Auvinen, Anssi

Deltour, Isabelle

Elliott, Paul

Feychting, Maria

Heller, Joel

Huss, Anke

Johansen, Christoffer

Kromhout, Hans

Poulsen, Aslak Harbo

Schüz, Joachim

Smith, Rachel B.

Tettamanti, Giorgio

Toledano, Mireille B.

Vermeulen, Roel

Utrecht University Repository

Environment International 187 (2024) 108664Available online 21 April 20240160-4120/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Response to the Letter to the Editor regarding “Mobile phone use and brain tumour risk ¡COSMOS, a prospective cohort study”  A R T I C L E  I N F O   Handling Editor: Mark Nieuwenhuijsen Keywords Cell phones Radiofrequency fields Electromagnetic fields Non-ionizing radiation Brain neoplasms Cohort study       We thank Dr. Kundi for his interest in our study (Feychting et al., 2024). We take this opportunity to clarify some design features and to endorse the conclusions of our study. First, we wish to take note of a basic epidemiological concept, namely to distinguish between exposure time and follow-up (or risk) time. The follow-up time in a cohort study is the period during which incident cases of the studied disease are registered. This need not be the entire time from potential tumour initiation until diagnosis, as infor-mation about individual exposure histories can be collected when the cohort is established, before cohort participants have been diagnosed with the studied disease; this includes information on past exposure so that cumulative exposure over the entire exposure time becomes avail-able, which is more than 20 years for the early mobile phone users in COSMOS. Then the cohort is followed prospectively to identify various health outcomes. This is a well-established method used in numerous prospective cohort studies. One well-known example is the cohort of British doctors established in 1951, which collected smoking histories on 40,564 medical doctors (Doll and Hill, 1954). Doll and colleagues could already within three years demonstrate a higher lung cancer mortality among smokers. As we reported, COSMOS participants gave detailed information about their current and historical mobile phone use in the baseline questionnaire, covering the entire time period from the day they first started to use a mobile phone. Handheld mobile phones were introduced in 1987; thus, the longest latency possible was ~ 30 years, and 30.5 % of the COSMOS study population had used a mobile phone 15 years or longer (Feychting et al., 2024). Cancer development is a multistage process that encompasses tumour initiation, promotion, malignant conversion and progression (Dean and Moitra, 2018; Weston and Harris, 2003). This process in-volves a sequence of molecular changes that may eventually manifest in clinically detectable cancer. A number of mutational events occur during this process which can be caused by various agents, some of which may have the potential to initiate cancer, while others act as promotors or progressors. The mechanism by which non-thermal levels of non-ionizing radia-tion such as radiofrequency electromagnetic fields (RF-EMF) would affect cancer development, if any, is unknown (Roosli et al., 2019). The energy absorbed in tissues from non-ionizing radiation is too weak to break chemical bonds and is not believed to directly cause DNA damage (Challis, 2005). Thus, RF-EMF is unlikely to be an initiator of tumouri-genesis. Kundi argues that it would not be possible to observe an increased risk of brain tumours in the COSMOS study because brain tumours have too long latencies, using ionizing radiation as an example. Ionizing radiation is a known cancer initiator, as the absorbed energy is high enough to ionize molecules and damage DNA (Berrington de Gonzáles et al., 2018). It is more relevant, however, to discuss latencies or induction periods associated with different exposures, as these will vary depending on the mechanism by which the exposure affects cancer development (Rothman and Greenland, 1998). For ionizing radiation, higher brain tumour incidence is indeed observed several decades after exposure, for example among atomic bomb survivors (Brenner et al., 