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Archives of Toxicology (v.75, #4)
No Title by Fredrik Jonsson; Frédéric Y. Bois; Gunnar Johanson (pp. 189-199).
Physiologically based pharmacokinetic (PBPK) models are often optimized by adjusting metabolic parameters so as to fit experimental toxicokinetic data. The estimates of the metabolic parameters are then conditional on the assumed values for all other parameters. Meanwhile, the reliability of other parameters, or the structural model, is usually not questioned. Inhalation exposures with human volunteers in our laboratory show that non-conjugators lack metabolic capacity for methyl chloride entirely, and that elimination in these subjects takes place via exhalation only. Therefore, data from these methyl chloride exposures provide an excellent opportunity to assess the general reliability of standard inhalation PBPK models for humans. A hierarchical population PBPK model for methyl chloride was developed. The model was fit to the experimental data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. In a Bayesian analysis, it is possible to merge a priori knowledge of the physiological, anatomical and physicochemical parameters with the information embedded in the experimental toxicokinetic data obtained in vivo. The resulting estimates are both statistically and physiologically plausible. Model deviations suggest that a pulmonary sub-compartment may be needed in order to describe the inhalation and exhalation of volatile adequately. The results also indicate that there may be significant intra-individual variability in the model parameters. To our knowledge, this is the first time that the toxicokinetics of a non-metabolized chemical is used to assess population PBPK parameters. This approach holds promise for more elaborate experiments in order to assess the reliability of PBPK models in general.
Keywords: Methyl chloride PBPK Non-conjugators Intra-individual variability
No Title by Sara Hallgren; Taha Sinjari; Helen Håkansson; Per Darnerud (pp. 200-208).
The ability of the commercial polybrominated diphenyl ether (PBDE) preparation Bromkal 70-5 DE to alter thyroid hormone and vitamin A levels as well as microsomal enzyme activities was compared with that of the commercial polychlorinated biphenyl (PCB) preparation Aroclor 1254 in orally exposed female rats (Sprague-Dawley) and mice (C57BL/6 N). Additional mice were exposed to the PBDE congener 2,2',4,4'-tetrabromodiphenyl ether (DE-47), or to the PCB congener 2,3,3',4,4'-pentachlorobiphenyl (CB-105). For 14 days the animals were given approximately isomolar daily oral doses of Aroclor 1254, CB-105 (both 10 mg/kg body weight), Bromkal 70-5 DE or DE-47 (both at 18 mg/kg body weight). In addition, further groups of rats and mice received a higher dose of Bromkal 70-5 DE, 36 mg/kg body weight. Bromkal 70-5 DE and DE-47 decreased plasma free and total thyroxine (T4) levels in both rats and mice, although with lower potency than that of Aroclor 1254 and CB-105. By contrast, thyroid-stimulating hormone (TSH) levels were not significantly changed in any of the groups. Reduction of hepatic vitamin A levels was seen in rats after Aroclor 1254 and Bromkal 70-5 DE exposure. A similar tendency was seen also in mice, but the effects were significant only for concentration data and not the total amount. Induction of microsomal phase I enzymes, measured as ethoxy, methoxy and pentoxy resorufin O-dealkylase (EROD, MROD, PROD) activities, was greatest after exposure to Aroclor 1254/CB-105 but were also significant in the Bromkal 70-5 DE/DE-47-treated groups. However, induction of uridine diphosphoglucuronosyl transferase (UDPGT) was small and for most groups insignificant. In conclusion, the PBDE compounds studied, although having a lower potency than the PCB compounds, decreased thyroxine and vitamin A levels and induced microsomal enzyme activities. Rats were more sensitive to the observed effects than mice. Microsomal phase I activity might be related, directly or indirectly, to the T4 and vitamin A effects, whereas several factors (such as weak enzyme induction and lack of correlation with altered T4 and vitamin A levels) argue against any UDPGT-related effects.
Keywords: Polybrominated diphenyl ethers (PBDEs) Polychlorinated biphenyls (PCBs) Thyroid hormones Microsomal enzymes Vitamin A Bromkal Aroclor
No Title by Y. Maruyama; Y. Suzuki; A. Kazusaka; S. Fujita (pp. 209-213).
The uptake of norsalsolinol, a neurotoxin candidate causing parkinsonism-like symptoms, was studied in PC12 cells. The compound was actively taken up by the PC12 cells, with a K m value of 176.2±9.1 µM and a maximum velocity of 55.6±7.0 pmol/min per mg protein; norsalsolinol uptake was dependent on the presence of extracellular Na+. The uptake of norsalsolinol was sensitive to two dopamine transporter inhibitors, GBR-12909 and reserpine, but was less sensitive to desipramine, a noradrenaline transporter inhibitor. Dopamine competitively inhibited norsalsolinol uptake into PC12 cells with a K i value of 271.2±61.6 µM. These results suggest that norsalsolinol is taken up into PC12 cells mainly by the dopamine transporter.
