Carcinogenicity of Poorly Soluble Low Toxicity Particles: Commentary on Epidemiology as a Risk Assessment "Reality Check".

Inhaled particles that are poorly soluble or insoluble and of low toxicity ("poorly soluble low toxicity" or "PSLT" particles), can accumulate in the lung and at lung overload levels induce lung cancers in rats. The question of whether PSLT particles increase lung cancer risk in humans is complicated by large differences between rats and humans and the relatively large particle doses administered in animal studies even when compared with heavy human occupational exposures. We review the findings of epidemiological studies on occupational exposure to each of three different PSLT particles (carbon black, talc and taconite). The epidemiological evidence indicates that at even very high occupational exposure levels at which non-malignant respiratory diseases including pneumoconiosis and even talcosis are observed, lung cancer risks appear not to be elevated. Although positive human cancer risks might be predicted based on extrapolation from overload doses in rats to relevant exposures in humans, the epidemiological "reality check" based on the three examples indicates that these PSLT particles are unlikely to increase lung cancer risk in humans even at high occupational levels of exposure. Therefore, we propose that careful evaluation of the epidemiological evidence can serve as a "reality check" for human risk assessment and help balance the risk evaluation process.

Setting occupational exposure limits for antimicrobial agents: A case study based on a quaternary ammonium compound-based disinfectant.

Antimicrobial agents have become an essential tool in controlling the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and guidelines on their use have been issued by various public health agencies. Through its Emerging Viral Pathogen Guidance for Antimicrobial Pesticides, the US Environmental Protection Agency has approved numerous surface disinfectant products for use against SARS-CoV-2. Despite their widespread use and range of associated health hazards, the majority of active ingredients in antimicrobial products, such as surface disinfectants, lack established occupational exposure limits (OELs) to assist occupational health professionals in characterizing risks from exposures to these chemicals. Based on established approaches from various organizations, a framework for deriving OELs specific to antimicrobial agents was developed that relies on a weight-of-evidence evaluation of the available data. This framework involves (1) a screening-level toxicological assessment based on a review of the existing literature and recommendations, (2) identification of the critical adverse effect(s) and dose-response relationship(s), (3) identification of alternative health-based exposure limits (HBELs), (4) derivation of potential OELs based on identified points of departure and uncertainty factors and/or modification of existing alternative HBELs, and (5) selection of an appropriate OEL. To demonstrate the use of this framework, a case study is described for selection of an OEL for a disinfectant product containing quaternary ammonium compounds (quats). Three potential OELs were derived for this product based on irritation toxicity data, developmental and reproductive toxicity (DART) data, and modification of an existing HBEL. The final selected OEL for the quats-containing product was 0.1 mg/m3, derived from modification of an existing HBEL. This value represented the lowest resulting value of the three approaches, and thus, was considered protective of irritation and potential DART.

Ethylene Oxide: Cancer Evidence Integration and Dose-Response Implications.

The International Agency for Research on Cancer (IARC) and the United States Environmental Protection Agency (USEPA) classified ethylene oxide (EtO) as a known human carcinogen. Critically, both noted that the epidemiological evidence based on lymphoid and breast cancers was "limited," but that the evidence in animal studies was "sufficient" and "extensive" (respectively) and that EtO is genotoxic. The USEPA derived one of the highest published inhalation unit risk (IUR) values (3 × 10-3 per [µg/m3 EtO]), based on results from 2 epidemiological studies. We performed focused reviews of the epidemiological and toxicological evidence on the carcinogenicity of EtO and considered the USEPA's reliance on a genotoxic mode of action to establish EtO's carcinogenicity and to determine likely dose-response patterns. Higher quality epidemiological studies demonstrated no increased risk of breast cancers or lymphohematopoietic malignancies (LHM). Similarly, toxicological studies and studies of early effect biomarkers in animals and humans provided no strong indication that EtO causes LHM or mammary cancers. Ultimately, animal data are inadequate to define the actual dose-response shape or predict tumor response at very low doses with any confidence. We conclude that the IARC and USEPA classification of EtO as a known human carcinogen overstates the underlying evidence and that the IUR derived by USEPA grossly overestimates risk.

