National Toxicology Program

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Abstract for IMM96012 - Isonicotinic Acid Hydrazide (Isoniazid) (CASRN 54-85-3)

ABSTRACT

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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 Isoniazid (CAS No.54-85-3) in Female B6C3F1 Mice

NTP Report Number IMM96012

Summary

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 agentis Mycobacterium tuberculosis or M. kansasii.

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

The baseline toxicology studies aresummarized in Table ES-1. There were no significant changes inbody weights for any INH-treated group compared to controls. However,trend analysis of body weight changes over weekly intervals asa function of exposure revealed a tendency toward a reduced rateof weight gain for days 8 through 22 of exposure. Slight hepatomegalywas observed at the highest dose level. The WBC count was reducedby about 25% in the low dose group only. Mean corpuscular hemaglobin(MCH) and mean corpuscular hemaglobin concentration (MCHC) increasedslightly, but significantly, in the high dose group (150 mg/kg).SGPT levels were significantly decreased in two of the four dosegroups. SGPT values for the low (25 mg/kg) dose group were decreased20% 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 immunologystudies. 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 percentvalue. All other cell assessments were unaffected. No significanteffect of INH exposure was evident when each exposure group wascompared to controls. However, trend analysis indicated an impairedAFC response over the INH dose range tested. INH significantlyreduced serum anti-sRBC 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 absenceof effect under all other conditions. There was no effect of INHon the vascular clearance rate as reflected in the lack of effecton the half-life of the radiolabled sheep erythrocytes, even thoughhepatic uptake was marginally decreased in the 100 mg/kg groupwhen expressed as cpm/mg. INH exposure had no effect on NK cellactivity.

The results of the host resistancestudy are summarized in Table ES-3. INH exposure had no effecton the outcome of the Streptococcus pneumoniae host resistanceassay.

In summary, the data derived fromthis study indicate a low order of toxicity for INH. INH significantlyimpaired an antibody response to the antigen sRBC, as reflectedin serum anti-sRBC titers. The AFC response to sRBC was also decreasedas shown by trend analysis. All other immunological parametersassessed were essentially normal.


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 STUDY
INH-28-1-PO


 

Parameter Results Maximum Effect Dose Comment

 

Streptococcus pneumoniae No Effect      

 

Report Date: May 1996


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