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Abstract
The naturally occurring food constituentd-limonene has been found to cause tumors at high doses only in the kidney of the male rat in association with the development of hyaline droplet nephropathy. In contrast, neither kidney tumors nor the associated nephropathy have been found in female rats or mice at much higher doses. Adult male rats produce large quantities of a specific low-molecular-weight protein in the liver, which is known as α2U-globulin (α2U-g). With administration of sufficient doses ofd-limonene to male rats, this protein has been found to accumulate excessively in the P2 segment cells of renal proximal tubules, resulting in hyaline droplet formation as a manifestation of protein overload. Hyaline droplet accumulation is the first stage in a unique sequence of nephropathic lesions (also known as α2U-g nephropathy), including granular casts in the outer medulla and linear mineralization in the papilla. The mechanism underlying protein accumulation appears to be the reversible binding of chemical to α2U-g with subsequent prolongation of its half-life in the tubule cell. In the case ofd-limonene, the minor metabolited-limonene-1,2-oxide has been shown to be the primary chemical species that binds reversibly to α2U-g, impeding the normal process of lysosomal proteinase degradation of α2U-g. The ensuing nephropathy is associated with a sustained increase in compensatory renal tubule cell proliferation, which provides the putative mechanistic link with renal tumor formation possibly through tumor promotion of spontaneously initiated cells or enhanced spontaneous mutagenesis. This proposed mechanism has been supported by additional information, including negative genotoxicity tests ford-limonene and its oxide metabolites, experimentally verified tumor promotion, and enhanced cell proliferation primarily in P2 segment tubule cells in male F344 rats, but no such effects in the α2U-g-deficient NBR rat. The mechanism ofd-limonene tumor development does not appear to be possible in humans since neither the quantity nor the type of protein that bindsd-limonene ord-limonene-1,2-oxide is present. The deduction that the renal tumors induced in male rats are not relevant to human carcinogenicity in the hazard evaluation step of risk assessment completes the evaluation of human risk ford-limonene. Consequently, it can be concluded thatd-limonene does not pose any carcinogenic or nephrotoxic risk to humans. This determination would apply to other chemicals that induce renal tubule tumors exclusively in the male rat, by weighing data on a case-by-case basis supporting the involvement of α2U-g nephrotoxicity against other data that may indicate alternative mechanisms.