Classification or non-classification of substances with positive tumor findings in animal studies: Guidance by the German MAK commission.

One of the important tasks of the German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (known as the MAK Commission) is in the evaluation of a potential for carcinogenicity of hazardous substances at the workplace. Often, this evaluation is critically based on data on carcinogenic responses seen in animal studies and, if positive tumor responses have been observed, this will mostly lead to a classification of the substance under investigation into one of the classes for carcinogens. However, there are cases where it can be demonstrated with a very high degree of confidence that the tumor findings in the experimental animals are not relevant for humans at the workplace and, therefore, the MAK Commission will not classify the respective substance into one of the classes for carcinogens. This paper will summarize the general criteria used by the MAK Commission for the categorization into "carcinogen" and "non-carcinogen" and compare this procedure with those used by other national and international organizations.

Lifetime Occupational History, Respiratory Symptoms and Chronic Obstructive Pulmonary Disease: Results from a Population-Based Study.

Purpose: To ascertain the effect of lifelong occupational history, ambient air pollution, and biochemically verified smoking status on chronic obstructive pulmonary disease (COPD) in a general population of one the largest cities in Central Asia, Almaty. Patients and methods: 1500 adults (median age 49, interquartile range (IQR) 28 years), 50% females, were randomly selected from a registry of enlisted population of a primary care facility in Almaty, Kazakhstan and they filled in the questionnaire on demographics, respiratory symptoms (CAT and mMRC), smoking status, verified by exhaled carbon monoxide, and detailed lifetime occupational history. COPD was defined as postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) below lower limit of normal (LLN) using Belintelmed MAS-2 spirometer (Belarus). Results: 230 (15%) subjects had CAT≥10; 136 (9%) participants had mMRC score ≥2. Greater CAT score was associated with age, smaller income, and less exercise, but not with smoking or living closer to a major road. 26% of the population was ever exposed to vapors, gases, dusts, and fumes (VGDF). In age group 40 years and above (N=1024), COPD was found in 57 participants (prevalence 5.6%), more in men (8.7% vs 3.4%). In the multivariate model adjusted for age, sex, ever-smoking, income, and exercise, any exposure to VGDF increased the odds of COPD (odds ratio (OR) 1.71; 95% confidence interval (CI) 1.03; 2.84), more in the highest exposure category (OR 2.36 (95% CI 1.20; 4.66)). Conclusion: Lifetime exposure to VGDF, found in » of the general population, increased the odds of COPD independent of smoking by 71%.

Derivation of Occupational Thresholds of Toxicological Concern for Systemically Acting Noncarcinogenic Organic Chemicals.

Many substances in workplace do not have occupational exposure limits. The threshold of toxicological concern (TTC) principle is part of the hierarchy of approaches useful in occupational health risk assessment. The aim of this study was to derive occupational TTCs (OTTCs) reflecting the airborne concentrations below which no significant risk to workers would be anticipated. A reference dataset consisting of the 8-h threshold limit values-Time-Weighted Average for 280 organic substances was compiled. Each substance was classified into low (class I), intermediate (class II), or high (class III) hazard categories as per Cramer rules. For each chemical, n-octanol:water partition coefficient and vapor pressure along with the molecular weight were used to predict the blood:air partition coefficient. The blood:air partition coefficient along with data on water solubility and ventilation rate allowed the prediction of pulmonary retention factor and absorbed dose in workers. For each Cramer class, the distribution of the predicted doses was analyzed to identify the various percentile values corresponding to the OTTC. Accordingly, for Cramer classes I-III, the OTTCs derived in this study correspond to 0.15, 0.0085, and 0.006 mmol/d, respectively, at the 10th percentile level, while these values were 1.5, 0.09 and 0.03 mmol/d at the 25th percentile level. The proposed OTTCs are not meant to replace the traditional occupational exposure limits, but can be used in data-poor situations along with exposure estimates to support screening level risk assessment and prioritization.

A comprehensive list of asthmagens to inform health interventions in the Australian workplace.

