Investigative Ophthalmology & Visual Science, Vol. 30, No. 4, April 1989
Copyright © Association for Research in Vision and Ophthalmology
Buffering in Human Tears: pH Responses to
Acid and Base Challenge
Leo G. Carney, Thomas F. Mauger, and Richard M. Hill
The buffering capacity of tears collected from six young, healthy subjects was assessed using a
microtitration technique. Each subject provided, on six separate occasions, about 100 ix\ of tears,
collected in small amounts and with minimal mechanical stimulation over several hours. The pH of the
total stirred pool of tears from each subject was determined at the outset. This pool of tears was then
divided into two equal volume aliquots, the pH of each being determined following each titration step
of one of them with acid, and of the other with base. In all, 28 titration steps across the acid-base
spectrum were completed for each patient pool collected. A total of 1044 tear pH measurements were
made, all being done in a closed, temperature stabilized (36°C) microelectrode chamber having an
accuracy of within 0.04 pH units. For a comparative reference, an identical titration procedure was
used on degassed, demineralized distilled water (348 pH determinations). Buffering capacity was
found to show considerable intersubject variations, but in all cases the effect was more pronounced and
more uniform following acid titration. Local zones of enhanced buffering across the pH spectrum could
be identified, presumably reflecting the multiple buffering components (bicarbonate, protein and
others) present in tear fluid. Invest Ophthalmol Vis Sci 30:747-754,1989
The pH of tear fluid is just one of its many physicochemical properties that contribute to the health and
function of the anterior ocular tissues. Its values in
health,1 disease2 and after environmental stress3 have
all been investigated. Although fluctuations in the
normal pH of the preocular tear fluid have been
noted, this fluid usually maintains a relatively stable
pH environment for the anterior ocular tissues.1 This
stability, despite exposure to atmospheric changes, is
most often attributed to the buffering provided, as in
other extracellular fluids, by the bicarbonate system.4-5 Such tear fluid buffering may be an important
component of the defense mechanisms for the outer
tunics of the eye; although it could be overwhelmed
by any substantial challenge, such as a chemical
splash,6 it should serve to lessen such impact. Certainly, it has considerable relevance in determining
the efficacy of topically applied drugs, through the
influence of pH on the state of drug ionization.34
Despite its clear significance, relatively little is
known about the magnitude of tear fluid buffering, its
variability in the population, or the underlying mechanisms. Tear buffering action has been assessed previously in an in vitro system, but only for a limited
range of alkaline challenge solutions.7'8 An in vivo
microelectrode system has also been used to investigate tear film shifts in response to buffer instillation, 39 although the specificity of such an electrode
system has been questioned.10 Certainly effects on
this physiological parameter of age, disease and other
variables remain to be explored, in addition to those
more fundamental characteristics listed above.
In this report, we show results of tear buffering
using finely graded incremental acid and base challenges over an expanded pH spectrum.
Materials and Methods
The six subjects in the study had a mean age of 23
years, with a range of 22 to 27 years. All had good
general and ocular health, and none were contact lens
wearers. All agreed to participate after the nature of
the experiment was explained to them; the procedures following were approved by the Institutional
Review Board (Human Subjects Committee) of The
Ohio State University.
On six separate occasions, each subject contributed
a total of 100 to 120 jil of tears. The tears were collected with microcapillary tubes from the lower tear
prism, with care being taken to avoid mechanical
stimulation. Subjects were instructed to monitor tear
flow rate by observing the rate of tear accumulation
From the College of Optometry, The Ohio State University, Columbus, Ohio.
Supported in part by USPHS research grant EY-02383 (RMH)
and the Ohio Lions Eye Research Foundation.
Submitted for publication: March 2, 1988; accepted November
15, 1988.
Reprint requests: Leo G. Carney, OD, PhD, College of Optometry, The Ohio State University, 338 West Tenth Avenue, Columbus, OH 43210.
