Toxicological Concern Research Articles

Detection of Ochratoxin A in Tissues of Wild Boars (Sus scrofa) from Southern Italy

Ochratoxin A (OTA) is a secondary metabolite produced by fungi of the genera Aspergillus and Penicillium, known to contaminate various food substrates. Its toxic effects include direct nephrotoxicity, as well as observed teratogenic, immunogenic, and carcinogenic effects. Climate change may contribute to increased humidity and temperature, favouring fungal growth and, consequently, OTA spreading. Recent increases in wild boar populations, along with their omnivorous nature and their varied diet, define them as environmental bioindicators for contaminants like mycotoxins. This study aimed to assess the concentrations of OTA in kidney, liver, and muscle tissue samples from 74 wild boars that were hunted in different areas of Avellino, Campania region, between 2021 and 2022. Tissue samples underwent extraction, purification, and analysis using high-performance liquid chromatography (HPLC) coupled with a fluorescence detector. Results revealed OTA presence in 35.1% of tested wild boars. The highest OTA concentration was observed in the kidney and liver, with less in the muscle, indicating the presence of this mycotoxin in the wild boars and their surrounding environment. Consequently, there is a need to formulate rules for edible wildlife products. These findings emphasize the significant risk of OTA contamination in wild boar tissues, suggesting their potential as reliable environmental markers for mycotoxin prevalence and as a toxicological concern for human health.

Preclinical Safety Evaluation of SloIron CFTN-PS 5: a Pea-Derived Ferritin Product.

Ferritins are proteins present in plants and animals that are highly effective in storing iron and maintaining iron homeostasis. Iron deficiency anemia is a widespread nutritional disorder, and plant ferritins (phytoferritin) are potential sources of bioavailable iron with slow-release characteristics that prevent oxidative damage. These characteristics are related to receptor mediated endocytosis, the primary absorption mechanism in humans. However, the available toxicological data are insufficient to determine whether the use of phytoferritin as a nutritional supplement to enhance iron consumption in human populations is safe. Therefore, several GLP-compliant toxicology studies have been conducted with phytoferritin prepared from the seed of Psium sativum (trade name: SloIron CFTN-PS5). SloIron CFTN-PS5 was non-mutagenic and non-clastogenic in vitro and did not induce the formation of micronuclei in vivo. SloIron CFTN-PS5 was well-tolerated in a 90-day subchronic toxicity studies conducted in Sprague-Dawley rats at doses up to 1,950 mg/kg bw/day. These findings suggest that the oral consumption of SloIron CFTN-PS5 is of low toxicological concern, with a 90-day oral subchronic No Observed Adverse Effect Level (NOAEL) of 1,950 mg/kg-day, the highest dose tested.

Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific Acceptable Intakes.

The carcinogenic potency categorisation approach (CPCA) has recently been introduced by health authorities. In this model, structural features from recent literature, industry proposals, and analyses performed by health authorities, provide a rapid assessment of the potential acceptable intake (AI) for a nitrosamine impurity. As with other screening regulatory values (such as the ICH M7 Threshold of Toxicological Concern), the CPCA is conservative and can be considered a de minimis risk management framework. In cases where a nitrosamine drug substance-related impurity (NDSRI) is present below the CPCA limit, the framework provides resolution from a toxicological perspective (i.e., no further toxicology studies are required). Where an NDSRI is above the CPCA limit, the framework provides for the initiation of additional activities (i.e., the CPCA is not the only possible limit). Read-across approaches are described in both the CPCA and M7 guidance and can provide a limit with more specific applicability than the general model. The use of available experimental data (in vitro or in vivo), is valuable in order to provide an even more specific limit. The CPCA provides a framework; however, data should permit changing the AI from initial structural assessment, based on increasing data, to ultimately increase precision of the AI.

Derivation of human toxicokinetic parameters and internal threshold of toxicological concern for tenuazonic acid through a human intervention trial and hierarchical Bayesian population modeling.

