Why is dose response important

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More Content. Click here for Patient Education. Potency location of curve along the dose axis. Hypothetical dose-response curve. Comparison of dose-response curves Drug X has greater biologic activity per dosing equivalent and is thus more potent than drug Y or Z. Was This Page Helpful? Yes No. Drug—Receptor Interactions. Overview of Female Sexual Function and Dysfunction. It quantitatively defines the role of the dose of a chemical in evoking a biological response. In the absence of chemical no response is seen.

As chemical is introduced into the system the response is initiated at the threshold dose and increases in intensity as the dose is raised. Ultimately a dose is reached beyond which no further increase in response is observed. The dose-response relationship can be demonstrated for interactions of chemicals with biological receptors leading to physiological responses, therapeutic effects of drugs, or for toxic, lethal, teratogenic, mutagenic or carcinogenic effects of chemicals.

The data from these studies can be expressed as dose-response curves which can take the form of linear plots or a variety of reciprocal or logarithmic transformations. Two types of dose-response relationships are observed. The first is the incremental change in response of a single system or individual as the dose is increased. The second is the distribution of reponses in a population of individuals given different doses of the agent. The former are frequently used for the determination of the mechanism of interaction between the chemical and the biological system.

This text was critical of the unimolecular theory while providing support for the characteristic curve model, including detailed explanations concerning how it could be integrated into new developments reported with pharmacokinetic processes.

The same type of respectful deference was not shown to Schulz and his biphasic dose—response to be discussed immediately below , rather, just the opposite. Alfred J. Clark — [ 54 ]. We can thus see that dose—response debate and controversy did not start with the onset of the environmental revolution of the s and the issues over how to estimate the risk of carcinogens at very low doses. Of particular relevance to the present paper is that it was within this dynamic intellectual environment that the issue of the hermetic—biphasic dose—response emerged and evolved.

However, one thing is obvious right from the start: the unimolecular and the characteristic dose—response concepts originated within two opposing camps of mainstream scientists and, as a result, their conflicts would be followed, debated and respected. What would become the hormetic dose—response originated in an entirely different manner, emerging from the long-standing dispute between traditional medicine and homeopathy.

The initial data underlying this development were generated by Hugo Schulz — , a physician who was well trained in pharmacology and toxicology Figure 3.

This research was undertaken at the University of Greifswald in northern Germany, probably in late , with his first presentation on this topic to the scientific community occurring at a local meeting of Greifswald Medical Society in Schulz had done extensive laboratory research assessing the effects of various chemical disinfectants on the survival and metabolism of yeasts [ 53 ].

In fact, he was a young contemporary of Robert Koch who was doing similar research but with bacteria. Koch would soon become famous for his discoveries relating to the life cycle of anthrax. Hugo Schulz — [ 55 ].

The scientific path of Schulz would be different. In his studies on the effects of multiple chemical disinfectants, Schulz incorporated a broad dose—response feature, a time component as well as a metabolic measure along with the standard mortality endpoint used by others. As a result, Schulz observed an unexpected biphasic dose—response in which high doses were toxic and suppressed metabolism, while the opposite seemed to occur at low doses.

This troubled Schulz, making him think that he must have had some type of methodological error in his experiments. However, copious replications and other assessments gave him high confidence that his findings were real and reproducible as revealed in his reflective comment below [ 56 ]:. Sometimes, when working with substances that needed to be examined for their effectiveness in comparison to the inducers of yeast fermentation, initially working together with my assistant, Gottfried Hoffmann, I found in formic acid and also in other substances the marvelous occurrence that if I got below their indifference point i.

I first thought, as is obvious, that there had been some kind of experimental or observation error. But the appearance of the overproduction continually repeated itself under the same conditions. These findings should have been of considerable interest to Robert Koch and Joseph Lister, amongst others. The biphasic dose—response observations soon became integrated into a general biologically based dose—response framework by Schulz and his colleague at Greifswald, Rudolph Arndt.

So convinced of the correctness and generality of their conceptual dose—response model, the creators designated their model a biological law, called Arndtt—Schulz Law. In retrospect, this dose—response theory of Schulz and Arndt was conceptual and mostly intuitive, with the data supporting it limited but acceptable on their own merits. However, it was the integration across diverse studies and the interpretation of the data that were problematic.

