啮齿类动物致癌实验中增生性病变的病理学评估现状

目的介绍啮齿类动物致癌实验中增生性病变的评估现状,进而阐明增生性病变在人类致癌风险性评估中的重要作用。方法从增生性病变在致癌实验中的意义入手,进一步阐述致癌实验的病理学诊断过程中对增生性病变的评价现状、增生性病变与肿瘤发生的关系以及对增生性病变评价方法的定性使用。结果增生是致癌性评估中"重要证据"的组成部分。准确评估与肿瘤产生相关的增生性病变对于某一受试物种致癌风险性的确定以及最终确定对人类致癌性的潜在风险是至关重要的。结论为从事致癌风险性识别及评估工作的毒理学家、病理学家和其他科学家们提供与致癌风险性评价相关的资料,为客观、准确地评价化合物的致癌风险性提供重要的参考信息。     

药物致癌性的机制研究

 动物致癌性试验是药物非临床安全性评价的重要内容之一,在我国起步相对较晚。随着我国新药创制及相关领域的不断发展,初步具备了进行致癌性评价的条件。机制研究是致癌性评价的重要内容,结合暴露量分析、适应症与患者人群特征、同类化合物致癌性特征等进行利弊权衡,综合评估对人体的潜在风险,并最终通过说明书等方式进行风险控制。目前国际上正在着力于致癌机制的探索,有些已经被药品评价机构接受。文中对一些常见的机制研究进行总结分析,包括遗传毒性机制、药理学作用相关机制、苯巴比妥样CYP450诱导作用、致癌组织的种属差异等,以期为我国药物致癌性评价提供一定参考。     

药物致癌试验中常用动物历史对照数据研究进展

致癌试验是新药非临床安全性评价的重要内容,其目的是通过考察药物对动物的潜在致癌作用,以评价和预测人体在长期用药中的致癌风险。在致癌试验中,啮齿类动物不同品系的历史对照数据对解释罕见肿瘤和发病率异常的肿瘤非常有用。国外权威试验机构依靠病理工作组和同行评议结果,积累了相关动物大量的有价值的病理历史对照数据,从早期使用较多的F344大鼠和B6C3F1小鼠,到后来的SD大鼠、CD-1小鼠和Wistar大鼠,再到近年来广泛使用的p53~(+/-)和rasH2转基因小鼠,不同品系动物肿瘤发生具有不同的特点。目前,国内致癌试验日益增多,但可参照的背景数据仍然较少,如何正确积累和使用历史数据成为国内同行的一大难题。本文通过归纳和对比文献报道的实验动物肿瘤性病变的种类和发生率,发现不同品系啮齿类动物的肿瘤谱不同,且存在雌雄差异。相关背景数据丰富了致癌试验中自发性肿瘤历史对照数据,为致癌试验的开展提供支持。     

药物中、短期致癌试验的研究进展

啮齿类致癌性试验是创新药物安全性评价和上市风险控制内容的重要组成部分。新药上市申请时通常需提供必要的整体动物致癌性试验结果。对于明显存在可能引起致癌风险的情况,药政管理部门均要求在早期提交该项试验结果以支持长期用药的临床试验。而愈来愈多的证据表明,利用2种啮齿类动物评价药物致癌风险的经典范例存在诸多的局限性     

家兔用于药物生殖发育毒性评价的研究进展

生殖发育毒性评价是药物安全性评价的重要组成部分。家兔属兔科兔形目,是药物生殖发育毒性评价的非啮齿类哺乳动物模型之一,但是其相关研究较啮齿动物少,对不同种属动物模型进行药物生殖发育毒性评价有助于提高风险评估的准确性。从生育力与早期胚胎发育毒性试验、胚胎-胎仔发育毒性试验、围产期发育毒性试验和体外生殖发育毒性评价等方面综述了家兔在药物生殖发育毒性评价中的研究进展,并探讨了家兔在药物生殖发育毒性评价研究中存在的问题及今后的发展方向,以期为今后研究提供参考。     

