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Purpose of Review: This review summarizes the recent literature on the long-term outcome of sensitizer-induced and irritant-induced occupational asthma., Recent Findings: Recent studies of sensitizer-induced occupational asthma show that after the offending exposure has ceased, most patients report at least partial relief of symptoms. However, in the long term, the diagnosis may negatively impact their careers, incomes, and quality of life. The studies also offer new insights into diisocyanate-induced occupational asthma phenotypes and asthma remission rates. One third of these cases were in remission in long-term after reduction or cessation of exposure. The long-term prognosis of irritant-induced occupational asthma was demonstrated to be poorer than sensitizer-induced occupational asthma. Older age, low fractional exhaled nitric oxide levels and uncontrolled asthma at the time of diagnosis predicted uncontrolled asthma in the long term in patients with irritant and low-molecular-weight sensitizer induced occupational asthma., Summary: Recent studies provide further evidence of the long-term outcome of different occupational asthma phenotypes and the factors that affect them. These findings help us identify patients at risk of poor asthma outcomes, who need close monitoring and support. It should also be borne in mind that occupational asthma diagnosis may have wider-ranging negative impacts on patients' lives., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The impact of chronic occupational exposures to irritants on asthma remains discussed. We studied the associations between occupational exposures and asthma, with specific interest for chronic exposure to irritants, including disinfectants and cleaning products (DCPs) and solvents., Methods: Cross-sectional analyses included 115 540 adults (55% women, mean age 43 years, 10% current asthma) working at inclusion in the French population-based CONSTANCES cohort (2012-2020). Current asthma was defined by ever asthma with symptoms, medication or asthma attacks (past 12 months), and the asthma symptom score by the sum of 5 respiratory symptoms (past 12 months). Both lifetime and current occupational exposures were assessed by the Occupational Asthma-specific Job-Exposure Matrix. Associations were evaluated by gender using logistic and binomial negative regressions adjusted for age, smoking status and body mass index., Results: In women, associations were observed between current asthma and lifetime exposure to irritants (OR 1.05, 95% CI 1.00 to 1.11), DCPs (1.06, 95% CI 1.00 to 1.12) and solvents (1.06, 95% CI 0.98 to 1.14). In men, only lifetime exposure to DCPs (1.10, 95% CI 1.01 to 1.20) was associated with current asthma. Lifetime exposure to irritants was associated with higher asthma symptom score both in women (mean score ratio: 1.08, 95% CI 1.05 to 1.11) and men (1.11, 95% CI 1.07 to 1.15), especially for DCPs (women: 1.09, 95% CI 1.06 to 1.13, men: 1.21, 95% CI 1.15 to 1.27) and solvents (women 1.14, 95% CI 1.10 to 1.19, men: 1.10, 95% CI 1.05 to 1.15). For current exposures, no consistent associations were observed with current asthma and asthma symptom score., Conclusions: Lifetime occupational exposures to irritants were associated with current asthma and higher asthma symptom score. These exposures should be carefully considered in asthma management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Sulfur mustard (SM), a vesicating agent first used during World War I, remains a potent threat as a chemical weapon to cause intentional/accidental chemical emergencies. Eyes are extremely susceptible to SM toxicity. Nitrogen mustard (NM), a bifunctional alkylating agent and potent analog of SM, is used in laboratories to study mustard vesicant-induced ocular toxicity. Previously, we showed that SM-/NM-induced injuries (in vivo and ex vivo rabbit corneas) are reversed upon treatment with dexamethasone (DEX), a US Food and Drug Administration-approved, steroidal anti-inflammatory drug. Here, we optimized NM injuries in ex vivo human corneas and assessed DEX efficacy. For injury optimization, one cornea (randomly selected from paired eyes) was exposed to NM: 100 nmoles for 2 hours or 4 hours, and 200 nmoles for 2 hours, and the other cornea served as a control. Injuries were assessed 24 hours post NM-exposure. NM 100 nmoles exposure for 2 hours was found to cause optimal corneal injury (epithelial thinning [∼69%]; epithelial-stromal separation [6-fold increase]). In protein arrays studies, 24 proteins displayed ≥40% change in their expression in NM exposed corneas compared with controls. DEX administration initiated 2 hours post NM exposure and every 8 hours thereafter until 24 hours post-exposure reversed NM-induced corneal epithelial-stromal separation [2-fold decrease]). Of the 24 proteins dysregulated upon NM exposure, six proteins (delta-like canonical Notch ligand 1, FGFbasic, CD54, CCL7, endostatin, receptor tyrosine-protein kinase erbB-4) associated with angiogenesis, immune/inflammatory responses, and cell differentiation/proliferation, showed significant reversal upon DEX treatment (Student's t test; P ≤ 0.05). Complementing our animal model studies, DEX was shown to mitigate vesicant-induced toxicities in ex vivo human corneas. SIGNIFICANCE STATEMENT: Nitrogen mustard (NM) exposure-induced injuries were optimized in an ex vivo human cornea culture model and studies were carried out at 24 h post 100 nmoles NM exposure. Dexamethasone (DEX) administration (started 2 h post NM exposure and every 8 h thereafter) reversed NM-induced corneal injuries. Molecular mediators of DEX action were associated with angiogenesis, immune/inflammatory responses, and cell differentiation/proliferation, indicating DEX aids wound healing via reversing vesicant-induced neovascularization (delta-like canonical Notch ligand 1 and FGF basic) and leukocyte infiltration (CD54 and CCL7)., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Burn injuries including those caused by chemicals can result in systemic effects and acute lung injury (ALI). Cutaneous exposure to Lewisite, a warfare and chemical burn agent, also causes ALI. To overcome the limitations in conducting direct research on Lewisite-induced ALI in a laboratory setting, an animal model was developed using phenylarsine oxide (PAO) as a surrogate for Lewisite. Due to lack of a reliable animal model mimicking the effects of such exposures, development of effective therapies to treat such injuries is challenging. We demonstrated that a single cutaneous exposure to PAO resulted in disruption of the alveolar-capillary barrier as evidenced by elevated protein levels in the bronchoalveolar lavage fluid (BALF). BALF supernatant of PAO-exposed animals had increased levels of high mobility group box 1, a damage associated molecular pattern molecule. Arterial blood-gas measurements showed decreased pH, increased PaCO 2 , and decreased partial pressure of arterial O 2 , indicative of respiratory acidosis, hypercapnia, and hypoxemia. Increased protein levels of interleukin (IL)-6, CXCL-1, CXCL-2, CXCL-5, granulocyte-macrophage colony-stimulating factor, CXCL-10, leukemia inhibitory factor, leptin, IL-18, CCL-2, CCL-3, and CCL-7 were observed in the lung of PAO-exposed mice. Further, vascular endothelial growth factor levels were reduced in the lung. Pulmonary function evaluated using a flexiVent showed a downward shift in the pressure-volume loop, decreases in static compliance and inspiratory capacity, increases in respiratory elastance and tissue elastance. These changes are consistent with an ALI phenotype. These results demonstrate that cutaneous PAO exposure leads to ALI and that the model can be used as an effective surrogate to investigate vesicant-induced ALI. SIGNIFICANCE STATEMENT: This study presents a robust model for studying ALI resulting from cutaneous exposure to PAO, a surrogate for the toxic vesicating agent Lewisite. The findings in this study mimic the effects of cutaneous Lewisite exposure, providing a reliable model for investigating mechanisms underlying toxicity. The model can also be used to develop medical countermeasures to mitigate ALI associated with cutaneous Lewisite exposure., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Lewisite (LEW) is an arsenical vesicant that can be a potentially dangerous chemical warfare agent (CWA). Eyes are particularly susceptible to vesicant induced injuries and ocular LEW exposure can act swiftly, causing burning of eyes, edema, inflammation, cell death and even blindness. In our previous studies, we developed a LEW exposure-induced corneal injury model in rabbit and showed increased inflammation, neovascularization, cell death, and structural damage to rabbit corneas upon LEW exposure. In the present study, we further assessed the metabolomic changes to delineate the possible mechanisms underlying the LEW-induced corneal injuries. This information is vital and could help in the development of effective targeted therapies against ocular LEW injuries. Thus, the metabolomic changes associated with LEW exposures in rabbit corneas were assessed as a function of time, to delineate pathways from molecular perturbations at the genomic and proteomic levels. New Zealand white rabbit corneas (n = 3-6) were exposed to LEW vapor (0.2 mg/L; flow rate: 300 ml/min) for 2.5 min (short exposure; low dose) or 7.5 min (long-exposure; high dose) and then collected at 1, 3, 7, or 14 days post LEW exposure. Samples were prepared using the automated MicroLab STAR® system, and proteins precipitated to recover the chemically diverse metabolites. Metabolomic analysis was carried out by reverse phase UPLC-MS/MS and gas chromatography (GC)-MS. The data obtained were analyzed using Metabolon's software. The results showed that LEW exposures at high doses were more toxic, particularly at the day 7 post exposure time point. LEW exposure was shown to dysregulate metabolites associated with all the integral functions of the cornea and cause increased inflammation and immune response, as well as generate oxidative stress. Additionally, all important metabolic functions of the cells were also affected: lipid and nucleotide metabolism, and energetics. The high dose LEW exposures were more toxic, particularly at day 7 post LEW exposure (>10-fold increased levels of histamine, quinolinate, N-acetyl-β-alanine, GMP, and UPM). LEW exposure dysregulated integral functions of the cornea, caused inflammation and heightened immune response, and generated oxidative stress. Lipid and nucleotide metabolism, and energetics were also affected. The novel information about altered metabolic profile of rabbit cornea following LEW exposure could assist in delineating complex molecular events; thus, aid in identifying therapeutic targets to effectively ameliorate ocular trauma., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Acute irritant asthma is a preventable health consequence of a workplace exposure and has a number of adverse outcomes. While cases and case series are reported, little is known about the causes and incidence of this condition over prolonged periods of time., Aims: We aimed to estimate the reported incidence of irritant asthma referred to a national reporting scheme, and how this has changed over time., Methods: Cases of irritant asthma reported to SWORD, the UK-based Surveillance of Work-related Occupational Respiratory Diseases scheme, were grouped into four 5-year time periods from 1999 onwards. Likely causative exposures, job, work sector and incidence rates were analysed over time., Results: 307 actual cases equated to 1066 estimated cases; actual cases had a mean age of 46 years (SD 17.8); 70.7% were male. The annual incidence fell from 1.98 per million employed in the first 5-year period, to 0.56 in the most recent. Eleven occupational codes were associated with six or more attributed cases, and between them accounted for 38% of all cases. Thirteen exposure categories were associated with five or more cases. These were formaldehyde (n=5), cutting oils and coolants (n=6), isocyanates (n=6), pesticides and herbicides (n=6), welding fumes (n=7), paints (n=7), solder and colophony (n=7), solvents (n=9), fuel oil, diesel and ill-defined fumes (n=10), chlorine and hypochlorites (n=15), acids (n=23), smoke (n=25) and cleaning products and sterilising agents (n=39)., Conclusions: While the incidence of irritant asthma may have fallen, cases are persistently attributed to well-described causes. A persistence of cases attributed to cleaning agents was seen., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The vesicant sulfur mustard (SM) is a chemical warfare agent that causes acute and chronic injury to the cornea and proximal anterior segment structures. Despite clinical evidence of SM-exposure causing unexplained retinal deficits, there have been no animal studies conducted to examine the retinal toxicity of this vesciant. The cardinal hallmark of retinal response to stressors or injury is the activation of reactive gliosis, a cellular process largely governed by Müller glia. Previously we showed that corneal exposure to sodium hydroxide elicits rapid induction of reactive gliosis and results in retinal degeneration in a dose-related manner. Based on this evidence, we hypothesized that the vesicant nitrogen mustard (NM), an analog of SM, may also elicit reactive gliosis. To test this idea, we developed a mouse model of NM ocular injury and investigated corneal and retinal effects focusing on citrullination, a posttranslational modification (PTM) of proteins. This PTM was recently linked to alkali injury and has also been shown to occur in retinal degenerative conditions. Here, we demonstrate that corneal exposure to 1% NM causes a synchronous activation of citrullination in both the cornea and retina with hypercitrullination becoming apparent temporally and manifesting with altered cellular expression characteristics. A key finding is that ocular citrullination occurs acutely as early as 1-h post-injury in both the cornea and retina, which underscores a need for expeditious interception of this acute corneal and retinal response. Moreover, exploiting dose response and temporal studies, we uncoupled NM-induced retinal citrullination from its induction of retinal gliosis. Our findings demonstrate that hypercitrullination is a common corneo-retinal mechanism that sensitizes the eye to NM injury and suggests that counteracting hypercitrullination may provide a suitable countermeasure to vesicant injury., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: To prevent irritant contact eczema even in occupational fields with heavy-duty soiling, it is generally recommended to use 'mild' hand cleansers (mild detergent without grits, MC). On the other hand, since grit-containing cleansers (GC) show a higher washing power that minimizes washing time, their usage is generally preferred in specific occupational fields., Objectives: To compare whether a shorter, intense washing period might cause less skin damage than a longer washing period with an MC., Methods: Differences in cleaning time were first verified in a pilot study using standardized model dirt. In the main study, the forearms of 35 healthy volunteers were washed with three standardized procedures over a period of 3 days, either using 2 min of MC with/without hand brush or 1-min GC. Clinical scoring, transepidermal water loss (TEWL), corneometry, colourimetry and scaliness/roughness (Visioscan) were used to evaluate the epidermal barrier, topography and irritation., Results: The pre-study showed that washing time doubled when using MC vs. GC. Using GC resulted in stronger barrier disruption, even after a shorter washing period - median ΔT4-T1 TEWL 0.96 g/m 2 /h vs. 4.91 g/m 2 /h respectively, p < 0.0001. The most harmful procedure for the skin was the additional application of a hand brush (18.86 g/m 2 /h)., Conclusions: Short-time washing with GC damages the skin barrier more significantly in comparison to a longer application of an MC. When washing with MC, the strongest irritant reaction occurred when accompanied with hand brushing., (© 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: The short-term asthma outcome of irritant-induced asthma (IIA) is poorer than that of