Abstract
Metabolite profiles (metabolomics) of plasma samples of Wistar rats dosed with di(2-ethylhexyl)phthalate (DEHP – 3000 ppm) and dibutylphthalate (DBP – 150, 1000 and 7000 ppm) were individually determined in 28 days dietary studies. In addition, profiles of combined exposure to 3000 ppm DEHP and either 150, 1000 or 7000 ppm DBP were determined. High dose levels induced more profound metabolite changes in males than in females for both compounds. At 150 ppm DBP (NOEL for toxicity) there were very few (<false positives rate), inconsistent changes, demonstrating a metabolomic NOEL. A part of the total metabolite profile was consistent with a pattern of changes indicative of peroxisome proliferation, confirmed by increased cyanide-insensitive Palmitoyl-CoA oxidation. Simultaneous administration of 3000 ppm DEHP and 150 ppm DBP did not result in relevant changes when compared to the metabolite profile of 3000 ppm DEHP alone. Co-administration of 1000 ppm DBP induced marginal additional changes relative to the profile of 3000 ppm DEHP alone. Simultaneous exposure to high dose levels of DEHP and DBP resulted in a profile that was significantly different compared to the individual compounds. A quantitative statistical analysis of the data revealed that the effect of combined treatment on the metabolites was less than additive.
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