1. Brussels, October 2001 EU-Japan-Korea-USA Current State of Knowledge about Electromagnetic Fields, Mobile Telephony and Health b.veyret@piom.u-bordeaux.fr

2. Brussels, October 2001 EU-Japan-Korea-USA Frequency Spectrum 1 fm 1 GHz

3. Brussels, October 2001 EU-Japan-Korea-USA Scientific approaches Biological models Dosimetry Biological models Dosimetry animals cells Foundations epidemiology humans

4. Brussels, October 2001 EU-Japan-Korea-USA Biophysical intercation Biochemical changes Biological effect Health effect

5. Brussels, October 2001 EU-Japan-Korea-USA Definition of SAR SAR: specific absorption rate SAR: rate of power absorption per unit of mass (watt / kilogramme; W/kg) SAR is proportional to the temperature increase in the tissue SAR: specific absorption rate SAR: rate of power absorption per unit of mass (watt / kilogramme; W/kg) SAR is proportional to the temperature increase in the tissue

6. Brussels, October 2001 EU-Japan-Korea-USA Thermal versus nonthermal A thermal biological effect is due to an increase in temperature at high SAR level A nonthermal effect occurs at low SAR level with a negligible input of power and no temperature increase At medium SAR level the thermoregulation system prevents any temperature increase. Athermal effects might occur due to stress. A thermal biological effect is due to an increase in temperature at high SAR level A nonthermal effect occurs at low SAR level with a negligible input of power and no temperature increase At medium SAR level the thermoregulation system prevents any temperature increase. Athermal effects might occur due to stress.

7. Brussels, October 2001 EU-Japan-Korea-USA Mobile telephones / base stations Handsets - medium-level: up to 1/2 of guidelines - head-only exposure (so far) - SAR < 1.6-2 W/kg Base stations - low-level: often < guidelines / 10,000 - whole-body exposure - SAR < 0.08 W/kg Handsets - medium-level: up to 1/2 of guidelines - head-only exposure (so far) - SAR < 1.6-2 W/kg Base stations - low-level: often < guidelines / 10,000 - whole-body exposure - SAR < 0.08 W/kg

8. Brussels, October 2001 EU-Japan-Korea-USA Sources of scientific information Peer-reviewed articles Review articles Reports (COST 244bis, Stewart s group, Zmirou s group, FDA, etc.) Monographs (WHO, IARC, ICNIRP, etc.) Peer-reviewed articles Review articles Reports (COST 244bis, Stewart s group, Zmirou s group, FDA, etc.) Monographs (WHO, IARC, ICNIRP, etc.)

9. Brussels, October 2001 EU-Japan-Korea-USA WHO database Cancer relevant or related completed ongoing total epidemiology 8 18 26 bioassays 6 8 14 sensitized in vivo 11 7 18 acute in vivo 22 5 27 in vitro 50 26 76 Total 97 64 161 Cancer relevant or related completed ongoing total epidemiology 8 18 26 bioassays 6 8 14 sensitized in vivo 11 7 18 acute in vivo 22 5 27 in vitro 50 26 76 Total 97 64 161

10. Brussels, October 2001 EU-Japan-Korea-USA WHO database Non cancer completed ongoing total epidemiology 4 0 4 human 45 21 66 acute in vivo 32 10 42 in vitro 15 10 25 Total 96 41 137 Non cancer completed ongoing total epidemiology 4 0 4 human 45 21 66 acute in vivo 32 10 42 in vitro 15 10 25 Total 96 41 137

11. Brussels, October 2001 EU-Japan-Korea-USA Epidemiology 1/2 Study of the link between exposure and disease –mobile telephony: 3 case-control (Hardell 1999, Muscat 2000, Inskip 2001) and 2 cohort studies (Morgan 2000, Johanson 2001) –Main focus on brain cancer –Negative results but link with laterality of use? Limited by exposure assessment, evolving technology, short latency, etc. Study of the link between exposure and disease –mobile telephony: 3 case-control (Hardell 1999, Muscat 2000, Inskip 2001) and 2 cohort studies (Morgan 2000, Johanson 2001) –Main focus on brain cancer –Negative results but link with laterality of use? Limited by exposure assessment, evolving technology, short latency, etc.

