Systemic and immunotoxicity induced by topical application of perfluorohexane sulfonic acid (PFHxS) in a murine model.

Per- and polyfluoroalkyl substances (PFAS) are a large group of stable synthetic surfactants that are incorporated into numerous products for their water and oil resistance and have been associated with adverse health effects. The present study evaluated the systemic and immunotoxicity of sub-chronic 28- or 10-day dermal exposure of PFHxS (0.625-5% or 15.63-125 mg/kg/dose) in a murine model. Elevated levels of PFHxS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. Liver weight (% body) significantly increased and spleen weight (% body) significantly decreased with PFHxS exposure, which was supported by histopathological changes. Additionally, PFHxS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen with genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells, NK cells, and CD11b+ monocyte/macrophages in the spleen along with increases in CD4+ and CD8+ T-cells, NK cells, and neutrophils in the skin. These findings support dermal PFHxS-induced liver damage and immune suppression. Overall, data support PFHxS absorption through the skin and demonstrate immunotoxicity via this exposure route, suggesting the need for further examination.

Effects of inhaled tier-2 diesel engine exhaust on immunotoxicity in a rat model: A hazard identification study. Part II. Immunotoxicology.

Diesel exhaust (DE) is an air pollutant containing gaseous compounds and particulate matter. Diesel engines are common on gas extraction and oil sites, leading to complex DE exposure to a broad range of compounds through occupational settings. The US EPA concluded that short-term exposure to DE leads to allergic inflammatory disorders of the airways. To further evaluate the immunotoxicity of DE, the effects of whole-body inhalation of 0.2 and 1 mg/m3 DE (total carbon; 6 h/d for 4 days) were investigated 1-, 7-, and 27-days post exposure in Sprague-Dawley rats using an occupationally relevant exposure system. DE exposure of 1 mg/m3 increased total cellularity, number of CD4+ and CD8+ T-cells, and B-cells at 1 d post-exposure in the lung lymph nodes. At 7 d post-exposure to 1 mg/m3, cellularity and the number of CD4+ and CD8+ T-cells decreased in the LLNs. In the bronchoalveolar lavage, B-cell number and frequency increased at 1 d post-exposure, Natural Killer cell number and frequency decreased at 7 d post-exposure, and at 27 d post-exposure CD8+ T-cell and CD11b+ cell number and frequency decreased with 0.2 mg/m3 exposure. In the spleen, 0.2 mg/m3 increased CD4+ T-cell frequency at 1 and 7 d post-exposure and at 27 d post-exposure increased CD4+ and CD8+ T-cell number and CD8+ T-cell frequency. B-cells were the only immune cell subset altered in the three tissues (spleen, LLNs, and BALF), suggesting the induction of the adaptive immune response. The increase in lymphocytes in several different organ types also suggests an induction of a systemic inflammatory response occurring following DE exposure. These results show that DE exposure induced modifications of cellularity of phenotypic subsets that may impair immune function and contribute to airway inflammation induced by DE exposure in rats.

Toxicological Effects of Inhaled Crude Oil Vapor.

PURPOSE OF REVIEW: The purpose of this review is to assess the toxicological consequences of crude oil vapor (COV) exposure in the workplace through evaluation of the most current epidemiologic and laboratory-based studies in the literature. RECENT FINDINGS: Crude oil is a naturally occuring mixture of hydrocarbon deposits, inorganic and organic chemical compounds. Workers engaged in upstream processes of oil extraction are exposed to a number of risks and hazards, including getting crude oil on their skin or inhaling crude oil vapor. There have been several reports of workers who died as a result of inhalation of high levels of COV released upon opening thief hatches atop oil storage tanks. Although many investigations into the toxicity of specific hydrocarbons following inhalation during downstream oil processing have been conducted, there is a paucity of information on the potential toxicity of COV exposure itself. This review assesses current knowledge of the toxicological consequences of exposures to COV in the workplace.

Optimization of Aspergillus versicolor Culture and Aerosolization in a Murine Model of Inhalational Fungal Exposure.

