Benzene exposure and risk of benzene poisoning in Chinese workers.

OBJECTIVES: Benzene is a known haematoxin and leukemogen that can cause benzene poisoning (BP), that is, a persistent reduction in white cell counts that is strongly associated with increased risk of lymphohaematopoietic malignancies. Data are needed on the exposure-response, particularly at low doses and susceptible populations for clinical and regulatory purposes. METHODS: In a case-cohort study among 110 631 Chinese workers first employed 1949-1987 and followed up during 1972-1999, we evaluated BP risk according to benzene exposure level and investigated risk modification by subject (sex, attained age) and exposure-related factors (latency, exposure windows, age at first benzene exposure, coexposure to toluene) using excess relative risk and excess absolute risk models. RESULTS: There were 538 BP cases and 909 benzene-exposed referents. The exposure metric with best model fit was cumulative benzene exposure during a 5-year risk window, followed by a 9-month lag period before BP diagnosis. Estimated excess absolute risk of BP at age 60 increased from 0.5% for subjects in the lowest benzene exposure category (>0 to 10 ppm-years) to 5.0% for those in the highest category (>100 ppm-years) compared with unexposed subjects. Increased risks were apparent at low cumulative exposure levels and for workers who were first exposed at <30 years of age. CONCLUSIONS: Our data show a clear association between benzene exposure and BP, beginning at low cumulative benzene exposure levels with no threshold, and with higher risks for workers exposed at younger ages. These findings are important because BP has been linked to a strongly increased development of lymphohaematopoietic malignancies.

Lung cancer mortality associated with protracted low-dose occupational radiation exposures and smoking behaviors in U.S. radiologic technologists, 1983-2012.

In the Japanese atomic bomb survivors, risk of lung cancer has been shown to increase with greater acute exposure to ionizing radiation. Although similar findings have been observed in populations exposed to low-dose, protracted radiation, such studies lack information on cigarette smoking history, a potential confounder. In a cohort of 106 068 U.S. radiologic technologists, we examined the association between estimated cumulative lung absorbed dose from occupational radiation exposure and lung cancer mortality. Poisson regression models, adjusted for attained age, sex, birth cohort, pack-years smoked and years since quitting smoking, were used to calculate linear excess relative risks (ERR) per 100 mGy, using time-dependent cumulative lung absorbed dose, lagged 10 years. Mean cumulative absorbed dose to the lung was 25 mGy (range: 0-810 mGy). During the 1983 to 2012 follow-up, 1090 participants died from lung cancer. Greater occupational radiation lung dose was not associated with lung cancer mortality overall (ERR per 100 mGy: -0.02, 95% CI: <0-0.13). However, significant dose-response relationships were observed for some subgroups, which might be false-positive results given the number of statistical tests performed. As observed in other studies of radiation and smoking, the interaction between radiation and smoking appeared to be sub-multiplicative with an ERR per 100 mGy of 0.41 (95% CI: 0.01-1.15) for those who smoked <20 pack-years and -0.03 (95% CI: <0-0.15) for those who smoked ≥20 pack-years. Our study provides some evidence that greater protracted radiation exposure in the low-dose range is positively associated with lung cancer mortality.

Benzene exposure-response and risk of lymphoid neoplasms in Chinese workers: A multicenter case-cohort study.

BACKGROUND: While international agreement supports a causal relationship of benzene exposure with acute myeloid leukemia, there is debate about benzene and lymphoid neoplasm risks. METHODS: In a case-cohort study with follow-up of 110 631 Chinese workers during 1972-1999, we evaluated benzene exposure-response for non-Hodgkin lymphoma (NHL), lymphoid leukemias (LL), acute lymphocytic leukemia (ALL), and total lymphoid neoplasms (LN). We estimated benzene exposures using state-of-the-art hierarchical modeling of occupational factors calibrated with historical routine measurements and evaluated cumulative exposure-response using Cox regression. RESULTS: NHL and other specified LN were increased in exposed vs unexposed workers. However, there was no evidence of exposure-response for NHL or other specified LN. Based on a linear exposure-response, relative risks at 100 parts per million-years (RR at 100 ppm-years) for cumulative benzene exposure using a 2-year lag (exposure at least 2 years before the time at risk) were 1.05 for NHL (95 percent confidence interval (CI) = 0.97, 1.27; 32 cases), 1.11 for LL (95% CI < 0, 1.66; 12 cases), 1.21 for ALL (95% CI < 0, 3.53; 10 cases), and 1.02 for total LN (95% CI < 0, 1.16; 49 cases). No statistically significant exposure-response trends were apparent for these LN for 2 to <10-year or ≥10-year lags. NHL risks were not significantly modified by sex, age, or year at first exposure, attained age, or time since exposure. CONCLUSION: Given the study strengths and limitations, we found little evidence of exposure-response for benzene and NHL, LL, ALL, or total LN, although NHL and other specified LN were increased in exposed vs unexposed individuals.