Tenuazonic acid (TeA), a mycotoxin produced by Alternaria alternata, contaminates various food commodities and is known to cause acute and chronic health effects. However, the lack of human toxicokinetic (TK) data and the reliance on external exposure estimates have stalled a comprehensive risk assessment for TeA. To bridge this gap, a human TK trial and population-based TK (PopTK) modeling were applied to determine human TK parameters of TeA, and the results were applied for risk screening using population biomonitoring data and threshold of toxicological concern (TTC)-based approaches. Ten healthy volunteers participated in the TK trial during which the volunteers ingested a bolus dose of TeA at the (external) TTC (1500 ng/kg bw). Blood, urine, and fecal samples were collected over 48 h and analyzed using UPLC-MS/MS. Concentration-time profiles were fit with a multi-compartmental PopTK model using a hierarchical Bayesian population structure. Utilizing a probabilistic framework, fitted TK parameters were used to derive internal TTC (iTTC) values for comparison to blood and urine biomonitoring data. Risk screening with data from five diverse biomonitoring cohorts was performed using Hazard Quotient (HQ) and probabilistic individual margin of exposure (IMOE) approaches. TeA was estimated to have a population median half-life of 1.9 [90% CI: 1.4-2.7] hours and volume of distribution of 4.4 [3.1-6.1] L/kg, with inter-individual variability geometric standard deviations of 2.4- and 1.7-fold, respectively. Probabilistic lower confidence bound iTTCs were derived of 0.5 nmol/L in blood and 2.53 nmol/kg-d urinary excretion. Risk screening HQs were mostly >1 for the three blood biomonitoring cohorts and < 1 for the two urinary biomonitoring cohorts; results from probabilistic IMOE calculations were qualitatively consistent. A comprehensive human TK study was performed for TeA for the first time, demonstrating the importance of integrating TK and population variability for a more comprehensive risk evaluation, particularly for interpreting biomonitoring data. The results for TeA point to the critical need for toxicity data to move beyond TTC-based risk screening. A critical gap in food safety research was addressed studying the toxicokinetics of tenuazonic acid (TeA) in humans and using these data to derive an internal threshold of toxicological concern (iTTC) for comparison to human biomonitoring data. The innovative approach-combining a human intervention trial with population-based toxicokinetic modeling-accounts for inter-individual variability and provides a more comprehensive understanding of population exposure to TeA. The resulting probabilistic iTTC and risk screening methodologies offer improved tools for interpretation of biomonitoring data. These findings have significant implications for food safety regulations and public health protection, potentially influencing future mycotoxin risk assessment strategies.

A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods.

There is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent for predicting local respiratory effects from inhalation exposure to irritants. The current study introduces a concept for applying in vitro and in silico methods for inhalation exposure safety assessment. Three in vitro systems, representing the upper (MucilAir™-nasal epithelial tissue) and lower (A549 cells and human precision-cut lung slices) human respiratory regions, were exposed to six respiratory irritants. These irritant exposures were conducted as liquid droplets, aerosol, or vapors, and samples were collected over 24 h. Cytotoxicity, cytokine release, epithelial resistance, oxidative stress, and mitochondrial membrane potential were measured. To determine the human relevance of in vitro exposures, airway surface depositions were predicted by simulating airborne concentrations equivalent to the Cramer class III inhalation threshold of toxicological concern limit of 0.47 mg/person/day using an in silico model. A > 100-fold margin of exposure was calculated comparing lowest concentrations showing in vitro effects to in silico simulated values. While further studies are needed, this manuscript presents a basic requirement for employing non-animal methods to inform inhalation exposure safety assessments by combining in vitro and in silico assays.

Re-evaluation of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives.

The Panel on Food Additives and Flavourings (FAF) provides a scientific opinion re-evaluating the safety of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives. Butane, isobutane and propane are short-chain (C3-C4) alkanes, which are in gaseous state at room temperature. Their currently permitted use in food is in vegetable oil pan spray (for professional use only) and water-based emulsion spray as propellants at quantum satis. They can also be used in food colour preparations with a maximum residual limit of 1 mg/kg in food. Two interested business operators (IBOs) provided information in response to the call for data published by EFSA reporting typical and maximum use levels. The toxicological hazards of the three gases via inhalation are known, however this route of exposure is not considered relevant for their safety assessment as food additives. Existing EU specifications for the three food additives already contain limits for the toxic impurity 1,3-butadiene (1,3-BD), however due to a lack of information on the manufacturing processes used, uncertainties do remain regarding the potential presence of other impurities not listed in the current EU specifications for food additives. Based on their physicochemical properties, the three gases are considered by the Panel to be of low toxicological concern when used as food additives and their dietary exposure very low. The Panel concluded that the use of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives at the currently permitted uses and use levels does not raise a safety concern. The Panel made some recommendations for amending existing EU specifications for butane (E 943a), isobutane (E 943b) and propane (E 944).

