A refined QSAR model for prediction of chemical asthma hazard.

BACKGROUND: A previously developed quantitative structure-activity relationship (QSAR) model has been extern ally validated as a good predictor of chemical asthma hazard (sensitivity: 79-86%, specificity: 93-99%). AIMS: To develop and validate a second version of this model. METHODS: Learning dataset asthmagenic chemicals with molecular weight (MW) <1 kDa were identified from reports published in the peer-reviewed literature before the end of 2012. Control chemicals for which no reported case(s) of occupational asthma had been identified were selected at random from UK and US occupational exposure limit tables. MW banding was used in an attempt to categorically match the control group for MW distribution of the asthmagens. About 10% of chemicals in each MW category were excluded for use as an external validation set. An independent researcher utilized a logistic regression approach to compare the molecular descriptors present in asthmagens and controls. The resulting equation generated a hazard index (HI), with a value between zero and one, as an estimate of the probability that the chemical had asthmagenic potential. The HI was determined for each compound in the external validation set. RESULTS: The model development sets comprised 99 chemical asthmagens and 204 controls. The external validation showed that using a cut-point HI of 0.39, 9/10 asthmagenic (sensitivity: 90%) and 23/24 non-asthmagenic (specificity: 96%) compounds were correctly predicted. The new QSAR model showed a better receiver operating characteristic plot than the original. CONCLUSIONS: QSAR refinement by iteration has resulted in an improved model for the prediction of chemical asthma hazard.

Isocyanate exposure and asthma in the UK vehicle repair industry.

BACKGROUND: Organic diisocyanates are a common cause of occupational asthma, particularly in motor vehicle repair (MVR) workers. The UK Health & Safety Laboratory provides screening for urinary hexamethylenediamine (UHDA), a biomarker of exposure to 1,6-hexamethylene diisocyanate (HDI). The UK Surveillance of Work-related and Occupational Respiratory Disease scheme (SWORD) has collected reports of occupational asthma since 1996. AIMS: To compare trends in HDI exposure with trends in the incidence of work-related asthma attributed to isocyanates or paint spraying in MVR workers reported to SWORD. METHODS: Two-level regression models were used to estimate trends in UHDA levels and work-related asthma in MVR workers reported to SWORD. The direction and magnitude of the trends were compared descriptively. RESULTS: From 2006 to 2014, there was a significant decline in the number of urine samples with detectable levels of UHDA (odds ratio = 0.96; 95% confidence intervals 0.94-0.98) and minimal change in those over the guidance value (1.03; 1.00-1.06). Over the same period, there was a significant decline in all asthma cases attributed to isocyanates or paint spraying reported to SWORD (0.90; 0.86-0.94) and a non-significant decline among MVR workers (0.94; 0.86-1.02). CONCLUSIONS: The simultaneous decrease in HDI exposure and incident cases of asthma reported to SWORD is temporally consistent with a reduction in exposure to airborne isocyanate leading to a reduction in asthma. Although this is not direct evidence of a causal relationship between the two trends, it is suggestive.

The impact of national-level interventions to improve hygiene on the incidence of irritant contact dermatitis in healthcare workers: changes in incidence from 1996 to 2012 and interrupted times series analysis.

BACKGROUND: Reducing healthcare-associated infections (HCAI) has been a priority in the U.K. over recent decades and this has been reflected in interventions focusing on improving hygiene procedures. OBJECTIVES: To evaluate whether these interventions coincided with an increased incidence of work-related irritant contact dermatitis (ICD) attributed to hand hygiene or/and other hygiene measures in healthcare workers (HCWs). METHODS: A quasi-experimental (interrupted time series) design was used to compare trends in incidence of ICD in HCWs attributed to hygiene before and after interventions to reduce HCAI with trends in the same periods in control groups (ICD in other workers). Cases of ICD reported to a U.K. surveillance scheme from 1996 to 2012 were analysed. The time periods compared were defined objectively based on the dates of the publication of national evidence-based guidelines, the U.K. Health Act 2006 and the Cleanyourhands campaign. RESULTS: The reported incidence of ICD in HCWs attributed to hygiene has increased steadily from 1996 to 2012 [annual incidence rate ratio (95% confidence interval): hand hygiene only 1.10 (1.07-1.12); all hygiene 1.05 (1.03-1.07)], whereas the incidence in other workers is declining. An increase in incidence of ICD in HCWs attributed to hand hygiene was observed at the beginning of the Cleanyourhands campaign. CONCLUSIONS: The increasing incidence of ICD in HCWs combined with the popularity of interventions to reduce HCAI warrants increased efforts towards identifying products and implementing practices posing the least risk of ICD.

