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1.
Arch Toxicol ; 94(6): 1787-1877, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32542409

RESUMO

The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as "omics" approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.

2.
Arch Toxicol ; 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518961

RESUMO

The aim of the present study was to use an in vitro-in silico approach to predict the in vivo acute liver toxicity of monocrotaline and to characterize the influence of its metabolism on its relative toxic potency compared to lasiocarpine and riddelliine. In the absence of data on acute liver toxicity of monocrotaline upon oral exposure, the predicted dose-response curve for acute liver toxicity in rats and the resulting benchmark dose lower and upper confidence limits for 10% effect (BMDL10 and BMDU10) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL10 value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL10-BMDU10 of 1.1-4.9 mg/kg bw/day also matched the oral dose range of 1-3 mg PA/kg bw/day at which adverse effects in human are reported. A comparison to the oral toxicity of the related pyrrolizidine alkaloids (PAs) lasiocarpine and riddelliine revealed that, although in the rat hepatocytes monocrotaline was less toxic than lasiocarpine and riddelliine, due to its relatively inefficient clearance, its in vivo acute liver toxicity was predicted to be comparable. It is concluded that the combined in vitro-PBK modeling approach can provide insight in monocrotaline-induced acute liver toxicity in rats, thereby filling existing gaps in the database on PA toxicity. Furthermore, the results reveal that the kinetic and metabolic properties of PAs can vary substantially and should be taken into account when considering differences in relative potency between different PAs.

3.
Arch Toxicol ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367273

RESUMO

Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration-response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose-response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.

4.
Toxicol In Vitro ; 67: 104891, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32446838

RESUMO

Cardiotoxicity is an important toxicological endpoint for chemical and drug safety assessment. The present study aims to evaluate two stemcell-based in vitro models for cardiotoxicity screening of chemicals. Eleven model compounds were used to evaluate responses of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) using beating arrest as a readout and the analysis of electrophysiological parameters measured with a multi-electrode array (MEA) platform of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results revealed that the hiPSC-CM MEA assay responded to all compounds. The mESC-CM beating arrest assay was not responsive to potassium channel blockers and showed a lower sensitivity to sodium channel blockers and Na+/K+ ATPase inhibitors compared to the hiPSC-CM MEA assay. Calcium channel blockers and a ß-adrenergic receptor agonist showed comparable potencies in both models. The in vitro response concentrations from hiPSC-CMs were highly concordant with human effective serum concentrations of potassium and sodium channel blockers. It is concluded that both in vitro models enable the cardiotoxicity screening with different applicability domains. The mESC-CM beating arrest assay may be used as a first step in a tiered approach while the hiPSC-CM MEA assay may be the best starting point for quantitative in vitro to in vivo extrapolations.

5.
Mol Nutr Food Res ; 64(13): e2000063, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32421213

RESUMO

SCOPE: High-level exposure to aflatoxin B1 (AFB1) is known to cause acute liver damage and fatality in animals and humans. The intakes actually causing this acute toxicity have so far been estimated based on AFB1 levels in contaminated foods or biomarkers in serum. The aim of the present study is to predict the doses causing acute liver toxicity of AFB1 in rats and humans by an in vitro-in silico testing strategy. METHODS AND RESULTS: Physiologically based kinetic (PBK) models for AFB1 in rats and humans are developed. The models are used to translate in vitro concentration-response curves for cytotoxicity in primary rat and human hepatocytes to in vivo dose-response curves using reverse dosimetry. From these data, the dose levels at which toxicity would be expected are obtained and compared to toxic dose levels from available rat and human case studies on AFB1 toxicity. The results show that the in vitro-in silico testing strategy can predict dose levels causing acute toxicity of AFB1 in rats and human. CONCLUSIONS: Quantitative in vitro in vivo extrapolation (QIVIVE) using PBK modeling-based reverse dosimetry can predict AFB1 doses that cause acute liver toxicity in rats and human.

