The Effects of Ozone on Human Health
An Interview with William McDonnell
From the Environmental Review Newsletter
Volume One Number One, January 1994
Bill McDonnell received an M.D. from Washington University in St. Louis and a Ph.D. in Epidemiology from the University of North Carolina at Chapel Hill. He has worked for the U.S. Environmental Protection Agency since 1979 and is also on the faculty of the Schoool of Medicine at the University of North Carolina. He is a clinical researcher studying the human health effects of ozone exposure. Ozone is an important component of air pollution; it is produced by the action of sunlight on exhaust gasses and combustion products.
ER: Dr. McDonnell what is the source of ozone that people are breathing at street level?
WM: It comes from automobiles to a large extent and from other sources of combustion exhausts.
ER: Why is ozone of such concern to health scientists?
WM: Ozone is a very reactive molecule. It is a very powerful oxidizing agent, so it reacts with a number of of biological molecules causing damage to the lungs. [Oxidizing agents remove electrons from other molecules changing their structure and function. ed.]
ER: How does ozone cause damage in the lung?
WM: Ozone is a powerfull oxidant and damages the cells lining the airway. These include epithelial lining cells and cells of the immune system. I don't think we really know whether they are damaged directly or not. We do have markers of epithelial cell damage though. There are enzymes that are found only inside epithelial cells and after ozone exposure these enzymes are found outside the cells. The cells spill their contents into the airway. So that is a sign of cell damage and cell death.
In addition, the airway is lined with nerve receptors that can sense pain or stretch. Something stimulates these neural receptors. It could be ozone directly or the reaction products of ozone with the compounds in the surface liquids or it could be something that is spilling out of the injured epithelial cells. When these nerves are stimulated they send signals to the head. Those signals are: Do not take a deep breath: do more rapid, shallow breathing. Ozone can cause the sensation of some discomfort in the chest: pain on taking a deep breath, a sensation of being short of breath, and coughing also. These signals may be protective of the deep lung. People just cannot or will not take a deep breath following a big ozone exposure.
This nerve stimulation also causes people to develop a bit of constriction of the airway. If we expose a person for two hours in the lab we find they have some small amount of narrowing of the airways. The airway constriction is not anything like an asthma attack however.
There are a number of other responses to ozone going on at the same time: over a period of days one develops an inflammatory response. Accompanying this inflammation is an increase in airway reactivity, and these two responses are probably related to each other. When you have increased airway reactivity, the airway responds to the same stimulus by constricting more. People with asthma tend to have increased airway reactivity; that is one of the reasons when they breathe pollens or cold air they develop more constriction of the airways.
We are not saying that a single ozone exposure is like an asthma attack, but for an asthmatic in particular, if they already have increased airway reactivity and then they get more inflammation and airway reactivity from the ozone exposure, that could be problematic. That could put them at greater risk of having an asthma attack if they then breathe something that normally stimulates their asthma.
ER: What's the duration of increased airway reactivity from ozone?
WM: In non-astmatics, it is no more than two or three days; hours to a few days. We have been able to deduce this from exposing humans to ozone in the lab: doing a single exposure and then looking at the response over a period of time.
ER: When you give your test subjects an ozone exposure in the lab, what is an acute exposure?
WM: Anywhere from one to seven hours at a concentration of 80 to 400 parts per billion.
ER: What is the concentration of ozone that is normally in the air, about 20 parts per billion?
WM: It varies depending on where you are, but that is about right.
ER: So you're giving your test subjects a pretty high dose.
WM: Right. Los Angeles can get above 300 parts per billion of ozone, and Mexico City can get above 400 parts per billion. 400 parts per billion is worse case ambient. The magnitude of the response to ozone really depends on three things: the concentration of ozone in the air, how long you breath it, and how much you breath during exposure. The product of those three variables indicates how much ozone was inhaled over time. For example, we might expose somebody for one hour at 400 parts per billion and get a particular response, or expose somebody at 80 parts per billion for eight hours and get the same magnitude of response. So when you start talking about causes, you have to be clear about what the concentration, what the duration, and what the ventilation are. One or two numbers alone do not give you the picture.
The other part of the asthma story is there have been several epidemiology studies where people have compared hospital admissions and ozone levels on that same day. A number of people have found a relationship: on days that there are high ozone exposures, either later that day or the next day there tend to be more admissions to hospitals and emergency rooms for asthma. I'd say I am building a case from the laboratory from what we know about the mechanisms of cell damage, ozone might make asthmatics more responsive to other things in their environment. There is pretty good evidence that something is happening with ozone and asthma, but we need some more work to be certain that it is occurring. There are some animal data that suggest that an acute ozone exposure makes you more likely to get an respiratory infection.
