IRON
Explanation
This metal has not been previously evaluated for a maximum
tolerable intake by man by the Joint FAO/WHO Expert Committee on Food
Additives. WHO reports are available on Nutritional Requirements for
Iron (WHO, 1970, 1973 and 1974).
Iron oxides and hydrated iron oxides were evaluated for an
acceptable daily intake for man (based on use as colours), by the
Joint FAO/WHO Expert Committee on Food Additives in 1974, 1978 and
1979. An ADI of 0.5 mg/kg bw was established. No toxicological
monograph was issued.
Introduction
Iron is an essential trace element required by all forms of life.
In man it is required for the synthesis of haem proteins which
function in the process of oxygen transport and oxidative metabolism.
They include haemoglobin, myoglobin, the cytochromes as well as
catalase and peroxides. Other enzyme systems such as succinic
dehydrogenase, mitochondrial NADH-dehydrogenase and xanthine oxidase
contain non-haem iron. In other enzyme systems, e.g., aconitase, iron
is a co-factor. Iron occurs as a natural constituent of all foods of
plant and animal origin, and may also be present in drinking-water. In
food it occurs in three forms, iron oxides, inorganic and organic
salts, and organic complexes such as the haem iron. The chemical form
of iron is important in assessing its biological availability. In
addition, food may be fortified with iron salts or elemental iron.
Most of the iron in the diet (U.S.) is derived from meat and grain
products. The average daily intake of iron for males, age 20-34, is
estimated to be 17 mg/day, and for females 9-12 mg/day. Iron
fortification of cereal products (U.S.) could increase the intake of
iron up to 5 mg/day for males, and 1 mg/day for females. However, in
some countries the iron intake may be much higher, because of the
contamination of food during its preparation. In Ethiopia
Contamination of the cereal grain, with iron-rich soil, during
harvesting and threshing may result in an iron intake of 500 mg/day.
The contaminating iron is primarily in the form of oxides and
hydroxides (Hofvander, 1968). The Bantu diet contains large amounts of
iron which is mainly derived from the vessels used in cooking and the
preparation of fermented alcoholic beverages (Bothwell et al., 1964).
The alcoholic drink contained an average of 4 mg iron/100 ml (range
0.5 to 15). Most of the iron present in the drink is in the ionisable
form (Bothwell et al., 1964).
The level of iron in foods ranges from low (1.68 mg iron/l MJ)
for many fruits, vegetables and fats, to medium (1.68-4.6 mg/l MJ) for
red meats, chicken, eggs, whole wheat flour, etc., to high (4.8 mg
iron/l MJ) for such foods as organ tissues, fish, green vegetables and
tomatoes (NAS, 1979). Detailed information on the chemical form of
iron in food is not available. In a study in which the food consumed
in a typical six-week diet of 32 young men, it was shown that although
the total daily intake of iron was 17.2 mg, only 1 mg was in the form
of haem iron (Bjorn-Rasmussen et al., 1974).
Many factors may affect the chemical form of iron (or added iron)
in food during thermal processing, e.g., conversion of the ferric ion
to ferrous ion, particularly in the presence of ascorbic acid (Lee &
Clydesdale, 1980a). The change in iron profile resulting from the
baking process depends on the type of iron added to the enriched
flour, but the major effect is the formation of insoluble forms of
iron (Lee & Clydesdale, 1980b).
Other important dietary sources of iron include water, beverages
and iron medication. The iron content of water is usually low, but may
be as high as 5 ppm (0.0005%) in some well water (Taylor, 1970). It is
usually present as ferric hydroxide. Cider and wine may contain 2 to
16 ppm (0.0002 to 0.0016%) of iron (McDonald, 1963). Iron medication
may consist of ferrous or ferric salts or organic iron compounds. They
may contain 50 mg or more of iron per average dose.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Most of the available data have been derived from studies with
humans. In general, the rat and other animal species do not provide a
good model for humans, since there are large interspecies differences.
For example, absorption of non-haem iron is more efficient in the rat
than in humans, and haem iron is less efficiently absorbed. Growth
requirements for iron in the rat are greater, and the dietary intake
is about 100 times greater than that of humans, expressed on a body
weight basis, The data reviewed in this section are derived from
studies with humans.
