Hazard characterisation for significant mycotoxins in food.

This review updates the current status of activities related to hazard characterisation for mycotoxins, with special reference to regulatory work accomplished within the European Union. Because the relevant information on these topics is widely scattered in the scientific literature, this review intends to provide a condensed overview on the most pertinent aspects. Human health risk assessment is a procedure to estimate the nature and potential for harmful effects of mycotoxins on human health due to exposure to them via contaminated food. This assessment involves hazard identification, hazard characterisation, exposure assessment, and risk characterisation. Mycotoxins covered in this review are aflatoxins, ochratoxin A, cyclopiazonic acid, citrinin, trichothecenes (deoxynivalenol, nivalenol, T-2, and HT-2 toxins), fumonisins, zearalenone, patulin, and ergot alkaloids. For mycotoxins with clear genotoxic/carcinogenic properties, the focus is on the margin of exposure approach. One of its goals is to document predictive characterisation of the human hazard, based on studies in animals using conditions of low exposure. For the other, non-genotoxic toxins, individual 'no adverse effect levels' have been established, but structural analogues or modified forms may still complicate assessment. During the process of hazard characterisation, each identified effect is assessed for human relevance. The estimation of a 'safe dose' is the hazard characterisation endpoint. The final aim of all of these activities is to establish a system, which is able to minimise and control the risk for the consumer from mycotoxins in food. Ongoing research on mycotoxins constantly comes up with new findings, which may have to be implemented into this system.

kc-hits: a tool to aid in the evaluation and classification of chemical carcinogens.

MOTIVATION: The evaluation of chemicals for their carcinogenic hazard requires the analysis of a wide range of data and the characterization of these results relative to the key characteristics of carcinogens. The workflow used historically requires many manual steps that are labor-intensive and can introduce errors, bias and inconsistencies. RESULTS: The automation of parts of the evaluation workflow using the kc-hits software has led to significant improvements in process efficiency, as well as more consistent and comprehensive results. AVAILABILITY AND IMPLEMENTATION: https://gitlab.com/i1650/kc-hits.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The IARC Monographs: Updated Procedures for Modern and Transparent Evidence Synthesis in Cancer Hazard Identification.

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals, and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.

Concordance between sites of tumor development in humans and in experimental animals for 111 agents that are carcinogenic to humans.

Since the inception of the IARC Monographs Programme in the early 1970s, this Programme has developed 119 Monograph Volumes on more than 1000 agents for which there exists some evidence of cancer risk to humans. Of these, 120 agents were found to meet the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs, compiled in 2008-2009 and published in 2012, provided a review and update of the 107 Group 1 agents identified as of 2009. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. The Group I agents reviewed in Volume 100, as well as five additional Group 1 agents defined in subsequent Volumes of the Monographs, were used to assess the degree of concordance between sites where tumors originate in humans and experimental animals including mice, rats, hamsters, dogs, and non-human primates using an anatomically based tumor nomenclature system, representing 39 tumor sites and 14 organ and tissue systems. This evaluation identified 91 Group 1 agents with sufficient evidence (82 agents) or limited evidence (9 agents) of carcinogenicity in animals. The most common tumors observed in both humans and animals were those of the respiratory system including larynx, lung, and lower respiratory tract. In humans, respiratory system tumors were noted for 31 of the 111 distinct Group 1 carcinogens identified up to and including Volume 109 of the IARC Monographs, comprising predominantly 14 chemical agents and related occupations in category VI; seven arsenic, metals, fibers, and dusts in category III, and five personal habits and indoor combustions in category V. Subsequent to respiratory system tumors, those in lymphoid and hematopoietic tissues (26 agents), the urothelium (18 agents), and the upper aerodigestive tract (16 agents) were most often seen in humans, while tumors in digestive organs (19 agents), skin (18 agents), and connective tissues (17 agents) were frequently seen in animals. Exposures to radiation, particularly X- and γ-radiation, and tobacco smoke were associated with tumors at multiple sites in humans. Although the IARC Monographs did not emphasize tumor site concordance between animals and humans, substantial concordance was detected for several organ and tissue systems, even under the stringent criteria for sufficient evidence of carcinogenicity used by IARC. Of the 60 agents for which at least one tumor site was identified in both humans and animals, 52 (87%) exhibited tumors in at least one of the same organ and tissue systems in humans and animals. It should be noted that some caution is needed in interpreting concordance at sites where sample size is particularly small. Although perfect (100%) concordance was noted for agents that induce tumors of the mesothelium, only two Group 1 agents that met the criteria for inclusion in the concordance analysis caused tumors at this site. Although the present analysis demonstrates good concordance between animals and humans for many, but not all, tumor sites, limitations of available data may result in underestimation of concordance.

