bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of Methylene Chloride (Nitromors) Poisoning, Effects on Carboxyhaemogiobin Levels
Authors: Hughes Niall J. , Tracey Joseph A.
Published: December 2008

The literature contains only one report of methylene chloride poisoning after ingestion.1 Unfortunately carboxyhaemoglobin (COHb) levels were not obtained in this case. We now describe a fatal case where a similar amount of the solvent was ingested and after which toxicology screening was done.
Pentachlorophenol Carcinogenicity: Extrapolation of Risk from Mice to Humans
Authors: Reigner Bruno G. , Bois Frederic Y. , Tozer Thomas N.
Published: December 2008

1 Pentachlorophenol (PCP) has been found to be carcinogenic in mice. The objective of this study was to extrapolate to humans the risk of cancer from data obtained in mice using information on disposition, serum protein binding and metabolism of PCP across species.

2 A review of the literature indicates that neither PCP nor a mutagenic metabolite, tetrachlorohydroquinone (TCHQ), has been specifically identified as responsible for the carcinogenicity. In addition, the occurrence of TCHQ as a metabolite of PCP in humans is still questionable. Therefore, cancer risk assessment is performed on the assumption that PCP itself is responsible for the carcinogenicity.

3 For interspecies extrapolation, a new method in which interspecies differences in clearance and serum protein binding are taken into account is used. The method gives estimates of equivalent human doses of PCP which are up to 4 times smaller than those obtained using body surface area. For both interspecies extrapolation methods, the estimated virtually-safe doses of PCP are smaller than the average daily intakes reported in groups of subjects nonspecifically exposed to PCP. Corresponding extra risks of cancer for lifetime exposure are from 20 to 140 times greater than the acceptable extra risk (10-6).

The results obtained with this approach indicate that PCP is a possible public health hazard.
Methyl Mercury, Mercuric Chloride, and Silver Lactate Decrease Superoxide Anion Formation and Chemotaxis in Human Polymorphonuclear Leucocytes
Authors: Obel Niels , Hansen Birte , Christensen Margot M. , Nielsen Søren Lyhne , Rungby Jørgen
Published: December 2008

Cytotoxic effects of mercuric chloride, methyl mercury, and silver lactate on polymorphonuclear leucocytes have been examined by assaying superoxide anion formation capability and chemotaxis of metal-exposed cells. Both superoxide anion formation and chemotaxis were negatively affected by all three metal compounds. Both bacteriotoxic functions were affected in a dose-dependent fashion, the functional deficits were seen at doses not affecting cell viability. Dose-response curves were remarkably similar for all three compounds. The bacteriotoxic capacity of polymorphonuclear leucocytes may be hampered by mercury and silver.
Effect of Saline Cathartics on Gastrointestinal Transit Time of Activated Charcoal
Authors: Orisakwe O.E. , Ogbonna E.
Published: December 2008

The effects of saline cathartics on the gastrointestinal transit time of activated charcoal were investigated in six healthy volunteers. The study shows that the mean gastrointestinal transit times of charcoal alone were 29.3 h and 24.4, 15.4, 17.3 and 17.5 h with sodium chloride, sodium sulphate, magnesium sulphate alone and Andrew's Liver Salt respectively. Some volunteers complained of slight abdominal discomfort in all the phases except the Andrew's Liver Salt phase.
Hepatotoxicity Associated with Dietary Iron Overload in Mice
Authors: Omara Felix O. , Blakley Barry R. , Wanjala Lusimbo S.
Published: December 2008

1 Weanling male CD-1 mice were fed 120 (control), 5000 and 8000 mg of iron kg-1 for seven weeks. The haematocrit ( P=0.265), water consumption ( P=0.170) and percentage body weight ratios of kidney, spleen and heart were not affected by iron supplementation.

2 Iron supplementation reduced weight gain ( P=0.023), increased weight of liver ( P=0.0001), the iron deposition index and concentration of iron in the liver ( P<0.01). A strong correlation between liver iron concentration and level of iron in the diet ( r=0.989) was observed. Histologically, the deposition of iron was restricted to the hepatocytes, Kupffer cells and splenic macrophages.

3 Consumption of 5000 and 8000 mg of iron kg-1 resulted in hepatic damage, as judged by elevated serum alkaline phosphatase and alanine aminotransferase activities ( P<0.05).

4 This study indicates that prolonged feeding of excess dietary iron has the potential to cause hepatic accumulation of iron with resultant liver toxicity, and that mice may be a suitable model to study the mechanisms of dietary iron overload.
The Role of Flumazenil in the Management of Patients With Acute Alteration of Mental Status in the Emergency Department
Authors: Chern Tzyh-Lih , Hu Sheng-Chuan , Lee Chen-Hsen , Deng Jou-Fang
Published: December 2008

1 There are a few case reports which suggest that flumazenil can be used as a diagnostic tool in coma of unknown aetiology but no large scale studies have proved its efficacy and cost-effectiveness.

