Part 8

Mittelstaedt called attention to the fact that pregnant rabbits were more easily affected by the barium administration than nonpregnant ones, and noted abortion in one case.[199]

One gram of the barium carbonate killed a dog in eight hours. A second dog died in fifteen hours. Both of these animals vomited so that a portion of this must have been lost.[200] Barium carbonate was formerly employed as a rat poison.[201]

Of barium chlorid 0.6 gram, fed in aqueous solution, caused death in a dog in forty-eight minutes if vomiting was prevented.[202]

In Tidy's hands 2 grams of the barium nitrate caused death in a small terrier in three and three-fourth hours. This dog had slight convulsions, was almost unable to stand, and had vomiting and purging. The reflexes were diminished. A small dog recovered only completely in five days after being fed 0.66 gram, while a large dog after being fed 1.3 grams only recovered after two days.

In cats 0.8 gram of barium carbonate when introduced into a wound caused on the third day languor, slow respiration, feeble pulse, twitching of hind legs, dilated pupils, and death.[203]

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FOOTNOTES:

[192] Magnus, R. Wirkungsweise u. Angriffspunkt einiger Gifte am Katzendarm. Archiv. f. Gesam. Physiol., vol. 108, p. 44, 1905.

NOTE.--Reports on the histological changes in acute barium poisoning can be found in Pilliet, A., and Malbec, A. Note sur les Lesions Histologiques du Rein Produits par les Sels de Baryte sur les Animaux. Comp. Rend. Hebd. Soc. de Biol., vol. 4, p. 957. 1892.

Literature on the pharmacology of barium not otherwise referred to is as follows: Boehm, R. Ueber d. Wirkungen d. Barytsalze auf d. Thierkörper. Arch. f. Exp. Path., vol. 3, p. 217. 1875.--Sommer, F. Beitr. z. Kennt. d. Baryum-Vergiftung. Dissert., Würzburg, 1890.--Neumann, J. Ueber den Verbleib der in den thierischen Organismus eingeführten Bariumsalzen. Archiv. f. Gesam. Physiol., vol. 36, p. 576. 1885.--Hefftner, A. Ausscheidung körperfremder Substanzen im Harn, Ergeb. d. Physiol., pt. 1, p. 121. 1903.--Binet, P. Recherches Compar. sur l'Action Physiol. des Métaux, Alcalins et Alcalino-terreux. Rev. Méd. de la Suisse Romande, vol. 12, pp. 535, 607. 1892.--Cyon, M. Ueber d. toxisch. Wirkung. d. Baryt u. Oxalsäureverbindungen. Archiv. f. Anat., Physiol. u. Wissens. Med., 1866, p. 196.--Mickwitz, L. Vergleich. Untersuch. ü. d. Physiol. Wirkung d. Salze d. Alcalien u. Alcal. Erden. Dissert., Dorpat, 1874.--Heilborn, F. Ueber Veränderungen im Darme nach Vergift. mit Arsen, Chlorbarium und Phosphor. Dissert., Würzburg, 1891.--Reincke, J. J. Ein Fall mehrfacher Vergiftung durch kohlensäuren Baryt. Viertelj. f. gerichtl. Med., n. s., vol. 28, p. 248. 1878.--Orfila, Mémoire sur l'Empoisonnement par les Alcalis Fixes. Journ. de Chimie Méd., 2 s., vol. 8. p. 200. 1842.--Santi, L. Se nel Veneficio per Sali di Bario questo Metallo passa alla Urina? Gazz. Chem. Ital., vol. 33, pt. 2, p. 202. 1903.--Weber, F. R. Barium Chloride. Milwaukee Med. Journ., vol. 12, pp. 39, 60. 1904.--Rabuteau. De l'Innocuité des Sels de Strontium Comparée à l'Activité du Chlorure de Baryum. Gaz. Méd. de Paris, 3 s., vol. 24, p. 218. 1869.--The very early literature is considered in detail by Bary.

[193] Bary, A. Beitr. z. Baryumwirkung. Dissert., Dorpat, 1888, p. 100.

