Abstract
In 2013, 60 scientists, representing a larger group of 174 scientists from 26 nations, met in Halifax, Nova Scotia to consider whether – using published research – it was logical to anticipate that a mixture of chemicals, each thought to be non-carcinogenic, might act together in that mixture as a virtual carcinogen. The group identified 89 such chemicals, each one affecting one or more Hallmark(s) – collectively covering all Hallmarks of Cancer – confirming the possibility that a chemical mixture could induce all the Hallmarks and function as a virtual carcinogen, thereby supporting the concern that chemical safety research that does not evaluate mixtures, is incomplete. Based on these observations, the Halifax Project developed the Low-Dose Carcinogenesis Hypothesis which posits “…that low-dose exposures to [mixtures of] disruptive chemicals that are not individually carcinogenic may be capable of instigating and/or enabling carcinogenesis.” Although testing all possible combinations of over 80,000 chemicals of commerce would be impractical, prudence requires designing a methodology to test whether low-dose chemical mixtures might be carcinogenic. As an initial step toward testing this hypothesis, we conducted a mini review of published empirical observations of biological exposures to chemical mixtures to assess what empirical data exists on which to base future research. We reviewed studies on chemical mixtures with the criteria that the studies reported both different concentrations of chemicals and mixtures composed of different chemicals. We found a paucity of research on this important question. The majority of studies reported hormone related processes and used chemical concentrations selected to facilitate studying how mixtures behave in experiments that were often removed from clinical relevance, i.e., chemicals were not studied at human-relevant concentrations. New research programs must be envisioned to enable study of how mixtures of small doses of chemicals affect human health, starting, when at all possible, from non-malignant specimens when studies are done in vitro. This research should use human relevant concentrations of chemicals, expand research beyond the historic focus on endocrine endpoints and endocrine related cancers, and specifically seek effects that arise uniquely from exposure to chemical mixtures at human-relevant concentrations.
Funding source: California Breast Cancer Research Program
Award Identifier / Grant number: 17UB-8702
Funding source: National Institute of Health-National Institute of Environmental Health Sciences
Award Identifier / Grant number: Conference travel grant R13ES023276
Research funding: Goodson: The California Breast Cancer Research Program (17UB-8702). National Institute of Health-National Institute of Environmental Health Sciences. Conference travel grant R13ES023276.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.
| ABBREVIATION | MEANING |
|---|---|
| 1-OHP | 1-hydroxypyrene |
| 2,3,4,5 TCB | Tetrachlorobiphenylol |
| 2,4,6 TCB | Trichlorbiphenylol |
| 4-t-OP | 4-tert-octylphenol |
| AAF | Acetylaminofluorine |
| ACT | Acetaminophen |
| AGD | Anogenital distance |
| AhR | Aryl hydrocarbon receptor |
| AHRR | AhR receptor repressor |
| ALACH | Alachlor |
| Aid | Aldrin |
| ARNT | AhR nuclear translocator |
| ARS | Sodium arsenate |
| ATR | Atrazine |
| BaP | Benzo[a]pyrene |
| BBN | N-butyl(N-hydroxybutyl)nitrosamine |
| BBP | Butylbenzylphthalate |
| BDE 100 | Brominated diphenyl ether 100 |
| Berga | Bergamottin |
| BENZ | Benzanthracene |
| BHP | Benzylhydroxyparaben |
| BP | Butylparaben |
| BP3 | Benzophenone 3 |
| BPA | Bisphenol-A |
| BPAF | Bisphenol-AF |
| BPC | Bisphenol-C |
| BPS | Bisphenol-S |
| BRCA | Breast cancer |
| CaBK-D9k | Calbindin-D9k |
| CBP | Chlorobiphenylol |
| CFU | Colony forming units |
| Chlor | Chlordane |
| CHRY | Chrysene |
| CLP | Chlorpyriphos |
| COMT | Catechol-o-methyltransferase |
| Cou | Coumestrol |
| C×43 | Connexin 43 |
| DAB | Dimethylaminobenzene |
| DAI | Daidzein |
| DBN | Dibutylnitrosamine |
| DBP | Dibutylphthalate |
| DCBP | Dichlorobiphenylol |
| DCHP | Dicyclohexyl phthalate |
| DDD | Dichlorodiphenyldichlorethane |
| DDE | Dicholorodiphenyldichloroethelene |
| DDT | Dichlorodiphenyltrichloroethane |
| DEHP | Diethylhexylphthalate |
| DEN | Diethylnitrosamine |
| DEP | Diethylphthalate |
| DES | Diethylstilbestrol |
| DHBP | Dihydroxybenzophenone |
| DHPN | Dihydroxypropylnitrosamine |
| DHT | Dihydrotestosterone |
| DiBP | Diisobutylphthalate |
| Diel | Dieldrin |
| DiHP | Diisoheptylphthalate |
| DMD | Mix of DEN, MNU, DHPN |
| DMN | Dimethylnitroasmine |
| DPP | Dipentylphthalate |
| El | Estrone |
| E2 | Estradiol |
| E3 | Estriol |
| EE2 | Ethinyl estradiol |
| EHEN | Ethylhydroxyethylnitrosamine |
| End | Endrin |
| endosul-a | Endosulfan-alpha |
| endosul-b | Endosulfan-beta |
| Entero | Enterodiol |
| Enterol | Enterolactone |
| EP | Ethyl paraben |
| ER | Estrogen receptor |
| ERE | Estrogen response element |
| ESR1 | Gene for ER-alpha |
| EV | Estradio-valerate |
| FIN | Funasteride |
| FLT | Flutamide |
| Fluoroan | Fluoranthene |
| Galax | Galoxolide |
| GD | Gestation day |
| Gen | Genestein |
| Glabri | Glabridin |
| HCB | Hexachlorobiphenyl |
| HCBz | Hexachlorobenzene |
| HCH | Hexachlorohexane |
| HHCB | Hexahydrohexamethylcyclopentabenzopyran |
| HMEC | Human mammary epithelial cells (benign) |
| HRBEC | High risk breast epithelial cell |
| HSD | Hydroxysteroid dehydrogenase |
| IBP | Isobutylparaben |
| IHC | Immunohistochemistry staining |
| Lin | Linuron |
| LOAEL | Lowest observed adverse effect level |
| MBC | Methylbenzylidene camphor |
| MBzP | Monobenzylphthalate |
| MEHP | Monoethylhexylphthalate |
