Here we have reported numerous associations between current concentrations of biomarkers of exposure to PFAS, phenol, and paraben chemicals and previous cancer diagnoses over multiple NHANES cycles. Of note, the PFAS chemicals PFDE, PFNA, and PFUA were associated with increased odds of prior melanoma diagnosis among women, but not men. Also, among women, concentrations of BPA, BP3, and two dichlorophenols were associated with greater odds of ovarian cancer. Both dichlorophenols showed positive associations with the odds of every cancer type assessed, particularly among women. Finally, greater odds of previous cancer diagnoses among White women were observed with higher PFAS exposure, while Black and Mexican American women were more likely to have a previous cancer diagnosis with increased phenol/paraben exposure.

Numerous epidemiology studies have investigated potential associations between PFAS exposure and melanoma, but no notable effects have been found and most studies assessed only PFOA and PFOS exposures. Importantly, melanoma is the fifth most common cancer in the U.S. and recent estimates indicate increasing incidence in higher-income countries [19]. While the proportion of melanoma diagnoses is higher among White individuals, survival rates have been shown to be significantly lower among individuals who are Black, Hispanic, Asian American, Native American, and Pacific Islander [20]. Two large scale cohort studies have shown a null association between PFOA exposure and melanoma [21, 22], but both studies estimated exposure using indirect modeling rather than biomarker measurements, potentially leading to exposure misclassification and inability to account for inherent biological differences between participants such as PFAS elimination. Previous occupational exposure studies have also reported null associations between PFOA/PFOS and malignant melanoma, but these studies report low melanoma case numbers and are composed of mostly men (>80% male) [23,24,25]. One occupational study observed increased odds of melanoma with higher exposure to PFOS, but that cohort included only 5 cases of melanoma, reducing the reliability of their results [26]. Importantly, these occupational cohort studies utilized job-exposure matrices to ascertain PFAS exposure levels and thus their results are highly susceptible to exposure misclassification. Though the cohort study design is preferable to cross-sectional studies, the lack of biomonitoring data on the study participants presents a significant limitation to these studies. Further investigation of prospective associations is needed, especially in women based on findings from our study that phenols (DCP25, DCP24, BP3) and PFAS (PFDE, PFNA, and PFUA) were positively associated with previous melanoma diagnosis.

Sex-specific associations between PFAS chemicals and previous melanoma diagnosis, suggest that sex-mediated mechanisms may be at play. Previous work has shown that women are more likely than men to be diagnosed with melanoma, but metastasis and mortality rates are higher among men than women [27]. Differences in melanoma outcomes based on sex may be driven by sex-specific differences in perturbations to biological processes such as cellular immortality, inflammation, oxidative stress, and hormone disruption, which are mechanisms that have been shown to be both influenced by chemical exposures and linked to cancer [10]. For example, a previous review highlighted evidence of sex differences in immune homeostasis (e.g., differences in lymphocyte activation), oxidative stress (e.g., differences in anti-oxidant enzyme levels), and sex hormones (e.g., differences in estrogen levels) [28]. The important role of estrogens during human pregnancy can shed light on how estrogens may also be implicated in cancer development and progression. Estrogens are critical for maintenance of pregnancy as they stimulate blood vessel formation in the uterus. Because melanoma tumor cells express estrogen receptors [29], this angiogenic property of estrogens that is so critical during pregnancy may also promote nourishment of malignant melanomas. Further, it is plausible that environmental toxicants which exhibit estrogenic activity could exacerbate this process. Toxicological evidence for estrogenicity of PFAS is mixed: a recent in vitro study demonstrated PFAS interaction with estrogen receptor-α [30]; another recent study used in vitro and in silico methods to show that particular interactions with the estrogen receptor surface can result in PFAS exerting both estrogenic and antiestrogenic activities [31]; and other recent studies have shown no effect on estrogen levels with PFAS exposure [32, 33]. Clearly, the sexually dimorphic nature of melanoma warrants further investigation in future prospective studies, both in terms of baseline level risk between men and women and the ability of estrogenic environmental insults to further increase risk.

