Showing papers on "Toxicity published in 1979"

N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat

Abstract: The synethesis of a new retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide, which has useful biological properties, is described. This retinoid was more potent than retinyl acetate in reversing keratinization caused by retinoid deficiency in tracheal organ culture. It was markedly less toxic than retinyl acetate when fed p.o. to rats over 2-week or 6-month periods. It was an effective agent for inhibition of the development of breast cancer induced in rats by N-nitroso-N-methylurea, although it was not as potent as retinyl acetate in this regard. However, the lesser toxicity of 4-hydroxyphenylretinamide makes it a superior agent for prevention of breast cancer. High-pressure liquid chromatographic analyses of liver and breast extracts from rats treated for 6 months with retinoids show the pharmacokinetic basis for the superiority of 4-hydroxyphenylretinamide; this retinoid and its metabolites were found in high concentrations in breast tissue, without any measurable accumulation in the liver or evident liver toxicity. In contrast, chronic feeding of retinyl acetate caused marked deposition of retinyl esters in the liver and severe hepatotoxicity. Whole mounts of rat mammary glands, made after chronic feeding of 4-hydroxyphenylretinamide, showed that it had a marked antiproliferative effect on mammary epithelium.

Inhibition of cis-platinum nephrotoxicity by diethyldithiocarbamate rescue in a rat model.

Abstract: The nephrotoxic effects of cis-dichlorodiammineplatinum(II) (NSC-119875) administered to male F344 rats at the median lethal dose (LD50; 7.5 mg/kg) were inhibited by treatment with sodium diethyldithiocarbamate (500 or 750 mg/kg) between 1 and 4 hr after cis-platinum administration. Those animals receiving cis-platinum alone had mean serum blood urea nitrogen levels of 234 mg/dl at the time of maximal toxicity (day 5); kidney sections revealed large areas of degeneration and necrosis. When dithiocarbamate rescue was carried out after cis-platinum treatment, mean blood urea nitrogen levels were in the range 56-95 mg/dl; kidney sections were grossly normal with a barely discernible band of degeneration at the corticomedullary junction. Gastrointestinal toxicity was observed in greater than 95% of the cis-platinum-treated rats but was totally absent in those receiving subsequent rescue treatment. A significant decrease in weight loss was also observed in the dithiocarbamate-rescued rats. Based on the chemistry of platinum-sulfur interactions and the observed time-dependence of the rescue treatment, it is suggested that dithiocarbamate exerts its effects via competitive chelation and removal of platinum coordinated to protein-bound sulfhydryl groups of the kidney tubule cells.

Possible correlation between induction modes of hepatic enzymes by PCBs and their toxicity in rats.

Abstract: Acute toxicity of individual PCBs, which were categorized as either phenobarbital (PB)- or 3-methylcholanthrene (MC)-type inducers, was examined in young male Wistar rats, comparing their effects on growth rate, organ weight and liver lipid content, 5 days after a single i.p. injection. PB-type PCBs (2,4,3',4'- and 2,5,2'5'-tetrachlorobiphenyl), which slightly increased a content of cytochrome P450, did not show any significant toxicity at a dose of 100 mg/kg. On the contrary, MC-type PCBs (3,4,5,3',4'-pentachloro- and 3,4,5,3',4',5'-hexachlorobiphenyl), which markedly increased a content of cytochrome P448, strongly reduced growth rate and weights of thymus and spleen at a dose of 10 mg/kg. Liver enlargement accompanied by fatty liver was also observed only with MC-type PCBs. 3,4,3',4'-Tetrachlorobiphenyl was also toxic at a dose of 50 mg/kg, in keeping with its weak MC-type-inducing ability. Pretreatment with MC affected neither growth rate, spleen weight, nor liver lipid content. These results suggest that the toxic potency of PCBs is related to their MC-type inducing ability, but the toxic characteristics are different from those of MC itself.

