Cr Cl3

RDA Workshop: New Approaches, Endpoints and Paradigms for RDAs of Mineral Elements

Deliberations and Evaluations of the Approaches, Endpoints and Paradigms for Boron, Chromium and Fluoride Dietary Recommendations1'2 CURTISS

D. HUNT3 AND BARBARA

J. STOECKER

Workshop Discussion Group Co-Chairpersons 4U.S. Department of Agriculture, Agricultural Research Service, Grand Fork Human Nutrition Research Center, Grand Fork, North Dakota 58202 and Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK 74078-000]

ABSTRACT The 10th edition (1989) of the Recom mended Dietary Allowances provided estimated safe and adequate daily dietary intakes (ESADDI) for chro mium and fluoride and summarized the substantial evi dence for boron essentiality in animals. New endpoints, approaches and paradigms to use to formulate dietary guidance for these elements were reviewed by a discussion group that met as part of a national work shop. Deliberations of the group are summarized to facilitate future discussions on dietary guidance for these elements. The category, "provisional RDA" was recommended to replace the current ESADDI category because of the ambiguities associated with the ESADDI. A provisional RDA would be defined for a dietary substance that meets one of two sets of crite ria: class 1, clear evidence of essentiality but uncertain or limited quantitative data or endpoints to define di etary requirements; and class 2, strong evidence of essentiality, and clear nutritional benefit based on rea sonably certain quantitative data, but lack of clear in formation on function or endpoints to use for deficiency dietary requirements. A summary of background infor mation and possible approaches for assigning provi sional RDAs for boron, chromium and fluoride is pre sented. J. Nutr. 126: 2441S-2451S, 1996.

' Presented at the workshop "New Approaches, Endpoints and Para digms for RDAs of Mineral Elements" held in Grand Forks, ND on September 10-12, 1995. This workshop was presented jointly by the USD A, ARS, Grand Forks Human Nutrition Research Center and School of Medicine, University of North Dakota. The publication of conference proceedings was supported by International Life Sciences Institute, Led erle Consumer Health, National Livestock and Meat Board, Quaker Oats, U.S. Borax Inc., and the U.S. Department of Agriculture, Agricultural Research Service. Guest Editors for this workshop were Forrest H. Niel sen, W. Thomas Johnson, and David B. Milne, USDA, ARS, Grand Forks Human Nutrition Research Center, Grand Forks, ND. 2 Other members of the Workshop Discussion Group included

INDEXING KEY WORDS:

•boron •chromium •fluoride •human

RDAs

The 10th edition of the Recommended Dietary Al lowances (RDA)5 (NRC 1989) provided estimated safe and adequate daily dietary intakes (ESADDI) for chro mium and fluoride and summarized the substantial ev idence for boron essentiality in animals. New ap0022-3166/96 $3.00 ©1996 American Institute of Nutrition. 244 IS

Yisheng Bai (USDA ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND|, James R. Coughlin (Coughlin and Associ ates, Laguna Niguel, CA|, John N. Hathcock (Council for Responsible Nutrition, Washington, D.C.|, Lynn A. Larsen (Food and Drug Ad ministration, Washington, D.C.), Henry C. Lukaski (USDA ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND), Susan L. Meacham (Winthrop University, Rock Hill, SC|, Charlene Rainey (Nutrition Research Group, Irvine, CA), Philip L. Strong (U.S. Borax Inc., Valencia, CA). 3To whom correspondence should be addressed: USDA, ARS, GFHNRC, P.O. Box 9034, Grand Forks, ND 58202-9034. 4 U.S. Department of Agriculture, Agricultural Research Service, Northern Plains Area is an equal opportunity/affirmative action em ployer and all agency services are available without discrimination. 5Abbreviations used: ESADDI, estimated safe and adequate daily dietary intake; RDA, Recommended Dietary Allowance; TDS, U.S. Food and Drug Administration Total Diet Study.

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preaches, endpoints and paradigms to use to formulate dietary guidance for these elements were reviewed re cently by a discussion group and deliberations of the group are summarized to facilitate future discussions on dietary guidance for these elements. The status category, estimated safe and adequate daily dietary intake (ESADDI), was created (NRC 1980) for nutrients with databases insufficient for developing

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SUPPLEMENT

an RDA, but for which potentially toxic upper intakes were known. There is a need to replace the ESADDI category because of ambiguities in interpretation of values provided. For example, the term "safe" as used in the ESADDI can be misinterpreted as the upper safe limit of intake. Ambiguities are best eliminated by re naming the category; "provisional RDA" could be a

BORON Current RDA status of boron The text accompanying the ommended Dietary Allowances "boron has long been known growth of most plants." "There

10th edition of the Rec (NRC 1989) noted that to be essential for the is substantial evidence

to establish the essentiality of [boron] in animals . . .. Boron deficiency has been reported in studies in rats, chickens, and humans. Boron appears to affect calcium and magnesium metabolism and may be needed for membrane function. Boron deficiency signs may be re lated to the level of vitamin D and possibly other nutri ents in the diet." The text also noted that "many di etary constituents are either essential for, or comple mentary to, the proper utilization of calcium, including . . . boron." "Evidence for a requirement in laboratory animals has been presented for [boron] but . . . the requirement has not been quantified. Deficiency in hu mans has not been established for [boron]. Hence, there are no data from which a human requirement could be estimated and no provisional allowance can be given." As described in the 10th edition of the Recom mended Dietary Allowances (NRC 1989), the RDAs are based in principle on one or more of six kinds of evi dence. It is now possible to suggest approaches, endpoints and paradigms for establishing a provisional al lowance for boron because new data pertinent to four of these kinds of evidence are available: boron intakes of apparently healthy people from their food supply, boron balance studies that measure nutrient status in relation to boron intake, adequacy of molecular func

Boron intakes of healthy people Good estimates of boron intake are now available because of improvements in boron analytical technol ogy. Recent analyses of food and personal care products (Anderson et al. 1994, Hunt et al. 1991, lyengar et al. 1990) indicate that usual adult human dietary boron consumption in the United States is in the range of 12 mg [0.092-0.185 mmol]/d, not 10-25 mg [0.925-2.31 mmol]/d as calculated earlier (Ploquin 1967). However, all recently calculated intakes are probably less than actual intakes by more than 10% because the calcula tions were based on the Food and Drug Administration Total Diet Study (TDS) (Pennington 1983). Diets con structed from the TDS food lists for U.S. men and women aged 25-30 y do not provide sufficient energy for weight maintenance despite energy adjustments with sucrose, followed by a 10% increase in all foods (Hunt et al. 1992). Because boron is present in most all plant food sources and this boron apparently is well absorbed, "background" boron concentrations occur in human blood and tissue (Restuccio et al. 1992). The main sources of boron in the diet are drinking water (with major fluctuations between geographical loca tions), fruits, vegetables, legumes and nuts (Varo et al. 1980).

