Ionising radiation and cardiovascular disease: systematic review and meta-analysis

Dear Editor,
Although our preceding articles [1,2] have not been cited, this review makes reasonable remarks that we uttered many times: “Diagnosis (by a physician knowing the patient’s history) could vary with dose”; and the “interstudy variation in unmeasured confounders or effect modifiers” [3]. Indeed, a mixture of more and less reliable data assessed together is a limitation of systematic reviews and metaanalyses. The systematic approach is hardly applicable to the topic, where bias, conflicts of interest, politics and economics are intermingled. Apparently, certain writers exaggerating medical and environmental consequences of the slight anthropogenic increase in the radiation background contribute to a strangulation of the atomic energy [4]. This complies with the interests of fossil fuel producers. Nuclear power has returned to the agenda because of concerns about increasing global energy demand and climate changes. Health burdens are the greatest for power stations based on coal and oil. The burdens are lower for natural gas and much lower for atomic energy. The same ranking applies to the greenhouse gas emissions and hence potentially for the climate change [5]. However, durable peace is needed because nuclear facilities are potential targets. In a sense, such facilities are a guarantee of peace [6].
Potential biases of epidemiological studies are known: unfounded classification of spontaneous conditions as radiation-induced, conclusions about incidence increase of diseases without adequate control, etc. [7-9]. Some studies with negative results were neither included in databases nor cited in reviews. Other bias and confounders have been discussed [10-13]. Of particular importance are the dose-dependent selection, self-selection and recall bias noticed in various cohorts exposed to low-dose radiation [14-16]. It can be reasonably assumed that people knowing their higher doses would be more motivated to undergo medical checkups being at the same time given more attention. Therefore, diagnostics would be a priori more efficient in patients with higher doses.
Furthermore, among limitations of epidemiological studies has been the disregard for the natural radiation background (NRB). Individual doses from NRB are expected to range from 1.0 to 10 mSv/year; some national averages are ≥10 mSv/year [17,18]. For comparison, in the International Nuclear Workers Study (INWORKS), many workers received 2-4 mSv/year [19] i.e. around the global average from NRB. The mean cumulative doses in the INWORKS (red bone marrow - 17.6 mGy, colon - 19.2 mGy) protracted over years (follow-up 1950-2005) [20] are comparable with NRB. These and other considerations about INWORKS have been summarized: “Failure to account for natural background radiation exposure, the differences in which potentially dwarf the occupational exposures of the study cohort” [21]. By analogy with other environmental factors, an evolutionary adaptation to NRB can be reasonably assumed. Cells and organisms might have retained some capacity to repair the damage from higher radiation levels than today’s NRB. The experimental evidence in favour of hormesis and adaptive responses to ionizing radiation is considerable; such evidence has been obtained also in humans; references are in [2,9].
Elevated risks of cardiovascular diseases have been found in Chernobyl, MPA and Techa river cohorts. For example, the average dose from external gamma-radiation (protracted over years of employment) was ~ 0.54 Gy in men and 0.44 Gy in women in a study, where the frequency of lower extremities arterial disease was found to correlate with the cumulative external dose [22]. Among MPA workers with total absorbed external gamma-ray doses > 0.1 Gy the incidence of cerebrovascular diseases (CeVD) was significantly higher compared to those exposed to lower doses; the same for 0.01 Gy alpha-particle dose to the liver from incorporated plutonium [23,24]. Risks of cardiovascular diseases and, in particular, of ischemic heart disease, were found in the Techa River cohort to be even higher than in the Life Span Study (LSS) of atomic bomb survivors in Japan, where the exposure was acute and the bias could have also been operative. Analogously, the excess relative risk of CeVD per dose unit in MPA workers was higher than in LSS; references are in [2,9]. Remarkably, the dose-dependent incidence increase in CeVD and ischemic heart disease among MPA workers was not accompanied by an increase in mortality, which can be attributed to the dose-dependent diagnostic efficiency with the recording of mild and borderline cases in exposed people. For comparison, the UNSCEAR (2006) could not make any conclusions about immediate causal relationships between doses ≤ 1-2 Gy and the excess incidence of cardiovascular diseases. Some later publications of the International Organizations mentioning lower doses, cited in [3], might have been influenced by biased epidemiological studies. The doses associated with heart injury in experimental animals have been much higher than in the above-named cohorts; references are in [2,9]. Remarkably, the review [3] does not discuss animal experiments and hormesis. Doubtful correlations between low-dose exposures and non-malignant diseases call in question the cause-effect character of such correlations for malignancies. The correlations may be caused or influenced by bias, in particular, the dose-dependent selection and self-selection noticed in exposed populations. Individuals with higher doses must be generally more motivated to undergo medical checkups and given more attention. Even in blind studies e.g. of MPA workers, the subjects and probably also some medical personnel knew individual employment histories, from which cumulated doses could be inferred, potentially influencing the self-reporting and diagnostic thoroughness. Considering the above, diagnostics must be a priori more efficient in people with higher dose estimates.
The medical surveillance of populations exposed to low-dose ionizing radiation is important; but more consideration should be given to potential bias. Among others, “the very high rates of circulatory disease” [25] in some cohorts may be caused by the overdiagnosis tendency of cardiovascular diseases in unclear post- and ante-mortem cases. The overdiagnosis is one of the reasons of comparatively high cardiovascular incidence and mortality in Russia [26]. In the author’s opinion, epidemiological studies would hardly add much reliable information on the effects of low doses and dose rates. The screening effect and increased attention of exposed people to their own health will probably result in new reports on elevated health risks in areas with enhanced natural or anthropogenic radiation background. In particular, data from biased studies should not be used for radiological protection recommendations. Lifelong animal experiments are a promising approach to the research of dose-response relationships. The life duration is a sensitive endpoint attributable to radiation exposures, which can measure the net harm or potential benefit (within a certain range according to the concept of hormesis) from low-dose exposures.
References
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