Derivation of Guideline Values

The following section is taken directly from the WHO chemicals background document on saxitoxins (WHO, 2020) which discusses the considerations for the derivation of provisional guideline values for exposure to saxitoxin in more detail. The GV for acute exposure through drinking-water is derived for bottle-fed infants, as the most sensitive subgroup in a population. This is considered appropriate for this cyanotoxin group because the GV is for acute exposure, and there is a relatively small margin of safety, as described below. All other default assumptions were applied as described in WHO (2009, 2017) for deriving the acute drinking-water GV, and in WHO (2003) for deriving the recreational GV.

FAO (2004) identified a LOAEL for mild symptoms of 2.0 pg/kg bw, based on a review of human cases of paralytic shellfish poisoning (PSP). More recently, EFSA (2009) reviewed about 500 cases of human PSP described in case reports that had estimated the consumption of STXs associated with a range of symptoms. This analysis identified a LOAEL for STXeq of 1.5 pg/kg bw by assuming an adult body weight of 60 kg. Because many individuals did not show symptoms at much higher estimated intakes, EFSA (2009) reasoned that the LOAEL must be very near the threshold for effects in sensitive individuals. Therefore an uncertainty factor of 3 was applied to the LOAEL "to estimate a NOAEL", establishing an acute reference dose (ARfD) for STXeq of 0.5 pg/kg bw. An uncertainty factor for intraspecies variation was not applied because documented human cases included a wide spectrum of people (occupation, age, and sex).

The GVs are derived from data from poisoning events caused by mixtures of STXs, with total STXs expressed as STX concentration equivalents (STXeq). The GVs therefore apply to total STXs in a sample, not just the parent compound, STX.

These values are supported by data from animal studies: the use of the lowest acute no observed adverse effect level (NOAEL) for neoSTX of 87 pg/kg bw after gavage administration as a point of departure leads to the derivation of an ARfD for neoSTX of 0.87 pg/kg bw (applying an uncertainty factor of 100). This value is of the same order of magnitude as the reference values obtained with human data (Testai et ah, 2016).

Calculation of acute drinking-water guideline value for saxitoxins


GVacute = guideline value for acute exposure

LOAEL = lowest-observed-adverse-effect level (1.5 pg STXeq/kg, based on the human data on PSP reports)

bw = body weight (default = 5 kg for an infant)

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 where surface water is used as the source of drinking-water)

UF = uncertainty factor (3, for use of a LOAEL rather than a NOAEL)

C = daily drinking-water consumption (default = 750 mL for an infant).

Calculation of recreational water guideline value for saxitoxin

The calculation is based on a scenario of a child playing in bloom-infested water:


GVrecreation = guideline value for recreational exposure LOAEL = lowest observed-adverse-effect level (1.5 pg STXeq/kg, based on human poisoning data) bw = body weight (default = 15 kg for a child)

UF = uncertainty factor (3, for use of a LOAEL rather than a NOAEL) C = daily incidental water consumption (default = 250 mL for a child).

Considerations in applying the provisional guideline values

As indicated above, for assessing risk, the cumulative detection of both STX and its structural analogues should be evaluated against the GVs.

This is generally expressed as STXeq. STXeq can indicate concentration equivalents - calculated by simple addition of the concentrations of all analogues present, each being quantified against an analytical standard for that analogue. This represents a conservative approach to protect human health in most cases, assuming that all analogues have comparable characteristics and toxicity to STX. An exception is when the more potent neoSTX is the dominant congener present (see below). A more precise, usually less conservative approach is to determine STX toxicity equivalents by multiplying the concentration of each analogue by the respective toxicity equivalence factor (TEF) before addition. Where available, oral toxicities should be used in preference to relative i.p. toxicities. Munday et al. (2013) provides the acute oral toxicities of some analogues while a table of TEFs based on i.p. toxicity in mice has been published by EFSA (2009).

The acute GVs for STXs are based on acute exposure data. A time limit for tolerating concentrations up to 3 pg/L cannot be given because of the lack of data on effects at low doses. Thus, in contrast to other cyanotoxins, short-term and lifetime exposure GVs were not developed, and short-term exceedances of the acute GV should not be permitted. Although there is currently no evidence of health impairments from chronic exposure to low doses of STXs, it is always prudent to implement control measures to reduce the presence of toxic cyanobacterial blooms or their impact on drinking-water supplies as soon as possible (see Chapters 6-10). Limited data show that STX concentrations in drinking-water have almost always been at trace levels (see section 2.4.5), indicating that conventional water treatment is generally effective, provided that cell lysis is avoided (see Chapter 10).

The drinking-water GV for STXs uses an allocation factor of 100% for drinking-water; however, it may be appropriate to consider reducing the allocation factor for drinking-water in locations with increased risk of coincident water and shellfish exposure (marine or freshwater). However, it should be noted that GVs for STX in marine shellfish are comparatively high and, in locations where contamination of shellfish is a concern, drinking-water containing STX would contribute a relatively small additional exposure. Nevertheless, it is recommended that health authorities jointly consider and manage such a scenario, particularly given the relatively steep dose-response relationship for these toxins.

For the drinking-water acute GV, the lower body weight and higher likely water intake of an infant (as a function of body weight) were used because a GV based on adults could allow exposure of infants to a concentration of STXs close to the LOAEL. For a 60 kg adult consuming 2 L of drinking-water per day, a 5-fold higher concentration than the acute GV would be tolerable.

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