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Influences of ultraviolet rays on health and prevention by sunscreen agents:
- With reference to efficacy of the hypoallergenic sunscreen containing natural ceramide in sensitive skin -

Masamitsu Ichihashi, MD (Chairperson):
Professor Emeritus, Kobe University; Director, Sun Clinic and Sun Care Institute

Tatsuya Horikawa, MD:
Associate Professor, Division of Dermatology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine

Toshinori Bito, MD:
Research Associate, Division of Dermatology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine

It has been pointed out that sunburns caused by ultraviolet rays result in not only cosmetic problems but also adverse effects on health, such as induction of skin cancers and cataract. There is an effort underway in Japan to protect from ultraviolet rays. In 2003, the Ministry of the Environment established "A practical guide for UV protection -Exposure, effects and prevention-." In this round-table talk, three dermatologists are invited to discuss the importance of ultraviolet protection.

Advantages and disadvantages of ultraviolet rays: Disadvantages more than advantages
Ichihashi: Thank you for joining us today. Ultraviolet rays are useful, for example, in the treatment of skin diseases, but the recent interest is increasingly focusing on the adverse effects. The sunlight with a wavelength of 290 to 400 nm is called ultraviolet rays, and they are classified into ultraviolet-A (UV-A: wavelength, 320-400 nm), ultraviolet-B (UV-B: wavelength, 290-320 nm) and ultraviolet-C (UV-C: wavelength, 200-290 nm) according to their wavelength (Figure 1). Of these, UV-C hardly reaches the surface of the earth because of absorption to atmospheric oxygen and the ozone layer, and artificial UV-C is used in germicidal lamps in medical field. UV-A has the largest radiation among the ultraviolet rays reaching the earth's surface. About 90-95% of the total radiation we are exposed to are UV-A. The amount of UV-B reaching the earth's surface is much smaller than that of UV-A. However, its influence against organisms is estimated to be 1000 times larger than that of UV-A.
First of all, I would like to ask Dr. Horikawa to explain the influences of ultraviolet rays, especially UV-A and UV-B, on human health. What types of diseases are known to be mediated by ultraviolet rays?

Horikawa: The influences of ultraviolet rays are classified into acute and chronic ones. The acute effects are caused by a single exposure, while the chronic effects are induced by long-term, repetitive exposures (Table 1).
Sunburn is a well-known acute symptom, and eczema and dermatitis can be caused in photosensitive patients. In healthy people, too, skin immunity is known to be decreased by ultraviolet rays.
The chronic symptoms caused by ultraviolet rays include photoaging such as spots and wrinkles, skin diseases such as skin cancers and benign tumors, and eye diseases such as keratitis, cataract and pterygium.

Ichihashi: Regarding the lowered skin immunity caused by ultraviolet rays, skin diseases due to herpes simplex relapse most commonly during the summer in younger patients and during the winter in the elderly, who have less chances to go outdoors. In addition, recent studies have indicated the involvement of EB virus in the pathogenesis of hydroa vacciniforme, a type of photosensitivity disorders.
By the way, how much is the incidence rate of skin cancers possibly related to ultraviolet rays?

Bito: We performed mass examination for skin cancers in ordinary people at Kasai City of Hyogo Prefecture and Ie Village of Okinawa Prefecture. The prevalence of solar keratosis, a type of precancerous lesions strongly associated with ultraviolet rays, was 128 patients per 100,000 adults at Kasai and 577 patients at Ie, showing about 4.5 times larger value at Ie, where the annual amount of ultraviolet radiation is twice that in Kasai. We also found a tendency toward developing solar keratosis in people who had more opportunities to work outdoors and those who had fair skin that immediately becomes red by exposure to sunlight.

Ichihashi: It was also demonstrated that that the incidence rate of solar keratosis was significantly higher in patients with seborrheic keratosis, so called verruca senilis.
Among the Japanese, 17-18% of people have the type I skin that readily becomes red upon exposure to sunlight but contains only a small amount of melanin causing suntan, 13-14% have the type III skin that hardly becomes red but tanned within several days, and the remaining 70% have the type II skin that becomes moderately red and turns into brown (Figure 2). Of the three types, people with type I skin who are susceptible to skin damage by ultraviolet rays should take reliable protection measures against ultraviolet rays.How about the "advantages" of ultraviolet rays?

