Date of Award
Doctor of Philosophy (PhD)
Physiology and Pharmacology
Cadium (Cd) is a naturally occurring metal with well documented toxic effects on humans and animals. MT is an endogenous protein that binds Cd and other metals; its role in relation to metabolism, homeostasis and detoxication of metals has yet to be fully elucidated. The dynamics of Cd and Mt were studied in individual rats (3 per group. Each rat served as its own control with blood sampled collected at -20, 0, 6, 12, 24, , 48, 72, and 96h via surgically inserted jugular cannula. Several cadmium chloride concentrations (2.5, 1.25, and 0.25 mg Cd/kg) or saline were investigated as a short course (single IP injection at T=Oh) or subchronic (multiple injections over 2 months) with 3 rates per dose. Feces, urine and whole blood were collected at each time point and blood was separated into whole blood, plasma, erythrocytes (RBC), polymorphonuclear leukocytes (PMN), lymphocytes (Ly) and monocytes (M). Liver, kidney, spleen and lung were collected at T=96h when the animals were euthanized. Quantitative determinations were made by electrothermal atomic absorption spectrometry (EAAS) for total Cd and by the Cd Saturation Assay (CSA) for MT. Cd and MT levels were elevated in a dose-response manner for all tissues and blood components except in the PMNs. The sequence of control (basal) blood MT concentrations was: plasma > RBC > M > Ly >PMN, compared to plasma > *M ≥ *Ly > RBC > PMN, for the 1.25 mg/kg (medium) exposure group at T = 12h. Similarly, the sequence of basal blood Cd concentrations was: whole blood > plasma > RBC ≥ Ly ≥ M ≥ PMN, compared to "whole blood > *RBC >> plasma > *M ≥ *Ly ≥ PMN for the medium exposure group at T = 2h. Significant differences (*p<0.05) were evident in longitudinal comparisons (concentration versus time) and between doses in both experimental protocols.
The evidence presented in this thesis clearly establishes Cd levels in RBCs and whole blood as reliable short-and long-term indices of exposure and possible of body burden. MT levels in plasma and RBCs constitute similar markers. Further, Cd in lymphocytes shows promise as a long-term indicator and in monocytes as a short-term index of exposure. Post mortem examination of subchronic organs did not support the contention of Cd-induced MT protection, but rather that of Cd accumulation and dose-dependent toxicity.
The in vivo jugular cannulation approach developed has both advantages and disadvantages. Body fluid samples can be collected over a 96-h time period from the same animal, thereby reducing inter-animal variation. The dynamics of Cd uptake and distribution and MT induction can thus be assessed in a single animal and be linked to the corresponding tissue results. The main disadvantage is that replicate sampling at a specific time point is limited by the volume of blood that can be drawn. However, this limitation is partially compensated by the ability to collect many samples over an extensive time period permitting longitudinal statistical comparisons with fewer animals. Another limitation is that the sample collection period is short compared to the time involved in chronic exposures.
Smith, Lisa M.J., "The Dynamics of Cadium and Metallothionein Accumulation in Peripheral Blood Cells and Selected Organs of Rats" (1993). Open Access Dissertations and Theses. Paper 2904.