The dose makes the poison

Highlights: • A critical review of a previous study was performed. • Exposure to the same concentrations do not result in equivalent doses among species. • Inter-species variations should be considered in experimental design. • Ranges of low-dose for effects of microcystins in animals and humans should be defined. • Chronic toxicity and especially carcinogenicities of microcystins need further studies. Some microcystins (MCs) might cause hepatotoxicity in animals and humans. MC-LR is also a tumor promoter and a suspect carcinogen. In 2010, the International Agency for Research on Cancer (IARC) classified MC-LR as a possible human carcinogen (Group 2B). Recently, an article entitled "Long-term, low-dose exposure to microcystin toxin does not increase the risk of liver tumor development or growth in mice" was published in Hepatology Research by Meaghan Labine and Gerald Y. Minuk. However, the experimental design was flawed and the conclusion is misleading. 1 μg/L MC-LR in drinking water is the provisional guideline value established by the World Health Organization (WHO) for humans in 1998, based on a tolerable daily intake (TDI) of 0.04 μg/kg body mass (BM). Assuming the mice drink 1.5 mL/10 g BM of water per day, the exposure dose would be 0.15 μg/kg/d BM, about 270-fold less than 40 μg/kg/d, the no-observed-adverse-effect level (NOAEL). Thus, the dose of MC-LR was too small and "unlikely to result in liver tumor development or enhance existing tumor growth", even with a long-term (28 weeks) exposure. Presumably, they didn't consider inter-species variations between mice and humans, including toxicokinetics and toxicodynamics. Ranges of "low-dose" MCs for animals and humans should be defined. Also, the authors misunderstood or misrepresented several previous studies. Before drawing final conclusions on the carcinogenicity of MCs, further well-designed experiments are warranted.