A Practical Approach, Second Edition=Ronald D. Ho.pdf

428 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONI. INTRODUCTIONThe objective of this chapter is to provide the methodologies for evaluations used during theperformance of reproductive toxicity studies. Traditional developmental and reproductive toxicity(DART) studies in rodents are a major source of data on the effects of potential developmental andreproductive toxicants. Reproductive toxicities include structural and functional alterations that mayaffect reproductive competence (fertility, parturition, and lactation). Evaluations of fertility, pregnancy,lactation, and maternal and paternal behaviors provide measures of the consequences ofreproductive injury. These evaluations provide information concerning gonadal function, estruscyclicity, mating behavior, conception, parturition, lactation, weaning, and the growth and developmentof the offspring. Developmental toxicities are generally those that affect the F 1 or F 2generations. The four manifestations of developmental toxicity as described by Wilson 1 are mortality,dysmorphogenesis (structural alterations), alterations to growth, and functional alterations.Mortality due to developmental toxicity may occur at any time from conception to adulthood.Dysmorphogenic effects are generally seen as malformations or variations to the skeleton or visceraof the offspring. Alterations to growth are generally seen as growth retardation, although excessivegrowth or early maturation may also be seen. Functional alterations could include any persistentchange in normal physiologic or biochemical function, but typically only reproductive function anddevelopmental neurobehavioral effects are measured in these studies.A. Brief Overview of DART Study GuidelinesThe purposes of DART studies are to determine whether a test substance has the potential to causeadverse effects on the male and female reproductive system or the developing conceptus, and todetermine a developmental and/or reproductive no observable adverse effect level (NOAEL) forthe test substance. The developmental or reproductive NOAEL is the highest treatment level testedthat shows no developmental or reproductive effects, respectively. It should be noted that DARTstudy designs were not developed to cover every male and female reproductive parameter, developmentalparameter, specific target organ, or mechanism of toxicity. For example, traditional DARTstudies do not provide information on maternal endocrine status, the levels of an agent or itsmetabolites in the milk and the fetus or pup, placental pathology, or reproductive senescence.The reproductive cycle has historically been divided into three segments for DART studies.Segment I study (also known as reproduction and fertility studies) covers the period of premating,cohabitation and mating, and early pregnancy through implantation (gestation day [GD] 6 in therat). Segment II study (also known as teratology or developmental toxicity studies) covers pregnancyfrom implantation through major organogenesis (closure of the hard palate; GD 15 in the rat) upto the day before delivery. Segment III study (perinatal and postnatal studies) covers late pregnancyand postnatal development (usually until weaning at postnatal day [PND] 21). Multigenerationalstudies (studies covering two to three generations) are required for chemicals that pose a low-levelchronic exposure risk in humans. Combination studies such as Segment I and II and Segment IIand III studies are acceptable as long as all required parameters and minimum study requirementsfor each segment are met. Another example of an acceptable combinatory study is the 90-DayRepeated Dose Subchronic Study with a One-Generation Reproduction Study.DART study guidelines have been promulgated by the U.S. Food and Drug Administration(FDA), 2–7 the U.S. Environmental Protection Agency (EPA), 8–11 the Japan Ministry of Agriculture,Forestry and Fisheries (MAFF), 12,13 Canada, 14,15 Great Britain, 16 World Health Organization, 17 andthe Organization for Economic Cooperation and Development (OECD). 18–22 The ICH (InternationalConference on Harmonization of the Technical Requirements for Registration of Pharmaceuticalsfor Human Use) 6,7,23 has been concerned with unifying the study guideline requirements for pharmaceuticalsafety assessment for the European Union, Japan, and the FDA. Guideline compliantreproductive and fertility studies must be performed in accordance with associated Good Laboratory© 2006 by Taylor & Francis Group, LLC