Advancing nutrition science to meet evolving global health needs.

Populations in crisis!A global overview of health challenges and policy efforts within the scope of current nutrition issues, from persistent forms of undernutrition, including micronutrient deficiency, to diet-related chronic diseases. Nutrition science has evolved from a therapeutic and prevention emphasis to include a focus on diets and food systems. Working and consensus definitions are needed, as well as guidance related to healthy diets and the emerging issues that require further research and consensus building. Between nutrient deficiency and chronic disease, nutrition has evolved from focusing exclusively on the extremes of overt nutrient deficiency and chronic disease prevention, to equipping bodies with the ability to cope with physiologic, metabolic, and psychological stress. Just what is 'optimal nutrition', is that a valid public health goal, and what terminology is being provided by the nutrition science community? Nutrition research on 'healthspan', resilience, and intrinsic capacity may provide evidence to support optimal nutrition. Finally, experts provide views on ongoing challenges of achieving consensus or acceptance of the various definitions and interventions for health promotion, and how these can inform government health policies.Nutrition topics that receive particular focus in these proceedings include choline, NAD-replenishment in neurodegenerative diseases, and xanthophyll carotenoids. Choline is a crucial nutrient essential for cellular metabolism, requiring consumption from foods or supplements due to inadequate endogenous synthesis. Maternal choline intake is vital for fetal and infant development to prevent neural tube defects. Neurodegenerative diseases pose a growing health challenge, lacking effective therapies. Nutrition, including NAD-replenishing nutrients, might aid prevention. Emerging research indicates xanthophyll carotenoids enhance vision and cognition, potentially impacting age-related diseases.

The Botanical Safety Consortium: A public-private partnership to enhance the botanical safety toolkit.

Botanical dietary supplement use is widespread and growing, therefore, ensuring the safety of botanical products is a public health priority. This commentary describes the mission and objectives of the Botanical Safety Consortium (BSC) - a public-private partnership aimed at enhancing the toolkit for conducting the safety evaluation of botanicals. This partnership is the result of a Memorandum of Understanding between the US FDA, the National Institute of Environmental Health Sciences, and the Health and Environmental Sciences Institute. The BSC serves as a global forum for scientists from government, academia, consumer health groups, industry, and non-profit organizations to work collaboratively on adapting and integrating new approach methodologies (NAMs) into routine botanical safety assessments. The objectives of the BSC are to: 1) engage with a group of global stakeholders to leverage scientific safety approaches; 2) establish appropriate levels of chemical characterization for botanicals as complex mixtures; 3) identify pragmatic, fit-for-purpose NAMs to evaluate botanical safety; 4) evaluate the application of these tools via comparison to the currently available safety information on selected botanicals; 5) and integrate these tools into a framework that can facilitate the evaluation of botanicals. Initially, the BSC is focused on oral exposure from dietary supplements, but this scope could be expanded in future phases of work. This commentary provides an overview of the structure, goals, and strategies of this initiative and insights regarding our first objectives, namely the selection and prioritization of botanicals based on putative toxicological properties.

Development of a consensus approach for botanical safety evaluation - A roundtable report.

Botanical safety science continues to evolve as new tools for risk assessment become available alongside continual desire by consumers for "natural" botanical ingredients in consumer products. Focusing on botanical food/dietary supplements a recent international roundtable meeting brought together scientists to discuss the needs, available tools, and ongoing data gaps in the botanical safety risk assessment process. Participants discussed the key elements of botanical safety evaluations. They provided perspective on the use of a decision tree methodology to conduct a robust risk assessment and concluded with alignment on a series of consensus statements. This discussion highlighted the strengths and vulnerabilities in common assumptions, and the participants shared additional perspective to ensure that this end-to-end safety approach is sufficient, actionable and timely. Critical areas and data gaps were identified as opportunities for future focus. These include, better context on history of use, systematic assessment of weight of evidence, use of in silico approaches, inclusion of threshold of toxicological concern considerations, individual substances/matrix interactions of plant constituents, assessing botanical-drug interactions and adaptations needed to apply to in vitro and in vivo pharmacokinetic modelling of botanical constituents.

Industry Actions to Address Quality Issues for Dietary Supplements, Botanicals, and Other Natural Products.

