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The present study describes the metabolic changes observed in a dietary subacute toxicity experiment with the ergot alkaloid α-ergocryptine in Sprague–Dawley rats. The observed effects on metabolic and hormonal parameters were described separately from the general toxicological effects, in view of the important role of dopamine agonists in metabolism (e.g. ergot alkaloids in fescue toxicosis). The rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28–32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). Total cholesterol and high-density lipoprotein (HDL)-cholesterol were decreased dose dependently in females but the ratio HDL-cholesterol/total cholesterol was only decreased at 20 mg/kg body weight. Triglycerides and glucose concentrations were decreased in the highest dose groups of both sexes. Serum urea concentrations were increased in the 20, 100 and 500 mg/kg dose groups. Insulin, glucagon and liver glycogen were increased in the highest dose group at the end of the study, when the animals were allowed to eat prior to blood sampling and necropsy. Prolactin, T4 and FT4 were decreased in the 20, 100 and 500 mg/kg dose groups of both sexes. Follicle-stimulating hormone (FSH) was decreased in the 20, 100 and 500 mg/kg female dose groups and luteinizing hormone (LH) was increased in the 20, 100 and 500 mg/kg male dose groups. It is postulated that the observed effects on food intake, metabolism (lipid and carbohydrate) and hormonal parameters are due to an interaction of ergocryptine with central dopaminergic activities, which comprise a major functional component of a central regulatory system for metabolism.

The dietary subacute toxicity of the ergot alkaloid alpha-ergocryptine was studied in Sprague-Dawley rats. Rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28-32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). The present study describes the general toxicological effects; the effects on metabolic and hormonal parameters will be reported separately. Body weight, body weight gain, food intake and food efficiency were all decreased with a U-shaped dose-response curve, as in both sexes the ranking severity of effects was in the order 100-20-500 and 4 mg/kg diet. Other changes with a U-shaped dose-response relationship included: hematological parameters (decreased MCV and MCH), serum enzyme activities (slightly increased/decreased ALAT, ASAT, GGT), increased serum urea concentrations, decreased glomular filtration (creatinine and urea clearances), decreased absolute organ weights, increased and decreased relative organ weights, atrophy of thymus and in females atrophy of ovary and uterus with in the mid-dose groups no detectable morphological features of an oestric cycle in the uterus. Other parameters, including increased relative liver, heart and ovarian weights and necrosis of the tail, were influenced in a dose-related manner or only in the high dose group. The U-shaped changes for the parameters mentioned above might be caused by the U-shaped dose-response relationship for food intake, which may be explained by the dopaminergic properties of alpha-ergocryptine. It is concluded that in rats fed ergocryptine for 28 days the dose-effect curve is rather steep and that the NOAEL is 4 mg/kg diet.

This study evaluated the effect of dietary cadmium (Cd) on atherosclerosis in the rabbit. Cholesterol was added to the diet to initiate and/or accelerate atherogenesis. Cd was added to the diet at two dose levels. Uptake of Cd was 55 micro gram/kg body weight (BW)/day at the low dose level and 1350 micrograms/ kg BW/day at the high dose level. Five groups of rabbits were fed five different diets for 9 months: (1) basal diet without additional constituents; (2) background diet, which was basal diet to which cholesterol had been added; (3) the low-dose level Cd diet, which was background diet to which 2 mg Cd/kg had been added; (4) high-dose level Cd diet, which was background diet to which 50 mg Cd/kg had been added; and (5) basal diet to which 50 mg Cd/kg had been added. Dietary cholesterol increased blood total leucocyte count, serum and liver total cholesterol concentrations, serum total bilirubin concentration, low-density lipoprotein vitamin E concentration and induction of atherosclerotic plaques in the aorta and coronary arteries. Cd in the diet increased liver and kidney Cd concentrations in a dose-dependent way, decreased prothrombin time and temporarily increased urea and creatinine clearances. Slight kidney damage was induced by Cd only in animals fed the high-dose level Cd diet (with or without cholesterol). Dietary Cd partly counteracted the dietary cholesterol-induced increases of serum and liver total cholesterol concentrations, and tended to reduce plaque formation in the aorta. Dietary Cd in rabbits fed cholesterol-containing diets influenced cholesterol metabolism and tended to decrease atherosclerosis in a dose-related fashion. This is in contrast with limited epidemiological human data. Dietary Cd also decreased serum ferritin concentration and increased serum transferrin concentration. Free iron concentration is associated with myocardial infarction in man and augments the development of atherosclerosis in rabbits. It is concluded that the observed reduction in atherogenesis is related to dietary Cd-induced changes in cholesterol metabolism, increased rheology of blood and/or, most likely, reduced free iron concentration.

