Toxicological and epidemiological approaches to carcinogenic potency modeling for mixed mineral fiber exposure: the case of fibrous balangeroite and chrysotile.

CONTEXT: Excess mesothelioma risk was observed among chrysotile miners and millers in Balangero, Italy. The mineral balangeroite has been identified in an asbestiform habit from the Balangero chrysotile mine (Italy). Previous studies did not contain a detailed description of the fiber dimensions, thus limiting possible approaches to estimating their carcinogenic potential. OBJECTIVES: To reconstruct excess mesothelioma risk based on characteristics of mixed fiber exposure. METHODS: The lengths and widths of particles from a sample of balangeroite were measured by transmission electron microscopy (TEM). Statistical analysis and modeling were applied to assess the toxicological potential of balangeroite. RESULTS: Balangeroite fibers are characterized as asbestiform, with geometric mean length of 10 µm, width of 0.54 µm, aspect ratio of 19, and specific surface area of 13.8 (1/µm). Proximity analysis shows dimensional characteristics of balangeroite close to asbestiform anthophyllite. Modeling estimates the average potency of balangeroite as 0.04% (95% CI 0.0058, 0.16) based on dimensional characteristics and 0.05% (95% CI-0.04, 0.24) based on epidemiological data. The available estimate of the fraction of balangeroite in the Balangero mine is very approximate. There were no data for airborne balangeroite fibers from the Balangero mine and no lung burden data are available. All estimates were performed using weight fractions of balangeroite and chrysotile. However, based on reasonable assumptions, of the seven cases of mesothelioma in the cohort, about three cases (43%) can be attributed to fibrous balangeroite. CONCLUSION: The presence of different types of mineral fibers in aerosolized materials even in small proportions can explain observed cancer risks.

Dimensions of elongate mineral particles and cancer: A review.

CONTEXT: Based on a decade-long exploration, dimensions of elongate mineral particles are implicated as a pivotal component of their carcinogenic potency. This paper summarizes current understanding of the discovered relationships and their importance to the protection of public health. OBJECTIVES: To demonstrate the relationships between cancer risk and dimensions (length, width, and other derivative characteristics) of mineral fibers by comparing the results and conclusions of previously published studies with newly published information. METHODS: A database including 59 datasets comprising 341,949 records were utilized to characterize dimensions of elongate particles. The descriptive statistics, correlation and regression analysis, combined with Monte Carlo simulation, were used to select dimensional characteristics most relevant for mesothelioma and lung cancer risk prediction. RESULTS: The highest correlation between mesothelioma potency factor and weight fraction of size categories is achieved for fibers with lengths >5.6 µm and widths ≤0.26 µm (R = 0.94, P < 0.02); no statistically significant potency was found for lengths <5 µm. These results are consistent with early published estimations, though are derived from a different approach. For combinations of amphiboles and chrysotile (with a consideration of a correction factor between mineral classes), the potency factors correlated most highly with a fraction of fibers longer than 5 µm and thinner than 0.2 µm for mesothelioma, and longer than 5 µm and thinner than 0.3 µm for lung cancer. Because the proportion of long, thin particles in asbestiform vs. non-asbestiform dusts is higher, the cancer potencies of the former are predicted at a significantly higher level. The analysis of particle dimensionality in human lung burden demonstrates positive selection for thinner fibers (especially for amosite and crocidolite) and prevailing fraction of asbestiform habit. CONCLUSION: Dimensions of mineral fibers can be confirmed as one of the main drivers of their carcinogenicity. The width of fibers emerges as a primary potency predictor, and fibers of all widths with lengths shorter than 5 µm seem to be non-impactful for cancer risk. The mineral dust with a fibrous component is primarily carcinogenic if it contains amphibole fibers longer than 5 µm and thinner than 0.25 µm.

Elongate mineral particles (EMP) characteristics and mesothelioma: Summary and resolution for session I of the Monticello II conference.

The summary contains a consensus opinion regarding the current state of the science about the dimensions of Elongate Mineral Particles (EMPs) as a factor impacting their carcinogenicity.

Excitable systems: A new perspective on the cellular impact of elongate mineral particles.