low-molecular-weight (LMW) sensitizer-induced occupational asthma (OA)., Objectives: To evaluate the long-term asthma outcome of IIA and LMW-induced OA and to determine which baseline features are associated with a poor long-term outcome., Methods: This follow-up questionnaire study assessed 43 patients diagnosed with IIA and 43 patients with LMW-induced OA at the Finnish Institute of Occupational Health in 2004-2018. The baseline results were analyzed to detect features associated with uncontrolled asthma (Asthma Control Test [ACT] score of ≤19, or ≥2 exacerbations or ≥1 serious exacerbation within 1 year) at follow-up., Results: The median interval since OA diagnosis was 6.3 years (interquartile range [IQR]: 4.4-11.3 years). Uncontrolled asthma was more frequent with IIA than with LMW-induced OA (58% vs 40%, adjusted odds ratio [OR]: 3.60, 95% confidence interval [CI]: 1.20-10.81). Poor symptom control was the main factor for this difference (median [IQR] ACT score of 18 [15-22] vs 21 [18-23], P = .036, respectively). Among all participants, older age (OR: 1.08 per year, 95% CI: 1.02-1.15), a fractional exhaled nitric oxide (FeNO) value <20 ppb (OR: 5.08, 95% CI: 1.45-17.80), and uncontrolled asthma at baseline (OR: 3.94, 95% CI: 1.31-11.88) were associated with uncontrolled asthma at follow-up., Conclusions: Long-term asthma control of IIA appears to be inferior to that of LMW-induced OA. Older age, a low FeNO value, and uncontrolled asthma at baseline might indicate a worse long-term outcome among those with IIA and LMW-induced OA., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: In this narrative review, we aim to highlight novel research findings on both acute/subacute irritant-induced asthma (IIA) and chronic exposure IIA (also called 'low dose' IIA)., Recent Findings: Novel case series showed that acute and subacute IIA cases had similar causal agents (e.g., acid or base aerosols/fumes, dusts, mixtures) but had occurred in different circumstances (accidents vs. regular work). Acute and subacute IIA cases had similar clinical characteristics but poorer short-term outcomes than sensitizer-induced occupational asthma patients. Novel large epidemiological studies reported associations between chronic occupational exposure to irritants and current adult-onset asthma and poor asthma control, and with a specific asthma endotype characterized by neutrophilic inflammation and oxidative stress. Recent studies reconfirmed the association of the use of disinfectants and cleaning products (especially sprays) with IIA. A role for genetic susceptibility has been suggested., Summary: Recent literature provided further understanding of both acute/subacute and chronic exposure IIA, in terms of causes, possible mechanisms, and consequences such as poor asthma control. Research is needed to clarify several aspects of IIA, including its frequency (still likely underestimated), modulating factors, and mechanisms. Research aiming at improving irritant exposure assessment, including intensity/duration, and determining relevant exposure windows would be welcome., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the associations between the evolution of household use of cleaning products with the asthma symptom score and its evolution over 8 years., Methods: Our study is based on 509 women participating in the last two surveys of the Epidemiological study on the Genetics and Environment of Asthma (EGEA) study (EGEA2: 2003-2007 (44 years, 19% current smokers) and EGEA3: 2011-2013). We assessed an asthma symptom score and the use of household cleaning products through standardised questionnaires. We studied longitudinal associations of the evolution of weekly use of irritant or spayed cleaning products with (1) the asthma symptom score at EGEA3 and a stable symptom score between EGEA2-EGEA3 (negative binomial models) and (2) the incidence/evolution of asthma symptoms between EGEA2-EGEA3 (logistic/polytomous logistic regressions). Models accounted for familial dependence and were adjusted for age, smoking status, body mass index and occupational exposure to asthmagens., Results: Persistent and increased (40% and 16%, respectively) weekly use of irritants or sprays were associated with a higher risk of asthma symptoms at EGEA3 (Mean Score Ratio (MSR)=1.51 (95% CI 1.06 to 2.14) and 1.33 (95% CI 0.85 to 2.08), respectively). A decreased use (19%) was associated with a lower risk of symptoms at EGEA3, compared with a persistent use (MSR=0.59 (95% CI 0.39 to 0.88)). We also observed an association between an increased use of sprays and the incidence of asthma symptoms (OR=2.30 (95% CI 1.08 to 4.91)), compared with no weekly use of irritants/sprays., Conclusions: This longitudinal study, with repeated assessment of exposure and respiratory health, supports the hypothesis that a persistent or increased weekly use of sprayed cleaning products over time may have an adverse effect on the evolution of asthma symptoms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The role of chronic occupational exposures to irritants in asthma remains not well-defined. Few studies have examined their associations with asthma and its control., Objective: To study the associations of occupational exposures with asthma and its control, with specific interest for irritants, including disinfectants and cleaning products (DCPs) and solvents., Methods: Analyses included 4,469 adults (3,792 with neither asthma nor respiratory symptoms, 677 with current asthma; 75.9% women, mean age 54 years) of a case-control study (2018) from the French NutriNet-Santé cohort. Current asthma was defined by ever asthma with symptoms, medication or asthma attacks in the past 12 months, adult-onset asthma by age at first asthma attack older than 16 years, and uncontrolled asthma was defined by an Asthma Control Test score less than 20. Ever/current exposures were assessed with the Occupational Asthma-specific Job Exposure Matrix. Associations were evaluated by multinomial logistic regressions adjusted for sex, age, smoking status, and body mass index., Results: Ever exposures to sensitizers (high molecular weight [HMW]: OR 1.53, 95% CI 1.18-2.00; and low molecular weight [LMW]: OR 1.42; 95% CI 1.09-1.87), irritants (OR 1.32; 95% CI 1.03-1.68), and DCPs (OR 1.43; 95% CI 1.10-1.85) were associated with current adult-onset asthma. Significant associations between ever exposures and uncontrolled adult-onset asthma were observed for high molecular weight (OR 2.69; 95% CI 1.52-4.78) and low molecular weight (OR 2.27; 95% CI 1.24-4.37) sensitizers, irritants (OR 2.32; 95% CI 1.36-3.95), and DCPs (OR 2.59; 95% CI 1.48-4.54). Results were similar for current exposures, with higher ORs. No association was observed with solvents., Conclusions: Occupational exposures to both sensitizers and irritants were associated with current adult-onset asthma and uncontrolled asthma. Irritant and sensitizing agents should be carefully considered in asthma management., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Irritant-induced asthma (IIA) is a phenotype of asthma caused by the inhalation of irritant agents. Definite, probable, or possible IIA have been described, depending on the concentration of the inhaled irritants and the onset of respiratory symptoms respective to the time of exposure. Definite IIA represents approximately 4% to 14% of all cases of new-onset work-related asthma. Agents responsible for IIA can be encountered as fumes, gases, aerosols, or dusts. The most frequent are chlorine, nitrogen oxides, sulfur dioxide, ammonia, acetic acid, solvents, and cleaning materials. Although the diagnosis of definite IIA is based on a suggestive clinical history along with evidence of reversible airflow limitation and/or nonspecific bronchial hyperresponsiveness, possible IIA cannot be diagnosed with certainty because the relationship between exposure and the onset of symptoms is difficult to establish. This article reviews the epidemiology, pathophysiology, diagnostic approach, and management of IIA., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Sulfur mustard (SM) is a notorious, bifunctional alkylating vesicant that was first used in warfare during World War I in 1917 and since then has been deployed in numerous skirmishes with its most recent documented use being during the Middle Eastern conflicts. Apart from its use in combat and terrorist activities, continual threat of accidental exposure from old stockpiles and improperly discarded munitions is ever present, especially to the innocent and unassuming civilian populations. SM can cause devastating injuries, depending on the dosage of SM exposure, route of exposure, as well as the physiological conditions of the individuals exposed. The most common routes of exposure are ocular, dermal, and exposure to the lungs and respiratory tissues through inhalation. Eyes are the most susceptible organ to SM-induced toxicities owing to their high moisture content and rapidly dividing cells. Additionally, ocular injury causes the most expeditious disablement of individuals even upon whole-body exposures. Therefore, it is imperative to understand the mechanisms underlying SM-induced ocular toxicity and design therapeutic interventions to prevent/mitigate ocular injuries. Ocular SM exposure may cause a wide range of symptoms such as inflammation, lacrimation, itching, dryness, photophobia, edema of the cornea/sclera/retina/iris, conjunctivitis, degradation of the corneal layer, fusion of two or more ocular layers, neovascularization, fibrosis, and temporary or permanent structural damage to one or more ocular layers. These symptoms may lead to vision impairments, resulting in partial or complete blindness that may be permanent. The highly toxic and exceedingly notorious nature of SM makes it a highly regulated chemical, requiring very expensive licensing, security, and safety requirements; thus, the more easily accessible analogue, nitrogen mustard (NM) that mimics SM-induced toxicity and injuries is employed in plethora of studies conducted in different animal models and culture systems. This review provides a comprehensive account of the injuries and symptoms that occur upon ocular SM exposures in human patients as well as studies in animal (in vivo, ex vivo) and cell (in vitro) models of SM and NM ocular exposures. Special emphasis has been laid on highlighting the strengths and lacunae in the research as well as the possible unexplored avenues of mechanisms underlying mustard-induced ocular injury that can be explored in future research endeavors. Furthermore, development of therapeutic interventions and targets of interest in the ocular system exposed to SM and NM, based on studies in human patients as well as in vivo, ex vivo, and in vitro models has been discussed in great depth, providing a valuable knowledge database to delineate pathways associated with vesicant-induced toxicity, and strategies/diagnostic tools against SM-induced toxicity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Diagnosis of contact allergy (CA) to Amerchol L-101 (AL-101), a marker for lanolin allergy, is problematic. Positive patch test reactions are frequently doubtful or weakly positive and difficult to associate with clinical relevance., Objective: To gain further insight on the allergic or irritant nature of skin reactions induced by AL-101 patch test., Methods: We re-tested in a dose-response fashion, 10 subjects with AL-101 CA and performed comprehensive transcriptomic analysis (gene arrays, quantitative real-time polymerase chain reaction [qRT-PCR]) of samples of their skin reactions., Results: Eight of the 10 CA subjects reacted positively upon re-test, whereas two did not react. Most of AL-101 positive patch tests expressed an allergy signature with strong activation of gene modules associated with adaptive immunity and downregulation of cornification pathway genes. In addition, the breadth of gene modulation correlated with the magnitude of patch test reactions and the concentration of AL-101 applied. However, we observed that some of the positive patch test reactions to AL-101 expressed no/few allergy biomarkers, suggesting the induction of an irritant skin inflammation in these samples., Conclusions: This study confirms that AL-101 is an allergen that can cause both contact allergy and contact irritation. Our results also highlight that molecular profiling might help to strengthen clinical diagnosis., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Work is a substantial contributing factor of adult-onset asthma. A subtype of occupational asthma (OA) is caused by irritant agents, but knowledge of the clinical outcomes of irritant-induced asthma (IIA) is incomplete., Objectives: To evaluate whether the clinical picture of IIA differs from that of sensitizer-induced OA., Methods: This retrospective study analyzed acute and subacute IIA patients diagnosed in an occupational medicine clinic during 2004 to 2018. Sixty-nine patients fulfilled the inclusion criteria, and their characteristics were analyzed at the time of the diagnosis and 6 months later. The results were compared with those of 2 subgroups of sensitizer-induced OA: 69 high-molecular-weight (HMW) and 89 low-molecular-weight (LMW) agent-induced OA patients., Results: Six months after the diagnosis, 30% of the patients with IIA needed daily short-acting β-agonists (SABA), 68% were treated with Global Initiative for Asthma, 2020 report (GINA) step 4-5 medication, and 24% of the patients had asthma exacerbation after the first appointment. IIA depicted inferiority to LMW-induced OA in daily need for SABA (odds ratio [OR]: 3.80, 95% confidence interval [CI]: 1.38-10.46), treatment with GINA step 4-5 medication (OR: 2.22, 95% CI: 1.08-4.57), and exacerbation (OR: 3.85, 95% CI: 1.35-11.04). IIA showed poorer results than HMW-induced OA in the latter 2 of these features (OR: 2.49, 95% CI: 1.07-5.79 and OR: 6.29, 95% CI: 1.53-25.83, respectively)., Conclusions: Six months after the OA diagnosis, a significant proportion of the patients with IIA remain symptomatic and the majority of these patients use asthma medications extensively suggesting uncontrolled asthma. The short-term outcomes of IIA appear poorer than that of sensitizer-induced OA., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: The biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation., Methods: We used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status., Results: Prevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5)., Conclusion: Occupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Chemotherapy causes intestinal mucositis, which includes villous atrophy and altered mucosal barrier function. However, there is an uncertainty regarding how the reduced small-intestinal surface area affects the mucosal permeability of the small marker probe mannitol (MW 188), and how the mucosa responds to luminal irritants after chemotherapy. The aims in this study were to determine (i) the relationship between chemotherapy-induced villus atrophy and the intestinal permeability of mannitol and (ii) how the mucosa regulate this permeability in response to luminal ethanol and sodium dodecyl sulfate (SDS). This was investigated by treating rats with a single intraperitoneal dose of doxorubicin, irinotecan, or 5-fluorouracil. After 72 h, jejunum was single-pass perfused and mannitol permeability determined at baseline and after 15 min luminal exposure to 15% ethanol or 5 mg/mL SDS. Tissue samples for morphological analyses were sampled from the perfused segment. All three chemotherapeutics caused a similar 30% reduction in villus length. Mannitol permeability increased with irinotecan (1.3-fold) and 5-fluorouracil (2.5-fold) and was reduced with doxorubicin (0.5-fold), suggesting that it is not epithelial surface area alone that regulates intestinal permeability to mannitol. There was no additional increase in mannitol permeability induced by luminal ethanol or SDS in the chemotherapy-treated rats compared to controls, which may be related to the relatively high basal permeability of mannitol compared to other common low-permeability probes. We therefore suggest that future studies should focus on elucidating the complex interplay between chemotherapy in combination with luminal irritants on the intestinal permeability of other probes.

