7
Animal and Human Studies Addressing Health Effects

INTRODUCTION

Studies to evaluate the potential of RF fields to impact biological systems have been conducted in both humans and animals. Although the interaction of RF fields with humans is of prime importance and concern, the number of human laboratory studies is quite small compared to the literature available on animal studies. Moreover, many areas of biologic investigation are more efficiently and appropriately conducted using various animal species. Animal studies provide an integrated system that can be used in studies where experimental variables can be controlled, specific hypotheses can be explored, and exposure can be precisely assessed. Given the uncertainty and the relatively low power of RF epidemiologic studies to ascertain the relationship between RF exposure and possible adverse health effects, and the small number of human laboratory studies, investigations in animals are especially important in the evaluation of RF for potential adverse effects.

There are, however, limitations to animal studies for risk-assessment purposes that one must bear in mind. Extrapolation of experimental results from laboratory animals to humans remains somewhat tentative, both because of important biologic differences between humans and animals and because the mechanisms (and hence the biologically relevant exposure parameters) by which the effects may arise are often unknown. Furthermore, studies using laboratory animals are typically carried out at exposure levels much higher than found in the environment. There are questions as to the applicability of these laboratory study conditions to the low RF levels experienced by humans exposed to the PAVE PAWS signal.



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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy 7 Animal and Human Studies Addressing Health Effects INTRODUCTION Studies to evaluate the potential of RF fields to impact biological systems have been conducted in both humans and animals. Although the interaction of RF fields with humans is of prime importance and concern, the number of human laboratory studies is quite small compared to the literature available on animal studies. Moreover, many areas of biologic investigation are more efficiently and appropriately conducted using various animal species. Animal studies provide an integrated system that can be used in studies where experimental variables can be controlled, specific hypotheses can be explored, and exposure can be precisely assessed. Given the uncertainty and the relatively low power of RF epidemiologic studies to ascertain the relationship between RF exposure and possible adverse health effects, and the small number of human laboratory studies, investigations in animals are especially important in the evaluation of RF for potential adverse effects. There are, however, limitations to animal studies for risk-assessment purposes that one must bear in mind. Extrapolation of experimental results from laboratory animals to humans remains somewhat tentative, both because of important biologic differences between humans and animals and because the mechanisms (and hence the biologically relevant exposure parameters) by which the effects may arise are often unknown. Furthermore, studies using laboratory animals are typically carried out at exposure levels much higher than found in the environment. There are questions as to the applicability of these laboratory study conditions to the low RF levels experienced by humans exposed to the PAVE PAWS signal.

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy It should be noted that there is a considerable literature investigating the thermal effects of RF exposure in animals. Much of this literature is focused on 2450 MHz experimentation (outside the frequency range of interest for the PAVE PAWS radar) although other frequencies are also occasionally investigated. Because thermal responses are clearly outside the range of expected biologic responses to the PAVE PAWS exposures, this report does not consider in detail work performed at exposure levels that are designed to produce elevated temperatures in exposed animals. Reference to exposures at 2450 MHz is made occasionally where studies at the more relevant frequencies are lacking; however, the 2450 MHz work is not reviewed comprehensively. CANCER—HUMAN STUDIES There are no laboratory studies in humans with exposures to RF energy and cancer as the direct endpoint of investigation. Such studies would clearly cross ethical boundaries and would not be acceptible. Futhermore, RF fields lack sufficient energy to disrupt chemical bonds so there is little theoretical basis for suspecting that such fields would cause mutations or other genotoxic effects. There are a few human studies investigating possible indirect and nongenotoxic effects relevant to cancer that will be discussed in the section on immunological and endocrine function studies. CANCER—STUDIES IN ANIMAL MODELS Several different approaches and animal models have been used in laboratory animal cancer studies. The selection of a specific model depends largely upon the hypothesis chosen to evaluate a particular underlying mechanism. For example, if one desires to test RF for its potential to be a complete carcinogen (an agent that by its application alone can cause cancer), animals are exposed to RF over a long period of time, usually 1 1/2 to 2 years. The extended period of exposure is necessary to ensure adequate time for slowly developing cancers to be manifest. During the exposure period, whatever the length, it is important to keep exposures to other possibly confounding agents to a minimum. In this regimen, the animals are usually observed during the major portion of their lifetime and the occurrence of tumors, in number, type, and time of development, are the critical endpoints. This type of study should include several dose groups and requires a relatively large number of animals, particularly if the natural incidence of a tumor type is low. As one would surmise, studies evaluating complete carcinogenicity are expensive due to both the length of time and the number of animals involved. Because carcinogenesis is a multi-step process, another experimental approach is to assume the agent of interest (RF) acts as either an initiator or a promoter where a two-phase protocol is required for testing. “Initiation” is de-

