Chapter III: Part 3

_Experiment No. 14._--On March 1, 1906, a black rabbit weighing 2,721.6 grams was fed at 12.15 p.m. with a concentrated aqueous extract of 250 grams of the fresh _Astragalus mollissimus_ collected in September, 1905. On March 2 it weighed 2,438 grams; at 2.58 p.m. it still resisted efforts to turn it on its back; at 3.15 p.m. it could be turned on its back with ease. March 6 the weight was 2,338.8 grams; March 7 the animal was very dull, would not eat, pupils dilated, hind legs paralyzed; died during the night; weight, 2,267.9 grams.

The stomach walls were pale save at the dependent portion near the cardiac end, where there was a hemorrhagic, ulcerated area about 1-1/2 by 1-1/2 inches. The intestines were full of gas, but not hemorrhagic. The uterus contained eight immature foeti. The uterine walls were hemorrhagic. The kidneys weighed 9-1/2 grams; their medullæ were dark and the straight tubules well defined. The cerebral dural vessels were congested and the spinal dural vessels were well defined. The bladder was found contracted. The blood gave no bands for methæmoglobin, but showed merely those of oxyhæmoglobin on spectroscopic examination.

_Experiment No. 15._--Control experiments made by feeding water were negative, except when a large quantity (150 c.c.) of water was given to a rabbit weighing 1,020.5 grams. The animal died in 12 hours with marked pallor of the tissues (hydræmia), a pathological condition quite different from that obtained by feeding extracts of the loco plants, and no such results were secured with the amount of water used in our feeding experiments, 50 to 70 c.c.

=SUBCUTANEOUS INJECTIONS.=

_Experiment No. 16._--On February 28, 1906, a white rabbit weighing 581.2 grams was injected subcutaneously at 10.35 a.m. with a concentrated aqueous extract of 83 grams of fresh _Astragalus mollissimus_ collected in September, 1905, and preserved with chloroform. The temperature before injection was 102.1°F. At 1.40 p.m. the animal was dull; at 3.12 p.m. the temperature registered 99.8°F. The animal died during the night. The post-mortem examination was negative. Stomach pale; heart relaxed save left ventricle, which seemed contracted; dural vessels of the brain dilated; kidneys perhaps normal. No microscopical examination.

_Experiment No. 17._--February 28, 1906, at 10.25 a.m., a guinea pig weighing 496 grams was injected subcutaneously with a concentrated aqueous extract of 83 grams of the fresh _Astragalus mollissimus_ preserved in chloroform water. At 1.40 p.m. there was muscular twitching. The animal was dull and could be easily turned on his back. The hind legs began to show weakness. At 1.50 p.m. the hind legs were almost completely paralyzed and the animal could be easily turned on his back. Muscles of the limbs twitched and semen was expelled. Animal died at 2.15 p.m.

Post-mortem showed dural vessels of cord and brain full of blood. Stomach pinker than normal: mesenteric vessels dilated. Heart almost empty of blood. Kidneys congested.

=SUMMARY OF FEEDING EXPERIMENTS ON RABBITS.=

These experiments indicate that an acute form of poisoning may be induced by feeding concentrated aqueous extracts of _Astragalus mollissimus_ and _Aragallus lamberti_ from Hugo, Colo., and Imperial, Nebr., to rabbits, and that if the extract is given in smaller and repeated doses a more prolonged or chronic condition may follow.

The rabbits showing the chronic effects of these plants exhibit symptoms which have a marked parallelism with those reported as occurring in larger herbivora (horses and cattle) on the range when locoed; that is, the loss of appetite (Experiment No. 9), the emaciation and loss in weight (Experiment No. 9), the dullness and stupor, with more or less anesthesia (Experiment No. 7), the disturbance in the visual function (Experiment No. 9), and the mental symptoms (Experiment No. 6). The occasional abortion compares with what has been observed in larger animals. The dried _Astragalus mollissimus_ and _Aragallus lamberti_ still retained their poisonous properties, as we were able to kill with aqueous extracts of the dried plants made in the laboratory under the proper conditions.

=EXPERIMENTS ON SHEEP.=

_Experiment No. 1._--On May 31, 1906, a sheep weighing 32.2 kilos was fed with a concentrated aqueous extract of 1,000 grams of the fresh _Astragalus mollissimus_ preserved in chloroform water. The temperature at 11 o'clock, the time of feeding, was 103.4°F. At 11.45 a.m. this dose was repeated. At 12 o'clock the temperature was 104.1°F. At 12.45 the animal urinated. At 1.10 p.m. a similar extract of 2,000 grams was fed. The total liquid used was 1,500 c.c. On June 1 no symptoms were noted. On June 5 an extract of 3,000 grams of fresh _Aragallus lamberti_ and 3,000 grams of _Astragalus mollissimus_ was fed. After feeding this the animal could be easily turned over on its back and its ear pricked with impunity. The animal at this time weighed 30.8 kilos. On June 6, at 11 a.m., the temperature was 104°F. The sheep had numerous soft stools, and was very dull, and would not eat. On June 7 the temperature was 103.7°F. and the sheep still refused to eat. On the 8th the temperature was 103.2°F. at 10.40 a.m., and the stools were still numerous and soft.

There were then fed 640 c.c., representing the aqueous extract of 4,000 grams of the fresh _Aragallus lamberti_. The animal could be easily turned on its back. It weighed at this time 28.57 kilos. On June 9, at 10.47 a.m., the temperature was 103.4°F. The sheep still did not eat, but had no diarrhea. It now weighed 27.9 kilos, and the temperature was 103°F. at 10.45 a.m.

On June 13 the animal began to eat, and 1,700 c.c. of fluid, representing 5,500 grams of the fresh _Aragallus lamberti_, were fed. The temperature at 12.30 p.m. was 103°F. On June 14 the temperature was 103.4°F., the animal weighed 28.3 kilos, and refused food. On June 16 the weight was 28.3 kilos; the temperature at 2 p.m. was 103.5°F. There was no diarrhea.

On June 19 the aqueous extract of 1,000 grams of the dried _Astragalus mollissimus_ was fed with 420 c.c. of water. The temperature was 102.6° F. On June 20 the temperature was 102.9°F. at 10.45 a.m.