747
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748
Vol. 30
INVESTIGATIVE OPHTHALMOLOGY G VISUAL SCIENCE / April 1 9 8 9
14
13
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7 8 9 10 11 12 13 14
pH(H 2 0)
Fig. 1. Buffering capacity of tears shown as a comparison of tear pH change to that of a water reference solution upon titration with
hydrochloric acid or sodium hydroxide. The sequence of titration levels for both HCl and NaOH to produce these pH changes is listed, with
each challenge dose being given in microgram equivalents. Direction of increasing base challenge or decreasing acid challenge is left to right on
diagram and downward on scale. Diagonal is equal response line. Results are mean (A) and standard deviation (B) of measurements for all six
subjects on six separate occasions.
in the microcapillary tubes, and to cease collection if
flow rate noticably increased.
A period of several hours was needed for each subject to accumulate the required volume, with each
subsequent sample being sealed and then refrigerated
upon collection until testing. Any variation in the
subject's normal activities, diet or health were noted.
At least 1 day was allowed to elapse before the next
tear collection occasion. For each subject, their collected tears were pooled and mixed in a closed vessel
with minimal air space. The initial pH of each of
these was measured using a closed-chamber, temperature stabilized (36°C) microelectrode system. Tear
samples were drawn into the microelectrode with a
manually operated suction device, which also allowed the samples to be subsequently evacuated into
the closed-vessel for progressive titration. The pooled
tears were then divided into two 50 fi\ aliquots. One
50 fi\ aliquot was progressively titrated with a total of
21 jig equivalents of hydrochloric acid, pH measurements being made at the following incremental titration levels: 0.02, 0.05, 0.10, 0.20, 0.40, 0.60, 0.80,
1.00, 1.50, 2.00, 3.00, 5.00, 11.00, and 21.00 ng
equivalents. The second 50 (A aliquot was progressively titrated with a total of 1.45 ^g equivalents of
sodium hydroxide, pH measurements being made at
the following incremental titration levels: 0.001,
0.0025, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.085,
0.12,0.19,0.33, 0.76, and 1.45 ng equivalents. These
acid and base challenge doses were established empirically in pilot trials so that similar volumes of each
challenge solution were used, the total volume of
added acid and base being 300 (A.
An identical sequence was carried out, on 12 separate occasions, using degassed demineralized distilled
water to establish a comparative reference (348 pH
determinations).
The accuracy and reliability of the pH measurement system was established by making a series often
consecutive readings on buffer standards of different
pH levels (2.00, 6.77, 7.10, 7.50, 7.90, 10.00) after
conventional calibration procedures. No reading
from any of these series was found to differ by as
much as 0.04 of a pH unit from the nominal value of
the standard.
Results
The tear pH responses to these incremental titrations were analyzed in comparison to the pH response of the reference solution (unbuffered distilled
water). Any deviations of the tear response from the
response of the reference solution thus indicate the
enhanced resistance of the nonaqueous tear components to pH challenge by acid or base. Comparing the
tear response with that of an unbuffered reference
solution also eliminates any bias from asymmetrical
challenge doses. For the unchallenged tears, the mean
pH value for the six subjects was 7.50 ±0.16 (SD).
In Figure 1, the mean responses of all six subjects
determined on six separate occasions, and at the initial and subsequent 28 titration levels, together with
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BUFFERING IN HUMAN TEARS / Corney er ol
No. 4
the standard deviations about those means, are
shown. The most substantial deviation from the diagonal equal response line and hence increased resistance to pH change is in the range from tear pH 7.0 to
pH 7.7, when the comparison unbuffered water
values range from about pH 3.5 to pH 8.0. Beyond
this plateau in the direction of increasing acid challenge, the tear pH falls precipitously to that of the
water reference; less prominent zones of resistance to
acid challenge are also present. The resistance to pH
change with increasing base challenge is less substantial and less uniform. The standard deviations indicate that greatest variability in response is encountered, as would be expected, in those zones of acidic
challenge where the pH is changing rapidly.
The mean responses of each of these six individual
subjects from their six trials is shown in Figure 2.
