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Prepared
by: Dr. Charlene DeHaven, Clinical Director
EFFECTS OF HYDROQUINONE©
Adverse Effects of Hydroquinone© — Topical
hydroqui- none is frequently used throughout the world
as a skin bleaching agent. It may be found in concentrations
up to 10-15% but preparations containing concentrations
above 2% are required by the FDA to have a doctor’s prescription.
The Cosmetic Ingredient Review (CIR) Expert Panel says
that hydroquinone is safe in concentrations of 1% or less
for water-based cosmetic preparations designed for discontinu-
ous, brief use followed by rinsing from the skin and/or
hair. The CIR Expert Panel states it should not be used
in “leave- on” cosmetic formulations. In spite of this,
internet sites can easily be found that offer topical
hydroquinone in concentra- tions over 2% and very commonly
as high as 4% or more.
The World Health Organization of the United Nations states:
“It is recommended that over-the-counter sales of creams
containing hydroquinone be restricted. Health education
programs should be developed to discourage the use of
hydroquinone-containing creams...”
Although chemically similar substances are found in some
plants, hydroquinone for cosmetic use is chemically synthesized.
Hydroquinone was originally introduced years ago as a less
toxic alternative to mercury-based bleaching agents, which were
potentially very toxic. Attention is now being focused on the
potential toxicities and adverse effects of hydroquinone itself.
Hydroquinone is easily absorbed from the skin and its
absorption increases dramatically by placing alcohols
in the preparation. It reacts with the functional parts
of individual cells and effects cellular metabolism. Applying
hydroqui- none to skin and then exposing the skin to sunlight
also markedly increases potential toxicity. It is very
rapidly absorbed from the GI tract. In the presence of
moisture and at room temperature, hydroquinone can metabolize
to quinone which causes much worse eye irritation than
hydro- quinone, leading to conjunctivitis (red eye) and
erosions of the cornea (open sores over the central eye).
Mechanism of Action — Hydroquinone has
cytotoxic (cell- killing or cell-damaging) activity on
the pigment-producing cell of the skin, the melanocyte.
The cell-toxic activity of hydroquinone is caused by a
free-radical oxidation mecha- nism. Free radical development
has the potential to damage the melanocyte on its own
or also damage neigh- boring cells or their physical structures.
Because this free- radical effect also harms the genetic
material within the pigment-producing cell, it can encourage
the cell to develop into a cancerous (malignant) cell.
Comparison with other Agents — Arbutin
glycoside, which is of plant origin, decreases the production
of the skin pigment, melanin. The arbutin inhibits an
enzyme called tyrosinase which is.required for one of
the chemical steps in melanin forma- tion. This inhibition
of pigment formation occurs without cytotoxic (cell-damaging)
activity. Kojic acid, an alphahydroxy acid and also derived
from plants, is another enzyme inhibitor of tyrosinase.
It decreases pigment production in a way like arbutin.
Laser treatments have been used for pigmentation irregu-
larities but require a surgical procedure and have their
own list of potential complications.
Potential Adverse Effects — It was once
thought that concentrations of hydroquinone of 2% or less
had negligible potential for adverse effects. We now know
this is not true, as the medical literature reports problems
occurring with lesser concentrations. Another earlier
myth was that only heavily pigmented skin, as in Blacks,
suffered from adverse effects related to hydroquinone
use. This also is untrue, as side effects in Asians, Hispanics
and Caucasians have been reported in the medical literature.
The potential adverse effects involving inflammation (redness)
and cell damage (related to free radical damage), potentially
resulting in the development of malig- nant cells, are
of the most concern.
Inflammation — Redness (also called erythema),
an indicator of inflammation, reliably occurs in guinea
pig skin exposed to hydroquinone in concentrations of
2% up to 5% in a tested population to which it was applied
5 days per week for 13 weeks. This redness goes away after
the treatment is stopped but the skin has suffered the
effects of inflammation during the exposure period. In
these guinea pigs, kidney damage was seen if the hydroquinone
was given orally but not if it was applied to the skin
in concentra- tions from 2% to 5%. Visible inflammation
also occurs in human populations using hydroquinone and
is found in the majority of users and with any concentration
of the hydro- quinone. Since the substance is toxic to
cells, even if redness cannot be seen with the naked eye,
there is ongo- ing inflammation accompanying the cell
damage associ- ated with the substance. This is a type
of irritant dermatitis, or skin inflammation caused by
an irritating substance.
Eczema — This is an allergic response
to a substance to which the skin can become sensitized.
It may begin with an inflammatory response but the subject
can become so sensitive to the product that they develop
skin inflammation when only a tiny amount of substance
is applied to the skin.
Possible Systemic Absorption—Hydroquinone is readily
absorbed from the skin and can be detected in urine as the
intact parent substance (rather than a metabolite) after the
2% cream is applied. The evidence relating to kidney toxicity
of orally ingested material raises concerns here, considering
that hydroquinone applied to the skin must get through the
blood stream and the rest of the body in order to be found in
urine. This raises other questions about the cancer-causing
(malignant) potential and other cell-damaging (cytotoxic)
properties of hydroquinone that could occur with systemic
absorption (passage through the skin to the remainder of the
body). Blood cell toxicity and leukemia have been associ-
ated with hydroquinone absorbed throughout the body.
Dyschromia — This term refers to abnormal
discoloration. Even though hydroquinone is applied for
skin bleaching, its end result can be the formation of
large patches of very uneven skin color. This dyschromia
is very unsightly and difficult to treat.
