TCS Daily

Of Mice and Men

By Joel Schwartz - April 17, 2006 12:00 AM

By far the most serious health claim about air pollution is that it kills tens of thousands of Americans each year, mainly due to exposure to fine particulate matter (PM2.5). However, an embarrassment for proponents of today's historically low air pollution levels as a cause of death is that the evidence is almost solely circumstantial, being based on statistical studies reporting small correlations between air pollution levels and risk of premature death.

These observational epidemiology studies could be taken more seriously if they were also supported by evidence from randomized, controlled studies that eliminate the possibility of confounding by non-pollution factors. Such studies can't, of course, be done with people, but they can be done with animals.

However, researchers have been unable to kill animals with air pollution at levels anywhere near as low as the levels found in ambient air. As a recent review of particulate matter toxicology concluded:

"It remains the case that no form of ambient PM -- other than viruses, bacteria, and biochemical antigens -- has been shown, experimentally or clinically, to cause disease or death at concentrations remotely close to US ambient levels."[i]

This position has been challenged recently, however.

The Journal of the American Medical Association (JAMA) published the results of a study that claimed PM2.5 at current ambient levels increases Americans' risk of developing heart disease. The study exposed mice to PM2.5 for 6 months, or about one-fourth of a typical mouse lifespan.[ii] Mice fed a high-fat diet and exposed to PM2.5 had more than a 50 percent greater rate of atherosclerosis (as measured by arterial plaque area) and other signs of heart disease, when compared with a control group that was fed a high-fat diet but not exposed to PM2.5. Mice on a low-fat diet also showed signs of increased heart disease with PM2.5, but the effect wasn't statistically significant.

The National Institutes of Health (NIH) highlighted the study with a press release that begins:

"[T]est results with laboratory mice show a direct cause-and-effect link between exposure to fine particle air pollution and the development of atherosclerosis...[The study] may explain why people who live in highly polluted areas have a higher risk of heart disease."[iii]

The study caused a minor media sensation, with both journalists and health experts claiming the study provides strong evidence that PM2.5 is causing serious harm to human beings.[iv]

Despite the enthusiastic reception, there's much less here than meets the eye. The mice used in the study were genetically engineered in ways that make them unrepresentative of even real-world mice, much less of humans. The mice were designed to lack the gene for apolipoprotein E (ApoE), a key substance for fat and cholesterol metabolism. As a result, these ApoE "knockout" mice have blood cholesterol levels 5 to 6 times greater than normal mice when fed regular rat chow. ApoE knockout mice have 14 times the cholesterol of normal mice when both are fed a high-fat diet.[v]

These are stupendous cholesterol levels. For comparison, medical authorities define "high cholesterol" as a serum cholesterol level greater than 240 milligrams per deciliter (mg/dl). That's only about 20 percent greater than the average cholesterol level in American men.[vi] Only one-in-50 American men exceeds 1.5 times the U.S. average, and only one-in-500 exceeds twice the average.[vii]

The very reason for using such grossly unrealistic mice to study PM2.5, is that PM2.5 does not kill regular mice or other animals at PM concentrations relevant to real-world human exposures. For that matter, PM2.5 didn't actually kill the high-cholesterol mice in the study either.

The NIH press release downplayed the vast gulf between the genetically engineered mice and normal mice, stating only that the mice in the study were "genetically programmed to develop atherosclerosis at a higher-than-normal rate." This creates the false impression that the genetic alteration was relatively mild and served merely to create a realistic analogy to humans with elevated heart-disease risk.

If you build a house out of cards, you would expect even a gentle breeze to knock it down. But this doesn't tell you much about the ability of a real house to withstand a gentle breeze. Likewise, if you design an artificial mouse that can't regulate its fat or cholesterol levels, it isn't any surprise that even a minor environmental insult can cause it some health problems. But this doesn't tell you much about the effects of air pollution on regular mice or on people.

Unfortunately, news articles on the study failed to provide the context that would have revealed the study's real-world irrelevance. The Nexis database included 10 news reports on the study. Seven didn't even mention that the mice had been genetically engineered, leaving the impression that PM2.5 caused heart disease in "typical" mice.

The other three news outlets followed NIH's lead, creating the impression that the mice in the study were merely analogous to people with a higher-than-average risk of heart disease. For example, according to the Los Angeles Times, the mice were "bred to be susceptible to developing heart disease."[viii] This is a bit like doing a study on people who weigh 500 pounds and describing them merely as "overweight."

