Volume 11 Supplement 1

Approaching complexities in health and environment

Open Access

Associations between environmental factors and incidence of cutaneous melanoma. Review

  • Katarina Volkovova1Email author,
  • Dagmar Bilanicova1, 2,
  • Alena Bartonova3,
  • Silvia Letašiová4 and
  • Maria Dusinska1, 3
Contributed equally
Environmental Health201211(Suppl 1):S12

https://doi.org/10.1186/1476-069X-11-S1-S12

Published: 28 June 2012

Abstract

Background

Cutaneous melanoma is one of the most serious skin cancers. It is caused by neural crest-derived melanocytes - pigmented cells normally present in the epidermis and, sometimes, in the dermis.

Methods

We performed a review of current knowledge on the risk factors of cutaneous melanoma. Relevant studies were identified using the PubMed, Science Direct, Medline, Scopus, Scholar Google and ISI Web of Knowledge databases.

Results

Melanoma incurs a considerable public health burden owing to the worldwide dramatic rise in incidence since the mid-1960s. Ultraviolet radiation exposure is the predominant environmental risk factor. The role of geographical (latitude) and individual factors such as skin type, life style, vitamin D levels and antioxidant protection, sunburn, and exposure to other environmental factors possibly contributing to melanoma risk (such as cosmetics including sunscreen, photosensitising drugs, and exogenous hormones) are reviewed in this article. Recently, both rare high risk susceptibility genes and common polymorphic genes contributing to melanoma risk have been identified.

Conclusions

Cutaneous melanoma is a complex cancer with heterogeneous aetiology that continues to increase in incidence. Introduction of new biomarkers may help to elucidate the mechanism of pathogenesis and individual susceptibility to the disease, and make both prevention and treatment more effective.

Background

Cutaneous melanoma is one of the most serious skin cancers. It is caused by neural crest-derived melanocytes - pigmented cells normally presented norma in the epidermis and, sometimes, in the dermis [1]. Incidence of melanoma is increasing. While in US the lifetime risk of melanoma in 1935 was one in 1 500 persons, in 1960 it was one in 600 persons, and in 2000 it was one in 75 persons [2]. The progression of the melanocyte to a malignant melanoma involves various sequential steps: development of benign naevocellular naevus preneoplastic dysplastic naevus primary melanoma and metastatic melanoma [3]. There are four main types of cutaneous malignant melanoma [4, 5]: a) Superficial spreading malignant melanoma which is the most common among Caucasians and accounts for 70 percent of all melanomas. It usually occurs in adults and may develop anywhere on the body but appears with increased frequency on the upper back of both men and women and on the legs of women; b) Nodular melanoma (accounting for 15 to 30 percent of all melanomas), a dome-shaped, pedunculated or nodular lesion that may occur anywhere on the body. It is commonly dark brown or reddish brown but may occasionally be amelanotic. Nodular melanomas tend to rapidly invade the dermis from the onset with no apparent horizontal growth phase. These tumors are frequently misdiagnosed, because they may resemble blood blisters, hemangiomas, dermal nevi or polypi; c) Lentigo maligna melanoma (which accounts for 4 to 10 percent of all melanomas) originates from lentigo maligna. Untreated lentigo maligna tends to exhibit horizontal or radial growth with epidermal involvement for many years (often decades) before it enters the vertical growth phase and invades the dermis to become lentigo maligna melanoma. This change is often indicated clinically by the development of focal papular or nodular areas; d) Acral lentiginous melanoma (2 to 8 percent of all melanomas) occurs on the palmar and plantar surfaces, the digits and the subungual areas.

Although the prognosis of thin melanoma is relatively good, prognosis decreases with increased thickness of the lesions. The diminished prognosis is mainly due to the well established tendency of melanoma to metastasize, which accounts for 75 percent of all deaths associated with skin cancer. In addition, melanomas are highly resistant to most forms of chemotherapy and radiation; therefore, cure of the disseminated disease is uncommon [6]. In women, melanoma often develops in the extremities, most commonly the lower limbs. In men, melanoma is most often found on the trunk, on the area between the shoulders and hips. In both sexes, melanoma can appear on the palms or soles and under the fingernails or toenails [7].

Methods

An extensive literature search was performed to review current knowledge on cutaneous melanoma including epidemiological studies addressing risk factors of cutaneous melanoma between 1998 and 2010. Relevant studies were identified using the PubMed, Science Direct, Medline, Scopus, Scholar Google and ISI Web of Knowledge databases.

Results – Melanoma risk factors

Sunlight exposure

Sun exposure plays a primary and supporting role in most melanoma tumors. There is evidence that for the four main cutaneous types of melanomas, the pattern of excess sunlight exposure which is most damaging varies [8, 9, 5]. The environmental human carcinogen present in sunlight is ultraviolet (UV) irradiation [10]. The sun emits UVA (λ=320-400 nm), UVB (λ=280-320 nm), and UVC (λ=200-280 nm) ultraviolet radiation. While UVC radiation is ecologically not relevant since it is absorbed by oxygen and ozone in the Earth’s atmosphere, the longer wavelength UV-B (280–315 nm) and UV-A (315–400 nm) radiation have significant effects on the biota. 98.7% of the ultraviolet radiation that reaches the Earth's surface is UVA [11, 12]. The molecular mechanisms by which UV radiation exerts its varied effects are not fully understood; however, it is thought that UV irradiation plays a critical role in melanoma formation [1]. Currently, it is thought that the DNA damaging, carcinogenic, inflammatory, and immunosuppressive properties of UVR all contribute to initiation, progression, and metastasis of primary melanoma [13]. Reactive oxygen species (ROS) overproduction may stimulate malignant transformation to melanoma. Changes in ROS signalling pathways play also important role in the damaging action of UVA and UVB irradiation on the skin [14].

Natural photoprotection

The term photoprotection designates the mechanisms that nature has developed to minimize the damage that the human body suffers when exposed to UV-irradiation. This damage mostly occurs on the skin, but other parts of the body (especially the testicles) can be affected by UV-light. Photoprotection of the human skin is achieved by the extremely efficient internal conversion of molecules which originally absorb the UV-photon - endogenous chromophores: DNA nucleotides, urocanic acid, proteins, amino acids, melanin and their precursors and metabolites [15]. Internal conversion is a photochemical process that converts the energy of the UV-photon into small amounts of heat. These small amounts of heat are harmless. The energy of the UV-photon not transformed into heat leads to the generation of various harmful reactive chemical species (e.g. singlet oxygen or hydroxyl radical) [16, 17].

In DNA this photoprotective mechanism evolved four billion years ago. The purpose of this extremely efficient photoprotective mechanism is to prevent direct and partially indirect DNA damage. The ultrafast internal conversion of DNA reduces the lifetime of DNA in the excited state to only a few femtoseconds (10-15s) – in this way the excited DNA does not have enough time to react with other molecules [18, 19, 17]. The absorption spectrum of DNA shows strong absorption for UVB-radiation and much lower absorption for UVA-radiation (Fig. 1).
Figure 1

UVR absorption spectra of molecules important to UV-induced health effects DOPA-melanin-synthetic model of eumelanin (J Longstreth et al, 1998)

It is thought that photoprotection of melanin developed later in the course of evolution. There are two types of skin melanin: eumelanin, a black-brown pigment which is insoluble and is found in brown/black hair and brown eyes, pheomelanin, reddish pigment which is alkali-soluble and is found in red hair and red feathers [20]. All healthy individuals have varying degrees of eumelanin in their skin, while pheomelanin is present only in individuals who carry the corresponding genetic trait. It is thought that eumelanin protection against nutrient photolysis and, specifically, photolysis of folate (owing to the direct connection between folate and reproductive success), was a prime selective inducer which resulted in deeply pigmented skins among people living under high UVB radiation throughout most of the year. The importance of increased eumelanin production to prevent future direct and indirect DNA damage, individual fitness of protection of sweat glands and maintenance of thermoregulatory capability is also thought to have contributed to increased melanization [21]. Eumelanin dissipates more than 99.9% of the absorbed UV radiation as heat. This means that less than 0.1% of the excited melanin molecules will undergo harmful chemical reactions or produce free radicals [22].

DNA damage

The predominant component of sunlight, UVA, penetrates fivefold deeper into skin than UVB due to its longer wavelengths [23, 24]. Whereas UVA can indirectly damage DNA through the formation of reactive oxygen radicals, UVB can directly damage DNA causing apoptosis of keratinocytes by forming sunburn cells [25]. It has been shown that 92% of all melanoma are caused by indirect DNA damage and that only 8% of all melanoma are caused by direct DNA damage [26].

Direct DNA damage and sunburn

Since the action spectrum of sunburn is identical to the absorption spectrum of DNA, it is generally accepted that direct DNA damage is the cause of sunburn [27]. It can occur when DNA directly absorbs UVB photons. UVB light causes the formation of covalent linkages between pairs of thymine and cytosine bases in DNA and forms pyrimidine dimers (cyclobutane dimer). The radiation excites DNA molecules in skin cells, causing aberrant covalent bonds between adjacent cytosine bases by producing a dimer. During DNA replication, DNA polymerase incorporates an incorrect base opposite to an aberrant base, causing a mutation. The mutation caused by direct DNA damage can lead to skin cancers. The second most frequent UV photoproducts are 6-4 photoproducts (6-4 PPs), which are pyrimidine adducts and their Dewar valence isomers formed by the photo isomerisation of 6-4 PPs by wavelengths longer than 290nm [2833]. These reactions are quite common: each cell in the skin might experience 50-100 reactions during every second of sunlight exposure. Most of these genetic lesions are corrected by the mechanism of nucleotide excision repair. If the damage remains uncorrected, the genetic information may be permanently mutated.

