Risk of lung adenocarcinoma from smoking and radiation arises in distinct molecular pathways.

KRAS mutations of lung adenocarcinoma (LADC) are associated with smoking but little is known on other exposure-oncogene associations. Hypothesizing that different inciting agents may cause different driver mutations, we aimed to identify distinct molecular pathways to LADC, applying two entirely different approaches. First, we examined clinicopathologic features and genomic signatures of environmental exposures in the large LADC Campbell data set. Second, we designed a molecular mechanistic risk model of LADC (M3LADC) that links environmental exposure to incidence risk by mathematically emulating the disease process. This model was applied to incidence data of Japanese atom-bomb survivors which contains information on radiation and smoking exposure. Grouping the clinical data by driver mutations revealed two main distinct molecular pathways to LADC: one unique to transmembrane receptor-mutant patients that displayed robust signatures of radiation exposure and one shared between submembrane transducer-mutant patients and patients with no evident driver mutation that carried the signature of smoking. Consistently, best fit of the incidence data was achieved with a M3LADC with two pathways: in one LADC risk increased with radiation exposure and in the other with cigarette consumption. We conclude there are two main molecular pathways to LADC associated with different environmental exposures. Future molecular measurements in lung cancer tissue of atom-bomb survivors may allow to further test quantitatively the M3LADC-predicted link of radiation to transmembrane receptor mutations. Moreover, the developed molecular mechanistic model showed that for low doses, as relevant e.g. for medical imaging, smokers have the same radiation risk compared with never smokers.

Selection of reference groups in the Life Span Study of atomic bomb survivors.

In cohort studies, unbiased estimation of exposure-outcome associations requires selection of an appropriate reference group of unexposed individuals. We illustrate strategies for analyzing cohort data with multiple potential reference groups. We analyzed the association between radiation exposure and incidence of first primary solid cancer among 105,444 participants of the Life Span Study (Hiroshima and Nagasaki, Japan, 1958-2009). Potential reference groups included zero-dose survivors at different ground distances from the hypocenter (internal) and city residents who were not in either city at the time of the bombings (external). DS02R1 weighted absorbed colon doses were estimated by the DS02 dosimetry system. Piecewise constant hazard models estimated excess relative risks of first primary solid cancer. We focused on sex-averaged excess relative risks and the shape of the dose-response curve. A model with internal standardization provided a sex-averaged excess relative risk of 0.510, 95% confidence interval: (0.414, 0.612) per gray of weighted absorbed colon dose, as well as strong evidence of a curvilinear dose response among males (P = 0.008). Selection of not-in-city residents as the reference group resulted in a larger excess relative risk of 0.560, 95% confidence interval: (0.467, 0.657) per gray, and reduced evidence of a curvilinear dose response among males (P = 0.042). These differences were particularly apparent at weighted absorbed colon doses < 1 gray. In cohort studies, selection of an appropriate reference group requires understanding of the nature of unmeasured confounding to which the results could be sensitive.

Relationship between anthropometric factors, radiation exposure, and colon cancer incidence in the Life Span Study cohort of atomic bomb survivors.

PURPOSE: We examined colon cancer risk in atomic bomb survivors to investigate whether excess body weight after the bombings alters sensitivity to radiation effects. METHODS: Of the 56,064 Japanese atomic bomb survivors with follow-up through 2002 with self-reported anthropometric data obtained from periodic mail surveys, 1,142 were diagnosed with colon cancer. We evaluated the influence of body mass index (BMI) and height on radiation-associated colon cancer risk using Poisson regression. RESULTS: We observed a similar linear dose-response relationship for the 56,064 subjects included in our analysis and the entire cohort of Japanese atomic bomb survivors [excess relative risk (ERR) per Gray (Gy) = 0.53, 95 % confidence interval (CI) 0.25-0.86]. Elevation in earliest reported BMI, BMI reported closest to colon cancer diagnosis, and time-varying BMI were associated with an elevated risk of colon cancer [relative risk (RR) per 5 kg/m(2) increase in BMI = 1.14, 95 % CI 1.03-1.26; RR = 1.16, 95 % CI 1.05-1.27; and RR = 1.15, 95 % CI 1.04-1.27, respectively]. Height was not significantly related to colon cancer risk. Inclusion of anthropometric variables in models had little impact on radiation risk estimates, and there was no evidence that sensitivity to the effect of radiation on colon cancer risk depended on BMI. CONCLUSIONS: Radiation exposure and BMI are both risk factors for colon cancer. BMI at various times after exposure to the atomic bombings does not significantly influence the relationship between radiation dose and colon cancer risk, suggesting that BMI and radiation impact colon cancer risk independently of each other.

