SMOKE GETS IN YOUR EYES

FOCUS: Controversy reigns over the effects on the heart of passive
smoking. Until this has been resolved, the results of important
studies on heart disease will be fogged by uncertainty

EVEN second-hand cigarette smoke is bad for your heart, a major study
in The New England Journal of Medicine concluded earlier this year. No
surprises there. But in addition to publishing the authors' estimate
of how dangerous passive smoking is, the journal took the unusual step
of running an editorial in the same issue that appeared to rubbish the
research findings.

According to the researchers, from Tulane University in New Orleans,
nonsmokers exposed to environmental tobacco smoke (ETS) face a 25 per
cent increased risk of coronary heart disease. The dissenting
editorial writer, John Bailar from the University of Chicago, said an
increased risk of such magnitude was not plausible given how dilute
second-hand smoke becomes in air.

The stark disagreement in the very same issue of the journal
illustrates how contentious the subject is. Tobacco companies are keen
to downplay the risks, antismoking campaigners are keen to talk them
up. And even respected scientists are in serious disagreement or are
undecided on how much passive smoking contributes to the population's
burden of heart disease.

Researchers such as Richard Doll at the University of Oxford, one of
the world's leading authorities on smoking and health, admits the jury
is still out. In the face of this, many doctors say it would be
prudent for people to minimise their exposure to cigarette
smoke - especially if they already have symptoms of coronary disease.

But for researchers investigating other causes of heart disease, the
uncertainty surrounding passive smoking is a real problem. How can you
measure how significant other factors, such as diet, genetics and
exercise, are in causing heart disease, when you don't know how much
allowance to make for passive smoking?

The controversial 25 per cent figure, reported in the NEJM by Jiang He
and his colleagues at the Tulane University School of Public Health
and Tropical Medicine (vol 340, p 920), was achieved by pooling many
different statistical results - a "meta-analysis". It included the
results of 18 international studies and has a strong claim to be the
most reliable yet on heart disease risks due to passive smoking.

So why was Bailar, a respected expert on the analysis of medical
studies, so sceptical?

A back-of-the-envelope calculation explains his concern. People who
smoke 20 cigarettes a day face a 75 to 80 per cent higher risk of
developing heart disease than nonsmokers, and studies suggest that
passive smokers breathe in about 1 per cent of the amount inhaled by
direct smokers. As such, they should also face about 1 per cent of the
extra heart disease risk faced by smokers. In other words, just 0.75
per cent - more than 30 times lower than the figure found by Jiang He
and his colleagues.

This huge discrepancy is dividing medical scientists into two camps.
On one side are those who believe it reveals the existence of a highly
non-linear effect of tobacco smoke on the body, where just a whiff can
trigger a dramatic increase in risk.

On the other side are those who, like Bailar, suspect the discrepancy
highlights fundamental flaws in the methods used to assess the risks
from passive smoking. Some go further, arguing that in the drive to
discourage smoking, implausible results are not being questioned as
rigorously as they should.

No one is accusing Jiang He and his colleagues of shoddy research.
Even Bailar concedes that their meta-analysis of 18 studies is up to
scratch. What worries him is whether even the best meta-analysis is
capable of reliably detecting small risks. In his editorial, Bailar
argues that there are many ways in which a meta-analysis of passive
smoking studies can give spuriously high risk figures. They range from
publication bias, in which the meta-analysis is affected by a tendency
of researchers only to publish studies finding significant extra risk,
to outright Iying by smokers or ex-smokers, who tell researchers they
have never smoked.

But it is the sheer size of the figure found by He and his colleagues that
most worries Bailar: "I find it hard to understand how environmental
tobacco smoke, which is far more dilute than actively inhaled smoke, could
have an effect that is such a large fraction of the added risk of coronary
heart disease among active smokers," he says.

Malcolm Law of the Wolfson Institute oi Preventive Medicine in London
backs Jiang He's results, having reached similar conclusions in the
British Medical Journal six months earlier (vol 315, p 973). Law notes
that if you compare people who actively smoke just five cigarettes a
day with people who smoke 20 a day, the increased risk is also
non-linear (see Graph). The lighter smokers increase their risk of
heart disease by 40 per cent. The people who smoke four times as many
cigarettes only double their risk. "So we shouldn't be surprised by
the passive smoking finding," he says.

Jiang He told New Scientist that he was "very surprised and
disappointed" by Bailalr's criticisms. "Our study is a very complete
meta-analysis," he insists. "We have searched for all studies on a
relationship between passive smoking and coronary heart
disease - including unpublished studies." He also rejects the charge
of implausibility: "There are many potential mechanisms by which
passive cigarette smoking results in coronary heart disease."

But to make sense of the results, these mechanisms must explain how
just a little cigarette smoke can trigger the bulk of the heart
disease risk caused by exposure to tobacco. And one such, says Doll,
is platelet aggregation.

Clumping together whenever blood vessels are damaged, platelets are
part of the body's repair mechanisms. But even relatively small
increases in platelet aggregation have been implicated in a
substantially higher risk of heart disease. Some research also
suggests that passive smoking may boost platelet aggregation enough to
create the extra heart disease risks found by the meta-analysis
(Circillntion, vol 83, p 38).

It is a line of argument that fails to convince Robert Nilsson, an
expert on cellular toxicology at the University of Stockholm.
"Although it seems that platelet aggregation is affected by active
smoking, adequate evidence showing that it may account for the large
effect from ETS is lacking," he says. Doll agrees: "lt makes a
plausible story, but not a wholly convincing one."

A host of other mechanisms has also been suggested, from cell damage
to increases in cholesterol, yet no obvious smoking gun has emerged.
"It is puzzling," says Doll. "T don't wholly agree with Bailar. On
balance, I think there is something in it - but nobody can say for
sure at the moment." He says the current state of knowledge suggests
that the best that can be said is that passive smoking may increase
the risk of heart disease. Finding out for certain will be "an
intriguing and difficult problem".

However, Nilsson remains concerned: "Because all tobacco smoke is seen
as a major health risk, some scientists and physicians seem to have
shelved their efforts to analyse the possible effects of passive
smoking rigorously."

And one unfortunate consequence, he says, is that the heart disease
risk figure of 25 per cent might be erroneously set in stone - and
therefore skew other heart disease research. If the 25 per cent figure
is an exaggeration, it would provide a smoke screen behind which other
sources of heart disease could slip past researchers, undetected.

Pinning down the correct risk figure has nothing to do with "letting
the tobacco companies off the hook", says Nilsson. "Exposure to
tobacco smoke is a major confounder in many investigations," he says.
"It is therefore extremely important to be able to define correctly
the levels of risk involved."