In Silico Assessment of Acute Oral Toxicity for Mixtures.

While exposure of humans to environmental hazards often occurs with complex chemical mixtures, the majority of existing toxicity data are for single compounds. The Globally Harmonized System of chemical classification (GHS) developed by the Organization for Economic Cooperation and Development uses the additivity formula for acute oral toxicity classification of mixtures, which is based on the acute toxicity estimate of individual ingredients. We evaluated the prediction of GHS category classifications for mixtures using toxicological data collected in the Integrated Chemical Environment (ICE) developed by the National Toxicology Program (United States Department of Health and Human Services). The ICE database contains in vivo acute oral toxicity data for ∼10,000 chemicals and for 582 mixtures with one or multiple active ingredients. By using the available experimental data for individual ingredients, we were able to calculate a GHS category for only half of the mixtures. To expand a set of components with acute oral toxicity data, we used the Collaborative Acute Toxicity Modeling Suite (CATMoS) implemented in the Open Structure-Activity/Property Relationship App to make predictions for active ingredients without available experimental data. As a result, we were able to make predictions for 503 mixtures/formulations with 72% accuracy for the GHS classification. For 186 mixtures with two or more active ingredients, the accuracy rate was 76%. The structure-based analysis of the misclassified mixtures did not reveal any specific structural features associated with the mispredictions. Our results demonstrate that CATMoS together with an additivity formula can be used to predict the GHS category for chemical mixtures.

Time extrapolation in regulatory risk assessment: The impact of study differences on the extrapolation factors.

In human risk assessment, time extrapolation factors (EFs) account for differences in exposure duration of experimental studies. We calculated EFs based on N(L)OEL (no (lowest) observed effect level) ratios, dividing shorter-term by longer-term values. The 'oral' datasets comprised 302 EFs (subacute-subchronic) and 1059 EFs (subchronic-chronic). The 'inhalation' datasets contained 67 EFs (subacute-subchronic) and 226 EFs (subchronic-chronic). The experimental EF distribution oral:subchronic-chronic showed that study parameters like deviation in dose selection and spacing influence mainly the data variance. Exclusion of these influences led to a dataset representing more realistically the difference of N(L)OELs with prolonged treatment. This dataset showed a GM of 1.5, indicating that the impact of a longer treatment period on the study N(L)OEL is on average not high. A factor of 1.5 seemed to be also sufficiently conservative for subacute-subchronic and subchronic-chronic extrapolation (inhalation or oral exposure). EFs for groups of similar compounds did not differ, but for compounds with low and high NOEL values. Relatively toxic compounds (GM 1) might thus not require time extrapolation. Within and between chemical variance was analysed in the dataset oral:subchronic-chronic (GSD 4.8). The variance between chemicals should be considered within extrapolation by selecting an appropriate percentile for which a chemical variance factor is suggested. In risk assessment, often a combination of EFs is required. Our analysis indicates that such a combination will result in an accumulation of non-toxicological variance and therefore unrealistically high EFs. Further evaluations are needed to identify appropriate chemical variance factors for these situations.

Accelerating the Pace of Chemical Risk Assessment.