On June 21 500 c.c., representing the aqueous extract of 1,000 grams of the dried _Astragalus mollissimus_, were again fed. The animal now weighed 26.9 kilos. On June 26 the animal weighed 26 kilos, and its gait was very uncertain. The temperature was 104.2°F. It was fed 300 c.c. of fluid, representing the extract of 400 grams of the dried _Astragalus mollissimus_. On June 29 the animal weighed 26.8 kilos and the temperature was 102.8°F. It was fed the extract of 1,000 grams of dried _Astragalus mollissimus_ in 500 c.c. of water. On June 30, at 10.45 a. m., the temperature was 104.2°F. The animal was very dull and died at night.

At autopsy the intestines and stomach merely appeared pale. There were no worms, and the lungs and other organs appeared normal.

_Experiment No. 2._--A lamb weighing 15.4 kilos was fed on July 6, at 1.10 p.m., with 640 c.c. of fluid, representing the extract of 2,000 grams of _Astragalus mollissimus_. At 1.17 p.m. the animal could be turned on its back, and it regained its feet with difficulty. At 1.24 p. m. it urinated and had a stool. The lamb died during the night.

The autopsy the following morning showed the heart filled with clots; lungs normal save for hypostatic congestion. The cerebral and dural vessels were dilated. About 1-1/2 teaspoonfuls of bloody serum were found at the base of the brain. There was none in the lateral ventricles, and no clots. The kidneys exhibited no marked congestion. There was no fluid found in the peritoneal or the pleural or pericardial cavities. The first stomach, however, contained small hemorrhagic spots, and the second was black. There were small hemorrhages in the intestines.

_Experiment No. 3._--July 13, 1906, a sheep weighing 19.5 kilos was fed with 640 c.c. of fluid, representing the extract of 2,000 grams of _Aragallus lamberti_. The temperature at the time of feeding, 1.10 p. m., was 105.3°F. At 1.49 p.m. the sheep could be easily turned on its back. At 2.23 p.m. the temperature was 103.6°F. At 3.42 p.m. the temperature was 103.5°F. At 4.20 p.m. the respiration was fairly rapid. On July 14, at 11.15 a.m., the temperature was 103.6°F. The sheep would run about but could easily be turned over. It had not eaten, but there was diarrhea present. July 15, at 3.30 p.m., the temperature was 104°F. The animal had eaten. On July 17 the temperature was 104°F. and the animal weighed 18.8 kilos. On the 27th it weighed 17.2 kilos; on August 29, 20.8 kilos.

_Experiment No. 4._--A lamb weighing 19 kilos was fed August 21, 1906, with 740 c.c., representing the aqueous extract of 2,500 grams of the fresh _Astragalus mollissimus_, shipped to Washington in September, 1905. This animal ate at night, but the following day was dull. When seen on August 27 there was diarrhea present and the animal was still dull. On the 28th the animal died, weighing 16.7 kilos. There was no autopsy on account of decomposition.

_Experiment No. 5._--A lamb weighing 15.6 kilos was fed on September 4, 1906, with an aqueous extract representing 3,500 grams of the dried _Aragallus lamberti_, 1,000 c.c. of water being used. The temperature at the time of feeding was 104.3°F. At 2.48 p.m. the animal on rising to its feet developed a slight tremor of the fore legs and showed marked disinclination to stand on its feet. The temperature was 104°F. The animal died at 4.25 p.m. The post-mortem was negative, save for some reddening of the second stomach.[157]

These feeding experiments in sheep can not be considered quantitative, because, as is shown later, aqueous extracts of dried plants are often inactive, yet poisonous principles may be obtained from the plants by treatment with digestive fluids.

Extracts of dried loco plants vary much in their toxicity; with some the writer was unable to kill rabbits, even when an extract of 300 grams of the dried plant was used. It is interesting to note that when the field station was established at Hugo, Colo., in 1905, almost all the aqueous extracts of dried specimens sent to Washington would produce the acute symptoms of poisoning in rabbits, but during the third season of its existence many of the samples sent from the same area were much less active, if not inactive.

* * * * *

FOOTNOTES:

[157] There was a slight odor of chloroform noticed on
opening the stomach, so that perhaps the imperfect removal of
the chloroform due to a hurried evaporation of the extract
should be taken into consideration in this case.

=LABORATORY EXPERIMENTS--CHEMICAL.=

The fact that the aqueous extract of 500 grams of the fresh _Astragalus mollissimus_, or of 200 grams (in some cases 100 grams) of the dried plant, when fed by mouth, would regularly kill a rabbit weighing about 907 grams, with certain definite clinical symptoms and pathological lesions, was at first arbitrarily selected as our test to aid in the isolation of the active principle. Later the production of chronic symptoms by the aqueous extract or digestion of 200 grams of these dried plants given in doses of 100 grams each on two successive days was considered essential. Carnivora, such as dogs and cats, vomit so easily as to render them unsuitable for these investigations. The aqueous extract was distilled with and without steam, also after acidifying with sulphuric acid, and likewise after the addition of magnesium oxid, but in all cases the distillate was inactive.

The concentrated aqueous extract was shaken by the Dragendorff method with petroleum ether, benzol, chloroform, ether, and amyl alcohol, both in alkaline and acid condition, but the shakings yielded no physiologically active body. Shakings by the Otto-Stas method also proved inactive. Lead acetate, lead subacetate, silver nitrate, mercuric chlorid, alcohol, phosphotungstic acid, trichloracetic acid, ammonium hydrate, sodium carbonate, sodium hydrate, Mayer's solution, uranyl acetate, silver oxid, and barium carbonate also failed to remove the active constituent. They gave heavy precipitates in all cases, but these proved inactive. Hydrocyanic acid was sought for with negative results. The pathological lesions in the very acute cases suggested in some respects oxalic acid, a saponin, a metal, or perhaps a toxalbumin as the active principle, but none of the precipitants for saponins, such as lead and copper, or the magnesium oxid method yielded a body which was active. Proteids were excluded by the fact that the various proteid precipitants--alcohol, trichloracetic acid, lead subacetate, mercuric sulphate or chlorid, and salting out with ammonium sulphate and sodium chlorid (complete saturation and half saturation)--failed to give an active precipitate. Glucosidal or alkaloidal bodies were also excluded. On dialysing for twenty-four hours, some of the active principle went into the dialysate and some remained in the dialyser. Ether yielded a precipitate from alcoholic solution which failed to kill. The possibility of the activity of the plants being due to its normal acidity was excluded by neutralizing the extract with sodium hydrate and precipitating the salts with alcohol. The filtrate proved active after removing the alcohol.

