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6
Chromium

SUMMARY

Chromium potentiates the action of insulin in vivo and in vitro. There was not sufficient evidence to set an Estimated Average Requirement (EAR) for chromium. Therefore, an Adequate Intake (AI) was set based on estimated mean intakes. The AI is 35 μg/day and 25 μg/day for young men and women, respectively. Few serious adverse effects have been associated with excess intake of chromium from food. Therefore, a Tolerable Upper Intake Level (UL) was not established.

BACKGROUND INFORMATION

Chromium occurs most commonly in valance states of +3 (III) and +6 (VI). Chromium III is the most stable oxidation state (Greenwood and Earnshaw, 1997) and presumably is the form in the food supply due to the presence of reducing substances in foods. Even a bolus dose of 5 mg chromium VI was reduced to chromium III in 0.5 L of orange juice (Kuykendall et al., 1996), and endogenous reducing agents within the upper gastrointestinal tract and the blood also serve to prevent systemic uptake of chromium VI (Kerger et al., 1997). However, chromium VI, which is a by-product of manufacturing stainless steel, pigments, chromate chemicals, and numerous other products, is strongly oxidizing, produces local irritation or corrosion, and is recognized as a carcinogen when inhaled (Greenwood and Earnshaw, 1997; O’Flaherty, 1994).



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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 6 Chromium SUMMARY Chromium potentiates the action of insulin in vivo and in vitro. There was not sufficient evidence to set an Estimated Average Requirement (EAR) for chromium. Therefore, an Adequate Intake (AI) was set based on estimated mean intakes. The AI is 35 μg/day and 25 μg/day for young men and women, respectively. Few serious adverse effects have been associated with excess intake of chromium from food. Therefore, a Tolerable Upper Intake Level (UL) was not established. BACKGROUND INFORMATION Chromium occurs most commonly in valance states of +3 (III) and +6 (VI). Chromium III is the most stable oxidation state (Greenwood and Earnshaw, 1997) and presumably is the form in the food supply due to the presence of reducing substances in foods. Even a bolus dose of 5 mg chromium VI was reduced to chromium III in 0.5 L of orange juice (Kuykendall et al., 1996), and endogenous reducing agents within the upper gastrointestinal tract and the blood also serve to prevent systemic uptake of chromium VI (Kerger et al., 1997). However, chromium VI, which is a by-product of manufacturing stainless steel, pigments, chromate chemicals, and numerous other products, is strongly oxidizing, produces local irritation or corrosion, and is recognized as a carcinogen when inhaled (Greenwood and Earnshaw, 1997; O’Flaherty, 1994).

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Function Chromium potentiates the action of insulin in vivo and in vitro (Mertz, 1969, 1993; Mertz et al., 1961). Schwarz and Mertz (1959) identified chromium as the element that restored glucose tolerance in rats. Impaired glucose tolerance of malnourished infants responded to an oral dose of chromium chloride (Hopkins and Majaj, 1967; Hopkins et al., 1968); subsequently, benefits of chromium chloride were reported in a patient receiving total parenteral nutrition (TPN) (Jeejeebhoy et al., 1977). A number of studies have demonstrated beneficial effects of chromium on circulating glucose, insulin, and lipids in a variety of human subjects and animal species; however, not all reports of supplementation are positive (Anderson, 1997; Anderson et al., 1991) (for reviews see Anderson, 1997; Mertz, 1993; Offenbacher et al., 1997; Stoecker, 1996). Progress in the field has been limited by lack of a simple, widely accepted method for identification of subjects who are chromium depleted, and thus who would be expected to respond to chromium supplementation, and by the difficulty in producing chromium deficiency in animals. Recent work by Davis and Vincent (1997a, 1997b) and Vincent (1999) suggests that a low molecular weight chromium-binding substance (LMWCr) may amplify insulin receptor tyrosine kinase activity in response to insulin. It is proposed that the inactive form of the insulin receptor (IR) is converted to the active form by binding insulin, which stimulates the movement of chromium from the blood into the insulin-dependent cells and results in the binding of apoLMWCr to chromium (Figure 6-1). The holoLMWCr then binds to the insulin receptor activating the tyrosine kinase. The ability of LMWCr to activate insulin receptor tyrosine kinase depends on its chromium content. When insulin concentration drops, the holoLMWCr is possibly released from the cell to terminate its effects. Physiology of Absorption, Metabolism, and Excretion Absorption estimates for chromium III, based on metabolic balance studies or on urinary excretion from physiological intakes, range from 0.4 to 2.5 percent (Anderson and Kozlovsky, 1985; Anderson et al., 1983, 1991, 1993a; Bunker et al., 1984; Doisy et al., 1971; Offenbacher et al., 1986). Most chromium compounds are soluble at the pH of the stomach, but less soluble hydroxides may form as pH is increased (Mertz,