Construction and evaluation of an open-source database for inhalation-based physiologically based kinetic modeling of selected categories for industrial chemicals

A physiologically based kinetic (PBK) model is used for predicting chemical concentrations of toxicological concern in target tissues. Such models are important for understanding toxicokinetics. However, it is challenging to obtain chemical-specific empirical parameter values used for PBK modeling. Thus, developing methods predicting these values is necessary. Herein, we researched PBK models of inhalation exposure to industrial chemicals and developed a database of parameters of approximately 200 chemicals in humans and rodents. Next, the chemicals in the database were classified into three categories (I, IIA, and IIB) based on the intermolecular interactions for humans and rats. Quantitative relationships between blood/air and tissue/blood partition coefficients and physicochemical parameters were derived for the chemicals in each category. Regression analyses of blood/air and fat/blood partition coefficients against Henry's law constant and log D at pH 7.4 for chemicals in category IIA for humans, in which van der Waals and dipole-dipole interactions were involved, yielded 0.88 and 0.54 coefficients of determination, respectively. Moreover, these methods worked for other categories and species. The metabolic parameters maximal velocity (Vmax) and Michaelis-Menten constant (Km) of the chemicals that are primarily metabolized by cytochrome P450 were calculated for humans and rats. Multiple regression analyses of logs Vmax and Km against the occurrence frequency of molecular fragments showed good correlations, respectively. The aforementioned models predicted values close to the reported values for test chemicals within the applicability domains. Our approach could also be applied to other chemicals within the domains that are not included in the database.

High-throughput screening of protein interactions with per- and polyfluoroalkyl substances (PFAS) used in photolithography.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used extensively across industries, including semiconductor manufacturing. Semiconductors are ubiquitous, and there is increasing global demand for semiconductors, e.g., for advanced technologies and the automotive industry. Despite their extensive use, the toxicity and bioaccumulation potential of PFAS used in photolithography, a critical process in semiconductor manufacturing, remain poorly understood. Moreover, most lack experimental data and standards for testing. Here, we identified 96 photolithography-relevant PFAS and developed a computational framework to evaluate their potential hazards through protein binding. By integrating molecular dynamics (MD) and docking, we predicted the binding affinities and positions of PFAS to five proteins-liver fatty acid binding protein (LFABP), serum albumin (SA), peroxisome proliferator-activated receptors α and γ (PPARα and PPARγ), and transthyretin (TTR). These proteins were chosen as their binding with PFAS has been linked to PFAS bioaccumulation and to hepatic, reproductive, developmental, and endocrine disruption. Comparisons with empirical data demonstrated our approach balances simulation speed and robustness, better estimating absolute and relative binding affinities than docking alone. PFAS-protein binding affinities were generally positively associated with fluorinated chain length and the presence of aromatic rings, but limited by the protein binding pocket dimensions. Notably, we identified 22 PFAS with stronger predicted binding than perfluorooctane sulfonic acid (PFOS), a known hazardous PFAS, to at least one target protein, suggesting the potential for toxicological concern. By enabling proactive evaluation of PFAS that are unavailable for experimental testing, this work contributes to safeguarding environmental and human health amidst rising semiconductor demands.

Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits.

Availability of toxicological data for pharmaceutical intermediates (IMs) used in the manufacture of small molecules is often limited. Scarcity of data - in particular, repeat-dose toxicity (RDT) - renders the calculation of health-based exposure limits (HBELs) problematic. Establishment of HBELs, including occupational exposure limits (OELs) and permitted daily exposures (PDEs) facilitating worker and patient safety respectively, is however essential. Historic 28-day oral rodent toxicity data was analysed for 103 GSK isolated IMs. No-observed (adverse) effect levels (NO(A)ELs) and critical effects were extracted. The 5th percentile (p05) of the NO(A)EL distribution was 15mg/kg/day. Substance specific HBELs were calculated, selecting the NO(A)EL as the Point of Departure (PoD); 99% of IMs (n=102) were assigned an oral PDE ≥1000μg/day and OEL ≥100μg/m3. A default oral PDE of 1000μg/day and OEL of 100μg/m3 is thus proposed for IMs. Evaluation of an additional PoD - benchmark dose lower confidence limit (BMDL) - further supported the default HBELs. The default oral PDE can also serve as a threshold of toxicological concern (TTC) for IMs. Default limits can aid in setting HBELs for novel data-poor IMs, as well as supporting waiving of RDT in the future through read-across.

Capturing Differential Quality of Experimental Evidence in a Predictive Quantum-Mechanical Model for Respiratory Sensitization.

