Toxicology of Industrial Compounds

are different. The compounds brought onto the European market are
labelled and need to fulfill only the legal demands of the specific category
to which they belong.
Testing is only obligatory when they reach the market and the type of
tests needed per category of chemicals is clearly outlined. In Europe legal
categories consist of dangerous compounds (88/379/EEC, 93/18/EEC), 1a,b
phytopharmaceuticals (91/414/EEC, 93/71/EEC), 2 biocides (93/C239/03), 3
cosmetics (76/ 768/EEC, 93/35/5/EEC) 4a,b and food additives. Of the latter
category the most comprehensive surveys are carried out by the Joint
Expert Committee on Food Additives (JECFA) of the World Health
Organization and the Food and Agriculture Organization of the United
Nations (Conning, 1993).
Less sophisticated in vitro studies have been performed on industrial
chemicals and agrochemicals than is the case for pharmaceuticals. The only
field in which isolated hepatocytes have already been incorporated into
routine screening of industrial chemicals for regulatory purposes is in
genotoxicity testing (Swierenga et al., 1991). The potentialities, however,
of in vitro testing for these compounds, in particular of the use of long-term
cultures, has not yet been explored in depth, although induction, inhibition,
biotransformation, chronic toxicity, interaction between chemicals and
mechanistic studies are of great interest for these compounds too.
Human exposure to chemical products such as pesticides, eventually
reaching the food chain as residues or of potential risk for workers and
operators spraying the fields, is such an interesting research area. For
example, Alachlor ® , a herbicide, of which millions of tons are used per
year, has been classified as a potential human carcinogen (Leslie et al.,
1989) because of tumour formation in rats and DNA damage observed in
isolated rat hepatocytes (Bonfanti et al., 1992).
In vivo studies concerning its biotransformation in rat, mouse and
monkey, however, pointed to the observation that Alachlor ® is metabolized
via different pathways in rodents and monkeys, suggesting a lower risk for
man than assumed (internal report Monsanto, 1988). In the future, this
type of biotransformation study could easily be performed with short- and
long-term cultures of hepatocytes derived from different species, including
man, providing relevant human information without interspecies
extrapolation.
Long-term hepatocyte cultures
V.ROGIERS ET AL. 209
During culture, hepatocytes undergo phenotypic changes as a function of
culture time affecting selectively components of phase 1 and/or phase 2
biotransformation (Nakamura et al., 1983; Guillouzo, 1986; Mooney et
al., 1992; Kocarek et al., 1993; Rogiers and Vercruysse, 1993). These
changes are interpreted as dedifferentiation. In the literature, data have