Abstract
Objective
Chronic lymphocytic leukemia (CLL) is generally considered to be non-radiogenic and is excluded from several programs that compensate workers for illnesses resulting from occupational exposures. Questions about whether this exclusion is justified prompted a Congressional mandate to the National Institute for Occupational Safety and Health (NIOSH) to, further, examine the radiogenicity of CLL. This study revisits the question of CLL radiogenicity by examining epidemiologic evidence from occupationally and medically-exposed populations.
Methods
A systematic review of radiation-exposed cohorts was conducted to investigate the association between radiation and CLL. Exploratory power calculations for a pooled occupational study were performed to examine the feasibility of assessing CLL radiogenicity epidemiologically.
Results
There is a bias against reporting CLL results, because of the disease’s presumed non-radiogenicity. In medical cohort studies that provide risk estimates for CLL, risk is elevated, though non-significantly, in almost all studies with more than 15 years average follow-up. The results of occupational studies are less consistent.
Conclusions
Studies with adequate follow-up time and power are needed to better understand CLL radiogenicity. Power analyses show that a pooled study might detect risk on the order of radiation induced non-CLL leukemia, but is unlikely to detect smaller risks.
Similar content being viewed by others
References
Ghia P, Caligaris-Cappio F (2006) The origin of B-cell chronic lymphocytic leukemia. Semin Oncol 33(2):150–156
Caporaso N (2006) Chips, candidate genes, and CLL. Blood 108(2):415–416
Sgambati MT, Linet MS, Devesa SS (2001) Chronic lymphocytic leukemia: epidemiological, familial, and genetic aspects. Marcel Dekker, Cheson BDNew York, pp 33–62
Goldin LR, Pfeiffer RM, Li X, Hemminki K (2004) Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 104(6):1850–1854
Wiernik PH, Ashwin M, Hu XP, Paietta E, Brown K (2001) Anticipation in familial chronic lymphocytic leukaemia. Br J Haematol 113(2):407–414
Amadori D, Nanni O, Falcini F et al (1995) Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: a population case–control study based on job titles. Occup Environ Med 52(6):374–379
Gonzalez CA, Agudo A (1999) Occupational cancer in Spain. Environ Health Perspect 107(Suppl 2):273–277
Lee E, Burnett CA, Lalich N, Cameron LL, Sestito JP (2002) Proportionate mortality of crop and livestock farmers in the United States, 1984–1993. Am J Ind Med 42(5):410–420
Institute of Medicine of the National Academies of Sciences (2003) Committee to review the health effects in Vietnam Veterans of exposure to herbicides (fourth biennial update). Veterans and agent orange: update 2002. The National Academies Press, Washington, DC, pp 372–377
Preston DL, Kato H, Kopecky K, Fujita S (1987) Studies of the mortality of A-bomb survivors. 8. Cancer mortality, 1950–1982. Radiat Res 111(1):151–178
Boice JD, Blettner M, Kleinerman RA et al (1987) Radiation dose and leukemia risk in patients treated for cancer of the cervix. J Natl Cancer Inst 79(6):1295–1311
Darby SC, Doll R, Gill SK, Smith PG (1987) Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. Br J Cancer 55(2):179–190
Boice JD, Engholm G, Kleinerman RA et al (1988) Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 116(1):3–55
National Research Council Committee on the Biological Effects of Ionizing Radiations (1990) Health effects of exposure to low levels of ionizing radiation: BEIR V. National Academy Press, Washington, DC