Partial hepatectomy reduces both metabolism and toxicity of benzene

Abstract: Removal of 70–80% of the liver reduced both the metabolism and the toxicity of benzene in rats. Metabolism was evaluated by measuring the levels of urinary metabolites in both sham‐operated and partially hepatectomized rats given 2200 mg/kg [3H]benzene sc. Toxicity was evaluated by measuring the incorporation of 59Fe into circulating erythrocytes according to the method of Lee et al. The observation that partial hepatectomy decreases benzene metabolism and protects against benzene toxicity indicates that the liver may play a primary role in the development of benzene‐induced bone marrow toxicity. The fact that benzene administration also reduces the ability of the liver to regenerate after partial hepatectomy suggests that the regenerating liver may serve as a model system in lieu of the bone marrow for studying the mechanism by which benzene inhibits cell proliferation.

Comparative toxicity of three halogenated dibenzofurans in guinea pigs, mice, and rhesus monkeys

Abstract: The chlorinated dibenzofurans have been reported to be present in a variety of polychlorinated biphenyls (PCBs)’” and in pentachlorophenol: They were also detected in the PCB-contaminated rice oil that was responsible for the human intoxication referred to as ‘Y~sho’.’.~ Polychlorinated dibenzofurans were also detected in tissues of patients with ‘Yusho’.’ A polychlorinated dibenzofuran fraction extracted from PCB’s was found to be highly toxic in chickens.* A mixture of polychlorinated dibenzofurans also caused toxic effects when fed to rats? 2,3,7,8Tetrachlorodibenzofuran (TCDF) has been evaluated for toxicity in chicks,” guinea pigs,” and mice.” The results reported in this manuscript extend earlier studies with TCDF in guinea pigs and mice, report the toxic effects in rhesus monkeys, and describe the toxic effects of 2,3,4,7,8-pentachlorodibenzofuran (PCDF) and 2,3,7&tetrabromodibenzofuran (TBDF) in guinea pigs.

Iron deficiency prevents liver toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Abstract: The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatocellular damage and porphyria in C57B1/6J mice, among a wide range of toxic effects. We compared the effect of TCDD toxicity in iron-deficient mice with that in mice receiving a normal diet. Porphyria did not develop in the iron-deficient animals, and these animals were also protected from hepatocellular damage and certain other toxic effects of TCDD.

Pharmacokinetic monitoring of high-dose methotrexate. Early recognition of high-risk patients.

Abstract: The administration of high-dose methotrexate (HDMTX) with leucovorin rescue carries with it a risk of severe toxicity which may be fatal. In the present study, patients with a 24-h serum concentration of 5 x10- M and an elimination half-life (T1/2) of 3.5 h during the first 24 h after the infusion were considered at low risk for toxicity and received conventional lowdose leucovorin rescue. Patients not meeting these criteria were considered at high risk for toxicity and received an escalated and extended course of leucovorin. The low-risk criteria were met following 109 of 114 HDMTX infusions administered to 30 patients. None of these patients developed toxicity with low-dose leucovorin. The 24-h serum concentration and the t1/2 exceeded the low-risk criteria following five HDMTX infusions administered to three patients. In two of these three patients leucovorin was continued until the MTX concentration was 10-8 M (168–265 h) and no toxicity developed. The third high-risk patient discontinued his leucovorin 11 days prior to a MTX serum concentration 10-8 M and developed moderate toxicity. Clinical features present in the three high-risk patients, which were not present in the low-risk group, included a pleural effusion in one patient and gastrointestinal obstruction in the other two patients. The identification of 3/30 high-risk patients in the present study was consistent with a historical control group in which 6/65 patients developed severe toxicity. These data indicate that patients meeting the criteria described herein are at low risk to develop toxicity with conventional leucovorin rescue and that high-risk patients may be identified early enough to reduce or prevent toxicity.

