Showing papers in "Drug and Chemical Toxicology in 1982"
TL;DR: Chloroform, a review of its Metabolism, Teratogenic, Mutagenic, and Carcinogenic potential, and its metabolism- teratogenic-mutagenic-and-carcinogenic properties in humans and animals.
Abstract: (1982). Chloroform: A Review of Its Metabolism, Teratogenic, Mutagenic, and Carcinogenic Potential. Drug and Chemical Toxicology: Vol. 5, No. 1, pp. 1-87.
63 citations
TL;DR: Undiluted 2-ethoxyethanol or water (control) was applied to the skin of pregnant Sprague-Dawley rats on days 7–16 of gestation, and females exhibited ataxia following treatment of the high-dose group, and weight gain was significantly reduced in the last half of gestation.
Abstract: Undiluted 2-ethoxyethanol or water (control) was applied to the skin of pregnant Sprague-Dawley rats on days 7–16 of gestation (sperm = day 1). Applications were made 4 times daily in volumes of 0.25 or 0.50 ml 2-ethoxyethanol. Females exhibited ataxia following treatment of the high-dose group, and weight gain was significantly (p<0.001) reduced in the last half of gestation. Litters were collected by caesarian section on day 21 of gestation, and fetuses were examined for external defects. Half of the fetuses were cleared and stained in alizarin red S for skeletal examinations, and half were examined for visceral defects by the Wilson technique. Intrauterine death was 100% in the high-dose group. In the lower dosage group, there was a significant increase in the number of pregnant females with 100% dead implants (p<0.001), a significant reduction in the number of live fetuses per litter (p<0.001), a significant reduction in fetal body weight (p<0.001), and a significant increase in the incidence ...
52 citations
TL;DR: Alcohol, sodium salicylate, caffeine, papaverine, nitrofurantoin, and five tricyclic antidepressants showed similar toxicity in all compared cellular systems, and the agents with a known or suspected metabolism-mediated liver toxicity indeed had a high differential hepatotoxicity in vitro.
Abstract: The cytotoxicity of 16 agents was compared in four different in vitro cellular systems: HeLa cells, Chang liver cells, freshly isolated rat hepatocytes in suspension, and primary monolayer cultures of postnatal rat hepatocytes. The compared cytotoxicity values had been obtained by different techniques: inhibition of spreading of HeLa cells by 50% after 24 hr incubation and leakage of lactate dehydrogenase (LDH) by 50% in Chang liver cells, isolated rat hepatocytes in suspension, and primary cultures of rat hepatocytes after 4, 1, and 3 or 24 hr incubation with the chemicals. Carbon tetrachloride, halothane, acetaminophen, and tetracycline were more toxic to the hepatocytes compared with the two cell lines. Alcohol, sodium salicylate, caffeine, papaverine, nitrofurantoin, and five tricyclic antidepressants showed similar toxicity in all compared cellular systems. Thus, the agents with a known or suspected metabolism-mediated liver toxicity indeed had a high differential hepatotoxicity in vitro
41 citations
TL;DR: It is suggested that cadmium induces gluconeogenesis which is dose and time dependent and Serum glucose, serum protein, SGOT and SGPT were increased in cad mium treated rats.
Abstract: Male Sprague-Dawley rats were injected intraperitoneally with 0, 0.25, 0.75 and 1.25 mg/kg/day for 14 days. At the end of 7 and 14 days treatment period, body weight gain, serum protein, serum glucose, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were measured. Glucose-6-phosphatase (G6-Pase), fructose-1, 6-di-phosphatase (FD-Pase), phosphoenol pyruvate carboxykinase (PEPCK) and pyruvate carboxylase (PC) in kidney and liver were determined. A significant decrease in body weight gain in rats treated with 1.25 mg cadmium for 7 and 14 days was observed. Serum glucose, serum protein, SGOT and SGPT were increased in cadmium treated rats. A significant increase in all four key gluconeogenic enzymes were observed in both kidney and liver tissues of rats treated with cadmium. The results of this study suggest that cadmium induces gluconeogenesis which is dose and time dependent.
41 citations
TL;DR: The steep slope of the concentration-mortality curve at each time interval reflected the narrow range of concentrations that produced mortality (LC1-LC99), and a "Concentration x Time = Constant" relationship was apparent from 0.25 to 10 minutes.
