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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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.
1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin (HCDD) was selected as the fourth xenobiotic to be investigated for effects on the immune system and host resistance because it was a major contaminant of pentachlorophenol which was shown to have immunosuppressive effects. The doses of HCDD were 0.056, 0.56, and 5.6 µg/kg administered daily for 14 days by gavage.
2,3,7,8-Tetrachlorodibenzodioxin (TCDD) was used as a comparative control. B6C3F1 female mice exposed to HCDD or TCDD showed no effects on body weight or body weight gain and the animals appeared normal throughout the experimental period.
Selected immunopathological studies (summarized in Table A-1) showed that the major target organ for HCDD was the liver, as manifested in hepatomegaly, areas of focal hydropic degeneration and centrilobular necrosis, and elevations in SGPT and total protein levels. The microsomal parameters associated with cytochrome P450 were increased as expected. Spleen and thymus weights were slightly decreased. Hematologic parameters were not changed from the control group or from the historical controls, except for a slight increase in peripheral blood reticulocytes. The lowest effect level in the immunopathology studies was 0.056 µg/kg for arylhydrocarbon hydroxylase and total serum protein. These two parameters should not necessarily be considered adverse effects, but physiological responses. A no effect level was not obtained.
HCDD produced several perturbations on the immune system of mice which are summarized in Table A-2. The number of splenic T lymphocytes was increased in HCDD exposed mice. The spleen IgM and IgG response was reduced to 16% of control, the DHR to KLH was reduced to 53% of control, and the MLR was reduced to 71% of control. There was no effect on NK cell activity, but there was a decrease in serum complement. The only effect seen on macrophage function was a decrease in hepatic phagocytosis. The lowest effect level for the immunological studies was 0.56 µg/kg for the IgM and IgG responses to SRBC. The no effect level was 0.056 µg/kg for the immunological studies.
Host resistance studies summarized in Table A-3 were conducted using two bacteria, (Listeria monocytogenes and Streptococcus pneumoniae), one virus (Herpes type 2), one protozoan (Plasmodium berghei) and one tumor model (B16F1O melanoma). The two models which showed increased resistance when the mice were exposed to HCDD were Listeria monocytogenes and Herpes virus type 2. A decreased resistance to Streptococcus pneumoniae occurred in mice exposed to the dioxins. The low doses of the dioxins decreased resistance to B16F10 melanoma, while the high doses demonstrated protection.
|Periodic Weights||No Effect|
|Histopathology||Focal areas of |
and Centrilobular necrosis
|Leucocyte Diff||No Effect|
|Microsomal Protein||Increased||44%||Yes||Based on total liver|
|Cytochrome P450 Content||Increased||503%||Yes||Based on total liver|
|Aminopyrine Demethylase||Increased||155%||Yes||Based on total liver|
|Aniline Hydroxlase||Increased||138%||Yes||Based on total liver|
|AHH||Increased||473%||Yes||Based on total liver|
|T & B Cell Enumeration||T Cells Increased||20%||No|
|IgM AFC to sRBC||Decreased||84%||Yes|
|IgG AFC to sRBC||Decreased||84%||Yes|
|IgM Recovery (day 28)||Decreased||60%||Yes|
|IgM Recovery (day 60)||Decreased||35%||Yes|
|DHR to KLH||Decreased||47%||Yes|
|Mitogen Response: Con A||Decrease||47%||Yes||Suboptimal Conc|
|Mitogen Response: Con A||No Effect||Optimal Conc|
|Mitogen Response: PHA||No Effect|
|Mitogen Response: LPS||No Effect|
|Mixed Lymphocyte Response||Decrease||29%||Yes|
|NK Cell Activity||No Effect|
|Ser Comp 28 Day Recovery||Increased||85%||No||Low dose|
|Ser Comp 28 Day Recovery||Decreased||38%||No||High dose|
|Cell #||No Effect|
|Adherence to Plastic||No Effect|
|Differential||Shift||Slight shift towards Monocytes based on percent|
No Effect using absolute values
|Phagocytosis||No Effect||Chicken RBC's|
|Adherance of cRBC||No Effect||Adherance to Macs|
|5'ND||No Effect||Experimental Unit is|
|PDE||No Effect||a pool of 4 mice|
|LAP||No Effect||3 pools per assay|
|Beta glucuronidase||No Effect|
|Herpes virus type 2||Increased||63% to 13%||Yes||1 X 104 PFU|
|Streptococcus pneumoniae||Decreased||6% to 75%||Yes||2.4 X 107 CFU|
|Listeria, monocytogenes||Increased||56% to 0%||Yes||1 X 104 CFU|
|Plasmodium borghei||No Effect|
|Low dose||Decreased||5989 to 40069||No||3 X 105 Cells|
|High dose||Increased||5989 to 1445||No||3 X 105 Cells|
Report Date: May 1985