F.R. de Gruijl

Estimate of the wavelength dependency of ultraviolet carcinogenesis in humans and its relevance to the risk assessment of a stratospheric ozone depletion.

AbstractThe wavelength dependency of carcinogenesis is an important factor in risk assessments pertaining to sources of ultraviolet radiation, the most important of which is the sun. This wavelength dependency cannot be measured directly in humans, but it has been measured in hairless mice, and repr

Predictions of skin cancer incidence in the Netherlands up to 2015

Summary  Background  Skin cancer is an important, growing public health problem among white caucasians, causing a heavy burden on dermatologists and general practitioners.

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

The role of UVA-radiation—the major fraction in sunlight—in human skin carcinogenesis is still elusive. We here report that different UVA exposure regime (4 × 5 J/cm2 per week or 1 × 20 J/cm2 per week) caused tumorigenic conversion (tumors in nude mice) of the HaCaT skin keratinocytes. While tumorigenicity was not associated with general telomere shortening, we found new chromosomal changes characteristic for each recultivated tumor. Since this suggested a nontelomere-dependent relationship between UVA irradiation and chromosomal aberrations, we investigated for alternate mechanisms of UVA-dependent genomic instability. Using the alkaline and neutral comet assay as well as γ-H2AX foci formation on irradiated HaCaT cells (20–60 J/cm2), we show a dose-dependent and long lasting induction of DNA single and double (ds) strand breaks. Extending this to normal human skin keratinocytes, we demonstrate a comparable damage response and, additionally, a significant induction and maintenance of micronuclei (MN) with more acentric fragments (indicative of ds breaks) than entire chromosomes particularly 5 days post irradiation. Thus, physiologically relevant UVA doses cause long-lasting DNA strand breaks, a prerequisite for chromosomal aberration that most likely contribute to tumorigenic conversion of the HaCaT cells. Since normal keratinocytes responded similarly, UVA may likewise contribute to the complex karyotype characteristic for human skin carcinomas.

Molecular and immunologic mechanisms of cancer pathogenesis in solid organ transplant recipients.

The increased risk for the development of malignancies in transplant recipients is generally attributed to the debilitated immune system that results from chronic exposure to potent immunosuppressive drugs required to prevent graft rejection. While impaired immunity is clearly a key determinant, there is strong evidence that a constellation of other factors contribute to the pathogenesis of posttransplant cancers. In this article we discuss the underlying molecular and immunologic mechanisms that contribute to the development of de novo malignancies in transplant recipients, with particular focus on the two leading posttransplant neoplasia, skin cancer and Epstein–Barr virus (EBV)‐associated posttransplant lymphoproliferative disorder (PTLD).

The consequences for human health of stratospheric ozone depletion in association with other environmental factors

Due to the implementation of the Montreal Protocol, which has limited, and is now probably reversing, the depletion of the stratospheric ozone layer, only modest increases in solar UV-B radiation at the surface of the Earth have occurred. For many fair-skinned populations, changing behaviour with regard to exposure to the sun over the past half century - more time in the sun, less clothing cover (more skin exposed), and preference for a tan - has probably contributed more to greater levels of exposure to UV-B radiation than ozone depletion. Exposure to UV-B radiation has both adverse and beneficial effects on human health. This report focuses on an assessment of the evidence regarding these outcomes that has been published since our previous report in 2010. The skin and eyes are the organs exposed to solar UV radiation. Excessive solar irradiation causes skin cancer, including cutaneous malignant melanoma and the non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma, and contributes to the development of other rare skin cancers such as Merkel cell carcinoma. Although the incidence of melanoma continues to increase in many countries, in some locations, primarily those with strong sun protection programmes, incidence has stabilised or decreased over the past 5 years, particularly in younger age-groups. However, the incidence of non-melanoma skin cancers is still increasing in most locations. Exposure of the skin to the sun also induces systemic immune suppression that may have adverse effects on health, such as through the reactivation of latent viral infections, but also beneficial effects through suppression of autoimmune reactivity. Solar UV-B radiation damages the eyes, causing cataracts and pterygium. UV-B irradiation of the skin is the main source of vitamin D in many geographic locations. Vitamin D plays a critical role in the maintenance of calcium homeostasis in the body; severe deficiency causes the bone diseases, rickets in children and osteomalacia in adults. Although many studies have implicated vitamin D deficiency in a wide range of diseases, such as cancer and cardiovascular disease, more recent evidence is less compelling, with meta-analyses of supplementation trials failing to show a beneficial effect on the health outcomes that have been tested. It continues to be difficult to provide public health messages to guide safe exposure to the sun that are accurate, simple, and can be used by people with different skin types, in different locations, and for different times of the year or day. There is increasing interest in relating sun protection messages to the UV Index. Current sun protection strategies are outlined and assessed. Climatic factors affect the amount of UV radiation received by the skin and eyes, separately from the effect of ozone depletion. For example, cloud cover can decrease or increase the intensity of UV radiation at Earths surface and warmer temperatures and changes in precipitation patterns may alter the amount of time people spend outdoors and their choice of clothing. The combination of changes in climate and UV radiation may affect the number of pathogenic microorganisms in surface waters, and could have an impact on food security through effects on plant and aquatic systems. It remains difficult to quantify these effects and their possible importance for human health.

