Next generation risk assessment for occupational chemical safety - A real world example with sodium-2-hydroxyethane sulfonate.

Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted to assessments of consumer use of cosmetics and is not currently implemented in occupational safety assessments, e.g. under EU REACH. By contrast, a large proportion of regulatory worker safety assessments are underpinned by toxicological studies using experimental animals. Consequently, occupational safety assessment represents an area that would benefit from increasing application of NGRA to safety decision making. Here, a workflow for conducting NGRA under an occupational safety context was developed, which is illustrated with a case study chemical; sodium 2-hydroxyethane sulphonate (sodium isethionate or SI). Exposures were estimated using a standard occupational exposure model following a comprehensive life cycle assessment of SI and considering factory-specific data. Outputs of this model were then used to estimate internal exposures using a Physiologically Based Kinetic (PBK) model, which was constructed with SI specific Absorption, Distribution, Metabolism and Excretion (ADME) data. PBK modelling indicated a worst-case plasma maximum concentration (Cmax) of 0.8 µM across the SI life cycle. SI bioactivity was assessed in a battery of NAMs relevant to systemic, reproductive, and developmental toxicity; a cell stress panel, high throughput transcriptomics in three cell lines (HepG2, HepaRG and MCF-7 cells), pharmacological profiling and specific assays relating to developmental toxicity (Reprotracker and devTOX quickPredict). Points of Departure (PoDs) for SI ranged from 104 to 5044 µM. Cmax values obtained from PBK modelling of occupational exposures to SI were compared with PoDs from the bioactivity assays to derive Bioactivity Exposure Ratios (BERs) which demonstrated the safety for workers exposed to SI under current levels of factory specific risk management. In summary, the tiered and iterative workflow developed here represents an opportunity for integrating non animal approaches for a large subset of substances for which systemic worker safety assessment is required. Such an approach could be followed to ensure that animal testing is only conducted as a "last resort" e.g. under EU REACH.

Comparison of permitted daily exposure (PDE) values for active pharmaceutical ingredients (APIs) - Evidence of a robust approach.

Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.

Noise exposure assessment of occupational health and safety (OHS) consultants: A preliminary study.

No published noise exposure assessment of occupational health and safety (OHS) consultants exists. An assessment was performed to quantify the noise level of OHS consultants while they were on site at a client's facility. OHS consultants wore a dosimeter set to A-weighting, slow response, 60 s log interval and a criterion level of 85dBA with a 3 dB exchange rate. Both the projected time-weighted average (TWA) and projected dose were recorded. Of the 32 noise assessments collected, three had projected TWAs that exceeded the occupational exposure limit of 85 dBA. Nearly 75% of the projected TWA measurements were equal or greater than the Action Level of 80 dBA. According to best practices, occupational noise levels greater than 80 dBA present a risk for noise-induced hearing loss and, therefore, a hearing loss prevention program should be implemented.

PDE concept for controlling cleaning agent residues in pharmaceuticals- A critical analysis.

Cleaning agents (CAs) are used in multipurpose facilities to control carryover contamination of active pharmaceutical ingredients (APIs) to scientifically justified limits. While this is often done with the PDE methodology used for API impurities, it is unclear if it is justifiable and necessary for cleaning agents, which generally represent a comparatively lower health risk. Comparing calculated oral PDE values for CA ingredients (CAIs) from four companies with PDEs of a selected number of small-molecule APIs showed that the toxicity of CAIs is several orders of magnitude lower. Furthermore, a critical review of the toxicity and everyday exposure to the general population of the main CAIs functional groups showed that the expected health risks are generally negligible. This is particularly true if the associated mode of actions cause local toxicity that is usually irrelevant at the concentration of potential residue carryover. This work points towards alternative approaches to the PDE concept to control CAIs' contamination and provides some guidance on grouping and identifying compounds with lower health risks based on exposure and mode of action reasoning. In addition, this work supports the concept that limit values should only be set for CAIs of toxicological concern.

Toxicological assessment method for evaluating the occupational risk of dynamic olfactometry assessors.

