Page 667 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

632 SECTION | IX Gases, Solvents and Other Industrial Toxicants

VetBooks.ir absorption by inhalation. Gases with a high blood:gas par- Category 3 gases: These gases are relatively insoluble
in water and are not reactive in the extrathoracic and
tition coefficient tend to be slowly excreted by exhalation
tracheobronchial regions of the respiratory tract. These
due to the relatively large amount of the substance dis-
solved in the blood volume and the high affinity of the gases are not “scrubbed out” in the upper respiratory
gas for blood relative to its affinity for air. Gases with a tract and conducting airways and thus penetrate into
low blood:gas partition coefficient tend to be excreted by the deep pulmonary areas, where they are available for
exhalation relatively rapidly because of the relatively absorption into the systemic circulation. Examples
small amount present in the blood volume and the greater include benzene and most of the common anesthetic
affinity of the gas for air than for blood. However, respi- gases and vapors.
ratory excretion of gases that have a high affinity for lipo-
Based on the above categorization, the following
philic tissue compartments (including the adipose tissues),
equations can be used to derive RGDRs:
may be biphasic (have two compartment excretion kinet-
ics or even more complex patterns of excretion). This is V e
animal
most commonly observed with lipophilic gases that have SA ETh
RGDR Extra Thoracic 5
a low blood:gas partition coefficient and a tendency for V e human
SA ETh
tissue sequestration (i.e., large volumes of distribution
exceeding 1 L/kg). The initial phase of excretion is rela- V e
animal
tively rapid due to the fast removal of the gas from the SA TB
RGDR Tracheobronchial 5
blood tissue compartment during exhalation. This is fol- V e human
SA TB
lowed by an often much slower phase as the gas slowly
redistributes from lipophilic tissue compartments and/or Q alv
animal
sites of sequestration into the bloodstream, with subse- SA PU
RGDR Pulmonary 5
quent excretion by exhalation. Q alv human
SA PU
H B=G animal
Regional Gas Dose Ratios for Human Risk RGDR Systemic 5
H B=G human
Assessment Based on Animal Data
Human health risk assessment for gases commonly Abbreviations:
involves extrapolation from animal data to humans, i.e., Extrathoracic region: upper respiratory tract com-
the calculation of a human equivalent concentration prising the nose, mouth, oropharynx, laryngophar-
(HEC). The general formula for this calculation is: ynx and larynx.
Tracheobronchial region: conducting areas of the
3 3
HEC ðmg=m Þ 5 NOAEL ðmg=m Þ 3 RGDR
respiratory tract distal to the larynx including the
RGDR, regional gas dose ratio. trachea, bronchi and bronchioles (to the terminal
For the purposes of derivation of RGDR values, gases, bronchioles).
and vapors can be categorized into three general classes Pulmonary region: gas exchange areas of the lung
(US EPA, 2009): including the respiratory bronchioles, alveolar
ducts, alveolar sacs and alveoli.
Category 1 gases: These gases are highly water soluble
V e , respiratory minute volume.
and/or irreversibly reactive in the surface liquid/tissues SA ET , extrathoracic surface area.
of the extrathoracic and tracheobronchial regions of the SA TB , tracheobronchial surface area.
respiratory tract. Most of the toxicological effects of SA PU , pulmonary surface area.
these substances will occur at sites of first contact Q alv , alveolar ventilation rate ( 0.7 3 V e for rats).
within the respiratory system. Relevant examples H B/G , blood gas partition coefficient.
include hydrogen fluoride, chlorine, and acrolein.
Category 2 gases: These gases are moderately water
soluble, rapidly and reversibly reactive, and/or moder- Extrapolating Duration of Exposure
ately to slowly irreversibly metabolized within respira- for Human Risk Assessment
tory tissues. These intermediate gases have the
potential for both sites of contact and systemic toxic The duration of exposure in animal studies rarely corre-
effects, i.e., effects will likely occur both within the lates with the exact duration of interest in terms of human
respiratory tract and at remote sites following systemic risk assessment. Haber’s Law is commonly used to com-
absorption. Examples include the vapors of acetoni- pensate for these differences in human health risk assess-
trile, xylene, propanol, and isoamyl alcohol. ment. Ernest Warren and Fritz Haber noted during their