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1.
PCR-based typing of Hras1 minisatellite alleles was carried out in 226 non-small cell lung cancer (NSCLC) patients and 207 unaffected controls. Application of this method permitted detection of four common (a1 to a4) and 25 other alleles, differing from any common allele by one or more repeat units. Depending on their frequency in control group, these alleles were defined as intermediate or rare (the frequency over 0.5% or less than 0.5%, respectively). It was established that the frequency of rare alleles in the group of NSCLC patients (7.1%) was statistically significantly higher than in healthy individuals (2.2%, p = 0.002), while the difference in the distribution of common and intermediate alleles between the compared groups was not statistically significant. In addition, rare Hras1 alleles were more frequent (p = 0.02) among nonsmoking patients compared to the patients subjected to of tobacco carcinogens. The presence of "heavy" (a3-a4) alleles was associated with an increased risk of low-differentiated and/or actively metastasizing tumors and also with the risk of lung cancer in the patients under 50 years of age (p < 0.05). These data indicate that an approach including application of modern highly sensitive techniques of Hras1 allele typing in combination with preliminary examination of healthy control population can be employed for identifying carcinogenic risk groups as well as for prognosis of the NSCLC clinical course.  相似文献   

2.
The accident that occurred at the Chernobyl Nuclear Power Plant in 1986, released large quantities of radionuclides--among them radioiodine--into the atmosphere, thereby raising public concerns about its influence on thyroid structure and function, especially the development of malignancy. There were even reports about 700 deaths due to thyroid carcinoma in Russian Federation, Ukraine and Belarus, resulting from the accident. In this review we discussed the incidence of thyroid cancer in different parts of the world, especially in heavily contaminated countries, as Ukraine and Belarus, and the possible link between radioisotope activity in the thyroid and the development of malignancy. The study carried out in Minsk showed 40-fold increase of the incidence of thyroid cancer in the years 1986-1994, in comparison to the period 1977-1985. An increase of the incidence of thyroid cancer has generally been observed in many countries after the Chernobyl accident. We focused on the factors that may have an influence on this phenomenon, especially diagnostic tests, health care, social and environmental factors, like iodine level in water and soil. The results of molecular biology studies, e.g. RET translocation in carcinoma type RET/PTC1 in elderly and RET/PTC3 in children, and expression Ax1 and Gas6 in children were reviewed as well. We also mentioned other thyroid diseases, like nodular goitre, cysts, the disturbance of thyroid function and autoimmunity, possibly linked to the radiation after Chernobyl accident. Data obtained from the regions near Chernobyl showed no increased risk of other types of malignancy (leukaemia, Hodgkin's and non Hodgkin's lymphoma) in 1986-1996. In this article the epidemiology of thyroid diseases in Poland was also reviewed.  相似文献   

3.

Background

A possible increase in thyroid cancer in the young represents the most critical health problem to be considered after the nuclear accident in Fukushima, Japan (March 2011), which is an important lesson from the Chernobyl disaster (April 1986). Although it was reported that childhood thyroid cancer had started to increase 3–5 yr after the Chernobyl accident, we speculate that the actual period of latency might have been shorter than reported, considering the delay in initiating thyroid surveillance in the then Soviet Union and also the lower quality of ultrasonographic testing in the 1980s. Our primary objectives in the present study were to identify any possible thyroid abnormality in young Fukushima citizens at a relatively early timepoint (20–30 months) after the accident, and also to strive to find a possible relationship among thyroid ultrasonographic findings, thyroid-relevant biochemical markers, and iodine-131 ground deposition in the locations of residence where they stayed during very early days after the accident.

Methods and Findings

This is a cross-sectional study. We targeted the Fukushima residents who were 18 yr old or younger (including fetuses) at the time of the accident. Our examinations comprised a questionnaire, thyroid ultrasonography, thyroid-related blood tests, and urinary iodine measurement. We analyzed a possible relationship among thyroid ultrasonographic findings (1,137 subjects), serum hormonal data (731 subjects), urinary iodine concentrations (770 subjects), and iodine-131 ground deposition (1,137 subjects). We did not find any significant relationship among these indicators, and no participant was diagnosed to contract thyroid cancer.