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy fined as a genotoxic event where the carcinogen interacts with the DNA and introduces genetic changes that may later result in malignancy. “Promotion” is operationally defined, where the promoting agent is applied subsequent to initiation and generally over a protracted period of time. Promotion is associated with a number of subcellular events that are generally non-genotoxic and is responsible for the conversion of initiated cells to cancerous cells. To evaluate RF as an initiator, one high dose of RF would be given, followed by repeated exposure to a known promoter (e.g., 12-O-tetradecanoylphorbol-13-acetate, TPA) over a long term. If RF were to be investigated for possible promotional effects, the animals would be treated with a known initiator (e.g., 7,12-dimethyl benz[a]anthracene, DMBA), and subsequently exposed to RF over a long term (months). These initiation/promotion approaches have the advantage of using fewer animals over a shorter period of time resulting in less cost. However, a given model is usually limited to evaluating a specific type of cancer. Because current knowledge on possible biological mechanisms of the RF exposures is limited, other than thermal effects of high doses, the applicability of these studies to cancer development in humans exposed to RF may also be limited. Long-Term Animal Bioassays Long-term animal bioassays, often conducted in two species (usually rats and mice), and in both male and female animals for two years, provide a reasonable surrogate for human-lifetime exposure. A relatively small number of long-term animal bioassays have been performed exposing rats and mice to RF signals between 10 and 2000 MHz. Almost all of the studies performed at non-thermal levels have indicated no pathological or carcinogenic effects. This includes studies with a focus on brain cancer at 836 and 860 MHz (1.1 to 1.6 W/kg, Adey and others 1999, 2000; ~1 W/kg, Zook and Simmens 2001, respectively), as well as complete histopathology in lifespan and hematology studies at 835/847, 800, and 2450 MHz (1.3 W/kg, LaRegina and others 2003; up to 12.9 W/kg, Spalding and others 1971; 0.3 W/kg, Frei and others 1998; respectively). Although some pathological effects have been reported at thermal levels (Roberts and Michaelson 1983; Prausnitz and Susskind 1962), the only report of an increased tumor incidence with long-term RF exposure at non-thermal levels was by Chou and others (1992). They reported a small increase in overall tumor occurrence in rats exposed for 24 months to 2450 MHz (SAR of 0.15-0.4 W/kg). There was no effect in the Chou and others study on a number of other parameters including metabolism, immune function, hematology, serum chemistry, thyroxin levels, protein parameters, growth, or open-field behavior. It should be noted that the one bioassay cancer study investigating a frequency (435 MHz) most closely related to the PAVE PAWS frequency also found no overall increase in cancer in exposed animals (1.0 mW/cm2; Toler and others 1997). Some organs (specifically the adrenal

