The global epidemic of breast cancer will claim the lives of 1 million women a year by the year 2000, say researchers. We badly need better drugs and new approaches to prevent this disease.

This need has provided the impetus for a raft of international trials in which the drug tamoxifen is being given to healthy women to see if it prevents breast cancer. Many thousands of woman are being recruited into the trials: the target figures are 16 000 in the US, 20 000 in Italy and 50 000 in an international trial coordinated in Britain, which has only recently begun to recruit women. But these initiatives have proved highly controversial.

Tamoxifen is a complex chemical that usually opposes, but sometimes mimics, the effect of the female hormone oestrogen. It is already widely prescribed for women who have had surgery for breast cancer to prevent recurrence. Cancer specialists consider it relatively benign in comparison to the ‘slash, burn and poison’, approach of many cancer therapies.

But the use of tamoxifen in healthy women to prevent breast cancer crosses lines in ways that many critics consider unacceptable. It commonly causes minor side effects – hot flushes, for example – and occasionally causes potentially fatal ones, such as cancer of the womb lining. And many people see the trials as part of a group of treatments for women that involve unnecessary hormonal manipulation.

Controversies over the use of tamoxifen in healthy women have prompted congressional and public hearings in the US. In the latest of a series of hitches, the US prevention trial tem-porarily stopped recruitment after it became clear that one of the directors of the trial had been involved with fraudulent research in a separate study (‘Trials on trial’, ¿ìè¶ÌÊÓƵ, 28 May). In Britain, a heated debate over a possible risk of liver cancer, which is linked with the drug in animal studies, caused the Medical Research Council to withdraw from the trial.

These arguments about tamoxifen, particularly its use in healthy women, are the main reason for picking up Tamoxifen and Breast Cancer. Anyone taking this drug or contemplating taking it is likely to find out far more here than in the doctor’s surgery or attached to a consent form for hospital treatment.

Will tamoxifen prevent breast cancer? Perhaps. Can the drug cause life-threatening side effects? Certainly. Will tamoxifen also prevent heart disease, as the pro-tagonists claim? Doubtful, say Michael DeGregorio and Valerie Wiebe.

They have several useful calculations at their fingertips. Taking the US trial, in which 8000 women will receive tamoxifen, the figures look like this. Out of 8000 women, 62 may avoid breast cancer. But 1300 may have hot flushes, 1136 may have vaginal discharges, 272 may have skin rashes, between 31 and 53 may get endometrial cancer, 24 may have deep-vein blood clots requiring hospitalisation and 24 may develop life-threatening blood clots in the lungs.

The known, the unknown and the purely speculative, the proponents’ line and the critics’ comments, are all here, laid out on the table for the reader to decide. We need this information, because women are choosing to take tamoxifen to prevent breast cancer, even though they have heard there may be side effects. ‘Partially out of fear and partially out of desire to help others down the road, these women march forward bravely while doctors and scientists on both sides eagerly await the results,’ say the authors.

The only problem non-American readers may have with this book is the general introduction to treatment for breast cancer. The perspective is American and treatment differs internationally and even within countries.

It is worth bearing in mind that one of the authors, Michael DeGregorio, testified before the US Congress on the possible risks of tamoxifen as a prophylactic drug in healthy women. Commentators have cast people involved in the tamoxifen debate into two factions, the interventionists and the anti-interventionists. Yet this book does not come over as anti-interventionist; the authors point out that drugs may have a place in future breast cancer prevention.

The tale of tamoxifen has lessons for the new science of chemoprevention – giving people drugs to prevent disease. In the future we can expect to see many more drugs of this ilk, directed to intervene in disease processes at a very early stage. But the congressional hearings on tamoxifen, the uproar from women’s groups and the debate still running in the media have made two things clear.

Protagonists of the tamoxifen trials have assumed it is acceptable to cause one disease to prevent another. But the public does not seem to be prepared to swop hazards in this fashion. And neither is it prepared to label the healthy as ill and subject them to toxic drugs simply because they inherit susceptibility to a particular disease.

If chemoprevention is to find its place in our quest for better health, it must be as safe as any other effective public health measure.

Cathy Read is a doctor and freelance journalist who writes on health and the environment, based in California.

Up until the last few years, many thousands of women in Britain underwent
hysterectomies every year to cure heavy periods. Then endometrial ablation
arrived on the scene, which was much less invasive, required only a short
stay in hospital and appeared to have fewer side effects. The technique
is now routine in half of all hospitals with gynaecological departments
and between 8000 and 12 000 women underwent the treatment last year.

