M. W. Charles

Time Variations in the Risk of Cancer Following Irradiation in Childhood

The Japanese atomic bomb survivors and three other cohorts of children exposed to radiation are analyzed, and evidence is found for a reduction in the radiation-induced relative risk of cancers other than leukemia with time following exposure. Multiplicative adjustments to the excess risk either of the form exp[-delta.(time since exposure)] or of the form [time since exposure] gamma give equivalent goodness of fit. Using the former type of adjustment an annual overall reduction of 6.9-8.6% in excess relative risk is indicated (depending on the year after which this reduction might take effect). Using the second type of multiplier an adjustment to the excess relative risk varying between [time after exposure]-2.0 and [time after exposure]-3.2 fits best overall. All these reductions are statistically significant at the 5% level. There is no significant variation by cohort, by sex, by cancer type, or by age at exposure group in the degree of annual reduction in excess relative risk. Although time-adjusted relative and absolute risk models give equivalently good fits within each cohort, there is significant variation between cohorts in the degree of increase of risk with time in the absolute risk formulation, in contrast to the lack of such heterogeneity for the relative risk formulation. It is shown that if the range of observed reductions in relative risk is assumed to operate 40 or more years after exposure in the youngest age groups, the calculated UK population risks would be reduced by 30-45% compared to those based on a constant relative risk model.

Mammography—oncogenecity at low doses

Controversy exists regarding the biological effectiveness of low energy x-rays used for mammography breast screening. Recent radiobiology studies have provided compelling evidence that these low energy x-rays may be 4.42 +/- 2.02 times more effective in causing mutational damage than higher energy x-rays. These data include a study involving in vitro irradiation of a human cell line using a mammography x-ray source and a high energy source which matches the spectrum of radiation observed in survivors from the Hiroshima atomic bomb. Current radiation risk estimates rely heavily on data from the atomic bomb survivors, and a direct comparison between the diagnostic energies used in the UK breast screening programme and those used for risk estimates can now be made. Evidence highlighting the increase in relative biological effectiveness (RBE) of mammography x-rays to a range of x-ray energies implies that the risks of radiation-induced breast cancers for mammography x-rays are potentially underestimated by a factor of four. A pooled analysis of three measurements gives a maximal RBE (for malignant transformation of human cells in vitro) of 4.02 +/- 0.72 for 29 kVp (peak accelerating voltage) x-rays compared to high energy electrons and higher energy x-rays. For the majority of women in the UK NHS breast screening programme, it is shown that the benefit safely exceeds the risk of possible cancer induction even when this higher biological effectiveness factor is applied. The risk/benefit analysis, however, implies the need for caution for women screened under the age of 50, and particularly for those with a family history (and therefore a likely genetic susceptibility) of breast cancer. In vitro radiobiological data are generally acquired at high doses, and there are different extrapolation mechanisms to the low doses seen clinically. Recent low dose in vitro data have indicated a potential suppressive effect at very low dose rates and doses. Whilst mammography is a low dose exposure, it is not a low dose rate examination, and protraction of dose should not be confused with fractionation. Although there is potential for a suppressive effect at low doses, recent epidemiological data, and several international radiation risk assessments, continue to promote the linear no-threshold (LNT) model. Finally, recent studies have shown that magnetic resonance imaging (MRI) is more sensitive than mammography in detecting invasive breast cancer in women with a genetic sensitivity. Since an increase in the risk associated with mammographic screening would blur the justification of exposure for this high risk subgroup, the use of other (non-ionising) screening modalities is preferable.

