Minimum latency effects for cancer associated with exposures to radiation or other carcinogens.

BACKGROUND: In estimating radiation-associated cancer risks a fixed period for the minimum latency is often assumed. Two empirical latency functions have been used to model latency, continuously increasing from 0. A stochastic biologically-based approach yields a still more plausible way of describing latency and can be directly estimated from clinical data. METHODS: We derived the parameters for a stochastic biologically-based model from tumour growth data for various cancers, and least-squares fitted the two types of empirical latency function to the stochastic model-predicted cumulative probability. RESULTS: There is wide variation in growth rates among tumours, particularly slow for prostate and thyroid cancer and particularly fast for leukaemia. The slow growth rate for prostate and thyroid tumours implies that the number of tumour cells required for clinical detection cannot greatly exceed 106. For all tumours, both empirical latency functions closely approximated the predicted biological model cumulative probability. CONCLUSIONS: Our results, illustrating use of a stochastic biologically-based model using clinical data not tied to any particular carcinogen, have implications for estimating latency associated with any mutagen. They apply to tumour growth in general, and may be useful for example, in planning screenings for cancer using imaging techniques.

Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset.

BACKGROUND: Acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced. METHODS: We assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables. RESULTS: There were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0-3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures. CONCLUSIONS: Our more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication.

Effects of confounding and effect-modifying lifestyle, environmental and medical factors on risk of radiation-associated cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. It has been known for some considerable time that radiation is associated with excess risk of CVD. A recent systematic review of radiation and CVD highlighted substantial inter-study heterogeneity in effect, possibly a result of confounding or modifications of radiation effect by non-radiation factors, in particular by the major lifestyle/environmental/medical risk factors and latent period. METHODS: We assessed effects of confounding by lifestyle/environmental/medical risk factors on radiation-associated CVD and investigated evidence for modifying effects of these variables on CVD radiation dose-response, using data assembled for a recent systematic review. RESULTS: There are 43 epidemiologic studies which are informative on effects of adjustment for confounding or risk modifying factors on radiation-associated CVD. Of these 22 were studies of groups exposed to substantial doses of medical radiation for therapy or diagnosis. The remaining 21 studies were of groups exposed at much lower levels of dose and/or dose rate. Only four studies suggest substantial effects of adjustment for lifestyle/environmental/medical risk factors on radiation risk of CVD; however, there were also substantial uncertainties in the estimates in all of these studies. There are fewer suggestions of effects that modify the radiation dose response; only two studies, both at lower levels of dose, report the most serious level of modifying effect. CONCLUSIONS: There are still large uncertainties about confounding factors or lifestyle/environmental/medical variables that may influence radiation-associated CVD, although indications are that there are not many studies in which there are substantial confounding effects of these risk factors.

Radiation exposure and leukaemia risk among cohorts of persons exposed to low and moderate doses of external ionising radiation in childhood.

BACKGROUND: Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear. METHODS: We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted. RESULTS: Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59-2.85), CML (n = 61) = 1.77 (95% CI 0.38-4.50), and ALL (n = 71) = 6.65 (95% CI 2.79-14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards. DISCUSSION: We found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

Lympho-hematopoietic malignancies risk after exposure to low dose ionizing radiation during cardiac catheterization in childhood.

Pediatric patients with congenital heart disease (CHD) often undergo low dose ionizing radiation (LDIR) from cardiac catheterization (CC) for the diagnosis and/or treatment of their disease. Although radiation doses from a single CC are usually low, less is known about the long-term radiation associated cancer risks. We aimed to assess the risk of lympho-hematopoietic malignancies in pediatric CHD patients diagnosed or treated with CC. A French cohort of 17,104 children free of cancer who had undergone a first CC from 01/01/2000 to 31/12/2013, before the age of 16 was set up. The follow-up started at the date of the first recorded CC until the exit date, i.e., the date of death, the date of first cancer diagnosis, the date of the 18th birthday, or the 31/12/2015, whichever occurred first. Poisson regression was used to estimate the LDIR associated cancer risk. The median follow-up was 5.9 years, with 110,335 person-years. There were 22,227 CC procedures, yielding an individual active bone marrow (ABM) mean cumulative dose of 3.0 milligray (mGy). Thirty-eight incident lympho-hematopoietic malignancies were observed. When adjusting for attained age, gender and predisposing factors to cancer status, no increased risk was observed for lympho-hematopoietic malignancies RR/mGy = 1.00 (95% CI: 0.88; 1.10). In summary, the risk of lympho-hematopoietic malignancies and lymphoma was not associated to LDIR in pediatric patients with CHD who undergo CC. Further epidemiological studies with greater statistical power are needed to improve the assessment of the dose-risk relationship.

