Local bone-marrow exposure: how to interpret the data on stable chromosome aberrations in circulating lymphocytes? (some comments on the use of FISH method for dose reconstruction for Techa riverside Residents)

Abstract

The method of fluorescence in situ hybridization (FISH) applied to peripheral blood T lymphocytes is used for retrospective dose estimation, and the results obtained from the analysis of stable chromosomal aberrations are usually interpreted as a dose accumulated in the red bone marrow (RBM). However, after local internal exposure of the RBM, doses derived from FISH were found to be lower than those derived from direct measurements of radionuclides accumulated in the bodies of exposed persons. These results were obtained for people residing near the Techa River contaminated by ^89,90Sr (beta-emitters) in 1949–1956 (Chelyabinsk Oblast, Russia). A new analysis has been performed of the combined results of FISH studies (n = 178) undertaken during 1994–2012 for persons living on the Techa Riverside. Analysis confirms the lower slope of the translocation yield per Gy (8.0 ± 0.7 × 10⁻³) for Techa residents in comparison with FISH data for donors with external exposures (11.6 ± 1.6 × 10⁻³, Tawn et al., Radiat Res 184(3):296–303, 2015). It was suggested that some portion of T cells remained unexposed, because they represented the descendants of T cell progenitors, which had migrated to the thymus before the start of ^89,90Sr intakes. To clarify this problem, the dynamics of T-cell Genera (TG), combining all descendants of specific T-cell progenitor reaching the thymus, was considered. Rates of TGs produced by RBM over different age periods of human life were estimated with the use of the mathematic model of T-cell homeostasis (Bains, Mathematical modeling of T-cell homeostasis. A thesis submitted for the degree of Doctor of Philosophy of the University College London. http://discovery.ucl.ac.uk/20159/1/20159.pdf, 2010). The rate of TG loss during the lifetime was assumed to be very small in comparison with production rate. The recirculation of mature T lymphocytes in contaminated RBM was taken into account. According to our model estimates, at the time of blood sampling, the fraction of exposed T lymphocytes (whose progenitors were irradiated) ranged from 20 to 80% depending on the donors’ age at the start of exposure to ^89,90Sr. Dose to T lymphocytes, estimated from FISH studies, should be about 0.6–0.9 of RBM dose for residents of the upper Techa region and about 0.4–0.8 in the middle Techa region. Our results could explain the lower value of translocation yield per Gy obtained for Techa residents. The approaches for further model improvement and validation are discussed in this paper.

Appendix

Equations used for calculations of doses to lymphoid progenitors and lymphocyte clonotypes

Weighted dose to lymphoid progenitors (D _LP) represents dose accumulated by the progenitors during their radiation exposure in RBM before they leave it and start to generate lymphocyte clonotypes in thymus.

D _LP is calculated as average value weighted in accordance with proportion of descendants of each precursor in the peripheral blood at the time of sampling:

$$D_{\text{LP}} = \frac{1}{{P_{\text{TG}} \left( {{\text{age}}_{\text{samp}} } \right)}}\mathop \int \limits_{{t_{0} }}^{{t_{\text{samp}} }} p_{\text{TG}} ({\text{age}})D_{\text{RBM}} (t, {\text{age)d}}t,$$

where t is the calendar time (years); t _o is the time of the beginning of exposure; and t _samp is the time of blood sampling; age = t − t _birth is the age of a donor (years), which varies from age₀ = t _o − t _birth to age_samp = t _samp − t _birth; P _TG (age_samp) is the normalization constant which represent total number of T-cell Genera produced for the period from age₀ to age_samp (calculated as integral of function from Eq. 2, arb. units); P _TG (age) is the age-dependent number of T-cell Genera produced per year (given in Eq. 2, arb. units); and D _RBM (t, age) is the absorbed dose in RBM (mGy), which is a function of calendar time, age and residence history of individual donor and is calculated with the use of TRDS-2016.

Weighted dose to lymphocytes in circulation (D _LC) represents dose accumulated by the lymphocytes in the period of their circulation in human body under radiation exposure; during the circulation, the lymphocytes spent 88% of the time in the extra-skeletal lymphoid tissues (ELT) and the remaining 12%—in the red bone marrow (RBM).

D _LC is calculated as average value weighted in accordance with the proportion of the lymphocytes that are included in the circulation regime at each age; also the fractions of time spending by circulating lymphocytes in ELT and RBM:

$$D_{\text{LC}} = \frac{1}{{P_{\text{TG}} \left( {{\text{age}}_{\text{samp}} } \right)}}\mathop \int \limits_{{t_{0} }}^{{t_{\text{samp}} }} P_{\text{TG}} ({\text{age}})\left[ {0.88\dot{D}_{\text{ELT}} (t, {\text{age}}) + 0.12\dot{D}_{\text{RBM}} (t, {\text{age}})} \right]{\text{d}}t,$$

where $P_{\text{TG}} ({\text{age}})$ is the number of T-cell Genera produced for the period from age₀ to age and switched to circulation mode (calculated as integral of function from Eq. 2, arb. units); $\dot{D}_{\text{RBM}} (t, {\text{age}})$ is the absorbed dose rate (mGy/year) in RBM, which is function of calendar time, age and residence history of individual donor and is calculated with the use of TRDS-2016. $\dot{D}_{\text{ELT}} (t, {\text{age}})$ is the absorbed dose rate (mGy/year) in ELT, which is function of calendar time, age and residence history of individual donor and is calculated with the use of TRDS-2016.