A system and methods of the present invention advantageously provide efficient mail processing and handling that, as compared to existing procedures, enhances detection of biological, germ, chemical, or other harmful agents within the mail being processed or handled. A system and methods additionally provide a higher level of quality and consistency for processing and handling mail so that concerns over contamination of postal workers and potential mail recipients are reduced. A system and methods further provide enhanced detection of contaminated mail contents, mail, mail equipment, mail containers, and mail personnel due to exposure or contact with harmful agents associated with mail. The system and methods preferably includes the use of at least one harmful agent sensor associated with mail processing equipment.