Effect of Piperonyl Butoxide on Cell Replication and Xenobiotic Metabolism in the Livers of CD-1 Mice and F344 Rats

Abstract

Male CD-1 mice were fed diets containing 0 (control), 10, 30, 100, and 300 mg/kg/day piperonyl butoxide (PBO) and 0.05% sodium phenobarbital (NaPB) and male F344 rats were fed diets containing 0 (control), 100, 550, 1050, and 1850 mg/kg/day PBO and 0.5% NaPB for periods of 7 and 42 days. In both species PBO and NaPB increased relative liver weight and whereas PBO produced a midzonal (mouse) or periportal/midzonal (rat) hypertrophy, NaPB produced a centrilobular hypertrophy. In the rat, individual cell necrosis was also observed at 42 days after high doses of PBO. Replicative DNA synthesis, assessed as the hepatocyte labeling index following implantation of 7-day osmotic pumps containing 5-bromo-2'-deoxyuridine during Study Days 0-7 and 35-42, was increased in mice given 300 mg/kg/day PBO and NaPB for 7 days and in rats given 550 and 1050 mg/kg/day PBO and NaPB for 7 days and 1050 mg/kg/day PBO for 42 days. While PBO had no effect on body weights in mice, the body weights of rats given 550, 1050, and 1850 mg/kg/day PBO for 42 days were reduced to 92, 89, and 70% of control, respectively. PBO induced microsomal cytochrome P450 content and mixed function oxidase activities in the mouse and rat, although the effects were less marked than those produced by NaPB. In summary, this data demonstrates that PBO can produce liver enlargement in the mouse and the rat which is associated with induction of xenobiotic metabolism, hypertrophy, and hyperplasia. The hepatic effects of PBO in the mouse were similar to but less marked than those produced by NaPB. In the rat high doses of PBO were hepatotoxic and resulted in a marked reduction in body weight Thus while the reported formation of eosinophilic nodules in mouse liver by PBO may occur by a mechanism(s) similar to that of NaPB and other nongenotoxic enzyme inducers, the reported tumor forma-1 Presented in part at the Annual Meeting of the Society of Toxicology, Baltimore, Maryland, March 5-9, 1995, and Anaheim, California, March 10-14, 1996.2 To whom correspondence should be addressed. tion in rats at greater than the maximum tolerated dose is most likely associated with marked enzyme induction in conjunction with a regenerative hyperplasia resulting from PBO-induced hepatOtOxicity. O 1997 Sodtty of Toriralogy.Piperonyl butoxide (a-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene, PBO) is a commonly used synergist for naturally derived pyrethrins. PBO is registered for applications on a variety of crops (including fruits and vegetables), livestock, lawn and turf, mosquitoes, agricultural premises, food-processing plants, dairies, pets, and residential dwellings. Nearly 50% of the amount of PBO produced is distributed for use in indoor residential products (unpublished PBO Task Force data). As a result, humans could potentially be exposed to low levels of PBO from dietary and residential sources.Although PBO has not been extensively studied in humans, several investigations have demonstrated that PBO is not mutagenic in a wide range of short-term tests (White ...

The Safety Assessment of Piperonyl Butoxide

“…Both PBO and NaPB produced a stimulation of cell replication after 7 but not 42 days of treatment in the mouse (Phillips et al, 1997). Like NaPB, PBO also increased relative liver weight in CD-1 mice and produced liver hypertrophy, although a difference in the lobular distribution of this effect was noted.…”

“…The treatment of male C57BL/10 and DBA/2 mice with 500 mg/kg/day PBO by intraperitoneal injection induced some hepatic microsomal CYP-dependent enzyme activities (Fennell et al, 1980), whereas in another study the treatment of male CD-1 mice with 100 and 300 mg/kg/day PBO by dietary administration for 42 days resulted in increased microsomal total CYP content (Phillips et al, 1997).…”

“…Several studies have shown that PBO is an inducer of hepatic xenobiotic metabolism in the mouse and rat (Fennell et al, 1980;Goldstein et al, 1973;Lake et al, 1973;Phillips et al, 1997;Wagstaff and Short, 1971). Phillips et al (1997) characterized the induction of enzyme activities in both the mouse and rat and compared it to the classic inducer, phenobarbital.…”

“…Phillips et al (1997) characterized the induction of enzyme activities in both the mouse and rat and compared it to the classic inducer, phenobarbital. Four groups of 16 male F-344 rats were fed PBO in the diet at 100, 550, 1050, or 1850 mg/kg body weight/day.…”

“…Many studies have demonstrated that PBO can induce CYP forms and CYP-dependent enzyme activities in mice and rats (Adams et al, 1993a,b;Goldstein et al, 1973;Hodgson and Philpot, 1974;Hodgson et al, 1995;Fennell et al, 1980;Lake et al, 1973;Mugumura et al, 2006;Phillips et al, 1997;Ryu et al, 1996Ryu et al, , 1997Wagstaff and Short, 1971;Watanabe et al, 1998). The induction of CYP forms has been evaluated by the measurement of enzyme activities, mRNA levels, and CYP apoprotein levels.…”