A global review of the state of the evidence of household air pollution's contribution to ambient fine particulate matter and their related health impacts.

Direct exposure to household fine particulate air pollution (HAP) associated with inefficient combustion of fuels (wood, charcoal, coal, crop residues, kerosene, etc.) for cooking, space-heating, and lighting is estimated to result in 2.3 (1.6-3.1) million premature yearly deaths globally. HAP emitted indoors escapes outdoors and is a leading source of outdoor ambient fine particulate air pollution (AAP) in low- and middle-income countries, often being a larger contributor than well-recognized sources including road transport, industry, coal-fired power plants, brick kilns, and construction dust. We review published scientific studies that model the contribution of HAP to AAP at global and major sub-regional scales. We describe strengths and limitations of the current state of knowledge on HAP's contribution to AAP and the related impact on public health and provide recommendations to improve these estimates. We find that HAP is a dominant source of ambient fine particulate matter (PM2.5) globally - regardless of variations in model types, configurations, and emission inventories used - that contributes approximately 20 % of total global PM2.5 exposure. There are large regional variations: in South Asia, HAP contributes âˆ¼ 30 % of ambient PM2.5, while in high-income North America the fraction is âˆ¼ 7 %. The median estimate indicates that the household contribution to ambient air pollution results in a substantial premature mortality burden globally of about 0.77(0.54-1) million excess deaths, in addition to the 2.3 (1.6-3.1) million deaths from direct HAP exposure. Coordinated global action is required to avert this burden.

Cookstove Emissions and Performance Evaluation Using a New ISO Protocol and Comparison of Results with Previous Test Protocols.

In 2018, the International Organization for Standardization (ISO) 19867-1 "Harmonized laboratory test protocols" were released for establishing improved quality and comparability for data on cookstove air pollutant emissions, efficiency, safety, and durability. This is the first study that compares emissions [carbon dioxide, carbon monoxide, total hydrocarbons, methane, nitrogen oxides, fine particulate matter (PM2.5), organic carbon, elemental carbon, and ultrafine particles] and efficiency data between the ISO protocol and the Water Boiling Test (WBT). The study examines six stove/fuel combinations [liquefied petroleum gas (LPG), pellet, wood fan, wood rocket, three stone fire, and charcoal] tested in the same US EPA laboratory. Evaluation of the ISO protocol shows improvements over previous test protocols and that results are relatively consistent with former WBT data in terms of tier ratings for emissions and efficiency, as defined by the ISO 19867-3 "Voluntary Performance Targets." Most stove types remain similarly ranked using ISO and WBT protocols, except charcoal and LPG are in higher PM2.5 tiers with the ISO protocol. Additionally, emissions data including polycyclic aromatic hydrocarbons are utilized to compare between the ISO and Firepower Sweep Test (FST) protocols. Compared to the FST, the ISO protocol results in generally higher PM2.5 tier ratings.

Evaluation of performance of household solar cookers.

Household solar cookers were evaluated according to ASAE (American Society of Agricultural Engineers) Standard S580.1 - Testing and Reporting Solar Cooker Performance. Per ASAE S580.1, standardized cooking power at a temperature difference of 50°C between ambient air and cooking vessel water temperatures (± 95% confidence interval) was 198 (± 32) W for a parabolic-type cooker, 65 (± 12) W for a box-type cooker, and 25 (± 9) W for a panel-type cooker. ASAE S580.1 specifies standardized cooking power as a single measure of performance, and additional measures of performance, including thermal efficiency and water heating times, were evaluated. The issue of water evaporation was examined. Clarifications for ASAE S580.1 wind velocity specification are recommended. ASAE S580.1 is specified as a normative reference in the ISO (International Organization for Standardization) 19867-1:2018 standard for laboratory testing of cookstoves, and a specified deviation for average wind velocity, ≤1.5 m/s, is based on recommendations from this study and concurrence from other ISO working group experts.

Mutagenicity- and pollutant-emission factors of pellet-fueled gasifier cookstoves: Comparison with other combustion sources.

