Introduction

Hand dermatitis (HD) can have a significant impact on quality of life of those affected. It may interfere with activities both at work and in the home and can be associated with social and psychological distress.^1,2 The chronic form, chronic hand dermatitis (CHD) affects up to 10% of the population, which can have a considerable societal impact.² Canadian Guidelines for the management of chronic hand dermatitis have been published to help guide management of this burdensome condition.³ This article provides helpful practical guidance for the general practitioner in the management of patients with HD.

Abbreviations: CHD – chronic hand dermatitis; ENT – ear, nose, and throat; HD – hand dermatitis; KOH – potassium hydroxide; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroid(s)

Diagnosing HD – Important points to cover:

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposure to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum as needed.

Figure 1.
Examples of hand dermatitis(HD)

Determining if HD is Acute or Chronic

Figure 2.
Establish diagnosis of acute hand dermatitis and chronic hand dermatitis (CHD). HD – hand dermatitis

• It is important to first differentiate between acute and chronic forms of HD, as the treatment options may vary.
• Acute HD lasts less than 3 months or occurs only once in a calendar year.
• CHD lasts for at least 3 months and/or patients experience at least 2 relapses in a calendar year.

TIP: Could This Be Tinea?

• Check the feet for signs of tinea pedis and onychomycosis.
• Look for an active border suggestive of tinea.
• Take a skin scraping for KOH microscopy and culture.

TIP: Could This Be Psoriasis?

• Check the feet, scalp, elbows, knees, gluteal cleft and umbilicus for signs of psoriasis.
• Check the nails for signs of psoriasis: pitting, onycholysis, subungual hyperkeratosis, splinter hemorrhages, salmon patches (oil drops).

Prevention, Avoidance and Patient Education

• Every patient with HD, whether acute or chronic, should protect their hands and avoid irritants and exacerbating factors.
• Avoid wet work, frequent hand washing and alcohol-based hand sanitizers.
• Gloves should be worn to protect the hands: cotton gloves at home, or during the night; gel padded gloves for friction and protective gloves for wet work and irritant exposure.
• The following tips are provided for patients on what to use, what to avoid and helpful common practices.

Assessing and Encouraging Patient Adherence

• Ask patients to bring products and prescriptions to follow up appointments to assess usage.
• More frequent patient follow up visits improve adherence.
• Provide education on the disease, treatment options and potential side effects of therapy.
• Choose treatment in agreement with the patient.
• Suggest joining a support group or organization, such as the Eczema society of Canada ( https://eczemahelp.ca/).

Emollient Therapy

• All patients with HD should use a bland, rich emollient to help restore the skin barrier, and apply frequently throughout the day.
• Regular application may prevent itching and reduce the number of flares.
• For hyperkeratotic eczema, patients should use an emollient with keratolytic agent (salicylic acid 10-20% or urea 5-10%).
• Unscented petroleum jelly is inexpensive and helpful for many patients.

Management of Acute HD

• It is important to make a diagnosis of acute HD so that treatment can be started as quickly as possible to maximize the outcome and prevent chronic involvement.
• Patients with HD should be adequately counselled on prevention and avoidance strategies.
• Avoidance of irritants, potential allergens and regular use of emollients is essential.
• Early treatment includes control of flares with a potent or super-potent topical corticosteroid (TCS) applied twice daily. For example, clobetasol propionate 0.05% ointment applied twice daily is generally effective in acute flares.
• For less severe flares, consider betamethasone valerate 0.1% ointment applied twice daily until controlled.
• In more severe cases, systemic steroids (prednisone, intramuscular triamcinolone) should be considered. Prednisone starting at 40-50 mg orally once a day and tapering over three weeks is an effective treatment course.
• Avoid short courses of prednisone as the condition may flare again, so a tapering dose is advised.
• Look for signs of infection and treat concomitantly.
• Try to identify any allergen exposures and recommend avoidance. If allergy is suspected, the patient should be referred for patch testing.
• Once controlled, consider maintenance therapy with topical calcineurin inhibitors (TCIs), such as tacrolimus 0.1% ointment twice daily when necessary, or twice weekly as maintenance therapy.

Figure 3.
Severity-based treatment algorithm for the management of hand dermatitis (HD). CS – corticosteroid; TCS – topical corticosteroid

QoL Consideration

• Patients with mild or moderate CHD who have a significant impact on QoL should be managed as severe CHD.

Did You Know?

• Hydrocortisone topical agents should not be recommended for most cases of HD because it is rarely effective and patients may become sensitized.
• Hydrocortisone is responsible for the majority of allergies to topical steroid products.

Management of Chronic HD

• The treatment plan for CHD depends on whether it is mild, moderate or severe.

Management of Mild CHD

• Patients with mild CHD should be educated on proper prevention and avoidance strategies as outlined earlier.
• Regular emollient therapy should be used to restore and maintain the skin barrier.
• TCS therapy should be initiated with betamethasone valerate 0.1% ointment twice daily for 4-8 weeks.
• If not responding, adherence to the treatment plan should be assessed. Ask the patient to bring medication to follow up appointment to assess amount of product actually used.
• The patient can then be counselled on proper use of the product and provide support for ongoing management.
• If not responding with an adequate trial, a higher potency TCS, such as clobetasol priopionate 0.05% ointment should be prescribed as next line therapy. Reassess after 2 weeks. If not responding to an adequate trial of a potent or super potent TCS, the patient should be considered to have moderate CHD.

Figure 4.
Treatment algorithm for the management of mild chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

TIP: Always assess adherence, reconsider the diagnosis and rule out contact allergens, concomitant infection or colonization when patients do not respond to therapy.

Management of Moderate CHD

• In addition to regular use of emollients, patients with a diagnosis of moderate CHD should be given a 4-8 week trial of a moderate TCS, such as betamethasone valerate 0.1% ointment, or a super potent TCS, clobetasol propionate 0.05% ointment for a 2-week trial. If improved, the patient can continue this as necessary, for control of the condition.
• Another option is maintenance with a TCI, such as tacrolimus 0.1% ointment twice a day as needed, or twice weekly for maintenance. If not improved, reconsider the diagnosis and assess the patient for adherence.
• If a diagnosis of moderate CHD is confirmed, consider treating the patient with a course of phototherapy, if accessible. If unavailable or the patient does not respond, consider treating as severe CHD.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 5.
Treatment algorithm for the management of moderate chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Safety Tip

When patients show signs of adverse effects to TCS, including
atrophy or telangiectasias or they cannot tolerate topical steroid
use, consider TCI (tacrolimus ointment 0.1%) as a non-steroid
topical therapy option for treatment and maintenance.

When to Refer

• Patients with CHD should be referred to a dermatologist when:
  • They may require patch testing
  • They are not responding to therapy
  • Condition is worsening instead of improving
  • Require phototherapy

Management of Severe CHD

• Patients who are diagnosed with severe CHD, patients with mild to moderate CHD who have failed an adequate trial on therapy, or patients who have a significant impact on the QoL, should be treated as having severe CHD.
• Treatment should be initiated with a potent or super-potent TCS, such as clobetasol propionate 0.05% ointment twice a day for 4-8 weeks (2 weeks on dorsal hands if super potent). If improved, patients may continue to use on an as needed basis, or switch to a TCI for ongoing maintenance therapy.
• Patients should be reassessed at 4-8 weeks. If they are not responding to therapy, consider adherence and review proper care.
• A course of phototherapy may also be considered if available.
• Treatment with oral alitretinoin (30 mg orally, once a day) is the next line of therapy based on best available evidence.⁴ Alitretinoin should be prescribed by those who are comfortable with prescribing retinoids.
• As with all retinoids, caution should be used in females of child bearing potential due to teratogenic potential. Monitoring of therapy with regular blood tests for hepatotoxicity and alterations in lipid profile is also recommended.
• If the patient responds to therapy, it should be continued for 3-6 months and reassessed at that time. Patients may discontinue therapy at this point, and continue with ongoing maintenance with topical therapy. If, in the future, they experience a flare, they can be retreated with alitretinoin.⁵
• If a patient does not respond to 12 weeks of alitretinoin, they should be referred for confirmation of diagnosis and other treatment options, which would include treatment with immunosuppressive therapy such as cyclosporine, methotrexate, mycophenolate mofetil or azathioprine.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 6.
Treatment algorithm for the management of severe chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Conclusion

HD can have a significant burden on the patient with an impact on
QoL. Early diagnosis of acute or chronic HD is important for optimal
management. Other conditions such as tinea manuum and psoriasis
need to be ruled out and managed appropriately. Once a diagnosis of
HD is confirmed, treatment depends on the severity of the disease.
A treatment algorithm has been developed to assist the general
practitioner to make a diagnosis and either refer or treat accordingly.
Whichever treatment option is prescribed, all patients should be
educated on emollient therapy, hand protection and avoidance of
irritants or allergens, which may be contributing to their disease.

