Flavor and Extract Manufacturers Association

Washington, DC, United States

Flavor and Extract Manufacturers Association

Washington, DC, United States
SEARCH FILTERS
Time filter
Source Type

Alhusainy W.,Wageningen University | Alhusainy W.,Nestlé | van den Berg S.J.P.L.,Wageningen University | Paini A.,Wageningen University | And 11 more authors.
Toxicological Sciences | Year: 2012

The alkenylbenzene estragole is a constituent of several herbs and spices. It induces hepatomas in rodents at high doses following bioactivation by cytochrome P450s and sulfotransferases (SULTs) giving rise to the ultimate carcinogenic metabolite 1'-sulfooxyestragole which forms DNA adducts. Methanolic extracts from different alkenylbenzene-containing herbs and spices were able to inhibit SULT activity. Flavonoids including quercetin, kaempferol, myricetin, apigenin, and nevadensin were the major constituents responsible for this inhibition with Ki values in the nano to micromolar range. In human HepG2 cells exposed to the proximate carcinogen 1'-hydroxyestragole, the various flavonoids were able to inhibit estragole DNA adduct formation and shift metabolism in favor of glucuronidation which is a detoxification pathway for 1'-hydroxyestragole. In a next step, the kinetics for SULT inhibition were incorporated in physiologically based biokinetic (PBBK) models for estragole in rat and human to predict the effect of co-exposure to estragole and (mixtures of) the different flavonoids on the bioactivation in vivo. The PBBK-model-based predictions indicate that the reduction of estragole bioactivation in rat and human by co-administration of the flavonoids is dependent on whether the intracellular liver concentrations of the flavonoids can reach their Ki values. It is expected that this is most easily achieved for nevadensin which has a Ki value in the nanomolar range and is, due to its methylation, more metabolically stable than the other flavonoids.


Adams T.B.,Flavor and Extract Manufacturers Association | Gavin C.L.,Flavor and Extract Manufacturers Association | McGowen M.M.,Flavor and Extract Manufacturers Association | Waddell W.J.,University of Louisville | And 7 more authors.
Food and Chemical Toxicology | Year: 2011

This publication is the thirteenth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Since then, the number of flavoring substances has grown to more than 2600 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic and aromatic terpene hydrocarbons as flavoring ingredients are evaluated. The group of aliphatic and aromatic terpene hydrocarbons was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic potential. © 2011 Elsevier Ltd.


Alhusainy W.,Wageningen University | Alhusainy W.,New York Medical College | Williams G.M.,New York Medical College | Jeffrey A.M.,New York Medical College | And 4 more authors.
Food and Chemical Toxicology | Year: 2014

The alkenylbenzene methyleugenol occurs naturally in a variety of spices and herbs, including basil, and their essential oils. At high dose levels methyleugenol induces hepatocarcinogenicity in rodents following bioactivation to 1'-sulfooxymethyleugenol which forms DNA adducts. This study investigated whether the inhibitory effect of the basil flavonoid nevadensin on sulfotransferase (SULT)-mediated bioactivation of methyleugenol observed in vitro would also be reflected in a reduction of DNA adduct formation and a reduction in an early marker for liver carcinogenesis in an 8-week rat study. Co-exposure to methyleugenol and nevadensin orally resulted in a significant inhibition of liver methyleugenol DNA adduct formation and in inhibition of hepatocellular altered foci induction, representing indicators for initiation of neoplasia. These results suggest that tumor formation could be lower in rodent bioassays when methyleugenol would be dosed in a matrix containing SULT inhibitors such as nevadensin compared to experiments using the pure methyleugenol. © 2014 Elsevier Ltd.


Alhusainy W.,Wageningen University | Alhusainy W.,Nestlé | Paini A.,Wageningen University | Paini A.,Nestlé | And 9 more authors.
Molecular Nutrition and Food Research | Year: 2013

Scope: The present work investigates whether the previous observation that the basil flavonoid nevadensin is able to inhibit sulfotransferase (SULT)-mediated estragole DNA adduct formation in primary rat hepatocytes could be validated in vivo. Methods and results: Estragole and nevadensin were co-administered orally to Sprague-Dawley rats, at a ratio reflecting their presence in basil. Moreover, previously developed physiologically based biokinetic (PBBK) models to study this inhibition in rat and in human liver were refined by including a submodel describing nevadensin kinetics. Nevadensin resulted in a significant 36% reduction in the levels of estragole DNA adducts formed in the liver of rats. The refined PBBK model predicts the formation of estragole DNA adducts in the liver of rat with less than twofold difference compared to in vivo data and suggests more potent inhibition in the liver of human compared to rat due to less efficient metabolism of nevadensin in human liver and intestine. Conclusion: Given the role of the SULT-mediated DNA adduct formation in the hepatocarcinogenicity of estragole, the results of the present study suggest that the likelihood of bioactivation and subsequent adverse effects in rodent bioassays may be lower when estragole is dosed with nevadensin compared to dosing of pure estragole. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Alhusainy W.,Wageningen University | Alhusainy W.,Nestlé | Paini A.,Wageningen University | Paini A.,Nestlé | And 11 more authors.
Toxicology and Applied Pharmacology | Year: 2010