Fitting the armitage-doll model to radiation-exposed cohorts and implications for population cancer risks

The Armitage-Doll model of carcinogenesis is fitted to Japanese bomb survivors with the DS86 dosimetry and to three other radiation-exposed cohorts. The model is found to provide an adequate description of solid cancer incidence and also, to a lesser extent, of that of leukemia as a function of radiation dose when up to two radiation-affected stages are assumed. For non-leukemias the optimal model is one in which there are two radiation-affected stages separated by two additional stages. In the case of leukemia one radiation-affected stage or two adjacent stages provide suitable fits. There appear to be significant differences between the optimal models fitted to each cohort, although there is no heterogeneity within the Japanese data set by sex, by cancer type, or by age at exposure. Low-dose and low-dose-rate population risks for a population having the cancer and overall mortality rates of the current UK population are calculated on the basis of the optimal models fitted to the Japanese data to be about 8.3 x 10(-2) excess cancer deaths person-1 Sv-1, 10.1 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 1.40 years of life lost person-1 Sv-1. Risks for a population having the mortality rates of the current Japanese population are about 6.5 x 10(-2) excess cancer deaths person-1 Sv-1, 7.8 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 0.89 years of life lost person-1 Sv-1. It is a feature of the Armitage-Doll model, and other multistage models of carcinogenesis, that if radiation acts at more than one stage then (inverse) dose-rate effects may arise as a result of interactions between the effects of a protracted dose at the various radiation-affected stages. However, it is shown in this paper that these three measures of cancer risk in general display fairly slight dependence on administered dose in the range 0.001 to 1.0 Sv and on the length of the time over which the dose is administered in the range 1 to 100 years. Dose-rate effects resulting from the protraction of a radiation exposure over many years acting on (the same) cells at various stages of a multistep process of carcinogenesis are therefore expected to be slight. Dose-rate effects which have been observed in epidemiological studies and cellular radiobiology may thus find their explanation in other phenomena such as short-term intracellular repair.

The risk of non-melanoma skin cancer incidence in the Japanese atomic bomb survivors

The latest Japanese atomic bomb survivor non-melanoma skin cancer incidence dataset is analysed and indicates substantial curvilinearity in the dose-response curve, consistent with a possible dose threshold of about 1 Sv, or with a dose-response in which the excess relative risk is proportional to the fourth power of dose, with a turning-over in the dose-response at high doses (> 3 Sv). The time distribution of the radiation-induced excess risk is best described by a model in which the relative excess risk is proportional to a product of powers of time since exposure and attained age. The fits of generalized relative risk models with exponential functions of time and age at exposure (and in particular of attained age) to adjust the relative risk are less satisfactory, as also are the fits of other models in which products of powers of time since exposure, age at exposure and attained age adjust the excess absolute risk. Sensitivity analyses indicate the importance of likely adjustments to the Hiroshima neutron doses for the optimal model parameters, particularly if values of the neutron relative biological effectiveness (RBE) of more than 5 are assumed. If adjustments recently proposed are made to the Hiroshima neutron doses, then using the optimal model (in which excess risk is proportional to the fourth power of dose) the best estimate of the neutron RBE is 1.3 (95% CI < 07.1). However, uncertainties in skin dose estimates for the atomic bomb survivors means that the findings with respect to the neutron RBE and the non-linearity in the dose-response curve should be treated with caution.

Variations with time and age in the risks of solid cancer incidence after radiation exposure in childhood

The Japanese atomic bomb survivor incidence data set and data on five other groups exposed to ionizing radiation in childhood are analysed and evidence found for a reduction in the radiation-induced relative risk of cancers other than leukaemia with increasing time since exposure. Overall, reductions of 5.7-6.1 per cent per year of time since exposure are indicated, depending on the time at which the reduction is presumed to start, and all the reductions are statistically significant at the 5 per cent level. There is no significant heterogeneity in the speed of the reductions in relative risk with time by cohort, by cancer type, sex, or age at exposure group. There is a significant reduction of relative risk with increasing age at exposure, but adjustment for age at exposure does not markedly affect the time trends of relative risk. For all of the groups considered, there is a statistically significant increase in the excess absolute risk with increasing time since exposure. However, by contrast with the relative homogeneity of the time trends of relative risk, there is statistically significant heterogeneity by cancer type within the Japanese cohort (P = 0.05) and between the cohorts (P < 0.0001) in the speed of increase of the excess absolute risk with time since exposure.

