The power of science, including toxicology, is ever present but often misunderstood and even misused and abused. Therefore, it becomes incumbent upon the toxicologist to carefully explain the details of our science. In many ways, toxicology remains a paradox. The words of Paracelsus, the 16th-century Swiss-German physician and alchemist, continue to remind us that the line between light and dark, good and evil, poison and medicine, is but a fine one that we as toxicologists labor to divine. “Alle Ding sind gift, und nichts ohne Gift; allein die Dosis macht, dass ein Ding kein gift ist.” (Literally: “All things are poison and nothing is without poison; only the dose makes a thing not a poison.” In other words, The dose makes the poison.)

The basic goal of toxicology is to elucidate the magnitude of the expression of a particular hazard along the continuum of exposure. This concept is defined as risk. Risk is therefore composed of two elements: hazard (toxicity) and exposure. Without exposure, there is no risk, no matter how great the hazard. Without a hazard, there is no risk, even at high levels of exposure. Take for example the case of a rattlesnake. The venom of a rattlesnake is poisonous, and we would all agree the potential for hazard (or toxicity) is great. If one were to walk in the woods and get bitten by a rattlesnake, the combination of hazard (venom) and exposure (bite) makes the risk of injury great. However, think about a scenario where the rattlesnake is behind a plate of glass at the zoo. The hazard is the same in both examples; the venom is just as poisonous. In this second scenario, however, because the snake cannot bite the person standing in front of it, there is no exposure. In this case, removing the exposure has removed the risk. In another example of the application of hazard and exposure to define risk, picture walking in those same woods and coming across a bunny. The potential hazard is insignificant (with the possible exception of the incident involving President Jimmy Carter in the fishing boat), and so no matter how much exposure to the bunny the person has, the risk of harm is inconsequential.

Principles of Toxicology
To understand the concept of hazard, in foods as well as drugs, we must first understand four basic principles of toxicology—dose matters, timing is critical, people differ and things change.

So let’s begin with the first of our basic principles: Dose matters. A good example of dose matters in the food area comes from the world of vitamins. Most fat-soluble vitamins have both recommended intakes as well as tolerable upper intake levels (ULs). An adequate intake of vitamin A is essential for vision, cell differentiation, membrane structure and function, reproduction, immune system function and organ development. However, there is the potential for harmful effects of long-term overdoses of preformed vitamin A (retinol and retinyl ester), including liver damage. And although adequate intake of vitamin A is necessary for normal fetal development, excessive intake of vitamin A during the first 3 months of pregnancy can cause birth defects. For this reason, the Institute of Medicine recommends a UL for vitamin A of 10,000 IU per day in adults.

We can also examine a compound used for pest control: warfarin. Warfarin is an anticoagulant used in a number of rodenticides to kill household and farm pests as well as a drug to protect people against heart attacks, strokes and blood clots. Thus, the same chemical is used to both kill pests and save human lives; it is only the dose that separates the poison from the medicine.

The concept of “timing is critical” can be demonstrated by the pharmaceutical example of thalidomide, a drug once approved in Europe for nausea and to alleviate morning sickness in pregnant women. Shortly after the drug began selling in Germany, between 5,000 and 7,000 infants were born with phocomelia (malformation of the limbs). It was recognized in this case that the timing of exposure was as important as the dose for teratogenic effects. Today, however, thalidomide is used to treat people for a number of conditions including erythema nodosum leprosum, multiple myeloma and various other cancers, for some symptoms of HIV/AIDS, sarcoidosis, graft-versus-host disease, rheumatoid arthritis and a number of skin conditions that have not responded to usual treatment but with the precaution regarding its potential to cause birth defects if taken during a specific period of pregnancy. Therefore, when used outside this critical period of human development, thalidomide does not produce the adverse effects that were so tragically manifested during its use as a morning-sickness therapy.

The fact that people differ is reflected in our genetic makeup in something we call polymorphisms, or very small changes in our DNA that cause our bodies to respond differently to certain chemicals, including those used as food ingredients. For example, in the case of the artificial sweetener aspartame, products such as Equal carry a warning label: “Phenylketonurics: contains phenylalanine.” Phenylketonuria (PKU) occurs in approximately 1 in 10,000 babies born in the U.S. PKU babies must inherit two mutant genes (one from each parent) for a specific enzyme (phenylalanine hydroxylase), resulting in the body’s inability to break down the essential amino acid phenylalanine, leading to toxic levels of this amino acid. Loss or reduction of activity of this enzyme can result in mental retardation, organ damage and unusual posture and can, in cases of maternal PKU, severely compromise pregnancy. People without this polymorphism can safely consume and enjoy aspartame-sweetened beverages and foods.

Finally, the fourth basic principle, things change, is based on the fundamental role of metabolism in how our bodies handle exogenous chemicals. A good example of “things change” is the food-drug interaction that occurs with a common fruit juice. Grapefruit juice can be part of a healthful diet; it contains vitamin C and potassium. But among all fruit juices, grapefruit juice possesses the highest ability to interact with many drugs. This happens because the juice increases the absorption of the drug into the bloodstream and decreases excretion rate. When there is a higher concentration of a drug, you tend to have more adverse events. For example, if you drink a lot of grapefruit juice while taking certain statin drugs to lower cholesterol, too much of the drug may stay in your body, increasing your risk for liver damage and muscle breakdown that can lead to kidney failure.

