Enclosed you will find our revised manuscript, entitled Sunlight for better or for worse?. One version with, one without track changes.

Transcription

1 Noordwijk, Dear Editor, Enclosed you will find our revised manuscript, entitled Sunlight for better or for worse?. One version with, one without track changes. In response to the reviewers constructive and useful comments, the manuscript has been substantially revised. The page numbers mentioned in this response refer to pages in the manuscript with track changes. Their specific comments have been addressed as follows: Reviewer1: The review article provides an overview of the health effects of sun exposure and the possibly involved mechanisms. The review is well organized; however, some point should be address: 1. In general, explanations/hypothesis of the findings should be added, for instance what is the possible explanation that chronic exposure increases melanoma risk in Southern Europe, whereas in North-western Europe it is associated with relative low risks The text has been revised to include a description of a possible explanation of the differences in melanoma risk of regular exposure in Southern Europe compared to North-western Europe (page 21) 2. I suggest to include a figure showing the biosynthesis of vitamin D and its relationship with UV light Such a figure has been included now, although we are still in doubt whether such a figure should be shown. There are numerous reviews containing such a figure. Generally these reviews are specifically focused on vitamin D. Our review is focused on sunlight and on biological effects of sunlight other than vitamin D. We therefore think that the requested figure will not be missed by the readers of this review. 3. Why no association between the blood levels of 25-hydroxyvitamin D and melanoma risk was found but positive association with risk of non-melanoma skin was found? We could not find an explanation of this phenomenon in the literature. The authors of the meta-analysis state that: Differences in results for the association between vitamin D blood levels and CM and NMSC are somewhat surprising. In particular, it is not easy to explain the lack of association with melanoma risk, as this tumour, like non-melanoma skin cancer,

2 recognises the exposure to ultraviolet light as its main risk factor. It may be relevant to note that all studies that have focused on NMSC are either cohort or nested case-control studies, in which therefore the measurement of vitamin D levels is done on blood samples taken at the time of study inception, i.e. before the diagnosis of cancer. Instead, this is not the case for melanoma: in particular, the two studies that found an increased risk (with borderline statistical significance) are two cohort studies; the nested case-control study also found an increased risk, although smaller; while the two large-sized case-control studies found no association and. The case-control design is suboptimal when investigating the association between vitamin D and cancer incidence, as the tumour itself might reduce the 25(OH)D blood levels (although the mechanism is still unclear), leading to a potential reverse causation bias. We think that we should not bother the potential reader with this information. 4. In table 4, explain what the asterisk means The explanation has been added to the legend of table In section explain the mechanism of action of UVA light The explanation has been added. 6. In section define cis-uca cis-uca has been replaced by cis-urocanic acid. 7. Table 7 does not show the effects of vitamin D. Table 7 concerns the biological effects of (sun)light. One of the biological effects of sunlight is the photosynthesis of vitamin D. The consequences of (the photosynthesis) of vitamin D are prominently mentioned in table Which are the physiological doses of UVA and UVB? In page 10 and 13 the physiological was replaced by suberythematal. On page 11 and 15 the physiological doses of UVA were defined as 8-20 J/cm² 9. Define RCTs in the text RCTs was replaced by randomized controlled trials. 10. In abbreviations: "UVB, ultraviolet radiation of wavelength basal" replace basal by nm Has been done. 11. Define skin types Has been done. 12. Include data of solar radiation as function of latitude.

3 The following sentence has been added in page 4: UV radiation is highest at the equator and gradually diminishes with increasing latitude on both the Northern and Southern Hemispheres. Reviewer 2: I read this review with great interest and I found it very interesting with useful information on this very sensitive and debated topic. Following several comments to improve this review - However, I think it should be better explained the criterion by which the manuscripts were selected to be included in this review. In fact, I noticed that many other interesting articles useful to discuss this topic were arbitrary excluded. Please, describe exactly the criterion adopted in this review. Although for almost all topics the literature search and the review was systematic, this review is not systematic for all topics. Under Methods, we have added our inclusion criteria. For the topics skin cancer, colon-, breast-, prostate cancer, non-hodgkin lymphoma, multiple sclerosis, and blood pressure all original studies were included that met our inclusion criteria, unless a systematic review or meta-analysis was available. For the remaining subjects, we tried to give a summary of the literature, and selected among the numerous publications those articles and reviews, that were relevant and represented the general opinion on these subjects quite well, with a preference for recent articles. Pag. 5: I do not understand the connection of several sentences starting from Simultaneously, the advent of widely available,... until the end of the paragraph skin colour and sunlight. I think the inclusion of further comments could help to understand the insertion of these sentences. What will occur to the skin pigmentation based on the greater exposition to artificial light and numerous sources of bright light? Similarly, what should occur to the skin in population living prevalently in indoor environments? Are there studies that investigated this topics? The first part of this paragraph relates to the change of exposure of the skin to sunlight in recent generations. The second part to the change of exposure of the eyes to bright light. In the revision we made the distinction between these two subjects more clear. As far as we know there are no studies available on the effect of (the change of) bright light exposure to the skin; with the exception of a few studies on the effect of UV-emitting artificial light bulbs.