Occupational allergic contact dermatitis and major allergens in France: temporal trends for the period 2001-2010.

BACKGROUND: Occupational allergic contact dermatitis (OACD) is one of the most common occupational skin diseases in developed countries, but data about its temporal trends in incidence remain sparse. OBJECTIVES: The aim of this study is to describe OACD trends in terms of industrial activities and main causal agents in France over the period 2001-2010. MATERIALS AND METHODS: Data were collected from the French National Network of Occupational Disease Vigilance and Prevention (RNV3P, Réseau National de Vigilance et de Prévention des Pathologies Professionnelles). All OACD considered probably or certainly associated with an occupational exposure were included in the study. Trends were examined (i) on annual crude numbers of OACD and (ii) on reported odds ratios of OACD calculated using logistic regression models. RESULTS: Overall, 3738 cases of OACD were reported and the mean age of OACD cases was 35 years, 52% being women. The most frequent occupations were hairdressers, health care workers, cleaning staff and masons. The total number of OACD cases remained stable over the study period, but increases in OACD related to isothiazolinones (P = 0·002), epoxy resins (P = 0·012) and fragrances (P = 0·005) were observed. Conversely, decreases were noted for cement compounds (P = 0·002) and plant products (P = 0·031). These trends highlight specific sectors and exposures at risk of OACD. CONCLUSIONS: Trends in OACD depend on the nature of exposure. Observed decreases were consistent with prevention measures taken during the study period, and the increases observed serve to highlight those areas where preventative efforts need to be made to reduce skin allergies in the workplace.

Assessing the impact of national level interventions on workplace respiratory disease in the UK: part 2--regulatory activity by the Health and Safety Executive.

OBJECTIVE: To investigate whether interventions implemented by the UK Health and Safety Executive addressing exposure to isocyanate-based spray paints in motor vehicle repair (MVR), flour dust in craft bakeries, rosin-based solder flux fume (RBSFF) in the electronics industry, metalworking fluids and wood dust coincided with a decline in incidence of work-related short latency respiratory disease (SLRD) or asthma in the target groups. METHOD: Changes in the incidence of SLRD reported to a UK-based surveillance scheme were compared using a longitudinal, negative binomial regression model with ß distributed random effects. An interrupted time series design was used and comparisons according to inclusion or exclusion in the target group were made by including a statistical interactions expressed as a ratio of incidence rate ratios (RIRRs) in the model. RESULTS: The incidence of SLRD attributed to flour dust significantly increased relative to all other agents (RIRR: 1.10; 95% CI 1.06 to 1.16) whereas SLRD attributed to RBSFF significantly declined relative to all other agents (0.94; 0.90 to 0.99). No significant changes in the incidence of SLRD attributed to wood dust (1.03; 0.91 to 1.16) or spray paints (1.03; 0.95 to 1.11) relative to all other agents were observed. A higher proportion of reports originated from the industries targeted by the intervention for RBSFF (65/107; 61%) than spray painting (27/93; 27%) or wood dust (16/42; 38%). CONCLUSIONS: These data support a beneficial effect of interventions to reduce exposure to RBSFF but an increase in SLRD attributed to flour dust may indicate increased exposure or increased awareness of the problem.

Assessing the impact of national level interventions on workplace respiratory disease in the UK: part 1--changes in workplace exposure legislation and market forces.

