North American contact dermatitis group patch test results: 2011-2012.

BACKGROUND: Patch testing is an important diagnostic tool for assessment of allergic contact dermatitis (ACD). OBJECTIVE: This study documents the North American Contact Dermatitis Group (NACDG) patch-testing results from January 1, 2011, to December 31, 2012. METHODS: At 12 centers in North America, patients were tested in a standardized manner with a series of 70 allergens. Data were manually verified and entered into a central database. Descriptive frequencies were calculated, and trends analyzed using χ statistics. RESULTS: Four thousand two hundred thirty-eight patients were tested; of these, 2705 patients (63.8%) had at least 1 positive reaction, and 2029 (48.0%) were ultimately determined to have a primary diagnosis of ACD. Four hundred eight patients (9.6%) had occupationally related skin disease. There were 7532 positive allergic reactions. As compared with previous reporting periods (2009-2010 and 2000-2010), positive reaction rates statistically increased for 6 allergens: methylchloroisothiazolinone/methylisothiazolinone (5.0%; risk ratios [RRs]: 2.01 [1.60-2.52], 1.87 [1.61-2.18]), lanolin alcohol (4.6%; RRs 1.83 [1.45-2.30], 2.10 [1.79-2.47]), cinnamic aldehyde (3.9%; 1.69 [1.32-2.15], 1.53 [1.28-1.82]), glutaral (1.5%; 1.67 [1.13-2.48], 1.31 [1.00-1.71]), paraben mix (1.4%; 1.77 [1.16-2.69], 1.44 [1.09-1.92]), and fragrance mix I (12.1%; RRs 1.42 [1.25-1.61], 1.24 [1.14-1.36]). Compared with the previous decade, positivity rates for all formaldehyde-releasing preservatives significantly decreased (formaldehyde 6.6%; RR, 0.82 [0.73, 0.93]; quaternium-15 6.4% RR 0.75 [0.66, 0.85]; diazolidinyl urea 2.1%; RR, 0.67 [0.54, 0.84]; imidazolidinyl urea 1.6%, 0.60 [0.47, 0.77]; bronopol 1.6%; RR, 0.60 [0.46, 0.77]; DMDM hydantoin 1.6%; RR, 0.59 [0.54, 0.84]). Approximately a quarter of patients had at least 1 relevant allergic reaction to a non-NACDG allergen. In addition, approximately one-fourth to one-third of reactions detected by NACDG allergens would have been hypothetically missed by T.R.U.E. TEST (SmartPractice Denmark, Hillerød, Denmark). CONCLUSIONS: These data document the beginning of the epidemic of sensitivity to methylisothiazolinones in North America, which has been well documented in Europe. Patch testing with allergens beyond a standard screening tray is necessary for complete evaluation of occupational and nonoccupational ACD.

Contact sensitivity to preservatives in Singapore: frequency of sensitization to 11 common preservatives 2006-2011.

BACKGROUND: Preservatives are indispensable agents used to prevent bacterial and fungal contamination of cosmetics, personal care products, domestic preparations, and industrial products. OBJECTIVE: We evaluated patch-test data at the National Skin Centre, Singapore, from 2006 to 2011 to identify the trends in preservative contact allergies. METHODS: All patients with suspected contact dermatitis were patch tested to 4 preservatives within the modified European standard series. Patients were also tested with 7 preservatives from our special series if clinically indicated. RESULTS: Three thousand one hundred seventy-seven patients were tested to preservatives in the standard series. Sensitization frequencies were all greater than 1%: parabens (2.58%), methylchloroisothiazolinone/methylisothiazolinone (1.75%), quaternium 15 (1.43%), and methyldibromoglutaronitrile (1.2%). There was no change in trends in sensitization frequencies from 2006 to 2011, with no increase in sensitization frequency to methylchloroisothiazolinone/methylisothiazolinone. The sensitization frequencies for methyldibromoglutaronitrile/phenoxyethanol and diazolidinylurea were 2.03% and 1.37%, respectively, and remained less than 1% for bronopol, imidazolidinyl urea, and 2-phenoxyethanol. A rate of 0% was seen for 1,3-dimethylol-5,5-dimethyl hydantoin and formaldehyde; 9.4% of positive patch-test results became positive only at day 7. CONCLUSIONS: Preservatives are common causes of allergic contact dermatitis. This should be considered when introducing new preservatives into the market. Day 7 readings are important to detect late reactions.

Cutaneous delayed-type hypersensitivity in patients with atopic dermatitis: reactivity to topical preservatives.

