INT J TUBERC LUNG DIS 11(7):722–732 © 2007 The Union

REVIEW ARTICLE

Historical statistics support a hypothesis linking tuberculosis and air pollution caused by coal
G. A. Tremblay
Phoresia Biotechnology Inc., Laval, Québec, Canada SUMMARY

Tuberculosis (TB) is generally considered to be linked to industrialisation and urbanisation. Peaking in the 1800s and receding slowly after, the disease declined sharply in the West after World War II. TB has made a comeback in the last 20 years in developing countries such as China and India. Because socio-economic conditions alone cannot explain the connection between industrialisation and TB, factors remain to be determined in the aetiology of the disease. Historical statistics on coal consumption and

TB disease in Canada, USA and China are correlated. A hypothesis linking TB and air pollution is developed in the context of industrialisation. A model is proposed whereby triggering of the interleukin-10 (IL-10) cascade by carbon monoxide in lung macrophages promotes the reactivation of Mycobacterium tuberculosis. K E Y W O R D S : tuberculosis; coal; air pollution; carbon monoxide; IL-10

THE INVENTION of the blast furnace and the steam engine were key developments that led to industrialisation. From that point on, fossil fuel has driven the evolution of the world as we know it today; with progress and technical innovations, changes in lifestyle ensued promptly. However, as humans unlocked their creative potential in mechanics, they may also have unleashed the avatar of progress. A century-old belief blamed foul air or miasmas for diseases such as tuberculosis (TB), malaria, rheumatism and cholera. A number of scientists, including Florence Nightingale and William Farr, supported the theory. Nevertheless, miasmas fell into disgrace when Louis Pasteur discarded spontaneous generation and it became clear that micro-organisms were largely responsible for mankind’s ills. Mycobacterium tuberculosis, the agent responsible for TB—also called phthisis or consumption—was identified in 1882 by the German physician Robert Koch. At the time, TB claimed about one death in six in Europe. TB has made a comeback in the last 20 years, mostly in parts of the developing world. In 2004, 9 million new TB cases were diagnosed and approximately 2 million persons died of TB around the world. More than 80% of all TB patients live in sub-Saharan Africa and Asia. People infected with the human immunodeficiency virus (HIV) are more susceptible to TB.1 In Africa, for example, HIV is said to drive the TB epidemic.2 TB has been termed a ‘social disease’ because it is linked to poverty, overcrowding and unsanitary con-

ditions. Improvements in living conditions are therefore likely to affect TB incidence. There is general agreement that the TB epidemic increased dramatically in Europe in the eighteenth and nineteenth centuries and began to decline thereafter.3 TB is intrinsically linked to industrialisation. For example, both industrialisation and TB occurred later in Japan.4 As there is no obvious reason to believe that there was less poverty before industrialisation, and considering that overcrowding is relevant to all communicable diseases, one is forced to question why industrialisation and TB go together. Another unresolved issue concerns the decline of TB in the West. For example, between 1850 and 1910, TB death rates declined in England and Wales much faster than indicators of social deprivation.5 It seems therefore that social factors alone cannot explain the decline in TB incidence. There may in fact have been some degree of confusion between social and environmental factors. For example, in a 1911 study,6 Marie-Davy compared TB mortality and the average number of windows per household (Figure 1) in Paris arrondissements (urban districts) between 1858 and 1902. Scientists of the time were aware that inadequate aeration of houses was related to the development of TB in residents; Figure 1 may also indicate high levels of indoor air pollution in urban households. In recent years, air pollution has been identified as a risk factor for TB. Mishra et al. linked biomass cooking fuels and TB:7 based on a 1992–1993 survey

Correspondence to: Guy A Tremblay, 3126, 5ième Rue, Laval, Québec H7V 1M1, Canada. Tel: ( 1) 514 436 9272. e-mail: guy.tremblay@gmail.com Article submitted 24 September 2006. Final version accepted 26 January 2007.

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cascade is discussed. The observations shed new light on TB biology and epidemiology and emphasise the importance of environmental health.

