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Mechanisms Knowledge of the basic interaction mechanisms of radiofrequency (RF) electromagnetic fields (EMFs) with cellular and subcellular (molecular) structures provides a basis for extrapolation of existing knowledge to fu- ture technologies and exposure conditions. Thus, research on interaction mechanisms is an important topic and a relevant part of most research programs worldwide. In Europe and the United States, such research has been ongoing for decades. Some of the interaction mechanisms that have been identified so far are well understood and widely accepted. Those include mechanisms that lead to thermal effects in biological tissues and forces exerted at high field strengths that result in dielectrophoresis,1 electroporation,2 and pearl chain formation3 of cells (Schwan 1982, 1985; Holzapfel et al. 1982). The responses of cells to elevated temperature are well documented and seem to be independent from the heating source. The electroporation effects are technically used, for example in pharmacology and for basic scientific research in the integration of external DNA into cells. For wireless com- munication devices electroporation is not relevant as it becomes significant 1 Dielectrophoresis is defined as the lateral motion imparted on uncharged particles as a result of polarization induced by nonuniform electric fields. 2 Electroporation is a mechanical method used to introduce polar molecules into a host cell through the cell membrane. In this procedure, a large electric pulse temporarily disturbs the phospholipid bilayer, allowing molecules like DNA to pass into the cell. 3 Chains of living or nonliving particles (pearl chains) form along the lines of force of electro- magnetic fields (including RF fields). 

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 IDENTIFICATION OF RESEARCH NEEDS only at very high field strengths. The minimum RF signal that can modify the transport of ions and molecules is an open question. The basic question still under debate is whether there are other inter- action mechanisms of low-intensity RF electromagnetic fields that could have health consequences. Of particular interest is the possible existence of health effects that occur due to the accumulation of multiple, long-term, low-intensity RF exposures. Currently, the most appropriate ways to answer these basic questions include the use of biophysical4 (theoretical), biochemical, and biological ap- proaches. At the physical and chemical levels, the prime goal is to identify a candidate mechanism that could overcome the various sources of “noise” in the biological system. From the biochemical and biological perspective, two approaches were suggested at the workshop to identify mechanisms that may be operating at low exposures: Successive- or multiple-hypothesis testing based on hazard mecha- • nisms or stress responses that are relevant for cancer (Roti Roti 2007). The pitfall of this approach seems to be that the number of parameters to be tested is high and not all parameters are known. The use of high-throughput screening methods (Leszczynski 2007) • such as genomics,5 proteomics,6 metabolomics,7 and others not yet devel- oped (the so called “-omics”). Such methods have already been used in EMF research programs. The pitfall of these methods is the very high num- ber of reactions that might be detected. Many of those reactions might be of no relevance or be false positives. Thus all findings need to be validated using complementary methods. From the biophysical perspective a series of mechanisms has been suggested by various investigators. Those mechanisms include but are not limited to: 4A biophysical approach is one that applies physical principles and methods to biological problems. 5 Genomics is a branch of biotechnology concerned with applying the techniques of genetics and molecular biology to the genetic mapping and DNA sequencing of sets of genes or the complete genomes of selected organisms using high-speed methods. 6 Proteomics is a branch of biotechnology concerned with applying the techniques of molecu- lar biology, biochemistry, and genetics to analyzing the structure, function, and interactions of the proteins produced by the genes of a particular cell, tissue, or organism, including the organization of the information in databases. 7 Metabolomics is the systematic study of the unique chemical fingerprints that specific cellular processes leave behind—specifically, the study of their small-molecule metabolite profiles.

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 MECHANISMS Temperature rise (“heating”), • voltage-gated ion channels (includes action potential-related • channels), ion channel electro-denaturation, • membrane enzyme electro-conformational coupling, • magnetically sensitive radical pair reactions, • magnetite-based mechanical coupling, and • temporary membrane pore creation. • None of these possible mechanisms has so far been positively identified as a candidate for causation of health effect. Testing for the sensitivity of the central nervous system (CNS) to detect modulated RF signals using the pattern recognition capability of the brain and neural networks would improve our understanding of the minimum signal level that biological systems can sense and distinguish from back- ground noise. It was noted at the workshop that mechanisms can be modeled theo- retically with the use of software-based nonlinear cell models that describe field-induced molecular changes (Weaver 2007; Gowrishankar et al. 2006). It was also noted (D’Inzeo 2007) that investigation of doses occurring on the microscopic level may lead to a better understanding of possible interac- tions of RF electromagnetic fields on the cellular and subcellular level. The utility of this observation is supported by recent findings (Barnes and Kwan 2005) that suggest a higher energy absorption at the microscopic scale, e.g., at the boundary between cellular structures with different dielectric proper- ties. Several national and international expert groups, including the World Health Organization, have requested more research into micro-dosimetry and appropriate dielectric models as a medium- to long-term research need. Some research programs in Europe already include such investigations. It is unclear whether low-level RF exposure can trigger effects through stimulation of cellular thermo-receptors. It is also currently unclear if a non- linear biological mechanism exists that could lead to demodulation effects. As a result, different modulations and wave characteristics would affect biological systems differently. There is some research with respect to this question underway, such as an experiment being conducted in the UK.8 Knowledge is lacking concerning the effects of electromagnetic fields on ion and molecular transport through the cell membrane. Work is ongoing at the Massachusetts Institute of Technology, and the outcome should be eval- uated before further work is initiated (Weaver and Chizmadzhev 2006). 8 http://www.mthr.org.uk/research_projects/HO_funded_projects_excell.htm Accessed Sep- tember 20, 2007.

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 IDENTIFICATION OF RESEARCH NEEDS The committee’s evaluation of presentations and discussions at the workshop has resulted in the identification of the following research needs and gaps. Research Needs 1. Effects of RF electromagnetic fields on neural networks are re- search needs. There are indications that neural networks are a sensitive biological target. 2. Investigations of doses occurring on the microscopic level are needed to better understand possible interactions of RF electromagnetic fields on the cellular and subcellular level. Several national and inter- national expert groups, including the World Health Organization, have requested more research into micro-dosimetry and appropriate dielectric models as a medium- to long-term research need. Research Gaps Research Ongoing 1. Mechanisms that can be modeled theoretically with the use of software-based nonlinear cell models that describe field-induced molecular changes. It is currently unclear if a nonlinear biological mechanism exists that could lead to demodulation effects. There is some research with respect to this question underway. Judged to Be of Lower Priority 2. It is unclear whether low-level RF exposure can trigger effects through stimulation of cellular thermo-receptors. 3. Knowledge is lacking concerning the effects of electromagnetic fields on ion and molecular transport through the cell membrane.