摘要:

Trichloroethylene (TCE) is metabolized to chloral hydrate (CH) by the cytochrome P‐450 monooxygenase system. CH can either be oxidized by chloral hydrate dehydrogenase to trichloroacetic acid (TCA) or reduced by alcohol dehydrogenase to trichloroethanol (TCEtOH). The oxidation reaction requires NAD+, while the reduction reaction requires NADH. Since ethanol (EtOH) is known to alter the NAD+/NADH ratio in the hepatocyte, it was coadministered with TCE in an attempt to alter the metabolism of TCE. This would provide a means for predicting interactions of ethanol on the hepatotoxicity and carcinogenicity of TCE. Male Sprague‐Dawley rats were administered oral doses of either 1.52, 4.56, or 22.8 mmol/kg TCE, with the treatment group receiving an additional 1.52, 4.56, or 22.8 mmol/kg EtOH, respectively. Blood and urine samples were collected over 72 h. The clearance of TCE appeared to be saturated at the 4.56 mmol/kg dose, as evidenced by prolonged residence times for TCE in the body. Consistent with this result, there was an attenuation of the increases in the levels of TCEtOH and TCA in blood. However, the time to peak concentration of these metabolites was delayed with increasing doses and their residence time in the body was prolonged. Therefore, the area under the curve (AUC) for TCEtOH and TCA continued to increase with the higher doses of TCE. Measurement of the net output of these metabolites in urine confirmed that, although metabolism was saturated, the net metabolic conversion of TCE increased. As predicted, EtOH decreased blood levels of TCA, but only at early times at the high dose. EtOH did increase the urinary TCEtOH/TCA ratio at all dose levels. These results are consistent with the hypothesis of a more reduced state in the hepatocyte caused by the generation of excessive reducing equivalents by EtOH metabolism. The metabolism of TCE is shifted toward reduction to TCEtOH, away from oxidation to TCA. However, the effect was prominent only at extremely high doses of TCE and EtOH.

ISSN:0098-4108    

DOI:10.1080/15287398909531359

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

A case‐control study of household dogs was conducted to determine if exposure to sidestream cigarette smoke and chemicals in the home, use of topical insecticides, and obesity are associated with the occurrence of bladder cancer. Information was obtained by interview from owners of 59 dogs with transitional‐cell carcinoma of the bladder and 71 age‐ and breed size‐matched control dogs with other chronic diseases or neoplasms. Bladder cancer risk was unrelated to sidestream cigarette smoke and household chemical exposures. Risk was significantly increased by topical insecticide use (OR =1.6 for 1–2 applications per year and OR = 3.5 for >2 applications per year; X2trend;P=.008). This risk was enhanced in overweight or obese dogs. Further studies of this canine model may facilitate identification of specific carcinogens present in insecticides commonly used on pet animals and in the environment.

ISSN:0098-4108    

DOI:10.1080/15287398909531360

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Male and female Fischer 344 rats were fed diets containing 0, 1.0, 2.0, or 5.0% titanium dioxide (TiO2) coated mica for up to 130 wk. The dosage regimen produced no consistent or biologically important changes in survival, body weight gains, or hématologic or clinical chemistry parameters. Ophthalmoscopic examinations during wk 104 revealed a dose‐related increase in the incidence of cataracts in male but not female rats. However, the incidences of microscopic cataracts were similar in all groups of male and female rats. The high dose of TiO2‐coated mica was associated with a slightly increased incidence of adrenal medullary hyperplasia in males, but there was no evidence of progression of this change to either benign or malignant pheochromocytoma and there was no evidence of an adrenal medullary proliferative response in females. The incidence of mononuclear cell leukemia was elevated in high‐dose males that survived to the termination of the study, but there was no evidence that TiO2‐coated mica either induced or hastened the onset of the disease. Under the conditions of this experiment there was no evidence that TiO2‐coated mica produced either carcinogenic or toxicologic effects at dietary concentrations as high as 5.0%.

ISSN:0098-4108    

DOI:10.1080/15287398909531361

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

A major obstacle to the use of short‐term test results for predicting carcinogenicity is the nonavailability of methods that generate unequivocal estimations of potential carcinogenicity, even in the case of contrasting test results. We compared different mathematical classification methods such as linear discriminant analysis, theK‐nearest neighbor rule (KNN), and a new ad hoc classification method called dynamic carcinogenicity assessment (DYCA). The DYCA was developed by us to explicitly reflect the biological results. Through an analysis of a real data base we pointed out the advantages and limitations of these methods. KNN was clearly inferior to the other two algorithms. The novel DYCA approach was more sensitive to carcinogens, whereas linear discriminant analysis proved better for the identification of noncarcinogens.

ISSN:0098-4108    

DOI:10.1080/15287398909531362

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Rats develop pulmonary hypertension over a 2‐wk period of continuous ingestion of monocrotaline dissolved in drinking water (20 mg/l). The relationship between monocrotaline concentration and duration of exposure was investigated by giving male rats (initial body weight 100 g) monocrotaline in drinking water (5,10, 20, 40, or 60 mg/l) for 0, 1, 2, 4, 6, 10, or 20 d. Rats were killed 20 d after initiating treatment, and increased lung and right ventricular to body weight ratios were measured as indices of pulmonary hypertension. The accumulative dose of monocrotaline delivered over a 10‐d period using a drinking water concentration of 10 mg/l (18 mg/kg) produced the same degree of right ventricular hypertrophy and lung weight increases as the doses ingested over a 4‐d period by rats consuming 20 or 40 mg/l monocrotaline water (14 and 29 mg/kg). Phenobarbital pretreatment did not substantially alter the time course of toxicity induced with 20 mg/l monocrotaline water. Ingestion of 60 mg/l monocrotaline water for 1 d (11 mg/kg) resulted in right ventricular hypertrophy at 20 d. Since accumulative doses of less than 11 mg/kg did not produce toxicity and all doses greater than 14 mg/kg did, this range may be considered a threshold for inducing toxicity. However, organ weight increases following threshold exposures reversed over a 4‐wk period. Increases in the wall thickness of pulmonary arteries correlated with the development of right ventricular hypertrophy. Pulmonary inflammation was not an early response to monocrotaline administration, since there was no change in the proportion of cell types recovered in lung lavage fluid during the first 6 d of monocrotaline treatment.

