Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring

Abstract

A toxicokinetic (TK) model was developed to describe the inhalation exposure in humans to methyl formate (MF), a catalyst used in foundries, and to discuss biological monitoring. The TK model consisted of four compartments: MF, the metabolites--methanol (MeOH) and formic acid (FA)--and, in addition, a urinary compartment describing the saturable reabsorption of FA. Levels of MeOH and FA in urine, from an experimental study (100 ppm MF, 8 h at rest), validated the present model. The TK model describes well the general behaviour of MeOH and FA in urine after MF exposure. A nonlinear and a linear relationship respectively, was predicted between MF exposure and FA or MeOH excretion in urine, and this has previously been seen after occupational MF exposure. The present model has been modified to simulate MeOH exposure as well. Generally low exposures (concentration or exercise) produce only marginal increases in FA urinary excretions, but when exposure is elevated, urinary FA excretion increases because of saturation in the mechanism of reabsorption. Using FA urinary excretion as the critical indicator, because of its link to health effects, an occupational exposure limit value for MF of no greater than 50 ppm should be selected (based on predictions with the TK model). MeOH in urine can be considered as a biomarker for MF at low exposure, because of lower background values and of a linear relationship with exposure. At higher exposures, however, FA could be used as a biomarker as it becomes progressively more sensitive. But the use of biological monitoring for MF is difficult because of individual variations in background values. Under the present state of knowledge both FA and MeOH should be used to estimate only group exposures, rather than individual exposures.

Urinary methanol and formic acid as indicators of occupational exposure to methyl formate

“…All these results were also used to validate a toxicokinetic (TK) model developed to describe the inhalation exposure to MF in humans (Nihlen and Droz 2000).…”

Medical toxicology and public health—Update on research and activities at the centers for disease control and prevention, and the agency for toxic substances and disease registry

“…At low levels, formate has a half-life of 1-3 hours, but the half-life can be prolonged at higher levels, likely due to saturation of elimination pathways or continued production [32]. Formate and methanol levels are good markers for occupational exposure [33][34]. Much of the data for inhalational and dermal exposure to methanol come from literature involving chronic exposure or case reports, and the known toxicokinetics may be altered in the case of a massive acute exposure.…”

Acute airway irritation of methyl formate in mice

“…In this way, MF may be metabolised to methanol, a weak sensory irritant (Schaper 1993), and two potent airway irritants, formic acid and formaldehyde cf (Nielsen et al 1999; Wilkins et al 2001). The metabolism has been substantiated from increased methanol and formic acid in urine of MF-exposed subjects (Nihlen and Droz 2000; Sethre et al 2000a, b). Increased airway irritation of organic compounds due to enzymatic degradation of the parent compound has recently been shown for styrene and naphthalene (Lanosa et al 2010).…”

“…MF is taken up through the lungs (Schrenk et al 1936; Nihlen and Droz 2000) and the skin (Gettler 1940; DFG 2010). The odour threshold of MF is about 600 ppm (Amoore and Hautala 1983).…”

“…The nasal mucosa contains several enzymes, including carboxyesterases and cytochrome P450, which may degrade esters through hydrolysis and oxidation, respectively (Nihlen and Droz 2000; Peng et al 1995). In this way, MF may be metabolised to methanol, a weak sensory irritant (Schaper 1993), and two potent airway irritants, formic acid and formaldehyde cf (Nielsen et al 1999; Wilkins et al 2001).…”