[ Citation in PubMed ] [ Related Articles ]
It is EHP's 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 (LD50) was 28,000 mg/kg and that lung and liver 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 ill-conceived 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.
Betsy D. Carlton
Chemicals Toxicology
Rhodia Inc.
Raleigh, North Carolina
References and Notes
1. Lieberman MW, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. Noll CS. Chemistry and Technology of Silicones. New York:Academic Press, 1968.
3. OECD. Acute Oral Toxicity. Guideline 401. Paris:
Organisation for Economic Co-operation and Development, 1987.
4. Consumer Product Safety Commission. Hazardous Substances and Articles; Administration and Enforcement Regulations. 16 CFR § 1500 (1997)
5. FDA. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Washington, DC:Food and Drug Administration, 1982.
6. FDA. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Redbook Draft. Washington, DC:Food and Drug Administration, 1992.
7. Environmental Protection Agency. State Registration of Pesticide Products. 40 CFR § 162.10 (1997).
8. U.S. Environmental Protection Agency. Health Effects Testing Guidelines. 40 CFR § 798 (1997)
9. Japanese MAFF. Acute Oral Toxicity Test. 59 NohSan #4200. Tokyo:Japanese Ministry of Agriculture, Forestry and Fisheries, 1985.
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 of scientific 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 µg/g). Migration of CS-D4 from an implant occurs at a rate of about 0.58 µg/day (3) which, for a 60-kg women, equates to a 0.010 µg/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 (5-7) 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) would consider compounds with acute LD50 values of 5-15 g/kg to be practically nontoxic, whereas compounds with LD50 values of > 15 g/kg are considered relatively harmless. Based on the data presented by Lieberman et al. (1) and using these widely accepted criteria, one should interpret that CS-D4 is practically nontoxic and the inappropriately prepared breast implant distillate is relatively harmless. Lieberman et al. (1) further suggest that by comparing ip LD50 values to the oral LD50 values of carbon tetrachloride and trichloroethylene, "the value for CS-D4 indicates that this compound exhibits toxicity comparable to these other agents." Conventional toxicity tables (8,9) comparing LD50 values show that the ip LD50 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. (1)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. (5-7) 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). The data of Lieberman et al. (1) (contrary to the authors' interpretations) also reaffirm this conclusion of low systemic toxicity. Although the authors acknowledge funding from Consumer Advocates for Product Safety (CAPS), they fail to note that funding for CAPS is obtained through attorneys for plaintiffs in the breast implant litigation.
Robert G. Meeks
Toxicology and Risk Assessment
Dow Corning Corporation
Midland, Michigan
E-mail: robert.meeks@dowcorning.com
References and Notes
1. Lieberman MW, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. Noll CS. Chemistry and Technology of Silicones. New York:Academic Press, 1968.
3. Yu L, LaTorre G, Marotta, J, Batich C, Hardt N. In vitro measurement of silicone bleed from breast implants. Plast Reconstr Surg 97:756-764 (1996).
4. Kala SV, Lykissa ED, Neely MW, Lieberman MW. Low molecular weight silicones are widely distributed after a single subcutaneous injection in mice. Am J Pathol 152(3):645-649 (1998).
5. Plotzke KP, Crofoot SD, Beattie JG, Salyers KL, Mast RW. Disposition and metabolism of octamethylcyclotetrasiloxane (D4) in male and female rats following repeated nose-only vapor inhalation exposure. Toxicologist 30(1):16 (1996).
6. Salyers KL, Varaprath S, McKim JM, Mast RW, Plotzke KP. Disposition and metabolism of octamethylcyclotetrasiloxane (D4) in F-344 rats: effect of classical inducing agents. Toxicologist 30(1):15 (1996).
7. Crofoot SD, McMahon JM, Hubbel BG, Seaton MJ, Plotzke KP. Absorption and disposition of octamethylcyclotetrasiloxane in female Fischer 344 rats following delivery in two carriers via gavage. Toxicologist 36(1):143 (1997).
8. Klaassen CD. Principles of toxicology. In: Casarett and Doull's Toxicology: The Basic Science of Poisons (Klaassen CD, Amdur MO, Doull J, eds). 3rd ed. New York:Macmillan Publishing Company, 1986;11-32.
9. Loomis TA. Essentials of Toxicology. 3rd ed. Philadelphia, PA:Lea & Febiger, 1978.
10. McKim JM Jr, Wilga PC, Kolesar GB, Choudhuri S, Madan A, Dochterman LW, Breen JG, Parkinson A, Mast RW, Meeks RG. Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study. Toxicol Sci 41(1):29-41 (1998).
