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Showing papers on "Toxicity published in 1972"


Journal ArticleDOI
TL;DR: Chloroacetaldehyde, a probable metabolite of 2-chlorc- ethanol (ethylene chlorohydrin), was studied in a number of animal systems, in in oitro hemolysis tests, and in tissue cultures to obtain a toxicity profile of the compound.

430 citations


Journal ArticleDOI
TL;DR: Biochemical parameters of lead toxicity including urinary excretion of δ-aminolevulinic acid were greater in iron-deficient rats fed lead than in rats receiving adequate diets and lead.

211 citations


Journal ArticleDOI
TL;DR: Mercury was found to be more toxic than copper and zinc, which had similar levels of toxicity, and the continued addition of these metals to confined waters should give cause for concern.

179 citations


Journal ArticleDOI

170 citations


Journal ArticleDOI
TL;DR: It was shown that if certain precautions were rigorously observed then methotrexate toxicity could nearly always be avoided, much larger doses than those usually employed could be given, and metotrexate resistance could occasionally be overcome.

136 citations


Journal ArticleDOI
TL;DR: Relationships can be demonstrated between the acute hepatotoxicity of some pyrrolizidine alkaloids and the amounts of pyrrolic metabolites found in livers of rats given the alkaloid, suggesting that toxic effects are caused by such metabolites.

132 citations


Journal ArticleDOI
TL;DR: The exact parallelism between depression of liver microsomal mixed function oxidase activity and resistance to the lethal effects of carbon tetrachloride affords strong evidence for the view that metabolism of CO2 by the livermicrosomal drug-metabolizing system is a necessary prerequisite for the toxicity of this liver poison.

131 citations


Journal Article
TL;DR: The data demonstrate the futility of trying to improve the therapeutic efficacy of cyclophosphamide by pretreatment with drugs that alter its rate of activation and provide a rational basis for the ineffectiveness of such an effort.
Abstract: Experiments were designed to investigate the metabolism of cyclophosphamide in vitro and in vivo following the administration of known stimulators and depressors of rat hepatic microsomal mixed-function oxidase activity, the antitumor efficacy of cyclophosphamide as a function of its metabolism, and the toxicity of cyclophosphamide as a function of its metabolism. Regarding the metabolism of cyclophosphamide by hepatic microsomal preparations, the following observations were made. ( a ) Pretreatment with Phenobarbital of male and female rats and of female mice increased the rate of metabolism 7-, 23-, and 7-fold, respectively. ( b ) pretreatment of male rats with 3-methylcholanthrene depressed metabolism to 33% of that of controls, but similar pretreatment of female mice did not alter the rate of metabolism. ( c ) The Km for cyclophosphamide metabolism by microsomes obtained from male rat liver changed from 1.39 mm to 0.57 and 0.58 mm after phenobarbital and 3-methylcholanthrene pretreatment, respectively. ( d ) Pretreatment of male rats with thioacetamide, morphine, or cobalt chloride depressed metabolism to 12, 48, and 8% of control, respectively. ( e ) Male rats bearing the Walker 256 carcinosarcoma i.m. showed a depressed ability to metabolize cyclophosphamide. In vivo cyclophosphamide metabolism in rats paralleled in vitro metabolism. Thus, at early time points, blood levels of alkylating activity were ( a ) increased following pretreatment with phenobarbital, ( b ) decreased following pretreatment with 3-methylcholanthrene or cobalt chloride, ( c ) decreased when the animal bore the Walker 256 carcinosarcoma i.m., and ( d ) lower in female compared with male rats. Walker 256 carcinosarcoma cells grown i.m. in the hindlegs of male and female rats were used to evaluate therapeutic efficacy. The dose of cyclophosphamide that inhibits tumor growth in male rats by 50% was 0.7 mg/kg. Similar median effective doses were obtained in female rats and in male rats pretreated with phenobarbital or cobalt chloride. 3-Methylcholanthrene pretreatment increased the median effective dose of cyclophophamide to 3.5 mg/kg. For estimation of the toxicity of cyclophosphamide, blood leukocyte counts were made at various intervals following injection of cyclophosphamide. Little difference in the decline of the number of leukocytes or in their subsequent return to normal levels was observed between control male rats; female rats; and phenobarbital-, 3-methylcholanthrene-, or cobalt chloride-pretreated male rats. Pretreatment with phenobarbital did accelerate leukocyte depression and also increased the magnitude of depression. In methylcholanthrene-pretreated male rats and in female rats, the magnitude of depression was somewhat less and recovery rates were somewhat altered. Administered by itself, phenobarbital, 3-methylcholanthrene, or cobalt chloride had no effect on tumor growth or blood leukocyte levels. The data demonstrate the futility of trying to improve the therapeutic efficacy of cyclophosphamide by pretreatment with drugs that alter its rate of activation. In addition, the data provide a rational basis for the ineffectiveness of such an effort.

