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Abstract for IMM89050

Immunotoxicity of Silicone 180-Day Report in Female B6C3F1 Mice

CASRN: 9016-00-6
Chemical Formula: (C2H6OSi)x-
Molecular Weight: 74.15

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

There is widespread use of silicone-containing medical devices in many surgical and medical specialties. A variety of aesthetic and reconstructive prostheses contain silicone such as breast, chin, ear and joint prostheses. There are silicone hydrocephalus shunts, fallopian tube clips, cardiac valves, drug release capsules and intraocular lenses to name just a few of the many applications of implantable silicone. It is estimated that, prior to FDA sanctions, 130,000 American women had breast implantation procedures. Non-implantable applications of silicone include their use in tubing for drains, catheters, dialysis machines and blood oxygenators.

There is a paucity of data available on the status of the immune system in the presence of silicone implants. These studies were designed to determine the potential effects of silicone on the immune system and host resistance to selected microbial and tumor models.

These studies were NOT designed to determine the potential immunogenicityof the silicone implants. However, it is possible that if present,continuous antigenic stimulation may alter some of the immuneassays that were performed in these experimental animals.

These studies were conducted over a 3 year period. The initial protocol was approved and studies conducted between 23 Oct 89 and 19 Apr 90. Since there were no dose-response studies in the initial protocol, additional dose-response studies were carried out when statistical significance occurred. In addition a study was conducted to clarify the Natural Killer Cell results. The dose levels and the duration of exposure were based on the known and perceived use. For the silicone fluid and gel, one ml was selected which was estimated to represent 1/20 of the body weight of the mouse. There were 2 study durations. A 10-day exposure period was selected because it is the peak time of the initial inflammatory response. The 180-day study provides for evaluation of the immune status during the chronic phase where the capsule is well formed. The studies reported here are for the 180-day implantation period. Studies related to 10 days of implantation are in a separate report entitled, "Immmunotoxicity of Silicone in Female B6C3F1 Mice - 10 Day Exposure."

The baseline toxicology data are summarized in Table ES-1. The primary objective of the toxicology studies was to characterize the toxicological profile produced by treatment with silicone. Subcutaneous implantation of the silicone preparation produced no significant changes in any of the parameters measured. There was no implant-related mortality from exposure and no overt signs of toxicity. There were no gross pathologic findings at the time of necropsy. For the most part, body weight and body weight gain were not altered by the implants. Selected hematologic and serum chemistry parameters were not different from the vehicle control group and were within the historical control range of the MCV Immunotoxicology Program. Body weight was not adversely affected by the silicone implant. There were no significant changes in the weight of the brain, liver, spleen, thymus, lungs or kidneys. Bone marrow cellularity, CFU-M and CFU-GM stem cells were unaffected by the implants.

Table ES-2 summarizes the immunology studies. Implantation of mice with silicone preparations produced no effects on indicators of humoral immunity, such as changes in B cell number, proliferative ability or ability to differentiate into antibody-producing cells to a T-dependent antigen. Indicators of cell-mediated immunity were also unaffected as seen in a lack of effect on T lymphocyte numbers and subset analysis, and spleen cell response to the T-dependent antigen, indicating that the regulatory T cells were similar tothose of control mice. Proliferative capacity, as measured byresponse to T cell mitogens and to allogeneic cells, was unaffected by silicone implants. Differentiation and the killing mechanism of T cells were intact as seen in a CTL response. Indicators of innate immunity that were unaffected included macrophage numbers and function and complement activity. Changes in natural killer cell function were slightly decreased.

Table ES-3 summarizes the three host resistance studies that were conducted. Implantation of mice with the silicone preparations did not produce any changes in host resistance to two bacterial models or one tumor host resistance model.