Based on data collected from 1999 to 2015, uterine cancer was one of few cancers increasing in incidence and mortality in the United States [34]. Uterine cancer is the fourth most commonly diagnosed cancer among U.S. women, and previous work has shown racial disparities in both incidence and histological types, with White women showing higher incidence rates than other racial/ethnic groups, and Black women showing higher mortality than other racial/ethnic groups due to diagnoses at more advanced stages of disease [35]. In our study, we observed numerous differences between racial groups, with most associations being significant and positive in White women compared to other racial groups. Notably, increased exposure to PFOA and PFOS was associated with significantly greater odds of previous uterine cancer diagnosis among Other Hispanic women relative to White women, while increased exposure to PFDE, PFNA, and PFUA were significantly associated with greater odds of previous uterine cancer diagnosis among both White and Other Hispanic women. It has been established that elevated circulating estrogens and greater rates of obesity are strongly linked to risk of uterine cancer [36]. Though the links between these factors and endocrine-disrupting chemicals including PFAS and phenols/parabens remain controversial, these may represent modifiable risk factors for targeted intervention strategies.

We observed an inverse association between PFOS exposure and odds of previous thyroid cancer diagnosis among women, while all other associations with thyroid cancer were null. To our knowledge, only one previous study has explored associations between PFAS exposure and risk of thyroid cancer. That community-based analysis found that those living in an area known to have experienced PFAS contamination of drinking water showed greater risk ratios of thyroid cancer relative to those living in unexposed control areas [37]. Additionally, one previous biomonitoring study found that increased urinary levels of the parabens MPB, EPB, and PPB were positively associated with odds of thyroid cancer [38]. Importantly, both previous studies assessed thyroid cancer outcomes among both men and women combined, while our analysis was only able to assess previous thyroid cancer diagnoses in women due to low case numbers among men. Future work should aim to better characterize endocrine disruptor associations with thyroid cancer by disentangling associations between men and women, and by using biomonitoring exposure assessment methods.

Ovarian cancer is the leading cause of death among gynecological cancers and is the seventh most commonly diagnosed cancer among women around the world [39]. Black women are disproportionately affected and have higher odds of more aggressive tumor stages [40]. Ovarian cancer, despite being less common than other cancer types among women, has a low 5-year survival rate due to the advanced stage at which it is usually diagnosed; about 75% of women are diagnosed in late-stage disease and face a 5-year survival rate of about 29% [41]. Current clinical researchers are putting considerable effort into identifying effective screening strategies but there have been no approved protocols to-date [42]. Clearly, identifying environmental exposures that puts one at greater risk of developing ovarian cancer is critical for furthering screening and prevention efforts.

Our results suggest that various environmental chemicals (PFUA, BPA, BP3, and DCP25) are associated with previous diagnosis of ovarian cancer among all women. Previous work has shown that exposure to environmental toxicants can influence cells to undergo the epithelial-mesenchymal transition (EMT), a process, defined by epithelial cells losing their cell-to-cell adhesion properties and becoming migratory, that may be crucial in the transformation of benign cells into malignant cells [43]. Upon treating ovarian cancer cells with BPA, a previous study observed that mRNA expression and protein levels of vimentin and snail, two protein families involved in the EMT, were increased. Further, protein levels of E-cadherin, a cell adhesion protein, were decreased following treatment with BPA [44]. Similarly, another study utilizing a different type of ovarian cancer cell line found that treatment of cells with BPA resulted in stimulated cell migration via upregulation of matrix metalloproteinases and N-cadherin [45]. Ovarian cancer is known to be hormonally driven; about 50% of ovarian cancer cells in humans express higher levels of estrogen receptor-α and -β relative to cells from a normal ovary or benign tumor cells [46]. Accordingly, both previous studies used treatment with estradiol as a positive control and observed that the effects of BPA treatment were similar to that of estradiol, indicating the importance of mitigating exposures to estrogenic chemicals for ovarian cancer prevention.

A previous review illustrates that BPA can regulate the expression of genes in ovarian cancer cells which act on pathways implicated in many of the key characteristics of cancer. For example, genes involved in cell proliferation can be upregulated by BPA, while other genes involved in apoptosis can be downregulated by BPA [47]. However, despite the large number of studies that have implicated BPA in the initiation and/or progression of ovarian cancer, no epidemiology studies to our knowledge have evaluated associations between BPA exposure, or any other phenols, and ovarian cancer. This highlights a significant gap in the environmental epidemiology literature and presents an opportunity to explore impactful mechanisms by which environmental estrogenic compounds may contribute to onset and progression of ovarian cancer.

