Pathology of "toxic oils" and selected metals in the MRL/lpr mouse.

The Toxic Oil Syndrome epidemic that occurred in Spain in 1981 and affected nearly 20,000 people was caused by ingestion of oil mixtures that contained analine-denatured rapeseed oil. To date, an animal model in which to identify the actual etiologic agents(s) and to investigate the pathogenesis of the disease has not been discovered. In this study, the MRL/lpr was used to assess the histopathological response of 3 "toxic oils" and 3 metals. The oils tested were a denatured rapeseed oil collected from a family who were affected by the Toxic Oil Syndrome epidemic in Spain (CO756) plus two synthesized oils (RSD and RSA). Female mice, 7 weeks of age, received an undiluted (neat) or a 1:10 diluted dose of each oil; mercury (50 ppm), cadmium (100 ppm), or lead (50 ppm). Half of each group was killed after 5 weeks of exposure and the remaining mice after 10 weeks of exposure. Body and organ weights (liver, kidney, thymus, and spleen) were recorded and selected organs were collected for histopathology. Ten weeks after treatment, body weights (BW) of the cadmium and lead groups were significantly suppressed, and the body weight of the C0756-neat group was significantly increased compared to their respective controls. Kidney/BW were decreased in the RSA-neat and RSA 1:10 groups after 10 weeks of exposure, and the kidney/BW in the mercury and cadmium groups were increased. Spontaneous development (12 weeks of age) and progression (17 weeks of age) of histopathological lesions are described for selected organs examined in the naïve mice as are changes that resulted from exposure to the "toxic oils" and metals. C0756-neat, mercury, and lead suppressed progression of the glomerulonephritis that normally occurs in the MRL/lpr mouse. Also of interest were lesions that included mononuclear cuffing of hepatic bile ducts, progression of the granulomas that formed in the renal glomeruli, vessels in the lymphoid organs that contained tightly packed lymphocytes, and the presence of plasma cells in the thymus. All 3 oils stimulated early development of the lymphoproliferative syndrome characteristic of the MRL/lpr mouse as demonstrated by an increase in the thymus/BW and spleen/BW ratios after 5 weeks of treatment. These data contribute to our knowledge of spontaneous disease progression in the thymus, spleen, lymph nodes, and kidneys in the MRL/lpr mouse and the effects of 3 different "toxic oils" and metals on the development and progression of those lesions.

The correlation between serum selenium and blood selenium in cattle.

The selenium (Se) concentration of paired blood and serum samples from cattle was determined by 2 methods: 1) atomic absorption spectroscopy using hydride generation (HG-AAS), and 2) inductively coupled argon plasma emission spectroscopy using hydride generation (ICP). Samples from 327 cattle were analyzed by HG-AAS, and samples from 344 cattle were analyzed by ICP. The data were examined by linear regression analysis, and the technique of inverse prediction was utilized to determine prediction intervals for estimating blood Se concentration from known serum Se concentration. The correlation coefficients, by simple linear regression of serum Se on blood Se, were 0.79 (r2 = 0.62) and 0.88 (r2 = 0.77) for the HG-AAS data and the ICP data, respectively. For the HG-AAS data, the inverse prediction formula for estimating blood Se when serum Se is known, at the 95% prediction interval, was [formula; see text]. For the ICP data, the inverse prediction formula for estimating blood Se when serum Se is known, at the 95% prediction interval, was [formula; see text]. The prediction intervals were quite wide, and the accuracy of estimating blood Se from a known serum Se was not useful for diagnostic purposes. The use of serum Se concentration to assess nutritional status of cattle with respect to Se does not appear to be appropriate.

Immunotoxicity assessment of gentamycin and liquamycin.

