|Year : 2021 | Volume
| Issue : 3 | Page : 101-107
The overestimation of medical consequences of low-dose exposures: Cui bono?
Sergei V Jargin
Department of Pathology, Peoples' Friendship University of Russia, Moscow, Russia
|Date of Submission||24-Jun-2021|
|Date of Decision||20-Aug-2021|
|Date of Acceptance||24-Aug-2021|
|Date of Web Publication||22-Oct-2021|
Sergei V Jargin
Department of Pathology, Peoples' Friendship University of Russia, Miklukho-Maklaya 6, Moscow 117198
Source of Support: None, Conflict of Interest: None
After the Chernobyl disaster appeared papers overestimating medical consequences of low-dose radiation exposures. Examples have been discussed previously; an updated overview of selected studies is provided here. Various kinds of bias can be found in the epidemiological research reporting elevated health risks from low doses of ionizing radiation: Interpretation of spontaneous conditions as radiation-induced, dose comparisons disregarding the natural background, publication bias, etc. Admittedly, all relevant parameters cannot always be taken into account in epidemiological research. Several examples of potentially biased reports on Mayak Production Association workers and Techa river valley residents are analyzed here. Doubtful correlations between exposures to low radiation doses and nonmalignant conditions, discussed in this commentary, call into question the cause-effect character of such correlations for malignancies revealed by the same scientists. Correlations can be caused or influenced by dose-dependent selection and self-selection. Individuals with higher doses were probably more motivated to undergo medical checkups and given more attention. The medical surveillance of exposed populations is important; but more consideration should be given to potential bias. A promising approach to the study of dose-response relationships are lifelong experiments in different animal species that can reveal the net harm or potential benefit (within a certain range according to the concept of hormesis) from low-dose exposures to ionizing radiation.
Keywords: Cancer risk, Chernobyl accident, east urals radioactive trace, ionizing radiation
|How to cite this article:|
Jargin SV. The overestimation of medical consequences of low-dose exposures: Cui bono?. Environ Dis 2021;6:101-7
| Introduction|| |
After the Chernobyl disaster appeared numerous papers, where diseases among residents of contaminated territories were regarded to be radiogenic.,, Several articles overestimating Chernobyl consequences were commented previously.,, If some earlier publications were doubtful, later ones by the same researchers can be also unreliable so long as the attitude and motivations remain the same. Potential motives in the former Soviet Union included financing, foreign help, international scientific cooperation, and careers.,, Moreover, the Chernobyl disaster has been “exploited in attempts to strangle development of atomic energy, the cleanest, safest and practically inexhaustible means to meet the world's energy needs.” Various kinds of bias can be found in the epidemiological research reporting elevated cancer risks from low radiation doses: Interpretation of sporadic diseases as radiogenic, dose comparisons ignoring natural background, conclusions about incidence increase without appropriate control,, “forcing a positive slope to the relative risk dose-response curve,” inaccurate citation etc. Other biases and confounders have been discussed., A recent example: Statistically significant elevation of the skin cancer risk was detected in the cohort of Mayak Production Association (MPA) employees. The workers and probably also some medical staff knew personal employment histories, from which cumulated doses could be inferred, potentially influencing the diagnostic quality and self-reference. Doses to the skin were not indicated. The subjects were exposed mainly to γ-radiation characterized by a relatively high penetration depth so that the part of energy absorbed in the skin was proportionately low. No wonder that the “premalignant skin lesions and actinic keratoses… were very rare in members of the study cohort.”
| The Hypothesis|| |
According to our hypothesis, the overestimation of the causality between radiation and certain pathological conditions in the MPA workers and Techa river population started approximately in 2005. Earlier studies reported no increase in cancer incidence at doses below 520 mSv or generally in MPA employees. The existence of a threshold was regarded possible.,,, The morbidity with incapacity for work did not depend on the cumulative dose. The leukemia risk per 1 Gy was found to be 3.5 times lower in the Techa river population than in survivors of the atomic bombings of Hiroshima and Nagasaki (life span study [LSS]), i.e., effectiveness of the acute impact was expectedly higher than that of protracted or fractionated exposures., Of note, the risk of solid cancers in LSS tended to decrease with age, whereas in the Techa river cohort it increased,, which is typical for spontaneous cancer and suggestive of the screening effect. No significant increase in cancer morbidity and mortality was found in the residents of territories contaminated due to the 1957 Kyshtym accident, i.e., the east urals radioactive trace (EURT); while later analyses by the same researchers detected a significant increase in solid cancer mortality versus external control. As mentioned above, the attitude has changed around 2005: The same researchers started to stress a comparable level of leukemia and solid cancer risk per dose unit in the MPA, Techa river as well as in the LSS cohorts.,,,, An explanation of the changed attitude could be new data obtained and modern methods applied at a later date. This is a potential field for further analysis including self-questioning by authors.