[194] Onsum, J. Ueber d. toxisch. Wirkung. der Baryt und Oxalsäureverbindungen. Arch. f. Path. Anat., vol. 28, p. 234. 1863.

[195] Brodie, B. C. Further Experiments and Observations on the Action of Poisons on the Animal System. Philos. Trans., vol. 102, p. 218. 1812.

[196] Tidy, C. M. On Poisoning by Nitrate of Baryta. Med. Press and Circ., vol. 6, p. 448. 1868.

[197] Glover, R. M. On the Physiological and Medicinal Properties of Bromine and Its Compounds. Edinb. Med. & Surg. Journ., vol. 58, p. 341. 1842.

[198] Kissner, G. Ueber Baryum Vergiftungen u. deren Einfluss auf d. Glykogengehalt der Leber. Scholten, 1896, p. 11.

[199] Mittelstaedt, F. Ueber chronische Bariumvergiftung. Dissert., Greifswald, 1895, p. 19.

[200] Pelletier, D. Observations sur la Strontiane. Annal. de Chimie, vol. 21, p. 119. 1797.

[201] Christison, R. Treatise on Poisons. Edinburgh, 1845, p. 579.--Crampe. Bewährte Mittel gegen Feldmäuse. Deutsch. Landw. Presse, vol. 5, p. 530. 1878.--Felletar, E. Fälle von Intox. mit kohlensäur. Baryum. Pest. Med.-Chir. Presse, vol. 28, p. 1072. 1892.

[202] Husemann, T. Ein Beitrag z. Kennt. d. Barytvergiftungen. Zeits. f. pract. Heilk., vol. 3, p. 235. 1866. In this article Husemann has collected many cases of poisoning by barium in animals.

[203] Christison, R. Treatise on Poisons. Edinburgh, 1845, p. 579.

=BARIUM POISONING IN MAN.=

The high toxicity of barium was called attention to by early observers, but it was attributed by some to admixed arsenic. The reports of feeding experiments with barium on animals have varied markedly, but now care is being advised in the use of barium salts.[204]

Barium was introduced into medicine in the treatment of scrofula, but has fallen into disuse, and only recently attention has been called to it on account of its action on the circulatory system. Filippi,[205] however, says, "The effects on the heart and on the pressure are already the first indication of poisoning." This metal has also been used in the treatment of chronic diseases of the spinal cord, as multiple sclerosis and paralysis agitans.[206]

After the administration to a woman of 1/12 grain (0.005 gram) of barium chlorid three to five times a day for a few days, a total of 2-1/4 grains (0.135 gram), the patient developed rapid respiration, tenderness over the epigastrium, nausea, constipation, cramps in the limbs, loss of appetite, weakness, great emaciation, dysuria, some deafness with tinnitus, difficulty in speaking and thinking, with vertigo.[207] In this case the eyes were glassy, the vision indistinct, and the cheeks flushed. Kohl after the use of small doses of the same noted salivation, swelling of the gums, and falling out of the teeth, with a mercurial odor to the breath. Christison[208] states: "I have known violent vomiting, gripes, and diarrhea produced in like manner by a quantity not exceeding the usual medicinal doses." According to Kennedy few persons are able to bear 1/8 grain (0.0075 gram) of barium chlorid.[209]

In Carpenter's case after three doses of 1.6 grains (0.070 gram) of barium chlorid the patient developed almost lethal symptoms.[210] Carpenter calls attention to the drowsiness which developed in this patient after the administration of barium, a fact which had already been noted by Christison.[211]

A cartarrhal affection of various mucous membranes and a swelling of various glands have been noted, especially of the lymph and salivary glands, and in the male the testes have at times swollen.[212] The inflammation of the glands may pass on to suppuration. The skin becomes dry and shows a tendency to crack. Febrile attacks are reported after the repeated use of small doses of barium.

Scheibler[213] has called attention to the possibility of producing _chronic_ barium poisoning in man from the use of barium in the manufacture of food products.