METHODS
Historical statistics of disease in Canada, as incidence per 100 000 population, are gathered from Statistics Canada Historical Statistics on ‘Annual rates of notifiable diseases, Canada, 1926 to 1975’ (series B517– 525).12 For electricity production, ‘Electric utilities— number of customers by class, 1920 to 1975’ (series Q97–101) is used.12 Electricity production is expressed as percentage of maximum customers over the period interval. ‘Principal statistics of the Canadian coal mining industry, 1918 to 1976’ (series Q137–142) is used for the numbers of employees in the coal industry.12 Number of coal employees is expressed as percentage of maximum over the period. Bacille CalmetteGuérin (BCG) vaccination in Canada, expressed as total number of vaccine shots, was compiled by Malissard.13 US Department of Energy Official Energy Statistics provides historical statistics on coal consumption by sector in million short tons from 1949 to 2005,14 and the Centers for Disease Control and Prevention (CDC) Division on Tuberculosis Elimination Statistics data on historical TB in the US (incidence/100 000 between 1953 and 2005).15 Data on coal consumption (exajoules) in China are taken from the China Statistical Yearbook 2003,16 and TB notification rate (/100 000) from the WHO TB report 2005.17 The poverty headcount index represents the percentage of the population living in households with income per person below the poverty line. The headcount index is provided by the World Bank Policy Research Working Paper Series.18 Pearson correlation coefficients, R2 and P number were calculated using Microsoft Excel mathematical functions. Pearson correlation is carried out with data from the corresponding figure for the given time period

Figure 1 TB mortality rate as related to the average number of windows per household in Paris urban districts or arrondissements between 1858 and 1902. pop population.

on 90 000 households, the study provides evidence that women in biomass-using households are three times more likely to report TB than those in households using cleaner fuels. Another Indian study found that households using wood or dung cakes as fuel had 2.5 times more clinically confirmed TB.8 Cigarette smoking is now recognised as a risk factor for TB infection.9 Miners in coal and gold mines are also prone to TB, although it is considered an effect of silicosis.10,11 Based on the observation that industrialisation and TB coincide, and on the assumption that a determinant factor remains to be identified in the TB epidemic, historical statistics of disease and energy were compared to assess the impact of environmental factors on TB. The present hypothesis suggests that pollution caused by combustion of coal and possibly town gas during industrialisation aggravated the historical TB epidemic in the West and the present epidemic in developing parts of the world. The possibility that carbon monoxide (CO) and particulate matter (PM) activate the interleukin-10 (IL-10) anti-inflammatory

Table Pearson partial correlation coefficients relating disease incidence or notification rate (China), electrification and indicators of coal consumption in Canada, USA and China
Canada Disease incidence per 100 000 population TB Typhoid fever Whooping cough Diphtheria Scarlet fever Poliomyelitis‡ Employees in the coal industry (1940–1975) 0.97 0.87 0.85 0.77 0.55 0.31 Electricity, total number of customers (1940–1975) 0.95 0.86 0.87 0.76 0.55 0.21 USA Residential coal consumption, million short tons (1953–1990) 0.99* China Total coal consumption in exajoules (1982–2002) 0.95†

* Correlation in the US for residential coal is done with TB incidence/100 000 population. When using TB death rate/ 100 000 in the US, the correlation was also 0.99. † In China, TB notification rate/100 000 is used. ‡ Correlations for the period 1940–1964. TB tuberculosis.

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in the Table. Steel industry numbers, population data and electric drive figures for Norway are from Statistike Centralbyrå,19,20 whereas TB mortality figures (/100 000) are taken from Wood.21 The progress of urban gas lighting (total number of gas lights installed) in Paris is from Bouteville,22 whereas TB mortality figures (/1000) in Paris are derived from Barnes.23 Waldron provides the number of notified workplace accidents during World War II,24 and TB historical statistics (total number of cases) for England and Wales are from the United Kingdom’s Statutory Notifications of Infectious Diseases (NOID).25

RESULTS
TB decline in twentieth century North America Figure 2 shows the incidence of notified diseases and BCG vaccination in Canada between 1926 and 1975. There was a global downward trend of all diseases over the period. TB incidence rose after 1930 (Figure 2A), increased further with the advent of WWII to peak in 1944, and declined steadily after the war. In contrast, whooping cough increased around 1935, but not at the onset of the war (Figure 2C). Scarlet fever shows cyclic behaviour every 8 years or so (Figure 2D). An

Figure 2 Incidence of notified disease (A, C–F) in Canada during the twentieth century. Vertical dotted lines highlight WW II. In B, BCG vaccination in the province of Quebec (solid line), in the province of Newfoundland (dotted line) and in the rest of Canada (dashed line) are shown. pop population.