A report from the 2013 international workshop: radiation and cardiovascular disease, Hiroshima, Japan.

Two longitudinal cohort studies of Japanese atomic bomb survivors-the life span study (LSS) and the adult health study (AHS)-from the Radiation Effects Research Foundation (RERF) indicate that total body irradiation doses less than 1 Gy are associated with an increased risk of cardiovascular disease (CVD), but several questions about this association remain.In particular, the diversity of heart disease subtypes and the high prevalence of other risk factors complicate the estimates of radiation effects. Subtype-specific analyses with more reliable diagnostic criteria and measurement techniques are needed. The radiation effects on CVD risk are probably tissue-reaction (deterministic) effects, so the dose-response relationships for various subtypes of CVD may be nonlinear and therefore should be explored with several types of statistical models.Subpopulations at high risk need to be identified because effects at lower radiation doses may occur primarily in these susceptible subpopulations. Whether other CVD risk factors modify radiation effects also needs to be determined. Finally, background rates for various subtypes of CVD have historically differed substantially between Japanese and Western populations, so the generalisability to other populations needs to be examined.Cardiovascular disease mechanisms and manifestations may differ between high-dose local irradiation and low-dose total body irradiation (TBI)-microvascular damage and altered metabolism from low-dose TBI, but coronary artery atherosclerosis and thrombotic myocardial infarcts at high localised doses. For TBI, doses to organs other than the heart may be important in pathogenesis of CVD, so data on renal and liver disorders, plaque instability, microvascular damage, metabolic disorders, hypertension and various CVD biomarkers and risk factors are needed. Epidemiological, clinical and experimental studies at doses of less than 1 Gy are necessary to clarify the effects of radiation on CVD risk.

Radiation and cancer risk in atomic-bomb survivors.

With the aim of accurately assessing the effects of radiation exposure in the Japanese atomic-bomb survivors, the Radiation Effects Research Foundation has, over several decades, conducted studies of the Life Span Study (LSS) cohort, comprising 93 000 atomic-bomb survivors and 27 000 controls. Solid cancer: the recent report on solid cancer incidence found that at age 70 years following exposure at age 30 years, solid cancer rates increase by about 35%  Gy(-1) for men and 58% Gy(-1) for women. Age-at-exposure is an important risk modifier. In the case of lung cancer, cigarette smoking has been found to be an important risk modifier. Radiation has similar effects on first-primary and second-primary cancer risks. Finally, radiation-associated increases in cancer rates appear to persist throughout life. Leukaemia: the recent report on leukaemia mortality suggests that radiation effects on leukaemia mortality persisted for more than 50 years. Moreover, significant dose-response for myelodysplastic syndrome was observed in Nagasaki LSS members even 40-60 years after radiation exposure. Future perspective: given the continuing solid cancer increase in the survivor population, the LSS will likely continue to provide important new information on radiation exposure and solid cancer risks for another 15-20 years, especially for those exposed at a young age.

Accounting for Unfissioned Plutonium from the Trinity Atomic Bomb Test.

