Diabetes, Diabetic Complications, and Phosphate Toxicity: A Scoping Review.

This article presents a scoping review and synthesis of research findings investigating the toxic cellular accumulation of dysregulated inorganic phosphate-phosphate toxicity-as a pathophysiological determinant of diabetes and diabetic complications. Phosphorus, an essential micronutrient, is closely linked to the cellular metabolism of glucose for energy production, and serum inorganic phosphate is often transported into cells along with glucose during insulin therapy. Mitochondrial dysfunction and apoptosis, endoplasmic reticulum stress, neuronal degeneration, and pancreatic cancer are associated with dysregulated levels of phosphate in diabetes. Ectopic calcification involving deposition of calcium-phosphate crystals is prevalent throughout diabetic complications, including vascular calcification, nephropathy, retinopathy, and bone disorders. A low-glycemic, low-phosphate dietary intervention is proposed for further investigations in the treatment and prevention of diabetes and related diabetic pathologies.

Coordinating Nigeria's micronutrient deficiency control programs is necessary to prevent deficiencies and toxicity risks.

Nigeria has an alarming prevalence of micronutrient deficiencies that has persisted over decades. National Micronutrient Deficiency Control (MNDC) guidelines describe several interventions to address the issue. This study identified and described currently implemented interventions, assessed coverage and coordination of the interventions, and considered the risk of overdosage and gaps. Methods included reviews of policy and program documents, key informant interviews, market, and pharmacy visits. The study found that an array of MNDC interventions were being implemented, including public health supplementation, mandatory fortification, point-of-use fortification, biofortification, promotion of dietary diversity, voluntary fortification, and ad hoc individual supplement use. Insufficient coordination existed for government, private, and civil society interventions within the health sector and between health and other sectors. Dosages of micronutrients supplied by different interventions were set independently of each other and target populations overlapped. Inadequate implementation of various interventions appeared to reduce the risk of excessive micronutrient intakes, but increased the risk of deficiencies. The risk of excessive intakes will likely increase with improved implementation and scale-up. There is a need to develop effective coordination structures for MNDC in Nigeria that will critically examine the landscape, decide modalities for different interventions, and ensure that both deficiencies and risk of excessive intakes are minimized.

Neurological Complications of Nutritional Disease.

Vitamins and minerals have essential functions in the body, from signal transduction to acting as cofactors for numerous enzymatic processes. Nutritional deficiencies and excess of certain vitamins and minerals can have profound effects on the central and peripheral nervous systems from early development into adulthood. This article summarizes the role of various nutritional factors in the nervous system and the neurological symptoms that can arise from deficiency or excess.

Nutrients Turned into Toxins: Microbiota Modulation of Nutrient Properties in Chronic Kidney Disease.

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of death. Some uremic toxins are ingested with the diet, such as phosphate and star fruit-derived caramboxin. Others result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves. These nutrients include l-carnitine, choline/phosphatidylcholine, tryptophan and tyrosine, which are also sold over-the-counter as nutritional supplements. Physicians and patients alike should be aware that, in CKD patients, the use of these supplements may lead to potentially toxic effects. Unfortunately, most patients with CKD are not aware of their condition. Some of the dietary components may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins, such as trimethylamine N-Oxide (TMAO), p-cresyl sulfate, indoxyl sulfate and indole-3 acetic acid. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of death and cardiovascular disease and there is evidence that this association may be causal. Future developments may include maneuvers to modify gut processing or absorption of these nutrients or derivatives to improve CKD patient outcomes.

Tracking Se Assimilation and Speciation through the Rice Plant - Nutrient Competition, Toxicity and Distribution.

Up to 1 billion people are affected by low intakes of the essential nutrient selenium (Se) due to low concentrations in crops. Biofortification of this micronutrient in plants is an attractive way of increasing dietary Se levels. We investigated a promising method of Se biofortification of rice seedlings, as rice is the primary staple for 3 billion people, but naturally contains low Se concentrations. We studied hydroponic Se uptake for 0-2500 ppb Se, potential phyto-toxicological effects of Se and the speciation of Se along the shoots and roots as a function of added Se species, concentrations and other nutrients supplied. We found that rice germinating directly in a Se environment increased plant-Se by factor 2-16, but that nutrient supplementation is required to prevent phyto-toxicity. XANES data showed that selenite uptake mainly resulted in the accumulation of organic Se in roots, but that selenate uptake resulted in accumulation of selenate in the higher part of the shoot, which is an essential requirement for Se to be transported to the grain. The amount of organic Se in the plant was positively correlated with applied Se concentration. Our results indicate that biofortification of seedlings with selenate is a successful method to increase Se levels in rice.