The negative results in looking for active alkaloidal, or glucosidal, or proteid bodies suggested that perhaps the action was due to some inorganic constituent. The writer then boiled the extract three minutes and as the filtrate was still found active and the proteid precipitate inactive became convinced of the inorganic nature of the active constituents, and finally incinerated the plant. The acid extract from this was also active, but death was delayed several hours. This was believed to be due to the insoluble form into which the compound was converted.[158] In fact, the question of solubility and the avoidance of an acid reaction, which of itself may kill, are the main points to keep in mind.

These experiments indicated that the injurious action toward rabbits of the _Astragalus mollissimus_ and _Aragallus lamberti_ collected at Hugo, Colo., was due to one or more inorganic constituents,[159] but it does not follow that all loco plants have the same poisonous principle nor that the same species occurring on all soils has the same poisonous action.[160]

Of _Astragalus mollissimus_ from Imperial, Nebr., collected in 1906, 200 grams were ashed in a platinum bowl and extracted with water. This aqueous extract when neutralized produced no marked symptoms in a rabbit and the weight of the animal remained about the same.

The ash undissolved after this extraction was then treated with acetic acid and water overnight, and after carefully evaporating off the acetic acid on the bath (tested by litmus paper) the residue was fed, partly in solution and partly suspended in water, to a rabbit weighing 1,800.2 grams. Next day the rabbit weighed 1,771.8 grams, showed paralysis of the limbs, and died during the morning. The stomach was intensely reddened and contracted.

An extract of a similar ash was made by boiling the same amount with a large quantity of 94 per cent alcohol. This was evaporated in vacuo and taken in water and fed to a rabbit weighing 1,459.9 grams. On the sixth day the animal died, having lost 70.9 grams in weight. The stomach showed reddening but no ulcers.

An acetic acid aqueous extract, made from the ash after the alcoholic extraction, proved inactive, showing that the alcohol had removed the active bodies. A 70 per cent alcohol extract of another ashed lot proved active, killing the rabbit overnight.

Of _Astragalus mollissimus_ from Imperial, Nebr., 200 grams were ashed in a platinum bowl and the ash treated with acetic acid water. After freeing from acid, one half of the solution and emulsion was fed one day and the second half fed the following day. The rabbit at the time of feeding weighed 1,275.7 grams. Fourteen days later the animal died, weighing 1,105.6 grams. No autopsy.

A similar extract of the ash from between 100 and 150 grams of the same dried plant produced death in a rabbit weighing 1,190 grams in two hours and fifty-eight minutes.

The acetic acid extract of the ash of 125 grams of a mixture of the dried _Astragalus mollissimus_ and _Aragallus lamberti_ received from Hugo, Colo., June, 1907, after freeing from acid, was fed to a rabbit weighing 1,304 grams on July 29. On July 30 it weighed 1,332.4 grams. August 1 it weighed 1,219 grams, and it died the same day. The stomach was reddened and showed ulcers.

A similar extract from 250 grams of the same dried plants on boiling gave a heavy precipitate, but this precipitate was inactive, while the filtrate killed a rabbit in four hours.

Of dry _Aragallus lamberti_ collected in September, 1906, 200 grams were extracted with water and fed to a rabbit weighing 1,516.7 grams. Two days later the animal weighed 1,360 grams and died the same day.

The ash from 200 grams of the same dried plant was extracted with acetic acid, and after evaporating off the acid this was fed to a rabbit weighing 2,045.3 grams. Seven days later the animal weighed 1,729.3 grams, having lost 316 grams in weight.

The ash from 250 grams of the same species of plant, after similar treatment with acetic acid, induced death in a rabbit weighing 2,069 grams in 2 hours and 20 minutes. The stomach was inflamed.

* * * * *

FOOTNOTES:

[158] Work is now being done by the writer on the inorganic
constituents of various plants.

[159] Scattered throughout the veterinary literature one
finds cases of poisoning in animals with symptoms similar to
those occurring in locoed animals which are attributed to
eating plants grown on a peculiar soil, as in Oserow, Ueber
Krankh. d. Pferde, welche Aehnlichkeit mit der Cerebro-spinal
meningitis haben, aber durch Vergiftungen mit Gräsern von
Salzgründen (Salzmooren) verursacht werden, Journ. f. Allgem.
Veterinär-Medicin, St. Petersburg, p. 486, 1906. Abstract in
Jahresber. über d. Leistungen auf dem Gebiete d.
Veterinär-Medicin, vol. 26, p. 226, 1906.--Compare also Étude
sur Quelques Plantes Vénéneuses des Regions Calcaires, Bul.
Soc. Cent. de Méd. Vét., vol. 48, p. 378. 1894.

[160] After completing this work the writer found that Sayre
had said that he "had the suggestion that the harm coming
from this plant is due to the inorganic constituents; this
clue has been followed up, but like the others has brought us
no nearer to the solution of the problem." Kans. Acad. Sci.
Trans., vol. 18, p. 144. 1903.

=EFFECT OF THE AQUEOUS EXTRACT OF ASHED LOCO PLANTS.=

The filtrate from the ash from 200 grams of dried _Astragalus mollissimus_, from Imperial, Nebr., after similar treatment with acetic acid water and freed from free acid, killed a rabbit in several hours.

Hydrochloric acid also rendered the toxic agent of the ash soluble in water, but proved unsuitable for our work, as it was found impossible to obtain neutral residues by mere evaporation on the bath. At first one of the heavy metals or members of the H_{2}S group[161] was suspected, but on passing H_{2}S into the slightly acid extract of the ash no active precipitate resulted, but the filtrate remained active.[162] A special Marsh test was, however, made for arsenic and antimony with negative results. A test for tungsten with zinc and hydrochloric acid proved negative.