Rats were injected with gentamycin (GEN) or the oxytetracycline, liquamycin 200 (LA200), and multiple immune responses were measured to assess the immunotoxicity of these antibiotics. Animals were treated by sc or im injection for 12 days with either GEN or LA200 given at a therapeutic dose or at 10-, 50-, or 100-fold greater concentrations. The following immune parameters were assessed in each animal: delayed-type hypersensitivity (DTH), natural killer (NK) cell cytotoxicity, antibody production, and synthesis of interleukin 2 (IL2) and gamma interferon (IFN). The DTH response and IFN production in GEN- and LA200-injected animals were suppressed in a dose-dependent manner. Production of IFN was significantly suppressed in all groups treated with LA200. Suppression of DTH was evident when GEN or LA200 were given at the recommended therapeutic dose. Both LA200- and GEN-treated rats had suppressed NK cell cytotoxicity, but only at the highest dosages. Antibody production was suppressed in a dose-dependent manner in LA200-treated rats. Synthesis of IL2 was suppressed in rats treated with the high dose of GEN. Body weight loss occurred, and hepatic and renal toxicity were apparent at the 2 highest dosages of GEN or LA200. It was apparent that relatively high doses of GEN and LA200 can suppress specific and non-specific cell-mediated immune responses. Also, the data suggest the certain immune responses (eg, DTH reaction and possibly IFN production) may be suppressed at the recommended therapeutic doses in the absence of other signs of toxicity. These results indicate that these antibiotics should not be administered at doses or exposure periods in excess of those recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

The two faces of selenium-deficiency and toxicity--are similar in animals and man.

The purpose of this review article is to demonstrate the close parallelism of daily requirements, biological activity and minimum and maximum tolerable levels of selenium for animals and man. In addition, the carcinogenic/anticarcinogenic properties of selenium are discussed and a postulate of how these dichotomous effects may occur in accordance with selenium-induced immunomodulation is presented. A review of pertinent literature pertaining to the biological action of selenium in animals and man, including deficiency, toxicity, carcinogenicity and effects on immunity, is included to support these concepts. The predominant biochemical action of selenium in both animals and man is to serve as an antioxidant via the selenium-dependent enzyme, glutathione peroxidase, and thus protect cellular membranes and organelles from peroxidative damage. The signs and symptoms of selenium deficiency closely simulate each other for animals and man. Severe deficiency is characterized by cardiomyopathy while moderate deficiency results in less severe, myodegenerative syndromes such as muscular weakness and pain as well as a variety of other selenium-associated diseases. Clinical manifestations of many of these disorders require contributory factors, such as stress, to precipitate symptoms which are documented for animals and implicated for humans. Current evidence suggests that a daily selenium consumption for man of approximately 30 micrograms is necessary to prevent the selenium-deficient syndrome, Keshan disease, while approximately 90 micrograms/day/adult should be the minimum daily requirement for optimum biological performance. Recognizing that humans in several countries do not meet the proposed minimum daily requirement of 90 micrograms, several compelling reasons are presented in deriving this minimal daily nutritional intake. Selenosis can occur in laboratory animals, livestock, and humans following long-term exposure to selenium concentrations as low as 5 mg selenium/kg of diet (5 ppm). The selenium-induced lesions for all species are similar, which once again illustrates a positive corollary for selenium effects in both animals and man. From compilation of available data, the maximum tolerable level for selenium in man could be considered in the range of 1000 to 1500 micrograms/day. This is in contrast to the currently recommended maximum human tolerable level of 500 micrograms/day. The amount of selenium that can be tolerated, however, is dependent upon individual biological variation, nutritional status and general state of health.(ABSTRACT TRUNCATED AT 400 WORDS)

Immune responses in rats supplemented with selenium.