More specifically, Schulz was interested both in chemical disinfection and in testing features of homeopathy. With respect to the latter, Schulz learned of an study in which the homeopathic preparation called veratrine was used to successfully treat gastroenteritis in humans [ 58 ]. This intrigued Schulz who went to Koch to obtain a pure culture of the bacterium causing the disease. Schulz wanted to test whether the veratine could actually kill the causative agent, and thereby obtain insight into the possible mechanism of the homeopathic treatment.

However, regardless of the dose, veratine was unable to kill this disease-causing agent. While some scientists may have questioned the reliability of the veratine findings of Bloedau [ 58 ], Schulz and Arndt did not. They came to this conclusion by linking the yeast findings that indicated that the large number of chemical disinfectants tested acted differently at low dose, enhancing survival.

Thus, Arndt and Schulz developed the hypothesis that most agents act biphasically and that they induce adaptive survival enhancing responses at low doses. They then applied this concept not only to veratine but also to homeopathic drugs in general. It was within this context that they derived the perspective that they had discovered the underlying explanatory principle of homeopathy.

It was with the public announcement of this theory that the problems of Schulz and this biphasic dose—response model, and eventually the term hormesis, would begin. The problem for Schulz and his model was that homeopathy and traditional medicine were in a major and longstanding conflict over which medical practice would come to dominate society [ 59 , 60 ].

There was much animosity over the issue. By linking his biphasic dose—response theory to homeopathy, Schulz ensured that it would become the object of profound criticism and would be rejected by the biomedical community. This should not have been hard to predict. The biomedical community would go to great lengths to marginalize Schulz and his dose—response model.

This started right away as is evident in the contemporary literature and from multiple perspectives. The contemporary research rival Hueppe argued that the findings of Schulz should not be rejected even though he made the profound error of associating it with homeopathy [ 57 ].

However, most critics were not so sympathetic. This may be best seen in the copious writings of Clark, who became a leading critic. Clark did his best to link Schulz with the high dilution Hahnemann wing of homeopathy see Calabrese [ 61 ], Tables 1—3 for numerous examples of such efforts by Clark.

The statements of Clark were also inconsistent with a substantial series of independent reports in the biological literature that were strongly supportive of the Schulz dose—response model [ 63 , 64 , 65 , 66 , 67 ]. However, the views of Clark would carry the day, as Clark and many of his colleagues in the British pharmacological community were prominent leaders in the domain of traditional medicine and extremely accomplished researchers in their own right.

When matched against such a profoundly accomplished and committed opposition, Schulz would have little chance to influence the direction of the field. Despite the profound difficulties that Schulz endured, many researchers published findings of biphasic dose—response relationships, especially in the area of plants, microbiology and entomology with both chemicals and radiation. The findings of Schulz stimulated numerous doctoral dissertations [ 69 , 70 , 71 , 72 , 73 ] that generally confirmed and extended his findings.

Numerous other dissertations addressing the stimulation of bacterial growth by low doses of toxic agents were conducted under the direction of Charles Winslow, the Yale University professor of bacteriology and longtime editor-in-chief of the Journal of Bacteriology and later the American Journal of Public Health. Of particular interest was that the agents were usually tested over a broad concentration range with six or more doses.

Most of the agents tested displayed low dose stimulation, including the salts of lead, mercury, nickel, tin, titanium and strontium.

The work of Hotchkiss revealed that the stimulatory response was strongly influenced by the nature and the quality of the study design. Experiments with large numbers of doses, especially with multiple treatments below the toxic threshold, displayed consistent stimulatory responses in this low dose zone. The work of Hotchkiss was to stimulate a long line of subsequent graduate students at Yale University to extend these findings [ 63 ]. Furthermore, the study design features implemented by Hotchkiss under the direction of Winslow created a type of research standard for the assessment hormetic-like biphasic dose—responses in terms of number of doses, dose range and spacing, and replications.

This research was significant as it led to the general recognition by the s that disinfectants display a biphasic dose—response, with knowledge of this phenomenon becoming so recognized and accepted that it became incorporated into standard microbiological texts during the middle decades of the 20th century [ 76 , 77 , 78 ].

The biphasic effects of disinfectants on bacteria were paralleled with similar findings concerning the effects of various toxic inorganic agents on the ammonification, nitrification and nitrogen-fixation in soil by various bacterial species.

