Neutron RBEs for mouse skin at low doses per fraction

The effect of low doses of 240 kVp X rays or of 3 MeV neutrons has been investigated using skin reactions on mouse feet as the biological system. Eight or nine repeated small doses of radiation were used, followed by graded "top-up" doses to bring the reactions into a detectable range. By comparing dose-response curves, the RBE has been determined for neutron doses per fraction ranging from 0.25-1.0 Gy. The data are consistent with a limiting RBE of between 7 and 10 at very low doses. A review of other published RBE values for low doses per fraction shows a wide range of RBEs . Very few studies show a plateau value for the RBE. These findings are more consistent with dose-response data that fit a linear-quadratic model than with a multitarget single-hit model.     

Measurement of Individual Doses of Radiation by Personal Dosimeter Is Important for the Return of Residents from Evacuation Order Areas after Nuclear Disaster

To confirm the availability of individual dose evaluation for the return of residents after the accident at the Fukushima Dai-ichi Nuclear Power Plant (FNPP), we evaluated individual doses of radiation as measured by personal dosimeters in residents who temporarily stayed in Evacuation Order Areas in Kawauchi village, which is partially located within a 20 km radius of the FNPP. We also compared individual doses with the external radiation doses estimated from the ambient dose rates and with doses estimated from the concentrations of radionuclides in the soil around each individual’s house. Individual doses were significantly correlated with the ambient doses in front of the entrances to the houses (r = 0.90, p<0.01), in the backyards (r = 0.41, p<0.01) and in the nearby fields (r = 0.80, p<0.01). The maximum cumulative ambient doses in the backyards and fields around the houses were 6.38 and 9.27 mSv/y, respectively. The maximum cumulative individual dose was 3.28 mSv/y, and the median and minimum doses were 1.35 and 0.71 mSv/y. The estimated external effective doses from concentrations of artificial radionuclides in soil samples ranged from 0.03 to 23.42 mSv/y. The individual doses were moderately correlated with external effective doses in the backyards (r = 0.38, p<0.01) and in the fields (r = 0.36, p<0.01); however, the individual doses were not significantly correlated with the external effective doses in front of the entrances (r = 0.01, p = 0.92). Our study confirmed that individual doses are low levels even in the evacuation order area in Kawauchi village, and external effective dose levels are certainly decreasing due to the decay of artificial radionuclides and the decontamination of contaminated soil. Long-term follow-up of individual doses as well as internal-exposure doses, environmental monitoring and reconstruction of infrastructure are needed so that residents may return to their hometowns after a nuclear disaster.     

The low-dose problem in radiobiology

Three aspects of the problem of "low doses" in radiobiology are discussed, they are: (1) universality of the stimulatory effect of penetrating radiation on biological objects, (2) the doses used, and (3) the damages induced by irradiation with these doses.     

Glucocorticoid regulation of phenylethanolamine N-methyltransferase in vivo.

In vivo, supraphysiological doses of glucocorticoids are required to restore adrenal medullary phenylethanolamine N-methyltransferase (PNMT, E.C. 2.1.1.28) activity after hypophysectomy. However, in vitro, phenylethanolamine N-methyltransferase gene expression appears normally glucocorticoid-responsive. To explore this paradox, rats were given dexamethasone or the type II-specific glucocorticoid RU28362 (1-1000 micrograms/day), and adrenal phenylethanolamine N-methyltransferase activity and mRNA levels were determined. At low doses (1-30 micrograms/day), neither steroid altered mRNA whereas at higher doses (100-1000 micrograms/day), mRNA rose 10- to 20-fold, with dexamethasone approximately 3 times as potent as RU28362. In contrast, enzyme activity fell with low doses of either steroid, consistent with suppression of ACTH and endogenous steroidogenesis. At higher doses of RU28362, enzyme activity remained low and unchanged despite increased mRNA expression, whereas higher doses of dexamethasone progressively restored the enzyme to normal. These findings suggest 1) that glucocorticoid regulation of phenylethanolamine N-methyltransferase activity occurs largely independent of gene expression; 2) that glucocorticoid effects on enzyme activity are primarily indirect, probably through cosubstrate regulation and/or enzyme stabilization; and 3) that these effects are not mediated via a classical (type II) glucocorticoid receptor mechanism, given the high doses of dexamethasone and corticosterone required and the inability of RU28362 to mimic the effects of these less selective steroids.     