2 Fifty five patients with acute alteration of mental status of unknown aetiology were enrolled prospectively during a time period of one year. Flumazenil was injected intravenously in a regimen of 0.3 mg in the first minute followed by alternate 0.2 mg, 0.3 mg doses every minute until a total dose of 1 mg was given or until the patients responded.

3 Patients were divided into two groups based on their response to flumazenil: Group 1, responders and Group 2, non-responders. The hospital stay was shortened significantly and interventional procedures, such as CT of brain and endotracheal intubation, were rendered unnecessary in several patients in Group 1. The Group 1 patients had a more favourable outcome than that of Group 2.

4 We concluded that flumazenil may serve as a useful tool in diagnosis and management of carefully selected patients with acute alteration of mental status.
Amelioration of Cisplatin Toxicity in Rat Renal Cortical Slices by Dithiothreitol In vitro
Authors: Zhang J.G. , Zhong L.F. , Zhang M. , Ma X.L. , Xia Y.X. , Lindup W.E.
Published: December 2008

1 The protective effects of dithiothreitol (DTT) on cisplatin-induced nephrotoxicity were investigated with rat renal cortical slices.

2 The nephrotoxic effects of cisplatin (2 mmol l-1) were manifested in several ways: the Na+ and water content were increased while K+ was decreased. The malondiadehyde (MDA) concentration in the slices and the lactate dehydrogenase (LDH) released into the medium were increased. The uptake of p-aminohippurate (PAH), the synthesis of glucose and the glutathione (GSH) concentration in the slices were all decreased.

3 Despite a DTT-related increase in platinum (Pt) uptake by the slices, DTT (0.5-2 mmol I-1 ) ameliorated all these toxic effects of cisplatin in a concentration related manner.

4 The results suggest that the protective mechanism of DTT is its antioxidative action, DTT is also a metal chelator, however, and so a protective effect via chelation of Pt by DTT cannot be excluded.
Comparison of Two Methods for Determining the Toxicokinetics of Fluazifop-butyl after Intravenous Dosing in Rats
Authors: Rawlings John M. , McLean Provan W. , Wilks Martin F. , Batten Peter L.
Published: December 2008

1 We have described and compared the use of two blood sampling techniques to measure the kinetics of fluazifop-butyl, a selective herbicide. Following intravenous administration of radiolabelled compound, blood samples were collected from female rats either by tail vein puncture or from chronically implanted catheters inserted in tethered rats. Urine samples were also collected from tethered animals.

2 Both techniques indicate that fluazifop-butyl is rapidly eliminated from blood into urine (t½3-4.5 h) and the overall blood concentration profiles were comparable between the two methods. However, by using cannulated rats, kinetic data were obtained from individual animals, providing. evidence of inter-animal variation and allowing compartmental and statistical analysis.

3 The tethered rat technique is relatively simple and reliable. Compared to tail vein bleeding, results obtained from cannulated animals are more informative, providing comprehensive data from a small number of rats. It is therefore the preferred method for our kinetic based research studies using compounds known to exhibit multicompartmental elimination kinetics.
Bronchospasm Induced by Intravenous Adenosine
Authors: Drake I. , Routledge P.A. , Richards R.
Published: December 2008

1 Adenosine is well known to cause bronchoconstriction when inhaled, but to date there has been only one report following the intravenous route.

2 Adenosine caused bronchoconstriction in two patients (the only two with asthma) out of 26 treated with the drug. In one subject the duration of response was much longer than previously reported following inhalation.

3 We suggest that adenosine may aggravate bronchospasm in some asthmatics and alternative treatments for supraventricular tachycardia should be considered in this group.
Effects of Chronic Manganese Toxicity on Tissue Levels and Urinary Excretion of Nicotinamide Nucleotides in Rats
Authors: Patel A.B. , Pandya A.A.
Published: December 2008

Male rats were exposed to manganese sulphate i.p. daily for a period of four weeks to see its effects on tissue levels and urinary excretion of total nicotinamide nucleotides (TNN). Increased levels of TNN were observed in blood and brain while the levels were found to be decreased in liver. There was a progressive increase in the excretion of TNN during the experimental period, TNN levels in blood and urine might serve as useful biological indicators of Mn toxicity.
Human Volunteer Studies with Non-Pharmaceutical Chemicals: Metabolism and Pharmacokinetic Studies
Authors: Wilks M.F. , Woollen B.H.
Published: December 2008

1 Human volunteer studies are an essential part of drug development but their use in the area of non-pharmaceutical chemicals has so far been very limited. Such studies can have considerable value in the assessment and improvement of the safe use of chemicals.

2 Once metabolic pathways and target metabolites have been identified in volunteers this information can be used in studies in the workplace or in the general population. Studies should be performed selectively only if there is both a toxic hazard and a significant exposure potential. In addition, they should only be carried out if the required information cannot be obtained in any other way.

3 Volunteer studies with non-pharmaceuticals have become increasingly acceptable in the light of established international guidelines, no-fault compensation, improvements in study design and technical developments which allow the use of very low dose levels. The final decision on whether to carry out a study must always rest with an independent ethical committee.