References

1. Diepgen TL, Agner T, Aberer W, et al. Management of chronic hand eczema. Contact Dermatitis 2007;57:203-10, doi:10.1111/j.1600- 0536.2007.01179.x.
2. Agner T. Hand eczema. In: Johansen JD, Frosch PJ, Lepoittevin J-P, editors. Contact dermatitis. 5th ed. Berlin: Springer-Verlag; 2011. p. 395-406
3. Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, Agner T, Barber K, Bissonnette R, Ho V, Shear NH, and Toole J. Canadian Hand Dermatitis Management Guidelines. J Cut Med Surg 2010; 14(6): 267-284
4. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. Br J Dermatol 2008;158:808-17, doi:10.1111/j.1365- 2133.2008.08487.x.
5. Bissonnette R, Worm M, Gerlach B, et al. Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol 2009;162:420-6, doi:10.1111/j.1365-2133.2009.09572.x.
6. Veien NK, Larsen P, Thestrup-Pedersen K, and Schou G. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate British Journal of Dermatology Volume 140( 5): 882-886, May 1999
7. Krejci-Manwaring J, McCarty MA, Camacho F, Manuel J, Hartle J, Fleischer A Jr and Feldman SR: Topical tacrolimus 0.1% improves symptoms of hand dermatitis in patients treated with a prednisone taper. J Drugs Dermatol. 7:643-646. 2008. PubMed/NCBI
8. Thestrup-Pedersen K, Andersen KE, Menne T, and Veien NK. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single blind placebo controlled study. Acta Derm Venereol 2001; 81: 353-355
9. Granlund H, Erkko P , Eriksson E , and Reitamo S. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema. Acta Dermato-venereologica [1996, 76(5):371-376]

¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Division of Dermatology, St. Paul’s Hospital, Vancouver, BC, Canada

ABSTRACT

Parabens are preservatives used in a variety of personal care, cosmetic, pharmaceutical and food products. Studies have confirmed the ubiquitous presence of parabens, with levels detected in wastewater, rivers, soil and house dust. Parabens have also been detected in human tissues and bodily fluids, but it is the discovery of these chemical compounds in the breast tissue of patients with breast cancer that has raised public concern over their use. It is hypothesized that the estrogenic properties of parabens may play a role in breast cancer development. However, studies investigating the health effects of parabens are conflicting. At this point, there is an insufficient amount of data suggesting serious consequences from paraben use and exposure to warrant drastic avoidance measures or government regulations.

Key Words:
parabens, preservatives, cosmetic products, breast cancer, spermatotoxicity, regulations, environment

Introduction

Parabens are preservatives that are used in a wide range of cosmetic, pharmaceutical and some food products. Parabens are esters of para-hydroxybenzoic acid and commonly include methylparaben, ethylparaben, propylparaben and butylparaben.¹ The recent health concerns regarding parabens stem from a study published in 2004 that detected parabens in breast tissue from patients with breast cancer.² Public pressure has persuaded several governments to introduce regulations on the use of parabens in consumer products. In this review, we examine the data regarding the health effects of parabens to provide physicians and patients with a better understanding of this issue.

Consumer Products and Parabens

Parabens have been used in food, cosmetic and pharmaceutical products since the 1930s. Their use in cosmetic consumer products is more prevalent than their utility elsewhere. Products found to contain parabens include hand soap, body lotion, shampoo, conditioner, face lotion, facial cleansers, foundation, lipstick, mascara, hair spray/mousse/gel, toothpaste and sunscreen.^1,3,4 One study identified parabens in 44% of cosmetics tested.³ In personal care products tested in the US, concentrations of methylparaben up to 1.0% were found, with lipsticks containing the highest concentration ranging from 0.15% to 1.0%.¹ The other parabens are used at concentrations lower than methylparaben in personal care products. Methylparaben and propylparaben are the most commonly used parabens in pharmaceutical products at concentrations of up to 20%;¹ both of these preservatives are also used in food products such as jams, jellies, fillings and toppings at concentrations of up to 0.1%.^1,5

Parabens in the Environment

Parabens have been found in urban streams into which treated or untreated effluent from wastewater treatment plants flows.^6,7 Consequently, these chemical compounds have been identified in rivers and drinking water sources.^6,8 Parabens have been detected in soil from agricultural fields, possibly from irrigation or fertilization practices.^9,10 The dust in houses has also been found to contain parabens.^11,12 Although commercially used parabens are of synthetic origin, some parabens are produced by living organisms, specifically by plants and microbes, e.g., a marine bacterial strain belonging to the genus Microbulbifer.¹³ Plants such as blueberries, carrots, olives, strawberries and others produce parabens (mainly methylparaben) for its presumed antimicrobial activity.^14-16 Overall, the concentrations of parabens within the environment are low with water concentrations around 7 ng/L and effluent concentrations up to 6 µg/L, soil concentrations range from 0.5 to 8 ng/g while house dust contained up to 2400 ng/g.7-11

Parabens in the Human Body

Parabens can enter the human body through the skin and parenterally. The average daily total personal paraben exposure is estimated to be 76 mg, with cosmetics and personal care products accounting for 50 mg, 25 mg from pharmaceutical products, and 1 mg from food.^17-19 Parabens applied to the skin are metabolized by keratinocyte carboxylesterases and the conjugated metabolites are excreted in urine and bile.^20,21 Oral or intravenous parabens are metabolized by esterases within the intestine and liver.¹ Parabens have been detected in urine, serum, breast milk and seminal fluid, but most worrisome has been the detection in breast tissue from patients with breast cancer.^2,22-26 Some have hypothesized that the higher concentration in the upper lateral breast near the axilla correlates with exposure from underarm deodorant and an increased incidence of breast cancer development in the area.^27,28 Still absolute concentrations indicate that levels of paraben within human fluids and tissue are low with average urine concentrations reported in the US ranging from 0.5 to 680 ng/mL and breast tissue concentrations ranging from 0 to 5100 ng/g of breast tissue (the median being 85.5 ng/g).^25,26 These low concentrations should be interpreted in the context of known estrogenic effects of parabens, which are discussed in the next section.

Toxicity and Adverse Effects of Parabens

Human and animal studies have failed to show that parabens have any acute toxicity by various routes of administration. As such, many of the studies examining paraben toxicity have focused on the long-term effects of chronic exposure.

The estrogenic activity of parabens was first identified in 1998 and has since been validated in vitro and in vivo.^1,29,30 Parabens bind human estrogen receptors, although with affinities 10,000 to 1,000,000 times less than estradiol.^29,31 Butylparaben and propylparaben have higher estrogenic activity than methylparaben or ethylparaben, but butylparaben and propylparaben are detected at concentrations 10 to 1000 times less than methylparaben in humans.³² The estrogenic effects in vivo have been demonstrated by uterotrophic (uterine growth) assays in mice and rats.^1,33 However, this effect did not prevent implantation of a fertilized egg, which is considered the most sensitive measure of estrogen toxicity.^33,34 As mentioned, it has been hypothesized that the estrogenic activity of parabens may promote breast cancer development. The concentration of estradiol in normal human breast tissue is 55.3 pg/g, suggesting there is a safety margin of 10 to 1000 times for parabens to approximate normal estradiol activity.^1,25,32 The paraben breast cancer data shows no or low parabens in a subset of patients and there are no comparisons with normal controls.^2,25 Hence, having not established a clear correlation, it is difficult to put forth a causal relationship between parabens and breast cancer development.