Emissions from solid-fuel burning cookstoves are associated with 3 to 4 million premature deaths annually and contribute significantly to impacts on climate. Pellet-fueled gasifier stoves have some emission factors (EFs) approaching those of gas-fuel (liquid petroleum gas) stoves; however, their emissions have not been evaluated for biological effects. Here we used a new International Organization for Standardization (ISO) testing protocol to determine pollutant- and mutagenicity-EFs for a stove designed for pellet fuel, the Mimi Moto, and for two other forced-draft stoves, Xunda and Philips HD4012, burning pellets of hardwood or peanut hulls. The Salmonella assay-based mutagenicity-EFs (revertants/megajouledelivered) spanned three orders of magnitude and correlated highly (r = 0.99; n = 5) with EFs of the sum of 32 particle-phase polycyclic aromatic hydrocarbons (PAHs). The Mimi Moto/hardwood pellet combination had total-PAH- and mutagenicity-EFs 99.2 and 96.6% lower, respectively, compared to data published previously for the Philips stove burning non-pelletized hardwood, and 100 and 99.8% lower, respectively, compared to those of a wood-fueled three-stone fire. The Xunda burning peanut hull pellets had the highest fuel energy-based mutagenicity-EF (revertants/megajoulethermal) of the pellet stove/fuel combinations tested, which was between that of diesel exhaust, a known human carcinogen, and a natural-draft wood stove. Although the Mimi Moto burning hardwood pellets had the lowest fuel energy-based mutagenicity-EF, this value was between that of utility coal and utility wood boilers. This advanced stove/fuel combination has the potential to greatly reduce emissions in contrast to a traditional stove, but adequate ventilation is required to approach acceptable levels of indoor air quality.

Chemical composition, structures, and light absorption of N-containing aromatic compounds emitted from burning wood and charcoal in household cookstoves.

N-containing aromatic compounds (NACs) are an important group of light-absorbing molecules in the atmosphere. They are often observed in combustion emissions, but their chemical formulas and structural characteristics remain uncertain. In this study, red oak wood and charcoal fuels were burned in cookstoves using the standard water boiling test (WBT) procedure. Submicron aerosol particles in the cookstove emissions were collected using quartz (Q f ) and polytetrafluoroethylene (PTFE) filter membranes positioned in parallel. A back-up quartz filter (Q b ) was also installed downstream of the PTFE filter to evaluate the effect of sampling artifact on NACs measurements. Liquid chromatography-mass spectroscopy (LC-MS) techniques identified seventeen NAC chemical formulas in the cookstove emissions. The average concentrations of total NACs in Q b samples (0.37 ± 0.31 - 1.79 ± 0.77 µg m-3) were greater than 50% of those observed in the Q f samples (0.51 ± 0.43 - 3.91 ± 2.06 µg m-3), and the Q b to Q f mass ratios of individual NACs had a range of 0.02 - 2.71, indicating that the identified NACs might have substantial fractions remaining in the gas-phase. In comparison to other sources, cookstove emissions from red oak or charcoal fuels did not exhibit unique NAC structural features, but had distinct NACs composition. However, before identifying NACs sources by combining their structural and compositional information, the gas-particle partitioning behaviors of NACs should be further investigated. The average contributions of total NACs to the light absorption of organic matter at λ = 365 nm (1.10 - 2.57%) in Q f and Q b samples (10.7 - 21.0%) are up to 10 times larger than their mass contributions (Q f 0.31 - 1.01%, Q b 1.08 - 3.31%), so the identified NACs are mostly strong light absorbers. To explain more sample extracts absorption, future research is needed to understand the chemical and optical properties of high molecular weight (e.g., MW > 500 Da) entities in particulate matter.

Field-based emission measurements of biomass burning in typical Chinese built-in-place stoves.

