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Abstract for IMM96012

Immunotoxicity of Isoniazid in Female B6C3F1 Mice

CASRN: 54-85-3
Chemical Formula: C6H7N3O
Molecular Weight: 137.1413
Report Date: May 1996

Abstract

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009.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.

Isonicotinic acid hydrazide (INH, Isoniazid), an analogue of pyridoxine (vitamin B6),is a white crystalline solid that is moderately soluble in waterand slightly soluble in alcohol and chloroform. INH is practicallyinsoluble in ether and benzene. INH is a first-line antimycobacterialagent in the treatment of tuberculosis where the infecting agent is Mycobacterium tuberculosis or M. kansasii.

Isonicotinic acid hydrazide (INH) was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the chemical manager. Thus, the purpose of these studies was to determine the effect of INH on the immune system.

The baseline toxicology studies are summarized in Table ES-1. There were no significant changes in body weights for any INH-treated group compared to controls. However, trend analysis of body weight changes over weekly intervals as a function of exposure revealed a tendency toward a reduced rate of weight gain for days 8 through 22 of exposure. Slight hepatomegaly was observed at the highest dose level. The WBC count was reduced by about 25% in the low dose group only. Mean corpuscular hemoglobin (MCH) and mean corpuscular hemaglobin concentration (MCHC) increased slightly, but significantly, in the high dose group (150 mg/kg). SGPT levels were significantly decreased in two of the four dose groups. SGPT values for the low (25 mg/kg) dose group were decreased 20% compared to the vehicle controls. At the 150 mg/kg dose level,the decrease was 24%. Exposure to INH decreased the albumin toglobulin ratio 24% in the high dose group.

Table ES-2 summarizes the immunology studies. The absolute number of TH cells was decreased by 35% at the low dose only, and the total number of T cells was increasedby 17% at the 50 mg/kg exposure only when expressed as a percent value. All other cell assessments were unaffected. No significant effect of INH exposure was evident when each exposure group was compared to controls. However, trend analysis indicated an impaired AFC response over the INH dose range tested. INH significantly reduced serum anti-s RBC titer over the dose range tested eventhough the spleen AFC response was only marginally affected. INHwas without effect on the MLR. A 44% increase in cytotoxic T cellactivity was seen at the 50 mg/kg dose level, but only at an E:Tratio of 1.5:1. This effect appears to be spurious given an absence of effect under all other conditions. There was no effect of INH on the vascular clearance rate as reflected in the lack of effect on the half-life of the radio labled sheep erythrocytes, even though hepatic uptake was marginally decreased in the 100 mg/kg group when expressed as cpm/mg. INH exposure had no effect on NK cellactivity.

The results of the host resistance study are summarized in Table ES-3. INH exposure had no effect on the outcome of the Streptococcus pneumoniae host resistance assay.

In summary, the data derived from this study indicate a low order of toxicity for INH. INH significantly impaired an antibody response to the antigen sRBC, as reflected in serum anti-sRBC titers. The AFC response to sRBC was also decreased as shown by trend analysis. All other immunological parameters assessed were essentially normal.

Studies

Table ES-1
Summary Table for Toxicology Studies
INH-28-1-PO

 

Parameter Result Maximum Effect Dose Comment

 

Body Weight        
  Day 8 No Effect      
  Day 15 No Effect      
  Day 22 No Effect      
  Day 29 No Effect      

 

Weight Changes        
  Day 8-1 No Effect      
  Day 15-1 No Effect      
  Day 22-1 No Effect      
  Day 29-1 No Effect      

 

Pathology        
  Gross Pathology No Effect      
  Histopathology Not done      

Organ Weights
    Liver Increased +13% 150 mg/kg  
    Spleen No Effect      
    Thymus No Effect      

 

Hematology
  RBCs No Effect      
    Hemoglobin No Effect      
    Hematocrit No Effect      
    MCV No Effect      
    MCH Increased +2% 100 mg/kg  
    MCHC Increased +3% 100 mg/kg  
    Platelets No Effect      
    Reticulocytes Decreased -25% 25 mg/kg  
  Leukocytes Decreased -25% 25 mg/kg  
    Leukocyte Diff        
      Lymphocytes Decreased -29% 25 mg/kg  
      Neutrophils No Effect      
      Eosinophils No Effect      

 

Chemistries        
  SGPT Decreased -24% 150 mg/kg  
  Albumin No Effect      
  BUN No Effect      
  Glucose No Effect      
  Total Protein No Effect      
  Globulin No Effect      
  Alb/Glob Ratio Decreased -24% 150 mg/kg  

 

Table ES-2
Summary Table for Immunology Studies
INH-28-1-PO

 

Parameter Results Maximum Effect Dose Comment


 

Surface Markers
Ig+ No Effect      
CD3+ Increased +17% 50 mg/kg % Values
CD4+CD8- No Effect      
CD4-CD8+ Decreased -35% 25 mg/kg Absolute Values
CD4+CD8+ No Effect      


 

IgM Humoral Immune Response to Sheep Erythrocytes
Spleen IgM AFC to sRBC No Effect      
Serum Titers to sRBC Decreased -46% 150 mg/kg  


 

       
Proliferation Assay, Mixed Leukocyte Response
MLR No Effect      


 

       
Cytotoxic T Lymphocyte Activity        
CTL Increased +44% 50 mg/kg 1.5/1 E:T Ratio


 

       
Functional Activity of the Reticuloendothelial System
RES Decreased -22% 100 mg/kg Liver cpm/mg


 

       
NK Cell Activity
1:100 No Effect      
1:50 No Effect              
1:25 No Effect      


 

 

Table ES-3
Summary Table for Host Resistance Studies
INH-28-1-PO

 

Parameter Results Maximum Effect Dose Comment

 

Streptococcus pneumoniae No Effect