activities were observed in individuals of R. decussata, with strong impairments at
low levels of exposure, while high levels of paracetamol elicited sharp increases in
this parameter. The same organisms also showed higher levels of glutathione
reductase activity. Changes in R. philippinarum only involved increased GSTs
activity. Despite the interspecific changes, it was possible to conclude that oxidative
stress conditions were in place in both species after paracetamol exposure, despite
the extent of the metabolic response. Again the problematic of paracetamol toxicity
was studied, but under the scope of global changes scenarios. By being an estuarine
species, R. philippinarum may be subjected to strong salinity fluctuations, whose
amplitude may even increase in the future as a consequence of droughts. The study
by Correia et al. [60] evidenced not only the response toward pro-oxidative conditions caused by paracetamol, and the extent of the defensive biological response, but
also the modulation of such effects by salinity variations. In general, the activity of
antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione-S-transferases, glutathione reductase), nonenzymatic defenses (glutathione levels), and
peroxidative damage (lipoperoxidation) strongly fluctuated according to the salinity
values. This set of results is indeed significant, since it implies that contamination,
biological responses, and consequent damages are likely to be impacted and altered,
with unpredictable consequences, but changes in abiotic conditions such as salinity,
which are likely to vary under a scenario of global change in the future. Gibbula
umbilicalis is a marine mollusk which showed to be responsive to paracetamol
[61]. When exposed to ecologically relevant amounts of paracetamol for a short
period of 96 h, individuals of this species responded by decreasing their catalase
activity and lipoperoxidation levels, evidencing the antioxidant nature of this
response, which is similar to other changes reported for other marine organisms. A
limited but significant antioxidant response toward the presence of paracetamol was
also established in the marine mollusk Phorcus lineatus, as shown by Almeida and
Nunes [25]. In this study, individuals of this species chronically exposed to this drug
were able to trigger an activation of their antioxidant mechanism catalase, thus
preventing the occurrence of oxidative damage. Oxidative stress was the main
underlying mechanism suggested to be the causal factor for the delay in the regeneration of injured tissues of the polychaete Diopatra neapolitana, as described by
Freitas et al. [62]. In this study, mechanical injuries inflicted in individuals of the
mentioned species were allowed to regenerate in the presence of several concentrations of paracetamol. For organisms exposed to the higher levels, the onset and
progress of the tissue regeneration were significantly compromised. To discuss this
finding, authors suggest that the excess of ROS produced during the metabolism of
paracetamol, which is one of the main causative agents of the toxicity by this drug,
can compromise the efficacy of the healing process. To support this assumption,
authors state that oxidative alterations are of paramount importance for the onset of
physiological processes of recovery in many organisms, given the role of regulators
of cell proliferation and tissue differentiation attributed to ROS and also to nitric
oxide (NO) intermediates. Following tissue injury, inflammatory processes with the
involvement of immune cells are likely to be established, and such conditions are
prone to the occurrence of such reactive oxygen species. When in excess, the
Ecotoxicological Effects of the Drug Paracetamol: A Critical Review of Past. . .
137
low levels of exposure, while high levels of paracetamol elicited sharp increases in
this parameter. The same organisms also showed higher levels of glutathione
reductase activity. Changes in R. philippinarum only involved increased GSTs
activity. Despite the interspecific changes, it was possible to conclude that oxidative
stress conditions were in place in both species after paracetamol exposure, despite
the extent of the metabolic response. Again the problematic of paracetamol toxicity
was studied, but under the scope of global changes scenarios. By being an estuarine
species, R. philippinarum may be subjected to strong salinity fluctuations, whose
amplitude may even increase in the future as a consequence of droughts. The study
by Correia et al. [60] evidenced not only the response toward pro-oxidative conditions caused by paracetamol, and the extent of the defensive biological response, but
also the modulation of such effects by salinity variations. In general, the activity of
antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione-S-transferases, glutathione reductase), nonenzymatic defenses (glutathione levels), and
peroxidative damage (lipoperoxidation) strongly fluctuated according to the salinity
values. This set of results is indeed significant, since it implies that contamination,
biological responses, and consequent damages are likely to be impacted and altered,
with unpredictable consequences, but changes in abiotic conditions such as salinity,
which are likely to vary under a scenario of global change in the future. Gibbula
umbilicalis is a marine mollusk which showed to be responsive to paracetamol
[61]. When exposed to ecologically relevant amounts of paracetamol for a short
period of 96 h, individuals of this species responded by decreasing their catalase
activity and lipoperoxidation levels, evidencing the antioxidant nature of this
response, which is similar to other changes reported for other marine organisms. A
limited but significant antioxidant response toward the presence of paracetamol was
also established in the marine mollusk Phorcus lineatus, as shown by Almeida and
Nunes [25]. In this study, individuals of this species chronically exposed to this drug
were able to trigger an activation of their antioxidant mechanism catalase, thus
preventing the occurrence of oxidative damage. Oxidative stress was the main
underlying mechanism suggested to be the causal factor for the delay in the regeneration of injured tissues of the polychaete Diopatra neapolitana, as described by
Freitas et al. [62]. In this study, mechanical injuries inflicted in individuals of the
mentioned species were allowed to regenerate in the presence of several concentrations of paracetamol. For organisms exposed to the higher levels, the onset and
progress of the tissue regeneration were significantly compromised. To discuss this
finding, authors suggest that the excess of ROS produced during the metabolism of
paracetamol, which is one of the main causative agents of the toxicity by this drug,
can compromise the efficacy of the healing process. To support this assumption,
authors state that oxidative alterations are of paramount importance for the onset of
physiological processes of recovery in many organisms, given the role of regulators
of cell proliferation and tissue differentiation attributed to ROS and also to nitric
oxide (NO) intermediates. Following tissue injury, inflammatory processes with the
involvement of immune cells are likely to be established, and such conditions are
prone to the occurrence of such reactive oxygen species. When in excess, the
Ecotoxicological Effects of the Drug Paracetamol: A Critical Review of Past. . .
137