M.J. van Logten

Effect of triphenyltin hydroxide on the immune system of the rat

To evaluate the functional significance of triphenyltin hydroxide (TPTH)-induced lymphopenia and lymphocyte depletion in thymus-dependent areas of spleen and lymph nodes, various immune function studies were carried out after 3 or 4 weeks TPTH exposure. Weaned male rats were fed a diet containing 25 mg TPTH/kg, a concentration that did not influence food intake and weight gain. TBTO exposure was continued during the course of the function tests. As parameters of the cell-mediated immunity in 2 experiments the delayed-type hypersensitivity reactions to ovalbumin and tuberculin were significantly suppressed. No effect was observed on allograft rejection, splenic clearance of Listeria monocytogenes at days 5 and 6 after infection, and responsiveness of thymocytes to different T-cell mitogens. In contrast, the response of splenic lymphocytes to the T-cell mitogen phytohaemagglutinin was significantly suppressed. As TPTH treatment reduced the number of spleen cells, mitogenic response calculated per whole spleen was significantly depressed. Regarding the humoral immunity, no effect was observed on serum IgM and IgG levels, on the thymus-independent IgM response to E. coli lipopolysaccharide (LPS), and on the primary and secondary IgM and IgG response to the thymus-dependent antigen tetanus toxoid. Also, no effect was found on phagocytic and killing capacity of macrophages as demonstrated by unaltered splenic clearance of L. monocytogenes at days 1 and 2 after infection. Slightly enhanced mortality of TPTH-treated animals was observed in a L. monocytogenes mortality assay. Finally, TPTH did not increase the susceptibility of rats to endotoxin (LPS).

Role of the endocrine system in the action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the thymus

Several experiments were conducted to study the involvement of the adrenal and the pituitary gland in the acute toxic effects of TCDD. Adrenalectomized or hypophysectomized rats were treated with a single oral dose of 10 or 20 microgram of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight. The reduced growth rate, the hepatotoxic effects and thymic involution induced by TCDD were not prevented by the adrenalectomy. The pituitary gland did not appear to be involved in causing thymic involution. In fact, the thymic effects of TCDD intoxication were even somewhat increased in hypophysectomized rats. Treatment with growth hormone failed to prevent thymic involution or the influence of TCDD on the liver.

Toxicity of sodium bromide in rats: effects on endocrine system and reproduction.

Bromide has a low acute oral toxicity, with LD50 values in rodents ranging from 3500 to 7000 mg/kg body weight. It is rapidly absorbed and steady-state serum levels have been reached in rats within 4 weeks. The biological half-life of bromide, and consequently the serum levels, are strongly dependent on chloride intake. Feeding of sodium bromide to rats for 90 days in concentrations of 0, 75, 300, 1200, 4800 and 19,200 mg/kg diet led to a complex of changes in the endocrine system, thyroid activation being the most prominent. Furthermore, in the highest dose groups a decrease in spermatogenesis in the testes and decreased secretory activity of the prostate or a reduction in the number of corpora lutea in the ovaries were found. A three-generation reproduction study of the same dietary concentrations showed in the two highest dose groups a decrease in fertility which appeared to be reversible upon bromide withdrawal. Macroscopically, no changes in the offspring were observed. From these studies a no-effect level for bromide ion of 240 mg/kg diet was determined, corresponding to a tentative Acceptable Daily Intake (ADI) of 0.12 mg/kg body weight. This is in good agreement with a preliminary ADI of 0.1 mg/kg established in an experiment with human volunteers, but is considerably lower than the ADI of 1 mg/kg estimated by FAO/WHO. It is suggested that bromide exerts an inhibitory effect on the thyroid, resulting in an increased hormonal stimulation of this organ by the pituitary gland.

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.

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.

The influence of dietary chloride on bromide excretion in the rat

Abstract The influence of graded doses of chloride in drinking water on the excretion rate of bromide was investigated in the rat. Bromide half-like varies from 2.5 days during high chloride intake to 25 days during low chloride intake. It is concluded that chloride will have a marked influence on the no-effect level of bromide.