Indirect DNA damage and melanoma

Malignant melanoma is mainly caused by indirect DNA damage. A limited number of molecules in tissue weakly absorb UVA irradiation. After UVA irradiation absorption, these molecules (endogenous photosensitizers) converts to their long-lived triplet state that allows the transfer of energy to oxygen molecules. The transferred energy leads to an energetically excited oxygen molecule (singlet oxygen), which is highly reactive. Some of the endogenous photosensitizers have been identified, for example, flavins [34], NADH/NADPH [35], urocanic acid [36], and some sterols [37]. 3-hydroxypyridine derivatives comprising a wide range of skin biomolecules, such as enzymatic collagen cross-links, B6 vitamin, and likely advanced glycation end products in chronologically aged skin, constitute a novel class of UVA photosensitizers, capable of skin photooxidative damage [38]. Wenczl et al. [39] demonstrated that UVA-irradiated cultured human melanocytes are photosensitized also by chromophores as pheomelanin and/or melanin intermediates. UVB natural chromophores may also exhibit similar phototoxic properties. Babu and Joshi [40] suggested that UVB-sensitized tryptophan produces singlet oxygen (1O2) and superoxide radicals (O2-.), and these reactive forms of oxygen may contribute to membrane-, cytoplasm- and DNA-damaging effects.

Singlet oxygen, hydroxyl radical and hydrogen peroxide are reactive oxygen species (ROS) considered to be most responsible for producing oxidative stress in cells and organisms [41]. Oxidative stress is caused by imbalance between ROS production and a biological system's ability to readily detoxify these reactive intermediates or easily repair the resulting damage. Thus, oxidative stress is accepted as a critical pathophysiological mechanism in cancererogenesis [42]. Reactive chemical species can reach DNA by diffusion and the bimolecular reaction will damage the DNA [43]. Singlet oxygen interacts preferentially with guanine to produce 8-oxo-7,8-dihydroguanine (formed by the loss of two electrons). Further removal of two electrons from this product can yield spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G --> T and G --> C conversions. Hence, they are of interest as examples of endogenous DNA damage that may initiate cancer [41, 44].

Ozone depletion and skin cancer

The radical increase of melanoma that has occurred in the last years has been associated with ozone depletion caused by ozone depleting substances (ODS) of anthropogenic origin, resulting in higher UVB radiation reaching the ground. Decreases in ozone have generated worldwide concern leading to adoption of the Montreal Protocol banning the production of ODS such as chlorofluorocarbon (CFC), other fully halogenated CFCs (freons), carbon tetrachloride, hydrochlorofluorocarbons, hydrobromofluorocarbons, methylchloroform, important industrial substances like halons (bromofluorocarbon compounds) and methyl bromide. Ozone depleting substances were used in automobile and truck air conditioning units, domestic and commercial refrigeration and air conditioning/heat pump equipment, aerosol products, portable fire extinguishers, insulation boards, panel and pipe covers and pre-polymers (The Montreal Protocol on Substances that Deplete the Ozone Layer, 2000). The level of UVB in sunlight is a strong function of latitude, whereas UVA is not. It is not surprising that the ratio of non-melanoma skin cancer incidence in Australia/Norway is an order of magnitude higher than for cutaneous malignant melanoma [45]. Based on studies which have found that 92% of all melanoma are caused by indirect DNA damage from UVA [46], we assume that other main hazard factors (pigmentary traits, ethnic origin, benign nevi, or family history) and not ozone depletion are responsible for radical increase of melanoma last years.

Sunburn and sunscreens

An increased risk of melanoma was seen with increasing number of sunburns for all ages, not just childhood. The magnitude of risk for five sunburns per decade was shown to be highest for adult and lifetime sunburns [47].

Although sunscreens prevent sunburn [4850], epidemiological or laboratory evidence that they prevent melanoma in humans is still missing.

Sunscreens have traditionally been divided into organic (chemical) absorbers and inorganic (physical) blockers on the basis of their mechanism of action. The organic compounds absorb high- intensity UV rays with their excitation to a higher energy state. Excess energy is dissipated by emission at longer wavelengths or relaxation by photochemical process such as isomerization and heat release. These organic compounds include para-aminobenzoic acid (PABA) and PABA esters, salicylates, cinnamates, benzophenons, butyl methoxydibenzoylmethane (Parsol 1789), drometrizole trisulphonic (Mexoryl XL), terephthalydene dicamphor sulphonic acid (Mexoryl SX), methylene bisbenzotriazol tetramethylbutylphenol (tinasorb M) and anisotriazine (Tinasorb S).

The inorganic agents, which protect the skin by reflecting and scattering UV, are nanoforms of titanium dioxide (TiO2) and zinc oxide (ZnO). These sunscreens are very efficient, photostable and offer protection extending into the UVA and visible range of the electromagnetic spectrum with almost negligible irritation. However, these molecules which reflect/scatter UV can cause whitening of the skin. Therefore, metal oxides are now frequently processed as microfine or nanoparticles (10-50 nm). Nanoparticles reflect/scatter and absorb UVA and UVB, and they are transparent on the skin, thus enhancing the cosmetic acceptability of the product [51].

It was thought that the UV-filter acts as "artificial melanin" but most of sunscreen organic chemicals cannot dissipate the energy of the excited state as efficiently as melanin or DNA (Table.1) and, therefore, the penetration of sunscreen ingredients into the lower layers of skin increases the amount of ROS [52, 53].
Table 1

Dissipation of photon energy by natural and synthetic organic chromophores

UV-absorber

Other names

Percentage of molecules that dissipate the photon energy

DNA

 

> 99.9 %

natural melanin

 

> 99.9 %

2-ethylhexyl 4-(dimethylamino) benzoate

Padimate-O, octyldimethyl PABA, OD-PABA

10%

4-Methylbenzylidene camphor

(4-MBC), (MBC), Parsol 5000, Eusolex 6300

30%

Menthyl anthranilate

(MA), Methyl-2-aminobenzoate, meradimate

60%

Ethylhexyl methoxycinnamate

(2-EHMC), (EHMC), EMC, Octyl methoxycinnamate, OMC, Eusolex 2292, Parsol

81%

Inorganic sunscreen agents (metal oxides) screen UVA/UVB radiation efficiently, but can also generate harmful reactive oxygen species and radicals when subjected to UVA/UVB radiation [54, 55].

DNA damage can be reduced by topical sunscreen which stays on the surface of the skin; it is important that the sunscreen blocks both UVA and UVB [56]. However, if sunscreen penetrates the epidermal barrier and gets into contact with living tissue, the DNA damage can be amplified many times, causing damage to living tissue even at very low concentrations (e.g. 10 μmol/L) [5759].

Skin penetration of organic UV filters such as ethoxylated ethyl-4-aminobenzoate (PEG-25 PABA), benzophenone, benzophenon-3 (oxybenzon), salicylic compounds, octocrylene, octylmethoxycinnamate has been reported [52, 60, 61]. Skin penetration of metal nanoparticles also causes mistrust of sunscreen products usage [62].

In general, the penetration of rabbit skin > rat > pig > monkey > human, with the pig skin being about 4 times or more and the rat skin up to about 9 times more permeable than human skin for certain compounds [63]. Penetration can also vary depending on the bulk composition of the compound studied. In most safety testing experiments pretreated chemicals isolated from sunscreens are used, but incorporated sunscreen chemicals in cosmetic creams/lotions presented as oil-in-water (O/W) or water-in-oil (W/O) emulsion enhance the penetration of these pretreated chemicals into the skin [60, 64]. Also the formulation vehicle in which the sunscreen is presented to the skin has a significant effect on absorption into the skin [65]. Alcohol-based formulations appear to increase sunscreen absorption. In addition, some sunscreen chemicals may enhance the skin absorption of other sunscreens when applied in combination [66].

Some ingredients in sunscreens protect only against direct DNA damage, but increase indirect DNA damage [59, 58, 67]. It is assumed that this causes an increase in melanoma cases found repeatedly in sunscreen users compared to non-users [6871]. Other studies have found decreased melanoma risk with increased sunscreen use [7274]. Discrepancies in reported claims may be caused by differences in the frequency of use, quantities used and the sun protection factor (SPF) of sunscreens. Sunscreens used before likely protected only against UVB, whereas currently sunscreens often have both UVA and UVB protection. Furthermore, although most studies include skin phototype and sun sensitivity, results were not statistically adjusted to account for the sun sensitivity of study participants (i.e. individuals with increased risk for sunburn are more likely to develop melanoma, but they are also most likely to use sunscreens [51].

