Citation:

Gray, E. AND P. FOSTER. CH 21: Toxic Responses of the Reproductive System. Casarett & Doull's Toxicology: The Basic Science Of Poisons. McGraw-Hill Education, New York, NY, , N/A, (2017).

Impact/Purpose:

Review and update of a book chapter on " Toxic Responses of the Reproductive System" for students, and professional toxicologists. Invited update, our third version

Description:

Any evaluation of toxicity to reproduction will have as an important consideration that events may not only be on the adults having impact on their likelihood to have children, but also impact the viability and quality of life of their potential offspring and feasibly even affect later generations. That chemicals can adversely affect reproduction in males and females is not a new concept, one only has to look at the importance of drugs as contraceptives to realize how sensitive the reproductive system can be to external chemical influences to disrupt this process. Of course in these cases, the failure of normal reproduction is a desired outcome in a contraceptive, but unfortunately we have had a number of catastrophes in which such failure has been unintentional. Many of the classic examples in chemical workers, or contamination of groundwater from chemical exposure such as dibromochloropropane (DBCP) or kepone (chlordecone) have shown the sensitivity of human reproduction to these specific exposures (reviewed by Cannon et al., 1978; Faroon et al., 1995; Winker and Rudiger, 2006). There have been significant improvements in our ability to test for effects on reproduction for chemicals, agrochemicals, and drugs, but unfortunately such adverse episodes continue to occur in, for example, the more recent reports of the effects of 2-bromopropane in chemical workers (both male and female) in Korea (reviewed by Boekelheide et al., 2004). Recent trends in human fertility, fecundity—changing social influences (age at which women have their first child), and the knowledge that populations in many western countries are no longer self-sustaining, coupled with the advent of assisted reproductive techniques (ARTs), where according to a recent paper 5.9% of all live births in Denmark used these ARTs (Andersen et al., 2005), all point to the potential for declines in normal human reproduction. Underlying all these issues with human reproductive performance is the concept that exposure to environmental chemicals and drugs may be contributing to these declines. The advent of the endocrine disruptor debate provided a major impetus to the examination of the methods used in screening and testing for reproductive (and other) toxicity, and highlighted a number of shortfalls, not least in how we should evaluate the latent effects on adults of in utero exposures. However, this chapter will not specifically address the emerging issue of the fetal origins of adult disease as proposed by Barker (see Barker et al., 1989, 1993; Barker, 1995, 1999). This chapter will take the reproductive cycle (Fig. 20-1) as the biological basis for the description of toxicity to reproduction rather than an encyclopedic approach. The basic biology of the different life stages and processes that are requisites for normal reproduction will be discussed and, where possible, the differences between experimental animals and humans highlighted (see Tables 20-1 and 20-2). These processes will then be placed into perspective by reference to a number of case studies of selected chemicals chosen to illustrate a range of modes of action and how they can perturb reproduction. Special attention will be focused on endocrine disruption, methods proposed for screening and testing and the selection of agents with specific pharmacologies (eg, estrogen or antiandrogen) to illustrate the types of toxicities produced at different life stages. The chapter will also provide basic information on testing methodologies for chemicals, pesticides, and drugs, but placed into the reproductive cycle framework. Thus, it will examine the life stages that are exposed and when specific evaluations are undertaken. Lastly, we have included a section on the evaluation of data and weight of evidence, specifically how one looks at concordance of end points with examples of the types of profiles observed (based on

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