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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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.
Immunotoxicity of Lithium Carbonate in Female B6C3F1 Mice
NTP Report Number IMM85001
Lithium Carbonate was selected for evaluation because there are data in the literature showing that this drug produces consistent effects on the bone marrow. There is a minimal amount of data on the effects of Lithium Carbonate on the immune system. The doses of Lithium Carbonate were initially established based on probe studies and then modified based on the dose response data that became available. The first doses were 50, 200 and 400 mg/kg; the period of exposure was 14 days and the route of exposure was gavage. Doses were modified to 100, 300 and 400 mg/kg in repeat and later studies because of a lack of effect at 50 and 200 mg/kg.
A summary of the results of the immunopathology studies is presented in Table S-1. Lithium Carbonate at doses up to 400 mg/kg produced a slight decrease in weight gain, a major diuresis, mild hepatitis and spleen hyperplasia (specifically an increase in the number of germinal centers). There was a dose dependent decrease in liver and thymus weight. There was a dose dependent increase in leukocyte and erythrocyte number and a concommitant increase in hemoglobin and hematocrit. These changes can be accounted for by an increase in bone marrow activity, as seen in an increase in cell number and stem cells; the increase in stem cells is based on the number of stem cells per femur. No increase was noted in the stem cells based on 105 cells. A dose dependent increase in total protein and albumin occurred, which may be a function of the mild chemically induced hepatitis. However, no increase in SGPT was seen.
A summary of the immune studies is outlined in Table S-2. Lithium Carbonate produced a dose dependent shift in the ratio of T cells to B cells. B cell number increased, with an associated increase in response to the B cell mitogen, lipopolysaccharide. No changes were seen in the ability of the mice to produce specific IgM or IgG antibody to the T dependent antigen sheep erythrocytes. The decrease in the number of T cells was not associated with changes in the response to the T cell mitogens, Concanavalin A and Phytohemagglutinin, and allogeneic cells (MLR) or in the ability of the mice to develop a delayed hypersensitivity response to keyhole limpet hemocyanin or dinitrofluorobenzene. NK cell activity and serum complement levels were unaffected by exposure to Lithium Carbonate. Macrophages were a target for Lithium Carbonate. The phagocytic activity of the fixed macrophages of the liver and mobile macrophages derived from the peritoneal cavity was mildl! y suppressed. An increase in 5'nucleotidase was seen and is congruent with a more immature cell. However, an increase in Β-glucuronidase was seen and could explain the increased resistance to Listeria monocytogenes.
Two pathogens were used to evaluate host resistance in mice exposed to Lithium Carbonate. Plasmodium yoelii was used because it represents a model in which antibody and, thus, B lymphocytes play an important role in host resistance. Mice exposed to Lithium Carbonate showed no change in resistance to Plasmodium yeolii. Listeria monocytogenes was selected as the second pathogen because host resistance is primarily mediated by T cells and macrophages. Mice exposed to Lithium Carbonate and challenged to Listeria monocytogenes were slightly more resistant than either the vehicle or the comparative controls. The increased resistance may be due to increased lysosomal activity of macrophages. Results from the host resistance studies support the data from the immunological assays.
Lithium Carbonate up to maximum tolerated doses administered daily for 14 days produced minimal effects on the immune system. Although there was a change in the ratio of B and T cells, differentiated function of these cells was not altered. Macrophages were a target, with a slight to mild decrease in phagocytic activity and an increase in the activity of Β-glucuronidase.
|Periodic Weights||Slight decrease||5%||Yes|
|Gross Pathology||Diuresis||not determined||Yes|
|Histopathology||Hepatitis||mild||same in two higher doses|
|Spleen hyperplasia||high dose|
|Leucocyte Diff||No effect|
|DNA Synthesis||No effect|
|Stem Cells||No effect|
|T & B Cells||B cells increased||22%||Yes|
|T cells decreased||20%||Yes|
|IgM AFC to SRBC||No Effect|
|IgG AFC to SRBC||No Effect|
|DHR to KLH||No Effect|
|DHR to DNFB||No Effect|
|Mitogens- Con A||No Effect|
|- PHA||No Effect|
|NK Cell Activity||No Effect|
|Serum Complement||No Effect|
|Cell #||No Effect|
|Adherence to Plastic||No Effect|
|Adherence of CRBC||Decreased||44%||Yes|
Report Date: June 1986