Factors Influencing Gas Exchange in the Lung

It’s pretty safe to say we breathe stuff in. We breathe in all kinds of crazy things — mostly unintentionally (various types of air pollutants of all types and kinds, insects (I hate inhaling bugs), other people’s germs). But what people sometimes find surprising is that we also exhale a lot of crazy stuff.

In fact, exhaling chemicals is one of the ways that we get rid of them — especially vapors (like alcohol). If you’re diabetic you may exhale larger than normal quantities of ketones (your breath may have an acetone or nail polish remover smell). If you drink alcohol, one way your body gets rid of it is through exhaling — pretty cool right?

In this post I want to talk about people. More specifically, I want to talk about how people differ in their ability to exhale and inhale chemicals — this is a big challenge for the fields of inhalation toxicology and toxicokinetics (toxicokinetics is the subfield that measures how chemicals get distributed throughout the body, and then how they leave the body; and one of my specialties — making mathematical models to simulate the distribution and elimination of chemicals).

Why do these differences in ability to exhale and inhale chemicals matter? Well, for some people it’s the difference between DUI/DWI charges and going free when driving after drinking alcohol. For others, this can mean the difference between life, death, postoperative memories or emergence issues following general anesthesia.

So What Exactly Is This Difference Between People I’m Speaking of Anyway?

People display differences in their ability to exhale and inhale chemicals. Some of these differences are purely structural (the anatomy or structure of their lungs are driving some of the difference). For others, it could be that their blood chemistry or blood proteins are different and that leads to differences in how well chemicals can go from the watery part of the blood into the air and vice-versa.

So let’s break this down a little more. We’ll start with the structural differences and some lung anatomy and lung injury.

When we breathe, air enters our nose or mouth, travels down the trachea, and then through a series of branching tubes called bronchi and bronchioles, until the air gets to the deepest layer of the lung — the alveoli. The alveoli are like little bags that fill up with air when we inhale, and contract when we exhale.

It’s All About the Gas Exchange!

The alveoli are important because that’s where gas exchange happens — it’s not quite like the transaction at the grocery store or the hardware store where you drop off an empty propane tank and get a new one; that’s a different type of gas exchange. Gas exchange at the alveolus is when the oxygen from the air crosses the alveolar membrane, and goes into the blood. The carbon dioxide in our blood crosses the alveolar membrane, and goes into the air.

So structurally speaking, what could be different? We all have airways, we all have alveoli, this seems rather straight forward, right? Well, it’s not quite that straightforward.

We All Exchange Gases Differently, and That’s Okay

What you need to know is that people, all people, are different in how they exchange gases, including oxygen, including carbon dioxide, and also alcohol (or ethanol). And these differences are what makes inhalation toxicology, and the use of exhaled air as a biomarker for intoxication difficult (I’m looking at you Breathalyzers!).

These differences drive a lot of the uncertainty with respect to things like Breathalyzer readings/results, and these are the things that make it harder for forensic toxicologists and analysts who use breath concentrations to know what the real value of a gas is in your blood using your expired air.

This is also why, from an evidentiary standpoint, I always prefer to see multiple and different (we call them orthogonal) measures for the same endpoint (e.g., intoxication). Having multiple lines of evidence of the same measure is just good science.

If you’d like to know more on why having multiple lines of evidence is important, read my post about measurement error. I promise, it’s really good.

With that out of the way, let’s talk about the structural differences that can lead to population differences in the amount of gas/vapors in your blood.

Structural Differences

One of the main structural differences we can see between people is a type of lung injury called fibrosis. Fibrosis is literally a bunch of fibers, think blood clot and scab if you pick your mosquito bites, that are laid down in an injured tissue to stop the bleeding in a tissue. To me, it looks like microscopic pick up sticks (see picture above), except they’re in your lungs.

So imagine if your lungs are filled with pick up sticks. They literally make it harder for you to breathe, and they cut off air access to nearby alveoli. What this means functionally is that less oxygen and carbon dioxide will be exchanged.

Another structural issue is mucus. Normally mucus is produced as a defense mechanism in our lungs — trapping fungal spores, viruses, bacteria, particulate matter, and other stuff we inhale — and sending it up and out of our airways into our stomach. The mechanism moving the mucus up and out of the lungs is called the mucocilliary elevator. Neat, eh?

Sometimes, the elevator stops working. Or sometimes our mucus is so thick the elevator can’t work. In these cases we begin to get airway blockages. And airway blockages aren’t good. They prevent the downstream alveoli from actually getting any air, which means our ability to exchange oxygen and carbon dioxide goes down. And our ability to exchange other gases/vapors also goes down.

People with COPD, asthma, chronic bronchitis, cystic fibrosis, some allergies, and other diseases all suffer from some type of mucus clearance issue.

