Showing papers on "Toxicity published in 1976"

Oxygen toxicity: augmentation of antioxidant defense mechanisms in rat lung.

Abstract: In studies directed at determining the activities of selected enzymes in lung tissue after in vivo exposure to hyperoxia, 70-day-old rats were exposed to 85% or 90% O2 for 1-14 days. After 7 days of exposure to 90% O2 (1atm), superoxide dismutase activities in mitochondrial and cytosolic fractions increased, respectively, to 245 and 145% of control; glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase activities increased, respectively, to 317, 175, and 413% of control. The levels of reduced glutathione and total nonprotein sulfhydryl compounds were elevated to 195% and 365% of control. Similar changes were observed in rats exposed to 85% O2 for up to 14 days, but to a lesser degree. The changes are interpreted as a reflection of the overall magnitude of oxidant-induced lung injury-reparative processes. The results suggest that hyperoxia induces an increase in lung "antioxidant" defense capabilities. This apparent adaptive response may be important in decreasing the susceptibility of lung tissue to continued O2 toxicity.

Degradation, metabolism and toxicity of synthetic pyrethroids.

Abstract: Synthetic pyrethroidal compounds undergo biodegradation in mammals both oxidatively and hydrolytically, and depending on the type of compound, either of the pathways may predominate. Thus, (+) - or (+/-) -trans isomers of the chrysanthemumate ester of primary alcohols such as fenothrin, furamethrin, proparthrin, resmethrin, and tetramethrin (and possibly permethrin, too) are metabolized mainly through hydrolysis of the ester linkage, with subsequent oxidation and/or conjugation of the component alcohol and acid moieties. On the other hand, the corresponding (+)-cis enantiometers and chrysanthemumate of secondary alcohols like allethrin are resistant to hydrolytic attack, and biodegraded via oxidation at various sites of the molecule. These rapid metabolic degradations, together with the presumable incomplete absorption from the gastrointestinal tract, would generally contribute to the low acute toxicity of synthetic pyrethroids. These compounds are neither skin irritants nor skin sensitizers, and inhalation toxicity as well as dermal toxicity are fairly low. Neither is teratogenic in rats, mice, and/or rabbits or mutagenic on various bacterial strains. Subacute and chronic feeding of higher amounts of the compounds to rats invariably causes some histopathological changes in liver; however, these are neither indicative nor suggestive of tumorigenicity. Based on existing toxicological information, the present recommended use patterns might afford sufficient safety margin on human population. However, in extending usage to agricultural pest control, much more extensive investigations should be forthcoming from both chemical and biological aspects, since there is scant information on the fate of these pyrethroids in the environment. Also several of the compounds may be very toxic to certain kinds of fish and arthropods.

Paraquat toxicity: proposed mechanism of action involving lipid peroxidation.

Abstract: The purpose of this study was to investigate the hypothesis that paraquat pulmonary toxicity results from cyclic reduction-oxidation of paraquat with sequential generation of superoxide radicals and singlet oxygen and initiation of lipid peroxidation. In vitro mouse lung microsomes catalyzed an NADPH-dependent, single-electron reduction of paraquat. Incubation of paraquat with NADPH, NADPH-cytochrome c reductase, and purified microsomal lipid increased malondialdehyde production is a concentration dependent manner. Addition of either superoxide dismutase or a single oxygen trapping agent 1,3-dipheylisobenzo furan inhibited paraquat stimulated lipid peroxidation. In vivo, pretreatment of mice with phenobarbital decreased paraquat toxicity, possibly by competing for electrons which might otherwise reduce paraquat. In contrast, paraquat toxicity in mice was increased by exposure to 100% oxygen and by deficiencies of the antioxidants selenium, vitamin E, or reduced glutahione (GSH). Paraquat, given IP to mice, at 30 mg/kg, decreased concentrations of the water-soluble antioxidant GSH in liver and lipid soluble antioxidants in lung. Oxygen-tolerant rats, which hae increased activities of pulmonary enzymes which combat lipid peroxidation, were also tolerant to lethal doses of paraquat as indicated by an increased paraquat LT50. Furthermore, rats chronically exposed to 100 ppm paraquat in the water had elevated pulmonary activities of glucose-6-phosphate dehydrogenase and GSH reductase.These results were consistent with the hypothesis that lipid peroxidation is involved in the toxicity of paraquat.

The Serum Digitalis Concentration — Does It Diagnose Digitalis Toxicity?