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outbreak of typhoid fever occurred in 1927; it declined sharply then steadily afterwards, to almost disappear (Figure 2E). Diphtheria also decreased after 1930, came back to some extent before WWII and virtually disappeared after the war, presumably as a consequence of vaccination (Figure 2F). Of all the diseases shown in Figure 2, TB is perhaps the disease most closely associated with WWII. This can be explained by the arrival of the mass workforce in manufactures involved in the war effort, considering that factory and construction labourers were the prime targets of TB in the 1930s.26 The cyclic behaviour of scarlet fever was somewhat altered by the war, and the increase in diphtheria may also have something to do with living and working conditions during the war. The number of BCG vaccine shots administered in the province of Quebec, Newfoundland and the rest of Canada are shown in Figure 2B. It is likely that BCG vaccination had only a limited impact on the decline of pulmonary TB in Canada and elsewhere after WWII. First, TB decreased in countries where BCG was not administered, such as the USA and the Netherlands. Second, in Canada, the vaccine was mostly administered in Quebec and Newfoundland (Figure 2B), and only exceptionally in the rest of Canada, whereas no boundaries were observed in TB incidence. Finally, BCG is a controversial vaccine, with an efficacy that has been reported to vary between 0 and 80%.27 In addition, three meta-analyses carried out in the mid-1990s have shown a protective overall effect of 50%,28–30 with greater efficacy for disseminated forms and meningitis but lesser efficacy in the case of pulmonary TB. As regards anti-tuberculosis drugs, streptomycin (SM) did not become available before 1948, and resistance soon developed. Introduced in 1952, isoniazid reduced resistance when used in combination with SM.31 However, the decline in TB incidence in 1952 is not sharper than before, as could have been expected if the anti-tuberculosis drugs had had 100% effect (Figure 2A), and if it was administered systematically. Figure 3A shows the number of coal workers, the number of customers of electric utilities and TB rates in Canada after WWII, based on data obtained from Statistics Canada.32 One important advance of the postwar era was the electrification of homes. In Canada, gasoline and electricity replaced coal as the principle means of heating households. The relative number of coal workers during that period is used to illustrate the decline of the coal industry in Canada, mainly due to the loss of the residential market. In Canada, TB declined to levels below 20/100 000. This drop precedes that of coal employees, which may reflect a delay in the lay off of the workforce relative to the evolution of the coal market. Nonetheless, the timelines of TB decline and the indicators of residential coal consumption do coincide. A similar pattern of TB decline is observed between 1953 and 1975 in the United States, where BCG

Figure 3 A. TB incidence (solid line), total number of coal employees in the coal industry (dashed line) and electric utility customers (dotted line) in Canada between 1940 and 1975. B. Historical US domestic coal consumption (dashed line) and TB incidence (solid line) between 1953 and 2003. pop population.

was not administered (Figure 3B). Data for residential coal consumption in the USA are available. TB declines in the US again coincide with a reduction in residential coal consumption. A peak in TB incidence in 1977 is visible and the increase in TB due to the HIV epidemic between 1990 and 1997 can be seen. As for residential coal, its use has almost completely disappeared by 1980. Modern-day TB epidemic in China Overall coal consumption in China,16 when compared to TB notification rates,17 shows an apparent close relationship between global increases in coal consumption and TB disease notification rates (Figure 4A). TB incidence and coal use have increased in a similar fashion in the last 20 years, with simultaneous peaks around 1986, 1990 and 1996, and a corresponding drop around 2000. In sharp contrast to trends in TB notifications and coal consumption in China, Figure 4B shows that overall poverty for rural and urban areas decreased during the same period in China.18 Social deprivation cannot, therefore, explain the increase in TB notifications (Figure 4A). China is the largest consumer and producer of coal in the world. Today, coal is widely used in China as a source of energy for both electricity production and household use.33 Coal largely dominates the energy

