Reproductive/developmental toxicity studies assessment

Note 2 There may be extensive public information available regarding potential reproductive and/or developmental effects of a particular class of compounds (e.g., interferons) where the only relevant species is the non-human primate. In such cases, mechanistic studies indicating that similar effects are likely to be caused by a new but related molecule, may obviate the need for formal reproductive/developmental toxicity studies. In each case, the scientific basis for assessing the potential for possible effects on reproduction/development should be provided. 

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422, US-EPA OPPTS 870.3650) comprises a basic repeated dose toxicity study and a fertility/developmental toxicity screening test and, therefore, can be used to provide initial information on possible effects on a limited number of reproductive performance parameters. The test does not provide complete information on all aspects of reproduction, has a relatively short period of exposure, and does not provide evidence for dehnite claims of no reproductive effects, while positive results are useful for initial hazard assessment. Furthermore, results regarding repeated dose toxicity are influenced by the pregnant state of the female animals (see also Sections 4.7.3.1 and 4.7.5.2.2). 

Reproductive toxicity studies in animals provide important information for evaluating the potential developmental toxicity in children. Developmental toxicity effects assessed in reproductive toxicity studies include fetal growth retardation, malformations, fetal loss, decreases in peri- and postnatal growth and survival, retarded... 

Buck GM, Lynch CD, Stanford JB, Sweeney AM, Schieve LA, Rockett JC, Selevan SG, Schrader SM (2004) Prospective pregnancy study designs for assessing reproductive developmental toxicants. Environ Health Perspect, 112(1) 79-86. 

The need for reproductive and developmental toxicity studies is dependent on the product, the clinical indication, and the intended patient population [50,52], Consideration is based on the nature of any expressed products and/or inappropriate biodistribution. Effects to the reproductive system that were identified in exposure and general toxicity assessments that suggest a cause for concern must be addressed in these more specific studies. If studies are necessary, study designs will likely need to be altered to accommodate selection of relevant animal model, dose selection, and dosing frequency. 

Once an assessment has determined that the data indicate human risk potential for reproductive and developmental toxicity, the next step is to perform a quantitative evaluation. Dose-response data from human and experimental animal reproductive and developmental toxicity studies are reviewed to identify a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and/or to derive a benchmark dose (BMD). Duration adjustments of the NOAEL, LOAEL, or BMD are often made, particularly for inhalation exposures when extrapolating to different exposure scenarios. Such adjustments have not been routinely applied to developmental toxicity data. The subcommittee recommends that duration adjustments be considered for both reproductive and developmental toxicity... 

To demonstrate how the subcommittee s recommended evaluative process can be applied to specific agents, the subcommittee evaluated two compounds of interest to the Navy jet propulsion fuel 8 (JP-8) and hydrofluorocarbon (HFC) 134a. These assessments demonstrate that the subcommittee s recommended process can be used to evaluate compounds for which varying amounts of data are available. For example, several reproductive and developmental toxicity studies have been conducted for HFC 134a however, just one developmental toxicity study has been conducted for JP-8. The subcommittee calculated a UEL based on at least one endpoint for each compound, accounting for uncertainties due to deficiencies in the database. Regardless of the quantity of data available, the subcommittee found that considerable scientific judgment was needed to conduct the evaluations. 

Data to assess the potential of JP-8 to adversely affect reproduction and development are sparse. One study (Puhala et al. 1997) reported measurements of human exposures and the values for the components of jet fuels analyzed that were far below the TWA threshold limit values (see Tabel A-2). Data on the absorption of volatile hydrocarbon components of JP-8 suggest that systemic exposure is likely, by any route of exposure. The single published developmental toxicity study (Cooper and Mattie 1996) did not report an adverse effect on embryonic or fetal development in rats with oral treatment at up to 2,000 mg/kg/d on days 6-15 of pregnancy, except for a decrease in body weight of offspring. 

Two types of studies specifically designed to assess developmental toxicity are discussed in this section the prenatal developmental toxicity study and the developmental neurotoxicity study. Several other types of studies, although not solely designed to assess developmental toxicity, can be used for that purpose. They include single- and multigeneration reproduction studies, reproductive assessment by continuous-breeding studies, and serial mating (dominant lethal) studies discussed in later sections. 

Parental Hazards (Effects). For assessment of reproductive and developmental risk, parental hazards, both paternal and maternal, must be identified and evaluated. Parental hazards can be expressed as altered nutritional state, functional impairment, and systemic toxicity. Because of possible indirect affects, knowledge and evaluation of non-reproductive/non-developmental toxicity studies are useful. This information is available by examination of subchronic and chronic toxicity studies. 

For most pharmaceuticals, developmental toxicity studies are conducted in rodents and rabbits. However, for certain pharmaceuticals, the nonhuman primate is the only relevant species in which developmental toxicity studies can be conducted. This is particularly the case for many human therapeutic proteins that bind only to human and nonhuman primate receptors or antigens, and consequently developmental studies conducted in other species are not relevant for assessing human risk (see Chapter 6). Therefore, in order to evaluate potential adverse effects of these human therapeutic proteins on reproduction and development, nonhuman primate models have been developed that can address various aspects of the reproductive process (Vogel and Bee, 1999 Hendrickx et al., 2002,2005 Weinbauer, 2002). 

High confidence in an ora RfD can be achieved if the database is made up of at least one two-generation reproductive toxicity study, two chronic oral toxicity studies in two different species, and two developmental toxicity studies in different species. For compounds that pose only acute health hazards because low doses are degraded and/or excreted, chronic studies may not be as critical in deriving an RfD a.s special studies assessing specific end points, such as neurotoxicity (Ciemanee et ai, 1996). 

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