Purpose: Irritant contact dermatitis (ICD) is a major cause of occupational disease. The aim was to review the relation between exposure to occupational irritants and ICD and the prognosis of ICD., Methods: Through a systematic search, 1516 titles were identified, and 48 studies were included in the systematic review., Results: We found that the evidence for an association between ICD and occupational irritants was strong for wet work, moderate for detergents and non-alcoholic disinfectants, and strong for a combination. The highest quality studies provided limited evidence for an association with use of occlusive gloves without other exposures and moderate evidence with simultaneous exposure to other wet work irritants. The evidence for an association between minor ICD and exposure to metalworking fluids was moderate. Regarding mechanical exposures, the literature was scarce and the evidence limited. We found that the prognosis for complete healing of ICD is poor, but improves after decrease of exposure through change of occupation or work tasks. There was no substantial evidence for an influence of gender, age, or household exposures. Inclusion of atopic dermatitis in the analysis did not alter the risk of ICD. Studies were at risk of bias, mainly due to selection and misclassification of exposure and outcome. This may have attenuated the results., Conclusion: This review reports strong evidence for an association between ICD and a combination of exposure to wet work and non-alcoholic disinfectants, moderate for metalworking fluids, limited for mechanical and glove exposure, and a strong evidence for a poor prognosis of ICD., (© 2021. The Author(s).)

