Page 665 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

630 SECTION | IX Gases, Solvents and Other Industrial Toxicants

VetBooks.ir effectively resulting in extremely short diffusion distances; in the blood (particularly blood triglycerides) can signifi-
cantly increase the blood:gas partition coefficient of lipo-
and (3) gases absorbed through the alveoli are rapidly
philic xenobiotics and thus affect their inhalation absorption
removed by the blood, thus maintaining the diffusion con-
centration gradient (Rozman and Klaassen, 2001; Witschi kinetics (Lin et al., 2002). Ingestion of a high-fat meal dur-
and Last, 2001; Renwick, 2008; Valentine and Kennedy, ing or before inhalation may result in an increased absorbed
2008). There are two exceptions: (1) CO absorption is diffu- dose of an inhaled lipophilic gas and affect the rate of excre-
sion limited (the basis for its use in the lung diffusion tion by exhalation of such substances.
capacity test or determination of the DLCO; referred to as The alternate extremes are gases that are ventilation
the TLCO or transfer capacity in Europe), and (2) the pres- limited (Rozman and Klaassen, 2001; Witschi and Last,
ence of interstitial lung disease that increases the pulmonary 2001; Renwick, 2008; Valentine and Kennedy, 2008).
diffusion distance, resulting in diffusion-limited absorption Ventilation-limited gases are highly soluble in blood
for gases (notably oxygen). (tend to be hydrophilic or, in rare cases, zwitterion-like)
In a broad sense, the rate of establishment of the equi- and often have low octanol:water partition coefficients
librium between the respiratory airspaces and the blood- (Fiserova-Bergerova and Diaz, 1986). Again, other fac-
stream depends on: (1) whether or not uptake of the gas is tors, such as the affinity of the particular gas to protein
perfusion limited; and (2) whether or not the uptake of and other elements in blood, may also significantly
the gas is ventilation limited (Rozman and Klaassen, impact the blood:gas partition coefficient, e.g., a high
2001; Witschi and Last, 2001; Renwick, 2008; Valentine affinity for erythrocytes or blood proteins may result in a
and Kennedy, 2008). These innately characteristic proper- high blood:gas partition coefficient irrespective of other
ties of a substance are directly related to the blood:gas physicochemical properties (Veltman et al., 2009). The
partition coefficient, an innate physicochemical property majority of a ventilation-limited gas present in alveoli is
of the substance. The blood:gas partition coefficient is the removed during each respiratory cycle because of its high
ratio of the substance’s concentration in the gaseous phase affinity for blood, i.e., replenishment of the gas in the
and the blood phase at equilibrium. For substances with gas-exchange regions is dependent on the subsequent
low blood:gas partition coefficients (i.e., substances that inhalation of fresh gas. In this situation, relatively small
have a low affinity for dissolving in blood), the ability of changes in respiratory minute volume can produce rela-
blood in blood:gas exchange regions of the lungs to tively large effects on the rate of transfer of the gas from
absorb the substance is rapidly saturated, and thus only a the respiratory system to the blood and tissues. The rate
small amount of the substance in the respiratory tract is of pulmonary blood perfusion has little effect on the
removed by blood during passage through the pulmonary rate of transfer of the gas from the respiratory system
circulation. In such circumstances, changes in the respira- to the blood because virtually all of the gas is removed
tory minute volume have relatively little effect on the rate from the gas-exchange site during each pulmonary circu-
of transfer of the gas from the alveolar spaces to the lation, i.e., increasing the rate of blood flow through the
bloodstream. However, small changes in the rate of flow lung during each circulation would result in little addi-
of blood through the respiratory tract (i.e., pulmonary per- tional gas absorption and decreasing the rate of blood
fusion) have proportionally large effects on the rate of flow through the lung would result in little reduction of
transfer of the gas from the respiratory system to the absorption. The time to blood:gas equilibration for gases
blood; i.e., increasing pulmonary perfusion results in that are ventilation limited is at least 1 h and often much
more rapid removal of the gas from the site of equilibra- longer (days or, in some cases, never).
tion (the alveolar membranes) and thus a proportionally Gases may also be absorbed in the upper respiratory
more rapid rate of transfer of the gas from the respiratory tract, particularly the nasal cavity (Rozman and Klaassen,
system to the bloodstream occurs and vice versa. Thus, 2001; Witschi and Last, 2001; Renwick, 2008; Valentine
for gases with a low blood:gas partition coefficient, blood and Kennedy, 2008; Morris and Buckpitt, 2009). In this
gas equilibration occurs relatively quickly (B8 21 min case, gases may be systemically reversibly absorbed via
for relatively blood-insoluble gases), and the absorption diffusion processes in which the mucus:blood:tissue:air
of such gases is described as being perfusion limited. As partition equilibria (and associated coefficients) are
a general rule, perfusion-limited gases tend to be spar- important; alternatively, the gas may react with tissue
ingly soluble in water, are relatively lipophilic and hydro- macromolecules in the upper respiratory tract (including
phobic, and have high octanol:water partition coefficients enzymes with subsequent metabolism). In general, gases
(Fiserova-Bergerova and Diaz, 1986). However, other fac- that are absorbed in the upper respiratory tract tend to be
tors, such as the affinity of the particular gas to protein highly soluble in aqueous solutions (particularly in the
and other elements in blood, may also significantly mucous lining of the upper respiratory tract), or highly
impact the blood:gas partition coefficient (Veltman et al., reactive (i.e., site-of-first-contact toxicants), or both
2009). Notably, alteration in the level of lipid components (Renwick, 2008). In such cases, the nasal cavity can be