Significant Reduction In Food Consumption Research Articles

Exploring the mechanisms underlying the toxicity of boric acid against the land snail, Theba pisana.

The land snail, Theba pisana, is one of the most important threats facing agriculture around the globe. Boric acid (BOA) is currently used as a safe alternative molluscicide to control land snails in sustainable agriculture, but the mechanisms of toxicity have not yet been investigated. The present study characterizes the lethal and sub-lethal (0.5 and 1mg g-1 ) toxic effects of BOA-contaminated food for 14 days by examining physiological, biochemical and histopathological indicators in T. pisana to understand the mechanisms underlying its toxic action. BOA was found to be lethal against T. pisana with LC50 values of 24.7 and 8.05 mg g-1 after 3 and 7 days of exposure, respectively. BOA sublethal concentrations led to a significant reduction in food consumption and growth of snails after 14 days of exposure. BOA also caused a significant increase in testosterone levels, whereas an opposite effect was observed in estradiol levels. An increase in progesterone levels in snails in the 0.5mg g-1 BOA group and a decrease in the 1mg g-1 BOA group were observed after all exposure times. Moreover, the lipid peroxidation level and catalase activity were elevated, whereas acetylcholinesterase activity was inhibited in the treated snails. Alteration in glutathione-S-transferase activity was noticed after exposure to both sublethal concentrations. In addition, BOA induced histopathological alterations in the digestive gland of T. pisana. Our findings provide novel insights into how physiological, biochemical and histopathological alterations can be used to explore the mechanisms underlying BOA toxicity against snails. © 2022 Society of Chemical Industry.

Evaluation of Potential Sustainable Bedding Substrates Focusing on Preference, Behavior, and Stress Physiology in Rats—A Pilot Study

Simple SummaryThe use of animals in research is currently a very controversial and emotionally discussed topic; however, to date, animals still play a pivotal and fundamental role in the advancement of biomedical research. Housing conditions of laboratory animals are especially important, as they constitute an overarching factor independent of the respective experiments. In this pilot study, we investigated different types of bedding, i.e., substrates which are used to house laboratory rats. Bedding is a crucial environmental factor for rats as it has a significant influence on their well-being and the animals tend to have a lifelong exposition to a single type of substrate. Our objective for this pilot study was to evaluate corncob and spelt as ecological alternatives to the most commonly used aspen wood chip bedding. Although the rats’ behavior was not changed by different types of bedding substrates, we detected that the rats liked to consume spelt, which could potentially lead to confounding results, when the animals are tested for certain scientific hypotheses. Therefore, this is a crucial factor to consider when planning an experiment that fulfills high-quality scientific outcomes while simultaneously complying with important animal welfare considerations.Ensuring optimal housing conditions for laboratory animals is a crucial prerequisite for high-quality and ethically justifiable in vivo science. In addition to guaranteeing animal welfare and promoting scientific validity, environmental sustainability is also increasingly gaining attention in laboratory animal facilities. Consequently, comprehensive management of such aspects is one of the core tasks of any research vivarium. Hygienic monitoring and adhering to standardized experimental protocols have been highlighted in the past; nevertheless, various environmental aspects of housing animals still need to be evaluated in greater depth. In this pilot study, we aimed at assessing the suitability of spelt and corncob as economical and ecologically friendly bedding substrates as compared with commonly used aspen wood chips. Therefore, following a descriptive study design, we examined the preferences of male and female Wistar rats for corncob and spelt under specific conditions. In addition, we evaluated potential effects on behavior, metabolism, and stress physiology. The type of bedding did not seem to influence behavior in the observed parameters but did have time- and sex-dependent effects on blood glucose. Furthermore, housing animals on spelt led to a significant reduction in food consumption, probably compensated for by the intake of spelt, and although it did not influence glucose levels, it may have certainly impacted the nutrient supply. Our descriptive pilot study, therefore, highlights the importance of a thorough condition-associated evaluation of even seemingly marginal environmental factors, when balancing potential cost-benefit advances in sustainability and questions of standardization and reproducibility of experimental protocols.

