On the Modern Methods of Studying Poisons
“Just as heat may, according to amount, warm your hands, cook your meats, or burn your house down, so arsenic is in minute dose an efficient tonic, in larger dose a powerful alterative, and in still greater amount a horrible poison.”
A poison has, for people in general, the interest which belongs to all things that combine the qualities of mystery and power. With this conception is also associated the idea of ability for good as well as for evil, and the not unjust belief that such agents, like fire, are good slaves, but bad masters, and may be as useful in small amounts as they are hurtful in large ones.
Among civilized people, therefore, deadly substances, such as opium, arsenic, and nux vomica, have been recognized as means of good when rightly employed; and although held in dread as medicines by many, are yet among the safest of all drugs, because, when they begin to cause evil in the body, they announce their effects in the shape of symptoms so decisive as at once to lead to their abandonment. At the same time, it may be said of them again, that, like fire, or rather heat, they so vary in influence according to the quantity used, that with one or another dose they become, as it were, altogether different in the results they bring about; for just as heat may, according to amount, warm your hands, cook your meats, or burn your house down, so arsenic is in minute dose an efficient tonic, in larger dose a powerful alterative, and in still greater amount a horrible poison; while just the same account may be rendered of nux vomica, or its active principle, strychnia.
Barbarous nations seem to know of these agents only for the chase, or for evil in some shape, and use them to make deadly their arrows, to destroy a foe, or in the trial by ordeal, of which Mr. Lea has given so admirable a description in his recent work on “Superstition and Force.”
These uses of poisons by savages have been the chief means of attracting the attention of travellers to certain substances which, in one way or another, have proved of the utmost value, when, from the hands of the barbarian, they have passed into the busy fingers, and under the acute eye, of the civilized man of science. As instances of this, the famous woorara of South America, and the Calabar bean, may be cited. The first, an arrow poison, used throughout Brazil and Guiana, has come to be an indispensable agent in the physiological laboratory; and the latter, an ordeal poison, has been shown to possess, almost alone, the power to contract the pupil of the eye, just as bella-donna has been longer known to have the ability to cause its dilatation or enlargement, — both being thus of value in certain diseases of the eye.
A vast amount of ingenious care has been spent upon the definition of poisons; and with every descriptive phrase of them all it is easy enough to find a cause of quarrel, while few will really differ as to what are truly poisons. As a general rule, the body contains, in uncombined form, none of the poisonous substances known to outside nature. Phosphorus exists as phosphoric acid in union with alkaline bases, and is only poisonous when isolated. Carbonic acid, a poison when inhaled, is found in limited amount in the body; but with these exceptions, and that of a minute quantity of the salts of copper in the bile, or of this metal and of lead in the blood, the rule holds good; so that a poison might be aptly defined as an agent which has no normal existence in the body of man.
If any reader be curious enough to look at the older classifications of poisons, he will find that the more ancient toxicologies divide them into irritants, narcotics, and acro-narcotics.
This answered well enough when but little was known as to these agents, except that they gave rise to certain general effects, which are rudely indicated in the arrangements above referred to. Modern toxicology, of which Orfila and Christison were the parents, has utterly destroyed the value of these classifications; but, while it has brought to light a vast amount of fruitful knowledge, it has only introduced confusion into every new effort at so relating them to one another as to make possible a distinct classification. The chief obstacle lies in the fact, that almost every poison acts, not on one, but on numerous organs of the body; so that it is anything but easy to decide either the order in which different vital parts undergo attack, or which organ when injured is most potent in occasioning the fatal result. Besides this, so small a number of poisons have been thoroughly studied, that it is only a very few as to which we are at all well informed. The difficulties to which I allude will be much more readily understood, as I proceed to describe how certain poisons have been investigated, and the results of these researches; so that I shall not attempt to point out further the annoyances of the classifier.
My chief object is briefly to sketch the history of three well-known poisons, and to explain, as clearly as may be, the methods by which the modern toxicologist attempts to discover upon what organs they act, and how they affect them.
For this purpose, let us select a nerve poison, a muscle poison, and a blood poison. Nerve poisons may very well be represented by the most famous of them all, — the well-known woorara, or wourali, of South America. The ever-blessed adventurer who is said to have given to Europe the potato and the pipe was also the first to describe woorara, which he speaks of as follows: —
“There was nothing whereof I was more curious, than to finde out the true remedies of these poisonous arrowes; for besides the mortalitie of the wound they make, the partie shot indureth the most insufferable torment in the world, and abideth a most uglie and lamentable death, sometimes dying starke mad, sometimes their bowels breaking out of their bellies, and are presently discoloured as blacke as pitch, and so unsavoury as no man can endure to cure or attend them, and it is more strange to know that in all this time there was never Spaniard, either by gift or torment that could attaine to the true knowledge of the cure, although they have martyred and put to invented torture I know not how many of them. But every one of these Indians know it not, no, not one among thousands, but their soothsaiers and priests who do conceale it and only teache it from the father to the sonne.”
Later travelers, as De la Condamine and Bancroft, gave more explicit accounts of this agent; but, as usual, Humboldt’s statements have been proved to be the most reliable.
All over South America and the Isthmus the natives employ certain weeds whose juices they boil, in combination with numerous inert materials, until a thick extract is obtained, which is known as woorara, curare, wourali, and the like. That made on the Isthmus is a poison for the muscular tissue of the heart, and is also called corroval, whilst all of the Brazilian arrow poisons are of a different nature, and act chiefly on the nerves of motion. It is with these latter poisons that we propose first to deal. They reach Europe in gourds or little earthen pots, some of which are now before me, as well as on the points of arrows or spears dipped in the fresh extract and allowed to dry. The extract itself is a resinous-looking substance, in appearance resembling aloes.
Let us suppose such a material to have been placed in our hands for examination. How shall we treat it in order to discover its powers as a poison? — a simple matter it may seem to some of my readers, but one as regards this agent which has occupied the careful attention of several of the first intellects of the day. Let us see how our present knowledge about it was reached. De la Condamine, and all the observers up to the time of Fontana, merely recorded the obvious external effects on animals, and this was what they saw.
A morsel of woorara is introduced under the skin of an animal, as a rabbit. In a minute the creature lies down, too weak to walk, then the head falls, the hind legs become useless; the fore legs are next palsied, the rabbit rolls over. The breath becomes quick and labored, and within a few minutes the animal dies, usually without convulsions, more rarely with them. The outward phenomena tell us only that we are dealing with an active and probably a painless poison.
Fontana began to analyze the symptoms more closely, but was wrong in his final conclusion, that it destroys the power of the muscles to respond by movement to stimulus or, as we would say, deprives them of irritability. In 1811 the famous Sir Benjamin Brodie discovered that, if an animal be poisoned with woorara, the heart continues to beat for a time after other movements cease; and that, if then we imitate breathing by blowing air at intervals into the lungs, the heart may keep on pulsating for hours, or even so long that, the poison being filtered out of the body by the excretions, life may finally be preserved. Now here was the needed clew, since it thus became clear that the heart ceased to beat in this poisoning, not because it was directly attacked, but because something had interfered with the power to breathe, which in warm-blooded beings is instantly essential to the motion of the heart.
Two German physicians, one of whom, Virchow, is now among the first savans and politicians of Prussia, next pointed out that woorara destroys primarily the activity of the voluntary muscles, but leaves untouched that of the involuntary ones, as the heart. This was only a step towards generalizing the facts; it brought nothing new.
Kölliker, and, about the same time, Claude Bernard, the greatest name in living physiology, at length solved the problem, and showed that in reality this poison only seems to palsy the muscles because it kills the nerves of motion.
Let us run over the evidence which has brought us to this point. The instrument we use, if I may so call it, is the frog, which possesses a value for physiological investigation quite incalculable. Depopulate the frog-ponds of Europe, and the toxicologist would almost lose his science. This little creature has for him these useful peculiarities, — it is cold-blooded and tenacious of life; its functions are more independent than those of warm-blooded animals, so that when one, as breathing, ceases, the others are not at once annihilated. There are three reasons for this: first, the individuality of function which is shown by the heart continuing to beat for hours after excision; and second, as I think the fact, that whereas in mammals all the blood goes from the heart through the lungs, and is checked more or less when breathing stops, in reptiles only a part takes this channel, so that we have a possible circulation, even when respiration is at an end. Finally, in the frog, the skin is an active agent in carrying on respiration, and enables it to survive a long time the loss of its lungs. The extent to which these peculiarities protect is seen best in the snapping-turtle, which can hardly be killed by woorara. Respiration stops, but the heart goes on acting, and after several days the flaccid mass becomes alive and vicious as before.