Abstract: We propose that an investigation of the serum digitalis concentration as a test for digitalis toxicity should (1) study patients with similar toxic manifestations, (2) obtain control concentrations from nontoxic patients with symptoms suggesting toxicity, (3) define criteria for toxicity and nontoxicity, (4) select representative patients, (5) describe the study population and (6) analyze how much diagnostic information the serum digitalis concentration provides that cannot be inferred from other observations. To determine if available evidence validates the digitalis concentration as a test for toxicity 27 reports were reviewed. No investigation employed symptomatic controls. Of five studies most consistent with points 1-5 only three demonstrated higher mean serum digitalis concentrations in toxic patients. Whether knowledge of the digitalis concentrations was diagnostically more useful than knowledge of the digitalis dosage, renal function, serum potassium concentration and cardiac status was not determined in any study. The usefulness of the serum digitalis concentration as a test for digitalis toxicity is therefore not established.

Influence of dietary zinc on lead toxicity in the rat.

Abstract: An investigation of the influence of dietary zinc (8, 35, 200 ppm) on the toxicity of dietary lead (0, 50, 200 ppm) in the young male rat in a seven week period indicated that as dietary zinc increased, the severity of lead toxicity decreased. Evidence included decreased lead concentration in blood, liver, kidneys, and tibias; decreased excretion of urinary delta-aminolevulinic acid; decreased accumulation of free erythrocyte porphyrins; decreased inhibition of kidney delta-aminolevulinic acid dehydrase activity; and a decrease in apparent lead absorption. Infected zinc did not afford protection against lead toxicity. The data indicate that the protective effect of zinc on lead toxicity is largely mediated by an inhibition of lead absorption at the intestinal level.

Phase II evaluation of bleomycin. A Southwest oncology Group study.

Abstract: Bleomycin given intravenously (i.v.) or intramuscularly (i.m.) in twice-weekly doses of 10 mg/m2 was evaluated for efficacy and toxicity in 382 patients. Responses were observed in 11/27 Hodgkin's diseases, 10/30 lymphomas, 9/22 squamous cell cancers of ectodermal origin, 12/26 germinal cancers, and 3/8 renal adenocarcinomas. The i.m. route is less likely to casue pulmonary toxicity or hypotension than the i.v. route. Advanced age and total doses exceeding 200 mg were associated with a higher risk of lung toxicity. All responders had shown at least improvement upon receiving 200 mg; higher total doses should be used only in responding patients.

Oxygen and toxicity inhibition of amino acid biosynthesis

Abstract: ALTHOUGH oxygen is of therapeutic benefit for various human diseases, its usefulness is limited by its toxicity1,2. In spite of progress, the cause of the convulsions observed in humans and other animals exposed to hyperbaric oxygen remains unknown3,4, and the biochemical basis of the lung damage resulting from chronic exposure to increased oxygen tensions is poorly understood5. Oxygen toxicity, although necessarily expressed in different ways, affects various life forms from bacteria to man3,4. There is considerable theoretical basis and experimental evidence for mechanisms of toxicity shared at the cellular and subcellular levels, and research on basic sites of toxicity has often involved tissue cultures or bacteria2. The growth and respiration of Escherichia coli is rapidly, but reversibly, inhibited by hyperbaric oxygen in minimal salts medium6. Significant protection for some microbes against the growth-inhibitory effects of hyperbaric oxygen has been obtained with nutritional supplements, including yeast extract7. We have now found that E. coli E-26, the source of which has been identified previously6, is protected from oxygen toxicity by yeast extract because of its amino acid content: a mixture of 20 amino acids gave similar protection.

Teratology and percutaneous toxicity studies on hair dyes

Abstract: Twelve hair dye formulations were tested for systemic toxicity by topical application twice weekly for 13 wk to groups of 12 New Zealand white rabbits and for teratologic effects following applications to groups of 20 pregnant Charles River CD rats on days 1, 4, 7, 10, 13, 16, and 19 of gestation. The three semipermanent formulations were applied as is, and the nine oxidation dyes were mixed 1:1 with 6% hydrogen peroxide just prior to application, as in normal use. The formulations induced a broad spectrum of dyes and dye intermediates used or considered useful in oxidative and semipermanent hair color products. In the teratology study no biologically significant soft tissue or skeletal changes were noted. Similarly, the mean numbers of corpora lutea, implantation sites, live fetuses, and resorptions per pregnancy, as well as numbers of litters with resporptions, were not significantly affected by the dye treatment. In the percutaneous toxicity study there was no evidence of compound-induced systemic effects. Microscopic examination of 25 tissues from each animal gave no indication of histomorphologic evidence of toxicity. No dye discoloration of urine was seen at any time during the test or at necropsy. Some of the dye groups showed epidermal hyperplasia, which was probably a reflection of slight irritation due to the frequency of application of the oxidation formulations.

Intracellular effects of chronic arsenic administration on renal proximal tubule cells.

