tooluniverse-toxicology

Toxicology Assessment via Adverse Outcome Pathways & Signal Detection

Systematic toxicology analysis that links molecular initiating events (MIEs) through adverse outcome pathways (AOPs) to apical adverse outcomes, then triangulates with real-world FAERS signals, FDA label data, and toxicogenomic associations.

Domain Reasoning

Toxicity has many mechanisms, and the first interpretive question is temporal: is this acute toxicity (immediate effect from a high dose) or chronic toxicity (cumulative damage from long-term low-dose exposure)? Acute and chronic toxicity operate through different mechanisms — acute hepatotoxicity may reflect direct mitochondrial damage, while chronic hepatotoxicity may involve fibrosis from repeated low-level inflammation. They also have different regulatory frameworks: acute toxicity is captured by LD50 and emergency protocols, while chronic toxicity requires long-term carcinogenicity and repeat-dose studies.

LOOK UP DON'T GUESS

• Adverse outcome pathways for a chemical: query AOPWiki_list_aops and AOPWiki_get_aop; do not describe mechanisms from memory.
• FAERS adverse event signals: retrieve from FAERS_count_reactions_by_drug_event and FAERS_calculate_disproportionality; never estimate PRR values.
• FDA label warnings: call DailyMed_parse_adverse_reactions and related tools; do not state boxed warnings from memory.
• CTD chemical-gene and chemical-disease associations: query CTD_get_chemical_gene_interactions and CTD_get_chemical_diseases; do not infer gene targets without database evidence.
• EPA CompTox hazard values and ToxCast/Tox21 bioactivity: query CompTox_get_hazard_data and CompTox_get_bioactivity_summary/CompTox_get_bioactivity_assays; never estimate an LD50, a hazard classification, or an assay hit-call rate from memory — this is exactly the kind of chemical-specific quantitative data that must come from the database.

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COMPUTE, DON'T DESCRIBE

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

When to Use This Skill

Triggers:

• "What are the toxicity mechanisms for [drug/chemical]?"
• "Find adverse outcome pathways for [chemical]"
• "What AOPs are relevant to [target/organ/effect]?"
• "FAERS signal analysis for [drug]"
• "Toxicogenomic profile for [chemical]"
• "What is the mechanism of hepatotoxicity / cardiotoxicity / neurotoxicity for [drug]?"

Use Cases:

1. AOP Tracing: Map chemical MIE through key events to apical outcome using AOPWiki
2. Real-World Signal Detection: Quantify FAERS adverse event signals with PRR/ROR
3. Label Safety Mining: Extract FDA boxed warnings, contraindications, nonclinical toxicology
4. Toxicogenomics: Chemical-gene-disease associations from CTD
5. Integrated Mechanism Report: Combine AOP pathway + real-world signals into unified narrative

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KEY PRINCIPLES

1. AOP-first thinking - Frame all toxicity in terms of MIE → Key Events → Adverse Outcome
2. Report-first approach - Create report file FIRST, update progressively
3. Evidence grading mandatory - T1 (regulatory/clinical) through T4 (computational/AOP annotation)
4. Distinguish mechanism from signal - AOPWiki = mechanism; FAERS = real-world signal
5. Disambiguation first - Resolve drug/chemical identity before any queries
6. English-first queries - Always use English names in tool calls

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Evidence Grading

Tier	Symbol	Criteria
T1	[T1]	FDA boxed warning, clinical trial toxicity finding, regulatory label
T2	[T2]	FAERS signal PRR > 2, AOP with high biological plausibility, CTD curated
T3	[T3]	CTD inferred association, AOP annotation with moderate plausibility, screening-level CompTox ToxVal
T4	[T4]	Text-mined CTD entry, early-stage AOP annotation, isolated ToxCast/Tox21 assay hit with no cross-source corroboration

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Workflow Overview

Chemical/Drug Query
|
+-- PHASE 0: Disambiguation
|   Resolve name -> identifiers (ChEMBL, PubChem CID, SMILES)
|
+-- PHASE 1: Adverse Outcome Pathway Mapping (AOPWiki)
|   List AOPs by keyword; retrieve key events, MIEs, and biological plausibility scores
|
+-- PHASE 2: Real-World Adverse Event Signals (FAERS)
|   Top reactions by drug; disproportionality (PRR); serious event filter
|
+-- PHASE 3: FDA Label Safety Mining
|   Boxed warnings, contraindications, nonclinical toxicology, adverse reactions
|
+-- PHASE 4: Toxicogenomics (CTD)
|   Chemical-gene interactions; chemical-disease associations
|
+-- PHASE 4c: Quantitative Hazard & HTS Bioactivity (EPA CompTox)
|   Curated dose-based hazard values (ToxVal); ToxCast/Tox21 assay hit rates
|
+-- SYNTHESIS: Integrated Toxicology Report
    AOP-linked mechanism + FAERS signal + CTD gene targets + Risk classification

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Phase 0: Disambiguation

Objective: Establish compound identity before any database queries.

