QUANTITATIVE STUDIES ON THE GASTRO-INTESTINAL

ABSORPTION OF DRUGS

I. THE INHIBITORY ACTION OF PHENOL ON ABSORPTION’

TORALJ) SOLLMANN, IAUL J. HANZLIK AND J. DOUGLAS PILCHER

From the Pharmacological Laboratory of Western Reserve University, Cleveland, Ohio

Received for publication, November 17, 1909.

I. INTRODUCTION

In the course of an investigation2 of the effects of phenol on the circu-

lation, we were impressed by the following phenomena:
When phenol is injected intravenously, it causes a sharp fall of blood
pressure, apparently due to cardiac and vaso-motor depression, the
cardiac factor predominating. A similar fall results if the phenol is
introduced into thelimentary canal, but there is a conspicuous difference
in the time relations and also in the fatal dose. With intravenous
injection, the effect is very fleeting, so that, within five minutes after
the injection, the animal either has died or the blood pressure has
returned to practically normal. The disintoxication of the phenol
must therefore occur very promptly. If, on the other hand, the adminis-
tration has been by the alimentary canal, the blood pressure does not
recover, and death occurs, as a rule, only after several hours. Further,
the fatal dose of phenol is very much higher by the alimentary canal than
by the vein-the individual variations are too great to obtain accurate
figures, but an average ratio of 10:1 would be approximately correct.
These facts-the persistent action, delayed death, and low toxicity-
would seem to indicate a slow absorption from the alimentary canal; hut

1 A preliminary communication of some of the results was made at Baltimore

meeting of the American Society of Biological Chemists. (Proceedings, 1:184, 1909).
2 This investigation will be the subject of a future communication.

J
410 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

such a conclusion would be sharply contradicted by the further fact that

the effects of phenol develop very promptly indeed after oral administra-
tion. Usually within five, at most within ten minutes, the fall of blood
pressure and the peculiar convulsive twitchings have practically reached
their maximum intensity and undergo but little change for several hours,
or until death approaches.
The prompt onset on the effects shows that the absorption of the
phenol must start off with great rapidity; the slow progress, on the other
hand, when contrasted with the fleeting action on intravenous injection,
indicates that the absorption continues for hours. In other words, it
would seeni that there must be a profound change, a great slowing of the
rate of absorption, after the first few minutes. In some manner, the
phenol would seem to inhibit its own absorption.
A similar combination of rapid onset and slow progress of their effects
on oral administration, seems to exist in the case of a number of other
poisons such as chloroform and chboral, and perhaps formaldehyde
and strophanthus and possibly with many others. The subject has not
attracted very much attention and, so far as we know, has never been
seriously investigated. On account of the relative ease and accuracy
with which phenol can be quantitatively determined,3 it appeared to us
as peculiarly suitable for approaching the investigation of this general
problem. It does not by any means follow that th mechanism is the
same in all these cases; but the results with phenol would not only be
interesting in themselves, but they would also indicate the most promis-
ing directions for the investigation of the other substances. Work on
these has been started and we hope to present them in the succeeding
numbers of this series.
Our present problem, therefore, resolved itself into a quantitative
study of the absorption of phenol from the aliment.ary canal, with the
view of determining the mechanism of the inhibitory action on absorp-
tion, which we surmised from the course of the symptoms and which we
confirmed by direct chemical examination.

Operative Methods
Before proceeding to the presentation of our results, we would premise
that they were performed on cats and dogs, in a state of complete anas-

‘The analytical methods are described in the Appendix.

 - - - . .

PHENOL ON ABSORPTION 411

thesia. With dogs, this was obtained by morphin, 2 centigram per

kilogram body weight, hypoderimcally, followed! in half an hour by
ether. With cats, we used a mixture of ethyl carbamate 20 gm.; mor-
phin sulphate, 1 gm.; atrophin sulphate, 20 mg. ,water, q. s. 100 cc. Three
cubic centimeters of t.his solution per kilogram of bodly weight were
administered by rectum, and supplemented by a few whiffs of ether, if
necessary. This method ive have found eminently satisfactory with
these animals, provided a full hour is allowed to elapse before starting
the operation.
All the phenomena of absorption were quantitatively as well as quali-
tatively alike in both classes of animals, so that they will generally be
grouped together. The phenol usually in the dose of about 1 gram of
the melted crystallized phenol per kilogram of body weight was adminis-
tered by pushing the needle of an accurately working hypodermic
syringe the wall of the doubly
through ligated stomach or intestinal
loop; the syringe being washed and the washings assayed and subtracted.
The results from the stomach and intestine were also so similar that
they will be grouped together. The blood pressure was taken with a
mercury manometer damped so as to record only the mean pressure.
In many of the experiments a membrane manometer was also inserted
to register the excursions. The animals were invariably tracheotomized,
and to avoid shock, the skin was usually closed over the viscera and the
animals were kept artificially warmed.

II. THE COURSE OF THE ABSORPTION OF PHENOL

This may be deduced: (a) from the average absorption by different

animals killed at various intervals after the administration; and (b)

by dividing the phenol among several ioops in the same animal, the ioops
being then excised at successive intervals. Both methods gave concor-
dant results.

(a) The Influence of the Time of Sojotirn, as Judged from the Separate
Experiments of the Series

This may be seen from table I. The second and third columns show
the averages of all the experiments of the series: in the succeeding columns
there have been excluded the experiments in which definite disturbing
factors were present (such as shock, small doses, etc., as will be explained
later).
412 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

TABLE I

Absorption of phenol accordiag to time of sojourn

ENTIRE SERIES RESTRICTED SERIES

TIME OF SOJOURN OF PHENOL
IN ALIMENTARY CANAL
Number of j Averar Number of Extremes of Average
Cases Absorption5 Cases Absorption Absorption5

Less than 5 minutes 6 20 3 10-43 28

6 to 20 minutes 25 19 5 14-39 25
Half hour 26 27.5 14 14-66 38
One hour 19 37 16 21-69 43
Two hours 5 43 4 32-58 43
2to5hours 3 44 3 42-48 44

Total of all periods.... 84 30.6 45 10-69 38 5

* - Percentage of phenol actually administered.

(b) The Influence of the Time of Sojourn, as Jv’.dged from Separate Loops
in a Sir&gle Animal

Experiment 120 (dog) gave the results shown in table II, the phenol
being administered simultaneously into eight loops:

TABLE II

Percentage of phenol absorbed from intestinal loops when excised at various times after
administralion

TIME OF SOJOURN IN LOOPS ABSORPTION PERCENTAGE AVERAGE

FROM LOOP G FROM LOOP b

lOminutes 17.2 18.5 17.9

Half hour 30.0 lost 30.0
Onehour 14.7 34.1 24.4
Two hours 40.3 46.0 43.2

Notwithstanding the considerable individual variations in different

animals and even in different ioops (which would be expected in view
of the explanation of the phenomenon which we shall give), the three
sets of averages, obtained by these various methods, agree very well,
showing the very rapid absorption (18 to 28 per cent) within the first
five minutes; the serious check from here to 30 minutes. (Total absorp-
tion averages 27 to 38 per cent); and the very slow almost imperceptible
 1

11

PHENOL ON ABSORPTION 413

absorption after an hour. (Total absorption averages 44 per cent.) An

absorption of over 45 per cent is altogether exceptional.
The course of the retardation may be shown even better by calculating
the rate of absorption for five minute periods, as is done in table III.

TABLE III

Percentage of phenol absorbed per five minutos during

PER CENT

First five minutes 20

5toiOminutes 4
lOto 30 minutes 2
to ihour 1
ito 2hour
After 2 hours

(The data for this table were calculated from a graphic absorption-
curve, compiled from the averages, but in which the minor and evidently
accidental irregularities were disregarded.)

III. IDENTICAL BEHAVIOR OF CATS AND DOGS

We made the statement that the phenomena are quantitatively

identical for the two classes of animals. In the total series (restricted),
33 cats showed an average absorption of 38 per cent; 16 dogs, an average
of 30 per cent. The difference falls well within the limits of variation
shown by animals of the same species.

