mims-harvard/tooluniverse-adverse-outcome-pathway

Adverse Outcome Pathway & Regulatory Risk Assessment

Distinct from drug safety (see tooluniverse-toxicology): this skill targets environmental and industrial chemicals where the focus is AOP stressor mapping, GHS classification, LD50 hazard quantification, and IARC carcinogen status — not FAERS signals or FDA drug labels.

When to Use

Apply when researcher asks about:

• "What AOPs are associated with [pesticide/solvent/industrial chemical]?"
• "What is the GHS hazard classification for [compound]?"
• "What is the LD50 for [compound]?"
• "Is [compound] a carcinogen (IARC classification)?"
• "Which genes does [chemical] interact with (CTD)?"
• "Regulatory risk assessment for [environmental chemical]"
• "What diseases are associated with [chemical] exposure?"

Do NOT use for FDA-approved drugs with FAERS data — use tooluniverse-toxicology instead.

Key Tools

| Tool | Purpose | Key Params | |------|---------|-----------| | AOPWiki_list_aops | Discover AOPs by keyword | keyword (organ, effect, or target name) | | AOPWiki_get_aop | Full AOP details: MIE, key events, stressors | aop_id (int) | | PubChemTox_get_toxicity_summary | Narrative toxicity overview | cid (PubChem CID) | | PubChemTox_get_ghs_classification | GHS hazard category + pictograms | cid | | PubChemTox_get_carcinogen_classification | IARC/NTP/EPA carcinogen status | cid | | PubChemTox_get_toxicity_values | LD50/LC50 by route and species | cid | | PubChemTox_get_acute_effects | Signs and symptoms of acute exposure | cid | | CTD_get_chemical_gene_interactions | Chemical-gene molecular interactions | input_terms (name or MeSH ID) | | CTD_get_chemical_diseases | Chemical-disease associations | input_terms | | PubChem_get_CID_by_compound_name | Resolve compound name to PubChem CID | name |

Workflow

Phase 1: Compound Identity Resolution

Resolve chemical name to PubChem CID before all PubChemTox calls.

PubChem_get_CID_by_compound_name(name="benzo[a]pyrene")
-> cid: 9153 (use for all PubChemTox calls)

Note: CTD tools accept the chemical name directly (input_terms param) — no CID needed.

Phase 2: AOP Discovery

Find relevant AOPs by searching organ targets and mechanism keywords.

AOPWiki_list_aops(keyword="lung")          # organ-level
AOPWiki_list_aops(keyword="DNA damage")    # mechanism-level
AOPWiki_list_aops(keyword="AhR")           # receptor-level

Select 2-4 candidate AOPs from results, then retrieve full details:

AOPWiki_get_aop(aop_id=58)  # returns MIE, key events, stressors, biological plausibility

Key fields in AOPWiki_get_aop response:

• stressors: list of chemicals that trigger this AOP (check if query compound is listed)
• molecular_initiating_event: the first molecular perturbation
• key_events: ordered chain of biological events
• adverse_outcome: apical regulatory endpoint

Phase 3: Hazard Quantification (PubChemTox)

Run all four hazard queries in parallel using the resolved CID:

PubChemTox_get_ghs_classification(cid=9153)        # GHS category + pictogram
PubChemTox_get_carcinogen_classification(cid=9153)  # IARC Group 1/2A/2B/3
PubChemTox_get_toxicity_values(cid=9153)            # LD50 by route/species
PubChemTox_get_acute_effects(cid=9153)              # signs/symptoms

Note: PubChemTox_get_target_organs sometimes returns no data — treat as optional.

Phase 4: Toxicogenomics (CTD)

Map chemical to gene targets and disease associations:

CTD_get_chemical_gene_interactions(input_terms="benzo[a]pyrene")
CTD_get_chemical_diseases(input_terms="benzo[a]pyrene")

Cross-reference CTD gene targets with AOP key event genes from Phase 2.