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy glands) did show slight trends toward increased cancer in RF exposed animals; however, the number of tumors was small and no statistically significant differences could be determined between the exposed and control groups. Radiation- or Chemically Initiated and Transgenic Animal Studies Similar to long-term animal bioassays, studies in which tumors have been initiated by means other than RF have been mostly negative. Many different initiation models have been used in these studies in which rodents have been exposed to radiofrequencies between 800 and 1500 MHz. The experimental models used include: brain tumors initiated in rats with ethyl nitrosourea (836 and 860 MHz, approximately 1 W/kg) (Adey and others 1999, 2000; Zook and others 2001, respectively); benz(a)pyrene initiated sarcomas in rats (900 MHz, 0.075 and 0.27 W/kg) (Chagnaud and others 1999); dimethyl-benzanthracine-initiated rat mammary tumors (900 MHz, SARs from 0.017 to 0.07 W/Kg) (Bartsch and others 2002; Anane and others 2003); diethyl nitrosamine-induced hepatomas in rats (929 and 1500 MHz) (Imaida and others 1998); and radiation-induced mouse lymphomas (902 MHz, 0.35 W/kg) (Heikkinen and others 2001). In all of these cited cancer studies, no adverse effects of RF exposure were noted. In addition to chemicals and radiation, genetically initiated animal models (transgenic mice) have also been studied in RF carcinogenicity testing. No effects of RF exposure on mutagenicity or tumor development were found using pKZ-1 transgenic mice (900 MHz, 4 W/kg) (Sykes and others 2001). Another study by Repacholi and others (1997) in Pim-1 mice reported an association between long-term RF exposure [900 MHz, 0.13-1.4 W/kg] and mortality from a certain sub-type of lymphoma. A subsequent study performed at multiple dose levels with more uniform and more fully characterized exposure (900 MHz, multiple levels to 4.0 W/Kg) did not confirm the positive effects reported in the original study (Utteridge and others 2002). Tumor-Cell Injection Studies A few studies of tumor progression, using non-thermal RF exposure levels, have been conducted by injecting tumor cells into mice and determining growth rate, survival, and metastatic progression. Although increased survival of the host, as well as inconsistent evidence of either augmentation or suppression of immune function has been reported in response to thermal levels of RF exposure, no such effects were observed in studies using lower levels of exposure (Salford and others 1993, 915 MHz, up to 8.3 W/kg; Higashikubo and others 1999, 836 and 847 MHz, 0.75 W/kg).

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy Summary of Animal Cancer Studies Most animal bioassay studies have not demonstrated increased cancer risk resulting from long- or short-term RF exposure at non-thermal levels. In the very few studies at thermal levels within the frequency range of interest (10-2000 MHz), only inconsistent evidence of exposure effects have been reported, and those have not been confirmed in similar or replicate studies. HUMAN BEHAVIORAL STUDIES Most of the RF behavioral studies in humans have focused on frequencies associated with cellular telephony (800/900 to 1800 MHz). Areas of investigation have included hypersensitivity to exposure, sleep, memory, attention behaviors, or other cognitive functions. A wide range of subjective health responses have been attributed to RF exposures (see review, Sandstrom and others 2001), including headaches, fatigue, dizziness, and nausea. The number of reports, however, from studies actually conducted under controlled research conditions, is quite small. In those blind studies (where exposure or non-exposure status was not known by the researchers or subjects during experimentation), Koivisto and others (2001, Hietanen and others (2002), Zwamborn and others (2003), found no effects of RF exposure. The studies examining sleep patterns in people exposed to RF fields have presented mixed results with some effects reported, although the positive responses remain relatively ill-defined. An initial report by Mann and Roschke (1996) suggested that RF exposure (900 MHz) resulted in decreased latency to sleep onset and a reduction in rapid eye movement (REM) sleep. These observations were not replicated in further studies (Wagner and others 1998, 2000). Borbely and others (1999) and Huber and others (2003) reported changes in the spectral power in non-REM sleep but REM sleep and onset latency were unaffected. A reduction in the percentage of slow-wave sleep was observed by Lebedeva and others (2001) when subjects were exposed throughout the night. In humans exposed to a 900 MHz at 1 W/kg SAR, Huber and others (2000, 2002) observed changes in the spectral power of EEG patterns in the initial phases of sleep, but when the exposure was to a continuous-wave signal, no significant effects occurred. Two other recent studies (Mann and Roschke, 2004) found no changes in sleep patterns and no evidence of sleep disturbances due to RF exposure. Cognitive function has been the focus of a number of recent studies evaluating performance and RF exposure. Preece and others (1999) observed decreased choice reaction time in people exposed to analog 902 MHz fields. However, digital signals did not produce such changes. Nor were there effects from exposure in simple reaction times or in spatial memory. The choice reaction time changes were ascribed to possible thermal impacts of the signal. In another study at 902

