Makris et al. (also known as the “Williamsburg Workshop”) to provide scientific input into DNT protocol design and to evaluate its appropriateness for use in risk assessment (Kimmel et al. 1990). Expert scientists from government, industry, public interest groups, and academia reviewed a range of representative chemicals and envi- ronmental exposures, including drugs (canna- bis, cocaine, methadone, and phencyclidine) (Hutchings 1990), ethanol (Driscoll et al. 1990), the anticonvulsant phenytoin (Adams et al. 1990), and environmental contami- nants such as methylmercury (Burbacher et al. 1990), lead (Davis et al. 1990), polychlori- nated biphenyls (Tilson et al. 1990), and ion- izing radiation (Schull et al. 1990). Based on data available for these known human devel- opmental neurotoxicants, the workshop par- ticipants concluded that DNT methodologies were adequate for detecting DNT. A number of specific issues directly relevant to design and usefulness of DNT studies were extensively evaluated by participants (Buelke-Sam and Mactutus 1990; Levine and Butcher 1990; Stanton and Spear 1990; Tyl and Sette 1990). Additionally, workshop participants addressed the relationship between biologic end points specified by DNT guidelines and adverse find- ings observed in humans after exposure to the developmental neurotoxic agents under con- sideration. A major conclusion of the work- shop was that the DNT protocol would have identified each of the agents presented at the workshop as a potential developmental neuro- toxicant (Francis et al. 1990), although the critical effects and the dose at which the effects were observed could vary across species. The workshop participants also concluded that the laboratory animal is an adequate surrogate for humans because many of the biologic and behavioral mechanisms underlying these neu- rologic functions are shared between humans and laboratory animals. The predictive power of DNT guideline studies was attributed largely to the scope of neurobehavioral and neuropathologic tests used that can evaluate neurologic functions across multiple domains (i.e., sensory, motivational/arousal, cognitive, and motor). Collaborative studies of the Japanese Teratology Society. The Japanese Teratology Society established the Behavioral Teratology Meeting as a satellite meeting of the Japanese Teratology Society in 1982. This group spon- sored a number of collaborative studies con- ducted primarily by pharmaceutical industry, and contract laboratories (Tanimura 1985). The first effort involved 21 institutions that investigated the effects of parametric vari- ables (water temperature, number of trials) on performance in a water T-maze and two- way shuttle box (Mizutani 1984). This was followed by a larger study involving 46 labo- ratories that investigated the effects of six 20 chemicals (chlorpromazine, ethanol, hydroxy- urea, methylazoxymethanol, phenylalanine, and vitamin A) (Mizutani 1985). These studies demonstrated that the T-maze test was reliable, but possibly not as sensitive as needed, and sug- gested the need for more complicated learning paradigms for this method (Tanimura 1986). Workshops were then held between 1988 and 1990, with three subgroups: reflexes and sen- sory function, activity and emotionality, and learning (Tanimura 1992). Subsequently, a core battery test draft for behavioral develop- mental toxicity was proposed. Its utility was examined with three positive behavioral terato- gens during 1993–1997: phenytoin (Fukunishi et al. 1998; Tachibana et al. 1996), retinoic acid (Nishmura et al. 2001), and nicotine (Tachibana et al. 1998). The numbers of par- ticipating laboratories were 32, 28, and 18, respectively. It was concluded that the pro- posed core battery of tests is useful as a method to detect postnatal developmental disorders, including behavioral dysfunction, in rats. The IPCS Study. The IPCS collaborative study was an interlaboratory evaluation of neurobehavioral screening methodologies used in adult and DNT studies (MacPhail et al. 1997; Moser et al. 1997e). A total of eight laboratories participated in proficiency stud- ies (Moser et al. 1997a), and the full study evaluated seven neurotoxic positive control chemicals [triethyl tin, acrylamide, parathion, p,p´- dichlorodiphenyltrichloroethane (DDT), toluene, N,N´-methylene bisacrylamide, and lead acetate] in adult male rats (Moser et al. 1997b, 1997c). The study examined variabil- ity associated with the test methods and rea- sons for differences. The overall conclusion of this extensive study was general “agreement across laboratories in terms of their ability to detect dose-related changes in behavioral end points with prototypic neurotoxic agents” (Catalano et al. 1997). The study results were also reviewed at a workshop held in 1995 in Capri, Italy (Tilson et al. 1997) and were pre- sented in a symposium at the 1996 meet- ing of the Society of Toxicology (Moser et al. 1997d). ILSI workshop on DNT testing. In 1999, ILSI established a working group of scientists from government, industry, academia, and nonprofit nongovernmental organizations (Mileson and Ferenc 2001) that was charged with evaluating revisions to the published U.S. EPA DNT guideline that were also included in the draft OECD TG 426. Some of these changes were implemented by the U.S. EPA Office of Pesticide Programs (OPP) when it issued Data Call-In notices for organophos- phate pesticides with tolerances (U.S. EPA 1999b). The revisions included extension of the offspring dosing period through to the age of weaning, ensuring that the pups are exposed to the test substance, increasing the number of offspring evaluated neuropatholog- ically, and collecting chemical-class–specific biomarker data. The extension of the dosing period during the lactation period raised sev- eral issues, specifically in the areas of pharma- cokinetic/toxicokinetic data needs, behavioral testing, and neuropathologic evaluation. Overall, the working group agreed that the current DNT test protocol was based upon solid scientific principles and experience, that there were opportunities to revise and improve some aspects of the U.S. EPA guide- line study, and that further research would be valuable in providing the scientific basis for development of TG 426 (Cory-Slechta et al. 2001; Dorman et al. 2001; Garman et al. 2001; OECD 2003). Further considerations of methodologic issues related to the conduct of the DNT study include an ILSI workshop on the direct dosing of preweaning mammals. This workshop culminated in a monograph on direct dosing that has broad application to study design for many areas of research, for example, pharmaceuticals, environmental pol- lutants, and academic research (Moser et al. 2005; Zoetis and Walls 2003). The Japanese Interlaboratory Study. An interlaboratory evaluation of neurobehavioral screening methodologies (used in DNT stud- ies as well as adult neurotoxicity studies) was carried out by 11 safety research laboratories in Japan (Okazaki et al. 2003). The study examined technical problems in evaluating the neurotoxic potential of chemicals, conducting a variety of neurobehavioral tests on rats after either acute or repeated (28-day) exposure to acrylamide or 3,3´-iminodiproprionitrile. All laboratories detected neurotoxicity of both chemicals. The report identified interlabora- tory differences in test method sensitivity and concluded that it is important to standard- ize the methods and criteria and to improve observers’ skills (Okazaki et al. 2003). The Behavioral Test Methods Workshop. In 2003, a workshop was conducted to dis- cuss experimental procedures and practices that could help enhance the utility of behav- ioral data as a reliable index of neurotoxicity and in the safety evaluation of chemical sub- stances (Slikker et al. 2005). Workshop par- ticipants included individuals from all sectors of the neuroscience community: academia, government, testing laboratories, industry, and nonprofit nongovernmental organiza- tions. Overall conclusions from the workshop were that consensus can be reached on the fundamentals of behavioral assessment and that aspects such as experimental design, test method selection, training of technical staff, validation, control of confounding factors, data variability, data analysis, and data inter- pretation should be carefully considered in the planning and conduct of behavioral safety assessment (Slikker et al. 2005). ovlume 117 | number 1 | January 2009 • Environmental Health Perspectives