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Titanium dioxide

Associated High Confidence AOPs

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Associated AOPs with Level of Relevance 1
AOPs with at least 1 KE associated with chemical, where the KE(s) are neither MIE nor AO

AOP Identifier	AOP Title	AO Classification	OECD Status	Coverage Score	KE Identifier	KE Name
AOP:15	Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations	Genetic Disease	WPHA/WNT Endorsed	0.25	KE:155	Inadequate DNA repair
AOP:21	Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2	Unclassified	WPHA/WNT Endorsed	0.2	KE:317	Altered, Cardiovascular development/function
AOP:23	Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	Unclassified	WPHA/WNT Endorsed	0.1	KE:274	Reduction, Testosterone synthesis by ovarian theca cells
AOP:27	Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)	Gastrointestinal System Disease	Under Development	0.25	KE:149	Increase, Inflammation
AOP:27		Gastrointestinal System Disease	Under Development	0.25	KE:1115	Increase, Reactive oxygen species
AOP:37	PPARα activation leading to hepatocellular adenomas and carcinomas in rodents	Cancer; Gastrointestinal System Disease	Under Development	0.2	KE:716	Increase, cell proliferation (hepatocytes)
AOP:39	Covalent Binding, Protein, leading to Increase, Allergic Respiratory Hypersensitivity Response	Respiratory System Disease	Under Development	0.2	KE:272	Activation/Proliferation, T-cells
AOP:40	Covalent Protein binding leading to Skin Sensitisation	Integumentary System Disease	WPHA/WNT Endorsed	0.2	KE:272	Activation/Proliferation, T-cells
AOP:41	Sustained AhR Activation leading to Rodent Liver Tumours	Cancer; Gastrointestinal System Disease	Under Review	0.6	KE:854	Alterations, Cellular proliferation / hyperplasia
					KE:853	Changes/Inhibition, Cellular Homeostasis and Apoptosis
					KE:139	N/A, Hepatotoxicity, Hepatopathy, including a constellation of observable effects
AOP:69	Modulation of Adult Leydig Cell Function Subsequent to Decreased Cholesterol Synthesis or Transport in the Adult Leydig Cell	Reproductive System Disease	-	0.2	KE:645	Decreased Cholesterol, Decreased Testosterone Production by Adult Leydig Cells
AOP:80	Nicotinic acetylcholine receptor activation contributes to accumulation of damaged mitochondrial DNA and leads to colony loss/failure	Unclassified	-	0.12	KE:664	Overwhelmed, Mitochondrial DNA repair mechanisms
AOP:104	Altered ion channel activity leading impaired heart function	Unclassified	-	0.25	KE:699	Increased, cardiac arrthymia
AOP:105	Alpha2u-microglobulin cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)	Cancer; Urinary System Disease	-	0.17	KE:710	Increase, Regenerative cell proliferation (tubular epithelial cells)
AOP:107	Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the rat	Cancer; Gastrointestinal System Disease	Under Review	0.2	KE:716	Increase, cell proliferation (hepatocytes)
AOP:109	Cytotoxicity leading to bronchioloalveolar adenomas and carcinomas (in mouse)	Cancer; Respiratory System Disease	-	0.2	KE:734	Increase, Regenerative cell proliferation (terminal bronchiolar epithelial cells)
AOP:110	Inhibition of iodide pump activity leading to follicular cell adenomas and carcinomas (in rat and mouse)	Cancer; Endocrine System Disease	-	0.14	KE:739	Increase, Hypertrophy and proliferation (follicular cell)
AOP:114	HPPD inhibition leading to corneal papillomas and carcinomas (in rat)	Cancer	-	0.33	KE:777	Increase, Inflammation (corneal cells)
AOP:114		Cancer	-	0.33	KE:778	Increase, Regenerative cell proliferation (corneal cells)
AOP:115	Epithelial cytotoxicity leading to forestomach tumors (in mouse and rat)	Cancer	-	0.4	KE:149	Increase, Inflammation
AOP:115		Cancer	-	0.4	KE:781	Increase, Regenerative cell proliferation (forestomach epithelial cells)
AOP:116	Cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)	Cancer; Urinary System Disease	-	0.25	KE:710	Increase, Regenerative cell proliferation (tubular epithelial cells)
AOP:117	Androgen receptor activation leading to hepatocellular adenomas and carcinomas (in mouse and rat)	Cancer; Gastrointestinal System Disease	Under Development	0.25	KE:716	Increase, cell proliferation (hepatocytes)
AOP:119	Inhibition of thyroid peroxidase leading to follicular cell adenomas and carcinomas (in rat and mouse)	Cancer; Endocrine System Disease	-	0.14	KE:739	Increase, Hypertrophy and proliferation (follicular cell)
AOP:121	Urinary bladder calculi leading to urothelial papillomas and carcinomas (in mouse and rat)	Cancer; Urinary System Disease	-	0.2	KE:795	Increase, Regenerative cell proliferation (urothelial cells)
AOP:136	Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors	Benign Neoplasm; Respiratory System Disease	Under Review	0.14	KE:870	Increase, Cell Proliferation
AOP:149	Peptide Oxidation Leading to Hypertension	Cardiovascular System Disease	Under Development	0.2	KE:937	KE7 : Impaired, Vasodilation
AOP:149	Peptide Oxidation Leading to Hypertension	Cardiovascular System Disease	Under Development	0.2	KE:933	KE6 : Depletion, Nitric Oxide
AOP:150	Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF	Unclassified	WPHA/WNT Endorsed	0.14	KE:317	Altered, Cardiovascular development/function
AOP:164	Beta-2 adrenergic agonist activity leading to mesovarian leiomyomas in the rat and mouse	Cancer; Reproductive System Disease	-	0.17	KE:1042	Proliferation/Clonal Expansion, smooth muscle
AOP:167	Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.	Reproductive System Disease; Cancer	-	0.14	KE:1067	Proliferation/Clonal Expansion, aberrant basal cells
AOP:207	NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans	Reproductive System Disease	-	0.38	KE:1281	Increased, DNA Damage-Repair
					KE:1115	Increase, Reactive oxygen species
					KE:1262	Apoptosis
AOP:212	Histone deacetylase inhibition leading to testicular atrophy	Reproductive System Disease	WPHA/WNT Endorsed	0.17	KE:1262	Apoptosis
