Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern.

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.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Advancing the science on chemical classes.

BACKGROUND: Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators. OBJECTIVE AND METHODS: While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios. RESULTS: Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management. DISCUSSION AND CONCLUSION: Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management).

The Florence Statement on Triclosan and Triclocarban.

The Florence Statement on Triclosan and Triclocarban documents a consensus of more than 200 scientists and medical professionals on the hazards of and lack of demonstrated benefit from common uses of triclosan and triclocarban. These chemicals may be used in thousands of personal care and consumer products as well as in building materials. Based on extensive peer-reviewed research, this statement concludes that triclosan and triclocarban are environmentally persistent endocrine disruptors that bioaccumulate in and are toxic to aquatic and other organisms. Evidence of other hazards to humans and ecosystems from triclosan and triclocarban is presented along with recommendations intended to prevent future harm from triclosan, triclocarban, and antimicrobial substances with similar properties and effects. Because antimicrobials can have unintended adverse health and environmental impacts, they should only be used when they provide an evidence-based health benefit. Greater transparency is needed in product formulations, and before an antimicrobial is incorporated into a product, the long-term health and ecological impacts should be evaluated. https://doi.org/10.1289/EHP1788.

Meeting report: consensus statement-Parkinson's disease and the environment: collaborative on health and the environment and Parkinson's Action Network (CHE PAN) conference 26-28 June 2007.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. METHODS: In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. RESULTS: We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. CONCLUSIONS: PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.

The new tapestry of risk assessment.

Neurotoxicology is entering a new phase in how it views and practices risk assessment. Perhaps more than any of the other disciplines that comprise the science of toxicology, it has been compelled to consider a daunting array of factors other than those directly coupled to chemical and dose, and the age and sex of the subject population. In epidemiological investigations, researchers are increasingly cognizant of the problems introduced by allegedly controlling for variables classified as confounders or covariates. In essence, they reason, the consequence is blurring or even concealing interactions of exposure with modifiers such as the individual's social ecology. Other researchers question the traditional practice of relying on values such as NOAELs when they are abstracted from a biological entity that in reality represents a multiplicity of intertwined systems. Although neurotoxicologists have come to recognize the complexities of assessing risk in all its dimensions, they still face the challenge of communicating this view to the health professions at large.

New conceptual frameworks and challenges in the investigation and practice of environmental reproductive health.

Although much research focuses on the role of single variables affecting reproductive health, it is essential to remain aware of complex interactions among many variables in the real world. Potential relationships between biologic levels of the essential micronutrient zinc and the response to exposure to teratogens are illustrative.

Exposure to phthalates in neonatal intensive care unit infants: urinary concentrations of monoesters and oxidative metabolites.

OBJECTIVE: We previously demonstrated that among 54 infants in neonatal intensive care units, exposure to polyvinyl chloride plastic medical devices containing the plasticizer di(2-ethylhexyl) phthalate (DEHP) is associated with urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP) , a DEHP metabolite. In this follow-up report, we studied the neonates' exposure to DEHP-containing devices in relation to urinary concentrations of two other DEHP metabolites, and to urinary concentrations of metabolites of dibutyl phthalate (DBP) and benzylbutyl phthalate (BzBP) , phthalates found in construction materials and personal care products. MEASUREMENTS: A priori, we classified the intensiveness of these 54 infants' exposure to DEHP-containing medical products. We measured three metabolites of DEHP in infants' urine: MEHP and two of its oxidative metabolites, mono(2-ethyl-5-hydroxylhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) . We also measured monobutyl phthalate (MBP) , a metabolite of DBP, and monobenzyl phthalate (MBzP), a metabolite of BzBP. RESULTS: Intensiveness of DEHP-containing product use was monotonically associated with all three DEHP metabolites. Urinary concentrations of MEHHP and MEOHP among infants in the high-DEHP-intensiveness group were 13-14 times the concentrations among infants in the low-intensiveness group (p

Human exposure to phthalates via consumer products.

Phthalate exposures in the general population and in subpopulations are ubiquitous and widely variable. Many consumer products contain specific members of this family of chemicals, including building materials, household furnishings, clothing, cosmetics, pharmaceuticals, nutritional supplements, medical devices, dentures, children's toys, glow sticks, modelling clay, food packaging, automobiles, lubricants, waxes, cleaning materials and insecticides. Consumer products containing phthalates can result in human exposures through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Historically, the diet has been considered the major source of phthalate exposure in the general population, but all sources, pathways, and their relative contributions to human exposures are not well understood. Medical devices containing di-(2-ethylhexyl) phthalate are a source of significant exposure in a susceptible subpopulation of individuals. Cosmetics, personal care products, pharmaceuticals, nutritional supplements, herbal remedies and insecticides, may result in significant but poorly quantified human exposures to dibutyl phthalate, diethyl phthalate, or dimethyl phthalate. Oven baking of polymer clays may cause short-term, high-level inhalation exposures to higher molecular weight phthalates.

Use of di(2-ethylhexyl) phthalate-containing medical products and urinary levels of mono(2-ethylhexyl) phthalate in neonatal intensive care unit infants.

