A toxicological evaluation of lithium orotate.

Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events. Nonetheless, there have been some concerns in the scientific literature regarding orotic acid, and pharmaceutical lithium salts are known to have a narrow therapeutic window, albeit, at lithium equivalent therapeutic doses 5.5-67 times greater than typically recommended for supplemental lithium orotate. To our knowledge, the potential toxicity of lithium orotate has not been investigated in preclinical studies; thus, we conducted a battery of genetic toxicity tests and an oral repeated-dose toxicity test in order to further explore its safety. Lithium orotate was not mutagenic or clastogenic in bacterial reverse mutation and in vitro mammalian chromosomal aberration tests, respectively, and did not exhibit in vivo genotoxicity in a micronucleus test in mice. In a 28-day, repeated-dose oral toxicity study, rats were administered 0, 100, 200, or 400 mg/kg body weight/day of lithium orotate by gavage. No toxicity or target organs were identified; therefore, a no observed adverse effect level was determined as 400 mg/kg body weight/day. These results are supportive of the lack of a postmarket safety signal from several decades of human consumption.

A toxicological evaluation of geranylgeraniol.

Geranylgeraniol (GGOH) is an isoprenoid compound found in annatto seeds and an intermediate of the mevalonate pathway found within organisms serving various functions. Toxicological studies on its safety profile are not readily available. To assess the safety of GGOH, a molecularly distilled, food grade annatto oil, consisting of approximately 80% trans-GGOH, was subjected to a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and an in vivo mammalian micronucleus test in order to investigate its genotoxic potential and a 90-day repeated-dose oral toxicity study in rats in order to investigate its potential subchronic toxicity and identify any target organs. No evidence of mutagenicity or genotoxic activity was observed under the applied test systems. In the 90-day study, male and female Hsd. Han Wistar rats were administered daily doses of 0, 725, 1450, and 2900 mg/kg bw/day by gavage. Treatment-related adverse effects were observed in the forestomach at all dose levels and in the liver at the intermediate- and high-dose levels. Based on these results, the lowest observed adverse effect level (LOAEL) for local effects and the no observed adverse effect level (NOAEL) for systemic effects were determined as 725 mg/kg bw/day.

A toxicological evaluation of a fulvic and humic acids preparation.

Humic substances are ubiquitous in soils and waters. These complex superstructures are derived from the decomposition of dead plant and animal matter and are vital to soil health. Their heterogenous composition is specific to their site of origin and is comprised of weakly bound aggregates of small organic compounds that can sequester minerals and make them available to plants. As such, they may possess potential nutritional value for humans, and extractions of fulvic and humic acids can be produced that could be suitable for such purposes. For this reason, we evaluated the toxicological profile of a specific preparation (blk. 333) of fulvic and humic acids derived from a lignite deposit in Alberta, Canada and found it to lack genotoxic potential in a bacterial reverse mutation test, in vitro mammalian chromosomal aberration test, and in vivo mammalian micronucleus test. No general or organ toxicity was observed in Wistar rats following 90 days of continuous exposure, and a no observed adverse effect level (NOEAL) was determined at 2000 mg/kg bw/day, the highest tested dose. Our results suggest the feasibility of further evaluation for development of the preparation as a nutritional supplement in food.

A toxicological evaluation of monomethylsilanetriol (MMST) stabilized in acacia gum, a novel silicon preparation.

Monomethylsilanetriol (MMST), a silicon-containing compound, has been sold in dietary supplements. However, toxicological studies on its safety profile are not readily available. To assess the safety of MMST stabilized in acacia gum, a novel delivery form of MMST, in accordance with internationally accepted standards, the genotoxic potential and repeated-dose oral toxicity of Living Silica® Acacia Gum Stabilized Monomethylsilanetriol (formerly known as Orgono Acacia Gum Powder®), a food grade product consisting of 80 ± 10% acacia gum and 2.8% (SD ± 10%) elemental silicon from MMST, was investigated. A bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, an in vivo mammalian micronucleus test, and a 90-day repeated-dose oral toxicity study in rats were performed. No evidence of mutagenicity or genotoxic activity was observed under the applied test systems. In the 90-day study, male and female Hsd.Han Wistar rats were administered daily doses of 0, 500, 1000, and 2000 mg/kg bw/day by gavage. No mortality or treatment-related adverse effects were observed, and no target organs were identified. Therefore, the no observed adverse effects level (NOAEL) was determined as 2000 mg/kg bw/day (201 mg MMST/kg bw/day), the highest dose tested.

