- Email: [email protected]
The new recreational drugs in the emergency department
Abstracts / Toxicology Letters 238S (2015) S2–S11
addictive potential, including onset of craving and withdrawal syndrome after cessation of long-term use. Experimental studies investigating cathinones remain limited. Cathinones variably enhance monoamine concentrations in the brain, as assessed using in vitro and in vivo studies, in relation to either an uptake blockage or a release or both. Cathinone-mediated stimulation of dopamine transmission confirms their high potential for addiction. Not surprisingly, cathinones elicit locomotor activation in animals. They induce self-administration behavioral with potent reinforcing properties. To date, only rare studies investigated mechanisms of toxicity, toxicokinetics, metabolism, psychological and somatic effects as well as potential for addiction of cathinones. The congress presentation aims at reviewing in vitro and in vivo experimental investigations on cathinones in order to describe current findings and persistent gaps. http://dx.doi.org/10.1016/j.toxlet.2015.08.030
CEC2-4 Toxicovigilance of new psychoactive substances – Perspectives from the EU Early Warning System M. Evans-Brown EMCDDA, Lisbon, Portugal In recent years a large open market in substances which mimic the effects of drugs such as cannabis, MDMA, cocaine, ketamine, and heroin has developed in Europe. Known as new psychoactive substances, the EU Early Warning System (EWS), operated by the EMCDDA, now monitors more than 500. In 2014, for example, 101 substances were reported for the first time to the EWS. This included 31 cathinones, 30 cannabinoids, 9 phenethylamines, 5 opioids, 5 tryptamines, 4 benzodiazepines, 4 arylalkylamines and 13 substances that do not conform to the aforementioned groups. By July this year, more than 40 new substances had been reported. Mirroring the growth in this availability is their use and reports of serious harms. A core function of the EWS is to identify signals of such serious harms and respond through risk communication and risk assessment. Using case studies I will overview how the EWS detects and manages signals related to serious adverse events through its toxicovigilance system (ToVS), including the timely communication of risks to its partners. This will include an examination of how we collect and use data from a pan-European network as well as from our monitoring of open source information. http://dx.doi.org/10.1016/j.toxlet.2015.08.031
CEC2-5 New psychoactive substances: Data from the STRIDA project M. Bäckberg 1,∗ , O. Beck 2,3 , A. Helander 2,3 1
The Swedish Poisons Information Centre, Stockholm, Sweden Karolinska Institutet, Department of Laboratory Medicine, Stockholm, Sweden 3 Karolinska University Laboratory, Stockholm, Sweden 2
Introduction: In order to assess the occurrence and trends of new psychoactive substances (NPS) and collect information about their acute clinical effects and associated health risks, the Swedish Poisons Information Centre (PIC) together with the Karolinska Insti-
S5
tutet and the Karolinska University Laboratory initiated project called STRIDA. The project started in January 2010, and is ongoing. Methods: Patients with admitted or suspected intoxications by NPS are recruited to the STRIDA project by caregivers at emergency departments or intensive care units, following consultation with the PIC. Urine and/or blood samples are collected and sent to the Karolinska University Laboratory for drug analysis. Flexible multi-component liquid chromatography–tandem mass spectrometry (LC–MS/MS) and LC-high-resolution MS (LC-HRMS) methods, which are continuously updated to cover the current panel of NPS, are used to identify both traditional and new drugs. At present, the methods allow for identification and quantification of about 150 NPS (parent drugs and/or their metabolites). The analytical results are matched with data on clinical features collected during consultations with the PIC and retrieved from medical records. Results: Samples from about 2000 intoxication cases have been analysed, originating from hospitals all over the country. The yearly number of STRIDA cases has increased each year. The age range of patients is 11–71 years with the majority (∼60%) being 25 years or younger, and ∼75% being men. In 80% of the samples submitted for laboratory investigation, one or more psychoactive substances have been found, including NPS as well as classical narcotics. About 40% of the cases tested positive for NPS of which one fifth involved only one psychoactive substance. Several outbreaks of severe intoxications related to NPS belonging to different psychoactive drug classes (i.e. MDPV, methoxetamine, ethylphenidate and MT-45) have been noticed over the years. Conclusion: The STRIDA project has become a useful source to identify trends and occurrence of NPS use in Sweden, and to detect prominent clinical signs and toxicity associated to acute exposure. Polydrug use is a common feature among STRIDA patients, making the assessment of a unique toxidrome related to a specific substance difficult. The wide and variable range of NPS appearing on the drug market, which is partly driven by mechanisms related to legislative control, places great demands on the project to continuously update the methods used for NPS detection. http://dx.doi.org/10.1016/j.toxlet.2015.08.032
