Chronic occupational exposure: risk of multiple primary malignancies in nuclear workers

Technical Summary: Chronic Occupational Exposure and Risk of Multiple Primary Malignancies in Nuclear Workers

Problem Statement
The incidence of multiple primary malignancies (multiple PM) is rising globally, driven partly by improved cancer survival rates. While acute radiation exposure (e.g., atomic bomb survivors) has been linked to increased multiple PM risk, the specific effects of chronic occupational radiation exposure on multiple PM incidence remain unclear. A significant gap exists in understanding how chronic exposure to external gamma-rays and internal alpha-radiation (specifically from incorporated plutonium) influences the development of multiple primary tumors. Furthermore, methodological challenges, such as distinguishing true multiple primaries from metastases and accounting for non-uniform internal dose distribution, have limited previous epidemiological assessments in nuclear worker cohorts.

Methodology
This retrospective cohort study analyzed 22,377 workers from the Mayak Production Association (PA) in Russia, employed between 1948 and 1982 in reactor, radiochemical, and plutonium production plants. The cohort was followed from the date of hire until the diagnosis of a primary malignancy, death, loss to follow-up, or December 31, 2023.

• Case Definition: The study focused on 385 workers with morphologically verified multiple primary malignancies. Cases were strictly defined as topographically distinct tumors, verified via histology or instrumental examination, excluding metastases. Tumors diagnosed within 6 months were classified as synchronous; those separated by more than 6 months were metachronous.
• Dosimetry: The study utilized the "Mayak Workers Dosimetry System – 2013" (MWDS-2013). Due to the non-uniform distribution of incorporated plutonium, risk analyses were stratified by organ system:
  • Organs of main plutonium deposition (lungs, liver, bone): Lung absorbed doses were used for both external gamma and internal alpha exposure.
  • Other solid organs: Colon absorbed doses were used as a proxy for external gamma exposure.
• Statistical Analysis: Excess Relative Risk per unit dose (ERR/Gy) was estimated using Poisson regression (EPICURE software). The analysis employed a linear dose-response model ($\lambda = \lambda_0 \times (1 + \beta_1 D)$), adjusting for sex, attained age, calendar period, and non-radiation factors (smoking, alcohol). The study analyzed risks for:
  1. Single primary malignancies.
  2. The first multiple primary malignancy (synchronous or first metachronous).
  3. The second metachronous multiple primary malignancy.

Key Results

• Multiple PM in Organs of Main Plutonium Deposition:

  • First Multiple PM: A statistically significant association was found with both external gamma-rays (ERR/Gy = 1.37; 95% CI: 0.25–5.23) and internal alpha-radiation (ERR/Gy = 3.37; 95% CI: 1.07–9.26). These associations remained significant after adjusting for smoking, alcohol, and employment period.
  • Second Multiple PM: In the basic model, the risk was significantly associated only with internal alpha-radiation (ERR/Gy = 6.07; 95% CI: 1.25–33.98). However, this association became statistically insignificant when additional adjustments were added for smoking status, time intervals between diagnoses, and age at the first diagnosis. No significant association was found with external gamma-rays.

• Multiple PM in Other Solid Organs:

  • First Multiple PM: A significant linear association was observed with external gamma-ray doses (ERR/Gy = 0.52; 95% CI: 0.14–1.12). No effect of internal alpha-radiation was detected.
  • Second Multiple PM: No statistically significant association was found with external gamma-rays in the basic model. A significant association with gamma-rays emerged only in specific subgroups (e.g., current smokers, intervals of 6 months to 5 years) or when internal alpha-dose adjustments were excluded.

• Single Primary Malignancies:

  • Single PM in plutonium-deposition organs showed a strong association with internal alpha-radiation (ERR/Gy = 4.77).
  • Single PM in other organs showed a significant association with external gamma-rays (ERR/Gy = 0.18).

Significance and Claims
The authors claim that this study provides evidence linking the incidence of multiple primary malignancies to chronic occupational exposure to both external gamma-rays and internal alpha-radiation from incorporated plutonium.

• Differentiation of Risk Factors: The study highlights a distinct pattern where internal alpha-radiation is a primary driver for multiple PM in organs where plutonium accumulates (even for the second tumor in the basic model), whereas external gamma-rays are more strongly associated with the first multiple PM and PM in other solid organs.
• Temporal Dynamics: The persistence of alpha-radiation risk for the second multiple PM in deposition organs is attributed to the continuous nature of internal exposure from long-lived plutonium, whereas external gamma exposure ceased upon the end of employment.
• Methodological Rigor: The study emphasizes the importance of morphological verification to exclude metastases and the necessity of separating dose metrics based on organ-specific plutonium deposition to accurately assess risk.

Limitations
The authors note several limitations, including the relatively small number of multiple PM cases (reducing statistical power), incomplete internal alpha-exposure data for a portion of the cohort, and the heterogeneity of biological effectiveness between gamma and alpha radiation. Consequently, the authors advise caution in interpreting combined risk estimates across different tumor sites.