Increasing non-cosmetic exposure and sensitization to isothiazolinones require action for prevention: Review.

Frequent use of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and MI in cosmetic products has been the main cause of widespread sensitization and allergic contact dermatitis to these preservatives (biocides). Their use in non-cosmetic products is also an important source of sensitization. Less is known about sensitization rates and use of benzisothiazolinone (BIT), octylisothiazolinone (OIT), and dichlorooctylisothiazolinone (DCOIT), which have never been permitted in cosmetic products in Europe. BIT and OIT have occasionally been routinely patch-tested. These preservatives are often used together in chemical products and articles. In this study, we review the occurrence of contact allergy to MI, BIT, OIT, and DCOIT over time, based on concomitant patch testing in large studies, and case reports. We review EU legislations, and we discuss the role of industry, regulators, and dermatology in prevention of sensitization and protection of health. The frequency of contact allergy to MI, BIT, and OIT has increased. The frequency of contact allergy to DCOIT is not known because it has seldom been patch-tested. Label information on isothiazolinones in chemical products and articles, irrespective of concentration, is required for assessment of relevance, information to patients, and avoidance of exposure and allergic contact dermatitis.

Cobalt nanoparticles cause allergic contact dermatitis in humans.

BACKGROUND: Cobalt (Co) causes allergic contact dermatitis (ACD) and the emerging use of Co nanoparticles (CoNPs) warrants gaining further insight into its potential to elicit ACD in sensitized individuals. OBJECTIVES: The aims of the study were to clarify to what extent CoNPs may elicit ACD responses in participants with Co contact allergy, and to evaluate whether the nanoparticles cause a distinct immune response compared with cobalt chloride (CoCl2) in the skin reactions. METHODS: Fourteen individuals with Co contact allergy were exposed to CoNPs, CoCl2, a Co-containing hard-metal disc (positive control), and an empty test chamber (negative control) by patch testing. Allergic responses were evaluated clinically by a dermatologist at Days 2, 4 and 7. At Day 2, patch-test chambers were removed, and remaining test-substance and skin-wipe samples were collected for inductive-coupled plasma mass spectrometry (ICP-MS) analysis. Additionally, skin biopsies were taken from patch-test reactions at Day 4 for quantitative real-time polymerase chain reaction analysis, histopathology and ICP-MS analysis of Co skin penetration. RESULTS: Patch testing with CoNPs elicited allergic reactions in Co-sensitized individuals. At all timepoints, clinical assessment revealed significantly lower frequencies of positive patch-test reactions to CoNPs compared with CoCl2 or to the positive control. CoNPs elicited comparable immune responses to CoCl2. Chemical analysis of Co residues in patch-test filters, and on skin, shows lower doses for CoNPs compared with CoCl2. CONCLUSIONS: CoNPs potently elicit immune responses in Co-sensitized individuals. Even though patch testing with CoNPs resulted in a lower skin dose than CoCl2, identical immunological profiles were present. Further research is needed to identify the potential harm of CoNPs to human health.

Preservatives in non-cosmetic products: Increasing human exposure requires action for protection of health.

The widespread use of skin sensitizing preservatives is well-known. Contact allergy to preservatives is often caused by their presence in cosmetic products. Preservative use in non-cosmetic products is less well-known. We have reviewed European Union (EU) legislations on classification and labelling, biocides and cosmetics, concerning conditions for use of the most used sensitizing preservatives (including formaldehyde-releasing substances, isothiazolinones and parabens). We have analysed temporal trends in their use in non-cosmetic products (tonnes, number of products, concentrations), based on annual reports to the Swedish Products Register 1995-2018; and we discuss implications for stakeholders. Major changes over time are that the use of most of the preservatives has increased by tonnes and/or by number of products, and that several use concentrations have declined following harmonized classification as a skin sensitizer with low concentration limits for this classification. We conclude that the massive increase in use of preservatives is alarming, and that urgent action is needed for protection of health. Their use in non-cosmetic products is broad, increasing and often undisclosed. In the EU, legislations concerning chemicals can provide relevant restrictions to reduce their use and associated health risks, monitored by efficient surveillance. Prevention would be benefited by better coordination between legislations.

