Superfund Research Program

Neurotoxic and Mutagenic Actions of Superfund Chemicals

Project Leader: Glen E. Kisby
Grant Number: P42ES010338
Funding Period: 2000-2006

Project-Specific Links

Final Progress Reports

Year:   2005 

Research Problem: Organochlorine solvents are common contaminants of groundwater and pose a particularly important long-term health hazard to humans. Of the many organochlorine solvents, vinyl chloride poses a greater threat to humans because it is highly prevalent, a common breakdown product of other solvents (e.g., trichloroethylene, pentachloroethylene), and is tentatively associated with long-term neurological dysfunction and brain cancer. The major metabolite of vinyl chloride is chloroacetaldehyde (CAA), which is also found as a chlorination by-product in drinking water and a toxic metabolite of some anti-cancer drugs. CAA is known to have neurotoxic, mutagenic, and oncogenic properties. Dr. Kisby and his research team propose that CAA induces these effects by a mechanism similar to vinyl chloride.

Accomplishments: Project researchers have previously shown that CAA is toxic to both neurons and non-neural cells at concentrations that would be expected to occur in humans after exposure to organochlorines at Superfund hazardous waste sites. The researchers have demonstrated that DNA repair, especially base excision repair (BER) and nucleotide excision repair (NER), plays an important role in protecting both neurons and non-neural cells from the acute and delayed toxic effects of CAA.  The increased sensitivity of neurons deficient in both BER and NER (double null mutants) to CAA, and the ability of CAA to directly perturb BER and NER proteins levels, is recent evidence that is consistent with this hypothesis.  They have also tested their hypotheses using two different neural (i.e., neurons, astrocytes) and non-neural (fibroblasts, epithelial cells) cell types, which allowed them to understand the relative sensitivity of different tissues to CAA. They found that neurons and epithelial cells exhibit a similar sensitivity to CAA-induced toxicity while other cell types are either insensitive (i.e., astrocytes) or their response is highly variable (i.e., fibroblasts).  The researchers’ findings strongly suggest that DNA lesions play a significant role in CAA-induced toxicity. They expect to confirm this hypothesis as DNA damage studies are completed.

Like organochlorine solvents, metals such as cadmium are among the most prevalent contaminants at Superfund sites, and low, non-cytotoxic concentrations of these contaminants could perturb cellular DNA repair mechanisms. The investigators hypothesized that non-toxic concentrations of metals could render neuronal or non-neuronal cells vulnerable to CAA.  Consistent with this hypothesis, they found that non-cytotoxic concentrations of cadmium influence BER and NER to adversely affect DNA repair in metal-exposed neurons.  Their findings demonstrate that low concentrations of cadmium perturb BER and NER such that neurons exposed to both metals and organochlorine solvents would be more vulnerable to injury than when exposed to each compound separately. 

Significance: Organochlorine solvents (e.g., TCE, DCE, PCE, and VC) and heavy metals (e.g., Cd) are among the top 50 substances on the 1997 ATSDR Superfund priority list, and the U.S. EPA has identified these chemicals as major contaminants in municipal water supplies and soils. While many studies have suggested an association between exposure to organochlorine solvents and neurological dysfunction in humans, very few have studied the mechanisms by which these agents induce nervous tissue injury. The investigators’ studies demonstrate that organochlorine solvents with genotoxic properties (e.g., vinyl chloride) kill neuronal cells directly by damaging DNA and/or indirectly by perturbing DNA repair. While most studies have focused on the toxicological properties of a specific metal or organochlorine solvent, no study has assessed these effects after exposure to both contaminants.  The ability of metals to perturb neuronal DNA repair suggests that exposure to both Superfund contaminants would induce more injury to the brain than if exposed separately to each contaminant.  A better understanding of these underlying molecular events may provide important information about the mechanisms responsible for protecting the brain from the toxic and oncogenic properties of organochlorine solvents and metals and may allow investigators to identify biomarkers of solvent/metal exposure.