The mucous membranes coming into immediate contact with arsenic reveal chronic catarrhal states: coryza with dryness of the nose, laryngitis with hoarseness, bronchial catarrh, conjunctivitis, oedema of the lids, blepharadenitis, also otitis media by progression of the pharyngeal catarrh to the tubes and middle ear. The bones may also be drawn into involvement. Lewin mentions (Eulenburg’s Encyclopedia) a man who worked in an arsenic factory for 34 years. In his markedly reddened and thickened nose the septum was destroyed, the entire mucous membrane was converted into an ulcer, the left and right turbinates were covered with ulcers and crusted; a fragment of the superficially necrotized vomer was removed as a sequestrum. More rarely a joint inflammation appears. H. Schulz mentions one on himself in that he suffered from an arthralgia of the ankle after working for a long time with arsenic.
The nervous system is markedly influenced, motor and sensory arsenical neuritis having been observed and produced experimentally in animals. Paralysis and disturbances of coordination are the result. The paralysis may appear as early as 24 hours after the ingestion of the poison and may disappear in 2-3 days, but it may also persist; or reappear only during convalescence from an acute intoxication.
The nervous diseases are associated with frequent, severe, tormenting, tearing, cutting, sticking, lancinating pains. They are often present during rest and become increased on movement or pressure. Pains like those of sciatica and facial neuralgia are observed in hut workers. The paralysis remains longest in the toes. With the beginning of nerve involvement paraesthesias are noted: crawling, formication, numbness with a feeling of rippling in the urethra and disturbanceses of deep sensibility.
The perception of pressure and temperature is often markedly reduced, but the toes and fingers may be hyperesthetic; a sensation of cold may occur; paralysis of the vocal cords, amblyopia, atrophy of the optic nerve with amaurosis are questionable, herpes zoster rare. The tendon reflexes, including the patellar reflexes are lost and may not return even after recovery. The pupillary reflexes may be absent and with the disturbances in coordination which are observed at the time of improvement may present a tabetic-like picture, “Tabes arsenicalis”.
After 8-14 days weakness appears then paralysis which can also involve the back and limb muscles. The muscles most commonly used are most markedly involved and as a rule the extensors more than the flexors. Neck and throat muscles may also participate, more rarely the sphincters.
About two weeks after the onset of the paralysis, atrophy is noted. Electrical investigation indicates the most diverse disturbances up to complete reaction of degeneration. Likewise manifestations of motor irritation are observed: trembling, athetoid movements, spasmodic contractions of the great toe, arms and legs. During the sixth week the paralysis improves but cure may not occur for as long as 5 years; residuals with paralytic contractures may remain.
Insomnia, sensation of vertigo, headaches are frequent, irritation, depression, poor memory occurs, the thoughts are dissociated, indeed stupor may be present, more rarely coma and epileptic states.
The peripheral nerves as well as the central nervous system are considered the point of attack of arsenic. Diseases of the anterior horn cells, degeneration of Goll’s column and alterations in the pons and medulla are found in the spinal cord and a neuritis of the paralyzed extremities has been found repeatedly.
Albumin is found in the urine in considerable amounts, the result of epithelial fatty degeneration. More rarely copper oxide reducing substances are found. Frequently oedema and “dropsy” are reported as terminal phenomena. Pulmonary tuberculosis is often added as a complicating disease.
Occasionally a parenchymatous oophoritis is observed.
Anatomico-pathologically the acute gastro-intestinal form of poisoning is characterized by a hemorrhagic necrotic inflammation of the gastro-intestinal mucous membrane, partly with pseudo- membranous deposits; Peyer’s patches and the solitary follicles are markedly swollen. In the subacute and chronic poisoning the fatty degeneration of the cells in the liver, kidneys, heart, vesssel endothelium, and pulmonary epithelium predominates. At times the spleen is swollen. The adrenal damages are also worthy of note: also inflammatory swelling, hemorrhages, nuclear cell degeneration.
