FEMA GRAS assessment of derivatives of basil, nutmeg, parsley, tarragon and related allylalkoxybenzene-containing natural flavor complexes

Food and Chemical Toxicology

Published On 2023/5/1

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 flavoring ingredients in food. In this publication, tenth in the series, NFCs containing a high percentage of at least one naturally occurring allylalkoxybenzene constituent with a suspected concern for genotoxicity and/or carcinogenicity are evaluated. In a related paper, ninth in the series, NFCs containing anethole and/or eugenol and relatively low percentages of these allylalkoxybenzenes are evaluated. The Panel applies the threshold of toxicological concern (TTC) concept and evaluates relevant toxicology data on the NFCs and their respective constituent congeneric groups. For NFCs containing allylalkoxybenzene constituent(s), the estimated intake of the constituent is compared to the TTC for compounds with structural …

Journal

Food and Chemical Toxicology

Published On

2023/5/1

Volume

175

Page

113646

Authors

Fred Guengerich

Fred Guengerich

Vanderbilt University

Position

Professor of Biochemistry

H-Index(all)

175

H-Index(since 2020)

51

I-10 Index(all)

0

I-10 Index(since 2020)

0

Citation(all)

0

Citation(since 2020)

0

Cited By

0

Research Interests

Enzymology

drug metabolism

cytochrome P450

mutagenesis

University Profile Page

Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

Position

H-Index(all)

84

H-Index(since 2020)

48

I-10 Index(all)

0

I-10 Index(since 2020)

0

Citation(all)

0

Citation(since 2020)

0

Cited By

0

Research Interests

Toxicology

Biochemistry

University Profile Page

Samuel M. Cohen

Samuel M. Cohen

University of Nebraska Medical Center

Position

Professor of Pathology and Microbiology

H-Index(all)

82

H-Index(since 2020)

39

I-10 Index(all)

0

I-10 Index(since 2020)

0

Citation(all)

0

Citation(since 2020)

0

Cited By

0

Research Interests

toxicology

chemical carcinogenesis

urinary tract cancer

Other Articles from authors

Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

Regulatory Toxicology and Pharmacology

Risk assessment of nutrients: There must be a threshold for their effects

Nutrients serve physiological functions in a dose-dependent manner and that needs to be recognized in risk assessment. An example of the consequences of not properly considering this can be seen in a recent assessment by the European Food Safety Authority (EFSA). EFSA concluded in 2022 that the intake of added and free sugars should be “as low as possible in the context of a nutritionally adequate diet”. That conclusion of EFSA is based on the effects on two surrogate endpoints for an adverse effect found in randomized controlled trials with high sugars intake levels: fasting glucose and fasting triglycerides. The lowest intake levels in these trials were around 10 energy% and at this intake level there were no adverse effects on the two outcomes. This indicates that the adverse effects of sugars have an observable threshold value for these two endpoints. The most appropriate interpretation from the vast …

Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

Food Chemistry

Absorption and intracellular accumulation of food-borne dicarbonyl precursors of advanced glycation end-product in a Caco-2 human cell transwell model

This study aimed to better understand whether and how the reactive 1,2-dicarbonyl precursors of advanced glycation end products (AGEs), glyoxal (GO) and methylglyoxal (MGO), cross the intestinal barrier by studying their transport in the in vitro Caco-2 transwell system. The results reveal that GO, MGO and Nε-(carboxymethyl)lysine (CML), the latter studied for comparison, are transported across the intestinal cell layer via both active and passive transport and accumulate in the cells, albeit all to a limited extent. Besides, the transport of the dicarbonyl compounds was only partially affected by the presence of amino acids and protein, suggesting that scavenging by a food matrix will not fully prevent their intestinal absorption. Our study provides new insights into the absorption of the two major food-borne dicarbonyl AGE precursors and provides evidence of their potential systemic bioavailability but also of factors …

Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

Current Research in Toxicology

In vitro-in silico study on the influence of dose, fraction bioactivated and endpoint used on the relative potency value of pyrrolizidine alkaloid N-oxides compared to parent …

Pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) are phytotoxins found in food, feed and the environment. Yet, limited data exist from which the relative potency of a PA-N-oxide relative to its corresponding PA (REPPANO to PA) can be defined. This study aims to investigate the influence of dose, fraction bioactivated and endpoint on the REPPANO to PA of a series of pyrrolizidine N-oxides using in vitro-in silico data and physiologically based kinetic (PBK) modeling. The first endpoint used to calculate the REPPANO to PA was the ratio of the area under the concentration–time curve of PA resulting from an oral dose of PA-N-oxide divided by that from an equimolar dose of PA (Method 1). The second endpoint was the ratio of the amount of pyrrole-protein adducts formed under these conditions (Method 2). REPPANO to PA values appeared to decrease with increasing dose, with the decrease for Method 2 …

Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

Archives of Toxicology

Evaluating the in vitro developmental toxicity potency of a series of petroleum substance extracts using new approach methodologies (NAMs)

The present study evaluates the in vitro developmental toxicity and the possible underlying mode of action of DMSO extracts of a series of highly complex petroleum substances in the mouse embryonic stem cell test (mEST), the zebrafish embryotoxicity test (ZET) and the aryl hydrocarbon receptor reporter gene assay (AhR CALUX assay). Results show that two out of sixteen samples tested, both being poorly refined products that may contain a substantial amount of 3- to 7-ring polycyclic aromatic compounds (PACs), induced sustained AhR activation in the AhR CALUX assay, and concentration-dependent developmental toxicity in both mEST and ZET. The other samples tested, representing highly refined petroleum substances and petroleum-derived waxes (containing typically a very low amount or no PACs at all), were negative in all assays applied, pointing to their inability to induce developmental toxicity in vitro …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Medicinal Chemistry

Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO …

Samuel M. Cohen

Samuel M. Cohen

University of Nebraska Medical Center

Pediatrics

Biomarker Assessment of Nicotine Exposure Among Adolescent E-Cigarette Users: 2018–2019

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Fred Guengerich

Fred Guengerich

Vanderbilt University

Chemical Research in Toxicology

In Vivo and In Vitro Induction of Cytochrome P450 3A4 by Thalidomide in Humanized-Liver Mice and Experimental Human Hepatocyte HepaSH cells

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Fred Guengerich

Fred Guengerich

Vanderbilt University

Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes

Data are presented on the formation of potentially toxic metabolites of drugs that are substrates of human drug metabolizing enzymes. The tabular data lists the formation of potentially toxic/reactive products. The data were obtained from in vitro experiments and showed that the oxidative reactions predominate (with 96% of the total potential toxication reactions). Reductive reactions (e.g., reduction of nitro to amino group and reductive dehalogenation) participate to the extent of 4%. Of the enzymes, cytochrome P450 (P450, CYP) enzymes catalyzed 72% of the reactions, myeloperoxidase (MPO) 7%, flavin-containing monooxygenase (FMO) 3%, aldehyde oxidase (AOX) 4%, sulfotransferase (SULT) 5%, and a group of minor participating enzymes to the extent of 9%. Within the P450 Superfamily, P450 Subfamily 3A (P450 3A4 and 3A5) participates to the extent of 27% and the Subfamily 2C (P450 2C9 and P450 2C19 …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

Proteomics, modeling, and fluorescence assays delineate cytochrome b5 residues involved in binding and stimulation of cytochrome P450 17A1 17, 20-lyase

Cytochrome b5 (b5) is known to stimulate some catalytic activities of cytochrome P450 (P450, CYP) enzymes, although mechanisms still need to be defined. The reactions most strongly enhanced by b5 are the 17,20-lyase reactions of P450 17A1 involved in steroid biosynthesis. We had previously used a fluorescently labeled human b5 variant (Alexa 488-T70C-b5) to characterize human P450 17A1-b5 interactions, but subsequent proteomic analyses indicated that lysines in b5 were also modified with Alexa 488 maleimide in addition to Cys-70, due to disulfide dimerization of the T70C mutant. A series of b5 variants were constructed with Cys replacements for the identified lysine residues and labeled with the dye. Fluorescence attenuation and the function of b5 in the steroid lyase reaction depended on the modified position. Apo-b5 (devoid of heme group) studies revealed the lack of involvement of the b5 heme in …

Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis

Background:and Purpose–Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop a physiologically based pharmacokinetic (PBPK) model, that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor. Experimental Approach–We developed a PBPK model describing the bile acid homeostasis using glycochenodeoxycholic acid as an exemplary BA. We compared interindividual differences by scaling the total amount of bile acids with an empirical scaling factor and alternatively by sampling randomly from a distribution describing the BSEP abundances using Markov Chain Monte Carlo simulations. Next, the effects of the BSEP-inhibitor bosentan on the bile acid levels were simulated. Key Results–The developed model adequately predicted the in vivo BA dynamics. An empirical scaling factor of 0.5 or 1.5 could readily describe the variations within and between data in human volunteers. Bosentan treatment disproportionally increased the maximum BA concentration in individuals with a large total BA pool or low BSEP abundance. Conclusion and Implications-Especially a large total BA pool size and a low BSEP abundance were predicted to be risk factors for rapid saturation of BSEP and subsequent intrahepatic BA accumulation. This model provides a first estimate of safe therapeutic external dose levels of compounds with BSEP-inhibitory …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Angewandte Chemie

