ABSTRACT
Abbreviations ......................................................................................................... 338 15.1 Introduction .................................................................................................. 338 15.2 Risk Assessment ........................................................................................... 338 15.3 Hazard Assessment for Ovarian Toxicity .....................................................340 15.4 Screening Environmental Agents for Ovarian Toxicity ............................... 342
15.4.1 Approaches to Testing Environmental Agents ................................. 342 15.4.2 Testing Guidelines for Environmental Chemicals ............................ 342 15.4.3 Ovarian End Points Evaluated in Guideline Screening Studies
for Environmental Chemicals ........................................................... 343 15.4.4 Examples of Environmental Chemicals That Have Been Shown
to Target the Ovary ...........................................................................346 15.5 Screening Pharmaceuticals for Ovarian Toxicity ......................................... 349
15.5.1 Approaches to Testing Pharmaceuticals ........................................... 349 15.5.2 Testing Guidelines for Pharmaceuticals ........................................... 349 15.5.3 Ovarian End Points Assessed for Pharmaceutical Products ............ 350 15.5.4 Ovarian End Points Assessed in Developmental and
Reproductive Toxicity (DART) Studies for Pharmaceuticals .......... 350 15.5.5 Ovarian End Points Assessed in Repeated-Dose Toxicity
Studies for Pharmaceuticals ............................................................. 350 15.5.6 Ovarian End Points Assessed in Carcinogenicity Studies
for Pharmaceuticals .......................................................................... 352 15.5.7 Pharmaceuticals Demonstrating Ovarian Toxicity ........................... 352
15.6 Summary ...................................................................................................... 356 Disclaimer .............................................................................................................. 356 References .............................................................................................................. 356
CDER Center for Drug Evaluation and Research EMEA European Medicines Agency EPA U.S. Environmental Protection Agency FDA U.S. Food and Drug Administration ICH International Committee on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use NTP National Toxicology Program OECD Organisation for Economic Co-operation and Development PDMA Pharmaceuticals and Medical Devices Agency (Japan)
For environmental agents and pharmaceuticals, reproductive toxicity has been dened as the occurrence of biologically adverse effects on the reproductive systems of females or males following exposure. The toxicity may be expressed as alterations to the female or male reproductive organs, the related endocrine system, or pregnancy outcomes. Manifestations can include adverse effects on puberty onset and attainment of full reproductive function, gamete production and transport, reproductive cycle normality, sexual behavior, fertility, implantation, gestation, parturition, lactation, pre-and postnatal development and growth, premature reproductive senescence, or modications in other functions dependent on the integrity of the reproductive systems (EPA, 1996; ICH, 2000; OECD, 2008b). The main functions of the ovaries are (1) to produce ova (the eggs necessary for fertilization) and (2) to secrete steroid hormones, namely, estrogen during the follicular preovulatory phase of the female reproductive cycle and progesterone during the luteal or postovulatory phase of the cycle. Thus, any agent that targets the ovaries or the hormones they produce may be classied as an ovarian toxicant. Alterations can range from a reversible perturbation of the hormone levels (endocrine changes) to permanent damage such as follicular insufciency or ovarian cancers. However, it should be noted that ovarian cancer is not a single disease. There are over 30 types/subtypes of malignancies, each with its unique histopathological appearance, biologic behavior, and possible etiology (Hildreth et al., 1981) (see Chapters 12 through 14).