Abstract: Arsenic is one of the more common toxic elements in the environment. The kidney accumulates this element and plays a major role in its metabolism and excretion. Mitochondria have been found in vitro to be highly sensitive to the toxicity of this element. Combined oxygen electrode and electron microscopic studies were conducted on kidneys of rats exposed to arsenate in the drinking water at concentrations of 40, 85, or 125 ppm for 6 weeks to evaluate in vivo mitochondrial toxicity. Decreased state 3 respiration and respiratory control ratios were observed in kidneys of rats given the 85 and 125 ppm dose levels. Ultrastructural alterations, which consisted of swollen mitochondria and increased numbers of dense autophagic lysosome‐like bodies, were confined to proximal tubule cells of these same animals. This study places renal arsenate mitochondria/ toxicity into an in vivo context and points to the value of using complementary techniques for assessing the subacute or chronic toxicity of environmental agents.

Role of iron deficiency in inducing susceptibility to manganese toxicity.

Abstract: Daily intraperitoneal administration of manganese chloride (15 mg/kg) to rats, maintained on an irondeficient diet, produced marked alterations in the activity of succinic dehydrogenase, monoamine oxidase, and in the morphology of the liver. Manganese accumulation was also significantly increased in such rats than after similar treatment to normally fed rats. Iron deficiency leads to increased absorption of manganese which is responsible for increased susceptiblity to manganese toxicity in these animals.

Structure and action of bleomycin.

Abstract: The structures of bleomycins and of other bleomycin-phleomycin group of antibiotics were described. The activity of bleomycins and their derivatives in causing strand scission of SV40 viral DNA suggests that the beta-aminoalanine amide moiety and the carbamoyl group are involved in this reaction. More than one guanido group in the terminal amine of bleomycin-phleomycin group antibiotics caused irreversible renal toxicity in dogs. Pulmonary toxicity varied depending on the terminal amines. A bleomycin-inactivating enzyme which distributes widely in animal cells was shown to be a new aminopeptidase B which hydrolyzes beta-aminoalanine amide group. At least one of the reasons for activity against squamous cell carcinoma was shown to be due to the lower content of this enzyme. The inhibitor of this enzyme was synergistic to bleomycin in inhibiting growth of cells, thus suggesting the intracellular action of this enzyme. Selected for further study from the bleomycins containing various terminal amines, bleomycin 5033 which showed the same activity against squamous cell carcinoma in mouse skin as the bleomycin used at present and lower toxicity than the latter, and bleomycin A5196 which showed stronger activity and stronger toxicity but lower lung toxicity than the latter.

Reduction of ifosfamide toxicity using dose fractionation.

Abstract: Ifosfamide was given in iv doses of 600 to 1200 mg/sq m/day for 5 days to 32 cancer patients, refractory to prior therapy, in an attempt to investigate the possibility of reducing toxicity by dose fractionation Microscopic hematuria occurred in 14% and gross hematuria in only 10% of the patient trials Azotemia did not occur in any patient on this study Reversible myelosuppression was comparable to that found by other investigators Other side effects such as nausea and mental confusion occurred infrequently Ifosfamide produced antitumor effect in 7 of 27 evaluable patients This study indicates that the renal and bladder toxicity of ifosfamide can be substantially reduced if the drug is administered in iv infusions of 1 to 2 hr daily for 5 days

Influence of Dietary Selenium on Lead Toxicity in the Rat

Abstract: An investigation of the influence of dietary selenium (0015, 005, 050, 10 ppm) on toxicity of dietary lead (0 and 200 ppm) in the young male rat indicated that selenium was mildly protective against the toxic effects of lead, but only up to 050 ppm selenium At the excess selenium dietary level an exaggeration of lead toxicity was observed Criteria employed to judge the effects of dietary selenium on lead toxicity included tissue lead concentration and urinary delta-aminolevulinic acid excretion One exception to the exaggeration effect of excess selenium on lead toxicity was the protective effect of selenium on liver delta-aminolevulinic acid dehydratase activity Since lead depressed kidney selenium concentration, lead may act as an antagonist to selenium metabolism

Toxicology of vindesine (desacetyl vinblastine amide) in mice, rats, and dogs.

Abstract: Comparative acute intravenous toxicity studies of vinblastine sulfate (VLB), vincristine sulfate (VCR), and vindesine1 in mice and rats indicated that vindesine was more toxic than VLB and less toxic than VCR. Rats were able to tolerate larger repeated doses of vindesine than dogs. Rats given intravenous doses totaling 0.15 mg/kg‐wk vindesine for 3 months developed no remarkable signs of toxicity. Doses of 0.3 mg/kg‐wk or greater produced anorexia, depressed blood cell counts, atrophic intestinal mucosa, inhibition of spermatogenesis, extramedullary hematopoiesis, and infections. Dogs were given total weekly intravenous doses of 0.04, 0.08, 0.1, or 0.16 mg/kg vindesine for 3 months. The only observed effect in the two lower dose groups was inhibition of spermatogenesis. Groups receiving 0.1 or 0.16 mg/kg developed leukopenia, slight erythropenia, inhibition of spermatogenesis, focal skeletal muscle degeneration, elevated lactic dehydrogenase, and an increase in bone marrow myeloid: erythroid ratio. No evi...

