET, and MET may be an inducer of CYP 2E 1. The two pathways of DCM, the oxidative via CYP 2E l and the metabolism via GSH/GSH-S-transferase seem to be independent.
Analysis of Polychlorinated Dioxins and Furans in Samples of the Toxic Oil Syndrome
Authors: Guitart Raimon , Nørgaard Lars , Mariani Giulio , Posada Manuel , Abaitúa Ignacio , Gelpi Emilio , Fanelli Roberto
Published: December 2008

1 Polychlorinated dioxins (PCDDs) and furans (PCDFs) are known to produce a wide range of toxic effects.

2 PCDDs and PCDFs are typical contaminants of chlorinated phenols, and pentachlorophenol and related compounds have been shown to be widely distributed among selected oil samples taken from the 1981 Spanish toxic oil epidemic.

3 Six control and eight case oil samples were analysed using GC/MS for PCDDs and PCDFs. Only small concentrations, normally below 1 ng g-1, of the higher chlorinated PCDDs and PCDFs were detected. There were no statistical differences between the case and control oils.

4 These levels seem to be too low to elicit toxic effects, although they could be enough to potentiate the toxicity of other xenobiotics present in the oils. However, it is uncertain whether the levels of these compounds measured in 1990 reflect the levels present when the oils were consumed in 1981, or whether or not the levels measured in crude oils are representative of fried oils.
interactive Potential of Omega-3 Fatty Acids with Clofibrate or DEHP on Hepatic Peroxisome Prolifieration in Male Wistar Rats
Authors: Wysynski Anna-Marie , Baldwin Linda A. , Leonard Denise A. , Calabrese Edward J.
Published: December 2008

The interactive potential of three known peroxisome proliferators, omega-3 fatty acids, clofibrate and di(2-ethylhexylphthalate (DEHP), was evaluated in male weanling Wistar rats for the effect on peroxisomal beta-oxidation. Omega-3 fatty acids were supplied by menhaden oil which was fed in six regimens: low fat (5% w/w), low fat and clofibrate (0.3% w/w) or DEHP (0.25% w/w), high fat (20% w/w), high fat and clofibrate or DEHP in the aforementioned concentrations. Induction of peroxisomal beta-oxidation was measured by changes in liver-to-body weight ratio, fatty acyl-CoA oxidase (FAO) activity, and peroxisomal bifunctional enzyme (PBE) quantity. Analysis of transformed data indicated a less than additive response in FAO activity with no deviation from additivity seen with liver-to-body ratios and PBE.
Desferrioxamine Treatment Reduces Histological Evidence of Lung Damage in Rats after Acute Nitrogen Dioxide (NO2) intoxication
Authors: Meulenbelt J. , Dormans J.A.M.A. , van Bree L. , Rombout P.J.A. , Sangster B.
Published: December 2008

1 In previous studies a rat inhalation model was developed to investigate the efficacy of treatment in acute NO2 intoxication.

2 Desferrioxamine was administered intravenously to study its effect on histological alterations in lung tissue in rats after acute NO2 exposure.

3 Twenty four hours after exposure to 175 ppm NO2 for 10 minutes the lung injury observed by light microscopy in the desferrioxamine treated rats was less pronounced than in the saline treated rats.

4 Desferrioxamine appeared to provide more protection with a dose of 100 mg kg-1 24 h-1 than with 200 mg kg-1 24 h-1.
Urinary Protein Excretion and the Diagnosis of Graft Rejection or Renal Dysfunction in Renal Transplant Patients
Authors: Hossein-Nia Mojgan , Mellotte George J. , Foxall Peta , Bending Mike R. , Holt David W.
Published: December 2008

Urinary proteins have been found to be a sensitive marker of renal damage caused by nephrotoxic agents. An electrophoretic method was used to investigate the potential value of the pattern of urinary protein excretion in 14 cyclosporin-treated renal transplant patients, to differentiate between graft rejection episodes and other causes of renal dysfunction. Urinary protein excretion consistent with renal damage was observed in all of the patients studied, with no marked differences between those with signs of graft rejection, those with renal dysfunction, or those with stable renal function.
Human Pentachlorophenol Poisoning
Authors: Jorens Philippe G. , Schepens Paul J.C.
Published: December 2008

Pentachlorophenol (PCP) was, and still is, one of the most frequently used fungicides and pesticides, Its toxicity is due to interference with oxidative phosphorylation. Acute and chronic poisoning may occur by dermal absorption, inhalation or ingestion. Chronic poisoning occurs mainly in sawmill workers or people living in log homes treated with PCPcontaining wood protecting formulations. Quantitative determination of PCP in urine and serum is useful to detect occupational or subclinical exposure.

The clinical features of acute and chronic PCP poisoning can be classified systematically into effects on the skin, metabolism (fever), the haematopoietic tissue, the respiratory system, the central and peripheral nervous system, the kidney and the gastrointestinal tract.

Although PCP is not classified as a human carcinogen, some epidemiological observations suggest that exposure to chlorophenols in general and PCP solutions in particular may result in an increased risk for certain malignant disorders such as nasal carcinoma and soft tissue sarcoma. There is concern that contamination of PCP-solutions with products such as chlorodibenzo-p-dioxins is the real cause of this suspected carcinogenicity.