Each subject is seen to be relatively consistent within
the overall pattern of response described above. However, two-way analysis of variance shows that there
are statistically significant intersubject variations (P
< 0.001; Table 1).
An estimate of the total buffering capacity provided by tears can be obtained by integrating the area
bounded by the individual response curve and the
equal response diagonal. This was done for each subject and for each of the six tear collection occasions.
The mean results for each subject in response to acid
and base challenges are shown in Figure 3. The
greater total resistance to pH challenge can be seen to
reside in the acid challenge direction (paired t-test, P
< 0.001), where also the intersubject variability is
less.
A critical feature of these pH response curves
sometimes masked in the composite graphs is the
usual presence of several quite prominent subunits of
resistance to pH change. While almost always discernible in individual trials, slight variations in their
appearance between subjects and in repeated trials on
any one subject can result in their diminished prominence in the composite graphs. Results from the six
individual measurement trials, with these resistance
points indicated, are shown for a representative subject (subject 1) in Figure 4. A high degree of repeatability is seen amongst this subject's trials. Considered
overall for all six subjects, there was no statistically
significant variation among trials (ANOVA, F5,35
= 0.998, P = 0.437).
Discussion
This titration technique provides quantifiable assessment of the resistance of tear fluid to pH change.
The buffering is more substantial in response to acid
challenge than it is to challenge with base. The values
749
found here are of similar but slightly lower magnitude
than those found with the limited titrations reported
earlier.7-8 Because of differing experimental conditions, direct comparison with the published values
derived from rabbit tears1' is not possible, but variations may be expected because of the functional and
biochemical differences in tears acquired from this
source. Of considerable relevance is the finding that
the tear buffering is apparently nonuniform across
the pH spectrum. This may be interpreted as being
indicative of multiple buffering systems within each
tear sample, each becoming predominant at specific
pH values.
The major buffering system present within the
tears is usually assumed to be the bicarbonate system, 35 although recent measurements of bicarbonate
ion concentration in tears are of lower values than
earlier estimates.12 The substantial buffering capacity
indicated by the plateau in the responses in the tear
pH range of 7.0 to 7.7 may be a reflection principally
of this bicarbonate system. However, other buffering
systems would be expected to contribute in tears just
as in other biological fluids. The major nonbicarbonate buffer components would likely be the various
protein fractions present in tears.
The buffer capacity of any protein is a composite
effect of the actions of its various dissociable groups.
A chemical buffer will normally be most effective if
its pK' is close to the pH under challenge. In the case
of proteins, the presence of numerous acidic and
basic groups means that a single pK' cannot be assumed. Rather, each of these various groups is titrated when acid or base is added; the resulting titration curve reflects the many possible pK' values
within a given protein molecule. A major contribution to total protein buffering is usually attributed to
the imidazole group of histidine,13 which has a pK'
value within the physiological pH range (pK' 6.4 to
7.0). This possibly contributes importantly to the
plateau pH response found here for tears. Beyond the
physiological range, other dissociable groups, with
their pK' values spread across the pH spectrum (eg,
arginine, pK' 11.9 to 13.3; aspartic acid, pK' 4.0), may
contribute to the buffer action.13 These may explain
the subtle but measurable discontinuities in pH response across the extensive pH challenge doses used
here (eg, in Fig. 4). Although these groups may play a
lesser role in buffering within the common physiological limits, the buffer action of any solution containing multiple buffer elements nevertheless does reflect
the additive buffering contributions of each element.
