Oxygen
Page 16
An awful fate befell many of the young women hired to paint radium onto the dials of watches, so that they would glow in the dark. The original luminous watches had been designed for soldiers fighting in the trenches during the First World War, but their novelty stimulated a
110 • TREACHERY IN THE AIR
consumer fad in the 1920s. To point the tips of their paint brushes, the girls were taught to moisten the bristles with their lips. At the time, radium was still hailed as a panacea and was sold for a variety of medical purposes, as elixirs, snake oils and aphrodisiacs. The girls were told that radium would put a glow in their cheeks and give them a smile that shone in the dark, and they would sometimes paint their nails, lips and teeth.
Within a year their teeth began to fall out and their jaws disintegrated.
When they began to sicken and die in large numbers, doctors found that their bodies, even their bones, contained large amounts of radon and other radioactive substances. Not surprisingly, the watch companies rejected the link and government regulators concluded that existing evidence did not warrant further investigation. An editorial in the New York World called a trial in 1926 “one of the most damnable travesties of justice that has ever come to our attention.”
Although the watch companies eventually agreed to pay token financial compensation, they never admitted their guilt or submitted to formal regulation. One worker, Catherine Wolfe Donahue, sued the Radium Dial company in 1938. She testified in a Chicago courtroom that she and a co-worker had once asked their supervisor, Rufus Reed, why the company had not posted the results of the physical examinations that had been carried out during the 1920s. Reed had apparently responded: “My dear girls, if we were to give a medical report to you girls, there would be a riot in the place.” The medical community finally instituted a dose limit for radon in 1941, but the confusion and vested interests had concealed the delayed effects of radiation, and few people, even within the Manhattan Project that built the first atomic bomb, predicted the full horror of nuclear fallout.
Nuclear fallout is the settling of unconsumed radioactive waste left over from the atomic blast, and can be dangerous for a long time. The explosion causes intense firestorms and whirlwinds stretching high into the air, and the atmospheric disruption often provokes rain. After both Nagasaki and Hiroshima, the air was so full of radioactive ash that the rain was dark and tarry — the infamous ‘black rain’. In Hiroshima, the black rain fell over a wide area that stretched from the centre of the town to the surrounding countryside, polluting water and grass alike. Fish died in the rivers, cows died in the fields.
Tens of thousands of survivors of Hiroshima and Nagasaki, who were uninjured by the initial blast, found they had not escaped the bomb after all. Within days, their hair began to fall out and their gums began to
Oxygen Poisoning and X-Irradiation: A Mechanism in Common • 111
bleed. The victims suffered from bouts of extreme fatigue and excruciat-ing headaches. They were weakened by nausea, vomiting, anorexia and diarrhoea. Painful sores filled their throats and mouths. They bled from the mouth, nose and anus. Those with the most acute symptoms died in a few months. Others were blinded by cataracts in the space of two years.
Many died from cancer years, or even decades, later. Leukaemia is the cancer most commonly linked with radiation poisoning. The characteristic ‘blue stigmata’ of radiation victims are a sign of leukaemia. The stigmata are formed by clumps of proliferating white blood cells. For 30
years after the nuclear bomb, the number of cases of leukaemia in Hiroshima remained 15 times higher than the rest of Japan. The incidence of other cancers with longer incubation periods, such as lung, breast and thyroid cancer, all began to rise after about 15 years.
As the threat of nuclear war has receded, safety concerns about nuclear power plants and other potential sources of radiation have sharpened in focus. Confidence in reactor safety was undermined by two serious accidents, one in 1979 at the Three Mile Island nuclear power plant in Pennsylvania and the other in 1986 at Chernobyl in the Ukraine.
Chernobyl was the worst reactor accident in history, with 31 people dying of direct radiation poisoning, and thousands more exposed to high doses of radiation. Even without accidents, fears of leakage and contamination are increasing. In England, reprocessing of nuclear waste at Sellafield has raised legitimate concerns about the high incidence of leukaemia in nearby villages. Other groups exposed to above-normal levels of radiation are also at higher risk of leukaemia. The so-called Balkan War syndrome (claimed by some to be a form of leukaemia) among troops who had been stationed in Kosovo, and among potentially thousands of local people, is attributed to the use of armour-piercing depleted-uranium shells. Even commercial aircrews may have a relatively high risk of leukaemia, as they are subjected to higher levels of cosmic radiation at flight altitudes.
With such a history, it is not surprising that even medical x-rays and radiotherapy generate fears, sometimes hysteria, about radiation poisoning. No nuclear power stations have been built in the United States since the late 1970s. The existence of a ‘safe’ radiation dose has been debated for decades without consensus. As one expert puts it, the most practical approach is to limit human exposure to ionizing radiation and hope for the best.
