Derivation of thresholds for inhaled chemically reactive irritants: Searching for substance-specific common denominators for read-across prediction.

Emergency response planning guideline values are used to protect the public when there has been a short-term chemical release. These values serve the purpose of identifying areas where a hazard exists if the concentration of hazardous chemicals is exceeded for the specified exposure duration. This paper focuses on carbonyl chlorides, a class of highly irritant/corrosive chemical intermediates characterized by the reactive moiety R-COCl. Despite their unifying property of reacting with nucleophilic biopolymers/peptides lining the airways of the respiratory tract, their adverse outcome pathway (AOP), in addition to surface area dose, appears to be dominated by their site(s) of major deposition (liquid) or retention (gas) within the respiratory tract. Thus, the physicochemical properties "phase" and "lipophilicity" become more decisive for the AOP than the chemical structure. This complicates the grouping of portal-of-entry irritant chemicals for the read-across prediction of chemicals, especially those with semivolatile properties. Phosgene (COCl2) served as a template to predict emergency response planning levels 2 (non-incapacitating, reversible injury) and 3 (nonlethal) for related chemicals such as SOCl2, formates, and acid chlorides. A rationale and guide to the systematic characterization of uncertainties associated with the lung region, water solubility of the vapor phase, and chemical specificity is given. The approach described in this paper highlights the regional differences and outcomes that are phenotypically described as irritation of the respiratory tract. Especially for such a data-lean group of chemicals, reliable read-across predictions could reduce the uncertainty associated with the derivation of values used for emergency-related risk assessment and management. Likewise, the approach suggested could improve the grouping and categorization of such chemicals, providing a means to reduce animal testing with potentially corrosive chemicals. Overall, the course taken for read-across predictions provided valid estimates as long as emphasis was directed to the physicochemical properties determining the most critical regional injury within the respiratory tract.

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.

Comprehensive tackling to the safe handling of hazardous drugs: a multidisciplinary approach to clinical practice.

OBJECTIVES: The aim of this study is to present the adaptation and implementation of the recommendations of the National Institute for Safety and Health at Work (Instituto Nacional de Seguridad y Salud en el Trabajo - INSHT) in the authors' hospital to achieve a safer handling of hazardous drugs. MATERIAL AND METHODS: In 2016, INSHT published the first document on hazardous drugs in Spain. In the authors' center, a project was developed to implement the recommendations presented in that document in 2 phases: 1) analysis: to identify drugs and processes susceptible to not being handled as hazardous, and to search for safer alternatives and preventive measures; and 2) development: to ensure information, training, the adaptation of standardized work procedures, the minimization of risks associated with handling, safety devices, personal protective equipment (PPE), as well as health monitoring. RESULTS: The authors detected 80 commercial presentations manipulated without adhering to safety conditions, mainly oral (74%) from lists 1 (7.5%), 2 (37.5%) and 3 (55%) of the National Institute for Occupational Safety and Health. The following measures were envisaged to reduce the risk: introducing new presentations (4 lower doses, 1 liquid dose) and centralizing new preparations in the pharmacy service (11 oral formulas, 6 parenteral drugs). Management, spillage and exposure procedures were adapted. Safety measures were included in the prescription and administration applications, and there were some indications of risks in the storage. Overall, 48 referents and 690 nurses were trained. Each unit was provided with PPE and safety devices (e.g., closed systems, RX CRUSH®). The steps prior to the administration were moved to the patient's bedside to align patient and professional safety. During the first 6 months after the implementation, 22 cases of pregnancy (64% among the nursing staff), 4 cases of lactation, and 1 case of conceiving problems were reported. In the cases of oxytocin and the repackaging of list 3, risk management was applied. CONCLUSIONS: The multidisciplinary approach has allowed to achieve a global and safer control of hazardous drugs with a minimal impact on the center. It is important to continuously evaluate the effects of these measures, and to take into account the data of this analysis and any possible new evidence. Int J Occup Med Environ Health. 2020;33(5):621-34.

USP General Chapter <800>: Considerations for Oncology Nursing Practice.

OBJECTIVES: To describe the nurse leader's role in implementing the hazardous drug safe-handling standards from USP General Chapter <800> that are most relevant to oncology nursing practice, and to provide strategies for reducing nurses' exposure to hazardous drugs. DATA SOURCES: Published literature indexed in PubMed, CINAHL, textbooks, and clinical expertise. CONCLUSION: Nurse leaders are essential to promoting a safe environment for nurses handling hazardous cancer drugs. IMPLICATIONS FOR NURSING PRACTICE: Several barriers and challenges to handling hazardous drugs exist and must be overcome before oncology nurses' exposure can be reduced.

