Are we overtreating intraductal papillomas?

BACKGROUND: The management of intraductal papillomas (IDPs) diagnosed on core needle biopsy (CNB) remains controversial regarding whether excision is required. We evaluated whether excision of IDPs might be overtreatment based on a consecutive patient population where all IDPs were routinely excised. MATERIALS AND METHODS: We retrospectively reviewed the records of consecutive patients treated with excision of IDPs at our institution from 2009 to 2016. We evaluated the rate of upgrade of IDPs on CNB and factors predicting for malignant upgrade. RESULTS: Of 153 CNB specimens, 136 (88.9%) were IDPs without atypia and 14 (9.2%) showed atypia. The overall upgrade rate on final pathology was 7.3% with 1.3% for invasive cancer, 2.7% for ductal carcinoma in situ, and 3.3% for atypical ductal hyperplasia. Of the 14 patients with atypia on CNB, two of these patients (14.2%) were found to have ductal carcinoma in situ. In the absence of atypia on CNB, upgrade rates were 1.5% for invasive and 1.5% for in situ carcinoma. Personal history of breast cancer and magnetic resonance imaging-guided biopsy predicted for malignant upgrade. CONCLUSIONS: IDPs on CNB have a low chance of harboring an occult malignancy. Given the low probability of upgrade to invasive breast cancer, it is reasonable to consider watchful surveillance in the absence of a prior personal history of breast cancer or atypia on CNB.

Dogs in the Workplace: A Review of the Benefits and Potential Challenges.

Pet dogs, therapy dogs, and service dogs can be seen in workplaces with increasing frequency. Although dogs may provide many benefits to employees and employers, their presence may introduce additional hazards and concerns to the work environment. Therefore, decisions to accept dogs in the workplace may include many considerations including the health, safety, and well-being of employees, legal and cultural sensitivities, and animal welfare. The present paper serves to introduce the issue of dogs in the workplace and outline the potential benefits and challenges to their presence. The legal accommodations afforded to certain types of dogs in workplace settings are discussed, and the research findings pertaining to the potential benefits of dogs on human health and well-being are summarized. The paper concludes with considerations for human resource management personnel in the areas of diversity, employee relations, ethics and corporate responsibility, organizational and employee development, safety and security, and legal considerations, as well as suggested topics for future research.

Evaluation of the irritancy and hypersensitivity potential following topical application of didecyldimethylammonium chloride.

Didecyldimethylammonium chloride (DDAC) is a dialkyl-quaternary ammonium compound that is used in numerous products for its bactericidal, virucidal and fungicidal properties. There have been clinical reports of immediate and delayed hypersensitivity reactions in exposed individuals; however, the sensitization potential of DDAC has not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAC following dermal exposure in a murine model. DDAC induced significant irritancy (0.5 and 1%), evaluated by ear swelling in female Balb/c mice. Initial evaluation of the sensitization potential was conducted using the local lymph node assay (LLNA) at concentrations ranging from 0.0625-1%. A concentration-dependent increase in lymphocyte proliferation was observed with a calculated EC3 value of 0.17%. Dermal exposure to DDAC did not induce increased production of IgE as evaluated by phenotypic analysis of draining lymph node B-cells (IgE (+) B220(+)) and measurement of total serum IgE levels. Additional phenotypic analyses revealed significant and dose-responsive increases in the absolute number of B-cells, CD4 (+) T-cells, CD8 (+) T-cells and dendritic cells in the draining lymph nodes, along with significant increases in the percentage of B-cells (0.25% and 1% DDAC) at Day 10 following 4 days of dermal exposure. There was also a significant and dose-responsive increase in the number of activated CD44 (+) CD4 (+) and CD8 (+) T-cells and CD86 (+) B-cells and dendritic cells following exposure to all concentrations of DDAC. These results demonstrate the potential for development of irritation and hypersensitivity responses to DDAC following dermal exposure and raise concerns about the use of this chemical and other quaternary ammonium compounds that may elicit similar effects.

A Role for Regulatory T Cells in a Murine Model of Epicutaneous Toluene Diisocyanate Sensitization.

