Lead poisoning and lead absorption

TABLE XII.—FEEDING EXPERIMENTS.

TABLE XIII.—INHALATION EXPERIMENTS.

The experiments definitely bring out one all-important fact—namely, that lead dust circulating in the air is many times more dangerous than lead actually swallowed; for even if the animals which were exposed to the inhalation of dust swallowed the whole of the quantity contained in the respired air, they would only obtain one-tenth of the amount the other fed animals were getting. It is, of course, impossible to suppose that the whole of the lead contained in the inhaled air reached the lung. It can only have been the smaller particles which did so. Therefore the ratio is many more than ten times between the fed and the inhaling animal; in all probability only one-tenth of the contained lead in the respired air reaches the lung. Under these circumstances the ratio of poisoning via the lung to poisoning via the intestinal canal is as 100 : 1.

Table XIII. deals with the question of inhalation.

Every care was taken during these experiments to avoid any vitiation of such experiments by the actual swallowing of lead dust by the animals exposed to breathing. Moreover, all the animals were carefully controlled, in that an animal of somewhat similar weight at the same time was subjected to the ingestion of the same lead compound, but in much bigger quantities, via the mouth.

It will be seen immediately, on comparing Tables XI. and XII. with Table XIII., that the rate of poisoning by means of dust is greatly in excess of the rate of poisoning by feeding, even where poisoning by feeding actually occurred. Also that the amount of dust present in the air inhaled shows a marked correlation with the date of appearance of the first symptoms of poisoning, and that where the quantity of dust is very much reduced the poisoning was delayed longer than might have been expected, and that when poisoning did appear the symptoms were much less pronounced than with the more dusty atmospheres; and this although the quantity of lead obtained would be relatively the same over the range of time the animals were exposed.

The knowledge gained in dealing with industrial poisoning clinically receives very strong corroboration from these inhalation experiments, for it is a well-known fact that many persons engaged in dusty trades exhibit a species of immunity to lead poisoning. It is true that some susceptible persons, as has already been pointed out, very rapidly show signs of poisoning, even with a dosage producing no effect in other persons working under similar conditions; and it is highly probable that these persons have arrived at a species of equilibrium by which they are able to excrete the lead ingested, and so prevent any accumulation and general damage to their tissues. Directly, however, the dosage is increased, signs of poisoning come on, as in the case of animals Nos. 10 and 11. For some seventy to eighty days little or no sign of poisoning was seen with the small dosage commenced with. At the end of this time, as no symptoms appeared, the quantity of lead in the air was increased, with the result that poisoning rapidly became manifest.

We have also in these inhalation experiments, in Cases 21 and 22, definite evidence that a low-solubility glaze—that is to say, glaze containing fritted lead—is capable of setting up lead poisoning when taken via the lung, as when such glaze is inoculated, although it produces no such symptoms when given via the mouth, except, perhaps, when it is complicated by excessive alcohol.

Symptoms exhibited by Experimental Animals.

—The cat is peculiarly susceptible to lead poisoning. In lead works it is impossible to keep a cat any length of time, as it rapidly dies of poisoning.

All the animals subjected to lead absorption, and definitely suffering from symptoms of lead poisoning, exhibited the following symptoms:

1. Slight increase of weight over the first period of poisoning, lasting from one to three weeks.

2. A progressive diminution in weight, progressing until the animal exhibited definite signs of poisoning.

3. Wasting, especially of the spinal muscles (the erector spinæ and in the lumbar region), out of proportion to the determined loss of weight; pinched facies, with frequent exhibition of running from the eyes and nose, even when not exposed to the action of lead dust, merely by inoculation.

4. Various types of paralysis, particularly in the cat; the muscles of the back and of the quadriceps extensor of the hind-legs show signs of paralysis. In the cat the quadriceps extensor is paralyzed sooner than the extensor communis digitorum in man. The cats show loss of power in the hind-limbs by inability to jump. The reflexes, particularly the knee-jerks and elbow-jerks, are first of all increased, and latterly become lost.