Boron status in relation to boron intake Boron balance is influenced by at least three pro cesses: gut absorption, blood transport and urinary ex cretion. Certain aspects of these processes are relevant to assessments of boron balance as an approach to es tablishing an RDA for boron.

Boron absorption and excretion The bioavailability of boron in water (normally pres ent as undissociated boric acid) or boron in a readily soluble inorganic form apparently is very high. For ex ample, in a recent metabolic study (Hunt et al. 1994), postmenopausal women, fed a low boron diet (0.36 mg [0.033 mmol] B/d) and supplemented with 2.87 mg [0.265 mmol] B/d (as sodium tetraborate), excreted 89% of their total daily boron intake in the urine and only 3% (within analytical error) of the intake in the feces. The bioavailability of boron in foods is also appar ently very high. Urinary excretion data collected from rats indicated that the absorption of an intrinsically labeled 10Bdose from broccoli was complete because 100% of the 10Bdose was recovered in the urine (Vanderpool et al. 1994). In the human metabolic study de scribed above (Hunt et al. 1994), the amount of boron excreted in the urine of the women fed the low boron

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term for a category that provides dietary guidance but acknowledges limitations of the data used to set it. A provisional RDA would be defined for a dietary sub stance that meets criteria set for one of two classes of nutrients: class 1, clear evidence of essentiality but uncertain or limited quantitative data or endpoints to use for defining dietary requirements; and class 2, strong evidence of essentiality and clear nutritional benefit based on reasonably certain quantitative data, but lack of clear information on function or endpoints to use for defining dietary requirements. Specific ap proaches for assigning provisional RDAs for each of the three elements, boron, chromium and fluoride, are discussed below.

tion in relation to boron intake and human boron deple tion/repletion studies.

APPROACHES

TO B, Cr AND F DIETARY RECOMMENDATIONS

Boron transport

Adequacy of molecular function in relation to boron intake To date, five naturally occurring, well-defined, bio logical boron oxy compounds have been identified; they are all ionophoric macrodiolide antibiotics (Schummer et al. 1994) produced by certain bacteria. There is universal agreement that vascular plants, dia toms and some species of marine algal flagellates have acquired an absolute requirement for boron (Loomis and Durst 1992, Lovatt 1985). Although a specific bio chemical role for the element in the metabolism of higher plants remains to be elucidated, the unambigu ous characteristics of both boron deficiency and boron toxicity are sufficient to define precisely the boron re quirements of many plant species (Lovatt and Dugger 1984). As described below, findings from numerous studies indicate that animals or humans fed low boron diets (<0.3 mg [0.028 mmol] B/kg), and then fed diets supple mented with inorganic boron, in amounts (~ 2 //g [~0.185 ¿¿mol]/g) equivalent to that found in diets com prising mainly fruits and vegetables, show changes in several aspects of animal and human physiology. The response to dietary boron was typically more pro nounced during concurrent nutritional insult (i.e., vita min D deficiency). Thus, the endpoints described be low, when taken together, can be used to establish a provisional RDA for boron. For the sake of continuity, approaches relevant to human boron depletion-reple tion studies, as well as molecular function, are exam ined together.

Vitamin D metabolism At physiological concentrations, inorganic boron is essentially present in biological fluids only as the mononuclear species B(OH)3 and B(OH)4~. The uncharged B(OH)3, probably the dominant boron species in the gut, blood and urine (Spivack and Edmond 1987), forms unique, easily reversible complexes with several bio logically important polyhydroxy compounds. These li gands (i.e., riboflavin) typically contain adjacent hydroxyl groups in the cis position (Zittle 1951). The rele vant cisoid diol conformations are also present in several biologically important sugars and their deriva tives (sugar alcohols, -onic and -uronic acids), such as mannose, ribose, galactose and fructose (Zittle 1951). Therefore, because boron is capable of forming com plexes with a large number of ligands, it is doubtful that there is a specific boron transport mechanism. Fur thermore, because all available data suggest that in gested boron is well-absorbed, and because the average total daily boron intake (1000-2000 /xg [92-184 /¿mol]) greatly exceeds total blood boron (~213 //g [~19.7 ¿¿mol], blood boron concentrations are probably tran siently defined by a single meal and highly influenced by a snack (Vanderpool and Johnson 1992).

Vitamin D and boron metabolism apparently are closely linked. Boron supplementation of a low boron diet decreased the incidence of mortality in vitamin Ddeficient chicks (0 vs. 26%) (Hunt 1989). Furthermore, dietary boron stimulated growth in vitamin D-deficient, boron-deprived chicks but did not markedly af fect growth in chicks receiving adequate vitamin D nutriture (Bai and Hunt 1995, Hunt and Herbei 1994, Hunt and Nielsen 1981). In vitamin D-deficient chicks fed low dietary boron, boron supplementation mark edly improved plasma 1,25-dihydroxycholecalciferol concentrations (145 ±60 vs. 66 ±30 nmol/L), whereas in the vitamin D-adequate chicks, the boron supple mentation decreased these concentrations (126 ±32 vs. 201 ±74 nmol/L) (Bakken 1995). In communitybased studies with mixed groups of volunteers (men and women on or not on estrogen therapy), boron sup plementation (49 d), after consumption of a low boron diet (63 d), increased slightly serum 25-hydroxycholecalciferol (Nielsen et al. 1990, Nielsen et al. 1992) and did not affect serum 1,25 dihydroxycholecalciferol con centrations (Nielsen et al. 1990).