| MEP | Monoethylphthalate |
| MnBP | Monobutylphthalate |
| MNNG | Methylnitronitrosylguanidine |
| MNU | Methylnitrosourea |
| MP | Methylparaben |
| MTT | Thiazolyl blue tetrazolium bromide |
| MXC | Methoxychlor |
| Narin | Narigenin |
| NHL | Non-Hodgkins lymphoma |
| NP | Nonylphenol |
| OC | Organochlorine |
| OCDF | Octachlorodibenzofuran |
| OCP | Organochloride pesticide |
| OCS | Octachlorostyrene |
| OHP | Hydroxypyrene |
| OHPCB | Hydroxylated polychlorinated biphenyl |
| OP | Octylphenol |
| OXFF | Oxyfluorofen |
| P | Progesterone |
| PAH | Polycyclic aromatic hydrocarbon |
| PCB | Polychlorinatedbiphenyl |
| PCDD | Pentachlorodibenzodioxin |
| PCDF | Pentachlordibenzofuran |
| PCNA | Proliferating cell nuclear antigen |
| PFNA | Perfluorononanoic acid |
| PFOA | Perfluorooctanoic acid |
| PFOS | Perfluorooctane sulfonate |
| phenobarb | Phenobarbital |
| PND | Post-natal day |
| PNU | Propylnitrosourea |
| PP | Propylparaben |
| PPARG | (nuclear) peroxisome proliferator activated receptor gamma |
| PRO | Procymidone |
| Prochl | Prochloraz |
| PS | Phenyl salicylate |
| PxR | Pregnane X receptor |
| resorc | Resorcinol monobenzoate |
| SIM | Simvastatin |
| T | Testosterone |
| TAM | Tamoxifen |
| TBPC | Trophoblast progenitor cell |
| TCDD | Tetrachlorodibenzodioxin |
| TCDF | Tetrachlorodibenzofuran |
| TEXB | Total effective xenoestrogen burden |
| TNC | trans-nonachlor |
| TOX | Toxaphene |
| Tonal | Tonalide |
| TBT | Tributylin |
| TRC///L | Triclosan |
| vCTB | Villus cytotrophoblasts |
| Vz | Vinclozolin |
| XE | Xenoestrogen |
| YES | Yeast estrogen screen |
References
1. Goodson, WH3rd, Lowe, L, Carpenter, DO, Gilbertson, M, Manaf Ali, A, Lopez de Cerain Salsamendi, A, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015;36(Suppl 1):S254–96. https://doi.org/10.1093/carcin/bgv039.Search in Google Scholar
2. Carpenter, DO, Arcaro, KF, Bush, B, Niemi, WD, Pang, S, Vakharia, DD. Human health and chemical mixtures: an overview. Environ Health Perspect 1998;106(Suppl 6):1263–70. https://doi.org/10.1289/ehp.98106s61263.Search in Google Scholar
3. Kortenkamp, A, Faust, M, Scholze, M, Backhaus, T. Low-level exposure to multiple chemicals: reason for human health concerns? Environ Health Perspect 2007;115(Suppl 1):106–14. https://doi.org/10.1289/ehp.9358.Search in Google Scholar
4. Herbst, AL, Ulfelder, H, Poskanzer, DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971;284:878–81. https://doi.org/10.1056/nejm197104222841604.Search in Google Scholar
5. Hatch, EE, Palmer, JR, Titus-Ernstoff, L, Noller, KL, Kaufman, RH, Mittendorf, R, et al. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA 1998;280:630–4. https://doi.org/10.1001/jama.280.7.630.Search in Google Scholar
6. Verloop, J, van Leeuwen, FE, Helmerhorst, TJ, van Boven, HH, Rookus, MA. Cancer risk in DES daughters. Cancer Causes Control 2010; 21:999–1007. https://doi.org/10.1007/s10552-010-9526-5.Search in Google Scholar
7. Brian, DD, Tilley, BC, Labarthe, DR, O’Fallon, WM, Noller, KL, Kurland, LT. Breast cancer in DES-exposed mothers: absence of association. Mayo Clin Proc 1980;55:89–93. PMID: 7354650.Search in Google Scholar
8. Greenberg, ER, Barnes, AB, Resseguie, L, Barrett, JA, Burnside, S, Lanza, LL, et al. Breast cancer in mothers given diethylstilbestrol in pregnancy. N Engl J Med 1984;311:1393–8. https://doi.org/10.1056/nejm198411293112201.Search in Google Scholar
9. Titus-Ernstoff, L, Hatch, EE, Hoover, RN, Palmer, J, Greenberg, ER, Ricker, W, et al. Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer 2001;84:126–33. https://doi.org/10.1054/bjoc.2000.1521.Search in Google Scholar
10. Palmer, JR, Wise, LA, Hatch, EE, Troisi, R, Titus-Ernstoff, L, Strohsnitter, W, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2006;15:1509–14. https://doi.org/10.1158/1055-9965.EPI-06-0109.Search in Google Scholar
11. Hoover, RN, Hyer, M, Pfeiffer, RM, Adam, E, Bond, B, Cheville, AL, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 2011;365:1304–14. https://doi.org/10.1056/NEJMoa1013961.Search in Google Scholar
12. Tournaire, M, Devouche, E, Espié, M, Asselain, B, Levadou, A, Cabau, A, et al. Cancer risk in women exposed to diethylstilbestrol in itero. Therapie 2015;70:433–41. https://doi.org/10.2515/therapie/2015030.Search in Google Scholar
13. Troisi, R, Hatch, EE, Palmer, JR, Titus, L, Sampson, JN, Xu, X, et al. Estrogen metabolism in postmenopausal women exposed in utero to diethylstilbestrol. Cancer Epidemiol Biomarkers Prev 2018;27:1208–13. https://doi.org/10.1158/1055-9965.EPI-18-0135.Search in Google Scholar
14. Krieger, N, Wolff, MS, Hiatt, RA, Rivera, M, Vogelman, J, Orentreich, N. Breast cancer and serum organochlorines: a prospective study among white, black, and Asian women. J Natl Cancer Inst 1994;86:589–99. https://doi.org/10.1093/jnci/86.8.589.Search in Google Scholar
15. van’t Veer, P, Lobbezoo, IE, Martín-Moreno, JM, Guallar, E, Gómez-Aracena, J, Kardinaal, AF, et al. DDT (dicophane) and postmenopausal breast cancer in Europe: case-control study. BMJ 1997;315:81–5. https://doi.org/10.1136/bmj.315.7100.81.Search in Google Scholar
16. Schecter, A, Toniolo, P, Dai, LC, Thuy, LT, Wolff, MS. Blood levels of DDT and breast cancer risk among women living in the north of Vietnam. Arch Environ Contam Toxicol 1997;33:453–6. https://doi.org/10.1007/s002449900276.Search in Google Scholar
17. Hunter, DJ, Hankinson, SE, Laden, F, Colditz, GA, Manson, JE, Willett, WC, et al. Plasma organochlorine levels and the risk of breast cancer. N Engl J Med 1997;337:1253–8. PMID: 10385143. https://doi.org/10.1056/nejm199710303371801.Search in Google Scholar
