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1.  Non-Malignant Thyroid Diseases Following a Wide Range of Radiation Exposures 
Radiation research  2010;174(6):877-888.
Background
The thyroid gland is one of the most radiosensitive human organs. While it is well known that radiation exposure increases the risk of thyroid cancer, less is known about its effects in relation to non-malignant thyroid diseases.
Objectives
The aim of this review is to evaluate the effects of high and low dose radiation on benign structural and functional diseases of the thyroid.
Methods
We examined the results of major studies from cancer patients treated with high-dose radiotherapy or thyrotoxicosis patients treated with high doses of iodine-131, patients treated with moderate to high dose radiotherapy for benign diseases, persons exposed to low doses from environmental radiation and survivors of the atomic bombings who were exposed to a range of doses. We evaluated radiation effects on structural (tumors, nodules), functional (hyper- and hypothyroidism), and autoimmune thyroid diseases.
Results
Following a wide range of doses of ionizing radiation, an increased risk of thyroid adenomas and nodules was observed in a variety of populations and settings. The dose response appeared to be linear at low to moderate doses, but in one study there was some suggestion of a reduction in risk above 5 Gy. The elevated risk for benign tumors continues for decades following exposure. Considerably less consistent findings are available regarding functional thyroid diseases including autoimmune diseases. In general, associations for these outcomes were fairly weak and significant radiation effects were most often observed following high doses, particularly for hypothyroidism.
Conclusions
A significant radiation dose-response relation was demonstrated for benign nodules and follicular adenomas. The effects of radiation on functional thyroid diseases are less clear, partly due to the greater difficulties studying these diseases.
doi:10.1667/RR1953.1
PMCID: PMC3927789  PMID: 21128812
2.  Thyroid Cancer Rates and 131I Doses from Nevada Atmospheric Nuclear Bomb Tests: An Update 
Radiation research  2010;173(5):10.1667/RR2057.1.
Exposure to radioactive iodine (131I) from atmospheric nuclear tests conducted in Nevada in the 1950s may have increased thyroid cancer risks. To investigate the long-term effects of this exposure, we analyzed data on thyroid cancer incidence (18,545 cases) from eight Surveillance, Epidemiology, and End Results (SEER) tumor registries for the period 1973-2004. Excess relative risks (ERR) per Gray (Gy) for exposure received before age 15 were estimated by relating age-, birth year-, sex-, and county-specific thyroid cancer rates to estimates of cumulative dose to the thyroid that take age into account. The estimated ERR per Gy for dose received before one year of age was 1.8 (95% confidence interval (CI), 0.5-3.2). There was no evidence that this estimate declined with follow-up time or that risk increased with dose received at ages 1-15. These results confirm earlier findings based on less extensive data for the period 1973-1994. The lack of a dose-response for those exposed at ages 1-15 is inconsistent with studies of children exposed to external radiation or 131I from the Chernobyl accident, and results need to be interpreted in light of limitations and biases inherent in ecologic studies, including the error in doses and case ascertainment resulting from migration. Nevertheless, the study adds support for an increased risk of thyroid cancer due to fallout, although the data are inadequate to quantify it.
doi:10.1667/RR2057.1
PMCID: PMC3865880  PMID: 20426666
3.  A Pooled Analysis of Thyroid Cancer Incidence Following Radiotherapy for Childhood Cancer 
Radiation research  2012;178(4):365-376.
Childhood cancer five-year survival now exceeds 70–80%. Childhood exposure to radiation is a known thyroid carcinogen; however, data are limited for the evaluation of radiation dose-response at high doses, modifiers of the dose-response relationship and joint effects of radiotherapy and chemotherapy. To address these issues, we pooled two cohort and two nested case-control studies of childhood cancer survivors including 16,757 patients, with 187 developing primary thyroid cancer. Relative risks (RR) with 95% confidence intervals (CI) for thyroid cancer by treatment with alkylating agents, anthracyclines or bleomycin were 3.25 (0.9–14.9), 4.5 (1.4–17.8) and 3.2 (0.8–10.4), respectively, in patients without radiotherapy, and declined with greater radiation dose (RR trends, P = 0.02, 0.12 and 0.01, respectively). Radiation dose-related RRs increased approximately linearly for <10 Gy, leveled off at 10–15-fold for 10–30 Gy and then declined, but remained elevated for doses >50 Gy. The fitted RR at 10 Gy was 13.7 (95% CI: 8.0–24.0). Dose-related excess RRs increased with decreasing age at exposure (P < 0.01), but did not vary with attained age or time-since-exposure, remaining elevated 25+ years after exposure. Gender and number of treatments did not modify radiation effects. Thyroid cancer risks remained elevated many decades following radiotherapy, highlighting the need for continued follow up of childhood cancer survivors.
