bluuebunny/crossref_metadata_2025 huggingface dataset:
Complexation of intracellular cyanide by hydroxocobalamin using a human cellular model
Authors: Astier Alain , Baud Frederic J
Published: December 2008

1 The rational for administering hydroxocobalamin (OHCbl) as an antidote to cyanide poisoning is based on the high affinity ofCN ion for cobalt compounds. However, only few data are available on the influence of OHCbl on the intracellular cyanide pool.

2 In human fibroblasts incubated for 10 min with 500 μM of [14C] cyanide, the accumulation ratio was 25 at 37°C (10.45 ± 1.51 mM) and 11.9 at 4°C.

3 Using the monoblastic U-937 cell line, a rapid uptake of radioactive cyanide was observed with a maximum accumulation ratio of 1.97 at 5 min.

4 A linear relationship between cyanide uptake by U-937 cells and cyanide concentration in incubation medium (10-500 μM; 5 min) was found suggesting a first order process (k= 0.25 min-1).

5 After incubation of fibroblasts with 500 μM of OHCbl, a 75% decrease of intracellular cyanide was observed, with concomittant formation of intracellular cyanocobalamin CNCbl (intracellular/extracellular ratio: 158).

6 These findings suggest that OHCbl is able to penetrate into heavily cyanide loaded cells and to complex cyanide to the non-toxic CNCbl form.
Immunohistochemical properties of dipyrone-induced cytochromes P450 in rats
Authors: Kraul H. , Pasanen M. , Sigusch H. , Stenbäck F. , Park S-S. , Gelboin HV , Pelkonen O.
Published: December 2008

1 Rat hepatic cytochrome P450s induced by dipyrone were studied enzymatically, immunochemically and immunohistochemically.

2 Dipyrone administered to male Wistar rats increased pentoxyresorufin O-depentylation (PROD), ethoxyresor ufin O-deethylation (EROD) and 7-ethoxycoumarin O- deethylation (ECOD) activities up to 44-, 1.9-, and 2.6-fold, respectively. Aryl hydrocarbon hydroxylase (AHH) activ ity was not affected.

3 Immunoinhibition with the monoclonal antibody (Mab) 2-66-3 (to CYP2B1/2) markedly decreased PROD and EROD activities, but not AHH activity. The Mab 1-7-1 (to CYP1A1/2) was without effect.

4 Histochemically, the Mab 2-66-3 gave a strong and uniform staining in livers from dipyrone-treated rats, whereas the Mab 1-7-1 gave a positive reaction in a narrow perivenous strip.

5 The induction pattern as well as inhibition by the Mabs convincingly demonstrate the predominant production of CYP2B1/2 in the induction spectrum of dipyrone. The increase in enzyme activities other than PROD may be due to the overlapping substrate specificity of CYP2B1/2 enzymes. The immunohistochemical analysis also indi cated the participation of CYP1A1/2.
Effect of short-term dietary administration of eugenol in humans
Authors: Rompelberg Cjm , Vogels Jtwe , de Vogel N. , Bruijntjes-Rozier Gcdm , Stenhuis WH , Bogaards Jjp , Verhagen H.
Published: December 2008

1 In order to study the antigenotoxic potential of eugenol in humans, ten healthy non-smoking males ingested a daily amount of 150 mg eugenol or the placebo for seven consecutive days. After a washout period of one week, groups ingesting eugenol or the placebo were crossed and received the other treatment for seven consecutive days.

2 On days 8 and 22 blood samples were taken for the assessment of standard clinical biochemical parameters. To study the possible antigenotoxic effect of eugenol, on day 8 and 22 blood samples were collected and exposed in vitro to the established genotoxic agents mitomycin C and vinblastine. After exposure the percentage of cells with chromosome aberrations and micronuclei was deter mined in cultured white blood cells. On days 8 and 22 paracetamol (500 mg p.o.) was administered as test substance to measure phase-II biotransformation capa city. Glutathione-S-transferase (GST) activities were determined in erythrocytes and blood plasma.

3 No significant differences in the clinical biochemical parameters were detected between the eugenol-period and the placebo-period, indicating that daily administration of 150 mg eugenol for 7 days has no toxic affects.

4 No significant differences on the cytogenetic para meters were found after ingestion of eugenol. Thus, there are no indications for an antigenotoxic potential of eugenol in humans, consuming daily 150 mg eugenol for 7 days.

5 A significant reduction in α-class GSTs in plasma (P<0.05), but not in the other measured biotransformation parameters, was found in volunteers during the eugenol- period as compared to the placebo-period. This may either reflect GST-inhibition by eugenol or protection against background damage of liver cells by eugenol.
Alternatives to the 2-species bioassay for the identification of potential human carcinogens
Authors: Ashby J.
Published: December 2008

It is proposed that the standard 2-species rodent cancer bioassay protocol, as perfected by the US National Toxicology Program (NTP), has already fulfilled its most useful role by providing an unequalled carcinogenicity database by which to re-assess the type of carcinogen worthy of definition. Continued use of this resource and time consuming protocol can no longer be justified, except in rare circumstances of high and protracted human exposure to a chemical of unknown carcinogenicity. In those rare instances an enlarged bioassay of three or four test species should perhaps be considered, there being nothing fundamental about the rat/mouse combination. In the large majority of cases, however, a practical estimation of the carcinogenic potential of a chemical can be formed in the absence of lifetime carcinogenicity bioassay data. This can be achieved by its sequential study, starting with an appreciation of its chemical structure and anticipated reactivity and mammalian metabolism. After the short- term evaluation of a range of additional properties of the agent, including its genetic toxicity, rodent toxicity and tissue-specific toxicity, confident predictions of the genotoxic and/or non-genotoxic carcinogenic potential of the agent can be made. In most situations these predictions will be suitable for framing hazard reduction measures among exposed humans. In some situations it may be necessary to evaluate these predicted activities using limited bioassays, a range of which are considered. Extensions of these limited carcinogenicity bioassays to a standard 2-year/2-species bioassay can only be supported in cases where the non-carcinogenicity of the agent becomes the important thing to define.

