Lipton IV 
NITROGEN MUSTARDS 
by 
M. A. Lipton, Ph.D. 
Instructor of Physiology, University of Chicago 
I have been asked to speak about a series of new agents that may 
be encountered in the event of chemical warfare. I call them new, 
because they were not in the last war, and because they have been 
developed as a result of research since the last war. By a series 
of compounds, I mean that there are five, or six, or more compounds 
closely related chemically, physiologically, and toxicologically. 
These compounds are known as nitrogen mustards. The formulas for 
the nitrogen mustards are secret. 
Now, because I am speaking of new compounds the lecture necessarily 
has certain limitations. In the first place, since I am speaking 
of a series of compounds which show some variability in action, I 
must generalize in giving the properties of a class rather than any 
of the individual members of the series; that is necessary in order 
to save time. And secondly, because the compounds are new and have 
not been investigated for twenty-five or thirty years, as mustard 
and phosgene and chlorpicrin have, much of the information which I 
shall give is sparse and has been obtained with laboratory animals. 
It is necessary to extrapolate from laboratory animals to man. In 
most cases, I think this extrapolation is quite justified, particu- 
larly because the data I will present have been obtained with five 
or six species of animals, varying from the ordinary laboratory 
mouse up to and including the monkey. 
Dr. McLean has pointed out that the vesicants of which we are 
speaking as a class are much more than vesicants; that is, they are 
pulmonary irritants, they cause eye damage, and they are systemic 
poisons. All of those characteristics hold for the nitrogen mustards 
as well as for mustard itself. 
The nitrogen mustards are also persistent agents. The persistence 
will vary with, the particular nitrogen mustard. The most volatile 
member of the series which is known is five times as volatile as 
mustard, consequently its persistence will be less. Heavy contamina- 
tion with the vapor of the most volatile nitrogen mustard will last 
for two or three hours. On the other hand, the less volatile members 
are half or less than half as volatile as mustard, consequently they 
will persist much longer. With these members of the series the vapor 
may be relatively insignificant relative to the droplets of liquid 
which may land on machinery, on personnel, or the terrain. Some of 
the members have so little volatility that we may expect their use 
as aerosols. They will very likely be dispersed as atomized spray 
rather than in the form of vapor. 
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All of the nitrogen mustards have considerable vesicant action, and 
they are systemic poisons in exactly the same way that mustard is a 
systemic poison; that is, large amounts may affect the nervous 
system, the gastro-intestinal tract, and the hemopoietic system. 
I may say at the outset that none of the nitrogen mustards is more 
toxic than mustard itself. If we speak of the toxicity in terras 
of different organs which may conceivably be affected, we will find 
that the nitrogen mustards are not as good vesicants as mustard. 
They definitely are vesicants, but they are not quite as good as 
mustard; let us say half or a third as potent as mustard. 
On the other hand, the effects on the eyes are perhaps somewhat 
stronger than in the case of mustard. I will speak somewhat more 
about the eye damage later, and Dr. Hughes tomorrow will speak to 
you also quite extensively on the subject. 
So far as the respiratory tract is concerned it seems from the in- 
formation gained that we can say that the most toxic member of the 
nitrogen mustards is not more toxic than mustard itself. 
Well, then, why concern ourselves with nitrogen mustards? I do not 
profess to be a military expert in any sense, but there are certain 
advantages which I think will be fairly evident. Perhaps the 
greatest offensive advantage to these compounds is that, insidious 
as mustard is, the nitrogen mustards are still better in this 
direction. They have practically no odor. The odor would be very 
easy to mistake, even to the trained observer. The individual 
odors of the series may vary from practically odorless to mildly 
fishy and perhaps something like soft soap. These odors are quite 
easily overlooked. 
Another offensive advantage to the nitrogen mustards is that they 
are perhaps a little more difficult to decontaminate with the usual 
decontaminants. Finally, the greatest offensive advantage to the 
nitrogen mustards, and this is common to almost any new warfare 
agent, is simply that they are new and that they are consequently 
novel in chemical warfare. 
