Use of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Bioaccumulation Assessments for Fish

ABSTRACT

A scientific workshop was held in 2006 to discuss the use of in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) data in chemical bioaccumulation assessments for fish. Computer-based (in silico) modeling tools are widely used to estimate chemical bioaccumulation. These in silico methods have inherent limitations that result in inaccurate estimates for many compounds. Based on a review of the science, workshop participants concluded that two factors, absorption and metabolism, represent the greatest sources of uncertainty in current bioaccumulation models. Both factors can be investigated experimentally using in vitro test systems. A variety of abiotic and biotic systems have been used to predict chemical accumulation by invertebrates, and dietary absorption of drugs and xenobiotics by mammals. Research is needed to determine whether these or similar methods can be used to better predict chemical absorption across the gills and gut of fish. Scientists studying mammals have developed a stepwise approach to extrapolate in vitro hepatic metabolism data to the whole animal. A series of demonstration projects was proposed to investigate the utility of these in vitro–in vivo extrapolation procedures in bioaccumulation assessments for fish and delineate the applicability domain of different in vitro test systems. Anticipating research progress on these topics, participants developed a “decision tree” to show how in vitro information for individual compounds could be used in a tiered approach to improve bioaccumulation assessments for fish and inform the possible need for whole-animal testing.

Key Words:

• fish
• bioaccumulation
• bioconcentration
• metabolism
• biotransformation
• absorption

ACKNOWLEDGMENTS

This workshop was co-sponsored by the International Life Sciences Institute—Health and Environmental Sciences Institute (ILSI-HESI) and the Society of Environmental Toxicology and Chemistry (SETAC), and was organized by an ILSI-HESI Emerging Issues Bioaccumulation Workgroup. Financial support for the workshop was provided by ILSI-HESI. We thank the individuals who participated in the workshop, most of whom did so at their own expense. We also thank Dr. Keith Sappington and Dr. Larry Burkhard for constructive reviews of this report. The information in this document has been funded in part by the U.S. Environmental Protection Agency.

This article has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Notes

^aExtent of bioconcentration predicted from chemical K_ow in the absence of metabolism.

^bExtent of bioconcentration measured in a reliable test: < K_ow-only—bioaccumulation is less than that predicted from chemical K_ow (column 2); ∼ K_ow-only—bioaccumulation is approximately equal to that predicted from chemical K_ow (column 2).

^ck_met is the rate of whole-fish metabolism estimated from in vitro and/or in vivo test results, as described in the text.

^dMetabolic pathways are determined by best professional judgment based on existing data for fish and/or mammals. Where data are lacking, likely metabolic pathways may be based on QSARs and/or knowledge-based expert systems as described in the text.