Leukemia Mortality and Occupational Ionizing Radiation Exposure A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Environmental Health of the College of Medicine October 5, 2011 By Robert D. Daniels B.S. Thomas Edison State College, June 1996 Committee Chair: S. Pinney, Ph.D. ABSTRACT Context: Nearly four million U.S. workers are potentially exposed to ionizing radiation in the course of their employment each year. Although, evidence exists that unequivocally establishes ionizing radiation as a human carcinogen, little is known about the effects of protracted low-dose exposures. Objective: Conduct a case-control analysis examining the relation between protracted low-dose ionizing radiation exposure and leukemia in a cohort of U.S. nuclear workers. Methods: Each case was matched to four controls on attained age. Ionizing radiation exposures were assessed using measurements and employment histories. Conditional logistic regression analyses were conducted using general relative risk models to estimate the excess relative risk (ERR) of all leukemia, leukemia excluding CLL, AML, CML, and CLL while controlling for potential confounding by race, sex, benzene exposure, social economic status, and either hire date or birth date. Results were tested under differing exposure lag assumptions and time windows of exposure. Results: There were 369 leukemia cases identified in a population of 105,245 U.S. nuclear workers. Positive, but imprecise risk estimates were observed for all outcomes excluding CLL, although the observed dose response for non-CLL leukemia, AML, and CML showed attenuated risk in the low dose (<10 mGy) and high dose (>100 mGy) regions. The linear ERR per 10 mGy absorbed dose to bone marrow was 0.009 (95% CI:-0.014, 0.051). A three-piece linear spline model best fit the non-CLL data, where slope estimates (ERR∙10 mGy -1) were statistically significant in the first two segments: -0.68 (95% CI: -0.92, -0.33) for doses ≤8.0 mGy; 0.20 (95% CI: 0.082, 0.35), dose=8<-46 mGy; and -0.016 (95% CI: <- 0.022, 0.018), dose=46+ mGy. Leukemia risks were characterized by a “wave-like” function of time, where peak risks were observed from exposures occurring from five to ten years prior to the age at death of the index AML case (ERR∙10 mGy -1 = 0.76; 95% CI: 0.047, 2.7) and from 10-15 years for CML ii (ERR∙10 mGy -1 = 0.44; 95% CI: <0, 2.4). Rate ratio modification was not observed in any model, although risk estimates in most linear models tested were confounded by sex, race, and hire date or birth date. This confounding disappeared in piecewise models that provided a better fit to the complex dose- response. Conclusions: This study of leukemia radiogenicity from protracted occupational radiation exposure is the largest ever conducted. Estimates from linear ERR models were in fair agreement with other studies; however, the non-linearity of the dose response contributed to the imprecision of estimates. Leukemia risks were observed to vary with time since exposure, where large and monotonic increases in myeloid leukemia risk were evident for exposures accrued in select windows of time prior to the age of the case at death. Future research should be focused to better evaluate the shape of the dose-response, particularly in the low-dose range, which is critical for risk assessment purposes. Moreover, examinations of temporal patterns of risk appear to be crucial in future studies examining risk factors for leukemia. iii iv PREFACE This research was funded by the National Institute for Occupational Safety and Health (NIOSH) following competitive award as an intramural research project under the National Occupational Research Agenda (NORA). The project proposal was reviewed and strongly recommended for funding by both internal NIOSH and external peer reviewers. In addition, tripartite review, involving representatives from labor, management, and the scientific community was conducted in accordance with NIOSH policy. This research complies with the requirements of the Federal Policy for Protection of Human Subjects (10CFR745 or, where applicable, 45CFR46), and was reviewed by the NIOSH Human Subjects Review Board (HSRB) to ensure that the rights and welfare of study subjects are protected (Protocol No.: HSRB 08-DSHEFS-04-XP). Additional reviews were conducted by the respective IRBs of the University of Cincinnati (Protocol No.: 10-01-14-01) and the U.S. Department of Energy (Protocol No.: CDOE-(11)- 118). These reviews were necessary because: • The project serves to satisfy the University's requirements for dissertation research for the NIOSH Principal Investigator. As such, the UC faculty members participating on the dissertation committee are collaborative partners. • The project complies with the requirements for IRB review of health research and related studies at DOE facilities in accordance with guidance in the DOE Access Handbook (DOE EH/0556, 2003). Disclaimer: Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health (NIOSH).Citations to Web sites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organizations or their programs or products. The findings and conclusions in the report are those of the author and do not necessarily represent the views of NIOSH. v ACKNOWLEDGMENTS This study was conducted under the NIOSH Occupational Energy Research Program, which was founded and managed under a long standing agreement between the U.S. DOE and the U.S. DHHS. The research described herein was made possible through the cooperation and support of the DOE and their employees and contractors. Current and former staff at DOE headquarters, including Ms. M. Lawn, Dr. G. Petersen, and Dr. B. Richter, ensured that NIOSH investigators were allowed access to all essential documents at the various study sites, as well as provided ongoing encouragement for completion of the study. Employees from the Portsmouth Naval Shipyard (PNS), Hanford Site, Savannah River Site (SRS), Oak Ridge National Laboratory (ORNL), Idaho National Laboratory (INL) and the Los Alamos National Laboratory (LANL) provided numerous sources of information that were required to complete this complex study. This study was also made possible through the continued support of NIOSH co- investigators, including Dr. S. Bertke who provided guidance in statistical methods and Ms. K. Waters, who assisted in computer programming. I am also very grateful to my dissertation committee: Dr. S. Pinney, Dr. M. Schubauer-Berigan, Dr. C.R. Buncher, Dr. R. Hornung, and Dr. H. Spitz, for their encouragement and valuable input throughout all phases of this research project. vi Contents 1.0 Introduction ..................................................................................................................................... 1 2.0 Leukemia .......................................................................................................................................... 4 2.1 Description ............................................................................................................................. 4 2.2 Acute Lymphocytic Leukemia (ALL)........................................................................................ 5 2.3 Acute Myeloid Leukemia (AML) ............................................................................................. 6 2.4 Chronic Myeloid Leukemia (CML), ......................................................................................... 6 2.5 Chronic Lymphocytic Leukemia (CLL) ..................................................................................... 7 2.6 Leukemia Trends .................................................................................................................... 8 2.7 Risk Factors .......................................................................................................................... 10 2.7.1 Lifestyle factors .................................................................................................... 10 2.7.2 Environmental factors ......................................................................................... 15 2.7.3 Therapy-related myeloid neoplasms ................................................................... 47 2.7.4 Genetic Factors .................................................................................................... 47 3.0 Study Cohort .................................................................................................................................. 49 3.1 Definition .............................................................................................................................. 49 3.1.1 Vital Status Ascertainment .................................................................................. 50 3.1.2 Results .................................................................................................................. 52 3.2 Facility Descriptions ............................................................................................................. 54 3.2.1 Hanford ................................................................................................................ 57 3.2.2 INL ........................................................................................................................ 60 3.2.3 LANL ....................................................................................................................