Modular Training Programme
MODULE 1: INTRODUCTION TO RISK ASSESSMENT AND MANAGEMENT, WITH SPECIAL ATTENTION TO CHEMICAL RISK ASSESSMENT
Module leaders: Assoc prof Annika Hanberg, Dr Mattias Öberg and Prof Helen Håkansson, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Content: The course module will include fundamental concepts in toxicology, epidemiology, exposure and risk assessment, and will also cover risk assessment and risk management in regulatory decision-making. Standardized test guidelines and GLP will be covered. Attention will be paid to interpretation possibilities and evaluation of data from different test systems, handling of uncertainties and data gaps, and other critical issues in health risk assessment. Particular focus will be given to identification of critical effects, extrapolation to humans and sensitive groups, application of assessment factors and allocation of health-based guidance values. Specific risk assessments of problematic chemicals will be discussed.
- Concepts in toxicology and risk analysis
- Standardized test guidelines, testing strategies and GLP
- Web-based information sources in toxicology and risk assessment, including a computer-based exercise
- Epidemiological principles, interpretation of results in epidemiology
- Introduction to exposure assessment
- Assessment of effect data (QSAR, in vitro, in vivo, epidemiology)
- Introduction to standard setting
- Classification and labelling
- Risk perception, risk communication and risk management
- Risk assessment of chemicals in Europe, REACH and ECHA
- Risk assessment and food safety, EFSA
- European procedure for occupational exposure limits, SCOEL
- Examples of problematic risk assessment (e.g. Dioxin, trichloroethylene, PFOS, cadmium)
- Group work on exposure assessment, hazard characterization and risk characterization
MODULE 2: ROLE OF ADME IN RISK ASSESSMENT
Module leader: Dr Shirley Price, Division of Biochemical Sciences, Faculty of Health and Medical Sciences, University of Surrey, UK
Content: A good knowledge of the principles of xenobiotic metabolism is central to toxicology because many compounds undergo enzymic metabolism to form toxic metabolites. Similarly, many toxicants are inactivated by the action of xenobiotic metabolising enzymes. Toxicokinetics is the study of the rates of absorption, distribution, metabolism and excretion of toxicants, and is central to an understanding of the exposure of target tissues to toxicants. This module focuses on toxicokinetics and xenobiotic metabolism with particular emphasis on risk assessment. It also covers an overview of lung, oral and intestinal absorption; metabolism – phases I and II; skin absorption and metabolism; stereoselectivity in drug metabolism and toxicology; enzymology and molecular biology; distribution and excretion; toxicodynamic effects, reactive molecules and dose response curves; basic xenobiotic metabolism and the implications for drug development; techniques for measuring xenobiotics; plasma monitoring for therapeutic optimisation; basic pharmacokinetics; bioavailability; interspecies comparison in drug metabolism and toxicokinetics; extrapolation of data from animals to man; and pharmacokinetic modelling. These concepts will be illustrated throughout by ‘real world’ examples.
- Lung, oral and intestinal absorption
- Metabolism - Phase I and II
- Skin absorption and metabolism
- Stereoselectivity in drug metabolism and toxicology
- Enzymology and molecular biology
- Distribution and excretion
- Toxicodynamic effects, reactive molecules and dose-response curves
- Basic xenobiotic metabolism and the implications for drug development
- Techniques for measuring xenobiotics
- Plasma monitoring for therapeutic optimisation
- Basic pharmacokinetics
- Bioavailability
- Interspecies comparison in drug metabolism and toxicokinetics
- Extrapolation of data from animals to man
- Pharmacokinetic modelling
- Case studies on the importance of metabolism in interpreting toxicity data and in deriving uncertainty factors
- Case study on the use of toxicokinetic models in route-to-route and interspecies extrapolation
MODULE 3: IDENTIFICATION AND ASSESSMENT OF GENOTOXIC AND NON-GENOTOXIC CARCINOGENS
Module leaders: Prof Emanuela Corsini, Department of Pharmacological Sciences, Faculty of Pharmacy, University of Milan and Prof Angelo Moretto, International Centre for Pesticides and Health Risk Prevention, University of Milan, Italy.