A Call to Action to Bring Safer Parenteral Micronutrient Products to the U.S. Market.

The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) started an intensive review of commercially available parenteral vitamin and trace element (TE) products in 2009. The chief findings were that adult multi-TE products currently available in the United States (U.S.) provide potentially toxic amounts of manganese, copper, and chromium, and neonatal/pediatric multi-TE products provide potentially toxic amounts of manganese and chromium. The multivitamin products appeared safe and effective; however, a separate parenteral vitamin D product is needed for those patients on standard therapy who continue to be vitamin D depleted and are unresponsive to oral supplements. The review process also extended to parenteral choline and carnitine. Although choline and carnitine are not technically vitamins or trace elements, choline is an essential nutrient in all age groups, and carnitine is an essential nutrient in infants, according to the Food and Nutrition Board of the Institute of Medicine. A parenteral choline product needs to be developed and available. Efforts are currently under way to engage the U.S. Food and Drug Administration (FDA) and the parenteral nutrient industry so A.S.P.E.N.'s recommendations can become a commercial reality.

Nature via nurture: effect of diet on health, obesity, and safety assessment.

Food is not only vital for the health and well-being of any living being, but it is a potential source of harmful chemicals, both natural and man-made. Further complicating this is the fact that most nutrients themselves are potentially toxic when consumed in excess. Deficiencies in some of these same nutrients may cause effects that resemble toxicosis or enhance the toxic potential of other nutrients or exogenous chemicals and drugs. This review discusses some of the nutritional and metabolic mechanisms involved and the implications of excess and deficiency in macronutrients and micronutrients in toxicologic pathology. In addition, we review the adverse effects of ad libitum (AL) overfeeding on metabolic, endocrine, renal, and cardiac diseases, and many cancers and the healthful effects of moderate dietary restriction (DR) in modulating obesity and controlling spontaneous and induced diseases of laboratory animals used in toxicology and carcinogenicity studies for human safety assessment.

Micronutrients in parenteral nutrition: boron, silicon, and fluoride.

Boron may be beneficial for bone growth and maintenance, central nervous system function, and the inflammatory response, and silicon may be beneficial for bone maintenance and wound healing. Fluoride is not an essential element but amounts provided by contamination may be beneficial for bone strength. Fluoride toxicity may be a concern in parenteral nutrition. Further studies are warranted to determine whether there are optimal amounts of boron and silicon that should be delivered to typical and special population patients receiving parenteral nutrition. In addition, further studies are needed to determine whether providing the dietary guideline of adequate intake amounts of fluoride parenterally would prevent or treat parenteral nutrition osteopenia.

Micronutrient supplementation in adult nutrition therapy: practical considerations.

Preexisting micronutrient (vitamins and trace elements) deficiencies are often present in hospitalized patients. Deficiencies occur due to inadequate or inappropriate administration, increased or altered requirements, and increased losses, affecting various biochemical processes and resulting in organ dysfunction, poor wound healing, and altered immune status with deleterious sequelae. Guidelines for the 13 essential vitamins and 10 essential trace elements have been established. These recommendations, however, are applicable to healthy adults and not to critically ill patients, in whom decreased serum levels may indicate actual deficiencies or a deficiency due to redistribution. Benefits of supplementation over and above the daily requirements, which may not result in increased serum levels, are also unclear and may, in fact, be detrimental. Vitamin requirements are increased in disease states, but a similar recommendation for trace elements has not been initiated except for selenium (Se) and zinc (Zn). In practice, a multivitamin preparation and a multiple trace element admixture (containing Zn, Se, copper, chromium, and manganese) are added to parenteral nutrition formulations. Most enteral nutrition preparations also contain adequate amounts of vitamins and trace elements, although bioavailability may be an issue. Detailed information about individual micronutrient use specifically in hospitalized adult patients receiving nutrition therapy will be discussed, emphasizing the practical and clinical aspects. Clinicians are encouraged to think of micronutrients not as nutritional supplements alone but also as therapeutic agents and nutraceuticals.

Regulatory frameworks for copper considering chronic exposures of the population.

Copper is an essential nutrient that is toxic in excess. Copper intakes from a balanced diet appear to meet the needs of most healthy individuals, because overt deficiency and toxicity are rare. Some uncertainty, however, persists because of limitations in currently available biomarkers used to assess copper status and the paucity of data available to establish tolerable upper levels of intake. Current policies and regulations pertaining to food fortification, nutritional supplements, and drinking water appear to be effective in providing for adequate copper intakes in many populations, although high levels of exposure, through overzealous fortification, supplementation, or drinking water exposure, may be possible under some circumstances. Surveillance and monitoring programs to evaluate copper exposures of human populations should continue and should be refined as new biomarkers become available.