Residential combustion emission contributes significantly to ambient and indoor air pollution in China; however, this pollution source is poorly characterized and often overlooked in national pollution control policies. Few studies, and even fewer field-based investigations, have evaluated pollutant emissions from indoor biomass burning. One significant feature of Chinese household biofuel stoves is that many are built on site. In this study, 112 tests were conducted to investigate pollutant emission factors and variations for 11 fuel-stove combinations in actual use in the field. Results showed that, compared to those emission tests under controlled fuel burning conditions, EFs of methane, sulfur dioxide, particulate matter, and organic carbon from the field-based uncontrolled tests were higher, but carbon monoxide, nitrogen oxides, and elemental carbon were not significantly different. Controlled burning tests may be unrepresentative of real-world fuel burning. Pollutant emissions from uncontrolled burning tests had much higher variations compared with controlled tests. Most pollutant emissions from indoor straw burning are higher than that in open burning, except nitrogen oxides. The typical built-in-place home stoves in China had low efficiencies and high pollutant emissions that were rated as Tier 0 (the worst) or Tier 1 of a four-tier scale according to the International Organization for Standardization, International Workshop Agreement 11-2012. Effective interventions are expected to lower pollutant emissions from residential combustion to improve air quality and to protect human health.

Light absorption of organic carbon emitted from burning wood, charcoal, and kerosene in household cookstoves.

Household cookstove emissions are an important source of carbonaceous aerosols globally. The light-absorbing organic carbon (OC), also termed brown carbon (BrC), from cookstove emissions can impact the Earth's radiative balance, but is rarely investigated. In this work, PM2.5 filter samples were collected during combustion experiments with red oak wood, charcoal, and kerosene in a variety of cookstoves mainly at two water boiling test phases (cold start CS, hot start HS). Samples were extracted in methanol and extracts were examined using spectrophotometry. The mass absorption coefficients (MACλ, m2 g-1) at five wavelengths (365, 400, 450, 500, and 550 nm) were mostly inter-correlated and were used as a measurement proxy for BrC. The MAC365 for red oak combustion during the CS phase correlated strongly to the elemental carbon (EC)/OC mass ratio, indicating a dependency of BrC absorption on burn conditions. The emissions from cookstoves burning red oak have an average MACλ 2-6 times greater than those burning charcoal and kerosene, and around 3-4 times greater than that from biomass burning measured in previous studies. These results suggest that residential cookstove emissions could contribute largely to ambient BrC, and the simulation of BrC radiative forcing in climate models for biofuel combustion in cookstoves should be treated specifically and separated from open biomass burning.

Differential exposure and acute health impacts of inhaled solid-fuel emissions from rudimentary and advanced cookstoves in female CD-1 mice.

BACKGROUND: There is an urgent need to provide access to cleaner end user energy technologies for the nearly 40% of the world's population who currently depend on rudimentary cooking and heating systems. Advanced cookstoves (CS) are designed to cut emissions and solid-fuel consumption, thus reducing adverse human health and environmental impacts. STUDY PREMISE: We hypothesized that, compared to a traditional (Tier 0) three-stone (3-S) fire, acute inhalation of solid-fuel emissions from advanced natural-draft (ND; Tier 2) or forced-draft (FD; Tier 3) stoves would reduce exposure biomarkers and lessen pulmonary and innate immune system health effects in exposed mice. RESULTS: Across two simulated cooking cycles (duration ~ 3h), emitted particulate mass concentrations were reduced 80% and 62% by FD and ND stoves, respectively, compared to the 3-S fire; with corresponding decreases in particles visible within murine alveolar macrophages. Emitted carbon monoxide was reduced ~ 90% and ~ 60%, respectively. Only 3-S-fire-exposed mice had increased carboxyhemoglobin levels. Emitted volatile organic compounds were FD ≪ 3-S-fire ≤ ND stove; increased expression of genes involved in xenobiotic metabolism (COX-2, NQO1, CYP1a1) was detected only in ND- and 3-S-fire-exposed mice. Diminished macrophage phagocytosis was observed in the ND group. Lung glutathione was significantly depleted across all CS groups, however the FD group had the most severe, ongoing oxidative stress. CONCLUSIONS: These results are consistent with reports associating exposure to solid fuel stove emissions with modulation of the innate immune system and increased susceptibility to infection. Lower respiratory infections continue to be a leading cause of death in low-income economies. Notably, 3-S-fire-exposed mice were the only group to develop acute lung injury, possibly because they inhaled the highest concentrations of hazardous air toxicants (e.g., 1,3-butadiene, toluene, benzene, acrolein) in association with the greatest number of particles, and particles with the highest % organic carbon. However, no Tier 0-3 ranked CS group was without some untoward health effect indicating that access to still cleaner, ideally renewable, energy technologies for cooking and heating is warranted.