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Western diet (0.36 mg/d) also equalled total daily boron intake. The women may have exhibited obligatory uri nary boron loss because, in addition to urinary boron losses, an amount of boron equal to 12% of boron in take was also recovered from the feces. If plant and animal boron absorption mechanisms are analogous, the organic forms of boron per se are probably unavail able to humans; the organic forms of boron in soil must be mineralized to be available to plants (Gupta et al. 1985). However, the strong association between polyhydroxyl ligands and boron is easily and rapidly re versed by change in pH, heat or the excess addition of another low molecular polyhydroxyl ligand (Zittle 1951). Thus, within the intestinal tract, most ingested boron is probably converted to B(OH)3, the normal endproduct of hydrolysis of most boron compounds (Greenwood and Earnshaw 1984) and subsequently ab sorbed. High boron intakes from typical natural foodstuffs may stimulate an uncharacterized mechanism that limits boron absorption. For example, two ruminant species, cows (Green and Weeth 1977) and sheep (Brown et al. 1989) were found to excrete only 30 and 41%, respectively, of total dietary boron in the urine when fed natural foodstuffs. The boron intakes on a body weight basis were considerably higher in these animals (cow, 0.715 [0.066 mrnol]; sheep, 0.667 mg [0.062 mmol] B/kg body wt) than in humans fed 0.36 or 3.23 mg B/day (0.005 mg [0.0005 mmol] or 0.048 mg [0.004 mmol] B/kg body weight respectively).

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SUPPLEMENT

Mineral metabolism

Boron supplemented to a low boron diet reduced gross bone abnormalities in the vitamin D-deficient chick (Bai and Hunt 1995, Hunt et al. 1994). At the microscopic level, the boron supplement decreased the height of the abnormally thickened growth plate (Hunt 1989, King et al. 1991) and increased chondrocyte den sity in the proliferative zone of the growth plate in vitamin D-deficient chicks; these findings suggest that boron has some role in the maturation of the growth plate (Hunt et al. 1994). Furthermore, the boron supple ment alleviated distortion of the marrow sprouts, a characteristic of vitamin D deficiency (Hunt 1989).

Boron and energy substrate utilization Dietary boron can significantly ameliorate or rem edy certain vitamin D deficiency-induced perturba tions in energy substrate utilization in the chick. For example, dietary boron decreases the abnormally ele vated concentrations of plasma glucose in the vitamin D-deficient chick (Hunt 1989). In postmenopausal women fed a low magnesium, marginal copper diet (Nielsen 1989), a daily dietary intake of 3.23 mg (0.299 mmol) boron for 49 d, compared with a daily intake of 0.23 mg (0.021 mmol) for 63 d, decreased fasting serum glucose concentrations (in the normal range) approxi mately 6%. Boron supplemented to a low boron diet increased the abnormally depressed concentrations of plasma tri glycéridesin the vitamin D-deficient chick (Hunt and Herbei 1994). In one of the community-based studies mentioned above (Nielsen et al. 1992), boron repletion after a period of boron depletion, also increased serum triglycéride concentrations (in the normal range) ap proximately 12%. Finally, supplemental boron mark edly decreased plasma insulin concentrations in the vitamin D-deprived rat fed a low boron diet (Hunt and Herbei 1991-1992a), and also decreased peak pancre atic insulin secretion by nearly 75% from isolated, per fused pancreata from chicks fed a low boron diet (Bakken 1995).

Human boron depletion/repletion

studies

Findings from studies of subjects maintained on diets containing low amounts of boron, followed by correction of the deficit with measured amounts of bo ron, were summarized above as an integral part of the discussion on assessment of molecular function. With few exceptions, findings from these studies mirror those from other boron deprivation studies with ani mals. As was the case for evidence of physiological function, it is suggested that the endpoints described for human depletion/repletion boron studies, when

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Dietary boron ameliorates the deleterious effects of vitamin D deficiency on several aspects of mineral me tabolism through uncharacterized mechanisms. For ex ample, vitamin D deficiency induced elevated concen trations of plasma total alkaline phosphatase activity in the chick (Hunt et al. 1983, Lacey and Huffer 1982). Vitamin D-deficient chicks fed 3.33 mg boron/kg diet, compared with those fed 0.16 mg boron/kg diet, exhib ited a 60% reduction in plasma alkaline phosphatase activity (Hunt and Herbei 1994). In the same animals, the boron supplement improved plasma ionized cal cium concentrations. Dietary boron also influences tissue mineral con tent. For example, in the vitamin D-deficient rat fed a low boron diet, supplemental dietary boron improved the apparent absorption and retention of calcium and phosphorus and increased femur magnesium concen trations (Hegsted et al. 1991). Dietary boron increased femoral calcium and phosphorus concentrations in vi tamin D-adequate, but not -inadequate chicks (Hunt et al. 1994). The findings from these two studies indi cate that further research is needed to ascertain whether an interaction between boron and vitamin D affects calcium mobilization and retention. Also, in the vitamin D-, boron-deprived rat, supplemental boron depressed cardiac calcium and elevated cardiac phos phorus concentrations (Hunt and Herbei 1991-1992b). Dietary boron probably affected cardiac mineral metab olism indirectly through unknown mechanisms be cause it did not affect cardiac boron concentrations. Dietary boron influences mineral metabolism in humans; the influence is modulated by magnesium nutriture. For example, in postmenopausal women housed in a metabolic unit and fed low amounts of magnesium (109 mg [4.48 mmol] Mg/d) and boron (0.36 mg [0.033 mmol] B/d), supplemental boron (2.87 mg [0.265 mmol] B/d) decreased the percent of calcium intake lost in the urine. On the other hand, boron increased the percent of calcium intake lost in the urine of postmenopausal volunteers fed slightly more than the recommended amount of magnesium (340 mg [14.0 mmol] Mg/d) (Hunt et al. 1994). Boron supplementation also in creased urinary calcium loss in both sedentary and ath letic free-living premenopausal women consuming self-selected typical Western diets (Meacham et al. 1995). In addition, compared with all other volunteers, sedentary control subjects supplemented with boron exhibited the highest serum total magnesium concen trations. Finally, serum phosphorus concentrations were lower in the boron-supplemented volunteers than in placebo-supplemented volunteers. In a different study of older volunteers fed a marginal copper diet (men and women on or not on estrogen therapy), boron repletion after boron depletion decreased serum calcitonin and ionized calcium, but not total calcium con centrations (Nielsen et al. 1990).