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incidence between 1953 and 1990. The correlation of 0.95 between total coal consumption and TB notification rate in China is also high. The strong correlations in Canada, USA and China between coal consumption and TB disease therefore highlight the possibility that coal consumption directly impacts on TB disease. Coal and industrialisation Before industrialisation in Europe, wood became scarce and expensive, while coal became affordable. Charcoal and coal combustion yield more energy than wood; inventions and innovations led to the blast furnace and the steam engine. One key feature of industrialisation is the development of the steel industry. The advent of this industry may be considered a consequence of innovations in the process of iron smelting. The blast furnace is a metallurgical furnace used for smelting, notably iron ore. Charcoal or coke, limestone and iron ore are fed into the blast furnace while air is blasted at the bottom. Iron is reduced to metal by charcoal, which yields oxides of carbon as products of combustion. Beginning in the UK in 1709, the use of coke (baked bituminous coal) instead of charcoal (baked wood) in blast furnaces was of paramount importance in the advent of the industrial revolution, as it enabled the production of iron that was cheaper and less brittle. In turn, the availability of coal on the market spurred the use of and technological innovations on the steam engine, as well as the development of heavy industry. This serves to illustrate how industrialisation boils down to coal. TB and industrialisation There is some agreement that TB incidence peaked around 1800 in Western Europe.35 TB accounted for 25% of deaths in New York city between 1810 and 1815.36 However, according to Barnes,23 TB in Paris peaked around 1865, whereas in Norway it peaked around 1900.21 Therefore, based on the present hypothesis, the peak in TB disease depends on the extent of air pollution and industrialisation in an area; in China, for example, industrialisation may be considered to be occurring now. TB numbers before the 1900s are difficult to find. In Norway21 and Japan,4 for example, industrialisation occurred later than in the rest of Europe, as did the rise in TB incidence. Figure 5 shows TB incidence between 1855 and 1945 in Norway. Beginning slowly around 1840, Norway industrialised its pulp and paper industry and introduced steel works. The number of steel workers jumped from 1608 to 7161 employees and from 9.3% to 22.8% of the total workforce between 1860 and 1870.19 The late onset of industrialisation, exemplified by the emergence of the steel industry in Norway (Figure 5), coincides with a delayed increase in TB incidence.

Figure 4 A. Tuberculosis notification rates (solid line) and total coal consumption (dashed line) in China between 1980 and 2002. B. Poverty in China as a whole, in urban and rural areas: percentage of the population living in households with income per person below the poverty line between 1981 and 2001. pop population.

landscape of the country;16 estimates suggest that 330 million people use coal for domestic purposes.34 According to Finkelman et al., coal stoves and small coal boilers provide more than 50% of the energy for urban households, and 22% of rural households rely on coal.33 Low-grade coal is often burned in cheap, poorly vented or even unvented stoves, resulting in various illnesses.33 Correlation between energy and disease The Table correlates notified disease, coal employees and electrification in Canada between 1940 and 1975, and coal consumption and TB disease indicators in China and the USA. The Pearson correlations are derived from the data used in Figures 2 and 3. In Canada, although the onset of TB precedes indicators of residential coal consumption, the Pearson partial correlation coefficient of 0.97 is strongest compared to other notified diseases for the same period. It is interesting to note that the negative correlation for electricity of 0.95 is strongest for TB compared to other diseases, as is the case for coal. Also, the correlations for electric utility customers are similar in absolute value to those of coal employees for notified disease in Canada, indirectly indicating that the electricity market develops at the expense of the coal market. In the US, again, a very strong correlation of 0.99 is found linking residential coal consumption and TB

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and mainly composed of (vol%) H2 27–30%, CO 35– 45%, carbon dioxide (CO2) 10–15%, H2O 15–25%, hydrogen sulphide (H2S) 0.2–1.2% and hydrogen chloride (HCl) 50–500 ppm.40 A passage in the book by Flora Tristan describes a scene at the coal gasification factory, the Gas Light and Coke Company’s Horseferry Road Works, in London in the 1830s:
Two rows of furnaces on each side were fired up [. . .] The foreman told me that stokers were selected from among the strongest, but that nevertheless they all became consumptive after seven or eight years of toil and died of pulmonary consumption.41

Figure 5 Mortality due to TB in Norway between 1855 and 1945 (solid line) with indicators of industrial development shown on the timeline (diamonds). Electric motor drive in the manufacturing industry between 1900 and 1938 in Norway (dashed line). pop population.