But leading gynaecologists are concerned by the phenomenal growth in
popularity of endometrial ablation, not least because surgeons may use the
technique without any formal training or supervision. ‘(Some) gynaecologists
went off and taught themselves. As a result, there have been a number of
serious complications from the technique,’ says Victor Lewis, President
of the British Society of Gynaecological Endoscopy.

Four or more women are believed to have died as a result of the operation.
‘I think four is a conservative figure, but I fear it may be more. I know
of life-threatening complications which were not reported,’ says Alan Gordon,
a former president of the society.

The uncertainty over endometrial ablation and other minimally invasive
techniques, such as ‘keyhole’ surgery, has led to calls for new surgical
procedures to be evaluated as rigorously as new drug treatments and for
surgeons to become accredited in new techniques.

Early next year, at least one of five large randomised controlled trials
are due to publish their results. This type of trial is the ‘gold standard’
used for more than 40 years to compare new drugs with existing treatments,
but normally before the drugs are made widely available.

Endometrial ablation and a family of related techniques destroy the
endometrium, the cells of the womb lining. The endometrium thickens each
month to prepare the uterus for a fertilised egg and, if conception does
not happen, endometrial cells are shed along with blood – the monthly period.

HEATED LOOP OR LASER

The operation is carried out through a hysteroscope, a tube inserted
through the cervix into the cavity of the womb. The most commonly used technique,
called transcervical endometrial resection (TCRE), uses an electrically
heated loop of wire to cut away strips of the womb lining.

An alternative technique, endometrial laser ablation (ELA), uses the
heat from a laser to kill the cells of the lining. Light from a neodymium-YAG
laser is fed down an optical fibre inserted into the hysteroscope. The surgeon
then drags the tip of the laser fibre across the endometrium in lines to
vaporise the tissue. Women who have been treated with these techniques usually
have scanty periods or no periods at all.

TCRE was popularised in Britain by Jacques Hamou, a gynaecologist at
the Tenon Hospital in Paris. In 1988 Hamou first visited Oxford to demonstrate
TCRE and returned in the following two years. Soon afterwards Adam Magos,
then clinical lecturer at the University of Oxford, began to perform TCRE.

In 1989, Magos reported on 16 women treated with TCRE in the British
Medical Journal. These early results were remarkably good: surgery was completed
successfully in 15 women and 13 were discharged from hospital the day after
surgery. Six months after treatment six women were having no periods at
all and the remainder had lighter, shorter periods.

‘Gynaecologists in Britain suddenly decided this was the thing to do
and did it. Now up to 50 per cent of gynaecologists are doing it, some have
done it in very large numbers. No other country in the world has taken it
up as enthusiastically,’ says Lewis.

The new technique was widely acclaimed in the media and consumer pressure
grew. It is hardly surprising that endometrial resection should appeal
more to women than a hysterectomy does. In 1985 nearly 20 000 women had
their wombs removed because of menorrhagia, or excessive menstrual bleeding.
This drastic solution involves seven days in hospital and up to three months’
convalescence.

Hysterectomy also causes substantial complications, such as infection
of the surgical wound and urinary tract, which is reported in up to 45
per cent of women treated. Even if a woman’s ovaries are left intact, after
a hysterectomy she is likely to go through the menopause four years earlier
than normal. Women who opt for endometrial resection need only a brief hospital
stay and need minimal time off work. They avoid both the early menopause
and the psychological trauma associated with loss of the womb.

It is not only patients that are enthusiastic about these ‘minimally
invasive’ techniques of surgery. Their popularity attracts patients to private
practices and to hospitals competing for business in Britain’s new NHS trust
system. TCRE and even endometrial laser ablation are also cheaper than hysterectomy.
Raymond Garry, consultant gynaecologist at the South Cleveland Laser Centre
has calculated the cost of a hospital stay for a hysterectomy is £965
while the cost of laser treatment is £232.

But both TCRE and ELA demand skilled hand-eye coordination: a fibre
optic camera threaded through the hysteroscope displays the inside of the
womb on a TV screen. The surgeon must watch the screen to guide the instruments
in the confined space of the womb. It is relatively easy for someone who
is inexperienced in this technique to accidentally perforate the womb. Many
vulnerable organs lie nearby and bowels, bladders and arteries have all
been perforated.

But the real incidence of complications and deaths is unknown, because
no proper audit has been carried out. A postal survey of hospitals offering
endometrial resection that came out in 1990 reported complications in 3
per cent of cases. In 1991, a survey by the Royal College of Obstetricians
and Gynaecologists reported a ‘low’ rate of complications. Although leading
gynaecologists say that at least four women may have died from endometrial
resection in the past two years, only one death is mentioned in the two
surveys.

