Tt. Tori et al., DEVELOPMENT AND PERSISTENCE OF PLACENTAL GLUTATHIONE-S-TRANSFERASE POSITIVE FOCI IN LIVERS OF MALE F344 RATS EXPOSED TO O-NITROTOLUENE, Cancer letters, 95(1-2), 1995, pp. 167-173
In a previous 13-week study of o-nitrotoluene, a chemical-related incr
ease in liver weight, hepatocellular vacuolization, and oval cell hype
rplasia in male F344 rats was reported. In this study, the occurrence
and change in number and size of hepatic foci in male F344 rats fed a
diet containing 5000 ppm o-nitrotoluene or a control diet for 13 weeks
, 26 weeks, and 13 weeks followed by a 13-week recovery period (26-wee
k stop-exposure) were evaluated. The livers were stained immunohistoch
emically for placental glutathione S-transferase (PGST), a marker of h
epatic preneoplasia, and quantified stereologically using computer-ass
isted image analysis. Exposure to o-nitrotoluene induced PGST-positive
(PGST+) liver foci in all treatment groups. The 26-week continuous-ex
posure group produced more PGST+ liver foci (961.4 foci/cm(3) versus 4
45.4 foci/cm(3)) and greater mean focus volume (4.34 mu m(3) versus 1.
34 mu m(3)) than the 13-week continuous-exposure group. In the 26-week
stop-exposure group, there were fewer PGST+ liver foci (181.4 foci/cm
(3)) than observed with continuous exposure at 13 weeks or 26 weeks; h
owever, the mean focal volume in the stop-exposure group at 26 weeks (
5.33 mu m(3)) was greater than that at 13 weeks (1.34 mu m(3)) or 26 w
eeks of continuous exposure (4.34 mu m(3)). These findings demonstrate
that (1) PGST+ foci are observed after only 13 weeks of exposure to o
-nitrotoluene; (2) the number and size of foci increase with continued
exposure for 26 weeks; and (3) although the number of PGST+ foci decr
eases with time after chemical exposure is discontinued, many PGST+ fo
ci do not regress but increase in size during the recovery period of 1
3 weeks. The persistence and increase in size of these foci, even in t
he absence of chemical exposure, suggest the potential for a hepatocar
cinogenic effect in long-term studies for o-nitrotoluene.