We investigate how the geometry of elongate mineral particles (EMPs) in contact with cells influences esotaxis, a recently discovered mechanism of texture sensing. Esotaxis is based on cytoskeletal waves and oscillations that are nucleated, shaped, and steered by the texture of the surroundings. We find that all EMPs studied trigger an esotactic response in macrophages, and that this response dominates cytoskeletal activity in these immune cells. In contrast, epithelial cells show little to no esotactic response to the EMPs. These results are consistent with the distinct interactions of both cell types with ridged nanotopographies of dimensions comparable to those of asbestiform EMPs. Our findings raise the question of whether narrow, asbestiform EMPs may also dominate cytoskeletal activity in other types of immune cells that exhibit similar esotactic effects. These findings, together with prior studies of esotaxis, lead us to the hypothesis that asbestiform EMPs suppress the migration of immune cells and activate immune signaling, thereby outcompeting signals that would normally stimulate the immune system in nearby tissue.

Letter to the Editor: Epidemiology holds a key to the validation of toxicological models for elongate mineral particles.

The authors reply to the comments of Drs. Gualtieri and di Giuseppe on the short communication by Wylie and Korchevskiy - Carcinogenicity of fibrous glaucophane: how to fill data gaps? (2021 Current Research in Toxicology Volume 2, pp. 202-203). The role of epidemiology in establishing the toxicity of elongate mineral particles is emphasized. The validation of quantitative structure-activity relationship (QSAR) models by disease outcome is mentioned as one of the most important tools in advancing the new approaches in mineral particle toxicology.

Dimensional characteristics of the major types of amphibole mineral particles and the implications for carcinogenic risk assessment.

Context: Though some significant advances have been made in recent decades to evaluate the importance of size and morphology (habit) of elongate mineral particles (EMPs), further research is needed to better understand the role of each dimensional metric in determining the levels of cancer potency.Objective: To determine dimensional parameters most relevant for predicting cancer potency of durable elongate particles, specifically amphibole and durable silicate minerals generally.Methods: A database on dimensional and other relevant characteristics of elongate amphibole mineral particles was created, containing particle-by-particle information for 128 099 particles. Integral statistical characteristics on dimensionality of various amphibole types and morphological habits of EMPs were calculated, compared, and correlated with published mesothelioma and lung cancer potency factors.Results: The highest absolute Pearson correlation (r = 0.97, r2 = 0.94, p < 0.05) was achieved between mesothelioma potency (RM) and specific surface area. The highest correlation with adjusted lung cancer potency was found with particle aspect ratio (AR) (r = 0.80, r2 = 0.64, p < 0.05). Cluster analysis demonstrates that fractions of thin fibers (width less than 0.15 and 0.25 µm) also closely relate both to lung cancer and RM. Asbestiform and non-asbestiform populations of amphiboles significantly differ by dimensionality and carcinogenic potency.Conclusions: Dimensional parameters and morphological habits of EMPs are the main drivers for the observable difference in cancer potency among amphibole populations.

Dimensional determinants for the carcinogenic potency of elongate amphibole particles.

CONTEXT: Carcinogenic properties of particulates depend, among other factors, on dimensional characteristics that affect their ability to reach sensitive tissue, to be removed or retained, and to interact with the cells. OBJECTIVE: To model mesothelioma and lung cancer potency of amphibole particles based on their dimensional characteristics and mineral habit (asbestiform vs. nonasbestiform) utilizing epidemiological data and detailed size information. METHODS: The datasets from recently created depository of dimensional information of elongate mineral particles were used to correlate mesothelioma and lung cancer potency with the fraction of particles in a specific size range and the ratio of length and width in different powers. In addition, the cancer potency factors were estimated and compared for 30 asbestiform, 15 nonasbestiform, and 10 mixed datasets. RESULTS: For particles longer than 5 µm, the highest correlation with mesothelioma potency was achieved for width <0.22 µm, and with lung cancer <0.28 µm. The statistical power of the correlation was observed to lose significance at a maximum width of 0.6-0.7 µm. Mesothelioma potency correlated with length in the power of 1.9 divided by width in the power of 2.97, lung cancer potency with length in the power of 0.4 divided by width in the power of 1.17. The predicted cancer potencies of asbestiform, nonasbestiform, and mixed categories were significantly different. CONCLUSION: While additional studies in this direction are warranted, this paper should serve as an additional confirmation for the role of fiber dimensions in the carcinogenicity of amphibole elongate mineral particles (EMPs).

Carcinogenicity of fibrous glaucophane: How should we fill the data gaps?

•The modeled glaucophane mesothelioma potency is 0.0085 % vs. 0.5 % for riebeckite.•Lung cancer potency of glaucophane is 0.36 % vs. 4.82 % for Australian crocidolite.•The fibrosity index of glaucophane (0.77) is typical for non-asbestiform amphiboles.

