PRINCIPLES OF TOXICOLOGY

392 PROPERTIES AND EFFECTS OF ORGANIC SOLVENTS
observed following prolonged exposure. While dioxane has been reported to be carcinogenic based
on animal data, the mutagenicity data have been generally negative, suggesting an epigenetic mechanism
(see Chapter 13).
16.13 TOXIC PROPERTIES OF REPRESENTATIVE HALOGENATED SOLVENTS
Many halogenated (e.g., chlorinated, brominated, fluorinated) solvents are widely used in industry for
metal degreasing extraction processes, refrigerants or aerosol propellants, paint removers, fumigants,
as precursors in the manufacture of fluorocarbons, and as chemical intermediates in numerous chemical
syntheses. They are largely nonflammable, and they generally exhibit potent anesthetic properties;
several halogenated alkanes are the systemic anesthetic agents of choice in contemporary surgery (e.g.,
enflurane, halothane). Halogenated hydrocarbon anesthetics have negative effects on muscular rhythmicity
and contractility as well as nerve conduction velocity (negatively chronotropic, inotropic and
dromotropic, respectively) at concentrations that typically are effective for anesthesia.
Halogenated compounds may exhibit strong dermal irritant effects. Brominated compounds are
more toxic systemically and locally than chlorinated compounds, while fluorine replacement of the
chlorine may decrease the observed toxicity. A drawback to the widespread use of halogenated alkanes
is that some of these compounds (e.g., 1,2-dichloroethane) have been shown to induce liver cancer in
rodent bioassays, although this rarely has been confirmed in human epidemiology studies. Also, many
highly substituted halogenated alkanes are environmentally persistent.
Chronic exposure to certain haloalkanes has been implicated in human cases of degenerative cardiac
disease. This speculation has resulted in investigations of the cardiodepressant mechanisms of
haloalkanes, their capacity for interference with energy production, and their effect on intracellular
calcium transport between subcellular compartments. Halogenated alkanes may sensitize the heart to
endogenous epinephrine or to β-adrenergic agonist drugs. The cardiotoxicity of low-molecular-weight
halogenated hydrocarbons is considerably greater than that of low-molecular-weight unsubstituted
hydrocarbons. Systemic toxicity of chlorinated haloalkanes to humans typically increases with
increasing molecular size, the degree of halogen substitution, and the number of unsaturated bonds
(e.g., progression from ethanes to ethenes). Conversely, halogenated substitution of the aromatic ring
may significantly decrease the systemic responses in humans.
Halogenated aliphatics, particularly those with short alkyl chains and one or more chlorine or
bromine atoms, constitute a class of chemicals that are acutely nephrotoxic and hepatotoxic in
experimental animals. Experimental evidence suggests that the nephrotoxicity is related to metabolic
products, rather than the parent haloalkane.
Representative Halogenated Methane Compounds
Structures of methyl chloride and bromide are shown in Figure 16.20. Methyl chloride (or chloromethane)
is used as a refrigerant, aerosol propellant, “blowing” agent for plastic foams, solvent,
and as a chemical intermediate in methylating reactions. Industrial exposure typically has involved
operations in which foamed plastic is cut or shaped. While methyl chloride use as a refrigerant is rare,
occasional exposure reports related to leaking equipment still occur. Since methyl chloride is an
odorless gas at room temperature, its use should be restricted to well-ventilated areas. Inhalation is
considered the only significant route of toxic exposure under typical industrial environments. Most
cases of intoxication by chloromethane have involved air concentrations above 500 ppm and the major
problem encountered in mild exposure is a state similar to drunkenness or inebriation. The onset of
symptoms following exposure to methyl chloride may be confused with mild viral illness; in cases of
more severe intoxication the symptoms can be delayed for many hours and may be mistaken for viral
encephalitis or heavy-metal poisoning. Toxicity of selected halogenated methanes increases in the
following order: methyl iodine, methyl bromide, methyl chloride.