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During the past several decades, the use of ultrasound technology in the clinical setting has greatly increased. Because nearly every pregnant woman receives at least one sonographic procedure today, there has been developing concern about the safety of such procedures. Since ultrasound exposure can result in hyperthermia and other physiological effects, the determination of a threshold or no-effect exposure has become a high-priority goal. Animal research has been important to the study of the effects of various exposures at all stages of pregnancy, since the clinical use of ultrasonography can occur during the preimplantation, organogenic, and fetal stages. Animal experiments using various mammalian species have been able to determine no-effect exposure levels for embryonic loss, congenital malformations and neurobehavioral effects. The preponderance of evidence from these studies indicates that, in the absence of a thermal effect, ultrasonography represents no measurable risk when used at recommended intensity levels.

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The objective of the investigations presented in this review was to determine if there are adverse effects due to chronic prenatal microwave exposure in rats at term and/or alterations in neonatal and adult offspring psychophysiologic development and growth. Following the establishment of a nonhyperthermal power density level of microwave radiation, pregnant rats were exposed throughout pregnancy to continuous wave 915 MHz, 2450 MHz, or 6000 MHz radiation at power density levels of 10, 20, or 35 mW/cm2, respectively. Teratologic evaluation included the following parameters: maternal weight and weight gain; mean litter size; maternal organ weight and organ weight/body weight ratios; body weight ratios of brain, liver, kidneys, and ovaries; maternal peripheral blood parameters including hematocrit, hemoglobin, and white cell counts; number of resorptions and resorption rate; number of abnormalities and abnormality rate; mean term fetal weight. Mothers were rebred, and the second, nonexposed litters were evaluated for teratogenic effects. Exposed offspring were evaluated using the following perinatal and adult tests: eye opening, surface righting, negative geotaxis, auditory startle, air righting, open field, activity wheel, swimming, and forelimb hanging. Offspring were also monitored for weekly weight and weight gain. Animals exposed to 915 MHz did not exhibit any consistent significant alterations in any of the above parameters. Exposure to 2450 MHz resulted only in a significantly increased adult offspring activity level compared to nonexposed offspring. Offspring exposed to 6000 MHz radiation exhibited an initial slight, but significant, retardation in term weight, while mothers had a significantly reduced monocyte count. No changes in any of the other term parameters were observed. A few postnatal parameters were affected in offspring exposed to 6000 MHz. Weekly weights were lower in the exposed offspring, but they recovered by the fifth week. Eye opening was delayed, and there were changes in the water T-maze and open field performance levels. Several organ/body weight ratios differed from those of the control offspring. These results indicate that exposure to 6000 MHz radiation at this power density level may result in subtle long-term neurophysiologic alterations. However, in the absence of a hyperthermic state, the microwave frequencies tested, which included frequencies used in cellular phones and microwave ovens, do not induce a consistent, significant increase in reproductive risk as assessed by classical morphologic and postnatal psychophysiologic parameters.

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An ultrasound exposure tank was specifically designed for experimental bioeffects studies. Thirty-six pregnant rats were anesthetized, immersed to the axilla in a water tank, and exposed on Day 15, 17, and 19 of gestation. Twelve rats were exposed to 5.0 MHz pulsed ultrasound of effective pulse duration equal to approximately 0.170 microseconds, pulse repetition rate (PRF) 1 kHz, and a spatial peak, temporal peak intensity (lsptp) of 500 W/cm2, representing a clinically appropriate exposure level. The spatial peak pulse average (lsppa), spatial peak temporal average (lspta), and instantaneous maximum (lm) intensities were determined to be 100 W/cm2, 24 mW/cm2, and 230 W/cm2, respectively. The maximum rarefraction pressure, pr, was measured as 12.5 x 10(5) Pa, and the total power was 2.5 mW. Twelve other rats were exposed to 1500 W/cm2, lsptp, and 12 were sham insonified. Since the focal area was about 0.05 cm2, computer controlled stepper motors moved the rats through the ultrasound field to ensure uniform exposure of the abdominal/pelvic region. Total exposure time was 35 min. A miniature thermocouple was implanted in a few rats to verify that no significant temperature increase took place due to exposure. A total of 278 offspring were maintained until postnatal Day 60 when they were subjected to two of four behavioral tests in random order within sexes. The results indicate no consistently observed dose-related alterations in adult behavior due to prenatal fetal exposure to 5.0 MHz ultrasound below an intensity (lsptp) of 1500 W/cm2.

