Developmental toxicity information sources

The subcommittee reviewed sources of information that are specifically designed to assess reproductive and developmental toxicity and sources of information that are not as specific, but often contain some information. The subcommittee s summaries briefly describe the type of information provided by each source, the quality-control procedures (e.g., peer review), and how useful that source is in identifying exposures that pose a risk of reproductive and developmental toxicity in humans. 

In addition to DART, there are a number of additional sources of information that the Navy should consider using to evaluate the reproductive and developmental toxicity potential of agents. These sources are described in Appendix B. 

Box B-1 Sources of Information Specific to Reproductive and Developmental Toxicity... 

SOURCES OF INFORMATION SPECIFIC TO REPRODUCTIVE AND DEVELOPMENTAL TOXICITY... 

The list of alternative tests for reproductive toxicity, at variable stage of development, is fairly long given the complexity of the reproductive cycle and the multiple cell types and functions involved. An official source of information on alternative test development is the website of the European Centre for the Validation of Alternative Methods (ECVAM) (http //ecvam-dbalm.jrc.ec. europa.eu/ updated to 15 June 2013). Forty methods are listed for the area of reproductive toxicity. They are split into four categories effects on female fertility (n = 8), effects on male fertility n= 10), developmental toxicity (n = 21), and genotoxicity-mutagenicity (n= 1). Only eight of these methods have been developed up to fully defined protocols that can be downloaded from the same website ... 

Another important source of information on the status of alternative test development, with particular emphasis on the requirements for cosmetics testing, is a review paper published in 2011 by Adler and coauthors [9], Table 1 summarizes those relevant for reproductive toxicity. Several assays refer to the detection of endocrine effects on steroidogenesis based on a variety of cell types, and, as already mentioned, they will be dealt with in another chapter of this book. The other tests can be subdivided in placental toxicity/transport, preimplantation toxicity, female and male toxicity, and developmental toxicity. The tests that are suitable for detecting developmental toxicity include the EST, the whole-embryo assay, the micromass test (all three already described above), the zebrafish embryo teratogenicity assay, and the frog embryo teratogenesis assay (FETAX). 

The Food Quality Protection Act of 1996 mandated USA EPA to "upgrade its risk assessment process as part of the tolerance setting procedures" (3), The changes to risk assessment were based in part on recommendations from the National Academy of Sciences report (22), The act required an explicit determination that tolerances were safe to children. US EPA was required to use an extra 10-fold safety factor to take into account both pre-/post natal developmental toxicity and the completeness of the database, unless US EPA determined, based on reliable data, that a different margin would be safe. In addition, US EPA must consider available information on 1/ aggregate exposure from all non-occupational sources 2/ effects of cumulative exposure to the pesticide plus others with a common mechanism of toxicity 3/ effects of in utero exposure 4/ the potential for endocrine disrupting effects. 

There are an estimated 50,000 to 60,000 industrial chemicals in common use. We know very little about the reproductive and developmental effects of the majority of these chemicals. In addition, there are no safety testing requirements for natural products. In 1986, the voters of the State of California passed a law requiring the Governor of the state to publish, at least annually, a list of chemicals known to the state to cause cancer or reproductive toxicity . This effort is an excellent source of information on chemicals that can cause birth defects or reproductive harm. 

Evaluate type of toxicity. Use the above sources of information to determine the type of toxicity associated with each chemical involved in the proposed experiment. Are any of the chemicals to be used acutely toxic or corrosive Are any of the chemicals to be used irritants or sensitizers Will any select carcinogens or possibly carcinogenic substances be encountered For many substances, it will be necessary to consult the listings of carcinogens in this chapter (see Tables 3.4 and 3.5) to identify chemical similarities to known carcinogens. Are any chemicals involved in the proposed experiment suspected to be reproductive or developmental toxins or neurotoxins ... 

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