Absorption
The amount of dietary iron absorbed depends on many factors
including dietary ingredients, source of dietary iron, iron content of
the diet and the body needs for iron. Studies in which a single
foodstuff biosynthetically labelled with Fe55 (vegetables grown in
hydroponic media containing 55Fe, and meat from animals injected i.v.
with 55Fe) was fed to normal human subjects showed that food iron of
animal origin was better absorbed than that of vegetable origin (5-20%
for meats, as opposed to 1-10% for vegetable iron) (Layrisse et al.,
1973). Further evaluation of mixtures of foods showed interactions
affecting the absorption of non-haem iron, whereas the absorption of
haem iron remained unchanged (Layrisse, 1975). A number of inhibitors
and enhancers of non-haem iron absorption have been identified.
Inhibitors include carbonates, oxalates, phosphates and tannates
(Conrad, 1970). Other substances increase absorption, e.g., ascorbic
acid, tricarboxylic acids, amino-acids and sugars (Conrad, 1970). Thus
protein sources, and foods containing high levels of ascorbic acid can
cause significant increases in the absorption of non-haem iron. Food
additives such as phosphates, and EDTA may cause a significant
decrease in the absorption of non-haem iron. The possible inhibitory
effects of fibre, phytates and phosphates from vegetable sources have
not been clearly established (NRC, 1979). Iron from the animal iron
storage compounds ferratin and haemosiderin is less well absorbed than
vegatable iron, but its absorption may be altered by the same factors
that influence the absorption of non-haem iron (Layrisse et al., 1975;
Kahn et al., 1968). Iron from ionisable ferric salts is less well
absorbed than that from ferrous salts. Iron from contaminants of food,
e.g., ferric hydroxide, is less well absorbed than non-haem iron, and
iron is not absorbed from ferric oxide (Derman, 1977)
Most iron is absorbed in the duodenum and upper jejunum. With the
exception of haem, it appears that food iron must be in an ionisable
form before it can be absorbed. Gastric HC1 is required for the
release of the iron from the non-haem fraction. In vitro studies on
the amount of ionisable iron in foods following treatment with gastric
juice have been used on index of the maximum amount Of iron that will
be available for absorption. Variables involved in determining the
amount of ion absorbed include (1) the quantity of a ferrous ion
available, since in normal subjects, there is a progressive decrease
in the percentage absorption as the dose increases (Bothwell & Finch,
1962); (2) Valency Of the iron since ferric salts are only half as
well absorbed as ferrous salts (Brise & Hallberg, 1962); and (3) the
mucosal regulation of absorption in which the body iron stores appear
to be a major factor, since individuals with low body stores show
increased absorption and those with excess iron stores show decreased
absorption (NRC, 1979). The amount of iron taken up by the mucosal
cell and subsequently transferred into the body in normal subjects is
regulated so that excessive iron does not store in the body.
The maximum uptake and transfer of haem iron occurs in the
duodenum. The haem is absorbed unchanged by the mucosal cells, and
iron is released from the porphyrin ring, within the cell. The iron
derived from the haem then enters the same pool as the non-haem iron.
The absorbed iron is bound to transferrin, and is transported to
storage sites in the liver, spleen, and erythropoietic bone marrow.
The iron is stored as ferretin and haemosiderin.
Iron requirements
The total body iron for an adult male has been estimated to be
about 4 g and for the female 2.5 g (ca. 38 mg/kg bw). The largest
fraction of the iron is present in red cell haemoglobin, approximately
60% in the male and 85% in the female. The other major concentrations
of iron occur in ferretin and haemosiderin, with lesser amounts in
myoglobin, erythroid marrow and cell enzymes (NAS, 1979).
The basal iron losses in the male are extremely small, and the
major losses occur through red blood cells entering the gut lumen.
Smaller losses occur from sloughing of intestinal cells, the iron
content of bile, as well as in urine (Green et al., 1968). The basal
exchange rate of iron in the normal adult male has been estimated to
be 12 µg/kg/day (6 µg/kg/day in individuals with iron deficiency). In
the adult female, the iron loss through menstrual blood losses has
been estimated to be 1.4 mg or average of 20 µg/kg/day. In addition,
there are major requirements during pregnancy. The amount of iron lost
with pregnancy and delivery has been estimated to be 2.5 mg/day
(Beaton et al., 1970). There is little information on iron loss in
infancy and childhood. The requirements for growth have been estimated
to be 30 mg/kg bw (Smith et al., 1955).
Internal iron exchange is primarily in response to the need for
iron for haemoglobin synthesis.
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
No long-term feeding studies are available. However, a number of
studies in which rats or mice were repeatedly injected i.m. with iron
dextran preparations reported the development of injection-site
tumours. Tumours distant from the injection site were not observed. No
injection-site rumours were reported in one study with monkeys.
