National Toxicology Program

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Abstract for IMM96002 - Isonicotinic acid hydrazide (Isoniazid) (CASRN 54-85-3)

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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 IMM96002

Summary

Isonicotinic acid hydrazide (INH, Isoniazid), an analogue of pyrodoxine(vitamin B6), is a white crystalline solid that ismoderately soluble in water and slightly soluble in alcohol andchloroform. INH is practically insoluble in ether and benzene.INH is a first-line antimycobacterial agent in the treatment oftuberculosis where the infecting agent is Mycobacterium tuberculosisor Mycobacterium kansasii.

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

The studies were conducted in female B6C3F1mice. The animals were administered isonicotinic acid hydrazidedaily for 14 days at doses of 25, 50 and 100 mg/kg by oral gavage.In some of the studies, an additional 150 mg/kg dose group wasadded to better characterize the dose-response relationship forthe assay. In all studies, isonicotinic acid hydrazide was preparedas a solution in deionized water.

The baseline toxicology studies are summarized in Table ES-1.Daily oral administration of INH to female B6C3F1mice for 14 days at 25, 50 and 100 mg/kg (and 150 mg/kg for astandard toxicity evaluation) did not affect body weight gain/lossnor was any organ gross pathology observed. There was a modestincrease in liver and kidney weight in animals exposed to 150mg/kg and a small, but significant, increase in spleen weightin the 100 mg/kg group only. Hematology was unremarkable.

Table ES-2 summarizes the immunology studies.B cell and T cell numbers including T cell subsets were not alteredby INH. Serum titers of IgM anti-sRBC were decreased 33% in animalsgiven 100 mg/kg INH and the results of trend analysis were positive.INH exposure for 14 days did not alter spleen IgM antibody-formingcell activity. The mixed leukocyte response was essentially normal.Cytotoxic T cell activity appeared to be stimulated at 25 and50 mg/kg, but no effect was detected at 100 mg/kg. Natural killercell activity remained normal at all INH dose levels nor was thefunctional activity of the reticuloendothelial system affected.

The results of the host resistance studies are summarized in Table ES-3.INH had essentially no effect in the B16F10 melanoma and Listeria monocytogenes host resistance assays. However, INH at 100mg/kg did tend to afford some protection in the Streptococcus pneumoniae host resistance assay.

Overall, at relatively high exposure levels, INH may adverselyaffect the antibody cell response while stimulating cytotoxicT cell activity.


Table ES-1
SUMMARY TABLE FOR TOXICOLOGY STUDIES
INH-14-1-PO

 

Parameter Result Maximum Effect Dose Comment

 

Body Weight        
  Day 8 No Effect      
  Day 15 No Effect      
Weight Changes        
  Day 8-1 No Effect      
  Day 15-1 No Effect      

 

Pathology        
  Gross Pathology No Effect      
  Histopathology Not Done      
  Organ Weights        
    Liver Increased 18% 150 mg/kg  
    Spleen Increased 21% 100 mg/kg  
    Lungs No Effect      
    Thymus No Effect      
    Kidney Increased 8% 150 mg/kg
% Body Wt

 

Hematology        
  RBCs No Effect      
    Hemoglobin No Effect      
    Hematocrit No Effect      
    MCV No Effect      
    MCH No Effect      
    MCHC Increased 1% 100 mg/kg  
    Reticulocytes No Effect      
  Leukocytes No Effect      
    Leukocyte Diff        
      Lymphocytes No Effect      
      Neutrophils No Effect      
      Eosinophils No Effect      

Table ES-2
SUMMARY TABLE FOR IMMUNOLOGY STUDIES
INH-14-1-PO

 

Parameter Results Maximum Effect Dose Comment

 

Surface Markers
Ig+ No Effect      
CD3+ No Effect      
CD4+CD8- No Effect      
CD4-CD8+ No Effect      
CD4+CD8+ No Effect      

 

IgM Humoral Immune Response to Sheep Erythrocytes
Spleen IgM AFC to sRBC No Effect      
Serum Titers to sRBC Decreased -33% 100 mg/kg  

 

Proliferation Assay, Mixed Leukocyte Response
MLR Decreased -15% 50 mg/kg  

 

Cytotoxic T Lymphocyte Activity
CTL Increased 57% 50 mg/kg 0.75/1 E:T Ratio

 

Functional Activity of the Reticuloendothelial System
RES No Effect      

 

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-14-1-PO

 

Parameter Results Maximum Effect Dose Comment

 

Listeria monocytogenes No Effect      
Streptococcus pneumoniae No Effect      
B16F10 Melanoma No Effect      

 


Report Date: November 1995

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