bluuebunny/crossref_metadata_2025 huggingface dataset:
Depletion of Plasma Glycine and Effect of Glycine by Mouth on Salicylate Metabolism During Aspirin Overdose
Authors: Patel D.K. , Ogunbona A. , Notarianni L.J. , Bennett P.N.
Published: December 2008

1 The metabolism of aspirin was investigated in 45 patients who had taken self-administered overdose of aspirin and were treated with fluids only, glycine, N-glycylglycine by mouth, or by sodium bicarbonate i.v.

2 The major metabolite recovered in the urine of patients treated with oral fluids, glycine or N-glycylglycine was salicyluric acid, which accounted for means of 51%, 47% and 38% of the total, respectively; salicylic acid comprised 19%, 29% and 29%. In contrast, salicylic acid (42%) was the major urinary metabolite recovered from patients treated with sodium bicarbonate.

3 Plasma glycine concentrations in healthy volunteers who had taken no aspirin remained constant through the day and were not affected by a therapeutic dose (500 mg) of aspirin. Plasma glycine was consistently lower in patients with aspirin overdose than in these healthy volunteers, suggesting depletion of available glycine.

4 Orally administered glycine and N-glycylglycine increased plasma glycine. While the fraction of total salicylate recovered as salicyluric acid was not altered, the maximum rate of excretion of salicyluric acid was higher in patients who received glycine than in the control group; there was no significant difference in the maximum rate of excretion of salicyluric acid between the group that received glycine and the group that received N-glycylglycine. 5 The data suggest that exogenous glycine increases the rate of formation of salicyluric acid in salicylate overdose.
Immunotoxic Effects of Hexachlorobenzene on the Pathogenesis of Systemic, Pneumonic and Hepatic Virus Infections in the Mouse
Authors: Carthew P. , Edwards R.E. , Smith A.G.
Published: December 2008

A quantitative histopathological method has been developed for the evaluation of the effects of hexachlorobenzene (HCB) on the pathogenesis of three virus infections in the mouse. Hexachlorobenzene was selected because a substantial amount of immunotoxicological data already exists with which we could compare our results. To establish the validity of the method a systemic virus infection (mouse cytomegalovirus, MCMV), a pneumonia causing virus (pneumonia virus of mice, PVM) and a hepatitis virus (mouse hepatitis virus, MHV) were used. We have compared the existing data with the actual pathological effects of hexachlorobenzene on virus disease processes, to gain a more realistic idea of the value of the risk assessment to be derived from extrapolating the in-vitro data in particular, to the in-vivo situation. The results show that the data derived from previous studies on the immunotoxicity of HCB were accurate in predicting the exacerbation of the viral hepatitis, especially in immunodeficient athymic 'nude' mice.

It is proposed that this histopathological technique could be a useful technique in the evaluation of host resistance changes following exposure to potentially immunotoxic compounds, but caution will have to be exercised in interpretation in relation to human disease.
Acute Poisoning with Methidathion: A Case
Authors: Zoppellari R. , Targa L. , Tonini P. , Zatelli R.
Published: December 2008

An acute poisoning in a 50-year-old man who ingested approximately 6.2 g of the phosphorus ester methidathion is described. The patient was treated with three haemoperfusions 23, 44 and 115 h after ingestion, with continuous gastric lavage, atropine and pralidoxime administration and with prolonged mechanical ventilation.

Haemoperfusion was an ineffective epuration technique since it removed only 0.22% of the ingested methidathion.

The clinical course wavered because of a probable redistribution of phosphorus ester from fat to blood. A plasma level higher than 100 μg l-1 was associated with the most serious phases. Methidathion was present in the plasma until the sixth day, in the urine until the seventh and in the gastric juice until the eighth. Its absence in the fat biopsy made on the tenth day was an aid to therapy.

The phosphorus ester did not inhibit lymphocyte neuropathy target esterase (NTE), neither did it induce development of delayed polyneuropathy.
Evaluation of Severity Indexes of Patients with Paraquat Poisoning
Authors: Suzuki Kouichiro , Takasu Nobukatsu , Arita Seizaburo , Ueda Akinori , Okabe Toru , Ishimatsu Shinichi , Tanaka Shigeru , Kohama Akitsugu
Published: December 2008

1 Three indexes for evaluating the severity of paraquat poisoning based on plasma-paraquat concentration are presently in use; the curves of Proudfood et al. and Scherrmann et al. and the SIPP. Their effectiveness in determining the prognosis of patients with paraquat poisoning was evaluated.

2 To determine which index was more accurate, contingency tables of the three indexes were obtained and compared; Proudfoot's curve vs the SIPP Scherrmann's curve vs the SIPP. Proudfoot's curve and the SIPP were applied to patients admitted within 24 h after intoxication. Scherrmann's curve and the SIPP were applied to patients admitted more than 24 h after intoxication. The proportions of patients with true positive and true negative results to total patients were compared by a ratio test.

3 Proudfoot's curve was found to be more accurate than the SIPP for predicting the prognosis of patients admitted within 24 h (P < 0.05). No significant difference, however, was noted between Scherrmann's curve and the SIPP in determining the prognosis of patients admitted after more than 24 h.