But these voluntary surveys have been criticised. ‘Both those audits
are totally unscientific. The true complication rate is almost certainly
higher than 3 per cent. Most of our colleagues are responsible, but one
of the problems with any audit is to ensure completeness of returns. People
may be reluctant to participate in voluntary studies when they have adverse
outcomes,’ says Garry.

DEATH RATES

If the number of deaths from endometrial ablation is as high as some
gynaecologists believe, it has a mortality rate higher than hysterectomy.
The mortality rate for abdominal hysterectomy in fit women of reproductive
age is believed to lie somewhere between 0.6 and 6 in 10 000. According
to Lewis, the mortality rate for endometrial resection, a less invasive
technique, could be as high as 1 in 1000.

Reports from surgeons suggest that serious complications are most likely
to occur while the gynaecologist is still on the ‘learning curve’, which
can last for anything between 10 and 80 operations. Studies have shown that
50 per cent of perforations of the womb take place in the first five operations
a surgeon carries out.

‘The Royal College of Surgeons and the Royal College of Obstetricians
and Gynaecologists are looking seriously at regulations for controlling
the introduction of new techniques and training of people before they are
allowed to carry them out without supervision,’ says Gordon Stirrat, professor
of obstetrics and gynaecology at Bristol Maternity Hospital. Such rules
have already been introduced in Australia for techniques such as endometrial
resection and similar rules are being introduced in Canada. As yet there
is no such requirement in Britain or the rest of Europe.

Gynaecologists in Britain are encouraged to attend courses which typically
last one or two days and are lucky if they get to assist on two operations
in that time. Supervision afterwards may be difficult to find. Surgeons
in the US routinely learn new operations on animals but Britain’s more stringent
animal legislation does not permit this. At Garry’s laser endoscopy course
at South Cleveland Hospital, gynaecologists practise on simulators, skinning
chicken pieces with surgical instruments under video control.

The safety of the operation itself is not the only cause for concern.
No one knows whether women who have the operation in their thirties will
start having periods again in their forties. No one knows if there will
be any serious, long-term side effects, such as an increased susceptibility
to cancer. Yet if the treatment had been a drug, it would have been entered
into carefully controlled clinical trials long before it was generally available
on prescription.

Next year, a national audit will begin, coordinated by the British
Society for Gynaecological Endoscopy, the Royal College of Obstetricians
and Gynaecologists and the Department of Health. Patients will be entered
on the National Cancer Register, a system which tracks patients with various
conditions for their whole life so that long-term effects can be studied.

Gynaecologists are not expecting any link with cancer but, as Lewis
points out, the unexpected can always happen. For example, long-term follow
up of men who had their prostate glands resected for urinary problems revealed
an elevated risk of coronary heart disease.

At least some of the questions surrounding endometrial ablation will
be answered by the results of the randomised controlled trials due to be
published early next year. The first, of 200 women in Bristol, was conducted
by a team led by Stirrat.

Stirrat says that the trial showed TCRE to be as satisfactory as hysterectomy
in treating heavy periods. The incidence of immediate complications was
comparable in the two techniques. In the longer term, 46 per cent of women
who had hysterectomies reported problems, compared with around 2 per cent
for TCRE.

However, several women did still have unacceptable bleeding after TCRE
and 15 were dissatisfied with the results four months later. Two women relapsed
more than a year after the operation. A small but significant number of
women also suffered period pains related to TCRE.

Although the Bristol findings indicate that TCRE is a preferable treatment
to hysterectomy, many will argue that this kind of information should have
been available at a far earlier stage. ‘Up until now, changes have happened
only gradually,’ says Stirrat. But the growth of endometrial ablation ‘accelerated
at a pace which has surprised and shocked many people’. He argues that new
techniques should be compared with the currently accepted method. It is
unscientific and unethical not to do so, he says.

The calls for better regulation of new techniques were supported last
month in a report by the government’s Advisory Group on Health Technologies.
It called for all new health technologies to be evaluated rigorously before
widespread use. Another government report due next month, from the Advisory
Council on Science and Technology, will address how well advances in medical
research improve cost-effectiveness and delivery of health care.

Ironically, by the time any changes are made, endometrial resection
may be past its heyday. A promising intrauterine device that releases hormones
into the womb is undergoing clinical trials as a treatment for heavy periods.
In five years’ time endometrial resection could be history, but it may have
made the use of future techniques safer.

Cathy Read is a freelance writer who specialises in health issues.