Clinical and analytical toxicology of dietary supplements: a case study and a review of the literature.

The use of dietary supplements has grown dramatically in the last decade. A large number of dietary and herbal supplements escape regulatory and quality control; components of these preparations are poisonous and may contain, among other toxins, heavy metals. Uncontrolled use of dietary and herbal supplements by special populations, such as the military, may therefore pose a health risk. Clinical symptoms are not always properly attributed to dietary supplements; patients often do not mention supplement use to their health care provider. Therefore, a health risk estimate is hard to make on either the individual or the population level. The literature on this issue was reviewed and discussed in the light of a representative clinical-chemical case study. This case study was performed on a host of preparations that were used by one single individual in the military. Both essential (chromium, copper, zinc, and iron) and poisonous (arsenic, lead, and nickel) trace elements were determined using inductively coupled plasma combined with optical emission spectrometry (ICP-OES) or with mass spectrometry (ICP-MS). Arsenic and lead were detected at exposure levels associated with health risks. These health risks were detected predominantly in hormone-containing supplements and the herbs and botanicals used for performance enhancement. To the extent that this is a representative sample, there is an underestimation of supplement use and supplement risk in the US military, if not in the general population. Since clinical symptoms may be attributed to other causes and, unless patients are specifically asked, health care providers may not be aware of their patients' use of dietary supplements, a strong support of laboratory diagnostics, such as a toxicological screening of blood or urine, is required. In addition, screening of the preparations themselves may be advised.

Risk assessment of micronutrients.

Risk assessment of micronutrients has to take into account two different intake-response relationships; the risk of deficiency, which decreases with increase in intake, and the risk of toxicity, which increases with increase in intake. The available databases on micronutrients tend to focus on benefits at low intakes, and there are usually few reliable data on hazard identification and characterisation at high intakes. Application of the usual default uncertainty factors for species differences, human variability and database inadequacy could result in "recommended" upper intake levels that would cause deficiency. There have been a number of comprehensive reviews that have used low, and largely arbitrary, uncertainty factors to establish tolerable upper intake levels for vitamins and minerals. A recent FAO/WHO Workshop developed a structured approach to the application of a single composite uncertainty factor. Risk-benefit approaches have been developed recently that balance the risk of toxicity against the risk of deficiency, and offer the potential for more scientifically based methods.

[Justifying the use of primary tissue culture method for evaluation of sodium fluoride safety in nutrition products].

Toxicity of sodium fluoride added to nutrition products is assessed through peculiarities of kidney tissue culture growth in vitro--over 75% inhibition of cell clumps growth supports high toxic influence of sodium fluoride, the growth decrease from 63% to 74% signifies lower degree, the growth inhibition less than 62% demonstrates very low toxicity of the chemical.

Food supplements and European regulation within a precautionary context: a critique and implications for nutritional, toxicological and regulatory consistency.

In this paper, we review European legislation in the field of micronutrient food supplements and find it wanting. It is shown that the precautionary principle, embedded in European food legislation, pre-empts innovative developments in this field. In view of the scientific advances in micronutrients research, we subsequently critique the precautionary perspective and propose a novel outlook on micronutrients food supplements regulation. However, this requires a transition from the "survival" approach of the current deficiency-related RDAs to a "health-optimization" approach of a n(ew)-RDA. Genomic integrity is central in this envisioned transition.

Toxicology of micronutrients: adverse effects and uncertainty.

The establishment of safe upper intake levels for micronutrients must consider the intake-response relations for both deficiency and toxicity. Limited data are available on the toxicities of most micronutrients, and few studies that meet the criteria considered essential for the risk assessment of other chemicals in food, such as pesticides and food additives, have been performed. In some cases, the application of large uncertainty factors, which are used to establish the amount of a chemical that would be safe for daily intake throughout life, could result in nutritionally inadequate intakes of micronutrients. As a consequence, lower than normal uncertainty factors have been applied to determine safe or tolerable intakes of many micronutrients. There is no clear scientific rationale, on the basis of the metabolism and elimination of micronutrients or the nature of the adverse effects reported for high intakes, for the use of reduced uncertainty factors for micronutrient toxicity. A review of recent evaluations of selected vitamins and minerals shows little consistency in the application of uncertainty factors by different advisory groups, such as the Institute of Medicine in the United States and the Scientific Committee on Foods in the European Union. It is apparent that, in some cases, the uncertainty factor applied was selected largely to give a result that is compatible with nutritional requirements; therefore, the uncertainty factor represented part of risk management rather than hazard characterization. The usual risk assessment procedures for chemicals in food should be revised for micronutrients, so that the risks associated with intakes that are too low and too high are considered equally as part of a risk-benefit analysis.

