National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/7263

Abstract for IMM89050 - 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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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)
180-Day Report

in Female B6C3F1 Mice
NTP Report Number IMM89050

Summary

There is widespread use of silicone-containing medical devicesin many surgical and medical specialties. A variety of aestheticand reconstructive prostheses contain silicone such as breast,chin, ear and joint prostheses. There are silicone hydrocephalusshunts, fallopian tube clips, cardiac valves, drug release capsulesand intraocular lenses to name just a few of the many applicationsof implantable silicone. It is estimated that, prior to FDA sanctions,130,000 American women had breast implantation procedures. Non-implantableapplications 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 immunesystem in the presence of silicone implants. These studies weredesigned to determine the potential effects of silicone on theimmune system and host resistance to selected microbial and tumormodels.

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 initialprotocol was approved and studies conducted between 23 Oct 89and 19 Apr 90. Since there were no dose-response studies in theinitial protocol, additional dose-response studies were carriedout when statistical significance occurred. In addition a studywas conducted to clarify the Natural Killer Cell results. Thedose levels and the duration of exposure were based on the knownand perceived use. For the silicone fluid and gel, one ml wasselected which was estimated to represent 1/20 of the body weightof 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 180-dayimplantation period. Studies related to 10 days of implantationare in a separate report entitled, "Immmunotoxicity of Siliconein Female B6C3F1 Mice - 10 Day Exposure."

The baseline toxicology data are summarized in Table ES-1. Theprimary objective of the toxicology studies was to characterizethe toxicological profile produced by treatment with silicone.Subcutaneous implantation of the silicone preparation producedno significant changes in any of the parameters measured. Therewas no implant-related mortality from exposure and no overt signsof toxicity. There were no gross pathologic findings at the timeof necropsy. For the most part, body weight and body weight gainwere not altered by the implants. Selected hematologic and serumchemistry parameters were not different from the vehicle controlgroup and were within the historical control range of the MCVImmunotoxicology Program. Body weight was not adversely affectedby the silicone implant. There were no significant changes inthe 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 immunology studies. Implantation ofmice with silicone preparations produced no effects on indicatorsof humoral immunity, such as changes in B cell number, proliferativeability or ability to differentiate into antibody-producing cellsto a T-dependent antigen. Indicators of cell-mediated immunitywere also unaffected as seen in a lack of effect on T lymphocytenumbers and subset analysis, and spleen cell response to the T-dependentantigen, 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 unaffectedby silicone implants. Differentiation and the killing mechanismof T cells were intact as seen in a CTL response. Indicators ofinnate immunity that were unaffected included macrophage numbersand function and complement activity. Changes in natural killercell function were slightly decreased.

Table ES-3 summarizes the three host resistance studies that wereconducted. Implantation of mice with the silicone preparationsdid not produce any changes in host resistance to two bacterialmodels or one tumor host resistance model.


Table ES-1
SUMMARY TABLE FOR TOXICOLOGY STUDIES
180-DAY STUDY
SIL-180-1-SC

Results
ParameterFLUIDGELELAPUComments
General
Body WeightNo EffectNo EffectNo EffectNo Effect 
Gross PathologyNo EffectNo EffectNo EffectNo Effect 
Organ Weights
Liver No EffectNo Effect No EffectNo Effect 
SpleenNo EffectNo EffectNo EffectNo Effect  
LungsNo EffectNo EffectNo EffectNo Effect 
ThymusNo EffectNo EffectNo EffectNo Effect 
KidneyNo EffectNo EffectNo EffectNo Effect 
BrainNo EffectNo EffectNo EffectNo Effect 
Hematology
RBCsNo EffectNo EffectNo EffectNo Effect 
ReticsNo EffectNo EffectNo EffectNo Effect 
LeukocytesNo EffectNo EffectNo EffectNo Effect 
Leukocyte DiffNo EffectNo EffectNo EffectNo Effect 
Serum Chemistries
SGPTNo EffectNo EffectNo EffectNo Effect 
AlbuminNo EffectNo EffectNo EffectNo Effect 
BUNNo EffectNo EffectNo EffectNo Effect 
GlucoseNo EffectNo EffectNo EffectNo Effect 
Total ProteinNo EffectNo EffectNo EffectNo Effect 
GlobulinNo EffectNo EffectNo EffectNo Effect 
Bone Marrow
CellularityNo EffectNo EffectNo EffectNo Effect 
DNA SynthesisNo EffectNo EffectNo EffectNo Effect 
Stem CellsNo EffectNo EffectNo EffectNo Effect 
CFU-GMNo EffectNo EffectNo EffectNo Effect 
CFU-M No Effect 22% IncNo EffectNo EffectPer 105 cells


