Hair Dye Ingredients and Potential Health Risks from Exposure to Hair Dyeing

Abstract

Given the worldwide popularity of hair dyeing, there is an urgent need to understand the toxicities and risks associated with exposure to chemicals found in hair dye formulations. Hair dyes are categorized as oxidative and nonoxidative in terms of their chemical composition and ingredients. For several decades, the expert panel's Cosmetic Ingredient Review (CIR) has assessed the safety of many of the chemicals used in hair dyes; however, a comprehensive review of hair dye ingredients and the risk of exposure to hair dyeing has not been documented. Herein, we review the safety of the various chemicals in oxidative and nonoxidative hair dyes, toxicities associated with hair dyeing, and the carcinogenic risks related to hair dyeing. While many compounds are considered safe for users at the concentrations in hair dyes, there are conflicting data about a large number of hair dye formulations. The CIR expert panel has ratified a number of coloring ingredients for hair dyes and banned a series of chemicals as carcinogenic to animals and unsafe for this application. The use of these chemicals as raw materials for producing hair dyes may result in the synthesis of other contaminants with potential toxicities and increased risk of carcinogenesis. It is an open question whether personal or occupational hair dyeing increases the risk of cancer; however, in specific subpopulations, a positive association between hair dye use and cancer occurrence has been reported. To address this question, a better understanding of the chemical and mechanistic basis of the reported toxicities of hair dye mixtures and individual hair dye ingredients is needed. It is anticipated that in-depth chemical and systems toxicology studies harnessing modern and emerging techniques can shed light on this public health concern in the future.

Full text

Hair Dye Ingredients and Potential Health Risks from Exposure to
Hair Dyeing
This manuscript is part of a special collection: Chemical Exposures and Impact on Human Health.
Lin He, Freideriki Michailidou, Hailey L. Gahlon, and Weibin Zeng*
Cite This: Chem. Res. Toxicol. 2022, 35, 901−915
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ABSTRACT: Given the worldwide popularity of hair dyeing, there is an urgent need
to understand the toxicities and risks associated with exposure to chemicals found in
hair dye formulations. Hair dyes are categorized as oxidative and nonoxidative in
terms of their chemical composition and ingredients. For several decades, the expert
panel’s Cosmetic Ingredient Review (CIR) has assessed the safety of many of the
chemicals used in hair dyes; however, a comprehensive review of hair dye ingredients
and the risk of exposure to hair dyeing has not been documented. Herein, we review
the safety of the various chemicals in oxidative and nonoxidative hair dyes, toxicities
associated with hair dyeing, and the carcinogenic risks related to hair dyeing. While
many compounds are considered safe for users at the concentrations in hair dyes,
there are conflicting data about a large number of hair dye formulations. The CIR
expert panel has ratified a number of coloring ingredients for hair dyes and banned a
series of chemicals as carcinogenic to animals and unsafe for this application. The use
of these chemicals as raw materials for producing hair dyes may result in the synthesis of other contaminants with potential toxicities
and increased risk of carcinogenesis. It is an open question whether personal or occupational hair dyeing increases the risk of cancer;
however, in specific subpopulations, a positive association between hair dye use and cancer occurrence has been reported. To
address this question, a better understanding of the chemical and mechanistic basis of the reported toxicities of hair dye mixtures and
individual hair dye ingredients is needed. It is anticipated that in-depth chemical and systems toxicology studies harnessing modern
and emerging techniques can shed light on this public health concern in the future.
1. INTRODUCTION
About 33% of women over the age of 18 and more than 10% of
men over age 40 in Europe and the United States dye their
hair.
1
Given this popularity, it is critical to assess the toxicity
and carcinogenicity of hair dyes and their ingredients. Thanks
to the expert panel’s Cosmetic Ingredient Review (CIR), a
large number of candidate coloring ingredients have undergone
safety assessment prior to use in hair dyes.
Modern hair dyes are classified as oxidative or nonoxidative,
and their color durability is referred to as temporary (8−12
washings), semipermanent (∼24 washings), or permanent
(until hair grows out), in terms of their formulation (Table 1).
2
As far as the chemical composition is concerned, oxidative hair
dye products are often referred to as permanent or semi-
permanent, while nonoxidative hair dye products are
considered temporary or semipermanent. Nonoxidative
compounds are used in temporary and semipermanent hair
dyes, which are used to directly dye natural hair.
2−4
Oxidative
dyes were introduced as permanent hair dyes at the end of the
19th century and experienced explosive growth after 1970; a
variety of new permanent oxidative chemical hair dyes
currently dominate the global hair dye market. Permanent
hair dyes account for the highest market share of all modern
hair dyes in Asia, America, and Europe.
5
Because of the increasing number of users and the growing
economic share, hair dyeing has been pinpointed as a public
health concern, urgently needing evaluation of the toxicity and
carcinogenicity related to hair dyes. Because different hair dye
types with specific compounds have been employed, results of
hair dye-induced toxicity and carcinogenicity reported in the
literature have been inconclusive. This article reviewed the
existing literature and available data on the safety and risks
associated with established chemicals in hair dyes. We related
these compounds to their reported toxicities and carcinogenic
risks, identified the current gaps of knowledge in the field, and
proposed future directions.
Received: December 7, 2021
Published: June 6, 2022
Reviewpubs.acs.org/crt
© 2022 The Authors. Published by
American Chemical Society 901
https://doi.org/10.1021/acs.chemrestox.1c00427
Chem. Res. Toxicol. 2022, 35, 901−915

2. HAIR DYE INGREDIENTS
2.1. Hair Dye Categories. The chemical ingredients of
hair dyes vary among formulations that involve oxidative
reactions to achieve coloring and those using nonoxidative
processes.
2
Temporary and semipermanent hair dyes typically
rely on nonoxidative processes, while permanent hair dyes rely
on oxidative reactions (Table 1). Temporary hair dyes are
composed of water-soluble acidic and basic dyes bearing azo or
anthraquinone groups; they are generally regarded as more
benign because they are deposited on the hair surface and do
not penetrate into the hair cortex. They do not require an
oxidizing agent and are typically removed by a single
shampooing.
