Comment on "use of A-Bomb survivor studies as a basis for nuclear worker compensation". (Perspectives Correspondence).

I read with interest the letter of Wing and Richardson (2002), which raised concerns about using cancer risks derived from the Life Span Study (LSS) cohort of Japanese atomic-bomb survivor data in radiation worker compensation plans. Wing and Richardson (2002) criticized the methods of dose assessment for the LSS data and implied that there is significant dose misclassification in this data set. They also stated that the atomic-bomb survivors exhibit dose- and age-related selective survival, citing recent work of Stewart and Kneale (2000). They also implied that there is inconsistency between the cancer risks observed in the LSS and their variation with age, and those observed in certain occupationally and medically exposed groups. In this letter, I will show that these criticisms of the LSS are without foundation.

There are random and systematic uncertainties in the dose estimates in the LSS, as are also found in most occupationally exposed groups. Errors in dose assignments in the LSS arise from uncertainties in the location of survivors and those associated with shielding by neighboring structures (Jablon 1971; Roesch 1987). Uncertainties in dose estimates in the worker cohorts are caused by sampling variation in measurements from film badges and thermoluminescent dosimeters, adjustments made to doses below the limit of detection, and attenuation of externally measured dose by shielding (Gilbert 1998; Gilbert and Fix 1995). The errors in the Japanese dose estimates are thought to be log-normal with a geometric standard deviation of about 30% (Jablon 1971); the dosimetric errors in the radiation workers are of the same order (Kite and Britcher 1996). The National Council on Radiation Protection and Measurements (NCRP 1997) concluded that accounting for random and systematic errors in the LSS results in reduction in the cancer mortality risk coefficient by a factor of 0.84 [90% subjective confidence interval (CI), 0.69-1.0].

Although the overall effect of dosimetric errors on cancer risk coefficients derived from the LSS is slight, it is well recognized that such errors can substantially alter the evidence for modification of the cancer dose response by acute injury status (Little 2002a; Neriishi et al. 1991). Stewart and Kneale (2000) found significant differences of excess relative risk (ERR) in the LSS for leukemia and other end points, between survivors with two or more acute injuries and survivors not having any acute injuries, but did not take into account dosimetric errors. Little (2002a) analyzed the same data and showed that the findings of Stewart and Kneale (2000) largely disappeared if proper account was taken of dosimetric errors.

Stewart and Kneale (2000) also found significant heterogeneity in ERR by age group for various disease end points, which they used to argue for the delayed effects of acute injury in "vulnerable" age groups in the LSS. Wing and Richardson (2002) also highlighted this decrease of ERR at older ages in the LSS compared with the enhanced sensitivity at older ages observed in some worker cohorts. However, these findings in the LSS are commonly observed in many medically exposed groups [United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2000]. Various mechanistic models of carcinogenesis (Little 1995, 1996; Little et al. 1992) imply a reduction of ERR with increasing age at exposure. That these patterns are observed in many different populations suggests that the hypothesis proposed by Stewart and Kneale (2000) and Wing and Richardson (2002) to account for their occurrence in the LSS is unlikely to be correct.

The risks observed in the LSS are generally statistically consistent with those observed in occupationally (Cardis et al. 1995; Muirhead et al. 1999) and medically exposed groups (Little and Boice 1999; Little et al. 1999; UNSCEAR 2000). For example, Muirhead et al. (1999) estimated that the ratio of the leukemia ERR coefficient in U.K. nuclear workers to that in the LSS is 1.18 (90% CI, < 0-3.73), and the corresponding ratio for all malignant neoplasms excluding leukemia and lung cancer is 0.89 (90% CI, < 0-3.65). The ratio of lung cancer risk coefficients in the LSS and in groups of underground miners is close to the value suggested by the latest International Commission on Radiological Protection (ICRP 1994) model of lung dosimetry (Birchall and James 1994; Little 2002b). The general consistency of risks in the LSS and in medically and occupationally exposed groups implies that there are no serious biases in the LSS dosimetry.

The author declares he has no conflict of interest.

Mark P. Little

Department of Epidemiology and

Public Health

Imperial College Faculty of Medicine

London, United Kingdom

E-mail: [e-mail]

REFERENCES

Birchall A, James AC. 1994. Uncertainty analysis of the effective dose per unit exposure from radon progeny and implications for ICRP risk-weighting factors. Radiat Prot Dosim 53:133-140.

Cardis E, Gilbert ES, Carpenter L, Howe G, Kato I, Armstrong BK, et al. 1995. Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries. Radiat Res 142:117-132.

Gilbert ES. 1998. Accounting for errors in dose estimates used in studies of workers exposed to external radiation. Health Phys 74:22-29.

Gilbert ES, Fix JJ. 1995. Accounting for bias in dose estimates in analyses of data from nuclear worker morality studies. Health Phys 68:650-660.

International Commission on Radiological Protection (ICRP). 1994. Human Respiratory Tract Model for Radiological Protection. A Report of a Task Group of the International Commission on Radiological Protection. Ann ICRP 24(1-3):1-482.

Jablon S. 1971. Atomic Bomb Radiation Dose Estimation at ABCC. ABCC Technical Report 23-71. Hiroshima, Japan:Atomic Bomb Casualty Commission.

Kite AV, Britcher AR. 1996. Uncertainties in recorded photon radiation doses at Sellafield. Radiat Prot Dosimetry 67:23-32.

Little MP. 1995. Are two mutations sufficient to cause cancer? Some generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon, and Knudson, and of the multistage model of Armitage and Doll. Biometrics 51:1278-1291.

Little MP. 1996. Generalisations of the two-mutation and classical multi-stage models of carcinogenesis fitted to the Japanese atomic bomb survivor data. J Radiol Prot 16:7-24.

Little MP. 2002a. Absence of evidence for differences in the dose-response for cancer and non-cancer endpoints by acute injury status in the Japanese atomic-bomb survivors. Int J Radiar Biol 78:1001-1010.

Little MP. 2002b. Comparisons of lung tumour mortality risk in the Japanese A-bomb survivors and in the Colorado Plateau uranium miners: support for the ICRP lung model. Int J Radiat Biol 78:145-163.

Little MP, Boice JD Jr. 1999. Comparison of breast cancer incidence in the Massachusetts tuberculosis fluoroscopy cohort and in the Japanese atomic bomb survivors. Radiat Res 151:218-224.

Little MP, Hawkins MM, Charles MW, Hildreth NG. 1992. Fitting the Armitage-Doll model to radiation-exposed cohorts and implications for population cancer risks. Radiat Res 132:207-221.

Little MP, Weiss HA, Boice JD Jr, Darby SC, Day NE, Muirhead CR. 1999. Risks of leukemia in Japanese atomic bomb survivors, in women treated for cervical cancer, and in patients treated for ankylosing spondylitis. Radiat Res 152:280-292.

Muirhead CR, Goodill AA, Haylock RGE, Vokes J, Little MP, Jackson DA, et al. 1999. Occupational radiation exposure and mortality: second analysis of the National Registry for Radiation Workers. J Radiol Prot 19:3-26.

NCRP. 1997. Uncertainties in Fatal Cancer Risk Estimates Used in Radiation Protection. NCRP Report No. 126. Bethesda, MD:National Council on Radiation Protection and Measurements.

Neriishi K, Stram DO, Vaeth M, Mizuno S, Akiba S. 1991. The observed relationship between the occurrence of acute radiation effects and leukemia mortality among A-bomb survivors. Radiat Res 125:206-213.

Roesch WC, ed. 1987. US-Japan Joint Reassessment of Atomic Bomb Radiation Dosimetry in Hiroshima and Nagasaki, Vol 1. Hiroshima, Japan:Radiation Effects Research Foundation.

Stewart AM, Kneale GW. 2000. A-bomb survivors: factors that may lead to a re-assessment of the radiation hazard. Int J Epidemiol 29:708-714.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). 2000. Sources and Effects of Ionizing Radiation. Volume II: Effects. New York:United Nations.

Wing S, Richardson D. 2002. Use of A-bomb survivor studies as a basis for nuclear worker compensation [Letter]. Environ Health Perspect 110:A739.

Re: "Use of A-Bomb Survivor Studies as a Basis for Nuclear Worker Compensation"

Wing and Richardson (2002) suggested that it is inappropriate to apply radiation risk estimates derived from the follow-up of the Japanese atomic-bomb survivors to persons exposed chronically to low doses of radiation. They referred to a paper I co-authored (Doll and Wakeford 1997) in support of their claim that a raised risk of childhood cancer was not detected among the Japanese survivors irradiated in utero, in contrast to the elevated risk found in case-control studies of antenatal exposure to diagnostic X rays. In fact, only just over 750 Japanese children were exposed in utero during the atomic bombings of Hiroshima and Nagasaki, and two cases of childhood cancer were observed in this cohort against an expected number of, at most, 0.43 (Doll and Wakeford 1997; Yoshimoto et al. 1988). These limited data do indicate an excess risk of childhood cancer following intrauterine irradiation during the bombings; the pertinent question is whether the risk coefficient (risk per unit dose) that may be derived from the Japanese cohort study is compatible with the risk estimates that may be obtained from the findings of the case-control studies of fetal exposure (Boice and Miller 1999; Doll and Wakeford 1997; Wakeford 1995).