Impact of Reverse Causation on Estimates of Cancer Risk Associated With Radiation Exposure From Computerized Tomography: A Simulation Study Modeled on Brain Cancer.

Use of computed tomography (CT) scanning has increased substantially since its introduction in the 1990s. Several authors have reported increased risk of leukemia and brain tumors associated with radiation exposure from CT scans. However, reverse causation is a concern, particularly for brain cancer; in other words, the CT scan may have been taken because of preexisting cancer and therefore not have been a cause. We assessed the possibility of reverse causation via a simulation study focused on brain tumors, using a simplified version of the data structure for recent CT studies. Five-year-lagged and unlagged analyses implied an observed excess risk per scan up to 70% lower than the true excess risk per scan, particularly when more than 10% of persons with latent cancer had increased numbers of scans or the extra scanning rate after development of latent cancer was greater than 2 scans/year; less extreme values of these parameters imply little risk attenuation. Without a lag and when more than 20% of persons with latent cancer had increased scans-an arguably implausible scenario-the excess risk per scan was increased over the true excess risk per scan by up to 35%-40%. This study suggests that with a realistic lag, reverse causation results in downwardly biased risk, a result of induced classical measurement error, and is therefore unlikely to produce a spurious positive association between cancer and radiation dose from CT scans.

Reproductive factors, hormone use, and incidence of melanoma in a cohort of US Radiologic Technologists.

STUDY QUESTION: Are reproductive factors and exogenous hormone use associated with incidence of cutaneous melanoma while accounting for ultraviolet radiation (UVR) exposure across different life periods and sun sensitivity factors? SUMMARY ANSWER: Earlier age at menarche and late age at first birth, but not other estrogen-related factors were associated with an increased incidence rate of melanoma, with higher risks observed for earlier age at menarche and light hair color at age 15 years. WHAT IS KNOWN ALREADY: Although estrogens have been recognized as photosensitizing, previous studies have reported inconsistent findings for the association of melanoma with estrogen-related factors. Most have not collected detailed skin cancer risk factors and have not thoroughly investigated effect modification by ambient UVR and sun sensitivity. STUDY DESIGN, SIZE, DURATION: Participants in the US Radiologic Technologists study, an occupational cohort of 146 022 radiologic technologists (73% women), were included and followed during the four time periods (1983-1989, 1994-1998, 2003-2005 and 2012-2014). PARTICIPANTS/MATERIALS, SETTING, METHODS: Non-Hispanic white female participants who completed both the second (baseline) and third questionnaires, and did not report having cancer (except keratinocyte carcinoma) at baseline, were included and followed from their age at completion of the second (baseline) questionnaire until the earlier of first primary cancer diagnosis, including invasive melanoma of the skin, or completion of either the third or fourth questionnaire. Reproductive and exogenous hormonal factors were ascertained from the second (baseline) questionnaire, which also collected information on demographic, lifestyle factors and sun sensitivity factors. Ambient UVR was assigned by linking geocoded residential locations, based on self-reported residential history information collected from the third questionnaire to satellite-based ambient UVR data from the National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer database. To examine the association of reproductive factors, exogenous hormone use, and first primary invasive melanoma of the skin, we used Poisson regression to calculate rate ratios (RRs) and 95% likelihood-based CIs, adjusting for attained age, birth cohort, lifetime average annual ambient UVR, contraceptives and menopausal hormone therapy use. To address the effect modification of ambient UVR exposure and sun sensitivities on melanoma risk, we conducted likelihood-ratio tests for multiplicative interaction. MAIN RESULTS AND THE ROLE OF CHANCE: Over a median follow-up time of 17.1 years, 0.95% of eligible participants had an incident first primary melanoma (n = 444). Higher melanoma incidence rates were observed in participants with older attained age, blue/green/gray eye color, blonde/red/auburn natural hair color at age 15, fair skin complexion, and higher UVR. We found an increased incidence rate of melanoma in women who experienced menarche at an earlier age (13, 12 and <12 years vs ≥14 years: RR = 1.48, 95% CI = 1.11-1.98; 1.19, 0.89-1.61; 1.26, 0.93-1.73), and in women with older age at first birth (25-29 and ≥30 years vs <25 years; 1.09, 0.86-1.39; 1.48, 1.12-1.95; P-value for trend = 0.006). However, no significant association was observed for other reproductive factors, and for all exogenous hormone use. The associations of melanoma incidence for most reproductive factors and exogenous hormone use were not modified by ambient UVR, eye color, natural hair color at age 15 and skin complexion. The exception was that natural hair color at age 15 modified the associations of melanoma for age at menarche (P-value for interaction = 0.004) and age at first birth among parous women (0.005). In participants with blonde/red/auburn natural hair color at age 15, we found increased risk of melanoma among women who experienced menarche at age 13, 12 and <12 years (vs ≥14 years: RR = 3.54, 95% CI = 1.98-6.90; 2.51, 1.37-4.98; 2.66, 1.41-5.36, respectively; P-value for trend = 0.10). However, the association between age at menarche and melanoma was null in participants with brown/black natural hair color at age 15. LIMITATIONS, REASONS FOR CAUTION: Information on reproductive history and exogenous hormone use was self-reported. We did not have information on specific doses or formulations of exogenous hormone medications or breastfeeding. WIDER IMPLICATIONS OF THE FINDINGS: Women residing in areas of high ambient UVR and those with blonde/red/auburn natural hair color may constitute an additional high-risk group in need of more frequent skin cancer screening. Identifying susceptible periods of exposure or factors that modify UVR susceptibility may aid in guiding more targeted guidelines for melanoma prevention. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Impact of uncertainties in exposure assessment on thyroid cancer risk among cleanup workers in Ukraine exposed due to the Chornobyl accident.