WHO发布的生物相似物指导原则中安全性与有效性的探讨

目的进一步解析生物相似物(SBP)的指导原则。方法通过研究SBP的药效毒理学及临床试验等结果,评价其安全性和有效性。结果与结论大多数生物药物临床试验研究数据常常很有限,在批准生产销售前,申请人应提供药物警戒计划,上市后对这些制品的临床安全性进行进一步的密切监视和效益-风险评估。     

啮齿类动物致癌性试验的关注要点

啮齿类动物致癌性试验的目的是确定候选药物在动物中是否具有致癌性,以及如果存在致癌性风险,这种风险是否会转化至人类。药物相关的致癌作用可能表现为肿瘤发生率增加、背景肿瘤发生潜伏期缩短或罕见肿瘤的发生。本文重点讨论啮齿类动物致癌性试验中的一些具体而关键的内容,包括试验设计、实施、报告和结果解释分析的考虑要点。本文重点阐述致癌性试验进行的时间、试验设计的关键方面(剂量选择、种属选择、如何处理早期死亡和试验组终止等)、试验报告的一般内容和注意事项、致癌性试验数据的统计分析和结果阐述分析等。使用综合证据权重(WoE)方法解释致癌性试验结果,尤其对啮齿类动物致癌试验发现是否与人体致癌风险相关的评价是至关重要的。     

啮齿类动物致癌性试验的关注要点

啮齿类动物致癌性试验的目的是确定候选药物在动物中是否具有致癌性，以及如果存在致癌性风险，这种风险是否会转化至人类。药物相关的致癌作用可能表现为肿瘤发生率增加、背景肿瘤发生潜伏期缩短或罕见肿瘤的发生。本文重点讨论啮齿类动物致癌性试验中的一些具体而关键的内容，包括试验设计、实施、报告和结果解释分析的考虑要点。本文重点阐述致癌性试验进行的时间、试验设计的关键方面(剂量选择、种属选择、如何处理早期死亡和试验组终止等)、试验报告的一般内容和注意事项、致癌性试验数据的统计分析和结果阐述分析等。使用综合证据权重(WoE)方法解释致癌性试验结果，尤其对啮齿类动物致癌试验发现是否与人体致癌风险相关的评价是至关重要的。     

毒理学数据质量评价体系的研究进展

正风险评估是指暴露于风险源时,对人体健康和环境产生不良效果的事件发生可能性的评估,其目的是为了评价潜在风险,风险评估包括危害识别、危害特征描述、暴露评估和风险特征描述4个步骤。风险评估人员做出正确决策的基础来源于高质量的毒理学数据,毒理学数据在风险评估整个过程尤其在危害识别、危害特征描述2个环节中起着重要作用,在风险管理和毒作用预测中也扮演重要角色。从历史数据看,风险评估的结果主要基于体内试验数据,近年来体外试验的数据质量对评估过程日益重     

基于FMECA的LIMS风险评估在药物安全性评价流程中的应用研究

目的：探讨药物安全评价研究机构对实验室信息管理系统（LIMS）实施风险评估的方法，并基于评估结果制定措施降低风险，确保研究质量。方法：采用“故障模式、影响和危害性分析”（FMECA）方法，对LIMS实施整体的风险评估。首先确定风险评估的目的、范围、依据和评估工具，并建立风险评估组织，根据风险评估流程对LIMS实施的整体合规性风险评估过程进行梳理。结果与结论：通过对系统实施的整体合规性评估明确了风险来源，发现了会影响研究质量的风险，并制定了降低风险措施以保证系统的整体合规要求，进一步提升了药物安全评价研究的数据质量。FMECA方法可应用在用于药物安全性评价研究流程中的LIMS，对提升数据质量有很好的帮助。     

The numerical probability of carcinogenicity to humans of some antimicrobials: Nitro-monoaromatics (including 5-nitrofurans and 5-nitroimidazoles), quinoxaline-1,4-dioxides (including carbadox), and chloramphenicol

