Per- And Poly-Fluoroalkyl Substances (PFAS) Exposure and Risk of Breast, and Female Genital Cancers: A Systematic Review and Meta-Analysis PFAS Exposure and Risk of Breast and Female Genital Cancers

Main Article Content

Monireh Sadat Seyyedsalehi
Elizabeth Maria Kappil
Sirui Zhang
Tongzhang Zheng
Paolo Boffetta

Keywords

Breast Cancer, Occupational factors , Endometrial, Female genital, malignant , endocrine gland, Perfluorooctanoic Acid, hormone, PFAS, Perfluorooctane sulfonic acid

Abstract


Background: PFASs, synthetic chemicals, can be encountered by humans through occupational or environmental exposure, and some reports suggest that they can disrupt endocrine and hormonal activities. In this comprehensive review and meta-analysis, we explored the connection between exposure to PFASs and the risks of breast and female genital cancers. Methods: We systematically reviewed the literature from IARC Monographs, ATSDR documents, and PubMed (as of January 2024) for cohort, case-control, and ecological studies on PFAS exposure and breast or female genital cancers. Four reviewers independently screened studies, and data extraction included study design, patient characteristics, and effect size measures. The quality of studies was assessed using the modified version of the Newcastle-Ottawa Scale (NOS). Forest plots of relative risks (RR) were constructed for breast and female genital cancer. Meta-analyses were conducted using random-effects models, stratified analyses, dose-response assessments, and publication bias evaluation. Results: The meta-analysis included 24 studies, comprising 10 cohort, 13 case-control, and one ecological study. The summary relative risk (RR) of breast cancer for PFOA exposure was 1.08 (95% CI = 0.97-1.20; n=21), and for PFOS was 1.00 (95% CI = 0.85-1.18; n=12). The RR for ovarian cancer and PFAS was 1.07 (95% CI = 1.04-1.09; n=12). The stratification by quality score, year of publication, and exposure source did not reveal any differences. However, analysis by geographical region (p=0.01) and study design (p=0.03) did show differences, particularly in terms of incidence. Stratified analyses of the dose-response relationship did not reveal a trend in the risk of breast cancer or female genital cancers, and no publication bias was found for either cancer type. No results were available for cervical and endometrial cancers. Conclusion: In summary, we have found an association between PFAS exposure and ovarian cancer and a possible effect on breast cancer incidence in some specific groups. Although potential bias and confounding prevent conclusions regarding causality, these findings may hold significance for females who encounter such pollutants in their occupational or daily environments.


