Association of DDT and DDE with Birth Weight and Length of Gestation in the Child Health and Development Studies, 1959–1967

Lili Farhang1,2, June M. Weintraub1, Myrto Petreas3, Brenda Eskenazi4 and Rajiv Bhatia1,2

1 San Francisco Department of Public Health, San Francisco, CA
2 Public Health Institute, Oakland, CA
3 Hazardous Materials Laboratory, Department of Toxic Substances Control, California Environmental Protection Agency, Berkeley, CA
4 Center for Children's Environmental Health Research, School of Public Health, University of California at Berkeley, Berkeley, CA

Correspondence to Lili Farhang, Environmental Health Section, San Francisco Department of Public Health, 1390 Market Street, Suite 910, San Francisco, CA 94102 (e-mail: lili.farhang{at}sfdph.org).

Received for publication January 21, 2005. Accepted for publication April 13, 2005.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The pesticide p,p'-dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) are associated with negative reproductive outcomes in animals. In humans, however, the findings are inconsistent. Using data from the Child Health and Development Studies, a longitudinal study of 20,754 pregnancies among San Francisco Bay Area women from 1959 to 1967, the authors examined the effects of maternal serum DDT and DDE concentrations on preterm birth, small-for-gestational-age birth, birth weight, and gestational age in 420 male subjects. Data were analyzed using multivariate logistic regression for preterm and small-for-gestational-age birth and linear regression for birth weight and gestational age. Median serum concentrations of DDE were 43 µg/liter (interquartile range: 32–57; range: 7–153) and of DDT were 11 µg/liter (interquartile range: 8–16; range: 3–72), several times higher than current US concentrations. The adjusted odds ratio for preterm birth was 1.28 (95% confidence interval (CI): 0.73, 2.23) for DDE and 0.94 (95% CI: 0.50, 1.78) for DDT. For small-for-gestational-age birth, the adjusted odds ratio was 0.75 (95% CI: 0.44, 1.26) for DDE and 0.69 (95% CI: 0.73, 1.27) for DDT; none of the study results achieved statistical significance. Given the persistence of DDT in the environment and its continuing role in malaria control, studies using more robust data should continue to assess this relation.

birth weight; DDT; dichlorodiphenyl dichloroethylene; gestational age; hydrocarbons, chlorinated; infant, small for gestational age; preterm birth; serum


Abbreviations: CHDS, Child Health and Development Studies; CI, confidence interval; DDE, p,p'-dichlorodiphenyldichloroethylene; DDT, p,p'-dichlorodiphenyltrichloroethane; OR, odds ratio; PCB, polychlorinated biphenyl; SE, standard error


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Preterm birth and low-birth-weight birth are associated with infant mortality and a range of infant and childhood morbidities, including respiratory illness, infections, neurologic impairment, and developmental delays (1Go–9Go). In the United States, neonatal mortality is more than twice as likely in infants born preterm (10Go). Risk factors associated with preterm birth and low birth weight include socioeconomic status, race/ethnicity, and smoking (1Go, 2Go, 11Go). Some suggest that environmental contaminants such as organochlorine pesticides may also adversely impact fetal development (12Go).

The United States banned the organochlorine pesticide dichlorodiphenyltrichloroethane (technical DDT) in 1972. However, human health concerns continue because of its ongoing use in vector control and malaria prevention, its persistence in the environment, its accumulation in the human food chain, its long half-life in human tissues, and its resistance to metabolism (13Go–16Go). Developing fetuses are exposed to p,p'-dichlorodiphenyltrichloroethane (DDT) and its metabolites through in utero placental transfer (17Go, 18Go). Concerns regarding exposure to these chemicals stem from their potential role in endocrine disruption. DDT can mimic estrogen action; its major metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) can interfere with androgens (19Go).

Environmental exposure to organochlorine pesticides has been associated with adverse reproductive outcomes in animals (20Go–23Go). Findings regarding the relation of DDT and DDE to human reproductive outcomes are inconsistent. Some studies report that increased levels of DDT and DDE are not significantly associated with infant birth weight (24Go–29Go) or preterm birth (12Go, 30Go–32Go). Others report associations with preterm birth (12Go, 29Go, 30Go, 33Go, 34Go), lowered birth weight (35Go), small-for-gestational-age birth (12Go), and intrauterine growth retardation (36Go).

