The intramuscular (i.m.), oral (p.o.), and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu. The half-life for enrofloxacin following i.m. administration was 28.9 h, considerably longer than values calculated for other animals such as dogs, birds, rabbits, and tortoises. The 4 h maximum concentration (Cmax) of 1.64 micrograms/ml, following a single 5.0 mg/kg dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for 20 bacterial organisms known to infect fish. At 48 h post i.m. administration, the mean plasma enrofloxacin concentration was well above the MIC for most gram-negative fish pathogens. The gavage method of oral enrofloxacin administration produced a Cmax of 0.94 microgram/mL at 6-8 h. This Cmax was well above the reported in vitro MIC. A bath immersion concentration of 2.5 mg/L for 5 h was used in this study. The Cmax of 0.17 microgram/mL was noted on the 2 hour post-treatment plasma sample. Plasma concentrations of enrofloxacin exceeded published in vitro MIC's for most fish bacterial pathogens 72 h after treatment was concluded. Ciprofloxacin, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the red pacu using p.o., i.m., and bath immersion administration. The i.m. route is the most predictable and results in the highest plasma concentrations of the drug.

The kinetics of oxytetracycline (OTC) degradation in deionized water was studied under the influence of various environmental factors. The experiment was conducted with a solution of 10 g aqueous OTC /mL in 600-mL glass beakers under controlled laboratory conditions. The aqueous concentration of OTC was determined by high-performance liquid chromatography. Low temperatures (4ЊC) favored high drug stability, and high temperatures (43ЊC) speeded OTC degradation, resulting in a very short half-life of 0.26 Ϯ 0.11 d. Light exposure caused photodecomposition, reflecting degradation rates threefold higher than those under dark conditions. Acidic conditions (pH 3.0) favored drug stability (half-life ϭ 46.36 Ϯ 4.92 d), and alkaline conditions (pH 10.0) increased the degradation rate (half-life ϭ 9.08 Ϯ 4.22 d). The presence of a substrate (bentonite clay) resulted in an approximate 17% decrease in OTC concentration within 5 min of contact. Addition of organic matter (fish feed) along with the substrate resulted in a 41% decrease in OTC concentrations within 5 min of contact.

The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities. Implications for quantitative risk assessment approaches were discussed, as were implications of not considering MOA and dose in hazard characterization and labeling schemes. Most, but not all, participants considered the CAR and PPARα MOAs as not relevant to humans based on quantitative and qualitative differences. In contrast, cytotoxicity is clearly relevant to humans, but a threshold applies. Questions remain for all three MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs.

Chemically induced renal neoplasms in male rats, developed coincident with α 2u -globulin nephropathy, are not considered predictive of risk to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency. Criteria have been defined to establish the role of α 2u -globulin nephropathy in renal carcinogenesis, based on a proposed mode of action involving sustained tubular cell proliferation resulting from α 2u -induced nephropathy, with consequent development of neoplastic lesions. Recent NTP studies demonstrated inconsistencies with this proposed mechanism, including in some cases, far weaker kidney tumor responses than expected based on the extent of α 2u -globulin nephropathy. NTP studies with decalin, propylene glycol mono-t-butyl ether and Stoddard solvent IIC included extended evaluations of α 2u -related nephropathy, and were thus used in assessing the linkage between key events in 90-day studies with renal tumors in 2-year studies. This review revealed no or at best weak associations of tumor responses with renal α 2u -globulin concentrations, indices of cell turnover, or microscopic evidence of α 2u -associated nephropathy in prechronic studies. While tumor responses corresponded somewhat with a measure of cumulative α 2u -associated nephropathy (linear mineralization of the papilla) at the end of the 2-year studies, the severity of chronic nephropathy was generally in best agreement with the pattern of tumor response. These results suggest that while α 2u -globulin nephropathy may contribute to the renal tumor response, the critical component(s) of the nephropathy most closely associated with the development of tumors could not be clearly identified in this review.