National Toxicology Program

National Toxicology Program

Abstract from Report IMM20404 & IMM20502 on Elmiron

Range-Finding on the Immunotoxity of Elmiron in Female B6C3F1 Mice (CAS No. 37319-17-8)

Report Date: August 2012

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.


Elmiron is a sodium salt of pentosan polysulfate that is used in the United States for the relief and treatment of bladder pain resulting from interstitial cystitis. Carcinogenicity studies with EMR reported by the National Toxicology Program demonstrated an increased incidence of liver hemangiosarcoma, hepatocellular neoplasm, and malignant lymphoma in female B6C3F1 mice (NTP, 2004). Furthermore, Nyska et. al. (2002) reported on the toxicity of EMR in both rats and mice following 90 days of exposure and identified increased white blood cell and lymphocyte numbers and increased weights of the liver, kidney, lung, and spleen in both species. These authors also reported histopathological anomalies in the spleen of mice but not rats. These results suggest the potential for EMR to modulate the immune system.

The NTP requested that a dose range-finding study be conducted to establish the potential effects of EMR on the immune system. These studies were conducted in female B6C3F1 mice. In all studies except the B16F10 melanoma host resistance study, five EMR doses (63, 125, 250, 500, and 1000 mg/kg) were administered for 28 days by oral gavage. Three EMR doses (250, 500, and 1000 mg/kg) were administered in the B16F10 melanoma host resistance assay. EMR dosing solutions were prepared weekly in United States Pharmacopoeia-grade sterile water and were stored at 2-8ÂșC.

For the standard toxicological endpoints evaluated in these studies, exposure to EMR resulted in no overall effects on body weight or on body weight gain. Absolute liver weights were increased in a dose-dependent manner in one study, but not in a second study. Overall, the weights of major organs of the immune system, i.e., the thymus and the spleen, were unaffected over the 28-day exposure period. Absolute spleen weights were increased in one study but not in a dose-dependent manner. Hematological parameters were largely unaffected by EMR exposure, with the exception of dose-related increases in reticulocyte percentages.

Immunology studies: Total splenocyte numbers were increased at the 1000 mg/kg dose level. Absolute numbers of B cells and double-positive (i.e., CD4+CD8+) T cells were also increased at the 1000 mg/kg dose. In addition, increases in the absolute numbers of natural killer cells were observed following treatment with EMR at 250 and 1000 mg/kg, while macrophages were increased at the 63, 500, and 1000 mg/kg dose levels. Based on the results of the antibody-forming cell assay and serum anti-sheep red blood cell IgM antibody levels, there were no effects on the T-dependent antibody response. Furthermore, no overall effects were observed on cell-mediated immunity, as assessed by evaluating the mixed leukocyte response and anti-CD3 mediated T cell proliferation. Innate immunity, as assessed by the phagocytic activity of the fixed macrophages of the mononuclear phagocytic system and NK cell activity, was significantly modulated following exposure to EMR. An increase in phagocytosis of 51Cr-labeled sRBC was observed in the livers of mice treated with 1000 mg/kg EMR. Significant increases were also observed in NK cell activity in the 500 and 1000 mg/kg treatment groups.

Host resistance studies: EMR exposure for 28 days did not affect host resistance to the bacterial pathogen, Listeria monocytogenes. Host defense and protection from this organism is mediated by neutrophils, macrophages, and NK cells, which are all components of the innate immune response. In contrast, EMR exposure increased host resistance to the B16F10 melanoma lung tumor, which primarily evaluates the functional activity of NK cells. The decreased lung tumor burden following EMR exposure is consistent with the increases observed in NK cell activity in the immunology component of these studies.

In conclusion, exposure to EMR for 28 days by oral gavage did not affect humoral or cell-mediated immune function. However, innate immune functions were enhanced, as indicated by an increase in phagocytosis by the Kupffer cells of the liver, increased NK cell cytotoxic activity, and increased host resistance to the B16F10 melanoma tumor model.

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