The US NTP have evaluated the carcinogenicity of ∼400 chemicals over the past 20 years, at a cost of hundreds of millions of US dollars. The experience gained by that and related initiatives, worldwide, can now be harnessed to classify thousands of priority chemicals as being either probable carcinogens or probable non- carcinogens. That can now be achieved using a fraction of the earlier resources and in a fraction of the time that would be required for the conduct of 2-species bioassays.

The comfort factor for one group of people of the order of the present system, coupled to the comfort factor for another group of the delay in carcinogenicity assessment enforced by the present council of perfection, are the two main factors delaying transfer to a streamlined system for assessing the carcinogenic potential of chemicals to humans. A third delaying factor in the need for new and focused test data. Coordinated acquisition of such data could rapidly remove the first two obstacles.
Comparison of toxicity induced by HT-2 toxin on human and rat granulo-monocytic progenitors with an in vitro model
Authors: Lautraite S. , Parent-Massin D. , Rio B. , Hoellinger H.
Published: December 2008

HT-2 toxin is a trichothecene mycotoxin occuring naturally in various agricultural products. Many in vitro studies have shown that HT-2 toxin is a major metabolite of the parent compound T-2 toxin. In man as well as in animals both toxins have been shown to cause alimentary intoxications and haematological disorders. Granulo- monocytic progenitors (CFU-GM) from human umbilical cord blood and from rat bone marrow were cultured in the presence of HT-2 toxin (10-7 M to 10-10 M) for 14 days. The concentration-effect relationship was studied and the IC 50 were determined on Days 7, 10 and 14. The IC50 was 1.8 × 10-9 M, 3.5 × 10-9 M and 1.8 × 10-9 M for hu man cells, and 2 × 10 -9 M, 2.3 × 10-9 M and 2.2 × 10-9 M for rat cells. The results have been compared with previous findings for T-2 toxin. Although T-2 and HT-2 toxins had a similar IC50 on human and rat CFU-GM, the expression of their cytotoxicities was different. These findings are relevant to investigation of the cellular targets of T-2 and HT-2 in elucidating the mechanism of trichothecene haematotoxicity.
Triphenyltin acetate toxicity : a biochemical and ultrastructural study on mouse thymocytes
Authors: Bollo E. , Ceppa L. , Cornaglia E. , Nebbia C. , Biolatti B. , Dacasto M.
Published: December 2008

1 Triphenyltin acetate (TPTA) has been shown to exert in vivo a selective toxic effect on the immune system. To assess in vitro possible alterations induced by TPTA exposure, primary cultures of mouse thymocytes were incubated up to 24 h with graded amounts (1-12 μM) ofthe organotin.

2 The cytotoxic activity has been evaluated with the MTT colorimetric assay, the neutral red (NR) assay and the lactic dehydrogenase (LDH) cellular release. Cell pellets were fixed with 2.5% glutaraldehyde, resin-embedded and ultrathin sections were observed through transmission electron microscopy.

3 After 2 h of incubation, dose-dependent increases of cytotoxicity were observed in thymocytes submitted to MTT and NR tests (up to 41.43% and 18.9%, respectively), while 22 h later this overt effect on cell viability was noticed merely in cells exposed to 12 μM TPTA. Dose- dependent increases of LDH leakage in the culture medium were observed all throughout the study.

4 Morphological investigations revealed features (chro matin condensation, cell membranes fragmentation and formation of membrane bound apoptotic bodies) sugges tive of apoptosis.

5 This study indicates that TPTA is cytotoxic to mouse thymocytes: morphologically, the rising of apoptosis is likely to be recognized, as previously reported in different in vitro studies with other immunosuppressive agents as dioxin and corticosteroids.
Plant poisonings in children
Authors: Lamminpää Anne , Kinos Marja
Published: December 2008

1 Plant poisonings comprise 5% of all hospitalizations due to poisonings in children and plant inquiries to Poison Information Centre consist about 28% of calls concerning children.

2 A search of 71 cases of hospitalization due to plants in a 5 year period obtained from two children's hospitals in Helsinki were reviewed and 105 plant inquiries concern ing poisonings among children to the Poison Information Centre in a 6 month period were studied.

3 The most frequent plant poisonings involved lily-of the-valley, dumb cane and cotoneaster plant. Only 11% of the cases treated in hospital were evaluated to be unequivocal poisonings.

4 Mezereon, snowberry, cotoneaster plant, honeysuckle, and woody nightshade caused the most serious symptoms. Symptoms in mezereon poisoning were increased saliva excretion, haematuria and diarrhoea in a 1.2-year-old girl. Snowberries caused a semicomatose state and difficulty in urination, cotoneaster caused severe stomach ache, honeysuckle abudant gastrointestinal symptoms and muscle cramps, and nightshade led to prolonged high fever and sweating.

5 It appears that almost all plant poisonings could be treated with medical charcoal. Gastric evacuation is seldom required.
Elevated amylase is related to the development of respiratory failure in organophosphate poisoning
Authors: Matsumiya N. , Tanaka M. , Iwai M. , Kondo T. , Takahashi S. , Sato S.
Published: December 2008

1 A retrospective study of organophosphate(OP) poison ing in the intensive care unit was performed to analyze the incidence of respiratory failure.

