Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 2014-2021 (doi:10.1542/peds.2005-2440)
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Iron Fortification Reduces Blood Lead Levels in Children in Bangalore, India

Michael B. Zimmermann, MD, MSca, Sumithra Muthayya, PhDb, Diego Moretti, PhDa, Anura Kurpad, MD, PhDb and Richard F. Hurrell, PhDa

a Laboratory for Human Nutrition, Swiss Federal Institute of Technology, Zürich, Switzerland
b Institute of Population Health and Clinical Research, St John's National Academy of Health Sciences, Bangalore, India


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Chronic lead poisoning and iron deficiency are concentrated in urban children from lower socioeconomic strata, and both impair neurocognitive development. Our study objective was to determine if iron fortification reduces blood lead levels in urban, lead-exposed, iron-deficient children in Bangalore, India.

DESIGN, SETTING, AND PARTICIPANTS. A randomized, double-blind, controlled school-based feeding trial was done in 5- to 13-year-old iron-deficient children (n = 186). At baseline, a high prevalence of lead poisoning was found in the younger children. Subsequently, all 5- to 9-year-old children participating in the trial (n = 134) were followed to determine if iron fortification would affect their blood lead levels.

INTERVENTION. Children were dewormed and fed 6 days/week for 16 weeks either an iron-fortified rice meal (~15 mg of iron per day as ferric pyrophosphate) or an identical control meal without added iron. Feeding was directly supervised and compliance monitored.

OUTCOME MEASURES. Hemoglobin, serum ferritin, C-reactive protein, transferrin receptor, zinc protoporphyrin, and blood lead concentrations were measured.

RESULTS. The prevalence of iron deficiency was significantly reduced in the iron group (from 70% to 28%) compared with the control group (76% to 55%). There was a significant decrease in median blood lead concentration in the iron group compared with the control group. The prevalence of blood lead levels ≥10 µg/dL was significantly reduced in the iron group (from 65% to 29%) compared with the control group (68% to 55%).

CONCLUSIONS. Our findings suggest providing iron in a fortified food to lead-exposed children may reduce chronic lead intoxication. Iron fortification may be an effective and sustainable strategy to accompany environmental lead abatement.

Key Words: anemia • children • lead toxicity • iron deficiency • fortification

Abbreviations: WHO—World Health Organization • DMT1—divalent metal transporter 1 • AAS—atomic absorption spectroscopy

Iron deficiency is a major health problem worldwide, and children are particularly vulnerable because of their rapid growth and increased iron requirements.1 Similarly, chronic lead poisoning mainly affects young children because they have more hand-to-mouth activity and absorb lead more efficiently than adults.2,3 Both disorders tend to be concentrated in children from lower socioeconomic strata residing in urban environments.4,5 In developing countries, lead poisoning is an increasing health hazard as a result of rapid urbanization, the use of leaded fuels, and industrial pollution.6,7 In the larger cities of China, South Asia, and Africa, 20% to 78% of children have elevated blood lead levels.6–12 At the same time, the World Health Organization (WHO) estimates that nearly half of school-aged children in developing countries are iron-deficient.1 Both iron deficiency13,14 and lead poisoning15–17 can permanently impair neurocognitive development in children.

Because iron and lead share a common intestinal transporter that is upregulated during iron deficiency,18 iron-deficient diets may enhance lead absorption.19 Thus, increasing dietary iron intake should be beneficial in lead-exposed populations. Several cross-sectional studies have found an association between iron deficiency and lead poisoning,20–23 whereas others have not.24–27 Hammad et al21 reported that within strata of high, medium, and low environmental lead exposure, children with iron deficiency had significantly higher blood lead levels than iron-replete children. However, whether iron deficiency increases risk for lead poisoning remains unclear; it may simply cluster together with lead exposure in poor urban environments. If it is a causative factor, prevention and treatment of iron deficiency in children could help reduce risk of lead poisoning.28,29 Wright et al,30 in a longitudinal study of 1- to 4-year-old children, found a four- to fivefold increased risk of subsequent lead poisoning associated with baseline iron deficiency.