OBJECTIVE: To develop a comprehensive list of asthmagens which may occur in occupational settings in Australia. METHODS: Potential asthmagens considered for this list were identified through work health and safety classification databases in Australia and through lists developed by professional associations in other countries. Inclusion criteria were: there is evidence that the agent is asthmagenic; it is used in occupational settings; and it is available in Australia. RESULTS: The final list contained 277 asthmagens in 27 groups that may be found in occupational circumstances in Australia. Three other agents that have been documented as asthmagens in Australia were included: almond dust, fluoride (in aluminium pot room fumes); and sawdust from the Australian Blackwood. CONCLUSIONS: This is the first comprehensive and inclusive list of Australian occupationally relevant asthmagens to have been compiled. IMPLICATIONS: This list is specific for Australian workplace exposure to asthmagens. It will help focus policy and preventative practices and reduce the burden of occupational asthma. It will also be useful in future studies to identify those who are exposed to the asthmagens and provide information to assist regulators to identify industries, occupations, specific activities and existing exposure standards that can be targeted to improve worker health and welfare.

Comparison and Evaluation of Multiple Users' Usage of the Exposure and Risk Tool: Stoffenmanager 5.1.

Stoffenmanager is an exposure and risk assessment tool that has a control banding part, with risk bands as outcome and a quantitative exposure assessment part, with the 90th percentile of the predicted exposure as a default outcome. The main aim of the study was to investigate whether multiple users of Stoffenmanager came to the same result when modelling the same scenarios. Other aims were to investigate the differences between outcomes of the control banding part with the measured risk quota and to evaluate the conservatism of the tool by testing whether the 90th percentiles are above the measured median exposures. We investigated airborne exposures at companies in four different types of industry: wood, printing, metal foundry, and spray painting. Three scenarios were modelled and measured, when possible, at each company. When modelled, 13 users visited each company on the same occasion creating individual assessments. Consensus assessments were also modelled for each scenario by six occupational hygienists. The multiple users' outcomes were often spread over two risk bands in the control banding part, and the differences in the quantitative exposure outcomes for the highest and lowest assessments per scenario varied between a factor 2 and 100. Four parameters were difficult for the users to assess and had a large impact on the outcome: type of task, breathing zone, personal protection, and control measures. Only two scenarios had a higher measured risk quota than predicted by the control banding part, also two scenarios had slightly higher measured median exposure value than modelled consensus in the quantitative exposure assessment part. Hence, the variability between users was large but the model performed well.

[Comparative hygienic assessment of potential risk to workers under application of fungicides of different classes].

The comparative hygienic evaluation of working conditions in various application technologies of triazole fungicides (tebuconazole, dyfenoconazole, penconazole) strobilurine fungicides (azoxystrobin, pyraclostrobin, trifloxystrobin), ethylene-bis-dytiocarbamate fungicides (metiram, mancozeb), cianopyrrole fungicide (fludioxonil), anilide fungicides (benalaxyl-M, boscalid), anilinopirymidyne fungicides (cyprodynil, valifenal, pirymetanil). Potential complex risk of possible harmful effects of the investigated compounds on workers by inhalation and percutaneous admission, as well as a comparative analysis of received values was assessed. Determination of active substances in the samples was carried out by gas-liquid and high performance liquid chromatography. In the air of the working area were found triazoles 0.005-0.01 mg/m3, ethylene-bis-dytiokarbamates--0.01-0.02 mg/m3 at fan plants processing, anilinopirymidynes--0.19 mg/m3 at backpack plants processing. Listed values do not exceed the established hygienic standards in the air of the working area. Steam plants processing had not accompanied by the arrival of investigated compounds in the air of the working area. For all the studied crops processing technologies magnitude of the potential risk of possible harmful effects of study classes fungicides influence at the complex admission does not exceed the permissible level (was less than 1). Comparative analysis of complex risks for workers allowed to distribute fungicides according this criterion in the following order: cianopyrrole < strobilurynes < triazoles < anilides < anilinopirymidynes < ethylene-bis-dytiokarbamates.

[On the problem of the study of the chemical air pollution with chlororganic hydrocarbons at productions of polyvinyl chloride and epichlorohydrin].

