Toxicology of Industrial Compounds

332 ANTIOXIDANTS AND LIGHT STABILISERS: TOXIC EFFECT
not actually reflect the hydrolytic capacity of the in vivo system for a given
ester.
Liver enlargement and the induction of diagnostic enzyme activities is a
characteristic response of rodents to treatment with peroxisome
proliferators and results from a combination of both hypertrophy and
hyperplasia. According to current opinion, peroxisome proliferation and
liver growth are closely associated with the formation of hepatocellular
tumours in rats and mice (Hawkins et al., 1987; Lock et al., 1989; Bentley
et al., 1993). However, a number of feeding studies have demonstrated
that there may actually be two types of threshold with respect to dose
relationships: at very low doses, administration of peroxisome proliferators
will not result in any liver response at all (Bentley et al., 1993). With
increasing doses the first threshold will be exceeded with subsequent
stimulation of peroxisome proliferation and DNA synthesis.
As a result of several studies it is obvious that a limited extent of liver
growth does not automatically lead to tumour formation as has been
demonstrated, for example, with fenofibrate and diethylhexylphthalate in
carcinogenicity assays (Mitchell et al., 1985; Price et al., 1986; Keith et al.,
1991). Thus, a second threshold has to be exceeded at which the
magnitude of effects is sufficient to cause tumour development in rodents.
In addition, extended administration of the peroxisome proliferator
appears a necessary prerequisite to exceed this tumourigenic threshold.
Also, a large number of in vitro and in vivo studies have provided ample
evidence for a marked species difference in susceptibility to the effects of
peroxisome proliferators. Rats and mice are extremely sensitive while
hamsters show a markedly smaller response and non-human primates and
humans appear to be insensitive or non-responsive (Lake et al., 1989;
Bentley et al., 1993; Graham et al., 1994). The latter finding is supported
by epidemiological evidence from long-term treatment of patients with
hypolipidaemic agents (Bentley et al., 1993). Therefore the available
evidence strongly supports the conclusion that the effects of benzotriazolebased
light stabilisers in rodents are of no relevance to human safety
assessment.
The action of Compound F as a strong peroxisome proliferator in foetal
livers starting as early as day 15 of gestation suggests that treatment related
initiation of high level oxidative stress under conditions of poorly
developed foetal protection and detoxification systems. This view is
supported by substantially elevated hepatic malondialdehyde levels and
essentially depleted glycogen stores in hepatocytes of foetuses from treated
dams on day 21 of gestation. The latter indicates an extensive glucose
consumption, presumably via the pentose phosphate pathway, to supply
the hydrogen peroxide and lipid peroxide detoxifying glutathione
peroxidase system with the necessary reduction equivalents (NADPH).
Under conditions of limited degradation of hydrogen peroxide, this