Characterization of small radiophotoluminescence dosemeter in terms of HP(0.07) for extremity dose monitoring of medical personnel.

An additional extremity monitoring using a ring badge must be appropriately conducted for inhomogeneous exposure around radiation workers' extremity. Commercially available glass dosemeters are characterized in terms of Hp(0.07) for the application of additional extremity monitoring. A series of experiments demonstrated that the response of the model GD-352M radiophotoluminescence dosemeter fully matched the IEC's criteria for an extremity dosemeter for medical personnel. Although the model GD-302M has excellent angular dependence, the material and the shape of energy compensation filter still need to be optimized to improve its energy dependence in the range between 30 and 100 keV. The combine use of both types of glass dosemeters for 'paired dosemeter' together with introduction of a simple algorithm may be a promising method to improve the response in the energy range below 20 keV.

Long-term exposure to gaseous formaldehyde promotes allergen-specific IgE-mediated immune responses in a murine model.

It has long been questioned that whether exposure to formaldehyde in indoor environments may be a risk factor for developing allergen-specific IgE-mediated inflammatory responses, because there is limited clinical or experimental evidence that formaldehyde is involved in the cascade for IgE production. There is no known lower limit, below which there is no threat of serious allergic symptoms. The present study illustrates that the threshold limit of formaldehyde, 0.08 ppm (as defined by the World Health Organization), did not cause ovalbumin-specific IgE inflammatory immune responses, but higher than threshold concentrations of formaldehyde gas result in both enhanced allergen-specific IgE responses and NK (Natural Killer)-cell activity in peripheral blood cells in a murine model. Thus, formaldehyde gas may be involved in promoting allergic inflammatory effects in subjects primed with specific allergens by NK-cell activation. These results indicate that even threshold concentrations of formaldehyde gas may play a regulatory role for 'systemic' cell-mediated immune responses. The extensive use of adhesives for building materials has resulted in higher levels of indoor air pollutants. It is conceivable that increased time indoors may enhance pre-existing allergic symptoms by concomitant exposure to volatile organic compounds and formaldehyde. The affordable limit for formaldehyde might be much lower than currently established levels in indoor environments.

1-BP inhibits NF-kappaB activity and Bcl-xL expression in astrocytes in vitro and reduces Bcl-xL expression in the brains of rats in vivo.

1-Bromopropane (1-BP) has been widely used as a substitute for chlorofluorocarbon that destroys the ozone layer. Although the central neurotoxicity of 1-BP has been recently reported, a molecular mechanism is not clear. In particular, the effects on cells in brain have not been fully analyzed. Here, we studied the effects of 1-BP on the activation of transcription factors involved in anti-apoptotic function or cell survival in astrocytes. Astrocytoma cell lines, U251, U373 and VM, or murine primary astrocytes were used for in vitro assay. DNA binding activities of NF-kappaB in these cells induced by interleukin (IL)-1 or LPS were inhibited by 1-BP. Consequently, the treatment of U251 cells with 1-BP resulted in suppression of NF-kappaB reporter activity. Furthermore, 1-BP blocked IkappaBalpha degradation, which is important for NF-kappaB activation. In addition, the level of Bcl-xL mRNA, which is known as an anti-apoptotic gene, were reduced in U251 treated with 1-BP or in the brain from rat exposed to 1-BP (400 ppm, 12 weeks). These results suggest that subchronic inhalation exposure to 1-BP vapor may affect the Bcl-xL expression in astrocytes.

Antiepileptic action induced by a combination of vigabatrin and tiagabine.

