Combined Exposure to Multiple Mycotoxins: An Example of Using a Tiered Approach in a Mixture Risk Assessment

Abstract

Humans are exposed to mycotoxins on a regular basis. Exposure to a mixture of mycotoxins may, therefore, result in a combination of adverse effects, or trigger the same effects. This should be accounted for when assessing the combined risk of multiple mycotoxins. Here, we show the outcome of using different approaches in assessing the risks related to the combined exposure to mycotoxins. We performed a tiered approach using assessment groups with a common target organ (kidney, liver and haematologic system), or a common adverse effect (phenomenon) (reduced white blood cell count), to combine the exposure to mycotoxins. The combined exposure was calculated for the individuals in this assessment, using the Monte Carlo Risk Assessment (MCRA) tool. The risk related to this combined exposure was assessed using toxicological reference values, e.g., health based guidance values. We show that estimating the combined risk by adding the single compounds’ risk distributions slightly overestimates the combined risk in the 95th percentile, as compared to combining the exposures at an individual level. We also show that relative potency factors can be used to refine the mixture risk assessment, as compared to ratios of toxicological reference values with different effect sizes and assessment factors.

Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells

“…It appeared that the background (parameter a ) differed for some PFASs between different experiments, based on which it was decided to not use summary data for the further dose–response analysis to determine RPFs, but to run the PROAST analyses (in version 70.7tmp) with the following covariates: substance (parameter b and var) and substance experiment (parameter a ). Data of all PFASs were analyzed simultaneously to ensure the parallel curves required to derive RPFs (Bosgra et al 2009 ; Bil et al 2021 , 2022a , b ; van der Ven et al 2022 ; van den Brand et al 2022 ). Tab-delimited text files containing data on concentration, effect, and experiment number were made and analyzed as continuous data.…”

“…with parameters a , b , c , and d describing the response at dose 0 (background value), the potency of the PFAS, maximum fold change in response compared with background response (upper or lower plateau), and steepness of the curve (on a log-dose scale), respectively, was fitted with and without fixing parameter c to a large value to determine if a maximum fold change could be established. The model (with or without fixed parameter c ) with the lowest Akaike information criterion (AIC) was chosen to determine the RPFs and the corresponding 90% confidence intervals (Bil et al 2022a , b ; van den Brand et al 2022 ). PFOA was used as the index chemical.…”

Challenges and Future State for Mycotoxin Analysis: A Review From a Regulatory Perspective

“…Some options or approaches that might be possible include the use of a single TRV that is based on the combined effects specific to the mixture or implementation of a hazard index (HI) approach for noncarcinogenic mycotoxins. Thus far, limited toxicology data on the combined effects of mycotoxins and lack of mycotoxin effect biomarkers , has precluded the development of a combined-effects TRV, especially across chemically unsimilar groups. In addition, more data are needed to utilize a refined HI approach for use in human health assessments of mycotoxins.…”

Paired metagenomic and chemical evaluation of an aflatoxin contaminated dog kibble

“…Molecular tools have facilitated a paradigm shift in our understanding of the ecology of pathogenicity associated with human and animal foods[9]. A similar trend in mycotoxin risk assessment has evolved to consider simultaneous co-exposure to diverse mycotoxins[10]. Mycotoxins are secondary metabolites produced by fungi.…”