So bottom line: some people have lung injuries, and some have infections or other diseases that prevent mucus from being cleared, and these people just don’t breathe well. As a result, they don’t exchange oxygen and carbon dioxide well, and they also don’t exchange gases like alcohol very well, either.

Non-Structural (Biochemical and Physical Chemistry) Differences

There are many different types of non-structural differences. These could be due to differences in the amount or type of proteins in the blood (and when I say type of proteins in the blood, I’m generally referring to genetic differences that lead to structural differences in the proteins), the rate of ventilations (how often someone breathes in and out), the body temperature, metabolism rate (temperature tends to correlate with metabolism rate), and differences in how chemicals are metabolized, as well as differences in the absorption, distribution, and elimation/excretion through other routes (e.g., urine, feces, sweat) that occurs.

Other things that matter are more about the environment — the amount of the gases in the air at the alveoli. The other is more about the interplay of a person’s biochemistry (all those things in the previous paragraph) and the physical chemistry of the gas/vapor — we call it the air:blood partition coefficient, but it goes by another name — the Henry’s Law Coefficient or Henry’s Law Constant. Don’t worry — we’re gonna talk about these as well.

Henry’s Law Coefficient and Breathalyzers

When it comes to measuring the blood alcohol content, most people are familiar with breathalyzers. The breathalyzer measures the alcohol content in your exhaled breath, and uses that to infer your blood alcohol concentration (BAC). If your inferred BAC exceeds some levels, then you may be put into legal jeopardy.

Unfortunately, the story of how breathalyzers work is not quite that simple. And it has less to do with how the breathalyzer measure the alcohol content in the exhaled air — it has more to do with the actual biochemistry of each person — and each person is different.

But, just what determines how much alcohol moves from the blood and evaporates into your exhaled breath? The blood:air partition coefficient, sometimes called the Henry’s Law Coefficient.

In pharmacology/toxicology/biochemistry we use the term “blood:air partitioning coefficient” to describe the ratio of the blood alcohol concentration to the concentration of alcohol in the exhaled air. You’ll also run in to a lot of discussion of Henry’s Law, and sometimes even the “Henry’s Law Constant”, “Henry’s Law Volatility Constant”, or “Henry’s Law Solubility Constant”.

So what does Henry’s Law actually say? Well, here’s Henry’s Law in a nutshell:

At equilibrium and constant temperature, the amount of gas dissolved in a liquid is proportional to the partial pressure of the gas above the liquid. [https://doi.org/10.5194/acp-15-4399-2015]

The proportion is termed the Henry's Law Constant or the liquid:air partitioning coefficient 

Of Henry’s Law, 2 Liters of Pop, and the Sadness of Flat Pop

What’s really neat about Henry’s Law is that those of us who buy pop/soda/carbonated beverages experience it a lot. When you buy your favorite 2L of pop, you know how much pressure the contents are under. Try pressing on the outside of the plastic bottle — if it gives a lot, it’s lost a lot of the carbonation — it’s flat. That is Henry’s Law at work.

So let’s dig a little deeper (and bear with me, we’re getting back to breathalyzers shortly). Henry’s Law says that at equilibrium the amount of gas dissolved in a liquid is proportional to the partial pressure of the gas above the liquid.

So what’s this equilibrium business? It means the system’s more or less settled. The carbon dioxide in a 2L of pop at your favorite grocery store is most likely at equilibrium — the pressure in the system isn’t really changing assuming the temperature doesn’t change a lot.

When you first buy that bottle of pop — there isn’t a lot of empty space, and the contents are under quite a bit of pressure. So you know that the pressure of the gas in that little headspace (the area where there’s no pop/liquid) is super high — you can feel it when you twist that cap off, and you hear the gas hissing out as you open the cap. That pressure in the headspace is the partial pressure (we say partial pressure, because it’s the pressure that’s from just one gas; if you think of the atmosphere, it’s made up of a lot of gases, so the atmospheric pressure is actually the sum of the partial pressures of all the gases that are “part” of the atmosphere — hence, “partial” pressure — it’s the part of the atmospheric pressure represented by that one gas).

Now then, when you open up that 2L of pop for the first time, you just released a whole lot of pressure. Now let’s say you drink directly from the 2L (or you pour it into a glass like a civilized person) — you now have less carbonated pop in the bottle, and a much larger headspace in the bottle. Henry’s Law tells us what happens next: the carbon dioxide is going to leave the pop, and it’s going to fill up that headspace until we reach equilibrium.

What that means is that the partial pressure of the carbon dioxide above the surface of the pop is proportional to the concentration of carbon dioxide in the pop at some point in the future.

If you were to measure the instantaneous carbon dioxide concentration in the head space you will see it’s going to increase until we reach equilibrium. At that equilibrium point, the concentration of carbon dioxide in the head space will be proportional to the concentration in the pop.