18. Helzlsouer, KJ, Alberg, AJ, Huang, HY, Hoffman, SC, Strickland, PT, Brock, JW, et al. Serum concentrations of organochlorine compounds and the subsequent development of breast cancer. Cancer Epidemiol Biomarkers Prev 1999;8:525–32.Search in Google Scholar
19. Dorgan, JF, Brock, JW, Rothman, N, Needham, LL, Miller, R, Stephenson, HEJr, et al. Serum organochlorine pesticides and PCBs and breast cancer risk: results from a prospective analysis (USA). Cancer Causes Control 1999;10:1–11. https://doi.org/10.1023/a:1008824131727.10.1023/A:1008824131727Search in Google Scholar
20. Wolff, MS, Berkowitz, GS, Brower, S, Senie, R, Bleiweiss, IJ, Tartter, P, et al. Organochlorine exposures and breast cancer risk in New York City women. Environ Res 2000;84:151–61. https://doi.org/10.1006/enrs.2000.4075.Search in Google Scholar
21. Laden, F, Hankinson, SE, Wolff, MS, Colditz, GA, Willett, WC, Speizer, FE, et al. Plasma organochlorine levels and the risk of breast cancer: an extended follow-up in the Nurses’ Health Study. Int J Cancer 2001;91:568–74. https://doi.org/10.1002/1097-0215(200002)9999:9999<::aid-ijc1081>3.0.co;2-w.10.1002/1097-0215(200002)9999:9999<::AID-IJC1081>3.0.CO;2-WSearch in Google Scholar
22. Brody, JG, Aschengrau, A, McKelvey, W, Rudel, RA, Swartz, CH, Kennedy, T. Breast cancer risk and historical exposure to pesticides from wide-area applications assessed with GIS. Environ Health Perspect 2004;112:889–97. https://doi.org/10.1289/ehp.6845.Search in Google Scholar
23. Gatto, NM, Longnecker, MP, Press, MF, Sullivan-Halley, J, McKean-Cowdin, R, Bernstein, L. Serum organochlorines and breast cancer: a case-control study among African-American women. Cancer Causes Control 2007;18:29–39. https://doi.org/10.1007/s10552-006-0070-2.Search in Google Scholar
24. Itoh, H, Iwasaki, M, Hanaoka, T, Kasuga, Y, Yokoyama, S, Onuma, H, et al. Serum organochlorines and breast cancer risk in Japanese women: a case-control study. Cancer Causes Control 2009;20:567–80. https://doi.org/10.1007/s10552-008-9265-z.Search in Google Scholar
25. White, AJ, Teitelbaum, SL, Wolff, MS, Stellman, SD, Neugut, AI, Gammon, MD. Exposure to fogger trucks and breast cancer incidence in the Long Island Breast Cancer Study Project: a case-control study. Environ Health 2013;12:24. https://doi.org/10.1186/1476-069X-12-24.Search in Google Scholar
26. Holmes, AK, Koller, KR, Kieszak, SM, Sjodin, A, Calafat, AM, Sacco, FD, et al. Case-control study of breast cancer and exposure to synthetic environmental chemicals among Alaska Native women. Int J Circumpolar Health 2014;73:25760. https://doi.org/10.3402/ijch.v73.25760.Search in Google Scholar
27. Høyer, AP, Jørgensen, T, Grandjean, P, Hartvig, HB. Repeated measurements of organochlorine exposure and breast cancer risk (Denmark). Cancer Causes Control 2000;11:177–84. https://doi.org/10.1023/a:1008926219539.10.1023/A:1008926219539Search in Google Scholar
28. Romieu, I, Hernandez-Avila, M, Lazcano-Ponce, E, Weber, JP, Dewailly, E. Breast cancer, lactation history, and serum organochlorines. Am J Epidemiol 2000;152:363–70. https://doi.org/10.1093/aje/152.4.363.Search in Google Scholar
29. Charlier, C, Albert, A, Herman, P, Hamoir, E, Gaspard, U, Meurisse, M, et al. Breast cancer and serum organochlorine residues. Occup Environ Med 2003;60:348–51. https://doi.org/10.1136/oem.60.5.348.Search in Google Scholar
30. Cohn, BA, Wolff, MS, Cirillo, PM, Sholtz, RI. DDT and breast cancer in young women: new data on the significance of age at exposure. Environ Health Perspect 2007;115:1406–14. https://doi.org/10.1289/ehp.10260.Search in Google Scholar
31. Tang, M, Zhao, M, Zhou, S, Chen, K, Zhang, C, Liu, W. Assessing the underlying breast cancer risk of Chinese females contributed by dietary intake of residual DDT from agricultural soils. Environ Int 2014;73:208–15. https://doi.org/10.1016/j.envint.2014.08.001.Search in Google Scholar
32. Cohn, BA, La Merrill, M, Krigbaum, NY, Yeh, G, Park, JS, Zimmermann, L, et al. DDT exposure in utero and breast cancer. J Clin Endocrinol Metab 2015;100:2865–72. https://doi.org/10.1210/jc.2015-1841.Search in Google Scholar
33. 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;16:56. https://doi.org/10.1186/s12940-017-0269-6.Search in Google Scholar
34. Chang, S, El-Zaemey, S, Heyworth, J, Tang, MC. DDT exposure in early childhood and female breast cancer: evidence from an ecological study in Taiwan. Environ Int 2018;121:1106–12. https://doi.org/10.1016/j.envint.2018.10.023.Search in Google Scholar
35. Kaur, N, Swain, SK, Banerjee, BD, Sharma, T, Krishnalata, T. Organochlorine pesticide exposure as a risk factor for breast cancer in young Indian women: a case-control study. South Asian J Cancer 2019;8:212–14. https://doi.org/10.4103/sajc.sajc_427_18.Search in Google Scholar
36. López-Carrillo, L, Hernández-Ramírez, RU, Calafat, AM, Torres-Sánchez, L, Galván-Portillo, M, Needham, LL, et al. Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect 2010;118:539–44. https://doi.org/10.1289/ehp.0901091.Search in Google Scholar
37. Villeneuve, S, Cyr, D, Lynge, E, Orsi, L, Sabroe, S, Merletti, F, et al. Occupation and occupational exposure to endocrine disrupting chemicals in male breast cancer: a case-control study in Europe. Occup Environ Med 2010;67:837–44. https://doi.org/10.1136/oem.2009.052175.Search in Google Scholar
38. Parada, HJr, Gammon, MD, Chen, J, Calafat, AM, Neugut, AI, Santella, RM, et al. Urinary phthalate metabolite concentrations and breast cancer incidence and survival following breast cancer: the Long Island Breast Cancer Study Project. Environ Health Perspect 2018;126:047013.10.1289/EHP2083Search in Google Scholar PubMed PubMed Central
39. Carran, M, Shaw, IC. New Zealand Malayan war veterans’ exposure to dibutylphthalate is associated with an increased incidence of cryptorchidism, hypospadias and breast cancer in their children. N Z Med J 2012;125:52–63. PMID: 22864157.Search in Google Scholar
