Guxens et al. p-values of 0.002 and 0.02) [Supplemental Material, Figure 3 (http://dx.doi.org/10.1289/ ehp.1103469)]. However, excluding Gipuzkoa, which was the only region where NO2 and benzene were significantly associated with lower mental development scores in the group with high fruit and vegetable intake, did not have a meaningful effect on interactions between air pollutants and antioxidants, detoxification fac- tors, or socioeconomic variables (Supplemental Material, Table 4). In the group with low maternal fruits and vegetable consumption, results did not change meaningfully after additionally adjust- ing for noise annoyance, maternal smoking during pregnancy, maternal cotinine levels during pregnancy, parental social class, and parental country of origin, considered to be potential mediating factors (data not shown). Additionally adjusting for birth weight, birth height, birth head circumference, and gesta- tional age also did not meaningfully change the estimated coefficients (data not shown). Similarly, when we restricted the analysis to families without residential changes between the third trimester of pregnancy and the age at developmental testing [β (95% CI) = –2.89 (–5.91, 0.13) and –3.49 (–6.34, –0.63), respectively, for a doubling of each compound] or to women who spent > 15 hr/day at home during pregnancy [β (95% CI) = –4.38 (–7.72, –1.04) and –4.01 (–6.96, –1.07), respectively, for a doubling of each compound], relations remained consistent. Results were also com- parable to those shown for the main models when we repeated these sensitivity analyses among infants who were not breast-fed, in the low maternal vitamin D group, or in the high fruit-and-vegetable intake group (data not shown). Discussion In this study conducted in several regions of Spain, adverse effects of air pollutants on infant mental development in the second year of life were observed among subjects with low exposure to maternal consumption of fruits and vegetables. The protective effect of other factors was also tested showing a non- significant inverse association in non-breast- fed infants and infants with low maternal vitamin D. These findings were very stable in several sensitivity analyses. In Gipuzkoa, however, there was an overall adverse effect of prenatal exposure to residential air pollu- tion on mental development scores, regardless of exposure to these protective factors. An important advantage of this study was that air pollution was not clearly related with social class indicators (Vrijheid et al. 2010), and there was little or no evidence of confounding or modification by social class. NO2 and benzene are considered markers of toxic air pollutants rather than potential 148 causative agents themselves. A limitation of our study was that only NO2 and benzene were measured, instead of ultrafine particu- late matter (PM)—particularly the trace metal content—that seems to be the most neurotoxic component of residential air pollution (Block and Calderon-Garciduenas 2009). A second limitation was that noise annoyance during pregnancy was collected by a self-reported scale rather than by a direct measure of noise levels. Both air and noise pollution are associated with motor vehicle traffic, and recent studies have reported possible associations between chil- dren’s cognition and road traffic noise (Clark and Stansfeld 2007). Although our analy- ses were adjusted for noise annoyance, some residual confounding may remain. Another limitation was that parental intelligence, an important determinant of infant mental devel- opment, was not evaluated. Parental education level and social class did not confound or mod- ify the associations, but their inclusion in the model cannot completely eliminate possible residual confounding by parental intelligence. Finally, not all children initially recruited at birth (n = 2,505) were included in the analysis sample (25% loss to follow-up; n = 616), and loss to follow-up was related to lower social status. However, the inclusion in the analysis of a large set of variables related to participa- tion, and the consistent results obtained across strata of various socioeconomic factors, suggests that nonresponse is unlikely to have biased the results. A major strength of this study is the assessment of air pollution at the individual level using the most robust exposure assess- ment methods currently available for use in large observational studies (Aguilera et al. 2008). Assessments based on residential loca- tion should very precisely reflect exposure in early life. Moreover, associations persisted after taking into account time–activity pat- terns during pregnancy, such as hours spent at home. Additional strengths were the time window when exposure was assessed—the prenatal period—as well as the prospective design. Although pre- and postnatal exposures cannot be disentangled given that most chil- dren remained in the same residence in both periods, exposures during the postnatal period could also play a role in the mental develop- mental effects observed. Finally, the availabil- ity of extensive data on nutrition permitted us to explore potential protective mechanisms suggested in laboratory experiments exploring the role of air pollutants in the brain (Block and Calderon-Garciduenas 2009). Our results suggest that higher consump- tion of fruits and vegetables during pregnancy may have mitigated an adverse effect of ambi- ent air pollutants on infant mental develop- ment in our study population, whereas longer breast-feeding duration and higher maternal circulating vitamin D levels at pregnancy appeared to have less of an effect on associa- tions. Although maternal fruit and vegetable consumption was not related to maternal socioeconomic status, this was not the case for breast-feeding duration and maternal cir- culating vitamin D levels (data not shown). Although some residual confounding may remain, our results support the hypothesized biological mechanisms through which air pollutants may affect mental development, mainly related to neuroinflammation and lipid peroxidation through oxidative stress in the brain (Block and Calderon-Garciduenas 2009). Consistent with our results, Villarreal- Calderon et al. (2010) also found a sustained dorsovagal complex inflammation in mice exposed to Mexico city air, which were miti- gated by administration of dark chocolate, which is rich in polyphenols, potent anti- oxidants. Evidence of a protective effect of antioxidant intake on associations between air pollution and respiratory outcomes has also been found in several other studies, as reviewed by Romieu et al. (2008). The fact that negative associations between air pollution and mental development were observed among all infants from Gipuzkoa— rather than only those with potentially increased susceptibility—may be partly attributable to a more toxic mixture of air pollutants in that region. In Valencia and Sabadell, trace met- als contribute < 0.5% to fine particulate mat- ter mass (lead, 5.9–22.4 μg/m 3 ; manganese, 2.4–13.1 μg/m 3), similar to other European cities (Rivas-Lara 2008; Viana et al. 2008) [see Supplemental Material, Table 5 (http://dx.doi. org/10.1289/ehp.1103469)]. In contrast, Gipuzkoa, a region with high levels of indus- trial activity—mainly iron- and steelworks—has mean concentrations of trace metals in the fine PM fraction that greatly exceed those of other European cities [lead, 20.3–224.0 gμ/m 3; man- ganese, 10.2–124.0 gμ/m 3) (see Supplemental Material, Table 5) (Lertxundi et al. 2010). Fine PM and its components have not yet been measured in Asturias, which is also an industrial area with steelworks, glassworks, and chemical activity that could also have high levels of trace metals. However, because of geographic and meteorologic differences, there may be substan- tial disparities in dispersion patterns of various PM fractions in Gipuzkoa, where residents live primarily in narrow valleys where these par- ticles may be trapped, as opposed to Asturias, which is a coastal and less mountainous region. Among trace metals, lead levels have previously been related with impaired infant neuropsycho- logical development (Grandjean and Landrigan 2006). Although the Gipuzkoa region had high levels of lead in ambient air, lead was detected in a very low percentage of cord blood samples, and levels were similar across all four regions (see Supplemental Material, Table 5) (Llop ovlume 120 | number 1 | January 2012 • Environmental Health Perspectives