Screening for low aquatic bioaccumulation (1): Lipinski's ‘Rule of 5’ and molecular size

Abstract

Aquatic bioconcentration factors are critical in PBT assessment of industrial chemicals under REACH. Reliable indicators based on physico-chemical properties and molecular attributes of chemicals with low bioconcentration potential have been searched to de-prioritize non-accumulative chemicals in order to avoid unnecessary biotests that do not produce risk-relevant information. Developed to screen drug candidates, Lipinski's 'Rule of 5' identifies chemicals with poor oral absorption based on criteria in partitioning, molecular weight and hydrogen bonding. This parameter ensemble has been supplemented with molecular diameter and tested for its adequacy to filter chemicals with low bioconcentration potential. Perhaps (not) surprisingly, the application of the 'Rule of 5' fails to protectively identify non-accumulative compounds because other processes dominate the uptake in aquatic environments as compared with oral absorption. No robust evidence was found for cut-offs in bioconcentration related to molecular size. However, pragmatic thresholds in molecular weight (>650 g mol(-1)) and lipophilicity (log K(OW) < 3 or > 10) have been verified to securely de-prioritize 30-40% of chemicals of low concern with regard to the B criterion.

Screening for low aquatic bioaccumulation (2): physico-chemical constraints

“…The selection and quality assurance of three independent datasets of experimental BCF data have been described previously [11]. The CEFIC LRI BCF compilation for existing industrial chemicals [15] was used to establish the decision tree model.…”

“…Many thresholds have been focused on molecular size, assuming that membrane permeation of large molecules is limited [11]. However, although intuitively plausible, neither does the fluid mosaic structure of membranes support rigid thresholds nor is there systematic evidence for absorption limits from experimental studies with membranes, tissues or whole organisms [12].…”

“…However, although intuitively plausible, neither does the fluid mosaic structure of membranes support rigid thresholds nor is there systematic evidence for absorption limits from experimental studies with membranes, tissues or whole organisms [12]. There is no robust evidence for cut-offs in bioconcentration related to molecular size [11]. Rather, a modulating (smoothing) effect of molecular size on membrane permeation may exist [4,13].…”

“…The ensemble of molecular attributes according to Lipinski's 'Rule of 5' [14], molecular weight (MW4 500 g mol À1 ), hydrogen bonding capacity (AE hydrogen bond donors [expressed as AE OH þ NH]45, AE hydrogen bond acceptors [expressed as AE N þ O]410) and log K OW 45, was found to be inadequate to identify non-B compounds [11]. Possible reasons are key differences in the dominating processes during oral absorption of pharmaceutical drugs (bulk dissolution) and the uptake of waterborne environmental contaminants by aquatic organisms (continuous low-level exposure).…”

“…Possible reasons are key differences in the dominating processes during oral absorption of pharmaceutical drugs (bulk dissolution) and the uptake of waterborne environmental contaminants by aquatic organisms (continuous low-level exposure). Pragmatic thresholds in two individual attributes, MW (4650 g mol À1 ) and log K OW (53 or 410), have been suggested to safely de-prioritize 30 to 40% of chemicals of low concern with regard to the B criterion [11]. If bioaccumulative polybrominated compounds and organometallics are excluded from the applicability domain of the classification scheme, no false negatives are detected (sensitivity of 100%).…”