Sunscreen controversy

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Sunscreen has been proven to protect against the two most common forms of skin cancer: squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). However the most lethal form of skin cancer - malignant melanoma - has been shown by several epidemiological studies to be amplified by the use of sunscreen.[1][2][3][4][5]

Even though it is rare, malignant melanoma is responsible for 75 % of all skin cancer related death cases.[6]

The mechanism by which UV-radiation generates SCC and the BCC is very different from the mechanism that generates malignant melanoma. The direct DNA damage is responsible for sunburn, SCC and BCC. The direct DNA damage is indisputably reduced by sunscreen use. However the indirect DNA damage which is caused by free radicals and ROS can be amplified by the use of sunscreen, if it penetrates into the skin.[7]

In August 2007, the United States Food and Drug Administration tentatively concluded that "the available evidence fails to show that sunscreen use alone prevents skin cancer[...]"[8]

Several factors have contributed to the higher risk of melanoma among sunscreen users: 1) the absence of UVA filters combined with a longer exposure time of the sunscreen user 2) free radical generation of sunscreen chemicals that have penetrated into the skin 3) less vitamin D generation in sunscreen users. The medical literature focuses entirely on contribution number 1) and regards this to be the full explanation.(PMID 17415716 PMID 18022535 PMID 16086753) However the photobiological section of the scientific literature has shown that explanation number 2) has contributed to the higher melanoma rate in sunscreen users as well.

Contents

[edit] Are sunscreens photocarcinogenic?

[edit] Photomutagenic properties of sunscreen ingredients in contact with living tissue

It is essential that UV-absorbers are chemically and photochemically inert.[9] If this requirement is not met the sunscreen agent can react with cellular components such as DNA and protein.[9] In fact, it has been shown by many photobiological studies, that sunscreen in contact with viable cells has a negative effect for these cells when illuminated.[10][11][12][9] Some of these studies deal with photomutagenic properties others with phototoxic effects of the sunscreen chromophore. Xu et al. have shown that human melanocytes suffer more DNA damage from UV-illumination when in contact with padimate O then they do without this sunscreen ingredient.[10] Even at a very low concentration of 25 μmol/l the combination of padimate O with solar UV exposure can selectively damage this type of human skin cells. This concentration of the sunscreen ingredient is likely to be achieved in the skin.[10] The same ingredient had been studied by Knowland et al. and they found that sunscreens containing padimate O induce mutations and attack DNA when illuminated. Their results suggest that absorbed sunscreens could, while preventing sunburn, contribute to sunlight-related cancers.[11] Long et al. have studied the effects of padimate O in contact with mouse cells under illumination.[13] They found that illuminated padimate O damages DNA of mouse cells more than the UV-illumination does in the absence of padimate O.

PABA has been found to increase the formation of a particular DNA damage in human cells which in turn increases the risk of skin cancer.[14] PABA was banned as a sunscreen ingredient several years after these findings were published.

Several photobiological studies have reported that phenylbenzimidazole (PBI) causes DNA photodamage when illuminated while in contact with living tissue.[9][15][16] Mosley et al. tested the photomutagenic properties of PBI on bacteria and on human keratinocytes [9] Their study from 2007 confirmed the earlier findings. They found that human keratinocytes suffer an increased amount of DNA photodamage when they are in contact with PBM.[9] The combination of PBI in the 1-25μM concentration range and UV-light irradiation caused significant DNA damage in keratinocytes. It is the combination of light and PBM that has this effect. The samples with PBI alone or the one with light alone had a substantially lower amount of DNA damage. Their study clearly indicates that PBI can cause damages to DNA in human skin cells when in combination with solar light. They concluded that the sunscreen ingredient PBI can absorb the UV portion of the solar light and undergo a series of light induced reactions to cause adverse effects in humans.[9] Their results clearly indicate that PBI is photomutagenic.[9]

The DNA damaging effect of Phenylbenzimidazole sulfonic acid under illumination had already previously been measured by Stevenson et al.[15]

