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Animal carcinogenicity studies on radiofrequency fields related to mobile phones and base stations
Toxicology and Applied Pharmacology 207 (2005) S342 – S346 www.elsevier.com/locate/ytaap
Review
Animal carcinogenicity studies on radiofrequency fields related to mobile phones and base stations Clemens Dasenbrock* Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany Received 21 July 2004; revised 20 April 2005; accepted 20 April 2005 Available online 21 July 2005
Abstract Since a report in 1997 on an increased lymphoma incidence in mice chronically exposed to a mobile phone radiofrequency signal, none of the subsequent long-term studies in rodents have confirmed these results. On the other hand, several of the follow-up co- and carcinogenicity studies are still underway or are presently being initiated. Most of the published long-term studies used 1 exposure level only and suffer from a poor dosimetry which does not consider the animal’s growth. Additional points of criticism are a limited, in some cases, questionable histopathology and inadequate group sizes. Overall, if dealing with new chemicals or drugs, these studies would not be acceptable for registration with the responsible authorities. The major critical points are taken into consideration within the European co- and carcinogenicity projects (CEMFEC and PERFORM-A), which are in their final stages and in the US long-term studies in mice and rats which are about to be initiated. Nevertheless, the WHO evaluation for health risk assessment of long-term telephone use and base station exposure will start in late 2005. D 2005 Elsevier Inc. All rights reserved. Keywords: Radiofrequency; Mobile phones; Cancer; Animal studies
Contents Introduction . . . . Cancer studies . . . Initiation promotion Conclusion . . . . . References . . . . . Studies in progress.
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Abbreviations: CDMA, code division multiple access; CEMFEC, Acronym of the European project ‘‘Combined effects of electromagnetic fields with environmental carcinogens’’; CNS, central nervous system; DAMPS, digital advanced mobile phone systems; DCS, digital personal communications system; European, standard for digital mobile phone technology at 1800 MHz; DEN, diethylnitrosamine; DMBA, 7,12-dimethylbenz[a]anthracene; EMF, electromagnetic field; ENU, ethylnitrosourea; FDMA, frequency division multiple access; GLP, good laboratory practice according to national and OECD principles; GSM, global system for mobile communication; European, standard for cell phone systems; Gy, Gray; MHz, megahertz; MX, 3-chloro-4(dichloromethyl)-5-hydroxy-2(5H)-furanone; NADC, North American digital cellular; NIEHS/NTP, National Institute of Environmental Health Sciences/ National toxicology program; NMT, Nordic mobile telephones; ODC, ornithine decarboxylase; PERFORM-A, Acronym of the European project ‘‘In vivo research on possible health effects related to mobile telephones and base stations (carcinogenicity studies in rodents)’’; RF, radio frequency; SAR, specific absorption rate; TDMA, time division multiple access; TPA, 12-O-tetradecanoylphorbol-13-acetate; UMTS, universal mobile telecommunication system; UV, ultraviolet. * Present address: Boehringer-Ingelheim Pharma GmbH and Co.KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany. E-mail address: [email protected]. 0041-008X/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2005.04.032
YTAAP-10374; No. of pages: 5; 4C:
C. Dasenbrock / Toxicology and Applied Pharmacology 207 (2005) S342 – S346
Introduction After Repacholi et al. in 1997 observed a 2.4-fold lymphoma increase in transgenic pim1 mice chronically exposed to a GSM signal, several long-term studies related to mobile telephony were initiated. These studies have addressed either a possible direct tumor incidence-increasing effect or/and a tumor-promoting/co-carcinogenic effect of radiofrequency (rf). The following criteria were met by the reviewed studies discussed in this presentation: & long-term exposure to an rf signal related to mobile telephony, & co- or carcinogenesis including tumor promotion as study endpoint, and, if applicable, & publication in a peer-reviewed journal. Firstly, cancer studies will be discussed. The studies involve experiments without any pre-treatment of the animals; transgenic mice are included. All animals were long-term rf-exposed for 1.5 to 2 years and for minimum of 1 h per day, 4 – 7 days per week. Secondly, in initiation promotion and co-carcinogenicity studies before exposure to the rf signal(s), the animals usually were administered a (strong) carcinogen, e.g., 7,12dimethylbenz[a]anthracene (DMBA), diethylnitrosamine (DEN) or ethylnitrosourea (ENU), as a tumor-initiating chemical and were subsequently rf-exposed for several weeks or months. Other investigators in their co-carcinogenicity studies (Juutilainen et al., 2000) preferred simultaneous exposure to a carcinogen, e.g., MX, ionizing or UV radiation, and to the (non-ionizing) rf.
Cancer studies In the most quoted study, Repacholi et al. (1997) found a significant (2.4-fold) increase in lymphomas in female pim1 transgenic mice after 18 months (2 30 min/day) of exposure to a modulated 900 MHz GSM signal. In a far field, only one exposure level (‘‘dose’’) with a large variation (0.008 – 4.2 W/kg SAR [whole body]) was used for the non-restrained mice. Due to further shortcomings of the study, two re-evaluation studies were started. At first, Utteridge et al. (2002, 2003) could not confirm Repacholi’s results. Again, a modulated GSM signal (898.4 MHz, 217 Hz pulse, 0.6 ms pulse width) was used for exposure in a ‘‘ferris-wheel’’ system. Female heterozygous pim1 transgenic (lymphoma-prone) and wild-type mice (n = 120 per group) were rf-radiated in restrainer tubes for 1 h/day, 5 days/week during 24 months at 4 different SAR [whole body] levels of 0, 0.25, 1.0, 2.0 and 4.0 W/kg. In addition, a positive control treated with 50 mg/kg ENU and a nonrestrained cage control group were included in the study.