Evaluating the Performance of Household Liquefied Petroleum Gas Cookstoves.

Liquefied petroleum gas (LPG) cookstoves are considered to be an important solution for mitigating household air pollution; however, their performance has rarely been evaluated. To fill the data and knowledge gaps in this important area, 89 laboratory tests were conducted to quantify efficiencies and pollutant emissions from five commercially available household LPG stoves under different burning conditions. The mean thermal efficiency (±standard deviation) for the tested LPG cookstoves was 51 ± 6%, meeting guidelines for the highest tier level (Tier 4) under the International Organization for Standardization, International Workshop Agreement 11. Emission factors of CO2, CO, THC, CH4, and NOx on the basis of useful energy delivered (MJd) were 142 ± 17, 0.77 ± 0.55, 130 ± 196, 5.6 ± 8.2, and 46 ± 9 mg/MJd, respectively. Approximately 90% of the PM2.5 data were below the detection limit, corresponding to an emission rate below 0.11 mg/min. For those data above the detection limit, the average emission factor was 2.4 ± 1.6 mg/MJd, with a mean emission rate of 0.20 ± 0.16 mg/min. Under the specified gas pressure (2.8 kPa), but with the burner control set to minimum air flow rate, less complete combustion resulted in a visually yellow flame, and CO, PM2.5, EC, and BC emissions all increased. LPG cookstoves met guidelines for Tier 4 for both CO and PM2.5 emissions and mostly met the World Health Organization Emission Rate Targets set to protect human health.

A Laboratory Comparison of Emission Factors, Number Size Distributions, and Morphology of Ultrafine Particles from 11 Different Household Cookstove-Fuel Systems.

Ultrafine particle (UFP) emissions and particle number size distributions (PNSD) are critical in the evaluation of air pollution impacts; however, data on UFP number emissions from cookstoves, which are a major source of many pollutants, are limited. In this study, 11 fuel-stove combinations covering a variety of fuels and different stoves are investigated for UFP emissions and PNSD. The combustion of LPG and alcohol (∼1011 particles per useful energy delivered, particles/MJd), and kerosene (∼1013 particles/MJd), produced emissions that were lower by 2-3 orders of magnitude than solid fuels (1014-1015 particles/MJd). Three different PNSD types-unimodal distributions with peaks ∼30-40 nm, unimodal distributions with peaks <30 nm, and bimodal distributions-were observed as the result of both fuel and stove effects. The fractions of particles smaller than 30 nm (F30) varied among the tested systems, ranging from 13% to 88%. The burning of LPG and alcohol had the lowest PM2.5 mass emissions, UFP number emissions, and F30 (13-21% for LPG and 35-41% for alcohol). Emissions of PM2.5 and UFP from kerosene were also low compared with solid fuel burning but had a relatively high F30 value of approximately 73-80%.

Polycyclic Aromatic Hydrocarbons in Fine Particulate Matter Emitted from Burning Kerosene, Liquid Petroleum Gas, and Wood Fuels in Household Cookstoves.

