Persistent Organic Pollutants & Breast Cancer Risk

Institution: Cancer Prevention Institute of California
Investigator(s): Peggy Reynolds, Ph.D. - Peggy Reynolds, Ph.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16ZB-8501 Award: $1,910,517
Award Type: SRI Program Directed Awards
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle

This is a collaboration with: 16ZB-8501A -

Initial Award Abstract (2010)

Persistent Organic Pollutants (POPs) are a large, diverse group of synthetic toxic compounds that include organochlorine pesticides and some industrial chemicals. Originally introduced during the post WWII industrial boom, many of the older POPs, including DDT and polychlorinated biphenyls (PCBs) were banned in the 1970s due to concerns about health effects. These compounds don’t easily break down; they accumulate in the food chain, including people’s body fat. Consequently, most Americans today have detectable levels of these chemicals in their bodies. Polybrominated diphenyl ethers (PBDEs) and other brominated flame retardants (BFRs) are a newer class of POPs, initially introduced in the late 1970s as flame retardant additives to consumer and building products. The concentrations of these newer POPs in human tissue are increasing at an alarming rate and Californians have some of the highest levels in the world. While many of the older POPs are known or suspected carcinogens, their role in the development of breast cancer is uncertain; the health effects of the newer POPs are virtually unknown.

The primary objective of this study is to investigate the risk of breast cancer associated with both the older and newer POPs among participants in the California Teachers Study (CTS), a large on-going study of breast cancer among 133,479 female California professional school employees. We will also look for disparities in, and predictors of, body burden levels of these compounds and explore potentially important windows of susceptibility. Capitalizing on the unique resources collected over the 15 years since the CTS’ inception, this study will measure the levels of POPs in blood collected for two studies already underway. To identify disparities in, and predictors of, body burden levels of PBDEs/BFRs, we will utilize the approximately 360 blood specimens to be collected from CTS participants in 2010. A geographic information system (GIS) will be used to link the residential location of CTS members’ homes to the location of waste processing and manufacturing sites that may serve as sources of PBDE/BFR exposures. Survey and census data will be used to explore behavioral and sociodemographic predictors of body burden levels. Study participants are racially and ethnically diverse and from both rural and urban areas, so that analyses may identify disparities in exposure to these compounds.

These preliminary analyses will help us optimize selection of study subjects for the breast cancer risk analysis. This will be conducted among 2,000 CTS participants who have provided a blood specimen, 1,000 who will have been diagnosed with breast cancer and 1,000 women who remained breast cancer-free (controls) between 2007 and 2013. Concentrations of 15 PCBs, 4 organochlorine pesticides, 11 PBDEs, and 10 BFRs will be measured in their blood. Statistical models will be used to compare the levels of these POPs in women with breast cancer to the control women. Survey information will be used to account for differences in other known risk factors. Additional analyses will evaluate whether certain women may be especially susceptible to risks associated with these exposures due to the type of tumor they have, or by virtue of selected behavioral or genetic characteristics. For a subset of the CTS cohort, we will use questionnaire and birth file data to enhance exposure estimates for earlier time periods that may represent windows of increased vulnerability to the effects of these compounds.

This study is designed to overcome many limitations common to prior studies. By using the large number of biospecimens already being collected through the CTS parent grant, and with Dr. Petreas’ expertise in measuring multiple POPs in a single sample, our study offers an outstanding opportunity to investigate multiple compounds and susceptible subpopulations or potentially important windows of susceptibility. Advanced statistical techniques from genomics offer an innovative approach to the complexities of POPs exposures, which tend to be highly correlated and may act either synergistically or antagonistically to influence risk. This study could be the first large-scale epidemiologic study to evaluate the potential link between PBDEs/BFRs and breast cancer, as well as identify disparities in and determinants of exposure — information critical to public health and regulatory actions aimed at curbing such exposures. Finally, it directly addresses the ongoing concerns of breast cancer and environmental advocates about the role of these chemicals in breast cancer.

