bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Single Doses of Erythromycin and Roxithromycin May Increase the Effects of Midazolam on Human Performance
Authors: Mattila M. J. , Idänpään‐Heikkilä J. J. , Törnwall M. , Vanakoski J.
Published: March 2009

Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolamin vitroandin vivo.To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule form were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo‐controlled double‐blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam + erythromycin impaired digit symbol substitution and letter cancellation, and triazolam + roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg + erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg + erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg + roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg. Our results suggest that sedation produced by hypnotic doses of midazolam is enhanced by erythromycin and perhaps by roxithromycin after single oral doses. The combined effects of triazolam together with erythromycin and roxithromycin were unclear, partly due to the relatively lower dose of triazolam.
Effect of Zinc or S‐Adenosyl‐l‐methionine on Long Term Administration of Low Doses of Lead to Rats
Authors: Muñoz Juan J. , Roca Cristina , Santos José L. , Arroyo Miguel , de Salamanca Rafael E.
Published: March 2009

Two alternatives for the treatment of lead intoxication, administration of zinc or a thiol donor, S‐adenosyl‐L‐methionine (SAM), were analysed. Rats were exposed to lead (Pb)‐acetate (60 mg/1) in drinking water during 90 days; one group also received SO4Zn in water (40 mg/l), while another received both Pb and SAM (5 mg/24 hr intraperitoneally. Erythrocytic δ‐aminolaevulinic dehydratase (ALA‐D) activity was significantly reduced (P<0.001) both in rats receiving Pb alone and in rats receiving Pb and each of the other two treatments. The high erythrocytic uroporphyrinogen synthetase (URO‐S) activity noticed in Pb administered rats, was significantly (P< 0.001) reduced in animals treated either with zinc or with SAM. Hepatic ALA‐D activity tended to decrease while renal enzyme activity was not modified by the low level Pb exposure used in this work. Interestingly, SAM treated rats in both tissues exhibited significantly (P<0.01) higher activities of the enzyme. It is argued that SAM treatment causes a surplus of thiols that allows the full expression of ALA‐D catalytic activity.
Effects of Dietary α‐Tocopherol and β‐Carotene on Lipid Peroxidation Induced by Methyl Mercuric Chloride in Mice
Authors: Andersen Helle Raun , Andersen Ole
Published: March 2009

Exposure of male CBA mice to methyl mercuric chloride, CH3HgCl, (10–40 mg/1 in drinking water) for 2 weeks resulted in dose‐related Hg deposition and enhanced lipid peroxidation in liver, kidney and brain. Mice were fed well‐defined semisynthetic diets containing different levels of α‐tocopherol (10, 100 or 1000 mg/kg) or β‐carotene (1000, 10000 or 100000 IU/kg) for four weeks, two groups on each diet. The concentrations of α‐tocopherol and β‐carotene used corresponded to deficient, normal and high levels. During the last two weeks, one group on each diet was given 40 mg CH3HgCl/1 of drinking water. High dietary α‐tocopherol protected against CH3HgCl induced hepatic lipid peroxidation, whereas the α‐tocopherol deficient diet further enhanced CH3HgCl induced hepatic lipid peroxidation. Similar, though statistically non‐significant effects occured in the kidneys, α‐Tocopherol did not protect against CH3HgCl induced lipid peroxidation in the brain. Excess dietary β‐carotene further enhanced CH3HgCl induced lipid peroxidation in liver, kidney and brain. CH3HgCl significantly decreased the activity of total glutathione peroxidase (T‐GSH‐Px) and Se‐dependent glutathione peroxidase (Se‐GSH‐Px) in the kidneys in all dietary groups. High dietary α‐tocopherol enhanced the activity of Se‐GSH‐Px in liver and kidney compared to the activity in mice fed the normal level of α‐tocopherol. This occured in mice exposed to CH3‐HgCl as well as in unexposed mice, and the difference between CH3HgCl exposed and unexposed mice was not diminished. High dietary α‐tocopherol increased the activity of both Se‐GSH‐Px and T‐GSH‐Px in the brain of CH3HgCl‐exposed mice. The dietary level of β‐carotene did not affect the activity of the two enzymes in the organs investigated.
Effects of Interferon, Polyriboinosinic Acid‐Polyribocytidilic Acid and Steroids on the Cytochrome P450 System of Cultured Primary Mouse Hepatocytes *
Authors: Kuwahara Steven K. , Mannering Gilbert J.
Published: March 2009

Abstract:An earlier study from this laboratory showed that the hepatic murine cytochrome P450 (P450) system was depressed by interferonin vivobut induced in cultured primary hepatocytes. The current investigation attempted to resolve this contradiction. The P450 content of the cells used in the earlier study fell precipitously during the first 24 hr of culture and remained at the same low level throughout another 48 hr of incubation. This failure to maintain the P450 level suggested that the cells may not have been sufficiently viable to support the mechanisms involved in the depressant activity of interferon. Accordingly, a chemically defined medium containing hydrocortisone was devised which supported an acceptable level and function of the P450 system throughout a 72 hr incubation period. Functionality of the P450 system was evaluated by measuring aminopyrine N‐demethylase and benzo[a]pyrene hydroxylase activities. When this steroid supplemented medium was used, interferon depressed both activities by about 25%; however, neither activity was affected significantly by poly IC. On the other hand, benzo[a]pyrene hydroxylase activity was depressed by both poly IC and interferon in hepatocytes induced with dexamethasone or with dexamethasone plus 3‐methylcholanthrene. These studies emphasize the necessity of maintaining an acceptable level of homeostasis in cultured hepatocytes if one is to derive meaningful interpretations of certain biological events.
Effects of Dopamine D1and D2Receptor Agonists and Antagonists on Seizures Induced by Chemoconvulsants in Mice
Authors: Ögren S. O. , Pakh B.
Published: March 2009

