David B. Richardson

The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Estimates of radiation-related cancer risks

Abstract Cardis, E., Vrijheid, M., Blettner, M., Gilbert, E., Hakama, M., Hill, C., Howe, G., Kaldor, J., Muirhead, C. R., Schubauer-Berigan, M., Yoshimura, T., Bermann, F., Cowper, G., Fix, J., Hacker, C., Heinmiller, B., Marshall, M., Thierry-Chef, I., Utterback, D., Ahn, Y-O., Amoros, E., Ashmore, P., Auvinen, A., Bae, J-M., Bernar, J. S., Biau, A., Combalot, E., Deboodt, P., Diez Sacristan, A., Eklöf, M., Engels, H., Engholm, G., Gulis, G., Habib, R. R., Holan, K., Hyvonen, H., Kerekes, A., Kurtinaitis, J., Malker, H., Martuzzi, M., Mastauskas, A., Monnet, A., Moser, M., Pearce, M. S., Richardson, D. B., Rodriguez-Artalejo, F., Rogel, A., Tardy, H., Telle-Lamberton, M., Turai, I., Usel, M. and Veress, K. The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: Estimates of Radiation-Related Cancer Risks. Radiat. Res. 167, 396– 416 (2007). A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI −0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries

Abstract Objectives To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. Design Multinational retrospective cohort study of cancer mortality. Setting Cohorts of workers in the nuclear industry in 15 countries. Participants 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. Main outcome measurements Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. Results The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. Conclusions These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

Evidence of deteriorating semen quality in the United Kingdom: birth cohort study in 577 men in Scotland over 11 years

Abstract Objective: To determine whether the quality of semen has changed in a group of over 500 Scottish men born between 1951 and 1973. Design: Retrospective review of data on semen quality collected in a single laboratory over 11 years and according to World Health Organisation guidelines. Setting: Programme of gamete biology research funded by Medical Research Council. Subjects: 577 volunteer semen donors. Of these, 171 were born before 1959, 120 were born in 1960-4, 171 in 1965-9, and 115 in 1970-4. Main outcome measures: Conventional criteria of semen quality including semen volume (ml), sperm concentration (106/ml), overall motility (% motile), total number of sperm in the ejaculate (106), and total number of motile sperm in the ejaculate (106). Results: When the four birth cohort groups were compared a later year of birth was associated with a lower sperm concentration, a lower total number of sperm in the ejaculate, and a lower number of motile sperm in the ejaculate. The median sperm concentration fell from 98x106/ml among donors born before 1959 to 78x106/ml among donors born after 1970 (P=0.002). The total number of sperm in the ejaculate fell from 301x106 to 214x106 (P=0.0005), and the total number of motile sperm in the ejaculate fell from 169.7x106 to 129.0x106 (P=0.0065). Conclusion: This study provides direct evidence that semen quality is deteriorating, with a later year of birth being significantly associated with a reduced number of sperm in adult life. Key messages Key messages When men born in the 1970s were compared with men born in the 1950s, the total number of motile sperm in the ejaculate was reduced by almost 25% These data confirm previously published data from other countries that semen quality is changing, declining by about 2.1% per year Research is urgently required to examine the function as well as the number of sperm and to assess whether these changes are affecting human health and male fertility

Illustrating bias due to conditioning on a collider

That conditioning on a common effect of exposure and outcome may cause selection, or collider-stratification, bias is not intuitive. We provide two hypothetical examples to convey concepts underlying bias due to conditioning on a collider. In the first example, fever is a common effect of influenza and consumption of a tainted egg-salad sandwich. In the second example, case-status is a common effect of a genotype and an environmental factor. In both examples, conditioning on the common effect imparts an association between two otherwise independent variables; we call this selection bias.

Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study

Summary Background There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. Methods We assembled a cohort of 308 297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8·22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. Findings Doses were accrued at very low rates (mean 1·1 mGy per year, SD 2·6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2·96 per Gy (90% CI 1·17–5·21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10·45, 90% CI 4·48–19·65). Interpretation This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. Funding Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England.

Risk of cardiovascular disease measured by carotid intima-media thickness at age 49-51: lifecourse study

Abstract Objective: To quantify the direct and indirect effects of fetal life, childhood, and adult life on risk of cardiovascular disease at age 49–51 years. Design: Follow up study of the “Newcastle thousand families” birth cohort established in 1947. Participants: 154 men and 193 women who completed a health and lifestyle questionnaire and attended for clinical examination between October 1996 and December 1998. Main outcome measures: Correlations between mean intima-media thickness of the carotid artery (carotid intima-media thickness) and family history, birth weight, and socioeconomic position around birth; socioeconomic position, growth, illness, and adverse life events in childhood; and adult socioeconomic position, lifestyle, and biological risk markers. Proportions of variance in carotid intima-media thickness that were accounted for by each stage of the lifecourse. Results: Socioeconomic position at birth and birth weight were negatively associated with carotid intima-media thickness, although only social class at birth in women was a statistically significant covariate independent of adult lifestyle. These early life variables accounted directly for 2.2% of total variance in men and 2.0% in women. More variation in carotid intima-media thickness was explained by adult socioeconomic position and lifestyle, which accounted directly and indirectly for 3.4% of variance in men (95% confidence interval 0.5% to 6.2%) and 7.6% in women (2.1% to 13.0%). Biological risk markers measured in adulthood independently accounted for a further 9.5% of variance in men (2.4% to 14.2%) and 4.9% in women (1.6% to 7.4%). Conclusions: Adult lifestyle and biological risk markers were the most important determinants of the cardiovascular health of the study members of the Newcastle thousand families cohort at age 49–51 years. The limited overall effect of early life factors may reflect the postwar birth year of this cohort.