Oxygen‐18 Labeling Reveals a Mixed Fe− O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14α‐Demethylation

The 14α‐demethylation step is critical in eukaryotic sterol biosynthesis, catalyzed by cytochrome P450 (P450) Family 51 enzymes, for example, with lanosterol in mammals. This conserved three‐step reaction terminates in a C−C cleavage step that generates formic acid, the nature of which has been controversial. Proposed mechanisms involve roles of P450 Compound 0 (ferric peroxide anion, FeO2−) or Compound I (perferryl oxygen, FeO3+) reacting with either the aldehyde or its hydrate, respectively. Analysis of 18O incorporation into formic acid from 18O2 provides a means of distinguishing the two mechanisms. Human P450 51A1 incorporated 88 % 18O (one atom) into formic acid, consistent with a major but not exclusive FeO2− mechanism. Two P450 51 orthologs from amoeba and yeast showed similar results, while two orthologs from pathogenic trypanosomes showed roughly equal contributions of both …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

Ninety-eight semesters of cytochrome P450 enzymes and related topics—What have I taught and learned?

This Reflection article begins with my family background and traces my career through elementary and high school, followed by time at the University of Illinois, Vanderbilt University, the University of Michigan, and then for 98 semesters as a Vanderbilt University faculty member. My research career has dealt with aspects of cytochrome P450 enzymes, and the basic biochemistry has had applications in fields as diverse as drug metabolism, toxicology, medicinal chemistry, pharmacogenetics, biological engineering, and bioremediation. I am grateful for the opportunity to work with the Journal of Biological Chemistry not only as an author but also for 34 years as an Editorial Board Member, Associate Editor, Deputy Editor, and interim Editor-in-Chief. Thanks are extended to my family and my mentors, particularly Profs. Harry Broquist and Minor J. Coon, and the more than 170 people who have trained with me. I have …

Fred Guengerich

Fred Guengerich

Vanderbilt University

ACS catalysis

Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4

Most cytochrome P450 (P450) oxidations are considered to occur with the active oxidant being a perferryl oxygen (FeO3+, Compound I). However, a ferric peroxide (FeO2̅, Compound 0) mechanism has been proposed, as well, particularly for aldehyde substrates. We investigated three of these systems, the oxidative deformylation of the model substrates citronellal, 2-phenylpropionaldehyde, and 2-methyl-2-phenylpropionaldehyde by rabbit P450 2B4, using 18O labeling. The formic acid product contained one 18O derived from 18O2, which is indicative of a dominant Compound 0 mechanism. The formic acid also contained only one 18O derived from H218O, which ruled out a Compound I mechanism. The possibility of a Baeyer–Villiger reaction was examined by using synthesized possible intermediates, but our data do not support its presence. Overall, these findings unambiguously demonstrate the role of the …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Principles of Xenobiotic Metabolism (Biotransformation)

This chapter provides a general overview of metabolic reactions and their significance. Basic concepts and terminology related to biotransformation, activity, and toxicityToxicity are explained and discussed. Major enzymes involved in oxidationOxidation, reductionReduction, hydrolytic, and conjugationConjugation are covered including enzyme nomenclature, localization, catalytic cycle, coenzymes, relevance of individual enzymes, types of reactions, substrates and metabolites, influence of metabolic reactions on the activity/toxicity of xenobiotics, enzyme inhibition, and relevance if applicable.

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

The multistep oxidation of cholesterol to pregnenolone by human cytochrome P450 11A1 is highly processive

Cytochrome P450 (P450, CYP) 11A1 is the classical cholesterol side chain cleavage enzyme (P450scc) that removes six carbons of the side chain, the first and rate-limiting step in the synthesis of all mammalian steroids. The reaction is a 3-step, 6-electron oxidation that proceeds via formation of 22R-hydroxy (OH) and 20R,22R-(OH)2 cholesterol, yielding pregnenolone. We expressed human P450 11A1 in bacteria, purified the enzyme in the absence of nonionic detergents, and assayed pregnenolone formation by HPLC-mass spectrometry of the dansyl hydrazone. The reaction was inhibited by the nonionic detergent Tween 20, and several lipids did not enhance enzymatic activity. The 22R-OH and 20R,22R-(OH)2 cholesterol intermediates were bound to P450 11A1 relatively tightly, as judged by steady-state optical titrations and koff rates. The electron donor adrenodoxin had little effect on binding; the substrate …

2023/11/24

Article Details
Ivonne Rietjens

Ivonne Rietjens

Wageningen Universiteit

ALTEX-Alternatives to animal experimentation

Intestinal in vitro transport assay combined with physiologically based kinetic modeling as a tool to predict bile acid levels in vivo