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References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.
2. Sun YS, Zhao Z, Yang ZN, et al. Risk Factors and Preventions of Breast Cancer. Int J Biol Sci. 2017;13(11):1387-1397.
3. Lee CO. Gynecologic cancers: Part. I – Risk factors. Clin J Oncol Nurs. 2000;4(2):67-71.
4. Fenga C. Occupational exposure and risk of breast cancer. Biomed Rep. 2016;4(3):282-292.
5. Weiderpass E, Labrèche F. Malignant tumors of the female reproductive system. Saf Health Work. 2012;3(3):166-80.
6. Li Y, Fletcher T, Mucs D, et al. Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water. Occup Environ Med. 2018;75(1):46-51.
7. Gaines LGT. Historical and current usage of per- and polyfluoroalkyl substances (PFAS): A literature re-view. Am J Ind Med. 2023;66:353-378.
8. Langenbach B, Wilson M. Per- and Polyfluoroalkyl Substances (PFAS): Significance and Considerations within the Regulatory Framework of the USA. Int J Environ Res Public Health. 2021;18(21):11142.
9. Panieri E, Baralic K, Djukic-Cosic D, Buha Djordjevic A, Saso L. PFAS Molecules: A Major Concern for the Human Health and the Environment. Toxics. 2022;10(2):44.
10. International Agency for Research on Cancer. PFOA. IARC Working Group on the Evaluation of Car-cinogenic Risks to Humans, vol. 110. Some Chemicals Used as Solvents and in Polymer Manufacture. Lyon, IARC, 2017, pp. 37-110.
11. Zahm S, Bonde JP, Chiu WA, et al.Carcinogenicity of perfluorooctanoic acid and perfluorooctanesul-fonic acid. Lancet Oncol. 2024;25(1):16-17.
12. Seyyedsalehi MS, Boffetta P. Per- and Poly-fluoroalkyl Substances (PFAS) Exposure and Risk of Kid-ney, Liver, and Testicular Cancers: A Systematic Review and Meta-Analysis. Med Lav. 2023;114(5): e2023040.
13. Ding N, Harlow SD, Randolph JF Jr, Loch-Caruso R, Park SK. Perfluoroalkyl and polyfluoroalkyl sub-stances (PFAS) and their effects on the ovary. Hum Reprod Update. 2020; 26:724-752.
14. Chang ET, Adami HO, Boffetta P, Cole P, Starr TB, Mandel JS. A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and cancer risk in humans. Crit Rev Toxicol. 2014 May;44 Suppl 1:1-81.
15. Agency for Toxic Substances and Disease Registry.Toxicological Profile for Perfluoroalkyls. Atlanta, GA, ATSDR, 2021.
16. Dekkers OM, Vandenbroucke JP, Cevallos M, Renehan AG, Altman DG, Egger M. COSMOS-E: guidance on conducting systematic reviews and meta-analyses of observational studies of etiology. pLoS Med. 2019;16.
17. Moher D, Liberati A, Tetzlaff J, Altmann DG. The PRISMA Group. Preferred Reporting Items for Sys-tematic Reviews and Meta-Analyses: The PRISMA Statement. Ann Intern Med. 2009; 151:264-69.
18. Stang A, Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of non-randomized studies in meta-analyses. Eur J Epidemiol. 2010; 25:603–605
19. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88.
20. Higgins J.P, Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002, 21, 1539–1558.
21. Egger M, Davey Smith G, Schneider M, Minder CE. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34.
22. Gilliland FD, Mandel JS. Mortality among employees of a perfluorooctanoic acid production plant. J Occup Med. 1993;35(9):950-4.
23. Alexander BH, Olsen GW, Burris JM, Mandel JH, Mandel JS. Mortality of employees of a perfluorooc-tanesulphonyl fluoride manufacturing facility. Occup Environ Med. 2003;60(10):722-9.
24. Leonard RC, Kreckmann KH, Sakr CJ, Symons JM. Retrospective cohort mortality study of workers in a polymer production plant including a reference population of regional workers. Ann Epidemiol. 2008;18(1):15-22.
25. Bonefeld-Jorgensen EC, Long M, et al. Perfluorinated compounds are related to breast cancer risk in Greenlandic Inuit: a case control study. Environ Health. 2011;10:88.
26. Steenland K, Woskie S. Cohort mortality study of workers exposed to perfluorooctanoic acid. Am J Epidemiol. 2012;176(10):909-17.
27. Barry V, Winquist A, Steenland K. Perfluorooctanoic acid (PFOA) exposures and incident cancers among adults living near a chemical plant. Environ Health Perspect. 2013;121(11-12):1313-8.