Membrane lipids of brush border of the rat small intestine as affected by ionizing radiation]

It was established that single total X-ray irradiation in the doses of 0.1; 0.4; 1.0; 2.0; 3.0 and 6.0 Gy 24 hours after irradiation results in reliable changes in membrane lipids composition of brush border of enterocytes in doses over 1.0 Gy. By this changes under increase of dosage of irradiation it were marked differences in comparison with control in lipid-protein, total phospholipids-protein, cholesterol-protein and cholesterol-total phospholipids rations. In lipid composition major changes are connected with increase of lysophosphatidylcholine and lysophosphatidylethanolamine concentrations, decrease of sphingomyelin content and increase of that of phosphatidylethanolamine. Content of cholesterol and free fatty acids decreased reliably under irradiation in doses over 1.0 Gy as well. Data obtained proves that structural-functional properties of brush border membranes of enterocytes of small intestine are altered under irradiation in doses ranging from 1.0 to 6.0 Gy. Lower doses (0.1; 0.4) cause only trend of changes named above.     

Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 1. Comparison of risk coefficients for site-specific cancer mortality based on the DS86 and T65DR shielded kerma and organ doses

As a result of the reassessment of the A-bomb dosimetry, new (DS86) doses were calculated in 1986. In this paper, site-specific estimates of cancer mortality in the years 1950-1985, based on these new doses, are compared with those using the T65DR doses. The subjects of the study are 75,991 members of the Life Span Study sample for whom DS86 doses have been calculated. This reevaluation of the exposures does not change the list of radiation-related cancers. Most differences in dose response between Hiroshima and Nagasaki are no longer significant with the DS86 doses. The dose-response curve is closer to linear with the DS86 than the T65DR doses even for leukemia in the entire dose range, though, statistically, many other models cannot be excluded. However, in the low-dose range, the risk of leukemia remains nonlinear. Assuming a linear model at an RBE of 1, and using organ-absorbed doses, the risk coefficients derived from the two dosimetries are very similar, whereas those based on shielded kerma are about 40% higher with the new dosimetry. If RBE values larger than 1 are assumed, the disparity between the two dosimetries increases because the neutron dose is much greater in the T65DR. At an RBE of 10, for the five specific cancers, i.e., female breast, colon, leukemia, lung, and stomach, the increase in excess number of deaths per 10(4) PYSv under the DS86 varies from 12% (colon) to 133% (female breast). The magnitude of the effects of such modifiers of radiation-induced cancer as age at time of bomb and sex do not differ between the two dose systems.     

The research background for risk assessment of ethylene oxide: aspects of dose

Data for relationships between in vivo doses inferred from levels of hemoglobin (Hb) or DNA adducts and administered (by inhalation or injection) doses of ethylene oxide (EO) in mice, rats and humans are reviewed. At low absorbed doses or dose rates these relationships appear to be linear, whereas at higher dose rates deviations from linearity due to saturation kinetics of detoxification and of DNA repair as well as certain toxic effects have to be allowed for. If these factors are taken into consideration, a rather consistent picture is obtained for animal studies, with a variation by less than a factor 2 between estimates of adduct level increments or in vivo dose increments per unit of administered dose. Although the value for in vivo dose per unit of exposure dose (ppm-hour) in humans is uncertain because of unreliable data for the time-weighted average exposure level, the most likely value for this relationship, supported by data for ethene, agrees with data for the rodents. In the animal species testis doses are approximately one-half of the blood doses inferred from Hb adducts.     