40. Reeves, KW, Díaz Santana, M, Manson, JE, Hankinson, SE, Zoeller, RT, Bigelow, C, et al. Urinary phthalate biomarker concentrations and postmenopausal breast cancer risk. J Natl Cancer Inst 2019;111:1059–67. https://doi.org/10.1093/jnci/djz002.Search in Google Scholar
41. Ahern, TP, Broe, A, Lash, TL, Cronin-Fenton, DP, Ulrichsen, SP, Christiansen, PM, et al. Phthalate exposure and breast cancer incidence: a Danish Nationwide Cohort Study. J Clin Oncol 2019;37:1800–9. https://doi.org/10.1200/JCO.18.02202.Search in Google Scholar
42. Ennis, ZN, Pottegård, A, Ahern, TP, Hallas, J, Damkier, P. Exposure to phthalate-containing prescription drugs and the risk of colorectal adenocarcinoma: a Danish nationwide case-control study. Pharmacoepidemiol Drug Saf 2019;28:528–35. https://doi.org/10.1002/pds.4759.Search in Google Scholar
43. Surveillance and epidemiology end results, explorer tool. Available from: https://seer.cancer.gov/explorer/ [Accessed March 9 2020].Search in Google Scholar
44. Hwa Yun, B, Guo, J, Bellamri, M, Turesky, RJ. DNA adducts: formation, biological effects, and new biospecimens for mass spectrometric measurements in humans. Mass Spectrom Rev 2020;39:55–82. https://doi.org/10.1002/mas.21570.Search in Google Scholar
45. Hanahan, D, Weinberg, RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. https://doi.org/10.1016/j.cell.2011.02.013.Search in Google Scholar
46. Martincorena, I, Fowler, JC, Wabik, A, Lawson, ARJ, Abascal, F, Hall, MWJ, et al. Somatic mutant clones colonize the human esophagus with age. Science 2018;362:911–7. https://doi.org/10.1126/science.aau3879.Search in Google Scholar
47. Martincorena, I, Roshan, A, Gerstung, M, Ellis, P, Van Loo, P, McLaren, S, et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 2015;348:880–6. https://doi.org/10.1126/science.aaa6806.Search in Google Scholar
48. Rothman, KJ. Causes. Am J Epidemiol 1976;104:587–92. https://doi.org/10.1093/oxfordjournals.aje.a112335.Search in Google Scholar
49. Wensink, M, Westendorp, RG, Baudisch, A. The causal pie model: an epidemiological method applied to evolutionary biology and ecology. Ecol Evol 2014;4:1924–30. https://doi.org/10.1002/ece3.1074.Search in Google Scholar
50. Christiani, DC. Combating environmental causes of cancer. N Engl J Med 2011;364:791–3. https://doi.org/10.1056/NEJMp1006634.Search in Google Scholar
51. Bliss, CI. The toxicity of poisons applied jointly. Ann Appl Biol 1939;26:585–615. https://doi.org/10.1111/j.1744-7348.1939.tb06990.x.Search in Google Scholar
52. 1113Fukushima, S, Shibata, MA, Hirose, M, Kato, T, Tatematsu, M, Ito, N. Organ-specific modification of tumor development by low-dose combinations of agents in a rat wide-spectrum carcinogenesis model. Jpn J Cancer Res 1991;82:784–92. https://doi.org/10.1111/j.1349-7006.1991.tb02703.x.Search in Google Scholar
53. Kang, KS, Wilson, MR, Hayashi, T, Chang, CC, Trosko, JE. Inhibition of gap junctional intercellular communication in normal human breast epithelial cells after treatment with pesticides, PCBs, and PBBs, alone or in mixtures. Environ Health Perspect 1996;104:192–200. https://doi.org/10.2307/3432789.Search in Google Scholar
54. Arcaro, KF, Vakharia, DD, Yang, Y, Gierthy, JF. Lack of synergy by mixtures of weakly estrogenic hydroxylated polychlorinated biphenyls and pesticides. Environ Health Perspect 1998;106(Suppl 4):1041–6. https://doi.org/10.2307/3434149.Search in Google Scholar
55. Soto, AM, Fernandez, MF, Luizzi, MF, Oles Karasko, AS, Sonnenschein, C. Developing a marker of exposure to xenoestrogen mixtures in human serum. Environ Health Perspect 1997;105(Suppl 3):647–54. https://doi.org/10.1289/ehp.97105s3647.Search in Google Scholar
56. Payne, J, Rajapakse, N, Wilkins, M, Kortenkamp, A. Prediction and assessment of the effects of mixtures of four xenoestrogens. Environ Health Perspect 2000;108:983–7. https://doi.org/10.1289/ehp.00108983.Search in Google Scholar
57. Payne, J, Scholze, M, Kortenkamp, A. Mixtures of four organochlorines enhance human breast cancer cell proliferation. Environ Health Perspect 2001;109:391–7. https://doi.org/10.1289/ehp.01109391.Search in Google Scholar
58. Charles, GD, Gennings, C, Zacharewski, TR, Gollapudi, BB, Carney, EW. An approach for assessing estrogen receptor-mediated interactions in mixtures of three chemicals: a pilot study. Toxicol Sci 2002;68:349–60. https://doi.org/10.1093/toxsci/68.2.349.Search in Google Scholar
59. Silva, E, Rajapakse, N, Kortenkamp, A. Something from "nothing" - eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 2002;36:1751–6. https://doi.org/10.1021/es0101227.Search in Google Scholar
60. Rajapakse, N, Silva, E, Kortenkamp, A. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect 2002;110:917–21. https://doi.org/10.1289/ehp.02110917.Search in Google Scholar
61. Bae, DS, Hanneman, WH, Yang, RS, Campain, JA. Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes: application of cDNA microarray technology. Environ Health Perspect 2002;110(Suppl 6):931–41. https://doi.org/10.1289/ehp.02110s6931.Search in Google Scholar
62. You, L, Sar, M, Bartolucci, EJ, McIntyre, BS, Sriperumbudur, R. Modulation of mammary gland development in prepubertal male rats exposed to genistein and methoxychlor. Toxicol Sci 2002;66:216–25. https://doi.org/10.1093/toxsci/66.2.216.Search in Google Scholar
63. Mumtaz, MM, Tully, DB, El-Masri, HA, De Rosa, CT, Gene induction studies and toxicity of chemical mixtures. Environ Health Perspect. 2002;110(Suppl 6):947–56. https://doi.org/10.1289/ehp.02110s6947.Search in Google Scholar
64. Tinwell, H, Ashby, J. Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens. Environ Health Perspect 2004;112:575–82. https://doi.org/10.1289/ehp.6831.Search in Google Scholar
