Revisiting the Historic Strontium-90 Ingestion Beagle Study Conducted at the University of California Davis: Opportunity in Archival Materials

Abstract

Strontium-90 is a radionuclide found in high concentrations in nuclear reactor waste and nuclear fallout from reactor accidents and atomic bomb explosions. In the 1950s, little was known regarding the health consequences of strontium-90 internalization. To assess the health effects of strontium-90 ingestion in infancy through adolescence, the Atomic Energy Commission and Department of Energy funded large-scale beagle studies at the University of California Davis. Conducted from 1956 to 1989, the strontium-90 ingestion study followed roughly 460 beagles throughout their lifespans after they were exposed to strontium-90 in utero (through feeding of the mother) and fed strontium-90 feed at varying doses from weaning to age 540 days. The extensive medical data and formalin-fixed paraffin-embedded tissues were transferred from UC Davis to the National Radiobiology Archive in 1992 and subsequently to the Northwestern University Radiobiology Archive in 2010. Here, we summarize the design of the strontium-90 ingestion study and give an overview of its most frequent recorded findings. As shown before, radiation-associated neoplasias (osteosarcoma, myeloproliferative syndrome and select squamous cell carcinomas) were almost exclusively observed in the highest dose groups, while the incidence of neoplasias most frequent in controls decreased as dose increased. The occurrence of congestive heart failure in each dose group, not previously assessed by UC Davis researchers, showed a non-significant increase between the controls and lower dose groups that may have been significant had sample sizes been larger. Detailed secondary analyses of these data and samples may uncover health endpoints that were not evaluated by the team that conducted the study.

FIG. 1.

Kaplan-Meier survival curves for each dose group in the UC Davis strontium-90 ingestion study, generated from the data on non-stillborn dogs and dogs not placed on ancillary studies (the “true’ lifespan dogs). Numbers of animals in each dose group under these criteria are: D00 n = 78, D05 n = 71, D10 n = 39, D20 n = 59, D30 n = 59, D40 n = 57, D50 n = 60 and D60 n = 19. Ninety-five percent confidence intervals for each dose group are not shown due to the number of curves in one plot. Ninety-five percent confidence intervals are calculated by adding or subtracting the product of 1.96 times the standard error from the survival probability at a given time, with standard errors ranging from: D00 = 0.0127 to 0.0566, D05 = 0.0140 to 0.0593, D10 = 0.0253 to 0.0800, D20 = 0.0168 to 0.0651, D30 = 0.0168 to 0.0651, D40 = 0.0174 to 0.0662, D50 = 0.0165 to 0.0645 and D60 = 0.0512 to 0.1145. Survival curves with 95% confidence intervals can be visualized using an R script, found at https://github.com/WoloschakLab/NURA-Code, with access given upon request by contacting the corresponding author. Statistically significant differences in survival are summarized in Table 2.

FIG. 2.

Panel A: Boxplots of calculated total lifespan skeletal doses across the dose groups. Numbers of “true” lifespan animals in each dose group with dose information available are: D00 n = 77, D05 n = 70, D10 n = 39, D20 n = 58, D30 n = 56, D40 n = 54, D50 n = 57 and D60 n = 18. Differences in mean total lifespan doses between dose groups as found by pairwise Wilcoxon rank sum tests with Bonferroni correction are summarized in Table 3. Panel B: Boxplots of the lowest dose groups alone (D00 to D20), allowing for better visualization of the differences in these dose groups. There are no differences compared to Panel A, except for the exclusion of the higher dose groups and the change in the scale of the y-axis.

FIG. 3.

Panel A: Boxplots of calculated average daily skeletal doses, or the average daily skeletal dose rate, across the dose groups. Numbers of “true” lifespan animals in each dose group with dose rate information available are: D00 n = 77, D05 n = 70, D10 n = 39, D20 n = 58, D30 n = 56, D40 n = 54, D50 n = 57 and D60 n = 18. Differences in mean dose rates between dose groups as found by pairwise Wilcoxon rank sum tests with Bonferroni correction are summarized in Table 4. Panel B: Boxplots of the lowest dose groups alone (D00 to D20), allowing for better visualization of the differences in these dose groups. There are no differences compared to Panel A, except for the exclusion of the higher dose groups and the change in the scale of the y-axis.