The chief and main sign which was noted in the histological examination of the animals inoculated was one of minute microscopical hæmorrhages (this has already been referred to); these hæmorrhages were not confined to any particular position in the body nor to any one organ. In the animals which showed symptoms of epilepsy, occasionally thickening of the pia mater was found, but invariably in such cases small hæmorrhages were found immediately under the arachnoid, not covering any great area, but apparently causing pressure upon small areas of the cortex. In others, again, the hæmorrhages were found lower down in the brain, and a few in the spinal cord. At times a large amount of hæmorrhage was to be found present at the base of the brain, spreading downwards from the medulla into the spinal canal, but this only occurred in such animals as died with encephalopathic symptoms. In animals which had signs of more chronic poisoning—that is to say, gradual loss of body weight, emaciation, constipation, contraction of the abdomen, and paresis, particularly of the hind-limbs and the muscles of the back—hæmorrhages were found in the muscles, liver, spleen, lung, heart, various positions in the abdomen, in the spinal cord, in the nerve-supply of the affected muscle, and even in the brain, none of them large enough to produce absolute destruction of more than a very minute portion of the organ in which they were situated.

Now, all these symptoms, and, more important still, the phenomena of hæmorrhage, were found in all the animals which exhibited similar symptoms, whether they were poisoned by inhalation of dusty lead compounds or fed upon lead compounds associated with alcohol; but even in some of the animals which were fed upon lead compounds—particularly white lead—and which had exhibited no definite symptoms of paralysis, or, for that matter, any symptom referable to poisoning, here and there slight histological changes which were referable to minute hæmorrhages.

The experimental work therefore carries us very considerably forward in correlating the symptomatology and pathology of lead poisoning. The symptoms produced in susceptible animals by the actual inoculation of a lead compound differ only in degree and rapidity of onset from those produced in animals submitted to inhalation with similar compounds. Feeding, on the other hand—that is, ingestion by way of the gastro-intestinal canal—even in large quantities, did not produce poisoning to any great extent, except when some material such as alcohol was added, thereby breaking down the animal’s resistance. Another interesting fact is given—that if lead is taken by the mouth in addition to milk a great deal of the poisonous effect is got rid of; thus of two animals—Nos. 46 and 47—which received lead nitrate in their food, the one in water and the other in milk, the one which received it in milk showed no effects even after four months’ experiment, whereas at the end of four months the animal which was receiving the compound in its water died. This brings out a point already insisted upon—namely, that in all lead factories it is highly important that no work should be undertaken first thing in the morning, before the workers have had a proper meal, and that in the absence of a proper meal milk is the best substitute. It is highly probable that the soluble lead salt becomes united in some form of albuminate which is dealt with later, and perhaps turned into a sulphide and excreted without absorption. There is no possible doubt, from the large series of experiments which I have performed, that lead inhaled is far more poisonous than when absorbed in any other way; further, that the amount of poisoning produced differs somewhat according to the type of compound inhaled, and the experiments, moreover, give some suggestion as to the dose which is likely to produce poisoning. It is seen, where the animal is inoculated with white lead, the dose required to produce symptoms is below 1 gramme per kilogramme of body weight, but above 0·2 gramme per kilogramme of body weight. In feeding, 0·8 gramme, and even 1 gramme, per diem for eighteen months produces no effect, although the same quantity plus an excess of alcohol rapidly produces the disease. On the other hand, as small a dose as 0·1 gramme of nitrate of lead given in water for four months produced death.

Turning to the inhalation experiments, the quantity of dust breathed when as high as 0·0007 gramme per litre produced symptoms after only twelve inhalations for a period of about thirty-seven days; whereas when the dose was reduced to 0·0001 gramme per diem the time required to produce symptoms of poisoning was 120 days; in fact, this last dose (0·0001) for the animal under experiment was almost the lower limit, as this animal showed an almost steady line of weight for a considerable time, the weight remaining up for the first hundred days, a slight variation taking place from week to week until a progressive diminution set in.

