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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure MOE approach was conducted. The MOE is defined as ratio between toxicological threshold benchmark dose and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco high risk and cannabis low risk. Compared to medicinal products or other consumer products, risk assessment of drugs of abuse has been characterised as deficient, much of this is based on historical attribution and emotive reasoning 1. The available data are often a matter of educated guesses supplemented by some reasonably reliable survey data from the developed nations 2. Only in the past decade, have there been some approaches to qualitatively and quantitatively classify the risk of drugs of abuse. These efforts tried to overcome legislative classifications, which were often found to lack a scientific basis 3. UNODC suggested the establishment of a so-called Illicit Drug Index IDI , which contained a combination of a dose index the ratio between the typical dose and a lethal dose and a toxicology index concentration levels in the blood of people who died from overdose compared with the concentration levels in persons who had been given the drug for therapeutic use 4. King and Corkery 5 suggested an index of fatal toxicity for drugs of misuse that was calculated as the ratio of the number of deaths associated with a substance to its availability. Availability was determined by three separate proxy measures number of users as determined by household surveys, number of seizures by law enforcement agencies and estimates of the market size. Gable 6 provided one of the earliest toxicologically founded approaches in a comparative overview of psychoactive substances. In a follow-up study, Gable 7 refined the approach and now provided a numerical safety ratio, which allowed a rank-ordering of abused substances. Despite these early efforts for toxicology-based risk assessments, the most common methods are still based on expert panel rankings on harm indicators such as acute and chronic toxicity, addictive potency and social harm, e. The rankings of the two countries correlated very well 3 , 8. Similar studies were conducted by questioning drug users, resulting in a high correlation to the previous expert judgements 10 , 11 , The methodology was also criticized because a normalization to either the total number of users or the frequency of drug use was not conducted, which might have biased the result toward the harms of opiate use 14 and may have underrepresented the harms of tobacco The Margin of Exposure MOE is a novel approach to compare the health risk of different compounds and to prioritize risk management actions. The MOE is defined as the ratio between the point on the dose response curve, which characterizes adverse effects in epidemiological or animal studies the so-called benchmark dose BMD and the estimated human intake of the same compound. Clearly, the lower the MOE, the larger the risk for humans. In Europe, the MOE was introduced in as the preferred method for risk assessment of carcinogenic and genotoxic compounds In the addiction field, the MOE method was never used, aside from evaluating substances in alcoholic beverages 20 , 21 or tobacco products 22 , This study is the first to calculate and compare MOEs for other addiction-related substances. The only toxicological threshold available in the literature for all of the compounds under study was the LD Using the method of Gold et al. As shown in Supplementary Table S1 online, the full range of available LD50 values in different animal species is taken into account as a risk function assuming a normal distribution for BMDL10 rather than that a single value is entered into the calculation except methamphetamine and MDMA for which only one value was available in the literature. To determine the typical range of individual daily dosage, various textbook and internet sources 21 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 were evaluated Table 2. As no information about the most likely function for dosage distribution is available, a uniform probability distribution was entered into the calculation in this case Supplementary Table S1. The data used for calculation of population-based exposure is shown in Table 2. Prevalence data was available for all drugs except methadone; and amphetamine and methamphetamine were grouped together. The corresponding risk functions are shown in Supplementary Table S1 online. The detailed calculation formulae chosen for probabilistic risk assessment are shown in Supplementary Table S2 online. The margin of exposure values were calculated for individual exposure Figure 1 , population-based exposure calculated from prevalence data Figure 2 and population-based exposure calculated from sewage analysis Figure 3. For both individual and population-based scenarios, alcohol consumption was found to have the lowest margin of exposure. For individual exposure, heroin has the second lowest margin of exposure. However, considering worst-case scenarios e. On the other end of the scale, THC or cannabis can be consistently found to have high MOE values, as well as amphetamine-type stimulants and benzodiazepines. Margin of exposure for daily drug use estimated using probabilistic analysis left red bar: average; error bar: standard deviation; right gray bar: tolerant user; circle symbol for alcohol : value based on human data. Margin of exposure for the whole population based on prevalence data estimated using probabilistic analysis left red bar: average; error bar: standard deviation; right gray bar: tolerant user; circle symbol for alcohol and cannabis : value based on human data. Margin of exposure for the whole population based on sewage analysis estimated using probabilistic analysis left red bar: average; error bar: standard deviation; right gray bar: tolerant user; circle symbol for THC : value based on human. For sensitivity analysis, three different methods were applied: convergence testing during the probabilistic simulation, application of a factor to consider drug tolerance and comparison with human toxicological thresholds for some of the agents. Convergence was achieved for all calculated output MOE values. This means that the generated output distributions are stable and reliable. From the model input variables, the highest influence as expressed by rank of regression coefficients on the results is caused by the exposure, rather than the toxicological thresholds or the bodyweights. The sensitivity analysis data for tolerant users are additionally shown in Figure 1 — 3 based on the ratio between no-tolerance and high tolerance dosage as shown in Table 2 27 , 37 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , Even though the general results remain stable i. However, as the percentage of tolerant users is generally unknown, the most probable value of MOE would lie in the range between non-tolerant and tolerant users the gray-marked area in Figures 1 — 3. Finally, the sensitivity analysis results from application of human toxicity data for some of the compounds alcohol, nicotine and THC 21 , 55 , 56 , 57 are shown in Supplementary Table S3 online and marked in Figures 1 — 3. For the other compounds, a discrepancy between animal and human data was detected see discussion. Many governments in Europe have favoured more restrictive policies with respect to illicit drugs than for alcohol or tobacco, on the grounds that they regard both illicit drug abuse and related problems as a significantly larger problem for society Drug rankings can therefore be useful to inform policy makers and the public about the relative importance of licit drugs including prescription drugs and illicit drugs for various types of harm Our MOE results confirm previous drug rankings based on other approaches. Specifically, the results confirm that the risk of cannabis may have been overestimated in the past. In contrast, the risk of alcohol may have been commonly underestimated. Our results confirm the early study of Gable 6 who found that the margin of safety defined as therapeutic index varied dramatically between substances. In contrast, our approach is not based on a therapeutic index, which is not necessarily associated with risk, but uses the most recent guidelines for risk assessment of chemical substances, which also takes the population-based exposure into account. A major finding of our study is the result that the risk of drugs varies extremely, so that a logarithmic scale is needed in data presentation of MOE e. Figures 1 — 3. As expected, for an individual the difference between the impact of different drugs is not as large as for the whole society i. Nevertheless, we judge our results as more plausible. For an individual heavy consumer of either heroin or alcohol, the risk of dying from a heroin overdose or from alcoholic cirrhosis increased considerably in each case. However for the society as a whole, the several ten-thousands of alcohol-related deaths considerably outnumber drug overdose deaths. Hence, it is plausible that the MOE for alcohol can be lower than the one for heroin, purely because of the high exposure to alcohol in the European society see also Rehm et al. Nevertheless, as previously stressed, our findings should not be interpreted that moderate alcohol consumption poses a higher risk to an individual and their close contacts than regular heroin use Much of the harm from drug use is not inherently related to consumption, but is heavily influenced by the environmental conditions of the drug use 2 and this additional hazard is not included in a drug ranking based on animal toxicology. The first major problem of the approach is the lack of toxicological dose-response data for all compounds except alcohol and tobacco. No human dose-response data are available; also no dose-response data in animals, only LD50 values are published. Furthermore, no chronic-toxicity data long-term experiments are available, which are usually used for such kinds of risk assessment. Therefore, we can assess only in regards to mortality but not carcinogenicity or other long-term effects. The absence of such data is specifically relevant for compounds with low acute toxicity such as cannabis , the risk of which may therefore be underestimated. Additionally, the available toxicological thresholds i. LD50 values have considerable uncertainty for example, more than a factor of 10 for diazepam in different species. However it has been previously shown that the animal LD50 is closely related to fatal drug toxicity in humans The sensitivity analysis based on human data for ethanol shows that the average MOE result is similar to the result based on animal LD Our results for ethanol are also consistent with previous MOE studies of ethanol 20 , For cannabis and nicotine, the discrepancy in the sensitivity analysis can be explained in the chosen endpoints no dose response data on mortality in humans were identifiable in the literature. The rationale for choosing this endpoint was the exclusion of risk for the inadvertent and indirect ingestion of THC when hemp products are used as animal feed We were unable to identify dose-response information for other endpoints of cannabis e. Similar to cannabis, the sensitivity analysis for nicotine based on human data resulted in much lower MOE values. This again is based on a different endpoint increase of blood pressure in this case, which is expected to be more sensitive than mortality. We nevertheless think that the risks of cigarettes could have been underestimated in our modelling, because in contrast to the other agents, tobacco