Changes in chemical regulations worldwide have increased the demand for new data on chemical safety. New approach methodologies (NAMs) are defined broadly here as including in silico approaches and in chemico and in vitro assays, as well as the inclusion of information from the exposure of chemicals in the context of hazard [European Chemicals Agency, " New Approach Methodologies in Regulatory Science ", 2016]. NAMs for toxicity testing, including alternatives to animal testing approaches, have shown promise to provide a large amount of data to fill information gaps in both hazard and exposure. In order to increase experience with the new data and to advance the applications of NAM data to evaluate the safety of data-poor chemicals, demonstration case studies have to be developed to build confidence in their usability. Case studies can be used to explore the domains of applicability of the NAM data and identify areas that would benefit from further research, development, and application. To ensure that this science evolves with direct input from and engagement by risk managers and regulatory decision makers, a workshop was convened among senior leaders from international regulatory agencies to identify common barriers for using NAMs and to propose next steps to address them. Central to the workshop were a series of collaborative case studies designed to explore areas where the benefits of NAM data could be demonstrated. These included use of in vitro bioassays data in combination with exposure estimates to derive a quantitative assessment of risk, use of NAMs for updating chemical categorizations, and use of NAMs to increase understanding of exposure and human health toxicity of various chemicals. The case study approach proved effective in building collaborations and engagement with regulatory decision makers and to promote the importance of data and knowledge sharing among international regulatory agencies. The case studies will be continued to explore new ways of describing hazard (i.e., pathway perturbations as a measure of adversity) and new ways of describing risk (i.e., using NAMs to identify protective levels without necessarily being predictive of a specific hazard). Importantly, the case studies also highlighted the need for increased training and communication across the various communities including the risk assessors, regulators, stakeholders (e.g., industry, non-governmental organizations), and the general public. The development and application of NAMs will play an increasing role in filling important data gaps on the safety of chemicals, but confidence in NAMs will only come with learning by doing and sharing in the experience.

Effect of reduced use of organic solvents on disability pension in painters.

OBJECTIVE: To investigate whether the decreased use of paints based on organic solvents has caused a decreased risk for neuropsychiatric disorders in painters by studying their incidence in disability pensions. METHODS: The incidence of disability pension in Swedish painters who had participated in health examinations between 1971 and 1993 was studied through linkage with Swedish registers of disability pension over 1971-2010 and compared with the incidence in other construction workers as woodworkers, concrete workers and platers. When phasing out began in the 1970s, about 40% of paints were based on organic solvents and it had decreased to 4% in 1990s. The analysis was adjusted for age, time period, body mass index and smoking. RESULTS: The painters (n=23 065) had an increased risk of disability pension due to neurological diagnosis (n=285, relative risk (RR) 1.92, 95% CI 1.67 to 2.20) and psychiatric diagnosis (n=632, RR=1.61, 95 % CI 1.42 to 1.82). For neurological disorders there was a time trend with a continuously decreasing risk from 1980 onwards, but there was no such trend for psychiatric disorders. CONCLUSIONS: High exposure to organic solvents increased the risk for disability pension in neurological disorders, and the risk decreased when the use of organic solvents decreased. The painters also had an increased risk of disability pension due to psychiatric disorders, but the causes have to be further investigated.

Effectiveness and cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children (The BEEP trial): protocol for a randomised controlled trial.

BACKGROUND: Atopic eczema (AE) is a common skin problem that impairs quality of life and is associated with the development of other atopic diseases including asthma, food allergy and allergic rhinitis. AE treatment is a significant cost burden for health care providers. The purpose of the trial is to investigate whether daily application of emollients for the first year of life can prevent AE developing in high-risk infants (first-degree relative with asthma, AE or allergic rhinitis). METHODS: This is a protocol for a pragmatic, two-arm, randomised controlled, multicentre trial. Up to 1400 term infants at high risk of developing AE will be recruited through the community, primary and secondary care in England. Participating families will be randomised in a 1:1 ratio to receive general infant skin-care advice, or general skin-care advice plus emollients with advice to apply daily to the infant for the first year of life. Families will not be blinded to treatment allocation. The primary outcome will be a blinded assessment of AE at 24 months of age using the UK Working Party Diagnostic Criteria for Atopic Eczema. Secondary outcomes are other definitions of AE, time to AE onset, severity of AE (EASI and POEM), presence of other allergic diseases including food allergy, asthma and hay fever, allergic sensitisation, quality of life, cost-effectiveness and safety of the emollients. Subgroup analyses are planned for the primary outcome according to filaggrin genotype and the number of first-degree relatives with AE and other atopic diseases. Families will be followed up by online and postal questionnaire at 3, 6, 12 and 18 months with a face-to-face visit at 24 months. Long-term follow-up until 60 months will be via annual questionnaires. DISCUSSION: This trial will demonstrate whether skin-barrier enhancement through daily emollient for the first year of life can prevent AE from developing in high-risk infants. If effective, this simple and cheap intervention has the potential to result in significant cost savings for health care providers throughout the world by preventing AE and possibly other associated allergic diseases. TRIAL REGISTRATION: ISRCTN registry; ID: ISRCTN21528841 . Registered on 25 July 2014.

[Persistent organic contaminants in food : Exposure, hazard potential, and health assessment]. / Persistente organische Kontaminanten in Lebensmitteln : Exposition, Gefährdungspotenzial und gesundheitliche Bewertung.

Environmental emissions of organic contaminants are caused by man-made and natural combustion processes, industrial production facilities, and the release from products. Food represents the main source of human exposure for some of these compounds. This is the case for three groups of persistent organic contaminants: (1) per- and polyfluoroalkyl substances (PFAS), (2) polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and for (3) polycyclic aromatic hydrocarbons (PAHs). The issues regarding PCDD/F emissions were already recognized as a problem in the 1970s and have since then been effectively regulated; the impact of PFAS as global anthropogenic environmental contaminants was identified much later.A system of toxicity equivalency factors (TEF system) was established for the assessment of the toxic potency of a mixed exposure to PCDD/F and certain PCBs. For the health assessment and regulation of PAHs and PFAS, no such system has been implemented so far. For PFAS, a re-evaluation of the present tolerable daily intake values (TDI values) is currently being discussed, as new insights into toxicology and epidemiology have been gained.The persistence in the environment of the compound groups discussed here leads to entry into the food chain over long periods of time, even if access into the environment is minimized. This requires a long-term continuation of the monitoring of food stuffs and forward-looking risk assessment approaches and regulatory measures.

Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development.

Management of organic non-mutagenic impurities (NMIs) in medicinal products is regulated by the ICH Q3A, B and C guidelines that are applicable at late stages of clinical development (Phase III onwards) and as a consequence there is no guidance for the assessment and control of NMIs in early clinical trials. An analysis of several key in vivo toxicology databases supports the ICH Q3A defined concept that a lifetime dose to 1 mg/day of a NMI would not represent a safety concern to patients. In conjunction with routine (Q)SAR approaches, this 1 mg/day value could be used as a universal qualification threshold for a NMI during any stage of clinical development. This analysis also proposes that modification of this 1 mg/day dose using an established methodology (i.e. Modified Haber's Law) could support 5 mg/day or 0.7% (whichever is lower) as an acceptable limit for a NMI in a drug substance or product in early clinical studies (<6 months). Given the controlled nature of clinical development and the knowledge that most toxicities are dose and duration dependent, these proposed NMI limits provide assurance of patient safety throughout clinical development, without the requirement to commission dedicated in vivo toxicology impurity qualification studies.

The safety and efficacy of Diphoterine for ocular and cutaneous burns in humans.

CONTEXT: Diphoterine, developed by the French company Prevor, is a polyvalent, chelating, amphoteric and slightly hypertonic solution used in the management of chemical cutaneous and ocular burns. While used extensively in Europe and Canada, it is has not been approved by the United States Occupational Safety and Health Administration (OSHA) as an alternative to the water-rinse method due to a lack of evidence of its safety and efficacy on human subjects. An unbiased and extensive systematic review was undertaken in order to better understand Diphoterine's safety and efficaciousness on humans. OBJECTIVE: Review the safety and efficacy of Diphoterine for treating chemical burns of the skin and eyes in humans. METHODS: Data sources: Information sources included Pubmed, the National Library of Medicine's Medline Database and the "Publications" sections of the Prevor website. Search terms included Diphoterine, chemical burn, ocular burn and cutaneous burn. STUDY SELECTION: Any study type published through a peer-reviewed journal up to May 2016 was considered eligible. Published data must have included Diphoterine in the treatment of chemical burns on the skin or eyes as well as meet other specified criteria. Acceptable studies had to use either a quantitative (e.g. number of work days lost) or qualitative (e.g. level of erythema) approach when measuring cutaneous or ocular lesion outcomes. DATA EXTRACTION: Independent assessment of article inclusion by two authors using predefined criteria. RESULTS AND CONCLUSION: Diphoterine is safe and highly effective in improving healing time, healing sequelae and pain management of chemical burns on the skin and eyes of humans. Outcomes are significantly improved when compared to water or a physiologic solution equivalent. We recommend that this product be readily available to emergency responders and companies that expose their employees to hazardous chemical substances in order to improve healing sequelae, pain management and lost work days from these types of burns.