AOP:213	Inhibition of fatty acid beta oxidation leading to nonalcoholic steatohepatitis (NASH)	Gastrointestinal System Disease; Inherited Metabolic Disorder	-	0.17	KE:1115	Increase, Reactive oxygen species
AOP:228	NSAID induced PTGS2 inactivation to gastric ulcer	Gastrointestinal System Disease	-	0.2	KE:1411	Increased, leukocyte activation
AOP:245	Reduction in photophosphorylation leading to growth inhibition in aquatic plants	Unclassified	-	0.09	KE:40	Decrease, Mitochondrial ATP production
AOP:258	Renal protein alkylation leading to kidney toxicity	Urinary System Disease	Under Development	0.2	KE:40	Decrease, Mitochondrial ATP production
AOP:272	Deposition of energy leading to lung cancer	Cancer	WPHA/WNT Endorsed	0.29	KE:870	Increase, Cell Proliferation
AOP:272	Deposition of energy leading to lung cancer	Cancer	WPHA/WNT Endorsed	0.29	KE:155	Inadequate DNA repair
AOP:277	Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response	Immune System Disease	WPHA/WNT Endorsed	0.25	KE:202	Inhibition, Nuclear factor kappa B (NF-kB)
AOP:278	IKK complex inhibition leading to liver injury	Unclassified	-	0.12	KE:202	Inhibition, Nuclear factor kappa B (NF-kB)
AOP:280	α-diketone-induced bronchiolitis obliterans	Musculoskeletal System Disease; Respiratory System Disease	-	0.14	KE:149	Increase, Inflammation
AOP:286	Mitochondrial complex III antagonism leading to growth inhibition (1)	Unclassified	-	0.5	KE:1821	Decrease, Cell proliferation
AOP:286		Unclassified	-	0.5	KE:1771	Decrease, Adenosine triphosphate pool
AOP:287	Mitochondrial complex III antagonism leading to growth inhibition (2)	Unclassified	-	0.5	KE:1771	Decrease, Adenosine triphosphate pool
AOP:287		Unclassified	-	0.5	KE:1825	Increase, Cell death
AOP:290	Mitochondrial ATP synthase antagonism leading to growth inhibition (1)	Unclassified	-	0.5	KE:1821	Decrease, Cell proliferation
AOP:290		Unclassified	-	0.5	KE:1771	Decrease, Adenosine triphosphate pool
AOP:291	Mitochondrial ATP synthase antagonism leading to growth inhibition (2)	Unclassified	-	0.5	KE:1771	Decrease, Adenosine triphosphate pool
AOP:291		Unclassified	-	0.5	KE:1825	Increase, Cell death
AOP:293	Increased DNA damage leading to increased risk of breast cancer	Genetic Disease; Thoracic Disease; Cancer	Under Development	0.11	KE:1182	Increase, Cell Proliferation (Epithelial Cells)
AOP:294	Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer	Genetic Disease; Thoracic Disease; Cancer	Under Development	0.11	KE:1182	Increase, Cell Proliferation (Epithelial Cells)
AOP:296	Oxidative DNA damage leading to chromosomal aberrations and mutations	Genetic Disease; Chromosomal Disease	WPHA/WNT Endorsed	0.2	KE:155	Inadequate DNA repair
AOP:299	Deposition of energy leading to population decline via DNA oxidation and follicular atresia	Unclassified	-	0.14	KE:1115	Increase, Reactive oxygen species
AOP:311	Deposition of energy leading to population decline via DNA oxidation and oocyte apoptosis	Unclassified	-	0.14	KE:1115	Increase, Reactive oxygen species
AOP:321	Reduced environmental pH leading to thinner shells in Mytilus edulis	Unclassified	-	0.18	KE:592	Reduced, survival
AOP:321		Unclassified	-	0.18	KE:10042	Abnormal development
AOP:335	AOP for urothelial carcinogenesis due to chemical cytotoxicity by mitochondrial impairment	Cancer; Urinary System Disease	-	0.2	KE:795	Increase, Regenerative cell proliferation (urothelial cells)
AOP:348	Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory	Unclassified	Under Development	0.2	KE:406	decreased, Fertility
AOP:349	Inhibition of 11β-hydroxylase leading to decresed population trajectory	Unclassified	Under Development	0.12	KE:406	decreased, Fertility
AOP:362	Immune mediated hepatitis	Gastrointestinal System Disease; Immune System Disease	-	0.12	KE:1817	Apoptotic cell death
AOP:368	Cytochrome oxidase inhibition leading to increased nasal lesions	Unclassified	-	0.33	KE:1825	Increase, Cell death
AOP:383	Inhibition of Angiotensin-converting enzyme 2 leading to liver fibrosis	Gastrointestinal System Disease	Under Development	0.17	KE:1115	Increase, Reactive oxygen species
AOP:386	Deposition of ionizing energy leading to population decline via inhibition of photosynthesis	Reproductive System Disease	-	0.12	KE:1115	Increase, Reactive oxygen species
AOP:387	Deposition of ionising energy leading to population decline via mitochondrial dysfunction	Reproductive System Disease	-	0.25	KE:40	Decrease, Mitochondrial ATP production
AOP:387		Reproductive System Disease	-	0.25	KE:1115	Increase, Reactive oxygen species
AOP:388	Deposition of ionising energy leading to population decline via programmed cell death	Reproductive System Disease	-	0.2	KE:1864	Increase, Programmed cell death
AOP:397	Bulky DNA adducts leading to mutations	Genetic Disease	Under Development	0.33	KE:155	Inadequate DNA repair
AOP:399	Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos)	Unclassified	-	0.12	KE:1821	Decrease, Cell proliferation
AOP:406	SARS-CoV-2 infection leading to hyperinflammation	Unclassified	-	0.17	KE:1869	Diminished protective oxidative stress response
AOP:410	GSK3beta inactivation leading to increased mortality via defects in developing inner ear	Unclassified	-	0.1	KE:1825	Increase, Cell death
AOP:413	Oxidation and antagonism of reduced glutathione leading to mortality via acute renal failure	Unclassified	-	0.33	KE:1115	Increase, Reactive oxygen species
AOP:413		Unclassified	-	0.33	KE:1607	Increase, Necrosis
AOP:416	Aryl hydrocarbon receptor activation leading to lung cancer through IL-6 toxicity pathway	Cancer	-	0.17	KE:1115	Increase, Reactive oxygen species
AOP:420	Aryl hydrocarbon receptor activation leading to lung cancer through sustained NRF2 toxicity pathway	Cancer	-	0.25	KE:870	Increase, Cell Proliferation
AOP:432	Deposition of Energy by Ionizing Radiation leading to Acute Myeloid Leukemia	Hematopoietic System Disease; Cancer	-	0.18	KE:870	Increase, Cell Proliferation