Damiani et al. tested the spectral stability of UV-absorbers and their ability to produce oxidative stress. The generation of free radicals and oxidative stress (via ROS) was measured via the induction of lipid oxidative damage. The amount of lipid peroxidation that was generated by UVA radiation in the presence of each respective UV-absorber was regarded as a measure of their capacity to generate harmful ROS. Their studies showed that photostability of sunscreen chromophores does not necessarily imply absence of free radical generation. They point out that upon light exposure the UV-absorbing molecules may act as photooxidants via generation of free radicals and reactive oxygen species.[17] They did indeed find proof for two of the tested compounds that oxidative damage to lipids is augmented by UVA-induced ROS generated from these two compounds. UV-absorbers can promote the formation of ROS through photosensitization reactions and thereby the lipid oxidation is amplified. They found that the amount of oxidative damage is related to the energy dissipation mechanism of the UV-absorber. Two of the UV absorbers have an efficient dissipation system to convert the energy of the UV-radiation into small amounts of harmless heat. While these two molecules do not increase the oxidative damage to lipids, two other UV-absorbers - devoid of an energy dissipation system - yield greatly increased oxidative damage. An efficient energy dissipation system improves photostability and avoids the generation of free radicals and ROS. The authors have proven that sunscreen chromophores which do not dissipate the energy of the UV-light efficiently produce more oxidative stress and they amplify the damage from the free radical chain reactions.[17]

Researchers have repeatedly criticized that certain sunscreen ingredients are structurally and functionally similar to photosensitizers that are known to generate free radicals.[11][10][17] Many sunscreen ingredients have been shown to generate singlet oxygen under illumination.[18] Singlet oxygen is a type of reactive oxygen species, which can generate indirect DNA damage and thereby cause malignant melanoma. Several popular UV-filters have been demonstrated to generate free radicals.[17] These chemically reactive species may react with tissue and cell components and induce oxidative damage.

Often the photostability of a sunscreen chemical is regarded as a crucial property for its photoprotection. However, it has been shown that spectral stability does not necessarily imply absence of radical generation. [19]

[edit] Penetration into the skin

Due to the harmful effects that sunscreen chromophores can have when in contact with living tissue, there is a concern about the absorption of organic filters into the skin.[20] The desirable site of action is restricted to the skin surface or within only the uppermost layers of the stratum corneum.[21] The stratum corneum consists of dead cells and so the sunscreen ingredients are not in contact with viable tissue. It is often assumed that little or none of a topically applied substance is absorbed into the body.[22] As long as these requirements are met the sunscreen acts as an inert filter, reducing the intensity of UV-radiation that acts on the deeper tissue of the skin. Those medical doctors who endorse the use of sunscreen assume that little or none of the topically applied sunscreen would be absorbed into the skin. They treat sunscreen like an inert filter that does not get into contact with living tissue in relevant amounts. Chatelain et al. criticized "The question whether UV filters acts [sic?] on or in the skin has so far not been fully answered. Despite the fact that an answer would be a key to improve formulations of sun protection products, many publications carefully avoid addressing this question."[23] [24]

Sunscreen is a topically applied cosmetic product. From a medical point of view, the penetration of the active ingredients into the deeper layers of skin is highly undesireable.[7]

While it is known that sunscreen which gets into contact with living tissue is having a damaging effect on this tissue when illuminated many medical doctors claim that sunscreen does not pass the epidermal barrier into the human skin in amounts large enough to cause damage. The dispute whether sunscreen is photocarcinogenic or not ultimately ends in the question whether the harmful effects of the absorbed sunscreen are dominating over the UV-filtering effect of the topical sunscreen. Xu et al.[10] have found that concentrations of sunscreen likely to be achieved in the skin were sufficient to harm cultured human cells.

Several scientific studies have investigated which amount of the sunscreen chemicals can penetrate through the epidermal barrier. When the photoactive ingredients are absorbed into the skin they are in contact with living tissue.

