The present study describes the selection, analysis and risk assessment of genotoxic and carcinogenic ingredients of botanicals and botanical preparations which can be found in food and plant food supplements (PFS). F...The present study describes the selection, analysis and risk assessment of genotoxic and carcinogenic ingredients of botanicals and botanical preparations which can be found in food and plant food supplements (PFS). First an inventory was made of botanical ingredients that are of possible concern for human health because of their genotoxic and/or carcinogenic properties. In total, 30 botanical ingredients were selected and subsequently judged for their actual genotoxic and/or carcinogenic potential. Among the 30 compounds considered, 18 compounds were judged to be both genotoxic and carcinogenic. Interestingly, the majority of these compounds belong to the group of alkenylbenzenes or unsaturated pyrrolizidine alkaloids. Subsequently, based on available carcinogenicity data and estimated daily human exposure that was determined focusing on the intake from PFS, the Margin of Exposure (MOE) was calculated for the alkenylbenzenes estragole, methyleugenol, safrole and β-asarone. Calculating the MOEs for intake estimates of these alkenylbenzenes from PFS resulted in MOE values that were generally lower than 10,000 and often lower than 100. In some cases the MOE was even below 10 meaning that the estimated daily intake is in the range of dose levels causing malignant tumors in experimental animals. This result indicates that the use of PFS containing the genotoxic carcinogens estragole, methyleugenol, safrole or β-asarone might raise a potential concern for human health and would be of high priority for risk management.展开更多
目的:致癌性试验是药物非临床安全性评价和上市风险控制的重要组成部分,由于其试验周期长、费用高,且试验设计、实施以及结果评估和解释十分复杂,FDA要求申办方在致癌性试验正式开展前,预先向药品审评中心(CDER)提交"特别方案评估&...目的:致癌性试验是药物非临床安全性评价和上市风险控制的重要组成部分,由于其试验周期长、费用高,且试验设计、实施以及结果评估和解释十分复杂,FDA要求申办方在致癌性试验正式开展前,预先向药品审评中心(CDER)提交"特别方案评估"(Special Protocol Assessment,SPA)的申请文件,针对拟开展的啮齿动物致癌性试验设计,征求FDA的审评意见。本文将详细介绍并探讨美国FDA关于致癌性试验SPA的流程及相关法规的要点,以期为国内药物研发机构、临床前合同研究组织(Contract Research Organization,CRO)、注册申报机构以及监管机构提供参考。方法:结合FDA致癌性试验"特别方案评估"指导原则的要求和相关工作经验,从致癌性试验方案提交FDA审评部门前的准备、提交程序、SPA审评文件材料内容的关注要点,以及FDA相关审评部门和致癌性评估执行委员会(ECAC)内部审评流程等方面予以介绍。结果与结论:申办方应了解并熟悉致癌性试验SPA文件提交和评估的过程,并严格按照法规要求,加强与监管部门的沟通交流,从而获取科学性意见和建议,为顺利开展长期致癌性试验提供帮助。展开更多
The concentration of carcinogenic polycyclic aromatic hydrocarbons （c-PAHs） present in the sediment and water of Peninsular Malaysia as well as in the cockle Anadara granosa was investigated. Samples were extracted ...The concentration of carcinogenic polycyclic aromatic hydrocarbons （c-PAHs） present in the sediment and water of Peninsular Malaysia as well as in the cockle Anadara granosa was investigated. Samples were extracted and analysed with gas chromatographymass spectrometry. The concentrations of total carcinogenic polycyclic aromatic hydrocarbons （t-PAHs） were measured between 0.80±0.04 to 162.96 ±14.74 ng/g wet weight （ww） in sediment, between 21.85± 2.18 to 76.2± 10.82 ng/L in water samples and between 3.34 ±0.77 to 46.85 ± 5.50 ng/g ww in the cockle tissue. The risk assessment of probable human carcinogens in the Group B2 PAHs was calculated and assessed in accordance with the standards of the United States Environmental Protection Agency （US EPA）. Case I in the toxicity assessment analysed the cancer risk to consumers of Malaysian blood cockle. Case II assessed the risk of cancer from exposure to PAHs from multiple pathways. The average cancer risk of case I and case II were found to be classifiable as unsafe according to the US EPA standard. The cancer risk due to c-PAHs acquired by the ingestion of blood cockle was （8.82 ± 0.54） × 10^ 6 to （2.67 ± 0.06） × 10^-2, higher than the US EPA risk management criterion. The non-cancer risks associated with multiple pathways in Kuala Gula, Kuala Juru and Kuala Perlis were higher than the US EPA safe level, but the non-cancer risk for eating blood cockle was below the level of US EPA concern.展开更多