OBJECTIVE: The 2004 amendment to the Control of Substances Hazardous to Health 2002 regulations (COSHH 2004) introducing workplace exposure limits (WELs) was enacted in the UK in 2005. This study aimed to determine whether introducing this legislation coincided with a reduction in the incidence of work-related short latency respiratory disease (SLRD) attributed to the agents with a WEL. The second objective was to determine whether changes in legislation, WELs and market forces coincided with a reduction in the incidence of SLRD attributed to glutaraldehyde and latex. METHOD: Reports of SLRD made to the Surveillance of Work-related and Occupational Respiratory Disease scheme were used to estimate the change in incidence within reporters between two time periods (interrupted time series design) using a longitudinal, negative binomial regression model with ß distributed random effects. A statistical interaction term was included in the model to make comparisons between the groups defined by suspected causal agent and/or occupation, essentially comparing two interrupted time series. Time periods were defined prospectively representing the changes in legislation or market forces. RESULTS: The introduction of the COSHH 2004 legislation in the UK coincided with a significant reduction in reports of SLRD attributed to agents with a WEL relative to those without a WEL (ratio of incidence rate ratios: 0.70; 95% CI 0.52 to 0.93) and a significant reduction in SLRD attributed to glutaraldehyde in healthcare workers (0.20; 0.07 to 0.57) and latex in all workers (0.37; 0.16 to 0.85). CONCLUSIONS: These data are consistent with a beneficial effect of legislation aiming to reduce workplace exposures.

Development of mechanism-based structural alerts for respiratory sensitization hazard identification.

This study outlines how mechanistic organic chemistry related to covalent bond formation can be used to rationalize the ability of low molecular weight chemicals to cause respiratory sensitization. The results of an analysis of 104 chemicals which have been reported to cause respiratory sensitization in humans showed that most of the sensitizing chemicals could be distinguished from 82 control chemicals for which no clinical reports of respiratory sensitization exist. This study resulted in the development of a set of mechanism-based structural alerts for chemicals with the potential to cause respiratory sensitization. Their potential for use in a predictive algorithm for this purpose alongside an externally validated quantitative structure-activity relationship model is discussed.

Acute ill-health in sheep farmers following use of pesticides.

BACKGROUND: Sheep farmers often complain of acute ill-health, known colloquially as 'dipper's flu', immediately after treating sheep with pesticides. There have been few prospective epidemiological studies to determine it's nature and incidence. Aims To determine the nature and frequency of symptoms occurring in farmers treating sheep for ectoparasites. METHODS: In a longitudinal study, farmers who planned to treat their sheep for ectoparasites were recruited. Farmers kept a symptom diary for 7 days after starting pesticide treatment. Symptoms reported on days 1-6 were compared to those reported on day 7 via the McNemar's test and with previously published literature definitions of dipper's flu. A principal component analysis (PCA) was carried out on new symptoms occurring on days 1 and 2. RESULTS: Of 781 farmers recruited, 352 farmers (45%) completed the symptom diary. In the 7 days after starting pesticide treatment, symptom complex reporting typically peaked on day 2, but few farmers (7 or less; <2%) were identified as having dipper's flu using literature definitions. However, PCA identified two new patterns of symptom complexes that accounted for 35% of the variance. A pyrexial factor consisted of four symptom complexes (feeling generally ill; feeling sweaty, shivery, feverish, hot or cold; feeling unusually tired; and having a headache) and a respiratory factor consisted of three symptom complexes (runny, stuffy, blocked or irritated nose; cough, shortness of breath or wheeze; and eye irritation). CONCLUSIONS: Existing definitions of dipper's flu do not adequately describe symptoms that occur following the treatment of sheep for ectoparasites.

Has European Union legislation to reduce exposure to chromate in cement been effective in reducing the incidence of allergic contact dermatitis attributed to chromate in the UK?

