Ethe. ation N. Ninth Annua Symposium December 1, S. DEPARTMENT OF EALTH AND HUMAN ERVICES ational Institutes of ealth

Transcription

1 Instit tute Other Low-Dose Studies al Ca ancer ation N.S. DEPARTMENT OF EALTH AND HUMAN ERVICES ational Institutes of ealth Ethe l S. Gilbert Radiation Epidemiology Branch National Cancer Institute Ninth Annua al Gilbert W. Beebe Symposium December 1, 2010

2 Reasons studiess other than the A-bomb survivors are needed Need data on Protracted or low-dose rate exposure Non-Japanese popu pulations Exposure to radionuclides I 131 Radon

3 Desirable characteristics of studies used for risk assessment Reasonably accurate dose estimates for individual subjects Need to quantify risk as a function of dose Precise estimates of pa arameters that quantify risk as a function of dose Quantifying small risks Limited potential for confounding requires very large sample sizes Small risks especially vulnerable to confounding

4 Predicted relativee risks* for adult male exposed at low dose rates Dose Solid ca ancers Leukemia 1 Gy G 0.5 Gy Gy Gy Gy *Based on BEIR VII models de eveloped from A-bomb survivor data

5 Studies emphasized in this presentation Dose estimates for individuals Dose-response analysess performed Doses not extremely low Some subjects have dose es exceeding 0.1 Gy Pooled analyses when available My apologies if your fav orite study is not included!

6 Today s Presentation Protracted low-let external radiation Nuclear Workers Diagnostic Medical Techa River Cohort Chernobyl Clean-up Workers Iodine -131 Chernobyl, Semipalatinsk, Hanford Radon Residential Radon Studies Radiation Studies

7 N uclear Workers

8 Why study workers? Dose estimates obtaine ed from personal dosimeters worn by workers Exposures deliberately to the worker limited as a protection Provide a direct assessment of risks at low doses and dose rates

9 Studies of Workers at Individual Facilities Population Hanford Site Country US Publication Date(s) 1978,, 1993 Oak Ridge Nat l Lab. US 1985, 1991 Atomic Energy Authority UK 1985, 1993 Sellafield Plant UK 1986, 1994, 1999 Rocky Flats Weapons Plant US Atomic Energy of Canada Canad da Atomic Weapons Establish. UK Savannah River Plant US 1988, 1999 Mound Laboratory US 1991 Los Alamos Nat l Lab. US 1994 Rocketdyne US 1999, 2006 Mallinckrodt Chemical US 2000

10 Studies of Workers at Individual Facilities Population National Registry of Radiation Workers National Dose Registry Nuclear reactor workers Nuclear industry workers Nuclear power workers Nuclear power workers Atomic Energy Commission National Electricity Co. Nuclear workers Idaho National Engineering and Environmental Lab. Nuclear industry workers Country Publication Date UK 1992, 1999, 2009 Canada 1998, 2001 Finland 2002 Japan 1997, 2003 US 2004 Canada 2004 France 2004 France 2005 Belgium 2005 US 2005 Australia 2005

11 Two Large Worker Studies 15-country study Coordinated by the International Agency for Research on Cancer (IARC) Cardis et al. 2005; 2007 National Registry of Radia ation Workers (NRRW) in the UK Muirhead et al Most exposure received by males

12 15-Country Nucle ear Worker Study 407,300 workers in main study population Includes most workers in previous studies in US, UK, and Canada Several new studies in US and other countries Cardis et al. 2005; 2007

13 15-Country Study (Cancer deaths) United States (2,841) United Kingdom (2,273) Japan* (432) Canada (417) France (348) Sweden (194) Belgium (90) Hungary (40) Finland (34) Lithuania (25) Spain (25) Korea (21) Switzerland (24) Australia (20) Slovakia (10) *Included only in leukemia analyses Cardis et al. 2005

14 Dosimetry for 15-Country Study Extensive attention given to dosimetry Dosimetry subcommitte ee Questionnaires on dosimetry practices and radiation environments Special studies of representative facilities Testing of several representative ti dosimeters Objective: Develop factors for converting recorded doses to organ doses and evaluate uncertainties in these factors Thierry-Chef et al. 2007