Dextran alone failed to produce injection-site rumours. Mice and rats
injected with iron-sorbitol citric acid complex or saccharated iron
oxide developed few if any injection-site tumours (IARC, 1973).
Special studies on mutagenicity
A number of ferrous and ferric salts have been tested for
mutagenicity using the following organisms. Saccharomyces cerevisiae
strain D-4, Salmonella typhimurium strains. TA-1535, TA-1537, and
TA-1538 with and without activation. Plate tests as well as suspension
tests were run with the Salmonella strains. Ferrous lactate, ferric
pyrophosphate, ferric orthophosphate and sodium ferric pyrophosphate
were inactive in all the systems used. Ferrous sulfate was active in
the suspension tests with activation. The results indicate that the
active agent is a frame shift mutagen which strongly reverts strain
TA-1537. Ferrous gluconate was mutagenic for indicator strain TA-1538
in activation tests with primate liver preparations. It was inactive
in the other tests (Litton Bionetics, 1974, 1975a, 1975b, 1976a,
1976b).
Special studies on reproduction
Rat
An eight-generation reproduction study was carried out in Wistar
rats. Dog food containing 570 mg of iron/lb as iron oxide was fed
continuously. Rats ate an estimated 25 mg of iron/day, assuming
20 g/day of dog food consumption. No signs of toxicity were evident;
reproduction performance was superior to expected values (Carnation
Co., 1967).
In a study in which iron (iron dextran) was administered to
groups of six-week-old Sprague-Dawley rats by intramuscular injection
according to the following schedule - weeks 7 and 8, 1 × 20 mg/kg,
weeks 9 and 10, 2 × 20 mg/kg and weeks 11 and 12, 3 × 20 mg/kg - the
animals received no iron during the following week, and were then
bred. No iron was received during pregnancy. When the offspring were
six weeks old, some were randomly selected, and the treatment
repeated. The experiment was repeated for a total of five generations.
Total body iron was determined on the mothers and offspring of the
fifth generation. Reproduction parameters (litter size and growth)
were similar for treated and non-treated animals. Although treated
females had significantly more total body iron than controls,
differences in iron levels in offspring and controls were not
statistically significant (Fisch et al., 1975). When female rats were
injected i.m. with 99Fe two weeks prior to breeding, and the
offspring examined for distribution of radioactivity and non-haem
content, it was shown that 89% of the total foetal iron was present as
non-haem iron, and that 72% of this had originated from maternal iron
stores (Murray & Stein, 1970). The study was repeated under conditions
of maternal iron deficiency or overload. In the case of maternal iron
deficiency, it was shown that the foetal iron content was normal but
that more was present as haem iron and the foetus obtained more iron
from maternal absorption. Under conditions of maternal iron overload,
the foetal iron content was not increased and the foetus obtained less
iron from maternal absorption (Murray & Stein, 1971).
Special studies on teratogenicity
Ferrous sulfate, ferrous gluconate, ferrous lactate and ferric
sodium pyrophosphate were not teratogenic to the developing chick
embryo (Verrett, 1978). Teratologic evaluations of ferrous sulfate and
ferric sodium pyrophosphate have been carried out in rats and mice.
For studies in mice, groups each of approximately 24 pregnant
albino CD-1 mice were dosed by oral intubation with the test substance
from day 6 through day 16 of gestation. Body weights were recorded on
days 0, 6, 11, 15 and 17 of gestation. On day 17, all dams were
subjected to caesarean section and the number of implantation sites,
resorption sites and live and dead foetuses recorded. The body weight
of the live pups was also taken. The urinogenital tract of each dam
was examined in detail for abnormality. All foetuses were examined for
the presence of external congenital abnormalities. One-third of the
foetuses were examined for visceral abnormalities and the remaining
two-thirds for skeletal abnormalities.
For studies in rats, groups each of approximately 24 pregnant
female albino rats (Wistar derived stock) were dosed daily by oral
intubation from day 6 of gestation through day 15. Body weights were
recorded on days 0, 6, 11, 15 and 20. On day 20, all dams were
subjected to caesarean section, and observations for dams and foetuses
similar to those described in the mouse study were carried out.
Ferrous sulfate showed no maternal toxicity or teratogenic effect
at dose levels up to 160 mg/kg bw in mice and 200 mg/kg bw in rats
(Food and Drug Research Laboratories, 1974). Ferric sodium
pyrophosphate showed no maternal toxicity or teratogenic effects at
dose levels up to 160 mg/kg bw in mice or rats (Food and Drug Research
Laboratories, 1975).
