We used three separate data processing methods to identify and (semi-)quantify compounds in the samples. Full method descriptions, confidence levels for compound identification, and information on accuracy and variability are provided in sections S.1.4-7, S.2.1, and S.2.4. First, we used a targeted approach with TraceFinder software version 4.1 (Thermo Scientific) to conduct quantitative analysis based on standards for 62 compounds (listed in Table ). Analytes included a variety of toxins, pharmaceuticals and illicit drugs known to be found in wastewater and/or sludge, and several compounds chosen for their relevance to COVID-19 treatment and prevention. Concentrations in the sludge extracts were determined based on a calibration curve that ranged from 0.1 ng/mL to 100 ng/mL. We used a separate method in TraceFinder to screen our data using an in-house database of approximately 1800 compounds. The database contains exact MS1 and MS2 masses and retention times for many compounds that have previously been measured in house or by collaborators with the same (or very similar) instrument methods used in this project. The database also contains MS1 and MS2 masses that are provided in the Thermo Scientific EFS_HRAM database in TraceFinder (without retention times). Compound identifications using the screening method were based on exact mass matches for MS1 and MS2 masses, isotope pattern matching, and retention time matching where available. Only the Full MS/AIF data was used in the TraceFinder methods. The third method used Compound Discoverer version 3.1 software (Thermo Scientific), and identified compounds based on the ddMS2 data for the 5-week composite samples and spectral matches with the mzCloud database. The full MS data for the daily and weekly samples was then screened for the identified compounds. Peak areas were used for semi-quantitative trend analysis for the compounds identified with Compound Discoverer and TraceFinder screening methods. Each identification was assigned a confidence level based on available evidence. In the main text, identifications based on analytical standards are referred to as "confirmed" while confident screening results (from TraceFinder and Compound Discoverer) are "probable" and screening results where more ambiguity remains are listed as "tentative" . More information, including detailed, software specific confidence levels for each identification, is available in sections S.1.4-7, and section S.2.2.