Changes in tropospheric air quality related to the protection of stratospheric ozone in a changing climate.

Ultraviolet (UV) radiation drives the net production of tropospheric ozone (O3) and a large fraction of particulate matter (PM) including sulfate, nitrate, and secondary organic aerosols. Ground-level O3 and PM are detrimental to human health, leading to several million premature deaths per year globally, and have adverse effects on plants and the yields of crops. The Montreal Protocol has prevented large increases in UV radiation that would have had major impacts on air quality. Future scenarios in which stratospheric O3 returns to 1980 values or even exceeds them (the so-called super-recovery) will tend to ameliorate urban ground-level O3 slightly but worsen it in rural areas. Furthermore, recovery of stratospheric O3 is expected to increase the amount of O3 transported into the troposphere by meteorological processes that are sensitive to climate change. UV radiation also generates hydroxyl radicals (OH) that control the amounts of many environmentally important chemicals in the atmosphere including some greenhouse gases, e.g., methane (CH4), and some short-lived ozone-depleting substances (ODSs). Recent modeling studies have shown that the increases in UV radiation associated with the depletion of stratospheric ozone over 1980-2020 have contributed a small increase (~ 3%) to the globally averaged concentrations of OH. Replacements for ODSs include chemicals that react with OH radicals, hence preventing the transport of these chemicals to the stratosphere. Some of these chemicals, e.g., hydrofluorocarbons that are currently being phased out, and hydrofluoroolefins now used increasingly, decompose into products whose fate in the environment warrants further investigation. One such product, trifluoroacetic acid (TFA), has no obvious pathway of degradation and might accumulate in some water bodies, but is unlikely to cause adverse effects out to 2100.

Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2021.

The Environmental Effects Assessment Panel of the Montreal Protocol under the United Nations Environment Programme evaluates effects on the environment and human health that arise from changes in the stratospheric ozone layer and concomitant variations in ultraviolet (UV) radiation at the Earth's surface. The current update is based on scientific advances that have accumulated since our last assessment (Photochem and Photobiol Sci 20(1):1-67, 2021). We also discuss how climate change affects stratospheric ozone depletion and ultraviolet radiation, and how stratospheric ozone depletion affects climate change. The resulting interlinking effects of stratospheric ozone depletion, UV radiation, and climate change are assessed in terms of air quality, carbon sinks, ecosystems, human health, and natural and synthetic materials. We further highlight potential impacts on the biosphere from extreme climate events that are occurring with increasing frequency as a consequence of climate change. These and other interactive effects are examined with respect to the benefits that the Montreal Protocol and its Amendments are providing to life on Earth by controlling the production of various substances that contribute to both stratospheric ozone depletion and climate change.

Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2020.

This assessment by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) provides the latest scientific update since our most recent comprehensive assessment (Photochemical and Photobiological Sciences, 2019, 18, 595-828). The interactive effects between the stratospheric ozone layer, solar ultraviolet (UV) radiation, and climate change are presented within the framework of the Montreal Protocol and the United Nations Sustainable Development Goals. We address how these global environmental changes affect the atmosphere and air quality; human health; terrestrial and aquatic ecosystems; biogeochemical cycles; and materials used in outdoor construction, solar energy technologies, and fabrics. In many cases, there is a growing influence from changes in seasonality and extreme events due to climate change. Additionally, we assess the transmission and environmental effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the COVID-19 pandemic, in the context of linkages with solar UV radiation and the Montreal Protocol.

Environmental effects of stratospheric ozone depletion, UV radiation and interactions with climate change: UNEP Environmental Effects Assessment Panel, update 2019.

This assessment, by the United Nations Environment Programme (UNEP) Environmental Effects Assessment Panel (EEAP), one of three Panels informing the Parties to the Montreal Protocol, provides an update, since our previous extensive assessment (Photochem. Photobiol. Sci., 2019, 18, 595-828), of recent findings of current and projected interactive environmental effects of ultraviolet (UV) radiation, stratospheric ozone, and climate change. These effects include those on human health, air quality, terrestrial and aquatic ecosystems, biogeochemical cycles, and materials used in construction and other services. The present update evaluates further evidence of the consequences of human activity on climate change that are altering the exposure of organisms and ecosystems to UV radiation. This in turn reveals the interactive effects of many climate change factors with UV radiation that have implications for the atmosphere, feedbacks, contaminant fate and transport, organismal responses, and many outdoor materials including plastics, wood, and fabrics. The universal ratification of the Montreal Protocol, signed by 197 countries, has led to the regulation and phase-out of chemicals that deplete the stratospheric ozone layer. Although this treaty has had unprecedented success in protecting the ozone layer, and hence all life on Earth from damaging UV radiation, it is also making a substantial contribution to reducing climate warming because many of the chemicals under this treaty are greenhouse gases.

