title: Use of read-across to simplify the toxicological assessment of a complex mixture of lysimeter leachate metabolites on the basis of chemical similarity and ADME behavior.
abstract: This paper describes the further development of a read-across approach applicable to the toxicological assessment of structurally-related xenobiotic metabolites. The approach, which can be applied in the absence of definitive identification of all the individual metabolites, draws on the use of chemical descriptors and multi-variate statistical analysis to define a composite "chemical space" and to classify and characterize closely-related subgroups within this. In this example, consideration of the descriptors driving grouping, combined with empirical evidence for lack of significant further biotransformation of metabolites, leads to the conclusion that, in the absence of any specific structural alerts, the relative toxicity of metabolites within a single grouping will be determined by their relative systemic exposure as described by their ADME characteristics. The in vivo testing of a smaller number of exemplars, selected to have representative ADME properties for each grouping, is sufficient, therefore, to evaluate the toxicity of the remainder. The approach is exemplified using the metabolites of the herbicide S-metolachlor, detected in the leachate of a soil lysimeter.
authors.affiliation: Syngenta, Product Safety Department, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom. Electronic address: laurence.hand@syngenta.com.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hand
authors.affiliation: Syngenta, Product Safety Department, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors.forename: Kevan
authors.initials: K
authors.lastname: Richardson
authors.affiliation: Syngenta, Product Safety Department, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Hadfield
authors.affiliation: Syngenta, Product Safety Department, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Whalley
authors.affiliation: Syngenta, Product Safety Department, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Rawlinson
authors.affiliation: Syngenta, Product Safety Department, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors.forename: Ewan D
authors.initials: ED
authors.lastname: Booth
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D004781:Environmental Exposure / Q000009:adverse effects; D004784:Environmental Monitoring / Q000295:instrumentation* / Q000379:methods; D006801:Humans; D008956:Models, Chemical; D015233:Models, Statistical; D015394:Molecular Structure; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D018570:Risk Assessment; D012989:Soil Pollutants / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D018675:Toxicity Tests / Q000379:methods*; D066007:Toxicokinetics; D015262:Xenobiotics / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000081:Acetamides; D012989:Soil Pollutants; D015262:Xenobiotics; C000188:alachlor
keywords: ADME; Lysimeter; Read-across; Relevance; S-metolachlor