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Archives of Toxicology (v.75, #5)

Careers in toxicology in Europe – options and requirements by Robert A. Ettlin; Erik Dybing; Carl Eistrup; Roy Forster; Ernest S. Harpur; Christian M. Hodel; Werner Kobel; Ed Nelson; Iona Pratt; Henry Stemplewski; David Virgo (pp. 251-261).

In view of the lack of information regarding careers for toxicologists in Europe, the Individual Members of EUROTOX organised a workshop on careers in toxicology during the EUROTOX Congress 2000 in London. Toxicologists are mainly employed in academia, regulatory agencies, contract research organisations (CROs) and the chemical and pharmaceutical industries. There are also a few governmental institutes involved with toxicological work other than teaching or regulation. Toxicologists can also work as independent consultants, especially for commercial organisations. The requirements for starting a career in any of the above organisations, the need and the advantages and disadvantages of specialisation, and further career prospects are summarised and briefly discussed. The organisations, and also working as an independent toxicology consultant, offer interesting professional work of relevance to modern-day society. There is currently a shortage of toxicologists not only in the traditional field of risk assessment but also especially in new areas, e.g. toxicogenomics. This shortage may be at least in part due to insufficient training opportunities. Further consideration of career opportunities is planned and will be published in due course.

Keywords: Toxicology Career Academia Consultant Contract Research Industry Regulatory agency

No Title by Maria A. Stander; Thalma W. Nieuwoudt; Pieter S. Steyn; Gordon S. Shephard; Edmond E. Creppy; Vikash Sewram (pp. 262-269).

The toxicokinetics of ochratoxin A were investigated in vervet monkeys (Cercopithecus aethiops). Three female monkeys were treated intravenously with ochratoxin A at doses, respectively, of 0.8, 1.5 and 2 mg/kg body weight (BW). Blood and urine samples were collected over a period of 21 days. Plasma and urine extracts were analysed by high-performance liquid chromatography (HPLC) with either fluorescence or negative ion electrospray ionization mass spectrometric detection. The clearance of ochratoxin A from plasma followed a two-compartment model. The elimination half-life of ochratoxin A in the monkeys was determined to be 19–21 days and the average total body clearance was 0.22±0.07 ml/h per kg and the average apparent distribution volume of the central compartment was 59±9 ml/kg and the peripheral compartment was 59±20 ml/kg. No evidence was found for any metabolic conversion of ochratoxin A.

Keywords: Ochratoxin A Toxicokinetics Cercopithecus aethiops Intravenous Negative ion electrospray ionization mass spectrometry

No Title by Ricarda Thier; Jürgen Lewalter; Silvia Selinski; Hermann M. Bolt (pp. 270-273).

In view of the established extrapulmonary cancer sites targeted by smoking a multiplicity of compounds and mechanisms might be involved. It has been debated that smoking caused increased incidence of N-methylvaline at the N-terminus of haemoglobin. Because this could indicate a relevance of methylating nitrosamines in tobacco smoke, data are presented from an industrial cohort of 35 smokers and 21 non-smokers repeatedly monitored between 1994 and 1999. In general, N-methylvaline adduct levels in haemoglobin of smokers were approximately 50% higher than those of non-smokers. The smoking-induced methylation of haemoglobin is likely to be caused by dimethylnitrosamine (N-nitroso-dimethylamine), a major nitrosamine in side-stream tobacco smoke. The biomonitoring data emphasise the potential value of N-methylvaline as a smoking-related biomarker and call for intensified research on tobacco smoke compounds that lead to macromolecular methylation processes.

Keywords: Smoking N-Alkylvaline N-Methylvaline N-Cyanoethylvaline N-Hydroxyethylvaline Haemoglobin adducts Nitrosamines Dimethylnitrosamine Tobacco smoke

No Title by Perrine Hoet; Jean-Pierre Buchet; Christine Sempoux; Tetsuo Nomiyama; Jacques Rahier; Dominique Lison (pp. 274-283).