Abstract:Dopamine agonists and antagonists with different affinities for D1and D2receptors in the brain were assessed for their ability to affect clonic seizures in mice induced by chemoconvulsants. The dopamine D2antagonists remoxipride (5‐20 mg/kg) and raclopride (5‐20 mg/kg), haloperidol (2.5 and 5 mg/kg) and the D1antagonist SCH 23390 (0.3, 1.5 mg/kg) did not markedly modify seizures induced by pentylenetetrazole, picrotoxin or bicuculline. The dopamine D2agonist quinpirole only weakly blocked the action of pentylenetetrazole while the D1agonist SKF 38393 (1‐10 mg/kg subcutaneously) caused a dose‐dependent blockade of pentylenetetrazole‐induced seizures. The D1/D2agonist apomorphine given at “postsynaptic” doses (1 and 2 mg/kg) blocked pentylenetetrazole‐induced seizures. The protection afforded by apomorphine against pentylenetetrazole seizures appeared to be associated with its activation of both D1and D2receptors since both raclopride and SCH 23390 blocked the action of apomorphine. Reserpine and the two partial dopamine autoreceptor agonists, (—)3‐PPP and HW‐165, at high (non‐autoreceptor selective) doses induced seizures in animals treated with the subconvulsive dose of pentylenetetrazole. The overall results suggest that dopamine receptor blockade has a minor or limited effect on seizures caused by GABA inhibition. The anticonvulsant effect of dopamine agonists such as apomorphine appears to be mediated by postsynaptic dopamine D1and D2receptors. Stimulation of dopamine D1receptors can reduce seizure activity caused by GABA receptor blockade possibly by facilitation of GABA transmission in the striatum and substantia nigra.
Effect of β‐Adrenergic Agents on Human Neutrophil Granulocyte Activation with N‐Formyl‐methionyl‐leucyl‐phenylalanine and Phorbol Myristate Acetate
Authors: Opdahl H. , Benestad H. B. , Nicolaysen G.
Published: March 2009

Abstract:Generation of reactive oxygen intermediates by activated polymorphonuclear neutrophil granulocytes plays an important role in development of microcirculatory injury. The effect of the β2‐adrenergic receptor agonists (β2‐agonists) isoprenaline and terbutaline on the chemiluminescence or oxygen consumption of human granulocytes in response to activation with n‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) and phorbol myristate acetate (PMA) was examined. The β2‐agonist effect on activated cell aggregation and volume change was examined as well. As E. Coli lipopolysaccharide and FMLP may prime granulocytes for enhanced generation of reactive oxygen intermediates in response to other activators, the effect of β2‐agonists on the priming effect of these agents was also investigated. Results: 1) Optimal concentrations of β2‐agonists decrease the human granulocyte generation of reactive oxygen intermediates in response to activation with FMLP by 40‐60%, without affecting the response to PMA. 2) β2‐Agonists modify the priming effect of FMLP on activation with PMA, but do not interfere with the priming effect of E. Coli lipopolysaccharide on activation with FMLP. 3) Isoprenaline have different effects on generation of reactive oxygen intermediates and cell aggregation in FMLP‐activated granulocytes. 4) High concentrations of isoprenaline and terbutaline have contrasting non‐specific effects on the chemiluminescence, but not on the oxygen consumption, of activated granulocytes.
Inhibitory Effects of Calcium Channel Antagonists on Motor Dysfunction Induced by Intracerebroventricular Administration of Paraquat
Authors: Yoshimura Yasuo , Watanabe Yasuo , Shibuya Takeshi
Published: March 2009

Abstract:This study reports the effects of Ca2+channel blockers (Ca antagonists) on intraneuronal Ca2+([Ca2+]i) movements and on the disturbance of rotarod performance produced in rats by intracerebroventricular administration of paraquat. Paraquat (50 nmol) produced a decrement in rotarod performance which was present at 30 min. and maximal at 60 min. and was not associated with overt behavioural changes; larger doses of paraquat (100‐400 nmol intracerebroventricularly) produced paresis and convulsions which severely disrupted rotarod behaviour. The disruption of rotarod performance after paraquat (50 nmol intracerebroventricularly) was significantly reduced by giving Ca antagonists (flunarizine, verapamil and nicardipine) not only intraperitoneally 15 min. after paraquat but also intracerebroventricularly immediately before paraquat. The order of pharmacological potency was flunarizine ≥ verapamil > nicardipine. In contrast, intracerebroventricular administration of Bay K 8644, a Ca agonist, enhanced the disruption of rotarod performance caused by paraquat (50 nmol). Inin vitrostudies, paraquat markedly potentiated the rapid increase in [Ca2+]ilevels evoked by 50 mM KCl in rat brain synaptosomal fraction, although paraquat alone produced a small prolonged rise in [Ca2+]ilevels which had a slow onset. The above results suggest that paraquat induced neurotoxicity is associated with increased [Ca2+]ilevels in brain neuronal cells, and that paraquat might effect on membrane activity instability.
Gastrointestinal Dialysis of Digoxin Using Cholestyramine
Authors: Rawashdeh Nayel M. , Al‐Hadidi Hakam F. , Irshaid Yacoub M. , Battah Abdel‐Kader H.
Published: March 2009

