Engelina M. den Tonkelaar

Semichronic toxicity study of sodium bromide in rats.

Abstract A 90-day toxicity study was carried out in rats on diets containing 0, 75, 300, 1200, 4800 and 19200 ppm sodium bromide. The animals on the highest level did not groom themselves sufficiently and exhibited signs of motor incoordination. The male animals in this group showed significant growth retardation. Plasma bromide levels increased within 3 weeks to a plateau. In all groups, except in the highest dosage group, these plateaus were directly proportional to the bromide concentrations in the diets, as were the bromide concentrations in brain and kidneys after 13 weeks. Total molar halogen concentration in plasma, however, remained constant throughout the investigation. No striking effects on hematological and biochemical parameters were seen except for a doubling of the percentage of neutrophil granulocytes in the highest dosage group. In female animals on 1200, 4800 and 19200 ppm and in male animals on 19200 ppm bromide an increase of relative thyroid weight was found. In male rats an increase of the relative weight of the adrenals was found in the 19200 ppm group and a decrease of relative prostate weight was seen in the two highest dosage groups. Histopathologically a dose-related disturbance of the endocrine system and some of its target organs was found.

Hexachlorobenzene toxicity in pigs

Hexachlorobenzene Toxicity in Pigs. den Tonkelaar, E. M., Verschuuren, H. G., Bankovska, J., de Vries, T., Kroes, R., and van Esch, G. J. (1978). Toxicol. Appl. Pharmacol. 43 , 137–145. A 90-day toxicity study was carried out in which pigs received 0.05, 0.5, 5.0, and 50 mg/kg/day of hexachlorobenzene (HCB). Special attention was given to the induction of porphyria and microsomal liver enzymes and the concentration of HCB in blood and tissues. Animals given the highest dose (50 mg/kg) showed clinical signs associated with porphyria and died during the experiment. At lower dosages these signs were not observed. An increased excretion of coproporphyrin was found in the 5.0- and 0.5-mg/kg groups, as well as induction of microsomal liver enzymes accompanied by increased liver weight (at 5.0 mg/kg) and characteristic histopathological changes in the liver. The concentration of HCB in blood and tissues was elevated at all dosages. Concentrations in fat were approximately 500 times greater than those in blood, while the concentration in liver was higher than in the kidneys and brain. Under the conditions of this experiment, a no-effect level was judged to be 0.05 mg/kg/day of HCB.

Toxicity of methylmercury chloride in rats III. Long-term toxicity study

Four groups, each of 25 male and 25 female weanling rats, were given dietary levels of 0, 0.1, 0.5 and 2.5 ppm MeHgCl for 2 years. Observations were made on behaviour, growth, food intake, haematology, serum enzymes, urinalysis, microsomal liver enzymes, organ weights and histology with special reference to the nervous system, histochemistry of the kidneys and cerebellum and on tissue Hg concentrations. Significant findings included a slight growth reduction in females at 2.5 ppm, increased relative kidney weight at 2.5 ppm and histochemical changes in kidney enzymes at 2.5 ppm. No effect was seen on the nature or incidence of pathological lesions or tumours at any level. From the results obtained in the short-term, reproduction and long-term studies, the no-toxic effect level for rats appears to be between 0.1 and 0.5 ppm MeHgCl in the diet. Exposure of the Dutch population does not appear to present a health hazard at the moment because the mean intake of total Hg is still far below the intake deemed to be safe.

Toxicity of methylmercury chloride in rats I. Short-term study.

In the range-finding test, 6 groups of 4 male and 4 female weanling rats were given dietary levels of 0, 0.1,0.5, 2.5, 12.5 and 250 ppm methylmercury chloride (MeHgCl) for 2 weeks. Signs of central nervous system toxicity, weight loss and high mortality appeared at 250 ppm but not at lower levels. No haematological changes were observed at 0.1-12.5 ppm. The relative weights of the liver in females on 2.5 and 12.5 ppm and of the kidneys in females on 12.5 ppm were significantly increased; the effects in males were less marked. Total mercury concentration in the kidneys increased proportionally with increasing dietary levels of MeHgCl. In the short-term test, 5 groups of 15 male and 10 female weanling rats were given dietary levels of 0, 0.1, 0.5, 2.5 and 25 ppm MeHgCl for 12 weeks. Toxic signs, weight loss and restricted food intake were observed at 25 ppm starting from week 9 onwards. Haematological, serum enzyme and urinalysis changes were seen at 25 ppm. Liver microsomal enzyme activity was increased non-significantly and liver glycogen was depressed at 25 ppm. Organ weight changes were evident at 25 ppm and histological changes seen in the spleen, kidneys, brain, spinal cord and peripheral nerves were confined to the 25 ppm level. Histochemical changes in kidney enzymes occured at 2.5 and 25 ppm. Hg concentrations in blood, hair, kidneys, liver and brain were higher at 12 weeks than 6 weeks and generally increased with increasing MeHgCl level in the diet.

Short-term toxicity of pentachlorophenol in rats

Abstract Pentachlorophenol (PCP) was fed to rats at dietary levels of 0, 25, 50 and 200 ppm for 12 weeks. Growth was decreased in the group of female rats fed 200 ppm. The treatment had no effect on food intake and behaviour. Liver weight was increased at the 50 and 200 ppm dose levels accompanied by an increased activity of microsomal liver enzymes. In week 6 higher haemoglobin and haematocrit values were found in the groups of males fed 50 and 200 ppm. In week 11 the haemoglobin values and the number of erythrocytes were decreased in the same groups of males. A possible explanation is discussed. A striking dose-related decrease of calcium deposits in the kidney is found. The no-toxic-effect level for all criteria is considered to be 25 ppm.