It is critical for future studies to understand the effects of endocrine active compound exposures on survivors of hormonally-driven cancers. Our findings highlight that across multiple tumor types, individuals with a prior cancer diagnosis have elevated body burdens of a range of toxicants. Hormonally-driven cancers are often treated with hormone therapy to reduce or alter the circulating concentrations of hormones [48]. Exposure to endocrine active compounds could subvert the effects of these therapies and cause disease progression and recurrence [49]. For example, approximately 70% of breast cancers express the estrogen receptor [50]. These breast cancers are often treated with antiestrogen therapies. Unexpected exposure to estrogenic xenobiotic compounds could promote the growth and spread of estrogen receptor-positive tumors. This potential impact on long term cancer patient outcomes is particularly salient in light of the high rates of distant recurrences in estrogen-positive breast cancer survivors up to 20 years following the cessation of treatment [51]. Our findings build upon a growing literature showing that cancer survivors are an important population for endocrine active chemical biomonitoring and interventions.

We observed that various associations between environmental chemical exposures and previous cancer diagnoses were modified by race. Environmental exposures may differ by racial groups through various sources. For example, chemicals such as phthalates, phenols, and parabens may be found at higher concentrations in certain beauty products (e.g., hair straightening chemicals and skin-lightening creams) that are marketed to Black, Asian, and Latina women [52]. Another example is evidenced by disparities in PFAS water contamination, with a recent report from the Natural Resources Defense Council indicating that many counties in California with higher CalEnviroScreen scores (indicating greater pollution and socioeconomic disadvantage) also had higher detected PFAS in drinking water systems [53]. A previous study in NHANES showed that significant racial disparities exist in biomonitored environmental toxicants, including several exposures included in this analysis [16]. Of note, the aforementioned study observed that non-White racial groups had much higher concentrations of chemical biomarkers including DCP25, MPB, PPB, BPS, and PFDA, while White participants had higher levels of other chemicals including BPF, BP3, PFOA, and PFOS. These exposure levels partly contextualize our findings that White men had higher odds of previous prostate cancer with elevated exposures to BP3 and BPF, and White women had higher odds of previous ovarian cancer with elevated exposures to PFOS and PFOA. Additionally, despite greater increases of uterine cancer incidence among Black women compared to White women [54], we observed that White women were more likely to have previous uterine cancer with increasing biomarker levels of PFDE, PFNA, and PFUA. Interestingly, Nguyen and colleagues showed that Black women had higher concentrations of PFNA than White women, suggesting that the positive association between PFNA and previous uterine cancer among White women compared to Black women may not be influenced by trends in incidence or exposure levels to PFNA between racial groups. Finally, we observed that Mexican-American women had higher odds of previous breast cancer with elevated exposure to MPAH, and other Hispanic women had higher odds of previous breast cancer with elevated exposure to BP3. Accordingly, a previous review article demonstrates that Hispanic women are at greater risk of breast cancer-specific mortality when compared to non-Hispanic White women [55]. There may also be underlying metabolic factors influencing the relationship between endocrine-disrupting chemicals and cancer risk. For example, a previous multi-omics investigation identified differences in genetic and epigenetic loci relevant for xenobiotic metabolism based on genetic ancestry, which may be relevant since endocrine-disrupting chemicals are metabolized by overlapping enzymes, including cytochrome p450 [56]. Future prospective studies should not only consider disparities in exposure and cancer risks, but also evaluate potential sources of environmental contamination to endocrine-disrupting chemicals to guide potential interventions.

