Perspectives on alternatives to current animal testing techniques in preclinical toxicology

It has not been possible in this review to consider thoroughly all possible methods of alternative toxicology testing, but the examination of acute toxicity tests, eye irritancy testing, and fetal toxicity testing should provide a reasonable introduction to the meaning and scope of the concept of alternatives in the field. Greater attention to and support for alternatives to animal testing will not only provide ways to alleviate animal stress and societal pressures, but will in addition bring major benefits to the science of toxicology. An empirical search for in vitro tests that correlate with various toxic endpoints will not only be insufficient, it will be detrimental. Developing superior methods for safety evaluation will be much more possible if in vitro tests are investigated mechanistically. Cell cultures, both animal and human, will be used to their full potential only when culture techniques are considerably improved. Fully defined growth media that will support the growth of a wide range of defined cells must be developed. It is now possible to maintain and grow many different types of cells that express differentiated function in vitro. For example, changing culture conditions allowed one group of investigators to establish a thyroid cell line that expressed differentiated thyroid cell characteristics even after three years of continuous culture (148). Beating heart cells can be maintained for a week in good condition and have been used to investigate anesthetic (149) and isoproterenol (150) cardiotoxicity. Computer-assisted structure-activity relationships in toxicology have not yet been developed. As toxicology data bases and our understanding of mechanisms improve, so will the potential applicability of quantitative structure-toxicity relationships (61, 151, 152). Current techniques are slowly being improved, refined, and applied where appropriate. Yet even as new tests or approaches become available, a lack of general acceptance can retard their use. In toxicology testing, established methods tend to be set in stone. Even where new approaches seem an improvement and have widespread scientific support, explicit or implicit guidelines are slow to change. Replacing the classic LD50 test with an acute test using fewer animals was proposed in 1968 (44) and has been reproposed many times since, for example. With the exciting advances now taking place in the disciplines that contribute to toxicology (e.g. molecular biology, cell biology), the time is opportune for academic, industrial, and regulatory toxicologists to explore new avenues for safety evaluation. This will mean discarding tests that no longer do what they are meant to and developing new ones that provide better assessments of potential human hazards.