No specific antidote exists for the treatment of (acute) PCP poisoning. The basis of the treatment of acute poisoning is intensive supportive care with prevention of dangerous rise in temperature. Use of PCP-based products as indoor wood preservatives poses an unacceptable risk to human health.
Implications of Animal Welfiare on Toxicity Testing
Authors: Meyer Otto
Published: December 2008

The testing strategy for chemical substances is discussed with regard to obtaining improved quality of data for health assessment while respecting the ethical responsibility for consideration of the welfare of the animals involved. Ensuring animal welfare without indulging too much in anthropomorphism leads to better research/testing, Current trends in toxicity testing will result in tests involving more sophisticated techniques, better quality of laboratory animals, and eventually the use of fewer animals,
Benefits of Good Laboratory Practice as a Tool to Improve Testing
Authors: Turnheim Dian
Published: December 2008

The Organization for Economic Cooperation and Development (OECD) has promoted Good Laboratory Practice (GLP) since the mid 1970s. This paper describes the development of the concept through international harmonisation, Quality Assurance (QA), and compliance monitoring. Ultimately this process permits Mutual Acceptance of Data (MAD). An important aspect of the OECD's programme is the promotion of related training and information exchange.
A Physiologically Based Mathematical Model of Dermal Absorption in Man
Authors: Auton T.R. , Westhead D.R. , Woollen B.H. , Scott R.C. , Wilks M.F.
Published: December 2008

A sound understanding of the mechanisms determining percutaneous absorption is necessary for toxicological risk assessment of chemicals contacting the skin. As part of a programme investigating these mechanisms we have developed a physiologically based mathematical model. The structure of the model parallels the multi-layer structure of the skin, with separate surface, stratum corneum and viable tissue layers. It simulates the effects of partitioning and diffusive transport between the sub-layers, and metabolism in the viable epidermis. In addition the model describes removal processes on the surface of the skin, including the effects of washing and desquamation, and rubbing off onto clothing.

This model is applied to data on the penetration of the herbicide fluazifop-butyl through human skin in vivo and in vitro. Part of this dataset is used to estimate unknown model parameter values and the remainder is used to provide a partial validation of the model. Only a small fraction of the applied dose was absorbed through the skin; most of it was removed by washing or onto clothing. The model provides a quantitative description of these loss processes on the skin surface.
Efficacy of 4-Methylpyrazole in Ethylene Glycol Poisoning: Clinical and Toxicokinetic Aspects
Authors: Harry P. , Turcant A. , Bouachour G. , Houze P. , Alquier P. , Allain P.
Published: December 2008

Potentially fatal ethylene glycol intoxication in an adult with normal renal function was treated with 4-methylpyrazole administered three hours after the incident occurred. The plasma ethylene glycol concentration was 3.5 g 1-1 on admission. The metabolic acidosis present on admission resolved within four hours, and the subsequent clinical course was uneventful. The apparent plasma half-life of ethylene glycol was 16 h and the mean renal and plasma clearances of ethylene glycol were 24 and 25 ml min-1, respectively. These results support the hypothesis that complete blockade of hepatic metabolism of ethylene glycol is achieved by 4-methylpyrazole. The only side-effect observed as a result of treatment was a transient slight increase in serum transaminase activity.
Absence of Changes in Metallothionein RNA in the Rat Testes Made Refractory to Cadmium Toxicity by Zinc Pretreatment
Authors: Wahba Zakaria Z. , Miller Mark Steven , Waalkes Michael P.
Published: December 2008

Testicular toxicity and interstitial cell tumours induced by cadmium are prevented by zinc or by low dose cadmium pretreatments. The mechanism of this tolerance is unknown, though metallothionein (MT) is thought to play a role in tissue resistance to cadmium toxicity. Thus, the possible involvement of the testicular MT gene in metal-induced tolerance to cadmium toxicity was studied. Rats were pretreated with zinc (1.0 mmol kg-1, s.c.). Histological examination of the testes indicated such pretreatments prevented the necrotizing effects of subsequent doses of cadmium (20 ?mol kg-1, s.c.) administered 24 h later. RNA was extracted from testes or liver 24 h after zinc pretreatment, and analysed by the slot blot technique using the p2A10 cDNA probe to the MT gene. Zinc pretreatment had little effect on MT RNA in the testes, and such pretreatments did not alter testicular cadmium-binding protein capacity. In contrast, RNAs derived from livers of zinc pretreated rats showed marked increases in MT RNA and MT protein. Hence, the testicular MT gene does not appear to play a major role in the induced tolerance to cadmium toxicity and carcinogenesis generated by zinc.
Osmolal and Anion Gaps in Patients Admitted to an Emergency Medical Department
Authors: Aabakken Lars , Johansen Kjerstin S. , Rydningen Else-Berit , Bredesen Jan E. , Øvrebø Steinar , Jacobsen Dag
Published: December 2008

1 Osmolal and anion gaps are helpful in the diagnosis and evaluation of intoxications with methanol and ethylene glycol. Reported reference values for osmolal gap and anion gap are -1 (± 6) mosm kg-1 H2O and 16 (± 2) mmol I -1, respectively. However, we have repeatedly found unexplained increased gaps in patients admitted to our department, and the relevance of the established reference values has been questioned.