Practically all the animals poisoned manifested a very distinct diminution in body weight; in four only other symptoms of poisoning appeared first. This is a fact that is often to be noted amongst lead-workers, and if a progressive diminution in weight takes place, there is strong reason for supposing that a considerable alteration in the metabolism of the body has taken place; but it does not follow that microscopical hæmorrhages or other definite effects of poisoning are present, although such is probable.

Finally, in summing up the conclusions to be drawn from the above experiments, it has been suggested that such experiments as inoculation, experimental inhalation, or even feeding, are no criterion of the circumstances under which industrial workers become infected with lead. It is perhaps hardly necessary to refer to this point, but for the fact that it is possible this book may be made use of by those who are not in the habit of dealing with experimental pathology. One of the first and most important matters in dealing with any form of poisoning is to obtain knowledge of the actual symptoms both clinically and physiologically, as well as pathologically, of the effects of any drug, and to determine if the symptoms so produced in an experimental animal conform to the symptoms as seen in man. For the purpose, therefore, an animal is required which is susceptible to the poison, and therefore cats were used in the foregoing experiments, as it is absolutely impossible to keep a domesticated cat in any white lead works, for the animals invariably become poisoned by lead.

The second point in prosecuting an inquiry into the pathology of any disease is to determine the train of poisoning when definite dosage, both in quantity and compound, is made use of. By feeding an animal with a compound only, the absorption through the gastro-intestinal canal could be studied; whereas by inoculating some of the compound—in suspension if it be insoluble, or in solution if it be soluble—into the subcutaneous or muscular tissue, the direct action of the body fluids on the compound may be studied; and, furthermore, its absorption by the membranes—that is, the cell membranes and the animal tissues—are determined. It is necessary to give at first a dose big enough to produce definite symptoms, and then to gradually decrease the dose to find the minimum amount producing symptoms within a reasonable amount of time. Inoculation experiments therefore give an answer to a number of these questions, and are the basis upon which further inquiry is conducted; they form a criterion from which it is possible to judge the effect of inhalation, and the same remarks which have been made with regard to inoculation refer to inhalation experiments. It is essential first of all, in the experimental animals, to subject them to rigorous enough conditions to obtain definite symptoms, and then, by varying the experiments, to study the amount, entrance, and general behaviour, of the poison, correlating the evidence so obtained from the definite knowledge already gained with the previous experiments.

It is hoped that this brief note on experimental evidence will assist in the elucidation of the foregoing experiments to those who are not conversant with the application of experimental evidence.

Further Experiments relating to Lead Poisoning amongst Painters.

—A series of further experiments were made, with particular reference to lead poisoning exhibited by painters; and as these experiments and their results could not have been undertaken without the previous knowledge gained of the pathology of lead poisoning due to the inhalation of particles of dust floating in the air, their discussion has been reserved until the previous section had been dealt with.

It has been supposed by some that surfaces painted with lead paint give off certain emanations containing the metal lead as an organic compound. As the incidence of lead poisoning amongst painters is exceedingly high, as far as any statistical evidence can be obtained (see p. 48), it would seem that the painter is peculiarly exposed to infection by lead dust; and if, in addition, organic compounds of lead were given off, he would be still more liable to lead poisoning.

Two methods of experiment were used:

1. The exposure of animals to the fumes given off from freshly painted surfaces, the paints used being compounded with white lead, lead sulphate, zinc sulphide, and zinc oxide.

Animals were exposed in a cage similar to that used in the inhalation experiments previously described, but, instead of blowing in the contaminated air, the cages were so arranged that boards freshly painted with the special paint under experiment were introduced into the cage daily, the animals remaining the whole time in the chamber. Special precautions were taken with regard to ventilation.

