CHAPTER VI_Lead poisoning and lead absorption

PATHOLOGY--_Continued_[A]

[A] This chapter is the work entirely of one of us (K. W. G.)

It was thought that some light might be thrown on chronic intoxication

produced by lead salts if direct experiment were made upon animals,

resembling in the arrangement of such experiments, as far as possible,

the industrial conditions under which human beings contract lead

poisoning.

The animals chosen for the experiments were cats, as it is a fact of

common knowledge that it is impossible to keep cats in lead works,

particularly white-lead, because they rapidly become poisoned if

allowed to stray about the works. The same holds good in the case of

dogs.

From the statistics already given in Chapter IV., and from the remarks

in the chapter on Ætiology, there was no doubt whatever that dust

played a most important rôle in the production of industrial lead

poisoning. In attempting, therefore, to copy the industrial conditions,

it is essential to submit the animals experimented upon to infection

by means of air in which lead dust is suspended. A large number of

experiments have been carried out in the first place, by myself[1],

and later in conjunction with Dr. Goodbody[2], and another series of

experiments were also undertaken by myself[3]. Further experiments are

still in progress in this and other directions.

The methods of experiment adopted were as follows:

1. =Breathing Experiments=--_First Series._--A. The animals

experimented upon were placed in a large closed chamber at one end of

which an electric fan was fitted in such a way that the air was kept

in constant motion. The lead dust was introduced by means of a funnel

through the roof in a definite quantity during timed intervals. By

means of an aspirating jar and a tube inserted into the side, samples

of air were withdrawn from time to time during the experiments, and

submitted to chemical analysis to determine the quantity of lead

circulating in the air. These samples were drawn off at the level of

the animals’ heads. Great care was taken to eliminate any swallowing of

dust by the animals during the experiments, by protecting their coats

from the dust and carefully brushing them at the conclusion of each

exposure.

_Second Series._--B. In other experiments a chamber containing two

separate compartments was constructed, and lead dust suspended in

air was blown into the two compartments by means of an electric fan

situated outside. The apparatus was so arranged that the draught of

air from the fan passed through two separate boxes, in which the lead

compound under experiment was kept agitated by means of small fans

situated in the boxes and driven by a second electric motor. In this

way two different samples of lead were experimented on at one and the

same time, the air current driving in the dust through the two boxes

being equal on the two sides; the quantity of dust was therefore

directly proportional to the compound used. Samples of the dusty air

were aspirated off and subjected to analysis, as in the first series.

In this series of experiments the animals were so arranged that only

their heads projected into the dust chamber during exposure.

2. =Feeding Experiments.=--Feeding experiments were carried out by

mixing a weighed dose of the lead compound experimented with, and

adding this to a small portion of the animal’s first feed in the

morning. It was found that unless the lead was well incorporated with

the animal’s food it would not take the lead in the dry form; and in

dealing with white lead and other dust, it was necessary to give the

compound in a similar form to that in which a man would obtain it under

industrial conditions, which of course precluded the use of a solution.

The amount of lead given by the mouth as a control to the inhalation

experiments was from seven to ten times the dose which could be taken

by the animal during its exposure in the cage, and the dose was given

daily, and not every third day as in the inhalation experiments. All

the compounds used in the inhalation experiments were given to animals

by the mouth, the animals’ weights being carefully noted.

In a further series of feeding experiments a soluble salt of lead

was added to the animals’ food (water or milk), the salt in this case

being the nitrate. The quantity added was much smaller than in the dust

experiments. 0·1 gramme was given daily.

3. =Inoculation Experiments.=--As a further control to both the

breathing and feeding experiments, the various lead compounds similar

to those used in the other experiments were inoculated into animals.

The insoluble salts gave some difficulty in the technique of injection,

but by using a large needle, and making the suspension of the material

in the syringe, the difficulty was overcome. The quantity of material

inoculated varied; it was calculated in fractions of a gramme per

kilogramme body weight, the quantity of fluid used being the same in

all cases--namely, 10 c.c.--and inoculations were made subcutaneously

and intramuscularly in the muscles of the back after previous shaving.

In only one case was localized inflammation produced, and this was when

the acetate was the salt employed.

None of the animals exhibited any signs of discomfort during the

experiments from the presence of lead dust in the air; once or twice

sneezing was noticed, but this was an uncommon occurrence. This point

is of practical importance, as the lead dust contained in the air in

white-lead and other factories is not of itself irritating to the

mucous membrane of the lung. The animals subjected to this form of

experiment were no doubt absorbing much larger doses of lead than are

persons engaged in the manufacture of lead compounds.

The only ascertainable difference in the ultimate pathological lesions

produced in animals, whether inhaling large quantities or minimal

quantities of dust, was the rate at which the poisoning took place. In

certain experiments it was found that the animals maintained a kind

of equilibrium, much as do workmen engaged in dusty lead processes.

It was found, moreover, that some animals showed a certain amount of

tolerance to the effect of lead dust, in that their weights remained

almost constant, but an increase in the quantity of lead present in the

air immediately produced progressive diminution in the body weight; and

as this diminution in the body weight approached to one-third of the

animal’s initial weight, so symptoms of chronic poisoning supervened.

In addition to the animals inhaling lead dust over prolonged periods,

certain other inhalation experiments were made for the determination

of lead dust in the lung as opposed to the stomach. In the inhalation

experiments proper, where the animals were exposed to inhalation every

other day or every third day, for only an hour at a time, the quantity

of lead present in the air was not very large, and it was thought

essential to determine if, in exceedingly dusty atmospheres, any

appreciable amount of lead could be found in the stomach. Ten animals

were submitted to the inhalation of air heavily charged with various

types of lead dust. The animal was exposed to the dust for an hour

and a half to two hours; at the end of this time it was anæsthetized,

and when the respirations had ceased, and the animal was dead,

sulphuretted hydrogen was blown into the lung and into the stomach.

