Journal of Exposure Science and Environmental Epidemiology (2012) 22, 191–197 r 2012 Nature America, Inc. All rights reserved 1559-0631/12
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Selenium and maternal blood pressure during childbirth ELLEN M. WELLSa,b, LYNN R. GOLDMANa,c, JEFFERY M. JARRETTd, BENJAMIN J. APELBERGe, JULIE B. HERBSTMANf, KATHLEEN L. CALDWELLd, ROLF U. HALDENa,g AND FRANK R. WITTERh a
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA Department of Environmental Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA c George Washington University School of Public Health and Health Services, Washington, DC, USA d Inorganic and Radiation Analytical Toxicology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA e Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA f The Columbia Center for Children’s Environmental Health, Columbia University Mailman School of Public Health, New York, New York, USA g Swette Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, Tempe, Arizona, USA h Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA b
Evidence suggests selenium concentrations outside the nutritional range may worsen cardiovascular health. This paper examines the relationship between selenium and maternal blood pressure (BP) among 270 deliveries using umbilical cord serum as a proxy for maternal exposure levels. Multivariable models used linear splines for selenium and controlled for gestational age, maternal age, race, median household income, parity, smoking, and prepregnancy body mass index. Non-parametric analysis of this dataset was used to select spline knots for selenium at 70 and 90 mg/l. When selenium was o70 mg/l, increasing selenium levels were related to a non-statistically significant decrease in BP. For selenium 70–90 mg/l, a 1 mg/l increase was related to a 0.37 mm Hg (95% confidence interval (CI): 0.005, 0.73) change in systolic and a 0.35 mm Hg (0.07, 0.64) change in diastolic BP. There were very few selenium values 490 mg/l. Other studies indicate that the maternal/cord selenium ratio is 1.46 (95% CI: 1.28, 1.65). This u-shaped relationship between selenium and BP is consistent with a dual role of selenium as an essential micronutrient that is nonetheless a toxicant at higher concentrations; however, this needs to be studied further. Journal of Exposure Science and Environmental Epidemiology (2012) 22, 191–197; doi:10.1038/jes.2011.42; published online 23 November 2011
Keywords: blood pressure, pregnancy, selenium, umbilical cord.
Introduction Selenium is an antioxidant and promotes thyroid and immune system function (Brown and Arthur, 2001). The recommended daily allowance for selenium, currently 55 mg/day (60 mg/day during pregnancy), is needed to maximize glutathione peroxidase synthesis (Institute of Medicine, 2000). Either selenium deficiency or excess may lead to adverse health effects (Institute of Medicine, 2000); globally, deficiency is a larger concern than excess (Combs, 2001). In North America, daily requirements for selenium are generally met or exceeded (Institute of Medicine, 2000; Combs, 2001). It has been questioned whether selenium intake in excess of recommended levels might contribute to development of cardiovascular disease (Navas-Acien et al.,
1. Address all correspondence to: Dr. Lynn R. Goldman, Department of Environmental Health Sciences, Case Western Reserve University School of Medicine, 2300 Eye St., NW, Suite 106, Washington, DC 20037, USA. Tel.: þ 1 202 994 5179. Fax: þ 1 202 994 3773. E-mail:
[email protected] Received 29 March 2011; accepted 14 June 2011; published online 23 November 2011
2008). Additionally, increased selenium intake may contribute to diabetes and cardiovascular outcomes (Stranges et al., 2010). Elevations in blood pressure (BP) during pregnancy are of concern due to possible chronic sequelae (Kaaja and Greer, 2005; Lykke et al., 2009). However, few studies have explored selenium and BP during pregnancy. Research in the United Kingdom suggested preeclamptic mothers have less selenium compared with healthy mothers (Rayman et al., 2003; Mistry et al., 2008); in contrast, a study among African mothers suggested the opposite (Mahomed et al., 2000). Other work implicated selenium supplementation with decreased risk of gestational hypertension among Chinese mothers (Han and Zhou, 1994) and supplementation in a clinical trial was related to a decrease in preeclampsia among Iranian mothers (Tara et al., 2010). The relationship of selenium and BP may depend on whether nutritional needs for selenium have been met. This study evaluates the relationship between selenium exposure as measured in umbilical cord serum and maternal BP in a cross-sectional study of mothers giving birth in Baltimore, Maryland. Additionally, previous studies were used to create a maternal/cord selenium ratio in order to estimate maternal selenium in the current study.
