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EC number: 200-889-7
CAS number: 75-65-0
Citing studies by Hard et al. (1993) and Swenberg and Lehman-McKeeman
(1999), Hard states that one pathway leading to renal tubule tumor
formation in male rats only is induction of alpha-2u-globulin
(alpha-2u-g) nephropathy. Hard provides the following description of
alpha-2u-g nephropathy: “In this syndrome, a xenobiotic binds
non-covalently to circulating α2u-g synthesized in the male rat
liver. Being a low-molecular-weight protein, α2u-g is freely filtered
through the glomerulus, and approximately half of the ultrafiltrate is
absorbed into the second segment of proximal convoluted tubule (P2) and
catabolized by the hydrolytic enzymes of renal lysosomes. The loose
binding of a xenobiotic to α2u-g significantly retards the lysosomal
degradation of the protein, resulting in hyaline droplet (and α2u-g)
accumulation in tubule cells, secondary cytotoxicity, cell loss and
compensatory tubule cell regeneration, sustained during the period of
exposure. Prolonged cytotoxicity and regenerative cell proliferation is
considered to be the mode of action leading to renal tubule tumor
formation. Additional characteristic morphological features of α2u-g
nephropathy include granular cast formation at the junction between the
outer stripe of outer medulla (OSOM) and inner stripe of outer medulla
(ISOM), representing the lodging of sloughed cell debris at the point
where tubule lumen narrows from the pars recta into the thin descending
limb of Henle. As well, linear mineralization occurs in the papilla
after several months of treatment, probably at the pre-bend segment of
Henle’s loop.” A second possible pathway involves dose-related
enhancement of chronic progressive nephropathy by tertiary butyl
alcohol. Chronic progressive nephropathy is itself a risk factor for the
development of renal tubule neoplasia.
Hard et al., 1993. Hazard evaluation of chemicals that cause
accumulation of alpha 2u-globulin hyaline droplet nephropathy, and
tubule neoplasia in the kidneys of male rats. Environ. Health Perspect.
Swenberg JA and Lehman-McKeeman LD, 1999. Alpha 2-Urinary
globulin-associated nephropathy as a mechanism of renal tubule
carcinogenesis in male rats. In: Species Differences in Thyroid, Kidney
and Urinary Bladder Carcinogenesis. CC Capen, E Dybing, JM Rice and JD
Wilbourn (eds). International Agency for Research on Cancer, Lyon. IARC
Scientific Publications No. 147, pp. 95-118.
Hard cites the following observations from the 13-week and 2-year NTP
studies in rats and mice as well as published studies by others to
support one or both modes of action as the most likely explanation for
renal tumor formation in male rats in the NTP study with tertiary butyl
- Increase in hyaline droplet accumulation within renal tubule
epithelium and tubule lumens in male rats at all dose levels where
animals survived to study termination; lesion more prominent but not
increased in severity at higher dose levels; protein composition of
droplets and angular crystalline shape confirmed with use of Mallory
Heidenhain and Lee’s methylene blue basic fuchsin stains; protein
droplet accumulation was specific to male rats only; not reported in
female rats or mice of either sex.
- Focal tubule mineralization at the “corticomedullary” junction in all
female rat groups, including controls; effect was significantly
increased in 3 highest male dose groups; no granular cast formation; no
effect in mice of either sex.
- Severity of the spontaneous, background lesion, chronic progressive
nephropathy (CPN) was exacerbated in treated male rats; dose-related
increase in incidence but not severity between female groups; severity
classified as minimal in all female groups, including controls; effect
not reported in mice of either sex.
- Diffuse or papillary hyperplasia of the urinary bladder transitional
cell lining in most male rats but only a few female rats in the
high-dose group; hyperplasia occurred in conjunction with grossly
visible bladder calculi in the males but not the females; chronic
bladder inflammation was present in a few high-dose male and female
rats; chronic inflammation and diffuse or focal papillary hyperplasia of
the transitional cell lining of the bladder present in most or all male
mice in the mid- and high-dose groups; urinary bladder hyperplasia and
chronic inflammation present in high-dose group female mice.
