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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009.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