Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety.

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals-i.e., the field of kinetics-often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

The effects of cadmium on the development of Drosophila and its transgenerational inheritance effects.

A new focus in toxicology research is the impact of parental exposure to environmental toxic substances on the characteristics of offspring. In the present study, newly produced eggs of Drosophila melanogaster were treated with different concentrations of cadmium (0, 1, 2, 4, 8 mg/kg) to study the effects of development. The results showed that cadmium changed the larval body length and weight, prolonged the pupation and eclosion time, and changed the relative expression levels of development-related genes (baz, ß-Tub60D, tj). Furthermore, the parental Drosophila (F0) were treated with cadmium (4.5 mg/kg) from egg stage, and when grows to adults, they mated in standard medium to produce the de-stressed offspring (F1-F4) to assess the transgenerational effects of developmental delay. The results showed that the delayed effects of the pupation and eclosion time could be maintained for two generations, and the inhibiting effects of juvenile hormone (JH) and ecdysone (20-hydroxyecdysone, 20E) could be maintained for two or three generations. More importantly, cadmium increased the expression of DNA methylation-related genes (dDnmt2, dMBD2/3) in the ovaries (F0-F2) and testicles (F0 and F1). In addition, cadmium accumulated in parental Drosophila (F0) was not transmitted to offspring through reproductive pathway. These results demonstrate that the developmental toxicity caused by cadmium could be transmitted to the de-stressed offspring, and the observed transgenerational inheritance effects may be associated with epigenetic regulation, underscoring the need to consider fitness of future generations in evaluating the toxicity and environmental risks of cadmium.

Tubing determination in an hematology oncology clinic.

United States Pharmacopeia (USP) Chapter <800> for hazardous drug (HD) handling in healthcare settings requires HD be primed intravenously with a non-HD solution prior to dispensing. This review details our clinic's algorithm for determining tubing needs for medications used in an hematology oncology clinic. Factors to consider are volume, irritant and vesicant properties, and compatibility with hydration solution.

Is secondary chemical exposure of hospital personnel of clinical importance?

INTRODUCTION: There is increasing concern among hospital personnel about potential secondary exposure when treating chemically contaminated patients. OBJECTIVE: To assess which circumstances and chemicals require the use of Level C Personal Protective Equipment (chemical splash suit and air-purifying respirator), to prevent secondary contamination of hospital personnel treating a chemically contaminated patient. METHODS: The US National Library of Medicine PubMed database was searched for the years 1985 to 2020 utilizing combinations of relevant search terms. This yielded 557 papers which were reviewed by title and abstract. After excluding papers on biological or radiological agents, or those not related to hospital personnel, 38 papers on chemicals remained. After a full-text review, 13 papers without an in-depth discussion on the risk for secondary contamination were omitted, leaving 25 papers for review. The references of these papers were searched and this yielded another seven additional citations, bringing the total to 32 papers. INCIDENCE OF SECONDARY TOXICITY: Secondary toxicity in hospital personnel is rare: a large-scale inventory of 120,000 chemical incidents identified only nine cases, an occurrence of 0.0075%. SKIN CONTACT AS A SECONDARY EXPOSURE ROUTE: Skin exposure is rare under normal hygienic working conditions, reflected by the very small number of cases reported in the literature: two cases with corrosive effects due to unprotected contact and one case of presumed skin absorption. INHALATION AS A SECONDARY EXPOSURE ROUTE: Most case reports described secondary toxicity as a result of inhalation. The chemicals involved were irritating solid particles (capsaicin spray/CS), toxic gases formed in the stomach of patients (arsine/hydrazoic acid/phosphine) and vapours from volatile liquids (solvents). FEATURES OF SECONDARY TOXICITY: Reported symptoms after secondary inhalation were generally mild and reversible (mostly irritation of eyes and respiratory tract, nausea, headache, dizziness/light-headedness) and did not require treatment. In many cases, special circumstances increased exposure: treatment/decontamination of multiple patients, regurgitation of the chemical agent from the stomach, or inadequate room ventilation. USE OF MORE THAN STANDARD PERSONAL PROTECTIVE EQUIPMENT: Normal hygienic precautions prevent direct skin contact from exposure to common chemical agents. When solid particle contamination is extensive, a mask and eye protection should be applied. Splash proof outer clothing (splash suit) and eye protection is preferred if (partial) wet decontamination is performed on single patients. Adequate ventilation, careful removal of clothing in case of solid particles contamination and adequate disposal of gastric content reduces exposure. Hospital staff can be rotated if symptoms occur, which can be odour-mediated. The use of more elaborate personal protective equipment with an air-purifying respirator (Level C) is only necessary in exceptional cases of contamination with highly toxic volatile chemicals (e.g., sarin). It should also be considered when decontaminating a large number of patients. CONCLUSIONS: The risk of secondary contamination and subsequent toxicity in hospital personnel decontaminating or treating chemically contaminated patients is small. Normal hygienic precautions (gloves and water-resistant gown) will adequately protect hospital staff when treating the majority of chemically contaminated patients. More extensive protection is only necessary infrequently and there is no reason to delay critical care, even if more elaborate protection is not immediately available.

Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity.

A group of triazole compounds was selected to investigate the confidence that may be associated with read-across of a complex data gap: repeated dose toxicity. The read-across was evaluated using Assessment Elements (AEs) from the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF), alongside appraisal of associated uncertainties. Following an initial read-across based on chemical structure and properties, uncertainties were reduced by the integration of data streams such as those from New Approach Methodologies (NAM) and other existing data. In addition, addressing the findings of the ECHA RAAF framework, complemented with specific questions concerning uncertainties, increased the confidence that can be placed in read-across. Although a data rich group of compounds with a strong mechanistic basis was analysed, it was clearly demonstrated that NAM data available from publicly available resources could be applied to support read-across. It is acknowledged that most read-across studies will not be so data rich or mechanistically robust, therefore some targeted experimentation may be required to fill the data gaps. In this sense, NAMs should constitute new experimental tests performed with the specific goal of reducing the uncertainties and demonstrating the read-across hypothesis.

Review of economic data on closed system transfer drug for preparation and administration of hazardous drugs.

OBJECTIVES: The objectives of this study were to review economic data on the use of closed system drug transfer devices (CSTDs) for preparing and administering hazardous drugs, and to evaluate the quality of data reporting as defined by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). METHODS: All references from a recent Cochrane review about CSTDs were evaluated for inclusion. A literature review was also conducted. Articles containing economic data about the use of CSTDs were retained for analysis. Two researchers independently graded the articles according to the 24-item CHEERS checklist. RESULTS: Of the 138 articles identified initially, 12 were retained for analysis. Nine of these studies did not report acquisition costs or did not detail acquisition costs. Six studies reported economic benefits associated with the used of CSTDs, all related to extending the beyond-use date. The mean number of CHEERS criteria fulfilled by the included articles was 9.2 (SD 2.4). CONCLUSIONS: CSTDs are costly to acquire. However, few studies have examined the economic impact of these devices, and the existing studies are incomplete. As a result, hospitals planning to implement these devices will be unable to make a sound economic evaluation. Robust economic evaluation of CSTDs is needed.

Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management.

The KMD (kinetically-derived maximum dose) is an increasingly advocated concept that uses toxicokinetic data in the top dose selection for toxicity testing. Application of this concept may have serious regulatory implications though, especially in the European Union. The basic assumption is that the relationship between internal and external dose (IED) shows an inflection point where linearity transits into non-linearity due to saturation of underlying processes; top doses in toxicity tests should not be above the inflection point, provided human exposures are well below this point. A critical analysis of the KMD concept and its underlying assumptions shows, however, that the IED relationship is non-linear over the whole dose range, without any point of inflection. The KMD concept thus aims to estimate a non-existing point, rendering it invalid for use in toxicity testing. Moreover, the concept ignores the key question in toxicology: What kind of toxic effects occur at which doses? These and several other reservations against the KMD concept are discussed and illustrated with three existing applications of the KMD approach. Hence, we recommend to abolish the KMD concept for selecting top doses in toxicity testing. This requires the updating of regulations, guidance documents and OECD test guidelines.

