Maternal and Early Life Exposure to Manganese in Rural Bangladesh

Mar 2, 2009 - Manganese exposure to pregnant women and mothers from tube-wells in rural Bangladesh and possible implications for fetal and infant ...
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Environ. Sci. Technol. 2009, 43, 2595–2601

Maternal and Early Life Exposure to Manganese in Rural Bangladesh K A R I N S . L J U N G , †,‡ M A R I A J . K I P P L E R , † WALTER GOESSLER,§ ´ R,† G. MARGARETHA GRANDE BARBRO M. NERMELL,† AND M A R I E E . V A H T E R * ,† Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77, Stockholm, Sweden, School of Population Health M431, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia, and Institut fu ¨r Chemie - Analytische Chemie, Karl-Franzens-Universita¨t, Universitt¨splatz 1, 8010 Graz, Austria

Received November 6, 2008. Revised manuscript received January 22, 2009. Accepted February 4, 2009.

Manganese exposure and biomarker concentrations during early pregnancy and lactation were investigated in 408 women living in an area with elevated concentrations of both arsenic and manganese in drinking water derived from wells. About 40% of the water samples had manganese concentrations above the World Health Organization’s guideline value and showed a strong inverse correlation with arsenic concentrations. Water manganese was found to correlate to urine concentrations, but not to blood or breast milk concentrations. No correlations were found among manganese concentrations in urine, blood, or breast milk. Compared to other populations, manganese concentrations in both urine and blood, but not breast milk, were elevated in the Bangladeshi women and more similar to those of occupationally exposed groups. The lack of associations with water manganese is likely due to variable exposure via water and food, and differences in bioavailability, as well as a complex and/or strict regulation of intestinal manganese absorption, in turn being influenced by nutritional as well as physiological and genetic factors. The results indicate that elevated maternal manganese exposure does not necessarily lead to exposure of breast-fed infants, stressing the importance of breast feeding in high manganese areas. However, the implications of fetal exposure from elevated maternal exposure need further investigation.

Introduction Manganese (Mn) is ubiquitous in the earth’s crust and appears frequently at elevated concentrations in groundwater in most countries (1). Although Mn is an essential element, it may cause neurotoxicity at elevated exposures, in particular following inhalation in the workplace (2). Signs of Mn toxicity have also been observed in young patients receiving total parenteral nutrition (3, 4). Intake via water and food has not been previously considered a health risk as homeostatic mechanisms strictly regulate the gastrointestinal absorption and excretion which occurs mainly via the bile (5-7). * Corresponding author phone: +46 8 728 75 40; fax: +46 8 33 69 81; e-mail: [email protected]. † Karolinska Institutet. ‡ The University of Western Australia. § Karl-Franzens-Universita¨t. 10.1021/es803143z CCC: $40.75