The point of departure for a consideration of the metabolic effects of arsenic is the fact that under long continued small doses in animals and man an increase of weight and sense of strength is observed. Horses are given arsenic by hostlers to obtain increase in weight, animated gait and a glistening coat. Animal investigations with therapeutic doses frequently result in a better appearance, increase of weight and greater growth of the arsenic animal in contrast to controls.
This fact is utilized practically in arsenic eating in Styria, the arsenic drinkers in Whitebeck and perhaps a knowledge of this action is the basis for the use of fumes of arsenic containing tobacco as it is said to occur in certain areas of China.
Even if the increase in weight is often attributed to the improvement in general well being or increased appetite, still this does not explain it entirely. Because the increase in weight is observed with a constant diet so that a direct effect on the dissimulation and assimilation processes may be assumed. In general the basis seems to consist in an increase of assimilatory processes.
The experimental results show a great dependence upon the dose and the individual sensitivity. According to Nishiura 0.005-1 mg. of arsenic in rat investigation nearly always increases the gas metabolism and only exceptionally produces a depression; on the contrary large doses reduce the temperature and the gas exchange. In man chronic arsenic medication (0.01-0.15 sodium cacodylate per day) in general produces a reduction of the basal metabolism. Simultaneously with the decrease of metabolism the weight increases. This is shown most distinctly in men who previously had an increased gas exchange. To these belong particularly those affected by hyper-thyroidism, and they require very careful watching with arsenic medication. The sensitization for arsenic through hyperthyroidism, which we also found in phosphorus, has been experimentally confirmed. In rats fed with thyraden, doses of arsenic produce a reduction of the artificially increased metabolism, which have no effect in normal animals.
Under small doses of arsenic the protein metabolism on the whole shows a tendency to addition and there is lessened nitrogen excretion. Such a conclusion may be drawn from investigations in sheep by Weiske and studies in men with atoxyl give results in sense of a slowing of protein metabolism. On the other hand it has been demonstrated that toxic doses of arsenic always increase the excretion of nitrogen also protein destruction.
In any case with larger doses of arsenic the situation is similar to phosphorus and with smaller doses of arsenic it is still doubtful whether the addition actually involves the protein metabolism. A parallel with the metabolic promotion through phosphates seems likely. Arsenic resembles phosphorus to a great extent in respect to effect on carbohydrate metabolism and the liver action.
The fatty degeneration of the liver found in arsenic poisoning has been previously mentioned. The glycogen content of the liver diminishes very rapidly under arsenic, many times even after a few hours, and moreover before fatty infiltration is recognizable. It seems here as in phosphorus poisoning, that an increase in the blood sugar does not occur, so that here as there, one must assume a utilization of glycogen in the liver itself. The muscle glycogen (according to Rosenbaum l.c.) seems to diminish less in acute poisoning but considerably in chronic poisoning. Glycosuria is not observed constantly in experimental arsenic poisoning, on the contrary (according to Luch singer, l.c) there is an easily provoked alimentary glycosuria, exactly as with phosphorus. On the other side Begemann saw an artificially produced alimentary glycosuria become less and disappear under long continued doses of arsenic.
Likewise an influence of sugar economy certainly exists but the end results are apparently contradictory and dependent upon the dose and the previous conditions. A further proof in the direction of diabetes is afforded by the observation of Hiratas. After subcutaneous injections of arsenic the cells of the islands of Langerhans increase.
Increased amounts of lactic acid in the blood reduce the CO2 content of the blood in arsenic just as in phosphorus poisoning. Increased lactic acid is also found in the liver, muscles, and especially in the intestine and kidneys, moreover also in the urine. This increased appearance of acid substances, lactic acid in particular can also be associated with increased protein destruction as with alteration of carbohydrate metabolism. Nothing is known about the influence of fat metabolism by arsenic except the already mentioned fatty infiltration of the organs and vessels.