contains a multicomponent mixture of toxicants. Previous risk assessment of tobacco both financed and co-authored by the tobacco industry have looked at various compounds but not included nicotine itself 22 , These values are reasonably consistent with our MOE for nicotine of 7. However, it would be advisable for future risk assessments of tobacco smoking to include modelling of a combined MOE, which considers all toxic compounds. The second major problem is the uncertainty in data about individual and population-wide exposure due to the illegal markets. There is a scarcity of epidemiological studies of cannabis use by comparison with epidemiological studies of alcohol and tobacco use Due to both problems or in other words the large uncertainty in input data of exposure , we cannot calculate with point estimates. To overcome this, we are using a probabilistic calculation methodology that takes the whole distribution of the input variables into account. For example, for the exposure a random sample of the number of days of annual drug use is combined with a random sample in the range of the usual dosages of the drug to provide an estimate for dosage. The downside of the probabilistic approach is that the output also is not a single numerical value but rather a likelihood distribution. Nevertheless, using graphical approaches Figs. Our approach contains some further limitations: Drug interactions cannot be taken into account as we just do not have any toxicological data on such effects e. However, polydrug use in humans is common, especially of illicit drugs with ethanol or benzodiazepines Addiction potential and risk of use e. Aside from the limitations in data, our results should be treated carefully particularly in regard to dissemination to lay people. Such statements taken out of context may be misinterpreted, especially considering the differences of risks between individual and the whole population. A main finding of our study is the qualitative validation of previous expert-based approaches on drug-ranking e. Nutt et al. Currently, the MOE results must be treated as preliminary due to the high uncertainty in data. The analyses may be refined when better dose-response data and exposure estimates become available. As the problem is multidimensional 15 , it would also make sense to establish some form of harm or risk matrix 64 that may be more suitable than a single indicator. Currently, the MOE results point to risk management prioritization towards alcohol and tobacco rather than illicit drugs. The high MOE values of cannabis, which are in a low-risk range, suggest a strict legal regulatory approach rather than the current prohibition approach. The methodology for comparative quantitative risk assessment was based on a previous study conducted for compounds in alcoholic beverages 20 with the exception that probabilistic exposure estimation was conducted 65 , 66 , The MOE approach was used for risk assessment 18 , As none of these thresholds neither human data nor animal data was available for the illicit drugs, LD50 values from animal experiments were selected instead and extrapolated to BMDL. The exposure was calculated for individual scenarios of daily drug use, as well as for population based scenarios using drug prevalence data and sewage analysis data for Europe, which is a promising complementary approach for estimating the drug use in the general population. Monte Carlo simulations were performed with , iterations using Latin Hypercube sampling and Mersenne Twister random number generator. The distribution functions and detailed calculation methodology is specified in Supplementary Tables S1—S2 online. Coomber, R. Assessing the real dangers of illicit drugs - Risk analysis as the way forward? Fischer, B. Public Health , — Ranking the harm of alcohol, tobacco and illicit drugs for the individual and the population. Article Google Scholar. Towards the Creation of an Illicit Drug Index. World drug report King, L. An index of fatal toxicity for drugs of misuse. Gable, R. Toward a comparative overview of dependence potential and acute toxicity of psychoactive substances used nonmedically. Drug Alcohol Abuse 19, — Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction 99, — Nutt, D. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet , — Drug harms in the UK: a multicriteria decision analysis. Morgan, C. Harms and benefits associated with psychoactive drugs: findings of an international survey of active drug users. Carhart-Harris, R. User perceptions of the benefits and harms of hallucinogenic drug use: A web-based questionnaire study. Substance Use 15, — Kalant, H. Drug classification: science, politics, both or neither? Addiction , — Claridge, L. Drugs and harm to society. Lancet , Caulkins, J. Basing drug scheduling decisions on scientific ranking of harmfulness: false promise from false premises. Crump, K. A new method for determining allowable daily intakes. The use of the benchmark dose approach in health risk assessment. Opinion of the Scientific Committee on a request from EFSA related to a harmonised approach for risk assessment of substances which are both genotoxic and carcinogenic. EFSA J. Lachenmeier, D. Comparative risk assessment of carcinogens in alcoholic beverages using the margin of exposure approach. Cancer , E—E Xie, J. A probabilistic risk assessment approach used to prioritize chemical constituents in mainstream smoke of cigarettes sold in China. Cunningham, F. A novel application of the Margin of Exposure approach: Segregation of tobacco smoke toxicants. Food Chem. Shulgin, A. The background and chemistry of MDMA. Psychoactive Drugs 18, — Gold, L. Comparison of cancer risk estimates based on a variety of risk assessment methodologies. Thomas, K. Comparing illicit drug use in 19 European cities through sewage