Members of the ammonium sulphid group were then suspected, but while ammonium hydrate alone gave a heavy white precipitate, this precipitate, as also the black one with ammonium sulphid, proved inactive save when not thoroughly freed from acid (used for solution). The action of this ammonium sulphid precipitate on rabbits was watched for sixteen days, but without result. Nevertheless, the writer still suspected some of the rare earths.[163]

Sestini[164] had found that if certain plants were nourished with a solution of a beryllium salt, in the ash of these plants could be shown the presence of beryllium.

Two grams of beryllium chlorid were fed in aqueous solution to a rabbit weighing 1,800.2 grams. In four days this animal lost 241 grams and died. The stomach showed the same general pallor seen in chronic locoed rabbits, but no ulcers. The tests for beryllium by Sestini's method, however, failed to show beryllium in the active loco plants examined.

Thorium chlorid, cerium chlorid, and lanthanum chlorid in 2-gram doses and zirconium chlorid in 3-gram doses produced no chronic symptoms in rabbits or, in fact, any disturbance. Titanium chlorid, 2.5 grams, evaporated in the air and then fed in an emulsion to a rabbit, also proved inactive, but this inactivity may have been due to its insolubility.

Thallium nitrate c. p., in aqueous solution, in 2-gram doses, killed a rabbit weighing 2,154.6 grams in two hours and fifteen minutes. The stomach in this case, while pink, was not hemorrhagic.

Zirconium chlorid has an astringent taste, and if fed repeatedly will cause the metallic astringent action. On boiling an acetic acid solution of the ash with sodium acetate a precipitate formed.[165]

The presence of zirconium was thus suspected and Dr. E. C. Sullivan, of the United States Geological Survey, estimated it to be present in the ash of a sample of _Aragallus lamberti_ in about 0.01 per cent zirconium oxid, with also 0.1 per cent titanium dioxid.[166]

Zirconium chlorid, 3 grams, was fed in aqueous solution to a rabbit weighing 850.5 grams. This rabbit lost 96 grams in seven days, and was then fed 3 grams more of the same solution and the following day 2 grams more. It died eight days later, weighing 656 grams. The stomach and intestines were contracted, but showed no ulcers. However, 4 grams killed a rabbit in two hours and thirty-two minutes.

The filtrate, after treating an active solution of the ash with hydrogen peroxid, proved active, thus showing that zirconium was not entirely responsible for the poisonous action.

Yttrium, while not found in the plant, was administered as yttrium chlorid to a rabbit weighing 1,530 grams in 2-gram doses in solution. This animal gained 113.4 grams in five days.

Didymium chlorid c. p., in 3-gram doses, was fed to a rabbit weighing 1,020 grams. This rabbit lost 70 grams in four days.

The administration of manganese acetate[167] in 2-gram doses was followed by a gain in weight of a rabbit of 42.5 grams, while a dose of 3 grams killed a rabbit weighing 1,077 grams in two hours and thirty minutes. Wohlwill[168] has emphasized the fact that the members of the iron group owe their comparative harmlessness to not being absorbed by the gastro-intestinal tract.

No zinc was found in the plant.[169]

It is well recognized that potassium salts given hypodermically are decidedly toxic and that ammonium salts given per os will kill, so that the writer considered the possibility of other members of the group being responsible for the injurious action. The fact that the alkaline distillate of the plant proved inactive eliminated the ammonium salts.

Cæsium chlorid c. p., 2 grams, was fed in aqueous solution to a rabbit weighing 1,077.2 grams. In six days this animal lost 255 grams in weight, when it died.[170]

A second rabbit, weighing 1,020.5 grams, was fed with 2 grams of the same solution and lost 368 grams in twenty-one days. The spectroscopic test, however, failed to show cæsium in the ashed plant. Rubidium chlorid c. p., in 2-gram doses, proved inactive. The platinum chlorid precipitate from the extract of the plant proved inactive.

The fact that the filtrate after precipitation of the phosphates by tin and nitric acid and H_{2}S was active excluded the phosphoric acid radical, and the filtrate after treatment with BaCO_{3} and AgO being active excluded the H_{2}SO_{4} and HCl radicals as the toxic body. Fluorine was proved to be absent.

A radio-active substance was suspected, but Dr. L. J. Briggs, Physicist of Bureau of Plant Industry, reported that the dried plant showed no special amount of radio-activity.[171]

Power and Cambier, Sayre, and Kennedy had previously called attention to the abundance of calcium in the plant, and the writer's investigations confirm this. Pharmacologists are averse to believing calcium given per os poisonous. The writer has, however, fed 5 grams of the acetate of calcium in solution to a rabbit weighing 652 grams. This animal died in two hours, with marked irritation of the stomach, the result being due to the so-called "salt action." Much larger amounts were fed in divided doses, but without injury. Calcium phosphate and calcium sulphate in 2-gram doses proved harmless to a rabbit weighing about 1,400 grams. Three grams of magnesium acetate[172] were fed in solution for five successive days to a rabbit weighing 1,417 grams, but without apparent effect.

Strontium acetate c. p., in 2-gram doses, likewise caused no disturbance.[173] No strontium in any amount recognizable by chemical tests was proved in the plant. So that by a process of exclusion the writer was forced to think of barium as the main cause of the trouble.

The writer noted that if the ashed plant was extracted with H_{2}SO_{4} water and this extract freed from sulphuric acid with PbCO_{3} and H_{2}S the solution proved inactive to rabbits and also that after this extraction the acetic acid extract of the ash failed to kill. In other words, the sulphate of our body was insoluble in water. At times in passing H_{2}S into active solutions of the ashed plant freed from the acetic acid by evaporation the filtrate and likewise the precipitate were inactive. Noyes and Bray[174] have noted that if H_{2}S is passed into certain solutions in the presence of an oxydizing agent, such as ferric iron, H_{2}SO_{4} would be formed, which would throw any barium out of solution.

In one blood-pressure record made with a dog (vagi nerves cut), a rise in blood pressure (a characteristic physiological action of barium) was seen to follow the intravenous injection of the aqueous extract of the plant, in spite of its normal acid reaction.

