National Toxicology Program

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Abstract for IMM84001 - 1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin (HCDD) (CASRN 57653-85-7)

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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 1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin (HCDD)
(CAS No. 57653-85-7)in Female B6C3F1 Mice


NTP Report Number IMM84001

Summary

ABSTRACT

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.


Table A-1

SUMMARY TABLE FOR IMMUNOPATHOLOGY STUDIES
1,2,3,6,7,8 HEXACHLORODIBENZO-p-DIOXIN

ParameterResultsMaximum
Effect
Dose
Dependent
Comments
Periodic Weights No Effect
 
Gross Pathology Hepatomegaly 
Histopathology Focal areas of
hydropic degeneration
and Centrilobular necrosis
Yes 
Organ Weights 
          Liver Increased 33% Yes 
          Spleen Decreased 23% Yes 
          Thymus Decreased 27% Yes 
          Lungs No Effect 
          Kidney No Effect 
          Brain No Effect 
          Hematology 
          RBC's No Effect
          Retics Decreased 38% Yes
          Leucocytes No Effect
          Leucocyte Diff No Effect
Serum Chemistries
          SGPT Increased 111% Yes
          AlbuminNo Effect
          BUNNo Effect
          GlucoseNo Effect
          Total Protein Decreased12% Yes
Microsomal Parameters
     Microsomal ProteinIncreased 44% YesBased 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




Table A-2

SUMMARY TABLE FOR IMMUNOPATHOLOGY STUDIES
1,2,3,6,7,8 HEXACHLORODIBENZO-p-DIOXIN

ParameterResultsMaximum
Effect
Dose
Dependent
Comments
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
 
Serum Complement Decreased 62% Yes
Ser Comp 28 Day Recovery Increased 85% No Low dose
Ser Comp 28 Day Recovery Decreased 38% No High dose
 
Macrophage (Fixed)
             Liver Decreased 30% No Middle Dose
             Spleen Increased 29% No Middle Dose
             Lungs Increased 213% No Middle Dose
 
Macrophage (Peritoneal)
    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    Covaspheres
    Phagocytosis No Effect    Chicken RBC's
    Adherance of cRBC No Effect   Adherance to Macs
 
    Ectoenzymes
       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

Table A-3

SUMMARY TABLE FOR IMMUNOPATHOLOGY STUDIES
1,2,3,6,7,8 HEXACHLORODIBENZO-p-DIOXIN

OrganismResults
(Resistance)
Maximum
Effect
Control/Exposed
Dose
Dependent
Comments
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
B16F10 Melanoma
          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

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