Published on Web 03/02/2009

 2009 American Chemical Society

However, several recent studies have reported associations of excessive Mn intake from drinking water and food with behavioral and intellectual performance in preschool or school children (8-13). The Mn concentration in food varies with both food item and location. The adequate daily intake (ADI) level for Mn is 1.8-2.6 mg for adults (14), generally supplied by normal dietary intake with grains, beverages (especially tea), and vegetables providing approximately 33%, 20%, and 18%, respectively, in adult males (15). Since many Asian diets are primarily vegetarian with rice constituting the staple food (16), Mn intake is likely higher than for populations with a more meat-based diet. This is supported by estimations of the dietary Mn intake in six Asian countries, including Bangladesh, ranging from 2.8 mg/day in the Philippines to 11 mg/day in Pakistan (17) and well above the ADI. There are recent reports of increased infant mortality in relation to Mn in drinking water (18) and a case of pediatric manganism following excessive water Mn exposure (19). The increased risk of Mn-related neurotoxicity is supported by a number of experimental studies with low-dose Mn exposure early in life (20-23). Because of the concern for neurotoxic effects from excessive Mn intake, the World Health Organization (WHO) has recently set a health-based guideline value for drinking water at 400 µg/L, based on the assumption of drinking water providing 20% of the daily Mn intake (1, 24). The exposure period responsible for developmental Mn toxicity remains a major uncertainty. The most critical window of exposure is probably during early development when the blood-brain barrier is not yet fully developed and the brain is most susceptible to toxic insult (25, 26). Since Mn is essential for normal fetal and child growth as well as development, it is actively transported across the placenta (27) resulting in higher Mn concentrations in cord blood than in maternal blood (28). Gastrointestinal Mn absorption is increased during pregnancy, especially during the growth spurt of the third trimester (28-30), mainly via up-regulation of the divalent metal transporter 1 (DMT1) in the intestine (31). Thus, there is concern that elevated maternal exposure during pregnancy may result in excessive uptake and subsequent excessive fetal exposure and toxicity (32). The aim of the current study was to assess maternal and early life Mn exposure in relation to elevated Mn concentrations in drinking water in rural Bangladesh. The study is integrated with an ongoing longitudinal study on the effects of early life exposure to arsenic (As), which is present in many of the wells in the area (33). In Bangladesh, more than 90% of the population now retrieves drinking water from groundwater sources and the presence of As has received much attention (34). In addition to As, elevated Mn concentrations have been found in many wells (35-38). The British Geological Survey (35) found in a national survey of groundwater quality in Bangladesh that about one-third of the wells had Mn concentrations above the guideline value for drinking water at the time of the study (500 µg/L). Similar results were found in the Araihazar upazila, where one-third of the 51 community wells reportedly had Mn concentrations above the current WHO guideline value of 400 µg/L (39). The exposure assessment in the present study is based on Mn concentrations in drinking water retrieved from the tube wells as well as maternal blood, urine, and breast milk. Although there seem to be no satisfactory biomarkers for Mn exposure, elevated blood and urine concentrations have been reported in groups of people with excessive Mn exposure (40-42). It has been suggested that erythrocytes may provide a better biomarker for Mn in blood than serum, since most VOL. 43, NO. 7, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY

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of the Mn in blood is associated with the red blood cells (RBC). This is especially true in pregnancy, when the plasma expansion causes a change in hematocrit in early pregnancy. Moreover, plasma Mn levels are often very low compared to whole blood levels and are more reflective of short-term Mn intake than of long-term status (43).

Experimental Section Study Area and Population. This study on Mn exposure is a follow-up of ongoing research on adverse effects of early life exposure to As via drinking water in Matlab, a poor rural subdistrict in the east central plain of Bangladesh, about 53 km southeast of Dhaka. The International Centre for Diarrheal Disease Research in Dhaka, Bangladesh (ICDDR,B) is running a Health and Demographic Surveillance System (HDSS) through their central health facility and four subcenters in each of the residential areas of Matlab, referred to as blocks A, B, C, and D. More than 95% of the population of about 110,000 in the study area retrieve their drinking water from tube-wells (44). Pregnancy was identified by urine test in women reporting amenorrhea at the time of the monthly routine home visit, usually in gestational week 8. Socioeconomic data were collected in the MINIMat trial and socioeconomic status (SES) was ascertained by a wealth index created from information on household assets as described by Saha and co-workers (45). From the 2,119 women who were enrolled between January and December 2002, 500 women were randomly selected for evaluation of maternal exposure to Mn of which 462 gave birth to a child. There was no difference in age, socio-economic status, parity, or area of residence by blocks between those who did and did not participate in the study. The study was approved by both the ethical committee at ICDDR,B and at Karolinska Institutet, Sweden. Oral and written consent regarding sample collection was obtained from all participants. Sampling. Water samples were collected in a parallel study investigating As in all functioning tube wells in the Matlab area in 2002-2003 (44). Samples were available for 265 of the 500 randomly selected women and came from 255 different water sources. Prior to sampling, family members were interviewed about their current and historical drinking water sources. A water sample was collected from the tube wells in acidified vials after about 30 strokes to ensure fresh water was sampled. Mn analysis was carried out at Karolinska Institutet, Sweden, where pH was checked to ensure precipitation had not occurred. From the 500 randomly selected women, 421 had provided a blood sample around the 14th gestational week (GW14), with some variation in sampling time (25/75 percentiles: GW13.5/15.2; total range GW9-23), before initiation of micronutrient supplementation (see Supporting Information for details on supplementation). The erythrocyte cell portion (red blood cells) was available from 408 of these women. Blood samples were also collected six months postpartum and were available for 146 of the women who had donated a sample in GW14. Mn was analyzed in the erythrocyte fraction, while nutritional markers, such as ferritin and zinc, were analyzed in plasma (46). Spot urine samples were collected at the health clinic in GW14 and were available for 412 of the selected women, while spot samples of breast milk were collected during a clinical visit two months postpartum as described by Kippler et al. (47), and were available for 68 of the women. For detailed information on sampling materials and procedures, please see the Supporting Information. Analysis. Concentrations of Mn and certain other elements in drinking water (W-Mn), erythrocytes (B-Mn), urine (U-Mn), and breast milk (BM-Mn) were measured with inductively coupled plasma mass spectrometry (ICP-MS). 2596

