Although evidence linking environmental chemicals to breast cancer is growing, mixtures-based exposure evaluations are lacking.
This study aimed to identify environmental chemicals in use inventories that co-occur and share properties with chemicals that have association with breast cancer, highlighting exposure combinations that may alter disease risk.
The occurrence of chemicals within chemical use categories was characterized using the Chemical and Products Database. Co-exposure patterns were evaluated for chemicals that have an association with breast cancer (BC), no known association (NBC), and understudied chemicals (UC) identified through query of the Silent Spring Institute’s Mammary Carcinogens Review Database and the U.S. Environmental Protection Agency’s Toxicity Reference Database. UCs were ranked based on structure and physicochemical similarities and co-occurrence patterns with BCs within environmentally relevant exposure sources.
A total of 6793 chemicals had data available for exposure source occurrence analyses. 50 top-ranking UCs spanning five clusters of co-occurring chemicals were prioritized, based on shared properties with co-occuring BCs, including chemicals used in food production and consumer/personal care products, as well as potential endocrine system modulators.
Results highlight important co-exposure conditions that are likely prevalent within our everyday environments that warrant further evaluation for possible breast cancer risk.
Most environmental studies on breast cancer have focused on evaluating relationships between individual, well-known chemicals and breast cancer risk. This study set out to expand this research field by identifying understudied chemicals and mixtures that may occur in everyday environments due to their patterns of commercial use. Analyses focused on those that co-occur alongside chemicals associated with breast cancer, based upon in silico chemical database querying and analysis. Particularly in instances when understudied chemicals share physicochemical properties and structural features with carcinogens, these chemical mixtures represent conditions that should be studied in future clinical, epidemiological, and toxicological studies.
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All data used for these analyses are publicly available, either through CPDat  ToxRefDB , or the CompTox Chemicals Dashboard . Script associated with these analyses are publicly available through the Ragerlab Github repository . Data that were combined and analyzed in generating results for this specific study are provided as supplemental material (Supplementary Tables 1–10, provided online through the Ragerlab-Dataverse repository ).
IBCERCC. Breast Cancer and the Environment: Prioritizing Prevention. Report of the Interagency Breast Cancer and Environmental Research Coordinating Committee (IBCERCC) 2013 [cited 2021 Jun 1]. Available from: https://www.niehs.nih.gov/about/assets/docs/ibcercc_full_508.pdf.
Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum Genet. 2008;124:31–42.
Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int. 2013;2013:747318.
IOM. Breast Cancer and the Environment: A Life Course Approach: The Institute of Medicine (IOM) of the National Academies; 2012 [cited 2021 Jun 1]. Available from: https://www.nap.edu/catalog/13263/breast-cancer-and-the-environment-a-life-course-approach.
WCRF. Diet, nutrition, physical activity and breast cancer: World Cancer Research Fund (WCRF); 2018 [cited 2021 Jun 1]. Available from: https://www.wcrf.org/wp-content/uploads/2021/02/Breast-cancer-report.pdf.
Hiatt RA, Brody JG. Environmental determinants of breast cancer. Annu Rev Public Health. 2018;39:113–33.
Gray JM, Rasanayagam S, Engel C, Rizzo J. State of the evidence 2017: an update on the connection between breast cancer and the environment. Environ Health. 2017;16:94.
Rodgers KM, Udesky JO, Rudel RA, Brody JG. Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms. Environ Res. 2018;160:152–82.
Carlin DJ, Rider CV, Woychik R, Birnbaum LS. Unraveling the health effects of environmental mixtures: an NIEHS priority. Environ Health Perspect. 2013;121:A6–8.
Dionisio KL, Frame AM, Goldsmith MR, Wambaugh JF, Liddell A, Cathey T, et al. Exploring consumer exposure pathways and patterns of use for chemicals in the environment. Toxicol Rep. 2015;2:228–37.