Long-term experiment with canned meat treated with sodium nitrite and glucono-δ-lactone in rats

Abstract A long-term toxicity experiment was carried out in rats fed a diet containing 40% canned meat treated with either 0·5 or 0·02% sodium nitrite with or without glucono-δ-lactone. This experiment, in which special attention was paid to the detection of a possible carcinogenic effect, was designed to study the possible formation of nitrosamines from nitrite and the secondary amines present in meat, under the conditions of an acid pH and pasteurization. The parameters studied included haematology, clinical biochemistry, histopathology, α-foeto-protein in the serum and the DNA content of the liver cell nuclei. There was no evidence of any preneoplastic change or tumour formation that could be attributed to the feeding of this canned meat.

Short-term oral and dermal toxicity of MCPA and MCPP.

The herbicieds 2-methyl-4-chlorophenoxy acetic acid (MCPA) and 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP or mecoprop) were tested for 90 days in rats. The compounds were added to the diet at levels of 0, 50, 400, and 3200 ppm. Growth, food intake, mortality, haematology, blood and liver chemistry, organ weights and histopathology were used as criteria. The main effects of both compounds were growth retardation and elevated relative kidney weights at levels of 400 ppm and more. The 50 ppm dose level can be considered as a no-toxic-effect level in the 90-day study. In subacute dermal studies in rabbits during 3 weeks the dosages were 0, 0.5, 1.0 and 2 g MCPA or MCPP per kg body weight. Therafter followed a recovery period of 2 weeks. Growth, mortality, skin reaction, haematology, organ weights (MCPP) and histopathology were recorded and determined. Both compounds caused slight to moderate erythema at all dose levels, whereas elasticity of the skin was decreased. In both experiments the skin returned to normal during the recovery period. Weight loss was observed at all dose levels. In the MCPA experiment high mortality and histopathological changes in the liver, kidneys, spleen and thymus were recorded at the two highest dose levels. The cause of this could have been either the treatment with MCPA or a dysbacteria infection which developed during the experiment. Oral and intraperitoneal acute toxicity of MCPP for the rat were found to be 1210 and 402 mg/kg, respectively. After a single oral or dermal application of MCPA to the rabbit, the compound was excreted unchanged in the urine.

Long-term toxicity and reproduction studies with metaldehyde in rats

Rats received 0, 200, 1000 and 5000 ppm metaldehyde in the diet for 2 years. Reproduction studies over three generations using the same dietary levels were carried out. In the third litter of each generation attention was paid to possible embryotoxic or teratogenic effects. The parameters studied included growth, food intake, behaviour and survival, haematology, clinical biochemistry, organ weight, histopathology, reproductive performance and teratogenicity. At 5000 ppm the relative liver weight was increased and this was accompanied by an increase in liver microsomal enzyme activity. The most striking observation was a dose-related development of posterior paralysis in females due to a transverse lesion of the spinal cord. The latency period was more than 550 days. Three rats with posterior paralysis showed a transverse lesion of the spinal cord. No significant histological damage to other organs was seen. The tumour incidence was not increased in any of the metaldehyde dosage groups. The reproduction study confirmed the findings of the long-term test. Posterior paralysis appeared in at least 50% of the females on 5000 ppm metaldehyde in all 3 generations. Some were affected at 1000 ppm but none at 200 ppm. Histologically, a fracture or distortion of thoracic vertebrae and subsequent compression of the spinal cord was found. The onset of paralysis was related to the time of delivery. The reproductive performance was susceptibility in this respect to metaldehyde. Apart from one male rat on 200 ppm with clinical posterior paralysis without transverse lesions in the spinal cord, this level was without toxic effects both in the long-term and 3-generation reproduction study.

Protective action of dithiocarbamates on experimental liver damage produced by carbon tetrachloride

Abstract The protective action of dithiocarbamates on CCl 4 -induced liver damage in rats was assessed with liver function tests (BSP retention test and SGPT). When given immediately before CCl 4 , all dithiocarbamates tested showed a protection against CCl 4 hepatotoxicity except for zineb and some “polymer” dithiocarbamates. For zineb it appears plausible that this was caused by a delayed absorption. No protection was found when one of the dithiocarbamates studied was given 1 hr after CCl 4 administration. From studies with some metabolites and related compounds it appears that only substances containing a carbon disulphide group have a protective action. Probably these compounds function as effective free radical scavengers. In addition, inhibition of microsomal liver enzyme activity and a lowering of body temperature could also be contributing factors.

The wholesomeness of irradiated mushrooms

Abstract Six groups, each of ten male and ten female rats, received for 90 days either a standard diet or a diet containing 25% non-irradiated mushrooms, 25% 175- or 350-krad γ-irradiated mushrooms or 25% 250- or 500-krad electron-irradiated mushrooms. The mushrooms were cooked before the preparation of the diets. Concomitant with this 90-day test, a breeding experiment was carried out with four groups of 20 rats given the standard diet or a diet containing 25% mushrooms, non-irradiated or treated with the higher dose of γ or electron irradiation. From these animals three generations were bred. Animals of the first generation were used for a long-term toxicity test and animals of the third generation for a second 90-day test. No effects attributable to the treatment were observed on growth, food intake, composition of blood and bone marrow, the activity of serum glutamic-pyruvic transaminase, prothrombin time, organ weights or histopathology. The feeding of diets containing irradiated mushrooms had no effect on reproduction in these animals.