Maleic hydrazide,carcinogenicity study in rats

The carcinogenicity of maleic hydrazide is discussed by several national and international organizations because of contradictory results of a number of carcinogenecity studies carried out in the past. Because maleic hydrazide is used in agriculture on edible crops, an oral carcinogenicity study with rats was carried out for 28 months at dietary levels of 0, 1.0 and 2.0% maleic hydrazide which contained less than 1.5 mg hydrazine/kg product as impurity.In this study as well as in an experiment with mice carried out with the same batch of maleic hydrazide at the International Agency for Research on Cancer (IARC) in Lyon, France, treatment did not affect tumour incidence and it was concluded that maleic hydrazide itself is not a carcinogen. Most likely the presence of relatively high levels of hydrazine as an impurity was responsible for the contradictory results in studies as reported previously.Furthermore the results of this study showed that 1.0 and 2.0% maleic hydrazide in the diet caused proteinuria and increased protein/creatinine ratio's in the urine in both sexes without detectable histopathological changes in kidney or urinary tract. From this study, based on the effects of kidney function the “no-toxic” effect level is considered to be lower than 1.0% maleic hydrazide in the diet of rats.     

Manipulation of toxicity and tissue distribution of tubercidin in mice by nitrobenzylthioinosine 5'-monophosphate

The i.v. administration of tubercidin, an analog of adenosine, in a single dose of 45 mg/kg caused death in about 90% of B10D2F₁ mice so treated. Serum and urine analysis, as well as histological examination of tissues, related the lethality of tubercidin to hepatic injury, which was markedly reduced when mice were treated with the inhibitor of nucleoside transport, nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), at i.p. doses higher than 10 mg/kg 30 min prior to tubercidin injection. With high NBMPR-P doses (100 mg/kg, i.p.) followed by tubercidin injection (45 mg/kg, i.v.), kidney damage and high mortality occurred. The tissue distribution of ³H following [G-³H]tubercidin administration paralleled hepatic or renal injury: NBMPR-P treatment decreased the content of tubercidin-derived ³H in liver and increased that in kidney. Furthermore, the half-life of the decline in tubercidin levels in serum during the first minute after [³H]tubercidin administration was longer in NBMPR-P-treated mice (26 sec) than in untreated mice (10 sec), with the result that ³H levels in serum were more than ten times higher in the former than in the latter at an early stage during the distribution of tubercidin. Within 15 min after i.p. administration, the tissue distribution of [³H]tubercidin was complete. The i.p. administration of tubercidin caused ascites and the appearance of amylase in the peritoneal fluid evidently because of peritonitis and pancreatic injury. Administration of NBMPR-P by the i.p. route, but not by the i.v. route, prevented these injuries and shifted the ld₅₀ of i.p. injected tubercidin (5 mg/kg) to markedly higher values (a 4-fold increase with NBMPR-P at 100 mg/kg). The protection of mice by NBMPR-P against lethal injuries caused by i.p. injected tubercidin was consistent with the inhibition by NBMPR-P of tubercidin accumulation in mesentery and pancreas. The tissue specificity of the NBMPR-P influence on the tissue distribution of tubercidin may reflect differences in NBMPR-P pharmacokinetics and/or in properties of the nucleoside permeation mechanism among various tissues.     

Development of tissue resistance to toxic effects of chemicals

Evidence has been presented from both the published literature and the author's own work that after repeated administration of various chemicals which induce degenerative changes, resistance develops in the target tissue to the toxic effects. Such a resistance develops only after an induced lesion, and it is not specific to the inducing agent, but extends to agents causing similar lesions. The resistance lasts during the period of exposure to the noxious agent and for varying times thereafter. It is looked upon as an adaptation mechanism to the adverse environment; thus it is of epidemiological interest. This phenomenon is of significance also in the safety studies of chemicals. The present practice of performing histopathology examinations solely in prolonged dosing studies may overlook what happened in the early stages of the exposure to potentially toxic agents. The resistance is also of clinical interest, since the toxic effect may not manifest in long-term therapy even though the pharmacologic effect does not diminish. The continuing pharmacologic effect implied that the phenomenon is not related to a pharmacokinetic change. Apart from this, its mechanism has not been established.     

Effect of several endogenous substances--including porphyrins, hematin, and carbon monoxide--on hepatic clearance of sulfobromophthalein

Using mice, we explored the involvement of endogenous substances including δ-aminolevulinic acid, coproporphyrin, protoporphyrin, hematin and carbon monoxide in hepatic dysfunction induced by drugs or chemicals. These substances were administered individually at less than LD₁₀ doses and sulfobromophthalein (BSP) excretion was studied. δ-Aminolevulinic acid caused significant BSP retention when given 30 min before BSP or after daily treatment for 1 or 6 days. Coproporphyrin administration did not produce significant BSP retention. Protoporphyrin produced significant BSP retention 30 min, but not 24 h before BSP administration. Intravenous administration of hematin 30 min before BSP caused BSP retention. Exposure of mice to air containing 250 to 1900 ppm of carbon monoxide for 4 h caused significant BSP retention. These results, considered together with the knowledge that several recognized hepatotoxins also are known to be porphyrogenic, support the hypothesis that certain endogenous substances such as those studied may contribute to the hepatotoxic effects of selected drugs and chemicals.     

