PRINCIPLES OF TOXICOLOGY

16.13 TOXIC PROPERTIES OF REPRESENTATIVE HALOGENATED SOLVENTS 395
damage and cardiac sensitization in animal studies, although the latter has been demonstrated in
animals only when adrenaline is injected and the practical significance of these findings to industry is
considered to be low.
Although studies with methylene chloride in an Ames test with Salmonella typhimurium TA98 and
TA100 resulted in increased reversions in both strains of bacteria, observed effects were limited. Other
tests of genotoxic potential are typically negative.
Methylene chloride was not positive in a pulmonary tumor assay in strain A mice. Although it is
regulated by USEPA and some occupational agencies as a potential carcinogen, methylene chloride
does not appear to present a practical risk of carcinogenesis in humans at currently acceptable levels
of exposure.
Chloroform (see Figure 16.22), or trichloromethane, was used for many years as an anesthetic,
solvent, insecticide, and chemical intermediate. Because of delayed liver injury and reports of cardiac
sensitization, its use as an anesthetic is obsolete. Chloroform is presently considered a carcinogen by
USEPA and some other agencies, based on animal studies. Chloroform may be produced at low levels
during the chlorination/disinfection of water.
As with other volatile solvents, inhalation is considered the main exposure route for chloroform.
Much of the toxicological information available has been developed following the interest in chloroform
as a CNS depressant or anesthetic, and high concentrations of chloroform may result in narcosis,
anesthesia, and death. Rapidly absorbed and distributed in all organs, chloroform is exhaled for the
most part unchanged, or as carbon dioxide. Chloroform appears to be the most cardiotoxic of the
anesthetics, with effects that are the least reversible. It is known to cause permanent hepatic and renal
injury following sufficient exposures, and hepatic necrosis has been reported in humans following
ingestion of pharmaceutical preparations containing 16.5 percent chloroform.
Signs of severe chloroform exposure in humans include a characteristic sweetish odor on the breath,
dilated pupils, cold and clammy skin, initial excitation alternating with apathy, loss of sensation,
abolition of motor functions, prostration, respiratory depression, cardiac sensitization to adrenaline,
unconsciousness, coma, and death. Lethal exposures to chloroform may be delayed and may result
from associated kidney or liver damage. Responses associated with exposure to chloroform concentrations
below the anesthetic level, including occupational exposures, are typically inebriation and
excitation passing into CNS depression.
PHYSIOLOGIC RESPONSE TO CHLOROFORM IN HUMANS
Concentration (ppm) Response
200–300 Odor threshold
4100 Vomiting, sensation of fainting
14,000–16,000 Narcotic limiting concentration
Chloroform appears to be unique among the smaller chlorinated aliphatics in that it is the only one
that has been reported to be teratogenic and highly embryotoxic in animals. It has been found in
Figure 16.22 Chloroform.