The Dermal Exposure Risk Management and Logic eTookit: Characterizing and managing dermal exposure during emergency management operations.

OBJECTIVE: Emergency management and operations (EMO) personnel require up-to-date information to make informed decisions during natural and man-made disasters. However, information gaps present challenges for accessing human health risk assessment and risk management strategies for dermal exposure. This article describes the development of a decision support system, the Dermal Exposure Risk Management and Logic (DERMaL) eToolkit. DESIGN: The DERMaL eToolkit provides information on key resources used in emergency incidents. Resources were classified according to response phase, resource categories, and information category and evaluated on reliability, accessibility, and preference by subject matter experts in emergency management fields. These rankings were used to generate a value of information score, unique for each resource, which aids in developing reference lists for users during each incident phase. RESULTS: This tool will identify and prioritize information resources on dermal risks, and can readily find the most relevant information to suit EMO needs. CONCLUSION: The DERMaL eToolkit can be used as an aid in finding information resources targeted to scenario-driven needs by providing well-vetted and prioritized resources related to dermal hazards, exposure, and risk assessments for EMO.

Implications of applying cumulative risk assessment to the workplace.

Multiple changes are influencing work, workplaces and workers in the US including shifts in the main types of work and the rise of the 'gig' economy. Work and workplace changes have coincided with a decline in unions and associated advocacy for improved safety and health conditions. Risk assessment has been the primary method to inform occupational and environmental health policy and management for many types of hazards. Although often focused on one hazard at a time, risk assessment frameworks and methods have advanced toward cumulative risk assessment recognizing that exposure to a single chemical or non-chemical stressor rarely occurs in isolation. We explore how applying cumulative risk approaches may change the roles of workers and employers as they pursue improved health and safety and elucidate some of the challenges and opportunities that might arise. Application of cumulative risk assessment should result in better understanding of complex exposures and health risks with the potential to inform more effective controls and improved safety and health risk management overall. Roles and responsibilities of both employers and workers are anticipated to change with potential for a greater burden of responsibility on workers to address risk factors both inside and outside the workplace that affect health at work. A range of policies, guidance and training have helped develop cumulative risk assessment for the environmental health field and similar approaches are available to foster the practice in occupational safety and health.

Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches.

Uncertainties in understanding all potential modes-of-action for asthma induction and elicitation hinders design of hazard characterization and risk assessment methods that adequately screen and protect against hazardous chemical exposures. To address this challenge and identify current research needs, the University of Cincinnati and the American Cleaning Institute hosted a webinar series to discuss the current state-of-science regarding chemical-induced asthma. The general consensus is that the available database, comprised of data collected from routine clinical and validated toxicological tests, is inadequate for predicting or determining causal relationships between exposures and asthma induction for most allergens. More research is needed to understand the mechanism of asthma induction and elicitation in the context of specific chemical exposures and exposure patterns, and the impact of population variability and patient phenotypes. Validated tools to predict respiratory sensitization and to translate irritancy assays to asthma potency are needed, in addition to diagnostic biomarkers that assess and differentiate allergy versus irritant-based asthmatic responses. Diagnostic methods that encompass the diverse etiologies of asthmatic responses and incorporate robust exposure measurements capable of capturing different temporal patterns of complex chemical mixtures are needed. In the absence of ideal tools, risk assessors apply hazard-based safety assessment methods, in conjunction with active risk management, to limit potential asthma concerns, proactively identify new concerns, and ensure deployment of approaches to mitigate asthma-related risks.

OCCUPATIONAL ALLERGY.