There is growing evidence that T-lymphocyte dysfunction contributes to the development of hypertension. IL-4 and IFN-gamma are important regulators of T-lymphocyte function. Therefore, we investigated the effect of neutralizing antibodies against IL-4 (alpha-IL-4) and IFN-gamma (alpha-IFN-gamma) on the development of hypertension in NZBNZWF1 hybrid compared to normotensive NZW control mice. Antibody-producing cells were encapsulated and injected intraperitoneally in mice at 6,8 and 10 weeks of age. This treatment resulted in significant levels of antibody in the serum. At 12 weeks of age blood pressure was recorded under anesthesia. Mean arterial blood pressure (MAP) increased in NZBNZWF1 hybrids between the age of 6 and 12 weeks. This increase was inhibited by treatment with alpha-IL-4, but was not affected by alpha-IFN-gamma. Treatment with alpha-IL-4 did not influence MAP in normotensive NZW or C57B1/6J mice. However, in these mice, treatment with alpha-IFN-gamma increases MAP. This increase in MAP by alpha-IFN-gamma was prevented by simultaneous treatment with alpha-IL-4. The present study demonstrates the influence of endogenous IL-4 and IFN-gamma on blood pressure.

Ergot alkaloids, produced by the fungus Claviceps purpurea, are found in small amounts in foodstuffs. The human disease ergotism, caused by high intake of ergot alkaloids, is well known; however, little is known about the toxicity of these compounds. The subacute toxicity of an ergot alkaloid, ergometrine maleate, was therefore studied. Sprague-Dawley rats were treated with 0, 2, 10, 50 and 250 mg ergometrine maleate/kg diet for 4 wk. Plasma glucose levels were decreased in females at 50 and 250 mg/kg. Thyroxin levels were decreased at 50 (males only) and 250 mg/kg. At the high dose level, organ weights of heart, liver, ovaries and kidneys were increased. In male rats a slight dose-related increase in the incidence of enlarged mediastinal lymph nodes and, to some extent, of enlarged parathymal lymph nodes, was seen. Histopathological examination revealed evidence of increased glycogen storage in the liver of animals treated with 250 mg/kg. The no-observed-effect level in this study was 10 mg/kg.

An acute (4-hr) and a sub-acute (4-wk) inhalation toxicity study of germanium metal powder (purity 99.8%, mean particle size 2.0–2.4 μm) were carried out in young adult Wistar rats. Exposure of five male and five female rats to 3.86 or 5.34 g/m 3 for 4 hr resulted in the death of one rat at each exposure level. Four groups of five male and five female rats were exposed to 0, 9.9, 65.1 or 251.4 mg/m 3 for 6 hr/day, 5 days/wk for 30 days. Two additional (recovery) groups of five male and five female rats exposed to 0 or 251.4 mg/m 3 were kept untreated for 31 days after exposure. At the end of the treatment period, fasting blood glucose was decreased in males exposed to the high concentration. In females of this group, blood creatinine and urea levels, and urine volumes were increased, but urine density was decreased. Increased blood creatinine levels and urine volume and decreased urine density were also observed in females exposed to 65.1 mg/m 3 . The absolute and relative lung weights were increased in rats in the mid- and high-concentration groups. Histopathological examination revealed: accumulation of particulate material in the lungs of all treated groups, accumulation of alveolar macrophages in the mid- and high-concentration groups, and alveolitis mainly in the high-concentration group. After the 4-wk recovery period, urine volume was increased in males that had been exposed to germanium. In exposed rats of both sexes, lung weights were still increased and histopathological changes were present, but to a lesser extent than at the end of the exposure period. It was concluded that the 4-hr LC 50 value of germanium metal powder in rats is > 5.34 g/m 3 . The no-adverse-effect level in the 4-wk study was 9.9 mg/m 3 air.

