The truth about Hydroquinone

By Dr Askari Townshend / 01 Jul 2014

Dr Askari Townshend presents the facts about this controversial skincare ingredient

For a drug that has been used by millions of people for decades, giving great improvements to their pigmentation disorders, hydroquinone (HQ) has a bad reputation. How and why it started I’m unsure, but the two comments I often hear (in my experience, usually from those that don’t use it) is that it can cause cancer and has been banned. Neither of these is entirely true – there have been no reports or evidence of human malignancy as a result of hydroquinone use. In 2001, countries of the European Union had hydroquinone banned from over-the-counter products yet in the USA, hydroquinone is still available up to 2% over the counter.

Every so often there is a media story, quite rightly, exposing the risks of the illegal
sale of strong HQ products in the UK. Unfortunately, these are often accompanied by medical comments overstating the risks. I was recently asked to comment for Channel 4 News, but made it clear that I am a great fan of this useful medicine and would not do any more than state the facts - they found someone else. Here I present the facts without the spin.
HQ is a phenol compound known by several names including quinol and 1-4 dihydroxy benzene. It is an anti-oxidant with several uses that take advantage of it being a soluble reducing agent – it is a major component of black and white photographic developers. In dermatology, HQ has long been used to treat pigmentation disorders and is very effective in doing so. The first (and rate limiting) step of melanogenesis is the oxidation of tyrosine to dopaquinone catalysed by tyrosinase. As a tyrosinase inhibitor, HQ interferes with melanogenesis and results in a reduction of the amount of pigment (melanin) in skin.
Pigmentation disorders are common, especially in darker skin types. Excluding vitiligo, El-Essawi et al1 found that 56% of 401 Arab-Americans complained of skin discolouration. When using larger groups (1,074 and 1,000), Alexis et al2 and Dunwell et al3 found 20% and 23% complaints respectively. The most common diagnoses were post-inflammatory hyperpigmentation (PIH), melasma and solar lentigines. By far, the most common condition causing PIH is acne. At their Skin of Color Centre in New York, Alexis et al4 surveyed 1412 patients and found that acne was the most common reason for attendance, as it was for white patients, followed by dyschromia which did not feature in the top ten reasons for patients with white skin.
Dyschromia in dark skins can be difficult to treat as there is a greater risk of PIH after peel or laser treatment than when treating white skins. HQ is particularly useful in treating this patient group and is also used as a prophylactic adjunct with peels and laser to reduce the risks. It is important to treat the underlying condition (e.g. acne) before tackling the resulting dyschromia. 
There are a wide range of topical lightening agents including other tyrosinase inhibitors such as retinoids, kojic acid, azelaic acid and arbutin. Many preparations combine these ingredients (and others) for greater efficacy. A Cochrane review of interventions for melasma found that: 4% HQ is more effective than 2%; combining 4% HQ with tretinoin is more effective than either alone and the addition of a mild steroid e.g. fluocinolone acetonide, is even more effective.5

There is no doubt that HQ is a potent treatment for pigmentation disorders, but what about safety? As with almost all of the topical alternatives, HQ can cause irritation and dryness. However, this is more common with tretinoin and azelaic acid.5 Advice to avoid strong sunshine and wear good quality, high protection SPF is applicable to all topical treatment. This is not just because many of them make the skin more sensitive to sunlight, but also because the sun will drive the problem of melanogenesis.

Every so often there is a media story, quite rightly, exposing the risks of the illegal sale of strong HQ products in the UK. Unfortunately, these are often accompanied by medical comments overstating the risks.

The biggest myth about HQ is that it causes cancer. As you might expect, there have been several studies (both animal and human) looking at any possible link. McGregor6 found an increased incidence of renal tubule adenomas in male rats but this was after they had been given 25 times the normal human dose (orally rather than topically). He said, “This disease is particularly prominent in male rats,” and concluded, “the increased incidence of renal tubule adenomas in HQ-dosed male rats is without human consequence.” This confirmed the conclusion already put forward by Hard et al7 and Hard.8
A real, but often overstated, risk is one of exogenous ochronosis (EO). Ochronosis refers to brownish-yellow or ochre coloured collections of pigment found in patients carrying the disease. It is an inherited condition in which the enzyme homogentisic acid oxidase is missing, allowing homogentisic acid (and its oxide alkapton) to accumulate. EO was first described in 19128 after phenol use on a leg ulcer, and presents as a blue/ black discolouration in the skin without the systemic problems of endogenous ochronosis. The blue appearance is due to the depth of the pigment (Tyndall effect). The condition can develop after topical use of HQ, phenol, resorcinol or oral anti- malarials.9