The concept of "dietary supplements" is either a blessing for those focused on healthy lifestyles and personal management thereof or a crisis fraught with snake oil and drug analogs that are insidiously poisoning the gullible. Lost in this chatter is the role the ethical, and customer-focused industry takes to drive self-directing/self-governing initiatives to demonstrate unequivocally their position as responsible corporate citizens, meeting the needs of the ever-growing body of wellness-seekers.

Dietary guidance for lutein: consideration for intake recommendations is scientifically supported.

Lutein, a yellow xanthophyll carotenoid found in egg yolks and many colorful fruits and vegetables, has gained public health interest for its putative role in visual performance and reducing the risk of age-related macular degeneration. The National Academies of Sciences, Engineering and Medicine's recommended Dietary Reference Intakes (DRIs) focus on preventing deficiency and toxicity, but there is a budding interest in establishing DRI-like guidelines for non-essential bioactives, like lutein, that promote optimal health and/or prevent chronic diseases. Lupton et al. developed a set of nine criteria to determine whether a bioactive is ready to be considered for DRI-like recommendations. These criteria include: (1) an accepted definition; (2) a reliable analysis method; (3) a food database with known amounts of the bioactive; (4) cohort studies; (5) clinical trials on metabolic processes; (6) clinical trials for dose-response and efficacy; (7) safety data; (8) systematic reviews and/or meta-analyses; (9) a plausible biological rationale. Based on a review of the literature supporting these criteria, lutein is ready to be considered for intake recommendations. Establishing dietary guidance for lutein would encourage the consumption of lutein-containing foods and raise public awareness about its potential health benefits.

Bioactive nutrients - Time for tolerable upper intake levels to address safety.

There is increasing interest by consumers, researchers, and regulators into the roles that certain bioactive compounds, derived from plants and other natural sources, can play in health maintenance and promotion, and even prolonging a productive quality of life. Research has rapidly emerged suggesting that a wide range of compounds and mixtures in and from plants (such as fruits and vegetables, tea and cocoa) and animals (such as fish and probiotics) may exert substantial health benefits. There is interest in exploring the possibility of establishing recommended intakes or dietary guidance for certain bioactive substances to help educate consumers. A key aspect of establishing dietary guidance is the assessment of safety/toxicity of these substances. Toxicologists need to be involved in both the development of the safety framework and in the evaluation of the science to establish maximum intake/upper limits.

The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline.

The increasing consumption of amino acids from a wide variety of sources, including dietary supplements, natural health products, medical foods, infant formulas, athletic and work-out products, herbal medicines, and other national and international categories of nutritional and functional food products, increases the exposure to amino acids to amounts far beyond those normally obtained from the diet, thereby necessitating appropriate and robust safety assessments of these ingredients. Safety assessments of amino acids, similar to all food constituents, largely rely on the establishment of an upper limit [Tolerable Upper Intake Level (UL)] considered to be a guide for avoiding high intake, above which adverse or toxic effects might occur. However, reliable ULs have been difficult or impossible to define for amino acids because of inadequate toxicity studies in animals and scarce or missing clinical data, as well as a paucity or absence of adverse event reporting data. This review examines 2 amino acids that have been associated with in-market adverse events to show how quality specifications might have helped prevent the adverse clinical outcomes. We further highlight the importance of various factors that should be incorporated into an overall safety assessment of these and other amino acids. In addition to the traditional reliance on the established UL, well-defined quality specifications, review of synthesis and production strategies, potential interactions with drugs, contraindications with certain disease states, and cautionary use within certain age groups should all be taken into consideration.

Assessing Natural Product-Drug Interactions: An End-to-End Safety Framework.

The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach.

A quality dietary supplement: before you start and after it's marketed--a conference report.

Consumers worldwide are turning to dietary supplements as one part of their personal goal to lead healthier and more active lives. In truth, the quality of life now supersedes the length of life as no one would trade living to one hundred (the last forty with compromised physical abilities and decreased mental acuity) for 80 years of travel, time with family, and intellectual pursuits. If there is the possibility of preventing a disease or debilitating condition through efficient lifestyle changes (additions, subtractions, modifications) and to also avoid the costly and escalating medical and pharmaceutical treatments that accompany having the disease/condition, then a sensible individual would focus on their overall health and wellness…proactively, instead of reactively. However, an important caveat is that over-regulation or inappropriate application of current regulations can increase the price of dietary supplements and nutritional products and thus cause underutilization of the potentially beneficial physiological attributes of these products. Conversely, strict adherence to regulatory guidelines could result in safer dietary supplements and fewer adverse reactions requiring medical attention. If new regulations or stricter interpretation/application of existing regulations result in certain dietary supplements being taken off the market, will continued demand create a completely unregulated, underground economy that will create unforeseen problems? More research should be supported by government agencies to determine the effectiveness of dietary supplements, nutritional products and complementary medicine in reducing personal and societal medical costs and further contribution to the overall health of the population.

