Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach

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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 MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2 mg/kg bodyweight for heroin to 531 mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the “high risk” category with MOE < 10, the rest of the compounds except THC fall into the “risk” category with MOE < 100. On a population scale, only alcohol would fall into the “high risk” category, and cigarette smoking would fall into the “risk” category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. 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. The methodology was based on comparing the “therapeutic index” of the substances, which was defined as the ratio of the median lethal dose (LD50) to the median effective dose (ED50). The results were expressed in a qualitative score as safety margin from “very small” (e.g. heroin) to “very large” (e.g. cannabis). 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.g. the approaches of Nutt et al. 8 ,9 in the UK and of van Amsterdam et al.

3 in the Netherlands. 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 ,12. The major criticism that was raised about these “panel” based approaches was the necessity of value judgements, which might depend upon subjective personal criteria and not only upon scientific facts 13. 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 15. Problematic may also have been the nomenclature applied in previous studies, mixing up “hazard” and “risk” into the term “drug harm”. In chemical and toxicological risk assessment, the term “harm” is not typically used, while hazard is the “inherent property of an agent or situation having the potential to cause adverse effects when an organism, system, or (sub)population is exposed to that agent”. Risk is defined as “the probability of an adverse effect in an organism, system, or (sub)population caused under specified circumstances by exposure to an agent” 16 .

In the context of the European research project “Addiction and Lifestyles in Contemporary Europe – Reframing Addictions Project”, the aim of this research was to provide a comparative risk assessment of drugs using a novel risk assessment methodology, namely the “Margin of Exposure” (MOE) method. 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. The BMD approach was first suggested by Crump 17. and was later refined by the US EPA for quantitative risk assessment 18. In Europe, the MOE was introduced in 2005 as the preferred method for risk assessment of carcinogenic and genotoxic compounds 19. In the addiction field, the MOE method was never used, aside from evaluating substances in alcoholic beverages 20 ,21 or tobacco products 22 ,23. 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 LD50. The LD50 values taken from the ChemIDplus database of the US National Library of Medicine and from Shulgin 24 are shown in table 1. Using the method of Gold et al. 25. the LD50 values were extrapolated assuming linear behaviour (as no other information on dose-response is available) to BMDL10 values. 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). The mean values of BMDL10 range from 2 mg/kg bodyweight (bw) for heroin and cocaine up to 531 mg/kg bw for ethanol.


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