Another major area of study has been the effect of parabens on the male reproductive system, but findings are conflicting.³⁵ One in vitro study found that human sperm were not viable when exposed to parabens at concentrations of 1 mg/mL.³⁶ In vivo studies in mice did not replicate this result, with no spermatotoxic effects at paraben concentrations of 1%.³⁷ Conflicting results have also been reported in rats, with one study showing decreased sperm number and activity while another study found no adverse reproductive effects.^35,38 In humans, men with fertility problems including low sperm count and decreased motility were assayed for paraben exposure by measuring urine paraben levels.²³ No correlation between sperm count or motility and parabens levels was found.

Parabens, as is the case for many preservatives, can be allergenic in a small subset of the population. This sensitization commonly manifests as an eczematous rash. The rates of reported sensitization to parabens range from 0.5% to 3.5%.¹⁷ These rates of sensitization are amongst the lowest of all preservatives.^17,18 In addition, there are reports of immediate immunoglobulin Emediated allergic reactions to parabens resulting in urticaria and, in one case, bronchospasm.^39,40 However, these immediate allergic reactions are extremely rare.

Government and Regulatory Control of Parabens

Government regulatory boards have examined parabens and most have agreed that current concentrations of parabens are safe for consumer use. The European Union (EU) has set up limits on paraben use that have also been reviewed by the European Scientific Committee on Consumer Products (SCCP). In 2006, the SCCP concluded that parabens can be safely used in cosmetic products at concentrations of 0.4% for any individual paraben and 0.8% for total paraben concentrations.^1,41 These limits echo the legislative limits put in place by the EU. The Danish government went further in 2011 by banning the use of parabens in personal care products intended for children younger than 3 years of age. This decision is based on the possibility of high systemic absorption from an immature metabolism and skin barrier dysfunction.⁴² In the United States, the Cosmetic Ingredient Review (CIR) assesses ingredients for safety and is reviewed by the US Food and Drug Administration (FDA). The CIR has recommended the same maximum paraben concentrations as suggested by the SCCP and as legislated by the EU.¹ However, it should be noted that the CIR recommendations are only guidelines and manufacturers are not required to follow them. Likewise in Canada, there are no laws regulating paraben concentrations, but Health Canada agrees with the FDA and the CIR in regards to the safety of parabens and the adoption of maximum concentration guidelines.⁴³

Alternatives to Parabens

There are numerous preservatives that could be used in place of parabens. Some other commonly used preservatives include formaldehyde, quaternium-15, imidazolidinyl urea, diazolidinyl urea and dimethyloldimethyl hydantoin.¹⁸ These preservatives more commonly cause allergic reactions and some pose more serious health implications, such as formaldehyde and its causal link with cancer.¹⁸ The use of “natural” preservatives has been advocated, including grapefruit seed extract (GSE).⁴⁴ Unfortunately, GSE can interact with medications due to its ability to inhibit CYP3A4, an important enzyme involved in drug metabolism.⁴⁵ Other natural preservatives include thymol, cinnamaldehyde, allyl isothiocyanate, citric acid, ascorbic acid and rosemary extract.^46,47 These natural preservatives inhibit microbial growth in vitro, but the few studies testing antimicrobial activity in food products have provided equivocal results.^46,48,49 Therefore, further studies to determine their efficacy, safety and toxicology are warranted before widespread use.

Conclusion

The expectation of long shelf lives and microorganism-free consumer products mandates the use of preservatives. Ideally, preservatives should be active at low concentrations against a wide variety of microorganisms without interfering with other ingredients in the product, while also remaining nontoxic to humans and available at low cost to manufacturers. Parabens have been used for over 80 years and, despite reports of adverse reactions, they have proven to be amongst the safest and most well tolerated preservatives. Although the possible association of parabens with decreased sperm quality and breast cancer does warrant continued examination, the current data does not support drastic regulations or personal restrictions to exposure. Other recently regulated chemicals, such as phthalates and bisphenol A, may serve as archetypes for continued vigilance and investigation.^50,51

References

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34. Daston GP. Developmental toxicity evaluation of butylparaben in Sprague- Dawley rats. Birth Defects Res B Dev Reprod Toxicol. 2004 Aug;71(4):296-302.
35. Kang KS, Che JH, Ryu DY, et al. Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). J Vet Med Sci. 2002 Mar;64(3):227-35.
36. Song BL, Li HY, Peng DR. In vitro spermicidal activity of parabens against human spermatozoa. Contraception. 1989 Mar;39(3):331-5.
37. Oishi S. Effects of butyl paraben on the male reproductive system in mice. Arch Toxicol. 2002 Jul;76(7):423-9.
38. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol. 2004 Nov;42(11):1845-9.
39. Grzanka A, Misiolek H, Filipowska A, et al. Adverse effects of local anaesthetics – allergy, toxic reactions or hypersensitivity. Anestezjol Intens Ter. 2010 Oct;42(4):175-8.
40. Kajimoto Y, Rosenberg ME, Kytta J, et al. Anaphylactoid skin reactions after intravenous regional anaesthesia using 0.5% prilocaine with or without preservative–a double-blind study. Acta Anaesthesiol Scand. 1995 Aug;39(6):782-4.
41. U.S. Food and Drug Administration. Parabens. Available at: http://www. fda.gov/cosmetics/productandingredientsafety/selectedcosmeticingredients/ ucm128042.htm. Updated: October 31, 2007. Accessed: October 4, 2012.
42. Boberg J, Taxvig C, Christiansen S, et al. Possible endocrine disrupting effects of parabens and their metabolites. Reprod Toxicol. 2010 Sep;30(2):301-12.
43. Health Canada. Consumer product safety: Safety of cosmetic ingredients.
44. von Woedtke T, Schluter B, Pflegel P, et al. Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained. Pharmazie. 1999 Jun;54(6):452-6.
45. Brandin H, Myrberg O, Rundlof T, et al. Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy. Eur J Clin Pharmacol. 2007 Jun;63(6):565-70.
46. Schirmer BC, Langsrud S. Evaluation of natural antimicrobials on typical meat spoilage bacteria in vitro and in vacuum-packed pork meat. J Food Sci. 2010 Mar;75(2):M98-M102.
47. Kunicka-Styczynska A, Sikora M, Kalemba D. Antimicrobial activity of lavender, tea tree and lemon oils in cosmetic preservative systems. J Appl Microbiol. 2009 Dec;107(6):1903-11.
48. Fratianni F, De Martino L, Melone A, et al. Preservation of chicken breast meat treated with thyme and balm essential oils. J Food Sci. 2010 Oct;75(8):M528-35.
49. Hakkim FL, Mathiraj, Essa MM, et al. Evaluation of food protective property of five natural products using fresh-cut apple slice model. Pak J Biol Sci. 2012 Jan;15(1):10-8.
50. Erler C, Novak J. Bisphenol a exposure: human risk and health policy. J Pediatr Nurs. 2010 Oct;25(5):400-7.
51. Kamrin MA. Phthalate risks, phthalate regulation, and public health: a review. J Toxicol Environ Health B Crit Rev. 2009 Feb;12(2):157-74.

¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Division of Dermatology, St. Paul’s Hospital, Vancouver, BC, Canada

ABSTRACT

Parabens are preservatives used in a variety of personal care, cosmetic, pharmaceutical and food products. Studies have confirmed the ubiquitous presence of parabens, with levels detected in wastewater, rivers, soil and house dust. Parabens have also been detected in human tissues and bodily fluids, but it is the discovery of these chemical compounds in the breast tissue of patients with breast cancer that has raised public concern over their use. It is hypothesized that the estrogenic properties of parabens may play a role in breast cancer development. However, studies investigating the health effects of parabens are conflicting. At this point, there is an insufficient amount of data suggesting serious consequences from paraben use and exposure to warrant drastic avoidance measures or government regulations.

