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Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD
3 To whom correspondence should be addressed. E-mail: jvanderv{at}cfsan.fda.gov.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • nutrient upper levels • nutrition status
The establishment of tolerable upper intake levels (ULs)4 was considered necessary because the consumption of some, if not all, nutrients at some multiple of the requirement level will cause harm. Some of the earliest research on nutrient additions to the diet explored the potential that the excess intake of a nutrient may cause harm (1). The fact that essential nutrients can be toxic at some level above the requirement was and still is hard for many laypeople to understand and accept. As expressed by a senior government program administrator some years ago, the use of the phrase nutrient toxicity as a description of harm from the consumption of very high levels of some nutrients was an oxymoron. He argued that the term nutrient meant that something was good and that toxicity meant that something was bad. Furthermore, he insisted that research on the potential harmful effects of the consumption of a nutrient had to be given some other title for fear that the public and the members of the United States Congress would question the value of such research.
The reality is that some nutrients consumed at very high levels can cause serious illness and even death. For many years the leading cause of chemical-poisoning deaths among young children was iron supplement tablets (2,3). Often, these iron tablets were prescribed for the child's mother during pregnancy and the child was able to open the container and consume multiple tablets. The consumption of other trace elements was also associated with poisonings. The toxicities of the trace elements molybdenum and selenium were well known long before the discoveries that both are essential nutrients. Selenium was first reported to be toxic in 1842, and molybdenum was first reported to be harmful to cattle in 1938 (4,5). These elements are now known to be essential components of many enzymes in living tissues. Other elements and organic substances were recognized to be essential nutrients long before it was discovered that they could also be toxic when they were consumed at very high levels. In some cases, scientists in the field met this revelation with disbelief. For example, the long-term consumption of very high levels of vitamin B-6 has been shown to cause peripheral neuropathies not too dissimilar to some of the conditions that the vitamin was supposed to correct (6). Not only were high levels of some nutrients harmful, but also the impact on health was often found to be irreversible. For example, very high levels of vitamin A during pregnancy have a probability of causing teratogenic effects in humans (7).
The safety factor between the intake requirement of a nutrient and the upper intake level of the nutrient at which harm (toxicity) occurs is different for each nutrient. Some scientists who had first studied the onset of nutrient toxicity attempted to derive some algorithms that could be used to predict or generalize the level of safety for all nutrients (8). However, it soon became evident that even among general categories of nutrients, such as fat-soluble vitamins A and D or essential trace elements, the tolerances for excess intakes could be vastly different. Consequently, the traditional toxicology practices used to establish safe exposure levels for food additives and environmental contaminants for humans must be modified when they are applied to essential nutrients. For example, it may not be possible to apply a 10-fold safety factor to the highest level at which no observed adverse effect is found and still meet nutritional requirements.
The intake level at which a nutrient can cause harm is dependent on many factors, including the duration of intake and the form of the nutrient. Among other factors, the level at which a nutrient intake becomes toxic depends on the absorption, metabolism, and excretion of the nutrient. When some nutrients such as iron are consumed and absorbed in excess, they are safely stored in body tissues (9). If the level of the nutrient exceeds the storage capacity of the tissues, however, the health of the cells is compromised and organ failure can occur (10). Another factor is the interaction between nutrients. In those situations in which the level of one nutrient affects the function or excretion of another nutrient, the level of intake and storage of the latter nutrient dictates the level at which the former nutrient becomes toxic. One such relation is between zinc and copper (11,12). High levels of zinc can cause copper deficiency in animals (13). If the absorption of copper and tissue copper levels are low, then the levels at which zinc toxicity symptoms occur are far lower than the levels at which zinc toxicity symptoms occur when the levels of absorption and storage of copper are high.
Finally, nutrient toxicity is affected by overall nutritional status, genetic traits, and environmental factors. Malnutrition has been associated with an increased risk of Blackfoot disease, with is caused by chronic intakes of 10 µg of inorganic arsenic compounds/kg–1 · d (14). The impact of an individual's genetic profile on iron toxicity is well known. Individuals who have the double recessive genes for hemochromatosis have less of an ability to regulate iron absorption, which results in iron accumulation in soft tissues that can lead to organ failure over time (10). The impact of the environment is less well documented. However, exposures to substances that affect changes in absorption or excretion of nutrients are frequently associated with the accumulation of nutrients in the body. For example, the chronic consumption of high levels of ethanol is associated with the accumulation of iron in the liver and other tissues (15).
