Do non-targeted effects increase or decrease low dose risk in relation to the linear-non-threshold (LNT) model?

Abstract

In this paper we review the evidence for departure from linearity for malignant and non-malignant disease and in the light of this assess likely mechanisms, and in particular the potential role for non-targeted effects. Excess cancer risks observed in the Japanese atomic bomb survivors and in many medically and occupationally exposed groups exposed at low or moderate doses are generally statistically compatible. For most cancer sites the dose-response in these groups is compatible with linearity over the range observed. The available data on biological mechanisms do not provide general support for the idea of a low dose threshold or hormesis. This large body of evidence does not suggest, indeed is not statistically compatible with, any very large threshold in dose for cancer, or with possible hormetic effects, and there is little evidence of the sorts of non-linearity in response implied by non-DNA-targeted effects. There are also excess risks of various types of non-malignant disease in the Japanese atomic bomb survivors and in other groups. In particular, elevated risks of cardiovascular disease, respiratory disease and digestive disease are observed in the A-bomb data. In contrast with cancer, there is much less consistency in the patterns of risk between the various exposed groups; for example, radiation-associated respiratory and digestive diseases have not been seen in these other (non-A-bomb) groups. Cardiovascular risks have been seen in many exposed populations, particularly in medically exposed groups, but in contrast with cancer there is much less consistency in risk between studies: risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, a cause-and-effect interpretation of the reported statistical associations for cardiovascular disease is unreliable but cannot be excluded. Inflammatory processes are the most likely mechanism by which radiation could modify the atherosclerotic disease process. If there is to be modification by low doses of ionizing radiation of cardiovascular disease through this mechanism, a role for non-DNA-targeted effects cannot be excluded.

Fig. 1

Dose–response (+95% CI) for leukaemia and solid cancer in the most current Japanese atomic bomb survivor mortality data (dataset analysed in Refs. [6,8,39]).

Fig. 2

Dose–response for breast cancer (+95% CI) in Massachusetts TB fluoroscopy vs. A-bomb (reproduced from Ref. [63]).

Fig. 3

Leukaemia (+90% CI) in National Registry for Radiation Workers vs. linear part of linear-quadratic model fitted to Japanese atomic bomb survivor mortality data by BEIR VII [4] (reproduced from Ref. [14]).

Fig. 4

Lung cancer (+95% CI) in various residential radon studies, and extrapolations from underground miner data (reproduced from Ref. [89]).