Identical Behavior of the Stomach and lntestincs

In the total (restricted) series, the average absorption was as follows:

PER CENT.

32 cases of injection into stomach 36.4

11 cases of injection into entire intestine 42.9

9 cases of injection into short loops of intestine 41 .3

In several experiments, the dose of phenol was distributed in equal

portions over several ligated segments of the alimentary canal, with the
results shown in table IV.
 4, .

414 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

TABLE IV

A bsorption from. separate segments of the alimentary canal

PERCENTAGE OF PHENOL ABSORBED FROM

SERIAL NUMBER
. S

I .

Dog 92 - 45 32 57 56 10 40
Dog 100 70 47 50 60 49 - 55
Average of 92 and 100 (70) 46 41 58.5 52.5 (10) 48
Cat Si 24 - - 65* - 45
Cat 103 - - 65 65 - - 65

5Entire intestine.

It is seen that the differences are not constant and fall quite within
the limits of ordinary variations.

iv. PERCENTAGE OF PHENOL REMAINING UNABSORBED IN STOMACH WHEN

THE PYLORUS REMAINS OPEN

The efficiency of gastric lavage in phenol poisoning would depend

entirely upon the quantity of phenol which does not leave the stomach,
either for the circulation or for the intestine. We have already seen that
a considerable amount is not absorbed, but there remains the possibility
that, in a short time, the phenol would be rendered inaccessible to the
stomach-tube by passing into the intestine. To determine this practical

TABLE V

Percentage of phenol recovered from the

- __stomach, with
__
open pylorus

PERCENTAGE OP TEE ADMINISTERED PHENOL

SERIAL NUMBER
TIME
SOJOURN
OF
OF
_________ _____________ -- -,

PHENOL Remaining in Recovered from AbsorbI

the Stomach the Intestine

Cat 88 3min. 92.2 0.6 7.2

Cat 12 7mm. 69.6 12.0 18.4
Cat 104 8mm. 89.3 0 10.7
Cat 113 1 hour 72 5 23
Cat 111 lto2hours 14 12 74
Cat 90 3 hours 49.3 2.8 47.9
 1-...,,.-v.. ,,s,-.

PHENOL ON ABSORPTION 415

point, the phenol was injected into the stomach with the cardiac end
ligated, but the pyloric end left patent. The results are shown in table V.
It is seen that, as a rule, very little qf the phenol escapes into the intestine:
the pylorus being presumably tetanically contracted. Gastric lavage even
after 3 hours, would remove a considerable part of the administered
phenol and this treatment should therefore be tried, no matter how late
the patient comes under observation.

V. IS PHENOL EXCRETED iNTO THE ALIMENTARY CANAL?

Inquiring into the mechanism of the retention of the large part of the
phenol in the alimentary tract, the first suggestion would perhaps be
that the phenol might be ieexcreted into the lumen, the retention thus
being illusory. To test this matter the phenol was confined in a ligated
portion of the alimentary canal, arid sought for, after death, both in this
portion and in the remainder, which had not been in direct contact with
the phenol.
Placing the phenol into the stomach in five experiments, lasting from
3 minutes to 3 hours, there was absorbed from 8 to 48 per cent, whilst
only from 0.0025 to 1.1 per cent could be recovered from the intestine.
The average absorption was 28 per cent; the average intestinal excre-
tion 0.4 per cent. The intestine, therefore, participates only to a very
slight extent in the excretion of phenol, and this cannot account for the
retention. The excretion into the stomach is even less. In four experi-
ments in which the phenol remained in the ligated intestine for to 1
hour, with absorption of 18 to 44 per cent, the stomach contained from 0
to 0.013 per cent; the average absorption being 31 per cent; the average
excreted into the stomach, 0.0035 per cent. In one of the experiments,
the stomach was distended with water, in another, with oil, to see
whether the excretion could be facilitated by diffusion. Both were
negative, the water-stomach containing only 0.004 per cent of the
phenol, the oil-stomach none whatever.

VI. INFLUENCE OF PHENOL ON THE ABSORPTION OF OTHER SUBSTANCES

Having shown that phenol checks its own absorption, we inquired

whether it also checks the absorption of other substances. In one series
416 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

of experiments, we determined the absorption of sodium iodid4 (0.1

gm. per kg.) from the ligated stomach. Three cats absorbed the follow-
ing percentages of the iodid.
TABLE VI
Absorption of sodium iodid from stomach
PER CENT OF
SERIAL NUMBER TIME OF SOJOURN 10010 ABSORBED

Cat 39 9 mm. 2.4

Cat 40 28A mm. 21.8
Cat 41 50mm. 88.8

To a fourth animal (cat 38), phenol (1 gni. per kg.) was administered
with the iodid. In an hour, there was absorbed of the phenol 31 per
cent; of the iodid, only 48.6 per cent; indicating that the phenol checks
the absorption.
In another series, the iodid was placed in one ligated ioop of intestine
and the mixed iodid and phenol in another. After half an hour the
absorption of the iodid averaged in two cats 43 and 44): for iodid alone
29.4 per cent, for the iodid-phenol loops, 28.1 per cent. Here there
is practically no difference.
In a third series, however, the inhibitory effect of phenol is very strik-
ing. In dogs 107 and 112, concentrated phenol (1 gui. per kg.) was left
in a loop for 10 minutes. The loop was then thoroughly washed and
divided in the middle by a ligature. Two loops of equal length were
then prepared at each end. Ten cubic centimeters of 1 per cent NaI
were then introduced into each of the four loops and left for half an hour.
Considerably more iodid was absorbed from each of the loops which had
not been treated with phenol, the iodid absorption from the four phenol
loops averaging only 19.6 per cent, whilst the absorption from the con-
trol loops averaged 47.4 per cent.
In dog 115, the same disposition was adopted, but 25 per cent alcohol
was used instead of the 1 per cent iodid. The loops and contents were
distilled and diluted to an equal volume. The specific gravity of the
distillates from the two control loops was higher than that from the
phenol loops (averaging 0.996 against 0.991). In other words, more
alcohol had been absorbed froni the control loops. We may, there-
fore, conclude that phenol checks the absorption of alcohol, as well as
of iodid.
Analytical method in Appendix.
 PHENOL ON ABSORPTION 417

VII. THE RETENTION IS NOT DUE TO CORROSIVE CHANGES

We may now inquire into the mechanism by which phenol checks

absorption. The local corrosive or coagulative or necrotic actions
of phenol on the absorbing epithelium furnish a tempting explanation
of the inhibited absorption. Were this correct, we would expect that
the retention would vary in the same direction as the concentration of
the phenol; we would further expect that other corrosive agents or
protoplasmic poisons would cause a similar inhibition. We tested the
matter as follows:

(a) Effect of Dilution

As we have stated, the average absorption of concentrated phenol,

in our restricted series, amounts to 38.5 per cent. In four animals,
in which the same dose was administered as a 5 per cent aqueous solu-
tion, the absorption averaged 31.3 per cent; i. e., it was practically
identical. In four animals, the same doses of both the concentrated
and the diluted phenol were placed in separate ioops (using in all 7
loops for the dilute and 6 ioops for the concentrated). The average
absorption of the dilute phenol amounted to 20.1 per cent, that of the
concentrated to 35.4 per cent. Dilution therefore hinders, rather than
favors, the absorption, so that the retention cannot be attributed to
such gross local anatomical changes as would be proportional to the
concentration.

(b) The Effect o( the Stomach-contents

The feeding of the animals was generally so timed that the stomach
would be empty at the operation. In one animal, however, the
stomach was filled with food and in another with hair; both gave rather
low absorption percentages (16 and 23 per cent), agreeing with the
effect of dilution.

