Iron deficiency associated with higher blood lead in children living in contaminated environments. (Children's Health Articles).

The evidence that iron deficiency increases lead child exposure is based primarily on animal data and limited human studies, and some of this evidence is contradictory. No studies of iron status and blood lead levels in children have accounted for environmental lead contamination and, therefore, the source of their exposure. Thus, no studies have directly determined whether iron deficiency modifies the relationship of environmental lead and blood lead. In this study, we compared blood lead levels of iron-deficient and iron-replete children living in low, medium, or highly contaminated environments. Measurements of lead in paint, soil, dust, and blood, age of housing, and iron status were collected from 319 children ages 1-5. We developed two lead exposure factors to summarize the correlated exposure variables: Factor 1 summarized all environmental measures, and Factor 2 was weighted for lead loading of house dust. The geometric mean blood lead level was 4.9 [micro]g/dL; 14% exceeded 10 [micro]g/dL. Many of the children were iron deficient (24% with ferritin < 12 ng/dL). Seventeen percent of soil leads exceeded 500 [micro]g/g, and 23% and 63% of interior and exterior paint samples exceeded 5,000 [micro]g/g. The unadjusted geometric mean blood lead level for iron-deficient children was higher by 1 [micro]g/dL; this difference was greater (1.8 [micro]g/dL) after excluding Asians. Blood lead levels were higher for iron-deficient children for each tertile of exposure as estimated by Factors 1 and 2 for non-Asian children. Elevated blood lead among iron-deficient children persisted after adjusting for potential confounders by multivariate regression; the largest difference in blood lead levels between iron-deficient and -replete children, approximately 3 [micro]g/dL, was among those living in the most contaminated environments. Asian children had a paradoxical association of sufficient iron status and higher blood lead level, which warrants further investigation. Improving iron status, along with reducing exposures, may help reduce blood lead levels among most children, especially those living in the most contaminated environments. Key words: children, environmental exposure, epidemiology, iron deficiency, lead poisoning. Environ Health Perspect 109:1079-1084 (2001). [Online 3 October 2001] http://ehpnet1.niehs.nih.gov/docs/2001/109p1079-1084bradman/abstract.html

**********

Childhood lead exposure is one of the most significant environmental health threats that affect children(1-3). Adverse effects of lead include cognitive deficits, neurotoxicity, behavior disorders, slowed growth, reduced heme synthesis, and impaired hearing (1,3-9). Although health and regulatory programs designed to reduce lead exposure are proving successful (10), many young children in the United States still have blood lead levels > 10 [micro]g/dL, the Centers for Disease Control and Prevention (CDC) level of concern (1,10-12). The prevalence of elevated blood lead levels among minority, low-income inner-city children remains several times the national average (10-12). These same children are also more likely than others to be iron deficient, a condition that affects up to 6% of young children nationally (13-16), with insufficient iron intake in up to one-third of children in some communities (17).

It is biologically plausible that iron deficiency could lead to higher lead levels in children. Controlled animal studies consistently demonstrate higher lead levels in iron-deficient animals than in iron-replete controls (18-23). The mechanism for enhanced absorption is likely to be substitution of [Fe.sup.+2] with [Pb.sup.+2] and increased active transport into the body (19,22,24,25). Similarly, it is possible that [Pb.sup.+2] may occupy vacant [Fe.sup.+2] sites in the hematopoeitic system, thereby reducing lead excretion. Clinical studies of chelation therapy suggest that iron-deficient children may retain more lead in their bodies (26,27). It is also possible that iron deficiency modifies behavior, increasing pica or hand-to-mouth behavior in children and thereby increasing ingestion exposures to lead in their environment (28,29).

Despite the consistency of results in animal studies, the findings in human studies are less definitive. Experimental studies of iron deficiency and lead uptake in human adults are not consistent (19,30-33). Several epidemiologic studies in children support a correlation between iron deficiency and higher blood lead (15,34-36). Other studies have found no relationship between iron intake or low iron stores and blood lead in children (37,38); however, these studies either used diet to measure iron status (38) or studied older children (10-18 years) and did not control for age (37), which is an important factor affecting lead absorption (39).

To date, no studies examining iron status and blood lead in children account for environmental lead contamination, and thus the source of a child's exposure. Iron deficiency may be directly associated with lead uptake and systemic retention, or lead and iron deficiency may be independent factors, both of which may be related to another factor, such as poverty. Because the sociodemographic characteristics of children who are likely to be iron deficient also puts them at higher risk of lead exposure (10), it is not certain to what extent iron deficiency directly affects blood lead levels. Nor have any studies attempted to quantify the level of protection that sufficient iron status may confer on a child. In this study we evaluate whether iron deficiency is related to increased blood lead in children living in contaminated environments; we also account for major covariates, including socioeconomic status and child age.

