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Comparative Toxicity of Stable Rare Earth CompoundsJoseph G. Graca PhD a b , Frederick C. Davison DVM a & Joyce B. Feavel MT aa Pharmatox Laboratories, Inc. , PO Box 1006, University Station, Ames , Iowab Department of Physiology and Pharmacology , College of Veterinary Medicine and the AmesLaboratory of the US Atomic Energy Commission, Iowa State University , Ames , IowaPublished online: 29 Apr 2013.

To cite this article: Joseph G. Graca PhD , Frederick C. Davison DVM & Joyce B. Feavel MT (1964) Comparative Toxicityof Stable Rare Earth Compounds, Archives of Environmental Health: An International Journal, 8:4, 555-564, DOI:10.1080/00039896.1964.10663717

To link to this article: http://dx.doi.org/10.1080/00039896.1964.10663717

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555

Comparative Toxicity of

Stable Rare JOSEPH G. GRACA, PhD

FREDERICK C. DAVISON, DVJ\1

AND

Earth Compounds JOYCE B. FEAVEL, l\IT

A:VIES, IOWA

III. Acute Toxicity of Intravenous Injections of Chlorides and

Chelates in Dogs

Studies of physiological responses to stable rare earths in animals following parenteral administration have been limited. Radioisotope studies of rare earth metabo­lism 1 in rats have shown that deposition takes place primarily in the liver and skele­ton. Approximately SOo/o of an intramus­cularly injected dose of lanthanum is deposited in the liver and 2So/o in the skele­ton. A progressive decrease in liver deposi­tion and an increase in skeletal deposition is seen with successive members of the lantha­nide series. The skeleton absorbs SOo/o to 65o/o of the heavier rare earths with rela­tively small amounts accumulating in the

Submitted for publication Dec 4, 1962. Present address of Dr. Graca : Pharmatox Labo­

ratories, Inc., Ames, Iowa. Department of Physiology and Pharmacology,

College of Veterinary Medicine and the Ames Laboratory of the US Atomic Energy Commission, Iowa State University.

The experiments reported here are part of a proj eet on comparative toxicity of stable rare earth compounds supported by the US Atomic Energy Commission (contract No. AT [ 11-1]-1170).

liver. Excretion of the injected lighter lan­thanons is primarily fecal (via the liver). With the heavier members excretion is pri­marily renal. Other studies 2 of the metabo­lism of lanthanum and yttrium chelates have shown that although lanthanum-edetate ( ethylenediaminetetraacetic acid) chelates form stable complexes in vitro, the mam­malian organism is capable of dissociating these complexes in varying degrees. Laszlo 3

has reported that lanthanun1 complexes are distributed more homogeneously than are the ionized forms.

Anticoagulant properties of rare earths have been studied rather extensively in vitro and in vivo, since they were thought to pos­sess clinical usefulness as anticoagulants. These effects have been studied in lower animals 4 ·6 and in man. Dyckerhoff and Goossens 7 in a study of coagulation time in dogs and in humans reported that neodymi­um salts were harmless to man. Later studies by Beaser, Segel, and Vandam 8 in a study of 18 patients treated with doses far

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below the expected level of tox1c1ty as de­termined in animals disputed the conclusion that these compounds were harmless. In 1950 Vincke and Sucker 9 reported that ne­odymium-3-sulfo-isonicotinate was a com­pound sufficiently soluble and free of toxic effects for clinical use. Neodymium appears to be the only rare earth introduced clinically as an anticoagulant.

The mechanism of anticoagulant action was described by Dyckerhoff and Grune­wald 10 as an antiprothrombin effect. Beller and Mammen 11 in tests utilizing newer tech­niques found that the anticoagulant effect was accomplished by reducing factor VII and factor X, leaving prothrombin normal. In independent studies, Hunter and Walk­er 12 reported that intrinsic blood thrombo­plastin generation time was impaired in the circulating blood by the inhibition of two normal serum thromboplastin constituents, the Christmas factor (FTC, factor IX) and factor X, and also by reduction in activity of factor VII ( SPCA, stable factor) activi­ty. They suggested that "neodymium acts as an antimetabolite of calcium by replacing it from combination with one or more of the protein factors in coagulation."