The Trinity test device contained about 6 kg of plutonium as its fission source, resulting in a fission yield of 21 kT. However, only about 15% of the Pu actually underwent fission. The remaining unfissioned plutonium eventually was vaporized in the fireball and after cooling, was deposited downwind from the test site along with the various fission and activation products produced in the explosion. Using data from radiochemical analyses of soil samples collected postshot (most many years later), supplemented by model estimates of plutonium deposition density estimated from reported exposure rates at 12 h postshot, we have estimated the total activity and geographical distribution of the deposition density of this unfissioned plutonium in New Mexico. A majority (about 80%) of the unfissioned plutonium was deposited within the state of New Mexico, most in a relatively small area about 30-100 km downwind (the Chupadera Mesa area). For most of the state, the deposition density was a small fraction of the subsequent deposition density of Pu from Nevada Test Site tests (1951-1958) and later from global fallout from the large US and Russian thermonuclear tests (1952-1962). The fraction of the total unfissioned Pu that was deposited in New Mexico from Trinity was greater than the fraction of fission products deposited. Due to plutonium being highly refractory, a greater fraction of the Pu was incorporated into large particles that fell out closer to the test site as opposed to more volatile fission products (such as Cs and I) that tend to deposit on the surface of smaller particles that travel farther before depositing. The plutonium deposited as a result of the Trinity test was unlikely to have resulted in significant health risks to the downwind population.

Methods and Findings on Diet and Lifestyle Used to Support Estimation of Radiation Doses from Radioactive Fallout from the Trinity Nuclear Test.

The Trinity nuclear test was detonated in south-central New Mexico on 16 July 1945; in the early 2000s, the National Cancer Institute undertook a dose and cancer risk projection study of the possible health impacts of the test. In order to conduct a comprehensive dose assessment for the Trinity test, we collected diet and lifestyle data relevant to the populations living in New Mexico around the time of the test. This report describes the methodology developed to capture the data used to calculate radiation exposures and presents dietary and lifestyle data results for the main exposure pathways considered in the dose reconstruction. Individual interviews and focus groups were conducted in 2017 among older adults who had lived in the same New Mexico community during the 1940s or 1950s. Interview questions and guided group discussions focused on specific aspects of diet, water, type of housing, and time spent outdoors for different age groups. Thirteen focus groups and 11 individual interviews were conducted among Hispanic, White, and Native American participants. Extensive written notes and audio recordings aided in the coding of all responses used to derive ranges, prevalence, means, and standard deviations for each exposure variable for various age categories by region and ethnicity. Children aged 11-15 y in 1940s or 1950s from the rural plains had the highest milk intakes (993 mL d), and lowest intakes were among 11- to 15-y-olds in mountainous regions (191 mL d). Lactose intolerance rates were 7-71%, and prevalence was highest among Native Americans. Meat was not commonly consumed in the summer in most communities, and if consumed, it was among those aged 11-15 y of age or older who had relatively small amounts of 100-200 g d. Most drinking and cooking water came from covered wells, and most homes were made of adobe, which provided more protection from external radiation than wooden structures. The use of multiple approaches to trigger memory and collect participant reports on diet and other factors from the distant past seemed effective. These data were summarized, and together with other information, these data have been used to estimate radiation doses for representative persons of all ages in the main ethnic groups residing in New Mexico at the time of the Trinity nuclear test.

The Methodology Used to Assess Doses from the First Nuclear Weapons Test (Trinity) to the Populations of New Mexico.

Trinity was the first test of a nuclear fission device. The test took place in south-central New Mexico at the Alamogordo Bombing and Gunnery Range at 05:29 AM on 16 July 1945. This article provides detailed information on the methods that were used in this work to estimate the radiation doses that were received by the population that resided in New Mexico in 1945. The 721 voting precincts of New Mexico were classified according to ecozone (plains, mountains, or mixture of plains and mountains), and size of resident population (urban or rural). Methods were developed to prepare estimates of absorbed doses from a range of 63 radionuclides to five organs or tissues (thyroid, active marrow, stomach, colon, and lung) for representative individuals of each voting precinct selected according to ethnicity (Hispanic, White, Native American, and African American) and age group in 1945 (in utero, newborn, 1-2 y, 3-7 y, 8-12 y, 13-17 y, and adult). Three pathways of human exposure were included: (1) external irradiation from the radionuclides deposited on the ground; (2) inhalation of radionuclide-contaminated air during the passage of the radioactive cloud and, thereafter, of radionuclides transferred (resuspended) from soil to air; and (3) ingestion of contaminated water and foodstuffs. Within the ingestion pathway, 13 types of foods and sources of water were considered. Well established models were used for estimation of doses resulting from the three pathways using parameter values developed from extensive literature review. Because previous experience and calculations have shown that the annual dose delivered during the year following a nuclear test is much greater than the doses received in the years after that first year, the time period that was considered is limited to the first year following the day of the test (16 July 1945). Numerical estimates of absorbed doses, based on the methods described in this article, are presented in a separate article in this issue.

Estimated Radiation Doses Received by New Mexico Residents from the 1945 Trinity Nuclear Test.

The National Cancer Institute study of projected health risks to New Mexico residents from the 1945 Trinity nuclear test provides best estimates of organ radiation absorbed doses received by representative persons according to ethnicity, age, and county. Doses to five organs/tissues at significant risk from exposure to radioactive fallout (i.e., active bone marrow, thyroid gland, lungs, stomach, and colon) from the 63 most important radionuclides in fresh fallout from external and internal irradiation were estimated. The organ doses were estimated for four resident ethnic groups in New Mexico (Whites, Hispanics, Native Americans, and African Americans) in seven age groups using: (1) assessment models described in a companion paper, (2) data on the spatial distribution and magnitude of radioactive fallout derived from historical documents, and (3) data collected on diets and lifestyles in 1945 from interviews and focus groups conducted in 2015-2017 (described in a companion paper). The organ doses were found to vary widely across the state with the highest doses directly to the northeast of the detonation site and at locations close to the center of the Trinity fallout plume. Spatial heterogeneity of fallout deposition was the largest cause of variation of doses across the state with lesser differences due to age and ethnicity, the latter because of differences in diets and lifestyles. The exposure pathways considered included both external irradiation from deposited fallout and internal irradiation via inhalation of airborne radionuclides in the debris cloud as well as resuspended ground activity and ingestion of contaminated drinking water (derived both from rivers and rainwater cisterns) and foodstuffs including milk products, beef, mutton, and pork, human-consumed plant products including leafy vegetables, fruit vegetables, fruits, and berries. Tables of best estimates of county population-weighted average organ doses by ethnicity and age are presented. A discussion of our estimates of uncertainty is also provided to illustrate a lower and upper credible range on our best estimates of doses. Our findings indicate that only small geographic areas immediately downwind to the northeast received exposures of any significance as judged by their magnitude relative to natural radiation. The findings presented are the most comprehensive and well-described estimates of doses received by populations of New Mexico from the Trinity nuclear test.

Projected Cancer Risks to Residents of New Mexico from Exposure to Trinity Radioactive Fallout.

