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Characteristics of the Spectrum of Proliferative Lesions Observed in the Kidney and Urinary Bladder of Fischer 344 Rats and B6C3F1 Mice Jeffrey C. Wolf Toxicol Pathol 2002 30: 657 DOI: 10.1080/01926230290166742 The online version of this article can be found at: http://tpx.sagepub.com/content/30/6/657

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TOXICOLOGIC PATHOLOGY, vol 30, no 6, pp 657– 662, 2002 Copyright C 2002 by the Society of Toxicologic Pathology DOI: 10.1080/0192623029016674 2

Characteristics of the Spectrum of Proliferative Lesions Observed in the Kidney and Urinary Bladder of Fischer 344 Rats and B6C3F1 Mice JEFFREY C. WOLF Experimental Pathology Laboratories, Inc, Research Triangle Park, North Carolina 27709, USA ABSTRACT Many rodent renal and bladder carcinogens rely upon epigenetic mechanisms of carcinogenesis ; such mechanisms are likely to inuence the spectrum of urinary tract tumors observed in control and treated animals. This is reected in several features of chemically induced rodent urinary tract neoplasms, including a low overall tumor incidence, an increased prevalence of urinary tract tumors in rats compared to mice and males compared to females, the tendency for epithelial tumors to predominate over nonepithelial types, and demonstrated links to chronic progressive nephropath y and urolithiasis. Such tendencies are also characteristic of spontaneous urinary tract tumors in rodents. Data to support these observations can be derived from large historical databases such as the Toxicology Data Management System, maintained by National Toxicology Program. Keywords.

Kidney; urinary bladder; neoplasia; Fischer 344 rats; B6C3F1 mice; National Toxicology Program.

INTRODUCTION From 1990 to 1996, tumors of the kidney, renal pelvis, and urinary bladder were reported to occur in approximately 25 of every 100,000 persons in the United States, and were associated with the deaths of approximately 7 of every 100,000 persons (1). In the United States, bladder cancer is the fth most common human malignancy (2). Epidemiological evidence has implicated certain substances (eg, cigarette smoke, analgesic abuse, aniline dyes) as causative factors in the pathogenesis of kidney and/or urinary bladder neoplasms (3, 4). Based upon results of rodent carcinogenicity studies, it is likely that further exogenous risk factors for human urinary tract tumors have yet to be dened (5). Risk assessment decisions that pertain to environmental issues and human health are frequently based on the results obtained from rodent carcinogenicity studies. Insight into the mechanisms of comparative carcinogenesis in rodents and humans may be gained by periodically monitoring large historical databases for tumor incidences and trends. The National Toxicology Program/National Institute of Environmental Health Sciences (NTP/NIEHS) maintains a computerized data bank, the Toxicology Data Management System (TDMS), comprised of tumor incidences compiled from the NTP’s 2-year carcinogenesis studies. The TDMS incorporates 5 to 7 years’ worth of data from peer-reviewed studies in which Fischer 344/N (F344 ) rats or B6C3F1 mice were utilized (6 – 8). Since the early 1970s, F344 inbred rats and B6C3F1 hybrid mice have been the standard strains used in the National Cancer Institute Bioassay Program, and in toxicity and carcinogenicity studies of the NTP/NIEHS. Both rodent strains are genetically stable, phenotypically uniform, relatively

long-lived, sensitive to a wide variety of carcinogens and tend to produce fewer spontaneous tumors compared to other strains (9, 10). Although a 74% concordance of results has been demonstrated between F344 rats and B6C3F1 mice in carcinogenicity studies (11), the relevance of these results to human health risk are often less clear (12). POTENTIAL FACTORS IN RODENT URINARY TRACT CARCINOGENESIS There are several features of the rodent urinary tract (UT) that may inuence the spectrum and relative incidence of local tumor development. The kidney possesses enzyme systems for both Phase I and Phase II xenobiotic transformation reactions (13). Cytochrome P-450 levels in the kidney are approximately 20% those of the liver (14). Consequently, electrophilic substances produced by metabolic transformation may become concentrated in the kidney, potentially promoting DNA adduct formation (15). Another characteristic of the rodent kidney is a relatively high incidence of chronic progressive nephropathy (CPN), a spontaneously developing degenerative disease that is observed primarily in older individuals (especially male rats). Theoretically, the increased cell turnover that accompanies CPN could increase the probability for error during DNA replication, decrease the opportunity for DNA repair of such errors, and provide a stimulus for the clonal proliferation of mutated cells (15 – 17). It has been suggested that at least 1 chemical (hydroquinone ) may exert its tumorigenic effects upon the kidney via enhancement of CPN (15, 18, 19). A phenomenon that appears to be entirely restricted to the male rat kidney (excluding androgenized female rats and some genetically altered mice) is the ability of certain chemicals (eg, D-limonene, unleaded gasoline ) to cause renal tumors via a2u -globulin nephropathy (16, 20). For the urinary bladder, urine stasis is a potential carcinogenesis factor. Not only does urine provide an effective storage and transport medium for carcinogens that are eliminated through the urinary tract (21), both human and rodent urine are known to contain growth factors (eg, epidermal growth