2 Osmolal and anion gaps were determined in an unselected population of patients consecutively admitted to an emergency medical department. In the case of unexplained gaps, the blood samples were analysed with respect to the presence of alcohols and organic acids.

3 We included all accessible patients admitted during 14 days. Appropriate blood samples were obtained in 177 patients (88 male, 89 female), with a mean age of 65 years (range 17-94).

4 The mean and (standard deviation) for osmolal and anion gaps in our material were 5.2 mosm kg-1 H2O (7.0) and 12.9 mmol/l (4.2). Neither methanol nor ethylene-glycol was detected in serum from any patients. Small amounts of ethanol were found in 5 patients, and high lactate levels explained in part the most extensively increased anion gaps. However, the calculated analytical standard deviation accounted entirely for the variation in our material, and we suggest that the present reference values be adjusted.
Comparative Aluminium Mobilizing Actions of Several Chelators in Aluminium-Loaded Uraemic Rats
Authors: Gómez M. , Domingo J.L. , del Castillo D. , Llobet J.M. , Corbella J.
Published: December 2008

The relative effectiveness of deferoxamine (DFO), 1,2-dimethyl-1,3-hydroxypyrid-4-one (L1), and citric and succinic acids in mobilizing and promoting excretion of aluminium (Al) were compared in female uraemic rats which had previously received aluminium nitrate nonahydrate i.p. in a daily dose of 45 mg kg-1for 3 weeks (5 days/week). Chelators were administered s.c. at doses equal to one-eighth of their respective LD50for five days. L1 was also given p.o. in doses of 200 mg kg-1day-1. Total urines were collected 24 h after each chelator administration. Total urinary Al excreted over the 5-day period, expressed as mg kg-1, were: controls, 3.4; DFO-treated, 4.5 (P<0.05); citric acid-treated, 3.7; and succinic acid-treated, 2.7. Although the daily amounts of Al excreted into urine by L1-treated rats were significantly higher ( P<0.001) than those of the controls, most animals died during the period of treatment.

Measurements of Al in selected tissues 24 h after the last administration of each chelator revealed that none of the compounds significantly altered the Al concentration in bone, kidney, and brain, whereas only DFO and succinic acid significantly reduced the levels of Al in spleen. Moreover, L1 (given s.c. or p.o.) and citric acid treatment led to a significant reduction in the liver Al burden. These results indicate the need for further investigations to determine the toxicity and the therapeutical safety margins of L1.
Systemic Paraphenylenediamine (PPD) Poisoning: A Case Report and Review
Authors: Ashraf Waseem , Dawling Shiela , Farrow Lew J.
Published: December 2008

A case of suicidal poisoning with paraphenylenediamine (PPD) is reported. The patient presented with typical features of severe oropharyngeal oedema and rhabdomyolysis, He suffered sudden cardiac death within 4 hours of admission despite full supportive treatment. The diagnosis was only established after his death. Systemic poisoning with paraphenylenediamine (PPD) is rare in western countries, and therefore a high degree of awareness and circumstantial evidence is required to make an early diagnosis. The classical and other less commonly reported features of this poisoning are discussed. There is no specific antidote available but some guidelines for management of such a case are reviewed.
Dextran Sulphates Protect Porcine Arterial Endothelial Cells from Free Radical Injury
Authors: Hiebert Linda M. , Liu Ji-Min
Published: December 2008

1 The ability of dextran sulphate to protect cultured porcine arterial endothelial cells injured by addition of xanthine and xanthine oxidase (X/XO) or hydrogen peroxide to cell medium was examined using a variety of drug preparations. Cell damage was assessed by determining cell viability (by trypan blue exclusion) and release of lactate dehydrogenase into the medium.

2 Dextran sulphates of average molecular weight (Mr) 5000, 8000 (hydrogenated or unhydrogenated) at 0.05, 0.5, 5 and 50 μg ml-1 medium, added 24 h prior to X/XO, protected cells, whereas dextran sulphate Mr 500,000 was protective only at 0.5 μg ml-1.

3 None of the dextran sulphates used showed any toxic effect on cells in concentrations up to 500 μg ml-1 medium.

4 When the duration of pretreatment with dextran sulphate Mr 8000 was varied, 6 h was required for a protective effect on cells damaged by X/XO, which was enhanced with durations of 16 and 24 h.

5 Dextran sulphates had a similar protective effect on cells damaged by hydrogen peroxide.

6 This study suggests that dextran sulphates may prevent conditions resulting from free radical injury.
Effects of Lead Poisoning of Rats During Pregnancy on the Reproductive System and Fertility of their Offspring
Authors: Coffigny Hervé , Thoreux-Manlay Annick , Pinon-Lataillade Ghislaine , Monchaux Georges , Masse Roland , Soufir Jean-Claude
Published: December 2008

1 The effects of lead poisoning during pregnancy were tested on female Sprague-Dawley rats that inhaled 5 mg m-3 lead oxide for 13 days during gestation. At the end of gestation, the respective blood lead levels of dams and fetuses were 71.1 and 83.2 μg 100 ml-1, indicating lead poisoning.

2 In the 90 day-old male offspring of the exposed dams, testis weight and histology, and epididymal weight and sperm reserve, were all similar to those of control males. Spermatozoa mobility and morphology were normal.

