Dioxin risks in perspective: past,present, and future

The United States Environmental Protection Agency (USEPA) and other U.S. and international agencies have focused extensive efforts on the evaluation of the potential health risks of exposures to chlorinated dioxins (PCDDs), furans (PCDFs), and related dioxin-like polychlorinated biphenyls (PCBs). Extensive regulatory efforts over the past 20 years have also been made to control emissions of these compounds and thus to reduce exposures in the general population. This paper reviews the available information on temporal trends in emissions, environmental levels, intake levels through foods, and human body burdens of dioxins. This paper also provides an overview and comparison of recent hazard assessments for dioxins from U.S. and international agencies. Available data on emissions, environmental and food levels, and human body burdens of dioxins in the general population indicate a several-fold reduction in exposures and body burdens in the general population over the three decades from 1970 to 2000. U.S. and international hazard assessments concur on certain aspects, but disagree on fundamental issues including the likelihood of a threshold for carcinogenic dose-response and the degree of safety factors needed in deriving a protective exposure limit. These disagreements have significant consequences for interpreting the potential health risks of current background dioxin exposure levels. However, whatever the degree of health risk that may be associated with current background exposures, the general population is experiencing several-fold lower exposures, and, therefore, lower health risks, currently compared to 30 years ago. In light of the dramatic declines in exposure already observed, further efforts to reduce exposures through attempts to control emissions or food levels should be carefully evaluated to understand the likely efficacy of the efforts and the relative costs and benefits.     

Algal assay evaluation of trace contaminants in surface water using the nonionic surfactant,triton X-100

Triton X-100, a nonionic surfactant, has been found to be capable of neutralizing the toxic effect of selected organic compounds in algal assays using 10% Bristol's medium. This nonionic surfactant does not seem to affect specific growth rates of Chlorella cultures when it is added alone to the medium but it accelerates growth inhibition when coupled with metals. By administering a series of increasing Triton concentrations in assays with natural waters, Chlorella growth that was once arrested in the test waters became revitalized and growth was more profuse as the concentration of Triton increased. The results indicate that Triton has the ability to alleviate the toxic stresses of organic mixtures that are contaminating many southern Ontario lakes. The bioavailability of these trace organics such as PCB, DDT, chlordane and dieldrin was confirmed in the study lakewaters from bioaccumulation in fish tissues.     

Intake of chemical contaminants through fish and seafood consumption by children of Catalonia, Spain: health risks.

The intake of arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), polybrominated diphenylethers (PBDEs), polychlorinated diphenylethers (PCDEs), hexachlorobenzene, and polycyclic aromatic hydrocarbons through fish and seafood consumption by children of Catalonia, Spain, was assessed. In 2005, samples of the 14 most consumed marine species in Catalonia were randomly acquired in various cities of the country. Analysis of the above chemical contaminants were determined according to the appropriate analytical techniques and the daily intakes were estimated. For most pollutants, intake was higher in boys than in girls. Average exposure of children to contaminants through fish and seafood consumption did not exceed the respective tolerable daily intake of those pollutants for which it has been already established (metals, PCDD/Fs plus dioxin-like PCBs, HCB, and PAHs). In relation to body weight, intake by children of most contaminants was higher than that found for other age groups of the general population of Catalonia.     

Ecotoxicogenomics: linkages between exposure and effects in assessing risks of aquatic contaminants to fish

Understanding the biological effects of exposures to chemicals in the environment relies on classical methods and emerging technologies in the areas of genomics, proteomics, and metabonomics. Linkages between the historical and newer toxicological tools are currently being developed in order to predict and assess risk. Being able to classify chemicals and other stressors based on effects they have at the molecular, tissue, and organismal levels helps define a systems biology approach to development of streamlined, cost-effective, and comprehensive testing approaches for evaluating environmental hazards. The challenges of the individual technologies and the combinations of tools for ecotoxicogenomics are discussed in application to aquatic toxicology with a particular emphasis on fish testing.     

