In this article, we continued our examination of the relationships of POPs with diabetes and metabolic syndrome by studying BFRs. Among six BFRs, PBB-153 and PBDE-153 were significantly associated with both diabetes and metabolic syndrome, although dose-response relationships did not appear to be the same between these two chemicals. Thus, these data provide limited support for the proposition that besides chlorinated POPs, other chemicals with properties of persistence in adipose tissue and endocrine disruptors may also disturb glucose and lipid metabolism.
However, evidence in favor of this conclusion is much stronger for chlorinated POPs (1
) than for the brominated POPs, which were the focus of this article. In our previous studies on chlorinated POPs (1
), most chemicals belonging to the PCB and organochlorine pesticide classes showed strong associations with diabetes and metabolic syndrome. Despite the chemical and physical similarities among PCBs, PBBs, or PBDEs, most chemicals belonging to PBDEs, except PBDE-153, were not clearly associated with diabetes and metabolic syndrome.
In fact, there is an important difference in exposure route of PBDEs from chlorinated POPs or PBBs. At first, like chlorinated POPs, diet was regarded as a major pathway of exposure to PBDEs because they also bioaccumulate in food chains (13
). However, recent studies discovered that the main exposure route of PBDEs in the general population is house dust, not diet, because it is used as an additive to retard fire and flames in a variety of commercial and household products (14
). Humans are exposed to PBDEs in house dust in direct inhalation, ingestion, and dermal exposure (5
). Unlike PBDEs, PBBs were prohibited in the U.S. in the 1970s after an accidental human exposure in Michigan (15
). Thus, their main exposure route would be diet, which is similar to that for chlorinated POPs (15
). These different exposure routes were reflected in the correlations among serum BFR concentrations. Serum concentrations of five chemicals belonging to PBDEs showed very strong mutual correlations, consistent with common exposure sources. However, a serum PBB-153 concentration showed, at most, weakly positive associations in comparison with associations with PBDEs. As PBDEs were measured among the NHANES participants in whom PCBs were not measured, we could not examine the correlation between PCBs and PBDEs. However, other studies with simultaneous measurement reported no association between these two chemicals (16
Therefore, serum concentrations of chlorinated POPs or PBBs, with exposure primarily through food, may reflect a cumulative lifetime dose of exposure. However, serum concentrations of PBDEs may be a mixture of more recent exposure to indoor pollution and cumulative low exposure to diet. These considerations appeared to be well reflected in the associations with age. PBBs and chlorinated POPs (1
) were strongly associated with age, while most PBDEs were not, or even inversely, associated with age. Unlike traditional toxicological effects due to acute high-dose exposure, disturbance of glucose and lipid metabolism due to POPs in adipose tissue as endocrine disruptors may require long-term exposure. Thus, we think that serum concentrations of PBDEs may not reflect a biologically important long-term dose. Furthermore, toxicological studies have shown that different exposure routes led to different pharmacokinetics in terms of uptake, distribution, and elimination (17
However, PBDE-153 tended to stand out from other PBDEs in several ways. Even though PBDE-153 showed an inverse association with age, opposite to that of PBB-153, serum concentrations of PBDE-153, compared with other PBDEs, were more positively correlated with those of PBB-153. In addition, both the higher concentrations in men and the inverse association with BMI were similar to those of PBB-153 but different from other PBDEs. It may be that PBDE-153 has different pharmacokinetics from other PBDEs.
The significant associations of PBB-153 and PBDE-153 need further discussion in relation to their differing dose-response curves. Interestingly, in our previous studies (1
), we also found nonlinear dose-response relations of PCBs with various outcomes, including plateaus or inverted U-shaped associations. Among various subclasses of POPs, PCBs are the subclass that has most similar structures to BFRs (5
). Thus, a similar dose-response curve between PCBs and BFRs may be biologically plausible. In fact, in addition to PCBs, most chlorinated POPs showed an association that was much steeper across lower background concentrations than across higher background concentrations. Although a linear dose-response relation is generally regarded by epidemiologists as a criterion for causality, the possibility of inverted U-shaped associations with endocrine disruptors has been suggested by some experimental studies (a strong effect across low doses but a weakened or no effect at high doses) (18
). Although researchers cautioned that low-dose effects cannot be extrapolated from animal studies to humans (19
), our findings on PCBs, PBBs, or PBDEs suggest that this concept might also apply in the human body.
This nonlinear dose-response curve may explain previous epidemiological findings in the Michigan cohort with accidental high exposure to PBBs (20
). In fact, this prospective cohort study did not show any association between PBB concentrations and incident diabetes. However, serum concentrations of the reference group in the Michigan cohort were already much higher than those of current participants. No association in subjects with high exposure to POPs but strong associations in subjects with background exposure to POPs were similarly observed with chlorinated POPs (21
Even though it is still unclear what biological mechanism is involved in the association of POPs with diabetes and metabolic syndrome, the potential of xenobiotics to disrupt glucose and lipid metabolism in mammals is a well-developed theory in toxicology (8
). Indeed, many of the early toxicity responses in animal studies with a range of pollutants note glucosuria, dyslipidemia, increased gluconeogenesis, and fatty liver (8
). Furthermore, dioxin-like compounds exert their effects through binding to the aryl-hydrocarbon receptor, which is thought to antagonize peroxisome proliferator–activated receptors (9
The inverse association of PBB-153 and PBDE-153 with BMI was interesting. In fact, both of these POPs showed positive associations with waist circumference after adjusting for BMI. In our previous studies (1
), PCBs were also inversely associated with BMI but positively associated with waist circumference, while other chlorinated POPs were weakly and positively associated with both BMI and waist circumference. The exposure to POPs may affect visceral adipose tissue differently than subcutaneous adipose tissue, and these effects may depend on POP subclass. Furthermore, even though POPs are generally observed to be positively associated with obesity, associations between POPs and obesity would not be simple. For example, a high intake of fatty food is related to both a high POP exposure and obesity. On the contrary, an increase of adipose tissue mass itself dilutes the concentrations of POPs. Furthermore, some experimental studies have reported that the exposure to endocrine disruptors itself can induce obesity (22
). As these mechanisms do not all act in the same direction, the associations between POPs and obesity may be diverse.
This study has several limitations. First, the current findings should be interpreted with caution due to the cross-sectional nature of this study. Even though our results are biologically plausible because some PBDEs are reported to cause the disturbance of glucose and lipid metabolism in adipose tissue (7
), we could not exclude the possibility that changes in metabolic state due to disease could have created the associations we observed. Second, BFRs were not measured in the same population as chlorinated POPs in the NHANES, so we could not simultaneously consider the effect of chlorinated POPs. There may be a possibility of synergistic effects that multiple POPs reinforce each other's toxicity in the general population, as we discussed previously (21
). Third, inference should be made cautiously in light of the multiple comparisons intrinsic in this investigation.
Along with our previous findings on chlorinated POPs, our current study suggests that the background exposure to some brominated POPs may be closely related to disturbance of glucose and lipid metabolism in the general population. Prospective studies of the relation of POPs with diabetes and metabolic syndrome are needed because both the exposure and the disease have substantial prevalence and the public health significance of such a relation could be marked.