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The guidelines for risk assessment of plant protection products (PPPs) and other non-pharmaceuticals were developed over three decades ago and have generally not been updated to incorporate advance- ments in toxicology and exposure sciences. These guidelines recommend using maximum-tolerated-dose (MTD) even when human relevance of such high doses is mostly limited due to orders of magnitude margin-of-exposure. Conducting animal studies at such high doses often requires further mode-of-action (MoA) studies elucidating human relevance. In order to improve data, ILSI/HESI-ACSA technical committee proposed a tiered approach with emphasis on determining systemic dose of parent and/or metabolite(s) in test animals as biological effects are reflective of systemic rather than administered dose. Any deviation from linearity in systemic dose (saturation of absorption or elimination) in animal studies may have profound toxic effect(s) not expected to occur in likely human exposure scenarios and should be avoided. Toxicity studies should ideally be conducted at kinetically lin- ear doses or slightly above the point of departure from linearity or kinetically-derived maximum dose (KMD) as the systemic dose nonlinearity is a more sensitive parameter occurring much earlier than the MTD endpoints. Therefore, determining systemic dose, especially KMD, in study animals is an improvement to hazard assessment of PPPs and other non-pharmaceuticals allowing toxicologists to bet- ter understand findings in animals at systemically linear as well as nonlinear doses to likely human expo- sures which can easily be accomplished using core study animals as outlined below. Determining systemic dose in studies will also increase the understanding of initial potential MoA of a PPPs and other non-pharmaceuticals and reduce the use of animals by avoiding unnecessary additional MoA studies.
Examination of the Extended One-Generation Reproductive Toxicity Study Guideline
Authors:Shakil A Saghir, Ph.D. and Michael A Dorato, Ph.D.
This whitepaper discusses ways to make the EOGRTS guideline easier to follow; suggesting procedures to select relevant doses, and monitor the systemic exposure at different life stages for better interpretation of the data.