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Safety Assessment of Extractables, Leachables, and Impurities
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
This value should then be compared with predicted Cramer class and the associated TTC. Cramer classification is a long-standing method of assessing likely toxicity of chemicals and assigning TTCs to them (Cramer et al. 1978). For nongenotoxic endpoints, a TTC may be derived using a decision tree; the structural class of the chemical is derived and a safe level of exposure assigned based on the makeup of the structure. The TTC is a risk assessment tool for which conservative, generally oral, thresholds are derived based on the chemical structure of the substance. The TTC is derived from extensive analysis of chronic toxicity data of substances by regulatory bodies (such as the FDA) and research groups. Substances are divided into three classes, termed Cramer classes, in ascending order of toxicity [class I being the lowest toxicity (simple chemicals, with structures associated with known metabolism and end products), while with Cramer class III compounds, there is no initial presumption of safety]. The values for Cramer classes I, II, and III are as follows: 1800 μg/day, 450 μg/day, and 90 μg/day, respectively, in a 70 kg human. It is considered that in the majority of substances, exposure at or below these thresholds should not constitute undue risk to the patient (Kroes et al. 2004; Leeman et al. 2014). So for example, a Cramer class III substance may be present in dialysis tubing at concentrations that could result in a per-session dose of 175 μg, which is higher than the daily TTC. However, the total weekly exposure over three sessions would be 525 μg, and dividing this by 7 gives a prospective daily total of 75 μg/day, which should be acceptable in this particular set of patients.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP2D6 is involved in the metabolism of diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea), a widely used herbicide and antifouling biocide (Figure 3.115) (Abass et al. 2007). Diuron has been classified as a slightly hazardous (toxicity class III) pesticide by World Health Organization. Diuron has been characterized as a “known/likely” human carcinogen by the US Environmental Protection Agency based on the data that diuron induces urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinoma in the male rat, and breast carcinoma in female NMRI mice. In human liver microsomes, only N-demethylated diuron is formed. Recombinant CYP1A1, 1A2, 2C19, and 2D6 catalyze the N-demethylation of diuron with high activities. Relative contributions of human CYP1A2, 2C19, and 3A4 to hepatic diuron N-demethylation are estimated to be ~60%, 14%, and 13%, respectively. In studies of rats and dogs, N-(3,4-dichlorophenyl)urea is the predominant metabolite in the urine. Small amounts of N-(3,4-dichlorophenyl)-N-methylurea, 3,4-dichloroaniline, 3,4-dichlorophenol, and unchanged diuron are also detected (Hodge et al. 1967). In a hospitalized patient, diuron is completely metabolized, mainly via demethylation and didemethylation with the corresponding metabolites detected in the blood and urine. In addition, high levels of hydroxyphenyldi-uron and moderate levels of 3,4-dichloroaniline are detected in the urine (Van Boven et al. 1990). In a human postmortem case, diuron and its demethylated, didemethylated, and hydroxylated metabolites are all identified in plasma and urine. Diuron levels are as high as 5 mg/l in plasma and 3 mg/l in urine and the total concentration of diuron plus metabolites in plasma is approximately 100 mg/l, with an estimated ingestion of at least several grams (Verheij et al. 1989). In the postmortem case, N-demethyldiuron is the major metabolite, whereas in the hospitalized case, N-didemethyldiuron is the primary metabolite in blood and N-demethyldiuron is dominant in urine.
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Liliane O. Ortlieb, Ícaro P. Caruso, Nathane C. Mebus-Antunes, Andrea T. Da Poian, Elaine da C. Petronilho, José Daniel Figueroa-Villar, Claudia J. Nascimento, Fabio C. L. Almeida
The toxicity risk calculations search for substructures within the chemical structure being indicative of specific toxicity according to a reference database (Registry of Toxic Effects of Chemical Substances database – RTECS), which covers compounds of different toxicity classes49,63. The absence of risky fragments suggests a low risk concerning the toxicity class under investigation63. For these studies, the toxicity classes related to mutagenic, tumorigenic, or irritant effects or being associated with reproductive effects are considered. The results for all compounds showed they do not present any toxicological risks for those classes. It is important to emphasise that these results do not eliminate the need for traditional toxicological tests.
Toxicokinetics of perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in male and female Hsd:Sprague dawley SD rats following intravenous or gavage administration
Published in Xenobiotica, 2020
Anika L. Dzierlenga, Veronica G. Robinson, Suramya Waidyanatha, Michael J. DeVito, Max A. Eifrid, Seth T. Gibbs, Courtney A. Granville, Chad R. Blystone
These data provide a direct comparison across the class for straight chain PFAS, supporting the literature on TK of carboxylate PFAS, and allowing for better comparison of toxicity values across the class. This is the first study to do this comparison using an oral administration and in Sprague Dawley rats, which are provide valuable insights in toxicity data described in the literature. Of particular note is that this study uses the same rat strain used in the NTP 28-day toxicity class comparison study (National Toxicology Program 2019), facilitating a direct correlation between toxicokinetics and target sites for toxicity, which can be modelled for human extrapolation and risk assessmentThe generation of a potency estimate, using these data, would determine if a given replacement PFAS is more, less, or equal to the toxicity of legacy ones. Thorough knowledge of PFAS disposition and elimination in rats is critical for the extrapolation of nonclinical findings to the human population and will assist in regulatory decision-making.
Efficacy of an organophosphorus hydrolase enzyme (OpdA) in human serum and minipig models of organophosphorus insecticide poisoning
Published in Clinical Toxicology, 2020
Michael Eddleston, R. Eddie Clutton, Matthew Taylor, Adrian Thompson, Franz Worek, Harald John, Horst Thiermann, Colin Scott
Pilot minipig studies of poisoning with commercial formulations of WHO toxicity class II dimethoate and chlorpyrifos insecticides showed that the latter did not cause clinical effects or inhibition of AChE (unpublished observations), despite the use of doses equivalent to those believed to cause substantial human poisoning [8]. We, therefore, selected a potent WHO Class I toxicity fat-soluble insecticide, methyl parathion, for clinical studies alongside dimethoate, and assessed OpdA’s pharmacodynamic effect on profenofos poisoning. Commercial formulations (including solvents and other adjuvants) used for these studies were dimethoate EC40 (emulsifiable concentrate [36] at 400 g/L of active ingredient [AI]) (dose: 2.5 mL/kg, 1000 mg/kg of AI; BASF SE, Ludwigshafen, Germany), methyl-parathion EC60 (dose: 2 mL/kg, 1200 mg/kg AI; Cheminova, Lemvig, Denmark), and profenofos EC50 (dose: 3 mL/kg, 1500 mg/kg AI; Syngenta, Basel, Switzerland). These AI doses markedly exceed the rat oral LD50s of 150 mg/kg, 14 mg/kg, and 358 mg/kg, respectively, for each insecticide [29].