ER: So the possibility of pneumonia comes up?
WM: That's right. Or colds or flu. There is some information that suggests we ought to be concerned with acute ozone exposures having some relationship to respiratory infection.
The third thing we worry about when we discuss acute ozone exposures is exacerbation of other ongoing respiratory disease. For example, a person may have emphysema or chronic bronchitis, and they breathe ozone acutely, and they get symptoms and constriction of the airways and they can't take a deep breath. This can push some borderline people over into requiring medical care.
So asthma, respiratory infection, and exacerbation of existing respiratory disease are three big concerns. That is the acute side of things.
From our chamber experiments, when you see cell damage and inflammation and a lot of cell repair you think to yourself, What if this exposure happened on a weekly basis for twenty or thirty or fifty years? It is not that we have any evidence from the humans that says, We know ozone is going to cause chronic lung disease. It is just that we worry when we see this much damage and repair going on all the time that if this were to happen a number of times, might it result in some chronic respiratory disease?.
We can expose rats for long periods of time to ozone and we do see chronic, permanent type changes after a year and a half of exposure.
And while they do not see frank emphysema or frank fibrosis in terms of what would make a person clinically ill, they do see that there are a number of changes in the structure of the lung tissues that occur in response to ozone exposure. One wonders if you have another species (because human and rat lungs are really quite different in their structure) or if you had a different pattern of exposure, whether you might be able to produce clinical chronic lung disease. We are out on the edge of what is known, but from animal evidence we know there is a permanent change in the structure of the lung.
ER: In rats.
WM: In rats, that's right. It worries me that given this damage and given the number of humans that are exposed for years of their lives to pretty high concentrations of ozone that we could be seeing the same. It is conceivable to me that recurrent ozone exposure could cause chronic lung disease in some people.
ER: Have there been any epidemiology studies for chronic exposure to the development of lung cancer?
WM: There has been surprisingly little. On the basis of the biochemistry, one might suspect that maybe there should be, because ozone is a very powerful oxidant. It can act like a free radical and there may be DNA damage. [Free radicals are highly reactive molecules that can damage many chemical components of cells. ed.] There have not been that many animal studies done with an eye toward cancer, but you would expect with so many animals having been exposed, if ozone were causing lung cancer we would have seen it.
ER: I was wondering if ozone might synergise with tobacco smoke or something else to increase cancer risk?
WM: Yes, you might expect that people who smoke cigarettes might have increased risk, much like asbestos. Asbestos has a much more powerful lung cancer effect in cigarette smokers than it does in nonsmokers. It is really difficult to see because smoking is such a big part of the risk. You are going to be looking for a small ozone effect on top of a very big smoking effect. Even though I'll grant you, with asbestos they found a big effect.
I think things like asthma and other chronic lung diseases are more likely and probably going to involve a larger proportion of the population than cancer. I have come to believe that the acute responses such as asthma attacks and hospital admissions are having a greater public health impact because it involves more people and it can occur multiple times. You can have an asthma attack a lot of different times. I think the acute responses play a very large role in public health impact. We certainly also worry about the chronic responses.
ER: I was thinking about how ozone causes damage to lung cells. You have free radicals in your lung fluids. Is there any experimental work with antioxidants to counteract them?
WM: There were a couple of pilot studies using humans in chambers; looking at giving people Vitamin C, but there was no dramatic effect. It was only reported though as a pilot study; there was never a full blown study done. So in humans we haven't looked too much. There is starting to be some work with that in animals.
Another approach would be to treat animals or humans with antioxidants and then expose them and see whether their acute responses change. It would be easy to load people up with Vitamin C, and I think they are probably trying that with animals, but I'm not aware that there have been any real results there. It is something we really ought to know. It would be of great interest to the public because people could be taking vitamin E's and C's.
ER: How much variation is there in how people respond to ozone?
WM: This is a fascinating topic to me. There is a huge range of individual variability in the magnitude of response to ozone. There is a huge range in terms of the symptoms and the inability to take a deep breath. I can put two guys in the chamber that are normal, healthy, 18-30 year old, white, never smoking males without allergy, asthma, or hay fever. I can stick them in the chamber and I can have one guy (at 400 parts per billion) who will have no response whatsoever, and I can have another guy who is coughing and having big time chest discomfort and has reduced his ability to take a deep breath by half and is saying "Let me out of here." Those are the extremes. It's like height distribution where some are relatively short and others are taller than average. There's an average response to a given exposure to ozone (concentration, duration, ventilation) and there are individuals that have larger responses than that and individuals that have smaller responses.
