Bromate Disposition and Mechanisms of Toxicity at High and Low
Doses [Project #4042]
ORDER NUMBER: 4042
DATE AVAILABLE: October 2012
PRINCIPAL INVESTIGATORS:
Joseph A. Cotruvo, Richard J. Bull, Brian S. Cummings, Don Delker, Guo Zhongxian,
Jeffrey Fisher, Oscar Quinones, Shane A. Snyder, and Choon Nam Ong
ABSTRACT:
The current risk assessments for BrO3- (bromate ion) are based upon a summation of all
tumor types in the male rat. EPA assumed a genotoxic mode of action and utilized linear
dose response in the low dose region. This project produced decomposition kinetics data
for bromate exposure in vitro and by oral gavage and intravenous (IV) injection to rats at
a range of low to high dosages. The project studied gene and protein expression in male
and female rats and in vitro studies in cell culture assays to distinguish between genotoxic
and non genotoxic modes of action. There were substantive differences in gene and
protein expression in male vs. female rats as a result of BrO3- treatment. The kinetics
studies demonstrated rapid disappearance of BrO3- from rat blood in vivo and after both
oral and IV exposures. The 28 day studies demonstrated for the first time that
organobromine compounds are generated in vivo in a dose response manner during
metabolism of bromate, and also that there is a substantial level of organobromine
compounds in the unexposed control rats. 3-Bromotyrosine modified proteins were
shown to accumulate in the rat kidney and testes.
The pharmacokinetic data produced in this study provide perspective on the relationships
between external and systemic doses of BrO3- that will be useful in the assessment of
projected BrO3- cancer risk in humans. The renal tumors in male rats that are produced at
doses <96 mg BrO3-/L are largely, if not entirely, secondary to an α-2u-globulin-induced
nephropathy, an effect not observed in humans. There was no increase in p53 tumor
suppressor gene expression with even the highest doses suggesting that oxidative damage
at high doses has little to do with the carcinogenic effects of BrO3-. Therefore, the cancer
data from male rats are not appropriate as a basis for estimating cancer risk in humans.
Thyroid and testicular tumors induced in rats treated with other chemicals have
frequently been subject to less than linear extrapolation of carcinogenic risk to low doses.
The results of this study suggest that for the kidney, at least, genotoxic mechanisms do
not appear to be important at low doses and perhaps not even at the high doses used in the
cancer bioassays. Some evidence indicates that variations of the same mechanism are
likely to result in non-genotoxic contributions to carcinogenic effects in the other target
organs. Bromide (Br-) that results from BrO3- degradation in vivo may be responsible for
the thyroid carcinogenicity. It could be estimated that an MCLG of about 20 µg/L could
be derived from a conclusion that all of the tumors induced in the rat are through nongenotoxic mechanisms. One question is whether formation of bromotyrosine-substituted
©2012 Water Research Foundation and International Ozone Association. ALL RIGHTS RESERVED.
proteins resulting from BrO3- treatment are responsible for these carcinogenic responses
in test animals as well. A Physiologically Based Pharmacokinetic (PBPK) model is being
developed that will integrate the results of this and other related studies. It is expected to
be available in 2012.
RESEARCH PARTNERS:
 International Ozone Association
 Environment Agency of Abu Dhabi
 Veolia Water
 Metropolitan Water District of Southern California
 PUB, National Water Agency of Singapore
 Los Angeles Department of Water and Power
 Calleguas Municipal Water District
 Long Beach Water Department
 Walkerton Clean Water Centre
©2012 Water Research Foundation and International Ozone Association. ALL RIGHTS RESERVED.