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2.4 Genotoxicity
Atrazine was tested for possible mutagenic potential in nearly 100 tests conducted either by the
sponsor or independently in external laboratories. These studies covered different end-points in both
eukaryotes and prokaryotes in vivo and/or in vitro. A summary of selected studies conducted in vitro
is presented in Table 10, and selected studies conducted in vivo in Table 11.
Brusick (1994) had reviewed a large number of reports and publications (non-plant studies)
from the years 1977 to 1992 on the genetic toxicity of atrazine, the results of which were positive in
six cases, using two approaches. One was the “expert judgement” in which conflicting results were
resolved by thoroughly reviewing each study and critically assessing the detailed data. The second
approach used a computer-assisted “weight-of-the-evidence” method. The conclusions reached about
the genotoxicity of atrazine were “equivocal” using the first method and “negative” using the second.
The weight-of-the-evidence (computer) model, which was originally developed by the International
Commission for Protection against Environmental Mutagens and Carcinogens (ICPEMC), was considered
by Brusick to be more relevant for assessing atrazine using such a large database. The author
concluded also that the positive responses reported for atrazine in plant systems cannot be assumed to
be relevant to effects in mammals, especially when differences in metabolite profiles between plants
and mammals are known to exist.
In a later review of the genetic toxicity of atrazine by Brusick (2000), data from 21 additional
publications from the years 1993 to 2000 were evaluated and summarized. These studies included
both standard and non-standard assays. Of the 17 studies using conventional assays for genetic toxicology,
12 were reported as giving negative results while five gave positive results. On the basis of a
critical assessment of these four in-vitro assays and one in-vivo assay reported in four papers (Guigas
et al., 1993; Della Croce et al., 1996; Gebel et al., 1997; Lioi et al., 1998), it was evident that all
had serious deficiencies and the positive responses were attributed to inappropriate study design or
technique. Taking these limitations into consideration, the weight of evidence indicates that atrazine
is not genotoxic.
Additional studies using novel, but not-yet-validated techniques including single-cell gel electrophoresis
(Comet assay), flow cytometry, and differential gene expression, have reported positive
findings. These techniques must be carefully evaluated, validated and confirmed by independent
investigators before they can be used in decision-making regarding the genotoxic potential of any
chemical including atrazine (Brusick, 2000).
2.5 Reproductive toxicity
(a)
Multigeneration studies
In a two-generation study of reproductive toxicity , which complied with GLP and US EPA test
guidelines, groups of 30 male and 30 female Sprague-Dawley rats were fed diets containing atrazine
technical (purity, 97.6%) at a concentration of 0, 10, 50 and 500 ppm, for 10 weeks before mating
and further during mating, gestation and rearing of offspring. Thirty male and 30 female F 1
pups from
each group were selected and after 12 weeks exposure to the treated diets were mated to derive the
F 2
generation. F 2
pups were killed 21 days after birth. Histology of reproductive organs and tissues
was conducted from 30 rats of each sex from the control groups and groups at the highest dose of the
F 0
and F 1
, and five of each sex of the control group and group at the highest dose for the F 2
generations.
The mean daily intakes at 0, 10, 50 and 500 ppm in the period before mating were 0, 0.7, 3.6
and 36.1 mg/kg bw per day for F 0
males and 0, 0.8, 4.0 and 40.7 mg/kg bw per day for F 0
females,
ATRAZINE 37–138 JMPR 2007