By far the largest case-control study of childhood cancer and antenatal radiographic examinations is the Oxford Survey of Childhood Cancers (Bithell and Stewart 1975). A highly statistically significant excess relative risk (ERR) associated with a diagnostic X-ray examination of 40% was obtained from the Oxford Survey, but reliable estimates of fetal doses appropriate for this study are not easily derived (Mole 1990). Bithell (1993) obtained an ERR coefficient from the Oxford data of 51 per sievert, but he believed that the uncertainty of this estimate could be as much as an order of magnitude. Further, Wakeford and Little (In press) suggest that there are good reasons from the Oxford data for believing that this risk estimate may be a systematic overestimate by perhaps as much as a factor of four. In comparison, the Japanese data for in utero irradiation provide an ERR coefficient for childhood cancer of 23 per sievert, although, again, the uncertainty of this estimate is large (Delongchamp et al. 1997). The ERR coefficient derived from the Japanese cohort is only of marginal statistical significance, but the limited data available from this source must be emphasized. Once proper account has been taken of the uncertainties present in the analyses of both data sets, it cannot reasonably be concluded that risk estimates are incompatible (Wakeford and Litfle. In press).

The case-control studies of childhood cancer and fetal X-ray exposure are important because they demonstrate an excess risk associated with doses near 10 mSv, doses an order of magnitude below those received in other epidemiologic studies showing an excess risk of cancer following irradiation (UNSCEAR 2000). The interpretation of the findings of these case-control studies has been questioned (Boice and Miller 1999), but Doll and Wakeford (1997) believed that the available evidence provides strong grounds for a causal explanation of the association. However, the point estimates of risk obtained from a comparatively small ERR in the face of many uncertainties should not be overinterpreted, and it cannot be claimed with any confidence that the risk coefficient derived from the Oxford Survey is discrepant with that derived from the limited data from the Japanese survivors exposed in utero (Wakeford and Little. In press). I suspect that Wing and Richardson (2002) have been overoptimistic in the accuracy that they have assigned to two risk estimates that superficially appear to suit their argument.

Although the author is employed by British Nuclear Fuels plc (BNFL), he does not feel there is a genuine conflict of interest, because the Doll and Wakeford paper referred to by Wing and Richardson argues for a non-zero risk of cancer at low doses of radiation.

Richard Wakeford

British Nuclear Fuels plc

Risley, Warrington,

Cheshire, United Kingdom

E-mail: Richard. [e-mail]

REFERENCES

Bithell JF. 1993. Statistical issues in assessing the evidence associating obstetric irradiation and childhood malignancy. In: Neue Bewertung des Strahlenrisikos: Niedrigdosis-Strahlung und Gesundheit (Lengfelder E, Wendhausen H, eds). Munich:MMV Medizin Verlag, 53-60.

Bithell JF, Stewart AM. 1975. Pre-natal irradiation and childhood malignancy: a review of British data from the Oxford Survey. Br J Cancer 31:271-287.

Boice JD Jr, Miller RW. 1999. Childhood and adult cancer following intrauterine exposure to ionizing radiation. Teratology 59:227-233.

Delongchamp RR, Mabuchi K, Yoshimoto Y, Preston DL. 1997. Mortality among atomic bomb survivors exposed in utero or as young children, October 1950-May 1992. Radiat Res 147:385-395.

Doll R, Wakeford R. 1997. Risk of childhood cancer from fetal irradiation. Br J Radiol 70:130-139.

Mole FIH. 1990. Childhood cancer after prenatal exposure to diagnostic X-ray examinations in Britain. Br J Cancer 62:152-166.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). 2000. Sources and Effects of Ionizing Radiation. Volume II: Effects. New York:United Nations.

Wakeford R. 1995. The risk of childhood cancer from intrauterine and preconceptional exposure to ionizing radiation. Environ Health Perspect 103:1018-1025.

Wakeford R, Little MP. In press. A review of risk coefficients for childhood cancer after intrauterine irradiation. Int J Radiat Biol.

Wing S, Richardson D. 2002. Use of A-bomb survivor studies as a basis for nuclear worker compensation [Letter]. Environ Health Perspect 110:A739.

Yoshimoto Y, Kato H, Schull WJ. 1988. Risk of cancer among children exposed in utero to A-bomb radiations, 1950-84. Lancet 2:665-669.