The recently published study on the Pharmacokinetics of ceftiofur sodium in Peekapoo dogs following a single intravenous and subcutaneous injection (Yang et al., 2020) generated feedback that raises important questions for scientific journals, publishers and peer reviewers, as well as those working in animal‐based research more broadly.

The authors of the study met the Journal's requirements for animal studies. According to the guidelines current at the time the study was submitted, US authors should comply with the US National Research Council's Guide for the Care and Use of Laboratory Animals; the US Public Health Service's Policy on Humane Care and Use of Laboratory Animals; and the Guide for the Care and Use of Laboratory Animals; UK authors should comply with the Animals (Scientific Procedures) Act 1986 Amendment Regulations (SI 2012/3039); and European authors outside of the UK should comply with Directive 2010/63/EU. Authors outside of the United States, UK or the European Union were “encouraged to adhere to animal research reporting standards, for example the ARRIVE reporting guidelines” and required to state whether experiments were performed “in accordance with relevant institutional and national guidelines and regulations for the care and use of laboratory animals”.

But is this fair and equitable? The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were updated in July 2020 (Percie du Sert et al., 2020). The driver for the development of these guidelines was not animal welfare per se, but poor reproducibility of animal‐based research. The updated guidelines require basic information about experimental animals, such as strain, sub‐strain, sex, age, weight, their health and immune status, genetic modification status, genotype and previous exposures (listed under “ARRIVE Essential 10”), but list provision of details about animal housing, husbandry, care and monitoring as recommended (listed under “ARRIVE Recommend Set”). While drawing attention to these positions in the ARRIVE Recommended Set may act as a prompt to ensure the welfare of research animals, compliance with the ARRIVE Guidelines does not ensure that the same standards of animal welfare, for example as required by the Directive 2010/63/EU, are met.

Furthermore, it is difficult for an international journal's editors and peer reviewers to determine whether institutional and national guidelines, whether combined with the ARRIVE guidelines or not, are equivalent to the specified United States, UK or EU legislation and guidelines. Indeed, the International Council for Laboratory Animal Science states that “ICLAS believes that a statement of IACUC approval is sometimes not sufficient to confirm humane science. More information is required before an editor accepts the manuscript as meeting international best practice standards of humane science” (International Council for Laboratory Animal Science, 2013). In short, the Journal's Guidelines re‐enforce existing inequitable animal welfare requirements for researchers in different countries.

As to the specific concerns raised, because Dr Richez is based in the EU I will refer to the Directive 2010/63/EU (hereafter, “the Directive”) in this discussion.

According to the Directive, the isolation of a social species like dogs for prolonged periods (Annex III, Section B:4 states that “Dogs shall not be single‐housed for more than 4 hr at a time”) is considered a severe procedure (Annex VIII, Section III). In addition, it states that “dogs shall where possible be provided with outside runs.” The more severe a procedure, the stronger the justification required for the use of an animal model. Additionally, one could argue that the longer the confinement, the more need for outdoor runs.

According to the Directive's Article 4: Principle of Replacement, Reduction and Refinement, based on Russell and Birch's now well‐established “3Rs” (Russell & Burch, 1959), “Member states shall ensure that, wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used instead of a procedure” (Article 4:1). Researchers should actively and continuously seek alternatives to animal models, such as those listed on nc3rs.org.uk, or provide robust scientific justification for their use of animals and methodology (ICLAS, 2012). While most institutional animal care and ethics committees require specific justification for the use of an animal model, this is not a universal requirement and such justifications may not be included in resulting publications. This is an oversight that journals and publishers should seek to address so that the scientific community—beyond ethics committee members and peer reviewers—can form their own opinions and provide feedback.

In relation to the acquisition of animals, the Directive requires that “Member states shall ensure that animals belonging to the species listed in Annex I [including dogs, cats, non‐human primates, rodents, rabbits, frogs and zebra fish] may only be used in procedures where those animals have been bred for use in procedures” (Article 10). This would exclude the use of animals sourced from a pet market.

From a scientific perspective, the sourcing of animals from a pet market raises questions about potential confounders that might influence pharmacokinetics. The dogs were confirmed healthy by physical examination, but we do not know that subclinical conditions that may have important impacts on pharmacokinetics (Martinez & Modric, 2010; Modric & Martinez, 2011) could be ruled out.

