title: Toxicological assessment of a prototype e-cigaret device and three flavor formulations: a 90-day inhalation study in rats.
abstract: A prototype electronic cigaret device and three formulations were evaluated in a 90-day rat inhalation study followed by a 42-day recovery period. Animals were randomly assigned to groups for exposure to low-, mid- and high-dose levels of aerosols composed of vehicle (glycerin and propylene glycol mixture); vehicle and 2.0% nicotine; or vehicle, 2.0% nicotine and flavor mixture. Daily targeted aerosol total particulate matter (TPM) doses of 3.2, 9.6 and 32.0 mg/kg/day were achieved by exposure to 1 mg/L aerosol for 16, 48 and 160 min, respectively. Pre-study evaluations included indirect ophthalmoscopy, virology and bacteriological screening. Body weights, clinical observations and food consumption were monitored weekly. Plasma nicotine and cotinine and carboxyhemoglobin levels were measured at days 28 and 90. After days 28, 56 and 90, lung function measurements were obtained. Biological endpoints after 90-day exposure and 42-day recovery period included clinical pathology, urinalysis, bronchoalveolar fluid (BALF) analysis, necropsy and histopathology. Treatment-related effects following 90 days of exposure included changes in body weight, food consumption and respiratory rate. Dose-related decreases in thymus and spleen weights, and increased BALF lactate dehydrogenase, total protein, alveolar macrophages, neutrophils and lung weights were observed. Histopathology evaluations revealed sporadic increases in nasal section 1-4 epithelial hyperplasia and vacuolization. Following the recovery period, effects in the nose and BALF were persistent while other effects were resolved. The no observed effect level based upon body weight decreases is considered to be the mid-dose level for each formulation, equivalent to a daily TPM exposure dose of approximately 9.6 mg/kg/day.
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Werley
authors.affiliation: b WIL Research Laboratories , Ashland , OH , USA.
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Kirkpatrick
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Oldham
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Jerome
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Langston
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Lilly
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Donna C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: a Regulatory Affairs, Altria Client Services Inc , Richmond , VA , USA and.
authors.forename: Willie J
authors.initials: WJ
authors.lastname: Mckinney
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D003367:Cotinine / Q000097:blood; D066300:Electronic Nicotine Delivery Systems; D005260:Female; D005421:Flavoring Agents / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000097:blood; D019055:No-Observed-Adverse-Effect Level; D009666:Nose / Q000187:drug effects / Q000473:pathology; D017207:Rats, Sprague-Dawley; D059550:Toxicity Tests, Subchronic
chemical_list: D000336:Aerosols; D005421:Flavoring Agents; D009538:Nicotine; D007770:L-Lactate Dehydrogenase; D003367:Cotinine
keywords: E-cigaret; rodent; subchronic inhalation