2 The patients were treated initially with gastrointest inal decontamination including gastric lavage and the administration of activated charcoal with cathartic. Further management included intravenous pralidoxim and atropine and ventilatory support.

3 Of the 32 OP poisoning patients, 16 patients developed respiratory failure and received ventilatory support. 4 An increase in plasma amylase above the normal range on the day of admission was related to the development of respiratory failure.

5 In OP poisoning, the elevation of amylase level was predictive of the subsequent respiratory failure.
Survival after paraquat poisoning in a HIV positive patient
Authors: Ragoucy-Sengler C. , Pileire B.
Published: December 2008

From 1987 to 1994, 31 cases of acute paraquat poisoning were managed in the CHRU of Pointe à Pitre (FWI). Eighteen patients died, 13 survived. Biological indexes accurately predicted patient's outcome in all cases out of one. In the last case biological parameters were mislead ing : the corresponding patient survived despite consistent clinical and biological prognosis of death. The unexpected survivor was West Indian, male, agricultural worker of 26 years who alleged drunk about 300 ml of gramoxone (20% v/v paraquat) in a suicide attempt. The patient was HIV infected (Elisa+, Western-Blot+) and presented an AIDS syndrome (CD4 count inferior to 200 cells/mm3) estab lished since 10 months and treated by AZT. We could not identify any other distinguishing features among the unexpected survivor and the rest of the patients. This observation suggests that the immunological status of the patient could explain this protection from paraquat toxicity
Potentiation of occupational carbon tetrachloride toxicity by ethanol abuse
Authors: Manno M. , Rezzadore M. , Grossi M. , Sbrana C.
Published: December 2008

1 Two separate cases of acute occupational poisoning following exposure to vapours of a fire extinguishing liquid are described. Analytical, clinical, pathological and toxicological data leave little doubt that toxicity was due, in both cases, to inhalation of carbon tetrachloride present at high concentrations (>15% and 78% by weight, respectively) in the fire extinguishing liquid.

2 Both subjects were admitted to hospital, 4 and 8 days after exposure, respectively, and developed severe hepato-nephrotoxicity with hepatomegaly, increased va lues of serum transaminases, blood urea nitrogen (BUN), creatinine, γ-glutamyl-transpeptidase (γ-GT), bilirubin and uric acid and, finally, anuria. They recovered in about three to four weeks, after several haemodialytic sessions.

3 Interestingly, in both cases the other workers exposed under the same conditions and for the same period of time as the two patients showed no signs or symptoms of toxicity. The reason for the observed different suscept ibility to CCl4 is attributable to an abnormally high ethanol abuse by the two workers, as reported in the clinical records and confirmed by their relatives and collegues (120 and 250 g per day, respectively). Daily ethanol intake by the coworkers was less than 50 g for all subjects.

4 Although the potentiating effect of ethanol on the toxicity of CCl4 is well known in experimental animals, as a result of cytochrome P-450 induction, direct evidence in humans reported in the literature so far was limited by the lack of information, in all published reports, on the presence or absence of effects in non-alcoholic exposed 'controls', when these were present.
Increased sister chromatid exchange (SCE) frequencies in lymphocytes from traffic policemen exposed to automobile exhaust pollution
Authors: Chandrasekaran R. , Samy Plp , Murthy Pbk
Published: December 2008

Sister chromatid exchange (SCE) frequencies were deter mined in peripheral lymphocytes from traffic policemen drawn from various busy traffic points of Madras metro in India. These policemen were under constant exposure to automobile exhaust pollution during their 8 h work schedule. Analysis of SCE frequencies revealed a sig nificantly greater number of SCE/cell in these policemen as against the matched control population. Sixty percent of these subjects who remained in the service after 5 years showed insignificant but higher values of SCE than in the initial analysis.
Morphological alterations in the hippocampus following hypobaric hypoxia
Authors: Shukitt-Hale B. , Kadar T. , Marlowe BE , Stillman MJ , Galli RL , Levy A. , Devine JA , Lieberman HR
Published: December 2008

1 The morphological consequences of hypobaric hypox ia, exposure to reduced pressure atmospheres, were examined in the hippocampus of male Fischer 344 rats. Severe chronic hypoxia can produce permanent neuronal damage with hippocampal structures being especially vulnerable.

2 Hippocampal morphology was studied using histolo gical observations after a 4 day exposure to sea level, 5500 m, or 6400 m. Two groups tested at 6400 m were sacrificed at different intervals following exposure, 72 and 144 h, to examine the effect of post-exposure time on neuronal damage.

3 Histological damage was observed in rats' brains following exposure to altitude, with cell degeneration and death increasing as altitude increased. In addition, it was found that the longer the time following exposure before sacrifice, the more noticeable the damage, suggest ing delayed neurotoxicity. Increases in the number of damaged cells following altitude were significant for the CA3 region of one 6400 m group; however, other differ ences did not reach statistical significance. Rats exposed to altitude for 4 days ate less and lost significantly more weight than did animals at sea level.

