National Toxicology Program

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Abstract for IMM96003 - 3'-Azido-3'-deoxythymidine (AZT) (CASRN 30516-87-1)

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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

The Immunotoxicity of 3'-Azido-3'-deoxythymidine (AZT) (CAS No.30516-87-1) in Female B6C3F1 Mice

NTP Report Number IMM96003

Summary

3'-Azido-3'-deoxythymidine (AZT) is presently being used successfully for the treatment of HIV positive individuals and is also used for the treatment of AIDS patients. Currently, AZT is considered by some as a standard treatment to prevent maternal transmission of the AIDS virus by treating the mother in the last weeks of pregnancy and continuing treatment with the baby. Previous studies by Luster et al.1 showed that some of the anti-HIV drugs had adverse effects on the immune system. Cao et al.2 showed the B lymphocyte was a target for the 2',3' dideoxyadenosine. Because of the long duration of treatment of humans, a six-month daily dosing study of AZT was recommended by the Food and Drug Administration.

3'-Azido-3'-deoxythymidine 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 potential effects of 3'-azido-3'-deoxythymidine on the immune system.

The studies were conducted in female B6C3F1 mice. The animals were treated daily for 180 days by oral gavage. The in-life phase of the study was conducted between September 26, 1996 and May 7, 1997. AZT was prepared weekly as a solution in Maalox Therapeutic Concentrate (T.C.).

The baseline toxicology studies are summarized in Table ES-1. Oral administration of AZT at 50, 125, 250 and 500 mg/kg/day for 180 days significantly decreased body weight and rate of weight gain at the 500 mg/kg dose level when the 5 studies are combined. A significant dose-dependent increase in relative spleen weight was seen, reaching 31% at the 500 mg/kg dose. These studies confirmed the significant decreases in the erythroid elements seen in other animal and clinical studies. These significant effects were observed at all dose levels for erythrocyte number (28%), hemoglobin (10%), mean corpuscular volume (30%), mean corpuscular hemoglobin (24%) and mean corpuscular hemoglobin concentration (4%) resulting in a NOAEL with these parameters of below 50 mg/kg. The percent reticulocytes were significantly increased at all dose levels from 20% to 95%. The leukocyte number was significantly decreased only at the high dose by 21%. In evaluating the bone marrow, no alteration was seen in the CFU-E (colony-forming units-erythrocytes); however, there were increases in CFU-GM (colony-forming units-granulocytes/monocytes) and CFU-M (colony-forming units-macrophage).

Table ES-2 summarizes the immunology studies. In the immune parameters evaluated, no alteration was seen in the T-dependent antibody-forming cell response to s-RBC; however, a significant decrease was observed with the serum IgM antibody titer up to 16%. When expressed as lytic units per spleen, the cytotoxic T lymphocyte cell response showed a significant dose-dependent decrease up to 66%. Significant high dose decreases were also observed in the natural killer cell number and in the number of CD4+ spleen cells.

In conclusion, adverse toxicological effects are present in mice treated with AZT for 180 days as seen in a decrease of body weight at the high dose and a significant decrease in the erythroid elements at all doses. Increases were seen in the CFU-GM (colony-forming units-granulocytes/monocytes) and CFU-M (colony-forming units-macrophage). Adverse immunotoxicological effects are present in mice treated with AZT for 180 days as seen in a decrease in the serum sRBC titer, cytotoxic T lymphocyte response, and absolute T helper cells and NK cells, resulting in NOAEL of below 125 mg/kg, 50 mg/kg and 250 mg/kg, respectively. Information on these immune alterations could be beneficial when using AZT in the treatment of AIDS patients

 

Table ES-1
Summary Table for Toxicology Studies
AZT-180-1-PO
Parameter Results Maximum
Effect
Dose Comment
Body Weight (Combined)

        Day 1

No Effect

 

 

 

        Day 15

No Effect

 

 

 

        Day 29

No Effect

 

 

 

        Day 43

No Effect

 

 

 

        Day 57

No Effect

 

 

 

        Day 71

Decrease

 

 

 

        Day 85

Decrease 6% 500 mg/kg

 

        Day 99

Decrease 7% 500 mg/kg

 

        Day 113

Decrease 7% 500 mg/kg

 