Acute toxicity
Compound Species Route LD50/mg Reference
iron/kg
Ferrous fumarate Mouse Oral 516 Weaver et al., 1961
Rat Oral 2329 Weaver et al., 1961
Ferrous gluconate Mouse Oral 457 Weaver et al., 1961
Rat Oral 865 Weaver et al., 1961
Dog Oral 464 Weaver et al., 1961
Ferrous sulfate Mouse Oral 305 Weaver et al., 1961
Rat Oral 780 Weaver et al., 1961
Dog Oral 600 Weaver et al., 1961
Elemental iron Rat Oral 60-100 g/kg Shanas & Boyd, 1969
Ferric chloride Mouse Oral 500 Hoppe et al., 1955
Rat Oral 28 Hoppe at al., 1955
Ferrous carbonate Mouse Oral 3800 Hoppe et al., 1955
The effects of toxic doses of iron are characterized by initial
depression, rapid and shallow respiration, coma, convulsion,
respiratory failure and cardiac arrest. Diarrhoea and vomiting also
occur. Post-mortem examination reveals congestion and haemorrhagic
areas of the GI tract, or erosion and sloughing of the
gastrointestinal mucosa if death is delayed one or two days.
Long-term studies
Cat
Cats were maintained on cat chow containing 1900 ppm (0.19%)of
iron (equivalent to 0.27% iron oxide) for periods of two to nine
years. No adverse effects were reported (Ralston Purina, 1967).
Mink
Ten males and three females were fed iron oxide as 0.75% of their
diet (Kellog Co., 1968). Reproduction, whelping, and lactation were
seen to be similar to that of controls. Six male and four female pups
were then continued on the iron oxide diet until pelting (165 days).
Although fur quality and growth were normal, these mink had acute
nephrosis and hepatosis at pelting.
Dog
Ten dogs were fed from one to nine years on diets containing iron
oxide colorant at 570 mg/lb. Daily consumption was estimated at
428 mg/dog. Two Labradors fed one year had loose droppings, otherwise
there were no adverse effects observed (Carnation Co., 1963).
Dogs were injected with iron oxide i.v. each week for 6-10 weeks,
until a total of 0.5 or 1.0 g/kg of iron was administered to each of
two dogs, The four dogs were then followed for seven years. Hepatic
function tests and biopsies of liver, spleen, pancreas and other
organs were performed. Haemochromatosis was not induced, but
blindness, with lesions similar to retinitis pigmentosa, developed in
all dogs. No control group was included in this study (Brown et al.,
1957).
OBSERVATIONS IN MAN
Acute toxicity of iron ingested from normal dietary sources has
not been reported. However, there are numerous reports of acute
toxicity resulting from the ingestion of large overdoses of medicinal
iron, especially in small children. Death has occurred from the oral
ingestion of ferrous sulfate at doses ranging from 40 to 1600 mg/kg
(average value 900 mg/kg) (Hoppe et. al., 1955; NRC, 1977).
Iron deficiency is a major health problem. It occurs most
frequently in children, and in women of child bearing age, especially
pregnant and multiparous women. Iron deficiency is rare in adult
males, and is usually related to pathological internal bleeding. Iron
deficiency anaemia is the end stage of iron deficiency, but other
clinical effects of iron deficiency are not well characterized.
However, one important aspect of iron deficiency that has been
observed in studies with experimental animals is that it may result in
an increased absorption of toxic heavy metals. In contrast to the
widespread occurrence of iron deficiency, iron overload is a rare
condition that only occurs in a number of special situations. These
are special dietary situations or certain disease states which cause a
breakdown of the normal control of iron absorption. The end result is
an excessive body store of iron.
The Bantu of South Africa consume a diet with a very high iron
content, derived mainly from the use of iron utensils used for cooking
and the preparation of alcoholic beverages. It is estimated that the
average Bantu male consumes between 50 and 100 mg of iron daily from
beer (Bothwell et al., 1963). About 80% of the iron present in the
beer is in an ionisable form and it appears to be absorbed to the same
degree as ferric salts (Bothwell et al., 1963). Although Bantu
ingesting 100 mg of iron daily from alcoholic beverages absorb enough
iron to cause varying degrees of siderosis by middle age, there is no
evidence of abnormally high absorption rates. In fact, Bantu have a
lesser percentage absorption of iron than white subjects, presumably
due to the fact that they already have a body overload of iron
(Pirzio-Biroli & Finch, 1960). Most of the Bantu exhibit only mild to
moderate degrees of increase in body stores of iron siderosis. There
is no evidence that these deposits exert deleterious effects. However,
severe cases of siderosis are associated with fibrosis and cirrhosis
of the liver, as well as deposition of iron in the pancreas, adrenals,
thyroid, pituitary and heart in a manner similar to that found in
idiopathic haemochromatosis. The etiology of these severe adverse
effects is complicated by the presence of additional factors such as
alcoholism and malnutrition, with the possible presence of other toxic
materials in the alcoholic beverages (Bothwell, 1964).