Studies

Table ES-1
Summary Table for Toxicology Studies
180-Day Study
SIL-180-1-SC
Results
Parameter FLUID GEL ELA PU Comments
General
Body Weight No Effect No Effect No Effect No Effect  
Gross Pathology No Effect No Effect No Effect No Effect  
Organ Weights
Liver No Effect No Effect No Effect No Effect  
Spleen No Effect No Effect No Effect No Effect  
Lungs No Effect No Effect No Effect No Effect  
Thymus No Effect No Effect No Effect No Effect  
Kidney No Effect No Effect No Effect No Effect  
Brain No Effect No Effect No Effect No Effect  
Hematology
RBCs No Effect No Effect No Effect No Effect  
Retics No Effect No Effect No Effect No Effect  
Leukocytes No Effect No Effect No Effect No Effect  
Leukocyte Diff No Effect No Effect No Effect No Effect  
Serum Chemistries
SGPT No Effect No Effect No Effect No Effect  
Albumin No Effect No Effect No Effect No Effect  
BUN No Effect No Effect No Effect No Effect  
Glucose No Effect No Effect No Effect No Effect  
Total Protein No Effect No Effect No Effect No Effect  
Globulin No Effect No Effect No Effect No Effect  
Bone Marrow
Cellularity No Effect No Effect No Effect No Effect  
DNA Synthesis No Effect No Effect No Effect No Effect  
Stem Cells No Effect No Effect No Effect No Effect  
CFU-GM No Effect No Effect No Effect No Effect  
CFU-M No Effect 22% Inc No Effect No Effect Per 10[5] cells

Table ES-2
Summary Table for Immunology Studies
180-Day Study
SIL-180-1-SC

Cell Surface Markers (Percent Value)