(c) The Effect of the Vehicle

A few experiments were majie to test the practical question whether

different diluents have any influence on the absorption, the solutions
being placed in separated ligated loops.
418 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

Three ioops with 5 per cent watery solution averaged 33 per cent
absorbed, one loop with 5 per cent solution in 50 per cent and two in
95 per cent alcohol averaged 18 per cent; four loops with concentrated
phenol averaged 48 per cent. A single loop with 5 per cent solution in
glycerine absorbed 27 per cent and one with 5 per cent phenol in olive
oil absorbed 68.5 per cent. Omitting the last two data as too limited
in number, it would appear that dilution with alcohol hinders absorp-
tion somewhat more than dilution with water; although the experi-
ments of Clarke and Brownt have shown that the difference is not
sufficiently large to be of any practical value in phenol intoxication.

(d) The Effect of Formaldehyde

The actions of this agent on protoplasm presents some analogies

with that of concentrated phenol and if the impediment to absorp-
tion were due to this chemical action, a preliminary treatment of the
epithehum with formaldehyde would presumably prevent altogether
the absorption of phenol. In each of two animals, therefore, four
loops of intestine were ligated. Two of these were filled with 40 per
cent formaldehyde, the two others, as control, with normal saline solu-
tion. After ten minutes, the loops were rinsed and filled each with the
same quantity of phenol. The absorption in the control-loops aver-
aged 38 per cent; in the formaldehyde ioops, 46 per cent. The for-
maldehyde therefore favored the absorption, instead of impeding it
as would he expected if the inhibition were due to the local chemical
action.
(e) The Effect of Sodium Fluoride

The negative results with dilution, whilst they speak against the
corrosive action as the correct explanation, leave open the possibility
t.hat phenol might injure the absorbing power of the epithelium in vir-
tue of a direct toxic action; analogous to that of sodium fluoride which
would be more or less independent of the concentration. It was
found, however, that sodium fluoride does not check the absorption of
phenol, so that this explanation does not appear probable.

T. \V. Clarke and E. 1). Brown: The Value of alcohol in carbolic acid poisoning.
Journ. Amer. Med. Assn., March 17, 1906.
rr

PHENOL ON ABSORPTION 419

In each of two cats, four loops of intestine were ligated. One was
filled with 0.3 per cent NaF for five minutes and another for fifteen
minutes. The other two loops were left empty as controls. All the
loops were then washed and in each was placed the same quantity of
phenol and left for half an hour.
In cat 45, the absorption from the two fluoride loops averaged 36 per-
cent; from the control loops, 35.5 per cent. In cat 46, the fluoride loops
averaged 37 per cent, the control loops 35.5 per cent.

(f) Post Mortem Absorption

The fact that the fluoride does not interfere with the absorption o
phenol suggests rather strongly that the phenol absorption does not
require the vitality of the epithelium. Some interest, therefore,
attaches to determinations of the absorption of phenol when this is
placed in the stomach or intestine after the death of the animals.
We found that considerable absorption occurs, hut much less than in
the living animal.

We made a total of thirteen of these determinations; nine on dogs’

stomachs, one on a cat’s stomach, and three on cats’ intestines. The
phenol was administered as usual, in the dose of 1 gram per kilogram;
with the cats just after death; with the dogs, at different times up to
several hours after death. The viscus was returned to the abdomen and
removed after one hour. The absorption in the thirteen experiments
varied from 2 to 47.5 per cent, with an average of 16 per cent; half of the
experiments showed hn absorption of less than 8.5 per cent.
In three cats we maintained the blood pressure at 25 to 90 mm. for
ten minutes post mortem, by cardiac massage with intermittent carotid
injections of saline solution under pressure. The absorption was from
7.5 to 14 per cent, average 11.5 per cent.

Whilst these results are in harmony with the conclusion that the
absorption of phenol is independent of the vitality of the epithelium,
we would not attach much weight to them: for we have no facts to
prove that the mechanism of this postmortem absorption is the same
as the mechanism during life.
420 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

VIII. PHENOL CHECKS ABSORPTION EVEN WITHOUT LOCAL CONTACT

We showed in the previous sections that the phenomenon under

consideration is not conditioned on the corrosive action of phenol.
This is confirmed by the fact that the administration of phenol checks
the absorption of further doses of phenol, even when these are placed
on an intestinal surface which has been protected from direct contact
with the preceding doses. This is shown by the following experiments:

(a) In two dogs, 0.2 gram of concentrated phenol per kilogram of

body weight, was placed in a ligated loop of intestine; half an hour later,
an equal dose was placed in a second loop; and this was repeated
at
half-hour intervals until a total of five doses
The had been given.
animals were killed half an hour after the last dose. The first dose had
therefore sojourned 2 hours, the last half an hour. As we have shown,
the absorption is usually arrested within half an hour; so that, if the
action were purely local, the last dose should have been absorbed about
as well as the first. The average of the two dogs, however, show a
steady decline in the absorbing power:
PER CENT.

First dose remained 2 hours in ileum, absorption averaged 74.5

Second dose remained 2 hours in jejunum, absorption averaged .... 67
Third dose remained 1 hours in colon, absorption averaged 26.5
Fourth dose remained 1 hour in rectum, absorption averaged 27
Fifth dose remained hour in duodenum, absorption averaged 7.5

The force of the proof here involves the assumption that the absorp-
tion in each ioop was indeed practically arrested within half an hour.
To exclude any possibility of doubt, we made another series of experi-
ments:

(b) The phenol was again administered in fractional doses by

successive loops; but each loop was excised before the next dose was
injected. In this way the absorption of each dose could be detei mined
separately. Each successive dose was equal in amount and allowed
to remain in the intestine for an equal length of time (ten minutes).
The following percentage of absorption was obtained:
 I
PHENOL ON ABSORPTION 421

TABLE VII

Absorption of phenoifram successive loops

SERIAL NUMBER 102 106 108

PERCENTAGE OF PHENOL ABSORBED.

First dose. 86 30 32
Second dose . 23 25 39
Third dose . 16 26 27
Fourth dose 12 22 26
Fifth dose 0 23 30
Sixth dose 0 13 22
Seventh dose
Eighth dose
Ninth dose

It is seen that the absorption at a certain point deteriorates and is

checked and eventually arrested, although there has been no previous
direct contact with the phenol.
(c) In this series we attempted to determine the absorption of
successive doses from the same loop, in the hope of determining whether
direct contact checked absorption more effectually and showing thereby
whether a strictly local action had any share whatever in the phenome-
non. For this purpose, we proceeded as follows: Equal doses were
injected in close succession into four ioops. At the end of ten minutes,
two of these were excised and the other pair were thoroughly flushed
until they ceased to have the odor of phenol. They were then again
ligated and the same dose placed again in this pair, and also into a
fresh pair of loops. After a sojourn of ten minutes, these were all
excised.
The results in experiment 109 were as follows:
Absorption from first set of doses averaged 38 per cent.
Absorption from second set of doses averaged for pair in previous
contact with phenol, 13.5 per cent.
Absorption from second set of doses avei aged for fresh pair, 4.3 per
cent.
It is seen that the absorption averaged higher in the loops which
had been in contact with the phenol; in other words, direct contact
does not seem to contribute to the check of the absorption. It must
422 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

be confessed that this method is rather crude, since we could not be

certain that we had removed the phenol completely in washing the
intestine. In fact, we shall show that the intestinal wall may contain
considerable phenol which cannot be removed by a brief washing.
This, however, renders our results all the more convincing; for the
phenol remaining from the first dose would apparently lower the absorp-
tion of the second dose by so much; whereas, the results showed it
to be greater than that of the fresh loops. Indeed, it would seem that
the local contact with phenol tends to counteract the inhibitory effect.
(d) Finally, in experiment 108 (quoted above), we allowed intervals
increasing to 40 minutes to elapse between the successive doses, with
the hope of showing that the check would pass off with the excretion
of the phenol. The result was, however, negative; the action of the
phenol persisting through this time.

IX. THE EXTENT OF THE ABSORBING AREA DOES NOT INFLUENCE THE

ABSORPTION PERCENTAGE

This was determined by placing equal doses of phenol simultaneously

into a short and in a long loop in the same animal, for the same length of
time. To assure good distribution, the injection into the longer loop
was divided among a half dozen separated punctures.
The absorbing percentage was found to be:
Dog 100: 10 cm. loop, 54.7 per cent; 80 cm. loop, 55.1 per cent.
Cat 103: 10 cni. loop, 64.8 per cent; 65 cm. loop, 64.5 per cent.
The fact that the extent of the absorbing surface has practically no
influence on the rate of absorption, is of considerable interest. Its
main importance in the present connection is as further evidence that
the checking nichanism does not consist in local injury of the cells; for
the local injury would tend to be less and the absorption consequently
greater, if the same quantity of phenol is distributed over a consider-
ably greater surface.

