Kundi risk for long-term ipsilateral use, it is hardly an explanation for the increased overall risk of ipsilateral use revealed in several investigations (Hardell et al. 2002a, 2005a, 2006a; Hepworth et al. 2006). When considering the discussion above, the conditions for a causal interpretation of the observed association between mobile phone use and brain tumors are not fully met. However, discussion of the potential violation of the con- ditions of temporal relation as well as popula- tion and environmental equivalence revealed that it must in all likelihood have reduced the observed association. Because of the important result on ipsilateral mobile phone use, a spuri- ously increased risk due to recall bias cannot be completely dismissed. In such a situation, evidence from other sources may increase or decrease confidence in a causal relation between mobile phone use and cancer. Additional evidence. Since the 1930s there has been a scientific controversy about effects of high-frequency EMF other than thermal. Absorption of electromagnetic energy is now well understood and poses no principal dif- ficulty of integration into Maxwell’s theory of electromagnetism. The rate of absorption of electromagnetic energy in a homogenous volume of biological tissue is proportional to the temperature increase within this volume. Therefore, at high levels of EMF exposure, sig- nificant heating occurs that can be dangerous to health. Exposure standards have been issued that limit exposure to thermally safe levels. However, telecommunication and broadcast- ing applications of high-frequency EMF are not only radiating energy but also informa- tion. This is done by modulation of the high- frequency carrier. The modulation frequencies could be of biological significance and evoke nonthermal effects. In addition, the high-fre- quency signal itself could cause effects at low levels in combination with the simultaneous presence of the earth magnetic field (Chiabrera et al. 2000). In principle, interactions between EMF and matter are subject to two descrip- tions, classical or quantum electrodynamics. In a living cell, many important processes occur by electron transfer across membrane struc- tures in a well-organized manner, ions cross selective channels, proteins get activated and deactivated by cascades of precisely regulated enzymes—all processes that occur on a quan- tum scale. Recently, by application of “omics” research (for an overview, see Vanderstraeten and Verschaeve 2008), it has been shown that cells may respond with activation of proteins and genes at nonthermal levels of exposure, a process that was also observed in vivo (Karinen et al. 2008). However, because of the lack of a mechanistic model, these results are uncertain as to their interpretation with respect to rel- evant long-term health effects. It has long been speculated (Lai and Singh 1997; Phelan et al. 322 1992) that free radical formation is involved in EMF-induced health effects. Although there is some evidence of formation of free radicals at nonthermal levels of EMF (Simkó et al. 2006), there are many difficulties with this approach. It would be much too simplistic to assume that free radicals are directly produced by the interaction with the EMF. Rather, these radicals are produced by the cell itself as an intermediate step of the response to sensing the field (Friedman et al. 2007). Concerning prior epidemiologic evidence of a relationship between high-frequency EMF other than those used in mobile telecommuni- cation and brain tumors, despite some reports of increased risk (Berg et al. 2006; Grayson 1996; Szmigielski 1996; Thomas et al. 1987), the evidence is inconclusive to date. Results of epidemiologic studies of mobile phone use summarized above indicate an asso- ciation that is of moderate strength and in the range delineated for passive smoking and lung cancer. There is no meaningful indicator of exposure dose available, but longer latencies are associated with higher risk estimates, and there are indications that risk is higher in rural areas where phones typically radiate at higher intensities (Hardell et al. 2005b). These aspects do increase confidence in a causal relationship. In the case that epidemiology faces prob- lems due to short exposure durations, lifetime animal bioassays gain importance in estab- lishing a carcinogenic risk. Unfortunately, standard procedures cannot be applied for exposure to microwaves from mobile phones. In hundreds of animal carcinogenicity assays, it has been shown that even for DNA reac- tive agents, exposure during most of the life span of the animals at the maximum tolerated dose is necessary to significantly increase inci- dence. Such high exposures are impossible for high-frequency EMF because of interference with heating. Hence, it is necessary to apply levels that are much too low for an increased incidence to be expected. Some solutions to this problem have been proposed: a) coexpo- sure or prior exposure to a known carcino- gen; b) implantation of tumor cells; and c) use of animal strains with a habitually increased tumor incidence. Because of the unknown mechanism of action, none of these attempts can be evaluated according to their suitability. More than 30 long-term and medium-term animal assays have been published in the past decade, most of which do not comply with basic criteria (Kundi 2003), and there is no suitable model for brain tumors. Application of ethylnitrosourea during gestation results in an increased incidence of brain tumors but increases incidence of many other tumors as well. A further problem is the much smaller size of laboratory rodents, resulting in a completely different exposure pattern at tele- communication frequencies. In contrast to humans using a mobile phone with a localized exposure at the side of the head the phone is held, animal exposure is a whole-body expo- sure. Although devices have been constructed that result in a predominant head irradiation (Adey et al. 2000), pattern and distribution within the brain will still be completely differ- ent from human exposures. It is not surpris- ing then that up to now only a few animal experiments have found some indication of an increased cancer risk (e.g., Hruby et al. 2008; Repacholi et al. 1997; Shirai et al. 2007). Interpretation of epidemiologic findings would be much easier if genotoxicity of mobile telecommunication signals could firmly be established. In vitro experiments have brought about diverse results that at present provide only equivocal evidence for genotoxic effects. Additionally, in the case of genotoxicity assays, procedures widely used for assessing envi- ronmental and nutritional toxicants may not be ideally suited for the study of EMF. For example, if, as suggested by Lai and Singh (2004), exposure-induced effects imply activa- tion of the Fenton reaction, cells rich in free iron would be responsive while others would not. Hence, overall evidence without consider- ing mechanistic hypotheses is of limited value. Nevertheless, about one quarter of published genotoxicity studies found an effect of low- level exposures (Vijayalaxmi and Obe 2004; Vijayalaxmi and Prihoda 2008). Overall, animal and in vitro experi- ments do not reduce confidence in a causal relationship but do not provide unequivo- cal support either. The main problem is the lack of a coherent research strategy that unifies strengths of different disciplines to unravel the intriguing problem of low-level EMF health effects from a biophysical perspective. Conclusions Epidemiologic evidence compiled in the past 10 years starts to indicate an increased risk, in particular for brain tumors (glioma, men- ingioma, acoustic neuroma), from mobile phone use. Considering biases that may have been operating in most studies, the risk esti- mates are rather too low, although recall bias could have increased risk estimates. The net result, when considering the different errors and their impact, is still rather an elevated risk. The magnitude of the brain tumor risk is moderate, but it has to be borne in mind that estimates are still from short durations of exposure. From the perspective of public health, an increase of brain tumor incidence of ≥ 50% poses substantial problems for neurosurgical care, but the individual perspec- tive is less dramatic: in industrial countries, the lifetime brain tumor risk is 4–8 per 1,000. If mobile phone use should increase these figures to 6–12 per 1,000, the individual risk is still low. ovlume 117 | number 3 | March 2009 • Environmental Health Perspectives