  • Treffel and Gabard have determined that 6 hours after application the percentage of sunscreen that came into contact with the epidermis is 4% (benzophenone-3), 9% (ethylmethylmethoxycinnamate) and 7% (ethylhexylsalicylate).[25]
  • Hayden et al have investigated the amount of sunscreen that can be found in the urine after topical application. [22] Nine volunteers applied a commercially available SPF15+ sunscreen (Ingredients: oxybenzone, octylmethoxycinnamate, octyl salicylate and octocrylene), and then their urine samples were collected for 48 hours. They estimated that within 10 hours between 1 and 2% of the applied oxybenzone was absorbed into the body.
  • Jiang et al. found that 10 % of the chemical UV-filter benzophenone-3 has passed through the skin into the body.[26]

Knowland et al. pointed out that it is difficult to distinguish between the protective effect of the surface film and the harmful effects of the sunscreen ingredients that are in contact with dividing cells.[11] He is furthermore asking whether the absorption of sunscreen into the skin and the associated damaging effects are relevant to the paradox that sunscreens do not seem to prevent melanoma and to the suggestion that sunscreens might encourage, rater than prevent, sunlight-related cancers.[11] The beneficial shielding of the surface film of sunscreen can be compromised if the photoexcited sunscreen agents react chemically with cellular components. DNA, in particular, is susceptible to genotoxic damage caused by photo-excited xenobiotic compounds.[15]

[edit] The Temporal Design of Experiments

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The absorption of the sunscreen ingredients into the skin does not occur instantaneously, but the sunscreen concentration in the deeper levels of the skin increases over time.[27] For this reason the amount of time between the topical application of sunscreen and the end of the illumination period is an important parameter. Illumination of those sunscreen chromophores which have penetrated the stratum corneum is harmful because the chromophores amplify the generation of ROS.[27]

Several experiments on mice have shown a protective effect of sunscreens against melanoma even with sunscreen ingredients that are strong free radical generators (like PABA). The temporal design of those experiments performed in 1982, 1985 and 1990 differ substantially from the mode of human use of sunscreen. In these experiments the mice were treated with sunscreen, and then immediately irradiated for only 10 minutes[28] [29] or for 3 to 7 minutes[30] after this time the irradiation stopped and the next sunscreen + irradiation treatment was done after a 2 day break. Within these 10 minutes the sunscreen does not penetrate through the epidermal barrier. For this reason the mice were not affected by the photosensitaziation effect of the sunscreen chemicals as it is described in the study by Kerry Hanson.[27] Despite the obvious discrepancy between such an experimental design and a real situation of sunscreen use, these experiment have been widely used as arguments to promote the use of sunscreen. Obviously human use has a different time-pattern because most sunscreen users stay in the sun longer than 10 minutes. This longer time allows the sunscreen to diffuse into the skin which leads to the generation of chemically reactive species.[27] Kerry Hanson et al. have shown for the three sunscreen ingredients octocrylene, octylmethoxycinnamate, or benzophenone-3 that the first 20 minutes the protective effect dominates over the harmful effects, but then after the sunscreen chemicals had time to absorb into the skin the number of ROS and free radicals is higher for the sunscreen user than for the non-user.[27]

[edit] Epidemiological connection between malignant melanoma and sunscreen use

Most medical statistics, that have investigated the effect of sunscreen use, have found an increase of malignant melanoma cases associated with sunscreen use.[1][2][3][4][5][31][32][33] Garland et al. have compared the population of Queensland with the rest of Australia, because in Queensland the use of sunscreen has been promoted the earliest and the strongest compared to the rest of Australia. Garland found that the increased use of sunscreen was related to a steep rise in the number of melanoma cases. At the time of this study (1992) Queensland had the highest incidence number of melanoma cases in the world. In other parts of Australia the use of sunscreen had been promoted only later, and the melanoma rates increased in these other parts with the same a delay.[1]

Philippe Autier et al. have performed a case-control study with 418 melanoma cases and 438 healthy controls in France Belgium and Germany.[3] They stated that "due to the divorce between public health messages and results from epidemiological studies, prevention programmes should not affirm that sunscreen use prevents cutaneous melanoma."

