title: Acute effects of a low-dose atropine/scopolamine mixture as a food contaminant in human volunteers.
abstract: To verify the assumptions in our previous risk assessment of an atropine/scopolamine mixture in buckwheat flour, we performed a randomized, double-blind, placebo-controlled cross-over study in 20 healthy, adult volunteers. The volunteers ingested a traditional Slovenian buckwheat meal, made of boiled buckwheat flour to which alkaloids were added. In addition to the placebo they ingested 0.12/0.10, 0.37/0.29, 1.22/0.95, 3.58/2.81 and 12.10/9.50 µg kg(-1) body mass (BM) of the atropine/scopolamine mixture. The changes in body temperature, heart rate, salivary and sweat secretion, pupil size, near-point vision and subjective symptoms were recorded regularly for 4 h after the ingestion. Decreased salivary and sweat secretion, increased heart rate and pupil size and reduced near-point vision accompanied by characteristic subjective symptoms were observed at 12.10/9.50 µg kg(-1) BM. At doses of 0.37/0.29 and 1.22/0.95 µg kg(-1) BM, a significant decrease in the heart rate was noted, which we consider to be a critical effect of a low-dose exposure to the atropine/scopolamine mixture. Although this did not have any clinical relevance in our subjects, it may have serious implications if it occurred in people with pre-existent cardiac conditions or those on medications that may cause bradycardia. No significant changes in the observed end points were noted at 0.12/0.10 µg kg(-1) BM. We estimate that the NOAEL (No Observed Adverse Effect Level) for the atropine/scopolamine mixture lies between the lower two administered doses. Applying the uncertainty factor of 10, we propose a new provisional Acute Reference Doses (ARfDs) of the mixture, i.e. 0.01 µg kg(-1) BM for each alkaloid, and a further refinement using higher-tier approaches.
authors.affiliation: Department of Infectious Diseases and Environmental Risks, National Institute of Public Health, Trubarjeva 2, 1000 Ljubljana, Slovenia. lucija.perharic@siol.net
authors.forename: Lucija
authors.initials: L
authors.lastname: Perharič
authors.forename: Katja Ažman
authors.initials: KA
authors.lastname: Juvan
authors.forename: Lovro
authors.initials: L
authors.lastname: Stanovnik
mesh_terms: D000293:Adolescent; D000328:Adult; D001285:Atropine / Q000633:toxicity*; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology; D003296:Cooking; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D023381:Endpoint Determination; D019612:Fagopyrum / Q000737:chemistry; D005433:Flour / Q000032:analysis; D005506:Food Contamination / Q000032:analysis*; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment; D012601:Scopolamine / Q000633:toxicity*; D023382:Toxicity Tests, Acute; D055815:Young Adult
chemical_list: D001285:Atropine; D012601:Scopolamine