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Quaternary ammonium compounds (QACs), a large class of chemicals that includes high production volume substances, have been used for decades as antimicrobials, preservatives, and antistatic agents and for other functions in cleaning, disinfecting, personal care products, and durable consumer goods. QAC use has accelerated in response to the COVID-19 pandemic and the banning of 19 antimicrobials from several personal care products by the US Food and Drug Administration in 2016. Studies conducted before and after the onset of the pandemic indicate increased human exposure to QACs. Environmental releases of these chemicals have also increased. Emerging information on adverse environmental and human health impacts of QACs is motivating a reconsideration of the risks and benefits across the life cycle of their production, use, and disposal. This work presents a critical review of the literature and scientific perspective developed by a multidisciplinary, multi-institutional team of authors from academia, governmental, and nonprofit organizations. The review evaluates currently available information on the ecological and human health profile of QACs and identifies multiple areas of potential concern. Adverse ecological effects include acute and chronic toxicity to susceptible aquatic organisms, with concentrations of some QACs approaching levels of concern. Suspected or known adverse health outcomes include dermal and respiratory effects, developmental and reproductive toxicity, disruption of metabolic function such as lipid homeostasis, and impairment of mitochondrial function. QACs' role in antimicrobial resistance has also been demonstrated. In the US regulatory system, how a QAC is managed depends on how it is used, for example in pesticides or personal care products. This can result in the same QACs receiving different degrees of scrutiny depending on the use and the agency regulating it. Further, the US Environmental Protection Agency's current method of grouping QACs based on structure, first proposed in 1988, is insufficient to address the wide range of QAC chemistries, potential toxicities, and exposure scenarios. Consequently, exposures to common mixtures of QACs and from multiple sources remain largely unassessed. Some restrictions on the use of QACs have been implemented in the US and elsewhere, primarily focused on personal care products. Assessing the risks posed by QACs is hampered by their vast structural diversity and a lack of quantitative data on exposure and toxicity for the majority of these compounds. This review identifies important data gaps and provides research and policy recommendations for preserving the utility of QAC chemistries while also seeking to limit adverse environmental and human health effects.

We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.S. EPA's ToxCast platforms. We mapped these assays to key characteristics of carcinogens and found they collectively assess 5 of 10 characteristics. We ranked all 1061 chemicals screened in Phases I and II of ToxCast by their activity in the selected cancer pathway-related assays using Toxicological Prioritization Index software. More chemicals used as biologically active agents (eg, pharmaceuticals) ranked in the upper 50% versus lower 50%. Twenty-three chemotypes are enriched in the top 5% (n = 54) of chemicals; these features may be important for their activity in cancer pathway-related assays. The biological coverage of the ToxCast assays related to cancer pathways is limited and short-term assays may not capture the biology of some key characteristics. Metabolism is also minimal in the assays. The ability of our approach to identify chemicals with cancer hazard is limited with the current input data, but we expect that our approach can be applied with future iterations of ToxCast and other data for improved chemical prioritization and characterization. The novel approach and proof-of-concept exercise described here for ranking chemicals for potential carcinogenicity concern is modular, adaptable, and amenable to evolving data streams.

US EPA's Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well-established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays. We grouped the ToxCast assays into defined sets to examine o-phthalate activity and potency. This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform us of sensitive upstream toxicity endpoints and may assist in the rapid identification of environmental chemical hazards for screening and prioritization. However, this case study shows that the absence of positive results in ToxCast in vitro assays cannot be interpreted as absence of related in vivo toxicity, and limited biological coverage by the assays remains a concern.

Polycyclic aromatic hydrocarbons (PAH) are a class of chemicals common in the environment. Certain PAH are carcinogenic, although the degree to which genetic variation influences susceptibility to carcinogenic PAH remains unclear. Also unknown is the influence of genetic variation on the procarcinogenic effect of in utero exposures to PAH. Benzo[a]pyrene (B[a]P) is a well-studied PAH that is classified as a known human carcinogen. Within our Polish cohort, we explored interactions between maternal exposure to airborne PAH during pregnancy and maternal and newborn single nucleotide polymorphisms (SNPs) in plausible B[a]P metabolism genes on B[a]P-DNA adducts in paired cord blood samples. The study subjects included non-smoking women (n = 368) with available data on maternal PAH exposure, paired cord adducts, and genetic data who resided in Krakow, Poland. We selected eight common variants in maternal and newborn candidate genes related to B[a]P metabolism, detoxification, and repair for our analyses: CYP1A1, CYP1A2, CYP1B1, GSTM1, GSTT2, NQO1, and XRCC1. We observed significant interactions between maternal PAH exposure and SNPs on cord B[a]P-DNA adducts in the following genes: maternal CYP1A1 and GSTT2, and newborn CYP1A1 and CYP1B1. These novel findings highlight differences in maternal and newborn genetic contributions to B[a]P-DNA adduct formation and have the potential to identify at-risk subpopulations who are susceptible to the carcinogenic potential of B[a]P. [ABSTRACT FROM AUTHOR]