Revival: Biological Effects of Low Level Exposures to Chemical and Radiation (1992)

BIPHASIC DOSE-RESPONSE RELATIONSHIPS 73

txL/kg) and returned to basal level by 6 hr.84 Serum transaminases in these
rats undergoing sham operation and partial hepatectomy were not altered.
However, these enzymes were significantly elevated in chlordecone-treated
rats following CC1 4 administration (100 /*L/kg). CCl4-induced serum

enzyme elevations were significantly lower in two-days post-partial hepa­
tectomy rats than in sham operated rats. If the early-phase ( 6 -hr) stimula­
tion of hepatocellular regeneration is critical for recovery, protection by
partial hepatectomy should be phased out by seven days, since stimulated
hepatocellular regeneration phases out by then.81 Seven-days post-partial
hepatectomy rats maintained on chlordecone diet were not protected from
chlordecone-potentiated CC1 4 hepatotoxicity, indicating the importance of
the early-phase tissue repair.82 83 The protection against hepatotoxic and
lethal effects of the chlordecone + CC1 4 combination by previously stimu­
lated hepatocellular regeneration might be explained by two consequences
of stimulated cell division:

1. The hepatocellular architecture is renovated by the newly divided cells.


2. Because of the well-known resistance of the newly divided cells,39’116-118 the
   permissive progression of toxicity is obtunded.

The pivotal importance of the early-phase stimulation of hepatocellular
regeneration is also evident when one considers that a large (or massive)
dose of CC1 4 is toxic because of the suppression of the early phase tissue
repair, since the second wave of hepatocellular regeneration (48 hr) remains
intact.84

Additional Evidence in Support of a Critical Role for the
Early-Phase Stimulation of Cell Division and Tissue Repair

Table 4.5 presents a variety of experimental manipulations that permit a

rigorous experimental verification of the existence of, and the critical role

played by, inducible tissue repair in the final outcome of toxic injury. All of

the evidence for the existence of a hormetic mechanism was derived through

efforts to understand the mechanism of chlordecone potentiation of halo-

methane toxicity (Table 4.5).

Partial Hepatectomy

If the basic premise, that suppression of the early-phase ( 6 -hr) stimula­

tion of cell division and tissue repair is the mechanism of chlordecone

potentiation of CC1 4 injury, is valid, then a preplacement of cell division in

the liver should result in protection against the interactive toxicity of chlor­

decone + CC14. When CC1 4 was administered at 2 days after partial hepa­

tectomy at a time of maximally stimulated hepatocellular division, a

remarkable protection was observed.81 At 7 days after partial hepatectomy,

when the stimulated cell division phases out, the interactive toxicity

becomes fully manifested again.81 In these studies, microsomal cytochrome