In the case of tear fluid, the presence of a unique
pattern of protein constituents14 may be of significance in ultimately interpreting its overall pattern of
pH response. While other buffering components,
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rT
750
Vol. 3 0
INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / April 1989
SUBJECT 2
080
060
040
020
0 10
005
0 02
0 00
0.0001
0002S
0.000
0 01
0.02
003
0 04
0 05
0 085
0 12
0.19
-y
1 2 3 4
0
1 2
3 4
5 6 7 8 9 10 11 12 13 14
pH(H2O)
0
1 2
3 4
5
5 6 7 8 9 10 11 12 13 14
pH (H 3 O)
6 7 8 9 10 11 12 13 14
pH (H 2 O)
SUBJECT 6
13
/
12
11
/y
10
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a
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9
2 7
I
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6
5
;
:
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4
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1
5 6
7 8 9 10 11 12 13 14
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0
0
0 60
0 40
0 20
0 10
005
0 02
0 00
0 0001
00025
0 005
001
0 04
0 OS
0 085
0 12
0 19
0 33
0 75
3
2
5 00
3 00
?00
1 50
1 00
1 45
NaOH
1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH (H 2 O)
Fig. 2. Results plotted, as in Figure 1, for the mean responses for each subject over six separate trials.
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No. 4
751
BUFFERING IN HUMAN TEARS / Carney er ol
Table 1. Two-way analysis of variance of pH responses to acid or base challenge of tears from six subjects
Source
Degrees of
freedom
Sum of
squares
Mean
square
Subjects (S)
Titration level (T)
SXT
Error
5
28
140
870
23.88
8280.22
31.12
74.81
4.78
295.72
0.22
0.09
1043
8410.03
Total
such as phosphate compounds, should also contribute to the total response, low concentrations may
preclude any major buffering role.
The results clearly indicate then the presence of
buffering constituents in human tears. A further way
of quantifying this buffering as it changes across the
spectrum of pH challenges is to find at each point the
range of challenge levels over which no significant
difference in the tear pli is found. Such a statistical
test must of necessity include a dependence on the
accuracy of the measurement procedure. We used
Tukey's studentized range (HSD) test for multiple
comparisons, using a significance level of P < 0.05, to
illustrate this. The results for the composite of the six
subjects are shown in Figure 5. As increasing acid
challenges (from the untitrated position) are presented, a substantial range of challenges producing no
statistical difference in pH exists at first, demonstrating the considerable tear buffering present. Further
challenges in the acid direction and those in the base
direction produce smaller ranges of pH responses that
are statistically indistinguishable. Such a statistical
test may have application in comparative studies of
buffering stability.
This statistical approach to describing buffering capacity, illustrated in Figure 5, also adds support to
our description above of the presence of discrete
zones of buffering resistance. The most extensive
range of statistically indistinguishable pH responses is
centered around titration level 14, which for the composite data of these six subjects is at tear pH 7.4.
Other zones of such buffering are centered around
approximate titration levels of 3, 22 and 26. These
zones approximate tear pH values of 2.1, 9.0 and
10.3, respectively, and together with the above 7.4 pH
value, could be considered to represent the pK' values
of human tears. These population values show reasonable qualitative consistency with those indicated
in Figure 4 for zones of enhanced pH resistance in
individual trials for one subject.
There are considerable intersubject variations in
both the form of the response curves (Fig. 2) to these
finely graded incremental challenges, and in the
overall buffering capacity provided by the tears (Fig.
3). While there is some variability in the response to
F ratio
Significance
55.54
3439.30
2.59
P< 0.001
P< 0.001
Not
acid challenge (indicated by the large standard deviations in Fig. 1), this is principally a consequence of
the precipitous change in pH which ultimately occurs
with titration in this direction. Base challenge also
produces substantial individual variations, noticeable
both in the form of the response curves and the total
tear buffering in that titration direction. In the absence of any rapid change in pH, this is more probably an accurate reflection of variations in individual
chemistry.
There are important clinical implications of this
resultant net tear buffering. It helps provide a stable
pH environment for the anterior ocular tissues, despite the unique variations in the ambient environment that exists for this body fluid. Among those
variations are those associated with prolonged eyelid
closure during sleep.1516 It may be relevant to the
ocular response to chemical splash.1718 The small tear
volume means that total tear buffering capacity will
be limited. Nevertheless, while tear wash-out effects3
and even corneal buffering19 may be predominant,
tear buffering should contribute to the overall response to challenge. It most certainly is of relevance
o
Subject *
1
2
3
4
5
6
1
2
3
4
5
6
f-—ACID RANGE—»| | — BASE RANGE—-|
Fig. 3. Total buffering capacity of each subject's tears as determined by integration of deviation of the response curve from the
equal response line. The mean capacity for each subject's tears was
determined for the six separate trials following both acid and base
challenge.