Address correspondenc e to: Dr. Jeffrey C. Wolf, Experimental Pathology Laboratories , Inc, P.O. Box 12766, Research Triangle Park, North Carolina 27709, USA. Presented at the satellite symposium of the National Toxicology Program at the annual meeting of the Society of Toxicologic Pathology, Phoenix, Arizona, June 24 – 25, 2000.


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factor, transferrin) that can stimulate urothelial cell proliferation and consequently tumorigenesis (22– 25). One carcinogenic mechanism that may or may not be unique to rodents is the well-documented association of bladder tumor formation with the presence of uroliths, microcrystalluria, and urine precipitates (26, 27, 28).

TABLE 1.—Ranked incidence of spontaneous kidney and urinary bladder neoplasms in F344 rats and B6C3F1 mice from selected NTP studies. Species

Sex

Site

Rat Rat Mouse Rat Mouse Mouse Rat Mouse Total

m f m m m f f f

Kidney Kidney Kidney Bladder Bladder Kidney Bladder Bladder

Number of tumors

n

%

32 13 11 8 7 6 3 0 80

2,381 2,372 2,356 2,363 2,331 2,363 2,372 2,303 18,841

1.34 0.55 0.46 0.34 0.30 0.25 0.13 0.00 0.42

SPONTANEOUS UT TUMORS IN F344 RATS AND B6C3F 1 MICE The rodent urinary tract appears to be an uncommon site for spontaneous tumor formation. Compared to other organs, the incidences of tumors in the kidney and bladder have been ranked as high as 10th (renal tumors in male mice) and as low TABLE 2.—Types of spontaneou s kidney and urinary bladder neoplasms in as18th (bladder tumors in male rats) (29). In order to docF344 rats from selected NTP studies. ument the incidence of spontaneous urinary tract tumors in Kidney Bladder F344 rats and B6C3F1 mice, data was compiled from 46 studies in the TDMS database (“NTP Historical Control InforEpithelial Epithelial Tubular adenoma Papilloma mation 2000” data available at , last updated 2/24/00 . Specically, Oncocytoma , benign Mesenchymal Transitional cell pelvic papilloma Leiomyoma the data was screened to include male and female negative Transitional cell pelvic adenoma/carcinoma Leiomyosarcoma control animals from chronic (2-year) inhalation, feed and Mesenchymal water studies. Studies in which animals were exposed to a Lipoma Liposarcoma delivery vehicle (eg, corn oil) or extensively manipulated Sarcoma (eg, gavage studies) were excluded. Embryonal Nephroblastoma Spontaneous, primary tumors were present in 80 of the Stromal nephroma 18,824 (0.42% ) kidney and urinary bladder tissues exam( ) ( ) ined Table 1 30 . No spontaneous ureteral or urethral tumors were recorded for F344 rats and B6C3F1 mice from TABLE 3.—Types of spontaneou s kidney and urinary bladder neoplasms in the selected studies. The incidence of urinary tract tumors B6C3F1 mice from selected NTP studies. was 0.59% for F344 rats and 0.26% for B6C3F1 mice. These Kidney Bladder gures are essentially consistent with previously reported incidences ( < 1%) for UT tumors in F344 rats and B6C3F1 Epithelial Epithelial Tubular adenoma Papilloma mice (29, 31). Although UT tumors appear to occur more Tubular adenocarcinom a Mesenchymal frequently in other rat and mouse strains (Sprague-Dawley Transitional cell pelvic papilloma/carcinoma Hemangioma and Wistar rats, CD-1 mice), the incidence of such neoplasms Mesenchymal Hemangiosarcoma Fibrous histiocytoma Leiomyosarcoma is generally reported to be < 2% (29). In F344 rats from the Hemangiosarcoma Sarcoma selected studies, UT tumors were more than twice as common Pelvic hemangiom a ( ) Pelvic hemangiosarcom a in males compared to females 0.84% vs 0.34% , primarily Sarcoma due to the relatively high number of renal adenomas diagnosed in the male mice. In B6C3F1 mice, there were almost 3 times as many tumors in males (0.38% vs 0.13%), due in TABLE 4.—Relative incidences of spontaneous epithelial and nonepithelial part to the complete lack of bladder tumors observed in the urinary tract tumors in F344 rats and B6C3F1 mice from selected NTP studies. female mice. For rats, kidney tumors outnumbered bladder Number of tumors Total tumors % tumors by greater than 4:1 (0.95% vs 0.23%), and in mice this ratio was greater than 2:1 (0.36% vs 0.15%). Overall, the most Rats Epithelial 46 56 82.1 common site for urinary tract tumor formation was the male Nonepithelial 10 56 17.9 rat kidney (1.34% ) and the least common site was the female Mice mouse bladder (0.00% ). Epithelial 15 24 62.5 Nonepithelial 9 24 37.5 Categories and specic types of urinary tract neoplasms encountered in the selected studies are listed (Tables 2 and 3). For the F344 rats, 82.1% of the tumors were epithelial types (papillomas, adenomas, carcinomas, oncocytomas), vs TABLE 5.—Relative incidences of spontaneou s benign and malignant urinary tract tumors in F344 rats and B6C3F1 mice from selected NTP studies. tumors of mesenchymal or embryonal tissue origin (Table 4). In B6C3F 1 mice, 62.5% of the tumors were epithelial. Of the Number of tumors Total tumors % urinary tract neoplasms identied in F344 rats, 71.4% were Rats given benign diagnoses (or were of tumor types generally Benign 40 56 71.4 considered to be benign), whereas in B6C3F1 mice this gure Malignant 16 56 28.6 was 58.3% (Table 5). The renal tubular adenoma of the male Mice Benign 14 24 58.3 rat was the single most common urinary tract tumor in the Malignant 10 24 41.7 ). selected studies (0.97% incidence in male ratsDownloaded from tpx.sagepub.com by guest on July 15, 2011

