[Red Yeast Rice Incident Research Report Vol. 3] Kobayashi Pharmaceutical's Beni-Koji CholesteHelp Industrial Mutant Strain and the L-Tryptophan Incident: Safety Evaluation Issues Raised by Past Cases

Kunsei Club Co., Ltd. (located in Hayashima-cho, Tsukubo-gun, Okayama Prefecture) continues to disseminate its 'Red Yeast Rice Incident Research Report' series with the aim of presenting the scientific and legal issues of the Kobayashi Pharmaceutical red yeast rice incident to society at large. The third report addresses the topic of industrial mutant strains and the L-Tryptophan incident—safety evaluation issues raised by past cases.

[Abstract] This report redefines Beni-Koji CholesteHelp not as a 'traditional food' but as a 'fermentation product designed for high production of a specific component,' pointing out that existing food safety evaluation frameworks may not be sufficient to explain it. Beni-Koji CholesteHelp was not a 'food that contains red yeast rice,' but a Foods with Function Claims product that used the BP-412 strain, selected and modified to enhance monacolin K production, and formulated the fermented product directly without purification. Its design premise is fundamentally different from traditional naturally fermented foods with a long history of consumption. The 1989 Showa Denko L-Tryptophan incident was a case of health damage from a fermentation product also aimed at high production of a specific component. Mutant strains, manufacturing processes, and byproducts were extensively investigated, but even after more than 30 years, a single causative substance has not been identified. The core question emerging from this comparison is: 'What kind of safety evaluation was conducted for a product designed for long-term ingestion of unpurified fermented material derived from a strain engineered for monacolin K production, and how were the grounds for that evaluation disclosed and verified?'

1. Types of Product Design for 'High Production of Target Components' in Fermentation Products

In the field of fermentation production for food and pharmaceuticals, the use of strains selected or modified for high production of target components is an established manufacturing technology. Sodium glutamate (Ajinomoto, etc.), citric acid, amino acids like lysine and threonine, and various antibiotics all use this method. However, in these products, the target component is extracted and purified from the fermentation broth before being made into the final product. The final product contains only the target substance and is not designed for ingestion of the entire fermented material including cells and byproducts.

An important distinction exists here. Traditional fermented foods like miso, natto, cheese, and soy sauce are consumed as unpurified fermented products, but they have a history of consumption spanning millennia, and their safety is supported by historical and epidemiological knowledge. Beni-Koji CholesteHelp does not fall into this category. The BP-412 strain was selected and modified to enhance monacolin K production (Gunze Patent JP2009095304A), and the metabolite composition of its fermented product may differ from that of traditional red yeast rice. The safety evaluation question posed by the structure of 'long-term ingestion of unpurified fermented material from a strain designed for high production of a specific component' cannot be answered by the consumption history of traditional fermented foods.

2. Overview of the L-Tryptophan Incident (1989)

In 1989, consumers in the United States who took L-Tryptophan supplements manufactured by Showa Denko developed eosinophilia-myalgia syndrome (EMS) in large numbers, resulting in serious health damage including deaths. The main points of contention in the incident were as follows:

- Use of an industrial mutant strain (a high-productivity mutant strain, including genetically modified ones) - Changes in the manufacturing process (possible simplification of the purification process) - Possibility of contamination with impurities (specific trace components)

Extensive investigations were conducted to determine the cause, but even after more than 30 years, a single causative substance has not been identified. Nevertheless, Showa Denko lost the lawsuits and provided compensation totaling several hundred billion yen.

3. Structural Comparison with the Beni-Koji CholesteHelp Incident

The common axis for comparing both incidents is that they involve 'fermentation products where a specific component is produced in high quantities using an industrial mutant strain.' While the L-Tryptophan incident started with the issue of 'possible impurity contamination in a purified product,' Beni-Koji CholesteHelp is structurally different in that 'no purification process exists.' The following comparison table organizes this difference.

Comparison Item L-Tryptophan Incident (1989, USA) Beni-Koji CholesteHelp Incident (2024, Japan)

① Strain Used / Manufacturing Purpose Strain with enhanced L-Tryptophan production (Showa Denko) Purpose: High production of L-Tryptophan BP-412 strain (selected and modified to enhance monacolin K production) Purpose: High production of monacolin K

② Purification Process L-Tryptophan was purified for product formulation (however, potential issues with the purification process were pointed out) No purification process. Solid-state fermented material was directly formulated.

③ Nature of the Ingested Substance Purified L-Tryptophan (product formulated after isolating the target component. However, potential issues with the purification process were pointed out) The entire fermented product from the BP-412 strain (the whole fermented material, including cells and byproducts, was encapsulated. No purification process existed)

④ Direction of Cause Investigation Industrial mutant strain, manufacturing process, and impurities were directly investigated Explanation centered on puberulic acid. Safety verification of the industrial mutant strain itself is insufficient.

⑤ Determination of Causative Substance Single causative substance remains unidentified even after 30+ years Puberulic acid is widely recognized as the causative substance in a relatively short time (scientific evidence verification needed)

⑥ Compensation Showa Denko provided compensation totaling several hundred billion yen Compensation is underway, but verification challenges remain regarding the causative substance and mechanism.

⑦ Lessons Learned Reaffirmed the importance of purification and quality control when using industrial mutant strains The issue of safety evaluation for using fermented material from industrial mutant strains directly as food.

4. Differences in the Direction of Cause Investigation

In the L-Tryptophan incident, the high-production strain, manufacturing process changes, and byproducts were directly investigated, and the investigation process was widely published as scientific papers and administrative documents. In contrast, in the Beni-Koji CholesteHelp incident, the explanation for the cause has centered on puberulic acid. What this report aims to question is not the scientific validity of puberulic acid itself, but whether the question 'What kind of safety evaluation was conducted for long-term ingestion of unpurified fermented material derived from a strain designed for monacolin K production, and were the grounds for that evaluation disclosed and verified in a verifiable manner?' was directly examined during the cause investigation process.

Furthermore, one point should be confirmed regarding the timeline of cause identification. In the L-Tryptophan incident, the causative substance has not been identified even after more than 30 years. This is a precedent showing the difficulty of cause investigation and demonstrates the challenge of scientifically establishing causality in health damage cases involving complex fermentation products. In the red yeast rice incident as well, 'how the process of cause identification and the scientific evidence were disclosed and verified' is an issue worthy of continued examination.

5. The Significance of the Presence or Absence of a Purification Process

In the L-Tryptophan incident, the possibility that impurities were introduced due to problems in the purification process of the purified L-Tryptophan product was the issue. That is, the problem was examined based on the premise of 'purifying the target component for product formulation,' and the issues in that process were questioned.

In contrast, in the case of Beni-Koji CholesteHelp, a purification process did not exist by design. The structure of directly encapsulating the solid-state fermented material from the industrial mutant strain BP-412, created for monacolin K production, has a different starting point from the L-Tryptophan incident. It is not a 'problem in the purification process,' but rather 'long-term ingestion of the entire unpurified fermented material.'