Regarding the fate of animals, the Directive specifies that breeders, suppliers and users of animals for scientific purposes record their fate (32). It states that “animals such as dogs and cats should be allowed to be rehomed in families as there is a high level of public concern as to the fate of such animals” (26). In addition, it specifies that “should Member States allow rehoming, it is essential that the breeder, supplier or user has a scheme in place to provide appropriate socialisation to those animals in order to ensure successful rehoming as well as to avoid unnecessary distress to the animals and to guarantee public safety.”(26). In this case, the author has been informed that the dogs were rehomed with members of the research team, though the study does not reveal their age and developmental stage at the time of the experiment, the potential impact of isolation housing on their socialization, and any steps taken to ensure that they were appropriately socialized for rehoming. We know that early socialization impacts animal behaviour and welfare later in life (Dietz et al., 2018).

While not all guidelines require reporting on the fate of animals following experimental procedures, there is a growing expectation from animal protection organizations and the wider community for greater openness around the use of research animals. Hence, a number of countries have adopted “openness agreements” such as the Concordat on Openness on Animal Research in the UK (Understanding Animal Research, 2014). The Concordat is underpinned by a recognition that the social licence of the use of animals in research depends on demonstration that animals are used in a responsible way that is aligned with community expectations.

The concerns highlighted by Dr Richez underscore the challenge international journals have to navigate in managing studies submitted by researchers from diverse communities, with perhaps varied expectations around animal welfare. This is complicated by the reality that peer reviewers tend to be subject matter experts rather than animal welfare experts.

Accreditation of institutions by an international body, for example through an organization such as AAALAC International (aaalac.org), provides assurance that institutions are meeting at least some international animal welfare requirements. Beyond this, given the international nature of scientific publication, there is a need to harmonize legislation governing the use of animals for scientific purposes (Gettayacamin & Retnam, 2017).

In the meantime, journals and publishers can play their role by regularly reviewing their animal welfare and ethics requirements to ensure that these are equitable and contemporary (e.g. see the British Journal of Pharmacology's revised checklist for animal experimentation (British Journal of Pharmacology, 2020)), and reflect a high standard of animal welfare where animal models must be used.

In the interests of reproducibility and transparency around methodology, adherence to the ARRIVE Essential 10 and Recommend Set should be required for all authors.

I commend Dr Richez for noting concerns about the welfare of the animals involved in the experiment and taking the step of writing to the Journal. Just as postmarketing pharmacovigilance is an important component of safety and quality control when it comes to pharmaceuticals, postpublication critique by scientific peers is a critical component in ensuring that author guidelines together with the editorial and peer‐review process are working as they should in upholding and promoting the welfare of animals used for scientific purposes.

As research institutions increasingly measure performance of their team members through the quality and impact of publications, journals and their publishers are in a unique position to promote the 3Rs in the interests of good science and good welfare (Hubrecht & Carter, 2019).

最近发表的关于单次静脉内和皮下注射皮克福狗的头孢噻呋钠药代动力学的研究（Yang等人，2020年）产生了反馈，这给科学期刊，出版商和同行审稿人以及从事动物研究的人 提出了重要问题基于更广泛的研究。

该研究的作者符合《华尔街日报》对动物研究的要求。根据提交研究时的现行指南，美国作者应遵守美国国家研究委员会的《实验动物的护理和使用指南》；美国公共卫生服务局关于人文关怀和实验动物使用的政策；以及《实验动物的护理和使用指南》；英国作者应遵守《 1986年动物（科学程序）法》修正案（SI 2012/3039）；英国以外的欧洲作者应遵守指令2010/63 / EU。美国，英国或欧盟以外的作者“被鼓励遵守动物研究报告标准，

但这公平公正吗？2020年7月更新了《动物研究：体内实验报告（ARRIVE）指南》（Percie du Sert等人，  2020年）。制定这些指南的动因本身并不是动物福利，而是动物研究可重复性差。更新后的指南要求提供有关实验动物的基本信息，例如品系，亚品系，性别，年龄，体重，它们的健康和免疫状况，基因修饰状况，基因型和以前的暴露（列于“ ARRIVE Essential 10”下），但列表根据建议提供有关动物住房，畜牧业，照料和监测的详细信息（列在“到达建议集”下）。虽然提请注意ARRIVE推荐集中的这些位置可能会提示确保研究动物的福利，但遵守ARRIVE准则并不能确保动物福利的标准相同，例如2010/63号指令的要求/ EU，满足。

此外，国际期刊的编辑和同行审稿人很难确定机构和国家指南（无论是否与ARRIVE指南结合）是否等于指定的美国，英国或欧盟法律和指南。实际上，国际实验动物科学理事会指出：“ ICLAS认为，获得IACUC批准的声明有时不足以证实人文科学。在编辑接受该手稿符合国际人文科学最佳实践标准之前，需要更多信息”（国际实验动物科学理事会，  2013年）。简而言之，《期刊指南》对不同国家的研究人员加强了现有的不平等的动物福利要求。

