Toxicology of Industrial Compounds

230 PEROXISOME PROLIFERATION
intended usage of the particular compound. While hypolipidaemic agents
are only administered to a restricted population of humans, exposure to
industrial chemicals such as plasticisers is obviously far more widespread.
For example, based on food surveillance surveys the daily human exposure
to DEHA was reported to be 16 and 8.2 mg per person per day in 1987
and 1990, respectively (MAFF 1987, 1990). In another study, where
DEHA intake was assessed by measuring urinary levels of the major
metabolite 2-ethylhexanoic acid, a median value of 2.7 mg per person per
day was reported (Loftus et al., 1994).
Apart from likely human exposure, consideration should be made of the
relative potency of the particular compound to produce peroxisome
proliferation and liver tumours in rodents. Plasticisers such as DEHP and
DEHA are far less potent than certain therapeutic agents and
experimentally used compounds (Reddy et al., 1986; Barber et al., 1987;
Bentley et al., 1993; Lake and Lewis, 1993). Moreover rodent liver
peroxisome proliferators exhibit clear no effect levels for both peroxisome
proliferation and for tumour formation. For example, in the rat no effect
levels for liver tumour formation have been observed in studies with
several compounds including bezafibrate, clofibrate, DEHA and DEHP
(Hartig et al., 1982; NTP 1982a, b). In addition, the threshold for tumour
formation in rodents is appreciably greater than the threshold for
peroxisome proliferation (Hartig et al., 1982; Reddy et al., 1986; Bentley
et al., 1993).
Several mechanisms have been proposed to account for why peroxisome
proliferators produce tumours in rodent liver. If these various hypotheses
are combined then a role for increased cell replication in peroxisome
proliferatorinduced hepatocarcinogenesis may be readily identified. For
example, if hepatocytes are transformed by either oxidative stress-induced
damage or by alternative mechanisms, such initiated cells may be promoted
to liver tumours by enhanced cell replication. Certainly peroxisome
proliferators are effective promoters of certain populations of initiated cells
and recent studies suggest that peroxisome proliferators can influence rates
of both cell replication and cell death in particular populations of
hepatocytes (Grasl-Kraupp et al., 1993; Popp and Cattley, 1993; Marsman
and Popp, 1994).
With respect to species differences, rats and mice are clearly responsive
species, whereas the majority of both in vivo and in vitro studies suggest
that primates including man are either essentially refractory or certainly
much less responsive to rodent peroxisome proliferators. However while
effects on peroxisome morphology and marker enzyme activities have been
extensively studied, few investigations have examined species differences in
peroxisome proliferator-induced cell replication and liver tumour
formation. As enhanced cell replication appears to play a role in peroxisome
proliferator-induced hepatocarcinogenesis in rats and mice, it would