The paper aims to propose a new method to evaluate the occupational exposure risk for examiners involved in dynamic olfactometry. Indeed, examiners are possibly exposed to hazardous pollutants potentially present in odorous samples. A standardized method to evaluate the examiners' occupational safety is not yet available and the existing models present some critical aspect if applied to real odorous samples (no uniform reference concentrations applied and presence of compounds for which no toxicity threshold is available). A deepening of assessment procedure to evaluate the occupation exposure risk for olfactometric assessors is necessary. This paper proposes a standardized approach for risk assessment in dynamic olfactometry. The proposed approach allows the quantification synthetic and conservative risk indices. In this model, the use of the hazard index for the odorous mixture was proposed to assess the non-carcinogenic risk; the calculation of the inhalation risk was applied to estimate the carcinogenic risk. Different databases can be used to retrieve proper occupational exposure limits, according to the proposed hierarchical basis. These implementations allow obtaining the complete characterization of real samples which can be used to calculate the minimum dilution factor for protecting the panellists' health.

Inhalation cancer risk assessment for environmental exposure to hexavalent chromium: Comparison of margin-of-exposure and linear extrapolation approaches.

Hexavalent chromium [Cr(VI)] exists in the ambient air at low concentrations (average upperbound ~0.1 ng/m3) yet airborne concentrations typically exceed EPA's Regional Screening Level for residential exposure (0.012 ng/m3) and other similar benchmarks, which assume a mutagenic mode of action (MOA) and use low-dose linear risk assessment models. We reviewed Cr(VI) inhalation unit risk estimates developed by researchers and regulatory agencies for environmental and occupational exposures and the underlying epidemiologic data, updated a previously published MOA analysis, and conducted dose-response modeling of rodent carcinogenicity data to evaluate the need for alternative exposure-response data and risk assessment approaches. Current research supports the role of non-mutagenic key events in the MOA, with growing evidence for epigenetic modifiers. Animal data show a weak carcinogenic response, even at cytotoxic exposures, and highlight the uncertainties associated with the current epidemiological data used in risk assessment. Points of departure from occupational and animal studies were used to determine margins of exposure (MOEs). MOEs range from 1.5 E+3 to 3.3 E+6 with a median of 5 E+5, indicating that current environmental exposures to Cr(VI) in ambient air should be considered of low concern. In this comprehensive review, the divergent results from default linear and MOE assessments support the need for more relevant and robust epidemiologic data, additional mechanistic studies, and refined risk assessment strategies.

Management of acute exposure to toxic gases in the oil & gas industry -a practical approach.

The objective of this work is to present the key elements in the design of emergency management and response plans in scenarios where there has been loss of containment of chemical agents of acute effect focused in the protection of not routinely exposed in a determined occupational environment. To this purpose, a validation of the current criteria for the management of accidental releases is carried out, taking into account hypothetical risk scenarios. The essential elements of the emergency management system are stated, from a systemic perspective and the corresponding risk control actions; recommendations for their implementation are showed, taking as prototype hydrogen sulfide, a highly toxic gas. Non controlled emissions of toxic gases of acute effect from an occupational standpoint represents a priority because of their human and financial high toll. Design and implementation of an appropriate emergency plan for uncontrollable emissions of toxics chemical agents must be addressed.

Quantitative differences between common occupational health risk assessment models.

OBJECTIVES: Methodological studies on occupational health risk assessment (OHRA) models are rarely reported. This study aimed to explore the quantitative differences between common OHRA models. METHODS: The risk ratios (RRs) in five typical industries (leather, wooden furniture manufacturing, printing and dyeing, printing, and garment manufacturing) were investigated using six OHRA models, namely the models from the US Environmental Protection Agency (EPA), Singapore, the Control of Substances Hazardous to Health (COSHH), Australia, Romania, and International Council on Mining and Metals (ICMM). The consistency, correlation, and reliability were evaluated for quantitative differences between the models. RESULTS: The order of the RRs obtained from the EPA, Singaporean, and COSHH models in the five industries was consistent with the order of the inherent risk levels in those industries. The EPA and Singaporean models could effectively distinguish the inherent risk levels of risk factors like xylene and ethyl acetate. The order of RR between the six models was: RR EPA  > RR COSHH  > RR Singaporean  > RR Australian  > RR Romanian and RR ICMM (P < .05). The EPA model had the weakest correlations with other models. The Singaporean model had positive correlations in RRs with the other models (P＜0.01). CONCLUSIONS: The EPA and Singaporean models exhibited good reliability since they could distinguish the inherent risk of the industry or risk factor and tended to get higher risk levels. The EPA model was independent and the Singaporean model had a good correlation with other models. More studies on OHRA methodology are needed.