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc FIGURE 6-1 Proposed mechanism for the activation of insulin receptor by LMWCr in response to insulin. LMWCr = low molecular weight chromium-binding substance, I = insulin, IR = insulin receptor. Adapted from Vincent (1999). 1969). The environment of the gastrointestinal tract and ligands provided by foods and supplements are important for mineral absorption (Clydesdale, 1988). Several dietary factors that affect chromium absorption will be discussed in the bioavailability section of this chapter. In humans consuming approximately 10 μg/day of chromium, about 2 percent was excreted in urine, but only 0.5 percent was excreted when intakes approached 40 μg/day (Anderson and Kozlovsky, 1985). These data suggest regulation of chromium absorption in these intake ranges. A number of studies have reported increased urinary excretion of chromium with aerobic exercise (Anderson et al., 1982, 1984, 1988b). A recent study using 53Cr demonstrated that acute and chronic resistive exercise may increase chromium absorption as determined by the increased urinary excretion of the 53Cr isotope (Rubin et al., 1998). Further studies will be needed to clarify how much of the observed beneficial effects of exercise on glucose and insulin metabolism may be due to improved chromium absorption. Chromium competes for one of the binding sites on transferrin (Harris, 1977). In rats fed physiological levels of 51CrCl3, more than

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 80 percent of the 51Cr in blood precipitated with the transferrin. Several studies have investigated possible interactions between iron and chromium. Human apo-transferrin in Earle’s medium bound chromium in the presence of citric acid, and iron uptake by apotransferrin was reduced by either aluminum or chromium (Moshtaghie et al., 1992). The excessive iron in hemochromatosis has been hypothesized to interfere with the transport of chromium, thereby contributing to the diabetes associated with this condition (Lim et al., 1983; Sargent et al., 1979). Supplementation of 925 μg/ day of chromium for 12 weeks did not significantly affect indexes of iron status in older adult men (Campbell et al., 1997), but one study in young men that provided a daily 200 μg supplement for 8 weeks found a tendency for a decrease in transferrin saturation (Lukaski et al., 1996). No long-term studies have addressed this question. In humans, chromium concentrates in liver, spleen, soft tissue, and bone (Lim et al., 1983). Similar patterns are seen in rats with accumulation in kidney, spleen, and bone as well as liver and testes (Hopkins, 1965; Kamath et al., 1997; Onkelinx, 1977). A three-compartment model with half-lives of 0.5, 5.9, and 83 days was originally proposed based on the distribution of 51Cr from 51CrCl3 in rats (Mertz et al., 1965). Onkelinx (1977) also proposed a three-compartment model in rats, but suggested different characteristics for the third compartment. Additional modeling work with patients having adult onset diabetes and normal control subjects utilized a compartment within the blood and slow and fast tissue compartments (Do Canto et al., 1995). A half-life for urinary excretion of chromium of 0.97 days for the diabetic group and 1.51 days for control subjects was calculated. The compartment that represented long-term tissue deposition had an extremely slow return rate of 231 days for patients with diabetes and 346 days for control subjects. Most ingested chromium is excreted unabsorbed in the feces (Mertz, 1969; Offenbacher et al., 1986). Excretion via bile is not a major contributor to fecal chromium (Davis-Whitenack et al., 1996; Hopkins, 1965). Most absorbed chromium is excreted rapidly in the urine (Anderson et al., 1983). A recent report from England indicated significant age-related decreases in the chromium concentrations in hair, sweat, and urine (Davies et al., 1997). Clinical Effects of Inadequate Intake Chromium deficiency has been reported in three patients who did not receive supplemental chromium in their TPN solutions