Performing a United States Pharmacopeia Chapter <800> Compliant Assessment of Risk.

United States Pharmacopeia Chapter <800>, which became effective on December 1, 2019, addresses handling of hazardous drugs in facilities that make compounded preparations. The Chapter includes minimum facility, engineering controls, personal protective equipment, and other requirements under which all hazardous drugs must be handled. For certain hazardous drugs, an assessment of risk may be performed to determine alternative containment strategies or work practices. This article addresses the legal enforceability of Unites States Pharmacopeia Chapter <800>, how to determine whether a drug is eligible for an assessment of risk, and details important considerations when performing assessments of risk.

Exposure Models for REACH and Occupational Safety and Health Regulations.

Model tools for estimating hazardous substance exposure are an accepted part of regulatory risk assessments in Europe, and models underpin control banding tools used to help manage chemicals in workplaces. Of necessity the models are simplified abstractions of real-life working situations that aim to capture the essence of the scenario to give estimates of actual exposures with an appropriate margin of safety. The basis for existing inhalation exposure assessment tools has recently been discussed by some scientists who have argued for the use of more complex models. In our opinion, the currently accepted tools are documented to be the most robust way for workplace health and safety practitioners and others to estimate inhalation exposure. However, we recognise that it is important to continue the scientific development of exposure modelling to further elaborate and improve the existing methodologies.

Advice to the European Commission as Regards Type and Criteria for Comprehensive Studies to Be Requested From Manufacturers: The Opinion of the Scientific Committee on Health, Environmental, and Emerging Risks (SCHEER).

The European Commission has established a priority list of 15 additives contained in cigarettes and roll-your-own tobacco subject to enhanced reporting obligations. The European Union (EU) Tobacco Products Directive (TPD) prescribes that Member States shall require manufacturers and importers of tobacco products to carry out comprehensive studies on these additives to assess their contribution to any of the properties listed in Article 6 of the TPD: toxicity or addictiveness, characterizing flavor, inhalation facilitation, nicotine uptake, and carcinogenic, mutagenic, or toxic for reproduction. The Scientific Committee on Health, Environmental, and Emerging Risks (SCHEER) has provided guidance on the type and criteria for comprehensive studies, and on the most suitable methodologies to test these 15 tobacco additives as well as additives on future updated lists. The SCHEER proposes a stepwise strategy as the most pragmatic and efficient way to assess the effects of tobacco additives. In addition to proposing specific steps and tests to be considered by industry, some general criteria were also identified such as no comparative testing (testing cigarettes with and without the additive) and no animal studies. As tobacco additives have no benefits for health, but rather may promote use of and addiction to an extremely toxic product, a risk-benefit analysis is not the appropriate paradigm for assessing the additive. When comprehensive studies confirm that additives have any of the properties listed in Article 6 of the TPD, regulatory actions should be considered. If uncertainties cannot be solved by comprehensive studies, the SCHEER recommends that the assessors consider the worst-case evaluation. IMPLICATIONS: In this article, the SCHEER proposes a stepwise strategy to assess (1) the toxic and addictive effects, (2) the characterizing flavor, and (3) facilitating inhalation properties of tobacco additives. The proposed steps and tests provide guidance to (1) Member State on which comprehensive studies should be requested and (2) tobacco industry on which strategy of testing should be applied to address the request and to prepare reports to be sent to the relevant authorities for the evaluation of tobacco additives "safety" to comply with the Tobacco Products Directive 2014/40/EU.

USP General Chapter <800> and Its Impact on Nursing Practice.

EDITOR'S NOTE: The Infusion Nurses Society (INS) and the Journal of Infusion Nursing (JIN) editors are pleased to debut Pharmacology Report, a recurring bimonthly column authored by Susan Kleppin, RPh, FASHP. Susan is an accomplished pharmacist in health-system pharmacy with significant experience in infusion therapy. Her column will discuss relevant pharmacology topics, including medications new to market, safe handling for hazardous drugs, and managing drug shortages. INS and JIN extend Susan a warm welcome.

Hazardous Drug Residues in the Home Setting: Worker Safety Concerns.

Safety concerns have existed for more than 40 years about how hazardous drug (HD) exposure contributes to adverse health outcomes in health care workers. Careless handling causes toxic HD residues to infiltrate hospital and ambulatory care settings and can even be tracked to patient homes. Little is known about the adverse health outcomes experienced by exposed caregivers. The December 1, 2019, release of new regulations will enforce health care organizations to minimize risk to all health care workers by implementing the US Pharmacopeia (USP) General Chapter<800>Hazardous Drugs-Handling in Healthcare Settings safety standards. Worker safety measures include wearing personal protective equipment, even in home care settings.

