The use of dietary or nutritional supplements in the United States is extensive and noticeably increasing (Miller, 1987b). People supplement their diets for several reasons, including uncertainty about the nutrient adequacy of their diets, a desire for a more positive standard of health than they perceive to be obtainable from medical consultation, and decisions to treat themselves for an illness. The use of dietary supplements is probably fostered by their wide availability, aggressive marketing, and media reports on studies suggesting that supplements may help to prevent or treat common health problems (Gussow and Thomas, 1986; McDonald, 1986).
Sales of dietary supplements increased sixfold in 15 yearsfrom $500 million in 1972 (Anonymous, 1981) to $3 billion in 1987 (Dickinson, 1987). Industry data show the market share for various supplements in 1986 as follows: multivitamins, 37%; vitamin C, 13%; calcium, 12%; B complex, 10%; and vitamin E, 9% (Dickinson, 1987). Guthrie (1986) calculated that Americans who supplement their diets spend an average of $32 per person annually, whereas for less than $10 per year, consumers can purchase a one-a-day multiple vitamin/mineral product that supplies approximately 100% of the Recommended Dietary Allowances (RDAs) for most nutrients.
In the U.S. population, dietary supplement use varies widely according to age, lifestyle, socioeconomic status, geographic location, and other characteristics. Variation in survey-based estimates of supplement use can be attributed to the population sampled; the season of the year the survey is conducted; definition of the term dietary supplement (e.g., in some studies only vitamin- and mineral-containing products are defined as supplements, but in others, products such as bee pollen, lecithin, and alfalfa tablets are included); and definition of the frequency of supplement use (e.g., daily use versus irregular use) (Kurinij et al., 1986; Looker et al., 1987; McDonald, 1986; Stewart et al., 1985). The use of dietary supplements among adults, children, the elderly, and health professionals is described in the following four sections.
Use of Dietary Supplements
The most current data on dietary supplement use in the United States have been collected by the U.S. Department of Agriculture (USDA) in the Continuing Survey of Food Intakes by Individuals (CSFII)a component of its Nationwide Food Consumption Survey (NFCS). In 1985, 45% of the men 19 to 50 years of age reported taking a dietary supplement either regularly or occasionallyup from 26% in 1977 (USDA, 1986). In 1986, 55% of the women 19 to 50 years of age took
supplements regularly or occasionallyup from 39% in 1977 (USDA, 1987b). Of the survey's low-income women 19 to 50 years of age, 45% took supplements during 1986 (USDA, 1987a).
The most comprehensive survey of dietary supplement use in the United States was conducted by the Food and Drug Administration (FDA) in 1980 through telephone interviews with 2,991 representative Americans over 15 years of age (Stewart et al., 1985). The FDA found that 35.9% of the men and 43.8% of the nonpregnant, nonlactating women consumed supplements daily. The supplement users were grouped into four categories: light users (who on average consumed the equivalent of 70% of the RDA for each nutrient), moderate users (168% of the RDA), heavy users (400% of the RDA), and very heavy users (777% of the RDA) (Levy and Schucker, 1987). The majority of the users took only one nutrient or combination product, although 10.9% of the sample consumed from 5 to 14 separate products (Stewart et al., 1985). Dietary supplement use was most prevalent in the western United States and among Caucasian people with relatively high incomes and at least a high school education.
The FDA investigators also noted that specialized vitamin and mineral preparations were most commonly taken by the heavy and very heavy users (28% and 14% of all users, respectively). The light and moderate users (42% and 16% of all users, respectively) favored the broad-spectrum, multinutrient products (Levy and Schucker, 1987). Compared to light and moderate users of dietary supplements, heavy and very heavy users were more likely to shop in health food stores, buy supplements through the mail, read specialized health literature, believe they had personal control over their health, engage in daily exercise, avoid involving their physicians in their decisions about supplements, and perceive specific rather than general health benefits from their supplements. The FDA investigators described the light and moderate users as people who consume supplements as insurance against dietary deficiencies. They described heavy and very heavy users as those who take supplements as part of an active effort to achieve better health.
Fairly high rates of dietary supplement use were also found in earlier national surveys conducted for the FDA. In 1969, 27% of the adults surveyed had taken a supplement on the day of the interview, and 57% of the sample said they had taken supplements at some time (National Analysts, Inc., 1972). Subjects most commonly took supplements to improve health, to obtain ''more pep and energy," to prevent colds, to reduce their risk of becoming ill, and to remain healthy while dieting. In 54% of the households contacted in 1973, at least one family member took supplements. The most frequent user was the homemaker (usually female), followed by the spouse and preteen child (FDA, 1974). In a similar study conducted in 1975, 47% of the households contained at least one member who took supplements. Again, the most frequent user was the female homemaker (FDA, 1976). The extent of dietary supplement use in the United States during the late 1970s was determined by Koplan et al. (1986), who evaluated data from the National Health and Nutrition Examination Survey (NHANES II). They found that 21.4% of adults in the United States took supplements daily and that another 13.5% took them at least once a week. Higher rates of supplement use were associated with women, whites, older age (ages 51 to 74 compared to ages 18 to 50), higher incomes, higher educational levels, and higher nutrient intakes from food.
Schutz et al. (1982) found that 67% of 2,451 randomly selected adults surveyed in seven western states took supplements over a 2-year period. Multiple vitamins with or without iron, vitamins C and E,. and the B complex vitamins were most commonly taken. The most frequently given reasons for taking supplements, selected from a list provided by the investigators, were "to prevent colds and other illnesses," "to give me energy," and "to make up for what is not in food." Factors found to be significantly associated with supplement use included age (higher use at younger ages), education (greater use at higher educational levels), sex (women were heavier users), and the perception that the nutritional quality of food had decreased over the past decade. When a subsample of 689 people was questioned further, 59% of the users reported that their supplements were of "some benefit" to their health, and another 34% found them to be of "great benefit" (Read et al., 1985). In a study of a subsample of 1,673 people, differences were found between those who took multivitamins/minerals and those who took individual supplements of either vitamins A, C, or E in the importance placed on the need for supplementation and where nutrition information was obtained (Read et al., 1987). Users of one of these nutrients were significantly more likely than users of multivitamins/minerals to have a lower opinion of today's food quality, to classify their diets as being either poor or very poor, to believe in the
value of unproven uses of nutrients as therapeutic agents, to rely on health food stores for nutrition information, and to feel that they would experience serious health problems if they were forced to discontinue their use of supplements.
Investigators have frequently studied or surveyed dietary supplement use among various population subgroups and small samples of adults (see, for example, Bootman and Wertheimer, 1980; Bowerman and Harrill, 1983; English and Carl, 1981; Read and Thomas, 1983; Rhee and Stubbs, 1976; Saegert and Saegert, 1976). The evidence accumulated over the past 20 years from these studies, as well as those mentioned above, conclusively demonstrates that dietary supplement use is popular in the United States. Today it is entirely possible that the majority of adults in the United States supplement their diets at least occasionally with extra vitamins and minerals.
The elderly might be expected to take dietary supplements in an attempt to prevent or cure chronic disease, to treat the symptoms of aging, or to prolong life. In fact, studies conducted more than 20 years ago indicate that between one-fourth and one-half of the elderly consumed supplements (Davidson et al., 1962; Le Bovit, 1965; Steinkamp et al., 1965).
In a more recent study, Hale et al. (1982) reported that among 3,192 ambulatory elderly participants, more than 46% of the women and 34% of the men took supplements. All were at least 65 years of age and enrolled in a health screening program. The participants typically consumed multivitamins or minerals, usually daily, as well as vitamins E and C. The users gave the following reasons for taking vitamin C (from most to least frequent): to treat deficiency states, to prevent coughs and colds, and to treat ophthalmic disorders, urinary tract infections, and rheumatic conditions. They used vitamin E primarily to treat or prevent deficiency states and leg cramps and as a vasodilator. In a study of 11,888 residents of a southern California retirement community, 62% of the men and 69% of the women were found to consume supplemental vitamins and minerals (Gray et al., 1986).
One of the most recent studies on dietary supplement use in the elderly involved 236 upper-class people from a retirement community in rural Maryland (Sobal et al., 1986). Fifty-three percent reported that they had taken supplements within the past 6 months, usually on a daily basis. A single multivitamin pill was usually consumed, but products containing vitamin C, potassium, calcium, B complex, vitamin E, and iron were popular as well. Participants most commonly justified their supplement use to combat tiredness (44% of users), to ensure good nutrition (30%), to increase energy (28%), and as treatment for illness (22%). Physicians were said to be most influential in the subjects' decision to consume these products. The investigators reported that the frequency and duration of supplement use was not significantly related to age, sex, level of education, reported health status, or frequency of worrying about health.
The studies described above as well as several others (see, for example, Garry et al., 1982; Gray et al., 1983; Kellett et al., 1984; McGandy et al., 1986; Ranno et al., 1988; Read and Graney, 1982; Yearick et al., 1980) over the past several decades demonstrate that many elderly people in the United States consume dietary supplements. In addition, the data indicate, as might be expected, that the elderly often take supplements to feel better and to treat the illnesses that afflict them as they age.
