I.VEGETABLE AND ANIMAL TOXINS.
The vegetable toxins possess the characteristic property of being innocuous, and of being almost completely devoid of poisonousness, when they are absorbed by the intestines; we can see, from this, how greatly they differ from the poisons proper.51
The vegetable toxins known are quite numerous; nevertheless our knowledge regarding them is very incomplete. Our review of them will be chiefly descriptive.
Many of the leguminous plants are poisonous, either because of emanations exhaled by them, or by reason of their alkaloids, or because of some toxins contained in them. We shall commence with these.
Abrin.—This toxin, which was studied in particular by Warden and Waddell,52then by Kobert53and de Hellin,54is found in the fruit of the Leguminosæ, Abrus precatorius (wild licorice, or jequirity). Its name was given it by Warden and Waddell, who discovered both its toxic nature and the vegetable toxin; the toxin is found only in the seeds. To extract it, the seeds are macerated in water, and the solution filtered and precipitated with alcohol; the precipitate which forms is collected and dissolved in distilled water, from which it is again precipitated by adding powdered ammonium sulphate. The precipitate is then collected and submitted to dialysis in order to eliminate the ammonium sulphate. The abrin so obtained forms an albuminoid substance55stable at 100° C., and possessing rotatory power; it liquefies starch paste, and is extremely toxic. One milligramme suffices to kill a rabbit within several hours. It must be observed, however, that, as is the case with all the toxins, abrin acts or kills only after a period of incubation which generally exceeds twenty-four hours.
It is possible to vaccinate an organism so as to withstand a lethal dose of abrin, but it requires quite a long time; it is effected by injecting intoa suitable animal very small doses of the substance, and increasing the quantity gradually. Rabbits which have been rendered highly immune towards venoms are capable of resisting without inconvenience doses of abrin which are ordinarily fatal; and the blood serum afforded by them contains a specific antibody for the substance.
Ricin.—This vegetable toxalbumin has been studied particularly by Stillmark,56by Dixon,57and Thuson.58It is found in the seeds of the castor plant; three or four of the seeds suffice to cause a gastroenteritis accompanied by serious symptoms and even by death.
It was first isolated by P. Ehrlich, by treating the seeds with lukewarm water, and precipitating the aqueous solution with alcohol. The toxalbumin is soluble in water, but on boiling the solution, the substance loses in great measure its activity.
Ricin possesses considerable activity. 0.00003 Gm. suffice to kill a rabbit when injected hypodermically; 0.2 Gm. are fatal to man. The action is not immediate, but follows a period of incubation. Ehrlich has shown that, exercising precaution, it is possible to create, as with abrin, a condition of tolerance or habituation, and in consequence to cause the formation of a specific antibody.
Robin.—This toxic albuminoid was obtained from the bark of an Acacia (Robinia Pseudacacia) by Power and Cambier,59by exhausting with water at a temperature of about 30° C., and precipitating the infusion with alcohol. The substance is analogous to ricin, and like this, possesses powerful toxic properties.
Toxicity of the Vegetable Diastases.—The diastases, which have been treated of in a volume of the Encyclopédie Léauté,60and to which we would refer the reader who is desirous of more complete details, develop powerfully energetic toxic properties when injected into the organism. Thusamylasecauses, when injected subcutaneously, a considerable rise of temperature, but without any other toxic symptoms.Invertinorsucrasewas studied by Roussy under the namepyretogenin, but it appears probable that this diastase was not the only substance present in the product, but that there were present reducing diastases, as we have already shown in the first volume of this collection, devoted to the phenomena of reduction within the living organism.
The pyretogenin of Roussy gives rise to an attack of violent fever, but it loses all activity when heated to 80-100° C.
Through his researches, Roussy clearly demonstrated,61for the first time, that the fever may cause the formation within the blood of a substance clearly belonging to the class of soluble ferments or zymases. Now, it is well known that within the animal economy there exist many ferments of this character; and experiment has shown that they can, at a given period and under various influences, leave the cells in which they are normally localized, pass into the blood plasma, and reach the nervous centers, where they cause serious effects. We have already dwelt upon the mechanism of autointoxication of the organism. The toxic action of certain digestive diastases has been shown by Hildebrandt, who has demonstrated that 0.1 Gm. of pepsin is capable of killing a rabbit in two or three days.
II.TOXINS FROM MUSHROOMS.