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TABLE 6.—Chemicals associated with site-specic tumor induction in the kidney. Technical report number

Levels of evidence of carcinogenicit y Chemical name

1-Amino-2,4-dibromoanthraquinone 1-Amino-2-methylanthraquinone 2-Amino-4-nitrophenol O-Anisidine hydrochloride Anthraquinone Aspirin, phenacetin, and caffeine 3 -Azido-3 -deoxythymidine (AIDS initiative) Benzofuran o-Benzyl-p-chlorophenol 2,2-Bis(bromomethyl)-1,3-propanediol Bromodichloromethane 1,3-butadiene Tert-butyl alcohol Chlorinated parafns: C12, 60% chlorine Chloroform Chloroprene Chlorothalonil C.I. Acid orange 3 C.I. Direct blue 218 C.I. Pigment red 3 C.I. Pigment red 23 Cinnamyl anthranilate Coconut oil acid diethanolamine 479 Condensate 422 Coumarin 463 D & C Yellow number 11 401 2,4-Diaminopheno l dihydrochloride 400 2,3-Dibromo-1-propanol 319 1,4-Dichlorobenzene ( p-dichlorobenzene) 478 Diethanolamine 423 3,4-Dihydrocoumarin 1,2-Dihydro-2,2,4-trimethylquinoline (Monomer) 456 323 Dimethyl methylphosphonat e 493 Emodin 466 Ethylbenzene 496 Fumonisin B1 382 Furfural 482 Furfuryl alcohol 356 Furosemide 252 Geranyl acetate 361 Hexachloroethane 366 Hydroquinone 291 Isophorone 486 Isoprene D-Limonene 347 408 Mercuric chloride 359 8-Methoxypsoralen 369 Alpha-methylbenzy l alcohol 348 Methyldopa sesquihydrat e 491 Methyleugenol 313 Mirex 266 Monuron 006 Nitrilotriacetic acid (NTA) Nitrilotriacetic acid trisodium 006 Monohydrate Nitrilotriacetic acid trisodium 006 Monohydrate 416 o-Nitroanisole 341 Nitrofurantoin 358 Ochratoxin A 468 Oxazepam 485 Oxymetholone 232 Pentachloroethane 465 Phenolphthalein 367 Phenylbutazone 333 N-phenyl-2-naphthylamine 476 Primidone (Primaclone) 470 Pyridine 409 Quercetin 457 Salicylazosulfapyridine 311 Tetrachloroethylene 450 Tetrauoroethylen e 475 Tetrahydrofuran 384 1,2,3-Trichloropropane 449 Triethanolamine 391 Tris(2-chloroethyl)phosphate 076 Tris(2,3-dibromopropyl)phosphate Number of chemicals causing tumors in KIDNEY 74

Salmonella

383 111 339 089 494 067 469 370 424 452 321 434 436 308 000 467 041 335 430 407 411 196