What’s happening immediately is that some of the carbon dioxide is leaving the pop and entering the headspace; other carbon dioxide molecules are leaving the headscape and entering the pop. Eventually the amount of carbon dioxide leaving the pop and entering the headspace doesn’t really change — that’s equilibrium.

Assuming we are making our measurements at the same temperature, we would assume the proportionality constant (i.e., the Henry’s Law Coefficient) to be the same after we drink some pop and reach equilibrium as before we even opened the pop.

Why does the pop go flat? Well, because the head space is larger, it takes more carbon dioxide to fill that space, and the pressure when we cap it will likely be much less than when the bottle was filled at the bottling plant. Thus, there is less carbon dioxide in the pop, making it taste flat.

So how does this all relate back to breathalyzers?

Breathalyzers, Henry’s Law, and a Lack of Equilibrium

The section title kind of gives away the main point: it all comes back to Henry’s Law and equilibrium (and temperature).

Are our lungs, the alveolus, bronchioles, bronchi, trachea, and through to your mouth/nose a closed system like a closed 2L pop bottle? Nope, our respiratory tract isn’t a closed system — it’s completely open to the environment. Our entire respiratory tract is a lot more like a 2L pop bottle without a cap, than a 2L pop bottle with a cap on it.

Why does it matter that our respiratory tract is open?

Simple — the oxygen, carbon dioxide, alcohol, and any other gas you exhale will never reach equilibrium with the atmosphere at the alveolus, because we keep inhaling and exhaling. Our alveolus will never reach equilibrium with the atmosphere until we’re dead.

If the gases at our alveoli ever reach equilibrium with the atmosphere we are breathing then Henry’s Law states we aren’t going to perform gas exchange. If the partial pressure of oxygen in the atmosphere were lower than the partial pressure of oxygen in our blood, we will suffocate — this is exactly how non-reactive asphyxiant gases operate (and how they lead to feelings of euphoria) — these gases displace the oxygen either from a room, or from our respiratory tract, and make it so that oxygen doesn’t cross into our blood at the alveoli.

Back to alcohol — there’s not much alcohol in our atmosphere (even in a bar). Thus, the amount of alcohol in the air we exhale will be proportional to the amount in our blood. But here’s the kicker — Henry’s Law only works at equilibrium; since we don’t reach equilibrium, it is hard for us to say what a reasonable blood:air partition coefficient should be for a person at any instantaneous state because it is constantly changing. There has been a great deal of research on this identifying that the blood:air partition coefficient changes as a function of BAC.

So what causes some of these blood:air partition coefficient differences in people? We’re not entirely sure, but it likely has to do with differences in how alcohol is transported in the blood, and differences in how alcohol transports across cell membranes, especially at the alveoli. It has been demonstrated previously that alcohol can interact with proteins embedded in membranes and activate or inhibit them to different degrees, as well as disrupt membranes to different degrees, depending upon lipid content. Proteins, protein amounts, localization, and differences in lipid content of membranes are all known to vary person-to-person, and within the same person over time.

Breathalyzers Assume What?

A little known fact — breathalyzers assume everyone has the same blood:air partition coefficient, also known as the Henry’s Law Coefficient, or Henry’s Law Constant. But the problem is — we don’t. Different people have different blood:air partition coefficients.

In inhalation toxicology, these person-to-person differences in the blood:air partition coefficient can cause us a lot of grief. It means that we have to use distributions of values to really model the human population effectively. If we don’t do that, then we won’t get a very accurate assessment of how an environmental exposure to a gas or vapor can translate into toxicity, and we may do a poor job of setting a safe exposure level.

For breathalyzers, assuming everyone has the same Henry’s Law Coefficient, or blood:air partition coefficient means that some people will likely be called over the legal BAC limit when they are not (a false positive), and others will be below the legal BAC limit when they are actually above the legal BAC (a false negative).

For this reason, I advise clients on the prosecutors’ side to always ensure there is a a wealth of additional evidence to prove intoxication. And for my defense clients, I advise them to show me all of the evidence that the prosecution has, including any blood tests that were performed, videos of the encounter, witness statements, and anything else we can use to independently assess the degree of intoxication of the subject.

Raptor Pharm & Tox, Ltd is Here to Help

If you have any inhalation toxicology needs, make sure to contact Raptor Pharm & Tox, Ltd. Our experts have led government expert panels on assessing inhalation toxicology risks of chemicals. We build inhalation toxicology models for clients to solve all kinds challenges.

We understand the forensic toxicology needs/requirements of both prosecutors and defense attorneys when it comes to DUI/DWI cases. We will assess the science, and we have the experience to explain it to lay audiences, so they become comfortable and familiar with the scientific evidence.