Key Words:
parabens, preservatives, cosmetic products, breast cancer, spermatotoxicity, regulations, environment

Introduction

Parabens are preservatives that are used in a wide range of cosmetic, pharmaceutical and some food products. Parabens are esters of para-hydroxybenzoic acid and commonly include methylparaben, ethylparaben, propylparaben and butylparaben.¹ The recent health concerns regarding parabens stem from a study published in 2004 that detected parabens in breast tissue from patients with breast cancer.² Public pressure has persuaded several governments to introduce regulations on the use of parabens in consumer products. In this review, we examine the data regarding the health effects of parabens to provide physicians and patients with a better understanding of this issue.

Consumer Products and Parabens

Parabens have been used in food, cosmetic and pharmaceutical products since the 1930s. Their use in cosmetic consumer products is more prevalent than their utility elsewhere. Products found to contain parabens include hand soap, body lotion, shampoo, conditioner, face lotion, facial cleansers, foundation, lipstick, mascara, hair spray/mousse/gel, toothpaste and sunscreen.^1,3,4 One study identified parabens in 44% of cosmetics tested.³ In personal care products tested in the US, concentrations of methylparaben up to 1.0% were found, with lipsticks containing the highest concentration ranging from 0.15% to 1.0%.¹ The other parabens are used at concentrations lower than methylparaben in personal care products. Methylparaben and propylparaben are the most commonly used parabens in pharmaceutical products at concentrations of up to 20%;¹ both of these preservatives are also used in food products such as jams, jellies, fillings and toppings at concentrations of up to 0.1%.^1,5

Parabens in the Environment

Parabens have been found in urban streams into which treated or untreated effluent from wastewater treatment plants flows.^6,7 Consequently, these chemical compounds have been identified in rivers and drinking water sources.^6,8 Parabens have been detected in soil from agricultural fields, possibly from irrigation or fertilization practices.^9,10 The dust in houses has also been found to contain parabens.^11,12 Although commercially used parabens are of synthetic origin, some parabens are produced by living organisms, specifically by plants and microbes, e.g., a marine bacterial strain belonging to the genus Microbulbifer.¹³ Plants such as blueberries, carrots, olives, strawberries and others produce parabens (mainly methylparaben) for its presumed antimicrobial activity.^14-16 Overall, the concentrations of parabens within the environment are low with water concentrations around 7 ng/L and effluent concentrations up to 6 µg/L, soil concentrations range from 0.5 to 8 ng/g while house dust contained up to 2400 ng/g.7-11

Parabens in the Human Body

Parabens can enter the human body through the skin and parenterally. The average daily total personal paraben exposure is estimated to be 76 mg, with cosmetics and personal care products accounting for 50 mg, 25 mg from pharmaceutical products, and 1 mg from food.^17-19 Parabens applied to the skin are metabolized by keratinocyte carboxylesterases and the conjugated metabolites are excreted in urine and bile.^20,21 Oral or intravenous parabens are metabolized by esterases within the intestine and liver.¹ Parabens have been detected in urine, serum, breast milk and seminal fluid, but most worrisome has been the detection in breast tissue from patients with breast cancer.^2,22-26 Some have hypothesized that the higher concentration in the upper lateral breast near the axilla correlates with exposure from underarm deodorant and an increased incidence of breast cancer development in the area.^27,28 Still absolute concentrations indicate that levels of paraben within human fluids and tissue are low with average urine concentrations reported in the US ranging from 0.5 to 680 ng/mL and breast tissue concentrations ranging from 0 to 5100 ng/g of breast tissue (the median being 85.5 ng/g).^25,26 These low concentrations should be interpreted in the context of known estrogenic effects of parabens, which are discussed in the next section.

Toxicity and Adverse Effects of Parabens

Human and animal studies have failed to show that parabens have any acute toxicity by various routes of administration. As such, many of the studies examining paraben toxicity have focused on the long-term effects of chronic exposure.

The estrogenic activity of parabens was first identified in 1998 and has since been validated in vitro and in vivo.^1,29,30 Parabens bind human estrogen receptors, although with affinities 10,000 to 1,000,000 times less than estradiol.^29,31 Butylparaben and propylparaben have higher estrogenic activity than methylparaben or ethylparaben, but butylparaben and propylparaben are detected at concentrations 10 to 1000 times less than methylparaben in humans.³² The estrogenic effects in vivo have been demonstrated by uterotrophic (uterine growth) assays in mice and rats.^1,33 However, this effect did not prevent implantation of a fertilized egg, which is considered the most sensitive measure of estrogen toxicity.^33,34 As mentioned, it has been hypothesized that the estrogenic activity of parabens may promote breast cancer development. The concentration of estradiol in normal human breast tissue is 55.3 pg/g, suggesting there is a safety margin of 10 to 1000 times for parabens to approximate normal estradiol activity.^1,25,32 The paraben breast cancer data shows no or low parabens in a subset of patients and there are no comparisons with normal controls.^2,25 Hence, having not established a clear correlation, it is difficult to put forth a causal relationship between parabens and breast cancer development.

Another major area of study has been the effect of parabens on the male reproductive system, but findings are conflicting.³⁵ One in vitro study found that human sperm were not viable when exposed to parabens at concentrations of 1 mg/mL.³⁶ In vivo studies in mice did not replicate this result, with no spermatotoxic effects at paraben concentrations of 1%.³⁷ Conflicting results have also been reported in rats, with one study showing decreased sperm number and activity while another study found no adverse reproductive effects.^35,38 In humans, men with fertility problems including low sperm count and decreased motility were assayed for paraben exposure by measuring urine paraben levels.²³ No correlation between sperm count or motility and parabens levels was found.

Parabens, as is the case for many preservatives, can be allergenic in a small subset of the population. This sensitization commonly manifests as an eczematous rash. The rates of reported sensitization to parabens range from 0.5% to 3.5%.¹⁷ These rates of sensitization are amongst the lowest of all preservatives.^17,18 In addition, there are reports of immediate immunoglobulin Emediated allergic reactions to parabens resulting in urticaria and, in one case, bronchospasm.^39,40 However, these immediate allergic reactions are extremely rare.

Government and Regulatory Control of Parabens

Government regulatory boards have examined parabens and most have agreed that current concentrations of parabens are safe for consumer use. The European Union (EU) has set up limits on paraben use that have also been reviewed by the European Scientific Committee on Consumer Products (SCCP). In 2006, the SCCP concluded that parabens can be safely used in cosmetic products at concentrations of 0.4% for any individual paraben and 0.8% for total paraben concentrations.^1,41 These limits echo the legislative limits put in place by the EU. The Danish government went further in 2011 by banning the use of parabens in personal care products intended for children younger than 3 years of age. This decision is based on the possibility of high systemic absorption from an immature metabolism and skin barrier dysfunction.⁴² In the United States, the Cosmetic Ingredient Review (CIR) assesses ingredients for safety and is reviewed by the US Food and Drug Administration (FDA). The CIR has recommended the same maximum paraben concentrations as suggested by the SCCP and as legislated by the EU.¹ However, it should be noted that the CIR recommendations are only guidelines and manufacturers are not required to follow them. Likewise in Canada, there are no laws regulating paraben concentrations, but Health Canada agrees with the FDA and the CIR in regards to the safety of parabens and the adoption of maximum concentration guidelines.⁴³

Alternatives to Parabens

There are numerous preservatives that could be used in place of parabens. Some other commonly used preservatives include formaldehyde, quaternium-15, imidazolidinyl urea, diazolidinyl urea and dimethyloldimethyl hydantoin.¹⁸ These preservatives more commonly cause allergic reactions and some pose more serious health implications, such as formaldehyde and its causal link with cancer.¹⁸ The use of “natural” preservatives has been advocated, including grapefruit seed extract (GSE).⁴⁴ Unfortunately, GSE can interact with medications due to its ability to inhibit CYP3A4, an important enzyme involved in drug metabolism.⁴⁵ Other natural preservatives include thymol, cinnamaldehyde, allyl isothiocyanate, citric acid, ascorbic acid and rosemary extract.^46,47 These natural preservatives inhibit microbial growth in vitro, but the few studies testing antimicrobial activity in food products have provided equivocal results.^46,48,49 Therefore, further studies to determine their efficacy, safety and toxicology are warranted before widespread use.