Parameter FL GEL ELA PU Comments
B Cells No Effect 12% Decr No Effect No Effect Studies Repeated for Dose Response
CD4+CD8- No Effect 22% Incr No Effect 15% Incr
CD4-CD8+ 42% Incr 45% Incr 34% Incr 28% Incr
CD4+CD8+ No Effect 95% Incr No Effect No Effect
Cell Surface Markers (Absolute Number)
Parameter FL GEL ELA PU Comments
B Cells No Effect 18% Decr No Effect No Effect Studies Repeated for Dose Response
CD4+CD8- 64% Incr 68% Incr 66% Incr 60% Incr
CD4-CD8+ 59% Incr 76% Incr 49% Incr 45% Incr
CD4+CD8+ No Effect 200% Incr No Effect No Effect
Repeated with Dose Response of the FL Material
Cell Surface Markers (Absolute Number)
Parameter VH 0.5 ml 1.0 ml 2.0 ml Comments
B Cells No Effect No Effect No Effect No Effect Repeat Study Dose Response
CD4+CD8- No Effect No Effect No Effect No Effect
CD4-CD8+ No Effect No Effect No Effect No Effect
CD4+CD8+ No Effect No Effect No Effect No Effect
Repeated with Dose Response of the GEL Material
Cell Surface Markers (Absolute Number)
Parameter VH 0.5 ml 1.0 ml 2.0 ml Comments
B Cells No Effect No Effect No Effect No Effect Repeat Study Dose Response
CD4+CD8- No Effect No Effect No Effect No Effect
CD4-CD8+ No Effect No Effect No Effect No Effect
CD4+CD8+ No Effect No Effect No Effect No Effect
Repeated with Dose Response of the ELA Material
Cell Surface Markers (Absolute Number)
Parameter VH 14.13 mm2 28.26 mm2 56.52 mm2 Comments
B Cells No Effect No Effect 11% Incr No Effect Repeat Study Dose Response
CD4+CD8- No Effect No Effect 29% Incr No Effect
CD4-CD8+ No Effect No Effect 29% Incr 22% Incr
CD4+CD8+ No Effect No Effect No Effect No Effect
Repeated with Dose Response of the PU Material
Cell Surface Markers (Absolute Number)
Parameter VH 14.13 mm2 28.26 mm2 56.52 mm2 Comments
B Cells No Effect No Effect No Effect No Effect Repeat Study Dose Response
CD4+CD8- No Effect No Effect No Effect No Effect
CD4-CD8+ No Effect No Effect No Effect No Effect
CD4+CD8+ No Effect No Effect No Effect No Effect
IgM AFC to sRBC (T-Dependent)
Day 4 IgM
Parameter FL GEL ELA PU Comments
PFC/106 No Effect No Effect 57% Incr No Effect Repeat Study for Dose Response
PFC/Spleen No Effect No Effect 62% Incr No Effect
Repeated with Dose Response of the ELA Material: No Effect
IgM AFC to sRBC (T-Dependent)
Day 5 IgM
Parameter FL GEL ELA PU Comments
PFC/106 No Effect No Effect No Effect No Effect  
Spleen Cell Proliferative Response to Mitogens and Allogenic Cells
Stimulus FL GEL ELA PU Comments
Con A No Effect No Effect No Effect No Effect  
PHA No Effect No Effect No Effect No Effect  
LPS No Effect No Effect No Effect No Effect  
Medium No Effect No Effect No Effect No Effect  
F(ab')2 + BSF-1 No Effect No Effect No Effect 17% Decr  
MLR No Effect No Effect No Effect No Effect  
Cytotoxic T-Cell Response
Parameter FL GEL ELA PU Comments
Lysis 94% Incr No Effect No Effect No Effect Repeat Study of FL invalid
Natural Killer Cell Response
Parameter FL GEL ELA PU Comments
NK Cell Activity No Effect 35% Decr 39% Decr No Effect Dose-Response Study to be Performed
Repeated (180 Days) with Dose Response of the ELA Material
Parameter VH 14.13 mm2 28.26 mm2 56.52 mm2 Comments
NK Cell Activity No Effect 30% Incr No Effect No Effect Dose-Response Study Performed
Repeated (180 Days) with Dose Response of the GEL Material
Parameter VH 0.5 ml 1.0 ml 2.0 ml Comments
NK Cell Activity No Effect No Effect No Effect 53% Decr Dose-Response Study Performed
Time Course Studies
Repeated with Dose Response of the GEL Material at 30 Days
Parameter VH 1.0 ml 2.0 ml 3.0 ml Comments
NK Cell Activity No Effect No Effect No Effect 23% Decr Dose-Response Study Performed
Time Course Studies
Repeated with Dose Response of the GEL Material at 60 Days
Parameter VH 1.0 ml 2.0 ml 3.0 ml Comments
NK Cell Activity No Effect No Effect No Effect No Effect Dose-Response Study Performed
Time Course Studies
Repeated with Dose Response of the GEL Material at 90 Days
Parameter VH 1.0 ml 2.0 ml 3.0 ml Comments
NK Cell Activity No Effect No Effect No Effect 23% Decr Dose-Response Study Performed
Time Course Studies
Repeated with Dose Response of the GEL Material at 180 Days
Parameter VH 1.0 ml 2.0 ml 3.0 ml Comments
NK Cell Activity No Effect No Effect No Effect 28% Decr Dose-Response Study Performed
Serum Complement
Parameter FL GEL ELA PU Comments
CH 50 No Effect No Effect No Effect No Effect  
C3 No Effect No Effect No Effect No Effect  
Macrophage Functions
Functional Activity of Reticuloendothelial System
Parameter FL GEL ELA PU Comments
Vascular Clearance No Effect No Effect No Effect No Effect  
Liver Uptake No Effect 26% Incr No Effect No Effect  
Spleen Uptake No Effect No Effect No Effect No Effect  
Repeated with Dose Response of the GEL Material: No Effect on Liver Uptake Covasphere Phagocytosis
Parameter FL GEL ELA PU Comments
Phagocytosis 27% Incr No Effect No Effect No Effect  
Repeated with Dose Response of the FL Material: No effect on Chicken Erythrocyte Phagocytosis
Parameter FL GEL ELA PU Comments
Phagocytosis No Effect No Effect No Effect No Effect  
Peritoneal Cell Differential
Parameter FL GEL ELA PU Comments
% Lymph's No Effect No Effect 28% Incr No Effect  
Absol Mono's No Effect 26% Decr No Effect No Effect  

Table ES-3
Summary Table for Host Resistance Studies
180-Day Study
SIL-180-1-SC
Results
Model FLUID GEL ELA PU Comments
Listeria monocytogenes No Effect No Effect No Effect No Effect  
Streptococcus pneumoniae No Effect No Effect No Effect No Effect  
B16F10 No Effect No Effect No Effect No Effect