Journal of Dental Research

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Physicochemical Mechanisms of Dental Caries

Walter E. Brown
J DENT RES 1974 53: 204
DOI: 10.1177/00220345740530020701

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Physicochemical Mechanisms of Dental Caries
WALTER E. BROWN
American Dental Association Research Unit, National Bureau of
Standards, Washington, DC 20234, USA
The term "physicochemical mechanism" im-
mediately implies a model of the system
which takes into account thermodynamic,
kinetic, structural, and temporal consider-
ations. In the present case, thermodynamic
properties are expressed primarily in terms
of solubility of the tooth mineral. Essential
for understanding this subject are the var-
ious ways to express solubility, both mathe-
matically and diagramatically. Kinetic con-
siderations are more varied and include dis-
solution (and precipitation) steps, diffusion
of ions through a host of media, generation
of organic acids in plaque, and the many
chemical and structural factors that regulate
the rates of these processes. Structural con-
siderations have primarily two levels: (1)
crystal structure, where the information has
bearing on solubilities and rates of dissolu-
tion, and (2) ultrastructure, where the pri-
mary interest is related to the organization
and form of the lesion, intercrystalline
spaces available for diffusion, and structural
factors within the lesions that provide in-
sight into the processes that have taken
place. By temporal considerations I mean
an understanding of how rapidly the over-
all caries process and the various component
steps take place. The time scale for each of
these needs to be known if we are to prop-
erly assess the relative importance of ther-
modynamic and kinetic factors, and if we
are to seek means for attacking vulnerable
steps in the process.
Usually, a physicochemical model is cre-
ated as a vehicle for quantitatively tying
together experimental data; the model is
considered satisfactory only when it ac-
counts for the data within their estimated
errors. With rare exceptions, this is not the
This research was supported, in part, by Grant
DE-02659 from the National Institute of Dental Re-
search, National Institutes of Health, Bethesda, Md.
204
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case with caries models, nor is it the intent
of this paper. Instead, the models to be
described are qualitative in their consid-
eration of kinetic processes, and quantita-
tive only in their use of thermodynamic
(that is, solubility) data to provide a frame
of reference for predicting the course of
reactions. These models are outgrowths of
earlier attempts2 to take into consideration
a combination of thermodynamic and ki-
netic factors.
Equilibrium Models
Models of this type take into account only
those thermodynamic considerations that
affect the equilibrium composition of the
solution within the lesion. Crucial processes
such as transport of ions into and out of the
lesion are ignored. Equilibrium models are
useful despite this limitation because, un-
doubtedly, any set of circumstances that
leads to high concentrations of dissolved
mineral in the lesion will have deleterious
effects. Three types of equilibrium models
are described here. The first makes use of
the "generalized quaternary phase diagram"
(see Figs 1-3, and appendix for descrip-
tion) to provide an overall view of the
important parameters. The other two are
based on Donnan equilibriums: (1) von
Bartheld's model, which takes into account
effects caused by the presence of positively
charged proteins on the surface of the tooth,
and (2) a model, described here for the
first time, entailing equilibrium through a
cation-selective membrane.
PHASE-DIAGRAM CONSIDERATIONS.-It is gen-
erally accepted that the pH within plaque
can get as low as 4.5, or perhaps 4.0. It is
immediately apparent from examination of
the phase diagram (Figs 2, 3) that all
solutions in this pH range saturated with
hydroxyapatite have calcium and phosphate
 rzrx|l
I I F

1.0

Supersatu ration

2.0

3.0

u
. I
*I 4.0
E
u
a

1d Under s atu ra ti on
u
I) 5.0
ta

6.0 5.0 4.0 3.0 2.0 1.0

-Log10(Phosphorus Concentration)
FIG 1.-Phase diagram for solubility of hydroxyapatite in ternary system
Ca(OH) 2-H3PO4-H20. Solid line, isotherm; broken lines, dissolution-precip-
itation lines wih Ca/P =5:3; dotted lines, removal of components H3PO4 or
Ca (OH) 2. Concentration in M/liter. Reprinted with permission of pub-
lisher.2

1.0
=4.0

2.0-
5.0
1-

Ca 3.0-
Ca
co
= - 6.0
4.0-

co
C-
=7.0
5.01
,
pH= 8.0

pU(+) = 4

7.0 6.0 5.0 4.0 3.0 2.0 1.0

-LogOt(H3PO4 Concentration)
FIG 2.-Phase diagram for solubility of hydroxyapatite in generalized
quaternary system, Ca (OH) ,-HPO4-H20-HX or MOH (appendix) with
lines of constant pH. U (-) represents concentration of excess acid and
U (+) represents concentration of excess base. Concentration in M/liter.
Reprinted with permission of publisher.'9
205
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206 BROWN 2 Dent Res Supplement to No. 2

1. 18. 20.
p [(Ca24) (OH-)2] = 14.0 16.0 18.0 20.0
Pf(H+)8(po43 )] = 38.2 34.9 31.5 28.2
pU(-)=l I I I - I I

3 pU-=
\
\
\
\
t\\< \ <
\
XH=6~~pH=
\ PH5
0
U 4 \ \
pU(-)=4 \ \ \ \H=
\
5
c)
0
6 pU(±)4 =pH=8
pU(+)=3 pH=9
7

8 OHAP ISOTHERMS AT 25 C

a
'I2 1 1 10 9 8 7 6 5 4 3 2 1 U

-LOG (Phosphorus Conc)

FIG 3.-Phase diagram similar to Figure 2 shows lines of constant Ca (OH) 2
and H8PO4 activity. Concentration in M/liter.