They found that the regular sunscreen user unaware of the dangers linked to exaggerated UV-exposure have a 12 times higher risk when compared to aware subjects who never use sunscreen.[3]

Within the group of people unaware of the dangers linked to exaggerated UV-exposure the sunscreen users have a 3.36 times higher risk for melanoma than the non-user.[3]

Westerdahl et al.[2] have performed a case-control study on 571 patients with malignant melanoma and 913 healthy controls. All the patients and controls were asked about their history of sunburn, hair color, sunbathing habits (how long, how often) and - of course - use of sunscreen. They had found a significantly elevated risk for developing malignant melanoma associated with regular sunscreen use. Several adjustments were made with respect to the history of sunburns, hair color and other factors. They state that even in two groups that differ neither in sunbathing frequency nor in duration of each sunbathing session an increased risk for melanoma was found for those who always use sunscreen.

[edit] Lawsuits against sunscreen manufacturers

The results from the epidemiological studies have lead to lawsuits against sunscreen manufacturers.

These lawsuits limit themselves to the absence of UV-A filters.

[edit] Sunburn and malignant melanoma

Arrows indicate a causal connection
Arrows indicate a causal connection

A statistical correlation exists between the number of sunburns and the risk to develop melanoma. This statistical correlation has in the past been interpreted as a causal connection. The medical community took this correlation as an indication that sunburns cause melanoma. This has been shown to be wrong in several studies. Wolf and Kripke have shown that protecting against sunburn does not imply protection against other damaging effects of UV radiation [34] Genetic studies have investigated the mutations in the melanoma of skin cancer patients. The mechanism of DNA damage which produced the melanoma can be identified from the kind of mutation, and it was shown that 92% of all malignant melanoma in healthy humans originate from indirect DNA damage and only in 8% of the cases the melanoma originate from the direct DNA damage.[35]

(Indirect DNA damage is caused by reactive oxygen species (ROS), oxidative stress and free radicals)

[edit] Mechanisms of melanoma generation by the use of sunscreen

There are several contributors to the increased melanoma risk among sunscreen users:

  • Since the medical community had sent out the message that sunburn "causes" melanoma, many people feel safe as long as they apply sunscreen. In reality the cause of melanoma is the indirect DNA damage not the sunburn-causing direct DNA damage. One contributor to the harmful effects of sunscreen is the changed behaviour of the sunscreen user compared to the non-user. Sunscreen prevents any warning signal that the human skin usually generates when exposed to solar radiation. This absence of a warning signal gives a treacherous feeling of safety to the sunscreen-user. Since they are not afraid of a sunburn the sunscreen-users stay in the sun much longer and therefore they are exposed to a larger dose of radiation. This increases in turn the indirect DNA damage which is responsible for the development of almost all melanoma.[3]
  • UVB radiation stimulates the skin to generate more protective melanin. The UVB filters in sunscreen suppress this stimulus. Then the human body fails to recognise the danger and the skin does not produce this substance that would offer an efficient natural protection against UVB and UVA. Furthermore it can be speculated that the reduced tanning effect in the sunscreen user will cause him to spend more time in the sun thereby increasing the dose of harmful radiation.[3]
  • Another substantial contributor was the false assumption that little or none of the topically applied sunscreen would be absorbed into the skin. This has been proven wrong several times (see for example [22][36][25]).The medical community has treated sunscreen like an inert filter that does not get into contact with living tissue. Today it is well established that sunscreen does penetrate the epidermal barrier into the human skin in amounts which are large enough to cause serious damage due to an increase of photogenerated free radicals.[27] Photocatalytic substances can damage biological tissue even at very small concentrations. While non-catalytic substances need to be fairly concentrated to do harm, a photocatalyst combined with UV irradiation can be harmful even at concentrations as low as 10 μmol/l. [9] This is due to the repeated reaction of such a catalyst - one photocatalyst molecule can produce millions of free radicals (and more).

