Toxicology of Industrial Compounds

(Rodricks and Turnbull, 1987; Bentley et al., 1993). However, albeit at
high doses two compounds, namely ciprofibrate (Reddy et al., 1984) and
DL-040 (Lalwani et al., 1985), have been reported to produce hepatic
peroxisome proliferation in Cynomolgus and/or Rhesus monkeys. In
humans, studies have been conducted in patients treated with several
hypolipidaemic agents (all being rodent peroxisome proliferators) including
ciprofibrate, clofibrate, fenofibrate and gemfibrozil (Bentley et al., 1993).
While most studies have failed to detect any significant changes, clofibrate
was reported to produce a small increase in the number of peroxisomes
(Hanefeld et al., 1983) and ciprofibrate to produce a small increase in the
pro portion of the hepatocyte cytoplasm occupied by peroxisomes (cited in
Bentley et al., 1993). However, owing to the large interindividual variation
in peroxisome morphometrics observed in these studies, together with cell
to cell variations and lobular variations, it is difficult to attach any clear
biological significance to these findings (Bentley et al., 1993). Generally,
peroxisome proliferators have not been reported to produce any significant
effects on marker enzyme activities and/or peroxisomes in cultured primate
and human hepatocytes (Bieri, 1993; Bentley et al., 1993; Foxworthy and
Eacho, 1994).
Some studies have also examined species differences in effects on cell
replication. Both nafenopin and Wy-14,643 have been reported to
stimulate replicative DNA synthesis in rat, but not in Syrian hamster,
hepatocytes (Price et al., 1992; Lake et al., 1993). Although peroxisome
proliferators can stimulate DNA synthesis in cultured rat hepatocytes,
methylclofenapate was reported to be ineffective in guinea pig, marmoset
and human hepatocytes (Elcombe and Styles, 1989). Similarly, nafenopin
has also been reported not to induce replicative DNA synthesis in human
hepatocytes (Parzefall et al., 1991).
Risk assessment of rodent liver peroxisome proliferators
The key issues concerning the risk assessment of rodent liver peroxisome
proliferators include:
(a) Genotoxicity.
(b) Likely human exposure.
(c) Compound potency and no effect levels.
(d) Precise mechanism(s) of liver tumour formation.
(e) Species differences in response.
B.G.LAKE AND R.J.PRICE 229
Generally, peroxisome proliferators are considered to be non-genotoxic
agents (Bentley et al., 1993; Budroe and Williams, 1993) and hence should
be assessed differently from genotoxic carcinogens (Weisburger, 1994).
Human exposure to rodent peroxisome proliferators depends on the