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Multiple tumor sites

Dosed-feed Dosed-feed Gavage Dosed-feed Dosed-feed Dosed-feed Gavage Gavage Gavage Dosed-feed Gavage Inhalation Dosed-water Gavage Gavage Inhalation Dosed-feed Gavage Dosed-feed Dosed-feed Dosed-feed Dosed-feed

CE P SE P SE N

CE P NE P CE E

NE NE CE CE

SE EE CE CE

SE CE P CE P NE SE SE EE P

NE CE N CE P CE NE SE NE N

CE N NE P CE N EE CE SE CE CE CE EE CE P CE N NE CE SE NE P

CE P NE P CE N CE CE NE CE CE CE SE CE P CE N NE CE NE NE P

Yes Yes No Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes No No Yes Yes No Yes

Topical Gavage Dosed-feed Gavage Topical Gavage Topical Gavage

NE SE SE NE CE CE NE SE

EE EE SE NE CE NE NE NE

CE SE

CE CE

SE CE CE CE NE

NE CE CE CE SE

Yes Yes Yes No Yes Yes Yes Yes

Topical Gavage Dosed-feed Inhalation Dosed-feed Gavage Inhalation Dosed-feed Gavage Gavage Gavage Gavage Inhalation Gavage Gavage Gavage Gavage Dosed-feed Gavage Dosed-feed Dosed-feed Dosed-feed

SE SE NE CE CE SE SE EE N CE SE SE CE CE SE CE SE NE CE CE CE P

NE NE EE SE NE NE EE NE N NE SE NE SE NE EE NE NE NE CE CE NE P

NE IS EE SE NE CE SE NE N

NE NE NE SE CE SE NE SE N

NE EE

SE NE

NE EE

NE NE

NE EE CE

NE NE CE

NE P

NE P

Dosed-feed

P

P

Dosed-feed Dosed-feed Dosed-feed Gavage Dosed-feed Gavage Gavage Dosed-feed Gavage Dosed-feed Dosed-feed Dosed-water Dosed-feed Gavage Inhalation Inhalation Inhalation Gavage Topical Gavage Dosed-feed

E CE SE CE EE EE E CE EE NE EE SE SE SE CE CE SE CE EE CE P

E CE NE CE NE CE N SE SE NE NE EE NE SE SE CE NE CE NE CE P

CE or P Clear evidence, SE Some evidence, EE or E Equivocal evidence, NE or N No evidence, IS Inadequat e experiment . Downloaded from tpx.sagepub.com by guest on July 15, 2011 Positive, W Weakly positive, ? Inconclusive, Negative. Salmonella results: Totals include positive and equivocal responses, and those that may have been related to chemical exposure. Note. Blank space under the animal groups indicates no experiments were done.

No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No Yes Yes Yes Yes Yes

N CE NE

N SE CE

P CE SE NE CE CE

P CE NE EE CE CE

CE CE CE NE CE IS EE P

CE CE CE CE CE IS EE P

Yes Yes Yes Yes No Yes Yes Yes Yes No Yes Yes No Yes Yes Yes Yes Yes No Yes Yes

660


WOLF TABLE 7.—Chemicals associated with site-specic tumor induction in the urinary bladder.

Technical report number

Levels of evidence of carcinogenicity Chemical name

Salmonella

234 383 094 216 089 494 067 179 452 458 063 467 299 105 142 269 374 245 006 006

Allyl isothiocyanate 1-Amino-2,4-dibromoanthraquinone 4-Amino-2-nitrophenol 11-Aminoundecanoi c acid O-Anisidine hydrochlorid e Anthraquinone Aspirin, phenacetin, and caffeine p-Benzoquinon e dioxime 2,2-Bis(bromomethyl)-1,3-propanediol Butyl benzyl phthalate 4-Chloro-o-phenylenediamine Chloroprene C.I. Disperse blue 1 m-Cresidine p-Cresidine 1,3-Dichloropropene (Telone II) Glycidol Melamine Nitrilotriacetic acid (NTA) Nitrilotriacetic acid trisodium Monohydrate 006 Nitrilotriacetic acid trisodium Monohydrate 416 o-Nitroanisole 164 N-Nitrosodiphenylamine 457 Salicylazosulfapyridine 153 o-Toluidine hydrochloride Number of chemicals causing tumors in URINARY BLADDER

,

W

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Route

MR

FR

MM

FM

Gavage Dosed-feed Dosed-feed Dosed-feed Dosed-feed Dosed-feed Dosed-feed Dosed-feed Dosed-feed Dosed-feed Dosed-feed Inhalation Dosed-feed Gavage Dosed-feed Gavage Gavage Dosed-feed Dosed-feed Dosed-feed

