Introductory material (continued 2)
Reading edition
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 H2S was active excluded the phosphoric acid radical, and the filtrate after treatment with BaCO3 and AgO being active excluded the H2SO4 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 H2SO4 water and this extract freed from sulphuric acid with PbCO3 and H2S 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 H2S 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 H2S is passed into certain solutions in the presence of an oxydizing agent, such as ferric iron, H2SO4 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 BaSO4 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:
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.
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 BaSO4, and more complete if more BaCO3 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 H2SO4.
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 BaSO4.[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 BaSO4, which would correspond to 75.75 milligrams of barium acetate crystals—Ba(C2H3O2)2+H2O—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 BaSO4 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 BaSO4 from 1.998 grams of ash, or 173.88 milligrams of Ba(C2H3O2)2+H2O in 200 grams of the dried plant, but this ash also contained 0.27 per cent of SO3. The Bureau of Chemistry reported the barium to correspond to 2.9 milligrams of BaSO4 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 BaSO4 in 2.01 grams of ash, or 76.58 milligrams of Ba(C2H3O2)2+H2O 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 BaSO4, 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:
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:
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:
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.
FOOTNOTES:
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.
FOOTNOTES:
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 BaSO4 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, H2S 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 H2SO4, the sulphuric acid by PbCO3 and a little lead acetate, and the lead by H2S. 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 H2S, 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 H2S. 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. BaSO4 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 BaSO4. 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.
Of the same dried Astragalus missouriensis 200 grams were extracted with water and the extract treated with lead carbonate to remove any possible free sulphates and after filtering this was treated with H2S to remove the lead. As the preceding experiment showed that the aqueous extract of this dried plant was harmless without barium, the writer decided to add barium artificially, and 100 milligrams of barium phosphate,[227] crystallized, was added to the liquid and the whole fed to a rabbit weighing 2,423.9 grams. The following morning the rabbit was found dead. The autopsy was made by Dr. H. J. Washburn, of the Bureau of Animal Industry. He found that the suprarenals were enlarged and congested, and there were small areas of hepatization at the apex of each lung. There were also acute corrosion areas on the greater curvature of the stomach and over the upper portion of the duodenum.
Of the Astragalus missouriensis used in the preceding experiments, 200 grams were extracted thoroughly with water, and the extract corresponding to 100 grams, together with 80 milligrams of barium phosphate pure, was fed on March 12, 1908, to a rabbit weighing 1,261.5 grams. During this day the animal walked at times with an uncertain gait and the following morning it weighed 1,233 grams. It was then fed the rest of the solution, that is, the extract of the remaining 100 grams of the plant, but without any barium. The animal soon developed convulsions and died in a little over twenty-four hours after the original feeding. The autopsy, which was made by Dr. J. R. Mohler, of the Bureau of Animal Industry, showed that the mucous membrane of the stomach was markedly hemorrhagic and in areas gelatinous infiltration was very marked. In one portion of this hemorrhagic area there was distinct erosion. The large intestines were full of gas, the lungs were normal, the heart was relaxed, and the lungs collapsed. The blood vessels of the kidneys were markedly engorged.
Of the dried Astragalus nitidus (Woodland Park, Colo., October, 1907) which was reported by the Bureau of Chemistry as containing no barium, 200 grams were extracted with water and fed in 100-gram doses for two successive days. The animal increased steadily in weight and fifteen days after the first feeding had gained 99.2 grams. This amount of the plant was also extracted with water and the residue was then digested with pepsin and pancreatin in the thermostat, as in the previous case, and fed in two doses corresponding to 100 grams each. This animal increased in weight, gaining 60 grams in six days and 165 grams in addition after a further fifteen days.
An Astragalus mollissimus (Kit Carson County, Colo., December, 1906), which was also reported by the Bureau of Chemistry as containing no barium, was extracted with water, and a dose corresponding to an extract of 200 grams of the dried plant was fed in one dose without any serious result. The same amount of the dried plant was also similarly digested with pepsin and pancreatin and fed in two doses, but without the production of any symptoms, the rabbit gaining 60 grams in four days.