Photosensitive drugs

Drug-induced photosensitivity may occur in a variety of ways. Most reactions are generally classified as either phototoxic or photoallergic. Phototoxic reactions are chemically-induced reactions when the drug causes a deeper penetration of UVA light followed by cellular damage. This reaction can be seen with initial exposure to a drug and is perhaps dose-related [75, 76]. Photosensitization reactions of drugs lead to the formation of ROS and cause indirect DNA damage [7780]. It may occur due to topical or systemic drugs (Table 2) [81].
Table 2

Some drugs associated with photosensitivity reactions

Frequent

Less frequent

Amiodarone

Antidepressants (tricylic, MAOIs)

NSAIDs

Antifungals

Phenothiazines (particularly chlorpromazine)

Antimalarials

Retinoids

Benzodiazepines

Sulfonamides

Beta-blockers

Tetracyclines (particularly demeclocycline)

Carbamazepine

Thiazides

Griseofulvin

 

Oral contraceptives

 

Quinine

 

Quinolones

 

Retinoids

 

St John’s Wort

 

Sulphonylureas

Cancer risk of cosmetic ingredients

Cosmetic ingredients are absorbed through the skin. Some chemicals may penetrate the skin in significant amounts, especially when left on the skin for long periods, as in the case of facial makeup. Cancer risks from substances in cosmetic and personal care products have been reported (Table 3) [82].
Table 3

Cosmetic ingredients and cancer risk

Cosmetic substance

Risk

DEA (diethanolamine)

TEA (triethanolamine)

can result in formation of carcinogenic nitrosamines

Bronopol (2-bromo-2-nitropropane-1,3-diol)

may break down into formaldehyde and also cause the formation of nitrosamines

1,2-Dioxane in surfactants/detergents

contaminated with carcinogenic 1,4-dioxane

Artificial colours (as Blue 1 and Green 3)

Carcinogenic

Hair dyes

dark colours ingredients are carcinogenic

Cosmetic lanolin

can be contaminated with carcinogenic pesticides such as DDT, dieldrin, and lindane, in addition to other neurotoxic pesticides

Talc

Carcinogenic

Silica

may be contaminated with carcinogenic crystalline quartz

Components of temporary tattoos and hair dye ingredients, namely para-aminophenol (PAP) and para-phenylenediamine (PPD), have been reported to be carcinogenic and transformed in human skin [83, 84]. However, other studies suggest that consumer or professional exposure to hair dyes poses no carcinogenic or other human health risks [85]. Absorption spectra of these compounds that absorb also UVA /UVB light [86], and possible penetration of these ingredients from dyes, can cause UV-induced indirect DNA damage. According to members of Cosmetic Ingredient Review (CIR), many cosmetic ingredients are used without sufficient data to support safety, especially impurities, UV adsorption, photosensitization, and genotoxicity. Information about cosmetic ingredients such as benzoxiquine, melamine/formaldehyde resin, oxyquinoline, oxyquinoline sulfate etc. should be verified (CIR, 1997, 2006) [87].

Indoor environment

Outdoor workers can get three to nine times as much solar UVR exposure as indoor workers [88, 89]. Paradoxically, outdoor workers have a lower incidence of cutaneous malignant melanoma compared to indoor workers [9092]. It is supposed that indoor solar UVA exposure, which causes mutations, depletes vitamin D3 in the skin [93]. In the early 20th century, due to life style changes, people tended to stay indoors during the day, which drastically decreased their daily amount of cutaneous vitamin D3. The UV barrier created by window glass separated UVB from UVA, so that the vitamin D making UVB was excluded from our indoor working environment. It is hypothesized that this unnatural UV environment, which existed for decades in buildings and cars, caused cutaneous malignant melanoma incidence to increase steadily about 20–30 years later in the mid-1930s. Increased UVA exposure and decreased cutaneous Vitamin D3 levels may be responsible for the increasing incidence of melanoma [94] (Fig. 2). Melanoma cells can convert vitamin D3 to the hormone, 1,25-dihydroxyvitamin D3, or calcitriol, which causes growth inhibition and apoptotic cell death in vitro and in vivo [94].
Figure 2

Cutaneous vitamin D3 The cutaneous vitamin D3 “roller coaster” that indoor workers experience during the workweek and workyear compared to outdoor workers. The curve for indoor workers (solid) rises on some weekends and during most vacations, while for outdoor workers (dotted) cutaneous vitamin D3 remains fairly constant and above the theoretical line for ‘sufficient’ cutaneous vitamin D3. (Godar D.E., 2009).

Artificial UV lamps and ionizing radiation

Lamps used for sun tanning emit wavelengths in the short end of the UVA range. Despite claims from the tanning industry, artificial tanning is not a safe or useful way to increase systemic vitamin D levels [93, 95]. Many studies indicate a significantly increased risk of cutaneous melanoma subsequent to sunburn/sunlamp exposure, especially among individuals who are young, Caucasian, and female [9698]. A European study showed that 40 hours of sun bed use resulted in a 55% increased risk for melanoma [99].

More than 40 kinds of skin diseases such as sclerotic skin disease, vitiligo, atopic dermatitis, localized scleroderma etc. can be treated with artificial UVR by three types of phototherapy, namely, broadband UVB phototherapy, narrowband UVB phototherapy, and UVA phototherapy [100103]. Phototherapy combined with chemicals such as oral methoxsalen (psoralen) in combination with UVA radiation (PUVA) provides a highly effective therapy for psoriasis and many other skin conditions such as vitiligo [104, 105, 102, 101]. However, PUVA is carcinogenic and increases melanoma risk. This risk is greater in patients exposed to high doses of PUVA. It appears to be increasing with the passage of time, and should be considered in determining the risks and benefits of this therapy [106].

It is also suggested that people exposed to ionizing radiation, e.g., nuclear industry workers, subjects near nuclear test blasts, survivors of the atomic bombings of Japan, airline pilots and cabin attendants, recipients of medical radiation, and radiological technicians may be at increased risk of developing melanoma [107].

Sex hormones and stimulation of melanocytes

Normal and malignant pigment cells are known targets for many hormones. Besides alpha-melanocyte-stimulating hormones and the steroidal hormones estrogen, testosterone, and glucocorticoids, other factors produced by epidermal cells can stimulate melanocytes. Among these factors are the prostaglandins, vitamin D3, ETAF (epidermal cell-derived thymocyte activating factor), and interleukin-1 [108]. A relationship between the biological behaviour of melanoma and sex hormones action has been identified in several areas of research. These observations include different survival prognoses for females and males, the rarity of melanoma incidence in prepubescent children, pregnancy and effects of exogenous hormones [109111]. Estrogen, estradiol and progesteron receptors have been observed in human melanomas [112114] and, consequently, melanoma seems to be associated with female hormones.

Sex

The incidence of malignant melanoma is higher among females than males aged 15-30 years; after age 30, incidence is higher among males [115]. Generally older age and sex are associated with prognostically unfavourable primary cutaneous melanoma. Females have better prognosis than males but this difference disappears after age of 65. Younger patients have more favourable prognosis than older patients; this difference is more pronounced in women [116].

Pregnancy and melanoma

Melanoma is a major health care problem due to its growing incidence especially in the younger population. In some countries 30% to 35% of female melanoma patients are in their reproductive age [117] and, thus, melanoma can occur in pregnancy ([118, 119]. However, recent findings from more recent controlled studies suggest that the data do not support a more advanced stage, thicker tumors, increased metastases to lymph nodes, or a worsened survival of pregnant women diagnosed with localized cutaneous melanoma [120124]. Pregnancy generally does not increase the subsequent risk of having melanoma and there is no increased risk of melanoma developing during pregnancy [125]. Patients expressing estradiol receptors in melanoma cells have been reported to have a better prognosis [114]. There is little evidence that significant changes in nevi occur during pregnancy [126128].

Exogenous hormones

Recent multiple studies showed conflicting results on the association between oral contraceptive use and the development of cutaneous melanoma. While some studies suggest a cumulative dose-dependent increased risk of melanoma with use of estrogens [111], other reports demonstrate that hormone replacement therapy does not appear to enhance the risk for developing melanoma [120]. It is proposed, that estradiol therapy leads to a decrease of proliferation of melanoma cells and an increase in melanogenesis [114]. Endogenous estrogenic metabolite 2-methoxyestradiol was found to have potential preventive/therapeutic use for melanoma growth [129].

Skin type and melanocytotic hyperpigmentation

Malignant melanoma mainly afflicts people with white skin (the Caucasian population). Odd Ratio for influence by total nevi is 5.37, 95%CI 4.44 to 6.36. Particularly, dysplastic nevi confer much higher risks than most pigment characteristics [130].

Generally, melanoma and its precursor lesions nevi are melanocytotic hyperpigmentation caused by proliferation of active melanocytes. In multiple studies no clear evidence was found to associate melanocytes proliferation with steroid hormones regulation. On the other hand, increased melanin production by existing melanocytes (melanotic hyperpigmentation) is considered to be stimulated also by hormone regulation via melanocytic hormone receptors. Thus, the occurrence of hormone receptors in melanoma cells can be expected because melanoma cells can express pigment.

Melasma is an acquired hypermelanosis, occurring symmetrically on sun-exposed areas of the body. The pigmentation is due to overproduction of melanin by the pigment cells, melanocytes. Lesions are irregular light to dark brown macules and patches, usually involving the forehead, temples, upper lip, and cheeks. Asian and Hispanic females are most commonly affected [131133]. Other authors found possible role of androgenic hormones in melasma [134]. Typically, melasma happens by increased melanin production by existing melanocytes (melanotic hyperpigmentation) [135]. No increase in the number of melanocytes in melasma areas was noted, but these cells are larger, more dendritic and show increased melanogenesis producing especially eumelanin [136].

