title: In vitro exposure of human lymphocytes to trichothecenes: individual variation in sensitivity and effects of combined exposure on lymphocyte function.
abstract: The trichothecenes are mycotoxins produced by fungi of the genus Fusarium, which are commonly present in foods and feed of cereal origin. Owing to the lack of sufficient toxicological data for most of the trichothecenes, in vitro studies may contribute to risk assessments of these toxins. In the present report, human lymphocyte cultures were used to study the individual variation in sensitivity among humans and the effects on in vitro Ig production. Furthermore, proliferative responses of cells exposed to combinations of two of the toxins were studied. Four toxins, T-2 toxin, diacetoxyscirpenol (DAS), nivalenol (NIV) and deoxynivalenol (DON) were included in the study. All four of the tested trichothecenes effectively inhibited mitogen-induced lymphocyte proliferation. There were no statistically significant differences in sensitivity to the toxins between lymphocytes from female and male blood donors. The individual variation in sensitivity, evaluated as the range of IC50 values, was rather limited (within a factor of 3 to 4). Immunoglobulin production by pokeweed-stimulated human lymphocytes was also effectively inhibited with IC50 values similar to the IC50 values in the proliferation tests for DON and NIV. However, IC50 values for Ig synthesis in cultures exposed to T2 were approximately two to three times higher than the corresponding IC50 values found in the proliferation tests. At low levels of exposure, elevated Ig production was observed in lymphocyte cultures from four out of the five blood donors tested. This effect was most pronounced on IgA synthesis. Combinations of NIV with T2, DAS or DON resulted in additive toxicity in the lymphocyte proliferation test, while combinations of DON with T2 or DAS resulted in an inhibition that was slightly lower than what could have been expected from the inhibition produced by the individual toxins. In conclusion, the tested trichothecenes inhibited both proliferation and Ig production in human lymphocytes in a dose-dependent manner with limited variation in sensitivity between individuals. Enhanced Ig production was observed in cell cultures exposed to the lower doses of the toxins. Combined exposure to two of the toxins resulted mainly in additive or antagonistic effects, although synergistic effects cannot be excluded and should be further investigated. These findings indicate that the total intake of type A and B trichothecenes should be taken into account in risk assessments.
authors.affiliation: Division of Toxicology, National Food Administration, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Thuvander
authors.forename: C
authors.initials: C
authors.lastname: Wikman
authors.forename: I
authors.initials: I
authors.lastname: Gadhasson
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D013605:T-2 Toxin / Q000633:toxicity; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D007136:Immunoglobulins; D011500:Protein Synthesis Inhibitors; D014255:Trichothecenes; C038405:nivalenol; D013605:T-2 Toxin; C007262:deoxynivalenol; C001809:diacetoxyscirpenol