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Abstract-A promising tool for the risk assessment of chemical mixtures is the prediction of their toxicities from the effects of the individual components. For that purpose, concentration addition is uniformly regarded as valid for mixtures of similarly acting chemicals. Whether this concept or the competing notion of independent action is more appropriate for mixtures of dissimilarly acting chemicals is still in dispute. Therefore, the presented study analyzed and compared the predictive capabilities of both concepts for a multiple mixture designed of strictly dissimilarly acting compounds. Experimental investigations were conducted using a longterm bioluminescence inhibition assay with Vibrio fischeri. Results show an excellent predictive power of independent action, while concentration addition overestimates the mixture toxicity. Thus, the precise prediction of mixture toxicities depends on a valid assessment of the similarity/dissimilarity of the mixture components. However, concentration addition underestimates the EC50 of the mixture only by a factor of less than three. As the similarity of components is often unknown for mixtures found in the environment, it is concluded that concentration addition may give a realistic worst case estimation of mixture toxicities for risk assessment procedures.

Abstract-The prediction of combined effects based on the effects of the individual components of mixtures by using the pharmacological concepts of concentration addition and independent action might be a promising tool for the risk assessment of pollutant mixtures. To analyze and compare the predictive capabilities of the reference concepts for similarly acting chemicals, the overall toxicity of a multiple mixture was determined in a bioluminescence inhibition assay with Vibrio fischeri. The mixture was composed of 16 similarly and specifically acting chemicals, anticipated to have a common mode of action via weak acid respiratory uncoupling of oxidative phosphorylation. Results show that the observed mixture toxicity is rather well predicted by both concepts. Concentration addition shows an excellent predictive power; the median effective concentration (EC50) of the mixture is predicted with an error of about 10%. Independent action, in contrast, underestimates the EC50 of the mixture by a factor of a little more than three. With respect to risk assessment procedures, it may be concluded that concentration addition gives a valid estimation of the overall toxicity for multiple mixtures with similar and specific mechanisms of action of the mixture components in this type of biotest.

Background Human poisoning by pesticides has long been seen as a severe public health problem. As early as 1990, a task force of the World Health Organization (WHO) estimated that about one million unintentional pesticide poisonings occur annually, leading to approximately 20,000 deaths. Thirty years on there is no up-to-date picture of global pesticide poisoning despite an increase in global pesticide use. Our aim was to systematically review the prevalence of unintentional, acute pesticide poisoning (UAPP), and to estimate the annual global number of UAPP. Methods We carried out a systematic review of the scientific literature published between 2006 and 2018, supplemented by mortality data from WHO. We extracted data from 157 publications and the WHO cause-of-death database, then performed country-wise synopses, and arrived at annual numbers of national UAPP. World-wide UAPP was estimated based on national figures and population data for regions defined by the Food and Agriculture Organization (FAO). Results In total 141 countries were covered, including 58 by the 157 articles and an additional 83 by data from the WHO Mortality Database. Approximately 740,000 annual cases of UAPP were reported by the extracted publications resulting from 7446 fatalities and 733,921 non-fatal cases. On this basis, we estimate that about 385 million cases of UAPP occur annually world-wide including around 11,000 fatalities. Based on a worldwide farming population of approximately 860 million this means that about 44% of farmers are poisoned by pesticides every year. The greatest estimated number of UAPP cases is in southern Asia, followed by south-eastern Asia and east Africa with regards to non-fatal UAPP. Conclusions Our study updates outdated figures on world-wide UAPP. Along with other estimates, robust evidence is presented that acute pesticide poisoning is an ongoing major global public health challenge. There is a need to recognize the high burden of non-fatal UAPP, particularly on farmers and farmworkers, and that the current focus solely on fatalities hampers international efforts in risk assessment and prevention of poisoning. Implementation of the international recommendations to phase out highly hazardous pesticides by the FAO Council could significantly reduce the burden of UAPP.