Neutron RBE for induction of tumors with high lethality in Sprague-Dawley rats.

The effectiveness of fission neutrons is compared to that of gamma rays and X rays with regard to the induction of malignancies in male Sprague-Dawley rats. The analysis is based on autopsy results. It is focused on tumors that tend to be present in animals dying early, which is indicative of a high degree of lethality. The relative biological effectiveness (RBE) is deduced from a comparison of the cumulative hazard functions. Different nonparametric models-the constant relative risk model, a time shift model, and an acceleration model-are employed in the comparison, and the resulting values of RBE are seen to be substantially independent of the choice of model. The results are in good agreement with earlier studies of nonlethal lung tumors in the same series of experiments. At neutron doses of 20 to 60 mGy, the RBE of fission neutrons is about 50.

Analysis of lung tumour risk in radon-exposed rats: an intercomparison of multi-step modelling.

Three carcinogenesis modelling groups have both jointly and separately applied a multi-step carcinogenesis model with clonal expansion to one data set of lung tumours in rats exposed to radon (CEA, France). This study was designed to investigate the differences in modelling approach and fitting procedures used by the three groups in detail, and to explore possible discrepancies in the results. Using the same model assumptions and a (linear) radiation dependence on the first model step only, the three groups arrived at identical best fits, proving that the mathematical formalisms and fitting procedures do not lead to different results. However, when each group was allowed to find its own preferred fit for this data set, all three found a significantly better, but different fit to the data. All solutions indicated radiation to be an initiating agent and found additional radiation action necessary. The character of this additional radiation dependence, however, could not be unambiguously pinpointed. Tumour incidence data were described equally well when radiation dependence was taken into account in clonal expansion ("promotion") or in the second mutational step ("transformation"); extension to three model stages also resulted in an adequate description. The study showed that, although the three groups used one carcinogenesis model in principle, different model assumptions and/or different methods of finding the "best fit" could result in different descriptions of experimental data. This implies that on statistical grounds, different interpretations can be given for the action that radiation had in this data set. Different data, i.e. other data sets with age-dependent tumour data and/or information from cellular radiobiology experiments, are needed to specifically pin down the radiation dependence in the multi-step carcinogenesis process.

[Experimental study of different histologic types of pulmonary cancers induced by irradiation]. / Etude expérimentale des différents types histologiques de cancers pulmonaires induits par l'irradiation.

Recent epidemiologic studies suggested that some histologic types of carcinomas were preferentially induced in the lung by irradiation, whatever the mode of exposure and the radiation quality. Since smoking and other environmental airborne pollutants may be strong confounding factors in humans, we have investigated whether histological subtypes were dependent or not on the mode of exposure, in a large series of 9000 rats exposed to external and internal sources at high and low Linear Energy Transfer. Despite comparable overall risk coefficients in rats and humans, our results show that histological types are influenced not only by dose but also by radiation quality and heterogeneity of dose delivering. We suggest that extrapolation from one group to an other take this information in consideration.

Carcinogenic and cocarcinogenic effects of radon and radon daughters in rats.

It has been previously established that lung cancer could be induced in rats by exposure to radon and radon daughters. Although the oat-cell carcinomas that are common in humans were not found in rats, other histological types of lung carcinomas, especially squamous cell carcinomas and primitive lung adenocarcinomas, were similar to those observed in humans. A dose-effect relationship was established for cumulative doses varying from 25 to 3000 working-level-months (WLM), which was similar for medium and high cumulative doses to that observed in uranium miners. This experimental protocol was also used to study the potential cocarcinogenic effects of other environmental or industrial airborne pollutants such as tobacco smoke, mineral fibers, diesel exhausts, or minerals from metallic mine ores that may act synergistically with radon exposure. In rats exposed to radon and tobacco smoke combined, the incidence of lung cancers was higher by a factor of 2-4 according to the cumulative radon exposure and the duration of tobacco smoke exposure. When mineral fibers were injected intrapleurally, an increased incidence of malignant thoracic tumors was observed in rats exposed to radon and fibers combined, but synergistic effects resulted in additivity. With diesel exhausts or minerals from metallic ores, a slight, nonsignificant increase in the incidence of lung carcinomas was observed compared with rats exposed to radon alone. These results demonstrated that it is possible to establish the potential cocarcinogenic action, showing either multiplicative, additive, or no effect of various environmental or industrial airborne pollutants combined with radon exposure. This radon model is valid for investigating possible interactions between two occupational exposures.

[Importance of the role of dose rate on tumor induction in rats after radon inhalation]. / Importance du rôle du débit de dose sur l'apparition des cancers chez le rat après inhalation de radon.