6.
BMC Complement Med Ther ; 20(1): 80, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164648

RESUMO

BACKGROUND: The health benefits of botanicals is linked to their phytochemicals that often exert pleiotropic effects via targeting multiple molecular signaling pathways such as the peroxisome proliferator-activated receptors (PPARs) and the nuclear factor kappaB (NFκB). The PPARs are transcription factors that control metabolic homeostasis and inflammation while the NF-κB is a master regulator of inflammatory genes such as the inducible nitric-oxide synthase that result in nitric oxide (NO) overproduction. METHODS: Extracts of Maerua subcordata (MS) and selected candidate constituents thereof, identified by liquid chromatography coupled to mass spectroscopy, were tested for their ability to induce PPARγ mediated gene expression in U2OS-PPARγ cells using luciferase reporter gene assay and also for their ability to inhibit lipopolysaccharide (LPS) induced NO production in RAW264.7 macrophages. While measuring the effect of test samples on PPARγ mediated gene expression, a counter assay that used U2OS-Cytotox cells was performed to monitor cytotoxicity or any non-specific changes in luciferase activity. RESULTS: The results revealed that the fruit, root, and seed extracts were non-cytotoxic up to a concentration of 30 g dry weight per litre (gDW/L) and induced PPARγ mediated gene expression but the leaf extract showed some cytotoxicity and exhibited minimal induction. Instead, all extracts showed concentration (1-15 gDW/L) dependent inhibition of LPS induced NO production. The root extract showed weaker inhibition. Among the candidate constituents, agmatine, stachydrine, trigonelline, indole-3-carboxyaldehyde, plus ethyl-, isobutyl-, isopropyl, and methyl-isothiocyanates showed similar inhibition, and most showed increased inhibition with increasing concentration (1-100 µM) although to a lesser potency than the positive control, aminoguanidine. CONCLUSION: The present study demonstrated for the first time the induction of PPARγ mediated gene expression by MS fruit, root, and seed extracts and the inhibition of LPS induced NO production by MS fruit, leaf, root, and seed extracts and some candidate constituents thereof.

7.
Food Chem Toxicol ; 138: 111230, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32113951

RESUMO

The occurrence and accompanying risks of pyrrolizidine alkaloids (PAs) in Indonesian jamu were evaluated. PAs were detected in 34 out of 35 jamu containing PA-producing botanicals, in the range of 12.3-235,376 µg/kg. A total PA level of 5.9-3,421 µg/kg was found in 17 out of 23 jamu made of non-PA-producing botanicals pointing to contamination with PA-producing plants. Short-time consumption of jamu is unlikely to result in acute toxic effects, although one sample would exceed an intake of 10 µg PA/kg bw/day which may cause hepatic veno-occlusive disease (HVOD) in humans. The risk assessment for the genotoxic and carcinogenic potential of PAs revealed Margin of Exposure (MOE) values below 10,000 for 27 out of all samples analysed (46.6%), indicating a priority for risk management when assuming daily lifelong consumption. Assuming consumption for two weeks every year during a lifetime, and using Haber's rule, 13 out of 35 jamu samples containing PA-producing botanicals (37%) still pose a priority, while the jamu consisting of non-PA-producing botanicals would be of low priority (MOE>10,000). This study provides data that can support risk management actions in Indonesia to minimize the potential health risk for jamu consumers due to the occurrence of toxic PAs in these products.

8.
Crit Rev Toxicol ; 50(1): 1-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32162576

RESUMO

The Flavor and Extract Manufacturers Association (FEMA) Expert Panel relies on the weight of evidence from all available data in the safety evaluation of flavoring substances. This process includes data from genotoxicity studies designed to assess the potential of a chemical agent to react with DNA or otherwise cause changes to DNA, either in vitro or in vivo. The Panel has reviewed a large number of in vitro and in vivo genotoxicity studies during the course of its ongoing safety evaluations of flavorings. The adherence of genotoxicity studies to standardized protocols and guidelines, the biological relevance of the results from those studies, and the human relevance of these studies are all important considerations in assessing whether the results raise specific concerns for genotoxic potential. The Panel evaluates genotoxicity studies not only for evidence of genotoxicity hazard, but also for the probability of risk to the consumer in the context of exposure from their use as flavoring substances. The majority of flavoring substances have given no indication of genotoxic potential in studies evaluated by the FEMA Expert Panel. Examples illustrating the assessment of genotoxicity data for flavoring substances and the consideration of the factors noted above are provided. The weight of evidence approach adopted by the FEMA Expert Panel leads to a rational assessment of risk associated with consumer intake of flavoring substances under the conditions of use.