Pulmonary toxicity after radiation and bleomycin: a review

Abstract: The effects of bleomycin (BLM) and radiation on the lung are histologically similar Animal studies have indicated additive or synergistic effects from these 2 agents Review of the literature regarding clinical studies using BLM and irradiation indicates that the incidence of pulmonary toxicity increases when bleomycin is administered in conjunction with radiotherapy to the thorax Of 115 patients treated simultaneously with BLM and radiation to the thorax, 22 (19%) suffered pulmonary toxicity that was fatal in 11 (10%)

Clinical toxicologic and pharmacologic studies of gallium nitrate

Abstract: Gallium nitrate, administered intravenously to patients with advanced cancer, produced renal functional abnormalities consistently at a dose of 750 mg/m2. The toxicity at that dose could be modified by fluid loading and osmotic diuresis. Pharmacokinetic studies revealed a biphasic half-life, (T 1/2 alpha = 87 minutes and T 1/2 beta = 24.5 hours). Osmotic diuresis reduced the urinary concentration of gallium but did not affect serum levels or clearance.

Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C.

Abstract: Fifty-one patients with metastatic and/or recurrent gastrointestinal cancer received a regimen of continuous 5-fluorouracil infusion and mitomycin C. Among patients with colorectal cancer, 9 (33%) showed tumor regression, 10 showed objective tumor response 22 months after the onset of treatment. Three of 9 patients with gastric cancer were responders, one complete. The median survival was 11 months; 3 patients survived for 1 year or more, one for 21 months from the initiation of therapy. Half of 8 patients with pancreatic cancer showed some objective response, 3 with >50% tumor regression. Duration of response in these 3 cases is 5+, 10, and 10+ months. In our series, mild to moderate hematologic toxicity was encountered in 63% and tended to be cumulative. There were no serious infections, and 2 instances of prolonged thrombocytopenia. Partial alopecia developed in most patients; gastrointestinal toxicity was minimal. That this combination may cause pulmonary toxicity was suggested by the development of severe respiratory insufficiency without apparent cause in 3 patients, all of which had at least 2 cycles of treatment. A transient response to corticosteroids was obtained. One patient, free of tumor at autopsy, demonstrated a glomerular lesion previously described with mitomycin C toxicity, while 2 others developed a micro-angiopathic hemolytic anemia.

Platinate toxicity: past, present, and prospects.

Abstract: Using traditional toxicologic methods, four species were studied for their qualitative and quantitative predictiveness of the toxic effects of cis-dichlorodiammineplatinum(II) in man Of the four species studied, mouse, monkey, rat, and dog, the latter two gave the best overall results Using an in vivo rat model, it was found that except for chloroplatinic acid, eight of the tested analogs were less nephrotoxic than the parent drug, cis-dichlorodiammineplatinum(II) The in vitro renal toxicity screen using flounder tubules showed that of the 26 compounds studied, about half were less toxic than the parent compound This in vitro mini-tox system can be performed about 30 times faster and at one fiftieth the cost of the in vivo model The in vitro studies also provided evidence that the biochemical site of toxicity of platihates is on ATPases The latter studies suggested a basis for unifying the mechanistic interpretation of the toxic actions on such disparate target organs as the kidney, nerve, stomach, and inner ear

Physiological and biochemical aspects of ozone toxicity to rainbow trout (Salmo gairdneri)

Abstract: An acute toxicity curve for dissolved ozone (O3) in soft water at 10 °C, using 10–13-cm rainbow trout (Salmo gairdneri) as the test species was calculated. The 96-h LC50 (95%, confidence interval) ...

Acute toxicity studies of surfactants to Daphnia magna and Daphnia pulex.

