Use of Emerging Models for Developmental Toxicity Testing - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 27

through which scientifically validated alternative methods can be accepted for
regulatory use.
3.3.2 Advantages of Using Zebrafish to Assess
Developmental Toxicity
The processes involved in embryogenesis have been well studied in zebrafish and
functions of numerous genes have been shown to be highly conserved. Although
transparent zebrafish embryos offer unique advantages for assessing compound
effects on various developmental events, a comprehensive set of reference protocols
for assessing developmental toxicity has not yet been developed.
As strong support for use of zebrafish as a model for assessing toxicity, we
recently examined effects of 115 characterized compounds (Table 3.1) that were
commercially available or provided by the National Cancer Institute (NCI). In this
study, compounds were delivered by incubating animals in solution and we then
assessed LC 50 , developmental teratogenicity, and organ-specific toxicity. Teratoge-
nicity results were remarkably similar to LD 50 (compounds delivered in a single,
controlled dose) results in mammals, underscoring the value of using zebrafish to
predict toxicity in humans. A comparison of assay performance characteristics and
cost for toxicity testing for model systems is shown in Table 3.2.
3.4 NEW GUIDELINES FOR CHEMICAL TESTING
USING ZEBRAFISH
Supporting wider use of zebrafish for toxicity testing, the Organization for Economic
Cooperation and Development (OECD), an international organization helping gov-
ernments tackle the economic, social, and governance challenges of the globalized
economy, is currently validating standards to assess chemical toxicity using the fish
embryo toxicity (FET) test that has been developed from studies performed primarily
using zebrafish (Groth et al., 1993, 1994; Schulte and Nagel, 1994; Lange et al., 1995;
Roseth et al., 1996; Cheng et al., 2000; DIN, 2001; Nguyen and Janssen, 2001;
Wiegand et al., 2001; Bachmann, 2002; Nagel, 2002; Ferrari et al., 2003; Hallare
et al., 2004; Versonnen and Janssen, 2004; Versonnen et al., 2004; Braunbeck
et al., 2005; Kammann et al., 2006). Since these guidelines are likely to become
the gold standard for performing teratogenicity studies for chemicals and drugs, an
overview of general methods is included. Although the draft test guidelines are under
revision, the general principles are likely to remain largely unchanged.
3.4.1 General Principle of the Fish Embryo Test
The general principle of the test is based on chemical exposure of newly fertilized
zebrafish embryos for up to 48 h, which reflects acute toxicity. Zebrafish embryos are
individually exposed to a range of test concentrations in 24-well microtiter plates.