Conclusions

At the timepoint of 20–30 months after the accident, we did not confirm any discernible deleterious effects of the emitted radioactivity on the thyroid of young Fukushima residents. This is the first report in English detailing the thyroid status of young Fukushima residents after the nuclear disaster.  相似文献   

4.
Data on allelotyping of minisatellite sequence within the Hras1 protooncogene locus in 60 patients with lung adenocarcinoma (LAC) are presented. Allele distribution was analyzed with respect to the effect of tobacco smoke carcinogens (smoking factor). Results were compared with the analogous data obtained for patients with squamous-cell-carcinoma and for individuals without cancer. In contrast to the patients with squamous cell-carcinoma, the frequency of the Hras1 locus rare alleles in patients with lung-adenocarcinoma was higher than in individuals without cancer. More striking difference between the latter groups was demonstrated for nonsmoking patients (17.6% versus 2.7% of healthy individuals, P = 0.0005). In smoking LAC patients, higher frequencies of the common a4 allele (2.5 kb in size under the MspI/HpaII digestion) were found. Our findings point to the combined effect of endogenous and exogenous factors on the development of lung adenocarcinomas in humans. In this work, we discuss the possible mechanism of association between the rare minisatellite alleles and the predisposition to lung cancer.  相似文献   

5.
For the first time, a comparative analysis of thyroid cancer incidence in Ukraine after the Chernobyl accident was done in a cohort that is almost as large as the general population. On the basis of thyroid doses from radioactive iodine in individuals aged 1-18 years at the time of accident, geographic regions of Ukraine with low and high average accumulated thyroid doses were established and designated "low-exposure" and "high-exposure" territories, respectively. A significant difference of thyroid cancer incidence rates as a function of time between the two territories was found. That is, the increase in the incidence was higher in high-exposure regions than in low-exposure regions. The incidence rates varied substantially among the different attained age-groups, especially in the youngest one (up to 19 years old). The analysis that was adjusted for screening and technological effects also indicated that in the high-exposure regions, thyroid cancer incidence rates at the age of diagnosis of 5-9, 10-14 and 15-19 years were significantly higher in those born in 1982-1986 compared to those born in 1987-1991, while in the low-exposure regions, no significant difference was observed. The observed probable excess of radiation-induced thyroid cancer cases in adults exposed to radioactive iodine from the Chernobyl accident, especially in females, may be due to the high power of the present study. However, it should be noted that our investigation was not essentially free from ecological biases.  相似文献   

6.
A single accidental event such as the fallout released from the Chernobyl reactor in 1986 can expose millions of people to non-natural environmental radiation. Ionizing radiation increases the frequency of germline mutations in experimental studies, but the genetic effects of radiation in humans remain largely undefined. To evaluate the hereditary effects of low radiation doses, we compared the minisatellite mutation rates of 155 children born to Estonian Chernobyl cleanup workers after the accident with those of their siblings born prior to it. All together, 94 de novo paternal minisatellite mutations were found at eight tested loci (52 and 42 mutants among children born after and before the accident, respectively). The minisatellite mutation rate was nonsignificantly increased among children born after the accident (0.042 compared to 0.036, OR 1.33, 95% CI 0.80-2.20). Furthermore, there was some indication of an increased mutation rate among offspring born after the accident to workers who had received doses of 20 cSv or above compared with their siblings born before the accident (OR 3.0, 95% CI 0.97-9.30). The mutation rate was not associated with the father's age (OR 1.04, 95% CI 0.94-1.15) or the sex of the child (OR 0.95, 95% CI 0.50-1.79). Our results are consistent with both no effect of radiation on minisatellite mutations and a slight increase at dose levels exceeding 20 cSv.  相似文献   