65. You, L, Bartolucci, EJ. Gene expression profiles in mammary gland of male rats treated with genistein and methoxychlor. Environ Toxicol Pharmacol 2004;18:161–72. https://doi.org/10.1016/j.etap.2004.01.013.Search in Google Scholar
66. Crofton, KM, Craft, ES, Hedge, JM, Gennings, C, Simmons, JE, Carchman, RA, et al. Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism. Environ Health Perspect 2005;113:1549–54. https://doi.org/10.1289/ehp.8195.Search in Google Scholar
67. van Meeuwen, JA, Ter Burg, W, Piersma, AH, van den Berg, M, Sanderson, JT. Mixture effects of estrogenic compounds on proliferation and pS2 expression of MCF-7 human breast cancer cells. Food Chem Toxicol 2007;45:2319–30. https://doi.org/10.1016/j.fct.2007.06.011.Search in Google Scholar
68. Hass, U, Scholze, M, Christiansen, S, Dalgaard, M, Vinggaard, AM, Axelstad, M, et al. Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ Health Perspect 2007;115(Suppl 1):122–8. https://doi.org/10.1289/ehp.9360.Search in Google Scholar
69. Charles, GD, Gennings, C, Tornesi, B, Kan, HL, Zacharewski, TR, Bhaskar Gollapudi, B, et al. Analysis of the interaction of phytoestrogens and synthetic chemicals: an in vitro/in vivo comparison. Toxicol Appl Pharmacol 2007;218:280–8. https://doi.org/10.1016/j.taap.2006.11.029.Search in Google Scholar
70. Howdeshell, KL, Wilson, VS, Furr, J, Lambright, CR, Rider, CV, Blystone, CR, et al. A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rat in a cumulative, dose-additive manner. Toxicol Sci 2008;105:153–65. https://doi.org/10.1093/toxsci/kfn077.Search in Google Scholar
71. Cimino-Reale, G, Ferrario, D, Casati, B, Brustio, R, Diodovich, C, Collotta, A, et al. Combined in utero and juvenile exposure of mice to arsenate and atrazine in drinking water modulates gene expression and clonogenicity of myeloid progenitors. Toxicol Lett 2008;180:59–66. https://doi.org/10.1016/j.toxlet.2008.06.005.Search in Google Scholar
72. Kling, P, Förlin, L. Proteomic studies in zebrafish liver cells exposed to the brominated flame retardants HBCD and TBBPA. Ecotoxicol Environ Saf 2009;72:1985–93. https://doi.org/10.1016/j.ecoenv.2009.04.018.Search in Google Scholar
73. Christiansen, S, Scholze, M, Dalgaard, M, Vinggaard, AM, Axelstad, M, Kortenkamp, A, et al. Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environ Health Perspect 2009;117:1839–46. https://doi.org/10.1289/ehp.0900689.Search in Google Scholar
74. Bermudez, DS, Gray, LEJr, Wilson, VS. Modeling the interaction of binary and ternary mixtures of estradiol with bisphenol A and bisphenol AF in an in vitro estrogen-mediated transcriptional activation assay (T47D-KBluc). Toxicol Sci 2010;116:477–87. https://doi.org/10.1093/toxsci/kfq156.Search in Google Scholar
75. Rider, CV, Furr, JR, Wilson, VS, Gray, LEJr. Cumulative effects of in utero administration of mixtures of reproductive toxicants that disrupt common target tissues via diverse mechanisms of toxicity. Int J Androl 2010;33:443–62. https://doi.org/10.1111/j.1365-2605.2009.01049.x.Search in Google Scholar
76. Kjaerstad, MB, Taxvig, C, Andersen, HR, Nellemann, C. Mixture effects of endocrine disrupting compounds in vitro. Int J Androl 2010;33:425–33. https://doi.org/10.1111/j.1365-2605.2009.01034.x.Search in Google Scholar
77. Hotchkiss, AK, Rider, CV, Furr, J, Howdeshell, KL, Blystone, CR, Wilson, VS, et al. In utero exposure to an AR antagonist plus an inhibitor of fetal testosterone synthesis induces cumulative effects on F1 male rats. Reprod Toxicol 2010;30:261–70. https://doi.org/10.1016/j.reprotox.2010.06.001.Search in Google Scholar
78. Evans, RM, Scholze, M, Kortenkamp, A. Additive mixture effects of estrogenic chemicals in human cell-based assays can be influenced by inclusion of chemicals with differing effect profiles. PLoS One 2012;7:e43606.10.1371/journal.pone.0043606Search in Google Scholar PubMed PubMed Central
79. Boada, LD, Zumbado, M, Henríquez-Hernández, LA, Almeida-González, M, Alvarez-León, EE, Serra-Majem, L, et al. Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain). Environ Health 2012;11:28. https://doi.org/10.1186/1476-069x-11-28.Search in Google Scholar
80. Kim, YR, Jung, EM, Choi, KC, Jeung, EB. Synergistic effects of octylphenol and isobutyl paraben on the expression of calbindin-D₉k in GH3 rat pituitary cells. Int J Mol Med 2012;29:294–302. PMID: 23211298.https://doi.org/10.3892/ijmm.2011.823.Search in Google Scholar
81. Kim, SM, Jung, EM, An, BS, Hwang, I, Vo, TT, Kim, SR, et al. Additional effects of bisphenol A and paraben on the induction of calbindin-D(9K) and progesterone receptor via an estrogen receptor pathway in rat pituitary GH3 cells. J Physiol Pharmacol 2012;63:445–55.Search in Google Scholar
82. Brophy, JT, Keith, MM, Watterson, A, Park, R, Gilbertson, M, Maticka-Tyndale, E, et al. Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case-control study. Environ Health 2012;11:87. https://doi.org/10.1186/1476-069x-11-87.Search in Google Scholar
83. Mlynarcikova, A, Macho, L, Fickova, M. Bisphenol A alone or in combination with estradiol modulates cell cycle- and apoptosis-related proteins and genes in MCF7 cells. Endocr Regul 2013;47:189–99. https://doi.org/10.4149/endo_2013_04_189.Search in Google Scholar
84. Charles, AK, Darbre, PD. Combinations of parabens at concentrations measured in human breast tissue can increase proliferation of MCF-7 human breast cancer cells. J Appl Toxicol 2013;33:390–8. https://doi.org/10.1002/jat.2850.Search in Google Scholar
85. Scholze, M, Silva, E, Kortenkamp, A. Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method. PLoS One 2014;9:e88808. https://doi.org/10.1371/journal.pone.0088808.Search in Google Scholar