The animal was then rapidly dissected and staining looked for. The

tissues were further treated with acid and re-exposed to sulphuretted

hydrogen gas. In one animal only out of the ten was any staining

noticed in the stomach. In none of the others was any such staining

found, but very definite blackening was found in the larynx, trachea,

and macroscopically even in some of the bronchioles. Sections of the

lung were further submitted to histological examination, and by means

of micro-chemical tests with chromic acid and with iodine, and also

by comparing sections of the experimental animals and animals which

had not been subjected to lead dust inhalations, a very much larger

quantity of material was found present in the lungs of the inhalation

animals than in the normal animal. The dust was situated in the alveoli

and the alveolar cells, and often in the lymphatics. On examining

microscopically sections of the lungs of those animals exposed to

graduated inhalation over extensive periods, a far larger number of

blackened granules, dust, pigment, and other substances, was found than

in similar sections of animals which were under normal conditions and

had not been exposed to lead dust, although it is true such animals

show a very fair proportion of carbon particles taken up by the lung

tissue.

A further important fact was noticeable in animals Nos. 21 and 22

(see p. 101), which had been exposed to a low solubility glaze such

as is used in the Potteries. Low solubility glaze is compounded with

lead frit--that is to say, a lead glaze (or lead silicate) which has

been finely ground. The particles of this substance are much larger

than those of ordinary white lead, and in addition they are much more

angular. Of three animals exposed to this glaze, one actually died of

pneumonia (acute), and the other two suffered from some bronchial

trouble, both of them showing distinct signs of pneumonic patches and

old and chronic inflammation when examined histologically; whereas in

none of the other animals exposed to white lead dust or to the high

solubility glaze, which contained white lead as opposed to lead frit,

no such pneumonic or fibroid changes were found. This point is of some

pathological importance.

The inhalation experiments also throw some light on the quantity of

lead necessary to produce poisoning. The animals in the inhalation

experiments were exposed for varying periods, and constant estimations

made of the lead present in the air. In a number of instances samples

were taken from the cage air during the whole of the experiment, as

rapidly as possible. The quantity of lead floating in the air was found

to increase as the experiment progressed, although a large amount of

the lead introduced was caught on the side of the cage and deposited on

the floor.

In the later experiments the method of taking the samples continuously

during the experiment was abandoned, and four samples only were taken,

and the average recorded. A simple calculation will give the quantity

of lead dust it would be possible for an animal to inhale during the

whole of this period of exposure. The utmost tidal air in the case of a

cat would be taken at 50 c.c. Taking the average, about 0·27 gramme of

lead was inhaled during the half-hour of exposure.

=Feeding Experiments.=--Twelve feeding experiments of various types are

recorded. The method of experiment was as follows:

The compound under investigation was carefully weighed out each day

(0·5 to 1·0 gramme), the substance being some of the same compound

that was being made use of for inhalation experiments. In the case

of the white lead it was found essential to mix it with the animals’

food; they were given white lead in a small amount of their food, and

no further food was given for some little time after the dose of lead

had been swallowed. Low and high solubility glazes were also made

use of for feeding, and as a further experiment alcohol was given to

the animals in addition to the previous course of lead inhalation or

feeding, and the exposure to lead continued after the alcohol was

given. In addition to high solubility glazes, white lead, and flue

dust, a soluble salt of lead was also used, in one series the salt

being the nitrate. 0·1 gramme was given daily; and it is these two

nitrate animals (46 and 47) which showed distinct differences from the

white lead and other feeding experiments. In one case the lead was

given mixed with water, in the other mixed with milk. The animal which

was fed with the nitrate dissolved in water developed encephalopathy,

whereas the one in which the substance was mixed in milk exhibited no

signs, though fed for a similar period. Both the animals increased in

weight, which is an unusual effect in experimental lead poisoning.

The question of the addition of milk, which apparently prevented the

absorption of lead, is of very considerable importance, as it is highly

probable, as has been pointed out with regard to the precipitation of

lead by means of organic substances, that the albuminoid substances in

the milk precipitate the nitrate already in a state of solution; and it

may be argued from these experiments that mixing the white lead with

the food would tend to prevent the lead having a toxic or deleterious

effect, but even when the lead was given in the form of pills between

meals no poisonous effect was noticed. Further, the quantity of white

lead given was considerable, and it is highly questionable whether

the quantity of lead so taken would be dissolved by the gastric

juice excreted under normal circumstances in its entirety, as a

very considerable quantity would pass onwards through the pylorus

undissolved. Until the lead compound has become soluble it cannot react

with the albuminoid constituent of the food. Ordinary dry white lead or

litharge does not combine directly with albumin.

The majority of the experimental animals showed alteration in weight.

The most important point which is brought out by these experiments,

considering them from the point of view of inhalation, is the enormous

quantity of white lead the “feeding” animals swallowed without

producing any apparent symptoms. The quantities cited are the amounts

given per diem, whereas in the inhalation experiments the animals

were rarely exposed more than three days a week for an hour at a time

(see table, p. 101). The quantity of lead, therefore, given by the

gastro-intestinal canal was at least ten times as much, in many cases

fifteen or twenty times as much, as could be taken by the other animals

via the lung during inhalation, and yet these animals showed little or

no susceptibility to poisoning when fed with white lead or other lead

compounds, unless alcohol was given in addition.

