Improving trends estimates for specific work-related ill-health conditions when excess zeros are present in a voluntary health reporting scheme.

BACKGROUND: Trends in occupational disease incidence are estimated in voluntary reporting schemes such as The Health and Occupational Reporting (THOR) Network in the UK. Voluntary reporting schemes request responses even if no cases are observed to reduce uncertainty in non-response. This may result in false zeros that bias trends estimates. Analysis using zero-inflated models is unsuitable for specific health outcomes due to overestimates of the excess zeros. Here, we attempt to account for excess zeros while investigating condition-specific trends. METHODS: Zero-inflated negative binomial (ZINB) models were fitted to three THOR work-related ill health surveillance schemes Occupational Skin Disease Surveillance (437 reporters between 1996 and 2019), Occupational Physicians Reporting Activity (1094 between 1996 and 2019) and Surveillance of Work-Related and Occupational Respiratory Disease (878 between 1999 and 2019). The probability associated with a response being a false zero was estimated and applied in weighted negative binomial (wgt-NB) models fitted to specific ill-heath conditions. Three ill-health conditions from the three THOR schemes were considered; contact dermatitis, musculoskeletal and asthma, respectively. RESULTS: Wgt-NB models approximately estimated the incidence rate ratios reported by the ZINB models (eg, EPIDERM; ZINB=0.969, NB=0.963, wgt-NB=0.968) for all health outcome annual trends. This was consistent for specific health outcomes which also tended towards the null (eg, contact dermatitis; NB=0.964, wgt-NB=0.969), indicating potentially overestimated downward trends. Though as the ratio of excess zeros to true zeros decreased in rarer health outcomes, the influence on trends also decreased. CONCLUSIONS: Through weighting, we were able to adjust for excess zeros in health outcome-specific trends estimates. Though uncertainty is still present in underlying reporter behaviour meaning caution should be applied with interpretation of any results.

Occupational Asthma Caused by Quaternary Ammonium Compounds: A Multicenter Cohort Study.

BACKGROUND: Quaternary ammonium compounds (QACs) are used extensively for cleaning and disinfection and have been documented in scattered reports as a cause of occupational asthma (OA) through bronchoprovocation tests (BPTs). OBJECTIVE: To examine the clinical, functional, and inflammatory profile of QAC-induced OA compared with OA caused by other low-molecular weight (LMW) agents. METHODS: The study was conducted in a retrospective multicenter cohort of 871 subjects with OA ascertained by a positive BPT. Subjects with QAC-induced OA (n = 22) were identified based on a positive BPT to QACs after exclusion of those challenged with cleaning products or disinfectants that contained other potential respiratory sensitizers. They were compared with 289 subjects with OA caused by other LMW agents. RESULTS: Most subjects with QAC-induced OA were working in the health care sector (n = 14). A twofold or greater increase in the postchallenge level of nonspecific bronchial hyperresponsiveness was recorded in eight of 11 subjects with QAC-induced OA (72.7%) and in 49.7% of those with OA caused by other LMW agents. Although sputum assessment was available in only eight subjects with QAC-induced OA, they showed a significantly greater median (interquartile) increase in sputum eosinophils (18.1% [range, 12.1% to 21.1%]) compared with those with OA caused by other LMW agents (2.0% [range, 0% to 5.2%]; P < .001). CONCLUSIONS: This study indicates that QAC-induced OA is associated with a highly eosinophilic pattern of airway response and provides further evidence supporting the sensitizing potential of QACs. The findings highlight the heterogeneous nature of the pathobiologic pathways involved in OA caused by LMW agents.

Insufficient respiratory hazard identification in the safety data sheets for cleaning and disinfection products used in healthcare organisations across England and Wales.