Methods

Selection of households and participants. Participants in the study were part of an epidemiologic study of childhood lead exposure in Sacramento, California, one of three California sites studied by the California Department of Health Services (CDHS) from 1988 to 1990. We used information from the 1980 census to identify specific census tracts with many children between ages 1 and 6 years and a high prevalence of lead risk factors, including a high proportion of older housing, low income, and minority ethnicity. We selected specific census tracts after discussions with local health officials and firsthand observation. Eligible households were enumerated by door-to-door survey. Any household with a child between 1 and 6 years of age was considered eligible. Seventy-nine percent of 2,220 households in the study area were enumerated; 483 were eligible, and 232 households participated with a total of 382 children. Of the 382 children, 28 were missing information on environmental exposure and 35 were missing measurements of ferritin, a measure of iron status, for a total of 319 children for this analysis.

Environmental measurements of lead contamination. We collected up to three interior and three exterior paint samples from different areas of peeling and/or chipping paint. We collected paint samples from intact surfaces if there was no peeling or chipping paint available. Interior and exterior trim and porches were sampled in preference to walls and siding. We used the maximum interior and exterior paint lead level to characterize the dwelling. We collected front, side, and rear-yard soil samples from the top 2.5 cm or less of soil, and used the geometric mean of these soil lead levels for the data analysis. We collected house dust samples with a vacuum cleaner with an in-line filter trapping particles > 0.3 mm at 98% efficiency. Each sample was collected from the center of a room, with preference given to areas where children were reported to spend time. Values for both concentration of lead in house dust (micrograms per gram) and loading (amount of lead per unit area, micrograms per square meter) were reported. Environmental samples were digested in nitric acid and analyzed by atomic absorption spectroscopy. Additional information is presented in Sutton et al. (40).

Environmental data, particularly dust measurements, were missing from several homes. Dust, paint, and soil lead measures were highly correlated (40). For homes with only one absent medium (i.e., dust, paint, or soil) (n = 69 children), we estimated the level of lead in the missing medium from multivariate regression equations derived from the other complete measurements. Housing age was ascertained from county tax assessor data.

Questionnaire. Interviews were administered in English, Spanish, Vietnamese, Cambodian, or Tagalog to the primary caregiver of each child. Questions addressed the child's risk factors for lead exposure, ethnicity, income, education, access to medical care, previous screening for lead poisoning, participation in day care or school, use of vitamins with iron, dwelling renovation, general health status, and a variety of other demographic and health information.

Blood lead and iron status measures. We measured lead levels and iron status in blood samples obtained by venipuncture. Lead and iron status measurements were conducted at the Metabolic Nutrition Laboratory (MNL) at Children's Hospital Oakland. We performed laboratory analysis for blood lead using graphite furnace atomic absorption spectroscopy with a detection limit of 1 [micro]g/dL. MNL participates in the California Department of Health Services Lead Proficiency Testing Program, which, in turn, participates in national proficiency testing programs (41). The average percentage differences between measured and true concentrations for 46 external proficiency samples during batch runs was 9.2% for samples < 40 [micro]g/dL. Lead concentrations in the quality control samples were established from the mean of values obtained by five nationally recognized reference laboratories. The coefficient of variation for internal quality control measurements was < 10%. Iron-related measures included ferritin, hematocrit (Hct), hemoglobin (Hgb), and mean corpuscular volume (MCV).

Ferritin is an iron-storage protein that maintains sufficient blood iron when dietary intake is inadequate. Ferritin levels may decrease, indicating low iron intake, while other measures of iron status remain normal. Therefore, low ferritin is a highly sensitive and specific indicator of iron deficiency with or without anemia. If ferritin levels are depleted, later signs of iron deficiency may develop, including low hematocrit, hemoglobin, and mean corpuscular volume (42-44). Using ferritin as the primary measure of iron status reduces the potential to misclassify low iron status. We chose ferritin levels, a priori, as the primary determinant of low iron status. For defining iron deficiency, we used a ferritin cutoff value of [less than or equal to] 12 ng/mL (3,44,45,46). A secondary analysis used other measures of iron status--Hct, Hgb, and MCV. The age-specific cutoff values to define low iron status were < 33-34% for Hct, < 11-11.2 g/dL for Hgb (47), and < 67-73 fL for MCV (15,48).

Statistical analyses. We performed all statistical analyses using SAS PC software (49,50). Measures of blood and environmental lead and ferritin were log-transformed (40).

Initial analyses used simple linear regression and scatter plots to investigate the associations among ferritin, blood lead, and covariates. We then developed multiple linear regression models to assess associations between ferritin and the dependent variable, blood lead, while accounting for potential confounders that affect blood lead and/or iron status measures [age, sex, ethnicity, socioeconomic status (SES), and reported use of vitamins with iron] (1,14, 15,45)or were significant in the bivariate analysis. For example, bivariate analyses suggested that attendance in day care or school protected against lead exposure, perhaps because children who spent more time away from their homes may receive less exposure from home contamination. Thus, we controlled for this variable in the regression model.

We performed the above analyses using both a continuous measure of ferritin and a dichotomous measure ([less than or equal to] 12 or >12 ng/mL). We also examined other measures of iron status (Hgb, Hct, MCV), both individually and as a composite measure, where iron deficiency was assigned if ferritin, Hgb, Hct, or MCV was low (as defined above). Hgb, Hct, and MCV, all later signs of iron deficiency (13,44), were not consistently related to blood lead. The results for ferritin and the composite measure of iron status were consistently related to blood lead; of these, ferritin was the best predictor of blood lead. Therefore we report results only for ferritin.