An examination of the stomach after death showed, in the case of the

alcoholic animals, distinct evidence of gastritis, and there is some

reason to suppose that in such animals a degree of hyperacidity may

have existed, thereby promoting the rate of solution of the lead.

The increased susceptibility to lead poisoning through the agency of

alcohol is interesting. No. 6 received, in addition to its inhalations

or period of exposure in the dusty air, 50 c.c. of port wine per diem.

Symptoms of lead poisoning appeared a day sooner than in any other

animal, and if we eliminate this experiment, as the dust (flue dust

from blast-furnace) contained also arsenic and antimony, three days

sooner than the litharge animal, and twenty-five days sooner than the

other animals exposed to white lead dust. In addition, this animal was

the only one which actually died during the period of experiment; all

the other animals were killed at the end of two months and submitted

to histological examination; but the animal which had received alcohol

died with symptoms closely simulating lead encephalopathy in man. The

predisposing action of alcohol is still further emphasized by the

subsequent experiments with three animals exposed to white lead dust;

one was exposed thirty-seven and the other thirty days before symptoms

appeared, whereas when alcohol was given poisoning was apparent within

twelve days, and after only four inhalations.

In the case of animals fed with white lead, one after eight months,

and the other a year and a half, showed no signs of lead poisoning

at all, while the weights remained constant. At the end of this time

alcohol (50 c.c. of port wine) was added to the animals’ diet, and one

month after the addition of alcohol to the diet, the dose of white

lead being continued constant, encephalopathy ensued. In a second case

the animal was started on alcohol in addition to the white lead. In a

month it was showing signs of slight paresis. Again, an animal fed on

a low-solubility frit consisting of ground-up lead silicate, showed

no ill-effects after receiving a daily dose of this compound. At the

end of this time alcohol was added to its diet, and six months later

the animal developed symptoms of cerebral involvement, which continued

at intervals until a fatal attack of encephalopathy at the end of a

year. There is thus definite evidence to show that the addition of

alcohol to the animal’s diet undoubtedly hastened and determined the

appearance of lead poisoning, and this, taken in conjunction with the

inhalation experiments previously cited, is very strong evidence of the

increased susceptibility to lead poisoning produced by alcohol. This

supersensitiveness to lead through the medium of alcohol is a matter

of clinical experience to most persons who have had experience of

industrial lead poisoning, particularly those who have been engaged in

the routine examination of persons working in factories.

=Inoculation Experiments.=--In order to control both the feeding and

the inhalation experiments, and more particularly to obtain direct

information of the effect of lead upon the body tissues, resource was

had to the inoculation of the various lead compounds tested--namely:

(1) White lead, (2) litharge, (3) lead frit. These three compounds are

the three types of lead salt which are used in the Potteries, whilst

white lead and litharge are the compounds causing industrial poisoning

in the largest proportion of cases in other industries. As a further

control, the more soluble lead salts were also made use of--namely,

acetate, nitrate, and chloride--mainly for the purpose of establishing

some standard of poisoning both in rate and dose.

Several rather unexpected results were derived from the inoculation

experiments, which will be referred to.

The method of inoculation was to suspend the lead compound to be

tested in normal saline solution or distilled water. The animal was

then shaved, and the lead compound inoculated into the muscles of the

back. The corrosive action of these lead salts was avoided by using a

considerable quantity of diluent.

Lead frit is a constituent of low-solubility glaze--that is to say, a

glaze which has not more than 5 per cent. soluble lead when subjected

to the standard test of exposing 1 gramme of the glaze to a litre of

0·04 per cent. hydrochloric acid for an hour at room temperature. The

frit which was the constituent of this glaze is produced by heating

together litharge or lead and silica, the production being a yellow,

hard, glaze-like material looking very much like sugar-candy. It is not

by any means a compound of lead and silica of simple composition, as

different samples show a wide variation in their lead content; whilst,

in addition, the mode of its formation closely resembles that of an

alloy or amalgam, and allows of the formation of a eutectic entangling

in its meshes both of the constituents of which it is formed, so

that a certain amount of free lead, in addition to the silicates of

various descriptions, are present. At the same time the compound is

highly resistant to the action of mineral acids, and, of course, much

more insoluble and refractory than white lead, litharge, or other

lead oxides. The body fluids, however, particularly the fluids in the

subcutaneous and muscular tissue, definitely exert some action upon

this fritted lead, and it was found experimentally that symptoms of

poisoning could be produced in the experimental animals when even small

doses were administered. A gramme of frit was inoculated, and in all

but one case the animals showed definite signs of lead poisoning, and

in two instances actually died with symptoms of encephalitis.

By washing the frit with distilled water, a slight diminution in the

poisonousness was found, but by washing the frit with two or three

changes of dilute acetic acid (3 per cent.), and then with distilled

water, no pathological results followed inoculation. Water-washing

frit alone definitely reduces the poisonous effect, but not to the

same extent as the preliminary washing with acetic acid. On the other

hand, washing with hot water had a much greater effect than cold-water

washing.

Further evidence given by the inoculation experiments shows the

relationship between the more soluble and the insoluble lead salts.

The dose of acetate required to kill an animal was about 0·1 gramme

of acetate per kilogramme body weight. On the other hand, 0·1 gramme

of white lead produced no ill-effects, 0·5 gramme per kilogramme body

weight produced death in about two months. In addition, those animals

suffering from the more acute forms of poisoning developed definite eye

changes and retinal hæmorrhages. Tortuosity and increased size of the

retinal vessels were observed in several instances.