Interactive effects of changing stratospheric ozone and climate on tropospheric composition and air quality, and the consequences for human and ecosystem health.

The composition of the air we breathe is determined by emissions, weather, and photochemical transformations induced by solar UV radiation. Photochemical reactions of many emitted chemical compounds can generate important (secondary) pollutants including ground-level ozone (O3) and some particulate matter, known to be detrimental to human health and ecosystems. Poor air quality is the major environmental cause of premature deaths globally, and even a small decrease in air quality can translate into a large increase in the number of deaths. In many regions of the globe, changes in emissions of pollutants have caused significant changes in air quality. Short-term variability in the weather as well as long-term climatic trends can affect ground-level pollution through several mechanisms. These include large-scale changes in the transport of O3 from the stratosphere to the troposphere, winds, clouds, and patterns of precipitation. Long-term trends in UV radiation, particularly related to the depletion and recovery of stratospheric ozone, are also expected to result in changes in air quality as well as the self-cleaning capacity of the global atmosphere. The increased use of substitutes for ozone-depleting substances, in response to the Montreal Protocol, does not currently pose a significant risk to the environment. This includes both the direct emissions of substitutes during use and their atmospheric degradation products (e.g. trifluoroacetic acid, TFA).

Accurate measurement of androgen after androgen esters: problems created by ex vivo esterase effects and LC-MS/MS interference.

BACKGROUND: Ex vivo androgen prodrug conversion by blood esterases after oral androgen ester administration may result in an overestimation of the measured blood androgens. OBJECTIVE: We investigated whether blood collection tubes with esterase inhibitors decreased the conversion of testosterone undecanoate (TU) and dimethandrolone undecanoate (DMAU) to their active metabolites, testosterone (T), and dimethandrolone (DMA), providing a more accurate assessment of circulating T/DMA levels. METHODS: Blood was collected in tubes with/without esterase inhibitors from: (i) four healthy and four hypogonadal men receiving no androgens and spiked ex vivo with TU/DMAU; (ii) four men taking oral TU (Andriol® ); and (iii) eight hypogonadal men dosed with oral 316 mg TU and 15 healthy men with 200 mg DMAU. T/DMA levels were measured by LC-MS/MS. RESULTS: Sodium fluoride (NaF, an esterase inhibitor) decreased measured T levels by 14.2% in men not receiving TU. Increasing amounts of TU/DMAU added to blood collected into plain tubes resulted in a concentration-dependent overestimation of T/DMA that was reduced by collecting blood into NaF tubes (by 30-85%), and keeping samples at 4 °C and minimizing time prior to centrifugation. After oral TU/DMAU administration to men, when TU/DMAU levels were >15/10 ng/mL, respectively, blood collected in NaF tubes yielded lower measured T concentrations by 15-30% and DMA by 22% due to an additional inhibitory effect of NaF on blood esterases. CONCLUSION: NaF directly lowers plasma T/DMA levels measured by LC-MS/MS and also inhibits blood esterase activity. Overestimation of T/DMA in blood collected in tubes without NaF after oral TU/DMAU administration is important for pharmacokinetics studies in drug development clinical trials but may have limited impact in clinical practice/utilization because the differences between measured and true androgen values are modest and the wide therapeutic androgen efficacy ranges obviate the need for highly accurate androgen measurements during therapy.

Environmental effects of ozone depletion, UV radiation and interactions with climate change: UNEP Environmental Effects Assessment Panel, update 2017.

