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      Paracelsus Revisited: The Dose Concept in a Complex World.

      1
      Basic & clinical pharmacology & toxicology
      Wiley-Blackwell

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          Abstract

          At the time that Paracelsus coined his famous dictum, 'What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison', embryonic toxicology was a fairly focused discipline that mainly dealt with occupational poisonings and side effects of pharmaceuticals, such as mercury. While Paracelsus paved the way for the modern threshold concept and the no-adverse effect level, modern-day toxicology is now tussling with highly complex issues, such as developmental exposures, genetic predisposition and other sources of hypersusceptibility, multiple causes of underestimated toxicity, and the continuous presence of uncertainty, even in regard to otherwise well-studied mercury compounds. Further, the wealth of industrial chemicals now challenges the 'untested-chemical assumption', that the lack of documentation means that toxic potentials can be ignored. Unfortunately, in its ambition to provide solid evidence, toxicology has been pushed into almost endless replications, as evidenced by the thousands of toxicology publications every year that focus on toxic metals, including mercury, while less well-known hazards are ignored. From a public health viewpoint, toxicology needs to provide better guidance on decision-making under ever-present uncertainty. In this role, we need to learn from the stalwart Paracelsus the insistence on relying on facts rather than authority alone to protect against chemical hazards.

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          Most cited references34

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          The Matthew Effect in Science: The reward and communication systems of science are considered.

          R K Merton (1968)
          This account of the Matthew effect is another small exercise in the psychosociological analysis of the workings of science as a social institution. The initial problem is transformed by a shift in theoretical perspective. As originally identified, the Matthew effect was construed in terms of enhancement of the position of already eminent scientists who are given disproportionate credit in cases of collaboration or of independent multiple discoveries. Its significance was thus confined to its implications for the reward system of science. By shifting the angle of vision, we note other possible kinds of consequences, this time for the communication system of science. The Matthew effect may serve to heighten the visibility of contributions to science by scientists of acknowledged standing and to reduce the visibility of contributions by authors who are less well known. We examine the psychosocial conditions and mechanisms underlying this effect and find a correlation between the redundancy function of multiple discoveries and the focalizing function of eminent men of science-a function which is reinforced by the great value these men place upon finding basic problems and by their self-assurance. This self-assurance, which is partly inherent, partly the result of experiences and associations in creative scientific environments, and partly a result of later social validation of their position, encourages them to search out risky but important problems and to highlight the results of their inquiry. A macrosocial version of the Matthew principle is apparently involved in those processes of social selection that currently lead to the concentration of scientific resources and talent (50).
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            Polyfluorinated compounds: past, present, and future.

            Interest and concern about polyfluorinated compounds (PFCs), such as perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and an increasing number of other related compounds is growing as more is learned about these ubiquitous anthropogenic substances. Many of these compounds can be toxic, and they are regularly found in the blood of animals and humans worldwide. A great deal of research has been conducted in this area, but a surprising amount remains unknown about their distribution in the environment and how people ultimately become exposed. The utility of these compounds seems to ensure their continued use in one form or another for the foreseeable future, presenting a long-term challenge to scientists, industry leaders, and public health officials worldwide.
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              Why most discovered true associations are inflated.

              Newly discovered true (non-null) associations often have inflated effects compared with the true effect sizes. I discuss here the main reasons for this inflation. First, theoretical considerations prove that when true discovery is claimed based on crossing a threshold of statistical significance and the discovery study is underpowered, the observed effects are expected to be inflated. This has been demonstrated in various fields ranging from early stopped clinical trials to genome-wide associations. Second, flexible analyses coupled with selective reporting may inflate the published discovered effects. The vibration ratio (the ratio of the largest vs. smallest effect on the same association approached with different analytic choices) can be very large. Third, effects may be inflated at the stage of interpretation due to diverse conflicts of interest. Discovered effects are not always inflated, and under some circumstances may be deflated-for example, in the setting of late discovery of associations in sequentially accumulated overpowered evidence, in some types of misclassification from measurement error, and in conflicts causing reverse biases. Finally, I discuss potential approaches to this problem. These include being cautious about newly discovered effect sizes, considering some rational down-adjustment, using analytical methods that correct for the anticipated inflation, ignoring the magnitude of the effect (if not necessary), conducting large studies in the discovery phase, using strict protocols for analyses, pursuing complete and transparent reporting of all results, placing emphasis on replication, and being fair with interpretation of results.
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                Author and article information

                Journal
                Basic Clin. Pharmacol. Toxicol.
                Basic & clinical pharmacology & toxicology
                Wiley-Blackwell
                1742-7843
                1742-7835
                Aug 2016
                : 119
                : 2
                Affiliations
                [1 ] Department of Public Health, University of Southern Denmark, Odense, Denmark.
                Article
                NIHMS789324
                10.1111/bcpt.12622
                4942381
                27214290
                a85eaa15-2e08-4bd6-9e70-17abba6bd69c
                History

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