For Peer Review. Table I Dose-Response Characterization

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1 Page of 0 0 Table I Dose-Response Characterization Each chemical in the table below was categorized by using one of five possible categories (to determine the relevance and relative strength of the underlying evidence for each of the chemicals being considered) - as follows:. LDE (LOW DOSE EFFECT) - The ability of this chemical to exert this particular effect is not well characterized at a range of dose levels, but the evidence suggests that this chemical can exert this effect at low dose levels (i.e., levels that are deemed relevant given the background levels of exposure that exist in the environment and as further defined below).. LLDE (Linear Dose-Response with Low Dose Effects) The ability of this chemical to exert this particular effect is well characterized at a range of dose levels and the evidence suggests that a linear dose-response relationship exists with effects at low dose levels being evident (i.e., levels that are lower than the LOEL/LOAEL or threshold and deemed relevant given the background levels of exposure that exist in the environment). Note - a linear dose-response model implies no threshold. Effects at low doses are the same as at higher doses even if at a lesser extent. The effect is directly proportional to the dose.. NLDE (Non-linear Dose-Response with Low Dose Effects) The ability of this chemical to exert this particular effect is well characterized at a range of dose levels and the evidence suggests that a non-linear dose-response relationship exists with exaggerated effects at low dose levels being evident (i.e., levels that are lower than the LOEL/LOAEL or threshold and deemed relevant given the background levels of exposure that exist in the environment) Note a non-linear dose-response with low dose effect implies that the effect does not vary according to the dose of the agent. The effect at low doses may be the same as at the higher doses or different. The non-linear dose-response may have or not have a threshold. It is represented by a sigmoid curve. The non-linear dose-response at low doses may be a non-monotonic doseresponse (NMDR). THRESHOLD The ability of this chemical to exert this particular effect is well characterized at a range of dose levels, and a threshold has been established for this chemical that suggests that this action on this mechanism/pathway does not occur at low dose levels (i.e., levels that are lower than the threshold and deemed relevant given the background levels of exposure that exist in the environment).. UNKNOWN Although the ability of this chemical to exert this particular effect has been shown at higher dose levels, this effect is not well characterized at a range of dose levels, so a LOEL /LOAEL or a threshold has not been determined for this chemical and there is no evidence showing that this chemical exerts this action at low dose levels (i.e., levels that lower than the LOEL/LOAEL or threshold and are deemed relevant given the background levels of exposure that exist in the environment). A-I = in vivo animal models, A-CL = animal cell lines, A-PC = animal primary cells, H-PC = human primary cells, H-CL = human cell lines, H-E = Human epidemiological studies. With respect to the human primary cell (H-PC) data from ToxCast () : Unknown signifies that the compound was tested across a range of doses and showed statistically significant activity against the specified targets at the lowest test concentrations (~0.0 µm), therefore a threshold could not be established. Threshold in this dataset signifies that there was no activity against the targets at one or more of the lowest concentrations tested.

2 Page of Carcinogenesis 0 0 Review Team Chemical Name Disruptive Action on Key Mechanism/Pathway Low Dose Effect (LDE, LLDE, NLDE, Threshold, Unknown) Angiogenesis Diniconazole Vascular Cell Adhesion Molecule and Threshold (H-PC) () Angiogenesis Ziram Vascular Cell Adhesion Molecule and Threshold (H-PC) (,) Angiogenesis Chlorothalonil Thrombomodulin, Vascular Proliferation and Unknown (H-PC) () NLDE (A-in vivo) () Angiogenesis Biphenyl Angiogenic Unknown (H-PC) () Angiogenesis Tributyltin Vascular Cell Proliferation and Unknown (H-PC) () chloride Adhesion Molecule Signaling Angiogenesis Methylene Plasminogen Activating System and Unknown (H-PC) () bis(thiocyanate) Angiogenesis HPTE Vascular Cell Adhesion Molecule and Unknown (H-PC) () Threshold (A-I*) () LDE (A-I*) () *Extrapolated from in vivo data on the parent compound, Methoxychlor Angiogenesis PFOS Angiogenic Threshold (H-PC) () LDE (H-CL)() Angiogenesis Bisphenol AF Matrix Metalloproteinase Expression Unknown (H-PC) () and Estrogen Receptor Signaling Angiogenesis C.I. solvent Aryl-Hydrocarbon Receptor and Unknown (H-PC) () yellow Hypoxic Signaling Cypermethrin AR and ER expression, Reduction of ATP and Mitochondrial Enzymes, Mitochondrial Membrane Potential LLDE (A-I) () NLDE (A-I) () NLDE (H-CL) (,0,) Acrolein p Activation, DNA Repair Inhibition, PERK Phosphorylation, Mitochondrial Dysfunction, Cell Survival LLDE (A-I, A-CL, H-PC, H-CL) (-) NLDE () Threshold () Rotenone Cell Cycle, DNA Damage Response, Proliferation, Differentiation, Mitochondria LLDE (H-CL) (,,) NLDE (H-CL) (,) Unknown (H-CL,H-PC) () Copper p Activation, p Upregulation, Cell LLDE (H-CL) (0-) Viability Nickel Neutrophil Apoptosis, E-Cadherin Regulation, MMP Production LLDE (H-CL) () NLDE (H-CL) () Threshold (H-CL) () Cadmium p-dependent Apoptosis, Cell Proliferation LLDE (H-CL) (), Threshold (H-CL) () Diazinon AChE Activity, Neuronal Cytotoxicity Unknown (A-PC) () LLDE (H-CL) () Iron KRAS Mutations LLDE (A-I) () Malathion Lymphocyte Mutations, Cytotoxicity Unknown (H-PC, H-E) (,) Bisphenol A MMP- and MMP- Expression, Increased Migration, Invasion, EMT, Oxidative Stress, ER Signaling LDE (H-CL) (0,), Threshold (H-CL, H-PC) () Hexacholorobe nzene Activation of c-src, HER, STATb and ERK/ signaling LLDE (H-CL, A-I) () Sulfur dioxide MMP- Expression Unknown (A-PC) ()