Action of some micronutrients on the infestation and yield components of faba bean by the aphid, Aphis craccivora Koch (Aphididae, Homoptera) and the leaf miner, Liriomyza trifolii (Burgess) (Agromyzidae, Diptera).

Field experiments were carried out in the two growing seasons of 1999/2000 and 2000/2001 on faba bean (Vicia faba) plants in the Experimental Farm of Agriculture Research Station at Nubaria region, Alexandria, which is considered as a newly reclaimed calcareous soil. The present investigation aimed to evaluate the effect of spraying faba bean plants with certain micronutrients, i.e. Iron, Manganese and Zinc either in single double or triple combinations on the infestation by the aphid, Aphis craccivora Koch (Aphididae, Homoptera) and the leaf miner, Liriomyza trfolü (Burgess) (Agromyzidae, Diptera). The infestation by these insects was assessed using the parameters of Infestation grades as well as the injury indices. Faba bean plants cv. Giza Blanca were sprayed twice (45 and 66 days) after planting with the above-mentioned micronutrients. However, results of this investigation showed, with no doubt, that Mn, Zn and Fe individually or in double or triple combinations have increased to varied extents the infestation rates (%) of faba bean plants compared to the untreated ones. Such varied increases were mainly due to the metabolic roles of the used foliar sprays and their interactions, which indirectly affect the physio-biological actions of plants that may render them suitable for either A. craccivora or L. trifoii reproduction. This phenomenon might be also due to the different environmental factors. In both seasons, the relationship between nutrients applications and pests Infestation followed the same trend of increase in the percentages of infested plants. This assures and confirms the constant metabolic roles of such micronutrients. The biological seed weight (ton/fed.) was positively affected by the application of the used micronutrients. It is worth mentioning that the maximum response was observed in case of the triple treatment followed by the double and single treatments in a descending order. Application of the investigated micronutrients alone or in mixtures resulted in significant increases in yield and its components. Such increases were due to the fact that ions of Zn, Fe and Mn are cofactors of several enzymes, but rarely if ever with a high degree of specificity.

The facts and controversies about selenium.

Selenium is a trace element, essential in small amounts, but it can be toxic in larger amounts. Levels in the body are mainly dependent on the amount of selenium in the diet, which is a function of the selenium content of the soil. Humans and animals require selenium for normal functioning of more than about 30 known selenoproteins, of which approximately 15 have been purified to allow characterisation of their biological functions. Selenoproteins are comprised of four glutathione peroxidases, three iodothyronine deiodinases, three thioredoxin reductases, selenoprotein P, selenoprotein W and selenophosphate synthetase. Selenium is essential for normal functioning of the immune system and thyroid gland, making selenium an essential element for normal development, growth, metabolism, and defense of the body. Supportive function of selenium in health and disease (male infertility, viral infections, including HIV, cancer, cardiovascular and autoimmune diseases) is documented in great number of clinical examinations. A great number of studies confirm that selenium supplementation plays a preventive and therapeutical role in different diseases. Definitive evidence regarding the preventive and therapeutical role of selenium as well as the exact mechanism of its action should be investigated in further studies. Investigations in Croatia indicate a possibility of inadequate selenium status of people in the area.

Iron acquisition by teleost fish.

Iron is a vital micronutrient for teleost fish, being an integral component of proteins involved in cellular respiration and oxygen transfer. However, in excess iron is toxic, and fish need to balance uptake to prevent deficiency vs. potential toxicity. This review assesses the current physiological and molecular knowledge of the mechanisms of iron acquisition in the teleost fish. It focuses on freshwater teleost fish when assessing the gill as a possible site for iron acquisition, and includes a summary of geochemical processes that govern aquatic iron bioavailability. It focuses on marine teleost fish for assessing the mechanism of intestinal iron uptake. Physiological evidence indicates that iron preferentially crosses the apical membrane of both the gills and intestine in the ferrous (Fe2+) state. Molecular evidence supports this, demonstrating the presence of homologues in fish to the large Slc 11a family of evolutionary conserved proteins linked to Fe2+ transport. This symporter is probably linked to a reductase, which reduces either ferric (Fe3+) or organic complexed iron to Fe2+ prior to uptake.