SBIR-STTR Award

E-cigarette (E-cig) use has rapidly proliferated worldwide. It is speculated that E-cig use may exceed conventional cigarette use within 10 years. Cigarette smoking is the leading preventable cause of death and disability. As E-cigs are a relatively new product, studies are needed to determine their long-term detrimental effects, some of which may be similar to the long-term detrimental effects of nicotine. The lack of an appropriate method for E-cig delivery to animals and lack of an appropriate animal model are major barriers of the research field. We propose to develop a system designed for E-cig exposure to rodent models. We propose that E-cig exposure using our system can generate clinically relevant animal models with nicotine levels/PK comparable to those of human E-cig users for research of E-cig effects on human health, and allow investigators to uncover potential detrimental and beneficial effects related to E-cigs. Aim 1. To design and make a prototype for a product of efficient E-cig aerosol generation and exposure system delivering E- cig aerosol to rodent(s) through inhalation with characteristics equivalent to those inhaled by human E-cig users. This system includes hardware and software that control the number of E-cigs and timing of activation so as to regulate the dose of aerosol exposure. This device has variable E-cig holders for different sizes of E-cigs available in the market, and generates aerosol for testing different brands of E-cigs of investigators' choice. We will characterize the E-cig aerosol by measuring the aerosol particle size distribution and mass concentration in the breathing zone of the rodent exposure chamber to verify that the aerosol characteristics are equivalent to those in mainstream E-cigs that human E-cig smokers inhale. Aim 2. To validate this E-cig aerosol generation and exposure system with acute and chronic animal experiments to show that it produces E-cig animal models with nicotine PK comparable to that in human E-cig users. We will measure plasma nicotine and cotinine levels at a series of time points during and after rats or mice are exposed to E-cig aerosol in a free-moving or nose-only chamber. We will optimize the parameters (e.g., number of E-cigs and duration activated) of aerosol generation and exposure and determine if the system can generate rodent models with the concentrations of nicotine and cotinine resembling that in human ENDS users or other levels/PK as investigators choose for their research purposes. Our products will meet the need of the E-cig research community and greatly advance the field to enable testing potential toxicities of E- cig in animal models. Our products will be a powerful tool for studying the effects of E-cig smoking on cardiovascular, respiratory and nervous systems, on metabolism, pregnancy, development as well as teratogenicity and addiction of E-cigs. Therefore it will help inform regulators about the potential toxicity of E- cig products. We plan, in a future phase II project, to develop a commercial product line of E-cig generation and exposure systems including E-cig self-administration for rodents.

Public Health Relevance Statement:
Project Narrative As E-cigs are a relatively new product, studies are needed to determine their long-term detrimental effects on users while appropriate methods and devices for E-cig exposure to animal models are lacking. We propose to develop a system designed for E-cig exposure to rodent models. This system can generate clinically relevant animal models with nicotine levels/pharmacokinetics comparable to those of human E-cig users for research of E-cig effects on human health, and allow investigators to uncover potential detrimental and beneficial effects related to E-cigs.

Project Terms:
Acute; addiction; Aerosols; Air; Alveolar; Animal Experiments; Animal Model; Animals; Applications Grants; Benzene; Breathing; Cadmium; Carcinogens; Cardiovascular system; Cause of Death; Characteristics; Chronic; Cigarette; cigarette smoke; cigarette smoking; clinically relevant; Communities; Computer software; Cotinine; Cross-Sectional Studies; Data; Deposition; design; Development; Devices; disability; Dose; Drug abuse; Drug Administration Routes; Drug Kinetics; Electronic cigarette; Electronic Nicotine Delivery Systems; Exposure to; Formaldehyde; Future; Generations; Glycerol; Health; Heavy Metals; High School Student; Human; Industry; Intellectual Property; interest; invention; junior high school; Lead; Legal patent; Lung; Mainstreaming; Measures; Metabolism; Methods; Mus; nanometer; National Institute of Drug Abuse; Nervous system structure; Nicotine; Nicotine Dependence; Nitrosamines; Nose; Oral cavity; particle; Particle Size; Pharmaceutical Preparations; Phase; physical property; Plasma; Pregnancy; Proliferating; Propylene Glycols; prototype; Rattus; Research; Research Personnel; Respiratory System; response; Risk; Rodent; Rodent Model; Self Administration; Series; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Smoke; Smoker; Smoking; Surveys; Suspensions; System; Teratogens; Testing; Time; Tissues; Tobacco; tool; Toxic effect; Toxicology; Toxin; vapor; Youth