Asthma is of concern in occupational toxicology with significant public-health and economic costs. In the absence of benchmark in vivo and in vitro tests, the use of mechanistically sound in silico models is critical to inform hazard and to protect workers from exposure to potentially harmful substances. We recently reported on the computer-aided discovery and REdesign (CADRE) model for respiratory sensitization, which relies on a tiered structure of expert rules, molecular simulations, quantum-mechanics calculations and advanced statistics to accurately identify respiratory sensitizers from first principles. Here, we present an update to this model based on two years of testing in the pharmaceutical space, where we captured the heterogeneity of the underlying experimental evidence in two predictive tiers, thus allowing the practitioner to select an outcome based on their expert assessment of the data reliability and relevance. This user-based tuning of predictive models is critical for end points that lack consensus on what constitutes satisfactory evidence to support a decision in the handling of chemicals for occupational safety.

RIFM fragrance ingredient safety assessment, 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone, CAS Registry number 61315-75-1

The existing information supports the use of this material as described in this safety assessment.4-(4-Methyl-3-penten-1-yl)-2(5H)-furanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is not mutagenic. The clastogenicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for the genotoxicity endpoint material, and the exposure to 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is below the TTC (0.0025 μg/kg/day). The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class III material, and the exposure to 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is not expected to be photoirritating/photoallergenic. The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is not Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. For the risk assessment, 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone was not able to be risk screened as there were no reported volumes of use (VoU) for either North America or Europe in the 2019 IFRA Survey.

The analytical evaluation threshold for inorganic metal extractables and leachables analysis of medical devices

Chemical characterization of medical devices uses the analytical evaluation threshold (AET) to determine reportable organic extractables, as these chemicals may be of toxicological concern and should be addressed via toxicological risk assessment. The AET is not applicable to metal extractables due to the exclusion of toxicity data on inorganics from the dataset used to derive dose-based threshold (DBT) values. This results in minimal guidance for reporting metal extractables. Herein, an AET for metals, or mAET, is proposed as a reporting threshold for individual metal extractables. The mAET can ensure metals are reported that are at quantities that may present a patient safety risk. This may reduce the number of metals reported in a chemical characterization report, improving the efficiency of the overall biocompatibility evaluation by removing unneeded effort and resource time. Conversely, an analytical method's ability to report all metals at toxicologically relevant levels can be confirmed by comparing method sensitivity to mAET values. DBTs were developed for 70 metals, permitting mAET values to be determined. These mAET values were then compared to metal reporting limits from 13 previously conducted chemical characterization studies, which used varying extraction designs and analytical methods, to determine the impact of the mAET.

Evaluating the consistency of judgments derived through both in silico and expert application of the Cramer classification scheme

The Cramer classification scheme has emerged as one of the most extensively-adopted predictive toxicology tools, owing in part to its employment for chemical categorisation within threshold of toxicological concern evaluation. The characteristics of several of its rules have contributed to inconsistencies with respect to degree of hazard attributed to common (particularly food-relevant) substances. This investigation examines these discrepancies, and their origins, raising awareness of such issues amongst users seeking to apply and/or adapt the rule-set.A dataset of over 3000 compounds was assembled, each with Cramer class assignments issued by up to four groups of industry and academic experts. These were complemented by corresponding outputs from in silico implementations of the scheme present within Toxtree and OECD QSAR Toolbox software, including a working of a “Revised Cramer Decision Tree”. Consistency between judgments was assessed, revealing that although the extent of inter-expert agreement was very high (≥97%), general concordance between expert and in silico calls was more modest (∼70%). In particular, 22 chemical groupings were identified to serve as prominent sources of disagreement, the origins of which could be attributed either to differences in subjective interpretation, to software coding anomalies, or to reforms introduced by authors of the revised rules.

Trace element contamination biomonitoring: A comparative study between the polychaetes Alitta virens and Hediste diversicolor