In the studies reported here, chlorides, citrate complexes, and edetate complexes of rare earths were administered intravenously at ten-minute intervals to anesthetized dogs for a total of ten injections. Determinations of the comparative effects produced by the three types of compounds were made on heart rate, blood pressure, respiration, and clinical hematology. The objectives of this study were to determine differences of re­sponse produced by highly ionized chlorides as compared to the more stable chelates.

Materials and Methods

Chlorides of all rare earths except promethium and including yttrium were prepared as 5.00% aqueous solutions by the Ames Laboratory of the US Atomic Energy Commission. The edetate com­plexes were adjusted to contain an equivalent of 5.00% XCia. The citrate complexes were prepared from the chlorides as needed using a 1 :3 ratio of rare earth chloride to 5.00% sodium citrate. This concentration based on in vitro tests was found to

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be a minimum practical ratio which prevented pre­cipitation of the rare earth salts in blood serum as reported previously.13 The volume of citrate com­plex administered was adjusted to be equivalent in concentration to the other two solutions.

Adult dogs weighing between 5 and 15 kg were used in a randomized program. They were kept under observation and maintained on a standardized diet for at least two weeks prior to use. The ani­mals were anesthetized with an intravenous injection of approximately 30 mg/kg of pentobarbital so­dium. Blood pressure was recorded from the carotid artery using a strain gage manometer. A cannula was inserted into the left femoral vein and con­nected to an infusion bottle containing Ringer's solu­tion. Rare earth solutions were injected into the tubing just above the cannula. The right femoral vein was exposed and used for drawing blood samples directly.

The rare earths were administered in a dose of 10 mg/kg of XCla, or its equivalent in the chelates, at ten-minute intervals for a total of ten doses. This dosage was selected from previous experience in toxicity studies with mice and guinea pigs-" It was established at a level high enough to elicit measur­able physiological response and permit survival for 160 minutes. Control readings for each animal were taken just prior to the first injection. Blood samples were taken preanesthetically, and at 0, 10, 30, 60, 100, and 160 minutes. Blood studies included red, white, and differential cell counts, prothrombin time as measured by the Quick one-step method, coagulation time by the Lee and White four-tube method, hemo­globin was measured colorimetrically, and the sedi­mentation and hematocrit values were determined by the \Vintrobe method. Necropsies were performed at the conclusion of each experiment. Tissues taken for histopathological evaluation were liver, spleen, kidney, lung, sternum, mesentery lymph nodes, heart, adrenal, and ovaries or testes.

Nine dogs were used for each rare earth studied. Three were used for the chloride, three for the ci­trate complex, and three for the edetate complex. Three sets of control studies were made in which the procedure was identical with the test series except that the rare earths were left out. Sodium citrate was injected into 6 clogs, ammonium versenate into 6 dogs, and Ringer's solution alone was injected into 12 clogs.

Experimental Results

A difference in toxicity was found when equivalent doses of the three types of com­pounds were administered. In general, the chlorides were comparatively more toxic than the citrate or edetate complexes. Four­teen of 45 dogs treated with the chlorides did not survive the three-hour experimental

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period. Four of 45 citrate-treated and one of 45 edetate-treated dogs died before com­pletion of the experiment. Deaths were the result of circulatory failure produced by in­jection of the drug. Two factors appeared to predispose a fatal circulatory collapse. First, if the initial blood pressure was low or, secondly, if an injection produced an un­usually severe drop in blood pressure from which the animal could not respond.

Surviving animals were observed for one hour following the last injection, and data are included for the 160-minute interval. These last values for blood pressure, heart rate, and respiration should be interpreted in the light of the variation of decreasing anesthetic effect. The rare earths were not contributory to the depressant effects of the anesthetic.15

1. Effects on Blood Pressure.-The im­mediate blood pressure response to rare earth injections ranged from no effect in some dogs to a transient decrease, variable in amplitude from animal to animal, to a marked fatal decrease. With the chlorides, the first injection produced the most severe reaction, with lesser response upon subse­quent injections. Injection of citrates showed a reverse trend with an increasing transient drop in blood pressure following each injection. Decreases in blood pressure ranged from 5 to 20 mm Hg with recovery to previous levels in from 30 seconds to 2 minutes. The edetate complexes elicited no immediate change on the blood pressure.

The blood pressure in general showed a cumulative decline over the experimental period. There was no constancy of pattern among the various rare earths or types of compounds. These effects were in addition to those attributable to the anesthetic.

In Fig 1, the relative changes are com­pared for chlorides, citrates, and edetate complexes.

2. Effects on Heart Rate.-Injection of rare earths generally produced a decrease in heart rate with no apparent correlation with respect to the type of compound used. In occasional animals there was an increase in heart rate. Electrocardiograms showed no

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irregularities in cardiac rhythm or conduc­tion.

In Fig 2, the relative changes for heart rate are shown.

3. Effects on Respiration.-The effects on respiration were slight and variable. The chlorides appeared to be somewhat more stimulating than the citrates. There were no specific responses relating to the respiratory mechanisms. No alterations in rhythm or depth were noted resulting from the in­jections themselves or the cumulative effect in the series. The respiration rates are plot­ted in Fig 3.

4. Effects on Blood Constituents.-The most striking effects were marked increases in prothrombin and coagulation time. In chloride-treated animals, prothrombin time was over 100 seconds with most rare earths within one hour following the initial injec­tion. Citrate complexes also produced pro­longed prothrombin time which developed later and was not as marked. The edetate complexes had a lesser effect. It was evident that there was a decreasing effect with in­crease in atomic number. Ytterbium admin­istered in any form did not appreciably change prothrombin time from normal. Lutecium produced minimal change although prothrombin time for chlorides was in­creased greatly. Comparative values are shown in Fig 4.

Coagulation time was increased by all compounds in a comparable pattern described for prothrombin, with some in­teresting exceptions. Samarium chloride prothrombin time was greater than with the citrate, but coagulation time was reversed. Although ytterbium prothrombin time was not affected, the coagulation time was. For the most part the edetate complexes did not affect coagulation, except for increases with lanthanum, cerium, praseodymium, and eu­ropium. These values are shown in Fig 5. There were no other distinctive effects on the other blood constituents which could be attributed to the rare earths.

A consistent and marked leukopenia was found in all dogs regardless of the type com­pound used. Additional control studies re-

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Fig I.-Comparative blood pressure changes following injections of rare earth chlorides, citrate, and ecletate chelates in the dog.

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Fig 2.-Heart rate changes following intravenous injections of rare earth chlorides, citrate, and edetate chelates in the dog.

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Fig 3.-Comparative respiratory rates following intravenous injections of rare earth chlorides, citrate, and edetate chelates in the dog.

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vealed that this was not a characteristic reaction to the rare earths, but an effect pro­duced by pentobarbital. Details of this study are reported in a separate publication.15

Pathological Fndings.-No marked gross differentiating changes wen~ found on ne­cropsy. In the chloride-treated animals the lungs appeared slightly to moderately hyperemic. This was not found with the citrate- or edetate-treated animals. There was no evidence of internal hemorrhaging although the anticoagulant effects of the rare earths were evident by the pooling of blood at the incision sites. Histopathological ex­amination of the tissues demonstrated no evidence of acute damage resulting from the experimental procedure.

On the basis of the above findings pre­liminary studies were carried out to deter­mine if latent clinical or toxicological effects would develop after a single intravenous in­jection of SO mg/kg of neodymium chloride, praseodymium chloride, and cerium chloride. There were no immediate reactions to the injection. However, over a period of two or three weeks the animals deteriorated physi­cally and were emaciated and unthrifty. After about three weeks, extensive sub­serosal hemorrhages particularly over the colon, petechial renal hemorrhages, and evi­dence of liver damage (toxic hepatitis) were found.

Conclusion

The intravenous injection of stable rare earth chlorides, citrate, and edetate com­plexes in dogs did not result in any distinc­tive acute physiological changes in heart rate, blood pressure, or respiration. The injection of 100 mgjkg of rare earth compounds in 10 mgjkg increments at ten-minute intervals showed that the chlorides were the most toxic, and edetate complexes the least. Un­der the conditions of this experiment acute toxicity of the rare earths tested was low. In general, a decreasing toxicity was found with increasing atomic weight. This could be correlated with the higher stability con­stants of the heavier rare earths. Apparently chelation mechanisms found normally in the

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body have higher stability constants than those of the lower rare earths, but not as great as those at the upper range. In the animals that died, the symptoms were those of cardiovascular collapse occurring sudden­ly after an injection.

The only specific findings were in the hematological studies and were related to the anticoagulant properties of the rare earths. These developed rather rapidly with the chlorides and citrates and to a much lesser extent, if at all, with the edetate complexes. Although parenteral administration of rare earth compounds does not produce any im­mediate characteristic reaction, latent symp­toms associated with the anticoagulation mechanisms of the body do develop as shown in the single injection preliminary studies.

Summary

Stable rare earth chlorides, citrate, and edetate complexes were injected into a total of 135 anesthetized dogs. All rare earths, except promethium, were included. Yttrium was also included in the series. An amount of 100 mgjkg doses were administered in­travenously as 5% solutions, in 10 mgjkg increments at ten-minute intervals. Obser­vations were made on heart rate, blood pres­sure, and respiration. Blood samples were taken preanesthetically, and at 0, 10, 30, 60, 100, and 160 minutes for RBC, WBC, and differential counts, hemoglobin, hematocrit, sedimentation rate, prothrombin time, and coagulation time. No distinctive physiologi­cal response was found with any of the rare earths. Specific effects on blood constituents were an increase in prothrombin and coagu­lation times. The other constituents were not specifically affected by the rare earths.

The chlorides were most toxic and the edetate complexes the least. Acute toxicity was of a low order; however, latent symp­toms and pathology were found in single­injection preliminary studies. There also was a gradation of decreasing effects from the lower to the higher members of the atomic series. Gross and histopathological examinations were essentially negative.

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Fig 4.-Comparative prothrombin times following intravenous injections of rare earth chlorides, citrate, and edetate chelates in the dog.

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Fig 5.-Coagulation times following intravenous injections of rare earth chlorides, citrate, and edetate chelates in the dog.

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Joseph G. Graca, PhD, Pharmatox Laboratories, Inc., PO Box 1006, University Station, Ames, Iowa.

REFERENCES

1. Durbin, P. W.; Williams, M. H.; Gee, M.; Newman, R.; and Hamilton, J. G.: Metabolism of the Lanthanons in the Rat, Proc Soc Exp Bioi Med 91 :78-85, 1956.

2. Hart, H. E. ; Greenberg, J. ; Lewin, R. ; Spen­cer, H. ; Stern, K. G. ; and Laszlo, D. : Metabolism of Lanthanum and Yttrium Chelates, J Lab Clin Med 46:182-192, 1955.

3. Laszlo, D.; Ekstein, D. M.; Lewin, R.; and Stern, K. G.: Biological Studies on Stable and Ra­dioactive Rare Earth Compounds: 1. On the Distri­bution of Lanthanum in the Mammalian Organism, J. Nat Cancer Inst 13:559-573, 1952.

4. Heffter, A., and Heubner, W.: Handbuch der experimentellen Pharmakologie, Berlin: Springer­Verlag, 1930, vol 3, sect 3.

5. Guidi, G. : Contributo alia farmacologia delle terre rare : II neodimio, Arch Int Pharmacodyn 37: 305-348, 1930.

6. Vincke, E., and Oelkers, .H. A.: Zur Pharma­cologie der seltenen Erden: Wirkung auf die Blut­gerinnung, Arch Exp Path 187:594-603, 1937.

7. Dyckerhoff, H., and Goossens, N.: Uber die thromboseverhiitende Wirkung des Neodyms (Neo­dympraparat "Auer 144"), Ges Exp Med 106:181-192, 1939.

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8. Beaser, S. B.; Segel, A.; and Vandam, L.: The Anticoagulant Effects in Rabbits and Man of the Intravenous Injection of Salts of the Rare Earths, J Clin Invest 21:447-454, 1942.

9. Vincke, E., and Sucker, E.: Dber ein neues Antithromboticum, das N eodymsulfoisonicotinat, Klin Wschr 28:74-75, 1950.

10. Dyckerhoff, H., and Grunewald, 0.: Dber den Reaktionsmechanismus der H~mmung der Blutger­innung durch einige seltene Erden and durch Hepa­rin, Biochem Z 315:124, 1943.

11. Beller, F. K., and Mammen, E.: Der Angriff­spunkt der seltenen Erden N eodym im Gerinnungs­system, Arch Gynaek 187 :319-336, 1956.

12. Hunter, R. B., and Walker, W.: Anticoagu­lant Action of Neodymium 3-Sulfo-Isonicotinate, Nature (London) 178:47, 1956.

13. Graca, J. G.; Garst, E. L.; and Lowry, W. E.: Comparative Toxicity of Stable Rare Earth Com­pounds : I. Effect of Citrate Complexing on Stable Rare Earth Chloride Toxicity, AMA Arch Industr Health 15:9-14, 1957.

14. Graca, J. G.; Davison, F. C.; and Feavel, J. B.: Comparative Toxicity of Stable Rare Earth Compounds: II. Effect of Citrate and Edetate Complexing on Acute Toxicity in Mice and Guinea Pigs, Arch Environ Health 5:437-444, 1962.

15. Graca, J. G., and Garst, E. L.: Early Blood Changes in Dogs Following Intravenous Pentobar­bital Anesthesia, Anesthesiology 18:461-465, 1957.

If an underdeveloped countJ·y were to attain the United Nations goal of a 5% rate of annual economic growth in ten years, it would raise a present per capita income of $100 to about $123, if its rate of population growth stood at 2%. But, if population expansion continues at the present rate, to increase its rate of economic growth to 5% from, say, a current 3%, would require a rise in national income of about 50%. Even with its vast capital resources and technology, the United States required about 15 years following World War II to increase its national income by 40%.

The odds against this kind of "bootstrap" economic leap are overwhelming. Unless an underdeveloped country remains an insatiable sponge for foreign assistance--an impossible solution-a good part of its investment in industrialization and improvement of standards must come from its own resources. But the low-income countries find it almost impossible to steer these resources toward investment. The pressure to use all available resources for current con­sumption is too great. As population grows, it takes more and more investment of capital to make any appreciable change in material well-being. Furthermore, since increasing population rates have the effect of increasing the proportion of children among the total population, a larger portion of national output must be used to support a growing number of nonearning dependents. A family with many children finds it difficult to save, and a government that tries to finance industrial development out of taxes can expect less financial support from a population with many children. And, of course, much of whatever can be saved must be invested in non-revenue­producing expenditures such as schools and housing.-V.'M. D. McELROY: Birth Control: The Solution to the Population Crisis Lies in Improved Methods and Universal Acceptance of the Practice, 14:7-8 (May) 1963.

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