Cross-sectional studies generally report inverse associations between dietary iron and blood lead levels.22,31 However, studies have also suggested iron supplementation may elevate blood lead levels,32–35 raising concern that providing iron in high-risk populations may increase vulnerability to the adverse effects of lead. The US Centers for Disease Control and Prevention recommends an iron-rich diet for children at risk for lead poisoning but has emphasized the need for randomized trials to determine if providing iron to children will reduce their blood lead levels.4,36 Iron fortification is gaining momentum worldwide as a sustainable measure to combat iron deficiency,37 and new programs are being introduced in countries (eg, China, South Africa, India) where rapid urban and industrial development places children at risk for lead poisoning.38,39 In Bangalore, a city in south India with a population >6 million, 31% of children <12 years old have blood lead levels ≥10 µg/dL.8 As part of an iron fortification trial in Bangalore, we investigated whether providing iron would reduce blood lead levels in iron-deficient children.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was done in the Franciscan Institute, a primary school in Bangalore. The students in the school are from a crowded urban neighborhood without running water or proper sanitation. The school has a lunch-feeding program in which children are fed a simple rice meal daily. We screened a random selection of children in grades 1 through 4 (N = 109; aged 5–10 years) in March 2004 and found 30% were anemic and 51% iron-deficient according to WHO criteria.1

We conducted a randomized, double-blind, controlled efficacy trial of iron-fortified rice at the school from August 2004 to March 2005 (Fig 1). Ethical approval for the study was given by St John's Medical College in Bangalore and the Swiss Federal Institute of Technology in Zürich. Informed written consent was obtained from parents and oral assent from participating children. In preparation for the feeding trial, all children in grades 1 through 4 (N = 557) who gave consent were screened. Weight and height were measured and 5 mL of whole blood was collected by venipuncture for determination of hemoglobin, serum ferritin, serum transferrin receptor, serum C-reactive protein, and whole-blood zinc protoporphyrin. All children who were iron-deficient, defined as either serum ferritin <15 µg/L or transferrin receptor >7.6 mg/L,1,40,41 were invited to join the feeding trial (N = 186; aged 5–13 years). This included both nonanemic and mildly anemic children. Children with hemoglobin levels ≤90 g/L were excluded from the study and received oral iron supplementation.


Figure 1
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  		FIGURE 1 Flow diagram of the study. Hb indicates hemoglobin; SF, serum ferritin; TfR, serum transferrin receptor; ZPP, whole-blood zinc protoporphyrin; BLL, blood lead concentration.

 
The children were randomly assigned into 2 groups. One group received an iron-fortified rice meal at midday; the other received an identical control meal. Rice was fortified with iron using artificial rice grains produced by extrusion (10 mg iron/g of extruded rice) containing micronized ferric pyrophosphate (mean particle size 2.5 µm), mixed at 1:50 with natural rice grains, for a final concentration of 0.2 mg iron per gram of rice.42 One hundred grams of iron-fortified rice (including the extruded grains with iron) or unfortified rice (including no extruded grains) were used to prepare 3 simple, traditional rice meals: tomato rice, lemon rice, and mixed-vegetable rice. The 3 meals were designed to be similar in energy and nutrient content; on average, they contained ~2100 kJ (~500 kcal), 86 g carbohydrate, 13 g fat, 8.9 g protein, 15 mg vitamin C, and 1.8 mg iron. The fortified rice meals contained an additional 20 mg fortification iron per day. Based on estimated iron absorption from the micronized ferric pyrophosphate of 2% to 3%,43 consumption of the entire meal would provide an additional ~0.5 mg of absorbed iron per day.

The meals were prepared daily at the Institute of Population Health and Clinical Research at St John's National Academy of Health Sciences. Technicians used for the project supervised the cooking, packed the meal for each child in a color-coded container, and transported it to the school. The rice meals were fed 6 days a week, excluding school holidays, with the 3 rice meals given in a repeating sequence. Feeding was directly supervised each day, and daily leftovers from each child were weighed and recorded. For quality control, every week 1 of the iron-fortified and nonfortified rice meals was freeze-dried, ground, and the iron content measured in triplicate portions. The total duration of the feeding study was 30 weeks, the length of the school year. Both groups were dewormed using 400-mg oral doses of albendazole (Locost Standard Therapeutics, Bangalore, India) at baseline and again at 14 weeks. Hemoglobin, serum ferritin, transferrin receptor, C-reactive protein, and zinc protoporphyrin were measured at baseline and at 14 and 30 weeks. The study was double-blind.