The bleaching agent has been its cause and therefore
cannot be used in treatment. Lazer treatment is a possibility
but is not always effective, requires a surgical procedure and
has its own potential complications.
Exogenous Ochronosis — This is a type
of dyschromia that is particularly serious. Another variant
of this skin pigment disorder is inherited and can be
associated with malignan- cies, but this exogenous (meaning
‘caused outside the body’) type is associated with topical
hydroquinone use. It involves increased pigmentation of
the neck, back, face and parts of the extremities. The
majority of patients with this are Black and it is especially
seen in South African Blacks, who have up to a 27% use
of hydroquinone products for skin bleaching. This disorder
also occurs in Hispanics and Caucasians with hydroquinone
use. Treatment is frustrating because improvement occurs
so slowly after use of the agent is discontinued.
Macular Hyperchromia — This is an increased
pigmenta- tion of the area surrounding the eyes. It occurs
in up to one-third of African Blacks using hydroquinone
skin- bleaching products. It also improves extremely slowly
after the product is stopped.
Striae — Striae are the “stretch marks”
that also occur with pregnancy and rapid weight gain.
Their appearance has also been associated with the use
of hydroquinone. They are permanent and probably result
from skin inflammation and resultant scarring related
to the product.
Very rapid Repigmentation — One case
report was found in the medical literature of a case of
vitiligo that very rapidly repigmented after hydroquinone
was stopped. Vitiligo is a skin disorder manifested by
areas devoid of pigment and appearing as very pale mixed
with normally pigmented areas. A common treatment is to
apply skin bleaching products to the remaining pigmented
skin to encourage loss of melanin and a blending with
the depigmented skin. In this case, an improvement occurred
but was very rapidly lost within a few weeks as the skin
rapidly repigmented itself.
Fingernail Discoloration — A single case
was found in which the fingernails developed a brownish
discoloration with 4% hydroquinone-containing skin bleach
that also contained tretintoin. When the cream was stopped,
the nail discoloration gradually went away.
Hydroquinone Neuropathy — A single case
report involves the gradual development of increasing
weakness in the legs associated with topical hydroquinone
use. This person had used 2 hydroquinone bleaching preparations
for about 4 years. She stopped using the creams and 4
months later, her leg weakness resolved.
 References
“Hydroquinone Health and Safety
Guide”,
United Nations Environment Programme, World Health Organization,
Geneva 1996
“Exogenous Ochronosis in
a Mexican-American Woman”,
Cutis, KL Howard, BB Furner; 1990 Mar;45(3):180-2
“Effect of Antioxidants
on Radical Intensity and Cytotoxicity of Hydroqui-none”,
H Terasaka, F Takayama, K Satoh, S Fujisawa, H Sakagami;
Antican-cer Res; 2000 Sep-Oct;20(5B):3357-62
“Lack of Nephrotoxicity and Renal Cell Proliferation following
subchronic Dermal Application of
a Hydroquinone Cream”,
RM David, JC English, LC Totman, C Moyer, JL O’Donoghue;
Food Chem Toxicol; 1998 Jul;36(7):609-16
“Human In Vivo and In Vitro
Hydroquinone Topical Bioavailability, Metabo-lism, and
Disposition”,
RC Wester, J Melendres, X Hui, R Cox, S Serran-zana, H
Zhai, D Quan, HI Maibach; J Toxicol Environ Health A;
1998 Jun 26;54(4):301-17
“Inhibitors of Mammalian
Melanocyte Tyrosinase: In Vitro Comparisons of Alkyl Esters
of
Gentisic Acid with other Putative Inhibitors”,
EV Curto, C Kwong, H Hermersdorfer, H Glatt, C Santis,
V Virador, VJ Hearing Jr, TP Dooley;
Biochem Pharmacol; 1999 Mar 15;57(6):663-72
“Peroxidase-Mediated Mechanisms
are Involved in the Melanocytotoxic and
Melanogenesis-Inhibiting Effects of Chemical Agents”,
B Kasraee; Derma-tology; 2002;205(4):329-39
“DNA-Protein Crosslink
and DNA Strand Break Formation in HL-60 Cells Treated
with Trans,Trans-Muconaldehyde,Hydroquinone and their
Mixtures”,
RP Amin, G Witz; Int J Toxicol; 2001 Mar-Apr;20(2):69-80
“Exogenous Ochronosis.
An Update on Clinical Features, Causative Agents and Treatment
Options”,
CY Levin, H Maibach; Am J Clin Dermatol;2001;2(4):213-7
“Skin Diseases Associated
with the Cosmetic Use of Bleaching Products in Women from
Dakar, Senegal”,
A Mahe, F Ly, G Aymard, JM Dangou; Br J Dermatol; 2003
Mar;148(3):493-500
“Vitiligo. Therapeutic
Advances”,
K Jimbow; Dermatol Clin; 1998 Apr;16(2):399-407
“Nail Staining from Hydroquinone
Cream”,
SM Ozluer, J Muir; Australas J Dermatol; 2000 Nov;41(4):255-6
“Hydroquinone Neuropathy
Following Use of Skin Bleaching Creams: Case Report”,
C Karamagi, E Owino, ET Katabira; East Afr Med J; 2001
Apr;78(4):223-4
“Topical Use of Hydroquinone
for Depigmentation”,
MC Spencer; JAMA; 1965 194(9):114-116
“Hydroquinone”,
WHO working group, Environmental Health Criteria;1994,VI(157),178
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