Accidentally the writer found that Sprengel[175] had reported the presence of barium in _Astragalus exscapus_, a closely allied plant. Barium has also been found in the vegetable world by Scheele in 1788, and later by Eckard,[176] who found it in beech, while Forchhammer[177] proved it in birch, and Lutterkorth found it in the soil of the same area in which Eckard worked. Dworzak[178] noted the occurrence of traces of this element in wheat grown along the Nile, and Knop[179] found it in the soil. Doctor Balfour, of Khartum, Egypt, informed the writer that he knew of no cases in which this barium in wheat had produced poisoning. Hornberger[180] found barium both in the red beech grown in Germany and in the soil on which these trees grew. It has also been claimed that various marine plants may take up barium from the sea.[181]

Hillebrand[182] has called attention to the fact that the igneous rocks of the Rocky Mountains showed a higher percentage of barium than rock from other portions of the United States, so that under these conditions one might expect the presence of barium in plants growing in this region. A sample of _Aragallus lamberti_ and one of _Astragalus mollissimus_ were sent to the Bureau of Chemistry for spectroscopic examination for various elements and they reported traces of barium in each.[183]

With these arguments the writer felt sure of the presence of barium, and the matter was discussed with Dr. E. C. Sullivan, of the United States Geological Survey, and he kindly corroborated the conclusions reached as to the presence of barium, controlling its presence by means of the spectroscope, and estimated it roughly as 0.1 per cent BaO in the ash of a sample of _Aragallus lamberti_ (6.3 milligrams BaSO_{4} in 4 grams ash). This determination was made by Hillebrand's method.

Kobert has anticipated this result, saying that "all plants are in the position occasionally to take up barium combinations from the soil," and "the plants which thus contain barium may act injuriously to men and animals."[184]

* * * * *

FOOTNOTES:

[161] Swain, R. E., and Harkins, W. D. Arsenic in Vegetation
Exposed to Smelter Smoke. Journ. Amer. Chem. Soc., vol. 30,
p. 915. 1908.--Harkins, W. D., and Swain, R. E. The Chronic
Arsenical Poisoning of Herbivorous Animals. Journ. Amer.
Chem. Soc., vol. 30, p. 928, 1908.

[162] A similar extract was sent to the Bureau of Chemistry,
and that Bureau also reported an absence of the elements of
the H_{2}S group.

[163] Bachem, C. Pharmakologisches über einige Edelerden.
Arch. Internat. de Pharmacodyn., vol. 17, p. 363. 1907.

[164] Sestini, F. Esper. di Vegetaz. del Frumento con
Sostituz. della Glucina alla Magnesia. Staz. Sper. Agrar.
Ital., vol. 20, p. 256. 1891.--Di alcuni Elementi Chimici
Rari a Trovarsi nei Vegetabili. Staz. Sper. Agrar. Ital.,
vol. 15, p. 290. 1888.

NOTE.--The ammonium sulphid precipitate was very small if the
phosphates were first removed with tin and nitric acid.

[165] Böhm, C. R. Darstellung d. seltenen Erden, vol. 1, p.
40. 1905.

[166] Wait, C. E. Occurrence of Titanium. Journ. Amer. Chem.
Soc., vol. 18, p. 402. 1896.

NOTE.--There seem to be no records of any study of the
pharmacological action of titanium.

[167] Compare Jaksch, R. v. Ueber Mangantoxikosen und
Manganophobie. Münch. Med. Woch., p. 969. 1907.

[168] Wohlwill, F. Ueber d. Wirkung d. Metalle d.
Nickelgruppe. Arch. f. Exper. Path., vol. 56, p. 409. 1907.

[169] Laband, L. Zur Verbreitung des Zinkes im
Pflanzenreiche. Zeits. f. Untersuch. d. Nahrungs u.
Genussmittel, vol. 4, p. 489. 1901.

[170] Cæsium occurs in various plants and the possibility of
poisoning by this element must be considered. It is hoped
that the writer may be able to undertake a more thorough
pharmacological study of this element.

[171] Acqua, C. Sull'accumulo di Sostanze Radioattive nei
Vegetali. Atti della Reale Accad. dei Lincei, 5 s, vol. 16,
sem. 2, p. 357. 1907.

[172] Compare Meltzer, S. J. Toxicity of Magnesium Nitrate
When Given by Mouth. Science, vol. 26, p. 473. 1907.

[173] Burgassi, G. Modificaz. del Ricambio per Azione dello
Stronzio. Archiv. di Farmacol., vol. 6, p. 551. 1907.

[174] Noyes, A. A., and Bray, W. C. System of Qualitative
Analysis for the Common Elements. Journ. Amer. Chem. Soc.,
vol. 29, pp. 168, 172, and 191. 1907.

NOTE.--Barium sulphate is nontoxic on account of its
insolubility. Orfila fed 16-24 grams to dogs without causing
any disturbance. Bary, A. Beitr. z. Baryumwirkung. Dorpat,
1888, p. 25.

[175] Sprengel, C. Von den Substanzen der Ackerbrume und des
Untergrundes, Journ. f. Techn. u. OEkon. Chem., vol. 3, p.
313. 1828.

[176] Eckard, G. E. Baryt, ein Bestandtheil der Asche des
Buchenholzes. Annal. der Chem. u. Pharm., n. s., vol. 23, p.
294. 1856.

[177] Forchhammer, J. G. Ueber den Einfluss des Kochsalzes
auf die Bildung der Mineralien. Annal. d. Physik u. Chemie,
vol. 5, p. 91. 1905.--Lutterkorth, H. Kohlensäurer Baryt, ein
Bestandtheil des Sandsteines in der Gegend von Göttingen.
Annal. d. Chem. u. Pharm., n. s., vol. 23, p. 296. 1856.

[178] Dworzak, H. Baryt unter den Aschenbestandtheilen des.
Ægyptischen Weizen. Landw. Versuchs.-Stat., vol. 17, p. 398.
1874.

[179] Knop, W. Analysen von Nilabsatz. Landw.
Versuchs.-Stat., vol. 17, p. 65. 1874.--Compare also
Demoussy, E., Absorption par les Plantes de Quelques Sels
Solubles, Thése, Paris, 1899.--Knop, W., Einige neue
Resultate der Untersuchung über die Ernährung der Pflanze,
Ber. ü. Verhandl. d. königl. sächs. Gesells. d. Wissens. zu
Leipzig, Math. Phys. Cl., vol. 29, p. 113, 1877.--Suzuki, U.,
Can Strontium and Barium Replace Calcium in Phænogams? Bul.
Coll. Agric. Tokio Imp. Univ., vol. 4, p. 69, 1900-1902.

