The effects of nitrilotriacetate on cation disposition and urinary tract toxicity.

In this review a summary is presented of the experimental evidence that has led to the development of hypotheses to explain how the chronic ingestion of nitrilotriacetate (NTA), which is a non-mutagenic, non-metabolized and non-accumulating compound, might induce urinary tract toxicity that can lead to neoplasia. The hypotheses attribute the toxic process to alterations in divalent cation (M2+) distribution in the urinary tract during the processing of NTA for excretion in the urine. The hypotheses do not identify a 'carcinogen' per se but rather define conditions that must exist for the initiation and propagation of toxicity that is an essential precursor of and accompanies tumours associated with chronic, high dosage NTA ingestion. The proposed hypotheses are consistent with all available information on NTA toxicity and define ingestion doses that do not alter urinary tract M2+ distributions and do not initiate urinary tract toxicity after chronic exposure. The existence of no-effect doses that must be exceeded for the initiation and propagation of toxicity negates the validity of mathematical extrapolations of possible tumour incidence at doses below the threshold levels from the results obtained in chronic, high dosage experiments. The thresholds determined in the experimental animals are several orders of magnitude greater than human exposure via drinking-water based upon measured NTA concentrations in Canada where NTA has been used in detergents since 1970.