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (Brown et al., 1986; Freund et al., 1979; Jeejeebhoy et al., 1977). The first, a female who had received TPN for more than 3 years, developed unexplained weight loss and peripheral neuropathy. Her plasma glucose removal was impaired, plasma free fatty acids were elevated, and her low respiratory quotient indicated poor utilization of carbohydrates. The addition of 250 μg of chromium to the daily TPN solution for 2 weeks restored the glucose removal rate, increased her respiratory quotient, and allowed an insulin infusion to be discontinued. The other two patients responded similarly to chromium supplementation (Brown et al., 1986; Freund et al., 1979) Because chromium potentiates the action of insulin and chromium deficiency in TPN patients, impairs glucose utilization, and raises insulin requirements, it has been hypothesized that poor chromium status is a factor contributing to the incidence of impaired glucose tolerance and Type II diabetes. Prevalence of impaired glucose tolerance was 15.8 percent in adults from 40 to 74 years of age in the Third National Health and Nutrition Examination Survey (1988–1994) (Harris et al., 1998). Addressing this question is difficult because of the current lack of information about variability in dietary chromium intakes and because there is not an easily usable clinical indicator to identify potential study subjects with poor chromium status. There is considerable interest in chromium supplementation in Type II diabetes, but no large-scale controlled trials have been reported in the United States. In China, 180 subjects with Type II diabetes took either a placebo, 200 μg, or 1,000 μg of chromium as chromium picolinate daily for 4 months. Mean body weight of the subjects was 69 kg. Data collected at baseline and after 2 and 4 months of supplementation included standard health histories, fasting glucose and insulin, glycosylated hemoglobin, and glucose and insulin concentrations 2 hours after a 75-g glucose load. After 2 months, fasting and 2-hour insulin concentrations were decreased significantly at both supplement levels. Glycosylated hemoglobin and fasting and 2-hour glucose concentration decreased significantly in the higher (1,000 μg/day) dose group. The reductions in glucose and insulin concentrations were maintained for 4 months; additionally, glycosylated hemoglobin became significantly lower in both dose groups at 4 months (Anderson et al., 1997b). There are no data available on the basal dietary intake of chromium in these diabetic subjects. Also, no doses between 200 and 1,000 μg were tested in this study, nor were other forms of chromium supplemented.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR CHROMIUM Balance Studies Two men were monitored for 12 days in a metabolic ward and were in apparent balance when fed 37 μg/day of chromium (Offenbacher et al., 1986). Bunker and coworkers (1984) conducted metabolic balance studies with 22 apparently healthy elderly people between 69 and 86 years of age. These subjects had mean chromium intakes of 24.5 μg/day (12.8 μg/1,000 kcal) with a range of 13.6 to 47.7 μg/day for men and 14.5 to 30.3 μg/day for women. Of the 22 subjects, 16 were in equilibrium, three were in positive balance, and three were in negative balance. Urinary Chromium Excretion For healthy, free-living adults, the average urinary chromium excretion is typically 0.22 μg/L (Paschal et al., 1998) or 0.2 μg/day (Anderson et al., 1982, 1983) for both men and women. In another study, urinary chromium excretion was found to be approximately 0.5 percent of the amount in the diet when diets contained 40 μg of chromium. For persons whose diets contained only 10 μg of chromium, urinary excretion was approximately 2 percent. There was a negative linear relationship between dietary chromium in this range and percent urinary chromium excretion (Anderson and Kozlovsky, 1985). However, urinary chromium excretion appears to be related to recent chromium intake but has not been useful as a predictor of chromium status (Anderson et al., 1983). Further investigation of urinary chromium in response to very low levels of intake is warranted (Anderson et al., 1991). Plasma Chromium Concentration Reported plasma chromium concentrations have declined from greater than 3,000 nmol/L in the 1950s to 2 to 3 nmol/L in well-controlled studies conducted since 1978 (Anderson, 1987). This change can be attributed to improved analytic methods and better control of contamination. Because plasma chromium is very close to the detection limits for graphite furnace atomic absorption and easily contaminated, it is unlikely to be a viable clinical indicator (Veillon, 1989).