Besides controlling the experiments of feeding and inhalation, the

inoculation experiments play a still more important part, as they

furnish the correlation, necessarily, of the histological changes found

as the result of poisoning by means of lead. In all the animals which

have died of poisoning, certain definite trains of symptoms made their

appearance. These symptoms were in practically all particulars similar

to those observed in industrial lead poisoning in man, the onset of the

affection and its clinical course corresponding to the symptom-complex

in man, including those of cortical involvement, and often similar to

the classical Jacksonian variety.

Throughout these experiments the animals exhibited no signs of

irritation, and during the initial period, even, when loss of weight

was a noticeable feature, their appetites remained exceedingly good;

they were quite friendly, and purred loudly when stroked; but when

symptoms of poisoning became manifest, particularly the onset of

paralysis, a definite change in mental phenomena took place: the

animals became quarrelsome, highly apprehensive of danger without

cause, morose and lethargic by turns. At this stage, in more than

one instance, acute encephalopathy supervened. The mental change was

peculiarly striking in reference to Mott’s case, quoted on p. 71, as

in all respects it was exactly analogous with the train of symptoms

recorded in that case. To sum up, the symptoms produced in the

experimental animals by the lead compounds inoculated and respired, no

matter what the particular compound of lead experimented was, were as

follows:

1. Slight preliminary rise in weight at the commencement of the

experiment, lasting from one to two weeks.

2. Progressive loss of weight, mainly due to the disappearance of all

fat, subcutaneous, kidney, mesenteric, etc., with associated anæmia,

and the curious sunken and pinched faces commonly associated with

saturnine cachexia.

3. Paresis of various types.

In the cat the muscles first affected are those of the back and the

quadriceps extensor of the hind-limbs. The onset of the paralysis is

slow and insidious, but may be acute; as a rule weakness in the muscles

of the lumbar region and the spine are the first symptoms; secondly,

inability to jump, owing to the weakness of the quadriceps extensor,

while the animal tends to fall over when turning round quickly.

Encephalitis occurs, and is frequently fatal. As a rule the affection

is unilateral; complete loss of consciousness may occur, followed by

slow but complete recovery. The animals gave no evidence of suffering

pain, and, when recovered from an attack of encephalopathy, would at

once take milk, but seemed dazed and uncertain in their movements. When

the animals reached the stage of paralysis, they were destroyed under

anæsthetics, and subjected to post-mortem examination. The post-mortem

findings of a typical case were as follows:

The animal was emaciated, the fur easily pulled out, and the muscles

were exceedingly flaccid.

Rigor mortis was slow in making its appearance; the blood remained

fluid for a considerable time.

Practically no fat was to be found in the whole of the mesentery,

and the omentum was devoid of fat and shrivelled. The fat around the

kidneys had entirely disappeared. There was little orbital fat.

The peritoneum was thin and glistening, and very frail.

The whole of the mesenteric vessels, particularly in the region of the

large intestine and the ileo-cæcal valve, were engorged with blood;

whilst in the lower part of the small intestine, and often in the

duodenum, occasionally in the whole of the jejunum and ileum, traces of

minute hæmorrhages were found along the intestinal wall.

The liver was engorged with blood, as was the spleen.

The kidney capsule stripped easily, but was occasionally adherent here

and there. The whole of the cortical vessels were injected with blood,

the branching showing most distinctly.

A good deal of serous fluid was at times found underneath the kidney

capsule.

On section the cortex appeared engorged with blood, and showed here and

there, even to the naked eye, small hæmorrhages.

In the region of the appendix a few large mesenteric glands were

invariably found, whilst a few glands might also be found in the wasted

mesentery of the small intestine. In the region of the appendix the

glands were frequently dark in colour. On opening the gut, minute

hæmorrhages and ulcerated patches were to be found in the lower part of

the ileum; the ileo-cæcal valve, and the whole of the large intestine,

extending right up to the end of the appendix, was covered with a dark

slate-blue slime, in which lead could be easily recognized by chemical

processes.

Ulceration of the gastric mucous is uncommon, and only on one occasion

were any hæmorrhages found. In the thoracic cavity the lungs were

generally found to be emphysematous, and particularly in those animals

subjected to inhalation of lead frit containing angular particles of

lead glaze broncho-pneumonia was found.

The heart was flabby, and occasionally distinct roughening and

thickening of the valves was seen.

_Nervous System._--On opening the skull, hæmorrhages were frequently

found at the base of the brain, occasionally situated over the surface

of the cerebrum. Minute hæmorrhages were found often underneath the

arachnoid membrane, but the largest hæmorrhages were always found at

the base of the brain, and spreading down into the spinal canal along

the medulla.

On removing the cord, minute hæmorrhages were found along the surface,

irregular in distribution, and never very large. On section the brain

and cord appeared normal.

=Histology.=--A large number of sections were prepared from the animals

developing symptoms of poisoning; the various tissues are described

seriatim:

_Muscles._--These appear to have undergone general fatty degeneration.

The individual muscle fibres are indistinct in outline, and show

irregular areas stained by hæmatoxylin. Some infiltration may be seen

here and there between the muscle fibres, and minute hæmorrhages are

occasionally detected, the chief appearance being that of general

atrophy. The heart muscle shows similar degeneration, and the tendency

of the sarcolemma to break down and stain irregularly is apparent. In

many areas the muscle fibres stain poorly, if at all. Occasionally

minute hæmorrhages are found, passing between the muscle fibres.

