Issues of biochemical applications to risk assessment: how should the MTD be selected for chronic bioassays?

Early to mid 1950s Major emphasis on chronic toxicity rather than carcinogenicity Estimates of human exposure factored into procedures Early to mid 1960s Use of exaggerated (lethal) doses for qualitative screening of carcinogenicity potential Crude basis for dose selection Early to mid 1970s Lengthening of duration of dosing with maximal doses compatible with long-tenn survival of sufficient numbers of animals Slight improvements in crude basis for dose selection Early to mid 1980s Carryover of previous philosophy, but recognition of need for more seientifically valid basis of dose selection More definitive subehronic studies Critical role of dose-related kinetics Avoidance of nonphysiological conditions of treatment Recognition of the need for relevance to known or anticipated levels of human exposure Environmental Health Perspectives Vol. 76, pp. 169-174, 1987