2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Male Hartley guinea-pigs were exposed for 4 h to 5000 ppm HCFC-123 alone or blended with 5000 ppm HCFC-124, either once (single exposure) or on 5 consecutive days (repeated exposure).The animals were killed either 24 or 48 h after the last exposure. A transient cytolytic action of HCFC-123 was evident by increased mean serum levels of alanine aminotransferase at 24 h and isocitrate dehydrogenase at 24 and 48 h, both after a single or repeated exposure. The liver toxicity of HCFC-123 was confirmed by pathological examination of liver tissue, which showed mild (foci of necrotic hepatocytes) to moderate (multifocal random degeneration and necrosis) damage. Steatosis was also observed and was more pronounced after repeated exposure than after single. One animal out of 6 that were repeatedly exposed to the blend and sacrificed at 24 h showed liver lesions similar to halothane hepatitis. Although a few other animals responded markedly in the blend-treated group, on average, no significant difference in the biochemical or pathological lesions was found between the groups treated with HCFC-123 alone or with the blend. Urinary excretion of trifluoroacetic acid and chlorodifluoroacetic acid increased dose-dependently upon exposure to HCFC-123 and indicated accumulation after repeated exposure. No difference in metabolite excretion was found between animals treated with HCFC-123 alone or blended with HCFC-124. Treatment with HCFC-123 depleted hepatic glutathione levels by about 40 and 25% after single and repeated exposure, respectively; the amplitude of this reduction was not modified by co-exposure to HCFC-124. In conclusion, this study confirmed the hepatotoxicity of HCFC-123, based on biochemical, histopathological and metabolite studies, and found only very limited indication of a potentiation by HCFC-124 of this hepatotoxic effect.

Keywords: HCFC-123 HCFC-124 Hepatotoxicity Guinea-pigs

No Title by K. Abu-Spetan; A. Abdel-Gayoum (pp. 284-290).

Administration of gentamicin to rabbits intramuscularly at a dose of 80 mg/kg per day for 5 days induced nephrotoxicity exhibited by significantly (P<0.001) elevated serum urea and creatinine levels and a significant (P<0.001) decrease in renal cortical alkaline phosphatase (ALP) activity, in addition to tubular necrosis revealed by the histopathological examination of the kidney cortices. The deranged parameters returned to normal within 1 week of drug withdrawal, except the cortical ALP activity, which was still significantly lower compared to control. In contrast, feeding of 2% cholesterol-supplemented diet (CSD) to the rabbits for 15 days did not produce any nephrotoxic effects. However, the concurrent feeding of CSD for 15 days and gentamicin treatment at a dose of 80 mg/kg per day for 5 days, starting from day 10 of feeding, resulted in extensive nephrotoxic effects which were more severe than those observed with the gentamicin alone, with delayed recovery of the injured kidney following drug withdrawal. Gentamicin treatment produced significant elevation in serum total cholesterol, which was greater in animals fed with CSD. The serum triglyceride levels in the groups injected with gentamicin were also significantly greater than their respective controls. However, the serum phosphlipids were significantly reduced with gentamicin treatment and this reduction was greater in animals fed with cholesterol and treated with the drug. The liver cholesterol contents in animals fed with the CSD were significantly higher than those fed with the plain diet. However, the kidney cortices of the animals injected with the gentamicin showed significantly increased total phospholipid contents compared to their respective controls. On the other hand, the liver function was not altered in any of the experimental groups. In summary, the present results suggest that cholesterol feeding exacerbated the gentamicin-induced nephrotoxicity. Moreover, it delayed the period required by the injured kidney to recover back to normal. However, neither gentamicin treatment nor cholesterol feeding, or both together, had any injurious effects on the liver.

Keywords: High-cholesterol diet Gentamicin nephrotoxicity Rabbit

No Title by Nizar Abuharfeil; Adnan Jaran; Barakat Shabsough; Homa Darmani (pp. 291-296).

The effect of different concentrations (0, 0.1, 0.2, 0.4, and 0.8 mg/ml) of sodium nitrite on the anti-tumor activity of natural killer (NK) cells isolated from human peripheral blood was examined. Sodium nitrite induced significant inhibition (25.3–66.6%) of NK cell activity against WEHI-164 cells. This reduction in NK cell cytotoxicity was found to be partially due to inhibition of NK cell production of interferon-γ (25.7–92.8%) and tumor necrosis factor-α (26.6–76.6%). In addition, exposure to sodium nitrite resulted in a significant decrease (17.5–81.1%) in proliferation of control and interleukin-2-stimulated NK cells. Furthermore, the release of granzyme A and N-acetyl-β-D-glucosaminidase by NK cells was also decreased by 21.7–72.2% and 33.5–81.2%, respectively. Therefore, sodium nitrite is of environmental concern in view of its inhibitory effects on NK cell activity that might contribute to tumor promotion in vivo.

