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In Vivo and In Vitro Studies in Experimental Model Systems Studies performed using in vivo and in vitro (animal and cellular) experimental model systems are critical components of the effort to iden- tify adverse health effects of exposure to radiofrequency (RF) fields gen- erated by wireless communications devices. Experimental studies permit the evaluation of possible risks of RF exposure using well-studied model systems under closely controlled conditions. Well-designed studies in ex- perimental biological models permit the precise quantification of exposure levels, generate essential dose-response data, provide the opportunity to eliminate many external variables that could confound or otherwise alter responses to RF fields, and support comparisons of RF responses to those of chemical and other physical agents using large historical databases in which the effects of those agents have been evaluated in biological models with known ability to predict human responses. Experimental studies can also be designed to include specific endpoint evaluations that can generate important data concerning possible biological mechanisms of RF action. Conversely, however, an unavoidable limitation to data from experimental studies is the requirement to extrapolate data (a) between animal species and (b) from high exposure levels used in the laboratory to lower exposure levels to which humans are commonly exposed. Interspecies differences and high-dose to low-dose extrapolations remain important challenges to the interpretation and application of experimental data to assessments of human risk. The body of experimental data from studies designed to investigate the possible health effects of exposure to RF fields continues to expand. Well- designed bioassays will include consideration of dose-response relationships. 

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 IDENTIFICATION OF RESEARCH NEEDS The state-of-the-science does currently, or will soon, support reasonable conclusions related to the effects of RF exposure on a number of health- related endpoints in laboratory animals (Sienkiewicz 2007; Lai 2007; Roti Roti 2007) and cell-based model systems (Vijayalaxmi 2007). However, data gaps do exist, and a number of possibly critical health effects of RF fields remain to be investigated. In this regard, it should be noted that essentially all experimental studies of RF health effects have been descrip- tive (e.g., Chou et al. 1992; Vijayalaxmi and Obe 2004) in that they have not been designed to investigate specific hypotheses of disease causation. Indeed, lacking compelling biophysical and biochemical/molecular mecha- nisms through which RF exposure could play a role in disease causation, investigations of possible links between RF exposure and disease are neces- sarily empirical. Additional experimental research focused on the identifica- tion of potential biophysical, biochemical, and molecular mechanisms of RF action is therefore considered to be an important research need, because it serves as an essential element of a comprehensive hazard assessment. The following sub-sections are organized into Cancer, Cancer-related Endpoints: Genetic Toxicology, Cancer-related Endpoints: Other, and Non- cancer Health Effects. CANCER Perhaps the single most important question concerning the health effects of exposure to RF fields is the possible link between such exposures and cancer risk. Several well-designed, large-scale studies to evaluate the possible oncogenicity of chronic exposure to RF fields in laboratory animals have been conducted (Zook and Simmens 2001; La Regina et al. 2003; Anderson et al. 2004; Tillmann et al. 2007) or are currently in progress. In consideration of the size and strength of the emerging database for studies of the potential carcinogenicity and general toxicity of RF fields, and the quality of the studies that have been and are being conducted, there appears to be only limited value to be gained by initiating addi- tional oncogenicity studies using standard-bred animal models until ongo- ing studies have been completed. Following completion of these studies, a “weight-of-the-evidence” analysis can be conducted (for example, using criteria established by the International Agency for Research on Cancer) to synthesize and evaluate the entire data set. At that time, rational, informed decisions can be made concerning (a) the value of conducting additional oncogenicity studies in standard-bred laboratory animals and (b) specific design elements that can be incorporated into any such studies in order to address identified data gaps. Although a large database will soon be available to support evalua- tions of the possible oncogenicity of RF fields in standard-bred animals,

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 IN VIVO AND IN VITRO STUDIES IN EXPERIMENTAL MODEL SYSTEMS few studies have been conducted in which potential cancer risks have been evaluated using genetically engineered models in which animals demon- strate increased sensitivity to carcinogenesis. The results of such studies could be essential to assessing possible risks of RF exposure in susceptible subpopulations, including individuals with underlying disease, those with genetic alterations that predispose them to oncogenesis, and prior or simul- taneous exposure to other carcinogenic or potentially carcinogenic agents. The use of genetically engineered animals may also increase the sensitivity of laboratory studies to detect weak effects, and may be particularly suit- able to evaluate the possible interactions between RF fields and other agents in disease causation. The possible risks of neoplasia (the process of tumor formation) associ- ated with RF exposure in individuals that have been (or are currently) exposed to other environmental or occupational carcinogens may also be investigated experimentally through the use of multi-stage (“initiation-promotion” or co- carcinogenesis) cancer models (Adey et al. 1999, 2000; Zook and Simmens 2001; Bartsch et al. 2002; Anane et al. 2003; Yu et al. 2006). Several such studies have been performed in animal models for cancer in several different organ sites, with uniformly negative results. However, the overall database for RF fields and cancer would be strengthened considerably by additional studies using multi-stage model systems for cancer in tissues (such as the brain) that have been hypothesized to be targets of RF action. Currently the value of such studies is often limited by the lack of suitable animal models that demonstrate the (a) organ specificity and (b) background tumor re- sponses to make them suitable for use in hazard identification. CANCER-RELATED ENDPOINTS: GENETIC TOxICOLOGy As noted at the workshop (Lai 2007, Vijayalaxmi 2007), substantial effort has been put forth to evaluate the possible genetic toxicity of RF fields, both in vivo and in vitro. Although a number of positive outcomes have been reported, efforts to replicate the results of positive studies have generally failed. Furthermore, the majority of experimental studies designed to identify genotoxic effects of exposure to RF fields have not found sig- nificant mutagenic or clastogenic activity in any model system that is in broad general use for genetic toxicology evaluations. On this basis, most investigators in the field agree that no compelling body of evidence exists to support the hypothesis that RF fields are genotoxic. The committee con- cludes that additional studies using standard genetic toxicology test systems are unlikely to increase our understanding of the possible risks associated with RF exposure at this time. That said, additional genetic toxicology studies may be warranted should evidence of oncogenicity be identified in any of the ongoing chronic