Conclusion

The expectation of long shelf lives and microorganism-free consumer products mandates the use of preservatives. Ideally, preservatives should be active at low concentrations against a wide variety of microorganisms without interfering with other ingredients in the product, while also remaining nontoxic to humans and available at low cost to manufacturers. Parabens have been used for over 80 years and, despite reports of adverse reactions, they have proven to be amongst the safest and most well tolerated preservatives. Although the possible association of parabens with decreased sperm quality and breast cancer does warrant continued examination, the current data does not support drastic regulations or personal restrictions to exposure. Other recently regulated chemicals, such as phthalates and bisphenol A, may serve as archetypes for continued vigilance and investigation.^50,51

References

1. Cosmetic Ingredient Review Expert Panel. Final amended report on the safety assessment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben as used in cosmetic products. Int J Toxicol. 2008;27(Suppl 4):1-82.
2. Darbre PD, Aljarrah A, Miller WR, et al. Concentrations of parabens in human breast tumours. J Appl Toxicol. 2004 Jan;24(1):5-13.
3. Yazar K, Johnsson S, Lind ML, et al. Preservatives and fragrances in selected consumer-available cosmetics and detergents. Contact Dermatitis. 2011 May;64(5):265-72.
4. Witorsch RJ, Thomas JA. Personal care products and endocrine disruption: A critical review of the literature. Crit Rev Toxicol. 2010 Nov;40(Suppl 3):1-30.
5. Wang L, Zhang X, Wang Y, et al. Simultaneous determination of preservatives in soft drinks, yogurts and sauces by a novel solid-phase extraction element and thermal desorption-gas chromatography. Anal Chim Acta. 2006 Sep;577(1):62-7.
6. Yamamoto H, Tamura I, Hirata Y, et al. Aquatic toxicity and ecological risk assessment of seven parabens: individual and additive approach. Sci Total Environ. 2011 Dec;410-411:102-11.
7. Gonzalez-Marino I, Quintana JB, Rodriguez I, et al. Simultaneous determination of parabens, triclosan and triclocarban in water by liquid chromatography/ electrospray ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom. 2009 Jun;23(12):1756-66.
8. Pedrouzo M, Borrull F, Marce RM, et al. Ultra-high-performance liquid chromatography-tandem mass spectrometry for determining the presence of eleven personal care products in surface and wastewaters. J Chromatogr A. 2009 Oct;1216(42):6994-7000.
9. Ferreira AM, Moder M, Laespada ME. Stir bar sorptive extraction of parabens, triclosan and methyl triclosan from soil, sediment and sludge with in situ derivatization and determination by gas chromatography-mass spectrometry. J Chromatogr A. 2011 Jun;1218(25):3837-44.
10. Perez RA, Albero B, Miguel E, et al. Determination of parabens and endocrinedisrupting alkylphenols in soil by gas chromatography-mass spectrometry following matrix solid-phase dispersion or in-column microwave-assisted extraction: a comparative study. Anal Bioanal Chem. 2012 Mar;402(7): 2347-57.
11. Ramirez N, Marce RM, Borrull F. Determination of parabens in house dust by pressurised hot water extraction followed by stir bar sorptive extraction and thermal desorption-gas chromatography-mass spectrometry. J Chromatogr A. 2011 Sep;1218(37):6226-31.
12. Wang L, Liao C, Liu F, et al. Occurrence and human exposure of p-hydroxybenzoic acid esters (parabens), bisphenol A diglycidyl ether (BADGE), and their hydrolysis products in indoor dust from the United States and three East Asian countries. Environ Sci Technol. 2012 Nov 6;46(21):11584-93.
13. Peng X, Adachi K, Chen C, et al. Discovery of a marine bacterium producing 4-hydroxybenzoate and its alkyl esters, parabens. Appl Environ Microbiol. 2006 Aug;72(8):5556-61.
14. Kang YH, Parker CC, Smith AC, et al. Characterization and distribution of phenolics in carrot cell walls. J Agric Food Chem. 2008 Sep;56(18):8558-64.
15. Sellappan S, Akoh CC, Krewer G. Phenolic compounds and antioxidant capacity of Georgia-grown blueberries and blackberries. J Agric Food Chem. 2002 Apr;50(8):2432-8.
16. Huang WY, Zhang HC, Liu WX, et al. Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing. J Zhejiang Univ Sci B. 2012 Feb;13(2):94-102.
17. Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermatitis. 2005 Jun;16(2):57-66.
18. Sasseville D. Hypersensitivity to preservatives. Dermatol Ther. 2004;17(3): 251-63.
19. Soni MG, Carabin IG, Burdock GA. Safety assessment of esters of p-hydroxybenzoic acid (parabens). Food Chem Toxicol. 2005 Jul;43(7): 985-1015.
20. Darbre PD, Harvey PW. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol. 2008 Jul;28(5):561-78.
21. Pedersen S, Marra F, Nicoli S, et al. In vitro skin permeation and retention of parabens from cosmetic formulations. Int J Cosmet Sci. 2007 Oct;29(5):361-7.
22. Frederiksen H, Jorgensen N, Andersson AM. Parabens in urine, serum and seminal plasma from healthy Danish men determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). J Expo Sci Environ Epidemiol. 2011 May;21(3):262-71.
23. Meeker JD, Yang T, Ye X, et al. Urinary concentrations of parabens and serum hormone levels, semen quality parameters, and sperm DNA damage. Environ Health Perspect. 2011 Feb;119(2):252-7.
24. Ye X, Bishop AM, Needham LL, et al. Automated on-line column-switching HPLC-MS/MS method with peak focusing for measuring parabens, triclosan, and other environmental phenols in human milk. Anal Chim Acta. 2008 Aug;622(1-2):150-6.
25. Barr L, Metaxas G, Harbach CA, et al. Measurement of paraben concentrations in human breast tissue at serial locations across the breast from axilla to sternum. J Appl Toxicol. 2012 Mar;32(3):219-32.
26. Calafat AM, Ye X, Wong LY, et al. Urinary concentrations of four parabens in the U.S. population: NHANES 2005-2006. Environ Health Perspect. 2010 May;118(5):679-85.
27. Darbre PD. Environmental oestrogens, cosmetics and breast cancer. Best Pract Res Clin Endocrinol Metab. 2006 Mar;20(1):121-43.
28. Harvey PW. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis. J Appl Toxicol. 2003 Sep;23(5):285-8.
29. Routledge EJ, Parker J, Odum J, et al. Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol. 1998 Nov;153(1):12-9.
30. Harvey PW, Darbre P. Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women? J Appl Toxicol. 2004 May;24(3):167-76.
31. Blair RM, Fang H, Branham WS, et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci. 2000 Mar;54(1):138-53.
32. Golden R, Gandy J, Vollmer G. A review of the endocrine activity of parabens and implications for potential risks to human health. Crit Rev Toxicol. 2005 Jun;35(5):435-58.
33. Shaw J, deCatanzaro D. Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice. Reprod Toxicol. 2009 Jul;28(1):26-31.
34. Daston GP. Developmental toxicity evaluation of butylparaben in Sprague- Dawley rats. Birth Defects Res B Dev Reprod Toxicol. 2004 Aug;71(4):296-302.
35. Kang KS, Che JH, Ryu DY, et al. Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). J Vet Med Sci. 2002 Mar;64(3):227-35.
36. Song BL, Li HY, Peng DR. In vitro spermicidal activity of parabens against human spermatozoa. Contraception. 1989 Mar;39(3):331-5.
37. Oishi S. Effects of butyl paraben on the male reproductive system in mice. Arch Toxicol. 2002 Jul;76(7):423-9.
38. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol. 2004 Nov;42(11):1845-9.
39. Grzanka A, Misiolek H, Filipowska A, et al. Adverse effects of local anaesthetics – allergy, toxic reactions or hypersensitivity. Anestezjol Intens Ter. 2010 Oct;42(4):175-8.
40. Kajimoto Y, Rosenberg ME, Kytta J, et al. Anaphylactoid skin reactions after intravenous regional anaesthesia using 0.5% prilocaine with or without preservative–a double-blind study. Acta Anaesthesiol Scand. 1995 Aug;39(6):782-4.
41. U.S. Food and Drug Administration. Parabens. Available at: http://www. fda.gov/cosmetics/productandingredientsafety/selectedcosmeticingredients/ ucm128042.htm. Updated: October 31, 2007. Accessed: October 4, 2012.
42. Boberg J, Taxvig C, Christiansen S, et al. Possible endocrine disrupting effects of parabens and their metabolites. Reprod Toxicol. 2010 Sep;30(2):301-12.
43. Health Canada. Consumer product safety: Safety of cosmetic ingredients.
44. von Woedtke T, Schluter B, Pflegel P, et al. Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained. Pharmazie. 1999 Jun;54(6):452-6.
45. Brandin H, Myrberg O, Rundlof T, et al. Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy. Eur J Clin Pharmacol. 2007 Jun;63(6):565-70.
46. Schirmer BC, Langsrud S. Evaluation of natural antimicrobials on typical meat spoilage bacteria in vitro and in vacuum-packed pork meat. J Food Sci. 2010 Mar;75(2):M98-M102.
47. Kunicka-Styczynska A, Sikora M, Kalemba D. Antimicrobial activity of lavender, tea tree and lemon oils in cosmetic preservative systems. J Appl Microbiol. 2009 Dec;107(6):1903-11.
48. Fratianni F, De Martino L, Melone A, et al. Preservation of chicken breast meat treated with thyme and balm essential oils. J Food Sci. 2010 Oct;75(8):M528-35.
49. Hakkim FL, Mathiraj, Essa MM, et al. Evaluation of food protective property of five natural products using fresh-cut apple slice model. Pak J Biol Sci. 2012 Jan;15(1):10-8.
50. Erler C, Novak J. Bisphenol a exposure: human risk and health policy. J Pediatr Nurs. 2010 Oct;25(5):400-7.
51. Kamrin MA. Phthalate risks, phthalate regulation, and public health: a review. J Toxicol Environ Health B Crit Rev. 2009 Feb;12(2):157-74.