2020) and persons who received radiation treatment for tinea capitis as children (Sadetzki et al., 2005). However, many carcinogens known to cause DNA damage may also act as promotors and progressors, and a higher cancer incidence among people exposed to a specific agent may be evident within a few years after first exposure. Ionizing radiation is a good example as it also acts as a promotor (Berrington de Gonzáles et al., 2018). This is, for example, evident in a study of ionizing radiation from computed tomography (CT) scans during childhood and adolescence, where the highest excess relative risk (ERR) for brain cancer was observed 5 to < 10 years after exposure (ERR/100 mGy = 1.84; 95 % CI 0.78–3.76) (Hauptmann et al., 2023). A study of tinea capitis patients found an excess relative risk (ERR) for malignant brain tumours of 2.94 DOI of original article: https://doi.org/10.1016/j.envint.2024.108552. Contents lists available at ScienceDirect Environment International journal homepage: www.elsevier.com/locate/envint https://doi.org/10.1016/j.envint.2024.108664 Received 9 April 2024; Accepted 15 April 2024   Environment International 187 (2024) 1086642(95 % CI 0.39–13.95) per Gy with less than 20 years latency (Sadetzki et al., 2005) and observed raised risks also for longer latencies. Studies of Japanese atomic bomb survivors found an increased risk of leukaemia within a few years after exposure, whereas an increase in the incidence of solid tumours was evident after less than 15 years (Little, 2009). Kundi’s arguments about too short exposure time in COSMOS and the claim about a very long latency for brain tumours are not correct. Notably, one rationale of starting COSMOS was that some previous case-control studies reported associations between cumulative mobile phone use and especially glioma risk, after much shorter latencies than COSMOS now has been able to address (Baan et al., 2011), raising concerns as to whether protective measures were necessary. These studies had maximum exposure durations of ~ 15 years. The main value of COSMOS is the use of a study design that overcomes the well-known limitations of the case-control studies due to differential recall bias, and considerably extending the exposure duration as compared to previous studies. With an improved study design, no increased brain tumour risks were observed. As we discuss in the article, the main current limitation of our study, which will diminish with time, is the limited statistical power, especially for acoustic neuroma but also for meningioma (Feychting et al., 2024). Additional updates of the COSMOS cohort linkages to the cancer regis-ters are warranted to increase statistical power, allow analyses of longer latencies, and study potential carcinogenic effects from newer genera-tions of mobile technologies. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability No data was used for the research described in the article. References Baan, R., Grosse, Y., Lauby-Secretan, B., El Ghissassi, F., Bouvard, V., Benbrahim- Tallaa, L., et al., 2011. Carcinogenicity of radiofrequency electromagnetic fields. Lancet Oncol. 12, 624–626. https://doi.org/10.1016/s1470-2045(11)70147-4. Berrington de Gonzáles, A., Bouville, A., Rajaraman, P., Schubauer-Berigan, M., 2018. Ionizing radiation. In: York, N. (Ed.), Schottenfeld and Fraumeni Cancer Epidemi-ology and Prevention, Part 4th (thun MJ, Linet MS, Cerhan JR, Haiman CA, Schot-tenfeld D. Oxford University Press, NY, pp. 227–248. Brenner, A.V., Sugiyama, H., Preston, D.L., Sakata, R., French, B., Sadakane, A., et al., 2020. Radiation risk of central nervous system tumors in the life span study of atomic bomb survivors, 1958–2009. Eur. J. Epidemiol. 35, 591–600. https://doi. org/10.1007/s10654-019-00599-y. Epub 2020 Jan 25.  Challis, L.J., 2005. Mechanisms for interaction between RF fields and biological tissue. Bioelectromagnet. Suppl. 