Content: Chemicals, owing to a possible carcinogenic effect, are likely to endanger human health. This course module is designed to provide the participants with principles of genotoxicity and carcinogenesis and their application to risk assessment. A good knowledge of the principles of carcinogenesis is central to experimental toxicology and risk assessment. The information required for weighted risk assessment is provided by a systematic analysis of chemical and biological characteristics and thorough research into its mechanism of action. Topics covered will, therefore, include mechanisms of metabolic activation/deactivation of xenobiotics, interaction of xenobiotics with DNA, DNA repair, mechanisms of action, in vitro and in vivo assays, extrapolation of animal data to humans and novel models to assess carcinogenetic potential of chemicals. The main classes of genotoxic and carcinogenic agents and their mode of action will also be described. Central to this module will be the discussion of case studies aimed to provide the students with the tools necessary for a critical evaluation of animal data and their relevance to humans. In silico methods will also be discussed.
- Definition of genotoxic
- Test of mutagenicity
- Test of clastogenicity
- Evaluation and assessment of in vitro vs. in vivo tests (role of metabolism, dose issues)
- Epigenetics and its relevance in carcinogenicity
- Definition of carcinogen (genotox, non-genotox)
- Evaluation and assessment of in vivo carcinogenicity studies (statistics, background incidence, historical data, dose response, MTD, human relevance, IPCS framework, MOA, TTC)
- New methods: omics signature of carcinogens (in vitro/in vivo), transgenic models
- Use of (Q)SAR methods
- Case studies (phenobarbital/phenobarbital-like, dichlorvos, etc)
MODULE 4: EXPOSURE ANALYSIS IN RISK ASSESSMENT
Module leaders: Dr Mieke Lumens and Prof Bas Blaauboer, Institute for Risk Assessment Sciences, Utrecht University, The Netherlands
Content: Exposure assessment and modelling are essential components of any risk assessment. The way in which exposure is assessed and modelled varies significantly and can range from generic qualitative assessments to highly quantitative approaches involving complex modelling. Exposure assessment requires an understanding of chemical, biological and physical principles and may involve estimating exposures from one to multiple sources of exposure.
In order to fully appreciate risks that arise from industrial activities and environmental emissions, it is essential to quantify chemical and biological agents that are emitted into general environment. In this course module, participants will learn to relate environmental conditions to actual exposures experienced by human populations and ecosystems. They will learn how to directly measure exposure levels, how to decide on the best way to obtain representative exposure measurements, and how to analyse data that is obtained during exposure measurement surveys. Participants will also be introduced to fundamentals of exposure modelling, which allow investigators to infer exposure levels in absence of direct measurements of exposures. The growing amount of models aimed at estimating exposure with varying degrees of complexity leads to greater requirements for specialist expertise. Furthermore the recent move to towards developing genomic, proteomic and metabonomic methods to assess exposure adds further complexity to the field. These recent developments will be discussed during the course.
MODULE 5: IDENTIFICATION AND ASSESSMENT OF ORGAN TOXICITY, INCLUDING NEUROTOXICITY, IMMUNOTOXICITY
Module leaders: Prof. Dr. Regine Kahl and Dr. Wim Wätjen, Institute of Toxicology, Heinrich Heine University of Düsseldorf, Germany
Content: Identification of the target organ of toxicity is an important part of risk assessment. Organ toxicology is mainly assessed by animal experiments according to OECD guidelines although there is not yet a fixed international canon for the testing of neurotoxicity and immunotoxicity. The outcome of repeated dose studies is used for defining the no observed adverse effect level (NOAEL) or the benchmark does, respectively, as the starting point of risk assessment. A key problem in the use of animal data is the relevance for humans with respect to the species differences in the mode of action and in metabolism, with respect to differences in the route and duration of administration, and with respect to sensitivity differences within the human population. Safety and uncertainty factors are at present used to account for such differences. Efforts are made all over the world to develop animal-free alternative methods for the assessment of organ toxicology.