ISSN:0098-4108    

DOI:10.1080/15287398909531363

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

The effect of the microsomal enzyme inducer β‐naphthoflavone (βNF) on the development of organophosphorus‐induced delayed neuropathy (OPIDN) was examined in two laboratories (VPI and MSU), utilizing two strains of White Leghorn hens. A single intraperitoneal injection of βNF at 80 mg/kg body weight 48 h prior to administration of o‐tolyl saligenin phosphate (TSP), the neuroactive metabolite of tri‐o‐tolyl phosphate (TOTP), caused a significant increase in hepatic microsomal cytochrome P‐450 concentrations and aniline hydroxylase activities after 72 h in both strains. Hepatic carboxylesterase and cholinesterase activities were not affected by βNF treatment in either strain. Administration of TSP in single subcutaneous doses of 20 and 25 mg/kg body weight (VPI) or 30 and 60 mg/kg body weight (MSU) caused significant inhibition of whole‐brain neuropathy target esterase (NTE) activity 24 h postdosing, and hens subsequently developed clinical signs characteristics of OPIDN. βNF had no significant effect on NTE inhibition or on initiation or severity of OPIDN clinical signs. However, OPIDN clinical signs were less severe in the strain of bird (MSU) with the higher intrinsic hepatic carboxylesterase activity and the higher βNF‐induced cytochrome P‐450 concentration. The study indicates that microsomal enzyme induction, which has been shown to alleviate TOTP‐induced delayed neuropathy, could not alleviate OPIDN resulting from exposure to TSP. This study also suggests that strain may affect susceptibility to TSP‐induced delayed neuropathy.

ISSN:0098-4108    

DOI:10.1080/15287398909531364

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Endosulfan stereoisomer I (E‐I) inhibited the activity of calmodulin‐dependent Ca2+‐ATPase to an extent of 15–55% in a concentration range of 1–20 μMunder in vitro conditions without significantly affecting the basal enzyme activity. The less toxic isomer E‐II produced no significant inhibition of Ca2+‐ATPase activity up to a concentration of 40 μM. The inhibition of Ca2+‐ATPase by E‐I was noncompetitive with respect to substrate, free from the influence of calcium, and competitively inhibited calmodulin activation kinetics. Reconstitution with the exogenous addition of calmodulin (5 and 20 μg) restored the inhibited enzyme activity, indicating nonspecific binding of E‐l with calmodulin. Both calmodulin‐activated and basal enzyme activity was inhibited significantly in rats fed E‐I (3 mg/kg body weight) for 15 d. These data suggest that endosulfan may modulate calmodulin‐related events in neurons and result in its neurotoxicity.

ISSN:0098-4108    

DOI:10.1080/15287398909531365

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Previous studies from this laboratory have demonstrated significant deficits in cardiovascular function in rats exposed to the pesticide chlordimeform (CDM) when body core temperature (Tco) was maintained at 37°C. To investigate the roleTcoon CDM toxicity, similar experiments were conducted over a range ofTcovalues. Adult rats (n = 30) were anesthetized with sodium pentobarbital (35 mg/kg) and randomly assigned to one of six equal groups. Groups were paired andTcowas maintained in the rats in each of the respective group pairs at one of three levels (37, 35, or 33°C). Rats in one group at each temperature level (groups 737, T35, and T33) were injected intraperitoneally with 60 mg/kg of CDM. Animals in the corresponding temperature‐matched groups (groups C37, C35, and C33, respectively) received volume‐matched injections of normal saline vehicle and served as time‐paired controls. The electrocardiogram and heart rate (HR) were monitored throughout the experimental procedure. There was a significant decrease in HR in all CDM‐treated groups when compared to the control group animals. The magnitude of the observed cardiac effect was attenuated in the T35 group when compared to that of the other treated groups. Similarly, lethality rates (number of deaths/total) for the T37, 135, and T33 groups were 215, 0/5, and 3/5, respectively; there were no deaths among the control‐group animals. From these and previous data from this laboratory, we conclude there may be a beneficial effect of moderate hypothermia in rats exposed to toxic agents while more severe hypothermia appears to offer no advantage and may actually exacerbate the toxic effect.

ISSN:0098-4108    

DOI:10.1080/15287398909531366

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

An examination of the efficacy of several structural types of chelating agents in the removal of cadmium from its intracellular deposits in mouse liver and kidneys reveals that of the structural types examined, only dithiocarbamates and a vicinal dithiol were able to mobilize cadmium from such intracellular sites. Esters of L‐cysteine, a macrocyclic thioether, and a disulfide of a dithiocarbamate were unable to cause any appreciable decrease in either renal or hepatic cadmium levels. Charged groups such as car‐boxylic acid groups reduce the efficacy as well as the toxicity of the structural types that can otherwise mobilize such cadmium. It was also found that the administration of a cadmium‐binding polymer ip leads to only a very slight net excretion of cadmium, while the po administration of this polymer leads to no net additional cadmium excretion. Of the compounds newly reported here, some are approximately equal in cadmium‐mobilizing efficacy to the most effective of previously reported compounds.

ISSN:0098-4108    

DOI:10.1080/15287398909531367

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287398909531358

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor