The relationship between occupational exposure to organic solvents and metabolic syndrome in petroleum refinery workers in Tehran, Iran.

AIMS: The rising prevalence of metabolic syndrome has made it a major health concern. Chronic occupational exposure to organic solvents affects different systems of the body. This study aimed to investigate the association between exposure to organic solvents and the prevalence of metabolic syndrome in petroleum refinery workers. METHOD: This study was conducted in 2019-2020 on workers employed in an Iranian petroleum refinery. The demographic and occupational information on the participants was obtained using the interview method. Their height, weight, and blood pressure were measured by the occupational health team, and fasting blood samples were taken from them to measure the paraclinical parameters. RESULTS: In this study, 1009 petroleum refinery workers were analyzed. The prevalence of metabolic syndrome in workers was 20.1% and it was about two times higher in exposed workers (CI 95%: 1.61-3.35) compared to non-exposed ones. Factors associated with the prevalence of metabolic syndrome include age, higher BMI, exercise, and longer exposure to organic solvents. CONCLUSION: Findings of this study suggested that exposure to organic solvents is associated with increased prevalence of metabolic syndrome (the highest association was observed with elevated serum triglycerides). Besides, longer exposure to organic solvents increased the risk of developing metabolic syndrome.

The exposome and health: Where chemistry meets biology.

Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.

Industrial, Biocide, and Cosmetic Chemical Inducers of Cholestasis.

A frequent side effect of many drugs includes the occurrence of cholestatic liver toxicity. Over the past couple of decades, drug-induced cholestasis has gained considerable attention, resulting in a plethora of data regarding its prevalence and mechanistic basis. Likewise, several food additives and dietary supplements have been reported to cause cholestatic liver insults in the past few years. The induction of cholestatic hepatotoxicity by other types of chemicals, in particular synthetic compounds, such as industrial chemicals, biocides, and cosmetic ingredients, has been much less documented. Such information can be found in occasional clinical case reports of accidental intake or suicide attempts as well as in basic and translational study reports on mechanisms or testing of new therapeutics in cholestatic animal models. This paper focuses on such nonpharmaceutical and nondietary synthetic chemical inducers of cholestatic liver injury, in particular alpha-naphthylisocyanate, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, methylenedianiline, paraquat, tartrazine, triclosan, 2-octynoic acid, and 2-nonynoic acid. Most of these cholestatic compounds act by similar mechanisms. This could open perspectives for the prediction of cholestatic potential of chemicals.

[Mortality results in SENTIERI Project]. / Risultati dell'analisi della mortalità nel Progetto SENTIERI.

SENTIERI Project (Mortality study of residents in Italian polluted sites) studies mortality of residents in 44 sites of national interest for environmental remediation (Italian polluted sites, IPS). The epidemiological evidence of the causal association between causes of death and exposures was a priori classified into one of these three categories: Sufficient (S), Limited (L) and Inadequate (I). In these sites various environmental exposures are present. Asbestos (or asbestiform fibres as in Biancavilla) has been the motivation for defining six sites as IPSs (Balangero, Emarese, Casale Monferrato, Broni, Bari-Fibronit, Biancavilla). In five of these, increases in malignant neoplasm or pleura mortality are detected; in four of them, results are consistent in both genders. In six other sites (Pitelli, Massa Carrara, Aree del Litorale Vesuviano, Tito, "Aree industriali della Val Basento", Priolo), where other sources of environmental pollution in addition to asbestos are reported, mortality from malignant neoplasm of pleura is increased in both genders in Pitelli, Massa Carrara, Priolo, "Litorale vesuviano". In the time span 1995-2002, a total of 416 extra cases of malignant neoplasm of pleura are detected in the twelve asbestos-polluted sites. Asbestos and pleural neoplasm represent an unique case. Unlike mesothelioma, most causes of death analyzed in SENTIERI have multifactorial etiology; furthermore, in most IPSs multiple sources of different pollutants are present, sometimes concurrently with air pollution from urban areas: in these cases, drawing conclusions on the association between environmental exposures and specific health outcomes might be complicated. Notwithstanding these difficulties, in a number of cases an etiological role could be attributed to some environmental exposures. The attribution could be possible on the basis of increases observed in both genders and in different age classes, and the exclusion of a major role of occupational exposures was thus allowed. For example, a role of emissions from refineries and petrochemical plants was hypothesized for the observed increases in mortality from lung cancer and respiratory diseases in Gela and Porto Torres; a role of emissions from metal industries was suggested to explain increased mortality from respiratory diseases in Taranto and in Sulcis-Iglesiente-Guspinese. An etiological role of air pollution in the raise in congenital anomalies and perinatal disorders was suggested in Falconara Marittima, Massa-Carrara, Milazzo and Porto Torres. A causal role of heavy metals, PAH's and halogenated compounds was suspected for mortality from renal failure in Massa Carrara, Piombino, Orbetello, "Basso bacino del fiume Chienti" and Sulcis-Iglesiente-Guspinese. In Trento-Nord, Grado and Marano, and "Basso bacino del fiume Chienti" increases in neurological diseases, for which an etiological role of lead, mercury and organohalogenated solvents is possible, were reported. The increase for non-Hodgkin lymphomas in Brescia was associated with the widespread PCB pollution. Mortality for causes of death with a priori Sufficient or Limited evidence of association with the environmental exposure exceeds the expected figures, with a SMR of 115.8% for men (90% IC 114.4-117.2; 2 439 extra deaths) and 114.4% for women (90% CI 112.4-116.5; 1 069 extra deaths). These excesses are also observed when analysis is extended to all the causes of death (i.e. with no restriction to the ones with a priori Sufficient or Limited evidence): for a total of 403 692 deaths (both men and women), an excess of 9 969 deaths is observed, with an average of about 1 200 extra deaths per year. Most of these excesses are observed in IPSs located in Southern and Central Italy. The procedures and results of the evidence evaluation are presented in a 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI.

Resposta de vacas leiteiras à substituição total de milho por polpa cítrica e à suplementação com microminerais orgânicos I: consumo e digestão / Response of lactating cows to the total replacement of corn by citrus pulp and to the supplementation of organic trace minerals I: intake and digestion

Avaliou-se a resposta de vacas leiteiras à substituição total de milho maduro finamente moído por polpa cítrica peletizada. O teor dietético do milho foi 10 por cento e o de polpa 24 por cento nos tratamentos com milho, e o de polpa foi 33 por cento nas dietas exclusivas com polpa. Simultaneamente, foi avaliada a substituição total de fontes inorgânicas de Cu, Mn, Se, Zn e Cr por fontes orgânicas. Quatro dietas baseadas em silagem de milho foram geradas por arranjo fatorial dos dois fatores. Dezesseis vacas receberam os tratamentos em quadrado latino 4x4. O efeito da substituição de fontes inorgânicas por fontes orgânicas de microminerais não foi conclusivo. O consumo diário de matéria seca foi 19,4kg na polpa e 20,5kg na dieta com milho (P=0,03). O consumo de matéria orgânica digestível foi maior nas dietas com milho (P<0,01). Houve tendência de queda na taxa fracional de degradação ruminal in situ da MS da silagem de milho (P=0,11) e de aumento no tamanho da fração indigestível (P=0,15) nas dietas com milho, sugerindo que a degradação de forragens não determinou o menor consumo nas dietas com polpa. A substituição total de milho por polpa cítrica pode reduzir o consumo e a digestibilidade.