Abstract: The pharmacokinetic parameters of digoxin given intravenously (0.075 mg/kg) alone and following treatment with oral cholestyramine (8 gm in 50 ml water) were studied in rabbits. Pretreatment with cholestyramine produced a significant decrease in the serum concentration of digoxin and significantly enhances its systemic clearance as indicated by a statistically significant decrease in the area under the concentration‐time curve (AUC), half time of elimination (t1/2), and mean residence time (MRT). These findings indicate that the idea of gastrointestinal dialysis, known with activated charcoal, could be extended to ion‐exchange resins that could be a potentially useful adjunctive measure in the management of drug overdose especially with commonly used drugs with a low therapeutic index like digoxin.
Perchloroethylene‐Induced Reduction in Glial and Neuronal Cell Marker Proteins in Rat Brain
Authors: Wang Shu , Karlsson Jan‐Erik , Kyrklund Titus , Haglid Kenneth
Published: March 2009

Abstract: Rats were exposed to continous inhalation of 300 and 600 p.p.m. of perchloroethylene for 4 and 12 weeks. Exposure to 600 p.p.m. for 4 to 12 weeks resulted in a slower increase in brain weight. Brain region weights, total proteins and DNA were decreased in frontal cerebral cortex and brain stem but not in hippocampus after exposure to 600 p.p.m. for 12 weeks. Four marker proteins were measured to monitor the specific neurotoxic effects of perchloroethylene: S‐100 protein and glial fibrillary acidic protein as glial cell markers and neurone specific enolase and neurofilament 68 kD polypeptide as neuronal markers. The concentrations of glial and neuronal cytoskeletal proteins (glial fibrillary acidic protein and neurofilament 68 kD polypeptide) were reduced in frontal cerebral cortex. The total tissue contents of glial proteins (S‐100 protein and glial fibrillary acidic protein) were decreased in all 3 brain regions investigated (frontal cerebral cortex, hippocampus and brain stem). Neurone specific enolase was unchanged by perchloroethylene exposure. These results indicate that exposure to perchloroethylene reduces the number of brain cells, possibly glial cells, and interferes with the metabolism of cytoskeletal elements in both glial and neuronal cells.
Pharmacokinetics of Trazodone During Multiple Dosing to Psychiatric Patients
Authors: Nilsen Odd G. , Dale Ola , Husebe Børre
Published: March 2009

Abstract: Steady‐state pharmacokinetics of trazodone were investigated over a period of 4 weeks in seven psychiatric patients after repeated oral administrations of 50, 100, and 150 mg twice daily for one, one, and two consecutive weeks, respectively. Unchanged trazodone was determined by high performance liquid chromatography after a basic extraction. A steady‐state level of serum trazodone was achieved for the 50 mg dose within 36 hr, while a new steady state level after increasing the dose to 100 mg and then 150 mg twice daily apparently was achieved at 12 hr. Trazodone showed linear pharmacokinetics within the dosage range investigated. The following main parameters were calculated at steady state for psychiatric patients (mean±S.D.): t1/2 = 7.0±1.2, Vβ/F = 0.50±0.131/kg and Clt/F = 3.2±0.51/hr. These pharmacokinetic parameters did not differ significantly from those earlier reported in healthy subjects after a single dose administration of 100 mg when based on an oral availability of trazodone of 65%.
Protective Effects of Tannic Acid and Related Natural Compounds on Crotalus adamenteus Subcutaneous Poisoning in Mice
Authors: Kuppusamy Umah R. , Das Nagaratnam P.
Published: March 2009

Abstract:The plant natural products namely tannic acid and the flavonoids luteolin, kaempferol and apigenin exerted potent inhibition on the hyaluronidase enzyme. They were able to neutralize the haemorrhage induced byCrotalus adamenteusvenom in mice dose‐dependently from 0.12–2.4 mg/kg subcutaneously. In addition, they were able to antagonize the lethal activity of the venom when injected subcutaneously into mice and the order of potency was: tannic acid luteolin = kaempferol> apigenin. Tannic acid (24 mg/kg, subcutaneously) was able to reduce significantly the venom‐induced elevation of blood creatine kinase activity. It could also prolong the survival time(s) of mice, when injected immediately after the administration of venom. Experimental evidence is presented for the first time that malondialdehyde in liver and kidney is significantly elevated as a result of rattlesnake venom poisoning and that this effect can be controlled by tannic acid.
Effect of Subchronic Metformin Treatment on Macronutrient Selection in Genetically Obese Zucker Rats
Authors: Rouru Juha , Huupponen Risto , Santti Eriika , Koulu Markku
Published: March 2009

