Testing Times in Toxicology – In Vitro vs In Vivo Testing
Testing Times in Toxicology – In Vitro vs In Vivo Testing
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毒理学测试时间 – 体外与体内测试
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发表时间：
2013
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影响因子：
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通讯作者：
M. Tettamanti
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作者：
Shiranee Pereira;M. Tettamanti
“缺乏证据并不意味着没有证据”--卡尔·萨根，美国天文学家（1934-1996）在动物毒性测试的背景下，Hartung和McBride（2011）引用了上面的话来解释我们在活体动物测试中看到的谬误。然而，由于未知的原因，或者可能是由于缺乏更好和更人道的测试策略，动物试验已经成为过去，不幸的是，仍然是药物，化妆品，农用化学品和工业化学品毒性评估的金标准。即使科学发展到更强大，更精确的替代品，“人道和人性化”，尽管美国和欧盟的监管机构在过去50年中已经从市场上撤回了近50种重要药物，即使它们已经被证明是安全/有效的，已经过监管机构规定的所有动物研究和临床试验的测试。最严重和最大的悲剧是由沙利度胺和磺胺的使用造成的。最近的一种药物（drotalin alfa），曾经被认为是治疗严重脓毒症患者的有效药物，已经从市场上撤回，因为新的证据显示-在美国食品和药物管理局（FDA）批准该药物10年后-它对严重脓毒症根本无效。该药物于2011年10月25日被Eli Lilly and Company撤回。假阴性一直是动物试验中最大的和似乎无法克服的问题之一。一个阴性的动物试验可能意味着什么也没有或这么多的东西。不同的物种或仅仅是不同的实验变异可能会产生积极的结果。动物有不同的防御机制，可能会导致错误或扭曲的结果，被关在笼子里的压力，被关在非自然的条件下，被处理，本身，可能是结果变幻莫测的原因。此外，必须考虑啮齿动物至人的外推因子，这是动物毒性数据固有的和不可避免的。对压力的生理反应可能是阳性结果的附加物，伪装毒性指标，对毒性途径造成变化，夸大，或者可能只是触发在没有压力或其他变量的情况下可能不存在的毒性途径。由于分子和计算工具的进步，对基因、蛋白质和小分子如何相互作用以形成维持细胞功能的分子途径的科学理解已经迅速发展。这一知识使非动物方法比体内试验更有优势，消除了动物试验中由于实验室动物在毒理学试验期间遭受的疼痛、压力和痛苦而产生的变异的附加物-体外与体内试验Shiranee佩雷拉1和Massimo Tettamanti 2 1 CIBA，印度农业研究理事会，Chennai，印度; 2 I-CARE，意大利
“Absence of evidence is no evidence of absence” – Carl Sagan, US astronomer (1934-1996) In the context of animal toxicity testing Hartung and McBride (2011) evoked the above quote to explain the fallacies we see in live animal testing. However, for reasons unknown or maybe due to the lack of better and more humane testing strategies, animal testing was in the past and, unfortunately, continues to be the gold-standard in the toxicity evaluation of pharmaceuticals, cosmetics, agrochemicals, and industrial chemicals. Even with the evolution of science to more robust, precise alternatives, both “humane and human,” the shift has been slow despite the fact that regulatory authorities, both in the USA and the EU, have withdrawn close to 50 important drugs from the market in the last 50 years, even after they had been proved safe/efficacious, having been tested with the whole gamut of animal studies and clinical trials as prescribed by regulatory agencies. The worst and biggest tragedies resulted from the use of thalidomide and sulfanilamide. A more recent drug (drotrecogin alfa), once believed to be useful in treating patients with severe sepsis, has been withdrawn from the market because new evidence revealed – 10 years after the drug was approved by the US Food and Drug Administration (FDA) – that it is not effective for severe sepsis after all. This drug was withdrawn by Eli Lilly and Company on October 25, 2011. False negatives have been one of the biggest and seemingly insurmountable problems in animal testing. A negative animal test could mean nothing or so many things. A different species or simply a different experimental variation may yield positive results. Animals have different defense mechanisms that may lead to false or skewed results, and the stress of being caged, being held in unnatural conditions, and being handled, in itself, could be responsible for result vagaries. Furthermore, the rodent to human extrapolation factor, which is intrinsic and inevitable to animal toxicity data, must be considered. Physiological responses to stress may be an addon to a positive result, camouflage a toxicity indicator, pose variations to a toxicity pathway, exaggerate, or maybe just trigger a toxicity pathway that may be absent in the absence of stress or another variable. The scientific understanding of how genes, proteins, and small molecules interact to form molecular pathways that maintain cell function has evolved rapidly, thanks to advances in molecular and computational tools. This knowledge gives nonanimals methods the edge over in vivo testing, taking away that adjunct of variations that come in animal testing due to the pain, stress, and distress that laboratory animals suffer during Testing Times in Toxicology – In Vitro vs In Vivo Testing Shiranee Pereira 1 and Massimo Tettamanti 2 1 CIBA, Indian Council of Agricultural Research, Chennai, India; 2 I-CARE, Italy