Dionisio KL, Phillips K, Price PS, Grulke CM, Williams A, Biryol D, et al. The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products. Sci Data. 2018;5:180125.
Isaacs KK, Dionisio K, Phillips K, Bevington C, Egeghy P, Price PS. Establishing a system of consumer product use categories to support rapid modeling of human exposure. J Expo Sci Environ Epidemiol. 2020;30:171–83.
OECD. Internationally harmonised functional product and article use categories ENV/JM/MONO(2017)14. Organisation for Economic Co-operation and Development (OECD). Organisation for Economic Co-operation and Development, 2017.
Williams AJ, Grulke CM, Edwards J, McEachran AD, Mansouri K, Baker NC, et al. The CompTox Chemistry Dashboard: a community data resource for environmental chemistry. J Cheminform. 2017;9:61.
Grulke CM, Williams AJ, Thillanadarajah I, Richard AM EPA’s DSSTox database: History of development of a curated chemistry resource supporting computational toxicology research. Comput Toxicol. 2019;12.
EPA U. The Chemical and Products Database (CPDat) MySQL Data File 2020 [cited 2020 September 23]; Version 2:[Available from: https://epa.figshare.com/articles/dataset/The_Chemical_and_Products_Database_CPDat_MySQL_Data_File/5352997/2.
SSI. Mammary Carcinogens Review Database. Silent Spring Institute (SSI) 2021 [cited 2021 Nov 1]. Available from: http://sciencereview.silentspring.org/mamm_about.cfm.
Rudel RA, Attfield KR, Schifano JN, Brody JG. Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention. Cancer. 2007;109:2635–66.
Watford S, Ly Pham L, Wignall J, Shin R, Martin MT, Friedman KP. ToxRefDB version 2.0: Improved utility for predictive and retrospective toxicology analyses. Reprod Toxicol. 2019;89:145–58.
Harvey JB, Hong HH, Bhusari S, Ton TV, Wang Y, Foley JF, et al. F344/NTac rats chronically exposed to bromodichloroacetic acid develop mammary adenocarcinomas with mixed luminal/basal phenotype and Tgfbeta dysregulation. Vet Pathol. 2016;53:170–81.
Dunnick JK, Elwell MR, Huff J, Barrett JC. Chemically induced mammary gland cancer in the National Toxicology Program’s carcinogenesis bioassay. Carcinogenesis 1995;16:173–9.
EPA U. CompTox Chemicals Dashboard Batch Search 2020 [cited 2021]; 3.5:[Available from: https://comptox.epa.gov/dashboard/dsstoxdb/batch_search.
Rager JE, Clark J, Eaves LA, Avula V, Niehoff NM, Kim YH, et al. Mixtures modeling identifies chemical inducers versus repressors of toxicity associated with wildfire smoke. Sci Total Environ. 2021;775:145759.
Klaren WD, Ring C, Harris MA, Thompson CM, Borghoff S, Sipes NS, et al. Identifying attributes that influence in vitro-to-in vivo concordance by comparing in vitro Tox21 bioactivity versus in vivo DrugMatrix transcriptomic responses across 130 chemicals. Toxicol Sci. 2019;167:157–71.
Rager JE, Suh M, Chappell GA, Thompson CM, Proctor DM. Review of transcriptomic responses to hexavalent chromium exposure in lung cells supports a role of epigenetic mediators in carcinogenesis. Toxicol Lett. 2019;305:40–50.
Phillips KA, Wambaugh JF, Grulke CM, Dionisio KL, Isaacs KK. High-throughput screening of chemicals as functional substitutes using structure-based classification models. Green Chem. 2017;19:1063–74.
Leydesdorff L. On the normalization and visualization of author co-citation data: Salton’s Cosine versus the Jaccard index. J Am Soc Inf Sci Technol. 2008;59:77–85.
Rousseeuw PJ. Silhouettes: a graphical aid to the interpretation and validation of cluster analysis. J Computational Appl Math. 1987;20:53–65.