The next steps involved determining whether ferritin status modified the relationship between environmental lead and blood lead. We assigned each child to a high, medium, or low contaminated environment based on a composite measure of contamination. This measure was derived from a principal components analysis (minimum eigenvalue criteria = 1.0) that reduced the six correlated environmental variables (r = 0.15-0.65, p-value = 0.01 or less) (soil, indoor or outdoor paint, dust lead, lead loading, and housing age) to two independent environmental factors.

Table 1 presents the loadings for the variables in each factor. The first factor, Environmental Lead Factor 1, summarizes the largest share of the environmental data (eigenvalue = 2.52) and is primarily a general summary of the environmental lead variables. The second, Environmental Lead Factor 2, (eigenvalue = 1.4) is weighted most heavily by lead loading (the mass of lead per area of floor sample for house dust, micrograms per square meter) and reflects an effect of house dust lead loading that is independent from the overall household lead levels. We calculated contamination scores for each child by multiplying the loadings for each factor by the values of the associated variables and summing. We then assigned tertiles of these scores to high, medium, and low environmental contamination categories for each child.

Next, we conducted simple bivariate analyses to examine trends in blood lead levels between children with low ferritin and normal ferritin levels overall and within each level of environmental lead contamination. Results are presented for individual ethnic groups, all ethnic groups combined, and non-Asians combined. The bivariate analysis confirmed that Asians had a distinctly different relationship between blood lead levels and iron status at each level of environmental contamination. Our final model was run with and without Asians. Final results are presented for non-Asians only.

Finally, we developed a multivariate regression model with the dependent variable blood lead; the independent variables consisted of the covariates, main effects of iron status and environmental category, and an interaction term of these last two variables. We used this model to compute adjusted (least squares) mean blood lead levels for children with low and normal ferritin levels. This strategy allowed us to compare mean blood lead levels within and between environmental lead categories while adjusting for covariates, including age, sex, ethnicity, SES, reported use of vitamins with iron, and whether or not a child spent time in school or day care.

Results

Table 2 presents the study population distribution and blood lead and ferritin levels stratified by major covariates considered in the analysis. Overall, blood lead levels were similar to levels in the U.S. population as a whole at that time (geometric mean = 4.9 [micro]g/dL; maximum = 23 [micro]g/dL). However, 14% of the children exceeded 10 [micro]g/dL, the CDC level of concern. No trends with age were apparent. Blacks and Asians had higher lead levels than Hispanics and whites. Female children also had slightly higher blood lead. Higher SES, reported use of vitamins with iron, and time spent in school or day care were associated with lower lead levels.

The average ferritin level was 19.1 ng/mL (Table 2), with 24% of children having ferritin levels < 12 ng/mL. As expected, ferritin tended to increase with age. Ferritin level was somewhat lower among Hispanics, female children, those with low SES, and those who did not attend school or day care. Paradoxically, ferritin was slightly higher among children with no reported use of vitamins.

Environmental measurements demonstrate significant lead hazards in the homes of many participating children (Table 3). Seventeen percent of soil lead levels were > 500 [micro]g/g, a level associated with significant childhood exposure (1,2,51). Exterior paint lead levels were several times higher than interior paint, with 23% and 63% of interior and exterior paint samples, respectively, exceeding 5,000 [micro]g/g, the current Department of Housing and Urban Development action level for abatement (52). Seventy-six percent of homes were built before 1950, after which paint lead levels started to decline (53,54). The six environmental variables were significantly correlated (r = 0.15-0.65; p-value = 0.01).

Table 4 presents unadjusted geometric mean blood lead levels for children with low ferritin and normal ferritin levels in all ethnic groups. For the population as a whole, the mean blood lead level is slightly higher (by 1 [micro]g/dL) for children with low ferritin levels. This pattern persists within all ethnic groups, except for Asians, where children with normal ferritin levels appear to have higher blood lead levels. Excluding Asian children from the total population increases the difference in blood lead levels between children with low ferritin and those with normal ferritin levels to 1.8 [micro]g/dL.

After adjusting for the potential covariates (ethnicity, sex, age, SES, use of vitamins, and whether or not the child has spent time in school or day care), the geometric mean blood lead levels for non-Asian children with low ferritin and those with normal ferritin were 5.7 and 4.0 [micro]g/dl, respectively (t = 4.0, p-value < 0.01). Including Asian children in the model reduced the magnitude of the difference to 1.0 [micro]g/dl (t = 2.4, p-value = 0.02).

Figure 1 presents the adjusted geometric mean blood lead levels by ferritin status within low, medium, and high lead contamination categories for environmental lead factors (ELF) 1 and 2. We have not included Asian children in these adjusted analyses. Lead levels in children increase with the environmental measures of contamination, as shown in Figure 1. Children with low ferritin levels, regardless of the level of environmental contamination, have higher lead levels than do those with normal ferritin levels. The difference in blood lead levels between those with low and normal ferritin increases as the level of environmental contamination increases. (The mean difference in blood lead levels within each low, medium, and high contamination category for ELF1 = 0.7, 1.9, 3.2 [micro]g/dL, and for ELF2 = 1.7, 0.8, and 2.9 [micro]g/dL, respectively.) The results for both environmental factors are similar. The highest blood lead levels and the largest difference in mean blood lead levels between children with normal and low ferritin are seen in the highest contamination category (3 [micro]g/dL).