concentrations in the range 10-2 to 10-1M1 The Ca/P ratios of the solutions in the
liter. In view of rate considerations de- pH 4.0 to 4.5 range vary as a function of
scribed later, it is reasonable to believe that U (-). In this pH range, most of the phos-
the microorganisms residing immediately ad- phate ions are in the form H2PO4 . In the
jacent to the enamel surface, and therefore absence of significant concentrations of ions
potentially the most effective in producing other than calcium and phosphate (that is,
caries, would exist in a milieu that approx- U 0), electroneutrality would require the
imates the compositions in this corner of the solution to have a Ca/P ratio of 1:2. A
phase diagram. A reasonable area of future Ca/P ratio of 5:3, which is that of tooth
research, therefore, would be the study of enamel, can be achieved in the presence
acidogenic oral bacteria to determine if the of, for example, lactic acid only if the
cariogenic species can survive better at these lactate ion concentration is a little more
high concentrations than can the equally than twice the phosphate concentration.
acidogenic but noncariogenic species. Little Then the ten positive charges of five Ca2+
is known about the growth of acidogenic ions would be countered by negative
oral microorganisms in media that are kept charges of three H2PO4- ions and the neg-
saturated with hydroxyapatite. Their abil- ative charges of seven lactate ions. Low
ity to survive under these conditions could values of U (-) and consequent low Ca/P
well be the factor that determines their rel- ratios in the equilibrium solution at the
ative effectiveness. The presence of such caries site can be achieved only through the
high concentrations of phosphate may be a loss of calcium and lactate ions during the
particularly important factor because it is initial equilibration process. In any event,
such a metabolically active ingredient. In in caries mechanism and bacterial growth
this connection, bacterial growth studies of studies, investigations should be carried out
the type suggested should be carried out in to determine the effects of various values of
which chemical potential of H3PO4, rather U (-) that may be encountered in the solu-
than concentration of phosphate, is used as tions corresponding to the low pH range of
the independent variable. Chemical poten- the phase diagram.
tial of a component is a more basic variable, The solution concentrations within the
thermodynamically and kinetically, than is lesion that are predicted on the basis of the
concentration of the component. phase diagram for the pH range of 4.0 to

