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Table of contents
Contents:
  1. Books: In Vitro Methods in Toxicology
  2. Pharmacology
  3. Journal of Pharmacological and Toxicological Methods

Refinement alternatives are methods that either eliminate or minimize pain and distress or enhance the animal's well-being. The assessment of pain in animals is difficult, but generally one can recognize if an animal is in pain or predict that if a procedure would be painful to humans it would be painful to animals. Just recognizing this can change experimental design. Animal well-being can be enhanced by using appropriate handling techniques and cage sizes, as well as by environmental enrichment techniques well known to the psychological field.

Reduction alternatives are those methods that provide the correct amount of data for an experimental design. It is important to recognize that statistical input must be provided at the earliest stages of experimental design and not once the data has been collected. Not only will this provide better science, it will result in using the correct number of animals -- generally, fewer than when guessing what the correct number should be. These include the use of in vitro methods. Table 1 offers examples that demonstrate how in vitro methods have replaced animals, according to the Three Rs concept, in quality control tests of hormones and drugs, as well as in toxicological research.

According to Russell and Burch, the incorporation of the Three Rs into experimental design led not only to more humane research, but also to better science. Published in , The Principles of Humane Experimental Technique 1 became the foundation of all animal welfare legislation adopted in in both the United States and Europe.

Books: In Vitro Methods in Toxicology

In Russell and Burch reviewed the Three Rs concept with a dozen international colleagues, and confirmed its importance and usefulness. Today there are centers throughout the world that focus on the development, validation, and use of alternatives in the biomedical sciences including toxicology. As the science behind in vitro technology advances, and as results from new methods are shown to be both transferable and reproducible, these alternatives continue to gain acceptance.

Additionally, the scientific community has responded to the substantial public outcry for a decrease in animal use by considering the advantages and limitations of alternatives. Information about alternatives is widely available today through journals, databases, and sites on the World Wide Web devoted to the Three Rs.

These resources will be documented below. However, the word "alternative" has become politicized, and for many in the scientific or animal activist community, it conjures up an image very different from the thoughtful, humane experimental science proposed by Russell and Burch. As a result, at the meeting on the Three Rs, it was decided that the word "alternative" would, when appropriate, have one of the Three Rs in front of it i. Methods for increasing awareness and use of alternatives in the United States and Europe complement each other and, at the same time, demonstrate differences in the political and scientific approach to effecting change on each side of the Atlantic.

The current focus is on the safety testing of cosmetics. In the United States, animal welfare laws have forced institutions to establish ethical review committees and have encouraged the development of refinement procedures through these ethical committees. However, U. The FDA, through its Science Advisory Board Subcommittee on Toxicology, has taken the most active role and, as such, has truly encouraged the development and use of alternatives.

In , the U. ICCVAM is a consortium of 14 different federal agencies trying to help each other identify validated methods that each agency can then assess for its own individual regulatory use and acceptance. The U.

Political pressure to decrease animal testing has created a rush in recent years to get in vitro methods into the regulatory acceptance process. At the same time, the potential for many in vitro methods to be commerically profitable has resulted in a push to bring inadequately developed methods to the commercial market. As a result, validation has suffered from something of the "cart before the horse" phenomenon. Only recently has it been universally recognized that there was a need for a terminology of validation and a coordinated set of approaches.

The scientific community always has required that new methods be proven reproducible, published in peer-reviewed journals, and subjected to additional independent studies before becoming accepted as a new methodology for wide use, i. There are, of course, different experimental approaches to prove that an in vitro method provides the same information as an established animal test.

To reach international consensus with both the scientific and regulatory communities, an agreement was reached on the validation process of toxicity test procedures 3. Studies that were conducted according to these recommendations predominantly in Europe have produced significant and useful information, but have failed to provide validated methods that are accepted by the regulatory community.

Pharmacology

However, the effort provided ECVAM with valuable practical experience in creating a validation process 4. Based on this experience, both the OECD 5 and ICCVAM 6 have developed sets of criteria that describe a necessary set of information needed before regulatory acceptance can be considered and also have provided criteria for regulatory acceptance of methodology. Once these criteria gain international acceptance within the scientific community, it is anticipated that regulatory acceptance will occur.

The next stage of development is to identify the minimum set of criteria that have to be met to gain regulatory acceptance, as well as to consider approaches to implementation. In vitro methods are routinely used by all industries and regulatory bodies in toxicity testing, safety assessment, and risk evaluation, and offer unique advantages Table 2.

With the development and widespread use of the Ames Mutagenic Assay, non-animal testing became routine in both industry and regulatory laboratories. In fact, it is not uncommon to find that the only toxicity studies done and sometimes available in the public literature is an Ames test 7. Within the cosmetics industry, the last several years have seen a remarkable change in the approach to safety evaluation.

