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Risk assessments often must consider exposures that vary over time or for which the exposure duration of concern differs from the available data, and a variety of extrapolation procedures have been devised accordingly. The present experiments explore the relationship(s) between exposure concentration (C) and time (t) to investigate procedures for assessing the risks of short-term solvent exposures. The first hypothesis tested was that the product of C x t would produce a constant health effect (Haber's rule). The second hypothesis tested was that exposure conditions produce effects in proportion to the tissue concentrations created. Awake, adult, male Long-Evans (LE) rats were exposed to trichloroethylene (TCE) vapor in a head-only exposure chamber while pattern onset/offset visual evoked potentials (VEPs) were recorded. Exposure conditions were designed to provide C x t products of 0 ppm/h (0 ppm for 4 h) or 4000 ppm/h created through four exposure scenarios: 1000 ppm for 4 h; 2000 ppm for 2 h; 3000 ppm for 1.3 h; or 4000 ppm for 1h (n = 9-10/concentration). The amplitude of the VEP frequency double component (F2) was decreased significantly by exposure; this decrease was related to C but not to t or to the C x t product, indicating that Haber's rule did not hold. The mean amplitude (+/- SEM in muV) of the F2 component in the control and treatment groups measured 4.4 +/- 0.5 (0 ppm/4 h), 3.1 +/- 0.5 (1000 ppm/4 h), 3.1 +/- 0.4 (2000 ppm/2 h), 2.3 +/- 0.3 (3000 ppm/1.3 h), and 1.9 +/- 0.4 (4000 ppm/1 h). A physiologically based pharmacokinetic (PBPK) model was used to estimate the concentrations of TCE in the brain achieved during each exposure condition. The F2 amplitude of the VEP decreased monotonically as a function of the estimated peak brain concentration but was not related to the area under the curve (AUC) of the brain TCE concentration. In comparison to estimates from the PBPK model, extrapolations based on Haber's rule yielded approximately a 6-fold error in estimated exposure duration when extrapolating across only a 4-fold change in exposure concentration. These results indicate that the use of a linear form of Haber's rule will not predict accurately the risks of acute exposure to TCE, nor will an estimate of AUC of brain TCE. However, an estimate of the brain TCE concentration at the time of VEP testing predicted the effects of TCE across exposure concentrations and durations.

The ambient temperature (Ta) to house and study laboratory rodents is critical for nearly all biomedical studies. The ideal Ta for housing rodents and other animals should be based on their thermoregulatory requirements. However, fundamental information on the behavioral thermoregulatory responses of single- and group-housed rodents is meager. To address this issue, thermoregulatory behavior was assessed in individual and groups of CD-1 mice housed in a temperature gradient. Mice were housed in groups of five or individually while selected Ta and motor activity were monitored. Single- and group-housed mice displayed a circadian oscillation of selected Ta and motor activity with relatively warm T(a)s of approximately 29 degrees C selected during the light phase; during the dark phase selected Ta was reduced by 4 degrees C, whereas motor activity increased. Selected Ta of aged (11 months old) mice housed individually was approximately 1.0 degrees C warmer than the group-housed mice. Thermal preference of younger mice (2 months old) was similar for single- and group-housed animals. The operative Ta of mice housed in standard facilities was estimated by measuring the cooling rate of "phantom" mice modeled from aluminum cylinders. The results show that the typical housing conditions for single- and group-housed mice are cooler than their Ta for ideal thermal comfort.

The negative peak occurring approximately 160 ms after stimulation (peak N160) of flash evoked potentials (FEPs) of rats changes with repeated testing. Habituation, sensitization, and arousal have all been invoked to explain these changes, but few studies have directly tested these explanations. We examined within-session changes in peak N160 amplitude with repeated testing, and the modulatory effects of stimulus intensity and auditory white noise. Peak N160 amplitude increased with daily testing (between-session changes), and was larger at greater stimulus intensities. In contrast, peak N160 amplitude underwent within-session increases on early days and within-session decreases on later days. The within-session changes were not affected by stimulus intensity. In rats previously tested in a quiet environment, exposure to acoustic white noise increased motor activity and transiently decreased peak N160 amplitude, which then increased and subsequently decreased with continued photic and acoustic stimulation. Repeated testing in the presence of noise did not alter the within-session changes in peak N160 amplitude. Heart rate showed both within- and between-session decreases, but was unaffected by noise. The data suggest that the within-session changes in peak N160 amplitude may reflect a habituation-like response to the test environment.

Many toxic agents have been reported to produce acute, adverse effects on cardiac function. Often these data are missing from toxicological studies because of the difficulty and expense of monitoring cardiac parameters. We have developed a simple, inexpensive heart rate monitor (HRM) capable of continuously quantitating and displaying steady-state heart rate (HR) while simultaneously detecting the occurrence of arrhythmic events. This device incorporates many operator-selectable features designed to promote maximum versatility and use with a number of animal species over a variety of experimental conditions. The HR is computed from the electrocardiogram (ECG), using the reciprocal of the analog integration of the R-R interval. Adjustable trigger level and input polarity controls are provided to optimize compatibility with the ECG signal. A high-pass filter is employed to accommodate minor excursions in the signal baseline, and a precision rate generator is incorporated for calibration purposes. The HRM ca...