At this time, sunscreen is not tested in Europe, Japan or Australia for photocarcinogenic effects before it is released onto the market. In the US such testing became compulsory in 1978, and since then only 3 new substances have managed to fulfill these new requirements.[37] Even in the US most of the sunscreens that are sold had their ingredients permitted to the market before testing for photocarcinogenic effects became compulsory.[37]

[edit] Photochemical properties of sunscreen ingredients vs. melanin

In this mechanism the excited state of the melanin gives of the energy into the vibrational modes of the molecule (heat) by a process that is called internal conversion. This way melanin does not act as a photosensitizer. This photochemical process has been optimized by nature for melanin out of necessity. The internal conversion of melanin is so fast, that more than 99.9 % of the energy is dissipated as heat.[38]

Sunscreen ingredients do not possess this photoprotective property. They do not efficiently dissipate the absorbed energy. In fact many of those chemicals (e.g.: PABA, Benzophenone or Coumarin) are used as photosensitizers in chemical reactions. Coumarin is used as a dye in lasers. The property that makes it suitable for such an application is the long-lived excited state. Exactly this property makes it unsuitable for use in sunscreen. It will act as a photosensitizer for DNA damage which makes this substance photocarcinogenic.

[edit] Skin cancer as a group

Many laymen and even professionals consider the basal cell carcinoma, the squamous cell carcinoma and the malignant melanoma as one group - namely skin cancer. This grouping is problematic for two reasons:

  • the mechanism that generates the first two forms is different from the mechanism that generates the melanoma. The direct DNA damage is responsible for BCC and SCC while the indirect DNA damage causes melanoma.
  • the mortality rate of BCC and SCC is around 0.3 causing 2000 deaths per year in the US. In comparison the mortality rate of melanoma is 15-20% and it causes 6500 deaths per year.[39]

Many scientists argue that the sun-avoiding health message does decrease the less relevant forms of skin cancer and increase the incidence number of more frequently fatal melanoma.[40]

BCC and SCC malignant melanoma
Incidence number[39] 600 000 32 000
death cases[39] 2000 (0.3%) 6500 (20%)

[edit] Absorption of photoactive sunscreen ingredients into the skin

Photocatalytic substances produce free radicals (or reactive oxygen species) when illuminated with UV-light and then return to their original state - they are catalytic and they don't get consumed. This cycle can be repeated until a million free radicals are generated by each sunscreen-molecule. Concentrations as little as 10 μmol/l [9] or 25 μmol/l [10] have been shown to kill living tissue. The concentrations that are reached inside the human skin can be estimated from the recommended dose of 2 mg/cm2 [41] , the molecular weight of the specific ingredient (most of them are around 200 g/mol), their maximum concentration in a final sunscreen formulation and the fraction of sunscreen that is absorbed into the skin. Those who are endorsing the use of sunscreen report that after 24 hours "only" 10 % of the sunscreen ingredients have been absorbed into the skin.[42] With an allowed concentration for the UV-filter of 8% and a molar mass of = 277 g·mol-1 the resulting concentration is 57 μmol/l if the filter spreads out over a 1 cm deep layer. Assuming a 1 mm thick layer the concentration will be 570 μmol/l.

\mathrm{c= \frac{2 \frac{mg}{cm^2} * 0.08 * 0.10} {277\frac{g}{mol}* 1 cm}= 5.7 * 10^{{-8}}\ mol/cm^3 = 5.7 * 10^{{-5}}\ mol/l = 57\ *\ 10^{{-6}}\ mol/l \ \ }


\mathrm{c= \frac{2 \frac{mg}{cm^2} * 0.08 * 0.10} {277\frac{g}{mol}* 0.1 cm}= 5.7 * 10^{{-7}}\ mol/cm^3 = 5.7 * 10^{{-4}}\ mol/l = 570\ *\ 10^{{-6}}\ mol/l \ \ }

Reference storage [10][11][27] [17][12][9][15][16][14][21]

[edit] See also

[edit] References

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