Comparison of threshold of toxicological concern (TTC) values to oral reference dose (RfD) values.

Thousands of chemicals have limited, or no hazard data readily available to characterize human risk. The threshold of toxicological concern (TTC) constitutes a science-based tool for screening level risk-based prioritization of chemicals with low exposure. Herein we compare TTC values to more rigorously derived reference dose (RfD) values for 288 chemicals in the U.S. Environmental Protection Agency's (US EPA) Integrated Risk Information System (IRIS) database. Using the Cramer decision tree and the Kroes tiered decision tree approaches to determine TTC values, the TCC for the majority of these chemicals were determined to be lower than their corresponding RfD values. The ratio of log10(RfD/TCC) was used to measure the differences between these values and the mean ratio for the substances evaluated was ~0.74 and ~0.79 for the Cramer and Kroes approach, respectively, when considering the Cramer Classes only. These data indicate that the RfD values for Cramer Class III compounds were, on average, ~6-fold higher than their TTC value. These analyses indicate that provisional oral toxicity values might be estimated from TTCs in data-poor or emergency situations; moreover, RfD values that are well below TTC values (e.g., 2 standard deviations below the log10(Ratio)) might be overly conservative and targets for re-evaluation.

A Protocol for the Safe Use of Hazardous Drugs in the OR.

Hazardous drug (HD) use in the perioperative environment poses unique challenges and risks for exposure that can have adverse consequences for perioperative personnel. The United States Pharmacopeial Convention has implemented new standards to address the safe handling and administration of HDs by health care workers. To comply with these standards and minimize perioperative personnel's occupational exposure to HDs, a multidisciplinary team at an academic medical center in Boston that was performing an increased number and variety of operative and other invasive procedures using antineoplastic agents updated their protocol for the safe use of HDs in the OR. This article discusses HDs and the risks they pose to health care workers and outlines the new HD safety protocol for the OR that was part of a performance improvement plan to ensure compliance with new standards and staff member safety in the perioperative setting.

Decontamination efficacy of soapy water and water washing following exposure of toxic chemicals on human skin.

Aim of the study: Following exposure to toxic chemicals, skin uptake is a potential route of intoxication. Therefore, efficient methods for rapid skin decontamination to mitigate systemic effects are of utmost importance. In operational guidelines, skin decontamination is recommended to be performed by dry absorption and washing with water or soapy water. In the present study, evaluation of decontamination efficacy using water or soapy water was performed for five chemicals, three toxic industrial chemicals and two simulants for chemical warfare agents.Materials and methods: Decontamination was initiated at time points 5, 15, 45 and 120 min after exposure in order to evaluate the time window for efficient decontamination. Experiments were conducted utilizing an in vitro skin penetration model to allow exposure of toxic chemicals on human skin. Results: For all test substances, it was clearly demonstrated that decontamination had greater efficacy when initiated at the earliest time-point while decontamination after 120 min was less efficient. Adding soap to the water showed no significant improvement for any of the tested substances.Conclusion: These results are of reledvance for the development of efficient operational decontamination procedures.

Hazard characterization of silver nanoparticles for human exposure routes.