There is relatively little information on dietary supplement use by children. The most current data on supplement use among U.S. children I to 5 years of age comes from USDA's CSFII. The proportion of children taking supplements in 1985 and 1986 was 60 and 59%, respectively, up from 47% in 1977 (USDA, 1987b). Forty-four percent of the children from low-income families receiving food stamps were reported to take supplements in 1986; 47% of the children in similar families not receiving food stamps also took supplements (USDA, 1987a).
Two surveys provide data on the extent of dietary supplement use among children of all ages. Bowering and Clancy (1986) examined data from NHANES II and found that dietary supplement use among children decreased with agefrom 39% for 2-year-olds to slightly more than 10% for teenagers. No sex differences in supplement use were noted until the age of 13, when usage by boys plateaued at about 10% but began to increase among girls. Children were more likely to receive supplements if the head of the household was white and better educated. Also in NHANES II, supplements, generally multivitamins, were found
to be commonly consumed daily from the ages of 1 to 10; from 11 to 19 years, supplement use was more likely to be irregular (Looker et al., 1987). Kovar (1985) reported that approximately 36% of more than 15,000 children under 18 years of age who had participated in the National Health Interview Survey in 1981 took supplements during the 2 weeks before the interview. Supplement use was most common among children under 7 years of age.
In a more limited study, Farris et al. (1985) examined supplement use among 10- and 13-year-old children randomly selected from the biracial community of Bogalusa, Louisiana, between 1973 and 1977. Sixteen to 18% of the 10-year-olds and 12% of the 13-year-olds were found to consume supplements daily, typically multivitamins with or without iron. There were no race or sex differences in supplement use. Similarly, Sharpe and Smith (1985) reported supplement use to be 11% among the 1,616 children in northern Mississippi households that participated in the Aid to Families with Dependent Children program administered by the U.S. Department of Health and Human Services.
Thomsen et al. (1987), in their 1985 survey of 163 adolescents from rural-based Iowa high schools, provided data on the reasons for dietary supplement use among that group. The 86 subjects who took supplements most commonly agreed with the following statements for their use: "they made me healthy"; "my doctor tells me to take them"; and "they help give me energy." Fifty-six percent of the sample agreed that ''most teenagers need vitamin and mineral supplements."
In summary, dietary supplement use among children is not as extensive as it is among adults. Studies suggest that supplement use is highest at early ages, and then steadily declines until adolescence, when it may increase. Since most studies of supplement use focus on adults and the elderly, less information is available regarding the types of supplements children take, the nutrient doses involved, and the rationale for their use.
Several studies suggest that supplement use is common among health professionalsa group likely to argue that nutrient needs can and should be met from foods. Worthington-Roberts and Breskin (1984) discovered that nearly 60% of the 665 Washington State dietitians who responded to a mail questionnaire admitted that they regularly took supplementsusually multivitamins/minerals, vitamin C, and ironfor personal health. The investigators hypothesized that these dietitians took supplements to ensure an adequate intake of nutrients in light of their occasional dietary indiscretions and calorie restrictions to regulate weight.
Willett et al. (1981) found that 38% of 1,742 registered nurses surveyed in 10 states consumed multiple vitamins, 23% took vitamin C, 15% took vitamin E, and 4% took vitamin A. The use of supplements of vitamins A, C, and E increased progressively with age. Use of any of the four supplements was strongly associated with use of the other three.
Several surveys demonstrate that supplement use among physicians and medical students is not infrequent. Nine out of 36 family practice residents surveyed in one study said they "usually" supplemented their diets (Pally et al., 1984). In another, 14% of 595 faculty members from Harvard Medical School admitted to taking multivitamins daily. In addition, 14% said they took extra vitamin C to protect against colds (Goldfinger, 1982). Among new medical students at the University of Maryland School of Medicine, more than 60% said they "regularly," "usually," or "sometimes" took dietary supplements (Sobal and Muncie, 1985).
Several studies indicate that physicians exert the most influence on the public (their patients) in making decisions to take supplements (Kellett et al., 1984; National Analysts, Inc., 1972; Pally et al., 1984; Read and Graney, 1982; Sobal et al., 1986, 1987; Yearick et al., 1980). A 1983 survey revealed that 27% of 1,419 primary care physicians (representing family/general practice, internal medicine, and obstetrics/gynecology) in Maryland believed that supplementation was either "very" or "somewhat" important in contrast to 97% who believed that a balanced diet was important (Sobal et al., 1987). Dietary supplementation was considered important primarily among obstetricians/gynecologists, female physicians, and those who said they were more likely to take continuing medical education courses in nutrition.
One study suggests that physicians need to become more knowledgeable about the appropriate use of supplements. After reviewing the medical charts of 433 elderly patients admitted to several health-care facilities in New York State, Sorensen et al. (1979) concluded that physicians prescribed specific vitamins and minerals for 43 patients in the absence of a diagnosis of deficiency. For five patients, however, vitamin and mineral supplements were not prescribed even though the medical diagnosis indicated that they should have been.
Pharmacists may also be involved in the inappropriate promotion of supplements. Consumer Reports magazine reported that of 30 pharmacists visited in three states by reporters who pretended to suffer from fatigue, tension, or nervousness, 17 of them recommended vitamin supplements and one recommended an amino acid preparation (Anonymous, 1986).
Nutrient Adequacy and Supplement Use
The above review of survey data and other studies indicate that dietary supplementation is usually related to subjective perceptions of health, well-being, and balanced diets and to beliefs about food, vitamins, and minerals (Worsley, 1986). But by more objective measures, are supplements being used appropriately? The effect of supplementation on nutritional status has occasionally been compared among users and nonusers by measuring dietary intake and biological indices. In general, the studies show little correlation between nutrient needs and nutrient supplementation (Guthrie, 1986).
Bowerman and Harrill (1983) analyzed the 3-day dietary records of 150 adults living in Colorado and found no major differences in mean dietary intake among users and nonusers. Dietary intakes of protein, phosphorus, vitamin A, riboflavin, niacin, and vitamin C were above RDA levels for men as well as women. Women 19 to 50 years of age, however, consumed less than two-thirds of the RDA for both iron and zinc. In an analysis of NHANES I data obtained from 3,227 nonpregnant women 15 to 41 years of age, Kurinij et al. (1986) found that dietary supplement users consumed more nutrient-dense diets than did nonusers. Although intakes of calcium, iron, and vitamins A and C were less than 50% of the RDA for many subjects in both groups, a greater proportion of nonusers had low intakes of these four nutrients. Using data on adults from NHANES II, Looker et al. (1988) failed to find an association between daily use of dietary supplements (which in most cases contained iron) and either improved iron status or a lower prevalence of impaired iron status. In addition, daily supplement users were found to consume more vitamin C from foods and to eat more fruits and vegetables compared to nonusers. Read and Thomas (1983) discovered that 41 of 49 adult lacto-ovovegetarians ingested dietary supplements, but an analysis of their diets revealed that with the exception of iron (especially for females less than 51 years of age), they all met or surpassed the established RDAs for nine nutrients from food alone.
Several studies of elderly populations indicated that dietary supplement users consumed more nutrients from food than did nonusers (Garry et al., 1982; McGandy et al., 1986). In one study of 51 elderly people, dietary supplement use was found to be unrelated to dietary intake (Gray et al., 1983). Several studies show, however, that the diets of many elderly people fail to meet the RDAs for several nutrientsincluding calcium, zinc, vitamins B6, B12, D, E, and folate (Garry et al., 1982; McGandy et al., 1986). Yearick et al. (1980) reported that the majority of people they surveyed consumed diets low in calcium, vitamin A, thiamin, and iron and did not take supplements of these nutrients. Kirsch and Bidlack (1987) noted that many elderly people are at risk of nutrient deficiencies for reasons that include physiological decline, poor economic status, inadequate food intake, disease processes, and medical treatments. In addition, Ranno et al. (1988) found that the use or nonuse of supplements by 60 elderly volunteers was unrelated to the perceived adequacy of their diets.
Using data from NHANES II for children from 1 to 19 years of age, Bowering and Clancy (1986) and Looker et al. (1987) found no differences in iron status indicators (e.g., hemoglobin, transferrin saturation, serum ferritin) between dietary supplement users and nonusers. In addition, both sets of investigators found that supplement users consumed more vitamin C from food. Looker and colleagues also noted that the users consumed more fruits and vegetables. Breskin et al. (1985) studied the dietary intakes and related biochemical indices of several B vitamins and vitamin C among 30 children aged 3 1/3 to 9 years and found that mean intakes of most of these nutrients from food alone met the subjects' needs. Furthermore, there were no major differences in the nutrient content of the diets of supplement users and nonusers. Since no nutrient deficiencies in either group were evident from the biochemical measures, the investigators concluded that improvements in biochemical indices resulting from supplement use were only relative and did not suggest that
supplements were beneficial. Sharpe and Smith (1985) reported that low-income children in Mississippi who took supplements usually used preparations lacking in ironone of the nutrients most likely to be poorly supplied in their diets.