These results highlight the need to carefully consider the use of survey regression methods based on whether the study hypothesis is aimed at obtaining results that are generalizable or specific to vulnerable populations. NHANES oversamples racial/ethnic minorities, which can be very useful when trying to evaluate rare disease states as outcomes in those populations. However, when survey regression methods are applied, the results generated are targeted at being generalizable to the entire United States population rather than being truly representative of the study population, which has the desired larger population of minority groups. Thus, if an association is observed among a minority group but null among non-Hispanic White participants, the survey regression results will be influenced towards the null to account for the oversampling of the minority group. We observed this in our analysis with PFDE exposure and odds of previous ovarian cancer. Standard regression analysis showed a non-significant positive association, but sensitivity analyses revealed that the association was observed only among non-Hispanic White participants. Accordingly, survey regression methods also resulted in a positive association. Thus, survey regression methods will generate more generalizable results, but if there are true differences in associations between racial groups, the survey regression results will be more representative of non-Hispanic White participants than of the minority groups.

This analysis was subject to various limitations. First, our outcomes were previous cancer diagnoses and therefore causality cannot be determined. While we would have liked to account for the time between cancer diagnoses and biomarker measurement, this information was not available in NHANES. Further, because our exposures were measured after the cancer diagnoses occurred, reverse causation is a possibility if behavioral changes occurred. Subsequent treatment for cancer may also influence concentrations of endocrine-disrupting chemicals through altered metabolism, which may also be an important source of exposure misclassification among those with previous cancer diagnoses. Additionally, we have assumed that exposure biomarker measurements are accurate proxies of historical exposure levels, and so there is high risk for exposure misclassification. Despite this limitation, there is still utility in assessing PFAS and phenol/paraben profiles among previous cancer patients to inform prospective hypotheses in emerging cohort studies. Additionally, our results were likely subject to bias from unmeasured confounding factors such as family history of cancer or anatomical alterations such as ovariectomy and thyroidectomy. Our regression models may not have accounted for any correlations between covariates and biomarkers, possibly resulting in inflated associations. Similarly, we did not set multiple comparison thresholds, therefore some associations may be false positives. However, future prospective studies can build on our preliminary findings to perform targeted hypothesis testing on specific environmental contaminants. Another limitation includes potential outcome misclassification since previous cancer diagnosis was assessed using self-report questionnaire data. A previous study identified the validity of self-reported cancers with data from state cancer registries and while they identified fairly good accuracy (sensitivity of ≥ 0.9) for certain cancers (e.g., breast and prostate) [57], future studies should build on our preliminary findings using gold-standard cancer diagnosis for outcome phenotyping.

This study was also strong in a number of ways. Compared to previous studies, we leveraged NHANES data to investigate multiple classes of endocrine-disrupting chemicals to inform prioritization and hypothesis-driven investigation of environmental exposures in future prospective study designs. Additionally, our approach helps build the foundation for supervised multi-pollutant chemical mixtures analyses that intend to delineate chemical class-specific effects and potential interactions between chemicals. Multi-chemical class exposure assessment is becoming more common with technological advancements in high-throughput assays, however, these can be cost-prohibitive and time-consuming in certain contexts with limited resources. We also contribute toward reporting exploratory associations with understudied cancers in the context of endocrine-disrupting chemicals. For example, this is the first epidemiological study to assess phenols exposure in the context of previous ovarian cancer diagnosis. Further, this is the first NHANES analysis to investigate racial/ethnic disparities in associations between environmental exposures and previous cancer diagnoses. We also add to the current body of literature suggesting a role for estrogens in the onset and progression of ovarian cancer and melanoma, which could help inform future mechanistic and experimental studies as well as risk assessment and prevention efforts.

In conclusion, we report various associations between exposure to environmental chemicals and previous cancer diagnoses that have not been previously explored. Several PFAS chemicals were positively associated with odds of previous melanoma diagnosis among only women, and various PFAS and phenols were positively associated with odds of previous ovarian cancer diagnosis. These findings highlight a sexually dimorphic nature of melanoma risk, as well as a potential estrogen-dependent mechanism for both cancer types. We also showed differential associations between environmental exposures and previous cancer diagnoses by racial groups, underscoring racial disparities that exist both in innate risk of cancer outcomes and in exposures to environmental toxicants. Future work in prospective cancer studies should aim to explore the roles of estrogenic chemicals and estrogen disruption in the pathology of melanoma and ovarian cancer and consider racial disparities when evaluating cancer mechanisms and risk. Findings from this study can be used to help inform and prioritize toxicants for policies surrounding greater surveillance of chemical exposures and risk assessment in communities with existing or emerging risk of environmental contamination.