This article outlines the principles of radiobiology that can explain the time of onset, duration, and severity of the complex reactions of the lung to ionizing radiation. These reactions have been assayed biochemically, cell kinetically, physiologically, and pathologically. Clinical and experimental data are used to describe the acute and late reactions of the lung to both external and internal radiation including pneumonitis, fibrosis and carcinogenesis. Acute radiation pneumonitis, which can be fatal, develops in both humans and animals within 6 months of exposure to doses greater than or equal to 8 Gy of low LET radiation. It is divisible into a latent period lasting up to 4 weeks; an exudative phase (3-8 weeks) and with an acute pneumonitic phase between 2 and 6 months. The latter is an inflammatory reaction with intra-alveolar and septal edema accompanied by epithelial and endothelial desquamation. The critical role of type II pneumonocytes is discussed. One favored hypothesis suggests that the primary response of the lung is an increase in microvascular permeability. The plasma proteins overwhelm the lymphatic and other drainage mechanisms and this elicits the secondary response of type II cell hyperplasia. This, in its turn, produces an excess of surfactant that ultimately causes the fall in compliance, abnormal gas exchange values, and even respiratory failure. The inflammatory early reaction may progress to chronic fibrosis. There is much evidence to suggest that pneumonitis is an epithelial reaction and some evidence to suggest that this early damage may not be predictive of late fibrosis. However, despite detailed work on collagen metabolism, the pathogenesis of radiation fibrosis remains unknown. The data on radiation-induced pulmonary cancer, both in man and experimental animals from both external and internal irradiation following the inhalation of both soluble and insoluble alpha and beta emitting radionuclides are reviewed. Emphasis is placed on the data showing that alpha emitters are at least an order of magnitude more hazardous than beta/gamma radiation and on recent data showing that the more homogeneous the irradiation of the lung, the greater is the carcinogenic hazard which contradicts the so-called "hot particle" theory.ImagesFIGURE 6.

The International Commission on Radiological Protection (ICRP) provides models for the calculation of doses from intakes of radionuclides, including intakes of tritium as tritiated water (HTO) or organically bound tritium (OBT). The ICRP models for HTO and OBT are explained and the assumptions made are examined. The reliability of dose estimates is assessed in terms of uncertainties in central estimates for population groups. The models consider intakes of HTO and OBT by ingestion and inhalation by adults and children and doses to the fetus following intakes by the mother. The analysis includes uncertainties in the absorption of OBT to blood, incorporation of tritium into OBT in body tissues, retention times in tissues, transfer to the fetus and the relative biological effectiveness (RBE) of tritium beta emissions compared with gamma rays. Heterogeneity of dose within tissues and cells is also considered. For intakes as HTO, dose is predominantly due to distribution and retention of HTO in body water and it was concluded that adult doses are reliable to within a factor of 2. For intakes of OBT, the extent of incorporation into OBT in body tissues results in greater uncertainties with estimates relying on animal data for selected compounds. The analysis indicated that adult doses from OBT can be considered to be known to within a factor of 3. Greater uncertainties in estimated doses for children and for in utero exposures were considered. Central values from the uncertainty analyses of doses for HTO and OBT were greater than the corresponding ICRP dose coefficients by about a factor of 2, mainly due to the inclusion of uncertainties in RBE for tritium. A detailed assessment of doses using appropriate parameters and considering uncertainties would be of particular importance in situations where the dose may approach dose limits or constraints. For exposures to known forms of OBT, specific dose assessments may be required.

Tritium ((3)H) is a radioactive isotope of hydrogen. A number of factors combine to create a good deal of interest in tritium doses, both to workers and to members of the public. Tritium is ubiquitous in environmental and biological systems and is very mobile due to its occurrence as water. In this study we systematically review experimental data relating to tritium exposure with a view to assessing its low dose limiting relative biological effectiveness (RBE(max)). Interpretation of published experimental studies is complicated by the fact that the reference radiations varied, and doses and dose rates were frequently much higher than those normally received by humans. The four available animal carcinogenicity studies gave RBE values of about 2.5 with chronically-delivered gamma-ray reference, and about 1.2 with chronically-delivered X-ray reference. However, because of problems associated with the design and interpretation of the experiments, we do not consider that these RBE values should be taken to apply to the induction of cancer at low doses (i.e. they should not be interpreted as RBE(max)). Combining the six studies with chronic gamma-ray reference, with adequate quantitative data that examined endpoints apart from cell survival and related endpoints, yields an aggregate RBE estimate of 2.19 (95% CI 2.04, 2.33); the analogous combined RBE estimate using the three studies with chronic X-ray reference groups is 1.17 (95% CI 0.96, 1.39). Again, problems with the design, in particular the range of doses used in some of these studies, mean that these RBE values should also probably not be interpreted as RBE(max).

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We have used surface plasmon resonance to quantify the kinetics and stoichiometry of the interaction between p53 and nucleophosmin (NPM). Domains characterising the interface between the two proteins were identified by chemical cross-linking, proteolytic digestion and mass spectrometry based peptide mapping.We show that the C-terminal domain of NPM (residues 242-269) interacts with two regions of p53 (residues 175-196 and residues 343-363) which belong, respectively, to the DNA binding domain and the tetramerisation domain. Potential biological consequences of such interactions are discussed.