Radon exposure of the skin: I. Biological effects

Radon progeny can plate out on skin and give rise to exposure of the superficial epidermis from alpha emitters Po-218 (7.7 MeV, range approximately 66 microm) and Po-214 (6 MeV, range approximately 44 microm). Dose rates from beta/gamma emitters Pb-214 and Bi-214 are low and only predominate at depths in excess of the alpha range. This paper reviews the evidence for a causal link between exposure from radon and its progeny, and deterministic and stochastic biological effects in human skin. Radiation induced skin effects such as ulceration and dermal atrophy, which require irradiation of the dermis, are ruled out for alpha irradiation from radon progeny because the target cells are considerably deeper than the range of alpha particles. They have not been observed in man or animals. Effects such as erythema and acute epidermal necrosis have been observed in a few cases of very high dose alpha particle exposures in man and after acute high dose exposure in animals from low energy beta radiations with similar depth doses to radon progeny. The required skin surface absorbed doses are in excess of 100 Gy. Such effects would require extremely high levels of radon progeny. They would involve quite exceptional circumstances, way outside the normal range of radon exposures in man. There is no definitive identification of the target cells for skin cancer induction in animals or man. The stem cells in the basal layer which maintain the epidermis are the most plausible contenders for target cells. The majority of these cells are near the end of the range of radon progeny alpha particles, even on the thinnest body sites. The nominal depth of these cells, as recommended by the International Commission on Radiological Protection (ICRP), is 70 microm. There is evidence however that some irradiation of the hair follicles and/or the deeper dermis, as well as the inter-follicular epidermis, is also necessary for skin cancer induction. Alpha irradiation of rodent skin that is restricted to the epidermis does not produce skin cancer. Accelerator generated high energy helium and heavy ions can produce skin cancer in rodents at high doses, but only if they penetrate deep into the dermis. The risk figures for radiation induced skin cancer in man recommended by the ICRP in 1990 are based largely on x and beta irradiated cohorts, but few data exist below absorbed doses of about 1 Gy. The only plausible finding of alpha-radiation induced skin cancer in man is restricted to one study in Czech uranium miners. There is no evidence in other uranium miners and the Czech study has a number of shortcomings. This review concludes that the overall balance of evidence is against causality of radon progeny exposure and skin cancer induction. Of particular relevance is the finding in animal studies that radiation exposure of cells which are deeper than the inter-follicular epidermis is necessary to elicit skin cancer. In spite of this conclusion, a follow-on paper evaluates the attributable risk of radon to skin cancer in the UK on the basis that target cells for skin cancer induction are the cells in the basal layer of the inter-follicular epidermis-since this is the conservative assumption made by international bodies such as the International Commission on Radiological Protection (ICRP) for general radiological protection purposes.

A review of the risks of leukemia in relation to parental pre-conception exposure to radiation.

The apparent risk of childhood leukemia resulting from paternal pre-conception radiation exposure found among children of the Sellafield (West Cumbria, UK) workforce is compared with the apparent risk in a number of other epidemiological studies. In particular, the extent of the incompatibility of the leukemia pre-conception exposure risks in the offspring of the Sellafield workforce born in the village of Seascale with the risks for those born in the rest of west Cumbria, and with the risks in the offspring of the Japanese bomb survivors, the Ontario radiation workers, and the Scottish radiation workers is discussed. A variety of animal data relating to the possibility of leukemia arising as a result of parental pre-conception exposure is also considered. It is concluded that the extent of the inconsistency of the leukemia risks in the Seascale data with this body of epidemiological and experimental data makes it highly unlikely that the association observed in the West Cumbria dataset represents a causal relationship.

LNT--an apparent rather than a real controversy?

