Expert opinions on the acceptance of alternative methods in food safety evaluations: Formulating recommendations to increase acceptance of non-animal methods for kinetics.

Inclusion of alternative methods that replace, reduce, or refine (3R) animal testing within regulatory safety evaluations of chemicals generally faces many hurdles. The goal of the current work is to i) collect responses from key stakeholders involved in food safety evaluations on what they consider the most relevant factors that influence the acceptance and use of 3R methods and to ii) use these responses to formulate activities needed to increase the acceptance and use of 3R methods, particularly for kinetics. The stakeholders were contacted by e-mail for their opinions, asking the respondents to write down three barriers and/or drivers and scoring these by distributing 5 points over the three factors. The main barriers that obtained the highest aggregated scores were i) uncertain predictability 3R methods/lack of validation, ii) insufficient guidance regulators/industry and iii) insufficient harmonization of legislation. The major driver identified was the possibility of 3R methods to provide more mechanistic information. Based on the results, recommendations are given to enhance the acceptance and application of 3R toxicokinetic methods in food safety evaluations. These include steering of regulatory data requirements as well as creating (funding) opportunities for development and validation of alternative methods for kinetics and development of guidances.

Regulatory acceptance and use of serology for inactivated veterinary rabies vaccines.

In April 2013 the mouse antibody serum neutralization test (SNT) was formally incorporated into European Pharmacopoeia monograph 0451 for potency testing of inactivated veterinary rabies vaccines. The SNT is designed to replace the highly variable and pain and distress causing NIH mouse rabies challenge assay. The adoption of the SNT meets the European ambition (i.e., EC and CoE) to replace, reduce and/or refine laboratory animal testing. However, regulatory acceptance and use of 3R models, such as the SNT, remains challenging. This paper aims at clarifying the process of acceptance and use of the SNT. For this purpose it reconstructs the process and reveals barriers and drivers that have been observed by involved stakeholders to have played a role. In addition it extracts lessons to stimulate regulatory acceptance in similar future processes. The incorporation of the SNT into the monographs went relatively quick due to a thorough test development and pre-validation phase, commitment and cooperation of relevant stakeholders and a strong project coordination of the international validation study. The test was developed by the Paul Ehrlich Institut; a leading European OMCLs. This facilitated its European regulatory use. The use by industry is in a critical phase. At this stage product specific validation and the question whether the SNT will be accepted outside Europe are important influencing factors.

Regulatory acceptance and use of the Extended One Generation Reproductive Toxicity Study within Europe.

The two-generation study (OECD TG 416) is the standard requirement within REACH to test reproductive toxicity effects of chemicals with production volumes >100 tonnes. This test is criticized in terms of scientific relevance and animal welfare. The Extended One Generation Reproductive Toxicity Study (EOGRTS), incorporated into the OECD test guidelines in 2011 (OECD TG 443) has the potential to replace TG 416, while using only one generation of rats and being more informative. However, its regulatory acceptance proved challenging. This article reconstructs the process of regulatory acceptance and use of the EOGRTS and describes drivers and barriers influencing the process. The findings derive from literature research and expert interviews. A distinction is made between three sub-stages; The stage of Formal Incorporation of the EOGRTS into OECD test guidelines was stimulated by retrospective analyses on the value of the second generation (F2), strong EOGRTS advocates, animal welfare concern and changing US and EU chemicals legislation; the stage of Actual Regulatory Acceptance within REACH was challenged by legal factors and ongoing scientific disputes, while the stage of Use by Industry is influenced by uncertainty of registrants about regulatory acceptance, high costs, the risk of false positives and the manageability of the EOGRTS.

Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: expert opinions on the state of affairs and the way forward.

Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers.

Regulatory acceptance and use of 3R models: a multilevel perspective.

The importance placed on risk avoidance in our society has resulted in a broad range of regulations intended to guarantee safety of products such as pharmaceuticals and chemicals. Many of these regulations rely on animal tests. As a result, about 25% of the animal experiments in Europe are done for regulatory purposes. There are many initiatives that aim to replace, reduce, or refine laboratory animal use, but the regulatory acceptance and use of 3R models lags behind. The central question of this study is: "Which variables influence the regulatory acceptance and use of 3R models and in what way?" Regulatory acceptance is seen as one of the biggest hurdles 3R models face, but the rationale behind this is still underexplored. This study is an approach to filling that gap by combining opinions from experts in the field with literature on technology acceptance and risk regulation, resulting in a model of the variables that determine the process of the regulatory acceptance and use of 3R models.

Evaluation of research activities and research needs to increase the impact and applicability of alternative testing strategies in risk assessment practice.

The present paper aims at identifying strategies to increase the impact and applicability of alternative testing strategies in risk assessment. To this end, a quantitative and qualitative literature evaluation was performed on (a) current research efforts in the development of in vitro methods aiming for alternatives to animal testing, (b) the possibilities and limitations of in vitro methods for regulatory purposes and (c) the potential of physiologically-based kinetic (PBK) modeling to improve the impact and applicability of in vitro methods in risk assessment practice. Overall, the evaluation showed that the focus of state-of-the-art research activities does not seem to be optimally directed at developing in vitro alternatives for those endpoints that are most animal-demanding, such as reproductive and developmental toxicity, and carcinogenicity. A key limitation in the application of in vitro alternatives to such systemic endpoints is that in vitro methods do not provide so-called points of departure, necessary for regulators to set safe exposure limits. PBK-modeling could contribute to overcoming this limitation by providing a method that allows extrapolation of in vitro concentration-response curves to in vivo dose-response curves. However, more proofs of principle are required.

Factors stimulating or obstructing the implementation of the 3Rs in the regulatory process.

Approximately 30% of animal use within the European Union (EU) is done to meet regulatory requirements. The tests are often repetitive in nature and may cause severe suffering, due to the procedures used and to rigidly predefined end points. In addition, product evaluation procedures often take long and are very expensive. Over the last decades the heavy reliance on animal experimentation in this area has met serious objections, both ethical and economical in nature. This study describes obstacles and opportunities to implement the 3Rs in regulatory animal testing. The findings are based primarily on interviews with legislators, regulators, industry, science and animal welfare organisations and reflect shared perceptions of these respondents. In order to increase the application of the 3Rs in regulatory testing a number of technical, political and social obstacles must be overcome. This study offers insight into the persistent character of regulatory animal testing and can function as a starting point for further discussion on how to tackle these problems. To this end, several recommendations are made ranging from strategic test approaches and data sharing to strengthening the policy network and improving communication between 3Rs experts and regulators. The study is an initiative of the national project group "Regulatory Animal Testing", which consists of a group of Dutch experts on animal testing working for a variety of organisations in the field.1 They felt the need for cooperation to initiate a discussion at relevant levels and to identify possible solutions in order to implement the objectives of the three R's in testing for regulatory purposes without loss of scrutiny in safety and/or efficacy evaluation needed for product release.