The effect of ortho toluenesulfonamide and sodium saccharin on the urinary tract of neonatal rats.

The transplacental and postnatal effects of ortho-toluenesulfonamide (o-TS, 99.9% pure) and o-TS-free sodium saccharin on the urinary tract of neonatal rats, were examined in two experiments. In the first, o-TS in corn oil was administered by gavage throughout gestation and lactation at dosages of 0, 40, 100, or 250 mg o-TS/kg. After weaning, the pups were fed diets containing sufficient o-TS to provide the same dosages their respective dams received. Pups were killed at 8, 15, 21, and 105 days postpartum. The kidneys, urinary bladders, and urine filtrates were examined by light microscopy for calculi and the two organs were also examined histologically. A significant dose-response (p < 0.05) was found for the incidence of bladder calculi in 21-day-old pups and in 105-day old male and female rats. In a second experiment, male and female rats received one of the following dietary treatments for 100 days prior to mating: 0 (control), 2.5, 25, or 250 mg o-TS/kg, 250 mg o-TS/kg with 1% NH₄Cl in the drinking water, or 5% sodium saccharin. The dams were fed their respective diets during mating, gestation, and lactation. After weaning, the pups received their respective parents' diet. Pups were killed at 8, 21, and 105 days postpartum; kidneys, urinary bladders, and urine filtrates were examined as above. A significant dose-response (p < 0.05) was only found for the incidence of renal calculi and bladder lesions in 8-day-old pups from dams given diets that contained o-TS. However, there was no increased incidences of any urinary tract lesion in rats fed diets containing 250 mg o-TS and given 1% NH₄Cl in the drinking water, or in those fed a diet containing 5% sodium saccharin, or in older animals exposed only to o-TS. The administration of o-TS during gestation, lactation, and in the diet after weaning predisposes neonatal animals to urolithiasis and/or bladder lesions. These effects were not observed when a 1% solution of NH₄Cl was provided. Sodium saccharin, free of o-TS, did not have a similar effect.     

A carcinogenicity study of commercial saccharin in the rat.

Groups of 60 male and 60 female Charles River rats were fed diets containing sodium saccharin to provide daily doses of 0, 90, 270, 810, or 2430 mg saccharin/kg/day. The animals were treated for a period of 26 mo. Food consumption, body weight, and clinical examinations were conducted weekly on all rats. The animals were free of the bladder parasite Trichisomoides crassicauda. Four bladder tumors were found in treated animals: one male and one female from the 90-mg/kg group and two males given 810 mg/kg. The tumors were transitional cell papillomata, none of which were invasive. Three bladder calculi were observed grossly and several others were noted in urine samples examined microscopically. The presence of bladder calculi was not associated with saccharin treatment nor with the presence of bladder tumors. Saccharin administration was not accompanied by an increase in tumor incidence, although high doses were associated with reduced body weight in both sexes and decreased longevity in male rats.     

Vomitoxin (4-deoxynivalenol): effects on reproduction of mice and rats

Weanling male and female mice (F_o) were fed daily diets containing 4-deoxynivalenol (DON) at concentrations that resulted in a dose of 0 or 2.0 mg/kg body wt in Experiment I and 0, 0.375, 0.75, or 1.5 mg/kg body wt in Experiment II. The test diets were continuously fed to the F_o parents and their progeny for the entire duration of these two experiments, which were similar in design. After 30 days of dietary feeding, the mice were allowed to mate within experimental groups for a maximum of three 5-day trials. Females found to have mated successfully were allowed to litter normally. The F_1a progeny from 10 dams of each control and 1.5-mg DON/kg groups were cross-fostered at birth, whereas all of the remaining F_1a progeny were reared by their natural dams. The progeny were examined until 21 days of age and discarded. The F_o mice were rebred. The females bred to produce the F_1b litters were killed on Day 19 of gestation and their fetuses were examined for gross, visceral, and skeletal malformations. Reductions were observed in feed and water intakes and body weight of F_o male and female mice, the number of live pups and postnatal survivors, postnatal body weight of F_1a progeny, number of live fetuses, and mean fetal weight of F_1b fetuses. No adverse effects on fertility of F₀ male and female mice and no major malformations in F_1b fetuses were found. Cross-fostering offspring between control dams and 1.5-mg DON/kg-treated dams revealed that both postnatal survival and body weight were adversely affected by prenatal exposure as well as by a combined pre- and postnatal exposure. Male and female Sprague-Dawley rats were fed diets containing DON so as to deliver daily doses of 0.25, 0.5, or 1.0 mg/kg body wt. After 6 weeks of feeding, the rats were bred within groups and the males were then discarded. The mated females, maintained on their respective diets for the entire period of pregnancy, were killed on the last day of pregnancy and fetuses evaluated for effects on prenatal development. Except for dilation of renal pelvis and urinary bladder, the significance of which remains undetermined, no other adverse effect was observed.     