Abstract: Several experiments were designed to examine the acute toxicity of surfactants toDaphnia. Specific tests were designed to develop comparisons between existing acute toxicity data for fish and similar data forDaphnia, and to provide data on the effects of various environmental factors on resultant toxicity of surfactants toDaphnia. Acute toxicity data for a series of homologous linear alkyl benzene sulfonates (LAS) demonstrate increases of up to one order of magnitude in toxicity for each increase of two alkyl carbons. LC 50's obtained withDaphnia magna are similar to those obtained with bluegills,L. Macrochirus. Comparative tests withD. magna andD. pulex indicate no statistical differences in 48-hr LC 50 values for three anionic and two nonionic surfactants. A 50 mg/L concentration of suspended, naturally-occurring kaolin significantly reduced the toxicity of longer chain length LAS homologs and had no effect on nonionic surfactant toxicity. In tests with variable hardness concentrations, the acute toxicity of LAS toD. magna is a combined function of both culture and test water hardness. The toxicity of a nonionic surfactant toD. magna was higher in soft water and was not affected by culture water hardness levels. Unlike previously published data for fish, the results of acute toxicity tests withD. magna cultures previously exposed to 0.4 mg/L LAS for periods up to seven generations indicated no significant difference in LAS susceptibility compared to simultaneously tested unexposed controls.

Relation between toxicity and accumulation of various chlorophenols in goldfish.

Abstract: A study has been made of the relation between the toxicity and the accumulation in goldfish, Carassius auratus, of seven chlorophenols: 2-chlorophenol; 4-chlorophenol; 2, 4-dichlorophenol; 2, 4, 5-trichlorophenol; 2, 4, 6-trichiorophenol; 2, 3, 4, 6-tetrachlorophenol; and pentachlorophenol. An increase of the Cl-atom number in the chlorophenols caused an abrupt increase in toxicity to the fish and also increased the concentration ratios in their media to lethal or sublethal concentrations. On the other hand, the concentrations of the chlorophenls fbund in the dead fish in the media waried within the range of 75 to 268μg/g body weight, as compared with the LC50 values. The results suggest that the increase of toxicity from polychlorinated phenols is mostly due to their accumulation in the fish. Their concentrations in the fish eventually achieve a certain lethal level (roughlyl 100-200μg/g body weight), although the chemical form, locality, and physiological activity of the chlorophenols in the tissues of the fish must also be involved.

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: an approach to therapy against methanol poisoning.

Abstract: 4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 μM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.

Toxicity of Endotoxin to Chicks

Abstract: Large doses of purified lipopolysaccharide (LPS) purified from Escherichia coli induced clinical signs but no mortality in chicks. Five chicks survived a mean dose of 517 mg/kg. One individual that received LPS at 577 mg/kg recovered from clinical manifestations within two days. Attempts failed to produce a generalized Shwartzman-like reaction with two intravenous inoculations of LPS at about 24-hour intervals. Prior injection of uric acid did not protect chicks from LPS by intravenous exposure.

Intraocular Penetration of Subconjunctivally Administered 14C-Fluorouracil in Rabbits

Abstract: • Fluorouracil is given for a variety of neoplasms by various administrative routes. Toxicity of susceptible normal tissue limits systemic dosage, but at this level intraocular tissue may not receive tumor-inhibiting concentrations. Subconjunctival administration of 6.25 mg of 14 C-fluorouracil in 0.5-mL dosages resulted in a peak anterior chamber concentration of 69.5 μg/mL and a peak vitreous concentration of 10.5 μg/mL over the 12 hours tested. This resulted in no visible ocular damage. The intraocular levels achieved were greater than the concentration reported to inhibit selected tumors. The total dosage administered was considerably below the level of systemic toxicity.

Toxicity studies with decamethrin, a synthetic pyrethroid insecticide.

Abstract: Decamethrin is a synthetic pyrethroid insecticide that has been under investigation by the World Health Organization for use in some vector control programs. Decamethrin proved to be a highly toxic pyrethroid ester. The acute LD50 for adult female rats was 31 mg/kg by the oral route and 4 mg/kg by the intravenous route of administration. The LD50 was observed to be sex and age dependent, with higher values recorded for weanlings and males. Initial signs of decamethrin poisoning include profuse salivation and convulsive movements. Weakness, dyspnea, anorexia and staining of the fur were observed beyond the first day following compound administration. Absorption of decamethrin was rapid by the inhalation route and minimal by the dermal route of administration. No evidence of teratogenic activity was found in rats or mice at dose levels that produced marked maternal toxicity, and no persistent toxicity was observed in neonatal rats that received perinatal exposure to decamethrin. No mutagenic activity was detected in three different in vitro assays, with or without metabolic activation.

