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Accounting for endogenous thresholds in athletically banned substances

Article-Accounting for endogenous thresholds in athletically banned substances

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Confusion about which substances are prohibited and at what amount can make or break a supplement manufacturer.

Dietary supplements are a global, multibillion-dollar industry with thousands of players. With stakes this high, confusion about which substances are prohibited and at what amount can make or break a supplement manufacturer. The list of substances prohibited by organisations like the World Anti-Doping Agency (WADA) grows every year as new substances are developed for both legitimate medical needs and illegal markets. Chemicals/substances are placed on the WADA prohibited list when they meet at least two of the following criteria:

  • The substance has the potential to enhance performance
  • The substance has an adverse effect risk
  • The substance violates the spirit of sport

Generally, finished dietary supplements are only acceptable when prohibited chemicals are not detected above the analytically feasible detection threshold for that substance. These thresholds are established through development and validation of chemical analysis methods. The test methods are designed to detect the chemicals at the lowest possible amount while minimizing the probability of a false-negative result. The goal is two-fold:

  1. To maintain the rigor required by the industry to support and enhance consumer health, and
  2. To mitigate the risk of sanctions for drug-tested athletes

A primary concern is the group of substances classified as endogenous ingredients. Endogenous ingredients are chemical compounds produced by a botanical or animal source. Toxicologists are studying endogenous substances in ingredients to help the industry better understand the nature of these substances when developing formulations for use in dietary supplements. The endogenous nature of substances should be taken into account when organizations set thresholds for assessments and manufacturers formulate finished dietary supplement products.

Case study: Boldione

Boldione is currently listed by WADA as an endogenous anabolic androgenic steroid (AAS), when administered exogenously. Although boldione is not a phytochemical constituent of botanicals, meaning that the plant does not produce boldione in order to grow/thrive, boldione can occur naturally in a plant when a naturally-occurring phytosterol is transformed into boldione by certain mycobacterium in the plant’s environment.

Given that boldione can occur in this way, an endogenous threshold of 0.02 µg per serving for dietary supplements was established by toxicologists for NSF International’s Certified for Sport® program. This threshold was derived using endogenous boldione levels in human urine (1.33 ng/ml x 50 ml urine) multiplied by the maximum excretion rate of boldione in urine (34.45%). This amount of boldione is highly unlikely to cause a doping test failure. By comparison, typical performance-enhancing use levels of AAS are generally between 1.14 mg per day and 25 mg per day. Additionally, a health effects level of 0.3 mg per day was derived from a subchronic oral study in rats administered the AAS androstenedione. These values are orders of magnitude higher than the boldione per serving endogenous threshold used to assess products in NSF’s Certified for Sport® program.

Establishment of a risk-based acceptability criteria threshold for boldione does not violate anti-doping requirements. Instead, it simply considers the low levels of naturally occurring boldione while protecting athletes from doping risk and protecting public health. The endogenous nature in the food supply of an athletically prohibited substance should be taken into consideration when setting an acceptability criteria threshold.

Endogenous thresholds are essential to protecting athletes from doping risk and protecting public health. The process for developing risk-based endogenous thresholds can be complex and lengthy. Endogenous thresholds are still a relatively new concept for the industry, and it will take time for them to be understood, supported and potentially implemented. While the dietary supplement industry moves rapidly, the science of public health takes time because the stakes are extremely high.