Tissue levels of saccharin in the rat during two-generation feeding studies

A single oral dose of [³H]saccharin was given to female rats in late pregnancy. The concentrations of ³H in the tissues of fetal rats 6 to 12 hr after the dose were lower than those in the mother. However, the concentrations in fetal tissues, including bladder wall, decreased more slowly, so that by 48 hr they exceeded the corresponding values obtained for maternal tissues, suggesting the possibility of accumulation during chronic intake. Despite this, the steady-state concentrations of saccharin in the liver and kidneys of fetuses from mothers fed a 5% saccharin diet ad libitum were lower than the corresponding materal values, while the concentrations in the fetal bladder were similar or slightly higher. The concentrations of saccharin in the tissues of rats in utero were not markedly higher than those found in adult F₁ animals. The turnover of saccharin in the fetuses of animals maintained on 5% saccharin diet was similar to that seen after a single dose. The results showed no evidence of excessive accumulation in the bladder wall or other tissues of male rats during in utero exposure or during lactation, which could explain the reported sex and generation specificity of the tumorigenic response.     

The tissue distribution and pharmacokinetics of saccharin in the rat

The concentration of saccharin in the plasma of rats fed a 5% saccharin diet showed marked diurnal variations. In male rats given 1–10% saccharin diets for 22 days the concentrations in the kidneys and bladder were higher than the plasma, while other tissues contained less than the plasma. The concentrations of saccharin in the plasma and tissues of female rats given 5% saccharin diet were higher than males treated similarly. The decrease in saccharin concentration in the bladder wall on removal of 5% saccharin diet, and after iv administration of [³H]saccharin to normal rats, reflected the decrease in urine and plasma levels. The concentrations of saccharin in the plasma and tissues of male rats given 7.5 and 10% saccharin diets were higher than predicted by linear extrapolation from lower dietary levels. The plasma clearance of [³H]saccharin given iv was dose dependent in anesthetized rats with high doses showing a 60% decrease in clearance. A similar reduction (70%) in clearance was achieved by prior treatment of the rats with probenecid. Decreased plasma clearance was also demonstrated under steady-state infusion conditions, at plasma concentrations greater than 200–300 μg ml^?1. The concentrations of saccharin in the plasma of rats given 7.5 and 10% saccharin diets were sufficient to saturate plasma clearance and thus cause the elevated concentrations of saccharin observed in the tissues of such animals.     

Two generation reproduction and teratogenicity studies of feeding cyadox in Wistar rats

