RADIATION AND CANCER: CERTAIN TO UNKNOWN
THE ATOMIC bomb Life Span Study (LSS) and other studies have long shown that moderate-to-high doses of radiation cause leukemia and many types of solid cancer. The lack of knowledge regarding cancer effects at the dawn of the atomic era 60–70 y ago has clearly been changed to where there is little doubt that most of the major types of cancer are increased by acute radiation doses of at least 200–500 mGy. In particular, the LSS of atomic bomb survivors provides strong data at higher doses, but risks become fuzzy at ∼100–200 mSv and are unknown at doses on the order of 5–20 mSv. When cumulative doses are received at a low dose rate or as a large series of small exposures, the degree of risk becomes fuzzy in the vicinity of 100–200 mSv. There is a pressing need for better information on the health effects of cumulative low-dose or low dose-rate exposures, such as from medical or occupational sources. For instance, it has been estimated that 80 million computed tomography (CT) scans per year are being performed in the United States, of which about six million are scans of children (Goodman 2013). A study of the history of multiple CT scans allows one to extrapolate that over a million persons in the United States probably have received sufficient multiple CT scans to have had effective doses of >250 mSv (Sodickson et al. 2009).
To date, experimental studies have not provided definitive answers regarding low-dose risks: some data have implied there may be adverse biological effects in the range of 5–50 mSv, with suggestions that induced genomic instability or bystander effects may accentuate risk, while other data support a “no risk” interpretation due to adaptive responses, high-fidelity low-dose DNA repair, and other protective systems. There are also large uncertainties in extrapolating from homogeneous, and often genetically modified, animal models or in vitro cellular systems to human populations that have considerable variability in both genetic and environmental exposure cofactors.
Even though there is still much uncertainty about the magnitude of risk, if any, from low cumulative doses on the order of 5–50 mSv, that is not to say that nothing is known about the risk. It can be assumed reasonably that those risks are small: the weight of evidence indicates that larger risks can be ruled out, such as might be associated with doses of several hundred millisievert. Nevertheless, at least three types of factors work against obtaining precise epidemiologic estimates of low-dose risks in the 5–50 mSv range:
1. Many epidemiologic studies have fairly substantial dose uncertainties. While that tends to pose fairly minor problems for studies with a high, broad range of doses, the magnitude of dose uncertainties may approach or exceed the imputed doses in low-dose studies with a consequent large impact on any risk estimates from them;
2. Similarly, variations in study subjects’ levels of exposure from extraneous radiation sources such as background radiation and especially medical radiation exposures, produce random “noise” that introduces more variability into the dose-response estimates and may even produce bias in the dose response estimate if the levels of background or medical radiation exposure happen to be substantially correlated with the doses of interest. Again, the extraneous radiation exposure has relatively little impact on high-dose studies but can substantially weaken or bias low-dose studies; and
3. The impact of variation among individuals in known and unknown factors related to genetics, lifestyle, other environmental exposures, sociodemographics, diagnostic accuracy, medical care adequacy, etc., potentially has a greater effect on low-dose studies and their risk estimates.
All these factors tend to introduce random statistical noise, and possibly bias, into the risk estimates. Thus, the intrinsic uncertainties in epidemiologic studies mean that most individual studies have insufficient statistical power and precision to provide compelling answers regarding low dose risks.
STUDIES OF LOW DOSE, PROTRACTED, OR HIGHLY FRACTIONATED (LDPF) RADIATION EXPOSURES AND CANCER RISK
LDPF radiation exposure and total solid cancer
There have been recent provocative reports regarding risk based on studies with LDPF radiation exposures from occupational, environmental, or medical sources that warrant careful consideration. For instance, Jacob et al. (2009) summarized results from a series of occupational or environmental radiation studies and estimated that the weighted average risk for total solid cancers was slightly higher than for the corresponding age-gender matched subsets of the LSS atomic bomb data: the ratio of the average LDPF risk compared to the LSS risk was 1.2 [90% confidence interval (CI) 0.5, 1.9]. The authors concluded that, “The present analysis does not confirm that the cancer risk per dose for [LDPF] exposures is lower than for the atomic-bomb survivors.”
Data and analyses in addition to those reported by Jacob et al. (2009) are available. Of particular note, a recent widely publicized study by Mathews et al. (2013) reported heightened cancer risk after pediatric CT scans based on 680,000 children or adolescents who received CT scans and 10,000,000 with no record of such exposures. They reported an excess of total cancers, with special note of brain cancers and leukemia. Although the study was well conducted, certain partly unavoidable issues introduced extra uncertainties in the results: the potential for reverse causation (cancers were caused by the medical indications for the CT scans rather than by the CT dose), missing doses (CT retakes and CT exams outside the age- and time-period of the study), and implausible radiation-tumor associations (e.g., associations of radiation with melanoma and Hodgkin lymphoma but not with breast cancer).
