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© 2006 American Society for Nutrition J. Nutr. 136:2378-2383, September 2006

Nutritional Toxicology

Iron and/or Zinc Supplementation Did Not Reduce Blood Lead Concentrations in Children in a Randomized, Placebo-Controlled Trial1

Jorge L. Rosado2,*, Patricia López3, Katarzyna Kordas4, Gonzalo García-Vargas5, Dolores Ronquillo2, Javier Alatorre6 and Rebecca J. Stoltzfus4

2 School of Natural Sciences, Universidad Autónoma de Querétaro, Querétaro, Mexico; 3 Department of Nutritional Physiology, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico; 4 Division of Nutritional Sciences, Cornell University, Ithaca, NY; 5 School of Medicine, Universidad Juarez de Durango, Gomez Palacio, Mexico; and 6 Department of Psychology, Universidad Nacional Autónoma de México, Mexico City, Mexico

* To whom correspondence should be addressed. E-mail: jlrosado{at}avantel.net


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
There is increasing interest in the interaction of nutritional deficiencies with toxic metals. Iron deficiency and elevated blood lead concentrations (PbB) reportedly occur together, and zinc also plays an important role in lead metabolism. The objective was to evaluate the effect of zinc and/or iron supplementation on PbB of children attending schools in the neighborhood of a smelter complex for 6 mo. We conducted a double-blind, placebo-controlled field trial in 9 elementary schools located within a 3.5-km radius of a metal foundry in Torreón, Mexico. Of the 602 first-graders enrolled, 517 completed supplementation and had initial and final PbBs. Children were given either 30 mg of iron, 30 mg of zinc, both, or a placebo daily for 6 mo. Baseline and final measures included nutritional status and PbB. The overall prevalence of iron and zinc deficiencies was 12.1 and 30.3%, respectively, and 10.3% were anemic. The PbB concentration decreased in all experimental groups (P < 0.05). After controlling for initial PbB, groups administered zinc and/or iron did not have lower PbB concentrations than the placebo group (P < 0.05). In conclusion, iron supplementation of lead-exposed children significantly improved iron status but did not reduce PbBs. Zinc supplementation did not reduce PbBs independently of zinc nutritional status. Neither iron nor zinc can be recommended as the sole treatment for lead-exposed school children.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
With increased concerns about environmental pollution, the interaction of nutritional deficiencies with toxic metals has been of great interest. Iron deficiency (ID)7 is considered the most common single nutritional deficiency in the world, with an estimated one billion individuals worldwide having iron-deficiency anemia (IDA) (1). A high prevalence of zinc deficiency was reported in various countries (1–3). In Mexico, ~35 and 25% of the population have iron and zinc deficiency, respectively (2–5). Iron and zinc deficiency often occur simultaneously because the factors that exacerbate deficiency of one mineral also affect the other. Children with marginal deficiencies of zinc, iron, or both during development experience important health consequences including growth stunting (5,6), increased morbidity (7,8), and a reduction in neurocognitive function and learning capacity (9). Thus, strategies intended to improve the nutritional status of zinc and/or iron in children have received considerable attention.

The link between iron and zinc status, and blood lead concentrations (PbBs) is supported by human and animal studies. Children with ID are more likely to have elevated PbB even after controlling for age, sex, and socioeconomic variables (10–12). ID and elevated PbBs were also reported to occur together in disadvantaged pediatric populations (13). In addition, there is speculation that iron and lead compete for an absorptive pathway in the small intestine (14,15), and that in children consuming diets with inadequate amounts of iron, lead absorption is increased (16).