The Effect of Phenobarbital on Cyclophosphamide Antitumor Activity

Abstract: We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of microsomal enzyme induction by phenobarbital on the antileukemic activity and bone marrow toxicity of cyclophosphamide. Phenobarbital drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily phenobarbital intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without phenobarbital pretreatment showed a constant 90% (1-log) reduction in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas enzyme induction had no effect on the toxicity of the drug to normal bone marrow colony-forming units. Parallel survival studies confirmed the 1-log diminution in the antileukemic activity of cyclophosphamide in phenobarbital-pretreated mice. This phenobarbital-induced change in the antitumor activity of cyclophosphamide appears explainable on a pharmacokinetic basis. The Friedman and Boger assay for plasma alkylating metabolites showed that the reduction in the area under the plasma metabolite curve caused by enzyme induction exactly predicted the observed reduction in cyclophosphamide antitumor effect.

Methods to assess reproductive effects of environmental chemicals: studies of cadmium and boron administered orally.

Abstract: Results of a U.S.S.R.--U.S. cooperative laboratory effort to improve and validate experimental techniques used to assess subtle reproductive effects in male laboratory animals are reported. The present studies attempted to evaluate the reproductive toxicity of cadmium as cadmium chloride and boron as borax (Na2B4O7) and to investigate the mechanism of toxicity in the rat following acute and subchronic oral exposure. In vitro cell separation techniques, in vivo serial mating tests, and plasma assays for hormones were utilized. Effects on the seminal vesicle and prostate were evaluated with chemical and enzyme assays. Clinical chemistry was monitored routinely. Acute oral doses, expressed as boron were 45, 150, and 450 mg/kg while doses for cadmium equivalent were 6.25, 12.5, and 25 mg/kg. Rats were also allowed free access to drinking water containing either boron (0.3, 1.0, and 6.0 mg/l.) or cadmium (0.001, and 0.l mg/l.) for 90 days. Randomly selected animals were studied following 30, 60, and 90 days of treatment. These initial studies, utilizing a variety of methods to assess the reproductive toxicity of environmental substances in male animals, suggest that cadmium and boron at the concentrations and dose regimens tested are without significant reproductive toxicity.

The modification of gastrointestinal tolerance and responses to abdominal irradiation by chemotherapeutic agents.

Abstract: Groups of male DBA/2 mice were irradiated with partial abdominal exposures of x radiation ranging from 100 to 1,600 rads. Concomitant with radiation exposure and at 1 or 4 hours prior to, and at 1, 6, 24, or 48 hours after irradiation, various chemotherapeutic agents were administered, i.e., methotrexate, Cytoxan, adriamycin and BCNU. The results suggest that excessive gastrointestinal toxicity may result if aggressive chemotherapy is closely spaced with radiation exposure for the treatment of abdominal neoplasms. However, adjustment of dose and time patterns based on the proliferative responses of the mucosa may circumvent such toxicity to a large extent.

Clinical and Pharmacological Evaluation of Triazinate in Humans

Abstract: Summary Twenty-four patients with advanced solid tumors and seven with acute leukemia were treated with a triazine folate antagonist, triazinate, to determine the toxicity spectrum, the maximum tolerated dose, and the pharmacological disposition of the drug. Negligible toxicity was seen with single doses of 20 to 225 mg/sq m given as a 0.5-hr infusion. Single doses of 300 to 600 mg/sq m infused over 0.5 to 3 hr caused moderate to severe central neurological impairment with light headedness, somnolence, visual disturbances, weakness, and in one patient, severe respiratory distress and cyanosis. Skin, mucous membrane, and bone marrow toxicity were mild to moderate with single doses. When triazinate was given by a multiple-dose schedule every 12 to 24 hr, there was no neurological toxicity, but mucositis, skin toxicity, and myelotoxicity were increased. Five patients developed an erythematous to desquamative rash at the site of previous or concurrent radiotherapy. Serum disappearance of triazinate was at least biphasic. After the initial equilibrium, the serum half-time was 2 to 5 hr, with considerable variation from patient to patient. Single i.v. doses of 300 mg/sq m resulted in serum levels of 10 -3 m or higher for 8 hr and, with repeated doses, this level could be maintained. Administration p.o. resulted in serum concentrations Measurable objective solid tumor responses were not seen in this Phase 1 study, although two patients had stabilization of previously advancing disease. Decreases in peripheral blasts occurred in both types of acute leukemia, but improvement in the bone marrow was not observed.