In this study, we examine the association of serum levels of DDT and DDE with the birth weight and gestational age of male infants in a population of women during a period of high nationwide organochlorine pesticide usage.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Study participants
Data for this study come from the Child Health and Development Studies (CHDS), a longitudinal cohort study of 20,754 women, their pregnancies, and children born from those pregnancies in the San Francisco Bay Area during 1959–1967. Participants were members of the prepaid Kaiser Foundation Health Plan, reflecting a diverse metropolitan population with at least one employed household member. The study enrolled women when they first contacted participating facilities regarding a confirmed or possible pregnancy. Nearly 92 percent of all women with eligible pregnancies who were invited to participate were included in the cohort. Pregnant women who enrolled in the CHDS were interviewed after recruitment and later during their pregnancy (37Go), and multiple maternal serum samples were taken during pregnancy and postpartum. At least one sample was obtained for 89 percent of all CHDS pregnancies. Serum samples were subsequently divided into a package of four 2-ml vials and stored at –20°C at the National Institutes of Health. Maternal and pediatric medical records were abstracted throughout the follow-up period. The CHDS observed 89.4 percent of liveborn children until 5 years of age (37Go).

The 420 subjects included in this analysis were originally selected for a study of maternal serum concentrations of organochlorine contaminants and the risk of genital anomalies in male offspring. The original study included 155 male infants with hypospadias or cryptorchidism who survived for 2 years and 265 randomly selected male controls (38Go). As Bhatia et al. (38Go) did not find an association between maternal DDT and DDE levels and the development of hypospadias or cryptorchidism, cases and controls were combined in this analysis to assess the association of organochlorine pesticides and other adverse birth outcomes.

Laboratory assays
Laboratory methods have been described elsewhere (38Go). Briefly, serum conservators from the CHDS selected which serum sample would be provided. The majority of our samples were drawn in the postpartum period (n = 334), and the rest were drawn during the second (n = 32) and third (n = 54) trimesters. Given the long half-life of DDT and DDE and the high correlation among DDE levels measured at different times during gestation (39Go), these serum samples should accurately reflect body burdens over the entire pregnancy.

The requested samples were shipped on dry ice from the National Cancer Institute (Frederick, Maryland) to the Hazardous Materials Laboratory of the state of California in Berkeley, California, where they were stored at below –20°C until laboratory analysis. One ml of thawed serum was extracted with hexane/dichloromethane, cleaned through Florisil (U.S. Silica Company, Berkeley Springs, West Virginia), and eluted with hexane followed by hexane/dichloromethane. Analysis was performed by gas chromatography with electron-capture detection equipped with 60-m DB-XLB (Agilent Technologies, Palo Alto, California) and Rtx-5ms (Resick Corporation, Bellefonte, Pennsylvania) capillary columns. Standard quality assurance procedures included rigorous calibration procedures, traceability of all standards, and internal review and audit. In addition to DDT and DDE, several other organochlorines were measured (38Go, 40Go). Total cholesterol and triglycerides were determined enzymatically in small aliquots of serum. Target analytes, which measured above detection limits in more than 90 percent of our samples, included p,p'-DDE, p,p'-DDT, ß-hexachlorocyclohexane, hexachlorobenzene, oxychlordane, trans-nonachlor, polychlorinated biphenyl (PCB) 74, PCB 99, PCB 118, PCB 138, PCB 153, PCB 170, PCB 180, PCB 187, PCB 194, and PCB 203.

Each batch included nine samples, one method blank, one laboratory control (bovine serum fortified with target analytes), and one standard reference material (SRM 1589, a human serum from the National Institute of Standards and Technology, Gaithersburg, Maryland). An analyte was quantitated when its signal in a sample was at least three times its signal in the method blank. Laboratory controls and standard reference materials were used to evaluate background contamination, precision, accuracy, and analyte recovery.

