Reproductive/developmental toxicity studies development

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. 

The reproductive/developmental toxicity screening test can provide initial information on possible effects on reproduction and/or development and may make it possible to identify a substance as being toxic to reproduction, i.e., the test gives a clear positive result. However, this test offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. In addition, because of the study design (e.g., relatively small numbers of animals per dose level, relatively short smdy duration), the test will not provide evidence for definite claims of no effects. 

OECD (1996) OECD Guideline for Testing of Chemicals 422 Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. Paris, Organisation for Economic Co-operation and Development (http //www.oecd.org/dataoecd/18/ 30/1948410.pdf). 

Omalizumab and adalimumab are examples of monoclonal antibodies, developed for chronic non-life-threatening indication, that showed cross-reactivity to cynomolgus macaques as well as to humans. This broader species cross-reactivity allowed for a more thorough preclinical safety evaluation of the human monoclonal antibody developed for human use in the cynomolgus macaque. In the case of omalizumab, fertility studies and developmental tox-icitiy studies were conducted in macaques in addition to the chronic toxicity studies. For adalimumab, no reproductive and developmental toxicity studies were conducted. The value of conducting fertility and developmental studies in macaques with monoclonal antibodies is described in Chapter 17. 

Reproductive or developmental toxicity endpoints must be interpreted in the context of general toxicity that could also occur in the same animals. Toxic effects reported from other studies can be particularly valuable because excessive toxicity could significantly confound the interpretation of a reproductive or developmental toxicity study. Observations from studies of other toxicity endpoints might either strengthen or weaken the conclusions to be drawn from a reproductive or developmental study and provide information about target organs that should be evaluated further in developing animals. 

OECD (Organization for Economic Cooperation and Development). 1996. OECD Guidelines for Testing of Chemicals. Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test. TG No. 422. Organization for Economic Cooperation and Development, Paris, France. 

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. 

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). 

A review of reproductive and developmental toxicity studies of caffeine indicated that, at levels of 5 to 6 mg/kg of caffeine daily (about three or four cups of coffee), no adverse effects on pregnancy or fetal development are expected. The developmental toxicity no-observed-effect level (NOEL) of caffeine is 30 mg/kg daily (about 21 cups of coffee) and the reproductive toxicity NOEL is between 80 and 120 mg/kg daily (Christian and Brent 2001). 

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