The Environmental Effects Assessment Panel (EEAP) is one of three Panels of experts that inform the Parties to the Montreal Protocol. The EEAP focuses on the effects of UV radiation on human health, terrestrial and aquatic ecosystems, air quality, and materials, as well as on the interactive effects of UV radiation and global climate change. When considering the effects of climate change, it has become clear that processes resulting in changes in stratospheric ozone are more complex than previously held. Because of the Montreal Protocol, there are now indications of the beginnings of a recovery of stratospheric ozone, although the time required to reach levels like those before the 1960s is still uncertain, particularly as the effects of stratospheric ozone on climate change and vice versa, are not yet fully understood. Some regions will likely receive enhanced levels of UV radiation, while other areas will likely experience a reduction in UV radiation as ozone- and climate-driven changes affect the amounts of UV radiation reaching the Earth's surface. Like the other Panels, the EEAP produces detailed Quadrennial Reports every four years; the most recent was published as a series of seven papers in 2015 (Photochem. Photobiol. Sci., 2015, 14, 1-184). In the years in between, the EEAP produces less detailed and shorter Update Reports of recent and relevant scientific findings. The most recent of these was for 2016 (Photochem. Photobiol. Sci., 2017, 16, 107-145). The present 2017 Update Report assesses some of the highlights and new insights about the interactive nature of the direct and indirect effects of UV radiation, atmospheric processes, and climate change. A full 2018 Quadrennial Assessment, will be made available in 2018/2019.

Changes in air quality and tropospheric composition due to depletion of stratospheric ozone and interactions with changing climate: implications for human and environmental health.

UV radiation is an essential driver for the formation of photochemical smog, which includes ground-level ozone and particulate matter (PM). Recent analyses support earlier work showing that poor outdoor air quality is a major environmental hazard as well as quantifying health effects on regional and global scales more accurately. Greater exposure to these pollutants has been linked to increased risks of cardiovascular and respiratory diseases in humans and is associated globally with several million premature deaths per year. Ozone also has adverse effects on yields of crops, leading to loss of billions of US dollars each year. These detrimental effects also may alter biological diversity and affect the function of natural ecosystems. Future air quality will depend mostly on changes in emission of pollutants and their precursors, but changes in UV radiation and climate will contribute as well. Significant reductions in emissions, mainly from the energy and transportation sectors, have already led to improved air quality in many locations. Air quality will continue to improve in those cities/states that can afford controls, and worsen where the regulatory infrastructure is not available. Future changes in UV radiation and climate will alter the rates of formation of ground-level ozone and photochemically-generated particulate matter and must be considered in predictions of air quality. The decrease in UV radiation associated with recovery of stratospheric ozone will, according to recent global atmospheric model simulations, lead to increases in ground-level ozone at most locations. If correct, this will add significantly to future ground-level ozone trends. However, the spatial resolution of these global models is insufficient to inform policy at this time, especially for urban areas. UV radiation affects the atmospheric concentration of hydroxyl radicals, ˙OH, which are responsible for the self-cleaning of the atmosphere. Recent measurements confirm that, on a local scale, ˙OH radicals respond rapidly to changes in UV radiation. However, on large (global) scales, models differ in their predictions by nearly a factor of two, with consequent uncertainties for estimating the atmospheric lifetime and concentrations of key greenhouse gases and air pollutants. Projections of future climate need to consider these uncertainties. No new negative environmental effects of substitutes for ozone depleting substances or their breakdown-products have been identified. However, some substitutes for the ozone depleting substances will continue to contribute to global climate change if concentrations rise above current levels.

The human health effects of ozone depletion and interactions with climate change.