Cataract risk in US radiologic technologists assisting with fluoroscopically guided interventional procedures: a retrospective cohort study.

OBJECTIVES: To assess radiation exposure-related work history and risk of cataract and cataract surgery among radiologic technologists assisting with fluoroscopically guided interventional procedures (FGIP). METHODS: This retrospective study included 35 751 radiologic technologists who reported being cataract-free at baseline (1994-1998) and completed a follow-up questionnaire (2013-2014). Frequencies of assisting with 21 types of FGIP and use of radiation protection equipment during five time periods (before 1970, 1970-1979, 1980-1989, 1990-1999, 2000-2009) were derived from an additional self-administered questionnaire in 2013-2014. Multivariable-adjusted relative risks (RRs) for self-reported cataract diagnosis and cataract surgery were estimated according to FGIP work history. RESULTS: During follow-up, 9372 technologists reported incident physician-diagnosed cataract; 4278 of incident cases reported undergoing cataract surgery. Technologists who ever assisted with FGIP had increased risk for cataract compared with those who never assisted with FGIP (RR: 1.18, 95% CI 1.11 to 1.25). Risk increased with increasing cumulative number of FGIP; the RR for technologists who assisted with >5000 FGIP compared with those who never assisted was 1.38 (95% CI 1.24 to 1.53; p trend <0.001). These associations were more pronounced for FGIP when technologists were located ≤3 feet (≤0.9 m) from the patient compared with >3 feet (>0.9 m) (RRs for >5000 at ≤3 feet vs never FGIP were 1.48, 95% CI 1.27 to 1.74 and 1.15, 95% CI 0.98 to 1.35, respectively; pdifference=0.04). Similar risks, although not statistically significant, were observed for cataract surgery. CONCLUSION: Technologists who reported assisting with FGIP, particularly high-volume FGIP within 3 feet of the patient, had increased risk of incident cataract. Additional investigation should evaluate estimated dose response and medically validated cataract type.

Mortality in U.S. Physicians Likely to Perform Fluoroscopy-guided Interventional Procedures Compared with Psychiatrists, 1979 to 2008.

Purpose To compare total and cause-specific mortality rates between physicians likely to have performed fluoroscopy-guided interventional (FGI) procedures (referred to as FGI MDs) and psychiatrists to determine if any differences are consistent with known radiation risks. Materials and Methods Mortality risks were compared in nationwide cohorts of 45 634 FGI MDs and 64 401 psychiatrists. Cause of death was ascertained from the National Death Index. Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for FGI MDs versus psychiatrists, with adjustment (via stratification) for year of birth and attained age. Results During follow-up (1979-2008), 3506 FGI MDs (86 women) and 7814 psychiatrists (507 women) died. Compared with psychiatrists, FGI MDs had lower total (men: RR, 0.80 [95% CI: 0.77, 0.83]; women: RR, 0.80 [95% CI: 0.63, 1.00]) and cancer (men: RR, 0.92 [95% CI: 0.85, 0.99]; women: RR, 0.83 [95% CI: 0.58, 1.18]) mortality. Mortality because of specific types of cancer, total and specific types of circulatory diseases, and other causes were not elevated in FGI MDs compared with psychiatrists. On the basis of small numbers, leukemia mortality was elevated among male FGI MDs who graduated from medical school before 1940 (RR, 3.86; 95% CI: 1.21, 12.3). Conclusion Overall, total deaths and deaths from specific causes were not elevated in FGI MDs compared with psychiatrists. These findings require confirmation in large cohort studies with individual doses, detailed work histories, and extended follow-up of the subjects to substantially older median age at exit. © RSNA, 2017 Online supplemental material is available for this article.