Acute cases of poisoning in man from four or more grams of barium carbonate or chlorid or nitrate have been reported more or less frequently.[214] In the acute case of poisoning in man reported by Tiraboschi and Taito, no macroscopic changes were noted in the stomach mucosa.[215] Lopes[216] has reported one case of acute poisoning in man from less than 1 gram of barium chlorid. In this case paralysis of the limbs was a marked feature. Stern[217] cites Perondi and Lisfranc to the effect that "remarkably large doses of barium chlorid can be borne without injury by gradually increasing the doses (dissolved in much water)." Lisfranc[218] has suggested that the sensitiveness to poisoning by barium salts is greater in certain climates than in others.

No data are as yet available as to the influence of altitude and partial starvation on the toxicity of barium salts. As is well known, almost all recorded cases of locoed animals have occurred at a high altitude.

It must also be remembered that the addition of one salt to the solution of another may greatly increase the toxicity of the first one. Thus, the addition of a few milligrams of barium chlorid to a solution of a sulphocyanate renders the latter much more poisonous.[219] This may be due to the fact that the salts are more completely ionized.

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FOOTNOTES:

[204] According to v. Jaksch, "Sie ist bei der grossen Toxicität der Substanz immer ernst zu stellen." Vergiftungen, 1897, p. 79.

NOTE.--A thorough pharmacological study of some barium salt is much needed, and it is hoped that the writer will be able to complete this work.

[205] Filippi, E. Modificaz. del Ricambio Organice per Azione del Cloruro di Bario. La Sperimentale, vol. 60, p. 610. 1906; Sull' Azione Cardiaca del Chloruro di Bario. Archivio di Farmacol. Speriment., vol. 5, p. 122. 1906.

[206] Schulz, H. Vorles. ü. Wirkung. u. Anwendung d. unorganisch. Arzneistoffe. Leipzig, 1907, p. 234.--Hare, H. A. Use of Barium Chloride in Heart Disease. Med. News, vol. 54, p. 183. 1889.

[207] Ferguson, J. C. Symptoms of Poisoning from Muriate of Barytes. Dublin Quart. Journ. Med. Sci., vol. 1, p. 271. 1846.

[208] Christison, R., l. c., p. 580.

[209] Kennedy, H. Dose of the Muriate of Barytes. Lancet, vol. 2, p. 28. 1873.

[210] Carpenter, J. S. Barium Choride from a Clinical Standpoint. Med. News, vol. 59, p. 93. 1891.

[211] Christison, R., l. c., 1845, p. 578.

[212] Schulz, H. Vorles. ü. Wirkung. u. Anwendung d. unorganisch. Arzneistoffe. Leipzig, 1907, p. 233.--Schwilgué, C. J. A. Traité de Mat. Méd., 3 ed., vol. 1, p. 441. 1818.

NOTE.--According to the files of the Office of Poisonous-Plant Investigations, E. D. Smith reported in the Orange Judd Farmer, 1897, that locoed animals showed a swelling of various glands. As yet the writer has been unable to verify this reference.

[213] Scheibler, C. Ueber d. Verwendung giftiger Stoffe, besonders d. Barytverbindungen bei d. Zuckerfabrication. Chem. Zeit., vol. 11, p. 1463. 1887.

