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Current Status of Reactivity Models in Aquatic Toxicity . Mark Cronin Liverpool John Moores University England. Aquatic Toxicology. Aquatic Toxicity Prediction. Acute toxicity Chronic toxicity Endocrine disruption. Modes / Mechanisms of Action. Non-reactive Narcosis – baseline effect

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current status of reactivity models in aquatic toxicity

Current Status of Reactivity Models in Aquatic Toxicity

Mark Cronin

Liverpool John Moores University

England

aquatic toxicity prediction
Aquatic Toxicity Prediction
  • Acute toxicity
  • Chronic toxicity
  • Endocrine disruption
modes mechanisms of action
Modes / Mechanisms of Action
  • Non-reactive
    • Narcosis – baseline effect
    • Uncoupling
  • Reactive
    • Toxicity elevated above narcosis
  • Receptor Mediated
role of mechanism of action in predicting aquatic toxicity
Role of Mechanism of Action in Predicting Aquatic Toxicity
  • Mechanism based QSARs
  • Acute – Chronic Ratio (ACR)
  • Category formation

Vonk et al (2009) MOA Workshop Report - ATLA

role of reactivity in predicting aquatic toxicity
Role of Reactivity in Predicting Aquatic Toxicity
  • 40-70% of industrial chemicals are non-reactive
    • Toxicity can potentially be predicted accurately
    • Acute-chronic ratios may be consistent
  • For reactive chemicals
    • Grouping may be of assistance
narcosis and qsars
Narcosis and QSARs
  • Narcosis is reversible; a baseline effect
    • There are a number of narcotic mechanisms
    • Well accepted and understood, if not defined at the molecular level
    • Consistent ACR
  • QSARs need to be robust models
    • Log P models preferred
  • Domain needs to be defined
    • Ellison et al for Tetrahymena
electrophilic reactivity and qsars
Electrophilic Reactivity and QSARs
  • Mechanisms – see next slide
    • Acute toxicity greater than narcosis
    • ACR elevated
  • Traditionally difficult to model toxicity except within closely defined classes or mechanisms
generic acute fish mortality pathway for respiratory irritation
Generic Acute Fish Mortality Pathway for “Respiratory Irritation”
  • a direct-acting electrophile or can be abiotically or biotically transformed to an electrophile
  • molecular sites of action are specific nucleophiles, either thiol or amino-moieties, reactions are non-selective
  • molecular initiating event is covalent perturbation of proteins;
  • biochemical pathways affected are varied and result in general inhibition of cellular functions
  • cellular- and organ-level consequences are irreversible
  • target organ(s) or tissue(s) are the gill
  • key physiological response is general hypoxia
  • key target organ-response is sloughing of the gill epithelium
  • key organism response is a sharp reduction in blood oxygen level, asphyxiation, quickly leads to death

Schultz (2010); McKim – FATS publications

applications of reactivity in predicting aquatic toxicity
Applications of Reactivity in Predicting Aquatic Toxicity
  • Development of QSARs
  • Identification of narcotic / reactive / other mechanistic domains
    • Definition of reactive domains
  • Grouping to allow for read across
qsars using reactivity
QSARs Using Reactivity
  • Acute toxicity to Tetrahymena pyriformis of Michael Acceptors
  • Log (IGC50-1) = 1.05 (log RC50-1) + 1.53
  • n = 20, s = 0.39, r2 = 0.975, q2 = 0.973
  • F= 699, relationship covers 9 log units

Information from Schultz et al

calculated descriptors of reactivity
Calculated Descriptors of Reactivity
  • LUMO
  • HOMO
  • Electrophilicity index (w)
  • Superdelocalisability
  • Atomic charges
  • Limited to categories or do not capture protein reactivity
is a compound narcotic
Is a Compound Narcotic?
  • If it is:
    • We can predict toxicity
    • We can extrapolate ACR
  • If it isn’t
    • More information / testing may be required
  • How do we determine if a compound is narcotic?
methods to determine if a compound is narcotic
Methods to Determine if a Compound is Narcotic
  • Mode of action assignment
    • Verhaar
    • Russom (ASTER)
    • OASIS
  • Domain definition
  • Excess acute toxicity
    • Cytotoxicity
  • Reactivity
narcosis killer questions
Narcosis: Killer Questions
  • Are physico-chemical properties consistent with narcosis?
    • Solubility, volatility
  • Is your compound in a narcotic domain?
    • Classes / analogues
    • Verhaar / Russom / OASIS
    • MOA definitions
  • Is the compound “unlikely” to be activated through metabolism?
  • Is your compound reactive?
mechanistic basis for needing to understand reactivity
Mechanistic Basis for Needing to Understand Reactivity
  • Need to understand target nucleophile
  • Possible covalent interactions with nucleophile
  • How to capture the possibility of interactions
mapping toxicity onto the spectrum of soft hard nucleophiles
Mapping Toxicity onto the Spectrum of Soft-Hard Nucleophiles
  • Nucleophilic sites in amino acids

primary amino-groups of lysine and arginine

secondary amino-group in histidine

thiol-group of cysteine

S-atoms of methionine

mapping toxicity onto the spectrum of soft hard nucleophiles19
Mapping Toxicity onto the Spectrum of Soft-Hard Nucleophiles
  • Nucleophilic sites in amino acids

primary amino-groups of lysine and arginine

secondary amino-group in histidine

thiol-group of cysteine

S-atoms of methionine

Increasing Hardness

mapping toxicity onto the spectrum of soft hard nucleophiles20
Mapping Toxicity onto the Spectrum of Soft-Hard Nucleophiles
  • Nucleophilic sites in amino acids