Bile acid homeostasis is vital for numerous metabolic and immune functions in humans. The enterohepatic circulation of bile acids is extremely efficient, with~ 95% of intestinal bile acids being reabsorbed. Disturbing intestinal bile acid uptake is expected to substantially affect intestinal and systemic bile acid levels. Here, we aimed to predict the effects of apical sodium-dependent bile acid transporter (ASBT)-inhibition on systemic plasma levels. For this, we combined in vitro Caco-2 cell transport assays with physiologically based (PBK) modeling. We used the selective ASBT-inhibitor odevixibat (ODE) as a model compound. Caco-2 cells grown on culture inserts were used to obtain transport kinetic parameters of glycocholic acid (GCA). The apparent Michaelis-Menten constant (Km, app), apparent maximal intestinal transport rate (Vmax, app), and ODE’s inhibitory constant (Ki) were determined for GCA. These kinetic parameters were incorporated into a PBK model and used to predict the ASBT inhibition effects on plasma bile acid levels. GCA is transported over Caco-2 cells in an active and sodium-dependent manner, indicating the presence of functional ASBT. ODE inhibited GCA transport dose-dependently. The PBK model predicted that oral doses of ODE reduced conjugated bile acid levels in plasma. Our simulations match in vivo data and provide a first proof-of-principle for the incorporation of active intestinal bile acid uptake in a bile acid PBK model. This approach could in future be of use to predict the effects of other ASBT-inhibitors on plasma and intestinal bile acid levels.

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

Processive kinetics in the three-step lanosterol 14α-demethylation reaction catalyzed by human cytochrome P450 51A1

Cytochrome P450 (P450, CYP) family 51 enzymes catalyze the 14α-demethylation of sterols, leading to critical products used for membranes and the production of steroids, as well as signaling molecules. In mammals, P450 51 catalyzes the 3-step, 6-electron oxidation of lanosterol to form (4β,5α)-4,4-dimethyl-cholestra-8,14,24-trien-3-ol (FF-MAS). P450 51A1 can also use 24,25-dihydrolanosterol (a natural substrate in the Kandutsch-Russell cholesterol pathway). 24,25-Dihydrolanosterol and the corresponding P450 51A1 reaction intermediates, the 14α-alcohol and -aldehyde derivatives of dihydrolanosterol, were synthesized to study the kinetic processivity of the overall 14α-demethylation reaction of human P450 51A1. A combination of steady-state kinetic parameters, steady-state binding constants, dissociation rates of P450-sterol complexes, and kinetic modeling of the time course of oxidation of a P450 …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Nucleic Acids Research

Basis for the discrimination of supercoil handedness during DNA cleavage by human and bacterial type II topoisomerases

To perform double-stranded DNA passage, type II topoisomerases generate a covalent enzyme-cleaved DNA complex (i.e. cleavage complex). Although this complex is a requisite enzyme intermediate, it is also intrinsically dangerous to genomic stability. Consequently, cleavage complexes are the targets for several clinically relevant anticancer and antibacterial drugs. Human topoisomerase IIα and IIβ and bacterial gyrase maintain higher levels of cleavage complexes with negatively supercoiled over positively supercoiled DNA substrates. Conversely, bacterial topoisomerase IV is less able to distinguish DNA supercoil handedness. Despite the importance of supercoil geometry to the activities of type II topoisomerases, the basis for supercoil handedness recognition during DNA cleavage has not been characterized. Based on the results of benchtop and rapid-quench flow kinetics experiments, the forward …

Samuel M. Cohen

Samuel M. Cohen

University of Nebraska Medical Center

Donor Derived Cell-Free DNA as a Marker of Allograft Dysfunction in Pediatric Lung Transplant Recipients

PurposeDonor-derived cell-free DNA (dd-cfDNA) is utilized by some adult lung transplant (LTX) centers as a biomarker of allograft injury or dysfunction. An elevated level of dd-cfDNA may be predictive of acute cellular rejection, antibody mediated rejection (AMR), chronic lung allograft dysfunction , or acute infection. Therefore, dd-cfDNA may have a role as a surrogate test for graft surveillance versus invasive methods including bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy (TBBX). While there is an existing body of literature on the role of dd-cfDNA in adult LTX, there is limited understanding of its utility in pediatric patients. Non-invasive testing such as dd-cfDNA may be particularly helpful in young children with inherent challenges with TBBX.MethodsOur center performed three bilateral LTX in pediatric patients in which we used dd-cfDNA as an adjunctive method of graft surveillance …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Xenobiotica