BACKGROUND: Patients with atopic dermatitis (AD) have chronic dry skin to which they frequently apply skin care products containing preservatives, and they are predisposed to developing cutaneous delayed-type hypersensitivity. OBJECTIVE: We sought to compare the rates of positive patch test reactions to allergens on the North American Contact Dermatitis Group (NACDG) standard tray among patients with and without AD and to assess whether atopic patients in our database were more likely to patch test positive to preservatives. METHODS: A total of 2453 patients underwent patch testing to the NACDG standard screening series. The incidence of positive patch test reaction among patients with AD (n = 342) and without AD (n = 2111) was assessed. Statistical analysis was done using a χ(2) test. RESULTS: Compared with nonatopic patients, patients with AD were statistically more likely to have positive patch tests. AD was associated with contact hypersensitivity to quaternium-15, imidazolidinyl urea, DMDM hydantoin, and 2-bromo-2-nitropropane-1,3-diol but not to parabens, formaldehyde, or diazolidinyl urea. LIMITATIONS: Only patients suspected of having allergic contact dermatitis were tested. Our population was geographically limited to metropolitan Kansas City, MO, and metropolitan New York City, NY. CONCLUSIONS: Patients with AD should avoid the use of skin care products preserved with formaldehyde releasers.

Protective effect of an intrinsic antioxidant, HMH (5-hydroxy-1-methylhydantoin; NZ-419), against cellular damage of kidney tubules.

HMH (5-hydroxy-1-methylhydantoin; NZ-419) is a mammalian creatinine metabolite and an intrinsic antioxidant. HMH prevents the progression of chronic kidney disease in rats when a sufficient amount is taken orally. We assessed whether intrinsic and higher levels of HMH could protect tubular epithelial cells, LLC-PK(1) cells, against known cellular damage caused by xenobiotics, such as cisplatin and cephaloridine, or by hypoxia/reoxygenation treatment. Both cell damage and peroxidation, monitored as the leakage of lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively, from cells into the media, were inhibited by HMH in a concentration-dependent manner. The minimum effective concentration of HMH (2.5 µM) seemed to be too low for HMH to only be a direct hydroxyl radical scavenger. Additional antioxidant effect(s) inhibiting reactive oxygen species generation and/or modulating signal transduction pathways were suggested. The possibility that intrinsic HMH could be a protectant for the kidney was indicated. At the same time, for sufficient inhibition, higher concentrations than intrinsic HMH concentrations may be necessary. Patterns of efficacies of HMH on LDH and MDA against different kinds of cellular damage were compared with our reported data on those of corresponding, naturally occurring antioxidants. A common and specific inhibitory mechanism as well as common target(s) in kidney injuries were indicated.

Swimming pool contact dermatitis caused by 1-bromo-3-chloro-5,5-dimethyl hydantoin.

BACKGROUND: Bromo-3-chloro-5,5-dimethylhydantoin (BCDMH) is a chemical used as a disinfectant for recreational water. BCDMH was described as being responsible for an epidemic of irritant contact dermatitis in the UK (1983), and its sensitizing capacity was also discussed. OBJECTIVES: The aim of this study was to assess whether BCDMH used to disinfect swimming pools and spas can cause allergic contact dermatitis among its users. METHODS: Ten patients suffering from dermatitis associated with using swimming pools disinfected with BCDMH and 40 controls were studied. Several dilutions of BCDMH, 10% to 1 ppm, were patch tested. RESULTS: All 10 patients studied showed a positive patch test reaction to BCDMH 1% in petrolatum. At least one case showed occupational relevance, with a positive reaction even at 1 ppm. CONCLUSION: On the basis of the clinical findings, the positive patch test reactions to BCDMH, and the negative patch test reactions in controls, the suggested diagnosis was allergic contact dermatitis caused by BCDMH used as a disinfectant in the swimming pool water. Contact allergy should be taken into consideration when patients suffer from swimming pool-associated itchy dermatitis.

Non-fragrance allergens in specific cosmetic products.

OBJECTIVES: Reports about the nature of the ingredients responsible for allergic contact dermatitis caused by specific cosmetic products are scarce. METHODS: Between January 2000 and December 2010, the specific cosmetic products having caused allergic contact dermatitis, as well as the individual allergenic cosmetic ingredients present in them, were recorded by use of a standardized form. RESULTS: Among 11 different categories of cosmetic product, skin care products, followed by hair care and body-cleansing products, were most often involved. The presence of the allergenic ingredient(s) in a specific cosmetic product was confirmed according to the ingredient label in 959 of 1448 records. Six hundred and twenty-one of 959 concerned non-fragrance components, preservatives being responsible for 58% of them. Reactions to formaldehyde and formaldehyde-releasers were most often correlated with body-cleansing products, particularly 2-bromo-2-nitropropane-1,3-diol and skin care products. They were followed by the methylchloroisothiazolinone/methylisothiazolinone mixture, most frequently found as allergens in hair care and intimate hygiene products, and facial cleansers (in the last category together with diazolidinyl urea). Octocrylene was by far the most frequent (photo)allergen in sun care products. CONCLUSIONS: This study provides information on the presence and frequency of allergens in specific causal cosmetic products.

