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

Abstract

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.