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy MHz, Kovisto and others (2000) reported decreased response times in simple reaction and vigilance tasks with localized heating in the brain as the possible explanation for the effects. Using an improved experimental design, the same research group was unable to confirm the inital findings and reported no changes in the reaction times or error rates with exposure (Haarala and others 2003). There have been a few additional studies examining different cognitive functions and memory. Many of these studies show improved performance on recognition memory task (Lass and others 2002), improvement on cognitive tasks (Edelstyn and Oldershaw 2002), a field-dependent improvement in memory (males only) at 1800 MHz (Smythe and Costall 2003), and a facilitating effect on attention in mobile phone users (Lee and others, 2001). ANIMAL BEHAVIOR Alteration of behavior in animals has provided the foundation for human RF-exposure guidelines for the past two decades (ANSI C95.1-1982; NCRP, 1986; IEEE/ANSI C95.1-1992). However, nearly all of the reported studies, including those showing behavioral responses in exposed animals, have been conducted in an RF-intensity range that would be expected to produce thermal sensations and/ or heating of tissue (e.g., Brown and others 1994; Akyel and others 1991; D’Andrea and others 2003). Acute thermal responses in animals can include perception, aversion, work perturbation or work stoppage, decreased endurance, and even convulsions and death. Behavioral effects of RF in the non-thermal range, however, are more difficult to identify. Studies usually conducted in mice or rats and using nonthermal levels of RF exposure (and even some using thermal levels of exposure), have generally reported no effects on various aspects of behavior, including operant behavior (1.25 GHz at less than 7.6 W/kg, Akyel and others 1991; 1.3 GHz at less than 3 W/kg, Lebovitz 1981 and Lebovitz and Seaman 1983; 900 MHz at 17.5 to 75 mW/kg, Bornhausen and Scheingraber 2000); cognitive behavior (900 and 1800 MHz at 0.5 W/kg, Sienkowicz and others 2000); and performance and activity changes in rats exposed in utero (915 MHZ at 3.6 W/kg, Jensh and others 1982a,b). An additional study examined chick behavior (450 MHz at 5 mW/cm2, Sagan and Medici 1979). One report does suggest behavioral changes with apparent non-thermal acute RF exposures, including reduced aggressive behavior in rats (1.3 GHz at 0.65 mW/cm2, Frey and Spector 1986). Additionally, performance in spatial-navigation tests has been examined in a number of studies using radial-arm or water mazes (at 900 and 1800 MHz, 0.5 W/kg, Sienkiewicz and others 2000, and at 900 MHz, up to 3.5 W/kg, Dubreuil and others 2002), with no indication of adverse effects. There has been a report of reduced performance in a radial-arm maze at 2450 MHz by Lai and others (1994); however, Cobb and others (2004) were unable to demonstrate similar results in rats, also exposed at 2450 MHz, and other studies have also been unable to confirm Lai’s results

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy (Cosquer and others 2004; Cobb and others 2004; Cassel and others 2004). Yamaguchi and others (2003) reported no effects in a T-maze performance study at 1.4 GHz until the exposure reached clearly thermal levels (25 W/kg). With chronic low-level RF exposures, reports on behavioral effects have been generally negative (D’Andrea and others 1980), although positive reports at near-thermal levels (2.7 W/kg whole-body average) have been reported (Mitchell and others 1977, 1981, 1988) at 2450 MHz. Summary of Behavioral Studies Results from laboratory studies in humans have indicated subtle and transient effects; however, the health implications remain unclear. There is some evidence that acute exposure may result in minor facilitation effects on attention functions and decreases in some specific reaction times to stimuli. Effects on sleep have been reported but remain mixed and ill-defined. The available data are too sparse to determine if subjective responses can be caused by RF exposure, although the strongest studies indicate no effects on a range of endpoints. Disruption of complex behavioral performance in several animal species, under diverse exposure conditions, has been used as a basis for setting human exposure guidelines since 1982. The threshold SAR selected to establish the standard was chosen at 4 W/kg, a level based upon thermal effects and often (but not always) accompanied by an increase in core body temperature of ~1.0°C. Alteration of an assortment of other behaviors, both learned and unlearned, can also occur in animals at SARs between 1and 4 W/kg, subject to the frequency of the signal and the size of the animal. It appears that the behavioral changes due to RF exposure at these levels are reversible, and no consistent evidence exists for long-term, permanent effects. Extrapolation of animal data to humans has been useful in setting exposure standards. However, human ability to discriminate and cognitively act upon perception of intense RF fields is generally superior to that ability in animals and therefore animal data may tend to underestimate threshold levels for safety. OTHER PHYSIOLOGICAL STUDIES EEG and Brain Electrical Activity Humans exposed to mobile-phone RF fields have generally not shown effects of exposure on the spontaneous, awake electroencephalogram (EEG) (Hietanen and others 2000; Roschke and Mann 1997). However, possible changes have been observed when exposure was given during the performance of memory tasks or under other more demanding paradigms (Freude and others 1998, 2000; Eulitz and others 1998. Krause and others reported changes in EEGs of humans exposed to 902 MHz for both auditory tasks (Krause and others