Estragole is a natural constituent of several herbs and spices including sweet basil. In rodent bioassays, estragole induces hepatomas, an effect ascribed to estragole bioactivation to 1′-sulfooxyestragole resulting in DNA adduct formation. The present paper identifies nevadensin as a basil constituent able to inhibit DNA adduct formation in rat hepatocytes exposed to the proximate carcinogen 1′-hydroxyestragole and nevadensin. This inhibition occurs at the level of sulfotransferase (SULT)-mediated bioactivation of 1′-hydroxyestragole. The Ki for SULT inhibition by nevadensin was 4. nM in male rat and human liver fractions. Furthermore, nevadensin up to 20μM did not inhibit 1′-hydroxyestragole detoxification by glucuronidation and oxidation. The inhibition of SULT by nevadensin was incorporated into the recently developed physiologically based biokinetic (PBBK) rat and human models for estragole bioactivation and detoxification. The results predict that co-administration of estragole at a level inducing hepatic tumors in vivo (50. mg/kg bw) with nevadensin at a molar ratio of 0.06, representing the ratio of their occurrence in basil, results in almost 100% inhibition of the ultimate carcinogen 1′-sulfooxyestragole when assuming 100% uptake of nevadensin. Assuming 1% uptake, inhibition would still amount to more than 83%. Altogether these data point at a nevadensin-mediated inhibition of the formation of the ultimate carcinogenic metabolite of estragole, without reducing the capacity to detoxify 1′-hydroxyestragole via glucuronidation or oxidation. These data also point at a potential reduction of the cancer risk when estragole exposure occurs within a food matrix containing SULT inhibitors compared to what is observed upon exposure to pure estragole. © 2010 Elsevier Inc.


Da rocha M.S.,University of Nebraska Medical Center | Da rocha M.S.,São Paulo State University | Dodmane P.R.,University of Nebraska Medical Center | Dodmane P.R.,São Paulo State University | And 8 more authors.
Toxicological Sciences | Year: 2012

Essential oils from mint plants, including peppermint and pennyroyal oils, are used at low levels as flavoring agents in various foods and beverages. Pulegone is a component of these oils. In a 2-year bioassay, oral administration of pulegone slightly increased the urothelial tumor incidence in female rats. We hypothesized that its mode of action (MOA) involved urothelial cytotoxicity and increased cell proliferation, ultimately leading to tumors. Pulegone was administered by gavage at 0, 75, or 150 mg/kg body weight to female rats for 4 and 6 weeks. Fresh void urine and 18-h urine were collected for crystal and metabolite analyses. Urinary bladders were evaluated by light microscopy and scanning electron microscopy (SEM) and bromodeoxyuridine (BrdU) labeling index. Pulegone and its metabolites, piperitenone, piperitone, menthofuran, and menthone, were tested for cytotoxicity in rat (MYP3) and human (1T1) urothelial cells by the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. No abnormal urinary crystals were observed by light microscopy. Urine samples (18-h) showed the presence of pulegone, piperitone, piperitenone, and menthofuran in both treated groups. By SEM, bladders from treated rats showed superficial necrosis and exfoliation. There was a significant increase in the BrdU labeling index in the high-dose group. In vitro studies indicated that pulegone and its metabolites, especially piperitenone, are excreted and concentrated in the urine at cytotoxic levels when pulegone is administered at high doses to female rats. The present study supports the hypothesis that cytotoxicity followed by regenerative cell proliferation is the MOA for pulegone-induced urothelial tumors in female rats. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


PubMed | University of Minnesota, Flavor and Extract Manufacturers Association, Imperial College London, Vanderbilt University and 3 more.
Type: Review | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

p-Mentha-1,8-dien-7-al is a naturally occurring cyclic alpha,beta-unsaturated aldehyde that is used as a flavoring substance throughout the world. Due to the chemical structure and the potential DNA reactivity of the alpha,beta-unsaturated carbonyl moiety, a battery of genotoxicity assays was requested by the European Food Safety Authority. Previous genotoxicity studies on the substance gave mixed results, but both positive and negative results were hampered by not always being performed to any standard guideline. The new test battery data indicated some evidence of mutagenicity invitro, but an invivo comet/micronucleus combination assay performed in rats was concluded by the study directors to not result in any biologically relevant positive responses. However, EFSA concluded that the invivo assay gave evidence that p-mentha-1,8-dien-7-al was of potential genotoxic concern. The Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) has reviewed the newly available data and considered its interpretation relative to standard guidelines such as that established by the Organization for Economic Cooperation and Development, and has concluded that the results in the comet/micronucleus combination assay are consistent with the interpretation by the study directors; namely, that p-mentha-1,8-dien-7-al does not appear to have any invivo genotoxic potential.


PubMed | University of Minnesota, Flavor and Extract Manufacturers Association, Imperial College London, Vanderbilt University and 3 more.
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

This publication is the second in a series by the Expert Panel of the Flavor and Extract Manufacturers Association summarizing the conclusions of its third systematic re-evaluation of the safety of flavorings previously considered to be generally recognized as safe (GRAS) under conditions of intended use. Re-evaluation of GRAS status for flavorings is based on updated considerations of exposure, structural analogy, metabolism, pharmacokinetics and toxicology and includes a comprehensive review of the scientific information on the flavorings and structurally related substances. Of the 12 substituted thiophenes reviewed here, 11 were reaffirmed as GRAS based on their rapid absorption, metabolism and excretion in humans and animals; the low estimated dietary exposure from flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels; and the lack of significant genotoxic and mutagenic potential. For one of the substituted thiophenes, 3-acetyl-2,5-dimethylthiophene, it was concluded that more detailed exposure information, comparative metabolism studies and comprehensive toxicity data, including an in-depth evaluation of the mechanism of action for any adverse effects observed, are required for continuation of its FEMA GRAS status. In the absence of these data, the compound was removed from the FEMA GRAS list.

Loading Flavor and Extract Manufacturers Association collaborators
Loading Flavor and Extract Manufacturers Association collaborators