Showing papers on "Toxicity published in 1981"

Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound

Abstract: Benzoyl peroxide, a widely used free radical-generating compound, promoted both papillomas and carcinomas when it was topically applied to mice after 7,12-dimethylbenz[a]anthracene initiation. Benzoyl peroxide was inactive on the skin as a complete carcinogen or as a tumor initiator. A single topical application of benzoyl peroxide produced a marked epidermal hyperplasia and induced a large number of dark basal keratinocytes, effects similar to those produced by the potent tumor promoter 12-O-tetradecanoyl phorbol-13-acetate. Benzoyl peroxide, like other known tumor promoters, also inhibited metabolic cooperation (intercellular communication) in Chinese hamster cells. In view of these results caution should be recommended in the use of this and other free radical-generating compounds.

Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine.

Abstract: This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.

Central nervous system toxicity of high-dose systemic cytosine arabinoside

Abstract: Forty-nine adult patients with acute leukemia in relapse, refractory to conventional therapy, were studied. Increasing quantities of i.v. bolus high-dose cytosine arabinoside (cytarabine) were administered using the following schedules: 3 g/m2 every 12 hrs for 4-16 consecutive doses, or 4.5 g/m2 every 12 hrs for 12 consecutive doses. Patients ages ranged 16-76 year (median: 38). Thirty-seven patients had previously received either induction or maintainance therapy with conventional doses of cytarabine. Cerebral or cerebellar dysfunction attributable to cytarabine was observed in eight patients and appeared 6-8 days (mean: 6.6) after the first dose and lasted 3-7 days (mean: 4.7). None of 12 patients receiving up to 24 g/m2 total dose of 48 g/m2 developed reversible neurologic dysfunction. Four of six patients receiving 54 g/m2 developed CNS toxicity (irreversible in two cases), a significantly greater incidence compared to toxicity in patients receiving less than or equal to 48 g/m2 total dose (P less than 0.01). CNS toxicity was dose-related since patients treated for 12 consecutive doses of 4.5 g/m2 had significantly greater CNS toxicity than 12 consecutive doses at 3 g/m2 (P less than 0.04). Systemic cytarabine doses less than 54 g/m2 can be administered with minimal CNS side-effects.

A comparative study of the toxicity of Fusarium verticillioides (= F. moniliforme) to horses, primates, pigs, sheep and rats.

Abstract: An isolate of Fusarium verticillioides (MRC826) that induced experimental leukoencephalomalacia, also caused acute toxicity when fed to pigs and administered per rumen fistula to sheep. Pigs developed severe pulmonary oedema while sheep manifested severe nephrosis and hepatosis. A less toxic isolate (F. verticillioides MRC602), fed to baboons, resulted in acute congestive heart failure or hepatic cirrhosis, depending on the dose. Both isolates were toxic to rats and caused similar lesions, namely, hepatic cirrhosis and intraventricular cardiac thrombosis.

Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity

Abstract: Anionic liposomes containing doxorubicin were evaluated in mice for therapeutic potential in reducing the risks of chronic cardiotoxicity characteristic of long-term high-dose anthracycline therapy. Doxorubicin first was complexed to phosphatidylcholine and then entrapped in anionic vesicles. Quantitation of myocardial injury was accomplished through examination of thin sections of cardiac tissue by light microscopy. At treatment levels of either 20 or 40 mg/kg (total dose), mice receiving liposomal doxorubicin had toxicity scores indistinguishable from or only slightly greater than those of saline-treated controls. Similar total doses of free drug produced moderate to severe myocardial damage and yielded much higher toxicity scores. Mixture of free doxorubicin with empty liposomes did not alleviate cardiac toxicity, indicating that the drug must be entrapped within phospholipid vesicles for reduction in toxicity. The inhibition of body growth produced by free doxorubicin at both dose levels was also completely eliminated by encapsulation in liposomes. Doxorubicin liposomes were also tested for chemotherapeutic potential against L-1210 and P-388 murine leukemias. In all cases, treatment with liposomal doxorubicin produced increases in life-span greater than that observed for free drug. We conclude that anionic liposomes can function as efficacious carriers of doxorubicin. These vesicles possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.

Toxicity of interferon.