AOP:432		Hematopoietic System Disease; Cancer	-	0.18	KE:155	Inadequate DNA repair
AOP:439	Activation of the AhR leading to metastatic breast cancer	Thoracic Disease; Cancer	Under Development	0.22	KE:149	Increase, Inflammation
AOP:439	Activation of the AhR leading to metastatic breast cancer	Thoracic Disease; Cancer	Under Development	0.22	KE:1262	Apoptosis
AOP:441	Ionizing radiation-induced DNA damage leads to microcephaly via apoptosis and premature cell differentiation	Congenital Nervous System Abnormality; Nervous System Disease	-	0.14	KE:1262	Apoptosis
AOP:443	DNA damage and mutations leading to Metastatic Breast Cancer	Thoracic Disease; Cancer	Under Development	0.3	KE:1554	Increase Chromosomal Aberrations
					KE:155	Inadequate DNA repair
					KE:1172	Increased activation, Nuclear factor kappa B (NF-kB)
AOP:444	Ionizing radiation leads to reduced reproduction in Eisenia fetida via reduced spermatogenesis and cocoon hatchability	Unclassified	-	0.11	KE:1365	Increase, Apoptosis
AOP:451	Interaction with lung resident cell membrane components leads to lung cancer	Cancer	-	0.33	KE:1115	Increase, Reactive oxygen species
					KE:1497	Increased, recruitment of inflammatory cells
					KE:870	Increase, Cell Proliferation
AOP:452	Adverse outcome pathway of PM-induced respiratory toxicity	Respiratory System Disease	-	0.09	KE:1262	Apoptosis
AOP:456	Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced cardiovascular toxicity	Unclassified	Under Review	0.17	KE:317	Altered, Cardiovascular development/function
AOP:460	Antagonism of Smoothened receptor leading to orofacial clefting	Unclassified	Under Development	0.22	KE:1821	Decrease, Cell proliferation
AOP:460		Unclassified	Under Development	0.22	KE:1262	Apoptosis
AOP:464	Calcium overload in dopaminergic neurons of the substantia nigra leading to parkinsonian motor deficits	Nervous System Disease	-	0.05	KE:1825	Increase, Cell death
AOP:465	Alcohol dehydrogenase leading to reproductive dysfunction	Unclassified	-	0.12	KE:2050	Increase, developmental abnormalities
AOP:467	Knickkopf leading to mortality	Unclassified	-	0.11	KE:2050	Increase, developmental abnormalities
AOP:468	Binding of SARS-CoV-2 to ACE2 leads to hyperinflammation (via cell death)	Unclassified	-	0.25	KE:1497	Increased, recruitment of inflammatory cells
AOP:468		Unclassified	-	0.25	KE:1825	Increase, Cell death
AOP:478	Deposition of energy leading to occurrence of cataracts	Nervous System Disease; Monogenic Disease	Under Review	0.2	KE:870	Increase, Cell Proliferation
AOP:478	Deposition of energy leading to occurrence of cataracts	Nervous System Disease; Monogenic Disease	Under Review	0.2	KE:155	Inadequate DNA repair
AOP:480	Mitochondrial complexes inhibition leading to heart failure via decreased ATP production	Cardiovascular System Disease; Thoracic Disease	Under Development	0.2	KE:40	Decrease, Mitochondrial ATP production
AOP:482	Deposition of energy leading to occurrence of bone loss	Musculoskeletal System Disease	Under Review	0.14	KE:1825	Increase, Cell death
AOP:491	Decrease, GLI1/2 target gene expression leads to orofacial clefting	Unclassified	Under Development	0.33	KE:1821	Decrease, Cell proliferation
AOP:491		Unclassified	Under Development	0.33	KE:1262	Apoptosis
AOP:493	ERa inactivation alters AT expansion and functions and leads to insulin resistance and metabolically unhealthy obesity	Acquired Metabolic Disease	-	0.2	KE:1497	Increased, recruitment of inflammatory cells
AOP:493		Acquired Metabolic Disease	-	0.2	KE:2119	Insulin resistance, increased
AOP:495	Androgen receptor activation leading to prostate cancer	Reproductive System Disease; Cancer	-	0.22	KE:854	Alterations, Cellular proliferation / hyperplasia
AOP:495	Androgen receptor activation leading to prostate cancer	Reproductive System Disease; Cancer	-	0.22	KE:1183	Decreased, Apoptosis (Epithelial Cells)
AOP:500	Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis	Developmental Disorder Of Mental Health	-	0.29	KE:1115	Increase, Reactive oxygen species
AOP:500		Developmental Disorder Of Mental Health	-	0.29	KE:1262	Apoptosis
AOP:503	Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation	Reproductive System Disease; Cancer	Under Review	0.17	KE:1896	Genomic instability
AOP:509	Nrf2 inhibition leading to vascular disrupting effects through activating apoptosis signal pathway and mitochondrial dysfunction	Cardiovascular System Disease	-	0.14	KE:1365	Increase, Apoptosis
AOP:521	Essential element imbalance leads to reproductive failure via oxidative stress	Unclassified	-	0.14	KE:1115	Increase, Reactive oxygen species
AOP:524	Gluten-driven immune activation leading to celiac disease in genetically predisposed individuals	Immune System Disease; Gastrointestinal System Disease	-	0.11	KE:2255	Innate immune response, activation
AOP:535	Binding and activation of GPER leading to learning and memory impairments	Developmental Disorder Of Mental Health	-	0.11	KE:1262	Apoptosis
AOP:544	Inhibition of neuropathy target esterase leading to delayed neuropathy via increased inflammation	Nervous System Disease	-	0.17	KE:149	Increase, Inflammation
AOP:563	Aryl hydrocarbon Receptor (AHR) activation causes Premature Ovarian Insufficiency via Bax mediated apoptosis	Reproductive System Disease; Endocrine System Disease	-	0.17	KE:1262	Apoptosis
AOP:564	DBDPE-induced inhibition of mitochondrial complex Ⅰ leading to population decline via neurotoxicity and metabotoxicity.	Unclassified	-	0.09	KE:40	Decrease, Mitochondrial ATP production
AOP:569	Decreased DNA methylation of FAM50B/PTCHD3 leading to IQ loss of children via PI3K-Akt pathway	Developmental Disorder Of Mental Health	-	0.17	KE:1115	Increase, Reactive oxygen species
AOP:573	Inhibition, cytochrome oxidase leads to Increased, pulmonary edema	Respiratory System Disease	-	0.33	KE:1825	Increase, Cell death
AOP:574	Inhibition, cytochrome oxidase leads to Loss of olfactory function	Unclassified	-	0.33	KE:1825	Increase, Cell death