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Materials and methods The Baltimore THREE (Tracking Health Related to Environmental Exposures) Study is a cross-sectional study of mothers and infants conducted with approval of the Maternal and Fetal Research Committee, Department of Gynecology and Obstetrics, and the Johns Hopkins School of Medicine Institutional Review Board (Apelberg et al., 2007). Informed consent was not required for this study because collected biological samples would otherwise have been discarded and sample collection constituted no more than minimal risk. Strict procedures were developed to protect subject confidentiality. Owing to this design, maternal serum was not available. Mothers giving birth between November 2004 and March 2005 in the Johns Hopkins Hospital were eligible for inclusion (n ¼ 603 deliveries). Deliveries with multiple births (n ¼ 12) and births where cord blood was unavailable or of insufficient quantity (n ¼ 291) were excluded. These analyses also excluded mothers with missing data on selenium (n ¼ 13), BP (n ¼ 2), prepregnancy body mass index (BMI) (n ¼ 11), and median household income (n ¼ 3). One mother with admission systolic BP o20 mm Hg was also excluded. Data were collected from analyses of umbilical cord blood and maternal electronic medical records. Two study personnel extracted data from medical records; a random 10% sample was reviewed by study clinicians. Hospital staff took maternal BP measurements as part of routine medical care at admission and continuously while hospitalized for labor and delivery. BP at hospital admission and maximum BP (based on systolic) were abstracted. Reliability of these measurements was assessed using other variables within the dataset (Supplementary Information). Measurements with systolic BP Z140 mm Hg or diastolic BP Z90 mm Hg were considered ‘‘elevated’’, but not tantamount to a diagnosis of hypertension. Hypertension was classified as (1) all hypertension cases (pregnancy-related, chronic, or medication use) and (2) the subset of women with pregnancy-related hypertension diagnoses (Supplementary Information). Trained clinical staff collected umbilical cord blood using standard procedures (Witter et al., 2001). Serum samples were analyzed at the United States Centers for Disease Control and Prevention (CDC). Selenium was determined using National Institute of Standards and Technologytraceable, matrix-matched calibrators on inductively coupled plasma dynamic reaction cell mass spectrometry methodology adhering to Clinical Laboratory Improvement Amendments 0 88 standards (Xiao, 2006). Limit of detection (LOD) was 5 mg/l. Cotinine was measured using liquid chromatography in conjunction with atmospheric pressure ionization tandem mass spectrometry; LOD ¼ 0.015 ng/ml (Bernert et al., 1997). A mother was classified as a smoker if serum 192
cotinine was Z10 ng/ml (CDC, 2005) or if smoking during pregnancy was noted in the medical record. BMI was calculated as prepregnancy weight (kg)/height (m2). Median household income was obtained from the United States 2000 Census. The median income was based on a small census area called a block group, which includes 600–3000 individuals (Supplementary Information). Statistical analyses were performed using Stata 11 (College Station, TX, USA). Our hypothesis was that selenium’s effect may be concentration-dependent; however, there are no guidelines for umbilical cord selenium concentrations. Therefore, we used our data to identify cutoff points for spline models. Inflection points (where the dose–response changes direction) were identified visually using lowess curves of selenium with each BP measurement (Supplementary Information). The exact inflection point differed slightly for each BP measurement; for consistency, knots were chosen to approximate inflection points across all BP measures. Potential covariates were considered for inclusion based on previous publications (Rayman et al., 2003; Schulpis et al., 2004; Mistry et al., 2008) and bivariate comparisons of variables within this dataset (criteria of Po0.30 for one-way analysis of variances or t-tests). In addition to covariates included in our final models, we considered alcohol use, parity, medical insurance, anemia, cord blood lead levels, and cord serum fatty acids; these were eliminated based on likelihood ratio tests and observation of whether the selenium coefficient changed 410% following their inclusion. A series of final models (including gestational age, maternal age, maternal race, primiparity, income, BMI, and smoking) are presented with increasing levels of adjustment for confounders. We also ran models with selenium as a linear term. Models were evaluated using Akaike’s information criterion, likelihood ratio tests, normal quantile plots, and residual vs fitted value plots. Similar procedures were used for logistic models to evaluate hypertension and ‘‘elevated’’ BP. In order to put our findings into perspective with other studies that measured maternal serum selenium levels and not cord serum levels, previous reports were used to calculate maternal/umbilical cord serum selenium ratios. These were used to estimate maternal serum selenium levels in this population. Relevant articles were identified using PubMed. Summary data on maternal selenium and umbilical cord selenium were extracted and used to calculate study specific as well as an overall mean ratios weighted by study sample size.