Boron and growth cartilage and bone metabolism

APPROACHES

taken together, can be used to establish boron RDA.

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TO B, Cr AND F DIETARY RECOMMENDATIONS

a provisional

Suggested approaches for assigning a provisional RDA for boron

Hg [0.38-0.77 //mol] Cr/d for 6-12 mo. The ESADDI established for young children was 20-80 //g [0.381.54 //mol] Cr/d and for adolescents is 30-120 //g [0.582.31 //mol] Cr/d.

Dietary chromium sources and usual intakes

CHROMIUM In 1957, Schwarz and Mertz reported that a com pound, termed glucose tolerance factor, restored im paired glucose tolerance in rats fed a tonila yeast diet. Chromium was identified as the critical substance that potentiated insulin action (Schwarz and Mertz 1959). Since that time, chromium supplementation has been reported to correct chromium depletion in three pa tients receiving total parenteral nutrition (TPN) (Brown et al. 1986, Freund et al. 1979, Jeejeebhoy et al. 1977). Chromium supplementation generally, but not always, has relieved symptoms of impaired glucose tolerance in humans (Mertz 1993). Chromium is present in biological tissues in very low concentrations; this makes contamination a major problem in a clinical setting (Veillon 1989). Over the years, the reported concentration of chromium in se rum and urine has decreased by at least three orders of magnitude. The lower values reflect improvements in analytical instruments and greater attention to the sources of chromium contamination in sample collec tion and analysis. Chromium values for biological sam ples reported before 1980 are generally inaccurate.

Past recommendations for chromium in the Recommended Dietary Allowances The first ESADDI for chromium appeared in the 9th edition of the Recommended Dietary Allowances (NRC 1980). The ESADDI remained at 50-200 //g [0.96-3.85 //mol]/d for adults in the 10th edition (NRC 1989). The ESADDI established for infants was 10-40 //g [0.19-0.77 //mol] Cr/d for the first 6 mo and 20-40

Meat, poultry, fish and especially dairy products tend to be low in chromium. Fruits, vegetables and grain products have variable chromium concentrations (Anderson et al. 1992). Pulses, seeds and dark chocolate may contain more chromium than most other foods (Jorhem and Sundstrom 1993). Certain spices such as black pepper contain high concentrations of chromium but contribute little to the usual diet on a per serving basis (Anderson et al. 1992). Loss of chromium in the process of refining sugar has been noted (Wolf et al. 1974). However, processing also may add chromium to the food supply. Chromium is leached from stainless steel containers particularly when contents are acidic (Offenbacher and Pi-Sunyer 1983); some brands of beer contain significant amounts of chromium, presumably some comes from the brewing vessels (Anderson and Bryden 1983). Processed meats also apparently gain chromium during manufacture (Anderson et al. 1992). In addition to the variable chromium concentrations found in foods, there are differences in bioavailability and biological activity of chromium in various com plexes (Mertz et al. 1974). The best known chromium complex is the glucose tolerance factor; this complex has not been characterized but has been suggested to contain nicotinic acid, glycine, glutamate and cysteine (Mertz et al. 1974). A low-molecular-weight chromium binding material also has been identified in bovine co lostrum but availability of such a complex in mature milk is not known (Yamamoto et al. 1988). Chromium intakes for many people are below the lower range of the ESADDI (Anderson and Kozlovsky 1985, Bunker et al. 1984, Gibson and Scythes 1984, Offenbacher et al. 1986). Otherwise adequate diets can be formulated with less than 16 //g [0.31 //mol] Cr/4.0 Mf (Anderson and Kozlovsky 1985). Using self-selected diets composited for 7 d and analyzed for chromium, the mean chromium intake of 10 adult males was 33 ßg[0.63 //mol]/d (range 22-48 //g [0.42-0.92 //mol]) and intake for 22 females was 25 //g [0.48 //mol]/d (range of 13-36 //g [0.25-0.69 //mol]) (Anderson and Kozlovsky 1985). Overall, the above-mentioned studies have found 22-100% of the subjects to have chromium in takes less than 50 //g [0.96 //mol]/d. Factors affecting

chromium

Intestinal absorption with estimates in fasted 3% (Davis et al. 1995, balance study, two men

utilization

of trivalent chromium is low rats ranging from <0.5 to 2Mertz 1969). In a metabolic consuming an average of 36.8

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In summary, there is sufficient information to esti mate average boron consumption by adult Americans (between 1 and 2 mg/d), adequate understanding of bo ron status in relation to intake, and a clear indication that boron, in amounts typically consumed, affects mineral metabolism and energy substrate utilization. Taken as a whole, the experimental boron nutrition research data indicate an essential role for the element and a need for a provisional RDA, or similar status category, for this element. The approach to use in the determination of a provisional RDA should include consideration of daily boron intake, boron status in relation to boron intake and the response of human volunteers to boron supplementation after a period of boron depletion.

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SUPPLEMENT

rats 24 h after dosing (Chen et al. 1973). Common medications can enhance or impair chro mium absorption. Rats dosed orally with 40 mg [0.222 mmol] of aspirin exhibited markedly enhanced absorp tion of 51Crfrom 51CrCl3 (Davis et al. 1995). Intraperitoneal injection of 5 mg indomethacin [0.014 mmol]/kg body wt significantly increased 51Cr in blood, tissues and urine of rats,- this indicates that blocking the syn thesis of prostaglandins enhances chromium absorp tion (Kamath et al. 1995). Acute administration of sev eral antacids concomitantly with 51CrCl3 significantly reduced 51Cr in blood and tissues compared with con trols (Davis et al. 1995, Seaborn and Stoecker 1990). Much of the chromium in blood is transported by transferrin (Hopkins and Schwarz 1964). Iron uptake on apo-transferrin was reduced in vitro by either alumi num or chromium (Moshtaghie et al. 1992). Likewise rats injected intraperitoneally with 1 mg [0.019 mmol]/ kg chromium as chromium chloride daily for 45 d had significant reductions in serum iron, total iron-binding capacity and ferritin and in hemoglobin and hematocrit (Ani and Moshtaghie 1992). Two patients on low chromium TPN had weight loss that was restored with chromium supplementa tion (Freund et al. 1979, Jeejeebhoy et al. 1977). Periph eral neuropathy was seen in one of the patients and was reversed with chromium supplementation (Jeeje ebhoy et al. 1977).