12. Brussels, October 2001 EU-Japan-Korea-USA Epidemiology 2/2 Ongoing large case-control questionnaire study led by IARC and funded in part by EU: Interphone Head and neck tumours: glioma, meningioma, acoustic neurinoma, and parotid gland malignant tumours 14 countries involved Preliminary exposure assessment study in progress Results expected by 2004? Ongoing large case-control questionnaire study led by IARC and funded in part by EU: Interphone Head and neck tumours: glioma, meningioma, acoustic neurinoma, and parotid gland malignant tumours 14 countries involved Preliminary exposure assessment study in progress Results expected by 2004?

13. Brussels, October 2001 EU-Japan-Korea-USA Human laboratory studies Cognition Sleep EEG Blood pressure Subjective symptoms etc. Cognition Sleep EEG Blood pressure Subjective symptoms etc.

14. Brussels, October 2001 EU-Japan-Korea-USA Cognition Thuroczy 1997: cerebral circulatory disturbances, alteration of electrical activity Freude 1998, 2000: Slow brain-wave potential influenced in visual monitoring tasks Preece 1999: decrease in choice reaction times Koivisto 2000: decreased response times Lee 2001: mobile telephone users performed better in 1 out of 3 attention tests Thuroczy 1997: cerebral circulatory disturbances, alteration of electrical activity Freude 1998, 2000: Slow brain-wave potential influenced in visual monitoring tasks Preece 1999: decrease in choice reaction times Koivisto 2000: decreased response times Lee 2001: mobile telephone users performed better in 1 out of 3 attention tests

15. Brussels, October 2001 EU-Japan-Korea-USA Sleep Mann & Röschke 1996: alterations in sleep onset latency, REM sleep, EEG during REM sleep Wagner 1998: no alterations in sleep onset latency, REM sleep duration Borbély 1999: decreased waking duration, EEG increase in non-REM sleep Huber 2000: EEG increase in non-REM sleep Mann & Röschke 1996: alterations in sleep onset latency, REM sleep, EEG during REM sleep Wagner 1998: no alterations in sleep onset latency, REM sleep duration Borbély 1999: decreased waking duration, EEG increase in non-REM sleep Huber 2000: EEG increase in non-REM sleep

16. Brussels, October 2001 EU-Japan-Korea-USA EEG Reiser 1995: increase power 9.75-32 Hz Röschke & Mann 1997: No effects Hietanen 2000: statistically significant changes De Seze 2000: alterations of EEG patterns Krause 2000: Increase power in 8-10 Hz during memory task Reiser 1995: increase power 9.75-32 Hz Röschke & Mann 1997: No effects Hietanen 2000: statistically significant changes De Seze 2000: alterations of EEG patterns Krause 2000: Increase power in 8-10 Hz during memory task

17. Brussels, October 2001 EU-Japan-Korea-USA Blood pressure Braune 1998: increased resting blood pressure Lindholm, ongoing: no effects so far Braune 1998: increased resting blood pressure Lindholm, ongoing: no effects so far

18. Brussels, October 2001 EU-Japan-Korea-USA Subjective symptoms Oftedal, 2000; Sandström, 2001: warmth on the ear, headaches, etc. Koivisto, 2001: no association between symptoms and exposure (healthy subjects) Hietanen, 2001: no association between symptoms and exposure (hypersensitive subjects) Oftedal, 2000; Sandström, 2001: warmth on the ear, headaches, etc. Koivisto, 2001: no association between symptoms and exposure (healthy subjects) Hietanen, 2001: no association between symptoms and exposure (hypersensitive subjects)

