Histologic effects of high energy electron and proton irradiation of rat brain detected with a silver-degeneration stain.

Application of the degeneration sensitive, cupric-silver staining method to brain sections of male Sprague-Dawley rats irradiated 4 days before sacrifice with 155 Mev protons, 2-8 Gy at 1 Gy/min (N=6) or 22-l0lGy at 20 Gy/min (N=16) or with 18.6 Mev electrons, 32-67 Gy at 20 Gy/min (N=20), doses which elicit behavioral changes (accelerod or conditioned taste aversion), resulted in a display of degeneration of astrocyte-like cell profiles which were not uniformly distributed. Plots of 'degeneration scores' (counts of profiles in 29 areas) vs. dose for the proton and electron irradiations displayed a linear dose response for protons in the range of 2-8 Gy. In the 20-100 Gy range, for both electrons and protons the points were distributed in a broad band suggesting a saturation curve. The dose range in which these astrocyte-like profiles becomes maximal corresponds well with the dose range for the X-ray eradication of a subtype of astrocytes, 'beta astrocytes'.

Radiation quality and rat motor performance.

The effects of bremsstrahlung, electron, gamma, and neutron radiations were investigated on the motor performance of male Sprague-Dawley rats. Rats were irradiated at a midline tissue dose rate of 20 Gy/min +/- 1 with one of the following: 18.6-MeV electrons (N = 40) or 18.1-MVp bremsstrahlung (N = 57) from a linear accelerator, 60Co 1.25-MeV gamma-ray photons (N = 48), or reactor neutrons at 1.67 MeV tissue-kerma weighted-mean energy (N = 43). Radiation effects were determined by establishing median effective doses (ED50) for rats trained on an accelerod, a shock-avoidance motor performance test. ED50's were based on 10-min postexposure performance. The ED50's were 61 Gy for electrons, 81 Gy for bremsstrahlung, 89 Gy for gamma-ray photons, and 98 Gy for neutrons. In terms of relative biological effectiveness to produce early performance decrement (10 min from the start of irradiation), significant differences existed between the electrons and the other three fields and between the bremsstrahlung and neutron fields. These differences could not be explained by macroscopic dose distribution patterns in the irradiated animals. The data imply that different radiation qualities are not equally effective at disrupting performance, with high-energy electrons being the most effective and neutrons the least.

Prevention and treatment of the gastric symptoms of radiation sickness.

Currently available treatments for radiation-induced nausea and vomiting either are ineffective or reduce performance. The new antiemetic and gastrokinetic agent zacopride was tested in rhesus monkeys to assess its behavioral toxicity and its ability to inhibit radiation-induced emesis. Zacopride (intragastric, 0.3 mg/kg) or a placebo was given blindly and randomly in the basal state and 15 min before a whole-body 800 cGy 60Co gamma-radiation dose (except for the legs which were partially protected to permit survival of some bone marrow). We determined (1) gastric emptying rates; (2) the presence and frequency of retching and vomiting; and (3) the effect of zacopride on the performance of a visual discrimination task in nonirradiated subjects. No vomiting, retching, or decreased performance was observed after either placebo or zacopride in the control state. Following irradiation plus placebo, 70 emeses were observed in 5 of 6 monkeys, and 353 retches were observed in all 6 monkeys. In contrast, only 1 emesis was observed in 1 of 6 monkeys and 173 retches were seen in 4 of 6 monkeys after irradiation plus zacopride (P less than 0.01). Zacopride also significantly inhibited radiation-induced suppression of gastric emptying. When given after the first vomiting episode in a separate group of irradiated monkeys, zacopride completely prevented any subsequent vomiting. The present results demonstrate that intragastric administration of zacopride significantly inhibited radiation-induced retching, vomiting, and suppression of gastric emptying in rhesus monkeys and did not cause detectable behavioral side effects when given to nonradiated monkeys. This observation has important implications in the treatment of radiation sickness.

Radiation: behavioral implications in space.

Since future space missions are likely to be beyond Earth's protective atmosphere, a potentially significant hazard is radiation. The following behavioral situations are addressed in this paper: (1) space radiations are more effective at disrupting behavior; (2) task demands can aggravate the radiation-disruption; (3) efforts to mitigate disruption with drugs or shielding are not satisfactory and the drugs can be behaviorally toxic; and (4) space- and radiation-induced emesis combined may be synergistic. Thus, future space travel will be a demanding, exciting time for behavioral toxicologists, and while the circumstances may seem insurmountable at first, creative application of scientific expertise should illicit solutions, similar to demanding situations confronted before.

