MA5 Novel Methods for Bioaccumulation Assessment
203 Oregon Ballroom
8:00 AM - 12:00 PM, Monday
() Session Overview & Use of Pharmaceutical ADME Methods in a Tiered Approach for Bioaccumulation Assessment.
Weisbrod, A1, Dowty, M2, Wilke, D3, Obringer, C2, Cowan-Ellsberry, C1, 1 Procter & Gamble, Central Product Safety, Cincinnati, OH, USA2 Procter & Gamble Pharmaceuticals, Mason, OH, USA3 Procter & Gamble, Fabric & Home Care, Blue Ash, OH, USA
ABSTRACT- Globally, regulators use bioaccumulation potential to prioritize chemicals for risk assessment and management. The categorization of thousands of commercial substances for persistent, bioaccumulative, toxic (PBT) properties in Canada and Europe is moving swiftly and raising questions about how different data and methods could lead to more accurate and timely bioaccumulation assessments. Due to the scarcity of empirical data from traditional in vivo bioconcentration tests, bioaccumulation assessments frequently rely on predictions made by a few log Kow-based bioconcentration factor (BCF) models, which are unreliable for some chemical classes. There is an acute need to improve our prediction capability and to develop reliable alternatives to full bioconcentration tests. Since bioaccumulation is the culmination of absorption, distribution, metabolism, and excretion (ADME) processes, alternative data that would be useful in an assessment may come from: ADME models, BCF models that incorporate membrane permeability and metabolism, physiologically-based pharmacokinetic (PBPK) fish models, in vitro homogenate and cell systems from mammals and fish, passive sampling devices, rapid and modified in vivo fish tests, and population-level assessments. Estimates of the ADME properties of substances in several chemical classes (e.g. surfactants, pigments, fatty materials) were collected using high-through-put screening methods common for pharmaceutical discovery. The QMPR-Plus suite of models, Caco2 cells, and LLCPK-1 cells were used to examine membrane permeability and P-glycoprotein substrates in different tissues and species; the METEOR model and liver S9 assays were used to study biotransformation in mammals and fish. Results from these models and in vitro assays are compared to empirical BCF data. The comparisons show ADME information is valuable to understand differences in BCF model predictions, and indicate whether more extensive animal testing is warranted. These examples are shown in the context of a tiered approach for industry and regulatory authorities to build a weight of evidence about bioaccumulation potential.
Key words: ADME, bioaccumulation, absorption, biotransformation