Radiation carcinogenesis in experimental animals

Summary Exposure of man to relatively high doses of ionizing radiation is generally restricted to accidental situations, with very limited knowledge about the actual doses received. Animal experiments can be performed under standardized and controlled conditions and can provide information on the dose-response relationships for radiation carcinogenesis.The risk of inducing neoplastic late effects after total-body irradiation with relatively high doses has been demonstrated for larger animals, such as monkeys and dogs. The bone marrow, the mammary glands and the lungs are among the tissues with the highest susceptibility for radiation carcinogenesis. Experimental results on tumour induction in rodents are summarized with emphasis on the effectiveness in dependence on radiation quality and fractionation or dose rate.     

Cell kinetics and radiation pathology

Conclusion Radiation pathology is a general term describing the damage that occurs in tissues after irradiation. After the very low doses, received by the normal working population, no major pathology is seen. There is a hazard of cancer induction if DNA damage that has been inflicted in an individual cell is repaired in such a way that the DNA remains intact but rearranged. This radiation carcinogenesis is however a low risk compared with many chemical carcinogens in the environment and in cancer chemotherapy.The treatment of cancer by radiation is now commonly accepted as one of the most effective forms of treatment. It can kill tumour cells effectively, but the dose that can be given is limited by the normal tissues that are inevitably included in the beam. Cell function is maintained for some time even after very large doses. However normal tissues show a loss of function and structure because the proliferating subcompartment of each tissue is depleted as the radiation injured cells fail to divide and die. The time at which the cell deficit is detected varies from hours in some tissues to months or years in others. It depends upon the normal rate of cell turnover. The apparent sensitivity of each tissue therefore depends upon the time at which the assessment is made. Lung and kidney would appear very resistant at 1–3 months post irradiation, but would seem very radiosensitive at 6–12 months as their latent damage is expressed.The ultimate expression of radiation pathology is the death of the whole animal as the essential organ function fails. The time of this death is only comprehensible if the time sequence and the proliferation kinetics of the target cells are taken into account. It must be recognised that it is initial damage to the clonogenic cells, not to the differentiated cells per se that is important.     

Radiation embryology

Prenatal development, characterized by intensive cell proliferation, cell differentiation and cell migration, shows a high radiosensitivity. Therefore, radiation exposure of embryos and fetuses is of great concern for radiological protection and human health. Irradiation during gestation can cause death, growth disorders, malformations, functional impairment and malignant diseases in childhood. These effects are strongly dependent on the developmental stage at exposure and on the radiation dose. The first trimester of pregnancy is regarded as the period with the highest risk for malformation and cancer induction. The developing nervous system shows a special susceptibility to ionizing radiation over a long period and is therefore of great significance for risk estimation. Knowledge about radiation effects on prenatal development has been derived from animal experimentation and from the exposure of human embryos. There is evidence that doses between 1 and 10 cGy may lead to developmental anomalies and that the radiation response can be modified by additional factors.     

Radiation embryology

Summary Prenatal development, characterized by intensive cell proliferation, cell differentiation and cell migration, shows a high radiosensitivity. Therefore, radiation exposure of embryos and fetuses is of great concern for radiological protection and human health. Irradiation during gestation can cause death, growth disorders, malformations, functional impairment and malignant diseases in childhood. These effects are strongly dependent on the developmental stage at exposure and on the radiation dose. The first trimester of pregnancy is regarded as the period with the highest risk for malformation and cancer induction. The developing nervous system shows a special susceptibility to ionizing radiation over a long period and is therefore of great significance for risk estimation. Knowledge about radiation effects on prenatal development has been derived from animal experimentation and from the exposure of human embryos. There is evidence that doses between 1 and 10 cGy may lead to developmental anomalies and that the radiation response can be modified by additional factors.     

Is superoxide dismutase a physiological radioprotector

Summary Prolonged treatment with relatively low doses of ionizing radiation did not induce synthesis of superoxide dismutase, either inDrosophila melanogaster or in mice liver.Acknowledgment. This work was supported by the project No. R. III. 13.2.4.     

Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces “aging-like” effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.     

100 years of radiobiology: Implications for biomedicine and future perspectives

The development of radiobiology from the very early detection of the biological action of X-rays to the knowledge of today is described in sections on radiation chemistry and biochemistry, mutation and cancer induction, and embryonic damage, as well as the dependence of radiation response on radiation quality and temporal dose distribution (repair) and the interaction with other factors. For medicine radiobiology serves as a basis for radiotherapy and radiological protection. The effect of very low doses, and their possible biopositive effect (hormesis and adaptive response), is also discussed, as are the health hazard of radon, health risks after the Chernobyl accident, and space radiobiology. The radiobiology of the future will be concerned with biomolecular and genetic implications, problems of damage and repair, and connected problems like hormesis.     

Lack of effect of butylated hydroxytoluene on dimethylhydrazine-induced colon carcinogenesis in rats.

Rats were given 6600 ppm of butylated hydroxytoluene (BHT) in the diet along with 10 weekly oral doses of dimethylhydrazine (DMH, 30 MG/KG). The incidence and mean number of colonic tumors produced were similar to that of rats given DMH alone. Thus, BHT did not provide any protective effect against colon carcinogenesis.     

Les transformations des nucléoides deEscherichia coli déclenchées par les rayons X

Summary In order to obtain further knowledge on the action of radiation on living cells we studied the nuclear transformations ofE. coli after exposure to X-rays. Three different phenomena could be observed; One is producting the polychromosomal form of nucleoids, and is reversible. The second, which is probably a rapid lethal effect, expresses himself by the vesicular form of the nucleoids. The third is only concerned with very high doses. The hypothesis, that the fragmentation of nucleoids may be directly related to induction of lysogenic cells is postulated.     

Chemische Sensibilisierung der Strahlenschädigung bei Rattenembryonen

Summary A combined treatment involving a radio-sensitizing chemical and low doses of X-rays was investigated. Small quantities of iodoacetamide can cause an increase in the radiation damages of rat embryos. The possibility of inhibition of postirradiation repair mechanisms is discussed.     

Facilitation or inhibition of memory by morphine: a question of experimental parameters

The effects of morphine on memory are highly controversial. According to some investigators post-trial injections of morphine facilitate memory. Others, however, have reported impairment of memory after morphine injections. To investigate the extent to which this may be due to different experimental parameters, foot-shock intensity and dosage of morphine were systematically varied in a passive-avoidance task. It was found that post-trial administration of medium and relatively high doses of morphine facilitate retention performance following moderate levels of foot-shock. Under other conditions of dose and shock intensity, the drug was not effective or even impaired retention.     

Direct toxic effect of isoproterenol on cultured cardiac muscle cells

Summary Isoproterenol at relatively high doses (2.5 mg/ml) has a marked toxic effect on rat heart muscle cells cultivated in vitro. This effect is not prevented by propranolol and therefore is not mediated by beta adrenergic receptors.This work has been supported in part by a grant from the Muscular Dystrophy Association, Inc. to Prof. M. Aloisi.     

Biological effectiveness of solar UV radiation in humans

Solar UVB radiation is prejudicial to the health of humans in a number of ways. Erythema and photodermatoses are acute reactions of the skin; keratitis and conjunctivitis are acute reactions of the eye. Various types of skin cancer, accelerated aging of the skin, and cataract formation in the crystalline lens are reactions that appear with great latency. UV radiation can also cause damage to the immune system and DNA. For the period 1981–1991, an increase in erythemal effective UVB radiation of +(7±4)% per decade was measured in a non-pulluted high mountain area (Jungfraujoch, 3576m a.s.l., Switzerland). This increase is related to a decrease in stratospheric ozone. The effects on human health are discussed. A 10% ozone reduction increases non-melanoma skin cancer by 26% and cataract by 6 to 8%.     