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What has all this to do with oxygen, you may be wondering? The answer is that radiation exerts its biological effects through a mechanism that is very similar to the effects of oxygen poisoning. The mechanism hinges on an invisible thread of reactions, linking oxygen to water. The lethal effects of radiation and oxygen poisoning are both mediated by exactly the same fleeting intermediates along this pathway. These intermediates can be produced from either oxygen or water (Figure 7). In radiation poisoning, they are produced from water, in oxygen poisoning from oxygen. However, normal respiration also produces the same reactive intermediates from oxygen. Respiration can therefore be seen as a very slow form of oxygen poisoning. We shall see that both ageing and the diseases of old age are caused essentially by slow oxygen poisoning.
The fleeting intermediates produced by radiation and respiration are called free radicals. We discussed them briefly in Chapter 1. Later in the book, we will refer to free radicals many times. I use the term rather loosely for convenience. Not all of these fleeting intermediates are free radicals within the usual definition of the term. Applying the correct terminology, however, is cumbersome. Another umbrella term, ‘reactive oxygen species’, is even more cumbersome and also untrue — not all are especially reactive and some, such as nitric oxide (NO) are technically reactive nitrogen species. A third possible term, oxidants, is also incorrect: Hydrogen
Hydroxyl
Superoxide
peroxide
1 e –
1 e –
radical
1 e –
radical
H
1 e –
2O2
–
OH
O2
H2O
O2
Water
Oxygen
O –
OH
2
1 e –
H2O2
1 e –
Hydroxyl
Superoxide
radical
1 e –
Hydrogen
1 e –
radical
peroxide
Figure 7: Schematic representation of the intermediates between water and oxygen. Only changes in the number of electrons ( e–) are shown in each direction. The reactions also depend on the availability of protons, although this is not shown for simplicity. Because protons are positively charged, electron rearrangements tend to lead to compensatory proton rearrangements.
Oxygen Poisoning and X-Irradiation: A Mechanism in Common • 113
the superoxide radical, for example, is more likely to act in the opposite way (as a reductant). Given these difficulties with definitions, I will stic
k with the name free radicals.
To follow the argument in the rest of the book, all you really need to know is that free radicals are reactive forms of oxygen, produced continuously at low levels by respiration. However, this definition is over simple and inexact. In the rest of this chapter, then, we will take a closer look at what free radicals are, and how and why they are formed.
The splitting of water by radiation was first described by Becquerel, who began experimenting with radium soon after Marie Curie had isolated workable quantities. In the late 1890s, Becquerel had classified the known radioactive emanations according to their penetrating power. Emissions that are stopped by a sheet of paper were termed alpha rays (they are in fact helium nuclei); those stopped by a millimetre-thin sheet of metal were called beta rays (now known to be fast-moving electrons); and those penetrating a centimetre [2/5 inch] of metal were called gamma rays (electromagnetic rays, analogous to x-rays). All three types of radiation displace electrons from atoms, which gives the atoms an electric charge.
This is why the Curies could detect an electric field in the air around pitchblende. The loss or gain of electrons, giving a substance an electric charge, is called ionization, hence the term ionizing radiation. Radiation also produces many other effects, including heat generation, electron excitation, breaking of chemical bonds and nuclear reactions, such as nuclear fission, as we saw in Chapter 3.
Becquerel discovered that radium emits alpha rays and gamma rays.
These decompose water into hydrogen and oxygen. The decomposition of water was not in itself unexpected, as water had been shown to consist of a combination of hydrogen and oxygen by Laplace and Lavoisier in the 1770s. However, radiation cannot dissociate water directly into hydrogen and oxygen gases (which are made up of molecules of hydrogen and oxygen — H2 and O2 — each containing two atoms), because the ratio of hydrogen to oxygen atoms in water (H2O) is wrong:
H2O 씮 H2 + O2
Most people will remember having to balance chemical equations at school. The equation here will not do. We have two atoms of oxygen on the right side of the arrow and just one on the left. The immediate
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solution we might leap to is to double up the water side of the equation, so that everything balances:
2H2O 씮 2H2 + O2
But when we’re dealing with radiation, this will not do either. The problem is that we are not dealing with a chemical reaction between two molecules, but with an interaction between radiation energy and a single water molecule. Ionizing radiation always interacts with matter at the level of individual atoms, and it cannot produce hydrogen and oxygen molecules ‘just like that’. What it does produce stimulated debate throughout the twentieth century, as the products are normally so short-lived. Even the modern consensus is rather uneasy. A first step might be: H2O 씮 H+ + e– + •OH
Where H+ is a proton (a hydrogen atom that has lost an electron), e– is a dissolved, or solvated, electron and •OH is a free radical called the hydroxyl radical — a ferocious molecule that is among the most reactive substances known.
A free radical is loosely defined as any molecule capable of independent existence that has an unpaired electron. This tends to be an unstable electronic configuration. An unstable molecule in search of stability is quick to react with other molecules. Many free radicals are, accordingly, very reactive. Nonetheless, we should not assume that all free radicals are reactive. Molecular oxygen, for example, contains two unpaired electrons, and so can be classed as a free radical by some definitions. The fact that everything does not burst spontaneously into flame shows that not all free radicals are immediately reactive. We shall see why later in this chapter.