CEC2-6 The new recreational drugs in the emergency department D.M. Wood Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom There is increasing evidence of the use of novel psychoactive substances (NPS) (also known as “legal highs”) across Europe. Despite this evidence of increased use, there is limited understanding of the acute harms and Emergency Department presentations related to their use. Information on emergency department presentations related to the use of NPS can be obtained from a variety of different sources. Most European countries have poisons information services (for example the National Poisons Information Service (NPIS) in the UK, and data from contacts with these services for advice on the management of individuals with acute toxicity related to the use of NPS can be analysed to understand the frequency or presentations and the pattern(s) of acute toxicity. In addition, data is available from individual emergency departments. This can be collected through networks of departments with a specialist interest in acute recreational drug/NPS toxicity. An example of this would be the European Commission funded European Drug Emergencies Network (Euro-DEN) project run and co-ordinated by our group in London, UK. This initially collected
S6
Abstracts / Toxicology Letters 238S (2015) S2–S11
data from 16 sentinel emergency departments from 10 European countries between October 2013 and September 2014. During this data collection period, there were 5529 presentations involving 8709 drugs/NPS. Of these drugs/NPS, 5.6% were NPS and the most common were mephedrone and methedrone (both in the top 20 drugs reported to the Euro-DEN project). This project has now been continued as the Euro-DEN Plus project to continue data collection from October 2014 onwards; in addition it has been extended to include additional centres and European countries. Finally, it is possible to combine data from poisons information services with more detailed data from EDs and results of analytical screening of biological samples obtained from patients with acute drug/NPS toxicity. An example of this would be the STRIDA project in Sweden. In this presentation, information from national poisons information services, the Euro-DEN/Euro-DEN Plus project and the STRIDA project will be used to highlight the acute harms and Emergency Department presentations related to the use of Novel Psychoactive Substances. http://dx.doi.org/10.1016/j.toxlet.2015.08.033 CEC 3: Thresholds of Toxicological Concern – Basics and Latest Developments CEC3-1 Introduction into the tiered TTC concept K. Kosemund 1,∗ , S. Felter 2 1 Procter & Gamble, Global Product Stewardship, Schwalbach am Taunus, Germany 2 Procter & Gamble, Central Product Safety, Mason, OH, United States
The TTC (Threshold of Toxicological Concern) Concept is an important pragmatic first-tier risk assessment tool for evaluating low level human exposures to chemicals lacking sufficient toxicity data to support a chemical-specific risk assessment. The origins of TTC come from work by the U.S. Food and Drug Administration to develop an approach for assessing the safety of chemicals that could migrate at low levels from food packaging materials. Since then, TTC has evolved into a tiered tool that incorporates knowledge of chemical structure to bin untested chemicals into different potency categories. Reviews by major regulatory bodies have acknowledged the scientific foundation of TTC and its wide applicability for evaluating low level exposures as well as risk prioritisation for a wide range of uses to appropriately focus societal resources and to avoid unnecessary animal testing. This talk will provide an introduction to the tiered TTC concept and an overview of its current and potential uses within current regulatory landscapes. http://dx.doi.org/10.1016/j.toxlet.2015.08.036
CEC3-2 Cancer thresholds, Cohort of Concern and other excluded substance groups A. Boobis Imperial College, London, United Kingdom The TTC approach is based on generic human exposure threshold values, below which the probability of adverse effects on human health is considered to be very low. These thresholds were determined by distributional analysis of the points of departure for groups of compounds sharing broad structural characteristics on