Evaluation of rate-dependency and internal clock effects of D-amphetamine

The impact of two doses of d-amphetamine on rats' peak-interval performance was evaluated at two different points of training: with minimum training, 20 sessions, and with extended training, 120 sessions. At both points of training, none of the doses changed the location of the peak time; however, both doses caused a significant increase in the standard deviation of the response distribution during peak trials. Both results are incompatible with some previous empirical results, and with timing accounts that assume that dopamine modulates the pacemaker rate, but are compatible with a rate-dependent effect.     

Behaviour of lymphocytes from cancer patients and normal individuals cultured with phytohaemagglutinin.

Blood lymphocytes from cancer patients with solid tumours without any previous immunosuppressive treatment and from normal individuals, were cultured in vitro with a wide range of phytohaemagglutinin (PHA). Sixty two per cent of all the cancer patients studied show a minimal of no response to PHA in comparison with the normal population. The rest (38%), show a quantitative identical response than normals. However, the maximal response in these patients occur in the high PHA doses, while the normal individuals show their maximal activity with low PHA doses. The low or no PHA response showed by the 62% of patients, may indicate they have impaired cellular immunity. The high response showed by the other 38%, may indicate that the patients of this group have high cellular immunity capacity. This immunity, however, higher PHA doses are required to reach the maximal response compared with the seems to be different from that of normal individuals, since higher PHA doses are required in cancer patients to reach maximal response. These results also suggest that a large range of PHA doses may be important to detect the degree of cellular immunity in cancer patients compared with the normal population. One or two random PHA doses, may not show a distinction.     

Evidence for sedative effects of low doses of morphine in mice involving receptors insensitive to naloxone

Low doses of morphine (0.30–2.5 mg/kg) decrease in a dose-dependent manner spontaneous climbing behaviour in mice. This effect is not modified by administration of naloxone at doses up to 1.25 mg/kg. These morphine doses do not modify the locomotor activity but, when they are associated with naloxone (0.5 mg/kg), an obvious inhibition occurs. In rats, a hyperactivity follows the akinesia produced by a morphine administration (10 mg/kg). This hyperactivity is changed into a significant hypokinesia when the animals are treated with naloxone (0.05 mg/kg). These results might reveal a dual effect of low doses of morphine, the excitatory effect of morphine being antagonized by naloxone whereas no action on the sedative effect is observed.     

Uncertainties on lung doses from inhaled plutonium

In a recent epidemiological study, Bayesian uncertainties on lung doses have been calculated to determine lung cancer risk from occupational exposures to plutonium. These calculations used a revised version of the Human Respiratory Tract Model (HRTM) published by the ICRP. In addition to the Bayesian analyses, which give probability distributions of doses, point estimates of doses (single estimates without uncertainty) were also provided for that study using the existing HRTM as it is described in ICRP Publication 66; these are to be used in a preliminary analysis of risk. To infer the differences between the point estimates and Bayesian uncertainty analyses, this paper applies the methodology to former workers of the United Kingdom Atomic Energy Authority (UKAEA), who constituted a subset of the study cohort. The resulting probability distributions of lung doses are compared with the point estimates obtained for each worker. It is shown that mean posterior lung doses are around two- to fourfold higher than point estimates and that uncertainties on doses vary over a wide range, greater than two orders of magnitude for some lung tissues. In addition, we demonstrate that uncertainties on the parameter values, rather than the model structure, are largely responsible for these effects. Of these it appears to be the parameters describing absorption from the lungs to blood that have the greatest impact on estimates of lung doses from urine bioassay. Therefore, accurate determination of the chemical form of inhaled plutonium and the absorption parameter values for these materials is important for obtaining reliable estimates of lung doses and hence risk from occupational exposures to plutonium.     

The 3H-thymidine incorporation into G0 human lymphocytes induced by low doses of UVC radiation

The 3H-thymidine incorporation in human lymphocytes of healthy donors induced by UVC radiation under doses 0.0008-60 J/m2 was investigated. It was shown that the incorporation of 3H-thymidine increases under doses in interval 0.1-20 and is constant under doses higher than 20 J/m2. Under doses in interval 0.006-0.03 J/m2 near a half of all samples had the level of incorporation increased in comparison with control samples. We connect the presence, absence or variability of this effect with individual peculiarities of cells and with different activity of cell subpopulations that are different on morphological and physiological characteristics. The hypothesis about the role of this factor in the influence of low doses of pathogenic agents (UVC and X-radiation, chemical compounds) on human lymphocytes is discussed.     