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC,Canada

ABSTRACT

Propylene glycol (PG) is considered to be a ubiquitous formulary ingredient used in many personal care products and pharmaceutical preparations. It is an organic compound commonly found in topical corticosteroids (CS). Cutaneous reactions to PG are mostly irritant, but allergic contact dermatitis to PG is well-documented. Cosensitization to PG and topical CS can occur, making it challenging to choose the appropriate topical CS in a PG-allergic patient. This review is aimed at guiding clinicians in the selection of a suitable topical corticosteroid when presented with patients allergic to PG.

Key Words:
allergic contact dermatitis, corticosteroids, propylene glycol, topical

Propylene glycol (PG) is a colorless, viscous, nearly odorless liquid that is used as an intermediate for the synthesis of other chemicals.^1,2 It is a multifunctional excipient that is used in many products as a solvent, vehicle, humectant, or emulsifier.³ The annual PG production and global demand are rapidly increasing.³ Vehicles for topical corticosteroid preparations commonly include PG for enhancing stratum corneum penetration. In addition to topical steroids, PG can also be found in other topical pharmacologic preparations, including antibacterials, antifungals, benzoyl peroxide, and emollients,¹ Cutaneous reactions to PG have been recognized since 1952.¹

Sources of PG

Approximately half of the PG produced is used in the synthesis of other chemicals.² The other half is utilized in the manufacturing of many industrial and personal care products. PG is used as a plasticizer, solvent (in lacquers and varnishes), and as a component in antifreeze products, lubricants, cutting-fluids, and inks. It is found in many cosmetic and pharmaceutical preparations, food (for coloring, thickening, and flavoring), and household cleansers. In a recent study by the North American Contact Dermatitis Group (NACDG), personal care products were found to be the most common sources of exposure to PG (53.8%), followed by topical steroids, and other topical medicaments.³

Allergic Contact Dermatitis to PG

Cutaneous reactions to PG are classified into four groups: irritant contact dermatitis, allergic contact dermatitis (ACD), non-immunologic contact urticaria, and subjective or sensory irritation.⁴ The incidence of true ACD to PG is unknown. This is primarily attributed to the difficulty in determining the ideal concentration for patch testing that would be nonirritating, but high enough to elicit an allergic response. The majority of skin reactions to PG are irritant in nature, however, true allergic sensitization does occur. The most convincing evidence of allergic sensitization to PG is the development of systemic contact dermatitis after giving PG orally to PG-allergic patients.⁵ The overall prevalence of allergic reactions to PG was found to be relatively low (3.5%) by the NACDG.³ The NACDG currently recommends using a 30% aqueous PG solution for patch testing.³ In our experience at the University of British Columbia Contact Dermatitis Clinic, the prevalence of positive patch test reactions to PG over a 2 year period was 1.57% (13/828 patients). It was presumed that an increased individual susceptibility to irritation may also be associated with allergic reactivity through reduction of the skin’s barrier function and the release of cytokines.2 To confirm an allergy to PG, it has been recommended that positive patch test reactions should be followed by serial dilution patch tests, repeat open application tests or oral challenge tests, or all three of these assessments.⁴

PG and ACD to Topical Corticosteroids

The prevalence of ACD from topical corticosteroids (CS) is unknown. ACD to topical CS should be suspected if the
dermatitis worsens or does not improve during treatment. ACD can result from an allergy to the steroid molecule or to a component of the vehicle. CS are divided into four classes on the basis of structure and cross-reactivity pattern: classes A (hydrocortisone type), B (triamcinolone acetonide type), C (betamethasone type), and D.⁶ Class D is further divided into D1 (betamethasone dipropionate type) and D2 (methylprednisolone aceponate type). There are different screening markers that are used for patch testing to the corticosteroid classes. The screening markers used on the NACGD screening series are as follows: tixocortol-21-pivalate (class A), budesonide and triamcinolone acetonide (class B), clobetasol-17-propionate (class D1), and hydrocortisone-17-butyrate (class D2).6 Patch test reactions to class A steroids are the most common.⁷ Reactions to classes B and D steroids are less common, whereas reactions to class C steroids are extremely rare.⁷ The most common cross-reactions are between steroids in classes A and D2, followed by classes B and D2, and classes A and B.⁸

An investigation by the NACDG demonstrated that topical CS were responsible for 18.3% of the positive patch test reactions to PG.³ In a recent study, PG was found to be the most common allergen in topical CS, being present in 64% of the steroidal products.⁷ It was especially common in branded ointments and gels. Moreover, studies have reported a significant number of patients have a concomitant reaction to both topical CS and PG, which suggests the possibility of cosensitization.^3,8

Case Report

A 55-year-old female presented to our clinic with a history of severe recurrent eyelid dermatitis resulting in multiple visits to the emergency room and treatment with systemic steroids. Her left leg dermatitis also recently worsened. The patient’s past medical history was significant for a previously treated venous ulcer of the left leg and chronic venous insufficiency dermatitis. There was a positive family history of atopy, but she denied any personal history of atopy. She had been applying amcinonide 0.1% (Cyclocort®) and fusidic acid 2% (Fucidin®) ointments on the leg dermatitis for many years with only intermittent improvement. Patch testing was done with the 2010 NACDG screening series (Table 1). She was found to be allergic to PG, budesonide, lanolin alcohol, balsam of Peru, and glyceryl thioglycolate. We could not identify the source of PG (amcinonide 0.1% and fusidic acid 2% ointments are both PG-free), but this patient could have been sensitized to PG from her personal care products. She was most likely sensitized to budesonide from prolonged application of amcinonide 1% ointment (a class B corticosteroid). Fusidic acid 2% ointment contains lanolin, which was an additional factor for the persistence of her dermatitis. Given that she was allergic to both PG and budesonide, it would have been helpful to know which topical CS were PG-free. Ideally, we would have prescribed her a PG-free class C or D1 topical CS. Consequently, we switched her to tacrolimus 0.1% ointment (PG- and corticosteroid-free) for treating both the eyelid and leg dermatitis. Subsequently, the eyelid dermatitis cleared. Her leg dermatitis occasionally recurs secondary to underlying venous insufficiency, for which she continues compression stocking therapy.