In contrast to the effects observed in the Bantu, it should be
noted that in Ethiopia, contamination of cereal grain with iron-rich
soil may result in an iron intake of approximately 500 mg/day. This
has not been reported to result in siderosis. However, the
contaminating iron is present in the form of iron oxide and hydroxides
and is not readily available for absorption (Hofvander, 1968).
Idiopathic haemochromatosis is a disease which is characterized
by the long, slow accumulation of iron in tissues without evidence of
excessive dietary intake. The available information indicates that
this may be due to a defect in the mucosal and reticuloendothelial
handling of iron, resulting in increased rates of iron absorption even
under conditions of normal or enlarged iron stores, and also
abnormalities of the handling of iron within the body. These metabolic
defects may be caused by genetic factors. Clinical effects due to the
disease most often occur between the ages of 40 and 60. The disease is
more prevalent in males than females (Charlton & Bothwell, 1966). It
has been estimated that the incidence of idiopathic haemochromatosis
in the United States is about 1 in 10 000 (Butterworth, 1972; Crosby,
1971).
Iron overload also occurs in individuals with certain types of
anaemia, particularly when there are abnormalities in haemoglobin
synthesis such as thalassaemia major. The massive increases in body
burden of iron are due to increased absorption as well as the iron
derived from therapy in the form of numerous blood transfusions
(Bothwell & Finch, 1972).
The incidence of preclinical haemochromatosis (elevated serum
iron levels and increased iron excretion in a desferal iron excretion
test) in the general population is not known. However, a recent survey
conducted in a small community in Sweden (a population on a high iron
fortified diet) indicated that 9 of 197 men had persistently high
serum levels and abnormal indices of saturation (50%). Four of these
men were shown to have excessive iron stores (Olsson et al., 1978).
The adverse effects of excess dietary iron in normal individuals
has not been demonstrated. It is not uncommon for individuals to
ingest dietary iron supplements for extended periods. One subject was
reported to have ingested 60 mg of ferrous sulfate daily for 19 years
without any adverse effects (Murphy et al., 1953). In addition, non-
ionisable forms of iron would not be available for absorption.
However, there is concern that the individual with metabolic defects
that impair the ability to regulate iron absorption will be at risk
from excessive exposure to iron, primarily as a result of acceleration
of accumulation of iron in the body and an earlier onset of clinical
symptoms of the disease (Bothwell et al., 1978).
Recommended Dietary Allowances
The recommended Daily Dietary Allowances for Iron (Nutritional
Requirements) have been published by a number of national and
international organizations. For example, in the United States the NRC
(1980) published the following recommendations:
Infants 0.0-0.5 years 10 mg
0.5-1.0 years 15 mg
Children 1-3 years 15 mg
4-6 years 10 mg
7-10 years 10 mg
Males 11-14 years 18 mg
15-18 years 18 mg
19-22 years 10 mg
23-50 years 10 mg
50+ years 10 mg
Females 11-14 years 18 mg
15-18 years 18 mg
19-22 years 18 mg
23-50 years 18 mg
50+ years 10 mg
Pregnant *
Lactating *
* Increased iron cannot be met by the iron content of the United
States diet, nor by existing iron stores of many women; therefore the
use of 30-60 mg supplemental iron is recommended. Iron requirements
during lactation are not substantially different from those of non-
pregnant women, but continued supplementation for two to three months
after parturition is advisable in order to replenish stores depleted
by pregnancy (NRC, 1980).
WHO recommendations are contained in a number of reports (WHO,
1970, 1973 and 1974) and are summarized as follows:
Age Body weight Irona
kg mg
Children 1 7.3 5-10
1- 3 13.4 5-10
4- 6 20.2 5-10
7- 9 28.1 5-10
Male adolescents 10-12 36.9 5-10
13-15 51.3 9-18
16-19 62.9 5- 9
Female adolescents 10-12 38.0 5-10
13-15 49.9 12-24
16-19 54.4 14-28
Age Body weight Irona
kg mg
Adult man (moderately active) 65.0 5- 9
Adult woman (moderately active) 55.0 14-28
Pregnancy (later half) b
Lactation (first six months) b
a On each line the lower value applies when over 25% of calories
in the diet come from animal foods, and the higher value when animal
foods represent less than 10% of calories.
