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1.  Thyroid Cancer Incidence Patterns in Sao Paulo, Brazil, and the U.S. SEER Program, 1997–2008 
Thyroid  2013;23(6):748-757.
Thyroid cancer incidence has risen steadily over the last few decades in most of the developed world, but information on incidence trends in developing countries is limited. Sao Paulo, Brazil, has one of the highest rates of thyroid cancer worldwide, higher than in the United States. We examined thyroid cancer incidence patterns using data from the Sao Paulo Cancer Registry (SPCR) in Brazil and the National Cancer Institute's Surveillance Epidemiology End Results (SEER) program in the United States.
Data on thyroid cancer cases diagnosed during 1997–2008 were obtained from SPCR (n=15,892) and SEER (n=42,717). Age-adjusted and age-specific rates were calculated by sex and histology and temporal patterns were compared between the two populations.
Overall incidence rates increased over time in both populations and were higher in Sao Paulo than in the United States among females (SPCR/SEER incidence rate ratio [IRR]=1.65) and males (IRR=1.23). Papillary was the most common histology in both populations, followed by follicular and medullary carcinomas. Incidence rates by histology were consistently higher in Sao Paulo than in the United States, with the greatest differences for follicular (IRR=2.44) and medullary (IRR=3.29) carcinomas among females. The overall female/male IRR was higher in Sao Paulo (IRR=4.17) than in SEER (IRR=3.10) and did not change over time. Papillary rates rose over time more rapidly in Sao Paulo (annual percentage change=10.3% among females and 9.6% among males) than in the United States (6.9% and 5.7%, respectively). Regardless of sex, rates rose faster among younger people (<50 years) in Sao Paulo, but among older people (≥50 years) in the United States. The papillary to follicular carcinoma ratio rose from <3 to >8 among both Sao Paulo males and females, in contrast to increases from 9 to 12 and from 6 to 7 among U.S.males and females, respectively.
Increased diagnostic activity may be contributing to the notable rise in incidence, mainly for papillary type, in both populations, but it is not likely to be the only reason. Differences in iodine nutrition status between Sao Paulo and the U.S. SEER population might have affected the observed incidence patterns.
PMCID: PMC3675840  PMID: 23410185
2.  Lung, liver and bone cancer mortality in Mayak workers 
Workers at the Mayak nuclear facility in the Russian Federation offer the only adequate human data for evaluating cancer risks from exposure to plutonium. Risks of mortality from cancers of the lung, liver and bone, the organs receiving the largest doses from plutonium, were evaluated in a cohort of 17,740 workers initially hired 1948–1972 using, for the first time, recently improved individual organ dose estimates. Excess relative risk (ERR) models were used to evaluate risks as functions of internal (plutonium) dose, external (primarily gamma) dose, gender, attained age and smoking. By December 31, 2003, 681 lung cancer deaths, 75 liver cancer deaths and 30 bone cancer deaths had occurred. Of these 786 deaths, 239 (30%) were attributed to plutonium exposure. Significant plutonium dose-response relationships (p < 0.001) were observed for all 3 endpoints, with lung and liver cancer risks reasonably described by linear functions. At attained age 60, the ERRs per Gy for lung cancer were 7.1 for males and 15 for females; the averaged-attained age ERRs for liver cancer were 2.6 and 29 for males and females, respectively; those for bone cancer were 0.76 and 3.4. This study is the first to present and compare dose-response analyses for cancers of all 3 organs. The unique Mayak cohort with its high exposures and well characterized doses has allowed quantification of the plutonium dose-response for lung, liver and bone cancer risks based on direct human data. These results will play an important role in plutonium risk assessment.
PMCID: PMC4020282  PMID: 18528867
lung cancer; liver cancer; bone cancer; plutonium; ionizing radiation; nuclear workers
3.  CT scans in young people in Northern England: trends and patterns 1993–2002 
Pediatric radiology  2011;41(7):832-838.
Although CT can be greatly beneficial, its relatively high radiation doses have caused public health concerns.
To assess patterns in CT usage among patients aged less than 22 years in Northern England during the period 1993–2002.
Materials and methods
Electronic data were obtained from radiology information systems of all nine National Health Service trusts in the region.
A total of 38,681 scans had been performed in 20,483 patients aged less than 22 years. The number of CT examinations rose, with the steepest increase between 1997 and 2000. The number of patients scanned per year increased less dramatically, with 2.24/1,000 population aged less than 22 years having one scan or more in 1993 compared to 3.54/1,000 in 2002. This reflects an increase in the median number of scans per patient, which rose from 1 in 1993 to 2 by 1999. More than 70% of CT examinations were of the head, with the number of head examinations varying with time and patient age.
