Bladder tumours

Chen JJ, Ye ZQ and Koo MW. 2004. Growth inhibition and cell cycle arrest effects of epigallocatechin gallate in the NBT-II bladder tumour cell line. BJU Int 93(7) 1082-1086. 

Cyclamates are the salts of the cyclohexylsulfamic acid. In 1969 cyclamates were blamed for being carcinogenic following a study in which an increase in bladder tumours was observed in a study on a cyclamate-saccharin blend. Following publication of the study the FDA and a number of other health authorities banned cyclamate from use in foods and beverages. On the basis of additional studies it has meanwhile been accepted that cyclamate is not carcinogenic. 

Mechanistic studies carried out in the course of recent years indicated that sodium saccharin may be involved in the formation of specific proteins occurring in rat urine which may contribute to the formation of bladder tumours. Most scientists and regulatory authorities now share the view that the incidence of bladder tumours in male rats after saccharin ingestion is species-specific and therefore probably without any significance for humans. Accordingly, the former temporaiy ADI of 0-2.5 mg/kg of body weight has been raised to 0-5 mg/kg by JECFA21 and the SCF.22... 

Marhold J. 1953. [Second case of urinary bladder tumour following work with interproducts of dyes.] Procovni Lekarstivi 4 347. (Czech). (Summarized in Occupational Safety and Health Database, Dialog File 161, NIOSH Accession 00021815.)... 

Kolozsy Z. Histopathological self-control in transurethral resection of bladder tumours. Br J Urol 1991 67 162-164. 

Progress has been made using the ALA-protoporphyrin IX photosensitiser system in in vivo fluorimetry, because the fluorescent protoporphyrin concentration in tumour cells is much higher than in healthy cells. An example of its use is in the successful diagnosis of bladder tumours, giving superior results to visual examination. Anew generation of pentyl and hexyl esters show an even more intense fluorescence. 

Rat. Groups of 30 male Fischer 344 rats, eight weeks of age, were treated with ort/io-nitrosotoluene [purity not specified, recrystallized product] in the diet at a concentration of 3380 ppm (0.028 mol/kg of diet) for 72 weeks. A control group of 30 untreated male rats was used. The experiment was terminated at 93 weeks. Mean body weights were lower in the treated than in the control group. The incidence of fibromas of the skin was 1/27 and 19/29 p < 0.001, Fisher s exact test] that of fibromas of the spleen was 0/27 and 14/29 p 0.001, Fisher s exact test], that of hepatocellular carcinomas was 0/27 and 18/29 p < 0.001, Fisher s exact test] and that of urinary bladder tumours was 0/27 and 15/29 p < 0.01, Fisher s exact test] in control and treated groups, respectively (Hecht et al., 1982). 

Groups of 15 male Fischer 344 rats, six weeks of age, were administered 0 or 0.05% A-nitrosobutyl-/V-(4-hydroxybutyl)amine in the drinking-water for two weeks followed by ureteric ligation one week later to initiate bladder carcinogenesis. Catechol [purity unspecified] was administered at concentrations of 0 or 0.8% in the diet for 22 weeks and all animals were killed at week 24. Wlien catechol was administered after initiation, no increase in bladder tumours was produced (Miyata et al., 1985). 

Groups of 10 or 20 male Fischer 344 rats, six weeks of age, were given hydroquinone (purity, > 99%) in the diet at a concentration of 0.8% for 36 weeks alone or after exposure to 0.05% A -nitrosobutyl-A-(4-hydro ybutyl)amine in the drinking-water for four weeks to initiate bladder carcinogenesis. Hydroquinone alone did not affect body weight or bladder weight. Hydroquinone exposure alone did not induce bladder tumours and feeding of hydroquinone after initiator did not increase the incidence or multiplicity of bladder neoplasms induced by the initiatior alone (Kurata et al., 1990). 