Semichronic oral toxicity of cadmium: 1. Studies on rats

Cadmium (in the form of CdCl₂) was fed to groups of 20 male and 20 female rats each over a period of 3 months in concentrations of 0, 1, 3, 10 and 30 ppm. Appearance, behaviour, food consumption, growth and mortality of the treated rats of all groups were not affected during the 3-month period. The cadmium concentrations did not cause blood, liver or kidney damage. The systolic blood pressure of the treated animals was not increased. Autopsies and histopathological investigation of the animals showed no sign of any alterations. Cadmium accumulated dose-dependently in the kidneys and liver. Concentrations of cadmium up to 30 ppm in their feed were tolerated by rats over a period of 3 months without harm.     

Nephrotoxicity of phenolic bromobenzene metabolites in the mouse

Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 μmol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53–2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in adose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced in vivo administration of 4-bromocatechol could not be distinguishe histogically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.     

Isozymes of Aspartate Aminotransferase in Rat Liver during Acute Uraemia

Abstract. Total activity of aspartate-aminotransferase (GOT; EC 2.6.1.1) and activities of the cytoplasmic (c-GOT) and mitochondrial (m-GOT) isozymes were measured in rat liver 24 and 48 h after bilateral nephrectomy.
24 h after nephrectomy no significant differences in enzyme activities could be detected between uraemic animals and sham-operated controls. However 48 h after nephthrectomy the total activity of GOT increased significantly. Fractional tissue extraction revealed an elevation of only the cytoplasmic isozyme (c-GOT), due to a selective increase of this enzyme fraction. No significant change could be noticed of the mitochondrial isozyme (m-GOT). These results are discussed with regard to an increased gluconeogenesis in rat liver 48 h after bilateral nephrectomy.     

Proceedings. Natural hazards occurring in foods.

Eleven Nubian goats were fed with Jatropha curcas seeds at doses ranging from 0.25 g to 10 g/kg/day. All dose levels were found to be toxic with fatal consequences within 2 to 21 days. Liver biopsy samples taken 2 days after the start of feeding and subsequent biopsies showed congestion, varying degrees of fatty change, considerable reduction in glycogen content and necrosis of the hepatocytes. Lack of appetite, reduced water consumption, diarrhoea, dehydration, sunken eyes and a steadily deteriorating condition were important clinical signs of Jatropha intoxication intgoats. In all animals there was a decrease in the level of glucose and a marked rise in the concentration of arginase and glutamate oxaloacetate transaminase (GOT) in the serum. Post-mortem examination revealed haemorrhage in the rumen, reticulum, kidney, spleen and heart, catarrhal or haemorrhagic abomasitis and enteritis, congestion and oedema of the lung and excessive fluid in serous cavities.     

The effect of massive transplacental iron loading.

Intravenous injection of three doses of 50 mg Fe/kg (total dose 150 mg Fe/kg) as iron dextran into rabbits late in pregnancy (days 26, 28, and 30 of gestation) reduced the weight gain of the dams and increased fetal mortality. Three doses of 20 mg Fe/kg also increased fetal mortality, while three doses of 5 mg Fe/kg were without effect. Liver and kidney iron concentrations of the dams and offspring were markedly increased at the time of parturition by treatment with a total dose of 150 mg Fe/kg. At 6 weeks after birth the liver and kidney iron concentrations of offspring from treated dams were comparable to those from control dams. The liver and kidney iron concentrations of the treated dams were significantly reduced from the levels found immediately post-partum. In the rat, four i.v. doses of 200 mg Fe/kg as iron dextran on days 17, 18, 19, and 20 of gestation (total dose 800 mg Fe/kg) produced tremors, reduced body weight gain, and reduced food consumption in the dams. The growth and survival of the offspring were adversely influenced by these effects on the dam. The liver iron concentration in offspring of rats treated with 800 and 400 mg Fe/kg was increased at parturition, but had returned to normal at 4 weeks of age. No iron-induced pathology was evident in the offspring of either rabbits or rats after 14 and 18 weeks, respectively.     

Toxicity of methyl testosterone in the beagle dog

When methyl testosterone was administered orally to beagle dogs at dosage levels of 2, 4 and 6 mg/kg per day for 27 weeks, hepatotixicty was induced. The change induced was characterized by enlargement of periportal hepatocytes and the presence of haemosiderin within macrophages. There was some evidence of recovery over a 13-week period.