Results Population characteristics are shown in Table 1. Mean admission BP was 122.7 mm Hg (systolic) and 72.0 mm Hg (diastolic). Corresponding values for maximum BP were Journal of Exposure Science and Environmental Epidemiology (2012) 22(2)
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Table 1. Population characteristics, Baltimore THREE Study, 2004–2005. Category All Maternal age
Maternal race
Smoking Prepregnancy BMI
Median household income (neighborhood)
Parity Gestation ‘‘Elevated’’ admission BP ‘‘Elevated’’ maximum BP GH or preeclampsia Any hypertension Selenium categories
Characteristic
o20 years 20–29 years Z30 years Caucasian African American Asian Smoked during pregnancy Did not smoke o18.5 kg/m2 18.5–24.9 kg/m2 25.0–29.9 kg/m2 Z30.0 kg/m2 o$25,000 $25,000–50,000 4$50,000 First childbirth Second or higher Preterm delivery (o37 weeks) Not preterm delivery Yes No Yes No Yes No Yes No o70 mg/l 71–90 mg/l 490 mg/l
N
%
270 55 128 87 57 190 23 49 221 14 126 61 69 82 144 44 117 153 34 236 36 234 115 155 16 254 26 244 150 108 12
100.0 20.4 47.4 32.2 21.1 70.4 8.5 18.2 81.9 5.2 46.7 22.6 25.6 30.4 53.3 16.3 43.3 56.7 12.6 87.4 13.3 86.7 42.6 57.4 5.9 94.1 9.6 90.4 55.6 40.0 4.4
Abbreviations: BMI, body mass index; BP, blood pressure; GH, gestational hypertension; THREE, Tracking Health Related to Environmental Exposures. Percentages may not sum to 100 due to rounding. ‘‘Elevated’’ BP is systolic blood pressure Z140 mm Hg or diastolic BPZ90 mm Hg. Any hypertension includes gestational hypertension, preeclampsia, and chronic hypertension. Median household income is based on roughly 1500 persons in close geographic proximity, in the same census block group.
144.3 mm Hg and 77.1 mm Hg. Mean selenium was 69.9 mg/l (95% confidence interval (CI): 68.5, 71.4). Knots for selenium splines were chosen at 70 and 90 mg/l. Roughly half had selenium concentrations r70 mg/l, and very few (n ¼ 12) had concentrations 490 mg/l (Table 1). There was a consistent pattern in the relationship between selenium concentrations and maternal BP (Table 2). When selenium concentrations were o70 mg/l, increasing selenium levels were related to decreasing BP. However, when selenium concentrations were 70–90 mg/l, increasing selenium levels were related to increasing BP; these were statistically significant (Po0.05) or of borderline significance (Po0.10) for all measures except maximum diastolic BP. For selenium concentrations 490 mg/l there was a decrease in BP with increased selenium; however, there was a large uncertainty in this range as this group only has 12 individuals. There was no association between selenium and BP in models where selenium was a linear term (Table 2). Journal of Exposure Science and Environmental Epidemiology (2012) 22(2)
Results from multivariable logistic regression models for ‘‘elevated’’ BP were similar to admission and maximum BP. We did not observe any relationship of selenium with hypertension outcomes (Supplementary Information). A total of 11 studies with data on both maternal and umbilical cord selenium were identified (Wasowicz et al., 1993; Micetic-Turk et al., 2000; Osman et al., 2000; Kantola et al., 2004; Makhoul et al., 2004; Schulpis et al., 2004; Lorenzo Alonso et al., 2005; Butler Walker et al., 2006; Mistry et al., 2008; Rudge et al., 2009; Sakamoto et al., 2010). Studyspecific and overall maternal/cord selenium ratios are presented (Table 3, Figure 1). Individual maternal/cord selenium ratios ranged from 0.85 to 1.84, with a weighted average of 1.46 (95% CI: 1.28, 1.65). Applying this ratio to selenium concentrations in our study suggests that there is decreasing maternal BP with increasing selenium when maternal selenium is o102 mg/l and increasing maternal BP with increasing selenium when maternal selenium is 102–131 mg/l. 193