Tool Parameter Reference

| Tool | Required | Optional | Notes | |------|---------|---------|-------| | AOPWiki_list_aops | keyword | — | Use organ ("liver"), effect ("apoptosis"), or receptor ("PPARalpha") | | AOPWiki_get_aop | aop_id | — | Integer ID from list_aops output | | PubChemTox_get_toxicity_summary | cid | — | PubChem CID integer | | PubChemTox_get_ghs_classification | cid | — | Returns pictogram_labels e.g. "Health Hazard" | | PubChemTox_get_carcinogen_classification | cid | — | IARC Group in classifications[].classification | | PubChemTox_get_toxicity_values | cid | — | Values like "LD50 Rat oral 2400 mg/kg" | | PubChemTox_get_acute_effects | cid | — | Sometimes sparse; not all compounds have data | | CTD_get_chemical_gene_interactions | input_terms | — | Accepts name or MeSH ID (e.g., "D001564") | | CTD_get_chemical_diseases | input_terms | — | Filter DirectEvidence = "marker/mechanism" for curated | | PubChem_get_CID_by_compound_name | name | — | Returns CID + SMILES; required before PubChemTox calls |

Common Patterns

# Pattern: Confirm compound is a stressor in a specific AOP
aop = AOPWiki_get_aop(aop_id=58)
stressors = [s["name"] for s in aop["data"]["stressors"]]
# Check if query chemical appears in stressors list

# Pattern: Extract curated CTD disease associations only
diseases = CTD_get_chemical_diseases(input_terms="rotenone")
curated = [d for d in diseases["data"] if d.get("DirectEvidence")]

# Pattern: GHS carcinogen check
carcinogen = PubChemTox_get_carcinogen_classification(cid=9153)
iarc = [c for c in carcinogen["data"]["classifications"] if "IARC" in c.get("source", "")]

Reasoning Framework for Result Interpretation

Evidence Grading

| Grade | Criteria | Example | |-------|----------|---------| | Strong | AOP in OECD-endorsed status, compound listed as stressor, CTD + AOPWiki concordant | AOP 58 (AhR → liver tumor) endorsed, benzo[a]pyrene confirmed stressor | | Moderate | AOP under review or well-documented, compound class match but not individually listed | AOP links PPARalpha activation to liver effects; query compound is a fibrate analog | | Weak | AOP in development, compound not listed but shares MIE target via CTD gene overlap | CTD shows gene target overlap with AOP key event genes, but no direct stressor listing | | Insufficient | No AOP found, no CTD gene-disease link, hazard data sparse | Novel compound with no toxicological database entries |

Interpretation Guidance

• AOP weight-of-evidence assessment: OECD-endorsed AOPs have undergone expert review and represent the highest confidence mechanistic pathways. AOPs "under development" in AOPWiki may have incomplete key event relationships. Evaluate each AOP by: (1) biological plausibility of key event relationships, (2) empirical support (dose-response concordance), (3) essentiality of key events (blocking KE prevents AO).
• Key event relationship (KER) strength: Strong KERs have dose-response and temporal concordance between upstream and downstream key events. Moderate KERs have correlative evidence. Weak KERs are based on plausibility alone. The weakest KER in the chain determines the overall AOP confidence for that pathway.
• Stressor potency interpretation: LD50 values indicate acute toxicity (lower = more toxic). GHS categories: Cat 1 (LD50 <= 5 mg/kg, fatal), Cat 2 (5-50, fatal), Cat 3 (50-300, toxic), Cat 4 (300-2000, harmful), Cat 5 (2000-5000, may be harmful). IARC Group 1 = confirmed carcinogen, 2A = probable, 2B = possible, 3 = not classifiable. Always report route of exposure and species for LD50 values.
• CTD integration: CTD "direct evidence" (curated marker/mechanism) is stronger than "inferred" associations. When CTD gene targets overlap with AOP key event genes, this supports the mechanistic link between the compound and the adverse outcome.
• Regulatory context: For risk assessment, combine hazard identification (IARC, GHS) with exposure assessment. A potent carcinogen at negligible exposure may pose lower risk than a moderate toxicant at high exposure.

Synthesis Questions

1. Is the query compound explicitly listed as a stressor in the identified AOP, or is the link inferred from shared molecular targets (CTD gene overlap)?
2. Do the key event relationships in the AOP chain have sufficient empirical support (dose-response concordance, temporal sequence), or are there weak links that reduce confidence?
3. Are the hazard data (LD50, GHS, IARC) consistent across sources, and do they support the severity implied by the AOP adverse outcome?
4. Does the CTD gene-disease evidence corroborate the AOP's predicted adverse outcome, or are there discrepancies suggesting alternative pathways?
5. For regulatory decision-making, is the combined weight of evidence (AOP mechanism + hazard quantification + exposure context) sufficient to support a risk classification?

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Fallback Chains

| Primary | Fallback | When | |---------|---------|------| | AOPWiki_list_aops with specific keyword | Broader organ term | No results | | PubChemTox_get_target_organs | PubChemTox_get_toxicity_summary | Returns empty | | CTD_get_chemical_diseases | CTD_get_gene_diseases + gene from CTD interactions | Compound name not recognized |