Toxicology of Industrial Compounds

42 METABOLIC ACTIVATION OF INDUSTRIAL CHEMICALS
is excreted in urine. In man and dog the urine is slightly acidic, while in rat
and mouse it is slightly alkaline. Under acidic conditions the glucuronide is
hydrolyzed to generate the hydroxylamine in the bladder. In this case
glucuronidation is not a bioactivation, but rather a targeting
biotransformation: in man and dog the carcinogenic metabolite is targeted
to the bladder, due to the (necessary!) acidic local pH (Kadlubar et al.,
1981).
Conclusions
The above illustrates the importance of bioactivation in toxicity of
industrial chemicals. Is it possible to predict bioactivation from the
structure? As outlined above, in some cases the compound contains
structural elements which make bioactivation to a reactive intermediate
quite likely. Whether it does play a role in toxicity then is still uncertain.
Test systems to detect reactive intermediates depend on, for example, the
availability of the radiolabeled compound; in fact, a very high specific
radioactivity is required to detect low levels of binding. Alternatively,
radiolabelled glutathione can be used for those reactive intermediates that
readily bind to the thiol group of glutathione (Mulder and Le, 1988).
Whether such systems can pick up every relevant toxic reactive
intermediate remains to be seen.
For extrapolation of one species to the other it is important to have
insight into the metabolite that is responsible for the toxicity. Therefore, it
is more than just of academic interest to know the mechanism of toxicity in
safety assessment of industrial chemicals. Unfortunately, it is often not easy
to establish such a mechanism beyond reasonable doubt: it may require too
many rats to feel comfortable about it if we would have to do this for every
chemical used industrially!
References
ANDERS, M.W. (Ed.), 1985, Bioactivation of Foreign Compounds, Orlando, FL:
Academic Press.
ANDERS, M.W. and DEKANT, W., 1994, Conjugation-dependent Carcinogenicity
and Toxicity of Foreign Compounds, Orlando, FL: Academic Press.
BOND, J.A., 1989, Review of the toxicology of styrene, CRC Crit. Rev. Toxicol 19,
227–49.
DANKOVIC, D.A. and BAILER, A.J., 1994, The impact of exercise and
intersubject variability on dose estimates for dichloromethane derived from a
physiologically based pharmacokinetic model, Fund. Appl. Toxicol, 22, 20–5.
ECETOC, 1992, Technical report No. 52, Styrene toxicology. Investigations on the
potential for carcinogenicity, Brussels: Ecetoc.