9.
Arch Toxicol ; 94(4): 1349-1365, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32185416

RESUMO

Estragole, naturally occurring in a variety of herbs and spices, can form DNA adducts after bioactivation. Estragole DNA adduct formation and repair was studied in in vitro liver cell models, and a molecular dynamics simulation was used to investigate the conformation dependent (in)efficiency of N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine (E-3'-N2-dG) DNA adduct repair. HepG2, HepaRG cells, primary rat hepatocytes and CHO cells (including CHO wild-type and three NER-deficient mutants) were exposed to 50 µM estragole or 1'-hydroxyestragole and DNA adduct formation was quantified by LC-MS immediately following exposure and after a period of repair. Results obtained from CHO cell lines indicated that NER plays a role in repair of E-3'-N2-dG adducts, however, with limited efficiency since in the CHO wt cells 80% DNA adducts remained upon 24 h repair. Inefficiency of DNA repair was also found in HepaRG cells and primary rat hepatocytes. Changes in DNA structure resulting from E-3'-N2-dG adduct formation were investigated by molecular dynamics simulations. Results from molecular dynamics simulations revealed that conformational changes in double-stranded DNA by E-3'-N2-dG adduct formation are small, providing a possible explanation for the restrained repair, which may require larger distortions in the DNA structure. NER-mediated enzymatic repair of E-3'-N2-dG DNA adducts upon exposure to estragole will be limited, providing opportunities for accumulation of damage upon repeated daily exposure. The inability of this enzymatic repair is likely due to a limited distortion of the DNA double-stranded helix resulting in inefficient activation of nucleotide excision repair.

10.
Mol Nutr Food Res ; 64(6): e1900912, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32027771

RESUMO

SCOPE: To predict gut microbial metabolism of xenobiotics and the resulting plasma concentrations of metabolites formed, an in vitro-in silico-based testing strategy is developed using the isoflavone daidzein and its gut microbial metabolite S-equol as model compounds. METHODS AND RESULTS: Anaerobic rat fecal incubations are optimized and performed to derive the apparent maximum velocities (Vmax ) and Michaelis-Menten constants (Km ) for gut microbial conversion of daidzein to dihydrodaidzein, S-equol, and O-desmethylangolensin, which are input as parameters for a physiologically based kinetic (PBK) model. The inclusion of gut microbiota in the PBK model allows prediction of S-equol concentrations and slightly reduced predicted maximal daidzein concentrations from 2.19 to 2.16 µm. The resulting predicted concentrations of daidzein and S-equol are comparable to in vivo concentrations reported. CONCLUSION: The optimized in vitro approach to quantify kinetics for gut microbial conversions, and the newly developed PBK model for rats that includes gut microbial metabolism, provide a unique tool to predict the in vivo consequences of daidzein microbial metabolism for systemic exposure of the host to daidzein and its metabolite S-equol. The predictions reveal a dominant role for daidzein in ERα-mediated estrogenicity despite the higher estrogenic potency of its microbial metabolite S-equol.

11.
Cell Biol Toxicol ; 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32088792

RESUMO

Diethylstilbestrol (DES) is a synthetic estrogen and proven human teratogen and carcinogen reported to act via the estrogen receptor α (ERα). Since the endogenous ERα ligand 17ß-estradiol (E2) does not show these adverse effects to a similar extent, we hypothesized that DES' interaction with the ERα differs from that of E2. The current study aimed to investigate possible differences between DES and E2 using in vitro assays that detect ERα-mediated effects, including ERα-mediated reporter gene expression, ERα-mediated breast cancer cell (T47D) proliferation and ERα-coregulator interactions and gene expression in T47D cells. Results obtained indicate that DES and E2 activate ERα-mediated reporter gene transcription and T47D cell proliferation in a similar way. However, significant differences between DES- and E2-induced binding of the ERα to 15 coregulator motifs and in transcriptomic signatures obtained in the T47D cells were observed. It is concluded that differences observed in binding of the ERα with several co-repressor motifs, in downregulation of genes involved in histone deacetylation and DNA methylation and in upregulation of CYP26A1 and CYP26B1 contribute to the differential effects reported for DES and E2.

12.
Arch Toxicol ; 94(3): 959-966, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32065296

RESUMO

In the last decade, adverse outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of adverse outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of adverse outcome pathways in the safety assessment of food additives. The present paper describes the outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.