Identifying important life stages for monitoring and assessing risks from exposures to environmental contaminants: Results of a World Health Organization review

In this paper, we summarize exposure-related issues to consider in determining the most appropriate age ranges and life stages for risk assessment. We then propose a harmonized set of age bins for monitoring and assessing risks from exposures to chemicals for global use. The focus is on preconception through adolescence, though the approach should be applicable to additional life stages. A two-tiered set of early life age groups is recommended. The first tier involves the adoption of guidance similar to the childhood age groups recommended by the U.S. Environmental Protection Agency, whereas the second tier consolidates some of those age groups to reduce the burden of developing age-specific exposure factors for different regions. While there is no single “correct” means of choosing a common set of age groups to use internationally in assessing early life exposure and risk, use of a set of defined age groups is recommended to facilitate comparisons of potential exposures and risks around the globe, the collection of data and analyses of aggregate exposure and cumulative risk. Application of these age groups for robust assessment of exposure and risk for specific populations will require region-specific exposure factors as well as local environmental monitoring data.     

Signalling pathways and mechanisms of protection in pre- and postconditioning: historical perspective and lessons for the future

Ischaemic pre- and postconditioning are potent cardioprotective interventions that spare ischaemic myocardium and decrease infarct size after periods of myocardial ischaemia/reperfusion. They are dependent on complex signalling pathways involving ligands released from ischaemic myocardium, G-protein-linked receptors, membrane growth factor receptors, phospholipids, signalling kinases, NO, PKC and PKG, mitochondrial ATP-sensitive potassium channels, reactive oxygen species, TNF-α and sphingosine-1-phosphate. The final effector is probably the mitochondrial permeability transition pore and the signalling produces protection by preventing pore formation. Many investigators have worked to produce a roadmap of this signalling with the hope that it would reveal where one could intervene to therapeutically protect patients with acute myocardial infarction whose hearts are being reperfused. However, attempts to date to show efficacy of such an intervention in large clinical trials have been unsuccessful. Reasons for this inability to translate successes in the experimental laboratory to the clinical arena are evaluated in this review. It is suggested that all patients with acute coronary syndromes currently presenting to the hospital and being treated with platelet P2Y₁₂ receptor antagonists, the current standard of care, are indeed already benefiting from protection from the conditioning pathways outlined earlier. If that proves to be the case, then future attempts to further decrease infarction will have to rely on interventions which protect by a different mechanism.     

Benefits and risks of fish consumption Part II. RIBEPEIX, a computer program to optimize the balance between the intake of omega-3 fatty acids and chemical contaminants

In recent years, and based on the importance of fish as a part of a healthy diet, there has been a notable promotion of fish and seafood consumption. However, a number of recent studies have shown that fish may be a potential source of exposure to chemical pollutants, some of them with well known adverse effects on human health. Recently, we determined in 14 edible marine species the concentrations of eicosapentaenoic acid (EPA) and docosohexaenoic acid (DHA), as well as those of a number of chemical contaminants: Cd, Hg, Pb, polychlorinated dibenzo-p-dioxins and furans, polychlorinated biphenyls, hexachlorobenzene, polycyclic aromatic hydrocarbons, polychlorinated naphthalenes, polybrominated diphenylethers and polychlorinated diphenylethers. To quantitative establish the intake of these pollutants (risks) versus that of EPA + DHA (benefits), we designed a simple computer program, RIBEPEIX. The concentrations of EPA, DHA, and the chemical pollutants were introduced into the program. We here present how RIBEPEIX may be used as an easy tool to optimize fish consumption: most suitable species, frequency of consumption, and size of meals. RIBEPEIX can be useful not only for professionals (cardiologists, general physicians, nutritionists, toxicologists, etc.), but also for the general population. It is available at: http://www.fmcs.urv.cat/portada/ribepeix/.     

