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The placenta and umbilical cord were obtained following a normal live delivery from a volunteer donor who had received an accidental inhalation intake of plutonium 12 years prior to her pregnancy (Case 0777). Her employer estimated the intake to be about 73 Bq Class W plutonium. Based on bioassay results and clearance models in use at that time, they calculated her body content at the beginning of pregnancy to be about 5.6 Bq with an average concentration of approximately 60 mBq kg(-1). The placenta and cord from this pregnancy, along with the placenta and cord from a donor with no known exposure to plutonium (Case 0835), were divided and assayed for plutonium by ultrasensitive fission track analysis at two collaborating laboratories. Placental 239Pu concentration values obtained by the two laboratories for Case 0777 agreed within a factor of 2 and were several-fold greater than for the control, Case 0835, as well as values that had been reported by others for unexposed populations. There was no elevated concentration of plutonium in the umbilical cord from the exposed person. The data yielded values of 0.16 and 0.27 for placental to maternal concentrations (CPl: CM) that were of the same order of magnitude as the value of 0.1 the ICRP calculated for intakes before pregnancy.

Activation of gene transcription by radiation has been recently demonstrated in vitro. However, little is known on the specificity of these alterations on gene transcription. Prenatal irradiation is a known teratogen that affects the developing mammalian central nervous system (CNS). Altered neuronal migration has been suggested as a mechanism for abnormal development of prenatally irradiated brains. Fibronectin (FN), an extracellular glycoprotein, is essential for neural crest cell migration and neural cell growth. In addition, elevated levels of FN have been found in the extracellular matrix of irradiated lung. To test whether brain FN is affected by radiation, either FN level in insoluble matrix fraction or expression of FN mRNA was examined pre- and postnatally after irradiation. Mice (CD1), at 13 d of gestation (DG), served either as controls or were irradiated with gamma rays at 0.5 or 1 Gy. Control and irradiated animals were killed either at 13 DG, 14 DG, 17 DG, or 5, 6, or 14 d postnatal. Brain and liver were collected from offspring and analyzed for either total FN protein levels or relative mRNAs for FN and tubulin. Results of prenatal irradiation on reduction of postnatal brain weight relative to whole body weight and morphological reduction in cerebral cortex regions of postnatal brains are comparable to that reported by others. Insoluble matrix fraction (IMF) per gram of brain, liver, lung, and heart weight was not significantly different either between control and irradiated groups or between postnatal stages, suggesting that radiation did not affect the IMF. However, total amounts of FN in brain IMF at 17 DG were significantly different (p < .02) between normal (1.66 +/- 0.80 micrograms) and irradiated brains (0.58 +/- 0.22 microgram). FN mRNA was detectable at 13, 14, and 17 DG, but was not detectable at 6 and 14 d postnatal, indicating that FN mRNA is developmentally regulated. After 0.5 Gy of irradiation, expression of FN mRNA was reduced to 36% +/- 22% (1 h), 52% +/- 10% (1 d), and 76% +/- 10% (4 d) of the control level. After 1 Gy of irradiation, relative FN mRNA was 62% +/- 28% (1 h) and 75% +/- 3% (4 days) to the control level, respectively. This reduction was comparable to that reported by others for the cytoskeletal protein beta-actin. In contrast, mRNA for tubulin, another cytoskeletal protein, increased at 1 h after irradiation but then approached normal postnatally. The longer lasting alteration of FN may be more directly related to neural development, particularly if the reduction in FN is nonuniform.