PMCID: PMC3488851  PMID: 22857014
4.  Common Genetic Variants in Sex Hormone Pathway Genes and Papillary Thyroid Cancer Risk 
Thyroid  2012;22(2):151-156.
Background
Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.
Methods
We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.
Results
Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.
Conclusions
Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.
doi:10.1089/thy.2011.0309
PMCID: PMC3271376  PMID: 22224819
5.  Diabetes and Thyroid Cancer Risk in the National Institutes of Health-AARP Diet and Health Study 
Thyroid  2011;21(9):957-963.
Background
We hypothesized that diabetes may play a role in thyroid cancer risk due to the parallel secular rise in diabetes prevalence and morbidity in the United States, the higher prevalence of thyroid disorders among diabetics compared with the general population, and the potential roles of metabolic syndrome, obesity, and diabetes as precipitating factors in cancer development.
Methods
We assessed the association between self-reported diabetes and the risk of differentiated thyroid cancer in the NIH-AARP Diet and Health Study, a prospective cohort of 200,556 women and 295,992 men, 50–71 years of age, in 1995–1996. Diabetes status and information on potential confounders was ascertained using a self-administered questionnaire. During an average of 10 years of follow-up, 585 thyroid cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer and thyroid cancer subtypes in men and women according to diabetes status.
Results
Nine percent of the total baseline cohort reported a history of diabetes (7% of women, 10% of men). A nonsignificant 25% increase in thyroid cancer risk (HR = 1.25; 95% CI: 0.95–1.64) was associated with diabetes. Among women, the risk was significantly increased (HR = 1.46, 95% CI: 1.01–2.10). The risk was not elevated among men (HR = 1.04, 95% CI: 0.69–1.58). In this cohort, diabetic women with differentiated thyroid cancer were at somewhat higher risk of follicular thyroid cancer (HR = 1.92; 95% CI: 0.86–4.27) than papillary thyroid cancer (HR = 1.25; 95% CI: 0.80–1.97).
Conclusion
This study lends support to the hypothesis that diabetes increases the risk of differentiated thyroid cancer.
doi:10.1089/thy.2010.0396
PMCID: PMC3162644  PMID: 21767143
6.  Common genetic variants related to genomic integrity and risk of papillary thyroid cancer 
Carcinogenesis  2011;32(8):1231-1237.
DNA damage is an important mechanism in carcinogenesis, so genes related to maintaining genomic integrity may influence papillary thyroid cancer (PTC) risk. Candidate gene studies targeting some of these genes have identified only a few polymorphisms associated with risk of PTC. Here, we expanded the scope of previous candidate studies by increasing the number and coverage of genes related to maintenance of genomic integrity. We evaluated 5077 tag single-nucleotide polymorphisms (SNPs) from 340 candidate gene regions hypothesized to be involved in DNA repair, epigenetics, tumor suppression, apoptosis, telomere function and cell cycle control and signaling pathways in a case–control study of 344 PTC cases and 452 matched controls. We estimated odds ratios for associations of single SNPs with PTC risk and combined P values for SNPs in the same gene region or pathway to obtain gene region-specific or pathway-specific P values using adaptive rank-truncated product methods. Nine SNPs had P values <0.0005, three of which were in HDAC4 and were inversely related to PTC risk. After multiple comparisons adjustment, no SNPs remained associated with PTC risk. Seven gene regions were associated with PTC risk at P < 0.01, including HUS1, ALKBH3, HDAC4, BAK1, FAF1_CDKN2C, DACT3 and FZD6. Our results suggest a possible role of genes involved in maintenance of genomic integrity in relation to risk of PTC.
doi:10.1093/carcin/bgr100
PMCID: PMC3166197  PMID: 21642358
7.  The proportion of second cancers attributable to radiotherapy treatment in adults: a prospective cohort study in the US SEER cancer registries 
The lancet oncology  2011;12(4):353-360.
Background
As cancer survival improves, the long-term risks from treatments including the risk of developing a second cancer after radiotherapy become more important. The proportion of second cancers that may be related to radiotherapy is unknown.
