In vitro assays are widely employed to obtain intrinsic clearance estimates used in toxicokinetic modeling efforts. However, the reliability of these methods is seldom reported. Here we describe the results of an international ring trial designed to evaluate two in vitro assays used to measure intrinsic clearance in rainbow trout. An important application of these assays is to predict the effect of biotransformation on chemical bioaccumulation. Six laboratories performed substrate depletion experiments with cyclohexyl salicylate, fenthion, 4-n-nonylphenol, deltamethrin, methoxychlor, and pyrene using cryopreserved hepatocytes and liver S9 fractions from trout. Variability within and among laboratories was characterized as the percent coefficient of variation (CV) in measured in vitro intrinsic clearance rates (CLIN VITRO, INT; ml/h/mg protein or 106 cells) for each chemical and test system. Mean intralaboratory CVs for each test chemical averaged 18.9% for hepatocytes and 14.1% for S9 fractions, whereas interlaboratory CVs (all chemicals and all tests) averaged 30.1% for hepatocytes and 22.4% for S9 fractions. When CLIN VITRO, INT values were extrapolated to in vivo intrinsic clearance estimates (CLIN VIVO, INT; l/d/kg fish), both assays yielded similar levels of activity (<4-fold difference for all chemicals). Hepatic clearance rates (CLH; l/d/kg fish) calculated using data from both assays exhibited even better agreement. These findings show that both assays are highly reliable and suggest that either may be used to inform chemical bioaccumulation assessments for fish. This study highlights several issues related to the demonstration of assay reliability and may provide a template for evaluating other in vitro biotransformation assays.

No abstract

No abstract

The propylene glycol substances comprise a homologous family of synthetic organic molecules that have widespread use and very high production volumes across the globe. The information presented and summarized here is intended to provide an overview of the most current and reliable information available for assessing the potential environmental exposures and impacts of these substances across the manufacture, use, and disposal phases of their product life cycles.The PG substances are characterized as being miscible in water, having very low octanol-water partition coefficients (log Pow) and exhibiting low potential to volatilize from water or soil in both pure and dissolved forms. The combination of these properties dictates that, almost regardless of the mode of their initial emission, they will ultimately associate with surface water, soil, and the related groundwater compartments in the environment. These substances have low affinity for soil and sediment particles, and thus will remain mobile and bio-available within these media.In the atmosphere, the PG substances are demonstrated to have short lifetimes(I. 7-11 h), due to rapid reaction with photochemically-generated hydroxyl radicals.This reactivity, combined with efficient wet deposition of their vapor and aerosol forms, lends to their very low potential for long-range transport via the atmosphere.In the aquatic and terrestrial compartments of the environment, the PG substances are rapidly and ultimately biodegraded under both aerobic and anaerobic conditions by a wide variety of microorganisms, regardless of prior adaptation to the substances.Except for the TePG substance, the propylene glycol substances meet the OECD definition of "readily biodegradable", and according to this definition are not expected to persist in either aquatic or terrestrial environments. The TePG exhibits inherent biodegradability, is not regarded to be persistent, and is expected to ultimately biodegrade in the environment, albeit at a somewhat slower rate. The apparent ease with which microorganisms and higher organisms can metabolize the PG substances, along with their low log Pow and very high water solubility values, portends them to have very low potential for bioaccumulation and/or biomagnification in aquatic and terrestrial organisms. These same properties, along with their neutral structures and lack of biological reactivity, are the reasons for which the PG substances exhibit a base-line, non-polar narcosis mode of toxicity.The PG substances have been shown here to be practically non-toxic to essentially every aquatic and terrestrial animal and plant species tested. Collectively, the available wealth of information relating to persistence, bioaccumulation, and eco-toxicity of these substances allows a definitive conclusion of their categorization as not being PBT (i.e., persistently bioaccumulative/toxic). The PBT screening and categorization of substances on the Canadian Domestic Substances List (DSL) by Environment Canada has formally concluded that each member of this...

No abstract