Agricultural Chemical Safety Assessment: A Multisector Approach to the Modernization of Human Safety Requirements

Abstract

Better understanding of toxicological mechanisms, enhanced testing capabilities, and demands for more sophisticated data for safety and health risk assessment have generated international interest in improving the current testing paradigm for agricultural chemicals. To address this need, the ILSI Health and Environmental Sciences Institute convened a large and diverse group of international experts to develop a credible and viable testing approach that includes scientifically appropriate studies that are necessary without being redundant, and that emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Benefits of the proposed approach include improved data for risk assessment, greater efficiency, use of fewer animals, and better use of resources. From the outset of this endeavor, it was unanimously agreed that a tiered approach should be designed to incorporate existing knowledge on the chemistry, toxicology, and actual human exposure scenarios of the compound, with integration of studies on metabolism/kinetics, life stages, and systemic toxicities. Three international task forces were charged with designing study types and endpoints on metabolism/kinetics, life stages, and systemic toxicities to be used in the tiered approach. This tiered testing proposal departs from the current standardized list of hazard studies used by many national authorities, and represents the first comprehensive effort of its kind to scientifically redesign the testing framework for agricultural chemicals.

Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

“…Non-linear TK, in which metabolism or excretion pathways available at lower blood concentrations are partly or fully saturated with increasing dose, may be a clear confounder both in appropriately designing toxicological studies and evaluating results for hazard and human risk assessment. Use of TK to inform human-relevant dose selection in animal toxicity studies has been affirmed in recent reviews and Organization for Economic Cooperation and Development (OECD) guidance on conduct of the EOGRT study Carmichael et al 2006;Cooper et al 2006;OECD 443, 2012a). The guidance recommended that top dose level(s) should not exceed the inflection point of onset of TK non-linearity if the inflection point dose was well separated from human exposures, and further concluded that toxicity limited to doses above the onset of non-linear TK behavior was not quantitatively relevant to human risk.…”

A Tiered Approach to Systemic Toxicity Testing for Agricultural Chemical Safety Assessment

“…The findings in young adults are then taken into account during the assessment of the compound during different life stages, including reproduction, development, adolescence, and the elderly. The process for assessing the effects of agricultural chemicals on these life stages is the subject of the companion paper by the ACSA Life Stages Task Force (Cooper et al, 2006). A complete assessment can be made only by taking into account all of the data generated in the overall assessment.…”

“…Data are also generated to explore the effect of the chemical on reproduction and development. These studies have been considered by the ACSA Life Stages Task Force (Cooper et al, 2006). The data from these studies are used to identify and characterize the hazards of the substance, that is, what effects it causes and at which dose levels.…”

“…The Tier 1 extended one-generation reproduction study in rats proposed by the ACSA Life Stages Task Force (Cooper et al, 2006) also includes a comprehensive evaluation of hormonally mediated endpoints as they pertain to reproduction, growth, and development. The endpoints included are consistent with recent revisions of the U.S. EPA OPPTS 870.3800 test guidelines (U.S. EPA, 1998c) and OECD 416 test guidelines (OECD, 2001), and those that have been more recently proposed for the assessment of endocrine-modulating compounds.…”

“…As the proposed tiered testing approach for agricultural chemical safety assessment evolved, the ACSA Technical Committee and its task forces Carmichael et al, 2006;Cooper et al, 2006) worked toward the following objectives:…”