关于提出的具体问题，由于Richez博士居住在欧盟，因此在本讨论中将参考指令2010/63 / EU（以下简称“指令”）。

根据该指令，长期隔离诸如狗之类的社会物种（附件III，B节：4规定“狗不能一次单独饲养超过4个小时”）被认为是一项严格的程序（附件八，第三节）。此外，它指出“应在可能的情况下为狗提供外滑道。” 程序越严格，使用动物模型所需的理由就越强。另外，有人可能会说，禁闭时间越长，对户外跑步的需求就越大。

根据该指令的第4条：替代，减少和完善的原则，根据罗素（Russell）和伯奇（Birch）现已建立的“ 3R”（罗素和伯奇（Russell＆Burch，  1959）），“会员国应确保在可能的情况下采用科学上令人满意的方法或测试策略而不是不使用活体动物，应使用该策略代替程序（第4：1条）。研究人员应积极，持续地寻找动物模型的替代品，例如nc3rs.org.uk上列出的替代品，或者为动物的使用和方法论提供强有力的科学依据（ICLAS，  2012年））。尽管大多数机构动物护理和道德委员会都要求使用动物模型有特定的理由，但这不是普遍的要求，因此这些理由可能不会包含在最终的出版物中。这是期刊和出版商应寻求解决的一种疏忽，以便科学界（除了道德委员会成员和同行评审人员之外）可以形成自己的观点并提供反馈。

关于获得动物，该指令要求“成员国应确保属于附件一所列物种的动物（包括狗，猫，非人类灵长类，啮齿动物，兔子，青蛙和斑马鱼）只能是如果这些动物已被繁育用于程序，则用于程序”（第10条）。这将排除使用从宠物市场采购的动物。

从科学的角度来看，从宠物市场采购动物引起了关于可能影响药物动力学的潜在混杂因素的疑问。通过体格检查确认这些狗是健康的，但我们不知道可以排除可能对药代动力学产生重要影响的亚临床情况（Martinez＆Modric，  2010 ; Modric＆Martinez，  2011）。

关于动物的命运，该指令明确规定，出于科学目的，动物的繁殖者，供应商和使用者应记录其命运（32）。它指出：“由于人们高度关注这类动物的命运，因此应允许将诸如猫狗之类的动物安置在家庭中”（26）。此外，它明确规定：“成员国应允许重新归巢，繁殖者，供应商或使用者必须有适当的计划向这些动物提供适当的社交化，以确保成功实现重新归巢并避免不必要的困扰。动物，并确保公共安全。”（26）。在这种情况下，作者已获悉，这些狗已与研究小组成员重新安置在一起，尽管该研究并未在实验时透露它们的年龄和发育阶段，隔离住房对他们的社会化的潜在影响，以及为确保适当地社会化以进行重新安置而采取的任何步骤。我们知道，早期的社会化会影响生活的后期动物的行为和福利（Dietz等， 2018）。

尽管并非所有准则都要求按照实验程序报告动物的命运，但动物保护组织和更广泛的社区对使用研究动物的更大开放度的期望日益增长。因此，许多国家采用了“开放协议”，例如英国动物研究开放协约（Understanding Animal Research，  2014年）。《协和协定》的基础是认识到在研究中使用动物的社会许可取决于证明以符合社区期望的负责任方式使用动物。

Richez博士强调的担忧凸显了国际期刊在管理来自不同社区的研究人员提交的研究中所面临的挑战，这些研究对动物福利可能有不同的期望。同行评审通常是主题专家，而不是动物福利专家，这使情况变得复杂。

国际机构对机构的认可，例如通过AAALAC International（aaalac.org ）之类的组织，可以确保机构至少满足某些国际动物福利要求。除此之外，鉴于科学出版物的国际性，有必要协调有关管理动物用于科学目的的立法（Gettayacamin＆Retnam，  2017年）。

同时，期刊和出版商可以通过定期审查其动物福利和道德规范来确保其公平性和现代性，从而发挥作用（例如，参见《英国药理学杂志》针对动物实验的修订清单（英国药理学杂志，  2020年）） ，并反映了必须使用动物模型的高动物福利标准。

为了使方法学具有可重复性和透明性，所有作者都必须遵守ARRIVE Essential 10和推荐集。

我赞扬Richez博士注意到对参与实验的动物的福利的关注，并采取了撰写《日刊》的步骤。就像上市后的药物警戒性是药品安全和质量控制的重要组成部分一样，科学同行的发表后评论是确保作者指导方针以及编辑和同行评审过程能够如期维护的关键组成部分。促进用于科学目的的动物的福利。

随着研究机构越来越多地通过出版物的质量和影响力来衡量其团队成员的表现，期刊及其出版商在促进3R的发展方面具有独特的地位，以促进良好的科学和良好的福利（Hubrecht＆Carter，  2019）。