@bgicli/bgicli 2.1.1 → 2.2.1

package/data/skills/tooluniverse-chemical-safety/SKILL.md

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+---
+name: tooluniverse-chemical-safety
+description: Comprehensive chemical safety and toxicology assessment integrating ADMET-AI predictions, CTD toxicogenomics, FDA label safety data, DrugBank safety profiles, and STITCH chemical-protein interactions. Performs predictive toxicology (AMES, DILI, LD50, carcinogenicity), organ/system toxicity profiling, chemical-gene-disease relationship mapping, regulatory safety extraction, and environmental hazard assessment. Use when asked about chemical toxicity, drug safety profiling, ADMET properties, environmental health risks, chemical hazard assessment, or toxicogenomic analysis.
+---
+
+# Chemical Safety & Toxicology Assessment
+
+Comprehensive chemical safety and toxicology analysis integrating predictive AI models, curated toxicogenomics databases, regulatory safety data, and chemical-biological interaction networks. Generates structured risk assessment reports with evidence grading.
+
+## When to Use This Skill
+
+**Triggers**:
+- "Is this chemical toxic?" / "What are the toxicity endpoints for [compound]?"
+- "Assess the safety profile of [drug/chemical]"
+- "What are the ADMET properties of [SMILES]?"
+- "What genes does [chemical] interact with?"
+- "What diseases are linked to [chemical] exposure?"
+- "Predict toxicity for these molecules"
+- "Drug safety assessment for [drug name]"
+- "Environmental health risk of [chemical]"
+- "Chemical hazard profiling"
+- "Toxicogenomic analysis of [compound]"
+
+**Use Cases**:
+1. **Predictive Toxicology**: AI-predicted toxicity endpoints (AMES mutagenicity, DILI, LD50, carcinogenicity, skin reactions) for novel compounds via SMILES
+2. **ADMET Profiling**: Full absorption, distribution, metabolism, excretion, toxicity characterization
+3. **Toxicogenomics**: Chemical-gene interaction mapping, gene-disease associations from CTD
+4. **Regulatory Safety**: FDA label warnings, boxed warnings, contraindications, adverse reactions
+5. **Drug Safety Assessment**: Combined DrugBank safety + FDA labels + adverse event data
+6. **Chemical-Protein Interactions**: STITCH-based chemical-protein binding and interaction networks
+7. **Environmental Toxicology**: Chemical-disease associations for environmental contaminants
+
+---
+
+## KEY PRINCIPLES
+
+1. **Report-first approach** - Create report file FIRST, then populate progressively
+2. **Tool parameter verification** - Verify params via `get_tool_info` before calling unfamiliar tools
+3. **Evidence grading** - Grade all safety claims by evidence strength (T1-T4)
+4. **Citation requirements** - Every toxicity finding must have inline source attribution
+5. **Mandatory completeness** - All sections must exist with data minimums or explicit "No data" notes
+6. **Disambiguation first** - Resolve compound identity (name -> SMILES, CID, ChEMBL ID) before analysis
+7. **Negative results documented** - "No toxicity signals found" is data; empty sections are failures
+8. **Conservative risk assessment** - When evidence is ambiguous, flag as "requires further investigation"
+9. **English-first queries** - Always use English chemical/drug names in tool calls
+
+---
+
+## Evidence Grading System (MANDATORY)
+
+Grade every toxicity claim by evidence strength:
+
+| Tier | Symbol | Criteria | Examples |
+|------|--------|----------|----------|
+| **T1** | [T1] | Direct human evidence, regulatory finding | FDA boxed warning, clinical trial toxicity, human case reports |
+| **T2** | [T2] | Animal studies, validated in vitro | Nonclinical toxicology, AMES positive, animal LD50 |
+| **T3** | [T3] | Computational prediction, association data | ADMET-AI prediction, CTD association, QSAR model |
+| **T4** | [T4] | Database annotation, text-mined | Literature mention, database entry without validation |
+
+### Required Evidence Grading Locations
+
+Evidence grades MUST appear in:
+1. **Executive Summary** - Key toxicity findings graded