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Overall, there was no lymphoma increase in the rf-radiated groups of the various SAR levels. Secondly, at Serono-RBM, Ivrea, Italy, male and female pim1 transgenic mice were exposed to a modulated GSM signal (902 MHz, 217 Hz pulse, 0.5 ms pulse width). The study is part of the European project PERFORM-A (Dasenbrock et al., 2003), was blinded and run under GLP conditions. In a ferris-wheel system (Goerlitz et al., in press), tube-restrained mice (n = 50/group/sex) were rf-radiated for 1 h/day, 7 days/week, up to 18 months, at SAR levels [whole body] of 0, 0.5, 1.4, 4.0 W/kg. The draft report of this study is almost finalized (Oberto et al., in progress). Supplementary to the above experiments, Sommer et al. (submitted for publication) studied in female mice of the (high-leukemia) inbred strain AKR the long-term influence of a 9-month continuous rf exposure at 0.4 W/kg SAR [whole-body] to a GSM signal (890 MHz modulated). In a radial waveguide system, 168 females were sham- and 168 rf-radiated in their cages (7 mice per cage). No increase in the incidence of leukemia and lymphomas was detected, but only 1 ‘‘dose’’ was applied. Recently, the same group started an identical experiment testing the long-term rf radiation (1966 MHz modulated) at 0.4 W/kg SAR [whole body] using a generic UMTS test signal for bio-experiments (Bitz et al., 2004; Ndoumbe` Mbonjo Mbonjo et al., in press). The in-life phase is still in progress. La Regina et al. (2003) tube-exposed F344 rats in carousel systems for 4 h/day, 5 days/week during 24 months. Two different rf radiations (835.62 MHz FDMA, 847.74 MHz CDMA) at one brain SAR level of 1.3 T 0.5 W/kg each were applied to the animals. Each group (2 rf and 1 sham) consisted of 160 rats (80/80). No significant differences between treated and sham-exposed animals were found regarding any brain tumor and a number of non-CNS tumors. In two NTP-like carcinogenicity studies at the Fraunhofer ITEM, Hannover, Germany, in a ferris-wheel system (Goerlitz et al., in press), tube-restrained B6C3F1 mice were exposed for 24 months, 5 days/week, 2 h/day to a GSM signal cocktail at 902 MHz or to a DCS signal cocktail at 1747 MHz. One sham control and three rf groups (target SAR [whole body]): 0, 0.4, 1.3, 4.0 W/kg) per signal were complemented by one cage control group (n = 65/group/sex). This GLP study is also blinded and part of PERFORM-A, results will be available in spring 2005 (Dasenbrock et al., 2003, in progress). A further two identical NTP-like blinded GLP studies using Wistar rats were initiated within PERFORM-A at RCC Ltd., Itingen, Switzerland. A new ferris-wheel system was used (Froelich et al., 2001; Nikoloski et al., 2002). Again, rats of one sham control and three rf groups (target SAR [whole body]): 0, 0.3, 1.4, 4.0 W/kg) per signal (n = 65/group/sex) were exposed in restrainer tubes for 24 months, 5 days/week, 2 h/day to a GSM signal cocktail at 902 MHz or to a DCS signal cocktail at 1747 MHz; one cage control group was also included. Results will be
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available in late summer 2005 (Smith et al., in progress; Dasenbrock et al., 2003). Further long-term studies on a possible carcinogenic effect of rf signals as emitted by base stations are about to be initiated in the USA. Under the co-ordination of the NIEHS/ NTP program, unrestrained and individually caged B6C3F1 mice and Sprague –Dawley rats shall be exposed to 900 MHz GSM and 1900 MHz CDMA modulated signals (Melnick et al., 2003). It is planned to use ‘‘reverberation chambers’’ (Ladbury et al., 2003) for a 20-h intermittent rf exposure per day, 5 days/week, during 110 weeks. Exposure(s) will be started on gestation day 6, and after prestudies, three rf ‘‘doses’’ and 1 sham per signal will be used.
Initiation promotion and co-carcinogenicity studies Imaida et al. (1998a,b) rf-irradiated male F344 rats which had been pre-treated with 200 mg/kg DEN i.p. and subjected to subsequent 2/3 partial hepatectomy. After one further week of recovery, the restrained rats (n = 48/group) were sham- or rf-exposed for 90 min/day, 5 days/week, over 6 weeks to a pulse-modulated (a) 929.2 MHz or (b) 1.439 GHz EM near-field (SAR [liver]: (a) 2.0 –1.7 W/kg or (b) 1.9 –0.9 W/kg). The occurrence of pre-neoplastic liver cell foci was tested. The local body exposure to these two EMFs had no promoting effect on rat liver carcinogenesis in the described model. Only one rf ‘‘dose’’ was used though. Furthermore, Imaida et al. (2001) tested the influence of a 90 min/day, 5 days/week, 19 weeks lasting rf exposure to pulsed 1.49 GHz TDMA signals on DMBA-initiated skin cancer in ICR female mice. The skin local peak-specific SAR was 2.0 W/kg, the whole body average SAR was 0.084 W/kg. One restrained sham and one rf radiation group (n = 48 each) were complemented by a positive (TPA promotion) and a cage control group (n = 30 each). The 1.5 GHz near field exposure revealed no promoting influence on skin cancer. Adey et al. (1999) discovered that NADC signals (836.55 MHz TDMA modulation) had a ‘‘tumor-protective effect’’ on spontaneous and ENU-induced tumors of the CNS in rats. The on gestation day 18 in utero ENU-treated offspring of F344 rats was head-only tube-exposed in carousel systems for 2 h/day, 4 days/week, during 22 months. Only one brain SAR level of 0.7– 1.6 W/kg was tested in ENU- and sham-pre-treated rats (n = 30/sex/group). The same research group (Adey et al., 2000) repeated the experiment with a frequency-modulated 836.55 MHz signal (‘‘balanced speech’’) and increased group sizes (n = 45/sex/ group). Again, solely one (brain) SAR level (1.0 –1.2 W/kg) was tested. The ‘‘tumor-protective effect’’ could not be replicated. While an extensive histopathology of the brain was done, unfortunately, only tumors of the CNS were investigated. A comparable series of experiments was published by Zook and Simmens (2001). Again, in utero ENU-treated