The response of lactating cows to the total replacement of finely ground mature corn by pelleted citrus pulp was evaluated. Treatments with corn contained 10 percent corn and 24 percent citrus pulp while citrus diets contained 33 percent citrus pulp. The complete replacement of inorganic sources of Cu, Mn, Se, Zn, and Cr by organic sources was simultaneously evaluated. Four corn silage based diets were generated by a factorial arrangement of the two factors. Sixteen cows received the treatments in 4x4 latin squares. The effect of substituting inorganic by organic mineral sources was not conclusive. Daily dry matter intake was 19.4kg for citrus diets and 20.5kg with corn (P=0.03). The digestible organic matter intake was increased by corn supplementation (P<0.01). There was a trend for a decreased fractional rate of in situ ruminal degradation of corn silage dry matter (P=0.11) and for increased size of the indigestible fraction (P=0.15) in diets with corn, suggesting that degradation of forages did not determine the lower intake for citrus diets. The total substitution of corn by citrus pulp may decrease intake and digestibility.

Reduced fertility among shoe manufacturing workers.

OBJECTIVES: To investigate whether fertility is reduced among female shoe manufacturing workers exposed to organic solvents. METHODS: A retrospective study was conducted on time to pregnancy (TTP) among 250 Portuguese shoe manufacturing workers exposed to solvents and 250 unexposed women working in stores of food units and storehouses. Data on TTP and related factors were collected by face-to-face interviews. The participation rate was 92%, and 81% of the workers (197 exposed women and 209 unexposed women) provided data for the analyses. Exposure assessment was based on hygienic measurements in the workplaces. TTP data were analysed with discrete proportional hazards regression. RESULTS: Female exposure to solvents was associated with reduced fertility (adjusted fecundability density ratio (FDR) 0.55, CI 0.40 to 0.74 for low exposure, and FDR 0.70, CI 0.52 to 0.94 for high exposure). The findings were robust in different sensitivity analyses. A slightly stronger association was found among women with regular menstrual cycles. Exposure for less than 6 years was more strongly associated with reduced fertility (FDR 0.50, CI 0.30 to 0.83 and FDR 0.50, CI 0.28 to 0.90 for low and high exposure, respectively) than at least 6 years of exposure (FDR 0.60, CI 0.39 to 0.92 and FDR 0.86, CI 0.57 to 1.29 for low and high exposure, respectively). There was an interaction between solvent exposure and female smoking or use of coffee, the exposed women who smoke or use coffee being highly fecund. CONCLUSIONS: The findings provide further evidence that exposure to organic solvents is hazardous for female reproduction. The observed association may be related to any of the following solvents commonly used in shoe manufacturing: n-hexane and hexane isomers, toluene, methyl ethyl ketone, acetone, ethyl acetate and dichloromethane.

Life cycle risks for human health: a comparison of petroleum versus bio-based production of five bulk organic chemicals.

This article describes the development and application of a generic approach to the comparative assessment of risks related to the production of organic chemicals by petrochemical processes versus white biotechnology. White biotechnology, also referred to as industrial biotechnology, typically uses bio-based feedstocks instead of the fossil raw materials used in the petrochemical sector. The purpose of this study was to investigate whether the production of chemicals by means of white biotechnology has lower conventional risks than their production by petrochemical processes. Conventional risks are the risks of well-established processes, and not those related to genetically modified microorganisms and plants. Our approach combines classical risk assessment methods (largely based on toxicology), as developed by the life cycle assessment (LCA) community, with statistics on technological disasters, accidents, and work-related illnesses. Moreover, it covers the total process chain for both petrochemical and bio-based products from cradle to grave. The approach was applied to five products: the plastics polytrimethylene terephthalate (PTT), polyhydroxyalkanoates (PHA), polyethylene terephthalate (PET), polyethylene (PE), and ethanol. Our results show that the conventional risks related to the white biotechnology products studied are lower than those of the petrochemical products. However, considering the uncertainties with respect to the ranges of input data, the (incomplete) coverage of emissions by the environmental priority strategies (EPS) 2000 method, and the uncertainties of the assumptions made in this study (i.e., large to very large), the differences in results between bio-based and petrochemical products fall into the uncertainty range. Because of this, future research is necessary to decrease the uncertainties before we can conclude that the conventional risks of biotechnologically produced chemicals are lower than those of fossil-fuel-derived chemicals.

Human biomonitoring: state of the art.

Human biomonitoring (HBM) of dose and biochemical effect nowadays has tremendous utility providing an efficient and cost effective means of measuring human exposure to chemical substances. HBM considers all routes of uptake and all sources which are relevant making it an ideal instrument for risk assessment and risk management. HBM can identify new chemical exposures, trends and changes in exposure, establish distribution of exposure among the general population, identify vulnerable groups and populations with higher exposures and identify environmental risks at specific contaminated sites with relatively low expenditure. The sensitivity of HBM methods moreover enables the elucidation of human metabolism and toxic mechanisms of the pollutants. So, HBM is a tool for scientists as well as for policy makers. Blood and urine are by far the most approved matrices. HBM can be done for most chemical substances which are in the focus of the worldwide discussion of environmental medicine. This especially applies for metals, PAH, phthalates, dioxins, pesticides, as well as for aromatic amines, perfluorinated chemicals, environmental tobacco smoke and volatile organic compounds. Protein adducts, especially Hb-adducts, as surrogates of DNA adducts measuring exposure as well as biochemical effect very specifically and sensitively are a still better means to estimate cancer risk than measuring genotoxic substances and their metabolites in human body fluids. Using very sophisticated but nevertheless routinely applicable analytical procedures Hb-adducts of alkylating agents, aromatic amines and nitro aromatic compounds are determined routinely today. To extend the spectrum of biochemical effect monitoring further methods should be elaborated which put up with cleavage and separation of the adducted protein molecules as a measure of sample preparation. This way all sites of adduction as well as further proteins, like serum albumin could be used for HBM. DNA-adducts indicate the mutagenicity of a chemical substance as well as an elevated cancer risk. DNA-adducts therefore would be ideal parameters for HBM. Though there are very sensitive techniques for DNA adduct monitoring like P32-postlabelling and immunological methods they lack specificity. For elucidating the mechanism of carcinogenesis and for a broad applicability and comparability in epidemiological studies analytical methods must be elaborated which are strictly specific for the chemical structure of the DNA-adduct. Current analytical possibilities however meet their borders. In HBM studies with exposure to genotoxic chemicals especially the measurement of DNA strand breaks in lymphocytes and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in white blood cells has become very popular. However, there is still a lack of well-established dose-response relations between occupational or environmental exposures and the induction of 8-OHdG or formation of strand breaks which limits the applicability of these markers. Most of the biomarkers used in population studies are covered by standard operating procedures (SOPs) as well as by internal and external quality assessment schemes. Therefore, HBM results from the leading laboratories worldwide are analytically reliable and comparable. Newly upcoming substances of environmental relevance like perfluorinated compounds can rapidly be assessed in body fluids because there are very powerful laboratories which are able to elaborate the analytical prerequisites in due time. On the other hand, it is getting more and more difficult for the laboratories to keep up with a progress in instrumental analyses. In spite of this it will pay to reach the ultimate summit of HBM because it is the only way to identify and quantify human exposure and risk, elucidate the mechanism of toxic effects and to ultimately decide if measures have to be taken to reduce exposure. Risk assessment and risk management without HBM lead to wrong risk estimates and cause inadequate measures. In some countries like in USA and in Germany, thousands of inhabitants are regularly investigated with respect to their internal exposure to a broad range of environmentally occurring substances. For the evaluation of HBM results the German HBM Commission elaborates reference- and HBM-values.

Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1.

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.

Rat epidermal keratinocyte organotypic culture (ROC) as a model for chemically induced skin irritation testing.