To investigate the teratogenic potential and reproductive toxicity of cyadox, a growth promoting agent, Wistar rats (F₀) were fed with diets containing cyadox (0, 50, 150 and 2500 mg/kg) or olaquindox (150 mg/kg), approximately equivalent to cyadox 5, 15, 250 or olaquindox 15 mg/kg b.w./day across two generations. Half of the pregnant rats (F₀, F_1b) were subjected to caesarean section on gestational day 20 for teratogenic examination and the other half produced pups F_1a and F_2a, respectively. At the 250 mg/kg b.w./day cyadox group, body weights of F_1b pregnant rats and F_2a on day 21 after birth decreased; fetal body lengths and tail lengths decreased; the number of fetal resorptions increased significantly; litter weights, number of viable fetuses decreased; number of embryo resorptions increased significantly; number of liveborn F_1a, F_1b and F_2a decreased. No macroscopic or microscopic change of any significance was found in the reproductive organs. Significant increases in the incidence of cervial ribs or lumbar ribs in F_2a pups and significant increases of relative organ weight of testis and epididymis in F_1b were observed at the 250 mg/kg b.w./day cyadox group. The NOAEL for reproduction/development of cyadox for rats was estimated to be 150 mg/kg diet, which was equivalent to approximately 15 mg/kg b.w./day.     

Subacute toxicity studies with sodium saccharin and two hydrolytic derivatives

The subacute toxicity of sodium saccharin and 2 hydrolytic derivatives, o-sulfamoylbenzoic acid (Compound I) and ammonium o-carboxybenzene sulfonate (Compound II) was evaluated by feeding each of the compounds alone at a dietary level of 20 000 ppm to both beagle dogs and albino rats. Additionally, groups of dogs and rats were fed combinations of the 3 materials at levels up to 20 000 ppm (2000 ppm sodium saccharin, 9000 ppm of both compound I and II). Dogs were maintained on the test diets for 16 weeks, rats for 13 weeks.No signs of a pharmacotoxic response to the test materials were observed. Parameters determined for treated animals, including growth, food consumption, hematologic profiles, clinical blood chemistry studies, urinalyses, organ weight and ratio data, and both gross and microscopic pathologic evaluation, were not significantly different from control values. From these findings, it is suggested that there is little toxicologic hazard associated with ingestion of the 2 hydrolytic derivatives of sodium saccharin.     

Two generation reproduction and teratogenicity studies of feeding quinocetone fed to Wistar rats

To investigate the reproductive toxicity and teratogenic potential of quinocetone, a growth promoting agent, Wistar rats were fed different diets containing 0, 50, 300 and 1800 mg/kg quinocetone or 300 mg/kg olaquindox. Groups of 15 males and 30 females (F₀) were fed through a 10-week prebreed period as well as during mating, gestation, parturition and lactation. At weaning, 12 males and 24 females of F₁ generation weanlings per group were selected randomly as parents for F₂ generation. Selected F₁ weanlings were exposed to the same diet and treatment as their parents. At the highest quinocetone group, body weights in F₀ and F₁ rats, fetal body weight on day 21 after birth and number of viable fetuses in F₀ and F₁ generation significantly decreased. In teratogenicity study, groups of 12 males and 24 females were fed with the same diets through a 12-week prebreed period and matting periods. Pregnant rats were subjected to cesarean section on GD 20 for teratogenic examination. At the highest quinocetone group, body weights and feed efficiency, fetal body lengths, tail lengths, litter weights and number of viable fetuses significantly decreased. The NOAEL for reproduction/development of quinocetone for rats was estimated to be 300 mg/kg diet.     

The Effect of Combined Treatment with Niacin and Chromium (III) Chloride on the Different Tissues of Hyperlipemic Rats