Aquatic Tox

primary amino-groups of lysine and arginine

secondary amino-group in histidine

thiol-group of cysteine

S-atoms of methionine

Increasing Hardness

mapping toxicity onto the spectrum of soft hard nucleophiles21
Mapping Toxicity onto the Spectrum of Soft-Hard Nucleophiles
  • Nucleophilic sites in amino acids

Aquatic Tox

primary amino-groups of lysine and arginine

secondary amino-group in histidine

thiol-group of cysteine

S-atoms of methionine

Increasing Hardness

slide22
Excess Toxicity: If Seen in Vitro – Extrapolate to in Vivo:Pre-Michael Acceptors: Oxidised in the Air or Medium of the Assay

2- or 4-substituted

3-substituted

information from other species
Information from Other Species
  • Is a skin sensitiser a reactive acute toxicant in fish?
  • Is a non-sensitiser a narcotic?
  • Need to map toxicity onto electrophilic spectrum
information from other species24
Information from Other Species
  • Is a skin sensitiser a reactive acute toxicant in fish?
  • Is a non-sensitiser a narcotic
  • Need to map toxicity onto electrophilic spectrum

Aquatic Toxicity

Skin Sensitisation

primary amino-groups of lysine and arginine

secondary amino-group in histidine

thiol-group of cysteine

S-atoms of methionine

reactive groupings and categories
Reactive Groupings and Categories
  • Groups reactive (and hence non-reactive) chemicals together
  • Allows for (Q)SAR formation and read-across
  • Groupings can be formed on the basis of mechanistic knowledge
  • QSARs can be developed using in chemico data
slide26

Decreasing electrophilicity  decreasing reactivity

Increasing steric hindrance decreasing reactivity

Transition state effect decreasing reactivity

what about chemicals with more than a single mechanism
What About Chemicals with More Than a Single Mechanism?

Michael addition

Schiff base formation

Aromatic nucleophilic substitution

Schiff base formation

current status
Current Status
  • 2-D methods
    • Verhaar / Russom – type rules are accepted, have potential to be developed further
    • ECOSAR classes are accepted, relate to mechanism indirectly
  • Molecular Orbital
    • Little practical use
  • Reactivity Measurement
    • Great potential; little acceptance
what is needed in the european union
What is Needed In the European Union ...
  • Methods that work
  • Methods that are simple
  • Methods that can be justified
  • Methods that will be accepted by EChA, national regulatory agencies
what is needed in the european union30
What is Needed In the European Union ...
  • Methods that work
  • Methods that are simple
  • Methods that can be justified
  • Methods that will be accepted by EChA, national regulatory agencies
  • ... science is less important?
where does the moa fit within an its
Where Does the MOA Fit Within an ITS?
  • To select relevant QSARs
  • To select relevant analogues for chemical category development or read-across purposes
  • To rationalise/resolve disagreements in experimental data
  • Chemical similarity is context dependent i.e. dependent on the relevant parameters driving the toxicity
  • Mechanism of Action provides the frame of reference
conceptual its
Conceptual ITS

Chemical

MODE/MECHANISM

(Q)SAR, TTC

In vitro

Existing data

In vivo

Exposure information

Read-across/

Chemical Categories

Hazard information

Risk Assessment

MODE/MECHANISM

fish acute toxicity workflow 1
Fish Acute Toxicity Workflow 1

Compound

  • Is this a single organic compound of known structure

Domain of the assay

  • Inside of the solubility, volatility, stability domain of the assay?

Existing Data

  • Do satisfactory toxicity data already exist for this compound?

Other QSAR Predictions

  • Can reliable predictions of toxicity be made with an ad hoc QSAR or an expert system such as ECOSAR, TOPKAT, MultiCASE, TerraQSAR etc.?

Metabolism

  • Does the compound have significant and / or relevant metabolites?
fish acute toxicity workflow 4
Fish Acute Toxicity Workflow 4
  • In chemico information
conclusions current status of reactivity in fish acute toxicity
Conclusions: Current Status of Reactivity in Fish Acute Toxicity
  • Predicting narcotic vs non-narcotic mechanisms
  • Rationale grouping of chemicals
    • Descriptors for read-across / QSARs
  • Technology / models are here?
  • Needs
    • Expansion of domains
    • Practical workflows (to enter into ITS)
    • Case studies
    • Acceptance and implementation by industry, regulatory, wider scientific community
acknowledgements
Acknowledgements
  • This project was sponsored by Defra through the Sustainable Arable Link Programme
  • European Union 6th Framework OSIRIS Integrated Project (GOCE-037017-OSIRIS)
  • CAESAR Specific Targeted Project (SSPI-022674-CAESAR)
  • European Chemicals Agency (EChA) Service Contract No. ECHA/2008/20/ECA.203
  • InSilicoTox Marie Curie Project (MTKD-CT-2006-42328)

www.inchemicotox.org