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Vol 53 1974 PHYSICOCHEMICAL MECHANISMS OF CARIES
4.5 are unusually high. Experimental tech-
niques should be developed that will permit
sampling of the solution within the lesion
to check these predictions. These concen-
trations also could produce osmotic effects
that have not been fully anticipated, and
theoretical and experimental investigations
should be made to assess their possible ef-
fects.
Two other types of considerations related
to the phase diagram-the presence, in
enamel, of mineral with various solubilities,
and the possible effects due to the formation
of CaHPO4 * 2H20-are discussed in subse-
quent sections.
VON BARTHELD'S DONNAN-MEMBRANE MOD-
EL.-One of the few extant models for the
caries process is that of von Bartheld.3 He
suggested that the surface of the tooth is
impermeable to protein molecules. Then,
if the pK values for the proteins were suffi-
ciently high, the low pH produced by bacte-
ria would convert them into their cationic
forms. Through the use of the usual Don-
nan-membrane type of reasoning, he con-
cluded that the presence of the cationic
protein on the outside would cause the pH
on the inside of the lesion to be lower than
that in the milieu containing the protein.
The lower pH within the lesion was as-
sumed to increase the solubility of the min-
eral and therefore lead to enhancement of
caries formation.
A more direct analysis of this model can
be obtained through the use of Figure 3.
The presence of the cationic proteins on the
outside would make the U (+) value of its
imbibed solution more positive than that of
the solution within the tooth. At the same
time, since this is an equilibrium model, the
activity of the component Ca (OH) 2 (and of
H3PO4) would be the same outside as in-
side. The broken lines in Figure 3 are lines
of constant Ca (OH) 2 (and H3PO4) activ-
ity. Thus, on going from the outside to the
inside solution, one would move along a
line of constant Ca (OH) 2 activity in the
direction of more negative U (+) values
(that is, from the lower right toward the
upper left). In doing so, it is easily seen
that in general, the pH of the corresponding
solution would decrease, the calcium concen-
tration would increase, but the phosphate
concentration would decrease. The latter
fact makes the effect of lowered pH within
the lesion ambiguous, because it is no
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207
longer possible to say that the lower pH of
the solution inside the tooth leads to a
greater dissolution of enamel mineral.
There are two aspects of von Bartheld's
model that need further examination: (1)
What is the order of magnitude of concen-
tration of charges (in M/liter) within the
protein [that is, contribution to U (+) ] that
is likely to be found in proteins that coat
the tooth? (2) Does the effect lead to a sen-
sible Donnan-membrane potential?
CATION-SELECTIVE MEMBRANES.-Quite an-
other Donnan-type equilibrium results if one
assumes that the membrane (that is, the
plaque and the outer portion of the tooth)
is permselective. Membranes of this type
are well known (Sollner4). If only cations
can pass through the membrane, then cal-
cium ions can leave the interior solution
and be replaced by protons. The effect
of this process is to remove the component
Ca (OH) 2 from the interior. As shown in
the "appendix," removal of Ca (OH) 2 leads
to a net change in composition of the sat-
urated solution with a displacement along
the isotherm in the direction from the lower
left to upper right. Thus, this process can
lead to solution compositions in which the
concentrations of both calcium and phos-
phate are increased, differing in this respect
from von Bartheld's Donnan-membrane
model.
An anion-selective membrane, on the
other hand, would lead to a loss of H3PO4
from the lesion, as described in the "appen-
dix," and lead to a shift in composition
downward to the isotherm in the direction
of lower concentrations and higher pH's.
This, of course, is in the desired direction.
It is recommended, therefore, that research
be carried out to find the most effective
ways to make the enamel surface-plaque
membrane permselective to anions, and to
establish, by animal studies, whether this
would indeed be an effective mechanism for
preventing caries. Cationic surfactants of
various types are leading candidates for this
purpose.
I consider next the events that may take
place during the buildup of acid. Assume
that initially the tooth-plaque system is in
the quiescent state with relatively uniform
calcium, hydrogen, and other ion concen-
trations throughout. Increased production
of acid in the plaque generates a concentra-
tion gradient that causes diffusion of hydro-
208 BROWN
gen ions through the cation-permeable
tooth-plaque membrane into the lesion. The
increased acidity within the lesion causes
mineral to dissolve. The resulting greater
calcium ion concentration of the solution
within the lesion enhances outward diffusion
of these ions. Eventually, it is possible for
the concentration of calcium ions in the so-
lution within the lesion to become suffi-
ciently high (particularly when the concen-
tration of the calcium ions in the saliva on
the outside is very low) for the roles of the
calcium and hydrogen ions to become inter-
changed: the diffusion of calcium ions out-
ward now would be a driving force tending
to draw hydrogen ions inward. This process
may take place to the extent that the pH
within the lesion would be lower than that
on the outside. This type of phenomenon is
not uncommon in membrane equilibrium
and, through use of model experiments,5 we
have shown that it applies to solutions con-
taining calcium and phosphate ions.
From this description one might conclude
that once the calcium concentration on the
inside exceeded that on the outside, the rise
in the concentration of the calcium of the
inside solution could continue without limit.
This is not true, and I next consider what
would be the limiting condition (assuming
for the time being that we are dealing with
a membrane that is perfectly permselective
for cations).
The plaque acids result in low pH on the
outside of the tooth, thereby producing a
low value for the activity of calcium hydrox-
ide in the outside solution,
A Ca(OH)2 (out) = (Ca2+)0 (OH-)02, (1)
where (Ca2+)0 and (OH-)o are activities of
these ions in the outside solution. The ac-
tivity of calcium hydroxide in the lesion,
ACa(OH)9 (in) = (Ca2+)% (OH-),2, (2)
which now is greater than ACa(OH)2 (out),
will decrease as the hydrogen ions diffuse
into the lesion and calcium ions diffuse out
(that is, as the composition of the saturated
solution moves along the isotherm in the
direction of higher calcium and phosphate
concentrations and of lower pH's). When
ACa(OH)2 (in) decreases until it becomes
equal to ACa(OII)2 (out), net diffusion of
ions ceases, because the two solutions are
now at equilibrium with respect to the com-
ponent Ca (OH)2. (Because of the assumed
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J Dent Res Supplement to No. 2
permselectivity of the membrane, equilib-
rium for the component H3PO4 is neither
attainable nor relevant to these considera-
tions.) If we equate the two activities and