3,4
Semipermanent hair dyes consist of acidic
and basic dyes bearing azo groups, anthraquinones, triphenyl
methanes, or nitro derivatives as chromophores. Ionic
Table 1. Category and Composition of Modern Hair Dyes
dye category hair coloring
process composition hair dyeing type
temporary nonoxidative water-soluble acidic and basic dyes bearing azo or anthraquinone groups deposition on hair
semipermanent nonoxidative acid and basic dyes bearing azo groups, anthraquinones, triphenylmethanes and nitro
derivatives as chromophores ionic interactions or van der
Waals forces
permanent oxidative precursor agent, coupling agent and oxidizer penetration into hair
Figure 1. Chemical structures of hair dye ingredients. Chemical structures of the following hair dye ingredients are shown: p-phenylenediamine 1
(PPD), N-monoacetyl-p-phenylenediamine 2(MAPPD), N,N-diacetyl-p-phenylenediamine 3(DAPPD), N-phenyl-p-phenylenediamine 4,N,N-
bis(hydroxyethyl)-p-phenylenediamine 5, hydroxypropyl bis(N-hydroxyethyl-p-phenylenediamine) 6, 2-chloro-p-phenylenediamine 7, 4-methoxy-
m-phenylenediamine 8,p-methylaminophenol 9, 2-methyl-5-hydroxyethylaminophenol 10, 2,4-diaminophenol 11, hydroquinone 12,t-butyl
hydroquinone 13, toluene-2,5-diamine (CAS no: 95-70-5) 14, toluene-3,4-diamine 15, Disperse Blue 7 16, Disperse Violet 1 17, Disperse Yellow 3
18, Acid Violet 43 19, Basic Blue 99 20, HC Blue no. 2 21, HC Yellow no. 5 22, HC Red no. 7 23, 3-nitro-p-hydroxyethylaminophenol 24,4-
amino-3-nitrophenol 25, 4-amino-2-hydroxytoluene 26, 1-naphthol 27, resorcinol 28,o-phenylenediamine 29, 4-chloro-o-phenylenediamine 30,4-
aminobiphenyl 31, and di-n-butyl phthalate 32. Only the core chemical structures are shown. The sulfate or hydrochloride salts are omitted for
simplicity.
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Table 2. Detailed Characteristics of Major Hair Dye Ingredients
a
compound year
b
maximum allowable
concentration (%) LD50
(mg/kg)
c
toxicity carcinogenicity ref
N,N-bis(hydroxyethyl)-p-phenylenediamine 5sulfate salt 1984 ≤5 264 reduced body weight; darkened thyroid glands; decreased serum iron
concentration; delayed hypersensitivity; allergic contact dermatitis no evidence 10
N-phenyl-p-phenylenediamine 4,N-phenyl-p-phenylenediamine
HCl 1993 ≤1.7 464−1000 reduced body weight; degenerated seminiferous tubules; skeletal
malformations; skin irritation no evidence 11
hydroxypropyl bis(N-hydroxyethyl-p-phenylenediamine) 6HCl NA ≤0.4 2186 reduced body weight, mean serum glucose and total protein levels;
reproductive and developmental toxicity no evidence 12
4-methoxy-m-phenylenediamine 8, 4-methoxy-m-
phenylenediamine sulfate salt, 4-methoxy-m-phenylenediamine
HCl
1978 NA 400−500 skin irritation; mutagenicity animal
carcinogenicity 13
2-chloro-p-phenylenediamine 7, 2-chloro-p-phenylenediamine
sulfate salt 1984 ≤1.0 NA skin irritation; reduced body weight; ocular irritation no evidence 14
2-methyl-5-hydroxyethylaminophenol 10 NA ≤5 5700 skin irritation; mutagenicity; allergic contact dermatitis no evidence 15
p-methylaminophenol 9sulfate salt NA ≤1 NA increased rate of formation of methemoglobin; skin irritation no evidence 16
2,4-diaminophenol 11, 2,4-diaminophenol dihydrochloride salt 1993 ≤0.2 240 skin irritation; severe ocular irritation; mutagenicity no evidence 17
hydroquinone 12 1981 ≤1 627−743 nephrotoxicity; cytotoxicity; skin irritation; skin sensitization; skin
depigmentation; mutagenicity animal
carcinogenicity 18,19
t-butyl hydroquinone 13 1981 ≤0.1 480−800 reduced body weights; mutagenicity no evidence 20
toluene-2,5-diamine 14, toluene-2,5-diamine sulfate salt 1984 ≤498−102 skin irritation; skin sensitization; ocular irritation; reproductive toxicity;
skeletal malformation no evidence 21−23
toluene-3,4-diamine 15 1984 NA NA duodenal lesions; genotoxicity; skin sensitization no evidence 21,22
Disperse Blue 7 16 2002 NA NA mutagenicity no evidence 24
Disperse Violet 1 17 1988 ≤1 NA ocular irritation no evidence 25
Disperse Yellow 3 18 1992 NA NA nephrotoxicity; chromosomal aberrations; allergic contact dermatitis animal
carcinogenicity 26
Acid Violet 43 19 1984 ≤1 NA no significant toxicity no evidence 27
Basic Blue 99 20 1992 ≤2 >2000 skin irritation no evidence 28
HC Blue no. 2 21 1993 ≤1.7 1250−5000 mutagenicity no evidence 29
HC Yellow no. 5 22 2002 ≤1.6 555.56 skin irritation no evidence 30
HC Red no. 7 23 2005 ≤1 NA skin sensitization; mutagenicity no evidence 31
a
For chemical structures, refer to Figure 1.
b
The first yearly report by the Food and Drug Administration.
c
The oral LD50 in rats of aqueous solutions. Abbreviations: LD50, median lethal dose; NA, not
assessed.
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interactions or van der Waals forces are associated with the
deposition of these low molecular weight compounds on hair
structures. The hair color from semipermanent dyes is
generally retained over several shampoo applications. Perma-
nent hair dyes penetrate hair to change the natural hair color,
and they are more frequently associated with adverse reactions
and pose a higher risk to human health. Permanent hair dyes
require three components: (1) precursor agents, that is,
primary intermediates comprised of ortho-(o-) and para-(p-)
aromatic amines substituted with amino groups and/or
hydroxides; (2) coupling agents that are formed by aromatic
compounds meta-(m-) substituted with electron-donating
groups, such as m-phenylenediamines, resorcinol, naphthol,
and other derivatives; and (3) oxidizing agents in alkaline
media, predominantly hydrogen peroxide (H2O2) in the
presence of ammonia.
2.2. Hair Dye Ingredients: Chemical Characteristics
and Reported Toxicities. This section focuses on the
physical and chemical characteristics of widely used hair dye
chemicals (Figure 1) and the chemical basis of their reported
toxicities. Current knowledge regarding their safety (including
their relevant hydrochloride and sulfate salts) is summarized in
Table 2.
6−27
Aromatic amines, such as p-phenylenediamine (PPD, 1)
(Figures 1 and 2), constitute the main class of compounds
used as precursors in permanent hair dyes. The multiple
toxicological properties of PPD have been demonstrated in
previous studies; for instance, PPD induces apoptosis by
increasing reactive oxygen species.
28
During hair coloring, PPD
can penetrate the skin and be absorbed by the airway,
29
where
it can then be biotransformed into N-monoacetyl-p-phenyl-
enediamine (MAPPD, 2) and N,N′-diacetyl-p-phenylenedi-
amine (DAPPD, 3)(Figure 2). A study of the transformation
of PPD to MAPPD and DAPPD using reconstituted human
epidermis showed that the metabolite levels produced depend
on the dose of PPD. At concentrations of 250−1000 μM, the
formation of MAPPD was favored, while at doses below 250
μM, DAPPD was preferentially formed.