Abstract: Perfluoroisobutylene (PFIB) is a highly toxic, colorless gas. The 4-hour Approximate Lethal Concentration in male rats is 0.5 ppm (v/v). The median lethal concentration (LC50) was calculated for groups of 10 male Crl:CD® rats, exposed, nose-only, for either 0.25, 0.50, 1, 2, 5, or 10 minutes to various concentrations of PFIB. Atmospheric concentrations of PFIB were determined by gas chromatography (electron capture detector). No mortalities or signs of respiratory irritation were seen during exposure. Weight loss and respiratory impairment were evident up to 48 hours post-exposure. Affected rats either died with gross pathological signs of pulmonary congestion or recovered with no apparent residual effects. The 0.25-minute LC50 was 361 ppm (321–415 ppm, 95% Confidence Limits); the 10-minute LC50 was 17 ppm (15–19 ppm, 95% Confidence Limits). The steep slope of the concentration-mortality curve at each time interval reflected the narrow range of concentrations that produced mortality (LC1-LC99). In...
30 citations
19 citations
TL;DR: Ozone toxicity for cultured rat lung fibroblasts was concentration dependent and was affected by the manner in which ozone was delivered to the cells, i.e. cultures were either rotated with a thin moving overlay of medium or were stationary with a fixed layer of medium.
Abstract: Ozone toxicity for cultured rat lung fibroblasts was concentration dependent and was affected by the manner in which ozone was delivered to the cells, i.e. cultures were either rotated with a thin moving overlay of medium or were stationary with a fixed layer of medium between the cells and the gas phase. The influence of culture medium components and culture dish composition on the toxicity of ozone were also investigated. Cell viability, used to measure ozone toxicity, was quantified by the chromium-51 release assay, and by a viability index calculated from the percentage of cells stained with a vital dye combined with the decrease in cell number as determined by DNA measurements. During stationary ozone exposure, toxicity appeared to be mediated primarily by hydrogen peroxide and could be inhibited by catalase or fetal bovine serum when measured by the viability index. During rotated exposure, catalase and fetal bovine serum provided no protection when measured by the viability index, however, when measured by the chromium-51 release assay, fetal bovine serum was partially protective. The effect of ozone on the fibroblasts was not influenced by whether culture dishes were glass or plastic, or whether the culture medium was balanced salt solution or complete chemically-defined medium.
14 citations
TL;DR: It appears that the rhesus monkey as well as the chimpanzee is a good animal model to study GSH-related conjugation reactions with predictive value for man.
Abstract: As a measure of glutathione (GSH) conjugation, urinary, fecal and biliary excretion of thioethers and hepatic GSH content were measured in rhesus monkeys following administration of single doses of naphthalene and diethylmaleate (DEM). Naphthalene had little or no effect on hepatic GSH content and the excretion of thioethers into urine, feces or bile of rhesus monkeys which is similar to that observed in chimpanzees and humans and is in contrast to results obtained from rats. Apparently, conjugation of naphthalene and/or its metabolites with GSH does not play a major role in the metabolism of naphthalene in primates, whereas it is one of the major pathways in rodents. Rhesus monkeys, like chimpanzees, excreted about 13% of the various doses of DEM (30, 75 and 200 mg/kg) as thioethers into urine which is half of that excreted by rats. Six hrs after administration of 200 mg/kg DEM, the hepatic GSH content was decreased by 90% in the rhesus monkey. During the first day after this dose (200 mg/kg), th...
14 citations
TL;DR: The Pepper Sauce did not induce terata in Sprague-Dawley rats nor skin sensitization in guinea pigs, and vinegar, an ingredient of Pepper Sauce, was shown to contribute significantly to the ocular toxicity.
Abstract: An acute oral LD50 of Pepper Sauce* in male white Sprague-Dawley rats was determined to be 2358 ml/kg with upper and lower limits of 2975 and 1870 ml/kg, respectively, at the 095 confidence level In the female rats, the LD50 was determined to be 1952 m1/kg with upper and lower limits of 2435 and 1564 m1/kg, respectively, at the 095 confidence level This sex variation was found to be insignificantA subchronic oral toxicity evaluation of Pepper Sauce in male and female white Sprague-Dawley rats revealed no gross or microscopic pathological changes in the animals nor were any significant biochemical changes noted The growth rates remained within normal rangePepper Sauce was shown to be a mild skin irritant and a moderate to severe eye irritant in New Zealand albino rabbits; vinegar, an ingredient of Pepper Sauce, was shown to contribute significantly to the ocular toxicity The Pepper Sauce did not induce terata in Sprague-Dawley rats nor skin sensitization in guinea pigs
9 citations
TL;DR: At least one transferase is more inducible by phenobarbital than the others, and this appears to be the case with glutathione S-transferase.
