Chemical Safety & Toxicology Assessment

Comprehensive chemical safety analysis integrating predictive AI models, curated toxicogenomics databases, regulatory safety data, and chemical-biological interaction networks.

When to Use This Skill

Triggers:

• "Is this chemical toxic?" / "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?"
• "Drug safety assessment" / "Environmental health risk" / "Chemical hazard profiling"

Use Cases:

1. Predictive Toxicology: AI-predicted endpoints (AMES, DILI, LD50, carcinogenicity, hERG) via SMILES
2. ADMET Profiling: Absorption, distribution, metabolism, excretion, toxicity
3. Toxicogenomics: Chemical-gene-disease mapping from CTD
4. Regulatory Safety: FDA label warnings, contraindications, adverse reactions
5. Drug Safety: DrugBank safety + FDA labels combined
6. Chemical-Protein Interactions: STITCH-based interaction networks
7. Environmental Toxicology: Chemical-disease associations for contaminants

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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 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

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Evidence Grading System (MANDATORY)

Tier	Symbol	Criteria	Examples
T1	[T1]	Direct human evidence, regulatory finding	FDA boxed warning, clinical trial toxicity
T2	[T2]	Animal studies, validated in vitro	Nonclinical toxicology, AMES positive, animal LD50
T3	[T3]	Computational prediction, association data	ADMET-AI prediction, CTD association
T4	[T4]	Database annotation, text-mined	Literature mention, unvalidated database entry

Evidence grades MUST appear in: Executive Summary, Toxicity Predictions, Regulatory Safety, Chemical-Gene Interactions, Risk Assessment.

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Core Strategy: 8 Research Phases

Chemical/Drug Query
|
+-- PHASE 0: Compound Disambiguation (ALWAYS FIRST)
|   Resolve name -> SMILES, PubChem CID, ChEMBL ID, formula, weight
|
+-- PHASE 1: Predictive Toxicology (ADMET-AI)
|   AMES, DILI, ClinTox, carcinogenicity, LD50, hERG, skin reaction
|   Stress response pathways, nuclear receptor activity
|
+-- PHASE 2: ADMET Properties
|   BBB penetrance, bioavailability, clearance, CYP interactions, physicochemical
|
+-- PHASE 3: Toxicogenomics (CTD)
|   Chemical-gene interactions, chemical-disease associations
|
+-- PHASE 4: Regulatory Safety (FDA Labels)
|   Boxed warnings, contraindications, adverse reactions, nonclinical tox
|
+-- PHASE 5: Drug Safety Profile (DrugBank)
|   Toxicity data, contraindications, drug interactions
|
+-- PHASE 6: Chemical-Protein Interactions (STITCH)
|   Direct binding, off-target effects, interaction confidence
|
+-- PHASE 7: Structural Alerts (ChEMBL)
|   PAINS, Brenk, Glaxo structural alerts
|
+-- SYNTHESIS: Integrated Risk Assessment
    Risk classification, evidence summary, data gaps, recommendations

See phase-procedures-detailed.md for complete tool parameters, decision logic, output templates, and fallback strategies for each phase.

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Tool Summary by Phase

Phase 0: Compound Disambiguation

• PubChem_get_CID_by_compound_name (name: str)
• PubChem_get_compound_properties_by_CID (cid: int)
• ChEMBL_get_molecule (if ChEMBL ID available)

Phase 1: Predictive Toxicology

• ADMETAI_predict_toxicity (smiles: list[str]) - AMES, DILI, ClinTox, LD50, hERG, etc.
• ADMETAI_predict_stress_response (smiles: list[str])
• ADMETAI_predict_nuclear_receptor_activity (smiles: list[str])

Phase 2: ADMET Properties

• ADMETAI_predict_BBB_penetrance / _bioavailability / _clearance_distribution / _CYP_interactions / _physicochemical_properties / _solubility_lipophilicity_hydration (all take smiles: list[str])

Phase 3: Toxicogenomics

• CTD_get_chemical_gene_interactions (input_terms: str)
• CTD_get_chemical_diseases (input_terms: str)

Phase 4: Regulatory Safety

• FDA_get_boxed_warning_info_by_drug_name / _contraindications_ / _adverse_reactions_ / _warnings_ / _nonclinical_toxicology_ / _carcinogenic_mutagenic_fertility_ (all take drug_name: str)

