Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action ☆ Joan Colman b , Glenn E. Rice a, ⁎, J. Michael Wright a , E. Sidney Hunter III c , Linda K. Teuschler a , John C. Lipscomb a , Richard C. Hertzberg d , Jane Ellen Simmons c , Margaret Fransen b , Mark Osier b , Michael G. Narotsky c a National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH 45268, USA b Chemical, Biological and Environmental Center, SRC, Inc., Syracuse, NY 13212, USA c National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA d Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA abstract article info Article history: Received 30 October 2008 Revised 22 April 2010 Accepted 22 April 2010 Available online 4 February 2011 Keywords: Mode of action Developmental toxicity Drinking water disinfection byproducts (DBPs) Spontaneous abortion Full-litter resorption Cardiovascular malformation Neural tube defect Low birth weight Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmental effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps. Published by Elsevier Inc. Introduction Chemical disinfection of drinking water has reduced significantly the incidence of infectious waterborne disease, but reactions of disinfectants such as chlorine with natural organic matter in source waters produce chemical mixtures composed of hundreds of different disinfection byproducts (DBPs) (Krasner et al., 2001, 2006; Miltner et al., 1990; Richardson, 1998; Richardson et al., 1999, 2000a,b, 2003, 2008; Weinberg, 1999; Weinberg et al., 2002). Although inconsistent results have been reported across different epidemiological studies, some studies have reported associations between DBP exposure and increased risk of adverse developmental outcomes including term low birth weight or small for gestational age births (Gallagher et al., 1998; Hoffman et al., 2008; Infante-Rivard, 2004; Lewis et al., 2006, 2007; Wright et al., 2003, 2004), birth defects such as cardiovascular and neural tube defects (e.g., Cedergren et al., 2002; Chisholm et al., 2008; Dodds and King, 2001; Hwang et al., 2008; Klotz and Pyrch, 1998, 1999; Nieuwenhuijsen et al., 2008), spontaneous abortion (Savitz et al., 1995, 2005, 2006; Waller et al., 1998, 2001), and stillbirths (Dodds et al., 2004; Toledano et al., 2005). Because such epidemiological associations do not necessarily imply causality, developmental toxicity studies of individual DBPs have been undertaken (summa- rized in Klinefelter et al., 2001 and in this paper) to test the hypothesis that exposures to DBPs cause developmental effects. A number of individual DBPs cause adverse developmental effects in mammalian bioassays; however, to date, these toxicological studies do not identify any single DBP with sufficient potency to account for the relative risk estimates reported in the epidemiological literature. This observation has led some to hypothesize that exposures to mixtures of DBPs are associated with the developmental outcomes reported in epidemio- logical studies and that this hypothesis could be examined through toxicological experiments with DBP mixtures and components using methods for mixtures risk assessment (Simmons et al., 2002, 2004, Toxicology and Applied Pharmacology 254 (2011) 100–126 ☆ Notice. On behalf of all authors, the corresponding author declares there is no conflict of interest in this study. The views expressed in this paper are those of the authors and do not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ⁎ Corresponding author at: U.S. Environmental Protection Agency, National Center for Environmental Assessment, 26 West M.L. King Dr., Cincinnati, OH 45268, USA. Fax: +1 513 487 2539. E-mail address: rice.glenn@epa.gov (G.E. Rice). 0041-008X/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.taap.2011.02.002 Contents lists available at ScienceDirect Toxicology and Applied Pharmacology journal homepage: www.elsevier.com/locate/ytaap