30
PPD induces
dendritic cell (DC) activation after in vitro exposure to
oxygen in air, and a positive local lymph node assay (LLNA)
response in vivo, demonstrating its intracorporeal sensitizing
potential. The sensitizers produced by PPD oxidation in both
cases induced immune stimulation. In contrast, MAPPD and
DAPPD did not induce DC activation or give a positive LLNA
response.
31
The biotransformation of PDD to MAPPD or
DAPPD and the formation of sensitizers from PPD oxidation
are two distinct competing pathways. The formation of
sensitizing agents is promoted when increased PPD concen-
trations are present, leading to a series of PPD-related toxicities
(Figure 2).
N-Phenyl-p-phenylenediamine 4(Figure 1,Table 2)is
another common aromatic amine present in hair dyes. It has
been associated with toxic effects including body weight
reduction as a function of dose in rats, degeneration of the
seminiferous tubules, skeletal malformation, and skin sensitiza-
tion (Table 2).
32
The EU Scientific Committee on Consumer
Products (SCCP) identified limitations in some of these
studies, such as inadequate data inclusion and noncompliance
with the Organization for Economic Cooperation and
Development guidelines, but confirmed the strong potential
of N-phenyl-p-phenylenediamine to cause skin sensitization.
33
Exposure to the structurally related N,N-bis(hydroxyethyl)-p-
phenylenediamine 5(sulfate salt) is associated with reduction
in body weight, darkening of thyroid glands, decrease in serum
iron concentration, delayed hypersensitivity of guinea pig skin,
and allergic contact dermatitis (ACD).
6,34
Exposure to
hydroxypropyl bis(N-hydroxyethyl-p-phenylenediamine) hy-
drochloride salt 6is linked to reduced body weight, decreased
mean serum glucose, attenuated total protein levels, and
reproductive and developmental problems,
8
while exposure to
Figure 2. Mechanism of toxicity induced by p-phenylenediamine. An increase in reactive oxygen species is associated with PPD 1-induced
apoptosis. Dermal N-acetylation biotransforms PPD toward MAPPD 2and DAPPD 3; at concentrations up to 250 μM, it is beneficial to the
MAPPD formation, and at the concentration of 250−1000 μM, it is beneficial to the DAPPD formation. MAPPD and DAPPD fail to activate DCs
or cause a positive LLNA response, which are considered the markers of extracorporeal and intracorporeal sensitizing potential of chemical
compounds. PPD can induce DC activation after exposure to oxygen in air in vitro, and creates an LLNA response in vivo. The sensitizing PPD
oxidation provides some effective immune stimulation that is associated with PPD-induced toxicity. Abbreviations: ROS, reactive oxygen species.
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2-chloro-p-phenylenediamine 7and its sulfate salt were linked
to skin irritation, reduced body weight and ocular irritation.
10
It should be noted that 4-methoxy-m-phenylenediamine 8and
its hydrochloride and sulfate salts are unsafe for use in
cosmetic products due to their reported carcinogenicity in rats
and mice (Table 2).
9
Aminophenols are another class of ingredients that are
widely used in hair dyes. They are chemically synthesized by
the reduction of nitrophenols and can be used as primary
intermediates in manufacturing sulfur and azo dyes.
11
They
typically undergo reactions with oxidants to produce
corresponding imines that can chemically react with coupling
agents to produce indophenol dyes.
12
As a primary
intermediate, p-methylaminophenol 9(sulfate salt) reacts
with hemoglobin at a more rapid rate than p-aminophenol to
form methemoglobin, a form of oxidized hemoglobin, and
slightly irritates rabbit skin but is not considered a dermal
sensitizer.
12
The coupling agent, 2-methyl-5-hydroxyethylami-
nophenol 10 is used in oxidative hair dyes at a concentration of
≤5%. It can be mutagenic, and exposure can cause skin
irritation, and allergic contact dermatitis.
11
The Food and Drug
Administration (FDA) concluded that the maximum allowable
concentration of 2,4-diaminophenol 11 and its dihydrochloride
salt for use in hair dyes is 0.2%. Exposure to this compound
can lead to slight skin irritation, severe ocular irritation, and
mutagenicity (Table 2).
13
Hydroquinone 12 is used as an
antioxidant, fragrance, reducing agent, and polymerization
inhibitor in hair dyes, skincare products, and lipsticks.
14
Human skin absorbs hydroquinone from both aqueous and
alcoholic preparations, and excretion of this compound
involves the formation of glucuronide or sulfate conjugates.
15
This chemical may cause nephrotoxicity, cytotoxicity, skin
irritation, skin sensitization, skin depigmentation, and muta-
genicity.
14
The most noteworthy data are related to its
reported animal carcinogenicity, in which an increased
incidence of renal tubule cell tumors and leukemia was
observed in F344 rats; but so far, such adverse effects on
humans have not been described.
15
The acid-catalyzed reaction
of hydroquinone with isobutylene or t-butanol produces a new
crystalline solid, t-butyl hydroquinone 13, an ingredient which
can cause mild to moderate toxicity such as reduced body
weight and mutagenicity in rats when administered orally or
intraperitoneally (Table 2).
16
Diaminotoluene is chemically prepared from dinitrotoluene
via a catalytic hydrogenation procedure or from the reaction of
iron, hydrochloric acid, and dinitrotoluene. The two isomers,
toluene-2,5-diamine 14 and toluene-3,4-diamine 15,are
primary intermediates that can impart different colors to
permanent hair dyes.
17
For example, toluene-2,5-diamine and
its sulfate salt can color hair black, brown, gold, or gray, and
toluene-3,4-diamine makes hair brown, red, or gold.
17
Toluene-2,5-diamine 14 can be readily absorbed through the
skin, but 90% will be excreted within 24 h after absorption,
with a half-time excretion of 8 h.
19
These two compounds
manifested some adverse effects such as extreme skin
sensitization
35
and reproductive toxicity (Table 2); however,
a maximum concentration of 2% (calculated as free base) or
3.6% (calculated as sulfate salt) applied to the head was
considered safe with regard to systemic toxicity.
35
An Ames
test demonstrated that the presence of toluene-2,5-diamine in
an oxidative hair dye may cause mutagenicity in the TA98 test
strain.
36
Further studies are needed to determine the safety of
toluene-3,4-diamine as a hair dye ingredient.
Many nonoxidative ingredients are used in temporary and
semipermanent hair dyes.
20−27
The CIR concluded that there
is insufficient data available regarding the safety of Disperse
Blue 7.
20
Disperse Blue 7 16 is an anthraquinone-based dye
used as a hair ingredient in a few selected hair dyes. Disperse
Violet 1 17 is a diamino-anthraquinone dye used in temporary
and semipermanent hair dyes at a maximum concentration of
1%. To date, the only toxicity reported is ocular irritation.
