Page 179 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

146 SECTION | I General

VetBooks.ir in vivo toxicological data. Originally, in vivo experiments liver, whereas, following inhalation, a toxic compound is
more likely to be absorbed by the respiratory system.
were aimed at the prediction of acute systemic toxicity
Metabolism of xenobiotics can also occur in placenta, in
usually in rodents. Currently, more sophisticated, targeted
and multispecies approaches with well-defined endpoints the test dam and fetus. This can lead to changes in the
and experimental protocols are applied to toxicological balance of parent compound and metabolites, complicat-
studies, especially for regulatory testing. ing the picture even more in developmental toxicity tests.
As the science of toxicology evolves, an increasing The metabolism of an administered chemical should
number of in vitro alternative tests have been validated or be relevant to human or domestic animals and is critical
are currently under development. However, in some cases, for risk assessment exercises. The final toxic effect will
animal models in toxicity testing are irreplaceable, espe- depend on a balance between the level of toxic agent
cially in the tests required by the regulatory authorities to reaching the target tissue and its rate of elimination and/or
protect human and animal health. Furthermore, there is bioinactivation by mixed function oxidases, serum hydro-
public demand to know the toxicity risks posed in every- lases or binding to serum proteins. Furthermore, there are
day life, which necessitates the use of animal models interspecies differences regarding the metabolism of
comparable to humans. xenobiotics (Nebbia, 2001). For example, cats are at high
Although animals are relatively expensive experimen- risk of developing hepatotoxicity especially after paracet-
tal models compared to the alternative methods discussed amol administration. This is due to differences in bioacti-
later, there are several important reasons for their contin- vation of paracetamol, which occurs only in cats through
ued use. First, there is extensive information available on N-hydroxylation with the help of cytochrome P450 2E1,
their normal biochemical and physiological properties. during the oxidative reactions in phase I transformation
Second, the published data from the measurement of toxi- (Nebbia, 2001). Ruminants are less susceptible to organo-
cological endpoints in vivo, using models of relevance to phosphates (OPs) such as parathion than monogastrics,
humans and domestic/farm animals, makes animal testing because the rumen microflora play an important role by
a valuable tool to predict toxicity. reducing the nitro group of OPs to an amino group
The animals that are most commonly used in toxico- (Nebbia, 2001).
logical testing are rodents and rabbits (Table 9.1). Cats The majority of toxicological studies commonly
and dogs are used less frequently in toxicity testing (and employ administration of the agent in animal feed or
mostly in preclinical toxicology or phase I pharmacologi- water or by stomach intubation (i.e., by gavage) in order
cal studies), whereas nonhuman primates are rarely used to imitate a known or potential human or domestic animal
and mainly to study metabolism of toxic compounds. Not exposure. The use of oral gavage is commonly used in
included in this table are the studies conducted on com- administration of high doses of xenobiotics and in devel-
panion animals to determine safety limits in products that opmental toxicity tests, but is less practical in the case of
are directly applied to cats or dogs (EPA, 1998a). The long-duration studies. Inhalation is used when there is a
interested reader is referred to some more specialized need to duplicate industrial or environmental exposure to
books regarding animal toxicity testing (e.g., Arnold dusts, aerosols and fumes. In this case, nose, head or
et al., 1990; Gad, 2006) and some useful websites relevant whole body exposure chambers are used, depending on
to regulatory toxicological testing (e.g., https://www. the exposure time. For cutaneous administration, a toxic
epa.gov/test-guidelines-pesticides-and-toxic-substances/ agent may be injected intradermally or simply applied
series-870-health-effects-test-guidelines and http://www. topically on the skin or ears and sometimes covered with
oecd.org/chemicalsafety/testing/oecdguidelinesforthetestin a bandage. In the case of experimental studies where the
gofchemicals.htm). need for complete absorption of a tested compound is
considered essential, parenteral routes of administration
(intraperitoneal, intramuscular, intravenous, and subcuta-
Routes of Test Compound Administration
neous) are selected. However, the solubility and bioavail-
Toxicity testing in animal models is most useful if it imi- ability of the tested agent can also influence the degree of
tates the human or domestic/farm animal route of expo- absorption and how much of it is directly available in a
sure to chemical agents. Based on the medium of laboratory animal.
exposure in human and domestic animals, it is possible to Toxicokinetic and pharmacokinetic information on
decide which is the administration route of choice in ani- tested compounds and their comparison among laboratory
mal toxicological tests (Table 9.2). Depending on the animals and humans are also important to determine
route of administration, experimental evaluation may dif- dosing parameters and improve the toxicological data
fer because of variation in the absorption, metabolism and obtained. The administered dose in toxicological studies
elimination of a compound. Oral exposure can lead to should be decided taking into account many physico-
absorption by the digestive system and metabolism by the chemical parameters of chemical agents, biological