Evidence Associating Dietary Supplements with Chronic Diseases
Supplements are often taken in high doses with the aim of preventing or treating various health problems or promoting longevity. However, there are relatively few controlled studies concerning the effects of dietary supplements on the risk of specific chronic diseases. Therefore, very little is known about the health effects of chronic use of high-potency dietary supplements (Miller, 1987b). In one prospective study of 479 elderly people, investigators found no clear reduction in mortality from the use of dietary supplements over a 6-year period (Enstrom and Pauling, 1982). Similarly, no association was noted between the use of vitamin C supplements and subsequent mortality among 3,119 adults in California followed for 10 years (Enstrom et al., 1986).
In one case-comparison study, low doses of vitamin A supplements were found to be associated with a lowered risk of cancer (Smith and Jick, 1978). Gregor et al. (1980) reported an inverse association between vitamin A intake and lung cancer risk primarily due to the intake of liver (which is high in vitamin A) and vitamin A preparations. Another study has shown that dietary supplementation with both retinol and b-carotene reversed micronucleus formation (a marker for cellular genetic damage) in buccal mucosal cells among Filipino chewers of betel nut and tobacco (Stitch et al., 1984). As discussed in Chapter 11, however, the weight of the evidence does not show that vitamin A from foods or supplements has a protective effect against cancer (La Vecchia et al., 1988; Samet et al., 1985; Shekelle et al., 1981; Ziegler et al., 1984). However, several studies have shown an inverse relationship between the consumption of fruits and vegetables rich in b-carotene and a reduced risk of cancer at various sites. Several prospective studies are in progress to determine whether supplements of b-carotene (with and without other nutrients) have the same protective effect, but results are not expected before 1990 (DHHS, 1988; Greenwald, 1988).
Lipkin and Newmark (1985) conducted a pilot study of the effect of calcium supplements on proliferation of colonic cells in patients considered to be at increased risk for colon cancer. They reported that the administration of 1.2 g/day of calcium led to the reduction of colonic crypt labeling with tritiated thymidine, in vitro, that approximated the pattern seen in a low-risk control population.
Zinc intake from food and supplements was assessed in one case-control study of cancer. Kolonel et al. (1988) found that patients with prostate cancer who were 70 years old and older ingested more zinc (from supplements, but not from food) than did matched population controls prior to the onset of cancer.
Cameron and Pauling (1976, 1978) reported that 100 patients with terminal cancer at various sites who were given vitamin C at 10 g/day had a mean survival time more than 4.1 times greater than that of a group of matched controls who did not receive the vitamin. None of the patients in these studies had received chemotherapy. In two subsequent controlled studies, investigators failed to find differences in survival time among 127 patients with advanced cancer at various sites (Creagan et al., 1979) and 100 patients with advanced colorectal cancer who had not received chemotherapy (Moertel et al., 1985) and who were randomly assigned to treatment with either 10 g of vitamin C per day or a placebo. Because the focus of this report is the prevention of chronic diseases rather than their treatment, the committee has not included the literature on nutritional supplements as therapy for cancer or other diseases.
Coronary Heart Disease
An initial report (Vogelsang and Shute, 1946) of dramatic improvement in angina pectoris patients taking large doses of vitamin E was not confirmed in four placebo-controlled clinical trials (Anderson and Reid, 1974; Donegan et al., 1949; Makinson et al., 1948; Rinzler et al., 1950) and two double-blind trials (Anderson and Reid, 1974; Rinzler et al., 1950). Preliminary reports that vitamin E
might raise the concentration of HDL cholesterol (Barboriak et al., 1982; Hermann et al., 1979) were not confirmed in a randomized, double-blind, placebo-controlled study (Stampfer et al., 1983).
Spittle (1972) found that in healthy people under 25 years of age, cholesterol levels tended to fall with the addition of 1 g of vitamin C to their normal diets. Placebo-controlled studies, however, fail to show that vitamin C supplements lower serum cholesterol levels (Aro et al., 1988). For example, in a double-blind crossover study with 26 elderly female subjects, vitamin C in amounts as high as 2 g/day had no effect on serum cholesterol levels as compared to a placebo (Aro et al., 1988).
Most intervention studies in which calcium supplements were used demonstrate a mild short-term reduction in blood pressure in certain normotensive and hypertensive subjects (Belizan et al., 1983; Grobbee and Hofman, 1986; McCarron and Morris, 1985; Resnick et al., 1984; Singer et al., 1985). However, in some patients with hypertension and increased concentrations of plasma renin, blood pressure may actually rise in response to calcium supplementation (Resnick et al., 1984).
Supplementation of the diet of 12 adult men with more than 10 times the RDA of zinc in the presence of normal levels of copper for 5 weeks led to a significant decrease in HDL cholesterol but no change in total cholesterol (Hooper et al., 1980). Other studies have confirmed that zinc supplements suppress HDL levels (Chandra, 1984; Goodwin et al., 1985).
The evidence is contradictory as to whether chromium supplementation affects blood lipoproteins in a favorable manner. As the trivalent ion in chromium chloride or glucose tolerance factor (GTF), chromium lowered serum total cholesterol and raised the HDL fraction in healthy participants in supplementation trials (Anderson, 1986; Riales and Albrink, 1981; Simonoff, 1984). Other trials have not shown an effect from chromium supplementation on serum lipoprotein levels (Anderson et al., 1983; Rabinowitz et al., 1983; Uusitupa et al., 1983).
It is not known whether calcium supplements, commonly consumed by women in the United States, are useful in the prevention and treatment of osteoporosis. The results of short-term investigations (2 years or less) are mixed. In general, they show a slowing of cortical but not trabecular bone loss. All studies in which estrogen treatment was also used show that calcium supplementation is inferior to estrogen in slowing cortical bone loss and that estrogen completely prevents trabecular bone loss (Cann et al., 1980; Ettinger et al., 1987; Horsman et al., 1977; Lamke et al., 1978; Nilas et al., 1984; Recker and Heaney, 1985; Recker et al., 1977; Riis et al., 1987; Smith et al., 1981). (See Chapter 13 for further details.) The evidence relating calcium supplementation to fracture prevalence is scanty. The only relevant study was a nonrandomized, prospective assessment of the effect of various treatments on the occurrence of future vertebral fractures in patients with generalized osteopenia (Riggs et al., 1982). Eighteen women receiving calcium carbonate (1,500-2,500 mg/day) and 19 patients given a combination of calcium plus vitamin D (50,000 units once or twice a week) had 50% fewer vertebral fractures than did 18 untreated women and 27 patients given a placebo (p <.001). This decrease in fracture rate is impressive and suggests that a long-term, randomized, blind study of fracture rates among placebo- and calcium-treated postmenopausal and elderly women might provide information crucial to the formulation of recommendations for calcium intakes in the elderly.
Vitamin C is widely purported to help prevent or treat the common cold, as originally hypothesized by Linus Pauling (1986). However, the several studies conducted to test this hypothesis generally indicate that vitamin C taken even in gram quantities does not prevent colds and at best only reduces the frequency and severity of symptoms in cold sufferers (Anderson et al., 1972, 1974; Coulehan et al., 1974; Karlowski et al., 1975).
Excess vitamin and mineral consumption is associated with numerous acute adverse health effects. Most reported vitamin intoxications have resulted from the consumption of supplements, not
foods, although one notable exception is vitamin A poisoning among Arctic explorers who consumed polar bear liver (Greger, 1987; McLaren, 1984). There are laboratory animal data on the toxicity of single vitamins and minerals and clinical data on adverse health effects from high intakes of nutrients by individuals. Most of the data pertain to acute rather than chronic use.
Many case reports of human injury presumed to result from vitamin and mineral overdoses lack data on the actual dosages of nutrients consumed, formulation of the supplements, and periods of exposure. In addition, those reports rarely relate intake of the supplement to the levels of nutrients in a person's diet. It is difficult to determine the levels at which nutrient toxicities are likely to occur. Size, age, genetic disposition, and overall health, as well as the duration of supplementation and the quantity and form of nutrients consumed, greatly affect responses to nutrient overconsumption (Greger, 1987).
There are several comprehensive reviews of nutrient toxicity (see, e.g., Campbell et al., 1980; Rechcigl, 1978). The following paragraphs summarize some of the potential adverse health effects of excessive supplementation.
Toxicity has been observed in people who have either chronically or acutely consumed more than 10 times the RDA. Acute hypervitaminosis A occurs following a single massive dose of retinol (e.g., from ingestion of polar bear or seal liver). Chronic hypervitaminosis A results from continued ingestion of high doses (e.g., supplements). Symptoms of hypervitaminosis A include dryness of the skin, headache, anorexia, weakness, hair loss, joint pain, vomiting, irritability, enlarged liver and spleen, and in babies, a bulging fontanelle and increased intracranial pressure (Olson, 1988). The clinical manifestations and the published literature on hypervitaminosis A have been reviewed in detail by Bauernfeind (1980) and Kamm et al. (1984). Hypervitaminosis A has not been reported to be a public health problem in any population. Vitamin A toxicity is unlikely to occur from food, unless very large amounts of liver are ingested. However, the widespread availability of vitamin A preparations in very large doses, publicity about the use of vitamin A in treating acne and preventing cancer, and the increasing prevalence of food supplementation are causes for concern that hypervitaminosis A may become more common (Goodman, 1984). Uses of vitamin A supplements that exceed the RDA pose a potential for toxicity.