4 It appears that 4 days of exposure to altitudes less than or equal to 6400 m does produce changes in the CA3 subfield, but the damage is different than that seen with other models of non-transient ischemia.
Nitric oxide contributes to desipramine- induced hypotension in rats
Authors: Pentel PR , Wananukul W. , Scarlett W. , Keylerl DE
Published: December 2008

1 Anesthetized rats received the TCA desipramine (DMI) 60 mg kg-1i.p. Administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester-(L-NAME) 15 min after DMI reversed hypotension within 5 min (P < 0.05). In contrast to its beneficial effect on blood pressure, L-NAME worsened DMI-induced prolongation of the electrocardiographic QRS interval. Dexamethasone, an inhibitor of NOS induction, did not prevent DMI-induced hypotension.

2 To study the effect of L-NAME on survival, DMI was administered to anesthetized rats as a continuous i.v. infusion until death. Despite initially improving blood pressure, L-NAME decreased the mean survival time by 33% (P < 0.01) compared to control treatment. Adminis tration of the nitric oxide (NO) donor nitroglycerine to rats during DMI infusion likewise decreased the mean survival time.

3 L-NAME partially reversed the hypotensive effect of nitroprusside in both anesthetized and awake rats.

4 These data suggest that NO production attributable to constitutive NOS ( cNOS) activity aggravates the hypoten sion associated with DMI toxicity in the anesthetized rat, and contributes to the pathophysiology of this overdose. The shortened survival time produced by both increasing and decreasing NO production suggests that cNOS activity during DMI overdose is regulated and adaptive. Ongoing cNOS activity also contributed to nitroprusside-induced hypotension, and may represent a feature common to other drug-induced hypotensive states.
Perspective on the carcinogenic potential of phenytoin based on rodent tumor bioassays and human epidemiological data
Authors: Dethloff Lloyd A , Graziano Michael J , Goldenthal Edwin , Gough Alexander , de la Iglesia Felix A
Published: December 2008

1 Phenytoin is a hydantoin-type anticonvulsive agent used extensively for nearly sixty years in the prophylactic treatment of grand mal and psychomotor seizures.

2 Based upon somewhat contentious evidence of pheny toin-induced lymphoma in mice and upon epidemiologic evidence of an association between anticonvulsive ther apy and lymphoma in epilepsy patients, the International Agency for Research on Cancer (IARC) has collectively regarded these data as limited evidence of carcinogeni city.

3 Two year carcinogenicity studies of standard bioassay design conducted in mice and rats yielded statistically significant increased incidence of hepatocellular adeno mas in mice at phenytoin plasma concentrations approx imating the therapeutic anticonvulsive range. Tumor incidence in rats was not affected. Previous carcinogeni city studies have found similar increases in hepatic tumor incidence in mice.

4 Phenytoin is a known enzyme inducer and shows tumor promoting activity in chemically initiated mouse liver. Evidence for genotoxicity is weak or equivocal, consequently phenytoin-induced liver tumors appear to occur through nongenotoxic mechanisms.

5 Finally, despite six decades of extensive therapeutic use and thorough epidemiologic evaluation, there is no evidence for an association between liver cancer and phenytoin therapy in epilepsy patients. Thus, hepatocel lular neoplasia in phenytoin-treated rodents appears to be of little significance to man.
Evolution of lead toxicity in a population of children
Authors: Calderón-Salinas JV , Hernandez-Luna C. , Valdez-Anaya B. , Maldonado-Vega M. , Lopez-Miranda A.
Published: December 2008

A 3 years study was conducted to determine the evolution of blood lead concentrations (PbB) and free erythrocyte protoporphyrins (FEP) as indicators of absorption and biochemical damage in children (7-12 years old) living within one kilometer of a metallurgic factory that processes lead in Torreón, Coahuila, México. In addition, neuromuscular conduction velocity, motor coordination and IQ where determined as indicators of physiological damage. During this period of time the children showed increased lead blood concentrations of 19.2 ± 4.5 μg dl -1 at the beginning of the study to 27.5±4.9 μg dl -1 at the end. Likewise, FEP increased from 56.6±20.0 μg dl-1 to 92.9 ± 28.9 μg dl-1. Physiological damage was evident since motor coefficients as well as IQ tests were reduced significantly when compared to children (7 -12 years old) living 4.5 km away from the factory who showed PbB=8.9 ± 1.3 μg dl-1 and FEP=16.9 ± 4.7 μg dl-1 throughout the study. Based on these data it was possible to define three different groups with regards to lead toxicity sensitivity.
Experimental study of the detrimental effect of dopamine/glucagon combination in d,l- propranolol intoxication
Authors: Toet AE , Wemer J. , Vleeming W. , te Biesebeek JD , Meulenbelt J. , de Wildt DJ
Published: December 2008

1 Respiratory and cardiovascular failure are the princi ple toxic effects of β-blocker overdose. Respiratory arrest is the primary cause of death in β-blocker intoxicated rats.

2 The effect of glucagon, dopamine and the combination of glucagon/dopamine on respiratory and cardiovas cular function and survival time in β-blocker overdose was investigated in a model of acute d, l-propranolol (resp. 30 and 15 mg kg-1h-1in rat and rabbit) intoxication in spontaneously breathing rats and artifically ventilated rats and rabbits.

3 Glucagon (initial dose of 100 μg kg-1(bolus), followed by 1 μg kg-1min-1), dopamine (25 μg kg-1min-1) or the combination of glucagon/dopamine did not im prove survival time (ST) in d, l-propranolol intoxicated spontaneously breathing rats and artificially venti lated rats and rabbits, although some haemodynamic variables i.e. heart rate (HR), mean arterial blood pressure (MAP), left ventricular pressure (LVPmax) and the differentiated left ventricular pressure (LVdp/ dtmax) temporarily improved.