Exploring the benefits and challenges of establishing a DRI-like process for bioactives.

Bioactives can be defined as: "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status" (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Reg 69:55821-55822, 2004). Although traditional nutrients, such as vitamins, minerals, protein, essential fatty acids and essential amino acids, have dietary reference intake (DRI) values, there is no such evaluative process for bioactives. For certain classes of bioactives, substantial scientific evidence exists to validate a relationship between their intake and enhanced health conditions or reduced risk of disease. In addition, the study of bioactives and their relationship to disease risk is a growing area of research supported by government, academic institutions, and food and supplement manufacturers. Importantly, consumers are purchasing foods containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects. This conference, Bioactives: Qualitative Nutrient Reference Values for Life-stage Groups?, explored why it is important to have a DRI-like process for bioactives and challenges for establishing such a process.

Nutrient reference values for bioactives: new approaches needed? A conference report.

Nutrients can be classified as either "essential" or "non-essential," the latter are also termed bioactive substances. Whereas the absence of essential nutrients from the diet results in overt deficiency often times with moderate to severe physiological decrements, the absence of bioactive substances from the diet results in suboptimal health. Nutrient reference values are set by Codex Alimentarius and regulatory bodies in many countries, mostly for essential nutrients with recommended daily intakes. The IOM in the United States has defined a set of four DRIs that, when data are appropriate, include an EAR, a RDA that is derived from the EAR, an AI for nutrients without appropriate data to identify an EAR, and an UL. From the RDA, the United States derives a labeling value called the DV, which applies to older children and most adults. In Codex, the equivalents of the DVs are the NRVs to be used in calculating percentage values on food labels. Nothing in the IOM documents specifies that labeling values can be set only for what have been defined to date as essential nutrients. Indeed, the US Food and Drug Administration sets a labeling value for dietary fiber based on the IOM AI for this ingredient. This conference explores the definitions, concepts, and data on two of the best examples of bioactive substances that, perhaps, should have NRVs: lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids.

Lack of oral embryotoxicity/teratogenicity with D-ribose in Wistar rats.

The present oral embryotoxicity/teratogenicity study of d-Ribose (DR) was conducted in female rats; 28 rats/group were exposed via the diet to 0, 5, 10, or 20% DR (0.0, 4.25, 7.94, 9.91g/kg body weight/day), from day 0 of gestation until Caesarian section and maternal sacrifice on day 21. All animals survived to the end of the study. Fecundity index, gestation index, pre-implantation loss, post-implantation loss, and sex ratio were all unaffected by treatment with DR. External observations of fetuses and placentas were unremarkable across the study groups. Mean fetal and placental weights, across all viable fetuses, did not differ significantly between treated and control groups. Observations of visceral malformations, anomalies, and variations were unremarkable and did not differ between treated and control groups. In summary, administration of DR to pregnant rats at concentrations up to 20% of the diet resulted in no significant adverse effects on the developing embryo/fetus at doses that were not otherwise a severe metabolic stress on the dam. A No Observed Adverse Effect Level (NOAEL) for teratogenicity could be seen at a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of between 3.64 and 4.61g/kg body weight/day.

Sub-chronic (13-week) oral toxicity study with D-ribose in Wistar rats.

The present study evaluated the toxicity from sub-chronic administration of D-ribose (DR) to male and female albino Wistar rats. Groups of 20 male and 20 female rats were exposed via the diet to 0%, 5%, 10%, or 20% DR, seven days per week (mean daily intake of 0.0, 3.6, 7.6, and 15.0 g/kg body weight/day in males and 0.0, 4.4, 8.5, and 15.7 g/kg body weight/day in females), for 13 consecutive weeks. Mean feed consumption and feed conversion efficiency values were comparable across all study groups; however, and mean body weights of all treated animals were decreased relative to those of controls. Absolute cecal weights were increased in the mid- and high-dose animals, and the relative weights were increased in all treated animals. Analysis of microscopic histopathology revealed no evidence of changes that could be attributed to the DR treatment. It is scientifically reasonable to conclude that the present study supports a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of 3.6 and 4.4 g/kg body weight/day in male and female rats, respectively, as being the absolute no observed adverse effect level (NOAEL) for this substance.