+2. **Toxicity Predictions** - Every ADMET-AI endpoint with confidence note
+3. **Regulatory Safety** - FDA findings marked [T1]
+4. **Chemical-Gene Interactions** - CTD data marked by curation status
+5. **Risk Assessment** - Final risk classification with supporting evidence tiers
+
+---
+
+## Core Strategy: 8 Research Dimensions
+
+```
+Chemical/Drug Query
+|
++-- PHASE 0: Compound Disambiguation (ALWAYS FIRST)
+|   +-- Resolve name -> SMILES, PubChem CID, ChEMBL ID
+|   +-- Get molecular formula, weight, canonical structure
+|
++-- PHASE 1: Predictive Toxicology (ADMET-AI)
+|   +-- Mutagenicity (AMES)
+|   +-- Hepatotoxicity (DILI, ClinTox)
+|   +-- Carcinogenicity
+|   +-- Acute toxicity (LD50)
+|   +-- Skin reactions
+|   +-- Stress response pathways
+|   +-- Nuclear receptor activity
+|
++-- PHASE 2: ADMET Properties
+|   +-- Absorption: BBB penetrance, bioavailability
+|   +-- Distribution: clearance, volume of distribution
+|   +-- Metabolism: CYP interactions (1A2, 2C9, 2C19, 2D6, 3A4)
+|   +-- Physicochemical: solubility, lipophilicity, pKa
+|
++-- PHASE 3: Toxicogenomics (CTD)
+|   +-- Chemical-gene interactions
+|   +-- Chemical-disease associations
+|   +-- Affected biological pathways
+|
++-- PHASE 4: Regulatory Safety (FDA Labels)
+|   +-- Boxed warnings (Black Box)
+|   +-- Contraindications
+|   +-- Adverse reactions
+|   +-- Warnings and precautions
+|   +-- Nonclinical toxicology
+|
++-- PHASE 5: Drug Safety Profile (DrugBank)
+|   +-- Toxicity data
+|   +-- Contraindications
+|   +-- Drug interactions affecting safety
+|
++-- PHASE 6: Chemical-Protein Interactions (STITCH)
+|   +-- Direct chemical-protein binding
+|   +-- Interaction confidence scores
+|   +-- Off-target effects
+|
++-- PHASE 7: Structural Alerts (ChEMBL)
+|   +-- Known toxic substructures (PAINS, Brenk)
+|   +-- Structural alert flags
+|
++-- SYNTHESIS: Integrated Risk Assessment
+    +-- Aggregate all evidence tiers
+    +-- Risk classification (Low/Medium/High/Critical)
+    +-- Data gaps and recommendations
+```
+
+---
+
+## Phase 0: Compound Disambiguation (ALWAYS FIRST)
+
+**CRITICAL**: Resolve compound identity before any analysis.
+
+### Input Types Handled
+
+| Input Format | Resolution Strategy |
+|-------------|---------------------|
+| Drug name (e.g., "Aspirin") | PubChem_get_CID_by_compound_name -> get SMILES from properties |
+| SMILES string | Use directly for ADMET-AI; resolve to CID for other tools |
+| PubChem CID | PubChem_get_compound_properties_by_CID -> get SMILES + name |
+| ChEMBL ID | ChEMBL_get_molecule -> get SMILES + properties |
+
+### Resolution Steps
+
+1. **Input detection**: Determine if input is name, SMILES, CID, or ChEMBL ID
+   - SMILES: contains typical SMILES characters (=, #, [, ], (, ), c, n, o and no spaces in middle)
+   - CID: numeric only
+   - ChEMBL: starts with "CHEMBL"
+   - Otherwise: treat as compound name
+2. **Name to CID**: `PubChem_get_CID_by_compound_name(name=<compound_name>)`
+3. **CID to properties**: `PubChem_get_compound_properties_by_CID(cid=<cid>)`
+4. **Extract SMILES**: Get SMILES from PubChem properties (field: `ConnectivitySMILES`, `CanonicalSMILES`, or `IsomericSMILES` depending on response format)
+5. **Store resolved IDs**: Maintain dict with `name`, `smiles`, `cid`, `formula`, `weight`, `inchi`
+
+### Disambiguation Output
+
+```markdown
+## Compound Identity
+
+| Property | Value |
+|----------|-------|
+| **Name** | Acetaminophen |
+| **PubChem CID** | 1983 |
+| **SMILES** | CC(=O)Nc1ccc(O)cc1 |
+| **Formula** | C8H9NO2 |
+| **Molecular Weight** | 151.16 |
+| **InChI** | InChI=1S/C8H9NO2/... |
+```
+
+---
+
+## Phase 1: Predictive Toxicology (ADMET-AI)
+
+**When**: SMILES is available (from Phase 0 or provided directly)
+
+**Objective**: Run comprehensive AI-predicted toxicity endpoints
+
+### Tools Used
+
+All ADMET-AI tools take the same parameter format:
+
+| Tool | Predicted Endpoints | Parameter |
+|------|---------------------|-----------|
+| `ADMETAI_predict_toxicity` | AMES, Carcinogens_Lagunin, ClinTox, DILI, LD50_Zhu, Skin_Reaction, hERG | `smiles`: list[str] |