_Liver._--The hepatic cells show varied degeneration; the vessels

passing between the cells are engorged with blood, the cells being

frequently much distorted from their general arrangement, and here and

there completely obliterated by small areas of exudation as well as

actual hæmorrhages.

_Spleen._--The parenchyma shows masses of irregular spaces filled with

recently-shed blood; the individual cells show a granular degeneration,

with occasional basophile staining, the general appearance being one of

chronic congestion. Here and there cloudy swelling may be seen.

_Intestine._--Sections across the small intestine show atrophy of

the intestinal wall, slight degeneration of the muscular coats, with

infiltration and minute hæmorrhages.

_Large Intestine._--Here similar minute hæmorrhages are found, in

no case large enough to be seen by the naked eye. Areas of necrotic

tissue are also seen in which considerable quantities of lead sulphide

particles are found.

PLATE I

[Illustration: FIG. 1.--SECTION OF LARGE INTESTINE OF ANIMAL POISONED

BY INHALATION OF WHITE LEAD, SHOWING EXCRETION OF LEAD BY TISSUES.

(STAINED EOSIN AND HÆMATOXYLIN.) × 250.

The whole of the large intestine was stained black, the staining

commencing at the ileo-cæcal valve. No staining is observable in the

small intestine; the line of demarcation is sharp.]

[Illustration: FIG. 2.--INTESTINAL ULCERATION IN TURPENTINE POISONING.

(STAINED EOSIN AND HÆMATOXYLIN.) × 250.]

[Illustration: FIG. 3.--SECTION OF ANTERIOR CRURAL NERVE FROM ANIMAL

POISONED BY INHALATION OF WHITE LEAD DUST, SHOWING HÆMORRHAGE IN NERVE.

(STAINED HÆMATOXYLIN AND EOSIN.) × 250.

There was paralysis of the quadriceps extensor on the right side;

the left leg was unaffected and the left anterior crural nerve was

unaffected.]

PLATE II

[Illustration: FIG. 1.--SECTION OF LUNG OF ANIMAL EXPOSED TO INHALATION

OF WHITE LEAD DUST, SHOWING MASS OF LEAD IN THE LUNG SUBSTANCE.

(STAINED HÆMATOXYLIN AND EOSIN, AND TREATED WITH H₂S.) × 250.]

[Illustration: FIG. 2.--LUNG OF ANIMAL EXPOSED TO TURPENTINE VAPOUR.

(STAINED HÆMATOXYLIN AND EOSIN.) × 250.]

[Illustration: FIG. 3.--LUNG OF ANIMAL EXPOSED TO INHALATION OF WHITE

LEAD DUST, SHOWING CHRONIC INFLAMMATION WITH EXUDATION AND CAPILLARY

LEAKAGE AND HÆMORRHAGE. (STAINED HÆMATOXYLIN AND EOSIN.) × 250.]

_Lung._--Red or grey hepatization may be found, or a general appearance

of broncho-pneumonia, where the dust used contained angular or

insoluble substances. In animals subjected to prolonged inhalation,

particles of lead could be demonstrated in the alveolar cells, and in

the tissue beyond, either by staining with chromic acid or by means of

iodine. Staining by sulphuretted hydrogen is not very satisfactory, as

most animals resident in a large city show masses of carbon situated in

various parts of the alveolar cells. If, however, a section be treated

by means of iodine or chromic acid, and watched under the microscope

during the process, the particles of carbon are easily differentiated

from those of lead compounds.

_Nervous System._--Sections of the brain and spinal cord, and of the

nerve supplying the paralyzed muscles, all exhibited the same phenomena

of minute hæmorrhages. In later cases some change in the cells is

found, but as a rule, beyond a slight increase of the intracellular

substance, little or no change is found in the cellular elements of

the brain; but in the region of the surface minute hæmorrhages may

be constantly traced, spreading over the surface of the cortex. In

the cord, sections made in various situations failed to show any very

definite degeneration, and little or no hæmorrhage was observed amongst

the cells of the cord. Hæmorrhages could occasionally be seen on the

surface.

In a number of animals the anterior crural nerves supplying the

paralyzed quadriceps extensor muscles were examined carefully both

for degeneration and for hæmorrhages. Very few degenerated nerve

fibres were found, not more than would be accounted for by the minute

hæmorrhages, which were found passing in between the nerve bundles, and

here and there producing pressure on the nerve bundles themselves.

_Kidney._--In the kidneys minute microscopical hæmorrhages, some of

them quite large, were found in the cortex. The hæmorrhages are diffuse

and irregular, and apparently due here, as in other situations in the

body, to the breaking down of minute venioles rather than arterioles.

In many cases the change is capillary. Parenchymatous nephritis may be

seen, probably resulting from the transudation taking place from the

vessel walls.

The chief view brought out in the histological examination of the

various organs is one of capillary hæmorrhage. This phenomenon is

not peculiar to lead poisoning, but, from the work of Moore of

Liverpool[4], it would seem that all heavy metals, such as bismuth,

mercury, not excepting iron, tend to produce a curious generalized

yielding of the minuter vessel walls. Armit[5] has demonstrated a

similar effect with nickel. The phenomena is, however, typically

associated with lead poisoning, and may, we think, be regarded as the

definite factor of chronic lead poisoning.

