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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh081
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received October 10, 2003; accepted January 14, 2004
© 2004 Society of Toxicology

Neurotoxicology

Neurotoxicity Produced by Dibromoacetic Acid in Drinking Water of Rats

V. C. Moser 1*, P. M. Phillips 1, A. B. Levine 2, K. L. McDaniel 1, R. C. Sills 3, B. S. Jortner 4, and M. T. Butt 5

1 Neurotoxicology Division, NHEERL/ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC
2 University of North Carolina, Chapel Hill, NC
3 NTP, National Institute of Environmental Health Sciences, Research Triangle Park, NC
4 Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA
5 Pathology Associates Division of Charles River Laboratories, Frederick, MD

* To whom correspondence should be addressed. E-mail: moser.ginger{at}epa.gov.


  Abstract

An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.

Key Words: dibromoacetic acid, disinfection by-products, neurotoxicity, behavior, neuropathology, rats .


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