The device, called a tonometer, measures indirectly the amount of oxygen
reaching the cells lining the stomach. Tonometry is radical in the way it
focuses on conditions in a specific region of the body. For many years doctors
in intensive care units have concentrated on maintaining an adequate blood
flow and oxygen supply to the ‘vital’ organs, particularly the heart and
brain. In doing so they have relied heavily on general measurements, such
as pulse rate and blood pressure to monitor the progress of their patients.

More recently, doctors have begun to realise that it is also important
to maintain an adequate supply liver. The blood flow, and hence the oxygen
supply, to these organs is often inadequate in critically ill patients.
General measurements do not reflect this; a patient may have normal pulse
and blood pressure but may still not have enough oxygen reaching the gut.

If the oxygen deficiency persists, a chain of events is set off which
may eventually cause multi-organ failure. Oxygen deficiency can also make
the gut wall become ‘leaky’, allowing bacteria to pass into the blood stream.
Further damage may occur as the blood supply is resumed. This triggers the
release of substances which depress the release of substances which depress
the activity of the heart.

The tonometer is a flexible tube which passes through the nose into
the stomach. It has a silicone balloon on the end which is inflated with
saline. The device is used to calculate the pH, a measure of acidity, within
the cells lining the stomach.

The pH provides an indirect measure of the amount of oxygen available
to the cells. The pH of the cells remains within normal limits as long as
the oxygen supply is adequate. Once the oxygen supply falls to a critical
point, the cells switch to non-oxygen dependent (anaerobic) metabolism which
produces acid. The amount of acid in the cells then rises and the pH falls.

Rather than measuring acid or pH directly, the tonometer measures the
amount of carbon dioxide in the cells. Once the tonometer is inserted, dissolved
carbon dioxide in the stomach lining comes to an equilibrium with carbon
dioxide in the gas-permeable balloon. After 30 minutes. the doctor draws
out the saline through the tonometer tube and uses a standard blood gas
machine to measure the carbon dioxide content.

Doctors can calculate the pH from the amount of carbon dioxide using
a formula known as the Henderson-Hasselbalch usually treat patients monitored
this way with a drug to block acid secretion in the stomach.

If measurements with the tonometer suggest the stomach tissue is lacking
oxygen, doctors can intervene to reverse the trend either by giving the
patient more fluid or by administering a drug such as dopexamine to dilate
the blood vessels to the region.

Guillermo Gutierres of the University of Texas Health Science Center
has carried out tests with a tonometer on 80 typical intensive care patients
in Argentina. His team inserted a tonometer into the patients’ stomachs
on arrival and took one reading immediately and another 12 hours later.

Patients who had normal pH on arrival which was still normal 12 hours
later had a 27 per cent mortality rate. In contrast, patients who arrived
with low pH which stayed low beyond 12 hours had 87 per cent mortality.
Significantly, Gutierrez found that if a patient arrived with a low pH but
doctors were able to raise it to a normal level within 12 hours, their mortality
rate dropped to 36 per cent.

Nick Maynard, lecturer in surgery at Guy’s Hospital in London, has repeated
the Argentina study. His results, due to be presented to the Surgical Research
Society in London in January, show a similar trend but with an overall lower
mortality.

Maynard has also demonstrated that measurements of tissue pH are far
better than more general measurements of oxygen transport in predicting
how a patient will fare. ‘It shows global measurements are not sufficient,
we need to look at regional circulations, particularly of the gut and liver,’
he says. Tonometers are today used in only 12 per cent of intensive care
units in Britain.

The drug is based on a cocktail of nine different forms of the antiviral
molecule alpha-interferon. Somewhat surprisingly, it is claimed to work
only when taken at relatively low dosage – about 100 international units
a day – and administered in a lozenge, which is sucked slowly in the mouth.

Claims for Kemron are based on the results of a six-month trial in Kenya
involving 101 patients. According to doctors from the highly-respected Kenyan
Medical Research Institute (KEMRI) in Nairobi who carried out the study,
almost all the patients reported the disappearance of the majority of symptoms
associated with AIDS within six weeks of starting the treatment.

Research scientists in Britain warn that the results obtained so far
should be interpreted with caution. Some point out, for example, that attempts
to combat the symptoms of AIDS with high doses of interferon have so far
been disappointing. Others emphasise that the Kenyan studies were not carried
out with proper controls, and that this means that care is needed in interpreting
the results.

Nevertheless, the claimed results are intriguing enough to have convinced
several independent researchers that further studies should be carried out.
‘There may be something in it,’ says Joseph Hassett, an immunologist at
the Mount Sinai Hospital in New York, who is awaiting approval for a six-week
controlled trial in 35 patients with AIDS. ‘Even if only some of the improvements
that appeared in the Kenya study really work, it would be worth it.’

