Persistent organic pollutants (POPs) are chemicals that include polybrominated diphenyl ethers (PBDEs), per- and polyfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs), and organochlorine (OC) pesticides. POPs persist environmentally and biologically and often bioaccumulate [1–5]; thus low-level exposure is widespread despite cessation or restrictions on manufacture and use, and POPs continue to be detectable in a large portion of the U.S population [6, 7]. However, we know relatively little about the health effects of exposure to these compounds, including their impact on mortality. Considering the prevalence, persistence, and bioaccumulation of POPs, an association with mortality in the U.S. population would have significant public health implications.

PBDEs are mixtures of chemicals that have been used as flame-retardants in many consumer products such as upholstery, plastics, and cabinets [3, 8]. Exposure to PBDEs often occur through ingesting contaminated dust, food, and breastmilk; touching contaminated soil or commercial products; and inhaling contaminated air [9, 10]. Some studies have suggested that exposure to PBDEs is associated with changes to neurodevelopment [11, 12], however, our understanding of the human health effects due to exposure is limited. To date, we are unaware of any studies assessing the association between PBDEs and mortality in the general population.

PFASs consist of a group of manufactured chemicals that repel water and oil, making them resistant to stains [4, 13]. Because of this characteristic, PFASs have been used for consumer products such as cookware, sofas, carpets, clothing, food packaging, paints, and cleaning products [4, 13]. Thus, exposure to PFASs can occur through contact with products treated with PFASs; contact with contaminated water, soil, and outdoor air near the industrial sites that manufacture or use PFASs; and consumption of contaminated food [14–17]. As with PBDEs, questions about the health effects related to exposure of PFASs at the levels that are normally found in the environment remain. Although existing studies often report conflicting findings, PFASs have been reported to increase cholesterol [18, 19] and risk of cancer [20], affect the immune system [21, 22], and decrease fertility [23]. However, as with PBDEs, whether non-occupational exposure to PFASs increases morality risk is unknown.

PCBs include manufactured mixtures of chlorinated compounds that were used as lubricants and coolants in electrical equipment, as well as other industrial applications such as plasticizers and pigments [1, 24]. The production of PCBs in the U.S. ended in 1979 because of their persistence in the environment and concern about potential health effects [24] and many countries worldwide eliminated the production and use of PCBs in 2004, in accordance with the Stockholm Convention [25]. However, because PCBs persist in the environment for many years, exposure to PCBs persists through use of contaminated electronic equipment and consumption of contaminated soil, air, water, food, and breastmilk [1, 26–28]. Increasing evidence suggests that low-level exposure to PCBs may have adverse health consequences [29–32] and the Environmental Protection Agency (EPA) has classified PCBs as probable human carcinogens [24]; however, whether PCB exposure increase risk of mortality in the general population remains uncertain. Two prior studies have used NHANES data to analyze associations of PCBs with mortality in the general population, however, they were limited by relatively short follow-up times and the omission of considering education or other measures of socioeconomic status as potential confounders [33, 34].

Finally, OC pesticides are a class of pesticides that were used because of their effectiveness against a wide variety of insects. OC pesticides that were once in common use include dichlorodiphenyltrichloroethane (DDT), oxychlordane, dieldrin, hexachlorobenzene, hexachlorocyclohexanes, and trans-nonachlor [26]. Due to their persistence in the environment and evidence of health effects, the EPA has restricted or cancelled the use of many OC pesticides [26]. Additionally, the Stockholm Convention eliminated or restricted the use of many OC pesticides throughout the world in 2004 [25]. However, these compounds continue to persist in the environment and DDT is still in use in malaria-afflicted areas. Thus, exposure to OC pesticides can occur through consumption of contaminated food, water and breastmilk; presence during application or manufacture; and touching or ingesting contaminated soil [35, 36]. Hexachlorocyclohexanes, hexachlorobenzene, heptachlor, DDT, and dichlorodiphenyldichloroethylene (DDE)—a metabolite of DDT—are classified by the EPA as probable human carcinogenic agents [37–40]. One prior study using NHANES data to assess the association between OC pesticide exposures and mortality in the general population found no significant overall association [34]. However, this study was limited by a relatively short follow-up time and the omission of education or other measures of socioeconomic status as covariates [41].

Given the sparsity of data on the associations between POPs and mortality, our objective was to determine if higher exposure to POPs—including individual PFASs, OC pesticides, and individual or summary measures of non-dioxin-like PCBs, dioxin-like PCBs, and PBDEs—are associated with greater risk of mortality in persons aged 60 years and older. We hypothesized that higher exposure to POPs increases the risk of mortality in persons aged 60 years and older.

Our study found that serum measurements of PBDEs, PFASs, and PCBs are not clearly associated with increased mortality in the U.S. population aged 60 years or older. β-hexachlorocyclohexane, an OC pesticide, was associated with an increased risk of all-cause mortality. All four OC pesticides detectable in >90% of the sample (oxychlordane; p,p’-DDE; Trans-nonachlor; and β-hexachlorocyclohexane) were associated with increased risk of other-cause (non-cancer, non-cardiovascular) mortality. Exploratory analyses suggest these associations may be modified by sex, BMI, or PBDE exposures, but this requires further confirmation in an independent sample.