Trace elements (TEs) remain of significant toxicological concern as many are critical for global decarbonisation. TEs accumulate in sediments so benthic polychaetes (e.g. Hediste diversicolor and Alitta virens) are highly relevant for ecotoxicology. However, ecological/biological differences could influence TE accumulation and biomonitoring suitability. Exploiting multiple sympatric populations (Solent, UK), we measure sediment and tissue concentrations generating EFs (enrichment factors), AEIs (Adverse Effects Indexes) and tissue bioaccumulation factors. We also assess stable isotope compositions to elucidate diet influences. Despite diverse anthropogenic activity in the Solent, the majority of TEs present low levels of sediment contamination at the sites. For Ni, Pb and As, a combination of mean AEIs >1 and some sediment concentrations exceeding SQVs (Sediment Quality Values) indicate a slight toxicological risk. For Cu and Hg, high EFs and AEI scores confirm they are the greatest risk, thus requiring source identification/control. However, only mean As tissue concentrations reflect contaminated sites, therefore, identifying the As-source(s) is also a priority. Sediment and tissue concentration relationships were generally negative and not significant for both species. Although a significant negative relationship for Cd for A. virens requires further investigation, the lack of evidence for TE bioaccumulation from sediment may limit both species' biomonitoring suitability for low-contamination sites. Species differences in tissue concentration were also TE specific: H. diversicolor had significantly higher concentrations for Ag, Cu, Hg, Ni and Zn, whilst the reverse was true for Cd, Fe, Cr and As. Whilst ecological differences and that feeding sources are site and species-specific (as evidenced by C, N and S stable isotopes analysis) cannot be ignored, the diverse tissue concentrations strongly suggest different TE regulation strategies per species. Together these data will be important for ecotoxicologists and regulators to select the ‘best’ polychaete biomonitor and assess TE toxicity under future global decarbonisation trajectories for TE inputs.

Universally Applicable Methods for Comprehensive Risk Assessment of Elemental Impurities in Vitamin A and D Preparations

Background: Vitamin A and D deficiency in children is a common public health problem. In China, almost all children are administered vitamin A and D preparations daily and they should be consumed continuously until the age of 18. Children are sensitive to elemental impurities, including heavy metals. However, there are no regulatory requirements or reports on the risk assessment of elemental impurities in marketed vitamin A and D preparations. Objective: The aim of this study was to propose an accurate and efficient method suitable for samples from different manufacturers to detect elemental impurities and conduct risk assessments according to the ICH Q3D guidelines. Methods: We developed a universally applicable digestion method for capsules and an ICP–MS method for quantitative analysis of 28 elemental impurities in vitamin A and D formulations. These methods were validated according to the USP 233 guidelines. Elemental impurities in 15 batches of vitamin A and D products from 10 manufacturers and their capsule shells were determined, and risk assessment was conducted according to the International Council for Harmonization Q3D guidelines. Results: All elemental impurities of toxicological concern met the Q3D requirements. However, the concentrations of various elements, including those of lead (not detected to 4.1 μg/g), arsenic (not detected to 7 μg/g), aluminum (not detected to 888 μg/g), and palladium (not detected to 36 μg/g), varied markedly. Moreover, the lead content in one batch from one manufacturer exceeded the control threshold. Conclusion: In this study, we successfully developed an effective digestion method for processing capsules containing samples from different sources and a sensitive ICP–MS method for quantitative determination of 28 elemental impurities in vitamin A and D preparations. ICP–MS should be implemented for the evaluation and control of elemental impurities in vitamin A and D preparations. This will ensure safe long-term vitamin A and D supplementation in children

N-Nitrosamine drug substance related impurities (NDSRIs) – A proposal for the addition of subcategories to carcinogenic potency categorization approach categories 1 and 2 for NDSRIs with a molecular weight > 200 Da

The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs). Considering the carcinogenic potency of NAs with a molecular weight >200 Da (NDSRIs molecular weight is typically 200–600 Da), we propose that in the absence of any compound specific data, the lowest lifetime Acceptable Intake for NAs, such as NDSRIs, should be 10x less (i.e., 150 ng/day) than the ICH M7 Threshold of Toxicological Concern of 1500 ng/day, (even for NDSRIs that are considered CPCA Category 1 and 2) which would conservatively result in a theoretical cancer risk of <1 in 100,000.

The cliff-edge of toxicological concern: highlighting the potential issues of an over-reliance on "less-than-lifetime" thresholds.

The Threshold of Toxicological Concern (TTC) is a very well-established concept in applied toxicology, and has become a key tool for the pragmatic human health risk assessment of data-poor chemicals. Within the pharmaceutical sector, regulatory guidance on genotoxins defaults to a TTC of 1.5μg/day equating to a maximum lifetime cancer risk of 1 in 100,000. Higher doses for drug products where exposures are intermittent or otherwise "less-than-lifetime" (LTL) are also considered tolerable. This also allows substance-specific lifetime Acceptable Intakes (AIs) for known genotoxic carcinogens to be scaled up for shorter durations. The default TTCs for assessing LTL exposures build in conservatism such that there is deviation from strict linearity. However, close to the boundaries between LTL categories there can be such a difference in the default tolerable intakes that a health risk assessment can yield conflicting results. We have presented a theoretical case study based on our recent work that illustrates this apparent "cliff-edge." The total acceptable cumulative dose over a 56-day treatment is - in absolute terms - one third of that allowed over 28days, despite the maximum cancer risk of the longer exposure being an order of magnitude higher. Our analysis suggests the need for careful consideration of what might represent tolerable exposures in the region of the category limits, rather than simply adopting the hardline default. Where a potential patient exposure is found to be above a default value, there is real value in refining the cancer risk estimates using the Lifetime Cumulative Dose approach.