4 In conclusion, Proudfoot's curve proved a better index for predicting the outcome of patients who were admitted within 24 h. However, for the prognosis of patients admitted more than 24 h after the ingestion of paraquat, further study is required.
Distribution of Ethylene Oxide in Human Blood and its Implications for Biomonitoring
Authors: Föst U. , Hallier E. , Ottenwälder H. , Bolt H.M. , Peter H.
Published: December 2008

The distribution of radioactivity following the incubation of human blood with radiolabelled ethylene oxide was investigated in vitro. After incubation, the individual blood samples were separated into lymphocytes and high (Mr > 10,000) and low (Mr < 10,000) molecular fractions of erythrocyte cytoplasm and blood plasma. The radioactivity was determined in each sample by liquid scintillation counting.

In erythrocyte cytoplasm, the distribution of radioactivity showed marked interindividual differences and two distinct groups could be distinguished. The coincidence of these groups with 'conjugators' and 'non-conjugators', in terms of the enzymatic conjugation of methyl halides to glutathione in erythrocytes, suggests a common principle, such as enzyme polymorphism. Such polymorphism has been described for glutathione S-transferase μ in the human liver, an enzyme that efficiently conjugates epoxides. In the other blood compartments, the interindividual differences were either less significant or were not detectable.

Binding products with various macromolecules in blood, such as haemoglobin or lymphocyte DNA, are being discussed as biological monitors for occupational exposure to ethylene oxide. The observation that erythrocytes exhibit interindividual differences as described above make binding products with haemoglobin less suitable for biological monitoring of ethylene oxide exposure than, for example, DNA adducts in lymphocytes.
Oral Pharmacokinetics of Fluazifop-Butyl in Human Volunteers
Authors: Woollen B.H. , Hart T.B. , Batten P.L. , Laird W.J.D. , Davies D.S. , Dollery C.T.
Published: December 2008

1 Fluazifop-butyl, the active ingredient of FUSILADE, a selective herbicide, was administered orally to three male volunteers at a dose level of 0.07 mg kg-1 body weight. Over a period of 6 d between 80 and 93% of the dose was excreted in urine as the metabolite fluazifop, the majority within the first 24 h. Peak plasma concentrations of fluazifop occurred 1-2.5 h after administration.

2 The elimination of fluazifop from plasma and urine can be described by a one-compartment pharmacokinetic model and the elimination half-life was estimated from blood and urine data to be within the range 9-37 h. Fluazifop was found to bind to serum proteins.

3 The study indicates that the amount of fluazifop-butyl absorbed in exposed persons can be assessed by measuring fluazifop concentrations in urine.
Effects of Combined Exposure to Aluminium and Ethanol on Aluminium Body Burden and some Neuronal, Hepatic and Haematopoietic Biochemical Variables in the Rat
Authors: Flora S.J.S. , Dhawan Mamta , Tandon S.K.
Published: December 2008

The effects of the daily administration of aluminium (25 mg kg-1, orally), ethanol (10% v/v, in drinking water) or both to adult rats, for 6 weeks, on the amount of aluminium present in the tissues and the functioning of brain biogenic amines, hepatic and serum transaminases and some haematopoietic variables were investigated.

Ethanol alone was seen to inhibit the activity of δ-aminolevulinic acid dehydratase (ALAD), while aluminium alone elevated the activity of blood ALAD. However, aluminium and ethanol combined produced a more pronounced inhibition of blood ALAD and hepatic glutamic pyruvic transminase (GPT) than either aluminium or ethanol alone. Simultaneous exposure to aluminium and ethanol also produced a significant elevation in urinary δ-aminolevulinic acid (ALA) blood zinc protoporphyrin (ZPP), serum glutamic oxaloacetic transaminase (GOT) and brain homovanillic acid (HVA), and a depletion in brain dopamine (DA) and 5-hydroxytryptamine (5-HT) levels, when compared to rats given aluminium alone. The concentration of aluminium in the blood and liver was significantly higher in rats exposed to both aluminium and ethanol than in those exposed to aluminium alone. Thus the consumption of alcohol may increase the rat's susceptability to certain effects of aluminium.
Studies on the Mutagenicity of a Zinc Oxide-Hexachloroethane Smoke
Authors: Clode S.A. , Riley R.A. , Blowers S.D. , Marrs T.C. , Anderson D.
Published: December 2008

1 A suitable method has been developed for generating atmospheres of zinc oxide/ hexachloroethane smoke (ZnHCE).

2 The smoke was investigated using the Ames test and the micronucleus assay.

3 It was weakly mutagenic to the bacteria, but in the bone marrow no increases in micronuclei were detected up to toxic levels of the smoke.

4 The method used here could be applied to other pyrotechnic mixtures which give rise to complex mixtures of products.
Neurotoxicity of 1-Methoxycycloheptatriene - A Purkinje Cell Toxicant
Authors: Marrs T.C. , Allen Ingrid V. , Colgrave H.F. , McConnell R.
Published: December 2008

The toxicity of 1-methoxycycloheptatriene (1-MCHT), a sensory irritant, has been investigated in beagles. It was found to produce gross inco-ordination of the limbs at intravenous doses greater than 10 mg kg-1. The main histological abnormalities were in the cerebellum and consisted of Purkinje cell death and subsequent reactive gliosis. A few necrotic neurons were seen in the diencephalon, pons and medulla. Haematological abnormalities, e.g. leucocytosis with relative lymphopenia, were seen, while biochemical changes included hyperglycaemia and a rise in plasma aminotransferases. The no-effect dose for the histological and biochemical changes was the same. These abnormalities are compared with cerebellar changes observed in acrylamide and other toxic states.
Intentional Self-Poisoning with Glyphosate-Containing Herbicides
Authors: Menkes D.B. , Temple W.A. , Edwards I.R.
Published: December 2008

Four cases of self-poisoning with 'Roundup' herbicide are described, one of them fatal. One of the survivors had a protracted hospital stay and considerable clinical and laboratory detail is presented. Serious self-poisoning is associated with massive gastrointestinal fluid loss and renal failure. The management of such cases and the role of surfactant toxicity are discussed.
The Effect of Therapeutic Doses of Paracetamol on Sulphur Metabolism in Man
Authors: Blackledge H.M. , O'Farrell J. , Minton N.A. , McLean A.E.M.
Published: December 2008

1 This study was designed to investigate the effect of prolonged paracetamol intake on sulphur metabolism in patients. Six patients, taking paracetamol in doses of 2-4 g d-1and one taking 12 g d-1took part in the study. Daily (24-h) collections of urine, and also plasma samples from these patients were analysed and in one case a study with additional methionine was performed.

