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Table 1. Bladder Tumour Incidence in F,-Generation Male Rats in Two-Generation Bioassays of NaS . FDA Study' WARF Study' CHPB Study' IRDC Study' Dietary Level # per % Group Incidence # per % Group Incidence # per % Group Incidence # per % Group Incidence 0 29 3.0 20 0 42 0 324 (P 0.01 16 0 - - - - - - 0.05 - - 20 0 - - - - 0.1 27 0 - - - - - - 0.5 - - 20 5.0 - - - - 1.0 22 0 - - - - 658 0.8 3.0 - - - - - - 472 1.7* 4.0 - - - - - - 189 6.3* 5.0 21 5.0 20 35* 45 26.9* 120 12.5* 6.25 - - - - - - 120 16.7* 7.5 23 30.0* - - - - 118 31.4* ' Food and Drug Administration, reported by Taylor gW. (1980); Wisconsin Alumni Research Foundation, reported by Tisdel gw. (1974); Canadian Health Protection Branch, reported by Arnold tW. (1980a); International Research and Development Corp., reported by Schoenig 1W. (1985). b The background incidence for total bladder neoplasia at IRDC is 0.8% * Statistically significant lSEl1ll[1W

Bladder Hyperplasla (%) 30. A 20 ~ . + • 10-~ • • • 2 4 ~ • 6 Dietary NaS (%) Labelling Index 0.8 , C 0.6-~ 0.4 ; 0.2-I 0.0-~ , • _---, • + • 0 2 4 Dietary NaS (%) T + • + . 8 Bladder Tumors M 40' 30 - 20 - 10- • Light Transmittance (%) 100 • 80 ~ 60-i 40 ~ ~ 20, B + • - . • . 2 4 Dietary NaS ( %) . D T 2 4 Dietary NaS ( %) 6 i 6 + • • 8 ZSEiMOSz

Prevented by Increased urine pH and sodium concentration NH,C1 in the diet ~~-• or AIN 76A diet Increased urine volume and decreased osmolality • High urinary protein levels in male vs female (a2,-globulin) • Absent or less ~~. Urinary amorphous precipitate and crystals in female rats I • Urothelial cytotoxicity • Absent or less -~.~- • Urothelial hyperplasia and proliferation in female rats Bladder tumors Bladder tumor promotion in long-term bioassays in initiated rats .

Legend for Figures F'igure 1. Incidence of Urothelial Hyperplasia (A) and Bladder Tumors (B) in the IRDC Study of NaS in the Rat (Squire, 1985). Labelling Index Data (C) Taken from Cohen (].990), and Light Transmittance F5ndings (D) from a Recent Study (Cohen, Unpublished). Figure 2. Sequence of Urinary and Bladder Changes Observed in Male Rats Fed High Dietary Levels of NaS ~ . ~ w LM Z