Groups of female Fischer 344 rats, six to eight weeks old, were either left untreated (group A) or received a single intravesicular instillation of 0.3 mg A-methyl-A-nitroso-urea (group B), six intravesicular instillations of 2.5 mg methyl methanesulfonate at 14-day intervals (group C) or sequential treaments with 0.3 mg A-methyl-A-nitrosourea followed by six intravesicular instillations of 2.5 mg methyl methanesulfonate at 14-day intervals (group D). The numbers of rats with bladder tumours were (A) 0/25, (B) 7/29 (24%), (C) 2/27 (7%) and (D) 19/33 (58%) (Tudor et al., 1984). 

Historically, cyclamate was used in soft drinks in the United States from 1958 and in the United Kingdom from 1964, in combination with saccharin. In 1969, it was banned in the United States for use in general purpose foods on the basis of studies suggesting it may cause bladder tumours in laboratory animals. Several other countries, including the United Kingdom, followed suit. The ban on cyclamates was controversial and the original rat study has been heavily criticised. Subsequent studies on safety have implicated cyclohexylamine (the... 

The safety evaluation study for saccharin, on which the risk assessment was based that allowed the FDA ban to be lifted, was made available in 1983. It established a relationship between the dose of saccharin and the appearance of bladder tumours in male rats (the response). While it was found that saccharin was able to cause tumours in rats, the following points were important considerations in the risk assessment. 

It was found that the bladder tumours occurred at a dietary level of 3 per cent saccharin, a dose high enough to saturate excretion and cause physiological changes in the animals. 

Only male rats showed tumours females and other species did not show this response. The bladder tumours occurred only in rats that had been treated from the beginning of hfe, but not in rats that were treated only as adults. 

It was also found that, under the conditions that led to bladder tumours, mineral deposits (microcalculi) were present in the bladder, which is known to cause bladder cancer in rats. 

By extrapolation from the dose-response information in rats, it has been estimated that a o.oi per cent dietary level of saccharin, equivalent to about two cans of diet cola a day would lead to a lifetime risk of bladder tumours of 2.5 X 0.0000000001 (2.5 X io °) or 2.5 in ten thousand million This does not take into account the fact that (i) the bladder tumours occurred only in male rats treated in a particular way (2) the doses given were unrealistically high and (3) there is no human evidence for the effect. Thus even this estimate is erring very much on the side of caution. 

Cumming JA, Kirk D, Newling DW, Hargreave TB, Whelan P. A multi-centre phase two study of intravesical epirubicin in the treatment of superficial bladder tumour. Eur Urol 1990 17(l) 20-2. 

Lukkarinen O, Paul C, Hellstrom P, Kontturi M, Nurmi M, Puntala P, Ottelin J, Tammela T, Tidefeldt U. Intravesical epirubicin tvith and without verapamil for the prophylaxis of superficial bladder tumours. Scand J Urol Nephrol 1991 25(l) 25-8. 

Hetherington JW, Newling DW, Robinson MR, Smith PH, Adib RS, Whelan P. Intravesical mitomycin C for the treatment of recurrent superficial bladder tumours. Br J Urol 1987 59(3) 239 1. 

DeSesso, J. M. (1995). Anatomical relationships of urinary bladders oxrmpared Their potential role in the development of bladder tumours in humans and rats. Food Chem Toxicol 33, 705-714. 

This compound caused bladder cancer in experimental animals when these were exposed to levels of 5-7% of the diet but not if exposed to levels up to 5%. However, pharmacokinetic studies revealed that at these high exposure levels the plasma clearance of saccharin was saturated and therefore tissue levels would be higher than expected on the basis of a linear extrapolation from lower doses. Consequently, prediction of the incidence of bladder tumours at the lower exposure levels to which humans would be... 

Hasegawa, M., Yagi, K., Iwakawa, S., and Hirai, M. 2001. Chitosan induces apoptosis via caspase-3 activation in bladder tumour cells. Jpn. J. Cancer Res., 4 459-466. 

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