BIPHASIC DOSE-RESPONSE RELATIONSHIPS 69Figure 4.4. Proposed mechanism for the highly amplified interactive toxicity of
chlordecone + CCI4. The scheme depicts the concept of suppressed
hepatocellular regeneration, simply permitting what is normally limited liver
injury caused by a subtoxic dose of CCI4 to progress in the absence of
hepatolobular repair and healing mechanisms stimulated by the limited
injury. The limited hepatotoxicity from a low dose of CCI4 is normally
controlled and held in check by the hepatocellular regeneration and
hepatolobular healing. The chlordecone + CCI4 combination treatment
results in unabated progression of injury owing to a lack of tissue repair
obtunded due to lack of cellular energy. These events lead to complete
hepatic failure, culminating in animal death. Ongoing studies indicate that a
very similar mechanism is responsible for the amplification of CHCI3 and
BrCCI3 toxicity by chlordecone. Adapted from Mehendale16 and
Karunaratne.25frame, as the animal continues to exhale the remaining CC14, would be an
added critical defense mechanism. At later time points (12 hr and onwards),
most of the CC1 4 would have been eliminated by the animal, and hence
continued cellular regeneration during this time period and at later time
points allows for complete restoration of the hepatolobular architecture
during and after the progressive phase of injury.82 85
Administration of the same low dose of CC1 4 to animals maintained on
food contaminated with low dose of chlordecone results in initial injury by