PRINCIPLES OF TOXICOLOGY

Dominant Lethal Assays
Dominant lethal assays can be performed in any organism where early embryonic death can be
monitored. As described earlier, mammals are commonly used in dominant lethal assays, although it
is possible to do so with insects as well. The male animals (typically mice or rats) are treated with the
suspected mutagen before being mated with one or more females. Each week these females are removed
and a new group of females is introduced to the treated male. This process is repeated for a period of
6–10 weeks. The females are sacrificed before parturition, and early fetal deaths are counted in the
uterine horns. This test has become standardized, and a large number of compounds have been screened
in mouse studies. As with most in vivo mammalian assays, costs and commitment of resources can be
extensive. However, the applicability of the data is typically quite good. The dominant lethal test in
rodents is of significance for human modeling because it gives an indication of heritable chromosomal
damage in a mammal. Even though the endpoint of early fetal death may seem of minor significance
when considering only its effects on the human gene pool, it does provide a signal that viable heritable
chromosomal damage and gene mutations may also be produced.
Heritable Translocation Assay
Results of dominant-lethal assays frequently correlate well with another test used for determining
clastogenic effects in mammalian germ cells: the heritable translocation assay (HTA). Translocation
represents complete transfer of material between two chromosomes. In HTA procedures, male mice
are mated to untreated females after treatment with the test compound, and the pregnant females are
allowed to deliver. Male offspring are subsequently mated to groups of females. If translocations are
produced through genotoxic action, then the affected first-generation male progeny will be partially
or completely sterile; this can be noticed in the litter size produced from those females to which they
were mated.
Micronucleus Tests
Application of the micronucleus test to mammalian germ cells recently has been reported. This test
procedure is analogous to the bone marrow micronucleus test (somatic cells), but it involves the
sampling of early spermatids from the seminiferous tubules of male rats. The number of micronuclei
are quantified by using fluorescent stain and counting micronucleated spermatids. To date, the
technique has not been widely used in occupational evaluations.
Spermhead Morphology Assay
12.4 MAMMALIAN MUTAGENICITY TESTS 255
Some relatively new tests have been developed that evaluate the ability of a test chemical to induce
abnormal sperm morphology when compared to controls. It has been proposed that an increase in
abnormal sperm morphology is evidence of genotoxicity because there seems to be an association
between abnormal sperm morphology and chromosome aberrations. However, recent investigations
have reported that induction of morphologically aberrant sperm can be caused by nongenotoxic actions,
such as dietary restriction. In addition, some known mutagens, including 1,2-dibromo-3-chloropropane
(a pesticide with mutagenic, carcinogenic, and gonadotoxic properties), were reportedly
unable to induce production of spermhead abnormalities in mice, when tested. It should be noted that
sperm abnormalities are fairly common in humans and may occur at rates of 40–45 percent. Thus,
more verification is needed before strong conclusions can be drawn about the mammalian spermhead
morphology assay.