128 citations


Journal ArticleDOI
TL;DR: In this paper, natural pyrethrins and five synthetic analogs were given intravenously and orally to rats and the ratio of the acute toxicity by the two routes varied considerably.

116 citations


Journal ArticleDOI
TL;DR: Statistical comparison of redwing, starling and rat data indicated that redwings were more sensitive to chemicals than starlings, and both were moresensitive than rats.

113 citations


Journal Article
TL;DR: While toxicity appears to limit the usefulness of this compound as an antineoplastic agent, antileukemic activity was shown, and studies of other members of this class of agents are warranted.
Abstract: Summary 5-Hydroxy-2-formylpyridine thiosemicarbazone (5-HP) is the first of a relatively new class of antineoplastic agents, the α-( N )-heterocyclic carboxaldehyde thiosemicarbazones, to be studied in man. This study characterizes the toxicity and pharmacological disposition of the drug in 13 patients. Plasma levels of 5-HP decayed in biphasic mode with an initial half-life of 2.5 to 10.5 min. Of the administered dose, 47 to 75% was excreted within 24 hr, and the major metabolites (50 to 74% or urinary radioactivity) were glucuronide conjugates. A characteristically dark green urine resulted from the excretion of significant amounts of iron (2 to 11 mg/24 hr) in chelate form with 5-HP. The incorporation of thymidine- 3 H into DNA was inhibited in isolated normal and leukemic leukocyte suspensions after exposure in vitro and in vivo to 5-HP. Transient decreases in blast counts were observed in three of five patients with acute leukemia, although no remissions were obtained. No antitumor effects were noted in eight patients with solid tumors. Administration of larger doses of drug was limited by gastrointestinal toxicity. Mild myelosuppressant effects and hemolysis were noted in five patients treated with 5-day courses of drug. While toxicity appears to limit the usefulness of this compound as an antineoplastic agent, antileukemic activity was shown, and studies of other members of this class of agents are warranted.

Journal ArticleDOI
TL;DR: Various interferon preparations induced by viruses or by polyriboinosinic, and international reference standard interferons all exhibited enhancement of toxicity, in vivo or in vitro.
Abstract: Concentrations of the synthetic polymer polyriboinosinic·polyribocytidylic acid that produced no detectable toxicity in normal L cells produced marked cytotoxicity in L cells treated with interferon. This increase in the susceptibility of cells to the toxicity of the polymer was also observed in human cells and secondary mouse embryo cells treated with homologous interferons before exposure to the polynucleotides. The degree of enhancement of toxicity was dependent on the concentration of interferon to which the cells were exposed. The ratio of antiviral activity induced by interferon to enhancement of toxicity by interferon remained constant through about 1000-fold purification. Various interferon preparations induced by viruses or by polyriboinosinic·polyribocytidylic acid in vivo or in vitro, and international reference standard interferons all exhibited enhancement of toxicity. Both enhancement of toxicity and antiviral activity were destroyed by trypsin and by incubation at 56° for 1 hr, did not act on heterologous cells, were not sedimented by ultracentrifugation, and were not inactivated by ribonuclease, deoxyribonuclease, irradiation with ultraviolet light, or exposure to a pH of 2.

