Exposure to Ionizing Radiation and Leukemia Risk: Is There a Safe Threshold?

Exposure to high doses of radiation is rare outside of radiation therapy, but repeated or protracted low-dose exposure from occupational and environmental sources has become more common over the last 25 years. The average yearly dose of radiation has increased from 0.5 mGy in 1982 to 3.0 m/Gy in 2006, largely due to a rise in medical radiation exposure.1

Because ionizing radiation is a carcinogen linked to cancer development, its use in medical practice must be balanced against the associated health risks.

While most previous studies have examined cancer-associated mortality risk among people who have been exposed to high levels of radiation, there is little information on this risk for people exposed to repeated and prolonged low-dose exposure. In an analysis of the International Nuclear Workers Study (INWORKS), Klervi Leuraud, PhD, from the Institute for Radiological Protection and Nuclear Safety at Fontenay aux Roses in Cedex, France, and colleagues looked specifically at development of hematologic malignancies among workers from France, the United Kingdom, and the United States who were exposed to low-dose protracted or intermittent radiation.

According to the findings, even low accrued doses of radiation (<5 mGy) had an excess risk of leukemia-related mortality, suggesting that the potential threshold below which radiation is harmless should be very low.

All participants in the INWORKS study had been monitored for external exposure to radiation with personal dosimeters and were followed for up to 60 years after exposure. Workers were employed for at least one year at one of the following sites: the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France; the Departments of Energy and Defense in the United States; and nuclear industry employers included in the National Registry for Radiation Workers in the United Kingdom. Data were available from 1944 through 2005.

Overall, data from 308,297 radiation-monitored participants were analyzed. Participants were followed for 8.22 million person-years to assess deaths up to 2004 in France, 2001 in the United Kingdom, and 2005 in the United States. Causes of death were ascertained from the participants’ death certificates and coded according to the International Classification of Diseases.

Data on ionizing radiation were extracted from dose registry, government, and company records, which provided individual yearly estimates of whole-body exposure to external radiation. Dr. Leuraud and colleagues quantified the associations between the estimated radiation dose absorbed by bone marrow and leukemia, lymphoma, and myeloma mortality.
Participants were followed for a mean of 27 years, and 22 percent of the workers (n=66,632) were deceased at the time of follow-up.

Radiation doses were accrued at “very low rates” among individuals (mean = 1.1 Gy per individual per year). Among the total INWORKS population, the mean cumulative dose was 15.9 mGy: 11.6 mGy in French workers; 15.2 mGy for U.S. workers; and 18.2 mGy for U.K. workers.

Leukemia (excluding chronic lymphocytic leukemia [CLL]) was the reported cause of death in 538 individuals, lymphoma in 814 individuals, and multiple myeloma in 293 individuals.
Notably, of the deaths caused by leukemia excluding CLL, more than half (53%; n=281) occurred in people who had accrued a mean of less than 5 mGy of radiation exposure. As seen in TABLE, the excess relative risk (ERR) of leukemia mortality was 2.96 per Gy (90% CI 1.17-5.21), “most notably because of an association between radiation dose and mortality from chronic myeloid leukemia (CML; ERR=10.45/Gy; 90% CI 4.48-19.65).

The researchers also detected positive associations between cumulative dose and the excess relative risk of acute myeloid leukemia (AML; ERR=1.29; 90% CI –0.82 to 4.28) and acute lymphocytic leukemia (ALL; ERR=5.80; 90% CI NE to 31.57). Associations for Hodgkin lymphoma (ERR=2.94; 90% CI NE to 11.49), non-Hodgkin lymphoma (ERR=0.47; 90% CI –0.76 to 2.03), and multiple myeloma (ERR=0.84; 90% CI –0.96 to 3.33) were also observed, but were not as strong. Dr. Leuraud and colleagues also observed a negative association between radiation and development of CLL (TABLE).

“This study provides strong evidence of positive associations between protracted low-dose radiation exposure and risk of developing leukemia,” the authors concluded, adding that current radiation protection systems are based on a model derived from acute exposures, and assume that the risk of leukemia progressively diminishes at lower doses and dose rates.

“Our results provide direct estimates of risk per unit of protracted dose in ranges typical of environmental, diagnostic medical, and occupational exposure.”

Because radiation dose estimates are prone to measurement error, exposure misclassification was an unavoidable study limitation. “Outcome misclassification is also a potential concern in studies that rely on death certificates for classification of leukemia and lymphoma by subtype,” the authors noted.

The analysis also did not account for potential confounders of the associations being studied, including participants’ smoking status or exposure to other known causes of leukemia. In the future, Dr. Leuraud and colleagues added, similar studies should be conducted specifically among medical workers to examine their radiation-related risk.

References

  1. Mettler FA Jr, Thomadsen BR, Bhargavan M, et al. Medical radiation exposure in the U.S. in 2006: preliminary results. Health Phys 2008;95:502-7.
  2. Leuraud K, Richardson DB, Cardis E, et al. Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study. Lancet Haemotol. 2015;2:e276-e281.

TABLE. Excess Relative Risk per Gy of Cumulative Red Bone Marrow Dose for Causes of Death
Deaths Excess Relative Risk per Gy 90% confidence interval
Leukemia (excluding chronic lymphocytic leukemia) 531 2.96 1.17-5.21
Chronic myeloid leukemia 100 10.45 4.48-19.65
Acute myeloid leukemia 254 1.29 −0.82-4.28
Acute lymphocytic leukemia 30 5.80 NE-31.57
Chronic lymphocytic leukemia 138 −1.06 NE-1.81
Multiple myeloma 293 0.84 −0.96-3.33
Non-Hodgkin lymphoma 710 0.47 −0.76-2.03
Hodgkin lymphoma 104 2.94 NE-11.49
NE=not estimable

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