The document discusses how intuitive technologies like tablet PCs, digital pens, and surface computing can improve clinician efficiency and patient safety in healthcare settings. It identifies ways these technologies can impact patient safety positively by improving outcomes and staff response times. It also explores how they can enhance clinician efficiency by streamlining workflows and supporting mobile decision making. The document compares current states of clinician efficiency to potential future states enabled by intuitive technologies and explains how these technologies can coexist in today's hybrid electronic environments.
This document discusses trauma-informed care in Maryland and recommends prioritizing evidence-based practices (EBPs) that treat trauma. It summarizes current practices for identifying trauma, assessing trauma, and treating trauma. For each, it outlines several specific techniques and instruments used, along with challenges. It recommends implementing trauma-specific EBPs, like trauma-focused cognitive behavioral therapy (TF-CBT), within a trauma-informed system of care for children's mental health.
McKesson helps improve health care quality and patient safety while reducing health care costs.
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Evaluating impact of humanitarian action: a science or an art (Jo Puri, 3iE)ALNAP
This document discusses impact evaluations in humanitarian assistance. It notes that humanitarian interventions are complex to evaluate due to factors like selection bias, fragile states, concurrent interventions, and lack of baseline data. Some key points made include:
- Impact evaluations are needed to understand what works in humanitarian assistance and improve accountability.
- Methodologies must account for heterogeneity among affected populations and emergencies.
- The Pakistan 2005 earthquake response provides an example where impact evaluations could have better informed recovery efforts.
- Collecting baseline data immediately after emergencies and designing interventions for staged rollouts can help establish stronger counterfactuals for impact evaluations.
Embry Nov 2010 colloquium for uni manitoba faculty of medicineDennis Embry
The Community Medicine Department of the University of Manitoba sponsored a colloquium by Dr. Embry. This talk emphasizes scientific approaches to non-pharacuettical methods to prevent mental, emotional and behavioral disorders
This document outlines consultation resources provided by Regional Quality Managers and state trauma experts to support effective use of the CANS tool and implementation of trauma-informed practices. It describes:
1) Case consultation topics on CANS implementation, trauma-specific treatment, and agency/program needs. Providers can sign up for consultations.
2) Services provided by two state trauma experts - assistance using CANS effectively, assessing training needs, and enhancing trauma-informed practices.
3) National trauma consultation services - 12 clinical case consultations and ongoing support through group teleconferences, meetings, and a quarterly newsletter. The aim is to improve quality of care and outcomes for trauma-affected youth.
This document provides an overview of implementation science and introduces a conceptual framework for guiding the assessment and improvement of implementation processes. It engages participants in applying this framework to analyze factors that will influence health worker counseling and mother feeding practices related to the WHO guidelines on infant feeding in the context of HIV, assuming breastfeeding with ARVs is the national policy.
The document outlines the bare necessities for creating trauma-informed mental health inpatient services. It discusses integrating an understanding of trauma throughout programs, policies, and procedures to prevent re-traumatization. It recognizes the need to meaningfully involve trauma survivors in designing services and prioritizing safety, choice, and control. The document also acknowledges that while progress has been made, more work is needed to fully implement trauma-informed practices, such as establishing a shared definition, increasing training, screening for trauma history, and ensuring emotional and physical safety remain top priorities.
The document discusses how intuitive technologies like tablet PCs, digital pens, and surface computing can improve clinician efficiency and patient safety in healthcare settings. It identifies ways these technologies can impact patient safety positively by improving outcomes and staff response times. It also explores how they can enhance clinician efficiency by streamlining workflows and supporting mobile decision making. The document compares current states of clinician efficiency to potential future states enabled by intuitive technologies and explains how these technologies can coexist in today's hybrid electronic environments.
This document discusses trauma-informed care in Maryland and recommends prioritizing evidence-based practices (EBPs) that treat trauma. It summarizes current practices for identifying trauma, assessing trauma, and treating trauma. For each, it outlines several specific techniques and instruments used, along with challenges. It recommends implementing trauma-specific EBPs, like trauma-focused cognitive behavioral therapy (TF-CBT), within a trauma-informed system of care for children's mental health.
McKesson helps improve health care quality and patient safety while reducing health care costs.
Task Actions
Task Not Started ( 00:00:00 )
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Evaluating impact of humanitarian action: a science or an art (Jo Puri, 3iE)ALNAP
This document discusses impact evaluations in humanitarian assistance. It notes that humanitarian interventions are complex to evaluate due to factors like selection bias, fragile states, concurrent interventions, and lack of baseline data. Some key points made include:
- Impact evaluations are needed to understand what works in humanitarian assistance and improve accountability.
- Methodologies must account for heterogeneity among affected populations and emergencies.
- The Pakistan 2005 earthquake response provides an example where impact evaluations could have better informed recovery efforts.
- Collecting baseline data immediately after emergencies and designing interventions for staged rollouts can help establish stronger counterfactuals for impact evaluations.
Embry Nov 2010 colloquium for uni manitoba faculty of medicineDennis Embry
The Community Medicine Department of the University of Manitoba sponsored a colloquium by Dr. Embry. This talk emphasizes scientific approaches to non-pharacuettical methods to prevent mental, emotional and behavioral disorders
This document outlines consultation resources provided by Regional Quality Managers and state trauma experts to support effective use of the CANS tool and implementation of trauma-informed practices. It describes:
1) Case consultation topics on CANS implementation, trauma-specific treatment, and agency/program needs. Providers can sign up for consultations.
2) Services provided by two state trauma experts - assistance using CANS effectively, assessing training needs, and enhancing trauma-informed practices.
3) National trauma consultation services - 12 clinical case consultations and ongoing support through group teleconferences, meetings, and a quarterly newsletter. The aim is to improve quality of care and outcomes for trauma-affected youth.
This document provides an overview of implementation science and introduces a conceptual framework for guiding the assessment and improvement of implementation processes. It engages participants in applying this framework to analyze factors that will influence health worker counseling and mother feeding practices related to the WHO guidelines on infant feeding in the context of HIV, assuming breastfeeding with ARVs is the national policy.
The document outlines the bare necessities for creating trauma-informed mental health inpatient services. It discusses integrating an understanding of trauma throughout programs, policies, and procedures to prevent re-traumatization. It recognizes the need to meaningfully involve trauma survivors in designing services and prioritizing safety, choice, and control. The document also acknowledges that while progress has been made, more work is needed to fully implement trauma-informed practices, such as establishing a shared definition, increasing training, screening for trauma history, and ensuring emotional and physical safety remain top priorities.
INC Research provides clinical trial services with a focus on therapeutic expertise, trusted results, and a proven process. They have experienced teams with therapeutic and industry knowledge. Their Trusted Process involves (1) PlanActivation to strategize and prepare for trials, (2) QuickStart to efficiently launch trials with team collaboration, (3) ProgramAccelerate to actively manage trials, and (4) QualityFinish to smoothly complete trials and analyze results. INC Research specializes in areas like oncology, CNS, and cardiovascular trials.
Self-regulation and personality as key factors of decision making in emergenc...Tatiana Indina
1. The study examined the relationship between personality, self-regulation abilities, and decision-making efficiency among emergency professionals.
2. Results showed decision-making efficiency was positively correlated with traits like openness and agreeableness, and self-regulation abilities like modeling conditions and assessing results.
3. Highly efficient professionals had well-developed self-regulation and traits like openness, rationality and agreeableness. Less efficient professionals scored lower on self-regulation and higher in neuroticism.
Implementing ebp in community corrections the principles of effective interv...sevans-idaho
The document outlines an integrated model for implementing evidence-based practices in community corrections. It presents eight principles for effective offender interventions that are shown by research to reduce recidivism. These principles include using interventions that are specific and tailored to risk levels. Currently, most community corrections agencies do not apply these evidence-based strategies and principles. The model aims to bridge this gap and facilitate lasting organizational changes needed to adopt proven interventions.