19. Brussels, October 2001 EU-Japan-Korea-USA Animal models: in vivo

20. Brussels, October 2001 EU-Japan-Korea-USA 3 types of exposure systems

21. Brussels, October 2001 EU-Japan-Korea-USA Head-only exposure Loop antenna

22. Brussels, October 2001 EU-Japan-Korea-USA Whole-body exposure system ITIS

23. Brussels, October 2001 EU-Japan-Korea-USA Head-mainly exposure

24. Brussels, October 2001 EU-Japan-Korea-USA Cancer in vivo studies Bioassays Grafted tumours Sensitized models (carcinogens, ionizing radiation, genetic factors, etc.) Genotoxicity Bioassays Grafted tumours Sensitized models (carcinogens, ionizing radiation, genetic factors, etc.) Genotoxicity

25. Brussels, October 2001 EU-Japan-Korea-USA 2-year bioassays Adey 1999: 836.55 MHz, TDMA 2000: 836.55 MHz, FM Fisher 344 rats: No Effects Zook 2000: 850 MHz, MiRS - TDMA 850 MHz, FM Sprague Dawley rats: No Effects Adey 1999: 836.55 MHz, TDMA 2000: 836.55 MHz, FM Fisher 344 rats: No Effects Zook 2000: 850 MHz, MiRS - TDMA 850 MHz, FM Sprague Dawley rats: No Effects

26. Brussels, October 2001 EU-Japan-Korea-USA 2-year bioassays: ongoing Roti –847.74 MHz, CDMA, 835.62 MHz, FM –Fisher 344 rats Anderson –1616 MHz, IRIDIUM, Fisher 344 rats Dasenbrock –GSM-900, and 1800, B6C3F1 mice Dotti –GSM-900, and 1800; Wistar rats NIEHS, planned Roti –847.74 MHz, CDMA, 835.62 MHz, FM –Fisher 344 rats Anderson –1616 MHz, IRIDIUM, Fisher 344 rats Dasenbrock –GSM-900, and 1800, B6C3F1 mice Dotti –GSM-900, and 1800; Wistar rats NIEHS, planned

27. Brussels, October 2001 EU-Japan-Korea-USA Grafted tumours Salford, 1993: 915-MHz, CW and AM, up to 8.3 W/kg, Fisher rats, glioma injection in brain: No effect on tumour growth Roti Roti, 1999: 835.62-MHz FM or 847.74-MHz CDMA, 0.75 W/kg, glioma injection in brain: No effect on tumour growth Salford, 1993: 915-MHz, CW and AM, up to 8.3 W/kg, Fisher rats, glioma injection in brain: No effect on tumour growth Roti Roti, 1999: 835.62-MHz FM or 847.74-MHz CDMA, 0.75 W/kg, glioma injection in brain: No effect on tumour growth

28. Brussels, October 2001 EU-Japan-Korea-USA Chemically-induced tumours Chagnaud, 1999: GSM-900, whole-body, BP- induced tumors: No effects on tumour latency or survival nor on lymphocyte subpopulations, Shirai, 1999: local 923-MHz exposure, rat liver carcinogenesis chemically-induced : No effects. Adey, 1999, 2000: ENU-initiated brain tumors in Fisher 344 rats; 836.55 MHz, TDMA or FM: No effects on tumour growth. Shirai: ENU-initiated brain tumors, 1.5 GHz ongoing Chagnaud, 1999: GSM-900, whole-body, BP- induced tumors: No effects on tumour latency or survival nor on lymphocyte subpopulations, Shirai, 1999: local 923-MHz exposure, rat liver carcinogenesis chemically-induced : No effects. Adey, 1999, 2000: ENU-initiated brain tumors in Fisher 344 rats; 836.55 MHz, TDMA or FM: No effects on tumour growth. Shirai: ENU-initiated brain tumors, 1.5 GHz ongoing