4 Table 4. I do not understand what does the symbol * mean. I think this information was unintentionally omitted. This information has now been added to the legend of table 4. Modify the term photoadapatation with photoadaptation. Has been done. When the authors describe the effect of photoadaptation or in discussion section, I think that the manuscript J Photochem Photobiol B Jan 5;130: could be useful. We agree with the reviewer that this article on the use of heat stress as a proxy for the unperceivable effects of UV, particularly erythema, is very interesting. This could become a useful method for the prevention of sunburn. However, we think that this subject is beyond the scope of our review. We wanted to review the positive and negative effects of (sun)light and show that both too much and too little sunlight is harmful for our health. We did not want to focus on the prevention of sunburn. Most of information described at page 19 concerning the avoidance of the sun in the middle of the day, the use of sunlight-protective clothing and more less continuous use of sunscreens are prevalently related to the potential risk of erythema. I think that at list a mention to the UV index should be included in this revision. This index was developed by WHO, the United Nations Environment Programme, and the World Meteorological Organization. Many countries provide the UV index forecast which provides the expected risk of overexposure to UV radiation from the sun. This information is calibrated on different phototypes. We have added information on the UV index on this page (now page 20 and 21) I also suggest to introduce and discuss other two potential effects of solar radiation: o the potential effect of inactivation of influenza virus by solar radiation (Photochem Photobiol, 2007, 83: ). In this study, the expected inactivation of influenza A virus by solar ultraviolet radiation in several cities of the world during different times of the year was calculated. o The effect of UV radiation on hay fever prevalence (J Allergy Clin Immunol Feb;135(2):463-9). In this study the authors evidenced that childhood living in a state with moderate (3-5) or high (6-7) mean annual issued UV index were associated with increased prevalence of HF compared with that in a state with low mean annual issued UV index (0-2). For more than 10 years, I try to read and evaluate all studies on the effects of sunlight on health. Apart from the effects described in this manuscript many other new associations have been reported, such as a beneficial effect of sunlight on other types of cancer, rheumatoid arthritis, several types of virus infection (including influenza), asthma and hay fever. However, the evidence for these effects is not as strong as the ones described here. For instance the effects of UV on influenza as seen in observational (mainly ecological) studies,

5 could not be confirmed in an intervention study with UV (Photochem Photobiol Sci 2012;12:848-54). We decided to focus this review on the subjects with considerable and consistent evidence and, since this review was written for Cancer Research Frontiers, with special attention on the effects of (sun)light on cancer. Also other important references should be included and discussed in this review: -Byrne SN. How much sunlight is enough? Photochem Photobiol Sci Jun;13(6): Mason RS, Reichrath J. Sunlight vitamin D and skin cancer. Anticancer Agents Med Chem Jan;13(1): Zittermann A, Gummert JF. Sun, vitamin D, and cardiovascular disease. J Photochem Photobiol B Nov 3;101(2): Reichrath J. Skin cancer prevention and UV-protection: how to avoid vitamin D-deficiency? Br J Dermatol Nov;161 Suppl 3: Wong A. Incident solar radiation and coronary heart disease mortality rates in Europe. Eur J Epidemiol. 2008;23(9): Wallis DE, Penckofer S, Sizemore GW. The "sunshine deficit" and cardiovascular disease. Circulation Sep 30;118(14): As stated previously: for some subjects for which no systematic review or meta-analyses were available, we tried to give a summary of the literature and selected among the numerous publications those recent articles, that are relevant and represent the general opinion on these subjects. The references mentioned by the reviewer fit very well in this respect, therefore they were included as well, with the exception of the reference of Mason and Reichrath. There is a recent comprehensive review and meta-analysis (Caini et al. 2014, Eur J Cancer) on this subject (vitamin D and skin cancer). Reviewer 3: Overall, this systematic literature review was well done, and it is one of the first to look at both positive and negative effects of sunlight. - However, I am a little confused on how the relationship between sunlight and skin color relates to the rest of the article. The authors should consider narrowing the focus of their article, so it flows well.