The document provides an executive summary of recommendations from the American Dietetic Association's Evidence Analysis Library Oncology Evidence-Based Nutrition Practice Guidelines. It aims to provide medical nutrition therapy guidelines to manage cancer treatment symptoms, prevent weight loss, and maintain optimal nutrition. The summary outlines the target population, guideline objectives, narrative overview, role of nutrition therapy and dietitians, statement of intent, disclaimer, and recommendation rating system for the full guideline.
This white paper authored by Jason Oliveira discusses the marriage between business and clinical decision support systems within the healthcare industry.
This document summarizes Dr. Gaurav Bissa's presentation on decision making. It outlines the 5 steps of the decision making process: 1) defining the problem, 2) formulating hypotheses, 3) collecting facts, 4) conducting analysis, and 5) developing a solution. It also discusses techniques like intuitive decision making and employee involvement in decision making. Finally, it provides 3 "management lessons" using analogies about turkeys, birds, and cow dung to illustrate principles like how appearances can be deceiving and the risks of overconfidence.
Toxicity and Detoxification with Far InfraredSarah Adams
This document discusses various sources of toxicity in the environment and consumer goods. It provides information on the prevalence of toxic chemicals used commercially and approved for foods. Several statistics are presented showing the widespread detection of chemicals in human samples. Common sources of toxins discussed include air pollutants, chemicals, and heavy metals. Specific chemicals like benzene, formaldehyde, and pesticides are examined in more detail regarding their sources and health effects.
Cyclophosphamide is an alkylating agent used to treat white blood cell cancers and lymphoma. It works by being metabolized into phosphoramide mustard, which adds alkyl groups to DNA, forming crosslinks between and within DNA strands. This leads to DNA damage and ultimately cell death. The expression of genes coding for enzymes involved in cyclophosphamide metabolism, such as cytochrome P450 and ALDH, can affect how sensitive cancer cells are to the drug.
Chloroform is a colorless, sweet-smelling liquid that is produced commercially by heating a mixture of chlorine and chloromethane or methane. It has a variety of uses including as a solvent in the pharmaceutical industry, for producing dyes and pesticides, and as a refrigerant. Historically it was used as a surgical anesthetic but has been replaced by safer drugs. Chloroform is considered hazardous due to its toxicity if inhaled or ingested, and prolonged exposure may cause health issues like kidney and liver damage.
The document discusses cell division and the cell cycle. It describes the stages of interphase where the cell prepares for division. These stages are G1, S phase where DNA replicates, and G2. Mitosis is then described in its four stages: prophase, metaphase, anaphase and telophase. Cytokinesis, the final stage of cell division, is different between plant and animal cells. Factors involved in cell cycle control and cancer development are also mentioned.
Chloroform is a colorless, non-water soluble liquid with a pleasant odor that was originally used as an anesthetic. It is used in pesticides and may be released from chlorinated water. Chloroform is dangerous to humans above 50 ppb and can contribute to ambient ozone levels in high concentrations. Exposure can cause central nervous system depression, cardiovascular effects, liver damage, and possibly cancer if consumed in drinking water.
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceutic
The document discusses the International Risk Governance Council's (IRGC) risk governance framework. It introduces the framework and its key components: pre-assessment, characterization and evaluation, and management. It then discusses the role of vulnerability and resilience in the framework. Specifically, it defines risk, vulnerability, and resilience. The main objectives for resilience are to ensure continuity of urban services, limit losses in disasters, and enable fast recovery. Criteria are provided for securing continuity, reducing impact, and easing recovery. The conclusion calls for indicators to measure vulnerability and resilience according to the three main criteria and nine subcriteria.
This presentation provides an overview of risk assessment and management concepts. It defines key terms like hazard, risk, risk acceptance, analysis, assessment, evaluation, management, and communication. Specific risk assessment tools are explained like FMEA, FTA, HACCP, and PRA. The risk management process is outlined as system definition, hazard identification, risk estimation, evaluation, control, monitoring, and communication. Probability, severity, and risk priority numbers are defined for FMEA. Overall it provides context and definitions to understand applying risk assessment in a regulatory context.
The document discusses risk management on high technology programs. It outlines the agenda for a 4 hour session which will cover the principles of risk management, introduce Continuous Risk Management (CRM), illustrate each CRM process area with examples, and familiarize participants with identifying risks. The document then discusses the five principles of risk management and explains concepts like the Mission-Oriented Success Analysis and Improvement Criteria (MOSAIC) framework for assessing project risk.
The document proposes a framework called the Information Systems Risk Assessment Framework (ISRAF) that takes a hierarchical, context-centric approach to comprehensive risk management. The framework addresses key aspects of risk assessment including preparation, conducting assessment, analyzing risks both qualitatively and quantitatively, communicating results, and maintaining an organization's risk posture over time. It provides guidance on the risk assessment process and applying the results across the risk management life cycle to support various organizational decisions.
InvestigAction: a cognitive and organisational tool for learning from acciden...ALIAS Network
If you are interested in the topic please register to the ALIAS network:
http://network.aliasnetwork.eu/
to download other materials and get information about the ALIAS project (www.aliasnetwork.eu).
INC Research provides clinical trial services with a focus on therapeutic expertise, trusted results, and a proven process. They have experienced teams with therapeutic and industry knowledge. Their Trusted Process involves (1) PlanActivation to strategize and prepare for trials, (2) QuickStart to efficiently launch trials with team collaboration, (3) ProgramAccelerate to actively manage trials, and (4) QualityFinish to smoothly complete trials and analyze results. INC Research specializes in areas like oncology, CNS, and cardiovascular trials.
Self-regulation and personality as key factors of decision making in emergenc...Tatiana Indina
1. The study examined the relationship between personality, self-regulation abilities, and decision-making efficiency among emergency professionals.
2. Results showed decision-making efficiency was positively correlated with traits like openness and agreeableness, and self-regulation abilities like modeling conditions and assessing results.
3. Highly efficient professionals had well-developed self-regulation and traits like openness, rationality and agreeableness. Less efficient professionals scored lower on self-regulation and higher in neuroticism.
Implementing ebp in community corrections the principles of effective interv...sevans-idaho
The document outlines an integrated model for implementing evidence-based practices in community corrections. It presents eight principles for effective offender interventions that are shown by research to reduce recidivism. These principles include using interventions that are specific and tailored to risk levels. Currently, most community corrections agencies do not apply these evidence-based strategies and principles. The model aims to bridge this gap and facilitate lasting organizational changes needed to adopt proven interventions.
The document provides an executive summary of recommendations from the American Dietetic Association's Evidence Analysis Library Oncology Evidence-Based Nutrition Practice Guidelines. It aims to provide medical nutrition therapy guidelines to manage cancer treatment symptoms, prevent weight loss, and maintain optimal nutrition. The summary outlines the target population, guideline objectives, narrative overview, role of nutrition therapy and dietitians, statement of intent, disclaimer, and recommendation rating system for the full guideline.
This white paper authored by Jason Oliveira discusses the marriage between business and clinical decision support systems within the healthcare industry.
This document summarizes Dr. Gaurav Bissa's presentation on decision making. It outlines the 5 steps of the decision making process: 1) defining the problem, 2) formulating hypotheses, 3) collecting facts, 4) conducting analysis, and 5) developing a solution. It also discusses techniques like intuitive decision making and employee involvement in decision making. Finally, it provides 3 "management lessons" using analogies about turkeys, birds, and cow dung to illustrate principles like how appearances can be deceiving and the risks of overconfidence.
Toxicity and Detoxification with Far InfraredSarah Adams
This document discusses various sources of toxicity in the environment and consumer goods. It provides information on the prevalence of toxic chemicals used commercially and approved for foods. Several statistics are presented showing the widespread detection of chemicals in human samples. Common sources of toxins discussed include air pollutants, chemicals, and heavy metals. Specific chemicals like benzene, formaldehyde, and pesticides are examined in more detail regarding their sources and health effects.
Cyclophosphamide is an alkylating agent used to treat white blood cell cancers and lymphoma. It works by being metabolized into phosphoramide mustard, which adds alkyl groups to DNA, forming crosslinks between and within DNA strands. This leads to DNA damage and ultimately cell death. The expression of genes coding for enzymes involved in cyclophosphamide metabolism, such as cytochrome P450 and ALDH, can affect how sensitive cancer cells are to the drug.