4 Survival time was considerably reduced in d,l- propranolol intoxicated spontaneously breathing and artifically ventilated rats treated with a combination of glucagon /dopamine, which induced a decrease in PaO2and pH and an increase in PaCO2partly due to ventilation/perfusion mismatch.

5 The combination of glucagon/dopamine should be used carefully in the treatment of β-blocker overdose in man.
CYP enzymes catalyze the formation of a terminal olefin from 2-ethylhexanoic acid in rat and human liver
Authors: Pennanen S. , Kojo A. , Pasanen M. , Liesivuori J. , Juvonen RO , Komulainen H.
Published: December 2008

1 The metabolism of 2-ethylhexanoic acid (2-EHA) was studied in rat, mouse and human liver microsomes in vitro. The metabolites of 2-EHA were identified as methylated derivatives by gas chromatography-mass spectrometry.

2 2-Ethyl-1,6-hexanedioic acid was the main metabolite produced in rat, mouse and human liver microsomes. Unsaturated 2-ethyl-5-hexenoic acid, a terminal ole fin, was produced only in human liver microsomes and phenobarbital-induced rat liver microsomes. The cytochrome P450 (CYP) inhibitors metyrapone, SKF 525A, triacetyloleandomycin (TAO), quinidine and the cytochrome P450 reductase antibody abolished its formation both in rat and human microsomes.

3 The metabolites were analyzed also in vivo in urine of 2-EHA-exposed rats and in urine of sawmill workers exposed occupationally to 2-EHA. Both rat and human urine contained 2-ethyl-1,6-hexanedioic acid as the main metabolite and also 2-ethyl-5-hexenoic acid. Metyrapone, SKF 525A and TAO all decreased drastically the formation of 2-ethyl-5-hexenoic acid in the rat.

4 The data indicate that (1) several CYP families (CYP2A, CYP2B, CYP2D and CYP3A) could be responsible for the hepatic metabolism of 2-EHA, (2) the same metabolites were formed in rats and man and (3) an unsaturated terminal olefin, 2-ethyl-5-hexenoic acid is formed in the liver.
Correlation of hematologic markers of inflammation and lung function: a comparison of asymptomatic smokers and nonsmokers
Authors: McKarns Susan C , Smith Carr J , Morton Michael J , Payne Victoria M , Davis D Layten , Stringer Llewellyn W , Doolittle David J
Published: December 2008

Increased inflammation of the peripheral airways has been implicated as a cause of pulmonary function impairment. However, little information is available on the correlation between subclinical decrements of pul monary function and inflammation in asymptomatic individuals. A relationship between markers of inflam mation and lung function may be useful in predicting the early onset of lung function impairment. The purpose of this study was to investigate the correlation of hematolo gic markers of inflammation and spirometry in asympto matic smokers and nonsmokers. The specific objectives of this study were twofold. The first objective was to quantify and compare the spirometric measures of lung function in smokers and nonsmokers having similar demographic and lifestyle characteristics. The second objective was to define the correlation between these spirometric measure ments and hematologic markers of inflammation (white blood cells, monocytes, basophils, PGE1, IgG, and IgE). Systemic blood samples and spirometric measurements were obtained from 61 age-matched (33 ± 9 years) healthy, asymptomatic smokers and nonsmokers, with similar self- reported lifestyles (i.e., food, alcohol, vitamin consump tion and exercise). Both male and female smokers self- reported a higher coffee consumption (P < 0.05) compared to nonsmokers. Male smokers self-reported a trend toward current blue-collar versus white-collar occupation when compared with the nonsmokers. Body weight (77.6± 16.6 kg) did not differ between the smokers and non smokers. The male nonsmokers were taller than the male smokers (P < 0.05). All subjects were asymptomatic and had clinically normal spirometry. Compared to male nonsmokers, the male smokers had lower FEF25-75% and FEF75-85% values (P<0.05). No additional spirometric measurements, including FEV1/FVC, FEV1 and FVC were significantly different. The female smokers did not differ from the female nonsmokers (P<0.05) in any of the spirometric endpoints measured. Thirteen statistically significant (P < 0.05) correlations involving inflammatory (white blood cells, monocytes, basophils, and PGE1) or immunologic endpoints (IgE) and spirometric measure ments were observed in female smokers, female non smokers and male nonsmokers. No statistically significant correlations involving immunologic or inflammatory endpoints were observed in the male smokers. A better mechanistic understanding of the observed relationship between elevated hematologic inflammatory endpoints and reduced lung function may provide valuable insight into the clinical significance of these correlations.
Formation of DNA-adducts by selected sex steroids in rat liver
Authors: Feser W. , Blode RS Kerdar H , Reimann R.
Published: December 2008

1 We are reporting investigations into the potential of the steroid hormones chlormadinone acetate (CMA), cyproterone acetate (CPA), ethinylestradiol (EE2) gestodene (GEST), megestrol acetate (MGA), norethis terone acetate (NET-Ac), estradiol (E2), and progester one (P) to form DNA-adducts in rat liver in vivo.

2 Compound-related DNA-adduct spots were detected in male and female rat liver following CMA, CPA, and MGA using the32P-postlabeling-technique. Substance- specific DNA-adducts were also observed in male rats after administration of E2. The other compounds showed no DNA-adduct formation. After treatment with CMA, CPA or MGA, the relative adduct labeling (RAL) differed sex- and substance-specifically.
Changes in sexual behavior of adult male and female rats neonatally treated with vitamin D3
Authors: Mirzahosseini S. , Karabélyos Cs , Dobozy O. , Csaba G.
Published: December 2008

1 Neonatal treatment of rats with vitamin D3 resulted in a change of sexual behavior in adulthood.

2 2.5 mg vitamin D 3 completely inhibited the ejaculation of males without any apparent influence on sexual desire. 250 mg vitamin D3 influenced both the desire and ejaculation.