21
Acid Violet 43 19 can be used in any cosmetic product because
it showed no signs of significant toxicity.
23
Basic Blue 99 20 is
the most frequently used chemical product for hair tints.
13
HC
Table 3. Hair Dye-Related Toxicity from a Case Report Study
toxicity study
duration sex age ingredients exposure route symptom
timing
a
patch test
concen-tration
(%) positive
reaction
c
ref
ACD 2015 F 50 henna hair dyeing 4 d 0.01 1+ 40
ACD 2005 F 50 3-nitro-p-hydroxy
ethylaminophenol 24 and 4-
amino-3-nitrophenol 25
hair dyeing 1 d 1.00 1+ 43
contact
anaphylaxis 2017 F 56 Basic Blue 99 20 hair dyeing 10 min 0.10 3+ 37
ACD 2009 F 47 4-amino-2-hydroxytoluene 26 hair dyeing NA 1.00 2+ 44
ACD 2018 F 43 1-naphthol 27 hair dyeing 2 d 1.00 3+ 49
DLE 2016 F 32 p-phenylenediamine 1and toluene-
2,5-diamine 14
hair dyeing NA NA 2+ 55
angioedema 2018 F 29 p-phenylenediamine 1hair dyeing 1 d 1.00 3+ 61
neck and facial
swelling 2016 F 15 p-phenylenediamine 1hair dyeing 3 d NA 3+ 62
severe facial
swelling 2014 F 33 p-phenylenediamine 1hair dyeing 2 d NA 4+ 63
hair loss 2011 F 41 p-phenylenediamine 1hair dyeing 1 d 1.00 2+ 64
pneumothorax 2011 2F 19 ±1
b
p-phenylenediamine 1consumption NA NA NA 71
rhabdomyolysis 2013 M 3 p-phenylenediamine 1consumption 2 h NA NA 72
rhabdomyolysis 2002−2006 8M +
2F 23.2 ±7.6
b
p-phenylenediamine 1consumption NA 0.95 NA 73
a
Symptom timing indicates the duration from exposure to symptoms.
b
These studies describe more than one case, and the age is the mean value.
c
The positive reaction is calculated in terms of the patch test of corresponding ingredients at the patch test concentration. Abbreviations: F, female;
M, male; NA, not assessed.
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Blue no. 2 21 is exclusively used in hair dyes at a concentration
of ≤1.7%.
25
Although this compound is mutagenic, no
carcinogenic outcomes were observed in exposure studies
with rats and mice.
25
Formulations containing HC Yellow no.
522 are sold with a caution statement because of skin
irritation. While some concern still exists, the available safety
test data from the CIR expert panel demonstrated that HC
Yellow no. 5 had no animal carcinogenicity as a hair dye
ingredient at a concentration of ≤1.6%; the oral LD50 in rats is
555.56 mg/kg.
26
HC Red no. 7 has been confirmed as suitable
for use in hair dyes by the CIR expert panel up to
concentrations of 1% but may elicit skin irritation and
mutagenicity (Table 2).
27
3. HAIR DYE-INDUCED TOXICITIES AND ADVERSE
HEALTH EFFECTS
3.1. Contact Allergy and Hair Loss. Hair dyeing-induced
contact allergies occur frequently, which may further lead to
the occurrence of ACD and urticarial contact (Table 3).
37−40
ACD commonly occurs on the scalp, face, and hands of hair
dye users, manifesting as redness of the skin with vesiculation
or scaling (Table 3),
41,42
which reduces quality of life in the
affected individuals and can have negative socioeconomic
impacts. The presence of contact allergies is closely attributed
to the potent skin sensitizers contained in hair dyes, such as
aromatic amines including PPD, a prevalent hair dye
ingredient.
43
However, using permanent hair dyes containing
PPD at concentrations ≤0.67% is unlikely to induce skin
sensitization.
44
Recently, Goebel and co-workers
45
found that a
methoxymethyl side chain introduced into PPD not only
reduced the sensitizing intensity and the risk of allergic
induction but also resulted in excellent hair coloring perform-
ance.
As far as plant-based hair dyes are concerned, although the
public perceives them as safe, they can cause minor allergic
reactions. For example, a small number of case reports have
documented rare cases of ACD in users of plant-based hair
dyes that contain pure henna, black tea, and indigo powder
(Table 3).
46−48
There may be several explanations for this
finding. First, pure henna, black tea, and indigo powder all
contain about 15% tannins, large complex polyphenolic
molecules that could cause the observed ACD. Although
allergens in tannins have not been identified to date, the
tannin-induced allergenic response is associated with inhibition
of IL-8, IL-6, and TNF-αsecretion from stimulated human
mast cells.
49
The resulting color intensity that can be achieved
by some plant colorants, such as pure henna, is time
dependent.
47
Some darkening substances in proprietary
formulas, such as lemon oil, vinegar, eucalyptus oil, or clove
oil, may be added along with PPD to shorten the time of
application.
As hairdressers are exposed on a regular basis to hair dyes in
all steps of the dyeing process,
50
they face a significantly higher
skin sensitization risk than personal hair dye users.
51,52
The use
of protective gloves during hair coloring and warnings on the
product labels that a sensitivity test is needed before
application have decreased the incidence of hair dye-induced
allergies. With sufficient protection against local and systemic
exposure to oxidative hair dyes, hair coloring is unlikely to pose
a serious risk to human health.
53,54
The adoption of adequate
protective measures during the use of hair dye as well as
appropriate education and training of hairdressers are crucial
for lowering occupational risks and preventing hair dye-
induced skin sensitization.
55
Discoid lupus erythematosus (DLE) is an autoimmune skin
disease that may be caused by ACD (Table 3); it is
characterized by the development of autoantibodies that attack
the skin at the interphase level.
56,57
Systemic lupus
erythematosus (SLE) is another autoimmune disease manifest-
ing multisystem disorders in addition to skin lesions. Although
exposure to aromatic amines (such as PPD) may give rise to
the occurrence of lupus, several studies collectively confirm an
insignificant association between the use of hair dyes
containing PPD and the increased risk of SLE.
58−60
Never-
theless, skin exposure to hair dyes may induce other severe but
rare contact allergies, including neck and facial swelling and
angioedema (Table 3).
61−63
Angioedema is a type I hyper-
sensitivity reaction characterized by edema of the skin and
subcutaneous tissues that damages the airways and gastro-
intestinal tract and may even lead to life-threatening laryngeal
swelling.
Along with the increasing popularity of hair dye use, growing
complaints about hair dye-induced hair loss have been a
concern of dermatologists. Isik et al.
62
found that patients who
experienced hair loss after hair dyeing presented symptoms of
ACD before or at the time of hair loss, suggesting a close
correlation between hair dye-induced ACD and hair loss
(Table 3). H2O2, monoethanolamine, and PPD in hair dyes
have been proposed as the main causative ingredients of hair
dyeing-induced hair loss.
