Safety assessment of a wheat bran extract containing arabinoxylan-oligosaccharides: mutagenicity, clastogenicity, and 90-day rat-feeding studies.

Wheat bran extract (WBE) is a food-grade preparation that is highly enriched in arabinoxylan-oligosaccharides. As part of the safety evaluation of WBE, its genotoxic potential was assessed in a bacterial reverse mutagenicity assay (Ames test) and a chromosome aberration assay on Chinese hamster lung fibroblast cells. These in vitro genotoxicity assays showed no evidence of mutagenic or clastogenic activity with WBE. The safety of WBE was furthermore evaluated in a subchronic toxicity study on rats that were fed a semisynthetic diet (AIN 93G) containing 0.3%, 1.5%, or 7.5% WBE for 13 weeks, corresponding to an average intake of 0.2, 0.9, and 4.4 g/kg body weight (bw) per day, with control groups receiving the unsupplemented AIN 93G, AIN 93G with 7.5% inulin, or AIN 93G with 7.5% wheat bran. Based on this rat-feeding study, the no-observed-adverse-effect level (NOAEL) for WBE was determined as 4.4 g/kg (bw)/d, the highest dose tested.

Safety assessment of ProBiora3, a probiotic mouthwash: subchronic toxicity study in rats.

Streptococcus viridans are commensal bacteria that constitute a significant portion of the resident oral microflora. The objective of the present study is to investigate adverse effects, if any, of a blend of 3 natural strains, Streptococcus uberis KJ2, Streptococcus oralis KJ3, and Streptococcus rattus JH145 (probiotic mouthwash, ProBiora(3)). The blend is administered to rats orally once daily (5 days per week) at doses of 0, 10(6), or 10(9) colony-forming units of each strain for 14 weeks. No treatment-related adverse effects are observed in the physiological parameters during the study or in the evaluation of blood and tissue samples taken from the animals at the end. Results of an in vitro antibiotic susceptibility study demonstrate that all 3 ProBiora(3) strains are susceptible to commonly used therapeutic antibiotics. The results of these investigations reveal that the no-observed-adverse-effect level of the probiotic mouthwash is 2.16 x 10(9) colony-forming units per strain per kilogram of body weight per day, the highest dose used.

Effects of Garcinia cambogia extract on serum sex hormones in overweight subjects.

(-) Hydroxycitric acid (HCA), an active ingredient extracted from the Garcinia cambogia fruit rind, has been commonly used as a dietary supplement for weight management. Given the controversy over HCA related testicular toxicity in animal studies, we investigated changes in serum sex hormones levels as an extension of our previous double-blind placebo-controlled trial in human subjects, in which 44 participants received either G. cambogia extract (1667.3 mg/day equivalent to 1000 mg HCA/day) or placebo for 12 weeks. Compared to the placebo group, administration of the extract did not significantly alter the serum testosterone, estrone, and estradiol levels. Similarly, hematology, serum triacylglycerol and serum clinical pathology parameters did not reveal any significant adverse effects. The results of this preliminary investigation indicate that ingestion of G. cambogia extract at dose levels commonly recommended for human use does not affect serum sex hormone levels and blood parameters.

Safety assessment of non-animal chondroitin sulfate sodium: Subchronic study in rats, genotoxicity tests and human bioavailability.

Chondroitin sulfate, an amino sugar polymer made of glucuronic acid and N-acetyl-galactosamine, is used in dietary supplements to promote joint health. Commonly used chondroitin sulfate is of animal origin and can pose potential safety problems including bovine spongiform encephalopathy (BSE). The objective of the present study was to investigate potential adverse effects, if any, of microbial derived chondroitin sulfate sodium (CSS) in subchronic toxicity, genotoxicity and bioavailability studies. In the toxicity study, Sprague Dawley rats (10/sex/group) were gavaged with CSS at dose levels of 0, 250, 500 and 1000 mg/kg body weight (bw)/day for 90-days. No mortality or significant changes in clinical signs, body weights, body weight gain or feed consumption were noted. Similarly, no toxicologically relevant treatment-related changes in hematological, clinical chemistry, urinalysis and organ weights were noted. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. In vitro mutagenic and clastogenic potentials as evaluated by Ames assay, chromosomal aberration test and micronucleus assay did not reveal genotoxicity of CSS. In pharmacokinetic study in human, CSS showed higher absorption as compared to chondroitin sulfate of animal origin. The results of subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for CSS as 1000 mg/kg bw/day, the highest dose tested.