Fresh water fish,Channa punctatus,as a model for pendimethalin genotoxicity testing: A new approach toward aquatic environmental contaminants

Pendimethalin (PND) is one of the common herbicides used worldwide. Fresh water fish, Channa punctatus, was exposed to PND in aquaria wherein its LC50 value was recorded to be 3.6 mg/L. Three sublethal (SL) concentrations, namely, 0.9, 1.8, and 2.7 mg/L were selected for the evaluation of genotoxicity and oxidative stress generated in the fish. In vivo comet assay was carried out in the blood, liver, and gill cells after exposing the fish to aforesaid SL concentrations of PND for 24, 48, 72, and 96 h. The results of the comet assay demonstrated the genotoxicity of PND in all the three tissues. Induction of oxidative stress in the gill cells was affirmed by the increased lipid peroxidation (LPO) and decreased levels of reduced glutathione, superoxide dismutase, and catalase. Frequencies of erythrocytic nuclear abnormalities (ENA) and micronuclei (MN) were also used to assess the genotoxic potential of PND on C. punctatus. MN frequency did not show any enhancement after PND exposure, but the frequency of ENA such as kidney‐shaped nuclei, segmented nuclei and lobed nuclei, showed a significant increase after 24–96 h. Thus, ENA seems to be a better biomarker than MN for PND induced genotoxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1520–1529, 2016.     

Benefits and risks of pharmacotherapy for dysthymia: a systematic appraisal of the evidence.

BACKGROUND: Dysthymia is a prevalent form of subthreshold depressive disorder, associated with considerable disability and high co-morbidity. This paper systematically appraises the evidence for the efficacy and acceptability of the pharmacological treatment for this condition. METHODS: Randomised, controlled trials evaluating the efficacy of drug therapies for dysthymia were included. A comprehensive search of the literature was performed, aiming to avoid publication bias. Pooled relative risks (RR) and 95% CIs were calculated with the Random Effect Model method. The number needed to treat (NNT) and number needed to harm (NNH) were estimated for statistically significant results. RESULTS: Twenty-five trials were included for the main comparisons. Regarding placebo-controlled trials (n = 16), similar results were obtained in terms of efficacy for different groups of drugs, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other drugs (sulpiride, amineptine, and ritanserin). The pooled RR for treatment response was 0.68 (95% CI 0.57-0.81) for TCA and the NNT was 4.3 (95% CI 3.2-6.5); 0.68 (95% CI 0.56-0.82) for SSRIs (NNT 5.1; 95% CI 3.9-7.7); 0.59 (95% CI 0.48-0.71) for MAOIs (NNT 2.9; 95% CI 2.2-4.3). Other drugs (amisulpride, amineptine and ritanserin) showed similar results. The equivalent efficacy between antidepressants as found in trials where active medications were compared confirmed the efficacy findings from placebo trials. In general, patients treated with a TCA were more likely to report adverse events, compared with placebo and SSRIs. CONCLUSIONS: Pharmacotherapy for dysthymia appears to be an effective short-term treatment for dysthymic disorder. Newer antidepressants are equally effective and have better acceptability than TCAs, although their higher cost must be balanced against this assumed advantage.     

Data mining in pharmacovigilance: the need for a balanced perspective.

Data mining is receiving considerable attention as a tool for pharmacovigilance and is generating many perspectives on its uses. This paper presents four concepts that have appeared in various professional venues and represent potential sources of misunderstanding and/or entail extended discussions: (i) data mining algorithms are unvalidated; (ii) data mining algorithms allow data miners to objectively screen spontaneous report data; (iii) mathematically more complex Bayesian algorithms are superior to frequentist algorithms; and (iv) data mining algorithms are not just for hypothesis generation. Key points for a balanced perspective are that: (i) validation exercises have been done but lack a gold standard for comparison and are complicated by numerous nuances and pitfalls in the deployment of data mining algorithms. Their performance is likely to be highly situation dependent; (ii) the subjective nature of data mining is often underappreciated; (iii) simpler data mining models can be supplemented with 'clinical shrinkage', preserving sensitivity; and (iv) applications of data mining beyond hypothesis generation are risky, given the limitations of the data. These extended applications tend to 'creep', not pounce, into the public domain, leading to potential overconfidence in their results. Most importantly, in the enthusiasm generated by the promise of data mining tools, users must keep in mind the limitations of the data and the importance of clinical judgment and context, regardless of statistical arithmetic. In conclusion, we agree that contemporary data mining algorithms are promising additions to the pharmacovigilance toolkit, but the level of verification required should be commensurate with the nature and extent of the claimed applications.     

