Below is one of the many countless student discussions posted by this
author as a current student in Forensic Toxicology in during the 3rd week into the
course at the University of Cambridge
Q. What is a toxin?
A. A toxin is a poison of biological origin, normally a
protein expressed by the organism
For instance, botulinum toxin is a neurotoxic protein
produced by the bacterium Clostridium botulinum.
Another example, is
tetanus toxin, an extremely potent neurotoxin produced by Clostridium
tetani in anaerobic conditions and this
toxin causes tetanus (lock jaw in humans)
Other examples are mycotoxins, for instance aflatoxin B and
G expressed by the microfungi , Aspergillus flavus, that in small doses over
long exposure can cause liver cancer, and in large doses in one sitting causes
acute liver failure
Others are the different types of neurotoxins and
haematoxins expressed by vipers and cobras. The list goes on and on.
Q. What are the therapeutic and fatal doses of the various
poisons and drugs given in the list
A. As far as the therapeutic and lethal doses of other
poisons and drugs are concerned here are just two examples
Poison Therapeutic dose
Lethal dose
Arsenic Arsenic
trioxide 0.15 mg/kg IV 70 to 200 mg mg/kg/day
Paracetmaol 1-2 tablets bd – tds
(twice or three times a day
10–15 g (20–30 tab)
For arsenic this is found in a few medicinal preparations
For instance, Salvarsan, an organic arsenical, was
introduced in 1910 by Nobel laureate, physician and founder of chemotherapy,
Paul Ehrlich. His compound, which was one of 500 organic arsenic compounds,
cured syphilis.
Today, arsenic compound is still used in the treatment of
trypanosomiasis. Therapeutic doses of these compounds depends on the
formulation and preparation
For instances for acute promyelocytic leukemia (APL),
arsenic trioxide at a dose of 0.15 mg/kg body weight is given IV until bone
marrow remission; not to exceed 60 days.
Other formulation such as Tretinoin is given at 22.5 mg/m²
Arsenic exerts its toxicity by inactivating up to 200
enzymes, especially those involved in cellular energy pathways and DNA
synthesis and repair.
But what is more important is the long term exposure to
arsenic in the soil and drinking water
WHO estimated through drinking water, more than 200 million
people globally are exposed to higher than safe levels of arsenic (1). The
areas most affected are Bangladesh and West Bengal (1). Exposure is also more
common in people of low income and minorities (2).
Acute poisoning is
uncommon (1). The toxicity of arsenic has been described as far back as 1500 BC
in the Ebers papyrus (3).
The acute minimal lethal dose of arsenic in adults is
estimated to be 70 to 200 mg or 1 mg/kg/day (4)
As far as paracetamol is concerned, the therapeutic dose as
an analgesic is normally 1 -2 tablets x tds. But this depends on age
An overdose of 10–15 g (20–30 tablets) of paracetamol can
result in fatal hepatotoxicity (5, 6).
Patients who are malnourished, have been fasting, take
enzyme inducing drugs, or regularly drink alcohol to excess are at higher risk
of liver damage.
Again the fatal dose depends on a person's body weight, age
and other drug interaction. For instance if a person takes 5 g of paracetamol
together with alcohol, that dose probably would be the lethal dose for him,
especially if he / she is a small child.
Similarly, if he already has a liver disorder, and his
kidneys are already compromised with low GFR, low creatinine and urea
clearance, the lethal dose for
paracetamol can be would be much lower than 20 -30 tablets in one dose. It all depends on the patho-physiology state
of an individual
The same can be said for strychnine. A few minutes after ingestion, strychnine is
excreted unchanged in the urine, and accounts for about 5% of a sublethal dose
given over 6 hours (Boyd et al., (1983)
Higher doses over a longer period are fatal. Again this
depends on the body weight
I think it is very difficult to give any strict and specific
values for all these drugs / poisons especially the lethal doses because it is
not possible for us to carry studies on lethal doses using human subjects.
Most of toxicological studies are done using animal models,
and their lethal dosage per kg of body weight are then extrapolated into humans
Then again, the biochemistry and genetic make-up of animal
models may not necessary be the same for humans. But that is the best we can
do. We can’t carry out toxicological trails on humans
There are many other methods used for evaluating toxicity.
One common method is to determine the LD 50 (lethal dosage of a substance that
kills 50 % of a population in experimental animals),
Toxicologists can also use cell cultures and cell lines
studies in vivo exposure, skin
sensitization tests, Draize test, open epicutaneous test, optimization test,
split adjuvant test, guinea pig maximization test (GPMT), Buehler test, and
murine local lymph node assay (LLNA)…etc. etc.
Normally we would use some of these studies such as
developmental toxicology in embryotoxicity studies, genetic toxicity testing,
neuro-toxicological evaluation,
two-generation reproduction toxicity studies, carcinogenicity testing,
subchronic oral toxicity testing to better understand their toxico dynamics and
toxicokinetics (how they act on the body). The list goes on.
Most of these we would focus on the various experimental
animal models and methods used for toxicity testing. It depends what we want to
evaluate
These pre-clinical toxicity testing helps the toxicologist
to calculate out “No Observed Adverse Effect Level” which is needed to initiate
the clinical evaluation of products
under investigation such as a novel drug to be marketed much later after 10 -
15 years from cell-lines studies on toxicity, clinical efficacy, to various
phrases of clinical trials. It takes a very long time at high cost in R & D
before approval by FDA can be obtained
On the issue of adverse drug reaction and toxicity, post
marketing pharmaco vigilance is still observed and in place
So I cannot tell you exactly what each dose, therapeutic,
fatal or otherwise would be for the various poisons and drugs given in the list because of so many confronting factors
Some poisons like arsenic, lead and mercury are accumulative
at very low doses over many years, or they can also be acute at high doses if
administered in a single dose
I would like to leave this very complicated and very lengthy
subject here as this is a very complicated and controversial issue
There are already too many studies and published literature
on this with some studies contradicting each other.
References:
1. Naujokas, Marisa F.; Anderson, Beth; Ahsan, Habibul;
Aposhian, H. Vasken; Graziano, Joseph H.; Thompson, Claudia; Suk, William A. (3
January 2013). "The Broad Scope of Health Effects from Chronic Arsenic
Exposure: Update on a Worldwide Public Health Problem". Environmental
Health Perspectives. 121 (3): 295–302.
2. Joca, L; Sacks, JD;
Moore, D; Lee, JS; Sams R, 2nd; Cowden, J (2016). "Systematic review of
differential inorganic arsenic exposure in minority, low-income, and indigenous
populations in the United States". Environment International. 92-93:
707–15.
3. Howie, Frank (2013).
Care and Conservation of Geological Material. Routledge. p. 135. ISBN
9781135385217. Archived from the original on 2017-09-10.
4. https://pmj.bmj.com/content/79/933/391.full
5. Prescott
LF. Paracetamol overdosage: pharmacological considerations and clinical
management, Drugs, 1983, vol. 25 (pg. 290-314)
Google ScholarCrossrefPubMed
6 BMJ
Group, British National Formulary 59 March 2010, 2010LondonBMJ Group;
Pharmaceutical Press
7. Boyd RE, Brennan
PT, Deng JF, Rochester DF & Spyker DA (1983). Strychnine poisoning. Am. J. Med., 74: 507-512.
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