During pregnancy, melanocytic activity increases causing hyperpigmentation as observed in the linea nigra (dark line running up the tummy) and the areola and nipple [137139]. Occurrence of melasma (also known as chloasma) is also found to be associated with estrogen hormones [140, 141]: increased expression of estrogen receptors in melasma-affected skin has been demonstrated [141]. Melasma has been reported in 50-70% of pregnant women [142144] and in non pregnant women who are taking birth control pills [145]. It has been reported to exist only in 10% of men [146]. Sun exposure together with other exogenous factors (such as use of cosmetics and perfumes) are another risk factor for melasma [147]. It has been also thought to arise from endocrine disorders, genetic factors, other medications, nutritional deficiency and hepatic dysfunction [148].

Family history (germline mutations)

Approximately 5-10% of melanoma occurs in families with hereditary melanoma predisposition. About 40 % of familial melanoma is associated with chromosome 9p [149, 150]. Worldwide, approximately 20-40% of kins with familial melanoma harbour germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence. There are geographical variations in the incidence of CDKN2A mutations. The risk of melanoma in CDKN2A mutation carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population [151]. Another melanoma susceptibility gene, CDK4, accounts for only small number of families with germ mutations on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A [151]. Relative risk to cutaneous melanoma depends on anatomic differences such as body site for skin, or hair colour. These differences could be attributed to gene variability [152].

DNA polymorphisms/ somatic mutations

A panel of polymorphisms that appears to confer low-to-moderate risk for melanoma has been assessed through functional and genome-wide association studies. Suggested associations between genetic polymorphisms and melanoma were extensively reviewed [153157]. Vitamin D receptor (VDR) gene SNPs the FokI T allele was associated with increased melanoma risk (OR 1.42, 95% confidence interval CI 1.06-1.91). In a meta-analysis the FokI T allele was associated with increased melanoma risk (OR 1.19, 95%, CI 1.05-1.35), and the BsmI A allele was associated with reduced risk (OR 0.81, 95%, CI 0.72-0.92). However, other study showed opposite results: a significant association between the BsmI VDR polymorphism and increased melanoma risk (OR, 1.30, 95% CI, 1.11-1.53, the population attributable risk 9.2%.). FokI polymorphism did not appear to be associated with such risk (OR, 1.09; 95% CI, 0.99-1.21) [157, 158].

Mutations in the cell cycle gene CDKN2A (gene or mono-allelic loss at the locus) were connected with high risk of melanoma but results are not clear [159, 160]. The oncogenic mutations in the B-RAF and N-RAS genes constitute the initiating somatic events followed by loss of a major check point gene mainly CDKN2A or in some cases p53 or PTEN [159161].

The DNA repair process is important in protecting humans from cancer. Multiple DNA repair pathways are able to repair all kinds of DNA damage induced by exogenous and endogenous genotoxic agents, usually in an error-free manner. Recent reviews show links between the DNA repair pathways and cancer, particularly the association between nucleotide excision repair and melanoma development (154, 155, 156). Nucleotide excision repair gene xeroderma pigmentosum variant (XPV) [154], the c.1783G, p.595V alleles were associated with melanoma (OR 1.86 CI 1.27-2.71, and OR 1.84 1.29-2.63 respectively). XPD/ERCC2 SNP rs1318, variant C allele was associated with slightly increased melanoma risk (OR = 1.12, 95% CI 1.03-1.21, population attributable risk = 9.6%) [156].

Some of the genetic variants in the DNA repair gene XRCC1 have also been associated with melanoma. Patients with variant genotype had better overall survival. MC1R variants were associated with susceptibility to basal cell carcinoma of skin and there is an interaction with host factors and the XRCC3 gene [162]. ASIP and TYR pigmentation variants are also associated with cutaneous melanoma and basal cell carcinoma. These results suggest that both nucleotide as well as base excision repair deficiency may contribute to the development of cutaneous melanoma. However, recent results show that the repair of major DNA damage caused by cancer drugs is efficient in metastatic melanoma [156]. This implies that in addition to genome association studies, more research on DNA repair and cell cycle regulation is needed.

Conclusions

Cutaneous melanoma is a complex, heterogeneous cancer that is increasing in incidence. Multiple studies have identified major host and environmental risk factors for melanoma. The predominant environmental risk factor is exposure to UV radiation. Geographical and individual factors such as sex, skin type (particularly dysplastic nevi) and life style – outdoor/indoor life, sunburn, vitamin D and antioxidant protections are considered to be risk factors. Additionally, exposure to other environmental factors such as sunscreen, photosensitising drugs, and exogenous hormones may also increase the risk of melanoma. Recently, the association between rare high risk susceptibility genes and common polymorphic genes and development of melanoma risk have been identified. However, more epidemiological as well as mechanistic studies are needed to understand the causal mechanisms of melanoma development.

Notes

Declarations

Acknowledgements

The work has been funded by the EU FP6 coordination action HENVINET, contract no 037019.

We are thankful to Sonja Grossberndt, Evy Sivesind and to the whole HENVINET team for an excellent support. We are thankful to William A. Lahoz from NILU for his proof reading.

This article has been published as part of Environmental Health Volume 11 Supplement 1, 2012: Approaching complexities in health and environment. The full contents of the supplement are available online at http://www.ehjournal.net/supplements/11/S1.

Authors’ Affiliations

(1)
Slovak Medical University
(2)
University of Venice
(3)
NILU - Norwegian Institute for Air Research
(4)
Slovak University of Technology