The effect of zinc status on PbB has received much less attention, but some in vitro and in vivo studies suggest that zinc also seems to play an important role in lead metabolism. Kumar et al. (17) found that 3 mo of zinc treatment effectively reduced lead concentrations by 20 and 51%, in kidneys and lungs, respectively, of rats exposed to lead compared with untreated controls. In a similar study, Batra et al. (18) found that lead deposition was reduced in rats that received supplemental zinc. Zinc, given orally, is thought to block the intestinal absorption of lead by inducing metallothionein (19); it was also shown to antagonize lead-induced inhibition of a heme-synthesizing enzyme, {delta}-aminolevulinic acid dehydratase (ALAD) (18,20). In another study, workers exposed to both lead and zinc rather than to lead alone had reduced excretion of urinary {delta}-aminolevulinic acid (ALAU-U) and tended to have lower PbBs (21). These effects on ALAD activity and on ALA-U excretion are related to ALAD's sensitivity to the inhibitory action of lead and its dependence on zinc.

In the past few years, studies were conducted to examine the incidence and health consequences of lead exposure in children living near the largest smelter complex in Northern Mexico (22,23). Garcia-Vargas et al. (22) found a mean PbB of 27.6 µg/dL (1.33 µmol/L) among children 6–9 y old, living and attending schools close to the smelter complex. Another study found that similar PbBs in children 7–12 y old were associated with lower scores on motor and intelligence tests, compared with same-age children who lived 4.5 km away from the smelter and had much lower PbBs (21). In the present study, we conducted a randomized longitudinal placebo-controlled investigation to evaluate the effect of a 6-mo period of zinc and/or iron supplementation on PbB, micronutrient status, and anthropometrics of children attending schools in the neighborhood of this smelter complex. The effects of supplementation on children's behavior (24) and cognition (25) were also measured.


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Subjects and experimental design. This was a randomized, double-blind, placebo-controlled trial of iron and/or zinc supplementation, conducted in the city of Torreón, in northern Mexico. The main source of lead exposure in Torreón was a smelter company. First-grade children aged 6 and 7 y (n = 724) from 9 public elementary schools located within a 3.5-km radius of the foundry were invited to participate (Table 1). The sample size was calculated to detect a 13% change in PbB postsupplementation, with an {alpha}-level of 0.05 and 80% power, according to the formula for a comparison of 2 means. A 15% loss to follow-up was taken into account in the calculations. Parental written consent was given for 602 children, 527 completed the supplementation, 517 had initial and final PbB values, and 481 had in addition PbB values 6 mo after supplementation was completed. Children were excluded from the study if their PbB was >45 µg/dL (2.17 µmol/L) or hemoglobin (Hb)was <90 g/L. One child with a PbB >45 µg/dL was referred for clinical treatment. No children were excluded based on Hb. The study was approved by committees on human research at the Johns Hopkins Bloomberg School of Public Health and the Institute of Medical Sciences and Nutrition in Mexico City. An additional approval was given by the Ministry of Education in the state of Coahuila, where the study took place.


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  		TABLE 1 Characteristics of the children at baseline12

 
The children were evaluated at baseline (T1) for PbB, zinc protoporphyrin (ZPP), as well as biochemical indicators of zinc, iron, and copper status. Anthropometric measurements, including weight, height, and knee height were also taken at baseline. Children were supplemented for 6 mo (T2), after which they were evaluated for PbB, ZPP, and the same biochemical indicators as at baseline. After another 6 mo without supplementation (T3), all assessments were repeated. Participants were assigned randomly, by classroom and gender, to 1 of 4 treatments: iron only, zinc only, both iron and zinc, or placebo. Supplements contained 30 mg iron as ferrous fumarate, 30 mg zinc as zinc oxide, or the combined treatment of 30 mg iron plus 30 mg zinc. Most of the studies giving iron and zinc to school-age children used 20–30 mg/d or 3 mg/(kg·d) as dosages for each element. Iron dosage in the study is also at a level recommended by International Nutritional Anemia Consultive Group/The United Nations Children's Fund/WHO (26). Placebo contained excipients only. All supplements were made as white tablets and indistinguishable from each other. For the purpose of blinding, each supplement was given a letter code (A–D), and neither the researchers nor the participants were aware of which letter referred to which formulation. Participants were assigned to treatment according to randomization lists that were generated (STATA software) using the treatment codes.

