Development of Alternatives to Animal Use for Safety Testing and Hazard Assessment, continued.

Summary Problem Background/History Animal protection Toxicology and Safety Testing The Process of Change Implementation Definition	Motivation to Adopt In Vitro Testing and SAR: Two Models Obstacles to Implementation Validation International Controversy Current Challenges Literature Review/Bibliography
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Implementation:

The reform strategy of Spira, Rowan and CAAT relies upon productive dialogue and discussion between stakeholders and collaborative efforts to produce change. The scientific benefits of developing new methodologies have also been stressed. The focus of activity is always the respectful exchange of information between parties who may disagree on certain issues, but who are willing to work together to find mutually acceptable solutions. This policy differs profoundly from that pursued by many animal rights groups and defenders of the scientific status quo, who fear that such communication will result in a weakening of their position and unacceptable concessions. “Constructive negotiations are far more productive than ongoing confrontations,” as Spira often noted.

The policy of negotiation pursued by Spira, Rowan, the Hopkins Center and other individuals and groups throughout the world who have adopted a similar outlook has been greatly facilitated by adoption of the replacement, reduction, refinement (3Rs) definition of alternatives proposed by British researchers W.M.S. Russell and Rex Burch in their book The Principles of Humane Experimental Technique, published in 1959. Russell and Burch theorized that pain and distress in research animals inevitably result in inaccurate and misleading experimental data, therefore scientists and other laboratory personnel must eliminate animal suffering and the causes of suffering in order to produce reliable results (Russell and Burch, 1959). To that end, Russell and Burch proposed that scientists refine experimental procedures to eliminate causes of pain and distress, reduce the number of animals to the minimum required to achieve the experimental end, and replace animals whenever possible with either cell and tissue culture models (in vitro studies) or other methodologies. Russell and Burch’s 3Rs thus provide a blueprint for cooperation between scientists and animal protectionists, although they do not satisfy those who wish for immediate abolition of animal research or those who are averse to examining scientific policy and practice.

The cosmetics industry initially adopted the approach described above out of expediency - customers were demanding products that had not been tested on animals and both the media and the public were exerting a great deal of pressure on companies to develop alternative models of testing. Almost immediately many realized that the development of alternatives would benefit the industry in a number of ways. The biochemical assays and databases developed as alternatives would likely cost less and be more predictive of human response than the animal tests they were created to replace. Human cell and tissue culture in particular were regarded as highly promising methodologies which might prove quite useful, once preliminary research was able to identify certain biological endpoints which could be used to predict toxicity.

As historian John Parascandola has noted, “although pressure from the animal rights movement has played a key role in stimulating interest in alternatives to animal experimentation and testing, scientific and economic considerations have also figured prominently in these developments.” (Parascandola, 1991). Development of new methodologies is dependent on scientific advances and technical improvements in tissue culture techniques, for example, have greatly facilitated the development of alternatives just as molecular and cellular approaches have provided a method to explore early biological responses to chemical or physical agents and the role of these early effects in altered cellular structure and function (Sutter, 1995).

The Center for Alternatives to Animal Testing has been a unique resource in the United States because of its association with an academic institution. This affiliation has been crucial in establishing and maintaining CAAT’s reputation as a scientifically based organization attempting to balance the need to protect the health and safety of the public with the goal of reducing, refining and replacing animal use for research, education and testing. CAAT’s association with Johns Hopkins University, one of the premier research institutions in the world, has helped the organization attract scientists (traditionally distrustful of animal protection activity) willing to investigate the development of in vitro methods for product safety testing. CAAT has founded over 200 grant applications since 1981 and organized symposia, workshops and other forums to facilitate the exchange of information between researchers as well as between scientists, animal protectionists and the public (Zurlo & Goldberg, 1999).

