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As stated in our Introduction, DeSesso et al. (2019) attempted to replicate the Johnson, Goldberg, Mays, and Dawson (2003) trichloroethylene (TCE) drinking water study in pregnant rats, which reported “abnormal hearts” among offspring of treated dams. The Johnson et al. study has been heavily criticized (e.g., Hardin, Kelman, & Brent, 2005; Watson, Jacobson, Williams, Howard, & DeSesso, 2006) for design flaws (e.g., noncontemporary controls; data collected unevenly over several years; nonstandard microdissections of fetal hearts) as detailed in our article. Fetal cardiac defects were not observed in two high quality, robust studies (Carney, Thorsrud, Dugard, & Zablotny, 2006; Fisher et al., 2001) conducted according to contemporary guidance for developmental toxicity. Nevertheless, U.S. EPA has used the fetal “abnormal hearts” of Johnson et al., in part, as the basis for the TCE reference concentration (RfC)/reference dose (RfD). Thus, our study was designed to approximate Johnson et al. but enhanced to correct deficiencies and meet current EPA test guidance and data quality standards. The fetal cardiac findings did not repeat in our apical study, consistent with negative findings in oral gavage (Fisher et al., 2001) and inhalation (Carney et al., 2006) studies. These data suggest that the Johnson et al. results are spurious and not reproducible. Concerning Runyan et al.'s speculations (with no supporting data) regarding the irreproducibility of the Johnson et al. (2003) study by us and others, we point out that Fisher et al. (2001)—gavage and Carney et al. (2006)—inhalation were conducted within 2–4 years of Johnson et al. (2003), and the pharmacokinetics of TCE and trichloroacetic acid (TCA) as described by Fisher, Whittaker, Taylor, Clewell, and Andersen (1989) have not changed over the past 30 years. These data fail to support Runyan et al.'s speculations but do support the criticisms suggesting the increased cardiac malformations in Johnson et al. (2003) resulted from their microdissection technique. Runyan et al. do not challenge our key conclusion: no TCE-related cardiac malformations. Rather, they challenge our interpretation based largely on flawed dosimetric assumptions equating findings from in vitro systems to our in vivo rat study. Their statement that TCE exhibits “developmental and mechanistic responses to TCE exposure, all using doses below 1000 ppm in whole embryos or in vitro cardiac tissues” reveals a remarkable failure to appreciate that TCE concentrations in drinking water are not equivalent to systemic doses of TCE or embryonic exposures. We could not detect TCE in maternal blood of pregnant rats given 1,000 ppm TCE in drinking water (level of quantitation, 50 ng/ml = 50 ppb), likely due to substantial hepatic first-pass metabolism after oral administration. We note that TCE uptake was demonstrated by measurable plasma levels of TCA, a nonvolatile, oxidative metabolite of TCE, in maternal blood (Table 1). Assuming TCE blood concentration is 25 ppb (½LOQ) at the 1,000 ppm dose and linear toxicokinetics apply throughout our dose range (0.25–1,000 ppm), our study possibly encompassed TCE blood concentrations of 0.006–25 ppb. These worst-case blood and associated embryo concentrations are within or substantially below the doses in the tabulated studies cited by Runyan et al. as evidence that TCE may exhibit low-dose nonmonotonic effects on cardiac development. Both the absence of TCE-induced cardiac malformations and the TCE toxicokinetic data in our study indicate that the low-dose nonmonotonic effects asserted from mechanistic studies cited by Runyan et al. do not offer dosimetrically plausible evidence that TCE adversely impacts apical mammalian cardiac development. 600 ppm (4 hr) ND (0.006 ppb)a [ng/ml] ND (0.04 ppb) [ng/ml] ND (12.5 ppb) [ng/ml] ND (25 ppb) [ng/ml] ND (15 ng/ml)b As emphasized in our study, heart defects were not seen in fetuses of rat dams exposed to TCE by oral gavage or inhalation (Fisher et al., 2001; Carney et al., 2006, respectively) where TCE is quantifiable in maternal blood. For example, Fisher et al. (1989) reported peak blood TCE of 24 μg/ml immediately after a 4 hr 600 ppm inhalation exposure to pregnant rats (Table 1). We are surprised that Runyan et al. listed 15 papers from their laboratories in an accompanying table to support their contention. The problem with these studies in reference to our study is that none have demonstrated any link between the genetic and molecular changes in their test systems and heart malformations. Because cardiac malformations were not observed in three high quality rat developmental toxicity studies including our drinking water study, it remains conjectural that their studies demonstrate mechanism(s) by which in vivo TCE exposures can cause fetal heart defects in rats. Finally, we emphasize that the absence of TCE-induced cardiac malformations following treatment of pregnant rats by three routes of administration covering a broad spectrum of doses and resulting in a wide range of systemic TCE blood concentrations (Carney et al., 2006; DeSesso et al., 2019; Fisher et al., 2001) provides strong reassurance that real-world drinking water exposures to TCE are unlikely to present biologically plausible risks of adverse cardiac development. The authors acknowledge the Halogenated Solvents Industry Alliance and American Chemistry Council for funding. Dr. Pottenger is retired from the Olin Corporation, a member company of HSIA and a producer of TCE. Dr. Bevan is the Director, Scientific Programs at HSIA and was formerly a consultant to Westlake Chemical Company, a member of HSIA. Dr. Budinsky is an employee of The Dow Chemical Company, a member company of HSIA. The employer of Drs. Bus and DeSesso, Exponent, Inc., has contracts with HSIA. Dr. York is a consultant to HSIA. Drs. Coder and Sen and Ms. Lucarell are employees of Charles River Laboratories Ashland, the contract research organization that performed the research.