Of the Aragallus lamberti (Hugo, Colo., June, 1907), with an ash content of 12.44 per cent, 250 grams were ashed and the ash treated with acetic acid and, after evaporating off the acetic acid, was extracted with water and the ash digested with pepsin and pancreatin. The aqueous extract and the digestion products of the ash were then fed after concentration, but without any serious effects to the animal, indicating that in this plant the barium is in a form insoluble in water and in the ashing is further changed so that it can not now be made soluble by digestion—an opposite result to the experiment in which the barium was first rendered soluble by digestion and the digestion products ashed, suggesting a possibility that plants might be found in which the barium is not extracted by digestion, at present a hypothesis.
Of dried Astragalus decumbens (Ephraim, Utah, 1907), which was reported by the Bureau of Chemistry to contain no barium, 200 grams also failed to produce symptoms in rabbits by our test.
A solution containing 50 milligrams of barium acetate (crystallized) was mixed with an aqueous extract of 200 grams of the dried Aragallus lamberti which had proved inactive pharmacologically, but a precipitate formed (BaSO4?) and the extract still remained inactive, suggesting that the question of toxicity depended not only upon the presence of barium, but also whether other agents, such as sulphates, etc., might not be present in sufficient amount to render the barium insoluble; that is, pharmacologically inactive.
This Aragallus lamberti yielded an ash content of 37.3 per cent, and the SO3 group was estimated at 0.27 per cent of the ash, while a corresponding lot which was obtained two years later from the same area yielded an ash content of 12.44 per cent and a SO3 content of 0.24 per cent of the ash.
It may be urged that the full lethal dose of the barium was not always found in the plant, yet it must be remembered that the toxic action was the resultant of the action of the total constituents and that if the barium was removed the extract was practically harmless.
In looking back over the work the most suitable preparation for producing the characteristic symptoms in rabbits seems to be the freshly ground-up plant mixed with water and preserved in chloroform, for while the dried plant might contain barium, yet the aqueous extract was often inactive, suggesting, perhaps, the presence of something in the fresh plant which aided the solution of the barium, thus accounting for the variations in toxicity of aqueous extracts made from plants dried under varying conditions. The nature of the compound in which barium exists in the plant is as yet unknown and has not been investigated. It is important to remember that not only must barium be found in the plant to prove poisonous, but it must be in such a form that it can be extracted in the gastro-intestinal canal.
The amount of barium found in various species of loco plants will no doubt vary, and perhaps the pharmacological test on rabbits as the writer has used it may have to be modified for such plants, so that at present the wisest plan to test these plants is to determine their barium content and also make the physiological test, as has been proposed, and if the barium content runs low, say below 0.11 per cent of the ash, in plants yielding from 12 to 18 per cent of ash, then to increase the number of feedings on the rabbit. No doubt on ranges where a large number of loco plants are eaten, with little other food, plants with a very low barium content may be poisonous, but if large amounts of other food are fed the writer would expect few, if any, serious results.
As the writer’s work has been confined to the laboratory side of the loco-weed investigations no feeding experiments with barium salts have been made by him on large animals. Such experiments should, of course, be made under range conditions; that is, where the water and food supply is deficient.
FOOTNOTES:
THEORETICAL ANTIDOTE FOR LOCO-WEED POISONING.
