Novel Insights into Pyrrolizidine Alkaloid Toxicity and Implications for Risk Assessment: Occurrence, Genotoxicity, Toxicokinetics, Risk Assessment–A Workshop Report

Abstract

This paper reports on the major contributions and results of the 2nd International Workshop of Pyrrolizidine Alkaloids held in September 2020 in Kaiserslautern, Germany. Pyrrolizidine alkaloids are among the most relevant plant toxins contaminating food, feed, and medicinal products of plant origin. Hundreds of PA congeners with widespread occurrence are known, and thousands of plants are assumed to contain PAs. Due to certain PAsʼ pronounced liver toxicity and carcinogenicity, their occurrence in food, feed, and phytomedicines has raised serious human health concerns. This is particularly true for herbal teas, certain food supplements, honey, and certain phytomedicinal drugs. Due to the limited availability of animal data, broader use of in vitro data appears warranted to improve the risk assessment of a large number of relevant, 1,2-unsaturated PAs. This is true, for example, for the derivation of both toxicokinetic and toxicodynamic data. These efforts aim to understand better the modes of action, uptake, metabolism, elimination, toxicity, and genotoxicity of PAs to enable a detailed dose-response analysis and ultimately quantify differing toxic potencies between relevant PAs. Accordingly, risk-limiting measures comprising production, marketing, and regulation of food, feed, and medicinal products are discussed.

Cytotoxicity and Genotoxicity of Senecio vulgaris L. Extracts: An In Vitro Assessment in HepG2 Liver Cells

“…Results showed a slight loss in cell viability at the highest concentration tested, and a marked dose-dependent genotoxicity exerted by non-cytotoxic concentrations. Results are in line with the scientific literature, as evidence showed a low/null cytotoxic effect of retrorsine, riddelliine, senecionine, and seneciphylline in this cell line [ 48 ], and remarkable genotoxic effects of several PAs in liver cell lines, primary hepatocytes and other liver models [ 49 ].…”

The in vitro genotoxicity potency of mixtures of pyrrolizidine alkaloids can be explained by dose addition of the individual mixture components

“…That said, the BMD approach has also been demonstrated as a valuable tool for potency ranking, when the uncertainty of the measurements is also taken into consideration (Wheeldon et al, 2021). In the context of the experimental work presented here for a class of compounds whose genotoxicity potency varies over several orders of magnitude (Schrenk et al, 2022), the concept of using equipotent concentrations will minimize the bias that highly potent components of a mixture would introduce if equi-molar amounts were tested. We thus consider this approach well-suited for the purpose of understanding dose addition in respect of the genotoxicity endpoint.…”

“…We and others have previously demonstrated that the genotoxicity potency of individual pyrrolizidine alkaloids (PAs) varies widely due to structural differences (reviewed in Schrenk et al, 2022). Establishing and confirming absolute potency differences is of importance to ensure the risk of PA exposure is not overestimated as is the case of the current regulatory approach, which assumes that all PAs are as potent as their most potent representatives.…”

Formation of DHP-DNA Adducts from Rat Liver Microsomal Metabolism of 1,2-Unsaturated Pyrrolizidine Alkaloid-Containing Plant Extracts and Dietary Supplements

“…This was the first instance outlining a set of exogenous (not endogenous) DNA adducts being formed from a large class of chemical carcinogens. To date, this metabolic activation pathway, mediated by the formation of DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts, has been implicated in the metabolism of more than 25 individual PAs and PA N-oxides. − Here, we propose that these DHP-DNA adducts (DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4) are potential biomarkers of PA and PA N-oxide exposure and liver tumor initiation. ,, …”