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Jeffrey Brent

Publications and source records attributed to Jeffrey Brent.

7 recordsLinked to original sources
PubMed2005

Derivation of a chemical-specific adjustment factor (CSAF) for use in the assessment of risk from chronic exposure to ethylene glycol: application of International Programme for Chemical Safety guidelines.

The International Programme for Chemical Safety (IPCS) has developed a set of guidelines ("the Guidance") for the establishment of Chemical-Specific Adjustment Factors (CSAFs) for in the assessment of toxicity risk to the human population as a result of chemical exposure. The development of case studies is encouraged in the Guidance document and comments on them have been encouraged by the IPCS. One provision in the Guidance is for the determination of CSAFs based on human data. We present a case study of the use of the Guidance for the determination of the CSAF for ethylene glycol (EG) primarily utilizing clinically obtained data. The most relevant endpoint for this analysis was deemed to be acute renal injury. These data were applied based on an assessment of the known pharmaco/toxico-kinetic properties of EG. Because of the lack of both bioaccumulation of EG and reports of chronic or progressive renal injury from EG, it was concluded that the most appropriate model of chronic exposure is one of repeated acute episodes. The most relevant exposure metric was determined to be plasma glycolate concentration. Based on a prospective human study of EG-poisoned patients, the NOAEL for glycolate was found to be 10.1 mM. This value is similar to that obtained from animal data. The application of the Guidelines to this data resulted in a CSAF of 10.24, corresponding to a daily EG dose of 43.7 mg/kg/day. In 2000, Health Canada (HC) produced an animal data-based analysis of the maximum tolerated dose of EG. The results of our analysis are compared with those of HC, and the strengths and weaknesses of these two data types related to EG are discussed.

Ethylene Glycol↗
PubMed2003

Does urine alkalinization increase salicylate elimination? If so, why?

Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH > or = 7.5. Experimental and clinical studies confirm that urinary alkalinization increases salicylate elimination, although the mechanisms by which this occurs have not been elucidated. The conventional view is that ionisation of a weak acid, such as salicylic acid, is increased in an alkaline environment. Since the ionisation constant (pKa) is a logarithmic function then, theoretically, a small change in urine pH will have a disproportionately larger effect on salicylate clearance. Hence, elimination of salicylic acid by the kidneys is increased substantially in alkaline urine. However, as salicylic acid is almost completely ionised within physiological pH limits, alkalinization of the urine could not, therefore, significantly increase the extent of ionisation further and the conventional view of the mechanism by which alkalinization is effective is patently impossible. Further experimental studies are required to clarify the mechanisms by which urine alkalinization enhances salicylate elimination.

Adolescent↗
PubMed2002

Formate kinetics in methanol poisoning.

OBJECTIVE: We sought to describe the kinetics, dialysis clearance, and laboratory markers of formate (FA), the toxic metabolite of methanol (meOH). METHODS: Data were obtained from a prospective, multicenter study of fomepizole +/- dialysis for methanol poisoning. Inclusion criteria confirmed methanol exposure or suspicion of exposure plus either acidemia or abnormal osmolar gap. Dialysis indications were [meOH] > 50 mg/dL, pH < 7.1, refractory acidosis, or visual toxicity. Serial plasma formate, methanol, pH, and electrolyte measurements were made. Formate was determined by gas chromatography. Endogenous and dialysis elimination half-lives were calculated as t(1/2) = 0.693/Ke, with Ke (elimination constant) derived from the slope of log (FA) vs. time. Half-lives were compared with an unpaired Student's t-test. Dialysis clearance was calculated using the Fick Principle. Pearson correlation analysis compared initial formate with initial pH, serum bicarbonate, and anion gap. RESULTS: Eleven patients were treated in the study. Eight had detectable formate with mean [FA] of 15.1 mmol/L (range 0.5-34.8). Endogenous elimination half-life was 205 +/- 90 minutes. Elimination half-life during dialysis (n = 5) was 150 +/- 37 minutes, which was not different (t = 0.22; NS). The overall dialysis formate clearance rate was 223 +/- 25 mL/min. Correlation coefficients were: pH vs. formate r2 = 0.93; bicarbonate vs. formate r2 = 0.81; and anion gap vs. formate r2 = 0.76 (all p < 0.05). CONCLUSIONS: Although dialysis clears formate, it did not significantly enhance endogenous elimination in our series of patients. Low pH, low bicarbonate, and elevated anion gap correlate independently with formate presence.

Adult↗