2 The patients showed variable decrease in urinary output of inorganic sulphate but moderately raised plasma levels of inorganic sulphate.

3 Paracetamol metabolism was characterized by dominance of the glucuronidation pathway with the increase of the administered dose of paracetamol. Methionine added to the diet did not change this metabolic pattern. None of the subjects produced more than 0.6 mmol h-1paracetamol sulphate while total sulphur excretion was 7.5-26.7 mmol d-1.

4 Volunteers taking 3 g d-1paracetamol were also studied.

5 In persons taking a normal western diet containing over 20 mmol d-1sulphur amino-acids paracetamol metabolism will not lead to sulphur amino-acid depletion even if high daily doses are used.
Non-specificity of Clinical Signs and Symptoms Caused by Environmental Chemicals
Authors: Grandjean P. , Sandoe S.H. , Kimbrough Renate D.
Published: December 2008

1 A review of the scientific literature revealed that 220 environmental chemicals had caused documented systemic toxicity in humans. This number is relatively small compared to the large number of industrial chemicals in the environment.

2 A total of 149 of these chemicals were verified as neurotoxins, thus emphasizing the sensitivity of this target organ. Despite the exclusion of chemicals that cause airway irritation only, 99 chemicals caused adverse effects on the respiratory system. Toxicity to the liver, kidneys and blood forming organs was less frequent.

3 Most of the individual clinical effects had a very low specificity in cases of human intoxication. Of 80 major signs and symptoms, 17 had only a single documented chemical aetiology. However, the combination of two or more signs or symptoms was found to provide an improved guidance to aetiological diagnosis. The paucity of specific signs and symptoms is probably one of the reasons that only 220 environmental chemicals have been documented as causes of human disease.
Effects of a Cholecystokinin Receptor Antagonist on Rat Exocrine Pancreatic Response to Raw Soya Flour
Authors: Sundaram S. , Dayan A.D.
Published: December 2008

1 Raw soya flour (RSF) in the diet induces pancreatic hypertrophy and hyperplasia in the rat, changes ascribed to production of a high circulating level of cholecystokinin (CCK) due to inhibition of trypsin in the duodenum. Prolonged ingestion results in pancreatic adenomas and carcinomas.

2 L-364, 718, a potent, highly specific CCK antagonist was used to investigate the short-term role of CCK.

3 In rats fed 50% RSF and L-364, 718 5 mg kg-1p.o. twice daily for 4 d, there was inhibition of pancreatic hypertrophy and hyperplasia, which is further evidence that peripherally-acting CCK plays a major role in the generation of RSF-mediated changes in the pancreas.
The Formation of Methaemoglobin by 4-aminopropiophenone (PAPP) and 4-(N-hydroxy) aminopropiophenone
Authors: Marrs T.C. , Inns R.H. , Bright J.E. , Wood S.G.
Published: December 2008

Oral dosing of rats with the cyanide antidote 4-aminopropiophenone (PAPP), brought about peak methaemoglobin levels at 15-40 min, but peak levels were attained at 15-25 min after intravenous dosing. After both oral and intravenous administration at equimolar doses, 4-(N-hydroxy)aminopropiophenone (PHAPP), the putative methaemoglobin-producing metabolite of PAPP, produced higher peak levels of methaemoglobin than PAPP. Plasma from rats injected with PAPP was capable of forming methaemoglobin when added to naive rat erythrocytes. The identity of the metabolite responsible is discussed.
The Need for a Control Animal Pathology Database: An International Survey
Authors: McAuslane J.A.N. , Lumley C.E. , Walker S.R.
Published: December 2008

1 The sensitivity of long-term toxicity tests is impaired due to the 'background noise' of spontaneous lesions which are unrelated to treatment.

2 The need for a comprehensive source of computerized information concerning the occurrence and incidence of spontaneous lesions in control animals has been highlighted by initiatives in Europe and the USA. It is, however, essential to identify the potential users, and the type of information required for such a database to be of value.

3 This information has been acquired following an international survey of the pharmaceutical industry in Europe, Japan and the USA, including responses from 48 toxicologists and toxicopathologists representing 38 company groups.

4 Thirty-eight respondents indicated that they would use a historical control database that was regularly updated with the majority of respondents suggesting that they currently use external sources (Breeder's data, the literature, other companies) occasionally to acquire information on control animal pathology data.

5 The majority (94%) of the respondents indicated that a control animal database should contain information on both neoplastic and non-neoplastic lesions for use in evaluating long-term studies, in particular carcinogenicity studies.

6 The survey confirms the need for a historical control animal pathology database wider then those currently available.
Changes in Arterial Oxygen Tension after Gastric Lavage for Drug Overdose
Authors: Jorens Philippe G. , Joosens Eric J. , Nagler Jan M.
Published: December 2008

1 Changes in arterial oxygen tension after gastric lavage were investigated in a prospective study of 55 patients admitted for drug overdose.