Depletion of the stratospheric ozone layer has led to increased solar UV-B radiation (280-315 nm) at the surface of the Earth. This change is likely to have had an impact on human exposure to UV-B radiation with consequential detrimental and beneficial effects on health, although behavioural changes in society over the past 60 years or so with regard to sun exposure are of considerable importance. The present report concentrates on information published since our previous report in 2007. The adverse effects of UV radiation are primarily on the eye and the skin. While solar UV radiation is a recognised risk factor for some types of cataract and for pterygium, the evidence is less strong, although increasing, for ocular melanoma, and is equivocal at present for age-related macular degeneration. For the skin, the most common harmful outcome is skin cancer, including melanoma and the non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma. The incidence of all three of these tumours has risen significantly over the past five decades, particularly in people with fair skin, and is projected to continue to increase, thus posing a significant world-wide health burden. Overexposure to the sun is the major identified environmental risk factor in skin cancer, in association with various genetic risk factors and immune effects. Suppression of some aspects of immunity follows exposure to UV radiation and the consequences of this modulation for the immune control of infectious diseases, for vaccination and for tumours, are additional concerns. In a common sun allergy (polymorphic light eruption), there is an imbalance in the immune response to UV radiation, resulting in a sun-evoked rash. The major health benefit of exposure to solar UV-B radiation is the production of vitamin D. Vitamin D plays a crucial role in bone metabolism and is also implicated in protection against a wide range of diseases. Although there is some evidence supporting protective effects for a range of internal cancers, this is not yet conclusive, but strongest for colorectal cancer, at present. A role for vitamin D in protection against several autoimmune diseases has been studied, with the most convincing results to date for multiple sclerosis. Vitamin D is starting to be assessed for its protective properties against several infectious and coronary diseases. Current methods for protecting the eye and the skin from the adverse effects of solar UV radiation are evaluated, including seeking shade, wearing protective clothing and sunglasses, and using sunscreens. Newer possibilities are considered such as creams that repair UV-induced DNA damage, and substances applied topically to the skin or eaten in the diet that protect against some of the detrimental effects of sun exposure. It is difficult to provide easily understandable public health messages regarding "safe" sun exposure, so that the positive effects of vitamin D production are balanced against the negative effects of excessive exposure. The international response to ozone depletion has included the development and deployment of replacement technologies and chemicals. To date, limited evidence suggests that substitutes for the ozone-depleting substances do not have significant effects on human health. In addition to stratospheric ozone depletion, climate change is predicted to affect human health, and potential interactions between these two parameters are considered. These include altering the risk of developing skin tumours, infectious diseases and various skin diseases, in addition to altering the efficiency by which pathogenic microorganisms are inactivated in the environment.

The effects on human health from stratospheric ozone depletion and its interactions with climate change.

Ozone depletion leads to an increase in the ultraviolet-B (UV-B) component (280-315 nm) of solar ultraviolet radiation (UVR) reaching the surface of the Earth with important consequences for human health. Solar UVR has many harmful and some beneficial effects on individuals and, in this review, information mainly published since the previous report in 2003 (F. R. de Gruijl, J. Longstreth, M. Norval, A. P. Cullen, H. Slaper, M. L. Kripke, Y. Takizawa and J. C. van der Leun, Photochem. Photobiol. Sci., 2003, 2, pp. 16-28) is discussed. The eye is exposed directly to sunlight and this can result in acute or long-term damage. Studying how UV-B interacts with the surface and internal structures of the eye has led to a further understanding of the location and pathogenesis of a number of ocular diseases, including pterygium and cataract. The skin is also exposed directly to solar UVR, and the development of skin cancer is the main adverse health outcome of excessive UVR exposure. Skin cancer is the most common form of malignancy amongst fair-skinned people, and its incidence has increased markedly in recent decades. Projections consistently indicate a further doubling in the next ten years. It is recognised that genetic factors in addition to those controlling pigment variation can modulate the response of an individual to UVR. Several of the genetic factors affecting susceptibility to the development of squamous cell carcinoma, basal cell carcinoma and melanoma have been identified. Exposure to solar UVR down-regulates immune responses, in the skin and systemically, by a combination of mechanisms including the generation of particularly potent subsets of T regulatory cells. Such immunosuppression is known to be a crucial factor in the generation of skin cancers. Apart from a detrimental effect on infections caused by some members of the herpesvirus and papillomavirus families, the impact of UV-induced immunosuppression on other microbial diseases and vaccination efficacy is not clear. One important beneficial effect of solar UV-B is its contribution to the cutaneous synthesis of vitamin D, recognised to be a crucial hormone for bone health and for other aspects of general health. There is accumulating evidence that UVR exposure, either directly or via stimulation of vitamin D production, has protective effects on the development of some autoimmune diseases, including multiple sclerosis and type 1 diabetes. Adequate vitamin D may also be protective for the development of several internal cancers and infections. Difficulties associated with balancing the positive effects of vitamin D with the negative effects of too much exposure to solar UV-B are considered. Various strategies that can be adopted by the individual to protect against excessive exposure of the eye or the skin to sunlight are suggested. Finally, possible interactions between ozone depletion and climate warming are outlined briefly, as well as how these might influence human behaviour with regard to sun exposure.

Single-dose topical exposure to the pyrethroid insecticide, permethrin in C57BL/6N mice: effects on thymus and spleen.