Nickel penetration into stratum corneum in FLG null carriers-A human experimental study.

BACKGROUND: The filaggrin gene (FLG) plays a role in skin diseases, with the skin barrier function being impaired in FLG null carriers. The role of FLG status in relation to nickel penetration into the skin remains unclear. OBJECTIVES: To elucidate the association between FLG status and nickel penetration into stratum corneum (SC) in individuals without self-reported history of nickel allergy. METHODS: Forty participants (23 FLG wt and 17 FLG null) were exposed to a nickel solution (80 µg/cm2 ) which was applied onto 2 × 2 cm on their left forearm. After 4 h, the area was tape-stripped with 10 consecutive tapes. Nickel in each tape was quantified using inductively coupled plasma mass spectrometry. RESULTS: The average recovered nickel dose was 35%-48%. A tendency towards lower recovery was seen in FLG null carriers compared to FLG wt carriers, and lower recovery in those with history of skin and/or respiratory symptoms compared to those without such history. This was however not statistically significant. CONCLUSION: FLG null carriers had less nickel recovered by tape strips compared with FLG wt carriers and, compared with individuals without a history of skin and/or respiratory symptoms, indicating higher nickel penetration into SC for FLG null carriers, but further studies are needed.

Suitable test concentration of cobalt and concomitant reactivity to nickel and chromium: A multicentre study from the Swedish Contact Dermatitis Research Group.

BACKGROUND: In Sweden, cobalt chloride 0.5% has been included in the baseline series since the mid-1980s. A recent study from Stockholm showed that cobalt chloride 1% petrolatum (pet.) was more suitable than 0.5%. Cobalt chloride at 1.0% has been patch tested for decades in many European countries and around the world. OBJECTIVES: To study the suitability of patch testing to cobalt 1.0% vs 0.5% and to analyze the co-occurrence of allergy to cobalt, chromium, and nickel. RESULTS: Contact allergy to cobalt was shown in 90 patients (6.6%). Eighty (5.9%) patients tested positive to cobalt 1.0%. Thirty-seven of the 90 patients (41.1%) with cobalt allergy were missed by cobalt 0.5% and 10 (0.7%) were missed by cobalt 1.0% (P < .001). No case of patch test sensitization was reported. Allergy to chromium was seen in 2.6% and allergy to nickel in 13.3%. Solitary allergy to cobalt without nickel allergy was shown in 61.1% of cobalt-positive individuals. Female patients had larger proportions of positive reactions to cobalt (P = .036) and nickel (P < .001) than males. CONCLUSION: The results speak in favor of replacing cobalt chloride 0.5% with cobalt chloride 1.0% pet. in the Swedish baseline series, which will be done 2021.

Filaggrin gene mutations in relation to contact allergy and hand eczema in adolescence.

BACKGROUND: Filaggrin is an important protein for structure and function of the skin barrier. Filaggrin gene (FLG) mutations are known to result in dry skin, impaired skin barrier, and increased risk for atopic dermatitis. However, it is not clear whether these mutations are associated with contact allergy or hand eczema in adolescence. OBJECTIVES: The purpose of this study was to investigate whether FLG mutations are associated with contact allergy, self-reported hand eczema, or dry skin in adolescence. METHODS: We used data from the 16-year follow-up in the BAMSE cohort, information obtained from a Web-based questionnaire including questions on hand eczema and dry skin, from FLG mutation analysis (R501X, R2447X, 2282del4), and patch testing (n = 1822). RESULTS: Logistic regression analyses showed no statistically significant associations between FLG mutations and contact allergy (any contact allergy, nickel allergy, or fragrance allergy) according to patch test, or self-reported hand eczema at 16 years, or hand eczema ever. However, FLG mutations were associated with self-reported dry skin at 16 years. CONCLUSIONS: FLG mutations are associated with self-reported dry skin at 16 years. However, in this study no consistent associations were found between FLG mutations and contact allergy or hand eczema at 16.

