REGULATORY FRAMEWORK AND INFLUENCES

Particularly in the second half of the twentieth century, the regulation of toxicity testing increased tremendously in terms of practice and the types and duration of study conducted. Frequently, slightly different study designs were required in the United States, in Japan, or in Europe. This resulted in duplication of tests and greater use of animals, with associated increases in development costs, which were not associated with significantly better quality of safety evaluation. In phar-maceutical regulation, the progress of the ICH process has contributed greatly to the streamlining of testing programs. This has been driven by industry and the regulatory authorities from the three main pharmaceutical markets. The process is

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likely to continue for the foreseeable future, as our knowledge base develops and as new testing paradigms are produced and debated.

As new or unexpected effects have been detected, especially in the patient or consumer population, new studies or investigative programs have been added to the guidelines. The type of study conducted for a particular class of chemical has also been influenced by precedent, where scientifically irrelevant studies were conducted for regulatory advantage. Omission of the test from future programs for similar chemicals triggered questions from the box-ticking fraternity. The detection of unexpected effects in the human population, particularly for new drugs, inevitably has a huge influence on the practice of toxicological safety evaluation. In particular, the thalidomide tragedy had far reaching effects on testing regimens and methods, and the marked growth in regulatory toxicity and greater regulation can be charted from that point onward.

Legislation, Guidelines, and Animal Use

Animal welfare legislation is also an important factor to consider in toxicity testing, in terms of attainment of ideal housing standards and in the prevention or curtailment of suffering. In order to minimize the number of animals needed, it is important that testing is undertaken in healthy, unstressed animals, factors that have been reviewed in chapter 2. The restraints on excessive use of animals have become stronger over the last 25 years. In the United Kingdom, it is now necessary to seek special Home Office approval, for the use of nonhuman primates and the use of great apes is forbidden. Testing is discouraged in cases where the work is a simple repeat of a study, although the testing of drugs which have come

“off-patent” is a case where tests may be repeated because the original data files are not available to the generic producer. However, in many cases the new studies are conducted to the higher standards of the most recent legislation. Throughout this, the concept of the three Rs is central, the overall aim being to reduce the use of animals through refinement of investigative programs and, where possible, by introduction of methods that replace them altogether.

The move, away from animal experiments for routine toxicological safety evaluation, has been slow and will continue to be so while the science is still grow-ing and, in particular, while regulatory acceptance of the methodology is minimal.

However, progress is being made. Replacement may be exemplified by the use of in vitro screening tests for dermal or ocular irritancy and the replacement of the rabbit in pyrogen testing by use of theLimulus amebocyte lysate test for endo-toxins. Reduction has been achieved through regulatory acceptance of the local lymph node assay, instead of the guinea pig maximization tests in sensitization.

The use of sparse sampling regimens in rodent studies reduces the need for large numbers of satellite animals for toxicokinetic evaluation, an effect that can also be achieved by the use of smaller sample volumes and more sensitive analytical techniques. Refinement of technique includes reduction of suffering by offering environmental enrichment, particularly important in primates, careful selection of dose levels, and the reduction of pain. In particular, the evaluation of acute toxicity

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testing toward the evaluation of severe toxicity rather than death, as required by the classic LD50 test, has markedly reduced animal use and suffering. The LD50 is still a useful concept, however, and may be estimated from the results of early studies and from the single dose toxicity studies that are still required.

Legislative Influences on the Conduct of Testing

The way in which tests are conducted is influenced by a raft of legislation, aiming to protect workers from occupational exposure to hazardous chemicals and, in animal facilities, to allergens and diseases originating from the test system itself.

Regulation for the workplace is provided by the requirements of health, safety, and environmental control, which are present in many jurisdictions around the world. In the United Kingdom, for example, this is covered by the Health and Safety Executive and monitored through the provisions of COSHH (Control of Substances Hazardous to Health). These regulations are aimed at protecting the workers involved in the testing or production of new chemicals, and are the object of occupational toxicology. With some new medicines having therapeutic activity in microgram amounts, the protection of the workforce becomes of paramount importance, even if some of the purpose is slightly cynical and aimed at the avoidance of litigation. The records of worker health, which are retained as a result of legislative programmes such as COSHH will become an important epi-demiological source of data in the assessment of health effects in the future.

Regulatory Conservatism–The Way Forward

The inherent conservatism of regulatory authorities with regard to test models or methods is also a factor to consider. The general requirement is to use test systems or models that have been thoroughly validated, so that the data will provide a secure and fully understood basis for interpretation of the data and their significance for humans. This process of validation is complex and is often tied to extensive ring experiments—a series of similar or replicates of the same protocol performed in different laboratories around the world. There is an understandable tendency to use methods that are understood and have been shown to be reliable in scientific litera-ture. In this way, the local lymph node assay has gradually become more accepted in prediction of sensitivity reactions as a replacement for guinea pigs. The use ofin vitro models in regulatory toxicology is likewise made difficult; at this point, they are clearly acceptable in genotoxicity testing and may become so in some safety pharmacology tests, which can be considered to be a branch of toxicity testing.

The REACH (Registration, Evaluation and Authorisation of Chemicals) process in Europe has added a welcome boost to the efforts to validate and expandin vitro methods, as there is explicit guidance on avoiding unnecessary testing in animals.

Public Perceptions

A further, and important, influence is provided by public and political pressure.

This is rarely influenced by complete appreciation of the scientific data relating to a set of circumstances and is often based on a part set of the data. Partial

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understanding of a complete data set or complete understanding of a partial data set are unlikely to lead to a satisfactory understanding of the mechanisms, leading to a particular set of effects or variation from normal, however, normality is defined. Politics and science are often poor bedfellows and the use of science in political judgments, or vice versa, has to be carefully assessed according to the circumstances of the situation. The results may be overreaction and production of a set of regulations that can have worse consequences than the status quo.

REGULATION OF STUDY CONDUCT—GOOD