The potential of rat epidermal keratinocyte (REK) organotypic culture (ROC) with proper stratum corneum barrier as a model for screening skin irritants was evaluated. The test chemicals were selected from ECETOC database (1995) and the observed in vitro irritation potential was compared to ECETOC in vivo primary irritation index (PII), to EU risk phrases, and to the harmonized OECD criteria. Chemicals were applied onto the stratum corneum surface of ROC for 30 min and samples were taken from the underlying medium at 4 and 8 h after exposure. Cell membrane integrity (determined by LDH assay) and pro-inflammatory effect (determined by IL-1alpha release) were verified at both time points and correlated to PII values. The best correlation (R(2) = 0.831) was seen with LDH leakage test. Based on obtained data, chemicals were classified according to criteria defined by EU and OECD. From 12 chemicals, only two were incorrectly classified according to OECD criteria when using LDH leakage and IL-1alpha release as irritation markers. At the end of experiment, chemical-treated ROC cultures were fixed and histological changes were assessed. Typical signs for irritation were lightly stained cytoplasm, condensed nuclei, cellular vacuolization, eosinophilic cytoplasms, and blebbing. These irritation effects of chemicals were graded visually into four classes (A-D). The extent of morphological perturbations of the cultures mostly correlated with PII. The present results indicate the validity of the ROC model in predicting skin irritation potential of chemicals and show that the use of set of irritation markers with different mechanistic responses gives more information on irritation than if only one marker was used.

Lumiracoxib.

Lumiracoxib is a highly selective and potent cyclo-oxygenase (COX)-2 inhibitor, with a novel structure that conveys weakly acidic properties and a unique pharmacological profile. It is rapidly absorbed, with a relatively short plasma half-life. In well designed clinical trials of 1-52 weeks' duration in patients with osteoarthritis (OA) or rheumatoid arthritis, the efficacy of oral lumiracoxib 100-400 mg/day in decreasing pain intensity and improving functional status was greater than that with placebo and similar to those with nonselective NSAIDs or celecoxib 200mg once daily. In single- and multiple-dose well designed trials in patients with acute pain associated with primary dysmenorrhoea, dental or orthopaedic surgery or tension-type headache, lumiracoxib 100-800 mg once daily was more effective in relieving acute pain than placebo or controlled-release oxycodone 20 mg, and was at least as effective as selective COX-2 inhibitors or nonselective NSAIDs. Lumiracoxib was generally well tolerated in clinical trials, with a similar overall tolerability profile to those of placebo and other COX-2-selective inhibitors. In a large 52-week safety trial in patients with OA, lumiracoxib 400mg once daily had a rate of gastrointestinal ulcer complications that was approximately one-third to one-quarter of that of ibuprofen 800 mg three times daily or naproxen 500 mg twice daily. Lumiracoxib was not associated with an increase in cardiovascular events.

Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study.

BACKGROUND AND AIMS: Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract. METHODS: Twenty four healthy subjects (aged 18-45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B(2) (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E(2) (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour (51)Cr-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each treatment period by enzyme immunoassay. RESULTS: Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B(2) vs. placebo). Gastric PGE(2) was reduced by 69% by naproxen (P < 0.001 vs. placebo) and 29% by lumiracoxib (P < 0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (51)Cr-EDTA absorption increased significantly with naproxen but not lumiracoxib. CONCLUSIONS: Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.

Disruption of the blood-brain barrier and neuronal cell death in cingulate cortex, dentate gyrus, thalamus, and hypothalamus in a rat model of Gulf-War syndrome.