Background: Skin exposure to chemicals may induce an inflammatory disease known as contact dermatitis (CD). Distinguishing the allergic and irritant forms of CD often proves challenging in the clinic., Methods: To characterize the molecular signatures of chemical-induced skin inflammation, we conducted a comprehensive transcriptomic analysis on the skin lesions of 47 patients with positive patch tests to reference contact allergens and nonallergenic irritants., Results: A clear segregation was observed between allergen- and irritant-induced gene profiles. Distinct modules pertaining to the epidermal compartment, metabolism, and proliferation were induced by both contact allergens and irritants; whereas only contact allergens prompted strong activation of adaptive immunity, notably of cytotoxic T-cell responses. Our results also confirmed that: (a) unique pathways characterize allergen- and irritant-induced dermatitis; (b) the intensity of the clinical reaction correlates with the magnitude of immune activation. Finally, using a machine-learning approach, we identified and validated several minimal combinations of biomarkers to distinguish contact allergy from irritation., Conclusion: These results highlight the value of molecular profiling of chemical-induced skin inflammation for improving the diagnosis of allergic versus irritant contact dermatitis., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Competing Interests: The authors have no funding or conflicts of interest to declare.

Background: Contact dermatitis in construction workers (CWs) is frequent due to the widespread exposure to sensitizing substances and irritating agents and the wet and cold working conditions., Objective: Our objectives were to evaluate contact dermatitis characteristics among CWs who underwent patch test in northeastern Italy and to identify related allergens., Methods: Seven hundred ninety-five CWs were studied and their data were compared to 2.099 male white-collar workers. The associations between patch test results and occupations were assessed by multivariate logistic regression analysis. Incidence data were calculated from 1996 to 2016., Results: CWs with confirmed occupational dermatitis presented an increased risk to be sensitized to potassium dichromate [OR 3.1 (95%IC 2.0-4.8)], to thiurams [OR 8 .6 (95%IC 4.0-18.4)], and to epoxy resins [OR 12.7 (95%IC 6.1-26.4)]. Sensitization to chromate decreased significantly after 2004, following EU regulation of chromate content in concrete, while sensitization to epoxy resins and thiurams increased. The overall incidence of occupational contact dermatitis in CWs decreased significantly., Conclusion: Our study demonstrated the effectiveness of EU regulations in reducing chromate sensitization in CWs and the overall incidence of occupational contact dermatitis. However, sensitization to other haptens is increasing, though improvement of protective measures is compulsory., Competing Interests: All authors have no funding or conflicts of interest to declare., (Copyright © 2020 American Contact Dermatitis Society. All Rights Reserved.)