Evaluation of Natural Product Compositions for Appetite Suppression

ABSTRACTA change in homeostasis between food intake and energy expenditure is the hallmark of obesity. Many plant-based weight-management products are available in dietary supplement markets with no direct efficacy comparison. In this in vivo acute feed intake study in rats, the appetite suppression efficacy of well-known natural ingredients in the weight-loss market were evaluated. We tested pure caffeine, potato skin extract, Cissus quadrangularis extract, Garcinia cambogia extract, Crocus sativus extract, raspberry ketone isolated from Rubus idaeus, one commercial product (Appetrex), and one novel composition (UP601). Rats treated with potato skin extract, Crocus sativus bulb extract, and Cissus quadrangularis extracts showed statistically significant reduction in food consumption only at the 2-hour timepoint with 44.9%, 34.1%, and 44.3% reductions, respectively, after food provision at an equivalent human dosage of 2 g, 10 g, and 10 g, respectively. Garcinia cambogia fruit extract and raspberry ketone from Rubus idaeus showed statistically significant reduction in food consumption only at the 1-hour timepoint with 33.7% and 79.4% reductions, respectively, after food provision at an equivalent human dosage of 8 g and 5 g, respectively. UP601 and Appetrex were compared at 230 mg/kg. While 88.5%, 73.8%, and 63.1% reductions in food intake were observed for the UP601 treatment group, 64.2%, 27.5%, and 34.7% reductions in food intake were observed for rats treated with Appetrex at 1 h, 2 h, and 4 h after food provision. The composition UP601 demonstrated superior activity in food intake compared to any of the dietary supplements marketed for appetite suppression tested in this study.

English

This study aimed at determining the changes in food consumption, water intake, plasma and urine concentrations of some organic constituents which are often used in the assessment of renal function following two weeks’ administration of two doses of copper sulphate to Wistar rats. Fifteen adult male Wistar rats were randomly divided into three groups of five rats each. Group I (control group) received distilled water; groups II and III were given 100 and 200 mg/kg/day p. o of copper sulphate for 14 days, respectively. Significant reductions in food consumption and water intake were observed in group II when compared with the control and group III rats, but their body weight increased insignificantly throughout the study. The plasma urea concentrations of the treated rats were not significantly different from the control rats. The plasma creatinine levels of the experimental rats rose slightly, but not significantly different from the control rats. The creatinine and urea concentrations in the urine fell significantly in group II when compared with the control group. This was accompanied by decrease in creatinine clearance. Photomicrographs of the kidneys of both the control and experimental rats revealed no alteration in the histology of their renal tissue. It is concluded that acute copper sulphate administration to rats induced anorexia and suppression of renal function, thereby indicating the potential toxicity of the salt if ingested for a longer period.     Key words: Copper sulphate, kidney, creatinine, urea, rats.

A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice

Diet-induced obesity is a lifestyle-associated medical condition that increases the risk of developing cardiovascular disease, type 2 diabetes and certain types of cancer. Here we report the design of a closed-loop genetic circuit that constantly monitors blood fatty acid levels in the setting of diet-associated hyperlipidemia and coordinates reversible and adjustable expression of the clinically licensed appetite-suppressing peptide hormone pramlintide. Grafting of the peroxisome proliferator-activated receptor-α onto the phloretin-responsive repressor TtgR produces a synthetic intracellular lipid-sensing receptor (LSR) that reversibly induces chimeric TtgR-specific promoters in a fatty acid-adjustable manner. Mice with diet-induced obesity in which microencapsulated cells engineered for LSR-driven expression of pramlintide are implanted show significant reduction in food consumption, blood lipid levels and body weight when put on a high-fat diet. Therapeutic designer circuits that monitor levels of pathologic metabolites and link these with the tailored expression of protein pharmaceuticals may provide new opportunities for the treatment of metabolic disorders.

