Current problems associated with toxicity evaluation of medical device materials and future research needs.

The application of toxicology to the evaluation of medical device materials is reviewed. Strengths and weaknesses of systemic and local toxicity models are described. Developments needed to improve the methodology and predictability of assays for immunotoxicity and particulate toxicity are identified. Emerging methods are introduced for assessing adhesion, fibrosis, and blood compatibility.

Strategies for biological testing of biomaterials.

Current perspectives on empirical, modeling, and mechanistic methods of medical device safety testing are reviewed. Empirical approaches, such as the U.S. Pharmacopeial biological tests for plastics, evaluate the total system to discover aberrations and abnormalities. Models consist of a single aspect of an integrated approach, whereas mechanistic methods are based on a thorough knowledge of the materials and the organism's biological response. Empirical studies develop data on general hazard potential, such as overt toxicity. Model approaches target the specific application and specific hazard potential. Mechanistic studies identify the cause of toxicity and can produce advances in the biocompatibility of medical devices.

Biocompatibility test procedures for materials evaluation in vitro. II. Objective methods of toxicity assessment.

Methods of assessing the biocompatibility of materials for use in medical devices were evaluated. Ten materials were tested using quantitative, objectively graded in vitro biochemical and functional assays employing four cell lines (CCL 1, 74, 76, and 131) used in previous work and five primary cell types (human lymphocytes, polymorphonuclear leukocytes, and mixed leukocytes, mouse macrophages, and mouse embryo). The biochemical methods (DNA synthesis, protein synthesis, and ATP activity) demonstrated good agreement in toxicity ranking of the materials, regardless of which cell culture was used and, also, the cell cultures responded similarly for each method. Methods that measured functional characteristics of cells (adhesion and phagocytosis) were highly sensitive but had low toxicity ranking agreement and reproducibility. Assays (defined as method and cell culture combinations) using cell lines were more reproducible than assays using primary cell types. Significant differences in sensitivity were noted among the assay systems for particular material types. The in vitro assays were more sensitive to differences in material composition than was a 90-day assay by subcutaneous implantation in rats.

A review of 5-hydroxymethylfurfural (HMF) in parenteral solutions.

The chemical formation, toxicity, and pharmacokinetics of 5-hydroxymethylfurfural (HMF) and certain other decomposition products found in parenteral solutions are reviewed. Heat sterilization-induced hexose decomposition to furan derivatives is promoted at low pH. Based upon infusion studies with rats and dogs, HMF does not appear to be acutely toxic at concentrations ordinarily encountered in parenteral infusion solutions (e.g., 10 mg/liter). Dosages of parenterally administered HMF exceeding 75 mg/kg body wt have led to some toxic effects, including increased activity of hepatic enzymes, altered serum-protein fractions, increased relative spleen weight, and hepatic fatty degeneration. Approximately 50% of parenterally administered HMF is oxidized and eliminated by the kidneys. From a clinical standpoint, the amount of HMF formed as a result of the heat sterilization of parenteral solutions containing hexoses does not seem to pose any significant toxicologic problem.

Biocompatibility test procedures for materials evaluation in vitro. I. Comparative test system sensitivity.

Relative sensitivity of in vitro biocompatibility test systems was explored. Cellular responses of 12 standardized cell lines to 20 materials representing a range of toxicity were measured. Each cell line and material combination was tested in duplicate using four different culture methods, and each culture plate was examined by two graders. Results of the tissue culture assays were compared to those obtained for the same materials in vivo using a 5-day rabbit intramuscular implant assay. Methods involving measurement of cellular growth (colony counts or percent of confluence) in serum-fortified media extracts of test samples were generally more sensitive and discriminating than those in which test materials were placed directly in cell cultures (measurement of zone of growth inhibition). There was good agreement between graders for all test methods. Antibiotics were not used in the test program. Based upon sensitivity, reproducibility, ability to discriminate materials, and grader agreement, 4 of the 12 cell lines and 2 of the 4 test methods appeared most suitable for screening and evaluation of materials. Agreement of results using these four cell lines with intramuscular implantation tests for the 30 materials ranged from 60 to 90%.

Toxicity and metabolism of monoethylhexyl phthalate and diethylhexyl phthalate: a survey of recent literature.

The literature dealing with monoethylhexyl phthalate (MEHP), the principal metabolite of di (2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, is discussed. MEHP has been shown to be moderately toxic and, following oral administration, undergoes omega- and omega- 1 oxidation to yield the same metabolites as does DEHP. In plasma there is an equilibrium between MEHP absorbed to albumin and in free solution, whereas DEHP is bound to lipoproteins. Studies involving orally administered MEHP revealed the mild hepatic changes occurred but there was no bioaccumulation of the monoester. Studies of the rat and rabbit indicated that MEHP has no teratogenic effects.