15 Cumulative Dose Distribution

16 15-country Study: ERR/Gy (90% CI) All cancer excluding leukemia Non-CLL Leukemia 15-country 0.97 (.27, 1.8) 1.9 (<0, 7.1) A-bomb 0.26 (0.14, 0.41) 1.4 (0.1, 3.4) survivors* (linear) ) (linear-quadratic) *BEIR VII for adult males Cardis et al. 2007

17 15-Country Study: ERR/Gy Cardis et al. 2005

18 15-Country Study: Some Additional lresults Lung cancer ERR/Gy (90% CI) 1.85 ( 0.26, 4.0) All solid cancers Excluding cancers related to smoking* Excluding Canada 0.87 (0.02, 1.9) 0.62 ( 0.5, 2.2) 058( , 02 16) 1.6) Cardis et al. 2007

19 Comments on 15-Country Nuclear Workerr Study Generally well-conducted study Strong dosimetry Common core protocol set out details of study including Which workers to be inclu uded How analyses to be conducted Subject to limitations of low dose epidemiologic studies Likely bias due to confou nding by smoking Possible problems with Canadian data

20 National Registry of Radiation Workers (NRRW) 175,000 workers at several selected facilities in United Kingdom 87,300 of these workers also in IARC 15-country study Muirhead et al. 2009

21 Characteristics of Two Large Worker Studies Number Total Av. Number of person- Dose of workers Sv (Sv) cancers 15-country 407,391 7, ,024 NRRW 174,541 4,, ,107

22 Large Worker Studies: ERR/Gy (90% CI) All cancer Leukemia excluding excluding leukemia CLL 15-country 0.97 (0.27 7, 1.8) 1.9 (<0, 7.1) NRRW 0.28 (0.02,0.6) 1.7 (0.1, 4.3) A-bomb 0.26 (0.14, 0.41) 14( (0.1, 34) 3.4) survivors* (linear) ) (linear-quadratic) *BEIR VII for adult males

23 Medical Radiation Workers Population Number of workers US radiologists 6500 UK radiologists 2700 US technologists 146,000 US Army technologists 6600 Chinese x-ray workers 27,000 Danish radiation therapy workers 4200 Japanese technologists 12,200 Canadian radiation workers 73,100 Yoshinaga et al. 2004

24 Medical Radiation Workers Population Number of workers US radiologists 6500 UK radiologists 2700 US technologists 146,000 US Army technologists 6600 Chinese x-ray workers 27,000 Danish radiation therapy workers 4200 Japanese technologists 12,200 Canadian radiation workers 73,100 Yoshinaga et al. 2004

25 Medical Radi ation Workers US technologists 146,000 radiologic tech. First employed % female Survey data on disease incidence and cancer risk factors Chinese x-ray workers 27,000 workers First employed % female Both cohorts Cancer excesses for early years identified Doses estimated Dose-response analyses underway

26 Today s Presentation Protracted low-let external radiation Nuclear Workers Diagnostic Medical Techa River Cohort Chernobyl Clean-up Workers Iodine -131 Chernobyl, Semipalatinsk, Hanford Radon Residential Radon Studies Radiation Studies

27 Diagnostic Medical Radiation Studies Most studies limited by Very low doses and resul lting low statistical power Dose estimates often rely on subjects ability to recall the procedures they received Exceptions Scoliosis patients monitored with diagnostic x-rays Mean dose 0.11 Gy Nearly significant dose-response for breast cancer (Ronckers et al. 2008) TB patients monitored with fluoroscopies Cohorts in Massachusett ts and Canada

28 TB Fluoroscopy Patients: Breast Cancer Significant dose-respo onse in both Massachusetts and Canadian cohorts Massachusetts cohort Mean dose = 0.8 Gy Excess relative risk estimate significantly lower than A-bomb survivor estimate Excess absolute risk estimates comparable Little and Boice 1999

29 TB Fluoroscopy Patients: Lung Cancer No evidence of dose-response in either Massachusetts or Canadian cohort Lung Cancers Canadian TB patients 1178 Mean Dose (Gy) ERR/Gy (95% CI) 1 Gy 0.00 ( 0.06 to 0.07) A-bomb (0.3 to 1.0) Howe 1995; Davis et al. 1989