which appreciable toxicological information was available. The respective thresholds apply to any chemical given only its structure, to enable determination of the group in which it belongs. This means that unless a specific effect can be predicted from structure, it is not possible to take into account the nature of the adverse effect in the TTC approach. This includes carcinogenicity, as it is not currently possible to predict all carcinogenic effects from structure alone. However, the group of carcinogens of most concern, because of their potency and the assumption of linearity in their dose–response relationship, are those that cause cancer by a genotoxic mode of action and genotoxicity is largely predictable from structure. Hence, identification of structural alerts for genotoxicity is a key early step in the application of the TTC approach. Whilst, in theory, it would be possible to cover even the most potent genotoxic compounds with a suitably conservative TTC value, this would have to be so low that the approach would be of no practical value. Hence, several groups of potent genotoxic compounds, such as aflatoxins, are excluded from the TTC approach. These have been termed the Cohort of Concern. Certain other categories of compound are either not suitable or are currently not amenable to application of the TTC approach. These include those that might exhibit marked species differences in bioaccumulation, e.g. dioxins; potential for allergenicity, e.g. proteins; poorly represented in the database used to derive the TTC values, e.g. non-essential metals, compounds likely to be pharmacologically active; strong presumption of endocrine activity, i.e. steroids. In addition, as the assignment of TTC values depends on consideration of chemical structure, certain categories of substance have to be excluded, because they comprise either mixtures of a range of structures or their structures are unknown, e.g. polymers, botanical extracts. http://dx.doi.org/10.1016/j.toxlet.2015.08.037
CEC3-3 Non-cancer oral toxicity databases for TTC S. Barlow Consultant, Brighton, United Kingdom The original human exposure threshold values (TTC values) for non-cancer endpoints used in the TTC approach were derived by Munro et al. (1996) from oral, repeat-dose toxicity data. The Munro database contains studies mostly published before 1990 and there has been criticism of the reliability of the derived TTC values, given the age of the studies, lack of good coverage of some non-cancer endpoints such as reproductive and developmental toxicity, and the possibility that more modern studies on the same substances may yield lower overall no-observed-adverse-effect levels. To meet this concern and extend the work of Munro et al., databases have since been developed that contain more recent and diverse toxicity data, including the RepDose database and the COSMOS database. Several groups have also investigated the robustness of the original TTC values with respect to particular endpoints, such as reproduction and development, or particular types of chemical such as industrial chemicals, substances used in food contact materials, and pesticides. These have all confirmed that the original non-cancer TTC values are robust and sufficiently conservative for use in the TTC approach. Reference Munro, et al., 1996. Food Chem. Toxicol. 34, 829–867.
http://dx.doi.org/10.1016/j.toxlet.2015.08.038
addictive potential, including onset of craving and withdrawal syndrome after cessation of long-term use. Experimental studies investigating cathinones remain limited. Cathinones variably enhance monoamine concentrations in the brain, as assessed using in vitro and in vivo studies, in relation to either an uptake blockage or a release or both. Cathinone-mediated stimulation of dopamine transmission confirms their high potential for addiction. Not surprisingly, cathinones elicit locomotor activation in animals. They induce self-administration behavioral with potent reinforcing properties. To date, only rare studies investigated mechanisms of toxicity, toxicokinetics, metabolism, psychological and somatic effects as well as potential for addiction of cathinones. The congress presentation aims at reviewing in vitro and in vivo experimental investigations on cathinones in order to describe current findings and persistent gaps. http://dx.doi.org/10.1016/j.toxlet.2015.08.030
CEC2-4 Toxicovigilance of new psychoactive substances – Perspectives from the EU Early Warning System M. Evans-Brown EMCDDA, Lisbon, Portugal In recent years a large open market in substances which mimic the effects of drugs such as cannabis, MDMA, cocaine, ketamine, and heroin has developed in Europe. Known as new psychoactive substances, the EU Early Warning System (EWS), operated by the EMCDDA, now monitors more than 500. In 2014, for example, 101 substances were reported for the first time to the EWS. This included 31 cathinones, 30 cannabinoids, 9 phenethylamines, 5 opioids, 5 tryptamines, 4 benzodiazepines, 4 arylalkylamines and 13 substances that do not conform to the aforementioned groups. By July this year, more than 40 new substances had been reported. Mirroring the growth in this availability is their use and reports of serious harms. A core function of the EWS is to identify signals of such serious harms and respond through risk communication and risk assessment. Using case studies I will overview how the EWS detects and manages signals related to serious adverse events through its toxicovigilance system (ToVS), including the timely communication of risks to its partners. This will include an examination of how we collect and use data from a pan-European network as well as from our monitoring of open source information. http://dx.doi.org/10.1016/j.toxlet.2015.08.031
CEC2-5 New psychoactive substances: Data from the STRIDA project M. Bäckberg 1,∗ , O. Beck 2,3 , A. Helander 2,3 1
