Basics of Dose and Exposure
By way of background, we suggest to first take a look at “All Natural! All Safe? Everything is a Chemical!” One key message there is that source or origin of a chemical usually tells you very little if anything about its toxicity or ability to cause harm. Naturally occurring chemicals are not necessarily any more or less toxic than synthetic chemicals. For example, grapes contain certain naturally-occurring chemicals that are considered to be part of a healthy diet. Fermentation is a natural process involved when grape juices turn into wine but, as everyone knows, drinking excessive amounts of wine or any other alcoholic beverage can make you ill or even kill you.
So what does make a chemical ‘toxic’?
Dose is often cited simply as the most important determining factor for whether chemical will cause a harmful reaction. This idea was originally expressed by the Swiss physician Paracelsus (1496-1531): “Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy.”
Toxicologists often refer to a harmful reaction caused by a chemical as a toxic response. The relationship between dose and response can be visualized as a simple graph with dose on the x-axis and response on the y-axis. Two important points on a dose response curve that are illustrated in the accompanying figure are the “NOAEL” (No Observed Adverse Effect [or response] Level) and the “LOAEL” (Lowest Observed Adverse Effect Level). These doses are especially important to risk assessors when establishing safe levels of chemicals.
What determines dose?
In simplest terms: Amount x Frequency x Duration = Total dose over a specified period of time. Let’s start with doses of medications because that is easy to understand and explain.
You may consume a 500 mg pill (=amount) of drug “Y” every eight hours (=frequency) for two days (=duration) to reach a total ingested dose of 500 mg x 3 8-hr periods in a day x 2 days = 3,000 mg of “Y”.
The internal dose is the amount that stays in your body. This can often be different than the total dose due to elimination (for example in urine). Internal dose is expressed in terms of the amount in the body per kilogram of body weight. If you absorb 50% of the ingested total dose of “Y” and you weigh 60 kg, then your internal dose is 50% x 3,000 mg ÷ 60 kg = 25 mg per kg of body weight. A child absorbing drug “Y” equally well, but weighing only 10 kg the child would experience a larger internal dose of 150 mg per kg of body weight. (For more examples, watch Part 1 of the “The dose makes the poison” video resource recommended below.) In reality, while being absorbed, chemical substances can be transformed (metabolized) to facilitate elimination, or incorporated into biochemical pathways, or activated with potentially harmful effects. These processes occurring while the chemical is being taken into the body make calculations of internal dose at any given time more complex.
What’s the difference between ‘dose’ and ‘exposure’?
Exposure is sometimes defined as a measurement of the level at which one encounters any substance. That substance could be a glass of a fine wine or a medication that you ingest or other substances that that you inhale, apply to your skin (for example, a nicotine patch), or inject directly into your bloodstream. Many people are concerned with exposures to chemical substances in food or water, or in the air that you inhale, or in the environment that the skin is exposed to.
Route (or pathway) of exposure is another factor controlling how much of a substance gets absorbed into your body. The main routes of exposure to chemicals in the environment are by ingestion (gastrointestinal), dermal absorption (through skin), and by inhalation (through the lungs). For example, liquid mercury released from a broken thermometer will not be absorbed appreciably from the gastrointestinal tract if it is accidently ingested. Mercury is also not easily absorbed through skin. However, breathing vapors from that spilled mercury could result in a significant internal dose by inhalation.
An acute exposure is one of short duration whereas a chronic exposure is one that is repeated or prolonged for an extended period. Effects of a chemical can be different depending on whether the exposure is acute or chronic. Regulatory agencies often recommend safe exposure levels for multiple exposure durations, including acute and chronic.
Individual sensitivities also matter!
Who you are matters when it comes to how much toxicity you experience compared with another individual exposed to the same amount of the same chemical. Your age, overall health, and gender can also matter. People have different characteristics and susceptibilities at different times of their lives and also because of genetic predisposition. Some ethnic groups have greater tolerance to the intoxicating effects of alcoholic beverages. Diet, nutritional status, and amount of stress we are experiencing in our lives can also affect response to chemicals. These individual-specific factors are sometimes determined by level of education and other social and economic factors that impact our personal choices, behaviors, and overall lifestyle. Medications and other chemicals in a person’s body at the same time can sometimes intensify or diminish the response.