On the whole the intermediary metabolic effects of arsenic are very similar to those of posphorus. As with all substances which cause protein destruction in toxic doses, the results are revealed in heat economy. Small intravenously administered doses of arsenic produce an increase of temperature in rabbits. On the other hand the temperature falls considerably after toxic doses. Agents of protein destruction are pyrogenic!
Whether one can draw a hypothesis of the explanation of metabolic effects in arsenic as in phosphorus, wherein the oxidative splitting is depressed and the fermentative anoxybiotic is increased must be left undecided.
In any case reports are available where arsenic has accelerated autolytic processes in the liver. However, Hess and Saxl have seen a depression of autolysis from large doses.
ARSENIC EATING AND HABITUATION
Of special pharmacologic interest is the habitual ingestion of arsenic for the maintenance of health and increase of strength and power. The eating of arsenic for increasing strength was mentioned by Avicenna in 1165. The arsenic eaters of Styria are best known. They are very healthy people, usually men with laborious occupations. They begin eating arsenic at 18 but still reach old age, remain healthy, are happy, combative and sexually potent, which must be traced to the eating of arsenic. The disposition is happy and they regard arsenic as a good remedy against shortness of breath. The ingestion increases and diminishes with the moon; with a waning moon they take aloes in increasing doses until diarrhoea occurs. They proceed so far that they may swallow 0.4 g of arsenic without disturbance (maximal single dose is 0.005 g!). The complete well being of these arsenic eaters stands in sharpest contrast to the severe disturbances in chronic industrial arsenic poisoning. This contradiction is explained by experimental investigation in that with the slowly increasing ingestion of arsenic the intestinal epithelial obtains the ability to prevent or only very slowly absorb arsenic.
The amount excreted through the urine may fall to 0.3 Percent of the quantity ingested. Dogs who have tolerated continuous slow increase of arsenic by mouth for months up to many times the fatal dose die from acute arsenic poisoning from the usual dose when it is administered subcutaneously. Moreover a general cell habituation is not present but the habituation may be based upon the altered intestinal conditions. thus a high grade tolerance to dissolved arsenic introduced into the stomach does not exist as for the administration of a powder.
ACTION ON BLOOD
A favorable action of arsenic in anemias has long been observed but the action has not been explained up to the present.
The influence of arsenic on the number of red blood cells and the hemoglobin content in animal experimentation gives extremely variable findings, some investigators reporting an increase in the erythrocytes and of the hemoglobin, particularly in anemic animals, others find no alteration of the blood and still others
a decrease in the erythrocytes and of the hemoglobin. According to many investigators after medicinal doses in the healthy and sick there is usually a decrease of the erythrocytes, more rarely no change in the count. Here also the damages of the red blood cell picture through an organic arsenic compound must be included, as with atoxyl(the sodium salt of aminophenylarsenic acid). It produces a decrease in the number of erythrocytes and the hemoglobin content, moreover, a poikilocytosis and anisocytosis. This picture of intoxication which is similar to pernicious anemia may also support arsenic therapy of this disease in a homoeopathic sense. The conception that peripherally increased destruction of blood caused an increased regeneration of red blood in the bone marrow seemed at first to find some basis in the marked redness of the bone marrow in chronic arsenic poisoning, but exact investigation speak against the conception. There is no increase in the erythroblasts.
There is a distinct reduction of the oxygen utilization of the red blood cells whereby the anemic cells seem to be more sensitive than the normal, even 0.003 of arsenic acts distinctly depressing. English investigators could prove no increase under arsenic medication, but found that the erythrocytes became much more resistant to hemolysis and therein see the favorable action in pernicious anemia. Thiele could not confirm this report. Perhaps some light is thrown in this connection by investigations on the influence of the thyroid on the increased nitrogen excretion with O2 deficiency and the increased blood formation in high altitudes. It shows that after removal of the thyroid, O2 deficiency does not increase nitrogen excretion and that in athyroidetic animals the high altitude not only does not promote new blood formation but even depresses it. From the similarity of arsenic action to that of high altitudes the thought seems likely that the blood action or arsenic occurs through the thyroid, moreover, feeding thyroid can stimulate the formation of blood. Likewise Isaac believes that the thyroid has special significance in the blood regeneration by arsenic.