Another idiosyncrasy of Norway in regard to industrialisation is the early electrification of the country, early in the twentieth century, due to the abundance of large water basins; the capacity of water plants jumped from 10 MW in 1907 to 1250 MW in 1920 and to 2250 MW in 1939.37 The TB epidemic receded earlier in Norway than in other industrialised countries such as the UK, Canada or the US. As illustrated in Figure 5, early electrification, as exemplified by the use of electric motor drive in the manufacturing industry between 1900 and 1938, may explain the early decline in TB prevalence in Norway, although the decline seemed to start slightly before the onset of electrification. Nevertheless, electrification proceeded very rapidly in Norway. Again, as was the case in Canada and the US, the switch to a cleaner energy coincides with a dramatic decrease in the prevalence of TB. In the late nineteenth century, Japan opened to the world following the Meiji restoration, and reforms ensued. The silk industry financed the Meiji restoration to some extent. During the late nineteenth and early twentieth centuries, the industrial production of silk in Japan was revolutionised by the use of steam boilers for continuous, even heating of the reeling basins used to soften cocoons to be reeled into raw silk;38 coal was used to heat the steam boilers.39 TB incidence was high in the silk and spinning industry, and the young girls employed for spinning were the first victims. Later, a second phase of heavy industrialisation in the 1930s shifted the trend, and young men became the prime targets of TB (T Shimao, personal communication). Back in Europe, in the early nineteenth century, technical advances by the Scottish engineer William Murdoch and others introduced town gas, also called synthetic gas or syngas. Town gas was produced by gasification, a process whereby coal is heated in the presence of water vapour. Syngas produced with coal in processes with water-coal slurry systems is typically

Town gas was first used for lighting streets and homes using the gaslight or ‘bec de gaz’. The first gaslights had a notoriously bad reputation: they were very inefficient and leaked large amounts of unburned gas that added to the coal fumes in urban areas. An account by Lecouturier depicts industrialised Paris around the 1850s:
If you contemplate from the summit of Montmartre the congestion of houses piled up at every point of a vast horizon, what do you observe? . . . One is tempted to wonder whether this is Paris; and, seized with a sudden fear, one is reluctant to venture into this vast maze, in which a million beings jostle one another, where the air, vitiated by unhealthy effluvia, rising in a poisonous cloud, almost obscures the sun.23

Figure 6A depicts the progress of urban gas lighting in Paris—la ville lumière (the city of light)—during the nineteenth century.22 Between 1831 and 1852, all 13 000 urban lighting oil lamps of Paris were replaced by gaslights as gas pipelines were installed for urban, industrial and domestic usage. In Paris, the TB epidemic peaked in the middle of the century, around 1865 (Figure 6B), and receded slowly thereafter.23 It may be considered that a critical factor for the acute crisis in Paris is the introduction of gaslight. As town gas allowed night shifts in manufactures, it is likely that TB incidence increased among factory labourers during the course of the nineteenth century. In defence of the thesis is the shift in sex ratio for TB during that period: in 1830, two thirds of women suffered from TB, while in 1860 the trend reversed and two thirds of men suffered from TB;23 men then constituted the majority of the labour force in manufactures. The peak of the TB epidemic in Paris around 1865 can therefore be explained by the widespread use of town gas during that period. Thus, indirectly because of the advent of night shifts in the industry and directly due to town gas fumes, the utilisation of combustible town gas is likely to have had an impact on TB incidence during the nineteenth century. The decline in TB mortality towards the end of that century may be explained by improved combustion and lighting technologies, such as the Auer lamp invented by Dr Carl Auer von Welsbach in 1885,

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dents and the number of TB notifications in the UK during WWII, showing a concomitant increase in workplace accidents and TB in the UK during this time. Generally speaking, there was an increase in all types of workplace accidents. How can this be explained? According to Waldron, work was arduous in UK factories during the war:
. . . a large and often inexperienced workforce spent long hours in factories that were often poorly lit, badly heated and badly maintained. The requirement for complete blackout meant that ventilation systems were often inadequate, and this resulted in greater exposure than normal to some toxic substances. [. . .] there is no question that the number of cases of specific industrial diseases increased substantially [. . .].24

Figure 6 A. Total numbers of urban lighting oil lamps (grey) and town gas lamps (black) installed in Paris in 1831, 1848 and 1852. B. TB mortality rates in Paris during the nineteenth century. pop population.