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Histological and neurophysiological effects of in utero irradiation were examined following exposure of pregnant Wistar rat to 2.0 Gy X-irradiation or sham-irradiated on the 17th day of gestation. The 234 newborns were monitored for the age of appearance of four selected physiologic markers and the age of acquisition of five selected reflexes. Offspring were evaluated as young adults using selected behavioural tests. Postnatal growth was monitored weekly. Selected offspring were autopsied to determine the presence of morphologic central nervous system alterations. The results indicated that 2.0 Gy X-irradiation during the foetal period in rat gestation caused permanent alterations in the mature adult organism, which include non-recuperable growth retardation, morphologic changes in the brain such as microcephaly, abnormal cerebellar cortical cellular patterns, and alterations in the cell architecture of the hippocampus; diminished attainment of selected reflexes; alterations in the appearance of selected physiologic markers; and changes in adult test performance indicating significant hyperactivity among the irradiated offspring. Such exposure to X-irradiation during this period results in behavioural and morphologic alterations, which persist throughout life.

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The examination of pregnant women using diagnostic ultrasound has increased greatly over past decades in the United States. As sonography techniques have been altered and refined, there has been renewed interest concerning possible effects on the developing fetus, since exposures in mid-gestation occur during the sensitive period of brain development. The present study is concerned with possible neonatal functional deficits due to exposure of the fetus to ultrasound. An ultrasound exposure tank was designed specifically for controlled studies of bioeffects. Thirty-six pregnant rats were anesthetized, immersed to the axilla in a water tank and exposed on the 15th, 17th and 19th days of gestation. Twelve rats were exposed to 5.0 MHz pulsed ultrasound of effective pulse duration equal to approximately 0.170 microseconds, pulse repetition rate 1 kHz, and a spatial peak, temporal peak intensity (ISPTP) of 500 W/cm2, representing a clinically relevant exposure level. The spatial peak, pulse average intensity (ISPPA), spatial peak temporal average intensity (ISPTA) and maximum intensity (Im) were determined to be 100 W/cm2, 24 mW/cm2 and 230 W/cm2, respectively. The maximum rarefaction pressure, pr, was measured as 12.5 x 10(5) Pa, and the total power was 2.5 mW. Twelve other rats were exposed to 1500 W/cm2, ISPTP (ISPPA, 350 W/cm2; ISPTA, 58 mW/cm2; Im, 600 W/cm2). Twelve additional rats were sham-exposed. Since the focal area was about 0.5 cm2, computer-controlled stepper motors moved the rats through the ultrasound field to assure uniform exposure of the abdominal/pelvic region. Total exposure time was 35 min. Additionally, a miniature thermocouple was implanted in a few rats to verify that no significant increase in body temperature took place during exposure. All neonates were subjected to five reflex tests and observed for four physiological parameters. Postnatal growth also was monitored. Analyses of the data indicate there were no significant alterations in neonatal development or postnatal growth due to exposure to 5.0 MHz ultrasound below an intensity (ISPTP) of 1500 W/cm2. Studies continue to be completed at higher exposure levels to determine the margin of safety, and the animals will continue to be monitored and evaluated through young adulthood to determine if there are long-term behavioral effects due to fetal exposure to ultrasound.

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While it is clear that the levels and types of medical sonography that have been used in the past have no measurable risks, it would be inaccurate to label the modality of ultrasound as totally safe regardless of exposure. Most agents have reproductive risks and even teratogenic risks if the exposure is raised sufficiently. Thus the prudent use of sonography means that clinicians and designers of equipment have to maintain exposures far below the risks that have been demonstrated in animal studies and from the knowledge obtained about the physical changes that can be produced in humans as the absorbed dose is elevated. The reproductive risks were evaluated using five criteria: 1) human epidemiology, 2) secular trend data, 3) animal experiments, 4) dose response relationships, and 5) biologic plausibility. The analysis reveals that the human epidemiology does not indicate that diagnostic ultrasound presents a measurable risk to the developing embryo or fetus. Animal studies also indicate that diagnostic levels of ultrasound are safe and do not elevate the fetal temperature into the region where deleterious embryonic and fetal effects will occur. Because higher exposures of ultrasound can elevate the temperature of the embryo, the use of diagnostic procedures and the design of sonographic equipment should take into consideration the hyperthermic potential of higher exposures of ultrasound and the hypothetical additional risk of performing sonography on pregnant patients who are febrile. It would appear that if the embryonic temperature never exceeds 39 degrees C, then there is no measurable risk. We suggest that sonography (the field) and sonogram (the procedure) are the most appropriate and least anxiety provoking terms.