Guidelines for Determining the Probability of Causation Under the Energy Employees Occupational Illness Compensation Act of 2000; Final Rule. 42 CFR Part 81 (2202)
Radiation Exposure Compensation Act (1990) Public Law no. 101–426 (104 Stat. 925, 42 U.S.C. 2210)
National Institute for Occupational Safety and Health (2005) Report of public meeting to seek input on gaps in chronic lymphocytic leukemia (CLL) radiogenicity research held July 21, 2004. National Institute for Occupational Safety and Health; (NIOSH) 2006-100, Cincinnati, OH
Rozman C, Montserrat E (1995) Chronic lymphocytic leukemia. N Engl J Med 333(16):1052–1057
Gale RP, Foon KA (1987) Biology of chronic lymphocytic leukemia. Semin Hematol 24(4):209–229
Montserrat E , Rozman C (1995) Chronic lymphocytic leukemia: present status. Ann Oncol 6(3):219–235
Egret Siz: Sample Size, Power for Nonlinear Regression [computer program] (1997) Cytel Statistical Software Services, Version 1. Cytel Inc., Cambridge, MA
Land C, Gilbert E, Smith JM et al (2003). Report of the NCI–CDC working group to revise the 1985 NIH radioepidemiological tables. National Institutes of Health; NIH Publication No. 03-5387, Bethesda MD
Centers for Disease Control and Prevention (CDC) CDC Wonder Compressed Mortality Data. Accessed 09/28/2005. Available from: http://www.wonder.cdc.gov
Oscier D, Fegan C, Hillmen P et al (2004) Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 125(3):294–317
Schubauer-Berigan MK, Macievic GV, Utterback DF, Tseng C, Flora JT (2005) An epidemiologic study of mortality and radiation-related risk of cancer among workers at the Idaho National Engineering and Environmental Laboratory. National Institute for Occupational Safety and Health; NIOSH publication 2005-131, Cincinnati, OH
Muirhead CR, Goodill AA, Haylock RG et al (1999) Occupational radiation exposure and mortality: second analysis of the National Registry for Radiation Workers. J Radiol Prot 19(1):3–26
Ashmore JP, Krewski D, Zielinski JM, Jiang H, Semenciw R, Band PR (1998) First analysis of mortality and occupational radiation exposure based on the National Dose Registry of Canada. Am J Epidemiol 148(6):564–574
Ivanov VK, Tsyb AF, Gorsky AI et al (1997) Leukaemia and thyroid cancer in emergency workers of the Chernobyl accident: estimation of radiation risks (1986–1995). Radiat Environ Biophys 36(1):9–16
National Institute for Occupational Safety and Health (2001) PC-Life Table Analysis System version 1.0d. National Institute for Occupational Safety and Health
Holowaty EJ, Darlington GA, Gajalakshmi CK, Toogood PB, Levin W (1995) Leukemia after irradiation for endometrial cancer in Ontario. Cancer 76(4):644–649
Curtis RE, Boice JD, Stovall M, Flannery JT, Moloney WC (1989) Leukemia risk following radiotherapy for breast cancer. J Clin Oncol 7(1):21–29
Smith PG, Doll R (1982) Mortality among patients with ankylosing spondylitis after a single treatment course with X rays. Br Med J (Clin Res Ed) 284(6314):449–460
Hall P, Holm LE (1995) Cancer in iodine-131 exposed patients. J Endocrinol Invest 18(2):147–149
Kleinerman RA, Liebermann JV, Li FP (1985) Second cancer following cancer of the male genital system in Connecticut, 1935–82. Natl Cancer Inst Monogr 68:139–147
Shilnikova NS, Preston DL, Ron E et al (2003) Cancer mortality risk among workers at the Mayak nuclear complex. Radiat Res 159(6):787–798
Gilbert ES, Omohundro E, Buchanan JA, Holter NA (1993) Mortality of workers at the Hanford site: 1945–1986. Health Phys 64(6):577–590