Tools:

• PubChem_get_CID_by_compound_name (name: str) — get CID + SMILES
• ChEMBL_search_drugs (query: str) — get ChEMBL ID and max phase

Capture: generic name, SMILES, PubChem CID, ChEMBL ID, drug class.

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Phase 1: Adverse Outcome Pathway Mapping

Objective: Find AOPs relevant to the chemical's known or suspected toxicity mechanisms.

Tools

AOPWiki_list_aops:

• Input: keyword (str) — e.g., organ ("liver", "kidney"), effect ("apoptosis", "inflammation"), or target ("AhR", "PPARalpha")
• Output: List of AOP IDs, titles, and short descriptions
• Use: Discovery scan to identify candidate AOPs

AOPWiki_get_aop:

• Input: aop_id (int) — ID from list_aops result
• Output: Full AOP details including MIE, key events (KEs), key event relationships (KERs), biological plausibility, and weight-of-evidence
• Use: Retrieve mechanistic pathway details for selected AOPs

Workflow

1. Query AOPWiki_list_aops with organ-level keyword (e.g., "hepatotoxicity", "nephrotoxicity")
2. Query again with mechanism-level keyword (e.g., "oxidative stress", "mitochondria")
3. Select top 3-5 most relevant AOPs by title relevance
4. Call AOPWiki_get_aop for each selected AOP
5. Extract: MIE (molecular initiating event), key events in order, apical adverse outcome, biological plausibility score

Decision Logic

• AOP found: Extract full pathway; note plausibility level (high/moderate/low)
• No direct AOP match: Try broader organ or mechanism terms; document as "no AOP directly mapped"
• Multiple AOPs: Report all; highlight shared key events as high-confidence mechanisms

AOP Table Format

AOP ID	Title	MIE	Apical Outcome	Plausibility
123	...	...	...	High

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Phase 2: Real-World Adverse Event Signals (FAERS)

Objective: Quantify observed adverse events with statistical signal measures.

Tools

FAERS_count_reactions_by_drug_event:

• Input: drug_name (str), limit (int, default 50)
• Output: Top adverse reactions with counts
• Note: param is drug_name not drug

FAERS_calculate_disproportionality:

• Input: drug_name (str), reaction_meddra_pt (str)
• Output: PRR, ROR, IC with confidence intervals

FAERS_filter_serious_events:

• Input: drug_name (str), serious_type (str: "death", "hospitalization", "life-threatening")
• Output: Serious event count and case details

FAERS_stratify_by_demographics:

• Input: drug_name (str), reaction_meddra_pt (str)
• Output: Age/sex breakdown for specific reaction

Workflow

1. Get top 25 reactions via FAERS_count_reactions_by_drug_event
2. Filter to organ-system clusters matching the AOP outcomes from Phase 1
3. Calculate PRR for top 10 reactions via FAERS_calculate_disproportionality
4. Check serious events (deaths, hospitalizations) for highest-PRR reactions

Signal Thresholds

Signal Strength	PRR	Case Count
Strong	> 3.0	>= 5
Moderate	2.0-3.0	>= 3
Weak	1.5-2.0	>= 3
None	< 1.5	any

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Phase 3: FDA Label Safety Mining

Objective: Extract regulatory safety findings from approved drug labels.

Tools

• DailyMed_parse_adverse_reactions (drug_name: str)
• DailyMed_parse_contraindications (drug_name: str)
• DailyMed_parse_clinical_pharmacology (drug_name: str)
• DailyMed_parse_drug_interactions (drug_name: str)

Note: These tools apply to FDA-approved drugs only. Environmental chemicals will have no label data — document explicitly.

Workflow

1. Extract adverse reactions and note which match FAERS signals
2. Extract contraindications (highest evidence tier [T1])
3. Note pharmacological mechanism from clinical pharmacology section

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Phase 4: Toxicogenomics (CTD)

Objective: Map chemical-gene interactions and chemical-disease associations.