Competing Interests: The authors have no funding or conflicts of interest to declare.

Background: Exposures leading to irritant-induced asthma (IIA) are poorly documented., Methods: We retrospectively screened the medical records of patients with IIA diagnosed in an occupational medicine clinic during 2000-2018. We classified the cases into acute (onset after single exposure) and subacute (onset after multiple exposures) IIA. We analysed in detail, occupations, causative agents and their air levels in the workplace, exposure events and the root causes of high exposure., Results: Altogether 69 patients were diagnosed with IIA, 30 with acute and 39 with subacute IIA. The most common occupational groups were industrial operators (n=23, 33%), metal and machinery workers (n=16, 11%) and construction workers (n=12, 8%). Among industrial operators significantly more cases had subacute IIA than acute IIA (p=0.002). Forty cases (57%) were attributable to some type of corrosive acidic or alkaline chemical. Acute IIA followed accidents at work in different types of occupation, while subacute IIA was typical among industrial operators performing their normal work tasks under poor work hygiene conditions. The most common root cause was lack of information or false guidance in acute IIA (n=11, 36%) and neglect of workplace hygiene measures in subacute IIA (n=29, 74%)., Conclusions: Accidents are the main causes of acute IIA, whereas subacute IIA can develop in normal work in risk trades with poor work hygiene. Airborne strong acids or bases seem to be the most important causative agents of acute and subacute IIA. The different risk profiles of acute and subacute IIA should be considered in the prevention and identification of the cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors have no funding or conflicts of interest to declare.

Competing Interests: The authors have no funding or conflicts of interest to declare.

Background: Health care workers and hospital cleaning workers are at high risk regarding the development of occupational contact dermatitis (OCD)., Objectives: To determine the prevalence and risk factors of OCD in hospital cleaning workers., Methods: A questionnaire was conducted in 245 cleaning workers in our cross-sectional study. The 236 cleaning workers formed the study group. In workers who were prediagnosed with dermatitis, physical examination was performed in the Dermatology Outpatient Clinic, and when necessary, patch test, skin biopsy, and investigation for total immunoglobulin E were conducted. Patients with definite contact dermatitis were diagnosed as having OCD by using the Mathias criteria., Results: The prevalence rate of OCD was 21.6% and was significantly higher in female workers (26.4%) when compared with male workers (11.0%). Female sex; low educational level; cleaning the external surfaces of the medical equipment, monitors, and accessories; and mixing the cleaning products and use them while performing cleaning activities were determined as the independent risk factors for OCD., Conclusions: Occupational contact dermatitis was present at a high rate in hospital cleaning workers. The risk factors should be taken into consideration for prevention of OCD and improvement of the health status of hospital cleaning workers., Competing Interests: The authors have no funding or conflicts of interest to declare., (Copyright © 2021 American Contact Dermatitis Society. All Rights Reserved.)

Surfactants, many of which are used as detergents, can be found in many common household items, such as shampoos, conditioners, soaps, and cosmetics. One should recognize the multitude of surfactants that are used in today's products to identify any potential allergic contact dermatitis (ACD) or irritant contact dermatitis (ICD). Given their abundance in everyday products, it is understandable that many cases of occupational contact dermatitis that arise can be attributed to surfactants. The products most connected with ACD are cocamidopropyl betaine, oleamidopropyl dimethylamine, decyl glucoside, 3-dimethylaminopropylamine, amidoamine, and cocamide diethanolamine. Similarly, the most common surfactant-related causes of ICD are sodium lauryl sulfate and benzalkonium chloride. It is important for dermatologists to identify the causes and differentiate between the two, to adjust treatments and products accordingly. Here, the most frequently used surfactants, as well as their correlation between ACD and ICD, will be reviewed., Competing Interests: The authors have no funding or conflicts of interest to declare., (Copyright © 2021 American Contact Dermatitis Society. All Rights Reserved.)