Methods
We used the U.S. Surveillance, Epidemiology and End Results cancer registries to conduct a systematic analysis of 15 cancer sites that are treated routinely with radiotherapy. Relative risks (RR) for patients receiving radiotherapy versus patients not receiving radiotherapy were estimated using Poisson regression adjusted for age, stage and other potential confounders.
Findings
The cohort included 647,672 five-year adult survivors followed-up for an average of 7 additional years; 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 one, and varied from 1.08 (95%CI:0.79–1.46) after eye/orbit cancers to 1.43 (95%CI:1.13–1.84) after testicular cancer. In general the RR was highest for organs likely to have received >5Gy, decreased with increasing age at diagnosis and increased with time since diagnosis. We estimated a total of 3266 (95%CI:2862–3670) excess second solid cancers that could be related to radiation; 8% (95%CI:7%–9%) of the total in all radiotherapy patients (1+yr survivors) and 5 excess cancers/1,000 patients treated with radiotherapy by 15 years after diagnosis. Approximately half (54%) the excess cancers were in organs likely to have received >5Gy.
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.
doi:10.1016/S1470-2045(11)70061-4
PMCID: PMC3086738  PMID: 21454129
8.  Socio-economic variation in CT scanning in Northern England, 1990-2002 
Background
Socio-economic status is known to influence health throughout life. In childhood, studies have shown increased injury rates in more deprived settings. Socio-economic status may therefore be related to rates of certain medical procedures, such as computed tomography (CT) scans. This study aimed to assess socio-economic variation among young people having CT scans in Northern England between 1990 and 2002 inclusive.
Methods
Electronic data were obtained from Radiology Information Systems of all nine National Health Service hospital Trusts in the region. CT scan data, including sex, date of scan, age at scan, number and type of scans were assessed in relation to quintiles of Townsend deprivation scores, obtained from linkage of postcodes with census data, using χ2 tests and Spearman rank correlations.
Results
During the study period, 39,676 scans were recorded on 21,089 patients, with 38,007 scans and 19,485 patients (11344 male and 8132 female) linkable to Townsend scores. The overall distributions of both scans and patients by quintile of Townsend deprivation scores were significantly different to the distributions of Townsend scores from the census wards included in the study (p < 0.0001). There was a significant association between type of scan and deprivation quintile (p < 0.0001), primarily due to the higher proportions of head scans in the three most deprived quintiles, and slightly higher proportions of chest scans and abdomen and pelvis scans in the least deprived groups. There was also a significant association (p < 0.0001) between the patient's age at the time of the CT scan and Townsend deprivation quintiles, with slightly increasing proportions of younger children with increasing deprivation. A similar association with age (p < 0.0001) was seen when restricting the data to include only the first scan of each patient. The number of scans per patient was also associated with Townsend deprivation quintiles (p = 0.014).
Conclusions
Social inequalities exist in the numbers of young people undergoing CT scans with those from deprived areas more likely to do so. This may reflect the rates of injuries in these individuals and implies that certain groups within the population may receive higher radiation doses than others due to medical procedures.
doi:10.1186/1472-6963-12-24
PMCID: PMC3276411  PMID: 22283843
9.  I-131 Dose Response for Incident Thyroid Cancers in Ukraine Related to the Chornobyl Accident 
Environmental Health Perspectives  2011;119(7):933-939.
Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case–control studies, and studies of prevalent cancers.
Objective: To address this limitation, we evaluated the dose–response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study.
Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of I-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models.
Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose–response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43–6.34], and the EAR per 104 PY/Gy was 2.21 (95% CI, 0.04–5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size.
Conclusions: I-131–related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies.
