Dosimetric implications of pulmonary macrophage clusters observed within lungs of rats that have inhaled enriched UO2 particles.

Twenty-four Fischer 344 rats were exposed to enriched uranium dioxide (UO2) aerosols to give a mean initial lung burden of 291 +/- 89 (SD) micrograms. Groups of rats were killed at 1, 7, 180, 360, 540, and 720 days post-inhalation (PI). Their lungs were fixed and inflated. Sections cut from all five lung lobes were used to prepare CR-39 neutron-induced 235U fission fragment autoradiographs. A single traverse across a CR-39 autoradiograph of a tissue section, from the left lung of all the rats, was made using a motorized microscopic stage. The traverse was divided into 10 fields. The track counts per field were used to test for homogeneity of track distribution and to assess if there was any tendency for tracks to be related to the peripheral region of the lung. Full raster scans across the entire tissue image were made on left lung autoradiographs from two animals killed at each time point to assess the homogeneity of fission fragment track distribution throughout the entire section. There was no evidence of any temporal change in the proportion of tracks associated with the lung periphery. At all time points PI, the track distribution was significantly nonhomogeneous, suggesting a nonuniform pattern of tissue irradiation from the 234U alpha particles. At time points from 180 to 720 days PI, large clusters of macrophages were observed in some of the sections taken from all five lung lobes. The total number of macrophage clusters increased with time PI. These macrophage clusters produced many 235U fission fragment tracks within the CR-39 autoradiographs.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term clearance of inhaled UO2 particles from the pulmonary region of the rat.

This paper reports on an enriched uranium dioxide (UO2) mass clearance study undertaken with Fischer-344 rats. The UO2 had a uranium (U) isotopic composition of 0.79% 234U, 92.8% 235U, 0.34% 236U and 6.06% 238U, by mass, with an alpha-particle activity of 1.91 Bq micrograms-1. Forty-six rats were exposed to an enriched UO2 aerosol that had an activity median particle aerodynamic diameter ranging from 2.7 to 3.2 microns. The rats were killed from 1 to 720 d post-inhalation (PI). The mass of enriched UO2 present in the trachea, lung lobes, thoracic lymph nodes, kidneys, liver, spleen, gut, and the remainder of the carcass was assessed at death. At 720 d after exposure, 82% of the total body burden of enriched UO2 was in the lung, with a further 10% in the thoracic lymph nodes. This represented 17% and 2% of the original (5 d PI) lung burden. The mass clearance of enriched UO2 from the lung was fitted to a single exponential function, normalized to 100% at 5 d PI. The rate constant (k) was 2.8 X 10(-3) d-1, giving a clearance half-time of 247 d. Although statistical comparisons with the majority of published data were not possible, it appeared that both enriched UO2 and natural UO2 particles cleared at rates that were broadly similar, with a t1/2 in the rat lung of 150 to 300 d over the 5- to 720-d PI period. As a consequence of the 234U component in the inhaled UO2 particles, the rats killed at 720 d PI received a total mean accumulated alpha-particle dose averaged over the whole lung of 5.7 Gy. Histologic investigations of the rat lungs found that widespread lung disease was only observed in animals killed at 720 d PI.

Studies of alveolar cell morphometry and mass clearance in the rat lung following inhalation of an enriched uranium dioxide aerosol.

Seventy-three rats were exposed to an aerosol of enriched uranium dioxide (UO2), giving initial lung burdens of 26 to 447 micrograms at 6 days post-inhalation (PI). At 7 days PI 35 of these rats were further exposed to thermalised neutrons at a fluence of 1 x 10(12) neutrons cm-2. There was no significant difference between the two groups in the clearance rate of the UO2 particles from the lung, up to 590 days PI. The particles cleared relatively slowly over this period with a retention half-time in the lung of 160 to 176 days. Transmission electron microscope (TEM) studies of tissue from the alveolar region at 8 days PI showed that inhalation of UO2 particles significantly increased the sizes of macrophage and type II cells, and the number of macrophage and type I cells. There was also a significant increase in the size of lysosomal granules within the macrophages after exposure to the UO2 particles. The exposure to UO2, neutrons and 235U fission fragments had no significant effect on any of the cells above that observed in the animals exposed to UO2 alone. Additional rats were exposed to the same neutron fluence without prior UO2 inhalation. The alveolar cells of neutron-only exposed rats were, in size and number, typically no different from those in the completely unexposed control rats.