4 The practical aspects of the study should be specified in a detailed protocol conforming with the principles of good clinical practice. The safety of volunteers must be of paramount concern throughout. Depending on the nature of the chemical and the study, it may be advisable to carry out studies in a clinical facility where equipment is available for the treatment of any emergencies that might occur.

5 Numerous investigators have now shown that human volunteer studies are ethically acceptable, practicable and yield important information. The risk to volunteers is minimal and this approach can lead to an improved foundation for occupational hygiene standards, more accurate risk assessment and thus better protection of the workforce and the general population.
Prevalence of Food Additive intolerance
Authors: Madsen Charlotte
Published: December 2008

1 The existing prevalence estimates of food additive intolerance1-4 are being reviewed.

2 In the EEC report the estimated frequency of food additive intolerance is 0.03% to 0.15% based on data from patient groups.

3 The British population study results in a prevalence estimate of 0.026%. The challenged population is 81 children and adults with a history of reproducible clinical symptoms after ingestion of food additives.

4 In the Danish population study a prevalence of 1-2% is found in children age 5-16. In this study a total of 606 children mainly with atopic disease have been challenged.

5 The prevalence estimates vary with a factor 100. As the results vary so do the study populations.

6 If the different study populations are accounted for, a common conclusion can be drawn: Food additive intolerance is found in adults with atopic symptoms from the respiratory tract and skin. The prevalence estimates are questionable but may be less than 0.15%. In adults and children with reproducible, and with more subjective symptoms, such as headache and behavioural/mood change the prevalence is even lower (0.026%). Food additive intolerance is primarily found in atopic children with cutaneous symptoms where the additive is aggravating an existing disease. The prevalence of food additive intolerance in children age 5-16 is 1-2%.
Pulmonary Protein Synthesis Response to Ozone
Authors: Kelly F.J. , Birch S.
Published: December 2008

1 Exposure to either 800 or 1200 ppb ozone for 6 h did not influence the content or activity of mouse lung ribosomal RNA; in consequence pulmonary protein synthesis pathways were not altered.

2 Increasing the exposure period to 24 h had a marked effect on protein metabolism which depended on the dose of ozone employed. A dose of 800 ppb resulted in a 17% increase in lung protein content. Since both lung ribosomal capacity and fractional synthesis rates were unchanged at this time, it is concluded that both a lower ribosomal activity and an increased protein degradation rate were responsible for the decrease in content.

3 Exposure to 1200 ppb ozone for 24 h, paradoxically resulted in increases in both the fractional (33%) and total (19%) protein synthetic rates. These responses were due to an increased pulmonary ribosomal efficiency in the lung at this time.

4 We conclude that, in the short term, reduced pulmonary synthetic capacity is not a component of ozone-induced lung injury, but rather, this important component of the repair mechanism, can be up-regulated in response to lung injury.
Adverse Reactions to intravenous N-Acetylcysteine in Chinese Patients with Paracetamol (Acetaminophen) Poisoning
Authors: Chan Thomas Y.K. , Critchley Julian A.J.H.
Published: December 2008

The incidence of adverse reactions to intravenous N-acetylcysteine (NAC) was studied in 56 Chinese patients with paracetamol (acetaminophen) poisoning. Eight (14%) patients developed a skin rash (n= 7) or fever (n= 1) mostly during the initial high dose infusion of the antidote. In four subjects (three with toxic plasma paracetamol levels), the infusion was continued without a worsening of the adverse reaction. NAC was discontinued in the remaining four subjects in whom the paracetamol levels were subsequently found to be non-toxic. Intravenous chlorpheniramine was given to six subjects. All eight subjects completely recovered. In the dose that is recommended for the treatment of acute paracetamol poisoning, intravenous NAC is generally safe in Chinese but mild side effects are common. We recommend that the initial loading dose is given over 60 rather than 15 min.
Advantages and Disadvantages of Using Human Cells for Pharmacological and Toxicological Studies
Authors: Hawksworth Gabrielle M.
Published: December 2008

1 Marked species differences in the distribution and affinity of drug receptors, and in the patterns of biotransformation and susceptibility to the toxicity of xenobiotics, provide the impetus for using human tissues for pharmacological and toxicological studies.

2 Studies with intact cells facilitate the correlation of xenobiotic metabolism with cellular indices of toxicity, which can provide the mechanistic basis for understanding species differences in toxicity.

