Derivation of an occupational exposure limit (OEL) for methylene chloride based on acute CNS effects and relative potency analysis.
The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.
Storm
J E
JE
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Rozman
K K
KK
D000777:Anesthetics / Q000009:adverse effects*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D006801:Humans; D008752:Methylene Chloride / Q000009:adverse effects*; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure / Q000592:standards*; D051381:Rats; D012016:Reference Values; D012997:Solvents / Q000009:adverse effects; D014481:United States; D014489:United States Occupational Safety and Health Administration
D000777:Anesthetics; D012997:Solvents; D008752:Methylene Chloride