Reproductive and Developmental Toxicology Carole A Kimmel PhD Judy Buelke Sam

3.0 Testing Procedures and Guidelines

Standard testing procedures have been used to identify reproductive toxicity since the mid-1950s. However, the first testing guidelines in the United States were not written until 1966 by the U.S. Food and Drug Administration (FDA) for testing the developmental effects (with particular emphasis on teratogenicity) of potential new pharmaceutical agents (78). In 1982, the FDA published testing guidelines (Redbook I) for food additives (79). The Organization for Economic Cooperation and Development (OECD) issued international testing guidelines in the early 1980s for reproductive and developmental toxicity of industrial chemicals (80, 81). In 1982, EPA published its first guidelines for testing pesticides (82) and in 1985 for industrial chemicals (83).

During the last several years, many of these guidelines have been updated. The FDA participated as a member of the International Committee on Harmonization (ICH), which finalized a revised set of global testing guidelines for preclinical assessment of pharmaceuticals (84, 85). In 1993, the FDA published the draft Redbook II (86) and in 1997 clarified the approach to toxicity testing that had been outlined in Redbook I (79) based on level of concern. The 1997 publication is available at www.vcm.cfsan.fda.gov/~dms/opa-tg1.html. (site currently unavailable) The EPA has recently updated and expanded testing guidelines to include a more comprehensive evaluation of the reproductive toxicity of pesticides and industrial chemicals (87-89). The OECD guidelines are currently being revised. The most recent testing guidelines for pharmaceuticals and for pesticides and industrial chemicals are briefly described here. 3.1 Testing Pharmaceutical Agents for Reproductive Toxicity

Testing of potential new pharmaceuticals is conducted for three reasons: (1) to provide scientifically and ethically appropriate support for clinical trials, (2) to provide data used to establish exposure guidelines for worker safety, and (3) to provide information relevant to risk:benefit assessments in the product label for use by prescribing physicians. Before international acceptance of the ICH testing guidelines (84), preclinical testing for reproductive and developmental toxicity was conducted following different guidelines for U.S., European, or Japanese registration of a new pharmaceutical (90, 91). Harmonization has not altered the overall requirements to evaluate reproductive and developmental outcomes following parental exposure before mating and during pregnancy and lactation, and assessment of effects on the entire parental reproductive process. However, it has reduced testing redundancy and provided the flexibility necessary to design studies most appropriate for assessing the toxicity of individual compounds. Exposure periods, dose selection, and end points evaluated within these studies are chosen based on the following: (1) pharmacology of the compound; (2) the plan for clinical trials, including duration of treatment; (3) known or expected toxicity of the therapeutic class; and (4) the target medical condition and therapeutic population(s).

Preclinical reproductive and developmental studies traditionally have been designated as Segment I, Segment II, and/or Segment III studies based on timing of initiation and duration of parental exposure (Fig. 3.8). These studies are routinely conducted in rodents, although a second Segment II study in a nonrodent species, most often the rabbit, usually is required. Segment I studies are intended to evaluate estrous cycling, mating, testicular and sperm parameters, fertility parameters, and early embryonic development; parental treatment begins before mating (generally 2 weeks for females, 4 weeks for males) and continues in females through implantation (gd 5 or 6). Segment II studies are intended to evaluate embryo and organ development; maternal treatment is initiated once implantation has occurred (gd 6 in rodents, gd 7 in rabbits) and continues throughout the period of major organogenesis (to gd 15 in mice, gd 15-17 in rats, and gd 18-19 in rabbits). Segment III studies are intended to evaluate maternal processes of parturition and lactation, as well as fetal and offspring development through sexual maturity; maternal treatment begins at the end of organogenesis and continues through to weaning of the offspring (usually postpartum day 21 in rodents).

Figure 3.8. Exposure conventions for reproductive and developmental toxicity testing of pharmaceuticals. The Segment I, II, and III designations for these studies refer primarily to the reproductive and developmental events that occur during the discrete parental treatment period. The parameters monitored in any single-Segment or combined-Segment study may include relevant end points which are measured during and/or following the treatment period (diagram developed by J. A. Hoyt and J. Buelke-Sam, included with permission).

Figure 3.8. Exposure conventions for reproductive and developmental toxicity testing of pharmaceuticals. The Segment I, II, and III designations for these studies refer primarily to the reproductive and developmental events that occur during the discrete parental treatment period. The parameters monitored in any single-Segment or combined-Segment study may include relevant end points which are measured during and/or following the treatment period (diagram developed by J. A. Hoyt and J. Buelke-Sam, included with permission).

Currently, four studies are usually conducted for the majority of potential new pharmaceuticals: a Segment I study in treated male and female rodents; Segment II studies in rodents and rabbits; and a combined Segment II/III study in rodents which includes postnatal assessments of growth, physical development, and behavioral and reproductive performance of the offspring.

However, alternative exposure periods may be more appropriate to assess individual agents. These alternatives may include additional exposure period combinations (e.g., a combined Segment I/II study in rodents for compounds with no anticipated effects on mating and fertility and a single rodent combined Segment I/II/III study for compounds with no expected reproductive or developmental toxicity and anticipated long-term clinical exposures) (92). Other alternatives include more discrete exposure periods (e.g., gd 0-5 of pregnancy for agents that have anticipated adverse effects on implantation processes) (30). The standard reproductive and developmental assessments in these studies may be supplemented with any additional outcome parameters deemed appropriate for individual agents, based on considerations listed before (e.g., progressive histopathological evaluations or functional assessments of suspected target organs or systems) (93).

An additional component of these studies involves determining maternal blood levels and/or toxicokinetic parameters. Most often, such determinations are made within the Segment II exposure period but also may be applicable to other segments. These data allow a more direct comparison of maternal animal and human exposures and may also aid in interpreting reproductive outcome. Maternal blood level data are particularly valuable in verifying that maternal exposure did occur for studies in which no adverse maternal or developmental findings were seen. Placental transfer studies or milk excretion studies also may be conducted to determine embryo/fetal or neonatal exposures more directly.

Another aspect of testing is providing adequate preclinical support for pediatric testing and guidance in the product label for using many pharmaceuticals in the pediatric population (94, 95). Only 20% of the pharmaceutical products currently marketed in the United States include labeling information on safety and effectiveness in infants or children. The ICH guidelines (84) indicate that additional studies involving direct treatment of neonatal and young animals may be necessary to support pediatric clinical trials, in addition to appropriate repeated-dose toxicity studies, standard genotoxicity studies, a complete reproductive and developmental toxicity package (Segments I, II

and III studies), as well as safety data from previous adult human trials. The FDA (95) has defined four human age categories of concern: infant, neonate, child, and adolescent. Table 3.1 provides a general comparison for these categories in humans and several test species, although the comparable age ranges in these species vary depending on the developmental schedules of individual organs or systems. The need for preclinical juvenile studies, the test species for such studies, age categories to be covered, duration of exposure(s), as well as the parameters and ages for assessment of effects within any particular study, are currently being determined compound by compound.

Table 3.1. Comparative Age Categories

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