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Table 2. Change and 95% CI for maternal blood pressure (in mm Hg) during childbirth related to a 1 mg/l increase in umbilical cord serum selenium, Baltimore THREE Study, 2004–2005, n ¼ 270. Outcome
Linear model Selenium Change
95% CI
Spline model Selenium o70 mg/l Change
Selenium 71–90 mg/l
95% CI
Selenium Z91 mg/l
Change
95% CI
Change
95% CI
Admission SBP Model 1 Model 2 Model 3
0.07 0.05 0.08
0.08, 0.23 0.10, 0.20 0.07, 0.23
0.19 0.21 0.17
0.51, 0.13 0.53, 0.11 0.48, 0.14
0.41** 0.36* 0.37**
0.04, 0.77 0.01, 0.73 0.004, 0.73
0.25 0.16 0.09
1.03, 0.13 0.95, 0.63 0.86, 0.68
Admission DBP Model 1 Model 2 Model 3
0.02 0.02 0.05
0.11, 0.14 0.10, 0.14 0.07, 0.17
0.15 0.13 0.11
0.40, 0.11 0.38, 0.13 0.36, 0.14
0.26* 0.27* 0.30**
0.03, 0.55 0.02, 0.56 0.01, 0.60
0.33 0.38 0.36
0.96, 0.26 1.01, 0.25 0.98, 0.26
Maximum SBP Model 1 Model 2 Model 3
0.07 0.04 0.07
0.11, 0.25 0.14, 0.22 0.11, 0.25
0.29 0.33 0.24
0.67, 0.09 0.71, 0.05 0.61, 0.12
0.52** 0.46** 0.43**
0.34 0.23 0.13
1.26, 0.58 1.16, 0.71 1.04, 0.77
Maximum DBP Model 1 Model 2 Model 3
0.18 0.16 0.14
0.38, 0.02 0.37, 0.04 0.35, 0.07
0.59** 0.56** 0.52**
1.01, 0.17 0.99, 0.13 0.95, 0.10
0.17 0.18 0.19
0.02 0.03 0.02
1.05, 1.02 1.08, 1.01 1.03, 1.08
0.09, 0.97 0.02, 0.90 0.003, 0.85
0.31, 0.65 0.31, 0.67 0.31, 0.68
Abbreviations: CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure; THREE, Tracking Health Related to Environmental Exposures. *Po0.10. **Po0.05. Model 1: Blood pressureBselenium+gestational age. Model 2: Model 1+maternal age+maternal race. Model 3: Model 2+primiparity+median household income+smoking+prepregnancy body mass index.
Discussion We did not find any evidence of a linear relationship of selenium with BP across the entire range of blood concentrations. However, when modeling selenium as a spline, we saw both positive and negative relationships that were dependent upon the selenium concentration range. While these relationships were not all statistically significant at the Po0.05 level, they were consistent among different BP measurements. Maternal/cord selenium ratios calculated from previous work have a weighted average of 1.46. Variability between individual ratios could arise from differences in selenium intake, health status, selection criteria, or other genetic or environmental factors. Based on application of this ratio, this study reports a trend of lower maternal BP with increasing selenium when cord serum selenium is o70 mg/l (and maternal serum selenium Bo105 mg/l) and higher maternal BP with increasing selenium when cord serum selenium is between 70 and 90 mg/l (and maternal serum selenium B102–131 mg/l). There are too few observations over 90 mg/l to draw firm conclusions about effects in that range. 194