This study measures polycyclic aromatic hydrocarbon (PAH) compositions in particulate matter emissions from residential cookstoves. A variety of fuel and cookstove combinations are investigated, including: (i) liquid petroleum gas (LPG), (ii) kerosene in a wick stove, (iii) wood (10 and 30% moisture content on a wet basis) in a forced-draft fan stove, and (iv) wood in a natural-draft rocket cookstove. The wood burning in the natural-draft stove had the highest PAH emissions followed by the wood combustion in the forced-draft stove and kerosene burning. LPG combustion has the highest thermal efficiency (∼57%) and the lowest PAH emissions per unit fuel energy, resulting in the lowest PAH emissions per useful energy delivered (in the unit of megajoule delivered, MJd). Compared with the wood combustion emissions, LPG burning also emits a lower fraction of higher molecular weight PAHs. In rural regions where LPG and kerosene are unavailable or unaffordable, the forced-draft fan stove is expected to be an alternative because its benzo[a]pyrene (B[a]P) emission factor (5.17-8.24 µg B[a]P/MJd) and emission rate (0.522-0.583 µg B[a]P/min) are similar to those of kerosene burning (5.36 µg B[a]P/MJd and 0.452 µg B[a]P/min). Relatively large PAH emission variability for LPG suggests a need for additional future tests to identify the major factors influencing these combustion emissions. These future tests should also account for different LPG fuel formulations and stove burner types.

Mutagenicity and Pollutant Emission Factors of Solid-Fuel Cookstoves: Comparison with Other Combustion Sources.

BACKGROUND: Emissions from solid fuels used for cooking cause ~4 million premature deaths per year. Advanced solid-fuel cookstoves are a potential solution, but they should be assessed by appropriate performance indicators, including biological effects. OBJECTIVE: We evaluated two categories of solid-fuel cookstoves for eight pollutant and four mutagenicity emission factors, correlated the mutagenicity emission factors, and compared them to those of other combustion emissions. METHODS: We burned red oak in a 3-stone fire (TSF), a natural-draft stove (NDS), and a forced-draft stove (FDS), and we combusted propane as a liquified petroleum gas control fuel. We determined emission factors based on useful energy (megajoules delivered, MJd) for carbon monoxide, nitrogen oxides (NOx), black carbon, methane, total hydrocarbons, 32 polycyclic aromatic hydrocarbons, PM2.5, levoglucosan (a wood-smoke marker), and mutagenicity in Salmonella. RESULTS: With the exception of NOx, the emission factors per MJd were highly correlated (r ≥ 0.97); the correlation for NOx with the other emission factors was 0.58-0.76. Excluding NOx, the NDS and FDS reduced the emission factors an average of 68 and 92%, respectively, relative to the TSF. Nevertheless, the mutagenicity emission factor based on fuel energy used (MJthermal) for the most efficient stove (FDS) was between those of a large diesel bus engine and a small diesel generator. CONCLUSIONS: Both mutagenicity and pollutant emission factors may be informative for characterizing cookstove performance. However, mutagenicity emission factors may be especially useful for characterizing potential health effects and should be evaluated in relation to health outcomes in future research. An FDS operated as intended by the manufacturer is safer than a TSF, but without adequate ventilation, it will still result in poor indoor air quality. CITATION: Mutlu E, Warren SH, Ebersviller SM, Kooter IM, Schmid JE, Dye JA, Linak WP, Gilmour MI, Jetter JJ, Higuchi M, DeMarini DM. 2016. Mutagenicity and pollutant emission factors of solid-fuel cookstoves: comparison with other combustion sources. Environ Health Perspect 124:974-982; http://dx.doi.org/10.1289/ehp.1509852.

Cleaner cooking solutions to achieve health, climate, and economic cobenefits.

Nearly half the world's population must rely on solid fuels such as biomass (wood, charcoal, agricultural residues, and animal dung) and coal for household energy, burning them in inefficient open fires and stoves with inadequate ventilation. Household solid fuel combustion is associated with four million premature deaths annually; contributes to forest degradation, loss of habitat and biodiversity, and climate change; and hinders social and economic progress as women and children spend hours every day collecting fuel. Several recent studies, as well as key emerging national and international efforts, are making progress toward enabling wide-scale household adoption of cleaner and more efficient stoves and fuels. While significant challenges remain, these efforts offer considerable promise to save lives, improve forest sustainability, slow climate change, and empower women around the world.

Pollutant emissions and energy efficiency under controlled conditions for household biomass cookstoves and implications for metrics useful in setting international test standards.