Generally, subjects with some degree of impaired glucose tolerance are more responsive to chromium supplementation than other subjects (Mertz 1993). Trauma patients, and persons exercising very strenu ously exhibited increased urinary excretion of chro mium (Anderson et al. 1988, Borei et al. 1984). Meta bolic Stressors may exacerbate the deficiency state (An derson et al. 1984, Borei et al. 1984, Chang and Mowat 1992, Mertz 1969, Nielsen 1988).

Chromium toxicity Chromium is a transition element that can occur in a number of valence states including 0, +2, +3 and +6; chromium (III) is the most stable form in biological systems (Cohen et al. 1993, Losi et al. 1994, Mertz 1969). Chromium (VI) is a strong oxidizing agent that comes primarily from industrial sources (Von Burg and Liu 1993). Chromium (VI) consumed in small amounts is reduced to chromium (III) in the acidic environment of the stomach (Mertz 1969; O'Flaherty 1994; Sayato et al. 1980). Because trivalent chromium chloride is poorly absorbed, high oral intakes would be necessary to attain toxic levels (Mertz 1969). Tannery workers exposed to chromium (III)have ele vated body loads of chromium, but the chromium is excreted rapidly in the urine (Randall and Gibson 1987). Toxic effects of industrial exposure have been attributed primarily to airborne chromium (VI) com pounds including those obtained from welding stain less steel (IPCS 1988, Katz and Salem 1993, Von Burg and Liu 1993). Toxicity symptoms included allergic dermatitis and increased incidence of lung cancer (Losi et al. 1994, Nethercott et al. 1994, O'Flaherty 1994, Von Burg and Liu 1993).

Basis for dietary chromium recommendations Because no enzyme has been identified as an indica tor of chromium status and because of the very low concentrations of chromium in accessible tissues, it has not been possible to monitor status of a large group of subjects with variable chromium intakes. Long-term consequences of dietary intakes <50 //g [0.96 //mol]/d need to be determined because many people in the United States consume <50 /¿g chromium/d (Anderson et al. 1993b, Anderson and Kozlovsky 1985, Offenbacher 1992). Despite an increase in impaired glucose tolerance with age, age per se apparently is not a risk factor for chromium deficiency (Offenbacher 1992). When the original ESADDI for chromium was estab lished in 1980, most data on chromium concentrations in food, serum and urine had been obtained without using the types of background correction currently available on instruments; many early data are too high because of analytical problems and contamination (An derson 1987, Guthrie et al. 1978, Veillon et al. 1982). Currently available data suggest a recommendation

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//g [0.71 /LÃ-mol] Cr/d had a mean apparent net absorption of chromium of 1.8% (Offenbacher et al. 1986). Normal subjects given a dose of 51CrCl3 had a mean of 0.69% (range 0.3-1.3%) of the dose in the urine within 72 hours (Doisy et al. 1971). The amount of chromium present in the diet appar ently affects chromium absorption. Subjects consum ing approximately 10 //g [0.19 /xmol] chromium per day excreted approximately 2% of a 200 //g [3.85 //mol] dose in the urine while at chromium intakes of 40 ¿¿g [0.77 //mol], only 0.4-0.5% of the chromium was recovered in the urine (Anderson and Kozlovsky 1985). The presence of amino acids or ascorbic acid in a test meal enhanced chromium transport or absorption in animals (Bowling et al. 1990, Seaborn and Stoecker 1990). Three women consumed 1 mg [0.019 mmol] of chromium as chromium chloride with or without 100 mg ascorbic acid. Plasma chromium concentrations were consistently higher after the chromium dosed in conjunction with ascorbic acid (Offenbacher 1994). Subjects who consumed high sugar (35% of total calo ries) generally had increased urinary chromium excre tion compared with when they consumed only 15% of total calories from simple sugars (Kozlovsky et al. 1986). Compared with simple sugars, starch feeding generally increased tissue chromium in mice (Seaborn and Stoecker 1989). Absorption of 5lCr was elevated in zinc-deficient rats and was reduced by zinc administra tion (Hahn and Evans 1975). Oxalate increased andphytate decreased 5lCr in blood, whole body, and urine of

APPROACHES

TO B, Cr AND F DIETARY RECOMMENDATIONS

water was demonstrated many years ago (Dean et al. 1942); this negative correlation has been confirmed by a number of studies (Burt 1982). However, concerns have surfaced recently about excessive fluoride intakes, particularly from various dentifrices and the potential for fluorosis (Pendrys and Katz 1989). An additional area of current research is evaluation of the efficacy of pharmacologie doses of fluoride in the treatment of osteoporosis (Hedlund and Gallagher 1989, Pak et al. 1986, Pak et al. 1994, Resch et al. 1993, Riggs et al. 1994).

Past recommendations for fluoride in the Recommended Dietary Allowances In the 10th edition of the Recommended Dietary Allowances (NRC 1989), the ESADDI established for fluoride for adults was 1.5-4.0 mg [0.08-0.21 mmol]/ d. The ESADDI established for infants was between 0.1 [0.005] and 1.0 mg [0.053 mmol] F/d. For children and adolescents the ESADDI varied between 0.5-2.5 [0.026-0.132] and 1.5-2.5 mg [0.079-0.132 mmol] F/ d, respectively (NRC 1989). Fluoride was given an ESADDI on the basis of its beneficial effects on dental caries rather than clear-cut evidence of essentiality (NRC 1989).

Dietary fluoride sources and usual intakes Both tea and small marine fish consumed with their bones are rich sources of fluoride (Kumpulainen and Koivistoinen, 1977). Most of the variation in dietary fluoride intake stems from beverages. The fluoride con centration of drinking water varies widely within the United States; public health organizations recommend that fluoride concentrations of the drinking water should be between 0.7 [0.037] and 1.2 mg [0.063 mmol]/ L (NRC 1989). Cow's milk and human milk are low in fluoride. Manufacturers of concentrated infant formulas have agreed to prepare the formulas without added fluoride and assume that fluoridated water will be used for reconstitution of the formulas. Infants in the United States may consume 100 //g [5.26 //mol] F-kg^-d"1 from concentrated liquid formulas diluted with fluori dated water and 150 //g [7.89 //mol] F-kg^'-d'1 from powdered formulas diluted with fluoridated water (Ekstrand et al. 1994).