A large excess risk of thyroid cancer was observed among Belarusian/Russian/Baltic Chornobyl cleanup workers. A more recent study of Ukraine cleanup workers found more modest excess risks of thyroid cancer. Dose errors in this data are substantial, associated with model uncertainties and questionnaire response. Regression calibration is often used for dose-error adjustment, but may not adequately account for the full error distribution. We aimed to examine the impact of exposure-assessment uncertainties on thyroid cancer among Ukrainian cleanup workers using Monte Carlo maximum likelihood, and compare with results derived using regression calibration. Analyses assessed the sensitivity of results to various components of internal and external dose. Regression calibration yielded an excess odds ratio per Gy (EOR/Gy) of 0.437 (95% CI - 0.042, 1.577, p = 0.100), compared with the EOR/Gy using Monte Carlo maximum likelihood of 0.517 (95% CI - 0.039, 2.035, p = 0.093). Trend risk estimates for follicular morphology tumors exhibited much more extreme effects of full-likelihood adjustment, the EOR/Gy using regression calibration of 3.224 (95% CI - 0.082, 30.615, p = 0.068) becoming ~ 50% larger, 4.708 (95% CI - 0.075, 85.143, p = 0.066) when using Monte Carlo maximum likelihood. Results were sensitive to omission of external components of dose. In summary, use of Monte Carlo maximum likelihood adjustment for dose error led to increases in trend risks, particularly for follicular morphology thyroid cancers, where risks increased by ~ 50%, and were borderline significant. The unexpected finding for follicular tumors needs to be replicated in other exposed groups.

Breast cancer risk in Ukrainian women exposed to Chornobyl fallout while pregnant or lactating: standardized incidence ratio analysis, 1998 to 2016.

The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the 2-month period of radioiodine fallout (April 26, 1986-June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. The SIR was not significant for women pregnant at the time of the accident (SIR = 0.75; 95% CI 0.44, 1.18) or for women lactating anytime within 2 months of the accident (SIR = 0.96; 95% CI 0.48, 1.68). However, there was a non-significantly elevated risk for women lactating at the time of accident (SIR = 1.30, 95% CI 0.40, 3.01). The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

Risk of thyroid cancer in Ukrainian cleanup workers following the Chornobyl accident.

Although much is known about the radiation-related risk of thyroid cancer in those exposed at young ages, less is known about the risk due to adult exposure, particularly in men. We aimed to examine the association between thyroid radiation dose received during adulthood and thyroid cancer risk in men. We conducted a nested case-control study (149 cases; 458 controls) of male, Ukrainian cleanup workers who first worked in the Chornobyl zone between ages 18 and 59 years, with cases identified through linkage with the National Cancer Registry of Ukraine from 1988 to 2012. Individual thyroid doses due to external and internal exposure during the cleanup mission and during residence in contaminated settlements were estimated (total dose mean 199 mGy; range 0.15 mGy to 9.0 Gy). The excess odds ratio per gray (EOR/Gy) for overall thyroid cancer was 0.40 (95% CI: - 0.05, 1.48; p-value = 0.118). Time since exposure was borderline significant (p-value = 0.061) in modifying this association so that less time since exposure was associated with a stronger EOR/Gy. An elevated, but nonsignificant association was observed for follicular thyroid cancer (EOR/Gy = 1.72; 95% CI: - 0.25, 13.69; p-value = 0.155) based on a small number of cases (n = 24). Our findings for radiation-related overall thyroid cancer risk are consistent with evidence of increased risks observed in most of the other studies of adult exposure, though the magnitude of the effect in this study is lower than in the previous case-control study of Chornobyl cleanup workers.

Association between exposure to radioactive iodine after the Chernobyl accident and thyroid volume in Belarus 10-15 years later.

BACKGROUND: While there is a robust literature on environmental exposure to iodine-131 (131I) in childhood and adolescence and the risk of thyroid cancer and benign nodules, little is known about its effects on thyroid volume. METHODS: To assess the effect of 131I dose to the thyroid on the volume of the thyroid gland, we examined the data from the baseline screening of the Belarusian-American Cohort Study of residents of Belarus who were exposed to the Chernobyl fallout at ages ≤18 years. Thyroid dose estimates were based on individual thyroid activity measurements made shortly after the accident and dosimetric data from questionnaires obtained 10-15 years later at baseline screening. During baseline screening, thyroid gland volume was assessed from thyroid ultrasound measurements. The association between radiation dose and thyroid volume was modeled using linear regression where radiation dose was expressed with power terms to address non-linearity. The model was adjusted for attained age, sex, and place of residence, and their modifying effects were examined. RESULTS: The analysis was based on 10,703 subjects. We found a statistically significant positive association between radiation dose and thyroid volume (P < 0.001). Heterogeneity of association was observed by attained age (P < 0.001) with statistically significant association remaining only in the subgroup of ≥18 years at screening (P < 0.001). For this group, increase in dose from 0.0005 to 0.15 Gy was associated with a 1.27 ml (95% CI: 0.46, 2.07) increase in thyroid volume. The estimated effect did not change with increasing doses above 0.15 Gy. CONCLUSIONS: This is the first study to examine the association between 131I dose to the thyroid gland and thyroid volume in a population of individuals exposed during childhood and systematically screened 10-15 years later. It provides evidence for a moderate statistically significant increase in thyroid volume among those who were ≥ 18 years at screening. Given that this effect was observed at very low doses and was restricted to a narrow dose range, further studies are necessary to better understand the effect.

Role of radiotherapy and chemotherapy in the risk of leukemia after childhood cancer: An international pooled analysis.

Childhood cancer survivors are at increased risk for second primary leukemia (SPL), but there is little consensus on the magnitude of some risk factors because of the small size of previous studies. We performed a pooled analysis of all published studies with detailed treatment data, including estimated active bone marrow (ABM) dose received during radiation therapy and doses of specific chemotherapeutic agents for childhood cancer diagnosed from 1930 through 2000, in order to more thoroughly investigate treatment-related risks of SPL. A total of 147 SPL cases (of which 69% were acute myeloid leukemia [AML]) were individually matched to 522 controls, all from four case-control studies including patients from six countries (France, United Kingdom, United States, Canada, Italy and Netherlands). Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression, and the excess OR per Gray (EOR/Gy) was also calculated. After accounting for the other therapies received, topoisomerase II inhibitor was associated with an increased SPL risk (highest tertile vs none: OR = 10.0, 95% CI: 3.7-27.3). Radiation dose to the ABM was also associated with increased SPL risk among those not receiving chemotherapy (EOR/Gy = 1.6, 95% CI: 0.1-14.3), but not among those who received chemotherapy (CT). SPL were most likely to occur in the first decade following cancer treatment. Results were similar when analyses were restricted to AML. The evidence of interaction between radiation and CT has implications for leukemogenic mechanism. The results for topoisomerase II inhibitors are particularly important given their increasing use to treat childhood cancer.

Spatially varying age-period-cohort analysis with application to US mortality, 2002-2016.

Many public health databases index disease counts by age groups and calendar periods within geographic regions (e.g., states, districts, or counties). Issues around relative risk estimation in small areas are well-studied; however, estimating trend parameters that vary across geographic regions has received less attention. Additionally, small counts (e.g., $<10$) in most publicly accessible databases are censored, further complicating age-period-cohort (APC) analysis in small areas. Here, we present a novel APC model with left-censoring and spatially varying intercept and trends, estimated with correlations among contiguous geographic regions. Like traditional models, our model captures population-scale trends, but it can also be used to characterize geographic disparities in relative risk and age-adjusted trends over time. To specify the joint distribution of our three spatially varying parameters, we adapt the generalized multivariate conditional autoregressive prior, previously used for multivariate disease mapping. Specified in this manner, region-specific parameters are correlated spatially, and also to one another. Estimation is performed using the No-U-Turn Hamiltonian Monte Carlo sampler in Stan. We conduct a simulation study to assess the performance of the proposed model relative to the standard model, and conclude with an application to US state-level opioid overdose mortality in men and women aged 15-64 years.

Cancer incidence and mortality in the USA Astronaut Corps, 1959-2017.

OBJECTIVES: Cancer incidence and mortality are important outcomes in the surveillance of long-term astronaut health. We compare cancer incidence rates, cancer-specific mortality rates, and cancer case-fatality ratios in US astronauts with those in the US general population. METHODS: We use standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs) to index the incidence and mortality of various cancers against rates in the US general population, from the US astronaut cohort inception in April 1959 through 31 December 2017. We compare the lethality of these cancers using the relative case-fatality ratio. RESULTS: Overall cancer incidence and mortality were slightly lower than expected from national rates with SIR 82 (95% CI 63 to 104) and SMR 72 (95% CI 44 to 111) with a modest 14% reduction in case-fatality ratio. Prostate cancer and melanoma skin cancer had significant increases in incidence, with SIR of 162 (95% CI 109 to 232) and 252 (95% CI 126 to 452), respectively, though only melanoma had a significant increase in mortality, with SMR 508 (95% CI 105 to 1485). Lung cancer had a significant deficit of both cases and deaths, while colon cancer had sizeable (but not significant) reductions in incidence and mortality. CONCLUSIONS: The increase in incidence of melanoma is consistent with that observed in aircraft pilots, suggesting this may be associated with ultraviolet radiation or lifestyle factors rather than any astronaut-specific exposure. Reductions in lung cancer incidence and mortality, and trends towards such reductions in colon cancer, may be explained in part by healthy lifestyle, as well as differential screening among astronauts.

Methodological improvements to meta-analysis of low dose rate studies and derivation of dose and dose-rate effectiveness factors.

Epidemiological studies of cancer rates associated with external and internal exposure to ionizing radiation have been subject to extensive reviews by various scientific bodies. It has long been assumed that radiation-induced cancer risks at low doses or low-dose rates are lower (per unit dose) than those at higher doses and dose rates. Based on a mixture of experimental and epidemiologic evidence the International Commission on Radiological Protection recommended the use of a dose and dose-rate effectiveness factor for purposes of radiological protection to reduce solid cancer risks obtained from moderate-to-high acute dose studies (e.g. those derived from the Japanese atomic bomb survivors) when applied to low dose or low-dose rate exposures. In the last few years there have been a number of attempts at assessing the effect of extrapolation of dose rate via direct comparison of observed risks in low-dose rate occupational studies and appropriately age/sex-adjusted analyses of the Japanese atomic bomb survivors. The usual approach is to consider the ratio of the excess relative risks in the two studies, a measure of the inverse of the dose rate effectiveness factor. This can be estimated using standard meta-analysis with inverse weighting of ratios of relative risks using variances derived via the delta method. In this paper certain potential statistical problems in the ratio of estimated excess relative risks for low-dose rate studies to the excess relative risk in the Japanese atomic bomb survivors are discussed, specifically the absence of a well-defined mean and the theoretically unbounded variance of this ratio. A slightly different method of meta-analysis for estimating uncertainties of these ratios is proposed, motivated by Fieller's theorem, which leads to slightly different central estimates and confidence intervals for the dose rate effectiveness factor. However, given the uncertainties in the data, the differences in mean values and uncertainties from the dose rate effectiveness factor estimated using delta-method-based meta-analysis are not substantial, generally less than 70%.