Body-weight maintenance is required in a variety of behavioral and physiological studies. A PC-based animal-weighing system is described; it features automated data collection and allows for accurate control of body weight in test animals via manipulation of food intake. Major system components are a PC XT-compatible computer, Lotus 1-2-3 and National Instruments Measure software, and a digital electronic balance. The system is controlled by Lotus macros, which present menus to the user. Menus provide for the basic operations of the system, including establishing new data files, collecting weight data, printing, and transferring files to a laboratory minicomputer. The optional weight-maintenance algorithm calculates the amount of food necessary to maintain target body weights. Some important aspects of this algorithm, including maintenance-feeding and gain parameters, can be manipulated to reduce weight oscillation in test animals or to accommodate the maintenance of body weight of different animal species. The system facilitates acquisition and recording of weight data, minimizes the frequency of error, and reduces variability both within and across animals when body-weight maintenance is required.

A line- and load-regulated constant-current ac shock generator has been designed for animal behavior experiments. The self-contained unit has four operating modes, amplitude adjustment, and a leakage current detection circuit. A unique feature of this generator is that the good load regulation achieved by using a high-voltage source is preserved without such problems as arcing and high current density effects. Circuit schematics, along with a discussion of selected circuits, are included. Experimental data are presented to demonstrate the utility of the device.

A frequent problem in the radiofrequency (RF) irradiation of experimental animals in health effects studies is the temporal variation of the specific absorption rate (SAR) with animal movement. An RF power controller that regulates the energy absorption rate has been designed for use with transmission line exposure systems that utilize the power difference method to monitor the SAR. The controller operates by altering the incident power to the exposure cell in order to compensate for the change in RF energy absorption rate that is due to animal motion. A circuit diagram is presented as well as experimental data under three conditions of exposure. The controller is effective in maintaining the mean value of energy absorption rate at the setpoint value even for the case of a highly active animal.

A novel technique for remote determination of breathing frequency in unrestrained rodents using microwave radiation is described. Single mice were placed inside a rectangular waveguide operating at 2450 MHz. Because mice efficiently absorb radio frequency energy at 2450 MHz, any change in their absorption, as occurs rhythmically with breathing, can be detected by monitoring the changes in power transmitted through the waveguide. When the volume of the mouse increases during inspiration, transmitted power through the waveguide momentarily decreases — during expiration the reverse takes place. By differential amplification of the analog output of the power meter used to monitor transmitted power, breathing frequency can be easily recorded on conventional recording equipment. The microwave technique has a definite advantage over other methods in that breathing frequency can be remotely monitored without the need to attach wire leads or surgically implant telemetry probes. This greatly reduces unnecessary stress to the animal. By use of larger waveguides the principle of this technique may be applied to larger species.

Electromagnetic fields can interact with biological tissue both electrically and mechanically. This study investigated the mechanical interaction between brain tissue and an extremely-low-frequency (ELF) electric field by measuring the resultant vibrational amplitude. The exposure cell is a section of X-band waveguide that was modified by the addition of a center conductor to form a small TEM cell within the waveguide structure. The ELF signal is applied to the center conductor of the TEM cell. The applied ELF electric field generates an electrostrictive force on the surface of the brain tissue. This force causes the tissue to vibrate at a frequency equal to twice the frequency of the applied sinusoidal signal. An X-band signal is fed through the waveguide, scattered by the vibrating sample, and detected by a phase-sensitive receiver. Using a time-averaging spectrum analyzer, a vibration sensitivity of approximately 0.2 nmp-p can be achieved. The amplitude of the brain tissue vibrational response is constant for vibrational frequencies below 50 Hz; between 50 and 200 Hz resonant phenomena were observed; and above 200 Hz the amplitude fall-off is rapid.

A portable four-channel electroencephalogram (EEG) cassette recording system has been designed which offers good performance, is simple to construct, and moderate in cost. The recorder is compatible with a commercially available, portable, battery-operated power source, and is therefore usable in the field where line power is unavailable. The system incorporates a small, lightweight, portable, battery-powered oscilloscope which provides monitoring and playback capability. While a few experimental portable EEG recorders have been reported in recent years with more channel capacity or perhaps lighter weight, the engineering details of these units are rarely published and, in any event, would require a substantial effort for most electronics support shops to reproduce. The recording system described here, however, should be within the capability of most electronics support groups to assemble in a very short time and provide good performance.

