The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1 *0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Genetic susceptibility to environmental toxicants : the interface between human and experimental studies in the development of new toxicological concepts

The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological studies. If applied diligently, these possibilities may be combined to lead to new strategies of human-oriented toxicological research. This overview will present some outstanding examples for such strategies taken from the practically very important field of occupational toxicology. The main focus is placed on the effects of enzyme polymorphisms of the xenobiotic metabolism in association with the induction of bladder cancer and renal cell cancer after exposure to occupational chemicals. Also, smoking and induction of head and neck squamous cell cancer are considered.

Advances in gyro-stabilisation of vessel roll motion

The use of gyro-dynamic forces to counteract the wave-induced roll motion of marine vessels in a seaway was proposed over 100 years ago. These early systems showed a remarkable performance, reporting roll reductions of up to 95% in some sailing conditions. Despite this success, further developments were not pursued since the systems were unable to provide acceptable performance over an extended envelope of sailing and environmental conditions, and the invention of fin roll stabilisers provided a satisfactory alternative. This has been attributed to simplistic controls, heavy drive systems, and large structural mass required to withstand the loads given the low strength materials available at the time. Today, advances in material strength, bearings, motor technology and mechanical design methods, together with powerful signal processing algorithms, has resulted in a revitalized interest in gyro-stabilisers for ships. Advanced control systems have enabled optimisation of restoring torques across a range of wave environments and sailing conditions through adaptive control system design. All of these improvements have resulted in increased spinning speed, lower mass, and dramatically increased stabilising performance. This brief paper provides an overview of recent developments in the design and control of gyro-stabilisers of ship roll motion. In particular, the novel Halcyon Gyro-Stabilisers are introduced, and their performance is illustrated based on a simulation case study for a naval patrol vessel. Given the growing national and global interest in small combatants and patrol vessels, modem gyro-stabilisers may offer a significant technological contribution to the age old problem of comfort and mission operability on small ships, especially at loiter speeds.

A Memetic Algorithm for the location-based continuously operating reference stations placement problem in Network Real-Time Kinematic

Network Real-Time Kinematic (NRTK) is a technology that can provide centimeter-level accuracy positioning services in real time, and it is enabled by a network of Continuously Operating Reference Stations (CORS). The location-oriented CORS placement problem is an important problem in the design of a NRTK as it will directly affect not only the installation and operational cost of the NRTK, but also the quality of positioning services provided by the NRTK. This paper presents a Memetic Algorithm (MA) for the location-oriented CORS placement problem, which hybridizes the powerful explorative search capacity of a genetic algorithm and the efficient and effective exploitative search capacity of a local optimization. Experimental results have shown that the MA has better performance than existing approaches. In this paper we also conduct an empirical study about the scalability of the MA, effectiveness of the hybridization technique and selection of crossover operator in the MA.

Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults

CONTEXT AND OBJECTIVE: Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. DESIGN AND PARTICIPANTS: We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. RESULTS: Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. CONCLUSION: Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

Are we there yet? Early education responding to the challenges of climate disruption and sustainability

We are now in ‘The Critical Decade’ (Steffen & Hughes, 2013) when the world’s peoples must make strong choices if we are to avert the worst impacts of climate disruption. Yet, addressing climate disruption, challenging though this is, is not humanity’s biggest problem – rather, climate disruption is a symptom of unsustainable development models that depend on continuous economic growth that shape how we live.