To our knowledge, this study was the first to examine the effects of PBDE exposures on mortality in a human sample. Prior studies of the associations between exposure to PFASs and mortality were conducted in occupational settings and report either no association or lower mortality in workers exposed to PFASs [47–50]. Our results were similar; while our point estimates suggested PFASs were associated with decreased mortality these results were not statistically significant. Multiple prior studies report elevated risk of cancer-related mortality with PCB exposure in occupational and poisoning settings, although these results are not conclusive given concerns about unclear dose-response relationships and residual confounding [51–58]. Prior studies in NHANES using summaries of PCB exposures from 1999 to 2004 report associations between total PCB exposures and excess cardiovascular mortality, but not all-cause or cancer-related mortality, among adults 70 years or older over a mean of 4.1 years of follow-up [41] and associations between higher exposure to dioxin-like compounds and all-cause mortality in adults ages 40 or older over a mean of 4.6 years of follow-up [33]. Our results conflict with these prior findings as we found no association between PCBs and all-cause or cause-specific analyses and may be related to lack of adjustment for education or other measures of socioeconomic status, shorter follow-up time, and consideration of a smaller, different set of compounds in prior studies. Finally, prior studies of occupational OC pesticide exposure and mortality generally report found lower than expected rates of all-cause mortality in exposed persons, but likely suffer from healthy-worker bias [59–61] A prior study using data from NHANES reported no association between exposure to OC pesticides and all-cause mortality, cancer mortality, or cardiovascular mortality over a mean 4.1 year follow-up period in persons 70 years and older [41], but did not consider other-cause mortality. Thus, our finding of increased risk of other-cause (non-cancer, non-cardiovascular) mortality with greater exposure OC pesticides is novel. Given the heterogeneous nature of “other-cause” mortality and the wide-ranging causes of death that are ultimately attributable to underlying diabetes or dementia, it is plausible that our results for OC pesticide exposure and other-cause mortality is due to associated increased risk of diabetes or dementia. Several recent studies have linked OC pesticide exposure to incident diabetes or markers indicative of increased risk of diabetes [62–64] as well as to elevated risk for cognitive decline or dementia [65–67].

While our report of exploratory analyses considering the combined impact of PBDEs and OC pesticides is novel, several prior studies suggest modification of the POPs-mortality association by BMI, smoking, or ACR. While not statistically significantly in our analyses, the suggestion of greater mortality among overweight and obese individuals with high OC pesticide exposure is opposite than reported previously. [41, 68] Conversely, while we did not observe significant effect modification by ACR, our point estimates were often consistent with the prior report of greater mortality among those with high ACR and high OC pesticide exposure [69] or among current smokers with high OC pesticide exposure [70]. The suggestion that sex modifies the OC pesticide other-cause mortality association is potentially plausible given potential endocrine-disruption related effects of exposure [71], but requires further confirmation in other samples.

There are limitations to our study. First, our sample size for each analysis was relatively small, due to data availability or concerns about combining multiple years of exposure data in the face of changing lists of analytes assessed in different cycles and potential time trends in exposure. This limited our ability to detect small effect and our ability to further investigate the association with more refined cause-specific mortality categories. Similarly, although motivated by evidence of effect modification in other settings [34, 68–70], we consider our analyses of effect modification to be exploratory given our small sample. Future work in larger samples will be required to examine the effect of exposure within potentially susceptible sub-populations. We also view our analyses of the combined effect of PBDEs and OC pesticides to be exploratory, and were unable to consider combined effects of multiple classes of POPs, as PCBs, PFASs, and PBDEs/OC pesticidess were measured in different subsamples. As with any epidemiologic study, we cannot definitively rule out the possibility of bias or chance. However, we adjusted our analyses for many possible confounders, minimizing the potential for residual confounding. We used a nationally-representative sample and evaluated associations with mortality, limiting the potential for selection bias. Finally, as our exposure and outcome are objective outcomes, and mortality was assessed independently of exposure status, we expect minimal impact of measurement error and that any resulting bias would be towards the null.

Our study also has strengths. The data is from NHANES and is a nationally representative study [42], thus our findings are generalizable to the older U.S. population as a whole. Several aspects of our primary analyses were novel, including examination of the association of PBDEs with mortality and consideration of associations between POPs and non-CVD, non-cancer mortality. We were able to address several of the potential limitations of the previous literature, including addressing potential confounding by education and socioeconomic status. Additionally, our study benefited from relatively long follow-up times, ranging from 9 to 13 years, which minimizes the potential impact of reverse causation, whereby impending death impacts POPs exposure levels.

Our study provides evidence of an adverse association between exposure to OC pesticides and non-cancer, non-heart/cerebrovascular disease mortality in adults 60 years or older in the U.S. This association may be modified by several factors, including exposure to other POPs. Additional research to confirm this finding and determine how OC pesticides may impact other-cause mortality is warranted.