Reflections on the OECD guidelines for in vitro skin absorption studies.

At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16-18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.

Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2.

In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intravenous (i.v.) and inhalation (inhal.) routes, respectively, were established herein. However, it has been already recognised that there are acceptable differences in the PDE calculations, which may be based on data accessibility, company-specific science-policy decisions or expert judgments. These differences can cause up to a 3-fold lower or higher values. If unnecessarily high factors are applied, this would result in a very conservative PDE value and unneeded additional cleaning and higher manufacturing costs. The PDE values presented are considered to be protective against adverse and pharmacological effects observed in clinical trials and in this case, a very long postmarketing period of paracetamol.

International landscape of limits and recommendations for occupational exposure to engineered nanomaterials.

The increasing concern of possible adverse effects on human health derived from occupational engineered nanomaterials (ENMs) exposure is an issue addressed by entities related to provide guidelines and/or protocols for ENMs regulation. Here we analysed 17 entities from America, Europe and Asia, and some of these entities provide limits of exposure extrapolated from the non-nanosized counterparts of ENMs. The international landscape shows that recommendations are mostly made for metal oxide based ENMs and tonnage is one of the main criteria for ENMs registration, however, sub-nanometric ENMs are emerging and perhaps a novel category of ENMs will appear soon. We identify that besides the lack of epidemiological evidence of ENMs toxicity in humans and difficulties in analysing the toxicological data derived from experimental models, the lack of information on airborne concentrations of ENMs in occupational settings is an important limitation to improve the experimental designs. The development of regulations related to ENMs exposure would lead to provide safer work places for ENMs production without delaying the nanotechnology progress but will also help to protect the environment by taking opportune and correct measures for nanowaste, considering that this could be a great environmental problem in the coming future.

Assessment of silica dust exposure profile in relation to prevalence of silicosis among Indian sandstone mine workers: Need for review of standards.

BACKGROUND: In Indian mines, the prescribed exposure limit (PEL) for free silica dust is 0.15 mg/m3 which is much higher than those of OSHA and the ACGIH. Because of the reporting of high numbers of silicosis cases among Indian sandstone mine workers, the present study was designed to assess the dust exposure profile of the workers and to substantiate correlation of silica exposure with radiographic findings of silicosis. METHODS: A cross-sectional study of 1012 workers actively engaged in sandstone mining was conducted. Chest x-rays were evaluated by the ILO Classification for the detection of pneumoconiosis. Representative 26 personal dust samples were collected using a personal dust sampler and free silica content estimated. RESULTS: Radiographs compatible with silicosis were seen in 12.3% of workers, of which about 90% were ILO category 1 & 2. Prevalence of abnormal profusion increased from 2.9% to 13.1% to 22% as work exposure increased from <10 to 11 to 20 to >20 years, respectively. In dust samples, the mean silica concentration was 0.12 mg/m3 with 70% samples below the prescribed standard of 0.15 mg/m3 . CONCLUSION: The study indicates that silica exposure below the prescribed limit in India is likely to be harmful. The PEL for crystalline silica in India of 0.15 mg/m3 is not adequately protective. Hence, there is an urgent need to reduce exposure to silica in these workplaces to prevent silicosis and to review the present standards as the government of India remains committed to the elimination of silicosis by 2030.

Safety Assessment of Monosaccharides, Disaccharides, and Related Ingredients as Used in Cosmetics.