64,65
Based on histological examina-
tion conducted in animal tests, oxidative stress may be the
mechanism underlying hair-dye induced dermatitis.
64,65
H2O2
and monoethanolamine, in particular, were shown to
synergistically induce oxidative stress and cytotoxicity in
human keratinocytes, an observation that is consistent with
the histological data.
64,65
3.2. Respiratory Sensitization, Allergies, And Other
Diseases. Asthma and allergic rhinitis are common diseases
that can result in overwhelmingly negative socioeconomic
impacts.
66
Hairdressers are at a high risk of occupational
rhinitis and asthma because, in daily work, they are frequently
exposed to irritants and allergens such as persulfate and PPD in
hair dyes.
67,68
A case-control study from Norway
69
showed
that hairdressers over 40 years of age were more likely to suffer
asthma-like symptoms than nonhairdressers due to their long
occupational exposure to hair dye ingredients. Therefore,
hairdressers and hairdressing apprentices should undergo
continuous medical surveillance to monitor the risk factors
and reduce the chance of respiratory diseases linked to
occupational exposure.
3.3. Hair Dye Poisoning. Due to the easy availability and
high toxicity of PPD, people in the developing world who want
to commit suicide may attempt it by consuming this agent.
70
Hair dye poisoning may trigger the occurrence of some urgent
and fatal outcomes, like pneumothorax, rhabdomyolysis, and
acute kidney injury (AKI) (Table 3).
71−73
Orally ingesting
PPD causes severe trauma to the airway and may lead to
dyspnea, asphyxia, and other respiratory symptoms. If those
ingesting PPD suffer respiratory distress and chest pain, then
caution is needed regarding the occurrence of pneumothorax,
which can be diagnosed by sonography or bedside X-ray. The
pathological underpinning of rhabdomyolysis involves calcium
ions leaking from the smooth endoplasmic reticulum, resulting
in prolonged muscle contraction and irreversible changes in
muscle structure.
74
The most striking laboratory characteristic
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Table 4. Studies Assessing the Association between Hair Dye Use and Carcinogenic Risk
study study type publication
year original nation cases/
controls carcinogenic risk association analysis ref
Gago-Dominguez case-control study 2001 USA 897/897 bladder cancer 2.1-fold (P= 0.04) 94
Kogevinas case-control study 2006 Spain 152/166 bladder cancer OR, 0.80 (0.50−1.50) 95
Thun epidemiologic study 1994 USA NA
bladder cancer RR, 0.56 (0.32−0.99)
96
breast cancer RR, 0.95 (0.83−1.05)
non-Hodgkin’s lymphoma RR, 0.95 (0.74−1.23)
Hodgkin’s lymphoma RR, 0.55 (0.23−1.36)
multiple myeloma RR, 1.05 (0.75−1.47)
Henley comment 2001 USA NA bladder cancer RR, 1.08 (0.84−1.38) 97
Hartge case-control study 1982 USA 2982/5782 bladder cancer RR, 1.00 (0.90−1.20) 98
Ros case-control study 2012 The Netherlands 1385/4754 bladder cancer OR, 0.87 (0.65−1.18) 101
Koutros case-control study 2011 USA 61/102 bladder cancer OR, 3.30 (1.20−8.90) 105
Gago-Dominguez case-control study 2003 USA 33/12
a
bladder cancer OR, 2.90 (1.20−7.50) 106
37/17
a
bladder cancer OR, 2.50 (1.04−6.10) 94
Turati meta-analysis 2014 Italy 3657/5962 bladder cancer RR, 0.92 (0.77−1.09) 100
Boice case-control study 1995 USA 528/2628 breast cancer OR, 1.08 (0.87−1.30) 111
Koenig case-control study 1991 USA 398/790 breast cancer OR, 0.80 (0.60−1.10) 112
Cook case-control study 1999 USA 315/393
b
breast cancer RR, 1.10 (0.90−1.30) 115
204/138
b
breast cancer RR, 1.90 (1.40−2.50) 115
Zheng case-control study 2002 USA 608/609 breast cancer OR, 0.90 (0.70−1.20) 113
Nasca case-control study 1992 USA 1617/1617 breast cancer OR, 1.04 (0.90−1.21) 114
Heikkinen case-control study 2015 Finland 6567/21598 breast cancer OR, 1.23 (1.11−1.36) 116
Petro-Nustas case-control study 2002 Jordan 100/100 breast cancer OR, 8.62 (3.33−22.28) 117
Eberle prospective study 2019 USA NA breast cancer HR, 1.45 (1.10−1.90) 119
Nasca case-control study 1980 USA 118/233 breast cancer OR, 4.50 (1.20−15.78) 118
Gera meta-analysis 2018 UK NA breast cancer RR, 1.19 (1.03−1.37) 1
Xu meta-analysis 2021 China NA breast cancer OR, 1.07 (1.01−1.13) 120
Grodstein prospective study 1994 USA NA
hematopoietic cancer RR, 0.90 (0.70−1.20
136
non-Hodgkin’s lymphoma RR, 1.10 (0.80−1.60)
Hodgkin’s lymphoma RR, 0.90 (0.40−2.10)
multiple myeloma RR, 0.40 (0.20−0.90)
Miligi case-control study 1999 Italy 165/828 Hodgkin’s lymphoma OR, 0.70 (0.50−1.10) 138
134/828 multiple myeloma OR, 0.80 (0.50−1.20)
260/828 leukemia OR, 0.90 (0.70−1.30)
Benavente case-control study 2005 Spain 574/616 hematopoietic cancer OR, 1.20 (0.90−1.70) 139
Tavani case-control study 2005 Italy 446/1295 non-Hodgkin’s lymphoma OR, 1.03 (0.73−1.44) 142
158/1295 Hodgkin’s lymphoma OR, 0.68 (0.40−1.18)
141/1295 multiple myeloma OR, 1.17 (0.70−1.97)
Wong case-control study 2010 USA 649/1298 non-Hodgkin’s lymphoma OR, 0.93 (0.75−1.16) 147
Zahm case-control study 1992 USA
385/1432 non-Hodgkin’s lymphoma OR, 1.50 (1.10−2.20)
148
70/1432 Hodgkin’s lymphoma OR, 1.70 (0.70−4.00)
72/1432 multiple myeloma OR, 1.80 (0.90−3.70)
56/1432 leukemia OR, 1.00 (0.30−2.60)
Zhang case-control study 2009 USA 601/717 follicular lymphoma OR, 1.90 (1.10−3.30) 149
non-Hodgkin’s lymphoma OR, 1.30 (1.00−1.80) 150
Zhang case-control study 2009 USA 4461/5799 non-Hodgkin’s lymphoma OR, 1.30 (1.10−1.40) 151
Guo case-control study 2009 USA 261/247
c
non-Hodgkin’s lymphoma OR, 1.46 (1.10−1.95) 152
132/177
c
OR, 1.03 (0.75−1.42)
Cantor case-control study 1988 USA 622/1245 non-Hodgkin’s lymphoma OR, 2.00 (1.30−3.00) 153
Herrinton interview study 1994 USA women multiple myeloma OR, 1.00 (0.70−1.40) 140
men OR, 1.50 (0.75−2.90)
Koutros case-control study 2009 USA 175/679 multiple myeloma OR, 0.80 (0.50−1.10) 141
Mele case-control study 1995 Italy 254/1161 leukemia OR, 1.50 (0.60−3.70) 137
Cantor case-control study 1988 USA 578/1245 leukemia OR, 1.80 (1.10−2.70) 153
Chen case-control study 2006 USA 272/418
d
testicular germ cell tumor OR, 1.50 (1.00−2.20) 163
83/180
d
OR, 1.70 (1.00−2.80)
189/238
d
OR, 1.70 (1.10−2.60)
a
33/12 and 37/17 indicate subjects with the NAT2 slow acetylation phenotype and those with the CYP1A2 slow phenotype, respectively.