Maintaining good hearing: Calorie restriction, Sirt3, and glutathione

Reducing calorie intake extends the lifespan of a variety of experimental models and delays progression of age-related hearing loss (AHL). AHL is a common feature of aging and is characterized by age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. Sirtuins are a family of NAD+-dependent enzymes that regulate lifespan in lower organisms and have emerged as broad regulators of cellular fate. Our recent study indicated that mitochondrial Sirt3, a member of the sirtuin family, mediates the anti-aging effects of calorie restriction (CR) on AHL in mice. Interestingly, we also found that weight loss alone may not be sufficient for maintaining normal hearing. How does CR slow the progression of AHL through regulation of Sirt3? Here we review the evidence that during CR, Sirt3 slows the progression of AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system in mice. A significant reduction in food consumption in one's daily life may not be a desirable and realistic option for most people. Therefore, identification/discovery of compounds that induce the activation of SIRT3 or glutathione reductase, or that increase mitochondrial glutathione levels has potential for maintaining good hearing through mimicking the anti-aging effects of CR in human inner ear cells.

Effects of the soluble fiber complex PolyGlycopleX® (PGX®) on glycemic control, insulin secretion, and GLP-1 levels in Zucker diabetic rats

Aims The effects of the novel water soluble, viscous fiber complex PolyGlycopleX® [(α- d-glucurono-α- d-manno-β- d-manno-β- d-gluco), (α- l-gulurono-β- d mannurono), β- d-gluco-β- d-mannan (PGX®)] on body weight, food consumption, glucose, insulin, and glucagon-like peptide (GLP-1) levels were determined in Zucker diabetic rats (ZDFs). Such fibers are thought to improve glycemic control through increased GLP-1 induced insulin secretion. Main methods ZDFs were treated 12 weeks with normal rodent chow supplemented with cellulose (control, inert fiber), inulin or PGX® at 5% wt/wt and effects on body weight, glycemic control, and GLP-1 determined. Key findings In the fed state, PGX® reduced blood glucose compared to the other groups from week 5 until study termination while insulin was significantly elevated when measured at week 9, suggesting an insulin secretagogue effect. Fasting blood glucose was similar among groups until 7–8 weeks when levels began to climb with a modest reduction caused by PGX®. An oral glucose tolerance test in fasted animals (week 11) showed no change in insulin sensitivity scores among diets, suggesting an insulinotropic effect for PGX® rather than increased insulin sensitivity. PGX® increased plasma levels of GLP-1, while HbA 1c was markedly reduced by PGX®. Body weights were not changed despite a significant reduction in food consumption induced by PGX® up to week 8 when the PGX®-treated group showed an increase in body weight despite a continued reduction in food consumption. Significance PGX® improved glycemic control and reduced protein glycation, most likely due to the insulin secretagogue effects of increased GLP-1.

Bioaccumulation and toxic effects of cadmium on feeding and growth of an Indian pond snail Lymnaea luteola L. under laboratory conditions

Effects of dissolved cadmium exposure on the survival, feeding, growth rates and accumulation in Indian pond snails Lymnaea luteola L. were examined for a period of 7 weeks. The concentrations of cadmium tested were 0, 10, 32, 100, 320, 560, and 1000 μg l −1. Cadmium exposure significantly inhibited the feeding and growth rates. At higher Cd concentrations snails refused to consume food offered as plant Marsilia sp. leaves. Cadmium mainly accumulated in soft tissues in a dose-dependent manner. After 4 and 7 weeks of exposure, the no observed effect concentration (NOEC) of Cd was 10 μg l −1 and the lowest observed effect concentration (LOEC) was 32 μg l −1. Reduction of growth (decrease in wet weight) was noticed followed by a high mortality in higher Cd concentrations. Significant reduction in food consumption and growth rates was found at 32 μg l −1 and above Cd concentration. A significant relationship between Cd exposure and growth and feeding rates was noticed. The results obtained with these key aquatic organisms in the food chains complement those obtained with other aquatic organisms and gastropod snails. The findings of the present study and those of earlier studies suggested that Indian pond snail L. luteola are useful test organisms for ecotoxicology bioassays.

