The Dow Corning Siloxane Research Program: An Overview and Update

Medical Device & Diagnostic Industry Magazine
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An MD&DI May 1999 Column

Started in 1993, an ongoing series of studies examines the acute and long-term safety of exposure to the fundamental building blocks of many silicone materials.

From product design to biomaterial selection to manufacturing, the medical device industry is faced with an overriding objective—that of promoting superior care for patients. For those involved in the industry, the goal of high-quality care comes with a distinct challenge: most industry participants are not physicians and thus are not able to tend directly to the needs of patients. Instead, their contribution is to develop products that function properly and are safe. Today's regulatory environment lays out the rules, and it is the responsibility of manufacturers to live by both the spirit and the letter of those regulations. But beyond that is the commitment to product stewardship, to ensuring that devices are safe for everyone who comes in contact with them—manufacturers, distributors, and end-users—and also safe for the environment.

Siloxanes are the structural constituents of a variety of silicone materials that have long been used in healthcare. Photo courtesy of Dow Corning Corp. (Midland, MI).

Biomaterials engineered from various siloxanes have been used by the heathcare industry for more than 40 years. A substantial database of safety studies supports their widespread use; in fact, silicone-based biomaterials may be the most widely studied materials for use in medical applications and as ingredients in consumer products. To augment this extensive prior research, Dow Corning Corp. (Midland, MI) has undertaken an exhaustive program to broaden the understanding of the safety profile of six siloxanes that are the building blocks for many products made by the healthcare and personal-care industries. Studies conducted as part of the company's Siloxane Research Program incorporate state-of-the-art protocols and analytical techniques. Based on data collected to date, results are favorable for the biomaterials industry and for other industries that depend on siloxane materials: studies continue to show that there is not a human health effect associated with siloxanes in current applications.

SILICONE BUILDING BLOCKS

Volatile cyclic and linear methyl siloxane (VMS) and linear polydimethylsiloxane (PDMS) are the structural "ingredients" for a variety of silicone materials. They can also occur at very low levels in silicone tubing, gels, adhesives, and other silicone elastomers used to fabricate medical devices and device components, from coatings for pacemaker leads to tracheostomy tubes. For example, PDMS is used to lubricate hypodermic needles, and aqueous emulsions of PDMS are used to coat bottle stoppers and other medical and pharmaceutical components.

Beyond the healthcare industry, PDMS and VMS are used in a variety of everyday applications, including consumer products and over-the-counter medications. Thus, a broad portion of the population has daily contact with these siloxanes, primarily through dermal and inhalation routes, and, to a much lesser degree, by the oral route. For the general population, the level of contact with VMS and PDMS through use of medical products is much lower than contact with these siloxanes derived from everyday consumer products. However, because of the widespread use of VMS and PDMS, their safety profiles are of interest when one attempts to assess the overall safety of biomaterials in healthcare applications.

The goal of Dow Corning's $30 million research program, which the company manages with support from other silicone manufacturers, is to extend the understanding of the acute and long-term safety of exposure to siloxanes. Numerous past studies have shown siloxanes to be safe when used as intended; the new research is designed to improve the understanding of the effects (if any) of VMS and PDMS on the human body. Gathering and interpreting data from studies associated with the Siloxane Research Program is expected to span a 5- to 10-year period.

The program focuses on the following six methylsiloxanes:

PROGRAM DESIGN

The materials will be subjected to testing within four major areas of study: descriptive studies, fundamental research, human clinical studies, and exposure-assessment studies. In addition to providing valuable information related to consumer exposure to VMS and PDMS and expanding the knowledge base regarding the safety of silicones as biomaterials, results from the studies will help to ensure workplace safety for those involved in the fabrication of siloxane-based medical devices.

The descriptive toxicological studies in experimental animals determine the potential hazards of the materials. These laboratory studies, which employ EPA good laboratory practices (GLPs), assess various aspects of exposure to the materials based on different time frames. Many standard toxicological tests are part of this segment, which includes:

The fundamental research studies focus on pharmacokinetics and biochemical toxicology. These studies address how much siloxane actually enters a living organism, where it goes, how long it remains there, what effect (if any) it has while there, and how it leaves the body. Studies of this type are conducted with multiple routes of administration and doses, using both in vivo and in vitro methods and, in some cases, multiple species.

The primary goal of human clinical studies is to determine human response to siloxane exposures and to assess whether the animal studies are relevant to humans, both qualitatively and quantitatively. Human studies also help answer questions about potential risk to human populations.

Human clinical studies for the Siloxane Research Program are coordinated and managed by scientists from the University of Rochester (NY) and Dow Corning. These studies are being conducted concurrently with animal studies, so that parameters for both (animal and human) can be correlated and adjusted as the overall program progresses.