An incidence density sampling program for nested case-control analyses

Background: The nested case-control design can be a very efficient approach to an epidemiological investigation. In order to obtain unbiased estimates of relative risk, controls should be selected by incidence density sampling, which involves matching each case to a sample of those who are at risk at the time of case occurrence. Methods: This paper presents a simple computer program for incidence density sampling. This program was evaluated using data derived from a cohort study of mortality among workers employed in the nuclear weapons industry. Controls were selected for cases via incidence density sampling; an estimate of the exposure-mortality association was obtained via conditional logistic regression. After 100 iterations of this procedure, the average effect estimate was compared to the risk estimate obtained via proportional hazards regression. The same methods were used to evaluate a program for incidence density sampling that was proposed previously by Pearce in 1989.5 Results: Relative risk estimates obtained from nested case-control analyses conducted using the incidence density sampling program reported in this paper are unbiased. In contrast, the program for incidence density sampling proposed by Pearce5 tended to produce biased relative risk estimates; the magnitude of bias increased with increasing numbers of controls selected per case. Conclusions: The computer program described in this paper offers a simple approach to incidence density sampling for nested case-control analyses with exact matching on attained age and appropriate enumeration of the pool of eligible controls for each case. This method overcomes problems of bias inherent in a previously proposed program for incidence density sampling.

Ionizing Radiation and Chronic Lymphocytic Leukemia

The U.S. government recently implemented rules for awarding compensation to individuals with cancer who were exposed to ionizing radiation while working in the nuclear weapons complex. Under these rules, chronic lymphocytic leukemia (CLL) is considered to be a nonradiogenic form of cancer. In other words, workers who develop CLL automatically have their compensation claim rejected because the compensation rules hold that the risk of radiation-induced CLL is zero. In this article we review molecular, clinical, and epidemiologic evidence regarding the radiogenicity of CLL. We note that current understanding of radiation-induced tumorigenesis and the etiology of lymphatic neoplasia provides a strong mechanistic basis for expecting that ionizing radiation exposure increases CLL risk. The clinical characteristics of CLL, including prolonged latency and morbidity periods and a low case fatality rate, make it relatively difficult to evaluate associations between ionizing radiation and CLL risk via epidemiologic methods. The epidemiologic evidence of association between external exposure to ionizing radiation and CLL is weak. However, epidemiologic findings are consistent with a hypothesis of elevated CLL mortality risk after a latency and morbidity period that spans several decades. Our findings in this review suggest that there is not a persuasive basis for the conclusion that CLL is a nonradiogenic form of cancer.

Risk of cancer from occupational exposure to ionising radiation: retrospective cohort study of workers in France, the United Kingdom, and the United States (INWORKS).

Study question Is protracted exposure to low doses of ionising radiation associated with an increased risk of solid cancer? Methods In this cohort study, 308 297 workers in the nuclear industry from France, the United Kingdom, and the United States with detailed monitoring data for external exposure to ionising radiation were linked to death registries. Excess relative rate per Gy of radiation dose for mortality from cancer was estimated. Follow-up encompassed 8.2 million person years. Of 66 632 known deaths by the end of follow-up, 17 957 were due to solid cancers. Study answer and limitations Results suggest a linear increase in the rate of cancer with increasing radiation exposure. The average cumulative colon dose estimated among exposed workers was 20.9 mGy (median 4.1 mGy). The estimated rate of mortality from all cancers excluding leukaemia increased with cumulative dose by 48% per Gy (90% confidence interval 20% to 79%), lagged by 10 years. Similar associations were seen for mortality from all solid cancers (47% (18% to 79%)), and within each country. The estimated association over the dose range of 0-100 mGy was similar in magnitude to that obtained over the entire dose range but less precise. Smoking and occupational asbestos exposure are potential confounders; however, exclusion of deaths from lung cancer and pleural cancer did not affect the estimated association. Despite substantial efforts to characterise the performance of the radiation dosimeters used, the possibility of measurement error remains. What this study adds The study provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality. Although high dose rate exposures are thought to be more dangerous than low dose rate exposures, the risk per unit of radiation dose for cancer among radiation workers was similar to estimates derived from studies of Japanese atomic bomb survivors. Quantifying the cancer risks associated with protracted radiation exposures can help strengthen the foundation for radiation protection standards. Funding, competing interests, data sharing Support from the US Centers for Disease Control and Prevention; Ministry of Health, Labour and Welfare of Japan; Institut de Radioprotection et de Sûreté Nucléaire; AREVA; Electricité de France; US National Institute for Occupational Safety and Health; US Department of Energy; and Public Health England. Data are maintained and kept at the International Agency for Research on Cancer.

Estimation of the relative excess risk due to interaction and associated confidence bounds.

The relative excess risk due to interaction (RERI) provides a useful metric of departure from additivity of effects on a relative risk scale. In this paper, the authors show that RERI is identical to the product term in a linear odds ratio or a linear relative risk model. SAS and STATA codes are provided for fitting a linear odds ratio model that directly parameterizes RERI. In addition, this paper presents a method for obtaining likelihood-based 95% confidence bound estimates for RERI. The authors show that likelihood-based confidence intervals may differ substantially from the asymptotic confidence interval estimates advocated by previous authors. The approach presented in this paper should facilitate estimation of RERI and associated likelihood-based confidence bounds, by using standard statistical packages.