FIG. 4.

Scatterplot of the cumulative skeletal dose versus average skeletal dose rate for each dog, colored by dose group. Numbers of “true” lifespan animals in each dose group with dose and dose rate information available are: D00 n = 77, D05 n = 70, D10 n = 39, D20 n = 58, D30 n = 56, D40 n = 54, D50 n = 57 and D60 n = 18. Axes are log-transformed. Spearman’s rank correlation ρ = 0.978.

FIG. 5.

Panel A: Boxplots of the maximum measured body burden of strontium-90, or the peak burden, across the dose groups. Numbers of “true” lifespan animals in each dose group with peak burden information available are: D00 n = 77, D05 n = 70, D10 n = 39, D20 n = 58, D30 n = 56, D40 n = 54, D50 n = 57 and D60 n = 18. Differences in mean peak burdens between dose groups as found by pairwise Wilcoxon rank sum tests with Bonferroni correction are summarized in Table 5. Panel B: Boxplots of the lowest dose groups alone (D00 to D20), allowing for better visualization of the differences in these dose groups. There are no differences compared to Panel A, except for the exclusion of the higher dose groups and the change in the scale of the y-axis.

FIG. 6.

Grouped bar plots showing the causes of death that appear more than once for each dose group in the lower dose groups (D00 to D30). The frequencies for each identified cause of death are shown for both males and females. The causes of death shown in each panel are not representative of the comprehensive list of causes of death for each dose group. Panel A: D00 dose group causes of death. D00 n = 38 females and 40 males, some having causes of death not shown in this plot. “TCC” stands for transitional cell carcinoma. Panel B: D05 dose group causes of death. D05 n = 33 females and 38 males, some with causes of death not shown in this plot. Panel C: D10 dose group causes of death. D10 n = 18 females and 21 males, some with causes of death not shown in this plot. Panel D: D20 dose group causes of death. D20 n = 26 females and 33 males, some having causes of death not shown in this plot. Panel E: D30 dose group causes of death. D30 n = 27 females and 32 males, some having causes of death not shown in this plot.

FIG. 7.

Grouped bar plots showing the causes of death that appear more than once for each dose group in the higher dose groups (D40 to D60). The frequencies for each identified cause of death are shown for both males and females. The causes of death shown in each panel are not representative of the comprehensive list of causes of death for each dose group. Complete cause of death diagnosis frequencies for the D50 and D60 dose groups can be found in Supplementary Fig. S5 (https://doi.org/10.1667/RADE-24-00022.1.S1). Panel A: D40 dose group causes of death. D40 n = 30 females and 27 males, with some animals have causes of death not shown in this plot. Panel B: D50 dose group causes of death. D50 n = 30 females and 30 males, with some having causes of death not shown in this plot. Panel C: D60 dose group causes of death. D60 n = 7 females and 12 males, with some animals having causes of death not shown in this plot.

FIG. 8.

Grouped bar plot showing the percentages of dogs that developed congestive heart failure and mammary carcinoma as the cause of death across dose groups. The data used to generate this plot comes from the medical records of “true” lifespan animals with cause of death information. Animal counts in each dose group are: D00 n = 38 females and 40 males, D05 n = 33 females and 38 males, D10 n = 18 females and 21 males, D20 n = 26 females and 33 males, D30 n = 27 females and 32 males, D40 n = 30 females and 27 males, D50 n = 30 females and 30 males, D60 n = 7 females and 12 males. Congestive heart failure is abbreviated CHF and labeled black. Mammary carcinoma is abbreviated MC and labeled with stripes.

FIG. 9.

Grouped bar plot showing the percentages of dogs that developed the major radiation-associated neoplasias observed in the UC Davis strontium-90 ingestion study across dose groups. The data used to generate this plot comes from the medical records of “true” lifespan animals with complete histopathology reports at necropsy. D00 n = 77, D05 n = 69, D10 n = 39, D20 n = 55, D30 n = 59, D40 n = 57, D50 n = 60 and D60 n = 19. Myeloproliferative syndrome is abbreviated MPS and labeled black. Osteosarcoma is abbreviated OS and labeled with stripes. Squamous cell carcinoma is abbreviated SCC and labeled white.