PRINCIPLES OF TOXICOLOGY

260 MUTAGENESIS AND GENETIC TOXICOLOGY
• Extrapolation of test results in order to make a quantitative evaluation of the hazard of
exposures for humans
• Prioritization of human hazards caused by specific compounds
• Institution of remedial procedures that should be undertaken to minimize the human hazard
One of the most difficult areas of analysis is the correct application of mutagenicity tests to arrive
at a quantifiable human hazard from exposure to a given substance. There is frequently good
correlation between the mutagenicity and carcinogenicity of a substance in animal tests (Table
12.4). However, this may be misleading because models for carcinogenicity determination are
often characterized by chronic procedures utilizing very high doses in nonprimate species. These
may bear little resemblance to aspects of exposure in the human model, such as magnitude and
route of exposure, metabolic patterns, and environment (which are qualitative factors), and
exposure dose (which is quantitative).
As noted previously, the time and expense that are involved with lifetime carcinogenicity assays
have strongly influenced the use of test batteries as predictive measures of carcinogenic potential.
Among many others, Ashby and Tennant (1994), Anderson et al. (1994), Benigni and Giuliani (1987),
and Blake et al. (1990), have addressed the question of applicability of multiple test systems to the
classification of a substance as genotoxic or not, and carcinogenic or not. It is important in these efforts
to distinguish among “sensitivity” (ability to identify a known carcinogen), “specificity” (ability to
identify a noncarcinogen), and “accuracy” (correct results of either type). Parodi et al. (1990) reported
on qualitative correlations associated with studies of up to 300 substances conducted during the period
1976 through 1988. Initial measures of sensitivity, specificity, and accuracy were approximately 90
percent, if the decision is based solely on Salmonella assays. As more substances have been tested,
this estimate has ranged from 45 to 91 percent. Best results typically are reported for sensitivity, where
accuracy generally is on the order of 65 to 75 percent. Consideration of the quantitative correlation
between short-term genotoxicity tests and carcinogenic potency has yielded extremely variable
estimates, ranging from approximately 30 to over 90 percent. The overwhelming conclusion was that
a battery of test systems that addresses differing endpoints is required if the goal is to develop a
confident conclusion regarding predictivity.
As is the case with many areas of toxicology, one may choose between in vivo and in vitro test
systems, each with their attendant advantages and disadvantages. The testing of chemicals in experimental
animals has all the advantages of any intact in vivo system; that is, it has all of the biochemical
and physiological requirements to make anthropomorphization more reliable. However, in vivo
mutagenicity testing may require an investment of many thousands of dollars and a long period of
time. These disadvantages often force the tester to use a less expensive, well-established short-term
TABLE 12.4 Comparative Mutagenicity of Various Compounds
Compound
Established
human
carcinogen Bacteria Yeast Drosophila
Mammalian
cells
Epichlorohydrin N N O Y Y Y
Ethyleneimine N O Y Y Y Y
Trimethyl phosphate O Y O Y Y Y
Tris N Y O Y Y Y
Ethylene dibromide N Y Y Y Y N
Vinyl chloride Y Y Y Y Y Y
Chloroprene Y Y O O O Y
Urethane N Y Y Y Y O
N = no; Y = yes; O = not tested.
Human
cells