Table 1.
List of chemical mixtures targeting male reproductive development in the Earl Gray, Jr. laboratory, USEPA (as of October, 2016)
| Type of mixture | Mixture study designa: Chemicals in mixture |
Mechanism of individual chemicals | Mixture model(s) testedb |
Reference |
|---|---|---|---|---|
| Similar mechanisms of action, same signaling pathwayc |
B, EQ: Vinclozolin (VIN) + Procymidon (PROCYM) |
VIN and PROCYM: Androgen receptor (AR) antagonists | RA | (Andrew Hotchkiss and Earl Gray, Jr., unpublished; Howdeshell et al., 2008) |
| B, EQ: Di(n)butyl phthalate (DBP) + Benzyl butyl phthalate (BBP) |
DBP and BBP: inhibitors of fetal testosterone (T) synthesis with a one common active metabolite (monobutyl phthalate (MBP) |
RA | (Andrew Hotchkiss and Earl Gray, Jr., unpublished; Howdeshell et al., 2008) | |
| B, EQ: DBP + Diethylhexyl phthlate (DEHP) |
DBP and DEHP: inhibitors of fetal T synthesis with different active metabolites (MBP and monoethylhexyl phthalate (MEHP) |
DA, RA | Howdeshell et al., 2007 | |
| FR-D, EQ: BBP + DBP + DEHP + Diisobutyl phthalate (DiBP) + Dipentyl phthalate (DPeP) |
BBP, DBP, DEHP, DiBP, and DPeP: inhibitors of fetal T synthesis |
DA, RA | Howdeshell et al, 2008; Howdeshell et al. 2015 | |
| FR-D, EQ: BBP + DBP + DEHP + DiBP + DPeP + Dihexyl phthlate (DHP) + Diheptyl phthalate (DHeP) + Diisoheptyl phthalate (DiHeP) + dicyclohexyl phthalate (DCHP) |
BBP, DBP, DEHP, DiBP, DHP, DHeP, DiHeP, DCHP, and DPeP: inhibitors of fetal T synthesis |
DA, RA | Hannas et al., 2012 | |
| B, EQ: BBP + Linuron (LIN) |
BBP: inhibitor of fetal T synthesis LIN: AR antagonist and direct inhibitor of T synthesis |
DA | Hotchkiss et al. 2004 | |
| FR-D, EQ: DBP + PROCYM |
DBP: inhibitor of fetal T synthesis PROCYM: AR antagonist |
DA, RA | Hotchkiss et al. 2010 | |
| FR-D, EQ: VIN + PROCYM + Prochloraz (PROCL) + LIN + BBP + DBP + DEHP |
VIN and PROCYM: AR antagonists LIN: AR antagonist and direct inhibitor of T synthesis PROCL: AR antagonist and direct inhibitor of steroid hormone synthesis BBP, DBP, and DEHP: inhibitors of fetal T synthesis |
DA, RA, IA, TEQ |
Rider et al., 2008 | |
| FR-D, EQ: VIN + PROCYM + PROCL + LIN + BBP + DBP + DEHP + DiBP + DiHeP + DPeP |
VIN and PROCYM: AR antagonists LIN: AR antagonist and direct inhibitor of T synthesis PROCL: AR antagonist and inhibitor of steroid hormone synthesis BBP, DBP, DEHP, DiBP, DiHeP, DPeP: inhibitors of fetal T synthesis |
DA, RA, IA | Rider et al., 2010 | |
| FR-D, EQ: DBP + Pyrifluquinazon (PFQ) |
DBP: inhibitor of fetal T synthesis PFQ: Possible AR antagonist |
DA, RA | Earl Gray, Jr., under preparation | |
| Different signaling pathways, same target tissue |
B, EQ DBP + 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) |
DBP: inhibitor of fetal T synthesis TCDD: Aryl hydrocarbon receptor (AhR) agonist |
RA | Rider et al., 2010 |
| Converging AOPs, same target tissue |
B, EQ: DPeP + Simvastatin (SIM) |
DPeP: inhibitor of fetal T synthesis SIM: inhibitor of cholesterol synthesis (via inhibition of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase) resulting in reduced fetal T synthesis |
RA | Beverly et al., 2014 |
| Converging AOPs, same target tissue and different mechanisms of action, same signaling pathway |
18 chemical, FR-D, LOEL study: VIN + PROCYM + PROCL + PFQ + p,p’- dichlorodiphenyl dichloroethylene (pp’DDE) + LIN + PHTHALATES (BBP + DBP + DEHP + DiBP + DiHeP + DPeP+ DHeP+ DCHP+ DHP) + flutamide (FLUT) + finasteride (FIN) + SIM |
VIN, PFQ, FLUT, p,p’DDE and PROCYM: AR antagonists LIN: AR antagonist and direct inhibitor of T synthesis PROCL: AR antagonist and direct inhibitor of steroid hormone synthesis BBP + DBP + DEHP + DiBP + DiHeP + DPeP+ DHeP+ DCHP+ DHP: inhibitors of fetal T synthesis SIM: inhibitor of cholesterol synthesis (via inhibition of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase) resulting in reduced fetal T synthesis FIN: direct inhibitor of dihydrotestosterone (DHT) synthesis (via 5 alpha reductase) |
DA, RA, IA, | Justin Conley and Earl Gray, Jr., under preparation |
| 15 chemical FR-D, NOEL study: VIN + PROCYM + PROCL +PFQ+ pp’DDE+LIN + PHTHALATES (BBP + DBP + DEHP + DiBP + DiHeP + DPeP+ DHeP+ DCHP+ DHP) |
VIN, PFQ, p,p’DDE and PROCYM: AR antagonists LIN: AR antagonist and direct inhibitor of T synthesis PROCL: AR antagonist and direct inhibitor of steroid hormone synthesis BBP + DBP + DEHP + DiBP + DiHeP + DPeP+ DHeP+ DCHP+ DHP: inhibitors of fetal T synthesis |
DA, RA, IA, | Justin Conley and Earl Gray, Jr., ongoing |
a
Mixture study design: binary (B) or fixed ratio dilution (FR-D) design with equipotent doses (EQ), doses based on one-fifth the lowest observed effect level (LOEL), or doses based on twice the,no observed effect level (NOEL) for the individual chemicals for the top dose.
b
Mixture models tested include: dose addition (DA), integrated addition (IA), response addition (RA), and toxic equivalency factor (TEQ). Studies that did not specifically test a mixture model, but compared the data to the individual chemical responses were considered to have tested RA.
c
AOP: adverse outcome pathway.