Mushrooms are alimentary substances of the highest order, causing a general stimulation of the entire organism. The substances met with belong, according to their composition, to different classes—celluloses, sugars, and amylaceous substances, alcohols, acids, fats, astringents, essential oils, resins,alkaloids, and albuminoids. The study of the last only, the albuminoids and diastases, interests us here. The most important of these albuminoid substances,phallin, was discovered in 1890 by Kobert. Pouchet also has isolated a whole series of other toxic albuminoids, particularly from Amanita muscaria (Fly Agaric).
There are alimentary as well as toxic species in every possible variety among mushrooms, some species consisting chiefly of the edible kind, others consisting of the poisonous variety.
In consequence of the toxicity of mushrooms, great attention must be given to the treatment to which they are subjected when it is desired to utilize them for alimentary purposes. Thus the toxic principles of several varieties can be removed, and the mushrooms rendered edible by very simple means.
Pouchet has made a very ingenious comparison between the ethereal, alcoholic, saline, and aqueous extracts of mushrooms, and bacterial cultures. The analogy is striking as to the presence of toxin, toxalbumose, and albumoses more or less toxic; it is moreover not exaggerated, since, according to the classification generally admitted, mushrooms are nothing more than the very advanced representatives of a group the more simple members of which constitute the bacteria.
The same author has shown that phallin obtainedfrom the juice of the Fly Agaric will kill a guinea-pig weighing 600 grammes in one hour.
As we have already stated, it is the phalline to which the ordinary disorders which mushrooms cause are due. According to Kobert, a 1:250 000 solution of this substance causes an intense hemolysis, with all its disastrous consequences.
According to Pouchet, the flesh of mushrooms must be compared with meat that has been kept for some time to become tender, and it is well known that though this "tendering" process renders the meat more digestible, it may also allow the meat to acquire noxious properties, due to the presence of toxins.
Phallin is the type of those toxic albuminoids of unknown composition which exist in mushrooms, and which are comprised under the namesapotoxins. The intravenous injection of phallin into an animal, in the proportion of 1 part to 1 000 000 parts of body weight, causes sudden death within one minute; in the proportion of 1:5 000 000, death occurs in about three minutes; in the proportion of 1:50 000 000, death also occurs, but is greatly retarded. An injection of 0.0005 Gm. per kilo of body weight of animal causes solution of the blood corpuscles to such an extent that thirty minutes later the blood serum is strongly colored red, as well as the veins.
Instead of being easily altered under the influence of an elevated temperature, as are many of the albuminoid substances, whereby their toxic power is lost, phallin may be boiled for half an hour with water without undergoing any noticeable alteration. Pellegrini has observed that the dried juice of Amanita Phalloides (Death-cup) preserves its properties for more than a year.
According to a recent paper by Gillot, the symptoms of poisoning by mushrooms must be ascribed to albuminoids (phallin and albumose), alkaloids (muscarine, choline, or betaine), or to resinoids (cambogic and agaricic acids).
Thealkaloidsfound in mushrooms are:Muscaridine(an oxyneurine), which possesses considerable toxicity, and of which 0.00005 Gm. suffices to kill a frog;neurine(trimethylethylammonium hydroxide);choline(trimethyloxyethylammonium hydroxide);mycetomuscarine;anhydromuscarine(an oxyneurine); and a whole series of various betaines.
symptomatology.—It is quite natural to divide this symptomatology into three different periods; that of incubation, that of manifestation of symptoms, and that of termination.
The duration of the first period, that of incubation, is exceedingly variable; it very rarely lasts more than forty-eight hours, and becomes general only a few hours after absorption. Certain conditions influence the duration; firstly the quantity of mushrooms ingested, then the manner inwhich they were prepared; and, to some extent, the nature of the organism, whether child or adult, healthy or in poor health.
When it is a question of the more particularly alkaloid-containing mushrooms, especially when the poisoning is due to muscarine, the toxic symptoms generally develop rapidly, the first symptoms appearing about one hour after the ingestion of the mushrooms. On the other hand, if the poisoning is due to one of the albuminoid group, and particularly in the case of phallin, the period of incubation is longer, and may last ten, twenty, thirty, or even forty-eight hours and more.
The symptoms begin with dizziness and an indefinable sensation of being ill.
The second period is characterized chiefly by digestive and by nervous derangements. The digestive derangements are evidenced by very violent and painful vomiting, and diarrheas of choleraic or dysenteric character. The nervous derangements vary according to whether they are developed by an alkaloid, which causes delirium with hallucination, or by albuminoids, which cause depression, ataxo-adynamia, and stupor, these being particularly characteristic of the action of the toxic albuminoids.