7.
Within the time period 1990–1993, childhood thyroid cancer incidence due to the Chernobyl accident increased dramatically in Belarus, especially with regard to the birth cohort January 1, 1971, to May 31, 1986. This rise subsequently slowed down, i.e. during the period 1994–1996. The respective data were analysed and compared with the results of an analysis on the time dependence of thyroid cancer incidence in a pooled cohort of persons who had been exposed during childhood to external radiation with high dose rates. Concerning the period of 5–10 years following exposure, the excess absolute cancer risk per unit thyroid dose in the latter (external) exposure group was found to exceed the one in the Belarus group by a factor of two. This difference, however, is not statistically significant. The age-adjusted average excess absolute risk per unit thyroid dose for the period of 5–50 years following external childhood exposure was found to be 8 female and 14 male cases per 104 person-year · Gy, which is a factor about 2.5 times higher than for the non-adjusted risk in the pooled cohort, as reported by Ron et al. in 1995. Assessments of future excess thyroid cancer cases due to the Chernobyl accident were done on the basis of the time dependence of thyroid cancer risk following external exposure. The thyroid cancer incidence among the birth cohort considered in Belarus and for a period starting from the cessation of the available observation data (1 January 1997) and extending to 50 years after the Chernobyl accident has been estimated to be about 15,000 cases, with an uncertainty range of 5000–45,000 cases. According to our calculations, 80% of these cases exceed the baseline risk under enhanced thyroid surveillance. Received: 8 June 1999 / Accepted in revised form: 20 November 1999  相似文献   

8.
After the accident at the Chernobyl nuclear power plant, a considerable increase in the incidence of thyroid cancer among children in Belarus was observed. In the present study, the frequency of the c-ret protooncogene rearrangements in samples of thyroid carcinomas resected and diagnosed in 1998 from individuals in Belarus was investigated. The ret/PTC1 oncogene was detected in 19% of the samples, and the ret/PTC3r1 oncogene, in 14%. The number of ret/PTC1 rearrangements observed in tumor cells from the patients whose age at the time of the accident was from 1 to 10 years, was greater compared to those whose age at the time was from 10 to 20 years, irrespective of the year of surgery (1996 or 1998). The majority of the patients with ret/PTC3r1 rearrangements lived in Gomel oblast, which was contaminated by the Chernobyl meltdown.  相似文献   

9.
The thyroid gland is highly sensitive to radiation during childhood: the risk of thyroid tumours is increased for mean doses as low as 100 mGy and for higher doses, the risk increases linearly with the dose. Excess relative risk is important, being 7.7 for 1 Gy delivered to the thyroid gland during childhood. The risk of thyroid tumours is modified by several factors: a) age at exposure: in childhood, the risk decreases with increasing age at exposure and is not significant after 20 years; b) gender: females are two times more likely than males to develop thyroid tumours; c) genetic predisposition due to a defect in DNA repair mechanisms, and dietary and hormonal factors may modify the risk; d) the influence of fractionation and dose rate is not well established. Radioiodine 131 (1311) used for medical purposes has almost no tumourigenic effect on the adult thyroid gland. The consequences of the Chernobyl accident have clearly shown that the risk of thyroid cancer after exposure to 1311 in childhood is important, and that such exposure should be prevented by potassium iodine prophylaxis. RET/PTC rearrangements are found in 60-80% of papillary carcinomas and in 45% of adenomas occurring after radiation exposure. They are found in 5-15% of papillary carcinoma and in no follicular adenomas that occurred in the absence of radiation exposure.  相似文献   

10.

Objective

After the accident at the Chernobyl Nuclear Power Plant (CNPP), the incidence of thyroid cancer increased among children. Recently, a strong relationship between solid thyroid nodules and the incidence of thyroid cancer was shown in atomic bomb survivors. To assess the prognosis of benign thyroid nodules in individuals living in the Zhitomir region of Ukraine, around the CNPP, we conducted a follow-up investigation of screening data from 1991 to 2000 in the Ukraine.

Patients and Methods

Participants of this study were 160 inhabitants with thyroid nodules (nodule group) and 160 inhabitants without thyroid nodules (normal control group) intially identified by ultrasonography from 1991 to 2000. All participants were aged 0 to 10 years old and lived in the same area at the time of the accident. We performed follow-up screening of participants and assessed thyroid nodules by fine needle aspiration biopsy.

Results

Among the nodule group participants, the number and size of nodules were significantly increased at the follow-up screening compared with the initial screening. No thyroid nodules were observed among the normal control group participants. The prevalence of thyroid abnormality, especially nodules that could be cancerous (malignant or suspicious by fine needle aspiration biopsy), was 7.5% in the nodule group and 0% in the normal control group (P<0.001).

