COVID-19: Does Dose Make the Poison?

Updated: Jan 14

Victor Luca, 3-Jan-21.

Unpublished


The Swiss-German physician, Paracelsus (1493-1541) first stated that "dose makes the poison". Here I examine the relationship between the amount of viral dose and severity of disease and I make the analogy to radiation.


After working for more than two decades in the nuclear field, I have had the idea of dose-response beaten into me and I have had to teach it also.


What I mean by dose-response is how much of a quantity of radiation or a certain substance do we need to be exposed to in order to observe an adverse effect (i.e. illness). In radiation safety research we have become good at measuring acute doses of radiation delivered over relatively short time scales. For ionizing radiation (e.g. X-rays), dose is measured in units of mSv (milli Sievert). This is basically the amount of radiation that is being received by an individual. The graph in the figure shows five black dots that represent the experimentally measured risk of cancer (vertical axis) as a function of the measured dose in mSv (horizontal axis). We can relatively easily follow what happens at these high doses because people will develop cancer symptoms and we can see and measure them. These experimental points fall roughly on the straight blue line at these high doses. The line passes through the origin. That is, the zero dose and zero risk point.


This is like the radiation we receive from the sun. At high doses we can easily see an effect, including redness, soreness and blistering (sun burn). But as the dose is reduced it is harder to measure the amount of solar radiation and the effect that it has because it is no longer readily visible. Here we have the idea of acute versus chronic. In the left half of the graph there are no data points because it is not easy to measure either the dose or the effect which might take a long time to show up. So we are left to hypothesize what happens when we receive low doses or low exposures to the sun over long periods of time. Is there an effect and what kind?


In radiation research we talk about the linear no-threshold (LNT) model where the effect is assumed to be directly proportional to the dose in a linear fashion (straight blue line). What the blue line is saying is that any given dose will generate a proportional cancer risk. This is a very conservative hypothesis. An alternative hypotheses or model is described by the purple dashed line where at very low doses there is no effect (no cancer risk) until a certain point is reached (a threshold) where the cancer risk rises above zero and then becomes linear. There are other possibilities such as the green dashed line which indicates that at very low doses the cancer risk is negative. That is, small doses of radiation can actually be beneficial. In the case of radiation from the sun we know that small doses are necessary to stimulate the production of vitamin D which is beneficial in terms of wellbeing, including protecting from cancer.


Let’s now apply the radiation analogy to the situation of COVID-19 disease. A central question that scientists are grappling with is, what is the relationship between the amount of virus that a person receives (inoculum) and the severity of the disease? Back in 16th century the Swiss-German physician, Paracelsus, stated that “dose makes the poison” (see Figure). Paracelsus had a pretty good point way back then that has held up well right up to this day. For humans it appears that there is always a critical dose above which the body simply cannot cope. If I get bitten by a venomous snake, then the more venom that is injected during the bite the lower are my chances of surviving. For Australia’s Inland Taipan the lethal dose (LD50) is a mere 0.01 mg/Kg which means that if I weigh 100 Kg, then the dose required to kill me would be 1 mg.


The Kiwi eco-warrior, Pete Bethune was recently bitten on the calf by a fer-de-lance snake while he was on a patrolling mission in the jungle of Corcovado National Park in Costa Rica. The fer-de-lance doesn’t even rank in the top 10 (LD50 = 0.35 mg/Kg) but Bethune received quite a bit of venom and is lucky to be alive.

In so far as COVID-19 is concerned, the importance of the dose of the virus in the inoculum has received relatively little attention. It seems likely to me, and others, that “a dose-response relationship (infection intensity) is an important missing link in understanding COVID-19, both as a factor in the severity of disease and transmission dynamics”.


Evidence is now starting to mount that in the case of COVID-19 Paracelsus may once again have been right. Dose does make the poison. There is good evidence that people who receive a small dose of SARS-CoV-2 inoculum through the wearing of masks and physical distancing will not develop severe COVID-19 disease, whereas those that don’t, are more likely to become severely ill. In other words, they might give a positive RT-PCR test result but their symptoms will be mild.


It is also possible that the wearing of masks can assist in the development of immunity akin to that of a vaccine because for very low doses of inoculum, the body’s defenses are sufficient to deal with the viral attack. Let’s extend the war analogy. The body has a certain number of untrained troops and is invaded by a relatively small number enemy troops. Although the body is unprepared for the invasion, and has only a small number of poorly trained defense personnel, and little by way of equipment and weaponry, these turn out to be sufficient to ward off the attack because the invaders are few. Having repelled the first low-level invasion, the defending army (the body’s immune system) then has some idea of what to expect. The body’s immune system has learned the enemy’s tactics and what weapons it uses and it starts to build its army, detection systems and defensive weaponry. When the next enemy attack comes, the body is ready. A vaccine works in a similar fashion by training the immune system to be prepared for an attack by a given invader.


From the moment we started hearing the term “novel” Corona virus in December of 2019 we should have been alerted to the fact that we could start to observe things we had never seen before in virology. Thanks to rapid progress in the fields of virology, molecular virology, microbiology and biochemistry over the past decades and more recent experiences with Ebola, SARS, MERS and others we have developed effective vaccines and anti-viral agents for COVID-19 in record time. However, let us not forget the potential benefits that can accrue through limiting dose through physical distancing and the use of face masks. At least that is what the science is telling us so far. Let’s not forget the words of Paracelsus.



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