Vigabatrin, an inhibitor of GABA breakdown by GABA transaminase and of GABA transporter isoform 1 (GAT1), and tiagabine, a highly specific inhibitor of GAT1, have successfully been applied in the treatment of epilepsy. We investigated the effects of individual and combined application of these drugs on GAT1 expressed in Xenopus oocytes, and examined the effects on epileptiform discharges in the CA3 area of brain slices of genetically epileptic El and control ddY mice, and on the occurrence of seizures in El mice. Simultaneous application of vigabatrin and tiagabine inhibited epileptiform discharges induced by high-K+ solution in the brain slices in an antagonistic fashion. The degree of inhibition by tiagabine after pre-treatment with vigabatrin was additive in ddY mice and synergistic in El mice. In Mg2+-free solution, co-treatment by the two drugs produced additive inhibition in slices from both mouse strains, but pre-treatment with vigabatrin produced synergistic inhibition in slices only from ddY mice. In the slices from El mice, a combination of drugs resulted in additive effects in both co- and pre-treatment by the drugs. Although these drugs are also effective in vivo at suppressing seizure occurrence in El mice, the combined application does not show synergistic effects, but rather is antagonistic under the experimental conditions in this particular variant of epilepsy. The synergistic inhibition of epileptiform discharges in brain slices may, in part, have originated from the complex interaction with GAT1. In experiments on the GAT1 expressed in oocytes it could be demonstrated that synergistic inhibition occurs only at low concentration (0.1 nM) of vigabatrin. This illustrates that the oocytes may form a powerful test system for drug screening and investigation of complex drug interactions. These results present a novel interpretation of synergistic inhibition of certain epileptic discharges using vigabatrin and another drug, and that for successful synergistic treatment of epilepsies carefully designed timed dosage regimens are essential.

Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse.

A principal pathway of 2-methoxyethanol (ME) metabolism is to the toxic oxidative product, methoxyacetaldehyde (MALD). To assess the role of aldehyde dehydrogenase (ALDH) in MALD metabolism, in vitro MALD oxidation was examined with liver subcellular fractions from Japanese subjects who carried three different ALDH2 genotypes and Aldh2 knockout mice, which were generated in this study. The activity was distributed in mitochondrial fractions of ALDH2*1/*1 and wild type (Aldh2+/+) mice but not ALDH2*1/*2, *2/*2 subjects or Aldh2 homozygous mutant (Aldh2-/-) mice. These data suggest that ALDH2 is a key enzyme for MALD oxidation and ME susceptibility may be influenced by the ALDH2 genotype.

Individual differences in urinary cotinine levels in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes.

Urinary cotinine, one of the main metabolites of nicotine, has been widely used as a biomarker for assessment of direct or passive exposure to cigarette smoke. However, there is wide variation of the cotinine level among smokers who smoke the same number of cigarettes. To use urinary cotinine as a proper exposure-biomarker for cigarette smoke, interindividual variations of cotinine formation must be considered. Therefore, we studied the effects of genetic polymorphisms in drug metabolic enzymes on urinary cotinine levels among 190 male Japanese smokers (ages 19-66 years; mean, 40.6 years). Genetic polymorphisms in cytochrome P-450s (CYP1A1, CYP2A6, CYP2E1), and aldehyde dehydrogenase 2 (ALDH2) were determined by analyzing DNA isolated from peripheral blood. Cotinine in morning spot urine was analyzed by high-performance liquid chromatography. Lifestyle, i.e., smoking, alcohol consumption, and intake of coffee or tea, was examined using a questionnaire. The number of cigarettes smoked and CYP2A6 polymorphism were significantly associated with the urinary cotinine level. Especially, the urinary cotinine levels was drastically lower in CYP2A6-deleted homozygous (CYP2A6*4/*4) subjects than in CYP2A6*1 allele-positive subjects. The polymorphism in the CYP2E1 5'-flanking region was related to the urinary cotinine level in intermediate smokers (who smoke 11-20 cigarettes/day; P < 0.01). Polymorphisms in CYP1A1 or ALDH2, and consumption of alcohol, coffee, or tea were not associated with the urinary cotinine level.

Radiotherapy after hyperbaric oxygenation improves radioresponse in experimental tumor models.