This research was initially studied in by the well-known bacteriologist Lipman [ 79 ] from the University of California at Berkeley who was interested in assessing the impact of large quantities of waste alkali on the capacity of soil bacteria to perform ammonification and nitrification. Low dose stimulation responses by bacterial ammonifiers were commonly observed.

At the same time, Greaves [ 80 , 81 , 82 ] revealed that various chemical insecticides likewise induced hormetic-like biphasic dose—responses on the bacterial ammonification process. Greaves was unusual in his study designs, using from 20 to 30 concentrations over a wide concentration range.

The findings of Greaves were noted for their consistency of responses between replicate studies. Similar findings were also reported for various uranium compounds, again with strong study designs [ 83 ]. Lipmann and his colleagues would be the first group to apply the concept of hormesis to risk assessment in a legal case dealing with smelter works in California.

They presented data that low doses of toxic metals such as arsenic and lead stimulated rather than inhibited plant growth. See Calabrese [ 84 ] for a detailed description and assessment of this case. The story of hormetic-like biphasic dose—responses just briefly summarized for bacteria also occurred with fungi, yeast, insects and plants using various chemicals and radiation as inducing agents during the early decades of the 20th century. The findings were often reported by experienced investigators, typically with adequate to strong study designs and published in the leading journals of that era.

However, these findings were never adequately summarized and integrated during the 20th century. It was only during the resurgence of the hormesis concept at the very end of the 20th century that this extensive published network of early historical findings on hormetic dose responses was revealed to contemporary biological and biomedical scientists. Of further note was that a German language journal Cell Stimulation was published during the s.

Likewise, an academic journal-like publication called the Stimulation Newsletter was published that addressed the capacity of radiation to induce stimulation in plant growth.

The history of these activities has been reconstructed and published in an entire issue of the journal Human and Experimental Toxicology [ 63 , 64 , 65 , 66 , 67 ]. These findings were to force some investigators to struggle with the actual definition of the hormetic dose—response.

Perhaps the most significant theoretical debate centered on whether the low dose stimulation was a direct one or an overcompensation to a disruption in homeostasis, that is, some minor degree of toxicity. A number of extremely well designed and conducted studies with different biological models and inducing agents provided convincing evidence that a low dose stimulation may occur as a result of an overcompensation to an induced initial toxicity.

Of particular note were findings of Sarah Branham [ 85 ] Figure 4 of the University of Rochester who sought to provide a very explicit, detailed and advanced replication of the original findings of Schulz that stimulated interest in the biphasic dose—response concept. Her findings were striking in that she not only reported that low concentrations of numerous chemical disinfectants stimulated the growth of yeast colonies but also did so in a manner that clearly involved an overcompensation to an initial toxic response.

This type of dose-time—response was also reported by others such as Professor Elizabeth Smith [ 86 ] of the University of Wisconsin who reported that UV radiation induced a biphasic dose—response for mycelium growth in which the stimulatory response occurred only after the UV-induced initial damage with a rebound stimulation reflecting the overcompensation response. Large numbers of similar overcompensation stimulation dose—responses have now been reported and summarized [ 87 ].

Sara Branham Matthews — [ 88 ]. Of significance was that the reporting of a low dose stimulation after an initial toxicity was viewed by some as a refutation of the hormesis hypothesis. This was particularly the case in the area of radiation biology. For example, while Manfried Fraenkel argued that low doses of ionizing radiation can stimulate biological processes by a direct positive effect [ 89 ], Holzknecht and Pordes rejected the possibility of a direct stimulatory response without an initial induced damage [ 89 ].

The confusion over whether the Arndt—Schulz Law was the result of a direct response or a phenomenon following a response to damage became an important conceptual battle that was still evident several decades later. This dispute was important since it attracted many leading researchers in the field of radiation and its medical applications such as Holzknechzt, a former colleague of Roentgen and the person recognized as having created the first method of quantifying X-ray exposure.

He was also the first European professor of medical roetgenology [ 89 ]. Warren would continue to provide considerable leadership to the field, serving on the first US NAS BEAR Committee in —, being the chair of the Pathology Panel and a member of the Genetics Panel that recommended a switch from a threshold to a linear dose—response model for risk assessment purposes.