Toxicological evaluations of colostrum ultrafiltrate.

Colostrum has been consumed safely for many years as a food collected directly from cows. More recently, an ultrafiltrated bovine colostrum product has been developed; however, its safety in toxicology studies has not been extensively evaluated. To assess the safety of bovine colostrum ultrafiltrate, in accordance with internationally accepted standards, the genotoxic potential was investigated in a bacterial reverse mutation test, an in vitro chromosomal aberration test, and an in vivo mammalian micronucleus test. No mutagenicity or genotoxic activity was observed in these three tests. A 90-day repeated-dose oral toxicity study in Hsd.Han Wistar rats was conducted at doses of 0, 1050, 2100, and 4200 mg/kg bw/day by gavage. After 90 days of continuous exposure, no mortality or treatment-related adverse effects were observed, and no target organs were identified. The no-observed-adverse-effect level (NOAEL) was determined to be 4200 mg/kg bw/day, the highest dose tested.

A comprehensive toxicological safety assessment of an extract of Ageratum conyzoides.

A battery of toxicological studies was conducted to aid in the safety assessment of an ethanolic extract of Ageratum conyzoides for use as an ingredient in food. In accordance with internationally accepted standards, a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, an in vivo mammalian micronucleus test, and a 90-day repeated-dose oral toxicity study in rats were performed. In the first three applied test systems, no evidence of mutagenicity, clastogenicity or genotoxicity was revealed. Ageratum conyzoides did not cause mortality or toxic changes in Hsd.Han Wistar rats in the 90-day repeated dose oral (gavage) toxicity study at doses of 500, 1000 and 2000 mg/kg bw/d. The NOAEL was determined to be 2000 mg/kg bw/d for both male and female rats, the highest dose tested.

A Comprehensive Toxicological Safety Assessment of an Extract of Olea Europaea L. Leaves (Bonolive™).

A battery of toxicological studies was conducted to investigate the genotoxicity and repeated-dose oral toxicity of Bonolive™, a proprietary water-soluble extract of the leaves of the olive tree (Olea europaea L.), in accordance with internationally accepted protocols. There was no evidence of mutagenicity in a bacterial reverse mutation test and in an vitro mammalian chromosomal aberration test nor was any genotoxic activity observed in an in vivo mouse micronucleus test at concentrations up to the limit dose of 2000 mg/kg bw/d. Bonolive™ did not cause mortality or toxic effects in Crl:(WI)BR Wistar rats in a 90-day repeated-dose oral toxicity study at doses of 360, 600, and 1000 mg/kg bw/d. The no observed adverse effect level in the 90-day study was 1000 mg/kg bw/d for both male and female rats, the highest dose tested.

A comprehensive toxicological safety assessment of an aqueous extract of Polypodium leucotomos (Fernblock(®)).

A battery of toxicological studies was conducted in accordance with internationally accepted standards to investigate the genotoxicity and repeated-dose oral toxicity of Fernblock(®), a commercial aqueous extraction of the leaves of the tropical fern Polypodium leucotomos used for its oral and topical photoprotective properties. No evidence of mutagenicity was observed in a bacterial reverse mutation test or in vitro mammalian chromosomal aberration test nor was any genotoxic activity observed in an in vivo mouse micronucleus test. Two repeated-dose oral toxicity studies were conducted in male and female Wistar rats. In the first study, no mortality or toxic effects were observed and no target organs were identified at doses administered for 14 days by gavage up to the maximum dose of 5000 mg/kg bw/day. Based on these results, a 90-day study was conducted at 0, 300, 600, and 1200 mg/kg bw/day. No mortality or treatment-related adverse effects were observed and no target organs were identified. The NOAEL from the 90-day study was determined to be 1200 mg/kg bw/day, the highest dose tested.

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.