CARCINOGENESIS FROM INHALED 239PuO2 IN BEAGLES: EVIDENCE FOR RADIATION HOMEOSTASIS AT LOW DOSES?

Abstract

From the early 1970's to the late 1980's, Pacific Northwest National Laboratory conducted life-span studies in beagle dogs on the biological effects of inhaled plutonium ((238)PuO(2), (239)PuO(2), and Pu[NO(3)](4)) to help predict risks associated with accidental intakes in workers. Years later, the purpose of the present follow-up study was to reassess the dose-response relationship for lung cancer in the PuO(2) dogs compared to controls-with particular focus on the dose-response at relatively low lung doses. A PuO(2) aerosol (2.3 mum activity-median aerodynamic diameter, 1.9 mum geometric standard deviation) was administered to six groups of 20 young (18-mo-old) beagle dogs (10 males and 10 females) by inhalation at six different activity levels, as previously described in Laboratory reports. Control dogs were sham-exposed. In dose level 1, initial pulmonary lung depositions were 130 + or - 48 Bq (3.5 + or - 1.3 nCi), corresponding to 1 Bq g lung tissue (0.029 + or - 0.001 nCi g(-1)). Groups 2 through 6 received initial lung depositions (mean values) of 760, 2,724, 10,345, 37,900, and 200,000 Bq (22, 79, 300, 1,100, and 5,800 nCi) PuO(2), respectively. For each dog, the absorbed dose to lungs was calculated from the initial lung burden and the final lung burden at time of death and lung mass, assuming a single, long-term retention function. Insoluble plutonium oxide exhibited long retention times in the lungs. Increased dose-dependent mortality due to lung cancer (bronchiolar-alveolar carcinoma, adenocarcinoma, and epidermoid carcinoma) and radiation pneumonitis (in the highest exposure group) were observed in dogs exposed to PuO(2). Calculated lung doses ranged from a few cGy (lowest exposure level) to 7,764 cGy in dogs that experienced early deaths from radiation pneumonitis. Data were regrouped by lifetime lung dose and plotted as a function of lung tumor incidence. The lung tumor incidence in controls and zero-dose exposed dogs was 18% (5/28). However, no lung tumors were observed in 16 dogs with the lowest lung doses (8 to 22 cGy, mean 14.4 + or - 7.6 cGy), and only one lung tumor was observed in the next 10 dogs with lung doses ranging from 27 to 48 cGy (mean 37.5 + or - 10.9 cGy). By least-squares analysis, a pure-quadratic function represented the overall dose-response (n = 137, r = 0.96) with no apparent dose-related threshold. Reducing this function to three linear dose-response components, we calculated risk coefficients for each. However, the incidence of lung tumors at zero dose was significantly greater than the incidence at low dose (at the p < or = 0.053 confidence level), suggesting a protective effect (radiation homeostasis) of alpha-particle radiation from PuO(2). If a threshold for lung cancer incidence exists, it will be observed in the range 15 to 40 cGy.

Cancer immunotherapy: how low-level ionizing radiation can play a key role

“…As evidenced by the results of experimental studies conducted in the in vivo and in vitro systems, one of the most important underlying mechanisms of such tumor-inhibitory effects is up-regulation of both the innate and adaptive immunity. Numerous reports published between 1988 and 2014 indicate that exposures to LLR are potent stimulators of various anti-neoplastic functions of the immune system, including inhibition of inflammation and/or up-regulation of anti-inflammatory cytokines (evidence presented in Supplementary Table 3 and reviewed in [74, 80, 94, 170, 171]).…”

Microdosimetric Considerations of Lung Cancer Risks From Plutonium

“…The appearance of the paper by Fisher and Weller (2010) triggered further thoughts on this topic by Simmons and Richards (Simmons and Richards 2012). They noted the fact that, in the paper by Muggenburg et al (2008), a plot of the incidence of lung tumors as a function of dose appears to show a threshold at approximately 1 Gy.…”

“…At about the same time, Fisher and Weller published the results of their lifespan studies of beagles that had inhaled both plutonium dioxide and plutonium nitrate (Fisher and Weller 2010). Following inhalation, initial lung burdens ranged from 130 Bq to 215 kBq.…”

Commentary on Inhaled ²³⁹PuO₂ in Dogs — A Prophylaxis against Lung Cancer?

“…The authors of a study on inhaled 239 PuO 2 particles in beagle dogs, Fisher and Weller (2010) , identified the possibility of a beneficial health effect—lung tumor suppression at a low radiation dose. This was based on a statistical test they carried out “on the null hypothesis to determine the probability that the controls and the lowest dose groups have the same underlying probability of tumor incidence, and that tumor incidence is unrelated to dose (testing for a threshold effect).” Because of the infinitesimally small amount of plutonium in these studies, chemical toxicity does not need consideration.…”

“…For the lung tumor data (spontaneously-occurring plus radiation-induced) in Fig. 4 of Fisher and Weller (2010) , the LNT model would predict about 5 tumors in the 26 dogs that were exposed to a cumulative alpha-radiation dose in the range 8 to 48 cGy. The observed incidence of 0 tumors in the 16 dogs in the 8 to 22 cGy range and 1 tumor in the 10 dogs in the 27 to 48 cGy range suggests a beneficial effect, but the LNT statistical variations of these low tumor observations are too large to challenge the LNT prediction of 5 tumors.…”