7, S98–S106. https://doi.org/10.1002/bem.20119. Dean, M., Moitra, K., 2018. Biology of neoplasia. In: Thun, M.J., Linet, M.S., Cerhan, J.R., Haiman, C.A., Schottenfeld, D. (Eds.), Schottenfeld and Fraumeni Cancer Epidemi-ology and Prevention, Part 4th. Oxford University Press, New York, NY, pp. 9–18. Doll, R., Hill, A.B., 1954. The mortality of doctors in relation to their smoking habits; a preliminary report. Br. Med. J. 1, 1451–1455. https://doi.org/10.1136/ bmj.1.4877.1451. Feychting, M., Schuz, J., Toledano, M.B., Vermeulen, R., Auvinen, A., Harbo Poulsen, A., et al., 2024. Mobile phone use and brain tumour risk - cosmos, a prospective cohort study. Environ. Int. 185, 108552 https://doi.org/10.1016/j.envint.2024.108552. Epub 2024 Mar 2.  Hauptmann, M., Byrnes, G., Cardis, E., Bernier, M.O., Blettner, M., Dabin, J., et al., 2023. Brain cancer after radiation exposure from ct examinations of children and young adults: Results from the epi-ct cohort study. Lancet Oncol. 24, 45–53. https://doi. org/10.1016/S1470-2045(22)00655-6. Little, M.P., 2009. Cancer and non-cancer effects in Japanese atomic bomb survivors. J. Radiol. Prot. 29, A43–A59. https://doi.org/10.1088/0952-4746/29/2A/S04. Roosli, M., Lagorio, S., Schoemaker, M.J., Schuz, J., Feychting, M., 2019. Brain and salivary gland tumors and mobile phone use: Evaluating the evidence from various epidemiological study designs. Annu. Rev. Public Health 40, 221–238. https://doi. org/10.1146/annurev-publhealth-040218-044037. Epub 2019 Jan 11.  Rothman, K.J., Greenland, S., 1998. Modern epidemiology, 2nd ed. Lippincott-Raven Publishers, Philadephia, PA.  Sadetzki, S., Chetrit, A., Freedman, L., Stovall, M., Modan, B., Novikov, I., 2005. Long- term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat. Res. 163, 424–432. https://doi.org/10.1667/ rr3329. Weston, A., Harris, C.C., 2003. Multistage carcinogenesis. In: Kufe, D.W., Pollock, R.E., Weichselbaum, R.R., Bast, R.C., Gansler, T.S., Holland, J.F. (Eds.), Holland-frei cancer medicine, Part 6th. BC Decker, Hamilton (ON).  Maria Feychtinga,*, Joachim Schüzb, Mireille B. Toledanoc,d,e,f, Roel Vermeuleng,h, Anssi Auvineni,j, Aslak Harbo Poulsenk, Isabelle Deltourb, Rachel B. Smithc,d,e,f, Joel Hellerc, Hans Kromhoutg, Anke Hussg, Christoffer Johansenl, Giorgio Tettamantia, Paul Elliottc,d,e,m,* a Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden b International Agency for Research on Cancer (IARC/WHO), Environment and Lifestyle Epidemiology Branch, Lyon, France c Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK d Medical Research Council (MRC) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK e National Institute for Health Research (NIHR) Health Protection Research Unit in Chemical and Radiation Threats and Hazards, Imperial College London, London, UK f Mohn Centre for Children’s Health and Wellbeing, School of Public Health, Imperial College London, London, UK g Utrecht University, Institute for Risk Assessment Sciences, Utrecht, The Netherlands h University Medical Center Utrecht, Julius Center, The Netherlands i STUK – Radiation and Nuclear Safety Authority, Environmental Surveillance, Vantaa, Finland j Tampere University, Faculty of Social Sciences/Health Sciences, Tampere, Finland k Danish Cancer Institute, Copenhagen, Denmark l CASTLE Cancer Late Effect Research Oncology Clinic, Center for Surgery and Cancer, Rigshospitalet, Copenhagen, Denmark m NIHR Imperial Biomedical Research Centre, Imperial College London, London, UK * Corresponding authors at: Institute of Environmental Medicine, Box 210, SE-17177 Stockholm, Sweden (M. Feychting). Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK (P. Elliott). E-mail addresses: maria.feychting@ki.se (M. Feychting), p. elliott@imperial.ac.uk (P. Elliott). M. Feychting et al.                                                                                                                                                                                                                              

Response to the Letter to the Editor regarding “Mobile phone use and brain tumour risk − COSMOS, a prospective cohort study”

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Response to the Letter to the Editor regarding “Mobile phone use and brain tumour risk − COSMOS, a prospective cohort study”

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