The influence of sodium bromide in man: a study in human volunteers with special emphasis on the endocrine and the central nervous system.

Sodium bromide was administered orally in capsules to healthy volunteers in doses of 0, 4 or 9 mg Br-/kg/day using a double-blind design. Each treatment was given to seven males for 12 weeks and to seven non-pregnant females (not using oral contraceptives) over three full cycles. Special attention was paid to possible effects on the endocrine and central nervous systems. At the start and end of the study, a full medical history, the results of a physical examination, haematological studies and standard clinical chemistry and urine analyses were recorded for each subject. These showed no changes for individuals following treatment, except for some incidence of nausea associated with bromide-capsule ingestion. Mean plasma-bromide concentrations at the end of treatment were 0.08, 2.14 and 4.30 mmol/litre for males and 0.07, 3.05 and 4.93 mmol/litre for females of the 0-, 4- and 9-mg Br-/kg/day groups, respectively. Plasma half-life was about 10 days. In the females taking 9 mg Br-/kg/day (but in no other group) there was a significant (P less than 0.01) increase in serum thyroxine and triiodothyronine between the start and end of the study but all concentrations remained within normal limits. No changes were observed in serum concentrations of free thyroxine, thyroxine-binding globulin, cortisol, oestradiol, progesterone or testosterone, or of thyrotropin, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone before or after the administration of thyrotropin-releasing hormone and LH-releasing hormone. Analysis of neurophysiological data (EEG and visual evoked response) showed a decrease in delta 1- and delta 2-activities and increases in beta-activities and in mean frequency (Mobility parameter) in the groups on 9 mg Br-/kg/day, but all the findings were within normal limits.

Short-term toxicity study on sodium bromide in rats

Abstract Five groups, each of 4 female rats, received for 4 weeks either a standard diet or diets containing 300, 1200, 4800 or 19 200 ppm sodium bromide. The rats receiving 19 200 ppm sodium bromide did not clean themselves sufficiently and showed signs of motor incoordination in their hind legs. There was no clear influence on growth, food or water intake. During the first week of the experiment the plasma concentration of bromide increased rapidly, but by the third week a plateau level was reached. Only at the beginning of the experiment did the total halide concentration in the blood show a tendency to increase. In the highest dosage group about 50% of the chloride in the plasma, brain, kidneys and liver had been replaced by bromide. In the other treatment groups there was also a dose-related replacement of chloride by bromide. The relative weight of the kidneys of the animals in the 19 200 ppm group was increased significantly. There were no histological changes which could be attributed to the feeding of a diet containing sodium bromide.

Effect of food deprivation on low level hexachlorobenzene exposure in rats

The purpose of the present study was to determine if food deprivation could modify the biological activity of hexachlorobenzene (HCB) in the rat. Male and female Wistar rats were divided into 6 groups containing 6 animals. Groups 1, 3 and 5 were fed standard control diet ad libitum for 2 weeks. For the next 4 weeks their respective diets contained 0, 20 and 100 ppm HCB. Groups 2, 4 and 6 were also fed a standard control diet for 2 weeks but at an intake of approximately 50% of those groups fed ad libitum. For the following 4 weeks food deprivation was continued but the control diets were replaced with diets containing 0, 40 or 200 ppm HCB. The parameters measured were food, body weight changes, changes in tissue weights, microsomal enzyme activity and histopathology of liver, kidneys, adrenals and pancreas. Tissue residue profiles were established for plasma, liver, brain and adrenals. Food deprivation augmented the induction of microsomal enzyme activity by HCB in both males and females at both dose levels. Liver hypertrophy was observed in both males and females fed 200 ppm HCB and subjected to food libitum. Food deprivation resulted in a higher plasma, liver, brain and adrenal accumulation of HCB in both males and females.