A series of studies to further evaluate the developmental and reproductive toxicity of inhaled 1,3-butadiene was sponsored by the National Toxicology Program. Pregnant Sprague-Dawley rats (24-28/group) and Swiss (CD-1) mice (18-22/group) were exposed to atmospheric concentrations of 0, 40, 200, or 1000 ppm 1,3-butadiene for 6 hr/day on days 6 through 15 of gestation (dg) and killed on dg 18 (mice) or dg 20 (rats). Subsequently, the uterine contents were evaluated; individual fetal body weights were recorded; and external, visceral, and skeletal examinations were performed. In rats, maternal toxicity was observed in the 1000-ppm group in the form of reduced extragestational weight gain and, during the first week of treatment, decreased body weight gain. Under these conditions, there was no evidence of developmental toxicity in rats. In contrast, results of the mouse developmental toxicity study indicated that the fetus may be more susceptible than the dam to inhaled 1,3-butadiene. Maternal toxicity was observed in mice at the 200- and 1000-ppm 1,3-butadiene exposure levels, whereas 40 ppm and higher concentrations of 1,3-butadiene caused significant exposure-related reductions in the mean body weights of male fetuses. Mean body weights of female fetuses were also reduced at the 200- and 1000-ppm exposure levels. No increased incidence of malformations was observed in either study. Other studies addressing male reproductive and mutagenesis end points were performed with B6C3F1 mice (sperm-head morphology) and Swiss (CD-1) mice (dominant lethal study).(ABSTRACT TRUNCATED AT 250 WORDS)

A study with multiple exposure groups and large group sizes was performed to establish whether exposure to 60-Hz electric fields would result in reproductive and developmental toxicity. A response model was developed from previous results and tested in groups of rats exposed to electric fields at various field strengths. Female rats were mated, and sperm-positive animals randomly distributed among four groups: sham-exposed or exposed to 10, 65, or 130 kV/m, 60-Hz vertical electric fields. Animals were exposed for 19 hr/day throughout the experiment. During gestation, exposure to the higher field strengths resulted in slightly depressed weight gains of dams. Offspring were born in the field and remained with their dams through the suckling period. Numbers of pups per litter and pup mortality did not differ among the exposure groups. Dams exposed at 65 kV/m lost slightly more weight through the lactation period than the control group. Male pups exposed to higher field strengths gained slightly less weight from 4 to 21 days of age than did sham-exposed animals. At weaning, two F1 females per litter (randomly selected) continued on the same exposure regimen were mated at 11 weeks of age to unexposed males, and euthanized at 20 days of gestation. Uterine contents were evaluated, and all live fetuses were weighed and examined for external, visceral, and skeletal malformations. Fertility and gestational weight gain of F1 females were not affected by exposure, nor was prenatal viability or fetal body weight. No significant increase in the incidence of litters with malformations was observed. Although no developmental toxicity was detected, exposures produced physical changes in the dams, evidenced as a rust-colored deposit on the muzzle and ears (chromodacryorrhea) that increased in incidence and severity at 65 and 130 kV/m. Incidence of chromodacryorrhea was not significantly different between sham-exposed rats and those exposed at 10 kV/m.

In order to measure transplacental movements of plutonium without the complications of fetal accumulation, the fetal circulation of the guinea pig placenta (at 59 to 61 days of gestation) was perfused in situ. Dams were administered trace quantities of tritiated water (to indicate changes in maternal blood flow to the placenta) and 30 mu Ci/kg (i.e., approximately 500 micrograms/kg) of citrated 239Pu by intravenous injection. Plutonium-239 doses were large, approaching the LD50/30 (20 to 80 mu Ci/kg) for other species. Perfusion pressure, maternal cardiac rate, electrocardiogram, blood pressure, and respiratory rate were monitored continuously during each perfusion. Our measurements show that the clearance of plutonium from mother to fetus is small--2.5 +/- 0.5 microliter/min--an amount that is less than 20 per cent of the clearance of inorganic mercury. The indirect measurements of maternal blood flow to the placenta indicate that placental blood flow is greatly diminished in dams dosed with plutonium, which may partially account for the low clearance of plutonium.

Primates (Erythrocebus patas) were implanted with intracervical devices which slowly released d-norgestrel at either of two rates: 38 +/- 12 microgram/day (high dose, 4 animals) or 14 +/- 10 microgram/day (low dose, 3 animals). An additional 8 animals received placebo devices or were untreated controls. All animals were studied for 3 months of exposure, at which time they were necropsied and evaluated. The uterus in all of the high dose primates had endometrial stromal and epithelial hyperplasia and, in two primates, suppurative endometritis. Similar, but less severe, uterine changes were present in animals of the low dose group. Systemic effects included evidence of diminished menstrual cycling and an absence of corpora lutea at both dose levels. Our results indicate that local application of these levels of d-norgestrel for contraception produces effects similar to those from systemically administered d-norgestrel.