Thaul S, Page WF, Crawford H, O’Maonaigh H (2005). The five series study: mortality of military participants in US nuclear weapons tests. National Academy Press, Washington, DC
Silver SR, Daniels RD, Taulbee TD et al (2004) Differences in mortality by radiation monitoring status in an expanded cohort of Portsmouth Naval Shipyard workers. J Occup Environ Med 46(7):677–690
Frome EL, Cragle DL, Watkins JP et al (1997) A mortality study of employees of the nuclear industry in Oak Ridge, Tennessee. Radiat Res 148(1):64–80
Telle-Lamberton M, Bergot D, Gagneau M et al (2004) Cancer mortality among French Atomic Energy Commission workers. Am J Ind Med 45(1):34–44
Mohan AK, Hauptmann M, Freedman DM et al (2003) Cancer and other causes of mortality among radiologic technologists in the United States. Int J Cancer 103(2):259–267
Hall P, Berg G, Bjelkengren G et al (1992) Cancer mortality after iodine-131 therapy for hyperthyroidism. Int J Cancer 50(6):886–890
Darby SC, Reeves G, Key T, Doll R, Stovall M (1994) Mortality in a cohort of women given X-ray therapy for metropathia haemorrhagica. Int J Cancer 56(6):793–801
Blettner M, Zeeb H, Langner I, Hammer GP, Schafft T (2002) Mortality from cancer and other causes among airline cabin attendants in Germany, 1960–1997. Am J Epidemiol 156(6):556–565
Zeeb H, Blettner M, Hammer GP, Langner I (2002) Cohort mortality study of German cockpit crew, 1960–1997. Epidemiology 13(6):693–699
Movsas B, Hanlon AL, Pinover W, Hanks GE (1998) Is there an increased risk of second primaries following prostate irradiation? Int J Radiat Oncol Biol Phys 41(2):251–255
Brenner DJ, Curtis RE, Hall EJ, Ron E (2000) Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 88(2):398–406
Bokemeyer C, Schmoll HJ (1993) Secondary neoplasms following treatment of malignant germ cell tumors. J Clin Oncol 11(9):1703–1709
Travis LB, Boice JD, Travis WD (2003) Second primary cancers after thymoma. Int J Cancer 107(5):868–870
Lavey RS, Eby NL, Prosnitz LR (1990) Impact of radiation therapy and/or chemotherapy on the risk for a second malignancy after breast cancer. Cancer 66(5):874–881
Boice JD, Day NE, Andersen A et al (1985) Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries. J Natl Cancer Inst 74(5):955–975
Osterlind A, Rorth M, Prener A (1985) Second cancer following cancer of the male genital system in Denmark, 1943–80. Natl Cancer Inst Monogr 68:341–347
Redman JR, Vugrin D, Arlin ZA et al (1984) Leukemia following treatment of germ cell tumors in men. J Clin Oncol 2(10):1080–1087
Horwich A, Bell J (1994) Mortality and cancer incidence following radiotherapy for seminoma of the testis. Radiother Oncol 30(3):193–198
Kleinerman RA, Boice JD, Storm HH et al (1995) Second primary cancer after treatment for cervical cancer. An international cancer registries study. Cancer 76(3):442–452
Fossa SD, Langmark F, Aass N, Andersen A, Lothe R, Borresen AL (1990) Second non-germ cell malignancies after radiotherapy of testicular cancer with or without chemotherapy. Br J Cancer 61(4):639–643
Weiss HA, Darby SC, Fearn T, Doll R (1995) Leukemia mortality after X-ray treatment for ankylosing spondylitis. Radiat Res 142(1):1–11
Wick RR, Nekolla EA, Gossner W, Kellerer AM (1999) Late effects in ankylosing spondylitis patients treated with 224Ra. Radiat Res 152(6 Suppl):S8–S11
Inskip PD, Kleinerman RA, Stovall M et al (1993) Leukemia, lymphoma, and multiple myeloma after pelvic radiotherapy for benign disease. Radiat Res 135(1):108–124
Davis FG, Boice JD, Hrubec Z, Monson RR (1989) Cancer mortality in a radiation-exposed cohort of Massachusetts tuberculosis patients. Cancer Res 49(21):6130–6136
Ryberg M, Lundell M, Nilsson B, Pettersson F (1990) Malignant disease after radiation treatment of benign gynaecological disorders. A study of a cohort of metropathia patients. Acta Oncol 29(5):563–567
Moller H, Mellemgaard A, Jacobsen GK, Pedersen D, Storm HH (1993) Incidence of second primary cancer following testicular cancer. Eur J Cancer 29A(5):672–676
Hellbardt A, Mirimanoff RO, Obradovic M, Mermillod B, Paunier JP (1990) The risk of second cancer (SC) in patients treated for testicular seminoma. Int J Radiat Oncol Biol Phys 18(6):1327–1331
Hay JH, Duncan W, Kerr GR (1984) Subsequent malignancies in patients irradiated for testicular tumours. Br J Radiol 57(679):597–602
Damber L, Larsson LG, Johansson L, Norin T (1995) A cohort study with regard to the risk of haematological malignancies in patients treated with X-rays for benign lesions in the locomotor system. I. Epidemiological analyses. Acta Oncol 34(6):713–719
Storm HH (1988) Second primary cancer after treatment for cervical cancer. Late effects after radiotherapy. Cancer 61(4):679–688
Dent SF, Klaassen D, Pater JL, Zee B, Whitehead M (2000) Second primary malignancies following the treatment of early stage ovarian cancer: update of a study by the National Cancer Institute of Canada—Clinical Trials Group (NCIC-CTG). Ann Oncol 11(1):65–68
Harvey EB, Brinton LA (1985) Second cancer following cancer of the breast in Connecticut, 1935–82. Natl Cancer Inst Monogr 68:99–112
Travis LB, Curtis RE, Boice JD, Platz CE, Hankey BF, Fraumeni JF (1996) Second malignant neoplasms among long-term survivors of ovarian cancer. Cancer Res 56(7):1564–1570
Travis LB, Curtis RE, Storm H et al (1997) Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89(19):1429–1439
Volk N, Pompe-Kirn V (1997) Second primary cancers in breast cancer patients in Slovenia. Cancer Causes Control 8(5):764–770
Curtis RE, Hoover RN, Kleinerman RA, Harvey EB (1985) Second cancer following cancer of the female genital system in Connecticut, 1935–82. Natl Cancer Inst Monogr 68:113–137
Curtis RE, Boice JD, Stovall M et al (1994) Relationship of leukemia risk to radiation dose following cancer of the uterine corpus. J Natl Cancer Inst 86(17):1315–1324
Boice JD, Morin MM, Glass AG et al (1991) Diagnostic X-ray procedures and risk of leukemia, lymphoma, and multiple myeloma. JAMA 265(10):1290–1294
Gibson R, Graham S, Lilienfeld A, Schuman L, Dowd JE, Levin ML (1972) Irradiation in the epidemiology of leukemia among adults. J Natl Cancer Inst 48(2):301–311
Boivin JF, Hutchison GB, Evans FB, Abou-Daoud KT, Junod B (1986) Leukemia after radiotherapy for first primary cancers of various anatomic sites. Am J Epidemiol 123(6):993–1003
Travis LB, Hauptmann M, Gaul LK et al (2003) Site-specific cancer incidence and mortality after cerebral angiography with radioactive Thorotrast. Radiat Res 160(6):691–706
van Kaick G, Dalheimer A, Hornik S et al (1999) The German Thorotrast study: recent results and assessment of risks. Radiat Res 152(6 Suppl):S64–S71
Andersson M, Carstensen B, Storm HH (1995) Mortality and cancer incidence after cerebral arteriography with or without Thorotrast. Radiat Res 142(3):305–320
dos Santos Silva I, Malveiro F, Jones ME, Swerdlow AJ (2003) Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal. Radiat Res 159(4):521–534
Ron E, Doody MM, Becker DV et al (1998) Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group. JAMA 280(4):347–355
de Vathaire F, Schlumberger M, Delisle MJ et al (1997) Leukaemias and cancers following iodine-131 administration for thyroid cancer. Br J Cancer 75(5):734–739
