National Toxicology Program

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 is moderately soluble in water and slightly soluble in alcohol and chloroform. INH is practically insoluble in ether and benzene. INH is a first-line antimycobacterial agent in the treatment of tuberculosis where the infecting agent is Mycobacterium tuberculosis or Mycobacterium 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 studies were conducted in female B6C3F₁ mice. The animals were administered isonicotinic acid hydrazide daily 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 was added to better characterize the dose-response relationship for the assay. In all studies, isonicotinic acid hydrazide was prepared as a solution in deionized water.

The baseline toxicology studies are summarized in Table ES-1. Daily oral administration of INH to female B6C3F₁ mice for 14 days at 25, 50 and 100 mg/kg (and 150 mg/kg for a standard toxicity evaluation) did not affect body weight gain/loss nor was any organ gross pathology observed. There was a modest increase in liver and kidney weight in animals exposed to 150 mg/kg and a small, but significant, increase in spleen weight in 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 altered by INH. Serum titers of IgM anti-sRBC were decreased 33% in animals given 100 mg/kg INH and the results of trend analysis were positive. INH exposure for 14 days did not alter spleen IgM antibody-forming cell activity. The mixed leukocyte response was essentially normal. Cytotoxic T cell activity appeared to be stimulated at 25 and 50 mg/kg, but no effect was detected at 100 mg/kg. Natural killer cell activity remained normal at all INH dose levels nor was the functional 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 100 mg/kg did tend to afford some protection in the Streptococcus pneumoniae host resistance assay.

Overall, at relatively high exposure levels, INH may adversely affect the antibody cell response while stimulating cytotoxic T cell activity.

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

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

Table ES-3
SUMMARY TABLE FOR HOST RESISTANCE STUDIES
INH-14-1-PO

Report Date: November 1995

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