Associated AOPs with Level of Relevance 2
AOPs with at least 1 AO associated with chemical, and no associated MIE

AOP Identifier	AOP Title	AO Classification	OECD Status	Coverage Score	KE Identifier	KE Name
AOP:6	Antagonist binding to PPARα leading to body-weight loss	Symptom	WPHA/WNT Endorsed	0.12	KE:864	Decreased, Body Weight
AOP:7	Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female	Reproductive System Disease; Endocrine System Disease; Reproductive System Disease	Under Review	0.2	KE:406	decreased, Fertility
AOP:18	PPARα activation in utero leading to impaired fertility in males	Reproductive System Disease	Under Review	0.25	KE:406	decreased, Fertility
AOP:18		Reproductive System Disease	Under Review	0.25	KE:413	Reduction, Testosterone synthesis in Leydig cells
AOP:19	Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)	Reproductive System Disease	-	0.2	KE:337	N/A, Impairment of reproductive capacity
AOP:64	Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility	Reproductive System Disease	-	0.43	KE:406	decreased, Fertility
					KE:413	Reduction, Testosterone synthesis in Leydig cells
					KE:496	Increased apoptosis, decreased fetal/adult Leydig Cells
AOP:91	Sodium channel inhibition leading to reduced survival	Unclassified	-	0.17	KE:592	Reduced, survival
AOP:95	Ether-a-go-go (ERG) voltage-gated potassium channel inhibition leading to reduced survival	Unclassified	-	0.17	KE:592	Reduced, survival
AOP:99	Histamine (H2) receptor antagonism leading to reduced survival	Unclassified	-	0.14	KE:636	Decreased, survival
AOP:124	HMG-CoA reductase inhibition leading to decreased fertility	Reproductive System Disease	-	0.17	KE:330	Decrease, Fertility
AOP:139	Alkylation of DNA leading to cancer 1	Cancer	-	0.5	KE:885	Increase, Cancer
AOP:139	Alkylation of DNA leading to cancer 1	Cancer	-	0.5	KE:155	Inadequate DNA repair
AOP:148	EGFR Activation Leading to Decreased Lung Function	Respiratory System Disease	Under Development	0.25	KE:1250	Decrease, Lung function
AOP:173	Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis	Musculoskeletal System Disease; Respiratory System Disease	WPHA/WNT Endorsed	0.25	KE:1497	Increased, recruitment of inflammatory cells
AOP:173		Musculoskeletal System Disease; Respiratory System Disease	WPHA/WNT Endorsed	0.25	KE:1458	Pulmonary fibrosis
AOP:196	Volatile Organic Chemicals Activate TRPA1 Receptor to Induce Sensory Pulmonary Irritation	Respiratory System Disease	-	0.11	KE:1226	Increased Respiratory irritability and Chronic Cough,
AOP:205	AOP from chemical insult to cell death	Unclassified	-	0.33	KE:1263	Necrosis
AOP:205	AOP from chemical insult to cell death	Unclassified	-	0.33	KE:1262	Apoptosis
AOP:206	Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis	Musculoskeletal System Disease; Respiratory System Disease	Under Development	0.33	KE:149	Increase, Inflammation
AOP:206		Musculoskeletal System Disease; Respiratory System Disease	Under Development	0.33	KE:1276	Lung fibrosis
AOP:220	Cyp2E1 Activation Leading to Liver Cancer	Cancer; Gastrointestinal System Disease	WPHA/WNT Endorsed	0.6	KE:1393	Hepatocytotoxicity
					KE:1394	Induction, persistent proliferation/sustained proliferation
					KE:1395	Liver Cancer
AOP:241	Latent Transforming Growth Factor beta1 activation leads to pulmonary fibrosis	Musculoskeletal System Disease; Respiratory System Disease	-	0.17	KE:1458	Pulmonary fibrosis
AOP:242	Inhibition of lysyl oxidase leading to enhanced chronic fish toxicity	Unclassified	-	0.12	KE:636	Decreased, survival
AOP:302	Lung surfactant function inhibition leading to decreased lung function	Respiratory System Disease	Under Development	0.2	KE:1250	Decrease, Lung function
AOP:313	Stimulation of TLR7/8 in dendric cells leading to Psoriatic skin disease	Immune System Disease; Integumentary System Disease; Musculoskeletal System Disease	Under Development	0.2	KE:1709	Psoriatic skin disease
AOP:322	Alkylation of DNA leading to reduced sperm count	Reproductive System Disease	-	0.6	KE:1757	Reduce, Sperm count
					KE:155	Inadequate DNA repair
					KE:1365	Increase, Apoptosis
AOP:345	Androgen receptor (AR) antagonism leading to decreased fertility in females	Endocrine System Disease; Reproductive System Disease; Reproductive System Disease	Under Development	0.17	KE:406	decreased, Fertility
AOP:347	Toll-like receptor 4 activation and peroxisome proliferator-activated receptor gamma inactivation leading to pulmonary fibrosis	Musculoskeletal System Disease; Respiratory System Disease	-	0.11	KE:1458	Pulmonary fibrosis