28. Vieira VM, Hoffman K, Shin HM, Weinberg JM, Webster TF, Fletcher T. Perfluorooctanoic acid expo-sure and cancer outcomes in a contaminated community: a geographic analysis. Environ Health Per-spect. 2013;121(3):318-23.
29. Raleigh KK, Alexander BH, Olsen GW, et al. Mortality and cancer incidence in ammonium perfluorooc-tanoate production workers. Occup Environ Med. 2014;71(7):500-6.
30. Bonefeld-Jørgensen EC, Long M, Fredslund SO, Bossi R, Olsen J. Breast cancer risk after exposure to perfluorinated compounds in Danish women: a case-control study nested in the Danish National Birth Cohort. Cancer Causes Control. 2014;25(11):1439-48.
31. Wielsøe M, Kern P, Bonefeld-Jørgensen EC. Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study. Environ Health. 2017;16(1):56.
32. Mastrantonio M, Bai E, Uccelli R, Cordiano V, Screpanti A, Crosignani P. Drinking water contamination from perfluoroalkyl substances (PFAS): an ecological mortality study in the Veneto Region, Italy. Eur J Public Health. 2018;28(1):180-185.
33. Hurley S, Goldberg D, Wang M, Park JS, Petreas M, Bernstein L, Anton-Culver H, Nelson DO, Reynolds P. Breast cancer risk and serum levels of per- and poly-fluoroalkyl substances: a case-control study nested in the California Teachers Study. Environ Health. 2018;17(1):83.
34. Mancini FR, Cano-Sancho G, Gambaretti J, et al. Perfluorinated alkylated substances serum concentra-tion and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort. Int J Cancer. 2020;146(4):917-928.
35. Tsai MS, Chang SH, Kuo WH,et al. A case-control study of perfluoroalkyl substances and the risk of breast cancer in Taiwanese women. Environ Int. 2020;142:105850.
36. Itoh H, Harada KH, Kasuga Y, et al. Serum perfluoroalkyl substances and breast cancer risk in Japanese women: A case-control study. Sci Total Environ. 2021;800:149316.
37. Omoike OE, Pack RP, Mamudu HM, Liu Y, Wang L. A cross-sectional study of the association between perfluorinated chemical exposure and cancers related to deregulation of estrogen receptors. Environ Res. 2021;196:110329.
38. Velarde MC, Chan AFO, Sajo MEJV, et al. Elevated levels of perfluoroalkyl substances in breast cancer patients within the Greater Manila Area. Chemosphere. 2022;286(Pt 1):131545.
39. Li X, Song F, Liu X, et al. Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population. Environ Health. 2022;21(1):83.
40. Feng Y, Bai Y, Lu Y,et al. Plasma perfluoroalkyl substance exposure and incidence risk of breast cancer: A case-cohort study in the Dongfeng-Tongji cohort. Environ Pollut. 2022;306:119345.
41. Li H, Hammarstrand S, Midberg B, et al. Cancer incidence in a Swedish cohort with high exposure to perfluoroalkyl substances in drinking water. Environ Res. 2022;204(Pt C):112217.
42. Cathey AL, Nguyen VK, Colacino JA, Woodruff TJ, Reynolds P, Aung MT. Exploratory profiles of phe-nols, parabens, and per- and poly-fluoroalkyl substances among NHANES study participants in associa-tion with previous cancer diagnoses. J Expo Sci Environ Epidemiol. 2023;33(5):687-698.
43. Law HD, Armstrong BK, D'este C, et al. Relative rates of cancers and deaths in Australian communities with PFAS environmental contamination associated with firefighting foams: A cohort study using linked data. Cancer Epidemiol. 2023;82:102296.
44. Chang VC, Rhee J, Berndt SI, et al. Serum perfluorooctane sulfonate and perfluorooctanoate and risk of postmenopausal breast cancer according to hormone receptor status: An analysis in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer. 2023;153(4):775-782.
45. Winquist A, Hodge JM, Diver WR, et al. Case-Cohort Study of the Association between PFAS and Se-lected Cancers among Participants in the American Cancer Society's Cancer Prevention Study II LifeLink Cohort. Environ Health Perspect. 2023;131(12):127007.
46. Fenton SE, Ducatman A, Boobis A, et al. Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research. Environ Tox-icol Chem. 2021; 40:606-630.