Increased pancreatic cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. METHODS: Among 23 982 5-year TC survivors diagnosed during 1947-1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). RESULTS: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0-7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend<0.001), with an OR of 4.6 (95% CI 1.9-11.0) for ⩾25 Gy vs <25 Gy. Radiation-related risks remained elevated ⩾20 years after TC diagnosis (P=0.020). The risk increased with the number of cycles of chemotherapy with alkylating or platinum agents (P=0.057), although only one case was exposed to platinum. CONCLUSIONS: A dose-response relationship exists between radiation to the pancreas and subsequent cancer risk, and persists for over 20 years. These excesses, although small, should be considered when radiotherapy with exposure to the pancreas is considered for newly diagnosed patients. Additional data are needed on the role of chemotherapy.

Long-term Mortality in 43 763 U.S. Radiologists Compared with 64 990 U.S. Psychiatrists.

Purpose To compare mortality rates from all causes, specific causes, total cancers, and specific cancers to assess whether differences between radiologists and psychiatrists are consistent with known risks of radiation exposure and the changes in radiation exposure to radiologists over time. Materials and Methods The authors used the American Medical Association Physician Masterfile to construct a cohort of 43 763 radiologists (20% women) and 64 990 psychiatrists (27% women) (comparison group) who graduated from medical school in 1916-2006. Vital status was obtained from record linkages with the Social Security Administration and commercial databases, and cause of death was obtained from the National Death Index. Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for all causes and specific causes of death. Results During the follow-up period (1979-2008), 4260 male radiologists and 7815 male psychiatrists died. The male radiologists had lower death rates (all causes) compared with the psychiatrists (RR = 0.94; 95% CI: 0.90, 0.97), similar cancer death rates overall (RR = 1.00; 95% CI: 0.93, 1.07), but increased acute myeloid leukemia and/or myelodysplastic syndrome death rates (RR = 1.62; 95% CI: 1.05, 2.50); these rates were driven by those who graduated before 1940 (RR = 4.68; 95% CI: 0.91, 24.18). In these earliest workers (before 1940) there were also increased death rates from melanoma (RR = 8.75; 95% CI: 1.89, 40.53), non-Hodgkin lymphoma (NHL) (RR = 2.69; 95% CI: 1.33, 5.45), and cerebrovascular disease (RR = 1.49; 95% CI: 1.11, 2.01). The 208 deaths in female radiologists precluded detailed investigation, and the number of female radiologists who graduated before 1940 was very small (n = 47). Conclusion The excess risk of acute myeloid leukemia and/or myelodysplastic syndrome mortality in radiologists who graduated before 1940 is likely due to occupational radiation exposure. The melanoma, NHL, and cerebrovascular disease mortality risks are possibly due to radiation. The authors found no evidence of excess mortality in radiologists who graduated more recently, possibly because of increased radiation protection and/or lifestyle changes. © RSNA, 2016 Online supplemental material is available for this article.

A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers.

Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = ∞, 95% CI = 3.4, ∞). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders.

Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008.

Therapy-related acute myeloid leukemia (tAML) is a rare but highly fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing tAML risks over time are sparse. Among 426068 adults initially treated with chemotherapy for first primary malignancy (9 US population-based cancer registries, 1975-2008), we identified 801 tAML cases, 4.70 times more than expected in the general population (P < .001). Over time, tAML risks increased after chemotherapy for non-Hodgkin lymphoma (n = 158; Poisson regression Ptrend < .001), declined for ovarian cancer (n = 72; Ptrend < .001), myeloma (n = 62; Ptrend = .02), and possibly lung cancer (n = 65; Ptrend = .18), and were significantly heterogeneous for breast cancer (n = 223; Phomogeneity = .005) and Hodgkin lymphoma (n = 58; Phomogeneity = .007). tAML risks varied significantly by age at first cancer and latency and were nonsignificantly heightened with radiotherapy for lung, breast, and ovarian cancers. We identified newly emerging elevated tAML risks in patients treated with chemotherapy since 2000 for esophageal, cervical, prostate, and possibly anal cancers; and since the 1990s for bone/joint and endometrial cancers. Using long-term, population-based data, we observed significant variation in tAML risk with time, consistent with changing treatment practices and differential leukemogenicity of specific therapies. tAML risks should be weighed against the benefits of chemotherapy, particularly for new agents and new indications for standard agents.