Aspergillus versicolor is ubiquitous in the environment and is particularly abundant in damp indoor spaces. Exposure to Aspergillus species, as well as other environmental fungi, has been linked to respiratory health outcomes, including asthma, allergy, and even local or disseminated infection. However, the pulmonary immunological mechanisms associated with repeated exposure to A. versicolor have remained relatively uncharacterized. Here, A. versicolor was cultured and desiccated on rice then placed in an acoustical generator system to achieve aerosolization. Mice were challenged with titrated doses of aerosolized conidia to examine deposition, lymphoproliferative properties, and immunotoxicological response to repeated inhalation exposures. The necessary dose to induce lymphoproliferation was identified, but not infection-like pathology. Further, it was determined that the dose was able to initiate localized immune responses. The data presented in this study demonstrate an optimized and reproducible method for delivering A. versicolor conidia to rodents via nose-only inhalation. Additionally, the feasibility of a long-term repeated exposure study was established. This experimental protocol can be used in future studies to investigate the physiological effects of repeated pulmonary exposure to fungal conidia utilizing a practical and relevant mode of delivery. In total, these data constitute an important foundation for subsequent research in the field.

Discriminative Accuracy of the CAPTURE Tool for Identifying Chronic Obstructive Pulmonary Disease in US Primary Care Settings.

Importance: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in primary care. Objective: To evaluate the operating characteristics of the CAPTURE (COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool for identifying US primary care patients with undiagnosed, clinically significant COPD. Design, Setting, and Participants: In this cross-sectional study, 4679 primary care patients aged 45 years to 80 years without a prior COPD diagnosis were enrolled by 7 primary care practice-based research networks across the US between October 12, 2018, and April 1, 2022. The CAPTURE questionnaire responses, peak expiratory flow rate, COPD Assessment Test scores, history of acute respiratory illnesses, demographics, and spirometry results were collected. Exposure: Undiagnosed COPD. Main Outcomes and Measures: The primary outcome was the CAPTURE tool's sensitivity and specificity for identifying patients with undiagnosed, clinically significant COPD. The secondary outcomes included the analyses of varying thresholds for defining a positive screening result for clinically significant COPD. A positive screening result was defined as (1) a CAPTURE questionnaire score of 5 or 6 or (2) a questionnaire score of 2, 3, or 4 together with a peak expiratory flow rate of less than 250 L/min for females or less than 350 L/min for males. Clinically significant COPD was defined as spirometry-defined COPD (postbronchodilator ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity [FEV1:FVC] <0.70 or prebronchodilator FEV1:FVC <0.65 if postbronchodilator spirometry was not completed) combined with either an FEV1 less than 60% of the predicted value or a self-reported history of an acute respiratory illness within the past 12 months. Results: Of the 4325 patients who had adequate data for analysis (63.0% were women; the mean age was 61.6 years [SD, 9.1 years]), 44.6% had ever smoked cigarettes, 18.3% reported a prior asthma diagnosis or use of inhaled respiratory medications, 13.2% currently smoked cigarettes, and 10.0% reported at least 1 cardiovascular comorbidity. Among the 110 patients (2.5% of 4325) with undiagnosed, clinically significant COPD, 53 had a positive screening result with a sensitivity of 48.2% (95% CI, 38.6%-57.9%) and a specificity of 88.6% (95% CI, 87.6%-89.6%). The area under the receiver operating curve for varying positive screening thresholds was 0.81 (95% CI, 0.77-0.85). Conclusions and Relevance: Within this US primary care population, the CAPTURE screening tool had a low sensitivity but a high specificity for identifying clinically significant COPD defined by presence of airflow obstruction that is of moderate severity or accompanied by a history of acute respiratory illness. Further research is needed to optimize performance of the screening tool and to understand whether its use affects clinical outcomes.

Systemic toxicity induced by topical application of perfluoroheptanoic acid (PFHpA), perfluorohexanoic acid (PFHxA), and perfluoropentanoic acid (PFPeA) in a murine model.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic structurally diverse chemicals incorporated into industrial and consumer products. PFHpA, PFHxA, and PFPeA are carboxylic PFAS (C7, C6, C5, respectively) labeled as a safer alternative to legacy carboxylic PFAS due to their shorter half-life in animals. Although there is a high potential for dermal exposure, these studies are lacking. The present study conducted analyses of serum chemistries, immune phenotyping, gene expression, and histology to evaluate the systemic toxicity of a sub-chronic 28-day dermal exposure of alternative PFAS (1.25-5% or 31.25-125 mg/kg/dose) in a murine model. Liver weight (% body) significantly increased with PFHpA, PFHxA, and PFPeA exposure and histopathological changes were observed in both the liver and skin. Gene expression changes were observed with PPAR isoforms in the liver and skin along with changes in genes involved in steatosis, fatty acid metabolism, necrosis, and inflammation. These findings, along with significant detection levels in serum and urine, support PFAS-induced liver damage and PPARα, δ, and γ involvement in alternative PFAS systemic toxicity and immunological disruption. This demonstrates that these compounds can be absorbed through the skin and brings into question whether these PFAS are a suitable alternative to legacy PFAS.