Effects of an ascovirus (HvAV-3e) on diamondback moth, Plutella xylostella, and evidence for virus transmission by a larval parasitoid

Ascoviruses (AVs) are pathogenic to lepidopteran larvae, and most commonly attack species in the Noctuidae. The unique pathology includes cleavage of host cells into virion-containing vesicles which leads to the milky white colouration of the hemolymph as opposed to the clear hemolymph of healthy larvae. Recently, we showed that a Heliothis virescens AV (HvAV-3e) isolate is able to induce disease in Crocidolomia pavonana F. (Lepidoptera: Crambidae), affecting feeding, growth and survival of infected larvae. In this study, we investigated the effect of different variants of HvAV-3e on diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae) larvae, another non-noctuid host. In hemolymph inoculation bioassays fourth instar larvae showed a significant dose response to each of the HvAV-3e variants and significant differences between the virulence of the three variants were detected. Both second and fourth instars were readily infected with the virus and infected individuals demonstrated significant reductions in food consumption and growth. The majority of infected individuals died at the larval or pupal stage and individuals which developed into adults were usually deformed, less fecund than non-infected controls and died shortly after emergence. In transmission studies, Diadegmasemiclausum (Hymenoptera: Ichneumonidae), a key parasitoid of diamondback moth, infected healthy host larvae during oviposition following previous attack of HvAV-3e infected hosts. In choice tests D. semiclausum did not discriminate between infected individuals but host infection had no detectable impact on the development of immature D. semiclausum or on subsequent adults.

CHANGES IN THE VISCERAL FUNCTIONS OF PLASMODIUM BERGHEI‐INFECTED AND ‐UNINFECTED RATS FOLLOWING ADMINISTRATION OF ARTEMETHER

1. The effects of artemether (12.5, 25.0 and 50.0 mg/kg per day, i.m.), administered to different groups of Plasmodium berghei-infected and -uninfected adult Wistar rats for 1 week, were investigated. 2. The parameters evaluated were the feeding, drinking and urinating patterns of the rats and these were compared with those of rats that received normal saline. 3. Artemether caused a significant dose-dependent reduction in food consumption of both P. berghei-infected and -uninfected rats (P < 0.05). Food intake in infected rats was reduced by approximately 7 g/24 h. This reduction in food intake was further reduced during drug treatment with artemether. Artermether also reduced food intake in uninfected rats. The food consumption of rats that received 12.5 and 25.0 mg/kg artemether was restored after stopping treatment, in contrast with rats that received 50.0 mg/kg, in which the significant reduction in food consumption persisted 1 week after drug administration. 4. During treatment with artemether, the water intake of infected rats was significantly lower than that of uninfected rats in the 12.5 mg/kg artemether-treated group, but was significantly higher in infected rats than in uninfected rats dosed with 25.0 and 50.0 mg/kg artemether. 5. For all doses of artemether tested, a significant increase in urine output was observed in infected rats during treatment and 1 week after treatment, whereas in uninfected rats a significant increase in urine output was observed only following 25.0 and 50.0 mg/kg artemether 1 week after drug administration. 6. The present study confirms the anorexic activity of a high dose of artemether in both P. berghei-infected and -uninfected rats. It also indicates that high doses of the drug could cause impaired renal function in rats and that the significant increase in urine output could also be due to other effects of artemether, namely those on thirst, anti-diuretic hormone output and the osmotic pressure of the blood.