Keywords: Sodium nitrite Human NK cells

No Title by Toshiyuki Shoda; Kazuo Yasuhara; Matsuko Moriyasu; Tadakazu Takahashi; Chikako Uneyama; Masao Hirose; Kunitoshi Mitsumori (pp. 297-305).

In order to clarify the mechanism underlying testicular toxicity of nitrofurazone (NF), two experiments were performed. In experiment 1, sequential histopathological examination of testes after a single oral administration of 100 or 300 mg/kg NF to male rats demonstrated that degeneration of pachytene spermatocytes with an eosinophilic, shrunken appearance in stages VII–VIII and vacuolation of Sertoli cells were first observed 12 h after treatment. By 24 h, degeneration of pachytene spermatocytes in stages VII–XII and diplotene spermatocytes were observed. On post-treatment day 4, neither spermatocytes nor spermatids located inside the pachytene spermatocytes in stage VII were seen anywhere. Generation of seminiferous epithelium progressed with recovery to almost normal morphology after 12 weeks, although some morphological changes were still present. No lesions were apparent in spermatogonia, preleptotene spermatocytes, leptotene spermatocytes, zygotene spermatocytes or Leydig cells. Degenerate pachytene spermatocytes and some round spermatids seen after 24 h showed positive TdT-mediated dUTP-biotin nick end labeling (TUNEL). In addition, DNA laddering patterns were detected with agarose gel electrophoresis, and increased electron density of nuclei and cytoplasm of degenerating spermatocytes with nuclear chromatin focal aggregations were observed by electron microscopy, indicating that cell death was attributable to apoptosis. In experiment 2, sequential serum sex-related hormone levels were assayed after a single oral administration of 300 mg/kg NF to male rats and revealed a significant increase of testosterone and a decrease of progesterone at 6 h, and decreases of luteinizing hormone at 12 h and testosterone at 24 h. Prolactin tended to decrease from 12 h after treatment and the decrease was significant at 48 h. No significant changes were observed in levels of follicle-stimulating hormone or estradiol. The probability that NF damages germ cells by causing a hormonal imbalance is extremely low, since no pattern of hormonal imbalance that could be regarded as the cause of the testicular degeneration was observed until 12 h after NF treatment when pachytene spermatocytes began to degenerate. The present experiments suggest that NF damages Sertoli cells and pachytene spermatocytes in stages VII–XII directly.

Keywords: Nitrofurazone Testicular toxicity Rat Apoptosis Sertoli cells

No Title by Kai Janssen; Uta Eichhorn-Grombacher; Kirsten Schlink; Stefanie Nitzsche; Franz Oesch; Bernd Kaina (pp. 306-312).

The DNA repair enzymes O ⁶-methylguanine-DNA methyltransferase (MGMT) and apurinic/apyrimidinic endonuclease (APE, also known as Ref-1) play an important role in cellular defense against the mutagenic and carcinogenic effects of DNA-damaging agents. Cells with low enzyme activity are more sensitive to induced DNA damage and may confer a higher carcinogenic risk to the individuals in question. To study the level of variability of MGMT and APE expression in human, we analyzed in a long-time study MGMT and APE expression in peripheral blood mononuclear cells (PBMC) from healthy individuals. The data revealed high inter- and intraindividual variability of MGMT but not of APE. For MGMT, the interindividual levels ranged from 27 to 204 fmol/10⁶ cells (7.6-fold, 40 healthy individuals). The intraindividual variation was determined by measuring MGMT repeatedly over 42 days, and was found to vary from 1.4-fold to 3.5-fold. Averaging over the measurement period, some individuals displayed low MGMT activity compared to others. In contrast, APE expression showed only a 2.9-fold difference between individuals and a 1.2 to 2.3-fold intraindividual long-time variation, and thus was less variable than MGMT. MGMT and APE expression were not correlated. Overall the results showed variable MGMT and rather constant APE levels in PBMC of healthy individuals measured over a long period.

Keywords: DNA repair O6-Methylguanine-DNA methyltransferase (MGMT) Apurinic/apyrimidinic endonuclease (APE) Long-time kinetics Peripheral blood mononuclear cells

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Archives of Toxicology (v.75, #5)