The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants in vitro

1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C.2. Compared with that seen at 37 °C, the intrinsic clearance rates (Vmax/Km) of CYP2C9.1 and .2 were decreased (76 ∼ 82%), while that of CYP2C9.3 was unchanged at 34 °C. At 40 °C, CYP2C9.1, .2, and .3 exhibited increased (121%), unchanged and decreased (87%) intrinsic clearance rates, respectively. At 34 °C, the clearance rates of CYP2C19.1A and .10 were decreased (71 ∼ 86%), that of CYP2C19.1B was unchanged, and those of CYP2C19.8 and .23 were increased (130 ∼ 134%). At 40 …

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Food and Chemical Toxicology

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Trevor Penning

Trevor Penning

University of Pennsylvania

Food and Chemical Toxicology

RIFM fragrance ingredient safety assessment, 5-ethyl-2, 3, 4, 5-tetramethylcyclohexen-1-one, CAS Registry Number 17369-60-7

AM Api a,*, D. Belsito b, S. Bhatia a, M. Bruze c, P. Calow d, ML Dagli e, W. Dekant f, AD Fryer g, L. Kromidas a, S. La Cava a, JF Lalko a, A. Lapczynski a, DC Liebler h, Y. Miyachi i, VT Politano a, G. Ritacco a, D. Salvito a, TW Schultz j, J. Shen a, IG Sipes k, B. Wall a, DK Wilcox a a Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA b Member RIFM Expert Panel, Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USA c Member RIFM Expert Panel, Malmo University Hospital, Department of Occupational & Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo, SE 20502, Sweden d Member RIFM Expert Panel, Humphrey School of Public Affairs, University of Minnesota, 301 19th Avenue South, Minneapolis, MN 55455, USA e Member RIFM Expert Panel, University of Sao Paulo, School of Veterinary Medicine and Animal Science, Department of Pathology, Av. Prof. dr. Orlando Marques de Paiva, 87, Sao Paulo CEP 05508-900, Brazil f Member RIFM Expert Panel, University of Wuerzburg, Department of Toxicology, Versbacher Str. 9, 97078 Würzburg, Germany g Member RIFM Expert Panel, Oregon Health Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA h Member RIFM Expert Panel, Vanderbilt University School of Medicine, Department of Biochemistry, Center in Molecular Toxicology, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232-0146, USA i Member RIFM Expert Panel, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 …

Kalpana Joshi FMASc

Kalpana Joshi FMASc

Savitribai Phule Pune University

Food and Chemical Toxicology

RIFM fragrance ingredient safety assessment, 5-ethyl-2, 3, 4, 5-tetramethylcyclohexen-1-one, CAS Registry Number 17369-60-7

AM Api a,*, D. Belsito b, S. Bhatia a, M. Bruze c, P. Calow d, ML Dagli e, W. Dekant f, AD Fryer g, L. Kromidas a, S. La Cava a, JF Lalko a, A. Lapczynski a, DC Liebler h, Y. Miyachi i, VT Politano a, G. Ritacco a, D. Salvito a, TW Schultz j, J. Shen a, IG Sipes k, B. Wall a, DK Wilcox a a Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA b Member RIFM Expert Panel, Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USA c Member RIFM Expert Panel, Malmo University Hospital, Department of Occupational & Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo, SE 20502, Sweden d Member RIFM Expert Panel, Humphrey School of Public Affairs, University of Minnesota, 301 19th Avenue South, Minneapolis, MN 55455, USA e Member RIFM Expert Panel, University of Sao Paulo, School of Veterinary Medicine and Animal Science, Department of Pathology, Av. Prof. dr. Orlando Marques de Paiva, 87, Sao Paulo CEP 05508-900, Brazil f Member RIFM Expert Panel, University of Wuerzburg, Department of Toxicology, Versbacher Str. 9, 97078 Würzburg, Germany g Member RIFM Expert Panel, Oregon Health Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA h Member RIFM Expert Panel, Vanderbilt University School of Medicine, Department of Biochemistry, Center in Molecular Toxicology, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232-0146, USA i Member RIFM Expert Panel, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 …

Özkan Özden

Özkan Özden

Istanbul Üniversitesi

Food and Chemical Toxicology

Evaluation of biotoxins and toxic metal risks in mussels from the Sea of Marmara following marine mucilage

The mucilage phenomenon observed in the Sea of Marmara in 2021, has raised public concern about seafood safety. Mediterranean mussels serve as a vehicle in food chain, enabling the transfer of pollutants. Farmed and wild mussels were collected from 4 different stations throughout the fishing season. Biotoxins causing amnesic, paralytic, or diarrhetic shellfish poisonings (ASP, PSP, or DSP) were examined during monthly samplings. Potential health risks posed by cadmium, lead and arsenic were assessed. All health risks were evaluated considering 150 g/week mussel consumption considering different age groups of consumers (50, 60, 70 kg). Estimated Weekly Intake calculations of metals were determined to be lower than Provisional Tolerable Weekly Intake at all age groups throughout the sampling period in all stations. Target Hazard QuotientCd of mussels captured from Istanbul Strait was always …