X. THE INFLUENCE OF THE DOSE ON THE ABSORPTION RATE

In the production of a local injury, the absolute dose of the poison

is a factor altogether secondary in importance to the concentration
and to the area of application. A systemic action, on the other hand,
 PHENOL ON ABSORPTION 423

depends mainly upon the dose of the poison which reaches the circula-
tion in a given time. Since we have already shown that neither the
concentration nor the extent of absorbing surface have any influence on
the absorption of phenol, the establishment of the fact that the dose is
a predominant and constant factor would be another strong link in
the evidence that the check in absorption is produced by a systemic
and not by a local action; in other words, that it is caused by the phenol
which has been absorbed into the circulation and not by the phenol
which remains in the alimentary canal. The study of the influence of
the dose on the absorption is therefore of considerable interest.
We first attempted to determine this by giving single doses of differ-
ent magnitude to different animals, with the following results.

TABLE VIII

Absorption of phenol according to dose

EXTREMES OF AVERAGE
ABSORPTiON ABSORPTION
APPROXIMATE
ADMINISTERED DOSE (PEROF PHENOL
KG.) OFEXPERI- B

MENTS
Per cent. Gr. per kg. Per cent Gm. per
kg.

igram 45 10-64 0.1 -0.6 38.5 0.385

0.5grams 5 23-69 0.08 -0.23 42 0.14
0.04 to0.2grams 7 10-90 0.006-0.16 50.5 0.055

The results appear to show that with smaller doses, a somewhat

larger percentage is absorbed, but a much smaller absolute amount.
The individual variability in different animals is so great, however, that
a very much larger series of experiments with the smaller doses would
be needed to permit reliable quantitative conclusions. Here again,
much more useful data were obtained by administering successive
doses of phenol into successive loops of the same animal, so that, by
excision, the exact quantity absorbed at a given time could be deter-
mined.
The results are detailed in table IX.
All these experiments show that the absorption diminishes very
markedly toward zero as increasing doses become absorbed (although
the rate of decline differs in the three animals). It is also worthy of
especial notice that the decline depends not on the dose administered,
424 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

TABLE IX

Influence of the absorbed phenol on farther absorption

The columns headed A show the quantities of phenol (Gm. per Kg.), actually absorbed before the
loop was injected. The columns B show the percentage of phenol absorbed from the loopS
The heavy figures call attention to important changes in this percentage.

SERIAL NUMBER + DOG 102 DOG 106 DOG 108

0.035 gram 0.045 gram 0.06 gram

Quantity of Phenol (per Kg.) placed in each ______________ - -
successive loop
A B A B A B

First loop 0 86 0 30 0 32
Second loop 0.030 23 0.018 25 0.016 39
Third loop 0.038 16 0.033 26 0.030 27
Fourth loop 0.049 12 0.049 22 0.043 25
Fifth loop 0.057 0 0.062 23 0.055 30
Sixth loop 0.076 13 0.070 22
Seventh loop 0.083 11 0.080 6
Eighth loop 0.090 11 0.084 5
Ninth loop 0.097 0.086 0

but on t ie dose absorbed. Thus, the first administration caused a

very sharp decline in 102, very little in 106 and 108; this agrees with
the fact that the absorbed dose was twice as great in 102 than in the
others. The first dose injected, however, was smaller, namely 0.035
gm. per kg. in 102 against 0.045 in 106 and 0.06 in 108. This is a very
striking confirmation of the fact that the inhibitory action is systemic
and not local.
The rate at which the absorption declines differs in the three ani-
mals, as may be seen if we compare the doses required to reduce the
absorption to a given percentage:

TO REDUCE THE

ABSORPTION PER- REQUIRES AN ABSORPTION DOSE OF

CENTAGE TO-

(Expt) 102 106 108 109

20-25 (Dose) 0.030 0.049 0.070
13-16 0.038 0.076 <0.080
5-12 0.049 0.083 0.080 <0.155
0 0.057 >0.097 0.086 >0.155

The individual variability is emphasized by the fact that in two of

these experiments, the absorption was practically arrested by doses as
 PHENOL ON ABSORPTION 425

low as 0.057 and 0.086 grams per kilogram respectively; whilst, on the
other hand, in the usual experiments in which large doses of phenol
were given by a single administration, the absorption as we have seen,
averaged about 0.4 grams per kilogram and in some experiments
reached as high as 0.6 grams per kilogram. In other words, to stop
absorption, some experiments required ten times as large a dose as
others. It appears that the difference depends on the size of the
initial dose. It can be readily explained on the assumption that it
requires an appreciable, if small, interval of time to bring the inhibitory
mechanism into play; and since the initial rate of absorption of phenol
is very rapid, there may be absorbed considerably more phenol than
would be required to stop absorption if it had been introduced at a
rate which would permit it to exert its action pan pasu. This would
be entirely analogous to the fact that it is possible, by a very rapid
intravenous injection, to introduce much more than the true fatal
dose of a poison before death actually ensues
The extreme probability of this explanation is illustrated by the
fact that in cat 9, 0.4 gram of phenol per kilogram had been absorbed
within one and a half minutes-that is, before one would expect an
inhibitory mechanism for absorption to become effective. This
explanation also furnishes the key to the fact that, with single doses,
the absorption percentage was influenced to so surprisingly slight
degree by the size of the dose (38.5 per cent for 1 gm. per kg.; 50.5 per-
cent for 0.04 to 0.2 gm. per kg.): In both cases the main absorption
probably occurred before sufficient time had elapsed to allow the inhibi-
tory mechanism to enter into play.

XI. COINCIDENCE OF THE CHECK TO ABSORPTION WITH THE I)EVELOP-

MENT OF THE SYMPTOMS

The experiments just quoted were originally made to compare the

progress of the absorption and of the toxic symptoms; the stomach
being excised as soon as the blood pressure appeared to have reached
the minimum.
In cat 9, the pressure had fallen from 205 to 145 mm. in 1 minutes
after the injection; and it was found that 45 per cent of the phenol had
been absorbed. In cat 10, the pressure fell from 140 to 95 mm. in ft
426 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

minutes; it was found that 30 per cent had been absorbed. The phenol
twitching in this animal started within two minutes after the injection.
It will be recalled that the absorption is generally arrested when this
percentage is reached. This suggests that the arrest of absorption
coincides with the development of the toxic symptoms. However,
this might be only an accidental coincidence.

Xli. THE INFLUENCE OF BLOOD PRESSURE ON ABSORPTION

The experiments so far described establish that phenol checks

absorption by a systemic and not by a local action.
The mechanism of this systemic action still remains to be elucidated.
Since phenol produces a marked fall of blood pressure, this deserves
first consideration as a possible causative factor. Blood pressure
tracings were taken in all of our experiments, and permit an extensive
comparison.

We shall examine, in the first place, the influence of the initial blood
pressure; i. e., the pressure recorded just before the phenol was adminis-
tered. In this way we shall exclude to a large degree the effects of the
phenol itself. Our material presents the following data.

