Life Flow One
The Solution For Heart Disease
by
Karl Loren
Brit. J. industry. Med., 1965, 22, 172, 178-9
EFFECTS OF CALCIUM SODIUM
ETHYLENEDIAMINETETRA-ACETATE ON THE KINETICS OF DISTRIBUTION AND EXCRETION OF LEAD IN THE RATBY
N. Castellino and S. ALOJ
From the Institute of Industrial Medicine of the University and
The Institute of General Pathology of the University, Naples
(RECEIVED FOR PUBLICATION MARCH 19, 1965)
he effects of calcium sodium ethylenediaminetetra-acetate (CaN2EDTA) on the kinetics of distribution and excretion of lead (210PB) have been studied in rats. When the chelant was given intravenously, at 50mg/rat daily after a single intravenous injection of 100ug lead/rat, it greatly increased the urinary excretion of lead but reduced the faecal excretion. The greatest effects occurred in the rats treated with chelant shortly after the lead injection. When the chelant was given seven or more days after the lead the increase in lead excretion was negligible. CaNa2EDTA mobilized lead form every tissue, but the kinetic analysis of the disappearance of 210Pb showed the presence of two elimination phases. Lead ions weakly bound to the cells were rapidly removed by EDTA, whereas the lead fixed to endocellular constituents was only slowly removed. The chelant did not mobilize lead from bone.T
Probably CaNa2Edta entered the extravascular space but no the cells. Hence it only accelerated the passage of lead form the cells by lowering the concentration of lead outside them.
210Pb was also given orally in doses of 500ug lead/rat. About 18% of the dose was absorbed through the intestine to be distributed in all tissues. Rats treated orally with CaNa2EDTA showed an increase in urinary lead excretion and a reduction in lead fixed in the body.
Ethylenediaminetetra-acetic acid (EDTA) is widely used in the prevention and treatment of lead poisoning for its property of binding Pb+4 ions and so forming a relatively stable and not-toxic complex. Since EDTA may form complexes with other ions, in practice the drug is given as its calcium chelate (CaNa2EDTA) to prevent of loss of calcium from the body.
The EDTA has been given by different routes: intravenous, oral, and aerosol. Inhalation (Kehoe, 1955; Zambrano and Rossi, 1955; Teisinger and Srbová, 1956; Bell, Gilliland, Boland and Sullivan, 1956; Bastenier, Deslypere, and deGraef—Millet, 1958; Desoille, Albahary, Truhaut, and Boudène, 1958; Petrovic, Stankovic, Savicevic, and Poleti,1960; Albahary, Truhaut, Boudène, and Desoille, 1961; Williams, Matthews, and Judd, 1962; Castelliono and Grieco, 1964). The work of these authors among others shows that lead excretion is increased after EDTA administration, but where and how rapidly lead is mobilized is not satisfactorily known.
The metabolism of EDTA labeled with 14CaC-EDTA spreads rapidly from the vascular system and is not concentrated in any tissue. The compound is rapidly and totally excreted through the kidneys, and after six house 95% to 98% of the dose ids found in the urine. The compound is poorly absorbed by the gastrointestinal tract (in the rat a maximum of 18%; in man a maximum of 5%) and not at all through the skin. The low intestinal absorption of CaNa2EDTA has been confirmed by Srbová and Teisinger (1957), who found only 16.6% and 2.6% was absorbed in the rat and in man respectively.
* * * *
Oral Administration of Lead Acetate and CaNa2EDTA.
Tables 4 and 5 show the results obtained in two groups o frats, one of which had been treated with CaNa2EDTA contained less 210Pb fixed in soft tissues and in bone (P<0.01) and excreted more lead in the urine (P< 0.01). For soft tissues, CaNa2EDTA started before the injection of 210Pb, the chelant bound the metal ions as soon as they passed into the body fluids and before they could be fixed in the bone. These experiments indicated that lead absorbed through the intestine was not concentrated in the liver but was distributed throughout the whole organism; and that treatment with CaNa2EDTA by mouth did not modify the intestinal absorption of lead but increased its elimination in urine.