+| `ADMETAI_predict_stress_response` | Stress response pathway activation (ARE, ATAD5, HSE, MMP, p53) | `smiles`: list[str] |
+| `ADMETAI_predict_nuclear_receptor_activity` | AhR, AR, ER, PPARg, Aromatase nuclear receptor activity | `smiles`: list[str] |
+
+### Workflow
+
+1. Call `ADMETAI_predict_toxicity(smiles=[resolved_smiles])`
+2. Call `ADMETAI_predict_stress_response(smiles=[resolved_smiles])`
+3. Call `ADMETAI_predict_nuclear_receptor_activity(smiles=[resolved_smiles])`
+4. For each endpoint, interpret prediction:
+   - Classification endpoints: Active (1) = toxic signal, Inactive (0) = no signal
+   - Regression endpoints (LD50): Report numerical value with context
+   - All predictions graded [T3] (computational prediction)
+
+### Decision Logic
+
+- **Multiple SMILES**: Can batch up to ~10 SMILES in single call
+- **Failed prediction**: If ADMET-AI fails, note "prediction unavailable" (don't fail entire report)
+- **Confidence**: Note that AI predictions are [T3] evidence, not definitive
+- **hERG flag**: If hERG = Active, flag prominently (cardiac safety risk)
+- **AMES flag**: If AMES = Active, flag prominently (mutagenicity concern)
+- **DILI flag**: If DILI = Active, flag prominently (liver toxicity concern)
+
+### Output Table
+
+```markdown
+### Toxicity Predictions [T3]
+
+| Endpoint | Prediction | Interpretation | Concern Level |
+|----------|-----------|---------------|---------------|
+| AMES Mutagenicity | Inactive | No mutagenic signal | Low |
+| Carcinogenicity | Inactive | No carcinogenic signal | Low |
+| ClinTox | Active | Clinical toxicity signal | HIGH |
+| DILI | Active | Drug-induced liver injury risk | HIGH |
+| LD50 (Zhu) | 2.45 log(mg/kg) | ~282 mg/kg (moderate) | Medium |
+| Skin Reaction | Inactive | No skin sensitization signal | Low |
+| hERG Inhibition | Active | Cardiac arrhythmia risk | HIGH |
+
+*All predictions from ADMET-AI. Evidence tier: [T3] (computational prediction)*
+```
+
+---
+
+## Phase 2: ADMET Properties
+
+**When**: SMILES is available
+
+**Objective**: Full ADMET characterization beyond toxicity
+
+### Tools Used
+
+| Tool | Properties Predicted | Parameter |
+|------|---------------------|-----------|
+| `ADMETAI_predict_BBB_penetrance` | Blood-brain barrier crossing probability | `smiles`: list[str] |
+| `ADMETAI_predict_bioavailability` | Oral bioavailability (F20%, F30%) | `smiles`: list[str] |
+| `ADMETAI_predict_clearance_distribution` | Clearance, VDss, half-life, PPB | `smiles`: list[str] |
+| `ADMETAI_predict_CYP_interactions` | CYP1A2, 2C9, 2C19, 2D6, 3A4 inhibition/substrate | `smiles`: list[str] |
+| `ADMETAI_predict_physicochemical_properties` | LogP, LogD, LogS, MW, pKa | `smiles`: list[str] |
+| `ADMETAI_predict_solubility_lipophilicity_hydration` | Aqueous solubility, lipophilicity, hydration free energy | `smiles`: list[str] |
+
+### Workflow
+
+1. Call all 6 ADMET tools in parallel (independent calls)
+2. Compile results into Absorption / Distribution / Metabolism / Excretion sections
+3. Assess Lipinski Rule of 5 compliance from physicochemical properties
+4. Flag drug-drug interaction risks from CYP inhibition profiles
+
+### Decision Logic
+
+- **BBB penetrant + toxicity**: If BBB = Yes and any CNS toxicity endpoint active, flag as neurotoxicity risk
+- **Low bioavailability**: If F20% = Low, note absorption concerns
+- **CYP inhibitor**: If CYP3A4 inhibitor = Yes, flag high DDI risk
+- **Lipinski violations**: Count violations and report drug-likeness assessment
+
+### Output Format
+
+```markdown
+### ADMET Profile [T3]
+
+#### Absorption
+| Property | Value | Interpretation |
+|----------|-------|----------------|
+| BBB Penetrance | Yes | Crosses blood-brain barrier |
+| Bioavailability (F20%) | 85% | Good oral absorption |
+
+#### Distribution
+| Property | Value | Interpretation |
+|----------|-------|----------------|
+| VDss | 1.2 L/kg | Moderate tissue distribution |
+| PPB | 92% | Highly protein bound |
+
+#### Metabolism
+| CYP Enzyme | Substrate | Inhibitor |