Filaggrin variations are associated with PAH metabolites in urine and DNA alterations in blood.

Dermal chemical exposure is common in many professions. The filaggrin protein is important for the skin barrier and variations in the filaggrin gene (FLG) may influence the uptake of chemicals via the skin, and consequently, the degree of systemic effects. The aim of this study was to investigate, in chimney sweeps with occupational exposure to polycyclic aromatic hydrocarbons (PAH) from soot, the influence of variation in FLG on internal PAH dose and DNA alterations, including epigenetic, previously linked to cancer and cardiovascular disease. We used TaqMan PCR to genotype 151 chimney sweeps and 152 controls for four FLG null variants (R501X, R2447X, S3247X and 2282del4) which cause impaired skin barrier, and FLG copy number variation (12th repeat, CNV12) which potentially is beneficial for the skin barrier. The internal dose of PAH was represented by urinary PAH metabolites (e.g. 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene) that we measured by LC-MS/MS. We measured epigenetic alterations (methylation of AHRR and F2RL3) in blood by pyrosequencing; and DNA alterations (telomere length and mitochondrial DNA copy number) by real-time PCR. Hypomethylation of AHRR or F2RL3 is a risk factor for lung cancer and shorter telomere length a risk factor for cardiovascular disease. The frequencies of FLG null were 8.6 and 11.8% (p = 0.35), and CNV12 27.8 and 19.7% (p = 0.09) in chimney sweeps and controls, respectively. We found that among chimney sweeps working predominately with soot sweeping (high PAH exposure), CNV12 carriers had lower concentrations of PAH metabolites in urine compared with non-carriers (median 1-hydroxypyrene = 0.37 vs 0.86 µg/g creatinine respectively; p = 0.025 by linear regression models adjusted for age, BMI and smoking) compared to sweeps not carrying CNV12. Further, FLG null was associated with approximately 2.5% higher methylation of F2RL3 (cg03636183, p = 0.019 after adjustment for exposure group, age, BMI and smoking). FLG null was associated with approximately 7% shorter telomere length (p = 0.015, adjusted model). Our results suggest that FLG variations may influence the dose of PAH in highly exposed workers, possibly via dermal uptake. It also suggests that FLG variation may influence the degree of (epi)genotoxicity in the body. FLG variation is common in the working population and should be considered in risk assessment.

Nickel deposition and penetration into the stratum corneum after short metallic nickel contact: An experimental study.

BACKGROUND: Knowledge about the skin deposition and penetration of nickel into the stratum corneum (SC) after short contact with metallic items is limited. OBJECTIVE: To quantify nickel skin deposition and penetration into the SC after short contact with metallic nickel. METHODS: Sixteen nickel-allergic participants and 10 controls were exposed to 3 pure nickel discs and 1 aluminium disc on each volar forearm for 3 × 10 minutes. Before exposure, 1 forearm was irritated with 0.5% sodium lauryl sulfate under 24-hour occlusion. Immediately, as well as 24 and 72 hours after metallic disc exposure, outer SC layers were removed with adhesive tapes and the nickel content was measured. RESULTS: Nickel deposition and SC penetration capable of eliciting allergic nickel dermatitis were found immediately and after 24 hours. Significantly higher nickel amounts were found on normal skin and in the SC of nickel-allergic participants than in controls both immediately and after 24 hours, and on irritated skin immediately after exposure. CONCLUSIONS: Nickel deposition and SC penetration is considerable after nickel skin exposure of 3 × 10 minutes. Combined with the allergic responses resulting from the same exposures reported previously, this study highlights that short skin exposure to nickel-releasing items may cause allergic nickel dermatitis.

Neglected exposure route: cobalt on skin and its associations with urinary cobalt levels.

