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.

The OECD program to validate the rat uterotrophic bioassay: an overview.

The Organisation for Economic Co-operation and Development has undertaken an international validation program for the rodent uterotrophic bioassay. This validation program comprised two major parts. The first part was the development of a detailed background review document compiling the existing data on the bioassay's history, the molecular and physiologic basis for the bioassay's mechanistic relevance to detect estrogen agonists and antagonists, a review of important bioassay protocol parameters, and a review of the data generated by in vitro assays, previous uterotrophic bioassays, and developmental and reproductive assays to assess and support the overall predictivity of the uterotrophic bioassay. The second part was an extensive multiyear effort managed by a validation management group to demonstrate the operating characteristics of four protocols. The effort was conducted in two phases. The phase 1 results with the reference agonist ethinyl estradiol (EE) and antagonist ZM 189,154 has been published previously. This Environmental Health Perspectives mini-monograph is devoted to the phase 2 work using five weak estrogen agonists, bisphenol A, genistein, methoxychlor, nonylphenol, and o,p -DDT, as well as the negative substance dibutylphthalate. These data show that all protocols successfully detected increases in uterine weights when a sufficient dose level of the weak agonists was administered, whether the substances were known or provided as coded doses to the laboratory. The data with both the reference EE and all five weak agonists are reproducible over time and under a variety of different experimental conditions (e.g., animal strain, diet, housing, bedding, vehicle, animal age). In conclusion, all protocols now have sufficient data to support their validity.

Mutual acceptance of data: harmonised test methods and quality assurance of data--the process explained.

An essential aspect of the OECD is that it should not be considered a supranational organisation, but rather a center for discussion where governments express their points of view, share their experiences and search for common ground. This implies that decisions are made by consensus instead of majority. Once the Council, which is the highest authority of the OECD, adopts a formal Decision, such a decision is binding on all Member countries. The OECD Guidelines for the Testing of Chemicals, which are considered the leading international standard for safety testing, form an integrated part of such a binding Council Decision. An even more important part of that same Council Decision is that on Mutual Acceptance of Data, where it states that: 'Data generated in the testing of chemicals in an OECD Member country in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice (GLP) shall be accepted in other Member countries for purposes of assessment and other use relating to the protection of man and the environment.' In the various steps of the process of Test Guideline development, the National Co-ordinators of the Test Guideline Programme play an important role. The initiative to start the development of a particular guideline can be taken by the OECD Secretariat, by one or more Member countries or, most importantly, by the scientific community itself. Proposals, received by the Secretariat are discussed at the yearly Meeting of the National Co-ordinators. During these meetings, priorities for future activities are set and the approach that should be followed in dealing with the selected activities is discussed. Quite often, so-called Detailed Review Papers (DRP's) form the basis of a new or updated Guideline. These DRP's, which are either prepared by a Member country or by a consultant appointed by the Secretariat, describe the current 'state of the art' in scientific progress and technical possibilities of a well-defined area of research. After completion, either an expert meeting or a commenting round will be organised. All Member countries will have sufficient possibilities to express their views. When the DRP is acceptable to the experts of all Member countries, the next step is to actually develop a Test Guideline. Similar to the procedure followed for the DRP, the Test Guideline proposal will be circulated for comment to all Member countries and should reach the desks of relevant experts, nominated by their National Co-ordinator. Frequently, in addition to the commenting rounds, Test Guideline proposals are discussed in special expert meetings. Once the experts reach consensus on a particular Test Guideline, the proposal is put forward to the Meeting of the National Co-ordinators for approval. Since each guideline will form an integrated part of the earlier mentioned Council Decision, each new guideline also needs formal adoption by the Council before it becomes effective.

Dialogue and collaboration: a personal view on laboratory animal welfare developments in general, and on ECVAM's first decade in particular.

A personal view is presented on progress made during the last 25 years in applying the Three Rs (reduction, refinement, replacement) to animal testing in regulatory toxicology, with an emphasis on "good moments" (for example, international workshops on the principles and practical application of the validation process and on regulatory acceptance) and "not-so-good moments" (for example, the time taken to accept alternatives to the LD50 test and to accept in vitro tests for skin absorption as OECD Test Guidelines). The importance of dialogue and cooperation between international coordinating centres and scientific activities at the national level is stressed, as exemplified by the work of ECVAM during its first decade.