2 A significantly greater decrease was observed in smokers compared to non-smokers.

3 A correlation was found between the tricyclic antidepressant serum level and the observed oxygen tension decrease.

4 The usefulness, as well as the safety of the lavage procedure, in managing tricyclic antidepressants overdoses is controversial.
Computer Prediction of Possible Toxic Action from Chemical Structure; The DEREK System
Authors: Sanderson D.M. , Earnshaw C.G.
Published: December 2008

1 The development of DEREK, a computer-based expert system (derived from the LHASA chemical synthesis design program) for the qualitative prediction of possible toxic action of compounds on the basis of their chemical structure is described.

2 The system is able to perceive chemical sub-structures within molecules and relate these to a rulebase linking the sub-structures with likely types of toxicity.

3 Structures can be drawn in directly at a computer graphics terminal or retrieved automatically from a suitable in-house database.

4 The system is intended to aid the selection of compounds based on toxicological considerations, or separately to indicate specific toxicological properties to be tested for early in the evaluation of a compound, so saving time, money and some laboratory animals and resources.
The Effect of Organophosphorus Compounds on Serum Pseudocholinesterase Levels in a Group of Industrial Workers
Authors: Peedicayil Jacob , Ernest Kalpana , Thomas Molly , Kanagasabapathy A.S. , Stephen P.M.
Published: December 2008

This paper presents the findings of a study of serum pseudocholinesterase activity in a group of 36 industrial workers chronically exposed to organophosphorus (OP) compounds. The mean pseudocholinesterase level of the workers was significantly lower than that of 36 other workers without a history of similar exposure. Although there was a high incidence of clinical features suggestive of OP compound toxicity in the exposed workers, no significant correlation between serum pseudocholinesterase levels and clinical symptoms and signs was found. Six exposed workers, found to have low serum pseudocholinesterase levels, were transferred for 6 months to work areas which did not involve OP exposure, whereupon their levels rose significantly back to the normal range.
Clove Oil Ingestion in an Infant
Authors: Lane Brian W. , Ellenhorn Matthew J. , Hulbert Tim V. , McCarron Margaret
Published: December 2008

A case is presented in which a 7-month-old child developed central nervous system depression, urinary abnormalities and a large anion-gap acidosis after the accidental oral administration of clove oil. Supportive care and gastric lavage were sufficient for total recovery of the patient. Possible mechanisms of the depression and acidosis are discussed, and suggestions for treatment are presented.
Self-poisonings with Psychopharmacological Agents in Zagreb
Authors: Miličević G. , Prpić H.
Published: December 2008

1 A 5-year retrospective study of 1743 episodes of self-poisoning in 1608 adult patients, was undertaken to determine the frequency of self-poisoning with psychopharmacological agents, the frequency of each toxic agent usage and the epidemiological characteristics of the poisoned population.

2 The annual incidence of self-poisoning in Zagreb was 38.7 per 100 000 adult inhabitants. The anxiolytic-antipsychotic-antidepressant usage ratio was 8.8:1.5:1.0 in total self-poisoning, whereas it was 4.9:1.5:1.0 in patients with a previous history of self-poisoning. The use of anxiolytics decreased and the use of antidepressants increased during the 5 years.

3 The female—male ratio was 3.8:1 and 77% of self-poisoned persons were aged 15-44 years. The incidence of self-poisoning was 74% higher in the urban than in the rural population. The proportion of self-poisoned persons was 204% higher among the unemployed than in the population as a whole. There were 76% more repetitors among highly educated and 43% fewer repetitors among students than in the general population. The use of antipsychotics was 120% higher in males than in females. The use of antidepressants was 107% higher in the highly educated.

4 The increased use of antidepressants in self-poisoning is an alarming signal and caution in their prescription seems to be indicated.
Influence of Simultaneous Supplementation of Zinc and Copper During Chelation of Lead in Rats
Authors: Flora Swaran J. S.
Published: December 2008

The influence of zinc and copper supplementation during chelation therapy to reduce zinc and copper imbalance and promote lead elimination from the body, was investigated in rats poisoned with lead. The simultaneous supplementation of zinc and copper increased urinary lead excretion by calcium disodium ethylenediamine tetraacetic acid (CaNa2EDTA) compared to treatment with CaNa2EDTA alone. Combination therapy was effective in potentiating the depletion of blood and renal lead by CaNa2EDTA and meso 2,3-dimercapto succinic acid (DMSA). Combination therapy was also more effective in reducing hepatic lead by CaNa2EDTA and blood lead by 2,3-dimercapto propane sulphonate (DMPS). Zinc and copper supplementation produced a more effective reversal of inhibited blood δ-aminolevulinic acid dehydratase (ALAD) activity, urinary δ-aminolevulinic acid excretion and depleted body zinc and copper status.
Drug Interaction between Rifampicin and Cotrimoxazole in Patients with Tuberculosis
Authors: Bhatia R.S. , Uppal R. , Malhi R. , Behera D. , Jindal S.K.
Published: December 2008

1 Patients ( n = 15) who were admitted with complications of tuberculosis, were given antitubercular therapy (ATT) with rifampicin (RIF), for a minumum period of 15 d, and cotrimoxazole (CTZ), concurrently, for 5-10 d.