The supplements were distributed daily in each classroom (n = 23) during the school week by nursing students. The supplements were given individually to each child in the morning at the school, with the nurse making sure that the tablet was swallowed. For children who missed school, parents received an adequate supply of tablets for supplementation at home. During vacations, the tablets were distributed at the children's homes every 2 wk. Tablet usage was recorded daily by a student nurse at school and by the parents or caregiver during the summer vacation, based on parental reports.

    Anthropometry. Subjects were measured at baseline by the same examiner. Standardization and training of examiners was done following the WHO recommended methods as reviewed by Habicht (27). Weight was measured to the nearest 100 g using a pediatric scale (Torino, Model Express Plus) with children wearing no sweaters and no shoes. Height was measured to the nearest 1 mm using a standardized measuring board. Knee height was measured using a Knemometer to the nearest 1 mm.

    Biochemical determinations. A blood sample was collected from each child after an overnight fast at baseline, after 6 mo of treatment, and 6 mo after supplementation was completed. Plasma total zinc and copper concentrations were measured in duplicate samples by atomic absorption spectrophotometry using a Perkin-Elmer spectrophotometer. Zn and copper certified standards were used on each run of samples and were obtained from Perkin-Elmer (Analyst 700). A CV <5% was reached before analysis of actual samples. Hemoglobin concentration was determined in one drop of venous blood using HemoCue. Serum ferritin (SF) concentrations were determined in duplicate by immunoradiometric assay (Coat-A-Count Ferritin IRMA; Diagnostic Products). Cut-off points for anemia and ID were: Hb <124 g/L (adjusted for the altitude of 2300 m) (28) and SF ≥12 µg/L (29). Zinc protoporphyrin (ZPP) was determined in venous blood using a ZP Hematofluorometer (AVIV Biomedical). Lead in blood samples was determined by atomic absorption spectrophotometry adapted with a graphite furnace detector (Zeeman 5100, Perkin Elmer) according to the method described by Miller (30). A certified reference standard was used (SRM 955b, NIST). All samples were measured in duplicate with a CV of 5% with 3 different concentrations (5.01, 13.53 and 30.63 µg/dL). Recoveries ranged from 104 to 112% and the CV ranged between 3 and 10%. PbB was determined in the toxicology laboratory of the National Polytechnic Institute in México City. C-reactive-protein was analyzed as previously described (31).

    Data analysis. Height-for-age, weight-for-age, and weight-for-height Z-scores were computed using EpiInfo (CDC). Data were analyzed using SPSS v.10.0. Two outliers were removed from the analysis: ZPP at T1 with a concentration of 452 µmol/mol heme and SF at T1 of 432.1 µg/L. SF analysis was adjusted for the presence of C-reactive protein as an indicator of subclinical infection or inflammation, which could increase SF concentrations.

An ANOVA within group was performed to detect significant differences between baseline and postsupplementation values to determine short-term effects of supplementation (T2 – T1). Long-term effects were calculated by subtracting baseline values from final values (T3 – T1). To evaluate the effect of the treatments, between-group tests on change in outcomes were conducted using an ANOVA with pairwise comparisons using the Least Significant Difference test. PbB and ZPP analyses were adjusted for initial values. Values in the text are means ± SD. A difference was considered significant when P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
    Baseline characteristics. The baseline PbB was 11.4 ± 6.0 µg/dL (0.55 ± 0.29 µmol/L); 51% of the subjects had concentrations ≥10 µg/dL (0.48 µmol/L). The overall prevalences of iron (SF <12 µg/L) and zinc [Zn <65 µg/dL (<9.9 µmol/L)] deficiencies were 12.1 and 30.3%, respectively (Table 1). The supplementation groups did not differ in the prevalence of nutritional deficiencies or other demographic characteristics. However, children that received iron supplementation had a higher PbB at baseline than those that received zinc or placebo (Table 2, P = 0.015).