The Kenyan study was carried out by a group headed by researcher Davy
Koech, a graduate of Harvard Medical School. Trials conducted at KEMRI’s
clinic in Nairobi, in which 63 males and 38 females between the ages of
15 and 58 were treated with the drug, found that many of them lost most
symptoms associated with the disease, such as fatigue, weight loss, diarrhoea
and mouth sores.

The method of delivering the drug was developed by the Amarillo Cell
Culture Company (ACCC) of Amarillo, Texas, which had initially been cooperating
with Koech in studies of the use of alpha-interferon in treating cat leukaemia.
The interferon was provided by Hayabishara Biochemical Laboratories of Japan.

¿ìè¶ÌÊÓƵs at ACCC claim there is evidence that sucking a lozenge containing
the interferon may allow the molecule to penetrate membranes in the mouth.
‘The results we have had from Kemron have been quite spectacular,’ says
Joseph Cummins, president of ACCC. He suggests that the drug may be working,
not by acting on the body’s immune system directly, but by stimulating the
area around the tonsils into triggering the immune system. ‘Human beings
naturally produce a nasal secretion of interferon, but only very rarely.
All we are doing is what the body does naturally, in a daily dosage.’

The company acknowledges that the next step in assessing the drug’s
potential is to carry out controlled clinical trials. Already the US Army
is reported to have started its own trials of the drug in Manila. Roger
Wyatt, a researcher at ACCC, says that the Department of Health in Britain
has told him that the drug appears to qualify for exemption from some of
the normal procedures for testing new drugs because of its potential value
in the fight against AIDS.

Other research scientists are remaining cautious. Andrew Lever, a lecturer
in infectious diseases at St George’s Hospital in London, says that the
Kenyan study has a number of flaws. For example, he points out that false
positives for HIV tend to be more common in the African population, due
to high rates of other diseases, such as malaria.

There has also been widespread scepticism in response to the report
of Koech’s group that some of the patients in the trial reputedly became
seronegative, suggesting that the drug had somehow successfully eliminated
the virus from the body.

WHO has agreed to support further trials in Kenya, and the results are
being keenly awaited by the agency’s scientists. The WHO’s officials believe
that, if proved effective, Kemron might benefit poorer countries because
of its relative cheapness. For the moment, however, even though the Kenyan
government has already promised to mass-produce the drug, scientists are
cautious about the results being claimed by Koech and his colleagues for
its effectiveness.

‘We do not disbelieve the results, but another scientist of equal competence
should test the drug as well,’ said Gottlieb Lobe Monekosso, the regional
director of the WHO in Africa. ‘If he gets equal results, then we can all
get excited.’

RADON, the naturally occurring radioactive gas, may be an important cause of leukaemia, cancers of the kidney and the skin, and a number of cancers in children. Researchers at the University of Bristol have found a close linear correlation between radon exposure and certain cancers in 15 countries.

¿ìè¶ÌÊÓƵs already recognise radon as a significant cause of lung cancer. According to physicists in Bristol, led by Denis Henshaw, the gas is also responsible for up to 12 per cent of cases of myeloid leukaemia in Britain and up to a quarter of all cases of myeloid leukaemia worldwide.

To confirm the correlation that the international data appeared to show, the Bristol team considered regions of Canada in detail. Here, data on the incidence of cancer and data on radon levels were available for identical geographical areas. The results showed a highly significant correlation between radon and acute myeloid leukaemia for all age groups (see Diagram).

In Britain, radon is believed to cause up to 2500 deaths from lung cancer each year. Most of the alpha radiation from the gas is released in the respiratory tract, and scientists had until now assumed that the lungs bore the brunt of most of the damage associated with radon. It now appears that the link between radon and other cancers could be due to other mechanisms as well.

One is the tendency of radon to concentrate in fat cells within bone marrow. Alpha radiation from these cells may initiate leukaemia by damaging primitive blood cells in the surrounding tissue. An additional source of radiation may be so-called ‘radon daughters’ – the breakdown products of the gas – which are normally mixed with radon in room air.

The Bristol team has attempted to calculate the proportion of leukaemia due to radon and the proportion due to other types of natural background radiation. Their analysis, published in the current issue of The Lancet, suggest that alpha radiation is far more likely to cause leukaemia than has previously been appreciated (vol 335, p 1008).