Geochemistry-based coral palaeoclimate studies and the potential of ‘non-traditional’ (non-massive Porites) corals : recent developments and future progression

Understanding the natural variability of the Earth's climate system and accurately identifying potential anthropogenic influences requires long term, geographically distributed records of key climate indicators, such as temperature and precipitation that extend prior to the last 400. years of the Holocene. Reef corals provide an excellent source of high resolution climate records, and importantly represent the tropical marine environment where palaeoclimate data are urgently required. Recent decades have seen significant improvement in our understanding of coral biomineralisation, the associated uptake of geochemical proxies and methods of identifying and understanding the effects of both early and late, post depositional diagenetic alteration. These processes all have significant implications for interpreting geochemical proxies relevant to palaeoclimatic reconstructions. This paper reviews the current 'state of the art' in terms of coral based palaeoclimate reconstructions and highlights a key remaining problem. The majority of coral based palaeoclimate research has been derived from massive colonies of Porites. However, massive Porites are not globally abundant and may not provide material of a particular age of interest in those regions where they are present. Therefore, there is great potential for alternate coral genera to act as complimentary climate archives. While it remains critical to consider five key factors - vital effects, differential growth morphologies, geochemical heterogeneity in the skeletal ultrastructure, transfer equation selection and diagenetic screening of skeletal material - in order to allow the highest level of accuracy in coral palaeoclimate reconstructions, it is also important to develop alternate taxa for palaeoclimate studies in regions where Porites colonies are absent or rare. Currently as many as nine genera other than Porites have proven at least limited utility in palaeothermometry, most of which are found in the Atlantic/Caribbean region where massive Porites do not exist. Even branching taxa such as Acropora have significant potential to preserve environmental archives. Increasing this capability will greatly expand the number of potential geochemical archives available for longer term temporal records of palaeoclimate.

Investigating the mediating effects of emotional intelligence and coping on problem behaviours in adolescents

This study explored the mediating effect of emotional intelligence (EI) and coping strategies on problem behaviours in Australian adolescents. One hundred and forty-five adolescents (60 boys and 85 girls with a mean age of 12.02 years) completed self-report instruments of EI, stress coping strategies, and problem behaviours. The relationships between Emotional Management and Control and engagement in internalising and externalising behaviours were found to be mediated by the use of non-productive coping strategies. Mediation models of the relationship between problem behaviours and the Understanding Emotions and Emotional Recognition and Expression dimensions were found to be only partially mediated by the engagement in problem-focused and non-productive coping strategies. The results are discussed in regards to how coping strategies utilised in adolescence may produce more or less adaptive patterns of coping during adulthood. The development of emotional abilities may be required to improve coping outcomes for adolescents, which in turn may produce better psychological outcomes for adolescents in the long term.

Work zone items influencing driver speeds at roadworks: worker, driver and expert perspectives

Roadworks are essential to a safe and efficient road network, yet somewhat paradoxically the necessary work is often associated with increased risk to motorists and workers, as well as with traffic flow disruptions. A major source of increased crash risk at roadwork sites (work zones) is poor speed limit compliance. Speeding in work zones is examined in existing literature to the extent that major issues are known and some effective countermeasures are identified. However, as speeding remains a major problem in work zones, influences on driver behaviour arguably need to be better understood to achieve greater compliance and thus realise further gains in road safety. Current research on safety at Queensland roadwork sites has examined the views of workers, measured work zone speed profiles, and conducted an online survey of drivers (N=410). This paper focuses on survey participants’ ratings of 12 specific work zone items (including traffic control measures) in terms of their influence on speed choice. Repeated measures ANOVA revealed statistically significant differences (p<0.001) in the ratings of these items, with the most influential including visible presence of workers, visible police presence, and speed feedback displays. Those rated least influential included ’roadwork speed limits are enforced’ and ‘reduce speed’ signs and increased fines for speeding in work zones. The paper considers the alignment of these findings with those from other sources, including worker interviews and the literature, to provide a consolidated assessment of the influence of work zone items on driver speeds.