OBJECTIVES: Cobalt (Co) exposure is associated with adverse health effects including skin sensitisation, asthma and interstitial lung fibrosis. Exposure to Co in industrial settings is often assessed using air samples or biomonitoring in urine. Skin exposure is rarely measured. Aim of this study was to quantify and compare the importance of Co skin exposure and respiratory exposure in determining urinary Co concentrations. METHODS: Co skin exposure was measured in 76 hard metal workers by acid wipe sampling before and at the end of work shifts. Spot urine was collected during a 24-hour period from the start of a shift. Respiratory exposure was measured by personal inhalable dust sampling during a shift in 30 workers. Co was analysed by inductively coupled plasma mass spectrometry. RESULTS: Quantile regression modelling showed that a doubling of Co on skin before or at the end of shift increased the median urinary concentration of Co by 70% (p<0.001) or 32% (p<0.001), respectively. A doubling of Co in air increased median urinary Co by 38% (p<0.001). Co skin exposures were still significantly associated with urinary Co after excluding a group of workers with high respiratory exposure (33%, p=0.021 and 17%, p=0.002). CONCLUSIONS: The results indicate an association between Co skin exposure and urinary Co concentrations. This should be considered when using urinary Co as a biomarker of exposure.

Contamination of skin and surfaces by cobalt in the hard metal industry.

BACKGROUND: It is well known that hard metal workers have historically been affected by contact allergy to cobalt. Knowledge is sparse about occupational skin exposure to cobalt, in terms of skin doses and sources of exposure, which could be used to improve protection of workers. OBJECTIVES: To improve knowledge about skin doses and sources of skin exposure to cobalt within hard metal production, thereby facilitating better protection of workers. METHODS: Forty workers were sampled on the index finger by acid wipe sampling after 2 hours of work. The samples were analysed with inductively coupled plasma mass spectrometry. Cobalt spot testing was performed in the work environment. RESULTS: The highest skin doses were found among raw material workers. Skin doses among other production workers were also significant. Most office workers had low, but measurable, levels of cobalt on the skin. Glove use varied between workers. Cobalt was found on production equipment, on items in the canteen area, and on handles and buttons throughout the company. CONCLUSIONS: Cobalt skin doses were prominent, and originated from contact with raw materials, sintered materials, and contaminated surfaces. Cobalt was present on surfaces outside production areas. Companies need to identify and reduce skin exposure for protection of workers.

Chromium(III) release from chromium-tanned leather elicits allergic contact dermatitis: a use test study.

BACKGROUND: Chromium (Cr) is a common skin sensitizer. The use of Cr(VI) in leather is restricted in the EU, but that of Cr(III) is not. OBJECTIVES: To assess whether prolonged exposure to Cr-tanned leather with mainly Cr(III) release may elicit allergic contact dermatitis in Cr-allergic individuals. METHOD: Ten Cr-allergic subjects and 22 controls were patch tested with serial dilutions of Cr(III) and Cr(VI), and with leather samples. They then conducted a use test with a Cr-tanned and a Cr-free leather bracelet over a period of 3 weeks, for 12 h per day. Cr deposited on the skin from the bracelets was measured in the controls, and the diphenylcarbazide test for Cr(VI) and extraction tests for Cr(III) and Cr(VI) were conducted for the different leathers. RESULTS: Four of 10 Cr-allergic subjects developed positive reactions to the Cr-tanned bracelet within 7-21 days, whereas only 1 of 10 had a positive patch test reaction to this leather. Cr released from the Cr-tanned leather was most probably entirely Cr(III), with a quantifiable amount being deposited on the skin. CONCLUSIONS: This study strongly suggests that prolonged and repeated exposure to Cr-tanned leather with mainly Cr(III) release is capable of eliciting allergic contact dermatitis in Cr-allergic individuals.

Non-oxidative hair dye products on the European market: What do they contain?

