Developmental exposure to a mixture of unconventional oil and gas chemicals: A review of experimental effects on adult health, behavior, and disease.

Unconventional oil and natural gas extraction (UOG) combines directional drilling and hydraulic fracturing and produces billions of liters of wastewater per year. Herein, we review experimental studies that evaluated the potential endocrine-mediated health impacts of exposure to a mixture of 23 UOG chemicals commonly found in wastewater. The purpose of this manuscript is to synthesize and summarize a body of work using the same UOG-mix but with different model systems and physiological endpoints in multiple experiments. The studies reviewed were conducted in laboratory animals (mice or tadpoles) and human tissue culture cells. A key feature of the in vivo studies was the use of four environmentally relevant doses spanning three orders of magnitude ranging from concentrations found in surface and ground water in UOG dense areas to concentrations found in UOG wastewater. This UOG-mix exhibited potent antagonist activity for the estrogen, androgen, glucocorticoid, progesterone, and thyroid receptors in human tissue culture cells. Subsequently, pregnant mice were administered the UOG-mix in drinking water and offspring were examined in adulthood or to tadpoles. Developmental exposure profoundly impacted pituitary hormone concentrations, reduced sperm counts, altered folliculogenesis, and increased mammary gland ductal density and preneoplastic lesions in mice. It also altered energy expenditure, exploratory and risk-taking behavior, the immune system in three immune models in mice, and affected basal and antiviral immunity in frogs. These findings highlight the diverse systems affected by developmental EDC exposure and the need to examine human and animal health in UOG regions.

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.