take the negative logarithms, we have
pCaj + 2pOHj = pCa0 + 2pOH, (3)
or, if we substitute the expression for dis-
sociation of water, we obtain
pCaj - 2pHi = pCa0 - 2pH,. (4)
Rearranging we have,
pCaj - pCa, = 2 (pH1 - pH,). (5)
Thus, a given difference in pH between
the inner and outer solutions corresponds,
at the Donnan equilibrium, to twice as
large a difference in pCa. Note that the
signs are such that if the hydrogen ion con-
centration on the inside is greater than on
the outside, the calcium concentration also
will be greater on the inside. The relation-
ship between pCa and pH given by equa-
tion 5 is important even though it was de-
rived for the unrealistic situation where the
tooth-plaque membrane was assumed to be
perfectly cation selective. Equation 5 rep-
resents the extreme position on the iso-
therm that can be achieved for a given set
of conditions in the outside solution. On
this basis it is suggested that a survey be
made in which a correlation between cal-
cium hydroxide activity of saliva (and not
pCa or pH alone) and caries experience
would be sought. The conditions that apply
to a "leaky" membrane (that is, one which
transmits some phosphate ions) are dis-
cussed in greater detail under the section
on steady-state models.
As the final step in our examination of
the permselective membrane model, we can
make some quantitative comparisons be-
tween various calcium hydroxide activities
in saliva with the solution compositions that
would obtain in the lesion through the
use of the generalized quaternary phase di-
agram (Fig 3). For this purpose we assume
that pCa for saliva is about 3, (that is an
activity of about 1 mM/liter). The corre-
sponding Ca (OH) 2 activities for various
pH's of saliva are then given in the follow-
ing tabulation:
pH PAca (OH) 2
7 17
6 19
5 21
A series of lines of constant ACa(OH)2
Vol1 53 1974 PHYSICOCHEMICAL MECHANISMS OF CARIES
(broken lines) are shown superimposed on
the isotherms for various values of U (±) .
A saliva pH of 7 (PAca(OH)2 = 17) corre-
sponds to an activity of Ca (OH) 2' on the
line A. It is immediately apparent that all
attainable solutions within a lesion (which
must lie on or to the left of line A) will be
very dilute, and the pH for any solution
with a reasonable value of U (+) will be
greater than 7. Saliva with a pH of 6 would
correspond to line B (that is, pACa(O)2 =
19). Even here, the permissible solutions
within the lesion would not be particularly
acidic. In fact, the pH's of these solutions
would be higher than that of saliva (greater
than 6) for all solutions that have a pU (-)
greater than 2.5. At a saliva pH of 5, where,
in this case, pACa(OH)2 would be 21, the cor-
responding solutions within the lesion, line
C, all now lie in the region of the phase
diagram that is more acidic than pH = 5.
Thus, a pH in this range in the saliva
would lead to deleterious solution concen-
trations within the lesion. A similar effect
would be derived from calcium activities
substantially lower than the assumed 1 mM;
lower calcium activities would obtain if cal-
cium concentrations in salivary secretion
were decreased or strongly complexed by
other salivary components.
The aforementioned model in its present
form has three shortcomings: (1) Like all
equilibrium models, it fails to take into ac-
count transport processes. (2) It needs fur-
ther development to take into account the
effects of variable solubility of enamal min-
eral; calculations along this line are under
way. (3) Thus far we have considered the
saliva to be the sink into which components
from the lesion diffuse without significantly
changing its overall concentration. Actually,
the relevant saliva, that which is immedi-
ately adjacent to the surface of the lesion,
may differ considerably from secreted saliva,
particularly in its acidity and its calcium
and phosphate concentrations. Further con-
sideration should be given, therefore, to the
possibility that the unreacted acid diffusing
out of the plaque into the saliva coating the
surface of the plaque may have considerable
influence on the concentrations within the
lesion. Its effect would be transmitted to
the lesion by reducing the activity of cal-
cium hydroxide in the adjacent saliva, which
acts as the sink for diffusion products.
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209
Steady-State Models
During caries formation, diffusion of ions
into and out of the lesion are important
processes that must be taken into consid-
eration. To simplify considerations it is
common practice to examine the situation
at steady state (that is, when the composition
at any point within the diffusion system is
not changing at a significant rate) where the
mathematical description of the system be-
comes tractable.
Dissolution rate studies have been carried
out on hydroxyapatite pellets and enamel
slabs,6-8 but in most of these types of ex-
periments the dissolution takes place at the
surface rather than subsurface as it is in the
enamel lesion. Also, the dissolution rates in
these experiments appear to have been ex-
tremely high compared with those that take
place during caries formation. These facts
must be taken into account when transfer-
ring ideas derived from these experiments
to caries processes.
One of the outstanding kinetic studies on
artificial subsurface caries lesions is that of
Holly and Gray9 in which they showed that
diffusion through the plaquefree, relatively
intact, surface layer was the principal pro-
cess governing the rate of development of
the lesion. In view of this result, it is safe
to assume that transport through a more
complex membrane, consisting of the plaque
in addition to the intact layer, is rate con-
trolling in the caries process in vivo. This
view has several implications for the events
and conditions within the caries lesion;
these are discussed in greater detail in a
later section.
None of the aforementioned studies has
taken into account the possibility that in
the initial stage of the dissolution process
(that is, before steady state) the relative
rates of diffusion of calcium and phosphate
ions from the surface may not be the same
as that with which they dissolved. In other
words, there may be an accumulation of
either H3PO4 or Ca (OH) 2 in the unstirred
layer or in the solution within the lesion
before the steady state is reached. This ac-
cumulation would have the effect of shifting
the composition, respectively, either up or
down the isotherm, as described in the "ap-
pendix." In a lesion, this could come about
because of differences in the resistance to
flow of calcium and phosphate ions through
the enamel-plaque membrane, but in the
210 BRO WN
dissolution of a pellet it could result from
differences in the initial diffusion rates of
calcium and phosphate ions.
Although partial permselectivity of this
membrane, with calcium diffusion favored
over that of phosphate in the Ca/P ratio
greater than 5:3, would tend to drive the
composition of the saturated solution in the
direction of higher calcium and phosphate
concentrations and lower pH's, the relative
rates of transport of calcium and phosphate
ions would be expected to change as the
composition within the lesion shifted along
the isotherm. A steady state would be