Patch testing with formaldehyde and formaldehyde-releasers: multicentre study in Spain (2005-2009).

BACKGROUND: Formaldehyde and formaldehyde-releasers are common causes of allergic contact dermatitis. OBJECTIVES: To determine the frequency of sensitization to formaldehyde and seven formaldehyde-releasers. To establish and characterize groups of patients according to the results of patch testing. MATERIALS AND METHODS: We performed a 5-year retrospective study, in six Spanish hospitals, of patients with positive patch test reactions to formaldehyde or any of seven formaldehyde-releasers. RESULTS: The most frequent allergens were formaldehyde (1.72%), imidazolidinyl urea (1.05%), quaternium-15 (0.88%), and diazolidinyl urea (0.79%). Patients with sensitization to only formaldehyde had a higher frequency of occupational dermatitis (25%) than patients with sensitization to only formaldehyde-releasers (9.5%). The most common sites of dermatitis were the hands (31.7%) in patients with sensitization to only formaldehyde and the face and legs (31.3% and 24.6%) in patients with sensitization to only formaldehyde-releasers. We found a subgroup of 25 patients who were sensitized to both imidazolidinyl urea and diazolidinyl urea, and only 6 of these (24%) were also sensitized to formaldehyde. CONCLUSIONS: The inclusion of imidazolidinyl urea and diazolidinyl urea in the baseline series of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) should enable better classification of patients allergic to formaldehyde, and could aid in their management.

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.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 1. Characterization, frequency and relevance of sensitization, and frequency of use in cosmetics.

In this part of a series of review articles on formaldehyde-releasers and their relationship to formaldehyde contact allergy, formaldehyde-releasers in cosmetics are discussed. In this first part of the article, key data are presented including frequency of sensitization and of their use in cosmetics. In Europe, low frequencies of sensitization have been observed to all releasers: 2-bromo-2-nitropropane-1,3-diol 0.4-1.2%, diazolidinyl urea 0.5-1.4%, imidazolidinyl urea 0.3-1.4%, quaternium-15 0.6-1.9% (for DMDM hydantoin no recent data are available). All releasers score (far) higher prevalences in the USA; the possible explanations for this are discussed. The relevance of positive patch test reactions has been insufficiently investigated. In the USA, approximately 20% of cosmetics and personal care products (stay-on products: 17%, rinse-off products 27%) contain a formaldehyde-releaser. The use of quaternium-15 is decreasing. For Europe, there are no comparable recent data available. In the second part of the article, the patch test relationship of the releasers in cosmetics to formaldehyde contact allergy will be reviewed and it will be assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals who have contact allergy to formaldehyde.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 2. Patch test relationship to formaldehyde contact allergy, experimental provocation tests, amount of formaldehyde released, and assessment of risk to consumers allergic to formaldehyde.

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

Temporal trends of preservative allergy in Denmark (1985-2008).

BACKGROUND: Most cosmetics and industrial products contain preservatives. Preservative allergy is common and, historically, changing contact allergy epidemics caused by preservatives have been observed. In 1997, Alan Dillarstone predicted a stable development of preservative allergy following mandatory ingredient labelling on cosmetic products. OBJECTIVES: To investigate the development in the prevalence of preservative allergy in Denmark over a 24-year period (1985-2008) and to challenge the prediction made by Dillarstone. PATIENTS/METHODS: A retrospective analysis of patch test data was performed (n = 18179). Comparisons were made using a chi(2) test. Logistic regression analyses were used to test for associations. RESULTS: The development of preservative allergy mirrored those of other European patch test centres. The development was not dependent on sex or age group. The prevalence was higher among women and those aged 41-60 years. Formaldehyde allergy was persistently prevalent over the study years. The overall prevalence of preservative allergy increased significantly (P(trend) = 0.001), mainly because of patch testing with additional preservatives in recent years. CONCLUSIONS: Dillarstone's prediction was confirmed as the prevalence of contact allergy to individual preservatives remained relatively stable. However, the overall burden of preservative allergy seemed to increase. Introduction of new preservatives may add to the burden of contact allergy.