offspring of Sprague – Dawley rats was head-only tubeexposed in carousel systems for 6 h/day, 4 days/week, during 22 months. Two different doses of ENU (2.5 and 10 mg/kg bw) were administered on gestation day 15 to the pregnant females, and 860 MHz pulsed as well as continuous wave rf signals (one SAR level of 1.0 W/kg each) were applied to the offspring beginning in week 8. In contrast to the experiments of Adey et al. (1999, 2000), cage control groups were added. Per group, 60 rats each (30 males + 30 females) were used. The rf exposure did not promote the malignancy of brain tumors, and the limited histopathology performed on other organs did not reveal different tumor incidences in rf-radiated than in sham groups. Bartsch et al. (2002) chronically exposed DMBAinduced mammary tumor-bearing rats to a (217 Hz) pulsed 900 MHz GSM signal. For mammary tumor induction, female Sprague – Dawley rats (Hsd: SD) received a single intragastric dose of 8.75 mg/100 g bw on day 51. On the same day, rf exposure started (23 h/day, 7 days/week; 8.5– 11 months). Over 3 years, 3 identical experiments with group-housed rats (12 females per cage, n = 60 per sham and rf group each) were run. The young 150 g animals at the beginning of each experiment exhibited SARs [whole body] between 32.5 and 130 mW/kg, older 400 g rats, aged 11 months, between 15 and 60 mW/kg. Overall, there was no statistically significant effect of rf field exposure on (mammary) tumor latency and cumulative tumor incidence. Using a similar 900 MHz GSM signal and the same model but another source of Sprague – Dawley rats (Ico:OFA-SD), Anane et al. (2003) also reported negative results in terms of latency, multiplicity and tumor volume. The group size of 16 females, however, was low. Further differences were not only one, but 5 SARs (0.1, 0.7, 1.4, 2.2, 3.5 W/kg) tested in DMBA-induced (10 mg/rat) mammary tumor-bearing rats which were restrained during the daily 2-h exposure for only 9 weeks. Within the fourth partial project of PERFORM-A, the ARC, Seibersdorf, Austria, investigated possible effects of rf radiation (900 MHz GSM, 217 Hz pulsed) on mammary tumors induced on day 47 by 17 mg/kg DMBA. 100 females per group were sham- or rf-exposed to 0, 0.34, 1.43 and 4 W/kg (target SAR [whole body]) in a new ferriswheel system (Froelich et al., 2001; Nikoloski et al., 2002); one cage control group was also included. Results will be available by the beginning of 2005 (Hruby et al., in progress; Dasenbrock et al., 2003). In addition, an identical study was performed in Zhejang, China. Results should be available soon (Chiang et al., in progress). Heikkinen et al. (2001) examined the combined effect of ionizing and rf radiation in mice. They X-radiated female CBA/S mice with 4 Gy (1.33 Gy/week during 3 weeks) and simultaneously started rf exposure (0.35 W/kg SAR [whole body]). 50 females per group were used as cage controls (without any radiation) or restrained and sham- or rfradiated for 1.5 h/day, 5 days/week, for a period of 78
C. Dasenbrock / Toxicology and Applied Pharmacology 207 (2005) S342 – S346
weeks. One rf group was exposed to a continuous NMTtype frequency-modulated 902.5 MHz signal, the other to a pulsed (217 Hz) GSM signal at 902.4 MHz. The data based on a peer-reviewed histopathological examination of all major tissues did not show an enhancing effect of low-level rf radiation on tumorigenesis initiated by X-radiation. On the other hand, the (4 Gy) X-radiation itself resulted in an increased (24%) lymphoma incidence compared to less than 2% in the cage controls. In another model, Heikkinen et al. (2003) evaluated the effects of low-level rf radiation on UV-induced skin tumorigenesis in female ODC and in non-transgenic mice. Mice of the line K2 overexpressing the human ODC gene and their non-transgenic littermates were exposed, beginning in week 12 – 15, for 52 weeks to UV radiation or a combination of UV and pulsed rf radiation (0.5 W/kg SAR [whole body]). Three times a week, the UV dose (240 Jm 2, i.e. 1.2 human minimal erythema dose), and 5 days/week for 1.5 h/day, the 849 MHz pulsed DAMPS- or the 902.4 MHz pulsed GSM-type rf radiation or sham restraint were applied to 45 –49 mice per group. The (non-treated) cage control group consisted of 20 animals. The UV exposure led to macroscopic skin tumors in 11.5 and 36.8% of non-transgenic and transgenic mice, respectively. Overall, the rf exposures did not significantly enhance skin tumorigenesis. Finally and within the European project CEMFEC, the same research group co-exposed female Wistar rats to the mutagen/carcinogen MX via drinking water (19 Ag/ml) and rf-radiated the rats at two different [whole body] SAR levels of 0.3 and 0.9 W/kg. 72 non-restrained rats per group were sham- or rf-exposed for 2 h/day, 5 days/week, during 104 weeks to a 902.4 MHz GSM signal (217 Hz pulsed). A 4th group of 72 female rats served as cage control. The results will be published soon (Heikkinen et al., 2004, in preparation).
Conclusion Under the described experimental circumstances and with the shortcomings listed below, the animal cancer studies reviewed and published until now did not show a significant tumor-promoting or co-carcinogenic effect due to mobile phone-relevant rf radiation. The only exception was Repacholi’s study of 1997. Most of these studies, however, lack on several of the following points: (a) one exposure level (‘‘dose’’) only, (b) no justification for the selected rf dose(s), (c) inaccurate dosimetry, e.g., for growing animals, (d) no justification for the group size chosen and missing power analysis, (e) missing data on microbiological/parasitological animal health (e.g., FELASA, 2002), (f) no standardized tumor nomenclature and/or no peer review or PWG on histopathological diagnoses and (g) the DMBA mammary tumor model did not give reproducible tumor responses.
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By contrast and according to international testing guidelines for chemicals and pharmaceuticals, the ongoing studies of PERFORM-A as well as the initiated US studies involve 3 dose groups, are run under GLP conditions and are blinded. If technically feasible, the highest dose group is just below a thermal rf effect to the animals. Furthermore, these studies as well as the CEMFEC study use a standardized tumor terminology, e.g., the WHO/IARC nomenclature (IARC/WHO, 1992– 1997, WHO, 2001). Nevertheless, the International Agency for Research on Cancer (IARC) of the WHO is planning to schedule its monograph evaluation on cancer effects of radiofrequency related to mobile phones and base stations in October 2005.
References Adey, W.R., Byus, C.V., Cain, C.D., Higgins, R.J., Jones, R.A., Kean, C.J., Kuster, N., MacMurray, A., Stagg, R.B., Zimmerman, G., Phillips, J.L., Haggren, W., 1999. Spontaneous and nitosoureainduced primary tumors of the central nervous system in Fischer 344 rats chronically exposed to 836 MHz modulated microwaves. Radiat. Res. 152, 293 – 302. Adey, W.R., Byus, C.V., Cain, C.D., Higgins, R.J., Jones, R.A., Kean, C.J., Kuster, N., MacMurray, A., Stagg, R.B., Zimmerman, G., 2000. Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats exposed to frequency-modulated microwave fields. Cancer Res. 60, 1857 – 1863. Anane, R., Dulou, P.E., Taxile, M., Geffard, M., Crespeau, F.L., Veyret, B., 2003. Effects of GSM-900 microwaves on DMBA-induced mammary gland tumors in female Sprague – Dawley rats. Radiat. Res. 160, 492 – 497. Bartsch, H., Bartsch, C., Seebald, E., Deerberg, F., Dietz, K., Vollrath, L., Mecke, D., 2002. Chronic exposure to a GSM-like signal (mobile phone) does not stimulate the development of DMBA-induced mammary tumors in rats: results of three consecutive studies. Radiat. Res. 157, 183 – 190. Bitz, A., Boekelmann, V., Gerhardt, D., Hansen, V., Hombach, V., Streckert, J., Ndoumbe` Mbonjo Mbonjo, H., 2004. A generic UMTS test signal for bio-experiments. 