3 Also similar to control values were the pituitary weight in these male offspring, their plasma FSH, LH and testosterone levels, and the weight of their ventral prostate and seminal vesicles, the targets of the sexual hormones.

4 When male and female offspring of exposed dams were mated, their fertility was normal, with no increase in prenatal death or malformations, and no changes in the size or sex ratio of litters.

5 These results indicate that, under our experimental conditions, lead oxide inhalation by rats during pregnancy did not perturb reproductive function in their male offspring.
Dose Dependent Effects on Lymphoid Organs following a Single Dermal Application of Sulphur Mustard in Mice
Authors: Venkateswaran K.S. , Neeraja V. , Sugendran K. , Gopalan N. , Vijayaraghavan R. , Pant S.C. , Prakash A.O. , Malhotra R.C.
Published: December 2008

The effects of a single dermal application of sublethal doses [15.5, 7.75 and 3.88 mg kg-1] of bis(2-chloroethyl)sulphide [sulphur mustard, SM] on body weight, organ/body weight ratio, haematology, histology and cellularity of spleen and thymus were studied after 7 days, in Balb/c mice. A progressive fall in body weight was noticed from the fifth day onwards after SM treatment. A dose-dependent decrease in the relative weights of spleen, liver and peripheral lymph nodes, and an increase in adrenal weight were also seen. An increase in red blood cell count, packed cell volume and haemoglobin concentration following SM intoxication were also dose dependent. These changes, together with a significant reduction in the cellularity of the spleen and thymus and degenerative histological changes, show that a single sublethal dermal dose of SM can cause considerable dose dependent systemic effects in Balb/c mice.
Acute Dystonic Drug Reaction or Tetanus? An Unusual Consequence of a 'Whizz' Overdose
Authors: Humphreys A. , Tanner A.R.
Published: December 2008

The case history presented illustrates that, following an overdose of 'Whizz' and alcohol, a protracted dystonic syndrome can develop, clinically indistinguishable from tetanus. A prolonged period of ventilation may be necessary, but, in this case, complete recovery eventually occurred.
Intravenous Pyridoxine in Acute Ethanol Intoxication
Authors: Mardel S. , Phair I. , O'Dwyer F. , Henry J.A.
Published: December 2008

Intravenous pyridoxine was evaluated as an agent for the reversal of ethanol-induced central nervous depression in a randomised double blind controlled study of 108 patients presenting with a clinical diagnosis of acute ethanol intoxication to two accident and emergency departments. Level of consciousness, measured by a modified Glasgow coma scale, showed no significant change after a single 1 g dose of intravenous pyridoxine when compared to controls given saline, The mean fall in blood alcohol concentration after one hour was 33 mg dl -1 (7.2 mmol l-1) in both groups suggesting that pyridoxine has no antidotal action and no short term effect on the rate of metabolism of ethanol.
Clinical Toxicology of Ethylene Glycol Monoal Ethers
Authors: Browning Randall G. , Curry Steven C.
Published: December 2008

The glycol ethers constitute a family of organic solvents commonly found in industrial and household products. Because of their widespread availability and potential for serious toxicity, physicians should be aware of the clinical toxicology of these compounds. Until recently, knowledge of the toxic effects of glycol ethers has been derived from animal studies and a limited number of case reports and small case series. A growing body of data from epidemiological studies, controlled human studies, and studies using human tissue now allows for advancement in the understanding of the acute and chronic toxicity of these compounds. This review summarizes and evaluates human and pertinent animal literature on the clinical toxicology of glycol ethers, with a focus on the commonly encountered monoalkyl ethers of ethylene glycol. Management options for acute poisoning, as well as measures for the control of workplace exposures, are discussed.
Interaction of Nitrobenzoates with Haemoglobin in Red Blood Cells and a Haemolysate
Authors: Norambuena E. , Videla L.A. , LisSi E.A.
Published: December 2008

Haemoglobin, either in the intact red blood cells or in their haemolysate, readily reacts with mono- and di-nitrobenzoates. For all the nitroaromatics considered, the rate of the process is faster in the haemolysate than in the whole red blood cell. At low (< 8 mM) concentrations, almost quantitative production of methaemoglobin is observed and the process follows second order kinetics. At higher concentrations, the kinetics become complex and other haemoglobin derivatives are produced.

The bimolecular rate constants obtained at low substrate concentrations show little relationship to the nitroaromatic reduction potential. The data indicate that mono-nitrobenzoate derivatives are very active in oxidizing haemoglobin in in vitro erythrocyte suspensions, the activities being similar to that of 3,5-dinitrobenzoate. The measured reactivity follows the order m-nitrobenzoate > 3,5-dinitrobenzoate > p-nitrobenzoate > o-nitrobenzoate and the reactivity of all the compounds is considerably larger than that of nitrobenzene. The present results constitute the first kinetic data bearing on the reactivity of nitroaromatics with haemoglobin, both free and incorporated in the intact red cell. Furthermore, they indicate that the interaction of the nitroaromatics with haemoglobin, leading to total oxidation and transformation, in spite of the total disruption of the membrane, does not produce significant lipid-peroxidation, as measured by chemiluminescence emission, production of TBA reactive material and oxygen consumption.
5-Carboxyfluorescein Diacetate as a Probe for Measuring the Growth of Keratinocytes
Authors: Hanthamrongwit M. , Reid W.H. , Courtney J.M. , Grant M.H.
Published: December 2008