In the reaction above, the oxygen atom has lost a single electron, but we are still a long way from generating oxygen gas, or O2. In fact, to produce oxygen gas from water, a total of four electrons must be removed from two oxygen atoms. To reverse this process, to produce water from oxygen, as occurs during respiration, requires the addition of four electrons. These electrons must be added or lost one at a time, to produce a series of three possible intermediates: the hydroxyl radical (•OH), hydrogen peroxide (H
•–
2O2); and the superoxide radical (denoted O2
).1 These
1 There are many more possible intermediates, but these three are the most important. Their stability and reactivity depends partly on their protonation (whether they have hydrogen ions attached, as in hydrogen peroxide H2O2), and this depends on the conditions. The superoxide radical (O •–
•
2
), for example, is much more reactive when protonated (HO2 ).
Oxygen Poisoning and X-Irradiation: A Mechanism in Common • 115
intermediates are formed regardless of whether we are going from water to oxygen or vice versa (see Figure 7). They are responsible for more than 90 per cent of the biological damage caused by some forms of radiation.
Radiation can interact directly with all kinds of molecule, but in our bodies it is most likely to interact with water. This is largely a matter of probability. Our bodies contain between 45 and 75 per cent water, depending on age and body fat content. Children have the highest water content, up to 75 per cent of their body weight, while an adult man consists of about 60 per cent water. Adult women, who on average carry more subcutaneous fat than men, are about 55 per cent water. In addition to probability, the odds of an interaction between radiation energy and water is skewed by molecular factors. Some forms of radiation, such as gamma rays and x-rays, interact more readily with the bonds in water than they do with carbon bonds in organic molecules. This means that a fat elderly woman (with a low body-water content) is more likely to survive irradiation with x-rays than a young child.
The three intermediates formed by irradiating water, the hydroxyl radicals, hydrogen peroxide and superoxide radicals, react in very different ways. However, because all three are linked and can be formed from each other, they might be considered equally dangerous. Indeed, the three actually work together as part of an insidious catalytic system. We will consider each in turn, in the order that they are produced by radiation on route from water to oxygen.
Hydroxyl radicals (•OH) are the first to be formed. These are extremely reactive fragments, the molecular equivalents of random muggers. They can react with all biological molecules at speeds approaching their rate of diffusion. This means that they react with the first molecules in their path and it is virtually impossible to stop them from doing so. They cause damage even before leaving the barrel of the gun. If you ever hear someone talking about antioxidants that ‘scavenge’ hydroxyl radicals in the body, they won’t know what they’re talking about. Hydroxyl radicals react so quickly that they attack the first molecule they meet, regardless of whether it is a ‘scavenger’ or any other molecule. To scavenge hydroxyl radicals in the body, the scavenger would need to be present at a higher concentration than all other substances put together, to give it a higher chance of being in the way. Such a high level of any substance, even if
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benign, would kill you by interfering with the normal function of the cell.
Once hydroxyl radicals are formed, trouble escalates. When a hydroxyl radical reacts with a protein, lipid or DNA molecule, it snatches an electron to itself and then sinks back into the sublime chemical stability of water. But of course the act of snatching an electron leaves the reactant short of an electron, just as a mugger leaves the victim short of a handbag.
In the case of the hydroxyl radical, another radical is formed, this time part of the protein, lipid or DNA. It is as if having your handbag snatched deranges your mind and turns you into a mugger yourself, restless until you have snatched someone else’s bag. This is a fundamental feature of all free radical reactions — one radical always begets another, and if this radical is also reactive, then a chain reaction will ensue. Thus the cardinal feature of a free radical is an un
paired electron, while the cardinal feature of free-radical chemistry is the chain reaction.
We are all familiar with free-radical chain reactions when they happen in fatty foods such as butter: they are responsible for rancidity.
The fats in the butter oxidize and taste disgusting. The same type of reaction also takes place in cell membranes, which are made mostly of lipids. The process is then called lipid peroxidation. Trying to stop lipid peroxidation happening has caused much wailing and gnashing of teeth among researchers. Free-radical damage is less obvious when it affects proteins or DNA, but free-radical damage to DNA is one of the main causes of genetic mutation, and accounts for the high rates of cancer suffered by radiation victims.
A dramatic non-biological example of the power of free-radical chain reactions is the hole in the ozone layer. The devastation that can be caused by chlorofluorocarbons (CFCs) such as freon is a result of the formation of free radicals in the upper atmosphere. CFCs are quite robust molecules that survive buffeting by the weather in the lower atmosphere.
However, they are shredded by ultraviolet rays in the upper atmosphere, and disintegrate to release chlorine atoms. Being one electron short of a full pack, chlorine atoms are dangerously reactive free radicals. They can steal electrons from almost anything. Just one chlorine atom can set in motion a chain reaction that might destroy 100 000 ozone molecules.
According to the US Environmental Protection Agency, a single gram of freon will often destroy as much as 70 kilograms of ozone.
There are only two ways for a free-radical chain reaction to end: when two radicals react with each other, and their unpaired electrons