Lead metabolism was studied in the fetoplacental unit (FPU) of Wistar rats during the genesis of developmental abnormalities and embryonic death. Female rats were injected iv with tracer 210Pb(NO3)2, alone or in combination with 5 or 25 mg Pb(NO3)2/kg, at 9 or 15 days of gestation (dg). The distribution of lead and its effects were determined in the FPUs during the ensuing 30-h period and at 20 dg. Hemorrhage of the egg cylinder was noted as early as 6 h postinjection of 25 mg/kg at 9 dg. By 20 dg, fetuses exhibited characteristic stunting and external malformations (gastroschisis and severe skeletal defects). Administration of this dose at 15 dg produced petechial hemorrhage in fetal brain within 90 min; more massive hemorrhage was a consistent observation by 24 h. At 20 dg, embryo mortality was 44% in rats injected with 25 mg/kg at 9 dg and 100% in those injected at 15 dg. At 90 min after injection, lead content of 15-dg FPUs was 10 times that of the 9-dg FPUs, but the weights of the 15-dg FPUs were 16 times greater. Values remained relatively constant in 15-dg FPUs for 30 h, but early clearance was observed after injection at 9 dg, with a return to 90-min values by 20 dg. In the 15-dg FPUs, placental clearance was followed by fetal lead incorporation, which reached a maximum at 6 h. Fetal lead values were constant from 6 to 30 h after injection at tracer and 5-mg/kg dose levels, but values increased progressively at 25 mg/kg. Both temporal and quantitative relationships of fetal lead metabolism were disrupted by the 25-mg/kg dose, but the nature of the effect was determined by the stage of fetal development at exposure.

Female Wistar rats were injected intravenously with tracer levels of 210Pb, alone or combined with carrier Pb(NO3)2 at 5 or 25 mg/kg body weight at 9 or 15 days of gestation (dg). Tissue 210Pb distribution and retention, and lead excretion, were measured several times during the first 30 h and at 20 dg. Toxic effects following the administration of 25 mg/kg (a teratogenic dose) included an early decrease in hematocrit, hematuria, gastrointestinal hemorrhage, and diarrhea, as well as an eventual loss of body weight and an increase in spleen and kidney weights. The stage of pregnancy at injection did not affect the retention and distribution of lead in major organs other than the reproductive system. Following injection of the 25-mg/kg dose, deposition of lead in the liver, kidney, spleen, and lung was elevated. Disproportionately high plasma lead levels were also observed at early times after the injection of the 25-mg/kg dose, and may act as a significant factor in placental lead transfer and subsequent malformations or fetal mortality.

Mature female rats and their subsequent litters were exposed either to 112- or to 150-kV/m, 60-Hz electric fields or sham-exposed for 19 h daily through pre-breeding, breeding, and rearing periods of experimentation. Exposed females mated in equal percentages and reared litters of equal numbers, and mean body masses of pups were the same as those of sham-exposed animals. Thus, experiments to investigate electric-field effects on reproduction and development in rats are feasible at effective field strengths of 112 and 150 kV/m.

Exposure to radiation from internally deposited radionuclides during the prenatal and/or neonatal periods bears a distinct oncogenic potential. The fundamental mechanisms of perinatal radionuclide carcinogenesis seem to be generally similar to those that pertain to external radiation exposures and other carcinogenic agents, but unique interactions may be superimposed. Specific dose-effect relationships differ among radionuclides; in many studies, there have been dose-related increases in the incidence of tumours or decreases in age at tumour appearance following prenatal or neonatal radiation exposure. Tumour incidences may be decreased, especially at high dose levels; these are usually attributable to cell death, inhibited development of target tissues or to endocrine malfunction. Age-related differences in predominant tumour types and/or sites of tumour development are often detected, and are explainable by the existence of nuclide-specific target organs or tissues, dosimetric factors and developmental considerations.

