A detailed characterization of congenital defects and mortality following moderate X-ray doses during neurulation.

BACKGROUND: Both epidemiological and animal studies have previously indicated a link between in utero radiation exposure and birth defects such as microphthalmos, anophthalmos, and exencephaly. However, detailed knowledge on embryonic radiosensitivity during different stages of neurulation is limited, especially in terms of neural tube defect and eye defect development. METHODS: To assess the most radiosensitive stage during neurulation, pregnant C57BL6/J mice were X-irradiated (0.5 Gy or 1.0 Gy) at embryonic days (E)7, E7.5, E8, E8.5, or E9. Next, the fetuses were scored macroscopically for various defects and prenatal resorptions/deaths were counted. In addition, cranial skeletal development was ascertained using the alcian-alizarin method. Furthermore, postnatal/young adult survival was followed until 5 weeks (W5) of age, after X-irradiation at E7.5 (0.1 Gy, 0.5 Gy, or 1.0 Gy). In addition, body and brain weights were registered at adult age (W10) following X-ray exposure at E7.5 (0.1 Gy, 0.5 Gy). RESULTS: Several malformations, including microphthalmos and exencephaly, were most evident after irradiation at E7.5, with significance starting respectively at 0.5 Gy and 1.0 Gy. Prenatal mortality and weight were significantly affected in all irradiated groups. Long-term follow-up of E7.5 irradiated animals revealed a reduction in survival at 5 weeks of age after high dose exposure (1.0 Gy), while lower doses (0.5 Gy, 0.1 Gy) did not affect brain and body weight at postnatal week 10. CONCLUSIONS: With this study, we gained more insight in radiosensitivity throughout neurulation, and offered a better defined model to further study radiation-induced malformations and the underlying mechanisms.

Adaptive response of low linear energy transfer X-rays for protection against high linear energy transfer accelerated heavy ion-induced teratogenesis.

BACKGROUND: Adaptive response (AR) of low linear energy transfer (LET) irradiations for protection against teratogenesis induced by high LET irradiations is not well documented. In this study, induction of AR by X-rays against teratogenesis induced by accelerated heavy ions was examined in fetal mice. METHODS: Irradiations of pregnant C57BL/6J mice were performed by delivering a priming low dose from X-rays at 0.05 or 0.30 Gy on gestation day 11 followed one day later by a challenge high dose from either X-rays or accelerated heavy ions. Monoenergetic beams of carbon, neon, silicon, and iron with the LET values of about 15, 30, 55, and 200 keV/µm, respectively, were examined. Significant suppression of teratogenic effects (fetal death, malformation of live fetuses, or low body weight) was used as the endpoint for judgment of a successful AR induction. RESULTS: Existence of AR induced by low-LET X-rays against teratogenic effect induced by high-LET accelerated heavy ions was demonstrated. The priming low dose of X-rays significantly reduced the occurrence of prenatal fetal death, malformation, and/or low body weight induced by the challenge high dose from either X-rays or accelerated heavy ions of carbon, neon or silicon but not iron particles. CONCLUSIONS: Successful AR induction appears to be a radiation quality event, depending on the LET value and/or the particle species of the challenge irradiations. These findings would provide a new insight into the study on radiation-induced AR in utero.

Estimación ecográfica del peso fetal: ¿podemos mejorar nuestras predicciones? / Ultrasound estimation of fetal weight: can we improve our predictions?

Objetivos. a) Estudiar la validez de la estimación ecográfica del peso fetal y determinar qué fórmula permite mejores predicciones. B) Proponer una fórmula que se adapte mejor a nuestra población. Material y métodos. Estudio prospectivo en el que se incluyen 282 gestaciones únicas a término. Determinación del peso fetal mediante 17 fórmulas. Análisis de su validez mediante el error medio y el porcentaje de predicciones con un error menor del 10%. Resultados. Catorce fórmulas presentaron un error medio menor del 10%. Diez de ellas permiten más de un 65% de predicciones válidas, con un error inferior al 10%. Las que ofrecen mejores resultados son algunas de las propuestas por Hadlock y la de Aoki. La fórmula propuesta, usando 3 parámetros ecográficos, permite un 73,8% de predicciones válidas con un error inferior al 10% y un 87,9% con un error inferior al 15%. Conclusiones. La estimación por eco 2D tiene una validez limitada. La fórmula propuesta mejora las estimaciones en nuestra población (AU)

Objective. (a) To assess the validity of ultrasound estimation of fetal weight and to compare the accuracy of 17 sonographic formulae to predict fetal birth weight. (b) To propose a new formula that improves predictions in our population. Methods. We performed a prospective study that included 282 pregnant women at term. Seventeen formulae were used to predict fetal weight. To assess the accuracy of the predictions, the mean error and the percentage of estimations with a mean error of less than 10% were used. Results. Fourteen formulae provided a mean error lower than 10%. Ten of these formulae allowed estimations within ±10% of the actual birth weight in more that 65% of predictions. The most accurate formulae in predicting fetal weight were those of Hadlock and Aoki. With our formula, which employs three ultrasound parameters, 73.8% of estimations were valid with a mean error of 10% and 87.9% had an error of less than 15%. Conclusions. The accuracy of fetal weight estimation by ultrasound is limited and may improve with the new formula adjusted to our population (AU)

Dose-response and large relative biological effectiveness of fast neutrons with regard to mouse fetal cerebral neuron apoptosis.