Phase 5: Drug Safety

• drugbank_get_safety_by_drug_name_or_drugbank_id (query, case_sensitive, exact_match, limit - all 4 required)

Phase 6: Chemical-Protein Interactions

• STITCH_resolve_identifier (identifier: str, species: 9606)
• STITCH_get_chemical_protein_interactions (identifiers: list[str], species: int, required_score: int)

Phase 7: Structural Alerts

• ChEMBL_search_compound_structural_alerts (molecule_chembl_id: str)

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Risk Classification Matrix

Risk Level	Criteria
CRITICAL	FDA boxed warning OR multiple [T1] toxicity findings OR active DILI + active hERG
HIGH	FDA warnings 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 flags AND no CTD concerns
INSUFFICIENT DATA	Fewer than 3 phases returned data

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Report Structure

# Chemical Safety & Toxicology Report: [Compound Name]
**Generated**: YYYY-MM-DD | **SMILES**: [...] | **CID**: [...]

## Executive Summary (risk classification + key findings, all graded)
## 1. Compound Identity (disambiguation table)
## 2. Predictive Toxicology (ADMET-AI endpoints)
## 3. ADMET Profile (absorption, distribution, metabolism, excretion)
## 4. Toxicogenomics (CTD chemical-gene-disease)
## 5. Regulatory Safety (FDA label data)
## 6. Drug Safety Profile (DrugBank)
## 7. Chemical-Protein Interactions (STITCH network)
## 8. Structural Alerts (ChEMBL)
## 9. Integrated Risk Assessment (classification, evidence summary, gaps, recommendations)
## Appendix: Methods and Data Sources

See report-templates.md for full section templates with example tables.

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Mandatory Completeness Checklist

• Phase 0: Compound disambiguated (SMILES + CID minimum)
• Phase 1: At least 5 toxicity endpoints or "prediction unavailable"
• Phase 2: ADMET A/D/M/E sections or "not available"
• Phase 3: CTD queried; results or "no data in CTD"
• Phase 4: FDA labels queried; results or "not FDA-approved"
• Phase 5: DrugBank queried; results or "not found"
• Phase 6: STITCH queried; results or "no data available"
• Phase 7: Structural alerts checked or "ChEMBL ID not available"
• Synthesis: Risk classification with evidence summary
• Evidence Grading: All findings have [T1]-[T4] annotations
• Data Gaps: Explicitly listed

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Common Use Patterns

1. Novel Compound: SMILES -> Phase 0 (resolve) -> Phase 1 (toxicity) -> Phase 2 (ADMET) -> Phase 7 (structural alerts) -> Synthesis
2. Approved Drug Review: Drug name -> All phases (0-7) -> Complete safety dossier
3. Environmental Chemical: Chemical name -> Phase 0 -> Phase 1-2 -> Phase 3 (CTD, key) -> Phase 6 (STITCH) -> Synthesis
4. Batch Screening: Multiple SMILES -> Phase 0 -> Phase 1-2 (batch) -> Comparative table -> Synthesis
5. Toxicogenomic Deep-Dive: Chemical + gene/disease interest -> Phase 0 -> Phase 3 (expanded CTD) -> Literature -> Synthesis

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Limitations

• ADMET-AI: Computational [T3]; should not replace experimental testing
• CTD: May lag behind latest literature by 6-12 months
• FDA: Only covers FDA-approved drugs; not applicable to environmental chemicals
• DrugBank: Primarily drugs; limited industrial chemical coverage
• STITCH: Lower score thresholds increase false positives
• ChEMBL: Structural alerts require ChEMBL ID; not all compounds have one
• Novel compounds: May only have ADMET-AI predictions (no database evidence)
• SMILES validity: Invalid SMILES cause ADMET-AI failures

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Reference Files

• phase-procedures-detailed.md - Complete tool parameters, decision logic, output templates, fallback strategies per phase
• evidence-grading.md - Evidence grading details and examples
• report-templates.md - Full report section templates with example tables
• phase-details.md - Additional phase context
• test_skill.py - Test suite

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Summary

Total tools integrated: 25+ tools across 6 databases (ADMET-AI, CTD, FDA, DrugBank, STITCH, ChEMBL)

Best for: Drug safety assessment, chemical hazard profiling, environmental toxicology, ADMET characterization, toxicogenomic analysis

Outputs: Structured markdown report with risk classification (Critical/High/Medium/Low), evidence grading [T1-T4], and actionable recommendations