International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm–benefit analysis (HBA) and deemed the project to be appropriate. Although the process for conducting HBAs may not be new, the relevant factors and algorithms used in conducting them during the review process are deemed to be poorly defined or lacking by committees in many institutions. This paper presents the current concept of HBAs based on a literature review. References on cost or risk benefit from clinical trials and other industries are also included. Several approaches to HBA have been discovered including algorithms, graphic presentations and generic processes. The aim of this study is to better aid and harmonize understanding of the concepts of ‘harm’, ‘benefit’ and ‘harm–benefit analysis’.

International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm–benefit analysis (HBA) and deemed the project to be appropriate. The AALAS–FELASA working group on HBA has performed a literature review and based on this review, proposed a method for HBA. Examples of the working group’s approach are included in this report.

Interstitial fluid pressure (P(if)) is important for maintaining constant interstitial fluid volume. In several acute inflammatory reactions, a dramatic lowering of P(if) has been observed, increasing transcapillary filtration pressure and favoring initial and rapid edema formation. This lowering of P(if) seems to involve dynamic beta(1)-integrin-mediated interactions between connective tissue cells and extracellular matrix (ECM) fibers. beta(1)-Integrins are adhesion receptors responsible for the attachment of connective tissue cells to the ECM providing a force-transmitting physical link between the ECM and cytoskeleton. Disruption of actin filaments leads to lowering of P(if) and edema formation, suggesting a role for actin filaments. The aim of this study was to further investigate the role of the cytoskeleton in the control of P(if) by studying the effect of microtubuli fixation using paclitaxel and docetaxel. P(if) was measured with the micropuncture technique. Albumin extravasation (E(alb)) was measured using (125)I-labeled albumin. Paclitaxel and docetaxel were tested locally on foot skin in female Wistar rats. Paclitaxel (6 mg/ml) reduced P(if) from -1.5 +/- 1.0 mmHg in controls to -4.9 +/- 2.6 mmHg after 30 min (P < 0.05) in a dose-dependent manner (P < 0.05). Docetaxel caused a similar lowering of P(if). Both paclitaxel and docetaxel increased E(alb) compared with Cremophor EL and saline control (P < 0.05). Pretreatment with phalloidin before paclitaxel, causing fixation of actin filaments, abolished the lowering of P(if) caused by paclitaxel. This study confirms several previous studies demonstrating that connective tissue cells influence P(if) and edema formation.

This study shows that pretreatment with phalloidin, before the administration of dextran, abolishes the lowering of P(if) and edema formation, which is detected after i.v. injection of dextran alone.

In order for their research to be legitimate, scientists carrying out research using animals must comply with rules and regulations. The 3Rs (replacement, reduction and refinement) are one set of guidelines that help to promote the ethical use of animals for research. An important question is whether implementing the principles of the 3Rs in legal regulations, such as a Directive of the European Parliament and of the Council on the protection of animals used for scientific purposes, will increase compliance with the principles of the 3Rs in research organizations. Previous work suggests that organizational culture is just as important for directing behavior as are formalized rules and regulations. This article introduces the concepts of compliance and organizational culture and discusses their consequences on the implementation of the principles of the 3Rs.