In this initial study of non-smoking, predominately low-income pregnant women from Northern and Central California, we find that they are more highly exposed to lower-brominated PBDEs and OH-PBDEs compared to pregnant women from Salinas Valley, California, a nationally representative sample of U.S. pregnant women, and various populations of pregnant women from Europe and Asia. Moreover, despite the relatively small sample size and the inherent variability of measures of thyroid function, we find positive associations between TSH and serum concentrations of lower-brominated PBDE congeners and OH-PBDEs. These associations were statistically significant for individual chemicals (e.g. BDE-85, 4′-OH-BDE-49) and their weighted sum (e.g. Σ TTR-binders). In contrast, we report an inverse association between BDE-207 and TSH. Associations with total and free T4 were generally weak and inconsistent.
Our study is one of the most extensive characterizations to date of flame retardant exposures in pregnant women. We identified OH-PBDEs as well as congeners characteristic of penta-, octa-, and deca-BDE mixtures. Although California passed a state-wide ban on penta- and octa-BDE in 2003, PBDE exposures remain elevated in our contemporary study population sampled in 2008–2009. These high exposures likely reflect the unintended consequences of California’s furniture flammability standards. For example, the 1975 standard, Technical Bulletin 117, requires that polyurethane foam used in upholstered furniture sold in California must be able to withstand an open flame for 12 seconds. Historically, compliance with this standard was achieved by treating polyurethane foam with penta-BDE [3
]. Levels in our population were about three to six times higher than levels measured in a population of Mexican-immigrant women from the agricultural community of Salinas, California who were sampled in 1999–2000 [13
]. This difference may be partially explained by year of sample collection since PBDE levels in human tissue have increased over time in the U.S [38
]. It may also indicate that PBDEs were more widely used in California than Mexico since most of the women in the Salinas study were born in Mexico and lower-brominated PBDEs have two to 12 year half-lives in human blood [39
]. Indeed, a recent study found that California children had seven times higher levels of PBDEs in their serum compared to their Mexican counterparts [39
Relatively few published studies of OH-PBDEs or deca-BDE congeners exist to which we can compare our observations. OH-PBDEs in this population were higher than those found in pregnant women from Indiana [37
] and Japan [40
], and similar to levels found in Nicaraguan children working at a waste disposal site [41
]. BDE-209 was more difficult to quantify, but our 95th
percentile estimate suggests that some pregnant women may be highly exposed to deca-BDE. Future biomonitoring studies should measure deca-BDE congeners so we can more accurately characterize their potential health risks.
This is the first human study to examine and report an association between OH-PBDEs and TSH. One prior study examined correlations between 6-OH-BDE-47 and total T4
in umbilical cord blood serum and reported a negative but non-significant trend [42
Hydroxylated PBDEs may be more potent TH disrupters than the parent congeners. OH-PBDEs bind to both TTR and TBG with a higher affinity than do their parent congeners [43
]. In addition, some OH-PBDEs bind to TTR with a higher affinity than does T4
]. The consequences of this binding may be twofold. First, T4
displacement from these serum binding proteins may decrease serum half-life of T4
, which is approximately six days in humans [45
]. This effect may be enhanced by xenobiotic activation of liver enzymes that conjugate T4
and remove it from serum [8
]. Second, while TTR only caries about 15% of total T4
in the blood [45
], it may be an important mechanism by which T4
crosses the placenta [49
]. Thus, OH-PBDEs may gain access to the fetus in part by their ability to bind to TTR. Considering this, it is important that we found that ΣTTR binders was one of the strongest predictor of TSH in our study.
Hydroxylated PBDEs, but not their parent congeners, can also bind to both thyroid hormone receptors TRα and TRβ [50
]. Because TRβ mediates the negative feedback action of TH on both the hypothalamus and pituitary gland [5
], the combined effects of PBDEs and their hydroxylated metabolites on TH metabolism and on TH negative feedback may be difficult to predict. Likewise, the combined effects of these chemicals on TH action on development and on physiology may be difficult to evaluate.
Our findings also suggest that PBDEs are positively associated with TSH. In principle, this observation should indicate that these contaminants can reduce circulating levels of serum free and total T4
, which would be predicted by animal studies [6
]. However, associations between PBDEs and OH-PBDEs with free and total T4
were generally null. This may indicate that PBDEs affect circulating TSH levels by a mechanism that does not include changes in serum free or total T4
. It is not clear what mechanism would induce this pattern because increased serum TSH should either reflect a reduction or increase in serum T4
. If neither is the case, then it is possible that the normal relationship between hormones within this system has been altered. Alternatively, these associations could be spurious. However, the limited variability that we observed in the T4
measurements of our study population (CV < 15%) coupled with the endogenous variability of T4
], suggests we may require a larger sample size to observe potential associations between PBDEs and T4
, if they exist.
Surprisingly, OH-PBDEs were poorly correlated to PBDE congeners. This suggests that metabolism of PBDE congeners is not the only source of OH-PBDEs [53
] or that there are inter-individual differences in metabolism of xenobiotics [54
]. In either case, measurement of parent PBDEs cannot substitute for OH-PBDEs. Future research should identify influences on human OH-PBDE exposure including both sources and metabolic variability.
Our study results differ from human studies where serum concentrations of PBDEs are considerably lower. Many of these studies either report null associations of PBDEs and TH or effects suggestive of a hyperthyroid-like effect (e.g. a decrease in TSH). For example, Chevrier et al. [13
] reported an inverse association between individual PBDE congeners and their sum with serum TSH in 270 pregnant women. Differences in exposure levels and study design may partly explain these discrepancies. PBDEs may exert different effects on the thyroid system at different concentrations. Furthermore, because TH levels fluctuate throughout pregnancy [26
], the difference in the timing of TSH measurement may be important. Participants in Chevrier’s study were sampled in the late second and third semesters (~27th
week gestation) whereas our study population was sampled between the 19th
week of pregnancy.
Ours is the first human study to examine and find an inverse association between BDE-207 and TSH. Animal studies on thyroid toxicity of higher-brominated PBDEs are limited. BDE-209 does not bind to TTR [55
] nor does it produce hydroxlyated metabolites in human liver cells [21
]; therefore it is plausible that thyroid response varies by PBDE structure. Future studies should compare effects of lower- and higher-brominated congeners on TH action in humans.
While the sample size is limited, this study is important because we focused on a vulnerable but understudied population of ethnically diverse and predominately low-income pregnant women in California. We examined a broad range of chemical analytes and used state-of-the-art methods for analysis of PBDEs and TH. We eliminated potential confounding by smoking through our study design and evaluated the potential for confounding by age, race/ethnicity, parity, and SES. However, larger epidemiologic studies with data on more potential confounders and multiple measures of TH during pregnancy are needed to confirm the observed relationships. Future studies should also assess the health effects of moderate TH disruption since the majority of our participants had TH levels within the normal range.
In conclusion, the results of this cross-sectional, pilot study indicate that PBDE exposures are elevated in pregnant women in California, and suggest a relationship with thyroid function. Our results support including measurements of OH-PBDEs in evaluation of PBDE toxicity and weighting PBDEs and OH-PBDEs based on their ability for binding to TTR. This study supports previous research suggesting that brominated flame retardants can influence TH signaling during pregnancy, which requires further investigation as TH are critical to the health of pregnant women and child development. Lastly, this pilot study lays the basis for larger studies to examine the inter-relationships between PBDEs and OH-PBDEs, TH signaling during pregnancy, and adverse maternal and child health outcomes.