The fact that treatment of the loco-weed extract with a few drops of sulphuric acid, which will remove the barium, renders these extracts harmless, and even apparently nutritious, would suggest the theoretical antidotal treatment to be with sulphates, in the form, perhaps, of epsom salts, but perhaps alkaline bicarbonates may be present in the stomach, either due to lessened acidity of the stomach or from drinking alkaline waters, in which case the precipitation of the barium by sulphates would presumably be interfered with, and thus the treatment be rendered ineffectual.[228] It is interesting to note that most of the remedies proposed for the successful treatment of locoed animals contain sulphates.[229]
In Storer’s experiments on feeding rats with barium carbonate it was found that the barium carbonate would kill them, but if calcium carbonate was mixed with the barium the rats survived, suggesting an antidotal action. This apparent antagonism deserves further study and may lead to practical results.[230] A somewhat similar antagonism for at least a part of the action of barium has been claimed to exist between barium and potassium.[231] However, extracts of ashed plants, treated with acetic acid, which contained calcium and potassium, caused death in the experiments of the writer, but no work has yet been done by him as to the antidotal action of calcium carbonate on barium. Then, too, as Lüdeking[232] pointed out, large quantities of calcium chlorid may interfere with the precipitation of barium as a sulphate. It is well known that the presence of various salts influences the solubility of barium sulphate in water,[233] and the fact that barium has been found in solution in the urine in the presence of sulphates shows that the precipitation of barium as a sulphate in the body is not so simple as in test-tube experiments.[234] Again, in very dilute solutions, such as must necessarily occur at any one time in the stomach, the precipitate with sulphates only slowly forms and the barium may be absorbed before the insoluble compound can be formed.[235] Evidently an important point to be considered in the antidotal treatment of locoed animals with sulphates is the possibility of inducing a gastritis, with its attendant loss of weight. It therefore seems apparent that the proper treatment at present is preventive—that is, removal from the plants.
Lewin[236] has suggested the possibility of acquiring some immunity to barium, but our experiments point against the production of any practical immunity.
FOOTNOTES:
ACTION OF BARIUM ON DOMESTIC AND FARM ANIMALS.
Barium in the form of barium chlorid has been recently introduced into veterinary therapeutics by Dieckerhoff[237] in the treatment of constipation, but Winslow[238] says that "the doses required to produce catharsis in the horse are almost toxic," and he advises against the intravenous use of this remedy.
Fröhner[239] has carefully summarized the literature on the use of barium chlorid in veterinary work, and reports that its use in the Zürich clinic has recently been so unsatisfactory that it is now seldom employed and that in the last ten years the preponderance of reports in the literature are unfavorable to the use of this agent in colic.
After the administration per os, much of the barium must be carried off in the diarrheal stools. A number of deaths in horses have been attributed to the use of this agent. No doubt the presence of sulphates, etc., derived from the food would render the barium insoluble in the gastro-intestinal tract, and this would explain the lack of poisonous action in certain of the cases in which large doses of barium proved harmless.
Husard and Biron administered daily doses of 8 grams of barium chlorid to one horse, and the same amount of barium carbonate to a second horse, for several days. A fortnight later the first horse unexpectedly died, and the second a few days later. The post-mortem examination was negative.[240] A third horse fed with barium carbonate also died suddenly. Recently barium occurring in brine has given rise to acute poisoning in stock.[241]
In a case reported by Stietenroth[242] the horse died after the injection of 0.5 gram of barium chlorid into the jugular vein. A number of sudden deaths in horses after the intravenous injection of 0.7 gram and over of barium chlorid have been collected by Fröhner.[243] The lethal dose by mouth for acute poisoning with barium chlorid in horses lies between 8 to 12 grams, while cattle require much larger doses (40 grams)[244] to induce death.
Dieckerhoff advises against the use of barium chlorid in the treatment of constipation in sheep.
After a dose of 6 grams of barium chlorid a 2-year-old healthy ram appeared perfectly well, but the following day he was depressed, refused to eat, staggered, and became so weak that he was unable to stand. The muscles of the extremities were paralyzed and the animal died. “The post-mortem examination revealed œdema of the lungs, slight cloudiness of the heart muscles, numerous small hemorrhagic spots on the mucous membrane of the small intestine, and stagnation of the blood in the vessels of the small and large intestines. Similar symptoms and lesions were found in a lamb 4 months old which was given per os 6.0 grams of barium chlorid dissolved in 200 grams of distilled water.”[245]
Poisonings with barium carbonate have also been reported in pigs.[246] Domestic animals pastured in the neighborhood of barite deposits soon succumb,[247] and accidental cases of poisoning are reported in cows. Poisoning in dogs has also been reported after the subcutaneous use of this agent.[248] Linossier says that if the barium salts are used for any time the salts are deposited in various organs, largely in the kidneys, brain, and medulla, but especially in the bones.[249]
FOOTNOTES:
APPLICATION OF THE RESULTS OF THESE INVESTIGATIONS TO THE RANGE.
