Modelling the anorectic potencies of food-borne trichothecenes by benchmark dose and incremental area under the curve methodology

Fusarium spp. fungi produce a spectrum of trichothecene mycotoxins that often simultaneously contaminate cereal grains. These have the potential to contribute jointly to adverse effects such as anorexia and emesis. For the purposes of risk assessment and regulation, it is desirable to assign toxic equivalency factors (TEFs) to each of these trichothecenes, as has been successfully done for anthropogenic toxicants such as polyhalogenated aromatic hydrocarbons. As a first step towards this end, we employed a mouse model to compare the anorectic potencies of deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV), fusarenon-X (FUS-X), T-2 and HT-2 toxin (T-2 and HT-2) following oral exposure by gavage using two approaches. In the first approach, the US Environmental Protection Agency (US EPA) benchmark dose (BMD) method for continuous data was used to calculate the BMD relative to DON 2 h after dosing. The order of potency based on BMD values was: DON(1) ≈ 3-ADON(1) ≈ 15-ADON(1) < NIV(3) < HT-2(5) < FUS-X(9) << T-2(124). In a second approach, time course effects of each toxin at fixed doses were measured by calculating the incremental area under the curve (IAUC) over 16 h. DON caused significant feed refusal within the first 30 min after exposure, lasting only 3 h while for 3-ADON and 15-ADON, feed refusal lasted 6 h. NIV, FUS-X, T-2, and HT-2 toxins caused the longest duration of feed refusal, lasting up to 16 h. Based on IAUC values, the order of relative potency was as follows: DON(1) < 3-ADON(2) ≈ 15-ADON(2) < NIV(7) < FUS-X(10) << T-2(31) < HT-2(34). These results provide a foundation for developing consensus TEFs that will be amenable to future risk assessment of trichothecene mixtures.

Predictive Modeling of a Mixture of Thyroid Hormone Disrupting Chemicals That Affect Production and Clearance of Thyroxine

Thyroid hormone (TH) disrupting compounds interfere with both thyroidal and extrathyroidal mechanisms to decrease circulating thyroxine (T4). This research tested the hypothesis that serum T4 concentrations of rodents exposed to a mixture of both TH synthesis inhibitors (pesticides) and stimulators of T4 clearance in the liver (polyhalogenated aromatic hydrocarbons, PHAHs) could be best predicted by an integrated addition model. Female Long-Evans rats, 23 days of age, were dosed with dilutions of a mixture of 18 PHAHs (2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin like PCBs) and a mixture of 3 pesticides (thiram, pronamide, and mancozeb) for four consecutive days. Serum was collected 24 hours after the last exposure and T4 concentrations were measured by radioimmunoassay. Animals exposed to the highest dose of the mixture experienced a 45% decrease in serum T4. Three additivity model predictions (dose addition, effect addition, and integrated addition) were generated based on single chemical data, and the results were compared. Effect addition overestimated the effect produced by the combination of all 21 chemicals. The results of the dose- and integrated-addition models were similar, and both provided better predictions than the effect-addition model. These results support the use of dose- and integrated additivity models in predicting the effects of complex mixtures.