3 Human cells in suspension or primary culture reflect the variability in susceptibility to toxicity in a population.

4 The current limitation to these studies is scarcity of human material, the need for improved (cryo)preservation techniques for human hepatocytes/precision-cut slices and difficulties in predicting in vivo exposure-risk relationships from in vitro dose-response relationships.
To TEF or not to TEF? That is the question
Authors: Battershill J.
Published: December 2008

Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes for compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB). 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'hexaCB, and their monoortho analogs are AH-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds have utilized a toxic equivalency factor (TEF) approach for the hazard and risk assessment of polychlorinated dibenzo-p dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) congeners in which the TCDD or toxic TEQ = Σ([PCDFi X TEFi]n) + Σ([PCDDi x TEFi] n) equivalent (TEQ) of a mixture is related to the TEFs and concentrations of the individual (i) congeners as indicated in the equation (note: n = the number of congeners). Based on the results of quantitative structure-activity studies, the following TEF values have been estimated by making use of the data available for the coplanar and mono-ortho coplanar PCBs: 3,3',4,4'5-pentaCB,0.1; 3,3',4,4',5,5'-hexaCB,0.05 ; 3,3',4,4'-tetraCB,0.01; 2,3,3',4,4'-pentaCB,0.001 ; 2,3,4,4',5-pentaCB, 0.0001; 2,3,3',4,4',5-hexaCB,0.0003 ; 2,3,3',4,4',5'-hexaCB,0.0003; 2',3,4, 4',5-pentaCB,0.00005; and 2,3,4,4',5-pentaCB, 0.0002. Application of the TEF approach for the risk assessment of PCBs must be used with considerable caution. Analysis of the results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs may be both species-and response-dependent because both additive and non-additive (antagonistic) interactions have been observed with PCB mixtures. In the latter case, the TEF approach would significantly overestimate the toxicity of a PCB mixture. Analysis of the rodent carcinogenicity data for assessment of PCB mixtures that uses cancer as the endpoint cannot solely utilize a TEF approach and requires more quantitative information on the individual congeners contributing to the tumor-promoter activity of PCB mixtures.
Review of the Safety Assessment of Polychlorinated Biphenyls (PCBs) with Particular Reference to Reproductive Toxicity
Authors: Battershill Jon M.
Published: December 2008

1 The methods used to evaluate the toxicological effects of PCBs in animals have been reviewed.

2 The data show that Toxic Equivalency Factors (TEFs) could be developed to assess the potential toxicity of PCB mixtures for certain specific target organ effects (such as the liver and immune system) but would be inappropriate for other effects (e.g. thyroid function and neurochemical effects). More data on a wider range of individual PCB congeners and a method for systematically balancing toxicodynamic and toxicokinetic data are required before the TEF approach can be fully evaluated.

3 With the exception of the teratogenic effects seen in mice and the anti-oestrogenic effects reported in in vitro studies, there are insufficient data on individual PCB congeners to evaluate the structure-activity relationships for the effects of PCBs on reproduction. The data also show that individual PCBs may have opposing effects on a particular aspect of reproduction (for example individual PCB congeners may have either oestrogenic or anti-oestrogenic effects). Studies with individual PCB congeners have shown both enhancement and antagonism of the teratogenic effects of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) in the mouse. It is not possible to use TEFs to evaluate the reproductive effects of PCBs.

4 The mechanism(s) responsible for the effects of PCBs on postnatal neurobehavioural development in rodents and monkeys have not been elucidated. At least two groups of PCBs which might be responsible for the observed effects have been identified in this review, one affecting the dopaminergic system and the other group affecting thyroid hormone levels. Considerably more research would be required before the TEF approach could be applied to the effects of PCBs on postnatal neurobehavioural development. This would include research on an appropriate animal model to determine whether the critical toxicological mechanism is mediated through the Ah receptor.

5 The reproductive toxicity of complex PCB mixtures such as those found in foods will depend on the identities and relative proportions of individual PCB congeners in the mixture. It is not possible to give an accurate estimate of a NOAEL or LOAEL from the reproduction studies using commercial PCB mixtures which could be readily applied to the safety assessment of PCBs present as contaminants in food.

6 It is concluded that the data presented in this paper support the hypothesis that there is no satisfactory method derived from the available studies in laboratory animals for evaluating the potential risk of adverse effects on reproduction posed by contamination of foods with PCBs.
Elimination of Antipyrine and its Metabolites in Interferon Treated Hepatitis C
Authors: Sieck Jens O. , El-Yazigi Adnan , Ali Hatim , Døssing Martin , Saour Jalal , Raines Dale A. , Ernst Peter
Published: December 2008

1 To study the effect of interferon on hepatic drug metabolism in chronic hepatitis C, we examined nine patients before and at the end of 6 months of interferon treatment.

2 Routine liver function was determined together with the salivary clearance of antipyrine and the 48 h urinary excretion of the main metabolites of antipyrine: 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine before and after 6 months of interferon treatment.

3 Liver pathology, routine liver function, and antipyrine metabolism remained unchanged after patients were treated for 6 months with interferon for a histologically advanced but clinically compensated chronic hepatitis C.
Time to repeal the Delaney Clause
Authors: Driver H Elizabeth
Published: December 2008