Most cosmetics now on the market have not been tested on animals, although some of their ingredients may have been. This is due, in great part, to the available databases and knowledge of chemicals used in the cosmetics industry, but also in part to the development of new methods that have been evaluated by individual companies and incorporated into their safety assessment programs.

As new and never-tested chemicals are found to have potential for development into cosmetics, however, companies that do not use animal tests may find themselves uncertain about the safety of their products unless more, and more adequate, in vitro methods are developed. Within the chemical and pharmaceutical industries, in vitro methods are used in a very different context.

In vitro methods are used to screen compounds for their biological effect and to understand why a specific in vivo response has been obtained in one species and may not be seen in another. Additionally, screens are used to determine within a chemical class the presence or absence of a specific biological effect and to identify mechanism of action either desired or toxic of a chemical or group of chemicals.

It is being recognized that with the advances and changes in chemical synthesis, e. With the advances in genetics and genetic screening approaches, future development for these industries clearly will include the use of either genetically altered cells, or biological- and silicon-integrated chip systems and other complex and sophisticated systems yet to be envisioned. In the past, in vitro methodology was used as the last approach in product development to identify the underlying biology of undesired effects and, in some limited cases such as receptor binding , to assist in product development.

Only recently has this approach been questioned. Today, in vitro methods are used at earlier stages of chemical evaluations 8. The Scientific Group on Methodologies for the Safety Evaluation of Chemicals SGOMSEC has recognized that, at least in acute toxicity testing, in vitro methods can and should play a much more important role in the risk assessment process -- and, in fact, with the appropriate data in vitro methods might completely bypass animal use. In the introduction to 9 , a scheme is presented that can eliminate animal testing in acute oral toxicity.

Journal of Pharmacological and Toxicological Methods

It is presented here as Figure 1. The late Gerhard Zbinden, in his numerous and important contributions to in vitro alternatives, suggested that one did not have to find an alternative to the LD50, one just had to stop using it. It remains necessary, however, to determine acute oral toxicity for a series of related but independent reasons.

The fixed dose procedure, developed in Great Britain by the British Toxicological Society, has several features that demonstrate its applicability and dependence upon the Three Rs concept of alternatives. Animals are killed as soon as the first toxic signs are observed. Additionally, the experimental design reduces the number of animals considerably.

The ATC method has been developed and validated in Germany since It is based on a sequential dosing scheme in which one dose group is used at a time. Depending on the outcome of testing, in the next step the dose is either decreased or increased. A world-wide validation trial confirmed biostatistical prediction that the number of animals per test chemical can be reduced to an average of 7 in the ATC method without losing the accuracy of the LD test.

As was pointed out earlier, acute toxicity testing as envisioned in the SGOMSEC Workshop requires that a series of physico-chemical approaches, databases, and structure-activity relationships be evaluated prior to any biological testing. During recent years, there have been remarkable and rapid changes in structure-activity relationship studies. In the case of therapeutics, rational drug design is clearly a major approach. In the area of toxicology, there have been both commercial and non-commercial databases developed to explore structure-activity relationships. In the area of skin sensitization, incredible progress has been made.

The work of Barratt and colleagues, among others, 10 11 12 13 14 15 document the use of QSARs for corrosivity and skin sensitization testing. Although these methods are not percent predictive, in the area of corrosivity and skin sensitization studies, the success rates are quite remarkable. Coupled with other physico-chemical methodologies and in vitro studies, these QSARs clearly will eliminate the need for animal testing.

Due to the availability of these methods, and an abundance of knowledge about corrosivity, it is inappropriate to use either whole animals or humans for severe corrosivity studies. A recent paper by Goldberg and Maibach 16 has provided a review of dermal toxicity and the use of in vitro and other alternative approaches in risk assessment. Building a knowledgebase of these key events will assist in establishing the relevance of test systems. It is important to note that AOPs are designed to be parsimonious descriptions that can be used for regulatory purposes, rather than detailed mechanistic descriptions of systems toxicity networks.

The aim is to identify as many key events as necessary but as few as possible. In investigations using laboratory animals, increasing importance should be directed to characterizing the mode of action with less emphasis to end points based on histopathological criteria, body and organ weight, and blood chemistry. It focuses on regulatory hazard and risk assessment rather than on individual test methods. Many pieces of the puzzle are emerging from various places, e.

These structural alerts can be used to prioritize chemicals by NR-mediated pathways to hepatic steatosis. Similarly, Mekenyan and colleagues 78 computationally linked chemicals to MIEs involved in respiratory sensitization based on absorption into epithelial membranes physicochemical rules and electrophilic reactivity simulating metabolism. They further evaluated the predictive accuracy of their approach using known respiratory sensitizers.

Similarly, Roberts and Aptula 79 studied electrophilic reactivity in the context of skin sensitization potency.