Of special note, consumption of excessive amounts of vitamin A during early pregnancy is potentially teratogenic. A related retinoid, 13-cis-retinoic acid, is a known teratogen (Costas et al., 1987). Yet, according to a study by the New York State Department of Health, 16 of 492 women who delivered live-born infants without birth defects over an 11-month period took supplements containing high doses of vitamin A during their pregnancy. Three of the 16 took 25,000 IU or more per day; the other 13 took from 15,000 to 24,999 IU/day. The Centers for Disease Control consider this finding to be of public health concern (Costas et al., 1987).
In 1983, Schaumburg and colleagues reported on seven people who developed ataxia and sensory neuropathy after taking 2 to 6 g of pyridoxine daily for 2 to 40 months. When the supplement was discontinued, all patients noted an improvement in their neurological disability and gait and suffered less discomfort in their extremities. Subsequently, Berger and Schaumburg (1984) observed sensory neuropathy and symptoms resembling multiple sclerosis in a patient taking as little as 500 mg of pyridoxine daily for several years. Even smaller doses may cause problems. Pyridoxine toxicity was the apparent cause of neurological symptoms (including paraesthesia, bone pain, muscle weakness, and numbness) among 103 women attending a private clinic who were given supplements of this nutrient to treat premenstrual syndrome, depression, and other disorders (Dalton and Dalton, 1987). The women took an average of 117 ± 92 mg of this nutrient over a period ranging from more than 6 months to more than 5 years, and all developed high serum vitamin B6 levels. Within 3 months after discontinuing pyridoxine supplementation, 55% reported partial or complete recovery from their neurological symptoms; by 6 months, all had recovered completely.
No side effects were reported by 28 adults who had consumed vitamin E supplements in doses ranging from 100 to 800 IU/day for an average of 3 years (Farrell and Bieri, 1975). In a double-blind study of 202 adults given 600 IU of vitamin E per
day for 4 weeks, subjects experienced a considerable reduction in serum thyroid hormone levels (Tsai et al., 1978). In the female subjects, serum triglyceride levels became elevated. Neither development, however, was associated with clinical symptoms. Bendich and Machlin (1988), in their recent review of the literature concerning the safety of vitamin E, concluded that few side effects have been observed in humans at intakes as high as 3,200 IU/day. They concluded that the majority of reported side effects have been based on individual case reports or uncontrolled studies and on reports in letters to the editors of journals. These side effects have not been seen in large, well-controlled studies.
No adverse effects have been seen in healthy persons consuming up to 2,500 mg of calcium per day (Avioli, 1988). There is concern, however, that people with undiagnosed abnormalities of calcium metabolism could develop hypercalcemia with excessive calcium intake. High calcium intakes also appear to suppress bone remodeling, which could prevent repair of microfractures and eventually result in bone fragility (Meuleman, 1987). Calcium intakes greater than 1,500 mg/day may promote the development of urinary stones in some people (NIH, 1984).
People consuming more than 25 mg/day have developed nausea, epigastric distress, and a metallic taste in the mouth (Solomons, 1988). Larger doses of zinc are sometimes used as an emetic. Zinc deficiency as well as zinc excess impair immune system function. In one study, 11 healthy men given 300 mg of zinc for 6 weeks developed impaired lymphocyte and polymorphonuclear (PMN) leukocyte function. T cells exhibited reduced response to antigens; chemotactic migration and phagocytosis of PMN leukocytes were also impaired (Chandra, 1984). Large doses of zinc promote the loss of copper from the body, leading to copper deficiency anemia (Solomons, 1988).
In summary, to date there is no evidence that low levels of dietary supplements adversely affect the general population. The FDA's most recent national survey of dietary supplement use (Stewart et al., 1985) shows that the use of various nutrients among men and women in the 95th percentile was in most cases well below the toxic levels reported by Hathcock (1985) (see Table 18-1). However, several surveys show that some people ingest supplements in potentially harmful amounts (Bowerman and Harrill, 1983; Gray et al., 1983, 1986; Levy and Schucker, 1987; Read et al., 1981; Willett et al., 1981).
In 1986, the FDA and the American Dietetic Association asked physicians nationwide to document their patients' use of dietary supplements, as is currently done with drugs, and to report any harmful effects to FDA's Adverse Reaction Monitoring System. FDA plans to use such data to determine the extent to which these products pose risks to health and to determine the most effective course of action (ADA, 1986; Miller, 1987b).
Health professionals are also concerned about the public's use of dietary supplements for reasons other than the potential risks to health from nutrient overdoses. One reason is the complications attributable to supplementation that may occur in the diagnosis and treatment of certain diseases among people taking large doses of vitamins and minerals. Vitamin B6, for example, acts as an antagonist to L-dopa, which is used to treat Parkinson's disease (Dreyfus, 1988). Large vitamin C intakes may interfere with the results of clinical laboratory tests used to detect the presence of fecal and urinary occult blood (Levine, 1983).
Nutrients interact in the human body, so that relatively large intakes of one nutrient may affect the absorption, metabolism, or excretion of others and, therefore, affect their requirements. Ascorbic acid, for example, increases the absorption of nonheme iron in food and decreases the intestinal absorption of copper (Hornig et al., 1988). Copper bioavailability is also depressed by extra zinc (Solomons, 1988). Calcium excretion is increased by diets rich in protein and magnesium (Avioli, 1988). In fact, absorption of nutrients from supplements containing many vitamins and minerals at levels exceeding the RDAs may be low because of multiple nutritional interactions that undoubtedly occur after the product is ingested (Weight et al., 1988).
On several occasions, supplements have been found to be contaminated. In 1982, for example, the FDA warned physicians that some samples of two popular calcium supplementsbone meal and dolomitecould contain substantial amounts of
TABLE 18-1 Vitamin and Mineral Safety Indexesa
25,000 to 50,000 IU
Miller and Hayes, 1982
Miller and Hayes, 1982
Miller and Hayes, 1982
1,000 to 5,000 mg
Miller and Hayes, 1982
Itokawa, 1978; Miller and
Miller and Hayes, 1982;
Miller and Hayes, 1982;
Schaumburg et al., 1983
Miller and Hayes, 1982
Miller and Hayes, 1982
Miller and Hayes, 1982
Draper and Bell, 1978
Lantzsch and Schenkel, 1978
4 to 20 mg
Miller and Hayes, 1982
Miller and Hayes, 1982
a Adapted from Hathcock, 1985.
b Figures represent the highest published value for each nutrient, either the Recommended Dietary Allowances (RDA) (except those for pregnancy and lactation) or Estimated Safe and Adequate Daily Dietary Intakes (ESAADDI) (NRC, 1980), or the U.S. Recommended Daily Allowances (USRDA).
c However, only ~25 mg of riboflavin can be absorbed in a single oral dose given to an adult.
d More recent data suggest that the toxic dose of pyridoxine for some individuals is much lower. See text.
lead. The agency recommended that infants, young children, and pregnant and lactating women avoid these products (Miller, 1987a). Several commercial samples of spirulina, an alga available as a dietary supplement, were found to contain mercury at concentrations exceeding limits set by the FDA (Johnson and Shubert, 1986). Four major brands of fish oil capsules were found to be free of mercury, but they contained trace amounts of DDT metabolites and polychlorinated biphenyls. Frequently these pollutants appeared at levels lower than those considered to be a health hazard (Ebel et al., 1987). In the United States, 13 people developed selenium intoxication as a result of taking an improperly manufactured dietary supplement that contained 27.3 mg of selenium per tabletmore than 180 times the amount labelled and considered safe (Helzlsouer et al., 1985). Symptoms included nausea, abdominal pain, diarrhea, nail and hair changes, peripheral neuropathy, fatigue, and irritability. The woman who consumed the most selenium (2,387 mg over a 2.5 month period) experienced hair loss, fingernail tenderness and loss, nausea and vomiting, a sour-milk breath odor, and increasing fatigue (Jensen et al., 1984).
In other cases, supplements have failed to meet advertised claims. Carr and Shangraw (1987), for example, found that the majority of 35 commercial brands of calcium carbonate supplements failed to meet U.S. Pharmacopoeia (USP) standards for disintegration or dissolution of calcium carbonate-containing drugs. Studies by Shangraw (in press) confirmed that more than half the calcium carbonate supplements tested failed to meet the USP standard. These incidents raise questions about the bioavailability of nutrients obtained from supplements. Dietary supplements are considered to be foods and not drugs and are therefore exempt from USP standards. In general, the absorption of nutrients from soft elastic gelatin capsules appears to
be more efficient than absorption from tablets (Thakker et al., 1987). Factors that influence the bioavailability of nutrients from a supplement include the hardness of the tablet, the nature of its excipients, and substances used to coat the tablet (Shangraw, in press).
Only 19% of the 257 multivitamin and vitamin/ mineral products evaluated by Bell and Fairchild (1987) were found to contain "appropriate" levels of nutrients (defined by the authors as no nutrient present in amounts greater than 50 to 200% of the U.S. RDA or 50 to 100% of the Estimated Safe and Adequate Daily Dietary Intakes proposed by the Food and Nutrition Board). The authors noted that most of the supplements they evaluated contained some vitamins in amounts two or more times the U.S. RDA for adults. In contrast, half the supplements targeted for children and for pregnant and lactating women were deemed appropriate by the authors' definition.