The Choice of a Topical CS in a PG-allergic Patient

Given that PG is the most common allergen in topical CS, it is important to know which topical corticosteroid to prescribe to a PG-allergic patient. We have conducted a search of all topical CS available in Canada. We have excluded topical CS that contain other active ingredients (e.g., salicylic acid). We then searched carefully for preparations that are PG-free. Ingredients of the different topical CS were checked using the Compendium of Pharmaceuticals and Specialties (CPS) 2010 drug reference guide in addition to pharmaceutical company website searches. We have created a chart containing all PG-free topical CS available in Canada sorted on the basis of potency and structural class
(Table 2 on page 7).

Conclusion

PG is found in many products. The sensitizing potential of PG is well documented, but the true incidence of its role in ACD is unknown. PG is the most common allergen in topical CS. Cosensitization to PG and topical CS is possible. If patch testing is unavailable and the physician is highly suspecting PG allergy, we recommend prescribing any PG-free topical corticosteroid. Another option is to consider tacrolimus ointment, which is a PG-free steroid-sparing agent (pimecrolimus 1% cream contains PG). Empirically, one can prescribe a PG-free class C topical corticosteroid given the rarity of ACD to class C topical CS. Ideally, patch testing should be done if the clinical picture is suggestive of allergy to PG and/or topical CS. It is important to note that the steroid formulations discussed in this paper pertain only to topical CS products available in Canada, as products from other countries may contain different compositions of non-medicinal ingredients. We hope that this review will be of benefit in guiding physicians when choosing the appropriate topical corticosteroid in patients allergic to PG.

References

1. Catanzaro JM, Smith JG, Jr. Propylene glycol dermatitis. J Am Acad Dermatol 24(1):90-5 (1991 Jan).
2. Lessmann H, Schnuch A, Geier J, et al. Skin-sensitizing and irritant properties of propylene glycol. Contact Dermatitis 53(5):247-59 (2005 Nov).
3. Warshaw EM, Botto NC, Maibach HI, et al. Positive patch-test reactions to propylene glycol: a retrospective cross-sectional analysis from the North American Contact Dermatitis Group, 1996 to 2006. Dermatitis 20(1):14-20 (2009 Jan-Feb).
4. Funk JO, Maibach HI. Propylene glycol dermatitis: re-evaluation of an old problem. Contact Dermatitis 31(4):236-41 (1994 Oct).
5. Hannuksela M, Forstrom L. Reactions to peroral propylene glycol. Contact Dermatitis 4(1):41-5 (1978 Feb).
6. Jacob SE, Steele T. Corticosteroid classes: a quick reference guide including patch test substances and cross-reactivity. J Am Acad Dermatol 54(4):723-7 (2006 Apr).
7. Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis 19(1):38-42 (2008 Jan-Feb).
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ABSTRACT

Cosmetics are an important cause of allergic contact dermatitis (ACD). Fragrances and preservatives are the two most clinically relevant allergens found in cosmetic products. Patch testing remains the gold standard for identification of causative allergens. Common cosmetic allergens are reviewed. Practical methods of allergen avoidance are also discussed.

Key Words:
allergic contact dermatitis, fragrance, preservative, skin care

Introduction

The term “cosmetic” is used synonymously with “make-up” in the general population. However, it has a much broader definition and includes personal care products, hair care, nail products, and sunscreens.

There is an impressive array of cosmetic products available on the market today, with an even greater number of individual ingredients. The number of new products continues to increase and the rates of adverse cutaneous reactions are expected to rise. Therefore, given the widespread use of cosmetics, it is important to monitor their side-effects. It is estimated that the average woman uses 12 personal care products daily, which comprise 168 unique ingredients. The average man uses six personal care products each day with 85 unique ingredients.¹ Skin care products have been found to account for the majority of cases of allergic contact dermatitis (ACD) to cosmetics, followed by hair care and nail cosmetics.^2-5 The most common responsible cosmetic allergens are fragrances and preservatives.⁶

Epidemiology

The prevalence of cosmetic allergy is estimated at less than 1% in the general population.^7-9 However, since most people do not seek medical consultation for mild adverse reactions, the actual rates are likely much higher. Pooled data of seven different studies involving 30,207 patients patch tested for suspected contact dermatitis revealed that 9.8% of positive reactions were due to cosmetic allergens.¹⁰
A recent Danish study showed that the prevalence of ACD to cosmetic allergens has doubled between 1990 and 1998.¹¹ The majority of patients affected with ACD to cosmetic products are women between the ages of 20 and 55.^2,7-9

In addition, a study of 794 patients showed that 34% of patients would have been missed if they were only tested with NACDG (North American Contact Dermatitis Group) screening series of 65 allergens.¹² A European analysis of 5911 cosmetic-allergic patients found that one-third reacted only to a personal product and no other allergen.¹³ Thus, while the optimal number of allergens for patch testing to cosmetics is not firmly established, testing for additional allergens using a specialized cosmetic series and the patient’s own personal products would capture about 30% of additional patients that otherwise would have been missed.

Clinical Features of ACD

ACD may have acute and chronic forms. Acutely, it presents with pruritic papules, vesicles, and bullae. Chronic forms are more common and present with pruritic, scaly papules and plaques distributed in areas of most contact with the offending allergen. The distribution provides very useful clinical clues about the possible causative agent. Occasionally, ACD may produce autoeczematization resulting in a widespread or generalized cutaneous eruption. Allergens may also be transferred from other persons or even pets, resulting in “connubial” or “consort” dermatitis.^14-16

The main differential diagnostic possibilities for ACD are exacerbation of atopic dermatitis or irritant contact dermatitis, both of which are far more common than allergic contact reactions.

Classes of Allergens Responsible for ACD

Cosmetic ingredients can be classified into several categories: fragrances, preservatives, antioxidants, vehicles, ultraviolet absorbers, humectants, emollients, emulsifiers, acrylates, hair dyes, nail polish components, and others.

Preservatives and fragrances are the most frequently detected culprits; therefore, this review will primarily deal with these two classes of allergens.

Preservatives

Preservatives were identified as the most common cosmetic contact allergens in several recent studies.^6,17,18 They can be classified into three broad categories: antimicrobials, antioxidants, and ultraviolet light absorbers. The antimicrobial agents can be further divided into formaldehyde preservatives, formaldehyde-releasers, and non-formaldehyde-releasing preservatives. Formaldehyde-releasing preservatives (FRP) include quaternium-15, diazolidinyl urea, imidazolidinyl urea, 2-bromo-2-nitropropane-^1,3-diol, and DMDM hydantoin. Non-formaldehyde-releasing preservatives include parabens, methylchloroisothiazolinone-methylisothiazolinone (MCI-MI), methyldibromoglutaronitrile-phenoxyethanol (MDBGN-PE), and iodopropynyl butylcarbamate. Individuals allergic to formaldehyde may also be allergic to any of the FRPs.

Formaldehyde-sensitized individuals may experience a flare of ACD with a number of foods, including cod fish, caviar, coffee, shiitake mushrooms, smoked ham, maple syrup, and aspartame.¹⁹ Table 1 lists the top 20 NACDG screening allergens associated with cosmetic source in females.¹⁷

For comparison, Tables 2a and 2b list the top 10 allergens from the North American Contact Dermatitis Group (NACDG) and the Mayo Clinic Contact Dermatitis Group (MCCDG) identified in all patients presenting for patch testing. It is evident that many of the top allergens are from cosmetic sources.