TABLE 4
210Pb FOUND IN URINE, FAECES, AND GASTRO-
INTESTINAL TRACT ONE DAY AFTER 500ug LEAD GIVEN ORALLY
(percentage of dose)
|
Urine |
Gastro- Intestinal Tract |
Feces |
|||
|
Mean Control S.E. |
|
24 |
Total |
24 hour |
24 hour |
|
0:14 0.06 |
0.66 0.10 |
0.80 0.13 |
15.1 4.0 |
66.8 4.7 |
|
|
Mean CaNa2EDTA S.E. |
2.63
0.18 |
2.43
0.44 |
5:06
0.48 |
17.0
2.1 |
66.2
2.8 |
TABLE 5
210Pb/g. FRESH TISSUE ONE DAY AFTER 500UG LEAD GIVEN ORALLY
(percentage of dose)
Table 5
210Pb/g. FRESH TISSUE ONE DAY AFTER 500 ug LEAD GIVEN ORALLY
(percentage of dose)
Discussion
The results showed that CaNa2EDTA mobilized lead from all tissues with the exception of the bone. Lead, chelated in the EDTA molecule, passed into the plasma and was rapidly excreted by the kidney.
As the Pb-EDTA complex is excreted by the same route as EDTA itself, some lead ions, bound in the liver and in other parts of the body, were no longer excreted via the bile in faeces but were eliminated instead in the urine. This was shown by the increase in urinary excretion accompanied by a decrease in faecal excretion.
The kinetics of 210Pb removal from the different tissues explain the action of CaNa2EDTA and confirm the complexity of lead metabolism. Since the disappearance of 210Pb in rats be given EDTA still required two exponential terms for its expression, it seems that CaNa2EDTA accelerated the removal of lead without modifying its metabolism. Weakly bound or extracellular lead was rapidly removed, but lead strongly complexed inside the cells was still removed only very slowly. It seems unlikely that such acceleration as there was of this slow phase was brought about by any direct action of the chelant on lead in the cells. It is more likely that, by removing some of the extracellular lead, it increased the rate of transport out of the cells by increasing the concentration gradient. This hypothesis is confirmed by the results obtained in the rats treated with CaNa2EDTA some days after lead injection, when the rapid phases of 210PB disappearance were over. In these animals CaNa2EDTA had only a slight effect on the excretion of lead and on the percentages of metal fixed in the tissues. We therefore agree with Teisinger, et al. (1958a, b) that CaNa2EDTA passes into the extravascular space where it binds lead ions, but does not penetrate the cells.
CaNa2EDTA did not mobilize lead from bone, in which probably the metal, bound to other ions, is fixed as a stable organic compound. Previous researches showed that there are analogies between calcium and lead metabolism in the bone (Nishimura, 1957), and that lead is fixed by the osteons (Vincent, 1957). Discordant views, however, have been expressed on the possibilities of modifying the fixation of lead in bone. Some authors (Hunter and Aub, 1927: Nishimura, 1957) think that parathyroid hormones modify the fixation of lead in bone, whereas Calhoun, McLean, Hudson, and Aub (1954) found that neither a low nor a high calcium diet, nor parathyroid hormones, affected lead excretion. This problem needs further study. Our experiments showed that CaNa2EDTA lowered lead deposition only when the chelant was given before lead and are in agreement with previous work on the mobilization of radioactive metals with chelating agents by Foreman, Fuqua, and Norwood (1954) and by Catsch (1961) and Catsch and Schindewolf-Jordan (1961).
Finally, it has been supposed that the oral use of EDTA could increase the intestinal absorption of lead. The increase in urinary lead excretion would then depend on its higher absorption by the intestine and its more rapid removal out of the tissues. Our experiments show that the oral administration of CaNa2EDTA caused a great increase of urinary lead excretion without modifying its intestinal absorption: about 18% of the lead was absorbed by rats whether they were treated with EDTA or not.
|
Ref |
REFERENCES
Albahary C, Truhaut R, Boudène C, and Desoille H (1961).
Presse med., 69, 2121.
Bastenier H, Deslypere P, and deGraef-Millet (1958). Prac. 12TH
Internat. Congr. Occup. Hlth., Helsinki, 1957, Vol. III, p. 243
Bell RF, Gilliland JC, boland JR, and Sullivan BR (1956).
Arch. Industry. Hlth, 13, 366.
Calhoun JA, McLean R, Hudson JC, and Uub JC (1954).
Arch. Industr. Hyg., 9, 9.
Castellino N and Aloj S. (1964). Brit J. Industr. Med, 21, 308.
_________, and Grieco B (1964). Folio med. (Napoli), 47, 57.
Catsch, A. (1961). Fed Proc., 20, Suppl. 10. p. 206.
_________, and Schindewolf-Jordan D. (1961). Nature, 191, 715.
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