BACKGROUND: Hair dyeing is very common and may cause allergic contact dermatitis. Oxidative (often termed permanent or semi-permanent) hair dye products have constituted the focus of market surveys and toxicological risk assessments, while non-oxidative (semi-permanent, temporary or direct) products have not been assessed. OBJECTIVES: To identify the hair dye substances presently used in non-oxidative hair dye products in Europe. METHODS: Ingredient label data on eligible products in 5 European countries were collected, and 289 different non-oxidative hair dye products were included in this study. RESULTS: Up to 9 hair dye substances were present in each product. Sixty-eight individual hair dye substances were identified on the 289 product labels, and their occurrence ranged from 0.3% to 34%. There were differences concerning substances used and their number per product between products of different consistency and colour. CONCLUSIONS: The hair dye substances in non-oxidative hair dye products are different from those in oxidative hair dye products, and are currently not covered by patch test series. The toxicological and skin-sensitizing profile of the substances in non-oxidative hair dye products, as well as their concentrations, should be further investigated.

Self-testing for contact allergy to hair dyes - a 5-year follow-up multicentre study.

BACKGROUND: In 2011, a multicentre study was conducted in order to determine how hair dye manufacturers instructed consumers to perform a self-test prior to dyeing their hair, in order to identify individuals who are likely to react upon subsequent hair dyeing. A number of concerns were raised concerning the variability in instructions between products and producers, and the safety and validity of this tool. OBJECTIVES: To perform a 5-year follow-up study in order to determine whether manufacturers still recommend a self-test, and if so, whether the procedures have been changed. METHODS: During March 2016, a total of 40 oxidative hair dye products from 21 different manufacturers were bought in retail stores in 8 European countries. RESULTS: The consumers were instructed to perform a self-test prior to hair dyeing for 39 of the products; however, the procedures varied greatly regarding the method of application, the amount of hair dye applied, the location and size of the application area, the number of applications, whether or not rinsing was performed after application, the reading times, and how a positive reaction was defined. CONCLUSIONS: Self-testing is still recommended by almost all manufacturers of permanent hair dyes. There are major variations in the instructions, even in products from the same manufacturer. The previously raised concerns regarding safety and validity still remain.

Isothiazolinones are still widely used in paints purchased in five European countries: a follow-up study.

BACKGROUND: An increasing incidence of contact allergy to methylisothiazolinone (MI) has been seen, caused, in particular, by cosmetic products and paints. A study from 2015 showed that 93.0% of paints bought in five European countries contained MI. New regulations have been discussed for paints in the EU, which may have influenced this market. OBJECTIVES: To re-evaluate the use and concentrations of MI and four other isothiazolinones in water-based wall paints. METHODS: Water-based white wall paints (n = 60) were purchased in retail stores in five European countries: Denmark, France, Germany, Sweden, and the United Kingdom. The paints were analysed for isothiazolione content by the use of high-performance liquid chromatography coupled to ultraviolet detection, and the results were confirmed with high-performance liquid chromatography-tandem mass spectrometry. RESULTS: MI was identified in 55 (91.7%) of the paints, with concentrations ranging from 1.1 to 142.7 ppm. The other isothiazolinones were identified in 20.0% [methylchloroisothiazolinone (MCI)] to 88.3% [benzisothiazolinone (BIT)] of the paints. BIT concentrations varied significantly between countries, whereas MI and MCI concentrations did not. There were no statistically significant differences in MI, MCI and BIT concentrations between the current study and the 2015 study. CONCLUSIONS: MI and other isothiazolinones are widely used in paints available in Europe. Their use does not seem to be decreasing.

Extended documentation for hand dermatitis patients: Pilot study on irritant exposures.

BACKGROUND: Irritant exposure may be a contributory cause or the sole cause of (occupational) hand dermatitis. However, the documentation of irritant exposures in clinical practice is not standardized. OBJECTIVES: To examine the feasibility and usefulness of a form with different items addressing both occupational and non-occupational irritant exposures in a semiquantitative way. METHODS: Between May 2016 and May 2017, successive patients with work-related hand dermatitis, irrespective of aetiology, were examined in 9 specialized European departments. Department-specific investigation was supplemented with the above proforma. The results were recorded by use of an anonymized secured online documentation system in a pilot study. RESULTS: Altogether, 193 patients were included; 114 females and 79 males, with a mean age of 40 years (range 18-68 years). The most common occupational group comprised healthcare workers (n = 35); occupational exposure of the hands to gloves, dusts and water without detergents of >2 hours/day was seen in 54.5%, 24.4% and 24.3% of patients, respectively. Non-occupational exposures rarely exceeded 2 hours/day. CONCLUSIONS: It is hoped that the set of descriptors will offer a basis for (clinical) epidemiological studies assessing the role of irritant exposures in occupational hand dermatitis, and to support a high level of quality and consistency in daily patient care.

