Page 59 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

26 SECTION | I General

VetBooks.ir concept is simple. However, in reality it becomes com- in four categories related to the duration of the studies;
acute, subacute, subchronic and chronic (recall Fig. 1.8).
plex as one moves from parenteral administration to oral
Acute studies are usually of a day or less and may involve
intake, to dermal uptake, or inhalation exposure.
Distribution of the material will be influenced by the intraperitoneal, intravenous, or subcutaneous injection,
route of entry and the physicochemical properties of the gavage, dermal application or inhalation. Injections may
test agent. Metabolism for compounds varies dependent be given once or several times in the 24-h period. Acute
on the physicochemical properties of the material. In inhalation exposures are typically 4 6 h in duration. In
some cases, the material may be very inert and simply all cases, the observations are made over a 24-h period.
be transferred mechanically within the body with some Subacute studies typically involve repeated exposures
portion excreted over time. In other cases, especially with made on a daily, or 5 days per week, basis for 2 4 weeks
organic compounds, the metabolism may be quite with observations over the same period of time.
complex and result in metabolites that are either more Subchronic studies are usually conducted over a period of
toxic, less toxic, or have toxicity similar to the parent 1 3 months. In the case of inhalation exposures, these
compound. are typically conducted for 4 6 h per day, 5 days per
Excretion or elimination of the material and its meta- week. Chronic studies are usually conducted for more
bolites, if metabolized, may occur via the kidney (urine), than 3 months and, most typically, for 2 years.
gastrointestinal tract (feces), or the lungs (exhalation of I personally view the use of the terms—acute, subacute,
volatile compounds). In addition, the agent or metabolites subchronic and chronic—as jargon and prefer to commu-
may appear in tears, sweat, or exfoliated skin. Some spe- nicate the duration of studies in a specific manner, i.e.,
cies, such as the rat, may engage in coprophagy, ingestion number of days or months, or as short or long term.
of feces, such that the test material in the feces is ingested I prefer to use the terms acute, subacute, or chronic
and some portion may pass through the body multiple as descriptors of a medical condition.
times. Animals may be euthanized at various times during The kinds of toxicant-induced responses that may be
the course of the study and samples of various tissues col- encountered are broad, essentially mirroring the range of
lected and analyzed for the test agent or metabolites. disease processes that may occur in humans and other ani-
With small experimental subjects, it may be possible to mal species. In any well-conducted toxicity study, the
analyze all the tissues and obtain an estimate of the total investigator should use as broad an array of observational
body burden of the test agent and metabolites. techniques as are reasonably available to characterize the
In some short-term studies it may be possible to col- pattern of morbidity and mortality that may develop.
lect and analyze excreta and expired air, if the compound Inevitably, cost constraints will influence the choice of
is metabolized to a form that will be present in expired endpoints evaluated. It will be useful to prioritize the
air. This information, along with the results of tissue anal- potential endpoints as to their likely value in terms of the
yses, can provide an estimate of the total quantity in the information gained. It is crucial that detailed necropsies
body, excreta, and expired air for comparison with an be conducted on subjects euthanized at prescribed times
estimate of the quantity administered. This kind of mass and at termination of the study. Tissues should be col-
balance approach is obviously most feasible when radio- lected from any gross lesions and tissues identified in the
active or stable isotope tracers are used. One should not protocol as likely target tissues and processed for histo-
be surprised to find the estimated quantity recovered vary- pathological evaluation. It is now routine to establish a
ing from 75% to 125%; there will be a high degree of defined set of criteria for evaluating the various tissues
experimental variability when multiple samples are being and characterizing lesions. This approach allows the
collected and analyzed. Obviously, one should view with quantitative evaluation of any pathological findings on a
suspicion data tables showing recovery of exactly 100% group basis rather than restricting the evaluation to quali-
of the administered dose. Such values are typically the tative descriptions of responses in individual subjects.
result of an over zealous investigator normalizing the data Toxicity studies to evaluate exposure (dose)-response
to 100% recovery. For chronic exposure studies, it may relationships may extend from minutes to hours when bio-
be possible to use kinetic modeling to estimate the quan- chemical and physiological responses are being evaluated,
tity of the test agent or metabolites present in the experi- to hours to days when acute morbidity and mortality are
mental subjects at each exposure concentrations at being assessed, to weeks to months and finally to a signif-
various times after initiation of exposure. icant portion of the lifespan of the species, e.g., 2 years
for mice and rats when chronic effects, including cancer
induction, are being evaluated. With increased attention
Toxicant-Induced Responses
given to animal welfare considerations, emphasis is being
The types of studies typically used by toxicologists to given to using as few animals as possible to define the
investigate exposure response relationships can be placed acute morbidity and mortality of test materials. Rather