Many substances are already tested in the long-term rodent bioassay (RCB). Nonetheless, statements such as the following are common in the regulatory literature: “the significance of the carcinogenicity findings in rodents relative to the therapeutic use of drugs in humans is unknown.” (U.S. FDA prescribing information for nitrofurantoin). In the absence of epidemiological data, chemicals carcinogenic in RCBs are typically classified as either possibly or probably carcinogenic to humans, particularly without the -numerical probability for the carcinogenicity to humans- (PPV) of the classified substance. Through the biostatistics-based and regulatorily pertinent -predictive values approach- (PVA), the present study investigated the PPV of several antimicrobials relevant to human or veterinary medicine. A combination of structure-activity relationship, mutagenicity, and tumor-related histopathology was used to resolve reliable and pertinent PPVs. For 62 specific antimicrobials (e.g., carbadox), a 97.9% (or more) probability of carcinogenicity to humans was estimated. For nitrofurantoin, a 99.9% probability of carcinogenicity to humans was reckoned. Therefore, a risk-benefit evaluation on the in-force authorization of nitrofurantoin for uncomplicated human urinary infections is needed. A discussion was provided on the involved mechanisms of carcinogenic action and some regulatory implications of the findings. Neither this study nor the PVA aimed to encourage indiscriminate animal testing but the contrary, to reduce unnecessary or redundant in vivo testing by powering the predictivity of nonclinical toxicology.     

啮齿类动物毒性实验死亡原因分析推荐方法简介

毒性病理学是药物非临床安全性评价的重要组成部分,组织病理学评价结果是毒性实验重要指标之一,对毒性实验的结果和结论非常关键。啮齿类动物尤其是大鼠和小鼠是非临床毒性实验常用的实验动物。死亡原因分析是啮齿类动物毒性实验组织病理学评价的一个重要内容,有助于毒性病理学家更好地理解病变的生物学意义,进一步提高对啮齿类动物毒性实验的评价和结果的解释。本文简要介绍了啮齿类动物濒死终点指标的判断标准,老年啮齿类动物大体和组织学病变的分类,不同种属啮齿类动物死亡原因,动物品系、性别和数量对死亡原因分析的影响,以及啮齿类动物毒性实验死亡原因分析推荐方法等内容。以期为我国药物非临床安全性评价领域毒性病理学家更好地分析死亡原因及进一步提高啮齿类动物毒性实验的组织病理学评价和结果解释提供一定参考。     

Carcinogenesis bioassays: study duration and biological relevance.

Criticisms of the scientific value of rodent carcinogenicity bioassays have focused on the arguments that the studies are too long and that most organ-specific carcinogenic effects observed in experimental animals have little or no relevance to humans. For example, Davies et al. (Davies, T.S., Lynch, B.S., Monro, A.M., Munro, I.C., Nestmann, E.R., 2000. Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC Monographs. Food and Chemical Toxicology 38, 219-235) concluded that the duration of rodent bioassays should be no more than 18 months, based on their analysis of 210 International Agency for Research on Cancer (IARC) rodent carcinogens in which they report that most chemicals showed "tumorigenic effects" at or before 12 months. However, many of these "tumorigenic effects" reflect the occurrence of a single neoplasm, with most tumors occurring much later in the study. Reliance on a single tumor at an early time point as providing definitive evidence of rodent carcinogenicity is a dangerous practice that could produce both false positive and false negative outcomes. An extensive evaluation of the NTP database reveals that many rodent carcinogens produce later-appearing tumors that would not be detected as statistically significant in a 12-18 month study. Such a shortened duration study would be roughly equivalent to evaluating human cancer in subjects 30-50 years of age, which would result in markedly reduced study sensitivity. In fact, many investigators recommend extending the duration of rodent studies to 30 months or to a true lifetime to increase study sensitivity. We also do not agree with the second conclusion of Davies et al. (2000) that the mode of action of rodent carcinogenesis is sufficiently well understood to justify discounting the majority of organ-specific carcinogenic effects found in these studies. The consequences of performing rodent carcinogenicity studies with inadequate sensitivity, and then discounting most of the carcinogenic effects that are observed will be that potential human carcinogens will not be detected, thus forcing near total reliance on human studies for this purpose. This is not prudent public health policy.     