For the purposes of controlling the experiments of inhalation, two

other series of experiments were undertaken. In one instance an animal

was fed for two years on white lead; the animal was given 0·1 gramme

per day, and this was increased up to 0·5 gramme, and ultimately 1

gramme. This animal exhibited no symptoms whatever of lead poisoning,

and when it was killed, at the end of the time of experiment, showed

no apparent lesion, with the exception of very marked staining of the

colon and vermiform appendix. This staining of the large intestine

and the appendix, the engorgement of the vessels, particularly of

the omentum and mesentery, the enlargement of the lymphatic glands

in the neighbourhood of the colon, ileo-cæcal valve, and appendix,

suggest the absorption of lead in the upper part of the intestine, and

its discharge or elimination into the large intestine. That lead is

absorbed into the upper part of the intestine was demonstrated in the

following manner:

An animal was anæsthetized, an incision made, and a loop of intestine

pulled up and clamped off, a solution of lead chloride being run into

the loop by means of a hypodermic syringe. The mesenteric vein passing

from this loop of intestine was then carefully secured, a small opening

made in it, and the blood collected drop by drop until some 40 c.c.

had been collected, the time occupied being about three-quarters of an

hour. The blood thus collected was submitted to chemical examination,

and lead was demonstrated to be present. Lead therefore passes direct

from the intestine into the portal circulation.

In only one of the feeding experiments with solid compounds of lead was

any definite symptom of lead poisoning produced, and in this instance

the compound used was dust collected from the flues of a blast-furnace.

This dust was afterwards found to contain a considerable quantity of

arsenic. The experiment cannot therefore be regarded as conclusive.

With the more soluble salts of lead, however, such as the acetate,

lead poisoning may be set up by means of lead administered via the

intestinal canal: 1 gramme of lead acetate administered by means of a

hypodermic syringe through a catheter passed into the stomach of a cat

produced abortion in ten days, and death in three weeks. Four grammes

of acetate produced a similar effect in a dog in four weeks.

PLATE III

[Illustration: FIG. 1.--KIDNEY OF ANIMAL POISONED WITH WHITE LEAD

(INHALATION), SHOWING MICROSCOPICAL HÆMORRHAGES. (STAINED HÆMATOXYLIN

AND EOSIN.) × 250.]

[Illustration: FIG. 2.--KIDNEY OF MAN DYING OF CHRONIC LEAD POISONING.

(STAINED HÆMATOXYLIN AND EOSIN.) × 250.]

[Illustration: FIG. 3.--BRAIN OF YOUNG WOMAN DYING OF ACUTE LEAD

ENCEPHALOPATHY, SHOWING SMALL CEREBRAL HÆMORRHAGES. (STAINED

HÆMATOXYLIN AND EOSIN.) × 250.]

The two following cases, in which both chemical and histological

examination has been carried out on the tissues of persons who had been

employed in occupations which rendered them exposed to absorption of

lead, and who died with symptoms directly suggestive of lead poisoning,

may be added, as they confirm the experimental results given above in

all particulars:

CASE 1.--A woman aged twenty-one, employed in a litho-transfer works,

who died after a short illness during which the chief symptoms were

headache and mental clouding.

At the post-mortem examination no pathological lesions were

discoverable with the exception of a small gland which had become

calcareous, situated near the right bronchus. The brain was injected

over the left cerebral hemisphere, but no hæmorrhages were to be seen

with the naked eye. There were no other pathological signs. A portion

of the brain showing the injection and congestion were submitted to

histological and chemical analysis. Histologically the brain tissue

was found to be normal, with the exception of slight chromatolysis of

some of the larger cells; but interspersed about the whole section

in the slides examined, but more particularly in the area of the

cortex, minute microscopical hæmorrhages were found (see Fig. 3).

Here and there these hæmorrhages were seen related to the expanded

capillaries, all of which showed considerable engorgement with blood.

The arteries and veins themselves were, in addition, considerably

distended. There was no interstitial degeneration of the neuroglia

noticed. A few patches were found which apparently represented old

hæmorrhages undergoing gradual fibroid degeneration. In no case were

the hæmorrhages of a size that could be detected by the naked eye.

Two hundred and fifty grammes of the injected area of the brain were

submitted to chemical examination by the moist process described

in the chapter on Chemical Analysis. The nitric acid filtrate from

the electrolytic deposition gave a well-marked precipitate with

sulphuretted hydrogen, which was filtered off and recognized as lead.

There was only the merest trace of iron present. By colorimetric

estimation the quantity of lead found present in the brain estimated

as Pb was 0·0143 gramme. The quantity found in 250 grammes of brain

substance examined from the injected area was 0·0041 gramme.

CASE 2.--A man who had been employed in an electrical accumulator works

for a considerable time, and who had had a history of several attacks

of lead colic and one of lead paresis affecting both hands.

The man’s work in connection with lead ceased from the time of the

paresis, but some three years subsequently he died with cerebral

hæmorrhage.

Portions of the organs, brain, kidney, liver, and spleen, were examined

histologically, stained in the ordinary way with hæmatoxylin and eosin.

In the brain the same marked microscopical hæmorrhages were observed

as described in the previous case, and in addition many more areas of

old fibroid scars, very minute, but apparently corresponding to earlier

minute hæmorrhages. The kidney showed definite interstitial hæmorrhage

(see Plate III., Fig. 2), as did the liver and spleen.

A portion of the brain was further submitted to chemical examination,

and 0·0014 gramme of lead was determined as present.

The importance of this confirmatory evidence is undoubted, as the

presence of the capillary hæmorrhage existing in the tissues of a

person dying under suspicious circumstances when employed in a lead

process is confirmed by the chemical determination of lead in the

tissues.

The following tables, arranged under three headings, give some of the

experimental results obtained by submitting animals to the effect of

compounds of lead.

Table XI. gives the inoculation experiments.

The materials used in these experiments were those used in the

inhalation and feeding experiments. The experiments are also arranged

in such a manner that each series is a control one of the other.

