Letter re: "Cyclosiloxanes produce fatal liver and lung damage in mice".

LD50 for the distillate was 28 g/kg body weight; for D4, a component of the mixture , the LD 0 was 6-7 g/kg. According to the first edition of the now classical Casarett's and Doull's Toxicology (3), such values are not characteristic for highly toxic compounds. As a matter of fact, agents having an LD50 of 5-15 g/kg are usually classified as slightly toxic, and those having an LD50 of > 15 g/kg are labeled practically nontoxic. The latest edition of Casarett and Doull's Toxicology (4) no longer carries this classification, but provides the following on the spectrum of toxic doses: Some chemicals produce death in microgram doses and are commonly thought of as being extremely poisonous. Other chemicals may be relatively harmless after doses in excess of several grams. An accompanying table (4) lists the LD50 values for ethyl alcohol and sodium chloride as 10 g/kg and 4 g/kg, respectively. These are values similar to those found for the cyclosiloxanes. Alcohol and salt are freely available in many homes, supermarkets , and restaurants and are usually not perceived as being highly toxic. Lieberman et al. (1) also compared the toxicity of the cyclosiloxanes to the toxicity of carbon tetrachloride and trichloroethylene. Carbon tetrachloride has been identified as moderately toxic to laboratory animals (5), and trichloroethylene called relatively non-toxic (6). Clearly, there is a considerable discrepancy between the usual toxicity classification and the descriptors used by Lieberman et al. (1). It is also not justified to ascertain that cyclosiloxanes are widely distributed following subcutaneous injection. In their previous paper (2), Lieberman and colleagues deposited 250 mg of breast implant distil-late subcutaneously in the suprascapular area of mice. They then measured total and individual cyclosiloxanes in 10 organs and tissues up to 1 year after treatment. Again, the data are credible. Unfortunately, however , the paper (2) fails to provide data on mass balance, which is considered to be a de rigeur requirement in distribution studies. Nevertheless, from Figure 2B [Kala et al. (2)] it can be estimated that the average concentration of total cyclosiloxanes 6 weeks after the injection, when maximum values were obtained, is approximately 6 pg/g wet tissue. Assuming that there is a uniform concentration of cyclosiloxanes in all tissues (an assumption which overlooks the fact that the highest cyclosiloxane concentrations were found in tissues which contribute little to overall body mass such as lymph nodes, uterus, and …

values for ethyl alcohol and sodium chloride as 10 g/kg and 4 g/kg, respectively. These are values similar to those found for the cyclosiloxanes. Alcohol and salt are freely available in many homes, supermarkets, and restaurants and are usually not perceived as being highly toxic. Lieberman et al. (1) also compared the toxicity of the cyclosiloxanes to the toxicity of carbon tetrachloride and trichloroethylene. Carbon tetrachloride has been identified as moderately toxic to laboratory animals (5), and trichloroethylene called relatively nontoxic (6). Clearly, there is a considerable discrepancy between the usual toxicity classification and the descriptors used by Lieberman et al. (1).
It is also not justified to ascertain that cyclosiloxanes are widely distributed following subcutaneous injection. In their previous paper (2), Lieberman and colleagues deposited 250 mg of breast implant distillate subcutaneously in the suprascapular area of mice. They then measured total and individual cyclosiloxanes in 10 organs and tissues up to 1 year after treatment. Again, the data are credible. Unfortunately, however, the paper (2) fails to provide data on mass balance, which is considered to be a de rigeur requirement in distribution studies. Nevertheless, from Figure 2B [Kala et al. (2)] it can be estimated that the average concentration of total cyclosiloxanes 6 weeks after the injection, when maximum values were obtained, is approximately 6 pg/g wet tissue. Assuming that there is a uniform concentration of cyclosiloxanes in all tissues (an assumption which overlooks the fact that the highest cyclosiloxane concentrations were found in tissues which contribute little to overall body mass such as lymph nodes, uterus, and ovaries, whereas liver had < 1 pg/g and skeletal muscle approximately 6 pg/g), it then can be calculated that the total body burden away from the site of injection in a 25-g mouse would have been 150 pg cyclosiloxanes. This represents < 0.1% of all the material deposited in the suprascapular region. Where is the rest of the material? In the absence of a mass balance sheet that would provide complete data on distribution (and possible excretion) of the cyclosiloxanes, we must assume that > 99.9% of the injected material never left the site of deposition. Given these facts, it simply cannot be stated that "they are distributed widely." They are not.