FLUORIDE Factors affecting fluoride utilization Fluoride is the ionized form of the element fluorine and these terms are used interchangeably in the follow ing discussion. Fluorine is distributed in water, soil, plants and animals, but concentrations are highly vari able in different areas of the country. A negative correlation between tooth decay in chil dren and the fluoride concentration of their drinking

Most fluoride is incorporated in the bones and teeth; fluoride incorporation is thought to be proportional to intake. In infants, retention of a fluoride dose ranged from 75 to 87% (Ekstrand et al. 1994). This retention is higher than that seen in adults and may indicate that the infant has a greater capacity to deposit fluoride in

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lower than the 50-200 //g [0.96-3.85 //mol]/d for adults. There are very few reports that provide information on which to base future recommendations. In one study, subjects were fed low chromium diets (<20 //g [0.38 //mol]/d) for 14 wk. After 4 wk, 200 //g [3.85 /zmol] chromium (as CrCl3 ) or placebo was randomly assigned for 5 wk in a crossover trial. Chromium supplementa tion had no affect in subjects with normal glucose toler ance tests; however, the glucose tolerance test of eight subjects with initially impaired glucose tolerance dete riorated further during the placebo period and improved significantly during chromium supplementation (An derson et al. 1991). Less than 20 //g [0.38 /¿mol]chromium/d was sufficient to prevent impaired glucose tol erance in the control group, but how long normal glu cose tolerance could be maintained on such a low chromium intake is unknown. Based on current data, an infant consuming 750 mL of human milk would receive less than 1 //g [0.019 //mol] chromium/d (Anderson et al. 1993a, Casey and Hambidge 1984, Kumpulainen 1992). There is no indi cation of enhanced absorption of chromium from hu man milk compared with formula,- this suggests that the ESADDI of 10-40 //g [0.19-0.77 //mol] chromium/ d for infants is too high. There are no specific data on which to base a recommendation for children or adolescents. Suggested approaches for establishing dietary guid ance for chromium. Identification of a sensitive indica tor of chromium status that could be used in a clinical setting would promote the collection of additional data needed to determine a RDA for chromium. Effects of trivalent chromium on regulation of insulin receptors and on transport of iron by transferrin need evaluation. Additional studies seeking and utilizing sensitive endpoints for biological function of chromium are criti cally needed. Until then, the provisional RDA, or simi lar status category, for chromium should be based on usual dietary intakes determined by analyses that avoid all sources of chromium contamination. In addition, insulin and glucose tolerance responses to small sup plements (similar to usual dietary intakes) of chro mium by individuals fed low chromium diets could be used in establishing the provisional RDA until a more specific indicator of chromium status is determined.

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SUPPLEMENT

bone than the adult (Ekstrand et al. 1994).The primary route of excretion of fluoride is the kidney. Toxlcity

Basis for fluoride recommendations When daily intakes of fluoride in infants were less than 2.6 //g [0.137 //mol]/kg body wt, urinary fluoride exceeded intake; this indicates that fluoride was being released from the bone (Ekstrand et al. 1994). When fluoride was supplemented, intakes of fluoride from a single feeding plus the supplement averaged 36.6 /zg [1.93 /¿mol]/kgand infants were always in positive bal ance. Mean plasma peak fluoride concentration was 3.3 ¿¿mol/L at this level of supplementation (Ekstrand et al. 1994). In 1995 the American Academy of Pediatrics pub lished modified recommendations for fluoride supple mentation for children. Fluoride supplementation is no longer recommended from birth and suggested doses have been decreased during the first 6 y of life. If water fluoride concentrations are >0.6 //g [0.032 //mol]/mL, fluoride supplements are not recommended (Commit tee on Nutrition 1995). Additional guidelines from the Canadian Dental Association recommend that chil dren should use only a "pea-sized" amount of fluoridecontaining dentifrice and that this dentifrice should be used no more than twice daily (Clark 1993). Another pharmacologie application of fluoride is in the treatment of postmenopausal osteoporosis. Com pared with a placebo, a dose of 75 mg [1.79 mmol] sodium fluoride/d increased mineral density in the lumbar spine and other predominantly cancellous bone sites; however cortical bone was decreased and nonvertebral fractures were higher in the treatment group (Riggs et al. 1990). Subsequently, studies using lower

not associated with skeletal fragility or the painful lower extremity syndrome (Kleerekoper and Mendlovic 1993).

Suggested approaches for establishing dietary guidance for fluoride Recommendations for fluoridation of the water ply should consider reduction in dental caries vs. dence of enamel fluorosis. Fluoride balance throughout the life cycle are needed to establish mal fluoride intakes.

sup inci data opti

LITERATURE CITED Anderson, D., Cunningham, W.& Lindstrom, T. (1994) Concentra tions and intakes of H, B, S, K, Na, Cl, and NaCl in foods. J. Food Comp. Anal. 7: 59-82. Anderson, R. & Bryden, N. A. (1983| Concentration, insulin potentiation, and absorption of chromium in beer. J. Agrie. Chem. 31:308-311. Anderson, R. A. |1987) Chromium. In: Trace Elements in Human and Animal Nutrition (Mertz, W., éd.), pp. 225-244. Academic Press, Inc. New York, NY. Anderson, R. A., Bryden, N. A., Patterson, K. Y., Veillon, C., Andón, M. B. & Moser-Veillon, P. B. (1993a) Breast milk chromium and its association with chromium intake, chromium excretion, and serum chromium. Am. J. Clin. Nutr. 57: 519-523. Anderson, R. A., Bryden, N. A., Polansky, M. M. & Deuster, P. A. (1988) Exercise effects on chromium excretion of trained and untrained men consuming a constant diet. J. Appi. Physiol. 64: 249-252. Anderson, R. A., Bryden, N. A. & Polansky, M. M. (1992| Dietary chromium intake: freely chosen diets, institutional diets, and in dividual foods. Biol. Trace Elem. Res. 32: 117-121. Anderson, R. A., Bryden, N. A. & Polansky, M. M. (1993b) Dietary intake of calcium, chromium, copper, iron, magnesium, manga nese, and zinc: duplicate plate values corrected using derived nu trient intake. J. Am. Diet. Assoc. 93: 462-464. Anderson, R. A. & Kozlovsky, A. S. (1985) Chromium intake, ab sorption and excretion of subjects consuming self-selected diets. Am. I. Clin. Nutr. 41: 1177-1183. Anderson, R. A., Polansky, M. M. & Bryden, N. A. (1984) Acute effects on chromium, copper, zinc, and selected clinical variables in urine and serum of male runners. Biol. Trace Elem. Res. 6: 327-336. Anderson, R. A., Polansky, M. M., Bryden, N. A. & Canary, J. J. (1991) Supplemental-chromium effects on glucose, insulin, glucagon, and urinary chromium losses in subjects consuming con trolled low-chromium diets. Am. J. Clin. Nutr. 54: 909-916. Ani, M. & Moshtaghie, A. A. (1992) The effect of chromium on parameters related to iron metabolism. Biol. Trace Elem. Res. 32: 57-64. Arnow, P. M., Bland, L. A., Garcia-Houchins, S., Fridkin, S. & Fellner, S. K. (1994) An outbreak of fatal fluoride intoxication in a longterm hemodialysis unit. Ann. Intern. Med. 121: 339-344. Bai, Y. &.Hunt, C. (1995) Dietary boron improves indices of mar-