BACKGROUND: Exposure to cleaning and disinfection products has been associated with respiratory disorders such as asthma in cleaning and healthcare workers. Safety data sheets (SDSs) provide information on hazardous chemicals that are present in products to help users with risk assessment and implement appropriate control measures. However, they have potential limitations in identifying respiratory hazards due to a lack of regulatory test methods for respiratory sensitisation and irritation of chemicals. METHODS: SDSs were first used to identify chemicals on the database as respiratory sensitisers and irritants. A quantitative structure-activity relationship (QSAR) model and an asthmagen list established by the Association of Occupational and Environmental Clinics (AOEC) were used to identify potential respiratory sensitisers and irritants (by the AOEC list only) in the cleaning and disinfection products. RESULTS: From a total of 459 cleaning and disinfection products used in healthcare organisations across England and Wales, 35 respiratory sensitisers not labelled as such on the SDS were identified by QSAR or AOEC. Only 2% of cleaning and disinfection products contained at least one respiratory sensitiser as identified by their SDSs; this was increased to 37.7% of products when the QSAR or the AOEC list was used. CONCLUSIONS: A significantly higher proportion of cleaning products contain respiratory hazardous chemicals, particularly respiratory sensitisers than would be expected from the information provided by SDSs alone. Cleaners and healthcare workers may, therefore, be insufficiently protected.

Occupational Asthma and Its Causation in the UK Seafood Processing Industry.

OBJECTIVES: The processing of seafood (fish and shellfish) for human consumption can lead to health consequences, including occupational asthma (OA). Several non-UK studies have reported both respiratory outcomes and airborne levels of major allergens in seafood processing. However, there is a paucity of such evidence in the UK land-based seafood processing sector, which employs some 20 000 workers. METHODS: University of Manchester's Surveillance of Work-related and Occupational Respiratory Disease (SWORD) reporting system has been interrogated over the period 1992-2017 to define the incidence rate of OA cases that can be ascribed to the UK land-based processing sector, and the seafood species implicated. Airborne allergen monitoring data undertaken at Health and Safety Executive's laboratory from 2003 to 2019 have also been collated. RESULTS: The estimated annual OA incidence rate in seafood processors was 70 [95% confidence intervals (CIs) 48.9, 91.1] per 100 000 workers compared with 2.9 (95% CIs 2.8, 3.1) in 'all other industries'. The annual calculated percentage trend in OA (1992-2017) was -8.1% (95% CIs -15.9, 0.4) in seafood processing showing a similar trend to 'all other industries' (mean -7.0%; 95% CIs -7.8, -6.1). Prawns and salmon/trout were notably implicated by SWORD as causative species related to OA. There is a general paucity of available UK airborne allergen monitoring data, particularly concerning processing salmon or trout. Available airborne monitoring for salmon parvalbumin in seven processors ranged between the limit of detection and 816 ng m-3 (n = 64). Available air monitoring levels of the major shellfish allergen (tropomyosin) during processing of crabs and prawns ranged between 1 and 101 600 ng m-3 (n = 280), highlighting that high levels of exposure can occur. CONCLUSIONS: These data show an excess incidence of OA in the UK seafood processing industry during 1992-2017, with limited airborne monitoring data for the processing of prawn, crab, and salmon suggesting that significant exposure to major seafood allergens can occur in this industry. Further investigation of current levels of respiratory ill-health and the sources of allergen exposure are warranted.

Phenotyping Occupational Asthma Caused by Acrylates in a Multicenter Cohort Study.

BACKGROUND: While acrylates are well-known skin sensitizers, they are not classified as respiratory sensitizers although several cases of acrylate-induced occupational asthma (OA) have been reported. OBJECTIVE: To evaluate the characteristics of acrylate-induced OA in a large series of cases and compare those with OA induced by other low-molecular-weight (LMW) agents. METHODS: Jobs and exposures, clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge to acrylates (n = 55) or other LMW agents (n = 418) including isocyanates (n = 125). RESULTS: Acrylate-containing glues were the most prevalent products, and industrial manufacturing, dental work, and beauty care were typical occupations causing OA. Work-related rhinitis was more common in acrylate-than in isocyanate-induced asthma (P < .001). The increase in postchallenge fractional exhaled nitric oxide was significantly greater in acrylate-induced OA (26.0; 8.2 to 38.0 parts per billion [ppb]) than in OA induced by other LMW agents (3.0; -1.0 to 10.0 ppb; P < .001) or isocyanates (5.0; 2.0 to 16.0 ppb; P = .010). Multivariable models confirmed that OA induced by acrylates was significantly and independently associated with a postchallenge increase in fractional exhaled nitric oxide (≥17.5 ppb). CONCLUSIONS: Acrylate-induced OA shows specific characteristics, concomitant work-related rhinitis, and exposure-related increases in fractional exhaled nitric oxide, suggesting that acrylates may induce asthma through different immunologic mechanisms compared with mechanisms through which other LMW agents may induce asthma. Our findings reinforce the need for a reevaluation of the hazard classification of acrylates, and further investigation of the pathophysiological mechanisms underlying their respiratory sensitizing potential.