Realistic metrics and methods for testing household biomass cookstoves are required to develop standards needed by international policy makers, donors, and investors. Application of consistent test practices allows emissions and energy efficiency performance to be benchmarked and enables meaningful comparisons among traditional and advanced stove types. In this study, 22 cookstoves burning six fuel types (wood, charcoal, pellets, corn cobs, rice hulls, and plant oil) at two fuel moisture levels were examined under laboratory-controlled operating conditions as outlined in the Water Boiling Test (WBT) protocol, Version 4. Pollutant emissions (carbon dioxide, carbon monoxide, methane, total hydrocarbons, and ultrafine particles) were continuously monitored. Fine particle mass was measured gravimetrically for each WBT phase. Additional measurements included cookstove power, energy efficiency, and fuel use. Emission factors are given on the basis of fuel energy, cooking energy, fuel mass, time, and cooking task or activity. The lowest PM(2.5) emissions were 74 mg MJ(delivered)(-1) from a technologically advanced cookstove compared with 700-1400 mg MJ(delivered)(-1) from the base-case open 3-stone cookfire. The highest thermal efficiency was 53% compared with 14-15% for the 3-stone cookfire. Based on these laboratory-controlled test results and observations, recommendations for developing potentially useful metrics for setting international standards are suggested.

Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists.

A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.

Identification of phenylsulfone-substituted quinoxaline (WYE-672) as a tissue selective liver X-receptor (LXR) agonist.

A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.

A pilot simulation study of arsenic tracked from CCA-treated decks onto carpets.

A controlled simulation experiment was performed to assess whether dislodgeable arsenic can be tracked onto carpets via foot traffic from chromated copper arsenate (CCA) pressure-treated decks. The pilot simulation study demonstrated that it is possible to track arsenic from CCA-decks onto carpets under the test conditions evaluated. A total of nine CCA-decks and two non-CCA-treated control surfaces were tested under wet and dry conditions. Five participants walked in a controlled manner (60 cycles, 11 steps per cycle) across decks and then walked over various lanes of carpet to simulate the tracking of arsenic indoors on the bottoms of shoes under heavy foot traffic conditions. To determine if arsenic was transferred from the CCA-treated wood to the carpet via shoes, laboratory analysis was performed on three different types of samples: (1) wipe samples of dislodgeable arsenic from a 46 cm(2) area of carpet, (2) dust samples obtained from vacuuming a 7442 cm(2) area of carpet, and (3) extractions of 13 cm(2) carpet samples. Wipe samples were also taken directly from the deck lumber. Following digestion and extraction, the amount of arsenic in each sample was measured using Graphite Furnace Atomic Absorption Spectrometry. The mean arsenic concentration measured on the carpets was 2.52 microg/(100 cm(2)) and 2.05 microg/(100 cm(2)) with wipes for the dry and wet conditions, respectively, 4.69 microg/(100 cm(2)) and 0.68 microg/(100 cm(2)) with vacuumed dust for the dry and wet conditions, respectively, and 15.56 microg/(100 cm(2)) and 12.31 microg/(100 cm(2)) with carpet extractions for the dry and wet conditions, respectively. The mean arsenic concentration measured on the decks was 22.2 microg/(100 cm(2)) with wipes. Further research is needed to determine if indoor exposure to arsenic due to track-in from outdoor decks via foot traffic is significant compared to exposures from other sources.

Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.

2-phenyl-4-piperazinylbenzimidazoles: orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor.

Antagonism of the gonadotropin releasing hormone (GnRH) receptor has shown positive clinical results in numerous reproductive tissue disorders such as endometriosis, prostate cancer and others. Traditional therapy has been limited to peptide agonists and antagonists. Recently, small molecule GnRH antagonists have emerged as potentially new treatments. This article describes the discovery of 2-phenyl-4-piperazinylbenzimidazoles as small molecule GnRH antagonists with nanomolar potency in in vitro binding and functional assays, excellent bioavailability (rat %F>70) and demonstrated oral activity in a rat model having shown significant serum leuteinizing hormone (LH) suppression.