Richard Wakeford

Risks associated with low doses and low dose rates of ionizing radiation: why linearity may be (almost) the best we can do.

Deterministic and stochastic effects associated with high-dose ionizing radiation (x-ray) exposure have been known for almost as long as ionizing radiation itself (1–3). At lower doses, radiation risks are primarily stochastic effects, in particular, somatic effects (cancer) rather than the deterministic effects characteristic of higher-dose exposure (4–6). In contrast to deterministic effects, for stochastic effects, scientific committees generally assume that at sufficiently low doses there is a positive linear component to the dose response—that is, that there is no threshold (4–6). This does not preclude there being higher-order (eg, quadratic) powers of dose in the dose response that may be of importance at higher doses. It is on this basis that models linear (or linear-quadratic) in dose are often used to extrapolate the experience of the Japanese atomic bomb survivors (who were typically exposed at a high dose rate to moderate doses [average, 0.1 Sv]) to estimate risks from low doses and low dose rates (4–6). Most population-based cancer risk estimates are based primarily on the Japanese atomic bomb survivor Life Span Study (LSS) cohort data (4–6). However, evidence of excess risks comes from a large number of other studies as well. In the parallel editorial (7), evidence is presented for possible real (or at least “practical”) thresholds or “hormetic” (beneficial) effects of low doses of ionizing radiation. As we summarize here, and in contrast to the arguments of Tubiana et al (7), we judge that there is little epidemiologic or biologic evidence for these for cancer. The arguments are of three forms: (a) assessment of the degree of curvature in the cancer dose response within the Japanese atomic bomb survivors and other exposed groups (in particular, departure from linear or linear-quadratic curvature), (b) consistency of risks between the Japanese and other moderate- and low-dose cohorts, and (c) assessment of biologic data on mechanisms. Most of the information on radiation-induced cancer risk comes from (a) the Japanese atomic bomb survivors, (b) medically exposed populations, (c) occupationally exposed groups, and (d) environmentally exposed groups (6). In the higher-dose radiation therapy studies, where doses received are very much higher than in the LSS, sometimes in the range at which cell sterilization occurs, excess cancer risks per unit dose tend to be less than in comparable subsets of the LSS (8,9). However, as we show, risks in moderate- and low-dose medically and occupationally exposed groups are generally consistent with those in the LSS.

Systematic Review and Meta-analysis of Circulatory Disease from Exposure to Low-Level Ionizing Radiation and Estimates of Potential Population Mortality Risks

Background: Although high doses of ionizing radiation have long been linked to circulatory disease, evidence for an association at lower exposures remains controversial. However, recent analyses suggest excess relative risks at occupational exposure levels. Objectives: We performed a systematic review and meta-analysis to summarize information on circulatory disease risks associated with moderate- and low-level whole-body ionizing radiation exposures. Methods: We conducted PubMed/ISI Thomson searches of peer-reviewed papers published since 1990 using the terms “radiation” AND “heart” AND “disease,” OR “radiation” AND “stroke,” OR “radiation” AND “circulatory” AND “disease.” Radiation exposures had to be whole-body, with a cumulative mean dose of < 0.5 Sv, or at a low dose rate (< 10 mSv/day). We estimated population risks of circulatory disease from low-level radiation exposure using excess relative risk estimates from this meta-analysis and current mortality rates for nine major developed countries. Results: Estimated excess population risks for all circulatory diseases combined ranged from 2.5%/Sv [95% confidence interval (CI): 0.8, 4.2] for France to 8.5%/Sv (95% CI: 4.0, 13.0) for Russia. Conclusions: Our review supports an association between circulatory disease mortality and low and moderate doses of ionizing radiation. Our analysis was limited by heterogeneity among studies (particularly for noncardiac end points), the possibility of uncontrolled confounding in some occupational groups by lifestyle factors, and higher dose groups (> 0.5 Sv) generally driving the observed trends. If confirmed, our findings suggest that overall radiation-related mortality is about twice that currently estimated based on estimates for cancer end points alone (which range from 4.2% to 5.6%/Sv for these populations).