Dottorini ME, Lomuscio G, Mazzucchelli L, Vignati A, Colombo L (1995) Assessment of female fertility and carcinogenesis after iodine-131 therapy for differentiated thyroid carcinoma. J Nucl Med 36(1):21–27
Brincker H, Hansen HS, Andersen AP (1973) Induction of leukemia by 131-I treatment of thyroid carcinoma. Br J Cancer 28(3):232–237
Cardis E, Gilbert ES, Carpenter L et al (1995) Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries. Radiat Res 142(2):117–132
Cardis E, Vrijheid M, Blettner M et al (2005) Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries. BMJ 331(7508):77
Sont WN, Zielinski JM, Ashmore JP et al (2001) First analysis of cancer incidence and occupational radiation exposure based on the National Dose Registry of Canada. Am J Epidemiol 153(4):309–318
Zablotska LB, Ashmore JP, Howe GR (2004) Analysis of mortality among Canadian nuclear power industry workers after chronic low-dose exposure to ionizing radiation. Radiat Res 161(6):633–641
Howe GR, Zablotska LB, Fix JJ, Egel J, Buchanan J (2004) Analysis of the mortality experience amongst U.S. nuclear power industry workers after chronic low-dose exposure to ionizing radiation. Radiat Res 162(5):517–526
McGeoghegan D, Binks K (2000) The mortality and cancer morbidity experience of workers at the Springfields uranium production facility, 1946–95. J Radiol Prot 20(2):111–137
Kubale TL, Daniels RD, Yiin JH et al (2005) A nested case–control study of leukemia mortality and ionizing radiation at the Portsmouth Naval Shipyard. Radiat Res 164(6):810–819
Konogorov AP , Ivanov VK, Chekin SY, Khait SE (2000) A case–control analysis of leukemia in accident emergency workers of Chernobyl. J Environ Pathol Toxicol Oncol 19(1–2):143–151
Wiggs LD, Cox-DeVore CA, Wilkinson GS, Reyes M (1991) Mortality among workers exposed to external ionizing radiation at a nuclear facility in Ohio. J Occup Med 33(5):632–637
Wiggs LD, Johnson ER, Cox-DeVore CA, Voelz GL (1994) Mortality through 1990 among white male workers at the Los Alamos National Laboratory: considering exposures to plutonium and external ionizing radiation. Health Phys 67(6):577–588
Atkinson WD, Law DV, Bromley KJ, Inskip HM (2004) Mortality of employees of the United Kingdom Atomic Energy Authority, 1946–97. Occup Environ Med 61(7):577–585
Omar RZ, Barber JA, Smith PG (1999) Cancer mortality and morbidity among plutonium workers at the Sellafield plant of British Nuclear Fuels. Br J Cancer 79(7–8):1288–1301
Wartenberg D, Brown S, Mohr S, Cragle D, Friedlander B (2001) Are African-American nuclear workers at lower mortality risk than Caucasians? J Occup Environ Med 43(10):861–871
Hadjimichael OC, Ostfeld AM, D’Atri DA, Brubaker RE (1983) Mortality and cancer incidence experience of employees in a nuclear fuels fabrication plant. J Occup Med 25(1):48–61
Koshurnikova NA, Buldakov LA, Bysogolov GD, Bolotnikova MG, Komleva NS, Peternikova VS (1994) Mortality from malignancies of the hematopoietic and lymphatic tissues among personnel of the first nuclear plant in the USSR. Sci Total Environ 142(1–2):19–23
Boice JD, Holm LE (1997) Radiation risk estimates for leukemia and thyroid cancer among Russian emergency workers at Chernobyl. Radiat Environ Biophys 36(3):213–214
Rahu M, Tekkel M, Veidebaum T et al (1997) The Estonian study of Chernobyl cleanup workers: II. Incidence of cancer and mortality. Radiat Res 147(5):653–657
Hatch M, Ron E, Bouville A, Zablotska L, Howe G (2005) The Chernobyl disaster: cancer following the accident at the Chernobyl nuclear power plant. Epidemiol Rev 27:56–66
