Historical perspective on the use of animal bioassays to predict carcinogenicity: Evolution in design and recognition of utility

Abstract

The animal testing protocols used today to evaluate the carcinogenicity of chemicals are very different from those used in the earlier part of the 20th century. To explore how cancer bioassays have changed over time, we surveyed the literature discussing test design and interpretation from the 1930s to the present. We also analyzed compendia of bioassays published by the US Public Health Service (US PHS) from 1938 to 1978, and evaluated the data to understand the evolution of testing methodology (e.g., animals used, test duration) and the types of chemicals being studied. The cancer bioassay evolved in several stages. At the beginning of the 20th century, animal bioassays were primarily used to re-create known human diseases, whereas in the 1940s to 1960s, animal bioassays were largely used to evaluate the safety of chemicals in foods, drugs, and cosmetics. Beginning in the late 1960s and 1970s, chemicals primarily associated with occupational or environmental exposures were also evaluated. Testing strategies now emphasize a suite of tests including multiple in vitro tests and both short-term and long-term animal tests. The objectives of testing are broader, too, with test goals encompassing information regarding mode of action and other parameters aimed at evaluating potential species differences (e.g., in toxicokinetics) and their relevance for evaluating human risks. It is important to consider this evolution when evaluating the testing methodology and scientific conclusions in earlier eras. As toxicology continues to develop, testing methods will continue to change in concert with increased knowledge and understanding.

Keywords::

• Animal bioassays
• animal testing
• cancer bioassays
• chronic animal testing
• historical analysis
• US public health service

Notes

¹Similar difficulties in determining the exact shape of the doseresponse curve at low doses were also encountered in a later study (4800 rats total) involving N-nitrosodiethylamine or N-nitrosodimethylamine (Peto et al., 1991). Although such studies have not resolved the question of low-dose linearity for carcinogens, they have provided extensive data sets that have been used to formulate alternative models for assessing carcinogenic risk (SOT, 1981; Gaylor and Aylward, 2004).

²Recall that dermal studies of multicyclic aromatic compounds (e.g., skin painting studies) were not included in our analysis.