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy 2000a) and visual memory tasks (Krause and others 2000b). Additionally, Croft and others (2002) determined the resting EEG parameters to be changed during an auditory discrimination task. Several studies evaluating sleep parameters have examined EEG in human subjects as a way to assess RF impacts on sleep. These studies have been discussed above in the section on behavior and RF exposure in humans. Studies in a variety of animals, including rats, rabbits, cats, and monkeys have shown various changes in EEG measurements from the brain (rabbits at 30 MHz, 0.5-2 kV/m, Takashima and others 1979; cats at 147 MHz, unspecified SAR, Bawin and others 1973; rats at 945 MHz, unspecified SAR, Vorbyov and others 1997; rats at 900 MHz, 1.3 W/kg, Thuroczy and others 1994); however the types of changes are not consistent across studies nor have they generally been independently and systematically confirmed. Effects on Blood Pressure/Heart Rate A stimulation study in humans by Braune and others (1998) initially reported increases in heart rate (HR) and blood pressure (BP). However, these effects were not replicated in the same laboratory (Braune and others 2002), and were also not confirmed by an additional independent human study (Tahvanainen and others 2004). Animal studies have reported effects of RF exposure on BP and HR and other cardiac functions (e.g., Lu and others 1992); however, these have all been conducted at exposure levels in which thermal increases would be expected in the tissue. Blood Brain Barrier Studies Using RF exposures of 2450 MHz, Frey and others (1975) initially reported that at approximately 1 W/kg an increase in blood brain barrier (BBB) permeability was observed in rats. Using a 1.3 GHz RF signal, Oscar and Hawkins (1977) reported increased BBB permeability at 0.4 W/kg (CW) and 0.1 W/kg (PW). Preston and others (1979) suggested that the changes observed by Oscar and Hawkins may have been due to variations in blood flow, so Oscar and others (1981) subsequently determined that increased local brain blood flow did occur following RF exposure. In following up this finding, Oscar and co-workers used a technique to measure BBB permeability that is insensitive to blood-flow change, and reported no effect of RF radiation on BBB (Gruenau and others 1982). Thus the effect originally reported by Oscar and Hawkins (1977) was probably an artifact. Using techniques similar to those of Oscar and Hawkins, at 2450 MHz, Preston and others (1979) and Preston and Prefontaine (1980) reported no effect of RF exposure on BBB permeability at whole body SARs (0.02-6 W/kg) or at SARs in the head (0.08-1.8 W/kg). Additional efforts to establish the occurrence of the BBB effects observed by Oscar and Hawkins (1977) and Frey and others