Study of chili peppers and paprika contamination with alternaria toxins as health risk factors

At present, researchers show considerable interest in unregulated toxins of widespread fungi in nature, in particular, metabolites of microfungi of Alternaria genus. These toxins are potentially hazardous for human health and, under unfavorable conditions, capable of producing toxic metabolites, Alternaria toxins (AT), which have shown genotoxicity, mutagenicity and acute toxic effects. They are frequently detected not only in cereals and oilseeds, fruits, nuts, vegetables, but also in spices, especially dried red peppers. The aim of the study was to investigate the occurrence of Alternaria toxins in paprika and chili peppers sold on the domestic market as well as to assess their intakes by humans through their consumption. Concentration of 5 Alternaria toxins (alternatiol (AOH), alternariol monomethyl ether (AME), altenuene (ALT), tentoxin (TEN), tenuazonic acid (TeA)) was detected in 37 samples of dried red peppers marketed in Moscow and Moscow region in 2024 year including paprika (20 samples) and chili pepper (17 samples). The analysis of Alternaria toxins contamination was carried out by high-performance liquid chromatography coupled to tandem mass-spectrometric detection (HPLC-MS/MS). TeA was detected in 84 % of red pepper samples in concentration from 43 to 3295 µg/kg and TEN – in 40 % cases, in low levels ranging from 1.0 to 11 µg/kg. The occurrence of AT in paprika was higher than in chili pepper. Combined (2 or more toxins) contamination with Alternaria toxins was found only in paprika samples (65 %; the predominant combination is TeA and TEN). Intakes of Alternaria toxins associated with consumption of chili and paprika did not exceed the reference values and ranged from 0.0003 % (for TEN) to 0.24 % (for TeA) of the threshold of toxicological concern (TTC).

Результаты оценки контаминации перца чили и паприки альтернариатоксинами как факторы риска здоровью

At present, researchers show considerable interest in unregulated toxins of widespread fungi in nature, in particular, metabolites of microfungi of Alternaria genus. These toxins are potentially hazardous for human health and, under unfavorable conditions, capable of producing toxic metabolites, Alternaria toxins (AT), which have shown genotoxicity, mutagenicity and acute toxic effects. They are frequently detected not only in cereals and oilseeds, fruits, nuts, vegetables, but also in spices, especially dried red peppers. The aim of the study was to investigate the occurrence of Alternaria toxins in paprika and chili peppers sold on the domestic market as well as to assess their intakes by humans through their consumption. Concentration of 5 Alternaria toxins (alternatiol (AOH), alternariol monomethyl ether (AME), altenuene (ALT), tentoxin (TEN), tenuazonic acid (TeA)) was detected in 37 samples of dried red peppers marketed in Moscow and Moscow region in 2024 year including paprika (20 samples) and chili pepper (17 samples). The analysis of Alternaria toxins contamination was carried out by high-performance liquid chromatography coupled to tandem mass-spectrometric detection (HPLC-MS/MS). TeA was detected in 84 % of red pepper samples in concentration from 43 to 3295 µg/kg and TEN – in 40 % cases, in low levels ranging from 1.0 to 11 µg/kg. The occurrence of AT in paprika was higher than in chili pepper. Combined (2 or more toxins) contamination with Alternaria toxins was found only in paprika samples (65 %; the predominant combination is TeA and TEN). Intakes of Alternaria toxins associated with consumption of chili and paprika did not exceed the reference values and ranged from 0.0003 % (for TEN) to 0.24 % (for TeA) of the threshold of toxicological concern (TTC).

P19-43 Identification of chemical categories of E&Ls having PDEs below the proposed threshold of toxicological concern for non-genotoxic chemicals via intravenous (TTCiv)

P19-43 Identification of chemical categories of E&Ls having PDEs below the proposed threshold of toxicological concern for non-genotoxic chemicals via intravenous (TTCiv)