At baseline, because our subjects came from an unclean urban environment, we wanted to determine the potential bias of increased body lead on zinc protoporphyrin concentrations as a measure of iron status. In a small subsample of children (n = 20; aged 5–9 years), concentration of blood lead was determined on venous blood collected into EDTA-treated tubes with all collection materials verified as free of significant lead contamination (see subsequently). We found median (range) blood lead was 11.6 (2.6–24.1) µg/dL, and 65% of children had a blood lead levels ≥10 µg/dL. Subsequently, at the midpoint and final measurements of the study (14 and 30 weeks), blood lead concentration was measured in all 5- to 9-year-old children (N = 134) participating in the study. Younger children (<10 years old) were studied because they are at higher risk for chronic lead poisoning than older children.6,8,44

Laboratory Analyses
Hemoglobin was measured on the day of collection using an AcT8 Coulter Counter (Beckman Coulter, Krefeld, Germany) with 3-level controls provided by the manufacturer. Zinc protoporphyrin was measured on washed red blood cells within 48 hours of blood collection using a hematofluorometer (Aviv Biomedical, Lakewood, NJ) with 3-level control materials provided by the manufacturer. Normal reference values for zinc protoporphyrin on washed red cells are ≤40 µmol/mol heme.45 Serum samples were aliquoted and frozen at –20°C until analysis. C-reactive protein was measured using nephelometry (TURBOX; Orion Diagnostica, Espoo, Finland) with control material provided by the manufacturer; normal reference values are ≤10 mg/L. Serum ferritin and transferrin receptor were measured using immunoassays (RAMCO, Houston, TX). Iron deficiency was defined as either serum ferritin <15 µg/L or transferrin receptor >7.6 mg/L,1,40,41 and anemia was defined as a hemoglobin level <115 g/L.1 Iron in the rice meals was measured using atomic absorption spectroscopy (AAS) (Spectra AA-50; Varian Techtron Pty Ltd, Mulgrave, Australia).

Blood lead concentration was measured in duplicate by anodic stripping voltammetry using an ESA model 3010B blood lead analyzer (ESA, Ch, MA) with 3-level control material in the Department of Biochemistry and Biophysics at St John's Medical College in Bangalore. The method has an operating range of 1 to 100 µg/dL and a detection limit of 1 µg/dL. The relative standard deviation of the method in this laboratory is 5.8% at lead concentrations ≤10 µg/dL (n = 84) and 2.7% at concentrations >10 µg/dL (n = 88) within Centers for Disease Control and Prevention recommendations for precision.46 All blood collection materials used (needles, syringes, collection, and storage tubes) were checked for lead contamination by leaching with dilute nitric acid and analyzing the leachate for lead46 using AAS (Spectra AA-50; Varian Techtron Pty Ltd) and commercially available standard (Titrisol; Merck, Darmstadt, Germany) at the Human Nutrition Laboratory in Zürich. Materials were determined to be free of significant contamination if the leachate had a lead concentration <1 µg/L (the detection limit by AAS). Although not a threshold level below which lead has no adverse effect,17 a blood lead ≥10 µg/dL has been proposed by Centers for Disease Control and Prevention and the WHO as the "level of concern,"4,47 and we used this cutoff as 1 measure to assess lead burden in our population.

