摘要:

An approach to minimization of toxicity of a new compound is to elucidate the mechanisms of toxicity of analogous compounds and to clarify their structure‐toxicity relationships. A problem with this approach, however, is that such elucidation remains difficult. For quinolones, some improvements in this mechanistic approach have been achieved in the central nervous system (CNS), particularly with regard to their interaction with non‐steroidal anti‐inflammatory drugs (NSAIDs), and in genotoxicity and phototoxicity studies, particularly in comparison with other toxicities, such as to the cardiovascular, gastrointestinal, bone, reproductive, and developmental systems. This review concentrates on a description of the known effects of quinolones on various organ systems in experimental animals and humans. Given the logarithmic increase in the synthesis of new quinolones, it is questionable whether these drugs share similar safety and efficacy. Nevertheless, this mechanistic approach to the investigation and minimization of toxicity has produced satisfactory results to date and deserves to be continued.

ISSN:0098-4108    

DOI:10.1080/15287399509531978

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Hepatic enzymes that metabolize endogenous and xenobiotic compounds have been shown to be altered in adult rats that had been exposed to xenobiotics as neonates. Protein kinase C (PKC) is important in intracellular signaling and has been implicated in the regulation of hepatic monooxygenases. Therefore, we examined the effects of neonatal exposure to diethylstilbestrol (DE5) and phenobarbital (PB) on hepatic microsomal testosterone metabolism and on the alpha form of protein kinase C (PKCα) in adult rats. In adult males, neonatal exposure to DES altered adult testosterone metabolism such that 7α‐hydroxylation was increased by 58% but 2α‐, 16α‐, and 6β‐hydroxylations and conversion to androstenedione were decreased 31–44%. In contrast, adult males neonatally exposed to PB showed increased (20–27%) testosterone 2α‐ and 16α‐hydroxylations and androstenedione formation, but no effect was observed in the rate of 6β ‐ or 7α‐hydroxylations. Western blot analyses indicated that cytosolic PKCα levels in male rats neonatally exposed to PB were decreased by ∼63% relative to the vehicle control group but were not significantly altered in the DES males. The PKCα levels generally correlated (r =‐.75) with 16α‐hydroxytestos‐terone formation in all samples. These results show that neonatal treatment with DES or PB differentially alters hepatic monooxygenase enzyme activities and PKCα levels in adult rats.

ISSN:0098-4108    

DOI:10.1080/15287399509531979

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Intraspecies variation has been found to affect the physiological, behavioral, and biochemical responses to a variety of neurotoxicants, including the organophosphate diisopropyl fluorophosphate (DFP). However, there is little information on long‐term physiological responses to neurotoxicant exposure using strain as a dependent variable. In the present study, radiotelemetry methodology was used to continuously monitor core temperature, heart rate, and motor activity for 4 d following administration of 1.5 mg/kg DFP (SC) in four common strains of rat: Sprague‐Dawley (SD), Long‐Evans (LE), Fischer 344 (F344), and Wistar (WST). The F344 rat was least susceptible to DFP in terms of both a minimal hypothermic response and recovery of the day‐night difference in core temperature. The SD strain was unusual in that its heart rate was elevated relative to the other strains after DFP, in spite of a marked decrease in core temperature and motor activity. The LE strain exhibited the largest reduction in core temperature and heart rate following DFP. Serum and brain cholinesterase activity (ChE) measured 3 h after administration of 1.0 mg/kg DFP also indicated strain effects. The F344 showed less inhibition in these variables compared to the other strains, a response that may explain its attenuated thermoregulatory response to DFP. Overall, the inbred F344 rat demonstrated better resistance to DFP compared to the outbred strains. Therefore, the impact of genetic differences on sensitivity to neurotoxicants such as DFP could be an important tool in understanding the mechanism of action of these agents.

ISSN:0098-4108    

DOI:10.1080/15287399509531980

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

The effects of NO2or SO2on the bronchopulmonary reactions induced byCandida albicansin guinea pigs were evaluated. Thirty‐six guinea pigs (3 groups of 12 animals each) were sensitized with intraperitoneal injection of 10 mg ofC. albicans, given twice. Two groups of animals were exposed to about 5 ppm of NO2or SO2for 4 h/d, 5 d/wk; this exposure wasconducted atotal of 30 times during the study. The third group served as the control and was not exposed to these pollutants. Two weeks after the second sensitization, all the animals were subjected to inhalation exposure toC. albicans. For 42 h after the antigen challenge, the respiratory rates and expiration/inspiration ratios of the animals were automatically monitored. The number of animals showing tachypnea was significantly higher in the NO2exposure group than in the control from 15 h after antigen challenge. In the SO2exposure group, the number of animals showing prolonged expiration or prolonged inspiration, or both, was significantly higher than that in the control group, and the symptoms were observed from approximately 15 h after antigen challenge. These findings showed that delayed‐type dyspneic symptoms in guinea pigs were increased by exposure to NO2or SO2, although the symptoms and degree of dyspnea were different for the two gases.

ISSN:0098-4108    

DOI:10.1080/15287399509531981

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Risk assessment of exposure to chemicals having a toxic endpoint routinely uses the reference dose (RfD) approach based on uncertainty factors of 10. The purpose of this investigation was to evaluate whether the magnitude of the U.S. Environmental Protection Agency (EPA) 10× uncertainty factors has scientific merit when compared with data from recent human and animal experimental studies. A compilation and comparison of ratios between LOAEL/NOAEL (lowest observed adverse effect level/no observed adverse effect level) and subchronic/chronic values was made for six chlorinated compounds, namely, carbon tetrachloride, methylene chloride, pentachlorophenol, monochlorobenzene, chlorpyrifos, and 1,1‐dichloroethane. Data sets demonstrated that 91.3% of the LOAEL/NOAEL ratios were ≤6 while 87% of the ratios for the same parameter were ≤5. Furthermore, subchronic/chronic ratios were ≤3.5. From our investigation we concluded that automatic safety factors of 10× are not scientifically supportable and are overly conservative for the chlorinated compounds studied here.

ISSN:0098-4108    

DOI:10.1080/15287399509531982

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

INTRODUCTION TO BIOCHEMICAL TOXICOLOGY, Second Edition Edited byErnest HodgsonandPatricia E. LeviAppleton and Lange, East Norwalk, Connecticut, USA, 1994, 588 pp.

ISSN:0098-4108    

DOI:10.1080/15287399509531983

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399509531977

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor