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Comparative Chronic/Transgenic Dioxin Studies

TCDD (2,3,7,8- tetrachlorodibenzop- dioxin) is a multi-species carcinogen. Polychlorinated biphenyl (PCB) compounds have been found to bio accumulate and produce dioxinlike effects. These compounds occur in the environment as complex mixtures. A toxic equivalency factor (TEF) methodology has been used to predict toxicity relative to TCDD. While some comparative studies have examined the acute effects of exposure to dioxin-like compounds, none have investigated the toxic effects associated with chronic low-level exposure.

Battelle is presently conducting a series of seven chronic gavage studies in rats for the National Institute of Environmental Health Sciences (NIEHS) for TCDD and dioxin-like PCBs. Four distinct compounds have been tested. These compounds currently reflect approximately 80% of the total dioxin-like equivalent activity in the environment. A di-ortho substituted PCB is also being tested, since this is the most common type of PCB found in environmental and human samples. To test the additivity of the TEF concept for carcinogenicity, two mixture studies have also been included in the experimental design to assess additive effects.

Finally, special studies are performed at interim evaluations during the chronic studies in order to assess the progression of toxicity associated with repeated exposure. These studies include thyroid hormone determinations, cytochrome P450 determinations in liver and lung tissue, hepatic cell proliferation determinations, an assessment of gross and microscopic changes, and tissue residue analyses. An additional group of animals has also been included where dosing is discontinued to determine if toxic effects are reversible in nature.

Studies to examine the mechanism of PCB toxicity are in progress in transgenic mice. TCDD by dermal administration has been shown to induce skin tumors in certain transgenic mice. A comparative study is also being performed in transgenic mice to determine the mechanism of toxicity. Battelle has developed, validated, and employed methods to analyze select chemicals in the plasma, fat, liver, and lung of PCB-exposed animals and animals from other toxicokinetic studies. Toxicokinetic, transgenic, and chronic toxicology studies are currently in progress and are supported by their respective NIEHS contracts. The Principal Investigator for these studies is Dr. Milton Hejtmancik.

For more information concerning Toxicology studies, please contact Dr. Hejtmancik at (614) 424-4465, hejtman@battelle.org. For further information concerning Toxicokinetic studies, please contact Steve Graves at (614) 424-5636, gravess@battelle.org.