Statistical Analysis
Data processing and statistics were done using SPLUS-2000 (Insightful Corp, Seattle, WA) and Excel (XP 2002; Microsoft, Seattle, WA). Normally distributed data were expressed as means ± SD. By calculating a Box-Cox transformation, serum ferritin, transferrin receptor, zinc protoporphyrin, and blood lead concentrations were found to be not normally distributed. Their values were expressed as medians (range), and they were transformed for comparisons. To obtain optimal normalization, a square root transformation was done for serum ferritin and blood lead, and a –1/square-root transformation for transferrin receptor and zinc protoporphyrin. Because of the confounding effect of infection/inflammation on serum ferritin, serum ferritin data from children with an elevated C-reactive protein (~2% of children) were not included in the analysis.35 A 2-factor repeated-measures analysis of variance was done to compare effects of time and group and time-by-group interaction for hemoglobin, serum ferritin, C-reactive protein, transferrin receptor, zinc protoporphyrin, and blood lead. If the interaction effect was significant, t tests between groups and paired t tests within groups were done and adjusted for multiple comparisons (Bonferroni correction). McNemar's {chi}2 test with continuity correction was done to compare the change in frequencies of iron deficiency and blood lead concentrations <10 and ≥10 mg/dL. P values <.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tables 1 and 2 show the baseline characteristics of the subjects (N = 134). There were no significant differences between groups at baseline, with the exception of the gender ratio. The ratio of boys/girls in the iron and control groups was 46/20 and 34/34, respectively (P < .01). The mean weight of the rice meals was 414 g, and the daily mean (± SD) consumption of the rice meals was 288 ± 107 g in the iron group and 301 ± 107 g in the control group. The mean iron content of the fortified rice meals was 22.0 ± 4.7 mg. Based on the mean daily consumption of ~70% of the fortified rice meals, the additional iron provided by the meals to the iron group was ~15 mg per day. There were a total of 81 feeding days over the 16-week study period.


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  		TABLE 1 Characteristics of the 5- to 9-Year-Old Indian Schoolchildren Randomly Assigned to Receive the Iron-Fortified Rice Meals and the Control Meals Containing No Added Iron

 

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  		TABLE 2 Changes in Iron Status and Blood Lead Concentration in 5- to 9-Year-Old Indian Children Receiving the Iron-Fortified Rice or the No-Iron Control Rice

 
Four children were absent from school on retesting at 16 weeks: 3 in the iron group and 1 from the control group. Weights and heights between groups did not differ at 14 or 30 weeks. Over 70% of the children were iron-deficient at baseline, and the prevalence of mild anemia (hemoglobin levels: 90–115 g/L) was 21%. Because most of the children were iron-deficient but nonanemic, there was no significant change in hemoglobin in either group during the study; mean ± SD hemoglobin in the iron and control groups at 30 weeks was 117 ± 8 and 114 ± 10 g/L, respectively (not significant). There was also no change in the median (range) C-reactive protein during the study; at 30 weeks, the values were 3 (0–28) mg/L and 2 (0–22) mg/L in the iron and control groups, respectively (not significant).

Table 2 shows the changes in iron status and blood lead during the study. There were no significant gender differences in iron status or blood lead at any point during the study (data not shown). Compared with the control group, serum ferritin increased significantly in the iron group (P < .05). Transferrin receptor decreased significantly in both groups, with a nonsignificant trend toward a greater reduction in the iron group (P = .07). Zinc protoporphyrin decreased significantly in the iron group compared with the control (P < .05). Increased zinc incorporation into protoporphyrin is a measure of both iron-deficient erythropoiesis and chronic lead poisoning,48 and the improvement in this variable was likely the result of both the improvement in iron status and the reduction in blood lead concentrations. The prevalence of iron deficiency was significantly reduced in the treated group compared with the control group; at 30 weeks, the prevalence of iron deficiency was 28% in the iron group and 55% in the control group (P < .01). Compared with the control group, there was a significant decrease in median (range) blood lead concentration (µg/dL) in the iron group (P < .02) (Table 2 and Fig 2). There was also a sharp reduction in the number of children with a blood lead >10 µg/dL (P < .001) (Table 2 and Fig 3) in the iron group.


Figure 2
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  		FIGURE 2 Box and whisker plots showing blood lead concentrations in 5- to 9-year-old Indian children receiving either a daily iron-fortified rice meal (n = 66) or a nonfortified control meal (n = 68) at 14 and 30 weeks. The boxes contain data between the 25% and 75% percentiles with medians; whiskers represent the ranges.