基于美国FDA近五年批准的新药浅谈ICH S1指导原则的实施

致癌性研究是药物非临床安全性评价的重要内容之一,致癌性试验实施的复杂程度远远超出指导原则的要求。本文对美国FDA在2014-2018年5年期间批准的213个新药进行了梳理和分析,并结合ICHS1要求、文献报道和实际工作经验,从致癌性试验的必要性、致癌性试验结果提交时间、生物制品致癌性试验的决策、致癌性试验的试验类型选择、致癌性试验的剂量设计等几方面提出意见和建议,力求为国内同行、新药研发企业和审评机构提供参考。     

非临床毒性试验和致癌性试验动物死亡原因分析方法简介

本文简要介绍了美国国家毒理研究中心动物死亡原因分类、美国毒性病理学会颁布的判定毒性试验死亡原因的建议、英国亨廷顿生命科学公司病理部致癌性试验幼龄SD大鼠的死亡原因分析、美国华盛顿大学比较医学和比较病理学系啮齿类动物试验死亡原因分析推荐方法等内容,目的是为我国药物非临床安全性评价领域毒性病理学家更好地分析动物死亡原因及解释毒性试验和致癌性试验结果提供参考。     

An FDA perspective on the nonclinical use of the X-Omics technologies and the safety of new drugs

Work in the field "omics" (toxicogenomics, proteomics, and metabolomics) has exploded. It is hoped that 'omics' could be a tool for evaluation of general toxicology, reproductive toxicology, the carcinogenicity potential of pharmaceuticals and several other types of toxicity, eventually replacing the use of animals. Although much progress has been made in the standardization of procedures, challenges remain for evaluation of pharmaceuticals for regulatory purposes, because of off-target toxicologic effects, as well as issues of interpretation and the large number of biologic variables that can affect results. Such variables include species/strain, genetic variations, diet, age, dose, duration, and weight of animals. These variables also confound database compilations of expression profiles. The most promising use in the near future would be to clarify pathways for the various types of toxicity and carcinogenicity and get biomarkers for these pathways, to help assess relevance of nonclinical findings to humans.     

Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment.

Studies have shown that a majority of known human carcinogens also cause cancer in laboratory animals. The converse, however, is not as well established-known animal carcinogens are not equally predictive of human carcinogenicity. A particularly controversial aspect of interspecies extrapolation is application of rodent forestomach tumor data for predicting cancer risk in humans, given that a human counterpart for the rodent forestomach does not exist. Proliferative lesions in the rodent forestomach may result from a combination of factors related to route-specific tissue irritation and/or unnatural dosing regimens and are less likely to be relevant in evaluating human carcinogenic potential, particularly when tumors are exclusive to the forestomach. We review the comparative functional anatomy, physiology, tumor biology, tissue concordance, and historical regulatory practices in the use of forestomach tumors for cancer risk assessment, examining specific chemical examples. We also propose a standardized mode-of-action approach that combines multiple risk characterization criteria, including relevance to human exposure conditions, physiologically based toxicokinetics, genotoxicity, and comparative/mechanistic toxicology. Forestomach tumors associated with chronic irritation of the forestomach epithelium, particularly those induced by repeated oral gavage dosing, should not form the basis for carcinogenic classification or quantitative cancer potency estimates for humans. Genotoxic chemicals and those that cause tumors at multiple sites, at doses at or below the maximum tolerated dose, and in the absence of forestomach irritation, are more likely to be relevant human carcinogens. Cancer risk assessment that utilizes forestomach tumor data should consider relevant human exposures, systemic bioavailability, tissue dosimetry and concordance.     