OBJECTIVE: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in medical products made with polyvinyl chloride (PVC) plastic and may be toxic to humans. DEHP is lipophilic and binds noncovalently to PVC, allowing it to leach from these products. Medical devices containing DEHP are used extensively in neonatal intensive care units (NICUs). Among neonates in NICUs, we studied exposure to DEHP-containing medical devices in relation to urinary levels of mono(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP. DESIGN: We used a cross-sectional design for this study. PARTICIPANTS: We studied 54 neonates admitted to either of two level III hospital NICUs for at least 3 days between 1 March and 30 April 2003. MEASUREMENTS: A priori, we classified the infants' exposures to DEHP based on medical products used: The low-DEHP exposure group included infants receiving primarily bottle and/or gavage feedings; the medium exposure group included infants receiving enteral feedings, intravenous hyperalimentation, and/or nasal continuous positive airway pressure; and the high exposure group included infants receiving umbilical vessel catheterization, endotracheal intubation, intravenous hyperalimentation, and indwelling gavage tube. We measured MEHP in the infants' urine using automated solid-phase extraction/isotope dilution/high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Urinary MEHP levels increased monotonically with DEHP exposure. For the low-, medium-, and high-DEHP exposure groups, median (interquartile range) MEHP levels were 4 (18), 28 (58), and 86 ng/mL (150), respectively (p = 0.004). After adjustment for institution and sex, urinary MEHP levels among infants in the high exposure group were 5.1 times those among infants in the low exposure group (p = 0.03). CONCLUSION: Intensive use of DEHP-containing medical devices in NICU infants results in higher exposure to DEHP as reflected by elevated urinary levels of MEHP.

Environmental toxicants and developmental disabilities: a challenge for psychologists.

Developmental, learning, and behavioral disabilities are a significant public health problem. Environmental chemicals can interfere with brain development during critical periods, thereby impacting sensory, motor, and cognitive function. Because regulation in the United States is based on limited testing protocols and essentially requires proof of harm rather than proof of lack of harm, some undefined fraction of these disabilities may reflect adverse impacts of this "vast toxicological experiment" (H. L. Needleman, as quoted in B. Weiss & P. J. Landrigan, 2000, p. 373). Yet the hazards of environmental pollutants are inherently preventable. Psychologists can help prevent developmental disabilities by mobilizing and affecting public policy, educating and informing consumers, contributing to interdisciplinary research efforts, and taking action within their own homes and communities to reduce the toxic threat to children.

Human rights: necessary? Sufficient? Diversionary?

Claims of human rights have historically been a response to the violence and oppression brought by some people onto others. Focusing on the individual person, modern concepts of human rights inadequately address the relationships of individual people to their communities and rarely address relationships of people with other species and ecological systems more generally. During the past 50-100 years the world has undergone profound ecological change, and although concepts of human rights remain useful, their limits are becoming increasingly clear. Advances in ecological and biological sciences demonstrate dialectic relationships among components and the whole of complex systems. Where the individual begins and ends is unclear. A new ethic that incorporates new ecological understanding is essential in order to address the essentially new world of today. A deep sense of responsibility and an ethic of care, trust, respect, and reciprocity are essential to this undertaking.

In harm's way: toxic threats to child development.

Developmental disabilities result from complex interactions of genetic, toxicologic (chemical), and social factors. Among these various causes, toxicologic exposures deserve special scrutiny because they are readily preventable. This article provides an introduction to some of the literature addressing the effects of these toxicologic exposures on the developing brain. This body of research demonstrates cause for serious concern that commonly encountered household and environmental chemicals contribute to developmental disabilities. The developing brain is uniquely susceptible to permanent impairment by exposure to environmental substances during time windows of vulnerability. Lead, mercury, and polychlorinated biphenyls (PCBs) have been extensively studied and found to impair development at levels of exposure currently experienced by significant portions of the general population. High-dose exposures to each of these chemicals cause catastrophic developmental effects. More recent research has revealed toxicity at progressively lower exposures, illustrating a "declining threshold of harm" commonly observed with improved understanding of developmental toxicants. For lead, mercury, and PCBs, recent studies reveal that background-population exposures contribute to a wide variety of problems, including impairments in attention, memory, learning, social behavior, and IQ. Unfortunately, for most chemicals there is little data with which to evaluate potential risks to neurodevelopment. Among the 3000 chemicals produced in highest volume (over 1 million lbs/yr), only 12 have been adequately tested for their effects on the developing brain. This is a matter of concern because the fetus and child are exposed to untold numbers, quantities, and combinations of substances whose safety has not been established. Child development can be better protected by more precautionary regulation of household and environmental chemicals. Meanwhile, health care providers and parents can play an important role in reducing exposures to a wide variety of known and suspected neurodevelopmental toxicants that are widely present in consumer products, food, the home, and wider community.

Sewage sludge--looking upstream: the precautionary principle.

The health care industry makes a unique contribution to the potential public health and environmental impacts of sewage sludge production and disposal. As materials flow into and out of health care facilities, potentially hazardous substances, like mercury, solvents, and pharmaceutical compounds, are introduced into the waste stream and ultimately into sewage sludge. Although the hazards posed by these practices are often not fully understood or the risks quantified, concern about impacts on public health and the environment is fully justified. How to deal with the uncertainties surrounding the impacts of these practices becomes an ethical as well as a scientific question. A precautionary approach to materials manufacture, use, and disposal encourages us to look upstream and to re-design products and systems in ways that primarily prevent problems rather than dealing with them at the "end of the pipe." Early warning systems, shifting the burden of proof, alternatives assessment, and monitoring programs are suggested as interventions that might be used as part of a precautionary approach to addressing the generation and disposal of sewage in an industrial society.