Related Experiment Videos
Dimethylformamide pharmacokinetics following inhalation exposure in monkeys
S G Hundley1, K T McCooey, P H Lieder
1E. I. du Pont de Nemours & Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714.
Abstract:
Male and female cynomolgus monkeys received whole-body inhalation exposures to dimethylformamide (DMF) at concentrations of 30, 100, and 500 ppm for 6 hours a day, 5 days a week over a 13-week period. Serial blood samples were drawn at the conclusion of the first day of exposure and following 15, 29, 57, and 85 days of testing. Area under the plasma concentration curve (AUC) values were determined for DMF and "NMF" [N-methylformamide (NMF) plus N-(hydroxymethyl)-N-methylformamide (DMF-OH)]. Urine samples were also collected and assayed for DMF, NMF and DMF-OH. The systemic exposure to DMF increased disproportionately as the airborne DMF concentrations increased. DMF AUC values increased 19- to 37-fold in male and 35- to 54-fold in female monkeys as the inhalation concentrations increased 5-fold (100 to 500 ppm). These data are consistent with saturation of DMF metabolism as inhaled DMF concentrations increased from 100 to 500 ppm. AUC values, peak plasma concentrations, and plasma half-lives were essentially unaltered over the duration of the study within each exposure concentration tested. Estimated plasma half-lives ranged from 1 to 2 hours and 4 to 15 hours for DMF and "NMF" respectively. DMF was rapidly converted to "NMF" following 30 ppm exposures, with "NMF" plasma concentrations higher than DMF plasma concentrations at the 0.5 hour time-point. In plasma samples simultaneously assayed for DMF-OH and NMF, the concentration of DMF-OH exceeded, was equal to, or was less than NMF concentrations depending upon the plasma sample. DMF-OH was always the main urinary metabolite (56 to 95 percent) regardless of exposure level or time on study.
Insights
Dimethylformamide (DMF) inhalation in monkeys shows disproportionate exposure increases at higher concentrations, indicating saturated metabolism. N-methylformamide (NMF) and DMF-OH are key metabolites, with DMF-OH being the primary urinary form.
Area of Science:
- Toxicology
- Pharmacokinetics
- Environmental Health
Background:
- Dimethylformamide (DMF) is a widely used industrial solvent with potential health risks.
- Understanding DMF's metabolic fate and systemic exposure is crucial for risk assessment.
Purpose of the Study:
- To investigate the pharmacokinetic profile of DMF following inhalation exposure in cynomolgus monkeys.
- To determine the relationship between airborne DMF concentrations and systemic exposure levels.
- To identify and quantify major DMF metabolites in plasma and urine.
Main Methods:
- Cynomolgus monkeys (male and female) were exposed to DMF via whole-body inhalation (30, 100, 500 ppm) for 6 hours/day, 5 days/week over 13 weeks.
- Serial blood and urine samples were collected at multiple time points for analysis of DMF, N-methylformamide (NMF), and N-(hydroxymethyl)-N-methylformamide (DMF-OH).
- Area under the plasma concentration-time curve (AUC), peak plasma concentrations, and plasma half-lives were calculated.
Main Results:
- Systemic exposure to DMF (AUC) increased disproportionately with higher airborne concentrations, suggesting saturation of DMF metabolism at 100-500 ppm.
- Plasma AUC, peak concentrations, and half-lives for DMF and NMF remained stable over the study duration within each exposure group.
- DMF was rapidly converted to NMF, and DMF-OH was consistently the predominant urinary metabolite (56-95%).
Conclusions:
- Inhalation exposure to DMF at concentrations of 100-500 ppm leads to saturated metabolism in cynomolgus monkeys.
- NMF and DMF-OH are significant metabolites of DMF, with DMF-OH being the primary urinary metabolite.
- These findings are critical for understanding DMF toxicity and establishing safe exposure limits.