Acute and subchronic toxicity studies on Sel-Plex, a standardized, registered high-selenium yeast.

Selenium has been recognized as an essential nutrient for human health; however, its bioavailability is primarily dependent upon the type of selenium, elemental versus organic. In geographic areas low in selenium, there is the potential for animals (including humans) to become selenium deficient and this potential deficiency can be remedied by consumption of exogenous selenium, including selenium-enriched yeast (Saccharomyces cerevisiae) that contains high levels of organic selenium (e.g., selenized yeast). The present studies were conducted to investigate potential oral toxicity of a unique selenized yeast preparation (Sel-Plex) when administered to (1) adult female CHS Swiss mice ICo:OFI (IOPS Caw); (2) adult female CHS Sprague-Dawley rats; and (3) adult male and female Sprague-Dawley CD rats. For the 28- and 90-day toxicity studies, (1) adult male and female Sprague-Dawley CRL:CD(R)(SD) IGS BR strain rats and (2) adult male and female 6- to 7-month-old Beagle dogs were used. The LD50 for mice was >or=2000 mg Sel-Plex/kg (>or=4.06 mg Se/kg) and for rats, was greater than >or=2000 mg Sel-Plex/kg (>or=4.06 mg Se/kg). In the two 28-day studies, for rats, the no observed adverse effects level (NOAEL) was 50 mg Sel-Plex/kg/day (0.1 mg Se/kg/day), and for the dogs, the NOAEL was 22.5 mg Sel-Plex/kg/day (0.045 mg Se/kg/day). For the two 90-day studies, for rats the NOAEL for Sel-Plex was 114 mg/kg/day (0.23 mg Se/kg/day), and for dogs, the NOAEL was 30 mg Sel-Plex/kg/day (0.06 mg Se/kg/day): the latter being the NOAEL in the most sensitive species.

Genotoxicity studies on Sel-Plex, a standardized, registered high-selenium yeast.

Selenium, recognized as an essential nutrient for human health, is a component of proteins and enzymes required for various biological functions and is currently being used as a feed supplement for livestock in geographical areas that are naturally low in selenium. Selenium is structurally similar to sulfur, replacing the sulfur atom in stoichiometric amounts and thus functions through an association with proteins, termed selenoproteins. In geographic areas low in selenium, there is the potential for animals (including humans) to become selenium deficient and this potential deficiency can be remedied by consumption of exogenous selenium, including selenium-enriched yeast (Saccharomyces cerevisiae) that contains high levels of organic selenium (e.g., selenized yeast). A unique, standardized, registered high selenium food-grade baker's yeast (S. cerevisiae; Sel-Plex), was tested in the following battery of Genotoxicity assays; (1) a bacterial reverse mutation test (Ames test); (2) an in vitro mammalian chromosome aberration test; and (3) a mouse micronucleus test. Under the conditions of this assay, Sel-Plex showed no evidence of mutagenic activity in Salmonella typhimurium, in the bacterial reverse mutation test. Sel-Plex did not induce significant chromosomal aberrations in cultured human lymphocytes in the in vitro mammalian chromosome aberration test. Sel-Plex did not statistically increase the frequency or proportion of micronucleated immature erythrocytes in the mouse micronucleus test. Thus, from the studies presented here, the authors conclude that Sel-Plex is nongenotoxic.

Toxicology and pharmacology of sodium ricinoleate.