Assessing acute toxicity
For the purpose of discussion in this paper, acute toxicity is defined as a cause and an effect that is evident in terms of days and weeks and not months or years. Data on acute nutrient toxicity in humans are available for only some nutrients. Because it is unethical to plan and conduct clinical studies of nutrient toxicity with humans, the results of studies with animals have been the main source of acute nutrient toxicity data. Although data from studies with animals cannot be used directly to predict the levels of intake of a nutrient that will cause toxicity in humans, there has been a long practice of extrapolating data from such studies to humans if the animal model is considered relevant from biochemical and physiological perspectives.
It is well recognized that there are major differences in nutrient requirements and the ability to tolerate excess levels of nutrient consumption between species of animals; therefore, it is appropriate to apply an uncertainty factor when data are extrapolated between species. Such uncertainty may tend to underestimate the level at which a nutrient causes harm in humans, but the practice errs on the side of safety.
Animal studies also provide other useful information. The pathology observed in acute nutrient toxicity studies with animals may also result in the identification of biomarkers useful for the assessment of the acute toxicities of nutrients in humans. Such biomarkers are of significant importance in studies of the incidence of inadvertent acute human exposure, when and if such exposures occur. Some reports of such inadvertent acute human exposures have been published in the peer-reviewed literature. For example, acute vitamin A toxicity was observed in humans who consumed polar bear liver and fish liver (16,17). Other incidents have been submitted to regulatory agencies as adverse event reports. In general, these incidents resulted from errors in fortifying foods such as milk, errors in formulating dietary supplements, and actions by consumers such as storing acidic foods in copper or iron containers that resulted in transferring the elements to the food. The nutrient toxicity data obtained from studies of acute exposures in animals are also useful for the development of hypotheses that can be used to study the health effects of high chronic intake levels in humans.
In general, acute nutrient toxicity data alone are of marginal value in establishing ULs. Although acute nutrient toxicity data obtained from inadvertent human exposures cannot be used as the only source of information to establish a UL, in some instances these data can be used to enhance the mathematical models used to establish no adverse effect levels if data are available for other levels of exposure. Finally, acute toxicology data from studies of human exposures to high levels of nutrients are available for only some of the essential nutrients and elements. Among these are the vitamins A, D, pyridoxine, and nicotinic acid and the elements arsenic, copper, iodine, iron, potassium, sodium, selenium, and zinc (18–21). The ingestion of large quantities of vitamin C or magnesium causes acute gastrointestinal distress and diarrhea but does not appear to cause any lasting effect when intakes are returned to requirement levels (21). The potential for acute toxicity symptoms in humans as a result of the ingestion of excess levels of other essential nutrients remains a knowledge gap. Acute toxic effects of boron, nickel, and fluoride (20) have been observed in animal studies and would likely be observed in humans if humans consumed them at comparable levels. Because knowledge of acute toxicity is not essential for the establishment of a UL, the responsible scientific approach is to pursue such data from animal studies and instances of inadvertent human exposure, should such exposures occur.
Assessment of chronic exposure
The term chronic exposure, as used in this discussion, is defined as the consumption of a nutrient for periods of several months to several years. The establishment of a UL requires information on long-term nutrient intake and the associated relevant health effects. The sources of such data are large nutrition and health examination surveys, such as the National Health and Nutrition Examination Surveys (NHANES); long-term clinical trials in which nutrient intakes and health effects can be measured; and observational studies of free-living individuals in whom high levels of intake of a nutrient have been associated with a measurable health effect. In addition to the nutrients cited above with which acute toxicity has been observed, 7 more nutrients have been shown to cause adverse health effects when they are chronically consumed at high levels. These include the vitamins E, folic acid, and choline, and the elements calcium, molybdenum, phosphorus, and vanadium (18–21). No evidence of negative health effects from the intake of high levels of the remaining essential nutrients was found in studies with humans or animals. The lack of evidence for the remaining nutrients does not mean that potential negative health effects do not exist when these nutrients are consumed at very high levels. It may simply mean that adequate research has not been completed to date. The quality and the completeness of the existing databases for several nutrients were so limited that large uncertainty factors had to be applied to the data in the process of establishing the ULs.