5th International Congress of the European BioElectromagnetics Association (EBEA), Helsinki, Finland, September 2001, pp. 173 – 174. Dasenbrock, C., Hruby, R., Oberto, G., Smith, P., Kuster, N., 2003. Status of PERFORM-A: co- and carcinogenicity studies in rodents on radiofrequency related to mobile telephones and base stations. Abstract P-090. 6th International Congress of the European Bioelectromagnetic Association (EBEA), 13 – 15 November 2003, Budapest, p. 212. FELASA—Federation of European Laboratory Animal Science Association, 2002. Laboratory animals. Recommendations for the Health Monitoring of Rodent and Rabbit Colonies in Breeding and Experimentals Units, vol. 36, pp. 20 – 42. Froelich, J., Kainz, W., Ebert, S., Neubauer, G., Kuster, N., 2001. Exposure setups for simultaneous exposure of a large number of rats for risk assessment studies at the mobile communication frequencies 902 MHz and 1747 MHz. Proceedings of 5th International congress of the European Bioelectromagnetics Association (EBEA), 6 – 8 September 2001, Helsinki, p. 69. ISBN: 951-802-440-5. Goerlitz, B., Mueller, M., Ebert, S., Hecker, H., Kuster, N., Dasenbrock, C., in press. Effects of 1-week and 6-week GSM/DCS radiofrequency exposure on micronucleus formation in B6C3F1 mice. Radiat. Res. Heikkinen, P., Kosma, V.M., Hongisto, T., Huuskonen, H., Hyysalo, P., Komulainen, H., Kumlin, T., Lahtinen, T., Lang, S., Puranen, L.,
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Juutilainen, J., 2001. Effects of mobile phone radiation on X-rayinduced tumorigenesis in mice. Radiat. Res. 156, 775 – 785. Heikkinen, P., Kosma, V.M., Alhonen, L., Huuskonen, H., Komulainen, H., Kumlin, T., Laitinen, J.T., Lang, S., Puranen, L., Juutilainen, J., 2003. Effects of mobile phone radiation on UV-induced skin tumourigenesis in ornithine decarboxylase transgenic and non-transgenic mice. Int. J. Radiat. Biol. 79, 221 – 233. IARC/WHO, 1992 – 1997. International Classification of Rodent Tumours: Part I. The Rat. In: Mohr, U. (Ed.), IARC, Lyon. Sci Publ no. 122. Imaida, K., Taki, M., Yamaguchi, T., Ito, T., Watanabe, S., Wake, K., Aimoto, A., Kamimura, Y., Ito, N., Shirai, T., 1998a. Lack of promoting effects of the electromagnetic near-field used for cellular phones (929.2 MHz) on rat liver carcinogenesis in a medium-term liver bioassay. Carcinogenesis 19, 311 – 314. Imaida, K., Taki, M., Watanabe, S., Kamimura, Y., Ito, T., Yamaguchi, T., Ito, N., Shirai, T., 1998b. The 1.5 GHz electromagnetic near-field used for cellular phones does not promote rat liver carcinogenesis in a medium-term liver bioassay. Jpn. J. Cancer Res. 89, 995 – 1002. Imaida, K., Kuzutani, K., Wang, J., Fujiwara, O., Ogiso, T., Kato, K., Shirai, T., 2001. Lack of promotion of 7,12-dimethylbenz[a]anthraceneinitiated mouse skin carcinogenesis by 1.5 GHz electromagnetic near fields. Carcinogenesis 22, 1837 – 1841. Juutilainen, J., Lang, S., Ryto¨maa, T., 2000. Possible cocarcinogenic effects of ELF electromagnetic fields may require repeated long-term interaction with known carcinogenic factors. Bioelectromagnetics 21, 122 – 128. Ladbury, J.M., Wilson, P.F., Koepke, G.H., Lammers, T., 2003. Reverberation chamber: an evaluation for possible use as a rf exposure system for animal studies. Abstract 15-6 of the 25th Bioelectromagnetics Society Annual Meeting, June 22 – 27, 2003, Wailea, Maui, Hawaii; Abstract Book, pp. 150 – 151. La Regina, M., Moros, E.G., Pickard, W.F., Straube, W.L., Baty, J., Roti Roti, J.L., 2003. The effect of chronic exposure to 835.62 MHz FDMA or 847.74 MHz CDMA radiofrequency radiation on the incidence of spontaneous tumors in rats. Radiat. Res. 160, 143 – 151. Melnick, R.L., Bucher, J.R., Roycroft, J.H., Portier, C.J., Wilson, P.F., 2003. Health effects of cell phone radio frequency radiation: National Toxicology Program’s carcinogenicity studies in rats and mice. Abstract 15-7 of the 25th Bioelectromagnetics Society Annual Meeting, June 22 – 27, 2003, Wailea, Maui, Hawaii; Abstract Book, p. 152. Ndoumbe` Mbonjo Mbonjo, H., Streckert, J., Bitz, A., Hansen, V., Glasmachers, A., Gencol, S., Rozic, D., 2004. A generic UMTS test signal for RF bio-electromagnetic studies. Bioelectromagnetics 25, 415 – 425. Nikoloski, N., Kainz, W., Frauscher, M., Froehlich, J., Kuster, N., 2002. Exposure setups for simultaneous exposure of 17 rats for risk assessment studies at 902 MHz and 1747 MHz. Abstract 16-1 of the 24th
Bioelectromagnetics Society Annual Meeting, June 23 – 27, 2002, Quebec; Abstract Book, 108 – 109. Repacholi, M.H., Basten, A., Gebski, V., Noonan, D., Finnie, J., Harris, A.W., 1997. Lymphomas in EA-Pim1 transgenic mice exposed to pulsed 900 MHz electromagnetic fields. Radiat. Res. 147, 631 – 640. Sommer, A.M., Streckert, J., Bitz, A.K., Hansen, V.W., Lerchl, A., 2004. No effects of GSM-modulated 900 MHz electromagnetic fields on survival rate and spontaneous development of lymphoma in female AKR/J mice. BMC Cancer 4, 77. Utteridge, T.D., Gebski, V., Finnie, J.W., Vernon-Roberts, B., Kuchel, T.R., 2002. Long-term exposure of E-mu-Pim1 transgenic mice to 898.4 MHz microwaves does not increase lymphoma incidence. Radiat. Res. 158, 357 – 364. Utteridge, T.D., Gebski, V., Finnie, J.W., Vernon-Roberts, B., Kuchel, T.R., 2003. Response to the letters to the Editor sent by (1) Kundi, (2) Goldstein/Kheifets/van Deventer/Repacholi, and (3) Lerchl. Radiat. Res. 159, 276 – 278. WHO (World Health Organization), IARC International Agency for Research on Cancer, 2001. International classification of rodent tumors. In: Mohr, U. (Ed.), The Mouse. Springer Verlag, Heidelberg. Zook, B.C., Simmens, S.J., 2001. The effects of 860 MHz radiofrequency radiation on the induction or promotion of brain tumors and other neoplasms in rats. Radiat. Res. 155, 572 – 583
Studies in progress Chiang et al., in progress. Effects on DMBA-induced mammary tumours in rats by 6-month exposure to 902 MHz GSM wireless communication signals. Dasenbrock, C., et al., in progress. Carcinogenicity studies of 900 MHz GSM and 1800 MHz DCS wireless communication signals in B6C3F1 mice. Heikkinen, P., et al., in progress. Effects of radiofrequency radiation on 3chloro-4(dichlormethyl)-5-hydroxy-2(5H)-furanone (MX)-induced tumourigenesis in Wistar rats. Hruby, R., et al., in progress. 902 MHz GSM wireless communication signals: Effects on DMBA-induced mammary tumours in rats. NIEHS/NTP, in progress. Health effects of cell phone radio frequency radiation: National Toxicology Program’s carcinogenicity studies in rats and mice. Oberto, G., et al., in progress. Lymphoma induction and carcinogenicity study in pim 1 transgenic mice exposed to pulsed 900 MHz electromagnetic fields. Smith, P., et al., in progress. 902 MHz GSM and 1747 MHz DCS wireless communication signals: combined chronic toxicity/carcinogenicity study in the Wistar rat.