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Prior to ICP-MS analyses, the blood and breast milk samples were acid digested using high-temperature/high-pressure microwave-assisted UltraClave in order to obtain carbonfree samples. Concentrations of ferritin and Zn in plasma were available for samples collected in GW14, as described in more detail elsewhere (48). Urinary Mn concentrations were adjusted for variation in dilution by specific gravity (average 1.012 g/mL), measured by hand refractometer according to Nermell et al. (49). Quality Control. Certified reference material from the National Institute of Standards and Technology (NIST) was used for quality control of water concentrations while four commercial reference materials (Seronorm) were analyzed together with the biological samples (two reference materials each for blood and urine samples). Our results fell within the range of the certified values for the analysis of Mn, Fe, and As concentrations in water, and also for the blood and urine concentrations of Mn. For more detail, please see Table S1 in the Supporting Information. Statistical Analysis. Spearman’s rank correlation test (rs) was used to assess bivariate associations for continuous variables. Mann-Whitney U-Test was used to test for differences between two independent groups and Kruskal-Wallis test was used to test for differences among multiple independent groups. Pearson Chi-square was used when testing for differences between categorical variables. In the multivariate analyses, using linear regression, biomarker Mn concentrations were ln (natural logarithm) transformed whenever needed to meet the requirements of equal variance and normal distribution. The multiple regression models included variables that were significantly associated with biomarker Mn in the bivariate analyses. Tests for collinearity (tolerance and variance inflation factors) were performed. The statistical significant level was set to p < 0.05.

Results The 408 pregnant women who participated in the study were between 14 and 44 years of age, with an average age of 27 years (median 26). The women had up to 7 children, although most gave birth to either their first (32%) or second (28%) child. The body mass index (BMI) was on average 20 kg/m2, ranging from 14 to 29 kg/m2, with about one-third of the women having a BMI below 18.5 kg/m2. No significant differences were found among the four different residential blocks with regard to demographic variables. Table 1 shows the descriptive statistics for the analyzed water, urine, blood, and breast milk samples. Water, urine, and breast milk Mn concentrations were not normally distributed, as illustrated by the differences between the mean and median concentrations. One water sample (13,890 µg/L) and six urine samples in the range 350-2000 µg/L were omitted due to likely contamination. In addition, 18 urine samples with specific gravity 6000 µg/L, with a median of 228 µg/L and a mean of 720 µg/L (Table 1). While 162 of the 265 water samples (61%) were found below the WHO guideline value of 400 µg/L, 25% were above 1000 µg/L. As shown in Figure 1, the distribution differed among the administrative areas (blocks), although there were also marked variations within each block. Water samples collected from wells located in block C had significantly lower Mn concentrations (median 67 µg/L) compared to all other blocks. The water Mn concentrations found in block B (median 200 µg/L) also differed significantly from all other blocks, while no significant

TABLE 1. Descriptive Statistics of Manganese (Mn) Concentrations in Water, Urine, Blood (Erythrocytes) and Breast Milk Samples from Bangladeshi Women during Pregnancy and Lactation

N minimum 10th percentile 25th percentile mean median 75th percentile 90th percentile maximum

water µg/L

urine µg/La (GW14b)

blood Mn µg/kg (GW14)

blood Mn µg/kg (6moPPc)

breast milk µg/kg (2moPPd)

265 10 44 84 720 228 988 2,001 6,336

388 0.2 0.6 0.9 2.5 1.6 2.8 4.5 35

408 10 14 18 22 22 26 32 53

146 6.9 15 18 24 23 30 35 49

67 2.4 3.3 4.7 9.2 6.6 11.2 16.9 59

a Adjusted for variation in specific gravity (to average 1.012 g/L). post partum. d 2moPP ) 2 months post partum.