Lung cancer can be induced in rats, by radon daughter products, after exposure as low as 25 WLM (80 mJ.h.m-3) protracted over 4 to 6 months with a dose rate of 100 to 150 WL (2 to 3 mJ.m-3). The incidence of lung cancer is not increased and is equal to that of controls when the same cumulated dose is protracted over 18 months at 2 WL (0.042 mJ.m-3).

[Role of age at the moment of irradiation on the induction of tumors]. / Rôle de l'âge au moment de l'irradiation sur l'induction des tumeurs.

The probability that rats develop tumours following a 3 Gy exposure to gamma rays from cobalt 60 was observed to depend on age at exposure. Lifetime excess of neoplasia decreased by a factor of about 10 in 9-month-old rats as compared to animals irradiated in utero. The 3-month age group developed slightly fewer tumours than the group irradiated in utero, and tumour location was different. The higher incidence of tumours observed in the foetal group was mainly due to the high sensitivities of central nervous system and gonads during organogenesis.

[Carcinogenic effects of low-dose gamma ray irradiation]. / Effets cancérogènes de l'irradiation gamma à faible débit de dose.

For a dose of 3 Gy delivered by cobalt 60 gamma rays on rats, a reduction of the dose rate by a factor of 60 decreased the carcinogenic effectiveness by a factor of about 5. This decreased effect was essentially observed for carcinomas.

Lung carcinomas in Sprague-Dawley rats after exposure to low doses of radon daughters, fission neutrons, or gamma rays.

The effectiveness of radon-daughter inhalation and irradiation with fission neutrons and gamma rays in the induction of lung carcinomas in Sprague-Dawley rats at low doses is compared. Earlier reports which compared radon-daughter inhalations and neutron irradiations over a wider range of doses were based on dosimetry for the radon-daughter inhalations which has recently been found to be faulty. In the present analysis, low-dose experiments were designed to derive revised equivalence ratios between radon-daughter exposures, and fission neutron or gamma irradiations. The equivalence is approximately 15 working level months (WLM) of radon daughters to 10 mGy of neutrons (the earlier value was 30 WLM to 10 mGy). The relative biological effectiveness (RBE) of neutrons is 50 or more at a gamma-ray dose of 1 Gy. In these experiments with low doses and exposures, the lifetime incidences can be estimated from the raw incidences, while the derivation of the time dependence of the prevalence is essential for the estimation of RBE values and equivalence ratios.

Comparison of the induction of pulmonary neoplasms in Sprague-Dawley rats by fission neutrons and radon daughters.

Pulmonary carcinomas were recorded in a life-span experiment of male Sprague-Dawley rats exposed to fission neutrons. Mortality-corrected prevalences are obtained by the method of isotonic regression. In a second part of the paper a comparison is made with data obtained earlier for radon-daughter inhalations in the same strain of rats. A simultaneous maximum likelihood analysis is applied jointly to all experimental groups from the radon inhalation and the fission neutron study. The dependence of the resulting coefficients for the different groups on absorbed dose or inhalation dose permits a derivation of equivalence ratios. At low doses the equivalence ratio is 3 WLM (working level months) of radon-daughter exposure to 1 mGy of fission neutrons. At higher doses the equivalence ratio decreases. The neutron data are also utilized to derive mortality-corrected lifetime incidences of pulmonary carcinomas in the exposed animals. At low doses the relation is consistent with linearity, but sublinearity (dose exponent less than 1) cannot be excluded.

Metabolism of plutonium introduced as Tri-N-Butylphosphate complex in the rat and removal attempts by DTPA.

The metabolism of plutonium introduced as the Pu-Tri-N-Butylphosphate complex (Pu-TBP) was studied in rats after inhalation, injection and ingestion. Early translocation and distribution of 239Pu in organs for 30-400 days after inhalation exposure are presented. The tracheobronchial clearance was impaired at early times, followed from about one week by clearance from the deep lung as characterized by a half time of 100 days. Skeleton was the main organ for deposition of the transferable fraction. The bone burden reached a plateau value of 10% of Initial Lung Burden (ILB) at 50 days after inhalation, while retention in liver reached 2% of ILB at 50 days and decreased to 0.3% by 1 yr after inhalation. Thirty days after intramuscular injection, translocated plutonium (15% of injected activity) resulted in a skeletal deposit that was 17.5 times higher than the deposit in the liver. By both routes, inhalation and intramuscular injection, 239Pu was transported in the blood as a Pu-transferrin complex. However, therapy with 30 mumol . kg-1 DTPA was ineffective. This result, together with the magnitude of the skeletal deposit observed, indicate that Pu-TBP follows a specific metabolic pathway that results in a Pu-transferrin complex that is more stable than the complexes described after Pu nitrate or citrate contamination. Lastly, absorption of Pu-TBP from the gut was poor, reaching 0.015% of the Pu given by gavage, a value not significantly different from the values assumed by ICRP 30 for class W compounds.