 

Figure 3
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  		FIGURE 3 Histograms showing the distribution of blood lead concentrations in the 5- to 9-year-old Indian children (n = 66) receiving iron-fortified rice at 14 weeks (gray line) and after 30 weeks (black line).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our findings indicate that improving iron status in iron-deficient, lead-exposed children reduces their blood lead levels. The 33% reduction in median blood lead in the iron group reduced the prevalence of blood lead ≥10 µg/dL from 65% to 29%, a clinically meaningful reduction in population exposure. As shown in Figure 2, because blood lead levels tend to be log normally distributed in populations, even a modest decrease in the median and the geometric SD may significantly reduce the number of individuals with levels ≥10 µg/dL. This was achieved through iron fortification of a food staple, an approach that offers advantages over iron supplementation in that it is practical, sustainable, and reaches even the poorest and most disadvantaged groups (those most likely to be lead-exposed).6,7

Our results are generalizable in that children in this study had levels of lead exposure and iron deficiency common in developing countries. Mild-to-moderate elevations of blood lead are highly prevalent in children in the developing world.6–12 In urban areas of China and India, 20% to 60% of children have blood lead levels of 10 to 30 µg/dL.8–10 In poor areas of Johannesburg, South Africa, 78% of 6- to 9-year-olds have blood lead levels between 10 and 25 µg/dL.11 In 4- to 12-year-old children in Dhaka, Bangladesh, 70% had blood lead concentrations between 10 and 20 µg/dL.12 In contrast, ~20% of preschool-aged black children in US cities have mild-to-moderate elevations of blood lead (10–25 µg/dL).49,50 Our subjects had moderate iron deficiency, with low body iron stores but most without anemia. The WHO estimates 40% to 50% of 5- to 14-year-old children in developing countries are iron-deficient but not anemic.1 Lead exposure and iron status are important determinants of cognition in school-aged children. Several longitudinal studies have found cognitive performance in schoolchildren is most strongly related to recent or concurrent blood lead levels.51,52 Verbal learning and memory in schoolchildren may also be impaired by iron deficiency, even in the absence of anemia.53

However, there are also limits to the generalizability of our findings. Our study population was 5- to 9-year-old children, and the results may not apply to children <3 years old, the group at highest risk for both lead poisoning and iron deficiency.1,4,6 Moreover, iron fortification of food staples often does not effectively reach <2-year-old children in developing countries, and their iron requirements need to be met by complementary, "home-based" fortification of weaning foods.38,39 The study was of short duration (16 weeks) and blood lead was only measured twice. Although this was sufficient time to detect a decrease in blood lead (the half-life of lead in blood is ~5 weeks), the full extent of the reduction by an iron fortification program and whether it would be sustained over the long term is uncertain. The rice meal provided a greater amount of iron (~15 mg per day) than that provided by most fortification programs.39 For example, in Chile, wheat flour fortification with ferrous sulfate at a level of 30 ppm provides school-aged children with ~8 mg of extra iron per day.38 Thus, the more modest levels of iron provided by many fortification programs may not have the same impact as the higher levels given in this study.

Misclassification of iron status likely confounded many previous studies linking iron deficiency and lead poisoning.44 In this study, iron status was clearly defined using sensitive criteria (serum ferritin, transferrin receptor), and confounding of serum ferritin by infection was reduced by excluding values from children with an elevated C-reactive protein.40 We also measured zinc protoporphyrin in washed red cells, a measure of the adverse effects of both iron deficiency and lead toxicity on the bone marrow over the preceding 120 days.48 The improvement in the transferrin receptor in the control group was likely the result of the deworming treatment at baseline. Hookworm and other intestinal parasites are present in 50% to 70% of poor Indian children,54 and deworming treatment reduces gastrointestinal iron losses and can improve iron status.55 However, both groups were treated equally in this respect. Thus, the greater improvement in iron status and blood lead in the iron group compared with the control group was the result of the effects of the iron fortification.