[FIGURE 1 OMITTED]

Including Asian children in the model tended to reduce the significance and magnitude of the difference in means within each environmental category (about 1 [micro]g/dL) but did not alter the overall pattern. For example, the difference in mean blood lead between low and normal iron-status children in highly contaminated environments was 2.8 [micro]g/dL for ELF 1 when Asians were included (p-value = 0.02), but 3.2 [micro]g/dL when Asians were excluded (p-value = 0.01). Excluding the children with estimated environmental data also did not change the results. Finally, because more than one child may have come from the same household, we randomly selected one child from each household to assess possible bias introduced by the lack of independence. Although the statistical significance of some comparisons was reduced because of the smaller sample size, the overall results were not changed (data not shown).

Discussion

Overall, we found that children with iron deficiency, as measured by low ferritin level, had higher blood lead levels than children with normal iron levels. This relationship persisted after we stratified by the level of environmental contamination measured in their homes, with the largest difference in blood lead between iron-deficient and iron-replete children living in the most contaminated environments. These results suggest that inadequate iron status may amplify the effect of lead contamination in the environment by increasing absorption and possibly retention of lead in the body and/or increasing hand-to-mouth or pica behavior and thus lead ingestion (28,29).

Our finding is consistent with several studies that have reported higher proportions of children with elevated blood lead among those with low iron levels (15,16, 34-36). Yip and Dallman (15) found that the correlation of iron deficiency and blood lead was strongest among the youngest children (1-2 years), weaker in older children, and not significant in adults. This lack of correlation between iron and blood lead in older children (10-18 years) was also reported by Hershko et al. (37). The age distribution in our study is limited to young children, who are at highest risk for lead exposure, so our results cannot be generalized to findings for older children.

The relationship of iron status and blood lead varied within ethnic groups in this population, with Asian children having an apparently paradoxical association of sufficient iron status and higher blood lead. We have no clear explanation for this unexpected finding. We have speculated about the possibility of lead-contaminated foods or cooking utensils linking both iron and lead ingestion, but no data are available. The Asian participants in our study were primarily of Southeast Asian origin. It is possible that genetic polymorphisms for [delta]-aminolevulinic acid dehydratase (ALAD) alleles (55-58), or other differences in lead binding proteins could affect blood lead independently of iron status. It is also possible that this finding was caused by chance alone. Additional research is needed to explain intraethnic patterns of lead exposure and iron status.

Our results may be affected by misclassification of iron status or environmental lead exposure. Although low ferritin status is sufficient evidence of iron deficiency (44), normal ferritin status does not necessarily indicate iron sufficiency because ferritin is an acute-phase reactant and may be elevated by infection or inflammatory disease (44). Thus, some iron deficient children may have been misclassified as iron-replete on the basis of ferritin level, which would bias our results toward the null hypothesis. Similarly, the characterization of environmental lead exposure may have been misclassified because we could not consider a child's behavioral interaction with his or her environment within a given environmental contamination category. The presence of a lead hazard in the home is a necessary but not a sufficient prerequisite for exposure to lead. Children's exposures may vary widely depending on behavior. We also did not consider dietary sources of lead exposure other than possible use of imported pottery and home remedies.

Several factors limit the generalizability of our findings. As a cross-sectional study, it is impossible to determine the temporal pattern of exposure, iron deficiency, and blood lead, so we cannot infer causal relationships between these factors. Additionally, it is possible that iron deficiency is correlated with calcium deficiency, which may also enhance lead absorption (59-61). However, the evidence for an inverse relationship between blood lead and calcium intake in the normal physiologic range is uncertain (62). Several studies suggest that ingestion of calcium inhibits lead uptake (35,38,39,59-64), but the role of chronic calcium deficiency has not been fully elucidated (62). Studies of calcium intake and blood lead themselves may be confounded by sociodemographic factors and failure to account for proximate exposure sources.

In summary, we found that iron-deficient children averaged 1-2 [micro]g/dL higher blood lead than children with adequate iron status, with as high as a 3 [micro]g/dL difference for children in the most contaminated environments. By directly controlling for environmental contamination we avoided confounding by the simultaneous presence of sociodemographic lead exposure-risk factors. Because population blood lead levels are log-normally distributed (10), small average reductions in lead levels would significantly reduce the proportion of children exceeding 10 [micro]g/dL, the CDC level of concern. Thus, improving iron status in children could, if confirmed, help achieve important public health objectives of reducing blood lead levels below this threshold, particularly for children living in difficult-to-reach contaminated environments. Both iron deficiency and lead exposure disproportionately affect minority, poor, and urban children (10). Because iron deficiency has independent effects on cognitive functioning in children that are similar to those of lead poisoning (1,8,27,65,66), there should be important prophylactic benefits for children's health and development if organized intensive iron deficiency screening, nutritional counseling, and supplementation were implemented in areas where children are at high risk of both conditions (67). Because the relationship between nutritional factors and blood lead is likely to be a complex interaction of nutritional status, individual diurnal and secular nutrient intake patterns, meal frequency, behavior, caregiver ability, and environmental contamination, additional research is urgently needed to validate current hypotheses and quantify the specific benefits of sufficient iron status while accounting for calcium and other major nutrient cations. Because of uncertainties about the benefits of nutritional factors in reducing blood lead (62), improved nutritional status must be complemented with removal of lead from children's environments.