AOP:379	Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation	Cardiovascular System Disease	Under Development	0.29	KE:1869	Diminished protective oxidative stress response
AOP:379		Cardiovascular System Disease	Under Development	0.29	KE:1846	Thrombosis and Disseminated Intravascular Coagulation
AOP:382	Angiotensin II type 1 receptor (AT1R) agonism leading to lung fibrosis	Musculoskeletal System Disease; Respiratory System Disease	Under Development	0.5	KE:1115	Increase, Reactive oxygen species
					KE:1276	Lung fibrosis
					KE:1172	Increased activation, Nuclear factor kappa B (NF-kB)
AOP:384	Hyperactivation of ACE/Ang-II/AT1R axis leading to chronic kidney disease	Urinary System Disease	-	0.33	KE:1115	Increase, Reactive oxygen species
AOP:384		Urinary System Disease	-	0.33	KE:1603	Chronic kidney disease
AOP:398	Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia	Reproductive System Disease	Under Development	0.17	KE:406	decreased, Fertility
AOP:411	Oxidative stress Leading to Decreased Lung Function	Respiratory System Disease	-	0.25	KE:1250	Decrease, Lung function
AOP:414	Aryl hydrocarbon receptor activation leading to lung fibrosis through TGF-β dependent fibrosis toxicity pathway	Musculoskeletal System Disease; Respiratory System Disease	-	0.4	KE:1276	Lung fibrosis
AOP:414		Musculoskeletal System Disease; Respiratory System Disease	-	0.4	KE:1920	Altered gene expression, TGF-β dependent fibrosis pathway
AOP:415	Aryl hydrocarbon receptor activation leading to lung fibrosis through IL-6 toxicity pathway	Musculoskeletal System Disease; Respiratory System Disease	-	0.2	KE:1276	Lung fibrosis
AOP:418	Aryl hydrocarbon receptor activation leading to impaired lung function through AHR-ARNT toxicity pathway	Respiratory System Disease	-	0.6	KE:1115	Increase, Reactive oxygen species
					KE:1250	Decrease, Lung function
					KE:1825	Increase, Cell death
AOP:419	Aryl hydrocarbon receptor activation leading to impaired lung function through P53 toxicity pathway	Respiratory System Disease	-	0.5	KE:1250	Decrease, Lung function
AOP:419		Respiratory System Disease	-	0.5	KE:1262	Apoptosis
AOP:424	Oxidative stress Leading to Decreased Lung Function via CFTR dysfunction	Respiratory System Disease	-	0.17	KE:1250	Decrease, Lung function
AOP:425	Oxidative Stress Leading to Decreased Lung Function via Decreased FOXJ1	Respiratory System Disease	-	0.17	KE:1250	Decrease, Lung function
AOP:431	Increased tumor necrosis factor (TNF) leading to increased risk of gestational diabetes mellitus (GDM)	Inherited Metabolic Disorder	-	0.4	KE:1953	Gestational diabetes mellitus
AOP:431		Inherited Metabolic Disorder	-	0.4	KE:1952	Abnormal, Glucose homeostasis
AOP:457	Succinate dehydrogenase inhibition leading to increased insulin resistance through reduction in circulating thyroxine	Inherited Metabolic Disorder	-	0.17	KE:2119	Insulin resistance, increased
AOP:474	Succinate dehydrogenase inactivation leads to cancer by promoting EMT	Cancer	Under Development	0.2	KE:885	Increase, Cancer
AOP:492	Glutathione conjugation leading to reproductive dysfunction via oxidative stress	Reproductive System Disease	-	0.4	KE:406	decreased, Fertility
AOP:492		Reproductive System Disease	-	0.4	KE:1115	Increase, Reactive oxygen species
AOP:497	ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndrome	Inherited Metabolic Disorder; Disease Of Metabolism	-	0.38	KE:1115	Increase, Reactive oxygen species
					KE:2145	Metabolic syndrome
					KE:2119	Insulin resistance, increased
AOP:498	Increased LCN2/iron complex leading to neurological disorders	Nervous System Disease	-	0.25	KE:2150	Neurological disorder
AOP:501	Excessive iron accumulation leading to neurological disorders	Nervous System Disease	-	0.25	KE:2150	Neurological disorder
AOP:534	Succinate dehydrogenase (SDH) inhibition leads to cancer through oxidative stress	Cancer	-	0.5	KE:1115	Increase, Reactive oxygen species
					KE:885	Increase, Cancer
					KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:546	Succinate dehydrogenase inactivation leads to cancer through hypoxic-like mechanisms	Cancer	-	0.2	KE:885	Increase, Cancer
AOP:551	Increased Muscarinic M2 Receptor leading to Arrhythmia	Symptom	-	0.2	KE:1106	Occurrence, cardiac arrhythmia
AOP:554	β-adrenergic receptor agonists leading to arrhythmias.	Symptom	-	0.25	KE:1106	Occurrence, cardiac arrhythmia
AOP:559	Inhibition of acetylcholinesterase (AChE) leading to arrhythmias	Symptom	-	0.2	KE:1106	Occurrence, cardiac arrhythmia
AOP:560	Inhibition of Funny current (If) leading to Arrhythmias	Symptom	-	0.25	KE:1106	Occurrence, cardiac arrhythmia
AOP:562	HCN Channel Inhibition leading to Arrhythmias	Symptom	-	0.2	KE:1106	Occurrence, cardiac arrhythmia