2 The serum RIF levels were measured before the start of CTZ treatment and at the end of its administration.

3 The plasma half-life ( t½) of RIF increased significantly from 1.92 ± 0.57 h to 2.31 ± 0.134 h after CTZ treatment.

4 The mean serum levels of RIF increased significantly at 4 and 6 h after CTZ administration.
Effect of Four Thiol-Containing Chelators on Disposition of Orally Administered Mercuric Chloride
Authors: Nielsen J.B. , Andersen O.
Published: December 2008

Acute toxicity and the disposition of inorganic mercury depends on the route of exposure. Most previous studies on effect of chelators on inorganic mercury toxicity and toxicokinetics employed parenteral administration of both metal and chelator. However, the most prominent routes for human inorganic mercury exposure are the oral or pulmonary. BAL was previously considered the drug of choice in human intoxications with most heavy metals. This recommandation has been questioned during recent years due to the advent of the less toxic hydrophilic BAL analogues DMSA and DMPS. The present study, using oral administration of HgCl2labelled with203Hg, demonstrates that DMPS is superior to the other chelators in preventing mortality. Moreover, both DMSA and DMPS are superior to BAL and NAPA in alleviating acute toxicity and in preventing the undesirable distribution of orally administered mercury, especially to the brain. Further, oral administration of these chelators were more efficient than parenteral administration in reducing whole-body retention and organ deposition of orally administered mercuric chloride, most likely due to the prevention of intestinal uptake of mercury.
Toxicology and the Immune System: a Perspective
Authors: Kimber I.
Published: December 2008

The relationship of immunology to toxicology has not always been an easy one, and the product of this association, immunotoxicology, has not infrequently been viewed with a certain scepticism by some of those who consider themselves 'classical' toxicologists. A recent meeting of the British Toxicology Society ('Toxicology and the Immune System', New College Oxford, March 21-22, 1991) provided an opportunity for some remedial work toward a wider appreciation of the issues which exercise immunotoxicologists, and the ways in which they are being addressed. It is not the purpose of this short article to provide a comprehensive account of the scientific presentations, but rather to give a perspective, necessarily a personal one, of immunotoxicology in the context of the meeting.
Nephrotoxicity of 4-Aminophenol Glutathione Conjugate
Authors: Fowler Lynn M. , Moore Richard B. , Foster John R. , Lock Edward A.
Published: December 2008

4-Aminophenol ( p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known, but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to tissue macromolecules. Recent studies have shown that certain benzoquinol-glutathione conjugates can cause renal necrosis in rats. We have synthesized a putative glutathione conjugate of PAP. The effect on the kidney of this conjugate and the sulphate and N-acetyl conjugates, known metabolites of PAP, have been examined in Fischer 344 rats. 4-Amino-3-S-glutathionylphenol produced a dose-dependent (92-920 μmol kg-1) necrosis of the proximal tubular epithelium and altered renal excretory function. The lesion at the low dose was restricted to the pars recta of the proximal tubule in the medullary rays, while at the higher doses it affected the pars recta region of all nephrons. In contrast, PAP-o-sulphate and N-acetyl-4-aminophenol (paracetamol) caused no histological or functional alteration to the kidney at 920 μmol kg-1. The renal necrosis produced by 4-amino-3-S-glutathionylphenol was very similar to that produced by PAP (367-920 μmol kg-1), both functionally and histologically, except that smaller doses of the glutathione conjugate were required. These studies indicate that glutathione conjugation of PAP generates a metabolite that is more toxic to the kidney than the parent compound. A possible mechanism of toxicity (analogous to that reported for glutathione conjugates of certain quinones) involving oxidation to form a 1,4-benzoquinoneimine thioether that could redox cycle is discussed.
Analysis of the Immunotoxic Effects of Xenobiotics
Authors: Procházková J.
Published: December 2008

1 Current problems in immunotoxicology are reviewed with special attention to the sensitivity of the immune system to the effects of xenobiotics.

2 Sensitivity of target cells, route of exposure, dosage, mechanism of action and response of the immune system are discussed as the main factors responsible for the ultimate effects of drugs and chemicals.

3 The methodology of immunotoxicology is divided into two main steps: preclinical screening and the monitoring of exposed persons.

4 Conclusions are prescribed about future tasks in human immunotoxicology.
Induction of DNA Strand Breaks in Peripheral Lymphocytes by Soluble Chromium Compounds
Authors: Gao M. , Binks S.P. , Chipman J.K. , Levy L.S. , Braithwaite R.A. , Brown S.S.
Published: December 2008

1 Incubation of human lymphocytes with sodium dichromate (CrVI) at 37°C for 3 h resulted in a dose-dependent increase in DNA strand breaks without concurrent cytotoxicity. In contrast, chromium acetate hydroxide (CrIII) failed to induce DNA strand breaks at sub-cytotoxic concentrations.

2 DNA strand breaks were also detected in the peripheral lymphocytes of Wistar rats, 24 h after intratracheal instillation of sodium dichromate (1.3 and 2.5 mg kg-1 ). Instillation of chromium acetate hydroxide (up to 21.8 mg kg -1) failed to induce DNA strand breaks in peripheral lymphocytes. In accord with previous studies, hexavalent chromium was found to be more readily absorbed from the lungs into the peripheral blood than chromium in its trivalent form.