doi:10.1289/ehp.1002674
PMCID: PMC3222994  PMID: 21406336
Chernobyl nuclear accident; Chornobyl, Ukraine, 1986; dose–response relationship; incidence, thyroid neoplasms/epidemiology; iodine; radioactive; radiation
10.  Prospective study of body mass index, physical activity, and thyroid cancer 
Increased body size and physical inactivity are positively related to risk of several cancers, but only few epidemiologic studies have investigated body-mass index (BMI) and physical activity in relation to thyroid cancer. We examined the relations of BMI and physical activity to thyroid cancer in a prospective cohort of 484,326 United States men and women, followed from 1995/1996 to 2003. During 3,490,300 person-years of follow-up, we documented 352 newly incident cases of thyroid cancer. The multivariate relative risks (RR) of thyroid cancer for BMI values of 18.5 to 24.9 (reference), 25.0 to 29.9, and ≥30 kg/m2 were 1.0, 1.27, and 1.39 [95% confidence interval (CI)=1.05–1.85]. Adiposity predicted papillary thyroid cancers (RR comparing extreme BMI categories=1.47; 95%-CI=1.03–2.10) and, based on small numbers, suggestively predicted follicular thyroid cancers (RR=1.49; 95%-CI=0.79–2.82) and anaplastic thyroid cancers (RR=5.80; 95%-CI=0.99–34.19). No relation with BMI was noted for medullary thyroid cancers (RR=0.97; 95%-CI=0.27–3.43). The positive relation of BMI to total thyroid cancer was evident for men but not for women. However, the test of interaction (p=0.463) indicated no statistically significant gender difference. Physical activity was unassociated with thyroid cancer. The RRs of total thyroid cancer for low (reference), intermediate, and high level of physical activity were 1.0, 1.01, and 1.01 (95%-CI=0.76–1.34, p for trend=0.931), respectively. Our results support an adverse effect of adiposity on risk for developing total and papillary, and possibly follicular thyroid cancers. Based on only 15 cases, adiposity was unrelated to medullary thyroid cancers. Physical activity was unrelated to total thyroid cancer.
doi:10.1002/ijc.24913
PMCID: PMC2919690  PMID: 19795465
11.  Diagnostic X-ray examinations and increased chromosome translocations: evidence from three studies 
Controversy regarding potential health risks from increased use of medical diagnostic radiologic examinations has come to public attention. We evaluated whether chromosome damage, specifically translocations, which are a potentially intermediate biomarker for cancer risk, was increased after exposure to diagnostic X-rays, with particular interest in the ionizing radiation dose–response below the level of approximately 50 mGy. Chromosome translocation frequency data from three separately conducted occupational studies of ionizing radiation were pooled together. Studies 1 and 2 included 79 and 150 medical radiologic technologists, respectively, and study 3 included 83 airline pilots and 50 university faculty members (total = 155 women and 207 men; mean age = 62 years, range 34–90). Information on personal history of radiographic examinations was collected from a detailed questionnaire. We computed a cumulative red bone marrow (RBM) dose score based on the numbers and types of X-ray examinations reported with 1 unit approximating 1 mGy. Poisson regression analyses were adjusted for age and laboratory method. Mean RBM dose scores were 49, 42, and 11 for Studies 1–3, respectively (overall mean = 33.5, range 0–303). Translocation frequencies significantly increased with increasing dose score (P < 0.001). Restricting the analysis to the lowest dose scores of under 50 did not materially change these results. We conclude that chromosome damage is associated with low levels of radiation exposure from diagnostic X-ray examinations, including dose scores of approximately 50 and lower, suggesting the possibility of long-term adverse health effects.
doi:10.1007/s00411-010-0307-z
PMCID: PMC3075914  PMID: 20602108
12.  Papillary Microcarcinoma of the Thyroid among Atomic Bomb Survivors: Tumor Characteristics and Radiation Risk 
Cancer  2010;116(7):1646-1655.
Background
Radiation exposure is an established cause of clinical thyroid cancer, but little is known about radiation effects on papillary microcarcinoma (PMC) of the thyroid, a relatively common subclinical thyroid malignancy. Because the incidence of these small thyroid cancers has been increasing, it is important to better understand them and their relationship to radiation.
Methods
PMCs were identified in a subset of 7659 members of the Life Span Study of atomic-bomb survivors who had archived autopsy or surgical materials. We conducted a pathology review of these specimens and evaluated the histological features of the tumors and the association between PMCs and thyroid radiation dose.
Results
From 1958 to1995, 458 PMCs were detected among 313 study subjects. The majority of cancers exhibited pathologic features of papillary thyroid cancers. Overall, 81% of the PMCs were of the sclerosing variant and 91% were nonencapsulated, psammoma bodies occurred in 13% and calcification was observed in 23%. Over 95% had papillary or papillary-follicular architecture and most displayed nuclear overlap, clear nuclei, and nuclear grooves. Several of these features increased with increasing tumor size, but no association was found with radiation dose. A significant radiation-dose response was found for the prevalence of PMCs (estimated excess odds ratio/Gy=0.57; 95% CI: 0.01-1.55), with the excess risk observed primarily among females.