13.
Food Chem Toxicol ; 136: 111107, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31904473

RESUMO

Among naturally occurring plant constituents, the 1,2-unsaturated pyrrolizidine alkaloids (in the following termed 'PAs') play a distinct role because of the large number of congeners occurring in nature and the pronounced toxicity of some congeners. Several PAs are hepatotoxic in humans, experimental and farm animals and were shown to be potent hepatocarcinogens in laboratory rodents. Although the general mode of action leading to toxicity has been elucidated, i.e., being mediated by metabolic conversion of the parent molecule into a highly reactive electrophile capable of attacking cellular target molecules, major questions related to the risk assessment of PAs remain unresolved. It was the aim of a workshop held in September 2018 to shed more light on the occurrence, exposure, mode of action, toxicokinetics and -dynamics of PAs to improve the scientific basis for an advanced toxicological risk assessment. The contributions in nine chapters describe the scientific progress using advanced analytical methods, studies in subcellular fractions, cell culture, experimental animals and humans and the use of PBPK modeling and structure-activity relationship considerations aiming at a better understanding of PA toxicity and genotoxicity. Since PAs differ considerably in their toxic potencies and substantial species differences in sensitivity towards PA exposure exist, a special emphasis was placed on these issues.

14.
Chem Biol Interact ; 315: 108905, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31765606

RESUMO

Mineral oils are widely applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation.


Assuntos
Alquilantes/metabolismo , Microssomos Hepáticos/metabolismo , Naftalenos/metabolismo , Alquilação/fisiologia , Animais , Cromatografia Gasosa/métodos , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Oxirredução , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Ratos , Espectrometria de Massas em Tandem/métodos
15.
Food Chem Toxicol ; 135: 110870, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31604112

RESUMO

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. NFC flavor materials include a variety of essential oils and botanical extracts. The re-evaluation of NFCs is conducted based on a constituent-based procedure outlined in 2005 and updated in 2018 that evaluates the safety of NFCs for their intended use as flavor ingredients. This procedure is applied in the re-evaluation of the generally recognized as safe (GRAS) status of NFCs with constituent profiles that are dominated by alicyclic ketones such as menthone and carvone, secondary alcohols such as menthol and carveol, and related compounds. The FEMA Expert Panel affirmed the GRAS status of Peppermint Oil (FEMA 2848), Spearmint Oil (FEMA 3032), Spearmint Extract (FEMA 3031), Cornmint Oil (FEMA 4219), Erospicata Oil (FEMA 4777), Curly Mint Oil (FEMA 4778), Pennyroyal Oil (FEMA 2839), Buchu Leaves Oil (FEMA 2169), Caraway Oil (FEMA 2238) and Dill Oil (FEMA 2383) and determined FEMA GRAS status for Buchu Leaves Extract (FEMA 4923), Peppermint Oil, Terpeneless (FEMA 4924) and Spearmint Oil, Terpeneless (FEMA 4925).


Assuntos
Produtos Biológicos/química , Aromatizantes/farmacologia , Extratos Vegetais/farmacologia , Plantas/química , Aromatizantes/normas , Estados Unidos , United States Food and Drug Administration
16.
Toxicol Sci ; 173(1): 19-31, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626307

RESUMO

The present study assessed the potential of a generic physiologically based kinetic (PBK) model to convert in vitro data for estrogenicity to predict the in vivo uterotrophic response in rats for diethylstibestrol (DES), ethinylestradiol (EE2), genistein (GEN), coumestrol (COU), and methoxychlor (MXC). PBK models were developed using a generic approach and in vitro concentration-response data from the MCF-7 proliferation assay and the yeast estrogen screening assay were translated into in vivo dose-response data. Benchmark dose analysis was performed on the predicted data and available in vivo uterotrophic data to evaluate the model predictions. The results reveal that the developed generic PBK model adequate defines the in vivo kinetics of the estrogens. The predicted dose-response data of DES, EE2, GEN, COU, and MXC matched the reported in vivo uterus weight response in a qualitative way, whereas the quantitative comparison was somewhat hampered by the variability in both in vitro and in vivo data. From a safety perspective, the predictions based on the MCF-7 proliferation assay would best guarantee a safe point of departure for further risk assessment although it may be conservative. The current study indicates the feasibility of using a combination of in vitro toxicity data and a generic PBK model to predict the relative in vivo uterotrophic response for estrogenic chemicals.

17.
Food Chem Toxicol ; 135: 110949, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31751643

RESUMO

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, third in the series, considers NFCs composed primarily of constituents with the 3-phenyl-2-propenyl or a cinnamyl functional group, using the procedure outlined in 2005 and updated in 2018 to evaluate the safety of naturally-occurring mixtures for their intended use as flavor ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and organization of each NFC's chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of members of the congeneric groups and the NFC under evaluation. Six NFCs from the Myroxylon and Cinnamomum genera, Balsam Oil, Peru (FEMA 2117), Tolu Balsam Extract (FEMA 3069), Cassia Bark Extract (FEMA 2257), Cassia Bark Oil (FEMA 2258), Cinnamon Bark Extract (FEMA 2290) and Cinnamon Bark Oil (FEMA 2291) were evaluated and affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients.