b

GW14 ) gestational week 14.

c

6moPP ) 6 months

FIGURE 1. Histograms of the distribution of manganese (Mn) concentrations in water samples (µg/L) from Matlab tube wells in residential blocks A, B, C, and D. difference was found between the two blocks with the highest water Mn concentrations, blocks A and D (median values 643 and 654 µg/L, respectively). Interestingly, a positive association was found between water Mn concentrations and SES of the women (rs ) 0.13; N ) 265; p ) 0.03). This was not explained by differences in location as SES did not differ between blocks, but indicates that wells used by women who were better off in general had higher Mn concentrations. A strong inverse relationship was found between the concentrations of Mn and As in water (rs ) -0.54, p < 0.001) as shown in Figure 2, where the guideline values of 50 and 400 µg/L for As and Mn, respectively, have been marked with dotted lines. The inserted graph in Figure 2, where the axes have been log-transformed, shows that most samples either had Mn or As concentrations above the respective WHO drinking water guidelines. Only 15% of the 265 samples analyzed had concentrations of both Mn and As below the guideline values, while 8% of the sampled wells exceeded the guideline values for both Mn and As. A significant negative correlation was also found between water concentrations of Mn and Fe, although this relationship was less strong (rs ) -0.32, p < 0.001). However, at Mn concentrations below 500 µg/L (n ) 170), there was a positive correlation between Mn and Fe concentrations (rs ) 0.58, p < 0.001). Biological Samples. The median erythrocyte Mn concentrations (B-Mn) were similar in GW14 and at 6 months postpartum (6 moPP) with concentrations at 24 and 23 µg/

kg, respectively and ranges of 10-53 and 7-49 µg/kg (n ) 146). In the bivariate analysis, B-Mn in GW14 was negatively associated with age (rs ) -0.12; p ) 0.01), plasma ferritin (rs ) -0.17; p < 0.001; Figure 3), and erythrocyte calcium (rs ) -0.22; p < 0.001), but no significant correlation was found with Mn in water or urine. Similarly, B-Mn was not associated with plasma Zn, parity, or SES and no difference was found in B-Mn by block of residence. The B-Mn concentrations did not vary by gestational week within the span the blood samples had been collected (GW 9-23). In the multiple regression analysis, B-Mn was still associated with B-Ca (negative; p < 0.001) and plasma ferritin (negative; p ) 0.01), in decreasing order, but not significantly associated with age (negative; p ) 0.08). The median urinary Mn concentration (U-Mn) was found at 1.6 µg/L. Most values were found below 3 µg/L with the 75th percentile at 2.8 µg/L and the 90th percentile at 4.5 µg/L. There was an overall positive association between water and urinary Mn concentrations (rs ) 0.19, p ) 0.01; N ) 253). Urinary Mn was not associated with plasma ferritin, but highly associated with urinary Fe (rs ) 0.45, p < 0.001; N ) 243). A difference in urinary Mn concentration was found among the residential areas (blocks), where block D had an elevated median concentration of 2.5 µg/L (p < 0.01) compared to blocks A, B, and C which had similar concentrations of 1.2, 1.4, and 1.5 µg/L, respectively. VOL. 43, NO. 7, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY

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FIGURE 2. Association between water manganese (W-Mn) and arsenic (W-As) concentrations in investigated tube wells. The inserted graph has log-transformed axes. Guideline values are marked at 50 µg/L for As and 400 µg/L for Mn with dotted lines.

FIGURE 3. Association between erythrocyte manganese (B-Mn) and plasma ferritin, showing increasing B-Mn concentrations with decreasing plasma ferritin (n ) 408). With the exception of one value of 2012 µg/kg which was omitted due to likely contamination, all breast milk Mn concentrations were within the range 2-60 µg/kg, with a median value of 6.6 µg/kg. No correlations were found with Mn in water, blood (neither in gestational week 14 nor at 6 months postpartum), or urine. A strong correlation was found between Fe and Mn concentrations in the breast milk samples (rs ) 0.68, p < 0.001; N ) 67).

