Evaluation of Potential Toxicity from Co-Exposure to Three CNS Depressants (Toluene, Ethylbenzene, and Xylene) Under Resting and Working Conditions Using PBPK Modeling

Abstract

Under OSHA and American Conference of Governmental Industrial Hygienists (ACGIH®) guidelines, the mixture formula (unity calculation) provides a method for evaluating exposures to mixtures of chemicals that cause similar toxicities. According to the formula, if exposures are reduced in proportion to the number of chemicals and their respective exposure limits, the overall exposure is acceptable. This approach assumes that responses are additive, which is not the case when pharmacokinetic interactions occur. To determine the validity of the additivity assumption, we performed unity calculations for a variety of exposures to toluene, ethylbenzene, and/or xylene using the concentration of each chemical in blood in the calculation instead of the inhaled concentration. The blood concentrations were predicted using a validated physiologically based pharmacokinetic (PBPK) model to allow exploration of a variety of exposure scenarios. In addition, the Occupational Safety and Health Administration and ACGIH® occupational exposure limits were largely based on studies of humans or animals that were resting during exposure. The PBPK model was also used to determine the increased concentration of chemicals in the blood when employees were exercising or performing manual work. At rest, a modest overexposure occurs due to pharmacokinetic interactions when exposure is equal to levels where a unity calculation is 1.0 based on threshold limit values (TLVs®). Under work load, however, internal exposure was 87% higher than provided by the TLVs. When exposures were controlled by a unity calculation based on permissible exposure limits (PELs), internal exposure was 2.9 and 4.6 times the exposures at the TLVs at rest and workload, respectively. If exposure was equal to PELs outright, internal exposure was 12.5 and 16 times the exposure at the TLVs at rest and workload, respectively. These analyses indicate the importance of ⁽¹⁾ selecting appropriate exposure limits, ⁽²⁾ performing unity calculations, and ⁽³⁾ considering the effect of work load on internal doses, and they illustrate the utility of PBPK modeling in occupational health risk assessment.

Keywords:

• mixture formula
• mixtures
• PBPK
• synergism
• unity calculation

Acknowledgments

Details on the original modeling by Kannan Krishnan at the University of Montreal, assistance with figures by Som Lohitnavy, and manuscript review by Jeanne Nasci is gratefully appreciated.

This study was supported in part by a Cooperative Agreement from ATSDR (U61/ATU 881475) and NIEHS Quantitative Toxicology Training Grant (T32 ES07321).