Evaluations of reproductive and developmental toxicology, including teratology, were included as part of a broad screening study in Hanford Miniature swine (HMS) to detect effects of exposure to electric fields. One group (E) was exposed to a uniform, vertical, 60-Hz, 30-kV/m electric field for 20 h/day, 7 days/week; sham-exposed (SE) swine were housed in a separate, environmentally equivalent building. The first generation (F0) gilts were bred after 4 months of study; some were killed for teratologic assays at 100 days of gestation (dg), and the others produced an F1 generation of offspring. The pooled incidence of terata in these litters (teratologic assays and live births) was similar in the E and SE groups. The F0 females, which produced the F1 generation, were bred again after 18 months of exposure and were killed at 100 dg. Malformation incidence in E litters (75%) was significantly greater than in SE litters (29%). No consistent differences in litter size, fetal mass, or mass of fetal organs were detected. The F1 gilts were bred at 18 months of age; defective offspring were found in significantly more of the E litters (71%) than in SE litters (33%). These F1 females were bred again 10 months later and teratologic assays were performed on their second litters at 100 dg. The percentage of litters with malformed fetuses was essentially identical in the E and SE groups (70% and 73%, respectively). There appears to be an association between chronic exposure to a strong electric field and developmental effects in swine, although the change in incidence of malformations between generations and between the first and second breedings makes it impossible to conclude unequivocally that there is a cause-and-effect relation.

This report reviews and establishes patterns from the literature on experimental ultrasound exposures of inframammalian embryos and prenatal laboratory mammals. Exposure to ultrasound can produce adverse affects on development, and the sensitivity and responses of the test systems vary with the stage of development. Generally, however, deleterious effects are demonstrable only with exposure parameters that far exceed those used in clinical practice, and the few reports of mammalian embryotoxicity under clinically relevant exposure conditions have not been repeatable. Although it may be impossible to unequivocally establish absolute safety, there is a need for further studies to evaluate subtle and delayed indicators of developmental effects, potential mechanisms, and to attempt to estimate threshold exposure conditions.

Heavy distillate (HD), the highest-boiling coal liquid from the solvent-refined coal-II process (SRC-II), was administered by intragastric (IG) intubation to pregnant rats. Five dose levels of HD (0.09, 0.14, 0.18, 0.36 and 0.74 g kg-1), were given daily from 12 to 16 days of gestation and the rats were killed at 20 days of gestation. Maternal body weights and weights of the liver, kidneys, spleen, adrenals, thymus, ovaries and the gravid uterus were obtained. Gravid uteri were evaluated for prenatal mortality. Live fetuses were examined for malformations and weighed; fetal lungs were excised and weighed. Maternal (extragestational) weight gains and thymic weights diminished in all groups that received the SRC material. Adrenal weights were increased in all treated animals, except for those in the lowest-dose group (0.9 g kg-1). There was significant maternal mortality at 0.74 g kg-1 and increased intrauterine mortality at doses of 0.37 and 0.74 g kg-1. Placental weight was depressed, and the incidence of fetal anomalies was increased at 0.14 g kg-1 and all higher dose levels.

Experiments were performed to evaluate reproductive and developmental toxicology in rats and rabbits exposed to styrene oxide by inhalation. Female rats were exposed to 100 or 300 ppm styrene oxide or to filtered air for 7 h/day, 5 days/week for 3 weeks. Extensive mortality occurred in rats that received prolonged exposure to 100 ppm styrene oxide while 300 ppm was rapidly lethal. As a result exposures were terminated in this latter group and the group was eliminated from further study. The rats of the 0 and 100 ppm groups were then mated and exposed to 0 or 100 ppm styrene oxide daily through 18 days of gestation (dg). Female rabbits were artificially inseminated and exposed for 7 h daily to 0, 15, or 50 ppm styrene oxide through 24 dg. Both of these lower concentrations used for exposure of the rabbits produced mortality of does. The rats were killed at 20 dg and the rabbits at 30 dg. Pregnant animals were examined for toxic changes including altered tissue weights and histopathologic effects. Litters were evaluated using several measures of embryotoxicity, and live fetuses were examined for external, visceral, and skeletal malformations. Exposure during gestation appeared to increase preimplantation loss in rats, and tended to increase the incidence of resorptions in rabbits. In both species, fetal weights and crown-rump lengths were reduced by gestational exposure. The incidences of ossification defects of the sternebrae aned occipital bones were increased by gestational exposure of rats to styrene oxide. These results indicate that inhalation exposures at these concentrations produce reproductive and development toxicity, as well as maternal toxicity.

