Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

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The immune system of adult mice appears to be relatively insensitive to atrazine. For example,
exposure of female B6C3F 1
mice to 250 or 500 mg atrazine/kg bw per day for 14 days did not affect
antibody synthesis, natural killer (NK) cell activity or lymphocyte proliferation, but did decrease
body and lymphoid organ weights and shifted percentages of lymphocyte subpopulations (National
Toxicology Program, 1994). The number of spleen cells producing antibody was increased by 35%
in groups of mice exposed to atrazine at the lowest dose (25 mg/kg bw per day), but was similar to
control values at higher doses. The authors dismissed this result as biologically irrelevant, because
the antibody titre was not significantly decreased at this dose.
However, a recent peer-reviewed version of the original 1994 NTP report by Munson et al.
(Karrow et al., 2005) concluded that the data at the lowest dose may represent an actual increase
in numbers of antibody-producing cells in the spleen. Whether or not this type of enhancement is
beneficial or detrimental to the individual has yet to be determined. With atrazine at the highest
dose tested (500 mg/kg bw per day), resistance to an natural killer cell-dependent tumour-cell challenge
was decreased, but resistance to bacterial challenge (Listeria monocytogenes) was not affected.
However, animals at the highest dose experienced a 3% loss of body weight during dosing, vs a 10%
body-weight gain in controls, indicating marked overt toxicity at the highest dose, thus calling into
question the biological relevance of the observed immune effects at 500 mg/kg bw per day. Furthermore,
given the lack of effects on natural killer cell activity, even at the highest dose, it is difficult to
conclude that immune suppression was directly responsible for the apparent increased susceptibility
to a tumour-cell challenge.
In a separate study, the antibody response of C57Bl/6 female mice was suppressed 7 days
after a single exposure to a wide range of atrazine doses (27.3–875 mg/kg bw). However, suppression
was not dose–responsive, and no dose-related pattern of suppression or recovery was
apparent 2, 3 or 6 weeks after exposure (Fournier et al., 1992). Although the relatively short halflife
of atrazine may explain why these effects were not persistent, it does not provide a satisfactory
explanation for the lack of a dose–response relationship. Chemicals that are immunotoxic
in adult animals generally induce similar effects, but at lower doses or for a prolonged period
of time, if exposure occurs during development and maturation of the immune system (Luebke
et al., 2006).
The effects of exposure to atrazine during immune system ontogeny were therefore evaluated
in rats and mice. In replicate studies, exposure to atrazine at a dose of 35 mg/kg bw per day from day
10 of gestation until postnatal day 23 was found to suppress cellular and antibody-mediated immune
function in male, but not female rats (Rooney et al., 2003). However, preliminary data from recent
studies of dose–response did not corroborate suppressed function in developmentally exposed rats.
The basis for this discrepancy is as yet unknown (Robert W. Luebke, personal communication).
Studies of developmental exposure in mice indicated that the percentage of antibody-producing cells
in the spleens of immunized male offspring of mice implanted with time-release atrazine pellets
between days 10 and 12 of gestation was increased by approximately 33%; female offspring were
not affected (Rowe et al., 2006). Daily doses were in the same range as those used by Rooney et al.
(2003). The results for studies of developmental exposure results suggest that the immature immune
system of males may be more sensitive to the effects of atrazine than that of the adult. Nevertheless,
studies corroborating previous findings and those that incorporate a range of doses will be necessary
to adequately determine NOAELs and LOAEL for immune function, and the relative sensitivity of
the immune and endocrine systems in developing rodents.
3. Observations in humans
A large number of studies have been published on the association between exposure to triazines,
including atrazine, and cancer epidemiology. Concerning the studies reported until 1999, three
ATRAZINE 37–138 JMPR 2007