The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 25 monosaccharides, disaccharides, and related ingredients and concluded these are safe in the present practices of use and concentration described in the safety assessment. Many of these ingredients are common dietary sugars, dietary sugar replacements, or very closely related analogs and salts; 7 of the ingredients are listed by the Food and Drug Administration as generally recognized as safe food substances. The most commonly reported cosmetic function is as a skin-conditioning agent; other commonly reported functions are use as a humectant or as a flavoring agent. The Panel reviewed the animal and clinical data included in this assessment, acknowledged that the oral safety of many of these ingredients has been well established, and found it appropriate to extrapolate the existing information to conclude on the safety of all the monosaccharides, disaccharides, and related ingredients.

Congenital anomalies in the offspring of occupationally exposed mothers: a systematic review and meta-analysis of studies using expert assessment for occupational exposures.

STUDY QUESTION: Is there an association between maternal occupational exposure to solvents, pesticides and metals as assessed by expert-based assessment and congenital anomalies in the offspring? SUMMARY ANSWER: There is an association between maternal occupational exposure to solvents and congenital anomalies in the offspring, including neural tube defects, congenital heart defects and orofacial clefts. WHAT IS KNOWN ALREADY: One important environmental risk factor for development of congenital anomalies is maternal occupational exposure to chemicals in the workplace prior to and during pregnancy. A number of studies have assessed the association with often conflicting results, possibly due to different occupational exposure assessing methods. STUDY DESIGN, SIZE, DURATION: For this systematic review with meta-analysis, the search terms included maternal occupation, exposure, congenital anomalies and offspring. Electronic databases MEDLINE and EMBASE were searched for English studies up to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two reviewers independently screened all citations identified by the search. Case-control studies and cohort studies were included if (I) they reported on the association between maternal occupational exposure to solvents, pesticides or metals and congenital anomalies, and (II) assessment of occupational exposure was performed by experts. Data on study characteristics, confounders and odds ratios (ORs) were extracted from the included studies for four subgroups of congenital anomalies. Methodological quality was assessed using the Newcastle-Ottawa Scale. In the meta-analysis, random effects models were used to pool estimates. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 2806 titles and abstracts and 176 full text papers were screened. Finally, 28 studies met the selection criteria, and 27 studies could be included in the meta-analysis. Our meta-analysis showed that maternal occupational exposure to solvents was associated with neural tube defects (OR: 1.51, 95%CI: 1.09-2.09) and congenital heart defects (OR: 1.31, 95%CI:1.06-1.63) in the offspring. Also maternal occupational exposure to glycol ethers, a subgroup of solvents, was associated with neural tube defects (OR: 1.93, 95%CI: 1.17-3.18) and orofacial clefts (OR: 1.95, 95%CI: 1.38-2.75) in the offspring. Only one study investigated the association between maternal occupational exposure to solvents and hypospadias and found an association (OR: 3.63, 95%CI: 1.94-7.17). Results of the included studies were consistent. In our meta-analysis, we found no associations between occupational exposure to pesticides or metals and congenital anomalies in the offspring. LIMITATIONS, REASONS FOR CAUTION: A limited number of studies was included, which made it impossible to calculate pooled estimates for all congenital anomalies, analyse individual chemicals or calculate exposure-response relations. Bias could have been introduced because not all included studies corrected for potentially confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Employers and female employees should be aware of the possible teratogenic effects of solvent exposure at the workplace. Therefore, is it important that clinicians and occupational health specialist provide women with preconception advice on occupational solvent exposure, to reduce the congenital anomaly risk. STUDY FUNDING/COMPETING INTEREST(S): NSp was paid by the Graduate School of Medical Sciences (MD/PhD program), UMCG, Groningen, the Netherlands. EUROCAT Northern Netherlands is funded by the Dutch Ministry of Health, Welfare and Sports. There are no competing interests. REGISTRATION NUMBER: CRD42017053943.

Probabilistic risk assessment of occupational exposure to volatile organic compounds in the rendering plant of a poultry slaughterhouse.