(excerpted from Zurlo, Rudacille and Goldberg: Animals and Alternatives in Testing: History, Science and Ethics)

In vitro assays consist of three components--the biological model, the endpoint measurement, and the test protocol. The biological model is the system used for evaluation. The greater the ability of the biological model to represent the in vivo (whole animal) structure and function, the more valuable the data. An endpoint measurement is the yardstick used to predict toxicity (for example, cell death). The test protocol is the schedule of events defining the test; for example exposing liver cells to a test chemical for a certain period of time and measuring the defined endpoint at various times after rinsing the chemical from the dish of cells.

The neutral red assay is an example of an in vitro test designed to provide an indication of cell membrane integrity as an endpoint. In this test, cells are cultured in plastic petri dishes and treated with various concentrations of a test chemical. The neutral-red dye, which is added to the cell culture after rinsing out the test chemical, is accumulated and stored by cells. The amount of dye retained by the cells indicates the number of living cells in the dish. A general test like the neutral-red assay thus provides some indication of cellular responses to chemicals that can then be interpreted as an indication of acute toxicity.

Structure-Activity Relationships (SAR) provide another avenue for research. The hypothesis on which this concept is based states that the structure of a chemical inherently possesses all of the information necessary to predict its toxicity, including the manner in which both the parent chemicals and its metabolites will interact with the macromolecules of a cell. In SAR, biological effects are expressed in quantitative terms. A mathematical equation is prepared to correlate the toxin’s chemical properties with biologic effects. The relationship derived from the equation is used to make predictions about the toxicity of a chemical. Computers are used to establish this relationship.

The transition from animal models to human cells and tissues and other methodologies has been difficult for a number of reasons. First, the search for “quick fix” solutions has been proven a costly error in both economic and public relations terms. The development of alternatives is bound up with the progress of science in developing a deeper understanding of fundamental biological processes. Rarely if ever can a truly predictive test be created without some understanding of the mechanism which creates the effect it seeks to measure. Unfortunately, many members of the public and some animal protection groups believe that the only obstacle standing in the way of immediate abolition of animal use and adoption of alternatives is the stubbornness and ill will of conservative scientists. Unfortunately this is not the case. The replacement of in vivo tests with more predictive in vitro assays is part of an on-going process of scientific discovery, which does not adhere to any particular timetable or agenda. Naturally, many people would like to have replacement alternatives for most endpoints right now, just as many would like to have an AIDS vaccine right now, but both are dependent on the work of individual scientists and research groups and the process of individual insight and creative collaboration which is one of the hallmarks of science.

Notwithstanding these facts, it is clear that the fear of “giving in” to animal protectionists does underlie a great deal of resistance to the 3Rs among many scientists. For example, although many members of the Society of Toxicology are vocal advocates of more predictive tests which are better able to assess human response to chemicals (Goodman, 1999), they vehemently support continued animal testing and reject the 3Rs, for fear that a less militant response will be perceived as supporting the claims of animal protectionists that current animal models are irremediably flawed and ought to be replaced. As Gerhard Zbinden pointed out in 1987, “on balance, one comes to the conclusion that the predictive value of animal tests is not perfect, but better than its reputation.” Broad conclusions about the inefficacy of animal testing immediately alienate scientists who are aware of the utility of many existing protocols in protecting human health and safety.

Some scientists also resent criticism of current practices, and believe that attempts at reform tacitly imply that existing methodologies are cruel and/or inhumane. “When we advocate the Three R’s, we imply that we, as scientists, are currently doing something wrong, that we are a bit ashamed of being forced by necessity to do so, and that we would stop if we could. We appear to defend research use of animals as a necessary evil.” (Burke, 1991) Nonetheless, the underlying message of numerous surveys seems to be that most Americans are willing to accept the use of animals in scientific research when their concerns about animal suffering are taken seriously by the scientific community and adequately addressed. A greater understanding and acceptance of public ambivalence over animal use and the realization that animal use must be justified on a case by case basis and not merely in general terms, might help reduce resistance among scientists to adoption of the 3Rs.