Reduction and replacement of laboratory animals in toxicological testing and research. Interim report 1984-1987

The reasons reduction and replacement of laboratory animals are advancing rapidly in basic biomedical research, and why in industrial toxicology progress is much slower, are analyzed. Reference is made to a previous report from our laboratory, and the general concept of the program is outlined. Encouraging developments concerning acceptance of new concepts in acute toxicity testing by various regulatory agencies are reviewed (OECD, IKS, EEC, and Bureau of Pharmaceutical Affairs, Ministry of Health and Welfare, Japan). On the basis of new concepts proposed by the British Toxicology Society, a program which attempts to evaluate acute toxicity of chemicals as far as possible without causing mortality was started. Continuous in-cage monitoring of motility of animals, regular control of general health, body weight, food and water consumption, and body temperature are used as variables. The possibilities of reducing animal use in toxicology by application of toxicological screening procedures are explained. Screening tests under development include an operant conditioning technique to detect adverse drug interactions with ethanol and a procedure for the detection of nephrotoxic properties. The successful completion of a collaborative program designed to upgrade toxicity testing with contraceptive steroids and to abolish the 7-year beagle and 10-year monkey studies is reported. The application of in vitro cytotoxicity tests for assessment of irritant and corrosive properties of chemicals is discussed and some encouraging progress on regulatory acceptance of such tests (OECD) is reported. A new test developed at the institute is described. An in vitro model for the investigation of chemically induced changes of collagen synthesis in human fibroblasts is presented. Other cell culture methods under development include a culture system of chick brain, retina, and menings cells for the study of neurotoxic chemicals and neurobehavioral teratogens, primary hepatocyte cultures for the study of drug effects on DNA and protein synthesis and ploidy, using flow cytometry, and various in vitro models for the assessment of genotoxic and tumor-promoting activities and malignant cell transformation. The problem of analgesic treatment of animals with chronic pain was investigated. Several analgesics were evaluated, and treatment modalities providing demonstrable analgesia for prolonged periods of time in mice and rats were worked out.