Hot Beverages, Chemical Co-Exposures, and Esophageal Squamous Cell Carcinoma in the African Corridor: A Margin-of-Exposure Framework

The African esophageal squamous cell carcinoma (ESCC) corridor extends from Ethiopia to the Eastern Cape and contains some of the highest age-standardized ESCC incidence rates reported anywhere, with five-year survival below 5%. The corridor’s heterogeneous incidence (sex ratios from 1:1 to 7:1; tenfold variation between adjacent populations) has resisted single-factor explanation through more than half a century of investigation. We synthesize the multicenter evidence accumulated since the IARC 2018 Group 2A classification of very hot beverages (>65 °C), with particular attention to the African Esophageal Cancer Consortium (ESCCAPE) outputs and to whole-genome sequencing. We argue, on the convergent evidence of animal toxicology, human in vitro mucosa, and population genomics, that thermal exposure acts as a tumor promoter rather than an initiator. On this reading, the corridor’s heterogeneous burden reflects heterogeneous chemical co-exposure profiles operating against a shared thermal-promoter substrate. Extending the comparative margin-of-exposure (MOE) methodology to esophageal squamous carcinogenesis, we present an MOE framework distinguishing genotoxic compounds (within-mode-of-action additive) from thermal exposure (separate companion figure) and apply it to two corridor scenarios. The framework supports a four-lever prevention strategy combining tobacco control, alcoholic-strength reduction in unrecorded spirits, clean-cookstove deployment, and graduated thermal-exposure reduction.