3 Page 0 of 0 0 Phthalates MMP- and MMP- Expression LDE (H-CL) (), Unknown (H-CL, H-PC) () Iron ROI Generation, NFkB Activation, upa Unknown (H-CL) () Expression Biorhythms/Me GSKβ Activation, EMT Regulation Unknown (H-CL, H-E) (,) latonin Bisphenol A Inhibition of GJIC, Activation of mtor NLDE(H-CL, A-CL) (-) (BPA) pathway, downregulation of p, p Threshold (H-CL, H-PC) () and BAX, binding to ER-alpha, weakly binds to TH receptor and AR, Dibutyl phthalate (DBP) activation of ERK/ and p Activation of PPAR-alpha, inhibition of GJIC, expression of cyclin D and cdk-, activation of AhR/HDAC/c-Myc pathway NLDE (H-CL) () Unknown (H-CL, H-PC) () Chlorothalonil Upregulation of ErbB- tyrosine kinase and MAP kinase, aromatase inhibitor Threshold-based (i.e. non-linear) (A-I) () Unknown (H-PC) () Lindane Induction of MAPK/ERK Threshold-based (i.e. non-linear) (A-I) () Dichlorvos Expression of p, Bcl- and c-myc LLDE (A-I) () Methoxychlor Oxyfluorfen Diethylhexyl phthalate (DEHP) Linuron Nickel-derived compounds, (e.g. Nickel chloride) Binding to ER-alpha receptor, upregulation of cyclin D, downregulation of p Expression of Cypb and Cypa transcripts (markers of PPAR-alpha activation) Activation of PPAR-alpha, inhibition of GJIC LLDE (H-CL, A-CL) (,) Unknown (H-PC) () Threshold (A-I) (), Unknown (H-CL, H-PC) () Threshold-based (i.e. non-linear) (A-I) () Hypersecretion of LH, inhibition of Unknown (H-CL) () GJIC Epigenetic silencing of p LLDE (H-CL, A-PC) (0) Diethylstilbestrol Allelic loss and point mutation in LLDE (A-I) () ETRG- gene Reserpine Epigenetic modifications Unknown (A-PC) () Phenobarbital Reduces expression of the CDKNA LLDE (A-I) (,0) product p, CAR Activation Acetaminophen Cellular energy loss, mitochondrial LDE (H-CL, A-I, A-CL) (-,) damage, Telomerase activation Cotinine Telomerase activation LLDE (H-PC) () Nitric oxide p inactivation LLDE (H-PC, H-CL, A-CL, A-I) () Na-selenite p promoter methylation LLDE (A-CL, A-I) (,) Lead p inactivation LLDE (H-PC, H-CL, A-CL, A-I) () Bisphenol A Estrogen receptor activation, Cell LLDE (A-I, H-CL, H-E) (,)

