d-limonene mechanistic data and risk assessment: absolute species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion.
d-Limonene produces tumors only in the kidneys of male rats in association with hyaline-droplet nephropathy, which is due to the accumulation of the rat-specific, low molecular weight protein alpha(2u)-globulin in the P2 segment cells of renal proximal tubules. Human urine contains no alpha(2u)-globulin and, compared with the male rat, much less protein and almost no low molecular weight protein. Genotoxicity tests for d-limonene are negative, and the mechanism of tumorigenesis involves tumor promotion and enhanced cell proliferation. There is no risk of cancer for humans from d-limonene, since the binding of d-limonene to alpha(2u)-globulin would not occur.
Whysner
J
J
Toxicology and Risk Assessment Program, American Health Foundation, Valhalla, NY 10595-1599, USA.
Williams
G M
GM
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D053138:Cyclohexenes; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000473:pathology; D000077222:Limonene; D008297:Male; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D013729:Terpenes / Q000633:toxicity*
D002273:Carcinogens; D053138:Cyclohexenes; D013729:Terpenes; D000077222:Limonene