In this study, occupational exposure to volatile organic compounds (VOCs) in the rendering plant of poultry slaughterhouse was determined and subsequently, carcinogen and non-carcinogenic risks were assessed using the US Environmental Protection Agency (USEPA). National Institute for Occupational Safety and Health (NIOSH) methods of 1501 and 1600 were used to measure VOCs in the breathing zone of the workers. Samples were analyzed by GC/MS. Carcinogenic and non-carcinogenic risks and sensitivity analysis were carried out using Monte Carlo simulations technique. The concentration of benzene and CS2 was higher than the occupational exposure limits (OEL). The hazard quotient (HQ) values for all measured compounds was more than 1, which indicating the high potential for non-carcinogenic risks. Furthermore, the calculated Lifetime Cancer Risks (LCR) for carcinogenic compounds revealed that cancer risk due to benzene is higher than the maximum acceptable level provided by USEPA (10-6). Based on the sensitivity analysis, the concentration and exposure frequency are the most important variable influencing both carcinogen and non-carcinogenic risks. Therefore, the concentration levels of the VOCs and exposure frequency should be controlled using engineering control measures.

The Overview of Methods of Nanoparticle Exposure Assessment.

Nanotechnology is now widely used in industry as well as consumer products, such as electrical devices, cosmetics, medicine, and household appliances. In the life cycle of the nano-products, including production, use, and disposal, nanoparticles may be released to the environment. However, there is no current consensus on the best method for evaluating and characterizing nanoparticle exposure. Therefore, this chapter focuses on the nanoparticle exposure assessment methods and sampling techniques.

Development of a flowchart for risk assessment and allocation of preparation of monoclonal antibodies.

Monoclonal antibodies have expanded as a novel class of therapeutic agents. In contrast to appropriate guidelines for safe handling of cytotoxics, there are no real standards for the safe handling of monoclonal antibodies. Many questions have arisen whether monoclonal antibodies have to be prepared under controlled circumstances or can be prepared on the ward. We developed a flowchart which provides recommendations for the classification of monoclonal antibodies according to their toxicity profile and takes practical and financial issues into account. It allows oncology pharmacists worldwide to define which monoclonal antibodies can/must be prepared in pharmacy aseptic facilities and which monoclonal antibodies can be prepared on the ward.

Occupational Health Risk Assessment in the Electronics Industry in China Based on the Occupational Classification Method and EPA Model.

The awareness of occupational health risk management in the electronics industry is weak in China, and many Chinese occupational health management regulations have not been effectively implemented. China's current occupational hazards classification method and the Environmental Protection Agency (EPA) inhalation risk assessment model recognized internationally were used to perform health risk assessments for a chip manufacturing company in the electronics industry in order to determine the existing problems and put forward the optimization proposals of the occupational hazards classification method in China. The results showed that the detected concentrations of toxic and harmful chemicals in all testing points did not exceed the occupational health exposure limits in China. According to the EPA inhalation risk assessment model, the highest values of non-carcinogenic risks of ammonia, chlorine, fluoride, sulfuric acid, hydrogen chloride, ethylene glycol, phosphine, boron trifluoride, isopropanol, benzene, and xylene were 5.10, 67.12, 1.71, 45.98, 1.83, 1.43, 160.35, 46.56, 2.52, 5.55, and 5.37, respectively, which means workers in electronic chip manufacturing companies exposed to these chemicals have higher occupational health risks. However, on the basis of the occupational hazards classification method, the occupational health risks of exposure to the toxic and hazardous chemicals are relatively harmless operations. The evaluation results of the EPA inhalation risk assessment model are generally higher than those of the occupational hazards classification method. It's recommended to refine the value of occupational exposure limit B, taking more characteristics of the hazard factors into account and fuzzifying the parameters to optimize the occupational hazards classification method. At the same time, it is suggested that the electronic chip manufacturing company should conduct anti-virus risk management covering in three aspects: increasing the awareness of occupational hazards, enhancing system ventilation, and improving personal health management measures.