Review
Animal carcinogenicity studies on radiofrequency fields related to mobile phones and base stations Clemens Dasenbrock* Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany Received 21 July 2004; revised 20 April 2005; accepted 20 April 2005 Available online 21 July 2005
Abstract Since a report in 1997 on an increased lymphoma incidence in mice chronically exposed to a mobile phone radiofrequency signal, none of the subsequent long-term studies in rodents have confirmed these results. On the other hand, several of the follow-up co- and carcinogenicity studies are still underway or are presently being initiated. Most of the published long-term studies used 1 exposure level only and suffer from a poor dosimetry which does not consider the animal’s growth. Additional points of criticism are a limited, in some cases, questionable histopathology and inadequate group sizes. Overall, if dealing with new chemicals or drugs, these studies would not be acceptable for registration with the responsible authorities. The major critical points are taken into consideration within the European co- and carcinogenicity projects (CEMFEC and PERFORM-A), which are in their final stages and in the US long-term studies in mice and rats which are about to be initiated. Nevertheless, the WHO evaluation for health risk assessment of long-term telephone use and base station exposure will start in late 2005. D 2005 Elsevier Inc. All rights reserved. Keywords: Radiofrequency; Mobile phones; Cancer; Animal studies
Contents Introduction . . . . Cancer studies . . . Initiation promotion Conclusion . . . . . References . . . . . Studies in progress.
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Abbreviations: CDMA, code division multiple access; CEMFEC, Acronym of the European project ‘‘Combined effects of electromagnetic fields with environmental carcinogens’’; CNS, central nervous system; DAMPS, digital advanced mobile phone systems; DCS, digital personal communications system; European, standard for digital mobile phone technology at 1800 MHz; DEN, diethylnitrosamine; DMBA, 7,12-dimethylbenz[a]anthracene; EMF, electromagnetic field; ENU, ethylnitrosourea; FDMA, frequency division multiple access; GLP, good laboratory practice according to national and OECD principles; GSM, global system for mobile communication; European, standard for cell phone systems; Gy, Gray; MHz, megahertz; MX, 3-chloro-4(dichloromethyl)-5-hydroxy-2(5H)-furanone; NADC, North American digital cellular; NIEHS/NTP, National Institute of Environmental Health Sciences/ National toxicology program; NMT, Nordic mobile telephones; ODC, ornithine decarboxylase; PERFORM-A, Acronym of the European project ‘‘In vivo research on possible health effects related to mobile telephones and base stations (carcinogenicity studies in rodents)’’; RF, radio frequency; SAR, specific absorption rate; TDMA, time division multiple access; TPA, 12-O-tetradecanoylphorbol-13-acetate; UMTS, universal mobile telecommunication system; UV, ultraviolet. * Present address: Boehringer-Ingelheim Pharma GmbH and Co.KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany. E-mail address: [email protected]. 0041-008X/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2005.04.032
YTAAP-10374; No. of pages: 5; 4C:
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Introduction After Repacholi et al. in 1997 observed a 2.4-fold lymphoma increase in transgenic pim1 mice chronically exposed to a GSM signal, several long-term studies related to mobile telephony were initiated. These studies have addressed either a possible direct tumor incidence-increasing effect or/and a tumor-promoting/co-carcinogenic effect of radiofrequency (rf). The following criteria were met by the reviewed studies discussed in this presentation: & long-term exposure to an rf signal related to mobile telephony, & co- or carcinogenesis including tumor promotion as study endpoint, and, if applicable, & publication in a peer-reviewed journal. Firstly, cancer studies will be discussed. The studies involve experiments without any pre-treatment of the animals; transgenic mice are included. All animals were long-term rf-exposed for 1.5 to 2 years and for minimum of 1 h per day, 4 – 7 days per week. Secondly, in initiation promotion and co-carcinogenicity studies before exposure to the rf signal(s), the animals usually were administered a (strong) carcinogen, e.g., 7,12dimethylbenz[a]anthracene (DMBA), diethylnitrosamine (DEN) or ethylnitrosourea (ENU), as a tumor-initiating chemical and were subsequently rf-exposed for several weeks or months. Other investigators in their co-carcinogenicity studies (Juutilainen et al., 2000) preferred simultaneous exposure to a carcinogen, e.g., MX, ionizing or UV radiation, and to the (non-ionizing) rf.
Cancer studies In the most quoted study, Repacholi et al. (1997) found a significant (2.4-fold) increase in lymphomas in female pim1 transgenic mice after 18 months (2 30 min/day) of exposure to a modulated 900 MHz GSM signal. In a far field, only one exposure level (‘‘dose’’) with a large variation (0.008 – 4.2 W/kg SAR [whole body]) was used for the non-restrained mice. Due to further shortcomings of the study, two re-evaluation studies were started. At first, Utteridge et al. (2002, 2003) could not confirm Repacholi’s results. Again, a modulated GSM signal (898.4 MHz, 217 Hz pulse, 0.6 ms pulse width) was used for exposure in a ‘‘ferris-wheel’’ system. Female heterozygous pim1 transgenic (lymphoma-prone) and wild-type mice (n = 120 per group) were rf-radiated in restrainer tubes for 1 h/day, 5 days/week during 24 months at 4 different SAR [whole body] levels of 0, 0.25, 1.0, 2.0 and 4.0 W/kg. In addition, a positive control treated with 50 mg/kg ENU and a nonrestrained cage control group were included in the study.
