National Toxicology Program

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Abstract for IMM85001 - Lithium Carbonate (CASRN 554-13-2)

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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

Immunotoxicity of Lithium Carbonate in Female B6C3F1 Mice
(CAS No. 554-13-2)

NTP Report Number IMM85001

ABSTRACT

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.


Table S-1
SUMMARY TABLE FOR IMMUNOPATHOLOGY STUDIES
Lithium Carbonate
Parameter Results Maximum Effect Dose
Dependent
Periodic Weights Slight decrease 5% Yes
Gross Pathology Diuresis not determined Yes
Histopathology Hepatitis mild same in two higher doses
Spleen hyperplasia high dose 
Organ Weights
Liver Decrease 16% Yes
Spleen No effect  
Lungs No effect  
Thymus Decrease 32% Yes
Kidney No effect   
Brain No effect  
Hematology
RBC's Increase 26% Biphasic
Retics Decrease 40% Yes
Leucocytes Increased 45% Yes
Leucocyte Diff No effect  
Serum Chemistries
SGPT No effect  
Albumin Increase 15% Yes
BUN No effect  
Glucose Decrease 9% Yes
Total Protein Increase 18% Yes
Bone Marrow
Cellularity Increased 35% Biphasic
DNA Synthesis No effect  
Stem Cells No effect  

Table S-2
SUMMARY TABLE FOR IMMUNOLOGY STUDIES
Lithium Carbonate
Parameter Results Maximum Effect Dose
Dependent
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  
- LPS Increased 20% Yes
- Media Increased 20% Yes
MLR No Effect  
NK Cell Activity No Effect  
Serum Complement No Effect  
Macrophage (Fixed)
Liver Decreased 19% Yes
Spleen No Effect  
Lungs No Effect  
Macrophage (Peritoneal)
Cell # No Effect  
Adherence to Plastic No Effect  
Differential No Effect  
Phagocytosis SRBC Decreased 27% Yes
Phagocytosis CRBC Decreased 53% Yes
Adherence of CRBC Decreased 44% Yes
Ectoenzymes
5'ND Increased 65% Yes
LAP Increased 47% Yes
PDE Increased 55% Yes
Β-Glucuronidase Increased 67% Yes

Report Date: June 1986

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