TABLE X

Relation of absorption to the initial blood pret.ture

AVERAGE PER NUMBER OF
iNITIAL BLOOD PRESSURE CENT OF PHENOL EXPERIMENTS
ABSORBED
mm.
<40 13 7
45-80 26 20
85-110 3O 18
115-125 32 9
125-150 26 19
>150 30 13

It is seemi at once that a blood pressure below .40 mm. interferes notice-
ably with absorption; whilst with pressure above 45 mm. the averages
run fairly constant. It would therefore seem that the height of the
general blood pressure has little effect on the absorption of phenol, unless
it drops below 40 mm., when the absorption is very markedly checked.
This critical blood pressure corresponds to a state of profound shock.
The immediate cause of this shock varied in the different experiments.
All of the seven animals in which it occurred were cats, which appear
 PHENOL ON ABSORPTION 427

to be especially subject to shock. In three of these cats, the shock was

produced by submerging the animals in a warm saline bath; in one, it
was produced by hemorrhage; in one by an intravenous injection of
phenol; and in two, no specific cause could be assigned. Notwith-
standing the shock, the animals survived the phenol well-two were
killed at the end of an hour, two after half an hour; the others died in 23,
20 and 10 minutes. There was consequently sufficient time for the
absorption of the phenol to run its course.
Considering that these different causes of shock had a uniform effect
upon absorption, it is to be expected that the same check would occur
if the blood pressure is lowered to the critical point by means of phenol
itself. If so, one would expect that the percentage of absorption would
vary with the time elapsing between the administration of phenol and
the point when the pressure has fallen to 40 mm.
Our data on this question are shown in table XI. (Experiments running
less than half an hour being excluded, to insure the completion of the
absorption process).
TABLE XI

Absorption according to the time required to reach the critical blood-pressure

AVERAGE PER NUMBER OF
THE BLOOD PRESSURE FALLS TO 40 MM. CENT OF PHENOL EXPERIMENTS
ABSORBED

Bef ore injection 13 6

l0min.afterinjection 23 3
3Omin.afterinjection 43.5 7
>30 mm. after injection 38 20

It is seen that up to thirty minutes the percentage of absorption varies

strikingly with the time required to reach the critical fall of blood pres-
sure. There can, therefore, be no doubt that when phenol lowers the
blood pressure to the critical point, this furnishes a factor in checking
absorption. If, however, this event is postponed for half an hour, it
has no further influence. This indicates that absorption has already
been checked by some other factor.
How is it when the lowering of blood pressure by phenol does not reach
the critical level of 40 mm.? This may be seen from table XII.
Since the absorption of phenol is largely chedked within ten minutes
of phenol administration, we have tabulated the average absorption
percentage compared with the level of blood pressure which was reached
ten minutes after the administration of phenol: (Including only experi-
ments running longer than ten minutes).
428 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

TABLE XII
Absorption according to the blood pressure at the end of ten minutes after injection

AVERAGE PER NUMBER OF

BLOOD PRESSURE CENT OF PHENOL EXPERIMENTS
ABSORBED
mm.
<30 18 3
30-45 19.5 9
50-60 36 13
65-75 39.5 8
75-80 33 9
85-95 35 7
>95 42 4

By comparing this with table X, it will he seen that the results are
closely similar; from this we must conclude that the lowering of the
general blood pressure by phenol does not check the absorption, unless
the critical level of 40 mm. is reached.
We have also tabulated in table XIII the absorption percentage
according to the blood pressure pertaining at the end of thirty minutes-
the time when the absorption has come practically to a standstill (includ-
ing only experiments running longer than half an hour.)

TABLE XIII
Absorption according to the blood pressure at the end of half an hour after injection
AVERAGE PER NUMBER OF
BLOOD PRESSURE CENT OF PHENOL EXPERIMENTS
ABSORBED
mm.
<30 . 11 2
30-45 42.5 6
50-60 43 5
65-75 47 6
75-80 45 1
85-90 45 2

This also shows that the level of the blood pressure does not affect
absorption until the critical low point is reached. This point appears
to be lower than in the preceding tabulations (viz: below 30 mm.). This
may be readily understood; for if the attainment or the critical pressure
of 40 mm. is postponed beyond ten minutes, the absorption has already
reached its maximum and come to a standstill, as was shown by table
XI.
We have further tabulated the average absorption according to the
mean level of the blood pressure, during the first ten minutes and during
the entire course of the experiments.
 -.

PHENOL ON ABSORPTION 429

TABLE XIV
Absorption according to the mean blood pressure during the first ten minutes following
the injection
AVERAGE PER NUMBER 07
BLOOD PRESSURE CENT OF PHENOL EXPERIMENTS
ABSORBED
mm.
<35 14 6
35- 55 24 10
55- 75 30 16
80-100 31 31
105-130 38.5 8

The results are practically a duplication of those obtained with the

initial blood pressure (table X).

TABLE XV

Absorption according to the mean level of the blood pressure during the entire experiment

DURATION OP THE EXPERIMENTS 5 WIN. 10 MIN. 30 WIN. 1 HR. 2 HR8. >2 HRS.

BLOOD PRESSURE AVE RAGE PE B CENT OF PHENOL ABSORBED

nim.
< 35. 20 12 18 44
35- 50 11 30 39 37 41
60- 75 12 27 25.5 40.5 48
80-100 27 33 33 36
100-125 36 + 25
> 125 43 24

Table XV again shows a very conspicuous relation between the blood

pressure and absorption which is the more marked the shorter the
experiment. It can again be observed that the critical level appears
to be lowered by a longer sojourn-a matter which we have already
discussed.

In brief then, the tabulations comparing the average absorption with

the blood pressure, lead to the following conclusions:
1. The absorption is greatly checked when the blood pressure falls
below a certain critical level, namely, about 40 mm. Variations of
blood pressure between 40 and 75 mm. scarcely affect the absorption
and variations above 80 mm. certainly have no effect.
When phenol lowers the blood pressure to this critical level, this
constitutes a definite factor in the checked absorption. In the vast

.1
430 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCUER

majority of the exjieriments, however (something like 90 per cent,

accor(hng to table XI), the absorption becomes practically arrested
before the critical level is reached, and we must therefore seek the
common and essential cause of the checked absorption in another
direction than in the general blood presure.
This conclusion is borne out by a study of the blood pressure of
seven experiments in which the course of the absorption was followed
step by step, by the excision of the loops. This study shows that the
decrease in absorption appears to run quite independently from the
changes of blood pressure above the critical level. In three of the
experiments, there is absolutely no relation between blood pressure and
absorption. In an equal number the pressure and absorption vary in
the same direction; but the disproportion is so great that there can be
no causative connection between them.

XIII. ARTIFICIAL CHANGES OF GENERAL BLOOD PRESSURE +

The figures of dogs 102 and 106 indicate that an adrenalin rise of
1rssure has absolutely no effect on absorption. The amyl nitrite fall
appears to check absorption, but the data are not sufficient to exclude
accidental coincidence. We have also experimented with other
measures for modifying the general blood pressure.

HEMORRHAGE AND OVER TRANSFUSION

In this series of experiments, one set of animals were bled severely,

their blood being transfused into another set of animals. Concen-
trated phenol was then placed into the ligated stomach in the dose of
1 gram per kilogram. The results were as follows:
 + . ., +‘, . . .. . 1. . +

PHENOL ON ABSORPTION 431

TABLE XVI

Hemorrhage and overtransfusion on absorptioif

MEAN BLOOD-
BLOOD PRESSURE PRESSURE TIME OF I PER CENT
SERIAL NUMBER LOWERED BY DURING SOJOURN OF OF PHENOL
Hemorrhage FROM SOJOURN OF PHENOL ABSORBED
PHENOL

mm. +

Cat 50 150-100 75 hour 14

Cat 59 108-94 50 hour 34
Cat 61 150-30 20 20 mm. 18
Dog 85 143-60 65 1 hour 39

BLOOD PRESSURE
RAISED BY OVER-
TRANSFUSION FROM

Cat 52 95-(no record) 75 hour 24

Cat62 130-160 60 hour 34
Dog84 100-160 90 ihour 21

In cat 61 the pressure had sunk to the critical level.

The average absorption for the other three hemorrhage animals
is 29 per cent; for the three over-transfused animals it is 26 per cent.
It is therefore evident that alterations of the blood pressure produced
by hemorrhage or over transfusion, do not affect the absorption of
phenol (unless the pressure falls to the critical level.)