As for the period of termination, it results either in death or a cure. If the poisoning is due to phallin, death appears to be an almost inevitable consequence, as it occurs in 80 per cent. or more of the cases. The poisoning by the alkaloids is less dangerous, and the cure, when it does occur, is very rapid, almost immediate, in fact, while in the case of the toxic albuminoids the cure is very slow, and attended by relapses.
One characteristic of these toxalbumins is that they are apt to develop specific antitoxalbumins. This fact has been verified not only in the case of abrin, ricin, robin, and their analogues, but also in that of the vegetable and animal diastases possessing toxic properties even in the slightest degree only. These antibodies generally exhibit their actionin vitro. Thus antiricin exerts its antiagglutinative action on the erythrocytesin vitroin a saline medium in which the erythrocytes cannot live.
Here, again, as in the case of the antitoxins, it must be admitted that the antitoxalbumin possesses a specific affinity by virtue of which it unites chemically with the toxalbumin to give rise to a new substance which is devoid of toxicity.
The first antidiastase obtained by immunization methods, and according to the mechanism we have already seen, wasantiemulsin, obtained by Hildebrandt.62This antiemulsin counteracts, bothinvivoandin vitro, the specific action of emulsin. These studies have been followed by a large number of scientists, particularly by Camus and Gley,63Carnot, Mesnil,64and Charron and Levaditi,65in the case of trypsin; and Sachs66in the case of animal pepsin. Gessard67obtained a very activeantityrosinase, and Mohl anantiurease.
The most important researches regarding this subject have been published by Morgenroth, Briot,68and Korschum69onantilab(orantirennet). The researches of these authors have fully demonstrated that there is considerable difference between the various rennets, which had heretofore been confounded under one head; thus there is no difference whatever between animal rennet and the rennet extracted by Rosetti70from Cynara cardunculus (cardoon) so far as their coagulant action on milk is concerned, yet each yields an antibody which is strictly specific to itself. From a scientific pointof view we see, therefore, that the preparation of antidiastases permits us to differentiate certain diastases that could otherwise not be differentiated.
III.ANIMAL TOXINS.
As we have shown at the beginning of this chapter, certain diastases, and particularly those that are concerned with the digestive processes, pepsin, trypsin, etc., and which are produced in abundance by the entire living organism, possess quite clearly defined toxic properties, and sometimes to even a considerable extent.71
Hemialbumose, from which peptones are formed, is itself a dangerous toxin. It is generally believed that the toxic action of the peptones and of the products of digestion of the albuminoids is due not to the peptone itself, but to the more advanced products of digestion, alkaloidal products unquestionably closely allied to the ptomaines.
Nevertheless, the true peptones behave just like true poisons, when they are introduced hypodermically into the blood.72
Brieger has made us acquainted with a non-proteid substance, under the name of "peptotoxin," which is met with at the beginning of the putrefaction of albuminoids. This toxin, which is not a protein, is nothing else but a ptomaine. It is not altered by heat, and possesses a very high toxicity. Brieger claims that it is a hydroxylized derivative of an aromatic amide.73
Besides these facts, experiment has shown that the leucocytes, or white corpuscles, the defensive rôle of which we have noted in phagocytosis, owe their properties to the ferments which they secrete, and particularly to some of the digestive ferments. These white corpuscles are very rich in ferments of all kinds. Rossbach found in them amylase; Achalme found lipase, casease, and trypsin; and the study of immunity has brought to light a series of other ferments, the alexins or cytases (microcytase and macrocytase), which have an exceedingly important rôle to play.
It may easily be conceived that under certain circumstances a part or the whole of these ferments can pass into the blood of the fluids of the body, when they give rise to serious disturbances in certain cases, or confer immunity in others.
It is thus that, according to Gautier, the rise of temperature which characterizes fever is a consequence of the abnormal transudation of these normal ferments into the blood, and their transmission by the general circulation to the nervous centers.
However, it is not only in the leucocytes that we meet with these toxic digestive ferments; it appears quite probable, and has even been partially demonstrated, that they occur in a large number of other cellular elements.
It is not necessary here to dwell upon the formation of the antibodies of this group of active substances. The animal toxins are animal diastases, and we have seen in the preceding paragraph that these substances yield specific antibodies with great facility. For the rest, we will dwell more fully on these antibodies of the animal toxins in another volume of this collection, specially devoted to the study of these substances, and entitled "Les Serums Immunisants," to which we refer the reader who is desirous of obtaining more complete details than he can obtain in the present volume.