We examined the effect of radiotherapy after hyperbaric oxygen (HBO) breathing in experimental tumors using a tumor growth delay assay. Tumor models used were SCCVII (radiobiological hypoxic fraction: approximately 10%) and 9L tumors (containing less hypoxic cells) subcutaneously transplanted into C3H/He mice and Fisher 344 rats, respectively. Irradiation using X-rays was locally administered to the tumors immediately after decompression. HBO breathing enhanced the radiation response in SCCVII tumors but not in 9L ones. In the next experiment using SCCVII tumors, irradiation was administered 5, 15, 30, and 90 min after decompression. A significant growth delay was seen in the treated animals within 30 min after HBO breathing, and the tumor growth delay time was prolonged 1.61 times as long as that in radiotherapy alone. We concluded that: (1) radiotherapy after HBO breathing is effective for tumors with hypoxic cells; and (2) the time lapse from decompression to irradiation is an important factor in improving radiosensitivity. Radiotherapy after HBO breathing can be used to enhance the efficacy of clinical treatments.

Comparison of the frequency of T-cell receptor mutants and thioguanine resistance induced by X-rays and ethylnitrosourea in cultured human blood T-lymphocytes.

We have investigated two assays for measuring the induction of mutations using human T-lymphocytes isolated from leukocyte residue buffy coats obtained from normal donors. Variant cell frequency of T-cells defective in the T-cell receptor (TCR) gene expression was measured using a 2-color flow cytometry, and 6-thioguanine-resistant (TGr) cells were determined using a cloning technique at the HPRT gene after treatment with 250 kVp X-rays or ethylnitrosourea (ENU). The frequencies of TCR mutant cells as well as those of TGr cells increased with increasing doses of X-rays or concentrations of ENU studied. For TCR mutants, the induced mutation frequencies at D37 (giving 37% survival) were 31.7 x 10(-4) and 11.0 x 10(-4) for X-rays and ENU, respectively. For TGr T-cells, the induced mutation frequencies at D37 for the same mutagens were 14.4 x 10(-6) and 75.5 x 10(-6), respectively. Over the dose range studied the relationship appears to be linear between the mutation induction of TCR and that of TGr for X-rays or ENU. However, X-rays may induce more TCR mutants against less induction TGr T-cells, and ENU may cause a reverse result. The sensitivity of the assay of each biological endpoint in human blood T-lymphocytes may be different.

Low dose radiation-induced adaptive survival response in mouse spleen T-lymphocytes in vivo.

Induction of an adaptive survival response in B6C3F1 mice exposed to whole-body irradiation by low doses of X-rays (priming exposure) then to high doses of X-rays (challenge exposure) was examined. The adaptive survival response was determined by comparing the cloning efficiency of low dose-irradiated spleen T-lymphocytes to that of unprimed controls. Maximal expression of the adaptive survival response induced by exposure to low doses of X-rays occurred 7 hours after the priming exposure. The optimal low dose range for the induction of the adaptive survival response was 0.05-0.1 Gy. Thus, low dose X-irradiation induces the adaptive response in spleen T-lymphocytes of B6C3F1 mice as assessed by survival. The duration of this response is short, and there is an optimal low dose range. The Dq value for the primed cells was somewhat larger than that for the unprimed ones. Low dose exposure may enhance the capacity of spleen cells for repair during priming.

Individual variation and age dependency in the radiosensitivity of peripheral blood T-lymphocytes from normal donors.

To investigate individual variation and age dependency in normal cell radiosensitivity, we measured the in vitro radiosensitivity of cultured peripheral blood T-lymphocytes derived from 56 healthy male blood donors. Dose-survival tests using colony formation assay were done with exponential growing T-cells (day 3, PHA-stimulated cells). 6-Thioguanine (6-TG)-resistant mutation assays at the hypoxanthine phosphoribosyl transferase (HPRT) locus were done with G0 phase T-cells (day 0, unstimulated cells). The mean inactivation dose (MID) computed by integration of the fitted survival curves was 1.25 +/- 0.23 Gy (mean +/- SD). The X-ray dose required to kill 90% of the cells (D10) was 2.81 +/- 0.51 Gy. The MID ranged from 0.82 to 1.86 Gy with a coefficient of variation (CV) of 18%. The induced mutation frequencies (MF) per 10(6) cells at 2 Gy of X-rays ranged from 9.10 to 54.80 with a mean +/- SD value of 24.63 +/- 12.51 and a CV of 51%. It appears that the radiosensitivity of cell killing and mutagenicity varies among individuals. Although the spontaneous MF at the HPRT locus increases with age, the induced MF after exposure to 2 or 4 Gy of X-rays was not associated with age. Moreover, there were no significant correlations between age and MID values or the other dose-survival parameters. The findings indicate there is significant inter-individual variation in cellular radiosensitivity, but that in human T-lymphocytes aging does not affect the cytotoxic and mutagenic effects of X-irradiation.