Ricinoleic acid constitutes approximately 90% of the fatty acid content of castor oil. Castor oil is known for its purgative effects and can be used to induce labor. Both castor oil and ricinoleic acid are approved for use in food. The mechanistic basis for purgative actions likely includes the membrane-disruptive effects of detergent-like molecules, such as sodium ricinoleate (a 'soap'). These effects have been shown to be dose-related and to exhibit a threshold below which no laxative response was evident, in both animals and in humans. Castor oil was not toxic in subchronic feeding studies in rodents at doses ranging up to 10-20% of the diet. Sodium ricinoleate, as a surfactant, demonstrates predictable skin and mucus membrane irritant effects, and may induce a Type IV dermal sensitization response in those previously sensitized to it. However, food-grade castor oil and sodium ricinoleate are prepared in such a manner as to be free of the castor bean constituents that have been proven to be the source of reported Type I immediate hypersensitivity responses. Feeding studies with castor oil in rodents provide a basis for a no observable adverse effect level (NOAEL) estimate of 7,500 mg/kg/day and 5,000 mg/kg/day in mice and rats, respectively (). Applying an uncertainty factor of 100 to the lesser of these NOAELs, one can thus estimate an acceptable daily intake (ADI) in man to be 50 mg/kg, or 3,000 mg of castor oil per day in an average 60 kg person. As ricinoleic acid constitutes approximately 90% of castor oil, applying this calculation to the 3,000 mg/day estimated ADI in humans for castor oil (given the rapid hydrolysis of castor oil glyceride in the gastrointestinal tract), the acceptable daily intake of ricinoleic acid may be as high as 2,400 mg/person.

The importance of GRAS to the functional food and nutraceutical industries.

At a time when 150 million Americans spend over $20.5 billion on functional foods, nutraceuticals and dietary supplements, the Food and Drug Administration (FDA) is doing little to ensure that all the safe and efficacious products that could come to the market are allowed to do so. FDA has only responded slowly and reluctantly to Congressional action and to mandates from the Courts to implement the law. Additionally, FDA had set the bar too high for Health Claims and was forced by the Courts to implement a more reasonable standard, but the response, Qualified Health Claims, has failed to gain the confidence of the public because of the confusing wording of the claims demanded by FDA. Congressional efforts to assure consumer access to dietary supplements have been met with similar resistance from FDA. The Dietary Supplement Health and Education Act (DSHEA) was the product of a compromise with a lower threshold for demonstration of safety (reasonable expectation of no harm) that would be met by consumer self-policing and assumption of some risk. FDA has thwarted this effort by raising the bar for New Dietary Ingredient Notifications (NDIN) to what appears to be the higher threshold for the safety of food ingredients (reasonable certainty of no harm)--FDA apparently sees these two safety thresholds as a distinction without a difference. As a result, increasing numbers of dietary supplement manufacturers, unwilling to gamble the future of their products to a system that provides little hope for the FDA's response of "no objection", have committed the additional resources necessary to obtain Generally Recognized As Safe (GRAS) status for their supplements. The pressure on FDA and Congress for change is again building with increased dissatisfaction among consumers as the result of confusing labels. A second force for change will be a need to uncouple the FDA mandated substance-disease relationship and return to the substance-claim relationship to allow for progress in nutrigenomics and metabolomics, which will result in an increasing number of substance-biomarker claims.

Safety of ephedra: lessons learned.

The safe use of ephedra represents the best possible outcome of a convergence of variables, some with troubling potential outcomes. Commercially used ephedra and its products is prepared from Ephedra spp. and as such is subject to a variety of influences (including differences in species and strain; growth, harvest and storage conditions) all of which may influence the content of constituents (which may, in turn, affect the absorption, distribution, and metabolism of active constituents) and taken together, influences the net pharmacological effect. Further, as a natural substance with an easily perceived and desirable (i.e. weight-loss) pharmacological effect, ephedra is also susceptible to a variety of adulterants, both economic and efficacious. All of the foregoing represent potential for misadventure before ephedra even reaches the consumer. The consumer introduces a constellation of variables as well, including, but not limited to, acute and chronic diseases, inborn errors in metabolism, simultaneous use of prescription and over-the-counter drugs, dietary supplements, alcohol, illicit substances and certain foods (e.g. chocolate, caffeinated drinks), all or some of which may exert synergistic, additive or even antagonistic influences on the desired physiologic outcome. The foregoing not withstanding, the majority of the published nonclinical and clinical studies, and history of use, support the safety of ephedra at the proposed use levels. However, the reports of adverse events submitted to FDA raise concern about the risk associated with ephedra without establishing a direct causal relationship. Given the foregoing, how best can a decision on safety be made? Should the question actually be "can ephedra be as toxic as reported?"