6 We considered this at an early stage of the preparation of this manuscript. Skin pigmentation is correlated strongly with UV radiation. Since it is an important factor in regulating the penetration of UV rays into the skin, pigmentation has considerable effects on health. Migration, the rise of rapid long-distance transportation, and life-style changes have led to an exposure to sunlight completely different than that of our ancestors. The possible health consequences of this change in exposure are often underestimated. All things considered, we decided to include this paragraph in the review. We recognize, however that this paragraph might influence the flow of this article and therefore in the introduction an explanation of the importance of the relationship between skin pigmentation, sun exposure, and health was added. - In addition, considering no actual statistics are performed, I would like more information on the actual literature search. I know this is discussed in a footnote of a table at the end of the article, but it would make more sense in the actual text. I would also like to know how they chose the disease states they addressed (skin, colon, breast, and prostate cancer, NHL, multiple sclerosis, and metabolic syndrome). Were these chosen beforehand or as a result of what the literature discussed. Although for the majority of the topics the literature search and the review was systematic, this review is not systematic for all topics. Under Methods, we have added our inclusion criteria. For the topics skin cancer, colon-, breast-, prostate cancer, non-hodgkin lymphoma, multiple sclerosis, and blood pressure, all original studies were included that met our inclusion criteria, unless a systematic review or meta-analysis was available. For the remaining subjects, we tried to give a summary of the literature and selected among the numerous publications those recent articles and reviews that were relevant and represented the general opinion on these subjects quite well. We assume that in a final version table 2 will be placed under Methods. For more than 10 years now, I try to read and evaluate all studies on the effects of sunlight on health. Apart from the effects described in this manuscript many other new associations have been reported, such as a beneficial effect of sunlight on other types of cancer, rheumatoid arthritis, several types of virus infection (including influenza), asthma and hay fever. However, the evidence for these effects, is not as strong as the ones described in this manuscript. The evidence is mainly ecologic and sometimes conflicting. So the subjects for this review were chosen beforehand as can be deducted now from Methods and table 2. - In Table 1, they show that sunlight has a positive effect on certain skin conditions, such as psoriasis, but this is never addressed in the text. In the introduction we state that the influence of sunlight is well-established for a number of diseases, such as psoriasis. There are many original articles, reviews and textbook chapters on the beneficial effect of sunlight on psoriasis. This review concerns the less well established

7 effects of sunlight. Consequently psoriasis and other conditions are not addressed any further in this review. - I have a problem with several of the tables because the authors use the word "probably" in a lot of their table cells. By using the word probably, it implies that they are unsure of the results, but if previous research supports what they are saying then the word probably is not needed. It just makes it sound like the authors are unsure of the literature used in their article. It was possible to delete the word probable from all tables with the exception of table 7. In some cases the evidence in the literature is not convincing enough. For instance: there is evidence that vitamin D enhances immunotolerance and consequently might reduce the risk of MS, type 1 diabetes and non-hodgkin lymphoma. The proof is however not definitive and therefore we have to add possibly in the related cell. - On another note, I know this journal does not copy edit its manuscripts, so I wanted to make a couple of suggestions. Comma usage throughout the article is really inconsistent and oftentimes incorrect. I would suggest the authors look through their manuscript and try to be consistent with their punctuation usage. I know this is a minor thing, but it makes the manuscript easier to read when punctuation is used correctly. We have addressed this problem with the help of two colleagues with a PH D in English literature. - In addition, make sure all acronyms/abbreviations, no matter how common, are explained in the text because there is always one person that will not know what the acronym is referring to. We have addressed this problem. - Lastly, just be consistent with your formatting throughout the manuscript. When using reference numbers in the text, sometimes you have the period before the numbers and other times after the numbers. We did this on purpose: (1,2). :meaning that the references relate to the present sentence.. (1,2) :meaning that the references relate to several previous sentences. In the revised manuscript only (1,2). is used. Finally I would like to mention that a subtitle was added. We think this probably will increase the interest in this article. I hope you will find this article of interest for publication in Cancer Research Frontiers.

8 Han van der Rhee