Systemic Vasoconstriction by Means of Drugs

In this series, the administration of phenol was accompanied by

intravenous injection of the following drugs:
Ergot: Experiments 72 and 78; absorption, 21 and 18 per cent;
average 19k.
Strophanthus: Experiments 71 and 73; absorption, 12 and 25 per
cent; average 18.
Strophanthus and Caffeine: Experiments 74, 75, 76, 77; absorption
19, 24, 11, 25 per cent; average 20 per cent.
Average absorption for all these drugs, 19k.
Since the absorption averages normally 38.5 per cent, it is evident
that all these drugs lessen the absorption. This does not depend upon
 + r

432 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

blood pressureL for this, under the influence of phenol, averages about

the same as in1he phenol-poisoned animals without these drugs.

XIV. CHANGES IN THE LOCAL CIRCULATION

The absence of any important relation between, absorption and

generalS blood pressure does not exclude defective circulation as a
factor, perhaps the essential factor, in the inhibited absorption. We
must not forget that the general blood pressure does not always reflect
the degree or even the nature of the circulatory changes in a particular
vascular tract. It is therefore quite possible that phenol acts on the
circulation of the alimentary tract much more powerfully than is
indicated by the general blood pressure. An example of this is afforded
in the preceding paragraph, when we saw that vasoconstrictor drugs
lessened absorption, although the general blood pressure was maintained.
Again, the “critical level” at which absorption is checked, perhaps
represents only the level at which the compensatory mechanism which
tends to maintain the general blood pressure is paralyzed, so that now
the general blood pressure gives for the first time a true picture of the
local circulatory condition in the intestine. The next step in our
investigation was, therefore, to determine the influence of local changes
in the intestinal circulation on absorption.
In this series, a number of loops of intestine were closed with liga-
tures. Some of these loops were then subjected to the local measures
under investigation, whilst others were reserved as controls. Approxi-
mately equal doses of phenol were then placed in close succession in
each loop and after a given time, the animal was killed.
The results are summarized in table XVII.
It is plainly evident that measures which affect the local circulation
in the intestine influence the absorption of phenol in a very pronounced
degree, namely:
The absorption is:
Decreased with cold, division of nerves, epinephrin, and strophanthus;
Increased with nitrite, pinching, formaldehyde;
Variable with chioral, mustard, croton oil.
It may be noted that all the agents of the last class are violent
irritants and it would be expected that the circulation would vary
 PHENOL ON ABSORPTION 433

according to the degree of the inflammatory reaction which they

happen to produce in a given case. It is therefore not surprising that
their effect on absorption should also be variable. This is well illus-
trated by the Mustard loops in Experiment 119:
Equal quantities of an alcoholic solution of mustard oil were placed in
two loops each 10 cm. lon.g, one in the colon, the other in the duodenum.
Forty minutes later, both loops appeared dusky, congested, and were
filled with effusion. The duodenal loop contained the most fluid, and 9

TABLE XVII

Local vascular changes on absorption

I NUMBER OF
AVERAGE PERCENTAGE OF DIFFERENCE EXPERI-
PHENOL ABSORBED FROM IN AVERAGE MENTS IN
PERCENTAGE WHICH
LOCAL TREATMENT. .
BETWEEN ABSORPTION
THE TWO WAS
Treated Control LOOPS.5 HINDERED:

+ Loops Loops IMPROVED

Ice to peritoneal surface of ioop 13 42 -29 2 :0

Mesenteric nerves of loop torn 10 15 - 5 + 6 :0
Epinephrin in lumen 13 16 - 2 3 : 1
Strophanthus in lumen 16 19 - 2 1: 1
Chloral in lumen 7 + 12 - ft 1: 1
Mustard oil in lumen + 14 18 - ft 1: 1
Croton oil, several drops smeared
over epithelial surface 31 30 + 1 2 :2
Formaldehyde in lumen 46 38 + 8 1 :3
Intestines pinched with fingers for
several minutes preceding the ad-
ministration (causing bright red 22 14 + 8 0 : 2
congestion) +

Nitrite of sodium in lumen 27 12 + 15 0 : 2

* - signifies that the treatment decreases the average absorption; + signifies the reverse.

cc. were withdrawn. Concentrated phenol (about 0.45 gm.) was then
placed in each loop. Forty minutes later, the colon loop was still dark,
the duodenal loop was of normal color and had refilled with effusion.
The absorption from the duodenal loop was found to be 27 per cent;
from the colon ioop, only 1.3 per cent had been absorbed.

To judge from the effects of epinephrin, strophanthus and cold on

the one hand, and of nitrite and pinching on the other, it appears that
434 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

local vasoconstriction results in decreased absorption, and local

vasodilation, in increased absorption. However, it would not be safe
to generalize this rule as is shown by the decreased absorption after
division of the mesenteric nerves. Before proceeding further with this
subject, however, let us inquire into the other possibility, namely:

XV. IS THE INHIBITED ABSORPTION DUE TO PARALYSIS OF THE ABSORB-

ING EPITHELIUM?

As we have pointed out, the inhibitory action is not local, but

produced by the phenol which has been absorbed into the circulation.
This in itself speaks against injury to the epithelium, since direct con-
tact with the phenol would be expected to enhance any paralytic
action on the epithelium. The adverse presumption is strengthened
by the fact that only minimal amounts of phenol are excreted through
the alimentary canal; so that it could scarcely reach the absorbing
cells in effective concentration through the circulation. Further, we
have shown that the absorption of phenol is not further impeded by
such severe injury of the epithelium as may be produced by formal-
dehyde and fluoride. All this evidence is indirect, but it points strongly
to a negative conclusion.
Direct evidence could only be furnished by excluding all changes
in the circulation while the phenol is acting on the epithelium.
Artificial perfusion would approach this desideratum; but the ideal
conditions could only be realized with certainty by working in the
absence of any circulation. We made some experiments in both
directions.

The absorption of phenol from artificially perfused stomachs

(a) In two experiments (116 and 119) the stomach was excisedand
the orifice closed with ligatures and the gastric vessels perfused with
Locke’s solution. Fifty cubic centimeters of 4.4 per cent phenol were
then introduced into the viscus. Samples were removed at the end of
10, 20 and 50 minutes. The perfused solution was collected for each
period and its phenol estimated. The gastric mucosa became very edem-
atous, as may be seen from the table. The results of the two experi-
ments were nearly identical, so that we need only present the averages:
 PHENOL ON ABSORPTION 435

Transfusion into Stomach

Quantity of phenol solution introduced into st’omach 50 cc. At

the end of 10 and 20 minutes samples of 5 cc. were removed. At the
end of 50 minutes, the stomach contents measured 289 cc. Therefore
240 cc. of the perfusion-fluid has transfused through the mucosa.

Phenol concentration of stomach contents

PER CENT

The solution as introduced into the stomach contained 4.4 phenol

The stomach contents at the end of 10 minutes contained 2.57 phenol
The stomach content at the end of 20 minutes contained 1 .57 phenol
The stomach contents at the end of 50 minutes contained 0.48 phenol

A large part of the decreased concentration is due to dilutn from the

transudate.

Absorption of phenol into the perfusion fluid

The collected perfusion fluid corresponds to the following (lata

FLUID COLLECTED PER CENT OF FLOW PHENOL ABSORBED

AT END OF TOTAL FLUID PHENOL PER 10 MINUTES PER 10 MINUTES

10mm 425 0.031 425 0.129

20mm 500 0.009 500 0.048
50mm 1060 0.0085 349 0.017

This table shows indeed an apparent decrease in the absorbing power,

but it may be seen that this corresponds largely to the dilution of the
phenol by the transudate:
If we compare the average concentration of the stomach contents
with the average absorption in each period, we find the ratio to be
approximately:

FIRST PERIOD SECOND PERIOD THIRD PERIOD

Concentration 3.5 1
Absorption 7.5 3 1

It appears therefore, as if the absorption decreased t+wice as much as

the concentration. Another factor enters, however, which makes it
more than doubtful whether this excessive decrease is at all analogous
to the phenomenon in the intact circulation. This factor if the extreme
edema of the gastric walls.
436 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

The emptied stomach measured (average) : At the beginning of the

experiment, 150 cc. At the end of the experiment, 320 cc. an increase
of over 100 per cent. The phenol content of one of the stomachs was

estimated and amounted to 0.065 per cent (the stomach contents con-
taming 0.38
per cent and the perfusate 0.006 per cent).
In view of this complicating factor-the edema- we abandoned this
line of investigation and attempted to determine:

(b) The influence of phenol on absorption from excised intestine

Four loops of intestine, after the preliminary treatment to be described

below, were closed with ligatures, and placed in warm Locke’s fluid,
supplied with a slow stream of oxygen. Into each loop was introduced
10 cc. of 1 per cent sodium iodid solution. The loops were then left in
the fluid for 35 minutes, when the remaining iodid was estimated, and
the absorpt+ion calculated.
One of.the loops had been excised before the animal received phenol;
the others, 12 minutes after concentrated phenol in the dose of 1 gm.
per kg. had been introduced. Two of these loops had been in contact
with the injected phenol, whilst the other had been protected by liga-
tures from direct contact with the poison.
We thus secured: A control ioop taken before phenol was given;
A loop which had been exposed to the phenol carried through the
circulation, but protected from the loc&l action.
Two loops which had been exposed to the direct local action of phenol.

