Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets.

PURPOSE: After Glisson's description of rickets, it took two centuries to realize that rickets was due to the absence of antirachitic nutrients in the diet or lack exposure of the skin to ultraviolet rays. This bone disease caused by vitamin D deficiency was one of the most common diseases of children 100 years ago. This paper explores how the definition, diagnosis, and treatment of rickets shifted in the first decades of the twentieth century. MATERIAL AND METHODS: Although benefits of cod liver oil as food were known as early as the seventh century, cod liver oil was only proposed as medicinal for rickets in Northern Europe at the end of the eighteenth century. The relationship between rickets and nutritional deficiency was suspected and demonstrated between 1880 and 1915, at the same time of the discovery of other vital substances (vitamins) needed to prevent beriberi, scurvy, and pellagra. Understanding that the lack of photosynthesized vitamin D or the lack of dietary vitamin D was a similar risk of rickets was an important turn in the comprehension of the disease. We look at the sequence and turn of events related to the discovery of vitamin D. RESULTS: Rickets has been recognized first as a disease of urban living people. Cod liver oil had been used since 1700 as a nonspecific treatment for a range of diseases. Generations of children in cities of the north of Europe had learned to hate the taste and smell of the black oily liquid and then grown up to be parents who, in turn, hated to force it down their children's throats. Occasional papers before 1900 pointed to its efficacy for rickets, and most textbooks of the early 1900s mentioned it only as a treatment option. The discovery in the early 1900s that artificial and natural ultraviolet rays had both antirachitic activity allowed to produce antirachitic foods just by food irradiation with artificial ultraviolet irradiation. Clinical guidelines were adopted to propose exposure to sunlight or to artificial ultraviolet radiation to prevent rickets in children. By the mid-1920s, rickets was promoted as universal, at times invisible to non-experts, but present to some degree in nearly every young child regardless of race or class. It was thus used to promote the young disciplines of preventive medicine, pediatrics, and public health. Innovative advances were made in the understanding of vitamin D synthesis from 1915 to 1935. A public health campaign of the 1930s was a success to eradicate rickets, using irradiated ergosterol from yeast to enrich milk and other foods with vitamin D, ensuring that the general population was consuming sufficient vitamin D. CONCLUSION: Rickets therefore provides an excellent window into the early politics of preventive health and the promotion of targeted interventions in the world. It is also a relevant historical counterpoint for current debates over the role of risk factors (absence of light or sun) for disease (today's so-called "lifestyle" diseases).

History of UV Lamps, Types, and Their Applications.

The use of ultraviolet (UV) light, for the treatment of skin conditions, dates back to the early 1900s. It is well known that sunlight can be of therapeutic value, but it can also lead to deleterious effects such as burning and carcinogenesis. Extensive research has expanded our understanding of UV radiation and its effects in human systems and has led to the development of man-made UV sources that are more precise, safer, and more effective for the treatment of wide variety of dermatologic conditions.

On the history of phyto-photo UV science (not to be left in skoto toto and silence).

This review of the history of ultraviolet photobiology focuses on the effects of UV-B (280-315 nm) radiation on terrestrial plants. It describes the early history of ultraviolet photobiology, the discovery of DNA as a major ultraviolet target and the discovery of photoreactivation and photolyases, and the later identification of Photosystem II as another important target for damage to plants by UV-B radiation. Some experimental techniques are briefly outlined. The insight that the ozone layer was thinning spurred the interest in physiological and ecological effects of UV-B radiation and resulted in an exponential increase over time in the number of publications and citations until 1998, at which time it was realized by the research community that the Montreal Protocol regulating the pollution of the atmosphere with ozone depleting substances was effective. From then on, the publication and citation rate has continued to rise exponentially, but with an abrupt change to lower exponents. We have now entered a phase when more emphasis is put on the "positive" effects of UV-B radiation, and with more emphasis on regulation than on damage and inhibition.

Early animal models of rickets and proof of a nutritional deficiency hypothesis.