It is generally accepted that Selenium (Se) is necessary for optimum performance of the immune system. Selenium deficiency results in immune suppression but little is known concerning the effect of excess Se on immune function. Recent evidence suggests that oral Se supplementation may impede oncogenesis, but the mechanism of this action is currently unknown. Conversely, under certain conditions, Se is suspected of promoting neoplasia. The studies described herein delineate the effects of excess Se (0.5, 2.0 or 5.0 p.p.m.) on specific immune functions of Se-adequate rats, namely, antibody synthesis, delayed-type hypersensitivity (DTH), natural killer (NK) cell activity, prostaglandin E2 (PGE2) synthesis, and interleukin 1 (IL-1) activity. Selenium administered to female Sprague-Dawley rats for 10 weeks at 0.5 and 2.0 p.p.m. resulted in significant (P less than or equal to 0.01) enhancement of splenic NK activity while the NK response in the 5.0 p.p.m. Se-treated rats was equivalent to the non-Se-treated controls. Conversely, the DTH response was significantly (P less than or equal to 0.01) suppressed at all three dosages while antibody synthesis and prostaglandin E2 activity were significantly (P less than or equal to 0.05) reduced compared to the controls at the highest dosage of Se. IL-1 activity was unaffected by Se exposure. These data could partially explain the contradictory oncogenic characteristics of Se. For instance, tumours that are NK sensitive could be prevented and/or responsive to Se therapy, while NK insensitive neoplasms could be enhanced by Se supplementation due to the impaired function of both humoral and cell-mediated immunity.

Transplacental transfer and colostral concentrations of selenium in beef cattle.

Three groups of 20-month-old pregnant Hereford heifers received 3 regimens of selenium (Se) supplementation. Group 1 received pelleted alfalfa hay, soybean meal, which contained Se (0.313 mg/kg), and 90 mg of Se as sodium selenite/kg of salt-mineral mix ad libitum. Group 2 received the pelleted hay and soybean meal, and group 3 received only the pelleted alfalfa hay. At time of parturition, the mean whole blood Se concentrations were: group 1 = 0.250 mg of Se/kg of blood, group 2 = 0.162 mg/kg, and group 3 = 0.052 mg/kg, whereas the respective mean blood glutathione peroxidase (GSH-Px) values were 144, 80, and 30 mU/mg of hemoglobin. In comparison, the mean whole blood Se values for the calves were 0.242, 0.175, and 0.81 mg/kg, respectively, and their blood GSH-Px values were 154, 113, and 50 mU/mg of hemoglobin, respectively. Thus, the blood Se and GSH-Px values for each group reflected dietary intake of Se. The calf blood GSH-Px values were similar to their dams for group 1, but were 41% higher in group 2 and 67% greater in group 3. The data suggested that the fetus can sequester blood Se, accumulating values greater than the dam, and that larger amounts were concentrated in the fetus when smaller amounts were available from the dam. The colostrum contained modest to low amounts of Se proportionate to dietary intake of this element. However, milk 7 days after parturient contained inadequate amounts of Se to sustain blood Se values in calves and the milk from heifers with low normal blood Se was essentially void of Se (0.009 mg/kg). (ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of selenium levels and glutathione peroxidase activity in bovine whole blood.

Blood glutathione peroxidase activity and selenium levels were found to correlate well, indicating that glutathione peroxidase activity can be used to assess blood selenium levels in beef cattle. The glutathione peroxidase activity of blood is less stable than is the selenium concentration but when blood was stored at 4 degrees C, the glutathione peroxidase activity remained constant for seven days.

Alteration of natural killer cell-mediated cytotoxicity in rats treated with selenium, diethylnitrosamine and ethylnitrosourea.

Weanling, female Sprague--Dawley rats were divided into 14 separate groups. Three of these groups were administered 0.5, 2.0 or 5.0 ppm selenium (Se) in the drinking water for 10 weeks. Three groups received intraperitoneal injections of 1, 5 or 10 mg/kg diethylnitrosamine (DEN) twice weekly for 10 weeks. The remaining animals received 0.150% or 0.316% ethylurea (EU) in the feed and 1 or 10 ppm nitrite as sodium nitrite in the drinking water either alone or in combination. Separate groups of rats treated with cyclophosphamide (CY) were included as positive immuno-suppressed controls. Following the 10-week chemical exposure period, splenic natural killer (NK) cell-mediated cytotoxicity was assessed by a 4-h chromium release assay using YAC-1 tumor cells as targets. The NK cell cytotoxic response was enhanced in both the low and medium dose selenium-exposed groups. In contrast, rats exposed to 0.316% EU + 10 ppm NO2 had significantly depressed NK cell activity. CY treatment also resulted in a significant reduction of splenic NK cell cytotoxicity.

