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.

Influence of polymorphisms of GSTM1 and GSTT1 for risk of renal cell cancer in workers with long-term high occupational exposure to trichloroethene

Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTM1 and GSTT1 isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTM1 and GSTT1 genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTM1 (GSTM1 +) and 18 at least one functional GSTT1 (GSTT1 +). Among the 48 reference workers, 17 were GSTM1 + and 31 were GSTT1 +. Odds ratios for renal cell cancer were 2.7 for GSTM1 + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI.

Nephrotoxicity and nephrocarcinogenicity of dinitrotoluene : new aspects to be considered

Technical dinitrotoluene (DNT) is a mixture of 2,4- and 2,6-DNT. In humans, industrial or environmental exposure can occur orally, by inhalation, or by skin contact. The classification of DNT as an 'animal carcinogen' is based on the formation of malignant tumors in kidneys, liver, and mammary glands of rats and mice. Clear signs of toxic nephropathy were found in rats dosed with DNT, and the concept was derived of an interrelation between renal toxicity and carcinogenicity. Recent data point to the carcinogenicity of DNT on the urinary tract of exposed humans. Between 1984 and 1997, 6 cases of urothelial cancer and 14 cases of renal cell cancer were diagnosed in a group of 500 underground mining workers in the copper mining industry of the former GDR and having high exposures to explosives containing technical DNT. The incidences of both urothelial and renal cell tumors in this group were 4.5 and 14.3 times higher, respectively, than anticipated on the basis of the cancer registers of the GDR. The genotyping of all identified tumor patients for the polymorphic enzymes NAT2, GSTM1, and GSTT1 identified the urothelial tumor cases as exclusively 'slow acetylates'. A group of 161 miners highly exposed to DNT was investigated for signs of subclinical renal damage. The exposures were categorized semi-quantitatively into 'low', 'medium', 'high', and 'very high'. A straight dose-dependence of the excretion of urinary biomarker proteins with the ranking of exposure was seen. Biomarker excretion (alpha1-microglobulin, glutathione S-transferases alpha and pi) indicated that DNT-induced damage was directed toward the tubular system. New data on DNT-exposed humans appear consistent with the concept of cancer initiation by DNT isomers and the subsequent promotion of renal carcinogenesis by selective damage to the proximal tubule. The differential pathways of metabolic activation of DNT appear to apply to the proximal tubule of the kidney and to the urothelium of the renal pelvis and lower urinary tract as target tissues of carcinogenicity.

Pathological excretion patterns of urinary proteins in miners highly exposed to dinitrotoluene

A cohort of 161 underground miners who had been highly exposed to dinitrotoluene (DNT) in the copper-mining industry of the former German Democratic Republic was reinvestigated for signs of subclinical renal damage. The study included a screening of urinary proteins excreted by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and quantitations of the specific urinary proteins α 1-microglobulin and glutathione-S-transferase α (GST α) as biomarkers for damage of the proximal tubule and glutathione-S-transferase π (GST π) for damage of the distal tubule. The exposures were categorized semiquantitatively (low, medium, high, and very high), according to the type and duration of professional contact with DNT. A straight dose-dependence of pathological protein excretion patterns with the semiquantitative ranking of DNT exposure was seen. Most of the previously reported cancer cases of the urinary tract, especially those in the higher exposed groups, were confined to pathological urinary protein excretion patterns. The damage from DNT was directed toward the tubular system. In many cases, the appearance of Tamm-Horsfall protein, a 105-kD protein marker, was noted. Data on the biomarkers α 1-microglobulin, GST α, and GST π consistently demonstrated a dose-dependent increase in tubular damage, which confirmed the results of screening by SDS-PAGE and clearly indicated a nephrotoxic effect of DNT under the given conditions of exposure. Within the cluster of cancer patients observed among the DNT-exposed workers, only in exceptional cases were normal biomarker excretions found.