The Swedish Poisons Information Centre, Stockholm, Sweden Karolinska Institutet, Department of Laboratory Medicine, Stockholm, Sweden 3 Karolinska University Laboratory, Stockholm, Sweden 2
Introduction: In order to assess the occurrence and trends of new psychoactive substances (NPS) and collect information about their acute clinical effects and associated health risks, the Swedish Poisons Information Centre (PIC) together with the Karolinska Insti-
S5
tutet and the Karolinska University Laboratory initiated project called STRIDA. The project started in January 2010, and is ongoing. Methods: Patients with admitted or suspected intoxications by NPS are recruited to the STRIDA project by caregivers at emergency departments or intensive care units, following consultation with the PIC. Urine and/or blood samples are collected and sent to the Karolinska University Laboratory for drug analysis. Flexible multi-component liquid chromatography–tandem mass spectrometry (LC–MS/MS) and LC-high-resolution MS (LC-HRMS) methods, which are continuously updated to cover the current panel of NPS, are used to identify both traditional and new drugs. At present, the methods allow for identification and quantification of about 150 NPS (parent drugs and/or their metabolites). The analytical results are matched with data on clinical features collected during consultations with the PIC and retrieved from medical records. Results: Samples from about 2000 intoxication cases have been analysed, originating from hospitals all over the country. The yearly number of STRIDA cases has increased each year. The age range of patients is 11–71 years with the majority (∼60%) being 25 years or younger, and ∼75% being men. In 80% of the samples submitted for laboratory investigation, one or more psychoactive substances have been found, including NPS as well as classical narcotics. About 40% of the cases tested positive for NPS of which one fifth involved only one psychoactive substance. Several outbreaks of severe intoxications related to NPS belonging to different psychoactive drug classes (i.e. MDPV, methoxetamine, ethylphenidate and MT-45) have been noticed over the years. Conclusion: The STRIDA project has become a useful source to identify trends and occurrence of NPS use in Sweden, and to detect prominent clinical signs and toxicity associated to acute exposure. Polydrug use is a common feature among STRIDA patients, making the assessment of a unique toxidrome related to a specific substance difficult. The wide and variable range of NPS appearing on the drug market, which is partly driven by mechanisms related to legislative control, places great demands on the project to continuously update the methods used for NPS detection. http://dx.doi.org/10.1016/j.toxlet.2015.08.032
CEC2-6 The new recreational drugs in the emergency department D.M. Wood Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom There is increasing evidence of the use of novel psychoactive substances (NPS) (also known as “legal highs”) across Europe. Despite this evidence of increased use, there is limited understanding of the acute harms and Emergency Department presentations related to their use. Information on emergency department presentations related to the use of NPS can be obtained from a variety of different sources. Most European countries have poisons information services (for example the National Poisons Information Service (NPIS) in the UK, and data from contacts with these services for advice on the management of individuals with acute toxicity related to the use of NPS can be analysed to understand the frequency or presentations and the pattern(s) of acute toxicity. In addition, data is available from individual emergency departments. This can be collected through networks of departments with a specialist interest in acute recreational drug/NPS toxicity. An example of this would be the European Commission funded European Drug Emergencies Network (Euro-DEN) project run and co-ordinated by our group in London, UK. This initially collected
S6
Abstracts / Toxicology Letters 238S (2015) S2–S11
data from 16 sentinel emergency departments from 10 European countries between October 2013 and September 2014. During this data collection period, there were 5529 presentations involving 8709 drugs/NPS. Of these drugs/NPS, 5.6% were NPS and the most common were mephedrone and methedrone (both in the top 20 drugs reported to the Euro-DEN project). This project has now been continued as the Euro-DEN Plus project to continue data collection from October 2014 onwards; in addition it has been extended to include additional centres and European countries. Finally, it is possible to combine data from poisons information services with more detailed data from EDs and results of analytical screening of biological samples obtained from patients with acute drug/NPS toxicity. An example of this would be the STRIDA project in Sweden. In this presentation, information from national poisons information services, the Euro-DEN/Euro-DEN Plus project and the STRIDA project will be used to highlight the acute harms and Emergency Department presentations related to the use of Novel Psychoactive Substances. http://dx.doi.org/10.1016/j.toxlet.2015.08.033 CEC 3: Thresholds of Toxicological Concern – Basics and Latest Developments CEC3-1 Introduction into the tiered TTC concept K. Kosemund 1,∗ , S. Felter 2 1 Procter & Gamble, Global Product Stewardship, Schwalbach am Taunus, Germany 2 Procter & Gamble, Central Product Safety, Mason, OH, United States