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Overall, there was no lymphoma increase in the rf-radiated groups of the various SAR levels. Secondly, at Serono-RBM, Ivrea, Italy, male and female pim1 transgenic mice were exposed to a modulated GSM signal (902 MHz, 217 Hz pulse, 0.5 ms pulse width). The study is part of the European project PERFORM-A (Dasenbrock et al., 2003), was blinded and run under GLP conditions. In a ferris-wheel system (Goerlitz et al., in press), tube-restrained mice (n = 50/group/sex) were rf-radiated for 1 h/day, 7 days/week, up to 18 months, at SAR levels [whole body] of 0, 0.5, 1.4, 4.0 W/kg. The draft report of this study is almost finalized (Oberto et al., in progress). Supplementary to the above experiments, Sommer et al. (submitted for publication) studied in female mice of the (high-leukemia) inbred strain AKR the long-term influence of a 9-month continuous rf exposure at 0.4 W/kg SAR [whole-body] to a GSM signal (890 MHz modulated). In a radial waveguide system, 168 females were sham- and 168 rf-radiated in their cages (7 mice per cage). No increase in the incidence of leukemia and lymphomas was detected, but only 1 ‘‘dose’’ was applied. Recently, the same group started an identical experiment testing the long-term rf radiation (1966 MHz modulated) at 0.4 W/kg SAR [whole body] using a generic UMTS test signal for bio-experiments (Bitz et al., 2004; Ndoumbe` Mbonjo Mbonjo et al., in press). The in-life phase is still in progress. La Regina et al. (2003) tube-exposed F344 rats in carousel systems for 4 h/day, 5 days/week during 24 months. Two different rf radiations (835.62 MHz FDMA, 847.74 MHz CDMA) at one brain SAR level of 1.3 T 0.5 W/kg each were applied to the animals. Each group (2 rf and 1 sham) consisted of 160 rats (80/80). No significant differences between treated and sham-exposed animals were found regarding any brain tumor and a number of non-CNS tumors. In two NTP-like carcinogenicity studies at the Fraunhofer ITEM, Hannover, Germany, in a ferris-wheel system (Goerlitz et al., in press), tube-restrained B6C3F1 mice were exposed for 24 months, 5 days/week, 2 h/day to a GSM signal cocktail at 902 MHz or to a DCS signal cocktail at 1747 MHz. One sham control and three rf groups (target SAR [whole body]): 0, 0.4, 1.3, 4.0 W/kg) per signal were complemented by one cage control group (n = 65/group/sex). This GLP study is also blinded and part of PERFORM-A, results will be available in spring 2005 (Dasenbrock et al., 2003, in progress). A further two identical NTP-like blinded GLP studies using Wistar rats were initiated within PERFORM-A at RCC Ltd., Itingen, Switzerland. A new ferris-wheel system was used (Froelich et al., 2001; Nikoloski et al., 2002). Again, rats of one sham control and three rf groups (target SAR [whole body]): 0, 0.3, 1.4, 4.0 W/kg) per signal (n = 65/group/sex) were exposed in restrainer tubes for 24 months, 5 days/week, 2 h/day to a GSM signal cocktail at 902 MHz or to a DCS signal cocktail at 1747 MHz; one cage control group was also included. Results will be
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available in late summer 2005 (Smith et al., in progress; Dasenbrock et al., 2003). Further long-term studies on a possible carcinogenic effect of rf signals as emitted by base stations are about to be initiated in the USA. Under the co-ordination of the NIEHS/ NTP program, unrestrained and individually caged B6C3F1 mice and Sprague –Dawley rats shall be exposed to 900 MHz GSM and 1900 MHz CDMA modulated signals (Melnick et al., 2003). It is planned to use ‘‘reverberation chambers’’ (Ladbury et al., 2003) for a 20-h intermittent rf exposure per day, 5 days/week, during 110 weeks. Exposure(s) will be started on gestation day 6, and after prestudies, three rf ‘‘doses’’ and 1 sham per signal will be used.
Initiation promotion and co-carcinogenicity studies Imaida et al. (1998a,b) rf-irradiated male F344 rats which had been pre-treated with 200 mg/kg DEN i.p. and subjected to subsequent 2/3 partial hepatectomy. After one further week of recovery, the restrained rats (n = 48/group) were sham- or rf-exposed for 90 min/day, 5 days/week, over 6 weeks to a pulse-modulated (a) 929.2 MHz or (b) 1.439 GHz EM near-field (SAR [liver]: (a) 2.0 –1.7 W/kg or (b) 1.9 –0.9 W/kg). The occurrence of pre-neoplastic liver cell foci was tested. The local body exposure to these two EMFs had no promoting effect on rat liver carcinogenesis in the described model. Only one rf ‘‘dose’’ was used though. Furthermore, Imaida et al. (2001) tested the influence of a 90 min/day, 5 days/week, 19 weeks lasting rf exposure to pulsed 1.49 GHz TDMA signals on DMBA-initiated skin cancer in ICR female mice. The skin local peak-specific SAR was 2.0 W/kg, the whole body average SAR was 0.084 W/kg. One restrained sham and one rf radiation group (n = 48 each) were complemented by a positive (TPA promotion) and a cage control group (n = 30 each). The 1.5 GHz near field exposure revealed no promoting influence on skin cancer. Adey et al. (1999) discovered that NADC signals (836.55 MHz TDMA modulation) had a ‘‘tumor-protective effect’’ on spontaneous and ENU-induced tumors of the CNS in rats. The on gestation day 18 in utero ENU-treated offspring of F344 rats was head-only tube-exposed in carousel systems for 2 h/day, 4 days/week, during 22 months. Only one brain SAR level of 0.7– 1.6 W/kg was tested in ENU- and sham-pre-treated rats (n = 30/sex/group). The same research group (Adey et al., 2000) repeated the experiment with a frequency-modulated 836.55 MHz signal (‘‘balanced speech’’) and increased group sizes (n = 45/sex/ group). Again, solely one (brain) SAR level (1.0 –1.2 W/kg) was tested. The ‘‘tumor-protective effect’’ could not be replicated. While an extensive histopathology of the brain was done, unfortunately, only tumors of the CNS were investigated. A comparable series of experiments was published by Zook and Simmens (2001). Again, in utero ENU-treated