Based on external quality control samples, within-batch precision (expressed as the intrabatch coefficient of variation) was 2.7 percent for DDT and 3.0 percent for DDE. The interbatch coefficient of variation was 10.0 percent for DDT and 9.1 percent for DDE. Recoveries of internal standards were used to gauge overall data quality across all serum samples. Recoveries were 93 percent for DDT and 91 percent for DDE, and no corrections were made to the data.

Outcome measures
Four outcomes were assessed in this analysis: 1) preterm birth, defined as birth at less than 37 completed weeks of gestation; 2) small-for-gestational-age birth, defined as birth weight at less than the 10th percentile at each week of gestation, with a sample of 9,744 CHDS male livebirths as the standard; 3) birth weight, measured continuously in grams; and 4) gestational age, measured continuously in weeks. Birth weight was extracted by CHDS staff from clinical birth records and included in the CHDS data set. Gestational age was constructed from the number of completed weeks between the self-reported date of last menstrual period and birth. The date of the last menstrual period was obtained through CHDS interviews with mothers during pregnancy.

Statistical analysis
We examined the relation of DDT and DDE serum concentrations to birth outcomes using logistic regression for preterm birth and small-for-gestational-age birth and linear regression for birth weight and gestational age. DDE and DDT serum concentrations were modeled as both continuous and categorical variables. To increase the interpretability of results in models using continuous chemical measures, subjects' serum levels (µg/liter) were divided by the interquartile distance for DDT and DDE, and coefficients are reported per interquartile distance change in DDT and DDE. In models using categorical chemical measures, subjects were divided into four categories based on the quartile distribution of each chemical measure among the study population. Trend tests were constructed by modeling categorical variables as ordinal variables in these models.

Because of small numbers, African-American, Hispanic, Asian, and multiple/other race/ethnicity subjects were combined into a non-White category. Observations on maternal height or prepregnancy weight were missing for 25 percent of subjects. To address this, we imputed prepregnancy body mass index for those women who were missing only prepregnancy weight by calculating the median weight gained during pregnancy for women in each body mass index category and applied this weight change to the women whose weight was measured at the same point during their pregnancy. Body mass index was calculated as weight in kilograms divided by height in meters squared.

A "base" model was developed for each chemical and outcome that included serum cholesterol and triglycerides as continuous variables (grams/liter), as these are correlated with DDE and DDT concentrations. To control for the role of case-control status from the original study with our outcomes of interest, base models also included a term for case-control status, based on their designation in the initial genital anomalies study, and an additional interaction term for case-control status and chemical measure. In addition to all the variables in base models, demographic and behavioral variables were selected as covariates for further adjustment based on associations reported in the literature. Covariates were included in "full" multivariate models if the addition of each variable to base models changed the coefficient of the serum level by 10 percent or more. The covariates examined included maternal age, race, education, marital status, place of birth, occupation, smoking status, body mass index, and parity (table 1). All covariates changed either the DDT or DDE effect estimates for each of the four outcomes and, consequently, we decided to apply a uniform model that included all covariates for comparability across models. Finally, because of high percentages of missing values for many of the demographic and behavioral covariates, we included terms for missing values in each of the models where greater than 5 percent of values were missing (education, marital status, place of birth, occupation, smoking status, and body mass index). All analyses were conducted using the SPSS, version 11.5, statistical program (SPSS, Inc., Chicago, Illinois).


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TABLE 1. Demographic characteristics of the study sample from the US Child Health and Development Studies cohort, 1959–1967

 

    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Sociodemographic characteristics of the participants are described in table 1. The majority of women were multiparous, were White, and had completed high school. Over three fourths were married, and nearly one half were housewives. Almost a third reported smoking during their CHDS pregnancy.

Of 420 births in this population, 7.9 percent (n = 33) were born preterm, and 9.8 percent (n = 41) were born small for gestational age. The mean birth weight in grams was 3,350.7 (standard deviation: 527.0), and the mean duration of gestation was 39.5 (standard deviation: 2.2) weeks.

