Date: Fri, 16 Jun 2000 14:07:57 +1200

-----Original Message-----

From: USSW Date: Monday, 27 July 1998 17:05

Subject: NOTES ON THE IOM PROCEEDINGS - PART 3

NATIONAL ACADEMY OF SCIENCES

INSTITUTE OF MEDICINE

COMMITTEE ON THE SAFETY OF SILICONE BREAST IMPLANTS

SCIENTIFIC WORKSHOP - JULY 22, 1988

OTES ON THE PROCEEDINGS - PART 3

DONALD J. SCHAEZLER, PH.D., P.E., CIH

COMPANY DATA (MENTOR AND DOW CORNING)

MENTOR

Four speakers presented information, including three consultants, one of whom was Dr. Noel Rose. Dr. Rose is one of the premier immunologists in the country. I was surprised to hear him speak as an obvious member of Mentor's team.

Dr. Wixtrom, the first speaker, had a desk-top (i.e., no real results) presentation of the risk of extractable chemicals from silicone. he said D4 (a low molecular wgt cyclic siloxane) has known toxicity and is present at less than 50 ppm in the gel. He said this is an insignificant amount of Dr compared to its NOAEL (No Observed Adverse Effects Level) dosage in mammals of 2.3 mg/kg/day. This Is a legitimate comparison; it does not address the effects of other LMS (low molecular wgt silicones), the much higher concentrations observed by others, or the issue of the route of exposure and actual absorption of D4 in the quoted toxicology experiments. (For SBI, the route of exposure is by implant, and the absorption is 100%; in other studies the route may be by ingestion, and absorption from the gut may be low).

He also spoke about Platinum, claiming it is present in its elemental or zero- valence state, which is a non-toxic state. This can be contrasted to Cis-Plat, a powerful anti-tumor drug, in which Pt is present in the +6 state, and chlorplatinate, the original form of the catalyst, also a +6 compound. [This is very important; a speaker Friday contradicted this statement.]

Finally he spoke about silica in the shell; he said it is amorphous and is not expressed on the surface of the shell because it is enveloped in the silicone structure. He quoted electron microscopy analysis as proof.

Dr. White, a consultant, mentioned the NTP (Natl Toxicology Pgm) studies; he said they show no toxic, immune, or host resistance effects. They show reduction in Natural Killer Cells, but no effect on tumor resistance.

He then related results of Mentor Study and said there were no effects. He disputed results of Naim relative to Adjuvancy and of Golblum relative to antibody production.

He reported on studies of a mouse model for human SLE. The test showed no increased auto-antibody production for silicone implanted in the mouse. The test did show the expected increase for exposure to mercuric chloride and d- penicillamine (?).

Then Dr. Rose spoke on Autoimmunity, which requires epidemiologic evidence and Bioplausibility. There is no epi evidence for causation of autoimmune disease. He then rejected the plausibility of:

1. silicone as an antigen directly (not chemically plausible)

2. silicone as a hapten (i.e., its adsorption on to a protein, causing it to become an antigen; no pathologic evidence)

3. silicone as an Adjuvant (only the gel is effective, but only if homogenized; he could not reproduce Naim's results)

4. exacerbation in predisposed animals (no evidence)

Finally Dr. Purkait of Mentor spoke directly on the Mentor study. This study has 20,000 patients. He reported infection, capsular contracture, and rupture results to be within normal ranges. Rupture was only 1.3%, but that was only after 5 years. Prospective clinical studies with saline implants are in progress. 

DC had 3 speakers, all DC employees.

Dr. Lane spoke on silicone bleed. He said previous results by Yu(?) Indicated bleed rates of 0.3 grams per year and compare favorably to DC data.

Importantly, he indicated that even high molecular wgt components of silicone bleed; this means D4, for example, are still at low concentrations in the bleed material. He reported about 100 ppm of D4 and D5 and non-detectable Platinum and Fluorine. Results were somewhat different in products with a Barrier Coat (Silastic I) and those without (Silastic II) [This is important; it contradicts recent data by Baylor which indicates a greater concentration of LMS in the bleed material.]

Dr. Meeks reported on toxicology studies. He said PDMS (Poly-dimethyl siloxane, i.e., silicone) above MD4M (small polymer with only 4 siloxane units) had very low volatility, absorption by the body, or toxicity. Two studies reported were important. In the first, radio-labeled (C14) PDMS gel was implanted into mice without an implant shell. At about 20 weeks the mice were sacrificed, autopsies, and analyzed radiographically. There was rapid urinary excretion of silicone (molecular wgt not reported) and some migration to lymph nodes. There was no overt toxicity. [This raises a lot of questions; we need to see the results in writing.]

In the second study rats were exposed (by inhalation) to 7, 70, and 700 ppm D4 in air in order to study Absorption, Distribution, Metabolism, and Elimination of D4. After 7 days, they found:

1. Some CO2

2. Most D4 accounted for in feces, urine, expired air (non-obsorbed)

3. Slow elimination in the blood, because of typical lipo (fat) solubility.

4. Some liver enzyme induction.

5. Fat accumulation

A brief study with human volunteers studied results of inhalation exposures to D4.

In summarizing these results Meeks said there are 2 primary metabolites of D4 (in answer to questions they were identified as dimethylsilanediol and methylsilane triol); he said these are reactive and recombine to form other compounds. He also said that adsorption of D4(?) is 5%-10% orally, 8% dermally, and only 1% dermally with humans.

He also sais there was evidence of increased liver wgt, perhaps due to rapid cell division and induction of Cytochrome P450 enzyme, but that the liver returned to normal after removal of D4. [This begs the question of what if D4 cannot be removed, as in the case of SBI.]

Finally, he characterized the potential toxicity of D4 in SBI women, as calculated from DC and other studies. Using 0.3 grams/yr bleed, 700 ppm D4 in the bleed, 2 300 cc implants, LOAEL of 500 ppm in air for 6 hours per day, with 5% absorption of D4 from the air, the margin of safety was calculated to be more than 3 million. He said a margin of 100 is usually considered safe. [His calculations appear correct; the safety factor probably should be 1000; this ignores other components of bleed].

With respect to Platinum, he reiterated it is in the zero-valent form; he said it is present at 1 ppm in gel, 10 ppm in shell. He said the form of Pt may be sensitizers but are not toxic or allergenic like chlorplatinate. [Others dispute the 1 ppm and valence state.]

NOTE: I believe the DC data virtually prove that some silicones (perhaps the cyclic ones) can be metabolized and/or chemically converted to silicic acid in the body. This is the soluble form of silica and is in equilibrium with amorphous silica and perhaps certain silicates. This is the first time this has been so clearly demonstrated and contrasts sharply to denials of biochemical reactivity and conversion to silica.]

Dr. Klykken spoke on carcinogenic properties of silicone. He rejected relevance of the so-called solid state tumorogenesis in rats, to which FDA agrees, he says. New studies show no increased cancer attributable to silicone exposure.