Iron deficiency, which is the most frequent and widespread nutritional deficiency in the world, affects approximately one-third of the world's population1), and occurs most frequently in rapidly growing children aged 6 months to 3 years who have an inadequate dietary iron intake2). Iron deficiency is the only micronutrient deficiency that is also prevalent in virtually all developed countries3). The United States (US) National Health and Nutrition Examination Surveys (NHANES) 2003-2006 found that 14.4% of children aged 1-2 years were iron deficient4). To this end, one of the US national health objectives for 2010 was to reduce iron deficiency by 5%-9% in vulnerable populations, such as toddlers aged 1-2 years and pregnant women5).

Many cross-sectional studies have found that iron-deficiency anemia (or other indications of chronic severe iron deficiency) in infancy is associated with poor cognitive development, poor motor development, and behavioral problems6,7). Longitudinal studies find persisting differences in cognitive development among children with iron deficiency8,9). Most studies report lower scores despite iron treatment and correction of anemia7,10,11).

Prolonged breast-feeding, which is a risk factor for iron deficiency in infants, is associated with increased blood manganese and lead levels12,13). Infants breast-fed over a prolonged period tend to be iron deficient, and thus have higher blood levels of other metals. However, not all infants who are breast-fed for an extended period are iron deficient. This may be due to variations in the iron status of infants depending on whether they are provided with iron-rich food during the prolonged breast-feeding.

Inhalation of metals, such as manganese, lead, and cadmium, is the most common cause of adult toxic metal exposure in environmental and occupational settings14), whereas food intake is the major source of absorbed metals in neonates and infants, who are more vulnerable than adults to metals absorbed through the intestine15). Mechanisms of iron absorption are similar to those of other divalent metals, particularly manganese, lead, and cadmium16,17), and a diet deficient in iron can lead to excess absorption of manganese12,18,19,20), lead13,21,22), and cadmium23,24,25). The gastrointestinal absorption of such divalent metals appears to involve intestinal iron transporters, such as apical divalent metal transporter 1 (DMT1)16), which also mediates the uptake of the divalent metals26). Expression of DMT1 is up regulated in the presence of low iron stores27), explaining the increased metal uptake19,20,28) and higher blood concentrations of metals in iron-deficient individuals. Among divalent metals, both manganese and lead may adversely affect neurodevelopment in children29). Iron deficiency in children may affect cognitive impairment, resulting from the deficiency itself or from the increased metal concentrations caused by the iron deficiency. Therefore, iron deficiency combined with increased manganese or lead concentrations may further affect neurodevelopment.

Manganese is a naturally occurring element abundant in the environment and is an essential dietary nutrient for humans. Because manganese is an essential element, its absorption, disposition, and biliary excretion are actively controlled by homeostatic mechanisms to maintain specific concentrations. These processes also play an important role in manganese toxicokinetics, which differ from those of nonessential, toxic metals such as lead and cadmium. Over-exposure to manganese can cause a neurologic impairment clinically known as "manganism," a motor syndrome similar to, but differentiated from, idiopathic Parkinson disease30,31,32,33). Recent epidemiological evidence suggests that low-level environmental exposure to manganese may adversely affect neurodevelopment in children29). Claus Henn et al.34) found an inverted U-shaped relationship between blood manganese concentrations and neurodevelopment in 12-month-old infants, with both manganese deficiency and manganese excess associated with lower scores. In a study conducted in Quebec, children aged 6 to 13 years who had been exposed to drinking water containing elevated levels of manganese had significantly lower intelligence quotient (IQ) scores, with a 6.2-point difference observed between children in the highest vs. lowest manganese quintiles35). Manganese exposure has also been associated with an increased risk of hyperactive behavior problems36,37).

Inhalation of manganese is the most common environmental cause of manganism14). Another source is the presence of a portal systemic shunt due to liver cirrhosis or portal vein thrombosis, which prevents the clearance of manganese via biliary excretion38,39,40). Animal and human studies have also demonstrated that iron deficiency markedly enhances intestinal absorption of manganese18,28,41). Iron shares similar absorption mechanisms with essential divalent metals, particularly manganese16). Thus, a diet deficient in iron can lead to excess absorption of manganese; therefore, iron deficiency can be a risk factor for the subsequent accumulation of manganese in the central nervous system42,43,44).

Previous studies have shown that iron deficiency increases blood manganese concentrations in adults as well20,28,41,45). However, only a small number of case studies have examined the effect of iron deficiency on blood manganese levels in infants and children46,47). We, too, recently showed that blood manganese levels are elevated among iron-deficient infants12). Iron-manganese interactions underlie gender differences in blood manganese concentrations at different life stages. There are no gender differences in blood manganese concentrations before menarche, but blood manganese concentrations become higher in postpubertal women who have lower ferritin concentrations due to menstruation20,48). Moreover, blood manganese levels become lower after menopause due to correspondingly higher ferritin concentrations49).

Lead is a widespread environmental pollutant that can damage the central nervous, renal, cardiovascular, reproductive, and hematological systems. Recently, new evidence of adverse central nervous effects at increasingly low levels of exposure is rapidly published. Blood lead concentrations significantly below 10 µg/dL are associated with negative outcomes such as reduced IQ, executive function deficits, and attention deficit hyperactivity disorder29). One of the more notable recent findings is that the slope of the dose-effect relationship between blood lead concentration and neurodevelopment is not linear, but rather supralinear, such that the rate of decline in children's IQ scores is greater at blood lead levels below 10 µg/dL than at levels greater than 10 µg/dL. In early 2012, the US Centers for Disease Control (US CDC) concluded that a blood lead concentration of 5 µg/dL places a woman's fetus at increased risk of adverse effects and warrants follow-up testing, patient education, and nutritional, environmental, and behavioral interventions to reduce lead exposure29). Also in 2012, the US CDC abandoned use of the term "level of concern" regarding childhood lead poisoning, citing a lack of evidence that any blood lead level can be considered "safe"50).

