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
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 end-
points, 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.
INDEXING KEY WORDS:
•boron •chromium •fluoride RDAs
•human
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 ap-
0022-3166/96 $3.00 ©1996 American Institute of Nutrition.
J. STOECKER
Downloaded from jn.nutrition.org by on August 11, 2009
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
' 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
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.
244 IS
2442S 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
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.
BORON
Current RDA status of boron
The text accompanying the 10th edition of the Rec
ommended Dietary Allowances (NRC 1989) noted that
"boron has long been known to be essential for the
growth of most plants." "There 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, end-
points 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
tion in relation to boron intake and human boron deple
tion/repletion studies.
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 1-
2 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
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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 (Vand-
erpool 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
 APPROACHES TO B, Cr AND F DIETARY RECOMMENDATIONS
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 poly-
hydroxyl 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 end-
product 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).
Boron transport
At physiological concentrations, inorganic boron is
essentially present in biological fluids only as the mo-
nonuclear 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 hy-
droxyl 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).
2443S
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
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(<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
Vitamin D and boron metabolism apparently are
closely linked. Boron supplementation of a low boron
diet decreased the incidence of mortality in vitamin D-
deficient chicks (0 vs. 26%) (Hunt 1989). Furthermore,
dietary boron stimulated growth in vitamin D-defi-
cient, 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 community-
based 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-hydroxycholec-
alciferol (Nielsen et al. 1990, Nielsen et al. 1992) and
did not affect serum 1,25 dihydroxycholecalciferol con
centrations (Nielsen et al. 1990).
2444S SUPPLEMENT
Mineral metabolism
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 hu-
mans; the influence is modulated by magnesium nutri-
ture. 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 calci-
tonin and ionized calcium, but not total calcium con
centrations (Nielsen et al. 1990).
Boron and growth cartilage and bone 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
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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 (Bak-
ken 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
 APPROACHES TO B, Cr AND F DIETARY RECOMMENDATIONS
taken together, can be used to establish a provisional
boron RDA.
Suggested approaches for assigning a provisional
RDA for boron
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.
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
2445S
Hg [0.38-0.77 //mol] Cr/d for 6-12 mo. The ESADDI
established for young children was 20-80 //g [0.38-
1.54 //mol] Cr/d and for adolescents is 30-120 //g [0.58-
2.31 //mol] Cr/d.
Dietary chromium sources and usual intakes
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
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(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 utilization
Intestinal absorption of trivalent chromium is low
with estimates in fasted rats ranging from <0.5 to 2-
3% (Davis et al. 1995, Mertz 1969). In a metabolic
balance study, two men consuming an average of 36.8
2446S SUPPLEMENT
//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 andphy-
tate decreased 5lCr in blood, whole body, and urine of
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). Intraperito-
neal 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
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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, Offen-
bacher 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
 APPROACHES TO B, Cr AND F DIETARY RECOMMENDATIONS
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]chro-
mium/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 end-
points 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.
FLUORIDE
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
2447S
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
Downloaded from jn.nutrition.org by on August 11, 2009
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 re-
constitution 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 (Eks-
trand et al. 1994).
Factors affecting fluoride utilization
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
2448S SUPPLEMENT
bone than the adult (Ekstrand et al. 1994).The primary
route of excretion of fluoride is the kidney.
Toxlcity
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 hemodi-
alysis 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).
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/Lat 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 fluoride-
containing 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 nonver-
tebral fractures were higher in the treatment group
(Riggs et al. 1990). Subsequently, studies using lower
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
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 sup
ply should consider reduction in dental caries vs. inci
dence of enamel fluorosis. Fluoride balance data
throughout the life cycle are needed to establish opti
mal fluoride intakes.
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