Tools

CTD_get_chemical_gene_interactions:

• Input: input_terms (str) — chemical name or MeSH ID
• Output: Gene targets with interaction type (increases/decreases expression)
• Use: Find molecular targets mediating toxicity

CTD_get_chemical_diseases:

• Input: input_terms (str) — chemical name or MeSH ID
• Output: Disease associations with evidence type (curated/inferred)
• Use: Find downstream disease endpoints

Workflow

1. Query CTD with compound name; note curated (higher confidence) vs inferred entries
2. Cross-reference gene targets with Phase 1 AOP key events
3. Note which CTD disease endpoints match AOP apical outcomes

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Phase 4c: Quantitative Hazard & HTS Bioactivity (EPA CompTox)

Objective: Get curated, dose-based hazard values and quantitative high-throughput screening (HTS) bioactivity data — the kind of numeric, assay-level evidence AOPWiki (mechanism) and FAERS (real-world signal) don't provide.

Requires EPA_COMPTOX_API_KEY (free; request by emailing ccte_api@epa.gov). Without the key, these tools are excluded from tu list entirely (same gating pattern as Addgene/USPTO) rather than failing loudly — check for their presence before relying on this phase.

Tools

CompTox_search_chemical (word: str — name, CASRN, or InChIKey):

• Output: Matching dtxsid/dtxcid/casrn/preferredName records
• Use: Resolve chemical identity to a DTXSID — required input for every other CompTox call. Run this immediately after Phase 0's PubChem/ChEMBL disambiguation; DTXSID is a separate identifier space from PubChem CID / ChEMBL ID.

CompTox_get_hazard_data (dtxsid: str):

• Output: ToxVal records — points of departure (NOAEL/LOAEL/BMDL), lethality effect levels (LD50/LC50), reference doses, exposure limits, each tagged with source, species, and study type
• Use: The quantitative dose-response counterpart to AOPWiki's qualitative mechanism and DailyMed's label text — grade as T1/T2 per source (regulatory sources like EPA IRIS/ECOTOX rank higher than screening-level estimates; check the source field per record)

CompTox_get_bioactivity_summary (dtxsid: str):

• Output: Aggregate ToxCast/Tox21 hit counts (activeMc/totalMc, activeSc/totalSc) and cytotoxicity burst point (cytotoxMedianUm)
• Use: A fast "how promiscuous and how cytotoxic does this chemical look across ~700+ HTS assays" check before deciding whether per-assay drill-down is worth it

CompTox_get_bioactivity_assays (dtxsid: str):

• Output: Per-assay hit-call records (aeid, hitCall, ac50) — which specific biological targets/pathways the chemical activated
• Use: Drill into which assay endpoints (aeid) drove the summary hit count; cross-reference specific aeids against Phase 1's AOP key events when a mechanistic link is claimed — do not assume an HTS hit implies the AOP mechanism without checking the assay's actual target

Workflow

1. CompTox_search_chemical on the compound name to get its DTXSID
2. CompTox_get_hazard_data for curated dose-based hazard values; note source/species per record
3. CompTox_get_bioactivity_summary for the HTS overview; if activeMc/totalMc shows meaningful activity, drill into CompTox_get_bioactivity_assays
4. Cross-reference high-hit-rate assay targets against Phase 1's AOP key events and Phase 4's CTD gene targets — convergent evidence across three independent sources (AOP mechanism, CTD gene interaction, ToxCast assay target) is much stronger than any one alone

Decision Logic

• No DTXSID match: The compound may not be in the CompTox universe (common for very new drugs or non-registered mixtures) — document as "not in CompTox" rather than treating it as zero hazard
• Hazard records but no bioactivity: Chemical has traditional tox study data but hasn't been through ToxCast/Tox21 screening — do not infer bioactivity from hazard data or vice versa, they measure different things
• High assay hit rate with low cytotoxMedianUm: A large fraction of "hits" may just reflect general cytotoxicity (cell stress triggers many unrelated assays) rather than a specific mechanism — check whether hit aeids cluster around one pathway or are scattered, and flag a low cytotoxicity burst point as a reason to discount isolated hits

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Phase 4b: Toxin Reference Lookup (T3DB) — currently broken upstream, verified

Objective: Cross-reference a chemical/toxin against T3DB's curated toxin profiles (mechanism of toxicity, health effects, routes of exposure) via T3DB_search_toxins (query: str) and T3DB_get_toxin (toxin_id: str, e.g. T3D0001).