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752
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / April 1989
SUBJECT 1
Vol. 0 0
SUBJECT 1
TRIAL 2
TRIAL 1
/
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0.40
0.20
0.10
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0.02
0.00
0.0001
0.0025
0.005
0.01
0.03
0.03
0.04
0.05
0.085
0.12
0.19
1
/
•
1 2
3
4
9
10 11 12 13 14
/
2
3
4
5
8
PH
(H 2 O)
6
pH
(H 2 O)
pH
(H 2 O)
pH
(H 2 O)
8
SUBJECT 1
TRIAL 5
/
0
•
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.
•
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10 11 12 13 14
s.oo
TRIAL 6
/
11
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12
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10 11 12 13 14
SUBJECT 1
i3
/
9
6
.
4
3.00
2 00
1.50
1.00
0.80
0.60
0.40
0.20
0.10
0.05
0.02
0.00
0.0001
0.0025
0.005
0.01
/
3
/
y
2
•
\r
0.19
0.33
0.75
1
T
pH
(H 2 O)
pH
8
9
10 11 12 13 14
(H 2 O)
Fig. 4. pH response curves from the six individual trials of onerepresentativesubject (Subject 1). Points of increased resistance to pH change
are indicated by arrows.
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No. 4
753
BUFFERING IN HUMAN TEARS / Corney er ol
Fig. 5. Results of Tukey's
studentized range (HSD)
test for the composite of six
noncontact lens wearing
subjects. For each titration
level (abscissa, full circle),
ranges of statistically indistinguishable (P < 0.05) pH
responses for other challenge levels are given (ordinate, open circles). As
shown in the inset, position
15 is for unchallenged tears;
position 1 is for a titration
level of 21.00 jig equivalents
of HC1; position 29 is for a
titration level of 1.45 jig
equivalents of NaOH.
:
/
1
15
29
Acid Unchallenged Base
4 6 8 10 12 14 16 18 20 22 24 26 28
- A C I D RANGE
X
BASE RANGE
>
TITRATION LEVEL
in understanding and manipulating drug absorption
properties, 4 " through the influence of pH on the
state of ionization of drugs that are weak acids or
bases. Comeal permeability is less to ionized than to
nonionized molecules. Homatropine, tropicamide
and cyclopentolate are all examples of drugs which
are mostly ionized at physiologic pH and would exhibit low accessibility.2021 This pH stability is also
essential for some functions of the tear fluid itself, for
example through its effect on the antibacterial activity of lysozyme.22
The role of tear fluid buffering in damping tear pH
changes may also influence the success of contact lens
wear. Tear fluid pH has been demonstrated to be
important in protein adsorption onto hydrogel
lenses23; additionally, it influences the water content,
and hence oxygen permeability, dimensions and fitting characteristics of some current hydrogel contact
lenses.24 By diminishing the magnitude of tear fluid
pH shifts, particularly during the closed eyelid phase
of extended wear,1525 the integrity of the contact lens,
and hence ultimately the health of the cornea, are
protected, at least in part. Contact lens wearing itself
may possibly lead to altered tear buffering through
altered tear chemistry.26 Indeed, the intersubject variability in tear buffering may be one element contributing to some contact lens failures, particularly in
extended wear regimens.
In summary, we have quantified the buffering capacity of human tears, and have demonstrated the
considerable intersubject variability in this tear characteristic. The greatest extent of this buffering is to an
initial acid challenge, but local zones of enhanced
buffering distributed across the pH spectrum were
also identified.
Key words: tears, buffering capacity, pK', bicarbonate, proteins
References
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the conjunctival sac during postoperative inflammation of the
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3. Norn M: Tear pH after instillation of buffer in vivo. Acta
Ophthalmol 63(Suppl 173):32, 1985.
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / April 1989
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