Physiologically Based Pharmacokinetic Modeling of Cyclohexane as a Tool for Integrating Animal and Human Test Data

Hissink, A.M.; Kulig, B.M.; Krüse, Jacob; Freidig, Andreas P.; Verwei, Miriam; Muijser, Hans; Lammers, J.H.C.M.; McKee, Richard H.; Owen, D.E.; Sweeney, Lisa; Salmon, Florence

doi:10.1177/1091581809348718

Cited by 14 publications

(8 citation statements)

References 25 publications

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“…extrapolated from the rat NOAEL for cyclohexane inhalation to a HEC (on the basis of brain concentration of parent compound) using PBPK models. ( 145 ) While they note the MOE between the HEC and an OEL, no judgment was made as to the adequacy of the MOE. A similar example has been shown for N-methyl pyrrolidone.…”

Section: Other Dosimetry Considerationsmentioning

confidence: 99%

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Kuempel

Sweeney

Morris

et al. 2015

Journal of Occupational and Environmental Hygiene

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The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates.

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Section: Other Dosimetry Considerationsmentioning

confidence: 99%

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Kuempel

Sweeney

Morris

et al. 2015

Journal of Occupational and Environmental Hygiene

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“…These studies indicate that the potential for aliphatic and aromatic constituents to cause acute CNS effects is associated with concentrations of hydrocarbons in the CNS. Although there is evidence of distribution to the CNS during exposure, the hydrocarbon constituents quickly achieve steadystate and are then rapidly eliminated from the brain after exposure with half-times in the range of 2 h (Hissink et al 2007(Hissink et al , 2009. Because the aliphatic constituents become increasingly lipophilic with increasing molecular weight, concentrations in the brain increase with increasing carbon number to approximately C10.…”

Section: Acute Cns Effectsmentioning

confidence: 99%

Characterization of the toxicological hazards of hydrocarbon solvents

McKee

Adenuga

Carrillo

2015

Critical Reviews in Toxicology

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Hydrocarbon solvents are liquid hydrocarbon fractions derived from petroleum processing streams, containing only carbon and hydrogen atoms, with carbon numbers ranging from approximately C5-C20 and boiling between approximately 35-370°C. Many of the hydrocarbon solvents have complex and variable compositions with constituents of 4 types, alkanes (normal paraffins, isoparaffins, and cycloparaffins) and aromatics (primarily alkylated one-and tworing species). Because of the compositional complexity, hydrocarbon solvents are now identified by a nomenclature ("the naming convention") that describes them in terms of physical/ chemical properties and compositional elements. Despite the compositional complexity, most hydrocarbon solvent constituents have similar toxicological properties, and the overall toxicological hazards can be characterized in generic terms. To facilitate hazard characterization, the solvents were divided into 9 groups (categories) of substances with similar physical and chemical properties. Hydrocarbon solvents can cause chemical pneumonitis if aspirated into the lung, and those that are volatile can cause acute CNS effects and/or ocular and respiratory irritation at exposure levels exceeding occupational recommendations. Otherwise, there are few toxicologically important effects. The exceptions, n-hexane and naphthalene, have unique toxicological properties, and those solvents containing constituents for which classification is required under the Globally Harmonized System (GHS) are differentiated by the substance names. Toxicological information from studies of representative substances was used to fulfill REACH registration requirements and to satisfy the needs of the OECD High Production Volume (HPV) initiative. As shown in the examples provided, the hazard characterization data can be used for hazard classification and for occupational exposure limit recommendations. Introduction Scope and purpose of the documentThe present document summarizes information on the physical/ chemical properties and toxicological hazards of hydrocarbon solvents and provides examples of the ways in which the information on hazard characterization can be used for hazard classification and to set occupational exposure limits. Many of the toxicological studies were published separately, but the results are summarized herein and referenced in the appendices.Hydrocarbon solvents are liquid hydrocarbon fractions that are primarily produced by the distillation of petroleum feed stocks or their synthetic analogs (e.g., Fischer-Tropsch derived materials), sometimes followed by additional processing steps such as solvent extraction, hydrodesulfurization, or hydrogenation. 1 Most hydrocarbon solvents are complex substances with variable compositions and are best described as UVCB 2 (unknown and variable composition) substances, but some are single constituent (mono-constituent) substances. The complex and variable nature of these solvents is the consequence of their manufacturing processes. In short, most hydroca...

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“…As part of an overall program to develop a method to calculate occupational exposure levels (OELs) for hydrocarbon solvents, the acute central nervous system (CNS) effects of several hydrocarbon solvents and a reference substance were assessed. [1][2][3][4][5] The underlying principles for this program were that acute CNS effects are (1) a common property of hydrocarbon solvents 6 ; (2) sensitive indicators of toxicological effects; and (3) can be used as a basis for OEL recommendations. [7][8][9] As CNS effects are the most sensitive indicators of effects for most hydrocarbon solvents, protection against acute CNS effects affords protection against other neurological deficits as well as other chronic effects.…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral Effects of Acute Exposure to Aromatic Hydrocarbons

et al. 2010

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This article reports the results of neurobehavioral tests on representative aromatic constituents, specifically C(9) to C(11) species. The testing evaluated effects in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. Exposures ranging from 600 to 5000 mg/m(3), depending on the molecular weights of the specific aromatic constituents, produced minor, reversible effects on the central nervous system (CNS), particularly in the domains of gait and visual discrimination. There was little evidence of effects at lower exposure levels. There was some evidence of respiratory effects at 5000 mg/m(3) in 1 study, and there were also minor changes in body weight and temperature. The CNS effects became less pronounced with repeated exposures, corresponding to lower concentrations in the brain of 1 representative substance, 1,2,4-trimethyl benzene (TMB). At high exposure levels, the alkyl benzenes apparently induced their own metabolism, increasing elimination rates.

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Physiologically Based Pharmacokinetic Modeling of Cyclohexane as a Tool for Integrating Animal and Human Test Data

Cited by 14 publications

References 25 publications

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Characterization of the toxicological hazards of hydrocarbon solvents

Neurobehavioral Effects of Acute Exposure to Aromatic Hydrocarbons

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