Water disinfection is among the most important and beneficial public health advances of the 20th century. A consequence of water disinfection processes is the formation of a large number of unintended compounds from chemicals and organic material in the water, which are of potential public health concern. Haloacetic acids (HAAs) constitute approximately 50% of total measured halogenated disinfection by-products and are formed when chlorine-based disinfectants react with chemicals and organic material naturally present in the source water.
The National Toxicology Program (NTP) conducted a cancer hazard assessment of 13 HAAs—chlorine, bromine, and iodine containing mono-, di-, or trihaloacetic acids identified in disinfected drinking water—for potential listing in the Report on Carcinogens (RoC). NTP has forwarded its RoC listing recommendations to the Secretary of Health and Human Services.
This monograph used systematic review to identify the available, relevant scientific information and assess quality from human, experimental animal, and mechanistic studies for individual HAAs and used read-across principles to determine if the 13 HAAs could be evaluated as a chemical class or subclass(es). Mechanistic data based on the 10 key characteristics of carcinogens, along with disposition and toxicokinetic data, were reviewed and organized. Relative trends in chemical and mechanistic potencies were identified and compared with observed animal cancer endpoints. RoC listing criteria were applied to the scientific information to recommend RoC listing status.
Because only one epidemiology study was identified, the epidemiological data were considered inadequate to evaluate the relationship between exposure to any of the 13 HAAs and cancer in humans. Six of the HAAs were tested in experimental animals. Four HAAs (dichloroacetic acid, dibromoacetic acid, bromochloroacetic acid, and bromodichloroacetic acid) met RoC criteria for sufficient evidence of cancer. All four HAAs caused liver tumors in rodents, three also caused malignant mesotheliomas, and two also caused mammary gland cancer. Monochloroacetic acid and trichloroacetic acid did not meet the criteria for sufficient animal cancer evidence. No experimental animal cancer data were available for the remaining seven HAAs.
The primary key characteristics of carcinogens for the HAAs were electrophilicity, genetic toxicity, and oxidative stress and a read-across approach was used to define potential subclasses of carcinogens. Tri-HAAs are metabolized by P450 reductive dehalogenation, forming dihaloacetic acids via dihaloacetic acid radical intermediates, with bromine substitution on tri-HAAs generating a stronger leaving group than chlorine substitution. The data did not support grouping HAAs as a class or subclasses; however, read-across principles were used to evaluate two individual brominated tri-HAAs with sufficient metabolism and supporting mechanistic data. No experimental animal cancer data were available for either tribromoacetic acid or chlorodibromoacetic acid; however, they had similar properties to bromodichloroacetic acid, which had sufficient animal cancer evidence. In addition, tribromoacetic acid metabolized to dibromoacetic acid and chlorodibromoacetic acid metabolized to chlorobromoacetic acid, each of which caused cancer in experimental animals.
NTP recommended that dichloroacetic acid, dibromoacetic acid, bromochloroacetic acid, and bromodichloroacetic acid be listed in the RoC as reasonably anticipated to be human carcinogens based on sufficient evidence from studies in experimental animals and supporting mechanistic data. NTP recommended that chlorodibromoacetic acid and tribromoacetic acid be listed in the RoC as reasonably anticipated to be human carcinogens based on convincing relevant information that indicate these agents act through mechanisms likely to cause cancer in humans.
National Toxicology Program (NTP). 2018. Report on Carcinogens monograph on haloacetic acids found as water disinfection by-products. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 12. https://doi.org/10.22427/ROC-MGRAPH-12