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0 IDENTIFICATION OF RESEARCH NEEDS toxicity/oncogenicity bioassays of RF fields in laboratory animals, or in any future studies to be performed using genetically engineered animal models. In the event that RF fields are identified as being oncogenic in one or more of these studies, further genetic toxicology studies of RF fields may be warranted as a means to identify possible mechanisms underlying such oncogenicity. Should evidence of oncogenicity be identified in a genetically engineered animal model, additional genetic toxicology studies could be particularly valuable if conducted using cells demonstrating the same mo- lecular defect. Additional genetic toxicology studies could also be of value if performed in cells that demonstrate a predisposition to DNA damage, such as defects in the ataxia-telangiectasia (AT) gene (associated with AT)1 or deficiencies in DNA repair (e.g., xeroderma pigmentosum cells).2 CANCER-RELATED ENDPOINTS: OTHER Although substantial experimental data are emerging that can be used to evaluate the possible oncogenicity of RF fields, a number of potentially critical cancer-related endpoints have received only very limited study. These include: • Possible influences of RF exposure on the structure and function of the immune system. Modulation of immune surveillance provides a known mechanism through which exogenous agents may stimulate oncogenesis. The effects of RF on specific arms of host immune function have received very little study in validated immunotoxicology model systems. • Possible influences of RF exposure on the endocrine system. In consideration of the high incidence of hormone-dependent cancers in the population at large, modulation of hormone synthesis and/or action could also provide an indirect mechanism through which agents may stimulate or inhibit carcinogenesis in hormone-dependent tissues. • In vitro studies of the effects of RF exposure on cell proliferation, apoptosis,3 and biochemical and molecular pathways of known significance to carcinogenesis. Although labor-intensive and relatively narrow in scope, 1 Ataxia-telangiectasia is an inherited disorder with symptoms that may include telangiectasis (dilation of capillaries), ataxic (uncoordinated) gait, proneness to infection, defective humoral and cellular immunity, and increased risk of malignancies. 2 Xeroderma pigmentosum is a genetic condition inherited as a recessive autosomal trait that is caused by a defect in mechanisms that repair DNA mutations (as those caused by ultraviolet light) and is characterized by the development of pigment abnormalities and multiple skin cancers in body areas exposed to the sun. 3 Apoptosis is a genetically directed process of cell self-destruction that is activated either by a stimulus or removal of a suppressing agent or stimulus, and is a normal physiological process eliminating unwanted cells.

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 IN VIVO AND IN VITRO STUDIES IN EXPERIMENTAL MODEL SYSTEMS such studies may identify mechanisms through which RF may induce or stimulate neoplastic development. • Broadly based (whole genome) investigations of alterations in gene and protein expression in cells exposed to RF fields. Because no repro- ducible effects of RF exposure on cancer-related endpoints have yet been identified, genome-wide and proteome-wide screening studies can provide an unbiased (although untargeted) approach through which RF-induced changes in biological activities may be identified. Following the initial genome-wide/proteome-wide screening, targeted data analyses and further investigations of pathways that are modulated by RF will be required to identify alterations in gene or protein expression that may underlie neoplas- tic activity or other toxic effects of RF exposure. OTHER HEALTH EFFECTS (NONCANCER) In addition to cancer-related endpoints, data gaps exist in a number of other areas of toxicology in which knowledge is essential to support a complete evaluation of the possible health effects of RF exposure. These include: • Possible influences of RF exposure on fetal and neonatal develop- ment. Developmental and reproductive toxicity evaluations could include possible teratogenic4 effects at nonthermal exposure levels, effects on ma- ternal behavior, effects on male and female fertility, and effects on matu- ration patterns in neonatal and juvenile animals. Although clear evidence of teratogenicity has been demonstrated at RF exposure levels that induce temperature changes, the possible teratogenicity of RF fields at lower (non- thermal) exposure levels has been studied much less extensively. Similarly, the possible effects of RF exposure on neonatal and juvenile growth and development (for example, using endpoints included in perinatal and post- natal development, including maternal function, and toxicology evalua- tions) have received little study. • Possible influences of RF exposure on the structure and function of the immune system, including prenatal, neonatal, and juvenile exposures. In addition to possible effects on cancer risk (as discussed above), modulation of immune function could alter host resistance to infectious agents. This could be particularly important in juvenile animals (and children), since their immune system is less developed than in adults. • Possible influences of RF exposure on the structure and function of the central nervous system, including prenatal, neonatal, and juvenile exposures. Effects on the structure of the nervous system (including the 4 Teratogenic means to be of, relating to, or causing developmental malformations.