Chloroform is a colorless, sweet-smelling liquid that is produced commercially by heating a mixture of chlorine and chloromethane or methane. It has a variety of uses including as a solvent in the pharmaceutical industry, for producing dyes and pesticides, and as a refrigerant. Historically it was used as a surgical anesthetic but has been replaced by safer drugs. Chloroform is considered hazardous due to its toxicity if inhaled or ingested, and prolonged exposure may cause health issues like kidney and liver damage.
The document discusses cell division and the cell cycle. It describes the stages of interphase where the cell prepares for division. These stages are G1, S phase where DNA replicates, and G2. Mitosis is then described in its four stages: prophase, metaphase, anaphase and telophase. Cytokinesis, the final stage of cell division, is different between plant and animal cells. Factors involved in cell cycle control and cancer development are also mentioned.
Chloroform is a colorless, non-water soluble liquid with a pleasant odor that was originally used as an anesthetic. It is used in pesticides and may be released from chlorinated water. Chloroform is dangerous to humans above 50 ppb and can contribute to ambient ozone levels in high concentrations. Exposure can cause central nervous system depression, cardiovascular effects, liver damage, and possibly cancer if consumed in drinking water.
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceutic
The document discusses the International Risk Governance Council's (IRGC) risk governance framework. It introduces the framework and its key components: pre-assessment, characterization and evaluation, and management. It then discusses the role of vulnerability and resilience in the framework. Specifically, it defines risk, vulnerability, and resilience. The main objectives for resilience are to ensure continuity of urban services, limit losses in disasters, and enable fast recovery. Criteria are provided for securing continuity, reducing impact, and easing recovery. The conclusion calls for indicators to measure vulnerability and resilience according to the three main criteria and nine subcriteria.
This presentation provides an overview of risk assessment and management concepts. It defines key terms like hazard, risk, risk acceptance, analysis, assessment, evaluation, management, and communication. Specific risk assessment tools are explained like FMEA, FTA, HACCP, and PRA. The risk management process is outlined as system definition, hazard identification, risk estimation, evaluation, control, monitoring, and communication. Probability, severity, and risk priority numbers are defined for FMEA. Overall it provides context and definitions to understand applying risk assessment in a regulatory context.
The document discusses risk management on high technology programs. It outlines the agenda for a 4 hour session which will cover the principles of risk management, introduce Continuous Risk Management (CRM), illustrate each CRM process area with examples, and familiarize participants with identifying risks. The document then discusses the five principles of risk management and explains concepts like the Mission-Oriented Success Analysis and Improvement Criteria (MOSAIC) framework for assessing project risk.
The document proposes a framework called the Information Systems Risk Assessment Framework (ISRAF) that takes a hierarchical, context-centric approach to comprehensive risk management. The framework addresses key aspects of risk assessment including preparation, conducting assessment, analyzing risks both qualitatively and quantitatively, communicating results, and maintaining an organization's risk posture over time. It provides guidance on the risk assessment process and applying the results across the risk management life cycle to support various organizational decisions.
InvestigAction: a cognitive and organisational tool for learning from acciden...ALIAS Network
If you are interested in the topic please register to the ALIAS network:
http://network.aliasnetwork.eu/
to download other materials and get information about the ALIAS project (www.aliasnetwork.eu).
The document summarizes a state-of-the-art review on program fidelity and adaptation in substance abuse prevention. It finds that balancing both program fidelity (how closely a program follows the developer's components) and adaptation (modifying components to fit local needs) is critical for successful implementation of science-based prevention programs. The review examined over 100 published and unpublished studies from the past 25 years. It concluded that attention to both fidelity and adaptation during the complex implementation process is important. It proposed initial guidelines and identified unresolved issues requiring further attention from program developers, implementers, funders, and policymakers to better understand and apply the lessons on balancing fidelity and adaptation.
The document proposes an Information Systems Risk Assessment Framework (ISRAF) to improve organizational risk management. The framework aims to integrate risk assessment into the system development life cycle and business processes. It recommends a modular, hierarchical approach to conduct risk assessments at different tiers or levels of the organization. The framework provides guidelines on risk concepts, factors, analysis methods, assessment scales, and communicating results to stakeholders. The goal is to help organizations make more risk-based decisions through a systematic, repeatable risk assessment process.
This document discusses a pilot project to identify potential food safety risks in a proactive manner. The project studied risks related to pesticide use by reviewing scientific literature and EU projects. It identified drivers of change like climate change and economic crises that could increase pesticide use. Through horizon scanning, the project mapped weak signals and wild cards related to pesticides, like unintended nano-pesticide consequences or gene transfer from transgenic plants. Five weak signals and five wild cards with higher correlation to evaluated drivers were selected and entered into a database. The conclusions state that emerging risks identification requires a structured, forward-looking approach including analyzing drivers, developing scenarios, and identifying and interpreting weak signals linked to potential scenarios.
Human Health Risk Assessment Training ModuleJason Suwala
The document provides an overview of the risk assessment process, which includes problem formulation, exposure and toxicity analysis, and risk characterization. It discusses key components like identifying hazards, receptors, and pathways. Environmental and human samples are collected to quantify exposure. Toxicity values are used to evaluate hazards. The risk assessment process is iterative, starting with preliminary assessments and becoming more refined in site-specific assessments to accurately characterize risk.
Climate-smart Approaches to Agriculture: lessons from recent experienceFAO
This 3-sentence summary provides an overview of the key points about a project on climate-smart approaches to agriculture:
The project is funded by the European Community from 2012-2014 to build evidence and capacity for climate-smart agriculture in Malawi, Vietnam, and Zambia by researching synergies between food security, adaptation, and mitigation practices; identifying policy barriers to adoption; and developing strategic frameworks and investment proposals to increase productivity, resilience, and reduce emissions. The project aims to strengthen capacity through research, engaging local institutions, supporting national policy dialogues, and consulting stakeholders to guide climate-smart agriculture policies and investments.
Revised by Christian Reina
Version: 1.1
Date: September 18, 2009
Change log:
-Risk Based Audit approach
-Things to know
-Penetration Testing Stages
-OSI Model protocols
-Firewall generations
-Wireless
-Common Criteria ISO 15408
-Problem Management
-System Development Life Cycle
-Software Life Cycle
-Five rules of evidence
-Incident Response framework
-Evidence Lifecycle
-Fair Information Practices
The document discusses risk management frameworks and processes. It provides:
1) An overview of risk management, including highlighting risks at the project, program, and portfolio levels.
2) A risk management framework involving establishing context, risk identification, analysis, evaluation, and treatment.
3) Details of risk governance, including risk management plans, risk registers, governance documents, and ongoing and discrete risk activities.
The document discusses risk assessment and mitigation strategies for a bank. It outlines the process of assessing risk, which includes identifying prevalent risks, assessing their impact and frequency, developing controls, and reassessing exposures. It also evaluates options for mitigating risk, such as periodic assessments, maintaining a risk register, and reviewing contingency plans. Key considerations for selecting mitigation actions include ensuring effectiveness, cost efficiency, alignment with business operations, and consistency with regulatory requirements.