Abstract: The effects of partially purified human leucocyte interferon (PIF) and of a preparation purified by passage twice through a monoclonal antibody affinity chromatography column (NK21F) were compared with those of a control solution in healhty volunteers. After intramuscular injections both interferon preparations caused rises in pulse rate and body temperature, changes in circulating white cell counts, and various unpleasant symptoms, the most common of which were headache, malaise, and fever. Slightly lower doses of NK21F were given, and this was reflected in lower peak serum concentrations. Mean symptom scores, however, were not lower after NK21F than after PIF. Local inflammatory reactions eight hours after intradermal inoculations of these interferons were similar. Purification of interferon using a monoclonal antibody does not reduce the facets of its activity considered in this study. They are therefore inherent in the leucocyte interferon type selected by the antibody.

Anticonvulsant toxicity in vitro: possible role of arene oxides.

Abstract: Human lymphocytes incubated with a mouse hepatic microsomal drug metabolizing system were used to study the cytotoxicity of four anticonvulsants. In vitro toxicity assessed by trypan blue dye exclusion was significantly greater for compounds with relatively high clinical toxicity (mephenytoin and phenacemide) than those with only rare cytotoxic complications (phenytoin and phenobarbital). No toxicity occurred in the absence of microsomes and toxicity was enhanced by inhibitors of epoxide hydrolase suggesting that the cytotoxicity of the drugs may result from arene oxide metabolites. In vivo, the covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions. The method may be useful in assessing the potential of a drug for toxicity, the mechanism of cell damage and individual differences in cell defenses within the human population.

Lead Toxicity as Related to Glutathione Metabolism

Abstract: The effect of lead poisoning on glutathione metabolism was studied in rat pups born of dams receiving a commercial laboratory diet supplemented with 0.5% lead acetate. Results showed that the body weight gain of the first 3 weeks of life and at the age of 6 weeks was significantly less in both male and female pups nourished by lead-fed dams than those raised by dams receiving the lab diet. Lead ingestion decreased hematocrit levels and hemoglobin values and increased the weights of liver, kidney, spleen and brain. Concentrations of plasma free histidine, glutamic acid and serine were decreased in lead-poisoned rats but glycine levels were markedly increased. After 4 weeks of lead feeding, both sexes had an increased glutathione concentration in erythrocytes, liver and kidney. Isotope studies further indicated that the incorporation of cystine-35S was significantly increased in glutathione but decreased in protein of liver and kidney of lead-fed rats. Similarly, lead ingestion significantly increased glycine-1-14C incorporation into renal glutathione. However, the activities of glutathione reductase and glutathione peroxidase were unaffected by lead poisoning. The data suggest a compensatory mechanism operates to overcome the toxicity of ingested lead by maintaining a high concentration of glutathione in the liver and kidney.

Methotrexate Accumulation and Folate Depletion in Cells as a Possible Mechanism of Chronic Toxicity to the Drug

Abstract: Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. In this study the intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in nine of 12 red cell and three of five liver samples. It is proposed that persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.

Acute Toxicity of Nitrite to Rainbow Trout (Salmo gairdneri): Effects of pH, Nitrite Species, and Anion Species

Abstract: The toxicity of nitrite to rainbow trout is pH-dependent within the range considered acceptable to most freshwater aquatic life (pH 6.5–9.0). Both of the nitrite species, NO2− and HNO2, are toxic. It is recommended that nitrite criteria to protect freshwater aquatic life be based on total nitrite, and that such criteria reflect the pH dependence of nitrite toxicity. Variation in the toxicity of nitrite in the presence of chloride, sulfate, phosphate, and nitrate anions has also been demonstrated. It is concluded that the toxicity of nitrite to fishes, in addition to being pH-dependent, is also dependent in varying degrees upon many of the anions that are commonly found in natural aquatic environments.Key words: nitrite, pH, chloride, phosphate, sulfate, toxicity, rainbow trout, Salmo gairdneri

Difference in accumulation of puffer fish toxin and crystalline tetrodotoxin in the puffer fish,Fugu rubripes rubripes.

Abstract: In order to examine whether the innocuous cultured puffer fish, Fugu rubripes rubripes (Japanese name, torafugu), is able to accumulate orally administered tetrodotoxin (TTx) or not, a feeding test was carried out for 20 days using the toxic ovary of puffer fish, its methanol extract, and crystalline TTx, and the toxicity of various tissues was bioassayed. In the fish of the ovary-feeding group, all the tissues tested were already toxic on the 5th day, and the toxicity of most tissues increased gradually during the experimental period. In the fish of the methanol extract-feeding group, only the liver, skin, spleen, and gall-bladder were toxic on the 5th day, and the other tissues also became toxic after 20 days. However, the toxicity of most samples of this group were remarkably lower than those of the corresponding samples of the ovary-feeding group. In a striking contrast to the above two groups, the TTx-feeding group showed almost no toxicity in all the tissues throughout the experimental period.