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy (1975) have been unsuccessful (Ward and others 1982; Ward and Ali 1985; Merritt and others 1978). Pigs have been exposed repeatedly to 452 MHz fields intermittently for 8 h/d for 90 days. The BBB showed no leakage in exposed animals, nor did neurohistological and enzyme-histochemical preparations show any evidence of damage to nervous tissue in the brain (Sutton and others 1982). Further animal studies in mice also have demonstrated no BBB permeability changes with either a one-hour exposure at 4 W/kg (whole body) or after a lifetime of exposure at SARs ranging from 0.25, 0.5, 1.0, and 4.0 W/kg (whole body) (Finnie and others 2001, 2002). At 2450 MHz, Sutton and Carroll (1979) observed that BBB permeability was increased in rats when the temperature in the brain was 40° C or more. Furthermore, when the core body temperature of the rat was kept at 30° C during exposure of the head, the exposure time had to be lengthened to produce any disruptive effects on the BBB. These observations suggest that RF-induced hyperthermia may indeed be the cause of BBB disruption during exposure. Merritt and others (1978) also showed that BBB permeation in rats was impacted by providing either hot air or RF radiation to heat the animals to 40°C and concluded that hyperthermia was the causative factor, not RF energy per se. Williams and colleagues (1984a-d) report on a series of experiments in which they conclude that RF exposure (at 2450 MHz) produced BBB effects that result from temperature-dependent changes and not as a direct result of the RF energy. Fritze and others (1997) also found BBB permeability changes in rats consistent with thermal effects. A number of other papers have also demonstrated changes in BBB permeability resulting from thermal effects of RF exposure (Lin and Lin 1980, 1982; Goldman and others 1984; Neilly and Lin 1986; Moriyama and others 1991; Ohmoto and others 1996). There are a few papers that report BBB-permeation effects in animals exposed to RF fields below those considered to be “thermal.” Persson and others (1997) observed an increase in BBB permeability by about three-fold in animals exposed to CW 915 MHz radiation. However, the changes did not vary with SAR from 0.02 to 8.3 W/kg. Results using modulated RF exposure were not SAR dependent either, with the lowest SARs (0.0004-0.008 W/kg) demonstrating the greatest permeability changes, and at the highest SARs (1.7-8.3 W/kg) no modulated frequency was effective in increasing BBB permeation. The 1997 paper by Persson and others appears to include data from previous studies in their laboratory (Salford and others 1993, 1994; Persson and others 1992) and a recent paper (Salford and others 2003) from this research laboratory describes effects of 915 MHz RF on the BBB in rats exposed to very low SARs (< 0.2 W/kg). No exposure-response relationship was found in work performed in another laboratory (Chang and others 1982) in which only one of six RF exposure levels (at 1 GHz) affected BBB permeability in dogs.

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy IMMUNE- AND ENDOCRINE-FUNCTION STUDIES There are very few studies in humans examining endocrine status during or following exposure to RF fields. Mann and others (1998) observed no changes in serum melatonin, growth hormone, or luteinizing hormone levels during exposure of volunteers to 900 MHz, although cortisol production showed a small transient increase. No effect on urinary levels of 6-hydroxymelatonin sulfate was reported in humans exposed to 900 MHz fields (Bortkiewicz and others 2002). In addition, Radon and others (2001) observed no changes in melatonin, cortisol, or markers of immune function when humans were exposed for 4 hours to 900 MHz fields. In animals, most of the studies investigating immune and endocrine function have been performed at 2450 MHz, with only a few in the 10 MHz to 2000 MHz range. A few of those laboratory studies report alterations in various hormones (Abhold and others 1981) and neurotransmitters (Inaba and others 1992; Mausset and others 2001) at 900 MHz in animals exposed to low intensities (non-thermal levels) of RF. There are reported increases as well as decreases in immune-cell subpopulations, exposed at 900 MHz (Dasdag 2000), and decreased levels of immunoglobin titer and cellular-immunity function depending upon modulation frequency of the RF signal used for exposure (450 MHz, Lyle and others 1983). Most of the low-level exposure studies indicate no significant changes in hormone levels or activity (900 MHz, Vollrath and others 1997, and Heikkanen and Juutilainen 1999). In addition, a number of studies have been reported in which RF exposure, at levels insufficient to cause increased temperatures in tissue, does not produce observable changes in immune cell function, differentiation, mitogenic activity, or other hematological parameters (Djordjevich and others 1977; 100 MHz, Smialowicz and others, 1981a,b; 900 MHz, Chagnaud and Veyret 1999). A notable exception to these studies is the work of Toler and others (1988) who studied the changes in blood-borne factors during six months of exposure to a 435 MHz radiation at 0.3 W/kg. While most factors were not observed to undergo significant change, dopamine levels were found to drop almost immediately at the start of the exposure period, and remained depressed throughout the six-month exposure period. Dopamine levels at the end of the study period were only one-half those in the sham-exposed animals. Although not yet replicated, the results of this study are important to consider due to its size, the magnitude and duration of altered dopamine response, and because the exposure frequency (435 MHz) is the center frequency of the PAVE PAWS radar. Those studies in which effects have been observed in immune-system parameters or endocrine function are predominantly at exposure levels at 2450 MHz that are clearly in the thermal RF range (Gildersleeve and others 1988; Lu and others 1985, 1986, 1987; Michaelson and others 1961). Using thermal levels of RF exposure, one study found no effect on autoimmune response (Anane and