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Chronic toxicity of fluorine is called fluorosis; this condition has increased in recent years (Pendrys and Katz 1989; Pendrys et al. 1994). Enamel fluorosis was strongly associated with fluoride supplementation dur ing the first 6 y of life and with fluoride dentifrice use (Pendrys and Katz 1989). Fluorosis ranges from barely perceptible white striations to brownish stains (Com mittee on Nutrition 1995). The brownish mottling of teeth is a very obvious result of excessive fluoride in the water supply (Segreto et al. 1984). Fatal fluoride intoxication was observed in hemodialysis patients because of malfunction of a deionization system used to purify dialysis solutions. With normal renal function a serum fluoride of <2 //mol/L would be expected; the hemodialysis patients who suffered acute illness or death had serum fluoride concentra tions of 59-716 //mol/L. Symptoms of toxicity in cluded severe pruritus, headache, nausea and fatal ven tricular fibrillation (Arnow et al. 1994).

doses or slow-release sodium fluoride (25 mg [0.60 mmol] twice daily) combined with calcium supplemen tation have shown lower vertebral and peripheral frac ture rates (Pak et al. 1994; Prestwood et al. 1995; Resch et al. 1993). Further research is needed to clarify the "therapeutic window" for blood fluoride levels that is

APPROACHES TO B, Cr AND F DIETARY RECOMMENDATIONS

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W. (1985) Boron toxicity and deficiency: a review. Can. J: Soil Sci. 65: 381-409. Guthrie, B. E., Wolf, W. R. & Veillon, C. (1978) Background cor rection and related problems in the determination of chromium in urine by graphite furnace atomic absorption spectrometry. Anal. Chem. 50: 1900-1902. Hahn, C. J. & Evans, G. W. (1975) Absorption of trace metals in the zinc-deficient rat. Am. J. Physiol. 228: 1020-1023. Hedlund, L. R. & Gallagher, J. C. (1989) Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J. Bone Min. Res. 4: 223-225. Hegsted, M., Keenan, M., Siver, F. & Wozniak, P. (1991) Effect of boron on vitamin D deficient rats. Biol. Trace Elem. Res. 28: 243256. Hopkins, L. L., Jr. & Schwarz, K. (1964) Chromium (IH) binding to serum proteins, specifically siderophilin. Biochim. Biophys. Acta 90: 484-491. Hunt, C. & Herbei, J. (1991 - 1992a) Boron affects energy metabo lism in the streptozotocin-injected, vitamin D3-deprived rat. Mag nesium Trace Elem. 10: 374-386. Hunt, C. & Herbei, J. (1991-1992b) Effects of dietary boron on calcium and mineral metabolism in the streptozotocin-injected, vitamin D3-deprived rat. Magnesium Trace Elem. 10: 387-408. Hunt, C. & Herbei, J. (1994) Physiological amounts of dietary bo ron improve growth and indicators of physiological status over a 20-fold range in the vitamin Da-deficient chick. In: Trace Element Metabolism in Man and Animals, vol. 8 (Anke, M., Meissner, D. & Mills, C., eds.) pp. 714-718. Gersdorf, Germany. Hunt, C. & Nielsen, F. (1981) Interaction between boron and cholecalciferol in the chick. In: Trace Element Metabolism in Man and Animals, vol. 4 (Gawthorne, J. & White, C., eds.) pp. 597600. Australian Academy of Science, Canberra. Hunt, C. (1989) Dietary boron modified the effects of magnesium and molybdenum on mineral metabolism in the cholecalciferoldeficient chick. Biol. Trace Elem. Res. 22: 201-220. Hunt, C., Herbei, J. & Idso, J. (1994) Dietary boron modifies the effects of vitamin D3 nutriture on indices of energy substrate utilization and mineral metabolism in the chick. J. Miner. Bone Res. 9: 171-181. Hunt, C., Herbei, J. & Nielsen, F. (1994) Physiological amounts of dietary boron influence magnesium and calcium metabolism in the postmenopausal woman. FASEB J. 8: A430 (abs.). Hunt, C., Shuler, T. & Mullen, L. (1991) Concentration of boron and other elements in human foods and personal-care products. J. Am. Diet. Assoc. 91: 558-568. Hunt, J., Mullen, L. & Lykken, G. (1992) Zinc retention from an experimental diet based on the U.S. F.D.A. total diet study. Nutr. Res. 12: 1335-1344. IPCS (International Programme on Chemical Safety). (1988) Chro mium. Environmental Health Criteria 61. pp. 1-197. World Health Organization, Geneva. lyengar, G., Clarke, W. & Downing, R. (1990) Determination of boron and lithium in diverse biological matrices using neutron activation-mass spectrometry (NA-MS). Fresenius J. Anal. Chem. 338: 562-566. Jeejeebhoy, K. N., Chu, R. C., Marliss, E. B., Greenberg, G. R. & Bruce-Robertson, A. (1977) Chromium deficiency, glucose in tolerance, and neuropathy reversed by chromium supplementa tion, in a patient receiving long-term total parenteral nutrition. Am. J. Clin. Nutr. 30: 531-538. Jorhem, L. & Sundstrom, B. (1993) Levels of lead, cadmium, zinc, copper, nickel, chromium, manganese, and cobalt in foods on the Swedish market, 1983-1990. J. Food Comp. Anal. 6: 223-241. Kamath, S. M., Stoecker, B. J., Whitenack, M. D., Smith, M., Adeleye, B. O. &. Sangiah, S. (1995) Indomethacin and prostaglandin £2 analogue effects on absorption, retention, and urinary excretion of 51chromium. FASEB J. 9: A577 (abs.).