Abstract: The most common complication in individuals with ostomies is irritant contact dermatitis from the acidic stoma effluent coming into contact with the peristomal skin. Although protective powders are widely used for the treatment of peristomal skin, there is little scientific evidence to justify their use. The combined use of sodium carboxymethylcellulose cellulose fibers (SCCFs) together with a hydrocolloid dressing for fixation is an effective alternative in the management of these wounds. Here, the authors report a case series of three patients presenting at a stoma therapy clinic with peristomal skin lesions because of severe irritant contact dermatitis. Patients were men aged between 70 and 81 years, had been diagnosed with colon cancer (n = 2) or bladder cancer (n = 1), and had undergone a colostomy (n = 1), ileostomy (n = 1), or Bricker-type ureteroileostomy (n = 1). A semiocclusive care protocol was applied in a moist environment using SCCF and an extrathin hydrocolloid adhesive dressing, and the collection device was secured using adhesive resin and an ostomy belt. The combined use of SCCF and hydrocolloid dressings provided beneficial results to treat the dermatitis, with reduced discomfort after 7 days and lesions healing within 4 weeks., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Human exposure to wildfire-derived particulate matter (PM) is linked to adverse health outcomes; however, little is known regarding the influence of biomass fuel type and burn conditions on toxicity. The aim of this study was to assess the irritant potential of extractable organic material (EOM) of biomass smoke condensates from five fuels (eucalyptus, pine, pine needle, peat, or red oak), representing various fire-prone regions of the USA, burned at two temperatures each [flaming (approximately 640°C) or (smoldering approximately 500°C)] using a locomotor assay in zebrafish ( Danio rerio ) larvae. It was postulated that locomotor responses, as measures of irritant effects, might be dependent upon fuel type and burn conditions and that these differences relate to combustion byproduct chemistry. To test this, locomotor activity was tracked for 60 min in 6-day-old zebrafish larvae (25-32/group) immediately after exposure to 0.4% dimethyl sulfoxide (DMSO) vehicle or EOM from the biomass smoke condensates (0.3-30 µg EOM/ml; half-log intervals). All EOM samples produced concentration-dependent irritant responses. Linear regression analysis to derive rank-order potency indicated that on a µg PM basis, flaming pine and eucalyptus were the most irritating. In contrast, on an emission-factor basis, which normalizes responses to the amount of PM produced/kg of fuel burned, smoldering smoke condensates induced greater irritant responses (>100-fold) than flaming smoke condensates, with smoldering pine being the most potent. Importantly, irritant responses significantly correlated with polycyclic aromatic hydrocarbon (PAH) content, but not with organic carbon or methoxyphenols. Data indicate that fuel type and burn condition influence the quantity and chemical composition of PM as well as toxicity.

The in vivo rabbit test is the benchmark against which new approach methodologies for skin irritation are usually compared. No alternative method offers a complete replacement of animal use for this endpoint for all regulatory applications. Variability in the animal reference data may be a limiting factor in identifying a replacement. We established a curated data set of 2624 test records, representing 990 substances, each tested at least twice, to characterize the reproducibility of the in vivo assay. Methodological deviations from guidelines were noted, and multiple data sets with differing tolerances for deviations were created. Conditional probabilities were used to evaluate the reproducibility of the in vivo method in identification of U.S. Environmental Protection Agency or Globally Harmonized System hazard categories. Chemicals classified as moderate irritants at least once were classified as mild or non-irritants at least 40% of the time when tested repeatedly. Variability was greatest between mild and moderate irritants, which both had less than a 50% likelihood of being replicated. Increased reproducibility was observed when a binary categorization between corrosives/moderate irritants and mild/non-irritants was used. This analysis indicates that variability present in the rabbit skin irritation test should be considered when evaluating nonanimal alternative methods as potential replacements., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose The primary aim of this review was to identify environmental irritants known to trigger chronic cough through the life span and develop a comprehensive clinically useful irritant checklist. Method A scoping review was conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews, checklist, and explanation. English-language, full-text resources were identified through Medline, PsycINFO, SPORTDiscus, Web of Science, and ProQuest Dissertations and Theses Global. Results A total of 1,072 sources were retrieved; of these, 109 were duplicates. Titles of abstracts of 963 articles were screened, with 295 selected for full-text review. Using the exclusion and inclusion criteria listed, 236 articles were considered eligible and 214 different triggers were identified. Triggers were identified from North America, Europe, Africa, Asia, and Australia. Occupational exposures were also delineated. Conclusions A clinically useful checklist of both frequently encountered triggers and idiosyncratic or rare triggers was developed. The clinical checklist provides a unique contribution to streamline and standardize clinical assessment of irritant-induced chronic cough. The international scope of this review extends the usefulness of the clinical checklist to clinicians on most continents.

Background: Finn Chambers AQUA (FCA) is a development of the Finn Chambers (FC) test system in which the test chambers are mounted on a moisture-resistant adhesive patch. FCA has pre-fixed filter papers. Because the use of FCA does not require any extra taping or use of separate filter papers, a change from FC to FCA chambers may be beneficial for both patients and patch test technicians., Objectives: To investigate whether there are any differences regarding detection of contact allergy when simultaneous patch testing is performed with FC and FCA., Materials and Methods: Results from 434 dermatitis patients simultaneously tested with 10 allergens in both FC and FCA were evaluated., Results: There were no significant differences regarding detection of positive reactions between the two test systems. There were significantly more doubtful reactions to methylisothiazolinone, fragrance mix I and hydroperoxides of linalool when testing with FCA. We only observed significantly more doubtful reactions in FC regarding nickel(II)sulfate. Irritant reactions to formaldehyde were also significantly more common when using FCA., Conclusion: The FC and FCA had good agreement in detection of positive reactions. However, the results including doubtful and irritant reactions justify further research regarding optimization of the dose., (© 2020 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Exposure to cleaning and disinfection products has been associated with respiratory disorders such as asthma in cleaning and healthcare workers. Safety data sheets (SDSs) provide information on hazardous chemicals that are present in products to help users with risk assessment and implement appropriate control measures. However, they have potential limitations in identifying respiratory hazards due to a lack of regulatory test methods for respiratory sensitisation and irritation of chemicals., Methods: SDSs were first used to identify chemicals on the database as respiratory sensitisers and irritants. A quantitative structure-activity relationship (QSAR) model and an asthmagen list established by the Association of Occupational and Environmental Clinics (AOEC) were used to identify potential respiratory sensitisers and irritants (by the AOEC list only) in the cleaning and disinfection products., Results: From a total of 459 cleaning and disinfection products used in healthcare organisations across England and Wales, 35 respiratory sensitisers not labelled as such on the SDS were identified by QSAR or AOEC. Only 2% of cleaning and disinfection products contained at least one respiratory sensitiser as identified by their SDSs; this was increased to 37.7% of products when the QSAR or the AOEC list was used., Conclusions: A significantly higher proportion of cleaning products contain respiratory hazardous chemicals, particularly respiratory sensitisers than would be expected from the information provided by SDSs alone. Cleaners and healthcare workers may, therefore, be insufficiently protected., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Eyelid dermatitis is a common dermatologic complaint., Objective: To characterize patients with eyelid dermatitis., Methods: Retrospective analysis (1994-2016) of North American Contact Dermatitis Group data., Results: Of 50,795 patients, 2332 (4.6%) had eyelid dermatitis only, whereas 1623 (3.2%) also had dermatitis of the eyelids and head or neck. Compared with patients without eyelid involvement (n = 26,130), groups with eyelid dermatitis only and dermatitis of the eyelid and head or neck were significantly more likely to be female, white, and older than 40 years, and to have a history of hay fever, atopic dermatitis, or both (P < .01). Final primary diagnoses included allergic contact dermatitis (eyelid dermatitis only: 43.4%; dermatitis of the eyelid and head or neck: 53.5%), irritant contact dermatitis (eyelid dermatitis only: 17.0%; dermatitis of the eyelid and head or neck: 9.8%), and atopic dermatitis (eyelid dermatitis only: 13.1%; dermatitis of the eyelid and head or neck: 13.8%). Top 5 currently relevant allergens included nickel sulfate (eyelid dermatitis only: 18.6%; dermatitis of the eyelid and head or neck: 22.5%), fragrance mix I (eyelid dermatitis only: 16.5%; dermatitis of the eyelid and head or neck: 18.3%), methylisothiazolinone (eyelid dermatitis only: 16.5%; dermatitis of the eyelid and head or neck: 17.7%), gold sodium thiosulfate (eyelid dermatitis only: 14.7%; dermatitis of the eyelid and head or neck: 11.4%), and balsam of Peru (eyelid dermatitis only: 11.9%; dermatitis of the eyelid and head or neck: 12.6%). Both eyelid-involvement groups were significantly more likely to react to gold sodium thiosulfate, carmine, shellac, dimethylaminopropylamine, oleamidopropyl dimethylamine, and thimerosal (P < .05) compared with the no eyelid involvement group., Limitations: Lack of specific distribution patterns of eyelid dermatitis and no long-term follow-up data., Conclusion: Patch testing remains a critical tool in evaluating patients with eyelid dermatitis., (Published by Elsevier Inc.)

