Nutrients 2021, 13, 3785. https://doi.org/10.3390/nu13113785 www.mdpi.com/journal/nutrients Review Margin of Exposure Analyses and Overall Toxic Effects of Alcohol with Special Consideration of Carcinogenicity Alex O. Okaru 1 and Dirk W. Lachenmeier 2, * 1 Department of Pharmacy, University of Nairobi, Nairobi P.O. Box 19676-00202, Kenya; alex.okaru@gmail.com 2 Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weissenburger Straße 3, 76187 Karlsruhe, Germany * Correspondence: lachenmeier@web.de; Tel.: +49-721-926-5434 Abstract: Quantitative assessments of the health risk of the constituents of alcoholic beverages including ethanol are reported in the literature, generally with hepatotoxic effects considered as the endpoint. Risk assessment studies on minor compounds such as mycotoxins, metals, and other contaminants are also available on carcinogenicity as the endpoint. This review seeks to highlight population cancer risks due to alcohol consumption using the margin of exposure methodology. The individual and cumulative health risk contribution of each component in alcoholic beverages is highlighted. Overall, the results obtained consistently show that the ethanol contributes the bulk of harmful effects of alcoholic beverages, while all other compounds only contribute in a minor fashion (less than 1% compared to ethanol). Our data provide compelling evidence that policy should be focused on reducing total alcohol intake (recorded and unrecorded), while measures on other compounds should be only secondary to this goal. Keywords: alcohol; risk assessment; hepatotoxicity; dose–response relationship; margin of exposure; epidemiological methods 1. Introduction The epidemiological association of alcoholic beverages with cancer remains a topic that has continued to attract global attention for over a century with the first documented cases, cancer of the esophagus, being reported in 1910 [1,2]. Later in 1988, the World Health Organization (WHO)/International Agency for Research on Cancer (IARC) classified “alcohol drinking” as carcinogenic to humans (group 1) after establishing a causal link between alcohol use and malignancies of the oral pharynx, esophagus, and liver [1]. The promoters or causative factors in alcoholic beverages for developing carcinogenic lesions are a matter of continuing debate among scientists. However, alcohol being a multicomponent mixture, the potential contribution of each or all the compounds to carcinogenesis should not be overlooked. These substances occur as residues, contaminants, or even adulterants, in addition to being naturally occurring in either raw materials or fermentation by-products. Ethanol, the principal component of alcoholic beverages, is classified as a human carcinogen (group 1) by IARC. Other than ethanol, other IARC-classified carcinogenic compounds such as acetaldehyde, formaldehyde, acrylamide, aflatoxins, ochratoxin A, arsenic, lead, cadmium, ethyl carbamate, furan, safrole, 4-methylimidazole, N-nitrosodimethylamine (NDMA), 3-Monochloropropane-1,2-diol (3-MCPD), and benzene have occurred in alcoholic beverages. The contribution of these compounds to cancer is either synergistic or independent of each other. Understanding the contribution of each component is important in disentangling the mechanisms of carcinogenicity due to alcohol and ultimately aids in alcohol control policies. Nevertheless, epidemiological Citation: Okaru, A.O.; Lachenmeier, D.W. Margin of Exposure Analyses and Overall Toxic Effects of Alcohol with Special Consideration of Carcinogenicity. Nutrients 2021, 13, 3785. https://doi.org/10.3390/ nu13113785 Academic Editor: Peter Anderson Received: 29 July 2021 Accepted: 19 October 2021 Published: 25 October 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).