Incidence of radiation-induced skin tumours in mice and variations with dose rate.

Mice were exposed to weakly penetrating beta-particles from an external source, using 12 different surface doses ranging from 5.4 to 260 Gy and given at four different dose rates from 200 to 1.7 cGy/min. As in previous investigations, both epidermal and dermal tumours occurred with the latter predominating. The lowest surface dose to produce a statistically significant increase in skin tumours was 21.7 Gy, no effect being detected with doses of 5.4-16.3 Gy. The dose-response curves rose steeply when obvious increases occurred. Consideration of these findings and the fact that radiation-induced skin tumours can have an exceptionally long latent period leads to the suggestion that there is some relatively radioresistant factor which normally restrains potential radiation-induced cancer cells in the skin from becoming tumours until the skin is subjected to high local doses. Tumour-induction was unaffected by reducing the highest dose rate by a factor of 10 and the dose-response curves were almost identical. Further reductions of dose rate, encompassing a further factor of 10, in general resulted in fewer tumours.

Further experiments to study whether localised fission fragment irradiation of rat lung causes tumours.

Male albino rats inhaled an aerosol of 235UO2 (mass median aerodynamic diameter = 2.8 micrometers and geometric standard deviation = 1.6). Approximately 20 h or 7 d post-inhalation the rats were exposed briefly to 10(12) slow neutrons cm-2 in a nuclear reactor, causing the retained 235UO2 particles of approximate mass 40 or 400 micrograms to emit fission fragments which irradiated the lungs. The mean absorbed doses from the fission fragments were either 80 ot 800 cGy approximately and in addition the lungs were exposed to a background of alpha-rays throughout the rats' life-time from the retained 235UO2 which gave mean doses of about half that from the fission fragments. The animals were kept for their life-time and killed when they became moribund. Malignant tumours were found in the lungs (squamous cell carcinoma and adenocarcinoma) which were probably induced by the alpha-rays rather than the fission fragments. Because of insufficient numbers of animals in the experimental groups, however, some statistical uncertainty exists as to whether the fission fragments were in fact less effective than the alpha-rays per unit absorbed dose in causing malignant tumours of the lung.

Influence of macrophages on microdistribution of inhaled UO2 aerosol in rat lung.

Following the inhalation of an aerosol of UO2 (mass median aerodynamic diameter = 3 microns and geometric standard deviation = 1.6) the lungs of male albino rats were populated by foci containing UO2 particles. A method of neutron-induced autoradiography on Lexan plastic was used to reveal these foci in thin sections cut from the lung. For masses of UO2 in the lung that differed by more than a factor of 10 (39 to 450 micrograms) the number of foci per g of lung increased, but not in proportion to the mass of UO2 deposited. This limited increase in the number of foci was considered to result from physiological limitations on the number of alveolar macrophages available for engulfing the UO2 particles.

The carcinogenic effect of localized fission fragment irradiation of rat lung.

In a preliminary investigation of 'hot particle' carcinogenesis uranium oxide particles were introduced into the lungs of rats either by intubation of a liquid suspension of the particles or by inhalation of an aerosol. Subsequently the animals were briefly exposed to slow neutrons in a nuclear reactor, resulting in localized irradiation of the lung by fission fragments emitted from 235U atoms in the oxide particles. The uranium used in the intubation experiments was either enriched or depleted in 235U. Squamous cell carcinomas developed at the site of deposition of the enriched uranium oxide in many cases but no lung tumours occurred in the rats with the depleted uranium oxide, in which the lung tissue was exposed to very few fission fragments. Only enriched uranium oxide was used in the inhalation experiments. Pulmonary squamous cell carcinomas occurred after the fission fragment irradiation but were fewer than in the intubation experiments. Adenocarcinomas of the lung were seen in rats exposed to uranium oxide without subsequent irradiation by neutrons in the reactor and in rats irradiated with neutrons but not previously exposed to uranium oxide. It is concluded that (i) fission fragments were possibly implicated in the genesis of the squamous cell carcinomas, which only developed in those animals exposed to enriched uranium oxide and neutrons and (ii) the adenocarcinomas in the rats inhaling enriched uranium oxide only were likely to have been caused by protracted irradiation of the lung with alpha-rays emitted from the enriched uranium.