3 The results of this study indicate that fluorometric analysis of DNA unwinding (FADU) in peripheral lymphocytes might be a convenient method of measuring an important biological effect of chromium in occupationally-exposed workers.
Cigarette Smoke Inhibits Cytosolic but not Microsomal Epoxide Hydrolase of Human Lung
Authors: Petruzzelli Stefano , Franchi Marina , Gronchi Luca , Janni Alberto , Oesch Franz , Pacifici Gian Maria , Giuntini Carlo
Published: December 2008

The effect of cigarette smoke exposure on the activity of cytosolic and microsomal epoxide hydrolase (EH) has been investigated in human lung. Patients were classified as 'recent smokers' (n = 9) or 'non-recent smokers' (n = 10) according to whether they were or were not still smoking 1 month before surgery. Cytosolic EH was measured with [3H] trans-stilbene oxide as a substrate, whereas microsomal EH was measured with [7-3H]styrene oxide as a substrate. Microsomal EH activity did not differ between recent smokers (2.51 ± 0.93 nmol min-1mg-1) and non-recent smokers (2.74 ± 1.10 nmol min-1mg-1), whereas cytosolic EH activity was significantly lower in recent smokers (6.46 ± 1.79 pmol min-1mg-1) than in non-recent smokers (8.41 ± 2.09 pmol min-1mg-1, P < 0.05). Cytosolic EH activity was correlated with the number of days that had passed since the cessation of smoking (r = 0.58, P < 0.05) and the effect was dose-dependent, since the enzyme activity was inversely correlated with the number of cigarettes smoked per day (r = 0.85, P < 0.01). This suggests that recent smoking exposure inhibits the activity of cytosolic EH but not microsomal EH, and that the inhibition increases with the number of cigarettes smoked per day. The contribution of cytosolic enzymes to xenobiotic metabolism may be remarkable in extrahepatic tissues. The inhibition of cytosolic EH by tobacco smoke may reduce the inactivation of carcinogenic epoxides in human lung tissues and so may increase a person's susceptibility to lung cancer.
Studies on the Disposition and Metabolism of Hydrazine in Rats in vivo
Authors: Preece Nicholas E. , Ghatineh Simin , Timbrell John A.
Published: December 2008

1 Rats were given various doses of hydrazine orally and their plasma and liver hydrazine levels were determined (at various times up to 270 min after dosing) by gas chromatography/ mass spectrometry.

2 The increase in the peak plasma level and in the area under the plasma concentration-time curve (AUC) were not directly proportional to the dose.

3 The ratio of plasma to liver hydrazine varied with dose suggesting saturation of an uptake mechanism might be occurring.

4 In a separate experiment hydrazine was still detectable in the plasma and liver 24 h after dosing with hydrazine i.p.

5 Rats were given the same doses of hydrazine and urine was collected for 24 h after dosing and assayed for hydrazine and acetylhydrazine. The proportion of hydrazine and acetylhydrazine excreted declined with dose.

6 Liver samples were taken for histopathological examination 96 h after dosing. Only after the highest dose (81 mg kg-1) was there evidence of fatty liver, 96 h after a single dose, and a reduction in both liver and body weight.
The INVITTOX Data Bank of In- Vitro Techniques in Toxicology
Authors: Ungar Krys
Published: December 2008

The dissemination of information about methods in in-vitro toxicology is subject to a number of constraints which are identified and discussed, as are the ways in which INVITTOX seeks to address these problems. The continued interest of scientists in INVITTOX suggests that a real gap in information provision is being filled.
The Effect of Brassica Vegetable Consumption on Caffeine Metabolism in Humans
Authors: McDanell R.E. , Henderson L.A. , Russell K. , McLean A.E.M.
Published: December 2008

Ten healthy volunteers were used in two studies investigating the effect of short-term Brassica consumption on caffeine metabolism. In the first study volunteers were given three Brassica-containing meals, the last one 3 h prior to caffeine administration. In the second study volunteers were given two Brassica-containing meals and then fasted overnight before caffeine administration.

In both studies the mean plasma half-life of caffeine was reduced by approximately 20% following a Brassica diet, suggesting that Brassica vegetables stimulate caffeine metabolism.

When caffeine was given 3 h after the last meal, plasma caffeine concentrations over 6 h, were increased by up to 27% on the Brassica diet compared to controls. This may be due to a transient increased permeability of the intestine to caffeine, immediately following Brassica consumption. This effect was not seen in the second study where there was a 12-h period between the last meal and caffeine administration.

There was large interindividual variation in the effect of the Brassica diet on caffeine metabolism.
Elemental Mercury Vapour Toxicity, Treatment, and Prognosis After Acute, Intensive Exposure in Chloralkali Plant Workers. Part II: Hyperchloraemia and Genitourinary Symptoms
Authors: Bluhm Renata E. , Breyer Julia A. , Bobbitt Robert G. , Welch Larry W. , Wood Alastair J.J. , Branch Robert A.
Published: December 2008

Exposure to elemental mercury vapour is known to influence renal function; however, severe renal disease has not been consistently identified. Eleven men were evaluated for renal disease after acute, massive mercury poisoning. Significant hyperchloraemia was identified in this group of patients and a reversible renal tubular defect was suggested by low normal serum bicarbonate, a normal serum anion gap and a positive urinary anion gap. The only other evidence of renal dysfunction was transient, mild proteinuria in one of the 11 patients. During this same time period, neuropsychological impairment was identified on a test of cognitive and visual-motor function, 'Trailmaking B', in seven of the 11 patients. Additionally, dysuria and ejaculatory pain occurred without evidence of urological disease. These complaints were more frequent in those patients with impairement on 'Trailmaking B' suggesting a neurological basis for these symptoms. The findings of this study support earlier observations that the brain rather than the kidney is the critical target organ after elemental mercury vapour exposure.
Biological and Biological-Effect Monitoring of Workers Exposed to 4, 4' -Methylene-bis (2-chloroaniline)
Authors: Edwards J.W. , Priestly B.G.
Published: December 2008