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Blood Glucose and Insulin Concentration There is only one study in which subjects were given controlled low chromium diets (Anderson et al., 1991). Seventeen adults were provided diets that contained 5 μg of chromium per 1,000 kcal for 14 weeks. Glucose and insulin concentrations in response to a glucose load were monitored at baseline, 4, 9, and 14 weeks. After adapting to the diet for 4 weeks, subjects were assigned to placebo or chromium supplementation groups for 5 weeks followed by a crossover without washout for another 5 weeks (Anderson et al., 1991). As one approach to the analysis of these data (Anderson et al., 1991), the subjects who received the placebo for the first 9 weeks were analyzed separately. After 4 weeks on the diet containing 5 μg/1,000 kcal, there were no significant changes in variables measured. However, after subjects consumed 5 μg of chromium per 1,000 kcal for 9 weeks, a significant increase from baseline was observed in sums of glucose and in glucose at 90 minutes after the glucose load (Table 6-1). Supplementation with 200 μg of chromium as CrCl3 for 5 weeks tended (p < 0.10) to reduce sums of glucose and insulin concentrations in these subjects. Although this study suggests a role of chromium in regulating blood glucose concentrations, further studies using graded levels of intake between less than TABLE 6-1 Glucose and Insulin Concentrations of Eight Subjects Fed Low Chromium (5 μg/1,000 kcal) Diets for 14 Weeks and Supplemented with Placebo for 9 Weeks Followed by 200 μg CrCl3 for 5 Weeks   Week   0 4 9 14 Glucose (mmol/L)   Fasting 4.9 ± 0.2 4.8 ± 0.1 4.9 ± 0.1 5.1 ± 0.1 90 minute 4.2 ± 0.4 4.5 ± 0.4 5.0 ± 0.6a 4.4 ± 0.4 Sums (0–240 min) 33.6 ± 1.6 35.1 ± 1.4 37.0 ± 2.2 34.6 ± 1.6b Insulin (pmol/L)   Fasting 1,138 ± 5 1,133 ± 5 1,148 ± 6 1,149 ± 7 Sums (0–240 min) 1,146 ± 130 1,214 ± 167 1,577 ± 354 1,319 ± 281b a Different from baseline by paired t-test, p < 0.05. b Week 9 (end of placebo) vs. supplement by paired t-test, p < 0.10. SOURCE: Reanalysis of Anderson et al. (1991), by personal communication.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 5 μg/1,000 kcal and the usual dietary chromium levels (13 to 20 μg/1,000 kcal) and with different age groups are needed to estimate the average requirement for chromium. FACTORS AFFECTING THE CHROMIUM REQUIREMENT A number of dietary factors affect chromium absorption. Offenbacher (1994) noted plasma chromium concentrations in three women were consistently higher when they were given 1 mg chromium as CrCl3 with 100 mg ascorbic acid than when given 1 mg chromium without ascorbic acid. In rats, concurrent dosing with 51CrCl3 and ascorbic acid, as compared to dosing in water, produced significantly higher 51Cr in urine without decreasing 51Cr in tissues, a finding that suggests ascorbic acid enhanced 51Cr absorption (Davis et al., 1995; Seaborn and Stoecker, 1990). Consumption of diets high in simple sugars (35 percent of total kcal) increased urinary chromium excretion in adults (Kozlovsky et al., 1986). Urinary chromium excretion was found to be related to the insulinogenic properties of carbohydrates (Anderson et al., 1990). Carbohydrate source also had a significant effect on tissue chromium concentration in mice, with values generally being higher in those fed a starch diet (Seaborn and Stoecker, 1989). When amino acids were added to a test meal perfused through the intestinal lumen of rats, the absorption of chromium was increased two-fold (Dowling et al., 1990). In rats, phytate at high levels had adverse effects on 51Cr absorption (Chen et al., 1973), but lower levels of phytate did not have detrimental effects on chromium status (Keim et al., 1987). Oxalate (present in some vegetables and grains) enhanced 51Cr uptake (Chen et al., 1973). Bunker and coworkers (1984) commented that one subject in severe negative chromium balance ate a diet very high in fiber, but effects of high fiber diets on chromium absorption have not been investigated systematically. Habitual consumption of certain medications that alter stomach acidity or gastrointestinal prostaglandins may affect chromium absorption and retention in rats. When rats were dosed with physiological doses (less than 100 ng) of 51CrCl3 and prostaglandin inhibitors such as aspirin, 51Cr in blood, tissues, and urine was markedly increased (Davis et al., 1995). Medications, such as antacids or dimethylprostaglandin E2, reduced 51Cr absorption and retention in rats (Kamath et al., 1997).