Abstract: The induction of glutathione S-transferase activity by pheno-barbital was studied in the male mouse. Ion-exchange chromato-graphy and density gradient isoelectric focusing were used to characterize the induction. Two transferases were separated by column chromatography, one peak was induced by phenobarbital while the other peak was unaffected. Three peaks of transferase activity were observed when control or induced cytosol was applied and eluted from a density gradient isoelectric focusing column. The induced F2 peak had twice the activity of the F2 control. The amount of activity in the peak labeled F3 was unaltered with PB treatment. It appears that at least one transferase is more induc-ible by phenobarbital than the others.
8 citations
TL;DR: It was concluded that a dose level of 450 mg/kg/day of TCB applied dermally to rabbits induced slight systemic toxicity.
Abstract: Groups of five male and five female New Zealand albino rabbits were treated by skin application with either 0 (distilled water control), 30, 150 or 450 mg/kg undiluted trichlorobenzene (TCB) for 5 days/week for four weeks. No treatment related systemic effects were observed at any of the treatment levels when body weight, clinical chemistry and organ weight parameters were measured. Systemic effects due to dermal application of TCB were present only in rabbits given 450 mg/kg/day. These effects included a slight but statistically significant increase in the urinary coproporphyrin excretion in males and slight pallor of the liver at gross necropsy in both sexes. Localized effects at the site of application were present in all treated rabbits. These effects were characteristic of the response to dermal irritation. Grossly, the fur was matted by a fine white bran-like scales with variable degrees of erythema, fissures, erosions and ulcers. Histopathologically, there was inflammation and thickening of...
TL;DR: Chloramphenicol, an inhibitor of cytochrome P-450, blocked the increase of serum glutamate-oxaloacetate transaminase activity enhanced by methanol pretreatment of rats exposed to CCl4.
Abstract: The mechanism by which methanol potentiates CC14 hepatotoxicity was studied in rats. Chloramphenicol, an inhibitor of cytochrome P-450, blocked the increase of serum glutamate-oxaloacetate trans-minase activity enhanced by methanol pretreatment of rats exposed to CC14. Chloramphenicol also decreased microsomal lipid peroxidation in both CC14 and methanol-pretreated, CC14 -intoxicated animals when measured 30 minutes after exposure. Chloramphenicol prevented the loss of glucose 6-phosphatase activity after CC1 and methanol. Sodium salicylate, which lowers the level of NADPH in the hepatocyte, blocked mthanol potentiation of CC14 damage as measured by the elevation of serum GOT activity. Therejore, methanol may potentiate CC14 hepatotoxicity by stimulation of CC14 bioactivation by cytochrome P-450 via an increase in the level of reduced NAD(P)H in the liver.
TL;DR: Investigations on the metabolic efficiency of liver microsomes, both in vito and in vivo, clearly demonstrate that the preventive effect against CCl4 depends mainly on the impaired metabolic activity of endoplasmic reticulum.
Abstract: Both partial surgical hepatectomy and a challenge with a small dose of CC14 depress the metabolism of xenobiotics in the liver. Infact, hepatocytes become provided with metabolic activity rdtes which are peculiar of either embryo or newborn rat lver.These experiments have shown that partial surgical hepatectomy prevents rats from death caused by otherwise lethal doses of CC14. At the same time, sham-operated animals survive to a limited ex= tent after a large dose of the halogenocompound.Investigations carried out on the metabolic efficiency of liver microsomes, both in vitro and in vivo, clearly demonstrate that the preventive effect against CC14 depends mainly on the impaired metabolic activity of endoplasmic reticulum.
TL;DR: The data suggest that potentiation of T CEA hepatotoxicity by acetone may result in part, from alterations of TCEA bioactivation and hepatic GSH concentrations.
