metallothionein and triphosphoric-acid

Symptoms and signs in humans after excessive exposure to cadmium usually involve the gastrointestinal tract after single oral intake, the lung after acute inhalation, and the kidney after long-term exposure. These organs are usually considered to be the "critical" organs, i.e., the organs most sensitive at a certain type of exposure. The type of Cd-related damage that is most common in humans is probably the renal toxicity after long-term exposure. Most animal experiments, including the most recently published ones, have involved study of gross toxicity and tissue distribution after injection of cadmium in acute experiments. The observations in the older literature that the influence of chelating agents on Cd distribution and excretion is confined to the early period after acute Cd exposure has been confirmed and extended, and the relationship to the time course of metallothionein synthesis has been demonstrated. Although the injection experiments concerning cadmium distribution, particularly those employing repeated exposure, may furnish information that can form a basis for speculation about long-term toxicity to the kidney, there is a lack of direct studies in animals of possible beneficial effects of chelating agents on renal toxicity of cadmium after prolonged exposure. Among the few studies reported, either an increased renal toxicity or a lack of influence on renal toxicity has been observed. The problems in finding a treatment scheme that can be beneficial for the renal toxicity resulting from long-term cadmium exposure thus remain; however, the prospects of finding such schemes in the future seem favorable in view of some of the recent observations.

Topics: Animals; Cadmium; Chelating Agents; Dimercaprol; Edetic Acid; Humans; Metallothionein; Polyphosphates

The gastrointestinal absorption, transport, tissue deposition and excretion of cadmium was studied in adult male mice given a single oral LD50 dose of 109Cd-labeled CdCl2 alone or in combination with nitrilotriacetic acid (NTA), sodium tripolyphosphate (STPP) or ethylenediaminetetraacetic acid (EDTA). Blood, intestinal mucosa, liver and kidneys were analyzed for 109Cd at different times after exposure and the influence of the chelating agents on Cd binding to metallothionein and other tissue ligands was also studied. Acute toxicity was noted. Complex formation between Cd and EDTA was studied in solutions containing Cd:EDTA at 1:04 and 1:4 molar ratios. Adult male mice were exposed orally or by direct infusion into the stomach to either of the two solutions (containing an LD50 dose of Cd). Body retention and tissue deposition of Cd was recorded after 4 (direct infusion) or 21 days (oral exposure), and the mortality in different exposure groups observed. Adult male were also exposed to a low oral dose of 109Cd-labeled cadmium (0.5 mg/kg), followed by 18 months continuous administration of NTA, (500 ppm) STPP (500 ppm) or EDTA (50 ppm) in the drinking water or the chelating agent in combination with Cd (50 ppm), Cd alone (50 ppm) or deionized water. Whole-body retention of 109Cd, tissue deposition of 109Cd and total Cd and development of proteinuria were observed. When cadmium was given with an excess of EDTA, all Cd ions were bound in a 1:1 Cd-EDTA complex. Decreased acute toxicity was observed which was related to increased body elimination of cadmium. The Cd passes though the body still bound to EDTA and is excreted via the kidneys in this form. Similar results were found in mice exposed to Cd + NTA, while gavage of CD + STPP led to an initially decreased systemic uptake of Cd and thereafter to a prolongation of the biological half-time and thus a comparatively higher body retention of the metal. Cd may form a 2:1 complex with EDTA in the presence of excess cadmium. An increased retention and toxicity of cadmium was seen after direct infusion of this solution, while gavage resulted in a decreased toxicity. The effect of different chelating agents on acute cadmium toxicity and metabolism seemed to be due to changes in the stability of the administered chelate complexes, due to variation in pH and to the availability of metal binding ligands such as metallothionein in vivo. NTA, STPP and EDTA had no effect on the metabolism or toxicity of cadmium after long

Topics: Absorption; Administration, Oral; Animals; Biological Transport; Cadmium; Chelating Agents; Edetic Acid; Kidney; Metallothionein; Mice; Mice, Inbred CBA; Nitrilotriacetic Acid; Polyphosphates

Acute toxicity and organ distribution of cadmium was investigated in mice exposed to 1) single subcutaneous doses of 109Cd-labelled cadmium (3.2 mg (0.028 mmol)/kg b.wt.) alone or in combination with nitrilotriacetic acid, NTA (32 mg (0.167 mmol/kg b.wt.) or sodium tripolyphosphate, STPP (32 mg (0.087 mmol/kg b.wt.) and 2) single oral doses of cadmium (60 mg (0.53 mmol/kg b.wt.) alone or together with NTA (600 mg (3.14 mmol)/kg.b.wt.) or STPP (600 mg (1.63 mmol/kg b.wt.) Whole-body retention of radiolabelled cadmium as well as mortality was registered in all groups during 20-21 days. Five hours after exposure, 3-4 mice in each group were killed and cadmium distribution among proteins in liver and kidney studied by gel chromatography on a G-75 Sephadex column. Organ concentration of cadmium was also determined at sacrifice of all other mice after an observation time of 20-21 days. A markedly increased mortality was observed during the first 24 hours after subcutaneous exposure to Cd + NTA (70%) or Cd + STPP (40%) compared to Cd alone (0%). On the contrary, no mortality was seen after oral exposure to Cd + NTA (70%) or CD + STPP (while oral exposure to Cd alone or with NTA resulted in a mortality of about 45% during the same observation time. Five hours after subcutaneous exposure, liver cadmium concentrations were equal in all mice and bound mainly to a low molecular weight protein (probably metallothionein). In kidney, concentrations were about twice as high in mice given Cd + NTA or CD + STPP compared to mice given Cd alone. More cadmium was transferred to the kidneys in the presence of chelating agents. This was further supported by the decreased liver/kidney cadmium concentration ratio between 5 hours and 21 days. The increased mortality in mice given Cd + NTA or Cd + STPP may be due to an initially high accumulation of cadmium in liver, which may exceed the upper limit for metallothionein synthesis, whereby toxic damage of the hepatic cells and leakage of cadmium from the liver would occur. Five hours after oral exposure, cadmium retention in organs of mice given Cd + STPP was 4-6 times lower than in mice given Cd alone, while mice given Cd + NTA had slightly higher organ concentrations. The binding of more cadmium to metallothionein in liver of Cd + STPP-exposed mice 5 hours after exposure, may be due to the lower accumulation of cadmium in these mice compared to those given Cd alone or CD + NTA, where cadmium was bound mainly to high molecular prote

Topics: Animals; Cadmium; Chelating Agents; Kidney; Liver; Male; Metallothionein; Mice; Mice, Inbred CBA; Nitrilotriacetic Acid; Polyphosphates