Abstract: Metformin has been particularly recommended to be used in obese type 2 diabetic patients because of its weight decreasing and serum lipid profile normalizing effects. In the present study the effects of subchronic metformin treatment on macronutrient selection, weight gain and plasma insulin and glucose were investigated in 20 genetically obese male Zucker rats which were maintained on a free‐feeding self‐selection paradigm with three pure macronutrient diets of carbohydrate, fat and protein. Half of the rats were given metformin hydrochloride 320 mg/kg/day up to 18 days in drinking water. The other half of the animals received normal drinking water as a control. Metformin treatment significantly reduced 24 hr carbohydrate (P<0.01), fat (P<0.001) and protein (P<0.01) intake. The proportion of fat of the total consumed energy was significantly increased by metformin (P<0.01) while the proportion of protein was decreased (P<0.05). In hunger stimulated feeding experiment metformin decreased selectively protein intake (P<0.01). Changes in macronutrient selection were associated with reduced body weight gain in metformin treated rats (P<0.001). Metformin markedly reduced the hyperinsulinaemia (P<0.01) and plasma glucose levels (P<0.05), which suggests improved glucose tolerance after metformin treatment. It is concluded that subchronic metformin treatment can modify the composition of energy intake in a macronutrient selective manner.
Furosemide Treatment Causes Age‐Dependent Glucose Intolerance and Islet Damage in Obese‐Hyperglycaemic Mice
Authors: Sandström Per‐Erik , Sehlin Janove , Åmark Kerstin
Published: March 2009

Abstract:The effects of furosemide on fasting serum glucose, glucose tolerance and pancreatic islet morphology were studied inob/obmice of two age groups, 3 months and 8 months. A single dose of furosemide (200 mg/kg body weight) induced acute hyperglycaemia in the young (3 months) as well as the old (8 months)ob/obmice. Two days after the furosemide injection the glucose tolerance was markedly impaired in older animals, whereas it was normal in younger animals. Glucose tolerance in old mice varied markedly between individuals and showed two patterns. Thus, in one group of 8 months old mice, fasting serum glucose was elevated and glucose tolerance was very poor, whereas in the other group it was at least as good as in the saline‐injected controls. Histological analysis showed normal islet morphology in furosemide‐treatment young mice but an inflammatory reaction in islets from furosemide‐injected old animals. A significant correlation between the degree of islet abnormality and glucose tolerance was observed. The data suggest that susceptibility to develop furosemide‐induced long‐term glucose intolerance is associated with the development of the obese‐hyperglycaemic syndrome rather than being linked to the inheritance of theob/obgenome as such.
The Affinity of Human Serum Albumin for [3H]‐Digitoxin is Dependent on Albumin Concentration
Authors: Brørs Odd , Fremstad Dag , Poulsson Claire
Published: March 2009

Abstract: Binding of [3H]‐digitoxin to human serum albumin and human serum was investigated in order to characterize the relationship between binding and albumin concentration. Binding was determined by equilibrium dialysis at 37$dG, 24 hr was required to reach equilibrium. Volume shift and protein dilution were avoided by adding dextran 70 to the buffer compartment. [3H]‐Digitoxin binding both to purified albumin and to normal serum was markedly pH‐dependent, the bound/unbound ratio being highly significantly (P<0.001) inversely correlated to pH in the range 6–8.5. When albumin concentration was increased within the physiological range, the ratio bound/unbound [3H]‐digitoxin increased much less than expected from predictions using the law of mass action. Binding saturation experiments revealed that the equilibrium dissociation constant for [3H]‐digitoxin was increased at higher albumin concentrations without any decrease in the number of binding sites per albumin molecule. In conclusion, the results strongly indicate that binding estimates in therapeutic monitoring of digitoxin in patients with elevated or reduced albumin concentration should not be based on the law of mass action but on empiric relationships between albumin concentration and binding.
Hydrogen Peroxide‐Induced Broncho‐ and Vasoconstriction in the Isolated Perfused and Ventilated Guinea Pig Lung
Authors: Bannenberg G. , Kimland M. , Ryrfeldt Å. , Moldeus P.
Published: March 2009

Abstract:The effect of hydrogen peroxide on perfusion flow, airway conductance (Gaw) and dynamic compliance (Cdyn) of isolated perfused and ventilated guinea pig lungs was investigated. Hydrogen peroxide (50 μM in the perfusion buffer) induced a decrease in Gawand Cdynand perfusion flow during 5 min. of exposure. Hydrogen peroxide also caused an increase in the levels of thromboxane in the perfusate of the lung. The constrictor effects as well as the formation of thromboxane were inhibited by the cyclooxygenase inhibitor ibuprofen (50 μM). The thromboxane/prostaglandin endoperoxide receptor antagonist L‐670,596 (1 μM) abolished the effects of hydrogen peroxide on perfusion flow, Gawand Cdyn, but did not affect the formation of thromboxane. The thromboxane‐synthetase inhibitor carboxyheptylimidazole (100 μM) reduced both the hydrogen peroxide‐induced formation of thromboxane and vaso‐ and bronchoconstriction, suggesting a predominant role for thromboxane A2versus prostaglandin H2in these effects. A role for platelet‐activating factor in mediating the effect of hydrogen peroxide could not be supported, as the platelet‐activating factor receptor antagonist WEB 2086 (10 μM) did not affect hydrogen peroxide induced vaso‐ and bronchoconstriction. The results of this study show that hydrogen peroxide induces thromboxane A2mediated vaso‐ and bronchoconstriction in the isolated perfused and ventilated guinea pig lung. Platelet‐activating factor does not appear to play a significant role in the hydrogen peroxide‐induced vaso‐ and bronchoconstriction. Our results also suggest that the perfused guinea pig lung is more sensitive to hydrogen peroxide than the perfused rat lung.
Issues and Controversies Surrounding Qualitative Strategies For Identifying and Forecasting Cancer Causing Agents in the Human Environment
Authors: Huff James
Published: March 2009