Keywords: Dopamine transporter Norsalsolinol Parkinsonism PC12 cells
No Title by Jue-Long Wang; Kam-Chung Lee; Kwong-Yui Tang; Ti Lu; Cheng-Ho Chang; Chik-Keung Chow; Wei-Chuan Chen; Warren Su; Yee-Ping Law; Chung-Ren Jan (pp. 214-220).
Riluzole is an effective neuroprotective drug. Its effect on intracellular free Ca2+ levels ([Ca2+]i) has not been explored. This study examined the effect of riluzole on [Ca2+]i in IMR32 neuroblastoma cells using fura-2 as a Ca2+ probe. Riluzole 0.1–1 mM increased [Ca2+]i in a concentration-dependent manner. Removal of extracellular Ca2+ inhibited the response by 52±5%. The [Ca2+]i increase induced by 0.2 mM riluzole was unaltered by 0.1 mM La3+ or 10 µM verapamil, but was inhibited by 51±4% by 10 µM nifedipine. In Ca2+-free medium, pretreatment with 1 µM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) reduced the 0.2 mM riluzole-induced Ca2+ release by 44±3%; this reduction was augmented to 66±5% by additionally depleting the Ca2+ stores in the Golgi complex with 50 µM brefeldin A. Inhibition of inositol 1,4,5-trisphosphate formation by 2 µM U73122, a phospholipase C inhibitor, did not affect Ca2+ release induced by 0.2 µM riluzole. It was concluded that the neuroprotective agent riluzole increased [Ca2+]i in IMR32 neuroblastoma cells concentration-dependently by releasing Ca2+ from multiple stores in an inositol 1,4,5-trisphosphate-independent manner and also by inducing nifedipine-sensitive Ca2+ influx.
Keywords: Ca2+ Ca2+ stores Fura-2 IMR32 Neuroblastoma cells Riluzole
No Title by Neelam Dwivedi; Mukul Das; Subhash K. Khanna (pp. 221-226).
Previous studies indicate that benzanthrone, an anthraquinone dye intermediate, caused significant depletion of ascorbic acid (AsA). In this investigation the effect of benzanthrone on the status of different forms of AsA and other bio-antioxidants such as glutathione (GSH) was studied. Oral administration of benzanthrone (50, 125 or 250 mg/kg body weight) resulted in a significant increase of urinary AsA levels with a concomitant decrease in the urinary dehydroascorbic acid (DHA) content in both rats and guinea-pigs. Benzanthrone caused a dose-dependent decrease in hepatic, adrenal and serum AsA levels with a subsequent increase in DHA and diketogulonic acid (DKA) levels in both rats and guinea-pigs. Following benzanthrone treatment, rats showed an increase in the scorbutic index (to 1.01–1.21) of the liver, adrenal glands and serum compared to controls (0.12–0.24). The scorbutic indices of liver, adrenal glands and serum were also substantially increased (to 3.61–11.20) in benzanthrone-treated guinea-pigs compared to controls (0.16–0.38). Single oral administration of benzanthrone to guinea-pigs caused a dose-dependent depletion of GSH in liver (15–51%), adrenal glands (27–64%) and serum (32–86%). Furthermore, the depletion of GSH by benzanthrone in rats was of a lesser degree. This suggests that continued exposure of guinea-pigs to benzanthrone may lead to scurvy-type changes in this animal species but not to the same extent in rats, since the latter has the enzymatic capacity to synthesise AsA. Therefore, it can be hypothesised that benzanthrone per se, or its metabolites, interact with reduced GSH thereby causing its depletion. Furthermore, in order to replenish the depleted GSH levels, AsA might be oxidized to DHA and hence the decrease in AsA with the simultaneous increase in DHA was observed.
Keywords: Antioxidants Benzanthrone Ascorbic acid Scorbutic index
No Title by Kazuhiko Mori; Mayumi Shibano; Hiroshi Satoh; Kiyoshi Takasuna; Kazuhisa Furuhama (pp. 227-233).