Phase I Study of 2′-Deoxycoformycin in Acute Lymphoblastic Leukemia

Abstract: 2′-Deoxycoformycin (2′-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2′-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2′-dCF which were not associated with limiting toxicities. These results suggest that 2′-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.

Age, disease, and cimetidine disposition in healthy subjects and chronically ill patients

Abstract: Cimetidine induces reversible dose-related central nervous system (CNS) toxicity. Trough serum concentrations and the development of CNS toxicity correlate. We compared cimetidine kinetics in 12 healthy subjects and 31 patients. Six of the latter had normal renal and liver function, five had renal disease only, 12 had liver disease only, and eight had both renal and liver disease. Postmortem tissue distribution was assessed in 11 patients, and expressed as tissue : serum ratio. Average cimetidine total clearance (ClB) in milliliters per minute for each group was as follows: patients with renal and liver disease (182 ± 105), renal disease only (193 ± 24), liver disease only (463 ± 145), normal patients (510 ± 93), and healthy subjects (583 ± 140). Renal function was the major determinant of ClB, and the relationship was described by ClB = 4.2(CCr) + 140, r = 0.87, where CCr is creatinine clearance. Cimetidine clearance was affected little by age. Tissue : serum ratios from highest to lowest were as follows: kidney > stomach > liver > bone > brain > fat. Central and steady-state distribution volumes were not influenced by age or disease. There was enhanced CNS penetration in liver disease patients; their cerebrospinal fluid (CSF) : serum ratio was twice the normal. Our kinetic studies identify patient characteristics likely to result in elevated blood levels, and suggest that the greatest risk of CNS toxicity is in those with liver disease. Clinical Pharmacology and Therapeutics (1981) 29, 737–743; doi:10.1038/clpt.1981.104

High-dose cisplatin therapy using mannitol versus furosemide diuresis: comparative pharmacokinetics and toxicity

Abstract: The dose-limiting toxic effect of high-dose (100 mg/m2) cisplatin is renal insufficiency. Hydration with furosemide- or mannitol-induced diuresis has been reported to ameliorate this toxicity. Animal studies suggest that mannitol may be superior to furosemide in this regard. Twenty-two patients with advanced neoplasms refractory to conventional therapy were treated with cisplatin at a dose of 100 mg/m2 every 21--28 days. Patients were randomized to receive 37.5 g of mannitol by 6-hour infusion with cisplatin or 40 mg of furosemide prior to cisplatin therapy. Hydration with at least 1 liter of normal saline was given prior to cisplatin. Nephrotoxicity (creatinine greater than 2 mg/100 ml, creatinine clearance greater than 50 ml/minute) occurred in 19% of courses in the furosemide-treated group and in 28% of courses in the mannitol-treated group. Peak plasma platinum concentration, terminal half-life, urinary excretion, and percent protein-bound plasma platinum were similar in both groups. The use of cisplatin at this dose schedule resulted in similar toxicity and pharmacokinetics when using hydration with either furosemide or mannitol.

Acute toxicity of sodium selenite and selenomethionine in mice after ICV or IV administration.

Abstract: The acute intracerebroventricular administration of sodium selenite and selenomethionine in conscious mice produced neurotoxicity manifested by hyperreflexia, convulsions and dealth Selenite was 43-fold more toxic than selenomethionine on the basis of LD50 determination The intravenous administration of the selenium compounds resulted in predominantly cardio-respiratory effects, hind limb paralysis and death Selenite was 4-fold more toxic than selenomethionine A comparison of relative toxicity after icv or iv administration revealed that selenite is more toxic than selenomethionine and greater relative toxicity was noted via the icv route This toxicity difference may be attributed to the lack or low level of biotransformation of selenite by the CNS

1,3‐Dinitrobenzene: Toxic effects in vivo and in vitro

Abstract: When 1,3‐dinitrobenzene (1,3‐DNB) was given to rats orally as a 1% suspension in corn oil, the LD50 was 83 mg/kg with fiducial limits 56–124 mg/kg. The compound was equally toxic in both sexes. Signs of toxicity included reduction in ambulatory motion, ataxia, weakness, dyspnea, rapid heartbeat, cyanosis, coma, and eventual respiratory failure. When 1,3‐DNB was added to the daily drinking water in concentrations of 50, 100, and 200 mg/l for 8 wk, 3 of 6 male rats receiving the highest concentration died during wk 4 and another died during wk 5. Of a like number of females, one died during wk 6 and another during the wk 7. All other animals survived. Growth rate was reduced in both sexes and at 200 mg/l 1,3‐DNB in the water supply the animals lost weight. There were mild, consistent reductions in hematocrit and hemoglobin values. Enlarged spleens were present in both sexes at all concentrations; fibrosis with deposition of hemosiderin was present in all rats at 200 mg/l 1,3‐DNB. Testicutar atrophy was evid...