Toxicologic evaluation of Dichrostachys glomerata extract: subchronic study in rats and genotoxicity tests.

In western Cameroon, edible fruits and seeds from the plant Dichrostachys glomerata are commonly used as spices. Extract from the fruit pods has been reported as a good natural source of antioxidants and may provide health benefits. The objective of the present study was to investigate potential adverse effects, if any, of D. glomerata fruit pod extract (Dyglomera™) in a subchronic toxicity study and in genotoxicity studies. In the toxicity study, Sprague Dawley rats (20/sex/group) were gavaged with D. glomerata extract at dose levels of 0, 100, 1000 and 2500 mg/kg body weight (bw)/day for 90-days. Dyglomera™ administration did not result in mortality or show treatmentrelated changes in clinical signs of toxicity, body weights, body weight gain or feed consumption. Similarly, no toxicologically significant treatment-related changes in hematological, clinical chemistry, urine analysis parameters, and organ weights were noted. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. Mutagenic and clastogenic potentials as evaluated by Ames assay, in vitro and in vivo chromosomal aberration test and in vivo micronucleus test did not reveal any genotoxicity of the extract. The results of subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for D. glomerata extract as 2500 mg/kg bw/day, the highest dose tested.

Safety evaluation of zeaxanthin concentrate (OmniXan™): acute, subchronic toxicity and mutagenicity studies.

The available evidence suggests a beneficial effect of zeaxanthin against the progression of age-related macular degeneration (AMD). The objective of the present study was to investigate potential adverse effects of OmniXan™, a RR-zeaxanthin (65%) enriched product obtained from paprika (Capsicum annum fruits) in subchronic toxicity and mutagenicity studies. The oral LD50 of OmniXan(TM) in rats was greater than 2000 mg/kgbody weight (bw)/day. For the subchronic toxicity study, Wistar rats (10/sex/group) were gavaged daily with zeaxanthin concentrate at doses of 0, 4, 40 and 400 mg/kg bw/day for 90-days. No treatment related clinical signs and mortalities observed. Similarly, no treatment related toxicologically significant changes in body weight, feed consumption; ophthalmoscopic examination, neurological examination, hematology, urine analysis and organ weights were observed. Statistically significant changes observed in some clinical chemistry parameters were considered toxicologically and biologically insignificant and nonadverse. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. The results of mutagenicity testing using Salmonella typhimurium did not reveal any genotoxicity. The no observed-adverse-effect level (NOAEL) for zeaxanthin concentrate (OmniXan(TM)) was determined as 400 mg/kg bw/day, the highest dose tested. The findings of this subchronic toxicity and mutagenicity studies support safety of zeaxanthin concentrate.

Safety assessment of Apoaequorin, a protein preparation: subchronic toxicity study in rats.

Apoaequorin, a calcium-binding protein originally isolated from jellyfish is available commercially as a dietary supplement. The objective of the present study was to investigate potential adverse effects, if any, of Apoaequorin, a recombinant protein preparation, in rats following subchronic administration. For this study, Sprague-Dawley (Hsd:SD) rats (10/sex/group) were administered via oral gavage 0 (control), 92.6, 462.9, and 926.0mg/kg body weight (bw)/day of Apoaequorin preparation, for 90 days. The corresponding amount of Apoaequorin protein was 0, 66.7, 333.3 and 666.7 mg/kg bw/day, respectively. Administration of the Apoaequorin preparation did not result in any mortality. There were no clinical or ophthalmological signs, body weight, body weight gain, food consumption, food efficiency, clinical pathology or histopathological changes attributable to administration of Apoaequorin. Any changes noted were incidental and in agreement with those historically observed in the age and strain of rats used in this study. Based on the results of this study, the No Observed-Adverse-Effect Level (NOAEL) for Apoaequorin was determined as 666.7 mg/kg bw/day, the highest dose tested.