Previous studies have raised the possibility of reproductive and developmental changes in miniature swine chronically exposed to a strong 60-Hz electric field. Two replicate experiments on rats were performed to determine if similar changes could be detected in animals exposed under a comparable regime, which was based on average, induced-current densities and on the chronology of reproductive development, as dosimetrically and biologically scaled. Beginning at three months of age, female rats of the F0 generation and their subsequent offspring were chronically exposed to a 60-Hz electric field (100 kV/m unperturbed) for 19 h/day for the duration of experimentation. After four weeks of exposure, F0 female rats were mated to unexposed male rats during the field-off period. No significant developmental effects were detected in their litters, confirming our previous results with swine and rats. The F0 females were mated for a second time at 7.2 months of age, and the fetuses were evaluated shortly before term. In the first experiments, the incidence of intrauterine mortality was significantly less in exposed than in sham-exposed litters, and there was a tendency (P = .12) for an increased incidence of malformed fetuses in exposed litters. Neither end point was significantly affected in the second experiment. Copulatory behavior of the female F1 offspring, which were bred at three months of age, was not affected in either experiment. There was a statistically significant decrease in the fertility of F1 exposed females and a significant increase in the fraction of exposed litters with malformed fetuses in the first experiment; both end points were essentially the same in the sham and exposed groups of the second experiment. That the significant effects detected in the first experiment were not seen in the second may be attributed to random or biological variation. Alternatively, the finding may indicate that the response threshold for induction of malformations lies near 100 kV/m.

Individual nine-day rat embryos were exposed for 5 or 15 minutes to graded intensities of well-characterized focused beams of 3.2 MHz continuous wave ultrasound. Fetuses were examined for effects at 20 days of gestation. Analysis of the exposure-response relationships indicates an "apparent threshold" for prenatal mortality at 3 W/cm2 (95 per cent fiducial limits 0.5-6 W/cm2). Fetal size was unaffected at any exposure level and there were only a few malformations, which occured at 10.5 W/cm2 and above.

On days 12-16 of gestation pregnant rats were exposed to heavy distillate (HD), the highest-boiling material derived from the solvent refined coal-II (SRC-II) process, and the litters were examined at day 21. Adverse biological effects were observed in the group of animals exposed to an aerosol concentration of 0.66 mg 1-1 [1.8 microgram, mass medium aerodynamic diameter (MMAD)]; groups of animals exposed to lower aerosol concentrations (0.084 and 0.017 mg 1-1) were largely unaffected. Embryo lethality during mid- and late gestation appeared attributable to the coal liquid exposure. Fetuses from pregnant rats in the high exposure group were smaller in weight and length than fetuses from control animals, and skeletal ossification was reduced. Increased incidences of small lungs and cleft palate were observed in fetuses from the high exposure group. Pregnant rats in the high-exposure group gained less weight than controls during gestation; the reduced weight gain was accounted for by the reduced size of the fetuses and placentas. Even though maternal body weight (exclusive of the products of conception) was unaffected by the exposure, the weights of the maternal thymus, lung and spleen were altered in the high exposure group.