The Delaney Clause of the Federal Food, Drug, and Cosmetic Act, enacted in 1958, prohibits the addition to the human food supply of any chemical that had caused cancer in humans or animals. The aim was to prevent cancer in humans. The scientific knowledge on causes of cancer and mechanisms of carcinogenesis in the 1950s can be rationalised to justify enactment of this Clause at that time. Since then, important progress in the fields of mechanism of carcinogenesis and cancer causation, and in analytical chemistry permitting accurate determination of trace amounts of chemicals, suggests that the Clause requires modification based on current knowledge. The documented human carcinogens are DNA reactive or genotoxic. Thus, the Clause should emphasise prohibition of the addition to human foods of proven genotoxins that are likely human cancer risks by contemporary standards. Such genotoxic carcinogens are those reliably positive in a battery of three tests: the Ames test in Salmonella typhimurium; the Williams test with evidence of DNA repair in hepatocytes; and direct documentation of DNA adduct formation in the 32P-postlabelling technique of Randerath.
Development of a Rabbit Model to Investigate the Effects of Acute Nitrogen Dioxide Intoxication
Authors: Meulenbelt J. , van Bree L. , Dormans J.A.M.A. , Boink A.B.T.J. , Sangster B.
Published: December 2008

1 In previous studies a rat inhalation model was developed to investigate the effects of intervention after acute NO2 exposure. The object of the present study was to investigate whether acute NO2 intoxication induced comparable effects in rabbits as it does in rats. Where the effects of intervention in both species are similar, then the conclusions drawn from these studies may have more relevance for the treatment of man.

2 Biochemical variables in bronchoalveolar lavage and supernatant from lung homogenate, which may be relevant for the evaluation of lung injury and repair, were investigated and compared with histology.

3 After NO 2 exposure for 10 min, the pulmonary effects observed became more pronounced with increasing NO2 concentrations (0, 125, 175, 250, 400, 600 or 800 ppm) [1 ppm NO2 is 1.88 mg m-3]. The effects in rabbits were found to be broadly comparable with those in rats.

4 To achieve severe lung injury in rabbits without mortality, enabling investigations of the effects of intervention over several days, exposure to a NO2 concentration of 600 ppm for 10 min was most appropriate, while a concentration of 175 ppm NO2 was needed to attain comparable effects in rats.

5 The repair phase starts later, namely at 3 days after exposure in rats, compared to 5 days in rabbits.
Evaluation of the Genetic Toxicity of the Peroxisome Proliferator and Carcinogen Methyl Clofenapate, Including Assays Usin Muta TM Mouse and Big Blue™ Transgenic Mice
Authors: Lefevre P.A. , Tinwell H. , Galloway S.M. , Hill R. , Mackay J.M. , Elcombe C.R. , Foster J. , Randall V. , Callander R.D. , Ashby J.
Published: December 2008

The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S.typhimurium and E.coli (± S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (± S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue™) and lac Z (Muta™ Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue™ and Muta™ Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity, These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP.

The clastogenicity in vitro of the peroxisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also nonclastogenic.
Metabolic basis for high paracetamol dosage without hepatic injury: a case study
Authors: Tredger J. Michael , Thuluvath Paul , Williams Roger , Murray-Lyon Iain M.
Published: December 2008

1 Studies of paracetamol metabolism were performed in a 58-year-old female with rheumatoid arthritis who had consumed 15-20 g paracetamol daily for 5 years with out developing liver damage and data were compared with results in seven normal volunteers.

2 After a test dose of 2 g paracetamol, the formation of paracetamol sulphate and glucuronide conjugates detected in plasma from the patient was delayed by around 2 h relative to values in normal volunteers and the proportion of sulphate conjugates excreted in urine was 1.5 to 2 times those in normal volunteers (52% vs 26-35% of dose, respectively). The fractional metabolite clearance of paracetamol to glutathione-derived conju gates (0.28 ml min-1kg-1) in our patient was > 30% lower than in normal females.

3 A combination of slow paracetamol absorption, enhanced detoxication of paracetamol (by sulphation) and reduced metabolism to potentially cytotoxic metabolites may have reduced the risk of liver damage in this patient. The latter may have reflected pharmaco- genetic deficiencies in cytochrome P450 isoenzymes per sisting despite chronic alcohol consumption (40—60 g per day) or resulted from inhibition of paracetamol acti vation by concomitant ingestion of aminophylline.
Accumulation of hexachlorobenzene in humans: a long standing risk
Authors: To-Figueras J. , Barrot C. , Rodamilans M. , Gómez-Catalán J. , Torra M. , Brunet M. , Sabater F. , Corbella J.
Published: December 2008

1 Hexachlorobenzene (HCB) internal dose in the general population of Barcelona (Spain) was estimated after new indications of the carcinogenicity of this chemical in humans were recently reported. Hospital blood bank facilities and randomly selected volunteers were used for HCB analyses in serum ( n=100) and cerumen ( n=25). Other main organochlorine residues often found in human tissues and blood (pp'DDE, β-HCH,) were also determined.

2 HCB serum levels currently found (Range 0.7-19.7 ng ml-1; X ± s.d.: 4.13 ± 3.61; GM: 3.05) were compared to those found in a similar survey made in 1986 on the same population. The serum HCB levels showed a sig nificant decrease ( P<0.001) when compared to the for mer results and correlated with age ( P<0.001) suggest ing a progressive preponderance of a stable blood-adi pose equilibrium with fewer variations due to recent and variable intake of the chemical.