The median unadjusted serum concentrations of DDE were 43 µg/liter (interquartile range: 32–57; range: 7–153). For DDT, the median unadjusted serum concentration was 11 µg/liter (interquartile range: 8–16; range: 3–72). The interquartile distance for DDE measured 26 µg/liter and for DDT measured 8 µg/liter. The median concentrations of cholesterol and triglycerides were 3 g/liter and 2 g/liter, respectively. With recovery levels of 93 percent for DDT and 91 percent for DDE, recovery-adjusted results did not differ substantially from those not adjusted for recovery.

Overall, no statistically significant relations or trends were observed between serum measurements of DDT or DDE and birth weight or length of gestation. In the base model for preterm birth, the odds of preterm birth were 6 percent higher per interquartile distance increase in DDE (odds ratio (OR) = 1.06, 95 percent confidence interval (CI): 0.66, 1.70) and, with further adjustment, the odds of preterm birth increased by 28 percent (OR = 1.28, 95 percent CI: 0.73, 2.23). When assessing increasing DDT levels and preterm birth, we found inverse but nonsignificant associations per interquartile distance increase in both base (OR = 0.87, 95 percent CI: 0.51, 1.48) and full (OR = 0.94, 95 percent CI: 0.50, 1.78) models (table 2).


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TABLE 2. Adjusted odds ratios and beta coefficients for maternal serum DDE* and DDT* and preterm birth, small-for-gestational-age birth, birth weight, and gestational age for participants in the US Child Health and Development Studies cohort, 1959–1967

 
The odds of a small-for-gestational-age birth were 4 percent lower (OR = 0.96, 95 percent CI: 0.61, 1.51) in base models and 25 percent lower (OR = 0.75, 95 percent CI: 0.44, 1.26) in full models per interquartile distance increase in DDE. The odds of a small-for-gestational-age birth were 24 percent lower per interquartile distance increase in DDT (OR = 0.76, 95 percent CI: 0.48, 1.20); further adjustment did not materially change these results (table 2).

The results of analyses for birth weight and gestational age were also not statistically significant. An interquartile distance increase in DDE was associated with a decrease in infant birth weight of 34 g (standard error (SE): 36; p = 0.34) in the base model, and further adjustment reduced the decrease to 17 g (SE: 37; p = 0.65). An interquartile distance increase in DDT was associated with an increase in infant birth weight of 21 g (SE: 35; p = 0.55) and, after further adjustment, was associated with an increase of 32 g (SE: 37; p = 0.38). For gestational age, no significant associations were revealed (table 2).

In the analysis of the associations between outcomes and serum levels measured in quartiles, no statistically significant associations were found (table 2). For preterm birth, women whose serum levels were in the fourth quartile (≥57.5 µg/liter) had a 54 percent increased odds compared with women in the lowest quartile (≤31.6 µg/liter) after adjustment for covariates in the full model (OR = 1.54, 95 percent CI: 0.45, 5.34; ptrend = 0.89). There were decreased odds of preterm birth in all DDT categories when compared with the lowest referent category (≤8.1 µg/liter); however, none were statistically significant.

We also found no statistically significant association between small-for-gestational-age births and either serum DDT or DDE levels. Women in the highest DDE quartile had 9 percent decreased odds of a small-for-gestational-age birth in the base model (OR = 0.91, 95 percent CI: 0.32, 2.60; ptrend = 0.98); odds decreased upon further adjustment but were still not statistically significant (OR = 0.64, 95 percent CI: 0.18, 2.29; ptrend = 0.58) (table 2).

For the birth weight analysis by quartiles, none of the relations or trends were statistically significant, and the point estimates were very unstable. For example, there was an increase in birth weight in the second DDT quartile in the base model (ß = 128 g, SE: 74), which decreased by almost one third after adjustment in the full model (ß = 90 g, SE: 75) (table 2).

Similarly, the gestational age analysis did not reveal any statistically significant relations. There was a decrease in gestational age in the highest DDE quartile of the base model (ß = –0.22 weeks, SE: 0.35; ptrend = 0.81) when compared with the lowest, though the drop was smaller after adjustment for the covariates in the full model (ß = –0.10 weeks, SE: 0.38; ptrend = 0.90). In the full model for gestational age and DDT, the coefficients for the second and third quartiles were similar (second quartile ß = 0.36 weeks, SE: 0.33; third quartile ß = 0.41 weeks, SE: 0.33); there was no significant difference between the highest DDT quartile and the lowest (ß = 0.08 weeks, SE: 0.36; ptrend = 0.77).