Histamine releases induced by the fluoroquinolone antimicrobial levofloxacin (LVFX) were investigated using mast cells separated from various organs and peripheral basophils of dogs, being the most susceptible species to quinolone derivatives, in both in vivo and in vitro systems. An intravenous infusion of LVFX at 30 mg/kg over a 30-min period produced endogenous histamine release from 5 min, and a maximum at 30 min, in which the plasma LVFX concentration was approximately 50 µM. A close correlation (r=0.87, n=20) between histamine and LVFX concentrations in plasma during the infusion was observed. In the in vitro study, LVFX at 30 µM or more caused histamine release from mast cells separated from the liver and skin, but not from the gastric mucosa, lung, and peripheral basophils. More exactly, the liver mast cells were most susceptible to LVFX among the organs tested. On the other hand, compound 48/80, a prototype histamine liberator, elicited the histamine release from the liver or skin mast cells at 10 µg/ml, and the calcium ionophore A23187 at 1 µM exhibited the histamine release from the mast cells derived from all organs examined. Histochemical analysis revealed that the liver and skin mast cells had positive reaction for both alcian blue and safranin staining, but the gastric mucosa and lung mast cells were only positive for alcian blue staining, indicating that LVFX preferably activated the connective tissue-type mast cells rather than the mucosal-type mast cells. The degranulation of the liver and skin mast cells brought about by either LVFX or compound 48/80, unlike the calcium ionophore A23187, was blocked by pretreatment with pertussis toxin, suggesting the involvement of pertussis toxin-sensitive G proteins. The results obtained from the canine experiments strongly suggest that LVFX induces histamine release from the connective tissue-type mast cells distributed mainly in the liver, somewhat in the cutaneous tissue, through the activation of pertussis toxin-sensitive G proteins.
Keywords: Fluoroquinolone Histamine release Canine mast cells Heterogeneity
No Title by J. Pauluhn; B. Gollapudi; T. Hammond; A. Linscombe; A. Thiel; D. Zischka-Kuhbier (pp. 234-242).
Four groups of young adult male Brown-Norway rats (strain: BN/RijHsd) were either exposed whole-body (WB) to filtered air (negative control) or to respirable aerosols of monomeric diphenylmethane-4,4′-diisocyanate (MDI) at actual breathing zone concentrations of 9.2±1.5 and 118±8.6 mg/m3. One additional group was exposed to 11,0±14.4 mg/m3 MDI using a nose-only (NO) mode. Exposure was 1 h/day, one exposure per week on 3 consecutive weeks. MDI aerosols were generated using either a condensation (WB) or a dispersion-condensation (NO) principle with resultant MMADs of 2.4–3.1 µm and 1.2 µm (GSD≈1.5), respectively. Humidity ranged from ≈40% (WB) to ≈5% (NO). Positive controls received cyclophosphamide and colcemid. Micronuclei in polychromatic erythrocytes (MN-PCE) were counted in bone marrow smears prepared after the final exposure on post-exposure days 1, 2 and 7 and stained with acridine orange or Wright-Giemsa. Both the WB-exposure regimen and the 7-day sampling time point were based upon a previous study in which a significant increase in MN-PCE was reported to occur. Rats exposed to 118 (WB) and 110 mg/m3 MDI (NO) exhibited signs of respiratory distress, including hypothermia, and increased lung weights when compared to WB-exposed rats. The intensity of changes appeared to be slightly more pronounced in NO-exposed rats. At no time point did this study provide any evidence of an MDI-induced effect on the frequency of MN-PCE. No differences in outcome existed following staining with acridine orange or Wright-Giemsa. There was an absence of any effect on the frequency of mast cells and their frequency was low enough not to interfere with the outcome of study. Positive control groups exhibited significant increases in MN-PCE. In summary, monomeric MDI aerosol did not induce cytogenetic damage in Brown-Norway rats when investigated according to current testing guidelines.
Keywords: Diisocyanate inhalation Condensation aerosol Genotoxicity MDI Brown-Norway rat Inhalation exposure
No Title by Debbie N. Slamon; Tim H. Ward; John Butler; Vic W. Pentreath (pp. 243-250).
The effects of acute (24 h) exposure to the antidepressants amitriptyline, imipramine (both tricyclics), fluoxetine (a selective serotonin re-uptake inhibitor) and tranylcypromine (a monoamine oxidase inhibitor) on DNA damage in cultured C6 rat glioma cells were determined using an alkaline comet assay. The effects of manipulation of intracellular cyclic AMP by pretreatment with dibutyryl cyclic AMP (dBcAMP) and 3-isobutyl-1-methylxanthine (IBMX) were also studied. For fluoxetine, the effects of addition of exogenous glutathione (GSH) and pretreatment with L-buthionine sulfoximine (BSO) were also assessed. There were increases in DNA damage with increasing concentrations of antidepressants. IBMX pretreatment protected against antidepressant-induced DNA damage in C6 cells pretreated with dBcAMP. Addition of exogenous reduced GSH and BSO increased DNA damage after fluoxetine exposure. The data show that the antidepressants induce significant amounts DNA damage in C6 cells.
Keywords: Astrocytes Antidepressants Antioxidants DNA damage Comet assay