Abstract: Certain chemicals, mixtures of chemicals, exposure circumstances, life‐styles and personal or cultural habits, occupations, viruses, living conditions, and physical agents have been causally associated with cancers in humans. Most however are not considered potentially carcinogenic, and the proportion of ‘agents’eventually identified to cause cancer is projected to be relatively low. Current methods to identify carcinogenic potential of chemicals rely largely on short‐term in vitro and in vivo tests, mid‐ & long‐term in vivo assays, molecular mechanisms, epidemiological investigations, and structural‐activity‐effect‐relationships. Thus, the scientific and public health communities must continue to utilize available means and concomitantly strive to develop newer methods and tools to more easily, quickly, cheaply, and reliably identify carcinogens in the human milieu. Since adequate human studies are typically absent, the most useful method for identifying potential human carcinogens continues to be long‐term carcinogenesis experiments. Agents identified as causing cancers in humans have been shown to cause cancer in animals, and this knowledge, together with similarities in mechanisms of carcinogenesis across species, led to the scientific logic and public health strategy that chemicals shown clearly to be carcinogenic in animals should be considered as being likely and anticipated to present cancer risks to humans. The quest of hazard identification efforts is cancer prevention, largely by reducing or eliminating exposures to chemicals that cause cancer and other diseases.
CHEMICAL CARCINOGENS IN THE ENVIRONMENT: RISK ASSESSMENT FOR THE ENVIRONMENT
Authors: Nielsen Proben Aagaard
Published: March 2009

Abstract: The high priority of chemical carcinogens in environmental monitoring programmes is primarily due to a fear of a human exposure to these chemicals. Diseases like cancer are, however, also observed in indigenous populations of e.g. fish and shellfish, although these effects in general are rare events in the environment. High levels of carcinogens seem to be required for an influence on the prevalence of cancer, and an influence has almost exclusively been detected on the prevalence of liver tumours in populations of bottom‐dwelling fish. The most important ecological aspect of chemical carcinogens in the environment may be the genotoxic potential of the carcinogens. Induced mutations may result in effects on survival or growth of the exposed organisms. In germ cells induced mutations are transmitted to future generations, resulting in an anthropogenic increase in the background mutation rate. The structure and function of the ecosystem is in the long run somehow determined by the background mutation rate which raises the question whether an increase in the mutation rate is advantageous or disadvantageous from a population and evolutionary point of view. To date experimental knowledge is hardly available even on the type of changes to be expected.
Airborne carcinogens
Authors: Lewtas Joellen
Published: March 2009

Abstract: Air pollution has been recognized as a cancer risk for many years. More than 2,800 different chemicals have been identified in the air or emission sources. Only about 10% of these chemicals have been evaluated in bioassays for genetic or carcinogenic effects. Hydrocarbons, nitrogen‐containing organics, and halogenated organics account for nearly 60% of the airborne chemicals that have been studied in long term animal cancer bioassays or short‐term genetic bioassays. The sources that emit the highest number of these potentially carcinogenic chemicals are sources involving combustion (e.g., tobacco smoke, automobile exhaust, and coal combustion). Quantitative estimates of the risk of airborne carcinogens in outdoor air consistently show that polycyclic organic matter (POM) from products of incomplete combustion (PICs) make the largest single contribution to human cancer risk. Although the POM emissions from various air pollution sources are chemically similar and induce cancer by a similar genotoxic mechanism, the cancer risk per unit of exposure of these emissions may vary by several orders of magnitude. Among these combustion sources motor vehicle emissions account for the greatest cancer risk in outdoor air. Environmental tobacco smoke (ETS) and radon are the major sources of cancer risk from indoor exposures. There are, however, many uncertainties in identifying the important airborne carcinogens and quantitating the human cancer risk of air pollution. One important uncertainty is the role of atmospheric transformation products in human cancer.
Human Biological Monitoring of Occupational Genotoxic Exposures
Authors: Knudsen Lisbeth E. , Sorsa Marja
Published: March 2009

Human biological monitoring is a valuable tool for exposure assessment in groups of persons occupationally exposed to genotoxic agents. If the monitoring activity covers genetic material the term genetic monitoring is used. The methods used for genetic monitoring are either substance specific, e.g. the quantitation of identified DNA‐adducts or substance unspecific as is the measurement of DNA‐repair. The sample material used for analysis must be well characterized and subject to uniform processing for comparison of the results. Confounding factors of smoking, age and sex must be well controlled for and the biomonitoring results should preferentially be linked with accurate ambient air monitoring. In persons occupationally exposed to styrene the endpoints of DNA‐damage and DNA‐repair in genetic monitoring are methods of choice in exposure situations above the current Danish (25 ppm) or Finnish (20 ppm) occupational exposure limit value of styrene in ambient air.

The consideration of ethical issues in human genetic monitoring is an important but often overlooked aspect. This includes the scientific and preventional relevance of performing a test on individuals, pre‐ and post study information of donors and confidentiality as well as ownership of the results.
Cancer Risk Related to Genetic Polymorphisms in Carcinogen Metabolism and DNA Repair
Authors: Poulsen Henrik E. , Loft Steffen , Wassermann Karsten
Published: March 2009

Abstract:Chemical carcinogenesis involves metabolism in the body of the carcinogen to the ultimate carcinogen and its interaction with DNA. There is considerable interindividual variation in the metabolic ability to activate as well as detoxify the carcinogens and in the ability to repair the carcinogen‐DNA adducts. In many cases such differences occur as genetic polymorphisms and form the basis for variation in susceptibility to carcinogens and thereby to cancer risk.