4 Page of Carcinogenesis 0 0 Cyprodinil cycle/senescence NLDE (A-I) (,) Increased proliferation signaling, Aryl hydrocarbon receptor activation Unknown (H-PC, H-CL) (,,) Imazalil AR signaling NLDE (A-I) (,0) Threshold (H-CL, H-PC) () Maneb Nitric Oxide Signaling Unknown (A-CL, H-CL, H-PC) (,,) Methoxyclor ER signaling LDE (A-I) (,) NLDE (A-I) () PFOS Nuclear hormone receptors LLDE (A-I) (,) Phthalates CAR, ER signaling Unknown (H-CL) () LDE (A-I) (-) Phosalone Increased proliferation, PXR signaling Unknown (H-PC, H-CL) (,0,) Polybrominated ER signaling LDE (A-I) (,) diphenylethers (PBDEs) Prochloraz ER signaling LDE (A-I) (,) Trenbolone acetate Bisphenol A Insulin-like growth hormone- and AR signaling immune cell proliferation, proinflammatory cytokine induction Phthalates Immunomodulation of macrophages, lymphocytes, eosinophils, and neutrophils PBDEs Induction of pro-inflammatory cytokines (IL, IL and CRP), Inhibition of anti-inflammatory cytokines (IL) Atrazine Immunomodulation of T cell and B cells, Pro-inflammatory cytokines Vinclozolin Pro-inflammatory cytokine induction, NFkB activation -Nonylphenol Pro-inflammatory cytokine induction, NFkB activation, inos induction Pyridaben Chemokine signaling, TGF-b, FAK, HIF- a, IL-a Triclosan Chemokine signaling, TGF-b, FAK, IL-a Pyraclostrobin Chemokine signaling, TGF-b, IL-a Fluoxastrobin Chemokine signaling, EGR, HIF-a, IL- a Unknown, LDE (A-I, H-CL, H-E) (,) Threshold (H-PC) () LDE (A-I, H-CL, H-E) (,-0) Unknown (H-PC, H-CL, H-E) (,) Threshold (H-PC, H-CL) (,-) Unknown (H-PC, A-I) (,,) Unknown (H-PC, A-I) (,,,) Unknown (A-CL, H-CL, H-PC) (,,) Unknown (H-CL, H-PC, A-CL) (,,) Threshold (A-I) () Threshold (H-CL, H-PC, A-I) (,-) LDE (A-I, H-CL) (,) Unknown (H-CL, H-PC) () Unknown (H-CL, H-PC) ()

5 Page of 0 0 of Anti- Growth Bisphenol A Chemokine signaling, TGF-b pathway Threshold (H-PC) () Maneb DDT PIK/Akt signaling, Chemokine signaling, TGF-b, FAK, IGF-, IL-, IL-a Induces MDM, cyclin D, EF expression, disrupts gap junctions LDE (A-I) () NLDE (H-CL) () NLDE (A-CL), (-) NLDE (A-I) (-) Unknown (H-CL, H-PC) (,-) LDE (A-I) () Threshold (A-I) (,) Threshold (A-CL, A-I) () NLDE (A-I, H-CL, A-CL) (-) of Anti- chlorpyrifos Increases proliferation LDE (H-CL, H-PC) (,) Growth of Anti- folpet Disrupts G-S checkpoint kinases, LDE(A-C) () Growth downregulates p, promotes proliferation of Anti- atrazine Induces estrogen production and LDE(H-CL, A-I) (0-) Growth proliferation of Anti- Bisphenol A Reduced p, reduced connexin NLDE (H-CL, A-I) (,,,) Growth expression, increased proliferation Tumor Nickel reactive oxygen species and cellular NLDE (A-I) () Microenvironment stress Tumor BPA IL- expression, improper dendritic cell LLDE (A-I) () Microenvironment maturation and polarization, ROS NLDE (A-I) () production Tumor Butyltins (such Natural Killer cell inhibition LDE (A-I) () Microenvironment as TBT) Tumor methylmercury Chronic oxidative stress LDE (H-PC, H-CL) (,) Microenvironment Tumor Paraquat Chronic ROS production, cellular stress Unknown (A-I) (0) Microenvironment Genome Instability Lead Dysfunctional DNA repair, defect in telomere maintenance Unknown (A-CL) (,,), Threshold (H-CL, H-E) (,) Genome Instability Acrylamide Inactivation of DNA repair Unknown (A-CL, A-I, H-CL) (,) proteins/enzymes Genome Instability Quinones Affect free cysteine residues in Unknown (A-CL) () catalytic center of DNA methyltransferases (DNMT) Genome Instability Nickel Affect enzymes that modulate posttranslational histone modification LDE (H-E) (,) LDE (A-CL, H-CL) () Genome Instability Bisphenol A Epigenetic changes via interactions Threshold (H-PC) () with mirn Genome Instability Alloy particles (tungsten/nicke l/cobalt) Disruption of DNA damage/redox signaling involving Nrf, NFKB, Egr, etc. LDE (A-I) () Genome Instability Titanium dioxide NPs Genome Instability Benomyl Genome Instability Carbon nanotubes Decreased NADH levels and impaired mitochondrial membrane potential and mitochondrial respiration, ROS generation Spindle defects leading to formation of micronuclei Spindle defects leading to formation of micronuclei Unknown (A-PC) () Threshold (A-CL) (,) LLDE (A-CL) (,) Unknown (A-I) ()