The Institute of Medicine notes that adult nutritional requirements of selenium are met where serum selenium is 70–90 mg/l (Institute of Medicine, 2000). Based on estimated maternal selenium values in our study, roughly 75% of the current population would meet the lower level of this requirement. This is noticeably lower than other reports of serum selenium among US adults (Laclaustra et al., 2009) yet higher than many other reports (Table 3). Our results are consistent with previous observations of a similar biphasic relationship between selenium and cardiovascular mortality (Bleys et al., 2008) or hypertension (Laclaustra et al., 2009). Overall, however, studies that have directly assessed selenium and BP-related health outcomes have had inconsistent results; it is possible that this variety may reflect variability in baseline selenium levels in different populations. For example, several studies reporting that increased selenium is protective of cardiovascular disease have been performed in regions where selenium deficiencies are more prevalent (Broadley et al., 2006; Rayman, 2008). This study and Laclaustra et al. (2009) both identified biphasic relationships of selenium and cardiovascular outcomes; however, unlike the Laclaustra study, we do not Journal of Exposure Science and Environmental Epidemiology (2012) 22(2)
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Table 3. Maternal and umbilical cord selenium concentrations reported in previous studies. Study information
Selenium
Study Wasowicz et al. (1993) Micetic-Turk et al. (2000) Osman et al. (2000) Makhoul et al. (2004) Makhoul et al. (2004) Schulpis et al. (2004) Schulpis et al. (2004) Kantola et al. (2004) Kantola et al. (2004) Lorenzo Alonso et al. (2005) Butler Walker et al. (2006) Butler Walker et al. (2006) Butler Walker et al. (2006) Mistry et al. (2008) Mistry et al. (2008) Rudge et al. (2009) Sakamoto et al. (2010)
Location
Media
Method
Poland Slovenia Sweden Israel (preec.) Israel (controls) Greece Albania Finland (non-smokers) Finland (smokers) Spain Canada (Caucasians) Canada (Dene/Metis) Canada (Inuit) United Kingdom (preec.) United Kingdom (controls) South Africa Japan
Plasma Serum Serum Serum Serum Serum Serum Serum Serum Serum Plasma Plasma Plasma Serum Serum WB RBC
FM FIHG-AAS GFAAS AAS AAS GFAAS GFAAS AAS AAS AAS GFAAS GFAAS GFAAS GFAAS GFAAS ICP-MS ICP-MS
Maternal (M)
Cord (C)
M/C
N
Mean
N
Mean
Ratio
64 20 74 32 119 1118 820 63 15 48 132 92 144 25 27 62 81
35 62 71.89 86.64 84.1 68.3 37.4 110 111 90 124 119 119 39.7 58.4 104 192
64 20 74 38 130 1118 820 67 15 48 125 81 161 25 27 62 81
28.1 34 52.93 52.9 57.48 37.02 34.33 111 124 76.3 87 75 74 29 42.1 111 227
1.25 1.82 1.36 1.64 1.46 1.84 1.09 0.93 0.90 1.18 1.43 1.59 1.61 1.37 1.39 0.94 0.85
Abbreviations: AAS, atomic absorption spectroscopy; FIHG-AAS, flow injection hydride generation atomic absorption spectrometry; FM, LS-5 spectroflourometer; GFAAS, graphite furnace atomic absorption spectroscopy; ICP-MS, inductively coupled plasma mass spectrometry; M/C, maternal/ cord; preec., preeclampsia; RBC, red blood cells; WB, whole blood. All maternal samples were collected around the time of delivery except for Osman et al. (2000), where they were collected at gestational week 36. Selenium is measured in mg/l except for Sakamoto et al. (2010), which was measured in ng/g. Arithmetic means are presented except for Rudge et al. (2009), where the median was used. Maternal/cord ratio is calculated for this paper using the individual authors’ summary data.
