Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications.

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.

A comprehensive weight of evidence assessment of published acetaminophen genotoxicity data: Implications for its carcinogenic hazard potential.

In 2019, the California Office of Environmental Health Hazard Assessment initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of its genotoxicity. The objective of this analysis was to inform this review process with a weight-of-evidence assessment of more than 65 acetaminophen genetic toxicology studies that are of widely varying quality and conformance to accepted standards and relevance to humans. In these studies, acetaminophen showed no evidence of induction of point or gene mutations in bacterial and mammalian cell systems or in in vivo studies. In reliable, well-controlled test systems, clastogenic effects were only observed in unstable, p53-deficient cell systems or at toxic and/or excessively high concentrations that adversely affect cellular processes (e.g., mitochondrial respiration) and cause cytotoxicity. Across the studies, there was no clear evidence that acetaminophen causes DNA damage in the absence of toxicity. In well-controlled clinical studies, there was no meaningful evidence of chromosomal damage. Based on this weight-of-evidence assessment, acetaminophen overwhelmingly produces negative results (i.e., is not a genotoxic hazard) in reliable, robust high-weight studies. Its mode of action produces cytotoxic effects before it can induce the stable, genetic damage that would be indicative of a genotoxic or carcinogenic hazard.

Assessment of the biochemical pathways for acetaminophen toxicity: Implications for its carcinogenic hazard potential.

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death - thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

A critical review of the acetaminophen preclinical carcinogenicity and tumor promotion data and their implications for its carcinogenic hazard potential.

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

Selenium toxicokinetics after oral and intravenous administration in buffalo calves.

The blood levels, toxicokinetics and urinary excretion of selenium were investigated in healthy male buffalo calves after single oral and intravenous administration of selenourea at the dose rate of 0.75mg/kg (providing 0.48mg/kg selenium). The concentration of selenium in blood and urine was estimated spectrophotometrically. Following administration of the drug, the blood selenium disposition patterns exhibited two distinct peaks. The toxicokinetic parameters of selenium were determined by employing non-compartmental analysis. The values of AUC, t(1/2elm), Cl(B) and Vd(SS) were 18.46µgml(-1)h, 10.33h, 20.04mlkg(-1)h(-1)and 0.3lkg(-1), respectively, after oral administration and 23.97µgml(-1)h, 7.12h, 20.53mlkg(-1)h(-1) and 0.2lkg(-1), respectively, following intravenous injection of selenourea. The value of MRT was higher after oral dosing. The bioavailability of selenium, following oral administration of selenourea was 77%. Approximately, 22% of the total intravenous dose and 5.9% of total oral dose of selenium was excreted in urine within 24h of administration of selenourea. The data on blood Se levels may be of help in diagnosing the impeding selenium toxicosis and thus preventing mortality due to selenium toxicity.

Effect of reduced glutathione treatment on selenosis, blood selenium concentration and glutathione peroxidase activity after repeated short-term selenium exposure in buffalo calves.

Effects of repeated feeding of selenium, when given alone or along with reduced glutathione, on whole blood selenium levels, selenosis and glutathione peroxidase activity, was studied in buffalo calves. After feeding 2.5 mg/kg of BW sodium selenite, good correlation was found between the onset of selenosis and whole blood selenium concentrations. Adverse effects appeared when the whole blood selenium concentrations increased above 2 microg/ml and mortality occurred when they exceeded 3.4 microg/ml. Reduced glutathione, given i.v. at 5 mg/kg of BW arrested the progress of selenosis and prevented mortality which was 100% in the sodium selenite supplemented group; also a reduced whole blood selenium concentration was noted. Whole blood selenium concentrations were a better and more sensitive indicator of selenium status than glutathione peroxidase activity alone.

Blood selenium levels during different stages of selenosis in buffaloes and its evaluation as a diagnostic tool.

Selenium (SC) toxicity was experimentally induced in male buffalo calves following repeated oral administration of 0.3 mg selenourea/kg (providing 0.19 mg/Se kg) for 75 d. On the basis of the major toxic effects produced in the experimental animals, 10 additional clinical cases of selenosis were identified from field cases. In experimental selenosis blood Se increased from 0.70 +/- 0.08 microg/ml on day 0 to 3.12 +/- 0.01 microg/ml on day 75. Hair Se rose from 2.42 +/- 0.6 ppm on day 0 to 22.91 +/- 2.6 ppm by the 11th w. The erythrocyte glutathione peroxidase (GSH-Px) activity increased from 5.35 +/- 0.94 Eu/mg Hb (0 day) to 18.81 +/- 0.46 EU/mg Hb in the 11th week. Blood Se was of better diagnostic value than hair Se or erythrocytic GSH-Px activity. Signs occurred when Se levels were about 2.0 microg/ml and were prominent above 2.5-2.6 microg/ml: Se levels > or = 1.5-1.75 microg/ml were diagnostic of impending selenosis. The Se concentrations in blood from the field cases of Se toxicity in buffalo had excellent correlation with Se levels in the experimental cases.