Evaluation of carcinogenicity studies of medicinal products for human use authorised via the European centralised procedure (1995-2009)

Carcinogenicity data of medicinal products for human use that have been authorised via the European centralised procedure (CP) between 1995 and 2009 were evaluated. Carcinogenicity data, either from long-term rodent carcinogenicity studies, transgenic mouse studies or repeat-dose toxicity studies were available for 144 active substances contained in 159 medicinal products. Out of these compounds, 94 (65%) were positive in at least one long-term carcinogenicity study or in repeat-dose toxicity studies. Fifty compounds (35%) showed no evidence of a carcinogenic potential. Out of the 94 compounds with positive findings in either carcinogenicity or repeat-dose toxicity studies, 33 were positive in both mice and rats, 40 were positive in rats only, and 21 were positive exclusively in mice. Long-term carcinogenicity studies in two rodent species were available for 116 compounds. Data from one long-term carcinogenicity study in rats and a transgenic mouse model were available for eight compounds. For 13 compounds, carcinogenicity data were generated in only one rodent species. One compound was exclusively tested in a transgenic mouse model. Six compounds were tumourigenic in repeat-dose toxicity studies in rats. The majority of tumour findings observed in rodent carcinogenicity studies were considered not to be relevant for humans, either due to a rodent-specific mechanism of carcinogenicity, a high safety margin between exposures at the NOAEL (No Observed Adverse Effect Level) in rodents and recommended therapeutic doses in humans, or based on historical control data, a small effect size and lack of dose-response relationship and tumours typically observed in rodent strains used, or were considered not to be relevant for humans based on literature and clinical data or likely differences in metabolism/local concentrations between rodents and humans. Due to the high number of rodent tumour findings with unlikely relevance for humans, the value of the currently used testing strategy for carcinogenicity appears questionable. A revision of the carcinogenicity testing paradigm is warranted.     

Analysis of thresholds for carcinogenicity

Re-evaluations of large prominent studies, e.g. the ED01 study and N-nitrosodiethylamine, unequivocally have demonstrated that thresholds exist for carcinogenicity when the dose-response curves for animal studies done at high doses are calculated according to fundamental principles of chemistry. This requires dose to be on a logarithmic scale and percent tumors on a linear scale. Fifteen compounds approved by the Flavor and Extract Manufacturers Association (FEMA) expert panel as Generally Recognized As Safe (GRAS) have been reported to be carcinogenic in rodent studies. The thresholds for tumors of these flavors were at least several orders of magnitude greater than the estimated daily dose of these flavoring agents to individuals in the United States. Similarly, comparisons of thresholds of carcinogenicity of chemicals and drugs to which humans are exposed with their exposure levels suggest that experimental animals are more sensitive to carcinogenicity than humans. The animal studies should be viewed as providing evidence for the safety of these flavors and other compounds at current levels of human exposure.     

An evaluation of the carcinogenic hazard of 1,4-dichlorobenzene based on internationally recognized criteria

1,4-Dichlorobenzene (1,4-DCB) was shown to induce the formation of male rat renal tubule tumors and male and female mouse liver tumors when administered in a chronic bioassay. Since the original carcinogenicity findings, an extensive body of mechanistic information has been developed to elucidate the mode of action by which 1,4-DCB induces these effects and to evaluate the human relevance of the observed animal tumors. In addition, some regulatory and authoritative bodies (U.S. EPA and IARC) have developed rigorous scientific criteria for the amount and types of evidence needed to establish that a material causes kidney toxicity and tumors in male rats through a specific mechanism, alpha-2u-globulin nephropathy. This paper summarizes the mechanistic data developed for 1,4-DCB, which affords an understanding of the lack of human relevance of the male rat renal tubule tumors and mouse liver tumors; assesses that mechanistic data set utilizing the defined set of evaluation criteria formulated by U.S. EPA and IARC for alpha-2u-globulin nephropathy; and discusses the predictive power of mechanistic data developed to elucidate the mode of action of 1,4-DCB in inducing mouse liver tumors. Finally, there is a discussion of how some, but not all, regulatory and authoritative bodies have incorporated this substantial mechanistic data set for 1, 4-DCB into their cancer hazard evaluations and concluded that 1, 4-DCB presents little, if any, cancer hazard to humans.