Associated AOPs with Level of Relevance 3
AOPs with at least 1 MIE associated with chemical, and no associated AO

AOP Identifier	AOP Title	AO Classification	OECD Status	Coverage Score	KE Identifier	KE Name
AOP:62	AKT2 activation leading to hepatic steatosis	Gastrointestinal System Disease; Inherited Metabolic Disorder	-	0.25	KE:486	systemic inflammation leading to hepatic steatosis
AOP:118	Chronic cytotoxicity leading to hepatocellular adenomas and carcinomas (in mouse and rat)	Cancer; Gastrointestinal System Disease	-	0.5	KE:786	Increase, Cytotoxicity (hepatocytes)
AOP:118		Cancer; Gastrointestinal System Disease	-	0.5	KE:787	Increase, Regenerative cell proliferation (hepatocytes)
AOP:209	Perturbation of cholesterol and glutathione homeostasis leading to hepatotoxicity: Integrated multi-OMICS approach for building AOP	Gastrointestinal System Disease	-	0.25	KE:1287	Glutathione synthesis
AOP:209		Gastrointestinal System Disease	-	0.25	KE:1286	Down Regulation, GSS and GSTs gene
AOP:263	Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation	Unclassified	WPHA/WNT Endorsed	0.75	KE:1821	Decrease, Cell proliferation
					KE:1771	Decrease, Adenosine triphosphate pool
					KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:264	Uncoupling of oxidative phosphorylation leading to growth inhibition via ATP depletion associated cell death	Unclassified	Under Development	0.5	KE:1771	Decrease, Adenosine triphosphate pool
AOP:264		Unclassified	Under Development	0.5	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:265	Uncoupling of oxidative phosphorylation leading to growth inhibition via increased cytosolic calcium	Unclassified	Under Development	0.25	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:266	Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased Na-K ATPase activity	Unclassified	Under Development	0.33	KE:1771	Decrease, Adenosine triphosphate pool
AOP:266		Unclassified	Under Development	0.33	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:267	Uncoupling of oxidative phosphorylation leading to growth inhibition via glucose depletion	Unclassified	Under Development	0.4	KE:1821	Decrease, Cell proliferation
AOP:267		Unclassified	Under Development	0.4	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:268	Uncoupling of oxidative phosphorylation leading to growth inhibition via mitochondrial swelling	Unclassified	Under Development	0.25	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:282	Adverse outcome pathway on photochemical toxicity initiated by light exposure	Unclassified	Under Review	0.25	KE:1115	Increase, Reactive oxygen species
AOP:298	Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer via chronic ROS	Cancer; Gastrointestinal System Disease	Under Review	0.33	KE:1115	Increase, Reactive oxygen species
AOP:298		Cancer; Gastrointestinal System Disease	Under Review	0.33	KE:1753	Chronic reactive oxygen species
AOP:303	Frustrated phagocytosis-induced lung cancer	Cancer	Under Development	0.57	KE:1115	Increase, Reactive oxygen species
					KE:870	Increase, Cell Proliferation
					KE:1497	Increased, recruitment of inflammatory cells
					KE:1668	Frustrated phagocytosis
AOP:324	Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and cell death	Unclassified	-	0.25	KE:1115	Increase, Reactive oxygen species
AOP:325	Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell death	Unclassified	-	0.25	KE:1115	Increase, Reactive oxygen species
AOP:326	Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell death	Unclassified	-	0.25	KE:1115	Increase, Reactive oxygen species
AOP:327	Excessive reactive oxygen species production leading to mortality (1)	Unclassified	-	0.2	KE:1115	Increase, Reactive oxygen species
AOP:328	Excessive reactive oxygen species production leading to mortality (2)	Unclassified	-	0.4	KE:1115	Increase, Reactive oxygen species
AOP:328		Unclassified	-	0.4	KE:1771	Decrease, Adenosine triphosphate pool
AOP:329	Excessive reactive oxygen species production leading to mortality (3)	Unclassified	-	0.4	KE:1115	Increase, Reactive oxygen species
AOP:329		Unclassified	-	0.4	KE:1771	Decrease, Adenosine triphosphate pool
AOP:330	Excessive reactive oxygen species production leading to mortality (4)	Unclassified	-	0.4	KE:1115	Increase, Reactive oxygen species
AOP:330		Unclassified	-	0.4	KE:1365	Increase, Apoptosis