86. Orton, F, Ermler, S, Kugathas, S, Rosivatz, E, Scholze, M, Kortenkamp, A. Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products. Toxicol Appl Pharmacol 2014;278:201–8. https://doi.org/10.1016/j.taap.2013.09.008.Search in Google Scholar
87. Wang, J, Jenkins, S, Lamartiniere, CA. Cell proliferation and apoptosis in rat mammary glands following combinational exposure to bisphenol A and genistein. BMC Cancer 2014;14:379. https://doi.org/10.1186/1471-2407-14-379.Search in Google Scholar
88. Delfosse, V, Dendele, B, Huet, T, Grimaldi, M, Boulahtouf, A, Gerbal-Chaloin, S, et al. Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds. Nat Commun 2015;6:8089. https://doi.org/10.1038/ncomms9089.Search in Google Scholar
89. Hadrup, N, Pedersen, M, Skov, K, Hansen, NL, Berthelsen, LO, Kongsbak, K, et al. Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats. Arch Toxicol 2016;90:661–75. https://doi.org/10.1007/s00204-015-1452-6.Search in Google Scholar
90. Czarnota, J, Gennings, C, Colt, JS, De Roos, AJ, Cerhan, JR, Severson, RK, et al. Analysis of environmental chemical mixtures and non-Hodgkin lymphoma risk in the NCI-SEER NHL Study. Environ Health Perspect 2015;123:965–70. https://doi.org/10.1289/ehp.1408630.Search in Google Scholar
91. Conley, JM, Hannas, BR, Furr, JR, Wilson, VS, Gray, LEJr. A demonstration of the uncertainty in predicting the estrogenic activity of individual chemicals and mixtures from an in vitro estrogen receptor transcriptional activation assay (T47D-KBluc) to the in vivo uterotrophic assay using oral exposure. Toxicol Sci 2016;153:382–95. https://doi.org/10.1093/toxsci/kfw134.Search in Google Scholar
92. Pastor-Barriuso, R, Fernández, MF, Castaño-Vinyals, G, Whelan, D, Pérez-Gómez, B, Llorca, J, et al. Total effective xenoestrogen burden in serum samples and risk for breast cancer in a population-based multicase-control study in Spain. Environ Health Perspect 2016;124:1575–82. https://doi.org/10.1289/ehp157.Search in Google Scholar
93. Rivero, J, Henríquez-Hernández, LA, Luzardo, OP, Pestano, J, Zumbado, M, Boada, LD, et al. Differential gene expression pattern in human mammary epithelial cells induced by realistic organochlorine mixtures described in healthy women and in women diagnosed with breast cancer. Toxicol Lett 2016;246:42–8. https://doi.org/10.1016/j.toxlet.2016.02.003.Search in Google Scholar
94. Fiandanese, N, Borromeo, V, Berrini, A, Fischer, B, Schaedlich, K, Schmidt, JS, et al. Maternal exposure to a mixture of di(2-ethylhexyl) phthalate (DEHP) and polychlorinated biphenyls (PCBs) causes reproductive dysfunction in adult male mouse offspring. Reprod Toxicol 2016;65:123–32. https://doi.org/10.1016/j.reprotox.2016.07.004.Search in Google Scholar
95. Routti, H, Lille-Langøy, R, Berg, MK, Fink, T, Harju, M, Kristiansen, K, et al. Environmental chemicals modulate polar bear (Ursus maritimus) peroxisome proliferator-activated receptor gamma (PPARG) and adipogenesis in vitro. Environ Sci Technol 2016;50:10708–20. https://doi.org/10.1021/acs.est.6b03020.Search in Google Scholar
96. Guerra, MT, Furlong, HC, Kempinas, WG, Foster, WG. Effects of in vitro exposure to butylparaben and di-(2 ethylhexyl) phthalate, alone or in combination, on ovarian function. J Appl Toxicol 2016;36:1235–45. https://doi.org/10.1002/jat.3335.Search in Google Scholar
97. Seeger, B, Klawonn, F, Nguema Bekale, B, Steinberg, P. Mixture effects of estrogenic pesticides at the human estrogen receptor α and β. PLoS One 2016;11:e0147490. https://doi.org/10.1371/journal.pone.0147490.Search in Google Scholar
98. Zajda, K, Ptak, A, Rak, A, Fiedor, E, Grochowalski, A, Milewicz, T, et al. Effects of human blood levels of two PAH mixtures on the AHR signalling activation pathway and CYP1A1 and COMT target genes in granulosa non-tumor and granulosa tumor cell lines. Toxicology 2017;389:1–12. https://doi.org/10.1016/j.tox.2017.07.003.Search in Google Scholar
99. Adibi, JJ, Zhao, Y, Zhan, LV, Kapidzic, M, Larocque, N, Koistinen, H, et al. An investigation of the single and combined phthalate metabolite effects on human chorionic gonadotropin expression in placental cells. Environ Health Perspect 2017;125:107010. https://doi.org/10.1289/ehp1539.Search in Google Scholar
100. Wieczerzak, M, Namieśnik, J, Kudłak, B. Genotoxicity of selected pharmaceuticals, their binary mixtures, and varying environmental conditions - study with human adenocarcinoma cancer HT29 cell line. Drug Chem Toxicol 2019;4:1–11. https://doi.org/10.1080/01480545.2018.1529783.Search in Google Scholar
101. Ledda, C, Loreto, C, Bracci, M, Lombardo, C, Romano, G, Cinà, D, et al. Mutagenic and DNA repair activity in traffic policemen: a case-crossover study. J Occup Med Toxicol 2018;13:24. https://doi.org/10.1186/s12995-018-0206-9.Search in Google Scholar
102. Lee, YM, Kim, SA, Choi, GS, Park, SY, Jeon, SW, Lee, HS, et al. Association of colorectal polyps and cancer with low-dose persistent organic pollutants: a case-control study. PLoS One 2018;13:e0208546. https://doi.org/10.1371/journal.pone.0208546.Search in Google Scholar
103. Brinkmann, M, Hecker, M, Giesy, JP, Jones, PD, Ratte, HT, Hollert, H, et al. Generalized concentration addition accurately predicts estrogenic potentials of mixtures and environmental samples containing partial agonists. Toxicol In Vitro 2018;46:294–303. https://doi.org/10.1016/j.tiv.2017.10.022.Search in Google Scholar
104. Dairkee, SH, Luciani-Torres, G, Moore, DH, Jaffee, IM, Goodson, WH3rd. A ternary mixture of common chemicals perturbs benign human breast epithelial cells more than the same chemicals do individually. Toxicol Sci 2018;165:131–44. https://doi.org/10.1093/toxsci/kfy126.Search in Google Scholar