Certainly the stimulating action of arsenic on the red blood cells is decidedly dependent upon the previous state, the lability, sensitivity and on the dose. But there is also a destructive blood effect. And thus therapeutic use arranges itself immaterially of the school according to the simile rule.
Likewise the reports of the influence of arsenic on the white blood cells are contradictory. By administration of Fowler’s solution up to maximal doses the number of leucocytes diminishes often up to one half. Thereby the neutrophiles are particularly involved. If the lymphocytes are markedly increased, then they fall distinctly. But these alterations are by no means constant; in other cases the number of leucocytes increases. With toxic doses at first a decrease appears which is soon followed by a hyperleucocytosis if the dose has not been lethal.
That psyche and central and autonomic nervous systems succumb to the action of arsenic is obvious from observations of acute and chronic poisoning.
In his studies Pistorius observed immediately after the injection of arsenic and before the appearance of intestinal irritation, a vomiting which was of central origin in his opinion. Moreover he had the impression in his animals that by gradual poisoning via the subcutaneous route, at first those centers of the brain and medulla which communicate sensory impressions or transmit reflexes from the vessel nerve centers are paralyzed. Perhaps the leucopenia from arsenical medication is obtained through the autonomic nervous system similarly to the leucopenia obtained by intracutaneous wheals.
The respiratory center itself is also involved in arsenic action. Subcutaneous doses at first produce only an increase of respiratory frequency, perhaps a direct excitation of the vagus nerve. The respiratory center is in an “irritated” state so that excitation of the central end of the vagus leads to tetanus of the inspiratory muscles while otherwise only an acceleration of respiration occurs.
Studies by Ringer and Murell on frogs showed that the diminution of reflex excitability is traceable to central paralysis and is not the result of cardiac failure. The excitability of the motor nerves is retained longer, but then is lost and finally the excitability of skeletal muscle. How far the paralytic state in arsenic poisoning is conditioned directly central or from circulatory disturbances is also not as yet determined.
Conduction by peripheral nerves is reduced by arsenic. The paralysis observed in acute arsenic poisoning is probably provoked through a rapidly appearing paralysis of the intramuscular nerve endings. Arsenical neuritis has been observed after therapeutic doses.
HEART AND CIRCULATION
A marked influence of arsenic on the heart and vessels exists beyond any doubt according to the manifestations of poisonings.
Experimentally it has been demonstrated many times that a decrease in the cardiac frequency and finally standstill in diastole is provoked by large doses of arsenic. Very large doses of arsenic can produce an acute paralysis of the heart in which contractions no longer occur after electrical or mechanical stimuli. Loewi concludes from this that a paralysis of the cardiac ganglia as well as the muscle exists. Intravenous injections of large doses in mammals give corresponding slowing of the pulse and falling of the blood pressure, still the action on the blood pressure is not solely dependent upon the heart, but indeed similarly to phosphorus, on the adrenals and on the vascular system, especially on the splanchnics. With small doses of arsenic and subcutaneous injection in warm blooded animals Leeser saw at first an increase in the pulse frequency. We have here also the same conditions as in phosphorus and the phosphites. In the cardiac paralysis after larger doses Leeser found the heart still irritable after some hours, so that according to his experience the heart muscle itself is not paralyzed. According to S.G.Zondek the standstill caused by arsenic can be again removed through calcium ions, while potassium ions increase the action of arsenic.
