For radiation-related cancer risk evaluation, it is important to assess not only influences of individual risk factors but also their interactive effects (e.g., additive, multiplicative, etc.). Multivariate analysis methods adapted for interactive effects allow such assessments. We have used a multivariate analysis approach to investigate the pair-wise interactions of the previously identified three main etiological factors for lung cancer induction in Russian workers of the Mayak Production Association (PA) nuclear enterprise. These three factors are as follows: (1) body burden of inhaled plutonium-239 (239Pu), an influence on absorbed alpha-radiation dose; (2) cumulative, absorbed external gamma-radiation dose to the lung; and (3) level of cigarette smoking as indicated by a smoking index (SI). The SI represents the cigarettes smoked per day times years smoking. The Mayak PA workers were exposed by inhalation to both soluble and insoluble forms of 239Pu. Based on a cohort of 4,390 persons (77% male), we conducted a nested, case-control study of lung cancer induction using 486 matched cases and controls. Each case was matched to two controls. Matching was based on five factors: sex, year of birth, year work began, profession, and workplace. Three levels of smoking were considered: low (SI = 1 to 499), used as a reference level; middle (SI = 500 to 900); and high (SI = 901 to 2,000). For lung cancer induction, a supra-multiplicative effect was demonstrated for high external gamma-ray doses (> 2.0 Gy) plus high 239Pu intakes (body burden >2.3 kBq). This observation is consistent with the hypothesis of curvilinear dose-response relationships for lung cancer induction by high- and low-LET radiations. The interaction between radiation (external gamma rays or 239Pu body burden) and cigarette smoke was found to depend on the smoking level. For the middle level of smoking in combination with gamma radiation (> 2.0 Gy) or 239Pu body burden (> 2.3 kBq), results were consistent with additive effects. However, for the high level of smoking in combination with gamma radiation (> 2.0 Gy) or 239Pu body burden (> 2.3 kBq), results were consistent with the occurrence of multiplicative effects. These results indicate that low-dose risk estimates for radiation-induced lung cancer derived without adjusting for the influence of cigarette smoking could be greatly overestimated. Further, such systematic error may considerably distort the shape of the risk vs. dose curve and could possibly obscure the presence of a dose threshold for radiation-induced lung cancer.
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"Although models for either radionuclide using a quadratic dose response without a threshold were superior, models using a linear dose-response function were significantly improved by adding a threshold at 1 Gy. In the Mayak workers, studies of lung cancer have reported results consistent with the linear nothreshold risk model although some investigators have suggested a threshold for radiation-induced lung cancer (Kreisheimer et al. 2000; Tokarskaya et al. 2002). A bystander effect, in which the cells damaged by alpha particles transmit damage to neighboring nonirradiated cells, has been suggested as an explanation for non-linear dose-response relationships between alpha particle dose from radon and lung cancer (Brenner and Sachs 2002). "
[Show abstract][Hide abstract] ABSTRACT: Determination of radiation protection guidelines for persons working with plutonium has been complicated by limited human data on the biological behavior and subsequent health effects from internally deposited plutonium. One solution has been the use of animal models to predict likely health effects in humans. To compare the relationships between plutonium inhalation and lung fibrosis and lung cancer, data from life-span studies of beagle dogs given a single exposure to either plutonium-238 dioxide (238PuO2) or plutonium-239 dioxide (239PuO2) were analyzed. Estimates of the cumulative hazard of lung fibrosis and lung cancer after exposure to either were generated. The hazard of lung fibrosis was not consistent with a linear no-threshold model, although the magnitude of the threshold differed by radionuclide. In dogs given 239PuO2, the best model of lung fibrosis incorporated a linear dose-response function; a linear-quadratic dose-response function fit the data better in dogs given 238PuO2. At any given cumulative dose, the lung fibrosis hazard was greater for dogs given 238PuO2. In dogs given 238PuO2, with or without covariates, a quadratic dose-response function for lung cancer hazard fit better than a linear no-threshold model. In dogs given 239PuO2, models of lung cancer with the dose-response function as the sole predictor variable were consistent with a linear no-threshold model; however, a quadratic dose-response function with a cell-killing term fit better. These findings have implications for radiation protection because, while lung cancer hazard was dependent on cumulative dose, regardless of isotope, the lung fibrosis hazard depended on both cumulative dose and isotope.