It is possible that the increase in TB in the West during WWII is due to working conditions in manufactures involved in the war effort. In this regard, TB therefore translates into an industrial disease, considering the high rates of TB in construction and factory labourers in the 1930s. It also highlights the possibility that a specific workplace pollutant is involved in reactivation of the disease. Generally speaking, if poverty was such an important factor in the incidence of TB, the disease would have increased mostly in the 1930s, as poverty was rampant during the Great Depression. Considering that ventilation in the workplace was less than satisfactory in the first half of the twentieth

whose use spread around 1890. It may be noteworthy to mention that town gas is still used in industrialising parts of the world today where natural gas is rare or expensive, such as in China or South Africa.42 TB, industry and ventilation In a 1930 occupational hazards study, construction and factory labourers were found to be the prime target of TB, with a death rate of 227.3/100 000 compared to 180.0 for waiters, 173.3 for servant classes, 165.6 for teamsters and carriage drivers, 106.0 for coal mine operatives and 23.7 for physicians and surgeons,26 trends that are in sharp contrast with today’s occupational statistics. The prevalence of TB in industry and manufactures is a recurrent theme during the nineteenth and twentieth centuries. A 1914 paper by Hastings directly links TB and air pollution:
Among garment workers many cases of tuberculosis develop. This is due largely to long hours, dusty, badly ventilated, overcrowded rooms, in which they frequently use gas stoves, or gas flat irons and charcoal stoves. Cases of chronic gas poisoning are not unusual among these people from leaky gas stoves.43

TB made a comeback in the West during WWII. The war effort brought masses of workers into manufactures. Figure 7A shows carbon monoxide, nitrous fumes and lead intoxications in UK manufactures, while Figures 7A and 7B compare intoxication acci-

Figure 7 Reported workplace accidents in factories and tuberculosis notifications between 1937 and 1946 in the UK, showing A) number of carbon monoxide (solid line), nitrous fumes (dashed line) and lead (dotted line) poisoning notifications; and B) total number of pulmonary TB notifications.

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century, it is conceivable that the high incidence of TB in manufactures is explained by workplace air pollutants. Electricity gradually replaced internal combustion engines as the source of mechanical drive, and proper ventilation systems were installed in the industry. These changes occurred in parallel to the shift in household energy sources, thereby reducing the total burden of air pollution. Pertaining to the issue of ventilation, ‘open-air treatment’ or ‘sanatorium treatment’ was introduced in Germany by Hermann Brehmer in Görbersdorf, Silesia, in 1854.44 Although some variations existed between sanatoria (e.g., rest vs. exercise, altitude vs. sea level), open-air treatment was essentially based on exposing the patient to fresh air, night and day, in a remote area. In studies of sanatoria in England, it has been said that patients increased in weight within the first week (2–6 pounds), cough was seldom heard, and night sweats tended to cease within days.45,46 Sanatoria were generally considered beneficial. Strangely enough, no comparative study on the efficacy of sanatoria was ever carried out. Bardswell made a careful follow-up study of patients admitted to the King Edward VII sanatorium in Sussex between 1907 and 1914.47 He found that by 1916, 751 of 1707 (44%) patients had died, making sanatoria less than a panacea. In retrospect, and in the light of the present hypothesis, the sanatorium treatment may be regarded as a way to keep patients away from polluted urban, industrial and domestic environments.

DISCUSSION
The present analysis suggests that air pollution resulting from coal combustion directly affects TB incidence. Although the decrease in TB observed in the West can be explained by socio-economic factors, the use of anti-tuberculosis drugs and/or the BCG vaccine, the coincidence with coal consumption is nothing short of troubling. In China, HIV prevalence is low48 and therefore cannot explain the increase in TB in the last 20 years. The correlation may, however, reflect a direct association between coal consumption and TB incidence. In the case of China, notification rate instead of TB incidence was used (Figure 4). It should be added that a better health system in a wealthier state can result in increased TB notifications. Generally speaking, the evidence presented in the present paper should be regarded with caution given the inherent limitations of the ecological approach. The correlations are prone to the ecological fallacy, because no confounders can be tested. For example, in Canada, the overall improvement of the health system after WWII, concomitant with the electrification of cities, could explain a global decrease in TB. Nevertheless, it is an hypothesis to be investigated, as biomass cooking fuel7 and cigarettes9 have been identi-