[214] Schmidt's Jahrbücher, vol. 192, p. 131. 1881.--Walsh, J. Report of a Case of Poisoning by Chloride of Barium. Lancet, vol. 1, p. 211. 1859.--Walch. Seltener Fall einer tödlich. Vergiftung d. Baryta muriatica. Zeits. f. Staatsarznk., vol. 30, p. 1. 1835.--Carpenter, J. S. Barium Chloride from a Clinical Standpoint. Med. News, vol. 59, p. 93. 1891.--Eschricht. Dødeligt forløbende Forgiftning med salpetersurt Baryt. Ugeskrift for Laeger, vol. 4, p. 241. 1881.--Ogler and Socquet. Empoisonnement par le Chlorure de Baryum. Annal. d'Hyg. Publ., 3 s., vol. 25, p. 447. 1891.--Chevallier, A. Note sur un Cas d'Empoisonnement Déterminé par l'Acétate de Baryte. Annal. d'Hyg. Publ., 2 s., vol. 39, p. 395. 1873.--Courtin, Cas d'Empoisonnement par du Chlorure de Baryum. Rev. d'Hyg., vol. 4, p. 653. 1882.--Poisoning by a Baryta Compound. Pharm. Journ., 3 s., vol. 2, p. 1021. 1872.--Reichardt, E. Vergiftungsfall mit kohlensäurem Baryt. Arch. d. Pharm., 3 s., vol. 4, p. 426. 1874.--Lagarde, P. Acétate de Baryte livré sous le Nom de Sulfovinate de Soude. Union Méd., 3 s., vol. 14, p. 537. 1872.--Baum. Zwei Fälle von fahrlässiger Tödtung durch saltpetersäures Baryt. Zeits. f. Medizinalbeamte, vol. 9, p. 759. 1896.--Funaro, A. Sul Veneficio per Sali di Bario. L'Orosi, vol. 12, p. 397. 1894.

[215] Tiraboschi, A., and Taito, F. Avvelenamento da Bario. Il Risveglio Medico d'Abruzzo e Molise, vol. 1, p. 171. 1906.

NOTE.--A criticism of this case is to be found in Bellisari, G., Su Di un Presunto Avvelenamento da Bario. Il Risveglio Medico d'Abbruzzo e Molise, vol. 2, p. 15. 1907.

[216] Lopes, A. Caso Curioso de Envenenamento Pelo Chloret de Bario. Medicina Contempt., Lisbon, vol. 4, p. 109. 1886.

[217] Stern, E. Vergiftung mit Chlorbarium. Zeits. f. Medizinalbeamte, vol. 9, p. 383. 1896.

NOTE.--The writer has always theoretically questioned the danger of poisoning by loco weeds in well-fed and well-watered animals. Compare Stalker, M., The "Loco" Plant and Its Effect on Animals. Bur. Animal Industry, 3d Ann. Report (1886), p. 271. 1887.

[218] Lisfranc. Leçon sur l'Emploi du Muriate de Baryte contre les Tumeurs Blanches. Gaz. Méd. de Paris, 2 s., vol. 4, p. 215. 1836.

[219] Pauli, W., and Fröhlich, A. Pharmakodynam. Studien. Sitz. Kaiserl. Acad. d. Wissens. z. Wien, vol. 115, III, pt. 6, p. 445. 1906.

=PATHOLOGICAL LESIONS IN EXPERIMENTAL BARIUM POISONING.=

The post-mortem examinations in cases of acute experimental barium poisoning, according to Schedel,[220] show punctiform or large hemorrhagic effusion in the fundus ventriculi[221] and in the large and small intestines, contraction of the bladder, and hemorrhage into the walls of the bladder and uterus. The heart is usually found relaxed or the left ventricle contracted in systole, while the right is relaxed. Only once were ecchymoses under the endocardium seen. The liver and kidneys showed nothing special. The urine was free from albumen and sugar. In a few cases the lungs showed some infiltration with blood. In chronic cases, according to our own investigations in rabbits, there are no characteristic macroscopic lesions, a result which agrees with Mittelstaedt's report.[222] Nothnagel and Rossbach[223] claim that in chronic poisoning by barium the peripheral nerves are altered. The same negative results have also been reported in chronic poisoning in higher animals. Reynolds[224] noted a layer like a blood clot under the cerebellum in a horse fed with barium chlorid. Fuchs[225] has called attention to the fact that the flesh of cattle poisoned with barium chlorid was harmless, perhaps owing to a conversion into an insoluble salt, a fact which may be considered in the use of locoed animals for food.

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FOOTNOTES:

[220] Schedel, H. Beitr. z. Kennt. d. Wirkung des Chlorbariums. 1903, p. 13.

[221] After subcutaneous injection of barium chlorid, Lewin, by means of the spectroscope, has found barium in the stomach walls. Lewin, L. Schicksal körperfremder chem. Stoffe im Menschen u. besonders ihre Ausscheidung. Deutsch. Med. Woch., vol. 32, p. 173. 1906.