+|------------|-----------|-----------|
+| CYP1A2 | No | No |
+| CYP2C9 | Yes | No |
+| CYP2C19 | No | No |
+| CYP2D6 | No | No |
+| CYP3A4 | Yes | Yes (DDI risk) |
+
+#### Excretion
+| Property | Value | Interpretation |
+|----------|-------|----------------|
+| Clearance | 8.5 mL/min/kg | Moderate clearance |
+| Half-life | 6.2 h | Moderate half-life |
+```
+
+---
+
+## Phase 3: Toxicogenomics (CTD)
+
+**When**: Compound name is resolved
+
+**Objective**: Map chemical-gene-disease relationships from curated CTD data
+
+### Tools Used
+
+| Tool | Function | Parameter |
+|------|----------|-----------|
+| `CTD_get_chemical_gene_interactions` | Genes affected by chemical | `input_terms`: str (chemical name) |
+| `CTD_get_chemical_diseases` | Diseases linked to chemical exposure | `input_terms`: str (chemical name) |
+
+### Workflow
+
+1. Call `CTD_get_chemical_gene_interactions(input_terms=compound_name)`
+2. Call `CTD_get_chemical_diseases(input_terms=compound_name)`
+3. Parse gene interactions: extract gene symbols, interaction types (increases/decreases expression, binding, etc.)
+4. Parse disease associations: extract disease names, evidence types (marker/mechanism/therapeutic)
+5. Identify most affected biological processes from gene list
+
+### Decision Logic
+
+- **Direct evidence vs inferred**: CTD separates curated direct evidence from inferred associations
+- **Therapeutic vs toxic**: Disease associations can be therapeutic (drug treats disease) or adverse (chemical causes disease)
+- **Gene interaction types**: Distinguish between expression changes, binding, and activity modulation
+- **Prioritize marker/mechanism**: These indicate stronger causal evidence than simple associations
+- **Grade curated as [T2]**: Direct curated CTD evidence from literature
+- **Grade inferred as [T3]**: Computationally inferred associations
+
+### Output Format
+
+```markdown
+### Toxicogenomics (CTD) [T2/T3]
+
+#### Chemical-Gene Interactions (Top 20)
+| Gene | Interaction | Type | Evidence |
+|------|------------|------|----------|
+| CYP1A2 | increases expression | mRNA | [T2] curated |
+| TP53 | affects activity | protein | [T2] curated |
+| ...  | ... | ... | ... |
+
+**Total interactions found**: 156
+**Top affected pathways**: Xenobiotic metabolism, Apoptosis, DNA damage response
+
+#### Chemical-Disease Associations (Top 10)
+| Disease | Association Type | Evidence |
+|---------|-----------------|----------|
+| Liver Neoplasms | marker/mechanism | [T2] curated |
+| Contact Dermatitis | therapeutic | [T2] curated |
+| ... | ... | ... |
+```
+
+---
+
+## Phase 4: Regulatory Safety (FDA Labels)
+
+**When**: Compound has an approved drug name
+
+**Objective**: Extract regulatory safety information from FDA drug labels
+
+### Tools Used
+
+| Tool | Information Retrieved | Parameter |
+|------|---------------------|-----------|
+| `FDA_get_boxed_warning_info_by_drug_name` | Black box warnings (most serious) | `drug_name`: str |
+| `FDA_get_contraindications_by_drug_name` | Absolute contraindications | `drug_name`: str |
+| `FDA_get_adverse_reactions_by_drug_name` | Known adverse reactions | `drug_name`: str |
+| `FDA_get_warnings_by_drug_name` | Warnings and precautions | `drug_name`: str |
+| `FDA_get_nonclinical_toxicology_info_by_drug_name` | Animal toxicology data | `drug_name`: str |
+| `FDA_get_carcinogenic_mutagenic_fertility_by_drug_name` | Carcinogenicity/mutagenicity/fertility data | `drug_name`: str |
+
+### Workflow
+
+1. Call all 6 FDA tools in parallel (independent queries by drug name)
+2. Parse and structure each response
+3. Prioritize: Boxed Warnings > Contraindications > Warnings > Adverse Reactions
+4. All FDA label data is [T1] evidence (regulatory finding based on human/animal data)
+
+### Decision Logic
+
+- **Boxed warning present**: Flag as CRITICAL safety concern in executive summary
+- **No FDA data**: Chemical may not be an approved drug; note "Not an FDA-approved drug" and continue with other phases
+- **Multiple warnings**: Categorize by organ system (hepatic, cardiac, renal, CNS, etc.)