3 Cerumen analyses revealed detectable concentrations of HCB in all samples (Range: 160-4790 ng g -1 in extractable lipid basis) and confirmed the suitability of this matrix to assess the body burden of residues accumulated in adipose and lipid-rich tissues. The set of results shows that, although HCB exposure has been reduced, the overall population under study still accumulates significant amounts of this possible car cinogen.
Lead poisoning from Asian traditional remedies in the West Midlands - report of a series of five cases
Authors: Bayly G.R. , Braithwaite R.A. , Sheehan T.M.T. , Dyer N.H. , Grimley C. , Ferner R.E.
Published: December 2008

1 Traditional remedies are an unusual, but recognised cause of lead poisoning. Only two cases have previously been reported in this country.

2 We report a series of five cases of lead poisoning due to traditional remedies in the West Midlands. All devel oped typical clinical features.

3 Blood lead and zinc protoporphyrin (ZPP) concentra tions were elevated 2-10 times the upper limit of nor mal. The remedies contained up to 60% lead by weight. One also contained traces of mercury, another arsenic, and a third aluminium and tin.

4 Confirmation of the medicines as the cause of the poi soning was made in one patient by measurement of lead isotopic ratios.

5 The present morbidity from traditional remedies may be far greater than is realised, and will continue until such time as the supply of harmful preparations can be effec tively limited. There needs to be increased awareness of their dangers amongst doctors and the communities at risk. This will best be achieved by appropriately targeted education.
The risk of aspiration in Dettol poisoning: a retrospective cohort study
Authors: Chan Thomas Y.K. , Critchley Julian A.J.H. , Lau Joseph T.F.
Published: December 2008

1 To determine if the risk of aspiration is increased in 'Dettol' (4.8% chloroxylenol, pine oil and isopropyl alco hol) poisoning and the factors that may be responsible, a study was made of 89 patients and 89 matched control subjects with other forms of poisoning admitted to the Prince of Wales Hospital, Hong Kong.

2 Aspiration was more common in patients with Dettol poisoning (8% vs 3%, P = 0.16). There were more control subjects with drowsiness at presentation (54% vs 24%, P < 0.0001), but the use of gastric lavage (88% vs 64%, P < 0.001) and the occurrence of vomiting (62% vs 17%, P < 0.0001) were more common in patients with Dettol poisoning.

3 Our findings suggest that Dettol poisoning may be asso ciated with an increased risk of aspiration. This increase in risk may be related to the use of gastric lavage and the common occurrence of vomiting in patients with Dettol poisoning.
Guideline limit volumes for dosing animals in the preclinical stage of safety evaluation
Authors: Hull RM
Published: December 2008

Guideline limit volumes for dosing laboratory animals by oral and parenteral routes in the preclinical stage of safety evaluation were agreed following discussions by the Toxicology Subcommittee of the Association of the British Pharmaceutical Industry. The guideline values represent common practice rather than absolute maxima. Whilst the guideline values are expected to be of value to scientists and technical staff involved in study design and applica ble to the majority of routine safety evaluation studies, scope remains to make the case for special investigations. The need to carefully consider animal welfare and physi ology, current legislation, the use of appropriate dosing technology and formulations, and other practical aspects of study conduct, is emphasised.
Blood lead levels in North Carolina painters
Authors: Ennever Fanny K , Zaccaro Daniel J , Fernando Reshan A , Jones Bradley T
Published: December 2008

1 Blood lead levels were examined in 127 housepainters in North Carolina between April and September, 1993. Each participant filled out a questionnaire and gave a blood sample. The questionnaire covered the individual's work history, concentrating on paint-removal activities and personal protection, and also covered potential non- occupational sources of lead exposure. Blood samples were analysed for lead content using atomic absorption spectroscopy.

2 The geometric mean blood lead level was 0.33 μmol L-1 (6.8 jg dL-1). No blood lead samples were found to exceed the occupational standard of 1.93 μmol L-1 (40 μg dL-1). The three highest samples had levels between 0.97 and 1.45 μmol L-1 (20 and 30 μg dL-1); this represented 2.4% of the study sample.

3 No statistical association was found between blood lead levels in these painters and their painting activities, including using dust masks for personal protection.

4 Current painting practices in this group of North Carolina painters do not appear to elevate blood lead lev els above the occupational standard.
Renal filtration and excretion of aluminium in the rat: dose-response relationships and effects of aluminium speciation
Authors: Lote CJ , Wood JA , Thewles A. , Freeman M.
Published: December 2008

The known toxicity of aluminium, and the toxicity of agents (such as desferrioxamine) used to remove alumini um from the body, has prompted us to investigate whether there may be ways of enhancing aluminium excretion by exploiting the normal renal handling of aluminium. Aluminium (as sulphate or citrate) was administered intravenously to conscious rats at doses ranging from 25 μg (0.93 μmol) to 800 μg (29.6 μmol) aluminium, and alu minium excretion was monitored over the following 2 h. Measurements of the filterability of aluminium from the rat plasma, and the glomerular filtration rate (inulin clearance), enabled us to calculate the filtered load of alu minium, and hence determine aluminium reabsorption.