Running Head CURRENT TECHNIQUES IMPLEMENTED IN CONSTRUCTION INDUS.docxhealdkathaleen
Running Head: CURRENT TECHNIQUES IMPLEMENTED IN CONSTRUCTION INDUSTRY TO ELIMINATE SECURITY RISKS 2
CURRENT TECHNIQUES IMPLEMENTED IN CONSTRUCTION INDUSTRY TO ELIMINATE SECURITY RISKS 2
Current Techniques Implemented in the Construction Industry to Eliminate Security Risks
Group 4
Balaram Chekuri
Laxmi Sravani Vallurpallis
Mohan Kadali
Shivasai Pabba
Vaagdevi Jali
University of the Cumberlands
ITS835-41 Enterprise Risk Management
Residency Assignment Research Paper
Professor Dr. James C. Hyatt
10/20/2019
Statement of the Problem and it is Setting
Risk management has been one of the breakthroughs for the modern world, and at the same one of the intellectual achievements is the identification, transformation, or risk and going from a world that described risk as fate to a world that looks at risk as an area of study. Risk management is the utilization of risk analysis to come up with management strategies used to reduce risk. Whereby generally in project management there are the two techniques categories qualitative; that involves impact and probability assessment, expected value calculations and influence diagrams and quantitative; that typically focuses on the overall risk which is managed more with numerical approach, and has techniques such as decision trees, Monte Carlo analysis and sensitivity analysis (McNeil et al. 2015). In various fields, there is enormous risk faced, and at the same time, there is a corresponding quantitative technique that can be used to address the risk. The focus is on the quantitative risk management techniques; they are based on scientific, mathematical and statistical background, that promise to give thorough and detailed management and quantification of risk that is imperative for designing the response (Teixeira et al. 2015).
This paper, based on the construction industry, provides an overview of the analytic overview of different quantitative risk analysis techniques. There is a focus on building on the existing quantitative techniques that are best for the construction industry around the world when it comes to utilizing relevant techniques after a qualitative risk analysis. In addition to this, there is looking further into the techniques and their details.
Guiding Questions
· Does Your Risk Management Process Address Root Cause of Failure?
· Are there gaps in this field?
· What Does Your Business Performance Tell You About Risk?
· What Do Controls Tell You About Your Risks?
· The main focus is looking at the practitioners and researchers looking: at the reason why they should simplify the existing techniques?
· Which, at the same looks at the research gaps in this field and propose areas of further research for project risk management in construction, which will improve the existing techniques.
Assumptions
Project Risk manage ...
1) This document outlines an agenda for a workshop on programmatic risk management that covers topics such as risk management principles, basic statistics, Monte Carlo simulation theory, using Microsoft Project and Risk+ software, risk ranking, and building a credible schedule.
2) It discusses five key principles of managing programmatic risk: having a strategy rather than relying on hope, understanding that single point estimates are inaccurate without variance data, integrating cost, time and technical performance, using a risk management process and model rather than "driving in the dark," and ensuring effective risk communication.
3) The mechanics section describes how to set up a Risk+ simulation integrated with
This abstract discusses a risk-based approach to clinical data management. It identifies key risks like poor study design, lack of priority identification, and lack of understanding study goals. It proposes assessing these risks through factors like likelihood and impact. Risks can then be mitigated through proportional monitoring and documentation. The abstract recommends identifying high risks and implementing actions to address them, as well as utilizing powerful clinical data management systems to help manage risks.
Regulating technological risk: the case of genetically modified crops in IndiaSTEPS Centre
Presentation by Ian Scoones, STEPS Centre co-director, at a conference on the challenges of risk management for India, Bangalore, 15-16 February 2011. The conference was organised by the Indian Institute of Management Bangalore's Centre for Public Policy in association with the STEPS Centre.
http://www.risk-management-india.com/
Este documento fornece dados estatísticos sobre o mercado de trabalho no Brasil e em seus estados e subsetores industriais. Inclui informações sobre a população, emprego formal, evolução do saldo de empregos na indústria e construção civil no Brasil entre 2008-2012. Também fornece dados detalhados sobre emprego por estado, incluindo participação da população em carteira assinada.
101 propostas para modernização trabalhista - www.relacoesdotrabalho.com.brradarrt
Este documento apresenta 101 propostas para a modernização da legislação trabalhista brasileira. As propostas buscam promover maior flexibilidade nas relações de trabalho, reduzir custos para as empresas e incentivar a geração de empregos. Dentre as propostas, destacam-se a valorização da negociação coletiva, a flexibilização de jornadas de trabalho, incentivos à contratação de determinados grupos e a redução de encargos para as empresas. O documento também traz propostas relacionadas à saúde e segurança do trabalhador, benefí
O documento discute propostas para modernização trabalhista no Brasil. Apresenta dados sobre a redução da participação da indústria de transformação no PIB brasileiro nos últimos anos, além do alto nível de informalidade no mercado de trabalho, com mais da metade dos trabalhadores sem proteção da legislação atual.
O documento consolida a legislação brasileira sobre o benzeno, incluindo o Acordo Nacional do Benzeno de 1994, normas regulamentadoras, portarias e instruções normativas sobre limites de exposição, monitoramento ambiental e da saúde de trabalhadores, cadastramento de empresas, transporte e comercialização de produtos. Também apresenta convenções e recomendações da Organização Internacional do Trabalho sobre benzeno e limites de exposição adotados em outros países.
O documento resume as discussões de um seminário nacional sobre o benzeno, incluindo: 1) Diferentes modelos internacionais para definir limites de exposição ocupacional a carcinógenos; 2) A importância dos mecanismos de ação e dados epidemiológicos nisso; 3) Estudos sobre a incidência de leucemia no Brasil e a associação com exposição ao benzeno. Recomenda-se formar um comitê para estabelecer limites de exposição nacionais e medir concentrações de benzeno em
The document summarizes the position paper of the German AGS on establishing exposure-risk relationships for benzene. The AGS proposes risk-based occupational exposure limits (OELs) for benzene based on epidemiological data. It evaluates benzene's carcinogenicity and mode of action, as well as potential non-cancer effects. While linear extrapolation from high doses is proposed, the document acknowledges uncertainties in the mode of action and potential non-linearity at low doses. An OEL of 0.02 mg/m3, corresponding to a cancer risk of 1 in 100,000, is recommended as an acceptable risk level after 2013. Non-cancer effects are also possible at the tolerance risk level of 0.
The Health Watch study is a prospective cohort study of Australian petroleum industry workers that was set up in 1980 to study mortality and cancer incidence. Key findings from updates to the cohort include:
1) Overall, petroleum industry workers experienced lower mortality than expected, showing a "healthy worker effect." However, mesothelioma and melanoma mortality were significantly higher than expected among male workers.
2) A nested case-control study within the cohort found increased risks of leukemia, especially acute myeloid leukemia and chronic lymphocytic leukemia, associated with higher cumulative benzene exposure among male workers.
3) Risks of leukemia were also associated with longer durations of employment and evidence suggested peaks in exposure may also influence risk
McCluskey apresenta uma dissertação sobre distúrbios hematológicos relacionados ao benzeno em animais e humanos, avaliando a evidência de uma dose limiar. Ele revisa estudos epidemiológicos em trabalhadores expostos ao benzeno, incluindo as coortes de Pliofilm e China, e estudos em indústrias químicas, de petróleo e gás. Muitos estudos encontraram associação entre exposição ao benzeno e leucemia apenas acima de certos níveis de exposição cumulativa,
The document reports cancer incidence rates among workers in Brazil's Social Security system in 2006. It finds that acute myeloid leukemia was the 9th highest cancer site for males and 11th for females. It also details regional variation in cancer rates, finding the highest rates in the Northeast region, particularly in the states of Ceara and Paraiba. Additionally, it notes that cancer was the 15th highest cause of illness payments in 2006, accounting for 1.8% of all such payments that year.
O documento discute a incidência da leucemia mielóide aguda (LMA) no Brasil e no mundo. A taxa de incidência varia de acordo com a idade e região, sendo mais comum em indivíduos acima de 60 anos e áreas urbanas. Estudos estimam a taxa de incidência de LMA no Brasil entre 1 a 5,8 casos por 100 mil habitantes por ano.
Seminário Nacional do Benzeno (5 e 6 dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e
Mutagênicas - Experiências Internacionais e Nacional
Seminário Nacional do Benzeno ( 5 e 6 dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e
Mutagênicas - Experiências Internacionais e Nacional
The document discusses Germany's risk-based approach for setting occupational exposure limits (OELs) for carcinogens. It establishes acceptable and tolerable risk levels of 4 in 10,000 and 4 in 1,000, respectively. For each carcinogen, an exposure-risk relationship is derived to determine substance-specific acceptable and tolerable concentrations. A traffic light system is used to guide risk management measures based on risk levels. The approach aims to minimize exposures continuously rather than relying on a single threshold limit value. Examples are provided of how OELs have been derived for several carcinogens using this process.