Because supplements are considered to be foods and not drugs, there are few regulations governing their availability and sale in the United States. In 1973, the FDA attempted to establish definitions, standards of identity, and labeling requirements for supplements and proposed specifications for the minimum and maximum quantities of allowable nutrients in supplement preparations (Hile, 1979). FDA's attempts to implement these and subsequent regulations were defeated, however, by public opinion, lawsuits by affected parties, and congressional action. At present, the FDA is prohibited by law from (1) limiting nutrients in supplements to levels considered nutritionally useful, (2) classifying a dietary supplement as a drug because one or more of the nutrients it contains is present at a level beyond that considered nutritionally rational or useful, and (3) requiring the presence of only essential nutrients in supplements and prohibiting the inclusion of ingredients considered useless or as having no nutritional value (Malbin, 1976).
In the United States, dietary supplement use is widespread, especially among adults whose diets more closely meet the RDAs, women, and educated, higher-income whites. A large percentage of U.S. adults supplement their diets at least occasionally with vitamins and minerals; however, there appears to be little relationship between documented nutrient needs and the use of nutrient supplements. Furthermore, very few controlled studies have been conducted to examine the long-term health effects of supplement use and to assess their purported benefits in preventing or treating various chronic diseases. Several vitamins and minerals if consumed in excess can be toxic and cause numerous adverse health effects, but there is no evidence that the public is harming itself by the use of low levels of supplements.
Professional medical and nutrition societies agree that healthy people can and should obtain essential nutrients by eating a wide variety of foods. The following statement was issued jointly by the American Dietetic Association, American Institute of Nutrition, American Society for Clinical Nutrition, and the National Council Against Health Fraud (ADA, 1987):
Healthy children and adults should obtain adequate nutrient intakes from dietary sources. Meeting nutrient needs by choosing a variety of foods in moderation, rather than by supplementation, reduces the potential risk for both nutrient deficiencies and nutrient excesses. Individual recommendations regarding supplements and diets should come from physicians and registered dietitians.
Supplement usage may be indicated in some circumstances including:
Women with excessive menstrual bleeding may need to take iron supplements.
Women who are pregnant or breastfeeding need more of certain nutrients, especially iron, folic acid, and calcium.
People with very low calorie intakes frequently consume diets that do not meet their needs for all nutrients.
Some vegetarians may not be receiving adequate calcium, iron, zinc, and vitamin B12.
Newborns are commonly given, under the direction of a physician, a single dose of vitamin K to prevent abnormal bleeding.
Certain disorders or diseases and some medications may interfere with nutrient intake, digestion, absorption, metabolism, or excretion and thus change requirements.
Nutrients are potentially toxic when ingested in sufficiently large amounts. Safe intake levels vary widely from nutrient to nutrient and may vary with the age and health of the individual. In addition, high-dosage vitamin and mineral supplements can interfere with the normal metabolism of other nutrients and with the therapeutic effects of certain drugs.
The Recommended Dietary Allowances represent the best currently available assessment of safe and adequate intakes and serve as the basis for the U.S. Recommended Daily Allowances shown on many product labels. There are no demonstrated benefits of self supplementation beyond these allowances (ADA, 1987, p. 1342).
The American Medical Association (Council on Scientific Affairs, 1987), the American Heart Association (AHA, 1987), the National Institute on Aging (NIA, 1983), the U.S. Departments of
Agriculture and Health and Human Services (USDA/DHHS, 1985) in their report Dietary Guidelines for Americans, and the Surgeon General's Report on Nutrition and Health (DHHS, 1988) essentially agree with this statement. In addition, the American Academy of Pediatrics has stated that dietary supplements are not necessary for properly nourished and healthy children (AAP, 1980).
This committee agrees with the positions these organizations have taken on dietary supplements. It also agrees with Dodds (1987) that professionally trained nutritionists from accredited institutions of higher education, along with physicians and registered dietitians, should offer the public responsible recommendations on supplement use.
Directions for Research
· Investigators should continue to document the extent of dietary supplement use in the U.S. population and characterize the practice by various demographic and socioeconomic categories (e.g., sex, age, household income, region of country). Such studies should also describe the types and dosages of supplemental nutrients consumed and the reasons people give for using these products.
· Rigorous criteria need to be developed to enable the scientific community to document, in a more systematic and comprehensive manner, potential benefits as well as toxicities from the use of dietary supplements.
· An optimal system to monitor the use of dietary supplements should be developed. Its application would enable the scientific community, regulatory agencies, and the nutrient supplement industry to more effectively study, identify trends in, and evaluate this increasingly common practice.
· Most attention needs to be focused on further research to answer questions related to the potential benefits and risks from long-term dietary supplement use: Does supplement use affect mortality or general health status? Does supplement use help to prevent or treat health problems or chronic diseases in the general population or in particular population subgroups? By objective measures of need (e.g., inadequate nutrient intake from food, biochemical evidence of inadequacies), are supplements being used appropriately? What groups might be particularly vulnerable to health risks from the use of supplements? It is important to monitor the health effects from chronic high-dose levels of supplementation.
· More studies are needed to determine the quality of dietary supplement formulations, e.g., their potency, nutrient balance, nutrient bioavailability, and possible contamination with undesirable substances.
AAP (American Academy of Pediatrics). 1980. Vitamin and mineral supplement needs in normal children in the United States. Pediatrics 66:1015-1021.
ADA (American Dietetic Association). 1986. Pills Versus Food: An Emerging Controversy. Scientific Panel Alarmed Over Supplement Use; Calls on Physicians to Report Harmful Effects. Press release, May 5. Marketing and Communications Department, American Dietetic Association, Chicago. 4 pp.
ADA (American Dietetic Association). 1987. Recommendations concerning supplement usage: ADA statement. J. Am. Diet. Assoc. 46:1342-1343.
AHA (American Heart Association). 1987. Vitamin and Mineral Supplements: Position Statement. Report of the Nutrition Committee, American Heart Association, Dallas. 1 p.
Anderson, R.A. 1986. Chromium metabolism and its role in disease processes in man. Clin. Physiol. Biochem. 4:31-41.
Anderson, R.A., M.M. Polansky, N.A. Bryden, E.E Roginski, W. Mertz, and W. Glinsmann. 1983. Chromium supplementation of human subjects: effects on glucose, insulin, and lipid variables. Metabolism 32:894-899.
Anderson, T.W., and D.B.W. Reid. 1974. A double-blind trial of vitamin E in angina pectoris. Am. J. Clin. Nutr. 27: 1174-1178.
Anderson, T.W., D.B. Reid, and G.H. Beaton. 1972. Vitamin C and the common cold: a double-blind trial. Can. Med. Assoc. J. 107:503-508.
Anderson, T.W., G. Suranyi, and G.H. Beaton. 1974. The effect on winter illness of large doses of vitamin C. Can. Med. Assoc. J. 111:31-36.
Anonymous. 1981. The booming U.S. vitamins and minerals businesschanges and challenges. Nutr. Today 16:26.
Anonymous. 1985. Calcium: how much is too much? Nutr. Rev. 43:345-346.
Anonymous. 1986. The vitamin pushers. Consum. Rep. 51: 170-175.
Aro, A., M. Kyllästinen, E. Kostiainen, C.G. Gref, S. Elfving, and U. Uusitalo. 1988. No effect on serum lipids by moderate and high doses of vitamin C in elderly subjects with low plasma ascorbic acid levels. Ann. Nutr. Metabol. 32:133-137.
Avioli, L.V. 1988. Calcium and phosphorus. Pp. 142-158 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.
Barboriak, J.J., A.Z. el Ghatit, K.R. Shetty, and J.H. Kalbfleisch. 1982. Vitamin E supplements and plasma high-density lipoprotein cholesterol. Am. J. Clin. Pathol. 77: 371-372.
Bauernfeind, J.C. 1980. The safe use of vitamin A: A report of the International Vitamin A Consultive Group (IVACG). The Nutrition Foundation, New York. 44 pp.
Belizan, J.M., J. Villar, O. Pineda, A.E. Gonzalez, E. Sainz, G. Garrera, and R Sibrian. 1983. Reduction of blood pressure with calcium supplementation in young adults. J. Am. Med. Assoc. 249:1161-1165.
Bell, LS., and M. Fairchild. 1987. Evaluation of commercial multivitamin supplements. J. Am. Diet. Assoc. 87:341-343.
Bendich, A., and L.. Machlin. 1988. Safety of oral intake of vitamin E. Am. J. Clin. Nutr. 48:612-619.
Berger, A., and H.H. Schaumburg. 1984. More on neuropathy from pyridoxine abuse. N. Engl. J. Med. 311:986-987.
Bootman, J.L., and A.I. Wertheimer. 1980. Patterns of vitamin usage in a sample of university students. J. Am. Diet. Assoc. 77:58-60.
Bowering, J., and K.L. Clancy. 1986. Nutritional status of children and teenagers in relation to vitamin and mineral use. J. Am. Diet. Assoc. 86:1033-1038.