Biological studies on the degradation products of 3-[(s)-1'-phenylethylamino]propylaminobleomycin: a novel analog (pepleomycin)

Abstract: Pepleomycin (PEP), 3-[(S)-1'-phenylethylamino]propylaminobleomycin has potent activity and is less pulmonary toxic than bleomycin (BLM). Biological activity and toxicity of the following degradation products of PEP have been studied in detail: the product of carbamoyl migration (ISO), the product of decarbamylation (DC), the product of ring closure of the side chain on the pyrimidine moiety (RC), the depyruvamide product (DP) and the product of an enzymatic inactivation (DA). These degradation products showed much lower activity than PEP in vitro: antimicrobial and anti-HeLa activities, inhibition of DNA synthesis in AH66 cells and the DNA strand cleavage. Acute toxicity and pulmonary toxicity were tested in mice. Results indicated much lower acute toxicity corresponding to the decreased in vitro activity when compared to PEP. DP and RC did not cause lung fibrosis in mice, while ISO and DC showed 1/2.6 and 1/5.7 degree of pulmonary toxicity, respectively, in comparison with PEP.

Biological degradation of TCDD in rats.

Abstract: Apart from its high toxicity, the chemical stability and persistence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the environment bring about additional hazards. However, until now there has been no evidence for degradation of this dioxin in biological systems, and it is considered unusual that a compound which is insusceptible to biological attack should be so extremely toxic. In in vitro studies with microsomal preparation from mouse, rat and rabbit liver, as well as in vivo, no metabolite of TCDD has been detected by several workers. Recent data, showing a lower toxicity of TCDD in rats after stimulation of the hepatic mixed-function oxidase, suggested possible metabolic transformation of this compound. In the present study, we used tritiated TCDD to search for metabolites in the bile of rats and found marked changes in lipophilicity and mobility in TLC of the excreted radioactivity. Treatment with diazomethane yielded at least two new compounds. These observations hinted at the formation of phenolic hydroxyl groups in the dioxin molecule.

Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog.

Abstract: The effects of digoxin on monovalent cation active transport were determined in cardiac tissue obtained from dogs given inotropic, toxic, or lethal doses of digoxin. In hemodynamically monitored dogs, active uptake of the K+ analogue Rb+ was determined in vitro in a control myocardial biopsy, and then in serial biopsies from the same dog after the infusion of [3H]digoxin in doses sufficient to cause a sustained positive inotropic effect in the absence of toxicity, and finally after additional doses to induce overt toxicity. Nontoxic digoxin doses producing a mean increase of 20% in left ventricular (LV) dP/dt significantly reduced Rb+ active transport by 25% below control values. At the onset of digoxin-induced arrhythmias, maximal LV dP/dt was 53% above control whereas active Rb+ transport was reduced by 60% below baseline values (P less than 0.001). Control dogs given vehicle alone showed no significant change in contractility or in monovalent cation active transport. In another group of dogs given a lethal dose of digoxin, Rb+ active transport was reduced 59% below control levels at the onset of overt toxicity and was further reduced 80% below control at the time of onset of a fatal rhythm disturbance. When dogs were given high affinity digoxin-specific IgG or Fab fragments at the onset of overt toxicity, toxicity was rapidly reversed, and monovalent cation active transport increased to 51% of control at the time of restoration of sinus rhythm. Twenty-four hours after antibody reversal of arrhythmias, monovalent cation transport values approximated normal control levels. These data provide quantitative estimates of the extent of inhibition of monovalent cation transport by digoxin at inotropic, toxic, and lethal endpoints. Similar degrees of transport inhibition were present at the time of onset of digoxin-induced arrhythmias and at the time or arrhythmia reversal by digoxin-specific antibodies.