reached at some point on the isotherm
where the Ca/P ratio of the ions departing
by diffusion is the same as the Ca/P ratio
of the ions entering the solution by dissolu-
tion (that is, the Ca/P ratio of the solid).
Although initially the membrane may be
permselective to cations, there are at least
four reasons why one would expect phos-
phate transport to be increasingly favored
as the composition moves up the isotherm
in the direction of higher concentrations:
(1) The activity of H3PO4 would increase
and that of Ca (OH) 2 would decrease,
thereby altering the driving forces for dif-
fusion in favor of H3P04. (2) Protonation
of surfaces and molecules in the tooth-
plaque membrane would increase as the pH
decreased, thereby making them more ca-
tionic to facilitate anion diffusion. (3) It is
a general observation that the ability of a
permselective membrane to discriminate be-
tween ions is reduced when the concentra-
tion of solution is increased. (4) A Donnan-
membrane type potential, present because
of the initially favored cation transport,
would stimulate anion (that is, phosphate)
transport out of the lesion.
The equilibrium model for the cation
permselective membrane yielded a limiting
condition based on the point on the iso-
therm where the value of ACa(OH)2 is equal
to that in the saliva. The steady-state model
gives a limiting condition based on the
point on the isotherm where the Ca/P ratio
of the diffusing ions is the same as that of
the dissolving solid. One may ask how these
two limiting conditions are related. Both
models involve cation-selective membranes;
they differ in that the equilibrium model
assumes essentially perfect cation selectivity.
Since the steady-state model allows for some
phosphate transport, it seems reasonable to
assume that the ultimate limiting compo-
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J Dent Res Supplement to No. 2
sition for the steady-state model would be
the same as that for the equilibrium model;
but depending on the leakiness to phos-
phate ions, it generally will be at a lower
concentration.
These considerations of the steady-state
model, in which the intact layer plaque are
taken to be a complex permselective mem-
brane, lead to several recommendations for
future research.
First, surface charges on apatite (enamel)
crystals should be investigated as a function
of the composition of the solution (that is,
the position on the isotherm), first in the
ternary system and then with other compo-
nents. Surface-active constituents especially
should be investigated.
Second, the permselective properties of
enamel and plaque components under con-
ditions conducive to caries should be in-
vestigated. This work will require coopera-
tion between microbiologists, biochemists,
and membrane specialists.
Third, the nature of potentials and cur-
rents generated in the enamel-plaque mem-
brane should be established more clearly,
and their effects on ion transport should
be determined.
Cyclic Models
In view of the fluctuating character of
acid production within plaque, it is unlikely
that the steady-state model is strictly appli-
cable for more than a brief period during
each cycle of acid production. Mathematical
treatment of a cyclic caries process appears
to be hopelessly complex. However, there
are two points of interest that are brought
out by qualitative consideration of a cyclic
model.
CARIES AS AN AUTOCATALYTIC PROCESS.-Let
us assume that the period of acid production
in the plaque is relatively short compared
with the time required for diffusion of ions
out of the lesion, but that it is sufficiently
long so that the pH within the lesion ap-
proaches the equilibrium value for whatever
is required by the plaque acidity. For each
cycle of acid production the amount of min-
eral that dissolves will be proportional to
two quantities: the calcium and phosphate
concentrations within the lesion as deter-
mined by the pH (Figs 2, 3), and the vol-
ume of the lesion. The latter point is of
great interest here because it implies that
the rate of caries formation accelerates as
the volume of the caries lesion grows. Clin-
Vol 53 1974 PHYSICOCHEMICAL MECHANISMS OF CARIES
ical data should be sought to test this hy-
pothesis.
SINGULAR POINT AND FORMATION OF CA-
HPO4 2H20.-In a solution that is suffi-
ciently acid, the solubility of hydroxyapatite
becomes greater than that of CaHPO4'
2H20 and CaHPO4. Under these condi-
tions hydroxyapatite will dissolve until the
solution becomes saturated with respect to
the acid calcium phosphates, allowing them
to precipitate. In the ternary system with
synthetic hydroxyapatite, the pH's where
the reversals in relative solubilities occur
(that is, the "singular points") are about
4.3 and 4.8, respectively. In view of the
variable solubility of tooth enamel, the sin-
gular points can be much higher for the
more soluble portions of the mineral.10 As
a result, it is probable that one of thes&
salts will form in the lesion at pH's attain-
able in plaque. Actually, CaHPO4 *2H20,
even though it requires a lower pH, is more
likely to form than CaHPO4 (because it
crystallizes more readily than CaHPO4)
Once one of these salts has formed, for
example, during the height of acid produc-
tion by plaque bacteria, it can have an im-
portant effect by preserving acid conditions
within the lesion for a longer period than
one might expect from simply following the
pH of the plaque. As long as CaHPO4.
2H20 is present in the lesion, the system
would resist an increase in pH above the
singular point by dissolution of CaHPO4.
2HO, an acid salt, and precipitation of
hydroxyapatite, a basic salt. Thus, the
CaHPO4 . 2H,0 would act as a buffer to
preserve the high concentrations within the
lesion which, in turn, would presumably
maintain relatively high rates of diffusion
out of the lesion. The question that needs
to be investigated here is how much Ca-
HPO4 *2H,0 (or CaHPO4) can form under
the conditions prevailing during a single
cycle of acid production and the extent to
which this will "buffer" the solution within
enamel under conditions that simulate in
vivo caries.
In recent experiments in which enamel
mineral from advanced caries lesions was
pyrolyzed, we found that pyrophosphate
was indeed formed1"; this indicated that an
acid calcium phosphate was present in the
mineral. Noncarious enamel did not form
significant amounts of pyrophosphate under
similar conditions. This appears to be a
useful method for the study of conditions
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211
that have prevailed within a caries lesion.
Further pyrolysis studies of possible forma-
tion of acid calcium phosphates, both- in
vivo and in vitro, are needed to establish
the magnitude of this effect.
Variable Solubility of Tooth Mineral
Up to this point we have disregarded the
question of why the mineral in the "reac-
tion zone," which is quite distant from the
source of acid causing the dissolution, is
dissolved in preference to the mineral ad-
jacent to the "relatively sound outer layer."
The outer layer is thought to be at least
partially protected by presence of fluoride
and by coatings of insoluble materials (see
subsequent section on the presence of the
"intact enamel layer"). The von Bartheld
membrane theory implies that the pH is