b For women whose iron intake throughout life has been at the
level recommended in this table, the daily intake of iron during
pregnancy and lactation should be the same as that recommended for
non-pregnant and non-lactating women of childbearing age. For women
whose iron status is not satisfactory at the beginning of pregnancy,
the requirement is increased, and in the extreme situation of women
with no iron stores, the requirement can probably not be met without
supplementation (WHO, 1974)
An American Medical Association Committee on Iron Deficiency has
considered the possible risk of excessive iron intake in men if the
general diet is fortified with iron to improve the iron balance in
women. The Committee stated "The recommendation that the general diet
be fortified to further increase its iron content while improving iron
balance in women raises the possible risk of excessive iron intake in
men. Since iron intake parallels caloric intake, physically active men
who need iron least will take in the most. Adequate information is not
at present available on the hazard of iron overload, but it seems
likely that a dietary iron intake of 50 mg/day in a normal man, which
might result from the provision of a 20-mg daily iron intake for
women, would be well tolerated" (JAMA, 1972).
In addition, the American Academy of Pediatricians (AAP) Task
Force on Infant Nutrition has recommended the following range of iron
in infant formulas:
Lowest Adequate 0.26 mg/l MJ
Not to Exceed 4.35 mg/l MJ
(AAP, 1982).
Comments
Iron is an essential element. There are marked differences in
the nutritional requirements for iron in adult males and females, and
by children during periods of rapid growth and by adolescents. Iron
deficiency is one of the most common nutritional deficiencies in
children, in women of child bearing age, and pregnant women. It rarely
occurs in adult men, except in cases of chronic bleeding. Dietary iron
is poorly absorbed. The chemical form of the dietary iron is an
important factor in determining the amount of iron available for
absorption. Haem iron of animal origin is better absorbed than iron of
plant origin. Iron from ferrous salt is more readily absorbed than in
ferric salts, ionisable forms of iron are more readily absorbed than
other forms, such as elemental iron, ferric hydroxide and iron oxides.
The amount of dietary iron absorbed depends on many factors including
dietary ingredients, source of dietary iron, total iron content of the
diet and the body's need for iron. Further, the amount of iron
absorbed in normal subjects is subject to mucosal regulation, so that
excessive iron is not stored in the body, unless there is considerable
dietary overload as has been reported to occur under a number of
special conditions, such as that produced by an excessive intake of
iron associated with consumption of large volumes of alcoholic
beverages by the Bantu of South Africa, or because of certain disease
states such as idiopathic haemochromatosis which results in a
breakdown in the normal control of iron absorption and distribution.
In the case of the Bantu, the adverse effects are complicated by the
presence of additional factors such as alcoholism and malnutrition. It
is not known if excessive iron in the diet of individuals with iron
absorption defects will result in an acceleration of the disease, or
if it will result in art increased incidence of preclinical
haemachromatosis in the general population.
EVALUATION
The evaluation of maximum tolerable levels of iron in the diet
must be based on (1) the chemical forms of the iron; and (2) the
differences in requirement for iron by various age-groups, and males
and females. For iron oxides and ferric hydroxide (substances which
are virtually non-absorbable sources of iron), there is a wide margin
of safety between the amounts of nutritionally required iron and
levels of this form of iron that may contaminate food. In the case of
ionisable salts, iron from ferric salts is less well absorbed than
from ferrous salts (approximately two- to threefold), and could be
tolerated at higher levels. Because of the prevalence of iron
deficiency, the presence of some additional iron in the diet is
beneficial. Although the nutritional needs for iron have been
established, there is still some uncertainty as to the maximum level
of iron that can be tolerated. Normal individuals have taken
supplements of 50 mg Fe/day (ferrous iron) for long periods of time
without any adverse effects. It is not known if increased iron intake
will result in an increased incidence of preclinical haemachromatosis
in normal individuals with adequate iron intake. However, in the case
of individuals with genetic disorders that affect iron metabolism,
increased iron in the diet may result in an acceleration of the
clinical symptoms of the disease.
In addition, it is known that the iron requirements for females
during pregnancy and lactation can only be adequately met by iron
supplementation (30-60 mg/day).
Provisional maximum tolerable daily intake for man
[0.8] mg/kg bw
The evaluation applied to iron from all sources except for iron
oxides used as coloring agents, supplemental iron taken during
pregnancy and lactation and supplemental iron for specific clinical
requirements.
