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1.  Thyroid cancer in Ukraine after the Chernobyl accident (in the framework of the Ukraine–US Thyroid Project) 
As a result of the accident at the Chernobyl Nuclear Power Plant, millions of residents of Belarus, Russia, and Ukraine were exposed to large doses of radioactive iodine isotopes, mainly I-131. The purpose of the Ukraine–American (UkrAm) and Belarus–American (BelAm) projects are to quantify the risks of thyroid cancer in the framework of a classical cohort study, comprising subjects who were aged under 18 years at the time of the accident, had direct measurements of thyroid I-131 radioactivity taken within two months after the accident, and were residents of three heavily contaminated northern regions of Ukraine (Zhitomir, Kiev, and Chernigov regions). Four two-year screening examination cycles were implemented from 1998 until 2007 to study the risks associated with thyroid cancer due to the iodine exposure caused during the Chernobyl accident. A standardised procedure of clinical examinations included: thyroid palpation, ultrasound examination, blood collection followed by a determination of thyroid hormone levels, urinary iodine content test, and fine-needle aspiration if required. Among the 110 cases of thyroid cancer diagnosed in UkrAm as the result of four screening examinations, 104 cases (94.5%) of papillary carcinomas, five cases (4.6%) of follicular carcinomas, and one case (0.9%) of medullary carcinoma were diagnosed.
doi:10.1088/0952-4746/32/1/N65
PMCID: PMC3902783  PMID: 22394669
2.  PROJECTED LIFETIME CANCER RISKS FROM EXPOSURE TO REGIONAL RADIOACTIVE FALLOUT IN THE MARSHALL ISLANDS 
Health physics  2010;99(2):201-215.
Radioactive fallout from nuclear test detonations during 1946–1958 at Bikini and Enewetak atolls in the Marshall Islands (MI) exposed populations living elsewhere in the archipelago. A comprehensive analysis, presented in seven companion papers, has produced estimates of tissue-specific radiation absorbed dose to MI residents at all historically inhabited atolls from internal (ingested) and external radioactive components of fallout, by calendar year, and by age of the population at time of exposure. The present report deals, for the first time, with the implications of these doses on cancer risk among exposed members of the MI population. Radiation doses differed by geographic location and year of birth, and radiation-related cancer risk depends upon age at exposure and age at observation for risk. Using dose-response models based on committee reports published by the National Research Council and the National Institutes of Health, we project that, during the lifetimes of members of the MI population potentially exposed to ionizing radiation from weapons test fallout deposited during the testing period (1948–1958) and from residual radioactive sources during the subsequent 12 years (1959–1970), perhaps 1.6% (with 90% uncertainty range 0.4% and 3.4%) of all cancers might be attributable to fallout-related radiation exposures. The projected proportion of cancers attributable to radiation from fallout from all nuclear tests conducted in the Marshall Islands is 55% (28%–69%) among 82 persons exposed in 1954 on Rongelap and Ailinginae, 10% (2%–22%) for 157 persons exposed on Utrik, and 2% (0.5%–5%) and 1% (0.2%–2%), respectively, for the much larger populations exposed in mid-latitude locations including Kwajalein and in southern locations including Majuro. By cancer type, point estimates of attributable risk varied by location, between 12% and 95% for thyroid cancer, between 2% and 78% for leukemia, and between 1% and 55% for all cancers combined. The largest projected risks pertain to the Rongelap Island community and the lowest risks pertain to the populations resident on the southern-most atolls. While the projected cancer risks are smaller than those estimated by the National Cancer Institute in simplistic analyses conducted in 2004, these estimates of cancer risk are the best available as they are based on the most detailed dose reconstruction to date and comprehensively include populations at all locations and dose contributions from all nuclear tests.
doi:10.1097/HP.0b013e3181dc4e84
PMCID: PMC3892964  PMID: 20622551
Marshall Islands; cancer risk; fallout; nuclear testing
3.  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
4.  Radiation and the Risk of Chronic Lymphocytic and Other Leukemias among Chornobyl Cleanup Workers 
Background: Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear.
Objectives: We estimated relative risks of CLL and non-CLL from protracted exposures to low-dose ionizing radiation.