Biological assessment of the enhancement of tritium excretion by administration of diuretics and excessive water in mice.

This study was undertaken to determine whether or not the administration of diuretics and excess water after tritium exposure would have any positive reducing effect not only on the retention of tritium but also on the radiation damage of hematopoietic tissue in mice. When mice were treated with diuretics and excess water for a few days after injection of tritiated water (HTO), radioactivity within the body fluid and tissues was reduced, and the number of CFU-s, clonability of splenic T cells and proliferative activity assayed by Con-A blastogenesis were increased in comparison with those in the controls. When the mice were injected with a large dose of HTO (811 MBq/mouse) to assay survival, no mice treated with diuretic and excess water died 80 days after injection, while 80% of the controls died during the first month. The final committed dose in the mice treated early with diuretics was calculated to be 60% of that in the controls. These results suggest that treatment with diuretics and excess water is useful for practical purposes when a human is accidentally exposed to tritium.

Modification of radio-thermo-chemotherapy by AK-2123 and hydralazine in tumor bearing mice.

The effects of chemical modifiers of hypoxic radiosensitizer, a 3-nitrotriazole derivative AK-2123 (200 mg/kg) before treatment, and vasodilator of hydralazine (HDZ; 5.0 mg/kg) after treatment on tumor growth of SCCVII of mice were investigated in the radio-thermotherapy combined with mitomycin C (MMC; 2.0 mg/kg) or adriamycin (ADM; 3 mg/kg). The tumor treated by 10 Gy alone (tumor doubling time = 7.5 days), MMC alone (6.9 days), and hyperthermia (43 degrees C, 30 min; HT) alone (8.0 days) showed a slight growth delay (control: 5.6 days). Prolonged growth delay (23.2 days) was observed by MMC-radio-thermotherapy (MMC-10Gy/HT) than that (12.4 days) by 10 Gy/HT. The modification of MMC-radio-thermotherapy by HDZ administered between 10 Gy and HT (MMC-10 Gy/HDZ/HT) resulted in the significant prolongation of tumor growth delay (31.7 days). AK-2123 administration before this treatment, (MMC-AK-2123)-10 Gy/HDZ/HT), enhanced a further tumor growth delay (37.6 days) which is equal to that by 50 Gy alone and resulted in the highest dose modifying factor (DMF) of 5.2. While modification of ADM-radio-thermotherapy by AK-2123 and HDZ, (ADM-AK-2123)-10 Gy/HDZ/HT, gave the equal tumor growth delay to that by 30 Gy alone (DMF = 3.1). These high efficacies of radio-thermo-chemotherapy modified by AK-2123 and HDZ may be caused by tumor blood flow reduction.

Water soluble vitamin E (TMG) as a radioprotector.

Tocopherol monoglucoside (TMG), a water soluble derivative of vitamin E offers protection against deleterious effects of ionizing radiation, both under in vivo and in vitro conditions, to biological systems. TMG was found to be a potent antioxidant and an effective free radical scavenger. It forms a phenoxyl radical similar to trolox upon reaction with various one-electron oxidants. TMG protected DNA from radiation-induced strand breaks. It also protected thymine glycol formation induced by gamma-radiation. Gamma-radiation-induced loss of viability of EL-tumor cells and peroxidation of lipids in microsomal and mitochondrial membranes were prevented by TMG. TMG was nontoxic to mice when administered orally up to 7.0 g/kg body weight. The LD50 dose of TMG for ip administration in mice was 1.15 g/kg body wt. In rats, following oral and ip administration of TMG, the absorption (distribution) half lives were 5.8 and 3.0 min respectively and elimination half lives were 6.7 and 3.1 min respectively. Embryonic mortality resulting from exposure of pregnant mice to ionizing radiation (2 Gy) was reduced by 75% by ip administration of TMG (0.6 g/kg, body wt) prior to irradiation. TMG offered protection to mice against whole body gamma-radiation-induced lethality and weight loss. The LD50(30) of mice increased from 6 to 6.72 Gy upon post irradiation administration of a single dose of TMG (0.6 g/kg, body wt) by ip.

