Determining the Dose that Does the Damage

“It’s the dose that kills” is a key foundation in studying toxicology – even in the case of the chemical, water. But how do researchers discover the dose that hurts, but doesn’t kill?

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Toxins can be categorized by their effects on the body, sometimes called end points. These include:

  • Carcinogen
  • Genotoxin
  • Mutagen
  • Neurotoxin
  • Immunotoxin
  • Modulator of estrogen receptors

Most commonly, toxins may fit in more than one of these categories. In order for researchers to determine what effects a toxin has, they must determine dosages to apply to either molecular or in vivo studies. The first method to determining a dose would be to use any available information. This could be analyzing legislation identifying limits to exposure. For example, the potential carcinogen ethyl carbamate is regulated in alcoholic beverages through government regulation to decrease human exposure (IARC, 2010). The regulations for ethyl carbamate have been updated as new research is conducted. Therefore, another strategy to determine a dose is to review the literature and determine what the standard range of doses has been used elsewhere. If neither of these options is available, estimates of exposure can be analyzed. From these estimates, research studies can be designed at physiologically relevant or high doses.

Exposure: “the fact or condition of being affected by something or experiencing something : the condition of being exposed to something” ~Merriam Webster

The next challenge is to analyze in vivo research conducted and apply results to health and environmental legislation. Typically, dose values are expressed in units of mass per kilogram of body weight to aid in providing a useful measure. However, a toxin can have varied effects in different species, in different organs, and even differences between individuals of the same species! Thus, the best data is collected from human exposure to a toxin, as there is the least error in designing a health risk assessment.

A good example of a natural toxin that has been studied extensively in humans is deoxynivalenol (DON). Humans are primarily exposed to this natural toxin through foodstuffs as this toxin is produced by a fungus on wheat and corn. Studies have also been conducted on pigs as they have some similar physiological aspects to humans. It has been found that pigs are so sensitive that they eat less of the feed containing DON (Danicke et al, 2007). Not only are they sensitive, but the toxin is highly evolved to have many end points. One of these effects is an effect on peptide YY which suppresses hunger (Flannery et al, 2012). This evolutionary feat allows the fungus to reproduce more through a crop deterring the competition of herbivory for the same nutrients.

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Pigs fed a control diet (back) and a deoxynivalenol contaminated diet (front) ad libitum are shown. The decreased body mass of the deoxynivalenol fed pig is due to lower quantities of food intake (adapted from a course by Dr. Miller).

While data from human exposure is ideal and using animal models can be a successful substitute in some cases, molecular research and modelling can be useful tools for better understanding the mechanism of toxins. In the case of DON, its endpoints include stunting, decreased food intake, hepatic insulin like growth factor inhibition, disruptions to neurotransmitter proper function including dopamine and serotonin, dysregulation of body temperature, nausea, activation of a proto-oncogene called c-Fos etc (Bonnet et al., 2012; Dance et al, 2007; Flannery et al, 2012; Miller, 2016). Of note, these different endpoints are dose dependent.

DON is a toxin that has high human exposure, especially in developing countries. While 100% mitigation of this substance is unrealistic, regulations limiting exposure doses can lead to healthier communities. Forming these laws is a complex process that requires quality research with one of the major steps required – determining the dose the does the damage.

References:

Bonnet MS, Roux J, Mounien L, Dallaporta M, Troadec JD (2012) Advances in deoxynivalenol toxicity mechanisms: the brain as a target. Toxins (Basel)  4:1120-1138.

Danicke S, Valenta H, Doll S (2007) On the toxicokinetics and the metabolism of deoxynivalenol (DON) in the pig. Archiv Animal Nutrition 58: 169-180.

“exposure” Merriam-Webster.com. 2016. http://www.merriam-webster.com (27 March 2016).

Flannery BM, Clark ES, Pestka JJ (2012) Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY. Toxicol Sci 130:289-297.

IARC, (2010). IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 7. Lyon, France: International Agency for Research on Cancer. pp. 111-140.

Miller, D., 2016. Control and test pigs fed deoxynivalenol contaminated feed. Deoxynivalenol. Carleton University, unpublished.

Pieters MN, Bakker M, Slob W (2004) Reduced intake of deoxynivalenol in The Netherlands: a risk assessment update. Toxicol Lett 153:145-153.

Cover photo reference: https://www.jasondavies.com/wordcloud/

 

 Adelle has received her B.Sc. in Integrated Science with Biochemistry. Through her studies, she gained a reputation as an ideas person, an encourager to her peers, and a hard worker. She aims to continue exploring, innovating, and inventing at every opportunity that arises.

 

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