Development of a database on tumors and tumor sites in humans and in experimental animals for 'Group 1 agents identified through volume 109 of the IARC Monographs.

Volume 100 in the series of IARC Monographs on the Evaluation of Carcinogenic Risks to Humans comprises an update and review of relevant information on all agents determined to induce cancer in humans. These Group 1 agents are categorized in 6 Monographs (Volumes 100A-F) published in 2012. This paper describes the methodology and stringent criteria used in the creation of a comprehensive database on tumors noted in animals and humans for the carcinogens reviewed in Volume 100, and for additional Group 1 agents that were identified in subsequent Monographs through Volume 109. The development of this database involved the systematic collection of relevant data on tumors detected in humans and experimental animals identified by the Working Groups that conducted evaluations reported in the IARC Monographs. The database includes all human tumor sites identified by the Working Groups, along with all tumor sites for which there was sufficient evidence in experimental animals. This database provides a basis for assessing the degree of concordance between tumor sites observed in humans and experimental animals for Group 1 agents identified through Volume 109.

Key characteristics of 86 agents known to cause cancer in humans.

Since the inception of the International Agency for Research on Cancer (IARC) in the early 1970s, the IARC Monographs Programme has evaluated more than 1000 agents with respect to carcinogenic hazard; of these, up to and including Volume 119 of the IARC Monographs, 120 agents met the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs provided a review and update of Group 1 carcinogens. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers, and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. Data on biological mechanisms of action (MOA) were extracted from the Monographs to assemble a database on the basis of ten key characteristics attributed to human carcinogens. After some grouping of similar agents, the characteristic profiles were examined for 86 Group 1 agents for which mechanistic information was available in the IARC Monographs up to and including Volume 106, based upon data derived from human in vivo, human in vitro, animal in vivo, and animal in vitro studies. The most prevalent key characteristic was "is genotoxic", followed by "alters cell proliferation, cell death, or nutrient supply" and "induces oxidative stress". Most agents exhibited several of the ten key characteristics, with an average of four characteristics per agent, a finding consistent with the notion that cancer development in humans involves multiple pathways. Information on the key characteristics was often available from multiple sources, with many agents demonstrating concordance between human and animal sources, particularly with respect to genotoxicity. Although a detailed comparison of the characteristics of different types of agents was not attempted here, the overall characteristic profiles for pharmaceutical agents and for chemical agents and related occupations appeared similar. Further in-depth analyses of this rich database of characteristics of human carcinogens are expected to provide additional insights into the MOA of human cancer development.

Analyses of biomarkers of exposure to nephrotoxic mycotoxins in a cohort of patients with renal tumours.

The Czech Republic occupies the first place in the world in the frequency of renal and other urinary tract tumours, but their aetiology is unknown. To explore whether carcinogenic and nephrotoxic mycotoxins may contribute to kidney diseases in the Czech population, biomarkers of ochratoxin A (OTA) and citrinin (CIT) exposure were determined in biological specimens from a cohort of 50 patients with malignant renal tumours. Biomarker analyses in blood and urine samples used validated targeted methods for measuring OTA and CIT plus dihydrocitrinone (DH-CIT) after enrichment of analytes by specific immunoaffinity clean-up. OTA and CIT plus its metabolite DH-CIT were frequently detected in patient urine samples (OTA 62%; CIT 91%; DH-CIT 100%). The concentration ranges in urine were 1-27.8 ng/L for OTA, 2-87 ng/L for CIT and 2-160 ng/L for DH-CIT. The analyses of blood samples revealed also a frequent co-occurrence of OTA and CIT, in the ranges of 40-870 ng/L serum for OTA and 21-182 ng/L plasma for CIT. This first analysis of biomarkers in blood and urine samples of Czech patients revealed no major differences in comparison with published data for the general healthy Czech and European populations. Nonetheless, a frequent co-occurrence of CIT and OTA biomarkers in patient samples may be of interest with regard to potential interactions with other risk factors for renal disease.

Investigation of patulin and citrinin in grape must and wine from grapes naturally contaminated by strains of Penicillium expansum.