A recent writer has shown, that, comparing the rabbit and turtle, it takes only one ninety-sixth of a grain of woorara per pound of the animal to insure death in the rabbit, whilst in the turtle not less than the seventh of a grain per pound of the reptile’s weight must be directly injected into the veins in order to make very improbable its return to life. On one occasion three grains having been cast into the blood of a snapper weighing twenty-two pounds, it suddenly became feeble, and, extending its claws, lay still. During fifty-nine hours it was supposed to be dead; but at the close of this time, to, the observers’ amazement, feeble motions were seen, and within a few hours it was to appearance as well as ever, and both able and willing to justify its fame as the most savage of the dwellers in creek or mill-pond.
If, then, we stop the heart of a warm-blooded creature, respiration ceases. Let breathing terminate, and the heart quits beating. Whereas in a reptile only the former is true, and that not always, or of necessity, since in the alligator respiration may go on long after the heart is at rest. Mindful of these facts, we take a frog, and put under its skin a morsel of woorara. The symptoms are the same as in the rabbit; but if, just before a general relaxation of the limbs announces the coming of death, we open the chest, and expose the heart, we shall see it beating quietly, and continuing to do so for one or more hours after breathing has ceased. We are thus at once made sure that woorara does not act primarily on the heart. To vary the proof, we may blow now and then a little air into the lungs, and we shall find the flagging heart, under the influence of a properly aerated blood, at once quickening its beat anew; so that we are now doubly certain that the poison has not hurt this organ at least. Let us next expose in the hind legs the large nerve which conveys from the brain to the muscles the excitations which induce motion. We pinch or galvanize the nerve, but cause no muscular twitchings, as we may do for many hours in a frog killed by some other means, such as decapitation. We have learned thus that woorara poisons the nerves of motion, so that, as it assumes control, all movements except those of the heart at once cease and the will in vain calls upon the muscles to act when the nerves are made unable to carry its orders. Breathing depends on the regular action of muscles, to which an order to move is momently conveyed by nerves from certain parts of the brain. The poison cuts these nerve wires, if you like so to call them, and presently the breath goes in and out no longer, and the animal dies.
Meanwhile if we apply to the muscles themselves the irritations which have failed to influence them through their nerves, we see the part on a sudden convulsed. If we touch them, they move; if we galvanize them, they twitch; so that the muscles, it would seem, are themselves unpoisoned. We have learned, therefore, that the nerves of motion have been injured so as to act no longer, and that the muscles are intact. A little closer examination makes us suspect also that the irritability of the muscular fibres is increased and prolonged, rather than lessened.
We want next to ascertain if the nerves of sensation, or those of touch and pain, be altered as are the nerves of movement; but this is not easy to do, because the only mode of expressing pain is by some form of motion, as a leap or a cry, and these are impossible, owing to the palsy of the motor nerves. The brain may be clear, the power of feeling perfect, and even the muscles healthy, but if you have not a channel for conveying messages of movement to the latter, there is left no means of outwardly expressing pain.
We reach a certainty in the following way: The arteries in one hind leg, we will say the left, having been tied so that it has no communication by bloodvessels with the rest of the body, we put under the skin of the back a morsel of woorara. Presently the animal becomes paralyzed; all its motor nerves being out of action excepting those of the left leg, into which none of the poison can enter. Now it is known that this agent acts from without inwards, so that the spinal centres and those of the brain die last. We irritate the spine with a needle, and the left leg twitches, showing that its nerves of motion are healthy. But there is another less direct way to excite the spine, namely, by irritating a nerve of sensation; and if this be unpoisoned, and able to carry a message, we shall find that the spine will show the irritation by making the unpalsied left leg move. We pinch, therefore, the right leg, and suddenly the left leg jumps or moves; and so we learn that in the right leg (poisoned) the nerves of sense can carry to the spine and brain the irritation, and that this expresses itself by motion in the left leg, the only unpoisoned part.