Seminário Nacional do Benzeno (5 e 6 de dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e
Mutagênicas - Experiências Internacionais e Nacional
Seminário Nacional do Benzeno (5 e 6 de dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e
Mutagênicas - Experiências Internacionais e Nacional
Seminário Nacional do Benzeno (5 e 6 de dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e
Mutagênicas - Experiências Internacionais e Nacional
Acolyte Episodes review (TV series) The Acolyte. Learn about the influence of the program on the Star Wars world, as well as new characters and story twists.
El Puerto de Algeciras continúa un año más como el más eficiente del continente europeo y vuelve a situarse en el “top ten” mundial, según el informe The Container Port Performance Index 2023 (CPPI), elaborado por el Banco Mundial y la consultora S&P Global.
El informe CPPI utiliza dos enfoques metodológicos diferentes para calcular la clasificación del índice: uno administrativo o técnico y otro estadístico, basado en análisis factorial (FA). Según los autores, esta dualidad pretende asegurar una clasificación que refleje con precisión el rendimiento real del puerto, a la vez que sea estadísticamente sólida. En esta edición del informe CPPI 2023, se han empleado los mismos enfoques metodológicos y se ha aplicado un método de agregación de clasificaciones para combinar los resultados de ambos enfoques y obtener una clasificación agregada.
Here is Gabe Whitley's response to my defamation lawsuit for him calling me a rapist and perjurer in court documents.
You have to read it to believe it, but after you read it, you won't believe it. And I included eight examples of defamatory statements/
04062024_First India Newspaper Jaipur.pdfFIRST INDIA
Find Latest India News and Breaking News these days from India on Politics, Business, Entertainment, Technology, Sports, Lifestyle and Coronavirus News in India and the world over that you can't miss. For real time update Visit our social media handle. Read First India NewsPaper in your morning replace. Visit First India.
CLICK:- https://firstindia.co.in/
#First_India_NewsPaper
‘वोटर्स विल मस्ट प्रीवेल’ (मतदाताओं को जीतना होगा) अभियान द्वारा जारी हेल्पलाइन नंबर, 4 जून को सुबह 7 बजे से दोपहर 12 बजे तक मतगणना प्रक्रिया में कहीं भी किसी भी तरह के उल्लंघन की रिपोर्ट करने के लिए खुला रहेगा।
An astonishing, first-of-its-kind, report by the NYT assessing damage in Ukraine. Even if the war ends tomorrow, in many places there will be nothing to go back to.
1. Brazilian Benzene Seminar
Brasilia, Brazil
December 5, 2012
Rita Schoeny, Ph.D.
Senior Science Advisor,
Office of Science Policy, Office of Research and Development
U.S. EPA
1
2. Disclaimer
The views expressed in this presentation
are those do the author and do not
represent the policy of the U.S. EPA.
Some of this is EPA policy
2
3. So What Is EPA Policy?
Science Policy
Defaults, methods, Guidelines
Used when there are data or methodology gaps
Peer reviewed
Lots of documentation, which is publicly available
Policy based on science
May be set by EPA Executive Level
Generally involves regulations or other risk
management choices; science is peer reviewed, action
involves public comment; May be subject to Federal
Advisory Committee Act
Lots of documentation; may be docket; publicly
available
3
4. Examples
Science policy
Cancer Guidelines 2005
Set a reference dose for effects which are likely to
have a threshold
Quantitative adjustment to cancer risk for early life
exposure
Animal data are relevant to humans unless
demonstrated otherwise
4
5. Examples
Policy set on science
Drinking Water Regulations are set as close as
feasible to a Maximum Contaminant Level Goal
Consideration of residual risk after setting and
air regulation requiring Maximum Achievable
Control Technology
○ What we are currently doing for electrical power
plants
Cost / benefit choices
5
6. SDWA ‗96
Does the contaminant adversely affect Regulate with
public health?
NPDWR
Is the contaminant known or likely to occur in
PWSs with a frequency and at levels posing a
threat to public health?
These are questions,
Will regulation of the contaminant present a demonstrations of risk
meaningful opportunity for health risk reduction?
6
8. A lot has changed since ‗83
Exposure
Science in the
21st Century:
A Vision and A
Strategy
IPCS FRAMEWORK FOR ANALYSING THE
RELEVANCE OF A CANCER MODE OF ACTION
FOR HUMANS
8
9. NRC Silver Book
Recommendation
NRC Silver Book recommendation (Chapter
8 ―Improving Utility of Risk Assessment‖)
To make risk assessments most useful for risk
management decisions, the committee
recommends that EPA adopt a framework for risk-
based decision-making . . . that embeds the Red
Book risk assessment paradigm into a process
with initial problem formulation and scoping,
upfront identification of risk-management options
and use of risk assessment to discriminate among
these options.
9
10. Draft HHRA Framework
Silver Book on Utility
“Risk assessments
Planning & Scoping
and Problem Formulation should not be
Conceptual Analysis
conducted unless it is
clear that they are
Confirmation of Utility
Model Plan
Risk Assessment
designed to answer
Public/
Community/ specific questions, and
Effects Assessment
Stakeholder Exposure
Hazard Identification that the level of
Assessment
Involvement Dose Response
technical detail and
Risk Characterization
uncertainty and
variability analysis is
appropriate to the
Informing Decisions decision context” (NRC
2009, p. 247).
10
14. A Generalized Conceptual Model
(adapted from USEPA, 2002; 2003)
Sources Stressors Exposure Pathways/Routes Receptors Endpoints Risk Metrics
Activities that
generate/release
Stressors or Chemical,
types of stressor physical or
releases biological
agents Physical processes
that cause or interactions by which
an effect a stressor is brought
into to contact with Populations
receptor and/or
lifestages
exposed to Measures of
the stressor stressor
effects or
biological
systems Metrics by
affected which risk is
quantified
(e.g., disease
cases, hazard
quotients,
magnitude of
effect)
15. Sources Stressors Exposure Receptors Endpoints Risk
Pathways/ Metrics
Drinking water
disinfection Routes
Variable
mixture
nitrosamines;
dependent on Conceptual Model
treatment & Nitrosamines in Drinking Water
source water. Ingestion of
nitrosamine
mixture in
drinking water Consumers of
drinking
water;
includes
sensitive
populations
& life stages
Cancer,
any site or
type
Combined
risk of cancer
from subset
nitrosamines
in mixture
16. Cancer Guidelines: What‘s Different
from 1986?
Analyze data before invoking default options.
Mode of action is key in decisions
Weight-of-evidence narrative replaces the
previous ―A-B-C-D-E‖ classification scheme.
Two step dose response assessment
Model in observed range
Extrapolate from point of departure
Consider linear and non-linear extrapolation
Address differential risks to children
12/10/2012 16
17. Risk Assessment Science
Use Data Before Invoking Defaults
Analyze the available data
Is there too much uncertainty or Invoke a
is critical information lacking? default option
Y
N
Conduct risk assessment
17
18. Cancer Guidelines: What‘s Different
from 1986?
Analyze data before invoking default options.
Mode of action is key in decisions
Weight-of-evidence narrative replaces the
previous ―A-B-C-D-E‖ classification scheme.
Two step dose response assessment
Model in observed range
Extrapolate from point of departure
Consider linear and non-linear extrapolation
Address differential risks to children
12/10/2012 18
19. Human Animal Indirect,
Other
IARC US EPA NTP
Sufficient -- --
Carcinogenic to
Strong human Carcinogenic to Known to Be Human
humans
mechanistic humans Carcinogen
(Group 1)
Limited Sufficient data
-- Probably
carcinogenic to
Sufficient Strong humans
(Group 2A)
Inadequate Limited Strong
Likely to be
Sufficient -- carcinogenic to Reasonably
humans Anticipated to Be
Limited Limited -- Possibly Human Carcinogen
carcinogenic to
Strong & same humans
class as other (Group 2B)
Inadequate Inadequate carcinogens
Strong/ Inadequate
convincing Information to Assess
Inadequate Limited -- Not classifiable Suggestive Not classified
19
Zeise EEA Copenhagen Sept 3, 2010
20. Cancer Guidelines: What‘s Different
from 1986?