Hygienic assessment of working conditions at the chemical productions of polyvinyl chloride (PVC) and epichlorohydrin (EPCH) in East Siberia has shown that the employees are exposed to the chlororganic hydrocarbons of hazard category 1-2, out of them there were found to be more toxical pollutants such as vinyl chloride, 1.2-dicloroethane in the production of polyvinyl chloride; allyl chloride and epichlorohydrin in the production of epichlorohydrin. Multistageness of the technological processes, the absence of the isolation of main stages of the technological processes as well as the heating microclimate contribute to the chemical pollution of the air environment. In spite of the significant improvement of the hygienic situation at the productions mentioned in the recent 10 years according to the chemical factor due to the introduction of the complex of curative measures, the working conditions of the employees still belonged to the harmful category. According to the content of the harmful chemical substances in the air of the working zone and the parameters of microclimate, the working conditions of the employees working at the production of epichlorohydrin and in the shop of vinyl chloride production must be qualified as the harmful ones of the first category of the hazard and danger (Class 3.1), in the production shop for PVC- as the harmful ones which correspond to the second category of the hazard and danger (Class 3.2).

[The development of a comprehensive assessment of occupational risk by taking into account the total hazard of working conditions].

In the paper the methodological problems of establishing a general class of working conditions on the results of certification of workplaces are analyzed There is proposed the use of an additional parameter - the index of harm, characterizing the degree of correspondence of the general level of harmful occupational factors to applicable health standards with taking into account the nonequivalence of their display. The recommendations for the use of hazard index as the main criterion for a priori evaluation ofthe category ofsuspected occupational risk and the tool to establish by the correlation methods cause-and-effect relations between indices of health status and the impact ofoccupational factors are presented. As exemplified by real working conditions the possibilities of the use the index of harm as an indicator describing the hazard probability are considered with comprehensive assessment of occupational risk of health problems on the basis of the matrix method with the use of the table of vectors and nomograms "probability of harm - the severity of the consequences". The use of index of harm will permit to increase the objectivity of the assessment and the efficacy of management of occupational hazards in the workplaces.

Use of organic solvents in large research institutions in Japan.

OBJECTIVES: Laboratories in research institutions use organic solvents in research and development. Nevertheless, the types of solvents in use have been seldom reported. This study was initiated to elucidate types of organic solvents used in large research institutions in Japan, with a focus on possible different use among research fields. METHODS: In 2010-2011, 4517 laboratories in seven large research institutions were visited. In accordance with legal stipulations, air in each laboratory was collected in polyvinyl fluoride bags and analyzed by direct injection into a gas-chromatograph for 47 types of organic solvents. In evaluation, the laboratories were grouped by 5 research fields, i.e., agriculture, biology, medicine, natural science, and technology and engineering. RESULTS: Types of organic solvents commonly used in research activities were not diverse. Those commonly used were chloroform and 1,2-dichloroethane out of 7 Group 1 organic solvents (with high toxicities); 6 organic solvents, i.e., acetone and methyl alcohol in general, ethyl acetate, hexane and toluene in technology and engineering laboratories; and xylenes in medical fields out of 40 Group 2 organic solvents (with relatively low toxicities). Judging from solvent vapor concentrations, work environments in more than 99 % of laboratories were considered adequate. Nevertheless, use of chloroform in high-performance liquid chromatography (HPLC) resulted in inadequate environments in 30 laboratories (0.7 %). CONCLUSIONS: Organic solvents commonly used were not very diverse. Work environments in research laboratories were generally good, but the environment with use of chloroform in HPLC analysis remained yet to be improved.

A comprehensive analysis of plausible genotoxic covariates among workers of a polyvinyl chloride plant exposed to vinyl chloride monomer.