The Trinity nuclear test, conducted in 1945, exposed residents of New Mexico to varying degrees of radioactive fallout. Companion papers in this issue have detailed the results of a dose reconstruction that has estimated tissue-specific radiation absorbed doses to residents of New Mexico from internal and external exposure to radioactive fallout in the first year following the Trinity test when more than 90% of the lifetime dose was received. Estimated radiation doses depended on geographic location, race/ethnicity, and age at the time of the test. Here, these doses were applied to sex- and organ-specific risk coefficients (without applying a dose and dose rate effectiveness factor to extrapolate from a population with high-dose/high-dose rates to those with low-dose/low-dose rates) and combined with baseline cancer rates and published life tables to estimate and project the range of radiation-related excess cancers among 581,489 potentially exposed residents of New Mexico. The total lifetime baseline number of all solid cancers [excluding thyroid and non-melanoma skin cancer (NMSC)] was estimated to be 183,000 from 1945 to 2034. Estimates of ranges of numbers of radiation-related excess cancers and corresponding attributable fractions from 1945 to 2034 incorporate various sources of uncertainty. We estimated 90% uncertainty intervals (UIs) of excess cancer cases to be 210 to 460 for all solid cancers (except thyroid cancer and NMSC), 80 to 530 for thyroid cancer, and up to 10 for leukemia (except chronic lymphocytic leukemia), with corresponding attributable fractions ranging from 0.12% to 0.25%, 3.6% to 20%, and 0.02% to 0.31%, respectively. In the counties of Guadalupe, Lincoln, San Miguel, Socorro, and Torrance, which received the greatest fallout deposition, the 90% UI for the projected fraction of thyroid cancers attributable to radioactive fallout from the Trinity test was estimated to be from 17% to 58%. Attributable fractions for cancer types varied by race/ethnicity, but 90% UIs overlapped for all race/ethnicity groups for each cancer grouping. Thus, most cancers that have occurred or will occur among persons exposed to Trinity fallout are likely to be cancers unrelated to exposures from the Trinity nuclear test. While these ranges are based on the most detailed dose reconstruction to date and rely largely on methods previously established through scientific committee agreement, challenges inherent in the dose estimation, and assumptions relied upon both in the risk projection and incorporation of uncertainty are important limitations in quantifying the range of radiation-related excess cancer risk.

The Likelihood of Adverse Pregnancy Outcomes and Genetic Disease (Transgenerational Effects) from Exposure to Radioactive Fallout from the 1945 Trinity Atomic Bomb Test.

The potential health consequences of the Trinity nuclear weapon test of 16 July 1945 at Alamogordo, New Mexico, are challenging to assess. Population data are available for mortality but not for cancer incidence for New Mexico residents for the first 25 y after the test, and the estimates of radiation dose to the nearby population are lower than the cumulative dose received from ubiquitous natural background radiation. Despite the estimates of low population exposures, it is believed by some that cancer rates in counties near the Trinity test site (located in Socorro County) are elevated compared with other locations across the state. Further, there is a concern about adverse pregnancy outcomes and genetic diseases (transgenerational or heritable effects) related to population exposure to fallout radiation. The possibility of an intergenerational effect has long been a concern of exposed populations, e.g., Japanese atomic bomb survivors, survivors of childhood and adolescent cancer, radiation workers, and environmentally exposed groups. In this paper, the likelihood of discernible transgenerational effects is discounted because (1) in all large-scale comprehensive studies of exposed populations, no heritable genetic effects have been demonstrated in children of exposed parents; (2) the distribution of estimated doses from Trinity is much lower than in other studied populations where no transgenerational effects have been observed; and (3) there is no evidence of increased cancer rates among the scientific, military, and professional participants at the Trinity test and at other nuclear weapons tests who received much higher doses than New Mexico residents living downwind of the Trinity site.

Positive associations between ionizing radiation and lymphoma mortality among men.

The authors investigated the relation between ionizing radiation and lymphoma mortality in 2 cohorts: 1) 20,940 men in the Life Span Study, a study of Japanese atomic bomb survivors who were aged 15-64 years at the time of the bombings of Hiroshima and Nagasaki, and 2) 15,264 male nuclear weapons workers who were hired at the Savannah River Site in South Carolina between 1950 and 1986. Radiation dose-mortality trends were evaluated for all malignant lymphomas and for non-Hodgkin's lymphoma. Positive associations between lymphoma mortality and radiation dose under a 5-year lag assumption were observed in both cohorts (excess relative rates per sievert were 0.79 (90% confidence interval: 0.10, 1.88) and 6.99 (90% confidence interval: 0.96, 18.39), respectively). Exclusion of deaths due to Hodgkin's disease led to small changes in the estimates of association. In each cohort, evidence of a dose-response association was primarily observed more than 35 years after irradiation. These findings suggest a protracted induction and latency period for radiation-induced lymphoma mortality.