Estimation of radiation gonadal doses for the American-Ukrainian trio study of parental irradiation in Chornobyl cleanup workers and evacuees and germline mutations in their offspring.

Radiation doses of parents exposed from the Chornobyl accident as cleanup workers or evacuees were estimated in the National Cancer Institute-National Research Center for Radiation Medicine trio (i.e. father, mother, offspring) study aimed at investigating the radiation effects on germlinede novomutations in children as well as other outcomes. Paternal (testes) and maternal (ovaries) gonadal doses were calculated along with associated uncertainty distributions for the following exposure pathways: (a) external irradiation during the cleanup mission, (b) external irradiation during residence in Pripyat, and (c) external irradiation and (d) ingestion of radiocesium isotopes, such as134Cs and137Cs, during residence in settlements other than Pripyat. Gonadal doses were reconstructed for 298 trios for the periods from the time of the accident on 26 April 1986 to two time points before the child's date of birth (DOB): 51 (DOB-51) and 38 (DOB-38) weeks. The two doses, DOB-51 and DOB-38 were equal (within 1 mGy) in most instances, except for 35 fathers where the conception of the child occurred within 3 months of exposure or during exposure. The arithmetic mean of gonadal DOB-38 doses was 227 mGy (median: 11 mGy, range 0-4080 mGy) and 8.5 mGy (median: 1.0 mGy, range 0-550 mGy) for fathers and mothers, respectively. Gonadal doses varied considerably depending on the exposure pathway, the highest gonadal DOB-38 doses being received during the cleanup mission (mean doses of 376 and 34 mGy, median of 144 and 7.4 mGy for fathers and mothers, respectively), followed by exposure during residence in Pripyat (7.7 and 13 mGy for mean, 7.2 and 6.2 mGy for median doses) and during residence in other settlements (2.0 and 2.1 mGy for mean, 0.91 and 0.81 mGy for median doses). Monte Carlo simulations were used to estimate the parental gonadal doses and associated uncertainties. The geometric standard deviations (GSDs) in the individual parental stochastic doses due to external irradiation during the cleanup mission varied from 1.2 to 4.7 (mean of 1.8), while during residence in Pripyat they varied from 1.4 to 2.8 (mean of 1.8), while the mean GSD in doses received during residence in settlements other than Pripyat was 1.3 and 1.4 for external irradiation and ingestion of radiocesium isotopes, respectively.

Field Study of the Possible Effect of Parental Irradiation on the Germline of Children Born to Cleanup Workers and Evacuees of the Chornobyl Nuclear Accident.

Although transgenerational effects of exposure to ionizing radiation have long been a concern, human research to date has been confined to studies of disease phenotypes in groups exposed to high doses and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the Ukrainian National Research Center for Radiation Medicine, the US National Cancer Institute, in 2014-2018, initiated a genomic alterations study among children born in selected regions of Ukraine to cleanup workers and/or evacuees exposed to low-dose-rate radiation after the 1986 Chornobyl (Chernobyl) nuclear accident. To investigate whether parental radiation exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring constellations to study de novo mutations, minisatellite mutations, copy-number changes, structural variants, genomic insertions and deletions, methylation profiles, and telomere length. Genomic alterations are being examined in relation to parental gonadal dose, reconstructed using questionnaire and measurement data. Subjects are being recruited in exposure categories that will allow examination of parental origin, duration, and timing of exposure in relation to conception. Here we describe the study methodology and recruitment results and provide descriptive information on the first 150 families (mother-father-child(ren)) enrolled.

Occupational radiation exposure and excess additive risk of cataract incidence in a cohort of US radiologic technologists.