Risk Assessment for the Harmful Effects of UVB Radiation on the Immunological Resistance to Infectious Diseases

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. In this study, the effects of increased ultraviolet B(UVB, 280-315 nm) radiation on immune functions and the immunological resistance to infectious diseases in rats were analyzed according to this strategy. In a parallelogram approach, nonthreshold mathematical methods were used to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate, using a worst-case strategy (sensitive individuals, no adaptation), that exposure for approximately 90 min (local noon) at 40 degrees N in July might lead to 50% suppression of specific T-cell mediated responses to Listeria monocytogenes in humans who were not preexposed to UVB (i.e., not adapted). Additionally, a 5% decrease in the thickness of the ozone layer might shorten this exposure time by approximately 2.5%. These data demonstrate that UVB radiation, at doses relevant to outdoor exposure, may affect the specific cellular immune response to Listeria bacteria in humans. Whether this will also lead to a lowered resistance (i.e.,increased pathogenic load) in humans is not known, although it was demonstrated that UVB-induced immunosuppression in rats was sufficient to increase the pathogenic load. Epidemiology studies are needed to validate and improve estimates for the potential effects of increased UVB exposure on infectious diseases in humans. ImagesFigure 1Figure 2

Normalized ultraviolet (UV) induction of Langerhans cell depletion and neutrophil infiltrates after artificial UVB hardening of patients with polymorphic light eruption

Background  Ultraviolet (UV) B hardening has been widely used as a prophylactic treatment in patients with polymorphic light eruption (PLE). Recent investigations have shown that in patients with PLE Langerhans cells (LCs) and neutrophils display less migration from and to the epidermis after an intense UVB irradiation compared with controls.

Concurrent beneficial (vitamin D production) and hazardous (cutaneous DNA damage) impact of repeated low-level summer sunlight exposures†

The concurrent impact of repeated low‐level summer sunlight exposures on vitamin D production and cutaneous DNA damage, potentially leading to mutagenesis and skin cancer, is unknown.

Prevention and treatment of vitamin D deficiency in Dutch psychogeriatric nursing home residents by weekly half-body UVB exposure after showering: a pilot study

BACKGROUND in older people, induction of cutaneous vitamin D production by ultraviolet B (UVB) exposure may be preferable to oral supplementation: it cannot cause toxic levels, it helps to prevent polypharmacy and, moreover, there are indications that UVB exposure has beneficial effects on health and well being by mechanisms other than the vitamin D pathway alone. OBJECTIVE the aim of this pilot study is to investigate whether weekly, half-body, UVB irradiation after showering can increase serum 25-hydroxyvitamin D (25(OH)D) to sufficient levels, in a Dutch psychogeriatric nursing home population. METHOD subjects were eight psychogeriatric nursing home patients, mean age: 79 ± 8. Exclusion criteria were going outdoors into the sun more than once a week, the presence of actinic or cancer skin lesions and known resistance to body contact. The intervention consisted of weekly half-body UVB irradiation, after showering, over 8 weeks, with 0.5 minimal erythemal dose (MED). Main outcome measures were change in fasting serum levels of 25(OH)D and parathyroid hormone (PTH) at 0, 2, 4 and 8 weeks. RESULTS at baseline, mean serum 25(OH)D was 28.5 nmol/l. Mean serum 25(OH)D levels increased to 46.5 nmol/l. Median serum PTH levels decreased by 20% after 8 weeks of treatment. CONCLUSION an 8 week course of weekly, frontal half-body irradiation with UVB, at 0.5 MED, leads to an significant increase in 25(OH)D serum levels, but this period is too short to reach vitamin D sufficiency.

Predicted increased risk of squamous cell carcinoma induction associated with sunbed exposure habits.

Solar ultraviolet radiation (UVR) is recognized as the principal environmental cause of skin cancer. In particular, the risk of induction of squamous cell carcinoma (SCC) has been shown to increase with cumulative exposure to UVR. Models of risk of SCC induction have been developed but these do not include the use of sunbeds.