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Content archived on 2024-04-15

NON STOCHASTIC EFFECTS OF IRRADIATION IN MAN : DIAGNOSIS, PROGNOSIS AND TREATMENT OF ACUTE RADIATION INJURY

Objective

The contracts represent a joint effort of four Community laboratories to improve the scientific basis and the practice for the diagnosis and treatment of radiation accident victims. The participating laboratories have a long standing expertise in this area and, for many years, have cooperated closely in research and treatment. They now aim to develop a European network for radiation accident mangement to serve as a centre of expertise for the development of strategies to manage radiation accidents should they ever occur in the Community. Moreover, such a network will have an important role in the training of doctors and nurses in the particular handling of accident victims and, thereby, transmit the unique personnal experience of the participating groups to other institutions.
The diagnosis and treatment of cutaneous radiolesions have been evaluated. These evaluations involved biophysical, biochemical and biological assessments of both the skin and the underlying tissue after accidental irradiation, in order to improve therapeutic protocols.
The diagnosis and treatment of irradiation was also studied at the global level. The biological indicators were not the only factors here but equally the biological and pharmacological factors affecting haematopoietic tissue.

Quantitative image analysis of intensified fluorescence video microscopy has been developed at the Institut Curie, allowing the observation of chromatin structure alterations and apoptosis in live cells, under experimental irradiation conditions. It has been shown that deoxyribonucleic acid (DNA) intercalation with fluorescent probes (acridine orange or ethidium bromide), which does not occur in quiescent cells, reflects local DNA-protein interactions in the chromatin of live cells and provides a new tool to study subtle changes in the physiology of irradiated cells (gene activation) or the mechanisms of radiation induced apoptosis.
The electron microscopy analysis (Pr Said Kremlin Bicetre) of irradiated nerves (rat model) has shown specified ultrastructural alterations.

The variations of hematological and biological parameters have been studied in serial blood samples from patients during and after several modalities of total body irradiation (Pr Cosset; Institut Gustave Roussy). These parameters include blood cells counts, human leucocyte antigen (HLA) typing, chromosome aberrations, cortisol, adrenocorticotrophic hormone (ACTH), adrenaline and noradrenaline, thyroid hormones and thyroid stimulating hormone (TSH), amylase, etc.

Granulocytes were counted during and after a single dose (10 Gy, 4 hours) total body irradiation (TBI) in 25 patients, and during and after a fractionated (11 doses of 1.35 Gy over 4 days or 6 doses of 2 Gy over 3 days) TBI in 24 patients. A granulocyte peak was found to be a constant feature 8 hours after the start of the 10 Gy single dose TBI. The mean amplification factor is 3.5 but with large variations from patient to patient. The same peak was observed after the first fraction (1.35 Gy and 2 Gy) of fractionated TBI. It was then significantly lower than after 10 Gy. This peak could only provide the physicians with a supplementary parameter able to give a rough idea of the delivered dose. The large interindividual variations wou ld not allow a very precise retrospective evaluation of the dose given.

In the same patients, the kinetics of disappearance of lymphocytes in the blood stream was analyzed. The rate of lymphocytes still present was 50%, 8 hours after the beginning of a 10 Gy for 4 hours TBI, and 25%, 24 hours after the start of this same irradiation. This disappearance is clearly dose related; however, here again, the interindividual variations preclude any reliable retrospective evaluation of the dose. It could only represent an additional clue.

The expression of class I HLA was studied before and after a 10 Gy for 4 hours TBI in 8 patients. 24 hours after the beginning of this irradiation the mean expression of class I HLA was 38%: too low to permit a reliable HLA subtyping. The same studies performed at 6 hours showed a mean expressio of 74.9%: this would allow subtyping in most cases. Therefore, for class I HLA it is recommended to take blood samples as soon aspossible.
Preliminary results indicate that class II antigens expression could be even more sensitive to irradiation.

Precise cytogenetic analysis was performed for 6 patients during and after single dose TBI, and for 3 patients during and after fractionated TBI. Preliminary results show that the retrospective evaluation of the dose which is allowed by this method is extremely precise in the 2 to 8 Gy range. A trend was noted for overestimating the dose below 2 Gy, and for underestimating the dose above 8 Gy.

A constant rise of blood cortisol was detected in 13 patients after 10 Gy for 4 hours TBI. (mean amplification factor: 6.5). This peak is lower (amplification factor: 4.5) after a 1.35 to 2 Gy TBI.
An initial transitory increase in blood ACTH was also detected. The kinetics of the peaks ACTH, cortisol and granulocytes is consistent with the lymphocytes of an initial rise of ACTH inducing the cortisol rate, inducing itself a release of granulocytes by the bone marrow.

No significant variation in adrena line, noradrenaline, thyroid hormones or TSH levels could be detected after either single dose or fractionated TBI in 19 patients.

A constant and dose dependant increase in amylasemia after irradiation of the salivary glands was confirmed from an extensive analysis of 93 irradiated patients.

The study of chromosomal aberrations and blood cell counts in patients treated by sequential hemicorporeal irradiation (Pr Laugier, Hopital Tenon) has provided precise and unique dose related data concerning the biological effects of heterogenous body irradiation.
The genotoxic effect of protracted locoregional irradiation (50 to 60 Gy over 5 to 6 weeks for breast cancer radiotherapy) on peripheral blood lymphocytes were measured at the level of chromosomal aberrations, DNA repair efficiency and hypoxanthine guanine phosphoribosyltransferase (HGPRT) mutations in 14 patients. Irradiation led to a chromosomal aberration frequency in peripheral lymphocytes equivalent to 2 Gy of acute total body irradiation. DNA repair capacity was slightly but significantly altered.

30 patients with invalidating radiation induced fibrosis were treated topically with liposome encapsulated bovine superoxide dismutase (SOD). A clinical and paraclinical score, including telethermography, pH and plethysmography was used to evaluate the extent of fibrosis; it was significantly improved by SOD treatment.
The management of radiation accidents is typically hampered by the lack of information available on the extent of damage inflicted on the organism and on the amount of tissue spared from radiation which might bring about the recovery of the organism. It should now be possible to develop an expert system based on the experience of past accidents and to use a spectrum of biological indicators to determine the extent of damage, the likelihood of recovery and the risk of permanent damage with emphasis on effects on the haemopoietic and immune systems.

New treatment modalities have recently become feasible thanks to the development of bioengineered haemopoietic growth factors. It can be envisaged that a judicious treatment with these factors could allow an optimal stimulation to promote a more speedy and complete recovery of the haemopoietic and immune system.

The development of new techniques for the isolation of haemopoietic stem cells has enabled bone marrow transplantation to become a more reliable and safer procedure in cases of very severe radiation accidents. Moreover, new methods of supportive care have become available.

Finally, it may now be possible to reduce the risks to persons who have to participate in recovery operations by prophylactic measures. Haemopoietic injury could be mitigated after a planned radiation exposure during a rescue operation by reinfusing autologous stem cells taken previously from the patient. Such cells could be obtained most readily from blood. Factors,such as dextran sulphate, which mobilize stem cells from bone marrow into human blood so that greater numbers of stem cells can be collected, will be investigated. The logistics needed for the establishment of such banks will also be studied. (Ulm. Univ.).

Diagnosis and treatment of radiation accident victims must be based on a sound understanding of the underlying pathophysiological mechanisms of damage and recovery after total and partial body irradiation, including the definition of the conditions which might lead permanent damage.

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Coordinator

Centre International de Radiopathologie
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Address

92260 Fontenay-aux-Roses
France

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