Conclusion
Low-to-moderate doses of ionizing radiation appears to increase the risk of thyroid PMCs, even when exposure occurs during adulthood.
doi:10.1002/cncr.24872
PMCID: PMC2846973  PMID: 20120034
thyroid; papillary microcarcinoma; atomic bombs; radiation
13.  Early life exposure to diagnostic radiation and ultrasound scans and risk of childhood cancer: case-control study 
Objective To examine childhood cancer risks associated with exposure to diagnostic radiation and ultrasound scans in utero and in early infancy (age 0-100 days).
Design Case-control study.
Setting England and Wales.
Participants 2690 childhood cancer cases and 4858 age, sex, and region matched controls from the United Kingdom Childhood Cancer Study (UKCCS), born 1976-96.
Main outcome measures Risk of all childhood cancer, leukaemia, lymphoma, and central nervous system tumours, measured by odds ratios.
Results Logistic regression models conditioned on matching factors, with adjustment for maternal age and child’s birth weight, showed no evidence of increased risk of childhood cancer with in utero exposure to ultrasound scans. Some indication existed of a slight increase in risk after in utero exposure to x rays for all cancers (odds ratio 1.l4, 95% confidence interval 0.90 to 1.45) and leukaemia (1.36, 0.91 to 2.02), but this was not statistically significant. Exposure to diagnostic x rays in early infancy (0-100 days) was associated with small, non-significant excess risks for all cancers and leukaemia, as well as increased risk of lymphoma (odds ratio 5.14, 1.27 to 20.78) on the basis of small numbers.
Conclusions Although the results for lymphoma need to be replicated, all of the findings indicate possible risks of cancer from radiation at doses lower than those associated with commonly used procedures such as computed tomography scans, suggesting the need for cautious use of diagnostic radiation imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages.
doi:10.1136/bmj.d472
PMCID: PMC3037470  PMID: 21310791
14.  Comparison of second cancer risks from brachytherapy and external beam therapy after uterine corpus cancer 
Background
Adjuvant radiotherapy is common for uterine corpus cancer patients, yet the long-term carcinogenic effects of different types of radiotherapy have not been studied adequately.
Methods
Second primary cancer risks were quantified in a cohort of 60,949 individuals surviving one or more years of uterine corpus cancer diagnosed 1973–2003 in Surveillance, Epidemiology and End Results Program cancer registries. Incidence Rate Ratios (IRR) were estimated by comparing patients treated with surgery plus various types of radiotherapy with patients receiving surgery only.
Results
The IRRs of a second cancer were increased among irradiated patients compared with patients having surgery only (combination radiotherapy, IRR=1.26, 95% confidence interval [CI] 1.16–1.36; external beam therapy, IRR=1.15, CI 1.08–1.22; brachytherapy, IRR=1.07, CI 1.00–1.16). IRRs were highest for heavily-irradiated sites (i.e., colon, rectum, and bladder) and for leukemia following any external beam therapy, with the largest risks for solid cancers among ten-year survivors. Any external beam therapy had a 44% higher cancer risk at heavily-irradiated sites than brachytherapy when the two treatments were directly compared (five-year survivors: IRR=1.44, CI 1.19–1.75). We estimated that of 2012 solid cancers developing five or more years after irradiation, 213 (11%) could be explained by radiotherapy.
Conclusions
Radiotherapy for uterine cancer increases the risk of leukemia and second solid cancers at sites in close proximity to the uterus, emphasizing the need for continued long-term surveillance for new malignancies. The overall risk of a second cancer was lower following brachytherapy compared with any external beam radiotherapy.
doi:10.1158/1055-9965.EPI-09-0892
PMCID: PMC2866968  PMID: 20142245
endometrial adenocarcinomas; epidemiology; gynecologic malignancy; radiation; radiotherapy
15.  Nonradiation Risk Factors for Thyroid Cancer in the US Radiologic Technologists Study 
American Journal of Epidemiology  2009;171(2):242-252.