At all doses of administered aluminium, that adminis tered as sulphate was excreted less effectively than that administered as citrate. This difference was attributable to the much greater filterability of aluminium administered as citrate. However, for any given filtered load, the excre tion of aluminium administered as citrate was not signifi cantly different (in either fractional or absolute terms) from the excretion of aluminium administered as sulphate.

It seems likely that, following aluminium sulphate administration, the filtered aluminium may be an alumini um citrate form which is then reabsorbed in the same way as aluminium administered as citrate.

It is thus apparent that aluminium removal from the body could be further enhanced if it were possible to pre vent the tubular reabsorption of the aluminium species which is so effectively filtered following aluminium citrate administration.
Evaluation of the generation of genotoxic and cytotoxic metabolites of benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen using human liver microsomes and human lymphocytes
Authors: Wilson AS , Tingle MD , Kelly MD , Park BK
Published: December 2008

1 The ability of model stable epoxides and metabolites generated by human liver microsomes from benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen to produce cytotoxicity and genotoxicity in human periph eral lymphocytes has been investigated.

2 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) as well as metabolites generated from aflatoxin B1(30μM) and naph thalene (100μM) by an extracellular metabolising system were toxic to isolated resting mononuclear leucocytes (MNLs), whereas glycidol (100μM), benzo[a]pyrene (100μM) and tamoxifen (50μM) were not.

3 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) but not glycidol (100μM) were toxic to dividing lymphocytes only after a 72-h exposure. Tamoxifen (30μM), aflatoxin B1(30μM) and their metabolites were also toxic to dividing lymphocytes. Benzo[a]pyrene (100μM) and naphthalene (100/μM) were not toxic either in the absence or presence of the extracel lular metabolising system.

4 Benzo[a]pyrene (100/μM) and aflatoxin B1(30μM) were directly genotoxic to lymphocytes, this genotoxicity was significantly enhanced by the presence of the extracellular metabolising system. This indicates that both intracellular and extracellular bioactivation of these two compounds can produce genotoxicity. In contrast, naphthalene and tamoxifen were non-genotoxic.
Glucocorticoid amelioration of nephrotoxicity: a study of cephaloridine- methylprednisolone interaction in the rat
Authors: Harvey PW , Healing G. , Major IR , McFarlane M. , Purdy KA , Olatunde O. , Garcia Conesa MT , Everett DJ , Cockburn A.
Published: December 2008

Groups of ten male rats were treated with a high challenge dose of cephaloridine (CPH, 3750 mg kg -1), with methyl prednisolone (MP, 100 mg kg-1) or with cephaloridine and methylprednisolone (CPH + MP) by single subcutaneous injection. A control group received the injection vehicles only. Urine was collected from all animals daily over 18-h collection periods, up to 96 h after treatment. Blood was collected at 24, 48, 72 and 96 h after treatment. At necrop sy, kidneys were weighed, processed and examined histopathologically.

Results show that methylprednisolone significantly ameliorated the nephrotoxicity of the challenge dose of cephaloridine. CPH-only treated rats had severe toxic nephrosis characterised by acute tubular necrosis, and elevated blood urea and creatinine. By contrast, the major ity of CPH + MP treated rats had only a slight or moderate toxic nephrosis, and had lower blood urea and creatinine levels compared with rats treated with CPH only, indicat ing preservation of kidney function. Interestingly, rats treated with CPH + MP had higher urinary enzymes (alka line phosphatase, lactate dehydrogenase, gamma glu tamyltransferase and N-acetyl-B-glucosaminidase) as well as protein and glucose, compared with rats treated with CPH only. This is taken to indicate that rats treated with CPH only had such marked kidney damage and necrosis that the population of cells able to produce these marker enzymes was significantly and rapidly depleted, but the protection afforded by methylprednisolone allowed CPH + MP treated rats to sustain urinary enzyme output. Effects on urinary glucose and other parameters such as body weight and kidney weight demonstrate interactions between glucocorticoid pharmacology and cephaloridine nephrotoxicity. Finally, the significance of these findings is discussed in terms of a generic mechanism of protection conferred by glucocorticoids in certain types of nephrotox icity and related to similar findings in rats treated intra venously with cisplatin, an anti-neoplastic agent for which the clinical utility in man is often limited by adverse effects on the kidney.
A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man
Authors: Prentice DE , Meikle AW
Published: December 2008

This paper describes control of normal Leydig cell func tion and testosterone production. The macroscopic and histopathological appearances of spontaneous Leydig cell hyperplasias and tumors (LCT) in the rat are reviewed together with their incidence and hormonal status. Drugs which induce LCTs in chronic studies are discussed and include busereline, carbamazepine, cimetidine, finas teride, flutamide, gemfibrozil, histrelin, hydralazine, indomethacin, isradipine, lactitol, leuprolide, metronida zole, mesulergine, nafarelin, norprolac and vidarabine.