New approaches in human health risk assessment.

Studies on the precise impact of environmental pollutants on human health are difficult to undertake and interpret, because many genetic and environmental factors influence health at the same time and to varying degrees. Our chapter in the AMAP report was based on new approaches to describe risks and future needs. In this paper, we will introduce the issues associated with risk assessment of single chemicals, and present suggestions for future studies as well as a summary of lessons learned during the health-related parts of the European Union-funded FP7 project ArcRisk (Arctic Health Risks: Impacts on health in the Arctic and Europe owing to climate-induced changes in contaminant cycling, 2009-2014; www.arcrisk.eu).

The Monte Carlo technique as a tool to predict LOAEL.

Quantitative structure - activity relationships (QSARs) for the Lowest Observed Adverse Effect Level (LOAEL) for a large set of organic compounds (n = 341) are suggested. The molecular structures of these compounds are represented by Simplified Molecular Input-Line Entry Systems (SMILES). A criteria for the estimation quality of split into the "visible" training set (used for developing a model) and "invisible" external validation set is suggested. The correlation between the above criterion and the predictive potential of developed QSAR model (root-mean-square error for "invisible" validation set) has been detected. One-variable models are built up for several different splits into the "visible" training set and "invisible" validation set. The statistical quality of these models is quite good. Mechanistic interpretation and the domain of applicability for these models are defined according to probabilistic point of view. The methodology for defining applicability domain in QSAR modeling with SMILES notation based optimal descriptors is presented.

Implications for public health demands alternatives to inorganic and synthetic flocculants: bioflocculants as important candidates.

Chemical flocculants are generally used in drinking water and wastewater treatment due to their efficacy and cost effectiveness. However, the question of their toxicity to human health and environmental pollution has been a major concern. In this article, we review the application of some chemical flocculants utilized in water treatment, and bioflocculants as a potential alternative to these chemical flocculants. To the best of our knowledge, there is no report in the literature that provides an up-to-date review of the relevant literature on both chemical flocculants and bioflocculants in one paper. As a result, this review paper comprehensively discussed the various chemical flocculants used in water treatment, including their advantages and disadvantages. It also gave insights into bioflocculants production, challenges, various factors influencing their flocculating efficiency and their industrial applications, as well as future research directions including improvement of bioflocculants yields and flocculating activity, and production of cation-independent bioflocculants. The molecular biology and synthesis of bioflocculants are also discussed.

[Gas chromatography-mass spectrometric studies of volatile emissions from plants for the assessment of the effectiveness and chemical safety of the implementation of environment improving phytotechnologies].

The chromato-mass-spectrometric studies of volatile emissions of fresh-cut roses have revealed the persistence of wide range of organic compounds. The most large content was consist of terpene hydrocarbons. The contribution of oxygen-containing components (alcohols, ethers, aldehydes and ketones) varied in wide ranges in dependence on the content of the feeding solution. The significant part of plants ' volatiles has no hygienic norm. Among the substances released into the air space ofpremises with volatile emissions ofplants, a significant part has not hygienic standards. Purposeful change in composition of the mixture of volatile organic compounds released by the plants, in the combination with chemical-analytical control of the content of these substances by gas chromatography-mass spectrometry in terms of ecological and hygienic aspects may be useful in the development, use and determination of the optimal conditions of the implementation of environment improving phytotechnologies and evaluation of the efficacy and safety of their impact on public health.