The effects of cigarette smoke condensate (CSC) and all-trans retinol on the cell proliferative activity of vitamin A-deprived hamster tracheal epithelium have been studied in vitamin A-deficient, serum-free, hormone-supplemented medium in organ culture. In the absence of retinol, CSC induced a dose-dependent increase in labelig index (LI) during 12 days of culture. The basal cells were more sensitive to CSC exposure than non-basal cells during the first 6 to 8 culture days. However, in squamous metaplastic foci developing after culture day 6, both basal and non-basal cells in the mid-part of the epithelium were labeled. Physiological concentrations of all-trans retinol stimulated the non-basal LI and inhibited the basal cell LI. Compared with dimethylsulfoxide (DMSO), all retinol concentrations used in the present study inhibited the basal cell LI at each time point examined (4-12 days culture). Exposure of tracheal rings to retinol, either before or after exposure to CSC, or simultaneous exposure to retinol and CSC, clearly decreased the CSC-induced basal cell proliferative activity depending on the retinol concentration used. It is concluded from the present study that squamous metaplasia induced by vitamin A-deficiency or by CSC originates mainly from basal cells and that for the maintenance of these lesions, both basal and non-basal cells play a role. Furthermore, all-trans retinol inhibited CSC-induced basal cell proliferation. Chemicals/CAS: retinol, 68-26-8, 82445-97-4; Dimethyl Sulfoxide, 67-68-5; Vitamin A, 11103-57-4

Cofactors involved in respiratory tract carcinogenesis were studied in Syrian golden hamster or in rats using benzo(a)pyrene as the carcinogenic agent. These factors included severe tissue tissue damage induced by electro-coagulation, glass fibers administered by intratracheal instillation, acetaldehyde as irritant vapor, food restriction, and nutrients such as vitamin A and saturated and unsaturated fats. In addition, the effects of a combined exposure to four different major gaseous cigarette smoke components - methyl nitrate, isoprene, methyl chloride and acetaldehyde - and to one solid cigarette smoke component - norharman - were examined in short- and long-term inhalation studies. An interesting finding was the charcinogenicity of acetaldehyde, of which the possible mechanism is briefly discussed. Another conspicuous observation was the substantial increase in number and size of lipid droplets in alveolar fibroblasts of hamsters fed a high vitamin A diet. Chemicals/CAS: acetaldehyde, 75-07-0; benzo[a]pyrene, 50-32-8; beta carboline, 244-63-3; isoprene, 78-79-5; methyl chloride, 74-87-3; retinol, 68-26-8, 82445-97-4; Acetaldehyde, 75-07-0; Benzo(a)pyrene, 50-32-8; Benzopyrenes; Glass

Groups of 40 Syrian golden hamsters of both sexes were fed diets containing either 5% fat (control), 20% saturated fat (beef tallow) or 20% unsaturated fat (sunflower seed oil) from weaning and during the whole experimental period (up to 656 days). Respiratory tract tumours were induced by intratracheal instillation of benzo[a]pyrene attached to ferric oxide and suspended in saline. Mortality was slightly, but not statistically significantly higher in the high fat groups than in the low fat control group. Microscopic examination of the respiratory tract revealed an increased number of tumour bearing animals, an increased multiplicity of respiratory tract tumours and an increased total number of respiratory tract tumours in animals fed high fat diets. The tumour enhancing effect of fat was most pronounced in the high unsaturated fat group. Especially epidermoid papillomas, epidermoid carcinomas and combined epidermoid and adenocarcinomas contributed to the observed differences in tumour response amongst groups. It was concluded that dietary fat enhances benzo[a]pyrene-induced respiratory tract carcinogenesis in hamsters.

