A weight of evidence evaluation of the mode of action of isoeugenol

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology Pub Date : 2024-05-11 DOI:10.1016/j.yrtph.2024.105642

William J. Brock , Tracy Greene , Cynthia Van Landingham , Robinan Gentry

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引用次数: 0

Abstract

Isoeugenol is one of several phenylpropenoid compounds that is used as a fragrance, food flavoring agent and in aquaculture as a fish anesthetic. Carcinogenicity testing in rats and mice by NTP resulted in clear evidence of carcinogenicity (hepatic adenomas/carcinomas) in male mice only. A nongenotoxic threshold mode of action (MOA) is postulated for isoeugenol and is discussed considering the IPCS MOA and Human Relevance Framework. The weight of evidence indicates that isoeugenol is not genotoxic and that the carcinogenic outcome in male mice relates directly to the metabolism of individual compounds. Benchmark Dose (BMD) modeling was conducted to determine a Point of Departure (POD) and potential threshold of carcinogenicity. The results of the BMD evaluation for isoeugenol resulted in an estimated POD for carcinogenicity in the male mouse of 8 mg/kg with a lower limit of 4 mg/kg, representing a POD for the determination of an acceptable daily intake. With application of uncertainty factors, an ADI of 40 μg/kg is calculated. This daily dose in humans would be protective of human health, including carcinogenicity. A corresponding maximum residual level (MRL) of 3200 μg/kg fish is also estimated based on this POD that considers the threshold MOA.

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异丁香酚作用模式的证据权重评估。

异丁香酚是几种苯基丙烯化合物之一，被用作香料、食品调味剂和水产养殖中的鱼类麻醉剂。NTP 在大鼠和小鼠中进行的致癌性测试结果显示，只有雄性小鼠有明确的致癌证据（肝腺瘤/癌）。根据国际化学品安全方案的作用方式和人类相关性框架，推测异丁香酚具有非致癌阈值作用方式（MOA）。大量证据表明，异丁香酚不具有遗传毒性，雄性小鼠的致癌结果与单个化合物的新陈代谢直接相关。进行了基准剂量（BMD）建模，以确定致癌的出发点（POD）和潜在阈值。异丁香酚的基准剂量评估结果表明，雄性小鼠的估计致癌出发点剂量为 8 毫克/千克，下限为 4 毫克/千克，这是确定每日可接受摄入量的出发点剂量。应用不确定性因子计算得出的每日允许摄入量为 40 μg/kg。人体每日摄入这一剂量可保护人体健康，包括致癌作用。在考虑了阈值 MOA 的 POD 基础上，还估算出相应的最大残留量 (MRL) 为 3200 μg/kg。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Regulatory Toxicology and Pharmacology 医学-毒理学

CiteScore

6.70

自引率

8.80%

发文量

147

审稿时长

58 days

期刊介绍： Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health. Types of peer-reviewed articles published: -Original research articles of relevance for regulatory aspects covering aspects including, but not limited to: 1.Factors influencing human sensitivity 2.Exposure science related to risk assessment 3.Alternative toxicological test methods 4.Frameworks for evaluation and integration of data in regulatory evaluations 5.Harmonization across regulatory agencies 6.Read-across methods and evaluations -Contemporary Reviews on policy related Research issues -Letters to the Editor -Guest Editorials (by Invitation)