The aim of this study was to assess the frequency of chromosomal aberrations-including chromatid type aberrations (CTAs), chromosomal type aberrations, micronucleus (MN) comet assay, and XRCC1 399 Arg/Gln polymorphism-in peripheral blood lymphocytes of workers occupationally exposed to vinyl chloride monomer (VCM). A total of 52 workers and an equal number of controls were recruited into the study to explore the potential cytogenetic risk of occupational exposure to VCM. Questionnaires were administered to obtain details of habitual cigarette-smoking, alcohol-consumption pattern, and occupation, etc. The exposed subjects and controls were classified into two groups based on age (group I <40 years; group II ≥40 years), and exposed subjects were further classified based on exposure duration (>8 and ≥8 years). CTA, MN, and comet assay frequency were significantly greater in polyvinyl chloride (PVC) factory workers (p < 0.05) with long-duration work. CTA, MN, and comet assay values were found to be increased with age in exposed subjects as well as in controls, with exposed subjects showing a statistically greater degree. An extensively greater MN frequency was observed in smokers exposed to VCM than in the control group (P < 0.05). The mean tail length of exposed subjects was greater compared with controls. The study on XRCC1 399 Arg/gln polymorphism in PVC factory workers showed less significant difference in allele frequency compared with controls. In conclusion, this results of work provides evidence for an apparent genotoxic effect associated with VCM exposure. Our results reinforce the greater sensitivity of cytogenetic assays for biomonitoring of occupationally exposed populations. Statistics indicate that workers exposed to VCM are at carcinogenic risk and should be monitored for long-term adverse effects from their exposure.

[Workplace-related respiratory allergies. Current developments]. / Inhalationsallergien am Arbeitsplatz. Aktuelle Entwicklungen.

It is common that the inhalation of occupational allergens induces occupational airway diseases, but the inducers are diverse and complex, and the pathomechanism of the disease is not clear in every case. Only few allergens have been studied in detail (e.g., wheat flour and natural rubber latex), and most of the occupational airway sensitizers have only been documented as case reports. This review describes occupational type I aeroallergens according to their source (plant, animal, microbial, and chemical) and workplace application area. New aspects on the diagnosis and legal preventive regulations for occupational allergic airway diseases are described.

Stoffenmanager Nano version 1.0: a web-based tool for risk prioritization of airborne manufactured nano objects.

Stoffenmanager Nano (version 1.0) is a risk-banding tool developed for employers and employees to prioritize health risks occurring as a result of exposure to manufactured nano objects (MNOs) for a broad range of worker scenarios and to assist implementation of control measures to reduce exposure levels. In order to prioritize the health risks, the Stoffenmanager Nano combines the available hazard information of a substance with a qualitative estimate of potential for inhalation exposure. The development of the Stoffenmanager Nano started with a review of the available literature on control banding. Input parameters for the hazard assessment of MNOs were selected based on the availability of these parameters in, for instance, Safety Data Sheets or product information sheets. The conceptual exposure model described by Schneider et al. (2011) was used as the starting point for exposure banding. During the development of the Stoffenmanager Nano tool, the precautionary principle was applied to deal with the uncertainty regarding hazard and exposure assessment of MNOs. Subsequently, the model was converted into an online tool (http://nano.stoffenmanager.nl), tested, and reviewed by a number of companies. In this paper, we describe the Stoffenmanager Nano. This tool offers a practical approach for risk prioritization in exposure situations where quantitative risk assessment is currently not possible. Updates of this first version are anticipated as more data become available in the future.

[ASLE for chemicals in the air of workplace. History, contemporary state, prospects].

The authors followed historical background of occurrence, development, transformation and contemporary state of topic concerning ASLE for chemicals in the air of workplace over 1977-2010 in USSR and Russian Federation. The article covers prospects to improve regulation and methodic aspects of prompt regulation for industrial chemicals in the air of workplace.

Advanced Reach Tool (ART): development of the mechanistic model.