lower in the lesion than it is outside the
tooth, but this does not prescribe how the
partially demineralized region would be
protected. If the solubility of enamel min-
eral were the same throughout the enamel,
then I see no mechanism that would lead to
preferential dissolution in the reaction zone.
On the other hand, there are at least four
types of evidence that are in accord with the
view that there is sufficient variability in the
solubility of tooth mineral to account for
the subsurface nature of the lesion.
First, it is well known that tooth mineral
contains numerous impurities, some of which
are retained within the structure and, there-
fore, should affect solubility. Particle size
and morphology also may be important fac-
tors in enamel.
Second, the usual pattern of caries demin-
eralization shows variations in the extent of
dissolution that parallel the prisms, the lines
of Retzius, and the growth lines. This se-
lectivity in demineralization has been attrib-
uted12 to a variety of factors-thermody-
namic (solubility or chemical composition)
and kinetic (orientation of crystals, accessi-
bility to demineralizing agents, degrees of
mineralization)-but there appears to be no
general agreement as to the cause of the
pattern. In my opinion, the fine structure
of the pattern is of such a small scale com-
pared with the size of the lesion that one
must attribute the major role to differential
solubility. An interesting observation is the
manner in which the individual crystals in
enamel dissolve during caries attack. Quite
often the central portion of the crystal will
dissolve first (Scott13), leaving a tubelike
212 BROWN
relic. The difference in solubility between
the exterior and the interior must I)e a dom-
inant factor, otherwise the diffusion distance
would not have been increased so drastic-
ally. The same type of effect has been dem-
onstrated14 with synthetic OHAp crystals so
that the phenomenon cannot be attributed
solely to organic and fluoride coatings on
the crystallites. Thus it appears that al-
though the kinetic mechanism controlling
the overall rate of the caries process may
very well be diffusion, differences in solu-
bility have an overwhelming effect on dis-
solution within the microenvironments.
Third, the thermodynamic solubility of
enamel apatite in the ternary system Ca-
(OH) 2-H3PO4-H2O is being studied in our
laboratory15 by techniques that were success-
ful with synthetic hydroxyapatite and with
other calcium phosphates. It is clear from
these measurements that the apparent solu-
bility product decreases as the amount of
material that has been dissolved increases.
Further evidence for the elevated solubility
of enamel apatite was provided5 by the for-
mation of CaHPO4* 2H2O as a secondary
phase in apparent metastable equilibrium,
along with the enamel powder, with a solu-
tion having a pH of 5.2. Our measurements
with synthetic hydroxyapatite show that this
equilibrium should not occur at a pH greater
than 4.3, unless the enamel is more soluble
than synthetic apatite.
Fourth, a somewhat similar effect has been
reported by Gray and Francis16'17 who stud-
ied the solubility of enamel in various or-
ganic acid buffers. Their results indicate
that CaHPO *2H92O was formed at pH's of
more than 6.0. In the presence of other com-
ponents, the pH of the singular point be-
tween hydroxyapatite and CaHPO4 * 2H20 is
a function of the concentrations of the other
components; but in this case the effect can-
not be attributed to other components be-
cause it would be in the wrong direction.
Thus, the formation of CaHPO4 * 2H20 from
enamel apatite at a pH greater than 6.0 must
reflect the presence in enamel of an apatite
that is more soluble than well-stabilized, syn-
thetic hydroxvapatite.
Presentation of these four arguments has
been made in considerable detail because of
the importance that must be attributed to
this phenomenon. Not only should differ-
ential solubility be important in establishing
the physical nature of the caries lesion, but
it also may play an important role in the
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J Dent Res Supplement to No. 2
variation in caries susceptibility among indi-
viduals and among various tooth surfaces.
Although speculation on this has been with
us for a long time, the aforementioned rea-
sons strongly suggest that variable thermo-
dynamic properties are of considerable im-
portance and require further investigation:
(1) Solubility "spectra" as functions of posi-
tion in the enamel should be established.
(2) Similar studies should be carried out to
learn if there is a correlation between the
presence of large amounts of highly soluble
mineral with caries experience. (3) The solu-
bility of mineral in the "body of the lesion"
should be measured to ascertain that it is in-
deed a residue of less soluble mineral. (4)
Correlations of solubility with trace elements
in enamel and in synthetic apatites should
be made to establish the chemical nature of
the constituents causing elevated solubilities.
(5) The structural basis for elevated solu-
bilities should continue to be sought through
crystallographic studies of impure and de-
fect apatites.
General Considerations
The existence of mineral in enamel with
various solubilities has several other prac-
tical and theoretical implications. Mention
has already been made of how variable solu-
bility of enamel apatite increases the pH at
which enamel forms a singular point with
CaHPO4 * 2H20. Other implications have
to do with topics such as the subsurface form
of the lesion, the usefulness of clinical mea-
surements of enamel solubility, and the
tempo of events in the lesion.
SUBSURFACE FORM OF THE LESION.-Consid-
erable speculation has been devoted to the
causes of the peculiar structure of the enamel
lesion, which consists of four principal re-
gions: (1) The intact layer at the surface
of the lesion derives its existence, at least in
part, from the fact that it consists of mineral
of lower solubility, resulting from the pres-
ence of fluoride in the crystals and from dis-
solution-reprecipitation processes. These pro-
cesses are relatively rapid in this region, so
that more of the mineral has had the oppor-
tunity to recrystallize into a more perfect and
less soluble form. In this connection, our
measurements10 have indicated a "solubility
product" for the surface mineral, 10-57,
which is of the order 103 times smaller than
that of interior enamel. (2) The partially
demineralized body of the lesion presumably
consists of the residue of mineral from which
Vo 1 53 1974 PHYSICOCHEMICAL MECHANISMS OF CARIES
most of the more soluble fractions already
have been dissolved. (3) The reaction zone,
which lies between the body of the lesion
and the deeper, unaffected enamel, is the
region from which the more soluble fractions
are actively being lost by dissolution. (4)
The sound enamel deeper than the lesion
remains, for the moment, relatively unaf-
fected by dissolution because of its low
permeability.
Further research needs to be done to es-
tablish with more certainty the underlying
reasons for the existence of the various re-
gions in the caries lesion.
CAUSES FOR EXISTENCE OF THE INTACT
LAYER.-Considerable speculation has been
