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5.3 TOXICITY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS 259

liquid accumulating has become so large that it impairs gas exchange. In addi-
tion to water-solubility, the reactivity of the gas with airway proteins is impor-
tant. Thus, sulfur dioxide is removed effectively by the nose while ethanol is
partially absorbed. If a soluble gas is adsorbed on fine particles, it can he
58 59
transported deep to the lungs. '
The solubility coefficient 5 is used as a measure of water solubility. It is
the ratio between the concentrations in water and air phases at equilibrium.
Ethanol, a very soluble gas, has a solubility coefficient of 1 100 at 37 °C while
the coefficient for nitrous oxide, a poorly soluble gas, is 0.15.

The Importance of pH and pK a
Under physiological conditions, pK a (negative common logarithm of
the acid constant) of a compound largely determines its behavior at varying
pH. This is important because the dissolution of polar molecules in lipid bi-
layers is a difficult and slow process, and from a practical toxicokinetic
point of view, most polar compounds fail to penetrate biological mem-
branes to any significant extent. lonization of most weak acids and bases
depends on their dissociation constant and pH according to the Henderson-
62
Hasselbach equation:
log[AVHA] = pH - pK a (for weak acids)
+
log[5/BH ] - pH - pK a (for weak bases)
The proportion of ionized and unionized forms of a chemical compound
can be readily calculated according to the above equation. It can be easily
seen that pK a is also a pH value at which 50% of the compound exists in
ionized form. The ionization of weak acids increases as the pH increases,
whereas the ionization of weak bases increases when the pH decreases. As
the proportion of an ionized chemical increases, the diffusion of the chem-
ical through the biological membranes is greatly impaired, and this attenu-
ates toxicokinetic processes. For example, the common drug acetosalicylic
acid (aspirin), a weak acid, is readily absorbed from the stomach because
most of its dose is in an unionized form at the acidic pH of the stom-
6 63
ach. -
Lipid Solubility
Cell membranes are composed of lipid bilayers which contain large pro-
tein molecules and glycoproteins. To be able to penetrate through the cell
membrane, a compound has to dissolve in the lipid bilayer, where it diffuses
according to the concentration gradient across both sides of the membrane,
and after passing through the membrane, dissolve once more in the water
phase within the cell. Lipid-soluble compounds can reach high concentra-
tions in lipid-rich organs, such as the adipose tissue, brain, bone marrow,
and spleen. Lipid-solubility is often characterized by an octanol/water coef-
ficient which indicates the concentration ratio of the compound between
these two phases. For example, xylene, a non-polar lipid-soluble organic
solvent, has an octanol/water coefficient of 3200. In addition to polar or-
ganic compounds, many inorganic gases have low octanol/water coeffi-
cients. 62