Toluene diisocyanate (TDI) is a leading cause of chemical-induced occupational asthma which impacts workers in a variety of industries worldwide. Recently, the robust regulatory potential of regulatory T cells (Tregs) has become apparent, including their functional role in the regulation of allergic disease; however, their function in TDI-induced sensitization has not been explored. To elucidate the kinetics, phenotype, and function of Tregs during TDI sensitization, BALB/c mice were dermally exposed (on each ear) to a single application of TDI (0.5-4% v/v) or acetone vehicle and endpoints were evaluated via RT-PCR and flow cytometry. The draining lymph node (dLN) Treg population expanded significantly 4, 7, and 9 days after single 4% TDI exposure. This population was identified using a variety of surface and intracellular markers and was found to be phenotypically heterogeneous based on increased expression of markers including CD103, CCR6, CTLA4, ICOS, and Neuropilin-1 during TDI sensitization. Tregs isolated from TDI-sensitized mice were significantly more suppressive compared with their control counterparts, further supporting a functional role for Tregs during TDI sensitization. Last, Tregs were depleted prior to TDI sensitization and an intensified sensitization response was observed. Collectively, these data indicate that Tregs exhibit a functional role during TDI sensitization. Because the role of Tregs in TDI sensitization has not been previously elucidated, these data contribute to the understanding of the immunologic mechanisms of chemical induced allergic disease.

Investigations of immunotoxicity and allergic potential induced by topical application of triclosan in mice.

Triclosan is an antimicrobial chemical commonly used occupationally and by the general public. Using select immune function assays, the purpose of these studies was to evaluate the immunotoxicity of triclosan following dermal exposure using a murine model. Triclosan was not identified to be a sensitizer in the murine local lymph node assay (LLNA) when tested at concentrations ranging from 0.75-3.0%. Following a 28-day exposure, triclosan produced a significant increase in liver weight at concentrations of ≥ 1.5%. Exposure to the high dose (3.0%) also produced a significant increase in spleen weights and number of platelets. The absolute number of B-cells, T-cells, dendritic cells and NK cells were significantly increased in the skin draining lymph node, but not the spleen. An increase in the frequency of dendritic cells was also observed in the lymph node following exposure to 3.0% triclosan. The IgM antibody response to sheep red blood cells (SRBC) was significantly increased at 0.75% - but not at the higher concentrations - in the spleen and serum. These results demonstrate that dermal exposure to triclosan induces stimulation of the immune system in a murine model and raise concerns about potential human exposure.

Investigations into the Immunotoxicity and Allergic Potential Induced by Topical Application of N-Butylbenzenesulfonamide (NBBS) in a Murine Model.

N-Butylbenzene sulfonamide (NBBS) is a commonly used plasticizer found in numerous products. Due to its extensive use, lack of adequate toxicological data, and suspicion of toxicity based on the presence of structural alerts, it was nominated to the National Toxicology Program for comprehensive toxicological testing. The purpose of this study was to evaluate the potential for hypersensitivity and immune suppression following dermal exposure to NBBS using a murine model. NBBS tested negative in a combined irritancy/local lymph node assay (LLNA), classifying it as nonirritating and nonsensitizing. To estimate the immunosuppressive potential of NBBS, assays that assessed immunotoxicity were performed, including the immumnoglobulin (Ig) M response to T-cell-dependent antigen sheep red blood cells (SRBC), using the plaque-forming cell (PFC) assay and immune cell phenotyping. After a 28-d treatment with NBBS, mice exposed to the lowest concentration (25% NBBS) showed a significant increase in IgM-producing B cells in the spleen. No marked changes were identified in immune cell markers in the lymph node. In contrast to body weight, a significant elevation in kidney and liver weight was observed following dermal exposure to all concentrations of NBBS. These results demonstrate that dermal exposure to NBBS, other than liver and kidney toxicity, did not apparently induce immunotoxicity in a murine model.

Triclosan Induces Thymic Stromal Lymphopoietin in Skin Promoting Th2 Allergic Responses.

Triclosan is an antimicrobial chemical incorporated into many personal, medical and household products. Approximately, 75% of the U.S. population has detectable levels of triclosan in their urine, and although it is not typically considered a contact sensitizer, recent studies have begun to link triclosan exposure with augmented allergic disease. We examined the effects of dermal triclosan exposure on the skin and lymph nodes of mice and in a human skin model to identify mechanisms for augmenting allergic responses. Triclosan (0%-3%) was applied topically at 24-h intervals to the ear pinnae of OVA-sensitized BALB/c mice. Skin and draining lymph nodes were evaluated for cellular responses and cytokine expression over time. The effects of triclosan (0%-0.75%) on cytokine expression in a human skin tissue model were also examined. Exposure to triclosan increased the expression of TSLP, IL-1ß, and TNF-α in the skin with concomitant decreases in IL-25, IL-33, and IL-1α. Similar changes in TSLP, IL1B, and IL33 expression occurred in human skin. Topical application of triclosan also increased draining lymph node cellularity consisting of activated CD86(+)GL-7(+) B cells, CD80(+)CD86(+) dendritic cells, GATA-3(+)OX-40(+)IL-4(+)IL-13(+) Th2 cells and IL-17 A(+) CD4 T cells. In vivo antibody blockade of TSLP reduced skin irritation, IL-1ß expression, lymph node cellularity, and Th2 responses augmented by triclosan. Repeated dermal exposure to triclosan induces TSLP expression in skin tissue as a potential mechanism for augmenting allergic responses.