Effects of dibromoacetonitrile on rats following 13-week drinking water exposure

The subchronic toxicity of dibromoacetonitrile (DBAN), a disinfection by-product in drinking water, was studied in the rat. Male (180±18 g) and female (152±9 g) Sprague–Dawley rats (10 animals per group) were fed DBAN in organic-free distilled water at concentrations of 0.1, 1, 10 and 100 ppm for 13 weeks. Control rats received organic-free distilled water only. Water intakes in the highest dose males and females were reduced by 25 and 32% as compared to the controls, respectively ( P<0.05), with no significant reductions in food consumption and body weight gain. The organ to body weight ratio was significantly increased in the highest-dose males and females for kidneys but not for the brain, liver, spleen, thymus and testicles. In the males, decreases were detected in serum uric acid levels at 1 and 100 ppm, and in urinary uric acid at 10 and 100 ppm. Decreased serum protein was detected in the highest-dose males and decreased serum LDH was found in the highest-dose females. Both the white blood cell and lymphocyte counts were significantly elevated in the highest-dose females. A significant increase in hepatic catalase activity was observed only in males starting at 1 ppm, and increased palmitoyl-CoA oxidase (PCO) activity was found in males and females of the highest dose group. In the males, decreased thiobarbituric acid reactive substance (TBARS) level was detected in the liver at 1.0 and 100 ppm groups, while increased TBARS was found in the serum at 100 ppm DBAN. No treatment-related changes were detected in the activities of hepatic benzyloxyresorufin O-dealkylase (BROD), pentoxyresorufin O-dealkylase (PROD) and ethoxresorufin O-deethylase (EROD), and in hepatic UDP-glucuronosyltransferase (UDPGT) and glutathione S-transferases (GST). Although DBAN is a potent inhibitor of hepatic aldehyde dehydrogenase (ALDH) and GST in vitro, there was no evidence of suppression of these enzymes in the treated animals. Mild histological changes were detected in animals receiving the highest dose, consisting of collapsed angularity, increased epithelial height in the thyroid of both sexes, and cytoplasmic vacuolation and nuclear vesiculation in the thyroid of females, increased myeloid to erythroid ratio in the bone marrow of both sexes, and cytoplasmic inclusions in the proximal tubules of male kidneys. In summary, treatment effects occurred predominantly at 100 ppm and included in both sexes: increased kidney weights, histological changes in the thyroid and bone marrow, and increased peroxisomal enzyme activities; and in males: decreased serum and urinary uric acid levels, and indication of oxidative stress. The no-observed-adverse-effect level (NOAEL) was therefore judged to be 10 ppm, equivalent to 1.11 and 1.21 mg/kg/day in the males and females, respectively.

Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses

Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxicities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following single administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h after dosing and assayed by HPLC-ECD. Two other groups of rats were administered either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remaining in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reductions in food consumption and body weight after day 2. TK data on days 2-7 revealed marked changes compared to the PK parameters estimated on day 1. AUC (4367 ng x h/ml) on day 7 was 5-fold higher than AUC (905 ng x h/ml) on day 1. The volume of distribution at steady state (V(SS)) on day 7 (41.8 l) was 40% of the day 1 value of the V(SS) (104.3 l). Clearance (CL) was increased by 89% of the day 1 value, from 0.98 l/h to 1.85 l/h on day 7. The elimination t(1/2) of ARTE was also prolonged from 13.7 h (day 1) to 31.2 h (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats as a result of the systemic toxicity. Analysis of the injection sites showed that 38% and 91% of the total amount of ARTE single dose remained in the muscles at 24 h (after first injection) and 168 h (at 24 h after 7 daily multiple doses), respectively. Fast and slow absorption phases from muscle were seen with t(1/2) of 0.97 h and 26.3 h, respectively. The apparent elimination t(1/2) of ARTE after i.m. injection (13.7 h) was much longer than that after i.v. dosing (0.67 h) due to the prolonged muscle absorption phase. Acute toxicity data of artemisinin drugs demonstrated that animals receiving a high single ARTE dose in sesame oil died between days 5-11, similar to artemether. When animals received dihydroartemisinin formulated in 50% DMAC/oil, or artesunic acid and artelinic acid in 0.9% saline vehicle, they died between days 1 and 2. This suggests that delayed onset toxicity and death in the ARTE rats may also be due to slow absorption and prolonged drug exposure. Therefore multiple i.m. administrations cause anorexia and drug accumulation, possibly affecting the toxicokinetics and efficacy of the drug.

Effect of chronic central administration of glucagon-like peptide-1 (7-36) amide on food consumption and body weight in normal and obese rats.

Glucagon-like peptide (7-36) amide (GLP-1) acutely inhibits food and water consumption in rats after intracerebroventricular (icv) administration. To assess the potential for desensitization of these effects, we investigated the effects of chronic icv administration of GLP-1 on food consumption and body weight in Sprague-Dawley (SD) rats and Zucker (fa/fa) obese rats. In vitro functional densensitization of the GLP-1 receptor was not observed after overnight exposure of Rin m5F insulinoma cells to GLP-1 at concentrations up to 10 nM. Administration of GLP-1 to SD rats (30 microg icv twice a day for 6 days) resulted in significant reductions in 24-hour food consumption each day (25 +/- 1%). Continuous icv infusion of GLP-1 for 7 and 14 days significantly inhibited cumulative food consumption and reduced body weight in SD rats. In the genetically obese Zucker rat, chronic dosing with GLP-1 (30 microg icv) once a day for 6 days caused significant reductions in food consumption each day and a reduction in body weight. These results indicate that the GLP-1 pathways in the central nervous system controlling food consumption do not desensitize after chronic exposure to GLP-1 and suggest that agonists of the central GLP-1 receptor may be effective agents for the treatment of obesity.