+- **Nonclinical toxicology**: Grade as [T2] (animal data supporting human risk)
+
+### Output Format
+
+```markdown
+### Regulatory Safety (FDA) [T1]
+
+#### Boxed Warning
+**PRESENT** - Hepatotoxicity risk with doses >4g/day. Liver failure reported. [T1]
+
+#### Contraindications
+- Severe hepatic impairment [T1]
+- Known hypersensitivity [T1]
+
+#### Adverse Reactions (by frequency)
+| Reaction | Frequency | Severity |
+|----------|-----------|----------|
+| Nausea | Common (>1%) | Mild |
+| Hepatotoxicity | Rare (<0.1%) | Severe |
+| ... | ... | ... |
+
+#### Nonclinical Toxicology [T2]
+- **Carcinogenicity**: No carcinogenic potential in 2-year rat/mouse studies
+- **Mutagenicity**: Negative in Ames assay and in vivo micronucleus test
+- **Fertility**: No effects on fertility at doses up to 10x human dose
+```
+
+---
+
+## Phase 5: Drug Safety Profile (DrugBank)
+
+**When**: Compound is a known drug
+
+**Objective**: Retrieve curated drug safety data from DrugBank
+
+### Tools Used
+
+| Tool | Information | Parameters |
+|------|------------|------------|
+| `drugbank_get_safety_by_drug_name_or_drugbank_id` | Toxicity, contraindications | `query`: str, `case_sensitive`: bool, `exact_match`: bool, `limit`: int |
+
+### Workflow
+
+1. Call `drugbank_get_safety_by_drug_name_or_drugbank_id(query=drug_name, case_sensitive=False, exact_match=False, limit=5)`
+2. Parse toxicity information, overdose data, contraindications
+3. Cross-reference with FDA data from Phase 4
+
+### Decision Logic
+
+- **Toxicity field**: Contains LD50 values, overdose symptoms, organ toxicity data
+- **DrugBank ID**: Note if found for cross-referencing
+- **Conflict with FDA**: If DrugBank and FDA disagree, note discrepancy and defer to FDA [T1]
+- **Not found**: Chemical may not be in DrugBank; continue with other phases
+
+---
+
+## Phase 6: Chemical-Protein Interactions (STITCH)
+
+**When**: Compound can be identified by name or SMILES
+
+**Objective**: Map chemical-protein interaction network for off-target assessment
+
+### Tools Used
+
+| Tool | Function | Parameters |
+|------|----------|------------|
+| `STITCH_resolve_identifier` | Resolve chemical name to STITCH ID | `identifier`: str, `species`: int (9606=human) |
+| `STITCH_get_chemical_protein_interactions` | Get chemical-protein interactions | `identifiers`: list[str], `species`: int, `required_score`: int |
+| `STITCH_get_interaction_partners` | Get interaction network | `identifiers`: list[str], `species`: int, `limit`: int |
+
+### Workflow
+
+1. Resolve compound: `STITCH_resolve_identifier(identifier=compound_name, species=9606)`
+2. Get interactions: `STITCH_get_chemical_protein_interactions(identifiers=[stitch_id], species=9606, required_score=700)`
+3. Identify off-target proteins (not the intended drug target)
+4. Flag safety-relevant targets: hERG (cardiac), CYP enzymes (metabolism), nuclear receptors (endocrine)
+
+### Decision Logic
+
+- **High confidence (>900)**: Well-established interaction [T2]
+- **Medium confidence (700-900)**: Probable interaction [T3]
+- **Low confidence (400-700)**: Possible interaction, needs validation [T4]
+- **Safety-relevant targets**: Flag interactions with known safety targets
+- **No STITCH data**: Chemical may be too novel; note and continue
+
+---
+
+## Phase 7: Structural Alerts (ChEMBL)
+
+**When**: ChEMBL molecule ID is available (from Phase 0)
+
+**Objective**: Check for known toxic substructures
+
+### Tools Used
+
+| Tool | Function | Parameters |
+|------|----------|------------|
+| `ChEMBL_search_compound_structural_alerts` | Find structural alert matches | `molecule_chembl_id`: str, `limit`: int |