Immune stimulation following dermal exposure to unsintered indium tin oxide.

In recent years, several types of pulmonary pathology, including alveolar proteinosis, fibrosis, and emphysema, have been reported in workers in the indium industry. To date, there remains no clear understanding of the underlying mechanism(s). Pulmonary toxicity studies in rats and mice have demonstrated the development of mediastinal lymph node hyperplasia and granulomas of mediastinal lymph nodes and bronchus-associated lymphoid tissues following exposure to indium tin oxide. Given the association between exposure to other metals and the development of immune-mediated diseases, these studies were undertaken to begin to investigate the immuno-modulatory potential of unsintered indium tin oxide (uITO) in a mouse model. Using modifications of the local lymph node assay, BALB/c mice (five animals/group) were exposed topically via intact or breached skin or injected intradermally at the base of the ear pinnae with either vehicle or increasing concentrations 2.5-10% uITO (90:10 indium oxide/tin oxide, particle size <50 nm). Dose-responsive increases in lymphocyte proliferation were observed with a calculated EC3 of 4.7% for the intact skin study. Phenotypic analysis of draining lymph node cells following intradermal injection with 5% uITO yielded a profile consistent with a T-cell-mediated response. These studies demonstrate the potential for uITO to induce sensitization and using lymphocyte proliferation as a biomarker of exposure, and demonstrate the potential for uITO to penetrate both intact and breached skin.

Potential health effects associated with dermal exposure to occupational chemicals.

There are a large number of workers in the United States, spanning a variety of occupational industries and sectors, who are potentially exposed to chemicals that can be absorbed through the skin. Occupational skin exposures can result in numerous diseases that can adversely affect an individual's health and capacity to perform at work. In general, there are three types of chemical-skin interactions of concern: direct skin effects, immune-mediated skin effects, and systemic effects. While hundreds of chemicals (metals, epoxy and acrylic resins, rubber additives, and chemical intermediates) present in virtually every industry have been identified to cause direct and immune-mediated effects such as contact dermatitis or urticaria, less is known about the number and types of chemicals contributing to systemic effects. In an attempt to raise awareness, skin notation assignments communicate the potential for dermal absorption; however, there is a need for standardization among agencies to communicate an accurate description of occupational hazards. Studies have suggested that exposure to complex mixtures, excessive hand washing, use of hand sanitizers, high frequency of wet work, and environmental or other factors may enhance penetration and stimulate other biological responses altering the outcomes of dermal chemical exposure. Understanding the hazards of dermal exposure is essential for the proper implementation of protective measures to ensure worker safety and health.

Expression kinetics of miRNA involved in dermal toluene 2,4-diisocyanate sensitization.

Allergic disease is an important occupational health concern, with work-related asthma and allergic contact dermatitis being the most frequently diagnosed occupational illnesses. Diisocyanates, particularly toluene 2,4-diisocyanate (TDI), have been the leading cause of occupational asthma for many years. Understanding the mechanisms behind allergic disease is critical for treatment and prevention. Recently, the study of post-transcriptional regulation by microRNAs (miRNA) has shed light on mechanisms of allergic disease. The present studies report the expression of miRNA during the sensitization phase of an allergic response to TDI in a murine model. Female BALB/c mice were dermally exposed to TDI (0.1-15% [v/v]) or vehicle. RNA was isolated from superficial parotid lymph nodes at timepoints between 1 h and 15 days post-exposure and then miRNA expression was analyzed using array and real-time quantitative PCR analysis. Consistent changes in miRNA expression were identified for miR-21, miR-22, miR-27b, miR-31, miR-126, miR-155, miR-210, and miR-301a. Following TDI exposure, peak expression was observed by Day 4 for the majority of miRNA evaluated with trends in expression correlated to exposure concentration. Confirmed and predicted targets were identified using Diana-microT, miRanda, miRwalk, and Targetscan algorithms. Evaluation of mRNA expression of cytokine and transcription factor targets suggests that miRNA may have a central role early in TDI sensitization. Understanding the role of these miRNA and their specific mechanism of action in sensitization to TDI may provide pertinent information for the identification of other chemical sensitizers while also contributing to the treatment and prevention of allergic disease.