In the period between 1880 and 1930, the role of nutrition and nutritional deficiency as a cause of rickets was established based upon the results from 6 animal models of rickets. This greatly prevalent condition (60%-90% in some locales) in children of the industrialized world was an important clinical research topic. What had to be reconciled was that rickets was associated with infections, crowding, and living in northern latitudes, and cod liver oil was observed to prevent or cure the disease. Several brilliant insights opened up a new pathway to discovery using animal models of rickets. Studies in lion cubs, dogs, and rats showed the importance of cod liver oil and an antirachitic substance later termed vitamin D. They showed that fats in the diet were required, that vitamin D had a secosteroid structure and was different from vitamin A, and that ultraviolet irradiation could prevent or cure rickets. Several of these experiments had elements of serendipity in that certain dietary components and the presence or absence of sunshine or ultraviolet irradiation could critically change the course of rickets. Nonetheless, at the end of these studies, a nutritional deficiency of vitamin D resulting from a poor diet or lack of adequate sunshine was firmly established as a cause of rickets.

The evolution of current medical and popular attitudes toward ultraviolet light exposure: part 3.

In the 1930s, attitudes toward ultraviolet (UV) light exposure began to change significantly within the medical profession. UV radiation had been promoted as healthful since the century's start, and particularly after the discovery of its role in vitamin-D metabolism. Increasingly, however, attention would focus on the risks of UV light exposure from sunlamps and sunbathing. During this time, the American Medical Association established guidelines for the approval of UV lamps and the appropriate therapeutic uses of phototherapy. The landmark experiments of Findlay and other researchers, in which malignant skin tumors were induced in rodents after exposure to UV lamps or sunlight, would lead to widespread recognition of the carcinogenicity of UV radiation. The role of sunlight in the etiology of skin cancer was increasingly mentioned in articles in popular magazines in the 1940s and 1950s. There was rapid growth of the sunscreen industry as well, although product efficacy remained highly variable. In the 1950s, interest developed in the use of 8-methoxypsoralen ("the suntan pill") and dihyroxyacetone ("suntan in a bottle"). In spite of the known risks of UV exposure and attempts by physicians and other health professionals to educate the public and modify behavior, suntanning has remained tenaciously popular. Today, excessive UV light exposure is recognized as the major cause of the approximately 1.3 million cases of skin cancer in the United States each year.

The evolution of current medical and popular attitudes toward ultraviolet light exposure: part 2.

The 1920s and 1930s represented an extraordinary time in the shaping of modern attitudes towards ultraviolet light. Dermatologists and other physicians today are still confronting the effects of changes in social behavior that occurred at this time. The discovery that ultraviolet wavelengths played a role in vitamin D synthesis in the skin ushered in a period of enormous popularity for ultraviolet light exposure. A variety of other medical claims were soon made for ultraviolet radiation, including that it increased resistance to disease. The field of phototherapy rapidly expanded, and its use was employed by proponents for a host of unlikely medical conditions. Exposure to sunlight or ultraviolet lamps was widely promoted as a form of preventive medicine. Home sunlamps gained popularity and were aggressively marketed to the public. A suntan, which had previously achieved limited popularity, now was viewed as de rigueur in the United States and Europe. The role that medical advocacy of ultraviolet light exposure played in initially advancing the practice of sunbathing is not commonly appreciated today. Ironically, public health recommendations of the time were often diametrically opposed to those being made at present, since sunlight exposure is currently recognized as the major preventable cause of cancer of the skin.

Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis. 1977.

Chronic irradiation of mice with ultraviolet (UV) light produces a systemic alteration of an immunologic nature. This alteration is detectable in mice long before primary skin cancers induced by UV light begin to appear. The alteration results in the failure of UV-irradiated mice to reject highly antigenic, transplanted UV-induced tumors that are rejected by unirradiated syngeneic recipients. The immunologic aspect of this systemic alteration was demonstrated by transferring lymphoid cells from UV-irradiated mice to lethally x-irradiated recipients. These recipients were unable to resist a later challenge with a syngeneic UV-induced tumor, whereas those given lymphoid cells from normal donors were resistant to tumor growth. Parabiosis of normal mice with UV-irradiated mice, followed by tumor challenge of both parabionts with a UV-induced tumor, resulted in the growth of the challenge tumors in both WV-irradiated and unirradiated mice. Splenic lymphocytes from tumor-implanted UV-treated mice were not cytotoxic in vitro against UV-induced tumors, whereas under identical conditions cells from tumor-implanted, unirradiated mice were highly cytotoxic. Our findings suggest that repeated UV irradiation can circumvent an immunologic mechanism that might otherwise destroy nascent UV-induced primary tumors that are strongly antigenic.

