title: Assessing interactions of binary mixtures of Penicillium mycotoxins (PMs) by using a bovine macrophage cell line (BoMacs).
abstract: Penicillium mycotoxins (PMs) are toxic contaminants commonly found as mixtures in animal feed. Therefore, it is important to investigate potential joint toxicity of PM mixtures. In the present study, we assessed the joint effect of binary combinations of the following PMs: citrinin (CIT), ochratoxin A (OTA), patulin (PAT), mycophenolic acid (MPA) and penicillic acid (PA) using independent action (IA) and concentration addition (CA) concepts. Previously published toxicity data (i.e. IC25; PM concentration that inhibited bovine macrophage (BoMacs) proliferation by 25%) were initially analyzed, and both concepts agreed that OTA+PA demonstrated synergism (p<0.05), while PAT+PA showed antagonism (p<0.05). When a follow-up dilution study was carried out using binary combinations of PMs at three different dilution levels (i.e. IC25, 0.5∗IC25, 0.25∗IC25), only the mixture of CIT+OTA at 0.5∗IC25 was determined to have synergism by both IA and CA concepts with Model Deviation Ratios (MDRs; the ratio of predicted versus observed effect concentrations) of 1.4 and 1.7, respectively. The joint effect of OTA+MPA, OTA+PA and CIT+PAT complied with the IA concept, while CIT+PA, PAT+MPA and PAT+PA were better predicted with the CA over the IA concept. The present study suggests to test both IA and CA concepts using multiple doses when assessing risk of mycotoxin mixtures if the mode of action is unknown. In addition, the study showed that the tested PMs could be predicted by IA or CA within an approximate two-fold certainty, raising the possibility for a joint risk assessment of mycotoxins in food and feed.
authors.affiliation: Department of Animal Biosciences, Ontario Agriculture College (OAC), University of Guelph, Guelph, ON N1G 2W1, Canada. Electronic address: ohs@uoguelph.ca.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Life Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Cedergreen
authors.affiliation: Alltech Inc., Nicholasville, KY, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Yiannikouris
authors.affiliation: Trouw Nutrition Pvt. Ltd. India, Karnataka State 560065, India.
authors.forename: H V L N
authors.initials: HV
authors.lastname: Swamy
authors.affiliation: Department of Animal Biosciences, Ontario Agriculture College (OAC), University of Guelph, Guelph, ON N1G 2W1, Canada. Electronic address: nkarrow@uoguelph.ca.
authors.forename: Niel A
authors.initials: NA
authors.lastname: Karrow
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002953:Citrinin / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009183:Mycotoxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009793:Ochratoxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D010407:Penicillium / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A; D002953:Citrinin
keywords: Concentration addition (CA); Independent action (IA); Interaction; Mixture toxicity; Penicillium mycotoxins