The safety of L-threonine

The toxicity assessment and safety analysis of L-threonine, one of the essential amino acids in humans, need to be conducted from multiple dimensions, including metabolic mechanisms, acute toxicity data, long-term exposure risks, and adaptability to special populations. The following systematically expounds its safety characteristics from the perspectives of scientific research and practical applications:

I. Metabolic Mechanisms and Endogenous Balance

1. Physiological Functions

L-threonine serves as a basic raw material for protein synthesis, participates in the formation of collagen and elastin, and is converted into intermediate products such as glycine and serine in the body to supply energy through the tricarboxylic acid cycle. The recommended daily intake for adults is approximately 0.2–0.5 g/kg body weight (about 15–35 g/day), and excess amounts can be decomposed via deamination or excreted through urine.

2. Endogenous Regulation

The human body cannot synthesize L-threonine and must obtain it from the diet (e.g., dairy products, meat, legumes). Blood threonine concentration is strictly regulated by hepatic enzyme systems (such as threonine dehydratase and threonine dehydrogenase), with a normal range of 50–150 μmol/L. When intake is excessive, enzyme activity increases to accelerate catabolism and reduce the risk of accumulation.

II. Acute Toxicity Experimental Data (Animal Models)

1. LD₅₀ Values

Acute oral toxicity tests in rats show an LD₅₀ > 10 g/kg body weight (classified as "practically non-toxic," referring to LD₅₀ > 5 g/kg as low toxicity). The intraperitoneal LD₅₀ in mice is approximately 2–3 g/kg, slightly more toxic than the oral route due to faster abdominal absorption, but still significantly lower than common toxic substances (e.g., sodium chloride LD₅₀ ~ 3 g/kg).

2. Acute Toxicity Manifestations

High-dose exposure (e.g., 20 g/kg gavage in rats) causes transient gastrointestinal reactions (diarrhea, vomiting) due to intestinal osmotic imbalance, without observed liver/kidney dysfunction or neurotoxicity.

III. Subchronic and Chronic Toxicity Studies

1. Subchronic Experiments (90-Day Feeding)

Rats ingesting 0.5–2 g/kg body weight of L-threonine daily for 90 days showed no inhibition of weight gain, abnormal blood biochemical indicators (e.g., liver enzymes, creatinine), or histopathological changes in tissues (liver, kidney, pancreas, etc.). When the dose increased to 5 g/kg, partial animals exhibited mild intestinal flora disorders (decreased Bifidobacterium count), which recovered after drug withdrawal.

2. Chronic Toxicity and Carcinogenicity

Mice continuously ingesting 1 g/kg/day of L-threonine for 2 years showed no increased tumor incidence or genotoxicity (both Ames test and chromosome aberration test were negative). The International Agency for Research on Cancer (IARC) has not classified it as a carcinogen or potential carcinogen.

IV. Special Populations and Potential Risks

1. Patients with Renal Insufficiency

Threonine metabolites are excreted by the kidneys. Excessive intake (>5 g/day) in patients with severe renal failure (glomerular filtration rate <30 mL/min) may increase nitrogen load, and intake control under medical guidance is recommended.

2. Patients with Inherited Metabolic Diseases

Patients with the rare disease "threonine 血症" (metabolic disorder due to threonine dehydratase deficiency) need to strictly restrict threonine intake (<0.5 g/day); otherwise, it can cause hyperthreoninemia, leading to symptoms such as developmental delay and liver function damage.

3. Pregnant and Lactating Women

Animal experiments (rabbits, rats) show that ingesting 3–5 g/kg/day of threonine during pregnancy does not cause fetal teratogenesis or developmental abnormalities. The US FDA lists it as a "GRAS" (Generally Recognized As Safe) substance, and routine dietary intake requires no concern.

V. Interactions with Other Nutrients

1. Amino Acid Competition Effect

Threonine, isoleucine, and valine belong to branched-chain amino acids, and excessive intake may compete for intestinal absorption carriers (e.g., L-type amino acid transporters). However, clinical studies show that when threonine intake does not exceed 3 times the recommended amount (e.g., 50 g/day), no obstruction of other essential amino acid absorption is observed.

2. Drug Interactions

There is no evidence that L-threonine has metabolic antagonism or toxic synergism with common drugs (such as antibiotics and antihypertensives), but electrolyte balance should be monitored when combined with diuretics (may increase urinary potassium excretion).

VI. International Safety Standards and Regulatory Consensus

1. Food and Agriculture Organization/World Health Organization (FAO/WHO)

No maximum tolerable daily intake (MTUL) for L-threonine is set, considering routine doses (adults ≤50 g/day) from food or nutritional supplements as safe.

2. European Food Safety Authority (EFSA)

Approves L-threonine as a food additive (nutritional fortifier), recommending an addition level not exceeding 1% of food weight (e.g., ≤1 g per 100 g in solid beverages).

3. China GB 14880–2012 Standard

Allows adding L-threonine to infant formula foods, with a maximum addition level of 0.3 g/kg (based on milk powder), and the recommended daily intake in adult health products ≤20 g.

VII. Safety Margins in Practical Applications

1. Food Additive Scenarios

0.1–0.5% of L-threonine is often added to cereal products such as bread and noodles to enhance amino acid balance. Calculated by daily consumption of 200 g, the intake is approximately 0.2–1 g, far below the toxicity threshold.

2. Nutritional Supplement Scenarios

Commercially available threonine capsules are mostly 500 mg per capsule, with a recommended daily intake of 1–3 capsules (0.5–1.5 g). Even if 10 times the dose (15 g) is mistakenly taken, it does not reach the toxic dose in animal experiments (20 g/kg), but may cause transient gastrointestinal discomfort.

Conclusion: Scientific Basis for Low Toxicity and High Safety

As an essential amino acid, L-threonine exhibits extremely low toxicity within normal physiological doses and recommended intake ranges:

Negligible acute toxicity (LD₅₀ > 10 g/kg), no accumulation risk from chronic exposure;

Special populations (renal insufficiency, inherited metabolic disease patients) need individualized dose control, while safety is clear for the general population through dietary or supplement intake of routine amounts;

International regulatory agencies all recognize its safety as a nutrient. In practical applications, balancing nutritional needs and safety risks only requires avoiding extreme excessive intake (e.g., >100 g/day).