Sources,fates, toxicity,and risks of trifluoroacetic acid and its salts: Relevance to substances regulated under the Montreal and Kyoto Protocols

Trifluoroacetic acid (TFA) is a breakdown product of several hydrochlorofluorocarbons (HCFC), regulated under the Montreal Protocol (MP), and hydrofluorocarbons (HFC) used mainly as refrigerants. Trifluoroacetic acid is (1) produced naturally and synthetically, (2) used in the chemical industry, and (3) a potential environmental breakdown product of a large number (>1 million) chemicals, including pharmaceuticals, pesticides, and polymers. The contribution of these chemicals to global amounts of TFA is uncertain, in contrast to that from HCFC and HFC regulated under the MP. TFA salts are stable in the environment and accumulate in terminal sinks such as playas, salt lakes, and oceans, where the only process for loss of water is evaporation. Total contribution to existing amounts of TFA in the oceans as a result of the continued use of HCFCs, HFCs, and hydrofluoroolefines (HFOs) up to 2050 is estimated to be a small fraction (<7.5%) of the approximately 0.2 μg acid equivalents/L estimated to be present at the start of the millennium. As an acid or as a salt TFA is low to moderately toxic to a range of organisms. Based on current projections of future use of HCFCs and HFCs, the amount of TFA formed in the troposphere from substances regulated under the MP is too small to be a risk to the health of humans and environment. However, the formation of TFA derived from degradation of HCFC and HFC warrants continued attention, in part because of a long environmental lifetime and due many other potential but highly uncertain sources.     

Toxicology and the immune system: a perspective.

The relationship of immunology to toxicology has not always been an easy one, and the product of this association, immunotoxicology, has not infrequently been viewed with a certain scepticism by some of those who consider themselves 'classical' toxicologists. A recent meeting of the British Toxicology Society ('Toxicology and the Immune System', New College Oxford, March 21-22, 1991) provided an opportunity for some remedial work toward a wider appreciation of the issues which exercise immunotoxicologists, and the ways in which they are being addressed. It is not the purpose of this short article to provide a comprehensive account of the scientific presentations, but rather to give a perspective, necessarily a personal one, of immunotoxicology in the context of the meeting.     

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

Inflammopharmacology - Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner...     

Standard setting processes and regulations for environmental contaminants in drinking water: State versus federal needs and viewpoints

The primary objective of a standard setting process is to arrive at a drinking water concentration at which exposure to a contaminant would result in no known or potential adverse health effect on human health. The drinking water standards also serve as guidelines to prevent pollution of water sources and may be applicable in some cases as regulatory remediation levels. The risk assessment methods along with various decision making parameters are used to establish drinking water standards. For carcinogens classified in Groups A and B by the United States Environmental Protection Agency (USEPA) the standards are set by using nonthreshold cancer risk models. The linearized multistage model is commonly used for computation of potency factors for carcinogenic contaminants. The acceptable excess risk level may vary from 10(-6) to 10(-4). For noncarcinogens, a threshold model approach based on application of an uncertainty factor is used to arrive at a reference dose (RfD). The RfD approach may also be used for carcinogens classified in Group C by the USEPA. The RfD approach with an additional uncertainty factory of 10 for carcinogenicity has been applied in the formulation of risk assessment for Group C carcinogens. The assumptions commonly used in arriving at drinking water standards are human life expectancy, 70 years; average human body weight, 70 kg; human daily drinking water consumption, 2 liters; and contribution of exposure to the contaminant from drinking water (expressed as a part of the total environmental exposure), 20%. Currently, there are over 80 USEPA existing or proposed primary standards for organic and inorganic contaminants in drinking water. Some of the state versus federal needs and viewpoints are discussed.     