Incidence of various types of thoracic malignancy induced in rats by intrapleural injection of 2 mg of various mineral dusts after inhalation of 222Ra.

After inhalation of 222Ra at equilibrium with radon daughters, male Sprague-Dawley rats were inoculated intrapleurally with 2 mg of unleached or acid-leached asbestos fibres or glass fibres or quartz. The additive co-carcinogenic effects of this type of insult were demonstrated by the increased incidence of malignant thoracic tumours. In rats given mineral materials, bronchopulmonary carcinomas and mixed carcinomas were observed, as well as typical mesotheliomas and combined pulmonary pleural tumours, whereas in control rats inhaling radon alone, only bronchopulmonary carcinomas occurred. No significant differences in tumour incidence were observed between the groups of animals given the different types of dusts, but statistically significant differences were noted in survival times, according to the histological type of tumour. The co-carcinogenic effects of an insult of the pleura by mineral dusts following inhalation of radon are discussed in relation to a possible tumour-promoting effect by these agents.

Characterization of a major natural killer activity in rat lungs.

A high level of antitumoral cytotoxicity was observed in the lymphoid population extracted by perfusion from lung capillaries. The in vitro cytotoxicity against tumor cells was demonstrated with the murine lymphoma YAC-1 cells or with the syngeneic P 77 rat lung fibrohistiocytoma cells. It was demonstrated that this cytotoxic activity had the characteristics of natural killer activity. At the same effector to target ratio the efficiency of this population was higher than in blood or spleen. Since the total number of lymphoid cells arrested in the capillary of the lungs is very high the lungs seemed an immunologically privileged site. A close relationship was observed between this activity in vitro and the rapid elimination in vivo of same tumor cells trapped in lungs (more than 99% after 24 hours).

Mesotheliomas in rats following inoculation with acid-leached chrysotile asbestos and other mineral fibres.

The carcinogenicity of untreated UICC chrysotile A, of acid (oxalic and hydrochloric)-leached UICC chrysotile A, of crocidolite and of JM 104 glass fibres has been studied by intrapleural injection into rats. This experiment, carried out on 304 animals, demonstrated that when more than 80% of the Mg had been leached from chrysotile fibres by either hydrochloric or oxalic acid, the proportion of pleural mesotheliomas was either nil or dramatically lower than that obtained with untreated chrysotile. The carcinogenic effect of crocidolite was higher than that of 43.7% oxalic acid-leached chrysotile. The proportion of mesotheliomas observed in animals injected with JM 104 glass fibres was similar to that in animals injected with fibres from which 63.8% had been leached with oxalic acid. These results indicate that with regard to the induction of pleural carcinogenicity by chrysotile fibres, not only size characteristics but also parameters such as chemical composition and physiochemical properties must intervene.

Malignant bone tumours induced by a local injection of colloidal radioactive 144Cerium in rats as a model for human osteosarcomas.

Lung metastases were observed in 80% to 85% of rats bearing advanced malignant bone tumours (osteogenic osteosarcomas and angiosarcomas). These tumours were induced in 2-month-old Sprague-Dawley rats by inoculation of a colloidal suspension of radioactive cerium (144Ce) into the hind leg, in close contact to the bones of the knee joint. Twenty-eight rats were killed or died spontaneously shortly after detection of palpable tumours at the site of injection: the incidence of lung metastases was 73.3% and 53.8%, respectively, for osteogenic sarcomas and angiosarcomas, showing that most lung metastases are present at the time of diagnosis of the primary tumour. Tumour-cell kinetic parameters were studied in 49 rats bearing tumours following intraperitoneal injection of [3H]thymidine. The labelling index (LI) of the primary tumours was significantly lower in advanced tumours (7.2% for osteosarcomas and 10.1% for angiosarcomas) than than in tumors examined at the time of detection (12.2% and 13.5%, respectively). Mitotic indices (MI) of all tumours were less than 1%. From the curve of the percentage of labelled mitoses (PLM) at different times after [3H]thymidine injection, Ts (6.5 h) and TG2 (1.75 h) were determined. TC and TG1 were also evaluated (18 h and 9.25 h, respectively). These results show that malignant bone tumours induced in rats with 144Ce may be a good model for human osteosarcomas and may be useful in studying the numerous problems in the therapy of malignant bone tumours in man.