Benzocaine-induced methemoglobinemia attributed to topical application of the anesthetic in several laboratory animal species.

In a screening study, a common benzocaine-containing anesthetic was topically applied to the following species: dogs (n = 11), domestic shorthair cats (n = 38), Long-Evans rats (n = 22), Sprague-Dawley rats (n = 11), ferrets (n = 6), rhesus monkeys (n = 10), cynomolgus monkeys (n = 10), owl monkeys (n = 10), New Zealand White rabbits (n = 18), miniature pigs (n = 9), ICR mice (n = 4), C3H mice (n = 4), and C57BL/10SnJ mice (n = 24). All animals, except mice and rats, received a 2-second spray to the mucous membranes of the nasopharynx for an estimated dose of 56 mg. A 2-second spray to rodents' oral mucous membranes delivered too great a volume of fluid for these animals; therefore, an equivalent dose was applied to the oral mucosa membranes by use of a 23-gauge needle and syringe. Initial (baseline) blood samples, as well as 4 blood samples taken every 15 minutes after drug application, were analyzed for methemoglobin (MHb), using an oximeter. Positive MHb response (> 3 SD above baseline) was seen in individuals of all groups. The study was repeated in dogs several months later to confirm low response. Response to benzocaine spray was observed in most animals tested, with response peaking between 15 and 30 minutes after dosing. Positive MHb response ranged from 3.5 to 38%, was detected in > 95% of individual animals, and ranged from 15 to 60 minutes after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Initiation of urinary bladder carcinogenesis in rats by freeze ulceration with sodium saccharin promotion.

Sodium saccharin was previously shown to induce a significant incidence of transitional cell carcinoma of the bladder when administered to rats either immediately or beginning 2 weeks after ulceration of the bladder epithelium induced by freezing or cyclophosphamide injection. However, the marked regenerative hyperplasia following ulceration by either of these methods is not completely repaired until 3 to 4 weeks after ulceration. To determine whether initiation in this model was due to the ulceration and regenerative hyperplasia alone or if it was due to the administration of sodium saccharin acting on the hyperplastic epithelium, the effect of administering sodium saccharin at various times after ulceration was examined. Five-week-old F344 male rats were given sodium saccharin as 5% of the diet beginning either immediately (Group 1) or 2, 4, 6, or 18 weeks (Groups 2, 3, 4, or 5, respectively) after freezing of the bladder, and sacrificed 2 years after the start of the experiment. The incidences of rats with transitional cell carcinoma of the bladder were 11 of 36 rats (31%) in Group 1, 6 of 36 (17%) in Group 2, 12 of 40 (30%) in Group 3, 7 of 36 (19%) in Group 4, and 9 of 39 (23%) in Group 5. Sodium saccharin without prior ulceration induced a transitional cell papilloma in one rat, and freeze ulceration without subsequent sodium saccharin induced a transitional cell carcinoma in one rat. No bladder lesions were seen in the untreated control rats. Scanning electron microscopic examination of rats fed sodium saccharin after ulceration showed evidence of multifocal hyperplasia and significant surface changes either at Week 18 of the experiment (Groups 1 to 3) or 18 weeks after beginning sodium saccharin administration (Groups 4 and 5). These results indicate that freeze ulceration of the bladder induced irreversible changes in the epithelial cells related to bladder cancer initiation even though the regenerative hyperplasia is morphologically reversible, and that sodium saccharin promotes the tumorigenic expression of those freeze ulceration-induced cellular changes even after healing from the injury.

An assessment of the impact of urine cytology screening using a computer-based model of bladder cancer.

Utilizing a computer-based model of bladder cancer, the applications of various urine cytology screening strategies are assessed. Outcomes for patients diagnosed by screening with respect to numbers of cases diagnosed, mean length of life, and numbers of cancer deaths are compared with a similar population of patients diagnosed after the development of symptoms. Diagnostic and treatment modality costs can be used to predict the cost per man-year of life extension afforded by a screening program.

A general probabilistic model of carcinogenesis: analysis of experimental urinary bladder cancer.