Ensuring Healthcare Worker Safety When Handling Hazardous Drugs.

Hazardous drugs (HDs) are chemicals that demonstrate one or more of the following characteristics: carcinogenicity, genotoxicity, teratogenicity, reproductive toxicity, or organ toxicity. In addition, newer drugs with a structural or toxicity profile that mimics an agent known to be hazardous by one of the aforementioned criteria also should be treated as such. Any HD-handling activity can result in exposure for healthcare workers, as documented in a multitude of case reports and studies throughout the medical literature. Exposure to HDs has been associated with acute symptoms (e.g., nasal sores, hair loss, skin rash), adverse reproductive outcomes (e.g., infertility, miscarriage), genetic changes (e.g., chromosomal aberrations, sister-chromatid exchanges), and an increased occurrence of cancer.

Evaluating potential refinements to existing Threshold of Toxicological Concern (TTC) values for environmentally-relevant compounds.

The Toxic Substances Control Act (TSCA) mandates the US EPA perform risk-based prioritisation of chemicals in commerce and then, for high-priority substances, develop risk evaluations that integrate toxicity data with exposure information. One approach being considered for data poor chemicals is the Threshold of Toxicological Concern (TTC). Here, TTC values derived using oral (sub)chronic No Observable (Adverse) Effect Level (NO(A)EL) data from the EPA's Toxicity Values database (ToxValDB) were compared with published TTC values from Munro et al. (1996). A total of 4554 chemicals with structures present in ToxValDB were assigned into their respective TTC categories using the Toxtree software tool, of which toxicity data was available for 1304 substances. The TTC values derived from ToxValDB were similar, but not identical to the Munro TTC values: Cramer I ((ToxValDB) 37.3 c. f. (Munro) 30 µg/kg-day), Cramer II (34.6 c. f. 9.1 µg/kg-day) and Cramer III (3.9 c. f. 1.5 µg/kg-day). Cramer III 5th percentile values were found to be statistically different. Chemical features of the two Cramer III datasets were evaluated to account for the differences. TTC values derived from this expanded dataset substantiated the original TTC values, reaffirming the utility of TTC as a promising tool in a risk-based prioritisation approach.

[Rubber granules on synthetic turf pitches: safe or not safe for children?] / Rubbergranulaat op kunstgrasvelden.

Rubber granules from old car tyres used in synthetic turf pitches contain a significant number of carcinogenic and endocrine-disrupting chemicals. In 2017 the Dutch National Institute for Public Health and the Environment (RIVM) and the European Chemical Agency (ECHA) concluded that the risks for children are negligible. However, their reports contain some scientific inaccuracies and omissions which may have led them to underestimate the risks for children. It is therefore premature to conclude that it is safe for children to play on synthetic turf pitches with rubber granules. It is now primarily up to the parents to decide whether or not playing sports is acceptable in these circumstances. The Dutch government should, in accordance with ECHA recommendations, advise parents that their children ought to avoid hand-and-mouth contact with these granules as much as possible.

How to Develop and Maintain a Hazardous Drug List.

United States Pharmacopeia Chapter <800>, concerned with the handling of hazardous drugs in healthcare settings, requires that any entity handling such drugs maintain a hazardous drug list. While this list must include any drug found on the latest NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, entities are expected to include other drugs and substances of concern. This article provides guidance on the creation and maintenance of such a list.

Use of toxicant sensitivity distributions (TSD) for development of exposure guidelines for risk to human health from benzene.

This technique for setting guideline values differs from that currently used by regulatory agencies throughout the world. Data for benzene were evaluated from epidemiological studies on human populations (29 studies). Exposure durations were evaluated in terms of Long Term Exposure (LTE) and Lifetime Exposure. All data was reported as Lowest Observed Adverse Effect Levels (LOAEL) and converted into exposure doses using Average Daily Dose (ADD) and Lifetime Average Daily Dose (LADD). These values were plotted as a Toxicant Sensitivity Distribution (TSD) which was the cumulative probability of LOAEL-ADD and LOAEL-LADD. From the TSD plots, linear regression equations gave correlation coefficients (R2) ranging from 0.69 to 0.97 indicating normal distributions. Guideline Values (GVs) for LTE (8hr/day) and Lifetime (24hr/70yrs) exposure to benzene were calculated using data from human epidemiological studies as 5% level of cumulative probability (CP) of LOAEL-ADD and LOAEL-LADD from the cumulative probability distributions (CPD). The derived guideline values from the human epidemiological studies were 92 µg/kg/day for LTE and 3.4 µg/kg/day for lifetime exposure. GV for LTE is appropriate for occupational exposure and GV derived for lifetime exposure appropriate for the general population. The guideline value for occupational exposure limit was below all the guideline values developed by regulatory agencies. But the general population guideline is within the range of values formulated by European Union, ATSDR, EPAQS, USEPA and OEHHA for air quality for the general population. This is an alternative method which eliminates the application of safety factors and other sources of errors in deriving guideline values for benzene.