Maternal selenium, µg/L
300
200
100
0 0
100
200
300
Umbilical cord selenium, µg/L
Figure 1. Average maternal and umbilical cord selenium concentrations as reported previously (Table 3). Circles are scaled by the average of maternal and cord sample size of the individual studies; this ranges from n ¼ 15 to n ¼ 1118. The solid line indicates a maternal/cord ratio of 1; the dashed line represents the weighted average among maternal/cord ratios, 1.46. Journal of Exposure Science and Environmental Epidemiology (2012) 22(2)
observe a relationship with hypertension. There are several potential explanations for this, including that this study had lower selenium concentrations than Laclaustra (accounting for imputation to maternal values), smaller sample size and therefore less statistical power, and a younger population (with a small number of cases of diagnosed hypertension) compared with the Laclaustra et al study. There are some potential limitations to this study. We assayed total selenium and did not quantify the forms of selenium that are found in serum, selenium–cysteine, and selenium–methionine. Selenium–cysteine is immediately available to be incorporated into proteins, whereas selenium– methionine is a form of stored selenium that nonetheless can be made biologically available (Flores-Mateo et al., 2006). These different forms of selenium may have differential effects on BP. Also, selenium storage as selenium–methionine occurs in tissues; the factors involved with selenium storage and release of selenium–methionine into blood are not well understood. It is possible that such factors could confound the relationship between selenium and BP. BP was measured with an automated device during labor and delivery, and abstracted from electronic medical records. Potential limitations of this approach are that we did not use an average of repeated measurements but instead abstracted the BP at admission and the highest and lowest measurements. 195
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Also, measurements were taken during a potentially stressful time and may not reflect BP levels at other times. However, BP measurements were consistent for all participants, and there is no reason to assume that the process of labor and delivery would modify the relationship between selenium and BP. BP was recorded automatically rather than being charted by hand, eliminating one potential source of bias and error. Also, in comparing BP with diagnosed hypertension and other variables such as delivery mode (Supplementary Information), it seems that the measures produce consistent results. Therefore, it is reasonable to expect these measurements serve to describe relative BP within this population. Previous studies that assumed a linear relationship between selenium and BP produced results that are consistent with our findings, in that they reported small positive or no associations between selenium and BP (Jossa et al., 1991; Suadicani et al., 1992; Taittonen et al., 1997; Nawrot et al., 2007). A spline model is more appropriate given the nature of the statistical relationship and biological plausibility of that relationship because of the dual role of selenium as a nutrient at low levels and a toxicant at higher levels. We were able to obtain high-quality selenium measurements. Umbilical cord serum was used as a proxy for maternal serum selenium levels; these levels are highly correlated (Micetic-Turk et al., 2000; Rudge et al., 2009; Sakamoto et al., 2010). However, use of umbilical cord measures probably results in some misclassification of maternal exposure, which, if random, would attenuate the relationship between selenium and BP. Our exposure and outcome measurements reflect roughly the same time period, to the extent that BP is responding immediately to selenium levels this could be advantageous. However, it also is possible that selenium levels over time have chronic effects on BP. Previous work suggests that increasing maternal blood volume and fetal nutritional needs may affect selenium concentrations over the course of pregnancy (Kantola et al., 2004). It is currently unclear whether maternal selenium generally increases (Dawson et al., 2000), decreases (Kantola et al., 2004), or remains constant (Navarro et al., 1996) over the course of pregnancy. As we do not have information about maternal selenium levels over the course of pregnancy, we cannot evaluate whether these changes are important in this population. However, we are not aware of any evidence that changes in selenium over the course of pregnancy are differentially related to BP; therefore, we would expect any misclassification to either not affect or attenuate the relationships presented here. Another consideration is whether mothers deficient in selenium might transfer selenium at a higher rate to the fetus, as these elements are critical for the process of growth and development. This is supported by Schulpis et al. (2004), who reported much lower selenium levels in maternal serum among Albanians compared with Greeks, but only small 196
differences in cord serum selenium concentrations from the two populations. However, concentrations of umbilical cord serum selenium in this study are roughly twice as high as those reported by Schulpis. This suggests that umbilical cord serum selenium concentrations in our population would not be affected by maternal selenium deficiency. In this study, we employed flexible models to evaluate the relationship between selenium in umbilical cord serum, maternal BP during labor and delivery. Consistent with previous studies, our results show that there may be different effects of selenium exposure depending on the overall concentrations. This suggests that for some populations, selenium may be a factor in increased BP. Moreover, we stress the importance of applying flexible models when evaluating associations that are likely to have different relationships within different exposure ranges. These results should be verified in larger populations, ideally through the study of additional exposure and outcome biomarkers.
Conflict of interest The authors declare no conflict of interest.
Acknowledgements We thank Drs. John Bernert, Jochen Heidler, Joseph Hibbeln, Robert Jones, and Norman Salem, Jr. for contributing to data collection; Drs. Ana Navas-Acien and Ellen Silbergeld for advice; and Ruth Quinn and Tonya Shephard for project support. This work was supported in part by the Maryland Cigarette Restitution Program Research Grant, National Institute of Environmental Health Sciences grant 1R01ES015445 (RUH), and a United States Environmental Protection Agency Science to Achieve Results (STAR) Fellowship (EMW). The content and views presented in this work are solely the responsibility of the authors and do not necessarily represent those of US EPA, CDC, or NIH.
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Supplementary Information accompanies the paper on the Journal of Exposure Science and Environmental Epidemiology website (http://www.nature.com/jes)
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