National Toxicology Program

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Abstract for IMM90015 - Dapsone (CASRN 80-08-0)

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09-3566%20NTP-ITOX-R1.pdf). The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.

The Immunotoxicity of Dapsone (CAS No. 80-08-0) in Female C57Bl/6 Mice

NTP Report Number IMM90015

Introduction

Dapsone has been used to treat leprosy and dermatologic disorders as well as for prophylaxis against falciparum malaria. It has been shown to be useful in the treatment of Pneumocystis carinii pneumonia in AIDS patients. Use of dapsone in humans has resulted in a number of adverse reactions including bone marrow suppression and hypersensitivity. In light of these known adverse effects and its increasing use in AIDS related P. carinii pneumonia, the immunotoxicological potential of this drug was investigated.

Design

Dapsone was obtained from Sigma Chemical Co., Inc. Its identity was determined by NMR and mass spectral analysis and purity, as determined by HPLC, was approximately 96%. Dapsone was administered by oral gavage to female C57BL/6 mice at doses of 3.4, 13.5, and 54.0 mg/kg daily, seven days/week, for 30 consecutive days. The vehicle was 0.5% methylcellulose which was prepared by dissolving methylcellulose (Fisher Scientific) in double distilled water and stirring overnight at 5°C. Fresh dapsone suspensions were prepared weekly and stored at 5°C. Cyclophosphamide (Sigma) was used as a positive control and was administered i.p. using 25 mg/kg on 4 consecutive days prior to sacrifice.

Results

The baseline toxicology data are summarized in Table 1. No unusual observations were made for any of the experimental groups. No change in body weights were observed; however spleen weights were significantly higher in the high-dose group. Upon sacrifice, this group showed enlarged, dark red spleens. There were no effects of dapsone on non-immune organ weights. Spleen cell subset enumeration demonstrated a significant effect on B cells as evidenced by a decrease in Ly5+ cells at the highest dose level. This was not associated with a significant decrease in surface Ig+ cells. There were no effects on T cells or T cell subsets. Both NK1.1+ cells and Mac-1 + cells showed trends toward a treatment- related increase, but these were not statistically significant. No effects of dapsone were observed on spleen cell proliferative responses to T cell mitogens. However, there were increases in the proliferative response to LPS at the high dose levels (189% of control). Dapsone treatment had no effects on cell-mediated immunity (MLR response or CTL response) or NK cell activity. There was a significant increase in nucleated spleen cell numbers in the high dose group was noted (139% of control) although the PFC response following SRBC immunization was not altered. Erythropenia was observed at the high dose level and was associated with a decreased hematocrit, significant at both the middle and high dose levels. Leukocyte counts were also elevated in the high dose group.

Conclusion

Under these experimental conditions, with the exception of the highest dose, oral administration of dapsone did not result in a significant degree of immunotoxicity in C57BL/6 mice. The pattern of immunotoxicity that was observed appeared to be related to a marginal sensitivity in humoral immunity and manifested as augmented responses. In this regard, the possibility of a "rebound" effect cannot be ruled out.

Table 1: Summary of Dapsone Immunotoxicity

Parameter Dose (mg/kg) cyclophosphamide
  0 3.4 13.5 54.0 25 mg/kg
Body Weight (g) 19.4 19.2 18.9 20.2 No Data
Organ Weights:

Spleen (mg)

82.2 86.4 93.2 152.0* 61.1*

Spleen:Brain (%)

0.19 0.20 0.22 0.35* 0.14*

Thymus (mg)

58.5 57.5 58.2 56.6 34.1*

Thymus:Brain (%)

0.13 0.13 0.14 0.13 0.08*
 
Peripheral Leukocyte Count (10E3/mm3) 2.7 2.5 3.3 5.7* 1.7*
 
Spleen cell no. (x 10E7) 11.3 11.6 10.8 15.7* 6.7*
T cells (%) 35.9 36.3 38.5 36.2 44.7*
CD4 (%) 21.4 21.0 22.6 22.3 28.8*
CD8 (%) 14.0 14.7 13.9 13.3 17.5*
B cells (%) 59.9 57.5 56.4 55.3* 50.3*
CTL (% cytotox.) A 42.1 44.8 40.6 43.0 40.2
 
NK Cell Activity A (%cytotox.) 1.6 1.5 1.1 2.1 0.7
 
IgM PFC/10E6 cells 292 296 356 386 10*
 
IgM PFC/spleen (x 10E4) 3.31 3.45 4.03 6.08 0.08*
 
Lymphoproliferation 3H-TdR incorporation
(cpm x 10E3):
Concanavalin A 302 250224 316 88
PHA 261 218 198 251 91
LPS 61 50 63 88 19
Mixed Leukocyte Response 8.65 5.04 7.21 7.14 4.72

note:
    A - 25:1 ET ratio
    * = different from vehicle control at P less than 0.05


References:
   DeGowin RL (1967): Arch. Intern. Med. 120: 242-248.
   Green ST et al. (1988): Br. J. Clin. Pharmacol. 26: 487-488.
   Richardus JH et al. (1989): Leprosy Review 60: 267-273.
   Roy B et al. (1988): Internat. J. Lep. Mycobact. Dis. 56: 574-579.


Report Date: October 1991

NTIS # PB92-140383 [SUMMARY(1-15)]

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