Horikawa: We perform ultraviolet therapy for vitiligo vulgaris, atopic dermatitis and psoriasis in the field of dermatology. In particular, the narrow-band UV-B therapy using the radiation of 310-311 nm has recently been shown to have less adverse effects and higher therapeutic efficacy in patients with atopic dermatitis. The ultraviolet therapy using UV-A1 with a longer wavelength is also of recent interest. These therapies utilize the "disadvantages" of ultraviolet rays as benefits, for example, the inhibitory action against immune cells such as lymphocytes.

Ichihashi: It was also demonstrated that that the incidence rate of solar keratosis was significantly higher in patients with seborrheic keratosis, so called verruca senilis.
Among the Japanese, 17-18% of people have the type I skin that readily becomes red upon exposure to sunlight but contains only a small amount of melanin causing suntan, 13-14% have the type III skin that hardly becomes red but tanned within several days, and the remaining 70% have the type II skin that becomes moderately red and turns into brown (Figure 2). Of the three types, people with type I skin who are susceptible to skin damage by ultraviolet rays should take reliable protection measures against ultraviolet rays.How about the "advantages" of ultraviolet rays?

Horikawa: We perform ultraviolet therapy for vitiligo vulgaris, atopic dermatitis and psoriasis in the field of dermatology. In particular, the narrow-band UV-B therapy using the radiation of 310-311 nm has recently been shown to have less adverse effects and higher therapeutic efficacy in patients with atopic dermatitis. The ultraviolet therapy using UV-A1 with a longer wavelength is also of recent interest. These therapies utilize the "disadvantages" of ultraviolet rays as benefits, for example, the inhibitory action against immune cells such as lymphocytes.

Ichihashi: Biosynthesis of vitamin D3 has been conventionally regarded as the benefit of ultraviolet rays. However, exposure of the face or arms to sunlight for only a few minutes is sufficient for the synthesis of the daily requirement of vitamin D3. Also, we can take the vitamin from food. So, we need not take a sunbath. In conclusion, ultraviolet rays have more disadvantages than advantages in our daily life.e inhibitory action against immune cells such as lymphocytes.

Children in the greatest need of ultraviolet protection

Ichihashi: As Dr. Bito showed the results of skin cancer screening at Kasai and Ie, the incidence rate of solar keratosis is demonstrated to be associated with experience of sunburns accompanied by bullae during childhood. Also, the study in immigrants from England to Australia has shown that the risk of developing skin cancer was more than three times higher in the subjects who immigrated at the age of 0-9 years, compared to that of the people who immigrated after 10 years of age.
It is believed that we are exposed to a half of the lifetime ultraviolet radiation before 18 years of age, when we play outdoors most often. During the growth period, cell division is more active than that in adults. For example, the number of cells in an adult body is estimated to be about 60 trillions, whereas a baby has only about three trillions of cells. The cells in human body increase about twenty times with growth. Skin cells also increase about seven times. If exposed to ultraviolet rays during the period of active cell division, we will have a higher possibility of DNA synthesis with damaged genes for the cell division and, consequently, a higher risk of developing cancer.
When patients with xeroderma pigmentosum are exposed to sunlight several times during the first two months after birth, seborrheic keratosis develops at the age of one to two years and cancer may occur around four years old. However, these patients will have neither ephelides-like small pigmented spots nor seborrheic keratosis even at the age of seven years, if they completely avoid direct exposure to sunlight after birth. This means that xeroderma pigmentosum is a form of considerably accelerated photoaging seen in healthy people. Conversely, people at the age of 60 years could keep the skin of a 20-year-old, if reliable ultraviolet protection is made from childhood. Thus, we can say that children are in the greatest need of ultraviolet protection.

Protect against ultraviolet rays at least from March to September

Ichihashi: In 2002, World Health Organization (WHO) launched "Global solar UV index - A practical guide - 2002" to call self-control of sunbathing. In Japan, efforts are being made to promote protective measures against ultraviolet rays. For example, the description about recommendation of sunbathing was eliminated from the maternity passbook in 1998, and the Ministry of the Environment established "A practical guide for UV protection -Exposure, effects and prevention-" in 2003. Meanwhile, exhaustive nationwide actions against ultraviolet rays have been made since the early 1980's in Australia, where the prevalence of skin cancers is high. Practice of "slip (wear long sleeves)," "slop (use sunscreens) and "slap (wear a hat)" is called over radio and television, and public education about the causality between sunburns during childhood and skin cancer in adults is also actively done. Further, some other realistic measures, such as protection of trees aged more than 100 years for giving shade, are also made.