Suzan Mansour

Suzan Mansour

Future University

Food and Chemical Toxicology

Sunset Yellow dye effects on gut microbiota, intestinal integrity, and the induction of inflammasomopathy with pyroptotic signaling in male Wistar rats

Although concern persists regarding possible adverse effects of consumption of synthetic azo food dyes, the mechanisms of any such effects remain unclear. We have tested the hypothesis that chronic consumption of the food dye Sunset Yellow (SY) perturbs the composition of the gut microbiota and alters gut integrity. Male rats were administered SY orally for 12 weeks. Analysis of fecal samples before and after dye administration demonstrated SY-induced microbiome dysbiosis. SY treatment reduced the abundance of beneficial taxa such as Treponema 2, Anaerobiospirillum, Helicobacter, Rikenellaceae RC9 gut group, and Prevotellaceae UCG-003, while increasing the abundance of the potentially pathogenic microorganisms Prevotella 2 and Oribacterium. Dysbiosis disrupted gut integrity, altering the jejunal adherens junction complex E-cadherin/β-catenin and decreasing Trefoil Factor (TFF)-3. SY …

Andre Luiz Radunz

Andre Luiz Radunz

Universidade Federal da Fronteira Sul

Food and chemical toxicology

Chemical composition, antimicrobial and antioxidant activities of broccoli, kale, and cauliflower extracts

In the present study, chemical compositions, antimicrobial and antioxidant activities of the essential oils of Sideritis erythrantha var. erythrantha (SE) and Sideritis erythrantha var. cedretorum (SC), which are endemic taxa in Turkey, were investigated. The essential oils obtained by hydrodistillation were analyzed by gas chromatography–mass spectrometry (GC–MS). α-Pinene was the major component of the essential oils of SC and SE. SC essential oil was as effective as antibiotic against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus faecalis (VRE), ampicillin resistant Haemophilusinfluenzae and vancomycin sensitive E. faecalis. Similarly, SE essential oil was also as effective as antibiotic against VRE and ampicillin resistant H. influenzae. Antioxidant activities of the essential oils of SC and SE were determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH), β-carotene/linoleic …

Richard B van Breemen

Richard B van Breemen

Oregon State University

Food and Chemical Toxicology

Advancing botanical safety: A strategy for selecting, sourcing, and characterizing botanicals for developing toxicological tools

Increases in botanical use, encompassing herbal medicines and dietary supplements, have underlined a critical need for an advancement in safety assessment methodologies. However, botanicals present unique challenges for safety assessment due to their complex and variable composition arising from diverse growing conditions, processing methods, and plant varieties. Historically, botanicals have been largely evaluated based on their history of use information, based primarily on traditional use or dietary history. However, this presumption lacks comprehensive toxicological evaluation, demanding innovative and consistent assessment strategies. To address these challenges, the Botanical Safety Consortium (BSC) was formed as an international, cross-sector forum of experts to identify fit-for purpose assays that can be used to evaluate botanical safety. This global effort aims to assess botanical safety …

Lorella Marinucci

Lorella Marinucci

Università degli Studi di Perugia

Food and Chemical Toxicology

Acute and chronic cannabidiol treatment: In vitro toxicological aspects on human oral cells

Cannabidiol is gaining increasing interest for its potential anti-inflammatory, immunomodulatory, and antineoplastic effects. The purpose of this study is to investigate the biological effects of acute and chronic CBD administration on gingival fibroblasts and oral keratinocytes.Viability, morphology, migration, apoptosis and cell cycle, and expression of related genes (p53, BCL2, p21, and BAX) and of endocannabinoid system receptors (CB1, CB2 and GPR55) with real-time PCR and DNA damage with phospho-γ-H2AX immunofluorescence detection were analyzed. Concentrations between 100 μM and 0.001 μM were used: 50 μM (toxic dose), 25 μM (viability promoter), and 1 μM (nontoxic), were selected for subsequent chronic analysis.Acute treatment reveals significant effects than chronic, in particular in fibroblasts: concentrations ≥50 μM are highly cytotoxic, with increased apoptosis and reduced migration …

Chiara Dall'Asta

Chiara Dall'Asta

Università degli Studi di Parma

Food and Chemical Toxicology

The burden of disease due to dietary exposure to acrylamide in Italy: a risk assessment-based approach