References

  1. Situm M, Buljan M, Bulić SO, Simić D: The mechanisms of UV radiation in the development of malignant melanoma. Coll Antropol. 2007, 1: 13-16.Google Scholar
  2. Chang AE, Karnell LH, Menck HR: The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. Cancer. 1998, The American College of Surgeons Commission on Cancer and the American Cancer Society, 83: 1664-1678. 10.1002/(SICI)1097-0142(19981015)83:8<1664::AID-CNCR23>3.0.CO;2-G.Google Scholar
  3. Mehta RR, Bratescu L, Graves JM, Shilkaitis A, Green A, Mehta RG, Das Gupta TK: In vitro transformation of human congenital naevus to malignant melanoma. Melanoma Research. 2002, 12: 27-33. 10.1097/00008390-200202000-00005.Google Scholar
  4. Little JW: Melanoma: etiology, treatment, and dental implications. Gen Dent. 2006, 54: 61-66.Google Scholar
  5. Habif TP: Clinical dermatology: a color guide to diagnosis and therapy. St. Louis: Mosby. 1996, 714-715. 3rdGoogle Scholar
  6. Govindarajan B, Bai X, Cohen C, Zhong H, Kilroy S, Louis G, Moses M, Arbiser JL: Malignant Transformation of Melanocytes to Melanoma by Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MAPKK) Signaling. The J Biol Chem. 2003, 278: 9790-9795. 10.1074/jbc.M212929200.Google Scholar
  7. Brenner S, Mashiah J: Malignant Melanoma: It Pays to Be a Woman. SKINmed. 2003, 2: 183-187. 10.1111/j.1540-9740.2003.01819.x.Google Scholar
  8. Ivry GB, Ogle CA, Shim EK: Role of sun exposure in melanoma. Dermatol Surg. 2006, 32: 481-492. 10.1111/j.1524-4725.2006.32101.x.Google Scholar
  9. MacKie RM: Long-term health risk to the skin of ultraviolet radiation. Prog Biophys Mol Biol. 2006, 92: 92-96. 10.1016/j.pbiomolbio.2006.02.008.Google Scholar
  10. Matsumu Y, Ananthaswamy HN: Toxic effects of ultraviolet radiation on the skin. Toxicol Appl Pharmacol. 2004, 195: 298-308. 10.1016/j.taap.2003.08.019.Google Scholar
  11. Hölzle E, Hönigsmann H: UV-radiation--sources, wavelength, environment. J Dtsch Dermatol Ges. 2005, 3 (Suppl 2): 3-10.Google Scholar
  12. Madronich S, McKenzie RL, Björn LO, Caldwell MM: Changes in biologically active ultraviolet radiation reaching the Earth’s surface. J Photochem Photobiol B. 1998, 46: 5-19. 10.1016/S1011-1344(98)00182-1.Google Scholar
  13. Garibyan L, Fisher DE: How sunlight causes melanoma. Curr Oncol Rep. 2010, 12: 319-326. 10.1007/s11912-010-0119-y.Google Scholar
  14. Afanas'ev IB: Signaling by reactive oxygen and nitrogen species in skin diseases. Curr Drug Metab. 2010, 11: 409-414. 10.2174/138920010791526060.Google Scholar
  15. Longstreth J, de Gruijl FR, Kripke ML, Abseck S, Arnold F, Slaper HI, Velders G, Takizawa Y, van der Leun JC: Health risks. J Photochem Photobiol B: Biol. 1998, 46: 20-39. 10.1016/S1011-1344(98)00183-3.Google Scholar
  16. Peon J, Zewail AH: DNA/RNA nucleotides and nucleosides: direct measurement of excited-state lifetimes by femtosecond fluorescence up-conversion. Chem Phys Lett. 2001, 348: 255-262. 10.1016/S0009-2614(01)01128-9.Google Scholar
  17. Young AR: Chromophores in human skin. Phys Med Biol. 1997, 42: 789-802. 10.1088/0031-9155/42/5/004.Google Scholar
  18. Pecourt JML, Peon J, Kohler B: DNA Excited-State Dynamics: Ultrafast Internal Conversion and Vibrational Cooling in a Series of Nucleosides. J Am Chem Soc. 2001, 123: 10370-10378. 10.1021/ja0161453.Google Scholar
  19. Pecourt JML, Peon J, Kohler B: Ultrafast internal conversion of electronically excited RNA and DNA nucleosides in water. J Am Chem Soc. 2000, 122: 9348-9349. 10.1021/ja0021520.Google Scholar
  20. Ito S: The IFPCS presidential lecture: a chemist’s view of melanogenesis. Pigment Cell Res. 2003, 16: 230-236. 10.1034/j.1600-0749.2003.00037.x.Google Scholar
  21. Jablonski NG, Chaplin G: The evolution of human skin coloration. J Hum Evol. 2000, 39: 57-106. 10.1006/jhev.2000.0403.Google Scholar
  22. Meredith P, Riesz J: Radiative Relaxation Quantum Yields for Synthetic Eumelanin. Photochem Photobiol. 2004, 79: 211-216. 10.1562/0031-8655(2004)079<0211:RCRQYF>2.0.CO;2.Google Scholar
  23. He YY, Huang JL, Sik RH, Liu J, Waalkes MP, Chignell CD: Expression profiling of human keratinocyte response to ultraviolet A: implications in apoptosis. J Invest Dermatol. 2004, 122: 533-43. 10.1046/j.0022-202X.2003.22123.x.Google Scholar
  24. Hoffmann K, Kaspar K, Altmeyer P, Gambichler T: UV transmission measurements of small skin specimens with special quartz cuvettes. Dermatology. 2000, 201: 307-311. 10.1159/000051543.Google Scholar
  25. Eskandarpour M, Hashemi J, Kanter L: High Gene Mutation Rate May Contribute to Hereditary Skin Cancers. J Natl Cancer Inst. 2003, 95: 790-Google Scholar
  26. Davies H, Bignell GR, Cox C: Mutations of the BRAF gene in human cancer. Nature. 2002, 417: 949-954. 10.1038/nature00766.Google Scholar
  27. Parrish JA, Kurt F, Jaenicke R, Rox A: Erythema And Melanogenesis Action Spectra Of Normal Human Skin. Photochem Photobiol. 1982, 36: 187-191. 10.1111/j.1751-1097.1982.tb04362.x.Google Scholar
  28. Li G, Ho VC, Trotter MJ, Horsman DE, Tron VA: Mutation In Metastatic Melanomas And Primary Melanomas From Sun-Exposed And Sun-Protected Sites. J Eur Acad Dermatol Venereol. 1995, 4: 48-53. 10.1016/0926-9959(94)00071-7.Google Scholar
  29. Goodsell DS: The Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers. The Oncologist. 2001, 6: 298-299. 10.1634/theoncologist.6-3-298.Google Scholar
  30. Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T: DNA repair and mutagenesis. 2006, ASM Press, 1118: 1120-2ndGoogle Scholar
  31. Whitmore SE, Potten CS, Chadwick CA, Strickland PT, Morison WL: Effect of photoreactivating light on UV radiation-induced alterations in human skin. Photodermatol Photoimmunol Photomed. 2001, 17: 213-217. 10.1034/j.1600-0781.2001.170502.x.Google Scholar
  32. Matsunaga T, Hatakeyama Y, Ohta M, Mori T, Nikaido O: Establishment and characterization of a monoclonal-antibody recognising the Dewar isomers of (6-4) photoproducts. Photochem Photobiol. 1993, 57: 934-940. 10.1111/j.1751-1097.1993.tb02952.x.Google Scholar
  33. Mitchell DL, Rosenstein BS: The use of specific radioimmunoassays to determine action spectra for the photolysis of (6-4) photoproducts. Photochem Photobiol. 1987, 45: 781-786. 10.1111/j.1751-1097.1987.tb07882.x.Google Scholar
  34. Baier J, Maisch T, Maier M, Engel E, Landthaler M, Bäumler W: Singlet Oxygen Generation by UVA Light Exposure of Endogenous Photosensitizers. Biophys J. 2006, 91: 1452-1459. 10.1529/biophysj.106.082388.Google Scholar
  35. Sohal RS, Weindruch R: Oxidative stress, caloric restriction, and aging. Science. 1996, 273: 59-63. 10.1126/science.273.5271.59.Google Scholar
  36. Hanson KM, Simon JD: Epidermal trans-urocanic acid and the UV-A-induced photoaging of the skin. Proc Natl Acad Sci USA. 1998, 95: 10576-10578. 10.1073/pnas.95.18.10576.Google Scholar
  37. Albro PW, Bilski P, Corbett JT, Schroeder JL, Chignell CF: Photochemical reactions and phototoxicity of sterols: novel self-perpetuating mechanisms for lipid photooxidation. Photochem Photobiol. 1997, 66: 316-325. 10.1111/j.1751-1097.1997.tb03154.x.Google Scholar
  38. Wondrak GT, Roberts MJ, Jacobson MK, Jacobson EL: 3-Hydroxypyridine Chromophores Are Endogenous Sensitizers of Photooxidative Stress in Human Skin Cells. J Biol Chem. 2004, 279: 30009-30020. 10.1074/jbc.M404379200.Google Scholar
  39. Wenczl E, van der Schans GP, Roza L, Kolb RM, Timmerman AJ, Smit NPM, Pavel S, Schothorst AA: (Pheo)Melanin Photosensitizes UVA-Induced DNA Damage in Cultured Human Melanocytes. J Investig Dermatol. 1998, 111: 678-682. 10.1046/j.1523-1747.1998.00357.x.Google Scholar
  40. Babu V, Joshi PC: Tryptophan as an endogenous photosensitizer to elicit harmful effects of ultraviolet B. Indian J Biochem Biophys. 1992, 29: 296-298.Google Scholar
  41. Defedericis HC, Patrzyc HB, Rajecki MJ, Budzinski EE, Lijima H, Dawidzik JB, Evans MS, Greene KE, Box HC: Singlet oxygen-induced DNA damage. Radiat Res. 2006, 165: 445-451. 10.1667/RR3533.1.Google Scholar
  42. Mena S, Ortega A, Estrela JM: Oxidative stress in environmental-induced carcinogenesis. Mutat Res. 2009, 674: 36-44. 10.1016/j.mrgentox.2008.09.017.Google Scholar