The conventional ‘quality factor’ of the alpha particle with respect to gamma radiation is 20: broadly speaking this means that alpha radiation is 20 times as damaging to tissues as gamma radiation. The Bristol team calculates the real quality factor of alpha radiation is likely to be greater than 20, and may be as high as 180. The team says the findings may explain some of the clusters of leukaemia observed in Britain and say their observations warrant urgent investigation.

Ozone forms at street level when nitrogen oxides and hydrocarbons from
vehicle exhausts interact in the presence of sunlight. The US Environmental
Protection Agency (EPA) recommends that levels of ozone in the air should
not exceed 120 parts per billion (ppb), averaged over one hour. The World
Health Organization’s Air Quality Guidelines for Europe say that ozone levels
should not exceed the band between 76 and 100 ppb, also over one hour.

Research published at a joint meeting of the Americn Thoracic Society
and the American Lung Association, held earlier this year in Cincinnati,
suggests that the EPA may have to revise its limit. Hillel Koren, a scientist
at the University of North Carolina who works for the EPA, has found that
ozone causes inflammation in the lung even at low levels.

Koren exposed 10 nonsmoking males to air containing ozone at 100 ppb
and to air containing ozone at 80 ppb. Each exposure lasted more than six
hours, during which the men carried out moderate exercise. Eighteen hours
later, Koren’s team retrieved from the 10 men cells and fluid for analysis
from the alveoli, the small air sacs of the lungs.

Koren believes that this is a useful way to study the effects of pollution.
‘We are going to cells in the body which are in direct contact with the
pollutant,’ he says.

At both levels of ozone exposure, he found that macrophages – cells
that scavenge in the lungs – were less capable of consuming and destroying
bacteria than normal. In addition, there was a significant increase in cells
and chemicals in the body that produce inflammation, such as white blood
cells, fibronectin and lactate dehydrogenase. Exposure to ozone at a level
of 100 ppb also increased levels of protein and a hormone-like substance,
called prostaglandin E2, in the lung.

Prostaglandin E2 is a potent regulator of the immune system. It also
promotes inflammation. Further work by Koren has shown that macrophages
produce the prostaglandin in the alveoli. Koren collected and cultured macrophages
from the alveoli. He exposed the cells for two hours to air containing ozone
at concentrations of 100 ppb, 300 ppb and 1000 ppb. Tests for prostaglandin
E2 at the end of the experiment showed that the cells produced increasing
amounts as the concentration of ozone went up. Koren says that he will need
to carry out further tests to see if these dramatic changes persist in the
long term.

Research into the effect of ozone on the lungs suggests that people
become tolerant to the chemical after several days of exposure. A second
group of scientists, working for the EPA at Research Triangle Park in North
Carolina, reached this conclusion when they studied a group of healthy young
men.

The researchers exposed the men to ozone at 260 ppb for eight hours
on five successive days, while the men did moderate exercise. Tests to measure
the function of the lungs showed a clear fall in the amount of air that
the men could forcibly expel from the lungs within one second, a value known
as the FEV1, after the first day’s exposure. The results gradually returned
to normal over successive days, reaching normal three days after the last
exposure to ozone.

Koren now intends to investigate whether the biochemical changes in
the lung show a similar pattern. If so, he wants to know whether long-term
exposure to other pollutants also causes the inflammatory response to tail
off. If an exposed person fails to become tolerant after repeated exposure,
the effects of ozone on health could be much worse than scientists currently
believe.

One concern is that long-term exposure could induce fibrosis of the
lung, in which inflexible, nonfunctioning tissue replaces normal, flexible
tissue. Fibronectin, one of the substances that accumulate in response to
ozone, helps fibrosis to develop. It attracts fibroblasts, the cells that
make the insoluble protein, fibrin. Fibronectin also helps these cells to
grow and attach themselves to the tissue of the lungs.

Prostaglandin E2 could also be dangerous if the body continues to produce
large amounts of it. It suppresses the immune response in the lungs and
could make people more susceptible to lung infections. Koren says that even
if the lungs adapt to ozone, this could still be harmful. He asks whether
the mechanism by which compensation occurs may be the result of the damage.

Ozone is just one of many damaging agents in polluted air. Sulphur dioxide,
a product of combustion, becomes naturally oxidised in air to form sulphuric
acid. Ammonium in the air usually neutralises the acid to ammonium bisulphate
and ammonium sulphate. But, under certain weather conditions, high concentrations
of sulphuric acid may form. As a result, the EPA is considering making sulphuric
acid a ‘criteria pollutant’ – that is, a pollutant that it monitors in order
to assess air quality.