Ethylene oxide (CAS no 75-21-8), propylene oxide (CAS no 75-56-9), butylene oxide (CAS no 106-88-7), and styrene oxide (CAS no 96-09-3) were tested for teratogenic activity by inhalation exposure of rats and rabbits. Ethylene oxide and propylene oxide were tested at only one concentration in both species (150 ppm for ethylene oxide and 500 ppm for propylene oxide). Butylene oxide was tested at 250 and 1,000 ppm in both species, while styrene oxide was tested at 100 ppm in rats and 15 and 50 ppm in rabbits. For each of these four epoxides, the acute toxicity was similar for pregnant and nonpregnant rats. Styrene oxide was the most toxic in both species, and rabbits were more sensitive than rats. Rats exposed to propylene oxide for 7 h/d, 5 d/week for three weeks before breeding had a significant reduction in the number of corpora lutea. Fetal mortality was not increased, but significantly fewer mated rats were found pregnant following gestational exposure to styrene oxide, a finding suggesting preimplantation loss. In rabbits exposed to styrene oxide, the number of resorptions per litter was increased in concentration related manner, but differences were not statistically significant. Fetal examination revealed evidence of fetotoxicity with all four epoxides. There was no overt teratogenic activity, but a number of minor morphologic aberrations were detected.

Pregnant rats were housed in 85Kr atmospheres at 10, 15, or 20 days of gestation (dg) and killed after 4 hr of exposure to 37-40 nCi/ml. The 85Kr was present in the components of the fetoplacental unit (FPU) at concentrations (nCi/g) equivalent to approximately 2% of the concentration (nCi/ml) in the exposure atmosphere. Tissue distribution of 85Kr and the distribution of radiation dose did not suggest any unusual hazard to the fetus associated with exposure of pregnant animals. This conclusion was tested using 5-day exposures to a 1000-fold increased concentration: 40 muCi/ml. The main effects observed in pregnant rats exposed to 85Kr from 7-12 or 12-17 dg (estimated radiation dose of 5 X 10(3) rad to maternal lung and 5 X 10(5) rad to maternal skin surface) were deaths, impaired weight gain and skin lesions. Secondarily, the maternal toxicity led to indications of embryotoxicity, although the incidence of malformations was not increased by the estimated 50-rad dose to the FPU.

A series of three experiments was performed to determine the effects of 30-day exposures to uniform 60-Hz electric fields (100 kV/m) on reproduction and on growth and development in the fetuses and offspring of rats. In the first experiment, exposure of females for 6 days prior to and during the mating period did not affect their reproductive performance, and continued exposure through 20 days of gestation (dg) did not affect the viability, size, or morphology of their fetuses. In the second experiment, exposure of the pregnant rat was begun on 0 dg and continued until the resulting offspring reached 8 days of age. In the third experiment, exposure began at 17 dg and continued through 25 days of postnatal life. In the second and third experiments, no statistically significant differences suggesting impairment of the growth or survival of exposed offspring were detected. In the second experiment, a significantly greater percentage of the exposed offspring showed movement, standing, and grooming at 14 days of age than among-sham-exposed offspring. There was a significant decrease at 14 days in the percentage of exposed offspring displaying the righting reflex in the second experiment and negative geotropism in the third experiment. These differences were all transient and were not found when the animals were tested again at 21 days of age. Evaluation of the reproductive integrity of the offspring of the second experiment did not disclose any deficits.

This report reviews and establishes patterns from the literature on experimental ultrasound exposures of inframammalian embryos and prenatal laboratory mammals. Exposure to ultrasound can produce adverse affects on development, and the sensitivity and responses of the test systems vary with the stage of development. Generally, however, deleterious effects are demonstrable only with exposure parameters that far exceed those used in clinical practice, and the few reports of mammalian embryotoxicity under clinically relevant exposure conditions have not been repeatable. Although it may be impossible to unequivocally establish absolute safety, there is a need for further studies to evaluate subtle and delayed indicators of developmental effects, potential mechanisms, and to attempt to estimate threshold exposure conditions.

The primary goal of this paper is to consider factors that affect the availability and transport of actinides from maternal blood, through the placenta, to the conceptus. These factors, of particular importance in scaling results from animals to man, include the route and temporal pattern of administration, the mass and physicochemical state of material administered, metabolism of the pregnant animal and fetal organs or tissue, and species-specific changes in placental structure relative to stage of gestation at exposure. Preliminary concepts for descriptive and kinetic models are proposed to integrate these results, to identify additional information required for developing more comprehensive models, and to provide a basis for scaling to human pregnancies for purposes of radiation dosimetry.