Twenty three strains of Penicillium expansum, as a predominant species, were isolated from 23 (92%) out of 25 grape samples of 17 different grape varieties. The results of the identification of P. expansum strains were confirmed by a PCR method. Most of the isolates of P. expansum (21/23, 91%), when tested for toxigenicity, were bi-toxigenic: they produced citrinin (CIT) and particularly high amounts of patulin (PAT). A validated UPLC-MS/MS method for the determination of PAT and CIT was applied. The limits of quantification (LOQ) for PAT and CIT in grape must and toxigenicity testing samples were 100 and 2 ng/g, respectively. The results of PAT and CIT quantification in 23 grape must samples demonstrated the occurrence of PAT in 10 (43%) grape must samples (mean: 171 ng/g; median: 50 ng/g; and range: 143-644 ng/g) and the occurrence of CIT in two (9%) grape must samples (mean: 1 ng/g; median: 1 ng/g; and range: 2.5-3.5 ng/g). This is the first report on the natural occurrence of CIT in grape must. A validated HPLC-UV-VIS method for the determination of PAT in wine samples was applied, and concentrations in all 23 wine samples were below the LOQ (<10 ng/g).

Occurrence of ochratoxin A in Astragalus propinquus root and its transfer to decoction.

The aim of this study was to conduct a survey assessing (a) the ochratoxin A (OTA) content in different samples of Astragalus propinquus root (AR), one of the fundamental herbs in traditional Chinese medicine, and (b) the rate of OTA transfer to AR decoctions that are traditionally used to reduce general weakness and increase overall vitality. A validated method of high-performance liquid chromatography with fluorescence detection (HPLC-FLD) was used to determine OTA concentrations in AR samples and AR decoctions. The limit of quantification was 0.35 ng/g; the recovery of the HPLC method for AR samples was 82%; and the relative standard deviation (SD) of repeatability was 2.6%. All 40 tested AR samples were positive, with a mean value of 451.0 ng/g (range, 28.8-1700.0 ng/g). The transfer rate of OTA to decoctions, from a naturally contaminated and homogenized AR sample (internal reference material) with a concentration of OTA of 288.9 ng/g ± 12.3 (SD), was 83.4% ± 8.5 (SD). We believe it is necessary to continue OTA monitoring in AR and other herbal products, estimate the actual human usual intake, and perform health risk assessment.

Transfer of ochratoxin A from raw black tea to tea infusions prepared according to the Turkish tradition.

BACKGROUND: Ochratoxin A (OTA) is a natural contaminant of food including tea with multiple toxic effects, which poses a threat to human health. In terms of lifestyle, the Turkish population is a frequent visitor of tearooms, and the traditional Turkish tea preparation is one of the most popular ways of preparing tea infusion. RESULTS: The aim of this study was to investigate OTA transfer from raw black tea to the tea infusion prepared according to the Turkish tradition. A high-performance liquid chromatography method with a limit of quantification of 0.35 ng g-1 was used for OTA determination. The OTA amount in raw black teas from Turkey ranged from ≤0.35 ng g-1 up to 56.7 ng g-1 . An homogenised sample of black tea naturally contaminated with 55.0 ng g-1 was used to prepare infusions. The OTA transfer from the black tea to the infusion was found to be 41.5% ± 7%. CONCLUSION: These data are important for the realisation of a 'Total Diet study' (TDS). The TDS can be a complementary tool to estimate the population dietary exposure to OTA across the entire diet by analysing main foods prepared 'as consumed' (tea infusions) and not 'as purchased' (raw tea). © 2017 Society of Chemical Industry.

Mycotoxins as human carcinogens-the IARC Monographs classification.

Humans are constantly exposed to mycotoxins (e.g. aflatoxins, ochratoxins), mainly via food intake of plant and animal origin. The health risks stemming from mycotoxins may result from their toxicity, in particular their carcinogenicity. In order to prevent these risks, the International Agency for Research on Cancer (IARC) in Lyon (France)-through its IARC Monographs programme-has performed the carcinogenic hazard assessment of some mycotoxins in humans, on the basis of epidemiological data, studies of cancer in experimental animals and mechanistic studies. The present article summarizes the carcinogenic hazard assessments of those mycotoxins, especially aflatoxins (aflatoxin B1, B2, G1, G2 and M1), fumonisins (fumonisin B1 and B2) and ochratoxin A (OTA). New information regarding the genotoxicity of OTA (formation of OTA-DNA adducts), the role of OTA in oxidative stress and the identification of epigenetic factors involved in OTA carcinogenesis-should they indeed provide strong evidence that OTA carcinogenicity is mediated by a mechanism that also operates in humans-could lead to the reclassification of OTA.