105. Axelstad, M, Hass, U, Scholze, M, Christiansen, S, Kortenkamp, A, Boberg, J. EDC IMPACT: reduced sperm counts in rats exposed to human relevant mixtures of endocrine disrupters. Endocr Connect 2018;7:139–48. https://doi.org/10.1530/ec-17-0307.Search in Google Scholar
106. Yuan, S, Huang, C, Ji, X, Ma, M, Rao, K, Wang, Z. Prediction of the combined effects of multiple estrogenic chemicals on MCF-7 human breast cancer cells and a preliminary molecular exploration of the estrogenic proliferative effects and related gene expression. Ecotoxicol Environ Safety 2018;160:1–9. https://doi.org/10.1016/j.ecoenv.2018.05.025.Search in Google Scholar
107. Thrupp, TJ, Runnalls, TJ, Scholze, M, Kugathas, S, Kortenkamp, A, Sumpter, JP. The consequences of exposure to mixtures of chemicals: something from ‘nothing’ and ‘a lot from a little’ when fish are exposed to steroid hormones. Sci Total Environ 2018;619-620:1482–92. https://doi.org/10.1016/j.scitotenv.2017.11.081.Search in Google Scholar
108. Martins, M, Silva, A, Costa, MH, Miguel, C, Costa, PM. Co-exposure to environmental carcinogens in vivo induces neoplasia-related hallmarks in low-genotoxicity events, even after removal of insult. Sci Rep 2018;8:3649. https://doi.org/10.1038/s41598-018-21975-w.Search in Google Scholar
109. Conley, JM, Lambright, CS, Evans, N, Cardon, M, Furr, J, Wilson, VS, et al. Mixed "antiandrogenic" chemicals at low individual doses produce reproductive tract malformations in the male rat. Toxicol Sci 2018;164:166–78. https://doi.org/10.1093/toxsci/kfy069.Search in Google Scholar
110. Shao, Y, Chen, Z, Hollert, H, Zhou, S, Deutschmann, B, Seiler, TB. Toxicity of 10 organic micropollutants and their mixture: implications for aquatic risk assessment. Sci Total Environ 2019;666:1273–82. https://doi.org/10.1016/j.scitotenv.2019.02.047.Search in Google Scholar
111. Shao, Y, Hollert, H, Tarcai, Z, Deutschmann, B, Seiler, TB. Integrating bioassays, chemical analysis and in silico techniques to identify genotoxicants in surface water. Sci Total Environ 2019;650:3084–92. https://doi.org/10.1016/j.scitotenv.2018.09.288.Search in Google Scholar
112. Rotter, S, Beronius, A, Boobis, AR, Hanberg, A, van Klaveren, J, Luijten, M, et al. Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution. Crit Rev Toxicol 2018;48:796–814. https://doi.org/10.1080/10408444.2018.1541964.Search in Google Scholar
113. Smith, MT, Guyton, KZ, Gibbons, CF, Fritz, JM, Portier, CJ, Rusyn, I, et al. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 2016;124:713–21. https://doi.org/10.1289/ehp.1509912.Search in Google Scholar
114. IARC monographs on the evaluation of carcinogenic risks to humans volume 100. , Lyon, France: International Agency for Research on Cancer; 2012.Search in Google Scholar
115. Smith, MT, Guyton, KZ, Kleinstreuer, N, Borrel, A, Cardenas, A, Chiu, WA, et al. The key characteristics of carcinogens: relationship to the hallmarks of cancer, relevant biomarkers, and assays to measure them. Cancer Epidemiol Biomarkers Prev 2020;2019:1346. https://doi.org/10.1158/1055-9965.EPI-19-1346.Search in Google Scholar
116. Demetriou, CA, Degli Esposti, D, Pullen Fedinick, K, Russo, F, Robinson, O, Vineis, P. Filling the gap between chemical carcinogenesis and the hallmarks of cancer: a temporal perspective. Eur J Clin Invest 2018;48:e12933. https://doi.org/10.1111/eci.12933.Search in Google Scholar
117. Menzel, R, Swain, SC, Hoess, S, Claus, E, Menzel, S, Steinberg, CE, et al. Gene expression profiling to characterize sediment toxicity--a pilot study using Caenorhabditis elegans whole genome microarrays. BMC Genomics 2009;10:160. https://doi.org/10.1186/1471-2164-10-160.Search in Google Scholar
118. Christiansen, HE, Mehinto, AC, Yu, F, Perry, RW, Denslow, ND, Maule, AG, et al. Correlation of gene expression and contaminant concentrations in wild largescale suckers: a field-based study. Sci Total Environ 2014;484:379–89. https://doi.org/10.1016/j.scitotenv.2013.08.034.Search in Google Scholar
119. Vogel, VG, Costantino, JP, Wickerham, DL, Cronin, WM, Cecchini, RS, Atkins, JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727–41. Erratum in: JAMA 2006;296(24):2926. JAMA 2007;298(9):973. https://doi.org/10.1001/jama.295.23.joc60074.Search in Google Scholar
120. Cuzick, J, Sestak, I, Baum, M, Buzdar, A, Howell, A, Dowsett, M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:1135–41. https://doi.org/10.1016/s1470-2045(10)70257-6.Search in Google Scholar
121. Chlebowski, RT, Anderson, GL, Gass, M, Lane, DS, Aragaki, AK, Kuller, LH, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684–92. https://doi.org/10.1001/jama.2010.1500.Search in Google Scholar
122. Ribas, A, Puzanov, I, Dummer, R, Schadendorf, D, Hamid, O, Robert, C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015;16:908–18. https://doi.org/10.1016/s1470-2045(15)00083-2.Search in Google Scholar
123. Geyer, CE, Forster, J, Lindquist, D, Chan, S, Romieu, CG, Pienkowski, T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–43. Erratum in: N Engl J Med 2007;356(14):1487. https://doi.org/10.1056/nejmoa064320.Search in Google Scholar
124. Tewari, KS, Sill, MW, Long, HJ3rd, Penson, RT, Huang, H, Ramondetta, LM, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734–43. Erratum in: N Engl J Med 2017;377:702. https://doi.org/10.1056/nejmoa1309748.Search in Google Scholar
125. Kornblum, N, Zhao, F, Manola, J, Klein, P, Ramaswamy, B, Brufsky, A, et al. Randomized phase II trial of Fulvestrant Plus Everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol 2018;36:1556–63. https://doi.org/10.1200/jco.2017.76.9331.Search in Google Scholar
126. Rugo, HS, Finn, RS, Diéras, V, Ettl, J, Lipatov, O, Joy, AA, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 2019;174:719–29. https://doi.org/10.1007/s10549-018-05125-4.Search in Google Scholar