Exposure to the anti-microbial chemical triclosan disrupts keratinocyte function and skin integrity in a model of reconstructed human epidermis.

Triclosan is an anti-microbial chemical incorporated into products that are applied to the skin of healthcare workers. Exposure to triclosan has previously been shown to be associated with allergic disease in humans and impact the immune responses in animal models. Additionally, studies have shown that exposure to triclosan dermally activates the NLRP3 inflammasome and disrupts the skin barrier integrity in mice. The skin is the largest organ of the body and plays an important role as a physical barrier and regulator of the immune system. Alterations in the barrier and immune regulatory functions of the skin have been demonstrated to increase the risk of sensitization and development of allergic disease. In this study, the impact of triclosan exposure on the skin barrier and keratinocyte function was investigated using a model of reconstructed human epidermis. The apical surface of reconstructed human epidermis was exposed to triclosan (0.05-0.2%) once for 6, 24, or 48 h or daily for 5 consecutive days. Exposure to triclosan increased epidermal permeability and altered the expression of genes involved in formation of the skin barrier. Additionally, exposure to triclosan altered the expression patterns of several cytokines and growth factors. Together, these results suggest that exposure to triclosan impacts skin barrier integrity and function of human keratinocytes and suggests that these alterations may impact immune regulation.

Exposure to the immunomodulatory chemical triclosan differentially impacts immune cell populations in the skin of haired (BALB/c) and hairless (SKH1) mice.

Workers across every occupational sector have the potential to be exposed to a wide variety of chemicals, and the skin is a primary route of exposure. Furthermore, exposure to certain chemicals has been linked to inflammatory and allergic diseases. Thus, understanding the immune responses to chemical exposures on the skin and the potential for inflammation and sensitization is needed to improve worker safety and health. Responses in the skin microenvironment impact the potential for sensitization; these responses may include proinflammatory cytokines, inflammasome activation, barrier integrity, skin microbiota, and the presence of immune cells. Selection of specific mouse strains to evaluate skin effects, such as haired (BALB/c) or hairless (SKH1) mice, varies dependent on experimental design and needs of a study. However, dermal chemical exposure may impact reactions in the skin differently depending on the strain of mouse. Additionally, there is a need for established methods to evaluate immune responses in the skin. In this study, exposure to the immunomodulatory chemical triclosan was evaluated in two mouse models using immunophenotyping by flow cytometry and gene expression analysis. BALB/c mice exposed to triclosan (2%) had a higher number and frequency of neutrophils and lower number and frequency of dendritic cells in the skin compared to controls. Although these changes were not observed in SKH1 mice, SKH1 mice exposed to triclosan had a higher number and frequency of type 2 innate lymphoid cells in the skin. Taken together, these results demonstrate that exposure to an immunomodulatory chemical, triclosan, differentially impacts immune cell populations in the skin of haired and hairless mice. Additionally, the flow cytometry panel reported in this manuscript, in combination with gene expression analysis, may be useful in future studies to better evaluate the effect of chemical exposures on the skin immune response. These findings may be important to consider during strain selection, experimental design, and result interpretation of chemical exposures on the skin.

Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification.

BACKGROUND: Key characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents. OBJECTIVES: The goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs. METHODS: A committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity. DISCUSSION: KCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system. https://doi.org/10.1289/EHP10800.

Biological effects of inhaled crude oil. VI. Immunotoxicity.

Crude oil is an unrefined petroleum product that is a mixture of hydrocarbons and other organic material. Studies on the individual components of crude oil and crude oil exposure itself suggest it has immunomodulatory potential. As investigations of the immunotoxicity of crude oil focus mainly on ingestion and dermal exposure, the effects of whole-body inhalation of 300 ppm crude oil vapor [COV; acute inhalation exposure: (6 h × 1 d); or a 28 d sub-chronic exposure (6 h/d × 4 d/wk. × 4 wks)] was investigated 1, 28, and 90 d post-exposure in Sprague-Dawley rats. Acute exposure increased bronchoalveolar lavage (BAL) fluid cellularity, CD4+ and CD8+ cells, and absolute and percent CDllb+ cells only at 1 d post-exposure; additionally, NK cell activity was suppressed. Sub-chronic exposure resulted in a decreased frequency of CD4+ T-cells at 1 d post-exposure and an increased number and frequency of B-cells at 28 d post-exposure in the lung-associated lymph nodes. A significant increase in the number and frequency of B-cells was observed in the spleen at 1 d post-exposure; however, NK cell activity was suppressed at this time point. No effect on cellularity was identified in the BALF. No change in the IgM response to sheep red blood cells was observed. The findings indicate that crude oil inhalation exposure resulted in alterations in cellularity of phenotypic subsets that may impair immune function in rats.