The amount of substance used for the inoculation gives some rough idea

of the dose required to produce poisoning in an animal; but even this

question of dose in absolute quantities, administered hypodermically,

shows considerable variation in the degree of poisonous effect. The

first animal in Table XI. was inoculated with acetate, this being one

of the more soluble lead compounds, and was given it in three small

doses. The animal received 0·3 gramme per kilogramme of body weight,

whereas in No. 35 2 grammes of washed frit--that is to say, lead glaze

formed by fusing together litharge and silica--actually did produce

symptoms, but of a mild nature. Animal No. 33 only had 0·16 gramme,

being 0·05 gramme per kilogramme of body weight; and this caused acute

symptoms. 0·35 gramme of white lead in a 3·500 kilogramme animal

(No. 31) produced no symptoms at all. In the list of the inoculation

experiments, three animals only exhibited no symptoms--one of these

(No. 31) which was given white lead hypodermically, and Nos. 41 and 42,

which were inoculated with lead silicate or lead frit, which had been

previously treated with acetic acid or water.

Several practical points arise from these experiments, notably with

regard to the frits, as it is seen that a considerable amount of the

toxic properties contained in frit are removed by washing--most by

washing with acetic acid and water, but also to some extent by washing

with hot water alone, showing that in the ordinary production of

lead frit for pottery purposes a certain amount of lead in a soluble

condition as regards the body tissues was still present. This is no

doubt entangled in the true silicates in the forms of oxides, or even

as carbonate. Further, the toxicity of the lead compounds used may

certainly be arranged in the order of their solubility with regard to

the animal tissues, the acetate being the most poisonous, and the frit,

when washed, the least; but unwashed frit, even in relatively small

doses, may produce poisoning. This point is still further emphasized

in Table XIII. Animal No. 42, four months after previous inoculation,

showed no signs of poisoning. Lead nitrate in water was therefore given

in quantities of 0·01 gramme per diem; one month later this animal

developed poisoning.

Table XII. deals with the feeding experiments.

In these experiments acetate was given in one case only, and then

in the form of pills coated with keratin. It is impossible to say,

however, whether the animal ever received any soluble lead, as on one

or two occasions the keratin pills passed right through the animal

without dissolving. On the other hand, feeding with nitrate of lead

in water produced symptoms, but when the nitrate was given in milk no

symptoms appeared. It will be noticed it took a cat four months to

show any signs of poisoning taking 0·1 gramme per day; whereas the

animal receiving subcutaneous doses of 0·16 gramme of acetate showed

paralysis in fifteen days, and in twenty-two days was so ill that it

had to be destroyed under an anæsthetic. The same relationship in

time also obtains in the case of the animals fed on dry white lead.

In practically no instance did definite or severe poisoning follow

the feeding on dry white lead alone, even when quite large quantities

were taken. On reference to the inoculation experiments of Table XI.,

it will be seen that the inoculation of 2 grammes of dry white lead

produced definite symptoms, although the feeding cats had an amount

very largely in excess of this. The only animals fed on white lead or

frit exhibiting signs of lead poisoning were those which were given

alcohol in addition to the lead compound.

A comparison of the results given in Tables XI. and XII. shows that

animals which received lead compounds subcutaneously suffered much more

than the animals which received the lead via the gastro-intestinal

canal, even when the doses given via the mouth were exceedingly large.

It will follow, then, that the actual contact with the more intimate

fluids of the body, rather than the digestive juices, determines the

solubility and general distribution of the lead compound in the body.

This is confirmed by a recent paper by Straub[6].

The animals experimented upon by feeding were kept in the laboratory

under the same conditions as the inhalation animals, but were so

placed that under no circumstance could they obtain any lead dust

by inhalation. These animals were used as control to the breathing

experiments, the substance fed to the animals being in all cases the

same substance as was used for the various inhalation experiments; but

in addition a certain number of the animals were given alcohol, which

are referred to in Table XII. Alcohol was also given to animal No. 6 in

the inhalation series.

The animals fed with lead were fed with the same compound which was

used for the inhalation experiments, 0·4 to 1 gramme being given daily;

so that during the period these animals were exposed to lead dust the

other animals were taking the same compound via the intestinal canal,

but in much larger quantities, and yet they exhibited no signs of lead

poisoning.

TABLE XI.--INOCULATION.