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 IDENTIFICATION OF RESEARCH NEEDS blood-brain barrier) could impact a variety of behavioral, emotional, learn- ing, and other higher cognitive functions. It is important to note, however, that changes in central nervous system (CNS) function may also occur with- out histopathologic evidence of underlying structural damage. Such changes could be assessed through comprehensive neurobehavioral evaluations, such as functional observational batteries that are commonly included in nonclinical toxicology studies; through specialized evaluations of CNS function (e.g., motor activity, acoustic startle, and other more specific neuro- toxicology evaluations); and through electrophysiological assessments of CNS function (e.g., electroencephalograms). Neurobehavioral evaluations in juvenile animals exposed to RF may be particularly important, as the juvenile blood-brain barrier is less well developed than in adults; alterations in the blood-brain barrier could have both direct effects on CNS function, and could underlie neurotoxicity by allowing the entry into the brain of substances that are ordinarily excluded. The data gaps identified above can be addressed, at least initially, through the conduct of descriptive (empirical) toxicology, carcinogenesis, and molecular studies whose goal is general assessment of the impact of exposure to RF fields on toxicological or disease endpoints. Following com- pletion of this set of empirical studies, further progress in the evaluation of the possible health effects of RF exposure will depend on the conduct of hypothesis-driven investigations of putative mechanisms of RF action. At the present time, no generally accepted biological or molecular mechanism has been identified through which RF exposure may impact disease pro- cesses. Should exposure to RF fields be found to induce toxicity or increase the risk of any specific disease, the importance of fundamental mechanistic research in our understanding of these effects cannot be overstated, as it will provide the only realistic pathway to a complete assessment of any hazards posed to exposure to RF fields. 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. Additional experimental research focused on the identification of potential biophysical and biochemical/molecular mechanisms of RF action are considered to be of the highest priority.

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 IN VIVO AND IN VITRO STUDIES IN EXPERIMENTAL MODEL SYSTEMS Research Gaps Cancer Research Ongoing 1. In consideration of the size and strength of the emerging database for studies of the potential carcinogenicity and general toxicity of RF fields, there appears to be only limited value to be gained by initiating additional oncogenicity studies using standard-bred animal models until ongoing stud- ies have been completed. Following completion of these ongoing studies, a “weight-of-the-evidence” analysis can be conducted to synthesize and evaluate the entire data set. At that time, rational, informed decisions can be made concerning: a. the value of conducting additional oncogenicity studies in standard-bred laboratory animals, and b. design elements that should be incorporated into any such studies in order to address identified data gaps. 2. The use of genetically engineered animals may increase the sensi- tivity of laboratory studies to detect weak effects, and may be particularly suitable to evaluate the possible interactions between RF fields and other agents in disease causation. 3. The overall database for RF fields and cancer would be strength- ened by additional studies using multi-stage model systems for cancer in tissues (such as the brain) that have been hypothesized to be targets of RF action. At the present time, however, the value of such studies is often lim- ited by the lack of suitable animal models that demonstrate: a. appropriate organ specificity, and b. background tumor responses (incidence and latency) to make them suitable for use in hazard identification. Cancer-related Endpoints: Genetic Toxicology 4. Although genetic toxicology studies have failed to identify potential RF health effects (in part due to lack of replication of findings from key positive studies), additional genetic toxicology studies may be warranted should evidence of oncogenicity be identified in any of the ongoing chronic toxicity/oncogenicity bioassays of RF fields in laboratory animals, or in any future studies to be performed using genetically engineered animal models.

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 IDENTIFICATION OF RESEARCH NEEDS Cancer-related Endpoints: Other 5. A number of potentially critical cancer-related endpoints have re- ceived only very limited study. These include: a. possible influences of RF exposure on the structure and function of the immune system, b. possible influences of RF exposure on the endocrine system, c. in vitro studies of the effects of RF exposure on cell prolifera- tion, apoptosis, and biochemical and molecular pathways of known signifi- cance to carcinogenesis, and d. broadly based (whole genome) investigations of alterations in gene and protein expression in cells exposed to RF fields. Other Health Effects (Noncancer) 6. In addition to cancer-related endpoints, data gaps exist in a number of other areas of toxicology in which knowledge is essential to support a complete evaluation of the possible health effects of RF exposure. These include: a. possible influences of RF exposure on fetal and neonatal development, b. possible influences of RF exposure on the structure and function of the immune system, including prenatal, neonatal, and juvenile exposures, and c. possible influences of RF exposure on the structure and function of the central nervous system, including prenatal, neonatal, and juvenile exposures.