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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. For a sub-group of drugs, exposure estimation based on sewage analysis is available (Table 2) (not all drugs are available in sewage analysis due to different stabilities/degradation rates of the compounds, for details see Ref. 26). The corresponding risk functions are shown in Supplementary Table S1 online. Except for ethanol and nicotine, for which certain distributions could be fitted to the data for the European countries, uniform probability distributions were chosen in all other cases as only minimum/maximum prevalence values for Europe in total were available. The detailed calculation formulae chosen for probabilistic risk assessment are shown in Supplementary Table S2 online.
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. At least for the endpoint of mortality, the MOE for THC/cannabis in both individual and population-based assessments would be above safety thresholds (e.g. 100 for data based on animal experiments). In contrast, the risk of alcohol may have been commonly underestimated.
Our results confirm the early study of Gable6 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.
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 use14. Much of the harm from drug use is not inherently related to consumption, but is heavily influenced by the environmental conditions of the drug use2, 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. 2ff7e9595c
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