Horikawa: As it is likely that ozone destruction would continue to progress, it is important to take active protection measures against ultraviolet rays also in Japan. I suggest that we should be more careful of ultraviolet protection at least from March to September, when the ultraviolet radiation levels become high (Figure 3).

Ichihashi: Among the ultraviolet rays, the intensity of UV-B indeed varies with seasons, with about five-times higher radiation levels in the summer compared to the winter. On the contrary, the radiation levels of UV-A in the winter are as high as a half of those in the summer. UV-A has a weaker impact on organisms than UV-B, but is recently considered to be the cause of photoaging and possibly involved in lowered skin immunity.
In addition, ultraviolet rays reach the earth's surface on not only sunny days but also cloudy and rainy days. The amount of UV-B reaching the ground with thick cloud cover is reduced to 20-30% of that on a cloudless day, but with light cloud cover, the amount is estimated to be as high as 80%. Moreover, UV-A passes through glasses. We cannot be always safe even if we stay indoors.


Sunscreens are effective for ultraviolet protection

Ichihashi: We can use parasols, hats and sunglasses to protect ourselves from ultraviolet radiation.
A parasol of any colors and fabrics is believed to shade 90-95% of direct sunlight. The effect is decreased, however, if we lift it to a higher position. A hat is also effective for ultraviolet protection. A hat with a brim of 7 cm reduces the amount of ultraviolet radiation to the face by about 60%. However, neither parasols nor hats can prevent ultraviolet rays that scatter in the air and radiate laterally or reflect from walls and the ground. So, it is important to keep care and use sunscreens even with a parasol and a hat.
The sun protection factor (SPF) is used as an index of the protective effect of sunscreen agents against UV-B. SPF is defined as how much the minimum dose of ultraviolet radiation required to cause sunburn is increased by use of sunscreens in comparison to that in non-protected skin. In general, sunscreens with SPF of 30-50 are required when playing sports outdoors on sunny days or going to mountains and highlands in the summer, while SPF 15 seems to be enough when going out for one to two hours (Figure 4).

Bito: Protection against UV-A is also necessary for women who are anxious about getting tanned and for the prevention of photoaging.

Ichihashi: The protective effect of sunscreen agents against UV-A is classified into three grades according to protection grades of UV-A (PA). For usual outdoor activities, a sunscreen with PA++ or more is needed.
Optimal SPF and PA may vary with skin types of individuals (Table 2). Therefore, it is important to choose a sunscreen suitable for your skin with consideration of how and where you spend hours.

Problems of conventional sunscreens and criteria for selection

Ichihashi: Sunscreens consist principally of ultraviolet scattering agents and ultraviolet absorbers. Titanium oxide, for example, is used as a scattering agent, and there is a problem that sunscreens containing a large amount of such scattering agents give a white appearance of skin.

Bito: The content of the absorbers is increased to achieve higher SPF values, but this causes irritation to skin. So I would say there is no need to use sunscreens with unnecessarily high SPF. Also, sunscreens containing a large amount of scattering agents may not be favorable for men and children, because they make skin look white after application.

Horikawa: It is true that a thick application results in a white appearance of skin, but low doses cannot be fully effective.

Ichihashi: The usual dose of a sunscreen agent is 2 mg/cm2, but those with relatively high SPF values give a white appearance of skin even at this dose. In addition, sunscreens with considerably high SPF may cause irritation and skin troubles in some individuals. It is stipulated that the current upper limit of SPF values is 50 in Japan, and the higher values must also be labeled as 50. Higher SPF values indeed produce stronger protective effects against ultraviolet rays, but the increase in the protective effect becomes milder over SPF 30. These values may have significance as a guide for selecting sunscreens.

How to select a sunscreen for sensitive skin

Ichihashi: It is sometimes difficult for people with sensitive skin to use sunscreen agents because of skin irritation. So, some of such people do not intend to use them.

Bito: Sunscreen agents are not friendly to skin in fact, although they protect from ultraviolet rays. This could be a serious problem for patients with atopic dermatitis.

Horikawa: People whose skin easily becomes dry and chapped are regarded as having sensitive skin, as well as atopic dermatitis patients. It is considered that the barrier function is decreased in sensitive skin.

Ichihashi: As Dr. Horikawa said, dryness is an important factor for sensitive skin. Moisturizing is essential for the prevention of drying of skin, and there are three factors involved. They are sebum on the skin surface, sphingolipids in the intercellular space of the stratum corneum, and natural moisturizing factors mainly consisting of amino acids.