Abstract: We have recently reported that pretreatment of rats with acetone potentiates both the hepatic glutathione (GSH) depletion and subsequent hepatotoxicity caused by 1,1,2-trichloroethane (TCEA). To determine if acetone treatment enhances the bioactivation of TCEA, the covalent binding of 14C-TCEA to tissue proteins was assessed both in vivo and in vitro. Male, Sprague-Dawley rats were treated with acetone (0.5 ml/kg; po), fasted 16 hr prior to dosing with 14C-TCEA (1.2 mmole/kg; ip), and killed 4 hr later. Overnight fasting, alone resulted in a six fold increase in covalent binding of 14C-TCEA to hepatic proteins compared to non-fasted rats. Acetone pretreatment, however, did not cause an increase in binding of 14C-TCEA 4 hr after dosing compared to fasted controls, although it did produce a 30% further decrease in hepatic GSH. When microsomes from acetone treated rats were incubated with 14C-TCEA, covalent binding to protein was significantly increased (35%) over using, microsomes from fasted contro...
TL;DR: The myocardial ultrastructure of daunomycin-toxic mice showed foci of incipient changes, characterized hy sarcoplasmic translucency, vacuolation of membrane-limited components, degeneration of mitochondria and lysosomal aggregates.
Abstract: In an attempt to induce in mice the cardiomyopathy associated with daunomycin treatment and to ameliorate this disorder by a protective pretreatment -with ICRF-159 (razoxane), young male BDF mice were injected with daunomycin, 6 mg/kg, in multiple doses. A second group of mice were pretreated by injection with razoxane, 200 mg/kg, 24 hours before each daunomycin administration.Within three weeks of the third daunomycin injection one half of the unprotected mice were moribund and were sacrificed. Wce pretreated with razoxane survived the length of the experiment without exhibiting any disabilities. Myocardial tissue of all mice was processed for light and electron microscopic examination.The myocardial ultrastructure of daunomycin-toxic mice showed foci of incipient changes, characterized hy sarcoplasmic translucency, vacuolation of membrane-limited components, degeneration of mitochondria and lysosomal aggregates.Evaluation of mice pretreated with razoxane either failed to reveal ultrastructural a...
TL;DR: Two pilot experiments are reported in which various combinations of stress, modifiers of glucose metabolism, and sulfur deficiency were investigated using urinary sulfur levels and tissue glucose and glycogen levels as indicators, suggesting an anabolic reversal.
Abstract: Two pilot experiments are reported in which various combinations of stress, modifiers of glucose metabolism, and sulfur deficiency were investigated using urinary sulfur levels and tissue glucose and glycogen levels as indicators. Urinary sulfur levels increased under certain conditions of stress but decreased with the injection of Escherichia coli endotoxin, suggesting an anabolic reversal. Heart and blood glycogen levels fell in rats fed a sulfur-deficient diet. These results are discussed in relation to seasonal variations in protein and glucose metabolism.
TL;DR: A computerized system was designed for behavioral teratology studies to generate preprinted data recording/submission forms, calculate testing dates, generate a daily activity schedule for testing, and update established data sets for access by data entry personnel.
Abstract: A computerized system was designed for behavioral teratology studies to (1) generate preprinted data recording/submission forms, (2) calculate testing dates, (3) generate a daily activity schedule for testing, and (4) update established data sets for access by data entry personnel. The computer-generated forms are used to record data from the following behavioral/developmental tests for rats: pup weights, pinna detachment, surface righting, cliff avoidance, incisor eruption, eye opening, negative geotaxis, olfactory discrimination, swimming development, open field, swimming maze and operant visual discrimination learning. Three behavioral teratology studies have been conducted in our laboratory using this computerized system. The human error rates in these studies were 0.26, 0.34 and 0.46 percent, respectively. The advantages of this system include: (1) computer-calculated test dates; (2) elimination of manual data transcription; (3) more consistent data recording and scoring conditions; (4) bette...
TL;DR: A 21-day subchronic dermal toxicity of trifluoropropylmethylcyclotrisiloxane (TFP) was conducted in New Zealand white rabbits and gross pathologic examination revealed no treatment related causes of death and all organs and tissues were observed normal at the time of necropsy.
Abstract: A 21-day subchronic dermal toxicity of trifluoropropylmethylcyclotrisiloxane (TFP) was conducted in New Zealand white rabbits. One control and three treatment groups of male and female animals were administered with the test material at levels of 0, 40, 200 and 400 mg/kg/day for three weeks. Mortality, behavioral reactions, growth and food consumption were observed and measured along with hematology, clinical blood chemistry, relative organ weight and pathology parameters. Five animals died at the highest dose level during the test period. Treatment with two higher dosages generally resulted in reduced rate of weight gain, lower food consumption, depressed serum alkaline phosphatase activity and increased activity of the serum enzymes. No significant adverse effects were observed at lower levels of 40 mg/kg. Gross pathologic examination revealed no treatment related causes of death and all organs and tissues were observed normal at the time of necropsy. There were no chemical related microscopic changes found in any of the test animals.
