Journal of Environmental Science and Health Part C-Environmental Carcinogenesis & Ecotoxicology Reviews最新文献

The duration of anesthesia (related to protein binding of a drug) and the onset time (determined by the pKa) are important characteristics in assessment of local anesthetic agents. They are known to be affected by a number of factors. Early studies of antiarrhythmic diterpenoid alkaloids from plants Aconitum and Delphinium suggested that they possess local anesthetic activity due to their ability to suppress sodium currents of excited membranes. In this study we utilized toxicity, duration, and onset of action as endpoints to construct Quantitative Structure-Activity Relationship (QSAR) models for the series of 34 diterpenoid alkaloids characterized by local anesthetic activity using genetic algorithm-based multiple linear regression analysis/partial least squares and simplified molecular input line entry system (SMILES)-based optimal descriptors approach. The developed QSAR models correctly reflected factors that determine three endpoints of interest. Toxicity correlates with descriptors describing partition and reactivity of compounds. The duration of anesthesia was encoded by the parameters defining the ability of a compound to bind at the receptor site. The size and number of H-bond acceptor atoms were found not to favor the speed of onset, while topographic electronic descriptor demonstrated strong positive effect on it. SMILES-based optimal descriptors approach resulted in overall improvement of models. This approach was shown to be more sensitive to structural peculiarities of molecules than regression methods. The results clearly indicate that obtained QSARs are able to provide distinct rationales for compounds optimization with respect to particular endpoint.

The impact of climate change has been significant enough to endanger human health both directly and indirectly via heat stress, degraded air quality, rising sea levels, food and water security, extreme weather events (e.g., floods, droughts, earthquakes, volcano eruptions, tsunamis, hurricanes, etc.), vulnerable shelter, and population migration. The deterioration of environmental conditions may facilitate the transmission of diarrhea, vector-borne and infectious diseases, cardiovascular and respiratory illnesses, malnutrition, etc. Indirect effects of climate change such as mental health problems due to stress, loss of homes, economic instability, and forced migration are also unignorably important. Children, the elderly, and communities living in poverty are among the most vulnerable of the harmful effects due to climate change. In this article, we have reviewed the scientific evidence for the human health impact of climate change and analyzed the various diseases in association with changes in the atmospheric environment and climate conditions.

There is a concern of an increased risk of bladder cancer associated with the use of thiazolidinediones, a class of oral glucose-lowering drugs commonly used in patients with type 2 diabetes with a mechanism of improving insulin resistance. Human studies on related issues are reviewed, followed by a discussion on potential concerns on the causal inference in current studies. Pioglitazone and rosiglitazone are discussed separately, and findings from different geographical regions are presented. Randomized controlled trials designed for primarily answering such a cancer link are lacking, and evidence from clinical trials with available data for evaluating the association may not be informative. Observational studies have been reported with the use of population-based administrative databases, single-hospital records, drug adverse event reporting system, and case series collection. Meta-analysis has also been performed by six different groups of investigators. These studies showed a signal of higher risk of bladder cancer associated with pioglitazone, especially at a higher cumulative dose or after prolonged exposure; however, a weaker signal or null association is observed with rosiglitazone. In addition, there are some concerns on the causal inference, which may be related to the use of secondary databases, biases in sampling, differential detection, and confounding by indications. Lack of full control of smoking and potential biases related to study designs and statistical approaches such as prevalent user bias and immortal time bias may be major limitations in some studies. Overlapping populations and opposing conclusions in studies using the same databases may be of concern and weaken the reported conclusions of the studies. Because randomized controlled trials are expensive and unethical in providing an answer to this cancer issue, observational studies are expected to be the main source in providing an answer in the future. Furthermore, international comparison studies using well-designed and uniform methodology to clarify the risk in specific sexes, ethnicities, and other subgroups and to evaluate the interaction with other environmental risk factors or medications will be helpful to identify patients at risk.

Cyanobacteria produce toxic metabolites known as cyanotoxins. These bioactive compounds can cause acute poisoning, and some of them may promote cancer through chronic exposure. Direct ingestion of and contact with contaminated water is one of the many exposure routes to cyanotoxins. The aim of this article was to review the incidence of 13 cancers during a 10-year period in Serbia and to assess whether there is a correlation between the cancer incidences and cyanobacterial bloom occurrence in reservoirs for drinking water supply. The types of cancers were chosen and subjected to epidemiological analyses utilizing previously published data. Based on the epidemiological and statistical analysis, the group of districts in which the incidences of cancers are significant, and may be considered as critical, include Nišavski, Toplički, and Šumadijski district. A significantly higher incidence of ten cancers was observed in the three critical districts as compared to the remaining 14 districts in Central Serbia. These elevated incidences of cancer include: brain cancer, heart, mediastinum and pleura cancer, ovary cancer, testicular cancer, gastric cancer, colorectal cancer, retroperitoneum and peritoneum cancer, leukemia, malignant melanoma of skin, and primary liver cancer. In addition, the mean incidence of five chosen cancers was the highest in the three critical regions, then in the rest of Central Serbia, while the lowest values were recorded in Vojvodina. Persistent and recurrent cyanobacterial blooms occur during summer months in reservoirs supplying water to waterworks in the three critical districts. People in Central Serbia mainly use surface water as water supply (but not all the water bodies are blooming) while in Vojvodina region (control region in this study) only groundwater is used. Among the 14 "noncritical" districts, reservoirs used for drinking water supply have been affected by recurrent cyanobacterial blooms in two districts (Rasinski and Zaječarski), but the waterworks in these districts have been performing ozonation for more than 30 years. We propose that the established statistical differences of cancer incidences in Serbia could be related to drinking water quality, which is affected by cyanobacterial blooms in drinking water reservoirs in certain districts. However, more detailed research is needed regarding cyanobacterial secondary metabolites as risk factors in tumor promotion and cancerogenesis in general.