Alimentary Intoxications.—What we have already stated permits us to understand the phenomena of indigestion and botulism. The toxic substances form within the digestive tract when the nervous conditions modify the composition of the gastric juice, and arrest the flow of hydrochloric acid, the presence of which normally checks the development of the microbial flora, so rich within the stomach. The result is the production,within the organism, of all kinds of dangerous toxins. The same thing happens when the liver does not functionate normally, and this, affords us a knowledge of the mechanism by which foods that are most wholesome may become toxic by reason of poor digestion or poor assimilation.
The absorption of spoiled viands may,a fortiori, produce serious results. The alteration may be due not only to a bacterial infection, as in tainted meat, but it has also been proved that the flesh of an animal that has died of terror or madness may be very dangerous as a food, even after cooking, because, although there are toxins which are destroyed by a sufficient heat, there are ptomaines and certain toxins that resist destruction under these conditions.74
The use of preserved but spoiled beef, preserved ham or birds, sausages frequently, and pieces of pork tainted by sausage poison, gives rise to a succession of toxic symptoms the principal ones of which are dryness, constriction of the pharynx, bilious vomiting, diarrhea, dyspnea with pulmonary edema, etc. Fish and eggs are foods quite frequently capable of developing serious results; the same is the case with molluscs, mussels, oysters, lobsters, and snails. Lastly, moldy bread, spoiled cheese, putrid water, and spoiled vegetables themselves, are proper agents for determining attacks of botulic poisoning.
We have seen, at the beginning of this volume, that putrid meats contain ptomaines, which are among the most toxic alkaloidal bases. We have shown that Brieger has isolated from them neuridine, putrescine, muscarine, and guanidine; that Nencki has isolated hydrocollidine; and that Gautier and Etard have obtained from them parvoline—only to mention a few of them.
Lastly, there may develop within the gastrointestinal tract dangerous putrefactions, the products of which may enter the veins and arteries from the ileum (a portion of the small intestine) and be distributed throughout the organism. Although such poisonings occur, they do not immediately follow the ingestion of the spoiled or toxic foods, but they are always preceded by a period of incubation varying from several hours to several days.
These alimentary poisonings are recognized by a great physical depression, accompanied by vomiting and paralysis of the lower extremities, sweats, and diarrheas. In some cases there occur cutaneous eruptions; and when death happens, this occurs only several days later, and generally without being preceded by any great pain.
Urinary Toxins.—As we have already remarked several times, it is by the renal way that the organism voids its principal waste products.
We have seen also that it is by the kidneys that the toxins are eliminated in all pathological conditions. As a general rule, the urines are always more or less toxic. This toxicity of the urines must be attributed in the first place to the crystallizable organic principles (ptomaines and leucomaines75) which they contain; secondly, to the non-crystallizable76extractive matters not so well known; and lastly, to the saline substances, among which the potassium salts are the most active. We find these mineral salts particularly abundant under normal conditions in the urines of the herbivora. According to Bouchard, 0.18 Gm. of potassium chloride are sufficient to prove fatal to 1000 Gm. of living organism; a man excretes on the average 2.5 Gm. of this salt, and a rabbit excretes about double this quantity, weight for weight.
A very large number of hypotheses have been advanced regarding the toxicity of the urines. Wilson considers the urea as being responsible for it; Stadthagen77believes it to be due to the potassium salts, etc. Bouchard78was the first to recognize that the toxicity of the urines is due to a number of causes. We will not dwell further on these active principles which, in the last analysis,are no other than those that form in the various portions of the organism, and which are eliminated by the urine.
It is self-evident, and it has already been shown, that the toxicity of the urines varies greatly according to the malady, in consequence of the elimination of toxins by the urines. According to Bouchard, in infectious maladies the urines are twelve times more highly charged with toxins than is blood serum. Moreover, the toxicity of the urines is considerably augmented the moment there is the least febrile condition, no matter what the cause is.79
Even in the normal condition, the urinary toxicity varies greatly; and this is easily conceived since the physiological phenomena that control this secretion undergo incessant rise and fall. Thus, for example, the urines eliminated during sleep are less active than those produced during waking, because during sleep the elimination of cellular poisons is at a minimum. Exercise, walking, physical and intellectual labor, exert their portion of influence on these oscillations of toxicity; and this variation of toxicity is due not to any one variation in the mineral extractive matters, but rather more or less to the organic toxic products. We will not dwell further on this subject, but willsimply refer to the work by Charrin, already mentioned, for all supplementary details.
