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The TROPOspheric Monitoring Instrument (TROPOMI) observed unprecedented declines in NO2 vertical column densities (VCD) over the world’s most densely populated cities during the 2020 COVID-19 lockdowns. These favorable changes in NO2 air quality were correlated with sharp reductions in traffic volume and economic activity during the lockdowns. In this comprehensive global study, we provide revised estimates of the declines in anthropogenic emissions for 36 megacities using a novel methodology for disentangling the anthropogenic emissions from the meteorological transport and natural variability. We further quantify the uncertainty associated with changes in the a priori profile shape information during the lockdowns due to reduced emissions. Satellite NO2 retrieval techniques calculate an air mass factor that requires a priori NO2 profile shape information representative of the local atmosphere. This information, which is typically obtained from a chemical transport model (CTM), was not available for the early studies. This study also accounts for the satellite sampling errors resulting from the selective sampling of non-cloudy scenes during the study period. For our analysis, we used CTM simulations that were generated with and without COVID-impacted emissions. We perform retrievals of tropospheric NO2 columns with the NASA NO2 algorithm, and then use observed and simulated data to disentangle the meteorological transport from the contribution due anthropogenic emissions. We found that the meteorological transport was most significant source of variability ranging between − 35% and 22% of the change total tropospheric VCD. We also find that not accounting for changes in the a priori NO2 profile shape information during the lockdowns resulted in systematic retrieval errors that were up to 12% of the estimated decline, and the elimination of cloud contaminated scenes resulted in sampling errors that in general ranged between varied ±15%.