Research also suggests that sulphuric acid, combined with other pollutants
such as ozone, may be more harmful than either sulphuric acid or ozone alone.
To investigate this kind of effect, Richard Schlesinger and his colleagues
at the department of environmental medicine at New York University Medical
Center are exposing rabbits to mixtures of pollutants.

The researchers expose the rabbits to low levels of sulphuric acid or
ozone, or both, for two hours a day, five days a week for up to a year.
Macrophages taken from rabbits that had been exposed to the combination
of chemicals were less capable of destroying bacteria, a finding in keeping
with Koren’s work. Levels of substances that cause inflammation also changed,
but Schlesinger says it is too early to interpret these findings.

Douglas Dockery of the department of environmental science and physiology
at the Harvard School of Public Health in Boston has just completed a large
epidemiological study of the effects of air pollution on health. He examined
the link between episodes of air pollution and respiratory symptoms in children.
The families of 300 children in six American cities kept a diary of each
child’s respiratory symptoms for one year. During the study, scientists
measured local concentrations of ozone, sulphuric acid, nitrogen dioxide
and smoke particles, as well as acidity.

Between April and August, the months when air pollution tends to be
worst, the records showed that coughs and infections of the lower respiratory
tract were associated with higher levels of ozone and particulate matter
in the air. People tended to develop symptoms one to two days after peaks
of exposure to either ozone or smoke.

Dockery says that this and other evidence should persuade the EPA to
lower its ozone limit. Ten years ago, when the American government allowed
the limit to rise from 80 ppb to 120 ppb, there was little evidence that
levels of ozone below 250 ppb could damage health. ‘Since then, many studies
have suggested that damage occurs even below 120 ppb,’ says Dockery.

How far the limit comes down will depend on what risk people are prepared
to take, says Dockery. ‘I believe there are effects down to the lowest levels
you can detect. . . . At the moment, we’re probably seeing effects down
to 60 ppb. With more sensitive tests, you’d probably see an effect down
to 20 ppb.’

Chiron first announced its findings last May, but it failed to publish
the results immediately, thereby angering virologists who have been used
to international collaboration on such problems (This Week, 14 January 1989).

The company’s scientists believe that the hepatitis C virus (HCV) is
a major cause of non-A, non-B hepatitis – the form of the disease which
is caused by neither the hepatitis A virus nor the hepatitis B virus. In
London, another team has also found a virus which it believes causes non-A,
non-B hepatitis. However, because of Chiron’s refusal to collaborate, the
team in London does not know if its virus is the same as the one identified
by Chiron.

In the US, up to 10 per cent of blood transfusions are believed to result
in infection with non-A, non-B hepatitis. In Britain, the figure is much
lower. ¿ìè¶ÌÊÓƵs estimate that the chance of contracting the disease from
a blood transfusion is 1 in 300.

In the US, half of those infected develop the chronic form of the disease,
and 20 per cent of chronic carriers eventually develop cirrhosis of the
liver.

Elizabeth Fagan, one of the researchers in the London team, from the
Liver Research Unit at King’s College Hospital, said that doctors had been
crying out for a test for non-A, non-B hepatitis for years.

The researchers at Chiron did preliminary tests on 10 patients in the
US who were infected with non-A, non-B hepatitis as a result of blood transfusions.
All 10 had positive results to the new test for HCV during the course of
their illness.

Further tests on patients from Italy and Japan showed that 80 per cent
of these patients, who developed chronic non-A, non-B hepatitis after transfusions,
had antibodies to HCV (Science, vol 244, p 359).

The scientists at Chiron suggest that a person can become infected with
HCV by routes other than blood transfusions or injections. In their tests,
they found antibodies to HCV in almost 60 per cent of a group of patients
who had all the clinical signs of non-A, non-B hepatitis but no identifiable
source of infection.

Blood-transfusion centres all over the world are to put the test on
trial. Trials are already under way in the US and will start in Britain
within weeks. Ortho-Diagnostic Systems, a subsidiary of the pharmaceuticals
company Johnson & Johnson, will coordinate the trials. Ortho holds the
marketing rights for the blood test.

Until now, blood banks have not had any tests for HCV. Instead, they
have excluded blood that they suspect may be infected with non-A, non-B
hepatitis on the grounds of positive results to other tests, such as those
for abnormal liver function. Although such ‘surrogate’ screening has reduced
the incidence of non-A, non-B hepatitis, infected blood still slips through.

John Barbara, the head of microbiology at the North London Blood Transfusion
Service, and a principal researcher for the test for HCV, said that clinicians
must evaluate the test before they decide to use it. According to Barbara,
one of the first steps will be to find out what proportion of blood donors
are infected with HCV. At the same time, trials will examine whether a positive
result to Ortho’s test automatically means that the donor’s blood is infectious.

