chapter  11
120 Pages

Mode of Action Informs Endosulfan’s Pathways Leading to Developmental Male Reproductive Toxicity

This chapter is dedicated to the late Marion Miller-Sears, a professor in the Department of Environmental Toxicology, University of California, Davis, who encouraged me to pursue endosulfan’s male reproductive toxicity and whose enthusiasm for toxicology, teaching, and outreach mirrored my interests and provides fond memories. I greatly appreciate Jennifer Seed of the USEPA, who helped me understand the details of the mode of action during her reviews of this chapter; George Alexeeff, my graduate school friend and the director of the OEHHA, for giving me opportunities to grow as a toxicologist and teacher; and Anna Fan, editor and OEHHA supervising toxicologist, for asking me to write this chapter, “mothering” me through it by being both a dedicated scientist and caring mentor. I am very grateful that my husband and daughter only protested a little when my attention was so focused on putting together this big picture

from so many individual scientific puzzle pieces that I did not notice their reluctance to usually see only the back of my head or to hear so many details about male reproduction. This chapter describes postulated modes of action (MOAs)

for endosulfan, a legacy pesticide, to cause adverse effects during adult exposure and more severe, and usually irreversible, effects when exposure occurs during development. An MOA describes a biologically plausible causal relationship starting with the interaction of an agent with a cell, through physiological and tissue or organ changes, resulting in an adverse outcome that is supported by robust experimental and mechanistic data [1]. An MOA uses all existing knowledge from a range of methods, including bioassays and short-term in vivo, in vitro cellular platforms, as well as epidemiology, genetic studies, and emerging or novel technologies [2]. It is contrasted with “mechanism,” which has evolved to mean a more detailed biological and molecular description of causality[3]. An MOA encompasses toxicity pathways, a term that was described in Toxicity Testing in the 21st Century [4] as the cellular response pathways that can be defined by high-throughput in vitro cell culture platforms to assay signaling pathways that can result in an adverse outcome when they are sufficiently perturbed. International scientists concerned about uncertainties in the carcinogenic process and the human relevance of animal tumors prompted organizations such as the Risk Science Institute of the International Life Sciences Institute [5], the United States Environmental Protection Agency [6, 7], Health Canada [1], and the International Programme for Chemical Safety [8, 9] to convene scientific workshops to develop the MOA and human relevance framework (HRF) for carcinogens and then for noncarcinogens [10]. The MOA/species concordance/human relevance analysis [6, 9, 11] has continued to evolve as experience with it demonstrates its applicability for critical evaluation of a wide variety of data that have accumulated from individual peer-reviewed studies on adverse effects. Irreversible adverse effects that occur from exposure at early life stages, even though adverse effects in midadulthood may be reversible, are well suited for evaluation by the MOA/species concordance/HRF and its consideration of the weight of evidence supporting the animal data for different MOAs and their relevance to humans.