3 Sexual activity of females was depressed by both doses.

4 The experiments demonstrate that vitamin D3, a steroid in structure, given in the critical period of hormonal imprinting may influence steroid hormone-receptor commanded events for life, in a way similar to the effects exhibited by synthetic steroid hormone analo gues and benzpyrene in earlier studies.
Hepatotoxicity of N,N-dimethylformamide (DMF) in acute poisoning with the veterinary euthanasia drug T-61
Authors: Buylaert W. , Calle P. , De Paepe P. , Verstraete A. , Samyn N. , Vogelaers D. , Vandenbulcke M. , Belpaire F.
Published: December 2008

1 We report on a patient who was resuscitated after a suicide attempt with the veterinary euthanasia pro duct T-61 and treated with N-acetylcysteine (NAC) to prevent hepatotoxicity from N,N-dimethylformamide (DMF), the solvent of T-61.

2 Serum concentrations of DMF were high as compared with values published on occupational exposure.

3 The patient showed only a transient increase in liver enzymes with eventually a full recovery.

4 The hepatoprotective effect of NAC was studied in a rat model using the rise in serum sorbitol dehydrogenase (SDH) as a marker for DMF-induced hepatotoxicity.

5 Four series of randomized, controlled and double- blind experiments were carried out and consistently showed a lower increase in SDH in NAC-treated animals in each series. The difference was statistically significant only when the data of the 4 series were pooled. This is probably due to the large interindivi dual variations in the effect of DMF.

6 We hypothesize that in the rat NAC may have a protective effect. Whether NAC is also protective in patients, in which it is administered after exposure to DMF, cannot be concluded from the present experi ments.
Reference values for young normal Sprague-Dawley rats: weight gain, hematology and clinical chemistry
Authors: Lillie Len E , Temple Norman J , Florence L. Zack
Published: December 2008

1 Arterial blood from 63 male (315 - 500 g) and 60 female (210 - 290 g) healthy Sprague-Dawley rats was ana lyzed for 16 hematological and 22 clinical chemistry parameters.

2 Nine of these parameters were associated with growth and developmental changes in males between 38 - 78 days and females 49 - 89 days of age.

3 Weight gain in both sexes followed patterns consistent with other studies using this strain, but interexperi mental variation was as much as ± 22%.

4 Rectal temperatures of females averaged 37.28°C, being statistically greater (P < 0.05) than the average male at 36.99°C.

5 The data provide reference values for use in toxicolo gical and other investigations.
Combined dapsone and clofazimine intoxication
Authors: Hoetelmans Rmw , Otten Jmmb , Koks Chw , Soesan M. , Beijnen JH
Published: December 2008

We report clinical findings and pharmacokinetic data regarding a combined dapsone and clofazimine intoxica tion in a man, who ingested 50 tablets of dapsone (100 mg), 20 capsules of clofazimine (100 mg) and two tablets of rifampicin (600 mg). Oral administration of activated charcoal (50 grams) and sodium sulphate (20 grams) after gastric lavage resulted in an elimination half-life in plasma of 11.1 and 10.8 h for dapsone and its main metabolite, monoacetyldapsone, respectively. A rapid initial decrease of the plasma concentration of clofazi mine was observed after gastric lavage and administration of activated charcoal and sodium sulphate. 15 h after this treatment, clofazimine plasma levels remained relatively constant. Dapsone-induced methaemoglobinaemia (48% at admission) was treated successfully with methylene blue.
Review : Potential dangers from topical preparations containing methyl salicylate
Authors: Chan Thomas YK
Published: December 2008

Methyl salicylate (oil of wintergreen) is widely available in many over-the-counter liniments, ointments, lotions or medicated oils for the relief of musculoskeletal aches and pains. Ingestion of methyl salicylate poses the threat of severe, rapid-onset salicylate poisoning because of its liquid, concentrated form and lipid solubility. Excessive usage of these preparations in patients receiving warfarin may result in adverse interactions and bleedings. Methyl salicylate in topical analgesic preparations may cause irritant or allergic contact dermatitis and anaphylactic reactions. Physicians should fully appreciate the potential dangers from topical preparations containing methyl salicylate.
Biokinetics and biokinetic models in risk assessment
Authors: van Vliet PW , de Jongh J.
Published: December 2008

Risk assessment ofxenobiotics using animal data involves extrapolation from high doses to low ones, and from animal species to humans. In some cases it also involves extrapolation from one route of exposure to another. To assess the risk of exposure to xenobiotics, information on both biokinetics and biodynamics are needed. The contribution of biokinetics to risk assessment is the subject of this review. The review includes the general aspects of biokinetics of chemicals, the models available to describe the biokinetic behaviour of a chemical and a discussion of the class of biokinetic models that is considered most suited for application to risk assessment: the physiologi cally-based biokinetic (PBBK) models. The power of PBBK models is illustrated with a few examples.
Experimental studies on multiorgan toxicity of cyclosporine-A in rats using a radiopharmaceutical and comparison with histopathological findings
Authors: Shihab-Eldeen A. , Owunwanne A. , Junaid TA , Yacoub T.
Published: December 2008

Iodine-125 HIPDM was evaluated as a screening agent for studying multiorgan toxicity due to Cyclosporine-A (CsA) and the results were compared to histopathological findings of the tissues. The rats were injected subcuta neously with 50 mg/kg (body weight) of CsA or with equal volume of the vehicle, Cremophor-EL, for 7 consecutive days. A dose of 10 μCi of I-125 HIPDM was injected intravenously at the end of the treatment period. The results indicated that there was a significant increase in the uptake of 1-125 HIPDM in the kidney, liver, heart and blood compared to control rats (P < 0.05). However, there was a significant decrease in the uptake of 1-125 HIPDM in the spleen compared to control animals (P < 0.001). The lung and brain of CsA treated rats showed no change in the uptake of I-125 HIPDM when compared to control rats.

