Comparative Toxicity of Seven Aqueous Film-Forming Foam to In Vitro Systems and Mus.

The comparative toxicity of six per- and polyfluoroalkyl substance (PFAS)-free and one PFAS-containing aqueous film-forming foam (AFFF) was evaluated in an outbred mouse species as well as several in vitro assays. The in vivo toxicological profile of PFAS-free AFFFs in short-term, high-concentration exposures is different than that of a PFAS-containing AFFF. The PFAS-containing reference product induced increased liver weights, while the PFAS-free AFFFs were linked to either decreased or unaffected relative liver weights. The in vitro toxicological profile across PFAS-free AFFFs was uniform except in the Microtox® assay, where thresholds were variable and spanned several orders of magnitude. This direct comparison of products through short-term toxicity tests and in vitro screenings represents early data to support evaluation of potential regrettable substitutions when selecting alternative PFAS-free AFFFs. Further work in diverse taxa (e.g., aquatic organisms, terrestrial invertebrates, birds) and mammalian studies capturing sensitive life stages will refine and expand this data set across a range of risk-relevant toxicological endpoints. Environ Toxicol Chem 2023;42:2364-2374. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Reproductive and immune effects emerge at similar thresholds of PFHxS in deer mice.

Although perfluorohexane sulfonate (PFHxS) is structurally similar to perfluorooctane sulfonate (PFOS) and also widely detected in humans and the environment, comparatively fewer toxicity data exists on this 6-chain perfluoroalkyl sulfonic acid. In this study, repeated oral doses of PFHxS were administered to deer mice (Peromyscus maniculatus) to evaluate subchronic toxicity and potential effects on reproduction and development. Maternal oral exposure to PFHxS caused increased stillbirths, which is relevant for ecological risk assessment, and resulted in a benchmark dose lower limit (BMDL) of 5.72 mg/kg-d PFHxS. Decreased plaque formation, which is relevant for human health risk assessment, occurred in both sexes of adult animals (BMDL = 8.79 mg/kg-d PFHxS). These data are the first to suggest a direct link between PFHxS and decreased functional immunity in an animal model. Additionally, female animals exhibited increased liver:body weight and animals of both sexes exhibited decreased serum thyroxine (T4) levels. Notably, since reproductive effects were used to support 2016 draft health advisories and immune effects were used in 2022 drinking water health advisories released by the United States Environmental Protection Agency for PFOS and perfluorooctanoic acid (PFOA), these novel data can potentially support advisories for PFHxS because relevant points of departure emerge at similar thresholds in a wild mammal and corroborate the general understanding of per- and polyfluoroalkyl substances (PFAS).

Toxicology assessment for six per- and polyfluoroalkyl (PFAS)-free aqueous film forming foam (AFFF) products.

There is an urgent need to understand the toxicity hazards of aqueous film forming foam (AFFF) replacement products to ensure the balance between performance and toxicity hazards and avoid regrettable substitutions during the rapid phasing out of per- and polyfluoroalkyl substance (PFAS)-containing AFFFs. To address this need, we assessed the toxicity of six candidate PFAS-free products via literature review, estimation techniques, and incorporation of testing data from whole products and compared them against one PFAS-containing product. Then, we combined the relative hazards across human occupational exposure (e.g., concentrate, foam, or dilute exposures), human environmental exposure (e.g., training, emergency response, cleanup), and environmental exposure to aquatic, mammalian, and other terrestrial species using an index-based scoring system to quantify potential hazards across these domains. We found that most PFAS-free products in their concentrated form may cause dermal and ocular irritation, and aquatic toxicity may be a concern from direct or repeated environmental releases. Additionally, all PFAS-free AFFF products assessed contain chemicals that are notable as plausible hazards resulting from release uncertainties (e.g., concentration, release volume, release timing), but the PFAS-free AFFF products appear to have a lower likelihood of environmental persistence and bioaccumulation and to have lower oral human health toxicity than the PFAS-containing reference product. Decision makers can use this information alongside cost-benefit, sustainability, or life-cycle analyses to make a data-driven decision for the adoption of PFAS-free AFFF. Integr Environ Assess Manag 2023;19:1609-1618. © 2023 SETAC.

Next-generation PFAS 6:2 fluorotelomer sulfonate reduces plaque formation in exposed white-footed mice.

6:2 fluorotelomer sulfonate (6:2 FTS) has been used as a replacement for legacy per- and polyfluoroalkyl substances (PFAS). We assessed reproductive and developmental effects in a human-wildlife hybrid animal model based on the association of adverse effects linked to legacy PFAS with these sensitive life stages. In this study, white-footed mice were exposed orally to 0, 0.2, 1, 5, or 25 mg/kg-day 6:2 FTS for 112 days (4 weeks premating exposure plus at least 4 weeks mating exposure). Pregnancy and fertility indices were calculated, and litter production, total litter size, live litter size, stillbirths, litter loss, average pup weight, and pinna unfolding were assessed. Sex steroid and thyroid hormone serum levels were assessed. Body weight, histopathology, and immune function were also assessed in this study. Reproductive endpoints were not significantly altered in response to 6:2 FTS. Spleen weight increased in male mice dosed with 6:2 FTS. Immune function determined via a plaque-forming cell (PFC) assay was decreased in both male and female mice in the 2 highest doses. A low benchmark dose was calculated based on PFCs as the critical effect and was found to be 2.63 and 2.26 mg/kg-day 6:2 FTS in male and female mice, respectively. This study characterizes 6:2 FTS as being potentially immunotoxic with little evidence of effect on reproduction and development; furthermore, it models acceptable levels of exposure. These 2 pieces of information together will aid regulators in setting environmental exposure limits for this PFAS currently thought to be less toxic than other PFAS.