Analyze data before invoking default options.
Mode of action is key in decisions
Weight-of-evidence narrative replaces the
previous ―A-B-C-D-E‖ classification scheme.
Two step dose response assessment
Model in observed range
Extrapolate from point of departure
Consider linear and non-linear extrapolation
Address differential risks to children
12/10/2012 20
21. Mode of Action and Cancer
Assessment
MOA is the keystone to all aspects of
the assessment process
True for other endpoints
and is the major factor in
harmonization among risk
assessments
21
22. Why Do You Care about
MOA ?
MOA is key in Hazard Identification
Helps describe circumstances under which
agent is carcinogenic (High dose? Route?)
Relevance of data for humans
MOA determines choice of Low Dose
Extrapolation
Life stage risk
R esponse (T u m o r o r N on tu m o r D ata)
e)
os
D
on
it
m
Li
ce x
en
e)
E n v iro n m e n ta l E m p iric a l
fid
at
E x p o s u re L e v e ls on R ange of
ti m
C
5%
Es
o f In te re s t 9
O b s e rv a tio n
st
al
tr
e
ow
en
(L
(C
x
x
10%
lt
fau
De R ange of
ear E x tra p o la tio n
L in
x x
0%
L E D 10 E D 10
MOE x N O AEL
N o n lin e a r D e fa u lt
D ose x LO AEL
22
23. Breaking Down the Dichotomy
Cancer Non-Cancer
Threshold
Non-Threshold
Reversible
Irreversible
Safety Value
Risk value
RfD/RfC
Slope Factor
ADI/TDI
Unit Risk
MRL
Risk-Specific Dose
23
24. Mode of Action Exposure
―. . . a sequence of key Key event
events and processes,
starting with interaction of an
agent with a cell, proceeding
through operational and
anatomical changes, and
resulting in cancer Key event
formation. . . Mode of action is
contrasted with ―mechanism of
action,‖ which implies a more
detailed understanding and
description of events, often at the
molecular level, than is meant by
mode of action‖
Key event
Toxicity 24
25. Mode of Action Frameworks
U.S. EPA IPCS
Postulated mode of action
Hypothesized MOA: summary (theory of the case)
description and identification Key events
of key events Concordance of dose-
Experimental support: response relationships
Strength, consistency, Temporal association
specificity of association Strength, consistency and
Dose-response specificity of association of
concordance tumour response with key
Temporal relationship
events
Biological plausibility and
Biological plausibility and coherence
coherence Other modes of action
Consideration of the Uncertainties,
possibility of other MOAs Inconsistencies, and Data
Relevance to humans Gaps
Assessment of postulated
mode of action
25
26. MOA/Human Relevancy ILSI/IPCS
NO
Is the weight of evidence Proceed with
sufficient to establish a mode risk assessment
of action (MOA) in animals?
YES
Can human relevancy of the MOA be
YES reasonably excluded on the basis of
MOA not fundamental, qualitative differences in
Relevant key events between
animals and humans?
NO
Can human relevancy of the MOA be
reasonably excluded on the basis of NO
YES
MOA not quantitative differences in either Proceed with
Relevant kinetic or dynamic factors between Risk assessment
animals and humans?
26
27. Key Event
A “key event” is an empirically observable
precursor step that is itself a necessary
element of the mode of action or is a
biologically based marker for such an
element.
Key event is necessary, but not sufficient
If a key event doesn‘t occur, there is no
cancer
If one key event occurs, there may or may
not be cancer
27
28. Postulated Mode Of Action
Chloroform
Sustained Toxicity
Regenerative Cell Proliferation
Key Events
Tumor Development
28
29. Postulated Mode Of Action
Metabolism CP
DNA damage
Tumor
Development Mutations
29
30. Mode of Action Framework
Hypothesized MOA: summary description
and identification of key events
Experimental support:
Strength, consistency, specificity of association
Dose-response concordance
Temporal relationship
Biological plausibility and coherence
Consideration of the possibility of other
MOAs
Relevance to humans
12/10/2012 30
31. Based on ―Hill Criteria‖ for
Causality
―None of my nine viewpoints
Experimental support: can bring indisputable
Strength, consistency, evidence for or against the
cause-and-effect hypothesis
specificity of and none can be required
association as a sine qua non. What
they can do, with greater or
Dose-response less strength, is to help us
concordance to make up our minds on
the fundamental question —
Temporal relationship is there any other way of
explaining the set of facts
Biological plausibility before us, is there any other
and coherence answer equally, or more,
likely than cause and
effect?‖ Hill (1965)
12/10/2012 31
32. Experimental Support for
MOA
Strength, consistency, specificity of association
What is the level of statistical and biological
significance for each event and for cancer?
Do independent studies and different
experimental hypothesis-testing approaches
produce the same associations?
Does the agent produce effects other than those
hypothesized?
Is the key event associated with precursor
lesions?
Section
2.4.3.2
12/10/2012 32
33. Experimental Support for
MOA
Dose Response Concordance
○ Is precursor induced at lower dose than
tumors?
○ If greater incidence of the precursor
occurs, does incidence of tumor
increase?
○ If the precursor event is more severe is
there an increase in tumor incidence?
12/10/2012 33
34. Experimental Support for
MOA
Temporal Relationship
○ Do the precursor events occur
before tumors are observed?
○ Is this observed in independent
studies?
12/10/2012 34
35. Mode of Action: Bladder Tumors, Key Events
Cytotoxicity and Regenerative Hyperplasia
DMAIII Measurable Key
Metabolite Events in Target Tissue
SEM
Urothelial
Toxicity
BrdU
Sustained BrdU Labeling
Labeling
Regenerative
Proliferation
Hyperplasia Tumor
37. Experimental Support for
MOA
Biological plausibility and coherence
○ Does the MOA make sense given what
is known about carcinogenesis in
general, and for the case specifically?
○ Are carcinogenic effects and events
consistent across structural analogues?
○ Is the database on the agent internally
consistent in supporting the MOA,
including relevant non-cancer
toxicities?
12/10/2012 37
38. Nuclear Receptor Workshop
Possible Key Strength Consistency Specificity Temporal Biological Biological Coherence Key Event
Events Reproducibility Gradient Plausibility (Causal)
Dose- Associated
Response (Marker?)
Modulatory
?
Neither
CAR activation High, Required High High Earliest Not Yes High Causal
for tumors1,2 2 In vivo Knock out event, in determine Fits in a (DWolf)
Bear in mind studies1,2 studies1,2 vivo and in d logical (RPeffer)
that both ref #1 In vitro nuclear vitro14 (any sequence (RBars)
& #2 involve translocation3,4 Perhaps data?) No (RSchoeny)
initiation with PB- data that I (CElcombe)
den and a induced am aware Causal, under
rather short activation of. the
period of of the Only in experimental
treatment with phosphatas vitro (93, conditions
pb, 32 wk in e that 58) outlined in
ref #1 & 30 wk appears to Ref #1 & #2
in ref #2, we facilitate (JGoodman)
do not know the
what would translocati
happen in car on of CAR
ko mice if they from the
were treated cytoplasm
with pb for 2 to the
years nucleus is
(JGoodman) the very
earliest
event?
12/10/2012 38
39. MOA/Human Relevancy ILSI/IPCS
NO
Is the weight of evidence Proceed with
sufficient to establish a mode risk assessment
of action (MOA) in animals?
YES
Can human relevancy of the MOA be
YES reasonably excluded on the basis of
MOA not fundamental, qualitative differences in
Relevant key events between
animals and humans?
NO
Can human relevancy of the MOA be
reasonably excluded on the basis of NO
YES
MOA not quantitative differences in either Proceed with
Relevant kinetic or dynamic factors between Risk assessment
animals and humans?