The change in the uptake of I-125 HIPDM in these organs was assumed to indicate tissue response to the toxic effects of CsA. The radiopharmaceutical results were compar able with the histopathological findings in which the organs showed varying degrees of tissue degeneration. It is concluded that the lipophilic radiopharmaceutical, 1-125 HIPDM, can be used as an effective screening agent to study multiorgan toxicity due to CsA.
Lead: intestinal absorption and bone mobilization during lactation
Authors: Maldonado-Vega M. , Cerbón-Solorzano J. , Albores-Medina A. , Hernández-Luna C. , Calderón-Salinas JV
Published: December 2008

The aim of this study was to examine lead (Pb) intestinal absorption, its mobilization and redistribution during lactation in rats chronically exposed to lead. Lead and calcium (Ca) concentrations were measured in blood, milk, femurs, liver and kidney samples obtained from pregnant and lactating mother rats which were subjected to different schedules of exposure to Pb: 158 days before and during lactation (group A), 144 days before lactation (group B) and 14 days only during lactation (group C). Results were compared to those of non-pregnant but Pb- exposed matched rats and non-exposed control rats. In groups A and B during lactation, Pb in blood (PbB), liver and kidney increased while Pb in bone decreased. Since there was not an external source of Pb in group B during lactation, the results indicate resorption of Pb in bone as the main source of Pb in the organism. In group A, there was an additional increase of PbB when compared to group B as a result of Pb intestinal absorption. In group C a significant increase in PbB due to intestinal absorption and deposit in bone was found when compared to non- pregnant 144 days old rats, suggesting that the three processes intestinal absorption, bone resorption and bone absorption were taking place. These data indicate that Pb stored in bone as a result of prior maternal exposure, should be considered as a major source of self intoxication and of Pb in milk available to suckling pups.
Markedly altered colchicine kinetics in a fatal intoxication: Examination of contributing factors
Authors: Borron Stephen W , Scherrmann JM , Baud Frédéric J
Published: December 2008

1 Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive.

2 The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination.

3 We report a case of colchicine intoxication, compli cated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patient's survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death.

4 Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination.

5 Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit.

6 This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.
DNA strand breaks and poly (ADP-ribose) polymerase activation induced by crystalline nickel subsulfide in MRC-5 lung fibroblast cells
Authors: Zhuang ZX , Shen Y. , Shen HM , Ng V. , Ong CN
Published: December 2008

Nickel compounds are potent carcinogens. Their carcino genicity is believed to be associated with their solubility and cellular uptake. In the present study, we assessed the in vitro genotoxic effect of a water-insoluble nickel compound, crystalline nickel subsulfide (α-Ni 3S2) on human embryo lung fibroblast cell line (MRC-5 cells). DNA strand breaks was evaluated using single cell gel electrophoresis, or comet assay. The α-Ni3S2 induction of poly (ADP-ribose) polymerase (PADPRP), a nuclear enzyme associated with DNA damage and repair was also studied. Hydrogen peroxide (H2O2) was used as a reference compound. A dose-response relationship was found between α-Ni 3S2 concentrations (2.5 μg/cm2 to 20 μg/cm 2) and the comet tail length. The increase of PADPRP activity of α-Ni 3S2 treated MRC-5 cells was also significant and dose-dependent within the concentration range of 2.5 μg/ cm2 to 10 μg/cm 2. Close associations have been found between the comet length and PADPRP level for H2O2 (r=0.98) and α-Ni3S 2 (r=0.97). These results clearly suggest that α-Ni3S 2 is a potent agent in inducing DNA strand breaks, which may be closely related to its carcinogenic effects. Data from the present study also suggest that both comet assay and PADPRP determination are sensitive techniques for quantitative evaluation of DNA damage induced by nickel compounds.
Characterisation and uptake of paraquat by rat renal proximal tubular cells in primary culture
Authors: Chan Bsh , Lazzaro VA , Seale JP , Duggin GG
Published: December 2008

1 Uptake of the herbicide paraquat (PQ), by rat proximal tubular cells (PTC) in primary culture grown on a collagen coated support was investigated.

2 The uptake of PQ by PTC was predominantly from the basolateral side. The basolateral uptake of PQ was saturable with time and increasing concentrations, energy dependent and could be inhibited by certain organic cations. Using Michaelis Menten kinetics, the apparent Km was 778 ± 241 μM and Vmaxwas 0.97 ± 0.24 pmol/μg protein/15 min for the basolateral uptake of PQ. Cimetidine (5.7 ± 0.4 pg/μg protein/ 30 min, P < 0.001) was the most potent inhibitor of PQ uptake, followed by quinine (6.5 ± 0.4 pg/μg pro tein/30 min, P < 0.01) and then tetraethylammonium (8.2 ± 0.5 pg/μg protein/30 min, P < 0.05) when com pared with control (11 ± 1 pg/μg protein/30 min). N- methylnicotinamide, p-aminohippurate and putres cine did not inhibit the basolateral uptake of PQ. The sodium hydrogen exchange inhibitors, amiloride and its analogue, 5-(N,N hexamethylene) amiloride (HMA) inhibited both the apical and basolateral uptake of PQ.