devoted to this matter. The greater insolu-
bility of the outer layer as compared with in-
terior enamel already has been discussed and
is certainly a factor. However, since the in-
tact layer can form in vitro even when the
outer portion of the enamel has been re-
moved, there must be other factors. One of
these that has been suggested is the presence
of organic coatings or surface "poisons," such
as pyrophosphate, which slow the dissolution
of the exposed, outer portion of the enamel.
There are at least two other possible causes
that have not received much attention; both
are related to repair of this layer by precip-
itation. First, after production of acid by the
plaque ceases, and the relatively concentrated
solution within the lesion starts to become
diluted with normal saliva, precipitation of
hydroxyapatite can occur because the U (4-)
value of the diluting saliva will be more
positive than that of the solution from within
the lesion. The net effect is that the appli-
cable isotherm is shifted toward the lower
right so that the diluted solution now lies
in the region of supersaturation. Second, if
the intact layer has acted as a cation-selec-
tive membrane, the phosphate ions that have
penetrated the enamel with some difficulty
may now depart at an accelerated rate, leav-
ing behind a solution that now is super-
saturated. The role of remineralization can
become an extremely important one by mak-
ing the intact layer more impervious to ion
diffusion.
In addition to the reasons cited, Moreno18
suggests another, formation of CaHPO4.
2HO, that may lead to formation of the
intact layer. Further studies of the causes
for the intact layer and the role of remin-
eralization are recommended.
CLINICAL SOLUBILITY MEASUREMENTS.-
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213
Throughout the last several decades solubil-
ity measurements of various kinds have been
made on enamel in repeated efforts to cor-
relate "solubility" with caries experience.
The results of these measurements have not
been particularly informative, I believe, for
several reasons. First, many of the measure-
ments have been more indicative of rates of
dissolution than of solubility. Second, the
amount that dissolves has mistakenly been
used as the criteria for solubility rather than
the thermodynamic solubility (which is ex-
pressed in terms of a solubility product).
Third, the apparent thermodynamic solu-
bility is different if it is measured at the sur-
face as compared with that in the interior
of the enamel. Finally, each region of the
enamel has a spectrum of solubilities, and
any attempt to assign a single number to
the solubility is certain to be misleading.
It already has been recommended that ad-
ditional studies be made of the solubility
"spectrum" of teeth and that these results
be correlated with caries experience. It is
imperative, however, that clinically related
solubility studies be carried out on a more
sophisticated level than has been done in the
past.
TEMPO OF EVENTS IN THE CARIES LESION.-
Although it is unlikely that we can develop
a quantitative understanding of the rates
with which various processes occur in the
various lesion, a qualitative picture can be
of value. In view of the fact that the hy-
drogen ions are produced in the plaque and
are removed by reaction with the mineral in
the reaction zone, one might expect a rather
pronounced gradient in pH (increasing in-
ward) within the lesion. There are several
reasons why the pH gradient may be vir-
tually nonexistent, or possibly reversed from
what one would expect. First, the results of
Holly and Gray9 indicate that the rate con-
trolling processes occur in the intact layer;
thus, the relative rates of diffusion in the
body of the lesion should be rapid enough so
that sharp gradients would not be needed
to keep up with the reaction. Second, a
gradient in which the pH is much higher
in the vicinity of the reaction zone would,
in turn, require lower calcium and phos-
phate concentrations in this zone because of
the effect of pH on the solubility of apatite
(Fig 2). As a result, calcium and phosphate
ions would have to diffuse against concen-
tration gradients. Three considerations could
alter the latter situation: (1) Initial net loss
214 BR 0 WN
of Ca (OH) 2 from the reaction zone (that
is, in the ratio Ca/P > 5:3) could drive the
pH down so that the-calcium and phosphate
concentrations in this zone could be rela-
tively high. (2) The presence of the more
soluble mineral fractions in this zone would
enhance the driving forces for the outward
diffusion. (3) As we have seen with the
Donnan-membrane equilibriums, diffusion
against a concentration gradient is possible,
provided it is suitably coupled to another
process. Clearly additional experimental
and theoretical studies are needed to provide
a better understanding of this phenomenon.
If we summarize the considerations given
here and in earlier sections, it appears that
the factors controlling events in the body
of the lesion and in the reaction zone are
thermodynamic in nature (variable solubil-
ity), whereas those dominating events in the
intact layer and plaque are kinetic in nature
(restricted diffusion). The combined effects
of thermodynamic and kinetic factors can be
understood in general terms through the use
of generalized quaternary phase diagrams.
Much remains to be learned, however, about
the details of the events taking place within
the lesion and how they are controlled by
the conditions within the enamel-plaque
"membrane."
References
1. BROWN, W.E., and WALLACE, B.M.: Phase
Rule Considerations and the Solubility of
Tooth Enamel, Ann NY Acad Sci 131: 690-
693, 1965.
2. BROWN, W.E.: Physicochemical Aspects of
Decay and Decalcification, Proceedings of
the International Symposium on Calcified
Tissues, Dental and Surgical Materials and
Tissue Materials Interactions, University of
Nijmegen, Nijmegen, 1970.
3. VON BARTHELD, F.: Membrane Phenomena
in Carious Dissolution of the Teeth, Arch
Oral Biol (special suppl 6): 284-303, 1961.
4. SOLLNER, K.: An Outline of the Basic Elec-
trochemistry of Porous Membranes, J Dent
Res 53: 267-279, 1974.
5. PATEL, P.R.; CHUONG, R., and BROWN, W.E.:
Study of Dental Caries Mechanism Using
Experimental Models, abstracted, IADR
Program and A bstracts of Papers, No. 696,
1973.
6. HIGUCHI, W.I.; GRAY, J.A.; HEFFERREN, J.J.;
and PATEL, P.R.: Mechanisms of Enamel
Dissolution in Acid Buffers, J Dent Res 44:
330-341, 1965.
7. HIGUCHI, W.I.; MIR, N.A.; PATEL, P.R.;
BECKER, J.W.; and HEFFERREN, J.J.: Quan-
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J Dent Res Supplement to No. 2
titation of Enamel Demineralization Mecha-
nisms: III. A Critical Examination of the
Hydroxyapatite Model, J Dent Res 48: 396-
409, 1969.
8. GRAY, J.A.: Kinetics of Enamel Dissolution
During Formation of Incipient Caries-like
Lesions, Arch Oral Biol 11: 397-421, 1966.
9. HOLLY, F.J., and GRAY, J.A.: Mechanisms
for Incipient Carious Lesion Growth Utiliz-
ing a Physical Model Based on Diffusion
Concepts, Arch Oral Biol 13: 319-334, 1968.
10. PATEL, P.R., and BROWN, W.E.: Solubility
of Intact Human Tooth Enamel at 25 C,
abstracted, IADR Program and Abstracts of
Papers, No. 177, 1972.
11. CHOW, L.C., and BROWN, W.E.: The Forma-