30 CT: An Important Source of Diagnostic Medical Radiation Exposure* Other 85% CT 15% Other 30% CT 70% Percent of radiological exams Distribution of radiation dose delivered d * Data from a university department; Linton & Mettler, 2003

31 New Studies of CT Scans in Children UK Nationwide 250,000 exposed Age <22 at exposure First scan Israel ,000 exposed Age <18 at exposure First scan Cohort studies (plus nested case-control studies) Doses are being estimated Studies initiated by Elaine Ron Collaborators: Mark Pearce L. Parker, K. McHugh, K-P Kim, C. Lee, J. Lubin, A. Berrington Collaborators: Gabriel Chodick G. Horev, M.Shwarz, K-P Kim, C. Lee, R. Kleinerman

32 Studies in Countries of the Former Soviet Union

33 Mayak nuclear facility

34 Mayak Nuclear Facility Began operations in 1948 Mission was to produce plutonium for USSR nuclear weapons program Workers exposed to large protracted external doses and to plutonium Dose-response relationships demonstrated Being updated using impro oved dosimetry Persons living along the Techa River exposed to radioactive wastes

35 Techa River Cohort

36 Techa Riv ver Cohort 30,000 people who lived in river bank villages downstream of Mayak facility in the Primarily exposed to ex xternal sources and to Cesium-137 and Strontium-90 All ages and both sexess 58% female 40% under age 20 in 1950

37 Techa River Coh hort: Dosimetry Extensive efforts mad e to estimate individual doses that take account of details on residential history and personal habits Mean d ose Maximum dose Red bone marrow 0.3 Gy 2.0 Gy Stomach 0.03* Gy 0.5 Gy *75% from external sources

38 Techa River Cohort: ERR per Gy All cancer excluding leukemia Non-CLL Leukemia Mortality 0.92 (0.2 to 1.7) 6.5 (1.8 to 24) Incidence 1.0 (0.3 to 1.9) 4.9 (1.6 to 14) A-bomb ~ 0.5 survivors (linear) ~ 1.4 (linear-quadratic) Krestinina et al. 2005, 2009, 2010

39 Techa Rive r Cohort Risk estimates higher than but statistically compatible with those based on A-bomb survivors For solid cancer mortality, risk (ERR/Gy) increased with both age at entry and attained age Large dosimetry uncertainties

40 Chernobyl Accident in 1986 resulted in exposure to both I-131 and external dose

41 Chernobyl liquidators Most promising group for studying effects of external exposure Based on external comparisons, several studies have suggested excess leukemia

42 Leukemia in Chernobyl Liquidators: Two case-control studies Workers in Ukraine 71 leukemias; 501 mat tched controls Romanenko et al Workers in Belarus, Russia, Baltic countries 70 cases (40 leukemias, 20 NHL, 10 other) Kesminiene et al. 2008

43 Leukemia in Chern nobyl Liquidators Dosimetry Monitoring data not available for many subjects Individual dose estimatess based on Detailed dosimetry interview Time and motion analys sis Same methods used fo or both new studies

44 Two Leukemia Case-Control Studies in Chernobyl Liquidators Leukemias Dose (Gy) EOR/Gy (90% CI) Ukraine (mean) 3.4 (0. 5 to 9.8) Belarus/ Russia/Baltic (median) 4.8 (< 0 to 33)

45 Two Leukemia Case-Control Studies in Chernobyl Liquidators EOR/Gy (90% CI) CLL Non-CLL Ukraine 41( 4.1 (<0to 14.4) 2.7 (<0 to 13.5) 49 cases 32 cases Belarus/ Russia/Baltic 5.0 (<0 to 57) 4.7 (<0 to 76) 19 cases 21 cases

46 Chernobyl 40 million Ci of 40 million Ci of I-131 released

47 Chernobyl: Thyroid Cancer Large increases in childhood thyroid cancer in contaminated areas beginning about 4 years after the accident Several case-controlcontrol studies and two cohort studies with individual thyroid dose estimates have been conducted