Can the carcinogenic risks of radiation that are observed at high doses be extrapolated to low doses? This question has been debated through the whole professional life of the author--now nearing four decades. In its extreme form the question relates to a particular hypothesis (LNT) used widely by the international community for radiological protection applications. The linear no-threshold (LNT) hypothesis propounds that the extrapolation is linear and that it extends down to zero dose. The debate on the validity of LNT has increased dramatically in recent years. This is in no small part due to concern that exaggerated risks at low doses leads to undue amounts of societal resources being used to reduce man-made human exposure and because of the related growing public aversion to diagnostic and therapeutic medical exposures. The debate appears to be entering a new phase. There is a growing realisation of the limitations of fundamental data and the scientific approach to address this question at low doses. There also appears to be an increasing awareness that the assumptions necessary for a workable and acceptable system of radiological protection at low doses must necessarily be based on considerable pragmatism. Recent developments are reviewed and a historical perspective is given on the general nature of controversies in radiation protection over the years. All the protagonists in the debate will at the end of the day probably be able to claim that they were right!

Describing time and age variations in the risk of radiation-induced solid tumour incidence in the Japanese atomic bomb survivors using generalized relative and absolute risk models.

Generalized relative and absolute risk models, in which various functions of time and age modify the excess relative or absolute risk of radiation-induced cancer, are fitted to the Japanese atomic bomb survivor cancer incidence data set. Among generalized relative risk models, those in which a product of powers of time since exposure and attained age modify the relative risk provide the best fit. There are indications that the Armitage-Doll model (in its formulation as a generalized relative risk model) provides a poor fit to the data, possibly in part because of increasing age-adjusted cancer incidence rates in the Japanese cohort. Generalized absolute risk models, and in particular models in which either powers of time since exposure and attained age, or powers of time since exposure and age at exposure modify the excess absolute risk, provide a superior fit to any of the generalized relative risk models for all solid cancer sites analysed together. When six cancer subtypes are examined separately, only for respiratory cancers does this finding remain true, and for two other sites (female breast cancer and thyroid cancer) the generalized relative risk model yields a better fit than the generalized absolute risk model.

Radon exposure of the skin: II. Estimation of the attributable risk for skin cancer incidence

A preceding companion paper has reviewed the various factors which form the chain of assumptions that are necessary to support a suggested link between radon exposure and skin cancer in man. Overall, the balance of evidence was considered to be against a causal link between radon exposure and skin cancer. One factor against causality is evidence, particularly from animal studies, that some exposure of the hair follicles and/or the deeper dermis, as well as the inter-follicular epidermis, is required-beyond the range of naturally occurring alpha particles. On this basis any skin cancer risk due to radon progeny would be due only to beta and gamma components of equivalent dose, which are 10-100 times less than the alpha equivalent dose to the basal layer. Notwithstanding this conclusion against causality, calculations have been carried out of attributable risk (ATR, the proportion of cases occurring in the total population which can be explained by radon exposure) on the conservative basis that the target cells are, as is often assumed, in the basal layer of the epidermis. An excess relative risk figure is used which is based on variance weighting of the data sources. This is 2.5 times lower than the value generally used. A latent period of 20 years and an RBE of 10 are considered more justifiable than the often used values of 10 years and 20 respectively. These assumptions lead to an ATR of approximately 0.7% (0.5-5%) at the nominal UK indoor radon level of 20 Bq m(-3). The range reflects uncertainties in plate-out. Previous higher estimates by various authors have made more pessimistic assumptions. There are some indications that radon progeny plate-out may be elevated out of doors, particularly due to rainfall. Although average UK outdoor radon levels ( approximately 4 Bq m(-3)) are much less than average indoor levels, and outdoor residence time is on average about 10%, this might have the effect of increasing the ATR several-fold. This needs considerable further study. Ecological epidemiology data for the South West of England provide no evidence for elevated skin cancer risks at radon levels <100 Bq m(-3). Case-control or cohort studies would be necessary to address the issue authoritatively.