To assess risk from exposure, it is necessary to know the frequency, duration, and amount of exposure in a given population. Current exposure-assessment studies focus on people in three target population groups:

While much of the fundamental research program will be carried out by Dow Corning's health and environmental sciences department, the descriptive, human clinical, and exposure-assessment studies will be conducted by leading independent laboratories and consultants.

Dow Corning believes that the siloxane program is one of the largest voluntary studies by any company of its raw materials, and that it will ultimately provide more information about the safety of siloxanes than likely exists for any other comparable raw material currently available. An external science advisory board has been assembled to assist in understanding and interpreting results of the various components of the research program and to provide scientific advice and guidance. The board meets three times yearly to review the progress and direction of the studies and to discuss issues related to strategy and methodology. In addition, results of the research are routinely being reviewed with member companies of the Silicone Environmental Health and Safety Council of North America and with representatives of U.S. regulatory agencies. Results will be published in peer-reviewed scientific journals.

Through December 1996, study results focused primarily on D₄. Some data for D₅ are now becoming available and are discussed where appropriate. Additional data related to D₅ and the other materials will be available as the studies progress.

DESCRIPTIVE TOXICOLOGICAL STUDIES

Recent results from ongoing studies confirm effects observed in earlier 28- and 90-day studies by Dow Corning. For example, rats exposed to D₄ or D₅ developed enlarged livers. The organs returned to their normal size when exposure ceased, and no abnormality was detected in the liver cells.

Data derived from these studies are supplemented and complemented by other components of the program. For example, the liver biochemical and morphometric studies (described later in this article) augment information collected in descriptive studies and in earlier toxicological studies.

Range-finding reproductive studies with D₄ in rats showed reduced litter size and reduced number of fetal implantation sites at 500 and 700 parts per million (ppm). Results of these studies have been reported to the EPA as part of Dow Corning's ongoing communication with that agency. As a result of these findings, the company believes there is not a human health effect associated with the use of D₄ in current applications: the effects seen in rats occurred at concentrations far in excess of normal human exposure.

Regarding D₅, a two-generation reproductive study showed no effect on reproduction at the highest dose tested (160 ppm). Because of the different vapor pressures of D₄ and D₅, the highest dose tested for each of the materials differed (700 ppm versus 160 ppm, respectively). These levels are at or near the highest concentrations that can be achieved in the atmosphere based on the physical properties of the two materials.

FUNDAMENTAL RESEARCH STUDIES

Pharmacokinetic Studies. Single-exposure pharmacokinetic studies were conducted for male and female rats using three concentrations of D₄: 7, 70, and 700 ppm. Animals were exposed to radiolabeled D₄, and total amounts of C-14 were measured at specific time periods. This study was not designed to distinguish between the parent D₄ compound and metabolites of the compound.

Data from these single-exposure studies suggest that the primary route of excretion for D₄ and D₄ metabolites ("D₄") is via urine, followed by expired volatiles and feces. Studies in which male and female rats were subjected to repeated exposures had results similar to the single-exposure studies, except that expired volatiles appeared to be a more significant route of elimination than in the single-dose study. It is reasonable to conclude that there was very little bioaccumulation of D₄ in the study animals.

Plasma values of "D₄" at the three concentrations show an increase that is approximately proportional to increasing dose. At cessation of exposure, "D₄" disappeared from the blood in what appears to be a two-compartment model: that is, a fast distribution phase followed by a slow elimination phase. "D₄" in tissues virtually mimiced plasma levels, except that higher levels were found in lung tissue and fat than in other tissues. This result is expected, because the parent D₄ is lipid soluble and would deposit preferentially in fat and highly lipophilic tissues, from which it is then eliminated. Data show that approximately 5% of the inhaled D₄ dose is absorbed; that 80% to 90% of the original dose is eliminated by urine, expired air, and feces; and the half-life in the plasma ranges from 50 to 80 hours.

D₄ Metabolism Studies. HPLC profiles in urine collected from animals exposed to D₄ reveal seven major radioactive peaks corresponding to metabolites of D₄. No parent D₄ was found in urine, indicating that it is not excreted in the urine. All the peaks have been identified as monomer and dimer diols and the triol of D₄. Appearance of the triol species is significant, indicating that D₄ is apparently demethylated enzymatically in the body, which is presumptive evidence that D₄ is metabolized by the liver as an apparent first step. Similar metabolite profiles were observed in the urine following exposure by the three major routes: inhalation, intravenous, and oral. Route of administration does not affect the urinary metabolite profile.

D₄ Dermal Absorption Studies. Dermal absorption of D₄ was assessed through in vivo and in vitro studies. In the in vivo studies, undiluted D₄ was applied to the skin of young adult Sprague Dawley rats (male and female) for 6 hours. Excreta and expired air were collected for 96 hours following administration of the test sample. The dose site and carcass were examined at the termination of the study.

Most of the D₄ volatilized from the dose site and was trapped; the total recovery at 96 hours was 97%. Approximately 10% of the D₄ was absorbed, as determined by the amount of D₄ in the excreta, carcass, and expired CO₂, and the amount at the dose site. Most of the absorbed dose (approximately 60%) was eliminated via expired air.

A similar in vivo study was conducted using D₅ as the test material. Most of the D₅ volatilized from the dose site, while approximately 1% was absorbed as determined by the amount of D₅ in the excreta, carcass, and expired CO₂, and the amount at the dose site. Most of the D₅ absorbed in females was found in urine, whereas most of the D₅ absorbed in males was found at the dose site. As yet, no explanation is available for the differences between males and females and between D₄ and D₅.

In an in vitro study of absorption in skin from young adult rats, most of the D₄ volatilized from the dose site. The absorption was approximately 8%; there were no significant differences between the skin of male and female animals, and most of the absorbed dose remained in the skin. In a similar study using undiluted D₅, most of the sample again volatilized from the dose site. Absorption was calculated at approximately 1% as determined from the dose site and receptor fluid. Most of the recovered D₅ was found at the dose site, and there were no significant differences between male and female animals.

Liver Biochemical and Morphometric Studies. Additional studies were conducted to examine the observed effect of enlarged livers in rats following inhalation exposures to D₄. Results of the study confirm that the livers of rats enlarge in a dose-related manner following exposure to D₄, with increases in liver weight ranging from 25 to 35% following 28 or 90 days of exposure. When the effects of D₄ on liver metabolizing enzymes (particularly total cytochrome P450) are considered, data show a dose-related increase in enzyme activity. The positive control used for this study was phenobarbital; the pattern of increase in enzyme activity was similar to that observed for phenobarbital, although not to the same degree. In the case of the subfamily of cytochrome P450 that is specifically induced by phenobarbital, there was again a dose-related and time-related increase in enzyme activity. After 14 days of recovery, the enzyme activity virtually returned to its baseline values. The increase was about one-third to one-fourth that of phenobarbital for that subfamily of enzymes.

These results indicate that D₄ behaves similarly to phenobarbital in terms of increasing liver weight and enzyme activity. Exposure to D₄ apparently increases the level of enzyme necessary to metabolize D₄. This response is comparable to the response observed with other chemicals that act similarly to phenobarbital.

Further studies have been conducted to determine whether or not this increase in activity is related to an increase in cell size (hypertrophy) versus an increase in cell number (hyperplasia). These studies also employed phenobarbital as the positive control. Results again indicate that D₄ behaves similarly to phenobarbital: early hyperplasia is followed by a return to normal cell division, followed by hypertrophy.

THE PERSPECTIVE FOR SILICONES AS BIOMATERIALS

The results of studies to date show an encouraging picture for the continued use of silicones as biomaterials. Because very little siloxane material is found in finished products, exposure is extremely low under use conditions, and biomaterials containing these materials have a very high margin of safety in use.

As an example, one can consider over-the-counter medications and other medical applications. Translating the level of human exposure to the lowest dose of D₄ that did not show a reproductive effect in laboratory animals, the margin of safety for D₄ is several thousand to several hundred thousand, depending on the specific application or product.

Similar comparisons can be made with relation to silicone-based biomaterials. According to results obtained to date, typical silicone elastomer contains approximately 1 mg of D₄ per gram of elastomer. Using this concentration and assuming 1 g of elastomer and a 57-kg woman, the potential for exposure is 0.018 mg of D₄ per kilogram of body weight. Again comparing this level of exposure to the lowest dose of D₄ that did not show a reproductive effect, the margin of safety for D₄ is 2333, which is certainly acceptable. Furthermore, this margin of safety assumes that all the D₄ becomes available at one time, rather than through slow release over time, as would be the actual case. Other studies based on 700 µg of D₄ per gram of elastomer and migration rates of 0.2 mg per year give a margin of safety of 13,000,000, a figure significantly higher.

As additional research in the siloxane program proceeds, results will include data from ongoing human clinical studies and exposure-assessment studies. The latter group of studies will focus on the frequency, duration, and amount of exposure for the workforce associated with manufacturing D₄, D₅, and D₆; people using these materials as reactants or intermediates; consumers and users of silicone products; and the general public. Results of these studies will continue to provide an expanded base of knowledge regarding the use of silicones in healthcare applications.

ACKNOWLEDGMENTS

The Siloxane Research Program is sponsored in part by the Silicone Environmental Health and Safety Council of North America (Washington, DC).

Robert G. Meeks, PhD, is scientific director of toxicology and risk assessment at Dow Corning Corp. (Midland, MI).

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