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Abstract for IMM89051 - Silicone (CASRN 9016-00-6)

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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 Silicone
(CAS No. 9016-00-6)
10-Day Report

in Female B6C3F1 Mice
NTP Report Number IMM89051

Summary

There is widespread use of silicone-containingmedical devices in many surgical and medical specialties. A varietyof aesthetic and reconstructive prostheses contain silicone suchas breast, chin, ear and joint prostheses. There are siliconehydrocephalus shunts, fallopian tube clips, cardiac valves, drugrelease capsules and intraocular lenses to name just a few ofthe many applications of implantable silicone. It is estimatedthat in one year 130,000 American women undergo breast implantation.Non-implantable applications of silicone include their use intubing for drains, catheters, dialysis machines and blood oxygenators.

There is a paucity of data availableon the status of the immune system in the presence of siliconeimplants. These studies were designed to determine the potentialeffects of silicone on the immune system and host resistance toselected microbial and tumor models.

These studies were NOT designed todetermine the potential immunogenicity of the silicone implants.However, it is possible that, if present, continuous antigenicstimulation may alter some of the immune assays that were performedin these experimental animals.

These studies were conducted overa 2 year period. The initial protocol was approved and studiesconducted between 23 Oct 89 and 19 Apr 90. Since there were nodose-response studies in the initial protocol, additional dose-responsestudies were carried out when statistical significance occurred.The dose levels and the duration of exposure were based on theknown and perceived use. For the silicone Fluid and GEL, one mlwas selected which was estimated to represent 1/20 of the bodyweight of the mouse. There were 2 study durations. A 10-day exposureperiod was selected because it is the peak time of the initialinflammatory response. The 180-day study provides for evaluationof the immune status during the chronic phase where the capsuleis well formed. The studies reported here are for the 10-day implantationperiod. Studies related to 180 days of implantation are in a separatereport.

The baseline toxicology data are summarizedin Table ES-1. The primary objective of the toxicology studieswas to characterize the toxicological profile produced by treatmentwith silicone. Subcutaneous implantation of the silicone preparationproduced no significant changes in any of the parameters measured.There was no implant-related mortality from exposure and no overtsigns of toxicity. There were no gross pathologic findings atthe time of necropsy. For the most part, body weight and bodyweight gain were not altered by the implants. Selected hematologicand serum chemistry parameters were not different from the vehiclecontrol group and were within the historical control range ofthe MCV Immunotoxicology Program. Body weight was not adverselyaffected by the silicone implant. There were no significant changesin the weight of the brain, liver, spleen, thymus, lungs or kidneys.Bone marrow cellularity, CFU-M and CFU-GM stem cells were unaffectedby the implants.

Table ES-2 summarizes the immunologystudies. Implantation of mice with silicone preparations producedno effects on indicators of humoral immunity, such as changesin B cell number, proliferative ability or ability to differentiateinto antibody-producing cells to a T-dependent antigen. Indicatorsof cell-mediated immunity were also unaffected as seen in a lackof effect on T lymphocyte numbers and subset analysis, and spleencell response to the T-dependent antigen, indicating that theregulatory T cells were similar to those of control mice. Proliferativecapacity, as measured by response to T cell mitogens and to allogeniccells, was unaffected by silicone implants. Differentiation andthe killing mechanism of T cells were intact as seen in a CTLresponse. Indicators of innate immunity that were unaffected includedmacrophage numbers and function, natural killer cell activityand complement activity.

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



Table ES-1SUMMARY TABLE FOR TOXICOLOGYSTUDIES
10 DAY STUDIES
SIL-10-1-SC
Results
Parameter FLUID GEl ELA PU Comments
General
Body Weight 9% Incr 7% Incr No Effect No Effect  
Gross Pathology No Effect No Effect No Effect No Effect  
Organ Weights
Liver No Effect 11% Decr No Effect No Effect % Body Wt
Spleen 25% Incr 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 7% Decr 6% Decr 6% Decr No Effect Not Biologically Significant
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  
Total
Lymphocytes No Effect No Effect No Effect No Effect  
Serum Chemistries
SGPT No Effect 32% Decr 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 17% Decr No Effect No Effect  
Bone Marrow
Cellularity No Effect No Effect No Effect No Effect  
DNA Synthesis No Effect No Effect 29% Incr 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 No Effect No Effect No Effect  

Table ES-2
SUMMARY TABLE FOR IMMUNOLOGYSTUDIES
10 DAY STUDIES
SIL-10-1-SC
Results
Parameter FLUID GEl ELA PU Comments
% Value
B Cells No Effect No Effect No Effect No Effect  
T Cells 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  
CD4+CD8+ No Effect No Effect No Effect 57% Decr  
CD4-CD8- No Effect No Effect No Effect No Effect  
Absolute Value
B Cells No Effect No Effect No Effect 35% Incr  
T Cells No Effect No Effect No Effect 34% Incr  
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  
CD4-CD8- No Effect No Effect No Effect 134% Incr  

Repeated with Absolute Dose Response the PU material
  VH 14.1 mm2 28.3 mm2 56.5 mm2 Comments
CD4+CD8+ No Effect No Effect 37% Decr 37% Decr Not Biologically Significant
Results (cont.)
Parameter FLUID GEl ELA PU Comments
IgM AFC to sRBC T-Dependent Day 4 Response
PFC/106 Spleen Cells 26% Decr No Effect No Effect No Effect Repeat Dose Response for FL
PFC/Spleen No Effect No Effect No Effect No Effect  
Repeated with Dose Response of the FL material No Effect
IgM AFC to sRBC T-Dependent Day 5 Response
PFC/106 Spleen Cells No Effect No Effect No Effect No Effect  
PFC/Spleen No Effect No Effect No Effect No Effect  
Proliferation Assays
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 No Effect  
Cell-Mediated Immunity
MLR No Effect No Effect No Effect No Effect  
CTL No Effect No Effect No Effect No Effect  
Innate Immunity
NK Cell Activity No Effect No Effect No Effect No Effect  
RES Function No Effect No Effect No Effect No Effect  
cRBC Phagocytosis No Effect No Effect No Effect No Effect  
P.E. Differential No Effect No Effect No Effect No Effect  
P.E. Cell Macrophage Activation with Gamma Interferon No Effect 32% Decr No Effect 37% Decr Not Biologically Significant
CovaspherePhagocytosis No Effect No Effect No Effect 80% Incr Repeat Dose Response PU
Repeat Study with a DoseResponse of the PU material No Effect
Serum CH50 No Effect No Effect No Effect No Effect  
Serum C3 Levels No Effect No Effect No Effect No Effect  


 

Table ES-3

SUMMARY TABLE FOR HOST RESISTANCESTUDIES
10 DAY STUDIES
SIL-10-1-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  


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