Immunomodulatory effects of single topical exposure to permethrin were evaluated in 5-week-old female C57BL/6N mice. Mice exposed to 5-25 microl permethrin (equivalent to 220-1100 mg/kg body weight) on shaved interscapular skin were evaluated for altered body weight; splenic and thymic organ weight and cellularity; thymocyte cell surface expression, cellular apoptosis; splenic macrophage phagocytosis and hydrogen peroxide production; splenic B cell antibody production and T cell cytolytic activity; and mitogen-induced proliferation of splenocytes and thymocytes after in vivo or in vitro permethrin exposure. Topical permethrin application (25 microl) caused 32% inhibition of splenic T cell proliferation; in vitro exposure to permethrin also diminished splenocyte proliferation by 72% at 25 microM and 86% at 100 microM. permethrin did not appear to affect other leukocyte functional assays. Dose-related decreases in thymic cellularity of 52 and 80% were seen in mice exposed to 15 and 25 microl permethrin, respectively. Apoptosis was significantly increased in CD4(-)8(-) and CD4(-)8(+) thymocytes, and the CD4(+)CD8(+) thymocyte subpopulation was most severely diminished, suggesting possible chemical-induced apoptotic mechanism of thymic atrophy. Permethrin also caused splenic hypocellularity by 31% at 15 microl, and by 50% at 25 microl, an effect that may relate to inhibited proliferation or reduced seeding from the hypocellular thymus.

Topical permethrin exposure inhibits antibody production and macrophage function in C57Bl/6N mice.

Permethrin was applied to the shaved dorsal interscapular region of C57Bl/6N mice at doses of 0.5, 1.5 or 5.0 microl/day. These doses corresponded to approximately 22-220 mg/kg/day topical insecticide. Mice were exposed to permethrin in this manner daily for 10 or 30 consecutive days, or every other day for 7 or 14 exposures. The splenic macrophage chemiluminescent response was depressed in a dose-dependent manner at 2 and 10 days post-exposure to permethrin. Phagocytic ability of macrophages was not inhibited. Antibody production as shown by plaque-forming cell (PFC) assay decreased significantly after 10 consecutive days of exposure to permethrin. These data indicate that topical permethrin exposure may produce systemic immune effects.

Misoprostol therapeutics revisited.

Misoprostol, a prostaglandin E1 analog, is a racemate of four stereoisomers. On administration it rapidly de-esterifies to its active form, misoprostolic acid. Misoprostolic acid is 85% albumin bound and has a half-life of approximately 30 minutes. It is excreted in urine as inactive metabolites. No significant drug interactions have been reported. Besides its gastrointestinal protective and uterotonic activities, misoprostol regulates various immunologic cascades. It inhibits platelet-activating factor and leukocyte adherence, and modulates adhesion molecule expression. It protects against gut irradiation injury, experimental gastric cancer, enteropathy, and constipation. It improves nutrient absorption in cystic fibrosis. Misoprostol has utility in acetaminophen and ethanol hepatotoxicity, hepatitis, and fibrosis. It is effective in asthmatics and aspirin-sensitive asthmatic and allergic patients. It lowers cholesterol and severity of peripheral vascular diseases, prolongs survival of cardiac and kidney transplantation, synergizes cyclosporine, and protects against cyclosporine-induced renal damage. It works against drug-induced renal damage, interstitial cystitis, lupus nephritis, and hepatorenal syndrome. It is useful in periodontal disease and dental repair. Misoprostol enhances glycosoaminoglycan synthesis in cartilage after injury. It prevents ultraviolet-induced cataracts and reduces intraocular pressure in glaucoma and ocular hypertension. It synergizes antiinflammatory and analgesic effects of diclofenac or colchicine and has been administered to treat trigeminal neuralgic pain. It reduces chemotherapy-induced hair loss and recovery time from burn injury, and is effective in treating sepsis, multiple sclerosis, and pancreatitis.

Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study.