b
315/
393 and 204/138 indicate subjects using the single hair dye method and those using two or more methods, respectively.
c
261/247 and 132/177
indicate subjects using hair dye before 1980 and those using hair dye in and after 1980, respectively.
d
272/418, 83/180, and 189/238 indicate all
children, boys, and girls, respectively. Abbreviations: OR, odds ratio; RR, relative ratio; HR, hazard ratio.
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of rhabdomyolysis is a concentration of creatine phosphoki-
nase in the plasma >10,000 U/L. If patients do not receive
aggressive treatment, they will eventually die. Globally,
approximately 13.3 million humans suffer from AKI per year,
and more than 1 in 10 lose their life from this disease.
75
Individuals with AKI are also at a 9-fold risk of developing
chronic kidney disease that can give rise to other organ
dysfunctions. The characterized pathological manifestations of
AKI include glomerular hyperemia, acute tubular necrosis,
intratubular casts, and tubulointerstitial hemorrhages as well as
mesangial hyperplasia. Hair dye-induced AKI occurs in a dose-
dependent manner, but even with no intervention, the injured
kidney may recover over time.
74
3.4. Reproductive Toxicity and Disruption of Thyroid
Hormone Synthesis. Zebrafish embryos are suitable animal
models for studying how hair dyes affect embryonic growth.
Two studies by Manjunatha et al.
76,77
demonstrated that
exposure to hair dyes induced morphological and physiological
abnormalities in zebrafish embryos, which provoked interest in
determining whether hair dyes could affect human embryo
development. Abnormal birth weight in humans (live birth
weight <2500 g or >4000 g) reflects the poor health of the
fetus and mother, which could contribute to the occurrence of
obesity, malnutrition, hypertension, cardiovascular diseases,
and cancer in the child in the future.
78
In terms of hair dyeing,
the risk of infantile abnormal birth weight is elevated when
mothers have irregular menstruation or have used hair dyes
before pregnancy; the risk is increased if both factors exist.
79
Resorcinol 28 is widely used as a component in hair dyes
and cosmetics, and administration to rodents at high doses
(>520 mg/kg/d) over 2 years disrupted thyroid hormone
synthesis and caused goitrogenic effects.
80
Dermatological
clinical reports indicated that frequent external application of
ointments containing a high concentration of resorcinol (>34
mg/kg/d) to integrity-compromised human skin for several
months to years can also induce thyroid side effects.
80
However, a risk assessment study concluded that under real-
world conditions, exposure to resorcinol contained in hair dyes
and cosmetics was unlikely to cause human thyroid
dysfunction.
80
4. ASSOCIATION BETWEEN HAIR DYE USE AND
CANCER
4.1. Bladder Cancer. Bladder cancer is the most common
urinary tract tumor and ranks 11th among the most common
malignant tumors worldwide.
81,82
Occupational exposure to
arylamines is frequently found in employees who engage in
metal working, textile manufacture, driving, agriculture,
construction, and rubber tire production and is the first
identified cause of bladder cancer.
83
Hair dyes contain
arylamines;
84
therefore, hairdressers and barbers are at risk
of cancer from occupational exposure to arylamines. Findings
demonstrate that individuals who pursue these occupations,
particularly for longer than 10 years, experience a significantly
increased risk of bladder cancer.
82,85,86
On the contrary, some
epidemiologic studies observed no evidence of a causal
association between occupational exposure to hair dyes and
the increased risk for bladder cancer among male hair-
dressers.
87,88
Permanent hair dyes may contain o-phenylenedi-
amine
89
29 and 4-chloro-o-phenylenediamine 30 (Figure 1),
90
which have shown carcinogenicity in animal studies. These
chemicals can lead to the formation of 8-oxo-7,8-dihydro-2′-
deoxyguanosine (8-oxodG) that is a marker of oxidative
stress.
91
These findings indicate that the carcinogenicity of o-
phenylenediamines is related to the generation of oxidative
DNA damage, and 8-oxodG may be used as a biomarker to
predict the associated carcinogenicity. Moreover, many
permanent hair dyes contain 4-aminobiphenyl 31, which is
produced during the production of hair dyes where PPD is
used as the primary intermediate.
92
Airoldi and colleagues
found that 4-aminobiphenyl was a human bladder cancer
carcinogen and was positively associated with tumor grade.
93
Thus, it is a public health concern to determine if other
contaminants formed during hair dye production may
constitute an additional health risk to hair dye users.
Currently available epidemiological data are controversial
regarding whether hair dye use is a carcinogenic risk factor for
bladder cancer. One population-based, case-controlled study
found a positive association between the use of permanent hair
dyes and enhanced bladder cancer risk,
94
while the results of
other large-scale studies and a meta-analyses did not
corroborate this conclusion (Table 4).
95−100
Studies inves-
tigating other confounding factors, like duration of use,
frequency of use, age at first use, sex, and dye color, did not
find a significant association between hair dye use and bladder
cancer.
101−104
In addition, the New England Bladder Cancer
Study
105
found no significant association between permanent
hair dye use and increased bladder cancer risk in studies with
female participants, but suggested that female users with a
college degree had a greater risk of bladder cancer than
nonusers (OR = 3.3; 95% CI, 1.2−8.9). This study also found
that bladder cancer risk was higher among women with the
NAT2 slow acetylation phenotype compared to those with the
NAT2 rapid/intermediate acetylation phenotype (OR = 7.3;
95% CI, 1.6−32.6). A population-based study from the United
States
106
involving 363 non-Asian women demonstrated a 2.9-
fold increased risk of bladder cancer among women with the
NAT2 slow acetylation phenotype and a 2.5-fold increased risk
among those with the CYP1A2 slow phenotype who
exclusively used permanent hair dyes, perhaps due to a slower
detoxification capacity (Table 4). Significant positive fre-
quency- and duration-related dose−response associations were
reported in individuals with the NAT2 and/or CYP1A2 slow
phenotypes. A follow-up study from Sweden
107
involving
38,866 female and 6824 male hairdressers and analyzing their
malignancies over a period of 39 years demonstrated that the
risk of bladder cancer among male hairdressers gradually
decreased with follow-up time, albeit at the highest stand-
ardized incidence ratio (SIR) of 2.56 (95% confidence interval
[CI], 1.36−4.39) in the 1960s. In recent decades, this risk has
disappeared, with an SIR of 1.04 (95% CI, 0.74−1.40),
suggesting that modern hair colorants do not exert an
occupational bladder cancer risk in male hairdressers.