There is a requirement for a convenient and reliable method for evaluating the growth rate of human keratinocytes cultured on collagen-based substrates. Therefore, three methods of determining cell growth were first used to quantify the growth rate of the well-characterised L929 mouse fibroblast cell line on tissue culture plastic and the results compared. The methods used were the measurement of total cell protein, cell counting using an electronic Coulter counter and a fluorimetric assay employing 5-carboxyfluorescein diacetate (CFDA). The CFDA assay showed the highest correlation with seeding density of the L929 cells, and the lowest standard deviations. It was the most rapid and convenient method for processing large numbers of samples. Only viable cells can deacetylate the non-fluorescent CFDA to carboxyfluorescein, which is fluorescent and accumulates inside the cells. Therefore, the assay specifically quantifies only viable cells. Subsequently, this assay has been successfully applied to the measurement of human keratinocyte growth rate on collagen gels and sponges. We have demonstrated that keratinocytes grow equally well on gels and sponges, and that media containing low calcium concentrations (0.09 mM) favour rapid proliferation of keratinocytes. Our results show that the CFDA assay is an accurate, reliable and convenient method for quantifying cell growth in vitro. It is particularly valuable when growing cells on optically opaque substrata, such as collagen sponges, where growth cannot be monitored daily by microscopy.
Human Placental Mast Cells as an In Vitro Model System in Aspects of Neuro-Immunotoxicity Testing
Authors: Purcell W.M. , Atterwill C.K.
Published: December 2008

1 In both the developing and adult nervous systems, nerve growth factor (NGF) influences neuronal survival, differentiation and recovery following insult,

2 The effect of NGF upon human placental mast cells (HPMC) was investigated, since it is known that rodent mast cells express a functional receptor for NGF and secrete histamine upon challenge with this neurotrophic factor. Furthermore, human placental tissue contains a significant amount of NGF and expresses a NGF receptor.

3 HPMC were shown to secrete histamine in a concentration dependent manner in response to NGF (0.001-10.0 μg ml-1) in the presence of the lipid cofactor phosphatidylserine (10.0 μg ml-1).

4 NGF induced histamine release from isolated HPMC with an EC50of 0.1 μg ml-1NGF and maximal secretion of total cellular histamine of 22.3 ± 3.4% at 3.0 μg ml-1.

5 The response was shown to be a secretory process, dependent upon the presence of exogenous calcium ions and to be pH- and temperature-sensitive.

6 HPMC are suggested to be a suitable primary cell model for use in aspects of in vitro toxicity testing, in terms of assessing the neuro-immunotoxic potential of neurotrophic therapeutics. In addition, mechanistic studies concerning those xenobiotics which may exert their neurotoxic effect via interaction with neurotrophic factors and, or their receptors, may be studied in this human cell model.
The Use of Human Lung Slices in Toxicology
Authors: Fisher Robyn L. , Smith Mary S. , Hasal Steven J. , Hasal Katherine S. , Gandolfi A. Jay , Brendel Klaus
Published: December 2008

1 Successful use of agar-filled precision-cut rat lung slices in dynamic organ culture prompted the use of this technology with human lung.

2 The larger tissue mass of a human lung required that the trachea be cannulated with a balloon catheter and subsequently inflated with 4 liters of warm agar/medium mixture and then cooled before being precision-cut into 500 μm thick slices.

3 To characterize the human lung slices, viability and the effects of acrolein and nitrofurantoin were assessed over a period of 24 h using protein synthesis and nonprotein sulfhydryl content.

4 Control human lung slices synthesized protein at a linear rate and maintained a stable nonprotein sulfhydryl content for 24 h.

5 Slices incubated with acrolein exhibited no significant decrease in protein synthesis or nonprotein sulfhydryl levels until 24 h.

6 Incubation with nitrofurantoin exhibited a definite time- and dose-dependent inhibition of protein synthesis, and depletion of the cellular thiol pool.

7 These results indicate that this human lung tissue slice system may be used as an in vitro model to identify and screen pneumotoxicants.
The Effect of Activated Charcoal on the Absorption and Elimination of Astemizole
Authors: Laine Kari , Kivistö Kari T. , Neuvonen Pertti J.
Published: December 2008

1 The effect of activated charcoal on the absorption and elimination of astemizole and its metabolites was studied in healthy volunteers.

2 Subjects were divided into three groups containing seven subjects each. One group received 30 mg of astemizole with water only (control) and another group with 25 g of activated charcoal. The third group received multiple doses (12 g) of charcoal from 6 h onwards twice daily for 8 days. The concentrations of astemizole and its metabolites in plasma were measured by radioimmunoassay for 192 h.

3 Activated charcoal, administered immediately after astemizole ingestion, reduced the absorption of astemizole by 85% (P<0.001). Multiple doses of activated charcoal, administered throughout the period of astemizole elimination, had no significant effect on the rate of elimination or the area under the curve from 0 to 192 h.