+
+### Workflow
+
+1. If ChEMBL ID available: `ChEMBL_search_compound_structural_alerts(molecule_chembl_id=chembl_id, limit=20)`
+2. Parse alert types: PAINS (pan-assay interference), Brenk (medicinal chemistry), Glaxo (GSK structural alerts)
+3. Categorize severity: Some alerts are informational, others indicate likely toxicity
+
+### Decision Logic
+
+- **PAINS alerts**: May cause false positives in screening; note for medicinal chemistry
+- **Brenk alerts**: Known problematic substructures; flag if present
+- **No alerts**: Good sign but not definitive proof of safety
+- **No ChEMBL ID**: Skip this phase gracefully; note "structural alert analysis not available"
+
+---
+
+## Synthesis: Integrated Risk Assessment (MANDATORY)
+
+**Always the final section**. Integrates all evidence into actionable risk classification.
+
+### Risk Classification Matrix
+
+| Risk Level | Criteria |
+|-----------|----------|
+| **CRITICAL** | FDA boxed warning present OR multiple [T1] toxicity findings OR active DILI + active hERG |
+| **HIGH** | FDA warnings present OR [T2] animal toxicity OR multiple active ADMET endpoints |
+| **MEDIUM** | Some [T3] predictions positive OR CTD disease associations OR structural alerts |
+| **LOW** | All ADMET endpoints negative AND no FDA/DrugBank safety flags AND no CTD concerns |
+| **INSUFFICIENT DATA** | Fewer than 3 phases returned data; cannot make confident assessment |
+
+### Synthesis Template
+
+```markdown
+## Integrated Risk Assessment
+
+### Overall Risk Classification: [HIGH]
+
+### Evidence Summary
+| Dimension | Finding | Evidence Tier | Concern |
+|-----------|---------|--------------|---------|
+| ADMET Toxicity | DILI active, hERG active | [T3] | HIGH |
+| FDA Label | Boxed warning for hepatotoxicity | [T1] | CRITICAL |
+| CTD Toxicogenomics | 156 gene interactions, liver neoplasms | [T2] | HIGH |
+| DrugBank | Known hepatotoxicity at high doses | [T2] | HIGH |
+| STITCH | Binds CYP3A4, hERG | [T3] | MEDIUM |
+| Structural Alerts | 2 Brenk alerts | [T3] | MEDIUM |
+
+### Key Safety Concerns
+1. **Hepatotoxicity** [T1]: FDA boxed warning + ADMET-AI DILI prediction + CTD liver disease associations
+2. **Cardiac Risk** [T3]: ADMET-AI hERG prediction + STITCH hERG interaction
+3. **Drug Interactions** [T3]: CYP3A4 substrate/inhibitor, potential DDI risk
+
+### Data Gaps
+- [ ] No in vivo genotoxicity data available
+- [ ] STITCH interaction scores moderate (700-900)
+- [ ] No environmental exposure data
+
+### Recommendations
+1. Avoid doses >4g/day (hepatotoxicity threshold) [T1]
+2. Monitor liver function in chronic use [T1]
+3. Screen for CYP3A4 interactions before co-administration [T3]
+4. Consider cardiac monitoring for at-risk patients [T3]
+```
+
+---
+
+## Mandatory Completeness Checklist
+
+Before finalizing any report, verify:
+
+- [ ] **Phase 0**: Compound fully disambiguated (SMILES + CID at minimum)
+- [ ] **Phase 1**: At least 5 toxicity endpoints reported or "prediction unavailable" noted
+- [ ] **Phase 2**: ADMET profile with A/D/M/E sections or "not available" noted
+- [ ] **Phase 3**: CTD queried; gene interactions and disease associations reported or "no data in CTD"
+- [ ] **Phase 4**: FDA labels queried; results or "not an FDA-approved drug" noted
+- [ ] **Phase 5**: DrugBank queried; results or "not found in DrugBank" noted
+- [ ] **Phase 6**: STITCH queried; results or "no STITCH data available" noted
+- [ ] **Phase 7**: Structural alerts checked or "ChEMBL ID not available" noted
+- [ ] **Synthesis**: Risk classification provided with evidence summary