Live-verified status: both tools currently fail with HTTP 403 on every attempt (confirmed on multiple retries, both the search endpoint and a direct get_toxin call by known ID) — t3db.ca appears to be blocking the underlying request pattern entirely, not a transient outage tied to a specific query. Do not fabricate a toxin profile, mechanism, or health-effect list if this 403s — report T3DB as unavailable and fall back to CTD (Phase 4) and AOPWiki (Phase 1) for mechanistic toxicology instead, or DailyMed (Phase 3) if the chemical is also an FDA-approved drug. Re-check T3DB's live status with a cheap call before assuming this is still broken — it may be fixed by the time you read this.

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Synthesis: Integrated Toxicology Report

Structure:

# Toxicology Report: [Compound Name]
**Generated**: YYYY-MM-DD

## Executive Summary
Risk tier: CRITICAL / HIGH / MEDIUM / LOW / INSUFFICIENT DATA
Key finding summary (2-3 sentences)

## 1. Compound Identity
(disambiguation table)

## 2. Adverse Outcome Pathways [T3-T4]
(AOP table; pathway diagrams in text form)

## 3. Real-World Adverse Event Signals [T1-T2]
(FAERS top reactions + PRR table + serious events)

## 4. FDA Label Safety [T1]
(boxed warnings, contraindications, adverse reactions)

## 5. Toxicogenomics [T2-T4]
(CTD gene targets + disease associations)

## 6. Mechanistic Integration
(How AOP key events map to observed FAERS signals and CTD gene targets)

## 7. Risk Classification
(Final tier with rationale)

## Data Gaps & Limitations
(Missing data, confidence caveats)

Risk Classification

Tier	Criteria
CRITICAL	FDA boxed warning OR FAERS PRR > 5 with deaths OR multiple T1 findings
HIGH	FAERS PRR 3-5 serious events OR FDA warning (non-boxed) OR high-plausibility AOP
MEDIUM	FAERS PRR 2-3 OR CTD curated associations OR moderate-plausibility AOP
LOW	All signals < PRR 2; no regulatory warnings; low-plausibility AOP only
INSUFFICIENT DATA	Fewer than 3 phases returned usable data

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Fallback Chains

Primary Tool	Fallback 1	Fallback 2
AOPWiki_list_aops	Broaden keyword	Search by organ system
FAERS_count_reactions_by_drug_event	OpenFDA_search_drug_events	Literature search
DailyMed_parse_adverse_reactions	OpenFDA_search_drug_events	FAERS serious events
CTD_get_chemical_diseases	CTD_get_chemical_gene_interactions	PubMed search
CompTox_get_hazard_data	CTD_get_chemical_diseases	AOPWiki apical outcome only

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Tool Parameter Reference (Critical)

Tool	WRONG	CORRECT
FAERS_count_reactions_by_drug_event	drug	drug_name
AOPWiki_list_aops	query	keyword
CTD_get_chemical_gene_interactions	chemical	input_terms
CTD_get_chemical_diseases	chemical	input_terms

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Limitations

• AOPWiki: AOPs are in development; many lack high plausibility scores
• FAERS: Observational data; confounding by indication; underreporting bias
• CTD: Inferred associations have high false-positive rate
• T3DB: Both tools verified returning HTTP 403 as of this writing (upstream request-blocking, not a per-query issue) — treat as unavailable until re-verified live
• EPA CompTox: requires a free API key (EPA_COMPTOX_API_KEY, request via ccte_api@epa.gov) — schemas verified against the live production OpenAPI specs, but full response shapes were not live-tested end-to-end in this environment since no real key was available; DTXSID coverage skews toward chemicals with US regulatory/environmental relevance and may be sparse for newer or purely investigational drugs
• DailyMed: FDA-approved drugs only; no environmental chemical coverage
• Environmental chemicals: Primarily Phase 1 (AOP) + Phase 4 (CTD) data available
• Food additive/ingredient identity: This skill assesses a chemical's toxicity once you know what it is; it does not look up which foods/products actually contain a given additive or allergen, or a product's nutrient/ingredient label — for that, use tooluniverse-nutrition-food-composition (USDA FoodData Central, Open Food Facts) first, then bring the additive's identity here for hazard assessment

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References

• AOPWiki: https://aopwiki.org
• FAERS: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers
• CTD: http://ctdbase.org
• DailyMed: https://dailymed.nlm.nih.gov
• OpenFDA: https://open.fda.gov
• EPA CompTox: https://comptox.epa.gov/dashboard/ (API docs: https://comptox.epa.gov/ctx-api/docs/)