48 Chernobyl: Thyroid Disease Cohort studies in the Ukra aine and Belarus 13,000 persons in Ukraine 12,000 persons in Belarus Under 18 years in 1986 and screened for thyroid disease using ultrasound and palpation (Tronko et al. 2006; Zablotska et al. 2010) Case-control study in Bel arus and drussia 276 thyroid cancer cases under 15 years in 1986 and 1300 matched controls (Cardis et al. 2005)

49 Chernobyl: Thyroid Disease Dosimetry Cohort studies: Based on Individual in vivo thyroid measurements Interview data on location and dietary habits Case-control studies: Base ed on Interview data on location and dietary habits

50 Chernobyl: Thyroid Canc cer Prevalence Thyroid cancers Dose (Gy) EOR/Gy (95% CI) Ukraine (mean) 5.3 (1.7, 28) Belarus (mean) 2.2 (0.8, 5.5) Belarus/ (median) Russia (median) 45( (1.2, 78) 7.8) ERR/Gy based on external expos sure in childhood: (2.1, 29) Ron et al. 1995

51 Semipalatinsk Test Site (STS) 100+ atmospheric nuclear tests conduct ted by the former Soviet Union Study includes 3000 current residents of 8 villages near STS Exposed to both external and internal (I 131 ) Land et al Clinically screened with ultrasound for thyroid disease

52 STS: Thyroid Nodule Results Thyroid Mea an Nodules Dose (Gy) EOR/Gy (90% CI) External (0.4 to 5.4) Internal (I 131 ) (02t 0.6 (0.2 to 1.1) 11) RBE of internal relative to external: (01t (0.1 to 2.0) 20) Land et al. 2008

53 Hanford Thyroid Disease Study 3400 people exposed as children to I-131 releases from Hanford in eastern Washington State Clinically evaluated for thyroid disease Individual thyroid dos es Mean dose 0.1 Gy Davis et al. 2004

54 Hanford Thyroid Disease Study 19 thyroid cancers 249 thyroid nodules No evidence of a dose-response relation found for thyroid cancer thyroid nodules any of the 11 thyroid disease categories evaluated Davis et al. 2004

55 Today s Presentation Protracted low-let external radiation Nuclear Workers Diagnostic Medical Techa River Cohort Chernobyl Clean-up Workers Iodine -131 Chernobyl, Semipalatinsk, Hanford Radon Residential Radon Studies Radiation Studies

56 Residential Ra adon Studies 22 lung cancer case-control studies in North America, Europe, and China Objective: Provide direct evaluation of exposure-response response relationship Compare with results s from risks extrapolated from studies of underground miners

57 Pooling of Residen ntial Radon Studies Number of Studies North thamerica 7 4 China 2 1 Cases/ Controls Reference 4108/5301 Krewski /2015 Lubin 2004 Europe /14,208 Darby 2005 Total 22 12, 332/21,524

58 Comparability 3 of Results of Indoor Radon Studies of 2 Lung Cancer Odds ra atio 1 EPA Gansu China pooled RRs Shenyang Pooled European RRs NA pooled RRs IA CT MO-1 UT MO-2 Winn NJ-1 Radon slides courtesy of Jay Lubin Radon concentration (x), Bq/m 3

59 What have we learned from low dose stud dies? Protracted low-let ext ternal exposure Provide direct evidence increases cancer risks Epidemiology not up to providing direct evidence for extremely low doses (< ~ 0.1 Sv) Need to consider study that protracted exposure limitations Wide confidence intervals High potential for confounding Rarely informative regard ding shape of dose-response or modifying factors

60 What have we learned from low dose stud dies? Protracted t low-let ext ternal exposure Not possible to make precise comparisons of risks from protracted t and acute exposures A-bomb survivors remai in very important

61 What have we learned form low dose studies? I 131 : Chernobyl studies have provided direct evidence of risk Not clear whether or not risks from I 131 are lower than those from external exposure Radon: Residential studies have provided strong support that estimates based on underground miners are appropriate

62 Future Needs Protracted low-let external exposure Studies with data on important cancer risk factors to better address potential confounding Studies with data at th he higher end of the low dose range Exposure to I 131 Pooled analyses to increase precision and summarize data Data on adult exposure and in utero exposure Development and app plication of statistical methods that take account of dosimetry uncertainties

63 Thank you for your attention. Que stions?