A revised taxonomy of assistance animals.

The use of animals in various assistive, therapeutic, and emotional support roles has contributed to the uncoordinated expansion of labels used to distinguish these animals. To address the inconsistent vocabulary and confusion, this article proposes a concise taxonomy for classifying assistance animals. Several factors were identified to differentiate categories, including (1) whether the animal performs work or tasks related to an individual's disability; (2) the typical level of skill required by the animal performing the work or task; (3) whether the animal is used by public service, military, or healthcare professionals; (4) whether training certifications or standards are available; and (5) the existence of legal public access protections for the animal and handler. Acknowledging that some category labels have already been widely accepted or codified, six functional categories were identified: (1) service animal; (2) public service animal; (3) therapy animal; (4) visitation animal; (5) sporting, recreational, or agricultural animal; and (6) support animal. This taxonomy provides a clear vocabulary for use by consumers, professionals working in the field, researchers, policy makers, and regulatory agencies.

Evaluation of the hypersensitivity potential of alternative butter flavorings.

Concern has been raised over the association of diacetyl with lung disease clinically resembling bronchiolitis obliterans in food manufacturing workers. This has resulted in the need for identification of alternative chemicals to be used in the manufacturing process. Structurally similar chemicals, 2,3-pentanedione, 2,3-hexanedione, 3,4-hexanedione and 2,3-heptanedione, used as constituents of synthetic flavoring agents have been suggested as potential alternatives for diacetyl, however, immunotoxicity data on these chemicals are limited. The present study evaluated the dermal irritation and sensitization potential of diacetyl alternatives using a murine model. None of the chemicals were identified as dermal irritants when tested at concentrations up to 50%. Similar to diacetyl (EC3=17.9%), concentration-dependent increases in lymphocyte proliferation were observed following exposure to all four chemicals, with calculated EC3 values of 15.4% (2,3-pentanedione), 18.2% (2,3-hexanedione), 15.5% (3,4-hexanedione) and 14.1% (2,3-heptanedione). No biologically significant elevations in local or total serum IgE were identified after exposure to 25-50% concentrations of these chemicals. These results demonstrate the potential for development of hypersensitivity responses to these proposed alternative butter flavorings and raise concern about the use of structurally similar replacement chemicals. Additionally, a contaminant with strong sensitization potential was found in varying concentrations in diacetyl obtained from different producers.

Connectivity planning to address climate change.

As the climate changes, human land use may impede species from tracking areas with suitable climates. Maintaining connectivity between areas of different temperatures could allow organisms to move along temperature gradients and allow species to continue to occupy the same temperature space as the climate warms. We used a coarse-filter approach to identify broad corridors for movement between areas where human influence is low while simultaneously routing the corridors along present-day spatial gradients of temperature. We modified a cost-distance algorithm to model these corridors and tested the model with data on current land-use and climate patterns in the Pacific Northwest of the United States. The resulting maps identified a network of patches and corridors across which species may move as climates change. The corridors are likely to be robust to uncertainty in the magnitude and direction of future climate change because they are derived from gradients and land-use patterns. The assumptions we applied in our model simplified the stability of temperature gradients and species responses to climate change and land use, but the model is flexible enough to be tailored to specific regions by incorporating other climate variables or movement costs. When used at appropriate resolutions, our approach may be of value to local, regional, and continental conservation initiatives seeking to promote species movements in a changing climate. Planificación de Conectividad para Atender el Cambio Climático.

Immunotoxicity and allergic potential induced by topical application of dimethyl carbonate (DMC) in a murine model.

Dimethyl carbonate (DMC) is an industrial chemical, used as a paint and adhesive solvent, with the potential for significant increases in production. Using select immune function assays, the purpose of these studies was to evaluate the immunotoxicity of DMC following dermal exposure using a murine model. Following a 28-day exposure, DMC produced a significant decrease in thymus weight at concentrations of 75% and greater. No effects on body weight, hematological parameters (erythrocytes, leukocytes, and their differentials), or immune cell phenotyping (B-cells, T-cells, and T-cell sub-sets) were identified. The IgM antibody response to sheep red blood cell (SRBC) was significantly reduced in the spleen but not the serum. DMC was not identified to be an irritant and evaluation of the sensitization potential, conducted using the local lymph node assay (LLNA) at concentrations ranging from 50-100%, did not identify increases in lymphocyte proliferation. These results demonstrate that dermal exposure to DMC induces immune suppression in a murine model and raise concern about potential human exposure and the need for occupational exposure regulations.