We investigated the effects of a combined treatment with chromium (Cr) and niacin on the spleen, tongue, and lens tissues in terms of lipid peroxidation (LPO), glutathione (GSH), serum catalase (CAT), lactate dehydrogenase (LDH), serum cholesterol, and total lipid levels in normal and hyperlipemic rats. In this study, female 1-year-old Swiss albino rats were used. The rats were randomly divided into four groups. Group I rats (control) were fed with standard pellet chow. Group II rats were fed a lipogenic diet in which 2% cholesterol, 0.5% cholic acid, and 20% sunflower oil were added and were given 3% alcoholic water for 60 days. Group III rats were fed with the same lipogenic diet and were treated with a dose of 250 μg/kg body weight CrCI₃·6H₂O and 100 mg/kg body weight niacin, for 45 days, by gavage. The rats in group IV were fed with pellet chow and treated with 250 μg/kg body weight CrCI₃·6H₂O and 100 mg/kg body weight niacin, by gavage, for 45 days. After 2 weeks, the animals showed symptoms of hyperlipemia. On the 60th day, tissue and blood samples were taken. We have observed decreased CAT activity and GSH levels, increased LDH activity, cholesterol, total lipid, and LPO levels in hyperlipemic rats. Niacin and Cr administration to hyperlipemic rats increased tissue GSH levels and CAT activity and decreased tissue LPO levels and LDH activity, cholesterol, and total lipid levels compared with hyperlipemic rats. We conclude that the administration of a combination of niacin and chromium has a protective effect against oxidative damage to tongue, lens, and spleen tissues as a result of hyperlipemia.     

Three-generation reproduction study of rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet

A three-generation reproduction study was conducted to evaluate the effects of chronic, low-level ingestion of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Sprague-Dawley rats were maintained continuously on diets providing dose levels of 0, 0.001, 0.01, or 0.1 μg TCDD/kg/day. No significant toxicity was noted in the f₀ rats of either sex during the 90 days of TCDD ingestion prior to mating. Significant decreases in fertility and neonatal survival were observed in the f₀ generation rats receiving 0.1 μg TCDD/kg/day; these effects precluded continuation of this high dose level in subsequent generations. At 0.01 μg TCDD/kg/day, fertility was significantly decreased in the f₁ and f₂ but not f₀ generations. Other indications of toxicity seen at 0.01 μg TCDD/kg/day included decreases in litter size at birth, gestation survival (proportion of pups born alive), and neonatal survival and growth. Among the rats receiving 0.001 μg TCDD/kg/day, no effect on fertility, litter size at birth, or postnatal body weight was observed in any generation. No consistent effect on neonatal survival was observed at 0.001 μg TCDD/kg/day. In summary, the reproductive capacity of rats ingesting TCDD was clearly affected at dose levels of 0.01 and 0.1 μg TCDD/kg/day, but not at 0.001 μg TCDD/kg/day, through three successive generations.     

Subchronic and Reproduction Studies with Dibutyl Phenyl Phosphate in Sprague-Dawley Rats

Dibutyl phenyl phosphate (DBPP) was administered to male andfemale. Sprague-Dawley rats in their diets in separate subchronic(91-day) and two-generation reproduction studies. Dose levelsof DBPP were 5, 50, and 250 mg/kg/day in both studies. In thereproduction study, cross-fostering was performed between somehigh-exposure and control litter offspring and dams followinga second mating of F₀ animals. Compared to control animals,body weights were consistently lower in high-exposure adultanimals in both studies; this observation was less consistentin mid-exposure adult rats. High-exposure rats in the subchronicstudy had decreased erythrocyte counts and hematocrit and hemoglobinlevels. They also had increased absolute and/or relative liverweights with concomitant decreased hepatocytic vacuolation andincreased fatty accumulation. In the reproduction study, matingand fertility indices were comparable among the parental animalsin both generations, but survivability among high-exposure pupsreared by control dams appeared to be decreased. Urinary bladderhistopathologic changes, consisting of mononuclear cell infiltrationand transitional epithelial hyperplasia, were noted in mid-and high-exposure rats from both studies. The no observableadverse effect level in both of these studies was 5 mg/kg/ day.     

Dose--response study of hemorrhagic death by dietary butylated hydroxytoluene (BHT) in male rats

Male Sprague-Dawley rats were fed a 24% casein diet containing 0.58, 0.69, 0.83, 1.00, 1.20, or 1.44% butylated hydroxytoluene (BHT) ad libitum for 40 days. The rate of death was dose dependent and death occurred when BHT was given in amounts over 526 mg/kg/day. The LD50_{(40 days)} was 760 (669–864) mg/kg/day. In dead animals, a massive hemorrhage was found in the pleural and peritoneal cavities, and external hemorrhage was also observed in some animals. Furthermore, hemorrhage was observed in some organs such as epididymis, testis, and pancreas of the survivors in all groups given BHT, but it was not observed in the control group. The prothrombin index was decreased with all survivors given BHT. The extent of decrease was dependent on the daily dose of BHT. These observations suggest that BHT and/or its metabolite cause hemorrhage in rats.     