The condition of a creature thus affected seems to us to touch the extreme of horror, since for a time the brain may remain clear, the power to feel be perfect, and the capacity for escape or expression of feeling absolutely annihilated. In man this would hardly be the case, because the loss of breathing power would almost immediately kill by interfering with the heart’s action. We have learned, then, that this potent poison first kills the nerves of motion; that this soon in a warm-blooded, and much later in a cold-blooded animal stops the heart; that the nerves of feeling do not suffer from the poison, but only after a time from the checked circulation and the consequent want of blood to nourish and vivify them; and, finally, that the poison kills from circumference to centre. It only remains for the chemist to analyze the material used, and to extract a crystalline alkaloid, which is easily proved to be its active principle, and we shall have learned all that is now known as regards this most interesting poison.
We turn next, of course, to ask what uses this knowledge may be put to. The physiologist’s answer is satisfactory, the physician’s rather less so. There are many occasions in the laboratory where it is highly useful to possess an agent which has power to kill without disturbing the heart, — as when, for instance, we desire to exhibit the action of this organ to a class. All we have, then, to do is to give woorara, and keep up artificial breathing. We may then open the chest, and demonstrate the heart’s motions in such a way as forever to impress upon the memory of the student most important, nay, vital truths in medicine.
As to the use of woorara as a drug, there is in our minds a good deal of doubt. Given to persons who have lockjaw, it certainly stops, or may be made to stop, the awful convulsions of that disease; but as their cause lies only in the spine, and as woorara palsies the motor nerves alone, it seems likely that we are merely suppressing a symptom, and not altering the malady itself. If, however, as sometimes is the case, lockjaw proves fatal by the spasm it causes in the muscles with which we breathe, it seems possible that a limited use of the drug might so diminish this evil as to allow life to go on, and thus give added chances to the sufferer. Hitherto our experience is inconclusive, and the right-minded doctor, being of all folks the most sceptical, is thus far unconvinced of its value, and awaits the results of a larger number of cases; feeling, meanwhile, at full freedom to test its possible utility in a disease so unconquerable by ordinary methods.
The poisonous agents which have power to destroy life by acting directly on the heart are numerous. Among them we find aconite and digitalis well known as medicines, and useful to control tumultuous or over-excited activity in this essential organ. Several, also, of the Eastern arrow poisons belong to this class, — as the upas, of Borneo; and, finally, the corroval, an arrow poison of the Isthmus of Panama.
To point out precisely in what way these various agents influence the heart would require us to explain at length the whole physiology of this organ, and to discuss the function of the different nerves which enter it. We shall therefore content ourselves with relating what is known in regard to corroval, — a poison which thus far has been investigated only by two American toxicologists. Like woorara, this substance is a resinous-looking material, which, is certainly of vegetable origin. It is used as an arrow poison by the dwellers on the Rio Darien, but of the nature of the plants which yield it we know absolutely nothing. Thus far it is known only to savages, and to two or three students of poisons, nor, if it were used to kill man, would it be possible to detect it in the tissues. As in the case of woorara, let us relate briefly how the toxic characters of corroval were first investigated.
A frog was held while the operator placed a morsel of poison in a wound made in the back. In ten or twelve minutes it showed signs of lassitude, and in half an hour was totally motionless and dead. Nothing was seen to lead to the belief that the toxicologist was dealing with a substance differing from common woorara. The outward signs were alike. A second frog was then poisoned, after a little V-shaped opening had been so made as to expose the heart, whose natural beat was noted as being forty-five to the minute. In three minutes it was unaltered as to number, but had become irregular. Then it began to fail, beating thirty at the fifth minute, and ceasing half a minute later, the auricles continuing somewhat longer. As the organ failed, a strange fact was noted; at the instant when the great cavity of the heart—the ventricle—contracted so as to expel the blood into the arteries, it was observed that here and there on its surface little prominences arose, which were presumed to be due to these parts being palsied so that they yielded under the pressure from within. That this was a true view of the case was shown by pinching or galvanizing minute portions of a healthy, active heart, when the same appearances were noted at the points enfeebled by the over-stimulation to which they had been thus mechanically subjected. When the heart stopped, it could not be re-excited by a touch, or by electric currents, as was the case in woorara poisoning, or in death from violence.