However, there is another explanation for the nonapparent
carcinogenic risk of bladder cancer from modern hair dyes:
Aromatic amine-induced human urothelial cancers typically
have a latency time longer than 20 years,
108
so the neoplastic
onset time has not yet arrived. With the currently available
data, bladder cancer risk due to exposure to hair dyes should
be assessed on a case-by-case basis and the toxicological profile
and individual exposure should be taken into consideration.
4.2. Breast Cancer. Breast cancer is one of the most
common malignant tumors among women and the second
leading cause of cancer death in the world.
109,110
The present
evidence is inconclusive describing the link between personal
hair dye use and breast cancer risk. Several epidemiological
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case-control studies
111−115
have indicated that hair dyeing does
not increase the risk of breast cancer in women, even in those
with benign breast diseases. In contrast, several case-control
studies,
116−118
a prospective study,
119
and two meta-anal-
yses
1,120
reported that personal hair dye use was related to the
carcinogenic risk of breast cancer (Table 4). Early age at
menarche is associated with an increased risk for breast
cancer.
121
Each 2-year delay in onset of menstruation decreases
this risk by approximately 10%.
122
The early exposure to
menstruation and ovulation-associated hormones, linked with
an earlier menstruation onset, has been proposed as an
etiological factor for increased breast cancer risk.
123,124
Higher
estrogen levels have been reported in individuals that
experienced early menstruation onset, for several years after
menarche.
125,126
Endocrine disrupting chemicals (EDCs) are exogenous
agents that interact with estrogen receptors or estrogen
signaling pathways, disrupting the physiological function of
the endocrine system and the development of the mammary
tissue. This heterogeneous group of chemicals includes
parabens, bisphenols, and phthalates, widely used substances
in cosmetic and personal care products, and are present in hair
dyes.
127,128
EDCs can be transported from the bloodstream to
breast milk via passive diffusion and are then ingested by
infants through breast-feeding. The hormone levels in the
infants can be affected, and the growth of their germ cells can
be disrupted.
129
Exposure to hair dyes containing EDCs in
childhood may increase breast cancer risk, by lowering the age
at menarche but most likely without affecting breast density.
130
Indeed, a study by Llanos et al.
131
demonstrated that the use of
hair dyes containing EDCs is correlated with an elevated risk of
estrogen receptor-positive breast cancer. Adolescent use of hair
dyes containing EDCs may increase the risk of premenopausal
breast cancer.
132
Di-n-butyl phthalate 32 is an EDC that is
present in several hair dyes and personal-care products. In vitro
studies revealed a large group of genes associated with fertility
(inhibin, placental growth factor), the immune response
(tumor necrosis factor-induced proteins), and antioxidant
status (glutathione peroxidase) in normal human mammary
epithelial cells were altered after exposure to di-n-butyl
phthalate,
133
suggesting that these genes may be potential
biomarkers for predicting reproductive problems associated
with hair dye use.
The previously mentioned meta-analysis
120
concluded that
the use of hair dyes, especially temporary and permanent hair
dyes, increased breast cancer risk. However, an overall
correlation between hair dyes and breast cancer risk as a
function of race, timing of use, and dye color was not found. A
case-control study from western Washington
115
found that
young women using a single type of dyeing method (i.e.,
temporary, semipermanent or permanent dyes, straightener,
and bleaching following dyeing or frosting) did not experience
an increase in breast cancer risk (relative risk [RR] = 1.10; 95%
CI, 0.90−1.30), but those who used two or more methods did
have an increased risk (RR = 1.90; 95% CI, 1.40−2.50),
indicating that reproductive-age women who used just one
type of dyeing method avoided the increased risk of breast
cancer (Table 4). These conflicting conclusions are likely
explained by differences in individual subjects’molecular
phenotypes, ages, and hair dyeing methods.
4.3. Hematopoietic Cancer. Hematopoietic cancers
comprise a group of malignant tumors that occur in peripheral
blood, bone marrow, and the lymphohematopoietic system,
including leukemia, multiple myeloma (MM) and lymphoma.
The etiology of some disorders is still unclear to date.
Lymphomas originate from the lymphohematopoietic system
and are classified into Hodgkin’s lymphoma (HL) and non-
Hodgkin’s lymphoma (NHL) according to the lymphocyte
type in the tumor tissues.
Although two population-based case-control studies deter-
mined
134,135
that hair dye use is a risk factor for primary
myelodysplastic syndrome, a large number of studies have not
identified a significant association between personal hair dye
use and an overall increased risk of leukemia, HL, NHL, or
MM (Table 4).
136−142
Because the data are conflicting
regarding the potential carcinogenic effect of hair dye on the
hematopoietic system, further studies should be performed to
assess risk, for example, evaluating instances where hair dyes
applied have very low concentrations of oxidative chemicals. If
the duration of use is prolonged and the frequency of use is
increased, the risk of hair dye-induced leukemia and other
malignant lymphatic tumors is elevated.
96,143−145
Moreover, it
was reported that the lymphoma risk of hair dye users
compared to nonusers was elevated by 19%, and further
increased by 26% when the frequency of use was >12 times per
year.
142
The incidence of NHL has increased globally in recent
decades.
146
Occupational exposure to hair dyes may increase
the risk of diffuse large B cell lymphoma, a subtype of NHL. A
Shanghai hospital-based case-control study
147
revealed that
personal hair dye use was not associated with an elevated risk
of NHL or any NHL subtypes. In contrast, a population-based
case-control study from the United States
148
showed a positive
correlation between the use of permanent hair dyes and an
increased risk of NHL, which became stronger for longer
duration of use and earlier age of first use. Furthermore, several
long-term case-control studies
149−153
found that hair dye use
correlated with NHL risk and that this risk was significantly
enhanced in users who dyed their hair prior to 1980, but not in
those who used hair dyes in or after 1980 (Table 4). One
possible explanation for this observation could be from the
changes in hair dye formulation and the duration of use
differences before and after 1980.
4.4. Maternal Hair Dyeing-Induced Childhood Tu-
mors. As hair dyes contain EDCs, maternal hair dyeing during
the month before pregnancy, during pregnancy, or during
breastfeeding is considered a risk factor for offspring health.