An estimated 11 million workers in the USA are potentially exposed to agents that can become a cause of allergic diseases such as occupational asthma and allergic contact dermatitis, which can adversely affect health and well-being. Hundreds of chemicals (e.g. metals, epoxy and acrylic resins, rubber additives, and chemical intermediates) and proteins (e.g. natural rubber latex, plant proteins, mould, animal dander) present in virtually every industry have been identified as causes of allergic disease. In general, allergens can be classified as low molecular weight (chemical) allergens and high molecular weight (protein) allergens. These agents are capable of inducing immunological responses that are both immunoglobulin E and non-immunoglobulin E-mediated. Interestingly, the same chemical can induce diverse immune responses in different individuals. As new hazards continue to emerge, it is critical to understand the immunological mechanisms of occupational allergic disease. Specific understanding of these mechanisms has direct implications in hazard identification, hazard communication, and risk assessment. Such efforts will ultimately assist in the development of risk management strategies capable of controlling workplace exposures to allergens to prevent the induction of sensitisation in naïve individuals and inhibit elicitation of allergic responses. The purpose of this short review is to give a brief synopsis of the incidence, agents, mechanisms, and research needs related to occupational allergy.

A decision support framework for characterizing and managing dermal exposures to chemicals during Emergency Management and Operations.

Emergency Management and Operations (EMO) personnel are in need of resources and tools to assist in understanding the health risks associated with dermal exposures during chemical incidents. This article reviews available resources and presents a conceptual framework for a decision support system (DSS) that assists in characterizing and managing risk during chemical emergencies involving dermal exposures. The framework merges principles of three decision-making techniques: 1) scenario planning, 2) risk analysis, and 3) multicriteria decision analysis (MCDA). This DSS facilitates dynamic decision making during each of the distinct life cycle phases of an emergency incident (ie, preparedness, response, or recovery) and identifies EMO needs. A checklist tool provides key questions intended to guide users through the complexities of conducting a dermal risk assessment. The questions define the scope of the framework for resource identification and application to support decision-making needs. The framework consists of three primary modules: 1) resource compilation, 2) prioritization, and 3) decision. The modules systematically identify, organize, and rank relevant information resources relating to the hazards of dermal exposures to chemicals and risk management strategies. Each module is subdivided into critical elements designed to further delineate the resources based on relevant incident phase and type of information. The DSS framework provides a much needed structure based on contemporary decision analysis principles for 1) documenting key questions for EMO problem formulation and 2) a method for systematically organizing, screening, and prioritizing information resources on dermal hazards, exposures, risk characterization, and management.

A decision support framework for characterizing and managing dermal exposures to chemicals during Emergency Management and Operations.

Emergency Management and Operations (EMO) personnel are in need of resources and tools to assist in understanding the health risks associated with dermal exposures during chemical incidents. This article reviews available resources and presents a conceptual framework for a decision support system (DSS) that assists in characterizing and managing risk during chemical emergencies involving dermal exposures. The framework merges principles of three decision-making techniques: 1) scenario planning, 2) risk analysis, and 3) multicriteria decision analysis (MCDA). This DSS facilitates dynamic decision making during each of the distinct life cycle phases of an emergency incident (ie, preparedness, response, or recovery) and identifies EMO needs. A checklist tool provides key questions intended to guide users through the complexities of conducting a dermal risk assessment. The questions define the scope of the framework for resource identification and application to support decision-making needs. The framework consists of three primary modules: 1) resource compilation, 2) prioritization, and 3) decision. The modules systematically identify, organize, and rank relevant information resources relating to the hazards of dermal exposures to chemicals and risk management strategies. Each module is subdivided into critical elements designed to further delineate the resources based on relevant incident phase and type of information. The DSS framework provides a much needed structure based on contemporary decision analysis principles for 1) documenting key questions for EMO problem formulation and 2) a method for systematically organizing, screening, and prioritizing information resources on dermal hazards, exposures, risk characterization, and management.

Analysis of finite dose dermal absorption data: implications for dermal exposure assessment.