Bowerman, S.J., and I. Harrill. 1983. Nutrient consumption of individuals taking or not taking nutrient supplements. J. Am. Diet. Assoc. 83:298-305.
Breskin, M.W., C.M. Trahms, B. Worthington-Roberts, R.F. Labbe, and B. Koslowski. 1985. Supplement use: vitamin intakes and biochemical indexes in 40- to 108-month-old children. J. Am. Diet. Assoc. 85:49-56.
Cameron, E., and L. Pauling. 1976. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 73:3685-3689.
Cameron, E., and L. Pauling. 1978. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 75:4538-4542.
Campbell, T.C., R.G. Allison, and C.J. Carr. 1980. Feasibility of Identifying Adverse Health Effects of Vitamins and Essential Minerals in Man. Life Sciences Research Office, Federation of American Societies for Experimental Biology, Bethesda, Md. 76 pp.
Cann, C.E., H.K. Genant, B. Ettinger, and G.S. Gordan. 1980. Spinal mineral loss in oophorectomized women. Determination by quantitative computed tomography. J. Am. Med. Assoc. 244:2056-2059.
Carr, C.J., and R.F. Shangraw. 1987. Nutritional and pharmaceutical aspects of calcium supplementation. Am. Pharm. NS27:49-57.
Chandra, R.K. 1984. Excessive intake of zinc impairs immune responses. J. Am. Med. Assoc. 252:1443-1446.
Costas, K., R. Davis, N. Kim, A.S. Stark, S. Thompson, H.L. Vallet, and D.L Morse. 1987. Use of supplements containing high-dose vitamin ANew York State, 1983-1984. J. Am. Med. Assoc. 257:1292, 1297.
Coulehan, J.L., K.S. Reisinger, K.D. Rogers, and D.W. Bradley. 1974. Vitamin C prophylaxis in a boarding school. N. Engl. J. Med. 290:6-10.
Council on Scientific Affairs. 1987. Vitamin preparations as dietary supplements and as therapeutic agents. J. Am. Med. Assoc. 257:1929-1936.
Creagan, E.T., C.G. Moertel, J.R. O'Fallon, A.J. Schutt, M.J. O'Connell, . Rubin, and S. Frytak. 1979. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med. 301:687-690.
Crosby, W.H. 1978. The effect of nutrient toxicities in animals and man: iron. Pp. 177-192 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Dalton, K., and M.J.T. Dalton. 1987. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol. Scand. 76:8-11.
Davidson, C.S., J. Livermore, P. Andersen, and S. Kaufman. 1962. The nutrition of a group of apparently healthy aging persons. Am. J. Clin. Nutr. 10:181-199.
DHHS (U.S. Department of Health and Human Services). 1988. The Surgeon General's Report on Nutrition and Health. DHHS (PHS) Publ. No. 88-50210. Public Health Service, U.S. Department of Health and Human Services. U.S. Government Printing Office, Washington, D.C. 712 pp.
Dickinson, A. 1987. Benefits of Nutritional Supplements. Council for Responsible Nutrition, Washington, D.C. 55 pp.
Dodds, J. 1987. Message from the president. J. Nutr. Educ. 19: 153.
Donegan, C.K., A.L. Messer, E.S. Orgain, and J.M. Ruffin. 1949. Negative results of tocopherol therapy in cardiovascular disease. Am. J. Med. Sci. 217:294-299.
Draper, H.H., and R.R. Bell. 1978. Nutrient toxicities in animals and man: phosphorus. Pp. 109-112 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Dreyfus, P.M. 1988. Diet and nutrition in neurologic disorders. Pp. 1458-1470 in M.E. Shils and V.R. Young, eds. Modem Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.
Ebel, J.G., Jr., R.H. Eckerlin, G.A. Maylin, W.H. Gutenmann, and D.J. Lisk. 1987. Polychlorinated biphenyls and p,p'-DDE in encapsulated fish oil supplements. Nutr. Rep. Int. 36:413-417.
English, E.C., and J.W. Carl. 1981. Use of nutritional supplements by family practice patients. J. Am. Med. Assoc. 246:2719-2721.
Enstrom, J.E., and L. Pauling. 1982. Mortality among health-conscious elderly Californians. Proc. Natl. Acad. Sci. U.S.A. 79:6023-6027.
Enstrom, J.E., L.E. Kanim, and L Breslow. 1986. The relationship between vitamin C intake, general health practices, and mortality in Alameda County, California. Am. J. Public Health 76:1124-1130.
Ettinger, B., H.K. Genant, and C.E. Cann. 1987. Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium. Ann. Intern. Med. 106:40-45.
Farrell, P.M., and J.G. Bieri. 1975. Megavitamin E supplementation in man. Am. J. Clin. Nutr. 28:1381-1386.
Farris, R.P., J.L. Cresanta, L.S. Webber, G.C. Frank, and G.S. Berenson. 1985. Dietary studies of children from a biracial population: intakes of vitamins in 10- and 13-year-olds. J. Am. Coll. Nutr. 4:539-552.
FDA (U.S. Food and Drug Administration). 1974. Consumer Nutrition Knowledge Survey: Report I, 1973-74. DHEW Publ. No. (FDA) 76-2058. Division of Consumer Studies, Office of Nutrition and Consumer Sciences, Bureau of Foods, Public Health Service, U.S. Department of Health, Education, and Welfare, Washington, D.C. 109 pp.
FDA (U.S. Food and Drug Administration). 1976. Consumer Nutrition Knowledge Survey: Report II, 1975. DHEW Publ. No. (FDA) 76-2059. Division of Consumer Studies, Office of Nutrition and Consumer Sciences, Bureau of Foods, Public Health Service, U.S. Department of Health, Education, and Welfare, Washington, D.C. (various pagings).
Garry, P.J., J.S. Goodwin, W.C. Hunt, E.M. Hooper, and A.G. Leonard. 1982. Nutritional status in a healthy elderly population: dietary and supplemental intakes. Am. J. Clin. Nutr. 36:319-331.
Goldfinger, S. 1982. What do you do, doctor? Harv. Med.
Sch. Health Let. 7:3-6.
Goodman, D.S. 1984. Vitamin A and retinoids in health and disease. N. Engl. J. Med. 310:1023-1031.
Goodwin, J.S., W.C. Hunt, P. Hooper, and P.J. Garry. 1985. Relationship between zinc intake, physical activity, and blood levels of high-density lipoprotein cholesterol in a healthy elderly population. Metabolism 34:519-523.
Goto, S. 1978. Effect of nutrient toxicities in animals: calcium. Pp. 103-107 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Gray, G.E., A. Paganini-Hill, and R.K. Ross. 1983. Dietary intake and nutrient supplement use in a Southern California retirement community. Am. J. Clin. Nutr. 38:122-128.
Gray, G.E., A. Paganini-Hill, R.K. Ross, and B.E. Henderson. 1986. Vitamin supplement use in a Southern California retirement community. J. Am. Diet. Assoc. 86:800-802.
Greenwald, P. 1988. Current status of chemoprevention in humans. Pp. 266-279 in J.G. Fortner and J.E. Rhoads, eds. General Motors Cancer Research Foundation's Accomplishments in Cancer Research 1987. J.B. Lippincott Co., Philadelphia.
Greger, J.L. 1987. Food, supplements, and fortified foods: scientific evaluations in regard to toxicology and nutrient bioavailability. J. Am. Diet. Assoc. 87:1369-1373.
Gregor, A., P.N. Lee, F.J.C. Roe, M.J. Wilson, and A. Melton. 1980. Comparison of dietary histories in lung cancer cases and controls with special reference to vitamin A. Nutr. Cancer 2:93-97.
Grobbee, D.E., and A. Hofman. 1986. Effect of calcium supplementation on diastolic blood pressure in young people with mild hypertension. Lancet 2:703-706.
Gussow, J.D., and P.R. Thomas. 1986. Nutritional supplements: to pill or not to pill, is that the question? Pp. 268-341 in The Nutrition Debate: Sorting Out Some Answers. Bull Publishing, Palo Alto, Calif.
Guthrie, H.A. 1986. Supplementation: a nutritionist's view. J. Nutr. Ed. 18:130-132.
Hale, W.E., R.B. Stewart, J.J. Cerda, R.G. Marks, and F.E. May. 1982. Use of nutritional supplements in an ambulatory elderly population. J. Am. Geriatr. Soc. 30:401-403.
Hathcock, J.N. 1985. Quantitative evaluation of vitamin safety. Pharm. Times 51:104-113.
Helzlsouer, K., R. Jacobs, and S. Morris. 1985. Acute selenium intoxication in the United States. Fed. Proc. 44:1670.
Hermann, W.J., Jr., K. Ward, and J. Faucett. 1979. The effect of tocopherol on high-density lipoprotein cholesterol. A clinical observation. Am. J. Clin. Pathol. 72:848-852.
Hile, J.P. 1979. Vitamin and mineral products; revocation of regulations. Fed. Reg. 44:16005-16006.
Hooper, P.L, L Visconti, P.J. Garry, and G.E. Johnson. 1980. Zinc lowers high-density lipoprotein-cholesterol levels. J. Am. Med. Assoc. 244:1960-1961.