To evaluate the relative biological effectiveness (RBE) of low doses of neutrons on fetal nervous development, [C57BL/6J x C3H/He] hybrid (B6C3F1) mice were exposed to cyclotron-derived fast neutrons with peak energy of 10 MeV (0.02-1.0 Gy) or 137Cs-generated gamma-rays (0.1-2.0 Gy) on embryonic day 13.5. We then evaluated the incidence of neuronal apoptosis in the cerebral cortex 24 hours after irradiation. Neuronal apoptosis increased in a dose-dependent manner in both neutron- and gamma-ray-irradiated groups: even at the lowest dose, a minimal increase in the apoptotic index was noted in response to both types of radiation. The dose-response curves were best fitted to linear quadratic models, and the evaluated RBE was 9.8, which was considered to be large for a prenatal effect and acute tissue injury induced by a low dose of neutrons.

Teratological studies of prenatal exposure of mice to a 20 kHz sawtooth magnetic field.

In order to evaluate the importance of gestational age in possible effects due to exposure to a 20 kHz sawtooth magnetic field, pregnant ICR mice at gestational 2.5-15.5 days post-coitus, which is the most sensitive stage for the induction of major congenital malformations, were exposed in a carrousel irradiator. The mice were exposed to a 20 kHz intermediate frequency (IF) sawtooth magnetic field had a 6.5 microT peak intensity for 8 h/day. The animals were sacrificed on the 18th day of gestation; and the fetuses were examined for mortality, growth retardation, changes in head size, and other morphological abnormalities. From the above conditions, it is concluded that the exposure to a 20 kHz sawtooth magnetic field with 6.5 microT peak intensity does not inflict any adverse effect on fetuses of pregnant mice.

Developmental abnormalities induced by X-irradiation in p53 deficient mice.

In order to assess the influence of p53 inactivation on radiation-induced developmental effects, male mice heterozygous for the wild-type p53 allele (mimicking the human Li-Fraumeni syndrome) were crossed with C57BL females, and their heterozygous p53+/- progeny were mated with each other to obtain p53+/-, p53-/- and p53+/+ embryos. Pregnant females were X-irradiated with 0.5 Gy on days 1 (pre-implantation period), 8 or 11 (organogenesis period) of gestation. Dissection of the pregnant females occurred on day 19 of gestation. The p53 genotype of the foetuses was determined by PCR from small pieces of soft tissues. Exencephaly was the only external malformation found in the control group. It affected essentially p53-/- female foetuses. A number of p53+/- and p53+/- control foetuses also showed dwarfism, or underdevelopment. In the group irradiated on day 1, the frequency of abnormal foetuses was, paradoxically, lower than that found in the control group. As in that group, exencephaly and dwarfism constituted the only anomalies that were found. Exencephaly affected only homozygous p53-/- females, while dwarfism concerned either p53-/- or p53+/- foetuses, with a majority of females. Irradiation on day 8 of gestation induced a significant increase in the frequency of abnormal foetuses, compared to the control group. Various malformations were observed in addition to exencephaly, including gastroschisis, polydactyly, cephalic oedema and cleft palate. All malformed foetuses were either homozygous p53-/- or heterozygous p53+/- while most affected foetuses were females, as was the case for dwarf individuals. Irradiation on day 11 did not cause an increase in the frequency of abnormal foetuses, in comparison with the controls. However, a large spectrum of external malformations was again noticed, as in the group irradiated on day 8. All affected foetuses were homozygous p53-/- and there were slightly more abnormal females than males (3 out of 5). No dwarfs were found in this group. Overall, these results confirm the importance of the p53 tumour-suppressor protein for normal embryonic development. They clearly show that homozygous p53-/- (or heterozygous p53+/- to a lesser extent) foetuses are more at risk for radiation-induction of external malformations during the organogenesis period, and that the risk of developing such malformations is much higher for females than for males. In contrast to results published very recently by others, we found that malformed foetuses resulting from an X-irradiation with a low-dose during the highly sensitive period of gastrulation are able to survive to birth.

Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89.

This report presents detailed information on age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. These reference values provide needed input to prospective dosimetry calculations for radiation protection purposes for both workers and members of the general public. The purpose of this report is to consolidate and unify in one publication, important new information on reference anatomical and physiological values that has become available since Publication 23 was published by the ICRP in 1975. There are two aspects of this work. The first is to revise and extend the information in Publication 23 as appropriate. The second is to provide additional information on individual variation among grossly normal individuals resulting from differences in age, gender, race, or other factors. This publication collects, unifies, and expands the updated ICRP reference values for the purpose of providing a comprehensive and consistent set of age- and gender-specific reference values for anatomical and physiological features of the human body pertinent to radiation dosimetry. The reference values given in this report are based on: (a) anatomical and physiological information not published before by the ICRP; (b) recent ICRP publications containing reference value information; and (c) information in Publication 23 that is still considered valid and appropriate for radiation protection purposes. Moving from the past emphasis on 'Reference Man', the new report presents a series of reference values for both male and female subjects of six different ages: newborn, 1 year, 5 years, 10 years, 15 years, and adult. In selecting reference values, the Commission has used data on Western Europeans and North Americans because these populations have been well studied with respect to antomy, body composition, and physiology. When appropriate, comparisons are made between the chosen reference values and data from several Asian populations. The first section of the report provides summary tables of all the anatomical and physiological parameters given as reference values in this publication. These results give a comprehensive view of reference values for an individual as influenced by age and gender. The second section describes characteristics of dosimetric importance for the embryo and fetus. Information is provided on the development of the total body and the timing of appearance and development of the various organ systems. Reference values are provided on the mass of the total body and selected organs and tissues, as well as a number of physiological parameters. The third section deals with reference values of important anatomical and physiological characteristics of reference individuals from birth to adulthood. This section begins with details on the growth and composition of the total body in males and females. It then describes and quantifies anatomical and physiological characteristics of various organ systems and changes in these characteristics during growth, maturity, and pregnancy. Reference values are specified for characteristics of dosimetric importance. The final section gives a brief summary of the elemental composition of individuals. Focusing on the elements of dosimetric importance, information is presented on the body content of 13 elements: calcium, carbon, chloride, hydrogen, iodine, iron, magnesium, nitrogen, oxygen, potassium, sodium, sulphur, and phosphorus.

Developmental toxicity interactions of methanol and radiofrequency radiation or 2-methoxyethanol in rats.

This research was undertaken to determine potential interactions among chemical and physical agents. Radiofrequency (RF) radiation is used in numerous workplaces, and many workers are concurrently exposed to RF radiation and various chemicals. The developmental toxicity of RF radiation is associated with the degree and duration of hyperthermia induced by the exposure. Previous animal research indicates that hyperthermia induced by an elevation in ambient temperature can potentiate the toxicity and teratogenicity of some chemical agents. We previously demonstrated that combined exposure to RF radiation (10 MHz) and the industrial solvent, 2-methoxyethanol (2ME), enhanced teratogenicity in rats. Interactions were noted at even the lowest levels of 2ME tested, but only at hyperthermic levels of RF radiation. The purpose of the present research is to investigate if the interactive effects noted for RF radiation and 2ME are unique to these agents, or if similar interactions might be seen with other chemicals. Because methanol is widely used as a solvent as well as fuel additive, and, at high levels, is teratogenic in animals, we selected methanol as a chemical to address generalizability. Based on the literature and our pilot studies, 0, 2, or 3 g/kg methanol (twice, at 6-hour intervals) were administered on gestation day 9 or 13 to groups of 10 Sprague-Dawley rats. Dams treated on day 9 were given methanol and exposed to RF radiation sufficient to maintain colonic temperature at 41 degrees C for 60 minutes (or sham). Those treated on day 13 were given methanol plus either 0 or 100 mg/kg 2ME. Because we observed that methanol produced hypothermia, some groups were given the initial dose of methanol concurrently with the RF or 2ME, and others were given the first dose of methanol 1.5 hours prior to RF or 2ME. Dams were sacrificed on gestation day 20, and the fetuses were examined for external malformations. The results indicate that RF radiation or methanol on day 9 increased the incidence of resorbed fetuses, but no interactive effects were observed. The resorptions were highest in groups given the experimental treatments 1.5 hours apart. The higher dose of methanol also reduced fetal weights. Administration of 2ME or methanol on day 13 increased the rate of malformations, and there was evidence of a positive interaction between 2ME and methanol. Fetal weights were reduced by 2ME and methanol alone, but no interaction was observed. Also, separation of the dosing with the teratogens did not affect the results. These results point out that interactions in developmental toxicology, such as those of RF radiation, 2ME, and methanol that we have studied, are complex, and such interactions cannot be fully understood or predicted without more research. It is important that combined exposure effects be considered when developing both physical agent and chemical agent exposure guidelines and intervention strategies.