Fagan, together with her colleagues Roger Williams, at the unit, and
Arie Zuckerman, from the London School of Hygiene and Tropical Medicine,
have also isolated a virus that causes non-A, non-B hepatitis. They found
it in five patients who all had sudden and severe liver failure. All received
a liver transplant, but their transplanted livers all became infected. The
team has not yet sequenced the genetic material of the virus, but they have
looked at it under an electron microscope.

Interleukin 2 belongs to the same family of proteins as interferon,
which scientists first isolated more than 30 years ago. Since then, 13 similar
proteins, known as cytokines have been discovered. All the cytokines alter
the way cells behave and regulate their growth. These proteins have two
properties which make them attractive as possible anticancer agents: they
are toxic to tumour cells and they stimulate the body’s immune system. Interleukin
2 excited interest as a potential treatment for cancer because of its ability
to stimulate the proliferation of one type of cell in the immune system,
T lymphocytes. In some animal cancers, T lymphocytes play an important role
in rejecting tumours.

Steve Rosenberg, the head of the Surgical Branch of the Division of
Cancer Treatment at the National Cancer Institute in Bethesda, Maryland,
pioneered the early clinical trials of interleukin 2 and so-called lymphokine-activated
killer, or LAK, cells. Researchers prepared LAK cells by mixing ordinary
blood lymphocytes with interleukin 2. The cytokine activates the cells,
rendering them extremely toxic to tumours.

Rosenberg showed that the combination of interleukin 2 and LAK cells
was effective in treating certain rare tumours, including a virulent skin
cancer, called malignant melanoma, and cancer of the kidney. His work showed,
too, that these tumours were resistant to traditional forms of treatment
for cancer, including chemotherapy. Shares in companies producing interleukin
2 soared, but, despite the cheers on Wall Street, Rosenberg met with considerably
less enthusiasm among his medical colleagues.

He followed a practice that is traditional in the preliminary trials
of new chemotherapeutic agents by giving his patients the highest dose of
the drug that they could tolerate. The trials showed that, besides attacking
tumour cells, interleukin 2 produced widespread toxicity in the body. It
caused capillaries to leak and the body to retain fluid. These changes can
in turn lower the blood pressure and cause kidney failure. Some patients
suffered liver failure and stopped breathing. Most needed intensive care,
some needed to be put on ventilators and some died during treatment.

Nevertheless, there were benefits from treatment. Of 106 patients treated
with the combination of interleukin 2 and LAK, eight had a complete response
(the tumour disappeared) and 15 had a partial response (the tumour shrank
by more than half). This was partial success, at least in patients with
cancers that were otherwise untreatable. However, a number of cancer specialists
felt that the high level of toxicity outweighed the therapeutic gain.

Rosenberg’s approach used a series of injections to load patients with
interleukin 2. This causes a massive proliferation of blood lymphocytes,
which doctors then harvested and mixed with interleukin 2 to boost their
effects on tumours, before injecting them back into the patients.

Oliver and his colleagues aim to use lower doses of interleukin 2. They
believe that continuous intravenous infusion of the substance will stimulate
the production of lymphocytes but avoid the toxicity which resulted from
high doses.

Like Rosenberg, Oliver is using the patients’ response to gauge the
value of the treatment. But instead of pushing treatment to the limit, he
reduces the drug’s rate of the infusion into the body as soon as a patient
starts to feel unwell. According to Oliver, this approach increases the
number of lymphocytes in the body and also induces detectable LAK cells.
So far, he has treated 21 patients with cancers of the skin, kidney and
prostate.

Oliver believes that his team has only recently hit on an optimum dose.
‘We can’t say we are as good as Rosenberg’s group, because it will take
two years to see the patients participating in the trial through. But we
have begun to see comparable responses in patients on the treatment.’

To test the approach more thoroughly, Oliver and his colleagues are
starting a new trial involving between 50 and 60 patients with kidney tumours
and melanomas. In order to consolidate the new ‘softly-softly’ approach
to the drug, Oliver is investigating the possibility of treating patients
without having to keep them in hospital. He hopes that patients would then
be able to inject themselves with interleukin 2 in the same way that diabetics
give themselves insulin.

Oliver believes that the future of cancer therapy lies in using a combination
of treatments. The standard treatments for cancer – surgery, radiotherapy
and chemotherapy – all suppress the body’s immune system. Adding a cytokine
to boost the body’s immune system would be a logical way to counteract that
side effect.