Assessing the risks of capecitabine and its active metabolite 5-fluorouracil to freshwater biota

Capecitabine (CAP, prodrug) and 5-fluorouracil (5-FU, its active metabolite) are two of the most prominent cytostatics, for which no clear picture can be drawn regarding potential concentrations of effect for freshwater biota, with CAP being grouped in the least studied cytostatic, whereas 5-FU has been classified as of no and of high environmental risk. Accordingly, the present work aimed to assess the ecotoxicity of CAP and 5-FU in three freshwater species, which included a 72-h assay with the producer Raphidocelis subcapitata; a 96-h assay with the invertebrate secondary consumer Hydra viridissima; and a 96-h assay with embryos of the vertebrate secondary consumer Danio rerio. The following endpoints were monitored: yield and population growth rate for the algae; mortality, morphological alterations, and post-exposure feeding rates for the cnidarian; and mortality, hatching, and malformations for the fish. Overall, organisms' sensitivity to CAP decreased in the following order: R. subcapitata > H. viridissima > D. rerio, whereas for 5-FU, it decreased in the following order: H. viridissima > D. rerio > R. subcapitata. For CAP, no median lethal effective concentrations (LC/EC₅₀) were possible to compute for D. rerio, with no significant mortality or malformations registered in embryos exposed at concentrations up to 800 mg L^-1. For R. subcapitata, the EC₅₀s were 0.077 and 0.63 mg L^-1 for yield and growth rate, respectively, and for H. viridissima, the EC_50,30 min for feeding was 22.0 mg L^-1. For 5-FU, no EC_50s could be computed for R. subcapitata, whilst the EC_50s for H. viridissima mortality and feeding were 55.4 and 67.9 mg L^-1, respectively, and for D. rerio, the LC_50,96 h and EC_50,96 h (hatching and abnormalities) were 4546, 4100, and 2459 mg L^-1, respectively. Assuming similar modes of action for both compounds and their co-occurrence, the combined risk quotient of the two chemicals was determined to be 7.97, which represents a risk for freshwater biota. Anticipating the increased consumption of these compounds and cancer development trends worldwide, these impacts may be further aggravated.