Selenium deficiency of beef cattle in Idaho and Washington and a practical means of prevention.

The majority of beef cattle assayed for whole blood glutathione peroxidase (GSH-Px) activity in Idaho and Washington were deficient in selenium. Cattle in the more arid sections of these states tended to have higher selenium levels than those in areas with moderate and high rainfall. Animals pastured on irrigated forages had lower selenium concentrations than those grazed on dry land pasture. Cattle were supplemented by the addition of sodium selenite to a salt-mineral mixture. Ninety mg selenium per kg (ppm) salt-mineral mix fed to cattle significantly (P less than 0.001) elevated selenium (GSH-Px) levels well into normal ranges by 3 months when fed to extremely selenium deficient animals. Thirty ppm selenium was insufficient to raise GSH-Px levels into normal ranges. In addition, 20 ppm selenium was insufficient to sustain blood selenium concentrations of selenium adequate animals. Selenium given in the salt-mineral mix provided an effective, economical, and easily regulated source of dietary selenium. This supplement can be provided the entire year even under range conditions. Calves of cows placed on the 90 ppm selenium supplement had significantly (P less than 0.005) improved weaning weights (10 months) and an indication of a decreased incidence of infectious diseases.

Induction of humoral immunity to protein antigen without adjuvant in rats exposed to immunosuppressive chemicals.

An experimental protocol was designed to assess humoral immune responses in animals antigenically challenged without the aid of adjuvants. The antigen selected was keyhole limpet hemocyanin (KLH). An enzyme-linked immunosorbent assay (ELISA) was utilized as the technique to measure serum antibody levels. The procedure was tested for sensitivity by use of a known immunosuppressant (cyclophosphamide), two metals (lead and selenium), and three chlorinated hydrocarbons (polychlorinated biphenyls, pentachlorophenol, and toxaphene). KLH without adjuvant provoked an adequate humoral immune response when assessed by the ELISA. The antibody response was greater on d 15 than on d 8 following primary KLH challenge, while secondary challenge resulted in an additional 10-fold increase in antibody levels. Cyclophosphamide suppressed the later primary response (d 15) and the secondary response more so than the early primary response (d 8). Of the 5 chemicals tested, 4 resulted in significantly impaired antibody levels to KLH at some time during the response. The magnitude of the immune response elicited to KLH is compared to that reported for bovine serum albumin and ovalbumin administered with Freund's adjuvant.

Synergism of methylmercury and selenium producing enhanced antibody formation in mice.

Mice fed 1, 5, and 10 ppm methylmercury plus 6 ppm selenium for 10 wk had a significant increase in antibody synthesis. Since methylmercury singly depresses antibody synthesis and the response was greater than that produced by selenium alone, synergism between methylmercury and selenium occurred. In this case, the synergism is considered to be advantageous to a host, while exposure by other combinations of environmental contaminants may be detrimental. Mercury concentrations in the kidney were markedly elevated when methylmercury and selenium were administered simultaneously compared to when methylmercury was given without selenium supplement. These results indicate that data collected from individual pollutants may not be of value in predicting responses to multiple exposure.

Effect of dietary selenium on tumor induction by an oncogenic virus.

Mice exposed to selenium-supplemented or -deficient rations were inoculated with an oncogenic virus, Rauscher leukemia virus (RLV), Splenic lesions were not altered by dietary selenium supplementation or depletion. It is concluded that selenium does not affect neoplasia induced by RLV in mice.