        Day 127

Decrease 8% 500 mg/kg

 

        Day 141

Decrease 9% 500 mg/kg

 

        Day 155

Decrease 8% 500 mg/kg

 

        Day 169

Decrease 10% 500 mg/kg

 

        Day 181

Decrease 9% 500 mg/kg

 

Weight Changes (Combined)

        Day 15-1

No Effect

 

 

 

        Day 29-1

No Effect

 

 

 

        Day 42-1

No Effect

 

 

 

        Day 57-1

No Effect

 

 

 

        Day 71-1

No Effect

 

 

 

        Day 85-1

Decrease

21%

500 mg/kg

 

        Day 99-1

Decrease

22%

500 mg/kg

 

        Day 113-1

Decrease

20%

500 mg/kg

 

        Day 127-1

Decrease

21%

500 mg/kg

 

        Day 141-1

Decrease

22%

500 mg/kg

 

        Day 155-1

Decrease

21%

500 mg/kg

 

        Day 169-1

Decrease

23%

500 mg/kg

 

        Day 181-1

Decrease

20%

500 mg/kg

 

Pathology

        Gross Pathology

No Effect

 

 

 

        Hispathology

Not Processed

 

 

 

        Organ Weights

 

 

 

 

           Brain

No Effect

 

 

 

           Liver

Increase

24%

500 mg/kg

% Body Wgt

           Spleen

Increase

31%

500 mg/kg

% Body Wgt

           Thymus

No Effect

 

 

 

           Kidney

Increase

12%

50 mg/kg

Organ/Brain Ratio

Hematology

        RBCs

Decrease

28%

500 mg/kg

 

           Hemoglobin

Decrease

10%

500 mg/kg

 

           Hematocrit

Decrease

6%

500 mg/kg

 

           MCV

Increase

30%

500 mg/kg

 

           MCH

Increase

24%

500 mg/kg

 

           MCHC

Decrease

4%

500 mg/kg

 

           Platelets

Increase

33%

500 mg/kg

 

           Reticulocytes

Increase

95%

500 mg/kg

 

        Leukocytes

Decrease

21%

500 mg/kg

 

           Leukocyte Diff

 

 

 

 

             Lymphocytes

No Effect

 

 

 

             Neutrophils

No Effect

 

 

 

             Eosinophils

No Effect

 

 

 

Serum Chemistries

        SGPT

Decrease

17%

 

 

        Albumin

No Effect

 

 

 

        BUN

No Effect

 

 

 

        Glucose

No Effect

 

 

 

        Total Protein

No Effect

 

 

 

        Globulin

No Effect

 

 

 

        Alb/Glob Ratio

No Effect

 

 

 

Bone Marrow

        Cellularity

 

 

 

 

        DNA Synthesis

Increase

26%

125 mg/kg

 

        Stem Cells

 

 

 

 

          CFU-GM

Increase

39%

500 mg/kg

 

          CFU-M

Increase

55%

250 mg/kg

 

          CFU-E

No Effect

 

 

 

Table ES-2
Summary Table for Immunology Studies
AZT-180-1-PO
Parameter Results Maximum
Effect
Dose Comment
Surface Markers (Absolute Values)

     Ig+

Decrease

11% 250 mg/kg  

     CD3+

No Effect

 

 

 

     CD4+CD8-

Decrease

22% 500 mg/kg  

     CD4-CD8+

No Effect

 

 

 

     CD4+CD8+

No Effect

 

 

 

     NK1.1+CD3-

Decrease

23% 500 mg/kg  

     MAC-3+

No Effect

     
IgM Humoral Immune Response to Sheep Erythrocytes

IgM AFC/106 Cells

No Effect

     

      Serum Titer

Decrease

16% 500 mg/kg Log2
Lymphocyte Proliferative Response

      Con A

Increase

27% 125 mg/kg  

 

 

  250 mg/kg  
Proliferation Assays, i.e. Mixed Leukocyte Response

     MLR

No Effect

 

 

 

Cytotoxic T Lymphocyte Activity

     CTL

Decrease

66% 250 mg/kg LU/Spleen
Reticuloendothelial System

     Spleen

Increase

29% 500 mg/kg % Uptake
NK Cell Activity

     Lytic Units

No Effect

 

 

 

 


Report Date: May 2000

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