alpha 2u-globulin nephropathy and renal tumors in national toxicology program studies

Abstract

Chemically induced renal neoplasms in male rats, developed coincident with alpha(2u)-globulin nephropathy, are not considered predictive of risk to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency. Criteria have been defined to establish the role of alpha(2u)-globulin nephropathy in renal carcinogenesis, based on a proposed mode of action involving sustained tubular cell proliferation resulting from alpha(2u)-induced nephropathy, with consequent development of neoplastic lesions. Recent NTP studies demonstrated inconsistencies with this proposed mechanism, including in some cases, far weaker kidney tumor responses than expected based on the extent of alpha(2u)-globulin nephropathy. NTP studies with decalin, propylene glycol mono-t-butyl ether and Stoddard solvent IIC included extended evaluations of alpha(2u)-related nephropathy, and were thus used in assessing the linkage between key events in 90-day studies with renal tumors in 2-year studies. This review revealed no or at best weak associations of tumor responses with renal alpha(2u)-globulin concentrations, indices of cell turnover, or microscopic evidence of alpha(2u)-associated nephropathy in prechronic studies. While tumor responses corresponded somewhat with a measure of cumulative alpha(2u)-associated nephropathy (linear mineralization of the papilla) at the end of the 2-year studies, the severity of chronic nephropathy was generally in best agreement with the pattern of tumor response. These results suggest that while alpha(2u)-globulin nephropathy may contribute to the renal tumor response, the critical component(s) of the nephropathy most closely associated with the development of tumors could not be clearly identified in this review.

Figure 1

Relative increases of mean renal α_2u-globulin concentrations, following 3-month exposures to decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC) to male rats; d-limonene-treated animals were exposed for 2 weeks. All rats (n = 10) were approximately 18 weeks old at the time of measurements. Analysis of renal concentrations of a2u-globulin was performed in kidney homogenates using a competitive indirect ELISA technique. Doses used in the 2-week limonene studies were 75, 150, 300, 600, and 1,200 mg/kg. Doses or exposures in prechronic studies that were common to those in 2-year studies are indicated by ^. Significantly greater than controls, p ≤ 0.05.

Figure 2

Severity of hyaline droplet accumulation in renal proximal tubules of male rats (n = 10), following 3-month exposures to d-limonene, decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC). Data are presented as mean ± S.E.; *significantly greater than controls, p ≤ 0.05. Incidences of the lesion are presented in the box insert. Doses or exposures in prechronic studies that were common to those in 2-year studies are indicated by ^.

Figure 3

Tubular regeneration cluster count in a single longitudinal section of the renal cortex of male rats (n = 10), following 3-month exposures to d-limonene, decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC). Data are presented as mean ± S.E.; *significantly greater than controls, p ≤ 0.05. Numbers of animals with the lesion are presented in the box insert. Doses or exposures in prechronic studies that were common to those in 2-year studies are indicated by ^.

Figure 4

Granular cast count in a single longitudinal section of the renal outer medulla of male rats (n = 10), following 3-month exposures to d-limonene, decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC). Data are presented as mean ± S.E.; *significantly greater than controls, p ≤ 0.05. Numbers of animals with the lesion are presented in the box insert. Doses or exposures in prechronic studies that were common to those in 2-year studies are indicated by ^.

Figure 5

Severity of linear mineralization in the renal papilla of male rats (n = 30), following 2-year exposures to d-limonene, decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC). Additional dose in decalin treatment consisted of 15 male rats. Data are presented as mean ± S.E.; statistical analyses were not performed because of the low or zero incidences in controls. Numbers of animals with the lesion are presented in the box insert.

Figure 6

Severity of chronic nephropathy in male rats (n = 30), following 2-year exposures to d-limonene, decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC). Additional dose in decalin treatment consisted of 15 male rats. Data are presented as mean ± S.E.; *significantly greater than controls, p ≤ 0.05. Numbers of animals with the lesion are presented in the box insert.

Figure 7

Severity of renal tubular hyperplasia in male rats (n = 30), following 2-year exposures to d-limonene, decalin, propylene glycol mono-t-butyl ether (PGMBE), and Stoddard solvent IIC (SS IIC). Additional dose in decalin treatment consisted of n = 15 male rats. Data are presented as mean ± S.E.; *significantly greater than controls, p ≤ 0.05. Numbers of animals with the lesion are presented in the box insert.