offspring of Sprague – Dawley rats was head-only tubeexposed in carousel systems for 6 h/day, 4 days/week, during 22 months. Two different doses of ENU (2.5 and 10 mg/kg bw) were administered on gestation day 15 to the pregnant females, and 860 MHz pulsed as well as continuous wave rf signals (one SAR level of 1.0 W/kg each) were applied to the offspring beginning in week 8. In contrast to the experiments of Adey et al. (1999, 2000), cage control groups were added. Per group, 60 rats each (30 males + 30 females) were used. The rf exposure did not promote the malignancy of brain tumors, and the limited histopathology performed on other organs did not reveal different tumor incidences in rf-radiated than in sham groups. Bartsch et al. (2002) chronically exposed DMBAinduced mammary tumor-bearing rats to a (217 Hz) pulsed 900 MHz GSM signal. For mammary tumor induction, female Sprague – Dawley rats (Hsd: SD) received a single intragastric dose of 8.75 mg/100 g bw on day 51. On the same day, rf exposure started (23 h/day, 7 days/week; 8.5– 11 months). Over 3 years, 3 identical experiments with group-housed rats (12 females per cage, n = 60 per sham and rf group each) were run. The young 150 g animals at the beginning of each experiment exhibited SARs [whole body] between 32.5 and 130 mW/kg, older 400 g rats, aged 11 months, between 15 and 60 mW/kg. Overall, there was no statistically significant effect of rf field exposure on (mammary) tumor latency and cumulative tumor incidence. Using a similar 900 MHz GSM signal and the same model but another source of Sprague – Dawley rats (Ico:OFA-SD), Anane et al. (2003) also reported negative results in terms of latency, multiplicity and tumor volume. The group size of 16 females, however, was low. Further differences were not only one, but 5 SARs (0.1, 0.7, 1.4, 2.2, 3.5 W/kg) tested in DMBA-induced (10 mg/rat) mammary tumor-bearing rats which were restrained during the daily 2-h exposure for only 9 weeks. Within the fourth partial project of PERFORM-A, the ARC, Seibersdorf, Austria, investigated possible effects of rf radiation (900 MHz GSM, 217 Hz pulsed) on mammary tumors induced on day 47 by 17 mg/kg DMBA. 100 females per group were sham- or rf-exposed to 0, 0.34, 1.43 and 4 W/kg (target SAR [whole body]) in a new ferriswheel system (Froelich et al., 2001; Nikoloski et al., 2002); one cage control group was also included. Results will be available by the beginning of 2005 (Hruby et al., in progress; Dasenbrock et al., 2003). In addition, an identical study was performed in Zhejang, China. Results should be available soon (Chiang et al., in progress). Heikkinen et al. (2001) examined the combined effect of ionizing and rf radiation in mice. They X-radiated female CBA/S mice with 4 Gy (1.33 Gy/week during 3 weeks) and simultaneously started rf exposure (0.35 W/kg SAR [whole body]). 50 females per group were used as cage controls (without any radiation) or restrained and sham- or rfradiated for 1.5 h/day, 5 days/week, for a period of 78
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weeks. One rf group was exposed to a continuous NMTtype frequency-modulated 902.5 MHz signal, the other to a pulsed (217 Hz) GSM signal at 902.4 MHz. The data based on a peer-reviewed histopathological examination of all major tissues did not show an enhancing effect of low-level rf radiation on tumorigenesis initiated by X-radiation. On the other hand, the (4 Gy) X-radiation itself resulted in an increased (24%) lymphoma incidence compared to less than 2% in the cage controls. In another model, Heikkinen et al. (2003) evaluated the effects of low-level rf radiation on UV-induced skin tumorigenesis in female ODC and in non-transgenic mice. Mice of the line K2 overexpressing the human ODC gene and their non-transgenic littermates were exposed, beginning in week 12 – 15, for 52 weeks to UV radiation or a combination of UV and pulsed rf radiation (0.5 W/kg SAR [whole body]). Three times a week, the UV dose (240 Jm 2, i.e. 1.2 human minimal erythema dose), and 5 days/week for 1.5 h/day, the 849 MHz pulsed DAMPS- or the 902.4 MHz pulsed GSM-type rf radiation or sham restraint were applied to 45 –49 mice per group. The (non-treated) cage control group consisted of 20 animals. The UV exposure led to macroscopic skin tumors in 11.5 and 36.8% of non-transgenic and transgenic mice, respectively. Overall, the rf exposures did not significantly enhance skin tumorigenesis. Finally and within the European project CEMFEC, the same research group co-exposed female Wistar rats to the mutagen/carcinogen MX via drinking water (19 Ag/ml) and rf-radiated the rats at two different [whole body] SAR levels of 0.3 and 0.9 W/kg. 72 non-restrained rats per group were sham- or rf-exposed for 2 h/day, 5 days/week, during 104 weeks to a 902.4 MHz GSM signal (217 Hz pulsed). A 4th group of 72 female rats served as cage control. The results will be published soon (Heikkinen et al., 2004, in preparation).
Conclusion Under the described experimental circumstances and with the shortcomings listed below, the animal cancer studies reviewed and published until now did not show a significant tumor-promoting or co-carcinogenic effect due to mobile phone-relevant rf radiation. The only exception was Repacholi’s study of 1997. Most of these studies, however, lack on several of the following points: (a) one exposure level (‘‘dose’’) only, (b) no justification for the selected rf dose(s), (c) inaccurate dosimetry, e.g., for growing animals, (d) no justification for the group size chosen and missing power analysis, (e) missing data on microbiological/parasitological animal health (e.g., FELASA, 2002), (f) no standardized tumor nomenclature and/or no peer review or PWG on histopathological diagnoses and (g) the DMBA mammary tumor model did not give reproducible tumor responses.
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By contrast and according to international testing guidelines for chemicals and pharmaceuticals, the ongoing studies of PERFORM-A as well as the initiated US studies involve 3 dose groups, are run under GLP conditions and are blinded. If technically feasible, the highest dose group is just below a thermal rf effect to the animals. Furthermore, these studies as well as the CEMFEC study use a standardized tumor terminology, e.g., the WHO/IARC nomenclature (IARC/WHO, 1992– 1997, WHO, 2001). Nevertheless, the International Agency for Research on Cancer (IARC) of the WHO is planning to schedule its monograph evaluation on cancer effects of radiofrequency related to mobile phones and base stations in October 2005.
References Adey, W.R., Byus, C.V., Cain, C.D., Higgins, R.J., Jones, R.A., Kean, C.J., Kuster, N., MacMurray, A., Stagg, R.B., Zimmerman, G., Phillips, J.L., Haggren, W., 1999. Spontaneous and nitosoureainduced primary tumors of the central nervous system in Fischer 344 rats chronically exposed to 836 MHz modulated microwaves. Radiat. Res. 152, 293 – 302. Adey, W.R., Byus, C.V., Cain, C.D., Higgins, R.J., Jones, R.A., Kean, C.J., Kuster, N., MacMurray, A., Stagg, R.B., Zimmerman, G., 2000. Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats exposed to frequency-modulated microwave fields. Cancer Res. 60, 1857 – 1863. Anane, R., Dulou, P.E., Taxile, M., Geffard, M., Crespeau, F.L., Veyret, B., 2003. Effects of GSM-900 microwaves on DMBA-induced mammary gland tumors in female Sprague – Dawley rats. Radiat. Res. 160, 492 – 497. Bartsch, H., Bartsch, C., Seebald, E., Deerberg, F., Dietz, K., Vollrath, L., Mecke, D., 2002. Chronic exposure to a GSM-like signal (mobile phone) does not stimulate the development of DMBA-induced mammary tumors in rats: results of three consecutive studies. Radiat. Res. 157, 183 – 190. Bitz, A., Boekelmann, V., Gerhardt, D., Hansen, V., Hombach, V., Streckert, J., Ndoumbe` Mbonjo Mbonjo, H., 2004. A generic UMTS test signal for bio-experiments. 