1. 1. Colonic and tail skin temperature of the unrestrained Fischer rat were measured immediately after a 90 min exposure to 600MHz radiofrequency radiation in a waveguide-type system. Ambient temperature (Ta) was maintained at either 20, 28 or 35°C. The specific absorption rate (SAR) in dimensions of W/kg was controlled at a constant level through a feedback control circuit. 2. 2. The SAR needed to elevate colonie and tail skin temperature decreased with increasing Ta. For example, a 0.5°C elevation in colonic temperature occurred at SARs of 4.3, 0.9 and 0.5 W/kg when Ta was maintained at 20, 28 and 35°C, respectively. 3. 3. Data from the present study were combined with data from earlier studies to assess the impact of varying Ta on the thermogenic effect of RF radiation in different species. In species ranging in mass from 0.02 to 3.2 kg, a double logarithmic plot of body mass versus SAR needed to elevate colonie temperature by 0.5°C was linear and inverse with a high goodness of fit (r2 = − 0.94). 4. 4. The highly correlated allometric relationship shows that, as body mass decreases, the relative impact of 7, on the thermogenic effect of RF radiation increases.

The permeability of the blood-brain barrier to high-and low-molecular-weight compounds has been measured as a function of continuous-wave (CW) and pulsed-microwave radiation. Adult rats, anesthetized with pentobarbital and injected intravenously with a mixture of [14C] sucrose and [3H] inulin, were exposed for 30 min at a specific absorption rate of 0.1 W/kg to 1.7-GHz CW and pulsed (0.5-microseconds pulse width, 1,000 pps) microwaves. After exposure, the brain was perfused and sectioned into nine regions, and the radioactivity in each region was counted. During identical exposure conditions, temperatures of rats were measured in eight of the brain regions by a thermistor probe that did not perturb the field. No change in uptake of either tracer was found in any of the eight regions as compared with those of sham-exposed animals.

Many investigators have reported that microwave radiation can interact with the basic genetic apparatus of cells and cause abnormal biologic expression.1-6 These reports have left varying degrees of doubt as to whether the absorbed radiation energy was enough to cause generalized heating and, if so, whether this heating caused a temperature rise in the system which thus produced the observed e f f e ~ t . ~ . ~ In 1968, Webb and Doddsa described a dramatic, although apparently transient, inhibition of cell growth in response to microwave exposure. This paper is very significant for two reasons. First, the irradiation temperature was 12°C below the optimum growth temperature for the test organism, Escherichia coli. For generalized heating to produce the observed inhibition, the sample temperature would have to increase by more than 14"C, but their temperature monitoring indicated a rise of less than 1°C. Second, the forward power, after passing through a frequency doubler to produce 136-GHz radiation, was much too low (estimated at 7 pW) to produce generalized heating of the sample. Because our experiments have been greatly influenced by Webb and Dodds' report, their results should be reviewed. Cells of E. coli B were irradiated in two growth stages, lag and log phases, and samples were obtained every 30 min and assayed for colony forming units (CFU), that is, for the ability to form colonies on nutrient broth. In FIGURE 1, these data are plotted as the equivalent number of cell doublings that occurred during the irradiation period, expressed as N , / N t = 2,, where N o and N, represent the CFU concentration a t zero and various irradiation times, respectively, and n denotes the number of cell doublings. The control cultures respond as expected for the two growth stages, whereas the irradiated cultures in lag phase do not divide and those in log phase divide only once. Because the assay required the cells to grow, these data can be interpreted as demonstrating the effects of a blockage of cell division or growth, which is removed when the cells are withdrawn from the microwave field. There are other interpretations of these data, but they will be discussed later. Our objective was to use Webb and Dodds' system to determine which microwave frequencies and wave patterns in the environment might affect biologic systems in a nonthermal way and thus merit further detailed study.

A versatile temperature controlled microwave exposure chamber has been designed especially for use in microwave bio-effects research. The device uses a thermoelectric heat pump to cool the air in the chamber below ambient and a resistive heater for above ambient operation. A unique feature of the exposure chamber is that the radiating antenna can be either inside or outside of the chamber.

A multidisciplinary approach was employed to assess the possible biological effects of chronic exposure of rats to 100-MHz continuous wave (CW) radiofrequency (RF) radiation. Pregnant dams and later their offspring were exposed daily for 4 hr for up to 97 days of age. Specific absorption rates (SAR's) for rats of varying ages were determined by twin-well calorimetry. Between exposures, animals were evaluated using various developmental and biological indices. No difference was observed between 100-MHz-exposed and sham-exposed rats for complete blood counts, mitogen-stimulated response of lymphocytes, frequency of T- and B-lymphocytes, or antibody response to Streptococcus pneumoniae capsular polysaccharide. No mutagenic effect on the sperm cells of rats exposed for over 90 days to 100 MHz was observed using the Dominant Lethal Assay. The mean time to eye opening was significantly accelerated in exposed compared to sham-exposed rats. In rats exposed to 100 MHz, significant decreases in the activity of acetylcholinesterase were observed in the striatum and medulla oblongata of 22-day-old rats and in the midbrain of 40-day-old rats but not in 97-day-old animals.