Injury and repair as opposing forces in risk assessment

Recent advances in our understanding of the toxicodynamic events that follow infliction of injury have helped us to bridge the link between the tissue injury and the final outcome of that injury. In addition to infliction of tissue injury, toxic chemicals induce a biological compensatory response of tissue repair intended to overcome tissue injury through healing. Since stimulation of tissue repair is a simultaneous response accompanying injury, measuring this response in addition to quantifying injury might be helpful in tomorrow's risk assessment. Studies with model hepatotoxicants such as thioacetamide and CCl4, where tissue repair as well as injury were measured, reveal that endogenous mechanisms that drive the tissue repair response are responsible for more than just compensation for tissue injury. Up to a threshold dose, tissue repair is stimulated in a dose-dependent manner, and above this threshold it is both delayed and diminished. During this delay, tissue injury progresses unabated leading to tissue destruction and animal death. While dose-related stimulation of tissue repair leads to recovery, delayed and diminished tissue repair seen at the high doses leads to tissue destruction and animal death. These findings impact on the currently used maximum tolerated doses (MTDs) in cancer bioassays. MTDs represent maximal stimulation of cell proliferation thereby enhancing the likelihood of errors in DNA replication. Measuring tissue repair and injury as simultaneous biological responses to toxic agents might increase the usefulness of dose-response paradigms in risk assessment.