Measurement of health effects requires the use of biomarkers that assess the level of the nutrient stores in the body and the existence of harmful effects. Although such biomarkers are known for some nutrients like iron, biomarkers that can be used to assess the harmful levels of most nutrients have not been identified. Experience with the assessment of the iron status of the population during the NHANES surveys has demonstrated that the availability of multiple biomarkers for assessment of the health effects of a nutrient are important for the establishment of upper levels. In addition, the use of multiple biomarkers provides a way for checking on false interpretations if both a deficiency and an excess of a nutrient result in similar or identical symptoms. Examples are found for the nutrients vitamin B-6 and iodine. In the case of vitamin B-6, both deficiency and excess can result in peripheral neuropathies, whereas in the case of iodine, both a deficiency and an excess of iodine result in goiter (22).
In a study conducted in conjunction with the planning phase of the third NHANES (NHANES III), an expert panel could fully recommend the analysis of survey participants for only 4 nutrients for which biomarkers had been identified to assess the harmful effects of excess intake. The expert panel also indicated that biomarkers for 2 additional nutrients might provide questionable results (23). Part of the problem is that the ways of measuring the levels of biomarkers in humans need to be noninvasive, or at least minimally invasive, for use in population surveys such as NHANES. Granted, that report is now nearly 20 y old, but a recent search of the scientific literature revealed that progress on the identification of biomarkers for excess nutrient intakes remains poor despite a continued emphasis on the need for such markers (E. A. Yetley, Food and Drug Administration, personal communication, 2003).
Another major gap in the information needed to establish ULs is the availability of long-term nutrient exposure data. Thus, the accurate collection of food consumption data and the nutrient contents of the foods is vitally important. Other investigators have addressed these subjects in this supplement, and so this topic is not discussed here. Furthermore, it is necessary that the length of exposure be sufficiently long to ensure that the biomarker levels do not change with time. Finally, it is critical that both nutrient intakes and the health effects of those intakes be measured as accurately as possible for the same individuals to establish a reliable UL.
To illustrate these issues, recent data on folic acid is selected as an example. During the last decade the amount of folic acid added to the food supply has increased substantially. This increase was due to the requirement that folic acid be added to all fortified cereal products subject to standards of identity (24). The requirement was established as a public health measure to lower the number children born with neural tube defects (NTDs), which are serious birth defects that can result in infant mortality or serious disability. Research on the occurrence of NTDs provided strong evidence that women who consume additional folic acid before and during the beginning of pregnancy had a lower risk of delivering a child with NTDs (25,26). Researchers generally agreed that the level of folic acid in the food supply was adequate to meet the recognized nutritional needs of the population, and therefore, the additional folic acid performed a non-nutritional function. Furthermore, general evidence indicated that a level of folic acid intake that is too high could have an effect on individuals with vitamin B-12 deficiency and result in the masking of megaloblastic anemia. If the deficiency is permitted to persist, the result could be permanent peripheral neuropathies (25). Therefore a careful balance was necessary in the selection of suitable carrier foods to which the folic acid could be added. These carrier foods had to be consumed by the target population, and the added folic acid needed to remain stable during the processing and storage of the carrier foods. After extensive investigation of potential carrier foods, it was decided to establish a requirement that folic acid be added to all fortified cereal products for which a standard of identity exists. The term standard of identity refers to the regulated status of a food that is labeled with a name for which specific compositional requirements have been established by regulation under provisions of the Food Drug and Cosmetic Act.
The first task was to determine the level of dietary folic acid needed for women of childbearing age. The research was not sufficient to provide a precise level, so the United States Public Health Service recommended a level of 400 µg/d as the desired minimum (26). On the basis of the evidence in the scientific literature and expert opinion, 1 mg of folic acid/d was selected as the safe upper level. The next task was to determine the level of folic acid to be added to standardized cereal products to achieve the desired level of intake by women of childbearing age but that did not result in levels of intake that exceed 1 mg for other segments of the population (25).