- Mineralization within the kidney in all groups of rats, including
controls; 2 distinct types of mineralization occurred; “focal tubular
mineralization” at the corticomedullary junction occurred with equal
incidence in all female groups (slight increase in severity in higher
dose groups), in control males, and some exposed males; “linear
papillary mineralization” occurred in male rats only and there was a
clear dose-response for incidence; no effects in mice of either sex.
- Statistically significant exacerbation of severity (scale of 1 to 4)
of CPN in all dosed female rat groups (1.6 in controls versus 2.9 in
high-dose group) and high-dose group males (3.0 in controls versus 3.3
in high-dose group); slight increase in severity of CPN also observed at
interim sacrifice at higher doses; no effects in mice of either sex.
- Standard and extended evaluations of kidney sections from male rats
demonstrated a statistically significant increase in a special type of
renal tubule hyperplasia, i.e. atypical tubule hyperplasia (ATH) in the
high-dose group; ATH differs from foci of regeneration associated with
CPN; ATH is widely accepted as a sequential, preneoplastic stage in the
continuum leading to renal adenoma and carcinoma (Hard, 1986; Lipsky and
Trump, 1989; Hard, 1990; Dietrich and Swenberg, 1991; Nogueira et al.,
1993); while ATH was observed in kidneys of all male rat groups,
including controls, only a single ATH lesion was found in a high-dose
female rat; no effects in mice of either sex.
Hard GC, 1986. Experimental models for the sequential analysis of
chemically-induced renal carcinogenesis. Toxicol. Pathol. 14: 112-122.
Lipsky MM and Trump BF, 1988. Chemically induced renal neoplasia in
experimental animals. Int. Rev. Exp. Pathol. 30: 357-383.
Hard GC, 1990. Tumours of the kidney, renal pelvis and ureter. In:
Pathology of Tumours in Laboratory Animals. Vol. 1 – Tumours of the Rat,
second edition. VS Turusov and U Mohr (eds.). International Agency for
Research on Cancer, Lyon. IARC Scientific Publications No. 99, pp
Dietrich DR and Swenberg JA, 1991. Preneoplastic lesions in rodent
kidney induced spontaneously or by non-genotoxic agents: predictive
nature and comparison to lesions induced by genotoxic carcinogens.
Mutation Res. 248: 239-260.
Nogueira et al., 1993. Experimental models of renal carcinogenesis.
Cancer Res. Clin. Oncol. 119:190-198.
- A non-statistically significant distribution of renal tubule tumors
was found in all male rat groups after standard evaluation of the
kidney; extended evaluation of the kidneys combined with the standard
evaluation resulted in a statistically significant increase in the
mid-dose group for adenomas and carcinomas combined and for incidence of
multiple adenomas; renal tumor incidence was also statistically
significant in high-dose group males when a single renal tubule tumor
found on step-sectioning of kidneys from the 15-month interim sacrifice
was added to the results from the 2-year evaluation; no renal tubule
tumors were found in female rats or mice of either sex.
- Statistically significant increase in hyperplasia of the transitional
cell lining of the renal pelvis in mid- and high-dose group male rats
and high-dose group females; no progression of transitional epithelial
hyperplasia to benign or malignant neoplasms in either sex; no effects
in mice of either sex.
- Statistically significant increase in chronic inflammation of urinary
bladder with transitional cell hyperplasia in high-dose group male mice;
statistically significant increase in chronic inflammation in female
mice but only a few had hyperplasia of the transitional cell lining; no
evidence of progression of hyperplasia to urinary bladder neoplasia in
treated mice; no bladder effects in rats of either sex.
In an expert
evaluation conducted by Gordon C. Hard, the author examines the renal
tubule tumors observed in male rats exposed ad libitum to tertiary butyl
alcohol in the drinking water in an NTP carcinogenicity study and
postulates species differences and two modes of action for the observed
effects at high doses. It
is the author’s opinion that the renal tubule tumors observed in male
rats in the NTP carcinogenicity bioassay were most likely related to alpha-2u-g
nephropathy (a condition unique to male rats), a dose-related
enhancement of chronic progressive nephropathy (end-stage CPN is itself
a risk factor for renal tubule neoplasia), or possibly a combination of
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