TL;DR: It is unlikely that AMA will present a significant health hazard from skin contact under normal conditions of industrial handling, and there were no significant chemical related microscopic changes found in any of the test rabbits.
Abstract: A 28-day subchronic dermal toxicity of allyl methacrylate (AMA) was conducted in New Zealand white rabbits. Groups of six male and six female rabbits were treated with the test material at dose levels of 0, 25, 50 and 100 mg/kg/day for four weeks. One satellite group of male and female rabbits was also treated with 100 mg/kg/day of AMA. No overt signs of toxicity or abnormal behavior were seen among the rabbits during the treatment period. Two females from the 50 mg/kg/day group and two females at the highest dose level died during the course of the study. No mortalities and no significant adverse effects were observed in the low dose and control rabbits. Males treated with the highest dose level exhibited reduced weight gain and lower food consumption. The test material has no significant adverse effects on serum biochemistry, urine and hematological parameters or absolute and relative organ weights. No chemical related gross pathological alterations were observed in any of the organs or tissues examined at the time of necropsy except slight hemorrhage in the fascia of the skin of rabbits treated with 100 mg/kg/day of AMA. There were no significant chemical related microscopic changes found in any of the test rabbits. The animals of the satellite group appeared fully recovered following the 28-day dermal exposure to AMA. These results suggest that it is unlikely that AMA will present a significant health hazard from skin contact under normal conditions of industrial handling.
TL;DR: Both in vitro and in vivo peroxidative challenge of arachidonic acid content in hepatic microsomes causes comparable alterations of this parameter, whatever the initial fatty acid pattern following the dietary regimen.
Abstract: A PUFA-deficient diet causes deficiency synptoms and aiters the fatty acid pattern in liver microsomal lipids. However, CC1 lethality and sleeping time remain unchanged while the hepatic level of cytochrome P is only slightly lowered by the dietary regimen. In accordance, the amplitude of double bond shifting in microsomal lipids is far from being depressed in animals deprived of the peroxidative substrate. In fact, the experimental treatment does not impair intestinal absorption, liver uptake and metabolism of CC14 given orally. Finally, both in vititea and in vivo peroxidative challenge of arachidonic acid content in hepatic microsomes causes comparable alterations of this parameter, whatever the initial fatty acid pattern following the dietary regimen. These findings provide evidence excluding an influence of the fatty acid composition of the diet on the severity of damages due to halogeno-alkane exposure.
TL;DR: Increases in the relative weights of the kidneys, brain and testes of males at 30 mg/kg/day were correlated with decreased body weight gain in this group, and there were no effects on hematology or serum chemistry parameters, and no morphologic changes were found.
Abstract: Buflomedil was administered intravenously to rats at dosages of 1, 4, 12 or 30 mg/kg/day for up to three months. The no-adverse-effect dosage was considered to be 12 mg/kg/day. At 30 mg/kg/day several deaths and clinical signs, including ataxia, decreased activity, dyspnea and jerking movements after dosing, were observed. These were considered to result from the acute, exaggerated pharmacologic effects of buflomedil. Body weight gain and food consumption were decreased after six weeks in males at 30 mg/kg/day. Increases in the relative weights of the kidneys, brain and testes of males at 30 mg/kg/day were correlated with decreased body weight gain in this group. There were no effects on hematology or serum chemistry parameters, and no morphologic changes were found.
TL;DR: It is concluded that allyl methacrylate is not likely to be a sensitizer and exposure to this material in industrial handling situations will not present an appreciable risk of human skin sensitization.
Abstract: The skin sensitization potential of allyl methacrylate (AMA) was studied in Hartley albino guinea pigs. Two groups of guinea pigs (10 per compound) were subjected to repeated insult patch tests either with AMA or with dinitrochlorobenzene (DNCB). All guinea pigs treated with DNCB (positive control) were sensitized. None of the guinea pigs treated with AMA exhibited any evidence of sensitization and no reactions attributable to AMA were elicited as a result of exposure during the insult phase of the patch test. Based on these results, it is concluded that allyl methacrylate is not likely to be a sensitizer and exposure to this material in industrial handling situations will not present an appreciable risk of human skin sensitization,