AOP:331	Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and reduced cell proliferation	Unclassified	-	0.33	KE:1821	Decrease, Cell proliferation
AOP:331		Unclassified	-	0.33	KE:1115	Increase, Reactive oxygen species
AOP:332	Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferation	Unclassified	-	0.4	KE:1821	Decrease, Cell proliferation
AOP:332		Unclassified	-	0.4	KE:1115	Increase, Reactive oxygen species
AOP:333	Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation	Unclassified	-	0.8	KE:1821	Decrease, Cell proliferation
					KE:1115	Increase, Reactive oxygen species
					KE:1771	Decrease, Adenosine triphosphate pool
					KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:392	Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation	Unclassified	Under Development	0.4	KE:1867	Bradykinin system, hyperactivated
AOP:392		Unclassified	Under Development	0.4	KE:1497	Increased, recruitment of inflammatory cells
AOP:409	Frustrated phagocytosis leads to malignant mesothelioma	Cancer	-	0.62	KE:870	Increase, Cell Proliferation
					KE:1668	Frustrated phagocytosis
					KE:1115	Increase, Reactive oxygen species
					KE:1896	Genomic instability
					KE:1497	Increased, recruitment of inflammatory cells
AOP:438	reactive oxygen species generation leading to increased cardiovascular morbidity and mortality	Cardiovascular System Disease	-	0.17	KE:1115	Increase, Reactive oxygen species
AOP:438		Cardiovascular System Disease	-	0.17	KE:1919	Increased, Cardiac Dysregulation
AOP:446	PM-related Adverse outcome pathway frameworks on various systems	Respiratory System Disease	-	0.4	KE:1262	Apoptosis
					KE:1458	Pulmonary fibrosis
					KE:149	Increase, Inflammation
					KE:1115	Increase, Reactive oxygen species
					KE:1250	Decrease, Lung function
					KE:1993	Increase, Pneumonia
					KE:1497	Increased, recruitment of inflammatory cells
					KE:1198	Activation, Macrophages
AOP:447	Kidney failure induced by inhibition of mitochondrial electron transfer chain through apoptosis, inflammation and oxidative stress pathways	Urinary System Disease	-	0.17	KE:202	Inhibition, Nuclear factor kappa B (NF-kB)
AOP:447		Urinary System Disease	-	0.17	KE:1365	Increase, Apoptosis
AOP:448	ROS, inflammation, and activation of nAChR lead to increased incidence of cardiovascular morbidity and mortality	Cardiovascular System Disease	-	0.12	KE:1115	Increase, Reactive oxygen species
AOP:448		Cardiovascular System Disease	-	0.12	KE:1198	Activation, Macrophages
AOP:453	Reactive oxygen species and subsequent oxidative stress lead to increased incidence of digestive morbidity and mortality in the general population	Gastrointestinal System Disease	-	0.15	KE:1115	Increase, Reactive oxygen species
AOP:453		Gastrointestinal System Disease	-	0.15	KE:1198	Activation, Macrophages
AOP:463	The AOP framwork on silica nanopariticles induced hepatoxicity	Gastrointestinal System Disease	-	0.27	KE:149	Increase, Inflammation
					KE:1115	Increase, Reactive oxygen species
					KE:1262	Apoptosis
AOP:469	Reactive oxygen speicies overproduction leading to increased digestive morbidity and mortality in generation population	Gastrointestinal System Disease	-	0.15	KE:1115	Increase, Reactive oxygen species
AOP:469		Gastrointestinal System Disease	-	0.15	KE:1198	Activation, Macrophages
AOP:472	DNA adduct formation leading to kidney failure	Urinary System Disease	-	0.33	KE:149	Increase, Inflammation
					KE:1115	Increase, Reactive oxygen species
					KE:1825	Increase, Cell death
AOP:488	Increased reactive oxygen species production leading to decreased cognitive function	Cognitive Disorder	-	0.29	KE:1115	Increase, Reactive oxygen species
AOP:488		Cognitive Disorder	-	0.29	KE:1869	Diminished protective oxidative stress response
AOP:511	The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects	Cardiovascular System Disease	-	0.06	KE:1115	Increase, Reactive oxygen species
AOP:540	Oxidative Stress in the Fish Ovary Leads to Reproductive Impairment via Reduced Vitellogenin Production	Unclassified	-	0.22	KE:1115	Increase, Reactive oxygen species
AOP:540		Unclassified	-	0.22	KE:1262	Apoptosis
AOP:541	Excessive ROS generation leading to increased incidence of vascular calcification by VSMC phenotype switching	Cardiovascular System Disease	-	0.15	KE:1115	Increase, Reactive oxygen species
AOP:541		Cardiovascular System Disease	-	0.15	KE:1198	Activation, Macrophages

