Page 55 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

22 SECTION | I General

VetBooks.ir Exposure Time 1 Time 2 Time 3 Time 4 Time 5 metabolites. It may be useful to obtain preliminary infor-
Time postexposure
mation on retention kinetics from pilot studies. Some
organic compounds may be rapidly metabolized leading
to the need to schedule all of the sacrifices over a few
hours. On the other hand, certain inhaled relatively inher-
Serial sacrifice – ent materials may have long-term retention in the lungs
determine tissue extending over hundreds of days. It is important to
distribution and
body burden recognize that the quantity of material administered
may influence the kinetics of the material. Hence, it is
Excreta collection +
sacrifice desirable to use multiple administered exposure/dose
levels as an experimental variable. Without question,
FIGURE 1.7 Schematic rendering of an experimental design for evalu- the design of any particular toxicokinetic study requires
ating the kinetics of an administered toxicant.
the exercise of considerable professional judgment.
Toxicological research is not a “cookie cutter” or “check
However, the resulting data may be of limited relevance the box” science.
to other routes of intake. For example, it may not appro-
priately mimic oral intake since only a small fraction
of some toxicants may be absorbed from the gastrointesti- Acquiring Exposure (Dose)-Response Data
nal tract. In short, the route of administration should be
A schematic experimental design for a study to evaluate
matched to the route of concern for real-world exposure
exposure (dose)-response relationships for toxicants
to the agent.
is shown in Fig. 1.8. Recall the exposure response link-
With inhalation, the particle size distribution of the air-
age shown in Fig. 1.1. The design shown is typical of that
borne toxicant will influence what portion of the inhaled
which might be used in the conduct of a 2-year bioassay,
material will be deposited and where it is deposited in the
typically used to evaluate carcinogenicity, in rats and
various regions of the respiratory tract, i.e., the oropharynx,
mice. Recall the studies of Mauderly et al. (1987) and
tracheobronchial, or pulmonary regions. The pattern
McDonald et al. (2015) with exhaust from diesel engines.
of deposition, retention and subsequent translocation of
The same design, and indeed the same experiment, can be
the deposited material will depend on the size, chemical
used to evaluate other endpoints and to conduct shorter-
composition and dissolution properties of the deposited
term studies. The study should involve administration of
material. Differences among the various species are of
the material by a route matched to likely exposure condi-
paramount concern. Individuals interested in details on the
tions to be encountered with the agent. Administration of
conduct of inhalation toxicity studies will find the book an agent by gavage may be acceptable as a surrogate for
edited by McClellan and Henderson (1995) of interest ingestion, especially when it is desirable to administer
as well as a summary chapter by McClellan et al. (2006). specific quantities of material. However, I am not enthusi-
Recall also the studies of Wolff et al. (1987) on the fate of
astic about the repeated use of gavage as a substitute for
inhaled diesel exhaust particles.
ingestion of an agent in feed. The use of intratracheal
Another key decision is whether conduct of the toxico-
instillation as a surrogate for conducting inhalation expo-
kinetic studies may be facilitated by using a test agent
sures to an agent remains controversial. It is my profes-
labeled with radioactive or stable element tracers.
sional opinion that intratracheal administration is a
Analytical considerations for the initial toxicant as well as
nonphysiological mode for delivery of materials to the
any metabolites are of major importance in the conduct of
respiratory tract. It may result in exaggerated quantities of
toxicokinetic studies.
The schematic design (Fig. 1.7) shows a group of ani- Lifespan
mals maintained for collection of excreta and, perhaps, even Serial sacrifice observation
6 months 12 months 18 months
sampling of expired air. Data from these analyses can be or 24/30
used along with tissue analyses to obtain a mass-balance months
sacrifice
between the quantity administered and the quantity recov-
ered. The schematic design shows multiple times at which
animals will be euthanized and tissues collected for analysis.
This allows the development of a dynamic profile of how
the body handles the administered material. For organic
compounds, provision needs to be made for analyzing for Single level illustrated—preferable to use three exposure levels,
chamber controls and colony controls
both the parent compound and potential metabolites.
The selection of the sacrifice times will be guided by FIGURE 1.8 Schematic rendering of an experimental design for evalu-
the anticipated kinetic profile of the agent and its ating exposure (dose)-response relationships for a toxicant.