Several covariates were adversely and significantly associated with our outcomes, including being unmarried, current smoking, body mass index of less than or equal to 18, history of no previous pregnancies, non-White race/ethnicity, and being born outside California or outside a southeast US state. We did not see any statistically significant effects of hypospadias and cryptorchidism on any of our outcomes.

There were also no statistically significant associations between the DDE:DDT ratio and any of the outcomes. All findings remained unchanged when we restricted the analyses to controls from the original genital anomalies study, when we restricted all analyses to subjects who had complete data on all covariates, and when we examined birth weight, gestational age, and small-for-gestational-age births in term infants only (data not shown).

Our study's laboratory analysis included measures of several other organochlorine chemicals and PCBs in maternal serum including ß-hexachlorocyclohexane, hexachlorobenzene, oxychlordane, trans-nonachlor, PCB 74, PCB 99, PCB 118, PCB 138, PCB 153, PCB 170, PCB 180, PCB 187, PCB 194, and PCB 203. We assessed the role of confounding by these chemicals by including them in full models examining DDT or DDE and each of the four outcomes. The sum of 10 PCB congeners (tetra- to octa-chlorinated) was used as the measure of PCBs. We did not find evidence of confounding when we added these chemicals to our models (data not shown).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Neither maternal serum levels of DDT nor levels of its major metabolite DDE were significantly associated with preterm birth, small for gestational age, birth weight, or gestational age in male infants in this study of women participating in the Child Health and Development Studies from 1959 to 1967. These results cannot be generalized to female infants.

There is much variation in studies reporting on these relations (table 3). While our results are consistent with findings reported in a number of US and international studies examining birth weight (24Go–29Go) and preterm birth (30Go–32Go), others have illustrated divergent findings (29Go, 30Go, 33Go–36Go). Many of these studies reporting no association were smaller than our study, and the majority had lower exposure levels than ours did (24Go, 26Go–32Go). In some of these contrasting studies, researchers did not control for potential confounding factors such as occupation, age, and race/ethnicity (33Go–35Go). In addition, while some studies do not provide enough information to allow comparisons between chemical levels (25Go, 33Go, 34Go), for all other studies our concentrations of DDT and DDE were higher. For example, the recovery-adjusted median DDE level in the CHDS (47 µg/liter after adjusting for 91 percent recovery) was somewhat higher than that found in another prospective study conducted in the same time period (1959–1966), the US Collaborative Perinatal Project (36 µg/liter after adjusting for 70 percent recovery) (12Go).


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TABLE 3. Characteristics of studies examining DDT* and DDE* with birth weight and length of gestation

 
The Collaborative Perinatal Project was comparable in study design and time period to the CHDS but, unlike our study, found increasing odds of preterm and small-for-gestational-age birth associated with higher serum DDE concentrations. Infants whose mothers had serum DDE levels in the highest category (≥60.0 µg/liter) had adjusted odds ratios of 3.1 (95 percent CI: 1.80, 5.40) for preterm birth and 2.6 (95 percent CI: 1.30, 5.20) for small-for-gestational-age birth (12Go). Longnecker et al. (12Go) illustrated a linear exposure-response relation between DDE categories, while our study had no such appearance of linearity. Like our study, they found no association of DDT or the DDT:DDE ratio with preterm and small-for-gestational-age birth. DDT and DDE, while related, may affect humans via different physiologic mechanisms.

A possible explanation for the contrasting findings for DDE between the Collaborative Perinatal Project and the CHDS is that the population from the former was drawn from 12 university-based centers across the country, whereas the CHDS population was drawn from managed health-care facilities in northern California. Populations seeking health care from teaching hospitals may be different from populations covered through health insurance, the former representing primarily low-income populations and the latter representing employed persons and their partners. Differences in social position may influence results if social position indicates sensitivity to chemical effects, correlates with other environmental exposures that act synergistically with DDE, or confounds the association with DDE in unexpected ways.

