70 BIOLOGICAL EFFECTS OF LOW LEVEL EXPOSURES
the same mechanisms of bioactivation of CC1 4 and lipid peroxidation (Fig
ure 4.4). The liver injury in this case is slightly greater due to the approxi
mately doubled rate of bioactivation of CC1 4 in livers of animals preexposed
to chlordecone.15,55,106 The liver injury, thus initiated, enters the progressive
phase between 6 to 12 hr, and this phase is accelerated in the absence of
tissue repair mechanisms.82 85108109 The highly unusual amplification of
CC1 4 toxicity relates to the suppression of the initial hepatocellular regener
ation, otherwise ordinarily stimulated by CC1 4 within 6 hr (Figure 4.4).
The mechanism responsible for the abrogation of this hormetic mecha
nism of stimulated cell division is of significant interest. At this juncture,
experimental observations permit invoking a role for hepatocellular bank
ruptcy in cellular energy. Under conditions of increased hepatocellular
injury, mobilization of hepatic glycogen is initiated in order to stimulate
hepatocellular division.109-114 Under these conditions of increased demand
for cellular energy (augmented need for extrusion of extracellular Ca2+
from the cells, protection against free-radical mediated injury, etc.), the
hepatocytes are incapacitated due to insufficient availability of cellular
energy. As a result, stimulation of cell division, which normally occurs after
the administration of a low dose of CC14, cannot occur. The failure of cell
division has two important implications:
- Hepatolobular structure cannot be restored.
- Unavailability of newly divided, relatively resistant cells predisposes the
liver to continuation of liver injury during the progressive phase (6 to 12 hr
and beyond).14-16’55’114,115
Permissively progressive injury continues unabatedly as a consequence of
the mitigated tissue repair mechanisms, leading to massive hepatic fail
ure,5556’91" followed by animal death.14-16
Many studies have shown a biphasic increase in hepatocellular Ca2+ levels
in CC1 4 toxicity.111 The unusual aspect of excessive Ca2+ accumulation
observed in livers treated with the chlordecone + CC1 4 combination is that
it occurs at a dose of CC1 4 not ordinarily associated with the causation of
increased intracellular Ca2+. Furthermore, chlordecone alone, even at a 10-
fold higher dose than used in the interaction studies, does not increase
hepatocellular Ca2+.15,111 Although in vitro studies with cellular organelles
have been employed to speculate that the failure of organelle Ca2+ pumps
leads to increased cytosolic Ca2+ levels, our studies indicate that at no time
did these organelles contain decreased Ca2+.15,111 Indeed, the only signifi
cant change observed with regard to organelle Ca2+ is increased Ca2+ in the
organelles in association with increased liver injury.14111 Therefore, there is
no in vivo evidence for decreased Ca2+ content in the organelles, which is in
contradiction to the predictions from the in vitro findings.114115
The primary mechanism leading to a highly amplified toxicity is a failure
on the part of the biological events leading to hepatocellular division.
Increased accumulation of extracellular Ca2+ during the progressive phase