OBJECTIVES: Previous analyses of cataract in radiation-exposed populations have assessed relative risk; radiogenic excess additive risk (EAR), arguably of more public health importance, has not been estimated. Previous analysis of a large prospective cohort of US radiologic technologists (USRT) quantified excess relative risk of cataract in relation to occupational radiation dose. We aim to assess EARs of cataract. METHODS: We estimated EARs of cataract/cataract surgery in the USRT cohort using generalised additive models in relation to occupational radiation exposure, and assessed risk modification by a priori-selected cataract risk factors (diabetes, body mass index, smoking, race, sex, birth-year, ultraviolet B (UVB) radiation exposure). RESULTS: There were 11 345 cataract diagnoses and 5440 of cataract surgery during 832 462 and 888 402 person-years of follow-up, respectively. Cumulative occupational radiation exposure was associated with self-reported cataract, but not with cataract surgery, with EAR/104 person-year Gy=94 (95% CI: 47 to 143, p<0.001) and EAR/104 person-year Gy=13 (95% CI: <0 to 57, p=0.551), respectively. There was marked (p<0.001) variation of EAR by age and by diabetes status, with risk higher among persons ≥75 years and diabetics. There were indications of elevated risk among those with higher UVB radiation (p=0.045), whites (p=0.056) and among those with higher levels of cigarette smoking (p=0.062). Elevated additive risk was observed for estimated occupational radiation eye-lens doses <100 mGy (p=0.004) with no dose-response curvature (p=0.903). CONCLUSIONS: The elevated additive risks associated with low-dose radiation, if confirmed elsewhere, have important public health and clinical implications for radiation workers as well as regulatory measures.

Occupational radiation and haematopoietic malignancy mortality in the retrospective cohort study of US radiologic technologists, 1983-2012.

OBJECTIVES: To evaluate cumulative occupational radiation dose response and haematopoietic malignancy mortality risks in the US radiologic technologist cohort. METHODS: Among 110 297 radiologic technologists (83 655 women, 26 642 men) who completed a baseline questionnaire sometime during 1983-1998, a retrospective cohort study was undertaken to assess cumulative, low-to-moderate occupational radiation dose and haematopoietic malignancy mortality risks during 1983-2012. Cumulative bone marrow dose (mean 8.5 mGy, range 0-430 mGy) was estimated based on 921 134 badge monitoring measurements during 1960-1997, work histories and historical data; 35.4% of estimated doses were based on badge measurements. Poisson regression was used to estimate excess relative risk of haematopoietic cancers per 100 milligray (ERR/100 mGy) bone-marrow absorbed dose, adjusting for attained age, sex and birth year. RESULTS: Deaths from baseline questionnaire completion through 2012 included 133 myeloid neoplasms, 381 lymphoid neoplasms and 155 leukaemias excluding chronic lymphocytic leukaemia (CLL). Based on a linear dose-response, no significant ERR/100 mGy occurred for acute myeloid leukaemia (ERR=0.0002, 95% CI <-0.02 to 0.24, p-trend>0.5, 85 cases) or leukaemia excluding CLL (ERR=0.05, 95% CI <-0.09 to 0.24, p-trend=0.21, 155 cases). No significant dose-response trends were observed overall for CLL (ERR<-0.023, 95% CI <-0.025 to 0.18, p-trend=0.45, 32 cases), non-Hodgkin lymphoma (ERR=0.03, 95% CI <-0.2 to 0.18, p-trend=0.4, 201 cases) or multiple myeloma (ERR=0.003, 95% CI -0.02 to 0.16, p-trend>0.5, 112 cases). Findings did not differ significantly by demographic factors, smoking or specific radiological procedures performed. CONCLUSION: After follow-up averaging 22 years, there was little evidence of a relationship between occupational radiation exposure and myeloid or lymphoid haematopoietic neoplasms.

Meta-analysis of published excess relative risk estimates.

A meta-analytic summary effect estimate often is calculated as an inverse-variance-weighted average of study-specific estimates of association. The variances of published estimates of association often are derived from their associated confidence intervals under assumptions typical of Wald-type statistics, such as normality of the parameter. However, in some research areas, such as radiation epidemiology, epidemiological results typically are obtained by fitting linear relative risk models, and associated likelihood-based confidence intervals are often asymmetric; consequently, reasonable estimates of variances associated with study-specific estimates of association may be difficult to infer from the standard approach based on the assumption of a Wald-type interval. Here, a novel method is described for meta-analysis of published results from linear relative risk models that uses a parametric transformation of published results to improve on the normal approximation used to assess confidence intervals. Using simulations, it is illustrated that the meta-analytic summary obtained using the proposed approach yields less biased summary estimates, with better confidence interval coverage, than the summary obtained using the more classical approach to meta-analysis. The proposed approach is illustrated using a previously published example of meta-analysis of epidemiological findings regarding circulatory disease following exposure to low-level ionizing radiation.