Table 1. Loadings and eigenvalues for two environmental lead
factors derived from principal components analysis of
environmental exposure measures. (a)

                                                   Factor pattern

Components                                      Factor 1   Factor 2

Ln - Soil lead ([micro]g/g)                       0.75      -0.10
Ln -Indoor paint lead ([micro]g/g)                0.58      -0.32
Ln - Outdoor paint lead ([micro]g/g)              0.72      -0.08
Ln - Dust lead level ([micro]g/g)                 0.63      -0.49
Ln - Dust lead loading (b)([micro]/[m.sub.2])     0.30       0.83
House age (years)                                 0.79      -0.31
Eigenvalues                                       2.52       1.14

Ln, natural logarithm.

(a) Calculated with SAS Proc Factor, minimum eigenvalue = 1, no
rotation (49,50). (b) Lead loading = mass of lead per area of floor
sampled for house dust, micrograms per square meter.
Table 2. Distribution of demographic characteristics and geometric
mean blood lead and ferritin levels by demographic strata.

              Distribution of    Blood lead     Ferritin GM (a)
                total sample     GM (pg/dL)         (ng/mL)
Covariate        n = 382 (%)   ([+ or -] 1 SD)  ([+ or -] 1 SD)

Overall         381 (100) (b)   4.9 (2.5-9.5)    19.1 (8.1-45.1)
Age (years)
 1               59 (15)        5.4 (2.6-11.2)   13.3 (5.3-33.4)
 2               82 (22)        4.8 (2.6-9.0)    17.6 (7.5-41.7)
 3              102 (27)        5.0 (2.5-9.9)    19.7 (8.2-47.0)
 4               74 (19)        4.5 (2.5-7.9)    24.2 (11.8-49.9)
 5               64 (17)        4.8 (2.3-20.0)   19.9 (8.4-47.0)
Ethnicity
 Black           95 (25)        5.8 (3.3-10.0)   20.9 (9.2-47.5)
 Hispanic       152 (40)        4.4 (2.2-8.6)    16.8 (6.6-42.5)
 Asian           68 (18)        5.8 (2.9-11.6)   20.3 (8.4-48.9)
 Otherc          64 (17)        4.1 (2.0-8.4)    22.2 (11.8-41.7
Sex
 Female         194 (51)        5.1 (2.5-10.3)   16.9 (7.3-39.3)
 Male           187 (49)        4.6 (2.5-8.7)    21.5 (9.1-50.9)
SES
 Low            202 (53)        5.4 (2.9-10.1)   18.5 (7.5-46.1)
 Medium         116 (30)        4.7 (2.3-9.6)    18.2 (8.1-40.9)
 High            63 (17)        3.8 (2.1-7.1)    22.9 (10.8-46.1)
Reported use
 of vitamins
 with iron
 Yes             65 (17)        3.8 (2.0-7.2)    17.6 (7.8-39.6)
 No             316 (83)        5.1 (2.6-9.9)    19.5 (8.2-46.5)
Time spent
 in school
 /day care
 Yes            105 (28)   4.3 (2.3-8.2)    20.7 (9.5-45.2)
 No             276 (72)   5.1 (2.9-9.9)    18.5 (7.7-44.7)

GM, geometric mean.
(a) Thirty-five missing ferritin measurements; distribution of
reduced samples is very similar to total distribution, (b) One missing
blood lead measurement, (c) predominantly white.
Table 3. Descriptive statistics for environmental measurements of lead
and housing age. (a)

                       No.      No. of children
                     of homes      in homes
Medium              sampled (b)  with samples            Mean

Soil                   227            375          234 (c) [micro]g/g
Indoor paint           222            367        1,412 (c) [micro]g/g
Outdoor paint          219            360        8,430 (c) [micro]g/g
Dust concentration     188            312          180 (c) [micro]g/g
Lead loading           188            312           24 (c) [micro]g/g
Housing age            232            361           52 (d) (years)

Medium              (+ or -] 1 SD  Maximum

Soil                   104-529       2,664
Indoor paint          207-9,611    201,014
Outdoor paint        949-74,892    320,834
Dust concentration     79-411        3,105
Lead loading            5-105          886
Housing age             31-73          100

(a) Data from Sutton et al. (40). (b) Total number of homes in study:
232. (c) Geometric mean +1 SD. (d) Arithmetic mean [+ or -] 1 SD.
Table 4. Unadjusted blood lead levels by ethnicity and
ferritin status. (a)