文摘The present study describes the selection, analysis and risk assessment of genotoxic and carcinogenic ingredients of botanicals and botanical preparations which can be found in food and plant food supplements (PFS). First an inventory was made of botanical ingredients that are of possible concern for human health because of their genotoxic and/or carcinogenic properties. In total, 30 botanical ingredients were selected and subsequently judged for their actual genotoxic and/or carcinogenic potential. Among the 30 compounds considered, 18 compounds were judged to be both genotoxic and carcinogenic. Interestingly, the majority of these compounds belong to the group of alkenylbenzenes or unsaturated pyrrolizidine alkaloids. Subsequently, based on available carcinogenicity data and estimated daily human exposure that was determined focusing on the intake from PFS, the Margin of Exposure (MOE) was calculated for the alkenylbenzenes estragole, methyleugenol, safrole and β-asarone. Calculating the MOEs for intake estimates of these alkenylbenzenes from PFS resulted in MOE values that were generally lower than 10,000 and often lower than 100. In some cases the MOE was even below 10 meaning that the estimated daily intake is in the range of dose levels causing malignant tumors in experimental animals. This result indicates that the use of PFS containing the genotoxic carcinogens estragole, methyleugenol, safrole or β-asarone might raise a potential concern for human health and would be of high priority for risk management.
文摘目的:致癌性试验是药物非临床安全性评价和上市风险控制的重要组成部分,由于其试验周期长、费用高,且试验设计、实施以及结果评估和解释十分复杂,FDA要求申办方在致癌性试验正式开展前,预先向药品审评中心(CDER)提交"特别方案评估"(Special Protocol Assessment,SPA)的申请文件,针对拟开展的啮齿动物致癌性试验设计,征求FDA的审评意见。本文将详细介绍并探讨美国FDA关于致癌性试验SPA的流程及相关法规的要点,以期为国内药物研发机构、临床前合同研究组织(Contract Research Organization,CRO)、注册申报机构以及监管机构提供参考。方法:结合FDA致癌性试验"特别方案评估"指导原则的要求和相关工作经验,从致癌性试验方案提交FDA审评部门前的准备、提交程序、SPA审评文件材料内容的关注要点,以及FDA相关审评部门和致癌性评估执行委员会(ECAC)内部审评流程等方面予以介绍。结果与结论:申办方应了解并熟悉致癌性试验SPA文件提交和评估的过程,并严格按照法规要求,加强与监管部门的沟通交流,从而获取科学性意见和建议,为顺利开展长期致癌性试验提供帮助。
基金supported by the MOSTI Science Funding Project(No. 5450100)
文摘The concentration of carcinogenic polycyclic aromatic hydrocarbons （c-PAHs） present in the sediment and water of Peninsular Malaysia as well as in the cockle Anadara granosa was investigated. Samples were extracted and analysed with gas chromatographymass spectrometry. The concentrations of total carcinogenic polycyclic aromatic hydrocarbons （t-PAHs） were measured between 0.80±0.04 to 162.96 ±14.74 ng/g wet weight （ww） in sediment, between 21.85± 2.18 to 76.2± 10.82 ng/L in water samples and between 3.34 ±0.77 to 46.85 ± 5.50 ng/g ww in the cockle tissue. The risk assessment of probable human carcinogens in the Group B2 PAHs was calculated and assessed in accordance with the standards of the United States Environmental Protection Agency （US EPA）. Case I in the toxicity assessment analysed the cancer risk to consumers of Malaysian blood cockle. Case II assessed the risk of cancer from exposure to PAHs from multiple pathways. The average cancer risk of case I and case II were found to be classifiable as unsafe according to the US EPA standard. The cancer risk due to c-PAHs acquired by the ingestion of blood cockle was （8.82 ± 0.54） × 10^ 6 to （2.67 ± 0.06） × 10^-2, higher than the US EPA risk management criterion. The non-cancer risks associated with multiple pathways in Kuala Gula, Kuala Juru and Kuala Perlis were higher than the US EPA safe level, but the non-cancer risk for eating blood cockle was below the level of US EPA concern.