fied as risk factors for TB, and social factors may not convincingly explain the aetiology of the disease.5 The US Environmental Protection Agency estimated US coal emissions in 2000 by fuel combustion electric utilities for the principal pollutants: sulphur dioxide (SO2) 10 723 thousand short tons (tst), nitrogen oxides (NOx) 4573 tst, CO 234 tst, PM 10 m (PM10) 242 tst, PM 2.5 m (PM2.5) 116 tst, volatile organic compounds (VOC) 30 tst, and lead (Pb) 56 short tons.49 The prime pollutant in coal is SO2, followed by NOx. CO is substantially less, but partial combustion of coal is known to produce large amounts of CO, and it has been suggested that US tabulated data for CO emissions may be underestimated.50 Ash from coal combustion, or PM, is composed primarily of oxides of silicon, aluminium and iron. On the whole, coal is considered to be a very polluting fuel. Bygone coal furnace technologies are likely to have had an impact on indoor air pollutants and CO levels. They were not nearly as efficient as they are today, and therefore resulted in partial combustion of coal, indoor build-up of CO and heavy PM emissions. Today in China, low-grade coal is often burned in cheap, poorly vented or even unvented stoves, resulting in various illnesses.33 In addition, keeping stockpiles of moist lignite coal near a source of heat will result in CO leakage, a process reminiscent of industrial coal gasification. Considering the present hypothesis, the impact of coal on TB disease should transpose into a specific mechanism in vivo. A closer look at the physiological effects of CO and the biology of TB suggests a plausible mechanism whereby coal fumes shut down the immune response of the host. Termed the silent killer, CO is an odourless, tasteless and colourless gas with a well-known tendency to build up indoors. Identified in recent years as an intracellular signalling molecule, CO is generated endogenously by haeme oxygenase enzymes (HOs). The IL-10 anti-inflammatory pathway requires the activation of haeme oxygenase-1 (HO-1), which degrades the haeme of haemoglobin, yielding CO, biliverdin and iron as by-products.51 Anti-inflammatory action was found to be mediated by CO, as its removal blocks the effects of IL-10 and HO-1.52 A major effect of CO is the downregulation of tumour necrosis factor-alpha (TNF- ). TNF- plays a central role in the formation of granulomata and containment of TB.53,54 Inhibition of TNF- by drugs on trial has been linked to reactivation of TB.55,56 In addition, macrophages are of paramount importance in the defence against M. tuberculosis. Growth inhibition is mostly mediated by nitrogen oxide NO species57–60 promoted by TNF- . Interferon-gamma (IFN- ) and TNF- are central to the process, as they induce macrophage activation, inducible nitric oxide synthase (iNOS) expression and NO generation.60,61 On the other hand, M. tuberculosis encodes trun-

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cated haemoglobins (trHbs) whose function remains unclear. TrHbs have been associated with protection against nitrosative damage by virtue of their NO dioxygenase activity, utilisation of CO as a carbon source, O2/NO sensing, redox reactions, O2 delivery in hypoxic conditions and long term ligand/substrate storage.62–66 M. tuberculosis trHb has, along its haeme group, an a-polar tunnel system through the protein matrix endowed with more than one entry/exit points and is able to store diatomic molecules in its cavity.67 The model shown in Figure 8 details a mechanism whereby M. tuberculosis responds to macrophage nitrosative attack with the release of CO stored in trHb molecules, followed by suppression of immunity, a model termed ‘CO-doping’. In addition to actively protecting the bacilli through NO oxidation by trHb nitric dioxygenase activity, CO-doping functions to induce an IL-10-like response. As a result, a decline in TNF- production, macrophage activation and cellmediated immunity ensues. In either case, irrespective of the capacity of M. tuberculosis to actively trigger the IL-10 pathway, elevated ambient levels of CO result in lower levels of TNF- through activation of the IL-10 pathway. It is noteworthy to add that polymorphism in the slc11a1 (formerly Nramp1) gene has been identified as a factor of resistance to TB in mice.68 slc11a1 is thought to be an iron transporter localised to membranes of phagocytes in macrophages. Polymorphisms in IL-10 and TNF- have also been linked to pulmonary TB.69 The precise role of Slc11a1 in TB resistance remains to be elucidated: however, it has been

Figure 8 CO-doping model in the reactivation of latent tuberculosis. Release to macrophages of CO stored in trHb of M. tuberculosis, mimicking the IL-10 anti-inflammatory pathway, results in inhibition of gene transcription, TNF- production and leads to reduced macrophage activation, nitric oxide production and cell-mediated immunity. CO carbon monoxide; LPS lipopolysaccharide; TLR toll-like receptor; trHb truncated haemoglobins; TNF tumour necrosis factor; NO nitric oxide; HO haeme oxygenase; IL-10 interleukin-10; iNOS inducible nitric oxide synthase.