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  		TABLE 2 Biochemical indices in children supplemented with iron, zinc, both, or a placebo for 6 mo1

 
    Supplementation effects on lead status. PbB decreased in all groups after 6 mo of supplementation as well as 6 mo later. The changes in PbB did not differ among treatments. Long-term changes in PbB did not differ among the groups (Table 2).

    Supplementation effects on biochemical indicators of nutritional status. In the group receiving only Fe, Hb concentration increased significantly more than in the placebo group, but after another 6 mo, the change in Hb no longer differed from that of the placebo group. The Hb concentration of the groups receiving Fe and Fe+Zn increased after 6 mo of treatment, and in the long term, it was higher in all supplemented groups. Although all groups experienced an improvement in SF concentration, there was a significantly greater increase in children receiving either Fe or Fe+Zn than in children receiving placebo. However, the improvement in SF in children receiving Fe+Zn was less than that in children receiving Fe alone. This suggests that zinc antagonized the effect of iron treatment on SF (Table 2).

All supplemented groups had increases in plasma Zn concentrations, and these changes were significantly different from those in the placebo group. In the long term, only the group supplemented with Fe+Zn retained the increases over the placebo group. All groups experienced a significant reduction in plasma copper, but there were no differences among treatments. ZPP concentration was reduced in the Fe-supplemented group, and this change was significantly different from that in the group receiving placebo. Over the long term, the change in ZPP became significantly different from placebo in the Fe+Zn group (Table 2). SF was not available at the long-term assessment.


   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
Even though there was a decrease in PbB in all groups, which might be due to a general decrease in lead pollution in the area (32), this school-based randomized placebo-controlled trial demonstrated that iron supplementation of children exposed to lead from a smelting facility produced no additional reduction in blood lead concentrations, nor did zinc supplementation have an effect on the same children. The lack of an effect of iron and zinc supplementation on blood lead was maintained when measured after another 6 mo without supplementation. We also examined the effects of iron and/or zinc supplementation on the nutritional status of lead-exposed children. We found that in the short term, iron significantly improved iron status (both SF and Hb concentrations), and zinc improved serum zinc in these children. Over the long term, these improvements in micronutrient status could no longer be detected.

The limited number of studies investigating the effects of micronutrient supplementation on children's PbBs yielded similar results. Wolf et al. (33) compared the effects of oral iron and placebo given to Costa Rican infants with varying degrees of ID and anemia. They found the greatest decrease in lead levels among nonanemic children with depleted iron stores, followed by children with iron deficiency. Thus, the beneficial effect of iron supplementation on PbB appears to be dependent on iron status. In another study, iron-deficient children aged 2–5 y received 200 mg/d of ferrous sulfate (34). PbBs were compared after 4 mo between children with low [<17.5 µg/dL (<0.84 µmol/L)] and high PbB [17.5–40.0 µg/dL (0.84–1.93 µmol/L)], and between 2 high PbB groups, one receiving Fe and the other placebo. There were no group differences in PbB changes over time. In fact, the high PbB children given Fe, when compared with blood lead and Hb with placebo children, had a significant increase in blood lead over time. Finally administering supplemental Ca to produce a daily intake of 1800 mg was also unsuccessful in reducing PbBs of young children compared with placebo (35).

Children in our study had Hb and SF concentrations of 133 ± 8.0 g/L and 26.8 ± 15.5 µg/L (60.2 ± 34.8 pmol/L); only ~10.3% were anemic and 12.1% had low SF. No significant interactions were present between baseline Hb status and Fe supplementation on PbBs (data not shown), but the small number of deficient children does not permit conclusive statements about iron effects on PbB in this subgroup. Thus, our results do not rule out the possibility of a more beneficial effect of iron in reducing blood lead in ID populations. Cross-sectional studies found an association between ID and increased PbBs (36–39) and 2 recent longitudinal studies also concluded that ID is a predisposition to lead poisoning (12,40). In all of these studies, the effect was attributed to an increase in lead absorption among ID individuals.