2. An animal was placed in a chamber, and the compound to be tested was heated electrically by means of a coil surrounding the glass tube in which the compound was placed. The current was regulated by means of resistances, so that the thermo-couple and galvanometer gave a constant reading of 59° C. Air was constantly passed through the tube over the heated substance and into the animal’s cage, which was efficiently ventilated. In this way any emanations which were given off from the normal room temperature or up to 59° C. were carried over into the animal’s cage, and there breathed. The apparatus was so arranged that the heating coil extended close to the point of delivery into the cage.

The result of these experiments showed that the animals confined in cages and exposed to freshly painted surfaces, where the paint used was white lead, zinc oxide, or lead sulphate, very soon showed signs of poisoning, and they became emaciated and suffered from recurrent attacks of salivation. The animals exposed in the cages in which air was passed over either white lead paste, zinc paste, or lead sulphate paste, showed no signs of illness, although kept in the cage and subjected to the inhalation of any fumes which might be given off for three months, spending the whole of the day in the cage, but being removed during the night to separate cages.

It therefore seemed clear that, whatever illness was produced in the animals exposed to fresh paint, they were not suffering from absorption of lead, but of some other compound of which the paint was made. Various constituents of the paint were therefore tried—namely, the metallic bases, lead or zinc, and linseed-oil, with turpentine and lead acetate mixed with turpentine. The animal exposed to the turpentine alone very rapidly showed signs of disease—salivation, a tendency to diarrhœa, strabismus, but the latter only after a two-hour exposure, whilst the quantity of turpentine present in the cage air did not exceed 10 milligrammes per litre.

The animal exposed to turpentine and lead acetate exhibited few symptoms, but the same in kind as the animal exposed to turpentine alone. The linseed-oil animal showed no signs of disease whatever. The animals exposed to the metallic bases of the paint—namely, zinc oxide or white lead—showed no signs of poisoning as long as the compound itself was not thrown into the air in the form of dust; but when lead dust was present in the air the animal rapidly showed the ordinary signs of lead poisoning. The animal exposed to zinc oxide dust showed very little sign of discomfort, but by prolonged exposure early kidney disease was produced, and signs of chronic inflammation were detectable in the lung.

It is interesting to note in this connection that Lehmann[7] describes symptoms produced in cats when exposed to the vapour of turpentine. The animals which I exposed to turpentine vapour exhibited the same symptoms as those described by Lehmann. He gave no result of the histological inquiry of the animals so exposed, but in no case, apparently, was the animal killed after exposure. In my animals exposed to the vapour of turpentine very definite disease of the kidney was produced, the inflammation tending rather to the tubular than the interstitial variety of nephritis. The tubules were found blocked with débris, their contour irregular and destroyed, and their substance pale and almost hyaline; whilst areas of cloudy swelling, together with small hæmorrhages, were to be found scattered about the kidney. The heart muscle was flabby, and the heart tending to dilatation; whilst microscopically hæmorrhages could be found throughout the organ of a minute capillary nature, and passing between and disturbing the muscle bundles.

No changes of any sort were found in the tissues of the animals exposed to the emanations given off from white lead paste. By analyses these emanations were found to contain no lead, but traces of aldehyde, formic acid, and CO₂. It follows, therefore, that the effect of turpentine when inhaled by the painter must be to act as a contributory cause of lead poisoning, and it is interesting in this connection to recall the fact noted on p. 38, that Garrod has described gout as occurring constantly among painters. The statement already quoted, that gout is not common among workers in white lead factories, where the exposure to lead is very much greater than among painters, points to turpentine as the cause of the increased incidence of gout among house-painters rather than lead absorption. The importance of dust containing lead as a source of illness and lead poisoning in painters must not be minimized, as in sand-papering, etc. (see p. 137). The importance of lead dust inhaled in this way is perfectly understood. It is, however, highly probable that the combined action of the turpentine with the lead accounts for the fact that headache is a common symptom of early disease in painters, which is not the case among white-lead workers.

REFERENCES.