127. O’Neil, J, Benita, Y, Feldman, I, Chenard, M, Roberts, B, Liu, Y, et al. An unbiased oncology compound screen to identify novel combination strategies. Mol Cancer Ther 2016;15:1155–62. https://doi.org/10.1158/1535-7163.mct-15-0843.Search in Google Scholar
128. Preuer, K, Lewis, RPI, Hochreiter, S, Bender, A, Bulusu, KC, Klambauer, G. Deep Synergy: predicting anti-cancer drug synergy with Deep Learning. Bioinformatics 2018;34:1538–46. https://doi.org/10.1093/bioinformatics/btx806.Search in Google Scholar
129. Metzler, M. The metabolism of diethylstilbestrol. CRC Crit Rev Biochem 1981;10:171–212. https://doi.org/10.3109/10409238109113599.Search in Google Scholar
130. Boyd, J, Takahashi, H, Waggoner, SE, Jones, LA, Hajek, RA, Wharton, JT, et al. Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in utero. Cancer 1996;77:507–13. https://doi.org/10.1002/(sici)1097-0142(19960201)77:3<507::aid-cncr12>3.0.co;2-8.10.1002/(SICI)1097-0142(19960201)77:3<507::AID-CNCR12>3.0.CO;2-8Search in Google Scholar
131. Doherty, LF, Bromer, JG, Zhou, Y, Aldad, TS, Taylor, HS. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer 2010;1:146–55. https://doi.org/10.1007/s12672-010-0015-9.Search in Google Scholar
132. Harlid, S, Xu, Z, Panduri, V, D’Aloisio, AA, DeRoo, LA, Sandler, DP, et al. In utero exposure to diethylstilbestrol and blood DNA methylation in women ages 40-59 years from the sister study. PLoS One 2015;10:e0118757. https://doi.org/10.1371/journal.pone.0118757.Search in Google Scholar
133. Rivollier, F, Chaumette, B, Bendjemaa, N, Chayet, M, Millet, B, Jaafari, N, et al. Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: lessons from diethylstilbestrol. PLoS One 2017;12:e0174783. https://doi.org/10.1371/journal.pone.0174783.Search in Google Scholar
134. Dairkee, SH, Luciani-Torres, MG, Moore, DH, Goodson, WH3rd. Bisphenol-A-induced inactivation of the p53 axis underlying deregulation of proliferation kinetics, and cell death in non-malignant human breast epithelial cells. Carcinogenesis 2013;34:703–12. https://doi.org/10.1093/carcin/bgs379.Search in Google Scholar
135. Bäckström, CT, McNeilly, AS, Leask, RM, Baird, DT. Pulsatile secretion of LH, FSH, prolactin, oestradiol and progesterone during the human menstrual cycle. Clin Endocrinol (Oxf) 1982;17:29–42. https://doi.org/10.1111/j.1365-2265.1982.tb02631.x.Search in Google Scholar
136. 1Apter, D, Bützow, TL, Laughlin, GA, Yen, SS. Gonadotropin-releasing hormone pulse generator activity during pubertal transition in girls: pulsatile and diurnal patterns of circulating gonadotropins. J Clin Endocrinol Metab 1993;76:940–9. https://doi.org/10.1210/jc.76.4.940.Search in Google Scholar
137. Teeguarden, JG, Calafat, AM, Ye, X, Doerge, DR, Churchwell, MI, Gunawan, R, et al. Twenty-four hour human urine and serum profiles of bisphenol a during high-dietary exposure. Toxicol Sci 2011;123:48–57. https://doi.org/10.1093/toxsci/kfr160.Search in Google Scholar
138. Chen, LH, Shi, JR, Fang, YL, Liang, L, Chen, WQ, Chen, XZ. Serum bisphenol A concentration and premature thelarche in female infants aged 4-month to 2-year. Indian J Pediatr 2015;82:221–4. https://doi.org/10.1007/s12098-014-1548-7.Search in Google Scholar
139. Durmaz, E, Asci, A, Erkekoglu, P, Balcı, A, Bircan, I, Koçer-Gumusel, B. Urinary bisphenol A levels in Turkish girls with premature thelarche. Hum Exp Toxicol 2018;37:1007–16. https://doi.org/10.1177/0960327118756720.Search in Google Scholar
140. Berger, K, Eskenazi, B, Kogut, K, Parra, K, Lustig, RH, Greenspan, LC, et al. Association of prenatal urinary concentrations of phthalates and bisphenol A and pubertal timing in boys and girls. Environ Health Perspect 2018;126:97004. https://doi.org/10.1289/EHP3424.Search in Google Scholar
141. Howland, RE, Deziel, NC, Bentley, GR, Booth, M, Choudhury, OA, Hofmann, JN, Hoover, RN, et al. Assessing endogenous and exogenous hormone exposures and breast development in a migrant study of Bangladeshi and British girls. Int J Environ Res Public Health 2020;17:E1185. https://doi.org/10.3390/ijerph17041185.Search in Google Scholar
142. Hyman, AH, Simons, K. Beyond HeLa cells. Nature 2011;480:34. https://doi.org/10.1038/480034a.Search in Google Scholar
143. Capes-Davis, A, Bairoch, A, Barrett, T, Burnett, EC, Dirks, WG, Hall, EM, et al. Cell lines as biological models: practical steps for more reliable research. Chem Res Toxicol 2019;32:1733–6. https://doi.org/10.1021/acs.chemrestox.9b00215.Search in Google Scholar
144. Cantonwine, DE, Meeker, JD, Ferguson, KK, Mukherjee, B, Hauser, R, McElrath, TF. Urinary concentrations of bisphenol A and phthalate metabolites measured during pregnancy and risk of preeclampsia. Environ Health Perspect 2016;124:1651–5. https://doi.org/10.1289/ehp188.Search in Google Scholar
145. Vandenberg, LN, Hunt, PA, Gore, AC. Endocrine disruptors and the future of toxicology testing - lessons from CLARITY-BPA. Nat Rev Endocrinol 2019;15:366–74. https://doi.org/10.1038/s41574-019-0173-y.Search in Google Scholar
146. Vom Saal, FS. Flaws in design, execution and interpretation limit CLARITY-BPA’s value for risk assessments of bisphenol A. Basic Clin Pharmacol Toxicol 2019;125(Suppl 3):32–43. https://doi.org/10.1111/bcpt.13195.Search in Google Scholar
147. Hurley, SF, Matthews, JP. Cost-effectiveness of the Australian National Tobacco Campaign. Tob Control 2008;17:379–84. https://doi.org/10.1136/tc.2008.025213.Search in Google Scholar
148. Alberini, A, Ščasný, M. The benefits of avoiding cancer (or dying from cancer): evidence from a four- country study. J Health Econ 2018;57:249–62. https://doi.org/10.1016/j.jhealeco.2017.08.004.Search in Google Scholar
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