Associated AOPs with Level of Relevance 5
AOPs with at least 1 MIE and AO associated with chemical, and there exists a directed path between that MIE and AO

AOP Identifier	AOP Title	AO Classification	OECD Status	Coverage Score	KE Identifier	KE Name
AOP:423	Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway	Unclassified	-	0.33	KE:1115	Increase, Reactive oxygen species
AOP:423		Unclassified	-	0.33	KE:1817	Apoptotic cell death
AOP:505	Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway	Cancer	-	0.6	KE:149	Increase, Inflammation
					KE:1115	Increase, Reactive oxygen species
					KE:885	Increase, Cancer
AOP:513	Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway	Cancer	-	0.4	KE:1115	Increase, Reactive oxygen species
AOP:513		Cancer	-	0.4	KE:885	Increase, Cancer

Glossary of Terms

AOP: Adverse Outcome Pathway
MIE: Molecular Initiating Event
KE: Key Event
AO: Adverse Outcome
Coverage score: The fraction of KEs within the AOP, that are mapped to the chemical-associated toxicological endpoints
Level of relevance: Qualitative rank based on the kind of associated KEs within the corresponding AOP
AO classification: The disease category corresponding to the AO in the AOP obtained from Disease Ontology

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006974 - cellular response to DNA damage stimulus
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D001145 - Arrhythmias, Cardiac
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:2000225 - negative regulation of testosterone biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0050729 - positive regulation of inflammatory response GO:0002523 - leukocyte migration involved in inflammatory response
CTD - Disease	MESH:D007249 - Inflammation
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0072593 - reactive oxygen species metabolic process GO:1903428 - positive regulation of reactive oxygen species biosynthetic process GO:0050665 - hydrogen peroxide biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	MESH:D006967 - Hypersensitivity
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006915 - apoptotic process GO:0006884 - cell volume homeostasis
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D056486 - Chemical and Drug Induced Liver Injury MESH:D008107 - Liver Diseases
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:2000225 - negative regulation of testosterone biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006974 - cellular response to DNA damage stimulus
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D001145 - Arrhythmias, Cardiac
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0050729 - positive regulation of inflammatory response GO:0002523 - leukocyte migration involved in inflammatory response
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0042311 - vasodilation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006809 - nitric oxide biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006974 - cellular response to DNA damage stimulus
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006915 - apoptotic process GO:0043065 - positive regulation of apoptotic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Induce apoptosis of spermatogenic cells
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D007964 - Leukocytosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006754 - ATP biosynthetic process GO:0046034 - ATP metabolic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0043124 - negative regulation of I-kappaB kinase/NF-kappaB signaling
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008285 - negative regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006754 - ATP biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Induce apoptosis of spermatogenic cells
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D005313 - Fetal Death
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D000013 - Congenital Abnormalities
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Affects fertility
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Induce apoptosis of spermatogenic cells
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Induce apoptosis of spermatogenic cells
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006979 - response to oxidative stress
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D009336 - Necrosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D048629 - Micronuclei, Chromosome-Defective
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0043123 - positive regulation of I-kappaB kinase/NF-kappaB signaling
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Induce apoptosis of spermatogenic cells
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0050729 - positive regulation of inflammatory response GO:0043032 - positive regulation of macrophage activation GO:0002523 - leukocyte migration involved in inflammatory response
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D011297 - Prenatal Exposure Delayed Effects
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D003924 - Diabetes Mellitus, Type 2
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006915 - apoptotic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D053842 - Microsatellite Instability MESH:D043171 - Chromosomal Instability
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	Alterations in immune responses
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D015431 - Weight Loss
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:2000225 - negative regulation of testosterone biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D007248 - Infertility, Male MESH:D007247 - Infertility, Female MESH:D009845 - Oligospermia
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006915 - apoptotic process GO:0043065 - positive regulation of apoptotic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D005313 - Fetal Death
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D007248 - Infertility, Male MESH:D007247 - Infertility, Female MESH:D009845 - Oligospermia
DEDuCT - endocrine-mediated endpoint	Affects fertility
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D002471 - Cell Transformation, Neoplastic
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D008171 - Lung Diseases
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D011658 - Pulmonary Fibrosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0050729 - positive regulation of inflammatory response GO:0002523 - leukocyte migration involved in inflammatory response
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D009336 - Necrosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D011658 - Pulmonary Fibrosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D056486 - Chemical and Drug Induced Liver Injury
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006979 - response to oxidative stress
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D008103 - Liver Cirrhosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D012871 - Skin Diseases
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D009845 - Oligospermia
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D013927 - Thrombosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D007674 - Kidney Diseases
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D005355 - Fibrosis
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D018149 - Glucose Intolerance
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D006943 - Hyperglycemia
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D006943 - Hyperglycemia
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D009069 - Movement Disorders MESH:D014202 - Tremor
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0010917 - negative regulation of mitochondrial membrane potential GO:0051881 - regulation of mitochondrial membrane potential
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D001145 - Arrhythmias, Cardiac
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0050729 - positive regulation of inflammatory response GO:0002523 - leukocyte migration involved in inflammatory response
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D056486 - Chemical and Drug Induced Liver Injury
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0008284 - positive regulation of cell population proliferation GO:0008283 - cell population proliferation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006750 - glutathione biosynthetic process
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0004364 - glutathione transferase activity
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006979 - response to oxidative stress
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0006909 - phagocytosis
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0042311 - vasodilation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D001145 - Arrhythmias, Cardiac
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	-
CTD - Disease	MESH:D011014 - Pneumonia
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

Source	Evidence
AOP-Wiki	-
CTD - Phenotype	GO:0043032 - positive regulation of macrophage activation
CTD - Disease	-
DEDuCT - endocrine-mediated endpoint	-
NeurotoxKb - neurotoxic endpoints	-
REACH Dossier - experimental data	-
ToxCast invitrodb v4.2	-

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DISCLAIMER

TICToK is a knowledgebase of chemicals found in tattoo inks, compiled from publicly available regulatory and scientific resources. The chemical classifications presented in this knowledgebase are derived from multiple publicly available resources and are provided solely for informational purposes, and they are neither authoritative nor binding. The chemical-AOP mappings compiled in this knowledgebase serve as plausible hypotheses for research, and further experimental validation is required to definitively establish these potential toxicity mechanisms. The authors bear no responsibility for any errors, omissions, or inconsistencies originating from these external sources. Users are advised to exercise independent judgment when interpreting chemical classifications and any other data provided in this resource. Importantly, our sole goal to build this resource on tattoo ink chemicals is to enable future basic research on this topic, and it does not necessarily reflect the views or objectives of our employers or funders.

Titanium dioxide

Associated AOPs with Level of Relevance 1 AOPs with at least 1 KE associated with chemical, where the KE(s) are neither MIE nor AO

Associated AOPs with Level of Relevance 2AOPs with at least 1 AO associated with chemical, and no associated MIE

Associated AOPs with Level of Relevance 3AOPs with at least 1 MIE associated with chemical, and no associated AO

Associated AOPs with Level of Relevance 5AOPs with at least 1 MIE and AO associated with chemical, and there exists a directed path between that MIE and AO