Testosterone (T) in a hydroalcoholic gel has been developed as an effective and convenient open system for transdermal delivery of the hormone to men. Because the gel can be applied either to small or large areas of skin, it was important to assess whether the skin surface area on which the gel was applied was an important determinant of serum T levels. To answer this question, the pharmacokinetics of a transdermal 1% hydroalcoholic gel preparation of T was studied in nine hypogonadal men. The subjects applied in random order a 25-mg metered dose of T gel either four times at one site (left arm/shoulder) or at four different sites (left and right arms/shoulders and left and right abdomen) once daily (6-8 min) for 7 consecutive days. After 7 days of washout, each subject was then crossed over to the opposite regimen for another 7 days of treatment. Serum samples were collected for measurements of T, 5alpha dihydrotestosterone (DHT), and estradiol before, during (days 1, 2, 3, 5, and 7), and after (days 8, 9, 11, 13, and 15) application of T gel. Multiple blood samples were drawn on the 1st and 7th day after gel application; single samples were obtained just before the next T gel application on other days (24 h after the previous gel application). The T gel dried in less than 5 min, left no residue, and produced no skin irritation in any of the subjects. Mean serum T levels, irrespective of application at one site or four sites followed the same pattern: rising to 2- to 3- and 4- to 5-fold above baseline at 0.5 and 24 h after first application, respectively. Thereafter, serum T levels reached steady state and remained at 4- to 5-fold above baseline (at the upper limit of the normal adult range) for the duration of gel application and returned to baseline within 4 days after stopping application. The application of T gel at four sites (application skin area approximately four times that of one site) resulted in a mean area under the curve (AUC0-24h) for serum T levels on the 7th day (868 +/- 72 nmol*h/L, mean +/- SEM), which was 23% higher but not significantly different (P = 0.06) than repeated application at one site (706 +/- 59 nmol*h/L). This could be due to the limited number of subjects studied (n = 9). Mean serum DHT levels followed the same pattern as serum T, achieving steady-state levels by 2 days. The mean concentration of serum DHT on the 7th day was significantly higher after application at four sites (9.15 +/- 1.26 nmol/L, P < 0.05) than at one site (6.9 +/- 0.77 nmol/L). These serum DHT levels were at or above the normal adult male range. Serum DHT:T ratio was not significantly altered by T gel application. Serum estradiol levels followed the same pattern as serum T and showed no significant difference between the one- or four-site application. We conclude that transdermal daily application of 100 mg T gel resulted in similar steady levels of serum T. The surface area of the skin to which the gel was applied had only a modest impact on serum T and DHT levels. Mean serum levels of T and DHT was higher by 23% and 33%, respectively, despite application of the gel to four times the skin area in the four sites compared with the one site group. Because of the greater dosage flexibility provided, hydroalcoholic T gel application over multiple sites seems to be an effective and nonskin-irritating method of transdermal T delivery for hypogonadal men. Dose-ranging studies are required to determine dosage regimens for T gel application as a replacement therapy in hypogonadal men.

Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men.

Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the C(avg) in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone C(avg) rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.

Public health consequences of global climate change in the United States--some regions may suffer disproportionately.

Current risk assessments of the likely regional health impacts of global climate change (GCC) are hindered by two factors. First, dose-response relationships between weather parameters and many of the likely health effects have not been developed, and second, reliable estimates of future regional climates across the United States are still beyond the scope of current modeling efforts. Consequently, probabilistic risk estimates of most of the likely regional health impacts of GCC have such a high degree of uncertainty that their usefulness to health officials dealing with regional issues is very limited. With the numerous pressures on today's health care systems, it is understandable that the possible consequences of GCC have received scant attention from regional health care decision makers. Indeed, the consensus among this community appears to be that any increases in health effects associated with GCC will be easily handled by the current health care system. However, such a position may be naive as the potential exists that an unequal distribution of such effects could overwhelm some regions, whereas others may feel little or no impact. This review of the likely regional impacts of GCC has been structured as a semianalytical look at this issue of distributional effects. Because of the lack of dose-response information and reliable estimates of future regional climates, however, it takes a historical perspective. That is, it assumes that the quality and quantity of health risks a region faces under GCC will be directly related to its recent history of health risks from warm weather/climate-related diseases as well as to the size, characteristics, and distribution of the sensitive subpopulations currently residing within its borders. The approach is semiquantitative; however, it uses national data gathered on a regional level and as such should only be used to generate a hypothesis rather than test it. When applied to the United States, its outcome leads to the hypothesis that if indeed history repeats itself, some states or regions may be more greatly affected by GCC than others, not only because historically they are more prone to summer weather/climate-related diseases, but also because they contain a greater proportion of the sensitive subpopulations in the United States.

Health risks.