It is not necessary to obtain an agent which is more toxic than 
mustard, in the same way that it is not necessary to obtain a new 
bacterium which is more toxic than tetanus bacteria to cause trouble 
to clinicians. The nitrogen mustards are toxic enough to cause 
serious damage to those who are not acquainted with their properties. 
The nitrogen mustards, as I have said previously, arc more difficult 
to decontaminate than the usual agents, and they are even more insid- 
ious particularly since they are new. In a sense, this is a prophy- 
lactic lecture in which I shall attempt to acquaint you with a few 
characteristics of these compounds, so that wo might be able to work 
more efficiently and more quickly in case of an attack with these 
agents. 
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I should perhaps speak first of protection. As Dr. McLean has 
pointed out, with the vesicants protection is much more important 
than therapy. Once you have been burned you are burned and there 
isn’t much that can be done about it. On the other hand, so far 
as protection is concerned, the protection of the gas mask and 
impermeable clothing is quite as good for the nitrogen mustards as 
it is for mustard itself. 
The difficulty, of course, is to know when to put the gas mask on. 
Since these agents have little smell, it is necessary to rely upon 
the chemical indicators which are available. The chemical indicators 
can detect concentrations below that which will cause damage. 
Now, I would like to say something about the results of exposure to 
these various compounds since usually gas casualties are to be ex- 
pected in case these or any other agents are employed. I would like 
to consider the symptoms and treatment in terras of increasing con- 
centrations. Thus we may begin with a very low concentration, a 
concentration which would be extremely difficult to detect, and 
which would have slight effect. Certain symptoms are to be expected 
with such low concentrations but as the concentration goes up, 
various other phenomena may occur, and I will try to develop the new 
symptoms in terms of concentration. 
I may say at the outset, that of all the organs and tissues of the 
body the eyes are most sensitive to these agents, the respiratory 
tract comes next, and the skin, the hemopoietic system, the central 
nervous system and the G. I. tract are less susceptible. If we 
begin with non-lethal concentrations, which are at the limit of de- 
tection, at least by odor, wo may consider concentrations of five 
to ten micrograms per liter of air. A concentration of five to ten 
millionths of a gram per liter of air with an exposure period of 
five to ten minutes, is not lethal. But eye damage can and does 
occur as a result of a five to ten minute exposure to concentrations 
as low as this. 
The eye damage has an insidious background. Even more than with 
mustard, there are no immediate signs of irritation when the eye is 
exposed to a low concentration of the compound. One may be quite 
comfortable and unaivarc in a concentration high enough to cause eye 
damage. One or two hours after exposure there may be a mild irrita- 
tion and perhaps the beginning of lacrimation as a result of expo- 
sure, but examination of the eye will show no objective signs at all 
for two or three hours. 
After several hours there begins intermittent pain, lacrimation, and 
irritation, which come and go for a period of perhaps six to eight 
hours. At the end of this time, examination of the eye will show 
mainly a conjunctival reaction; i.e., an edema of the conjunctiva. 
At the end of about eight hours the pain becomes quite severe and is 
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continuous. At the end of ten to twelve hours there will be a 
miosis, and the pupil will be markedly contracted. If atropine is 
instilled in the eye to relieve the miosis, then the pain and head- 
ache will go also. There will be at this time a beginning mild 
corneal haziness or clouding, which is only superficial, and slit 
lamp examination will show that it is exterior to Bowman's membrane. 
The prognosis in damage of this type is quite good. In the absence 
of any secondary infection it would be expected that within eight to 
ten days the eye will heal completely, there will be no scarring and 
practically no injury to sight. 
With concentrations of this type it would be expected that respiratory 
damage would be very small. What one should expect would be usually a 
mild rhinitis and mild bronchitis. These occur and because of the 
nature of the compound, may be expected to remain for as long as two 
weeks before clearing up. 