Autointoxications.80—The cells of the organism having, as a whole, a life very much like that of the microbes, it is quite natural that among the excreted products of the living tissues there should be found the same substances formed as a result of the anaerobic fermentation of albuminoids. Experiment has demonstrated that this is so, and Armand Gautier has irrefutably proven the existence of these principles.81Bouchard was the first to demonstrate the toxic nature of muscle extract,82and Roger83established the fact that the toxicity of this extract is due to ferment-toxins; it has since been recognized that after death these toxins accumulate in the muscles.
The extract of kidney made rapidly by cold process by triturating the washed kidney with glycerin, and precipitating the glycerinic solution with alcohol, contains toxic ferments to which the name "hystozymes" has been given.84These ferments split up hippuric acid into benzoic acid and glycocoll. Lépine has likewise discovered in thekidney a very toxic pyrogenic substance.85Roger has given us evidence of the toxic properties of the liver, washed and pulped, and then sterilized by filtration through a porous diaphragm. This scientist has shown that the toxic properties are due to albuminoids, which lose their activity when heated to 100°C.86
It must be remarked that the organs we have studied are essentially reducers, and that the more powerful reducers yield the most toxic extracts. We find here a confirmation of Armand Gautier's views regarding the anaerobic origin of the toxic substances formed within the organism.87
Blood serum precipitated by alcohol affords products which possess very marked toxic power. It would appear that the toxic products we speak of here are thermogenic diastatic substances derived from the white blood corpuscles. In certain diseases the blood serum may acquire a high degree of toxicity. We will recur again presently to this property as a normal characteristic of the blood of various animal species, and will study it in greaterdetail in a future volume of this collection, devoted to the immunizing active principles.
Glandular Secretions.—On studying the venoms we will see that a certain number of these products are the result of glandular secretion. This is a general property of the glands; and it was Brown-Sequard who first drew attention to the rôle played by these glands, and to the importance of the products that they throw into the blood.88
P. Noel showed later that the testicular juice possesses a high degree of activity, which he attributed to an oxidizing ferment, and which we have already mentioned,spermine.
The greater number of the other glands contain proteid matters and various peptones, more or less toxic, with amides and alkaloids.
Particular mention must be made of the thyroid gland, the secretions of which exercise a powerful action on the nervous centers and on nutrition.89It appears reasonable to attribute to the secretions of this gland a very powerful antitoxic action, and the first proof of this fact is that the organisms deprived of this gland become the seat of serious derangements; the urines of such organisms become particularly toxic, while, on the other hand, the hypodermic injections of the aqueous extract ofthe gland, when the derangements spoken of exist, cause the immediate disappearance of the derangements caused by the excision of the gland.90
Attempts have been made to isolate the active principle of the glands. Notkine isolated atyroproteid,91which is not sensibly toxic to animals who still retain the gland, but which becomes toxic when the gland is excised. It seems probable, however, that this product is not the principal agent of the thyroid gland.
From the researches of Schaeffer, Roos, and Sigmund Fraenkel92it results that the active principle of the gland is not a toxin, but a purely chemical substance, a true leucomaine, which has received the namethyroantitoxin.
On the other hand, Baumann quite recently extracted from the thyroid gland an iodized substance, which he namedthyroiodine.93
Thesuprarenal capsules also possess properties that have often attracted the attention of physiologists during the last few years. They are considered as being, just like the thyroid gland, producers of antitoxins; they destroy, or seem todestroy, toxins that are artificially introduced into the circulation.
Albanèse94maintains that the function of the suprarenal capsules is to neutralize neurine, the toxic product of the disassimilation of the nervous system; this view, however, is opposed by Boinet95and Langlois.96On the contrary, it has been definitely proven that the suprarenal glands exert a specific action on the poisons of muscular origin. Abelous and Langlois97have in fact demonstrated that the alcoholic extract of the muscle of a decapsulated animal has the same properties as the extract of tetanized muscle; the decapsulated animal gives ergographic tracings analogous to those afforded by tetanized animals. The removal of the suprarenal capsule from an animal brings results, hence, analogous to those of fatigue—that is to say, that the toxic substances which accumulate as a result of the decapsulation resemble those that result from muscular exertion. The suprarenal capsules exert their action furthermore on other toxic products as well, as Guieysse98has shown, and particularly on the exogenous poisons. Inconclusion, it may be said that the matter concerns a most important rôle, and we cannot do better in this respect than to refer the reader to the memoir presented by Sergent and Bernard to the Académie de Médecine in 1902 and entitledl'Insuffisance Surrénale.99