[222] Mittelstaedt, F. Ueber chronische Bariumvergiftung. Dissert., Greifswald, 1895, p. 29.

[223] Nothnagel, H., and Rossbach, M. J. Handb. d. Arzneimittel, p. 81. 1904.

[224] Reynolds, M. H. A Study of Certain Cathartics. Minn. Agric. Exper. Sta., 15th Ann. Rept. 1907.

[225] Fuchs, C. J. Vergiftungsfälle durch salzsäuren Baryt beim Rindvieh. Thierärztl. Mittheil., vol. 5, p. 159. 1870. Fuchs suggests that further investigations on this point are desirable. The literature of this class of experiments is very scanty. See Fröhner and Knudsen, Einige Versuche über d. Geniessbarkeit d. Fleisches vergift. Thiere. Monats. f. Prakt. Thierheilk., vol. 1, p. 529. 1890.

=TOXICITY OF VARIOUS AQUEOUS EXTRACTS OF LOCO PLANTS.=

On October 21, 1907, a rabbit weighing 1,531 grams was fed with an extract of 95 grams of dried _Aragallus lamberti_ (Hugo, Colo., 1907), with an ash content of 12.44 per cent, with a barium content estimated as 2.6 milligrams of BaSO_{4} in 1 gram of ash. On the following day it weighed 1,517 grams, and the same dose was again administered. On October 23 the weight was 1,488 grams, and the dose was repeated. On the next day the weight was the same and the dose was repeated. On October 26 the weight was 1,446 grams, and again the same extract was given. On October 30 the animal weighed 1,502.5 grams; on October 31, 1,531 grams. The animal received a total extract of 475 grams of the dried plant without serious injury. This result was apparently contradictory to the earlier work.

On October 21, 1907, a rabbit weighing 1,743 grams was fed with an extract of 47.5 grams of the same dried plant. On the next day its weight was 1,729 grams, and the same amount of the extract was fed. On October 23 the weight remained the same, and the dose was repeated. On October 24 the weight was 1,658 grams, and the same amount of extract was fed. On October 26 the animal weighed 1,630 grams, when it was again fed with the same amount of extract. On October 28 the animal weighed 1,573.5 grams, but two days later the weight had risen to 1,644 grams. An extract of 237.5 grams had been administered. Here again the results appeared contradictory.

On October 21, 1907, a rabbit weighing 1,517 grams was fed with an extract of 77.5 grams. On the next day it weighed 1,545 grams, and the dose was repeated. On October 23 the animal weighed 1,531 grams, and the same amount of extract was given. On the following day it weighed 1,488 grams, and the dose was repeated. On October 26 it weighed 1,474 grams, and again the dose was repeated. On October 30 the weight had risen to 1,545 grams, and on October 31 it was 1,559 grams. This animal received in all an extract of 387.5 grams of the dried plant. An aqueous extract of 200 grams of the same in one dose also failed to produce the acute symptoms.

These feeding experiments show little of the characteristic action seen in the earlier experiments made with aqueous extracts either of the dry plant or of the fresh plant preserved with chloroform. In other words, the aqueous extract of the dried plant was only slightly poisonous, yet the plant from which the extract was made contained barium.

Of this same dried loco 200 grams were then extracted with water and digested with pepsin and finally with pancreatin in the thermostat (37.5°C.). The extract was concentrated and fed to a rabbit weighing 1,616 grams. After five hours and ten minutes the animal appeared weak in the fore legs and unable to support himself, and he died during the night. The intestines the following morning were found full of gas, the stomach red, the lungs seemed normal, and the heart was relaxed.

A rabbit weighing 1,545 grams was fed on November 15, 1907, with a preparation made in a similar manner, save that the plant was not extracted with water before digestion. On the next day it weighed 1,517 grams and on November 19, 1,361 grams. The following day the weight was 1,318 grams; on November 21, 1,233 grams, and on the next day 1,162 grams. The animal died during the night, and the autopsy was made the following morning.