It has been calculated that a medium estimate of food for cattle on green fodder is about 60 pounds (30 kilos) a day.[250] Calculating this entirely in terms of Aragallus lamberti and allowing 10 per cent of moisture for these plants (Sayre) would make 27 kilos of dry loco eaten by each animal per diem. In the analysis of the writer of one Aragallus lamberti from Hugo, Colo., it was found to yield 12.44 per cent of ash, and the barium content corresponded to 2.6 milligrams BaSO4 in each gram of the ash. This would correspond to 10.24 grams of barium acetate (Ba(C2H3O2)2 + H2O) or 9.15 grams of barium chlorid (BaCl2 + 2H2O) per diem. This amount daily administered would, theoretically, readily produce chronic poisoning owing to the accumulation in the system, as was shown in the case of rabbits.
There is, however, some question as to whether this full theoretical amount of loco plants is eaten on the range, and the estimate has been made that one-sixth of this amount only would be actually taken. It must be remembered, as Stalker pointed out, that locoed animals develop an especial taste for these plants and after a time reject other food, so that while the number of loco plants at first taken may be small, yet later, perhaps, it is greater. A part of this barium, however, may not be taken up by the system, but may pass out undissolved. No actual experiments have yet been made with cattle by feeding small doses of the pure salt.
No doubt more of the pure barium salts will be required to produce symptoms of poisoning in animals than would be necessary in the case of the form of barium found in the plant, as in the loco-weed the barium is probably better protected from precipitation than are the barium salts when dissolved in water alone.
FOOTNOTES:
CONCLUSIONS.[251]
(1) Conditions analogous to those met with in locoed animals occur in other portions of the world, especially Australia.
(2) The main symptoms described in stock on the range can be reproduced on rabbits by feeding extracts of certain loco plants. Those especially referred to here under the term “loco plants” are Astragalus mollissimus and Aragallus lamberti.
(3) The production of chronic symptoms in rabbits is a crucial test of the pharmacological activity of these plants.
(4) The inorganic constituents, especially barium, are responsible for this action, at least in the plants collected at Hugo, Colo. Perhaps in other portions of the country other poisonous principles may be found.
(5) A close analogy exists between the clinical symptoms and pathological findings in barium poisoning and those resulting from feeding extracts of certain loco plants. Small doses of barium salts may be administered to rabbits without apparent effect, but suddenly acute symptoms set in analogous to what is reported on the range.
(6) The administration of sulphates, especially epsom salts, to form insoluble barium sulphate would be the chemical antidote which would logically be inferred from the laboratory work, but of necessity this would have to be frequently administered and its value after histological changes in the organs have occurred remains to be settled. But even the treatment of acute cases of barium poisoning in man is not always successful, even when sulphates combined with symptomatic treatment are employed. The conditions under which the sulphates fail to precipitate barium must be considered. At present it seems best to rely on preventive measures rather than on antidotal treatment.
(7) Loco plants grown on certain soils are inactive pharmacologically and contain no barium. In drying certain loco plants the barium apparently is rendered insoluble so that it is not extracted by water, but can usually be extracted by digestion with the digestive ferments.
(8) The barium to be harmful must be in such a form as to be dissolved out by digestion.
(9) In deciding whether plants are poisonous it is desirable not merely to test the aqueous or alcoholic extract, but also the extracts obtained by digesting these plants with the ferments which occur in the gastro-intestinal tract.
(10) It is important that the ash of plants, especially those grown on uncultivated soil, as on our unirrigated plains, be examined for various metals, using methods similar to those by which rocks are now analyzed in the laboratory of the United States Geological Survey.
(11) It is desirable to study various obscure chronic conditions, such as lathyrism, with a view to determine the inorganic constituents of lathyrus and other families of plants.
FOOTNOTES: