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

It is EHPs stated editorial policy to serve as a forum for discussion of issues of environmental health, encouraging the expression of scientific opinion and fostering healthy scientific debate. Your editorial policy states that "all scientific articles are subject to rigorous peer review. The primary criteria are environmental significance and scientific quality." Based on these criteria , it appears that the journal has failed to hold the paper of Lieberman et al. (1) to these standards. This paper is a blatant and deliberate misdirection of the reader, providing misinterpretation of a poorly designed study that is not up to the standards of modern toxicology or EHP. Lieberman et al. (1) indicate that they distilled breast implant gel at 180°C at reduced pressure for 24 hr and imply that this material represents what would leak from implants. It is well known that silicone polymers can thermally depolymerize to form cyclic siloxanes under the authors' distillation conditions (2), but this does not represent "real life" conditions. Lieberman et al. (1) administered this distillate to mice by intraperitoneal (ip) injection at doses up to 35,000 mg/kg-surely an unacceptably high dose that would cause direct irritation. It is therefore no surprise that the identified ip median lethal dose (LD 0) was 28,000 mg/kg and that lung and iver lesions were noted. Perhaps the animal care committee should have requested a revision of the testing protocol before the study was initiated. Lieberman et al. (1) reported that one of the individual components of the distillate, identified as CS-4 based on an ip LD50 of 6,000-7,000 mg/kg, is equivalent in toxicity to oral exposures to carbon tetrachloride; they characterized the distillate and individual distillate materials as highly toxic. For regulatory purposes, any material with an LD50 greater than 2,000 mg/kg (3) or 5,000 mg/kg (4-9) is considered to be the highest dose necessary to test. Materials with LD50 values greater than these dose levels are considered to be virtually nontoxic. If this misinterpretation of toxicity data were to remain quietly in the annals of EHP, it would be merely a problem of editorial carelessness. However, this paper has been picked up by several of the news services (e.g., Reuters, BBC), with online and print media declaring "Silicones Kill Mice!" and no longer noting that the dose and dose route are responsible for the lethality, not the inherent toxicity of the material. By publishing this paper, EHP …

It is EHPs stated editorial policy to serve as a forum for discussion of issues of environmental health, encouraging the expression of scientific opinion and fostering healthy scientific debate. Your editorial policy states that "all scientific articles are subject to rigorous peer review. The primary criteria are environmental significance and scientific quality." Based on these criteria, it appears that the journal has failed to hold the paper of Lieberman et al. (1) to these standards. This paper is a blatant and deliberate misdirection of the reader, providing misinterpretation of a poorly designed study that is not up to the standards of modern toxicology or EHP.
Lieberman et al. (1) indicate that they distilled breast implant gel at 180°C at reduced pressure for 24 hr and imply that this material represents what would leak from implants. It is well known that silicone polymers can thermally depolymerize to form cyclic siloxanes under the authors' distillation conditions (2), but this does not represent "real life" conditions. Lieberman et al. (1) administered this distillate to mice by intraperitoneal (ip) injection at doses up to 35,000 mg/kg-surely an unacceptably high dose that would cause direct irritation. It is therefore no surprise that the identified ip median lethal dose (LD 0) was 28,000 mg/kg and that lung and iver lesions were noted. Perhaps the animal care committee should have requested a revision of the testing protocol before the study was initiated. Lieberman et al. (1) reported that one of the individual components of the distillate, identified as CS-4 based on an ip LD50 of 6,000-7,000 mg/kg, is equivalent in toxicity to oral exposures to carbon tetrachloride; they characterized the distillate and individual distillate materials as highly toxic. For regulatory purposes, any material with an LD50 greater than 2,000 mg/kg (3) or 5,000 mg/kg (4-9) is considered to be the highest dose necessary to test. Materials with LD50 values greater than these dose levels are considered to be virtually nontoxic.
If this misinterpretation of toxicity data were to remain quietly in the annals of EHP, it would be merely a problem of editorial carelessness. However, this paper has been picked up by several of the news services (e.g., Reuters, BBC), with online and print media declaring "Silicones Kill Mice!" and no longer noting that the dose and dose route are responsible for the lethality, not the inherent toxicity of the material. By publishing this paper, EHP has become a source for junk science reporters. The fact that the NIEHS is a well-respected scientific body only adds more credence to this illconceived and misinterpreted study.
I implore you be more attentive to the content of the articles published in EHP. It weakens the reputation of the NIEHS, feeds the junk science machine, and diminishes the credibility of all toxicologists when articles such as this are given space in a peer-reviewed scientific journal. In the February issue of EHP, Lieberman et al. (1) reported that the intraperitoneal (ip) injection of either cyclosiloxanes (CSs) from silicone breast implant distillate or CS-D4, a component of breast implant distillate, was lethal and caused liver and lung damage and increased hydroxyl radical formation. This paper is flawed and contains a number ofscientific issues that need to be addressed. Lieberman et al. (1) reported that a distillate from an explanted breast implant contains anywhere from 2 to 60% cyclosiloxanes, with CS-D4 being present at the highest concentration. It is well known that destructive distillation of a siloxane polymer or gel at high temperature under vacuum "cracks" the polymer causing, under these destructive conditions, the formation of large amounts of cyclosiloxanes (2). There is no doubt that the low molecular weight cyclosiloxanes collected by Lieberman et al. (1) were created during the distillation by a "cracking" process. The conditions required to crack a polymer do not exist in the human body. Our own analysis of an intact silicone breast implant shows that CS-D4 levels rarely, if ever, exceed approxmately 700 ppm (i.e., 700 pg/g). Migration of CS-D4 from an implant occurs at a rate of about 0.58 pg/day (3) which, for a 60-kg women, equates to a 0.0 10 pg/kg/day exposure to CS-D4.
Lieberman et al. (1) reported that after a single subcutaneous injection in mice of 250 mg (or about 10 g/kg body weight) of breast implant distillate, the cyclosiloxanes are widely distributed to many organs and can be detected as much as 1 year following a single injection. In their original paper (4), many of the values reported for tissue concentrations of cyclosiloxanes at 9 weeks and later appeared to be at or below the limit of detection of their analytical methodology and were well below what would be considered the limit of quantitation, making some of their conclusions misleading. In our own studies (5-2) using 14C-CS-D4 administration to rats by various routes of exposure, we also showed that CS-D4 was uniformly distributed to tissues, but with an elimination half-life of parent and metabolites of 50-200 hr, depending on the tissue, and < 0.0078% of the radioactivity left in tissues at 6 weeks postexposure. These data indicate that it is unlikely that CS-D4 would be found in tissues 1 year after administration.
As for the acute toxicity effects reported by Lieberman et al. (1), many of the reported findings oppose the conventional wisdom of toxicology. Administration of up to 1 mL of a substance into the peritoneal cavity of a 25-30-g mouse (which is equivalent to 2.4 L injected into the abdominal cavity of a human) basically represents the maximum dose that can be administered to a mouse and far exceeds the dose of CSs that could be encountered by humans under any condition, including women with breast implants. The LD50 values of -28 g/kg and 6-7 g/kg reported by Lieberman et al. (1) for the distillate and CS-D4, respectively, were used to indicate extreme toxicity, which is absurd. Credible references in toxicology (8,9)  Correspondence indicates that this compound exhibits toxicity comparable to these other agents." Conventional toxicity tables (8,9) comparing LD50 values show that the ip LD for sodium chloride is 4 g/kg. Thus, ordinary table salt is more toxic than either CS-D4 or breast implant distillate! To further put this into perspective relative to silicone breast implants, it would take about two 660-pound breast implants in an average size women to achieve a dose equivalent to the LD50 reported for CS-D4 by Lieberman et al. (1). This is based on the unrealistic assumption that all of the CS-D4 in an implant would be released at one time.
The histopathologic findings reported by Lieberman et al. (1) are an enigma. Tables 2 and 3 in their paper show the reported histopathologic changes and average grade of the reported lesions for implant distillate and CS-D4, respectively. The findings reported in these tables are clearly not dose related. For example, in Table 2 (1), the highest incidence (3 of 6 animals) of extensive necrosis was produced by the lowest dose (3.5 g/kg), which had the lowest incidence (1 of 6 animals) of individual cell necrosis. Conversely, a dose of 35 g/kg had a 1-of-6 incidence of extensive necrosis and a 5-of-6 incidence of individual cell necrosis. Further, the increases reported by Lieberman et al. (1) for the three liver enzymes ( Figure 3A and B) are minimal, relative to the high doses administered, and do not appear to be dose related. There is no indication in the figures that the observed values are statistically significantly different from control. Statistical significance is difficult to determine from examination of the figures because of the tremendous variability and the fairly consistent or uniform response across all the doses. The observation in this study that death of the animals occurred 5-8 days after the ip injections of either distillate or CS-D4 indicates that death was not due to a direct toxic effect of the test materials. The delayed deaths are consistent with an infectious process probably related to the quality of the test material or to a highly inflammatory process related to the route and volume of test material administered with a resultant peritonitis. It is perplexing that Lieberman et al. (1) apparently did not perform a microbiologic assessment on the test material or the animals at necropsy to rule out an infectious process. Certainly the apparent increase in free radical formation can be associated with an inflammatory response. It is also noteworthy that, in the study to assess free radical formation, the dose of CS-D4 administered was greater than the reported LD50 for this compound by this route.

Lieberman et al. (l)state in their discussion section that
We have no evidence that these compounds are metabolized, but it is clear they evoke strong biological responses. This is in marked contrast to all of the available literature. Studies by McKim et al. (10) clearly show that CS-D4 induces cytochrome P450 2B1/B2 in rats in a time, dose-dependent, and "phenobarbital-like" manner. In other words, it is an adaptive effect. Studies conducted by Plotzke et al. (5)(6)(7) and Varaprath et al. (11) provide compelling evidence that CS-D4 (and probably other cyclosiloxanes) are extensively metabolized by rats and that metabolism and subsequent elimination of hydrophilic metabolites in urine and feces is an important clearance mechanism from mammalian species. In particular, the rates of metabolism and clearance of CS-D4 and its metabolites (5,6) suggest that these compounds will not be unusually persistent in mammalian organisms and are inconsistent with the suggestion by Lieberman et al. (1) that these compounds will persist in mice for "at least a year..." in a number of organs and fat.
In summary, this paper [Lieberman et al. (1)] is deficient in several areas including data interpretation, review of existing and relevant research, and application of basic toxicology principles. The authors have ignored the central paradigm of toxicology as put forth by Paracelsus (12), which, as paraphrased, states "the dose makes the poison." Judge Sam C. Pointer, Jr., the federal judge overseeing the multidistrict breast implant litigation, appointed an expert scientific panel to review the available data on breast implants. Their toxicology review "reaffirmed the low systemic toxicity of silicone" (13) (1) published an interesting study on the toxicity of cyclosiloxanes. Briefly, they intraperitoneally injected mice with a breast implant distillate consisting of a mixture of cyclosiloxanes. After 4-14 days, they performed histopathologic studies and measured the formation of hydroxyl radical and levels of serum enzymes. The experiments are well done and the observations that were made are certainly believable. However, I am somewhat puzzled by the way the findings are interpreted. In several places Lieberman et al. stated that these compounds [i.e., hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6)] are highly toxic. Furthermore, the authors quoted a previous study which apparently showed that following a single subcutaneous injection, cyclosiloxanes are "widely distributed" throughout the body (2). Environmental Health Perspectives . Volume 107, Number 9, September 1999