Biography

Dr. Land received a Ph.D. in statistics from the University of Chicago, studied risk of radiation-related cancer at the Atomic Bomb Casualty Commission and the Radiation Effects Research Foundation in Hiroshima, Japan, and taught statistics at Oregon State University before joining the NCI in 1975. He has received the NIH Director's Award and a PHS Special Recognition Award, the Unit Commendation, Outstanding Service, and Meritorious Service Medals, and individual and group NIH Merit Awards for contributions to the epidemiology of radiation carcinogenesis and quantification of radiation-related risk. Dr. Land is a member of the National Council on Radiation Protection and Measurements and Committee 1, on Risk, of the International Commission on Radiological Protection. He is a Fellow of the American Statistical Association.

Research Interests

Our research focuses on epidemiologic studies to clarify the relation between cancer risk and exposure to ionizing radiation. Compared with most other known human carcinogens, a relatively large and well quantified base of knowledge exists on radiation related cancer risks. This knowledge base offers opportunities to explore more complex issues, such as biomarkers of radiation related cancer and risk modifiers, including lifestyle variables, other carcinogenic exposures, and host factors like age, sex, and genetic predisposition to certain cancers.

Japanese Atomic Bomb Survivors

Using a variety of approaches, a cohort of 94,000 survivors of the Hiroshima and Nagasaki atomic bombings and 26,000 non exposed subjects is being studied in collaboration with the Radiation Effects Research Foundation. In recognition of the unique value of the A-bomb survivor experience, the REB is devoting increased staff resources to this collaborative program.

• Site specific studies of cancer incidence. Cohort studies are used to quantify radiation dose-response and its relation to histological subtype of tumor, age at exposure, time following exposure, age at observation, and gender. A recent analysis of breast cancer incidence data showed that radiation-related risk was modified by attained age and exposure age, with particularly high dose-specific excess relative risks for diagnosis before 35 years of age and for exposure at ages under 20. Recent data on ovarian tumor incidence suggests that the dose response for benign tumors may be as strong as that for malignant tumors.
• Case control studies. Investigations are underway of main effects, as breast cancer risk factors, of hormone levels in stored serum and reproductive history based on mail survey data; another focus is interaction of these factors with radiation exposure.
• Case-case approaches. A previous report of extremely high, dose specific relative risks for early onset breast cancer (before age 35) suggests increased sensitivity to radiation among a genetically predisposed population subgroup. We are addressing this hypothesis through compilation of family cancer pedigrees for early-onset and later-onset cases, and exploring the potential for molecular assays of stored lymphocytes and archival tumor tissue for biomarkers of susceptibility.

Heritable Retinoblastoma and Susceptibility to Radiation Induced Bone Sarcoma

We are comparing bone sarcoma incidence data from patients treated by x ray during early childhood for bilateral retinoblastoma with patients treated by injection of 224Ra for tuberculosis and other benign disease. Preliminary analyses suggest that heritable retinoblastoma patients, whose baseline risk of bone sarcoma is already high, are unusually susceptible to radiation related bone sarcoma.

Cancer Risk Associated with Environmental Radiation

Increased risk of thyroid disease, including cancer, is a well established correlate of exposure to gamma and x ray radiation from external sources, but risk from exposure to radioactive iodine is less well defined. In a collaborative study involving thyroid screening of 3,000 village residents living near the Semipalatinsk nuclear test site in Kazakstan, we investigated the prevalence of thyroid nodules, a biomarker for thyroid cancer risk, as a function of estimated radiation dose from external and internal sources of radiation exposure. An important new activity is the development, by a Russian-NCI partnership, of an improved approach of individual dose reconstruction based on fallout patterns, biological transport of iodine through the food chain, and residential and dietary history. It is already clear that the new approach improves the fit for thyroid cancer and nodule prevalence as functions of external dose, and further work should help to improve our knowledge of risk associated with internal radioiodine exposure.

Algorithms for Expression of Risk

The 1985 report of the NIH Ad Hoc Working Group to Develop Radioepidemiological Tables, which was mandated by Congress, provides a scientific basis for adjudicating claims of radiation related injury, and is now legally mandated for use in claims against the government or its contractors associated with occupational exposure. This report was updated using more recent epidemiological dose-response data and a formal quantitative uncertainty analysis incorporating statistical and subjective assessments of uncertainty. The original tabular format is replaced by an interactive computer program that is accessible from our web site. Currently, we are adapting of the interactive program to develop an algorithm for estimating lifetime radiation-related cancer risk for arbitrary exposure histories.

Implications of Uncertainty for Radiation Protection

The current basis for risk-based radiation protection is the linear, no-threshold (LNT) hypothesis, which holds that, at low radiation doses, excess risk related to exposure is approximately proportional to dose. An alternative hypothesis is that radiation carcinogenesis is a threshold phenomenon, i.e., that there is no dose-associated risk below some "threshold" dose level. However, given current evidence that complex damage to cellular DNA is generated by even a single electron track, and that complex damage is repaired by an error-prone process (non-homologous end joining), the LNT hypothesis is supported by quantitative uncertainty analysis showing that upper probability limits on risk are little affected by the uncertain possibility of a low-dose threshold.

Medically- Exposed Populations

Cancer incidence and mortality following nasopharyngeal radium treatment for childhood eustachian tube dysfunction has been investigated among patients in The Netherlands. A non-significant excess of thyroid cancer was found, based on a small number of cases. In another project, increased breast cancer mortality among women who were treated as children for scoliosis, was related to reconstructed radiation dose to breast tissue. Cancer risk for stomach, pancreas, and lung was related to radiation dose associated with radiation therapy for gastric ulcer.

