The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

Abstract

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

“…Saturation of metabolic processes at high‐dose/exposure concentrations may result in transition to novel modes of action unique to those high‐dose levels, unrelated to modes of action that operate at lower doses also used in animal studies, and at substantially lower real‐world human exposures (Barton et al ., 2006; Carmichael et al ., 2006; Doe et al ., 2006; Foran, 1997; Slikker et al, 2004a, 2004b). The high‐dose toxicity findings are observed only under exposure concentrations that exhibit saturation of metabolic processes, and this lack of human relevance has been recognized in OECD guidance for the dose selection process in animal bioassays (OECD, 2011 28 July 2011).…”

Test No. 417: Toxicokinetics

“…presence in gut wall and portal circulation) and bioavailability (i.e. presence in systemic blood and in tissues) can arise from chemical degradation due to gut wall metabolism or efflux transport back to the intestinal lumen or presystemic metabolism in the liver, among other factors (10). Bioavailability of the toxic component…”

Glossary of reference terms for alternative test methods and their validation

“…Please note: bioavailability and absorption are not the same. The difference between, e.g., oral absorption (i.e., presence in gut wall and portal circulation) and bioavailability (i.e., presence in systemic blood and in tissues) can arise from chemical degradation due to gut wall metabolism or efflux transport back to the intestinal lumen or presystemic metabolism in the liver, among other factors (Barton et al, 2006;id). Bioconcentration: the accumulation of a chemical in tissues of an organism to levels greater than in the environment in which the organism lives.…”