4 The absorption of astemizole from the gastrointestinal tract can be effectively prevented with activated charcoal. Because astemizole is rapidly absorbed, charcoal should be administered as soon as possible in acute astemizole poisoning. Multiple doses of charcoal do not seem to shorten the elimination half-life of astemizole.
Suicidal Inhalation of Vehicular Exhaust in the Lothian and Borders Region of Scotland
Authors: Busuttil A. , Obafunwa J.O. , Ahmed A.
Published: December 2008

1 A 6-year retrospective study of the features of 79 consecutive completed suicides from exhaust fume inhalation (SEFI) in the Lothian and Borders region of Scotland was conducted. Full forensic autopsies with histological and toxicological studies were carried out.

2 The mean incidence is 2.0/100,000 population (M=3,7; F=0,4; P<>0.001); increasing since 1990. The age peak is in the 35-44 years age group (especially among males) and a significant ( P<0.001) proportion reside in rural areas.

3 SEFI is significantly ( P<0.05) higher during spring and summer; outdoor locations are prevalent during summer.

4 Most (75.6%) of the victims were in current employment. Psychiatric illness (30.7%), problems in marriage or relationships (28.2%) and financial difficulties (16.7%) were the major associated socio-medical factors.

5 The mean carboxyhaemoglobin (COHb) saturation was 74 ± 11.2%; fatal COHb saturation levels were still detectable in severely decomposed bodies. The blood alcohol concentration (BAC) in 37 of the victims ranged from 14-397 mg dl-1. No significant correlation exists between COHb saturation and the victim's age or BAC.

6 Attempts to reduce the incidence of SEFI must be directed principally to dealing with associated socio-medical problems. The reduction of the potential of vehicles to produce carbon monoxide and of directing exhaust fumes into the interior of the vehicle are important secondary preventative measures.
Further circumstantial evidence for the involvement of aflatoxin in primary liver cancer?
Authors: Neal Gordon E
Published: December 2008

Fifty-eight percent of hepatocellular carcinomas (HCCs) from Qidong, China, contain an AGG to AGT mutation at codon 249 of the p53 tumour suppressor gene, a mutation that is rarely seen in HCCs from Western countries. The population of Qidong is exposed to high levels of aflatoxin B1(AFB1), a fungal toxin that has been shown to induce the same mutation in cultured human HCC cells. To investigate the role of AFB1 and of these p53 mutations in hepatocarcinogenesis, normal liver samples from the United States, Thailand and Qidong (where AFB1 exposures are negligible, low and high, respectively) were examined for p53 mutations. The frequency of the AGG to AGT mutation at codon 249 paralleled the level of AFB 1 exposure, which supports the hypothesis that this toxin has a causative-and probably early-role in hepatocarcinogenesis.
Pulmonary Alveolar Phospholipoproteinosis Induced by Orasol Navy Blue Dust
Authors: Ballantyne Bryan
Published: December 2008

1 Orasol Navy Blue (ONB) is a water-insoluble nitroaromatic dye to which workers may be exposed to the dust.

2 Rats and guinea pigs exposed for 30 min to 173 mg m-3 did not show toxic signs or respiratory tract histopathology.

3 Rats, mice and guinea pigs were exposed 6 h a day for 20 or 100 days to 2.05 mg m-3 ONB dust (particle size, 33.6% < 5 μm). Except for decreased body weight of guinea pigs during the exposure period, no adverse signs were seen over a 1-year period from the first exposure. Respiratory tract histopathology was not seen in mice or guinea pigs. Rats showed scattered alveolar lesions characterized by aggregations of macrophages, PAS-positive debris, cholesterol, sudanophilia and birefringence, with preservation of the interstitium and no fibrogenic response. The number and size of these lesions was related to the duration of exposure.

4 The similarity of the lesions seen in the rat following exposure to ONB dust and those seen in humans from other exogenous causes of pulmonary alveolar phospholipoproteinosis suggests that overexposure of humans to a respirable dust of ONB may produce this lesion.

5 The rat is a convenient model to investigate pulmonary alveolar phospholipoproteinosis by exposure to respirable dusts.
Current Perspectives on Particulate Induced Pulmonary Tumours
Authors: Hext P.M.
Published: December 2008

1 Chronic exposure to insoluble particulates can lead to the development of pulmonary tumours. These have been classified as broncho-alveolar or squamous/epidermoid according to their histopathological characteristics and have been reported in inhalation studies in rats of materials ranging from diesel exhaust and silica to titanium dioxide.

2 The sequence of changes within the rat lung leading to tumours has been characterised. It is apparent that one prerequisite is that the lung load of the particulate matter must exceed the normal clearance capacity, either by overloading the normal alveolar macrophage mediated mechanism or by induction of toxicity with materials such as silica. This results in inflammatory responses, including, or resulting in, epithelial hypertrophy and/or hyperplasia and squamous metaplasia. The persistence of these tissue responses over chronic time periods can lead to tumorigenesis.

3 Research into the mechanisms involved in the initiation and progression of both the inflammatory response and subsequent tumorigenic response to lung particulate loading is in progress. Impairment of macrophage function and mobility by inert particles constitutes one route by which this can arise, as does toxicity to this cell type by biologically reactive particles. At the molecular level, the role of inflammatory mediators, especially the cytokines, has received much attention.