Discussion The observed inverse relationship between As and Mn concentrations in the sampled wells (Figure 2) is in agreement with previous studies from other areas of Bangladesh (37, 50, 51) as well as from other delta regions, such as the Mekong (52). The presence of As in drinking water is undoubtedly a more severe problem than the presence of Mn, as even fairly low As concentrations are associated with a considerable risk of various forms of cancer (53). However, this relationship is disturbing as seemingly “safe” water with regard to As contamination may actually also have adverse effects on health. The strong negative correlation between As and Mn in water is an important finding also because previous studies on the association between various health outcomes in relation to As exposure via drinking water (54, 55) might have been confounded by the high Mn concentrations at low As concentrations. In the few studies where both 2598

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elements were considered (11, 38, 56), both As and Mn were significantly associated with the test scores of the about 200 children, 6 years of age (38, 56). As the scientific basis for the health-based drinking water guideline for Mn is weak, and does not consider the potential risk for infants and small children who have both higher intestinal absorption and lower excretion compared to adults (57), the relatively high occurrence of wells with elevated levels of Mn may influence the health and development of infants consuming water and water-based formula and foods in the studied area. The normal and necessary daily intake of Mn for adults of about 2 mg is generally supplied via the diet, with water assumed to contribute approximately 20% (1). Based on the assumption of a daily water intake of 2 L on average, the intake of Mn in the Matlab area could range from a small fraction to more than twice the adequate daily intake from drinking water alone. Further, many inhabitants may drink more than 2 L a day, and thus have an even higher Mn intake. In addition, the largely rice-based diet in the area may contribute significantly to the daily Mn exposure, as rice contains relatively high amounts of Mn (15). For example, in a food study carried out by the Swedish National Food Administration, parboiled rice was found to hold almost 4 mg Mn per 100 g, brown rice contained 2.4 mg/100 g, and polished rice contained 0.9 mg/100 g, while potatoes held 0.2 mg/100 g and meat and fish rarely exceeded 0.01 and 0.1 mg Mn/100 g edible part, respectively (58). Another important point to consider with regard to exposure via diet is that crops grown locally may have elevated Mn concentrations as a result of irrigation with Mn-rich water as well as from elevated Mn concentrations in the soils in which the crops are grown. The lack of correlation between Mn concentrations in drinking water and in blood is thus likely due to the significant Mn intake via food as well as the marked variations in intake via both water and food, but also to variations in Mn bioavailability (6, 59-61). Moreover, the regulation of Mn absorption and excretion via bile is complex, being influenced by nutritional as well as physiological and genetic factors (7, 31, 41, 62, 63). Because Mn absorption is homeostatically regulated, increased exposure through food and water does not necessarily lead to increased body burden. However, as the gastrointestinal absorption of Mn occurs largely via the cation transporter DMT1, which is up-regulated at poor nutrient status (31, 64, 65), the prevalent malnutrition may have influenced the absorption of Mn from water and food. In fact, blood Mn increased with decreasing plasma ferritin levels, which is the main determining factor for DMT1 regulation. We also found that blood Mn increased with decreasing blood calcium, which may reflect the previously reported increased absorption of Mn at low intake of calcium (31, 62, 65), which is common in Bangladesh (17, 66). To evaluate any evidence of elevated Mn exposure on a population basis, the results on urine, blood, and breast milk concentrations from the current study were compared to findings in other studies in occupationally and environmentally exposed populations conducted worldwide. Figure 4 presents a summary of these results. More detailed information on the studies included is displayed in Tables S2-S4. The whole blood values presented for the Bangladeshi women are estimates since only the Mn concentration in the erythrocytes were analyzed (please see the Supporting Information for calculations). Breast milk and erythrocyte Mn values were converted to µg/L by using densities of 1.03 and 1.096 g/L, respectively. The results showed that the women living in the study area have elevated Mn concentrations in blood and urine compared to most other environmentally exposed populations, which averaged around 6-9 µg/L in blood and 0.1-0.7 µg/L in urine. In general, the Mn concentrations in blood and urine were more similar to those reported for occupationally exposed groups, mainly male

