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2.2 Postulated mode of action (theory of the case)
The postulated mode of action for thiacloprid-induced uterine adenocarcinomas involves
hormonal disruption caused secondarily by effects on the liver. Specifically, thiacloprid is a
strong inducer of hepatic microsomal cytochrome P450 enzymes, including aromatase, a key
enzyme in the synthesis of estrogens that catalyses the conversion of testosterone to estradiol
and of androstendione to estrone. The consequence is an increase in plasma estradiol levels
and a stimulation of the uterine endometrium over the entire lifetime, which may result in an
augmentation of the spontaneous incidence of uterine adenocarcinomas, especially in old and
acyclic rats.
2.3 Key events
The sequence of key events in the mode of carcinogenic action of thiacloprid in the uterus
includes:
•
•
•
•
induction of hepatic aromatase activity,
increased conversion of testosterone to estradiol and of androstendione to estrone,
increase in serum estradiol concentration,
long-lasting stimulation of the uterine endometrium.
The key events described above include changes in liver enzyme activities and alterations in
steroid hormone levels. These effects have been investigated and observed in female rats in short-term
mechanistic studies, while an increased incidence of uterine tumours was seen at terminal sacrifice
in a long-term study. The dose–response relationship and the temporal analyses of the key events and
tumour response are presented below.
2.4 Concordance of dose–response relationships
The NOAELs and LOAELs for the key effects in the mode of action of thiacloprid in the uterus
are provided in Table A2.
In all the studies evaluated, hepatocellular hypertrophy appeared to be the most sensitive
indicator of changes in liver metabolism, occurring at doses of 2.5 mg/kg bw per day and higher. A
biologically significant increase in hepatic aromatase activity was observed in a 4-week mechanistic
study at doses of 20.4 mg/kg bw per day and higher, and at higher doses in two further mechanistic
studies. Consistent with the augmented conversion of testosterone to estradiol and of androstendione
to estrone, increases in serum estradiol levels were seen in a one-generation study at 60.4 mg/kg bw
per day, the only dose tested in this study. Prolonged stimulation of the endometrium by estradiol
may result in an augmentation of the spontaneous incidence of uterine tumours. In the 2-year study
in rats, an increased incidence of uterine adenocarcinomas was seen at doses of 25 mg/kg bw per day
and higher.
Generally, there was good correlation between the doses causing induction of hepatic aromatase
activity and those causing an increased incidence of uterine tumours. However, there appeared to be
a lack of dose-concordance for uterine tumours and increases of serum estradiol levels, but this was
obviously due to the poor selection of dose levels and/or end-points investigated in the mechanistic
studies.
THIACLOPRID X-X JMPR 2006