4 Particulate induced lung tumours are perceived to be a phenomenon specific to the rat and their relevance to man is questionable.
Selective Inhibition of Gastrointestinal β-Glucuronidase by Poly(vinylbenzyl D-glucaro(1,4)lactonate). Part 2. Poly(vinylbenzyl D-Glucaro(1,4) lactonate) In vitro Inhibition Studies
Authors: Sacco C. , Calabrese E.J.
Published: December 2008

In vitro inhibition studies with β-glucuronidase from purified E. coli and mouse intestinal contents indicated that the polymer, poly(vinylbenzyl D-glucaro(1,4)lactonate, is an effective β-glucuronidase inhibitor. Purified E. coli β-glucuronidase was inhibited by 99.6% with 1 77 mM D-glucaro(1,4)lactone using the polymer-inhibitor. Similarly, 95% inhibition of β-glucuronidase activity of mouse intestinal contents was obtained with 177 mM and 50% inhibition was obtained with 31.5 mM D-glucaro(1,4)lactone based on the modified polymer. The structural requirements of an effective β-glucuronidase inhibitor based on the structure of the polymer-inhibitor are also discussed.
Redtide in the Philippines
Authors: Hartigan-Go K. , Bateman D.N.
Published: December 2008

1 Redtide is a marine phenomenon that poses great risk to the health and economic livelihood of people in coastal areas. Paralytic shellfish poisoning develops when a person consumes molluscs containing toxic dinoflagellates and suffers neurological and/or gastrointestinal manifestations.

2 Four redtide incidents in the Philippines are presented. The manner in which the problems were managed are described.

3 The clinical features of redtide poisoning in the Philippines included gastro-intestinal and neurological features with deaths secondary to ventilatory failure. Mortality ranged from 0% to 12% in the different redtide episodes.

4 There are many lessons to be learned in handling this kind of natural disaster. For an effective toxicovigilance programme, there must be a central co-ordinating responsible organization, a clear definition of roles and functions and good inter-agency co-operation. Appropriate surveillance procedures, resources to intensify surveillance at times of risks, prompt warning system, and the ability to impose bans on consumption are also necessary.

5 Poisons centres can play an important role during times of redtide. This may include toxicovigilant activities, such as early warning and educational campaigns to consumers, and seminars in the recognition and management of paralytic shellfish poisoning.

6 The contribution of the epidemiologists in investigating and monitoring the extent of public health damage and patterns of poisoning in a coastal community is emphasized.
Elemental Mercury Vapour Toxicity: Treatment and Levels in Plasma and Urine
Authors: Houeto P. , Sandouk P. , Baud F.J. , Levillain P.
Published: December 2008

1 We report two cases of acute mercury vapour intoxication in humans. The mercury vapour was released from smelting alloys (gold-mercury amalgam). The alloy was apparently contaminated with an unknown amount of mercury.

2 Within half an hour of the incident, the victims began having moderate headache, nausea, lumbar pain and shortness of breath at rest. The patients were treated with BAL (2,3 dimercaptopropanol), followed by DMSA (2,3 dimercaptosuccinic acid).

3 Serial measurements of mercury metal in plasma and in urine were made for ten days.

4 The results suggest that in spite of the treatment, relatively high concentrations of mercury remain in the plasma for a very long time, and this could be explained by the progressive release of mercury from red blood cells and tissues after oxidation. However, BAL and DMSA did not seem to be the most efficient antidotes. They reduce the piasma inorganic mercury uptake at concentrations of <50 μg l-1.
Metabolism and Genotoxicity of the Halogenated Alkyl Compound Tris(2,3-Dibromopropyl)phosphate
Authors: van Beerendonk G.J.M. , Nelson S.D. , Meerman J.H.N.
Published: December 2008

1 The genotoxicity of the flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) was studied in vivo. Results showed that Tris-BP was highly clasfogenic, but it could only initiate a low number of preneoplastic foci in the rat liver in vivo. In Drosophila, Tris-BP could be classified as a cross-linking agent, because it was more clastogenic than mutagenic. The use of completely deuterated Tris-BP as a metabolic probe revealed that cytochrome P450 and most likely the formation of 2-bromoacrolein (2BA) from Tris-BP is important for the observed genotoxic effects.

2 In contrast to the high mutagenicity of Tris-BP and 2BA in Salmonella typhimurium, we were unable to detect an increase in mutation frequency of 2BA on the hprt locus of human TK6 cell line. In another system, using a shuttle vector modified with 2BA:DNA-adducts, also no increase in mutation frequency could be detected in human cells. This low mutagenicity of 2BA corresponds with its low mutagenicity in Drosophila and its low induction of preneoplastic foci in the rat liver.

3 Several DNA adducts of 2BA have been identified, including an unstable 3-(bromooxypropyl)thymidine adduct which has the potential to form cross-links and a cyclic 3,N 4-(bromo)propeno-deoxycytidine adduct which can possibly be involved in the clastogenicity of Tris-BP.