Reproductive and developmental toxicity of perfluorooctane sulfonate (PFOS) in the white-footed mouse (Peromyscus leucopus).

Concerns about per- and polyfluoroalkyl substances (PFAS) stem from their ubiquitous presence in the environment, bioaccumulation, resistance to degradation, and toxicity. Previously, toxicity data relevant to ecological risk assessment has largely been aquatic, terrestrial invertebrates, or avian in origin. In this study, repeated oral exposures of perfluorooctane sulfonate (PFOS) were administered to white-footed mice (Peromyscus leucopus) to evaluate effects on reproduction and development. Prenatal exposure to high doses of PFOS caused neonatal mortality, though growth and development were unaffected by low doses. Additionally, parental (P) generation animals exhibited increased liver:body weight, increased hepatocyte cytoplasmic vacuolization, and decreased serum thyroxine (T4) levels. Total litter loss was selected as the protective critical effect in this study resulting in a benchmark dose low (BMDL) of 0.12 mg/kg-d PFOS. Importantly, PFOS exposure has been linked to reduced adult recruitment in myriad species and at similar thresholds to this study. Similarities in critical/toxicologic effects across taxa may add confidence in risk assessments at sites with multiple taxa or environments.

Patterns in Serum Toxicokinetics in Peromyscus Exposed to Per- and Polyfluoroalkyl Substances.

Per- and polyfluoroalkyl substances (PFAS) are compounds manufactured for use in paints, cleaning agents, fire suppressants, nonstick cookware, food containers, and water-resistant products. Concerns about PFAS stem from their ubiquitous presence in the environment, persistence, and variable/uncertain bioaccumulation and toxicity. In the present study, 5 perfluoroalkyl acids and one polyfluoroalkyl substance were administered to white-footed mice (Peromyscus leucopus) to elucidate the kinetics of each chemical over 28 d of exposure. Perfluorooctanoate, perfluorohexane sulfonate (PFHxS), and perfluorobutane sulfonate were administered to male and female mice via drinking water. Perfluorooctane sulfonate, perfluorononanoate, 6:2 fluorotelomer sulfonate, and PFHxS were administered to male and female mice via oral gavage. Blood samples collected after 14 or 21 and 28 d of exposure were analyzed for individual PFAS concentrations via liquid chromatography-tandem mass spectrometry. In general, a plateau in serum concentration in this toxicity test-relevant timeline depended on interactions between 1) the type of PFAS (i.e., perfluoroalkyl sulfonic acids [PFSAs] vs perfluoroalkyl carboxylic acids [PFCAs] vs polyfluorinated), 2) continuous versus bolus dosing, and 3) to a lesser extent, sex. Specifically, PFCAs were detected at higher concentration in females than males, whereas PFSAs were generally detected at similar levels across sex. An exception occurred when PFHxS yielded higher serum levels in males than females through bolus, but not continuous, dosing. Type of PFAS had the largest impact on serum concentrations, whereas sex had the lowest. As such, future work on the toxicokinetics of PFAS in common ecological receptors would be valuable to further explore these patterns. Environ Toxicol Chem 2021;40:2886-2898. © 2021 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Chronic oral toxicity of 3-nitro-1,2,4-triazol-5-one (NTO) in rats.

To evaluate the effects of chronic exposure to 3-nitro-1,2,4-triazol-5-one (nitrotriazolone, NTO), male and female rats were given ad libitum access to NTO in drinking water at concentrations of 0, 36, 110, 360, 1100, and 3600 mg/L for one year. NTO did not affect body weight, body weight gain, or food consumption in either sex. No treatment-related effects were observed in clinical chemistry and hematology parameters at the 6 month or one year sampling. At both the interim and final sampling, males and females from the 3600 mg/L group produced smaller volumes of urine that was darker, more concentrated, and contained more bilirubin than the controls. Total and motile sperm counts were not affected by NTO treatment. Absolute and relative organ weights did not differ between control and NTO treated groups for either sex. Spontaneous age-related neoplasms occurred in controls and NTO groups at rates consistent with published historic controls. NTO was generally non-toxic in females at the doses tested. Toxicity in males was limited to testicular toxicity as demonstrated in previous studies. Chronic exposure did not result in testicular toxicity at lower doses and the toxicity observed only in the high dose group in this study is less severe than that observed in shorter exposures of previous studies, suggesting differences may be associated with influences of study design on kinetics. A Benchmark Dose (BMD) of 1604 mg/L (76 mg/kg-day) and a Benchmark Dose Lower Bound (BMDL10) of 921 mg/L (44 mg/kg-day) were determined for chronic effects of NTO in male rats.