A Developmental and Reproductive Toxicology Program for Chemical Registration

Abstract

The goal of the chapter is to outline the process of testing molecules for potential developmental and reproductive toxicity (DART). Here, the entire process of DART testing is discussed, from the regulatory use of DART data to the conduct and interpretation of the various DART study designs. Although nonanimal DART testing strategies are envisioned by the new science of "21st Century Toxicity Testing", these high-content, high-throughput testing paradigms are not sufficiently mature from a scientific perspective to be acceptable on their own by regulatory agencies for chemical registration. Thus, these testing paradigms are not included in this chapter. While the scope of the chapter is broad, it is beyond the range of this chapter to describe all possible scenarios encountered in DART testing. For additional information, the reader is referred to other recent publications on this topic. The chapter is organized in a stepwise manner into three main topics: (1) Use of DART studies for chemical registration; (2) General considerations for all DART study designs; and (3) Descriptions of all DART study designs from a practical perspective, beginning with an initial range-finding study and ending with the complex Extended One-Generation Reproductive Toxicity Study (EOGRTS).

Applications of Zebrafish Embryo Models to Predict Developmental Toxicity for Agrochemical Product Development

“…These studies are conducted late in the agrochemical development process and are not only expensive and time-consuming but also involve a considerable number of animals. 1 Consequently, the significance of a teratogenic finding becomes pronounced given the substantial investment made in agrochemical development prior to regulatory developmental studies. Additional limitations in extrapolating the results from animal studies to predict effects in humans include incomplete understanding of the mechanisms of action of the chemicals leading to adverse effects, and species differences in toxicity targets.…”

“…Although regulatory developmental and reproductive study requirements may vary across different regulatory agencies, they include developmental toxicity and two-generation reproductive studies that are conducted in two species, a rodent species (usually rat) and a nonrodent species (rabbit). These studies are conducted late in the agrochemical development process and are not only expensive and time-consuming but also involve a considerable number of animals . Consequently, the significance of a teratogenic finding becomes pronounced given the substantial investment made in agrochemical development prior to regulatory developmental studies.…”

AmicroRNAor messengerRNApoint of departure estimates an apical endpoint point of departure in a rat developmental toxicity model

“…Of several toxicity studies conducted to support crop protection molecule registration, the guideline-driven developmental toxicity study examines effects on fetal endpoints just prior to parturition following exposure during embryofetal development (OECD, 2018). The conceptus endpoints analyzed are termed apical endpoints and include observations such as organ gross morphology, skeletal ossification/morphology, fetal body weight, and post implantation loss (embryo/fetal death) (Johnson et al, 2016). While guideline-driven developmental toxicity studies provide a detailed analysis of potential adverse effects at a high level of biological organization, this study design is time consuming, uses a large number of animals/study (>1,000), and has been criticized for lacking sensitivity and a comprehensive analysis of potential effects (Tweedale, 2017).…”