This report updates the analyses of Jacob et al. (2009) with a broader, semi-quantitative assessment. To avoid unclear selection criteria that might bias the conclusions, an objective criterion was used to assess the literature. Specifically, for total solid cancers, an attempt was made to locate all the English language LDPF studies that met the criteria of having at least 400 deaths or incident cases of total solid cancer and some assessment of dose and risk. This number was chosen subjectively as a minimum because risk estimates from large studies tend to be more precise and have better statistical power. In some cases, total solid cancer data were not available, so a fairly good approximation to that (e.g., all cancers except leukemia) was used.
A brief summary of the estimated risks in those studies is presented in Table 1. Because of the diversity of types of study analyses, adequacy of dose estimates, varying ages at exposure and follow-up, and noncalculable lower confidence bounds, a formal meta-analysis could not be conducted. However, the table shows that seven out of 19 studies had a statistically significant excess associated with LDPF exposure. If there were no association at all, one would expect only about one in 20 studies (5%) to show a statistically significant excess by chance. The fact that a third of the largest available studies showed an excess indicates that there is probably at least a small excess risk of solid cancers from LDPF exposures. It seems unlikely that the relatively large percentage of positive studies is due to publication bias, because large radiation studies that have >400 cancer cases are virtually always reported in the literature whether the results are statistically significant or not. However, for most of the studies, information on other exposures and risk factors, such as smoking and obesity, was not available. To the degree that those exposures and risk factors may have been correlated with cumulative radiation exposure, some bias (whether positive or negative) could have been introduced into the results of individual studies. For the occupational studies that used standardized mortality (incidence) ratios (SMRs/SIRs) for risk estimates, there probably was some negative bias in the results due to the “healthy worker effect” (Arrighi and Hertz-Picciotto 1994).
LDPF radiation exposure and leukemia
Besides the Mathews et al. (2013) study of CT examination risk (see above), another widely noted finding regarding leukemia incidence after CT scans was reported by Pearce et al. (2012). They estimated individualized doses to the red bone marrow and brain for 178,000 patients who had received CT scans and found an excess relative risk (ERR) for leukemia incidence of 36 (90% CI 5, 120) per gray, although questions have been raised about potential random and systematic uncertainties in that study (NCRP 2012).
Using a strategy to evaluate leukemia risk similar to that for solid cancers, all the LDPF studies that could be found that had at least 30 leukemia cases or deaths and risk estimates were compiled, usually excluding chronic lymphoid leukemia. A brief summary of risk estimates is presented in Table 2 from studies of LDPF occupational or environmental radiation exposures. Studies of leukemia risk after diagnostic radiation exposures also were examined, and even those without dose estimates were included so as to minimize study-selection bias. Considering occupational or environmental radiation exposures, 10 out of 16 studies (63%) showed statistically significant positive results. Adding in the medical radiation studies, of which seven out of 17 were significant, yields a total of 17 of the 33 LDPF leukemia studies (52%) that showed statistically significant excess risk, again indicating an effect from LDPF exposures. Since a substantial number and a high percentage of the leukemia studies showed a positive effect, the case for leukemia risk after LDPF exposures appears stronger than that for total solid cancers.
In summary, the LDPF epidemiologic studies of total solid cancer and leukemia provide evidence that is not unequivocal but for which the weight of evidence is in the direction of cancer risk occurring in association with LDPF exposures. It seems appropriate to regard the cancer risk from LDPF exposures as fuzzy rather than unknown. For leukemia, the studies of childhood leukemia subsequent to prenatal diagnostic medical exposure (not reviewed here) also provide support for risk from LDPF radiation exposure (Wakeford 2008).
LOW DOSE RADIATION EXPOSURE AND CARDIOVASCULAR DISEASE
Recently, interest in health endpoints other than cancer also has risen sharply; in particular, the degree of cardiovascular risk following doses under 1 Sv. The study of Japanese atomic bomb survivors showed a dose response curve for heart disease that appeared essentially linear, although the authors believed the risk below ∼0.5 Gy was quite uncertain because of the substantial variability around the lower-dose part of the regression line and the finding that a dose response analysis for the range 0–0.5 Gy was not statistically significant (Shimizu et al. 2010). However, a recent meta-analysis by Little et al. (2012) of ischemic heart disease risk at primarily mean doses under ∼0.5 Gy reported that two out of eight studies showed statistically significant positive associations, and the combined meta-analysis showed a significant positive association [ERR at 1 Sv of 0.10 (95% CI 0.04, 0.15) taking into account heterogeneity in risk among studies]. The authors also reported a statistically significant association for cerebrovascular disease [ERR at 1 Sv of 0.21 (95% CI 0.02, 0.39) accounting for study-risk heterogeneity]. However, several caveats need to be mentioned: Even though mean doses were under 0.5 Sv for most studies, for several the dose-response data were driven by the subset of doses above 0.5 Sv; most were occupational studies and had no ability to determine whether smoking, obesity, or other risk factors may have been confounders. A variety of other LDPF studies for cardiovascular disease have been reported (McGale and Darby 2005, 2008; UNSCEAR 2008) that could not be included in the aforementioned meta-analysis, mainly because insufficient dose information was available to estimate risk per Sievert. A number of these are shown in Table 3. Most are null (negative), even though the average cumulative doses were considerable for some of them. So at this point, risks of circulatory disease after LDPF exposure probably should be regarded as in the fuzzy category.