Exposure to triclosan augments the allergic response to ovalbumin in a mouse model of asthma.

During the last decade, there has been a remarkable and unexplained increase in the prevalence of asthma. These studies were conducted to investigate the role of dermal exposure to triclosan, an endocrine-disrupting compound, on the hypersensitivity response to ovalbumin (OVA) in a murine model of asthma. Triclosan has had widespread use in the general population as an antibacterial and antifungal agent and is commonly found in consumer products such as soaps, deodorants, toothpastes, shaving creams, mouthwashes, and cleaning supplies. For these studies, BALB/c mice were exposed dermally to concentrations of triclosan ranging from 0.75 to 3% (0.375-1.5mg/mouse/day) for 28 consecutive days. Concordantly, mice were ip injected with OVA (0.9 µg) and aluminum hydroxide (0.5mg) on days 1 and 10 and challenged with OVA (125 µg) by pharyngeal aspiration on days 19 and 27. Compared with the animals exposed to OVA alone, increased spleen weights, OVA-specific IgE, interleukin-13 cytokine levels, and numbers of lung eosinophils were demonstrated when mice were coexposed to OVA and triclosan. Statistically significant increases in OVA-specific and nonspecific airway hyperreactivity were observed for all triclosan coexposed groups compared with the vehicle and OVA controls. In these studies, exposure to triclosan alone was not demonstrated to be allergenic; however, coexposure with a known allergen resulted in enhancement of the hypersensitivity response to that allergen, suggesting that triclosan exposure may augment the allergic responses to other environmental allergens.

Toxicological analysis of limonene reaction products using an in vitro exposure system.

Epidemiological investigations suggest a link between exposure to indoor air chemicals and adverse health effects. Consumer products contain reactive chemicals which can form secondary pollutants which may contribute to these effects. The reaction of limonene and ozone is a well characterized example of this type of indoor air chemistry. The studies described here characterize an in vitro model using an epithelial cell line (A549) or differentiated epithelial tissue (MucilAir™). The model is used to investigate adverse effects following exposure to combinations of limonene and ozone. In A549 cells, exposure to both the parent compounds and reaction products resulted in alterations in inflammatory cytokine production. A one hour exposure to limonene+ozone resulted in decreased proliferation when compared to cells exposed to limonene alone. Repeated dose exposures of limonene or limonene+ozone were conducted on MucilAir™ tissue. No change in proliferation was observed but increases in cytokine production were observed for both the parent compounds and reaction products. Factors such as exposure duration, chemical concentration, and sampling time point were identified to influence result outcome. These findings suggest that exposure to reaction products may produce more severe effects compared to the parent compound.

Irritancy and allergic responses induced by exposure to the indoor air chemical 4-oxopentanal.

Over the last two decades, there has been an increasing awareness regarding the potential impact of indoor air pollution on human health. People working in an indoor environment often experience symptoms such as eye, nose, and throat irritation. Investigations into these complaints have ascribed the effects, in part, to compounds emitted from building materials, cleaning/consumer products, and indoor chemistry. One suspect indoor air contaminant that has been identified is the dicarbonyl 4-oxopentanal (4-OPA). 4-OPA is generated through the ozonolysis of squalene and several high-volume production compounds that are commonly found indoors. Following preliminary workplace sampling that identified the presence of 4-OPA, these studies examined the inflammatory and allergic responses to 4-OPA following both dermal and pulmonary exposure using a murine model. 4-OPA was tested in a combined local lymph node assay and identified to be an irritant and sensitizer. A Th1-mediated hypersensitivity response was supported by a positive response in the mouse ear swelling test. Pulmonary exposure to 4-OPA caused a significant elevation in nonspecific airway hyperreactivity, increased numbers of lung-associated lymphocytes and neutrophils, and increased interferon-γ production by lung-associated lymph nodes. These results suggest that both dermal and pulmonary exposure to 4-OPA may elicit irritant and allergic responses and may help to explain some of the adverse health effects associated with poor indoor air quality.