Might I return to the atropine just briefly to note that for some 
reason the headache and pain which are associated with miosis disappear 
with atropine. That is symptomatic treatment and ’will not correct the 
eye damage, but at least it will make the patient more comfortable. 
When we consider higher concentrations, concentrations of the order 
of one-tenth to two-tenths of a milligram per liter of air, dangerous 
and lethal effects may be expected. The eye damage is much more 
severe, and will be described in detail tomorrow. I might say that 
the cornea becomes very cloudy, photophobia and pain are present, and 
there is not much than can be done in the way of therapy. If secondary 
infections are avoided by the use of one of the sulfonamide drugs, then 
recovery can occur in ten to twelve weeks. The cornea may still remain 
permanently scarred, and there may be some impairment of vision. But, 
on the other hand, in the absence of infection complete blindness would 
not be expected as a result. 
I have some slides which I am quite sure you will see again tomorrow. 
I might just point to a .few to give you an indication of the damage 
that occurs. 
That is a rabbit eye, and this photograph was taken about three hours 
after 1.2 milligrams of one of the nitrogen mustards was instilled 
into it. Except for the reddening of the conjunctiva, there isn't 
much in the way of damage. 
The next slide was taken three weeks later. I think that the clouding 
of the cornea is quite evident, and you may see the exfoliation of 
the corneal epithelium. 
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The next series shows the progressive damage to a rabbit1s eye as a 
result of exposure to the saturated vapor of one of the nitrogen 
mustards. The first photograph was taken within an hour, and ekcept 
for mild conjunctival injection there is very little that can be 
seen. The second photograph was taken three boors after exposure 
and shows some conjunctival edema. The next was oaken four days 
after, and shows the corneal clouding. This, I believe was stained 
with fluorescein, and Indicates nicely the damage to the cornea. 
This next photograph was taken fourteen days after and you can see 
the beginning of blood vessel formation in the cornea. 
The last slide was taken thirty days after exposure to the vapor. 
That eye is irreparably damaged. The cornea is cloudy and ulcerated 
and it is expected that it will remain this way throughout the life 
of the animal. 
The concentrations which will cause eye damage as severe as those 
indicated in the slides will also cause respiratory symptoms much 
the same as those which will be found as a result of poisoning. 
There will be manifest a severe bronchitis, possibly aphonia and in 
very severe cases a pulmonary edema generally accompanied by bronchial 
pneumonia. There isn't much that one can do about the treatment. 
The patient may possibly be made somewhat more comfortable by inhala- 
tion of steam to relieve the congestion of the larynx c?.nd trachea. If 
there is a cough, codeine can be administered to relieve the coughing, 
and in the case of lung edema possibly oxygen will have a certain 
degree of value. The bronchial pneumonia which'is a complicating 
factor should be treated as bronchial pneumonias generally are. Just 
as there is a delayed action in the development of eye symptoms, so 
is there a delayed action in the development of the respiratory 
symptoms. 
Tilth experimental animals in the laboratory we uniformly find that 
the majority of deaths will occur four to five days after exposure. 
There may be very few symptoms for the first twenty-four hours, and 
the symptoms become progressively worse for periods as long as two 
weeks. If pulmonary edema and bronchial pneumonia are present, the 
prognosis is not good. 
Concentrations causing very severe eye and respiratory damage will 
generally cause skin symptoms and symptoms in the hemopoietic 
system. The skin may be very red and edematous. The lesions are 
somewhat more superficial than those obtained with mustard, but much 
of the same type, and so far as treatment is concerned there isn't 
much than can be done except possibly to relieve the pain and itching 
with a local anesthetic ointment. If blisters are present, the 
blisters should not be opened except under conditions of very rigid 
asepsis. If they are opened, they should be covered with sterile 
dressing and secondary infection should be avoided. 