Modeling mesothelioma risk factors from amphibole fiber dimensionality: mineralogical and epidemiological perspective.

Amphiboles are common rock-forming minerals but when they form asbestos, they are known carcinogens. Mesothelioma mortality among miners and millers per the unit of asbestiform amphibole exposure varies significantly across cohorts when asbestos exposure measurements are based on the membrane filter method. Because the cohorts were exposed to different occurrences of asbestiform amphibole, variance in mesothelioma potency (RM ) among cohorts is likely due to differences in exposure characteristics not reflected by the membrane filter method. In this paper using both linear and nonlinear models we correlate RM from four mining and milling cohorts with two-dimensional parameters of the exposure. The parameters are based on the proportion of elongated minerals that are >5 µm in length from each occurrence that also have either (a) width ≤ 0.15 µm, or (b) width ≤ 0.25 µm. Based on the models we derived, it was possible to quantify RM for the occurrences of asbestiform amphibole associated with mesothelioma excess but for which epidemiologically based RM has not been published. It was demonstrated that modeled RM for amphibole occurrences in nonasbestiform habits are lower (fibrous glaucophane) or not significant (cleavage fragments). The results of the study can be used in a risk assessment of elongated mineral particles and have implications for public policy and regulations.

Implementing undergraduate quality improvement.

BACKGROUND: All clinicians need to have knowledge and expertise to undertake quality improvement (QI). In 2016, a London medical school initiated a core QI and evidence-based practice module for fourth-year students. We describe the structure and content of the module and analyse QI projects (QIPs) and student feedback. METHODS: We collected data on QIPs, including number and location, adherence to QI methodology and level of improvement achieved. We also examined end-of-module feedback with free text analysis of the written comments. RESULTS: A total of 398 students completed 99 QIPs: 90% were based in secondary care and 10% were based in primary care. A total of 72 projects (72%) led to improvements in clinical care, with 14% achieving their stated aim. Adherence to methodology was high: 75% had a 'SMART (specific, measurable, achievable, realistic and timely)' aim; 96% implemented at least one plan-do-study-act (PDSA) cycle (range 1-4), and appropriate run charts for measures occurred in 80% of projects. QIPs were categorised based on their outcome: self-help and self-care, 12%; efficiency, 16%; prevention and early detection, 14%; drug safety, 11%; improvement to pathways and protocols, 44%; and improving patient experience 3%. The implementation challenges encountered were: suboptimal supervisor preparedness; student time limitations; and difficulties with the virtual learning platform. However, the experiences that QIPs offered in preparation for postgraduate training were appreciated by students. CONCLUSIONS: We have demonstrated that students are able to robustly apply QI methodologies, equipping them to act as agents for change, learning as they do, and meaningfully improving QI capacity and capability in local health systems.

The impact and potential value for medical students of implementing social prescribing projects in primary care.

Social prescribing is a method of referring patients for non-clinical care through community and voluntary organisations. As part of a new primary care curriculum at King's College London, half of the cohort of second-year medical students (n = 200) took part in 'Active Practice,' where they designed and implemented exercise-related social prescribing projects on their longitudinal placement in general practice. This study aimed to examine the impact and potential value of 'Active Practice' for the students, using thematic analysis of two semi-structured focus groups (n = 7, n = 8) and free-text comments from student (n = 315) and GP tutor (n = 15) evaluation questionnaires. Five themes emerged: changes in the students' attitudes and professional identity; satisfaction and enjoyment of the project; gain of skills and knowledge; effects on the students' own physical activity and their social circles; interactions with the rest of the curriculum. These align with General Medical Council outcomes for graduates and triangulate with feedback from the national student champion scheme for social prescribing. Learning points have been noted for future Active Practice cohorts.

Brief intervention for obesity in primary care: how does student learning translate to the clinical context?

This article was migrated. The article was marked as recommended. There is an international call for more sustainable approaches to healthcare and for graduating doctors to develop the competencies to address the behavioural, psychological and social determinants of health. Obesity is a global challenge, and the case for preventative health is evident. There is growing evidence to support brief interventions for obesity in primary care. The feasibility and acceptability of teaching within classroom contexts have been demonstrated, however there are known barriers to adopting these approaches with patients. It is unclear how well classroom learning translates to the clinical context. 329 final year medical students from Aristotle University of Thessaloniki attended training that had been developed through action research processes at King's College London and adapted to the local context. Students conducted brief interventions with 3,177 overweight or obese patients across 136 primary healthcare facilities over three rotations. Their reflective learning essays were coded for content and thematically analysed to illuminate their experiences. Emergent themes include students' insights into the drivers behind the obesity epidemic and psychosocial barriers to change; transformative experiences using patient-centred approaches to communication and behaviour change; progression in skills and attitudes to broaching obesity in clinical contexts; and insights into the factors that drive patient engagement. Their experiences indicate that facilitative approaches are acceptable to patients, and result in commitment to change where relevant to the patient's agenda.