We investigated the effects of a combined exposure to restraint stress and low doses of chemicals pyridostigmine bromide (PB), N, N-diethyl-m-toluamide (DEET), and permethrin in adult male rats, a model of Gulf-War syndrome. Animals were exposed daily to one of the following for 28 days: (i) a combination of stress and chemicals (PB, 1.3 mg/kg/day; DEET, 40 mg/kg/day; and permethrin, 0.13 mg/kg/day); (ii) stress and vehicle; (iii) chemicals alone; and (iv) vehicle alone. All animals were evaluated for: (i) the disruption of the blood-brain barrier (BBB) using intravenous horseradish peroxidase (HRP) injections and endothelial barrier antigen (EBA) immunostaining; (ii) neuronal cell death using H&E staining, silver staining, and glial fibrillary acidic protein (GFAP) immunostaining; and (iii) acetylcholinesterase (AChE) activity and m2-muscarinic acetylcholine receptors (m2-AChR). Animals subjected to stress and chemicals exhibited both disruption of the BBB and neuronal cell death in the cingulate cortex, the dentate gyrus, the thalamus, and the hypothalamus. Other regions of the brain, although they demonstrated some neuronal cell death, did not exhibit disruption of the BBB. The neuropathological changes in the above four brain regions were highly conspicuous and revealed by a large number of HRP-positive neurons (21-40% of total neurons), a decreased EBA immunostaining (42-51% reduction), a decreased number of surviving neurons (27-40% reduction), the presence of dying neurons (4-10% of total neurons), and an increased GFAP immunostaining (45-51% increase). These changes were also associated with decreased forebrain AChE activity and m2-AchR (19-25% reduction). In contrast, in animals exposed to stress and vehicle or chemicals alone, the above indices were mostly comparable to that of animals exposed to vehicle alone. Thus, a combined exposure to stress and low doses of PB, DEET, and permethrin leads to significant brain injury. The various neurological symptoms reported by Gulf-War veterans could be linked to this kind of brain injury incurred during the war.

Benefit and risk of organic ultraviolet filters.

Modern sunscreen products provide broad-spectrum UV protection and may contain one or several UV filters. A modern UV filter should be heat and photostable, water resistant, nontoxic, and easy to formulate. Identification of a substance that meets these criteria is as difficult as discovering a new drug; hundreds of new molecules are synthesized and screened before a lead candidate is identified. The most important aspect in the development of a new UV filter is its safety. In our laboratories, the safety of new ultraviolet filters is assessed by an initial in vitro screen including photostability, cytotoxicity, photocytotoxicity, genotoxicity, and photogenotoxicity tests. These tests are performed in mammalian, yeast, and bacterial cell systems. Skin penetration potential is measured in vitro using human skin or, when required by regulations, in vivo. Because modern sunscreens are selected on the basis of their retention on and in the stratum corneum and are formulated as poorly penetrating emulsions, they generally have very low to negligible penetration rates. The safety and efficacy of UV filters are regulated and approved by national and international health authorities. Safety standards in the European Union, United States, or Japan stipulate that new filters pass a stringent toxicological safety evaluation prior to approval. The safety dossier of a new UV filter resembles that of a new drug and includes acute toxicity, irritation, sensitization, phototoxicity, photosensitization, subchronic and chronic toxicity, reproductive toxicity, genotoxicity, photogenotoxicity, carcinogenicity, and, in the United States, photocarcinogenicity testing. The margin of safety of new UV filters for application to humans is estimated by comparing the potential human systemic exposure with the no-effect level from in vivo toxicity studies. Only substances with a safe toxicological profile and a margin of safety of at least 100-fold are approved for human use. Finally, prior to marketing, new UV filters undergo stringent human testing to confirm their efficacy as well as the absence of irritation, sensitization, photoirritation, and photosensitization potential in man. UV filters not only protect against acute skin injury, such as sunburn, but also against long-term and chronic skin damage, including cellular DNA damage, photoinduced immune suppression, and, by extension, skin cancer. The protection provided by modern sunscreens against UV-induced skin cancer was shown in animal photocarcinogenicity studies and confirmed by numerous in vitro, animal, and human investigations: UV filters protect the p53 tumor suppressor gene from damage and prevent UV-induced immune suppression. Recent studies suggest that sunscreens protect against precursor lesions of skin cancer, such as actinic keratoses. Additional benefits of ultraviolet filters include prevention of photodermatoses, such as polymorphic light eruption, and, possibly, photoaging. Modern sunscreens are safe for children and adults. Percutaneous penetration and irritation rates of topically applied substances in children and adults are similar. The principal protective measure is to keep children out of the sun and/or to cover them with protective clothes; however, sunscreens are a safe and effective and often the only feasible defense of children against UV radiation. In conclusion, sunscreens are safe protective devices that undergo stringent safety and efficacy evaluation.