Several previous studies have assessed the temporal relationship between iron deficiency and increased blood lead concentrations13,21,51,52). A longitudinal study showed an association between iron deficiency and high blood lead levels in young children, with blood lead levels ranging from <5 µg/dL to 40 µg/dL52). In another study of children aged 10-15 years, the mean blood lead concentration was found to be 6.9 µg/dL in iron-deficient children and 4.3 µg/dL in normal children, and that iron supplementation significantly decreased blood lead concentrations in the former group21). A clinical trial assessing the impact of iron supplementation on blood lead concentrations in infants with iron deficiency found that changes in blood lead concentrations corresponded closely with changes in iron status13,51). In contrast to the studies described above, others have found no association between iron deficiency and increased blood lead concentrations53,54,55,56,57,58,59). This discrepancy may be due in part to differences in the age distribution of the study subjects, the assumptions used, or the degrees of lead exposure. For example, no association was observed in studies where the subjects were older female children or adolescents53,55,60). In postmenarche women, estrogen promotes bone mineralization and redistributes blood lead into bone; thus, women have lower blood lead concentrations than men and there is no association between high blood lead levels and iron deficiency in postmenarche adolescents owing to the overshadowing effects of estrogen on lead levels61). Some studies of children with lower blood lead concentrations (11.0 µg/dL and 11.4 µg/dL) have reported no association54,58). However, longitudinal studies of children with blood lead levels in a similar range have shown an association between iron status and blood lead concentration in children following iron supplementation21,51,52). Furthermore, we recently observed an association between iron supplementation and blood lead levels in infants with very low blood lead concentrations (1.416-1.846 µg/dL)13). Such minor increases in blood lead concentrations due to iron deficiency may have toxicological implications in children, considering the lack of evidence that any level of lead in the blood can be considered "safe."

Cadmium is a ubiquitous environmental pollutant with a biological half-life in the body exceeding 10 years. Cadmium levels in the body accumulate with age, since only a minute part of the body burden (0.01%-0.02%) is excreted per day62). Cadmium has been reported to have cumulative effects on mortality and cardiovascular, renal, and developmental diseases62), and blood cadmium concentration is a valid biomarker of recent cadmium exposure63). Cadmium levels have been reported to increase as iron stores decrease in premenopausal women48,53,64,65,66,67,68,69,70). However, no association between iron deficiency and elevated cadmium levels has been observed in postmenopausal women71,72,73) or in men70,74), and few studies to date have analyzed the association between iron deficiency and elevated cadmium levels in children53). Furthermore, the studies performed in children have yielded conflicting results. Some studies reported an association between iron deficiency and cadmium75,76), whereas others found no such association77,78), and one study reported only an association between ferritin and cadmium concentrations in female adolescents53). Our recent study showed no association between iron deficiency and cadmium concentration in infants79). In contrast, assessment of the same study subjects showed that iron deficiency was associated with increased blood lead and manganese concentrations12,13). Our finding that iron deficiency and blood cadmium levels in infants are not related79) is compatible with some previous studies in children77,78) but not with others75,76). These discrepancies may be partly owing to differences in cadmium exposure levels or to the age distribution of study participants. For example, the two studies that found an association between iron deficiency and cadmium levels documented children living in an heavily air-polluted area of Turkey75) and children with blood cadmium concentrations more than 7 folds higher than those in our previous study76). The study subjects in our previous study were infants living in a nonpolluted area who had very low blood cadmium concentrations. Furthermore, most previous studies included children and/or adolescents as study subjects, but not infants53,75,76,77,78).

The placenta may act as a partial barrier to fetal exposure to cadmium80), and only 5%-10% of maternal blood cadmium is transferred to human milk owing to metallothionein binding of cadmium in blood cells81). Cadmium concentrations tend to increase with age62,74,82,83). Thus, the likelihood of exposure to cadmium may be reduced in infants and they may not show elevated blood cadmium levels associated with iron deficiency. In contrast, lead is more abundant than cadmium in sources to which infants may be exposed, thus lead is more often absorbed by infants with iron deficiency13). Manganese is abundant in foods as an essential element, and is also easily absorbed in subjects with iron deficiency20,29,32,33).

First, the data summarized here emphasize the importance of assessing iron and hematologic status in children when addressing environmental exposure to neurotoxic metals, such as manganese and lead, and related neurobehavioral effects. Given the high prevalence of iron deficiency in children, the epidemiology of iron deficiency should be studied to assess its role as an important susceptibility factor, especially when carrying out environmental health risk assessments concerning low exposure to neurotoxic metals in children. Second, these findings indicate the possible role of exposure to neurotoxic metals in aggravating iron-related developmental and behavioral problems in children. Third, increased blood manganese and lead concentrations are probably associated with prolonged breast-feeding, which is also a risk factor for iron deficiency. Thus, babies who are breast-fed for prolonged periods should be given plain, iron-fortified cereals, or other good sources of dietary iron.