The known mechanisms of LCT induction in the rat are reviewed together with other possible etiological factors. The incidence, clinical picture and etiological factors of LCTs in man are also surveyed. Hormone production in Leydig cells and LCTs in rats and man are compared. Differences between the two species are considered, par ticularly with regard to Leydig cell control mechanisms. The paper concludes that drug-induced LCTs in rats are most probably not predictive for man and their occurrence has little relevance in human safety assessment.
The generation of a human dermal equivalent to assess the potential contribution of human dermal fibroblasts to the sulphur mustard-induced vesication response
Authors: Lindsay CD , Upshall DG
Published: December 2008

1 A human dermal equivalent (HDE) gel was constructed from rat tail tendon collagen (type 1) and human dermal fibroblasts (HFs). Histological studies revealed that the HFs within the HDE gel matrix assumed the shape of differentiated dermal fibroblasts and were metabolically viable as determined by the MTT assay.

2 The HDE system was developed to determine if viable, differentiated HFs have the potential to contribute to tis sue damage by releasing the proteolytic enzyme elastase following exposure to sulphur mustard (HD). Elastase was measured, using the substrate suc-ala-ala-val-p- nitroanilide (SAAVNA), because of its association with various human pathological bullous skin diseases. An additional elastase substrate (suc-ala-ala-ala-p- nitroanilide ; SAAANA) was also used. A miniaturised assay was employed to measure lactate dehydrogenase (LDH), a cytosolic enzyme released following damage to the cell membrane.

3 Elastase levels (measured with SAAVNA) increased to over 740% of those in control culture medium at 24 h after exposure of the HDE to HD (2 mM) and may there fore be part of the mechanism associated with dermo- epidermal separation and blistering in humans follow ing exposure of skin to HD. LDH was released from the HDE after exposure to HD in a time dependent fashion, suggesting a steady leakage of cytosolic constituents after the initial exposure.

4 The results suggest that differentiated human dermal fibroblasts have the potential to contribute to the devel opment of the vesication response by releasing proteases such as elastase extracellularly after HD exposure. These types of studies cannot be conducted in humans on ethical grounds because of the mutagenic properties of HD. The HDE model therefore has an important advantage in studies on the mechanism of action of HD.
Ochratoxin A in human blood in relation to nephropathy in Tunisia
Authors: Maaroufi K. , Achour A. , Hammami M. , El May M. , Betbeder AM , Ellouz F. , Creppy EE , Bacha H.
Published: December 2008

The determination of ochratoxin A (OTA) in human blood in Tunisian populations is underway. The range of conta mination is between 0.7 to 7.8 ng ml-1for the general popu lation and 12 to 55 ng ml-1for people suffering from chron ic renal failure. It appears that 21 to 64% of people suffer ing from nephropathy are OTA positive with a detection limit of 1ng ml-1. This situation prompted us to search for possible association of OTA contamination and nephropa thy resembling Balkan endemic nephropathy. The classifi cation of the ill population into chronic interstitial nephropathy (CIN), chronic glomerular nephropathy (CGN), chronic vascular nephropathy (CVN) and others, indicated that the largest is the CIN group which is signifi cantly different from the other groups, and from the con trol (P < 0.005). Furthermore, it presented the highest OTA mean values (25 to 59 ng ml-1) compared with the control, CGN, CVN and other groups (6 to 18 ng ml-1) according to the designated region in Tunisia.

The rural population seems to be more exposed to ochratoxins in Tunisia, as has been previously reported in the Balkans and Western Europe.

Altogether, these results emphasise that in Tunisia an endemic ochratoxin-related nephropathy is probably occurring.
Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice
Authors: Kim DH , Kim EJ , Han SS , Roh JK , Jeong TC , Park JH
Published: December 2008

1 The present study was undertaken to examine the effects of H2-receptor antagonists including newly developed mifentidine derivatives, IY-80843 and IY-80845, on cytochrome P450(P450) in vitro and in vivo.

2 Initially, 3-methylcholanthrene-, phenobarbital-, ethanol- and dexamethasone-induced liver microsomes were prepared from male ICR mice to study in vitro effects of above chemicals on ethoxyresorufin O- deethylase(EROD), pentoxyresorufin O-dealkylase(PROD), p-nitrophenol hydroxylase and erythromycin N-demethy lase(ERDM) activities, respectively. It was found that hist amine, cimetidine and famotidine were not inhibitory to four enzyme activities. Meanwhile, mifentidine slightly inhibited EROD and PROD activities and its derivatives IY-80843 and IY-80845 strongly inhibited PROD, EROD and ERDM activities.

3 Prolongation of hexobarbital-induced sleeping time was determined in male ICR mice to confirm in vitro inhibito ry effects of mifentidine and its derivatives in vivo. It was observed that cimetidine, mifentidine, IY-80843 and IY- 80845 caused dose-dependent increases in the sleeping time, indicating the inhibition of P450 responsible for hexobarbital metabolism.

4 It was concluded that mifentidine and its derivatives are P450 inhibitors and that our newly synthesized IY-80843 is most inhibitory.

5 The present results indicate that mifentidine and its derivatives not only antagonise the H2-receptor but also inhibit P450 enzymes.