LAUSR

The article, “Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents” by Hrubec et al., provides the first published evidence that normal use of disinfectants containing alkyldimethylbenzylammonium chlorides (ADBAC)1 didecyldimethylammonium chloride (DDAC) causes birth defects in both mice and rats. Other adverse effects from ADBAC and DDAC exposure have long been known. Asthma and dermatitis induced by quaternary ammonium compounds (QACs) were identified in 1994 (Bernstein et al., 1994), while ocular inflammation and hypersensitivity were identified in 2009 (Hong & Bielory, 2009). Developmental and reproductive effects such as small litter size, increased resorptions, and late gestation fetal death were identified in the late 1980s (Cosmetic Ingredient Review, 1989; Neeper-Bradley, 1990, 1993; Tyl, 1989). More recently, these QACs have been shown to alter cholesterol synthesis (Herron et al., 2016), inhibit mitochondrial function (Datta et al., 2017; In acio et al., 2013), and interfere with estrogen signaling (Datta et al., 2017). In response to these data, the U.S. Food and Drug Administration (FDA) recently specifically requested additional information on the efficacy and safety of ADBAC (FDA, 2016). Because our results are consistent with those of earlier developmental toxicology studies, they add to a growing body of evidence identifying and describing QAC toxicity. As in earlier studies, we reported decreased fetal weight and an increase in both resorptions and late gestational death; however, we also evaluated endpoints not addressed previously. Specifically, our analysis of mid-gestation fetuses allowed us to determine the incidence of neural tube defects (NTDs). Although ADBAC and DDAC are frequently used in combination, all previous studies have evaluated the toxicity of the two compounds separately; our study is the first to evaluate ADBAC1DDAC in combination. Given that this is how many commercial products are formulated, this approach more accurately models human exposure. Dr. Hostetler is correct that some of the initial findings reported in our article were not derived from adequately controlled experiments. This was discussed at length in the article. These initial studies were included for two important reasons; first, they demonstrate the difficulty of preventing ambient exposure to ADBAC and DDAC, and second, they strongly support the conclusion that ambient exposure to ADBAC1DDAC is sufficient to cause birth defects. Indeed, the inclusion of these experiments provides clear evidence that the incidence of NTDs in orally dosed mice is increased or decreased by the presence and absence of ambient exposure, respectively. Dr. Hostetler’s concern, that NTDs were caused by moving mice during pregnancy, is highly unlikely because mice were moved on gestational day 1 or 2, which is prior to implantation. Further, commercial rodent suppliers routinely ship timed pregnant mice across the country without adverse effects. Equally unlikely is his assertion that ethanol, used to wipe down biosafety cabinets prior to working with animals, is sufficient exposure to cause the NTDs. Due to rapid evaporation, the ethanol is gone well before animal boxes are placed in the biosafety cabinet. In summary, our results, along with those from numerous animal, in vivo, and epidemiological studies, add to the growing concern that exposure to QACs may not be as safe as previously assumed. The steady rise in the number of products containing QACs and the environmental persistence of these chemicals has increased human exposure. Thus, we believe that the FDA’s assertion that additional studies to assess potential toxicity and harm associated with daily exposure to QACs is both timely and critical.