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    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 g/kg/day (6 g/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 g/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.

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    See Also:
       Toxicological Abbreviations
       IRON (JECFA Evaluation)