Table ES-2

SUMMARY TABLE FOR IMMUNOLOGYSTUDIES

180-DAY STUDY

SIL-180-1-SC
Cell Surface Markers (PercentValue)

ParameterFLGELELAPUComments
B CellsNo Effect12% DecrNo EffectNo EffectStudies Repeated for Dose Response
CD4+CD8-No Effect22% IncrNo Effect15% Incr
CD4-CD8+42% Incr45% Incr34% Incr28% Incr
CD4+CD8+No Effect95% IncrNo EffectNo Effect

Cell Surface Markers (AbsoluteNumber)

ParameterFLGELELAPUComments
B CellsNo Effect18% DecrNo EffectNo EffectStudies Repeated for Dose Response
CD4+CD8-64% Incr68% Incr66% Incr60% Incr
CD4-CD8+59% Incr76% Incr49% Incr45% Incr
CD4+CD8+No Effect200% IncrNo EffectNo Effect

Repeated with Dose Responsethe FL Material
Cell Surface Markers (Absolute Number)

ParameterVH0.5 ml1.0 ml2.0 mlComments
B CellsNo EffectNo EffectNo EffectNo EffectRepeat Study Dose Response
CD4+CD8-No EffectNo EffectNo EffectNo Effect
CD4-CD8+No EffectNo EffectNo EffectNo Effect
CD4+CD8+No EffectNo EffectNo EffectNo Effect

Repeated with Dose Responsethe GEL Material
Cell Surface Markers (Absolute Number)

ParameterVH0.5 ml1.0 ml2.0 mlComments
B CellsNo EffectNo EffectNo EffectNo EffectRepeat Study Dose Response
CD4+CD8-No EffectNo EffectNo EffectNo Effect
CD4-CD8+No EffectNo EffectNo EffectNo Effect
CD4+CD8+No EffectNo EffectNo EffectNo Effect

Repeated with Dose Responsethe ELA material
Cell Surface Markers (Absolute Number)

ParameterVH14.13 mm228.26 mm256.52mm2Comments
B CellsNo EffectNo Effect11% IncrNo EffectRepeat Study Dose Response
CD4+CD8-No EffectNo Effect29% IncrNo Effect
CD4-CD8+No EffectNo Effect29% Incr22% Incr
CD4+CD8+No EffectNo EffectNo EffectNo Effect

Repeated with Dose Responsethe PU material
Cell Surface Markers (Absolute Number)

ParameterVH14.13 mm228.26 mm256.52mm2Comments
B CellsNo EffectNo EffectNo EffectNo EffectRepeat Study Dose Response
CD4+CD8-No EffectNo EffectNo EffectNo Effect
CD4-CD8+No EffectNo EffectNo EffectNo Effect
CD4+CD8+No EffectNo EffectNo EffectNo Effect

IgM AFC to sRBC (T-dependent)
Day 4 IgM

ParameterFLGELELAPUComments
PFC/106No EffectNo Effect57% IncrNo EffectRepeat Study for Dose Response
PFC/SpleenNo EffectNo Effect62% IncrNo Effect

Repeated with Dose Responseof ELA material: No Effect
IgM AFC to sRBC (T-dependent)
Day 5 IgM