Subchronic toxicity and mutagenicity/genotoxicity studies of Irvingia gabonensis extract (IGOB131).

African Bush Mango from Irvingia gabonensis is a West African culinary fruit and the mucilage from this fruit seed is used to make traditional soups and sauces. Extract from the kernel (IGOB131) has been claimed for its health benefits. In the present investigations, potential adverse effects, if any, of IGOB131 were investigated in dose-response 90-day study and genotoxicity studies. In the subchronic study, Sprague Dawley rats (20/sex/group) were gavaged with I. gabonensis extract (IGOB131) at dose levels of 0, 100, 1000 and 2500 mg/kg body weight (bw)/day for 90-days. No treatment-related changes in clinical signs, functional observations, mortality, ophthalmologic observations, body weights, body weight gain or feed consumption were noted. Similarly, hematological, clinical chemistry, urine analysis parameters, and organ weights did not reveal any toxicologically significant treatment-related changes. No treatment-related macroscopic and microscopic abnormalities were noted at the end of treatment period. The mutagenicity as evaluated by Ames assay, in vitro and in vivo chromosomal aberration test and in vivo micronucleus assay did not reveal any genotoxicity of IGOB131. The results of subchronic toxicity study suggest the no-observed-adverse-effect level (NOAEL) for I. gabonensis extract (IGOB131) as ≥ 2500 mg/kg bw/day, the highest dose tested.

Safety assessment of lutein and zeaxanthin (Lutemax 2020): subchronic toxicity and mutagenicity studies.

Lutein and zeaxanthin, naturally occurring carotenoids, have shown to reduce the risk of cataracts and age-related macular degeneration. Lutemax 2020 is a lutein and zeaxanthin (including meso-isomer) enriched product obtained from Marigold flowers (Tagetes erecta L). The objective of the present study was to investigate adverse effects, if any, of Lutemax 2020 in acute and subchronic toxicity, and mutagenicity studies. In acute toxicity study in rats no lethality was noted at 2000 mg Lutemax 2020/kg body weight (bw). In the subchronic study, Wistar rats (10/sex/group) were administered (gavage) lutein/zeaxanthin concentrate at dose levels of 0, 4, 40 and 400mg/kg bw/day for 90-days. Compared with the control group, administration of lutein/zeaxanthin concentrate did not result in any toxicologically significant treatment-related changes in clinical observations, ophthalmic examinations, body weights, body weight gains, feed consumption, and organ weights. No toxicologically relevant findings were noted in urinalysis, hematology or clinical biochemistry parameters at the end of the treatment or recovery period. Terminal necropsy did not reveal any treatment-related gross or histopathology findings. The results of mutagenicity testing in Salmonella typhimurium did not reveal any genotoxicity. The no observed-adverse-effect level (NOAEL) for lutein/zeaxanthin concentrate was determined as 400mg/kg bw/day, the highest dose tested.

Safety assessment of mushroom ß-glucan: subchronic toxicity in rodents and mutagenicity studies.

Mushroom ß-glucan, a polymer of ß-(1,3/1,6)-glucan, has been claimed for its health benefits. The objective of this study was to assess the safety in-use of mushroom ß-glucan as dietary supplement and food ingredient. Hence, a subchronic toxicity and mutagenicity studies were conducted. In the subchronic toxicity study, Sprague Dawley rats (12/sex/group) were administered (gavage) mushroom ß-glucan at dose levels of 0, 500, 1000 and 2000 mg/kg body weight (bw)/day for 90 days. As compared to control group, administration of ß-glucan did not result in any toxicologically significant treatment-related changes in clinical observations, ophthalmic examinations, body weights, body weight gains, feed consumption, and organ weights. No adverse effects of the ß-glucan on the hematology, serum chemistry parameters, urinalysis or terminal necropsy (gross or histopathology findings) were noted. The results of mutagenicity studies as evaluated by gene mutations in Salmonella typhimurium, in vitro chromosome aberrations and in vivo micronucleus test in mouse did not reveal any genotoxicity of ß-glucan. Based on the subchronic study, the no observed-adverse-effect level (NOAEL) for mushroom ß-glucan was determined as 2000 mg/kgbw/day, the highest dose tested.