The development and testing of a dermal exposure system for pharmacokinetic studies of administered and ambient water contaminants

INTRODUCTION: In order to investigate the pharmacokinetics of water-borne chemicals while eliminating exposures by other routes, a dermal exposure system was developed to expose the hand and forearm of human subjects. METHODS: The goal was, primarily, to study the dermal pharmacokinetics of methyl tertiary butyl ether (MTBE), a water contaminant, and, secondarily, the ambient disinfection byproducts (DBPs). MTBE is used as a fuel oxygenate and DBPs result from chlorination of drinking water. The DBPs measured in the water and blood of the subjects were chloroform, bromodichloromethane, and dibromochloromethane. The dermal exposure system was constructed of inert and impervious materials. The interface between the glass and Teflon exposure tank and the subject was custom-made of clear Tedlar (polyvinylfluoride) so that the depth of the arm in the media could be monitored. RESULTS: Sampling of the water concentration of the test chemical, MTBE, demonstrated stability over the duration of the exposure. A temperature loss of about 1.5 degrees C occurred over the course of the 1-h exposure. Blood concentrations taken from 14 human subjects before, during, and after the 1-h exposure demonstrated that measurable MTBE and DBPs were absorbed. DISCUSSION: This system has the advantages of maintaining contaminant concentration and exposing an anatomically distinct body region, and the convenience of blood sampling.     

HRT: an analysis of benefits, risks and costs.

A cost-effectiveness analysis of hormone replacement therapy (HRT) was undertaken to assess the relative benefits of different treatment strategies, and to identify which factors most influence cost-effectiveness. The current lack of conclusive evidence on the effects of HRT, especially in relation to combined therapy and cardiovascular disease, necessitated the use of a large number of assumptions in our model. In terms of net health benefits, the potential reduction in cardiovascular disease would have greatest impact, and would overshadow any small increase in breast cancer risk possibly associated with long-term use. Net expenditure by the NHS will depend critically on the direct costs of treatment, rather than on any indirect costs incurred or averted as a result of side-effects. In terms of cost-effectiveness, long-term prophylactic treatment of hysterectomised women and treatment of symptomatic women with a uterus compare favourably with other accepted health care interventions.     

Benefits and risks of fish consumption Part I. A quantitative analysis of the intake of omega-3 fatty acids and chemical contaminants

In recent years, and based on the importance of fish as a part of a healthy diet, there has been a notable promotion of fish consumption. However, the balance between health benefits and risks, due to the intake of chemical contaminants, is not well characterized. In the present study, edible samples of 14 marine species were analyzed for the concentrations of omega-3 fatty acids, as well as a number of metals and organic pollutants. Daily intakes were specifically determined for a standard adult of 70 kg, and compared with the tolerable/admissible intakes of the pollutants, if available. Salmon, mackerel, and red mullet were the species showing the highest content of omega-3 fatty acids. The daily intakes of cadmium, lead, and mercury through fish consumption were 1.1, 2.0, and 9.9 μg, respectively. Dioxins and furans plus dioxin-like polychlorinated biphenyls (PCBs) intake was 38.0 pg WHO-TEQ/day, whereas those of polybrominated diphenyl ethers (PBDEs), polychlorinated diphenyl ethers (PCDEs), polychlorinated naphthalenes (PCNs) and hexachlorobenzene (HCB) were 20.8, 39.4, 1.53, and 1.50 ng/day, respectively. In turn, the total intake of 16 analyzed polycyclic aromatic hydrocarbons (PAHs) was 268 ng/day. The monthly fish consumption limits for human health endpoints based on the intake of these chemical contaminants were calculated for a 70 years exposure. In general terms, most marine species here analyzed should not mean adverse health effects for the consumers. However, the type of fish, the frequency of consumption, and the meal size are essential issues for the balance of the health benefits and risks of regular fish consumption.