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Abstract for IMM94002

Immunotoxicity of Atrazine in Female B6C3F1 Mice

CASRN: 1912-24-9
Chemical Formula: C8H14ClN5
Molecular Weight: 215.6866
Report Date: May 1994

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) has been reported to be the most commonly employed herbicide in the United States. Atrazine (ATZ) is routinely used in combating weeds in corn and sorghum crops and is also widely used in combination with other herbicides. As a result of its low biodegradability, it has a high potential for contaminating surface waters. Atrazine's potential environmental hazard for polluting drinking water has led Italy to ban this herbicide. Wide-spread contamination of ground water has been reported in the Midwest of the United States. Prior to these studies, the effect of atrazine on the immune system had only been studied to a limited extent.

Atrazine was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the chemical manager. Thus, the purpose of these studies was to determine the effect of atrazine on the immune system.

The baseline toxicology studies are summarized in Table ES-1. Mice exposed to atrazine at doses of 500 mg/kg have significant decreases in body weight at the end of the first and second week of exposure. In some studies the decrease in body weight was in excess of 10% of the vehicle control group. Body weight gain when evaluated over the first week period was significantly decreased at all dose levels, and when evaluated over the two week exposure period, both the middle (45%) and high (105%) dose groups were significantly decreased. While the liver weights were unaffected by the atrazine exposure, a dose-dependent decrease was observed in spleen (33%) and thymus (52%) weights. Additionally, kidney weights were decreased (15%) in the atrazine exposure animals at the high dose. No statistically significant effects were observed on leukocyte numbers, leukocyte differentials, reticulocytes or mean corpuscular hemoglobin concentrations. A statistically significant decrease was observed in the erythroid elements: erythrocytes (14%), hemoglobin (5%) and hematocrit (5%). An increase was observed in mean corpuscular hemoglobin which was dose related. However, the significant increase in mean corpuscular volume was observed only in the low dose group, and while the other dose levels were elevated compared to the vehicle control, they did not reach the level of statistical significance (p less than 0.05).

Table ES-2 summarizes the immunology studies. Exposure to atrazine decreased the absolute number of B cells (18%) and decreased the absolute number of CD4+CD8+(40%) T cell subset. Total T cells and the other T cell subsets were not affected. Atrazine had no effect on the humoral immune response to sheep erythrocytes, evaluated either in the plaque-formingcell assay (PFC) or as serum titers. The proliferative response to mitogens, Con A and LPS, were not affected. However, a dose-dependent increase was observed in the proliferative response to allogeneic cells as evaluated in the MLR. The animals receiving the high dose of atrazine had a response which was increased 30% compared to the vehicle controls. Overall, there was no significant effect on the CTL response, natural killer cell activity or the functional activity of the reticuloendothelial system.

The results of the host resistance studies are summarized in Table ES-3. In the two host resistance models evaluated, host resistance to Listeria monocytogenes was not affected, while a decrease in host resistance to the B16F10 Melanoma tumor model was observed.

In summary, although atrazine was administered at dose levels which produced significant decreases in terminal body weights and weight gain as well as effects on various erythroid elements, most of the functional assays used to evaluate immunocompetence were not adversely affected. However, due to the dose-dependent increase in the mixed leukocyte response and the dose-dependent decrease in host resistance to the B16F10 melanoma tumor model, atrazine was found to adversely affect the immune system and, thus, is considered to be an immunotoxic compound when administered under the experimental conditions used in this protocol.

Studies


Table ES-1
Summary Table for Toxicology Studies

ATZ-14-1-PO


Parameter Result Maximum Effect Dose Comment

Body Weight
Day 8 Decreased 4% 500 mg/kg
Day 15 Decreased 6% 500 mg/kg
Weight Changes
Day 8-1 Decreased 137% 500 mg/kg
Day 15-1 Decreased 105% 500 mg/kg
Pathology
Gross Pathology No Effect
Histopathology Not Done
Organ Weights
Liver No Effect
Spleen Decreased 33% 500 mg/kg
Thymus Decreased 52% 500 mg/kg
Kidney Decreased 15% 500 mg/kg
Hematology
RBCs Decreased 14% 500 mg/kg
Hemoglobin Decreased 5% 500 mg/kg
Hematocrit Decreased 5% 500 mg/kg
MCV Increased 11% 25 mg/kg Low Dose Only
MCH Increased 13% 25 mg/kg
MCHC No Effect
Reticulocytes No Effect
Leukocytes No Effect
Leukocyte Diff
Lymphocytes No Effect
Neutrophils No Effect
Eosinophils No Effect

Table ES-2
Summary Table for Immunology Studies

ATZ-14-1-PO


Parameter Results Maximum Effect Dose Comment

Surface Markers
Ig+ Decreased 18% 500 mg/kg
CD3+ No Effect
CD4+CD8- No Effect
CD4-CD8+ No Effect
CD4+CD8+ Decreased 40% 500 mg/kg

IgM Humoral Immune Response to Sheep Erythrocytes
Spleen IgM AFC to sRBC Increased 35% 25 mg/kg Not Biologically Significant
Serum Titers to sRBC No Effect

Proliferation Assays, i.e. Mitogens, Mixed Leukocyte Response
Con A No Effect
LPS No Effect
Medium No Effect
MLR Increased 30% 500 mg/kg

Cytotoxic T Lymphocyte Activity
CTL No Effect

Functional Activity of the Reticuloendothelial System
RES No Effect

NK Cell Activity
1:100 No Effect
1:50 No Effect
1:25 Decreased 40% 250 mg/kg Not Biologically Significant


Table ES-3
Summary Table for Host Resistance

ATZ-14-1-PO


Parameter Results Maximum Effect Dose Comment

Listeria monocytogenes No Effect
B16F10 Melanoma Decreased 207% 500 mg/kg