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

74 BIOLOGICAL EFFECTS OF LOW LEVEL EXPOSURES

Table 4.5. Evidence in Support of the Proposed Mechanism

Experimental

Manipulation Findings References

1. Preplaced cell division
   and tissue repair by partial
   hepatectomy

Protection from chlordecone + CCI4 81-84

2. Toxicity of a large
   dose of CCI4

Early-phase stimulation

of tissue repair is ablated

84,88

3. Hepatocytes isolated
   from chlordecone-treated rats
   incubated with CCI4
   (isolated hepatocytes
   do not divide in vitro)

No potentiation in contrast

to in vivo

119

4. Developing young
   rats have growing
   livers

Resilient to chlordecone + CCI4 121

5. Gerbils lack the
   early-phase tissue
   repair

Low dose of CCI4 is

highly toxic

41,42

Do not have early-

phase tissue repair

to suppress

Chlordecone does not

potentiate CCI4 toxicity

41,42

Preplaced tissue repair

by partial hepatectomy

Resiliency to CCI4 toxicity 122

6. CCI4 autoprotection Due to prestimulation of early-

phase tissue repair by the

protective dose

48

7. Selective ablation of
   the early-phase hormesis
   by colchicine

Prolongation of hepatotoxicity

of a low dose of CCI4 by 24 hr (until

the second phase of cell division at 48 hr

ensues to overcome injury)

128-130

Colchicine given 2 hr

before the protective dose

of CCI4

Abolishes CCI4 autoprotection

entirely

131

P-450 content is decreased by partial hepatectomy, but remains at the

decreased level even 7 days later, when protection is no longer evident.

Moreover, actual in vivo bioactivation, and overall disposition of 14 CC14,

are unperturbed by partial hepatectomy.86

Toxicity of Large Dose is Due to Ablation of the Hormetic Response

An implication of these findings is that the toxic effect of a large dose of
CC1 4 might be a consequence of suppressed early-phase cell division and
tissue repair. When a large dose of CC1 4 was administered, the early-phase
cell division 8185 108 109 normally stimulated by a low dose of CC1 4 was ablated
entirely.48’84 88 These findings indicate that the real difference between a low
and a high dose of CC1 4 is the presence or absence of hormetic response in