Time Trends in Per- and Polyfluoroalkyl Substances (PFASs) in California Women: Declining Serum Levels, 2011–2015

Declines in serum PBDEs in older California women may have reached a plateau (2011-2015)

Final Report (2018)

Persistent organic pollutants (POPs) are a large and diverse group of pervasive environmental contaminants of concern for breast cancer risk due to their toxic properties and ability to disrupt the endocrine system. The primary objective of this study was to investigate the risk of breast cancer associated with body burden levels of POPs among participants in the California Teachers Study (CTS). Originally this project was designed to focus on four broad classes of POPs compounds including: polybrominated diphenyl ethers (PBDEs) and other newer replacement brominated flame retardants (BFRs); organochlorine pesticides (OCPs); and polychlorinated biphenyls (PCBs). However, because our initial results indicated limited measurability of the newer replaement BFRs in blood, we replaced these compounds with perfluoroalkyl and polyfluoroalkyl substances (PFASs). Our project had three specific aims: (1.) describe disparities in, and predictors of, blood levels of PBDEs in a subset of 360 CTS members with no history of breast cancer; (2.) estimate the risk of breast cancer associated with body burden levels of POPs among the full CTS cohort; (3.) use questionnaire data and record linkage to birth files for a subset of the CTS to enhance exposure estimates for two potential windows of susceptability including the perinatal and early reproductive years.

To address Aim#1, we conducted a number of analyses among cancer-free controls, including geographic-based analyses that identified previously unrecognized sources of exposure – residential proximity to solid waste sites and drinking water contamination – as potentially important routes of exposure to PBDEs and PFASs, respectively. Temporal analyses of PBDE and PFAS levels indicated mixed success of regulatory and voluntary actions to reduce human exposures. Furthermore, these analyses highlighted disparites in exposure and rates of change in body burden levels associated with age, suggesting comparative differences in the relative importance of different exposures routes by age and/or possible age-related differences in the metabolisim and excretion of these compounds.

Overall our risk analyses for Aim#2 did not provide evidence of a relationship between any of the POPs and breast cancer risk. However, for certain selected subsets of study participants, there was some suggestion of both increased and decreased risks for some of the individual POPs compounds. While based on small numbers of cases and generally not statistically significant, the findings from these subset analyses might suggest that the effects of exposure are limited to specific subtypes of breast cancer, may vary by host factors related to endogenous hormone levels, and may exert either protective effects or increased risks. Conversely, they may be chance findings or artifacts of study design. Of primary concern is the possibility of reverse causation due to the fact that the blood specimens were collected after treatment and on average 35 months after diagnosis among the cases.

To address Aim#3, we conducted a preliminary evaluation of whether the risk of breast cancer was elevated among parous women who lived in close proximity to a solid waste facility that may have been a source of PBDE exposure at the time they were pregnant with their first child – a window of potential susceptibility. While these analyses showed no association, they were hindered by missing data on facility type and dates of operation that ultimately precluded our ability to continue to pursue them beyond this preliminary exploration.

In the future we hope to identify and apply for additional sources of funding to continue to explore breast cancer and other health effects associated with POPs in this cohort of women as well as in other study populations. Especially important considerations in future research would be to better understand how serum POPs levels may be influenced by the onset or sequelae of disease and by specific treatment protocols. Additionally, we hope to be able to explore the degree to which genetic factors and other host characteristics might influence the endogenous hormonal milieu in a way that impacts the potential risk associated with exposures to these compounds.

Conference Abstract (2016)

Association between Serum PBDE Levels and Residential Proximity to Solid Waste Facilities/Landfills or Toxics Release Facilities

Ruiling Liu1, David O. Nelson1, Susan Hurley1, Myrto Petreas2, Yunzhu Wang2, Tan Guo2, June-Soo Park2, Pamela Horn-Ross1, Leslie Bernstein3, Hoda Anton-Culver4, Andrew Hertz1, Peggy Reynolds1,5
1Cancer Prevention Institute of California; 2 California Department of Toxic Substances Control; 3Beckman Research Institute of the City of Hope, Department of Population Sciences; 4University of California Irvine, School of Medicine; 5Stanford University School of Medicine, Department of Health Research and Policy

