Derivation of Health- Based Reference Values

The following section is taken directly from the WHO chemicals background document on anatoxins (WHO, 2020) which gives the considerations for the derivation of provisional guideline values for exposure to anatoxin in more detail.

Acute exposure to ATX in animals led to deaths within minutes of gavage administration (Astrachan, Archer & Hilbelink, 1980; Fawell et ah, 1999). Since neither of the available repeated toxicity studies identified a nonlethal dose that caused lasting adverse effects, formal guideline values (GVs) (provisional or otherwise) cannot be derived based on the available information. In the 28-day study of Fawell et al. (1999), one of 20 animals in each of two dose groups died without signs that could be attributed to nontreatment effects. If it is conservatively assumed that these animals died from the effects of the toxin, the no observed adverse effect level (NOAEL) would be 98 pg/kg bw per day, but it could be as high as 2.46 mg/kg bw per day if these two animals were excluded (Fawell et ah, 1999). Although GVs cannot be derived due to inadequate data, a “bounding value”, or provisional health-based reference value, can be derived for short-term exposure using a highly conservative assumption to define the NOAEL at 98 pg/kg. This value is lower than the estimated NOAEL for exposure via drinking-water calculated from data in Astrachan, Archer & Hilbelink (1980) and the i.p. NOAEL for maternal toxicity identified by Rogers et ah (2005).

There is insufficient information to develop a long-term health-based reference value for ATX.

Default assumptions were applied as described in WHO (2009) for deriving the short-term drinking-water value and WHO (2003) for deriving the recreational water value.

Calculation of provisional short-term drinking-water health-based reference value for ATX


HBRVshorMcrm = short-term drinking-water health-based reference value

NOAEL = no-observed-adverse-effect level (98 pg/kg bw per day, based on Fawell et ah, 1999)

bw = body weight (default = 60 kg for an adult)

P = fraction of exposure allocated to drinking-water (default for shortterm exposure = 100%, considering that drinking-water is expected to be the most likely source of exposure)

UF = uncertainty factor (10 for interspecies variation x 10 for intraspecies variation); an uncertainty factor for database deficiencies was not applied since the NOAEL is lower than the i.p. NOAEL for maternal toxicity

C = daily drinking-water consumption (default = 2 L for an adult).

Calculation of provisional recreational water health-based reference value for anatoxin-a


HBRVrecreation = recreational water health-based reference value

NOAEL = no-observed-adverse-effect level (98 pg/kg bw per day, based on Fawell et ah, 1999)

bw = body weight (default = 15 kg for a child)

UF = uncertainty factor (10 for intraspecies variation x 10 for interspecies variation)

C = daily incidental water consumption (default = 250 mL for a child).

Considerations in applying the provisional health-based reference values

Derivation of the provisional health-based reference values for ATX follows a highly conservative approach. As a result of inadequate data, the provisional health-based reference values derived above do not represent WHO GVs and therefore are not intended for use as scientific points of departure for developing regulations or standards. Nevertheless, a “bounding value” may be useful to guide actions and responses by water suppliers and health authorities. Based on the limited currently available studies of acute and subchronic ATX toxicity, exposure up to the values provided is expected to be safe for adults. Since infants and children can ingest a significantly larger volume of water per body weight (e.g., up to 5 times more drinking-water/ kg bw for bottle-fed infants than for an adult), it is recommended that alternative water sources, such as bottled water, are provided for bottle- fed infants and small children when ATX concentrations are greater than 6 pg/L for short periods, as a precautionary measure.

The provisional drinking-water health-based reference value is based on a 28-day repeated dose study and so is applicable for short-term exposure. However, because ATX is acutely toxic, it is recommended that any exposure above this value be avoided.

The provisional health-based reference values are based on toxicological data for ATX. It is recommended that for assessing risk, total ATXs as gravimetric or molar equivalent are evaluated against the health-based reference values, based on a reasonable assumption that HTX has similar toxicity to ATX. There is evidence that dihydro-analogues of ATX and HTX are similarly toxic by the oral route of exposure; hence it would be prudent to include these in determinations of total ATXs, when present.

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