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Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling.
J Occup Environ Hyg. 2005 Mar; 2(3):127-35.JO

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.

Authors+Show Affiliations

Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, Colorado 80523, USA. dennison@colostate.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15764536

Citation

Dennison, James E., et al. "Evaluation of Potential Toxicity From Co-exposure to Three CNS Depressants (toluene, Ethylbenzene, and Xylene) Under Resting and Working Conditions Using PBPK Modeling." Journal of Occupational and Environmental Hygiene, vol. 2, no. 3, 2005, pp. 127-35.
Dennison JE, Bigelow PL, Mumtaz MM, et al. Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling. J Occup Environ Hyg. 2005;2(3):127-35.
Dennison, J. E., Bigelow, P. L., Mumtaz, M. M., Andersen, M. E., Dobrev, I. D., & Yang, R. S. (2005). Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling. Journal of Occupational and Environmental Hygiene, 2(3), 127-35.
Dennison JE, et al. Evaluation of Potential Toxicity From Co-exposure to Three CNS Depressants (toluene, Ethylbenzene, and Xylene) Under Resting and Working Conditions Using PBPK Modeling. J Occup Environ Hyg. 2005;2(3):127-35. PubMed PMID: 15764536.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling. AU - Dennison,James E, AU - Bigelow,Philip L, AU - Mumtaz,Moiz M, AU - Andersen,Melvin E, AU - Dobrev,Ivan D, AU - Yang,Raymond S H, PY - 2005/3/15/pubmed PY - 2005/5/25/medline PY - 2005/3/15/entrez SP - 127 EP - 35 JF - Journal of occupational and environmental hygiene JO - J Occup Environ Hyg VL - 2 IS - 3 N2 - 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. SN - 1545-9624 UR - https://www.unboundmedicine.com/medline/citation/15764536/Evaluation_of_potential_toxicity_from_co_exposure_to_three_CNS_depressants__toluene_ethylbenzene_and_xylene__under_resting_and_working_conditions_using_PBPK_modeling_ L2 - https://www.tandfonline.com/doi/full/10.1080/15459620590916198 DB - PRIME DP - Unbound Medicine ER -