tooluniverse-adverse-outcome-pathway

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Adverse Outcome Pathway & Regulatory Risk Assessment

不良结局路径（AOP）与监管风险评估

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.

与药物安全性不同（参见tooluniverse-toxicology）：本技能针对环境与工业化学品，核心内容为AOP应激源映射、GHS分类、LD50危害量化及IARC致癌物状态——而非FAERS信号或FDA药物标签。

When to Use

适用场景

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.

当研究人员询问以下问题时适用：

"[农药/溶剂/工业化学品]关联哪些AOP？"
"[化合物]的GHS危害分类是什么？"
"[化合物]的LD50数值是多少？"
"[化合物]是否为致癌物（IARC分类）？"
"[化学品]与哪些基因存在相互作用（CTD）？"
"[环境化学品]的监管风险评估"
"[化学品]暴露会引发哪些疾病？"

请勿将其用于带有FAERS数据的FDA获批药物——请改用

tooluniverse-toxicology

。

Key Tools

核心工具

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`

工具	用途	关键参数
`AOPWiki_list_aops`	通过关键词发现AOP	`keyword` （器官、效应或靶点名称）
`AOPWiki_get_aop`	获取完整AOP详情：MIE、关键事件、应激源	`aop_id` （整数）
`PubChemTox_get_toxicity_summary`	毒理学概述说明	`cid` （PubChem CID）
`PubChemTox_get_ghs_classification`	GHS危害类别 + 象形图	`cid`
`PubChemTox_get_carcinogen_classification`	IARC/NTP/EPA致癌物状态	`cid`
`PubChemTox_get_toxicity_values`	不同暴露途径与物种的LD50/LC50	`cid`
`PubChemTox_get_acute_effects`	急性暴露的体征与症状	`cid`
`CTD_get_chemical_gene_interactions`	化学品-基因分子相互作用	`input_terms` （名称或MeSH ID）
`CTD_get_chemical_diseases`	化学品-疾病关联	`input_terms`
`PubChem_get_CID_by_compound_name`	将化合物名称转换为PubChem CID	`name`

Workflow

工作流程

Phase 1: Compound Identity Resolution

阶段1：化合物身份解析

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.

在调用所有PubChemTox工具前，需将化学品名称解析为PubChem CID。

PubChem_get_CID_by_compound_name(name="benzo[a]pyrene")
-> cid: 9153（用于所有PubChemTox调用）

注意：CTD工具可直接接受化学品名称作为

input_terms

参数——无需CID。

Phase 2: AOP Discovery

阶段2：AOP发现

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

通过搜索器官靶点和机制关键词找到相关AOP。

AOPWiki_list_aops(keyword="lung")          # 器官层面
AOPWiki_list_aops(keyword="DNA damage")    # 机制层面
AOPWiki_list_aops(keyword="AhR")           # 受体层面

从结果中选择2-4个候选AOP，然后获取完整详情：

AOPWiki_get_aop(aop_id=58)  # 返回MIE、关键事件、应激源、生物学合理性

AOPWiki_get_aop

响应中的关键字段：

```
stressors
```
: 触发该AOP的化学品列表（检查查询化合物是否在列）
```
molecular_initiating_event
```
: 首个分子扰动事件
```
key_events
```
: 有序的生物学事件链
```
adverse_outcome
```
: 顶端监管终点

Phase 3: Hazard Quantification (PubChemTox)

阶段3：危害量化（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.

使用解析得到的CID并行运行以下四项危害查询：

PubChemTox_get_ghs_classification(cid=9153)        # GHS类别 + 象形图
PubChemTox_get_carcinogen_classification(cid=9153)  # IARC第1/2A/2B/3组
PubChemTox_get_toxicity_values(cid=9153)            # 不同途径/物种的LD50
PubChemTox_get_acute_effects(cid=9153)              # 体征/症状

注意：

PubChemTox_get_target_organs

有时无数据返回——视为可选工具。

Phase 4: Toxicogenomics (CTD)

阶段4：毒理基因组学（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.

将化学品映射至基因靶点及疾病关联：

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

将CTD基因靶点与阶段2中AOP的关键事件基因进行交叉验证。

Tool Parameter Reference

工具参数参考

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

工具	必填参数	可选参数	说明
`AOPWiki_list_aops`	`keyword`	—	使用器官（如"liver"）、效应（如"apoptosis"）或受体（如"PPARalpha"）作为关键词
`AOPWiki_get_aop`	`aop_id`	—	来自list_aops输出的整数ID
`PubChemTox_get_toxicity_summary`	`cid`	—	PubChem CID整数
`PubChemTox_get_ghs_classification`	`cid`	—	返回象形图标签，例如"Health Hazard"
`PubChemTox_get_carcinogen_classification`	`cid`	—	IARC分组信息位于 `classifications[].classification`
`PubChemTox_get_toxicity_values`	`cid`	—	返回数值，例如"LD50 Rat oral 2400 mg/kg"
`PubChemTox_get_acute_effects`	`cid`	—	数据有时较为匮乏；并非所有化合物都有相关数据
`CTD_get_chemical_gene_interactions`	`input_terms`	—	接受名称或MeSH ID（例如"D001564"）
`CTD_get_chemical_diseases`	`input_terms`	—	可筛选 `DirectEvidence` = "marker/mechanism"以获取经过整理的数据
`PubChem_get_CID_by_compound_name`	`name`	—	返回CID + SMILES；调用PubChemTox工具前必须使用该工具