The importance of indicators in monitoring water quality according to European directives.

Directive 2000/60/EC and subsequent legislation provide a list of priority substances to be measured and monitored in EU water bodies and require the adoption of analytical methods that ensure comparability of the data collected in all Member States. These regulations and standards have gradually improved water quality in the EU. However, new drugs, whose effects on ecosystems and health are still to be determined, are detected with growing frequency. The Member States are now called upon to characterize and monitor these pollutants in view of their possible inclusion in the priority substance list.

Future human health research directions for the Canadian Northern Contaminants Program.

Studies conducted in the mid-1980s and early 1990s demonstrated that persistent organic pollutants (POPs) and metals were reaching the Arctic ecosystem at unexpectedly high levels, many of which had no Arctic or Canadian sources. Epidemiological and toxicological studies in Canada and in other countries have found that these contaminants may pose a risk to human health. The objective of this paper is to provide the foundation for the discussion on future northern human health research under the Northern Contaminants Program (NCP) in Canada. This short discussion of human health priorities will help guide a path forward for future northern human health research in Canada to address on-going and new health concerns related to contaminants exposure in the Canadian Arctic.

Assessment of time to pregnancy and spontaneous abortion status following occupational exposure to organic solvents mixture.

PURPOSE: Due to increasing usage of chemicals in various industries, occupational exposure of women with these materials is unavoidable. Nowadays, some studies indicate adverse effects of exposure to these chemicals, especially organic solvents on the reproductive system of females. This study aimed to assess the relationship between spontaneous abortion and occupational exposure to organic solvents mixture in pharmaceutical industry. METHODS: This study was carried out in a pharmaceutical factory located in the suburb of Tehran in 2010. During the study, married women who were working in the factory laboratory units and had exposure to mixed organic solvents were compared with married women who were working in the packing units of the factory without occupational exposure to organic solvents in terms of spontaneous abortion frequency and duration of pregnancy using statistical methods. RESULTS: In this study, the frequency of spontaneous abortion in employees with and without exposure to organic solvents mixture was 10.7 and 2.9% respectively. This study showed that even after adjustment for confounding factors, there was a significant correlation between spontaneous abortion and occupational exposure to organic solvents mixture and this correlation increased with increasing levels of exposure to organic solvents. Also, a significant correlation was observed between occupational exposure to mixed organic solvents and waiting time to become pregnant (TTP). Furthermore, this study showed that even after adjustment for confounding variables, shift workers were significantly more affected by spontaneous abortion compared to daytime workers (P < 0.001). Also, in our study, synergistic effect between shift working and occupational exposure to organic solvents mixture on spontaneous abortion was seen. CONCLUSIONS: According to the results of this study, since there is probability of spontaneous abortion resulting from occupational exposure to various chemicals including organic solvents, recommendation to review the status of occupational exposure of workers can be helpful in improving fertility consultations and reproductive health.

Indicators as a tool for the evaluation of effective national implementation of the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

This paper briefly outlines the United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and what is meant by GHS implementation in terms of policy-related information for decision-makers plus a framework of actions to enable such policies to be effectively undertaken. The paper discusses the need for simple indicators to measure progress with GHS implementation. Two groups of indicators have been described that comprehensively reflect basic components of GHS implementation. The first group was presented as aggregated indicators or indices, for national capability evaluation. Indicators to evaluate management performance linked to stated objectives were presented as the second group. Information from an Organisation for Economic Co-operation and Development (OECD) published questionnaire on GHS implementation and a questionnaire by the Intergovernmental Forum on Chemical Safety (IFCS) on chemical safety that included GHS have provided the basic information for applying the management capability indicators approach. Through the use of information in these two questionnaires, country-relevant and regional progress with GHS implementation was illustrated. Despite the GHS implementation target of 2008 set by the Johannesburg Plan of Implementation, very few countries have reported they have achieved this target. The simple management indicators proposed in this paper are based on adoption of a questionnaire and a numerical scoring system that could be used to chart progress towards GHS implementation. It was concluded, therefore, that the use of indicators as described in this paper does provide a quick survey of the overall situation in a country and facilitates comparison between countries across regions in terms of GHS implementation. Furthermore such results may indicate which countries require additional assistance with GHS implementation thus strengthening policies and actions across all sectors and involving governments, business, trade, and civil society.