+- [ ] **Evidence Grading**: All findings have [T1]-[T4] annotations
+- [ ] **Data Gaps**: Explicitly listed in synthesis section
+
+---
+
+## Tool Parameter Reference
+
+**Critical Parameter Notes** (verified from source code):
+
+| Tool | Parameter Name | Type | Notes |
+|------|---------------|------|-------|
+| All ADMETAI tools | `smiles` | `list[str]` | Always a list, even for single compound |
+| All CTD tools | `input_terms` | `str` | Chemical name, MeSH name, CAS RN, or MeSH ID |
+| All FDA tools | `drug_name` | `str` | Brand or generic drug name |
+| drugbank_get_safety_* | `query`, `case_sensitive`, `exact_match`, `limit` | str, bool, bool, int | All 4 required |
+| STITCH_resolve_identifier | `identifier`, `species` | str, int | species=9606 for human |
+| STITCH_get_chemical_protein_interactions | `identifiers`, `species`, `required_score` | list[str], int, int | required_score=400 default |
+| PubChem_get_CID_by_compound_name | `name` | `str` | Compound name (not SMILES) |
+| PubChem_get_compound_properties_by_CID | `cid` | `int` | Numeric CID |
+| ChEMBL_search_compound_structural_alerts | `molecule_chembl_id` | `str` | ChEMBL ID (e.g., "CHEMBL112") |
+
+### Response Format Notes
+
+- **ADMET-AI**: Returns `{status: "success", data: {...}}` with prediction values
+- **CTD**: Returns list of interaction/association objects
+- **FDA**: Returns `{status, data}` with label text
+- **DrugBank**: Returns `{data: [...]}` with drug records
+- **STITCH**: Returns list of interaction objects with scores
+- **PubChem CID lookup**: Returns `{IdentifierList: {CID: [...]}}` (may or may not have `data` wrapper)
+- **PubChem properties**: Returns dict with `CID`, `MolecularWeight`, `ConnectivitySMILES`, `IUPACName`
+
+---
+
+## Fallback Strategies
+
+### Compound Resolution
+- **Primary**: PubChem by name -> CID -> properties -> SMILES
+- **Fallback 1**: ChEMBL search by name -> molecule -> SMILES
+- **Fallback 2**: If SMILES provided directly, skip name resolution
+
+### Toxicity Prediction
+- **Primary**: All 9 ADMET-AI endpoints
+- **Fallback**: If ADMET-AI fails for a compound, note "prediction failed" and continue with database evidence
+- **Note**: ADMET-AI may fail for very large or unusual SMILES
+
+### Regulatory Data
+- **Primary**: FDA labels by drug name
+- **Fallback**: If FDA returns no data, try alternative drug names (brand vs generic)
+- **Note**: Non-drug chemicals (pesticides, industrial) will not have FDA labels
+
+### CTD Data
+- **Primary**: Search by common chemical name
+- **Fallback**: Try MeSH name if common name fails
+- **Note**: Novel compounds may not be in CTD
+
+---
+
+## Common Use Patterns
+
+### Pattern 1: Novel Compound Assessment
+```
+Input: SMILES string for new molecule
+Workflow: Phase 0 (SMILES->CID) -> Phase 1 (toxicity) -> Phase 2 (ADMET) -> Phase 7 (structural alerts) -> Synthesis
+Output: Predictive safety profile for novel compound
+```
+
+### Pattern 2: Approved Drug Safety Review
+```
+Input: Drug name (e.g., "Acetaminophen")
+Workflow: All phases (0-7 + Synthesis)
+Output: Complete safety dossier with regulatory + predictive + database evidence
+```
+
+### Pattern 3: Environmental Chemical Risk
+```
+Input: Chemical name (e.g., "Bisphenol A")
+Workflow: Phase 0 -> Phase 1 -> Phase 2 -> Phase 3 (CTD, key for env chemicals) -> Phase 6 -> Synthesis
+Output: Environmental health risk assessment focused on gene-disease associations
+```
+
+### Pattern 4: Batch Toxicity Screening
+```
+Input: Multiple SMILES strings
+Workflow: Phase 0 -> Phase 1 (batch) -> Phase 2 (batch) -> Comparative table -> Synthesis