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy others 2003); however, many studies observed either increased or decreased immune-cell function (Bogolyubov and others 1987, 1988; Liburdy 1977, 1979, 1980; Takashima and Asakura 1983; Smialowicz and others 1981a,b, 1982a, 1982b) as well as the induction of stress markers (Cleary and others 1980). The reported effects appear to be similar to the effects of non-RF heating. Summary for Other Physiological Parameters The originally reported effects of low-level RF exposure on the BBB have not been confirmed. However, many investigators have produced results that indicate changes in the permeability of the BBB when a significant increase in temperature occurs as a result of absorption of RF energy. The thermal effects have been demonstrated through a range of endpoints, including uptake of radiotracers, dyes, and proteins. Some studies have even shown uptake of virus particles and drugs to be influenced by RF-produced thermal increases. Based on modeling studies, localized exposure of the head at 1.6 W/kg will produce a 0.1°C increase in brain temperature, an increase that is small in comparison to the temperature increases associated with changes in BBB permeability described above. The reports of permeability changes in the BBB at SARs <4 W/kg generally are not useful in arriving at exposure guidelines since the effects at these low levels have not been confirmed and no dose-response relationship has been established. RF studies investigating hematologic, immunologic, and endocrinologic endpoints in animals exposed to RF have produced both positive and negative results. However, most of the studies in which effects were observed have been performed at intensities of RF exposure expected to result in increased temperatures. In the few studies that have reported effects at non-thermal exposure levels, the observations are inconsistent across studies and not in general agreement with the larger body of evidence pointing toward non-effects at these levels. Certainly, there is a lack of evidence of RF-induced effects that can be directly related to adverse health responses. TERATOLOGY, REPRODUCTION, AND DEVELOPMENT Teratogenicity During pregnancy, heat stress in animals where maternal body temperatures are raised to thresholds of 40.5-42.0°C has been demonstrated to increase the incidence of birth defects (Boreham and others 2002; Bennet and others 1990). Similarly, RF exposure of pregnant rodents, sufficient to increase maternal core body temperature (whole-body average SARs of > 9 W/kg), has also been shown to be teratogenic (27 MHz, Lary and others 1982, 1983, 1986; 970 MHz, Berman and others 1992; 915 MHz, Jensh and others 1982a, 1997; Guillet and Michaelson 1977). Exposure to RF at ~3 W/kg at 2450 or 100 MHz has been reported to cause