suggested that Slc11a1 influences susceptibility to TB by regulation of IL-10 because a polymorphism in Slc11a1 was associated not only with TB, but also with a higher endotoxin-induced production of IL-10.70 In the scope of the CO-doping model, modification of the iron pool by Slc11a1 serves to desensitise the IL-10 pathway in lung macrophages or to capture available iron used in trHb haeme, thereby impacting on the anti-inflammatory activity of CO and/or the ability of M. tuberculosis to feed macrophages with CO. Another issue yet to be considered is the link between PM from coal combustion and the activation of the IL-10 pathway in fibrotic lungs. It is known that miners in coal and gold mines are more prone to TB as a result of silicosis.10,11 It has been shown that, in mice, the IL-10 pathway is activated in the course of fibrosis of the lung,71,72 but not in rats. Coal ash differs from wood ash, which could explain an enhanced activation of TB by coal as opposed to wood; TB existed before industrialisation, but presumably to a lesser extent. Logically, the amount of CO produced by the combustion of coal should be greater than that produced by the combustion of wood. In combustion experiments for different fuels in a laboratory system designed to mimic the fire pit used in Xuan Wei County in China, emissions of anthracite, bituminous coal and pine wood were compared.73 These results show that the total PM emissions for bituminous coal were 5.6-fold those of pine wood, whereas there were only 1.6-fold more CO emissions for bituminous coal than for pine wood. However, in China, the use of cheap grades of coal such as moist lignite may result in worse figures for CO.33 In conclusion, coal, the workhorse of progress, seems an inevitable step in the emergence of an industrialised country. Thus, in the light of the present hypothesis, the white plague will rise and vanish along the path of entry into modernity; the disease will fluctuate in the population in a complex interplay of factors: domestic and industrial use of various types of coal, combustion technologies, the number and gender of workers in manufactures, and the source of mechanical drive. Finally, as electrification progresses and poverty plummets, TB regresses to a bad memory—until AIDS brings it back on topic. Jean and René Dubos, in their book The White Plague, called TB a disease of ‘incomplete civilization’.74 It could also be said that TB is a disease of incomplete industrialisation. Although micro-organisms are causative agents of many illnesses, environmental health factors are not to be underestimated in the aetiology of the disease. The present evidence should prompt investigators to study the effects of air pollution, notably coal, in regard to TB. An epidemiological approach that can take into account confounders could substantiate the hypothesis. Furthermore, the impact of various air pollutants on the outcome of TB should be investigated in animal models.

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Acknowledgements
I would like to thank Dr D Menzies for critical review of the manuscript. I am also grateful to Dr T Shimao for information on historical facts pertaining to TB in Japan.

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RÉSUMÉ

On considère généralement que la tuberculose (TB) va de pair avec l’industrialisation et l’urbanisation. Avec un pic dans les années 1800 et une lente régression ultérieure, la maladie a décliné fortement en Occident après la deuxième guerre mondiale. La TB fait un retour dans les 20 dernières années dans les pays en développement comme la Chine et l’Inde. Comme les seules conditions socioéconomiques ne peuvent pas expliquer la connexion entre l’industrialisation et la TB, des facteurs étiologiques de

la maladie doivent encore être déterminés. On met en corrélation les statistiques historiques de consommation de charbon et de maladie TB au Canada, aux USA et en Chine. On élabore une hypothèse liant la TB et la pollution de l’air dans le contexte de l’industrialisation. Un modèle est proposé dans lequel la stimulation de la cascade IL-10 par le monoxyde de carbone dans les macrophages pulmonaires favorise la réactivation de Mycobacterium tuberculosis.
RESUMEN

La tuberculosis (TB) se considera generalmente vinculada con la industrialización y la urbanización. La enfermedad presentó el pico de frecuencia más alto en el siglo XIX, declinó luego lentamente y mostró una disminución drástica después de la segunda guerra mundial, en Occidente. Durante los últimos 20 años, la TB ha surgido de nuevo en países en desarrollo como China e India. Puesto que las condiciones socio-económicas por sí solas no explican la correlación entre industrialización y TB, deben determinarse los demás factores que con-

tribuyen a la etiología de la enfermedad. Las estadísticas históricas de consumo de carbón presentan una correlación con la incidencia de tuberculosis en Canadá, los Estados Unidos y China. Se plantea una hipótesis que asocia la TB con la contaminación atmosférica en el contexto de la industrialización. Se propone un modelo según el cual la activación de la cascada de la interleucina 10 por el monóxido de carbono en los macrófagos del pulmón promueve la reactivación de Mycobacterium tuberculosis.