  43. Ribeiro DT, Madzak C, Sarasin A, DI Mascio P, Sies H, Menck CFM: Singlet oxygen induced DNA damage and mutagenicity in a single-stranded SV40-based shuttle vector. Photochem Photobiol. 1992, 55: 39-45. 10.1111/j.1751-1097.1992.tb04207.x.Google Scholar
  44. Jia L, Shafirovich V, Shapiro R, Geacintov NE, Broyde S: Spiroiminodihydantoin lesions derived from guanine oxidation: structures, energetics, and functional implications. Biochemistry. 2005, 44 (Suppl 16): 6043-6051.Google Scholar
  45. Magnus K: The Nordic profile of skin cancer incidence. A comparative epidemiological study of the three main types of skin cancer. Int J Cancer. 1991, 47: 12-19. 10.1002/ijc.2910470104.Google Scholar
  46. Davies H, Bignell GR, Cox C: Mutations of the BRAF gene in human cancer. Nature. 2002, 417: 949-954. 10.1038/nature00766.Google Scholar
  47. Dennis LK, Vanbeek MJ, Beane Freeman LE, Smith BJ, Dawson DV, Coughlin JA: Sunburns and risk of cutaneous melanoma: does age matter? A comprehensive meta-analysis. Ann Epidemiol. 2008, 18 (Suppl 8): 614-627.Google Scholar
  48. Cripps DJ, Hegedus S: Protection factor of sunscreens to monochromatic radiation. Arch DenmatoL. 1974, 7: 202-204.Google Scholar
  49. Rothman S, Rubin J: Sunburn and paraaminobenzoic acid. J Invest Dermatol. 1942, 5: 445-457. 10.1038/jid.1942.59.Google Scholar
  50. Willis I, Kligmnan AM: Aminobenzoic acid and its esters: the quest for more effective sunscreens. ArchDermatoL. 1970, 102: 405-417.Google Scholar
  51. Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD: Sunscreens--what's important to know. J Eur Acad Dermatol Venereol. 2008, 22: 1110-1118. 10.1111/j.1468-3083.2007.02580.x.Google Scholar
  52. Hanson KM, Gratton E, Bardeen CJ: Sunscreen enhancement of UV-induced reactive oxygen species in the skin. Free Radical Biol Med. 2006, 41 (Issue 8): 1205-1212.Google Scholar
  53. Cantrell A, McGarvey , David J: Sun Protection in Man. Comprehensive Series in Photosciences. 2001, Elsevier, 495: 497-519.Google Scholar
  54. Arsac F, Hisao H: DNA Damage Photoinduced by Titanium Dioxide in the Presence of Anionic Vesicles under UV Illumination: Influence of Sodium Chloride Concentration. Journal of Oleo Science. 2007, 56: 595-601. 10.5650/jos.56.595.Google Scholar
  55. Hidaka H, Kobayashi H, Koike T, Sato T, Serpone N: DNA Damage Photoinduced by Cosmetic Pigments and Sunscreen Agents under Solar Exposure and Artificial UV Illumination. Journal of Oleo Science. 2006, 55: 249-261. 10.5650/jos.55.249.Google Scholar
  56. Autier P: Perspectives in melanoma prevention: the case of sunbeds. Eur J Cancer. 2004, 40: 2367-10.1016/j.ejca.2004.07.018.Google Scholar
  57. Armeni T, Damiani E, Battino M, Greci L, Principato G: Lack of in vitro protection by a common sunscreen ingredient on UVA-induced cytotoxicity in keratinocytes. Toxicol. 2004, 203: 165-178. 10.1016/j.tox.2004.06.008.Google Scholar
  58. Knowland J, McKenzie EA, McHugh PJ, Cridland NA: Sunlight-induced mutagenicity of a common sunscreen ingredient [abstract]. FEBS Letters. 1993, 324: s309-313. 10.1016/0014-5793(93)80141-G.Google Scholar
  59. Xu C, Green A, Parisi A, Parsons PG: Photosensitization of the Sunscreen Octyl p-Dimethylaminobenzoate b UVA in Human Melanocytes but not in Keratinocytes. Photochem Photobiol. 2001, 73: 600-604. 10.1562/0031-8655(2001)073<0600:POTSOP>2.0.CO;2.Google Scholar
  60. Couteau C, Perez Cullel N, Connan AE, Coiffard LJM: Stripping method to quantify absorption of two sunscreens in human. Int J Pharm. 2001, 222: 153-157. 10.1016/S0378-5173(01)00674-3.Google Scholar
  61. Simonsen L, Jørgensen A, Benfeldt E, Grotha L: Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis. Eur J Pharmaceut Sci. 2004, 21: 379-388. 10.1016/j.ejps.2003.11.004.Google Scholar
  62. Agren MS: Percutaneous absorption of zinc from zinc oxide applied topically to intact skin in man [abstract]. Dermatologica. 1990, 180: s36-39. 10.1159/000247982.Google Scholar
  63. Magnusson BM, Kenneth A, Walters KA, Roberts MS: Veterinary drug delivery: potential for skin penetration enhancement. Adv Drug Deliv Rev. 2001, 50: 205-227. 10.1016/S0169-409X(01)00158-2.Google Scholar
  64. Linn EE, Pohland RC, Byrd TK: Microemulsion for Intradermal Delivery Of Cetyl Alcohol and Octyl Dimethyl PABA. Drug Dev Ind Pharm. 1990, 16: 899-920. 10.3109/03639049009114917.Google Scholar
  65. Varvaresou A: Percutaneous absorption of organic sunscreens. J Cosmet Dermatol. 2006, 5: 53-57. 10.1111/j.1473-2165.2006.00223.x.Google Scholar
  66. Benson HAE: Assessment and Clinical Implications of Absorption of Sunscreens Across Skin. Am J Clin Dermatol. 2000, 1: 217-224. 10.2165/00128071-200001040-00003.Google Scholar
  67. Damiani E, Greci L, Parsons R, Knowland J: Nitroxide radicals protect DNA from damage when illuminated in vitro in the presence of dibenzoylmethane and a common sunscreen ingredient. Free Radic Biol Med. 1999, 26: 809-816. 10.1016/S0891-5849(98)00292-5.Google Scholar
  68. Garland C, Garland F, Gorham E: Could sunscreens increase melanoma risk?. Am J Public Health. 1992, 82: 614-615. 10.2105/AJPH.82.4.614.Google Scholar
  69. Westerdahl J, Ingvar C, Masback A, Olsson H: Sunscreen use and malignant melanoma. Int J Cancer. 2000, 87: 145-150. 10.1002/1097-0215(20000701)87:1<145::AID-IJC22>3.0.CO;2-3.Google Scholar
  70. Weinstock MA: Do sunscreens increase or decrease melanoma risk: An epidemiologic evaluation. J Investig Dermatol Symp Proc. 1999, 4: 97-100. 10.1038/sj.jidsp..Google Scholar
  71. Vainio H, Bianchini F: Cancer-preventive effects of sunscreens are uncertain. Scand J Work Environ Health. 2000, 26: 529-531. 10.5271/sjweh.578.Google Scholar
  72. Moloney FJ, Collins S, Murphy GM: Sunscreens: Safety, Efficacy and Appropriate Use. Am J Clin Dermatol. 2002, 3: 185-191. 10.2165/00128071-200203030-00005.Google Scholar
  73. Ródenas JM, Delgado-Rodríguez M, Herranz MT, Tercedor J, Serrano S: Sun exposure, pigmentary traits, and risk of cutaneous malignant melanoma: a case-control study in a Mediterranean population. Canc Causes Contr. 1996, 7: 275-283. 10.1007/BF00051303.Google Scholar
  74. Espinosa Arranz J, Sanchez Hernandez JJ, Bravo Fernandez P, Gonzalez-Baron M, Zamora Auñon P, Espinosa Arranz E, Jalon Lopez JI, Ordoñez Gallego A: Cutaneous malignant melanoma and sun exposure in Spain [abstract]. Melanoma Res. 1999, 9: s199-205. 10.1097/00008390-199904000-00013.Google Scholar
  75. Moore DE: Drug-induced cutaneous photosensitivity. Drug Saf. 2002, 25: 345-372. 10.2165/00002018-200225050-00004.Google Scholar
  76. Allen JE: Drug-induced photosensitivity. Clin Pharm. 1993, 12: 580-587.Google Scholar
  77. Pandey R, Mehrotra S, Ray RS, Joshi PC, Hans RK: Evaluation of UV-radiation induced singlet oxygen generation potential of selected drugs. Drug Chem Toxicol. 2002, 25: 215-225. 10.1081/DCT-120003261.Google Scholar
  78. Xiaa Q, Yin JJ, Cherng SH, Wamer WG, Boudreau M, Howard PC, Fu PP: UVA photoirradiation of retinyl palmitate—Formation of singlet oxygen and superoxide, and their role in induction of lipid peroxidation. Toxicol Lett. 2006, 163: 30-43. 10.1016/j.toxlet.2005.09.010.Google Scholar
  79. Iwamoto T, Hiraku Y, Okuda M, Kawanishi S: Mechanism of UVA-dependent DNA Damage Induced by An Antitumor Drug Dacarbazine in Relation to its Photogenotoxicity. Pharmaceut Res. 2008, 25: 598-604. 10.1007/s11095-007-9413-2.Google Scholar
  80. O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu Y-Z, Harwood CA, McGregor JM, Walker SL, Hanaoka F, Karran P: Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage. Science. 2005, 309: 1871-1874. 10.1126/science.1114233.Google Scholar
  81. Lee A, Thomson J: Adverse Drug Reactions. 2nd edtition. 2006, Pharmaceutical Press, 143-145.Google Scholar
  82. Steinma D, Epstein S: The Safe Shopper's Bible. A Consumer's Guide to Nontoxic Household Products, Cosmetics, and Food. 1995, New York: MacMillanGoogle Scholar
  83. Nohynek GJ, Ducheb D, Garrigues A, Meunier P-A, Toutaina H, Leclaire J: Under the skin: Biotransformation of para-aminophenol and para-phenylenediamine in reconstructed human epidermis and human hepatocytes. Toxicol Lett. 2005, 158: 196-212. 10.1016/j.toxlet.2005.03.014.Google Scholar
