Derivation of toxicity equivalency factors for marine biotoxins associated with Bivalve Molluscs

Abstract

Background Seafood toxins pose an important risk to human health, and maximum levels were imposed by regulatory authorities throughout the world. Several toxin groups are known, each one with many analogues of the major toxin. Regulatory limits are set to ensure that commercially available seafood is not contaminated with unsafe levels. Scope and Approach The mouse bioassay was used to measure the toxicity in seafood extracts to determine if a sample exceeded regulatory limits. The advantage of this approach was to provide an estimation of the total toxicity in the sample. As instrumental methods of analysis advance and serve as replacements to the mouse bioassay, the challenge is translating individual toxin concentrations into toxicity to determine whether regulatory limits have been exceeded. Such analyses provide accurate quantitation of the toxin Please note that this is an author-produced PDF of an article accepted for publication following peer review. The definitive publisher-authenticated version is available on the publisher Web site. analogues, by they have widely dissimilar potencies. Thus, knowledge of the relative toxicities is required for risk assessment and determining overall toxicity. The ratios between the toxicity of the analogues and that of a reference compound within the same toxin group are termed "Toxicity Equivalency Factors" (TEFs). Key Findings and Conclusions In this document, the requirements for determining TEFs of toxin analogues are described, and recommendations for research to further refine TEFs are identified. The proposed TEFs herein, when applied to toxin analogue concentrations determined using analytical methods, will provide a base to determine overall toxicity, thereby protecting human health. Highlights ► Marine toxins TEF are revised according to recent toxicology studies. ► TEF for each toxin group are proposed. ► The proposed TEF were agreed by a joint FAO-WHO working group.

Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL)

“…This fact should alert health authorities to the need for potential preventive measures. The oral LD 50 (232 µg/kg BW) and NOAEL (75 µg/kg BW) values determined in this study may be used as a starting point for further risk assessment processes leading to a safe seafood level for TTX in the EU [22]. …”

Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

“…Results indicated that OA is less toxic than DTX1 with oral LD 50 values of 760 and 487 µg kg -1 bw respectively, while DTX2 is the less potent with an oral LD 50 of 2262 µg kg -1 bw [29]. Those LD 50 values were lower than previously reported and differences could be related to the quality of the marine toxins utilized [19,[24][25][26][27][28]. Based in these results the order of oral toxic potency is DTX1 > OA > DTX2 in agreement with the PP2A inhibitory potency.…”

“…The previously described lethal oral doses of OA were 400 [21] 600 [22] and between 1000 -2000 μg kg -1 bw [23], with a described LD 50 of 880 μg kg -1 bw [24,25]. Some studies have reported values of DTX1 lethal dose below 300 μg kg -1 bw while others reported no deaths in mice at the oral dose 750 μg kg -1 bw [19,[26][27][28]. Regarding DTX2 an oral LD 50 of 2262 μg kg -1 bw has been recently established [29].…”

“…Therefore, to estimate the total toxicity of seafood samples there is a need to know the relative toxicity of OA regulated analogues [18]. This requires determination of Toxicity Equivalency Factors (TEFs) defined as the ratio between the toxicity of each analogue and that of the reference compound within the same toxin group [19]. European Food Safety Authority (EFSA) Panel on Contaminants in the Food Chain (CONTAM) has established the TEF values 1.0, 1.0 and 0.6 for OA, DTX1 and DTX2, respectively [20] based on the relative inhibitory effect on protein PP2A and on acute intraperitoneal (i.p.)…”

“…Regarding DTX2 an oral LD 50 of 2262 μg kg -1 bw has been recently established [29]. However, the quality of the marine toxins utilized in toxicological studies has been one of the largest sources of variation of the results reported in the literature [19]. Almost none of the previous data were obtained using certified reference materials (CRM) to assure the concentration and stability of the doses utilized.…”