The rejection of the Arndt—Schulz Law by key leaders in the radiation community such as Shields Warren over the fact that radiation often induced stimulation via an overcompensation response following damage was a significant judgment leading to the continued marginalization of the hormesis concept. These leaders failed to grasp that radiation and chemicals had the capacity to induce stimulatory responses at low doses via either direct as established below or overcompensation processes.

They also failed to recognize that the quantitative features of these dose—responses were similar regardless of the means of stimulation induction. In fact, it is particularly ironic that now, more than seven decades following such marginalizing judgments, the definition of hormesis incorporates the overcompensation response following a disruption in homeostasis concept along with a direct stimulation component [ 91 ].

This overcompensation stimulation concept of hormesis is in fact the same definition that was rejected by leaders such as Holzknecht and Warren. It therefore seems that these early leaders within the radiation community had derived a clear scientific understanding of the overcompensation concept but marginalized it to the point that it was not considered a significant biological phenomenon. Even when the stimulatory response was the apparent result of a direct stimulatory response, it was often not considered of particular importance.

The inclusion of the stimulatory dose range for agents such as disinfectants was for illustration of the completeness of the entire dose—response spectrum rather than for its biological significance. Even the well-known bacteriologist Otto Rahn [ 95 ] modeled the hormetic-biphasic dose—response.

He noted that this model was in fact widespread and generalizable. Importantly, he offered a mechanism, involving an enzymatic explanation for the low dose stimulatory response. Using an example of the effect of arsenic on zymase activity, he suggested that the toxic agent most likely acts as a catalyst, enhancing enzyme activity along with enzyme degradation.

He proposed that there was a shifting of the optimum enzyme activity with time from higher to lower concentrations of the toxic agent. While Rahn offered an early biostatistical-model based framework to assess biphasic dose—responses, this work, like that of many other investigators, failed to emerge and thrive during the first half of the 20th century, in contrast to its dose—response rivals.

While some of the blame for the failure of the hormesis concept to thrive can be placed on the actions of prominent scientists such as Clark [ 96 ], a substantial contributory factor to the early demise of the biphasic dose—response was due to the lack of leadership and organizational activity of prominent researchers in this area.

Further, a detailed assessment of essentially all the leading early hermetic-biphasic dose—response researchers has revealed that most redirected their scientific careers to governmental service or academic administration or other divergent but compelling research activities [ 97 ].

In many ways, the hormetic dose—response failed to thrive during this period due to a combination of factors, all of which converged, leading to its continuing marginalization and the exclusion of these findings from the mainstream of science and regulatory application.

The research on hormetic-like biphasic dose—response relationships in the first half of the 20th century was therefore reasonably substantial, competently conducted and fairly general, affecting a wide range of biological models, endpoints and agents.

It also became clear that the biphasic dose—response could occur via a direct stimulation or via an overcompensation to an initial disruption of homeostasis. Despite these general findings, the hormesis concept kept being tied to homeopathy due in large part to the work of Schulz, the misrepresentations of Clark, and the need for the homeopathic community to base their therapeutic practices on a well-substantiated hypothesis. Despite the various struggles encountered by the hormetic dose—response during the first half of the 20th century, a resurgence of interest occurred in this concept toward the end of the 20th century and beginning of the 21st century.

Propelling this resurgence was the shift to assess low doses of chemical agents and the use of large scale in vitro testing, which facilitates the use of a larger number of concentrations than typically used in in vivo studies. A third point of dose—response convergence was that hormetic-like biphasic dose—responses were reported very broadly and reproducibly across biological and biomedical subdisciplines, suggesting the widespread generality of the hormetic dose—response relationship [ 97 , 98 , 99 , , , ].

Finally, if the hormetic dose—response were acknowledged as the preferred dose—response model, it would significantly focus public health investments to more productive areas of societal public health concern.

Research activities in the area of dose—response have been funded by the United States Air Force and ExxonMobil Foundation over a number of years. However, such funding support has not been used for the present manuscript. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing policies or endorsement, either expressed or implied.

National Center for Biotechnology Information , U. Int J Mol Sci. Published online Dec 5. Edward J. Guido R. Sthijns, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Oct 11; Accepted Nov This article has been cited by other articles in PMC.