The activation mechanism is particularly related to the cytochromes P‐450 (CYPs), and four of these are known to activate carcinogens: CYP1A1, CYP1A2, CYP2E1, and CYP3A4. Increased cancer risk has been related to polymorphisms in the CYPs and other activating enzymes.

The DNA repair mechanisms show considerable complexity, and deficient repair mechanisms in certain human disorders are clearly related to increased cancer risk. Yet, there is no unambiguous epidemiological evidence available for cancer risk among individuals in general. In vivo methods have to be refined and developed for use in epidemiological studies.
The Relative Importance of Mutagens and Carcinogens in the Diet
Authors: Lutz Werner K. , Schlatter Josef
Published: March 2009

Known mutagens and carcinogens in the diet were compiled and the risk of cancer was estimated on the basis of average exposure levels in Switzerland and carcinogenic potencies from rodent bioassays. The analysis showed that, except for alcohol, the sum of all known dietary carcinogens could only explain a few percent of the cancer deaths attributed by epidemiologists to dietary factors. The discrepancy was explained by a “carcinogenicity” of excess macronutrients. This hypothesis was based on an evaluation of dietary restriction experiments in rats and mice, where a dramatic reducing effect on spontaneous tumour formation was seen. From these experiments, a "carcinogenic potency" was deduced for food in excess (TD50 approximately 16 g/kg per day). Overnutrition in Switzerland was converted into excess food intake and the cancer risk estimated on the basis of the TD50 value. The resulting risk of 60,000 cases per one million lives would allow to explain by overnutrition almost all "diet‐related" cancer deaths in humans.
Carcinogenicity and Drinking Water
Authors: Dayan Anthony D.
Published: March 2009

Abstract: Water is a powerful solvent that readily dissolves many natural and synthetic substances from the enviroment (e.g. inorganic salts, humic acids and pesticide residues). The processes of purification, disinfection and preparation and storage necessary to provide and distribute drinking water may introduce further chemicals, including some used for these purposes and others derived by interaction between them and the compounds of natural origin. The composition of drinking water, therefore, is complex and varies between sites and with the seasons. Modern technology is employed to minimise the amounts of many of these substances, but some may persist, including derivatives generated by halogenation and ozonation for disinfection.

Some of the substances are genotoxic in the laboratory and a few are proven experimental carcinogens ‐ all at much higher concentrations than those normally found in a drinking water supply.

Many ecological and epidemiological surveys have been done to compare the occurrence of various types of tumour in man with exposure to different types of drinking, but no consistent or reliable association has been found. There are serious and probably irremediable methodological weaknesses in these attempts, because of the difficulty of defining the nature of the waters consumed over a major part of life, and the variable composition of waters. The surveys do not permit even a realistic assessment of the upper confidence limit of the exclusion of the risk.

Thus, although there is some experimental indication of the possible presence of carcinogenic substances in most or all drinking waters, and of how they are formed, the concentrations are very low and there is no realistic evidence that they have caused harm to man. The problem is one of importance to all of us, but its very generality makes it almost impossible to explore. It is very important that the proven, vital benefits of water treatment far outweigh concern about this notional chemical risk.

‘… for blessed be water that giveth life…’

from an ancient Jewish prayer
On the Substitution for Carcinogens in the Working Environment
Authors: Goldschmidt Gitte , Olsen Erik , Svane Ole
Published: March 2009

The ultimate solution in prevention of occupational cancer risks would be to remove carcinogens from the working environment. Elimination of carcinogenic substances can be achieved by replacement of the carcinogen with non‐carcinogen(s) having the same functionality, or by using a different process that produces adequate results without the use of carcinogenic agents.

This paper presents selected methods and tools, which have been used for substitution purposes in practice. These are: 1. a strategy for substitution, 2. a tool for creating ideas on how to substitute, 3. a software package, SUBTEC, for solving some technical and industrial hygiene problems, and 4. a proposal for a strategy to deal with organizational and psychological barriers encountered when changes are to be introduced.
Some Ethical Considerations and the Status of Dietary Advice
Authors: Hill Michael
Published: March 2009

Dietary guide‐lines are currently given to whole populations whether the recipients have asked for it or not, and this raises ethical and practical problems. If we have not been asked for advice, what right do we have to tell people what they “ought” to eat? Are we sufficiently sure of the benefits of following our advice? Could we, in fact, be wrong about it? Are we sure of the absence of "side effects" of our advice? If not, are we sure that the balance between risk and benefit is favourable? Might our advice, in fact, do more harm than good? Would it not be better to restrict our advice to those at high risk of diet‐ related cancer? These issues are all discussed. Furthermore, the conclusions from the European Cancer Prevention (ECP) symposium and workshop on public education on diet and cancer are presented.