29. Brussels, October 2001 EU-Japan-Korea-USA DMBA -induced tumors Rat model of mammary tumors: - Anane 1999, 2000: GSM-900 and -1800, whole-body, several SAR levels - Bartsch 2001: GSM-900, whole-body, low SAR level: 0.1 W/kg 3 one-year studies: No delay in onset of malignant tumors Perform A: Hruby, GSM-900, several SAR levels: ongoing China; Chiang, ongoing Rat model of mammary tumors: - Anane 1999, 2000: GSM-900 and -1800, whole-body, several SAR levels - Bartsch 2001: GSM-900, whole-body, low SAR level: 0.1 W/kg 3 one-year studies: No delay in onset of malignant tumors Perform A: Hruby, GSM-900, several SAR levels: ongoing China; Chiang, ongoing

30. Brussels, October 2001 EU-Japan-Korea-USA Appearance of first malignant tumour 0.2.4.6.8 1 020406080100 Time (days) 1.4 W/kg Sham P = 0.22 DMBA GSM-1800 60 rats/group

31. Brussels, October 2001 EU-Japan-Korea-USA DNA fragmentation Increased DNA fragmentation reported by Lai and Singh 1995, 1996, (comet assay) in rats exposed to 2.45-GHz pulsed fields Failure of a replication study by Roti Roti 1999 Negative results in an analog mobile-phone study by Tice & Hook, 1999 Negative results in a GSM-900 study by Lagroye and Anane, 2000 Increased DNA fragmentation reported by Lai and Singh 1995, 1996, (comet assay) in rats exposed to 2.45-GHz pulsed fields Failure of a replication study by Roti Roti 1999 Negative results in an analog mobile-phone study by Tice & Hook, 1999 Negative results in a GSM-900 study by Lagroye and Anane, 2000

32. Brussels, October 2001 EU-Japan-Korea-USA B T Transgenic mice Repacholi 1997 Large effect but: –Exposure system? –Transgenic model? –Interpretation? Replication –Australia –Italy Repacholi 1997 Large effect but: –Exposure system? –Transgenic model? –Interpretation? Replication –Australia –Italy Sham Exposed

33. Brussels, October 2001 EU-Japan-Korea-USA Non-cancer in vivo studies Behaviour (only at high SAR levels) Hearing Memory and learning Blood Brain Barrier Heat Shock Proteins etc. Behaviour (only at high SAR levels) Hearing Memory and learning Blood Brain Barrier Heat Shock Proteins etc.

34. Brussels, October 2001 EU-Japan-Korea-USA Hearing Work of the Marino and Aran groups have yielded negative results on alterations of the functions of the inner ear More research in progress within the European GUARD programme Work of the Marino and Aran groups have yielded negative results on alterations of the functions of the inner ear More research in progress within the European GUARD programme

35. Brussels, October 2001 EU-Japan-Korea-USA Memory and learning Lai 1994: decreased learning in 12-arm maze, whole-body exposure to pulsed fields Sienkiewicz 2000, GSM 900, whole-body, low SAR: negative Dubreuil 2001: GSM 900, head only: negative Replication by Cobb, ongoing: negative so far Thuroczy, Sienkiewicz & Cassel : ongoing Long-term memory, Nagawa: negative Lai 1994: decreased learning in 12-arm maze, whole-body exposure to pulsed fields Sienkiewicz 2000, GSM 900, whole-body, low SAR: negative Dubreuil 2001: GSM 900, head only: negative Replication by Cobb, ongoing: negative so far Thuroczy, Sienkiewicz & Cassel : ongoing Long-term memory, Nagawa: negative