Purification of milligram quantities of human leptin from recombinant E. coli.

Leptin, the product of the obese (ob) gene, is a 16 kilodalton protein secreted from adipose tissue. Restoration of leptin to obese ob/ob mice leads to normalization of body weight. The effect of leptin in larger animals has not been explored, in part because of limited supplies of leptin. To date, the potency and yield of recombinant leptin purified from a variety of eukaryotic sources or from E. coli has been highly variable. While purification of leptin from E. coli inclusion bodies has afforded the greatest yield of protein, its potency is at least an order of magnitude lower than that of leptin secreted from E. coli or eukaryotic cells. The mechanistic basis of this difference in potency is not clear at present. The ability to purify significant quantities of highly active leptin will be crucial for the evaluation of leptin structure, as well as its function in additional animal models of obesity. We now report a facile protocol for the preparation of recombinant leptin using an E. coli expression system. 75-85 milligrams of leptin with a purity of greater than 97 % was prepared from a liter of recombinant E. coil. The procedure can be performed in less than 48 h and requires no chromatography. Intraperitoneal injection of 0.1 mg/kg renatured leptin into ob/ob mice results in a significant reduction in food consumption. The potency of this material is similar to the most potent recombinant leptin described to date. The ability to rapidly prepare large quantities of high specific activity material will hasten the definition of leptin's role in non-rodent models of obesity.

Hypophagia is induced by intracerebroventricular administration of nerve growth factor

In previous experiments examining the stimulatory effect of intracerebroventricular (icv) NGF treatment on basal forebrain choline acetyltransferase (ChAT) activity, many of the rats treated with the maximally effective dose of NGF appeared gaunt compared to the vehicle-treated control animals. The present experiments determined that icv infusion of NGF at a dose of 1.2 μg/day causes a significant reduction in food consumption during the entire period of treatment compared to untreated and vehicle-treated animals. Male rats infused with NGF lost an average of about 30 g of body wt during the first week after the start of infusion and did not gain appreciable weight during the second week of NGF treatment. The hypophagic effect of NGF is dose-dependent, centrally mediated, and reversible. There is no correlation between the stimulatory effect of NGF on basal forebrain ChAT and the inhibitory effect of NGF on weight gain. A therapeutic dose of NGF for Alzheimer's patients comparable to the rat dose for maximally stimulating central cholinergic neurons would approach 1 mg/day. If such therapy is applied, the potential exits for induction of hypophagia as a side effect of the NGF administration.

Subchronic toxicity studies in dogs and in utero rats fed diets containing Bacillus stearothermophilus α-amylase from a natural or recombinant DNA host

Beagle dogs and Fischer 344 rats were fed diets containing 0, 36 or 72 units Bacillus stearothermophilus α-amylase (Bsa)/g food or of Bacillus subtilis α-amylase (cBsa)/g food. The dogs (four/sex/group) received treated diets for 13 wk. For the rat studies, the parental (F 0) generation (12 males and 24 females/group for the Bsa study, and 26 rats/sex/group for the cBsa study) received treated diets for 13 or 4 wk, respectively, before breeding and through weaning of the F 1 pups; 20 F 1 rats/sex/group received treated diets for at least 13 wk (from weaning until necropsy). There were no treatment-related antemortem observations, reproductive effects or ophtalmic, haematological, macroscopic or microscopic findings in treated dogs or rats, and no differences were noted in body weights for dogs or parental rats. Mean body weights of F 1 pups from F 0 rats exposed to 72 units cBsa/g were significantly lower than those of the control animals on lactation day 28. This effect may have been related to the slight reduction in body weights and significant reduction in food consumption (gestation days 14–20) of the F 0 dams. However, this did not continue into the growth phase for the F 1 generation. In the Bsa studies, there were no treatment-related effects in clinical pathology values, and organ-weight data did not correlate with macroscopic or microscopic findings. Male dogs given cBsa had significantly lower albumin (36 units/g), calcium (36 and 72 units/g) and inorganic phosphorus (72 units/g) values compared with those of the control males; there were no treatment-related changes in blood chemistry values in rats. Based on the results of these studies, the no-observable-effect level for α-amylase fed to dogs or rats is 36 units/g food.

