Lethal Doses of Water, Caffeine and Alcohol

Today’s graphic is a whimsical look at lethal doses of chemicals we consume on a regular basis. Whilst it may be more common to view chemicals in a black and white framing of ‘toxic’ or ‘non-toxic’, the reality is more of a sliding scale of toxicity. The admission of too much of any chemical into the body can cause toxic effects, and even death – the only variant from chemical to chemical is how much is ‘too much’. For some chemicals, the amount will be very low, whilst for others, it may be almost impossibly high.

So, how can we compare the toxicities of differing chemicals, when they can all produce varying effects, and these effects all require the intake of differing amounts? One of the most commonly quoted figures when discussing the toxicity of chemicals is the LD50, which stands for ‘lethal dose 50%’, or ‘median lethal dose.’ This is the amount of a chemical required to cause death in 50% of the animals in the group it is tested on. The figures can be given for when the chemical is given orally, when it is applied to the skin, or when it is injected into the animal. The results of these tests can then be converted into figures for humans, and expressed in milligrams per kilogram of body weight. The smaller the lethal dose, the more toxic the chemical; thus, the LD50 provides a way of comparing the toxicities of all chemicals.

There are a number of caveats to the LD50 test. Firstly, as mentioned, it is the dose required to kill 50% of the test subjects. Therefore, it does not guarantee death – in fact, it’s possible to take more than the lethal dose and live, and take less of the lethal dose and die. For the purposes of clarification, other types of lethal dose data also exist: the LDLo (Lethal Dose Low) is the lowest dose known to have resulted in fatality in testing, whilst the LD100 (Lethal Dose 100%) is the dose at which 100% of the test subjects are killed.

Another issue with the lethal dose tests is the obvious fact that animals are not humans. The sensitivity of animals to different chemicals varies from species to species, and can also vary from that of humans. A prime example is that of the chemical theobromine, found in chocolate. Humans can stomach around 1000mg/kg of their body weight of theobromine; this is quite a large figure, and means it’s next to impossible for a human to eat enough chocolate to die of theobromine poisoning (an average 200g bar of milk chocolate contains a little under 300mg). Compare this to dogs, who can only tolerate around 300mg/kg of their body weight, and can therefore easily die as a result of eating too much chocolate. Therefore, there’s no guarantee that the figures converted from animal lethal dose tests are always reliable in humans.

Additionally, although lethal dose tests provide absolute figures, these will invariably vary from person to person dependent on a wide range of variables, including physical condition, and medical conditions they may be suffering from. The lethal dose of a compound also tells us little about what dose effects of its toxicity start to be manifested. Some chemicals may have a high lethal dose, but may cause toxic effects at a dose much lower than this.

A final issue with the lethal dose tests is one of ethics. There is obviously an aspect of animal cruelty involved in the tests, and for this reason they are now being widely phased out, with other methods for assessing toxicity preferred. Several alternatives have been developed:

• Fixed Dose Procedure: In this test, five male and five female rats are used. The chemical being tested is given to them orally at one of four fixed dose levels (5mg, 50mg, 500mg or 2000mg). Rather than trying to identify the dose at which death is the result, instead the test tries to identify the dose at which toxicity can be observed. Testing stops once this is seen. Although this still uses animal subjects, it drastically reduces the number of animals required, as well as the mortality rate.
• Up and Down Procedure: In this test, animals are tested one at a time, and observed for 1-2 days. If they survive, an increased dose is given to the next animal, whilst if they die, a decreased dose is given. Again, this reduces the number of animals required, but does not completely avoid their use.
• Acute Toxic Class Method: Still uses animals. A stepwise procedure, where three animals of the same sex per fixed dose level are used. Dependent on the outcome, a decision is made as to whether further testing is necessary.
• Cell-Based Screening Methods: Involves studying the effects of chemicals on cells removed from their biological environment in the lab. This alternative avoids the use of animals, and scientists hope that in the future, it will be able to be used exclusively.

To conclude, it’s clear that the LD50 method of categorising chemicals, whilst providing a useful comparison, has several flaws. For that reason, it is largely considered to be a somewhat outdated method for determining toxicity. Nonetheless, LD50 figures are still frequently quoted for various chemicals, and it is unlikely that references to them will ever be phased out completely, at least in more general parlance.

As a final note, the graphic provides the LD50 values for water, caffeine and alcohol (ethanol). It’s worth noting that, in the case of caffeine, drinking 118 cups of coffee would almost certainly see you dying of water poisoning before caffeine poisoning! The figure for alcohol is also especially variable, including whether or not you’re drinking on an empty stomach, as well as personal drinking history.

I’m indebted to Justin Brower for the content of this graphic, with whom I corresponded on the figures, who was able to provide some very useful feedback and suggestions. Justin runs the excellent blog ‘Nature’s Poisons‘ which, unsurprisingly, looks at the various poisonous chemical compounds found in nature and is well worth a read.

The graphic in this article is licensed under a  Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. See the site’s content usage guidelines.

References & Further Reading

• Toxicity testing without animals – Chemistry & Engineering News
• Toxicological Testing – S Parasuraman
• Glossary of Terms used in Toxicology – IUPAC