EO was reported as a big issue in South Africa, where HQ creams were sold from 1961. By 1969, there were increasing reports of EO being problematic, and by 1979 the numbers had reached “epidemic proportions”.10 Several factors have been suggested that may have contributed to this: Strong concentrations of HQ, use of additional depigmentation agents, alcohol lotion to increase absorption and lack of sunscreen use. The Apartheid regime may well explain the popularity of skin lightening creams in South Africa – the amounts used may have been greater than elsewhere. In a review, Levitt11 noted that long-term use of HQ-containing products, rather than high concentration, may be the greatest risk factor for the development of EO. HQ has been on sale in the USA since 1955 but despite acquiring 10 million users, only 28 cases were reported between 1983 and 2000, showing that EO is very rare. In 2006, the American Academy of Dermatology Association recommended, “no change in the status of either OTC or prescription HQ containing products”.12 This was in response to a proposed status change of HQ by the FDA in light of its assessment that the benefits of HQ products to the US public far outweigh the risks.
Before prescribing HQ it is important to exclude EO. This is easily done through asking patients about any history of HQ (or other depigmenting cream) use. If in doubt, careful examination with a dermatoscope or histology should be performed. The continued use of HQ will exacerbate EO and should be stopped immediately. Treatment of EO is challenging and should include application of sunscreens along with hydrocortisone and/or retinoic acid13. Additional treatments include antibiotics, dermabrasion (alone or in combination with CO2 laser) and Q-switched ruby laser (11, 13, 14), though these have variable results. In summary, 4% hydroquinone is a powerful and effective skin-lightening agent especially when used with tretinoin and a mild steroid. It is safe when used correctly and has no links to human malignancy with topical application, and EO is extremely rare. It can be used prophylactically with other treatments on those with dark skin to minimise the occurrence of PIH, and it should be considered as a first line treatment in these patients when appropriate. 

References

  1. El-Essawi D, Musial JL, Hammand A, et al, ‘A survey of skin disease and skin-related issues in Arab Americans’, J Am Acad Dermatol, 56 (2007), 933-938.
  2. Alexis AF, Sergay AB, Taylor SC, ‘Common dermatologic disorders in skin of color: a comparative practice survey’ Cutis, 80 (2007), 387-394.
  3. Dunwell P, Rose A, ‘Study of the skin disease spectrum occurring in an Afro-Caribbean population’ Int J Dermatol, 42 (2003), 287-289.
  4. Alexis AF, Sergay AB, Taylor SC, ‘Common dermatologic disorders in skin of color: a comparative practice survey’ Cutis 80 (2007), 387-394.
  5. Rajaratnam R, Halpern J, Salim A, Emmett C, ‘Interventions for melasma (Review)’, The Cochrane Library 7 (2010).
  6. McGregor D, ‘Hydroquinone: an evaluation of the human risks from its carcinogenic and mutagenic properties’ Crit Rev Toxicol, 37 (2007),887-914.
  7. Hard GC, Whysner J, English, JC, Zang E, and Williams, GM, ‘Relationship of hydroquinone-associated rat renal tumors with spontaneous chronic progressive nephropathy’ Toxicology and Pathology 25 (2007), 132-143,
  8. Beddard AP, Plumtre CM, ‘A further note on ochronosis associated with carboluria’, Q S Med, 5 (1912), 505-507.
  9. Charlín R, Barcaui CB, Kac BK, Soares DB, Rabello-Fonseca R and Azulay-Abulafia L, ‘Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy’, International Journal of Dermatology, 47 (2008), 19-23.
  10. Hardwick N, Van Gelder LW, Van der Merwe CA and Van der Merwe MP, ‘Exogenous ochronosis: an epidemiological study’ British Journal of Dermatology, 120 (1989), 229-238.
  11. Levitt J, (2007) ‘The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register’. Journal of American Academic Dermatology, 57(5), (2007), 854-72
  12. Stone SP, ‘American Academy of Dermatology Association response to Docket No. 1978N-065 and RIN number 0910-AF53’, Skin bleaching drug products for OTC human use, 21 (2006), CFRE Part 310.
  13. Levin CY, and Maibach H, ‘Exogenousochronosis. An update on clinical features, causative agents and treatment options’, American Journal of Clinical Dermatology 2 (2001), 213-217.
  14. Tan SK, Sim CS, and Goh CL, ‘Hydroquinone-induced exogenouso chronosis in Chinese-two case reports and a review’, International Journal of Dermatology 47 (2008), 639-640. 

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