154 • Alternatives to Animal Use in Research, Testing, and Education 
mals in Medical Experiments recommended that 
study of the consequences of not acquiring knowl- 
edge of acute toxicity of products be undertaken 
and that in the case of products such as drugs, 
LD 50 tests should be replaced by acute toxicity tests 
that emphasize the nature of the effects observed 
(18). 
Skin and Eye Irritation/ Corrosion Tests 
Irritation is the production of reversible tissue 
damage such as swelling, while corrosion is the 
production of irreversible tissue damage. Skin and 
eye irritation tests normally involve acute expo- 
sure. Repeated exposure can be used to test for 
allergic reactions, which involve the organism's 
immune system, and cumulative effects. Skin irri- 
tation studies are used to initially characterize a 
substance’s toxicity and to develop precautionary 
information for situations in which human skin 
or eye exposure is possible. 
Although it is not yet possible to reliably predict 
the degree of irritation or corrosion a substance 
will cause, a considerable body of knowledge ex- 
ists. The factors that determine damaging effects 
to eyes or skin are: 
• intimacy and duration of contact, 
• physical properties that determine the amount 
of penetration, and 
• the reactivity of the substance with tissues (10). 
Intimacy is affected by both the ability of the sub- 
stance to spread over the surface (such as soaps 
or detergents) and its concentration. Penetration 
of the skin or other membranes is greatest in sub- 
stances with small molecular size and with abili- 
ties to mix with both water and oil. A substance 
that can react with proteins and enzymes in tis- 
sues is especially damaging if it can penetrate to 
the delicate structures of the eye (50). 
Skin irritation tests are usually conducted on rab- 
bits, guinea pigs, rats, and mice, although other 
mammals may also be used. The test substance 
is applied to a small area of skin from which the 
fur has been clipped or shaved and may be held 
in place with a dressing. Using untreated skin of 
the same animal for comparison, the degree of red- 
ness or blistering is scored at intervals (e.g., 38,54). 
There are many similarities between the skin 
cells of humans and other mammals , but there are 
important differences as well. For example, there 
are structural differences that affect permeabil- 
ity (32). Animal models have been shown to be par- 
ticularly poor in the evaluation of mild irritants 
(27). The extrapolation of animal models is further 
complicated by large differences in the race, age, 
and skin condition of humans (21,26,58). 
The method most commonly used to evaluate 
eye irritation is the Draize test, which has remained 
largely unaltered since it was introduced more than 
40 years ago (9). A single dose of a substance is 
applied to one eye of at least three adult rabbits . 
The other eye remains untreated. The degree of 
irritation or corrosion to the cornea, iris, and con- 
junctiva is scored by comparison with standard 
pictures over a period of 3 days. The rabbits may 
be observed for 3 weeks to determine whether 
the effects are reversible. 
A substance shown to be highly corrosive to skin 
will be highly irritating to the eye and thus might 
not be tested. Similarly, a substance with a pH of 
2 or less (strongly acid) or 11.5 or more (strongly 
alkaline) is assumed to be highly irritating or cor- 
rosive to skin or eye and need not be tested (38,54). 
The cornea tolerates substances with a pH rang- 
ing from 3 to 11 variably, with the severity of a 
reaction depending in large part on a substance’s 
ability to affect protein structure or function 
(17,35). 
Repeated-Dose Toxicity Tests 
Humans are often exposed repeatedly to a sub- 
stance and this does not necessarily cause the same 
effects as an acute, one-time exposure. Chronic 
toxicity effects differ from acute toxicity ones when 
the test substance or its metabolites accumulate 
in the organism to a toxic level or when it causes 
irreversible toxic effects that accumulate with each 
administration (8). Rats are most frequently used, 
and testing in a second, nonrodent species, usu- 
ally a dog, is also common. 
Repeated or prolonged exposure to the test sub- 
stance is used in chronic, subchronic, and short- 
term toxicity tests. The term chronic generally 
