Pharmacological studies of ricin in mice and humans

Abstract

A highly sensitive enzyme-linked immunosorbent assay (ELISA) for determination of ricin in serum is presented. Using this method it was found that IV-injected ricin disappeared from the plasma of mice and cancer patients according to first-order kinetics. DBA mice were found to be more sensitive to ricin than C3H and B6D2 mice. When mice of the different strains were given the same dose of ricin, the concentrations found in liver, spleen, and kidneys were highest in the most sensitive mice. Ricin disappeared most rapidly from serum of the mice with the highest sensitivity. The inverse correlation between the rate of disappearance of ricin from serum and the tissue concentrations reached may be due to the fact that ricin is rapidly and firmly bound to cell surface receptors. Whole-body autoradiography after IV injection of 125I-labeled ricin showed the highest amount of radioactivity in liver, spleen, and adrenal cortex. Considerable amounts of radioactivity were also present in bone marrow, showing that the lack of myelosuppressive activity of ricin previously found in mice and dogs cannot be accounted for by the failure of ricin to reach the bone marrow. Part of the ricin in the tissues was present in the form of free chains, the highest fraction being present in the liver. In this tissue both the free A-chains and those present in whole ricin were found to be modified. However, the modified A-chains had retained their full capacity to inhibit protein synthesis in vitro. In cancer patients, toxicity appeared at about the same initial serum levels as in the mice, supporting the view that mouse data have a good predictive value for man. At each dose level the individual variations were modest, a finding that is important for eventual clinical use of this potent drug.

Ricin Toxicokinetics and Its Sensitive Detection in Mouse Sera or Feces Using Immuno-PCR

“…This constitutes about 50% of the injected ricin and is consistent with recovery amounts detected by others. The rest of ricin is thought to be associated with cells and thus not detectable in the sera [12], [13]. Previous attempts to determine ricin toxicokinetics in mice using ELISA methods only showed a linear degradation over 4 h [12], [13].…”

“…Ricin distribution in organs was previously determined by localization of radiolabelled toxins [12], [13]. Most ricin was found in the liver, spleen and the adrenal cortex of mice following iv intoxication.…”

“…Thus, little research data are available on the in vivo toxicokinetics of ricin and the dynamics of ricin following intoxication. Previous attempts at determining the distribution and fate of toxin employed radiolabelled ricin [12], [13]. While the location and intensity of radioactive label (either from intact or degraded toxin) can be discerned , this method is not practical for diagnostic uses in human biological samples.…”

Chemical Warfare Agents and Risks to Animal Health

“…The primary site of distribution of ricin is the liver, spleen, and adrenal cortex in the mouse. A high concentration was also found in the bone marrow (Godal et al, 1984). In rats, abrin is distributed primarily to the liver (12%) and kidney (3%; Lin et al, 1971).…”

“…Ricin is eliminated by first-order kinetics when injected via IV into mice and human cancer patients (Godal et al, 1984). The plasma half-life in humans is about 2 days (Kopferschmitt et al, 1983).…”