Our study faced several limitations. We may lack power to detect an effect on preterm and small-for-gestational-age births because of our small sample size, though we had adequate power to detect an effect in continuous models assessing birth weight and gestational age. For instance, in the fully adjusted interquartile distance model assessing preterm birth, the odds ratio was 1.28 (95 percent CI: 0.73, 2.23) per interquartile distance increase in DDE, and in the preterm categorical model, the comparison of quartile 4 with quartile 1 provided an odds ratio of 1.54 (95 percent CI: 0.45, 5.34) for the effect of DDE. Although the confidence intervals were wide, the point estimates may suggest a modest effect of higher DDE levels on the risk of preterm birth. With only 33 preterm births, it is likely that our lack of power limited our ability to detect a significant effect.

Our study undersampled adverse birth outcomes. Data for this study were originally used in a case-control analysis of cryptorchidism and hypospadias (38Go). To meet case inclusion criteria for that study, a diagnosis of cryptorchidism and/or hypospadias must have been present at 2 years of age. All randomly selected controls were also required to have been alive at 2 years of age. Therefore, the study population excluded all infants who died during the neonatal and postneonatal periods, when preterm birth and birth weight have the largest role in causing infant death. With the elimination of infant deaths, the proportion of preterm and low-birth-weight births in our sample was reduced when compared with the underlying cohort (7.9 percent in our study population were preterm vs. 10.4 percent in the underlying cohort of 9,927; 9.8 percent were small for gestational age vs. 10.5 percent in the underlying cohort; 4.5 percent were low birth weight vs. 7.3 percent in the underlying cohort). If DDT and DDE are harmful enough to cause preterm and low-birth-weight birth, we could have missed an association because our results were biased toward the null by excluding those infants who died in the first and second years of life. It is noteworthy that, in the Collaborative Perinatal Project, study researchers also undersampled adverse outcomes, and they hypothesized that the number of undersampled birth outcomes was likely too small to bear any effect on the analysis (12Go).

We managed missing values on demographic and behavioral covariates by including "missing" terms for the variables of interest in our adjusted multivariate models. To further assess the potential effect of these missing values, we repeated all analyses, imputing missing values by use of the Schafer stand-alone NORM program, version 2.02, for Windows (http://www.stat.psu.edu/~jls/misoftwa.html). In these findings, the role of confounding and our overall findings were unchanged.

It is possible that unmeasured confounding masked an exposure-outcome relation. For example, we had no information on diet, and if diet is associated with DDT exposure as well as better birth outcomes, failure to include diet in our analyses would obscure an association.

Our study has several strengths. We sampled a population from a large prospective cohort study with consistent procedures for recording infant birth outcomes. The CHDS enrolled subjects at a time of high domestic use of organochlorine insecticides (14Go), and chemicals were measured directly through maternal serum samples. Our results are comparable to measures of DDE from another analysis of CHDS-archived maternal serum (41Go) and also to those found in an analysis of archived serum collected between 1964 and 1971 in northern California (42Go). Detailed comparisons with these and other populations are made elsewhere (38Go, 43Go).

In our sample, maternal characteristics such as non-White race/ethnicity, low body mass index, history of no previous pregnancy, current smoking, and being unmarried were associated with adverse birth outcomes, findings that are in agreement with the reproductive health literature (1Go, 2Go, 7Go, 44Go). This consistency adds to our confidence in these data and strengthens our assessment that our sample properly represents known relations in the data.

In summary, while we cannot exclude the possibility of modest effects, our study does not provide epidemiologic support for a strong causal relation between DDT or DDE and adverse male infant birth outcomes. Given, however, ongoing use of DDT for malaria prevention, environmental persistence, documented adverse reproductive effects in animals, and inconsistent findings across human studies, continued investigation of the human impacts of DDT and DDE remains appropriate.


    ACKNOWLEDGMENTS
 
This study was funded by grant R29 ES09042 from the National Institute of Environmental Health Sciences.

The authors thank Drs. Bea van den Berg and Barbara Cohn for making CHDS specimens available for this study and Roberta Christianson for sharing her wealth of knowledge about the CHDS database. They also thank Rita Shiau for her input in the early phase of this work.

Conflict of interest: none declared.


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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