Fragrances

There are over 3000 different fragrances used in cosmetics today.²⁰ Not surprisingly, fragrances represent the second most common group of cosmetic allergens. Available tools to assess for fragrance allergy are fragrance mix I (FMI), fragrance mix II (FMII), and balsam of Peru. The components of these screening allergens are listed below:

Fragrance Mix I (8.0% in petrolatum)

• Amyl cinnamic alcohol 1.0%
• Cinnamic alcohol 1.0%
• Eugenol 1.0%
• Cinnamic aldehyde 1.0%
• Hydroxycitronellal 1.0%
• Geraniol 1.0%
• Isoeugenol 1.0%
• Oak moss absolute 1.0%
• Sorbitan sesquioleate (emulsifier) 5.0%

Fragrance Mix II (14.0% in petrolatum)

• Hydroxyisohexyl 3-cyclohexene carboxaldehyde (2.5%)
• Citral 1.0%
• Farnesol 2.5%
• Coumarin 2.5%
• Citronellol 0.5%
• Hexyl cinnamal 5.0%

Many of the specific fragrance ingredients are protected by the
Fair Packaging and Labeling Act as they are considered trade
secrets.¹⁹ It is important to keep in mind that many products
labeled as ‘unscented’, ‘hypoallergenic’, or even ‘fragrance-free’
do, in fact, contain masking fragrances.

Balsam of Peru

Balsam of Peru (BOP) (myroxylon pereirae resin) is an aromatic
fluid that comes from the bark of the tree Myroxylon balsamum,
a tree native to El Salvador.¹⁹ It is a complex mixture of many
ingredients, all of which have not yet been completely identified.
Key ingredients including benzoyl cinnamate, benzoyl benzoate,
benzoic acid, vanillin, and nerodilol can be found in the following
three groups of products: fragrance in perfumes and toiletries,
flavorings in foods and drinks, and medicaments. In the past,
FMI and BOP were able to detect approximately 90% of fragrance
allergies. However, with the increasing number of fragrances and
botanicals in use today, their screening ability is now estimated to
be around 60%.¹⁹ Thus, FMII and a number of botanical extracts
are now part of the 2010 NACDG screening series that comprise
70 allergens. Often, additional cosmetic and botanical series are
required to diagnose fragrance allergy. Patients with contact
allergy to BOP may also react to a number of substances that are
well known cross-reactants with BOP (Table 3). Thus, patients
should be appropriately counseled to avoid these agents.

Practical Considerations and Clinical Pearls

• Choose allergens carefully: based on history, occupation, hobbies, and distribution of dermatitis. Patch testing may need to be expanded beyond the NACDG screening series to include, for example, a cosmetic/botanical supplemental series. This series may be indicated in patients using a variety of make-up products or for those who use ‘all natural’ botanical products. Testing to personal care products may lead to identification of additional relevant allergens, as well as facilitate discovery of new and emerging allergens, as new compounds are being introduced at an escalating pace.
• Have a good working knowledge of common allergens and their sources: this is critical for choosing the correct allergens to test as well as for counseling patients on allergen avoidance.
• Have access to available resources: an excellent review of the main concepts of ACD is found in Contact Allergy: Alternatives for the 2007 NACDG Standard Screening Tray.19 Allergen information sheets are available to the members of the American Contact Dermatitis Society (ACDS) and can be found at www.contactderm.org. Identification of allergen-free products can be accomplished by generating a customized product list with the use of the Contact Allergen Management Program (CAMP) available to the members of the ACDS. Multiple allergens can be entered to generate a ‘shopping list’ of products that are safe to use in a patient with allergic contact dermatitis to their cosmetics.

Conclusion

Allergic contact dermatitis to cosmetics is an important cause of ACD overall. The main causes of cosmetic allergy are fragrances and preservatives. It is rewarding for both the patient and the physician if the responsible agent can be identified and subsequently removed from the patent’s environment. Patient satisfaction and compliance will also improve if meaningful counseling is provided, including detailed information on safe to use personal care products.

References

1. Environmental Working Group’s Skin Deep Cosmetic Safety Database. Available at: http://www.cosmeticsdatabase.com/research. Last accessed: March 1, 2011.
2. Eiermann HJ, Larsen W, Maibach HI, et al. Prospective study of cosmetic reactions: 1977-1980. North American Contact Dermatitis Group. J Am Acad Dermatol 6(5):909-17 (1982 May).
3. Adams RM, Maibach HI. A five-year study of cosmetic reactions. J Am Acad Dermatol 13(6):1062-9 (1985 Dec).
4. de Groot AC. Contact allergy to cosmetics: causative ingredients. Contact Dermatitis 17(1):26-34 (1987 Jul).
5. de Groot AC, Bruynzeel DP, Bos JD, et al. The allergens in cosmetics. Arch Dermatol 124(10):1525-9 (1988 Oct).
6. Wetter DA, Yiannias JA, Prakash AV, et al. Results of patch testing to personal care product allergens in a standard series and a supplemental cosmetic series: an analysis of 945 patients from the Mayo Clinic Contact Dermatitis Group, 2000-2007. J Am Acad Dermatol 63(5):789-98 (2010 Nov).
7. Romaguera C, Camarasa JM, Alomar A, et al. Patch tests with allergens related to cosmetics. Contact Dermatitis 9(2):167-8 (1983 Mar).
8. Adams RM, Maibach HI. A five-year study of cosmetic reactions. J Am Acad Dermatol 13(6):1062-9 (1985 Dec).
9. Kohl L, Blondeel A, Song M. Allergic contact dermatitis from cosmetics. Retrospective analysis of 819 patch-tested patients. Dermatology 204(4):334-7 (2002).
10. Biebl KA, Warshaw EM. Allergic contact dermatitis to cosmetics. Dermatol Clin 24(2):215-32 (2006 Apr).
11. Nielsen NH, Linneberg A, Menne T, et al. Allergic contact sensitization in an adult Danish population: two cross-sectional surveys eight years apart (the Copenhagen Allergy Study). Acta Derm Venereol 81(1):31-4 (2001 Jan-Feb).
12. Cohen DE, Rao S, Brancaccio RR. Use of the North American Contact Dermatitis Group Standard 65-allergen series alone in the evaluation of allergic contact dermatitis: a series of 794 patients. Dermatitis 19(3):137-41 (2008 May-Jun).
13. Uter W, Balzer C, Geier J, et al. Patch testing with patients’ own cosmetics and toiletries–results of the IVDK*, 1998-2002. Contact Dermatitis 53(4):226-33 (2005 Oct).
14. Wilkinson DS. Connubial photodermatitis. Contact Dermatitis 1:58 (1975).
15. Fisher AA. Consort contact dermatitis. Cutis 24(6):595-6, 668 (1979 Dec).
16. Morren MA, Rodrigues R, Dooms-Goossens A, et al. Connubial contact dermatitis: a review. Eur J Dermatol 2:219-23 (1992).
17. Warshaw EM, Buchholz HJ, Belsito DV, et al. Allergic patch test reactions associated with cosmetics: retrospective analysis of cross-sectional data from the North American Contact Dermatitis Group, 2001-2004. J Am Acad Dermatol 60(1):23-38 (2009 Jan).
19. Laguna C, de la Cuadra J, Martin-Gonzalez B, et al. [Allergic contact dermatitis to cosmetics]. Actas Dermosifiliogr 100(1):53-60 (2009 Jan-Feb).
20. Scheman A, Jacob S, Zirwas M, et al. Contact Allergy: alternatives for the 2007 North American contact dermatitis group (NACDG) Standard Screening Tray. Dis Mon 54(1-2):7-156 (2008 Jan-Feb).
21. Devos SA, Constandt L, Tupker RA, et al. Relevance of positive patch-test reactions to fragrance mix. Dermatitis 19(1):43-7 (2008 Jan-Feb).