                    Geometric mean blood lead
                         ([micro]g/dL)
   Ferritin
    status         Black     Hispanic    Asian

Low ferritin        6.6        5.5        4.6
 [+ or -] 1 SD    4.1-10.6   2.9-10.4   1.9-10.8
 n                   15         38         17
Normal ferritin     5.3        3.8        6.7
 [+ or -] 1 SD    3.1-9.2    2.0-7.2    3.6-12.3
 n                   63         93         41

                      Geometric mean blood lead
                        ([micro]g/dL)
   Ferritin                              Total without
    status        Other (b)   Total         Asians

Low ferritin        7.7         5.6          6.0
 [+ or -] 1 SD    3.8-15.5    2.8-11.0     3.3-11.0
 n                    8          78           61
Normal ferritin     3.8         4.6          4.2
 [+ or -] 1 SD     1.9-7.5    2.4-8.8       2.2-8.0
 n                   44         241           200

(a) Normal ferritin status: ferritin > 12 ng/mL; low ferritin status:
ferritin [less than or equal to] 12 ng/mL, (b) Predominantly white.

REFERENCES AND NOTES

(1.) CDC. Preventing Lead Poisoning in Young Children. A Statement by the Centers for Disease Control and Prevention. Atlanta, GA:Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, 1991.

(2.) ATSDR. The Nature and Extent of Lead Poisoning in Children in the United States: Report to Congress. Atlanta, GA:Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, 1988.

(3.) American Academy of Pediatrics. Committee on Environmental Health. Lead poisoning: from screening to primary prevention. Pediatrics 92:176-183 (1993).

(4.) Needleman HL, Gunnoe C, Leviton A, Reed R, Peresie H, Maher C, Barrett P. Deficits in psychologic and classroom performance of children with elevated dentine lead levels. N Engl J Med 300:889-695 (1979).

(5.) Needleman HL, Gatsonis CA. Low-level lead exposure and the IQ of children. A meta-analysis of modern studies. JAMA 263:673-678 (1990).

(6.) Schwartz J, Angle C, Pitcher H. Relationship between childhood blood lead levels and stature. Pediatrics 77:281-288 (1986).

(7.) Schwartz J, Otto D. Blood lead, hearing thresholds, and neurobehavioral development in children and youth. Arch Environ Health 42:153-160 (1987).

(8.) Wasserman G, Graziano JH, Factor-Litvak P, Popovac D, Morina N, Musabegovic A, Vrenezi N, Capuni-Paracka S, Lekic V, Preteni-Redjepi E, et al. Independent effects of lead exposure and iron deficiency anemia on developmental outcome at age 2 years. J Pediatr 121:695-703 (1992).

(9.) Wasserman GA, Graziano JH, Factor-Litvak P, Popovac D, Morina N, Musabegovic A, Vrenezi N, Capuni-Paracka S, Lekic V, Preteni-Redjepi E, et al. Consequences of lead exposure and iron supplementation on childhood development at age 4 years. Neurotoxicol Teratol 16:233-240 (1994).

(10.) Pirkle JL, Brody DJ, Gunter EW, Kramer RA, Paschal DC, Flegal KM, Matte TD. The decline in blood lead levels in the United States: the National Health and Nutrition Examination Surveys (NHANES). JAMA 272:284-291 (1994).

(11.) Brody DJ, Pirkle JL, Kramer RA, Flegal KM, Matte TD, Gunter EW, Paschal DC. Blood lead levels in the US population. Phase 1 of the Third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1991). JAMA 272:277-283 (1994).

(12.) Centers for Disease Control and Prevention. Blood lead levels--United States 1991-1994. Morb Mortal Wky Rep 46:141-146 (1997).

(13.) Dallman PR, Yip R, Johnson C. Prevalence and causes of anemia in the United States, 1976 to 1980. Am J Clin Nutr 39:437-445 (1984).

(14.) Sargent JD, Stuket TA, Dalton MA, Freeman JL, Brown MJ. Iron deficiency in Massachusetts communities: socioeconomic and demographic risk factors among children. Am J Public Health 88:544-550 (1996).

(15.) Yip R, Dallman PR. Developmental changes in erythrocyte protoporphyrin: the roles of iron deficiency and lead toxicity. J Pediatr 104:710-730 (1984).

(16.) Yip R. Multiple interactions between childhood iron deficiency and lead poisoning: evidence that childhood lead poisoning is an adverse consequence of iron deficiency. In: Recent Knowledge on Iron and Folate Deficiencies in the World (Hercberg S, Galan P, and Dupin H, eds). Paris:Colloque INSERM, 1990;523-532.

(17.) Eden AN, Mir MA. Iron deficiency in 1- to 3-year old children. A pediatric failure? Arch Pediatr Adolesc Med 151:986-988 (1997).

(18.) Mahaffey Six K, Goyer RA. The influence of iron deficiency on tissue content and toxicity of ingested lead in the rat. J Lab Clin Med 79:128-136 (1972).

(19.) Mahaffey K. Factors modifying susceptibility to lead toxicity. In: Dietary and Environmental Lead: Human Health Effects (Mahaffey K, ed). Amsterdam:Elsevier Science Publishers, 1985;373-419.