Previous studies found that iron may interfere with lead excretion and elevate blood lead concentrations (34,41). We did not find any evidence to support this claim. The earlier studies (34,41) were conducted using children with much higher lead concentrations before treatment [31.1 µg/dL (1.50 µmol/L) and 28.3 µg/dL (1.37 µmol/L), respectively] than our own [11.4 ± 6.0 µg/dL (0.55 µmol/L)]. In addition, one of the studies had a very small sample size, and thus limited power to detect changes (34); the other study did not randomize children to treatments (41) and all ID children received iron supplements, thus precluding the authors from comparing the efficacy of iron with placebo.

We did not find any effect of zinc supplementation on children's PbBs, even though there was a significant increase in plasma zinc in these children. Evidence from animal studies (18,42,43) suggests that zinc could be an antagonist to lead; moreover, a study with children found an inverse relation between zinc intake and PbB (44). Nevertheless, as in our study, Lauwerys et al. (45) found no benefits associated with 60 mg elemental zinc on PbB or ZPP in 10 lead smelter workers supplemented for 2 mo. In that study of adults, there was no evidence of zinc deficiency, whereas in our study, 30.3% of the children had low plasma zinc [<65 µg/dL (9.9 µmol/L)]. We performed an analysis of the effects of zinc in children with low plasma zinc and found no difference in the change in PbB between treated and untreated children (data not shown). Our study adds to the previous observation in adults that zinc supplementation does not reduce PbBs regardless of the initial zinc status.

There are several possible explanations for the limited efficacy of iron and zinc in this study. First, excess iron (46) and zinc are thought to inhibit lead absorption from the small intestine. However, it is not clear whether micronutrients given orally would play an equally protective role against inhaled lead as they do against lead absorbed from the intestine. Second, the supplementation in this study lasted for 6 mo. It is possible that with longer treatment or a higher dosage, the effect size would have been larger. However, it is also likely that we were not successful in lowering PbBs because the children in our sample had been exposed to lead for a long time and continued to be exposed during supplementation. Micronutrients, if given alone, may simply not be sufficient to rid the body of lead burdens.

We showed that supplementation with iron and zinc is useful for improving the micronutrient status of lead-exposed populations. These supplements, however, given daily at the levels of 30 mg/d for 6 mo to school-age children, were not very effective in lowering PbBs. Furthermore, when treatment was discontinued, whatever small improvements were observed in the Fe-supplemented group disappeared over time. This was a large, randomized, placebo-controlled trial and the strong design is a major strength of this study. Furthermore, our findings are generalizable to populations with low-to-moderate lead exposures. Most children in developed countries, such as the United States, in which the prevalence of lead exposure is comparatively low, have PbBs <15 µg/dL (0.72 µmol/L) (29). Furthermore, the accompanying iron and zinc deficiency anemia is also likely to be of low-to-moderate prevalence. In sum, iron and/or zinc supplementation are of limited application for treating lead toxicity.


   ACKNOWLEDGMENTS
 
We thank Carina Sosa for her contribution in data collection, Dr. Arturo Cebrian for his assistance in field work, Eunice Vera for chemical analyses, and Maria del Carmen Caamaño for her assistance in the development of the present manuscript.


   FOOTNOTES
 
1 Supported by funding from the Spencer Foundation, Chicago, IL. Back

7 Abbreviations used: ALAD, {delta}-aminolevulinic acid dehydratase; ALAU-U, urinary {delta}-aminolevulinic acid; Hb, hemoglobin; ID, iron deficiency; IDA, iron deficiency anemia; PbB, blood lead concentration; SF, serum ferritin; T1, time at baseline; T2, time after 6 mo supplementation; T3, time after another 6 mo without supplementation; ZPP, zinc protoporphyrin. Back

Manuscript received 30 January 2006. Initial review completed 22 March 2006. Revision accepted 24 May 2006.


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 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
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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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