NIH and the study authors also misled reporters about the relevance of the PM2.5 doses to real-world PM2.5 levels. The NIH press release claims "the fine particle [PM2.5] concentrations used in the study were well within the range of concentrations found in the air around major metropolitan areas." The press release also quotes one of the study's authors saying that "The average exposure over the course of the study was 15 micrograms per cubic meter, which is typical of the particle concentrations that urban area residents would be exposed to, and well below the federal air quality standard of 65 mcg/m3 over a 24-hour period."[ix]

In fact, the PM2.5 levels in the study were nothing like real-world PM2.5 levels. The mice were exposed to PM2.5 at 85 micrograms per cubic meter (mcg/m3) for 6 hours a day on 5 days of each week, and filtered air the rest of the time. Over the 6-month study period, this does indeed average out to about 15 mcg/m3, the level of the federal PM2.5 annual standard. But in the real world, areas that average 15 mcg/m3 of PM2.5 over a year rarely approach short-term PM2.5 levels of 85 mcg/m3.

For example, in the mouse study, the mice spent the equivalent of 1,560 hours per year breathing 85 mcg/m3 PM2.5 (30 hours per week x 52 weeks per year). In contrast, Modesto, California averaged 16 mcg/m3 of PM2.5 over the past year, but spent only 80 hours at 85 mcg/m3 or above.[x] Furthermore, 40 percent of those high-PM2.5 hours occurred between 11 PM and 6 AM, when most people are in bed. There were only 420 hours where Modesto exceeded even 50 mcg/m3 PM2.5.

Even areas with the highest PM2.5 levels in the country have far fewer hours of high PM2.5 than were used in the mouse study. For example, Riverside, California averaged 27 mcg/m3 PM2.5 over the past year, but had only 135 hours at or above 85 mcg/m3, and 1,055 hours above 50 mcg/m3 -- still much less than the 1,560 hours at 85 mcg/m3 in the JAMA mouse study.

Health effects depend not only on the average dose, but on the acute dose. For example, you could take 2 aspirins 4 times per day, or you could take 8 all at once. Either way, your average dose is 8 aspirins per day. But you're likely to suffer ill effects if you take all the aspirins at once. The mice received an analogously unrealistic daily PM2.5 exposure. NIH and the scientists involved in the study then created the false appearance that this unrealistic exposure schedule has some relevance to the real world.

There's nothing wrong with the JAMA mouse study in principle. It shows that when you take a mouse specially designed to have unrealistically stupendous cholesterol levels, feed it a high-fat diet, and repeatedly expose it to unrealistically high acute levels of PM2.5, that PM2.5 increases the extent of heart disease. The problem arose when the study's proponents claimed that this has something to do with the real-world PM2.5 risks faced by human beings.

It is no secret that environmentalists and regulators exaggerate environmental risks. But scientific authority is what imbues these risk claims with their public credibility. Unfortunately, public and journalistic trust in scientific authority is often misplaced.

(Incidentally, you can now find a summary of the JAMA mouse study on NIH's website. Its title? "Particulate air pollution and a high fat diet: A potentially deadly combination."[xi] )

The author is Visiting Fellow, American Enterprise Institute.

[i] L. C. Green and S. R. Armstrong, "Particulate Matter in Ambient Air and Mortality: Toxicologic Perspectives," Regulatory Toxicology and Pharmacology 38 (2003): 326-35.

[ii] Q. Sun, A. Wang, X. Jin et al., "Long-Term Air Pollution Exposure and Acceleration of Atherosclerosis and Vascular Inflammation in an Animal Model," Journal of the American Medical Association 294 (2005): 3003-10.

[iii] National Institutes of Health, "Air Pollution, High-Fat Diet Cause Atherosclerosis in Laboratory Mice," Washingon, DC, December 22, 2005,

[iv] Newspapers carrying articles on the study included the Los Angeles Times, Houston Chronicle, Philadelphia Inquirer, and several others.

[v] A. S. Plump, J. D. Smith, T. Hayek et al., "Severe Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice Created by Homologous Recombination in Es Cells," Cell 71 (1992): 343-53; S. H. Zhang, R. L. Reddick, J. A. Piedrahita et al., "Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein E," Science 258 (1992): 468-71.

[vi] See Table 70 in National Center for Health Statistics, Health, United States, 2005,

[vii] Based on National Health and Nutrition Examination Survey (NHANES) data on 4,090 adult men collected from 1999-2002. Data were downloaded from

[viii] M. Bustillo and M. Cone, "EPA Issues New Plan to Limit Soot," Los Angeles Times, December 21, 2005.

[ix] National Institutes of Health, "Air Pollution, High-Fat Diet Cause Atherosclerosis in Laboratory Mice."

[x] Hourly PM2.5 data were downloaded from the California Air Resources Board at

[xi] M. Lippmann, L. C. Chen and S. Rajagopalan, Particulate Air Pollution and a High Fat Diet: A Potentially Deadly Combination (Washington, DC: National Institutes of Health, 2005),


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