  84. Rojanapo W, Piangchai K, Anong T, Sopa Chutimataewin M, Tanyakaset M: Carcinogenicity of an oxidation product of p-phenylenediamine. Carcinogenesis. 1986, 7: 1997-2002. 10.1093/carcin/7.12.1997.Google Scholar
  85. Nohynek GJ, Fautz R, Benech-Kieffer F, Toutain H: Toxicity and human health risk of hair dyes. Food Chem Toxicol. 2004, 42: 517-543. 10.1016/j.fct.2003.11.003.Google Scholar
  86. Motz-Schalck L, Lemaire J: Photochemical and thermal modifications of permanent hair dyes. J Photochem Photobiol Chem. 2002, 147: 225-223. 10.1016/S1010-6030(01)00617-7.Google Scholar
  87. Andersen FA: Final Report on the Safety Assessment of Melamine/Formaldehyde Resin. Int J Toxicol. 1995, 14: 373-385. 10.3109/10915819509083598.Google Scholar
  88. Godar DE: UV doses worldwide. Photochem. Photobiol. 2005, 81 (4): 736-49. 10.1562/2004-09-07-IR-308R.1.Google Scholar
  89. Thieden E, Philipsen PA, Sandby-Møller J, Heydenreich J, Wulf HC: Proportion of lifetime UV dose received by children, teenagers and adults based on time-stamped personal dosimetry. J Invest Dermatol. 2004, 123: 1147-1150. 10.1111/j.0022-202X.2004.23466.x.Google Scholar
  90. Lee JAH: Melanoma and exposure to sunlight. Epidemiol Rev. 1982, 4: 110-136.Google Scholar
  91. Vagero D, Ringback G, Kiveranta H: Melanoma and other tumors of the skin among office, othe indoor, and outdoor workers in Sweden 1961–1979. Brit J Cancer. 1986, 53: 507-512. 10.1038/bjc.1986.80.Google Scholar
  92. Kennedy C, Bajdik CD, Willemze R, De Gruijl FR, Bouwes Bavinck JN: The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses, seborrheic warts, melanocytic nevi, atypical nevi, and skin cancer. J Invest Dermatol. 2003, 120: 1087-1093. 10.1046/j.1523-1747.2003.12246.x.Google Scholar
  93. Levine JA, Sorace M, Spencer J, Siegel DM: The indoor UV tanning industry: A review of skin cancer risk, health benefit claims, and regulation. J Am Acad Dermatol. 2005, 53: 1038-1044. 10.1016/j.jaad.2005.07.066.Google Scholar
  94. Godar DE, Robert J, Landry A, Lucas AD: Increased UVA exposures and decreased cutaneous Vitamin D3 levels may be responsible for the increasing incidence of melanoma. Med Hypotheses. 2009, 72: 434-443. 10.1016/j.mehy.2008.09.056.Google Scholar
  95. Weinstock MA, Fisher DE: Indoor ultraviolet tanning: what the data do and do not show regarding risk of melanoma and keratinocyte malignancies. J Natl Compr Canc Netw. 2010, 8: 867-873.Google Scholar
  96. Gallagher RP, Spinelli JJ, Lee TK: Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev. 2005, 14: 562-566. 10.1158/1055-9965.EPI-04-0564.Google Scholar
  97. Heckman CJ, Coups EJ, Manne SL: Prevalence and correlates of indoor tanning among US adults. J Am Acad Dermatol. 2008, 58: 769-780. 10.1016/j.jaad.2008.01.020.Google Scholar
  98. Marshall Jessica: Beware the A-ray. The New Scientist Volume. 2007, 194 (Issue 2610): 38-41.Google Scholar
  99. Autier P, Dore JF, Schifflers E, Cesarini JP, Bollaerts A, Koelmel KF, Gefeller O, Liabeuf A, Lejeune F, Lienard D: Melanoma and use of sunscreens: An EORTC case control study in Germany, Belgium and France. Int. J. Cancer. 1995, 61: 749-755. 10.1002/ijc.2910610602.Google Scholar
  100. Kroft EB, Berkhof NJ, van de Kerkhof PC, Gerritsen RM, de Jong EM: Ultraviolet A phototherapy for sclerotic skin diseases: a systematic review. J Am Acad Dermatol. 2008, 59: 1017-1030. 10.1016/j.jaad.2008.07.042.Google Scholar
  101. Gawkrodger DJ, Ormerod AD, Shaw L, Mauri-Sole I, Whitton ME, Watts MJ, Anstey AV, Ingham J, Young K: Guideline for the diagnosis and management of vitiligo. Br J Dermatol. 2008, 159: 1051-1076. 10.1111/j.1365-2133.2008.08881.x.Google Scholar
  102. Morison WL: Phototherapy and photochemotherapy: an update. Semin Cutan Med Surg. 1999, 18: 297-306. 10.1016/S1085-5629(99)80029-7.Google Scholar
  103. Wetzig T, Sticherling M, Simon J-C, Hegenbart U, Niederwieser D, Al-Ali HK: Medium dose long-wavelength ultraviolet A (UVA1) phototherapy for the treatment of acute and chronic graft-versus-host disease of the skin. Bone Marrow Transplant. 2005, 35: 515-519. 10.1038/sj.bmt.1704804.Google Scholar
  104. Lauharanta J: Photochemotherapy. Clin Dermatol. 1997, 15: 769-780. 10.1016/S0738-081X(97)00015-1.Google Scholar
  105. Lowe NJ, Chizhevsky V, Gabriel H: Photo (chemo) therapy: general principles. Clin Dermatol. 1997, 15: 745-752. 10.1016/S0738-081X(97)00017-5.Google Scholar
  106. Stern RS: The PUVA Follow up Study, The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol. 2001, 44: 755-761. 10.1067/mjd.2001.114576.Google Scholar
  107. Fink CA, Bates MN: Melanoma and ionizing radiation: is there a causal relationship?. Radiat Res. 2005, 164: 701-710. 10.1667/RR3447.1.Google Scholar
  108. Abdel-Malek ZA: Endocrine factors as effectors of integumental pigmentation. Dermatol Clin. 1988, 6: 175-183.Google Scholar
  109. Scoggins CR, Merrick IR, Douglas S, Reintgen DS, Noyes RD, Goydos JS, Beitsch PD, Urist MM, Ariyan S, Sussman JJ, Edwards MJ, Chagpar AB, Martin RCG, Stromberg AJ, Hagendoorn L, McMasters KM: Sunbelt Melanoma Trial: Gender-Related Differences in Outcome for Melanoma Patients. Ann Surg. 2006, 243: 693-700. 10.1097/01.sla.0000216771.81362.6b.Google Scholar
  110. Lange JR, Palis BE, Chang DC, Soong S-J, Balch CM: Melanoma in children and teenagers: An analysis of patients from the National Cancer Data Base. J Clin Oncol. 2007, 25: 1363-1368. 10.1200/JCO.2006.08.8310.Google Scholar
  111. Koomen ER, Joosse A, Herings RMC, Casparie MK, Guchelaar HJ, Nijsten T: Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case–control study. Ann Oncol. 2009, 20: 358-364.Google Scholar
  112. McCarty KS, Wortman J, Stower SS, Lugahn DB, McCarty KS, Seigler HF: Sex steroid receptor analysis in human melanoma. Cancer. 1980, 46: 1463-1470. 10.1002/1097-0142(19800915)46:6<1463::AID-CNCR2820460628>3.0.CO;2-Q.Google Scholar
  113. Im S, Lee ES, Kim W, On W, Kim J, Lee M, Kang WH: Donor Specific Response of Estrogen and Progesterone on Cultured Human Melanocytes. J Korean Med Sci. 2002, 17: 58-64.Google Scholar
  114. Sarti M, Visconti MA, Castrucci AML: Biological activity and binding of estradiol to SK-Mel 23 human melanoma cells. Braz J Med Biol Res. 2004, 37: 901-905. 10.1590/S0100-879X2004000600016.Google Scholar
  115. Zell JA, Cinar P, Mobasher M, Ziogas A, Meyskens FL, Anton-Culver H: Survival for patients with invasive cutaneous melanoma among ethnic groups: the effects of socioeconomic status and treatment. J Clin Oncol. 2008, 26: 66-75. 10.1200/JCO.2007.12.3604.Google Scholar
  116. Konstantinos L, Leiter U, Meier F, Eigentler T, Metzler G, Moehrle M, Breuninger H, Garbe C: Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer. 2008, 112 (No. 8): 1795-1780. 10.1002/cncr.23359.Google Scholar
  117. Pavlidis N: Cancer and pregnancy. Ann Oncol. 2000, 11: 247-255.Google Scholar
  118. Pavlidis NA: Coexistence of pregnancy and malignancy. The Oncologist. 2002, 7: 279-287.Google Scholar
  119. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics, 2003. CA Cancer J Clin. 2003, 53: 5-26. 10.3322/canjclin.53.1.5.Google Scholar
  120. Driscoll MS, Grant-Kels JM: Melanoma and pregnancy. G Ital Dermatol Venereol. 2008, 143: 251-257.Google Scholar
  121. O'Meara AT, Cress R, Xing G, Danielsen B, Smith LH: Malignant melanoma in pregnancy. A population-based evaluation. Cancer. 2005, 103: 1217-1226. 10.1002/cncr.20925.Google Scholar
  122. Lens MB, Rosdahl I, Ahlbom A, Farahmand BY, Synnerstad I, Boeryd B, Newton Bishop JA: Effect of Pregnancy on Survival in Women With Cutaneous Malignant Melanoma. Am J Clin Oncol. 2004, 22 ( No 21): 4369-4375. 10.1200/JCO.2004.02.096.Google Scholar
  123. Lens M, Bataille V: Melanoma in relation to reproductive and hormonal factors in women: current review on controversial issues. Canc Causes Contr. 2008, 19: 437-442. 10.1007/s10552-008-9110-4.Google Scholar
  124. Silipo V, De Simone P, Mariani G, Buccini P, Ferrari A, Catricala C: Malignant melanoma and pregnancy. Melanoma Res. 2006, 16: 497-500. 10.1097/01.cmr.0000232295.91536.09.Google Scholar