Methods: A nested case–control study was conducted in a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chornobyl nuclear power plant accident. Cases of incident leukemia diagnosed in 1986–2006 were confirmed by a panel of expert hematologists/hematopathologists. Controls were matched to cases on place of residence and year of birth. We estimated individual bone marrow radiation doses by the Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) method. We then used a conditional logistic regression model to estimate excess relative risk of leukemia per gray (ERR/Gy) of radiation dose.
Results: We found a significant linear dose response for all leukemia [137 cases, ERR/Gy = 1.26 (95% CI: 0.03, 3.58]. There were nonsignificant positive dose responses for both CLL and non-CLL (ERR/Gy = 0.76 and 1.87, respectively). In our primary analysis excluding 20 cases with direct in-person interviews < 2 years from start of chemotherapy with an anomalous finding of ERR/Gy = –0.47 (95% CI: < –0.47, 1.02), the ERR/Gy for the remaining 117 cases was 2.38 (95% CI: 0.49, 5.87). For CLL, the ERR/Gy was 2.58 (95% CI: 0.02, 8.43), and for non-CLL, ERR/Gy was 2.21 (95% CI: 0.05, 7.61). Altogether, 16% of leukemia cases (18% of CLL, 15% of non-CLL) were attributed to radiation exposure.
Conclusions: Exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase in risk of leukemia, which was statistically consistent with estimates for the Japanese atomic bomb survivors. Based on the primary analysis, we conclude that CLL and non-CLL are both radiosensitive.
doi:10.1289/ehp.1204996
PMCID: PMC3553431  PMID: 23149165
Chernobyl nuclear accident; Chornobyl; Ukraine; chronic lymphocytic leukemia; leukemia; matched case–control study; radiation; radiation dose–response relationship; radiation-induced leukemia
5.  COMPARISON OF INTERNAL DOSIMETRY FACTORS FOR THREE CLASSES OF ADULT COMPUTATIONAL PHANTOMS WITH EMPHASIS ON I-131 IN THE THYROID 
Physics in medicine and biology  2011;56(22):7317-7335.
S values for 11 major target organs for I-131 in the thyroid were compared for three classes of adult computational human phantoms: stylized, voxel and hybrid phantoms. In addition, we compared Specific Absorbed Fractions (SAFs) with the thyroid as a source region over a broader photon energy range than the x- and gamma-rays of I-131. S and SAF values were calculated for the International Commission on Radiological Protection (ICRP) reference voxel phantoms and the University of Florida (UF) hybrid phantoms by using Monte Carlo transport method, while the S and SAF values for the Oak Ridge National Laboratory (ORNL) stylized phantoms were obtained from earlier publications. Phantoms in our calculations were for adults of both genders. The 11 target organs and tissues that were selected for the comparison of S values are: brain, breast, stomach wall, small intestine wall, colon wall, heart wall, pancreas, salivary glands, thyroid, lungs, and active marrow for I-131 and thyroid as a source region. The comparisons showed, in general, an underestimation of S values reported for the stylized phantoms compared to the values based on the ICRP voxel and UF hybrid phantoms and a relatively good agreement between the S values obtained for the ICRP and UF phantoms. Substantial differences were observed for some organs between the 3 types of phantoms. For example, the small intestine wall of ICRP male phantom and heart wall of ICRP female phantom showed up to 8-fold and 4-fold greater S values, respectively, compared to the reported values for the ORNL phantoms. UF male and female phantoms also showed significant differences compared to the ORNL phantom, 4.0-fold greater for small intestine wall and 3.3-fold greater for heart wall. In our method, we directly calculated the S values without using the SAFs as commonly done. Hence, we sought to confirm the differences observed in our S values by comparing SAFs among the phantoms with the thyroid as a source region for selected target organs - small intestine wall, lungs, pancreas and breast as well as illustrate differences in energy deposition across the energy range (12 photon energies from 0.01 to 4 MeV). Differences were found in SAFs between phantoms in a similar manner to the differences observed in S values but with larger differences at lower photon energies. To investigate the differences observed in S and SAF values, the chord length distributions (CLDs) were computed for the selected source-target pairs and compared across the phantoms. As demonstrated by the CLDs, we found that the differences between phantoms in those factors used in internal dosimetry were governed to a significant degree by inter-organ distances which are a function of organ shape as well as organ location.
