Toxicology of Industrial Compounds

P.J.VAN BLADEREN AND B.VAN OMMEN 67
chloropropane evidence has been accumulating recently, implicating a
glutathione-mediated activation pathway in the renal and testicular toxicity
associated with this compound (Pearson et al., 1990). Interestingly,
consecutive formation of two episulfonium ions can occur, and in fact bis-
DNA-adducts have been identified (Humphreys et al., 1991). 1,2-
Dibromochloropropane could thus cross-link DNA strands as the initial
step leading to cell death.
Isoenzyme selectivity for both primary reactions has been studied
extensively. The alpha and theta class glutathione S-transferases are
responsible for the conjugation of EDB both in rats and man. For both of
these enzymes enormous differences in levels between individuals have been
found, which may be due to genetic differences, but are certainly also
influenced by induction. One might expect individuals with an increased
relative amount of glutathione S-transferases to be at increased risk.
Reversible glutathione conjugates acting as transporting
agents
Numerous substrates for glutathione conjugation exist where a formal
addition takes place: both the glutathionyl residue and the hydrogen atom
are added to the acceptor molecule. From a chemical point of view, this
reaction should be relatively easily reversible. Of course, the extent of the
occurrence of the reverse reaction depends on the position of the
equilibrium and is influenced by such conditions as the concentration of
the reactants and the pH. The biological consequences of this reaction
sequence would be that the original electrophile is detoxified initially, but
not permanently: it can be released again and thus appear in unexpected
parts of the body. The glutathione conjugate serves as a storage or
transport form for the alkylating agent. Systemic effects of highly reactive
compounds might be explained in this way.
For both isothiocyanates and isocyanates evidence for this pathway has
been obtained. Benzyl and allyl isothiocyanate are both naturally occurring
compounds that are excreted mainly as mercapturic acids in urine after
administration to rats (Brüsewitz et al., 1977). However, the mercapturate
in urine is unstable under basic conditions and reforms the free
isothiocyanate. The glutathione, cysteine as well as N-acetyl-cysteine
conjugates derived from these isothiocyanates are all toxic in vitro
(Bruggeman et al., 1986, Temmink et al., 1986). In vivo, the fact that the
conjugates are somewhat more unstable in urine probably plays a role in
the effects. Benzyl isothiocyanate is used for the treatment of bladder
infections (Brüsewitz et al., 1977), while allyl iso-thiocyanate causes
bladder tumors in male rats (Dunnick et al., 1982).
The extremely reactive and toxic methyl isocyanate, used in the
manufacture of carbamate pesticides, was released into the atmosphere in