The major conclusion is that the concept of general guide‐lines should be abandoned in favour of guide‐lines targeted to specific groups. In addition, it is concluded that the recent evidence had led to considerable confusion regarding dietary fibre and cancer, and also regarding dietary fat and cancer. The recent evidence strengthens the association between high intake of fresh fruit and vegetables and low risk of cancers at a number of sites.
Metabolism and Elimination of Inhaled Drugs and Airborne Chemicals from the Lungs
Authors: Bond James A.
Published: March 2009

Inhalation is a common route by which people are exposed to many toxic chemicals. Inhaled chemicals can deposit in various regions of the respiratory tract. The factors that determine deposition site include chemical reactivity and water solubility for gases and vapors, and shape, physical size, and density for particles. Metabolic activation of chemicals by respiratory tract tissues may play an important role in both the pathogenesis of diseases in these tissues or in modifying the effective dose to tissues distal to the respiratory tract. This paper is a review of the state‐of‐the‐knowledge regarding the regional distribution of xenobiotic metabolizing enzymes in the conducting airways and pulmonary tissue of several animal species, including humans. All segments of the respiratory tract, including the periphery of the pulmonary compartment, contain enzymes (Phase I and II) that metabolize xenobiotic compounds. In general, the data indicate that the pulmonary tissue has a higher metabolic activity toward inhaled chemicals than other regions of the respiratory tract, such as the trachea and bronchi. However, even within an anatomical region of the respiratory tract, there is a non‐uniform distribution of enzymes within the individual cell types. Significant species differences exist in metabolic activity toward a number of substrates. However, some generalities can be made. Firstly, the ratio of activating/inactivating enzyme activities in all species is, in general, less than 1. A second point is that this ratio is considerably higher in rodent animal species than humans. This indicates that caution needs to be exercised when extrapolating metabolic data derived from rodents to human metabolic capability.
BRL 38227 ‐ a Potassium Channel Opener, Antagonizes Digoxin‐Induced Convulsions
Authors: Chugh Yati , Saha N. , Sankaranarayanan A. , Sharma P. L.
Published: March 2009

Experimental evidence suggests that potassium channel openers play an important role in convulsions. In this study, the anticonvulsant activity of BRL 38227, a new potassium channel opener against digoxin‐induced convulsions, is reported. Intraventricular administration of digoxin (7.5 μg), induced “popcorn‐type” convulsions in ráts. BRL 38227, injected centrally increased the onset time of convulsions and decreased the mortality rate in a dose‐dependent manner. Pretreatment with 4‐aminopyridine, a potassium channel blocker antagonized the protective effect of BRL 38227. These findings show the involvement of potassium channels in digoxin‐induced convulsions. Further these results indicate that in the future potassium channels might be a target for new anticonvulsant drugs.
Active Transport of Benzylpenicillin Across the Blood‐Milk Barrier
Authors: Schadewinkel‐Scherkl Angelika‐Maria , Rasmussen Folke , Merck Carl‐Christian , Nielsen Poul , Frey Hans‐Hasso
Published: March 2009

Passage of benzylpenicillin across the mammary gland epithelium was studied both after systemic administration of benzylpenicillin in four goats and after intramammary infusion in three goats and two cows. The results after benzylpenicillin administration alone were compared with the results after combined administration of benzylpenicillin and probenecid. The studies on passage of benzylpenicillin through the blood‐milk barrier showed, when milk to plasma ultrafiltrate ratios of benzylpenicillin were plotted versus time for each half of the udders, that active transport takes place from blood to milk during steady‐state plasma concentrations. Active transport was demonstrated by inhibition with probenecid: (1) The entry of benzylpenicillin into milk was slowed down under the influence of probenecid. The AUC (area under the curve)‐values during the first 30 min. were reduced by 66±9% compared with the AUC‐values found without coadministration of probenecid. (2) In the presence of probenecid and during equilibrium between blood and milk concentrations, benzylpenicillin reached concentration ratios in the ultrafiltrates of milk and plasma which corresponded to those expected for diffusion alone. Without probenecid these ultrafiltrate concentration ratios were more than two times higher indicating an active transport of benzylpenicillin from blood to milk. After intramammary infusion of benzylpenicillin, active transport was demonstrated from milk into blood. The absorption rate for benzylpenicillin from the mammary gland was reduced by probenecid, as measured by the ratio of benzylpenicillin to urea absorption half‐life, which was increased by 40‐50% in the presence of probenecid.
15‐Deoxyspergualin Prolongs Pancreatic Islet Allo‐ and Xenograft Survival in Mice
Authors: Sandberg J.‐O. , Korsgren O. , Groth C.‐G. , Andersson A.
Published: March 2009

The new immunosuppressant 15‐deoxyspergualin was evaluated in allogeneic and xenogeneic pancreatic islet transplantation. In the allograft study 500 collagenase‐isolated C57BL/6 mouse islets were transplanted under the renal capsule of alloxan‐diabetic C57BL/Ks mice that were either 15‐deoxyspergualin‐treated (n = 15) or given saline only (n = 8). When 15‐deoxyspergualin was given (5 mg/kg b.wt. intraperitoneally) until day 28 after transplantation in a special dosage schedule, 10 out of 15 animals were normoglycaemic one week after transplantation and 6 were still normoglycaemic after ten weeks. All 8 control animals were hyperglycaemic after 18 days. Light microscopy showed graft rejection in hyperglycaemic mice, but only mild infiltration of lymphocytes in the grafts of normoglycaemic animals. In the xenograft study C57BL/Ks mice were transplanted under the renal capsule with 500‐750 foetal porcine islet‐like cell clusters. The grafts were examined for evidence of rejection with light microscopy at different time points after implantation. In the control animals given saline only (n = 37) there was progressive evidence of rejection starting on day seven. In 15‐deoxyspergualin treated animals (2.5 mg/kg intraperitoneally; n = 27) there was significantly less infiltration at days 7, 14 and 21. After 32 days there was, however, no difference between controls and 15‐deoxyspergualin treated mice. A doubling of the 15‐deoxyspergualin dose (5.0 mg/kg intraperitoneally; n = 5) did not further improve the survival of the xenografted islet‐like cell clusters. There was no synergistic effect when cyclosporine A (12.5 mg/kg intraperitoneally) was added to the 15‐deoxyspergualin therapy (n = 34). Cyclosporine A in itself was inefficient (n = 5) in protecting the xenograft from rejection. Thus, 15‐deoxyspergualin treatment induced marked prolongation of graft survival in an allogeneic adult islet transplant model (mouse to mouse) and delayed rejection in a foetal xenogeneic (pig to mouse) islet transplant model.
Ethylmorphine Metabolism in Isolated Rat Hepatocytes
Authors: Xu Bang Qian , Bjørneboe Anders , Ripel Åse , Aasmundstad Tor A. , Christophersen Asbjørg S. , Mørland Jørg
Published: March 2009