Impact of a Novel Diabetes Support System on a Cohort of Individuals With Type 1 Diabetes Treated With Multiple Daily Injections: A Multicenter Randomized Study.

OBJECTIVE: Achieving optimal glycemic control for many individuals with type 1 diabetes (T1D) remains challenging, even with the advent of newer management tools, including continuous glucose monitoring (CGM). Modern management of T1D generates a wealth of data; however, use of these data to optimize glycemic control remains limited. We evaluated the impact of a CGM-based decision support system (DSS) in patients with T1D using multiple daily injections (MDI). RESEARCH DESIGN AND METHODS: The studied DSS included real-time dosing advice and retrospective therapy optimization. Adults and adolescents (age >15 years) with T1D using MDI were enrolled at three sites in a 14-week randomized controlled trial of MDI + CGM + DSS versus MDI + CGM. All participants (N = 80) used degludec basal insulin and Dexcom G5 CGM. CGM-based and patient-reported outcomes were analyzed. Within the DSS group, ad hoc analysis further contrasted active versus nonactive DSS users. RESULTS: No significant differences were detected between experimental and control groups (e.g., time in range [TIR] +3.3% with CGM vs. +4.4% with DSS). Participants in both groups reported lower HbA1c (-0.3%; P = 0.001) with respect to baseline. While TIR may have improved in both groups, it was statistically significant only for DSS; the same was apparent for time spent <60 mg/dL. Active versus nonactive DSS users showed lower risk of and exposure to hypoglycemia with system use. CONCLUSIONS: Our DSS seems to be a feasible option for individuals using MDI, although the glycemic benefits associated with use need to be further investigated. System design, therapy requirements, and target population should be further refined prior to use in clinical care.

Systemic toxicity induced by topical application of heptafluorobutyric acid (PFBA) in a murine model.

Heptafluorobutyric acid (PFBA) is a synthetic chemical belonging to the per- and polyfluoroalkyl substances (PFAS) group that includes over 5000 chemicals incorporated into numerous products. PFBA is a short-chain PFAS (C4) labeled as a safer alternative to legacy PFAS which have been linked to numerous health effects. Despite the high potential for dermal exposure, occupationally and environmentally, dermal exposure studies are lacking. Using a murine model, this study analyzed serum chemistries, histology, immune phenotyping, and gene expression to evaluate the systemic toxicity of sub-chronic dermal PFBA 15-day (15% v/v or 375 mg/kg/dose) or 28-day (3.75-7.5% v/v or 93.8-187.5 mg/kg/dose) exposures. PFBA exposure produced significant increases in liver and kidney weights and altered serum chemistries (all exposure levels). Immune-cell phenotyping identified significant increases in draining lymph node B-cells (15%) and CD11b + cells (3.75-15%) and skin T-cells (3.75-15%) and neutrophils (7.5-15%). Histopathological and gene expression changes were observed in both the liver and skin after dermal PFBA exposure. The findings indicate PFBA induces liver toxicity and alterations of PPAR target genes, suggesting a role of a PPAR pathway. These results demonstrate that sustained dermal exposure to PFBA induces systemic effects and raise concerns of short-chain PFAS being promoted as safer alternatives.

Dermal Exposure to the Immunomodulatory Antimicrobial Chemical Triclosan Alters the Skin Barrier Integrity and Microbiome in Mice.