This paper describes the development of the mechanistic model within a collaborative project, referred to as the Advanced REACH Tool (ART) project, to develop a tool to model inhalation exposure for workers sharing similar operational conditions across different industries and locations in Europe. The ART mechanistic model is based on a conceptual framework that adopts a source receptor approach, which describes the transport of a contaminant from the source to the receptor and defines seven independent principal modifying factors: substance emission potential, activity emission potential, localized controls, segregation, personal enclosure, surface contamination, and dispersion. ART currently differentiates between three different exposure types: vapours, mists, and dust (fumes, fibres, and gases are presently excluded). Various sources were used to assign numerical values to the multipliers to each modifying factor. The evidence used to underpin this assessment procedure was based on chemical and physical laws. In addition, empirical data obtained from literature were used. Where this was not possible, expert elicitation was applied for the assessment procedure. Multipliers for all modifying factors were peer reviewed by leading experts from industry, research institutes, and public authorities across the globe. In addition, several workshops with experts were organized to discuss the proposed exposure multipliers. The mechanistic model is a central part of the ART tool and with advancing knowledge on exposure, determinants will require updates and refinements on a continuous basis, such as the effect of worker behaviour on personal exposure, 'best practice' values that describe the maximum achievable effectiveness of control measures, the intrinsic emission potential of various solid objects (e.g. metal, glass, plastics, etc.), and extending the applicability domain to certain types of exposures (e.g. gas, fume, and fibre exposure).

[Preclinical study as a basis for hygienic regulation of benzofuran derivatives].

Experiments on laboratory animals studied toxic effects of benzofuran derivatives obtained during anti-arrythmic drug Amiodarone production. Toxic effects were studied for single and subacute intake through intragastric, inhalation and epicutaneous routes. Recommendations are given for hygienic regulation of Amiodarone and intermediate products of its synthesis in the air of workplace.

Comparison of dust released from sanding conventional and nanoparticle-doped wall and wood coatings.

Introduction of engineered nanoparticles (ENPs) into traditional surface coatings (e.g., paints, lacquers, fillers) may result in new exposures to both workers and consumers and possibly also a new risk to their health. During finishing and renovation, such products may also be a substantial source of exposure to ENPs or aggregates thereof. This study investigates the particle size distributions (5.6 nm-19.8 µm) and the total number of dust particles generated during sanding of ENP-doped paints, lacquers, and fillers as compared to their conventional counterparts. In all products, the dust emissions from sanding were found to consist of five size modes: three modes under 1 µm and two modes around 1 and 2 µm. Corrected for the emission from the sanding machine, the sanding dust, was dominated by 100-300 nm size particles, whereas the mass and surface area spectra were dominated by the micrometer modes. Adding ENPs to the studied products only vaguely affected the geometric mean diameters of the particle modes in the sanding dust when compared to their reference products. However, we observed considerable differences in the number concentrations in the different size modes, but still without revealing a clear effect of ENPs on dust emissions from sanding.

Industrial-grade talc exposure and the risk of mesothelioma.

Industrial-grade talc deposits are complex mixtures of mineral particles and may vary substantially in composition across small geographical areas. Typical industrial-grade talc includes amphibole cleavage fragments, platy talc, serpentine minerals, talc in fibrous form, and a minor presence of transitional fibers. Industrial-grade talc was erroneously determined to be an asbestos-containing material due to an unintended consequence of Occupational Health and Safety Administration's (OSHA's) method for measuring airborne asbestos mandated in 1972. This error was repeated, most notably, by the National Institute for Occupational Safety and Health (NIOSH) in, 1980 for talc mined in northern New York State (NYS) by RT Vanderbilt Company (RTV). Subsequent exposure studies of northern NYS talc conducted through the, 1980s and one study published after, 2000 relied on the conclusion that talc was an asbestos-containing material to infer a causal relationship between talc and mesothelioma. The present review included (1) publications concerning talc's cancer-causing potential issued by organizations concerned with occupational and public health; (2) talc exposure studies and animal and cellular studies of RTV talc; (3) mesothelioma rates in northern NYS; and (4) mesothelioma mortality among RTV mining employees. The review indicated that failure to correctly identify the mineral characteristics of talc resulted in misleading reports concerning the carcinogenic potential of talc. However, the collective data from animal and cellular studies, mesothelioma rates in northern NYS, exposure studies, and a mortality analysis of RTV mining employees do not support a causal relationship between RTV talc and mesothelioma. This conclusion is applicable to all mineral components in RTV talc and to other industrial-grade talcs and mineral aggregates with the same components.

Primary prevention of occupational asthma: identifying and controlling exposures to asthma-causing agents.

