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278 CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGICAL CONSIDERATIONS

Cells are capable of repairing minor damage, but extensive damage leads
to cell death. This takes place through either necrosis, which is a chemical-
driven chaotic and passive process, or programmed cell death, apoptosis,
which is a genetically controlled and energy consuming process, Apoptosis is
also a part of normal cell physiology in organogenesis during the development
of the embryo before superfluous cells commit a form of cellular suicide by ac-
tivating their apoptotic programs. However, many chemicals, e.g., several
quinone oxidants, and heavy metals may overtly augment apoptosis in adults
when it can turn into a pathological process. Thus, cell death is a crucial toxic
injury which is affected by the rapidity of the cell injury as well as the target
organ. It is noteworthy that the dose of a compound may determine whether
cells will proliferate in a tissue or undergo apoptosis or necrosis (see Fig. 5.43
64 89 91
for necrosis and apoptosis). ' '
Cells in various tissues such as liver, kidney, or gastrointestinal tract, have
a remarkable capacity to repair injuries inflicted by chemicals. Furthermore,
the ability of most organs to fulfill their functions usually far exceeds require-
ments that they need to perform. For example, humans can live with one lung,
one kidney, and only part of their liver. In this regard, the central nervous sys-
tem is an exception because neuronal cells do not regenerate. However, even
neuronal cells are capable of compensating for an injury. This does not take
place through the replacement of dead cells but through the outgrowth of new
extensions of existing neurons and through the formation of new synapses,
i.e., contacts between neurons that allow chemical neurotransmission between
neurons. Even though many toxic effects are due to cell death, toxicity may

FIGURE 5.43 Left External and internal stimuli triggering various cellular responses including apto-
sis. Right Comparison of morphologic characteristics of necrosis (top) with apoptosis (bottom). A norma!
cell (top, A) usually begins the process of necrosis with an initial phase of generalized swelling (top, B),
which progresses to a dissolution of organelles and rupture of plasma membranes (top, C). The earliest
phase of apoptosis (bottom, A) involves retraction from adjacent cells, loss of specialized surface struc-
tures, shrinkage with condensation of cytoplasm, margination of compacted nuclear chromatin, and
localized protrusions of the cell surface. Nuclear fragmentation may occur at this time. In the next
phase, the protuberances of the cell surfaces separate into multiple membrane-bound bodies (apoptotic
bodies) that contain nuclear remnants and intact organelles. The apoptotic bodies are then engulfed and
degraded by resident tissue cells (bottom, C) or phagocytes. Note that the light microscopic appearances
of nuclear rupture and chromatin disintegration (karyorrhexis) may be seen in both late necrosis (top, C)
and apoptosis (bottom, B). Modified from Searle et al. l04