Occupational and work-related respiratory disease attributed to cleaning products.

OBJECTIVES: Exposure to cleaning products has been associated with adverse respiratory outcomes. This study aimed to investigate the medically reported incidence, trends in incidence and occupational determinants of work-related respiratory disorders attributed to cleaning agents and to explore the role of 'Quantitative Structure Activity Relationships' (QSAR) in corroborating the identification of chemical respiratory sensitisers. METHODS: Respiratory diagnoses attributed to cleaning agents were extracted from The Health and Occupation Research (THOR) surveillance network, 1989-2017. Incidence, trends in incidence and incidence rate ratios by occupation were investigated. Agents were classified by chemical type and QSAR hazard indices were determined for specific organic chemicals. RESULTS: Approximately 6% (779 cases) of the (non-asbestos) THOR respiratory cases were attributed to cleaning agents. Diagnoses were predominantly asthma (58%) and inhalation accidents (27%) with frequently reported chemical categories being aldehydes (30%) and chlorine/its releasers (26%). No significant trend in asthma incidence (1999-2017) was observed (annual average change of -1.1% (95% CI -4.4 to 2.4)). This contrasted with a statistically significant annual decline in asthma incidence (-6.8% (95% CI -8.0 to -5.6)) for non-cleaning agents. There was a large variation in risk between occupations. 7 of the 15 organic chemicals specifically identified had a QSAR generated hazard index consistent with being a respiratory sensitiser. CONCLUSION: Specific occupations appear to be at increased risk of adverse respiratory outcomes attributed to cleaning agents. While exposure to agents such as glutaraldehyde have been addressed, other exposures, such as to chlorine, remain important. Chemical features of the cleaning agents helped distinguish between sensitising and irritant agents.

Emerging trends in the UK incidence of occupational asthma: should we be worried?

While 15% of adult-onset asthma is estimated to have an occupational cause, there has been evidence of a downward trend in occupational asthma incidence in several European countries since the start of this millennium. However, recent data from The Health and Occupation Reporting network in the UK have suggested a possible reversal of this downward trend since 2014. We present these data and discuss possible explanations for this observed change in incidence trend. A high index of suspicion of occupational causation in new-onset asthma cases continues to be important, whether or not the recently observed increase in occupational asthma incidence in the UK is real or artefactual.

Progress with Structure-Activity Relationship modelling of occupational chemical respiratory sensitizers.

PURPOSE OF REVIEW: This appraises currently available computer-based ('in silico') models relating the molecular structure of low molecular weight compounds to their respiratory sensitization hazard. The present review places focus on the two main applications of such structure--activity relationship (SAR) models: hypotheses on disease mechanisms and toxicological prediction. RECENT FINDINGS: Analyses of the chemical structures of low molecular weight organic compounds known to have caused occupational asthma has led to the development of mechanistic alerts usually based on electrophilic reaction chemistry and protein cross-linking potential. Protein cross-linking potential has also been found to be a consistent feature of chemicals that have caused human cases of hypersensitivity pneumonitis. Stepwise iteration of quantitative SAR (QSAR) modelling has shown appreciable improvements in predictivity for occupational asthma hazard and useful prospects for practical application. A good case has also been made for the potential use of structural alert-based mechanistic SARs in predictive toxicology. SUMMARY: Further understanding of the molecular interactions between chemical respiratory sensitizers and components of human proteins have been obtained from in-vitro and in-silico techniques. There have been developments in both qualitative (mechanistic) SARs and QSARs, which offer potential for use in a predictive algorithm for the toxicological screening of industrial chemicals for respiratory sensitization potential.