Conclusions

Our study indicated that a thyroid nodule in childhood is a prognostic factor associated with an increase in the number and size of nodules in individuals living in the Zhitomir region of Ukraine.  相似文献   

11.
R. A. Mustard 《CMAJ》1975,113(2):109-113
This is a review of one surgeon''s personal experience with 85 patients with thyroid cancer treated over a 20-year period. The data confirm that for papillary thyroid tumours, with rare exceptions, the prognosis is excellent. Anaplastic lesions, however, are consistently lethal. Follicular carcinoma and medullary carcinoma fall between these extremes. A simple clinical classification is offered as a guide to operative management and a reliable index of prognosis. Patients with clinically apparent, "manifest cancer" have serious, life-threatening disease; many such patients die of their disease. Patients with "neck lumps not yet diagnosed" usually have papillary carcinoma; their prognosis is excellent. Patients whose thyroid tumours fall into the category of "malignant nodule" or "pathologist''s cancer" are particularly fortunate: in this series no such patient has died. The importance of age in relation to thyroid cancer is also confirmed: non of the patients first treated before the age of 40 years has died of cancer. For young patients with favourable disease the author recommends conservative surgical treatment, which avoids cosmetic deformity or functional disability, to be followed by administration of levothyroxine to suppress production of thyroid=stimulating hormone. For patients with "unfavourable" thyroid cancer valuable palliation can often be achieved by a combination of surgery and irradiation. Survival rates for the total series are 76% at 5 years and 60% at 10 years.  相似文献   

12.
BORIS, a member of the cancer-testis antigen family with testis specific expression, showed abnormal expression in various cancer types including prostate cancer. In our previous work, we identified the polymorphic minisatellite, BORIS-MS2, located in the promoter region of BORIS. BORIS-MS2 was revealed as a polymorphic minisatellite that contains seven alleles each with different numbers of the repeat unit. We assessed the association between the allelic variation of BORIS-MS2 and prostate cancer by a case-control study. Using a PCR-based method, 315 cancer-free male controls and 648 cases with prostate cancer were genotyped. There was no significant difference observed in the overall distribution of this minisatellite, which indicates that this polymorphism is not responsible for prostate cancer susceptibility in the Korean population. Additionally, two new rare alleles (9 and 19 copies) were detected in this study, which were identified only in cancer subjects. When we compared the clinicopathological information with the Jewett-Whitmore system of prostate cancer classification, the frequency of rare allele cases in the higher grade was significantly higher than in the total prostate group (P = 0.032). The higher grades in the Jewett-Whitmore system were associated with a poor prognosis. Therefore, this result suggests that the rare alleles of BORIS-MS2 may be used as a marker of poor outcome in prostate cancer patients.  相似文献   

13.
The Belarus-American (BelAm) thyroid study cohort consists of persons who were 0-18 years of age at the time of exposure to radioactive iodine fallout from the 1986 Chernobyl nuclear power plant accident and who have undergone serial thyroid screenings with referral for fine-needle aspiration biopsy (FNAB) using standardized criteria. We investigated thyrocyte nuclear abnormalities in cytological samples from FNABs in 75 BelAm subjects with single and multiple thyroid nodules and 47 nodular goiter patients from Leningrad, Russia, unexposed to Chernobyl fallout. Nuclear abnormalities examined included internuclear chromosome bridges and derivative nuclei with broken bridges (i.e., "tailed" nuclei), which are formed from dicentric and ring chromosomes and thus may be cellular markers of radiation exposure. Among subjects with single-nodular goiter, thyrocytes with bridges were present in 86.8% of the exposed BelAm cohort compared with 27.0% of unexposed controls. The average frequency of thyrocytes with bridges and with tailed nuclei was also significantly higher in the BelAm subjects than in controls. Among subjects with multinodular goiters, thyrocytes with bridges were present in 75.7% of exposed BelAm patients compared with 16.7% of unexposed controls; thyrocytes with tailed nuclei were observed in all of the BelAm subjects but in only 40% of controls, and the mean frequencies of bridges and tailed nuclei were significantly higher in the exposed group. Unusually, long bridges were detected in 29% of BelAm patients with single-nodular goiters and 35% of those with multinodular goiters, while no such abnormalities were observed among patients from the Leningrad region. In the exposed subjects from BelAm, we also found positive correlations between their estimated dose of Iodine-131 from Chernobyl fallout and the frequency of tailed nuclei (p = 0.008) and bridges (p = 0.09). Further study is needed to confirm that these phenomena represent consequences of radiation exposure in the human organism.  相似文献   