Variation in the risk of radiation-related contralateral breast cancer by histology and estrogen receptor expression in SEER.

Radiation exposure, particularly at a young age, is an established cause of breast cancer. It is not known whether radiation-related breast cancer risk varies by molecular subtype. We characterized the relative risk (RR) of contralateral breast cancer (CBC) related to radiotherapy by histology and estrogen receptor (ER) status of the CBC in five-year survivors in the Surveillance, Epidemiology, and End Results database using Poisson regression models adjusted for attained age and calendar year, age at and year of treatment, ER status of the first breast cancer, and disease stage. 205,316 female breast cancer survivors were followed for an average of 10 years from 1973 until 2007, during which time 6924 women developed a subsequent primary invasive breast cancer in the contralateral breast. The overall RR (and 95% confidence interval (CI)) of radiotherapy-related CBC was 1.11 (1.05-1.16). There was no heterogeneity in risk according to histology of the CBC (P > 0.50) for all ages or young age at exposure, but case numbers were small for subtypes other than ductal and lobular carcinomas. Information on ER status was available from 1990 onwards for 3546 CBC cases, of which 2597 (73%) were ER+ and 949 (27%) were ER-. The RRs were 1.10 (1.02-1.19) for ER+ CBC and 1.19 (1.04-1.35) for ER- CBC (P (difference) = 0.33). Among women treated age <35 years, radiation-related risk of CBC was non-significantly elevated for ER- (RR = 1.38, 95% CI: 0.96-1.97) but not for ER+ tumors (RR = 0.80, 95% CI: 0.47-1.35) (P (difference) = 0.09). We did not find clear evidence that radiation-related risk varies by histology or ER status, but our findings, which were the first to examine this question, were suggestive of possible differences by ER status that may merit further investigation.

RadRAT: a radiation risk assessment tool for lifetime cancer risk projection.

Risk projection methods allow for timely assessment of the potential magnitude of radiation-related cancer risks following low-dose radiation exposures. The estimation of such risks directly through observational studies would generally require infeasibly large studies and long-term follow-up to achieve reasonable statistical power. We developed an online radiation risk assessment tool (RadRAT) which can be used to estimate the lifetime risk of radiation-related cancer with uncertainty intervals following a user-specified exposure history (https://irep.nci.nih.gov/radrat). The uncertainty intervals constitute a key component of the program because of the various assumptions that are involved in such calculations. The risk models used in RadRAT are broadly based on those developed by the BEIR VII committee for estimating lifetime risk following low-dose radiation exposure of the US population for eleven site-specific cancers. We developed new risk models for seven additional cancer sites, oral, oesophagus, gallbladder, pancreas, rectum, kidney and brain/central nervous system (CNS) cancers, using data from Japanese atomic bomb survivors. The lifetime risk estimates are slightly higher for RadRAT than for BEIR VII across all exposure ages mostly because the weighting of the excess relative risk and excess absolute risk models was conducted on an arithmetic rather than a logarithmic scale. The calculator can be used to estimate lifetime cancer risk from both uniform and non-uniform doses that are acute or chronic. It is most appropriate for low-LET radiation doses < 1 Gy, and for individuals with life-expectancy and cancer rates similar to the general population in the US.

Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries.