Pyrrolizidine alkaloids, produced by a large number of poisonous plants with wide global distribution, are associated with genotoxicity, tumorigenicity, and hepatotoxicity in animals and humans. Mammalian metabolism converts pyrrolizidine alkaloids to reactive pyrrolic metabolites (dehydropyrrolizidine alkaloids) that form covalent protein and DNA adducts. Although a mechanistic understanding is currently unclear, pyrrolizidine alkaloids can cause secondary (hepatogenous) photosensitization and induce skin cancer. In this study, the phototoxicity of monocrotaline, riddelliine, dehydromonocrotaline, dehydroriddelliine, and dehydroretronecine (DHR) in human HaCaT keratinocytes under ultraviolet A (UVA) irradiation was determined. UVA irradiation of HaCaT cells treated with dehydromonocrotaline, dehydroriddelline, and DHR resulted in increased release of lactate dehydrogenase and enhanced photocytotoxicity proportional to the UVA doses. UVA-induced photochemical DNA damage also increased proportionally with dehydromonocrotaline and dehydroriddelline. UVA treatment potentiated the formation of 8-hydroxy-2'-deoxyguanosine DNA adducts induced by dehydromonocrotaline in HaCaT skin keratinocytes. Using electron spin resistance trapping, we found that UVA irradiation of dehydromonocrotaline and dehydroriddelliine generates reactive oxygen species (ROS), including hydroxyl radical, singlet oxygen, and superoxide, and electron transfer reactions, indicating that cytotoxicity and genotoxicity of these compounds could be mediated by ROS. Our results suggest that dehydropyrrolizidine alkaloids formed or delivered to the skin cause pyrrolizidine alkaloid-induced secondary photosensitization and possible skin cancer.

Long-term rodent bioassays have played a central role in protecting human health from carcinogens; for ethical and practical reasons their use is decreasing whereas genotoxicity testing has taken a pivotal role. However, this strategy--as presently implemented--is not sensitive enough to detect all genotoxic carcinogens, and cannot detect nongenotoxic carcinogens. Among the alternative approaches under study there is the ToxCast/Tox21 project. Following a previous study from our laboratory, here we present a new, more extensive analysis of ToxCast Phase I results, indicating that at the present state-of-art this approach is not able to predict the carcinogenicity of chemicals. Possible reasons for this mediocre performance are discussed, and opinions on ways to tune up the project in the next phases are presented.

Using a dataset with more than 6000 compounds, the performance of eight quantitative structure activity relationships (QSAR) models was evaluated: ACD/Tox Suite, Absorption, Distribution, Metabolism, Elimination, and Toxicity of chemical substances (ADMET) predictor, Derek, Toxicity Estimation Software Tool (T.E.S.T.), TOxicity Prediction by Komputer Assisted Technology (TOPKAT), Toxtree, CEASAR, and SARpy (SAR in python). In general, the results showed a high level of performance. To have a realistic estimate of the predictive ability, the results for chemicals inside and outside the training set for each model were considered. The effect of applicability domain tools (when available) on the prediction accuracy was also evaluated. The predictive tools included QSAR models, knowledge-based systems, and a combination of both methods. Models based on statistical QSAR methods gave better results.

Melamine contamination in food has resulted in sickness and deaths of human infants, pets, and farm animals in the past decade. The majority of the victims suffered from acute kidney injury, nephrolithiasis, and urolithiasis. Since then, animal studies have revealed the possible target organs of the melamine toxicity and the extent of the adverse effects of the contaminant. State-of-the-art analytical methods have been developed to achieve the "zero tolerance" aim for such economically motivated adulteration. These studies provide in-depth understanding of the melamine toxicity and promising analytical methods, which can help us safeguard our dairy food source.

Endocrine disruptors are well known to impair fertility. The aim of the present study was to investigate the effects of bisphenol A (BPA) and nonylphenol (p-NP) on human luteal function in vitro. In particular, in luteal cells isolated from 21 human corpora lutea progesterone, prostaglandin (PG) F2α, PGE2 and vascular endothelial growth factor (VEGF) release, as well as VEGF expression were evaluated. BPA and p-NP negatively affected both luteal steroidogenesis and luteotrophic/ luteolytic factors balance, without influencing VEGF mRNA expression. Actually, BPA and p-NP impaired human luteal cells function in vitro, underlining the already suggested correlation between phenols and reproductive failure.

Scientific opinion on the relationship between selenium and the risk of cancer has undergone radical change over the years, with selenium first viewed as a possible carcinogen in the 1940s then as a possible cancer preventive agent in the 1960s-2000s. More recently, randomized controlled trials have found no effect on cancer risk but suggest possible low-dose dermatologic and endocrine toxicity, and animal studies indicate both carcinogenic and cancer-preventive effects. A growing body of evidence from human and laboratory studies indicates dramatically different biological effects of the various inorganic and organic chemical forms of selenium, which may explain apparent inconsistencies across studies. These chemical form-specific effects also have important implications for exposure and health risk assessment. Overall, available epidemiologic evidence suggests no cancer preventive effect of increased selenium intake in healthy individuals and possible increased risk of other diseases and disorders.