Influence of dietary pectin on intestinal microfloral metabolism and toxicity of nitrobenzene

Intestinal microfloral metabolism of nitrobenzene is essential for the production of methemoglobin. Since dietary pectin alters intestinal microflora, these studies were designed to examine the effects of dietary pectin on nitrobenzene-induced methemoglobinemia. Male Fischer-344 rats were fed either AIN-76A (purified diet containing 5% cellulose), AIN-76A with 5% pectin replacing the cellulose, or NIH-07 (cereal-based diet containing 8.4% pectin) for 28 days. Following this period, nitrobenzene (200 mg/kg) was administered by gastric intubation, and methemoglobin concentrations were determined after 1, 2, 4, 8, and 24 hr. Nitrobenzene-induced methemoglobinemia was evident as early as 1 hr, peaked at 4 hr, and diminished thereafter in rats fed NIH-07 diet. In contrast, nitrobenzene-induced methemoglobinemia was not detectable in rats fed AIN-76A; however, inclusion of 5% pectin in this diet resulted in methemoglobinemia comparable to that of NIH-07-fed animals at 4, 8, and 24 hr. Administration of 400 or 600 mg/kg nitrobenzene resulted in significant diet-related differences in methemoglobinemia. Administration of 600 mg/kg nitrobenzene to animals fed NIH-07 resulted in the highest methemoglobin concentrations (64 ± 1%); those fed AIN-76A had the lowest (20 ± 5%), and those fed AIN-76A containing pectin had intermediate methemoglobin concentrations (44 ± 6%). No diet-related differences in the microbial population of the stomach or small intestine were observed. However, the number of anaerobes present in the ceca of rats fed AIN-76A containing pectin was 2 to 2.5 times greater than that of rats fed AIN-76A. In vitro reductive metabolism of [¹⁴C]nitrobenzene was significantly greater in the cecal contents of rats fed NIH-07 than that in the cecal contents of either of the groups fed the AIN-76A-based diets. These studies indicate that intestinal microfloral metabolism and red blood cell toxicity of nitrobenzene is markedly different in animals fed cereal-based versus purified diets. Furthermore, since inclusion of pectin into the purified diet diminishes the magnitude of these effects, differences in dietary composition of fermentable carbohydrates in cereal-based and purified diets may mediate differences in metabolism and toxicity of nitrobenzene.     

A two-generation reproductive toxicity study of the high-intensity sweetener advantame in CD rats

Rats received diets containing 0, 2000, 10,000, or 50,000 ppm advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-l-phenylalanine 1-methyl ester, monohydrate) for 2 generations. F₀ animals (30/sex/group) were treated from 10 weeks before pairing. Males continued until week 16; females through gestation and lactation. Once weaned, F₁ animals (25/sex/group) continued receiving the same diet until F₂ pups were weaned. Mean advantame intakes from each of the diets were 164, 833, and 4410 mg/kg bw/day among F₀ males, and 204, 1036, and 5431 mg/kg bw/day among F₁ males. F₀ and F₁ females had comparable intakes up to lactation, when intakes increased (up to 8447 mg/kg bw/day from 50,000 ppm diet). No treatment-related effects on mortality, body weights, reproduction, litter observations, or postnatal offspring development were noted. Atypical coloration of the feces and cage liners seen with test diets was attributed to excretion of test material/metabolites in the feces and urine. Slightly higher food consumption was seen in F₀ and F₁ animals, especially males, receiving 50,000 ppm. However, these differences were considered to be a secondary response to the high levels of non-nutritive material in the diet. The no-observed-adverse-effect level for reproductive and developmental toxicity was considered to be 50,000 ppm, the highest dietary concentration tested.     

