PRINCIPLES OF TOXICOLOGY

Drosophila Test Systems
The fruitfly (Drosophila melanogaster) has received wide use in the sex-linked recessive lethal test.
The endpoint phenotypic change monitored in this test is the lethality of males in the F 2 generation.
Brusick has gone to the extent of labeling Drosophila an “honorary mammalian model” by virtue of
its widespread application and correlation with positive mutagens in mammalian testing. Drosophila
melanogaster has also been utilized to monitor two types of chromosomal aberration endpoints through
phenotypic markers: loss and nondisjunction of X or Y sex chromosomes and heritable translocations.
The monitoring of translocations has the advantage of a very low background rate, facilitating
comparisons between controls and treated groups. Dominant lethal assays are also performed with
insects and can theoretically be applied in any organism where early embryonic death can be monitored.
The male is treated with the test agent, then mated with one or more females. If early fetal deaths occur,
these are demonstrative of a dominant lethal mutation in the germ cells of the treated male.
Plant Assays
A number of assay types are available in plant systems as well, including specific locus tests in corn
(Zea maize) and multilocus assays in Arabidopsis. Cytogenetic tests have been developed for Tradescantia
(micronucleus test), as have chromosomal aberration assays in the root tips of onions (Allium
sepa) and beans (Vicia faba). Finally, DNA adducts analysis is applicable to somatic and germinal
plant cell systems. It is anticipated that one or more plant species may prove to be useful indicators of
the potential for genetic damage that may be related to emissions of environmental pollutants.
12.4 MAMMALIAN MUTAGENICITY TESTS
12.4 MAMMALIAN MUTAGENICITY TESTS 253
Testing chemicals for mutagenicity in vivo in mammalian systems is the most relevant method for
learning about mutagenicity in humans. Mammals such as the rat or mouse offer insights into human
physiology, metabolism, and reproduction that cannot be duplicated in other tests. Furthermore, the
route of administration of a chemical to a test animal can be selected to parallel normal human
environmental or occupational conditions of oral, dermal, or inhalation exposures.
Human epidemiologic findings may also be compared with the results of tests done in animals.
While the monitoring of human exposures and their effects does not constitute planned, controlled
mutagenicity testing, human epidemiology offers the opportunity to monitor and test for correlations
suggested by other mutagenicity tests. Thus, these studies are the only opportunity for direct human
modeling of a chemical’s mutagenic potential. It is worth noting that despite extensive investigation,
to date no chemical substances have been positively identified as human mutagens. The advantages
and limitations of a wide variety of genetic test systems are presented in Brusick (1994).
One perceived disadvantage of in vivo mammalian test systems is the time they require and their
cost. A larger commitment of physical resources and personnel is required than is required with in
vitro testing. Human epidemiology studies are further complicated by the fact that not all of the
environmental variables can be controlled. Frequently, the duration and extent of exposure to single
or multiple compounds can only be estimated. Nevertheless, progress is being made to lessen the cost
and decrease the time required for in vivo mammalian testing. Also, new data handling, statistical
techniques, and increased cooperation from industry have increased the reliability of human epidemiology
studies. More regular sampling of workplace exposures has helped to improve the quality and
accessibility of human data.
Mutagenic potential can vary greatly across a class of analytes, as shown for the metals (Costa,
1996). Mutagenicity data for metals can be quite difficult to interpret due to the breadth of mechanisms
at work, as illustrated by differences between Cr, Ni, As, and Cd.