title: Pronamide: Human relevance of liver-mediated rat leydig cell tumors.
abstract: Dietary exposure to pronamide resulted in higher incidences of Leydig cell tumors (LCT) at 1000ppm in a 2-year cancer bioassay, but there were no testes effects at 40 or 200ppm, and no testes effects at 12-months at any concentration. A 90-day mode-of-action (MoA) study was conducted at concentrations of 0, 200, 1000 and 2000ppm. Standard parameters and stereological and proliferation analyses of LCs, targeted testis and liver gene expression, in vitro metabolism of testosterone by liver microsomes, and quantification of serum hormones and testosterone metabolites were evaluated. Increased testosterone metabolism due to increases in hepatic microsomal activity, alterations in serum hormone levels, and other data suggest that LCTs were mediated through a perturbation of the HPG-axis. Data suggest that this occurs after a threshold of exposure is reached, indicating a nonlinear/threshold dose-response. Pronamide-induced rat LCTs mediated by alterations to the HPG-axis have low relevance to humans due to quantitative differences in sensitivity between rats and humans to LCTs. Pronamide displayed no genotoxicity or direct endocrine effects. A margin of exposure approach for risk assessment and derivation of the chronic reference dose based on a point of departure of 200ppm is most appropriate and protective of human health.
authors.affiliation: The Dow Chemical Company, Midland, MI, USA.
authors.forename: Reza J
authors.initials: RJ
authors.lastname: Rasoulpour
authors.affiliation: The Dow Chemical Company, Midland, MI, USA. Electronic address: akandrus@dow.com.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Andrus
authors.affiliation: The Dow Chemical Company, Midland, MI, USA.
authors.forename: M Sue
authors.initials: MS
authors.lastname: Marty
authors.affiliation: The Dow Chemical Company, Midland, MI, USA.
authors.forename: Fagen
authors.initials: F
authors.lastname: Zhang
authors.affiliation: The Dow Chemical Company, Midland, MI, USA.
authors.forename: Johnson
authors.initials: J
authors.lastname: Thomas
authors.affiliation: The Dow Chemical Company, Midland, MI, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LeBaron
authors.affiliation: Dow AgroSciences, LLC, Indianapolis, IN, USA.
authors.forename: Sabitha
authors.initials: S
authors.lastname: Papineni
authors.affiliation: The Dow Chemical Company, Midland, MI, USA.
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Pottenger
authors.affiliation: Dow AgroSciences, LLC, Indianapolis, IN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Eisenbrandt
mesh_terms: D000818:Animals; D001549:Benzamides / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D007984:Leydig Cell Tumor / Q000139:chemically induced* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism*
chemical_list: D001549:Benzamides; D002273:Carcinogens; D006540:Herbicides; C001059:pronamide; D013739:Testosterone
keywords: Leydig cell tumor; Liver enzyme induction; Mechanisms; Pronamide; Testosterone metabolism