4,4'-Methylene- bis (2-chloroaniline) (MOCA), a curing agent used in polyurethane manufacture, is a genotoxic and carcinogenic amine. This study aimed to assess occupational exposure to MOCA using as indices: (1) the post-work urinary output of MOCA; (2) urinary thioethers, assuming that conjugation with glutathione might be a significant pathway for the elimination of putative electrophilic metabolites of MOCA; and (3) sister-chromatid exchange (SCE) frequency in peripheral lymphocytes as an indicator of genetic damage. Process workers at a polyurethane production unit were found to have up to 38 μmol MOCA mol -1 creatinine in their urine at the end of a work shift. Smaller quantities were found in the urine of laboratory and supervisory staff, but none was detected in the urine of a group of office and sales staff from an unrelated industry, who served as unexposed controls. There was no evidence of MOCA-related urinary thioether output. There was a graded increase in SCE frequency from controls to process workers, consistent with their apparent exposure to MOCA. Administration of MOCA to rats (5 daily i.p. injections of 125 or 250 mg kg-1 resulted in dose-related increases in MOCA excretion and in lymphocyte SCE frequency, but there was no change in thioether output. These results indicate that urinary thioether excretion is inappropriate for monitoring MOCA exposure, but that where MOCA exposure can be demonstrated, by the presence of MOCA in urine, this is associated with genetic damage in both man and in the rat.
Sex Hormones and Semen Quality in Welders Exposed to Hexavalent Chromium
Authors: Bonde Jens Peter , Ernst Erik
Published: December 2008

Recent experimental studies in rodents document the spermatotoxic effects of watersoluble hexavalent chromium. Welders comprise, worldwide, a major occupational group with acknowledged exposure to chromium. This study examines the relationship between semen quality and chromium in the urine and blood of a population of 30 tungsten inert gas (TIG) stainless steel welders, 30 mild steel welders and 47 non-welding workers. Each subject provided two to three semen samples. The chromium concentration ranged from 0.17 to 4.74 nmol mmol1 creatinine (median 1.08) in post-shift spot urine and from 6.0 to 46.4 nmol 1-1 in blood. None of several semen parameters deteriorated with increasing level of internal exposure to chromium. Low-level exposure to hexavalent chromium associated with TIG stainless steel and mild steel welding do not appear to be a major hazard for human spermatogenesis.
Indomethacin and Protein Binding of Methotrexate
Authors: Raveendran R. , Heybroek W. , Caulfield M. , Lawson M. , Abrams S.M.L. , Wrigley P.F.M. , Slevin M. , Turner P.
Published: December 2008

Indomethacin, a non-steroidal anti-inflammatory drug is known to increase the efficacy and toxicity of methotrexate, the widely used anti-cancer drug in man. The mechanism for this interaction has not been clearly established. However, since these drugs bind with albumin, a possible displacement of methotrexate by indomethacin from albumin might explain this interaction. To investigate the possible interaction an in-vitro protein-binding displacement study was carried out in 17 normal volunteers and in two groups of eight cancer patients. One group of patients had active disease and the other was in complete clinical remission. Serum samples were obtained and protein levels estimated. The protein binding of methotrexate was measured alone and with indomethacin using equilibrium dialysis. Statistical analysis of results suggested that the binding of methotrexate is not influenced by indomethacin, confirming that methotrexate is not displaced by indomethacin.
Determination of Heavy Metals in Human Liver
Authors: Bona M.-A. , Castellano M. , Plaza L. , Fernandez A.
Published: December 2008

The levels of Cr (2.49±0.89 ppm), Mn (5.08 ± 1.60 ppm), Ni (1.81±0.95 ppm) and Pb (4.43 ± 3.12 ppm) were measured in dessicated liver from 44 cases of sudden traumatic death considered as representative of the general population in our area, after ruling out the presence of any underlying disease.

Atomic absorption spectrophotometry and electrothermal atomitazion was carried out after hot, acid digestion, of the dessicated samples.

After cancelling the influence of age and cause of death, a significant, positive correlation between Cr/Mn (P = 0.0009; R = 0.493) and Cr/Ni ( P = 0.0245; R = 0.347) levels was found.
Determination of Amitriptyline in the Hair of Psychiatric Patients
Authors: Tracqui A. , Kreissig P. , Kintz P. , Pouliquen A. , Mangin P.
Published: December 2008

A study was conducted on 60 psychiatric patients to evaluate the reliability of a drug-exposure screening test based on gas chromatography/mass spectrometry analysis of hair samples for amitriptyline, and the possibility of using the hair concentrations of amitriptyline to monitor patients' therapeutic compliance. The qualitative test was found to be very reliable (sensitivity 93.3%; specificity 100%; positive and negative predictive values 100 and 93.8%) in assessing the consumer status of patients over a period of 2 months before analysis. Hair levels of amitriptyline ranged from 0 to 17.21 ng mg-1. A significant relationship ( r=0.563; P < 0.002) was found between the hair concentrations and the cumulative intake of amitriptyline over the studied period, but was not judged close enough to estimate one individual's therapeutic compliance. The results are discussed in the light of existing literature.
Dose Selection for Toxicity Studies: A Protocol for Determining the Maximum Repeatable Dose
Authors: Spurling N.W. , Carey P.F.
Published: December 2008

1 A three-stage protocol is described for a dose-ranging study which defines the maximum repeatable dose (MRD) and provides a preview of the toxicology of new, pharmacologically active, substances before commencing the first formal regulatory toxicity studies, usually of 2 or 4 weeks duration.

