Makris et al. selected from control and treated litters for evaluations of gross neurologic and behav- ioral abnormalities during postnatal develop- ment and adulthood (OECD 2007; U.S. EPA 1998). These include assessments of physi- cal development, behavioral ontogeny, motor activity, motor and sensory function, learning and memory, and postmortem evaluation of brain weights and neuropathology. History of DNT Test Guideline Development The evolution of DNT studies has its roots in scientific publications that began to appear in the early 1960s; the science has contin- ued to develop over the past four decades. Table 1. Historical contributions to the DNT guideline. Event Published research on DNT and behavioral testing CBTS Cincinnati Test Protocol Collaborative studies of the Japanese Teratology Society European Interlaboratory Collaborative Study Williamsburg Workshop Collaborative studies of the Japanese Teratology Society IPCS ILSI workshop on DNT testing Japanese Interlaboratory Study Behavioral Test Methods Workshop 2004–2008 ILSI RSI Working Group Table 2. History of the DNT guideline. Date 1960s–1980s 1978–1984 1984 1982–1985 1985–1988 1989 1993–1997 1995 2000 2003 2003 Date 1986 1991 1995 1996 1998 1998 2000 2003 2005 2007 18 An extensive scientific literature, composed of studies evaluating the potential for physical, pharmaceutical, and environmental agents to affect the development and function of the nervous system after prenatal and early post- natal exposure, provides a strong foundation for guideline development, implementation, and validation. Table 1 lists some of the key contributions to the development of the DNT guidelines. Table 2 briefly summarizes the his- tory of U.S. EPA and OECD DNT guideline development. Although prenatal developmen- tal toxicity test guidelines have existed for some time (e.g., OECD 1983), the first regu- latory protocol designed to evaluate DNT was developed and implemented by the U.S. EPA in support of hazard evaluation for specific solvents (U.S. EPA 1986), and a DNT guide- line applicable to the evaluation of both toxic substances and pesticides was finalized in 1991 (U.S. EPA 1991). In 1998, it was revised (U.S. EPA 1998) as part of a broader U.S. effort to harmonize testing guidelines within U.S. EPA program offices and with the OECD. In 1995, the OECD initiated the devel- opment of the DNT TG 426 (OECD 1995). The first draft of TG 426 was prepared after an expert consultation meeting (OECD 1996a), using the U.S. EPA DNT guide- line as the design template, and addressed a number of important issues and recom- mended improvements. The draft TG 426 Summary Evidence that developmental exposure to chemicals and drugs can alter behavioral function in young and adult animals Study to examine intra- and interlaboratory reliability and sensitivity of behavioral test methods Within-laboratory comparison of CBTS test protocol with the Cincinnati Test Protocol Interlaboratory methods evaluations and assessment of six reference chemicals Interlaboratory study to assess sensitivity of behavioral test procedures to detect neurotoxicity of methylmercury Workshop to evaluate the qualitative and quantitative comparability of animal and human data for DNT Three interlaboratory studies using behavioral teratogens comparability a core battery of tests Interlaboratory study using neurotoxic chemicals to evaluate test validity, reliability, and measurement variability Workshop to review U.S. EPA DNT behavioral test methods, pharmacokinetics, and neuropathology Interlaboratory study using neurotoxic chemicals to determine sensitivity of behavioral measures Expert workshop to address design, conduct, and analysis of behavioral tests for neurotoxicity evaluation Working group focused on variability, statistical analyses, positive controls, identification and analyses, interpretation of treatment-related effects, and application of DNT testing to public health protection References Irwin 1968, Spyker and Smithberg 1972, Barlow and Sullivan 1975, Butcher et al. 1979, Butcher and Vorhees 1979, Vorhees et al. 1979, Butcher and Nelson 1985, Adams 1986 Buelke-Sam et al. 1985, Kimmel and Buelke-Sam 1985, Kimmel et al. 1985 Vorhees 1985a, Vorhees 1985b, Vorhees 1985c Tanimura 1986, Tanimura 1992 Elsner 1986, Elsner et al. 1986, Suter and Schon 1986 Francis et al. 1990, Kimmel et al. 1990 Tachibana et al. 1996, Tachibana et al. 1998, Fukunishi et al. 1998, Nishmura et al. 2001 Catalano et al. 1997, MacPhail et al. 1997, Tilson et al. 1997 Cory-Slechta et al. 2001, Dorman et al. 2001, Garman et al. 2001, Mileson and Ferenc 2001 Okazaki et al. 2003 Slikker et al. 2005 Fenner-Crisp et al. 2005, Crofton et al. 2008, Holson et al. 2008 Raffaele et al. 2008,Tyl et al. 2008 ovlume 117 | number 1 | January 2009 • Environmental Health Perspectives Event U.S. EPA OPPTS published first draft DNT protocol for peer review and public comment U.S. EPA OPPTS published final DNT guideline (§83-6) OECD Working Group on Reproduction and Developmental Toxicity (Copenhagen) recommended development of OECD Developmental Neurotoxicity Test Guideline OECD expert consultation meeting (Copenhagen) provided recommendations for design of Draft OECD 426 U.S. EPA OPPTS issued minor revisions and harmonization of DNT guideline (OPPTS 870.6300) Draft TG 426 submitted to National Coordinators for expert review and comment OECD expert consultation meeting (Washington) held to review technical issues Draft TG 426 submitted to National Coordinators for expert review and comment OECD expert consultation meeting (Tokyo) convened to respond to remaining comments on Draft TG 426 OECD TG 426 approved by WNT; guideline finalized Reference U.S. EPA 1986 U.S. EPA 1991 OECD 1995 OECD 1996a U.S. EPA 1998 OECD 2003 OECD 2005b OECD 2007 WNT, the working group of the National Coordinators of the Test Guidelines Programme.