Triclosan is an antimicrobial chemical used in healthcare settings that can be absorbed through the skin. Exposure to triclosan has been positively associated with food and aeroallergy and asthma exacerbation in humans and, although not directly sensitizing, has been demonstrated to augment the allergic response in a mouse model of asthma. The skin barrier and microbiome are thought to play important roles in regulating inflammation and allergy and disruptions may contribute to development of allergic disease. To investigate potential connections of the skin barrier and microbiome with immune responses to triclosan, SKH1 mice were exposed dermally to triclosan (0.5-2%) or vehicle for up to 7 consecutive days. Exposure to 2% triclosan for 5-7 days on the skin was shown to increase transepidermal water loss levels. Seven days of dermal exposure to triclosan decreased filaggrin 2 and keratin 10 expression, but increased filaggrin and keratin 14 protein along with the danger signal S100a8 and interleukin-4. Dermal exposure to triclosan for 7 days also altered the alpha and beta diversity of the skin and gut microbiome. Specifically, dermal triclosan exposure increased the relative abundance of the Firmicutes family, Lachnospiraceae on the skin but decreased the abundance of Firmicutes family, Ruminococcaceae in the gut. Collectively, these results demonstrate that repeated dermal exposure to the antimicrobial chemical triclosan alters the skin barrier integrity and microbiome in mice, suggesting that these changes may contribute to the increase in allergic immune responses following dermal exposure to triclosan.

Decoding influenza outbreaks in a rural region of the USA with archetypal analysis.

We present the first application of archetypal analysis for influenza data from 2010 to 2018 in Montana, USA. Using archetypes, we decompose the data into spatial and temporal components, allowing for a more informed analysis of spatial-temporal dynamic trends during an influenza season. Initially, we reduce the dimension of the set of counties by using a mutual information measure on the influenza time series to create a smaller, maximal mutual information network. Archetypal analysis then describes the relationship between influenza cases across counties and regions in Montana. Finally, we discuss the potential implications this analysis can have for infectious disease modeling, particularly where data is sparse and limited.

Laboratory Techniques for Identifying Causes of Allergic Dermatitis.

This article reviews the laboratory's role in identifying causes of chemical-induced allergic dermatitis. Several topics will be discussed. Allergen hazard identification refers to testing of chemicals for their sensitization potential. Animal-based, in silico, in chemico, and in vitro tests have been developed to identify the skin sensitization hazard of potential chemical allergens, but only a few of these are accepted by regulatory agencies. Laboratory investigations have also evaluated the stability of several commercially available allergic contact dermatitis patch tests. Such studies are considered product testing and are usually conducted in analytical chemistry laboratories.

Timeliness of Early Childhood Vaccinations and Undervaccination Patterns in Montana.

INTRODUCTION: Early childhood vaccination rates are lower in rural areas than those in urban areas of the U.S. This study's objective is to quantify vaccine timeliness and the prevalence of undervaccination patterns in Montana and to measure the associations between timeliness and series completion by age 24 months. METHODS: Using records from January 2015 to November 2019 in Montana's centralized immunization information system, days undervaccinated were calculated for the combined 7-vaccine series. Undervaccination patterns indicative of certain barriers to vaccination, including parental vaccine hesitancy, were identified. Using multivariable log-linked binomial regression, the association between timing of vaccine delay and not completing the combined 7-vaccine series by age 24 months was assessed. Analyses were conducted in March 2020-August 2020. RESULTS: Among 31,422 children, 38.0% received all vaccine doses on time; 24.3% received all doses, but some were received late; and 37.7% had not completed the combined 7-vaccine series. Approximately 18.7% had an undervaccination pattern suggestive of parental vaccine hesitancy, and 19.7% started all series but were missing doses needed for multidose series completion. Although falling behind on vaccinations at any age was associated with failing to complete the combined 7-vaccine series, being late at age 12-15 months had the strongest association (adjusted prevalence ratio=3.73, 95% CI=3.56, 3.91) compared with being on time at age 12-15 months. CONCLUSIONS: Fewer than 2 in 5 Montana children were fully vaccinated on time for the combined 7-vaccine series. To increase vaccination rates, initiatives to increase vaccine confidence and remind parents to complete vaccine series are needed.

COVID-19 Incidence and Mortality Among American Indian/Alaska Native and White Persons - Montana, March 13-November 30, 2020.