LOW-DOSE RADIATION EXPOSURE AND CATARACT RISK
Most studies of cataract risk have used ophthalmological screening as their methodology; in such studies, the vast majority of positive findings are small opacities of limited clinical significance (Ainsbury et al. 2009; Shore et al. 2010). However, two recent studies of atomic bomb survivors have documented that both the prevalence and incidence of cataracts that required surgical removal are increased in relation to radiation dose at doses below 1 Gy (Neriishi et al. 2007, 2012). In the cataract incidence study, an estimated 32% (95% CI 9%, 53%) excess of cataract extractions was found at 1 Gy based on a linear dose response (Fig. 1). Though the nonlinear dose response term was not statistically significant, the best estimate of a dose threshold was at ∼0.5 Gy (95% CI 0.10 to 0.95 Gy). Based on these data and other supporting studies, the International Commission on Radiological Protection (ICRP) recently revised their estimate of the threshold dose for cataract induction downward from 5 Gy to 0.5 Gy for acute exposures (ICRP 2011). Hence, cataract risk for doses above ∼0.5 Gy is moving in the direction from fuzzy to certain, but for doses on the order of 0.2 Gy or below, the risk is fuzzy or unknown.
Of concern has been the ophthalmological risk for occupations where LDPF doses to the lens of the eye are considerable, especially medical specialists conducting interventional procedures under fluoroscopic guidance. A number of studies have been conducted of interventional cardiologists, catheterization laboratory personnel, radiologists, or radiologic technicians (Chodick et al. 2008; Kleiman et al. 2009; Milacic 2009; Ciraj-Bjelac et al. 2010, 2012; Vano et al. 2010, 2013; Mrena et al. 2011; Jacob et al. 2013). A summary of the results in Table 4 suggests there is occupational radiation cataract risk among interventional cardiologists and associated nurses/technicians, who receive the largest cumulative doses. However, those studies have been difficult to conduct and have potential sample selection biases, small sample sizes, and very uncertain dosimetry. The consistency in positive findings by the several medical worker studies that had substantial estimated cumulative doses but were below the previously ICRP-recommended dose threshold for cataract induction of 5 Gy of acute exposure suggests that a reduction in threshold dose was warranted.
The magnitude of radiation impacts on human health require fuller documentation, especially for low dose or low dose rate exposures. From the epidemiologic vantage point, that will require longer observation of existing irradiated cohorts and sometimes more accurate dose assessments. Additional studies of new cohorts also can be of value if the cohorts have characteristics to make them statistically informative:
* appropriate study designs and subject selection;
* a sufficient range of doses and a large enough cohort size to be able to detect risks;
* reasonably accurate individual dose information;
* an infrastructure that permits complete and accurate ascertainment of the diseases of interest;
* information on potential confounding or effect-modifying risk factors; and
* appropriate analyses and interpretations of the data.
Biosamples from subgroups of the irradiated cohorts could permit genomic, epigenetic, and functional biological assessments that provide a bridge to the many advances in experimental radiation biology and that also can be used to identify subsets of persons who are particularly susceptible to radiation-related cancer or other diseases.
To develop more clarity on cardiovascular disease risk from low-to-moderate radiation doses, current and future cohorts need to obtain information on other important exposures (e.g., smoking) and endogenous factors that might be confounding or effect-modifying variables. To improve our understanding of the biology of radiogenic cardiovascular disease, especially after whole-body exposures, more information is needed on the potential cardiovascular impact of damage to the liver, kidney, pituitary, and other organs, as well as to the microvasculature and endothelial tissue of the heart.
Regarding radiation-induced lens opacities from occupational or other LDPF radiation exposures, criteria for adequate and standardized lens photos would permit a uniform review of ophthalmological findings and increase comparability across studies. Current studies of cataract in interventional cardiologists and allied personnel have large intrinsic uncertainties in their retrospective dose estimates, even with the best dosimetric efforts (Jacob et al. 2013). Protocols for better dose information are needed to assure health protection of medical radiation workers and to provide more accurate future quantitative risk assessments. There currently is little information on the association of low-to-moderate radiation exposures with vision-impairing cataracts, which constitute the ocular health impact of greatest concern. Most studies have documented largely small, subclinical opacities; little is known from radiation studies about the frequency and rate with which those progress to vision-impairing cataracts.
In summary, there is much more to learn about the cancer risks from low-dose and low dose-rate exposures and about risks of cardiovascular and ophthalmologic diseases. To inform the radiation protection community regarding the impact of these health risks, there will be a need to give priority to epidemiologic studies that are carefully designed and conducted to address the issues, and to the parallel development of translational and radiobiological research to shed light on radiation-disease mechanisms and modifying factors.
The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan, is a public interest foundation funded by the Japanese Ministry of Health, Labour and Welfare and the U.S. Department of Energy (DOE). The research was also funded in part through DOE award DE-HS0000031 to the National Academy of Sciences. This publication was supported by RERF Research Protocols RP1-75 and RP3-00. The views of the author do not necessarily reflect those of the two governments.
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