I've spent a lot of time trying to figure this out. One of the first things we did is we re-exposed people just to make sure. Is somebody that's responsive one day going to be responsive another day? So we re-exposed people at the same concentration up to a year later and we found that these responses were reproducible. I have looked long and hard for predictors of this responsiveness to ozone, and the only thing that I have found is age. As you go from 18 to 65 you get less responsive with age.
ER: Perhaps because of a less vigorous immune response in older people?
WM: Well, that's possible. We don't know the answer. Age obviously is standing for something, and we don't know what it is. But we get the biggest changes in lung function in people that are between 18 and 25.
ER: Would the person who had a strong response at 20 not have it at 40 then?
WM: We haven't done any longitudinal studies. we've seen the age effect in three different studies so we know it's real, but we don't know how an individual behaves over time. But we do know that there is something about the individual that is stable for at least a year. It's not something that comes and goes like, "Oh, I had a cold last week and therefore I'm responsive this week." That would immediately bring up the question: Is it genetic or is it environmental? Is there something that happened in my early childhood that -- let's say I had pneumonia and therefore it's made me more responsive my whole life to ozone. Those kind of things are possibility. Or is susceptibility genetic? We've got two studies that are ongoing right now to try and look at that.
ER: Is there a possiblity that you might be causing some chronic damage in your test subjects? I'm thinking of the ethical responsibilities.
WM: By exposing these adults or children? Everything we do gets reviewed through the university's human rights committee, that's the legal or formal side of the question. We aren't exposing people to anything that they aren't getting in Los Angeles, at least on a bad day. Most of the exposures we do are much lower concentrations that 100 million people in this country might get in a year. We do multiple exposures on people in some studies, five days or so but those are not the routine. Normally we do a couple of exposures on a person. I think that if that very small amount of exposure were harming your average person, you would expect that it would be such a strong effect that you would be seeing damage in the epidemiology studies in the real world. That is, if four or five exposures were likely to cause lung damage you'd expect the people in Los Angeles who are getting a 100 exposures over the standard year for 20 years would be showing you something really clearly, and they're not.
ER: To give a perspective then, how does ozone exposure to the general population compare with the most important health threats?
WM: I would say compared to cigarettes it's very small. We have to distinguish between acute effects which we've already talked about. Ozone is not causing a very large fraction of chronic lung disease, if it is causing it at all. Cigarettes is causing the bulk of it clearly. That makes it more difficult to study. You're looking at a wart on the side of a hill.
ER: My understanding is that ozone is probably one of the most common components of urban smog. Other components of smog are volatile organic compounds and particulate matter. This is off the subject of ozone but how would you characterize the overall risk of urban smog when you include these other components?
WM: That's a tough question. Number one, I'm not sure what the risk of ozone is. Particulate matter is very interesting -- there's some recent reports out. They've been doing a lot of epidemiology on mortality and particulate levels on a daily basis, and they've been finding relationships between motality and particulates.
I'm not convinced that it's real, but the more I see it pop up in different places and by different authors, I'm having a harder time disbelieving it. So I reserve judgement on particles.
ER: So you've got a handful of studies right now that are suggestive of particulates correlating with some estimate of adverse health effects like hospital admissions?
WM: Yes. There's at least a handful that have shown definite effects. They're epidemiology studies though. I think part of the problem has been that if you found that correlation for ozone, we could say "from what we know about the cell damage that ozone causes acutely we could make a pretty strong biological case for why for why that might be happening. With particles, we really have not been able to identify this strong acute response. But there's a lot of good research with particles going on, at least there's this important potential finding and a lot of questions that need to be answered.
ER: In addition to ozone and particulates the other main components of smog are volatile organic compounds and oxides of nitrogen. How do these compare as health concerns?
WM: I don't know that we think that the volatile organic compounds themselves are having that much of a health effect. And I don't think the oxides of nitrogen that are in the air are having that much of a health effect. There are some suggestions they might at very high levels. But I think ozone is probably the most worrisome player in smog -- again, with the caveat the particles are right there and they're important too.
Copyright 1994 Environmental Review
Review (ISSN 1080-644X) published monthly at:
6920 Roosevelt Way NE STE 307
Seattle, WA. 98115