- Assessment of organ toxicology by OECD guidelines for the testing of chemicals in single and repeated dose toxicity studies
- Histopathology of the liver, the kidney, the lungs, the hematopoietic system, the nervous system and the immune system in laboratory animals
- Methods for assessing immunotoxicology and chemical sensitisation
- The role of ADME in organ toxicology
- Modes of action (MOA) of toxic effects in laboratory animals as compared to humans: characterisation of the relevance of animal experiments to human health
- Organ toxicity as starting point for cancer development
- Dose response relationships in organ toxicology and definition of no observed adverse effect levels (NOAELs) and benchmark doses (BMDs)
- Extrapolation of data from laboratory animals to humans: characterisation of subpopulations sensitive to specific organ toxicities
- Extrapolation of data from laboratory animals to humans: definition of safety/uncertainty factors and route to route extrapolation
- Safety pharmacology in drug development
- Alternative testing strategies in organ toxicology
MODULE 6: EPIDEMIOLOGY AND STATISTICS IN TOXICOLOGICAL RISK ASSESSMENT
Module leaders: Dr Mieke Lumens and Prof Bas Blaauboer, Institute for Risk Assessment Sciences, Utrecht University, Netherlands
Content: Epidemiology can play an important role is risk assessment. Environmental epidemiology research can provide important information for risk assessment on a population level. The general objectives of this course are to increase the knowledge of principles and methods used in epidemiology. The focus will be on the use of epidemiology for risk assessment; on topics of interest to toxicologists such as genetic epidemiology, environmental and occupational epidemiology, and biomarkers in epidemiology; on basic data analysis in epidemiology; and on the relative merits of toxicology and epidemiology in the risk assessment process. While risks associated with environmental exposures are generally small the exposed population can be large. To detect these small risks it is essential that refined methods of epidemiology are used. Course participants will learn about measurement errors, bias and confounding. Next to the more traditional epidemiological designs like cohort or case control studies, more recently developed designs like time series designs, spatial methods and gene-environment interaction studies to describe mechanisms and susceptible populations will be discussed
MODULE 7: IDENTIFICATION AND ASSESSMENT OF REPRODUCTIVE TOXICITY AND ENDOCRINE DISRUPTION
Module leaders: Assoc Prof Annika Hanberg, Prof Helen Håkansson, Institute of Environmental Medicine and Assoc prof Johanna Zilliacus, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
Content: The course will include fundamental concepts in reproductive and developmental toxicity. Special attention will be paid to the endocrine toxicity mode-of-action. The course will cover complexities/difficulties in risk assessment and risk management including regulatory decision-making. Standardized test guidelines of reproductive and endocrine disrupting effects will be covered. Specific attention will be given to the development of test strategies in OECD within the field. Attention will be paid to interpretation possibilities and evaluation of data from different test systems, handling of uncertainties and data gaps, and other problems in health risk assessment of reproductive toxicity and endocrine disruption. Particular focus will be given to identification of critical effects, extrapolation to humans and sensitive groups, application of assessment factors and allocation of health-based guidance values. Suggested limitations for EDCs in general risk assessment procedures will be discussed, e.g. shape of dose-response curve and epigenetic effects. Specific risk assessments of problematic chemicals will be discussed.
- Introduction to reproductive toxicity and endocrine disruption
- Introduction to endocrinology and nuclear receptor signalling
- Endocrine disruption – mechanisms, health effects, testing strategies
- Signalling pathways targeted by EDC
- Standardized test guidelines for reproductive toxicity, testing strategies for EDC
- Epidemiological studies of reproductive effects and endocrine disruption, interpretation of results
- Assessment of reproductive and EDC effect data (QSAR, in vitro, in vivo, epidemiology)
- Assessment of dose-response for endocrine effects
- Assessment of maternal toxicity
- Epigenetic effects of EDC, implications for risk assessment
- Regulatory aspects of reproductive toxicity and EDC - REACH, pesticides, CLP
- Examples of problematic risk assessment (e.g. Bisphenol A, Dioxin, vinclozolin)
- Group work on hazard and risk characterization
MODULE 8: SUPPLEMENTARY MODULE
Any other suitable course available in Europe on a specific aspect of risk assessment such as cosmetics, plant protection products and biocides, consumer products, medicines and veterinary drugs, contaminants in food, soil and water, industrial chemicals, occupational exposure, risk communication, 3Rs in risk assessment |
