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 comp
ensatory 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 q
uantifying injury might be helpful in tomorrow's risk assessment. Stud
ies with model hepatotoxicants such as thioacetamide and CCl4, where t
issue repair as well as injury were measured, reveal that endogenous m
echanisms that drive the tissue repair response are responsible for mo
re than just compensation for tissue injury. Up to a threshold dose, t
issue 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 d
eath. While dose-related stimulation of tissue repair leads to recover
y, delayed and diminished tissue repair seen at the high doses leads t
o tissue destruction and animal death. These findings impact on the cu
rrently 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 a
nd injury as simultaneous biological responses to toxic agents might i
ncrease the usefulness of dose-response paradigms in risk assessment.