Background: Hand eczema (HE) is a heterogeneous and burdensome disorder., Objective: To characterize the clinical characteristics, etiologies and allergen relevance in adults with HE referred for patch testing., Methods: Retrospective analysis (2000-2016) of North American Contact Dermatitis Group data (n = 37,113)., Results: Overall, 10,034 patients had HE, with differences of overlap between allergic contact, irritant contact, and atopic dermatitis. Allergic contact HE fluctuated, whereas atopic HE steadily increased, and irritant HE decreased over time. HE was associated with higher proportions of positive patch tests (67.5% vs 63.8%; χ 2 , P < .0001). The five most common clinically relevant allergens were methylisothiazolinone, nickel, formaldehyde, quaternium-15, and fragrance mix I. HE was associated with significantly higher odds of positive patch test reactions and clinical relevance in 13 and 16 of the 25 most common allergens, respectively, including preservatives, metals, topical medications, and rubber accelerators., Limitations: No data on HE phenotype., Conclusion: HE in adults was associated with higher proportions of positive patch tests, with a heterogeneous profile of allergens. Patch testing remains an important tool in the evaluation of patients with HE., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2020 American Academy of Dermatology, Inc. All rights reserved.)

Background: Scalp conditions are often multifactorial., Objective: To characterize patients with scalp involvement and patch-testing outcomes., Methods: Retrospective cross-sectional analysis of North American Contact Dermatitis Group data (1996-2016). Study groups included patients with scalp involvement (≤3 anatomic sites coded) with or without additional sites., Results: A total of 4.8% of patients (2331/48,753) had scalp identified as 1 of up to 3 affected anatomic sites. Approximately one-third of "scalp-only" individuals had a specific primary diagnosis of allergic contact dermatitis (38.6%), followed by seborrheic dermatitis (17.2%) and irritant contact dermatitis (9.3%). When adjacent anatomic sites were affected, allergic contact dermatitis was more frequently identified as the primary diagnosis (>50%). The top 5 currently clinically relevant allergens in scalp-only patients were p-phenylenediamine, fragrance mix I, nickel sulfate, balsam of Peru, and cinnamic aldehyde. Methylisothiazolinone sensitivity was notable when adjacent anatomic sites were involved. The top 3 specifically identified sources for scalp-only allergens were hair dyes, shampoo/conditioners, and consumer items (eg, hair appliances, glasses)., Limitations: Tertiary referral population., Conclusion: Isolated scalp involvement was less likely to be associated with allergic contact dermatitis than when adjacent anatomic sites were involved. Overlap with multiple diagnoses was frequent, including seborrheic dermatitis, irritant dermatitis, other dermatoses, or all 3. p-Phenylenediamine was the most common allergen., (Published by Elsevier Inc.)

Purpose: Case series on respiratory features of Aerotoxic Syndrome (AS). The term AS has been coined to describe the spectrum of clinical manifestations after aircraft fume events. Among these manifestations, neurological and respiratory symptoms are the most frequently reported complaints., Methods: Three cases of AS with relevant respiratory features are presented., Results: Cough and shortness of breath for 6 to12 months were the predominant symptoms in the first two cases. The first case also developed neurological symptoms affecting his central nervous system. In the third case, the patient complained for nine years about an unbearable cough triggered by odors, smells, and a variety of indoor and outdoor irritants, among other symptoms of multiple chemical sensitivity. In all three cases, the respiratory symptoms resolved after appropriate treatment., Conclusion: Our report aims at raising awareness on AS and calls for actions to improve the management of patients suffering from this syndrome.

Hand contact dermatitis is common, and irritant contact dermatitis (ICD) is more likely than allergic contact dermatitis (ACD) in both occupational and nonoccupational settings. Irritant contact dermatitis can have acute and chronic presentations, and hand hygiene products can contribute. The most common relevant hand contact allergens in North American patch test populations are methylisothiazolinone (MI), nickel, formaldehyde, quaternium-15, and fragrance mix I. In health care workers, rubber accelerators often are relevant as potential contact allergens. Clinically, it can be difficult to differentiate between ICD and ACD, and patch testing often is required for definitive diagnosis. When patch testing is indicated, supplemental allergen series in addition to a screening series often are needed. Management of hand contact dermatitis requires gentle skin care, avoidance of irritants and/ or allergens when appropriate, and prescription topical or systemic therapies or phototherapy when indicated.

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections., (© 2021 John Wiley & Sons Ltd.)

Background: Compounded cantharidin has been used for decades to treat molluscum contagiosum but lacks rigorous clinical evidence to support its safety and efficacy. VP-102 is a shelf-stable drug-device combination product that contains topical cantharidin (0.7% weight/volume [w/v]) and is being evaluated for the treatment of molluscum., Objectives: Our objective was to present pooled safety and efficacy analyses of VP-102 in the treatment of molluscum compared with vehicle., Methods: Participants aged ≥ 2 years were randomized 3:2 to topical administration of VP-102 or vehicle in two randomized, double-blind, vehicle-controlled phase III trials. Study drug was applied to all baseline and new lesions once every 21 days until clear or for a maximum of four applications. Assessors blinded to treatment counted all lesions at each study visit. All adverse events (AEs) were documented. Data were pooled for analyses., Results: In total, 310 participants received VP-102 and 218 received vehicle. Mean age was 7.5 years (range 2-60) for VP-102 and 6.8 (2-54) for vehicle. Complete clearance of all molluscum lesions at day 84 occurred in 50% of VP-102 participants and 15.6% of vehicle recipients (p < 0.0001). Mean molluscum lesion counts decreased 76% for VP-102 and 0.3% for vehicle at day 84 (p < 0.0001). The most common AEs in the VP-102 group were application site blistering, pruritus, pain, and erythema, which were generally mild or moderate in severity., Conclusions: Pooled analyses showed a significantly higher percentage of participants with complete molluscum lesion clearance and larger reductions in lesion counts with VP-102 than with vehicle. AEs were anticipated because of the pharmacodynamic properties of cantharidin., Trial Registration: ClinicalTrials.gov identifiers: NCT03377790 (first posted 19 December 2017) and NCT03377803 (first posted 19 December 2017). Video abstract: Pooled Results of Two Randomized Phase III Trials Evaluating VP 102, a Drug Device Combination Product Containing Cantharidin 0.7% (w/v) for the Treatment of Molluscum Contagiosum (MP4 131293 KB).