Darby SC, Whitley E, Howe GR et al (1995) Radon and cancers other than lung cancer in underground miners: a collaborative analysis of 11 studies. J Natl Cancer Inst 87(5):378–384
Rericha V, Kulich M, Rericha R, Shore DL, Sandler DP (2006) Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: a case-cohort study. Environ Health Perspect 114(6):818–822
Smith PG, Doll R (1981) Mortality from cancer and all causes among British radiologists. Br J Radiol 54(639):187–194
Doody MM, Mandel JS, Lubin JH, Boice JD (1998) Mortality among United States radiologic technologists, 1926–90. Cancer Causes Control 9(1):67–75
Sigurdson AJ, Doody MM, Rao RS et al (2003) Cancer incidence in the US radiologic technologists health study, 1983–1998. Cancer 97(12):3080–3089
Linet MS, Freedman DM, Mohan AK et al (2005) Incidence of haematopoietic malignancies in US radiologic technologists. Occup Environ Med 62(12):861–867
Pukkala E, Aspholm R, Auvinen A et al (2003) Cancer incidence among 10,211 airline pilots: a Nordic study. Aviat Space Environ Med 74(7):699–706
Langner I, Blettner M, Gundestrup M et al (2004) Cosmic radiation and cancer mortality among airline pilots: results from a European cohort study (ESCAPE). Radiat Environ Biophys 42(4):247–256
Muirhead CR , Bingham D, Haylock RG et al (2003) Follow up of mortality and incidence of cancer 1952–98 in men from the UK who participated in the UK’s atmospheric nuclear weapon tests and experimental programmes. Occup Environ Med 60(3):165–172
Muirhead CR, Bingham D, Haylock RG et al (2003). Mortality and cancer incidence 1952–1998 in UK participants in the UK atmospheric nuclear weapon tests and experimental programmes. National Radiological Protection Board; NRPB-W27, Didcot Oxfordshire
Richardson DB, Wing S, Schroeder J, Schmitz-Feuerhake I, Hoffmann W (2005) Ionizing radiation and chronic lymphocytic leukemia. Environ Health Perspect 113(1):1–5
Dyagil I, Adam M, Beebe GW et al (2002) Histologic verification of leukemia, myelodysplasia, and multiple myeloma diagnoses in patients in Ukraine, 1987–1998. Int J Hematol 76(1):55–60
Finch SC, Linet MS (1992) Chronic leukaemias. Baillieres Clin Haematol 5(1):27–56
Romanov SA, Vasilenko EK, Khokhryakov VF, Jacob P (2002) Studies on the Mayak nuclear workers: dosimetry. Radiat Environ Biophys 41(1):23–28
Kisselev M, Kellerer AM (2002) The potential for studies in other nuclear installations. On the possibility of creating medico-dosimetry registries of workers at the Siberian Chemical Industrial Complex (SCIC) and the Mountain Chemical Industrial Complex (MCIC) in Tomsk, Krasnoyarsk. Radiat Environ Biophys 41(1):81–83
Carpenter LM, Higgins CD, Douglas AJ et al (1998) Cancer mortality in relation to monitoring for radionuclide exposure in three UK nuclear industry workforces. Br J Cancer 78(9):1224–1232
Wiggs LD, Cox-DeVore CA, Voelz GL (1991) Mortality among a cohort of workers monitored for 210Po exposure: 1944–1972. Health Phys 61(1):71–76
Acknowledgment
Funding for this study was provided through an agreement between the U.S. Department of Energy (DOE) and the U.S. Department of Health and Human Services (DHHS). Required disclaimer - The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Silver, S.R., Hiratzka, S.L., Schubauer-Berigan, M.K. et al. Chronic lymphocytic leukemia radiogenicity: a systematic review. Cancer Causes Control 18, 1077–1093 (2007). https://doi.org/10.1007/s10552-007-9048-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10552-007-9048-y