  125. Karagas MR, Zens MS, Stukel TA, Swerdlow AJ, Rosso S, Osterlind A, Mack T, Kirkpatrick C, Holly EA, Green A, Gallagher R, Elwood JM, Armstrong BK: Pregnancy history and incidence of melanoma in women: a pooled analysis. Canc Causes Contr. 2006, 17: 11-19. 10.1007/s10552-005-0281-y.Google Scholar
  126. Grin CM, Rojas AI, Grant-Kels JM: Does pregnancy alter melanocytic nevi?. J Cutan Pathol. 2001, 28: 389-392. 10.1034/j.1600-0560.2001.028008389.x.Google Scholar
  127. Gunduz K, Koltan S, Sahin MT, Filiz E: Analysis of melanocytic naevi by dermoscopy during pregnancy. J Eur Acad Dermatol Venereol. 2003, 17: 349-351. 10.1046/j.1468-3083.2003.00792_2.x.Google Scholar
  128. Katz VL, Farmer RM, Dotters D: Focus on primary care: from nevus to neoplasm: myths of melanoma in pregnancy. Obstet Gynecol Surv. 2002, 57: 112-119. 10.1097/00006254-200202000-00023.Google Scholar
  129. Ghosh R, Ott AM, Seetharam D, Slaga T, Kumar AP, Addanki P: Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications?. Melanoma Res. 2003, 13: 119-127. 10.1097/00008390-200304000-00003.Google Scholar
  130. Chaudru V, Chompret A, Bressac-de Paillerets B, Spatz A, Avril MF, Demenais F: Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families. J Natl Cancer Inst. 2004, 96: 785-795. 10.1093/jnci/djh136.Google Scholar
  131. Victor FC, Gelber J, Rao B: Melasma: a review. J Cutan Med Surg. 2004, 8: 97-102.Google Scholar
  132. Kang WH, Yoon KH, Lee ES, Kim J, Lee KB, Yim H, Sohn S, Im S: Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol. 2002, 146: 228-237. 10.1046/j.0007-0963.2001.04556.x.Google Scholar
  133. Freitag FM, Cestari TF, Leopoldo LR, Paludo P, Boza JC: Effect of melasma on quality of life in a sample of women living in southern Brazil. J Eur Acad Dermatol Venereol. 2007, 22: 655-662.Google Scholar
  134. Adalatkhan H, Amani F: The Correlation between melasma, ovarian cysts and androgenic hormones (a case control study). Res Biol Sci. 2007, 2: 593-596.Google Scholar
  135. Cayce KA, McMichael AJ, Feldman SR: Hyperpigmentation: An Overview of the Common Afflictions. Dermatol Nurs. 2004, 16: 401-416.Google Scholar
  136. Grimes PE, Yamada N, Bhawan J: Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005, 27: 96-101. 10.1097/01.dad.0000154419.18653.2e.Google Scholar
  137. Amichaia B, Grunwald MH: Pigmentary demarcation lines of pregnancy. Eur J Obstet Gynecol Reprod Biol. 2007, 131: 239-240. 10.1016/j.ejogrb.2006.04.030.Google Scholar
  138. Barankin B, Silver SG, Carruthers A: The Skin in Pregnancy. J Cutan Med Surg. 2002, 6: 236-240. 10.1007/s10227-001-0045-6.Google Scholar
  139. Sceppa JA, Smith BL, Marghoob AA, Gottlieb GJ: Melanosis of the areola and nipple. J Am Acad Dermatol. 2008, 59 (Suppl 1): S33-S34.Google Scholar
  140. McLeod SD, Ranson M, Mason RS: Effects of estrogens on human melanocytes in vitro. J Steroid Biochem Mol Biol. 1994, 49: 9-14. 10.1016/0960-0760(94)90295-X.Google Scholar
  141. Lieberman R, Moy L: Estrogen receptor expression in melasma: results from facial skin of affected patients. J Drugs Dermatol. 2008, 7: 463-465.Google Scholar
  142. Elling SV, Powell FC: Physiological changes in the skin during pregnancy. Clin Dermatol. 1997, 15: 35-43. 10.1016/S0738-081X(96)00108-3.Google Scholar
  143. Winton GB, Lewis CW: Dermatoses of pregnancy. J Am Acad Dermatol. 1982, 6: 977-998. 10.1016/S0190-9622(82)70083-0.Google Scholar
  144. Black MM, Wilkinson JD: Skin diseases in pregnancy. In Principles and Practice of Obstetrics and Perinatology. Edited by: John Wiley. 1987, Philadelhia, 136-179.Google Scholar
  145. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC: Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol. 1981, 4: 698-710. 10.1016/S0190-9622(81)70071-9.Google Scholar
  146. Jadotte YT, Schwartz RA: Melasma: insights and perspectives. Acta Dermatovenerol Croat. 2010, 18: 124-129.Google Scholar
  147. Perez-Bernal A, Munoz-Perez MA, Camacho F: Management of Facial Hyperpigmentation. Disease Management. Am J Clin Derm. 2000, 1: 261-268. 10.2165/00128071-200001050-00001.Google Scholar
  148. Fitzpatrick TB, Eisen AZ, Wolff K, Freedburg IM, Frank AK: Dermatology in General Medicine. 1993, Mcgraw-Hill, 996-997.Google Scholar
  149. Kumar R, Smeds J, Lundh Rozell B, Hemminki K: Loss of heterozygosity at chromosome 9p21 (INK4-p14ARF locus): homozygous deletions and mutations in the p16 and p14ARF genes in sporadic primary melanomas. Melanoma Res. 1999, 9: 138-147. 10.1097/00008390-199904000-00005.Google Scholar
  150. Chaudru V, Chompret A, Bressac-de Paillerets B, Spatz A, Avril MF, Demenais F: Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families. J Natl Cancer Inst. 2004, 96: 785-795. 10.1093/jnci/djh136.Google Scholar
  151. Hansson J: Familial cutaneous melanoma. Adv Exp Med Biol. 2010, 685: 134-145. 10.1007/978-1-4419-6448-9_13.Google Scholar
  152. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA: Melanoma Genetics Consortium: Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002, 94: 894-903. 10.1093/jnci/94.12.894.Google Scholar
  153. Udayakumar D, Tsao H: Melanoma genetics: an update on risk-associated genes. Hematol Oncol Clin North Am. 2009, 23: 415-429. 10.1016/j.hoc.2009.03.011.Google Scholar
  154. Di Lucca J, Guedj M, Lacapère JJ, Fargnoli MC, Bourillon A, Dieudé P, Dupin N, Wolkenstein P, Aegerter P, Saiag P, Descamps V, Lebbe C, Basset-Seguin N, Peris K, Grandchamp B, Soufir N: Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk. Eur J Cancer. 2009, 45: 3228-3236. 10.1016/j.ejca.2009.04.034.Google Scholar
  155. Mocellin S, Verdi D, Nitti D: DNA repair gene polymorphisms and risk of cutaneous melanoma: a systematic review and meta-analysis. Carcinogenesis. 2009, 30: 1735-43. 10.1093/carcin/bgp207.Google Scholar
  156. Sarasin A, Dessen P: DNA repair pathways and human metastatic malignant melanoma. Curr Mol Med. 2010, 10: 413-418. 10.2174/156652410791317011.Google Scholar
  157. Mocellin S, Nitti D: Vitamin D receptor polymorphisms and the risk of cutaneous melanoma: a systematic review and meta-analysis. Cancer. 2008, 113: 2398-2407. 10.1002/cncr.23867.Google Scholar
  158. Randerson-Moor JA, Taylor JC, Elliott F, Chang YM, Beswick S, Kukalizch K, Affleck P, Leake S, Haynes S, Karpavicius B, Marsden J, Gerry E, Bale L, Bertram C, Field H, Barth JH, Silva ID, Swerdlow A, Kanetsky PA, Barrett JH, Bishop DT, Bishop JA: Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case-control comparisons and a meta-analysis of published VDR data. Eur J Cancer. 2009, 45: 3271-81. 10.1016/j.ejca.2009.06.011.Google Scholar
  159. Box NF, Duffy DL, Chen W, Stark M, Martin NG, Sturm RA, Hayward NK: MC1R Genotype modifies risk of mealnoma in families segregating CDKN2A mutations. Am J Hum Genet. 2001, 69: 765-773. 10.1086/323412.Google Scholar
  160. Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P, Calista D, Kanetsky PA, Pinkel D, Bastian BC: MC1R Germline Variants Confer Risk for BRAF-Mutant Melanoma. Science. 2006, 313: 521-522. 10.1126/science.1127515.Google Scholar
  161. Kumar R: BRAF Mutations in Metastatic Melanoma A Possible Association with Clinical Outcome. Clin Canc Res. 2003, 9: 3362-3368.Google Scholar
  162. Scherer D, Bermejo JL, Rudnai P, Gurzau E, Koppova K, Hemminki K, Kumar R: MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism. Int J Cancer. 2008, 122: 1787-1793.Google Scholar
  163. Cosmetic Ingredient Review (CIR) Expert Panel: Final Amended Report on the Safety Assessment of Oxyquinoline and Oxyquinoline Sulfate as Used in Cosmetics. Int J Toxicol. 2006, 25: 1-9.Google Scholar
  164. Cosmetic Ingredient Review Expert Panel: Final report on the safety assessment of benzoxiquine. Int J Toxicol. 1997, 16 (Suppl 1): 117-122.Google Scholar
  165. The Montreal Protocol on Substances that Deplete the Ozone Layer: Secretariat for The Vienna Convention for the Protection of the Ozone Layer & The Montreal Protocol on Substances that Deplete the Ozone Layer. 2000, 1-47.Google Scholar

Copyright

© Volkovova et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.