Shedding light on proteins, nucleic acids, cells, humans and fish.

I was trained as a physicist in graduate school. Hence, when I decided to go into the field of biophysics, it was natural that I concentrated on the effects of light on relatively simple biological systems, such as proteins. The wavelengths absorbed by the amino acid subunits of proteins are in the ultraviolet (UV). The wavelengths that affect the biological activities, the action spectra, also are in the UV, but are not necessarily parallel to the absorption spectra. Understanding these differences led me to investigate the action spectra for affecting nucleic acids, and the effects of UV on viruses and cells. The latter studies led me to the discovery of the important molecular nature of the damages affecting DNA (cyclobutane pyrimidine dimers) and to the discovery of nucleotide excision repair. Individuals with the genetic disease xeroderma pigmentosum (XP) are extraordinarily sensitive to sunlight-induced skin cancer. The finding, by James Cleaver, that their skin cells were defective in DNA repair strongly suggested that DNA damage was a key step in carcinogenesis. Such information was important for estimating the wavelengths in sunlight responsible for human skin cancer and for predicting the effects of ozone depletion on the incidence of non-melanoma skin cancer. It took experiments with backcross hybrid fish to call attention to the probable role of the longer UV wavelengths not absorbed by DNA in the induction of melanoma. These reflections trace the biophysicist's path from molecules to melanoma.

The historical aspects of photocarcinogenesis.

The concept of photocarcinogenesis is of fairly recent duration. Although cancer of the breast is described in the ancient Greek medical literature, skin cancer is not mentioned even as late as the 18th Century. This is most likely due to the poor survival of humans, 80% of people did not live past 40 years, and only 6% lived longer than 60 years. The first association of skin cancer (face and lip) with outdoor exposure dates to the middle of the 19th Century. About that time it was shown that it was Ultraviolet Radiation (UVR) that could cause skin and eye inflammation. It was not until the 20th Century that competent epidemiologic studies associated human skin cancer with chronic solar exposure, and it was shown that chemicals could augment the effects of UVR exposure. It has only been in the last quarter of a Century that it was found that UVR could cause immunologic changes that allow multiple skin cancers to develop. Advances in molecular biology have begun to show the cellular and molecular events that lead to UVR induced skin carcinogenesis.

Ultraviolet photobiology: its early roots and insights into DNA repair.

This is the first of a series of commentaries on classic papers on DNA repair that highlight the birth of this discipline. The roots go deep, and in this first commentary, I describe some of the earliest discoveries of the mechanism of absorption of UV light in cells, and its lethal and mutagenic effects. Most remarkably, a discovery of DNA repair by the use of split doses of UV light was reported in 1919. Later commentaries will take us sequentially through the early years of DNA repair.

The history of the UV radiation climate of the earth--theoretical and space-based observations.

In the Archean era (3.8-2.5 Ga ago) the Earth probably lacked a protective ozone column. Using data obtained in the Earth's orbit on the inactivation of Bacillus subtilis spores we quantitatively estimate the potential biological effects of such an environment. We combine this practical data with theoretical calculations to propose a history of the potential UV stress on the surface of the Earth over time. The data suggest that an effective ozone column was established at a pO2 of approximately 5 x 10(-3) present atmospheric level. The improvement in the UV environment on the early Proterozoic Earth might have been a much more rapid event than has previously been supposed, with DNA damage rates dropping by two orders of magnitude in the space of just a few tens of millions of years. We postulate that a coupling between reduced UV stress and increased pO2 production could have contributed toward a positive feedback in the production of ozone in the early Proterozoic atmosphere. This would contribute to the apparent rapidity of the oxidation event. The data provide an evolutionary perspective on present-day Antarctic ozone depletion.