Krishna S, Berridge B, Kleinstreuer N. High-throughput screening to identify chemical cardiotoxic potential. Chem Res Toxicol. 2021;34:566–83.
Lowe CN, Phillips KA, Favela KA, Yau AY, Wambaugh JF, Sobus JR, et al. Chemical characterization of recycled consumer products using suspect screening analysis. Environ Sci Technol. 2021;55:11375–87.
Beckers LM, Busch W, Krauss M, Schulze T, Brack W. Characterization and risk assessment of seasonal and weather dynamics in organic pollutant mixtures from discharge of a separate sewer system. Water Res. 2018;135:122–33.
Patlewicz G, Ball N, Booth ED, Hulzebos E, Zvinavashe E, Hennes C. Use of category approaches, read-across and (Q)SAR: general considerations. Regul Toxicol Pharm. 2013;67:1–12.
Yang C, Tarkhov A, Marusczyk J, Bienfait B, Gasteiger J, Kleinoeder T, et al. New publicly available chemical query language, CSRML, to support chemotype representations for application to data mining and modeling. J Chem Inf Model. 2015;55:510–28.
Wang J, Hallinger DR, Murr AS, Buckalew AR, Lougee RR, Richard AM, et al. High-throughput screening and chemotype-enrichment analysis of ToxCast phase II chemicals evaluated for human sodium-iodide symporter (NIS) inhibition. Environ Int. 2019;126:377–86.
Ring C, Sipes NS, Hsieh JH, Carberry C, Koval LE, Klaren WD, et al. Predictive modeling of biological responses in the rat liver using in vitro Tox21 bioactivity: Benefits from high-throughput toxicokinetics. Comput Toxicol. 2021;18.
Zhang Z, Wang S, Li L Emerging investigator series: the role of chemical properties in human exposure to environmental chemicals. Environ Sci Process Impacts. 2021;23:1839–62.
Mansouri K, Grulke CM, Judson RS, Williams AJ. OPERA models for predicting physicochemical properties and environmental fate endpoints. J Cheminform. 2018;10:10.
Rager JE, Strynar MJ, Liang S, McMahen RL, Richard AM, Grulke CM, et al. Linking high resolution mass spectrometry data with exposure and toxicity forecasts to advance high-throughput environmental monitoring. Environ Int. 2016;88:269–80.
Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, et al. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCast high-throughput data. Environ Health Perspect. 2016;124:1141–54.
Reif DM, Martin MT, Tan SW, Houck KA, Judson RS, Richard AM, et al. Endocrine profiling and prioritization of environmental chemicals using ToxCast data. Environ Health Perspect. 2010;118:1714–20.
Koval LE, Dionisio KL, Friedman KP, Isaacs KK, Rager JE. Dataset for Environmental Mixtures and Breast Cancer: Identifying Co-Exposure Patterns between Understudied vs Breast Cancer-Associated Chemicals using Chemical Inventory Informatics 2022 [cited 2022 May 27]. Available from: https://doi.org/10.15139/S3/UMPCKW.
CFR-Code of Federal Regulations Title 21. Sect. 81.10 (1977).
Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Lett. 2015;356:231–43.
Cardona B, Rudel RA. US EPA’s regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects. Mol Cell Endocrinol. 2020;518:110927.
Stillwell W. An Introduction to Biological Membranes Composition, Structure and Function. 2nd edition ed: Elsevier Science; 2016 June 30.
Trabert B, Sherman ME, Kannan N, Stanczyk FZ. Progesterone and breast cancer. Endocr Rev. 2020;41.
Kulkoyluoglu-Cotul E, Arca A, Madak-Erdogan Z. Crosstalk between estrogen signaling and breast cancer metabolism. Trends Endocrinol Metab. 2019;30:25–38.