2 Additionally, a range of toxicokinetic (TK) data relevant to protocol design for formal studies is generated.

3 Stage A is a dose incrementation process in which the MRD is provisionally determined and basic TK values generated.

4 In stage B the animals are dosed daily for at least 7 d, the MRD is substantiated and a wider range of TK data obtained.

5 In stage C, each of the dose levels identified for a formal study is administered once to investigate the relationship of doses to TK data.

6 This protocol can be completed using as few as 24 rats or six dogs (or primates).

7 Selection of dose levels for the first formal studies can be greatly aided by the results of a well-designed dose-ranging study including TK data.

8 For particularly toxic substances, the findings of studies based on this protocol have frequently been sufficiently clear to warrant early termination of their development.
Effect of Glycol Ethers on Plasma Osmolality
Authors: Browning Randall G. , Curry Steven C.
Published: December 2008

1 Glycol ethers and their alkoxyacetic acid metabolites produce a linear increase in plasma osmolality with increasing plasma concentration.

2 This change in osmolality may be too small to be clinically useful at concentrations expected in cases of acute human glycol ether poisoning.
Efficacy of Whole Bowel Irrigation Using Solutions with or without Adsorbent in the Removal of Paraquat in Dogs
Authors: Mizutani Taro , Yamashita Mamoru , Okubo Naomitsu , Tanaka Makoto , Naito Hiroshi
Published: December 2008

1 The efficacy of whole bowel irrigation with a solution containing either polyethylene glycol (PEG) with electrolyte or an adsorbent (Kayexalate™) with a cathartic (sorbitol) was investigated in 18 dogs who had been given 250 mg kg-1paraquat dichloride via a jejunal tube to eliminate the influence of gastric absorption.

2 Plasma paraquat concentrations 2 and 3 h after the initiation of bowel irrigation and at the end of the study (5 h later) were significantly lower in the bowel irrigation groups than in the control (no bowel irrigation) group.

3 The total body clearances of paraquat in the bowel irrigation groups were significantly greater than in the control group.

4 There were no significant differences between the two different irrigation solution groups in plasma paraquat concentration, the area under the plasma concentration time curve and the total body clearance.

5 In the PEG with electrolyte group, about 70% of the administered dose of paraquat was removed by means of bowel irrigation (n=4).

6 The adjunction of the adsorbent had no beneficial effects.

7 Haemodynamic changes associated with whole bowel irrigation were unremarkable except that right atrial and pulmonary arterial pressures were elevated in the latter part of the study.
Corticosterone does not cause Testicular Toxicopathology in the Rat: Relevance to Methylxanthines, ACTH and Stress
Authors: Harvey P.W. , Er J. , Fernandes C. , Rush K.C. , Major I.R. , Cockburn A.
Published: December 2008

1 Methylxanthines, ACTH and stress are well known to produce testicular pathology (e.g. seminiferous tubule atrophy). Methylxanthines, ACTH and stress alter hormone secretion, particularly from the pituitary-adrenocortical system. Consequently, it has recently been suggested that there may be a causal relationship between changes in endogenous physiological adrenocortical secretions, particularly corticosterone, and testicular pathology.1

2 This study tested the hypothesis that corticosterone mediates the testicular effects of both methylxanthine treatment and stress. Corticosterone was administered daily by subcutaneous injection to groups of 10 male rats at dose levels of 2 or 20 mg kg-1 in propylene glycol (1 ml kg-1) for 1 month (the shortest duration of methylxanthine or ACTH exposure known to produce testicular pathology). The highest dose of corticosterone resulted in plasma concentrations that closely matched values resulting from stress (200-700 ng ml-1) compared with controls (<25 ng ml-1).

3 The highest dose of corticosterone caused reduced body weight gain, lower thymus, adrenal, seminal vesicle and prostate weights, but did not induce any testicular pathology.

4 That a high, but physiologically relevant, dose of corticosterone did not cause testicular pathology in this experiment excludes this steroid in the direct aetiology of methylxanthine, ACTH and stress-induced testicular pathology. Other steroids secreted from the adrenal, in combination with corticosterone, may be involved.
Double Fatal Inhalation of Dichloromethane
Authors: Manno M. , Rugge M. , Cocheo V.
Published: December 2008

1 Two cases of lethal poisoning following acute inhalation of extremely high concentrations of dichloromethane (DCM) are reported. The concentrations of the solvent found in the blood of the two subjects collected at autopsy and analysed by gas chromatography/ mass spectrometry (572 and 601 mg 1-1) were compatible with those measured in the air a few hours after the discovery of the bodies (up to 168,000 ppm).

2 Extensive brain and lung oedema and congestion, microhaemorrhagic changes of the stomach and congestion in other organs were observed on macroscopic and microscopic examination of both subjects. In addition, and in both cases, high but not lethal carboxyhaemoglobin (COHb) levels (30%) were found in the blood collected at autopsy.

3 Narcosis and respiratory depression due to the effect of DCM on the central nervous system (CNS) appear to have played a critical role in the death of the two men. However, biotransformation of the solvent to toxic metabolites, including carbon monoxide (via oxidative dehalogenation by the cytochrome P450-dependent mixed function oxidase system) or formaldehyde, formic acid, inorganic chloride and carbon dioxide (via the glutathione-S-transferase pathway) may have also contributed significantly to fatal toxicity.