The animal was greatly emaciated and the subcutaneous fat had almost all disappeared. The mesenteric vessels were dilated, but the intestines were not dilated. The peritoneal cavity was normal. The kidneys were perhaps a little injected, and measured 3 cm. in length. The lungs were normal. The left ventricle was contracted and the rest of the heart relaxed. The liver was normal and the spleen apparently normal. The stomach walls were dark, owing to decomposition. No ulcers were seen. The suprarenals were perhaps a little enlarged. The examination of the brain was negative, and no clots were found.

A similar digestion from 200 grams of the same dried plant was then ashed and the ash treated with acetic acid and freed from acid by evaporation on the bath. The ash which was insoluble in water was ground up into a fine paste and the whole was fed to a rabbit weighing 992 grams. This animal died in forty minutes, showing the characteristic symptoms seen in acute cases already described. In the autopsy the lungs and other organs seemed perfectly normal macroscopically. The stomach walls, however, were reddened and ecchymotic, and the mesenteric vessels were dilated.

On January 8, 1908, a similar digestion of the same batch was treated with a few drops of sulphuric acid to remove the barium, and the filtrate was then treated with lead carbonate to remove the sulphuric acid. After careful filtering, H_{2}S was passed into the solution and after concentration was fed in one dose on January 9, 1908, to a rabbit. The following morning the rabbit had gained in weight. On January 14 this animal weighed 30 grams more than its initial weight.

The residue of this plant after such a digestion, examined by the Hillebrand method, showed no weighable amount of barium, so that it can be seen that barium in relatively large amount was found in the plant itself, but not after the digestion. It must therefore have been the aqueous digestion which produced the characteristic symptoms. The examination of this fluid for barium might, however, be misleading, as the large amount of proteids would unquestionably interfere with the determination of this amount of barium, unprotected by other salts and silica, so that this side of the investigation was not pursued. Control feedings with an emulsion of one-half gram each of pepsin and pancreatin proved inactive.

Of the same _Aragallus lamberti_ 200 grams were similarly digested and the barium was removed with a few drops of H_{2}SO_{4}, the sulphuric acid by PbCO_{3} and a little lead acetate, and the lead by H_{2}S. Such an extract it was shown in the previous experiment would not kill. However, to this extract was added 100 milligrams of crystallized barium acetate in a solution and a precipitate formed. Nevertheless, the liquid and the precipitate were fed on February 1, 1908, to a rabbit weighing 1,304 grams. On February 3 the animal weighed 1,233 grams; on February 4, 1,176 grams; February 5, 1,120 grams; February 6, 1,006 grams; February 7, 1,219 grams; February 8, 1,219 grams; February 10, 1,304 grams.

As a control for this animal, to make sure that the loss in weight was not due to the acetic acid set free by the treatment with H_{2}S, a similar aqueous extract of the same lot of _Aragallus lamberti_ was precipitated with very much more lead acetate than in the preceding cases and also with lead subacetate and then H_{2}S. After evaporating to dryness this was fed on February 8, 1908, to a rabbit weighing 1,035 grams. On February 11 it weighed 1,021 grams; on February 13, 1,091 grams, and on February 15, 1,120 grams, showing a gain in weight.

Of the dried _Astragalus missouriensis_ (Hugo, Colo., June, 1907) 400 grams with an ash content of 21.8 per cent and which was known to contain barium (3 mg. BaSO_{4} in each 2 grams of the ash) were extracted with water and fed in four doses corresponding to 100 grams each in a period of four days. On November 18, 1907, the first day of feeding, this rabbit weighed 1,856.7 grams. Fifteen days later it weighed 1,984.3 grams.

One hundred grams of this dried plant after extraction with water were found to leave about 51.1 grams[226] of the plant undissolved. This when ashed yielded 8.2 grams of ash. Two grams of this ash yielded 5 milligrams of BaSO_{4}. In other words, the aqueous extract of the plant was inactive and the barium was found practically unextracted in the residue of the plant.

Evidently the barium in these dried plants had been converted into an insoluble form by drying or by some peculiarity of its metabolism, and was not extracted by water, but could be extracted by digesting the plants with the combined digestive ferments, pepsin and pancreatin.