Clinical Humanities in Primary Care for Year 2 Medical Students: A Student perspective.

This article was migrated. The article was marked as recommended. As part of a new MBBS Curriculum at GKT Medical School, King's College London, second year medical students undertook a clinical humanities assignment during their longitudinal GP placement. Groups of students all produced a humanities output relating to medicine and patient care in the community. This article explores the experiences from the student perspective and key learning points for subsequent cohorts, identifying four themes from the feedback obtained in a student evaluation: Broadening horizons; teamworking and leadership, wider community care involvement and seeing patients through different eyes.

Health promotion in medical education: lessons from a major undergraduate curriculum implementation.

Despite the economic, environmental and patient-related imperatives to prepare medical students to become health promoting doctors, health promotion remains relatively deprioritised in medical curricula. This paper uses an in-depth case study of a health promotion curriculum implementation at a large UK medical school to provide insights into the experiences of teachers and learners across a range of topics, pedagogies, and teaching & assessment modalities. Topics included smoking cessation, behavioural change approaches to obesity, exercise prescribing, social prescribing, maternal and child health, public and global health; with pedagogies ranging from e-learning to practice-based project work. Qualitative methods including focus groups, analysis of reflective learning submissions, and evaluation data are used to illuminate motivations, frustrations, practicalities, successes and limiting factors. Over this three year implementation, a range of challenges have been highlighted including: how adequately to prepare and support clinical teachers; the need to establish relevance and importance to strategic learners; the need for experiential learning in clinical environments to support classroom-based activities; and the need to rebalance competing aspects of the curriculum. Conclusions are drawn about heterogeneous deep learning over standardised surface learning, and the impacts, both positive and negative, of different assessment modalities on these types of learning.

Enabling tomorrow's doctors to address obesity in a GP consultation: an action research project.

Obesity is a leading risk factor for morbidity and mortality, however, guidelines for prevention and management are relatively recently established. Little is known about what needs to be in place to put these into practice. This research provides an insight into how senior medical students consult with obese patients in general practice, the range of their learning needs, and the impact of various educational strategies that aim to bring their practice closer to current evidence-based guidelines. It centres on a series of compulsory but formative reflective case studies written by final year students at one large medical school on their GP rotation as they consult independently with obese patients with 'next room' GP tutor support. Analysis of these case studies was used to inform a three-year educational action research project. By systematically identifying and addressing learning needs, including barriers and enablers to best practice, we have demonstrated how senior medical students, and their GP tutors, can acquire the role legitimacy and role competency required for effective practice.

Methodologies for determining the sources, characteristics, distribution, and abundance of asbestiform and nonasbestiform amphibole and serpentine in ambient air and water.

Anthropogenic and nonanthropogenic (erosion) processes contribute to the continuing presence of asbestos and nonasbestos elongated mineral particles (EMP) of amphibole and serpentine in air and water of urban, rural, and remote environments. The anthropogenic processes include disturbance and deterioration of asbestos-containing materials, mining of amphibole- and serpentine-bearing rock, and disturbance of soils containing amphibole and serpentine. Atmospheric dispersal processes can transport EMP on a global scale. There are many methods of establishing the abundance of EMP in air and water. EMP include cleavage fragments, fibers, asbestos, and other asbestiform minerals, and the methods employed do not critically distinguish among them. The results of most of the protocols are expressed in the common unit of fibers per square centimeter; however, seven different definitions for the term "fiber" are employed and the results are not comparable. The phase-contrast optical method used for occupational monitoring cannot identify particles being measured, and none of the methods distinguish amphibole asbestos from other EMP of amphibole. Measured ambient concentrations of airborne EMP are low, and variance may be high, even for similar environments, yielding data of questionable value for risk assessment. Calculations based on the abundance of amphibole-bearing rock and estimates of asbestos in the conterminous United States suggest that amphibole may be found in 6-10% of the land area; nonanthropogenic erosional processes might produce on the order of 400,000 tons or more of amphibole per year, and approximately 50 g asbestos/km(2)/yr; and the order of magnitude of the likelihood of encountering rock bearing any type of asbestos is approximately 0.0001.