BACKGROUND: Primary prevention of occupational asthma requires timely identification and regulation of asthma-causing agents. METHODS: We examined 39 substances identified as causing allergic occupational asthma in the US to determine the basis for their identification and their regulatory status. We compared them with occupational asthmagens identified and regulated in the UK and Germany. RESULTS: US regulatory agencies have not established consistent, evidence-based methods to identify and control exposures to substances that cause occupational asthma. Occupational asthmagens are identified primarily by non-regulatory US organizations, and most are not regulated to prevent asthma. CONCLUSIONS: Implementing an evidence-based identification and regulatory process for occupational asthmagens will help to ensure primary prevention of occupational asthma in the US. This should include: establishing consistent identification criteria; publishing a list of occupational asthmagens; collecting use, exposure, and health effects information on asthma-causing substances; requiring medical surveillance and medical removal protection in addition to exposure limits; and stimulating development of safer alternatives.

An evaluation of the risks of lung cancer and mesothelioma from exposure to amphibole cleavage fragments.

Amphiboles are hydrated mineral silicates five of which occur in asbestiform habits as asbestos grunerite (amosite) asbestos, riebeckite (crocidolite) asbestos, anthophyllite asbestos, tremolite asbestos and actinolite asbestos] and non-asbestiform habits (grunerite, riebeckite, anthophyllite, tremolite and actinolite). The asbestiform varieties are characterized by long, thin fibers while non-asbestiform varieties such as cleavage fragments form short fibers with larger widths. The U.S. regulatory method for counting asbestos fibers (aspect ratio > or = 3:1, length > or = 5 microm) does not distinguish between asbestos and cleavage fragments. The method biases toward increased counts of non-asbestiform cleavage fragments compared to long, thin asbestos fibers. One consequence of this regulatory approach is that workers can be erroneously classified as exposed to concentrations of asbestos (asbestiform amphiboles) above the U.S. 0.1 f/mL exposure standard when in fact they are not exposed to asbestos at all but non-asbestiform amphibole cleavage fragments. Another consequence is that the known carcinogenic effects of asbestos may be falsely attributed to non-asbestiform amphibole cleavage fragments of the same mineral. The purpose of this review is to assess whether amphibole cleavage fragments pose the same risk of lung cancer and mesothelioma characteristic of amphibole asbestos fibers. We identified three groups of workers exposed to non-asbestiform amphiboles: two groups exposed to grunerite (Homestake gold miners and taconite miners) and one group exposed to industrial talc containing non-asbestiform tremolite and anthophyllite in St. Lawrence County, NY. In addition to assessing strength of association and exposure-response trends in the non-asbestiform amphibole cohorts, comparisons were also made with cohorts exposed to the asbestiform counterpart (positive control) and cohorts exposed to the mineral (e.g. talc) that does not contain amphiboles (negative controls). The cohorts exposed to non-asbestiform amphiboles had no excesses of lung cancer or mesothelioma. Similar results were observed in the negative control groups, in stark contrast to the excess risks of asbestos-related disease found in the asbestos cohorts. The only possible exception is the twofold increased risk of lung cancer where exposure was to industrial talc containing cleavage fragments of tremolite and anthophyllite. However, this risk is not considered attributable to the talc or amphibole cleavage fragments for several reasons. A similar increased risk of lung cancer was found in Vermont talc workers, studied in the same time period. Their exposure was to relatively pure talc. There was no relationship between lung cancer mortality and exposure measured as mg/m(3)years and years worked. A case-control study reported that all the lung cancer cases were smokers (or former smokers) and attributed the excess to smoking. There were two mesothelioma cases among the NY State talc workers exposed to cleavage fragments of tremolite and anthophyllite, but talc is not a plausible cause because of too short latency and potential for previous asbestos exposure. The positive controls of tremolite asbestos and anthophyllite asbestos exposed workers showed excess risks of both lung cancer and mesothelioma and positive exposure-response trends. St. Lawrence, NY talc does not produce mesotheliomas in animals while amphibole asbestos does. In sum, the weight of evidence fully supports a conclusion that non-asbestiform amphiboles do not increase the risk of lung cancer or mesothelioma.