Ch. 7— The Use of Animals in Testing • 153 
Pharmacokinetics 
Pharmacokinetic studies provide information 
about the mechanisms of absorption, about a sub- 
stance’s distribution among the various body com- 
partments, and about metabolism and elimination. 
They facilitate the interpretation of results from 
other tests and their extrapolation to humans be- 
cause the distribution and elimination of a foreign 
substance will often explain its toxicity or lack 
thereof. 
Absorption of a substance into the body can oc- 
cur by a variety of routes . If exposure is by inhala- 
tion, absorption can occur in the lungs, in the path- 
ways leading to the lungs, and sometimes in the 
gastrointestinal tract. If exposure is by mouth, ab- 
sorption would occur as the substance passes 
through the gastrointestinal tract. What is not ab- 
sorbed is excreted in the feces. With dermal ex- 
posure, the substance must be absorbed through 
the skin. If exposure is via injection into a body 
cavity, the substance cannot be removed without 
the involvement of other parts of the body. 
Once a substance is absorbed, it may be excreted 
unchanged. Excretion could be through the skin, 
in the urine, feces, semen, or breast milk, or, if 
it is volatile, in exhaled air. It might also be stored 
in tissues, organs, or body fluids, perhaps for the 
life of the organism. A substance might also be 
chemically modified until it can be excreted or until 
the body is unable to metabolize it any further. 
This metabolism normally takes place in the liver, 
the site where detoxification of substances takes 
place. A test substance or its metabolic products 
can react with the chemicals that make up the 
body, perhaps resulting in toxic effects. 
Pharmacokinetic studies are usually conducted 
through the sampling of body fluids, both those 
that are excreted (urine, saliva) and those that are 
not (blood, cerebrospinal fluid). Tissue samples are 
often taken, although normally not until the end 
of a study (4). 
Acute Toxicity Tests 
Acute toxicity testing is used to detect the toxic 
effects of single or multiple exposures occurring 
within 24 hours. These are frequently the first tests 
performed in determining the toxic characteris- 
tics of a substance and may serve as a basis for 
classification or labeling or for concerns about acci- 
dental exposure. The results are used to establish 
toxicity relative to other substances, to determine 
specific toxic effects, and to provide information 
on the mode of toxic action and the relationship 
between dose and adverse effects. Results may also 
help in designing long-term tests. 
Acute toxicity testing has its limitations, particu- 
larly because the end point is death. Death can 
come about in many ways and the mechanism is 
not conveyed in the numerical value of an LD S0 . 
In addition, the results may vary greatly both 
among and within species, with the animals’ sex, 
age, and diet, and with other test conditions. Acute 
toxicity testing, although not necessarily the clas- 
sic LD 50 procedures, will continue to be of inter- 
est because there are many substances for which 
the toxic effects of acute exposure are quite differ- 
ent from those produced bv chronic exposure (8). 
It may also continue to be used in selecting doses 
for long-term studies. Nonetheless, circumstances 
may be identified in which acute toxicity testing 
is not needed because other tests more relevant 
to the use should be performed. The Toxicity Com- 
mittee of the Fund for the Replacement of Ani- 
One of the most common acute toxicity tests is 
the LD 50 (from Lethal Dose for 50 percent), devel- 
oped in 192 7 for comparing batches of dangerous 
drugs (52). The LD 50 is calculated to be the dose, 
within statistically established confidence inter- 
vals, at which half the test animals can be expected 
to die upon exposure to a test substance. A sub- 
stance is administered once by the oral, dermal, 
or parenteral (injection into a vein or the body 
cavity) route or it is inhaled. The animals, usually 
rodents, are observed for 14 days and then sacri- 
ficed so that their organs and tissues can be evalu- 
ated for gross changes. Other measurements and 
observations can be added to increase the amount 
of information this test provides. 
A related procedure is the limit test . A high dose 
is given, often 5 g/kg body weight (54); if no ani- 
mals die, the test ends. This is based on the as- 
sumption that if an organism is not killed by an 
extremely large dose, it does not matter what dose 
it takes to actually cause death. Other tests using 
fewer animals have been devised and are receiv- 
ing growing acceptance (see ch. 8). 
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