The incidence of thyroid cancer has been rapidly increasing in the United States, but few risk factors have been established. The authors prospectively examined the associations of self-reported medical history, anthropometric factors, and behavioral factors with thyroid cancer risk among 90,713 US radiologic technologists (69,506 women and 21,207 men) followed from 1983 through 2006. Incident thyroid cancers in 242 women and 40 men were reported. Elevated risks were observed for women with benign thyroid conditions (hazard ratio (HR) = 2.35, 95% confidence interval (CI): 1.73, 3.20), benign breast disease (HR = 1.56, 95% CI: 1.08, 2.26), asthma (HR = 1.68, 95% CI: 1.00, 2.83), and body mass index ≥35.0 versus 18.5–24.9 kg/m2 (HR = 1.74, 95% CI: 1.03, 2.94; P-trend = 0.04). Current smoking was inversely associated with thyroid cancer risk (HR = 0.54). No clear associations emerged for reproductive factors, other medical conditions, alcohol intake, or physical activity. Despite few thyroid cancers in men, men with benign thyroid conditions had a significantly increased risk of thyroid cancer (HR = 4.65, 95% CI: 1.62, 13.34), and results for other risk factors were similar to those for women. Consistent with prior studies, obesity and benign thyroid conditions increased and current smoking decreased the risk of thyroid cancer. The novel findings for benign breast disease and asthma warrant further investigation.
doi:10.1093/aje/kwp354
PMCID: PMC3290908  PMID: 19951937
body mass index; hormones; motor activity; prospective studies; reproduction; smoking; thyroid diseases; thyroid neoplasms
16.  Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan 
Radiation research  2009;171(1):77-88.
Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-62). Cases with thyroid nodules (n=907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender, and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history, and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, p = 0.03) and GFRA1 -193C>G (rs not assigned, p = 0.05) and decreased risk with XRCC1 R194W (rs1799782, p-trend = 0.03) and TGFB1 T263I (rs1800472, p = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n=25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% confidence interval 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT p value = 0.02). Polymorphisms in RET signaling, DNA repair, and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways, such as genes in double strand break repair, apoptosis, and genes related to proliferation should also be pursued.
doi:10.1667/RR1327.1
PMCID: PMC2875679  PMID: 19138047
Thyroid nodules; single nucleotide polymorphisms; epidemiology; thyroid cancer; ionizing radiation; interaction
17.  Risk of Radiation-related Salivary Gland Carcinomas Among Hodgkin Lymphoma Survivors: A Population-based Analysis 
Cancer  2008;113(11):3153-3159.
Background
Radiotherapy for Hodgkin lymphoma (HL) increases the risk of salivary gland carcinomas (SGC); however the magnitude of the risk has not been assessed.
Methods
We evaluated risks of SGC among 20,928 one-year survivors of HL diagnosed between 1973 and 2003 in 11 population-based cancer registry areas of the Surveillance, Epidemiology and End Results (SEER) program. Observed-to-expected ratios (O/E) were assessed by radiation treatment, gender, age at HL diagnosis, calendar year of diagnosis, attained age, time since HL diagnosis, histologic type of SGC, and site of occurrence in the major salivary glands.
Results
Among 11,047 HL patients who received radiotherapy as part of initial treatment for HL, 21 developed subsequent invasive SGC (O/E=16.9; 95% confidence interval (CI) 10.4 to 25.8). Risk of radiation-related SGC was highest for younger HL patients (age <20 years: O/E=45.5, CI 12.4 to 116.5) and among 10-year survivors (O/E=23.9, CI 13.1 to 40.1), with risks remaining elevated for at least two decades after irradiation. Significant differences in risk by histologic type were observed with particularly high risk of developing mucoepidermoid carcinomas (O=14, O/E=44.2, CI 24.2 to 74.2) and adenocarcinomas (O=4, O/E=30.6, CI 8.3 to 78.2).
Conclusion
HL patients treated with radiotherapy experienced significantly increased risk of SGC particularly when exposed at young ages or for at least two decades following exposure. Although our results reflect the late effects of former HL treatment approaches, they point to the importance of long-term follow-up and heightened awareness of SGC risk in this population.
