Szlapinski Sandra K, Charrette Andrew, Guthrie Najla, Hilmas Corey J
KGK Science Inc, Division of Client Services, Department of Regulatory Affairs, London, ON, Canada.
Front Toxicol. 2023 Feb 2;5:1117729. doi: 10.3389/ftox.2023.1117729. eCollection 2023.
Caffeine, one of the most ubiquitous ingredients found in beverages and other ingested food products, has a long history of safe use. As a member of the methylxanthine class of stimulants, caffeine is not devoid of unwanted side effects at any serving level. Caffeine safety has been the subject of a safety workshop by FDA and the Institute of Medicine in the past decade. Thus, investigation into an alternate stimulant with similar pharmacology but improved safety is warranted. Paraxanthine (1,7-dimethylxanthine) is the predominant metabolite of caffeine in humans with similar stimulant properties. The few toxicity studies that are available for paraxanthine suggest that the molecule is relatively safe, although thorough characterization of its safety is required prior to widespread incorporation into foods/beverages. The aim of this study was to evaluate the toxicity of paraxanthine (Rarebird, Inc.) relative to caffeine through a battery of toxicological studies conducted in accordance with international guidelines. These studies evaluated the potential mutagenicity (bacterial reverse mutation, mammalian chromosomal aberration), genetic toxicity ( mammalian cell gene mutation) and acute, sub-acute and sub-chronic oral toxicity of paraxanthine in Sprague Dawley rats. There was no evidence of genetic toxicity or mutagenicity in the studies. An acute oral LD of 829.20 mg/kg body weight (bw) was established. There was no mortality or treatment-related adverse effects in the 14-day repeat dose oral toxicity study, wherein rats received low, mid, or high doses of paraxanthine (50, 100, or 150 mg/kg bw, = 5 rats/sex/group). The same findings were observed in the subchronic repeat-dose 90-day oral toxicity study at daily doses of paraxanthine of 100, 150, or 185 mg/kg bw which were compared to caffeine at 150 or 185 mg/kg bw ( = 10 animals/sex/group). However, mortality was reported in two animals in the high dose caffeine-treated animals. Therefore, the no observed adverse effect level (NOAEL) from the 90-day study was determined to be 150 mg/kg bw for caffeine and 185 mg/kg bw for paraxanthine for both male and female Sprague Dawley rats. These findings may suggest that paraxanthine could be a safer alternative to caffeine in humans.
咖啡因是饮料和其他摄入性食品中最常见的成分之一，其安全使用历史悠久。作为甲基黄嘌呤类兴奋剂的一员，无论摄入量多少，咖啡因都存在一些不良副作用。在过去十年中，美国食品药品监督管理局（FDA）和医学研究所举办了一次关于咖啡因安全性的研讨会。因此，有必要研究一种药理学特性相似但安全性更高的替代兴奋剂。对甲基黄嘌呤（1,7 - 二甲基黄嘌呤）是人体内咖啡因的主要代谢产物，具有类似的兴奋特性。现有的少量关于对甲基黄嘌呤的毒性研究表明，该分子相对安全，不过在广泛应用于食品/饮料之前，还需要对其安全性进行全面的特性描述。本研究的目的是通过一系列按照国际准则进行的毒理学研究，评估对甲基黄嘌呤（Rarebird公司生产）相对于咖啡因的毒性。这些研究评估了对甲基黄嘌呤在斯普拉格 - 道利大鼠体内的潜在致突变性（细菌回复突变、哺乳动物染色体畸变）、遗传毒性（哺乳动物细胞基因突变）以及急性、亚急性和亚慢性经口毒性。研究中没有发现遗传毒性或致突变性的证据。确定经口急性半数致死量为829.20毫克/千克体重（bw）。在为期14天的重复剂量经口毒性研究中，大鼠分别接受低、中、高剂量的对甲基黄嘌呤（50、100或150毫克/千克体重，每组雌雄各5只大鼠），未出现死亡或与治疗相关的不良反应。在为期90天的亚慢性重复剂量经口毒性研究中，对甲基黄嘌呤的日剂量为100、150或185毫克/千克体重，与咖啡因的150或185毫克/千克体重进行比较（每组雌雄各10只动物），观察到了相同的结果。然而，高剂量咖啡因处理组有两只动物死亡。因此，90天研究确定的未观察到有害作用水平（NOAEL），对于雄性和雌性斯普拉格 - 道利大鼠，咖啡因是150毫克/千克体重，对甲基黄嘌呤是185毫克/千克体重。这些发现可能表明，对甲基黄嘌呤对人类来说可能是一种比咖啡因更安全的替代品。