Hornig, D.H., U. Moser, and B.E. Glatthaar. 1988. Ascorbic acid. Pp. 417-435 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.
Horsman, A., J.C. Gallagher, M. Simpson, and B.E. Nordin. 1977. Prospective trial of oestrogen and calcium in postmenopausal women. Br. Med. J. 2:789-792.
Itokawa, Y. 1978. Effect of nutrient toxicities in animals and man: thiamine. Pp. 3-23 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Jensen, R., W. Closson, and R. Rothenberg. 1984. Selenium intoxicationNew York. J. Am. Med. Assoc. 251:1938.
Johnson, P.E., and L.E. Shubert. 1986. Accumulation of mercury and other elements by Spirulina (Cyanophyceae). Nutr. Rep. Int. 34:1063-1070.
Kamm, J.J., C.W. Ehmann, and K.O. Ashenfelter. 1984. Preclinical and clinical toxicity of selected retinoids. Pp. 287-326 in M.B. Sporn, A.B. Roberts, and D.S. Goodman, eds. The Retinoids, Vol. 2. Academic Press, New York.
Karlowski, T.R., T.C. Chalmers, L.D. Frenkel, A.Z. Kapikian, T.L. Lewis, and J.M. Lynch. 1975. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. J. Am. Med. Assoc. 231:1038-1042.
Kellett, M., E. Kelleher, J. Crutchfield, M. Dubes, S.C. Glasser, and G. Lazure. 1984. Vitamin and mineral supplement usage by retired citizens. J. Nutr. Elderly 3:7-19.
Kirsch, A., and W.R. Bidlack. 1987. Nutrition and the elderly: vitamin status and efficacy of supplementation. Nutrition 3:305-314.
Kolonel, L.N., C.N. Yoshizawa, and J.H. Hankin. 1988. Diet and prostatic cancer: a case-control study in Hawaii. Am. J. Epidemiol. 127:999-1012.
Koplan, J.P., J.L Annest, P.M. Layde, and G.L. Rubin. 1986. Nutrient intake and supplementation in the United States (NHANES II). Am. J. Public Health 76:287-289.
Kovar, M.G. 1985. Use of medications and vitamin-mineral supplements by children and youths. Public Health Rep. 100:470-473.
Kurinij, N., M.A. Klebanoff, and B.I. Graubard. 1986. Dietary supplement and food intake in women of childbearing age. J. Am. Diet. Assoc. 86:1536-1540.
Lamke, B., H.E. Sjöberg, and M. Sylvén. 1978. Bone mineral content in women with Colles' fracture: effect of calcium supplementation. Acta Orthop. Scand. 49:143-146.
Lantzsch, H.J., and H. Schenkel. 1978. Effect of specific nutrient toxicities in animals and man: zinc. Pp. 291-307 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
La Vecchia, C., A. Decarli, M. Fasoli, F. Parazzini, S. Franceschi, A. Gentile, and E. Negri. 1988. Dietary vitamin A and the risk of intraepithelial and invasive cervical neoplasia. Gynecol. Oncol. 30:187-195.
Le Bovit, C. 1965. The food of older persons living at home. J. Am. Diet. Assoc. 46:285-289.
Levine, M. 1983. New concepts in the biology and biochemistry of ascorbic acid. N. Engl. J. Med. 314:892-902.
Levy, A.S., and R.E. Schucker. 1987. Patterns of nutrient intake among dietary supplement users: attitudinal and behavioral correlates. J. Am. Diet. Assoc. 87:754-760.
Lipkin, M., and H. Newmark. 1985. Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N. Engl. J. Med. 313: 1381-1384.
Lipsitz, P.J. 1978. Nutrient toxicities in animals and man: magnesium. Pp. 113-117 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Looker, A.C., C.T. Sempos, C.L. Johnson, and E.A. Yetley. 1987. Comparison of dietary intakes and iron status of vitamin-mineral supplement users and nonusers, aged 1-19 years. Am. J. Clin. Nutr. 46:665-672.
Looker, A.C., C.T. Sempos, C. Johnson, and E.A. Yetley.
1988. Vitamin-mineral supplement use: association with dietary intake and iron status of adults. J. Am. Diet. Assoc. 88:808-814.
Makinson, D.H., S. Oleesky, and R.V. Stone. 1948. Vitamin E in angina pectoris. Lancet 1:102.
Malbin, I. 1976. Vitamin-mineral legislation. FDA Talk Paper, April 27, T76-32. U.S. Food and Drug Administration Press Office, Public Health Service, U.S. Department of Health, Education, and Welfare, Washington, D.C. 2 pp.
McCarron, D.A., and C.D. Morris. 1985. Blood pressure response to oral calcium in persons with mild to moderate hypertension. Ann. Int. Med. 103:825-831.
McDonald, J.T. 1986. Vitamin and mineral supplement use in the United States. Clin. Nutr. 5:27-33.
McGandy, R.B., R.M. Russell, S.C. Hartz, R.A. Jacob, S. Tannenbaum, H. Peters, N. Sahyoun, and C.L. Otradovec. 1986. Nutritional status survey of healthy noninstitutionalized elderly: energy and nutrient intakes from three-day diet records and nutrient supplements. Nutr. Res. 6:785-798.
McLaren, D.S. 1984. Vitamin A deficiency and toxicity. Pp. 192-208 in R.E. Olson, H.P. Broquist, C.O. Chichester, W.J. Darby, A.C. Kolbye, Jr., and R.M. Stalvey, eds. Nutrition Reviews' Present Knowledge in Nutrition, 5th ed. The Nutrition Foundation, Washington, D.C.
Meuleman, J. 1987. Beliefs about osteoporosis. A critical appraisal. Arch. Intern. Med. 147:762-765.
Miller, D.R., and K.C. Hayes. 1982. Vitamin excess and toxicity. Pp. 81-133 in J.N. Hathcock, ed. Nutritional Toxicology, Vol. 1. Academic Press, New York.
Miller, S.A. 1987a. Lead in calcium supplements. J. Am. Med. Assoc. 257:1810.
Miller, S.A. 1987b. Women's health: nutrition. Introductory remarks. Public Health Rep., suppl. July/August:20-22.
Moertel, C.G., T.R. Fleming, E.T. Creagan, J. Rubin, M.J. O'Connell, and M.M. Ames. 1985. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. N. Engl. J. Med. 312:137-141.
Moffitt, A.E., Jr. 1978. Effect of nutrient toxicities in animals and man: copper. Pp. 195-202 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
National Analysts, Inc. 1972. A Study of Health Practices and Opinions; Final Report, June 12. Report No. PB-210-978, Survey Conducted for the U.S. Food and Drug Administration. National Technical Information Service, Springfield, Va. 343 pp.
NIA (National Institute on Aging). 1983. Dietary Supplements: More Is Not Always Better. Publ. No. 1986-491-280/40002. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services. U.S. Government Printing Office, Washington, D.C. 2 pp.
NIH (National Institutes of Health). 1984. Osteoporosis: NIH Consensus Development Conference. National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases and the Office of Medical Applications of Research, Bethesda, Md. 87 pp.
Nilas, L, C. Christiansen, and P. Rodbro. 1984. Calcium supplementation and postmenopausal bone loss. Br. Med. J. 289:1103-1106.
NRC (National Research Council). 1980. Recommended Dietary Allowances, 9th ed. Report of the Committee on Dietary Allowances, Food and Nutrition Board, Division of Biological Sciences, Assembly of Life Sciences. National Academy Press, Washington, D.C. 185 pp.
Olson, J.A. 1988. Vitamin A, retinoids, and carotenoids. Pp. 292-312 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.
Pally, A., J. Sobal, and H.L. Muncie, Jr. 1984. Nutritional supplement utilization in an urban family practice center. J. Fam. Prac. 18:249-253.
Pauling, L. 1986. How to Live Longer and Feel Better. Avon Books, New York. 413 pp.
Rabinowitz, M.B., H.C. Gonick, S.R. Levin, and M.B. Davidson. 1983. Effects of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men. Diabetes Care 6:319-327.
Ranno, B.S., G.M. Wardlaw, and C.J. Geiger. 1988. What characterizes elderly women who overuse vitamin and mineral supplements? J. Am. Diet. Assoc. 88:347-348.
Read, M.H., and A.S. Graney. 1982. Food supplement usage by the elderly. J. Am. Diet. Assoc. 80:250-253.
Read, M.H., and D.C. Thomas. 1983. Nutrient and food supplement practices of lacto-ovo vegetarians. J. Am. Diet. Assoc. 82:401-404.
Read, M.H., V. Bhalla, I. Harrill, R. Bendel, J.E. Monagle, H.G. Schutz, E.T. Sheehan, and B.R. Standal. 1981. Potentially toxic vitamin supplementation practices among adults in seven Western states. Nutr. Rep. Int. 24:1133-1138.
Read, M., H.G. Schutz, R. Bendel, V. Bhalla, I. Harrill, M.E. Mitchell, E.T. Sheehan, and B.R. Standal. 1985. Attitudinal and demographic correlates of food supplementation practices. J. Am. Diet. Assoc. 85:855-857.
