Evaluation and modeling of the impact of coexposures to VOC mixtures on urinary biomarkers

Marchand, Axelle; Aranda-Rodriguez, Rocio; Tardif, Robert; Nong, Andy; Haddad, Sami

doi:10.3109/08958378.2016.1162232

Cited by 13 publications

(2 citation statements)

References 15 publications

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“…The predicted maximal venous blood concentrations ( Figure 5 and Figure 6 ) are below the Km values ( Table 3 ); significant competitive metabolic inhibition is not anticipated. Similarly, metabolic interaction was not seen in humans exposed to pairs of these compounds (toluene, ethylbenzene, and xylenes), with respect to expected metabolism data from single compound exposures at similar concentrations to the OEL [ 60 , 61 ]. Competitive metabolic inhibition could become more important to the array model if the whole fuel is accounted for through lumping, thereby increasing the additive metabolic load on each cytochrome subfamily.…”

Section: Discussionmentioning

confidence: 92%

Complex Mixtures: Array PBPK Modeling of Jet Fuel Components

Sterner

Covington

Mattie

2023

Toxics

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An array physiologically-based pharmacokinetic (PBPK) model represents a streamlined method to simultaneously quantify dosimetry of multiple compounds. To predict internal dosimetry of jet fuel components simultaneously, an array PBPK model was coded to simulate inhalation exposures to one or more selected compounds: toluene, ethylbenzene, xylenes, n-nonane, n-decane, and naphthalene. The model structure accounts for metabolism of compounds in the lung and liver, as well as kinetics of each compound in multiple tissues, including the cochlea and brain regions associated with auditory signaling (brainstem and temporal lobe). The model can accommodate either diffusion-limited or flow-limited kinetics (or a combination), allowing the same structure to be utilized for compounds with different characteristics. The resulting model satisfactorily simulated blood concentration and tissue dosimetry data from multiple published single chemical rat studies. The model was then utilized to predict tissue kinetics for the jet fuel hearing loss study (JTEH A, 25:1-14). The model was also used to predict rat kinetic comparisons between hypothetical exposures to JP-8 or a Virent Synthesized Aromatic Kerosene (SAK):JP-8 50:50 blend at the occupational exposure limit (200 mg/m3). The array model has proven useful for comparing potential tissue burdens resulting from complex mixture exposures.

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Section: Discussionmentioning

confidence: 92%

Complex Mixtures: Array PBPK Modeling of Jet Fuel Components

Sterner

Covington

Mattie

2023

Toxics

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“…These increases are clearly observable when the level of exposure to at least one of the two solvents is close to or exceeds its OEL. This phenomenon is more limited at lower exposure concentrations; indeed, as shown by Marchand et al (2016) in a study of humans exposed to mixtures of chloroform and three aromatic solvents, metabolic inhibition between chemicals during co-exposure is unlikely to occur or be detectable at concentrations equal to or lower than ¼ of the OEL. Nevertheless, under normal working conditions (exposure level below the OEL), it cannot be excluded that exposure to the TOL/MEK mixture might have more damaging effects than exposure to TOL alone due to a reduction in the concentration from which potential neurotoxicity might appear.…”

Section: Discussionmentioning

confidence: 97%

Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

et al. 2017

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1. Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK). 2. Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated. 3. Although the cytochrome P450 concentration was unchanged, and the activities of CYP1A2 and CYP2E1 isoforms were not additively or synergistically induced by co-exposure, TOL metabolism was inhibited by the presence of MEK (and vice versa). Depending on the relative proportions of each compound in the mixture, this sometimes resulted in a large increase in blood and brain concentrations. Apart from extreme cases (unbalanced mixtures), the amount of o-cresol and benzylmercapturic acid (and to a lesser extent 2,3-butanediols) excreted were proportional to the blood solvent concentrations. 4. In a co-exposure context, ortho-cresol and benzylmercapturic acid can be used as urinary biomarkers in biomonitoring for employees to relatively accurately assess TOL exposure.

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Mixtures Risk Assessment: Available Methods and Future Directions

et al. 2023

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Humans are simultaneously or sequentially exposed to many chemicals throughout their life, intentionally or unintentionally. These could include pesticides, pharmaceuticals, household products, and food additives. Individual control over exposure varies across personal, occupational, and environmental chemical exposure pathways. Personal lifestyle exposures such as firsthand tobacco smoke or alcohol are voluntary. Occupational exposure is “voluntary,” but the individual generally has less control over these exposures. On the other hand, individuals usually have few options for controlling environmental exposures under ordinary circumstances.

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Evaluation and modeling of the impact of coexposures to VOC mixtures on urinary biomarkers

Abstract: PBPK models for urinary biomarkers proved to be a good tool in quantifying exposure to VOC.

Cited by 13 publications

References 15 publications

Complex Mixtures: Array PBPK Modeling of Jet Fuel Components

Complex Mixtures: Array PBPK Modeling of Jet Fuel Components

Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

Mixtures Risk Assessment: Available Methods and Future Directions

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