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The unique susceptibility of the central nervous system to radiation exposure is attributable to its extensive period of development, the vulnerability of its neuronal cells, the migratory activity of many of its cells, its inability to replace mature neurons, and the complexity of the system itself. Radiation effects may be due to glial or neuronal cell death, interruption of migratory activity, impaired capacity to establish correct connections among cells, and/or alterations in dendritic development. These structural changes are often manifested as behavioral alterations later in life. Sensitivity to radiation (dose-response) is markedly similar among all mammalian species when developmental periods are compared. This review compares and contrasts human and animal behavioral data. Neonatal and postnatal adult behavioral tests have been shown to be sensitive, noninvasive measures of prenatal radiation exposure, although currently their predictive validity for humans is uncertain. Additional research is needed to determine the presence and significance of postnatal morphologic and functional alterations due to prenatal exposure to low levels of ionizing radiation.

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Two measures of postnatal development are described in this paper: the PAC50 and AD50. These measures proved to be more sensitive than the use of means in the evaluation of three radiation studies involving postnatal developmental evaluation. PAC50 is the percent of achievement of a goal by litters or offspring in an experimental group at the age when 50% of the control litters or offspring attain that goal. AD50 is the age (acquisition day) at which 50% of the litters or offspring in each group attain a specified developmental goal. This methodology is a useful technique for analyzing selected behavioral data following in utero X-irradiation and may prove to be a sensitive means of determining postnatal alteration due to prenatal exposure to a variety of suspect agents.

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Seventy pregnant adult Wistar strain rats were randomly assigned to 1 of 12 exposure groups; 9th or 17th day irradiation at the 0-, 0.1-, 0.2-, 0.4-, 0.6-, or 0.8-Gy dosage level. On the first day of postnatal life, litters were reduced to a maximum of eight pups per litter. A total of 508 pups were observed for the age of acquisition of five reflexes (air righting, surface righting, visual placing, negative geotaxis, auditory startle) and the appearance of four physiologic markers (pinna detachment, eye opening, vaginal opening, testes descent). A dose-response relationship for alterations in reflex acquisition and physiologic marker appearance was observed due to exposure above 0.2 Gy on the 17th day of gestation. Therefore, 0.2 to 0.4-Gy exposure may represent a threshold range for exposure on the 17th day using these postnatal parameters.

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Thirty-nine pregnant adult Wistar strain rats were randomly assigned to one of three exposure groups: 0, 0.75, or 1.50 Gy X-radiation total exposure. Animals were exposed from the 14th to the 18th days of gestation at 0, 0.15, or 0.30 Gy per day. At term, 15 rats were killed and morphologic analyses were completed. Twenty-four rats were allowed to deliver their offspring. On the first day of postnatal life, litters were reduced to a maximum of eight pups per litter, with equal numbers of male and female offspring wherever possible. A total of 187 pups were observed for the age of acquisition of five reflexes (air righting, surface righting, visual placing, negative geotaxis, auditory startle) and the appearance of four physiologic markers (pinna detachment, eye opening, vaginal opening, testes descent). There was significant dose-related weight reduction in term fetuses and offspring throughout the 86-day postnatal period. Postnatal growth rate (g gained/day) was unaffected. Adult offspring brain and gonadal weight and organ weight:body weight ratios were reduced. Using the PAC50 methodology, dose-related alterations occurred in the acquisition of several reflexes. All physiologic markers exhibited a dose-related delay in appearance. These results indicate that fractionated exposure to X-radiation during the fetal period in the rat results in dose-dependent alterations in postnatal growth and physiologic development. These studies are important for our understanding of the long-range effects of prenatal exposure to ionizing radiation late in gestation.