| Cataracts|| |
A similar tendency has been noticed in regard to radiation-related cataracts. Correlations between the cumulative dose and cataract incidence in the MPA cohort, have been doubted,, which pertains by inference also to another paper. Reportedly, the risk increase in all dose categories starting from 0.25 to 0.50 Sv was significant versus the 0–0.25 Sv category. Average doses were 0.54 ± 0.061 Gy in men and 0.46 ± 0.01 Gy in women. Dose-effect relationships were claimed for cataracts; but the well-known correlation of the latter with diabetes mellitus was not confirmed.,, Supposedly after some criticism, the topic of diabetes was removed from the subsequent article. There were no significant associations of the radiation dose with cataract removal surgeries, which is understandable if the cataracts were diagnosed relatively early in exposed individuals due to an increased attention to their own health and/or attention on the part of medics (dose-dependent selection and self-selection). In accordance with the hypothesis presented above, earlier publications by the same research group asserted that radiation-induced cataracts developed in MPA workers only following moderate-to-severe radiation sickness after exposures ≥4 Sv. A. K. Guskova, reviewing the data from Russia, indicated that chronic exposures ≤2 Gy were not associated with cataracts., According to the UNSCEAR, “minimum of 3–5 Gy are required to produce significant opacities in animals which are normally not prone to cataract development, as is the case for man… Minimum stationary opacities have been observed after single doses of 1–2 Gy. More dose is required when fractionated. The threshold for cataract for occupational exposure or lengthy fractionation is in the range of 6–14 Gy.” Later, UNSCEAR reports and reviews discussed lower thresholds and the no-threshold model of the cataract development.,,, Based predominantly on the epidemiological research, the International Commission on Radiological Protection (ICRP) revised preceding recommendations and proposed a threshold of 0.5 Gy for the development of cataracts.,, However, not all epidemiological studies support the lower threshold. The dose-dependent diagnostic efficiency and self-reporting, possibly related to a longer work history and hence to cumulative dose, may explain, for example, the above-average risk of cataracts in radiologic technologists., The discrepancy has been noticed between the findings for cataract history and cataract surgery, where risks for the latter were lower and generally not significant. As mentioned above, a similar pattern of significant excess relative risk (ERR) for cataract morbidity but nonsignificant ERR for cataract surgery has been reported in MPA workers.,, This agrees with the concept of dose-dependent diagnostic efficiency and recording of mild cases not requiring surgery. Among cohorts studied for radiation-associated cataracts, a significant ERR for cataract surgery has been reported only in LSS,,,, where a physiological effect of the acute exposure could have been indeed significant. As for experiments, doses were generally higher than averages in Chernobyl, MPA and Techa river populations. Some experiments in rodents investigated low doses and suggested that genetic factors have an influence on the susceptibility to radiation-induced lens opacities.,, Effects of low doses are not a priori denied here. Undoubtedly, cataracts can be caused by radiation; but doses and dose rates associated with risks, i.e., potential thresholds should be further studied. There is still a small number of studies that provide explicit biological and mechanistic evidence at doses <2 Gy.,
| Cardiovascular Diseases|| |
Elevated risks of nonmalignant diseases (cardiovascular, gastrointestinal, and bronchitis) have been reported in Chernobyl, MPA and Techa river cohorts.,,,,,,,,,,,,, The average dose from external γ-radiation was around 0.54 Gy in men and 0.44 Gy in women, for example, in the study, where the frequency of arterial disease of lower limbs was found to be associated with the cumulative external dose. The frequency of aortal atherosclerosis was significantly higher in MPA workers with cumulative doses ≥0.5 Gy than among those with lower doses; the same for ≥0.025 Gy cumulative liver dose of internal α-radiation. For cerebrovascular diseases (CeVD) these values were correspondingly ≥0.1 and ≥0.01 Gy. The ERR of CeVD per dose unit in MPA workers was reportedly even higher than in LSS,,, where bias could have also been operative. Risks of cardiovascular diseases and in particular, of ischemic heart disease, were found in the Techa River cohort to be higher than those computed on the basis of the linear no-threshold model. 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 explained by a dose-dependent diagnostic efficiency with recording of mild and borderline cases.