Radiation physics

A review is presented of the recent literature in the areas of physics which deal with radiation effects on man and animals. Some consideration is given to natural and artificial radiation sources such as cosmic rays, radon and high energy accelerators. The interaction of radiation with matter is treated if it is related to an energy deposition pattern relevant to biological effects. Dosimetry is also treated, with special emphasis on papers dealing with spatial dose distribution on a microscopic level, and radiobiological models relating the energy deposition pattern to biological effects are cited. New techniques in the medical application of radiation in diagnostics and therapy are briefly mentioned.     

Facilitation or inhibition of memory by morphine: a question of experimental parameters

Summary The effects of morphine on memory are highly controversial. According to some investigators post-trial injections of morphine facilitate memory. Others, however, have reported impairment of memory after morphine injections. To investigate the extent to which this may be due to different experimental parameters, foot-shock intensity and dosage of morphine were systematically varied in a passive-avoidance task. It was found that post-trial administration of medium and relatively high doses of morphine facilitate retention performance following moderate levels of foot-shock. Under other conditions of dose and shock intensity, the drug was not effective or even impaired retention.Results presented in part at the EBBS Meeting in Louvain-la-Neuve (Belgium), November 1980.     

Radiation physics

Summary A review is presented of the recent literature in the areas of physics which deal with radiation effects on man and animals. Some consideration is given to natural and artificial radiation sources such as cosmic rays, radon and high energy accelerators. The interaction of radiation with matter is treated if it is related to an energy deposition pattern relevant to biological effects. Dosimetry is also treated, with special emphasis on papers dealing with spatial dose distribution on a microscopic level, and radiobiological models relating the energy deposition pattern to biological effects are cited. New techniques in the medical application of radiation in diagnostics and therapy are briefly mentioned.     

Über einige pharmakologische Untersuchungen synthetischer Alkoxy-tropinderivate

Summary Some pharmacological properties of new synthetic alkoxy-tropine derivatives are reported. The tertiary compounds were relatively potent local anaesthetics with a low anti-cholinergic action. Acetylcholine inhibition, as well as the spasmolytic activityin vivo of the benzilic acid esters were markedly increased by quaternisation while their toxicity decreased. 6-Methoxytropine benzilic acid ester brom-methylate was the most active compound of this series. A pronounced inhibitory activity on neurogenically induced intestinal constriction was found in low doses, whereas larger doses exerted a ganglionic blocking effect.     

Increased radiation mortality by lead acetate

Summary The mortality of X-irradiated rats and mice was increased if a nontoxic dose of lead acetate was given i.v. 3 and 7 days following radiation. The increase was equivalent to 100 R for X-ray doses between 790 and 540 R.The basic experiments have been carried out 1967/1968 in the Heiligenberg-Institut.We are indebted to Mr Sunil Chaudhuri and Mr Thomas Beck for their technical assistance.     

Veränderungen der elektrischen Hirntätigkeit bei Katzen nach Röntgentotalbestrahlung

Summary In cats with chronically implanted electrodes, hippocampus and amygdala consistently showed spike discharges immediately after relatively low doses of total body x-irradiation (400 r) and reticular arousal thresholds were transitorily decreased. Thalamic recruiting thresholds increased later, while hippocampal seizure thresholds remained practically unaltered. Experiments with lower doses are in progress.

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This article is based on work performed under Contract No. AT-(04-1)-GEN-12 between the Atomic Energy Commission and the University of California at Los Angeles.     

Regulation of the cell cycle following DNA damage in normal and Ataxia telangiectasia cells

A proportion of the population is exposed to acute doses of ionizing radiation through medical treatment or occupational accidents, with little knowledge of the immedate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detrimental manifestations of radiation damage. Cytotoxic stress due to ionizing radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21^WAF1/CIPI, preventing the entrance into S-phase; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53as together with the retinoblastoma protein (Rb), with less defined functions during the G2 phase of the cell cycle. By comparing a variety of radioresistant cell lines derived from radiosensitive ataxia talangiectasia cells with the parental cells, some essential mechanisms that allow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition from G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation.