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Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials
1Food and Drug Administration, Center for Devices and Radiological Health, Rockville, Maryland 20852, USA. hml@cdrh.fda.gov
Abstract:
4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time.
Insights
4,4'-Methylenedianiline (MDA), a chemical from medical devices, poses health risks. A pharmacokinetic model shows hemodialysis patients may accumulate low MDA levels from device leaching, even with reuse.
Area of Science:
- Toxicology
- Pharmacokinetics
- Biomedical Engineering
Background:
- 4,4 '-Methylenedianiline (MDA) is a polyurethane degradation product found in medical devices.
- MDA is a known animal mutagen/carcinogen, hepatotoxic, allergenic, and a suspected human carcinogen.
Purpose of the Study:
- To develop a physiologically based pharmacokinetic (PBPK) model for MDA.
- To estimate MDA absorption, distribution, metabolism, and excretion in hemodialysis patients exposed via dialyzers.
Main Methods:
- A five-compartment PBPK model (liver, kidney, GI tract, slow/richly perfused tissues) was developed.
- Model parameters were derived from literature and calibrated/validated using rat and human worker data.
Main Results:
- PBPK modeling simulated MDA exposure in single-use and worst-case reuse hemodialysis scenarios.
- Results indicate potential for low-level accumulation of MDA and metabolites in dialysis patients.
Conclusions:
- Dialysis patients may accumulate MDA from leached materials in new or reused hemodialyzers.
- PBPK modeling provides a tool to assess risks associated with medical device leaching.