Model Of Radiation Carcinogenesis Research Articles

Initiation-promotion model of tumor prevalence in mice from space radiation exposures.

Exposures in space consist of low-level background components from galactic cosmic rays (GCR), occasional intense-energetic solar-particle events, periodic passes through geomagnetic-trapped radiation, and exposure from possible onboard nuclear-propulsion engines. Risk models for astronaut exposure from such diverse components and modalities must be developed to assure adequate protection in future NASA missions. The low-level background exposures (GCR), including relativistic heavy ions (HZE), will be the ultimate limiting factor for astronaut career exposure. We consider herein a two-mutation, initiation-promotion, radiation-carcinogenesis model in mice in which the initiation stage is represented by a linear kinetics model of cellular repair/misrepair, including the track-structure model for heavy ion action cross-sections. The model is validated by comparison with the harderian gland tumor experiments of Alpen et al. for various ion beams. We apply the initiation-promotion model to exposures from galactic cosmic rays, using models of the cosmic-ray environment and heavy ion transport, and consider the effects of the age of the mice prior to and after the exposure and of the length of time in space on predictions of relative risk. Our results indicate that biophysical models of age-dependent radiation hazard will provide a better understanding of GCR risk than models that rely strictly on estimates of the initial slopes of these radiations.

A bivariate limiting distribution of tumor latency time

The model of radiation carcinogenesis, proposed earlier by Klebanov, Rachev, and Yakovlev [8] substantiates the employment of limiting forms of the latent time distribution at high dose values. Such distributions arise within the random minima framework, the two-parameter Weibull distribution being a special case. This model, in its present form, does not allow for carcinogenesis at multiple sites. As shown in the present paper, a natural two-dimensional generalization of the model appears in the form of a Weibull-Marshall-Olkin distribution. Similarly, the study of a randomized version of the model based on the negative binomial minima scheme results in a bivariate Pareto-Marshall-Olkin distribution. In the latter case, an estimate for the rate of convergence to the limiting distribution is given.

A two-mutation model of radiation carcinogenesis: application to lung tumours in rodents and implications for risk evaluation

An attempt is made to develop a model for radiation carcinogenesis linking DNA damage to malignancy. A modification of the two-stage model for carcinogenesis developed by Knudson and Moolgavkar (see J. Natl. Acad. Sci. (USA), vol. 68, p. 1037-52, 1981) is combined with a linear-quadratic dose response model for cellular radiation effects to analyse radiation induced lung tumours in rodents for a variety of radiation types and conditions. The combined model provides the possibility of calculating the age dependent and dose dependent incidence of cancer simultaneously and is used to fit data of lung tumours in mice and rats exposed to different radiation types. The satisfactory application of the combined model to animal data has led to an examination of the implications of the model, which may prove to be far-reaching for the extrapolation of risk to low doses, the effect of life exposures and other aspects of radiation risk assessment.

Development of altered hepatocyte foci by separate and combined treatments with radiation and diethylnitrosamine in neonatal rats.

To establish an in vivo radiation carcinogenesis model using glutathione S-transferase placental form positive (GST-P+) hepatic foci, newborn rats were irradiated once by 0.5 Gy and 2 Gy of gamma ray or 0.15 Gy and 0.6 Gy of neutron with or without 0.05% phenobarbital (PB). When the rats were sacrificed at the 12th or 21st week, the incidence of GST-P+ foci induction by radiation alone was very low. The neutron was more sensitive than the gamma ray at week 12 and the reverse phenomenon was observed in the groups at week 21. PB combination showed an increased incidence of GST-P+ foci in gamma ray irradiated groups. The neutron irradiation combined with PB did not show any significant difference compared with the corresponding PB untreated groups. We also investigated the combined effect of diethylnitrosamine (DEN) and 0.75 Gy of gamma ray irradiation. Intraperitoneal injection of 0.15 mumol/g body weight of DEN at 1 hour after gamma ray irradiation showed significantly increased the number and area of GST-P+ foci compared with those of DEN alone or DEN at 1 hour before gamma radiation (P < 0.001). From these data, after more defined experiments, an in vivo radiation carcinogenesis model will be established by radiation alone or a combination of radiation and carcinogens.