Occupational and non-occupational risk factors in bladder cancer patients in an industrialized area located in former East-Germany [Berufliche und außerberufliche Risikofaktoren für das Harnblasenkarzinom in einem ehemaligen Industriegebiet der neuen Bundesländer]

Purpose: Several occupational carcinogens are metabolized by polymorphic enzymes. The distribution of the polymorphic enzymes N-acetyltransferase 2 (NAT2; substrates: aromatic amines), glutathione S-transferase M1 (GSTM1; substrates: e.g., reactive metabolites of polycyclic aromatic hydrocarbons), and glutathione S-transferase T1 (GSTT1; substrates: small molecules with 1-2 carbon atoms) were investigated. Material and Methods: At the urological department in Lutherstadt Wittenberg, 136 patients with a histologically proven transitional cell cancer of the urinary bladder were investigated for all occupations performed for more than 6 months. Several occupational and non-occupational risk factors were asked. The genotypes of NAT2, GSTM1, and GSTT1 were determined from leucocyte DNA by PCR. Results: Compared to the general population in Middle Europe, the percentage of GSTT1 negative persons (22.1 %) was ordinary; the percentage of slow acetylators (59.6%) was in the upper normal range, while the percentage of GSTM1 negative persons (58.8%) was elevated in the entire group. Shifts in the distribution of the genotypes were observed in subgroups who had been exposed to asbestos (6/6 GSTM1 negative, 5/6 slow acetylators), rubber manufacturing (8/10 GSTM1 negative), and chlorinated solvents (9/15 GSTM1 negative). Conclusions: The overrepresentation of GSTM1 negative bladder cancer patients also in this industrialized area and more pronounced in several occupationally exposed subgroups points to an impact of the GSTM1 negative genotype in bladder carcinogenesis. [Article in German]

European aspects of standard setting in occupational hygiene and medicine

Occupational standards concerning the allowable concentrations of chemical compounds in the ambient air of workplaces have been established in several countries at national levels. With the integration of the European Union, a need exists for establishing harmonized Occupational Exposure Limits. For analytical developments, it is apparent that methods for speciation or fractionation of carcinogenic metal compounds will be of increasing practical importance for standard setting. Criteria of applicability under field conditions, cost-effectiveness, and robustness are practical driving forces for new developments. When the European Union issued a list of 62 chemical substances with Occupational Exposure Limits in 2000, 25 substances received a 'skin' notation. The latter indicates that toxicologically significant amounts may be taken up via the skin. Similar notations exist on national levels. For such substances, monitoring concentrations in ambient air will not be sufficient; biological monitoring strategies will gain further importance in the medical surveillance of workers who are exposed to such compounds. Proceedings in establishing legal frameworks for a biological monitoring of chemical exposures within Europe are paralleled by scientific advances in this field. A new aspect is the possibility of a differential adduct monitoring, using blood proteins of different half-life or lifespan. This technique allows differentiation between long-term mean exposure to reactive chemicals and short-term episodes, for example, by accidental overexposure. For further analytical developments, the following issues have been addressed as being particularly important: New dose monitoring strategies, sensitive and reliable methods for detection of DNA adducts, cytogenetic parameters in biological monitoring, methods to monitor exposure to sensitizing chemicals, and parameters for individual susceptibilities to chemical toxicants.

The influence of fleet safety climate on occupational driver behaviours

The concepts of traffic safety culture and climate hold considerable impact on road safety outcomes. Data sourced from four Australian organisations revealed a five factor structure that was consistent with previous research, which were: management commitment; work demands; relationships; appropriateness of rules; and communication. Correlation and regression analyses were conducted to identify which aspects of fleet safety climate were related to driver behaviours. The findings suggest that organisations may be able to reduce the likelihood of employees engaging in unsafe driving behaviours as a result of fatigue or distractions through increasing aspects of fleet safety climate, including: management commitment; level of trust; safety communication; appropriateness of work demands; and appropriateness of safety policies and procedures. To assist practitioners in enhancing fleet safety climate and managing occupational road risks, recommendations are made based on these findings, such as fostering a supportive environment of mutual responsibility.