In other words, how each of us responds to any given chemical can get complicated! However, fundamental messages here are still that (1) dose is arguably still the single most important determinant of response and (2) no dose will occur without an exposure.
To summarize some basic relationships of key concepts discussed here: Internal dose of a chemical and an individual’s response to that chemical is dependent upon…
- level of exposure
- frequency of exposure
- route of exposure
- fraction absorbed by that route
- duration of exposure, and
- individual sensitivities
Understanding these concepts and the relationship of chemical exposure and dose, and the important role our individual characteristics have in our responses to chemicals is critically important to understanding toxicology.
All of the following resources, ordered from simplest to more comprehensive and complex, help to define and expand further on this topic.
- Glossary of terms at the SOT website: http://www.toxicology.org/gp/toxterms.asp
- Risk, hazard, and making sense of dose and response – i.e., relationship of what you’re exposed to how severely it effects the body (2:30 Risk Bites) https://www.youtube.com/watch?v=tm2JQVBMSU0&list=PLVlpUweVc-T6NvORFhQY_uLn_VkFGBOoG
- Crossing the Threshold of Dose Response – Threshold vs. no threshold dose response models (3:43, Risk Bites) https://www.youtube.com/watch?v=yyvX5hDBPBY&index=4&list=PLVlpUweVc-T6NvORFhQY_uLn_VkFGBOoG
- “Is It Safe? Evaluating Chemical Risks” Video by TEF in English, Spanish, and English with Japanese subtitles Currently at this link but that might change?An introduction to the relationship of exposure, dose and response other concepts and principles applied to understanding chemical hazards. The video discusses examples from everyday life. The English version of “Is It Safe?” is also available as a two-part series on YouTube:Part 1 (8:30): https://www.youtube.com/watch?v=2HyTIAtHaDYPart 2 (7:28): https://www.youtube.com/watch?v=FnmVFbexeEI
- “Is It Safe? Evaluating Chemical Risks” Primer A 23-page pamphlet that elaborates upon key concepts and principles introduced by the “Is It Safe?” video and provides tips for evaluating a media report on a toxicity issue. (link to the pdf)
- Basics of Toxicology (7:48, Flinn Scientific)Oriented toward students and teachers in labs where chemicals are present but the principles explained in the first half apply to any situationhttps://www.youtube.com/watch?v=KbOPLBYGKs8This video covers dose response curves, factors affecting dose (intake, route of exposure, duration of exposure, a person’s weight). Also defines LD50, ED50 and who sets standards for workplace exposures.
- “The dose makes the poison.” Parts 1 (8:10) and 2 (4:27)Part 1 covers several important toxicology fundamentals like dose response curves; thresholds; importance of knowing whether response is linearly related to dose or becomes non-linear as at either the lowest or highest doses; how a dose response plot can be used to estimate an LD50 (dose at which 50% of a population will respond); and how the same dose experienced by two different individuals varies depending on a person’s size.Part 2 expands upon the concept of thresholds of toxicity using several real-world examples. A key message here is that a substance that causes toxicity at a high dose will not necessarily be toxic at lower doses.https://www.youtube.com/watch?v=9bf4-bX8EHUhttps://www.youtube.com/watch?v=DDfh9tIoECg
- More on how non-chemical stressors can impact response to pollutants. “Non-Chemical Stressors and Cumulative Risk Assessment: An Overview of Current Initiatives and Potential Air Pollutant Interactions” by Ari S. Lewis et al., 2011: http://www.mdpi.com/1660-4601/8/6/2020/htmSome of the U.S. EPA-funded research focusing on understanding the role of nonchemical stressors and developing analytic methods for cumulative risk assessments: http://www.epa.gov/ncer/cra/recipients/index.html