Risk coefficients for childhood cancer after intrauterine irradiation: a review

Purpose: To review the estimates of the risk of childhood cancer per unit dose of radiation received in utero derived from the largest case‐control study of obstetric X‐ray examinations and to compare them with the childhood cancer risk coefficients obtained from the cohorts of Japanese atomic bomb survivors irradiated either in utero or as young children. Materials and methods: Data from the Oxford Survey of Childhood Cancers (OSCC) case‐control study of foetal exposure to diagnostic X‐rays and from the cohort studies of the Japanese survivors of the atomic bombings of Hiroshima and Nagasaki were used, together with associated dose estimates. Excess relative risk and excess absolute risk coefficients were compared, fully taking into consideration the various sources of uncertainty. Results: The excess relative risk coefficient for childhood (<15 years of age) cancer obtained from the OSCC was around 50 Gy−1, leading to an excess absolute risk coefficient for incident cases of about 8% Gy−1. However, the statistical, dosimetry, modelling and other uncertainties associated with these risk estimates are appreciable, and there is reason to believe that these coefficients could be systematic overestimates. When these uncertainties and those associated with the equivalent risk coefficients derived from the Japanese cohort exposed in utero are taken into account, the risk estimates for childhood cancer obtained from these two sources are compatible. These coefficients are consistent with the high relative risk of childhood leukaemia among the Japanese survivors exposed as children. The absence of cases of childhood solid tumours among the Japanese children irradiated after birth in contrast to the significant excesses found in both intrauterine exposure studies might be explained by the cells from which these cancers originate being predominantly sensitive only to exposure in utero. Conclusions: The consistency of the childhood cancer risk coefficients derived from the Oxford Survey and from the Japanese cohort irradiated in utero supports a causal explanation of the association between childhood cancer and an antenatal X‐ray examination found in case‐control studies. This implies that doses to the foetus in utero of the order of 10 mSv discernibly increase the risk of childhood cancer. However, uncertainties in risk estimates are such that it is difficult to conclude reliably from these epidemiological data what the level of risk at these low doses might be, beyond the inference that the risk is not zero or has been grossly underestimated.

A Systematic Review of Epidemiological Associations between Low and Moderate Doses of Ionizing Radiation and Late Cardiovascular Effects, and Their Possible Mechanisms

Abstract Little, M. P., Tawn, E. J., Tzoulaki, I., Wakeford, R., Hildebrandt, G., Paris, F., Tapio, S. and Elliott, P. A Systematic Review of Epidemiological Associations Between Low and Moderate Doses of Ionizing Radiation and Late Cardiovascular Effects, and Their Possible Mechanisms. Radiat. Res. 169, 99–109 (2008). The link between high doses of ionizing radiation and damage to the heart and coronary arteries is established. In this paper, we systematically review the epidemiological evidence for associations between low and moderate doses (<5 Gy) of ionizing radiation and late-occurring cardiovascular disease. Risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding factors. An examination of possible biological mechanisms indicates that the most likely causative effect of radiation exposure is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. However, a role for somatic mutation has been proposed that would indicate a stochastic effect. In the absence of a convincing mechanistic explanation of epidemiological evidence that is less than persuasive at present, a cause-and-effect interpretation of the reported statistical associations cannot be reliably inferred, although neither can it be reliably excluded. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.

A record-based case-control study of natural background radiation and the incidence of childhood leukaemia and other cancers in Great Britain during 1980-2006

We conducted a large record-based case–control study testing associations between childhood cancer and natural background radiation. Cases (27 447) born and diagnosed in Great Britain during 1980–2006 and matched cancer-free controls (36 793) were from the National Registry of Childhood Tumours. Radiation exposures were estimated for mother’s residence at the child’s birth from national databases, using the County District mean for gamma rays, and a predictive map based on domestic measurements grouped by geological boundaries for radon. There was 12% excess relative risk (ERR) (95% CI 3, 22; two-sided P=0.01) of childhood leukaemia per millisievert of cumulative red bone marrow dose from gamma radiation; the analogous association for radon was not significant, ERR 3% (95% CI −4, 11; P=0.35). Associations for other childhood cancers were not significant for either exposure. Excess risk was insensitive to adjustment for measures of socio-economic status. The statistically significant leukaemia risk reported in this reasonably powered study (power ∼50%) is consistent with high-dose rate predictions. Substantial bias is unlikely, and we cannot identify mechanisms by which confounding might plausibly account for the association, which we regard as likely to be causal. The study supports the extrapolation of high-dose rate risk models to protracted exposures at natural background exposure levels.

Intellectual aptitude tests and A levels for selecting UK school leaver entrants for medical school

An extension of A level grades is the most promising alternative to intellectual aptitude tests for selecting students for medical school

Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth

A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant approximately 50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy(-1) (equivalent to an excess absolute risk coefficient of about 3% Gy(-1)), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia.

Geographical distribution of preconceptional radiation doses to fathers employed at the Sellafield nuclear installation, West Cumbria.