The capillaries stand under the special influence of arsenic. Arsenic like phosphorus is an outstanding capillary poison. Above all the splanchnic vascular field is prominent arsenic action.
The action involves the capillary wall itself, because, after severe poisoning splanchnic stimuli no longer release any contraction. The intestinal capillary walls are markedly widened and completely filled with blood. There is a high grade stasis oedema with marked exudation which results in a pseudomembranous deposit on the intestinal mucous membrane. The capillaries of the other parts of the body are also involved even if not to the extent of the intestinal vessels. The severe vascular disturbances consist not only in a paralysis but also an increased permeability of the vessel wall. Through this comes the preparation for oedema. In dogs, and in rabbits with an artificial hydremia a marked oedema follows arsenic, an accelerated outpouring of intravenously injected fluid out of the vessels. Transudation occurs also in the pleura, the pericardium and brain ventricles. The peculiar fact that the intestinal wall capillaries succumb to arsenic action so rapidly is not as yet explained. Perhaps it may be associated with the fact that the gastro-intestinal mucous membrane is an important site of excretion for arsenic (even after parenteral introduction). Furthermore it is striking that the organs to which a special capacity for reduction is ascribed, as the intestinal mucosa and the liver also are special points of attack in arsenic poisoning.
GASTRO- INTESTINAL CANAL
The severe manifestation in the intestinal mucous membrane, particularly the large intestine in arsenic is explained most naturally by the capillary action. At the same time a cell damage due to excretion is to be considered just as in the kidneys.
The pseudomembranous deposits in the inflamed intestine consist of dead epithelial cells and hyaline droplets which are embedded in a congealed mass of transudate (pistorius, l.c.). In the small intestine only a hyperemia is found. The early vomiting even from parenterally introduced arsenic will be perceived as a reflex action of the excreted arsenic on the gastric wall. However an increased gastric secretion is observed from arsenic.
An acute inflammatory manifestation in the skin can appear in the form of pemphigus and dermatitis herpetiformis. Arsenical therapy of the affections follows the simile rule. The skin manifestations in poisoning are likewise observed in animal experimentation, especially erythematous eruptions and falling out of hair. Of particular interest is the communication reported by Geyer on the so-called Reichen-steiner disease which is produced by drinking arsenic containing waters. It is expressed by melanosis and hyperkeratosis. These chronic actions appear only after prolonged use of the water, while people newly arriving in the district react with intestinal catarrh and other digestive disturbances in the first few weeks. The hyperkeratosis, like psoriasis and lichen on the other side form a well known indication for arsenic, not only in homoeopathy but also in non-homoeopathic dermatology.
The formation of pigment, arsenical melanosis, is individually very different. Wherever the arsenic solution comes into contact with the pigment cells, a pigmentation appears after an interval. This pigment consists of melanin. However there is probably a connection between the formation of pigment and adrenal injury arsenic.
The persistent injection of an alcoholic arsenic solution continued over months into the grey mouse leads to a keratotic flat epithelial cancer. In other cases injection of arsenic is without influence. In regard to the severe damages of coal workers Belgian students have found arsenic regularly up to 0.06 Percent of the final product of coal and likewise in aniline dyes. The experimentally produced tar carcinoma, however, can hardly be traced to coal arsenic since arsenic-free tar produces carcinoma. It is well known that since antiquity (in Egypt, India, Greece and later Arabia) arsenic has always been employed as a cancer remedy, especially by means of external application. Paracelsus states that the cause of cancer is “a natural arsenic” and therefore he employed realgar against foul ulcers. This use has continued to the present in the form of Zeller’s paste and Poljsak’s salve which has been tested and recommended by Aschner. Arsenical keratitis and arsenical melanosis have actually been suggested as internally produced precursors of carcinoma. Moreover the malignant lung tumors (lymphosarcoma) in arsenic workers are considered the result of arsenic action. Arsenic may also just as roentgen and radium rays produce cancer as well as heal it under certain conditions.