[180] Hornberger, R. Ueber d. Vorkommen d. Baryums in d.
Pflanze und im Boden. Landw. Versuchs.-Stat., vol. 51, p.
473. 1899.

[181] Roscoe, H. E., and Schorlemmer, C. Treatise on
Chemistry, vol. 2, p. 455. 1897.

[182] Hillebrand, W. F. Analysis of Silicate and Carbonate
Rocks. Dept. Interior, U. S. Geol. Survey, Bul. 305, p. 18.
1907.

[183] This report came from the Plant Analysis Laboratory of
the Bureau of Chemistry, a different one from that which
later controlled the writer's tests quantitatively and
qualitatively. In other words, the conclusions of the writer
as to the presence of barium were controlled by three
separate individuals.

[184] Kobert, R. Kann ein in einem Pflanzenpulver gefundener
abnorm höher Barytgehalt erklärt werden durch direkte
Aufnahme von Baryumsalze durch die lebende Pflanze aus dem
Boden? Chem. Zeit., vol. 10, p. 491. 1899.

NOTE.--The writer has also found barium in entirely different
botanical families from the loco-weed, and it is hoped a
report can shortly be made of some of these.

NOTE.--The first sample of ash analyzed by the Bureau of
Chemistry had 0.21 per cent Fe_{2}O_{3}, 0.92 per cent
Al_{2}O_{3}, 0.98 per cent CaO, 0.37 per cent MgO, 5.50 per
cent SiO_{2}. The second lot was only examined for certain
constituents, and gave K_{2}O, 2.25 per cent; CaO, 1.20 per
cent; MgO, 0.41 per cent; P_{2}O_{5}, 0.52 per cent; and
SO_{3}, 0.24 per cent.

=TOTAL ASH DETERMINATIONS OF LOCO PLANTS.=

The reports of the ash analyses of the loco plants show marked variations in the total amount of the ash. Thus, from _Aragallus lamberti_ Dyrenforth obtained 4.32 per cent and O'Brine 13.52 per cent of ash. The Bureau of Chemistry analyzed two different samples of this dried plant and reported in one case 11.15 per cent and in the second 11.64 per cent of ash. O'Brine[185] obtained 13.52 per cent of ash from the same species. The writer's analysis[186] gave in one sample of _Aragallus lamberti_, collected at Hugo, Colo., in 1907, 18.8 per cent of ash; a second lot (1907), 12.44 per cent; a third (1906), 11 per cent, and a fourth (May, 1905) gave 37.3 per cent of ash.[187] One lot from Woodland Park, Colo. (October, 1906), gave 6.4 per cent. One lot from Hugo, Colo. (October, 1907), yielded 9.6 per cent.

In the case of _Astragalus mollissimus_, Wentz obtained 6.76 per cent, Sayre 12.01 per cent, Kennedy 20 per cent, O'Brine 12.15 per cent, while the sample analyzed by the Bureau of Chemistry gave 18.4 per cent of ash. One sample from Kit Carson County, Colo. (December, 1906), which proved inactive physiologically, gave an ash content of 6.9 per cent. A sample of _Astragalus missouriensis_ collected at Hugo, Colo., June, 1907, yielded an ash content of 21.8 per cent, and an _Astragalus missouriensis_ collected at Pierre, S. Dak., September, 1907, yielded 27 per cent. An _Astragalus nitidus_ from Custer, S. Dak. (July, 1907), gave 5.2 per cent ash, while an _Astragalus nitidus_ collected at Woodland Park, Colo., in October, 1906, yielded 7.8 per cent, and another specimen of _Astragalus nitidus_ also collected at Woodland Park, Colo., in October, 1907, gave 12.2 per cent. An _Astragalus drummondii_ from Custer, S. Dak. (July, 1907), gave 5.9 per cent. _Astragalus pectinatus_ (Hugo, June, 1907) yielded 6.1 per cent. A fresh (undried) specimen of _Astragalus mollissimus_ (unknown origin, November, 1907) yielded 3.8 per cent of ash. One sample of _Astragalus decumbens_ (Ephraim, Utah, August, 1907) gave 21.8 per cent of ash.

These determinations must necessarily be only approximate, as the plants were collected by different persons who exercised different degrees of care in freeing them from adherent soil, and possibly in drying the plants, so that the main value of these figures is their aid in determining the amount of barium present.

* * * * *

FOOTNOTES:

[185] The detailed analysis of O'Brine can be found on page
32 of this report.

[186] All ash and barium determinations were made from the
dried plants save when otherwise specified.

[187] Evidently these plants must have been imperfectly freed
from soil.

=BARIUM DETERMINATIONS IN THE ASH OF LOCO PLANTS.=

Attention has been called to the fact that in ashing plants containing barium a part at least of this barium is converted into the insoluble sulphate and a part into the carbonate, so that the characteristic pharmacological action of the ash will depend not upon the total barium present, but upon the form in which it occurs--little action if much BaSO_{4}, and more complete if more BaCO_{3} results. A further difficulty in the recognition of barium in plants is due to the fact that certain inorganic salts interfere with the precipitation by H_{2}SO_{4}.

A specimen of _Aragallus lamberti_ (Hugo, summer of 1907) with 12.44 per cent of ash was examined for its barium content by Hillebrand's method.[188] The method was as follows:

Two grams of the ash were first fused with sodium carbonate and the fused mass washed with water containing sodium carbonate. The residue was washed into a beaker and treated with a few drops of sulphuric acid. The residue now remaining was filtered and after ignition was treated with hydrofluoric and sulphuric acids. After evaporating off these acids, the residue was treated with sulphuric acid water, filtered, and then fused with sodium carbonate. After extracting with sodium carbonate water, the residue was dissolved in just enough hydrochloric acid and precipitated with sulphuric acid. The precipitate was dissolved in concentrated sulphuric acid and reprecipitated by water and weighed as BaSO_{4}.[189] So far as the writer can ascertain, there have been no control experiments made for this method to determine the experimental error.