OBJECTIVE--To examine whether the geographical distribution of births associated with preconceptional exposure of fathers to radiation at the Sellafield nuclear installation is consistent with the suggestion that this exposure explains the excess of childhood lymphoid malignancy in the adjacent village of Seascale. DESIGN--Retrospective birth cohort study. SETTING--Cumbria, West Cumbria health district, and Seascale civil parish. SUBJECTS--The 10,363 children born in Cumbria during 1950-89 to fathers employed at Sellafield. MAIN OUTCOME MEASURES--The doses of external whole body ionising radiation received by fathers at Sellafield in the total time and in the six months before conception of their children; the proportions of the collective doses associated with Seascale and the rest of West Cumbria. RESULTS--9256 children were born to fathers who had been exposed to radiation before the childs conception. Of these, 7318 had fathers who were exposed in the six months before conception. Overall 7% (38 person-Sv) of the collective total preconceptional dose and 7% (3 person-Sv) of the collective dose for the six months before conception were associated with children born in Seascale. Of all the children whose fathers worked at Sellafield, 842 (8%) were born in Seascale. The mean individual doses before conception were consistently lower in Seascale than in the rest of West Cumbria. CONCLUSIONS--The distribution of the paternal preconceptional radiation dose is statistically incompatible with this exposure providing a causal explanation for the cluster of childhood leukaemias in Seascale.

Long-term effects of radiation exposure on health

Late-onset effects of exposure to ionising radiation on the human body have been identified by long-term, large-scale epidemiological studies. The cohort study of Japanese survivors of the atomic bombings of Hiroshima and Nagasaki (the Life Span Study) is thought to be the most reliable source of information about these health effects because of the size of the cohort, the exposure of a general population of both sexes and all ages, and the wide range of individually assessed doses. For this reason, the Life Span Study has become fundamental to risk assessment in the radiation protection system of the International Commission on Radiological Protection and other authorities. Radiation exposure increases the risk of cancer throughout life, so continued follow-up of survivors is essential. Overall, survivors have a clear radiation-related excess risk of cancer, and people exposed as children have a higher risk of radiation-induced cancer than those exposed at older ages. At high doses, and possibly at low doses, radiation might increase the risk of cardiovascular disease and some other non-cancer diseases. Hereditary effects in the children of atomic bomb survivors have not been detected. The dose-response relation for cancer at low doses is assumed, for purposes of radiological protection, to be linear without a threshold, but has not been shown definitively. This outstanding issue is not only a problem when dealing appropriately with potential health effects of nuclear accidents, such as at Fukushima and Chernobyl, but is of growing concern in occupational and medical exposure. Therefore, the appropriate dose-response relation for effects of low doses of radiation needs to be established.

New models for evaluation of radiation-induced lifetime cancer risk and its uncertainty employed in the UNSCEAR 2006 report.

Abstract Little, M. P., Hoel, D. G., Molitor, J., Boice, J. D., Jr., Wakeford, R. and Muirhead, C. R. New Models for Evaluation of Radiation-Induced Lifetime Cancer Risk and its Uncertainty Employed in the UNSCEAR 2006 Report. Radiat. Res. 169, 660–676 (2008). Generalized relative and absolute risk models are fitted to the latest Japanese atomic bomb survivor solid cancer and leukemia mortality data (through 2000), with the latest (DS02) dosimetry, by classical (regression calibration) and Bayesian techniques, taking account of errors in dose estimates and other uncertainties. Linear-quadratic and linear-quadratic-exponential models are fitted and used to assess risks for contemporary populations of China, Japan, Puerto Rico, the U.S. and the UK. Many of these models are the same as or very similar to models used in the UNSCEAR 2006 report. For a test dose of 0.1 Sv, the solid cancer mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 5.4% Sv−1 [90% Bayesian credible interval (BCI) 3.1, 8.0]. At 0.1 Sv, leukemia mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 0.50% Sv−1 (90% BCI 0.11, 0.97). Risk estimates varied little between populations; at 0.1 Sv the central estimates ranged from 3.7 to 5.4% Sv−1 for solid cancers and from 0.4 to 0.6% Sv−1 for leukemia. Analyses using regression calibration techniques yield central estimates of risk very similar to those for the Bayesian approach. The central estimates of population risk were similar for the generalized absolute risk model and the relative risk model. Linear-quadratic-exponential models predict lower risks (at least at low test doses) and appear to fit as well, although for other (theoretical) reasons we favor the simpler linear-quadratic models.