A cohort study evaluation of maternal PCB exposure related to time to pregnancy in daughters

Abstract

Background: Polychlorinated biphenyls (PCBs) remain ubiquitous environmental contaminants. Developmental exposures are suspected to impact reproduction. Analysis of mixtures of PCBs may be problematic as components have a complex correlation structure, and along with limited sample sizes, standard regression strategies are problematic. We compared the results of a novel, empirical method to those based on categorization of PCB compounds by (1) hypothesized biological activity previously proposed and widely applied, and (2) degree of ortho- substitution (mono, di, tri), in a study of the relation of maternal serum PCBs and daughter's time to pregnancy.

Methods: We measured PCBs in maternal serum samples collected in the early postpartum in 289 daughters in the Child Health and Development Studies birth cohort. We queried time to pregnancy in these daughters 28-31 years later. We applied a novel weighted quantile sum approach to find the bad-actor compounds in the PCB mixture found in maternal serum. The approach includes empirical estimation of the weights through a bootstrap step which accounts for the variation in the estimated weights.

Results: Bootstrap analyses indicated the dominant functionality groups associated with longer TTP were the dioxin-like, anti-estrogenic group (average weight, 22%) and PCBs not previously classified by biological activity (54%). In contrast, the unclassified PCBs were not important in the association with shorter TTP, where the anti-estrogenic groups and the PB-inducers group played a more important role (60% and 23%, respectively). The highly chlorinated PCBs (average weight, 89%) were mostly associated with longer TTP; in contrast, the degree of chlorination was less discriminating for shorter TTP. Finally, PCB 56 was associated with the strongest relationship with TTP with a weight of 47%.

Conclusions: Our empirical approach found some associations previously identified by two classification schemes, but also identified other bad actors. This empirical method can generate hypotheses about mixture effects and mechanisms and overcomes some of the limitations of standard regression techniques.

Figure 1

Bootstrap distributions of the sum of weights within the Wolff et al. classifications of PCBs. The ‘other’ category includes PCB56 and PCB146.

Figure 2

Average bootstrap estimated weights for PCB congeners related to TTP after adjusting for race (African American vs all other) and whether the daughter was breastfed and grouped according to the degree of chlorine substitution on the ortho position (Kezios et al., [1]).

Figure 3

Bootstrap distribution of the estimated relative hazard of pregnancy based on a unit increase in the PCB scores associated with (A) a decrease in hazard (average score weights are provided in Table1, column 3) and (B) an increase in hazard (average score weights are provided in Table1, column 5).

Figure 4

The cumulative probability of pregnancy over cycle months in the four cases defined by the two PCB scores (i.e., PCB+, PCB-) cut at their medians to form the (High, Low), (High, High), (Low, Low) and (Low, High) groupings where PCB + is the score associated with a positive hazard slope (shorter TTP) and PCB- is the score associated with a negative hazard slope (longer TTP).