The database for the United States Department of Agriculture's 1987–1988 Nationwide Food Consumption Survey was used to obtain the distribution of food intakes for population segments and to establish a special database on the folic acid compositions of foods. In addition, general information on the use of dietary supplements was used to assess the contributions of folic acid from those sources. These data were used to calculate the distributions of folic acid intakes by age and gender. After extensive calculations were performed for various potential levels of folic acid addition, the analysis concluded that the addition of folic acid to cereals at a level of 140 µg/100 g of cereal grain products was the best fortification option (25). The analysis also showed that that level provided the greatest increase for women of childbearing age without significantly raising the risk of exceeding the established upper level for other segments of the population.
It was realized that with the inherent degree of uncertainty associated with the data in the databases used to make estimates of intake by population segments and the variability of individuals within those segments that some individuals would likely consume folic acid at levels greater than the upper level. The question of whether some of these individuals will develop peripheral neuropathies because of marginal vitamin B-12 status remains. The impact of this fortification measure could be fully assessed only after the measure was implemented.
The level of 140 µg/100 g of cereal was adopted in a proposed regulation for public comment and was established in a final rule after all comments submitted in response to the proposal were considered (24). For the most part, industry implementation of the regulation was prompt, and assessment of the impact of increased folic acid fortification on the folate status of the population is under way. The National Center for Health Statistics (NCHS) began collecting data on serum folate levels as part of NHANES IV. Preliminary data collected during 1999 and 2000 provide an opportunity to observe the changes in serum folate levels from those determined in NHANES III. Figures 1 and 2, prepared by NCHS (C. L. Johnson, NCHS, personal communication, 2003), demonstrate the dramatic changes in serum and erythrocyte folate levels that have been attributed mostly to the addition of folic acid to cereal products. Further analysis of data from NHANES IV should provide an opportunity to compare folic acid intake and serum and erythrocyte folate levels for individuals in different age groups. Because the number of individuals with marginal vitamin B-12 stores is small, it is unlikely that an association between high levels of folic acid intake and an increase in peripheral neuropathiess will be found among the NHANES IV population. However, the data from NHANES IV should provide an indication of the numbers of individuals with levels of intake that exceed 1 mg/d. That information, together with any rise or lack of a rise in the incidence of peripheral neuropathies in the general population, could be used to justify more in-depth studies in future surveys.
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For some nutrients the body stores are affected to a significant degree by the level of intake of the nutrient over the individual's lifetime. These nutrients are typically absorbed from the diet at low levels and have low levels of turnover in the body. Among these are calcium, phosphorus, iron, and copper. Both deficiencies and excesses in body stores change slowly according to the changes in the levels of these compounds in the human diet. Likewise, the impact of the nutritional status for these nutrients on long-term health is often influenced by lifetime exposure. Iron is used here as an example of the impact of lifetime exposure.
The iron needs of humans have been studied perhaps more than any other nutrient (27). There is widespread evidence that more people in the world suffer from iron deficiency than from a deficiency of any other nutrient (28). Over the last 50 y cereal products produced in the United States have been iron fortified, and the levels have been adjusted several times. Nevertheless, data from the NHANES surveys indicate that small numbers of individuals remain iron deficient, and these mostly comprise women of childbearing age and young children (29,30).
Iron deficiency can result in a decreased capacity for energy metabolism and work performance, altered body temperature regulation, and compromised immune function (31,32). Infants and young children with iron deficiency are at risk of impaired development of psychomotor skills and other cognitive functions (33). Some evidence even indicates that iron deficiency during pregnancy not only affects the mother's health but also may result in premature birth and low birth weight of the child (34).
For many years common wisdom maintained that the absorption of iron from the gastrointestinal tract is tightly regulated by the iron status of the individual. It now appears that the regulation of absorption is only partially effective in addressing iron deficiency. The form of iron in the diet, the levels of other nutrients in the diet, and the consumption of other substances can influence the level of iron absorption. For example, heme iron is better absorbed than nonheme iron (9). Vitamin C is known to enhance the absorption of iron, whereas calcium and phytate can lower the level of iron absorption (35). With the desire to eliminate iron deficiency in the United States, the recommended amount of iron fortification was revised upwards several times during the 1950s and 1960s.