During all of this time, and for twenty minutes after the heart ceased to beat, the frog leaped about with readiness and ease, so that it seemed pretty clear that corroval was a poison which paralyzed directly the tissues of the heart, without at first influencing any other portion of the economy. To put this beyond doubt, the experimenter tried to keep up the circulation by causing artificial breathing, which in the case of woorara was competent to sustain the hearts action. Here, however, the heart stopped as though no such means had been used. The same observation may be better made on the young alligator, because in this creature the breathing continues for some twenty minutes after the heart has ceased to pulsate, thus making it still more clear that the heart does not die owing to defect of respiration. Lastly, it was shown that when in a healthy frog the heart is cut out, or its vessels tied, voluntary and reflex motion disappear at about the same period as they do when corroval has been given; whence it was inferred that this agent destroys the general movements only because it first interrupts the circulation of the blood, without which they soon cease to be possible.
The contrast between woorara and corroval is very striking, since in the former the heart dies last, and in the latter it is the first organ to suffer.
We are aware thus far of scarcely a poison which acts entirely on a single organ. In every case it has been found that the noxious effects are finally felt by other parts in turn; and, so far as we can bather, these secondary poisonings are direct effects of the poison in many cases, and not merely results of the death of the organs first injured. Thus, while pointing out that in the reptile voluntary motion exists after the heart stops, but soon ceases on account of the arrest of circulation, we might have added, that, by a variation in the mode of experimenting, it can be made clear, that where, owing to a small dose of the poison, death comes slowly, the sensitive nerves first, and then the motor nerves, and last the muscles, are all directly and in turn affected by the poison. Finally let us add, that, given by the mouth, this agent usually causes convulsions, such as do not appear if the poison be put under the skin, — a fact for which we cannot in any way account, but which aptly illustrates how easy it is to deceive one’s self where such variation may arise in the symptoms caused by one and the same poison.
As an apt illustration of the difficulties which surround this study, it may not be out of place to mention the following incident. During the study of corroval it became desirable to learn the rate at which this material could be absorbed from the stomach. Accordingly a weighed morsel was pushed down the wide gullet of a large frog and into its stomach. The animal being left in a vase with a half-inch of water, the next day it was alive and well, to the operator’s surprise. Repeating the experiment, the frog was left under a bell-glass, on a dry plate. This time the corroval was found on the plate, so that it seemed to have been vomited, as to which operation as possible in a frog nothing had been hitherto known. The following day a full dose of corroval in a little alcohol and water was poured through a tube into the stomach, when instantly this organ, was inverted, and pushed up through the wide gullet and outside of the mouth, where the frog presently cleaned it most expertly with its fore legs. Its return was gradual, and over this act the creature seemed to possess no voluntary control.
As the power to turn the stomach inside out is rarely exercised, and therefore not anticipated, the reader may understand how easily it might deceive, if a poison having been given it were thus disposed of in the experimenter’s absence.
A favorite mode of suicide in France is to breathe a confined atmosphere in which is burning a pan of charcoal. For a long time it was supposed that, under these circumstances, the death which ensued was due to the carbonic acid set free as one of the products of combustion, in which case we should have asphyxia from deficiency of oxygen and excess of carbonic acid, — a mode of death as well understood as any death can at present be.
When, however, attention was called to the presence of another gas, in the mixed products of incomplete combustion, the toxic characters of this agent, now known as carbonic oxide, became subjects of inquiry. After several theories had been set forth, only to be pushed aside by the next coiner, Claude Bernard re-investigated the matter, and, with his usual happiness in discovery, pointed out what is, at least for the present, a well-accepted explanation of the mode in which this gas poisons.
Here for the first time we deal with an agent which enters the blood through the lung. Six hundredths of the volume of an atmosphere, the rest of which is common air, is fatal to a bird confined within it. The death is rapid, and usually convulsive. Upon examining the body of the poisoned animal, we are struck with the brilliant red color of the blood; and if at the same time we compare the appearances seen in a bird killed by carbonic-acid gas, we shall be still more impressed with the difference, because this latter gas colors the blood of a very dark hue.