Motor performance effects of propylene glycol dinitrate in the rat.

Propylene glycol dinitrate (PGDN), a major constituent of a liquid torpedo propellant, produces incoordination and impairment of balance in humans. This study was conducted to evaluate the rat as a model for PGDN-induced motor performance decrement, and to determine if direct application of PGDN onto neural tissue is a useful alternative to other routes of exposure. PGDN was injected onto the cisterna magna (ic) of adult Sprague-Dawley rats trained on the accelerod, a test of motor performance. Three groups of 13-14 male rats each received a single dose of either 5 or 10 microliters PGDN or 25 microliters sterile saline (control) while anesthetized with halothane. Accelerod performance was measured 12 min after ic injection, then hourly for 6 h, and at 24 h. Injections were evaluated using a five-stage screening criterion to eliminate grossly traumatized subjects, to verify the accuracy of the injection, and to determine the extent of mechanical damage. Eighteen out of 41 subjects passed the five-stage screen. A significant decrease in performance occurred during the first 2 h following injection of 10 microliters PGDN compared to the control and the 5-microliters groups. N significant differences were seen between the 5-microliter and control groups. These data confirm previous findings of PGDN-induced changes in human motor performance, suggesting that the rat may be a useful model for further PGDN neurobehavioral assessment. The data also indicate that ic injection may be an effective alternative to other routes of exposure for materials with appropriate chemical and biological properties if an evaluation screen is used.

Acute toxicity of petroleum- and shale-derived distillate fuel, marine: light microscopic, hematologic, and serum chemistry studies.

Rats were gavaged with 60, 48, 38, 30, or 24 ml/kg of either petroleum (P) or shale (S)-derived distillate fuel, marine (DFM). Surviving rats were killed 14 days after dosing. There was a slight difference in toxicity of the two fuels but neither fuel was very toxic. The LD50/14 was 43 ml/kg for P-DFM and 50 ml/kg for S-DFM. Lesions in rats that died indicated hepatic and renal toxicity. In another study, rats were gavaged with 24 ml/kg of either P- or S-DFM and killed at 1, 2, or 3 days after dosing. Prominent clinicopathologic findings included loss of body weight, hematologic evidence of dehydration, transient leukopenia, and serum chemistry and histopathologic alterations indicative of mild hepatic and renal toxicity.

Behavioral toxicity and efficacy of WR-2721 as a radioprotectant.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) is a promising protectant for radiation-induced lethality. However, treatment with WR-2721 also produces nausea, vomiting, diarrhea, and hypotension, which implies severe functional consequences. Three studies were conducted to assess the effects of WR-2721 on rat motor performance and weight and to assess the ability of WR-2721 to mitigate the early performance decrement (PD) produced by ionizing radiation. In the first study, rats trained on the accelerod motor performance task were give 200, 300, or 400 mg/kg WR-2721 intraperitoneally (ip). The highest dose used referenced the maximum tolerated dose in the rat, which is two-thirds the median lethal dose (590 mg/kg). The subjects were tested immediately after treatment, at 30-min intervals for 3 h, and again at 24 h. All groups (N = 6/group) demonstrated a significant decrease in accelerod performance compared to control levels across the eight test trials, which ranged from 24 to 44% in the 200 and 400 mg/kg dose groups, respectively. Performance returned to baseline levels at 24 h. Some deaths occurred at all dose levels. In the second study, motor performance was measured after exposure to radiation alone or a drug/radiation combination (N = 8/group). WR-2721 was administered 30 min before exposure to 130 Gy of gamma radiation from a 60Co source at a dose rate of 20 Gy/min. Rats were tested on the accelerod immediately after WR-2721 treatment and at 10, 15, 30, 60, and 120 min and 24 h following radiation. Performance was significantly depressed compared to control throughout the 24 h following radiation exposure, with and without WR-2721. The decrement produced by WR-2721 and radiation alone appeared to add up to the combined drug/radiation decrement found over the 15- to 120-min test periods. In the third study assessing the effects of WR-2721 on weight, untrained rats treated with 200 or 400 mg/kg WR-2721 exhibited significant weight loss that lasted up to 3 days. Weight returned to pretreatment levels in 15 days, and no deaths occurred. In summary, the data suggest that in the rat (1) WR-2721 is behaviorally toxic at doses relevant to radioprotection, (2) WR-2721 treatment along with the stress of motor performance may combine to lower the level at which lethalities occur, (3) WR-2721 does not protect for radiation-induced PD, and (4) WR-2721 combined with radiation disrupts performance more severely than either radiation or WR-2721 alone.

Effects of bremsstrahlung and electron radiation on rat motor performance.

Relatively high, rapidly delivered doses of ionizing radiation have been reported to produce an immediate decrement in performance (PD) in a number of animal species. This study investigated the effects of bremsstrahlung and electron radiation on the performance of rats unilaterally exposed by a linear accelerator (LINAC facility) at a midline tissue dose rate of 2000 rad/min. Relative radiation effects were determined by establishing median effective doses (ED50) for rats trained on the accelerod, which is a shock-avoidance test of motor performance. The ED50s were based on 10-min postexposure performance. Subjects were also tested at 15, 30, 60, and 120 min and 24 hr after exposure. Fifty-seven trained rats were exposed to bremsstrahlung radiation, and 40 trained rats were exposed to electrons. The ED50 was 8121 rad for the bremsstrahlung field and 6110 rad for the electron field, for a significantly different relative effectiveness of the electron field in producing PD of 1.35. The data imply that different radiation fields are not equally effective in producing PD.

Gamma radiation produced performance decrement in rat as assessed with the accelerod.

Early transient incapacitation (ETI) and/or performance decrement (PD) is a reduction in performance during the first 30 min after exposure to a relatively high, rapidly delivered dose of ionizing radiation. The accelerod provides a sensitive measure of functional impairment in neurotoxic evaluations of chemical agents and demonstrates that the motor performance of gamma-radiation-exposed Sprague-Dawley rats was significantly different from that of sham-radiated controls.

Evidence for endorphin-mediated cross-tolerance between chronic stress and the behavioral effects of ionizing radiation.

C57BL/6J mice exhibit a naloxone-reversible locomotor hyperactivity after exposure to ionizing radiation. These data implicate endogenous opiates in this radiogenic behavioral change. Similarly, endorphins mediate analgesia produced by chronic stress (e.g., foot shock or restraint) and levels of plasma Beta-endorphin are elevated following exposure to acute stress. Therefore, the present study sought to determine if behavioral cross-tolerance could be obtained between endorphin-producing stressors and radiation exposure. Repeated pretreatment with foot shock or restraint subsequently inhibited the locomotor-activating effects of radiation. These data are consistent with the hypothesis that cross-tolerance developed between the effects of stress-induced endogenous opiate release and the radiation-induced release of endorphins.

Comparison of accelerod and rotarod sensitivity in detecting ethanol- and acrylamide-induced performance decrement in rats: review of experimental considerations of rotating rod systems.

The relative sensitivity of two rotating rod techniques in detecting performance decrement in rats was assessed after treatment with either ethanol or acrylamide. Performance on the rod during acceleration at approximately 1 rpm/sec (accelerod) was compared to that obtained on the same rod operated at a constant speed of 20 rpm (rotarod). Rats trained to either task received a single oral dose of ethanol (0.5, 1.0, 1.5, or 2.0 g/kg) or a series of ip doses of acrylamide (25 or 50 mg/kg/day) before testing. Accelerod performance was significantly more disrupted at lower doses and for longer periods of time after ethanol ingestion than was rotarod performance. Likewise, task disruption resulted from repeated injections of acrylamide also appeared at lower cumulative doses using the accelerod. A higher proportion of the native subjects were successfully trained and the mean time for training to minimum performance standards was significantly less using the accelerod. The greater sensitivity of the accelerod technique in detecting neurotoxic effects is attributed primarily to the fact that this test provides a continuous measure of the upper limit of performance rather than the quantal or arbitrarily truncated measure that one usually obtains from the rotarod. In light of these findings, a review is presented of the primary experimental variables that affect the reliability of data obtained in neurotoxic evaluations using the accelerod and rotarod procedures.

Picture memory (pseudomatching) in rhesus monkeys.

Pseudomatching, the selection of the correct comparison stimulus without dependence on presentation of a sample stimulus, was demonstrated in monkeys being trained ostensibly on a matching-to-sample, shock-avoidance tast. Pseudomatiching occurred whenever the problem sets were not fully counterbalanced for key position and correct symbol and seemed to represent memorization of specific stimulus configurations. Some animals showed the capacity to memorize hundreds of different 4-choice problems as indicated by test trials on which the samples were omitted. To prevent pseudomatching contamination of matching-to-sample behavior one must arrange full counterbalancing and randomization of stimuli and reinforcements. Pseudomatiching test trials are also recommended.