Toxicology of Industrial Compounds

The bioactivation to reactive intermediates by oxidative, cytochrome
P450-mediated metabolism has been extensively studied. So much so, that
it is often overlooked that conjugation reactions may similarly convert
stable compounds into reactive, electrophilic metabolites (Anders and
Dekant, 1994). This is of some practical importance, because many rapid
in vitro toxicity screening tests, e.g. for genotoxicity, include only oxidative
biotransformation capacity (microsomal fractions plus NADPH). In such
screening systems the possibility that, for example, glucuronidation,
sulfation or glutathione conjugation may activate a chemical is not
assessed. Examples of bioactivation of industrial chemicals by glutathione
conjugation are various halogenated hydrocarbons, while in 2naphthylamine
toxicity glucuronidation may play a role. All in all,
however, little information is available on the role of conjugation. As a
consequence, it is unclear at present whether conjugation reactions are of
major concern for bioactivation of industrial chemicals in general. It
certainly seems worth while for reasons more than just scientific curiosity
to include conjugation reactions in test systems. This can be done by using,
for example, intact hepatocytes (or other cells), or by using a mix of
cosubstrates for conjugation in combination with an S9 fraction (consisting
of both cytosol and microsomal fraction). UDP glucuronic acid, a sulfate
activating system, glutathione, acetyl-CoA and S-adenosylmethionine
would cover the major conjugation reactions.
A role of bioactivation in the toxicity of many chemicals has been
demonstrated. Chemical groups that often are involved in mutagenic or
carcinogenic effects have been identified (‘alerting groups’). However, as yet
it is still impossible to predict with certainty the carcinogencity of a
compound based only on its chemical structure, although a panel of
experts can make quite good guesses (Wachsman et al., 1993).
In this chapter some of the major issues will be illustrated by the
examples vinyl chloride, styrene (versus styrene oxide), benzene,
dichloromethane, chloroform, 1,2-dibromoethane and 2-naphthylamine.
Vinyl chloride
G.J.MULDER 37
High exposure of workers to vinyl chloride in the past has led to the
realization that it may cause neoplasms in man, in particular
haemangiosarcomas in the liver. Vinyl chloride is a genotoxic compound
that acts as initiator of various types of tumors (Swaen et al., 1987).
The major routes of bioactivation of vinyl chloride are shown in
Figure 3.1. The most important first step is oxidation by (a) cytochrome
P450 species, resulting in a rather reactive epoxide, which readily
rearranges to chloroacetaldehyde. This may bind to DNA bases, especially
the N6 of adenosine or the N4 of cytidine, yielding N-ethenoadducts.
Glutathione provides protectionbecause it traps the reactive intermediates