To make clear what is to follow, the reader should carry in mind the following facts. The blood, in circulating, goes through the lung, and there gives up carbonic acid, and, receiving oxygen from the air, becomes bright red. Thus altered it is forced by the heart along the great arteries, until, finally entering the minute vessels called capillaries, it has between it and the tissues only walls of the utmost thinness. This vast mesh of tiny tubes makes the great markets of the body, in which occur a host of exchanges, of givings and gettings on the part alike of blood and tissues, such as muscle, nerve, and bone. The most important of these is the taking of oxygen by the tissues, and the giving up of carbonic-acid gas to the blood. The first gas is needful for a multitude of purposes, without which life must cease; the second, when retained, is poisonous; and, as the interchange depends for existence upon there being two gases, the loss of a hurtful one is made subservient to the getting of a useful one. Moreover, as the little blood rivers flow by nerve and bone, the materials which these must get rid of as the results of their waste are cast for the most part into the general volume of these streams; but, as regards the gases, we find them transported chiefly on or in the blood-globules, which float in myriads along these tiny streamlets. In the tissues they each get a load of carbonic acid, of which they lose the most in the lungs, replacing it with oxygen, and so are continually voyaging to and fro betwixt the sources of supply and demand. Imagine for a moment these millions of little carriers become incapable of transporting their destined freights, and such precisely is what occurs when an animal is made to breathe carbonic oxide gas.
Healthy blood shaken with carbonic acid becomes dark, and fresh contact with the air will redden it again. When once it has been poisoned by carbonic oxide, such changes are no longer possible, simply because the blood-globules have grown incapable of taking up any gas but the one which has poisoned them.
Neither can we cause them in any way to give up the hurtful carbonic oxide which has taken possession of them. A fatal attachment has been formed, and they refuse to return to their everyday duty.
The careful and elaborate series of analyses and experiments which brought Bernard to this conclusion it would be folly to attempt to make clear to any but the physiological chemist. So far they hate not been set aside by any more authoritative verdict.
Here, then, we have the curious case of asphyxia, or death from want of oxygen, not because the lungs have ceased to present it to the blood, but because that fluid has become unable to accept the gift. Hence results sudden cessation of every function which demands for its continuance unceasing change in the tissues which effect it, and so death follows as a matter of course.
I cannot hope that to any but very careful readers I may have been so happy as to make clear the history of these three poisons, as they act within the body, and sunder one or another of the many essential links which make the complete chain of life. One abolishes the power of the nerves of motion; one palsies the muscles of the heart, and one annihilates the function of the red blood-globules. These diverse modes of destructive activity are but instances of the wonderful variety of modes in which the fortress of life may be assailed.
The reader will not fail to have noticed that two of the three poisons here discussed are of comparatively recent introduction. The same statement applies to the two best-known kinds of upas, and to a third, admirably studied by Dr. William A. Hammond, while the same may be said of Calabar bean and other poisons used by savage tribes. Scarcely one of these could as yet be detected in the body of man, were it employed to destroy life; so that it is as well that these dangerous agents should be carefully guarded by the toxicologists into whose hands they may chance to fall. A recent writer in these pages, alluding to this subject, also points out that the same difficulty in detection applies to many of the poisonous substances which every year are made by chemists engaged in the study of complex organic compounds. Some of the bodies thus discovered are of the most deadly character; so that here again it is well that the awful power which they give should rest in the keeping of the trustworthy men of science whose industry has brought them to light. Poisoning, as a rule, has been a crime of the intelligent classes, rather than of the poor, or of those whose passions, being under less certain government, are apt to seek gratification by the most direct means. Of late, however, it has become so well known to educated persons, that the more accessible poisons are sure to be detected by the chemist, that I have no doubt this alone has tended to lessen their fatal use. The question of the relative ease with which poisonous drugs may be obtained leads to some reflections which have especial application in our own country.
In Europe, and particularly on the Continent, the sale of poisons is surrounded by the most stringent precautions, so that it is very difficult to procure them without a physician’s prescription; the doctor, as it were, coming between the apothecary and the public, to guard the latter from crime or injury. Here, however, the utmost laxity prevails, and although in some States rigid laws on the subject exist, they are daily disobeyed by almost every druggist, — the slightest excuse enabling almost any one to buy corrosive sublimate, arsenic, or opium. It is time that some effective measures be taken to check this evil, which not only invites to, crime but removes all restraint from those who desire to intoxicate themselves with opiates, ether, or chloroform.