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It is evident that significant permanent tissue hypoplasia can be produced following radiation exposure late in fetal development. Because two organs, brain and testes, are developmentally and functionally interrelated, it was of interest to determine whether fetal testicular hypoplasia was a primary or a secondary effect of fetal brain irradiation. Twenty-four pregnant Wistar strain rats were randomly assigned to one of four groups, and a laparotomy was performed on day 18 of gestation. The fetuses received sham irradiation, whole body irradiation, or only head/thorax or pelvic body irradiation at a dosage level of 1.5 Gy. Mothers were allowed to deliver and raise their offspring until postnatal day 30, when the offspring were weaned. At 60 days of age, 74 male offspring were allowed to mate with colony control females of similar age until successful insemination or until the males reached 90 days of age, when they were killed. Testes were weighed and processed for histologic examination. Direct radiation of testes, due to whole body or pelvic exposure, resulted in testicular growth retardation and significantly reduced spermatogenesis. Breeding activity of the males and the percent of positive inseminations were also slightly reduced. However, a significant percentage of male offspring receiving direct testicular radiation did produce offspring. Head/thorax-only irradiation did not adversely affect testicular growth or spermatogenesis. Therefore, the use of histologic analysis as the sole determinant of infertility may be misleading. This study indicates that testicular growth retardation and an increased infertility rate result from direct prenatal exposure of rat testes to X-radiation and are not necessarily mediated via X-irradiation effects on the central nervous system.

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Forty-five pregnant Wistar strain rats were exposed to 0.0, 0.4, 0.6, or 0.8 Gy X-radiation on the 9th or 17th day of gestation to determine if prenatal X-irradiation would result in alterations in postnatal growth or growth rate. The mothers delivered their offspring, and the litters were reduced to a maximum of eight per litter on the second postnatal day. The 336 offspring were weighed weekly from day 3 until day 86, at which time they were killed, an autopsy was performed, and selected organs were removed and weighed. Postnatal growth rates did not differ significantly in irradiated offspring compared to sham irradiated animals. Irradiation on the 9th day, at any of the 3 dosage levels, did not result in significant differences in weekly weight. Weekly weight remained significantly lower due to irradiation on the 17th day of gestation. The gonadal weight ratio was significantly reduced in males irradiated on the 9th day. There were no other statistically significant changes in organ weight or organ/body weight ratios due to these levels of prenatal X-irradiation on the 9th or 17th day of pregnancy. These results indicate that low level prenatal X-irradiation, on the 17th day of rat gestation, causes prenatal growth retardation, evident at birth, which is not recuperable postnatally. Exposure to X-radiation at this time, however, does not affect the rate at which offspring grow during postnatal life. Offspring are smaller because they never fully recover from the original radiation-induced prenatal growth retardation.

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The objective of this investigation was to determine the effect of low-dose prenatal X-irradiation on postnatal growth and neurobehavioral development, and whether alterations would manifest at dosages lower than those which produce anatomic malformations from exposure at the most sensitive period of organogenesis. Ninety-eight Wistar strain rats were exposed to 0.1, 0.2, or 0.4 Gy X-radiation of were sham irradiated on the 9th or 17th day of gestation. A conventional teratologic evaluation was completed on half of the animals (572 fetuses). The age of appearance of four physiologic markers and of acquisition of six reflexes was observed in 372 offspring. Exposure during early organogenesis at these levels had no effect on any of these parameters. Prenatal exposure to X-radiation on the 17th day of gestation at dosage levels greater than 0.1 Gy resulted in alterations in the appearance of three postnatal neurophysiologic parameters. Growth retardation throughout the postpartum period also was observed in the offspring. The induction of developmental and reflex alterations had a comparable threshold to the known threshold for anatomic malformations on the 9th day. These results indicate that all of the parameters studied had thresholds either at or above 0.2 Gy acute radiation, and that the postpartum developmental and reflex acquisition measures were not more sensitive indicators of exposure to X-radiation than growth parameters.

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Thirty-four pregnant Wistar rats were X-irradiated on the 9th or 17th day of gestation at a dosage level 0.4 Gy or 0.6 Gy or were sham-irradiated. All mothers were allowed to deliver their offspring, and litters were limited to a maximum of eight on day 2. On day 30, 224 offspring were weaned and raised until 60 days of age, at which time testing began. Each rat randomly received, in random order, three of the following six behavioral tests: Water T-maze, Conditioned Avoidance Response, Forelimb Hanging, Activity Wheel, Swimming, and Open Field. There were no statistically significant differences between the irradiated and control groups for maternal weight or weight gain or mean litter size, although the litter size of the 17th day 0.6-Gy group was slightly lower. Among offspring irradiated with 0.6 Gy on the 17th day, 3-day-old neonates' weights were significantly reduced. Offspring irradiated on the 17th day with 0.6 Gy exhibited higher Conditioned Avoidance Response 5th-day and retest avoidance scores than did the controls. There were also significant sex differences in responses within the irradiated and control groups for several tests, which were unrelated to radiation exposure. The results of this study indicate that low-level X-irradiation during the fetal period of rat gestation results in neonatal growth retardation and subtle behavioral alterations that may be manifested in adult life. Growth retardation may be the most sensitive indicator of subtle effects that result from low-level prenatal exposure to X-rays.

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Fifty-nine pregnant Wistar strain rats were sham irradiated or subjected to a 0.1 or 0.2 Gy exposure of X-radiation on the 9th or 17th day of gestation. Twenty-seven of the females were killed at term for teratologic analysis. The remaining mothers raised their young. At 60 days of age the 252 offsprings were randomly assigned three of six tests: open field, swimming, hanging, activity wheel, water T-maze, or conditioned avoidance response. Male offspring exposed at the 0.2 Gy level exhibited retarded growth only during the first few weeks of postnatal life. Female offspring exposed on the 17th day to 0.2 Gy X-radiation were growth retarded throughout the test period. Postnatal growth rates, however, were not significantly different between the irradiated and control groups. There were no significant alterations in adult behaviour due to prenatal X-irradiation. There were sex differences in activity wheel and forelimb hanging performance, unrelated to radiation exposure. These results indicate that prenatal low level X-irradiation on the 9th or 17th day of gestation does not result in significant alterations in adult behavioural performance in the rat, but prenatal growth retardation persists postnatally. Growth may be a more sensitive indicator of the effects of prenatal exposure to X-radiation than postnatal behaviour.

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Forty-one pregnant Wistar strain rats were irradiated with 0.6-Gy X rays or were sham irradiated on the 9th or 17th days of gestation to determine if this dosage level would result in alterations in postnatal neurophysiologic development. Half of the mothers were sacrificed at term, and the developmental status of 221 newborns was evaluated. The remaining mothers delivered and raised their litters. The 161 offspring were observed for the age of attainment of the following physiologic parameters: pinna detachment, eye opening, testes opening. Offspring were also tested for the acquisition of the following selected reflexes: surface righting, negative geotaxis, auditory startle, air righting, and visual placing. Term fetal weight was lower than the controls in the group irradiated on the 9th day but was recuperable postnatally. None of the 9 developmental tests performed postnatally were abnormal in the animals irradiated on the 9th day. Thus, at least with regard to these measures, the surviving embryos exposed during the all-or-none period could not be differentiated from the controls. Offspring irradiated on the 17th day exhibited retarded growth which persisted during neonatal life. The three-day-mean neonatal weight was significantly lower in the group irradiated on the 17th day compared to controls. There were no significant maternal body weight or organ/weight differences between the groups. Rats exposed in utero on the 17th day had a significantly delayed acquisition of air righting. These results demonstrate that 0.6-Gy in utero irradiation on the 17th day of gestation can cause subtle alterations in growth and development of the Wistar strain rat during postnatal life.

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A brief review of the literature precedes the presentation of a radiation behavioral teratology study. The various types of radiation and the units of measure used in radiation biology are discussed. The concept of the radiation-induced teratogenic "triad" of growth retardation, malformation, and death is presented. A discussion of stage- and dose-dependent sensitivity to prenatal irradiation is followed by an introduction to behavioral teratology as a new interdisciplinary area of investigation, emphasizing postnatal psychophysiologic analyses of the effects of prenatal exposure. In the present study, rats were exposed to an acute dosage level of 0.6 Gy (60 RAD) X-radiation on day 9 or 17 of gestation. The neonates were given five neonatal reflex tests, observed for the appearance of four physiologic markers, and, as young adults, subjected to three of six behavioral tests. The irradiated offspring exhibited retarded postnatal growth and altered reflex and behavioral activity. These results indicate that irradiation at a dosage level which does not cause overt morphologic malformations at birth does result in altered postnatal growth and psychophysiologic development.

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