“This is not a burning issue for me”: How citizens justify their use of wood heaters in a city with a severe air pollution problem

Although wood smoke pollution has been linked to health problems, wood burning remains a popular form of domestic heating in many countries across the world. In this paper, we describe the rhetoric of resistance to wood heater regulation amongst citizens in the regional Australian town of Armidale, where wood smoke levels regularly exceed national health advisory limits. We discuss how this is related to particular sources of resistance, such as affective attachment to wood heating and socio-cultural norms. The research draws on six focus groups with participants from households with and without wood heating. With reference to practice theory, we argue that citizen discourses favouring wood burning draw upon a rich suite of justifications and present this activity as a natural and traditional activity promoting comfort and cohesion. Such discourses also emphasise the identity of the town as a rural community and the supposed gemeinschaft qualities of such places. We show that, in this domain of energy policy, it is not enough to present ‘facts’ which have little emotional association or meaning for the populace. Rather, we need understand how social scripts, often localised, inform identity and practice.

How Modern Governments Made Prostitution a Social Problem: Creating a Responsible Prostitute Population

Table of Contents Acknowledgments Preface by Dr. Pat Carlen Introduction 1. Political Languages of Prostitution 2. Genealogical Analysis: Documenting The Disorder of Things 3. From Death Rituals to Health Practices 4. Policing Female Prostitutes 5. Private Remedies for Public Concerns 6. The Emergence of the Male Prostitute 7. From Procreation to Pleasure 8. HIV/AIDS and Prostitution Conclusion Bibliography Index

‘Children Ask the Damnedest Questions’: Sex(uality) Education as a Social Problem

Perspectives in Human Sexuality is an overview of key debates, research findings and theories in the area of sex and sexuality. This textbook written especially for undergraduate students offers a detailed and comprehensive introduction to sex and sexuality from an Australian and New Zealand perspective. It examines controversial issues such as sex and age, sex work and gay, lesbian and queer sex in a fair and balanced manner.

Sustainability in infrastructure investment : building the business case

Many infrastructure agencies adopt sustainability objectives at a corporate level and incorporate sustainability targets and indicators as part of corporate reporting processes. These objectives are expected to translate to all stages of the project delivery process, including project selection. For infrastructure capital works projects and programs, a robust project management approach involves the development of a business case to guide investment decision making. A key tool in the assessment of project options and selection of a delivery strategy is Cost Benefit Analysis (CBA). Infrastructure providers are required to undertake cost benefit analysis to support project selection through regulatory approval and budgetary processes. This tool has emerged through the prism of economic analysis rather than sustainability. A literature review reveals the limitations of CBA alone to effectively evaluate economic, environmental and social externalities or impacts that apply over a long time frame, and that are ultimately irreversible. Multi-Criteria Analysis (MCA) has been introduced as a means to incorporate a wider array of factors into decision making such as sustainability. This, however, presents new challenges with issues around how to transparently represent wider community values in the selection of a preferred solution. Are these tools effective in assessing the wider sustainability costs and benefits taking into account that these are public works with long life spans and significant impacts across institutional boundaries? The research indicates a need to develop clear guidelines for investment decision making in order to better align with corporate sustainability objectives. Findings from the literature review indicate that a more sustainable approach to investment decision-making framework should include: the incorporation of sustainability goals from corporate planning documents; problem definition and option generation using best practice investment management guidelines; improved guidelines for Business Case development using a combination of both Cost Benefit Analysis and Multi-Criteria Analysis; and an integrated public participation process.

Making climate change manageable : how accounting constructs new power-knowledge regimes

This paper examines the modern power of accounting to permeate new spheres and create new objects by examining how climate change becomes a new category for accounting’s attention. It outlines the socio-political problem space where accounting and climate change connect by tracing the emergence of the UK’s Climate Change Act (2008) to a specifically modern calculating attitude described here as ‘managing by the numbers’. It suggests the intersection of accounting and climate change was made possible by accounting’s role in tying disciplinary subjectivities and objectivities together whilst operating simultaneously at the level of individuals, organisations and government. Such that when faced with new unknowns we revert to previous ways of managing we have come to know and experienced throughout our formative years in schools, hospitals, firms and government departments. In this way, accounting’s emergence in the domain of managing climate change implies a transformation that cannot be explained merely as a practical response to a global warming problem, but rather as an example of a new power-knowledge regime that makes possible the management and control of a new organisational phenomenon called climate change.