Effect of polyunsaturated fatty acids on diphenyl hydantoin-induced genetic damage in vitro and in vivo.

Phenytoin sodium/diphenyl hydantoin (DPH) is used by a major segment of epileptics and neuro surgery patients with head injury to prevent seizures. DPH is a known mutagen, carcinogen, and teratogen. Essential fatty acids (EFAs) are critical for various tissues and were reported to act as anti-mutagenic agents. In the present study we assessed the effect of five EFAs on DPH-induced genetic damage both in vitro and in vivo. DPH induced significant genetic damage. Of all the EFAs (linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, dihomo-gamma-linolenic acid, and eicosapentaenoic acid) studied, all except eicosapentaenoic acid showed significant decrease in DPH induced genetic damage as assessed by micronucleus (MN) test. However, gamma-linolenic acid (GLA) was found to be the most effective in reducing the number of MN containing lymphocytes both in vitro and in vivo to control values. EFAs when tested alone produced insignificant increase in the amount of genetic damage but when tested in combination with DPH the number of micronuclei containing lymphocytes was reduced; but the DNA ladder pattern, an indication of DNA damage, was increased. This apparently paradoxical action of EFAs, especially of GLA, suggests that, in all probability, fatty acids induce apoptosis of cells that harbor significant DNA damage. Based on these results we suggest that GLA functions as a unique endogenous molecule that protects cells from accumulating genetic damage.

Sensitivity of petrolatum and aqueous vehicles for detecting allergy to imidazolidinylurea, diazolidinylurea, and DMDM hydantoin: a retrospective analysis from the North American Contact Dermatitis Group.

OBJECTIVE: To determine whether petrolatum or aqueous vehicles are more sensitive for detecting allergy to imidazolidinylurea (IU), diazolidinylurea (DU), and dimethylol dimethyl hydantoin (DM). The relationship of these allergens to formaldehyde sensitivity was also explored. METHODS: Retrospective analysis of patients patch-tested by the North American Contact Dermatitis Group. All patients were simultaneously tested to seven allergens (formaldehyde, IU in petrolatum [pet], IU aqueous [aq], DU pet, DU aq, DM pet, and DM aq). Data were analyzed in pairs with various "gold standard" definitions of "true allergy" and adjusting for correlated data. RESULTS: Reaction to at least one of the seven allergens occurred in 2,398 patients. In all cases except one (which just approached statistical significance), the petrolatum-based allergen was statistically significantly more sensitive than the same allergen in an aqueous base. Most of the patients allergic to the three preservatives were also allergic to formaldehyde, but most formaldehyde-allergic patients were not allergic to the IU, DU, or DM. CONCLUSION: Of these two vehicles, petrolatum is significantly more sensitive than an aqueous vehicle is for detecting allergy to IU, DU, and DM.

Structure and potential mutagenicity of new hydantoin products from guanosine and 8-oxo-7,8-dihydroguanine oxidation by transition metals.

In vitro work in this laboratory has identified new DNA lesions resulting from further oxidation of a common biomarker of oxidative damage, 8-oxo-7,8-dihydroguanine (OG). The major product of oxidation of OG in a nucleoside, nucleotide, or single-stranded oligodeoxynucleotide using metal ions that act as one-electron oxidants is the new nucleoside derivative spiroiminodihydantoin (Sp). In duplex DNA an equilibrating mixture of two isomeric products, guanidinohydantoin (Gh) and iminoallantoin (Ia), is produced. These products are also formed by the overall four-electron oxidation of guanosine by photochemical processes involving O(2). DNA template strands containing either Sp or Gh/Ia generally acted as a block to DNA synthesis with the Klenow exo(-) fragment of pol I. However, when nucleotide insertion did occur opposite the lesions, only 2'-deoxyadenosine 5-triphosphate and 2'-deoxyguanine 5-triphosphate were used for primer extension. The Escherichia coli DNA repair enzyme Fpg was able to remove the Sp and Gh/Ia lesions from duplex DNA substrates, although the efficiency was depended on the base opposite the lesion.

Transposition of the great arteries and hypocalcemia in a patient with fetal hydantoin syndrome.

We report a patient with fetal hydantoin syndrome (FHS) with associated d-transposition of the great arteries (d-TGA) and persistent hypocalcemia. d-TGA and hypocalcemia have each been individually reported once in association with FHS, but these patients were also prenatally exposed to phenobarbital. To our knowledge, this is the first report of these problems occurring after prenatal exposure to hydantoin alone. The combination of congenital heart disease and hypocalcemia in our patient raises the possibility of a hydantoin effect on neural crest migration.