Teratogenesis study of o-toluenediamine in rats and rabbits

o-Toluenediamine in corn oil was administered po to Sprague-Dawley rats at dosages of 10, 30, 100, or 300 mg/kg body wt/day during Days 6 through 15 of gestation. All animals were killed on Day 20 of gestation. A similar study was conducted with Dutch-Belted rabbits dosed po daily at 3, 10, 30, or 100 mg of o-toluenediamine/kg body wt/day from Days 6 through 18 of gestation. Rabbits were killed on Day 29 of gestation. Maternal toxicity was indicated at 300 mg/kg in rats and 100 mg/kg in rabbits by reduced body weight gain during gestation. Fetal body weight was reduced at the highest dosage in both rats and rabbits. In addition, at the high dosage, an increase in the number of resorption sites in rabbits were noted. Skeletal examination of rats showed increased incidence of missing sternebrae at 300 mg/kg and incompletely ossified vertebrae at 100 and 300 mg/kg in comparison to control fetuses. The effects on the fetus could be the result of maternal toxicity. There was no evidence of teratogenic effects or effects on the dams at dosages through 30 mg/kg body wt.     

Effects of Great Lakes Fish Consumption on the Immune System of Sprague–Dawley Rats Investigated during a Two-Generation Reproductive Study: II. Quantitative and Functional Aspects

The effects of Great Lakes fish contaminants on several quantitative and functional aspects of the immune system were investigated in the first (F₁) and second (F₂) generations of Sprague–Dawley rats. The F₀rats were fed either a control diet or diets containing 5 or 20% lyophilized chinook salmon from the Credit River of Lake Ontario (LO) and Owen Sound point of Lake Huron (LH). The F₁and F₂pups were exposed to fishin utero, through the dam's milk to 21 days old, and through the dam's respective diets to 13 weeks of age. The study included an F₁-reversibility (F₁-R) phase in which rats at 13 weeks of exposure to fish or control diets were switched to the control diet for 3 months. The most outstanding finding was a statistically significant increase in absolute spleen leukocytes and absolute and percentage lymphocytes in the F₂male rats fed the LH fish diets compared to the control and to those fed the LO fish diets with the 20% fish diets having higher cell numbers compared to the LO-5% fish diets. A parallel increase in the T-helper/inducer T-lymphocyte subset numbers was observed. Increased but statistically insignificant plaque-forming cell (PFC) numbers were obtained in the F₂male rats fed the LH fish diets compared to those fed the LO fish diets and in the F₁-R female group of rats fed the LH fish diet compared to those fed the LO fish diets. Phagocytosis by resident peritoneal macrophages was significantly increased in the F₁male and F₂female rats fed the fish diets compared to the control. The phagocytic activity was significantly higher in the F₂-generation male and female rats fed the LO diets compared to those fed the LH diets. Other parameters including lymphocyte transformation in response to mitogens, the number ofListeria monocytogenesbacteria surviving in the rat spleens, and the natural killer cell activity were not affected significantly by any of the treatments. Overall, the effects of diets containing chinook salmon from the LO and LH sources on the immune system of rats were minimal and were on quantitative rather than on functional aspects of the system. Further focused research would be required in order to establish conclusively that the immune system of cohorts who ingest Great Lakes fish frequently is at a greater risk for adverse effects.     