Notwithstanding these differences in the exposure to phenol,

exactly the same amount of iodid (11.1 per cent) diffused out of each
of the four loops. Evidently, then, phenol has no effect on the absorp-
tion of iodid when the circulation is excluded.
This experiment is again open to the objection that the diffusion
from an excised loop of intestine may be and probably is, carried on
through a different niechanism than the absorption in the intact
animal. The best proof of this is the very fact that phenol checks
absorption during life and not in the excised loop. The most conspicu-
ous difference between the experimental conditions during life and in
the excised ioop, however, is the absence of circulation in the immersed
intestine. So that the failure of phenol to check absorption from the
excised loops, again points to the conclusion that phenol inhibits
absorption by an action on the circulation. In view of the usual
________________________ +

PHENOL ON ABSORPTION 437

persistence of cellular activity in excised and immersed organs, it

would be expected that if the vital activity of the absorbing epithe-
hum had any share in the absorption of the iodid during life, it would
continue to contribute somewhat to the absorption from the excised
intestine. Further, if it did so contribute, we could expect it to be
paralyzed by phenol, had this poison such a paralyzant action on the
epithelium during life.
The absence of such a difference argues, therefore, strongly against
the existence of a paralyzant action.

XVI. THE DISTRIBUTION OF THE UNABSORBED PHENOL BETWEEN THE

INTESTINAL WALL AND CONTENTS

In the perfusion experiments, it was noted that the stomach wall

contained quite a large proportion of the phenol (wall = 0.226 gm.
of phnol; contents = 1.205 gm.). It appeared interesting to investi-
gate this distribution under other conditions, although the result
would have no bearing on the present inquiry. The results, as pre-
sented in table XVIII,6 show that a considerable part of the unabsorbed
phenol exists in the intestinal and gastric wall, in such a form that

TABLE XVIII
Distribution of unabsorbed phenol

A B C D E TOTAL

AVERAGE PERCENTAGEOFTHERETAINED ZRz O 0

PHENOL CONTAINED IN 0 Z
_________________________ _____ _____

Concent. phenol in two intestinal ioops

forhaif hourduring life 32.6 29.3 14.4 10.7 13.1 31
10 per cent phenol in one stomach for 70
minutes during life 62 6.5 5.0 6.6 19.9 40
10 per cent phenol in two stomachs for
one hour after death. 64 11.7 7.2 5.1 12.1 20

In explanation of this it may be added that the viscus was rinsed and these wash-
ings, with the contents, form column A. The wall was then maccrated in water for an
hour, the filtrate forming column B. The wall was again macerated with fresh water
for further three hours (C); and then again for further twenty hours (D). This thor-
oughly extracted tissue forms the material for column E. The figures present the
percentage of the total unabsorbed phenol, which is contained in each of the extracts.
438 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

washing removes it only very slowly and incompletely. This obtains

whether the phenol is administered during life or after death.
This phenol appears as “unabsorbed” in our regular experimental
results since the tissue was always distilled with the contents.

XVII. THE SPECIFIC EFFECTS OF PHENOL ON THE INTESTINAL CIRCU-

LATION

All the facts which we have obtained and presented indicate that
the mechanism by which phenol checks absorption must consist
exclusively in a slowing of the intestinal and gastric circulation,
obtainable after the absorption of the phenol and which does not
always run parallel to the general blood pressure. It now remains to
be shown that phenol actually produces a circulatory change of this
kind.
This might be demonstrated by measuring the changes of either the
volume or the circulation time in the intestine. With the purpose of
obviating the disturbing factors of peristalsis, we preferred the circula-
tion time over the onconietric method. The nlethylene blue method
of G. N. Stewart was used, injecting about + cc. of a 2 per cent solution
per kilogram of body weight into the cardiac end of the jugular
vein, and timing with a stop watch its arrival at a mesenteric artery,
and its passage froni here into the corresponding mesenteric vein.
The observation is greatly facilitated by the use of transmitted light.
The following results were obtained:

(a) Phenol Intravenously (0.03 gm. per kg.)

Seven experiments all showed a marked slowing of the circulation

time (from an average of 4.1 seconds before injection, to an average of
6.3 seconds half a minute after injection). Whilst the carotid pres-
sure fell in every case, there was no quantitative relation between the
fall of pressure and the slowing of the intestinal circulation; and the
latter recovered much more slowly than the carotid pressure.

(b) Concentrated or 10 per cent Phenol by Intestine, Observing a Loop

which is not in Contact with the Phenol

In all these experiments, the circulation time is markedly slowed and

this persists over forty minutes (average before injection = 4.8
 ,‘++. -‘+.. .-.. +. .,++ ,++‘, +. ., -+‘ -

PHENOL ON ABSORPTION 439

seconds; average of slowest circulation time after injection = 9.3

seconds). The average blood pressure before injection was 130 mm.;
the average pressure at the time of greatest slowing was 102 mm.;
the want of relation between carotid pressure and circulation time
is quite conspicuous. For instance, the data for one of the experi-
ments (133) run:
CIRCULATION CAROTID

TIME PRESSURE

Before phenol 4.2 155

S mm. after phenol 8.0 145
22 minutes after phenol 8.0 120

(c) Observation of the Injected Loop

Three experiments showed a primary, but very short quickening of

the circulation time, followed by a persistent slowing; but the slowing
is not quite as pronounced as in the loops (of the same animal) which
had not been in direct contact with the phenol (average intestinal
circulation time: Before phenol, 4.3 seconds; shortly after phenol,
3.0 seconds; some time after phenol, 6.5 seconds). In another experi-
ment, the primary quickening was absent, the intestinal circulation
being practically arrested from the start.
We may therefoie conclude that the direct local action of phenol
tends to produce a quickening of the intestinal circulation; but that
this is more than overbalanced by the slowing which results from the
systemic action and that the latter is independent of the carotid
blood pressure.

XVIII. THESE RESULTS, THEREFORE, FURNISH THE CRUCIAL

CONFIRMATION OF OUR CONCLUSIONS, NAMELY-

That the inhibitory effect of phenol on absorption is not due to any

direct local action on the epithelium, but to a slowing of the intes-
final circulation, brought about after the absorption of the phenol, and
independent of its effects on the carotid blood pressure.
440 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

SUMMARY AND CONCLUSIONS

I.? When phenol is placed in the alimentary canal, the absorption

is at first very rapid, but is quickly checked and soon practically
arrested.
II. The course of absorption was studied quantitatively. The
absorption curve varies for different individuals, but the general
phenomena are constant, and the average figures for several series
agree well.
III. The absorption is quantitatively identical in dogs and cats,
and for the stomach and intestines.
IV. When phenol is placed into the stomach, only traces pass into
the intestine; a large proportion could be removed by gastric lavage,
even several hours after the phenol was taken.
V. Only traces of phenol are excreted into the alimentary tract.
The prolonged presence of phenol, therefore, is not due to re#{235}xcretion.
VI. Phenol also checks the absorption of iodid and of alcohol.
VII. The retention of phenol is not due to corrosion, for
(a) The absorption is delayed rather than favored by dilution.
(b) The presence of food probably also hinders the absorption.
(c) Alcohol hinders the absorption.
(d) Irritation by formaldehyde favors the absorption.
(e) Injury of the intestinal epithelium by sodium fluoride does
not check absorption.
(f) A variable amount of phenol may be absorbed after death.
VIII. Phenol checks absorption even without local contact, f. i.
when it is inclosed in a ligated loop of intestine.
IX. The degree of absorption is not influenced by the length of the
intestinal surface to which the phenol is applied.
X. The interference with further absorption is proportional to the
amount of phenol which has been absorbed into the circulation; and
not to the amount which is present in the alimentary tract. Further
absorption may be completely arrested when 0.05 gram of phenol per
kilogram of body weight has been absorbed. With large doses, how-
ever, much larger quantities may be absorbed before the inhibitory
mechanism has time to act.