Silver nanoparticles (AgNPs) have been widely used for a multitude of applications without full comprehensive knowledge regarding their safety. In particular, lack of data on hazard characterization may lead to uncertainties regarding potential human health risk. To provide the foundation for human health risk assessment of AgNPs, this study evaluates existing hazard characterization data, including reported pharmacokinetics, symptoms, and their corresponding dose-response relationships. Human equivalent relationships are also provided by extrapolation from animal dose-response relationships. From the data analyzed, it appears that AgNPs may persist for long periods (from days to years) in the human body. It was found that AgNP toxicity on traditional major targets of exogenous substances were generally underestimated. Some omissions of toxicity on sensitive systems in the AgNP toxicity assessment require attention, such as reprotoxicity and neurotoxicity. The necessity of the establishment of toxicity tests specifically for nanomaterials is highlighted. The scientific basis of a toxicity testing strategy is advised by this study, which paves the way for the monitoring and regulation of the ENP utilization in various industries.

Personal Protective Equipment: Evaluating Usage Among Inpatient and Outpatient Oncology Nurses.

BACKGROUND: Chemotherapy agents have long been considered hazardous, and safety for healthcare providers when administering these drugs is a primary concern. Personal protective equipment (PPE) is known to decrease exposure to hazardous drugs. Studies report that PPE is underused among healthcare providers in inpatient and outpatient settings. OBJECTIVES: The purpose of this study was to examine the use of PPE among inpatient and outpatient nurses while administering hazardous chemotherapy agents. METHODS: This cross-sectional, descriptive study used the Hazardous Drug Handling Questionnaire (HDHQ) to measure nurses' self-reported use of PPE. FINDINGS: Results of the HDHQ indicated that nurses are not using PPE as recommended by hazardous drug administration guidelines. Interventions for proper PPE usage include interprofessional collaboration among oncology nurses, administrators, organizations, and healthcare systems to ensure the safety of healthcare providers, patients, and family caregivers.

USP <800>: Gaining Compliance Through Implementation of a Hazardous Drug Control Program.

Medical facilities in the United States are faced with the challenge of meeting the December 2019 requirements of U.S. Pharmacopeial Convention General Chapter <800> (USP <800>) Hazardous Drugs-Handling in Healthcare Settings. A 300-bed hospital in western Washington formed a practice improvement group to address the requirements of USP <800>. The development of a hazardous drug control program at the hospital not only met the requirements of USP <800> but also helped staff members understand what hazardous drugs are and the safety measures that are necessary when handling them.

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.

Flavored Versus Nonflavored Waterpipe Tobacco: A Comparison of Toxicant Exposure, Puff Topography, Subjective Experiences, and Harm Perceptions.

INTRODUCTION: Flavored waterpipe (WP) tobacco is the main type of tobacco used by young WP smokers, and a major factor attracting youth to smoke. However, evidence regarding the effect of limiting flavor on WP smokers' experience continues to be lacking. This study aims at evaluating the effect of flavor restriction on WP smokers' toxicant exposure, smoking topography, subjective experiences and harm perception. METHODS: Thirty-two WP smokers completed two, 45-minute ad libitum smoking sessions (preferred flavor vs non-flavored tobacco) in a crossover design pilot study. Plasma nicotine concentration and exhaled carbon monoxide (eCO) were measured before and after each smoking session. Puff topography was recorded throughout the smoking session. Participants completed survey questionnaires assessing subjective smoking experiences and harm perception. RESULTS: Significant differences were observed in plasma nicotine concentration between the two WP tobacco conditions, with a higher increase in plasma nicotine concentration following the flavored tobacco session. There were no significant differences between the two WP tobacco conditions for eCO and smoking topography measures. Compared with the non-flavored WP tobacco, we documented enhanced subjective smoking measures of satisfaction, calmness, taste, puff liking and enjoyment following the preferred flavored WP tobacco session. Cigarette harm perception was significantly higher among participants after smoking their preferred flavor compared with non-flavored WP tobacco. CONCLUSIONS: Limiting tobacco flavor has a substantial effect on WP smokers' nicotine exposure, subjective experience and harm perception. Therefore, eliminating or restricting WP flavors could be an essential element of comprehensive tobacco control policies to reduce the appeal of WP tobacco products for youth. IMPLICATIONS: This study highlights the important role of flavor in shaping WP smokers' experiences and exposures and the potential impact that regulating flavored WP tobacco may have on curbing WP use among youth in the US. Such regulations may reduce the appeal and the interest in WP smoking initiation and continued use.