39
40. Concordance Analysis of Key Events:
Cytotoxic Mode of Action
Key Event Rodents Humans Concordance analysis
Presence of of key events is for
Yes Yes
metabolite the MOA and not
Persistent Yes Possible necessarily
cytototoxicity
chemical specific
Persistent Chemical specific and
regenerative Yes Possible
generic information
proliferation
relevant to adverse
Tumors Yes Possible outcome is useful
41. α2μ Globulin and Male Rat
Kidney Tumors
Chemical-
a2u-Globulin a2u -Globulin
"Complex"
Renal Reabsorption Renal Reabsorption
Nucleus Nucleus
Heterolysosome Amino Acids Heterolysosome
Circulation Circulation
42. α2u-Globulin
The main story
Protein produced by male rats
MOA– functional changes in epithelial cells of
proximal tubules
•Hyaline droplets accumulate
•Tubule cell degeneration
•Regenerative cell proliferation
•Expansion of initiated renal
tubule cells
12/10/2012 42
43. Human Relevance of α2u-globulin
nephropathy – U.S. EPA
Humans do not possess a protein that is similar to α2u in
abundance or binding characteristics; thus, humans would not
be at risk of developing a chemically induced protein-mediated
nephrotoxic response.
Borghoff SJ and Lagarde WH, Toxicol Appl Pharmacol. 1993 Apr;119(2):228-35.
If male rat kidney tumors develop
In the absence of female rat kidney tumors
Male rats have increased hyaline droplets
Hyaline droplets contain a2u-Globulin
Characteristic nephrotoxicity
The male rat kidney tumors are not relevant for human health
risk and would not be included in a risk assessment.
44. Is the MoA for phenobarbital plausible in
humans?
Key event in MoA Plausible in humans?
Activation of CAR
Induction of CYP2B Increase via CAR can occur
Hypertrophy Yes
Cell proliferation Not likely, based on in vitro
and in vivo data
Inhibition of apoptosis Possible but not likely, based on
limited in vitro data
Selective clonal expansion Possible but not likely, none reported
Occurrence of liver tumors No, based on
epidemiological data
45. Cancer Guidelines: What‘s
Different from 1986?
Analyze data before invoking default options.
Mode of action is key in decisions
Weight-of-evidence narrative replaces the
previous ―A-B-C-D-E‖ classification scheme.
Two step dose response assessment
Model in observed range
Extrapolate from point of departure
Consider linear and non-linear extrapolation
Address differential risks to children
12/10/2012 45
46. MOA and Kids
Supplemental Guidance for Assessing
Susceptibility from Early-Life Exposure
to Carcinogens
Effects observed in childhood
Early life exposures that contribute to later
life effects
MOA determines whether quantitative
adjustment is made
46
47. Supplemental Guidance
Use age-specific values for
exposure and potency
When data permit, develop
separate potency estimates
for childhood exposure
In risk characterization, mutagenic MOA risk
is increased by age-dependent adjustment
factor (used with exposure info for age
group)
○ <2 yrs old, 10 fold
○ 2 to < 16yrs, 3 fold
No MOA, linear extrapolation without ADAF;
non-linear MOA, no ADAF
47
48. Framework for Determining This may actually get
a Mutagenic Mode of published at some
Action for Carcinogenicity point in time
Using EPA‘s 2005 Cancer
Guidelines and Supplemental
Guidance for Assessing
Susceptibility from Early-Life
Exposure to Carcinogens
48
49. Framework on Default MOA
― It should also be noted that there is no
‗default MOA.‘ The Cancer Guidelines offer
some default procedures to use when no
MOA can be determined.‖
•No MOA is not the same as a Mutagenic MOA
Determination of mutagenic MOA is as
scientifically rigorous as any other MOA
I found nothing in IPCS on a default MOA
49
50. To boldly go where no regulatory
toxicologist has gone before . . .
Mutagenicity is the induction of permanent,
transmissible changes in the amount,
chemical properties, or structure of the
genetic material. These changes may involve a
single gene or gene segment, a block of genes, parts of
chromosomes, or whole chromosomes. Effects on whole
chromosomes may be structural and/or numerical (e.g.,
aberrations and/or aneuploidy).
50
50
12/10/2012
51. Boldly part 2
Genotoxicity is the induction of alterations to
genetic material. It is a broader term than
mutagenicity in that genotoxicity refers to potentially
harmful effects on genetic material, which are not
necessarily persistent and transmissible. Genotoxicity
may be mediated directly or indirectly by chemical or
physical agents, and may or may not be associated with
mutagenicity. Tests for genotoxicity include tests for
mutagenicity, as well as other tests which provide an
indication of induced damage to DNA. For example, such
tests may include unscheduled DNA synthesis (UDS),
sister chromatid exchange (SCE), mitotic recombination,
DNA adduct formation, or DNA strand breaks.
51
12/10/2012
52. What does this definition
do?
Distinguishes between genotoxic and
mutagenic (U.S. EPA Guidelines refer to
―mutagenic MOA‖; Europe deals with
genotoxic).
Includes numeric changes in chromosome
as mutagenic
But not likely to be linear at low dose
Includes agents that generate reactive
oxygen species (ROS)
But need to consider low dose response
52
53. Framework: Multi-step
Process
Risk assessment
is an iterative
process
Visualize the Framework as series of
linear steps
Assemble data
Assess, weigh data quality
WOE for mutagenicity
WOE for MOA
53
54. Step 2: Evaluate Data
Quality
Look at primary papers
Judge against current
acceptability criteria
Cites publications for evaluating quality (e.g.
Cimino 2006, OECD, ICH, IWGT, DHHS
2006)
Keep, but weigh
54
55. Step 3 Gene- tox Tests Measure
Different Events
Genotoxicity Assays
Mouse Chromosome Ames Bacterial
Type of Damage
Lymphoma Aberrations CHO cells Mutagenicity
Point mutation Yes No Yes
Oligonucleotide
insertion or deletion
Yes No Yes
Allele Loss Yes No No
Small Chromosome
alteration
Yes ? No
Large Chromosome
alteration
Yes Yes No
Aneuploidy ? Yes No
Adapted from M. Moore (2004)
Cancer Hazard ID TERA’s Dose-Response Assessment Boot Camp 55
55
56. Step 3: WOE for Mutagenic
Activity
Categorize data – suggest use of our table in
Appendix A.
Put in all data with notes on quality
Use consistent terms for assay types or
endpoints: positive, negative, inconclusive,
contradictory
Present summary of
database
56
57. Concen- Cytotoxicity Duration of Results With Results Without Conform to Ref
In vitro Assays trations observed Exposure metabolic metabolic relevant
Test System activation (+ S9) activation (- S9) guideline
Gene Mutation
Bacterial
Salmonella, reverse mutation
E. coli, reverse mutation
Mammalian
CHO gene mutation, hprt locus
Mouse L5178Y, tk locus
Chromosome
Mutation
Micronucleus assay
Chromosomal aberrations
DNA Effects
Mammalian
Unscheduled DNA synthesis
Sister chromatid exchanges
Comet assay
DNA adduct analysis
Lower Eukaryote
Saccharomyces cerevisiae, gene
conversion
57
58. WOE for Mutagenic Activity
Conclusions across endpoints: some
endpoints carry more weight than others
○ e.g. Sperm head morphology may be caused
by modification of protein structure
○ Morphologic cell transformation does not
measure mutation
WOE for mutagenic activity: negative, data
are inadequate, data are of questionable
quality, data are equivocal, data are positive
58
60. Data Preference: WOE Mutagenic MOA
Cancer-relevant oncogene or tumor suppressor gene
mutations detected in target tissue after chemical exposure.
Surrogate gene mutations detected in target tissue after
chemical exposure.
Chemical-specific DNA adducts (known to be mutagenic
adducts) in target tissue after chemical exposure.
Primary DNA damage in target tissue after chemical
exposure.
Gene mutations or chromosome aberrations in surrogate
tissues after in vivo exposure.
DNA adducts or other measures of DNA damage and/or
repair or in surrogate tissues after in vivo exposure.
Mutations, cytogentic damage, DNA adducts and/or primary
DNA damage in vitro.