A common dermal exposure assessment strategy estimates the systemic uptake of chemical in contact with skin using the fixed fractional absorption approach: the dermal absorbed dose is estimated as the product of exposure and the fraction of applied chemical that is absorbed, assumed constant for a given chemical. Despite the prominence of this approach there is little guidance regarding the evaluation of experiments from which fractional absorption data are measured. An analysis of these experiments is presented herein, and limitations to the fixed fractional absorption approach are discussed. The analysis provides a set of simple algebraic expressions that may be used in the evaluation of finite dose dermal absorption experiments, affording a more data-driven approach to dermal exposure assessment. Case studies are presented that demonstrate the application of these tools to the assessment of dermal absorption data.

Dermal permeation of 2-hydroxypropyl acrylate, a model water-miscible compound: effects of concentration, thermodynamic activity and skin hydration.

UNLABELLED: The goal of these studies was to measure and interpret the skin permeability characteristics of 2-hydroxypropyl acrylate (HPA) as a model compound that is completely miscible with water. METHODS: In vitro permeation from HPA-H2O binary mixtures through human epidermis and silicone membranes was measured. Thermodynamic activities of HPA and H2O in these mixtures were determined. Permeation was also measured through epidermis and silicone from donor solutions with constant HPA activity but different H2O activities. Water uptake into desiccated human stratum corneum (SC) equilibrated with HPA-H2O mixtures was determined. RESULTS: Steady-state flux of HPA through silicone was a linear function of HPA activity but not HPA concentration. For epidermis on the other hand, flux increased with HPA activity only for HPA activities ≤ 0.35. At constant HPA activity, flux decreased 4.5-fold as water activity decreased from 1 to 0.8. Incubation of SC with HPA-H2O mixtures resulted in substantial changes in SC water content, dependent on the water activity of the mixture and consistent with measured SC water sorption data. CONCLUSIONS: These experiments provide unequivocal evidence of a substantial increase in epidermal barrier function resulting from SC dehydration. Dehydration-related alterations in the SC appear responsible for the observed flux characteristics.

Recommendations for biomonitoring of emergency responders: focus on occupational health investigations and occupational health research.

The disaster environment frequently presents rapidly evolving and unpredictable hazardous exposures to emergency responders. Improved estimates of exposure and effect from biomonitoring can be used to assess exposure-response relationships, potential health consequences, and effectiveness of control measures. Disaster settings, however, pose significant challenges for biomonitoring. A decision process for determining when to conduct biomonitoring during and following disasters was developed. Separate but overlapping decision processes were developed for biomonitoring performed as part of occupational health investigations that directly benefit emergency responders in the short term and for biomonitoring intended to support research studies. Two categories of factors critical to the decision process for biomonitoring were identified: Is biomonitoring appropriate for the intended purpose and is biomonitoring feasible under the circumstances of the emergency response? Factors within these categories include information needs, relevance, interpretability, ethics, methodology, and logistics. Biomonitoring of emergency responders can be a valuable tool for exposure and risk assessment. Information needs, relevance, and interpretability will largely determine if biomonitoring is appropriate; logistical factors will largely determine if biomonitoring is feasible. The decision process should be formalized and may benefit from advance planning.

Cumulative Risk Assessment (CRA): transforming the way we assess health risks.

Human health risk assessments continue to evolve and now focus on the need for cumulative risk assessment (CRA). CRA involves assessing the combined risk from coexposure to multiple chemical and nonchemical stressors for varying health effects. CRAs are broader in scope than traditional chemical risk assessments because they allow for a more comprehensive evaluation of the interaction between different stressors and their combined impact on human health. Future directions of CRA include greater emphasis on local-level community-based assessments; integrating environmental, occupational, community, and individual risk factors; and identifying and implementing common frameworks and risk metrics for incorporating multiple stressors.

In vitro human epidermal penetration of 1-bromopropane.