Most environmental lead is absorbed in the gut, and the beneficial effects of iron in this study may have been mediated through the divalent metal transporter 1 (DMT1), the common iron-lead transporter.18 Duodenal binding of iron and lead to DMT1 is competitive, but affinity of the transporter for iron is much higher than for lead. Thus, the presence of iron in the gut effectively inhibits uptake of lead. Although the iron group received 20 mg iron each day, it was given as a single lunch meal and therefore could only directly compete with lead for DMT1 for a few midday hours. Therefore, direct inhibition of lead absorption by iron is unlikely to completely explain our findings. A more likely mechanism is that, in iron deficiency, expression of DMT1 in the duodenum is sharply increased,18 increasing both iron and lead absorption.19,56 Repleting body iron in these children may have decreased their DMT1 expression and thereby decreased absorption of environmental lead.

Previous studies of iron supplementation to reduce body lead have produced conflicting results.32–34,57 In an uncontrolled study in Costa Rican infants with mean blood lead levels of 10 to 12 µg/dL, 3 months of oral iron supplementation decreased blood lead levels in those with iron deficiency, whereas intramuscular iron supplementation increased blood lead levels in those with iron-deficiency anemia.32 In an uncontrolled trial in iron-deficient children aged 18 to 30 months with blood lead levels of 25 to 55 µg/dL, iron supplementation for 6 months was associated with a slower decrease in blood lead level compared with nonsupplemented, iron-replete children.33 Similarly, in a controlled study, preschool children who received oral iron supplementation maintained higher blood lead levels than control subjects.34 A mechanism for these results was suggested by an animal study in which iron supplementation of lead-poisoned rats was associated with a redistribution of lead out of the kidneys and a decrease in urinary lead excretion.35 These studies suggested that providing iron could increase vulnerability to the adverse effects of body lead.32–35 In contrast, in an uncontrolled study in iron-deficient anemic Korean children with a mean blood lead of 7 µg/dL, supplementation with 3 to 6 mg/kg iron per day for 1 month significantly reduced the mean blood lead concentration.57 In our study, there was a clear decrease in blood lead with iron repletion. Besides differences in study design and methodology, there are several basic differences between our study and the previous studies that showed a potential adverse effect of iron.32–34 We studied older children, nearly all of who were iron-deficient but not anemic, and gave iron at much lower doses for a longer time period.

There has been a major push internationally toward iron fortification to combat anemia,37 and a main target group is young children.38,39 Both iron deficiency and lead poisoning during childhood can permanently impair cognition and intelligence,13–17 and their combined effects may be particularly severe.58 Because chelation therapy in lead-exposed children seems to produce no clear benefit on cognition,59 prevention of lead poisoning may be the only way to avoid neurotoxicity.60 Although not a solution to lead exposure, our data suggest providing iron in a fortified food to lead-exposed children is safe and may reduce chronic lead intoxication. If these findings are confirmed, iron fortification could be a simple, cost-effective strategy61 to accompany environmental lead abatement.


   ACKNOWLEDGMENTS
 
This work was supported by the Micronutrient Initiative (Ottawa, Canada) and the Swiss Federal Institute of Technology (Zürich, Switzerland).

We thank the participating children and the teachers at the Franciscan Institute (Bangalore, India). We thank Dr Paul Lohmann GmbH (Emmerthal, Germany) for providing the ferric pyrophosphate for the rice fortification. We also thank T.C. Lee (Rutgers University, New Brunswick, NJ) for providing technical assistance and rice-extrusion facilities.


   FOOTNOTES
 
Accepted Nov 23, 2005.

Address correspondence to Michael B. Zimmermann, MD, MSc, Laboratory for Human Nutrition, Swiss Federal Institute of Technology Zürich, Schmelzbergstrasse 7, LFV E 19, CH-8092 Zürich, Switzerland. E-mail: michael.zimmermann{at}ilw.agrl.ethz.ch

The authors have indicated they have no financial relationships relevant to this article to disclose.


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K. Kordas, B. Lonnerdal, and R. J. Stoltzfus
Interactions between Nutrition and Environmental Exposures: Effects on Health Outcomes in Women and Children
J. Nutr., December 1, 2007; 137(12): 2794 - 2797.
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