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 12 Months Method Used to Set the Adequate Intake No functional criteria of chromium status have been demonstrated that indicate response to dietary intake in infants. Thus, the recommended intakes of chromium are based on an Adequate Intake (AI) that reflects the observed mean chromium intake of infants principally fed human milk. Ages 0 through 6 Months. According to the method described in Chapter 2, the AI for chromium is based on the milk content from healthy, well-nourished mothers who are not taking supplements. The average concentration of chromium in human milk was estimated to be 0.25 μg/L (Anderson et al., 1993a; Casey and Hambidge, 1984; Casey et al., 1985; Engelhardt et al., 1990; Mohamedshah et al., 1998) (Table 6-2). Based on the consumption of 0.78 L/day of human milk (Chapter 2), the AI for chromium for infants ages 0 through 6 months is 0.2 μg/day after rounding. Ages 7 through 12 Months. Schroeder and coworkers (1962) reported a rapid decline in tissue chromium concentrations after birth. These tissue concentrations were generated before chromium measurement techniques were reliable (Anderson, 1987); nonetheless, the possibility that infants deplete their stores during the early months of life suggests that the AI possibly should not be based solely on human milk consumption. There are no specific data on the chromium concentration of weaning foods; this indicates an area of needed research. An average daily caloric intake for this age group is 845 kcal and human milk provides 750 kcal/L (Fomon, 1974). During the second 6 months of lactation, the average volume of human milk consumed by the infant is 0.6 L/day (Chapter 2). Therefore, calories provided by human milk would be 450 kcal (0.6 L of human milk × 750 kcal/ L) and the caloric content of the usual intake of complementary weaning foods would be 395 kcal (845–450). Based on an average concentration of 0.25 μg/L, the chromium intake from human milk would be 0.15 μg/day (0.6 × 0.25). With an additional 400 kcal from complementary foods and the chromium content of well balanced meals containing approximately 13.4 μg/ 1,000 kcal (Anderson et al., 1992), the amount of chromium

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc TABLE 6-2 Chromium Concentration in Human Milk Referencea Study Group Stage of Lactation Milk Concentration (μg/L) Estimated Chromium Intake of Infants (μg/d)b Casey and Hambidge, 1984 45 women 0–14 d 0.29 0.22 15–28 d 0.27 0.21 1–3 mo 0.28 0.22 4–6 mo 0.26 0.16 7+ mo 0.46 0.27 Casey et al., 1985 11 women, 26–39 y 8 d 0.27 0.21 14 d 0.22 0.17 21 d 0.28 0.22 28 d 0.26 0.20 Engelhardt et al., 1990     0.28 0.22 Anderson et al., 1993a 17 women 2 mo 0.18 0.14 Aquilio et al., 1996 14 women 21 d 1.2 0.93 Mohamedshah et al., 1998 6 women, 25–38 y 1–2 mo 0.09–0.46 0.07–0.36 a Maternal intakes were not reported in these studies. b Chromium intake based on reported data or concentration (μg/L) × 0.78 L/day for 0–6 months postpartum and concentration (μg/L) × 0.6 L/day for 7–12 months postpartum. consumed from weaning foods is estimated to be 5.36 μg/day. Therefore the amount of chromium consumed from human milk and complementary foods would be 5.5 μg/day (0.15 + 5.36). Downward extrapolation from an adult, according to the method in Chapter 2, would yield an average intake of 10 μg/day. An AI of 5.5 μg/day is set for infants ages 7 through 12 months based on consumption of chromium from human milk and complementary foods.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Chromium AI Summary, Ages 0 through 12 Months AI for Infants   0–6 months 0.2 μg/day of chromium 29 ng/kg/day 7–12 months 5.5 μg/day of chromium 611 ng/kg/day Special Considerations The mean concentration of chromium in cow milk and infant formula was reported to be 0.83 and 4.84 μg/L, respectively (Cocho et al., 1992). There is no information on the bioavailability of chromium in infant formula. Children and Adolescents Ages 1 through 18 Years Method Used to Set the Adequate Intake No data were found on which to base an Estimated Average Requirement for children and adolescents; therefore AIs have been set. In the absence of information on the chromium content of children’s diets, AIs for these age groups have been extrapolated from adults, ages 19 through 30 years, with use of the method described in Chapter 2 and rounding to the nearest 1 μg. Because urinary excretion of chromium is increased with exercise (Anderson et al., 1982, 1984, 1988b), metabolic weight (kg0.75) was used to extrapolate from the adult AI. Chromium AI Summary, Ages 1 through 18 Years AI for Children   1–3 years 11 μg/day of chromium 4–8 years 15 μg/day of chromium AI for Boys   9–13 years 25 μg/day of chromium 14–18 years 35 μg/day of chromium AI for Girls   9–13 years 21 μg/day of chromium 14–18 years 24 μg/day of chromium