Alcohol-related emergency department injury presentations in Queensland adolescents and young adults over a 13-year period

Introduction and Aims. The rate of alcohol-related emergency department (ED) presentations in young people has increased dramatically in recent decades. Injuries are the most common type of youth alcohol-related ED presentation, yet little is known about these injuries in young people. This paper describes the characteristics of alcohol-related ED injury presentations in young people over a 13-year period and determines if they differ by gender and/or age group (adolescents: 12–17 years; young adults: 18–24 years). Design and Method. The Queensland Injury Surveillance Unit (QISU) database collects injury surveillance data at triage in participating EDs throughout Queensland, Australia. A total of 4667 cases of alcohol-related injuries in young people (aged 12–24 years) were identified in the QISU database between January 1999 and December 2011, using an injury surveillance code and nursing triage text-based search strategy. Results. Overall, young people accounted for 38% of all QISU alcohol-related ED injury presentations in patients aged 12 years or over. The majority of young adults presented with injuries due to violence and falls, whereas adolescents presented due to self-harm or intoxication without other injury. Males presented with injuries due to violence, whereas females presented with alcohol-related self-harm and intoxication. Discussion and Conclusions. There is a need for more effective ways of identifying the degree of alcohol involvement in injuries among young people presenting to EDs.

Boosting the effects of a curriculum based injury prevention program through a school connectedness intervention : final report to NRMA-ACT Road Safety Trust

Injury is the leading cause of death among young people (AIHW, 2008). A primary contributing factor to injury among adolescents is risk taking behaviour, including road related risks such as risky bicycle and motorcycle use and riding with dangerous or drink-drivers. Injury rates increase dramatically throughout adolescence, at the same time as adolescents are becoming more involved in risk taking behaviour. Also throughout this period, adolescents‟ connectedness to school is decreasing (Monahan, Oesterle & Hawkins, 2010; Whitlock, 2004). School connectedness refers to „the extent to which students feel personally accepted, respected, included, and supported by others in the school‟ (Goodenow, 1993, p. 80), and has been repeatedly shown to be a critical protective factor in adolescent development. For example, school connectedness has been shown to be associated with decreased risk taking behaviour, including violence and alcohol and other drug use (e.g., Resnick et al., 1997), as well as with decreased transport risk taking and vehicle related injuries (Chapman et al., accepted April 2011). This project involved the pilot evaluation of a school connectedness intervention (a professional development program for teachers) to reduce adolescent risk taking behaviour and injury. This intervention has been developed for use as a component of the Skills for Preventing Injury in Youth (SPIY) curriculum based injury prevention program for early adolescents. The objectives of this research were to: 1. Implement a trial School Connectedness intervention (professional development program for teachers) in ACT high schools, and evaluate using comparison high schools. 2. Determine whether the School Connectedness program impacts on adolescent risk taking behaviour and associated injuries (particularly transport risks and injuries). 3. Evaluate the process effectiveness of the School Connectedness program.

Design and test of a custom instrumented leg press for injury and recovery intervention

There is an increasing desire and emphasis to integrate assessment tools into the everyday training environment of athletes. These tools are intended to fine-tune athlete development, enhance performance and aid in the development of individualised programmes for athletes. The areas of workload monitoring, skill development and injury assessment are expected to benefit from such tools. This paper describes the development of an instrumented leg press and its application to testing leg dominance with a cohort of athletes. The developed instrumented leg press is a 45° reclining sled-type leg press with dual force plates, a displacement sensor and a CCD camera. A custom software client was developed using C#. The software client enabled near-real-time display of forces beneath each limb together with displacement of the quad track roller system and video feedback of the exercise. In recording mode, the collection of athlete particulars is prompted at the start of the exercise, and pre-set thresholds are used subsequently to separate the data into epochs from each exercise repetition. The leg press was evaluated in a controlled study of a cohort of physically active adults who performed a series of leg press exercises. The leg press exercises were undertaken at a set cadence with nominal applied loads of 50%, 100% and 150% of body weight without feedback. A significant asymmetry in loading of the limbs was observed in healthy adults during both the eccentric and concentric phases of the leg press exercise (P < .05). Mean forces were significantly higher beneath the non-dominant limb (4–10%) and during the concentric phase of the muscle action (5%). Given that symmetrical loading is often emphasized during strength training and remains a common goal in sports rehabilitation, these findings highlight the clinical potential for this instrumented leg press system to monitor symmetry in lower-limb loading during progressive strength training and sports rehabilitation protocols.

Regulating Occupational Health and Safety in a Changing Labour Market

The traditional boundaries of labour law are becoming outmoded in a modern world in which active labour market participants vastly outnumber “employees”, and the world of work extends way beyond the workplace gate. There is convergence with labour market regulation. The contract of employment remains central but is no longer the sole object of study.