Journal Article
TL;DR: Side effects include nausea, vomiting, alopecia, uremia, hematuria, dysuria and frequency, urinary incontinence, hemopoietic suppression, elevated alkaline phosphatase and transaminase, and mental confusion.
Abstract: A derivative of cyclophosphamide, 2,3-( N,N 1-bis(2-chloroethyl)diamido-1,3,2-oxazaphosphoridinoxyd (Iphosphamide), was less toxic in experimental systems than cyclophosphamide, while it had a broader antitumor spectrum. We studied this agent in a clinical trial of 37 patients with histologically proved, far-advanced malignant disease. The study was designed mainly to determine toxicity and dosimetry of Iphosphamide. Curative effect of Iphosphamide in experimental animals depends on concentration rather than on total dose; therefore, single large doses of the agent were investigated in the first 31 patients. Side effects include nausea, vomiting, alopecia, uremia, hematuria, dysuria and frequency, urinary incontinence, hemopoietic suppression, elevated alkaline phosphatase and transaminase, and mental confusion. Because of nephrotoxicity at high single doses, a further 6 patients received smaller daily doses; however, at the small daily dose levels tubular damage also occurred, as evidenced by granular cylinders in the urine of all 6 patients. At the smaller dose range, nephrotoxicity was the only toxic manifestation. Therapeutic benefit was obtained only with high doses. In view of kidney toxicity at all dosage levels, attention should be given to urine microscopy and other kidney function tests in all patients being treated with Iphosphamide.

Journal ArticleDOI
01 Nov 1972-Lipids
TL;DR: The lungs became enlarged from edema and accumulation of fluid, and the animals died of lung congestion and injury similar to the effects of ozone toxicity, but significant changes occurred in fatty acid composition of the lipids of the serum and lung.
Abstract: Studies on the acute toxicity of the ozonides and hydroperoxides of methyl linoleate are reported High purity preparations of these compounds were injected intravenously or administered orally to adult male rats The lethal dose by iv injection of these compounds was virtually the same −007 mmol/100 g body wt No deaths were caused in a 24 hr period by single oral dosages of these compounds of ca 10-fold that causing death by the iv route The major effect of these compounds was on the lungs The lungs became enlarged from edema and accumulation of fluid, and the animals died of lung congestion and injury similar to the effects of ozone toxicity There was no destruction of vitamin E in the tissues of animals given lethal dosages of ozonides or peroxides intravenously, but significant changes occurred in fatty acid composition of the lipids of the serum and lung Arachidonic acid increased at the expense of linoleic and oleic acids in these tissues Only small amounts of peroxidic and TBA positive substances were detected in lung and serum, indicating that the injected ozonides and hydroperoxides were destroyed in the tissues


Journal ArticleDOI
TL;DR: Subchronische Gaben von Pyrazol, nicht dagegen von 4-Methylpyrazol führen bei Ratten und Mäusen zu toxischen Läsionen.
Abstract: Subchronische Gaben von Pyrazol, nicht dagegen von 4-Methylpyrazol, fuhren bei Ratten und Mausen zu toxischen Lasionen.


Journal ArticleDOI
13 Oct 1972-Nature
TL;DR: To counteract this toxicity, 5-formyl tetrahydrofolate, or leucovorin, has been given 12–36 h after high doses of methotrexate, allowing an improvement in the drug's therapeutic index.
Abstract: METHOTREXATE, a widely used and effective antineoplastic agent, is eliminated primarily by urinary excretion in man1. In species such as the rabbit, which possess hepatic enzymes capable of metabolizing methotrexate to inactive products, the drug is rapidly degraded and virtually non-toxic2. In species which do not metabolize the drug, such as mouse and man, the dose-limiting bone marrow and gastro-intestinal toxicity seems to result from persistence of low (10−7 to 10−9 M) plasma levels of methotrexate for many hours after its administration3,4. To counteract this toxicity, 5-formyl tetrahydrofolate, or leucovorin, has been given 12–36 h after high doses of methotrexate, allowing an improvement in the drug's therapeutic index5,6.

Journal ArticleDOI

Journal ArticleDOI
TL;DR: In general, the compound proved to be quite toxic and very irritating in the systems employed, and Alteration of pentobarbital sleeping time in mice was determined following administration by inhalation and intraperitoneal injection.

Journal ArticleDOI
TL;DR: Adriamycin, a new antitumor antibiotic, was administered for 3 mo to rabbits and dogs by iv injection of daily single doses of 0.125, 0.250 and 0.5 mg/kg body weight and behaves as a typical inhibitor of cellular reproduction.

Journal ArticleDOI
TL;DR: Chloroacetaldehyde is a very toxic and irritating compound in acute tests; in tests of longer duration, most of the parameters measured appeared to be normal in animals that survived its lethal activity.