3 The apical uptake of PQ was not saturable with increasing concentrations and was not inhibited by 2,4-dinitrophenol, but it was reduced by cimetidine ( P < 0.01), quinine ( P < 0.05) and a sodium potassium ATPase inhibitor, ouabain ( P<0.01).

4 It is concluded that PQ was taken up from the basolateral side of primary cultured rat PTC by an energy dependent transport system.
Methylene chloride induced mouse liver and lung tumours: An overview of the role of mechanistic studies in human safety assessment
Authors: Green Trevor
Published: December 2008

B6C3F1 mice exposed to high dose levels of methylene chloride by inhalation for 2 years had an elevated incidence of liver and lung tumours. These tumours were not increased in rats or hamsters exposed under the same or similar conditions. This paper gives an overview of research conducted over the last 10 years into the mechanism of action of methylene chloride as a mouse carcinogen and into the relevance of the mouse data to humans exposed to this chemical. Data are presented on the comparative metabolism and pharmacokinetics of methylene chloride in mice, rats, hamsters and humans, on the toxicity of methylene chloride to the target organs in the mouse, and on the genotoxicity of methylene chloride in vitro and in vivo. The enzyme which activates methylene chloride to its carcinogenic form has been isolated, sequenced, and cloned, and its distribution studied within cells, organs and between species. Evidence has been obtained to show that methylene chloride caused cancer in mice as a result of interactions between metabolites of the glutathione S-transferase pathway and DNA. Damage to mouse lung Clara cells and increased cell division are believed to have influenced the development of the lung tumours. The species specificity was a direct consequence of the very high activity and specific cellular and nuclear localisation of a theta class glutathione S-transferase enzyme which was unique to the mouse. Consequently, DNA damage was not detectable in rats in vivo, or in hamster and human hepatocytes exposed to cytotoxic dose levels of methylene chloride in vitro. These results provide evidence that the mouse is unique in its response to methylene chloride and that it is an inappropriate model for human health assessment.
Serotonin syndrome due to venlafaxine and maintenance tranylcypromine therapy
Authors: Hodgman Michael J , Martin Thomas G , Krenzelok Edward P
Published: December 2008

A number of novel serotonergic antidepressants have been introduced to clinical practice over the last decade. These medications are felt to be safe alternatives to the traditional tricyclic antidepressants and monoamine oxidase inhibitors, particularly in the overdose setting. Serious adverse reactions and drug interactions have been appreciated and fatalities have been reported. We describe the development of the serotonin syndrome in a 60 year old female on chronic tranylcypromine treatment following the inadvertent ingestion of a single dose of venlafaxine. Manifestations included an altered mental status that progressed to hyperthermia and coma. She recovered quickly and without complications. Health care providers and poison specialists need to be aware that this potentially serious syndrome can be precipitated by a single dose of a serotonin reuptake inhibitor in patients being treated with a monoamine oxidase inhibitor.
In vitro drug adsorption to charcoal, silicas, acrylate copolymer and silicone oil with charcoal and with acrylate copolymer
Authors: Cassidy SL , Hale A. , Buss DC , Routledge PA
Published: December 2008

1 The relative binding constants of four drugs to charcoal, silicone oil silicas and acrylate copolymers was studied using an in-vitro binding technique.

2 The maximum adsorption capacity (K2) was chosen as a measure of the degree of binding and calculated by fitting to the Langmuir equation.

3 Charcoal alone was shown to be the most effective of the adsorbents chosen. The possible use of silicone oils as an adsorbent delivery vehicle in treatment of overdose is discussed.
Rifampicin and isoniazid increase acetaminophen and isoniazid cytotoxicity in human HepG2 hepatoma cells
Authors: Nicod Laurence , Viollon Catherine , Regnier Any , Jacqueson Alain , Richert Lysiane
Published: December 2008

Acetaminophen (APAP) induced a concentration-depen dent (0-30 mM) cytotoxic effect in human HepG2 hepatoma cells which was significantly increased when intracellular reduced glutathione (GSH) content was decreased. The cytotoxic effect of APAP (0-30 mM) was significantly lower in day 3-treated compared to day 1- treated HepG2 cells. A 3-day preincubation of HepG2 cells with 5 ?M 3-methylcholanthrene (3MC), 50 ?M rifampicin (RFP) or 1 mM isoniazid (INH) significantly increased 15- 30 mM APAP cytotoxicity, of about 15-20% for INH and RFP and 35-50% for 3MC. The cytotoxicity of 10 mM APAP was also increased (about 20%) by a 3-day preincubation with INH but was not affected by 3MC and RFP.

INH induced a concentration-dependent (0 - 40 mM) cytotoxic effect in day-1 treated HepG2 cells and not significantly affected by decreases in intracellular GSH

concentrations. INH was not cytotoxic in day 3-treated HepG2 cells. A 3-day preincubation of HepG2 cells with 50 ?M RFP or 1 mM INH significantly increased 10- 40 mM INH cytotoxicity, respectively of about 10% and 10 - 25%. A 3-day preincubation with 3MC did not modify the cytotoxic effect of INH at these concentrations.

This is to our knowledge the first report of increases by INH and RFP of APAP and INH cytotoxicity in vitro in hepatocellular cells of human origin. It is in accordance with clinical observations of severe hepatotoxicity asso ciated with APAP or INH usage in patients receiving multiple drug therapy (INH, RFP) for tuberculosis or in alcoholics.