A 6-month dietary toxicity study of acidic sodium aluminium phosphate in beagle dogs

Sodium aluminium phosphate [NaAl 3H 14(PO 4) 8.4H 2O], a leavening acid, was administered to groups of six male and six female beagle dogs at dietary concentrations of 0, 0.3, 1.0 or 3.0% for 6 months. No adverse treatment-related clinical signs were observed. There were no statistically significant differences in mean body weights between test and control groups at any of the weekly determinations. Weekly mean food consumption values of all male treated groups did not differ significantly from those of the control group at any stage of the study. Statistically significant reductions in food consumption occurred sporadically in all treated groups of female dogs. No significant absolute or relative organ-weight differences were found between any of the treated groups and their respective controls. Haematological, blood chemistry and urinalysis data showed no toxicologically significant trends. Histopathological examination revealed no changes considered to be related to treatment. Thus dietary administration of sodium aluminium phosphate for 6 months at concentrations of 3% or lower caused no significant toxicological effects in beagle dogs.

Toxicity of technical X-factor to weanling rats. II. A subacute oral study.

Eighty male weanling rats were fed dietary levels of Technical X-factor (beta-isomer free BHC, a by-product obtained during the separation of lindane from Tech. BHC) at dosages of 10,50,250,750,1500 and 3000 ppm for 90 days. No overt signs of toxicity or mortality were observed at any of the dietary levels. However, a significant reduction in food consumption and growth was evident beyond 750 ppm. Pronounced hepatomegaly observed at 1500 and 3000 ppm was associated with histological alterations such as cellular hypertrophy, cytoplasmic vacuolisation and focal necrosis. Adrenals showed cortical hypertrophy and highly vacuolated cytoplasm. Though a significant increase in the levels of SGOT was noted at 3000 ppm dosage, no appreciable changes were observed in the levels of SGPT and SLDH. Technical X-factor appeared to possess low chronic toxicity compared to Tech. BHC as evidenced by the various parameters studied. The observed low chronic toxicity of X-factor is probably due to the absence if beta-isomer and altered composition of delta and alpha isomers.

Methylphenidate in severely retarded residents and the clinical significance of stereotypic behavior.

An attempt was made to evaluate a model predicting stimulant drug response based on attentional characteristics of the participants. Twenty-eight severely and profoundly mentally retarded residents took part in a double blind, placebo controlled trial of methylphenidate (Ritalin). Methylphenidate was administered, for one week each, in a low dose of 0.3 mg/kg and a high dose of 0.6 mg/kg. The results failed to show any clinically relevant differences between placebo and active drug conditions with the exception that methylphenidate caused a significant reduction in food consumption. A variety of subject characteristics, including level of stereotypy, hyperactivity, and IQ were unrelated to drug effect. One positive finding, unrelated to drug effects, was that subdivision of the group by degree of stereotypy provided substantial clinical information about individual subjects.

The absence of teratogenic hazard potential of p-phenylenediamine in Sprague-Dawley rats

Para-phenylenediamine (PPD) was administered by gavage to pregnant Sprague-Dawley Rats at dose levels of 5, 10, 15, 20, and 30 mg/kg/day on days 6 through 15 of gestation (day 0=day sperm was found in the vagina). A sham control group and a pair fed control group were studied at the same time. Pregnant animals were killed on day 20 of gestation and 1/3 of the fetuses were examined for visceral malformations and 2/3 for skeletal malformations and variations. Significant reductions in food consumption and weight gain were noted in the 30 mg/kg and pair fed control groups. Two pregnant rats given PPD at 30 mg/kg/day died but there were no deaths in any other dose groups. Fetal evaluations showed no biologically or statistically significant increase in malformations or developmental variations in any group. Therefore, although maternal toxicity was demonstrated at the two highest dose levels, there was no evidence of teratogenic or other embryotoxic effects.