4 Taken together, these data indicate that Tris-BP and 2BA may not effectively induce gene mutations in eukaryotic systems, but rather be potent clastogens. Risk assessment of these and related compounds should therefore be based on the knowledge of clastogens rather than mutagens.
Molecular Dosimetry of DNA Damage Induced by Polycyclic Aromatic Hydrocarbons; Relevance for Exposure Monitoring and Risk Assessment
Authors: Baan R.A. , Steenwinkel M.-J.S.T. , van den Berg P.T.M. , Roggeband R. , van Delft J.H.M.
Published: December 2008

Polycyclic aromatic hydrocarbons (PAH) form a large group of organic chemicals that are widely distributed in our environment as pollutants of air, water and soil. Several PAH are carcinogenic in rodents, while exposure to these compounds has been associated with various types of human cancer. Upon entering the body, PAH may be converted into reactive electrophilic species, which can give rise to the formation of DNA adducts. DNA adduct formation is considered to be the initial event in chemical carcinogenesis.

In this paper, two methods are illustrated that are widely used to determine PAH-DNA adduct formation, namely 32P-postlabelling, and immunochemical analysis with specific antibodies. The applications of the 32P-postlabelling assay comprise the following:

- A study of interspecies differences in PAH bioactivation in vitro, with microsomal preparations isolated from liver tissue of various rodent species and of human origin; the results indicate that there are considerable qualitative differences between the adduct patterns obtained, which is relevant with respect to extrapolation from animal to man.

- The analysis of DNA adduct formation in fish retrieved from marine environments polluted to various extents with PAH; results of these studies show a correlation between liver-DNA adduct levels in these fish and the degree of PAH contamination in the aquatic environment.

- Biomonitoring of PAH exposure through analysis of adducts in blood cells obtained from heavy and light smokers; the data show a fair correlation between PAH-DNA adduct levels in white blood cells and cotinine content in blood plasma, the latter being used as a marker for exposure to cigarette smoke. The activity of the detoxifying enzyme glutathione S-transferase M (GSTM1) was also determined in these individuals.

Immunochemical analysis with a benzo(a)pyrene(BP)-DNA-specific antiserum was used to investigate BP-adduct induction in situ, in different epithelial cell types—basal/non—basal cells—of hamster trachea exposed to BP in vitro, Histochemical staining of cell-specific cytokeratins was combined with adduct-specific immunostaining. The latter was quantified by immunofluorescence microscopy. The results show that removal of DNA adducts from the basal cells is more rapid during the first 24 h following exposure than from the non-basal cells.

The sensitive methods for molecular dosimetry of DNA damage, as illustrated in this paper, appear suitable for determining exposure of animals and humans to PAH. Further animal experiments and in vitro model studies will provide useful additional information that will help evaluate the relevance of biomonitoring data with respect to the health risk that may be associated with the exposure.
An Evaluation of Four Types of Freshwater Model Ecosystem for Assessing the Hazard of Pesticides
Authors: Leeuwangh Peter , Brock Theo C.M. , Kersting Kees
Published: December 2008

Experimental results are reported on four types of freshwater model ecosystem after administration of a single dose of chlorpyrifos. The fate, and primary and secondary effects of chlorpyrifos were compared between the model ecosystems, and were evaluated in the light of the predictive value of the current ecotoxicological hazard assessment procedure for pesticides. 'Slootbox', a fate model used in the ecotoxicological risk assessment of pesticides in the Netherlands, overestimated chlorpyrifos concentrations. The primary effects of chlorpyrifos can be predicted accurately on the basis of single species laboratory toxicity data. The population effects observed in the microecosystems, microcosms, and mesocosms were consistent between all experiments and with the single species tests. Community metabolism, as a functional endpoint, was less sensitive than the structural parameters measured. Secondary effects, both for structural and functional endpoints, varied between the micro- and mesocosm experiments. At the present 'state of the art' in ecotoxicology, no a priori prediction of secondary effects in natural ecosystems will generally be possible. 0.1 times the lowest acute L(E)C50 for chlorpyrifos, as measured in the current ecotoxicological hazard assessment procedure, matched the NOEC mesocosm for a single dose of chlorpyrifos. Recovery of populations affected by insecticide stress was found to depend on factors such as life cycle characteristics and ecological infrastructure, in addition to the toxicant concentration. The onset of (potential) recovery is likely to start at an approximate concentration of the EC10(48 h).
Chemical gastro-oesophagitis, upper gastrointestinal haemorrhage and gastroscopic findings following Dettol poisoning
Authors: Chan Thomas Y.K. , Sung Joseph J.Y. , Critchley Julian A.J.H.
Published: December 2008

1 Dettol liquid (chloroxylenol 4.8%, pine oil, isopropyl alcohol), a household disinfectant, has a corrosive action on the gastrointestinal mucosa when swallowed. The inci dence of upper gastrointestinal haemorrhage and gastro scopic findings following Dettol poisoning was studied in 89 patients.

2 Five patients (5.6%) developed minor haematemesis, in the form of coffee-coloured or blood-stained vomitus. One patient had a gastroscopy performed on the day after admission, showing signs of chemical burns in the oesoph agus and stomach. Gastroscopy was performed in one other patient on day 11 to rule out oesophageal stricture; the patient was normal. All patients completely recovered. 3 The data from this study suggest that upper gastroin testinal haemorrhage following Dettol poisoning tends to be mild and self-limiting. Gastroscopy, which may increase the risk of aspiration in patients with impaired consciousness, is not required unless other causes of gas trointestinal bleeding are suspected.