"For low-dose-rate exposure and for lung cancer, Equation 3 is expected to apply for gamma-ray doses up to at least 2000 mGy, since gamma-ray doses in this range were not found to contribute to an increase in lung cancer risk under circumstances of combined exposure to alpha and gamma radiations (Tokarskaya et al. 2002). Equations 1-3 should not be used for the very large doses that cause death from acute effects. "
[Show abstract][Hide abstract] ABSTRACT: Research is being conducted world-wide related to chemoprevention of future lung cancer among smokers. The fact that low doses and dose rates of some sparsely ionizing forms of radiation (e.g., x rays, gamma rays, and beta radiation) stimulate transient natural chemical and biological protection against cancer in high-risk individuals is little known. The cancer preventative properties relate to radiation adaptive response (radiation hormesis) and involve stimulated protective biological signaling (a mild stress response). The biological processes associated with the protective signaling are now better understood and include: increased availability of efficient DNA double-strand break repair (p53-related and in competition with normal apoptosis), stimulated auxiliary apoptosis of aberrant cells (presumed p53-independent), and stimulated protective immune functions. This system of low-dose radiation activated natural protection (ANP) requires an individual-specific threshold level of mild stress and when invoked can efficiently prevent the occurrence of cancers as well as other genomic-instability-associated diseases. In this paper, low, essentially harmless doses of gamma rays spread over an extended period are shown via use of a biological-based, hormetic relative risk (HRR) model to be highly efficient in preventing lung cancer induction by alpha radiation from inhaled plutonium.
"Studies looking at the interaction between radon (alpha particle) exposure and smoking have either found either a multiplicative interaction (Samet et al. 1991, Pershagen et al. 1994, Morrison et al. 1998, Melloni et al. 2000) or an interaction which is intermediate but closer to multiplicative (Hornung et al. 1995, NRC 1999). One study (Tokarskaya et al. 2002) has suggested that the balance between additive and multiplicative models depends on the smoking level (higher smoking levels make the interaction more multiplicative, lower smoking levels make the interaction more additive). There is one recent report for A-bomb survivors of a purely additive interaction (Pierce et al. 2003). "
[Show abstract][Hide abstract] ABSTRACT: The issue here is how to estimate age-specific values of lung cancer ERR at a given dose for the US population, in the presence of large differences in baseline rates caused by smoking status. The NCI approach, documented in the 2003 NCI-CDC report on revision of the NIH Radioepidemiological Tables (Land et al. 2003), differs from the NIOSH-IREP approach in the balance that is chosen between the additive and multiplicative models. Both codes use a linear combination of an additive and a multiplicative model: (ERR) US = y×(ERR) mult + (1-y) × (ERR) add , where the variable y varies between -0.1 and 1.1. Here, (ERR) mult is the site-, sex-, and age-specific excess relative risk obtained from the A-Bomb data, and (ERR) add is the same value, adjusted for the corresponding ratio between baseline rates in the two countries. y=0 corresponds to the additive model, y = 1 to the multiplicative model. The NCI approach is to sample from a probability distribution for y that is shown here. The solid line indicates that any value of y (from 0 to 1) is equally likely, while the dashed line, adopted for lung cancer, indicates that a 50% chance is given to pure additivity (y=0) and 50% weighting is distributed equally among any other value of y between 0 and 1. (There is also a small probability assigned to values of y less than 0 and greater than 1). The NCI approach was based on the results of Pierce et al (2003) in a recent analysis of A-bomb survivors.