+Output: Comparative toxicity table ranking compounds by safety
+```
+
+### Pattern 5: Toxicogenomic Deep-Dive
+```
+Input: Chemical name + specific gene or disease interest
+Workflow: Phase 0 -> Phase 3 (CTD expanded) -> Literature search -> Synthesis
+Output: Detailed chemical-gene-disease mechanistic analysis
+```
+
+---
+
+## Output Report Structure
+
+All analyses generate a structured markdown report with progressive sections:
+
+```markdown
+# Chemical Safety & Toxicology Report: [Compound Name]
+
+**Generated**: YYYY-MM-DD HH:MM
+**Compound**: [Name] | SMILES: [SMILES] | CID: [CID]
+
+## Executive Summary
+[2-3 sentence overview with risk classification and key findings, all graded]
+
+## 1. Compound Identity
+[Phase 0 results - disambiguation table]
+
+## 2. Predictive Toxicology
+[Phase 1 results - ADMET-AI toxicity endpoints]
+
+## 3. ADMET Profile
+[Phase 2 results - absorption, distribution, metabolism, excretion]
+
+## 4. Toxicogenomics
+[Phase 3 results - CTD chemical-gene-disease relationships]
+
+## 5. Regulatory Safety
+[Phase 4 results - FDA label information]
+
+## 6. Drug Safety Profile
+[Phase 5 results - DrugBank data]
+
+## 7. Chemical-Protein Interactions
+[Phase 6 results - STITCH network]
+
+## 8. Structural Alerts
+[Phase 7 results - ChEMBL alerts]
+
+## 9. Integrated Risk Assessment
+[Synthesis - risk classification, evidence summary, data gaps, recommendations]
+
+## Appendix: Methods and Data Sources
+[Tool versions, databases queried, date of access]
+```
+
+---
+
+## Limitations & Known Issues
+
+### Tool-Specific
+- **ADMET-AI**: Predictions are computational [T3]; should not replace experimental testing
+- **CTD**: Curated but may lag behind latest literature by 6-12 months
+- **FDA**: Only covers FDA-approved drugs; not applicable to environmental chemicals or supplements
+- **DrugBank**: Primarily drugs; limited coverage of industrial chemicals
+- **STITCH**: Score thresholds affect sensitivity; lower scores increase false positives
+- **ChEMBL**: Structural alerts require ChEMBL ID; not all compounds have one
+
+### Analysis
+- **Novel compounds**: May only have ADMET-AI predictions (no database evidence)
+- **Environmental chemicals**: FDA/DrugBank phases will be empty; rely on CTD and ADMET-AI
+- **Batch mode**: ADMET-AI can handle batches; other tools require individual queries
+- **Species specificity**: Most data is human-centric; animal data noted where applicable
+
+### Technical
+- **SMILES validity**: Invalid SMILES will cause ADMET-AI failures
+- **Name ambiguity**: Chemical names can be ambiguous; always verify with CID
+- **Rate limits**: Some FDA endpoints may rate-limit for rapid queries
+
+---
+
+## Summary
+
+**Chemical Safety & Toxicology Assessment Skill** provides comprehensive safety evaluation by integrating:
+
+1. **Predictive toxicology** (ADMET-AI) - 9 tools covering toxicity, ADMET, physicochemical properties
+2. **Toxicogenomics** (CTD) - Chemical-gene-disease relationship mapping
+3. **Regulatory safety** (FDA) - 6 tools for label-based safety extraction
+4. **Drug safety** (DrugBank) - Curated toxicity and contraindication data
+5. **Chemical interactions** (STITCH) - Chemical-protein interaction networks
+6. **Structural alerts** (ChEMBL) - Known toxic substructure detection
+
+**Outputs**: Structured markdown report with risk classification, evidence grading, and actionable recommendations
+
+**Best for**: Drug safety assessment, chemical hazard profiling, environmental toxicology, ADMET characterization, toxicogenomic analysis
+
+**Total tools integrated**: 25+ tools across 6 databases