Preclinical hazard evaluation strategy for nanomedicines.

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.

Prediction of Acute Oral Systemic Toxicity Using a Multifingerprint Similarity Approach.

The implementation of nonanimal approaches is of particular importance to regulatory agencies for the prediction of potential hazards associated with acute exposures to chemicals. This work was carried out in the framework of an international modeling initiative organized by the Acute Toxicity Workgroup (ATWG) of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) with the participation of 32 international groups across government, industry, and academia. Our contribution was to develop a multifingerprints similarity approach for predicting five relevant toxicology endpoints related to the acute oral systemic toxicity that are: the median lethal dose (LD50) point prediction, the "nontoxic" (LD50 > 2000 mg/kg) and "very toxic" (LD50<50 mg/kg) binary classification, and the multiclass categorization of chemicals based on the United States Environmental Protection Agency and Globally Harmonized System of Classification and Labeling of Chemicals schemes. Provided by the ICCVAM's ATWG, the training set used to develop the models consisted of 8944 chemicals having high-quality rat acute oral lethality data. The proposed approach integrates the results coming from a similarity search based on 19 different fingerprint definitions to return a consensus prediction value. Moreover, the herein described algorithm is tailored to properly tackling the so-called toxicity cliffs alerting that a large gap in LD50 values exists despite a high structural similarity for a given molecular pair. An external validation set made available by ICCVAM and consisting in 2896 chemicals was employed to further evaluate the selected models. This work returned high-accuracy predictions based on the evaluations conducted by ICCVAM's ATWG.

Unexploded Ordnance Management.

The purpose of this Clinical Practice Guide is to provide details on the procedures to safely remove unexploded ordnance from combat patients, both loose and impaled, to minimize the risks to providers and the medical treatment facility while ensuring the best outcome for the patient. Military ordnance, to include bullets, grenades, flares, and explosive ordnance, retained by a patient can be a risk to all individuals and equipment along the continuum of care. This is especially true from the point of injury to the first treatment facility. Management of patients with unexploded ordnance either on or in their body is a rare event during combat surgery. Loose munitions are usually noted and easily removed prior to the patient receiving medical treatment. However, impaled munitions provide a significant challenge. These are usually caused by large caliber, high-velocity projectiles. Patients who survive to arrive at a treatment facility must be triaged safely and simultaneously treated appropriately to ensure both the survival of the patient and the treatment team. Between WWII and the Somalia conflict, there have been 36 reported cases of unexploded ordnance from U.S. soldiers. Since 2005, there have been six known cases during the U.S. wars in Afghanistan and Iraq and one additional case in Pakistan. Optimal outcomes require a basic knowledge of explosives and triggering mechanisms, as well as adherence to basic principles of trauma resuscitation and surgery.

Dose-Related Severity Sequence, and Risk-Based Integration, of Chemically Induced Health Effects.

Risk assessment of chemical hazards is typically based on single critical health effects. This work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a "reference point profile" is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed. The overall impact at the same dose can also be derived by integrating contributions across all health effects following severity-weighting. In its generalized form the new impact metric relates to the probability of response for the most severe health effects. Reference points (points of departure) corresponding to defined levels of response can also be estimated. The proposed concept, which is evaluated for dioxin-like chemicals, provides an alternative for characterizing the low-dose region below the reference point for a severe effect like cancer. The shape and variability of the reference point profile add new dimensions to risk assessment, which for example extends the characterization of chemical potency, and the concept of acceptable effect sizes for individual health effects. Based on the present data the method shows high stability at low doses/responses, and is also robust to differences in severity categorization of effects. In conclusion, the novel method proposed enables risk-based integration of multiple dose-related health effects. It provides a first step towards a more comprehensive characterization of chemical toxicity, and suggests a potential for improved low-dose risk assessment.