Contact sensitization to methylisothiazolinone in Finland--a multicentre study

Background. Antimicrobials constitute the second most common cause of contact allergy to cosmetics. Methylisothiazolinone (MI), previously always used together with methylchloroisothiazolinone (MCI), has recently been approved in the EU for use on its own in cosmetics and also various industrial products. MCI has been classified as an extreme–strong and MI as a strong–moderate sensitizer. Objectives. To study the frequency of positive patch test reactions to MI, and its relevance and relation to MCI/MI sensitivity, in Finland. Methods. Over a period of 3 years (2006–2008), MI 0.1% (1000 ppm) and 0.03% (300 ppm) were patch tested in 10 821 patients at eight Finnish dermatological clinics. During 2008, patients with positive reactions to MI were asked to take part in a repeated open application test (ROAT). Results. Of the patients tested, 1.4% and 0.6% showed positive patch test reactions to 0.1% and 0.03% MI, respectively. Sixty‐six per cent of those who were MI‐positive were also positive to 100 ppm MCI/MI. Thirty‐three agreed to undergo the use test, and 10 of these gave positive results (30%). Conclusions. Our data show that MI used alone also potentially induces contact allergy. Careful monitoring is needed to determine whether or not this antimicrobial is safe to use in cosmetics.     

Contact allergy to common ingredients in hair dyes

Background. It is widely accepted that there is a molecular weight (MW) cut‐off of 500, such that single chemicals with MWs higher than 500 cannot be skin sensitizers. If true, this could serve as a useful principle for designing non‐sensitizing chemicals. Objectives. To assess whether the 500 MW cut‐off is a myth or a reality. Methods. A database of 699 chemicals tested for skin sensitization in guinea pigs or mice was analysed to establish the number of tested chemicals with MW > 500, and to establish whether any of these were sensitizers. Results. Only 13 (2%) of the 699 chemicals in the database have MW > 500. Of the 13 tested compounds with MW > 500 in the database, five are sensitizers and eight are non‐sensitizers. Conclusions. The 500 MW cut‐off for skin sensitization is a myth, probably derived from the widespread misconception that ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potency. The scarcity of sensitizers with MW > 500 simply reflects the general scarcity of chemicals with MW > 500.     

In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT)

Tyrosinase is a key enzyme that catalyses the initial rate‐limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT) had the greatest inhibitory effect and potency as the IC₅₀ value of 5‐HMT was lower than that of kojic acid, widely‐known tyrosinase inhibitor. Based on in silico docking simulation, 5‐HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5‐HMT topical treatment significantly reduced UVB‐induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5‐HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.     

Formaldehyde‐releasers in cosmetics in the USA and in Europe

Background: Frequencies of sensitization to formaldehyde among US patients patch tested for suspected contact dermatitis are higher than in Europe. Cosmetics are an important source of contact with formaldehyde. Objectives: To acquire data on the frequency of use of formaldehyde‐releasers in cosmetics sold in the USA and Europe and their use concentrations. To assess whether any observed differences may contribute to the discrepancies in sensitization rates. Methods: Enquiries with Food and Drug Administration (FDA), the European Cosmetics Association, and the Dutch Cosmetics Association. Reading the labels of skin care cosmetics in a local drugstore. Results: The FDA provided data on the presence of formaldehyde and releasers. Nearly one fifth of all cosmetics contain a releaser. In 25% of 496 examined skin care products, releasers were present. In comparable FDA data categories, the percentage was 24. No data were found on use concentrations of the releasers in cosmetics in either the USA or Europe. Conclusions: The percentages of stay‐on skin care products containing a formaldehyde‐releaser are virtually identical in the USA (FDA data) and our local drugstore sample. However, this does not necessarily imply that cosmetics play no part in the differences in formaldehyde sensitization rates.     