CDC. Fourth National Report on Human Exposure to Environmental Chemicals. Vol. 3: Analysis of pooled serum samples for select chemicals, NHANES 2005–2016. National Center for Environmental Health (U.S.), Division of Laboratory Sciences; National Center for Health Statistics (U.S.); National Health and Nutrition Examination Survey (U.S.). https://stacks.cdc.gov/view/cdc/105344. 2021.
USGS. USGS Water Data for USA 2021. Available from: https://waterdata.usgs.gov/nwis?
Ring CL, Arnot JA, Bennett DH, Egeghy PP, Fantke P, Huang L, et al. Consensus modeling of median chemical intake for the U.S. population based on predictions of exposure pathways. Environ Sci Technol. 2019;53:719–32.
Baker N, Knudsen T, Williams A Abstract Sifter: a comprehensive front-end system to PubMed. F1000Res. 2017;6.
Kapraun DF, Wambaugh JF, Ring CL, Tornero-Velez R, Setzer RW. A method for identifying prevalent chemical combinations in the U.S. population. Environ Health Perspect. 2017;125:087017.
Clark J, Avula V, Ring C, Eaves LA, Howard T, Santos HP, et al. Comparing the Predictivity of Human Placental Gene, microRNA, and CpG Methylation Signatures in Relation to Perinatal Outcomes. Toxicol Sci. 2021.
Wambaugh JF, Wang A, Dionisio KL, Frame A, Egeghy P, Judson R, et al. High throughput heuristics for prioritizing human exposure to environmental chemicals. Environ Sci Technol. 2014;48:12760–7.
Watford SM, Grashow RG, De La Rosa VY, Rudel RA, Friedman KP, Martin MT. Novel application of normalized pointwise mutual information (NPMI) to mine biomedical literature for gene sets associated with disease: use case in breast carcinogenesis. Comput Toxicol. 2018;7:46–57.
Taylor KW, Joubert BR, Braun JM, Dilworth C, Gennings C, Hauser R, et al. Statistical approaches for assessing health effects of environmental chemical mixtures in epidemiology: lessons from an innovative workshop. Environ Health Perspect. 2016;124:A227–A9. child lead exposure for the plaintiffs in a public nuisance case related to childhood lead poisoning. None of these activities were directly related to the present study. The other authors declare they have no actual or potential competing financial interests.
Drakvik E, Altenburger R, Aoki Y, Backhaus T, Bahadori T, Barouki R, et al. Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment. Environ Int. 2020;134:105267.
Rider CV, McHale CM, Webster TF, Lowe L, Goodson WH 3rd, La Merrill MA, et al. Using the key characteristics of carcinogens to develop research on chemical mixtures and cancer. Environ Health Perspect. 2021;129:35003.
Ragerlab. Ragerlab Github 2021 [cited 2021]. Available from: https://github.com/Ragerlab.
ToxPrint. ToxPrint: Altamira LLC; 2021 [cited 2021 August, 6]. Available from: https://toxprint.org.
The research described in this manuscript has been reviewed by the Center for Computational Toxicology and Exposure, U.S. EPA, and approved for publication. Approval does not signify that contents necessarily reflect the views and policies of the agency, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use. The authors would like to thank Drs. Peter Egeghy and Chris Corton for providing internal technical review of this manuscript.
This study was supported by the Institute for Environmental Health Solutions (IEHS) at the Gillings School of Global Public Health, RFA-18-01, ‘Identifying solutions that optimize the health of cancer survivors’, and through the National Institutes of Health (NIH) from the National Institute of Environmental Health Sciences, including grant funds (P42ES031007). Support was also provided by the Intramural Research Program of the Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
The authors declare no competing interests.
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Koval, L.E., Dionisio, K.L., Friedman, K.P. et al. Environmental mixtures and breast cancer: identifying co-exposure patterns between understudied vs breast cancer-associated chemicals using chemical inventory informatics. J Expo Sci Environ Epidemiol (2022). https://doi.org/10.1038/s41370-022-00451-8
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