Combined haploinsufficiency and genetic control of the G2/M checkpoint in irradiated cells

When cells are exposed to a dose of radiation large enough to cause chromosome aberrations, they become arrested at the G(2)/M checkpoint, facilitating DNA repair. Defects in checkpoint control genes can impart radiosensitivity. Arrest kinetics were monitored in mouse embryo fibroblasts at doses ranging from 10 mGy to 5.0 Gy of γ radiation over a time course of 0 to 12 h. We observe no significant checkpoint engagement at doses below 100 mGy. The checkpoint is only fully activated at doses where most of the cells are either bound for mitotic catastrophe or are reproductively dead. Atm null cells with ablated checkpoint function exhibited no robust arrest. Surprisingly, haploinsufficiency for ATM alone or in combination with other radioresistance genes did not alter checkpoint activation. We have shown previously that haploinsufficiency for several radioresistance genes imparts intermediate phenotypes for several end points including apoptosis, transformation and survival. These findings suggest that checkpoint control does not contribute toward these intermediate phenotypes and that different biological processes can be activated at high doses compared to low doses.     

Attempted vaccination of jirds (Meriones unguiculatus) against Brugia pahangi with radiation attenuated infective larvae

Jirds were vaccinated by three to five subcutaneous (SC) injections of infective larvae of Brugia pahangi which had been irradiated at 25, 45 or 90 krads from a 60Co source. They were challenged either SC or intraperitoneally. Vaccination with four doses of 50 larvae irradiated with 25 krads produced 49.3% resistance to IP challenge worms and 39.8% against SC challenge worms. Five doses of larvae irradiated with 45 krads produced 62% resistance to SC challenge. Three doses of larvae irradiated with 90 krads produced 74.9% resistance to SC challenge and five doses produced 76.2% resistance. The reasons why irradiated larvae produce resistance whereas normal larvae do not are discussed.     

Multivariate slope ratio assay with repeated measurements

A method is given for analyzing a slope ratio assay in which a test drug is compared with a standard drug, two or more response variates being measured on each subject at each of several successively increased drug doses. The method requires all subjects to receive the same number of doses, all subjects on the same drug to receive the same doses, the ratio of corresponding doses of the two drugs to be constant over the successive increases, and response variables to be measured only once on each subject at each dose with no missing data allowed. The technique is also applicable when doses are randomly assigned, provided there is no carry-over effect between doses. For each of the J response variates, the relative potency of the test drug with respect to the standard is defined and estimated in the usual way; a 100(1-alpha)% confidence region is then obtained for the vector of the J relative potencies. A procedure is given for testing the equality of some or all of the J relative potencies; an estimator of a common relative potency is obtained by a standard multivariate least squares method. A common relative potency is of interest because the multiple outcome variables are often different indicators of a general physiologic response. The procedures in the paper are illustrated by a simple example concerning the effects of two anesthetics on children.     

The F value for chromosome aberrations in atomic bomb survivors does not provide evidence for a primary contribution of neutrons to the dose in Hiroshima.

Brenner and Sachs (Radiat. Res. 140, 134-142, 1994) proposed that the ratio of interchromosomal to intrachromosomal exchanges, termed the F value, can be a cytogenetic fingerprint of exposure to radiations of different linear energy transfer (LET). Using published data, they suggested that F values are over 10 for low-LET radiations and approximately 6 for high-LET radiations. Subsequently, as F values for atomic bomb survivors were reported to be around 6, Brenner suggested that the biological effects of atomic bomb radiation in Hiroshima are due primarily to neutrons. However, the F values used for the survivors were means from individuals exposed to various doses. As the F-value hypothesis predicts a radiation fingerprint at low doses, we analyzed our own data for the survivors in relation to dose. G-banding data for the survivors showed F values varying from 5 to 8 at DS86 doses of 0.2 to 5 Gy in Hiroshima and around 6 in Nagasaki with no evidence of a difference between the two cities. The results are consistent with our in vitro data that the F values are invariably around 6 for X and gamma rays at doses of 0.5 to 2 Gy as well as two types of fission-spectrum neutrons at doses of about 0.2 to 1 Gy. Thus, apart from a possible effect at even lower doses, current data do not provide evidence to support the proposition that the biological effects of atomic bomb radiation in Hiroshima are caused mainly by neutrons.     