14.
The paper presents the data of thyroid ultrasound and laboratory studies in 233 persons exposed to radiation: 63 X-ray physicians, 36 Chernobyl accident liquidators, 31 patients with lymphogranulomatosis, receiving radiotherapy, and 103 individuals (a control group) who were physicians of various specialties whose professional activity is unassociated with radiation factors. Thyroid changes were found in 67.7% of the examinees after gamma teletherapy and in 31% in the control group; among X-rat physicians and Chernobyl accident liquidators, the occurrence of thyroid changes was equal--44.4%. Direct radiation exposure of the thyroid in a dose of above 30 Gy led to the development of postradiation fibrosis (22.5%) and postradiation thyroiditis (32.3%) with thyroid dysfunction that is most commonly presented by hypothyroidism (22.45%). Autoimmune thyroiditis (11.1%) more predominantly with subclinical hypothyroidism, and diffuse thyroid hyperplasia (19.4%) resulted from mixed internal and external radiation. Thyroid changes revealed in X-ray physicians mainly appeared as nodular masses (22.2%) without functional impairments but to be followed up. It is recommended that the annual preventive examination protocol be supplemented by thyroid ultrasound studies in X-ray physicians.  相似文献   

15.
PCR-based typing of Hras1minisatellite alleles was carried out in 226 non-small cell lung cancer (NSCLC) patients and 207 unaffected controls. Application of this method permitted detection of four common (a1toa4) and 25 other alleles, differing from any common allele by one or more repeat units. Depending on their frequency in control group, these alleles were defined as intermediate or rare (the frequency over 0.5% or less than 0.5%, respectively). It was established that the frequency of rare alleles in the group of NSCLC patients (7.1%) was statistically significantly higher than in healthy individuals (2.2%, P= 0.002), while the difference in the distribution of common and intermediate alleles between the compared groups was not statistically significant. In addition, rareHras1alleles were more frequent (P= 0.02) among nonsmoking patients (P= 0.02) compared to the patients subjected to of tobacco carcinogens. The presence of heavy (a3a4) alleles was associated with an increased risk of low-differentiated and/or actively metastasizing tumors and also with the risk of lung cancer in the patients under 50 years of age (P< 0.05). These data indicate that an approach including application of modern highly sensitive techniques ofHras1allele typing in combination with preliminary examination of healthy control population can be employed for identifying carcinogenic risk groups as well as for prognosis of the NSCLC clinical course.  相似文献   

16.
Germline mutation at eight human minisatellite loci has been studied among families from rural areas of the Kiev and Zhitomir regions of Ukraine, which were heavily contaminated by radionuclides after the Chernobyl accident. The control and exposed groups were composed of families containing children conceived before and after the Chernobyl accident, respectively. The groups were matched by ethnicity, maternal age, parental occupation, and smoking habits, and they differed only slightly by paternal age. A statistically significant 1.6-fold increase in mutation rate was found in the germline of exposed fathers, whereas the maternal germline mutation rate in the exposed families was not elevated. These data, together with the results of our previous analysis of the exposed families from Belarus, suggest that the elevated minisatellite mutation rate can be attributed to post-Chernobyl radioactive exposure. The mechanisms of mutation induction at human minisatellite loci are discussed.  相似文献   

17.
A vast amount of research articles devoted to the increase in childhood thyroid cancer incidence in the most contaminated by radionuclides territories of Belarus, Russia and Ukraine affected by the Chernobyl accident were published recent years. However, the amount of research studies of thyroid cancer incidence among the Chernobyl emergency workers (liquidators) is quite scanty. In the article results of the study of thyroid cancer incidence in the cohort of the Chernobyl liquidators (103427 persons) residing in 6 administrative regions of Russia (North-West, Volgo-Vyatsky, Central-Chernozemny, Povolzhsky, North-Caucasus and Urals) are described and discussed. For the period 1986-2003 eighty seven cases of thyroid cancer were detected in the cohort. Statistically significant excess of the incidence among liquidators over baseline incidence, SIR = 3.39 (95% CI: 2.73; 4.16), among men of Russia has been found. The highest thyroid cancer incidence (SIR = 6.49) was registered among liquidators who had been involved in mitigation works during April-July 1986. At the same time no statistically significant relationship between the incidence rate and external radiation dose, ERR = 1.68 (95% CI: -0.95; 6.46), was detected.  相似文献   