BACKGROUND: Improvements in cancer survival have made the long-term risks from treatments more important, including the risk of developing a second cancer after radiotherapy. We aimed to estimate the proportion of second cancers attributable to radiotherapy in adults with data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. METHODS: We used nine of the SEER registries to systematically analyse 15 cancer sites that are routinely treated with radiotherapy (oral and pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye and orbit, brain and CNS, and thyroid). The cohort we studied was composed of patients aged 20 years or older who were diagnosed with a first primary invasive solid cancer reported in the SEER registries between Jan 1, 1973, and Dec 31, 2002. Relative risks (RRs) for second cancer in patients treated with radiotherapy versus patients not treated with radiotherapy were estimated with Poisson regression adjusted for age, stage, and other potential confounders. FINDINGS: 647,672 cancer patients who were 5-year survivors were followed up for a mean 12 years (SD 4.5, range 5-34); 60,271 (9%) developed a second solid cancer. For each of the first cancer sites the RR of developing a second cancer associated with radiotherapy exceeded 1, and varied from 1.08 (95% CI 0.79-1.46) after cancers of the eye and orbit to 1.43 (1.13-1.84) after cancer of the testes. In general, the RR was highest for organs that typically received greater than 5 Gy, decreased with increasing age at diagnosis, and increased with time since diagnosis. We estimated a total of 3266 (2862-3670) excess second solid cancers that could be related to radiotherapy, that is 8% (7-9) of the total in all radiotherapy patients (≥1 year survivors) and five excess cancers per 1000 patients treated with radiotherapy by 15 years after diagnosis. INTERPRETATION: A relatively small proportion of second cancers are related to radiotherapy in adults, suggesting that most are due to other factors, such as lifestyle or genetics. FUNDING: US National Cancer Institute.

Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation.

We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial.

Solid cancers after allogeneic hematopoietic cell transplantation.

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.

Issues in Interpreting Epidemiologic Studies of Populations Exposed to Low-Dose, High-Energy Photon Radiation.

This article addresses issues relevant to interpreting findings from 26 epidemiologic studies of persons exposed to low-dose radiation. We review the extensive data from both epidemiologic studies of persons exposed at moderate or high doses and from radiobiology that together have firmly established radiation as carcinogenic. We then discuss the use of the linear relative risk model that has been used to describe data from both low- and moderate- or high-dose studies. We consider the effects of dose measurement errors; these can reduce statistical power and lead to underestimation of risks but are very unlikely to bring about a spurious dose response. We estimate statistical power for the low-dose studies under the assumption that true risks of radiation-related cancers are those expected from studies of Japanese atomic bomb survivors. Finally, we discuss the interpretation of confidence intervals and statistical tests and the applicability of the Bradford Hill principles for a causal relationship.

Dose-volume effects of breast cancer radiation therapy on the risk of second oesophageal cancer.

PURPOSE: To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer. MATERIALS AND METHODS: In a case-control study nested within a cohort of 289,748 ≥5-year survivors of female breast cancer treated in 1943-2003 in five countries, doses to the second primary cancer (DSPC) and individual dose-volume histograms (DVH) to the entire oesophagus were reconstructed for 252 oesophageal cancer cases and 488 matched controls (median follow-up time: 13, range: 5-37 years). Using conditional logistic regression, we estimated excess odds ratios (EOR) of oesophageal cancer associated with DVH metrics. We also investigated whether DVH metrics confounded or modified DSPC-related -risk estimates. RESULTS: Among the DVH metrics evaluated, median dose (Dmedian) to the entire oesophagus had the best statistical performance for estimating risk of all histological types combined (EOR/Gy = 0.071, 95% confidence interval [CI]: 0.018 to 0.206). For squamous cell carcinoma, the most common subtype, the EOR/Gy for Dmedian increased by 31% (95% CI: 3% to 205%) for each increment of 10% of V30 (p = 0.02). Adjusting for DVH metrics did not materially change the EOR/Gy for DSPC, but there was a borderline significant positive interaction between DSPC and V30 (p = 0.07). CONCLUSION: This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for Dmedian with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to Dmedian and V30 could potentially further reduce the risk of oesophageal cancer.

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Summary Bias Assessment and Meta-Analysis.

BACKGROUND: Ionizing radiation is an established carcinogen, but risks from low-dose exposures are controversial. Since the Biological Effects of Ionizing Radiation VII review of the epidemiological data in 2006, many subsequent publications have reported excess cancer risks from low-dose exposures. Our aim was to systematically review these studies to assess the magnitude of the risk and whether the positive findings could be explained by biases. METHODS: Eligible studies had mean cumulative doses of less than 100 mGy, individualized dose estimates, risk estimates, and confidence intervals (CI) for the dose-response and were published in 2006-2017. We summarized the evidence for bias (dose error, confounding, outcome ascertainment) and its likely direction for each study. We tested whether the median excess relative risk (ERR) per unit dose equals zero and assessed the impact of excluding positive studies with potential bias away from the null. We performed a meta-analysis to quantify the ERR and assess consistency across studies for all solid cancers and leukemia. RESULTS: Of the 26 eligible studies, 8 concerned environmental, 4 medical, and 14 occupational exposure. For solid cancers, 16 of 22 studies reported positive ERRs per unit dose, and we rejected the hypothesis that the median ERR equals zero (P = .03). After exclusion of 4 positive studies with potential positive bias, 12 of 18 studies reported positive ERRs per unit dose (P = .12). For leukemia, 17 of 20 studies were positive, and we rejected the hypothesis that the median ERR per unit dose equals zero (P = .001), also after exclusion of 5 positive studies with potential positive bias (P = .02). For adulthood exposure, the meta-ERR at 100 mGy was 0.029 (95% CI = 0.011 to 0.047) for solid cancers and 0.16 (95% CI = 0.07 to 0.25) for leukemia. For childhood exposure, the meta-ERR at 100 mGy for leukemia was 2.84 (95% CI = 0.37 to 5.32); there were only two eligible studies of all solid cancers. CONCLUSIONS: Our systematic assessments in this monograph showed that these new epidemiological studies are characterized by several limitations, but only a few positive studies were potentially biased away from the null. After exclusion of these studies, the majority of studies still reported positive risk estimates. We therefore conclude that these new epidemiological studies directly support excess cancer risks from low-dose ionizing radiation. Furthermore, the magnitude of the cancer risks from these low-dose radiation exposures was statistically compatible with the radiation dose-related cancer risks of the atomic bomb survivors.

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Rationale and Framework for the Monograph and Overview of Eligible Studies.

Whether low-dose ionizing radiation can cause cancer is a critical and long-debated question in radiation protection. Since the Biological Effects of Ionizing Radiation report by the National Academies in 2006, new publications from large, well-powered epidemiological studies of low doses have reported positive dose-response relationships. It has been suggested, however, that biases could explain these findings. We conducted a systematic review of epidemiological studies with mean doses less than 100 mGy published 2006-2017. We required individualized doses and dose-response estimates with confidence intervals. We identified 26 eligible studies (eight environmental, four medical, and 14 occupational), including 91 000 solid cancers and 13 000 leukemias. Mean doses ranged from 0.1 to 82 mGy. The excess relative risk at 100 mGy was positive for 16 of 22 solid cancer studies and 17 of 20 leukemia studies. The aim of this monograph was to systematically review the potential biases in these studies (including dose uncertainty, confounding, and outcome misclassification) and to assess whether the subset of minimally biased studies provides evidence for cancer risks from low-dose radiation. Here, we describe the framework for the systematic bias review and provide an overview of the eligible studies.

Ionising radiation and cancer risks: what have we learned from epidemiology?

PURPOSE: Epidemiologic studies of persons exposed to ionising radiation offer a wealth of information on cancer risks in humans. The Life Span Study cohort of Japanese A-bomb survivors, a large cohort that includes all ages and both sexes with a wide range of well-characterised doses, is the primary resource for estimating carcinogenic risks from low linear energy transfer external exposure. Extensive data on persons exposed for therapeutic or diagnostic medical reasons offer the opportunity to study fractionated exposure, risks at high therapeutic doses, and risks of site-specific cancers in non-Japanese populations. Studies of persons exposed for occupational and environmental reasons allow a direct evaluation of exposure at low doses and dose rates, and also provide information on different types of radiation such as radon and iodine-131. This article summarises the findings from these studies with emphasis on studies with well-characterised doses. CONCLUSIONS: Epidemiologic studies provide the necessary data for quantifying cancer risks as a function of dose and for setting radiation protection standards. Leukaemia and most solid cancers have been linked with radiation. Most solid cancer data are reasonably well described by linear-dose response functions although there may be a downturn in risks at very high doses. Persons exposed early in life have especially high relative risks for many cancers, and radiation-related risk of solid cancers appears to persist throughout life.