OBJECTIVE: Hexavalent chromate (chromate) in cement is a well-recognised cause of allergic contact dermatitis (ACD). Consequently in January 2005, following European Union legislation (EU Directive 2003/53/EC), the use or supply of cement containing >2 ppm of chromate was prohibited in the UK (COSHH 2004). This analysis of work-related ill-health surveillance aims to evaluate the effectiveness of this legislation. METHOD: Changes in the incidence of work-related ACD cases returned to The Health and Occupation Reporting network by dermatologists were analysed taking in to account attribution to chromate and occupation. RESULTS: There was a significant decline in the incidence of both ACD attributed to chromate (incidence rate ratio 0.48, 95% CI 0.36 to 0.64) and ACD not-attributed chromate (0.76, 95% CI 0.69 to 0.85) between the time period preceding the EU legislation (2002-2004) and the postlegislation period (2005-2009). However, the decline in ACD attributed to chromate was significantly greater (p=0.006). This decline was further increased in workers potentially exposed to cement (incidence rate ratio 0.37, p=0.001). The majority of the decline in incidence occurred during 2005. CONCLUSION: The timing of this significant decline in the UK incidence of chromate attributed ACD, and the greater decline in workers potentially exposed to cement strongly suggests that the EU Directive2003/53/EC was successful in reducing exposure to chromate in cement in the UK.

Occupation and work-related ill-health in UK construction workers.

BACKGROUND: Construction workers are at increased risk of work-related ill-health (WRI) worldwide. AIMS: To compare the incidence of medically reported WRI in occupations within the UK construction industry according to job title. METHODS: We calculated standardized incidence rate ratios (SRRs) using WRI cases for individual job titles returned to The Health and Occupation Reporting network by clinical specialists and UK population denominators. We counted frequencies of reported causal exposures or tasks reported by clinical specialists, occupational physicians and general practitioners. RESULTS: We found significantly increased incidence of WRI compared with other workers in the same major Standard Occupational Classification, i.e. workers with similar levels of qualifications, training, skills and experience, for skin neoplasia in roofers (SRR 6.3; 95% CI: 3.1-13.1), painters and decorators (2.1; 95% CI: 1.2-3.6) and labourers in building and woodworking trades (labourers, 6.6; 95% CI: 3.2-13.2); contact dermatitis in metal workers (1.4; 95% CI: 1.1-1.7) and labourers (1.6; 95% CI: 1.1-2.3); asthma in welders (3.8; 95% CI: 2.8-5.0); musculoskeletal disorders in welders (1.7; 95% CI: 1.1-2.8), road construction operatives (6.1; 95% CI: 3.8-9.6) and labourers (2.5; 95% CI: 1.7-3.7); long latency respiratory disease (mesothelioma, pneumoconiosis, lung cancer, non-malignant pleural disease) in pipe fitters (4.5; 95% CI: 3.2-6.2), electrical workers (2.7; 95% CI: 2.4-3.2), plumbing and heating engineers (2.3; 95% CI: 1.9-2.7), carpenters and joiners (2.7; 95% CI: 2.3-3.1), scaffolders (12; 95% CI: 8-18) and labourers (3.3; 95% CI: 2.6-4.1). CONCLUSIONS: UK construction industry workers have significantly increased risk of WRI. These data in individual construction occupations can be used to inform appropriate targeting of occupational health resources.

Epidemiology and trends in male subfertility.

The incidence and the causes of male infertility and male reproductive ill-health (in general) are important issues that remain poorly characterised. There does not appear to be a worldwide decline in semen quality but changes are more apparent in some regions than others. Furthermore, though the incidence of testicular cancer and congenital genital malformations had been increasing, the rate of increase has seemingly slowed over the past decade. Demographic data on UK fertility rates also provide scant evidence to suggest that infertility is increasing. Though this incidence data is reassuring, male infertility has been associated with an ever-increasing number of putative risk factors, including current exposures or parental exposures to occupational, lifestyle or environmental factors. It is currently unclear to what extent such risk factors (and others such as DNA damage) influence male infertility. Better characterisation of risk factors will aid our understanding of what is happening to male infertility. This brief review examines recent trends in male infertility and summarises the extent to which knowledge in this area has improved significantly.

The incidence of medically reported work-related ill health in the UK construction industry.