18.
On April 26, 1986, the worst nuclear reactor accident to date occurred at the Chornobyl (Chernobyl) power plant in Ukraine. Millions of people in Ukraine, Belarus and Russia were exposed to radioactive nuclides, especially (131)I. Since then, research has been conducted on various subgroups of the exposed population, and it has been demonstrated that the large increase in thyroid cancer is related to the (131)I exposure. However, because of study limitations, quantified risk estimates are limited, and there remains a need for additional information. We conducted an ecological study to investigate the relationship between (131)I thyroid dose and the diagnosis of thyroid cancer in three highly contaminated oblasts in Northern Ukraine. The study population is comprised of 301,907 persons who were between the ages of 1 and 18 at the time of the Chornobyl accident and were living in 1,293 rural settlements in the three study oblasts. Twenty-four percent of the study population had individual thyroid dose estimates and the other 76% had "individualized" estimates of thyroid dose based on direct thyroid measurements taken from a person of the same age and gender living in the same or nearby settlement. Cases include 232 thyroid cancers diagnosed from January 1990 through December 2001, and all were confirmed histologically. Dose-response analyses took into account differences in the rate of ultrasound examinations conducted in the three study oblasts. The estimated excess relative risk per gray was 8.0 (95% CI = 4.6-15) and the excess absolute risk per 10,000 person-year gray was estimated to be 1.5 (95% CI = 1.2-1.9). In broad terms, these estimates are compatible with results of other studies from the contaminated areas, as well as studies of external radiation exposure.  相似文献   

19.
BackgroundThe Chernobyl nuclear power plant accident occurred in Ukraine on April 26th 1986. In France, the radioactive fallout and thyroid radiation doses were much lower than in highly contaminated areas. However, a number of risk projections have suggested that a small excess in differentiated thyroid cancer (DTC) might occur in eastern France due to this low-level fallout. In order to investigate this potential impact, a case–control study on DTC risk factors was started in 2005, focusing on cases who were less than 15 years old at the time of the Chernobyl accident. Here, we aim to evaluate the relationship between some specific reports of potentially contaminated food between April and June 1986 – in particular fresh dairy products and leafy vegetables – and DTC risk.MethodsAfter excluding subjects who were not born before the Chernobyl accident, the study included 747 cases of DTC matched with 815 controls. Odds ratios were calculated using conditional logistic regression models and were reported for all participants, for women only, for papillary cancer only, and excluding microcarcinomas.ResultsThe DTC risk was slightly higher for participants who had consumed locally produced leafy vegetables. However, this association was not stronger in the more contaminated areas than in the others. Conversely, the reported consumption of fresh dairy products was not statistically associated with DTC risk.ConclusionBecause the increase in DTC risk associated with a higher consumption of locally produced vegetables was not more important in the most contaminated areas, our study lacked power to provide evidence for a strong association between consumption of potentially contaminated food and DTC risk.  相似文献   

20.
Thyroid cancer is one of the major health concerns after the accident in the Fukushima Dai-ichi nuclear power station (NPS). Currently, ultrasonography surveys are being performed for persons residing in the Fukushima Prefecture at the time of the accident with an age of up to 18 years. Here, the expected thyroid cancer prevalence in the Fukushima Prefecture is assessed based on an ultrasonography survey of Ukrainians, who were exposed at an age of up to 18 years to 131I released during the Chernobyl NPS accident, and on differences in equipment and study protocol in the two surveys. Radiation risk of thyroid cancer incidence among survivors of the atomic bombings of Hiroshima and Nagasaki and preliminary estimates of thyroid dose due to the Fukushima accident were used for the prediction of baseline and radiation-related thyroid cancer risks. We estimate a prevalence of thyroid cancer of 0.027 % (95 % CI 0.010 %; 0.050 %) for the first screening campaign in the Fukushima Prefecture. Compared with the incidence rate in Japan in 2007, the ultrasonography survey is predicted to increase baseline thyroid cancer incidence by a factor of 7.4 (95 % CI 0.95; 17.3). Under the condition of continued screening, thyroid cancer during the first fifty years after the accident is predicted to be detected for about 2 % of the screened population. The prediction of radiation-related thyroid cancer in the most exposed fraction (a few ten thousand persons) of the screened population of the Fukushima Prefecture has a large uncertainty with the best estimates of the average risk of 0.1–0.3 %, depending on average dose.  相似文献   

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