REFERENCES
AAP (1983) American Academy of Pediatricians Task Force on Infant
Nutrition. Recommended ranges of nutrient levels in infant
formulas (In press)
Beaton, G. et al. (1970) Iron requirements of menstruating women,
Am. J. Clin. Nutr., 23, 275-283
Bjorn-Rasmussen, E. et al. (1974) Food iron absorption in man:
Applications of the two-pool extrinsic tag method of measure haem
and non-haem iron absorption from the whole diet, J. Clin.
Invest., 53, 247-255
Bothwell, T. H. et al. (1978) Can iron fortification of flour cause
damage to genetic susceptibles. (Idiopathic haemochromatosis and
B-thalassaemia major) Human genetics variation in response to
medical and environmental agents: Pharmacogenetics and
ecogenetics, Human Genetics, Suppl., 1, 131-137
Bothwell, T. H. & Finch, C. A. (1962) Iron metabolism, Little Brown &
Co., Boston, 1962
Bothwell, T. H., Pirzio-Biroli, G. & Finch, C. A. (1958) Iron
absorption. 1. Factors influencing absorption, J. Lab. & Clin.
Med., 51, 24-36
Bothwell, T. H. et al. (1964) Iron overload in Bantu subjects. Studies
on the availability of iron in Bantu beer, Amer. J. Clin.
Nutr., 14, 47-51
Bonnet, J. P., Hagedorn, A. B. & Oiven, C. A. (1960) A quantitative
method for measuring the gastrointestinal absorption of iron,
Blood, 15, 36-44
Brise, H. & Hallberg, L. (1962) Absorbability of different iron
compounds, Acta Med. Scandinav., 171 (Suppl. 376), 23-38
Brown, E.G., Jr et al. (1957) Studies in iron transportation and
metabolism. X. Long-term iron overload in dogs, J. Lab. & Clin.
Med., 50, 862-893
Butterworth, C. E., Jr (1972) Iron "undercontamination", J. Amer.
Med. Assoc., 220, 581-582
Carnation Co. (1967) Rat multigeneration reproduction study. Rat iron
retention study (Unpublished studies). Submitted to WHO by the
United States Food and Drug Administration
Charltron, R. W. & Bothwell, T. H. (1966) Hemochromatosis: Dietary
and genetic aspects. In: Brown, E. B. & Moore, C. V., eds,
Progress in hematology, vol. V, Grune & Stralton, N.Y.,
pp. 298-323
Conrad, M. E. (1970) Factors affecting iron absorption. In:
Hallberg, L., Harwerth, H. G. & Vannotti, A., eds, Iron
deficiency. Pathogenesis - clinical aspects - therapy, Academic
Press, London and New York, pp. 87-114
Crosby, W. H. (1971) Potential hazards of iron overload. In:
Extent and meanings of iron deficiency in the U.S. Summary
proceedings of a workshop, 8-9 March, 1971, Food and Nutrition
Board, NAS-NRC, Washington, D.C., pp. 98-100
Derman, D. et al. (1977) Iron absorption from a cereal diet containing
cane sugar fortified with ascorbic acid, Brit. J. Nutr., 38,
261-269
Fisch, R. O. et al. (1975) Potential toxicity of iron overload in
successive generations of rats, Am. J. Clin. Nutr., 28,
136-139
FAO/WHO (1974) Eighteenth Report on Food Additives
Food and Drug Research Laboratories (1974) Teratologic evaluation of
FDA 71-64 (ferrous sulphate) in mice and rats. Unpublished report
from Food and Drug Research Laboratories, Inc., Waverly, N.Y.,
United States of America. Submitted to the World Health
Organization by the United States Food and Drug Administration
Food and Drug Research Laboratories (1975) Teratologic evaluation of
FDA 73-83 (ferric sodium pyrophosphate) in mice and rats.