Two groups of male and female Syrian golden hamsters, of which the trachea was severely injured by electrocoagulation, received 6 weekly intratracheal instillations of benzo[a]pyrene (BaP) + ferric oxide in saline or saline alone. Two comparable groups of hamsters were similarly treated but had an undamaged trachea. The experiment was terminated in week 82. Treatment with BaP resulted in hyper- and metaplastic lesions and tumours of the laryngeal, tracheal, bronchial and pulmonary epithelium. There was no evidence of an increased incidence of BaP-induced tumours in the injured trachea. Chemicals/CAS: benzo[a]pyrene, 50-32-8; Benzo(a)pyrene, 50-32-8

The subacute toxicity of selenium was tested by feeding sodium selenite to Syrian hamsters at dietary levels of 0.1, 1, 5, 10 and 20 ppm selenium for 42 days. General health, survival and organ weights were not adversely affected at any of the dose levels. Weight gain and food intake were relatively low in males fed the highest dose level. The differences from the control values were not statistically significant and there was no similar effect in females. Hamsters fed 10 or 20 ppm retained considerably higher levels of selenium in the liver than did the controls. Microscopic examination of the liver revealed degenerative changes in males and females in the 20-ppm group. The no-toxic-effect level of selenium fed in the diet for 42 days to Syrian hamsters was found to be 10 ppm, equivalent to an intake of about 0.7 mg selenium/kg body weight/day.

A variety of gastric lesions can be induced in rats by sodium metabisulfite, including the formation of scattered hyperplastic glands in the fundic mucosa which are exclusively lined by large uniform cells, laden with acidophilic granules. Light and electron microscopy, as enzyme histochemistry, showed that the cells lining these glands are hyperactive chief cells, containing a huge amount of pepsinogen granules. A time-sequence study revealed that the hyperactive chief cells arise from preexisting chief cells but are also capable of proliferation. The occurrence of glands exclusively lined by chief cells is highly unusual since mucous cells rather than chief cells are considered to be involved in the regeneration of gastric epithelium after physical or chemical damage. Chemicals/CAS: sodium metabisulfite, 7681-57-4, 7757-74-6; sulfurous acid, 7782-99-2; thiamine, 59-43-8, 67-03-8; sodium metabisulfite, 7681-57-4; Sulfites

The pseudostratified tracheal epithelium, composed of a heterogeneous phenotypically varying cell population, was studied with respect to the in vitro cell proliferative activity of differentiated epithelial cells. Ciliated tracheal epithelial cells so far have been considered to be terminally differentiated, nonproliferating cells. Tracheal organ cultures obtained from vitamin A-deprived Syrian Golden hamsters were cultured in a vitamin A-deficient, serum-free, hormone-supplemented medium. In vitamin A-deprived tracheal epithelium treated with physiologically active all-trans retinol and low cigarette-smoke condensate concentrations it is possible to stimulate the cell proliferation of both basal and columnar cells. Therefore, the probability of finding proliferating columnar cells was increased compared with the in vivo and the vitamin A-deprived situation in which cell proliferative activity is relatively low. In the presence of cigarette-smoke condensate in a noncytotoxic concentration, basal, small mucous granule, ciliated, and indifferent tracheal epithelial cells incorporated [methyl-3H]-thymidine into the DNA during the S phase. The finding that ciliated cells were labeled was supported by serial sections showing the same labeled ciliated cell in two section planes separated by 2 to 3 micron, without labeled epithelial cells next to the ciliated cell. Furthermore, a ciliated tracheal epithelial cell incorporating [methyl-3H]thymidine into DNA was also seen in tracheal cultures of vitamin A-deprived hamsters treated with all-trans retinol in a physiologic concentration.

Rats fed alkali-treated food proteins may develop nephrocytomegaly (NC). Lysinoalanine [LAL], an unusual amino acid formed in proteins during alkali-treatment, is the main causative factor. Whether NC occurs, seems, however, less dependent on the dietary level than on factors such as animal species, feeding period, chemical form of LAL, type and structure of the treated protein, and presence or absence in the diet of non-treated proteins of high quality. Possible human health implications are discussed.

The modifying effect of selenium as sodium selenite on chemically induced respiratory tract tumours was tested in Syrian golden hamsters. Groups of 40 hamsters per sex (controls 60 per sex) were fed the following semisynthetic diets: control diet (0.1 p.p.m. Se, low fat); high-Se diet (5 p.p.m.); high-fat diet (20% sunflower oil); or high-Se + high-fat diet. After an adaptation period of 30 days on the diets, respiratory tract tumours were induced by intratracheal instillation of benzo[a]pyrene attached to ferric oxide. The experimental period was 429 days for males and 374 days for females. Respiratory tract tumours included mainly epidermoid papillomas, epidermoid carcinomas and combined epidermoid and adenocarcinomas. Selenium included either in a low-fat or high-fat diet did not influence the tumour response in the respiratory tract or in other organs. Neither was there a correlation between the serum or liver Se levels in the presence of respiratory tract tumours. The tumour response in the respiratory tract and also in other organs was slightly respiratory tract and also in other organs was slightly enhanced by dietary fat.