FIGURE 4. Median and mean manganese concentrations in urine (U-Mn), whole blood (B-Mn, calculated from measured erythrocyte concentrations), and breast milk (BM-Mn) in the Bangladeshi women (9), compared to published data on environmentally ( ×) and occupationally (∆) exposed populations worldwide. The occupational data are encircled with rectangles, environmentally exposed data are circled with rings. For complete data and references, please see Supporting Information Tables S2-S4. It should be noted that the three highest B-Mn concentrations refer to women in late pregnancy, at which time the Mn absorption is increased (for further discussion, see text). workers (average about 8-12 µg/L in blood and 0.3-7 µg/L in urine). The most evident exceptions are the three values depicted in Figure 4 which all show mean blood Mn concentrations >15 µg/L. All three of these studies were of mothers at delivery carried out in France and in Canada, and the highly elevated blood Mn concentrations were a result of increased Mn absorption during late pregnancy (28, 32, 67). However, the pregnancy-related increase in blood Mn levels in the present study was probably small as the blood samples were collected in early second trimester (GW14) and the gastrointestinal Mn absorption increases mainly during the growth spurt in the third trimester (28-30). This is supported by the absence of increase in blood Mn within the overall range of gestational age (GW9-23) and also by the similarity of blood Mn levels at GW14 and 6 months postpartum, suggesting that the increase is more likely exposure-related than due to pregnancy. Although blood Mn levels increase in late pregnancy, it is likely that they, like Fe, decrease to prepregnancy levels fairly quickly after delivery. The likely finding of increased maternal Mn blood levels unrelated to the normal pregnancy-related increase may be of concern for fetal exposure and needs further investigation. Although elevated Mn concentrations were found in blood and urine of the studied women, the breast milk Mn concentrations were not particularly elevated compared to those of other studies (see Figure 4 and Table S4). According to ATSDR (68), the Mn concentration in human milk ranges from 3.4 to 10 µg/L. In support, the average concentrations in the studies presented in Figure 4 ranged from 3.1 to 13 µg/L, and the average concentration of 9 µg/L found in the Bangladeshi women was within this range. The finding of this study, that breast milk concentrations remained low in spite of elevated maternal blood and urine Mn concentrations, stresses the importance of breast feeding to avoid excessive Mn exposure from drinking water and/or infant foods. The lack of association between Mn in breast milk and blood indicates a strict regulation of Mn transport in the mammary gland. Similar results have been reported by Rossipal et al. (69), who found almost three times higher Mn concentrations in colostrum than in maternal serum, and by Leotsinidis et al. (70) who found no significant effect of

maternal mineral supplementation on milk Mn. We observed a strong positive association between Mn and Fe in breast milk of the Bangladeshi women, suggesting a common transporter in the mammary gland. Mn, like Fe, is transported in plasma bound to transferrin, and the uptake of both elements in the mammary gland is facilitated by the transferrin receptors (TfR) located on the plasma membranes (71). The divalent metal transporter-1 (DMT1) is known to play a role in the export of Fe from the endosomes to the cytoplasm (72, 73), whereas ferroportin (FPN1), localized throughout the mammary epithelial cell, is believed to transport Fe into the secretory vesicles, which are responsible for export to milk (72, 73). Possibly, Mn follows the same transport pathway as Fe, as has been shown for the intestinal uptake (31). We have previously reported that the toxic metal cadmium was strongly associated with both Mn and Fe in breast milk and probably uses the same transporters to enter into the breast milk (47).

Acknowledgments The present study is a follow-up of the AsMat and MINIMat studies and was funded by the Swedish International Development Agency (Sida)/SAREC, the EC project PHIME [FOOD-CT-2006-016253], and the Karolinska Institutet. The AsMat and MINIMat studies were funded by United Nations Children’s Fund (UNICEF), Sida, UK Medical Research Council, Swedish Research Council, Department for International Development (DFID), International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Global Health Research Fund-Japan, Child Health and Nutrition Research Initiative (CHNRI), United States Agency for International Development (USAID), and the World Health Organization. We also gratefully acknowledge the participation of all pregnant women and families in Matlab and the AsMat and MINIMat study teams. We also thank the reviewers for their helpful comments. We have no conflict of interest.

Supporting Information Available Details on the study, sampling materials and methods, analytical instruments, certified reference material, statistical programs, calculations, detailed results from quality control (Table S1), and three tables (S2-S4) presenting supporting VOL. 43, NO. 7, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY

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information to Figure 3, including references. This information is available free of charge via the Internet at http:// pubs.acs.org.

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