Polybrominated diphenyl ethers (PBDEs), chemicals commonly used as flame retardants, have been the source of some concern for a variety of health outcomes including breast cancer. Some studies have examined the relationship between characteristics of indoor environments and human PBDE body burden, but relatively few have considered the role of outdoor environments as potential exposure sources. We examined the association between serum PBDE levels in California women and residential proximity to solid waste facilities/landfills or toxics release facilities, which may release PBDEs into the environment. 481 participants (median age=66 years; range 40-94 years) from the California Teachers Study provided blood samples in 2011-2013, which were assayed for 19 PBDE congeners via Gas Chromatography/High Resolution Mass Spectrometry DFS. Information on solid waste facilities/landfills was obtained from the California Solid Waste Information System, and for toxics release facilities from the U.S. Environmental Protection Agency Toxics Release Inventory program. Facilities with potential for release of flame-retardants were identified and geocoded, and the distance to each participant’s residential address at time of blood draw was computed. Linear regression was used to examine the association between the proximity to those facilities and the serum levels of three most common PBDE congeners (BDE-47, -100 and -153), adjusting for age, race, body mass index and neighborhood (block group) socioeconomic status. Serum PBDE levels were lipid adjusted (ng/g lipid) and log-transformed for analysis. Subjects living within 10km (n=452) from any solid waste facility/landfill had approximately 45% higher serum BDE-47 levels than those living beyond 10km (p=0.04). Dose response was evident for residences within 3-9 km. Similar associations were not observed for BDE-100 or 153, or for proximity to toxics release facilities. Living within 10km of some solid waste facilities/landfills may be related to higher serum BDE-47 levels. More studies are needed to examine potential exposure routes. Acknowledgements: Funded by CBCRP grant #16ZB-8501.

Conference Abstract (2016)

Comparison of GC-HRMS and GC-MS/MS Methods for the Determination of Persistent Organic Pollutants in Human Serum

S.M.Crispo Smith1; Y Wang2; W Guo2; M. Petreas2; D. Nelson3; P. Reynolds3,4; R. Liu3; S. Hurley3; J-S. Park2
1Sequoia Foundation, La Jolla, CA
2California Department of Toxic Substance Control, Berkeley, CA
3Cancer Prevention Institute of California, Fremont, CA
4Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA

Serum analysis of persistent organic pollutants including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs), are routinely performed for California Biomonitoring studies, such as the California Teacher’s Study. The California Teacher’s Study measures levels of persistent organic pollutants in California teachers and administrators serum samples collected from 2011 to present, in an effort to establish links between breast cancer and pollutants. Serum samples are extracted using an automated solid-phase extraction system. The sample extracts required separate injections for PCBs/OCPs and PBDEs on two different columns (a 60m SGE HT8-PCB and a 15m Agilent DB-5ms, respectively) installed on gas chromatograph/high resolution mass spectrometer (GC–HRMS, ThermoFisher, Bremen, Germany). A method for the simultaneous determination of 15 PCBs (-66,-74,-99,-101,-105,-118,-138,-153,-156,-170 -180,-183,-187,-194,-203), 7 OCPs (hexachlorobenzene, b-hexachlorocyclohexane, o,p’-DDT, p,p’-DDT, p,p’-DDE, oxychlordane, and trans-nonachlor), and 5 PBDEs (-47,-99,-100,-153,-154) was developed using gas chromatography/triple-quadrupole tandem mass spectrometry (GC-MS/MS, Agilent, Santa Clara, CA) equipped with a 30m DB-5ms column (Agilent). The method was confirmed using samples from the Arctic Monitoring and Assessment Program. The ease of use, 24 minute run time, and low cost of maintenance made this new method attractive for the projects requiring high throughput, like California Biomonitoring projects. Serum data (n=47 for PCB/OCP and n=297 for BDE) produced from GC-HRMS and GC-MS/MS analysis were compared to determine feasibility of using the GC-MS/MS method as an alternative for these large studies. Sample concentrations were determined using average response factors for the GC-HRMS method while calibration curve interpolation was used for the GC-MS/MS method. Most compounds of interest showed linear relationships in the results between the GC-HRMS and GC-MS/MS with slopes of 1.0 ± 0.2 and Pearson’s r values > 0.9, indicating both methods to be generally comparable. However, BDE-47 by the GC-MS/MS method was underestimated by 25%, particularly at high concentrations. The cause of this discrepancy is under investigation. Meanwhile, the issue with BDE-47 was resolved by calculating concentrations using average response factors for the GC-MS/MS method. Our new method improves our throughput and will provide benefits to large cohort studies in the California Biomonitoring Program.

Disclaimer: The views expressed herein are those of the authors and do not necessarily reflect those of the California Department of Toxic Substances Control.