A theoretical model of two-stage carcinogenesis has been hypothesized. Variables that are modeled include the populations of normal, initiated, and transformed cells; mitotic rates of these cells; hyperplasia; and the probabilities of cell initiation and transformation during replication. The size of the cell populations can be estimated and mitotic rates determined directly from animal studies. Tumor occurrences at different time intervals following varying periods of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and sodium saccharin administration are known and are used in the indirect estimation of values for unobservable model variables. Model-based analyses suggest FANFT markedly increases the probability of cell initiation in addition to its experimentally verifiable effects on increasing the stem cell population and mitotic rates. Further, experimental results appear inconsistent with the hypothesis that FANFT increases the probability of cell transformation over background levels. Similarly, the effect of sodium saccharin was found to be attributable entirely to increases in stem cell populations and mitotic rates without influencing either the probability of initiation or the probability of transformation.

Multistage carcinogenesis in the urinary bladder.

The induction of cancer of the urinary bladder is a multi-stage process involving multiple exogenous and endogenous factors. Based on the classical initiation-promotion model, we have used N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) as initiator and sodium saccharin (SAC) or tryptophan as promoters. These latter chemicals have the properties expected of promoters: induction of hyperplasia, reversibility and nonmutagenicity. Also, tumors were induced whether the promoter was administered immediately after FANFT or beginning 6 weeks after FANFT was discontinued, but no tumors resulted if either promoter was given without initiation with FANFT. Factor(s) present in normal urine also are involved in the promotion process, in addition to the role of urine as a carrier of carcinogens. However, administration of SAC to animals with a rapidly proliferating bladder mucosa, induced by ulceration, pellet insertion, or in utero, resulted in bladder tumor induction, even without prior initiation with FANFT. To better understand the complex interaction of the multiple variables in bladder carcinogenesis, a stochastic computer model has been formulated based on long-term carcinogenicity and tissue kinetic studies in vivo. This model indicates the importance of cell proliferation and the development of hyperplasia in carcinogenesis.

Alterations in the rat kidney associated with sodium saccharin feeding.

Sodium saccharin has previously been demonstrated to induce hyperplasia and tumors of the urothelium of the rat urinary bladder. It was fed as 5% of the diet to male F344 rats for 2 years. In the present experiment, mild simple hyperplasia of the urinary bladder epithelium was again frequently observed, and a marked nodular and papillary hyperplasia of the urothelium of the kidney pelvis was also found in approximately half of the sodium saccharin-fed rats. This was infrequently associated with focal calcification of the renal papilla and pelvis. In contrast, rats fed sodium saccharin had a significantly reduced incidence of the interstitial nephritis frequently observed in older rats. No significant incidence was observed of lesions of tissues other than those of the urinary tract.

Delayed-type hypersensitivity, contact sensitivity, and phytohemagglutinin skin-test responses of heat- and cold-stressed calves.

Three-week-old Holstein bull calves were used to investigate the effect of a 2-week chronic heat (35 C) or cold (-5 C) exposure on delayed-type hypersensitivity (DTH) reactions to purified protein derivative after sensitization with heat-killed Mycobacterium tuberculosis, contact sensitivity (CS) reactions to 1-fluoro-2,4-dinitrobenzene, and phytohemagglutinin (PHA) skin tests. Heat exposure reduced expression of DTH reactions by 42% and CS reactions by 38% at 24 hours after elicitation of the responses. The PHA-induced skin tests were not affected after 1 week of heat exposure, but this reaction was reduced by 20% after 2 weeks of heat exposure. The immune response of calves exposed to cold air temperatures was more complex. Cold exposure suppressed CS reactions by 39% at the end of both the 1st and 2nd weeks. The PHA response was reduced by 39% after 2 weeks of cold exposure. The DTH response depended on duration of cold exposure. The DTH reaction was increased by 42% after 1 week, but was reduced by 14% after 2 weeks. These data are consistent with the hypothesis that environmental stressors alter host resistance by affecting the immune system. Furthermore, these stress-induced changes in immune events depend on the type of immune response, the nature of the environmental stressor, and the length of time that calves are exposed to the stressor.