Vol.:(0123456789) 1 3 Archives of Toxicology https://doi.org/10.1007/s00204-020-02851-x LETTER TO THE EDITOR, NEWS AND VIEWS Unique human cancer model for acetaldehyde based on Mendelian randomization Mikko Salaspuro 1  · Dirk W. Lachenmeier 2 Received: 13 July 2020 / Accepted: 13 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 In their extensive review on the mode of action-based risk assessment of genotoxic carcinogens, the authors conclude that local concentrations of ethanol and acetaldehyde in the digestive tract seem to play a major role in the development of cancer (Hartwig et al. 2020). We strongly agree with this statement for four major reasons. (1) Congruent mechanistic and epidemiological evidence, based on Mendelian rand- omization, highlights the crucial role of local acetaldehyde in alcohol-related upper digestive tract cancer. (2) Updated knowledge of the biochemical mechanisms regulating sali- vary acetaldehyde concentrations during and after alcohol drinking emphasizes the key role of oral microbes and aldehyde dehydrogenase 2 (ALDH2) enzyme in the local exposure to carcinogenic acetaldehyde via saliva. (3) The unique human cancer model based on ALDH2 deficiency offers entirely new possibilities for the quantitative assess- ment of the excess acetaldehyde exposure via saliva in rela- tion to increased alcohol-related oropharyngeal cancer risk. (4) Identifying a specific carcinogenic agent is a key factor in cancer prevention. 1. A single point mutation in the ALDH2 gene conclu- sively proves the causal role of local acetaldehyde in alcohol-related upper digestive tract and particularly in oropharyngeal and oesophageal cancers (Lachenmeier and Salaspuro 2017). Mutation results in deficient activ- ity of mitochondrial ALDH2 enzyme, which leads to markedly increased local acetaldehyde exposure via saliva following alcohol drinking and concomitantly to dose-dependently increased risk for oropharyngeal and oesophageal cancer. The worldwide carrier frequency of the mutation is about 600 million people of East-Asian descent. Because the mutation is randomized by nature, it lacks the bias caused by confounding factors typically reducing the informativeness of epidemiological stud- ies on alcohol-related cancer. Smoking, under-report- ing of alcohol consumption, diet, drinking habits, use of different types of alcoholic beverages, oral hygiene, human papillomavirus infection and body mass index can be assumed to be evenly distributed among ALDH2- deficient and ALDH2-active alcohol drinkers. No other genotoxic carcinogen has equally strong gene–epidemio- logical and gene–biochemical evidence for its carcino- genicity in humans. 2. The free acetaldehyde molecule is mutagenic and carci- nogenic due to its highly reactive –CHO group. After a dose of alcohol, mutagenic (> 100 µM) concentrations of free acetaldehyde are found in saliva and gastric juice of humans and in colonic contents of experimental animals. This is by and large due to the effective microbial oxida- tion of ethanol to acetaldehyde and the limited capacity of microbes and mucosal cells to eliminate locally formed free acetaldehyde from ethanol oxidation. A major part of ingested alcohol is metabolized in the liver via acetal- dehyde to acetate. The liver eliminates acetaldehyde so effectively that after a dose of alcohol, peripheral venous blood of ALDH2 actives does not contain measurable lev- els of free acetaldehyde (< 2 µM). In ALDH2-deficients, blood acetaldehyde levels after a dose of alcohol are only modestly elevated (6.4–12 µM), i.e. much lower than the corresponding concentrations in saliva. • Convincing evidence supports the major role of oral microbes in the formation of salivary acetaldehyde from ethanol (Nieminen and Salaspuro 2018; Salaspuro 2020). Without the presence of alcohol or tobacco smoke, human saliva does not contain measurable lev- els of acetaldehyde. After each sip of alcohol (5 ml of 40% vol alcohol for 5 s in the mouth), ethanol is dis- tributed within a few seconds to the mucosal surfaces * Mikko Salaspuro mikko.salaspuro@helsinki.fi 1 Research Unit On Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland 2 Chemisches Und Vetrinäruntersuchungsamt (CVUA) Karlsruhe, Karlsruhe, Germany