Of the above ash, 1.998 grams gave 5.2 milligrams of BaSO_{4}, which would correspond to 75.75 milligrams of barium acetate crystals-- Ba(C_{2}H_{3}O_{2})_{2}+H_{2}O--in 200 grams of the dried plant. The residue by the Hillebrand method after weighing was tested with the spectroscope and gave a bright spectrum for barium. The same ash was analyzed by the Bureau of Chemistry, using a shorter method, and they reported 2.7 milligrams of barium sulphate in 1.1217 grams of ash. A second sample collected earlier in the summer, with an ash content of 18.6 per cent, was shown to yield barium corresponding to 3.4 milligrams of BaSO_{4} in 2.5 grams of the ash.[190]

One lot of _Aragallus lamberti_ collected at Hugo, Colo., in May, 1905, and which gave an ash content of 37.3 per cent, was found to yield 3 milligrams of BaSO_{4} from 1.998 grams of ash, or 173.88 milligrams of Ba(C_{2}H_{3}O_{2})_{2}+H_{2}O in 200 grams of the dried plant, but this ash also contained 0.27 per cent of SO_{3}. The Bureau of Chemistry reported the barium to correspond to 2.9 milligrams of BaSO_{4} in 2.45 grams of the ash.

The _Astragalus missouriensis_ (Hugo, June, 1907), with an ash content of 21.8 per cent, gave 3 milligrams of BaSO_{4} in 2.01 grams of ash, or 76.58 milligrams of Ba(C_{2}H_{3}O_{2})_{2}+H_{2}O in 200 grams of the dried plant. The residue after weighing was tested spectroscopically and gave a bright barium spectrum.

The _Astragalus drummondii_ from Custer, S. Dak. (1906), _Astragalus mollissimus_ from Kit Carson County, Colo. (December, 1906), and _Astragalus nitidus_ from Woodland Park, Colo. (October, 1907), were reported by the Bureau of Chemistry to contain no barium.

The ash of the _Astragalus pectinatus_ (Hugo, June, 1907) was reported by the Bureau of Chemistry to show no barium on spectroscopic examination.

Two grams of active loco plant ash yielded from 5 to 6 milligrams of BaSO_{4}, but it can be easily seen that in multiplying this amount to correspond to 200 grams of the dried plant errors would be likely to arise, so that the whole amount of barium would not necessarily be accounted for.

* * * * *

FOOTNOTES:

[188] Hillebrand, W. F. Analysis of Silicate and Carbonate
Rocks. U. S. Geol. Surv. Bul. 305, p. 116. 1907. See also
Folin, O., On the Reduction of Barium Sulphate in Ordinary
Gravimetric Determinations, in Journ. Biol. Chem., vol. 3, p.
81. 1907.

[189] All the determinations of barium which resulted either
positively or negatively were made with the same bottle of
sodium carbonate and H_{2}SO_{4}, so that impurities in the
chemicals were thus eliminated.

[190] Report from Bureau of Chemistry.

=ANALYSIS OF SOILS.=

One sample of the soil from near Hugo, Colo., from which the _Aragallus lamberti_ was collected, was examined by the Bureau of Soils, and that Bureau reported the absence of barium and zirconium, at least of any recognizable by the chemical methods used, so that it can not be said that the barium came from any soil accidentally mixed with the ash. Traces of titanium were, however, found. Evidently the plant must collect minimal quantities of these elements from the soil and store them.

The water from a well of an adjacent area was examined by the Bureau of Chemistry and reported to contain 37.4 parts of calcium and 13.7 parts of magnesium in one million, and that the water contained no barium.[191]

* * * * *

FOOTNOTES:

[191] Barium has been found in well water in England. See
Thorpe, T. E., Contribution to the History of the Old Sulphur
Well, Harrogate, in Philos. Mag., 5 s., vol. 2, p. 50, 1876.

=FEEDING EXPERIMENTS WITH BARIUM SALTS ON ANIMALS IN THE LABORATORY.=

On these figures the writer took 0.2 gram of crystallized barium acetate c. p., using the acetate because acetic acid has been proved in certain loco plants by Power and Cambier, and after dissolving it in water fed it at 9.45 a.m. to a rabbit weighing 1,177 grams. The head soon fell forward so that the nose rested on the ground. At 10.58 a.m. the rabbit seemed unable to guide itself and would run into obstructions if forced to move. There was no diarrhea but it urinated several times. There was a peculiar tremor of the muscles noted. The animal would not startle by sudden noises and at 11.06 a.m. could be placed on its back with ease. The pupils appeared about normal. The whites of the eyes showed very prominently. At 11.35 a.m. the fore legs were paralyzed. The following morning the animal was dead, its weight being 1,120 grams. The heart was dilated; the stomach was not hemorrhagic, but rather pale.

A second rabbit, which weighed 1,630 grams, was fed with a solution of 0.5 gram of the same salt at 9.42 a.m. At 10.35 a.m. the animal passed soft stools and showed a marked disinclination to move, with evidence of pain. The diarrhea[192] became more marked and the animal's hind quarters were soiled with feces. At 10.48 a.m. there was marked incoordination of the limbs and inability to stand. Finally, at 10.56 a. m., convulsions began and the animal died at 11.02 a.m. The autopsy was made about two hours later. The animal was then rigid. The kidneys seemed rather congested. The intestines were relaxed; mesenteric vessels dilated. The pyloric region of the stomach appeared hemorrhagic.

A third rabbit, fed like the preceding with 0.5 gram of barium acetate, showed much the same result. In this case there was some retching, but the other symptoms were as above, the animal dying in one hour and five minutes. No hemorrhages were seen in the stomach walls. It was noted that after the administration of certain doses, 0.2 gram, there was no diarrhea.