OBJECTIVE: Self-reported work-related ill health (SWI) data show a high incidence of occupational ill health and a high burden of cancer attributable to occupational factors in the UK construction industry. However, there is little information on the incidence of medically reported work-related ill health (WRI) within this industry. This study aims to examine the incidence of WRI within the UK construction industry. METHOD: Standardised incidence rate ratios (SRRs) were used to compare incidence rates of reports of medically certified work-related ill health returned to The Health and Occupation Reporting network (THOR) within the UK construction industry with all other UK industries combined. RESULTS: Male UK construction industry workers aged under 65 years had significantly raised SRRs for respiratory (3.8, 95% CI 3.5 to 4.2), skin (1.6, 1.4 to 1.8) and musculoskeletal disorders (MSD; 1.9, 1.6 to 2.2). These SRRs were further raised for those working within a construction trade. The increased SRRs for skin disease within male construction industry workers were due to contact dermatitis (1.4, 1.2 to 1.6) and neoplasia (4.2, 3.3 to 5.3). For respiratory disease, the increased SRRs were due to non-malignant pleural disease (7.1, 6.3 to 8.1), mesothelioma (7.1, 6.0 to 8.3), lung cancer (5.4, 3.2 to 8.9) and pneumoconiosis (5.5, 3.7 to 8.0), but the SRRs for asthma (0.09, 0.06 to 0.11) and mental ill health (0.3, 0.1 to 0.4) were significantly reduced. CONCLUSION: The significantly raised SRRs for medically reported MSD and significantly reduced SRRs for mental ill health in construction workers confirm self-reported UK data. These SRRs provide a baseline of the incidence of WRI in the UK construction industry from which to monitor the effects of changes in policy or exposures.

Medically reported work-related ill-health in the UK agricultural sector.

BACKGROUND: Self-reported work-related ill-health (WRI) statistics suggest that agricultural workers in the UK are at an increased risk of musculoskeletal disorders (MSD), skin and respiratory disease. However, there is little comprehensive medically reported information on WRI in the UK agricultural sector. METHODS: Cases of WRI within the UK from 2002 to 2008, as reported to The Health and Occupation Reporting (THOR) network by occupational physicians, clinical specialists and general practitioners, were analysed. Directly standardized incidence rate ratios (SRRs) for the agricultural sector versus all other sectors were calculated for dermatological, musculoskeletal, respiratory and psychological illness, using as the standard population the UK working population as estimated from the Labour Force Survey. RESULTS: During 2002-08, 471 cases within the agricultural sector were reported to THOR (2% of all cases). Based on reports by clinical specialists, male agricultural workers aged <65 years had significantly raised SRRs for MSD (2.3, 95% CI 1.6-3.3), allergic alveolitis (32, 95% CI 19-51), asthma (1.9, 95% CI 1.2-3.0) and skin neoplasia (7.9, 95% CI 5.8-10.9) and a significantly reduced SRR for asbestos-related respiratory disease (0.4, 95% CI 0.2-0.7). Reports of mental ill-health in agricultural workers were low. CONCLUSIONS: These medically reported incidence data provide information on WRI in the UK agricultural sector. Consistent with other sources, there are increased risks for asthma, allergic alveolitis and MSD and a reduced risk for mental ill-health. The raised incidence of skin cancer requires confirmation and further comparison with reliable estimates of the incidence in the UK workforce.

Alkylation of sperm DNA is associated with male factor infertility and a reduction in the proportion of oocytes fertilised during assisted reproduction.