Childhood tumors are the second most common cause of
childhood death in developed countries,
154
in which leukemia
accounts for approximately 35.8% and ranks first.
155
Maternal
hair dye use in the first trimester of pregnancy increases the
risk of childhood acute lymphoblastic leukemia (ALL), and
breastfeeding elevates the risk of childhood acute myeloid
leukemia (AML). However, if children exhibited MLL (mixed
lineage leukemia) gene rearrangements and their mothers were
previously exposed to hair dye chemicals during pregnancy, an
elevated risk of ALL or AML was not observed.
156
Gao and
colleagues
157
found that the risk of maternal hair dyeing-
induced childhood leukemia was reduced by breastfeeding, and
if the breastfeeding duration reached 7−9months,the
reduction effect was more pronounced.
Neuroblastoma is the most common extracranial cancer in
infants under the age of 12 months, corresponding to
approximately 6−10% of global childhood tumors.
154
If hair
dye use takes place a month before pregnancy or during
pregnancy, the neuroblastoma risk in children is slightly
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increased, regardless of the type of hair dye used, and this
effect was doubled by maternal semipermanent hair dye
use.
158,159
Intriguingly, it was reported that mothers’use of
temporary hair dye was linked to a greater neuroblastoma risk
in children than maternal use of permanent hair dye.
154
Testicular germ cell tumor (TGCT) is a rare human tumor
with an estimated incidence of 8/100,000 and predominately
occurs in males aged between 15 and 44 years.
160,161
Development of TGCTs is hypothesized to be due to a
hormonal etiology related to EDCs. The United States
Servicemen’s Testicular Tumor Environmental and Endocrine
Determinants study
162
indicated that pregnant women
frequently using personal care products (e.g., face lotion)
containing EDCs during their pregnancy or breast-feeding may
increase the risk of TGCTs in their sons. Similarly, a study by
Chen et al.
163
suggested that maternal hair dyeing during the
month before pregnancy and during breastfeeding increased
the risk of malignant germ cell tumors (MGCTs) in their sons
and that breastfeeding also led to an elevated MGCT risk for
their daughters (Table 4).
164,165,166
5. CONCLUSIONS
Hair dyeing formulations are generally categorized into
oxidative and nonoxidative types. Based on the safety
assessment by the CIR expert panel and the FDA, a series of
oxidative and nonoxidative chemicals have been assessed as
safe for use in hair dyes, and an important aspect of this safety
is based on the concentration of the compound(s) found in the
hair dye. Personal or occupational exposure to hair dyes may
still cause several kinds of toxicity and side effects, in which
ACD is the most frequent with pneumothorax, rhabdomyol-
ysis, and AKI being the most life-threatening. Although
evidence in recent decades has not drawn a consistent
conclusion about the correlation between hair dye use and
risk of carcinogenesis, we cannot overlook that a positive
association of hair dye use and cancer occurrence is reported in
specific subpopulations. Moreover, maternal hair dyeing during
the month before pregnancy, during pregnancy, or during
breastfeeding is a risk factor for the occurrence of leukemia,
brain tumors, and MGCTs in the offspring. An increasing body
of studies indicates the need for ascertaining the association
between hair dyeing and the carcinogenic risks in more specific
subpopulations and investigating the molecular mechanism of
hair dye chemical-induced toxicity and carcinogenicity. Over-
all, the association between personal hair dye use and cancer
risk is likely to remain a debated topic. While the consensus
opinion from the major cancer research centers suggests that
there is not adequate evidence to link the practice of hair
dyeing to cancer, several studies highlight hair dye-related
toxicity and carcinogenicity as a public health concern. Given
the amount of conflicting data, more in-depth chemical and
systems toxicology studies are needed to better understand the
risks associated with exposure to hair dyes and to address this
important public health concern. Studies evaluating not only
the risk of exposure to isolated hair dye ingredients but also to
these compounds in the context of chemical mixtures will allow
an assessment of the cumulative risk (exposure to multiple
agents) and the interaction of exposures to multiple chemicals
present in combination in hair dyes. Systems-based strategies,
involving quantitative modeling, can shed light on the
exposure-induced cellular and molecular alterations that
might not be detected otherwise. It is anticipated that these
current and emerging methods in toxicology can allow for a
significantly superior assessment of complex mixtures such as
hair dyes and therefore further support data-driven and fact-
based evaluation of this public health concern.
■AUTHOR INFORMATION
Corresponding Author
Weibin Zeng −College of Animal Science and Technology,
Shihezi University, Shihezi 832003 Xinjiang, China;
Phone: +86-18992898513; Email: zwbdky@126.com
Authors
Lin He −Cancer Centre, Faculty of Health Sciences, University
of Macau, Macau 999078 SAR, China
Freideriki Michailidou −Department of Health Sciences and
Technology, ETH Zurich, 8092 Zurich, Switzerland;
Collegium Helveticum, Institute for Advanced Studies (IAS)
of the University of Zurich, ETH Zurich and Zurich
University of the Arts, 8092 Zurich, Switzerland
Hailey L. Gahlon −Department of Health Sciences and
Technology, ETH Zurich, 8092 Zurich, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chemrestox.1c00427
Author Contributions
L.H. and F.M. contributed equally to this work. L.H. wrote the
manuscript, collected data, and completed tables and figure
drawing. F.M. and H.G. wrote and edited the manuscript and
figures. W.E. was involved in the final approval of the
manuscript. All authors reviewed and approved the manuscript
prior to submission.
Notes
The authors declare no competing financial interest.
Search strategy and inclusion criteria: Peer-reviewed publica-
tions in English were searched in the PubMed, Web of Science,
Scopus, Embase, and OVID databases using the search
keyword “hair dye”during 1990−2021. All potential citations
were retrieved prior to April 7, 2021. Eligible studies that
evaluated hair dye ingredients, hair dye use-induced toxicity,
and hair dye use-related cancers met the inclusion criteria.
Biographies
Dr. Lin He published 15 SCI papers as first or co-first author during
the past five years. He is an oncologist in the Anhui Provincial
Maternal and Child Health Hospital.
Dr. Freideriki Michailidou is a Collegium Research Fellow at ETH
Zurich. Her current research encompasses biocatalysis and protein
engineering, sustainable production, and safety assessment of
fragrance ingredients.
Dr. Hailey Gahlon is a Group Leader in the Laboratory of
Toxicology at ETH Zurich. Her current research focuses on
understanding mechanisms of mitochondrial genome instability and
strategies to circumvent anticancer drug resistance.
Dr. Weibin Zeng is the Group Leader of the College of Animal
Science and Technology, Shihezi University. His current research
centers on animal reproduction and biotechnology.
■ACKNOWLEDGMENTS
F.M. thanks the Collegium Helveticum for financial support
under the Collegium Fellowship program.
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https://doi.org/10.1021/acs.chemrestox.1c00427
Chem. Res. Toxicol. 2022, 35, 901−915
910

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