(20.) Miller GD, Massaro TF, Massaro EJ. Interactions between lead and essential elements: a review. Neurotoxicology 11:99-119 (1990).

(21.) Barton JC, Conrad ME, Nuby S, Harrison L. Effects of iron on the absorption and retention of lead. J Lab Clin Med 92:536-547 (1978).

(22.) Ragan HA. Effects of iron deficiency on the absorption and distribution of lead and cadmium in rats. J Lab Clin Med 90:700-706 (1977).

(23.) Flanagan PR, Hamilton DL, Haist J, Valberg LS. Interrelationships between iron and lead absorption in iron-deficient mice. Gastroenterology 77:1074-1081 (1979).

(24.) Conrad ME, Umbreit JN, Moore EG. A role for mucin in the absorption of inorganic iron and other metal cations. A study in rats. Gastroenterology 100:129-138 (1991).

(25.) Conrad ME, Umbreit JN, Moore EG, Rodning CR. Newly identified iron-binding protein in human duodenal mucosa. Blood 79:244-247 (1992).

(26.) Markowitz ME, Rosen JF, Bijur PE. Effects of iron deficiency on lead excretion in children with moderate lead intoxication. J Pediatr 116:360-364 (1990).

(27.) Ruff HA, Markowitz ME, Bijur PE, Rosen JF. Relationships among blood lead levels, iron deficiency, and cognitive development in two-year-old children. Environ Health Perspect 194:180-185 (1996).

(28.) Lacey EP. Broadening the perspective of pica: literature review. Public Health Rep 105:29-35 (1990).

(29.) Federman DG, Kirsner RS, Federman GS. Pica: are you hungry for the facts? Conn Med 61:207-209 (1997).

(30.) Watson WS, Hume R, Moore MR. Oral absorption of lead and iron. Lancet 2:236-237 (1980).

(31.) Watson WS, Morrison J, Bethel MI, Baldwin NM, Lyon DT, Dobson H, Moore MR, Hume R. Food iron and lead absorption in humans. Am J Clin Nutr 44:248-256 (1986).

(32.) Mahaffey KR. Environmental lead toxicity: nutrition as a component of intervention. Environ Health Perspect 89:76-78 (1990).

(33.) Flanagan PR, Chamberlain MJ, Valberg LS. The relationship between iron and lead absorption in humans. Am J Clin Nutr 36:823-829 (1982).

(34.) Yip R, Norris TN, Anderson AS. Iron status of children with elevated blood lead concentrations. J Pediatr 98:922-925 (1981).

(35.) Hammad T, Sexton M, Langenberg P. Relationship between blood lead and dietary iron intake in preschool children. A cross-sectional study. Ann Epidemiol 6:30-33 (1996).

(36.) Wright RO, Shannon MW, Wright RJ, Hu H. Association between iron deficiency and low-level lead poisoning in an urban primary care clinic. Am J Public Health 89:1049-1053 (1999).

(37.) Hershko C, Konijn AM, Moreb J, Link G, Grauer F, Weissenberg E. Iron depletion and blood lead levels in a population with endemic lead poisoning. Isr J Med Sci 20:1039-1043 (1984).

(38.) Lucas S, Sexton M, Langenberg P. Relationship between blood lead and nutritional factors in preschool children: a cross-sectional study. Pediatrics 97:74-78 (1996).

(39.) Ziegler EE, Edwards DB, Jensen RL, Mahaffey KR, Fomon SJ. Absorption and retention of lead by infants. Pediatr Res 12:29-34 (1978).

(40.) Sutton PM, Athanasoulis M, Flessel P, Guirguis G, Haan M, Schlag R, Goldman LR. Lead levels in the household environment of children in three high-risk communities in California. Environ Res 88:46-57 (1995).

(41.) Fornes R. Personal communication.

(42.) Siimes MA, Addiego JE Jr, Dallman PR. Ferritin in serum: diagnosis of iron deficiency and iron overload in infants and children. Blood 43:581-590 (1974).

(43.) Cook JD, Skikne BS. Iron deficiency: definition and diagnosis. J Int Med 226:349-355 (1989).

(44.) Dallman PR, Slimes MA, Stekel A. Iron deficiency in infancy and childhood. Am J Clin Nutr 33:86-118 (1980).

(45.) Deinard AS, Schwartz S, Yip R. Developmental changes in serum ferritin and erythrocyte protoporphyrin in normal (nonanemic) children. Am J Clin Nutr 38:71-76 (1983).

(46.) Dallman PR. Iron deficiency and related nutritional anemias. In: Hematology of Infancy and Childhood (Nathan DG, Oski FA, eds). Philadelphia:W.B. Saunders, 1987;274-314.

(47.) Centers for Disease Control and Prevention. Criteria for anemia in children and childbearing-aged women. Morb Mort Wkly Rep 38:400-464 (1989).

(48.) Yip R, Johnson C, Dallman PR. Age-related changes in laboratory values used in the diagnosis of anemia and iron deficiency. A J Clin Nutr 39:427-436 (1984).