Read, M.H., M.A. Bock, R. Bendel, M. Mitchell, V. Bhallia, I. Harrill, H. Schutz, E. Sheehan, and B. Standal. 1987. Vitamin supplement users subgroup comparisons. Nutr. Rep. Int. 36:751-755.
Rechcigl, M., Jr., ed. 1978. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla. 518 pp.
Recker, R.R., and R.P. Heaney. 1985. The effect of milk supplements on calcium metabolism, bone metabolism, and calcium balance. Am. J. Clin. Nutr. 41:254-263.
Recker, R.R., P.D. Saville, and R.P. Heaney. 1977. Effect of estrogens and calcium carbonate on bone loss in postmenopausal women. Ann. Intern. Med. 87:649-655.
Resnick, L.M., J.P. Nicholson, and J.H. Laragh. 1984. Outpatient therapy of essential hypertension with dietary calcium supplementation. J. Am. Coll. Cardiol. 3:616.
Rhee, K., and A.C. Stubbs. 1976. Health food users in two Texas cities. Nutritional and socioeconomic implications. J. Am. Diet. Assoc. 68:542-545.
Riales, R., and M.J. Albrink. 1981. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am. J. Clin. Nutr. 34:2670-2678.
Riggs, B.L., E. Seeman, S.F. Hodgson, D.R. Taves, and W.M. O'Fallon. 1982. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. Comparison with conventional therapy. N. Engl. J. Med. 306:446-450.
Riis, B., K. Thomsen, and C. Christiansen. 1987. Does calcium supplementation prevent postmenopausal bone loss? A double-blind, controlled clinical study. N. Engl. J. Med. 316:173-177.
Rinzler, S.H., H. Bakst, Z.H. Benjamin, A.L. Bobb, and J.
Travell. 1950. Failure of alpha tocopherol to influence chest pain in patients with heart disease. Circulation 1:288-293.
Rivlin, R.S. 1978. Effect of nutrient toxicities (excess) in animals and man: riboflavin. Pp. 25-27 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Saegert, J., and M.M. Saegert. 1976. Consumer attitudes and food faddism: the case of vitamin E. J. Consum. Aff. 10: 156-169.
Samet, J.M., B.J. Skipper, C.G. Humble, and D.R. Pathak. 1985. Lung cancer risk and vitamin A consumption in New Mexico. Am. Rev. Respir. Dis. 131:198-202.
Schaumburg, H., J. Kaplan, A. Windebank, N. Vick, S. Rasmus, D. Pleasure, and M.J. Brown. 1983. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N. Engl. J. Med. 309:445-448.
Schutz, H.G., B. Read, R. Bendel, V.S. Bhalla, I. Harrill, J.E. Monagle, E.T. Sheehan, and B.R. Standal. 1982. Food supplement usage in seven Western states. Am. J. Clin. Nutr. 36:897-901.
Shangraw, R.F. In press. Factors to consider in the selection of a calcium supplement. Public Health Rep., suppl.
Sharpe, T.R., and M.C. Smith. 1985. Use of vitamin-mineral supplements by AFDC children. Public Health Rep. 100: 321-324.
Shekelle, R.B., M. Lepper, S. Liu, C. Maliza, W.J. Raynor, Jr., A.H. Rossof, O. Paul, A.M. Shryock, and J. Stamler. 1981. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet 2:1186-1190.
Simonoff, M. 1984. Chromium deficiency and cardiovascular risk. Cardiovasc. Res. 18:591-596.
Singer, D.R.J., N.D. Markandu, F.P. Cappuccio, G.W. Beynon, A.C. Shore, S.J. Smith, and G.A. MacGregor. 1985. Does oral calcium lower blood pressure: a double blind study. J. Hypertension 3:661.
Smith, E.L., Jr., W. Reddan, and P.E. Smith. 1981. Physical activity and calcium modalities for bone mineral increase in aged women. Med. Sci. Sports Exerc. 13:60-64.
Smith, P.G., and H. Jick. 1978. Cancers among users of preparations containing vitamin A: a case-control investigation. Cancer 42:808-811.
Sobal, J., and H.L. Muncie, Jr. 1985. Vitamin use and vitamin beliefs among students entering medical school. J. Nutr. Ed. 17:123-125.
Sobal, J., H.L. Muncie, Jr., and A.S. Baker. 1986. Use of nutritional supplements in a retirement community. Gerontologist 26:187-191.
Sobal, J., H.L. Muncie, Jr., C.M. Valente, B.R. DeForge, and D. Levine. 1987. Physicians' beliefs about vitamin supplements and a balanced diet. J. Nutr. Ed. 19:181-185.
Solomons, N.W. 1988. Zinc and copper. Pp. 238-262 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.
Sorensen, A.A., D.I. Sorensen, and J.G. Zimmer. 1979. Appropriateness of vitamin and mineral prescription orders for residents of health-related facilities. J. Am. Geriatr. Soc. 27:425-430.
Spittle, C.R. 1972. Atherosclerosis and vitamin C. Lancet 1: 798.
Stampfer, M.J., W. Willett, W.P. Castelli, J.O. Taylor, J. Fine, and C.H. Hennekens. 1983. Effect of vitamin E on lipids. Am. J. Clin. Pathol. 79:714-716.
Steinkamp, R.C., N.L. Cohen, and H.E. Walsh. 1965. Resurvey of an aging populationfourteen-year follow-up. J. Am. Diet. Assoc. 46:103-110.
Stewart, M.L., J.T. McDonald, A.S. Levy, R.E. Schucker, and D.P. Henderson. 1985. Vitamin/mineral supplement use: a telephone survey of adults in the United States. J. Am. Diet. Assoc. 85:1585-1590.
Stich, H.F., M.P. Rosin, and M.O. Vallejera. 1984. Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet 1:1204-1206.
Thakker, K.M., H.S. Sitren, J.F. Gregory III, G.L. Schmidt, and T.G. Baumgartner. 1987. Dosage form and formulation effects on the bioavailability of vitamin E, riboflavin, and vitamin B6 from multivitamin preparations. Am. J. Clin. Nutr. 45:1472-1479.
Thomsen, P.A., R.D. Terry, and R.J. Amos. 1987. Adolescents' beliefs about and reasons for using vitamin/mineral supplements. J. Am. Diet. Assoc. 87:1063-1065.
Tsai, A.C., J.J. Kelley, B. Peng, and N. Cook. 1978. Study on the effect of megavitamin E supplementation in man. Am. J. Clin. Nutr. 31:831-837.
USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals. Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service, Hyattsville, Md. 94 pp.
USDA (U.S. Department of Agriculture). 1987a. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals. Low-Income Women 19-50 Years and Their Children 1-5 Years, 1 Day, 1986. Report No. 862. Nutrition Monitoring Division, Human Nutrition Information Service, Hyattsville, Md. 166 pp.
USDA (U.S. Department of Agriculture). 1987b. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals. Women 19-50 Years and Their Children 1-5 Years, 1 Day, 1986. Report No. 86-1. Nutrition Monitoring Division, Human Nutrition Information Service, Hyattsville, Md. 98 pp.
USDA/DHHS (U.S. Department of Agriculture/Department of Health and Human Services). 1985. Nutrition and Your Health: Dietary Guidelines for Americans, 2nd ed. Home & Garden Bulletin No. 232. U.S. Government Printing Office, Washington, D.C. 24 pp.
Uusitupa, M.I.J., J.T. Kumpulainen, E. Voutilainen, K. Hersio, H. Sarlund, K.P. Pyörälä, P.E. Kovistoinen, and J.T. Lehto. 1983. Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in noninsulin-dependent diabetics. Am. J. Clin. Nutr. 38:404-410.
Vidor, G.I. 1978. Iodine toxicity in man and animals. Pp. 219-282 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Vogelsang, A., and E.V. Shute. 1946. Effect of vitamin E in coronary heart disease. Nature (London) 157:772.
Waterman, R.A. 1978. Nutrient toxicities in animals and man: niacin. Pp. 29-42 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. 1. CRC Press, West Palm Beach, Fla.
Weight, L.M., K.H. Myburgh, and T.D. Noakes. 1988. Vitamin and mineral supplementation: effect on the running performance of trained athletes. Am. J. Clin. Nutr. 47:192-195.
Willett, W., L. Sampson, C. Bain, B. Rosner, C.H. Hennek-
ens, J. Witschie, and F.E. Speizer. 1981. Vitamin supplement use among registered nurses. Am. J. Clin. Nutr. 34: 1121-1125.
Worsley, A. 1986. Health, wellbeing and dietary supplementation. Recent Adv. Clin. Nutr. 2:43-56.
Worthington-Roberts, B., and M. Breskin. 1984. Supplementation patterns of Washington State dietitians. J. Am. Diet. Assoc. 84:795-800.
Yearick, E.S., M.S. Wang, and S.J. Pisias. 1980. Nutritional status of the elderly: dietary and biochemical findings. J. Gerontol. 35:663-671.
Ziegler, R.G., T.J. Mason, A. Sternhagen, R. Hoover, J.B. Schoenberg, G. Gridley, P.W. Virgo, R. Altman, and J.F. Fraumeni, Jr. 1984. Dietary carotene and vitamin A and risk of lung cancer among white men in New Jersey. J. Natl. Cancer Inst. 73:1429-1435.