Water Exposure on the Hands in Adolescents: A Report from the BAMSE Cohort.

Water exposure on the skin of the hands has previously been studied in adults. The aim of this study was to investigate self-reported water exposure in adolescents in the BAMSE cohort in Stockholm, Sweden. A questionnaire including a question on daily water exposure on the hands was answered by 3,091 adolescents at age 16 years. Exposure < 10 times/day was reported by 28.7% and < 20 times/day by 3.1%; boys had somewhat higher exposure than girls (p = 0.03). In a multivariate analysis, adolescents with dry skin reported higher exposure (adjusted odds ratio (ORadj) 1.4; 95% CI 1.2-1.7), while no statistically significant exposure differences were found in relation to hand eczema or atopic dermatitis. Reported exposure may be considered as baseline exposure during a period of life with limited occupational and domestic duties.

Development, validation and testing of a skin sampling method for assessment of metal exposure.

BACKGROUND: Nickel, cobalt and chromium are frequent skin sensitizers. Skin exposure results in eczema in sensitized individuals, the risk being related to the skin dose. OBJECTIVES: To develop a self-sampling method for quantification of skin exposure to metals, to validate the method, and to assess its feasibility. METHODS: Defined metal doses (0.01-5 µg) were applied to the fingers of 5 participants. Skin areas (2 cm2 ) were sampled with 1% HNO3 , either as 0.1 ml on a swab, or as 0.5 ml on a wipe. Furthermore, 17 participants performed self-sampling by swab after 2 h of leisure activity. Samples were extracted in 1% HNO3 and analysed by inductively coupled plasma mass spectrometry. RESULTS: The sampling efficiency by swab was 46%, as compared with 93% for acid wipe sampling, for all tested doses. Most metal from the skin dose was detected in the first swab (33-43%). Despite lower sampling efficiency by swab, skin doses of metals following 2 h of leisure activity without hand washing were quantified in all participants, and ranged from 0.0016 to 0.15 µg/cm2 , from 0.00014 to -0.0020 µg/cm2 and from 0.00048 to -0.027 µg/cm2 for nickel, cobalt, and chromium, respectively. CONCLUSIONS: The results indicate a future potential of skin sampling by swab to detect and monitor metals on skin by self-sampling. This will contribute to better knowledge of metal skin exposure among dermatitis patients, workers, and the general population.

Hairdressers' skin exposure to hair dyes during different hair dyeing tasks.

BACKGROUND: The high risk of occupational skin disease among hairdressers, caused by skin exposure to irritants and sensitizers, such as hair dye substances, is of great concern. OBJECTIVES: The aim of the present study was to assess how the various tasks involved in hair dyeing contribute to hairdressers' exposure to hair dye, in order to enable the formulation of well-founded recommendations on working routines that will reduce exposure and prevent occupational disease. METHODS: Skin exposure to hair dye was measured for 20 hairdressers applying highlights and all-over hair colour with the hand rinsing technique. Resorcinol was used as a proxy for hair dye exposure. RESULTS: Applying hair dye and cutting the newly dyed hair were the tasks that contributed most to exposure in treatments for highlights. After cutting all-over-coloured hair, all hairdressers had measurable amounts of hair dyes on both hands. CONCLUSIONS: Hairdressers are exposed to hair dye ingredients during all steps of the hair dyeing procedure. Cutting newly dyed hair contributes significantly to exposure. For the prevention of occupational disease resulting from hair dye exposure, we suggest cutting hair before dyeing it, and wearing gloves during all other work tasks.