Comments on “Improved Modeling of Plutonium-DTPA Decorporation” (Radiat Res 2019; 191:201-10)

We read with interest the article ‘‘Improved modeling of plutoniumDTPA decorporation’’ by Dumit S. et al. (1) and some others by the same authors: ‘‘Validation of a system of models for plutonium decorporation therapy’’ (2), ‘‘USTUR case 0846: modeling americium biokinetics after intensive decorporation therapy’’ (Breustedt B. et al.,(3)). The authors wish to model the biokinetics of plutonium/americium (Pu/ Am) altered by a decorporation therapy with DTPA. To improve their previous modeling systems that assumed chelation only takes place in blood and interstitial fluids, they now at least add the liver as another site for Pu/Am-DTPA chelate formation. However, it is a pity that they imply that removal of Pu/Am in the liver results from chelation in liver compartments of rapid turnover [e.g. named Liver0 in (1)], i.e. in extracellular compartments such as interstitial fluids, but not in liver cells, which are the true compartment of storage for transuranics. It seems to us that considering the intracellular action, especially in liver cells, could improve the modeling of plutonium-DTPA decorporation. Note that there is new evidence for the existence of intracellular chelation of Pu/Am in rat liver (4), and there is no biological reason why this should be different in man. The authors quoted Grube et al. who ‘‘suggested that chelation of plutonium in the liver of a rat could be attributed to chelation that was occurring in the extracellular fluids of the liver’’ (5). We have previously explained that such extracellular chelation cannot lead to the efficacy levels observed in liver of DTPA-treated rats contaminated with plutonium (4). DTPA is hydrophilic, negatively charged and very quickly eliminated from the body, which is not conducive to its entry to cells. This is probably the main reason why the authors reject the possibility of the intracellular chelation. In this respect, the fraction of DTPA entering cells is expected to be very small. However, the chelation efficacy of Pu/Am in a given compartment mainly depends on the DTPA-to-Pu/Am molar ratio attained in this compartment, as previously discussed elsewhere (4). By the way, the authors themselves said ‘‘the remaining 1% of DTPA could still be sufficient for chelation’’ . . . of Am, as the injected amount of DTPA is at least 9 orders of magnitude higher than the number of Am atoms available for complexation.’’ The same reasoning can apply to the amount of DTPA penetrating cells and the number of Pu/Am atoms retained within these same cells. More specifically for liver cells, the ratio of the amount of DTPA in the liver to that in plasma is greater than of 1 in rats as soon as two hours after injection. This ratio reaches a maximum of 4 at four hours and is still greater than 3 at 48 hours (6). These data show that liver may accumulate DTPA, which is more easily explainable by its intracellular accumulation rather than by its long-lasting presence within extracellular fluids or bound to cell surfaces. Hepatocytes represent the main compartment of Pu/Am retention in the liver and these cells are responsible for the production of the bile prior to release into the intestinal lumen (or gallbladder). In addition, 0.12% of the injected DTPA dose is excreted into rat bile over 24 hours (7), which indicates at least this amount has previously entered hepatocytes (about 2.4 3 10 mol for 1 g of Na3Ca-DTPA injection). Such quantity of DTPA in hepatocytes is likely to be several orders of magnitude greater than that of Pu/Am present in this type cell at the time of treatment. This will favor a successful exchange of Pu/Am from their endogenous ligands to DTPA. Once Pu/Am-DTPA chelates are formed by intracellular chelation of Pu/Am internalized in hepatocytes, they will be excreted via the biliary route (7, 8), resulting in a delayed enhancement of activity cleared in feces as observed in rodents, dogs, pigs, as well as humans (9, 10). In order to confirm the relation between the presence of Pu/Am in hepatocytes at the time of DTPA administration and increased Pu/Am fecal excretion, a rat experiment has been performed and the results are as follows. First, let us remember that the distribution of plutonium among the two major cell types of the liver (hepatocytes and Kupffer cells) depends on its physicochemical form when injected: monomeric plutonium is essentially taken up by the hepatocytes whereas colloidal plutonium is mainly engulfed by the reticuloendothelial cells named Kupffer cells (11–13). Rats contaminated by the one or the other form of plutonium received a prophylactic treatment given one day prior to plutonium exposure at high dosage in DTPA (300 lmol.kg ) in order to induce a decorporation resulting mainly from delayed intracellular chelation (4). This treatment regimen significantly minimized liver accumulation of both forms of plutonium, and enhanced both urinary and fecal excretions of plutonium, as compared to untreated rat controls. The 3-day cumulative urinary and fecal excretion of monomeric plutonium (given as Pu-citrate) in pretreated rats was 4.2% and 17% of injected plutonium, respectively, while that of colloidal plutonium was 17.8% and 9% of injected plutonium, respectively (unpublished data). The ratio of fecal plutonium to urinary plutonium was then 4 for monomeric plutonium vs. 0.5 for colloidal plutonium. The results indeed confirm the relation between an intracellular chelation of Pu/Am present in hepatocytes and an enhanced excretion of Pu/Am in feces. Finally, the Pu/Am-DTPA chelates formed in hepatocytes are cleared by the feces after bile clearance whereas those formed in Kupffer cells or in cells of other tissues are eliminated by urine like those formed in extracellular compartments (4). Other unpublished results suggest that intracellular chelation could take place in other soft tissues than the liver such as the testes, the striated skeletal muscle, and the spleen. However, the proportion of the Pu/Am decorporated resulting from an intracellular chelation in all of these other tissues may be far lower than that resulting from the intracellular chelation occurring solely in the liver. According to the authors, ‘‘an increased plutonium urinary excretion is the main outcome of Ca-DTPA treatment in humans, whereas the effect on fecal excretion is presumably smaller and is poorly documented. Thus, only urinary excretion was taken into account by both injected Ca-DTPA and Pu-DTPA models’’ (1). It is a fact that fecal data have been infrequently collected in DTPA-treated patients (ex: inhalation case 0846 from USTUR: 1,130 urine measurements vs. 67 fecal measurements over a 7-day DTPA 1 Address for correspondence: Olivier GREMY, CEA, DSV, CEA/ DAM Ile de France Bruyères-le-Châtel, Arpajon cedex, France 91297, France; email: olivier.gremy@cea.fr.