Abstract Diisocyanates are a group of chemicals that are widely used in occupational settings. They are known to induce various health effects, including skin- and respiratory tract sensitization resulting in allergic dermatitis and asthma. Exposure to diisocyanates has been studied in the past decades by using different types of biomonitoring markers and matrices. The aim of this review as part of the HBM4EU project was to assess: (i) which biomarkers and matrices have been used for biomonitoring diisocyanates and what are their strengths and limitations; (ii) what are (current) biomonitoring levels of the major diisocyanates (and metabolites) in workers; and (iii) to characterize potential research gaps. For this purpose we conducted a systematic literature search for the time period 2000–end 2018, thereby focussing on three types of diisocyanates which account for the vast majority of the total isocyanate market volume: hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), and 4,4′-methylenediphenyl diisocyanate (MDI). A total of 28 publications were identified which fulfilled the review inclusion criteria. The majority of these studies (93%) investigated the corresponding diamines in either urine or plasma, but adducts have also been investigated by several research groups. Studies on HDI were mostly in the motor vehicle repair industry [with urinary hexamethylene diamine result ranging from 0.03 to 146.5 µmol mol−1 creatinine]. For TDI, there is mostly data on foam production [results for urinary toluene diamine ranging from ~0.01 to 97 µmol mol−1 creatinine] whereas the available MDI data are mainly from the polyurethane industry (results for methylenediphenyl diamine range from 0.01 to 32.7 µmol mol−1 creatinine). About half of the studies published were prior to 2010 hence might not reflect current workplace exposure. There is large variability within and between studies and across sectors which could be potentially explained by several factors including worker or workplace variability, short half-lives of biomarkers, and differences in sampling strategies and analytical techniques. We identified several research gaps which could further be taken into account when studying diisocyanates biomonitoring levels: (i) the development of specific biomarkers is promising (e.g. to study oligomers of HDI which have been largely neglected to date) but needs more research before they can be widely applied, (ii) since analytical methods differ between studies a more uniform approach would make comparisons between studies easier, and (iii) dermal absorption seems a possible exposure route and needs to be further investigated. The use of MDI, TDI, and HDI has been recently proposed to be restricted in the European Union unless specific conditions for workers’ training and risk management measures apply. This review has highlighted the need for a harmonized approach to establishing a baseline against which the success of the restriction can be evaluated.

BACKGROUND: The genotoxicity of benzene has been investigated in dozens of biomonitoring studies, mainly by studying (classical) chromosomal aberrations (CAs) or micronuclei (MN) as markers of DNA damage. Both have been shown to be predictive of future cancer risk in cohort studies and could, therefore, potentially be used for risk assessment of genotoxicity-mediated cancers. OBJECTIVES: We sought to estimate an exposure-response curve (ERC) and quantify between-study heterogeneity using all available quantitative evidence on the cytogenetic effects of benzene exposure on CAs and MN respectively. METHODS: We carried out a systematic literature review and summarized all available data of sufficient quality using meta-analyses. We assessed the heterogeneity in slope estimates between studies and conducted additional sensitivity analyses to assess how various study characteristics impacted the estimated ERC. RESULTS: Sixteen CA (1,356 individuals) and 13 MN studies (2,097 individuals) were found to be eligible for inclusion in a meta-analysis. Studies where benzene was the primary genotoxic exposure and that had adequate assessment of both exposure and outcomes were used for the primary analysis. Estimated slope estimates were an increase of 0.27% CA [(95% CI: 0.08%, 0.47%); based on the results from 4 studies] and 0.27% MN [(95% CI: −0:23%, 0.76%); based on the results from 7 studies] per parts-per-million benzene exposure. We observed considerable between-study heterogeneity for both end points (I 2 > 90%). DISCUSSION: Our study provides a systematic, transparent, and quantitative summary of the literature describing the strong association between benzene exposure and accepted markers of genotoxicity in humans. The derived consensus slope can be used as a best estimate of the quantitative relationship between real-life benzene exposure and genetic damage in future risk assessment. We also quantitate the large between-study heterogeneity that exists in this literature, a factor which is crucial for the interpretation of single-study or consensus slopes.

Diisocyanates have long been a leading cause of occupational asthma in Europe, and recently, they have been subjected to a restriction under the REACH regulations. As part of the European Human Biomonitoring project (HBM4EU), we present a study protocol designed to assess occupational exposure to diisocyanates in five European countries. The objectives of the study are to assess exposure in a number of sectors that have not been widely reported on in the past (for example, the manufacturing of large vehicles, such as in aerospace; the construction sector, where there are potentially several sources of exposure (e.g., sprayed insulation, floor screeds); the use of MDI-based glues, and the manufacture of spray adhesives or coatings) to test the usability of different biomarkers in the assessment of exposure to diisocyanates and to provide background data for regulatory purposes. The study will collect urine samples (analysed for diisocyanate-derived diamines and acetyl–MDI–lysine), blood samples (analysed for diisocyanate-specific IgE and IgG antibodies, inflammatory markers, and diisocyanate-specific Hb adducts for MDI), and buccal cells (micronucleus analysis) and measure fractional exhaled nitric oxide. In addition, occupational hygiene measurements (air monitoring and skin wipe samples) and questionnaire data will be collected. The protocol is harmonised across the participating countries to enable pooling of data, leading to better and more robust insights and recommendations.

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