Dechlorination by ultraviolet radiation: a suitable alternative to activated carbon in dialysis water systems?

Chlorine-based products are widely used in the water supply industry, and the potential for adverse effects in the haemodialysis setting is well documented. To date, the most commonly used method of chlorine removal has been granular activated carbon filters. An increasingly popular method of dechlorination is the use of high intensity, broad-spectrum UV systems to reduce both free chlorine and combined chlorine compounds (chloramines) into easily removed by-products. UV radiation has been successfully used in the pharmaceutical and food industries to destroy free chlorine and/or chloramines present in water, and kill all known spoilage microorganisms including bacteria, viruses, yeasts and moulds (and their spores). This nonchemical method can offer significant advantages and benefits compared to conventional dechlorination technologies currently employed in dialysis water systems. Whilst UV treatment at 254 nm wavelength has been routinely used for disinfection purposes in dialysis water systems, this paper considers whether UV radiation can be used as an alternative to more traditional methods of chlorine removal.

Radiocarbon-based assessment of fossil fuel-derived contaminant associations in sediments.

Hydrophobic organic contaminants (HOCs) are associated with natural organic matter (OM) in the environment via mechanisms such as sorption or chemical binding. The latter interactions are difficult to quantitatively constrain, as HOCs can reside in different OM pools outside of conventional analytical windows. Here, we exploited natural abundance variations in radiocarbon (14C) to trace various fossil fuel-derived HOCs (14C-free) within chemically defined fractions of contemporary OM (modern 14C content) in 13 samples including marine and freshwater sediments and one dust and one soil sample. Samples were sequentially treated by solvent extraction followed by saponification. Radiocarbon analysis of the bulk sample and resulting residues was then performed. Fossil fuel-derived HOCs released by these treatments were quantified from an isotope mass balance approach as well as by gas chromatography-mass spectrometry. For the majority of samples (n = 13), 98-100% of the total HOC pool was solvent extractable. Nonextracted HOCs are only significant (29% of total HOC pool)in one sample containing p,p-2,2-bis(chlorophenyl)-1,1,1-trichloroethane and its metabolites. The infrequency of significant incorporation of HOCs into nonextracted OM residues suggests that most HOCs are mobile and bioavailable in the environment and, as such, have a greater potential to exert adverse effects.

Environmental policies, politics, and community risk perception: case study of community contamination in Casper, Wyoming.

OBJECTIVES: We identify and explain factors that affected a community's perception of risk due to extensive industrial contamination and people's distrust of government agencies regarding the environmental investigations. METHODS: Intrinsic bounded case study methodology was used to conduct research about extensive environmental contaminations due to activities of an oil refinery in North Casper, Wyoming, and the citizens' response. Data were collected from multiple sources that included public testimonies, observations, public hearings and meetings minutes, newspaper articles, archived records obtained from federal and state environmental and health agencies, as well as industry records obtained through Freedom of Information Act (FOIA) requests. FINDINGS: The overarching theme that emerged was lack of trust due to several critical events and factors such as no response or delay in response time to community concerns, lack of transparency, perceived cover up, vague and fragmented communication by government and state officials, perception of pro-industry stance, and perceived unfair treatment. DISCUSSION AND CONCLUSION: People's perception of environmental risks and their willingness to accept official explanations and outcomes of environmental investigations are strongly affected by their direct experiences with government agencies and the evidence of influence the powerful industries exert over relevant investigations. The government cannot successfully address public and community concerns about environmental health impacts of contaminations and in turn the public perception of risk unless it adopts and implements policies, procedures, and protocols that are clear, timely, transparent, and free from industry influence.