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ginal vitamin D status but does not substitute for the vitamin. Book of Abstracts, New Approaches, Endpoints and Paradigms for Recommended Dietary Allowances |RDAs) of Mineral Ele ments 29 (abs.). Bakken, N. (1995) Dietary boron modifies the effects of vitamin D nutriture on energy metabolism and bone morphology in the chick. Masters of Science thesis, University of North Dakota, Grand Forks, ND. Borei, J. S., Majerus, T. C., Polansky, M. M., Moser, P. B. & Anderson, R. A. (1984) Chromium intake and urinary chromium excre tion of trauma patients. Biol. Trace Elem. Res. 6: 317-326. Brown, R. O., Forloines-Lynn, S., Cross, R. E. & Heizer, W. D. (1986) Chromium deficiency after long-term total parenteral nutrition. Dig. Dis. Sci. 31:661-664. Brown, T., McCormick, M., Morris, D. & Zeringue, L. (1989) Ef fects of dietary boron on mineral balance in sheep. Nutr. Res. 9: 503-512. Bunker, V. W., Lawson, M. S., Delves, H. T. & Clayton, B. (1984) The uptake and excretion of chromium by the elderly. Am. J. Clin. Nutr. 39: 797-802. Burt, B. A.(191982) The epidemiological basis for water fInundation in the prevention of dental caries. J. Public Health Policy 3: 391407. Casey, C. E. & Hambidge, K. M. (1984) Chromium in human milk from American mothers. Br. J. Nutr. 52: 73-77. Chang, X. & Mowat, D. N. (1992) Supplemental chromium for stressed and growing feeder calves. J. Anim. Sci. 70: 559-565. Chen, N. S. C., Tsai, A. & Dyer, I. A. (1973) Effect of chelating agents on chromium absorption in rats. J. Nutr. 103: 1182-1186. Clark, C. D. (1993) Appropriate uses of fluorides for children: guidelines from the Canadian Workshop on the evaluation of current recommendations concerning fluorides. J. Can. Med. Assoc. 149: 1787-1793. Cohen, M. D., Kargacin, B., Klein, C.B. & Costa, M. (1993) Mecha nisms of chromium carcinogenicity and toxicity. Crit. Rev. Toxicol. 23:255-281. Committee on Nutrition (1995) Fluoride supplementation for children: interim policy recommendations. Pediatrics 95: 777. Davis, M. L., Seaborn, C. D. & Stoecker, B. J. (1995) Effects of over-the-counter drugs on "chromium retention and urinary ex cretion in rats. Nutr. Res. 15: 202-210. Dean, H. T., Arnold, F. A., Jr. & Elvove, E. (1942) Domestic water and dental caries: additional studies of relation of fluoride domes tic waters to dental caries experience in 4,425 white children aged 12 to 14 years, of 13 cities in 4 states. Public Health Rep. 57: 1155-1179. Doisy, R. J., Streeten, D. H. P., Souma, M. L., Kalafer, M. E., Rekant, S. I. & Dalakos, T. G. (1971) Metabolism of chromium-51 in human subjects. In: Newer Trace Elements in Nutrition (Mertz, W. & Comatzer, W. E., eds.), pp. 155-168. Marcel Dekker, Inc. New York, NY. Dowling, H. J., Offenbacher, E. G. &.Pi-Sunyer, F. X. (1990) Effects of amino acids on the absorption of trivalent chromium and its retention by regions of the small intestine. Nutr. Res. 10: 12611271. Ekstrand, J., Fomon, S. J., Ziegler, E. E. & Nelson, S. E. (1994) Fluo ride pharmacokinetics in infancy. Pediatr. Res. 35: 157 Freund, H., Atamian, S. & Fischer, J. E. (1979) Chromium defi ciency during total parenteral nutrition. J. Am. Med. Assoc. 241: 496-498. Gibson, R. S. & Scythes, C. A. (1984) Chromium, selenium, and other trace element intakes of a selected sample of Canadian premenopausal women. Biol. Trace Elem. Res. 6: 105-116. Green, G. & Weeth, H. (1977) Responses of heifers ingesting bo ron in water. J. Anim. Sci. 46: 812-818. Greenwood, N. & Earnshaw, A. (1984) Chemistry of the Ele ments. Pergamon Press, Oxford, Great Britain.

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Schwarz, K. & Mertz, W. (1959) Chromium(III| and the glucose tolerance factor. Arch. Biochem. Biophys. 85: 292-295. Seaborn, C. D. & Stoecker, B. J. (1989) Effects of starch, sucrose, fructose, and glucose on chromium absorption and tissue concen trations in obese and lean mice. J. Nutr. 119: 1444-1451. Seaborn, C. D. & Stoecker, B. f. (1990) Effects of antacid or ascorbic acid on tissue accumulation and urinary excretion of 51chromium. Nutr. Res. 10: 1401-1407. Segreto, V. A., Camann, D., Collins, E. M. & Smith, C. T. (1984) A current study of mottled enamel in Texas. J. Am. Dent. Assoc. 108: 56-59. Spivack, A. & Edmond, J. (1987] Boron isotope exchange between seawater and the oceanic crust. Geochim. Cosmochim. Acta 51: 1033-1043. Vanderpool, R., Hoff, D. & Johnson, P. (1994) Use of inductively coupled plasma-mass spectrometry in boron-10 stable isotope ex periments with plants, rats, and humans. Environ. Health Perspect. 102 (suppl 7): 13-20. Vanderpool, R. & Johnson, P. (1992) Boron isotope ratios in com mercial produce and boron-10 foliar and hydroponic enriched plants. Agrie. Food Chem. 40: 462-466.

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