Detection of ozone toxicity during continuous exercise via the effective dose concept

Abstract: In evaluating O3 toxicity in humans, the effective dose, expressed as the simple product of concentration, exposure duration and ventilation volume (VE), has been applied only to resting or intermi...

Toxicity of lidocaine in adult, newborn, and fetal sheep.

Abstract: The relative central nervous system and cardiovascular toxicity of lidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of lidocaine into the jugular vein at the rate of 2 mg x kg-1 x min-1. An identical sequence of toxic manifestations occurred in the adult, newborn, and fetus: convulsions, hypotension, respiratory arrest, and circulatory collapse. Doses necessary to produce these manifestations were highest in fetuses and lowest in adults. For example, in order to elicit convulsions, 5.8 +/- 1.8 mg/kg of lidocaine was required in the adults, 18.4 +/- 2.2 in the newborns, and 41.9 +/- 6.0 in the fetuses. Measurements of lidocaine concentrations in blood demonstrated that these toxic symptoms occurred at levels which were not significantly different among the three groups. The results indicate that fetal and newborn lambs are no more sensitive to lidocaine toxicity than are adult sheep. The fact that the highest doses were required in the fetuses is probably related to the placental clearance of the drug into mothers and better fetal maintenance of arterial Po2 despite convulsions and respiratory arrest (cessation of breathing-like movements).

Threshold concentration of ozone causing an increase in bronchial reactivity in humans and adaptation with repeated exposures.

Abstract: To determine the lowest concentration of ozone that causes an increase in bronchial reactivity to histamine and to determine whether adaptation to this effect of ozone develops with repeated exposures, we studied 19 healthy adult subjects. Bronchial reactivity was assessed by measuring the rise in specific airway resistance (delta SRaw) produced by inhalation of 10 breaths of histamine aerosol (1.6% solution). In 5 subjects, bronchial reactivity was determined at 9:00 and 11:30 A.M. on 4 consecutive days without exposure to ozone (Group I). In 7 other subjects (Group II), bronchial reactivity was assessed at 9:00 and 11:30 A.M. on 3 consecutive days, and subjects were exposed to 0.2 ppm of ozone from 9:30 to 11:30 A.M. on the third day. Seven additional subjects (Group III) had bronchial reactivity assessed in a similar fashion for 2 days and then again on 3 consecutive days of 2-h exposures to 0.4 ppm of ozone. Pre-exposure bronchial reactivity of the groups was the same, and no change in bronchial reactivity occurred in the group tested repeatedly but not exposed to ozone. An increase in delta SRaw provoked by histamine was noted after the first exposure to 0.4 ppm but not to 0.2 ppm of ozone (p less than 0.025). With 3 repeated 2-h exposures to 0.4 ppm on consecutive days, however, the delta SRaw produced by histamine progressively decreased, returning to pre-exposure values after the third exposure. Our results indicate that the threshold concentration of ozone causing an increase in bronchial reactivity in healthy human subjects is between 0.2 and 0.4 ppm, and that adaptation to this effect of ozone develops with repeated exposures. The threshold concentration of ozone identified in other studies as causing changes in symptoms, lung volumes, or airway resistance was also between 0.2 and 0.4 ppm, and the time course of the development of tolerance to ozone in these other studies was similar to hat observed in our study. We propose that the appearance of symptoms, changes in pulmonary function, and the increase in bronchial reactivity may be caused by a change in the activity of afferent nerve endings in the airway epithelium.

Influence of pH on the toxicity of substituted phenols to fish

Abstract: The 96-hr LC50 values of six chloro-, bromo-, and nitro-substituted phenols to the guppy (Poecilia reticulata Peters) were determined by a semistatic method in the pH range of 5 to 8. The pH did not affect appreciably the toxicity of 4-chlorophenol, which is primarily nonionized over the whole range, but the toxicity of more acidic phenols decreased as the pH increased. The changes in toxicity were substantially smaller than they would be, if only the nonionized phenol form were toxic. The results could be explained by assuming that the phenate ion also contributes to the toxicity, but its molar toxicity decreases with rising pH.