Keywords

atomic bomb survivors, bone sarcoma, breast cancer, fallout exposure, genetic susceptibility, ionizing, lung cancer, radiation, radioactive iodine, Radioepidemiological Tables, retinoblastoma, radium implants, quantitative uncertainty analysis

Selected Publications

• Land CE, Gilbert E, Smith J, Hoffman FO, Apostoiae I, Thomas B, Kocher D. "Report of the NCI-CDC Working Group to revise the 1985 NIH Radioepidemiological Tables." (DHHS Publication No. 03-5387, 2003)
• Grosche B, Land C, Bauer S, Abylkassimova Z, Gusev B. "Health effects due to fallout from nuclear tests in Kazakstan," Radiation and Environmental Biophysics, 2002; 41(1):75-80.
• Ronckers CM, van Leeuwen FE, Hayes RB, Verduijn PG, Stovall M, Land CE. "Cancer incidence after nasopharyngeal radium irradiation." Epidemiology, 2002; 13:552-560.
• Land C. "Uncertainty, low dose extrapolation and the threshold hypothesis." J. Radiol. Prot. 2002 (September);22: A129-A135
• Carr ZA, Kleinerman RA, Weinstock R, Stovall M, Greim ML, Land CE. "Malignant neoplasms after radiation therapy for peptic ulcer." Radiation Research, 2002;157:668-77.
• Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, Stanczyk FZ, Stephenson HE Jr, Falk RT, Miller R, Schatzkin A, Allen DS, Fentiman IS, Key TJ, Wang DY, Dowsett M, Thomas HV, Hankinson SE, Toniolo P, Akhmedkhanov A, Koenig K, Shore RE, Zeleniuch_Jacquotte A, Berrino F, Muti P, Micheli A, Krogh V, Sieri S, Pala V, Venturelli E, Secreto G, Barrett-Connor E, Laughlin GA, Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE, Cauley JA, Kuller LH, Cummings SR, Helzlsouer KJ, Alberg AJ, Bush TL, Comstock GW, Gordon GB, Miller SR, Longcope C; "Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women." J Natl Cancer Inst. 2003; 95:1218-26.
• Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, Lubin JH, Preston DL, Preston RJ, Puskin JS, Ron E, Sachs RK, Samet JM, Setlow RB, Zaider M. "Cancer Risks Attributable to Low Doses of Ionizing Radiation - What Do We Really Know?" PNAS 2003; 100:13761
  
• Cologne JB, Sharp GB, Neriishi K, Verkasalo PK, Land CE, Nakachi K. "Improving the design of nested case-control studies: increasing efficiency using counter matching to select controls." Int J Epidemiol 2004 Jun;33(3):485-92.
• Carr ZA, Land CE, Kleinerman RA, Stovall M, Griem ML, Mabuchi K. "Coronary heart disease and stroke mortality after radiotherapy for peptic ulcer." Int J Onc Biol Physics (in press).

Collaborators

DCEG Collaborators

• Andre Bouville, Ph.D.; Alina Brenner, M.D., Ph.D.; Michele Doody, M.S.; Ethel Gilbert, Ph.D.; Richard Hayes, D.D.S., Ph.D.; Ruth Kleinerman, M.P.H., Martha Linet, M.D., Ph.D.; Nick Luckyanov, Ph.D.; Kiyohiko Mabuchi, M.D., Ph.D.; Elaine Ron, Ph.D.; Cecile Ronckers, Ph.D.; Alice Sigurdson, Ph.D.; Steve Simon, Ph.D.; Margaret Tucker, M.D.

Other NCI Collaborators

• Kenneth Kraemer, M.D., CCR
• Jeff Struewing, Ph.D., Laboratory of Population Genetics, CCR, NCI

Other Scientific Collaborators

• Suminori Akiba, M.D., Kagoshima University, Kagoshima, Japan
• Iulian Apostoaei, Ph.D., SENES Oak Ridge, Inc., Oak Ridge, TN
• David Brenner, Columbia University, NYC, NY
• John Cologne, Ph.D., Radiation Effects Research Foundation (RERF), Hiroshima, Japan
• Capri Mara Fillmore, M.D., University of Wisconsin-Madison, Milwaukee, WI
• Owen Hoffman, Ph.D., SENES Oak Ridge, Inc., Oak Ridge, TN
• Michinori Kabuto, Ph.D., National Institute for Environmental Studies, Tsukuba, Japan
• Timothy Key, Ph.D., Oxford University, Oxford, England
• Kazuo Neriishi, M.D., RERF, Hiroshima, Japan
• Donald Pierce, Ph.D., RERF, Hiroshima, Japan
• Dale Preston, Ph.D., RERF, Hiroshima, Japan
• Yukiko Shimizu, DMSc, RERF, Hiroshima, Japan
• James Smith, Ph.D., Centers for Disease Prevention and Control, Atlanta, GA
• Richard Stevens, Ph.D., University of Connecticut Health Sciences Center, Farmington, CN
• Brian Thomas B.S., SENES Oak Ridge, Inc., Oak Ridge, TN
• Shoji Tokuoka, M.D., Radiation Effects Research Foundation, Hiroshima, Japan
• Flora van Leeuwen, Ph.D., Netherlands Cancer Institute, Amsterdam, The Netherlands
• Peter Verduijn, M.D., Institute for Radioepidemiology, Maastricht, The Netherlands