47. Wen LL, Lin CY, Chou HC, Chang CC, Lo HY, Juan SH. Perfluorooctanesulfonate mediates renal tubular cell apoptosis through PPARgamma inactivation. PLoS One. 2016;11: e0155190.
48. Stanifer JW, Stapleton HM, Souma T, Wittmer A, Zhao X, Boulware LE. Perfluorinated chemicals as emerging environmental threats to kidney health: A scoping review. Clin J Am Soc Nephrol. 2018; 13:1479-1492.
49. Wan HT, Zhao YG, Wei X, Hui KY, Giesy JP, Wong CK. PFOS-induced hepatic steatosis, the mechanistic actions on beta-oxidation and lipid transport. Biochim Biophys Acta. 2012; 1820:1092-1101.
50. Hui Z, Li R, Chen L. The impact of exposure to environmental contaminant on hepatocellular lipid me-tabolism. Gene. 2017; 622:67-71
51. Mokra K. Endocrine Disruptor Potential of Short- and Long-Chain Perfluoroalkyl Substances (PFASs)-A Synthesis of Current Knowledge with Proposal of Molecular Mechanism. Int J Mol Sci. 2021;22(4):2148.
52. Kranthi Kumar K, Uma Devi B, Neeraja P. Integration of in silico approaches to determination of en-docrine disrupting perfluorinated chemicals binding potency with steroidogenic acute regulatory pro-tein. Biochem Biophys Res Commun. 2017; 491:1007–1014.
53. Kar S, Sepulveda MS, Roy K, Leszczynski J. Endocrine-disrupting activity of per- and polyfluoroalkyl substances: Exploring combined approaches of ligand and structure-based modeling. Chemosphere. 2017; 184:514–523.
54. Kang J, Choi J, Park J. Transcriptional changes in steroidogenesis by perfluoroalkyl acids (PFOA and PFOS) regulate the synthesis of sex hormones in H295R cells. Chemosphere. 2016; 155:436–443.
55. Mokra K. Endocrine Disruptor Potential of Short- and Long-Chain Perfluoroalkyl Substances (PFASs)-A Synthesis of Current Knowledge with Proposal of Molecular Mechanism. Int J Mol Sci. 2021;22(4):2148.
56. Kaiser AM, Zare Jeddi M, Uhl M, Jornod F, Fernandez MF, Audouze K. Characterization of Potential Ad-verse Outcome Pathways Related to Metabolic Outcomes and Exposure to Per- and Polyfluoroalkyl Substances Using Artificial Intelligence. Toxics. 2022 ;10(8):449.
57. Park SK, Peng Q, Ding N, Mukherjee B, Harlow SD. Determinants of per- and polyfluoroalkyl sub-stances (PFAS) in midlife women: Evidence of racial/ethnic and geographic differences in PFAS exposure. Environ Res. 2019; 175:186-199.
58. Singletary SE. Rating the risk factors for breast cancer. Ann Surg. 2003;237(4):474-82.
59. Ali AT, Al-Ani O, Al-Ani F. Epidemiology and risk factors for ovarian cancer. Prz Menopauzalny. 2023;22(2):93-104.
60. Kashyap N, Krishnan N, Kaur S, Ghai S. Risk Factors of Cervical Cancer: A Case-Control Study. Asia Pac J Oncol Nurs. 2019;6(3):308-314.
61. European Chemicals Agency (ECHA). Per- and polyfluoroalkyl substances (PFAS). Available on line at: https://echa.europa.eu/hot-topics/perfluoroalkyl-chemicals-pfas (Last Accessed 09-10-2024)
62. Key EPA Actions to Address PFAS. Available on line at: https://www.epa.gov/pfas/key-epa-actions-address-pfas (Last updated on October 1, 2024)
63. Mohammed AA. The clinical behavior of different molecular subtypes of breast cancer. Cancer Treat Res Commun. 2021; 29:100469.
64. Pierozan P, Jerneren F, Karlsson O. Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells. Arch Toxicol. 2018;92(5):1729-1739.
65. Gui SY, Chen YN, Wu KJ, et al. Association Between Exposure to Per- and Polyfluoroalkyl Substances and Birth Outcomes: A Systematic Review and Meta-Analysis. Front Public Health. 2022;10:855348.
66. Cohn BA, La Merrill MA, Krigbaum NY, et al. In utero exposure to poly- and perfluoroalkyl substances (PFASs) and subsequent breast cancer. Reprod Toxicol. 2020 Mar;92:112-119.
67. Gui SY, Chen YN, Wu KJ, et al. Association Between Exposure to Per- and Polyfluoroalkyl Substances and Birth Outcomes: A Systematic Review and Meta-Analysis. Front Public Health. 2022;10:855348.
68. Cohn BA, La Merrill MA, Krigbaum NY, et al. In utero exposure to poly- and perfluoroalkyl substances (PFASs) and subsequent breast cancer. Reprod Toxicol. 2020;92:112-119.