Curiouser and curiouser: Meta-analysis of venom toxicity of 160 lethal ophidian species shows extraordinary variance, and falsifies common assumptions, providing a basis for estimating human lethal doses.

Abstract

Background: This is the first meta-analysis to characterize intra-ophidian-species variation in whole venom. The largest meta-analysis possible at this time, it encompasses all known publicly available records of animal lethality studies over the past 100 years. These results are not artifacts of resistant test-animal-species, and show orders of magnitude beyond the 1.6 logs (40 fold change) range of lethal dose documented in literature between amphibians, lizards and mice. Methods: 1005 lethal dose study results for 160 of the most lethal venomous ophidian species in the world are analyzed. Results: LDLo does not differentiate from LD50 across studies, indicating the true range of toxicity is probably larger. The belief that for route of inoculation, IC<IV<IP<IM<SC has good support (R2 = 0.86). However, 8% of SC inoculations were the lowest (most toxic) dose. Within the mouse test species, for one route of inoculation, the mean LD range is 0.94 logs (8.89 fold change), and widest LD range is 2.15 logs (141 fold change, N = 26). Within 1 test species, for multiple routes of inoculation, mean LD range is 2.0 logs (98.97 fold change), and the widest LD range is 3.6 logs (4,150 fold change). For all test species and all routes of inoculation, the mean LD range is 2.97 logs (936.59 fold change) and widest LD range is 4.76 logs (57,471 fold change). The strongest correlate for range of lethal dose results is the number of studies (R2 = 0.56). The average variance appears to follow a power law from single test species and route, to single test species and multiple routes, to all test species and all routes, as a factor of 10 multiple for each. Conclusions: Scientists working with humans should use combined LDLo and LD50 meta-datasets for all data and calculate: mean, median, minimum, range, and standard deviations. Standard deviation multiples, or at minimum, standard error, will provide desired coverage. For estimating LD50 range and minimum lethal dose for species with little data, I recommend curating a meta-dataset of related snakes, and computational research to strengthen this.