R. Kroes

The induction of renal tumours by feeding basic lead acetate to mice and hamsters.

ImagesFigs. 2-3

Changes in the Nervous System and Musculature of Old Rats

Changes in the nervous system and musculature of normal 34-month-old rats are described. Wallerian degeneration as well as segmental demyelination were observed in the peripheral nervous system, with changes more severe in the sciatic than in the brachial nerves. Signs of nerve-fibre degeneration were also seen in the cord and lower brain stem. The degenerative changes were usually mild, but in a number of animals there was severe degeneration of the gracile tract and lateral columns. Other changes in the nervous system included lipochrome pigment in nerve cells and other cellular elements throughout brain and cord, and eosinophilic bodies in the lower brain stem and cord. In some animals the ventricular system in the brain was dilated. Changes in the skeletal musculature were believed to represent neurogenic muscular atrophy secondary to changes in the nervous system.

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.

The carcinogenicity of aflatoxin M1in rainbow trout

Summary Three groups, each initially of 250 trout, were fed a diet containing 5·8 ppb (b = 109) aflatoxin B1 (AFB1) or 5·9 or 27·3 ppb aflatoxin M1 (AFM1) for 16 months. A control group of 500 trout received the basal diet. In the early part of the study, a relatively high mortality rate resulted from underfeeding and infections. Toxin administration had no effect on the serum and liver enzymes studied and growth was unaffected up to month 12, although at month 15 there was a significant decrease in body weight in the two groups given AFM1. Autopsy of fish killed after 5, 9 and 12 months revealed ceroid degeneration of the liver in all four groups but no tumours or preneoplastic changes. Autopsy of survivors at month 16, however, revealed six with hepatocellular carcinoma and 11 with hyperplastic nodules in the 48 trout fed 5·8 ppb AFB1 and one with hepatocellular carcinoma and three with hyperplastic nodules in the 48 fed 27·3 ppb AFM1, but no evidence of such lesions was seen in the 49 fed 5·9 ppm AFM1 or in the 51 from the control group.

Study on the carcinogenicity of lead arsenate and sodium arsenate and on the possible synergistic effect of diethylnitrosamine

Abstract In a lifetime (29-month) carcinogenicity study, rats were treated with lead arsenate (PbHAsO 4 ) or sodium arsenate (Na 2 HAsO 4 ·7H 2 O) and the possibility that diethylnitrosamine (DENA) may exert a synergistic or additive action on the effects of these compounds was studied. Lead arsenate was fed in the diet at levels of 1850 or 463 ppm, while sodium arsenate was fed at a level of 416 ppm. Additional groups of rats were fed 463 ppm lead arsenate or 416 ppm sodium arsenate in combination with DENA given in an intubated dose of 5 μg/day on 5 days/wk. The rats receiving these diets were weaned by mothers receiving the same diet during lactation. Food intake levels (for the first 12 wk) and body weights were recorded, haematological studies were carried out after 12 months and complete gross and microscopic examinations were conducted at autopsy. At level of 1850 ppm, lead arsenate was toxic and caused intra- and extrahepatic bile-duct lesions. Intranuclear inclusions due to the ingested lead were present in the kidneys and liver, but only for the first 12 months. Other histopathological changes, commonly found in these rats, were equally divided between the groups. No differences were apparent either in the tumour incidence of the different groups or in the times at which tumours were detected. An adenoma in the renal cortex and a bile-duct carcinoma, both found in the group fed 1850 ppm lead arsenate, may have been indicative of a very weak carcinogenic action of this compound, but no definite conclusion used in this study. No additive or synergistic effect could be attributed to DENA, which also failed to induce tumours at the low dose level used, suggesting the possible existence of a no-effect level for this carcinogen.

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.

Short-term toxicity studies with triphenyltin compounds in rats and guinea-pigs

Short-term toxicity studies have been carried out in rats and guinea-pigs fed diets containing triphenyltin acetate (TPTA), triphenyltin hydroxide (TPTH) or triethyltin hydroxide (TETH) for 90 days at levels ranging from 0 to 50 ppm. The lowest dietary levels found to retard growth in rats and guinea-pigs respectively are as follows: 5 and 10 ppm for TETH; 25 and 5 ppm for TPTA; 50 and 20 ppm for TPTH. An increase in mortality was found in the following groups: rats on 10 ppm or more of TETH; guinea-pigs on 20 and 50 ppm TPTA and on 50 ppm TPTH. In rats and guinea-pigs given TETH, paralysis and pronation of the hindlegs developed. These toxic signs were not found in the TPTA- and TPTH-treated animals. This observation was correlated with the finding that only the TETH-treated animals developed interstitial oedema of the central nervous system. The water content of the brain and spinal cord was increased in rats and guinea-pigs at respective minimum levels of 5 and 10 ppm of TETH and in guinea-pigs on 20 ppm TPTA. In female rats given 50 ppm TPTA or TPTH the water content of the spinal cord was only increased. The changes in organ weights which could be related to the administration of the organotin compounds were confined to an increase of brain weight in rats and guinea-pigs given TETH, and in guinea-pigs given 5 ppm or more of TPTA and a decrease of thymus and/or spleen weights in rats and guinea-pigs receiving TETH. Guinea-pigs given 5–20 ppm TPTA or 2·5–20 ppm TPTH displayed lymphopenia accompanied in a number of animals by histological changes in the lymphopoietic system, viz. atrophy of the white pulp of the spleen was found. This possibly induced a decrease of general resistance, so that a mycotic infection developed in the animals. Hitherto, damage to the central nervous system was considered to be the most sensitive criterion for assessing the toxicity of organotin compounds, but the present work shows that the effect on lymphopoiesis is a more sensitive index of toxic action for triphenyltin compounds.

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.