br The use of a single serum
The use of a single serum measurement has generally been accepted as a reasonable proxy for chronic exposure levels of other POP com-pounds in healthy individuals, based on a number of analyses that have shown strong intra-individual correlations between serial measure-ments taken over time and a constancy of the relative exposure rankings (i.e., high/medium/low) across individuals over time (Gammon et al., 1997; Vo et al., 2008; Wolff et al., 2000b). The degree to which this supposition extends to the PBDEs, which have shorter half-lives than many of the legacy POPs, is not known. PBDE exposures, however, are ubiquitous and on-going. Thus, while a single serum measurement later in life, such as was used in this study, may not be a precise estimate of exposure for an earlier more etiologically-relevant time period, it BAY-598 likely provides a reasonable characterization of relative ranking among study participants. There are, however, several additional caveats related to this issue worth noting that may be especially germane to breast cancer studies. In particular, intra-individual changes in POPs body burden levels may vary substantially by lactation history and BMI (Vo et al., 2008; Wolff et al., 2000b; Chevrier et al., 2000; Rogan, 1996; Sasamoto et al., 2006; Sweeney et al., 2001; Wolff et al., 2005), which are also recognized risk factors for breast cancer. In our study, lactation history was not associated with PBDE levels and analyses limited to those who had never breastfed did not yield results that differed substantially from those based on all women (data not shown). BMI, however, was a sig-nificant confounder and our BMI-stratified analyses suggested a re-duced risk for BDE-47 only among obese women (Supplemental Table S4). In light of the many subset analyses that were conducted, and given that this finding was sensitive to whether BDE-47 was specified as an ordinal or continuous term, we tend to regard it as spurious. It is pos-sible however that it could be an artifact of the degree to which a single serum measurement taken later in life (and after diagnosis among cases) may differentially capture chronic exposures among women with varying BMI. Alternatively, it is possible this finding is reflective of toxicokinetic mechanisms that are influenced by body weight, percen-tage of body fat, or type of body fat– a supposition supported by compelling evidence summarized in a recent review of the role of adipose tissue in modulating POPs toxicity (La Merrill et al., 2013). Environment International 127 (2019) 412–419
In addition to BMI, changes in body weight also appear to be im-portant determinants of serum POPs concentrations (Chevrier et al., 2000; Sweeney et al., 2001; Wolff et al., 2005; La Merrill et al., 2013; Verner et al., 2008; Wolff et al., 2007). This is of concern because changes in body weight, particularly weight gain, are common among breast cancer patients, especially among those who receive che-motherapy (Makari-Judson et al., 2007; Vance et al., 2011). Our ability to fully consider changes in BMI was limited by the availability of se-rially-collected BMI data at relevant points in time. Specifically, we did not have updated BMI information at the time of blood collection but rather had to rely on BMI information collected in 2011–2012 (which ranged from as much as 4 years prior to within a year after blood col-lection). Based on these data (which would not necessarily capture changes in body weight related to diagnosis or treatment), we generally did not observe differences in PBDE risks among women who did and did not have substantial changes in body weight (Supplemental Table S5).
Beyond the concern of whether the use of a single serum measure-ment adequately serves as a valid proxy for chronic PBDE exposures, another concern is that earlier exposures during potentially important windows of susceptibility may not have been captured (Gray et al., 2017; Institute of Medicine of the National Academies, 2014; Mouly and Toms, 2016; Rodgers et al., 2018). Our attempts to indirectly ad-dress this issue by doing some focused analyses for participants who may have had the greatest opportunity of exposure by virtue of having been pregnant or undergone menopause during the peak windows of population exposures did not prove illustrative (data not shown). If risks are only posed by exposures during perinatal or pubertal development, the vast majority of our participants would not have been at risk as 75% were born before 1952 and all were born before 1972 – prior to the widespread use of these chemicals.