P CE P P P SE N N CE SE P CE CE P P CE CE P P P

E CE E N P CE E P CE EE P CE CE P P SE CE N P P

N CE N E P CE N N CE

N CE N N P CE N N CE

P CE EE IS P IS CE N P

P CE NE N P CE CE N P

Dosed-feed

E

E

N

N

Yes

Dosed-feed Dosed-feed Gavage Dosed-feed

CE P SE P

CE P SE P

CE N CE P

SE N CE P

Yes No Yes Yes

Yes Yes No Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes

25

CE or P Clear evidence, SE Some evidence, EE or E Equivocal evidence, NE or N = No evidence, IS Salmonella results: Positive, W Weakly positive, ? Inconclusive, Negative. Totals include positive and equivocal responses, and those that may have been related to chemical exposure. Note. Blank space under the animal groups indicates no experiments were done.

Regenerative hyperplasia or hyperplasia are types of nonneoplastic proliferative changes that may involve tubular or transitional epithelia. In the rodent kidney, such lesions are almost exclusively associated with CPN, whereas in the bladder they are most often sequelae to crystals, precipitates, or calculi. Metaplasia (squamous, glandular, or mucinous) has also been observed in the transitional epithelium of the renal pelvis or bladder, but is rarely seen in untreated control animals. CHEMICALLY INDUCED UT TUMORS IN F344 RATS AND B6C3F 1 MICE According to the NTP Special Report: “Numbers of Chemicals Associated with Site-Specic Neoplasia,” of 35 rodent organs, the kidney ranks second (after liver) as a site for chemically induced neoplasia (data available at , last

Inadequate experiment.

updated 7/27/00). There is at least some evidence of renal carcinogenicity associated with 57 of 347 chemicals tested by the NTP (Table 6). Of these chemicals, 51 have been demonstrated to affect the tubular epithelium, and 9 have been shown to affect the transitional epithelium. In the kidney, the vast majority of chemically induced tumors are derived from tubular or transitional epithelia. The urinary bladder ranks eleventh as a site for chemically induced tumors. At least some evidence of bladder carcinogenicity exists for 20 of 300 chemicals tested (Table 7). Both transitional and squamous epithelial tumors have been produced in the bladders of treated animals, and rare mesenchymal tumors have been observed (caused by C.I. Disperse Blue 1, for example). Clear evidence of ureteral carcinogenicity has been demonstrated for 2 of 57 chemicals tested. Both of these substances were associated with tumors in rat ureters, and 1 was associated with tumors in the ureters of mice (Table 8).

TABLE 8.—Chemicals associated with site-specic tumor induction in the ureter. Technical report number

Levels of evidence of carcinogenicit y Chemical name

Nitrilotriacetic acid (NTA) Nitrilotriacetic acid trisodium monohydrate Number of chemicals causing tumors in URETER 2 006 006

Salmonella

Route

MR

FR

MM

FM

Dosed-feed Dosed-feed

P P

P P

P

P

CE or P Clear evidence, SE Some evidence, EE or E Equivocal evidence, NE or N No evidence, IS Positive, W Weakly positive, ? Inconclusive, Negative. Salmonella results: Totals include positive and equivocal responses, and those that may have been related to chemical exposure. Note. Blank space under the animal groups indicates no experiments were done.

Inadequate experiment.



Yes Yes

Vol. 30, No. 6, 2002

URINARY TRACT TUMORS

As previously stated, the extent of agreement (concordance) between chronic bioassay results of F344 rats and B6C3F 1 mice is reported to be 74%. In NTP carcinogenicity studies, there is 71% interspecies agreement for the kidney and 65% for the urinary bladder. For each chemical tested, results were considered to be in agreement when there was at least some evidence of carcinogenicity in at least 1 sex of both species, or there was equivocal or no evidence of carcinogenicity in both species. Chemically induced tumors of the rodent kidney and urinary bladder share certain incidence characteristics with UT tumors that occur spontaneously: rats are affected more commonly than mice; males are affected more than females; the kidney is affected more than the bladder (the opposite of humans); epithelial tumors occur more frequently than tumors of mesenchymal or embryonal origin; and tumors of the renal tubular epithelium are more common than tumors of the renal transitional epithelium.

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and males compared to females, the tendency for epithelial tumors to predominate over nonepithelial types, and demonstrated links to CPN and urolithiasis. The nongenotoxic nature of many urinary tract carcinogens further indicates that caution must be applied when results of chronic rodent bioassay studies are extrapolated to humans. REFERENCES

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