[Survey of indoor radon concentrations in Fukuoka and Kagoshima prefectures].

It is now well established that radon and its daughter products account for nearly half of the average population exposure to ionizing radiations and that radon is the greatest single source of natural radiation to the population. Radon and its daughters are alpha-emitters, which are more biologically damaging than beta- and gamma-radiations. A nationwide survey of radon concentration was conducted by the National Institute of Radiological Sciences in order to estimate the contribution of radon and its daughters to the population dose in Japan. Authors surveyed indoor radon concentrations in Fukuoka and Kagoshima prefectures as part of this project. A passive type radon dosimeter, in which a sheet of polycarbonate film as the alpha-ray detector was mounted, was used to measure indoor radon concentrations. The resulting distribution of the average annual indoor radon concentrations in both prefectures can be characterized by an arithmetic mean of 24.4 Bq/m3 and a standard deviation of 13.1 Bq/m3, by a geometric mean of 22.2 Bq/m3, and by a median of 20.7 Bq/m3. The geometric means of the distributions for Fukuoka and Kagoshima were 25.4, and 18.4 Bq/m3, respectively. Radon concentrations were also generally high in winter and low in summer. Regarding the analysis of correlations between the concentrations and construction materials, radon concentrations were generally high in Japanese houses with earthen walls and in concrete structures. These results showed that seasons, the type of building materials, and regional differences were significant factors in the variation of indoor radon concentration.

[Relationship between cigarette smoking and physical complaints].

In order to evaluate the influence of cigarette smoking on health conditions, the authors analyzed results of the THI (Todai Health Index) questionnaire, which was administered to male employees of a large-sized enterprise in Osaka between 1984 and 1990. The smoking rate of male employees decreased over this period of time from 62.4% (1984) to 58.3% (1990) in this enterprise. Complaints regarding "respiratory organ", "digestive organ", "circulatory organ", "irregularity of daily life", "impulsiveness", and "many subjective symptoms" significantly increased with the amount of smoking. Many items of physical complaints in the THI questionnaire were also associated with smoking. These were coughing, sore throat, sputum, nausea when brushing teeth, loss of appetite, stomach pain, stomach problems, diarrhea, heartburn, gum problems, bad breath, heavy eyelids, itchy skin, face looked pale, shortness of breath, palpitation, feeling flushed or feverish, back pain, going to bed late and getting up late, weakness or fatigue, irregular meals, irritation, sensitive or nervous, eating salty or greasy food, and heavy drinker. It is therefore important in the health education of individual smokers to put special emphasis not only on the many diseases associated with smoking but also these physical complaints.

[Annual changes of THI (Todai Health Index) scores of workers in a large-sized enterprise].

To develop a well controlled working environment including a mental health supporting system, it is important to survey the health status of workers. The authors analyzed results of the Todai Health Index (THI), which was administered to employees of a large-sized enterprise in Osaka in 1984, 1986, and 1987. The results were as follows: 1) Female workers had more complaints of "eye and skin", "many subjective symptoms", "mental instability", and "psychosomatic disorder" than males. Male workers complained more of "aggressiveness", "lie scale", and "arousal" than females. 2) The authors could not detect any annual changes of each scale during the 3 years. These results are similar to previous reports. 3) Some people had continuous complaints of "psychosomatic disorder" and "neurosis". These results indicate that THI is useful in obtaining information regarding mentally high risked workers.