The metabolism of ethylmorphine has been studied in suspensions of isolated rat hepatocytes. Early during incubation, the two major metabolic intermediates detected were morphine and norethylmorphine following N‐ and O‐dealkylation of ethylmorphine, respectively. During subsequent incubation the concentration of the second metabolic intermediate, normorphine increased, before the concentration peaked at approximately 20 μM (100 μM ethylmorphine). Both morphine and normorphine were glucuronidated to form morphine‐3‐glucuronide and normorphine‐3‐glucuronide, respectively, which appeared to be the major metabolic end products. The percentage of ethylmorphine metabolized to morphine‐3‐glucuronide was found to be dependent on the initial concentration of ethylmorphine. With increasing initial ethylmorphine concentration the relative formation of morphine‐3‐glucuronide was reduced (29±10% at 5 μM, 18 ± 5% at 20 μM, and 15 ± 4% at 100 μM mean ± S.D., n=10). The concentrations of ethylmorphine and its metabolites were found to be higher in liver cells than in medium. Thus the ratios between the intra‐/extra‐cellular concentrations of ethylmorphine increased somewhat from an initial value of 4 during the period for which ethylmorphine could be detected intracellularly. The drug metabolites all exhibited ratios above 10 for the initial 100 min. of incubation. With time these ratios showed a decline, but even for prolonged incubation the ratios were 5 or higher for the end products. Thus considerable drug concentration gradients existed across the cell membrane of isolated rat hepatocytes.
Comparative Acute Lethality of 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD), 1,2,3,7,8‐Pentachlorodibenzo‐p‐dioxin and 1,2,3,4,7,8‐Hexachlorodibenzo‐p‐dioxin in the Most TCDD‐Susceptible and the Most TCDD‐Resistant Rat Strain
Authors: Pohjanvirta Raimo , Unkila Mikko , Tuomisto Jouko
Published: March 2009

We have previously demonstrated a more than 300‐fold difference in acute LD50 values for 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) between male Long‐Evans (Turku AB; L‐E) and Han/Wistar (Kuopio; H/W) rats after intraperitoneal exposure. In the present study, we compared the acute lethality of TCDD, 1,2,3,7,8‐pentachlorodibenzo‐p‐dioxin (PCDD) and 1,2,3,4,7,8‐hexachlorodibenzo‐p‐dioxin (HCDD) in these strains by intragastric administration. In agreement with previous data, H/W rats proved to be strikingly resistant to TCDD, since even the highest dose tested, 7200 μg/kg, was below the LD50 level for both genders. The corresponding LD50 values for female and male L‐E rats were 9.8 and 17.7 μg/kg, respectively. A similar strain difference was discovered for PCDD: the LD50 value was > 1620 μg/kg for female H/W rats and between 20 and 60 μg/kg for female L‐E rats. Surprisingly, the acute lethality of HCDD did not follow the same pattern. Female H/W rats turned out to be only about 10 times less susceptible to that congener than female L‐E rats (LD50 values 1871 and between 120 and 360 μg/kg, respectively). These findings do not support the widely accepted concept that sufficiently high doses of all dioxin congeners will produce the same effects. Either the higher chlorinated dioxins have toxic effects distinct from those of TCDD or the relative contribution of toxic impacts varies among these compounds.
The Role of Glutathione and Protein Thiols in CBrCl3‐Induced Cytotoxicity in Isolated Rat Hepatocytes
Authors: Jochmann C. , Klee S. , Ungemach F. R. , Younes M.
Published: March 2009

Abstract:The role of glutathione (GSH) and protein thiols in the pathobiochemical process of CBrCl3cytotoxicity was investigated in isolated hepatocytes. Administration of 0.5, 1.0 and 1.5 mmol/1 CBrCl3affected cellular viability as assessed by trypan blue exclusion, release of lactate dehydrogenase and loss of intracellular potassium in a dose‐dependent manner. Intracellular glutathione and the capacity to reduce 3‐(4,5‐dimethylthiazolyl‐2‐)‐2,5‐diphenyltetrazolium bromide (MTT, thiazolyl blue) decreased almost independently of the CBrCl3concentration. Protein thiols were not markedly oxidized in the presence of CBrCl3. However, compromising cellular defence mechanisms by either inhibition of glutathione regeneration or depletion of glutathione enhanced the cytotoxicity of CBrCl3and induced a loss of protein thiols in the late phase of cellular injury. Under these conditions the thiol‐dependent Na+, K+ATPase revealed high sensitivity towards CBrCl3. Thus, glutathione proved to exert effective cytoprotection, and sulfhydryl groups of particular proteins were supposed to be an important target of radical attack.