36. Brussels, October 2001 EU-Japan-Korea-USA Blood-brain-barrier BBB Persson & Salford 1997: increased BBB permeability at low SAR levels Fritze 1997: reversible effect seen only at high SAR Tsurita 2000: no effect even at high SAR Aubineau 2001: effect at 2 W/kg and inflammation of the dura mater. Ongoing search for threshold Mason: replication of Persson & Salford s data: ongoing Persson & Salford 1997: increased BBB permeability at low SAR levels Fritze 1997: reversible effect seen only at high SAR Tsurita 2000: no effect even at high SAR Aubineau 2001: effect at 2 W/kg and inflammation of the dura mater. Ongoing search for threshold Mason: replication of Persson & Salford s data: ongoing

37. Brussels, October 2001 EU-Japan-Korea-USA Heat Shock Proteins HSP de Pomerai 2000 Transgenic nematodes - 700 MHz CW - Low SAR Increase in HSP expression de Pomerai 2000 Transgenic nematodes - 700 MHz CW - Low SAR Increase in HSP expression

38. Brussels, October 2001 EU-Japan-Korea-USA Cellular models: in vitro

39. Brussels, October 2001 EU-Japan-Korea-USA In vitro: exposure systems Petri dishes

40. Brussels, October 2001 EU-Japan-Korea-USA In-vitro studies (1/3) CompletedOngoingTotal Cancer 38 23 61 Non-Cancer 36 19 55 Genotoxicity and DNA breaks Micronuclei, SCE, chromosome aberrations Obe, Maes & Verschaeve, Eberle, Tice, Roti Roti, Meltz, Scarfi, etc. Proliferation and transformation Fitzner, Kwee, Wobus, Lagroye, Bersani, etc. CompletedOngoingTotal Cancer 38 23 61 Non-Cancer 36 19 55 Genotoxicity and DNA breaks Micronuclei, SCE, chromosome aberrations Obe, Maes & Verschaeve, Eberle, Tice, Roti Roti, Meltz, Scarfi, etc. Proliferation and transformation Fitzner, Kwee, Wobus, Lagroye, Bersani, etc.

41. Brussels, October 2001 EU-Japan-Korea-USA In vitro studies (2/3) Gene expression - Leszczynski, ongoing: increased expression of hsp27 at 2 W/kg Enzyme activity: ODC - Byus, 1998, Litovitz,1997 - replication by Billaudel & Naraala Signal transduction - Byus, 1984 Gene expression - Leszczynski, ongoing: increased expression of hsp27 at 2 W/kg Enzyme activity: ODC - Byus, 1998, Litovitz,1997 - replication by Billaudel & Naraala Signal transduction - Byus, 1984

42. Brussels, October 2001 EU-Japan-Korea-USA In vitro studies (3/3) Role of free radicals - Juutilainen Calcium - Bawin, Blackman, Meyer Role of co-factors (UV, etc.)?? Role of free radicals - Juutilainen Calcium - Bawin, Blackman, Meyer Role of co-factors (UV, etc.)??

43. Brussels, October 2001 EU-Japan-Korea-USA Mechanisms Only well-established mechanisms is heating Others are being explored and tested in the laboratory: –Spatial and temporal temperature gradients –Membrane rectification –Absorption by magnetite –Radical pair mechanisms –etc. Only well-established mechanisms is heating Others are being explored and tested in the laboratory: –Spatial and temporal temperature gradients –Membrane rectification –Absorption by magnetite –Radical pair mechanisms –etc.

44. Brussels, October 2001 EU-Japan-Korea-USA Conclusions 200 studies related to mobile telephony have been completed / 100 more are ongoing. No constant reported positive finding at nonthermal levels Some key large-scale studies are in progress and their results should provide a solid database for risk assessment Known thermal effects are portable to 3G Assessment will have to be provided for both mobile telephones and base stations 200 studies related to mobile telephony have been completed / 100 more are ongoing. No constant reported positive finding at nonthermal levels Some key large-scale studies are in progress and their results should provide a solid database for risk assessment Known thermal effects are portable to 3G Assessment will have to be provided for both mobile telephones and base stations