+----+-------+---------------------------------------------------+

| No.| | |

| of | | |

|Ani-| | |

|mal.|Weight.|Total Compound used and Quantity. |

+----+-------+---------------------------------------------------+

| | Kgs. | |

| 16 | 3·200 |0·91 grm. lead acetate: (1) 0·16; (2) 0·5; (3) 0·25|

| 25 | 3·350 |Fritted lead: (1) 0·6; (2) 2·0 = 2·6 grms. |

| 28 | 3·050 |2 grms. white lead |

| 31 | 3·450 |0·35 grm. white lead |

| 32 | 2·900 |0·3 grm. frit |

| 33 | 3·150 |0·16 grm. PbO as acetate |

| 35 | 3·750 |2·0 grms. water-washed frit |

| 40 | 3·050 |1·0 grm. unwashed frit |

| 41 | 3·000 |1·0 grm. acetic acid and water-washed frit |

| 42 | 2·800 |1·0 grm. water-washed frit |

| 43 | 2·900 |Lead nitrate in water: 0·01 grm. per diem |

+----+-------+---------------------------------------------------+

+----+--------+---------------------------------------------------+

| No.| Number | |

| of | of | |

|Ani-| Inocu- | |

|mal.|lations.|Date of First Symptoms. |

+----+--------+---------------------------------------------------+

| | | |

| 16 | 3 |Forty-fifth day encephalopathy |

| 25 | 2 |Twenty-sixth day slight paralysis of left hind-limb|

| 28 | 1 |Fourth day aborted |

| 31 | -- |No symptoms |

| 32 | 1 |Eleventh day stiff joint; stepping not normal |

| 33 | 1 |Fifteenth day paralysis |

| 35 | 1 |Ninth day aborted |

| 40 | 1 |Forty-seventh day some muscular weakness |

| 41 | 1 |No symptoms |

| 42 | 1 |No symptoms |

| 43 | -- |Thirtieth day encephalopathy |

+----+--------+---------------------------------------------------+

+----+----------+-------------------+-------------------+

| No.| | | |

| of | | | |

|mal.| | |Weight. |

+----+----------+-------------------+-------------------+

| | | | Kgs. |

| 16 | 47 days |Died |1·750 |

| 25 | 26 days |Killed |3·200 |

| 31 | 1 year |Recovered |3·300 |

| 32 | 28 days |Paralysis; died |2·400 |

| 33 | 22 days |Paralysis; killed |2·150 |

| 35 | 1 year |Recovered, but thin|2·900 |

| 40 | 58 days |Died |2·250 |

| 41 | 5 months|Recovered |2·900 |

| 42 | 4 months|Recovered |2·950 |

| 43 | 5 months|Died |2·100 |

+----+----------+-------------------+-------------------+

TABLE XII.--FEEDING EXPERIMENTS.

+-----+-------+---------------------------+-------+------------------+

| No. | | | | First |

| Ani-| | | Sub- | of Poisoning |

+-----+-------+---------------------------+-------+------------------+

| | Kgs. | | | |

|11_a_| 3·850 |0·8 grm. |None |None |

| | 3·900 |After 8 months given |50 c.c.|1 month |

|12 | 3·800 |0·8 grm. dry white lead |50 c.c.|1 month slight |

| | 3·730 |0·4 grm. low-solubility |50 c.c.|6 months en- |

| | |0·1 grm. | | |

+-----+-------+---------------------------+-------+------------------+

+-----+---------+--------------------------------------+-------+

| No. | Total | | |

| of |Duration | | |

+-----+---------+--------------------------------------+-------+

| | | | Kgs. |

| 2 |2 months |Recovered | 2·000 |

| | | | |

| 9_a_|2 months |-- | 3·350 |

| | | | |

|11_a_|8 months |-- | 3·900 |

| | | | |

|12 |38 days |Died (encephalopathy) | 2·250 |

| | | | |

|13 |18 months|Recovered | 2·950 |

|14 |8 months |Given port wine | 3·750 |

| | | | |

| | | | |

|23 |1 year |No symptoms |4 ·600 |

| | | | |

| | | | |

|24 |6 months |Recovered | 4·350 |

| | | | |

|46 |4 months |Died cerebral symptoms | 3·200 |

| | | | |

|47 |4 months |Recovered[A] | 2·900 |

| | | | |

|49 |3 months |Recovered[A] | 2·650 |

| | | | |

|15 |1 year |No symptoms due to confinement in cage| 3·100 |

+-----+---------+--------------------------------------+-------+

[A] Increased in weight.

TABLE XIII.--INHALATION EXPERIMENTS.

+----+-------+----------------------------------+-------+------------+

| No.| | | | |

| of | | Compound of Lead | | |

+----+-------+----------------------------------+-------+------------+

| | Kgs. | | | |

| 1 | 3·000 |0·007 to 0·01 grm. flue dust from | A |11 of 1 hour|

| 2 | 3·580 |0·007 to 0·01 grm. litharge dust | A |12 |

| | | | | |

| 4 | 4·100 |0·001 to 0·007 grm. white lead | A |12 |

| 6 | 5·200 |0·001 to 0·007 grm. white lead | A |12 |

| 7 | 3·000 |0·001 to 0·007 grm. white lead; | A |11 |

| 10 | 4·500 |0·0001 to 0·001 grm. white lead | B |40 of 20 |

| 11 | 3·750 |0·0001 to 0·001 grm. white lead | B |40 of 20 |

| 21 | 3·900 |0·001 to 0·09 grm. low-solubility | B |14 of 1 hour|

| 22 | 3·900 |0·001 to 0·09 grm. low-solubility | B |26 |

| 30 | 3·500 |0·001 to 0·09 grm. low-solubility | B |14 |

+----+-------+----------------------------------+-------+------------+

+----+------------+--------+-----------------------+-------+

| No.| | | | |

+----+------------+--------+-----------------------+-------+

| | | | | Kgs. |

| | | | | |

| 22 |60 |80 days |Killed; old pneumonia | 2·500 |

| | | | | |

| 30 |45 |45 days |Killed | 2·450 |

| | | | | |

+----+------------+--------+-----------------------+-------+

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.

[1] GOADBY, K. W.: Journal of Hygiene, vol. ix., No. 1, 1909.

[2] GOADBY, K. W., AND GOODBODY: The Lancet, vol. ii., p. 988, 1909.

[3] GOADBY, K. W.: Report of the Committee on Lead, etc., in

Potteries, vol. iii., p. 478, 1910.

[4] MOORE: Private communication.

[5] ARMIT: Journal of Hygiene, vol. viii., No. 5, 1908.

[6] STRAUB: Berl. Med. Woch., p. 1469, 1911.

[7] LEHMANN: Archiv für Hygiene, vol. xxxiv., p. 321, 1899.