Respiratory sensitization: advances in assessing the risk of respiratory inflammation and irritation.

Respiratory sensitization provides a case study for a new approach to chemical safety evaluation, as the prevalence of respiratory sensitization has increased considerably over the last decades, but animal and/or human experimental/predictive models are not currently available. Therefore, the goal of a working group was to design a road map to develop an ASAT approach for respiratory sensitisers. This approach should aim at (i) creating a database on respiratory functional biology and toxicology, (ii) applying data analyses to understand the multi-dimensional sensitization response, and how this predisposes to respiratory inflammation and irritation, and (iii) building a systems model out of these analyses, adding pharmacokinetic-pharmacodynamic modeling to predict respiratory responses to low levels of sensitisers. To this end, the best way forward would be to follow an integrated testing approach. Experimental research should be targeted to (i) QSAR-type approaches to relate potential as a respiratory sensitizer to its chemical structure, (ii) in vitro models and (iii) in vitro-in vivo extrapolation/validation.

Further validation of computer-based prediction of chemical asthma hazard.

BACKGROUND: There is no agreed protocol for the prediction of low molecular weight (LMW) respiratory sensitizers. This creates challenges for occupational physicians responsible for the health of workforces using novel chemicals and respiratory physicians investigating cases of occupational asthma caused by novel asthmagens. AIMS: To iterate the external validation of a previously published quantitative structure-activity relationship (QSAR) model for the prediction of novel chemical respiratory sensitizers and to better characterize its predictive accuracy. METHODS: An external validation set of control chemicals was identified from the Australian Hazardous Substances Information System. An external validation set of asthmagenic chemicals was identified by a thorough search of the peer-reviewed literature from January 1995 onwards using the Medline database. The QSAR model was used to determine an 'asthma hazard index' (between 0 and 1) for each chemical. RESULTS: A total of 28 external validation asthmagens and 129 control chemicals were identified. The area under the receiver operating characteristic (ROC) curve for the model's ability to distinguish asthmagens from controls was 0.87 (95% CI 0.76-0.97). Using a cut-off hazard index of 0.5 resulted in sensitivity of 79% and specificity of 93%. For prior probability ranging from 1:300 to 1:100, the negative predictive value (NPV) was 1 and positive predictive value (PPV) 0.04-0.1 while for prior probability ranging from 1:20 to 1:3, the NPV was 0.91-0.99 and PPV 0.39-0.85. CONCLUSIONS: The ROC curve for this QSAR demonstrates good global predictive power for distinguishing asthmagenic from non-asthmagenic LMW organic compounds. Potential for utilization by occupational and respiratory physicians is evident from its predictive values.

Methods for the prediction of low-molecular-weight occupational respiratory sensitizers.

PURPOSE OF REVIEW: There is recognition that respiratory sensitization is an occupational hazard of high concern. Despite international regulatory requirements there is no established protocol for the efficient prospective identification of chemical respiratory sensitizers. We review the predictive behaviour of available methods and suggest a possible high-throughput protocol. RECENT FINDINGS: Animal or in-vitro tests specific to respiratory exposure and resulting in direct asthma-related outcomes have not been developed, although the use of a local lymph node assay originally designed for skin sensitization has been advocated in a respiratory context. Various methods have been used to develop quantitative structure-activity relationship models for prediction of low-molecular-weight organic chemical respiratory sensitizers. The estimated negative predictive value for all of the published models is 1, but their differences in positive predictive value can be exploited. SUMMARY: The most pragmatic as well as valid approach for screening large numbers of industrial chemicals for respiratory sensitization hazard is likely to consist of an algorithm starting with quantitative structure-activity relationship models. Further corroboration from animal or human data, however, may be required for chemicals with a positive result by quantitative structure-activity relationship.