Extension of a generalized state-vector model of radiation carcinogenesis to consideration of dose rate

Mathematical models for radiation carcinogenesis typically employ transition rates that either are a function of the dose to specific cells or are purely empirical constructs unrelated to biophysical theory. These functions either ignore or do not explicitly model interactions between the fates of cells in a community. This paper extends a model of mitosis, cell transformation, promotion, and progression to cases in which interacting cellular communities are irradiated at specified dose rates. The model predicts that lower dose rates are less effective at producing cancer when irradiation is by X- or gamma rays but are generally more effective in instances of irradiation by alpha particles up to a dose rate in excess of 0.01 Gy/day. The resulting predictions are compared with existing experimental data.

A stochastic model of radiation carcinogenesis: latent time distributions and their properties

A stochastic model of radiation carcinogenesis is proposed that has much in common with the ideas suggested by M. Pike as early as 1966. The model allows us to obtain a parametric family of substochastic-type distributions for the time of tumor latency that provides a description of the rate of tumor development and the number of affected individuals. With this model it is possible to interpret data on tumor incidence in terms of promotion and progression processes. The basic model is developed for a prolonged irradiation at a constant dose rate and includes short-term irradiation as a special case. A limiting form of the latent time distribution for short-term irradiation at high doses is obtained. This distribution arises in the extreme value theory within the random minima framework. An estimate for the rate of convergence to a limiting distribution is given. Based on the proposed latent time distributions, long-term predictions of carcinogenic risk do not call for information about irradiation dose. As shown by computer simulation studies and real data analysis, the parametric estimation of carcinogenic risk appears to be robust to the loss of statistical information caused by the right-hand censoring of time-to-tumor observations. It seems likely that this property, although revealed by means of a purely empirical procedure, may be useful in selecting a model for the practical purpose of risk prediction.

Radiation-induced lymphoid tumors and radiation lethality are inhibited by combined treatment with small doses of zinc aspartate and WR 2721.

Combined small doses of zinc aspartate and WR 2721 provided additive protection against radiation lethality in mice. Survival obtained with a small dose of WR 2721 which was ineffective alone could be enhanced to 83% by combining the drug with zinc aspartate, which on its own also displayed no effect. The survival of 25% provided by a higher dose of WR 2721 was increased significantly by adding zinc aspartate. Additivity was also tested in a model of radiation carcinogenesis. For this purpose, lethality and occurrence of lymphoid tumors induced by fractionated total-body irradiation were studied in C57B1/6 mice treated with zinc aspartate and WR 2721. In order to reveal additive effects, both agents were used at sub-optimal dosages. In mice subjected to 5 daily exposures of 1.9 Gy, the combination of zinc aspartate and WR 2721 was effective and enhanced the survival to 83% as compared with 25% afforded by WR 2721 alone (p < 0.005). Similarly, histological assessment of organ involvement with lymphoma revealed that zinc aspartate and WR 2721 alone did not bring about a significant reduction of lymphoma incidence. On the other hand, the combined agents diminished organ involvement with lymphoma to 9.1% as against 90% in the controls (p < 0.0005) and 62.5% with WR 2721 alone (p < 0.025). Thus, combined treatment with zinc aspartate and WR 2721 also inhibited radiation-induced lymphoid tumors.

The question of safe radiation thresholds for alpha emitting bone seekers in man.

The Evans hypothesis derived from the study of radium-exposed persons includes two major points: (a) the linear model of radiation carcinogenesis is incorrect, and (b) “practical” and/or absolute thresholds exist below which human radiation carcinogenesis does not occur. Analysis presented here indicates that neither aspect of this hypothesis can be supported, either from the study of residual radium burden or from cumulative rad exposure. This analysis in no way attempts to show that “practical” or absolute thresholds are impossible. Rather, the results of analyses show that no evidence for such thresholds has been presented through the studies of radium-exposed persons.