Effect of non-antiovulatory doses of norethindrone & depoprovera on implantation in rat

Clinical experimentation was carried out to assess the effect of nonantiovulatory doses of norethindrone and depo provera on implantation in rats. Norethindrone in doses of 25 and 50 mcg and depo provera in doses of 5 and 10 mcg, administered from day 0-5 of pregnancy, prevented implantation. Lower doses of either drug had no effect on implantation. All doses of both drugs decreased the activities of several lysosomal enzymes as well as a proteolytic enzyme. Treatments with either norethindrone or depo provera after day 5 of pregnancy had no effect on the successful completion of the pregnancy. Depo provera was found to be 5 times more effective than norethindrone. The study results are tabulated.     

Biphasic effects of translational inhibitors on liver tyrosine aminotransferase.

Low doses of cycloheximide or emetine cause rat liver tyrosine aminotransferase activity to rise up to twice the control levels in 2 h. By contrast, in the same interval no changes, or only a slight decrease, are produced by either drug at high dosage. Adrenalectomised animals display the same pattern of response. High doses of either antibiotic virtually afford a complete inhibition of 14C-labelled amino acid incorporation into liver and plasma proteins, whereas no more than a 30% decrease is observed with low doses. When administered in the course of the induction by cortisol, high doses of inhibitor prevent any further change in tyrosine aminotransferase activity, stabilising it at the level already attained; low doses, while slightly affecting the synthetic phase evoked by cortisol, drastically interfere with the deinduction. Six hours after various doses of either inhibitor the tyrosine aminotransferase activity is markedly increased, this late effect being largely dependent on the presence of adrenals. The amino acid incorporating actitivy of the liver may exceed that of controls, as observed particularly after small doses of emetine.     

Alternative approach to the treatment of diabetes mellitus

The influence of insulin preparations (Actrapid and Ransulin) on the glucose and insulin blood level has been studied in patients with diabetes mellitus. It has been shown that comparable changes in the measured parameters are achieved in most patients with oral doses of Ransulin that are two to three times higher than the doses of Actrapid.     

Action of ecdysoids,juvenoids, and non-hormonal agents on termination of pupal diapause in the flesh fly

Pupal diapause in Sarcophaga crassipalpis can be immediately terminated with high doses of ecdysterone or 5,β-hydroxyecdysterone. Within a range of lower doses diapause is not immediately terminated, but the duration of diapause is shortened. Injection of small doses at 3-day intervals is more effective than a single application of the same total amount. 5,β-hydroxy-ecdysterone is more effective than ecdysterone. The juvenoid isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate does not cause immediate termination of diapause but diapause is shortened. Simultaneous application of ecdysterone and the juvenoid synergistically produce a shorter duration of diapause than either hormone applied separately. Topical application of acetone and several other organic compounds can cause an immediate break of diapause. Neckligated pupae, however, do not respond to acetone treatment. Temperature shocks caused by brief exposure to high or low temperatures are ineffective.Although high doses of ecdysoids cause immediate termination of diapause, subsequent adult morphogenesis is protracted in direct proportion to the dose of ecdysoid. With the highest doses many flies fail to complete adult morphogenesis. Flies receiving high doses of ecdysoid are characterized by developmental abnormalities such as underdeveloped antennae, compound eyes, and mouthparts. By contrast, adultoids produced with juvenoids are characterized by abdominal abnormalities.