Toxicology of Industrial Compounds

40 METABOLIC ACTIVATION OF INDUSTRIAL CHEMICALS
avidly to thiol and amine groups in protein. In mice the kidney toxicity is
much more pronounced in males than in females; this sex-difference is due
to the much higher activity of the bioactivating cytochrome P450 species in
male mouse kidney than in the females (Pohl et al., 1984). Chloroform also
increased the tumor incidence in the liver and kidney in some experiments
(Reitz et al., 1990), at dose levels which damaged these organs. However,
there are no indications of mutagenicity or genotoxicity in in vitro or
animal in vivo systems. Therefore, most likely the increased tumor
frequency in animals is due to tissue toxicity, leading to increased cell
turnover and a mitogenic stimulus. This is an important distinction, at least
in some countries such as The Netherlands, because for such chemicals a
threshold approach is allowed, whereas for initiating chemicals a linear
extrapolation for carcinogenic risk is used.
Benzene
Benzene presents something of a mystery in the evaluation of its toxicity
mechanism (Swaen et al., 1989). Exposure to high levels of benzene has
been associated with leukaemia in man. However, in vitro it shows little
genotoxicity, and it hardly generates DNA adducts when it is given even at
high dose to animals. A candidate for DNA damage could have been the 1,
4-dihy-droxybenzene (hydroquinone) metabolite, which, however, does not
form DNA adducts readily. Recently a ring-opened metabolite, the
trans,trans-muconic dialdehyde has been proposed as a possible reactive
metabolite of benzene (Figure 3.4). Whether it really plays a role in
benzene toxicity is unclear as yet (Kline et al., 1993).
Dichloromethane
Dichloromethane can be metabolized by two pathways, an oxidative and a
conjugative route. Oxidation catalyzed by P450 yields carbon monoxide
(Figure 3.5). The glutathione pathway generates a reactive intermediate,
which is mutagenic and has been implicated in the hepatocarcinogenic
effect of dichloromethane in mice. It could be shown that the human liver
has a negligible activity of the glutathione transferase involved, so that the
risk for hepatocarcinogenesis in man is virtually non-existent (Green et al.,
1988; Reitz et al., 1989; Dankovic and Bailer, 1994). This example
illustrates how insight into the mechanism of bioactivation enables a more
reliable species extrapolation in terms of hazard and risk.
1,2-Dibromoethane
This compound can be conjugated with glutathione to form a reactive
thiiranium ion which forms adducts with DNA. This is the reason for the