The influence of dietary factors such as total composition, thermal processing, and the addition of vegetables and fruit on the tumour rate in rats was studied in a long-term experiment. Groups of 50 male and 50 female Wistar rats were fed one of the following diets: a semi-synthetic animal diet (A, control); diet A to which vegetables and fruit were added (B); an uncooked human diet (meat, bread and eggs) supplemented with semi-synthetic compounds (C); diet C with fried or baked products (D); a complete human diet consisting of heated products, vegetables and fruit prepared according to mean consumption figures in The Netherlands (E). The animal diets (A and B) contained 26.0 energy (E)% protein, 21.6 E% fat, 52.4 E% carbohydrate and 10.7% (w/w) fibre. The human diets contained 13.2 E% protein, 40.6 E% fat, 46.2 E% carbohydrate and 5% (w/w) fibre. The rats were fed ad lib. for 142 wk. In males and females fed human diets (C, D or E) hepatocellular vacuolization was observed. Male rats (but not female) fed the human diet had a significantly (P less than 0.02) higher incidence of epithelial tumours than those fed the animal diet. This increase was mainly due to tumours of the pituitary and thyroid. Frying and baking of food products (diet D) and the addition of vegetables and fruit (diet E) induced minor differences in tumour rate, but they were not statistically significant.

The effects of all-trans retinol and cigarette smoke condensate (CSC) on tissue morphology and cellular differentiation were investigated in vitamin A-deprived tracheal epithelium cultured in vitamin A- and serum-free hormone-supplemented medium. Physiological retinol concentrations prevented the development of hyperplasia and squamous metaplasia with or without keratinization, and induced differentiation to mucous cells. Squamous metaplastic foci with keratinization were observed during 12 days of culture with low retinol concentrations and with dimethylsulfoxide (DMSO) which was accompanied by an increased number of basal and indeterminate cells. CSC induced a dose-related hyperplasia and irregularly shaped foci of squamous metaplasia with atypical epithelial proliferation. In non-metaplastic epithelium, CSC exposure increased the number of ciliated cells. Hyperplasia and squamous metaplasia were inhibited if the tracheal rings were first treated with retinol followed by CSC exposure, or if the tracheas were simultaneously treated with retinol and CSC. CSC-exposure prior to retinol treatment induced similar histomorphological alterations as CSC alone. Chemicals/CAS: dimethyl sulfoxide, 67-68-5; retinol, 68-26-8, 82445-97-4; Dimethyl Sulfoxide, 67-68-5; Vitamin A, 11103-57-4

A significant difference in toxicity between 3 polychlorinated biphenyl (PCB) preparations was found in a prior study: Clophen A 60 and Phenoclor DP6 showing the highest, Aroclor 1260 the lowest, toxicity (Vos and Koeman, 1970) . A subsequent study revealed the presence of tetra- and pentachlorodibenzofuran in Phenoclor and Clophen (Vos et al. , 1970) . In the present study, application of 118 mg of the 3 PCB's (5 times per wk, for 38 days) on the back skin of rabbits also resulted in differences in toxicity. PCB-induced skin lesions were hyperplasia and hyperkeratosis of the epidermal and follicular epithelium. Histopathology of the liver included centrolobular degeneration, centrolobular liver cell atrophy, focal necrosis, and cytoplasmic hyalin degeneration. Definite hyperplasia and hyperkeratosis of the follicular epithelium of the ear skin were seen after the topical application of fractions of Phenoclor and Clophen eluted from chromatographic columns with 25% diethylether in hexane. The fraction from Aroclor caused a minimal hyperplasia and hyperkeratosis of the follicular epithelium. PCB-induced kidney lesions were hydropic degeneration of the convoluted tubules and tubular dilatation with the presence of casts. This dilatation was demonstrated also by a significantly increased relative percentage of the diameter which corresponds to the space of Bowman. Moreover, thymus atrophy and lymphopenia were found. Fecal coproporphyrin and protoporphyrin excretion was increased.