Safety assessment of a solid lipid curcumin particle preparation: acute and subchronic toxicity studies.

Curcumin, a polyphenol, is obtained from turmeric, the ground rhizomes of Curcuma longa L. Extensive research over the past half century has revealed several health benefits of curcumin. The objective of the present study was to investigate potential adverse effects, if any, of a novel solid lipid curcumin particle (SLCP) preparation in rats following acute and subchronic administration. The oral LD50 of the preparation in rats as well as in mice was found to be greater than 2000 mg/kg body weight (bw). In the subchronic toxicity study, Wistar rats (10/sex/group) were administered via oral gavage 0 (control), 180, 360, and 720 mg/kg bw/day of SLCP preparation for 90 days. Administration of the curcumin preparation did not result in any toxicologically significant treatment-related changes in clinical (including behavioral) observations, ophthalmic examinations, body weights, body weight gains, feed consumption, and organ weights. No adverse effects of the curcumin preparation were noted on the hematology, serum chemistry parameters, and urinalysis. Terminal necropsy did not reveal any treatment-related gross or histopathology findings. Based on the results of this study, the No Observed-Adverse-Effect Level (NOAEL) for this standardized novel curcumin preparation was determined as 720 mg/kg bw/day, the highest dose tested.

Safety assessment of Cissus quadrangularis extract (CQR-300): subchronic toxicity and mutagenicity studies.

Cissus quadrangularis has been used for centuries for therapeutic and culinary purposes. Extract from this plant (CQR-300) has been claimed for its health benefits. The objective of present investigation was to delineate adverse effects, if any, of CQR-300 in subchronic toxicity, and gentotoxicity studies. In the subchronic study, Sprague Dawley rats (20/sex/group) were administered (gavage) C. quadrangularis extract (CQR-300) at dose levels of 0, 100, 1000, and 2500 mg/kg body weight (bw)/day for 90 days. No treatment related clinical signs of toxicity, mortality or changes in body weights, body weight gain or food consumption were noted. Functional observation tests and ophthalmological examination did not reveal any changes. No toxicologically significant treatment related changes in hematological, clinical chemistry, urine analysis parameters, and organ weights were noted. No treatment related macroscopic and microscopic abnormalities were noted at the end of treatment period. The results of mutagenicity studies as evaluated by Ames assay, in vitro chromosomal aberration and in vivo micronucleus assay did not reveal any genotoxicity of CQR-300. Based on the subchronic study, the no-observed-adverse-effect level (NOAEL) for C. quadrangularis extract (CQR-300) determined as 2500 mg/kg bw/day, the highest dose tested.

Safety of vitamins and minerals: controversies and perspective.

Available information suggests that currently over 47% of males and 59% of females use dietary supplements for health benefits, and the number of users is rapidly increasing. However, numerous studies published over more than a decade have linked some supplements (including vitamins E, C, D, A, and B, as well as selenium) to no health benefits or even to adverse health effects. Recent studies with negative results, which drew media attention, include the following: a 2008 study on the ability of vitamin E and selenium to lower the risk of prostate cancer was halted amidst fear of potential harm; vitamin C may do more harm than good as it may protect cancer cells; intake of vitamins E and C by 15,000 male physicians for 10 years had no health benefits. In contrast, there are compelling cause and effect data linking the use of folic acid with consistent and significant reductions in fetal adverse pregnancy outcomes, demonstrating no beneficial effects of calcium and vitamin D supplements in improving bone strength and reducing fractures. These equivocal and conflicting findings on the effects of supplements on health outcomes have left consumers confused about their benefits and wary of the possible adverse effects of vitamin and mineral supplementation. The objectives of this session are to characterize the current state of the science as it relates to the impact of vitamin and mineral supplementation on human health, review the statutory and regulatory perspective of vitamin use from a safety perspective, assess the credibility of meta-analysis in the safety assessment of vitamins, and elicit the mechanisms of these interactions-pro-oxidant versus antioxidant effects and beneficial versus adverse effects.