Plant stinging hairs have fascinated humans for time immemorial. True stinging hairs are highly specialized plant structures that are able to inject a physiologically active liquid into the skin and can be differentiated from irritant hairs (causing mechanical damage only). Stinging hairs can be classified into two basic types: Urtica -type stinging hairs with the classical "hypodermic syringe" mechanism expelling only liquid, and Tragia -type stinging hairs expelling a liquid together with a sharp crystal. In total, there are some 650 plant species with stinging hairs across five remotely related plant families (i.e., belonging to different plant orders). The family Urticaceae (order Rosales) includes a total of ca. 150 stinging representatives, amongst them the well-known stinging nettles (genus Urtica ). There are also some 200 stinging species in Loasaceae (order Cornales), ca. 250 stinging species in Euphorbiaceae (order Malphigiales), a handful of species in Namaceae (order Boraginales), and one in Caricaceae (order Brassicales). Stinging hairs are commonly found on most aerial parts of the plants, especially the stem and leaves, but sometimes also on flowers and fruits. The ecological role of stinging hairs in plants seems to be essentially defense against mammalian herbivores, while they appear to be essentially inefficient against invertebrate pests. Stinging plants are therefore frequent pasture weeds across different taxa and geographical zones. Stinging hairs are usually combined with additional chemical and/or mechanical defenses in plants and are not a standalone mechanism. The physiological effects of stinging hairs on humans vary widely between stinging plants and range from a slight itch, skin rash (urticaria), and oedema to sharp pain and even serious neurological disorders such as neuropathy. Numerous studies have attempted to elucidate the chemical basis of the physiological effects. Since the middle of the 20th century, neurotransmitters (acetylcholine, histamine, serotonin) have been repeatedly detected in stinging hairs of Urticaceae, but recent analyses of Loasaceae stinging hair fluids revealed high variability in their composition and content of neurotransmitters. These substances can explain some of the physiological effects of stinging hairs, but fail to completely explain neuropathic effects, pointing to some yet unidentified neurotoxin. Inorganic ions (e.g., potassium) are detected in stinging hairs and could have synergistic effects. Very recently, ultrastable miniproteins dubbed "gympietides" have been reported from two species of Dendrocnide , arguably the most violently stinging plant. Gympietides are shown to be highly neurotoxic, providing a convincing explanation for Dendrocnide toxicity. For the roughly 648 remaining stinging plant species, similarly convincing data on toxicity are still lacking.

Background: This Phase 2, open-label study evaluated the safety, efficacy, systemic exposure, and impact on quality of life (QoL) with treatment using VP-102, a drug-device combination containing cantharidin (0.7% w/v) in subjects with molluscum contagiosum (MC)., Study Design: Pediatric subjects with MC (2&ndash;15 years of age) were eligible to enroll in this 12-week study. MC lesions were treated topically with VP-102 every 21 days until clearance (maximum of 4 treatments). Adverse events (AEs) and QoL outcomes (using the Children's Quality of Life Index, CDLQI) were documented at each visit. Rate of complete clearance and the percent reduction in lesions were measured at each visit on days 21, 42, 63, and 84 (end of study [EOS] visit). A group of 17 subjects with at least 21 MC lesions was evaluated for systemic cantharidin exposure via plasma samples obtained before the first application of VP-102, and at 2 hours, 6 hours, and 24 hours post-application., Results: A total of 33 subjects enrolled in the study (n=17 systemic exposure group, n=16 standard group). There were an equal number of male and female subjects. Subject mean (SD, range) age was 6.7 (3.3, 2&ndash;15) years, with a mean lesion count of 30 (26.1, 3&ndash;113). Complete lesion clearance was achieved in 48.5% of subjects, with a 90.4% reduction in lesions from baseline to the EOS visit. Mean CDLQI score decreased from 2.6 at baseline to 0.38 at the EOS visit. AEs were mild to moderate in severity and expected due to the pharmacodynamic action of cantharidin. There were no serious treatment-related adverse events and no study discontinuations due to treatment. In the systemic exposure group plasma cantharidin levels were below the lower limit of quantitation (LLOQ, 2.5 ng/mL) in 65 of 66 samples., Conclusions: VP-102 treatment resulted in a reduction in lesion counts and improved QoL. Treated subjects had a 48.5% rate of complete clearance of molluscum lesions. Negligible systemic cantharidin exposure was observed in the systemic exposure group. This data demonstrates safety and efficacy of treatment with VP-102 in MC; a widespread viral infection that does not have any current FDA-approved treatments. Significant Finding: Treatment of subjects with MC using VP-102 resulted in negligible systemic cantharidin exposure, as well as a reduction in lesion counts, improved QoL, and a demonstrated efficacy in clearance of new and baseline MC lesions. Meaning: Results of this Phase 2 study demonstrate efficacy and safety outcomes in using VP-102 in MC subjects, and large randomized clinical trials are warranted to compare topical VP-102 with a vehicle control in order to fully evaluate the use of the medication. ClinicalTrials.gov identifier: NCT03186378 J Drugs Dermatol. 2021;20(1):70-75. doi:10.36849/JDD.5626.

COVID-19 healthcare workers (HCWs) require frequent handwashing and use of personal protective equipment (PPE) to prevent infection. However, evidence is emerging that these practices are causing adverse effects on their skin integrity. A single-centre, cross-sectional study of HCWs from an Irish hospital was undertaken to evaluate the degree of COVID-19-related irritant contact dermatitis (ICD) between April and May 2020. Of 270 participants surveyed, 223 (82.6%) reported symptoms of ICD. The hands were the most commonly affected site (76.47%) and the most frequently reported symptom was dry skin (75.37%). Nearly all (268; 99.26%) HCWs had increased hand-washing frequency, but 122 (45.35%) did not use emollients. In the ICD group, 24.7% cited a history of dermatitis compared with 4.3% of unaffected staff (P < 0.001). The ICD group recorded PPE usage for an average of 3.15 h compared with the non-ICD group at 1.97 h (P = 0.21). Promoting awareness of COVID-19-related ICD is vital to highlight prevention and treatment for frontline staff., (© 2020 British Association of Dermatologists.)

The recent COVID-19 pandemic has resulted in increased hand hygiene and hand cleansing awareness. To prevent virus transmission, the Centers for Disease Control and Prevention recommends frequent hand washing with soap and water. Hand hygiene products are available in a variety of forms, and while each of these formulations may be effective against COVID-19, they may also alter skin barrier integrity and function. As health care workers and the general population focus on stringent hand hygiene, the American Contact Dermatitis Society anticipates an increase in both irritant contact and allergic contact hand dermatitis. Alcohol-based hand sanitizers with moisturizers have the least sensitizing and irritancy potential when compared to soaps and synthetic detergents. This article provides an overview of the most frequently used hand hygiene products and their associations with contact dermatitis as well as recommendations from the American Contact Dermatitis Society on how to treat and prevent further dermatitis., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)