The available evidence on the toxicity of silicones was recently reviewed by two independent bodies (7,8). The National Science Panel (7) concluded that The results of this review indicate that the silicones used in silicone breast implants are of very low toxicity to animals. Although there is documented evidence of local inflammatory reactions to silicone breast implant material in animals, there is no convincing evidence for a significant systemic inflammatory response.

The Independent Review Group (8) stated
The information supplied about the local and systemic toxicity, genetic toxicity, reproduction toxicity and carcinogenicity testing showed that they were all relatively bland substances in a range of animal and in vitro tests.... Tests looking with reliable, validated analytical techniques for the dissemination of silicones from implants in the body, including break down products of the polymers, have shown either no dissemination, or the presence of only very small amounts at distant sites following rupture of gel-filled implants, or after deliberate injection of the gel. Clearly, the findings by Lieberman et al. (1,2)-and there is no reason not to believe their data-would much better support the conclusions drawn by two recent review groups rather than their own interpretation of their data. Thus, terms used such as highly toxic and widely distributed are of concern. Given the actual data, these descriptors are not in line with current valid and thoroughly validated concepts of toxicology. They may be misused because, taken out of context without the accompanying hard data, they will lead to serious misrepresentations of the hazards associated with silicone breast implants.  (3)], are used, for example, to treat intestinal gas in humans. They are mixtures of both linear (polydimethylsiloxanes; PDMS), as the main component, and cyclic siloxanes (cyclopolydimethylsiloxanes; cPDMS) of different molecular masses. For drugs registered in Poland, the current producers' information on simethiconeor dimethicone-based drugs stated that the drugs are not completely absorbed in the intestine and some of them permit a daily intake as high as 400-640 mg/day.
To verify the statements, we recently performed a placebo-controlled study on intestinal absorption of siloxanes in rats (4). We examined the blood of Wistar rats fed 12 days with a granulated feed diet without siloxanes (LSM; Wytwornia Pasz w Motyczu, Poland) with added 5% PDMS (n = 5 animals), 5% cPDMS oil (n = 5), or without siloxanes (n = 5). Viscosity and molecular mass of siloxanes tested were equal to those most frequently used in oral drugs [viscosity of 300 centistokes (cST), which reflects molecular mass of about 15,000 Da; 1 cST = 10-6 m2/sec].
All animals used in the research were treated humanely according to Medical University of Gdansk institutional guidelines. The silicones were extracted from the rats' blood and quantitatively measured A 442 Volume 107, Number 9, September 1999 * Environmental Health Perspectives with 'H nuclear magnetic resonance (NMR) technique using an internal control (5). Blood samples from animals given feed without siloxanes showed no signals originating from the silicones tested. In all blood samples from animals given feed with siloxanes, they were detected. In samples from animals given feed with PDMS, the mean concentration (± standard deviation) of siloxanes of 26 ± 14 pg/cm3 was noted; in samples from animals given feed with cPDMS, the mean concentration of siloxanes of 70 ± 97 pg/cm3 was noted. The difference was not significant. These results conform well to those obtained previously in Rhesus monkeys by Calandra et al. (6). In our opinion, the absorption and toxicity of siloxane-based drugs should be more intensively studied. Our  (1) described the acute toxicity in mice after intraperitoneal injection of distillates containing either a mixture of cyclosiloxanes or a component of the mixture's distillate (octamethylcyclotetrasiloxane). The dose levels in the series of studies ranged from 3.5 to 35 g/kg. The median lethal dose of the distillate was 28 g/kg, or 1.68 kg for a 60-kg human.