The oral and dermal toxicity of hexachlorophene in rats

The single oral LD50 of hexachlorophene in adult male Sherman strain rats was 66 mg/kg, in females 56 mg/kg; in famale weanling rats the single oral LD50 was 120 mg/kg. The acute dermal toxicity was low. The iv LD50 in adult male rats was 7.5 mg/kg. Rats fed 500 ppm of hexachlorophene for 98 days developed leg weakness in 12–19 days. At sacrifice, after 98 days' exposure, status spongiosus was present throughout the white matter of the brain. Rats fed 100 ppm of hexachlorophene for 98 days did not develop leg weakness, but in 50% of the brains focal areas of status spongiosus were observed in the white matter. Rats fed 20 and 100 ppm of hexachlorophene for 258 days did not develop leg weakness. The brains of rats fed 20 ppm were normal, while the brains of some rats fed 100 ppm showed focal vacuolization of the white matter. One hundred parts per million reduced the survival of pups in the F₁ generation. This was statistically significant in the F_1b generation. The F₂ generation litters tended to be smaller. Reproduction was normal in rats fed 20 ppm or given hexachlorophene by oral intubation at doses as high as 10 mg/kg/day during day 7 to day 15 of pregnancy. Dermal application of 12 mg/kg/day of hexachlorophene for 30 days produced no microscopic changes in the brain and produced only erythema and desquamation of the treated skin. Doses of 24 and 48 mg/kg/day produced ulceration of the treated skin and status spongiosus of the entire white matter of the brain in some rats.     

Long-term aversion to a saccharin solution induced by repeated amphetamine injections

In rats repeated 2 mg/kg injections of d-amphetamine given 30 min after imbibition of a 0.1% saccharin solution proved to be as effective in reducing saccharin intake as 2 mg/kg injections of d-amphetamine given 30 min before presentation of this saccharin solution. Treatment with alpha-methyl-para-tyrosine blocked the effect on saccharin intake of amphetamine given before, but not amphetamine given after presentation of the saccharin. After amphetamine injections were terminated, subsequent saccharin vs. water preference testing showed that the amphetamine injections given after but not the injections given before resulted in a long-term aversion to the saccharin solution. In a second experiment, the 2 mg/kg dose of amphetamine was shown to facilitate intracranial self-stimulation as well as to induce an aversion to saccharin.     

Nicotine-induced taste aversion: characterization and preexposure effects in rats

Rats were trained to drink their 24 hr water intake during a single daily 30 min period. After stabilization, rats were presented with 0.1% (w/v) of sodium saccharin for 30 min. Immediately after removal of the saccharin solution, the animals were injected with saline, mecamylamine hydrochloride or hexamethonium hydrobromide; thirty minutes later, saline or nicotine, 0.05, 0.16, or 0.50 mg/kg were administered. Twenty-four hr later, rats were allowed access to both water and saccharin. Nicotine caused a dose-related decrease in the proportion of fluid consumed as saccharin solution during the 30 min testing situation. Neither mecamylamine nor hexamethonium alone decreased saccharin preference; however, 3 mg/kg of mecamylamine blocked the decrease of saccharin preference induced by nicotine. Preexposure of drug-naive rats to 0.5 mg/kg of nicotine for 2 or 4 days abolished the nicotine-induced taste aversions to saccharin when tested one day, or one week, after conditioning.     

Results of a 90-day safety assessment study in mice fed a glucan produced by Agrobacterium sp. ZX09

Salecan is a novel water-soluble glucan produced by Agrobacterium sp. ZX09. It has potential application as a food additive with a unique chemical composition and excellent physicochemical properties. The objective of this study was to investigate the acute and subchronic toxicity of Salecan. The oral LD50 of Salecan in ICR mice was greater than 3000 mg/kg body weight. In the subchronic study, ICR mice (10/sex/group) were fed diets containing 0%, 1.0%, 2.5% and 5.0% of Salecan (weight/weight) for 13 weeks. Based on the results from the subchronic study, the overall health, body weight gain, food consumption and clinical pathology parameters were comparable between the groups feed Salecan and the control. No dose-related effects were observed in the treated animals. The only exception was the observation that blood glucose in female mice fed Salecan was lower than in the control group. In addition, the fecal matter from Salecan fed mice exhibited increased water content versus the control animals. The no observed adverse effect level (NOAEL) of 14478 mg/kg body weight/day was determined. The results from this study support the conclusion that Salecan is non-toxic at the levels tested and does not pose a risk to human health when used in food.