On the Importance of Exposure Variability to the Doses of Volatile Organic Compounds

Abstract

The connection between occupational exposure to volatile organic compounds (VOCs) and the resulting internal doses is complicated by variability in air levels from day to day and by nonlinear kinetics of metabolism. We investigated long-term liver doses of VOCs and their metabolites using a physiologically based toxicokinetic model, to which 10,000 random 8-h exposures were inputted. Three carcinogenic VOCs were studied (i.e., benzene, perchloroethylene, and acrylonitrile); these compounds are all bioactivated in the liver and represent a wide range of an important toxicokinetic parameter Vmax/QL x KM. For each VOC, simulations were performed using mean air concentrations (muX) between 0.0003 and 1 mg/l (which covers both linear and saturated metabolism) and using coefficients of variation of exposure (CVX) between 0.23 and 2.18 (which includes most occupational settings). Two long-term measures of internal dose were examined, i.e., the area under the liver concentration-time curve (AUCL) and the area under the metabolic rate-time curve (AURC). Interestingly, both AUCL and AURC were linear functions of cumulative exposure (CE, mg x h/l air) even when metabolism was saturated and CVX was large. Yet, at a given CE, both AUCL and AURC were affected by CVX, with the magnitude of the effect increasing with Vmax/QL x KM (i.e., perchloroethylene < benzene < acrylonitrile). Nonetheless, the effects of CVX were typically only a few percent and should be of little consequence unless a VOC has large values of Vmax/QL x KM, muX,and CVX. We conclude that CE should be a sufficient predictor of the dose of either the parent chemical (VOC) or its metabolite in the liver, even when metabolism is nonlinear. We also observed that AUCL and AURC were sensitive to changes in values of model parameters in the high-variability scenarios, suggesting that (when CVX is large) the population variability of AUCL and AURC can be quite large at a fixed CE.

Modeling Human Metabolism of Benzene Following Occupational and Environmental Exposures

“…This behavior was unexpected, given current toxicokinetic models that indicate that saturable benzene metabolism should not be observed below about 3 to 10 ppm in humans (49,50). Thus, our results suggest that current toxicokinetic models for benzene are not accurate for air concentrations below 3 ppm.…”

Human Health Risk Assessment of Ambient Air in a Dispute Over Petrochemical Emissions

“…The risk of chronic effects and cancer generally depends on mean exposure relative to other statistical measures of air concentrations (Kenny S Crump, 1998;Stephen M Rappaport, 1991). This has been demonstrated for VOCs even when there is significant variability in concentration over time (S M Rappaport, Kupper, & Lin, 2005). The EPA recommends using the arithmetic mean to estimate the concentration term for cancer and chronic health risk regardless of distribution (U.S. Environmental Protection Agency, 1992).…”

Determination of polycyclic aromatic hydrocarbons in blood plasma of neurology patients

“…The bio accumulative effect of the volatile and particulate forms of these PAHs may be capable of neurological damage. Rappaport et al (2005), in their study, proposed Naphthalene as an alternate biomarker for the determination of PAHs in the body and the metabolites 1and 2-hydroxynapthalene in urine as an alternative to 1hydroxypyrene. Since naphthalene (two ring PAHs) sublimes into gaseous state, it will be a suitable biomarker for industrial exposure to airborne PAHs mixtures.…”

“…This may be a pointer that the source of absorption is not predominantly through inhalation, but may be dermal, food and air borne. According to Rappaport et al (2004) where there is a mixture of dermal and airborne exposure, an alternative marker correlating better with the higher number ring compounds could be more suitable as biomarker. Thus, any of the following three could be used as biomarker; Phenanthrene, Pyrene and Benz (a)Pyrene as corroborated by Sobus et al (2008).…”