At the same time a growing body of evidence indicates that some individuals, mostly adult men and postmenopausal women, may be consuming too much iron (36). Investigators have hypothesized that lifetime exposure to excess iron can result in increased risks of ischemic heart disease and cancer (37,38). The essence of these hypotheses is that the consumption of iron in amounts that exceed the capacity of iron storage proteins is a potent catalyst in free-radical reactions, such as lipid peroxidation, and that these free radicals can cause tissue damage (39,40). These hypotheses maintain that the control of iron absorption is not without limits and that very high levels of bioavailable iron can result in iron absorption in amounts exceeding the capacity of storage proteins, such as ferritin. Individuals who have an autosomal recessive disorder, commonly called hereditary hemochromatosis, absorb excessive amounts of iron from ordinary diets. The excess iron exceeds the storage capacity of reticuloendothelial cells and accumulates in the parenchymal cells in tissues. Typically, this process continues over years before the manifestation of disease symptoms occur (at ages 40–60 y in men and usually after menopause in women). Among the diseases associated with the disorder are liver cirrhosis, liver cancer, heart failure, pancreatic disease, and diabetes (41). The observations made for individuals with this disorder are unique and cannot be used to infer a risk for the general population, if for no other reason than the fact that individuals with hereditary hemochromatosis lack the ability to control iron absorption or have a higher set point for its control. It is clear, however, that extensive tissue and organ damage can occur if iron overload remains undetected and untreated.
It must be pointed out that the studies performed to date do not provide support for the hypotheses that individuals in the general healthy population are at greater risk for the development of heart disease or cancer as a result of high dietary iron intakes (39). However, data from NHANES III indicate that both elderly men and elderly women have serum ferritin levels higher than those detected in NHANES II. Early indications from NHANES IV (1999–2000) indicate that the rise in serum ferritin levels appears to be leveling off and has not changed from the levels detected in NHANES III, but the sample size for NHANES IV may be too small to determine this with certainty (A. C. Looker, NCHS, personal communication, 2003). The data are also difficult to evaluate because the methods used in NHANES II are different from those used in NHANES III and IV. However, it would not be totally unexpected if an increase in ferritin levels were detected among the current elderly population, because this is the first group to have received iron-fortified foods as part of their diets for most of their lifetimes. The knowledge gap that needs to be filled is determining whether the safe iron storage capacity of the tissues of any of the individuals in this population has been exceeded and, therefore, whether they are at increased risk for increased free-radical production.
Important knowledge gaps also exist about the nutrient stores in the body that cannot be measured by minimally invasive procedures. For example, the primary storage site for copper in the human body is the liver (42). Studies with animals demonstrate that serum copper levels and the activities of copper-containing enzymes are the last to change when copper stores are depleted (43). Consequently, the effects of chronic high levels of intake of the nutrients molybdenum and zinc may take months to have a measurable effect on blood copper levels in animals, whereas measurement of the levels in the liver will show a continuous decline. Alternatively, the impact of such nutrient interactions may be measured in the stores of nutrients in the livers of offspring. Therefore, biomarkers that can be measured by minimally invasive procedures need to be developed so that the amounts of nutrients stored in inaccessible body tissues can be assessed.
Minimizing the effects of nutrient–nutrient interactions
Extensive research demonstrates the existence of nutrient–nutrient interactions in both humans and animals. A major gap in knowledge, however, involves the ability to compensate for these interactions by adjusting the levels of all nutrients adversely affected. This knowledge is particularly important when a public health benefit can be derived by increasing the amount of a nutrient in the diet above the nutritional requirement, as is the case for the use of additional folic acid in cereals to reduce the incidence of NTDs in infants. If some individuals are being placed at risk for increased vitamin B-12 deficiency by increasing folic acid levels, could the risk be lowered by increasing the level of vitamin B-12 at the same time? Similarly, could the risk associated with high levels of dietary zinc be lowered by increasing the level of copper in the diet? More research is needed to answer these questions.
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FOOTNOTES |
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2 Author Disclosure: No relationships to disclose.
4 Abbreviations used: NHANES; national health and nutrition examination survey; NTD; neural tube defects; UL, tolerable upper intake level.
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LITERATURE CITED |
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