analysis. Total Environ. Musshoff, F. Cocain Und Cocainmetaboliten. Hunault, C. Land, T. Recent increases in efficiency in cigarette nicotine delivery: Implications for tobacco control. Nicotine Tob. Stat Extracts. Non-Medical Determinants of Health. Tobacco consumption. Global Health Observatory Data Repository. Tobacco control. Monitor: Prevalence - adult age-standardized. Leavitt, S. Addiction Treatment Forum 12, 1—8 Google Scholar. Drugs and human performance fact sheets. Global status report on alcohol and health - ed. World Health Organization, Geneva, Switzerland, Cocaine and crack. Jones, R. Clinical relevance of cannabis tolerance and dependence. Haney, M. Abstinence symptoms following oral THC administration to humans. Psychopharmacology Berl. Mayer, B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Stolerman, I. Nicotine tolerance in rats; role of dose and dose interval. Psychopharmacologia Berl. Minion, G. Severe alcohol intoxication: a study of consecutive patients. Vonghia, L. Acute alcohol intoxication. Farrell, M. Methadone maintenance treatment in opiate dependence: a review. BMJ , — Modesto-Lowe, V. Methadone deaths: risk factors in pain and addicted populations. Dose-concentration relationships of methadone and EDDP in hair of patients on a methadone-maintenance program. Forensic Sci. Parrott, A. Schifano, F. A bitter pill. Cook, P. Diazepam tolerance: effect of age, regular sedation and alcohol. Scientific opinion on the safety of hemp Cannabis genus for use as animal feed. Potential risks for public health due to the presence of nicotine in wild mushrooms. RN, 1—47 Lindgren, M. Electroencephalographic effects of intravenous nicotine—a dose-response study. Rossow, I. Can harm ratings be useful? Rehm, J. Why does society accept a higher risk for alcohol than for other voluntary or involuntary risks? BMC Med. A possible index of fatal drug toxicity in humans. Hall, W. Rolles, S. Questioning the method and utility of ranking drug harms in drug policy. Drug Policy 22, — Methadone substitution: medicolegal problems in Germany. Can resveratrol in wine protect against the carcinogenicity of ethanol? A probabilistic dose-response assessment. Cancer , — Caffeine intake from beverages in German children, adolescents and adults. Caffeine Res. Download references. The views expressed here reflect only the author's and the European Union is not liable for any use that may be made of the information contained therein. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the Ministry of Health and Long Term Care or of other funders. You can also search for this author in PubMed Google Scholar. All authors have been involved in the drafting of the article and the interpretation of the data and in critical revisions of the content. All authors have given final approval of the version to be published. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. Reprints and permissions. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Sci Rep 5 , Download citation. Received : 09 September Accepted : 07 January Published : 30 January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Environmental Science and Pollution Research International Journal of Mental Health and Addiction Journal of Orthopaedic Surgery and Research Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Addiction Epidemiology Health policy Risk factors. Abstract A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure MOE approach was conducted. A prospective whole-mixture approach to assess risk of the food and chemical exposome Article 15 July Effects of excessive alcohol drinking on nicotine biotransformation in rats Article Open access 30 June Introduction Compared to medicinal products or other consumer products, risk assessment of drugs of abuse has been characterised as deficient, much of this is based on historical attribution and emotive reasoning 1. Results The only toxicological threshold available in the literature for all of the compounds under study was the LD Table 1 Toxicological thresholds selected for calculating the margin of exposure Full size table. Table 2 Exposure data selected for calculating the margin of exposure see Supplementary Table S1 online for distribution functions used for calculation Full size table. Figure 1. Full size image. Figure 2. Figure 3. Discussion Many governments in Europe have favoured more restrictive policies with respect to illicit drugs than for alcohol or tobacco, on the grounds that they regard both illicit drug abuse and related problems as a significantly larger problem for society Methods The methodology for comparative quantitative risk assessment was based on a previous study conducted for compounds in alcoholic beverages 20 with the exception that probabilistic exposure estimation was conducted 65 , 66 , References Coomber, R. Article Google Scholar Nutt, D. Article Google Scholar Morgan, C. Article Google Scholar Kalant, H. Article Google Scholar Claridge, L. Article Google Scholar Caulkins, J. Article Google Scholar Xie, J. Article Google Scholar Thomas, K. Google Scholar Musshoff, F. Article Google Scholar Musshoff, F. Article Google Scholar Parrott, A. Article Google Scholar Rehm, J. Article Google Scholar King, L. Article Google Scholar Lachenmeier, D. Lachenmeier View author publications. View author publications. Ethics declarations Competing interests The authors declare no competing financial interests. Electronic supplementary material. About this article. Cite this article Lachenmeier, D. Copy to clipboard. Vivace Allyson N. Sanders Jeffrey L. Gum Journal of Orthopaedic Surgery and Research Publish with us For authors Language editing services Submit manuscript. Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search. Close banner Close. Email address Sign up. 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