The TTC (Threshold of Toxicological Concern) Concept is an important pragmatic first-tier risk assessment tool for evaluating low level human exposures to chemicals lacking sufficient toxicity data to support a chemical-specific risk assessment. The origins of TTC come from work by the U.S. Food and Drug Administration to develop an approach for assessing the safety of chemicals that could migrate at low levels from food packaging materials. Since then, TTC has evolved into a tiered tool that incorporates knowledge of chemical structure to bin untested chemicals into different potency categories. Reviews by major regulatory bodies have acknowledged the scientific foundation of TTC and its wide applicability for evaluating low level exposures as well as risk prioritisation for a wide range of uses to appropriately focus societal resources and to avoid unnecessary animal testing. This talk will provide an introduction to the tiered TTC concept and an overview of its current and potential uses within current regulatory landscapes. http://dx.doi.org/10.1016/j.toxlet.2015.08.036
CEC3-2 Cancer thresholds, Cohort of Concern and other excluded substance groups A. Boobis Imperial College, London, United Kingdom The TTC approach is based on generic human exposure threshold values, below which the probability of adverse effects on human health is considered to be very low. These thresholds were determined by distributional analysis of the points of departure for groups of compounds sharing broad structural characteristics on
which appreciable toxicological information was available. The respective thresholds apply to any chemical given only its structure, to enable determination of the group in which it belongs. This means that unless a specific effect can be predicted from structure, it is not possible to take into account the nature of the adverse effect in the TTC approach. This includes carcinogenicity, as it is not currently possible to predict all carcinogenic effects from structure alone. However, the group of carcinogens of most concern, because of their potency and the assumption of linearity in their dose–response relationship, are those that cause cancer by a genotoxic mode of action and genotoxicity is largely predictable from structure. Hence, identification of structural alerts for genotoxicity is a key early step in the application of the TTC approach. Whilst, in theory, it would be possible to cover even the most potent genotoxic compounds with a suitably conservative TTC value, this would have to be so low that the approach would be of no practical value. Hence, several groups of potent genotoxic compounds, such as aflatoxins, are excluded from the TTC approach. These have been termed the Cohort of Concern. Certain other categories of compound are either not suitable or are currently not amenable to application of the TTC approach. These include those that might exhibit marked species differences in bioaccumulation, e.g. dioxins; potential for allergenicity, e.g. proteins; poorly represented in the database used to derive the TTC values, e.g. non-essential metals, compounds likely to be pharmacologically active; strong presumption of endocrine activity, i.e. steroids. In addition, as the assignment of TTC values depends on consideration of chemical structure, certain categories of substance have to be excluded, because they comprise either mixtures of a range of structures or their structures are unknown, e.g. polymers, botanical extracts. http://dx.doi.org/10.1016/j.toxlet.2015.08.037
CEC3-3 Non-cancer oral toxicity databases for TTC S. Barlow Consultant, Brighton, United Kingdom The original human exposure threshold values (TTC values) for non-cancer endpoints used in the TTC approach were derived by Munro et al. (1996) from oral, repeat-dose toxicity data. The Munro database contains studies mostly published before 1990 and there has been criticism of the reliability of the derived TTC values, given the age of the studies, lack of good coverage of some non-cancer endpoints such as reproductive and developmental toxicity, and the possibility that more modern studies on the same substances may yield lower overall no-observed-adverse-effect levels. To meet this concern and extend the work of Munro et al., databases have since been developed that contain more recent and diverse toxicity data, including the RepDose database and the COSMOS database. Several groups have also investigated the robustness of the original TTC values with respect to particular endpoints, such as reproduction and development, or particular types of chemical such as industrial chemicals, substances used in food contact materials, and pesticides. These have all confirmed that the original non-cancer TTC values are robust and sufficiently conservative for use in the TTC approach. Reference Munro, et al., 1996. Food Chem. Toxicol. 34, 829–867.
http://dx.doi.org/10.1016/j.toxlet.2015.08.038