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

```python
# 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