1-Bromopropane (1-BP; CAS number 106-94-5), also known as n-propyl bromide, is a halogenated short-chain alkane used as an organic solvent with numerous commercial and industrial applications, including garment dry cleaning and vapor degreasing of metals. The purpose of this study was to determine the dermal absorption characteristics and corrosivity of 1-BP. Heat-separated human epidermal membranes were mounted on static diffusion cells. Different exposure scenarios were studied (infinite dose, finite dose, and transient exposure) using neat 1-BP and saturated aqueous solution as donor. Steady-state fluxes for infinite-dose neat 1-BP exposure averaged 625 to 960 µg cm(-2) h(-1). The finite-dose (10 µl/cm(2) = 13.5 mg/cm(2)) unoccluded donor resulted in penetration of <0.2% of the applied dose (22 µg/cm(2)). A 10-min transient exposure to infinite dose resulted in total penetration of 179 µg/cm(2). Steady-state 1-BP fluxes from neat application of a commercial dry cleaning solvent were similar (441 to 722 µg cm(-2) h(-1)). The permeability coefficient of 1-BP in water vehicle was 0.257 ± 0.141 cm/h. The absorption potential of 1-BP following dermal exposure is dependent upon the type and duration of exposure. Donor losses due to evaporation were approximately 500-fold greater than dermal absorption flux; evaporation flux was 420 mg cm(-2) h(-1). 1-BP is cytotoxic but not corrosive, based on results from a cultured reconstructed human epidermal model (EpiDerm Skin Corrosivity Test).

The evolution of skin notations for occupational risk assessment: a new NIOSH strategy.

This article presents an overview of a strategy for assignment of hazard-specific skin notations (SK), developed by the National Institute for Occupational Safety and Health (NIOSH). This health hazard characterization strategy relies on multiple SKs capable of delineating systemic (SYS), direct (DIR), and immune-mediated (SEN) adverse effects caused by dermal exposures to chemicals. One advantage of the NIOSH strategy is the ability to combine SKs when it is determined that a chemical may cause multiple adverse effects following dermal contact (e.g., SK: SYS-DIR-SEN). Assignment of the SKs is based on a weight-of-evidence (WOE) approach, which refers to the critical examination of all available data from diverse lines of evidence and the derivation of a scientific interpretation based on the collective body of data including its relevance, quality, and reported results. Numeric cutoff values, based on indices of toxic potency, serve as guidelines to aid in consistently determining a chemical's relative toxicity and hazard potential. The NIOSH strategy documents the scientific rationale for determination of the hazard potential of a chemical and the subsequent assignment of SKs. A case study of acrylamide is presented as an application of the NIOSH strategy.

Evaluation of asbestos exposure within the automotive repair industry: a study involving removal of asbestos-containing body sealants and drive clutch replacement.

Two independent assessments were performed of airborne asbestos concentrations generated during automotive repair work on vintage vehicles . The first involved removal of asbestos-containing seam sealant, and the second involved servicing of a drive clutch. Despite the relatively high concentrations (5.6-28%) of chrysotile fibers detected within bulk samples of seam sealant, the average asbestos concentration for personal breathing zone (PBZ) samples during seam sealant removal was 0.006 f/cc (fibers/cubic centimeter of air). Many other air samples contained asbestos at or below the analytical limit of detection (LOD). Pneumatic chiseling of the sealant material during removal resulted in 69% of area air samples containing asbestos. Use of this impact tool liberated more asbestos than hand scraping. Asbestos fibers were only detected in air samples collected during the installation of a replacement clutch. The highest asbestos corrected airborne fiber concentration observed during clutch installation was 0.0028 f/cc. This value is approximately 100 times lower than Occupational Safety and Health Administration's (OSHA) permissible exposure limit (PEL) of 0.1f/cc. The airborne asbestos concentrations observed during the servicing of vintage vehicles with asbestos-containing seam sealant and clutches are comparable to levels reported for repair work involving brake components and gaskets.