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Abstract for IMM98004 - Sodium Bromate (CASRN 7789-38-0)

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09-3566%20NTP-ITOX-R1.pdf). The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.

The Immunotoxicity of Sodium Bromate
(CAS No. 7789-38-0)

Dose Range-Finding Study in Female B6C3F1 Mice
NTP Study Number: IMM98004
Summary

Disinfection by-products (DBPs) are contaminants found in drinking water. Bromate is one of the DBPs formed during the ozonation of source water containing bromide. The maximum contaminant level is 10 mg/L. The average concentration of bromate in finished drinking water after ozonation is 2.9 mg/L1. The potential effects of drinking water contaminants to affect adversely the immune system is a concern of both the Environmental Protection Agency (EPA) and the National Institute of Environmental Health Sciences (NIEHS). Several drinking water DBPs have been identified and selected for evaluation of their potential effects on the immune system in a joint project between the EPA and the NIEHS.

The National Toxicology Program (NTP) requested that a dose range-finding study be performed in order to establish the potential effects of sodium bromate (SBM) on the immune system and to determine the doses that could be used in a full immunotoxicology study. These studies were conducted in female B6C3F1 mice. The animals were exposed to SBM based on the concentration of the test article in the drinking water. Five SBM concentrations of 80, 200, 400, 600 and 800 mg/L for 28 days were utilized. SBM solutions were prepared fresh every two weeks in tap water and stored refrigerated. The in-life phase of these studies was carried out between September 8, 1998 and February 9, 1999.

The baseline toxicology studies are summarized in Table ES-1. SBM was administered in the drinking water from water bottles for 28 days at 80, 200, 400, 600 and 800 mg/L. There was no statistically significant difference in drinking water consumption between animals exposed to SBM and the tap water controls. Exposure to SBM did not produce any signs of overt toxicity. There was no significant difference in body weight and body weight change between the exposed and control animals during the experimental period. No gross pathological lesions were observed in SBM-exposed animals; furthermore, there were no differences observed in the weights of thymus, liver, kidneys or lung. However, animals exposed to 80, 600 and 800 mg/L of SBM had a significant increase in absolute spleen weight of 20%, 28% and 23%, respectively. The increase was also reflected in relative spleen weight with 19%, 26% and 23%, respectively. The erythrocyte count, hemoglobin, hematocrit, MCV, platelet count, total leukocyte count, and counts of leukocyte differentials were unaffected by SBM. MCH and MCHC were significantly decreased (2%) when the animals were exposed to the highest dose of SBM; however, this decrease is not considered to be biologically relevant. A dose-related increase in reticulocytes, significant at the two high dose levels, was observed following exposure to SBM with the greatest increase (78%) observed at the highest dose level.

The immunological studies are summarized in Table ES-2. As in the toxicological parameters, exposure to SBM produced few changes in various immunological parameters. There were no changes in the absolute number of total T cells, CD4+ T cells, CD8+ T cells, natural killer cells and macrophages. However, an increase was observed in total spleen cells and B cells at the dose of 600 mg/L. The increase in B cell number was not considered to be biologically relevant for several reasons. First, no dose-related response was observed; secondly, there was no significant difference when the number of B cells was expressed as the percentage of total spleen cells; thirdly, the IgM antibody response to T-dependent antigen sheep erythrocytes was not altered after exposure to SBM. The effect of SBM on the activity of spleen T cells and natural killers (NK) cells was evaluated using the one-way mixed leukocyte response (MLR) and cytotoxic assay of YAC-1 cells, respectively. There was no alteration in MLR and NK activity after exposure to SBM. When the activity of peritoneal macrophages was evaluated using the cytotoxic/cytostatic assay of B16F10 tumor cells, the suppressive effect of peritoneal macrophages on the proliferation of B16F10 tumor cells was decreased by SBM at doses of 200, 400 and 800 mg/L. In the absence of macrophage stimulation, macrophages from the vehicle control animals produced a 32% suppression of the B16F10 tumor cell proliferation, which was decreased to 20% and 22% when the animals were exposed to 200 mg/L and 800 mg/L of SBM, respectively. Macrophages, stimulated with gamma interferon and LPS, from the vehicle control animals produced a 65% suppression of the B16F10 cell proliferation, which was decreased to 46%, 46% and 47% when the animals were exposed to 200 mg/L, 400 mg/L and 800 mg/L of SBM, respectively.

In conclusion, SBM, when administered in the drinking water at doses from 80 mg/L to 800 mg/L, produced minimal toxicological and immunotoxic effects in female B6C3F1 mice, with biologically significant effects only observed in spleen weights, reticulocyte counts and macrophage activity. Based on the results of this range-finding study, further investigation of the effect of SBM on the immune system may not be warranted.

 

Table ES-1
SUMMARY TABLE FOR TOXICOLOGY STUDIES
Parameter Result Maximum Effect Dose Comment
Body Weight

Day 1

No Effect

 

 

 

Day 8

No Effect

 

 

 

Day 15

No Effect

 

 

 

Day 22

No Effect

 

 

 

Day 29

No Effect

 

 

 

Weight Changes

Day 8-1

No Effect

 

 

 

Day 15-1

No Effect

 

 

 

Day 22-1

No Effect

 

 

 

Day 29-1

No Effect

 

 

 

Pathology

 Gross Pathology

No Effect

 

 

 

 Histopathology

Not Processed

 

 

 

Organ Weights
Liver No Effect

 

 

Spleen

Increase

28%

600 mg/L

Absolute Weight

Lungs

No Effect

 

 

 

Thymus

No Effect

 

 

 

Kidney

No Effect

 

 

 
Hematology

RBCs

No Effect

 

 

 

Hemoglobin

No Effect

 

 

 

Hematocrit

No Effect

 

 

 

MCV

No Effect

 

 

 

MCH

Decrease

2%

800 mg/L

Not Biologically Relevant

MCHC

Decrease

2%

800 mg/L

Not Biologically Relevant

Platelets

No Effect

 

 

 

Reticulocytes

Increase

78%

800 mg/L

 

Leukocytes

No Effect

 

 

 

Leukocoyte Diff

 

 

 

 

Lymphocytes

No Effect

 

 

 

Neutrophils

No Effect

 

 

 

Eosinophils

No Effect

 

 

 


 
Table ES-2
SUMMARY TABLE FOR IMMUNOLOGY STUDIES
Parameter Results Maximum Effect Dose Comment
Surface Markers (Absolute Values)

Ig+

Increase

23%

600 mg/L

 

CD3+

No Effect

 

 

 

CD4+CD8-

No Effect

 

 

 

CD4-CD8+

No Effect

 

 

 

CD4+CD8+

No Effect

 

 

 

NK1.1+CD3-

No Effect

 

 

 

MAC-3+

No Effect

 

 

 

IgM Humoral Immune Response to Sheep Erythrocytes

IgM AFC/106 Cells

No Effect

 

 

 

Serum Titer

No Effect

 

 

 

Proliferation Assays, i.e. Mixed Leukocyte Response

MLR Index

No Effect

 

 

 

Macrophage Activating Factor

Changes of % Suppression without stimulation

Decrease

36%

200 mg/L

 

Changes of % Suppression with stimulation

Decrease

30%

200 mg/L

 

NK Cell Activity

LU/107

No Effect

 

 

 

LU/spleen

No Effect

 

 

 

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