Unpublished report from Food and Drug Research Laboratories,
Inc., Waverly, N.Y., United States of America. Submitted to the
World Health Organization by the United States Food and Drug
Administration
Green, R. W. et al. (1968) Body iron excretion in man. A collaborative
study, Amer. J. Med., 45, 336-353
Greenberg, G. (1976) Sarcoma after intramuscular iron injection,
Br. Med. J., ii, 1508-1509
Hofvander, Y. (1968) Haematological investigations in Ethiopia with
special reference to a high iron intake, Acta Med. Scand.,
Suppl., 494, 1-74
Hoppe, J. O., Marcelli, G. M. & Tainter, M. L. (1955) A review of the
toxicity of iron compounds, Am. J. Med. Sci., 230(5), 558-571
IARC (International Agency for Research on Cancer) (1973) IARC
monographs on the evaluation of carcinogenic risk of chemical to
man. Some inorganic and organomellatic compounds, Vol. 2, Lyon
JAMA (1972) Iron in enriched wheat flour, farina, bread, buns and
rolls, 220, 855-859
Kellog Co. (1968) Mink feeding study (Unpublished study). Submitted to
WHO/FAO
Kuhn, I. N. et al. (1968) Observations on the mechanism of iron
absorption, Amer. J. Clin. Nutr., 21, 1184-1188
Lee, K. & Clydesdale, F. M. (1980b) Effect of baking on the ferrous of
iron in iron enriched bread, J. Food Sci., 45, 1500-1504
Lee, K. & Clydesdale, F. M. (1980a) Chemical changes of iron in food
drying processes, J. Food Sci., 45, 711-715
Layrisse, M. et al. (1975) Ferritin iron absorption in man, Blood,
45, 688-698
Layrisse, M. et al. (1973) Iron fortification of food: its measurement
by the extrinsic tag method, Blood, 41, 332-352
Litton Bionetics, Inc. (1976b) Mutagenic evaluation of compound. FDA
75-56. Ferrous lactate powder. Unpublished reports from the
United States Food and Drug Administration. Submitted to the
World Health Organization by the United States Food and Drug
Administration
Litton Bionetics, Inc. (1976a) Mutagenic evaluation of compound. FDA
75-36. Ferric pyrophosphate. Unpublished reports from the United
States Food and Drug Administration. Submitted to the World
Health Organization by the united States Food and Drug
Administration
Litton Bionetics, Inc. (1975b) Mutagenic evaluation of compound. FDA
73-28. Sodium ferric pyrophosphate. Unpublished reports from the
United States Food and Drug Administration. Submitted to the
World Health Organization by the United States Food and Drug
Administration
McDonald (1963) Arch. Intern. Med., 112, 82
Murray, M. J. & Stein, N. (1970) The contribution of maternal iron
stores to fetal iron in rats, J. Nutr., 100, 1023-1026
Murphy, J. W. et al. (1951) Acute poisoning report of a case and
review of the literature, Arch. pediat., 68, 303-308
National Research Council (NRC) (1979) Iron. Committee on medical and
biological effects of environmental pollutants. Sub-committee on
iron. University Park Publisher, Baltimore, MD, United States of
America
NRC (National Research Council) (1980) Recommended Dietary Allowances,
North Revised Edition. National Academy of Sciences, Washington,
D.C., United States of America
Olsson, K. S., Heedman, P. A. & Staugard, F. (1978) Preclinical
hemochromatosis in a population on a high iron fortified diet,
J. Amer. Med. Ass., 239, 1909-2000
Paton, G. R. & Allison, A. C. (1972) Chromosome damage in human cell
cultures induced by metal salts, Mutat. Res., 16, 332-336
Pirzio-Biroli, G. & Finch, C. A. (1960) Iron absorption. III. The
influence of iron stores on iron absorption in the normal
subject, J. Lab. & Clin. Med., 55, 216-220
Ralston Purina Cat Care Center (1968) Digestibility and cat
maintenance ration (Unpublished studies). Submitted to WHO by the
United States Food and Drug Administration
Robertson, A. G. & Dick, W. C. (1977) Intramuscular iron and local
oncogenesis, Br. Med. J., i, 946
Shanas, M. N. & Boyd, E. M. (1969) Powdered iron from 1681-1981:
Clin. Toxicol., 2, 37-44
Smith, N. J. et al. (1955) Iron stores in the first five years of
life, Pediatrics, 16, 166-173
Taylor, F. (1970) In: Tresh, Beale & Swelling, eds, The examination
of water and water supplies, 7th ed. Little Brown Co., Boston
Verrett, J. (1978) Toxic and teratogenic effects of GRAS salts.
Unpublished reports from the United States Food and Drug
Administration. Submitted to the World Health Organization by the
United States Food and Drug Administration
Weaver, L. C. et al. (1961) Comparative toxicology of iron compounds,
Am. J. Med. Sci., 241, 296-302
WHO Technical Report Series, No. 452 (1970) Requirements of ascorbic
acid, vitamin D, vitamin B12, folate and iron. Report of Joint
FAO/WHO Expert Group, Geneva
WHO Technical Report Series, No. 532 (1973) Trace elements in human
nutrition. Report of a WHO Expert Committee, Geneva
WHO Monograph Series, No. 61 (1974) Handbook on human nutritional
requirements, Geneva