Approximately one-third of IVF cases in the UK are attributed to male factor infertility and in the majority of cases the origin of male infertility is unknown. The integrity of sperm DNA is important both for the success of assisted reproduction and the implications for the off-spring. One type of DNA damage that has not been investigated with respect to fertility outcomes is the adduct N7-methyldeoxyguanosine (N7-MedG), a biomarker for exposure to alkylating agents. A prospective cohort of couples attending for IVF had their N7-MedG levels in sperm measured using an immunoslot blot technique to examine whether sperm N7-MedG levels are associated with male factor infertility, semen quality measures or assisted reproduction outcomes. Sufficient DNA for analysis was obtained from 67/97 couples and N7-MedG was detected in 94% of sperm samples analysed. Men diagnosed with male factor infertility had significantly higher mean levels of N7-MedG in their sperm DNA (P=0.03). Logistic regression analysis showed that N7-MedG levels were significantly negatively associated with the proportion of oocytes successfully fertilised irrespective of the method of fertilisation used (IVF or intra-cytoplasmic sperm injection; ICSI, P<0.001). Therefore exposure to DNA alkylating agents is significantly associated with male infertility and the proportion of oocytes fertilised during assisted reproduction. Reducing such exposure may improve male fertility but further work is required to determine the relative importance of exogenous and endogenous sources of exposure.

The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells.

The accumulation and toxicity of the weak base doxorubicin has been investigated as a function of extracellular pH, intracellular pH and the cellular pH gradient in cells previously cultured under normal (pH 7.4) and low-pH (6.8) conditions. Low-pH-adapted cells exhibit transmembrane pH gradients which substantially differ from normal cells at the same extracellular pH. No relationship was obtained between intracellular pH and the uptake or toxicity of doxorubicin in the two cell types. In contrast, doxorubicin accumulation and toxicity increased with increasing extracellular pH in both normal and low-pH-adapted cells. However, at the same extracellular pH, drug cytotoxicity was more pronounced in normal than in low-pH-adapted cells. The difference in doxorubicin accumulation and cytotoxicity at the same extracellular pH was found to be dependent on the difference in the transmembrane pH gradient of the two cell types. As the cellular pH gradient differs between tumour and normal tissue, this observation suggests a basis for enhancing cellular drug uptake in either tissue type.

Production and isolation of large quantities of monoclonal antibody using serum-free medium and fast protein liquid chromatography.

A method for the production and purification of monoclonal antibody on a large laboratory scale is described. It involves the growth of monoclonal antibodies in serum-free medium, ultrafiltration through an Amicon XM100A filter and fast protein liquid chromatography on a mono Q column with an ionic strength and pH elution gradient. Up to 30 mg of antibody per litre of cell culture supernatant was purified in one day. The procedure can be carried out at 4 degrees.

Development of a general ligand for immunoaffinity partitioning in two phase aqueous polymer systems.

The effect on the partition of erythrocytes in a two phase aqueous polymer system based on dextran T500 and polyethylene glycol (PEG) 8000 of a combination of immunoaffinity ligands, namely, rabbit immunoglobulin G (IgG) and PEG 1900-modified monoclonal IgG, was examined as a potential cell separation technique. Several hybridoma lines secreting mouse monoclonal IgG specific for the Fc receptor of rabbit IgG were raised. The monoclonal IgG was modified by cyanuric chloride attachment of PEG 1900, causing the modified antibody to partition predominantly into the PEG-rich upper phase of the systems. The PEG-modified monoclonal IgG was used as an affinity ligand in the two phase polymer system to specifically increase the partition of rabbit anti-NN glycophorin IgG. The rabbit IgG was applied together with the PEG-modified monoclonal IgG to increase the partition of human erythrocytes. The same system had no effect on the partition of rabbit erythrocytes. These experiments demonstrate that a monoclonal antibody can be modified and used as a general reagent with which to alter cell partition in two phase aqueous polymer systems in an immunologically specific manner.

A fluorometric assay of the degree of modification of protein primary amines with polyethylene glycol.

An alternative primary amine assay utilizing 4-phenylspiro[furan-2(3H),1'-phthalan]-3,3'-dione (fluorescamine) is compared with the frequently applied trinitrobenzenesulfonic acid assay as a means of estimating protein primary amine modification with cyanuric chloride attachment of polyethylene glycol (PEG). The results of the two assays are compared for three different proteins and several advantages of the fluorescamine assay are emphasized. In particular, the fluorescamine assay was found to be unaffected by free PEG up to 0.08% in the assay mixture. The fluorescamine assay can be used to measure the partition coefficients of native or PEG-modified protein in two-phase aqueous polymer systems.