NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

https://www.cell.com/cell/pdf/0092-8674%2893%2990719-7.pdf

p53-dependent apoptosis modulates the cytotoxicity of anticancer agents

The biochemistry and medical significance of the flavonoids.

Human intervention trials have provided evidence for protective effects of various (poly)phenol-rich foods against chronic disease, including cardiovascular disease, neurodegeneration, and cancer. While there are considerable data suggesting benefits of (poly)phenol intake, conclusions regarding their preventive potential remain unresolved due to several limitations in existing studies. Bioactivity investigations using cell lines have made an extensive use of both (poly)phenolic aglycones and sugar conjugates, these being the typical forms that exist in planta, at concentrations in the low-μM-to-mM range. However, after ingestion, dietary (poly)phenolics appear in the circulatory system not as the parent compounds, but as phase II metabolites, and their presence in plasma after dietary intake rarely exceeds nM concentrations. Substantial quantities of both the parent compounds and their metabolites pass to the colon where they are degraded by the action of the local microbiota, giving rise principally to small phenolic acid and aromatic catabolites that are absorbed into the circulatory system. This comprehensive review describes the different groups of compounds that have been reported to be involved in human nutrition, their fate in the body as they pass through the gastrointestinal tract and are absorbed into the circulatory system, the evidence of their impact on human chronic diseases, and the possible mechanisms of action through which (poly)phenol metabolites and catabolites may exert these protective actions. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these molecules interact with human physiological and pathological processes.

Dietary (Poly)phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases

5 The activity of cyclin-dependent protein kinase p34cdc2 is regulated by phosphorylation. In this study, we show that the presence of phosphatase inhibitors can have major effects on the levels of phosphorylation and the activities of the kinase extracted from cells. The combination of okadaic acid and sodium vanadate was most effective in protecting p34cdc2 against cellular phosphatases. In the absence of these inhibitors, p34cdc2 was dephosphorylated with an altered activity, indicating that phosphatase activities remained high during extractions. In contrast to when both inhibitors were used, lower activity of the kinase was found when only sodium vanadate was used, whereas higher activity was found in the presence of okadaic acid. Other conventional phosphatase inhibitors such as NaP, NaRS03 and glycero12-phosphate, were not effective in preventing dephosphorylation from p34cdc2 in whole cell lysates.

The Cell Cycle

Cancer therapy drugs, such as diamminedichloroplatinum (cisplatin), mitomycin C, etoposide and a number of other compounds, as well as energy-rich radiation, are known to act on cellular DNA. These agents are shown to induce nuclear accumulation of the so-called tumor-suppressor protein p53 in fibroblastoid cells, as well as in epithelioid normal and immortalized cells of murine, simian, and human origin. p53 accumulation starts a few hours after treatment and can remain detectable in surviving cells for at least 20 days. Accumulation occurs because of increased p53 protein stability and depends on ongoing translation. It is not the result of enhanced gene expression. A number of cell cycle inhibitors do not affect p53 protein accumulation, suggesting that the process may start from several points in the cell cycle. Since the increase in the nuclear p53 protein levels occurs within a few hours in most of the treated normal diploid cells, it is unlikely that the accumulated p53 protein is derived from a mutated p53 gene. The results obtained are in accordance with the view that the DNA damage-induced p53 accumulation may either inhibit cell growth, allowing DNA repair processes, or, in the case of severe damage, initiate apoptosis.

Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents.

Flavonoids are diphenyl propanoids widely distributed in edible plants. They play a dual role in mutagenesis and carcinogenesis. Some of them act as anticarcinogens or inhibit the growth of tumour cells, whereas others act as cocarcinogens, are mutagenic or able to induce DNA damage. To further elucidate this dual role, we investigated the influence of apigenin, luteolin and quercetin on the tumour suppressor protein p53, regarding p53 accumulation, cell cycle arrest, apoptosis, and biological activity. We found that incubation of the non-tumour cell line C3H10T1/2CL8 with these flavonoids resulted in induction of p53 accumulation and apoptosis. Apoptosis occurred out of the G2/M phase of the cell cycle. The G2/M arrest seems to be p53-dependent as it did not occur in p53 knockout fibroblasts which further supports the recent finding that p53 is involved in the G2/M checkpoint control. Differences between the flavonoids tested concerned p53 accumulation kinetics as well as the biological activity of accumulated p53 and might be due to different modes of flavonoid action. These data suggest that both aspects of flavonoid effects, i.e. inhibition of tumour growth through cell cycle arrest and induction of apoptosis, are functionally related to p53.

Flavonoids activate wild-type p53

Butyrate, a physiologically occurring agent, has been reported to decrease constitutively high expressed p53 levels in transformed cells. To elucidate whether butyrate also inhibits DNA-damage-induced p53 response we investigated the effects of butyrate and the anticancer drug mitomycin C in normal C3H10T1/2 cells harbouring wild-type p53. In comparison with p53-deficient fibroblasts we examined p53 protein level, cell cycle arrest, differentiation, and apoptosis. Butyrate induced G1 phase arrest, differentiation, and p53-independent increase in p21(waf1/cip1) protein. Moreover, butyrate induced p53-independent apoptosis, which was, as well as p53-mediated apoptosis, associated with a dose-dependent increase in Bax and c-Myc protein. Pretreatment with butyrate repressed dose-dependently mitomycin-C-induced p53 accumulation and interfered with p53-dependent cell cycle arrest. Butyrate further partially inhibited p53-mediated apoptosis, but low doses of butyrate were more effective than higher concentrations. This was reflected in an enhanced decrease in c-Myc and Bax protein in response to mitomycin C with low concentrations of butyrate. Our data indicate that the differentiation stimulus of butyrate, in association with p21(waf1/cip1) induction, and apoptosis, may explain antineoplastic effects of butyrate. Co-carcinogenic features of butyrate may result from inhibition of p53-mediated DNA damage response.

Butyrate modulates DNA-damage-induced p53 response by induction of p53-independent differentiation and apoptosis.

Dielectric breakdown of the red blood cell membrane and uptake of SV 40 DNA and mammalian cell RNA.

Epothilone A, a novel macrolide antibiotic, is produced by the myxobacterium Sorangium cellulosum. Similarly to paclitaxel (Taxol), epothilone A inhibits cell proliferation and induces apoptosis by binding to tubulin and stabilizing of microtubuli. Like paclitaxel, epothilone A induced apoptosis in neuroblastoma cells which exhibit constitutive cytoplasmic sequestration of p53 and, hence, an impaired DNA-damage-dependent apoptosis. However, in contrast to paclitaxel, epothilone A was also effective against a constitutively Pgp-expressing, multidrug resistant neuroblastoma cell line (SK-N-SH). Moreover, the efficacy of epothilone A was not impaired even though the Pgp level was further increased during treatment with the drug.

Gerhard Brandner

Papers

Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents.

Flavonoids activate wild-type p53

Butyrate modulates DNA-damage-induced p53 response by induction of p53-independent differentiation and apoptosis.

Dielectric breakdown of the red blood cell membrane and uptake of SV 40 DNA and mammalian cell RNA.

Epothilone A induces apoptosis in neuroblastoma cells with multiple mechanisms of drug resistance