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Total Radioactivity (total + radioactivity)
Selected AbstractsToxicokinetics of sediment-associated polybrominated diphenylethers (flame retardants) in benthic invertebrates (Lumbriculus variegatus, oligochaeta)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2004Matti T. Leppänen Abstract Polybrominated diphenylethers (PBDEs) are ubiquitous environmental contaminants showing rapid temporal increase in some sample types. The compounds are known to biomagnify in aquatic food webs and are assumed to archive into sediments and soils. Currently, no direct evidence indicates whether sediment-associated PBDEs are available for biota. The aim of the present study was to explore the uptake and elimination of two common congeners (47 and 99) in sediment-inhabiting invertebrates to shed light on possible bioavailability of sediment-associated PBDEs. Two clean lake sediments were spiked with environmentally relevant concentrations of 14C-labeled tetra- and pentabromo diphenylether, and oligochaetes (Lumbriculus variegatus) were exposed for three or four weeks to allow kinetic accumulation calculations. Subsequent depuration tests were performed after three weeks of exposure to obtain depuration rates. Both congeners were clearly bioavailable, and only slight differences in steady-state tissue concentrations were found between the four sediment-ingesting oligochaete treatments (biota sediment accumulation factors [BSAFs], 3.0,3.7). The tetrabromo diphenylether-exposed oligochaetes that did not ingest sediment had clearly lower influx rates (0.1 vs 1,3 nmol h -1) than sediment-ingesting worms. Also, the estimated BSAF (1.8) was statistically different from that of the sediment-ingesting oligochaetes. These findings support the significance of feeding behavior in bioaccumulation of very hydrophobic organic contaminants. Depuration of both congeners was biphasic, indicating two kinetically different compartments in L. variegatus. Compartment A made up 73 to 92% of total radioactivity in tissues and had relatively fast depuration rates (half-lives, 10.5,47.5 h); the smaller compartment B had very slow depuration rates. No significant biotransformation of PBDEs was evident. The present study clearly demonstrates that the sediment-associated PBDEs, like other hydrophobic organic contaminants of environmental concern, are not totally sequestered from sediment-inhabiting oligochaetes and are subject to trophic transfer. [source] Fate and effects of triclosan in activated sludgeENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2002Thomas W. Federle Abstract Triclosan (TCS; 5-chloro-2-[2,4-dichloro-phenoxy]-phenol) is a widely used antimicrobial agent. To understand its fate during sewage treatment, the biodegradation and removal of TCS were determined in activated sludge. In addition, the effects of TCS on treatment processes were assessed. Fate was determined by examining the biodegradation and removal of TCS radiolabeled with 14C in the 2,4-dichlorphenoxy ring in laboratory batch mineralization experiments and bench-top continuous activated-sludge (CAS) systems. In batch experiments with unacclimated sludge, TCS was mineralized to 14CO2, but the total yield varied as a function of test concentration. Systems that were redosed with TCS exhibited more extensive and faster mineralization, indicating that adaptation was a critical factor determining the rate and extent of biodegradation. In a CAS study in which the influent level of TCS was incrementally increased from 40 ,g/L to 2,000 ,g/L, removal of the parent compound exceeded 98.5% and removal of total radioactivity (parent and metabolites) exceeded 85%. Between 1.5 and 4.5% of TCS in the influent was sorbed to the wasted solids, whereas >94% underwent primary biodegradation and 81 to 92% was mineralized to CO2 or incorporated in biomass. Increasing levels of TCS in the influent had no major adverse effects on any wastewater treatment process, including chemical oxygen demand, biological oxygen demand, and ammonia removal. In a subsequent experiment, a CAS system, acclimated to TCS at 35 ,g/L, received two separate 4-h shock loads of 750 ,g/L TCS. Neither removal of TCS nor treatment processes exhibited major adverse effects. An additional CAS study was conducted to examine the removal of a low level (10 ,g/L) of TCS. Removal of parent equaled 94.7%, and biodegradation remained the dominant removal mechanism. A subsequent series of CAS experiments examined removal at four influent concentrations (7.5, 11, 20, and 50 ,g/L) of TCS and demonstrated that removal of parent ranged from 98.2 to 99.3% and was independent of concentration. Although TCS removal across all experiments appeared unrelated to influent concentration, removal was significantly correlated (r2 = 0.87) with chemical oxygen demand removal, indicating that TCS removal was related to overall treatment efficiency of specific CAS units. In conclusion, the experiments show that TCS is extensively biodegraded and removed in activated-sludge systems and is unlikely to upset sewage treatment processes at levels expected in household and manufacturing wastewaters. [source] New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humansFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2004M. Trellu Abstract Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax = 1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax = 0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1. [source] Hepatic Kupffer cell phagocytotic function in rats with erythrocytic-stage malariaJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 5 2002MICHAEL S NOBES AbstractBackground: In the erythrocytic phase of malaria, Kupffer cells show marked hypertrophy and hyperplasia and are filled with malarial pigment. However, phagocytic function in this state has not been well characterized. The aim of the present study was to use mouse Plasmodium berghei to infect rats with malaria and study the phagocytic function and morphology of Kupffer cells. Methods: We used a recirculating isolated perfused rat liver (IPRL) to quantitate Kupffer cell phagocytic clearance of radiolabeled albumin,latex over 120 min in high parasitemia (53 ± 6%; n = 7) and low parasitemia (,1%; n = 4) malaria-infected rats and littermate controls (n = 7 and n = 4, respectively). In a further group of high-parasitemic rats, perfusion was ceased after 7 min and liver radioactivity also measured. Electron microscopy was performed after perfusions. Results: In high-parasitemia malaria rats, clearance of radiolabeled latex from IPRL perfusate over 120 min was significantly (P < 0.01) faster than in controls, with a lower area under the curve (0.19 ± 0.02 vs 0.43 ± 0.07 /mL per min, respectively) and shorter half-life (t1/2k; 2.4 ± 0.6 vs 10.0 ± 2.3 min, respectively). Low-parasitemia rats were identical to controls. After 7 min perfusion in high-parasitemic rats (n = 4), total radioactivity in liver homogenates was higher than in controls (n = 4; 33.1 ± 6.2 vs 18.4 ± 1.9% of injected radiolabel; P < 0.05). Electron microscopy showed latex in Kupffer cells, more abundantly seen in high-parasitemic animals. Conclusions: Total Kupffer cell phagocytic activity of the liver is markedly increased in rats with a high parasitemic load of malarial P. berghei infection. This is presumed to reflect an upregulation of scavenger activity phagocytosing erythrocytes and their breakdown products. © 2002 Blackwell Publishing Asia Pty Ltd [source] ,-cyclodextrin reduces bioavailability of orally administered [3H]benzo[a]pyrene in the ratJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2005Goran Westerberg Abstract The excretion and plasma kinetics of total radioactivity were studied following single oral administration of [3H]benzo[a]pyrene after multiple oral administration of ,-cyclodextrin at 0, 5, 50, or 500 mg/kg/day. The AUC and Cmax values in male and female rats following administration of [3H]benzo[a]pyrene in combination with 5 to 500 mg/kg ,-cyclodextrin were considerably lower than that in rats administered [3H]benzo[a]pyrene alone. At all dose levels of ,-cyclodextrin, the excretion of total radioactivity was almost entirely via feces, with <2% recovered in urine, demonstrating either that absorption of the orally administered dose was low or that, for any absorbed material, biliary excretion was the main route of excretion. However, following administration of vehicle, up to 5% of the administered radioactivity was recovered in the urine, suggesting that absorption may have been reduced by the presence of ,-cyclodextrin in the intestine. At all dose levels of ,-cyclodextrin, there was minimal retention of radioactivity in the carcase at the end of the collection period. ,-Cyclodextrin did not affect the apparent terminal half-life of radioactivity. Therefore, the reduced systemic exposure of rats to radioactivity in the presence of ,-cyclodextrin is likely related to a reduced oral bioavailability. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:114,119, 2005 [source] In vivo distribution and metabolisation of 14C-imidacloprid in different compartments of Apis mellifera LPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 11 2004Séverine Suchail Abstract In vivo distribution of the neonicotinoid insecticide, imidacloprid, was followed during 72 h in six biological compartments of Apis mellifera L: head, thorax, abdomen, haemolymph, midgut and rectum. Honeybees were treated orally with 100 µg of 14C-imidacloprid per kg of bee, a dose close to the median lethal dose. Elimination half-life of total radioactivity in honeybee was 25 h. Haemolymph was the compartment with the lowest and rectum that with the highest level of total radioactivity during the whole study, with a maximum 24 h after treatment. Elimination half-life of imidacloprid in whole honeybee was 5 h. Imidacloprid was readily distributed and metabolised only by Phase I enzymes into five metabolites: 4/5-hydroxy-imidacloprid, 4,5-dihydroxy-imidacloprid, 6-chloronicotinic acid, and olefin and urea derivatives. The guanidine derivative was not detected. The urea derivative and 6-chloronicotinic acid were the main metabolites and appeared particularly in midgut and rectum. The olefin derivative and 4/5-hydroxy-imidacloprid preferentially occurred in head, thorax and abdomen, which are nicotinic acetylcholine receptor-rich tissues. Moreover, they presented a peak value around 4 h after imidacloprid ingestion. These results explain the prolongation of imidacloprid action in bees, and particularly the differences between rapid intoxication symptoms and late mortality. Copyright © 2004 Society of Chemical Industry [source] Human radiolabeled mass balance studies: objectives, utilities and limitationsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2009Natalia Penner Abstract The determination of metabolic pathways of a drug candidate through the identification of circulating and excreted metabolites is vitally important to understanding its physical and biological effects. Knowledge of metabolite profiles of a drug candidate in animals and humans is essential to ensure that animal species used in toxicological evaluations of new drug candidates are appropriate models of humans. The recent FDA final guidance recommends that human oxidative metabolites whose exposure exceeds 10% of the parent AUC at steady-state should be assessed in at least one of the preclinical animal species used in toxicological assessment. Additional toxicological testing on metabolites that have higher exposure in humans than in preclinical species may be required. The metabolite profiles in laboratory animals and humans are generally accomplished by mass balance and excretion studies in which radiolabeled drugs are administered to these species. The biological fluids are collected, analysed for total radioactivity and evaluated for a quantitative profile of metabolites. Thus, these studies not only determine the rates and routes of excretion but also provide very critical information on the metabolic pathways of drugs in preclinical species and humans. In addition, these studies are required by regulatory agencies for the new drug approval process. Despite the usefulness of these radiolabeled mass balance studies, there is little concrete guidance on how to perform or assess these complex studies. This article examines the objectives, utilities and limitations of these studies and how these studies could be used for the determination of the metabolite exposure in animals and humans. Copyright © 2009 John Wiley & Sons, Ltd. [source] | |||||||||||||