11. Seaton MJ, Plotzke KP, Salyers KL, Varaprath S. Metabolism of 14C-octamethylcyclotetrasiloxane in Fischer 344 rats. ISSX Proc 12:116 (1997).
12. Pagel W. Paracelsus: An Introduction to Philosophical Medicine in the Era of the Renaissance. New York:Karger, 1958.
13. Diamond BA, Hulka BS, Kerkvliet NI, Tugwell P. Silicone Breast Implants in Relation to Connective Tissue Diseases and Immunologic Dysfunction. A report by a National Science Panel to the Honorable Sam C. Pointer, Jr., coordinating judge for the federal breast implant multidistrict litigation.U.S. District Court for the Northern District of Alabama, Birmingham, AL, 17 November 1998.
In the February issue of EHP, Lieberman et al. (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).
According to Lieberman et al. (1), the LD50 for the distillate was 28 g/kg body weight; for D4, a component of the mixture, the LD50 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 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 µg/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 µg/g and skeletal muscle approximately 6 µg/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 µg 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.
Hanspeter Witschi
Institute of Toxicology and Environmental Health
University of California
Davis, California
E-mail: hrwitschi@ucdavis.edu
References and Notes
1. Lieberman WM, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. Kala SV, Lykissa ED, Neely MW, Lieberman MW Low molecular weight silicones are widely distributed after a single subcutaneous injection in mice. Am J Pathol 152: 645-649 (1998).
3. Casarett LJ, Doull JD, eds. Toxicology. The Basic Science of Poisons. 1st ed. New York:Macmillan, 1975.
4. Klaassen DC, Amdur MO, Doull J, eds. Casarett and Doull's Toxicology: The Basic Science of Poisons. 5th ed. New York:McGraw-Hill, 1996.
5. Roble H. Carbon tetrachloride. In: Encyclopedia of Toxicology (Wexler P, ed), Vol 1. San Diego, CA:
Academic Press, 1998;227-228.
6. Parent RA, Klein TR, Sharpe DE. Trichloroethylene. In: Encyclopedia of Toxicology (Wexler P, ed), Vol 3. San Diego, CA:Academic Press, 1998;372-374.
7. Diamond BA, Hulka BS, Kerkvliet NI, Tugwell P. Silicone Breast Implants in Relation to Connective Tissue Diseases and Immunologic Dysfunction. A report by a National Science Panel to the Honorable Sam C. Pointer, Jr., coordinating judge for the federal breast implant multidistrict litigation. U.S. District Court for the Northern District of Alabama, Birmingham, AL, 17 November 1998.
8. Silicone Gel Breast Implants. The Report of the Independent Review Group. Cambridge, UK:Jill Rogers Associates, 1998.
We read with great interest the paper by Lieberman et al. (1) on the toxicity of cyclosiloxanes. In addition to their important observations, it should be noted that siloxanes, as dimethicone [British Pharmacopeia (2)] or simethicone [U.S. Pharmacopeia (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 simethicone- or 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 with 1H 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 (ħ standard deviation) of siloxanes of 26 ħ 14 µg/cm3 was noted; in samples from animals given feed with cPDMS, the mean concentration of siloxanes of 70 ħ 97 µg/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 study was supported by the Polish State Committee for Scientific Research (KBN) (grant 4PO5D06612).
Jerzy Lukasiak
Zygmunt Jamrógiewicz
Bogdan Falkiewicz
Medical University of Gdansk and University of Gdansk
Gdansk, Poland
E-mail: bogdanf@chemik.chem.univ.gda.pl
References and Notes
1. Lieberman MW, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. Great Britain Medicines Commission. British Pharmacopeia 1993. London:Her Majesty's Stationery Office, 1993.
3. The United States Pharmacopeia, 22nd revision. Rockville, MD:U.S. Pharmacopeial Convention, 1990.
4. Lukasiak J, Jamrógiewicz Z, Czarnowski W, Krechniak J, Falkiewicz B. Assessment of polydimethylsiloxanes and cyclopolydimethylsiloxanes: intestinal absorption in rats with analysis of their blood concentrations using 1H NMR [in Polish]. Bromatol Chem Toksykol 32:99-101 (1999).
5. Jamrógiewicz Z, Lukasiak J, Mojsiewicz K. Application of the NMR spectrometry to speciation analysis of polydimethylsiloxane. Chem Anal (Warsaw) 42:659-666 (1997).
6. Calandra JC, Keplinger ML, Hobbs EJ, Tyler LJ. Health and enviromental aspects of polydimethylsiloxane fluids. Am Chem Soc Polymer Preprints 17:12-16 (1976).
In their recent publication, Lieberman et al. (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 sufficiently 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
References and Notes
1. Lieberman MW, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. WHO. Guidelines for Drinking Water Quality, Vol 1. Geneva:World Health Organization, 1993.
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 low-molecular-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 will be dreadfully misused. I also have other concerns about the work. If I had I been a reviewer, I would have considered this paper publishable only if the language and implications were modified.
Perhaps of greatest importance, this paper does not create confidence in EHP; there seems to have been a lack of diligence in the review of this manuscript. EHP should be a flagship among journals, but poor reviewing will set it adrift.
Frank N. Dost
Freeland, Washington
E-mail: jfdost@whidbey.com
References and Notes
1. Lieberman MW, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. Kala SV, Lykissa ED, Neely MW, Lieberman MW. Low molecular weight silicones are widely distributed after a single subcutaneous injection in mice. Am J Pathol 152(3):645-649 (1998).
[ Citation in PubMed ] [ Related Articles ]
Several of the scientists who responded to our paper (1) raised similar questions, mostly showing a concern about the high doses used in our study. However, we would like to point out that, to the best of our knowledge, our paper is the first to examine the LD50 of cyclosiloxanes (CSs). While there may be a difference of opinion about the interpretation of these data, for the first time there are data to discuss. Of equal importance is that we provide data on doses lower than the LD50. These data demonstrate elevated serum enzyme values and histopathologic changes following administration of CSs and CS-D4 at nonlethal doses (0.1 mL/mouse; ~ 3.5 g/kg). All of these considerations underscore the value of our work. Other studies have used similar doses and the same route of administration (0.1-1mL intraperitoneally) to examine the toxicity of organic compounds including siloxanes (2-4). In our studies, no effects were noted when 1 mL soy oil was administered as a control. Our studies were intended to examine the acute toxicity of these agents rather than to evaluate their chronic toxicity or to determine the minimal level at which they produced a toxic effect.
Another concern raised by readers was the comparison of cyclosiloxanes with carbon tetrachloride (CCl4) and trichloroethylene. We included this discussion to clarify the fact that even though the LD50 for CS-D4 is high (6-7 g/kg), it falls in the range of known toxic organic solvents such as CCl4 and trichloroethylene (2). Both CCl4 and trichloroethylene have been used at gram levels to study their acute toxicity by intraperitoneal injection (2,5,6). Witschi states that CCl4 is moderately toxic and trichloroethylene is relatively nontoxic. However, the Agency for Toxic Substances and Disease Registry (ATSDR) has published profiles on the toxicity of these compounds and the potential human exposure and health hazards of these solvents (5,6). In these documents they note that the maximum contaminant level (MCL) for each of these compounds in drinking water is 5 µg/L. Because CSs and these organic solvents have similar LD50 values in the gram per kilogram range, it is possible that after thorough study of the toxicity of the CSs,
similar MCLs may be set. In addition, trichloroethylene has been identified among the top 20 hazardous materials on the 1997 ATSDR priority list (ranked 15) (7). This fact emphasizes that compounds with LD50 values in this range are important public health concerns. Clearly there is considerable variation in the verbal descriptors of the toxicity of these compounds.
The point is raised that CSs show about the same acute toxicity as alcohol and sodium chloride and that these chemicals are freely available in most homes. The presumption is that, for this reason, we should have minimal concern about the toxicity of CSs. Yet we know that analysis of ethyl alcohol and sodium chloride has led to the opposite conclusion. Ethyl alcohol is an important liver toxicant, and many people worldwide suffer from liver disease as a result of chronic ethyl alcohol ingestion. Fetal alcohol syndrome is also well documented. As for sodium chloride, the relationship between ingestion of high amounts of salt and high blood pressure and stroke is well known. We emphasized the need for additional studies of CSs in the concluding two sentences of our paper:
Further, our studies have not evaluated possible long-term effects of CSs such as chronic inflammation, chronic pulmonary and liver disease, or neoplasia. Nevertheless, our results underscore the importance of a complete analysis of the toxicity of CSs.
Witschi also suggests that the phrase "cyclosiloxanes are widely distributed" is a misinterpretation of our data because only 0.1-0.5% is found in different organs (8). The term "widely distributed" is used not as an index of the abundance of CSs in different organs but as a statement of their presence. We would also like to point out that we only measured unmetabolized CSs in these studies. If these compounds were modified by biotransformation and existed as new, low-molecular species or bound to macromolecules, we would not have
detected them by our analysis. Further, most studies of siloxanes until recently were carried out without any quantitative assessment, that is, tissue level of siloxanes versus tissue injury (9). In recognition of this problem, our group has developed methods for the detection and quantitation of cyclosiloxanes in biological tissues (10).
Carlton and Meeks raise the issue of the preparation of the distillate and the fact that the "cracking" process at 180°C has no relationship to breakdown in the intact implant in vivo. In our paper we made no inferences about the relationship of distillate preparation to breakdown. Rather, we used the distillation process as a convenient way to produce a mixture of siloxanes, which we found migrated out of intact implants (11). We could have just as easily purchased the components from a chemical company, and in fact, that is what we did with the octamethylcyclotetrasiloxane (CS-D4). This purchased CS-D4 produced effects that were indistinguishable from those of the distillate.
Meeks also suggests that these mice died of infection. First, if they had died of infection, this would be an important finding because only mice exposed to the distillate or CS-D4 died or developed evidence of tissue injury. However, the histopathologic picture is not one of infection. The histopathology of the liver showed a classic pattern of chemically induced cell death, and the lung lesions were not typical of bronchopneumonia or lobar pneumonia.
Meeks raises the question of metabolism and clearance. He is accurate that we do not cite any of the references he has provided in our discussion. We were in error in not including the contribution of McKim et al. (12). The paper was published in 1998 and we simply missed it. All of the other references on CS-D4 metabolism that he cites are abstracts and not full-length, peer-reviewed articles. Meeks raises an important point. He interprets his data to mean that CS-D4 is metabolized and is rapidly cleared from the body. While this may be true, nevertheless, many compounds are metabolized via more than one metabolic pathway; some of the pathways lead to detoxification/inactivation and others lead to active chemical species that cause tissue injury, cell death, or neoplasia. The abundant literature on compounds such as aflatoxin, benzo(a)pyrene, acetylaminoflurene, and related compounds provide examples of this principle. We would also like to point out that the study Meeks refers to was an inhalation study, which may not be directly relevant to our findings.
We believe that much more work on the low molecular weight cyclosiloxanes is necessary. Inhalation studies like the one referred to by Meeks, ingestion studies like the one summarized by Lukasiak et al., and injection studies are all necessary to develop an understanding of the biologic importance of these agents.
We are confident that our paper represents an important contribution to the study of silicone toxicology and hope that it will encourage many additional studies in this area.
Michael W. Lieberman
Roberto Barrios
Geeta Kala
Subbarao V. Kala
Ernest D. Lykissa
Ching Nan Ou
Baylor College of Medicine
Houston, Texas
E-mail: mikel@bcm.tmc.edu
References and Notes
1. Lieberman MW, Lykissa ED, Barrios R, Ou CN, Kala G, Kala SV. Cyclosiloxanes produce fatal liver and lung damage in mice. Environ Health Perspect 107:161-165 (1999).
2. Lundberg I, Ekdahl M, Kronevi T, Lidums V, Lundberg S. Relative hepatotoxicity of some industrial solvents after intraperitoneal injection or inhalation exposure in rats. Environ Res 40:411-420 (1986).
3. Champoin R, Faulborn J, Bowald S, Erb P. Peritoneal reaction to liquid silicone: an experimental study. Graefe's Arch Clin Exp Ophthalmol 225:141-145 (1987).
4. Potter M, Morrison S, Wiener F, Zhang XK, Miller FW. Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice. J Natl Cancer Inst 86:1058-1065 (1994).
5. ATSDR. Toxicological Profile for Carbon Tetrachloride. Atlanta, GA:Agency for Toxic Substances and Disease Registry, 1989.
6. ATSDR. Toxicological Profile for Trichloroethylene. Atlanta, GA:Agency for Toxic Substances and Disease Registry, 1989.
7. Agency for Toxic Substances and Disease Registry. 1997 CERCLA Priority List of Hazardous Substances. Available: http://www.atsdr.cdc.gov/97list.html [cited 20 July 1999].
8. Kala SV, Lykissa ED, Neely MW, Lieberman MW. Low molecular weight silicones are widely distributed after a single subcutaneous injection in mice. Am J Pathol 152(3):645-649 (1998).
9. Potter M, Rose NR. Immunology of Silicones. New York:Springer, 1996.
10. Kala SV, Lykissa ED, Lebovitz RM. Detection and characterization of poly(dimethylsiloxane) in biological tissues by GC/AAED and GC/MS. Anal Chem 69:1267-1272 (1997).
11. Lykissa ED, Kala SV, Hurley JB, Lebovitz RM. Release of low molecular weight silicones and platinum from silicone breast implants Anal Chem 69:4912-4916 (1997).
12. McKim JM Jr, Wilga PC, Kolesar GB, Choudhuri S, Madan A, Dochterman LW, Breen JG, Parkinson A, Mast RW, Meeks RG. Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study. Toxicol Sci 41(1):29-41 (1998).
Last Updated: August 18, 1999