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc who took supplements, which is similar to the average dietary chromium intake (Appendix Table C-14). TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to individuals who are receiving chromium under medical supervision. Hazard Identification The toxicity of chromium differs widely depending on the valence state. This review is limited to evaluating trivalent chromium (III) because this is the principal form of chromium found in food and supplements. Hexavalent chromium (VI), which has a much higher level of toxicity than trivalent chromium, is not found in food. Ingested chromium III has a low level of toxicity which is due, partially, to its very poor absorption (Stoecker, 1999). Chromium supplement use (particularly chromium picolinate) has increased in popularity as a result of reports that chromium potentiates the action of insulin and reduces hyperglycemia and hyperlipidemia (Flodin, 1990). Several studies have demonstrated the safety of large doses of chromium III (Anderson et al., 1997a; Hathcock, 1997). The data on the potential adverse effects of excess intake of chromium III compounds are reviewed below. Chronic Renal Failure Chronic interstitial nephritis in humans has been attributed to ingestion of chromium picolinate in two case reports (Cerulli et al., 1998; Wasser et al., 1997). However, there is no evidence of kidney damage in experimental animals exposed for up to 2 years to oral chromium as chromium chloride, chromium trichloride, chromium picolinate, or chromium acetate (Anderson et al., 1997a; Schroeder et al., 1962).

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Genotoxicity Chromium VI is a well established human carcinogen, mutagen, and clastogen, but chromium III compounds are not. In vivo genotoxicity assays for chromium III have been negative (Cupo and Wetterhahn, 1985; Hamamy et al., 1987; Itoh and Shimada, 1996). Most studies of genotoxicity in cellular systems have yielded negative results as well (ATSDR, 1998), which in some cases may be due to poor uptake by cells. In eukaryotic cells, negative results were obtained for DNA fragmentation, unscheduled DNA synthesis, and forward mutation (Raffetto et al., 1977; Whiting et al., 1979). Mostly negative results were obtained in sister chromatid exchange assays (Levis and Majone, 1979; Stella et al., 1982; Venier et al., 1982), but both positive and negative results have been found for chromosomal aberrations (Fornace et al., 1981; Levis and Majone, 1979; Nakamuro et al., 1978; Newbold et al., 1979; Raffetto et al., 1977; Stella et al., 1982; Tsuda and Kato, 1977; Umeda and Nishimura, 1979). In prokaryotic cells, the genotoxicity results were mostly negative. Positive results of chromium III were found in intact cells; however, these results could be due to contamination of the test compounds with traces of chromium VI, which is readily taken up by cells (ATSDR, 1998). Several studies suggest that chromium III picolinate and tri-picolinate may cause DNA damage through the generation of hydroxyl radicals (Bagchi et al., 1997; Speetjens et al., 1999; Stearns et al., 1995). Carcinogenicity There is little evidence of carcinogenicity in humans or animals after oral intake of chromium III. Kusiak and coworkers (1993) reported increased mortality due to stomach cancer in gold miners in Canada. Although the authors suggest that chromium dust may be the causative agent, the study did not adjust for possible important confounding factors (e.g., role of dietary habits) and failed to show a clear pattern of disease incidence with increasing exposure. A 2-year feeding study in rats by Ivankovic and Preussmann (1975) showed no carcinogenicity after intake (5 days/week for 2 years) of 1, 2, or 5 percent chromium oxide (Cr2O3) baked in bread. Hepatic Dysfunction There are reports of hepatic adverse effects in humans (Fristedt et al., 1965; Kaufman et al., 1970; Loubieres et al., 1999). Several rat