According to the same research group, the incidence of CeVD was significantly increased among MPA workers with cumulative external doses ≥0.1 Gy., In particular, risk estimates by Azizova et al. were noticed to be significantly higher than those by other researchers. The UNSCEAR could not make any judgment about immediate causal relationships between exposures ≤1–2 Gy and the excess incidence of cardiovascular or generally of nonmalignant diseases. According to the ICRP, “there are excess risks of heart disease for patients given radiotherapy with estimated average heart doses of 1–2 Gy (single dose equivalent, after correction for dose fractionation effects).” The value 1–2 Gy [Table 1] may have resulted from added precaution and/or undervaluation due to bias in epidemiological studies. It is known that patients may develop cardiovascular diseases after radiotherapy with doses to the heart around 40 Gy. Lower doses were discussed,,,, being, however, far above the averages for MPA, Techa River and Chernobyl cohorts. The doses associated with heart injury in experimental animals have also been higher than in the above-named cohorts.,, In some experiments and epidemiological observations, low doses were protective against atherosclerosis. In accordance with the hypothesis discussed above, an earlier study found no association between the cumulative dose and frequency of ischemic heart disease in MPA workers. In the past, long-term observations found no differences of cardiovascular diseases in the latter cohort compared to the general population.
|Table 1: Radiation-related risks of cardiovascular conditions: Examples of potential overestimation versus consensus judgments (commented in the text)|
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In conclusion of this section, the evidence for a causal relationship of long-term cardiovascular risks with low-dose (<0.5 Gy) exposures is inconsistent and considered to be weak, while biological mechanisms are unclear. The few low-dose experimental studies existing at the moment emphasize the significance of dose rate in the atherosclerotic plaque formation, thus indirectly witnessing against the role of radiation as a cause of cardiovascular diseases in human populations chronically exposed to low doses.
| Discussion|| |
Doubtful correlations between low-dose exposures and nonmalignant conditions call into question the cause-effect character of such correlations for malignancies revealed by the same scientists.,,,,,, Self-questioning and doubts can stimulate scientific thought; therefore, the authors should reassess interpretations of their results. Questionable data (including those discussed here) are sometimes included into reviews and meta-analysis thus potentially influencing scientific opinions and official judgments. Stressing this problem has been one of the aims of this commentary. The author agrees with Prof. Mark P. Little that studies of questionable reliability “should therefore probably not be used for epidemiologic analysis, in particular for the Russian worker studies considered here.,,,” This might pertain also to some other studies. Reported dose-effect correlations may be caused or influenced by dose-dependent selection and self-selection noticed in various exposed cohorts., It can be reasonably assumed that individuals with higher doses would be averagely more motivated to undergo medical checkups and given more attention. Therefore, diagnostics must have been more efficient in people with higher doses. Epidemiological studies can account for some bias, which has not always been the case with Chernobyl-and EURT-related research.,, A more efficient blinding could have been helpful. As mentioned above in regard to skin lesions, the workers and probably some medics knew personal employment histories, from which cumulated doses could be inferred, potentially influencing the diagnostic thoroughness and self-reporting. Uncertainties in some epidemiological research should not cast doubt on this type of studies in general. Researchers are usually aware of possible bias, which may stimulate not only criticism but also constructive scientific thought.
| Conclusion|| |
The medical surveillance of cohorts exposed to low-dose ionizing radiation is necessary. Evidently, more consideration should be given to potential bias. The screening effect and increased attention of exposed people to their own health will probably result in future reports of enhanced cancer and other health risks in the areas with elevated anthropogenic or natural radiation background. Furthermore, hidden conflicts of interest and ideological bias should be taken into account, evaluating inclusion criteria of papers in reviews and meta-analysis that cover both sides of the low-dose effect controversy. A promising approach to the study of dose-response relationships is lifelong experiments in different animal species. The average life duration of animals would reflect the net harm or potential benefit (within a certain range according to the concept of hormesis) from low-dose exposures to ionizing radiation., For such ancient biological phenomena as hormesis, DNA repair and carcinogenesis, data may be conditionally generalizable across species., Further research using different animal species would add knowledge about their radio sensitivity thus making extrapolations to humans more accurate. Furthermore, studies combining epidemiological data with the evaluation of molecular markers may help to understand mechanisms and consequences of radiation exposures and the role of inherited sensitivity. In regard to potential ideological bias, the main strategy should be objective discussion as well as measures in support of scientific integrity to reassure the society that science is impartial and helpful to improve the decision-making.
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Conflicts of interest
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