There is convincing scientific evidence that the most frequent malignancy in childhood, acute lymphoblastic leukaemia (ALL) and in particular its major subtype B-precursor ALL (BCP-ALL), is related to patterns of exposure to infectious agents in early life. 1,2 Therefore, as already put forward by others, 3,4 it is likely that the current COVID-19 pandemic will impact on the risk of children of developing ALL and, consequently, on the ALL incidence on a population level. The underlying infections-related model acting on the two-hit hypothesis for ALL is the one developed by Greaves. According to this model, ALL results from two genetic hits, with the first occurring before birth, induced by prenatal exposures or random mutations. The second hit is induced by an abnormal reaction of the immune system to exposure to common infections, more commonly so in children with insufficient training of their immune system through lesser-than-required social

pairwise exposure to five occupational exposures: asbestos, respirable crystalline silica, metals (i.e. nickel, chromium VI), and polycyclic aromatic hydrocarbons (pah), on lung cancer risk, both overall and by major subtypes, while accounting for cigarette smoking. Material and Methods For the 14 pooled case-control studies of the SYNERGY project, occupational exposures to the five lung carcinogens were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) of lung cancer risks were computed for ever/ never exposures. Interactions on the additive and multiplicative scales were assessed in regression models by sex and adjusted for study, age, and smoking habits. Interactions on an additive scale were assessed by calculating the relative excess risk due to interaction (RERI).Results In men all pairwise joint effects of lung carcinogens were associated with an increased risk of lung cancer. However, exposure to asbestos/metals and to metals/pah resulted in negative RERIs, while in relation to adenocarcinoma exposure to chromium VI/silica showed a small synergistic effect (RERI 0.24, CI 0.02-0.46, p-value 0.05). In women pairwise joint effects were observed in relation to small cell lung cancer only; exposure to pah/silica resulted in a synergistic effect and a more than multiplicative effect (RERI 3.45, CI 0.10-6.8, p-value 0.01) and exposure to asbestos/silica in a more than multiplicative effect . Conclusions This is the first large analysis systematically reporting on joint effects of occupational lung carcinogens. Most joint effects showed additivity, or were slightly above additivity, except for small cell lung cancer in women but with less precision compared to males. Further research on interactions is warranted beyond pairwise and ever vs. never exposure.

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