5th International Congress of the European BioElectromagnetics Association (EBEA), Helsinki, Finland, September 2001, pp. 173 – 174. Dasenbrock, C., Hruby, R., Oberto, G., Smith, P., Kuster, N., 2003. Status of PERFORM-A: co- and carcinogenicity studies in rodents on radiofrequency related to mobile telephones and base stations. Abstract P-090. 6th International Congress of the European Bioelectromagnetic Association (EBEA), 13 – 15 November 2003, Budapest, p. 212. FELASA—Federation of European Laboratory Animal Science Association, 2002. Laboratory animals. Recommendations for the Health Monitoring of Rodent and Rabbit Colonies in Breeding and Experimentals Units, vol. 36, pp. 20 – 42. Froelich, J., Kainz, W., Ebert, S., Neubauer, G., Kuster, N., 2001. Exposure setups for simultaneous exposure of a large number of rats for risk assessment studies at the mobile communication frequencies 902 MHz and 1747 MHz. Proceedings of 5th International congress of the European Bioelectromagnetics Association (EBEA), 6 – 8 September 2001, Helsinki, p. 69. ISBN: 951-802-440-5. Goerlitz, B., Mueller, M., Ebert, S., Hecker, H., Kuster, N., Dasenbrock, C., in press. Effects of 1-week and 6-week GSM/DCS radiofrequency exposure on micronucleus formation in B6C3F1 mice. Radiat. Res. Heikkinen, P., Kosma, V.M., Hongisto, T., Huuskonen, H., Hyysalo, P., Komulainen, H., Kumlin, T., Lahtinen, T., Lang, S., Puranen, L.,
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Juutilainen, J., 2001. Effects of mobile phone radiation on X-rayinduced tumorigenesis in mice. Radiat. Res. 156, 775 – 785. Heikkinen, P., Kosma, V.M., Alhonen, L., Huuskonen, H., Komulainen, H., Kumlin, T., Laitinen, J.T., Lang, S., Puranen, L., Juutilainen, J., 2003. Effects of mobile phone radiation on UV-induced skin tumourigenesis in ornithine decarboxylase transgenic and non-transgenic mice. Int. J. Radiat. Biol. 79, 221 – 233. IARC/WHO, 1992 – 1997. International Classification of Rodent Tumours: Part I. The Rat. In: Mohr, U. (Ed.), IARC, Lyon. Sci Publ no. 122. Imaida, K., Taki, M., Yamaguchi, T., Ito, T., Watanabe, S., Wake, K., Aimoto, A., Kamimura, Y., Ito, N., Shirai, T., 1998a. Lack of promoting effects of the electromagnetic near-field used for cellular phones (929.2 MHz) on rat liver carcinogenesis in a medium-term liver bioassay. Carcinogenesis 19, 311 – 314. Imaida, K., Taki, M., Watanabe, S., Kamimura, Y., Ito, T., Yamaguchi, T., Ito, N., Shirai, T., 1998b. The 1.5 GHz electromagnetic near-field used for cellular phones does not promote rat liver carcinogenesis in a medium-term liver bioassay. Jpn. J. Cancer Res. 89, 995 – 1002. Imaida, K., Kuzutani, K., Wang, J., Fujiwara, O., Ogiso, T., Kato, K., Shirai, T., 2001. Lack of promotion of 7,12-dimethylbenz[a]anthraceneinitiated mouse skin carcinogenesis by 1.5 GHz electromagnetic near fields. Carcinogenesis 22, 1837 – 1841. Juutilainen, J., Lang, S., Ryto¨maa, T., 2000. Possible cocarcinogenic effects of ELF electromagnetic fields may require repeated long-term interaction with known carcinogenic factors. Bioelectromagnetics 21, 122 – 128. Ladbury, J.M., Wilson, P.F., Koepke, G.H., Lammers, T., 2003. Reverberation chamber: an evaluation for possible use as a rf exposure system for animal studies. Abstract 15-6 of the 25th Bioelectromagnetics Society Annual Meeting, June 22 – 27, 2003, Wailea, Maui, Hawaii; Abstract Book, pp. 150 – 151. La Regina, M., Moros, E.G., Pickard, W.F., Straube, W.L., Baty, J., Roti Roti, J.L., 2003. The effect of chronic exposure to 835.62 MHz FDMA or 847.74 MHz CDMA radiofrequency radiation on the incidence of spontaneous tumors in rats. Radiat. Res. 160, 143 – 151. Melnick, R.L., Bucher, J.R., Roycroft, J.H., Portier, C.J., Wilson, P.F., 2003. Health effects of cell phone radio frequency radiation: National Toxicology Program’s carcinogenicity studies in rats and mice. Abstract 15-7 of the 25th Bioelectromagnetics Society Annual Meeting, June 22 – 27, 2003, Wailea, Maui, Hawaii; Abstract Book, p. 152. Ndoumbe` Mbonjo Mbonjo, H., Streckert, J., Bitz, A., Hansen, V., Glasmachers, A., Gencol, S., Rozic, D., 2004. A generic UMTS test signal for RF bio-electromagnetic studies. Bioelectromagnetics 25, 415 – 425. Nikoloski, N., Kainz, W., Frauscher, M., Froehlich, J., Kuster, N., 2002. Exposure setups for simultaneous exposure of 17 rats for risk assessment studies at 902 MHz and 1747 MHz. Abstract 16-1 of the 24th
Bioelectromagnetics Society Annual Meeting, June 23 – 27, 2002, Quebec; Abstract Book, 108 – 109. Repacholi, M.H., Basten, A., Gebski, V., Noonan, D., Finnie, J., Harris, A.W., 1997. Lymphomas in EA-Pim1 transgenic mice exposed to pulsed 900 MHz electromagnetic fields. Radiat. Res. 147, 631 – 640. Sommer, A.M., Streckert, J., Bitz, A.K., Hansen, V.W., Lerchl, A., 2004. No effects of GSM-modulated 900 MHz electromagnetic fields on survival rate and spontaneous development of lymphoma in female AKR/J mice. BMC Cancer 4, 77. Utteridge, T.D., Gebski, V., Finnie, J.W., Vernon-Roberts, B., Kuchel, T.R., 2002. Long-term exposure of E-mu-Pim1 transgenic mice to 898.4 MHz microwaves does not increase lymphoma incidence. Radiat. Res. 158, 357 – 364. Utteridge, T.D., Gebski, V., Finnie, J.W., Vernon-Roberts, B., Kuchel, T.R., 2003. Response to the letters to the Editor sent by (1) Kundi, (2) Goldstein/Kheifets/van Deventer/Repacholi, and (3) Lerchl. Radiat. Res. 159, 276 – 278. WHO (World Health Organization), IARC International Agency for Research on Cancer, 2001. International classification of rodent tumors. In: Mohr, U. (Ed.), The Mouse. Springer Verlag, Heidelberg. Zook, B.C., Simmens, S.J., 2001. The effects of 860 MHz radiofrequency radiation on the induction or promotion of brain tumors and other neoplasms in rats. Radiat. Res. 155, 572 – 583
Studies in progress Chiang et al., in progress. Effects on DMBA-induced mammary tumours in rats by 6-month exposure to 902 MHz GSM wireless communication signals. Dasenbrock, C., et al., in progress. Carcinogenicity studies of 900 MHz GSM and 1800 MHz DCS wireless communication signals in B6C3F1 mice. Heikkinen, P., et al., in progress. Effects of radiofrequency radiation on 3chloro-4(dichlormethyl)-5-hydroxy-2(5H)-furanone (MX)-induced tumourigenesis in Wistar rats. Hruby, R., et al., in progress. 902 MHz GSM wireless communication signals: Effects on DMBA-induced mammary tumours in rats. NIEHS/NTP, in progress. Health effects of cell phone radio frequency radiation: National Toxicology Program’s carcinogenicity studies in rats and mice. Oberto, G., et al., in progress. Lymphoma induction and carcinogenicity study in pim 1 transgenic mice exposed to pulsed 900 MHz electromagnetic fields. Smith, P., et al., in progress. 902 MHz GSM and 1747 MHz DCS wireless communication signals: combined chronic toxicity/carcinogenicity study in the Wistar rat.