The numbers correspond to the sections of the text.

‘r ‘-q -: -- - -

PHENOL ON ABSORPTION 441

XI. The check of the absorption coincides in time with the devel-
opment of the toxic systemic effects of phenol.
XII. The fall of the general blood pressure arrests the absorption
of phenol only when the level of shock is reached (about 40 mm. of
mercury) . Variations ranging between 40 and 75 mm. have scarcely
any influence, and variations above 80 mm. are without influence on
absorption. Since the absorption is arrested in nearly all cases long
before the pressure has reached the critical point, the arrest cannot be
explained by the fall of general blood pressure.
XIII. Artificial changes of blood pressure, produced by hemorrhage
(short of the shock level) and over-transfusion, do not affect the
absorption. Vasoconstriction accompanied by rise of pressure (adrena-
lin) also has no influence. Vasoconstriction without rise of pressure
(ergot, strophanthus and caffeine) appear to check absorption.
Arnyl nitrite (systemically) also appears to check absorption. On
the whole, the effects of artificial changes in the systemic pressure are
not very striking.
XIV. On the other hand, local changes in the intestinal circulation
have the most conspicuous effect on the absorption, generally in the sense
that local vasocontriction diminishes absorption, whilst local vasodila-
tion increases absorption. Irritation may - act in either direction,
according to its grade.
XV. Phenol does not influence absorption in excised intestine.
This again indicates that toxic action on the intestinal epithelium is not
a factor in inhibiting the absorption.
XVI. A large proportion of the unabsorbed phenol exists in the
gastric or intestinal wall in such a way that washing removes it only
very slowly and imperfectly. This obtains whether the phenol is
administered during life or after death.
XVII. By measuring the circulation time, it could be demonstrated
that absorbed phenol slows the intestinal circulation in a specific
manner, quite independently of the changes in carotid pressure. The
direct localaction of the phenol tends to increase the intestinal circu-
tion, but this tendency is quickly overcome by the systemic action
when the phenol is absorbed.
XVIII. It appears, therefore, that the inhibitory effect of phenol
on absorption is not due to toxic action on the epitheliunl, but to a
specific slowing of the intestinal circulation.
442 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

APPENDIX-ANALYTIC METHODS

A. PHENOL

Distillation. The following method was used : The organ immedi-

ately after excision, is quickly cut into small pieces and transferred to a
liter flask. The utensils are rinsed with 10 per cent alcohol and this
is added to the flask with enough water to bring the mixture to about
300 cc. This is acidified with 25 per cent phosphoric acid and dis-
tilled over a free flame, adding water from time to time thromrh a separa-
tory funnel, until the distillate becomes phenol free (three or four drops
being tested by warming with Millon’s reagent).
Titration. The distillate is carefully mixed and accurately measured.
Ten cubic centimeters are placed in a glass-stoppered flask of 250 cc.
capacity, and mixed with 5 cc. of concentrated hydrochloric acid.
Tenth-normal V. S. bromin (U. S. P.) is added in small portions from a
graduated burette (taking care to prevent the escape of Br vapor) until
the brownish color of the liquid, persisting after standing ten minutes in
the stoppered flask, indicates the presence of an excess of bromin. Five
cubic centimeters of 5 per cent KI are then added quickly, the mixture
shaken, and the sides of the flask and stopper rinsed with distilled
water. Fifteen or twenty drops of chloroform are introduced, and the
mixture titrated with decinormal thiosulphate until the iodin is decolor-
ized.
Calculation. Subtract the number of cubic centimeters of T Na2S2O3
from the number of cubic centimeters of r Br used. This gives the
number of cubic centimeters of Br yielding free Br actually
. consumed
in the formation of tribromphenol. This number of cubic centimeters
is then multiplied by 0.001556 which is the equivalent in grams of
phenol of 1 cc. of Br. This result
-- now gives the amount in grams of
absolute phenol in 10 cc. of the distillate: multiplying by the factor pro-
portionate to the volume of the distillate gives the amount of phenol
recovered from the contents of organ. To obtain the amount of absolute
phenol absorbed subtract the amount recovered from the amount intro-
duced.
Our phenol was 97 per cent absolute phenol. Where concentrated
phenol was used, the phenol was dried in a desiccator and then weighed
accurately. The residue from the injection was determined by the U. S.
P. means of titration for phenol, and the amount subtracted from the
amount weighed. This gave the correct amount of absorbed phenol
introduced.
 ++ - , t’ 7 +- -- -V ‘: ‘ -- - + ,.

PHENOL ON ABSORPTION 443

The following tabulation of check determinations shows the limits of

error. It will be seen that they are negligible for our purpose:

ABSOLUTE PHENOL
MATERIAL TO WHICH PHENOL WAS ADDED PHENOL RECOVERED ERROR
(OHS.)
USED (oMs.) (0MB.)

250 cc. of 50 per cent alcohol 4.859 4.870 + 0.011

250 cc. of 10 per cent alcohol plus minced stomach,
distilled at once 4.889 4.896 + 0.007
Ditto, distilled after standing 24 hours 4.857 4.870 + 0.013

Life-experiments in which no absorption occurred also show a good

agreement. The following figures are from intestinal loDps:

PHENOL USED PHENOL ABSORBED ERROR

1.200 l .2059 + 0.0059

1.200 1.2002 +0.0002
0.792 0.7958 +0.0038
0.792 0.7994 +0.0074
+ 1.636 0.6918 +0.0558

B. DETERMINATIONS OF SODIUM IODIDE IN ANIMAL TISSUES

The organ or contents are carefully minced in a porcelain vaporating

dish, then the dish is placed in a drying oven not exceeding 100#{176}
C. until
contents are dry. Pulverized NaOH is added over a gentle flame and
the mixture fused into a mass. Then KNO3 is added (a little at a time)
until all of the organic matter is oxidized (care must be taken not to
add too much KNO3). If there is sputtering, the flame must be kept
as low as possible; then if the heat is gradually increased the organic
matter will disappear. After cooling the residue is taken up with hot
distilled water, filtered and washed until no more NaI appears in the
filtrate: the filtrate is then diluted to a definite volume and all aliquot
part taken for titration. Too great a quantity must not be taken for
titration since the differences in the coefficients of solubility of I in
CHCL3 and H2O will not permit of a complete extraction of the free
iodine if the volume is too large. The quantity used in our work was
10 cc. of a 250 cc. dilution.
Ten cubic centimeters of the filtrate are placed in an Erlenmeyer
flask, acidified with concentrated H2S04 and a small quantity (pinch)
of NaNO2 added. This liberates the iodine which is then shaken out
from the mixture with CHC13 and the 0HC13 solution washed until the
 ;A1

444 TORALD SOLLMANN, PAUL J. HANZLIK AND J. DOUGLAS PILCHER

washings remain neutral. This is then titrated with .f- Na2S2O3 care-
fully shaking after each addition of the volumetric solution until the
CHC13 solution remains colorless.
Factor: 1 cc. of Na, S2 03 = 0.0149 gm. Nal.
The following check determinations were macic by this method.

SODIUM IODIDE ADDED TO- IODIDE USED IODIDE RECOVERED

Stomach 0.749 0.674 -0075

Clotted blood 0.0312 0.03745 +0.006