Journal ArticleDOI
TL;DR: Embryo or fetal toxicity was observed to accompany the administration of the organolead compounds and was characterized by growth retardation and delayed ossification of bone and Marked fetal effects were observed only in maternal animals that exhibited severe organolesad toxicity and were, therefore, severely debilitated.

Journal ArticleDOI
TL;DR: Results show that cholestyramine significantly reduces the toxicity of endotoxin when placed in the peritoneal cavity, and that it effectively inhibits the passage of51Cr labeled endotoxin through the intestinal wall.
Abstract: Since there is evidence that cholestyramine improves diarrheal states where failure of bile salt reabsorption would not appear significant, a study was undertaken to examine the effect of this resin on the toxicity and absorption of bacterial endotoxin. Both the toxicity of intraperitoneal injections of a cholestyramine-endotoxin suspension, and the absorption of the suspension through everted gut sacs was compared with a similar Dowex I-X8 suspension in rats. The results show that cholestyramine significantly reduces the toxicity of endotoxin when placed in the peritoneal cavity, and that it effectively inhibits the passage of51Cr labeled endotoxin through the intestinal wall.

Journal ArticleDOI
TL;DR: Poly I:C is more lethal to mice following iv administration than ip, and there appear to be differences in mouse strain susceptibility, while in monkeys iv administration produced greater toxicity than im or ip administration.

Journal ArticleDOI
10 May 1972-Nature
TL;DR: Certain agents which inhibit the metabolic degradation of DMN were subsequently found to reduce its acute toxicity and hepatocarcinogenicity.
Abstract: SINCE the discovery of the hepatotoxic1 and carcinogenic2 effect of dimethylnitrosamine (DMN), the significance of various nitroso-compounds as potential carcinogens in man has aroused increasing attention3–8, especially since the demonstration of the endogenous production of nitrosocarcinogens from dietary amines or amides and sodium nitrite9–15. Cellular damage resulting from exposure to nitrosamines has been attributed to unidentified metabolite(s) which alkylate nucleic acids, rather than to the parent compounds themselves16–18 and certain agents (for example, aminoacetonitrile19–21, polycyclic aromatic hydrocarbons22,23, protein-free diet24,25) which inhibit the metabolic degradation of DMN were subsequently found to reduce its acute toxicity and hepatocarcinogenicity.

Journal ArticleDOI
TL;DR: The effect of a single sublethal dose of dieldrin on values for plasma corticosterone (free), nonesterified fatty acids, blood glucose, glucose tolerance, blood pyruvic acid, blood lactic Acid, and liver lactic acid has been investigated.
Abstract: The effect of a single sublethal dose of dieldrin on values for plasma corticosterone (free), nonesterified fatty acids, blood glucose, glucose tolerance, blood pyruvic acid, blood lactic acid, and liver lactic acid has been investigated. The blood glucose level is elevated and glucose tolerance is lowered, Indicating an impairment in the utilization of glucose. A significant increase is observed in the levels of other constituents. A correlation of these effects with adrenocortical activity has been attempted.

Journal ArticleDOI
TL;DR: The toxic effects of high-dose methimazole therapy (120 mg/day) were studied in 25 consecutive patients receiving such therapy, finding that eight patients had toxic reactions.
Abstract: The toxic effects of high-dose methimazole therapy (120 mg/day) were studied in 25 consecutive patients receiving such therapy. Nine of the 25 patients had toxic reactions, 8 of which were...


Journal ArticleDOI
TL;DR: A discussion of the toxicity of the two most widely used tear gases—chloroacetophenone (CN) and CS—on the respiratory system indicates that both agents are capable of inducing severe clinical toxicity dependent upon the concentration of the gas.
Abstract: A 4-month-old male infant developed pneumonitis following a prolonged exposure to tear gas (CS or orthochlorobenzylidene malononitrile). The patient had a persistent leukocytosis (white blood cell count 20,000 to 30,000/cu mm) with predominance of lymphocytes on peripheral blood smear and had a slow resolution of the pneumonitis radiologically. A discussion of the toxicity of the two most widely used tear gases—chloroacetophenone (CN) and CS—on the respiratory system indicates that both agents are capable of inducing severe clinical toxicity dependent upon the concentration of the gas.