[Evaluation of doses of simulation-irradiation by a 137Cs gamma-ray irradiation system].

A preliminary experiment was made for a 137Cs gamma-ray irradiation system, which was designed for the simulation-irradiation of gamma-rays when studying the biological effects of internal exposure. The dose rate of the system decreased according to the inverse square of the distance from the source. In simulation-irradiation, the difference was less than 2% in the integral absorbed dose between the measurement and the calculation. Consequently, it became evident that the present simulation fulfilled its function satisfactorily.

Determination of in vivo and in vitro radiosensitivity of mouse splenic T-lymphocytes using a T-cell cloning technique.

Recently the authors established a method for culturing mouse splenic T-lymphocytes with T-cell growth factor (TCGF) and feeder cells in vitro. Using this method, T-lymphocytes grow for approximately 14 days with population doubling times of 27-29 hr; cloning efficiencies (CEs) of mouse spleen cells ranged from three to twelve percent. Using this colony forming assay, in vivo and in vitro radiosensitivity of mouse splenic T-lymphocytes in the G0 phase and in vitro radiosensitivity of proliferating T-lymphocytes (cycling T-lymphocytes) were examined. For in vitro irradiation, the dose-survival curve of T-lymphocytes in G0 phase gave a D0 value of 0.99 Gy and a Dq value of 0.87 Gy and that of cycling T-lymphocytes gave a D0 value of 1.04 Gy and a Dq value of 0.19 Gy. For in vivo irradiation, the dose-survival curve of T-lymphocytes gave a D0 value of 1.01 Gy and a Dq value of 0.73 Gy. These results suggest that the recovering activity from sublethal damage of G0 T-lymphocytes was more effective than that of cycling T-lymphocytes. Furthermore, this colony forming assay system appears to be very useful for screening the effects of in vivo exposure to toxic and/or mutagenic agents and for comparing the effects of in vivo exposure with those of in vitro exposure to toxic agents as well as radiation.

Influence of donor age on the cytotoxicity and mutagenicity of ethylnitrosourea in cultured human T-lymphocytes.

The effects of age on the cytotoxicity and mutagenicity of N-ethyl-N-nitrosourea (ENU) in human peripheral blood T-lymphocytes were investigated using colony-forming assay in vitro. ENU was shown to induce a dose-dependent increase in cell killing and in mutation frequencies (MF). No significant correlation between age and ENU-induced 6-thioguanine-resistant (TGr) MF at the hypoxanthine phosphoribosyl transferase (HPRT) locus of the X-chromosome was found after treatment with the same concentration of ENU (1 mM or 2 mM). There were also no significant differences among different donor age groups and the sensitivity parameters for exposure to ENU. As X-rays, the cytotoxic and mutagenic effects of ENU in cultured human T-lymphocytes appear not to be associated with age. These results suggest that the repair of mutagen-induced DNA lesions does not decline with age. Such knowledge has implications for risk assessment and protection against environmental mutagens.

Effects of strong magnetic fields on cell growth and radiation response of human T-lymphocytes in culture.

Experiments were undertaken in order to verify whether or not a strong magnetic field would have any biological effects on the cell growth, viability and radiation response of mammalian cells. Magnetic field exposures were conducted using a superconducting magnet with freshly-isolated human peripheral blood T-lymphocytes maintained at their normal growing temperature of 37 degrees C. The static magnetic fields with intensities up to 6.3-tesla (T) exerted little influence on the cell growth and viability of actively-growing T-lymphocytes under normal cell-culture conditions. On the other hand, the T cells exposed to the magnetic fields (4 T-6.3 T) during PHA stimulation were inhibited in their cell growth when compared to controls. The effects of the magnetic fields with intensities up to 2 T on cell growth properties, however, were minimal in this system. Also, the radiosensitivity of T-lymphocytes previously exposed to the strong magnetic fields was more sensitive than that of control cells. These results suggest that exposure to a static magnetic field of 4 T or stronger might lead to physiological and growth abnormalities at the cellular level.