The health risks associated with ozone depletion will principally be those due to increased ultraviolet B (UV-B) radiation in the environment, i.e., increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). Quantitative risk estimates are available for some of the UV-B-associated effects, e.g., cataract and skin cancer; however, the data are insufficient to develop similar estimates for effects such as immunosuppression and the toxicity of alternatives. Ocular damage from UV exposures includes effects on the cornea, lens, iris, and associated epithelial and conjunctival tissues. The most common acute ocular effect of environmental ultraviolet radiation (UVR) is photokeratitis. Also known as snowblindness in skiers, this condition also occurs in other outdoor recreationists. Chronic eye conditions likely to increase with ozone depletion include cataract, squamous cell carcinoma, ocular melanoma, and a variety of corneal/conjunctival effects, e.g., pterygium and pinguecula. Suppression of local (at the site of UV exposure) and systemic (at a distant, unexposed site) immune responses to a variety of antigens has been demonstrated in both humans and animals exposed to UV-B. In experiments with animals these effects have been shown to worsen the course/outcome of some infectious diseases and cancers. There is reasonably good evidence that such immunosuppression plays a role in human carcinogenesis; however, the implications of such immunosuppression for human infectious diseases are still unknown. In light-skinned populations, exposure to solar UVR appears to be the most important environmental risk factor for basal and squamous cell carcinomas and cutaneous melanoma. Originally it was believed that total accumulated exposure to UVR was the most important environmental factor in determining risk for these tumors. Recent information now suggests that only squamous cell carcinoma risk is related to total exposure. In the cases of both basal cell carcinoma and melanoma, new information suggests that increases in risk are tied to early exposures (before about age 15), particularly those leading to severe sunburns. Testing of a number of the chlorofluorocarbon (CFC) alternatives indicates that most of these chemicals have low acute toxicity, and low to moderate chronic toxicity. Some chemicals that were originally proposed as alternatives have been dropped from consideration because these tests raised concerns about toxicity and/or manufacturing difficulties. In one instance, high accidental occupational exposure was associated with liver damage, underlining the need for care in the use of these substitutes. Recent quantitative risk estimates have been developed for cataract, melanoma, and all skin cancers combined. These estimates indicate that under the Montreal Adjustments, cataract and skin-cancer incidence will peak mid-century at additional incidences of just under 3 per 100,000 and about 7 per 100,000, respectively.

Simultaneous first-order and capacity-limited elimination kinetics after oral administration of verapamil.

In this study of the relationship between dose and plasma concentration of verapamil, controlled-release verapamil in doses of 120 mg, 180 mg, 360 mg, and 540 mg were examined. The 48 study subjects received verapamil daily during each of the 4 sequential 5-day dosing segments. Blood samples were collected frequently to obtain first-dose and steady-state (fifth dose) concentration profiles of verapamil. Plasma concentrations of R- and S-verapamil and R- and S-norverapamil were measured by stereospecific assay. Statistical comparisons of pharmacokinetic parameters and mean differences between doses were performed with analysis of variance models. At steady state, area under the concentration-time curve (AUC) values for R- and S-verapamil at both the 120-mg and 180-mg doses were about 1.5 times higher than the corresponding first-dose values. After both first and fifth doses, pharmacokinetic parameters for all four analytes were dose proportional between the 120-mg and 180-mg doses. A dose-proportional relationship also was found between the 360-mg and 540-mg dose levels. However, nonlinearity was found between the 180-mg dose and higher doses, suggesting saturable metabolic pathways. The dose-proportional relationship between the 360-mg and 540-mg doses suggests that other first-order metabolic pathways become dominant. Although results from this study are partially consistent with previously reported nonlinear verapamil kinetics, this is the first clinical study to demonstrate a dose-proportional relationship for verapamil at both low and high input rates (mg/hr). In addition, first-order disposition pathways of verapamil are probably nonexistent at medium input rates and become dominant at higher input rates.

The effect of co-administered drugs on oxaprozin binding to human serum albumin.

The binding of the non-steroidal anti-inflammatory drug oxaprozin to human serum albumin was studied by bioaffinity high-performance liquid chromatography using a column based on immobilized human serum albumin. Displacement studies using marker compounds for the major drug binding sites showed that oxaprozin has a high affinity for the benzodiazepine/indole site and binds to the warfarin site but with a significantly lower affinity. Biochromatography and ultrafiltration techniques were used to screen for possible competition and allosteric interactions between oxaprozin and potential co-administered drugs including non-steroidal anti-inflammatory drugs, antipyretics, hypoglycaemics, inhibitors of angiotensin-converting enzyme, anaesthetics, metal ions and anticancer agents. Competition occurred mainly with drugs bound at the benzodiazepine site (benzodiazepines, various non-steroidal anti-inflammatories).