doi:10.1002/cncr.23918
PMCID: PMC2868333  PMID: 18823043
Hodgkin lymphoma; subsequent salivary gland carcinoma; mucoepidermoid carcinoma; radiotherapy; risk
18.  Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980–2005 
Thyroid cancer incidence has been rising in the United States, and this trend has often been attributed to heightened medical surveillance and use of improved diagnostics. Thyroid cancer incidence varies by sex and race/ethnicity, and these factors also influence access to and utilization of healthcare. We therefore examined thyroid cancer incidence rates by demographic and tumor characteristics, based on 48,403 thyroid cancer patients diagnosed during 1980–2005 from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute. Rates varied by histologic type, sex, and race/ethnicity. Papillary carcinoma was the only histologic type for which incidence rates rose consistently among all racial/ethnic groups. Subsequent analyses focused on the 39,706 papillary thyroid cancers diagnosed during this period. Papillary carcinoma rates increased most rapidly among females. Between 1992–1995 and 2003–2005, they rose nearly 100% among White Non-Hispanics and Black females, but only 20–50% among White Hispanics, Asian/Pacific Islanders and Black males. Increases were most rapid for localized stage and small tumors; however, rates also rose for large tumors and tumors of regional and distant stage. Since 1992–1995, half the overall increase in papillary carcinoma rates was due to rising rates of very small (≤1.0 cm) cancers, 30% to cancers 1.1–2 cm, and 20% to cancers >2 cm. Among White females, the rate of increase for cancers >5 cm almost equaled that for the smallest cancers. Medical surveillance and more sensitive diagnostic procedures cannot completely explain the observed rises in papillary thyroid cancer rates. Thus, other possible explanations should be explored.
doi:10.1158/1055-9965.EPI-08-0960
PMCID: PMC2676561  PMID: 19240234
Incidence; Thyroid cancer; Papillary; SEER Program
19.  ROUTINE DIAGNOSTIC X-RAY EXAMINATIONS AND INCREASED FREQUENCY OF CHROMOSOME TRANSLOCATIONS AMONG U. S. RADIOLOGIC TECHNOLOGISTS 
Cancer research  2008;68(21):8825-8831.
The U.S. population has nearly one radiographic examination per person per year and concern about cancer risks associated with medical radiation has increased. Radiologic technologists were surveyed to determine whether their personal cumulative exposure to diagnostic x-rays was associated with increased frequencies of chromosome translocations, an established radiation biomarker and possible intermediary suggesting increased cancer risk. Within a large cohort of U. S. radiologic technologists, 150 provided a blood sample for whole chromosome painting and were interviewed about past x-ray examinations. The number and types of examinations reported were converted to a red bone marrow (RBM) dose score with units that approximated 1 mGy. The relationship between dose score and chromosome translocation frequency was assessed using Poisson regression. The estimated mean cumulative RBM radiation dose score was 49 (range 0 – 303). After adjustment for age, translocation frequencies significantly increased with increasing RBM dose score with an estimate of 0.004 translocations per 100 cell equivalents per score unit (95% confidence interval 0.002 to 0.007; P < 0.001). Removing extreme values or adjustment for gender, cigarette smoking, occupational radiation dose, allowing practice x-rays while training, work with radioisotopes, and radiotherapy for benign conditions did not affect the estimate. Cumulative radiation exposure from routine x-ray examinations was associated independently with increased chromosome damage, suggesting the possibility of elevated long-term health risks, including cancer. The slope estimate was consistent with expectation based on cytogenetic experience and atomic bomb survivor data.
doi:10.1158/0008-5472.CAN-08-1691
PMCID: PMC2586176  PMID: 18974125
Radiation exposure; diagnostic x-rays; chromosome translocations; FISH; risk factors
20.  Increased Frequency of Chromosome Translocations Associated with Diagnostic X-Ray Examinations 
Radiation research  2008;170(2):149-155.
Informative studies of cancer risks associated with medical radiation are difficult to conduct owing to low radiation doses, poor recall of diagnostic X rays, and long intervals before cancers occur. Chromosome aberrations have been associated with increased cancer risk and translocations are a known radiation biomarker. Seventy-nine U.S. radiologic technologists were selected for blood collection, and translocations were enumerated by whole chromosome painting. We developed a dose score to the red bone marrow for medical radiation exposure from X-ray examinations reported by the technologists that they received as patients. Using Poisson regression, we analyzed translocations in relation to the dose scores. Each dose score unit approximated 1 mGy. The estimated mean cumulative red bone marrow radiation dose score was 42 (range 1–265). After adjustment for age, occupational radiation, and radiotherapy for benign conditions, translocation frequencies significantly increased with increasing red bone marrow dose score with an estimate of 0.007 translocations per 100 CEs per score unit (95% CI, 0.002 to 0.013; P = 0.01). Chromosome damage has been linked with elevated cancer risk, and we found that cumulative radiation exposure from medical X-ray examinations was associated with increased numbers of chromosome translocations.
doi:10.1667/RR1422.1
PMCID: PMC2766815  PMID: 18666821
21.  Subclinical Hypothyroidism after Radioiodine Exposure: Ukrainian–American Cohort Study of Thyroid Cancer and Other Thyroid Diseases after the Chornobyl Accident (1998–2000) 
Environmental Health Perspectives  2008;117(5):745-750.