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy of CW, and modulated at 16, 60, and 120 Hz, on the development and differentiation of rat embryos. Using SARs of 0.2, 1.0, and 5.0 W/kg, no statistical differences between exposed and control embryos were observed following 48 hours of exposure. A few sporadic changes were observed under some exposure conditions, specifically increases in somite numbers at modulation frequencies of 16 and 120 Hz. Reproduction Temporary sterility was reported to occur in male rats exposed to 1.3 GHz at levels sufficient to cause intra-testicular temperatures of ~40°C (Lebovitz and others 1983, 1987). Longer-lasting alterations of reproductive efficiency have been observed with RF exposures producing temperatures greater than 45°C in animal testes. In several studies examining chickens exposed to moderately high levels of RF, the exposure was determined to cause a slight decrease in number of eggs laid (Krueger and others 1975; Giarola and Krueger 1974). However, in these studies, thermal parameters were not well characterized. A study at 900 MHz by Dasdag and others (1999) reported that exposure to RF for 1 month at 0.141 W/kg resulted in decreased diameter of seminiferous tubes, but no other effects were observed in a histological examination of all major organ tissues. There is some question with regard to the non-thermal nature of the observed effect since the study also reported an increase in rectal temperature. An additional report indicates an effect of low-level RF exposure on reproductive competance in rodents (Magras and Xenos 1997), although significant flaws in study design and control make the interpretation difficult. Summary: Reproduction and Development Although a number of studies have reported teratogenic effects of RF exposure in animal models, the positive results have almost always come from studies where significant temperature increases were observed in the dam. The few studies in which adverse effects on reproduction and/or development have been reported from non-thermal levels of RF exposure are relatively isolated. In addition, there appear to be possible species-specific differences in teratogenic responses to RF exposure suggesting that extrapolation of animal data to humans may not be straightforward. Examined in total, the available literature does not indicate any consistent effect of acute or chronic RF exposure on reproduction and development in animals unless significant temperature increases are produced. There are no human laboratory studies addressing this area of investigation.

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An Assessment of Potential Health Effects from Exposure to Pave Paws Low-Level Phased-Array Radiofrequency Energy IN VIVO STUDIES: CONCLUSIONS Relatively few human laboratory studies investigating the RF exposure for possible health effects have been performed. Almost all of these were conducted at fairly low intensity levels using frequencies relevant to cellular telephony. Results have been mixed in the areas of RF effects on sleep and other behaviors and brain activity as determined by EEG. The range of effects, however, has been inconsistent from study to study without robust replication or direct implications for health impacts. Futhermore, studies examining RF effects on hormone or immune parameters have almost universally been negative. With animal studies, across a wide range of biologic endpoints, a considerable number of studies have been conducted to evaluate the impact of RF exposure. The majority of laboratory studies have been performed at 2450 MHz, which is outside the frequency window of interest as defined for the purposes of this PAVE PAWS study (see Appendix A). However, in some cases, because little biological information was available from animals exposed at lower frequencies, some review of 2450 MHz data was utilized. The strong indication from the collected data suggests that various biological effects occur but generally only at field intensities where temperature is elevated in the biological target. Effects at non-thermal levels are seen only infrequently and seldom have they been independently replicated. Nonetheless, certain studies were sufficiently large, relevant to PAVE PAWS, and demonstrated robust and significant effects, suggesting that replication would be merited. Specifically, the Air Force-funded studies on blood-borne endpoints by Toler and others (1988) indicating depressed dopamine levels (and not to be confused with the Toler cancer studies noted earlier) deserve to be replicated utilizing exposure patterns more representative of the PAVE PAWS system than those used by Toler and others. REFERENCES Abhold, R.H., M.J. Ortner, M.J. Galvin, and D.I. McRee. 1981. Studies on acute in vivo exposure of rats to 2450-MHz microwave radiation. II. Effects on thyroid and adrenal axes hormones. Radiat Res 88:448-455. Adey, W.R., C.V. Byus, C.D. Cain, R.J. Higgins, R.A. Jones, C.J. Kean, N. Kuster, A. MacMurray, R.B. Stagg, and W. Haggren. 1999. Spontaneous and nitrosourea-induced 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., C.V. Byus, C.D. Cain, R.J. Higgins, R.A. Jones, C.J. Kean, N. Kuster, A. MacMurray, R.B. Stagg, and G. Zimmerman. 2000. Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats chronically exposed to frequency-modulated microwave fields. Cancer Res 60:1857-1863. Akyel, Y., E.L. Hunt, C. Gambrill, and C. Vargas, Jr. 1991. Immediate post-exposure effects of high-peak power microwave pulses on operant behavior of Wistar rats. Bioelectromagnetics 12:183-195. Albert, E.N., M.F. Sherif, N.J. Papadopoulos, F.J. Slaby, and J. Monahan. 1981a. Effects of nonionizing radiation on the purkinje cells of the rat cerebellum. Bioelectromagnetics 2:247-257.

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