The authors drew sweeping conclusions regarding this class of chemicals based on a minimalist investigation of toxicity. The acute doses administered by the intraperitoneal route were clearly excessive and were much greater than the limit doses recommended by the U.S. Environmental Protection Agency (EPA) and the Organisation for Economic Co-operation and Development (OECD) as maximum dose levels in studies of this type. Few compounds are tested at dose levels this high because of concerns regarding unnecessary pain and suffering of animals. A basic tenet of toxicology is that all chemicals have the potential to be toxic at sufficiendy high dose levels. The toxicity observed after administering extremely high dose levels is not useful for comparative purposes (because few compounds are tested at such high levels) or for risk assessment (because the dose levels are so much greater than potential human exposures to the agents of concern). Acute lethal studies conducted by the intraperitoneal route deliver a bolus dose with the equivalent of 100% absorption. Lethality is not a surprising finding under these conditions and would be observed with table salt and other substances generally considered to be innocuous. Furthermore, the conclusion that cyclic siloxanes are similar in toxicity to carbon tetrachloride and trichloroethylene is unfounded. The no-observed-adverse-effect level (a standard benchmark of toxicity) for carbon tetrachloride that has been used to set a drinking water standard is 1.0 mg/kg/day in a 12-week gavage study in rats (2). This was 3,500 times less than the lowest level used by Lieberman and colleagues (1). They did not present any evidence that carbon tetrachloride and trichloroethylene share a common mechanism of toxicity with the siloxanes.
In summary, the publication of Lieberman et al. (1) does not advance our understanding of the toxicity of this class of compounds. The paper is likely to be cited by plaintiffs in tort cases, but the study results are of limited use to those of us who are concerned with the safety evaluation and risk assessment of these substances. Gary J. Burin Technology Sciences Group Inc.
Washington, DC E-mail: gburin@tsgusa.com I recently read the paper "Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice" (1). Although siloxanes are not a particular interest of mine, I was curious. Lieberman et al. (1) administered the distilled mix at a rate of 3.5-35 g/kg body weight. As a toxicologist, I was intrigued because 35 g/kg is 3.5% of body weight, injected intraperitoneally yet! Toxicologically, such a dose is akin to hitting the mouse with a stick. Lieberman et al. reported that "some or all of the components of the distillate are lethal, with an LD50 for the distillate of about 28 g/kg." Do we ever find a substance that is not lethal at some dose? Lieberman et al. (1) then make the following statement: Our data demonstrate that a mixture of lowmolecular-weight CSs contained in breast implants is highly toxic and that at least one specific compound, CS-D4, is toxic as well.
Highly toxic indeed! Five grams per kilogram is usually considered virtually nontoxic in the world of pesticides, and here we are told that 28 g/kg is highly toxic. CS-D4 comes a bit closer at 6-7 g/kg. There appears to be a three-order-of-magnitude nomenclature problem here.
The finding of hydroxyl radical formation as a result of treatment with CS-D4 sparked a moment of interest, which died when I saw that the animals were given a lethal dose, and no dose-response information was obtained. [Lieberman et al.'s Figure 4 (1) does not disclose the dose, but it was found in text, fortunately nearby.] It also occurred to me that there was some missing context. Lieberman et al. (1) did not explain what fraction of an implant actually can be extracted in such a distillate, even though they quoted an earlier paper with that information (2). Approximately 1% of the implant can be considered mobile, if distillation describes mobility. Mobilization in vivo is obviously slow, unlike the intraperitoneal assault on the mice.
I am curious about the point of this paper. I do not follow the implant problem, but I know that it is highly charged politically and emotionally. As the newspapers tell us, implants are litogenic and produce much exercise for the courts. The only conclusion I can draw is that the terminology here is political. It is the kind of rhetoric that comes from activists who ignore science.
It is important to learn what happens to this foreign material placed in the body and to try to track the biological interactions. Lieberman et al. (1) make a small contribution, but I predict that this paper Environmental Health Perspectives * Volume 107, Number 9, September 1999