(49.) Carpenter AL, Shipp CE. Quick Results with SAS/Graph Software. Cary, NC:SAS Software Publishers, 1995.

(50.) SAS Institute, Inc. SAS-PC. Cary, NC:SAS Institute, Inc., 1995.

(51.) Madhaven S, Rosenmann K, Shehata T. Lead in soil: recommended maximum permissible levels. Environ Res 49:136-142 (1989).

(52.) U.S. HUD. Comprehensive and Workable Plan for the Abatement of Lead Based Paint in Privately Owned Housing. Report to Congress. Washington, DC:U.S. Department of Housing and Urban Development, 1990.

(53.) NRC. Highway Research Board. Environmental Considerations in Planning, Design and Construction. Washington, DC:National Academy of Science, National Research Council, 1973.

(54.) Consumer Products Safety Commission. Lead-containing paint-banned hazardous products. Fed Reg 42:44191-44202 (1977).

(55.) Hsieh LL, Liou SH, Chen YH, Tsai LC, Yang T, Wu TN. Association between aminolevulinate dehydrogenase genotype and blood lead levels in Taiwan. J Occup Environ Med 42:151-155 (2000).

(56.) Schwartz BS, Stewart WF, Kelsey KT, Simon D, Park S, Links JM, Todd AC. Associations of tibial lead levels with Bsml polymorphisms in the vitamin D receptor in former organolead manufacturing workers. Environ Health Perspect 108:199-203 (2000).

(57.) Wetmur JG, Lehnert G, Desnick RJ. The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1- 2 and 2-2 isozymes. Environ Res 56:109-119 (1991).

(58.) Ziemsen B, Angerer J, Lehnert G, Benkmann HG, Goedde HW. Polymorphism of delta-aminolevulinic acid dehydratase in lead-exposed workers. Int Arch Occup Environ Health 58:245-247 (1986).

(59.) Mahaffey KR, Gartside PS, Glueck CJ. Blood lead levels and dietary calcium intake in 1- to 11-year-old children: the Second National Health and Nutrition Examination Survey, 1976 to 1980. Pediatrics 78:257-262 (1986).

(60.) Johnson N, Tenuta K. Diets and lead blood levels of children with practice pica. Environ Res 18:369-376 (1979).

(61.) Blake KC, Mann M. Effect of calcium and phosphorus on the gastrointestinal absorption of [sup.203]Pb in man. Environ Res 30:188-194 (1983).

(62.) Ballew C, Bowman B. Recommending calcium to reduce lead toxicity in children: a critical review. Nutr Rev 59:71-79 (2001).

(63.) Sargent JD, Dalton MA, O'Connor GT, Olmstead EM, Klein RZ. Randomized trial of calcium glycerophosphate-supplemented infant formula to prevent lead absorption. Am J Clin Nutr 69:1224-1230 (1999).

(64.) Laraque D, McCormick M, Norman M, Taylor A, Weller SC, Karp J. Blood lead, calcium status, and behavior in preschool children. Am J Dis Child 144:186-189 (1990).

(65.) Pollitt E, Leibel RL. Iron deficiency and behavior. J Pediatr 88:372-381 (1976).

(66.) Lozoff B, Brittenham G, Viteri F, Wolf A, Urrutia J. Developmental deficits in iron-deficient infants: effects of age and severity of iron lack. J Pediatr 101:948-95 (1982).

(67.) Idjradinata P, Pollitt E. Reversal of developmental delays in iron-deficient anaemic infants treated with iron. Lancet 341:1-4 (1993).

Asa Bradman, (1,2) Brenda Eskenazi, (3) Patrice Sutton, (1) Marcos Athanasoulis, (1) and Lynn R. Goldman (4)

(1) Division of Environmental and Occupational Disease Control, California Department of Health Services, Berkeley, California, USA; (2) Center for Children's Environmental Health Research, School of Public Health, University of California, Berkeley, CA, USA; (3) Departments of Epidemiology and Maternal and Child Health, Center for Children's Environmental Health Research, School of Public Health, University of California, Berkeley, California, USA; (4) Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland, USA

Address correspondence to A. Bradman, Associate Director, Center for Children's Environmental Health Research, School of Public Health, UC Berkeley, 2150 Shattuck Ave., Suite 600, Berkeley, CA 94720-7380 USA. Telephone: [phone]. Fax: [phone]. E-mail: abradman@ socrates.berkeley.edu

We thank M. Haan for collaboration in conduct of the survey, L. Zahler for superb coordination of fieldwork, R. McLaughlin for data management, J. Irias for blood lead and iron parameter measurements, P. Flessel and G. Guirguis for environmental laboratory measurements and quality control, and S. Samuels for statistical consultation. We appreciate the advice of R.D. Schlag, D.F. Smith, and R.R. Neutra, who reviewed the questionnaire and study design; S. Cummins and B. Abrams for reviewing drafts of this manuscript; and B. Lubin for assistance on iron deficiency parameters.

This research was supported in part by the California Department of Health Services Childhood Lead Poisoning Prevention Program; NIEHS award P01 ES09605 and EPA award R826709.

Received 3 July 2000; accepted 4 April 2001.