ParameterFLGELELAPUComments
PFC/106No EffectNo EffectNo EffectNo Effect 

Spleen Cell ProliferativeResponse to Mitogens and Allogenic Cells

StimulusFLGELELAPUComments
Con ANo EffectNo EffectNo EffectNo Effect 
PHANo EffectNo EffectNo EffectNo Effect 
LPSNo EffectNo EffectNo EffectNo Effect 
MediumNo EffectNo EffectNo EffectNo Effect 
F(ab')2 + BSF-1No EffectNo EffectNo Effect17% Decr 
MLRNo EffectNo EffectNo EffectNo Effect 

Cytotoxic T Cell Response

ParameterFLGELELAPUComments
Lysis94% IncrNo EffectNo EffectNo EffectRepeat Study of FL invalid

Natural Killer Cell Response

ParameterFLGELELAPUComments
NK Cell ActivityNo Effect35% Decr39% DecrNo EffectDose-Response Study to be Performed

Repeated (180 Days) withDose Response of the ELA Material

ParameterVH14.13 mm228.26 mm256.52mm2Comments
NK Cell ActivityNo Effect30% IncrNo EffectNo EffectDose-Response Study Performed

Repeated (180 Days) withDose Response of the GEL Material

ParameterVH0.5 ml1.0 ml2.0 mlComments
NK Cell ActivityNo EffectNo EffectNo Effect53% DecrDose-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 ActivityNo EffectNo EffectNo Effect23% DecrDose-Response Study Performed

Time Course Studies
Repeated with Dose Response of the GEL Material at 60 Days

ParameterVH1.0 ml2.0 ml3.0 mlComments
NK Cell ActivityNo EffectNo EffectNo EffectNo EffectDose-Response Study Performed

Time Course Studies
Repeated with Dose Response of the GEL Material at 90 Days

ParameterVH1.0 ml2.0 ml3.0 mlComments
NK Cell ActivityNo EffectNo EffectNo Effect23% DecrDose-Response Study Performed

Time Course Studies
Repeated with Dose Response of the GEL Material at 180 Days

ParameterVH1.0 ml2.0 ml3.0 mlComments
NK Cell ActivityNo EffectNo EffectNo Effect28% DecrDose-Response Study Performed

Serum Complement

ParameterFL GEL ELA PU Comments
CH 50No EffectNo EffectNo EffectNo Effect 
C3No EffectNo EffectNo EffectNo Effect 

Macrophage Functions
Functional Activity of Reticuloendothelial System

ParameterFL GEL ELA PU Comments
Vascular ClearanceNo EffectNo EffectNo EffectNo Effect 
Liver UptakeNo Effect26% IncrNo EffectNo Effect 
Spleen UptakeNo EffectNo EffectNo EffectNo Effect 

Repeated with Dose Responseof the GEL Material: No Effect on Liver Uptake Covasphere Phagocytosis

ParameterFL GEL ELA PU Comments
Phagocytosis27% IncrNo EffectNo EffectNo Effect 

Repeated with Dose Responseof the FL Material: No effect
Chicken Erythrocyte Phagocytosis

ParameterFL GEL ELA PU Comments
PhagocytosisNo EffectNo EffectNo EffectNo Effect 

Peritoneal Cell Differential

ParameterFL GEL ELA PU Comments
% Lymph'sNo EffectNo Effect28% IncrNo Effect 
Absol Mono'sNo Effect26% DecrNo EffectNo Effect 


Table ES-3

SUMMARY TABLE FOR HOST RESISTANCESTUDIES
180-DAY STUDY
SIL-180-1-SC

Results
ModelFLUID GEL ELA PU Comments
Listeria monocytogenes No EffectNo EffectNo EffectNo Effect 
Streptococcus pneumoniae No EffectNo EffectNo EffectNo Effect 
B16F10No EffectNo EffectNo EffectNo Effect 


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