Process improvement strategy to prepare and administer bacillus Calmette-Guérin vaccine in compliance with United States Pharmacopeia chapter 800 standards.

PURPOSE: This case study describes a multidisciplinary initiative to promote the safe use, preparation, and administration of bacillus Calmette-Guérin (BCG) in patients with bladder cancer that is in compliance with United States Pharmacopeia chapter 800. SUMMARY: After an evaluation of a hospital's medication-use process for the preparation and administration of BCG identified inconsistencies with guideline-based procedures for the safe handling and manipulation of hazardous drug products, a revised medication-use process promoting the inclusion of pharmacy services was developed by pharmacy and urology clinic leaders. Implementation of the enhanced medication-use process included (1) the shift of BCG vaccine preparation from urology clinic nurses to a pharmacy equipped with the appropriate engineering controls for the safe preparation of hazardous product, (2) greater involvement by pharmacists in BCG order justification and verification, and (3) a process that ensured just-in-time preparation and delivery of medication for enhanced patient satisfaction. After initial process changes resulted in increased turnaround time from preparation to administration, a study on time to preparation, delivery, and administration was conducted and resulted in complete reduction of turnaround times and increased patient satisfaction. CONCLUSION: Through a multidisciplinary initiative involving pharmacists, physicians, nurses, and leadership, a new process to promote the safe preparation and administration of the tuberculosis vaccine Mycobacterium bovis BCG was developed and implemented. The results of a post-implementation time study indicated that a standardized approach to scheduling, preparing, and administering BCG was effective in managing the operations of BCG through having high clinic and patient satisfaction.

Randomized Controlled Trial of an Intervention to Improve Nurses' Hazardous Drug Handling

OBJECTIVES: To evaluate whether a web-based educational intervention improved personal protective equipment (PPE) use among oncology nurses who handle hazardous drugs. SAMPLE & SETTING: From 2015 to 2017, the authors partnered with 12 ambulatory oncology settings in the United States to enroll 396 nurses, 257 of whom completed baseline and primary endpoint surveys. METHODS & VARIABLES: In a cluster randomized controlled trial, 136 nurses in control settings received a one-hour educational module on PPE use with quarterly reminders, and 121 nurses in treatment settings received the control intervention plus tailored messages to address perceived barriers and quarterly data gathered on hazardous drug spills across all study settings. The primary outcome was nurse-reported PPE use. RESULTS: Control and intervention sites had suboptimal PPE use before and after the intervention. No significant differences were observed in PPE use knowledge or perceived barriers. Participants reported high satisfaction with the study experience. IMPLICATIONS FOR NURSING: Hazardous drug exposure confers notable health risks to healthcare workers. To improve hazardous drug handling, occupational healthcare workers, health systems, and professional organizations should consider coordinated efforts to implement policy and practice changes.

Incorporating regulatory guideline values in analysis of epidemiology data.

Fundamental to regulatory guidelines is to identify chemicals that are implicated with adverse human health effects and inform public health risk assessors about "acceptable ranges" of such environmental exposures (e.g., from consumer products and pesticides). The process is made more difficult when accounting for complex human exposures to multiple environmental chemicals. Herein we propose a new class of nonlinear statistical models for human data that incorporate and evaluate regulatory guideline values into analyses of health effects of exposure to chemical mixtures using so-called 'desirability functions' (DFs). The DFs are incorporated into nonlinear regression models to allow for the simultaneous estimation of points of departure for risk assessment of combinations of individual substances that are parts of chemical mixtures detected in humans. These are, in contrast to published so-called biomonitoring equivalent (BE) values and human biomonitoring (HBM) values that link regulatory guideline values from in vivo studies of single chemicals to internal concentrations monitored in humans. We illustrate the strategy through the analysis of prenatal concentrations of mixtures of 11 chemicals with suspected endocrine disrupting properties and two health effects: birth weight and language delay at 2.5 years. The strategy allows for the creation of a Mixture Desirability Function i.e., MDF, which is a uni-dimensional construct of the set of single chemical DFs; thus, it focuses the resulting inference to a single dimension for a more powerful one degree-of-freedom test of significance. Based on the application of this new method we conclude that the guideline values need to be lower than those for single chemicals when the chemicals are observed in combination to achieve a similar level of protection as was aimed for the individual chemicals. The proposed modeling may thus suggest data-driven uncertainty factors for single chemical risk assessment that takes environmental mixtures into account.