E cigarettes (E-cigs) are increasingly popular worldwide, in particular, among youths. E-cigs may contribute to nicotine addiction and are unlikely to discourage conventional cigarette smoking. Mainstream and second-hand E-cig aerosols contain, in addition to nicotine, detectable levels of toxins including carcinogens and heavy metals such as formaldehyde, benzene, nitrosamines, cadmium and lead. Therefore health risk and toxicology studies on animal models exposed to E-cig aerosol, not limited to nicotine, are urgently needed. We propose to develop a system designed for E-cig exposure to rodent models. With the support of our NIDA/NIH Phase I grant, we designed and built ten prototypes including hardware and software that control 3-4 E-cigs and timing of activation that can simulate the vaping pattern of E-cig users. We have characterized the aerosol particle size distribution and mass concentration in the breathing zone of the rodent exposure chamber. We have tested the prototype with acute and chronic rodent experiments. We have optimized the parameters of aerosol exposure and showed that the system can generate rodent models with nicotine circadian pharmacokinetics resembling human E-cig users. This application is to further develop and commercialize the product line for the E-cig research community. Aim 1. To build, upgrade and commercialize the product line of efficient E-cig aerosol generation and exposure systems delivering E-cig aerosol to rodents through inhalation with characteristics equivalent to those inhaled by human E-cig users. We will upgrade the system to integrate our ValveLink 8.2 technology. With USB connections, a computer can independently control up to 64 channels at 5-6 channels per animal exposure chamber. We will make E-cig holders for different E-cigs available in the marketplace including the NIDA standardize research E-cigarette (SREC). We will incorporate a Collison nebulizer to generate saline aerosol for control. We will make a product for rodent E-cig self-administration for studying addiction that includes software controlling two nose-poke sensors that either activate E-cigs or control aerosol when poked. Aim 2. To validate the E-cig aerosol generation and exposure system with acute and chronic animal experiments that produce E-cig exposure animal models for a variety of research needs including the study of addiction. We will test the system with behavioral experiments such as conditioned place preference (CPP), withdrawal signs with chronic intermittent E-cig exposure and E-cig self-administration experiments in rodents (rats or mice). In addition to validating the device, these experiments are significant in understanding E-cig reinforcement and dependence. Our products will meet the needs of the E-cig research community and advance the field to enable testing potential toxicities of E-cigs in animal models as well as facilitate new therapeutic discovery e.g., for nicotine addiction. Our products will be a powerful tool for studying the effects of E-cig vaping on the cardiovascular, respiratory and nervous systems, on metabolism, carcinogenesis, pregnancy and teratogenicity as well as their underlying mechanisms.

Public Health Relevance Statement:
Project Narrative As E-cigarettes (E-cigs) are a relatively new product, research is needed to determine their long-term detrimental effects on human users while appropriate methods and devices for relevant E-cig exposure in animal models are lacking. We propose to develop a system designed for E-cig exposure in rodent models. This system can generate clinically relevant animal models with nicotine levels/pharmacokinetics comparable to those of human E-cig users for research, and allow investigators to uncover potential detrimental and beneficial effects on human health as well as to develop therapeutics related to E-cig use.

NIH Spending Category:
Basic Behavioral and Social Science; Behavioral and Social Science; Brain Disorders; Drug Abuse (NIDA only); Substance Abuse; Tobacco

Project Terms:
Acute; addiction; Aerosols; Animal Experiments; Animal Model; animal model development; Animals; Applications Grants; Behavioral; Benzene; Blood; Blood Pressure; Breathing; Cadmium; carcinogenesis; Carcinogens; Cardiovascular system; Characteristics; Chronic; cigarette smoking; circadian; clinically relevant; Communities; Computer software; Computers; Dependence; design; Devices; Dose; Drug abuse; Drug Administration Routes; Drug Kinetics; Electrocardiogram; Electronic cigarette; electronic cigarette use; electronic cigarette user; experimental study; Exposure to; Formaldehyde; Generations; Glycerol; Grant; Hand; Health; Heavy Metals; Human; improved; Industry; Inhalation; interest; invention; Lead; Legal patent; Mainstreaming; Measures; Metabolism; Methods; Mus; National Institute of Drug Abuse; Nebulizer; Nervous system structure; Nicotine; Nicotine Dependence; nicotine vapor; Nitrosamines; Nose; novel therapeutics; off-patent; Oral cavity; Particle Size; Pattern; Pharmaceutical Preparations; Phase; physical property; Physiological; preference; Pregnancy; Propylene Glycols; prototype; Psychological reinforcement; Rattus; Research; Research Personnel; Respiratory System; response; Rewards; Risk; Rodent; Rodent Model; Saline; Schedule; Self Administration; sensor; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Smoke; Standardization; Substance Withdrawal Syndrome; System; Technology; Telemetry; Teratogens; Testing; Therapeutic; Tissues; tool; Toxic effect; Toxicology; Toxin; United States National Institutes of Health; vaper; vaping; vapor; Withdrawal; Youth