tion of Dicalcium Phosphate Dihydrate in
Tooth Enamel Treated with Acid Solutions,
abstracted, IADR Program and Abstracts of
Papers, No. 440, 1973.
12. DARLING, A.I.: Microstructural Changes in
Early Dental Caries, In Sognnaes, R.F.:
(ed): Mechanisms of Hard Tissue Destruc-
tion, Washington, DC: American Association
for the Advancement of Science, 1963, pp.
171-186.
13. SCOTT, D.B.; SIMMELINK, J.W.; and NYGAARD,
V.: Structural Aspects of Dental Caries, J
Dent Res 53: 165-178, 1974.
14. Scorr, D.B.; SWANCAR, J.R.; SIMMELINK, J.W.;
and SMITH, T.J.: Apatite Crystal Growth in
Biological Systems, in BROWN, W.E. and
YOUNG, R.A. (eds): International Sympo-
sium on Structural Properties of Hydroxy-
apatite and Related Compounds, New York:
Gordon and Breach, in press.
15. PATEL, P.R.; MILETTA, E.M.S.; and BROWN,
W.E.: Solubility Behavior of Powdered Hu-
man Tooth Enamel at 25 C, abstracted,
IADR Program and Abstracts of Papers, No.
807, 1971.
16. GRAY, J.A., and FRANCIS, M.D.: Physical
Chemistry of Enamel Dissolution, in Sogn-
naes, R.F. (ed): Mechanisms of Hard Tissue
Destruction, Washington, DC: American As-
sociation for the Advancement of Science,
1963, pp 213-260.
17. FRANCIS, M.D.: Solubility Behavior of Den-
tal Enamel and Other Calcium Phosphates,
Ann NY Acad Sci 131: 694-712, 1965.
18. MORENO, E.C., and ZAHRADNIK, R.T.: Chem-
istry of Enamel Subsurface Demineralization
in Vitro, J Dent Res, 53: 226-235, 1974.
19. BROWN, W.E.: Solubilities of Phosphates
and Other Sparingly Soluble Compounds, in
GRIFFITH, E.J., ET AL (eds): Environmental
Phosphorus Handbook, New York: John
Wiley & Sons, Inc., 1973.
Appendix
The purpose of this section is to provide
background and sources of information nec-
Vol 53 1974 PHYSICOCHEMICAL MECHANISMS OF CARIES
essary for the use of phase diagrams in con-
sidering caries mechanisms.
The solubility of the salt such as Ca5-
(P04) 30H, the prototype for enamel min-
eral, is best expressed in terms of a phase
diagram. Figure 1 shows the phase diagram
for the three-component system, Ca (OH) 2-
-H3PO4-H2O. The solid line represents the
demarcation between all those solutions that
are supersaturated with respect to hydroxy-
apatite and those that are undersaturated.
Therefore, it represents all the solutions that
are saturated with respect to hydroxyapatite.
The fact that the isotherm is a line rather
than a point signifies that the solubility of
hydroxyapatite is represented by an infinite
number of compositions and not by a single
"solubility." The reader is referred else-
where (page 216 of reference 19) for a de-
scription of the basic concepts necessary for
understanding the various types of phase
diagrams used in this discussion.
An important operation easily represented
on the phase diagram (Fig 1) is the addition
or removal of a component, Ca (OH) , or
H:PO4, and how this would affect the com-
position of the resulting saturated solution.
Consider first the effect of removing the com-
ponent Ca (OH) 2- If the initial composition
is at point c on the isotherm, removal of
Ca (OH) to point d places the solution in
2 of the concentration of acid or base that is
the region undersaturated with respect to
hydroxyapatite. Thus, hydroxyapatite will
dissolve, adding calcium and phosphate to
the solution in the ratio Ca/P = 5:3 until
the point e is reached. Dissolution then will
cease because the solution is saturated once
again. Note that the net effect caused by
removal of Ca (OH) 2 is to move the compo-
sition up the isotherm in the direction of
higher calcium and phosphate concentrations
and lower pH's. With each removal of
Ca (OH) the composition will move farther
2'
up the isotherm.
Consider next the removal of H3PO4.
Starting once again with an initial concen-
tration c, remove H3PO4 until point f is
reached. The solution is now supersaturated
and hydroxyapatite can precipitate until
composition g is reached where once again
saturation is obtained. Thus, the removal
of H3PO4 has just the opposite effect of re-
moval of Ca (OH) 2. These effects are direct
consequences of the positive slope of this
isotherm.
On the other hand, if calcium and phos-
phate are removed in the ratio Ca/P = 5:3
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215
there will be no net change in the composi-
tion of the solution after saturation is re-
gained. For example, remove calcium and
phosphate in the ratio Ca/P = 5:3 from the
solution of composition e until, for example
point d is reached. Dissolution of hydroxy-
apatite (ratio Ca/P = 5:3) will cause the
composition to move back up the broken
line until point e is reached. The point of
the latter exercise is to show that incremental
removals of calcium and phosphate from the
solution will result in net movement up or
down the isotherm depending on whether
the ratio Ca/P is more or less, respectively,
than 5:3. As discussed in this paper, the solu-
tion within the lesion could move up or
down the isotherm depending on whether
the permselective properties of the enamel-
plaque membrane favor calcium over phos-
phate in the ratio Ca ,P more or less than
5:3, respectively.
Figure 2 contains information about the
solubility of hydroxyapatite in the presence
of other components. The lines labeled with
various values of pU (±) are solubility iso-
therms for the indicated concentrations of
the "fourth component" (see pp 223-226 of
reference 19), which is taken to be either
an acid, U (-), or a base, U (+) . Thus the
quantity pU (-+-) is the negative logarithm
in the solution in the form of dissociated
ions. The pU (+) lines may be thought of as
contour lines defining a surface on which
pU (-+-) is the coordinate perpendicular to
the plane of the page. On this surface one
can construct lines that connect points with
a common pH (Fig 2).
Similarly, one can draw another series of
lines representing loci of constant calcium
hydroxide activity, (Ca2+) (OH-) 2 (dashed
lines in Fig 3). [It can be easily demonstrated
that these lines are also loci of constant
phosphoric acid activity, (H+) 3 (P043-) .]
These lines define the compositions of solu-
tions that can be in equilibrium with other
solutions by way of a Donnan membrane
mechanism.
To apply this diagram (Fig 3), consider
a compartment saturated with respect to
hydroxyapatite (for example, the lesion), in
communication with another solution, not
necessarily saturated (for example, saliva)
through a cation-permselective membrane.
The composition of the saturated solution
will fall on the appropriate isotherm in Fig-
ure 3. If its calcium hydroxide activity,
216 BROWN J Dent Res Supplement to No. 2

(Ca2+) (OH-) 2, were higher than that of the
other solution, its composition would lie to
the left of the line corresponding to the cal-
cium hydroxide activity of the other solution.
As Donnan equilibrium is approached, the
composition of the saturated solution would
move along its isotherm until it reached the
line for the calcium hydroxide activity in
the other solution, at which point net re-
placement of calcium ions by hydrogen ions
would cease. Note that in this process the
calcium hydroxide activity of the saturated
solution would decrease and that of phos-
phoric acid would increase.

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