Geographic differences in infectious disease mortality rates have been observed among American Indian or Alaska Native (AI/AN) persons in the United States (1), and aggregate analyses of data from selected U.S. states indicate that COVID-19 incidence and mortality are higher among AI/AN persons than they are among White persons (2,3). State-level data could be used to identify disparities and guide local efforts to reduce COVID-19-associated incidence and mortality; however, such data are limited. Reports of laboratory-confirmed COVID-19 cases and COVID-19-associated deaths reported to the Montana Department of Public Health and Human Services (MDPHHS) were analyzed to describe COVID-19 incidence, mortality, and case-fatality rates among AI/AN persons compared with those among White persons. During March-November 2020 in Montana, the estimated cumulative COVID-19 incidence among AI/AN persons (9,064 cases per 100,000) was 2.2 times that among White persons (4,033 cases per 100,000).* During the same period, the cumulative COVID-19 mortality rate among AI/AN persons (267 deaths per 100,000) was 3.8 times that among White persons (71 deaths per 100,000). The AI/AN COVID-19 case-fatality rate (29.4 deaths per 1,000 COVID-19 cases) was 1.7 times the rate in White persons (17.0 deaths per 1,000). State-level surveillance findings can help in developing state and tribal COVID-19 vaccine allocation strategies and assist in local implementation of culturally appropriate public health measures that might help reduce COVID-19 incidence and mortality in AI/AN communities.

Topical exposure to triclosan inhibits Th1 immune responses and reduces T cells responding to influenza infection in mice.

Healthcare workers concurrently may be at a higher risk of developing respiratory infections and allergic disease, such as asthma, than the general public. Increased incidence of allergic diseases is thought to be caused, in part, due to occupational exposure to chemicals that induce or augment Th2 immune responses. However, whether exposure to these chemical antimicrobials can influence immune responses to respiratory pathogens is unknown. Here, we use a BALB/c murine model to test if the Th2-promoting antimicrobial chemical triclosan influences immune responses to influenza A virus. Mice were dermally exposed to 2% triclosan for 7 days prior to infection with a sub-lethal dose of mouse adapted PR8 A(H1N1) virus (50 pfu); triclosan exposure continued until 10 days post infection (dpi). Infected mice exposed to triclosan did not show an increase in morbidity or mortality, and viral titers were unchanged. Assessment of T cell responses at 10 dpi showed a decrease in the number of total and activated (CD44hi) CD4+ and CD8+ T cells at the site of infection (BAL and lung) in triclosan exposed mice compared to controls. Influenza-specific CD4+ and CD8+ T cells were assessed using MHCI and MHCII tetramers, with reduced populations, although not reaching statistical significance at these sites following triclosan exposure. Reductions in the Th1 transcription factor T-bet were seen in both activated and tetramer+ CD4+ and CD8+ T cells in the lungs of triclosan exposed infected mice, indicating reduced Th1 polarization and providing a potential mechanism for numerical reduction in T cells. Overall, these results indicate that the immune environment induced by triclosan exposure has the potential to influence the developing immune response to a respiratory viral infection and may have implications for healthcare workers who may be at an increased risk for developing infectious diseases.

Biological effects of inhaled hydraulic fracturing sand dust. VIII. Immunotoxicity.

Hydraulic fracturing ("fracking") is a process used to enhance retrieval of gas from subterranean natural gas-laden rock by fracturing it under pressure. Sand used to stabilize fissures and facilitate gas flow creates a potential occupational hazard from respirable fracking sand dust (FSD). As studies of the immunotoxicity of FSD are lacking, the effects of whole-body inhalation (6 h/d for 4 d) of a FSD, i.e., FSD 8, was investigated at 1, 7, and 27 d post-exposure in rats. Exposure to 10 mg/m3 FSD 8 resulted in decreased lung-associated lymph node (LLN) cellularity, total B-cells, CD4+ T-cells, CD8+ T-cells and total natural killer (NK) cells at 7-d post exposure. The frequency of CD4+ T-cells decreased while the frequency of B-cells increased (7 and 27 d) in the LLN. In contrast, increases in LLN cellularity and increases in total CD4+ and CD8+ T-cells were observed in rats following 30 mg/m3 FSD 8 at 1 d post-exposure. Increases in the frequency and number of CD4+ T-cells and NK cells were observed in bronchial alveolar lavage fluid at 7-d post-exposure (10 mg/m3) along with an increase in total CD4+ T-cells, CD11b + cells, and NK cells at 1-day post-exposure (30 mg/m3). Increases in the numbers of B-cells and CD8+ T-cells were observed in the spleen at 1-day post 30 mg/m3 FSD 8 exposure. In addition, NK cell activity was suppressed at 1 d (30 mg/m3) and 27 d post-exposure (10 mg/m3). No change in the IgM response to sheep red blood cells was observed. The findings indicate that FSD 8 caused alterations in cellularity, phenotypic subsets, and impairment of immune function.