Background
Hypothyroidism is the most common thyroid abnormality in patients treated with high doses of iodine-131 (131I). Data on risk of hypothyroidism from low to moderate 131I thyroid doses are limited and inconsistent.
Objective
This study was conducted to quantify the risk of hypothyroidism prevalence in relation to 131I doses received because of the Chornobyl accident.
Methods
This is a cross-sectional (1998–2000) screening study of thyroid diseases in a cohort of 11,853 individuals < 18 years of age at the time of the accident, with individual thyroid radioactivity measurements taken within 2 months of the accident. We measured thyroid-stimulating hormone (TSH), free thyroxine, and antibodies to thyroid peroxidase (ATPO) in serum.
Results
Mean age at examination of the analysis cohort was 21.6 years (range, 12.2–32.5 years), with 49% females. Mean 131I thyroid dose was 0.79 Gy (range, 0–40.7 Gy). There were 719 cases with hypothyroidism (TSH > 4 mIU/L), including 14 with overt hypothyroidism. We found a significant, small association between 131I thyroid doses and prevalent hypothyroidism, with the excess odds ratio (EOR) per gray of 0.10 (95% confidence interval, 0.03–0.21). EOR per gray was higher in individuals with ATPO ≤ 60 U/mL compared with individuals with ATPO > 60 U/mL (p < 0.001).
Conclusions
This is the first study to find a significant relationship between prevalence of hypothyroidism and individual 131I thyroid doses due to environmental exposure. The radiation increase in hypothyroidism was small (10% per Gy) and limited largely to subclinical hypothyroidism. Prospective data are needed to evaluate the dynamics of radiation-related hypothyroidism and clarify the role of antithyroid antibodies.
doi:10.1289/ehp.0800184
PMCID: PMC2685836  PMID: 19479016
Chernobyl nuclear accident; Chornobyl; dose–response relationship; hypothyroidism; ionizing radiation
22.  Acoustic neuromas following childhood radiation treatment for benign conditions of the head and neck 
Neuro-Oncology  2008;10(1):73-78.
Childhood radiation exposure has been associated with an increased risk for developing several neoplasms, particularly benign and malignant thyroid tumors, but little is known about the risk of developing acoustic neuromas. The aim of this study was to confirm whether there is a risk for acoustic neuromas and, if so, to determine its magnitude and duration. We investigated the time trend and dose-response relationships for acoustic neuroma incidence in a cohort of 3,112 individuals who were irradiated as children between 1939 and 1962. Most of the patients were treated to reduce the size of their tonsils and adenoids and received substantial radiation exposure to the cerebellopontine angle, the site of acoustic neuromas. Forty-three patients developed benign acoustic neuromas, forty of them surgically resected, far in excess of what might be expected from data derived from brain tumor registries. The mean dose (±SD) to the cerebellopontine angle was 4.6 ± 1.9 Gy. The relative risk per Gy was 1.14 (95% confidence interval 1.0–1.3). The earliest case occurred 20.4 years after exposure and the latest 55 years after exposure (mean 38.3 ± 10.1 years). Our study provides support for an association between acoustic neuromas and childhood radiation exposure. Although acoustic neuromas are usually benign and often asymptomatic, many cause significant morbidity. Following childhood radiation exposure, they appear after a long latency and continue to occur many decades afterward. Any symptoms of an acoustic neuroma in a patient with a history of radiation to the head and neck area should be investigated carefully, and the threshold for employing imaging should be lowered.
doi:10.1215/15228517-2007-047
PMCID: PMC2600840  PMID: 18079359
Acoustic neuromas; dose-response relationships; radiation-related neoplasms
23.  Similar prevalence of founder BRCA1 and BRCA2 mutations among Ashkenazi and Non-Ashkenazi men with breast cancer: Evidence from 261 cases in Israel, 1976-1999 
To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma. A total of 21 BRCA2 6174delT and eight BRCA1 185delAG mutations were found. Similar frequencies of BRCA1 and BRCA2 mutation carriers were found among Ashkenazi (12.8%) and non-Ashkenazi Jews (9.1%). The combined prevalence of BRCA1/BRCA2 founder mutations among Ashkenazi Jewish men is slightly higher than for women, due to a higher frequency of BRCA2 mutations.
doi:10.1016/j.ejmg.2007.11.001
PMCID: PMC2386175  PMID: 18158280

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