On September 23, 1907, a rabbit weighing 1,757 grams was fed at 10.42 a. m. with 0.1 gram of the same barium acetate. The temperature at the time of feeding was 102.9°F. At 12.05 a.m. the animal urinated. Temperature, 101.4°F. On September 24 the animal weighed the same. Temperature at 10.55 a.m., 102.3°F. The same amount of barium was fed. At 3.40 p.m. the temperature was 102.5°F. On September 25 the animal weighed 1,800 grams. Temperature, 102.2°F. at 10.39 a.m. The dose of barium was repeated. At 3.55 p.m. the temperature was 101.4°F. On September 26 at 9.38 a.m. the temperature was 101.1°F., and again the barium was given. At 3.57 p.m. the temperature was 101.5°F. On September 27 the rabbit weighed 1,772 grams. The temperature at 9.53 a. m. was 102.3°F. The barium was fed for the fifth time. At 10.27 a.m. there were general convulsions. The eyes teared. At 10.32 a.m. soft stools appeared and the animal urinated. Stools were passed at various periods. At 11.30 a.m. there were no signs of pain on pinching the ear. At 11.58 a.m. the animal retched. The animal was lying with the fore legs wide apart and could not support itself. At 12.05 p.m. the temperature was 98°F. and the rabbit died shortly after.

The peritoneal cavity seemed normal. The small intestines were relaxed, while the mesenteric vessels were dilated. The kidneys seemed congested. The stomach walls were pink and in places covered with mucus. The heart was relaxed save the left ventricle, which seemed firm.

On September 23, 1907, a second rabbit, weighing 1,360 grams, was fed with a similar solution and the feeding was repeated at the same time the first rabbit was fed. On September 27 the animal weighed 1,416 grams. On this day a peculiar movement of the hind legs on jumping appeared, apparently due to an inability to draw the legs completely up, and the fore legs were spread wide apart, as if too weak to support the animal. The temperature had also fallen. On September 28 the animal had apparently recovered. Weight, 1,516 grams on October 21.

On September 23, 1907, a third rabbit, weighing 1,304 grams, was fed with 50 milligrams of barium acetate. This dose was repeated each time the other two rabbits were fed. On September 27 it weighed 1,304 grams. Marked muscular twitching appeared, with disinclination to move. Finally there were convulsions and paralysis of the limbs. No stools were seen. This animal lay quiet all night, apparently unable to move, and continued on its side until 3.15 p.m. on September 28, when it gradually recovered, weighing 1,346 grams on October 24.

On October 24, 1907, a rabbit weighing 1,346.5 grams was fed with a solution of 25 milligrams of crystallized barium acetate. On the next day the weight was 1,318 grams, and the dose was repeated. On October 26 it weighed 1,275.7 grams, and the dose was repeated; on October 30 it weighed 1,332 grams, and on October 31 its weight was 1,375 grams. The animal died at night on November 6; weight, 1,134 grams. The post-mortem examination, made with Dr. Meade Bolton, of the Bureau of Animal Industry, was negative save for the presence of necrotic tissue in one enlarged thyroid.

On October 24, 1907, a rabbit weighing 1,332 grams was fed with a solution of 25 milligrams of crystallized barium acetate. On the next day the animal weighed the same, and the dose was repeated. On October 26 it weighed 1,289 grams, and the same amount of barium was given. On October 28 the weight was 1,219 grams and two days later 1,289 grams.

On October 31, 1907, a rabbit weighing 723 grams was fed with a solution of 25 milligrams of barium acetate. This rabbit was fed in all nine times during a period of ten days. At the end of this time it weighed 779 grams and died six days later, weighing 723 grams. The post-mortem was negative.

A rabbit weighing 779 grams was also fed on October 31, 1907, with a similar amount of barium. This dose was repeated six times during an interval of eight days. At the end of that time the animal still retained its normal weight. On November 14, 1907, it weighed 709 grams, having lost 70 grams. Thus after daily doses of 0.1 gram of crystallized barium acetate no symptoms appeared until the fifth day, when death resulted. After the similar administration of 50 milligrams severe symptoms developed on the same day, but the animal recovered. After the administration of 25 milligrams on three successive days the animal died. In other cases of feeding 25 milligrams for several successive days, some lost weight and died; others merely lost in weight, but recovered.

Bary fed a rabbit weighing 0.9 kilogram a solution of 30 milligrams of barium chlorid on one day, on the second day 90 milligrams, and on the third day 30 milligrams. The only symptom noted was diarrhea. The animal died on the fifth day. In other words, after feeding small doses of barium salts for several days acute symptoms suddenly set in, showing a cumulative action. This cumulative action has been noted on man.[193]

Onsum[194] fed a medium-sized rabbit daily with small doses of barium carbonate, beginning with 20 milligrams. When the total amount reached 0.19 grams the rabbit died. The animal before death showed paralysis, respiratory disturbances, and fall in temperature. The sensibility of the cornea diminished, but the pupils responded to light. The stomach walls showed ecchymoses and the blood vessels of the brain, the spinal cord, and the abdominal vessels were dilated. Emboli in the pulmonary arteries were also noted.

In a rabbit the application of 0.66 gram of barium chlorid to a wound was followed in twenty minutes by convulsions, paralysis, and finally coma and death.[195]

Of barium nitrate 0.66 gram mixed with sugar and fed to a rabbit caused death in less than one hour, and 0.33 gram induced death in another rabbit in twenty-seven hours.[196]

Six grains (0.4 gram) of barium iodid fed in solution to a rabbit caused death the following day. On this day there were tremors of the neck and shoulders with convulsive movements of the limbs. There was also grinding of the teeth. "The mucous membrane of the stomach was rose-red at the cardia, and softened." Membranes of the cord and brain also were congested.[197]

For rabbits weighing 1,500 to 2,000 grams the lethal dose of barium chlorid on subcutaneous use is stated to be 0.05 to 0.06 grams.[198]

A rabbit weighing 1,106 grams was fed with a solution containing 50 milligrams of crystallized barium acetate c. p. and 50 milligrams of zirconium chlorid (pure). In fifty-seven minutes the animal showed difficulty in moving the fore legs, developing marked paralysis of the same about five hours later, and died the following morning--that is, twenty-two hours after feeding. The heart was found dilated, kidneys congested, stomach walls pink and covered in places with mucus and partly digested blood, and cerebral dural vessels dilated, but no clots were seen; bladder full.

Mixtures of 0.5 gram of calcium acetate and 50 milligrams of barium acetate failed to kill. Mixtures of titanium and barium were not tried, as no titanium salt soluble in water and of neutral reaction was accessible.

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]

* * * * *

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.