A classic pharmaceutical example of metabolism in defining the margin of safety between drug and toxic chemical occurs with the anti-inflammatory drug acetaminophen, which can be found in Tylenol. At low to moderate doses, acetaminophen enters the body and is rapidly converted into a pharmacologically inactive form by enzymes in the body and is readily eliminated via the kidneys. If a person takes excessive amounts of acetaminophen, however, there is a risk of liver damage. The reason for this is that once the usual metabolic pathway for elimination of the drug is overwhelmed, acetaminophen is metabolically activated via another pathway that results in a metabolite that damages the liver. Thus, at therapeutic levels, acetaminophen is changed into a chemical that is harmlessly excreted, while in overdose situations, it is changed into a form that can cause harm or even death.

Laying Perceived Hazards to Rest
Another very interesting aspect of risk assessment is the differentiation of real versus perceived hazards. It is often not easy, certainly with potentially conflicting news reports of harm from foods or drugs to which we are all exposed, to understand what we should ingest and what we should avoid! For example, the myth that “mercury” causes autism is among the most debunked of scientific theories, yet it persists because in 1998, The Lancet published a paper that suggested a link between the MMR (measles, mumps, rubella) vaccine and autism. The paper by Andrew Wakefield, M.D., drew considerable publicity and is credited with pushing vaccination usage down in the United Kingdom and the United States. The Wakefield study was not only retracted in 2014, but was also deemed an “elaborate fraud” by the British Medical Journal, resulting in the loss of Wakefield’s medical license.

At the same time, several studies, including those from the Institute of Medicine, found no evidence linking vaccines and autism. Repeated research agreed that there is no evidence of harm from thimerosal’s mercury compound (ethyl mercury) in vaccines.

At this point, we have looked at the important factors that affect the potential for a hazard to be expressed in an individual. Risk, however, is equal to hazard times exposure, which can be remembered by the simple acronym RITE (Risk Is Toxicity × Exposure). Although there is no plausible hazard from exposure to thimerosal from vaccines, it is also interesting and quite comforting for the consumer to know that thimerosal, which is used to prevent bacterial growth with repeated entry into a vial, was never used in the MMR vaccine or in vaccines for chickenpox or polio in the United States, because in the U.S., these were single-use products. Bluntly, no hazard, no exposure, no risk!

A final example of the role of exposure in evaluating risk can be found in our favorite morning beverage. Coffee is chemistry in a cup! It contains more than 1,000 aroma compounds, including caffeine and a spectrum of potential carcinogens. The health controversies surrounding coffee have been the focus of numerous studies addressing a long list of animal toxicities and human disease outcomes. Acrylamide, a product of roasting, is found in an array of food products, including coffee, and in fried, baked or toasted goods. According to the U.S. National Toxicology Program and the International Agency for Research on Cancer, there is clear evidence that acrylamide is a carcinogen.

A typical coffee drinker’s exposure to acrylamide of about 4–6 µg/day is equivalent to that detected in three to five cups of java. Despite these potential adverse health effects, many negative health myths about coffee drinking may now be transformed into validated health benefits due to more recent mechanistic and epidemiologic research studies. For example, the consumption of five or more cups of coffee daily is associated with improved glucose tolerance and reduced risk of type 2 diabetes, cardiovascular disease and some forms of cancer. Even in cases of toxic or carcinogenic chemicals in our food supply, dose matters!

Conclusions
The study of toxicology helps us elucidate the magnitude of a particular hazard along the continuum of exposure. To better understand the effects of the exposure and hazard in question, we must examine the dose and timing of the hazard, its specific effects in target populations and the fundamental role of metabolism of the toxic material. Doing so will allow us to develop an assessment both of hazard and exposure and thereby take the necessary steps to mitigate these risks for both foods and drugs. 

A. Wallace Hayes, Ph.D., DABT, is a visiting scientist at the Harvard T.H. Chan School of Public Health.

Claire L. Kruger, Ph.D., DABT, is president of Spherix Consulting.

Roger A. Clemens, Dr.Ph., is an adjunct professor in pharmacology and pharmaceutical sciences at the University of Southern California School of Pharmacy, International Center for Regulatory Science.

Suggested Reading
1. Blakemore C and S Jennet, eds., The Oxford Companion to the Body (New York: Oxford University Press, 2003).
2. Hayes, AW and CL Kruger, Hayes’ Principles and Methods of Toxicology, 6th ed. (Boca Raton, FL: CRC Press, 2014).
3. Heaton, A, ed., The Chemical Industry. (Dordrecht, Netherlands: Springer, 1994), 40.
4. Higdon, JV and B Frei. 2006. “Coffee and Health: A Review of Recent Human Research.” Crit Rev Food Sci Nutr 46:101–123.
5. Kim, JH and AR Scialli. 2011. “Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease.” Toxicol Sci 122:1–6.
6. Miller, MT. 1991. “Thalidomide Embryopathy: A Model for the Study of Congenital Incomitant Horizontal Strabismus.” Trans Am Ophthalmol Soc 81: 623–674.
7. U.S. Department of Health and Human Services. National Institutes of Health. 2007. “NTP Technical Report on the Toxicology and Carcinogenesis Studies of 4-Methylimidazole.” NIH Publication 07-4471.
8. Tareke, E et al. 2002. “Analysis of Acrylamide, a Carcinogen Found in Heated Food Stuffs.” J Agric Food Chem 50:4998–5006.
9. World Health Organization. International Agency for Research on Cancer (IARC). 2015. IARC Monographs, Volume 112.
10. www.drugs.com/monograph/thalidomide.html.