Common Patterns

常见模式

python

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python

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Pattern: Confirm compound is a stressor in a specific AOP

模式：确认化合物是否为特定AOP中的应激源

aop = AOPWiki_get_aop(aop_id=58) stressors = [s["name"] for s in aop["data"]["stressors"]]

Check if query chemical appears in stressors list

检查查询化学品是否在应激源列表中

Pattern: Extract curated CTD disease associations only

模式：仅提取经过整理的CTD疾病关联

diseases = CTD_get_chemical_diseases(input_terms="rotenone") curated = [d for d in diseases["data"] if d.get("DirectEvidence")]

Pattern: GHS carcinogen check

模式：GHS致癌物检查

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

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

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Reasoning Framework for Result Interpretation

结果解读的推理框架

Evidence Grading

证据分级

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

等级	标准	示例
强	AOP获得OECD认可，化合物被列为应激源，CTD与AOPWiki数据一致	AOP 58（AhR → 肝肿瘤）已获认可，苯并[a]芘被确认为应激源
中等	AOP处于审核阶段或有充分文献记录，化合物类别匹配但未单独列出	AOP将PPARalpha激活与肝脏效应关联；查询化合物为贝特类类似物
弱	AOP处于开发阶段，化合物未被列出但通过CTD基因重叠共享MIE靶点	CTD显示与AOP关键事件基因存在靶点重叠，但无直接应激源记录
不足	未找到AOP，无CTD基因-疾病关联，危害数据匮乏	新型化合物，无任何毒理学数据库条目

Interpretation Guidance

解读指南

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.

AOP证据权重评估：获得OECD认可的AOP经过专家评审，代表最高可信度的机制路径。AOPWiki中处于“开发中”的AOP可能存在关键事件关系不完整的情况。需从以下方面评估每个AOP：(1) 关键事件关系的生物学合理性，(2) 实证支持（剂量-反应一致性），(3) 关键事件的必要性（阻断关键事件可预防不良结局）。
关键事件关系（KER）强度：强KER具备上下游关键事件之间的剂量-反应和时间一致性。中等KER具备相关性证据。弱KER仅基于合理性推断。链条中最弱的KER决定了该路径的整体AOP可信度。
应激源效力解读：LD50数值表示急性毒性（数值越低，毒性越强）。GHS类别：第1类（LD50 ≤5 mg/kg，致命）、第2类（5-50 mg/kg，致命）、第3类（50-300 mg/kg，有毒）、第4类（300-2000 mg/kg，有害）、第5类（2000-5000 mg/kg，可能有害）。IARC第1组=确认致癌物，2A组=可能致癌物，2B组=疑似致癌物，3组=无法分类。报告LD50数值时需始终注明暴露途径和物种。
CTD整合：CTD中的“直接证据”（经过整理的标记/机制）比“推断”关联更具可信度。当CTD基因靶点与AOP关键事件基因重叠时，这支持了化合物与不良结局之间的机制关联。
监管背景：风险评估需结合危害识别（IARC、GHS）与暴露评估。暴露量可忽略的强致癌物，其风险可能低于高暴露量的中等毒性物质。

Synthesis Questions

综合分析问题

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)?
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?
Are the hazard data (LD50, GHS, IARC) consistent across sources, and do they support the severity implied by the AOP adverse outcome?
Does the CTD gene-disease evidence corroborate the AOP's predicted adverse outcome, or are there discrepancies suggesting alternative pathways?
For regulatory decision-making, is the combined weight of evidence (AOP mechanism + hazard quantification + exposure context) sufficient to support a risk classification?

查询化合物是否被明确列为已识别AOP中的应激源，还是通过共享分子靶点（CTD基因重叠）推断关联？
AOP链中的关键事件关系是否具备足够实证支持（剂量-反应一致性、时间序列），还是存在降低可信度的薄弱环节？
危害数据（LD50、GHS、IARC）在不同来源间是否一致，是否支持AOP不良结局所暗示的严重程度？
CTD基因-疾病证据是否证实了AOP预测的不良结局，还是存在差异提示其他路径？
对于监管决策，综合证据权重（AOP机制 + 危害量化 + 暴露背景）是否足以支持风险分类？

Fallback Chains

备选流程链

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

主工具	备选工具	触发场景
`AOPWiki_list_aops` （特定关键词）	更宽泛的器官术语	无结果返回时
`PubChemTox_get_target_organs`	`PubChemTox_get_toxicity_summary`	返回空数据时
`CTD_get_chemical_diseases`	`CTD_get_gene_diseases` + 来自CTD相互作用的基因	化合物名称未被识别时