The frequency of CT scans in this population more than doubled during the study period. This is partly, but not wholly, explained by an increase in the number of scans per patient.
PMCID: PMC3992619  PMID: 21594548
Radiation dose; Computed tomography; Trends; Child
4.  Non-Malignant Thyroid Diseases Following a Wide Range of Radiation Exposures 
Radiation research  2010;174(6):877-888.
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.
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.
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.
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.
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.
PMCID: PMC3927789  PMID: 21128812
5.  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.
PMCID: PMC3865880  PMID: 20426666
6.  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
7.  Common Genetic Variants in Sex Hormone Pathway Genes and Papillary Thyroid Cancer Risk 
Thyroid  2012;22(2):151-156.
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.
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.
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.
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.
PMCID: PMC3271376  PMID: 22224819
8.  Diabetes and Thyroid Cancer Risk in the National Institutes of Health-AARP Diet and Health Study 
Thyroid  2011;21(9):957-963.
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.
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.
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).
This study lends support to the hypothesis that diabetes increases the risk of differentiated thyroid cancer.
PMCID: PMC3162644  PMID: 21767143
9.  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.
PMCID: PMC3166197  PMID: 21642358
10.  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.
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.
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.
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.
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.
PMCID: PMC3086738  PMID: 21454129
11.  Socio-economic variation in CT scanning in Northern England, 1990-2002 
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.
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.
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).
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.
PMCID: PMC3276411  PMID: 22283843
12.  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.
PMCID: PMC3222994  PMID: 21406336
Chernobyl nuclear accident; Chornobyl, Ukraine, 1986; dose–response relationship; incidence, thyroid neoplasms/epidemiology; iodine; radioactive; radiation
13.  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.
PMCID: PMC2919690  PMID: 19795465
14.  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.
PMCID: PMC3075914  PMID: 20602108
15.  Papillary Microcarcinoma of the Thyroid among Atomic Bomb Survivors: Tumor Characteristics and Radiation Risk 
Cancer  2010;116(7):1646-1655.
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.
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.
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.
Low-to-moderate doses of ionizing radiation appears to increase the risk of thyroid PMCs, even when exposure occurs during adulthood.
PMCID: PMC2846973  PMID: 20120034
thyroid; papillary microcarcinoma; atomic bombs; radiation
16.  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.
PMCID: PMC3037470  PMID: 21310791
17.  Early life exposure to diagnostic radiation and ultrasound scans and risk of childhood cancer: case-control study 
The BMJ  2011;342:d472.
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.
PMCID: PMC3037470  PMID: 21310791
18.  Comparison of second cancer risks from brachytherapy and external beam therapy after uterine corpus cancer 
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.
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.
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.
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.
PMCID: PMC2866968  PMID: 20142245
endometrial adenocarcinomas; epidemiology; gynecologic malignancy; radiation; radiotherapy
19.  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.
PMCID: PMC3290908  PMID: 19951937
body mass index; hormones; motor activity; prospective studies; reproduction; smoking; thyroid diseases; thyroid neoplasms
20.  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.
PMCID: PMC2875679  PMID: 19138047
Thyroid nodules; single nucleotide polymorphisms; epidemiology; thyroid cancer; ionizing radiation; interaction
21.  Risk of Radiation-related Salivary Gland Carcinomas Among Hodgkin Lymphoma Survivors: A Population-based Analysis 
Cancer  2008;113(11):3153-3159.
Radiotherapy for Hodgkin lymphoma (HL) increases the risk of salivary gland carcinomas (SGC); however the magnitude of the risk has not been assessed.
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.
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).
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.
PMCID: PMC2868333  PMID: 18823043
Hodgkin lymphoma; subsequent salivary gland carcinoma; mucoepidermoid carcinoma; radiotherapy; risk
22.  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.
PMCID: PMC2676561  PMID: 19240234
Incidence; Thyroid cancer; Papillary; SEER Program
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.
PMCID: PMC2586176  PMID: 18974125
Radiation exposure; diagnostic x-rays; chromosome translocations; FISH; risk factors
24.  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.
PMCID: PMC2766815  PMID: 18666821
25.  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.
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.
This study was conducted to quantify the risk of hypothyroidism prevalence in relation to 131I doses received because of the Chornobyl accident.
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.
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).
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.
PMCID: PMC2685836  PMID: 19479016
Chernobyl nuclear accident; Chornobyl; dose–response relationship; hypothyroidism; ionizing radiation

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