doi:10.1088/0031-9155/56/22/020
PMCID: PMC3484894  PMID: 22040775
I-131; S value; Monte Carlo radiation transport; computational human phantoms
6.  Methods for Estimation of Radiation Risk in Epidemiological Studies Accounting for Classical and Berkson Errors in Doses 
With a binary response Y, the dose-response model under consideration is logistic in flavor with pr(Y=1 | D) = R (1+R)−1, R = λ0 + EAR D, where λ0 is the baseline incidence rate and EAR is the excess absolute risk per gray. The calculated thyroid dose of a person i is expressed as Dimes=fiQimes/Mimes. Here, Qimes is the measured content of radioiodine in the thyroid gland of person i at time tmes, Mimes is the estimate of the thyroid mass, and fi is the normalizing multiplier. The Qi and Mi are measured with multiplicative errors ViQ and ViM, so that Qimes=QitrViQ (this is classical measurement error model) and Mitr=MimesViM (this is Berkson measurement error model). Here, Qitr is the true content of radioactivity in the thyroid gland, and Mitr is the true value of the thyroid mass. The error in fi is much smaller than the errors in ( Qimes, Mimes) and ignored in the analysis.
By means of Parametric Full Maximum Likelihood and Regression Calibration (under the assumption that the data set of true doses has lognormal distribution), Nonparametric Full Maximum Likelihood, Nonparametric Regression Calibration, and by properly tuned SIMEX method we study the influence of measurement errors in thyroid dose on the estimates of λ0 and EAR. The simulation study is presented based on a real sample from the epidemiological studies. The doses were reconstructed in the framework of the Ukrainian-American project on the investigation of Post-Chernobyl thyroid cancers in Ukraine, and the underlying subpolulation was artificially enlarged in order to increase the statistical power. The true risk parameters were given by the values to earlier epidemiological studies, and then the binary response was simulated according to the dose-response model.
doi:10.2202/1557-4679.1281
PMCID: PMC3058406  PMID: 21423564
Berkson measurement error; Chornobyl accident; classical measurement error; estimation of radiation risk; full maximum likelihood estimating procedure; regression calibration; SIMEX estimator; uncertainties in thyroid dose
7.  RECONSTRUCTION OF RADIATION DOSES IN A CASE-CONTROL STUDY OF THYROID CANCER FOLLOWING THE CHERNOBYL ACCIDENT 
Health physics  2010;99(1):1-16.
A population-based case-control study of thyroid cancer was carried out in contaminated regions of Belarus and Russia among persons who were exposed during childhood and adolescence to fallout from the Chernobyl accident. For each study subject, individual thyroid doses were reconstructed for the following pathways of exposure: (1) intake of 131I via inhalation and ingestion; (2) intake of short-lived radioiodines (132I, 133I, and 135I) and radiotelluriums (131mTe, 132Te) via inhalation and ingestion; (3) external dose from radionuclides deposited on the ground; and (4) ingestion of 134Cs and 137Cs. A series of intercomparison exercises validated the models used for reconstruction of average doses to populations of specific age groups as well as of individual doses. Median thyroid doses from all factors for study subjects were estimated to be 0.37 and 0.034 Gy in Belarus and Russia, respectively. The highest individual thyroid doses among the subjects were 10.2 Gy in Belarus and 5.3 Gy in Russia. Iodine-131 intake was the main pathway for thyroid exposure. Estimated doses from short-lived radioiodines and radiotelluriums ranged up to 0.53 Gy. Reconstructed individual thyroid doses from external exposure ranged up to 0.1 Gy, while those from internal exposure due to ingested cesium did not exceed 0.05 Gy. The uncertainty of the reconstructed individual thyroid doses, characterized by the geometric standard deviation, varies from 1.7 to 4.0 with a median of 2.2.
doi:10.1097/HP.0b013e3181c910dd
PMCID: PMC2885044  PMID: 20539120
Chernobyl; radioiodine; dose reconstruction; thyroid
8.  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
9.  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
10.  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

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