Assuntos
Cinnamomum/química , Aromatizantes/toxicidade , Myroxylon/química , Óleos Voláteis/toxicidade , Extratos Vegetais/toxicidade , Animais , Linhagem Celular , Qualidade de Produtos para o Consumidor , Aromatizantes/química , Humanos , Nível de Efeito Adverso não Observado , Óleos Voláteis/química , Extratos Vegetais/química , Medição de Risco
18.
J Appl Toxicol ; 40(3): 330-341, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31808176

RESUMO

In vitro assays presently used for prenatal developmental toxicity (PDT) testing only assess the embryotoxic potential of parent substances and not that of potentially embryotoxic metabolites. Here we combined a biotransformation system, using hamster liver microsomes, with the ES-D3 cell differentiation assay of the embryonic stem cell test (EST) to compare the in vitro PDT potency of two 5-ring polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BaP) and dibenz[a,h]anthracene (DBA), and dimethyl sulfoxide extracts from five PAH-containing petroleum substances (PS) and a gas-to-liquid base oil (GTLb), with and without bioactivation. In the absence of bioactivation, DBA, but not BaP, inhibited the differentiation of ES-D3 cells into beating cardiomyocytes in a concentration-dependent manner. Upon bioactivation, BaP induced in vitro PDT, while its major metabolite 3-hydroxybenzo[a]pyrene was shown to be active in the EST as well. This means BaP needs biotransformation to exert its embryotoxic effects. GTLb extracts tested negative in the EST, with and without bioactivation. The PS-induced PDT in the EST was not substantially changed following bioactivation, implying that metabolism may not play a crucial role for the PS extracts under study to exert the in vitro PDT effects. Altogether, these results indicate that although some PAH require bioactivation to induce PDT, some do not and this latter appears to hold for the (majority of) the PS constituents responsible for the in vitro PDT of these complex substances.

19.
Mol Nutr Food Res ; 64(2): e1900880, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846197

RESUMO

SCOPE: It is investigated whether at realistic dietary intake bixin and crocetin could induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated gene expression in humans using a combined in vitro-in silico approach. METHODS AND RESULTS: Concentration-response curves obtained from in vitro PPARγ-reporter gene assays are converted to in vivo dose-response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD50 ) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPARγ-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw-1 for crocetin and bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD50 values for crocetin but not for bixin, pointing at better possibilities for in vivo PPARγ activation by crocetin. CONCLUSION: Based on a combined in vitro-in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of bixin and crocetin are likely to reach concentrations that activate PPARγ-mediated gene expression, without the need for a human intervention study.

20.
Crit Rev Toxicol ; 49(7): 567-579, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31854211

RESUMO

Botanicals and botanical preparations including plant food supplements as well as medicinal herbal supplements can contain possible beneficial health compounds, but also ingredients of concern. Compounds that are both genotoxic and carcinogenic have been found in herbal supplements and may raise a safety concern. Genotoxic carcinogens that can be present in botanicals and botanical preprations include especially pyrrolizidine alkaloids (PAs), aristolochic acids (AAs) and alkenylbenzenes (ABs). The present manuscript provides an overview of the levels of these compounds reported to date to be present in herbal supplements with an associated risk assessment. Exposure was estimated based on levels of PAs, AAs and ABs in individual supplements and their proposed uses. In addition a probabilistic exposure assessment was performed based on the distribution of the level of the compounds of concern in the food supplements and of the recommended uses, resulting in 5th to 95th percentile consumer exposure values. To evaluate the risk of these exposures, the margin of exposure (MOE) approach for lifetime exposure was used. To correct exposure estimates for shorter than lifetime exposure, Haber's rule as a first tier approach was applied. It is concluded that the proposed uses and use levels as well as the presence of AAs, ABs and PAs in food supplements should be carefully monitored to manage potential consumer risks. More information on estimated daily intake resulting from supplement use, as well as consequences of concomitant exposure will further improve the risk evaluation of products containing these compounds of concern.


Assuntos
Suplementos Nutricionais/efeitos adversos , Contaminação de Medicamentos , Carcinógenos/toxicidade , Humanos , Medição de Risco
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