Occupational contact allergy to formaldehyde and formaldehyde releasers

Background: Formaldehyde allergy is common and usually derives from formaldehyde‐releasing biocides in cosmetic and other products. Objectives: To analyse patterns of patch test reactions to formaldehyde and formaldehyde‐releasing compounds and the sources of sensitization. Patients/Methods: At the Finnish Institute of Occupational Health, we screened the patch test files for allergic reactions to formaldehyde and 12 formaldehyde‐releasing compounds. All patients with contact allergy to any of the substances were included, and their records were reviewed. Results: Between January 2001 and May 2007, we had patch tested 81 patients with formaldehyde allergy and 18 with independent allergy to some formaldehyde releaser. Of the formaldehyde allergies, 60 were new sensitizations, 25 of which were considered to be occupational. The most common source of occupational sensitization was metalworking fluids followed by creams and related products. Exposure to formaldehyde‐releasing preservatives in liquid soaps and other rinse‐off products was common in both occupational and non‐occupational cases. Reactions to formaldehyde‐releasing compounds were seen in 79% of the formaldehyde‐allergic patients. Conclusions: Occupational formaldehyde allergy was common and occurred in metalworkers, hairdressers, masseurs, and workers using protective creams, detergents, and liquid soaps. When compared with studies on general dermatological patients, contact allergy to formaldehyde releasers without formaldehyde allergy was rare.     

A human serum‐enriched medium formulation supports high viability and marker expression in primary melanocyte cultures from the outer root sheath and epidermis

Formulating clinically relevant melanocyte cultivation media that maintain the balance between proliferation and maturation to functional melanocytes is a major experimental and regulatory challenge. Within the translation of human melanocytes from the outer root sheath of human hair follicle (HUMORS), we developed a melanocyte medium free of chemical mitogens, chemical melanogenesis enhancers and bovine products, enabling proliferation as well as melanotic differentiation. The formulation involved the replacement of bovine pituitary extract (BPE) and bovine serum (FBS) with human serum (HS) combined with ascorbic acid, CaCl₂, epinephrine, L‐glutamine, insulin and fibroblast growth factor. The cultivation efficiency was characterized through proliferation and exertion of melanotic phenotype, gene and protein expression of melanotic markers and melanin content. Having established an application‐directed BPE‐free formulation, we then re‐formulated a research‐grade medium with BPE for purposes of even more effective in vitro cultivation, adjusted to specific requirements of HUMORS and normal human epidermal melanocytes (NHEM).     

Diverse types of dermatologic toxicities from immune checkpoint blockade therapy

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death 1 (PD‐1) receptor and its ligand (PD‐L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti‐CTCLA‐4 antibody or anti‐PD‐1/PD‐L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti‐PD‐1 and of 556 patients receiving anti‐PD‐L1, DT of any type and grade were reported in 1474 (～39%) and 95 (～17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti‐PD‐1/PD‐L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care     

Patch testing with the textile dyes Disperse Orange 1 and Disperse Yellow 3 and some of their potential metabolites, and simultaneous reactions to para-amino compounds

Background. It is known that, in vitro, human skin bacteria are able to split disperse azo dyes into the corresponding aromatic amines, some of which are sensitizers in the local lymph node assay. We hypothesize that the molecules of disperse dyes migrate onto the skin while garments are worn, and are metabolized and degraded by commensal skin bacteria. These molecules penetrate the skin and induce sensitization. Objectives. To evaluate the elicitation capacities of the possible azo-degradation products of the selected azo disperse dyes in patients allergic to them and to compare it with the elicitation capacities of other para-compunds. Methods. Ten patients allergic to Disperse Yellow 3 (DY3) and/or Disperse Orange 1 (DO1) were patch tested with a dilution series of the purified dyes 4-nitroaniline and p-aminodiphenylamine in concentrations equimolar to those of purified DO1 in the dilution series, as well as 4-aminoacetanilide and 2-amino-p-cresol in concentrations equimolar to those of purified DY3 in the dilution series. Results. Three patterns of patch test reactions could be seen. The 6 patients who were positive to DO1 and DY3 also reacted to p-aminodiphenylamine and 2-amino-p-cresol. Two patients were positive to DO1 only, and both reacted to p-aminodiphenylamine, but to neither 4-aminoacetanilide or 2-amino-p-cresol. Two patients did not react to DO1 or DY3 on this occasion. Conclusion. We show that it is possible that the major sensitizers in contact allergy to DO1 and DY3 are their metabolites, p-aminodiphenylamine and 2-amino-p-cresol, respectively, which might be formed by the azoreductase pathway of skin bacteria.