60
12/10/2012
61. What Has a Mutagenic MOA?
Cyclophosphamide
Cytotoxic, alkylating
Alkylating
Cytotoxic
61
62. Source
Application to Levels of
Organization Based on
Source to Outcome
Environmental
Contaminant
Exposure
Molecular Initiating Event Cellular Effects Individual Population Community
Toxicity Pathway
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
62
63. Application to Levels of
Organization Based on Source
to Outcome
Source
Community
Environmental
Contaminant
Population
Exposure Individual
Molecular Initiating Event Cellular Effects
Toxicity Pathway
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
63
64. Cancer Guidelines: What‘s Different
from 1986?
Analyze data before invoking default options.
Mode of action is key in decisions
Weight-of-evidence narrative replaces the
previous ―A-B-C-D-E‖ classification scheme.
Two step dose response assessment
Model in observed range
Extrapolate from point of departure
Consider linear and non-linear extrapolation
Address differential risks to children
12/10/2012 64
66. Take home message
In science, data before defaults
Scientifically based low dose
extrapolation before defaults
Science may inform policy; policy should
never affect science
66
68. Two Step Approach
Model data in the
observed range – to a
R e s p o n s e (T u m o r o r N o n tu m o r D a ta )
it
o
n
D
o
se
)
point of departure
im
L
ce x
Extrapolate below the
en
e)
E nv ironm e ntal d E m pirical
fi
at
n
E xpo sure Lev els C
o im
R ange of
st
of In terest 5% O b serv ation
lE
t9
tr a
es
w
POD
en
o
(L
(C
x
x
1 0%
lt
fa u R ange of
r De
ea
L in E xtrapo lation
x x
0%
L E D 10 E D 10
UF x NOAEL
N on lin ear D efau lt
D o se x LOAEL
68
69. Extend the Observed Range Using
Precursor Data
Objective of choosing POD is to set it as
close to environmental levels as
Supported by data
Appropriate to model
Cancer Guidelines say precursor data
are useful for this
Must have MOA
Section
3.2.2
69
70. Cacodylic Acid: BMDs and BMDLs
Feeding Drinking water
10% 1% 10% 1%
Endpoint Duration Duration
BMD BMDL BMD BMDL BMD BMDL BMD BMDL
(mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d)
104 104
Tumor weeks 7.74 5.96 6.80 2.22 weeks 1.92 1.21 0.88 0.14
10
weeks 1.36 1.04 0.42 0.32
104
Hyperplasia weeks 1.63 1.04 0.74 0.14
104
weeks 1.97 1.61 0.93 0.66
BrdU
10 weeks 0.65 0.29 0.54 0.07 Not determined. Available data not suitable for modeling.
labeling
3
weeks 0.68 0.18 0.31 0.02
Cytotoxicity No reliable dose-response data available
10 weeks 0.02 0.008 0.002 0.0007
70
71. Linear or Non-linear?
Two Step Dose Response Process
R e sp on se (Tum o r o r No n tu m o r D ata )
e)
os
D
on
it
Another Question First en
ce
Li
m
x
e)
E n v iro n m e n ta l E m p iric a l
fid
at
E x p o s u re L e v e ls on R ange of
t im
C
Es
o f In te re s t 5% O b s e rv a tio n
t9
al
es
tr
ow
en
(L
(C
x
x
1 0%
lt
fa u
De R ange of
e ar
L in E x tra p o la tio n
x x
0%
L E D 10 E D 10
UF x NOAEL
N on lin ear D efau lt
D ose x LOAEL
71
72. Is There Something Better?
Analyze the available data
Is there too much uncertainty or is
Invoke a
critical information lacking? Y default option*
N
Conduct risk assessment
72
73. Specify the sequence(s) of key
events
dosimetry Key event B1
Key event B2
Key event A1 Mode of
Action Assessment
endpoint
Key event A2
Key event A3
73
74. Source
Exposure
PBPK
Tissue dose
BBDR
Mode of action
Biologically Based
Dose Response
Model
Response
74
76. Reality check (I)
There are always data gaps
Arsenic
Formaldehyde
TCDD
phenobarbital
A BBDR model is a description of biological
structure with embedded empirical linkages
that cover the parts of the overall exposure-
dose-response linkage for which data are
missing.
76
77. Reality check (II)
As research improves our understanding of
the overall exposure-dose-response linkage,
the sophistication of the description of the
mode of action increases.
Corresponding iteration of the BBDR model
leads to more accurate predictions of dose-
response and time-course behaviors.
Will always be some degree of residual
uncertainty.
But is the default more uncertain?
77
78. And if no BBDR?
Two Step Dose Response Process
R e sp on se (Tum o r o r No n tu m o r D ata )
e)
os
D
on
it
m
Linear or Non-linear
Li
ce x
en
e)
E n v iro n m e n ta l E m p iric a l
fid
at
E x p o s u re L e v e ls on R ange of
t im
C
Es
o f In te re s t 5% O b s e rv a tio n
t9
al
es
tr
ow
en
(L
(C
x
x
1 0%
lt
fa u
De R ange of
e ar
L in E x tra p o la tio n
x x
0%
L E D 10 E D 10
UF x NOAEL
N on lin ear D efau lt
D ose x LOAEL
78
79. Mutagenesis Paradigm
Mutagens/Spontaneous
DNA Damaged DNA
Damage Sensing
Cellular Response
DNA Repair Incorrect No repair
Repair/Replication
Repaired DNA Mutant DNA Dead Cell
Demarini 70
79
80. Threshold?
Demonstrated Based on MOA
By inspection of the Mutagenic MOA has
dose response been linear
curve But should consider
Fitting models and biology of mutation
checking goodness
of fit
Statistical tests for
one model or
another
Does mutagenic MOA
mean low dose linear?
BBDR should be first
choice 80
81. In vitro Mutation Dose-Response: MMS & MNU
Doak et al., 2007
HPRT MF
MMS
MMS
NOEL = 1 mg/ml
MNU
MNU
No NOEL
2011 EMS Annual Meeting Pottenger 81
82. In vitro Mutation Dose-Response:
ENU Johnson et al., 2009
HPRT MF
ENU threshold dose-response (Lutz & Lutz model)
Slide from Pottenger 82
83. Take Home Message
MOA informs dose response
assessment
DNA damage is not mutation
Mutation is not cancer
Some genotoxicity endpoints may be
reasonable biomarkers
May be useful for extending the lower end of
dose response curve
Useful in MOA
83
84. Take home message 2
In science, data before defaults
Scientifically based low dose
extrapolation before defaults
Science may inform policy; policy should
never affect science
84
86. NRC 2009 Silver Book 1
Framing questions
and design step.
Risk Assessment is
not an end in itself.
Characterize
uncertainty and
variability
Default before data?
These are strictly my own opinions
86
87. NRC 2009 Silver Book 2
Dose response
Additivity to background is a major theme
○ How differentiate between exogenous and
endogenous damage?
○ DNA adducts biomarkers, could have major role
○ Does this mean linear all the time?
EPA has expressed preference for BBDR
○ Low dose data for adduct formation
○ Low dose data for mutation
○ Low dose data for other markers
Again my own opinions
87
88. Breaking Down the Dichotomy
Cancer Non-Cancer
Threshold
Non-Threshold
Reversible
Irreversible
Safety Value
Risk value
RfD/RfC
Slope Factor
ADI/TDI
Unit Risk
MRL
Risk-Specific Dose
88
Editor's Notes
May show in the amMake distinction between DA which is particular – to answer are DNA adducts causal. Not retro fitted risk assessments or dataThis is a pieces of the larger context for RA RMRisk assessment is not a linear process; one goes back and forth among the stepsOne size does not fit all; risk assessments should be designed to fit a purpose or purposesUnderstanding of available risk management options informs risk assessment planningStakeholder involvement will vary with assessment purpose, complexity, resourcesPeer review may be needed at several steps
I
Conceptual models are used to plan the risk assessment and associated data collection activities and are often revised periodically as data become available. They consist of two principal components: (1) a set of risk hypotheses that describe predicted relationships among stressor, exposure and health endpoint/response, along with the rationale for their selection; and (2) a diagram that illustrates the relationships presented in
Evaluate WOE across study but for a particular endpoint