28-Day dietary toxicity study of L-phenylalanine in rats

Shibui, Yusuke; Miwa, Tadashi; Kodama, Terutaka; Gonsho, Akinori

doi:10.2131/fts.1.29

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…However, for performing an equal variance test, we recommend Leven's homogeneity test (Levene, 1960), the sensitivity of which to the homogeneity of variance is not as high as that of Bartlett's test. Risom et al (2003), Shibui et al (2014), Tanaka et al (2019) and Masubuchi et al (2020) conducted toxicity or pharmacological studies using Levene's test. The authors of the present paper do not suggest Bartlett's test in the case of five animals per group.…”

Section: Selecting a Test Of Homogeneity Of Variance When The Number ...mentioning

confidence: 99%

Repeated dose administration toxicity studies - Use of <i>t</i>-tests in multiplicity data analysis

Kobayashi,

Pillai

2024

Fundam. Toxicol. Sci.

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In conducting repeated dose administration toxicity (RDAT) studies with rats and mice, a minimum of three dose groups and one control group are normally set for determing NOEL/NOAEL (no-observed effect level/no-observed adverse effect level) of the test item. For comparison of data among the groups, initially, the data are analysed by analysis of variance (ANOVA). If ANOVA shows a significant difference, then groups means are compared by a multiple comparison range test (MCRT). However, in RDAT studies, at the end of the long duration of the test substance administration, the distribution of the data obtained varies considerably among the groups and the number of animals decreases due to mortality/morbidity, especially in the high-dose groups. Increased variance in the distribution of the data and decreased animals in one or more groups may result in an insignificant ANOVA, though the low-dose group may show a marked difference compared to the control. Dunnett's multiple comparison test is commonly used to compare each treatment group with the control group. However, Dunnett's test has a lower ability to detect significant differences than the t-test, and its detection power decreases with the increase in the number of groups. Therefore, we recommend the t-test, by-passing ANOVA, which has a high detectable significant difference in the two-group test. In addition, the application of the t-test eliminates the need to select an MCRT. However, the final judgment of the adverse effects may be made based on the toxicological relevance in consideration of the statistical analysis results.

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Section: Selecting a Test Of Homogeneity Of Variance When The Number ...mentioning

confidence: 99%

Repeated dose administration toxicity studies - Use of <i>t</i>-tests in multiplicity data analysis

Kobayashi,

Pillai

2024

Fundam. Toxicol. Sci.

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“…While human safety data are limited, subchronic rodent toxicological studies of both phenylalanine and serine have already been published [21,22]. However, in the case of macronutrients such as amino acids, rodent findings have limited applicability to human risk assessment [23,24].…”

Section: Sleep Quality Mental Fatigue Macronutrient and Caloric Intakes Body Weight Changesmentioning

confidence: 99%

Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults

Miura¹,

Matsui²,

Cynober

et al. 2021

Nutrients

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Phenylalanine and serine are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe level of phenylalanine or serine supplementation is unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral phenylalanine and oral serine. Healthy male adults (n = 60, 38.2 ± 1.8y) completed graded dosages of either phenylalanine or serine supplement (3, 6, 9 and 12 g/d) for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, body weight, sleep quality and mental self-assessment. At low dosages, minor changes in serum electrolytes and plasma non-essential amino acids glutamine and aspartic acid concentrations were observed. Serine increased its plasma concentrations at high supplemental dosages (9 and 12 g/day), and phenylalanine increased plasma tyrosine concentrations at 12 g/day, but those changes were not considered toxicologically relevant. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of phenylalanine or serine without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of phenylalanine and serine supplementation in healthy adult males was determined to be 12 g/day.

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“…Based on the parameters including BW and food consumption measurement, organ weight, ophthalmic observation, red blood cell count, and blood glucose concentration measured after 4 weeks of ad libitum consumption of diet supplemented with phenylalanine, the authors proposed an NOAEL equal to 1.5% (w/w) for this amino acid (Shibui et al 2014 ). The NOAEL for phenylalanine then represents 1548 and 1555 mg/kg BW/day in male and female rats, respectively (Shibui et al 2014 ), and the LOAEL represents, respectively, 4903 and 4701 mg/kg BW/day (Shibui et al 2014 ). Thus, the NOAEL/UC ratios are 2.8 and 2.9 for male and female rats, respectively.…”

Section: Indispensable Amino Acidsmentioning

confidence: 99%

Tolerable amounts of amino acids for human supplementation: summary and lessons from published peer-reviewed studies

et al. 2021

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Amino acid supplementation may be indicated to correct for insufficient amino acid intake in healthy individuals, and in specific physiological or pathophysiological situations. However, there is a concern to not supplement beyond the tolerable upper intake level (UL) by determining parameters of no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for each amino acid. Since the NOAEL and LOAEL values are at least one order of magnitude different when comparing the values obtained in rats and humans, the aim of this review is to evaluate to what extent the amino acid UL measured in the rat model, when referenced to the dietary usual consumption (UC) and dietary requirement (RQ) for indispensable amino acids, may be used as an approximation of the UL in humans. This review then compares the ratios of the NOAEL or LOAEL over UC and RQ in the rat model with the same ratios calculated in humans for the nine amino acids (arginine, serine, glycine, histidine, leucine, lysine, methionine, phenylalanine, and tryptophan) for which this comparison can be done. From the calculations made, it appears that for these 9 amino acids, the calculated ratios for rats and humans, although rather different for several amino acids, remains for all of them in the same order of magnitude. For tryptophan, tyrosine, and valine, the ratios calculated in rats are markedly different according to the sex of animals, raising the view that it may be also the case in humans.

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28-Day dietary toxicity study of L-phenylalanine in rats

Cited by 5 publications

References 10 publications

Repeated dose administration toxicity studies - Use of <i>t</i>-tests in multiplicity data analysis

Repeated dose administration toxicity studies - Use of <i>t</i>-tests in multiplicity data analysis

Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults

Tolerable amounts of amino acids for human supplementation: summary and lessons from published peer-reviewed studies

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