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

62 BIOLOGICAL EFFECTS OF LOW LEVEL EXPOSURES

hepatic lesion is characterized by centrilobular necrosis,25 the extent of
injury depending upon the dose. Demonstration of the metabolism of CC1 4
to CHC1 3 and to C02,26,27 and covalent binding of CC1 4 to liver protein and
lipid,19,27 lend experimental support to the bioactivation theory of CC1 4
injury.15 28

Bromotrichloromethane and Chloroform Toxicity

Hepatotoxicity of BrCCl3, a brominated analog of CC14, is also due to its
metabolism to the same *CC1 3 radical formed from CC14.18 29-31 Much greater
toxicity of this compound29,30 in comparison to CC1 4 has been attributed to
the relative ease with which the C-Br bond can be cleaved.18 A clear inverse
relationship exists between the bond dissociation energy of this series of
halomethanes (BrCCl 3 < CC1 4 < FCC1 3 < HCC13) and their potency to
initiate free-radical reactions,12-16 to produce lipid peroxidation, and to pro­
duce liver necrosis.
With regard to CHC13, several investigations suggest that phosgene, a
reactive metabolite of CHC13, is responsible for its hepatotoxic,32 33 nephro­
toxic,34 and possibly its carcinogenic 32 35 effects. Hepatotoxic effects are due
to phosgene-mediated cellular glutathione (GSH) depletion in tandem with
the increased covalent binding to hepatocellular macromolecules.3236
Although, like CC14, CHC1 3 also needs metabolic activation to exert its full
necrogenic potential, unlike CC14, lipid peroxidation is not involved in hep­
atocellular necrosis. Recently, however, lipid peroxidation has been claimed
in CHC1 3 toxicity.37 38 A second important distinction is that, unlike CC14,
metabolism of CHC1 3 to a free-radical form has not been associated with its
necrogenic action.32 Recent studies on CHC1 3 toxicity have involved mouse
hepatocyte primary cultures 39 and Mongolian gerbils.40-42

Mechanism of CCI4-Autoprotection

A small dose of CC1 4 is known to protect against a subsequently adminis­

tered large dose of CC14.43-46 Several lines of evidence have accumulated43-46

to establish that the mechanism of this “autoprotection” is related to the

destruction of liver microsomal cytochrome P-450 by the initial protecting

dose of CC14. Reports 121319 47 demonstrating the destruction of a specific

form of cytochrome P-450 provide additional support for *CC1 3 free-radical

mediated destruction of cytochrome P-450. This presumably results in com­

promised bioactivation of a subsequently administered large dose of CC14.

Since bioactivation of CC1 4 is an obligatory step for CC1 4 injury, the subse­

quently administered large dose of CC1 4 cannot inflict massive liver injury

as would be ordinarily expected.1213 Recent time-course studies have

revealed that actual liver injury sustained by the autoprotected animal is

indistinguishable from that sustained by an animal not receiving the protec­

tive dose of CC14. These findings have prompted a search for an alternate