The aim of this study was to assess Italian consumers’ risk of cancer and burden of disease due to dietary exposure to acrylamide. Our model considered six age groups such as infants, toddlers, other children, adolescents, adults, and the elderly, and the consumption of 31 food items. Using a risk-assessment-based approach, we first characterized the risk of neoplastic effects using the margin of exposure method. Then the risk of kidney, endometrial, breast, ovarian cancer, and total cancer was estimated using adjusted cancer slope factors while the burden of disease was quantified using Disability-adjusted Life Years (DALYs). The highest risk for females was related to breast cancer while the lowest was for kidney cancer. We found a comparable risk of total cancer among Italian males and females, estimated at around 1.59 to 3.57 cases per 100,000 individuals annually with the burden ranging between 12.3 …

G. Allen Burton

G. Allen Burton

University of Michigan

Food and Chemical Toxicology

RIFM fragrance ingredient safety assessment, pyridine, 5-hexyl-2-methyl-, CAS Registry Number 710-40-7

ReP USP - Detalhe do registro: RIFM fragrance ingredient safety assessment, pyridine, 5-hexyl-2-methyl-, CAS Registry Number 710-40-7 Home About USP Schools USP Schools Escola de Artes, Ciências e Humanidades (EACH) Escola de Comunicações e Artes (ECA) Escola de Enfermagem (EE) Escola de Enfermagem de Ribeirão Preto (EERP) Escola de Educação Física e Esporte (EEFE) Escola de Educação Física e Esporte de Ribeirão Preto (EEFERP) Escola de Engenharia de Lorena (EEL) Escola de Engenharia de São Carlos (EESC) Escola Politécnica (EP) Escola Superior de Agricultura Luiz de Queiroz (ESALQ) Faculdade de Arquitetura e Urbanismo (FAU) Faculdade de Ciências Farmacêuticas (FCF) Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP) Faculdade de Direito (FD) Faculdade de Direito de Ribeirão Preto (FDRP) Faculdade de Economia, Administração, Contabilidade e …

Liang Ma

Liang Ma

Southwest University

Food and Chemical Toxicology

Transgenerational toxicity induced by maternal AFB1 exposure in Caenorhabditis elegans associated with underlying epigenetic regulations

Aflatoxin B1 (AFB1), usually seriously contaminates in grain and oil foods or feed, displayed significant acute and chronic toxic effects in human and animal populations. However, little is known about the transgenerational toxic effects induced by a maternal AFB1 intake at a lower dose on offspring. In our study, only parental wild-type Caenorhabditis elegans was exposed to AFB1 (0–8 μg/ml) and the following three filial generations were grown on AFB1-free NGM. Results showed that the toxic effects of AFB1 on the growth (body length) and reproduction (brood size, generation time and morphology of gonad arm) can be transmitted through generations. Moreover, the levels of MMP and ATP were irreversibly inhibited in the filial generations. By using RNomics and molecular biology techniques, we found that steroid biosynthesis, phagosome, valine/leucine/isoleucine biosynthesis and oxidative phosphorylation (p …

Phisit Khemawoot

Phisit Khemawoot

Mahidol University

Food and Chemical Toxicology

Sub-chronic oral toxicity of a water-soluble extract of Centella asiatica (Centell-S) in Wistar rats

BackgroundCentell-S, a water-soluble extract from Centella asiatica, is predominantly composed of madecassoside and asiaticoside, exceeding 80% w/w. Pursuing its development as an herbal medicinal product, Centell-S underwent sub-chronic toxicity assessment adhering to OECD GLP 408 standards.MethodsIn a study involving 100 Wistar rats, varying doses of Centell-S (50, 200, or 800 mg/kg/day) or a vehicle control were administered orally over 90 days. To evaluate Centell-S's safety profile, assessments included clinical observations, health examinations, clinical biochemistry analyses, and detailed anatomical pathology evaluations were conducted.ResultsOver the 90 days of treatment, the administration of Centell-S did not lead to any fatalities in the test animals. Clinical observations did not reveal any signs indicative of toxic effects. Notably, an increase in total white blood cell and lymphocyte counts …

Naveed Ahmad

Naveed Ahmad

Università degli Studi di Napoli Federico II

Food and Chemical Toxicology

Histotoxicity induced by copper oxide nanoparticles (CuO-NPs) on developing mice (Mus musculus)

The wide range of applications of nanoparticles (NPs) in various industries have led to serious consequences in terms of teratogenic toxicity. The aim of current work was to evaluate the teratogenic effects of copper oxide (CuO) nanoparticles in albino mice.In this experimental study, after mating, inseminated 40 female mice were divided randomly into 4 pools (1 control and 3 experimental), ten each. Doses were administered intravenously (We followed the protocol by Yaqub et al. (2018), intravenous application is faster route as compared to oral dosage)to all the experimental groups on the 6th day of gestation (GD), dose concentrations were 200, 133.3 and 100 mg/kg body weights respectively.The doses were prepared in sequence (1/2, 1/3, 1/4 0f LD50) according to already published work. The effects of CuO-NPs show linear relationship with the above sequence. The control group was administered only with …

