ENVIRONMENTAL
HEALTH
PERSPECTIVES
National Institutes of Health
U.S. Department of Health and Human Services
Maternal Exposure to Ambient Levels of
Benzene and Neural Tube Defects
among Offspring, Texas, 1999-2004
Philip J. Lupo, Elaine Symanski, D. Kim Waller, Wenyaw Chan, Peter H. Langlois, Mark A. Canfield, and Laura E. Mitchell doi: 10.1289/ehp.1002212 (available at http://dx.doi.org/)
Online 5 October 2010 ehponline.org
Discussion
We found a significant association between the prevalence of spina bifida in offspring
and maternal exposure to ambient levels of benzene as estimated from the 1999 U.S. EPA
ASPEN model. The association was greatest for those in the highest exposure group. Positive associations between benzene and spina bifida were also observed in lower exposure categories; however, there was no monotonic dose-response relationship. Our finding that the risk of having a spina bifida-affected infant was more than doubled for mothers living in census tracts with estimated benzene levels of 3 μg/m3 or greater is in keeping with a report classifying individuals living in areas with benzene levels > 3.4 μg/m3 as being at the greatest risk for adverse health effects (Sexton et al. 2007). There were also associations with toluene, ethylbenzene, and xylene and between BTEX and anencephaly; however, these associations were not statistically significant.
The association between benzene levels and spina bifida appears to be nonlinear. This is
supported by studies reporting nonlinear associations between personal exposure to benzene and various biomarkers (i.e., urinary metabolites and albumin adducts) of exposure using data collected on occupationally and environmentally exposed individuals, whereby exposuremetabolite curves became steeper at higher exposure levels (Kim et al. 2006; Lin et al. 2007).
Despite the strong correlations between the BTEX compounds, a significant association
with spina bifida was only seen with benzene. Scatter plots of benzene and each of the other
HAPs (toluene, ethylbenzene, and xylene) indicate that the correlations between pollutants are not as great at higher levels (Figure 1). In addition, we found lower correlations between
benzene and the other pollutants (toluene, ethylbenzene, and xylene) when we restricted the analyses to census tracts with the highest benzene levels (n = 119) ( ˆρ = 0.62, 0.71, and 0.77, respectively).
Benzene is known to cross the placenta and has been found in cord blood at levels equal
to or higher than maternal blood (ATSDR 2007). Moreover, benzene can lead to genetic toxicity by covalently binding to DNA and forming DNA adducts, which, if not repaired, disrupt the cell’s microenvironment, leading to inhibition of important enzymes, cell death, and alteration of other cells (ATSDR 2007; Kim et al. 2006; Lan et al. 2004). If this occurs during the critical window of development, the complex cellular processes involved in neurulation (e.g., folate metabolism, cell proliferation, cellular adhesion, and vascular development) may be disturbed, leading to NTDs.
Oxidative stress could also play a role in the teratogenic effect of benzene. Reactive
oxygen species (ROS) formed after benzene exposure leads to DNA stand breakage and
fragmentation leading to cell mutation (Hansen 2006; Xia et al. 2004). The importance of
oxidative stress as a mechanism of teratogenesis is suggested by several animal studies (Fantel 1996). Treatment of pregnant rabbits and mice with ROS inhibitors diminished the effect of teratogens and reduced the amount of DNA oxidation (Liu and Wells 1995; Parman et al. 1999; Wells et al. 1997). One study conducted in rats demonstrated that increased embryonic oxidation resulted in failure of neural tube closure (Morriss and New 1979).
Positive associations between maternal occupational exposures to organic solvents and
congenital malformations have been reported. One study assessing maternal occupational
exposure to benzene reported an odds ratio (OR) of 5.3 (95% CI: 1.4, 21.1) for neural crest
malformations (including NTDs) (Wennborg et al. 2005). In addition, among Mexican
Americans, mothers occupationally exposed to solvents were 2.5 times as likely (95% CI: 1.3, 4.7) to have NTD-affected pregnancies than control mothers (Brender et al. 2002). In a metaanalysis of five studies (not including the two previously discussed), mothers who were occupationally exposed to organic solvents had a 1.6 times greater odds (95% CI: 1.2, 2.3) of having an infant with a birth defect (including NTDs) (McMartin et al. 1998).
A potential limitation of this study is related to the exposure assessment, which relied on
modeled predictions of ambient air levels of BTEX (i.e., the ASPEN model) and may have
resulted in misclassification. Personal exposure is a function of outdoor and indoor pollutant levels, as well as individual behavior (i.e., time spent outdoors versus indoors) (Lee et al. 2004).
However, it has been shown that for benzene, the ASPEN model is a good surrogate for exposure measures based on personal monitoring (Payne-Sturges et al. 2004). An additional potential limitation is ASPEN data were only available for 1999 and not for the entire study period. This may be a suitable surrogate for other years as the sources of HAPs (e.g., emissions from roadways and industrial facilities) were unlikely to change during the study period (Grant et al. 2007; Sexton et al. 2007; Whitworth et al. 2008).
Additionally, information on maternal periconceptional use of folic acid and/or multivitamins (a potential confounder) was not available. However, this population represents pregnancies conceived after mandatory folic acid fortification (January 1998), and a recent study found little evidence of an association between neural tube defects and maternal folic acid intake or multivitamin use since fortification (Mosley et al. 2009). Finally, exposure misclassification due to use of maternal address at time of delivery is also a potential source of bias in this study. Since NTDs occur within the first 4 weeks after conception, address at delivery may be different than address during the critical
window of exposure (Selevan et al. 2000). However, our own analyses, using cases and controls from Texas included in the National Birth Defects Prevention Study with complete residential information during pregnancy, suggest there was no significant change in benzene exposure assignment when using address at delivery versus address at conception (Lupo et al. 2010a)
.
Strengths of this study include the use of a population-based birth defects registry that
employs an active surveillance system to ascertain cases throughout the state of Texas. This
should limit the potential for selection bias. Furthermore, the Texas Birth Defects Registry
includes information on pregnancy terminations reducing any potential bias due to the exclusion of these cases. An additional strength was the use of a relatively small (census tract-level) measure of exposure. Using larger geographic units to estimate exposure (e.g., counties) may not capture the spatial variability of benzene (Pratt et al. 2004).
Furthermore, separate analyses were conducted for spina bifida and anencephaly, as opposed to “lumping” the groups into a single phenotype. This is important as the effects of some exposures appear to be heterogeneous across the subtypes of NTDs (Lupo et al. 2010b; Mitchell 2005).
Conclusions
This study provides the first assessment of the relationship between maternal exposure to
ambient levels of BTEX and the prevalence of NTDs in offspring. Our analyses suggest that
maternal exposure to ambient levels of benzene is associated with the prevalence of spina bifida among offspring. We believe future investigations of air pollutants and NTDs should include additional measures of exposure (e.g., air pollutant monitoring and biomarker data) and additional covariate information (e.g., genotypes and nutrient status).