Horikawa: Recent studies have shown that the sensitive skin in patients with atopic dermatitis has decreased levels of ceramides, a class of sphingolipids. Ceramides not only mediate skin moisturization but also fulfill the intercellular space.
Therefore, when ceramides decrease, the barrier function of skin is impaired and various exogenous stimulants easily penetrate into skin (Figure 5). This subsequently causes dermatological symptoms such as inflammation. Then, supplementation of such skin with ceramides alleviates chapped skin and also improves the barrier function.
When people with sensitive skin use a sunscreen agent, some ingredients of the agent may act as irritants to skin. In addition, sunscreen ingredients can be easily absorbed to skin and may cause photocontact dermatitis when the barrier function of skin is impaired. Therefore, in addition to an appropriate selection of a sunscreen containing less skin irritants, recovery of the barrier function by supplementation with ceramides and any other means is necessary for people with sensitive skin.

Ichihashi: It is desirable that sunscreen agents for sensitive skin should not only protect against ultraviolet rays but also be less irritative and have a moisturizing effect.

Efficacy of the hypoallergenic sunscreen containing natural ceramide:
-Two barrier effects against both ultraviolet rays and skin irritants

Ichihashi: A hypoallergenic sunscreen agent containing natural ceramide has recently been developed. Could you explain this product?

Bito: It is AK-UV, which aims at reduction of irritation to skin and is also expected to have a moisturizing effect resulting from natural ceramide. In this product, the ultraviolet absorbers are encapsulated in microcapsules to avoid direct contact with skin for the reduction of skin irritation, which has been one of the problems in the conventional sunscreens. We expect that this will lead to the reduction of contact and photocontact allergic reactions. The microcapsules are made of hydrolyzed silk of high hydrophilicity, to which hydrophobic silicone is added. This sunscreen is easy to remove by normal washing. In addition, the moisturizing components such as natural ceramide are expected to act as the barrier against direct contact of the ultraviolet absorbers with skin and also to replenish ceramides in the stratum corneum (Figure 6). The safety of this product was studied by the skin patch tests in 25 healthy subjects. No appreciable adverse reactions were observed, and we can conclude that this sunscreen is safe.

Ichihashi: This product seems very useful from a viewpoint of the barrier function. We can expect two types of barrier effects through ultraviolet protection and skin moisturization.

Bito: Yes. Moreover, use of potentially allergenic substances, such as parabens and aroma chemicals, is reduced as much as possible to make this product hypoallergenic.
We investigated the safety of AK-UV in 36 patients with atopic dermatitis (mild to moderate) who visited the outpatient unit of the Department of Dermatology of Kobe University Hospital between January and August 2003. We asked the patients to apply an appropriate amount of the sunscreen to the dorsum of the hand and the face once before going out and at least every four hours while being outdoors. We observed the patients for four weeks.
As a result, no adverse reactions possibly associated with the test agent were observed in any of the 35 patients who completed the study. The safety was thus confirmed. We also carried out a questionnaire survey about the patients' feelings through the use of the test agent. More than half of the patients gave a response of メgoodモ to the questions about "adhesion to skin," "spreadability" and "overall feeling" (Table 3). Further, we examined the changes in the skin dryness scores according to the frequency of use. The dryness scores were significantly decreased in the patients who used the test agent every other day or everyday. This result suggests that the sunscreen could suppress drying of skin and improve the barrier function (Figure 7).

Ichihashi: This product has SPF 28 and PA++. The protective effects against ultraviolet rays are sufficient for usual daily life even during midsummer.

Horikawa: As this agent contains natural ceramide, atopic dermatitis patients with dry skin will appreciate its pleasant effect that makes their skin moisturized, in addition to the authentic effect as a sunscreen agent.
The barrier function of skin seems to be impaired in many of the people with sensitive skin due to decreases in ceramides. In such cases, use of moisturizing agents is important in skin care. Conventional sunscreens require a prior application of another moisturizing agent. AK-UV is advantageous in this point because a single application is sufficient. I believe that AK-UV would be useful for people with sensitive skin.

Ichihashi: I tried AK-UV and found that skin did not become white even though I applied sufficient doses, as the agent does not contain ultraviolet absorbers that could cause the phenomenon.
AK-UV is not only protective against ultraviolet rays but also less irritative and less allergenic. A moisturizing effect is also expected. We can say that AK-UV satisfies the requirements as an appropriate sunscreen agent for patients with atopic dermatitis and children.
Thank you for joining us today.