Reza Mahmoud Robati

Reza Mahmoud Robati

Shahid Beheshti University of Medical Sciences

Food and Chemical Toxicology

Screening the critical protein subnetwork to delineate potential mechanisms and protective agents associated with arsenic-induced cutaneous squamous cell carcinoma: A …

Recent studies show that complex mechanisms are involved in arsenic-induced malignant transformation of cells. This study aimed to decipher molecular mechanisms associated with arsenic-induced cutaneous squamous cell carcinoma (cSCC) and suggest potential protective factors. RNA-seq-based differentially expressed genes between arsenic-exposed human keratinocytes (HaCaT) and controls were used to construct a protein-protein interaction (PPI) network and discover critical subnetwork-based mechanisms. Protective compounds against arsenic toxicity were determined and their target interactions in the core sub-network were identified by the comparative toxicogenomic database (CTD). The binding affinity between the effective factor and target was calculated by molecular docking. A total of 15 key proteins were screened out as critical arsenic-responsive subnetwork (FN1, IL-1A, CCN2, PECAM1 …

Shaymaa Rezk

Shaymaa Rezk

Mansoura University

Food and Chemical Toxicology

Curcumin mitigates gentamicin induced-renal and cardiac toxicity via modulation of Keap1/Nrf2, NF-κB/iNOS and Bcl-2/BAX pathways

Gentamicin (GEN) is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Our study aimed to explore curcumin's (CMN) protective role against GEN-induced renal and cardiac toxicity. Rats were randomly classified into 4 equal groups; Control (cont), GEN (100 mg/kg b.wt, i.p.) for seven days, CMN (200 mg/kg b.wt, orally) for 21 days, and CMN + GEN groups. GEN caused renal and cardiac dysfunctions; increased urea, creatinine, uric acid, cystatin C, CK-MB, LDH, and troponin I serum levels. MDA level was elevated significantly while activities of SOD, CAT, and GSH level were reduced significantly in renal and cardiac tissues. GEN-intoxicated rats showed up-regulation of NF-κB, IL-1β, Keap1, HMOX1, and BAX with down-regulation of Nrf2, and Bcl-2 mRNA expression in renal and cardiac tissues. Also, GEN-induced up-regulation of renal mRNA expression of KIM-1, NGAL, and …

Mostafa Rezaei-Tavirani

Mostafa Rezaei-Tavirani

Shahid Beheshti University of Medical Sciences

Food and Chemical Toxicology

Screening the critical protein subnetwork to delineate potential mechanisms and protective agents associated with arsenic-induced cutaneous squamous cell carcinoma: A …

Recent studies show that complex mechanisms are involved in arsenic-induced malignant transformation of cells. This study aimed to decipher molecular mechanisms associated with arsenic-induced cutaneous squamous cell carcinoma (cSCC) and suggest potential protective factors. RNA-seq-based differentially expressed genes between arsenic-exposed human keratinocytes (HaCaT) and controls were used to construct a protein-protein interaction (PPI) network and discover critical subnetwork-based mechanisms. Protective compounds against arsenic toxicity were determined and their target interactions in the core sub-network were identified by the comparative toxicogenomic database (CTD). The binding affinity between the effective factor and target was calculated by molecular docking. A total of 15 key proteins were screened out as critical arsenic-responsive subnetwork (FN1, IL-1A, CCN2, PECAM1 …

Maarten Nauta

Maarten Nauta

Danmarks Tekniske Universitet

Food and Chemical Toxicology

Evaluating the health impact of increased linseed consumption in the Danish population

Consumption of linseeds has been suggested to have beneficial effects on human health. However, toxic constituents of linseed may compromise these benefits. We conducted a quantitative risk-benefit assessment to evaluate the overall health impact of increasing linseed intake up to 45 g/day in the Danish population (15–74 years). We quantified the risks associated with increased cadmium exposure and the benefits associated with increased intake of dietary fibre. Increased intakes of alpha-linoleic acid (ALA) were included in a sensitivity analysis. The overall health impact of different linseed intake scenarios was estimated in terms of Disability-Adjusted Life Years (DALYs). We found that the beneficial effects of linseed due to increased intake of dietary fibre outweighed the adverse health effects due to increased cadmium exposure in all scenarios. Up to 670 DALYs/100,000 individuals could be averted per …