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Now, the effects on the hemopoietic system are rather striking. Ex- 
posures to a dangerous concentration will cause a very marked leuko- 
penia. Following a heavy exposure there may be a very transitory 
leukocytosis. It is very transitory, and will generally last for 
less than twenty-four hours. This is followed by a precipitous drop 
in the total white blood count, until at the end of four or five 
days it is possible to get leukocyte counts as low as two or three 
hundred. Such low values are to be found only with lethal concentra- 
tions. On the other hand, it might be expected that counts as low 
as two or three thousand could be obtained with lower doses. The 
differential count shows that the lymphocytes drop immediately, while 
the heterophils show the transitory rise followed by agranulocytosis. 
In terms of prognosis, leukocyte counts below two thousand will be 
quite dangerous, and those below one thousand are usually lethal. 
On autopsy the bone marrow shows a complete aplasia. 
The symptoms that I have given are in terms of exposure to different 
concentrations of vapor. It is possible, of course, to be exposed 
by routes different from vapor. 
For example, if the skin is exposed, possibly by directing small 
droplets of liquid on it, we may find no eye damage at all. On the 
other hand, there will be certainly skin damage and enough may be 
absorbed to cause even leukopenia. 
If some liquid material is instilled into the eyes, there will be 
very serious edema and eye damage, but no respiratory, skin or 
hemopoietic damage. 
In general, considering the exposure to the vapor, one may say safely 
that the eye symptoms are the first to occur and occur with the 
smallest concentrations. These are followed by the respiratory 
symptoms and then by other symptoms. 
The nervous system is affected to different degrees by varying con- 
centrations. The initial effect on the nervous system.is cholinergic 
in type and can be treated by atropine. That is, there will be 
salivation, a congested intestine, diarrhea and so forth. These 
symptoms and some others may possibly occur in very low concentrations. 
On the other hand, after a certain concentration is reached the animal 
may show a flaccid paralysis, which can become fully generalized, and 
in such cases the animal is generally lost. 
The nitrogen mustards may possibly be used for water contamination, 
and they can cause significant gastrointestinal symptoms. They may 
cause pain, vomiting, bloody diarrhea and so forth. There isn't 
much than can be done for those symptoms, except again to make the 
patient comfortable, perhaps with barbiturates or the use of atropine. Lipton IV 
Now, I might turn from that and say something about first aid. Tbv 
begin with, the nitrogen mustards, as well as with mustard itself, 
cannot be treated by first aid when there is a vapor contamination. 
If there is vapor contamination, first aid will be quite useless. 
On the other hand, if there are drops of material placed upon the 
skin, and one can get at them within one or two or possibly a maximum 
of five minutes, then a certain amount of good may be done. In con- 
trast to mustard itself, the usual ointment issued by the army does 
not decontaminate the nitrogen mustards. It simply dilutes it. The 
removal of droplets from the skin can be effected very well by the 
dabbing technique, and Dr. McLean has mentioned the use of organic 
' solvents. In the absence of organic solvent, one may prescribe soap 
and water and lots of it. 
If the liquid agent enters the eyes, there is a very nasty problem. 
The only thing which can be done is to irrigate the eye as much as 
possible and as quickly as possible. I think that in all cases 
where the material is actually dropped into the eye the prognosis 
will be quite bad, and blindness may well result, unless the agent 
is removed in less than two minutes, and removing the agent quanti- 
tatively in less than two minutes impossible. 
There is very little more which can be said about the nitrogen 
mustards, and I might therefore attempt to once more give a symptomatic 
summary, 7/ith vapors the eyes are the organs which are most easily 
affected' and by the lowest concentrations. Higher concentrations may 
cause respiratory involvement, and in most cases death from vapor will 
occur as a result of respiratory involvement. If the liquid is en- 
countered, vesication and damage to the particular tissue which is 
exposed will undoubtedly result. If the material is ingested, gastro- 
intestinal and nervous symptoms will result. 
For the purpose of diagnosing exposure to the nitrogen mustards the 
leukopenia may be useful, for although it is much of the same nature 
as caused by mustard, it is more severe. 
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