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An Overview of the Outstanding Issues in the Risk Assessment of Methylene Chloride

  • Chapter
Oncogene and Transgenics Correlates of Cancer Risk Assessments

Part of the book series: NATO ASI Series ((NSSA,volume 232))

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Abstract

Methylene chloride is a liver and lung carcinogen in male and female B6C3F1 mice. Accurate assessment of human cancer risk for this chemical requires mechanistic knowledge of both target tissue dosimetry (pharmacokinetics) and of the tissue responses culminating in tumor development (pharmacodynamics). A major step in this direction was taken by Andersen et al. (Toxicol. Appl. Pharmacol., 87:185, 1987) who used a physiologically based pharmacokinetic (PBPK) model to define target tissue doses of methylene chloride and its metabolites, produced by either cytochrome P-450 or by glutathione (GSH) conjugation. With this approach they found that methylene chloride metabolism by GSH conjugation correlated better with observed tumor outcome than did metabolism via cytochrome P-450. The PBPK model was scaled to humans and used to predict human metabolism of methylene chloride by the GSH pathway. When these calculated dose surrogates were used as input to a linearized multistage (LMS) model, a human cancer risk of 3.7 X 10-8, for lifetime exposure at 1 mg/m3 was predicted, more than two orders of magnitude lower than the risk estimated when bioassay exposure concentrations were used as input to the LMS for high to low dose extrapolation, and a body surface area correction factor was used for scaling from mice to humans. This report reviews the essential features of the Andersen et al. PBPK assisted risk assessment and considers how on-going developments in biologically based risk assessment should lead to further refinement of the human health risk assessment for methylene chloride.

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Authors and Affiliations

  1. Chemical Industry Institute of Toxicology, Post Office Box 12137, 6 Davis Dr. Research Triangle Park, NC, 27709, USA

    Rory B. Conolly, Kannan Krishnan & Melvin E. Andersen

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  1. Rory B. Conolly
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  2. Kannan Krishnan
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  3. Melvin E. Andersen
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Editors and Affiliations

  1. Consulting in Health and Environmental Protection, Simpsonville, Maryland, USA

    Constantine Zervos

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© 1992 Springer Science+Business Media New York

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Conolly, R.B., Krishnan, K., Andersen, M.E. (1992). An Overview of the Outstanding Issues in the Risk Assessment of Methylene Chloride. In: Zervos, C. (eds) Oncogene and Transgenics Correlates of Cancer Risk Assessments. NATO ASI Series, vol 232. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3056-5_16

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  • DOI: https://doi.org/10.1007/978-1-4615-3056-5_16

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6333-0

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