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc studies show no morphological changes in livers following long-term ingestion of chromium compounds (Ivankovic and Preussmann, 1975; Mackenzie et al., 1958; Schroeder et al., 1965). Reproductive Effects There are no studies in humans to suggest that chromium III is a reproductive or developmental toxicant. However, various chromium III compounds have been studied in mice and rats with respect to their reproductive system toxicity. Chromium chloride (in drinking water) administered over 12 weeks reduced fertility in male mice, reduced the number of implantation sites and the number of viable fetuses, and delayed sexual maturity (Al-Hamood et al., 1998; Elbetieha and Al-Hamood, 1997). Intraperitoneal injections of chromium chloride (1, 2, or 4 mg/kg) for 5 days to male rats had no effect on testicular histology or sperm counts (Ernst, 1990). The ingestion of 1,000 μg/mL of chromium as chromium chloride in drinking water for 12 weeks led to significant reductions in the weight of the rat’s testes and seminal vesicles (Bataineh et al., 1997). Other Adverse Effects Other adverse effects observed after high chromium intakes include rhabdomyolysis (Martin and Fuller, 1998). Rhabdomyolysis is characterized by skeletal muscle injury and release of muscle cell contents into the plasma. Reports of chromium-induced rhabdomyolysis failed to account for other potential etiologic factors including strenuous exercise, weight lifting, trauma, seizure, sepsis, and alcohol and drug abuse. Identification of Distinct and Highly Sensitive Subpopulations Data suggest that individuals with preexisting renal and liver disease may be particularly susceptible to adverse effects from excess chromium intake (ATSDR, 1998). These individuals should be particularly careful to limit chromium intake. Dose-Response Assessment The limited studies on renal, hepatic, reproductive, and DNA damaging effects of chromium III do not provide dose-response information or clear indications of a lowest-observed-adverse-effect level (LOAEL) or no-observed-adverse-effect level (NOAEL). Thus,

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc there are insufficient data to establish a UL for soluble chromium III salts. Because of the current widespread use of chromium supplements, more research is needed to assess the safety of high-dose chromium intake from supplements. Data from randomized, doubleblind, controlled clinical trials and surveillance studies would be most useful for assessing the safety of chromium intake in humans. Intake Assessment National survey data are not available on the intake of chromium at various percentiles. According to data from the Third National Health and Nutrition Examination Survey, the average supplemental intake of chromium at the ninety-fifth percentile was 100 μg/day for men and 127 μg/day for women (Appendix Table C-14). Risk Characterization No adverse effects have been convincingly associated with excess intake of chromium from food or supplements, but this does not mean that there is no potential for adverse effects resulting from high intakes. Since data on the adverse effects of chromium intake are limited, caution may be warranted. RESEARCH RECOMMENDATIONS FOR CHROMIUM Controlled studies with low dietary intakes (less than 5 to 15 μg/1,000 kcal) to determine an Estimated Average Requirement. Chromium absorption, metabolism, and requirements during pregnancy and lactation. Information on variability in chromium concentration in the food and water supply. Development and validation of a useful clinical indicator to identify persons with marginal chromium status and investigation of effects of physiological levels of chromium supplementation in these patients. Investigation of possible relationships between chromium status and insulin resistance, impaired glucose tolerance, and Type II diabetes. Monitoring of any adverse effects of self-supplementation and of the design of controlled studies to assess potential beneficial, as well as adverse, effects of large-dose supplementation of chromium.

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