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Health effects from low level and environmental exposure to chrysotile John A Hoskins Independent Consultant, Haslemere, UK Abstract The disease potential of exposure to high levels of airborne respirable chrysotile fibre is well-known although the spectrum of diseases consequent upon exposure is controversial. Exposure is known to cause asbestosis and probably, also, lung cancer, particularly in cigarette smokers, but chrysotile seems increasingly unlikely to be responsible for producing mesothelioma. This spectrum of disease results predominately from heavy occupational exposure. Exposure to low levels of chrysotile, either occupationally or environmentally and particularly exposure to the levels found in the urban environment, does not produce attributable disease within the limitations of the epidemiological method. Nor does it produce any histopathological changes in the lungs. If it were not for the fact that chrysotile is unequivocally accepted as a carcinogen then the risk associated with such low level exposure would have been assessed as insignificant. However, carcinogens are judged by regulatory authorities to have no threshold of effect. Since this hypothesis cannot be tested authorities rely on the precautionary principle in the hope that this will reduce the level of cancer in the population. However, this overly cautious approach is unlikely to have any effect on human health and may have disadvantages for society at large. Introduction It is probable that high exposure to any bio-persistent airborne respirable mineral fibres will have an adverse clinical effect. This is well-known in the case of the asbestos minerals although the spectrum of diseases consequent upon such exposure is to a degree controversial and undoubtedly is consequent on the degree of bio-persistence of the fibre. Chrysotile is the commonest of the asbestos minerals and it is known that high level exposure will cause the fibrotic disease asbestosis, and that symptomatology is dose-dependent [1,2]. Chrysotile may also cause lung cancer although that is probably a rare occurrence except in cigarette smokers and the dose of fibre required is more uncertain. It is known that cigarette smoke increases the penetration of asbestos fibres into airway walls  and inhibits asbestos clearance  both of which may be pertinent to the mechanism of action. It is certain that smoking increases the risk of lung cancer developing in an asbestos exposed person but the relationship is complex [5-8]. Whether the other asbestos exposure related tumour, mesothelioma, results from chrysotile exposure is problematic [9-11] and few scientists or clinicians who specialise in asbestos related diseases believe it to be other than an extremely rare event. Some have been bold enough to be absolutely prescriptive: “There has probably never been an attributable, clinically and pathologically-proven, case of mesothelioma in any manufacturing industry, e.g. cement, friction products, or textiles, amongst the many tens of thousands of workers where chrysotile alone has been used.” . A minority, though, holds an opposing view [13-15]. Over a century of experience has shown that high occupational exposure is the only major risk factor for chrysotile associated disease. Exposure to low levels of chrysotile, either occupationally or environmentally and particularly exposure to the levels found in the urban environment, does not produce attributable disease within the limitations of the epidemiological method. Nor apparently are any histopathological changes found in lungs that have been exposed to a fibre concentration some one or two orders of magnitude below the level which would cause discernible clinical symptoms. Attempts to model low level exposure have, similarly, failed to detect an effect. In fact a report of a WHO task group expressed reservations about the reliability of risk assessment models applied to asbestos risk (all types) . They noted that variations over several orders of magnitude could occur. In the case of cancer they wrote: “In the general population the risks of mesothelioma and lung cancer attributable to asbestos cannot be quantified reliably and probably are undetectably low.” . It has been proposed that asbestosis is a necessary pre-requisite for lung cancer but a large number of 1 studies on exposed cohorts still leaves several questions unresolved and the topic is controversial [18- 20]. However, many pathologists have only been willing to ascribe lung cancer to asbestos exposure if asbestosis was present as well and this may have overestimated the asbestos dose needed to cause this tumour. A major problem in attributing carcinogenic properties to chrysotile lies in the contamination of major deposits, such as those in Québec, with fibrous tremolite . Fibrous tremolite is a highly carcinogenic amphibole mineral . The short-fibre chrysotile deposits of California which are devoid of tremolite  do not produce disease in those who work them [24,25]. A further complication is that workers were commonly exposed to other amphibole fibres, generally amosite or crocidolite which can affect the pattern of disease . Although it was hypothesised at one time that exposure to low levels of chrysotile, either occupationally or even at the levels found in the urban environment, would be dangerous. Experience has shown that this is not the case. Occupational experience has shown that on average above a certain level of exposure clinical symptoms of asbestosis can occur although these levels are very much higher than those to people exposed to ambient environmental pollution . Also, exposure to a fibre concentration below that which produces discernible clinical symptoms would still produce changes which could be detected histopathologically. Studies of asbestosis have concluded that there is a linear dose-response with a threshold below which no effect is experienced. The Ontario Royal Commission in 1984  considered the published studies and concluded that there was a linear dose-response relationship with no clinical manifestation below a level of occupational exposure of 25 fibres/mL.years a finding which was shortly after endorsed by Doll and Peto . Churg  looking at non-occupational exposure also found evidence of a threshold. To give an idea of the risks associated with fairly low exposure Peto et al. predicted that exposure to 0.25 fibres/mL for 35 y from age 20 in chrysotile textile manufacture, arguably the most dangerous of the chrysotile industries, may result in 0.8% increased risk of lung cancer or mesothelioma. However, the fibre measurements on which this was based were in some doubt and the authors stated the prediction was of doubtful accuracy. If chrysotile was unequivocally accepted as a non-carcinogen then the risk associated with such low level exposure would have been assessed as insignificant. The exposures found today in the chrysotile industry are maybe some 100 to 100,000 times less than they were in the past and so calculation of the risk they pose is extremely problematic. People are daily exposed to a large number of toxic, often carcinogenic, substances in very small amounts with apparently no effect [32,33]. This lack of effect is hardly surprising since adaptation is a key element of survival of the species. If the level of exposure is low the effect will be small since the basic tenet of toxicology is that while all compounds are poisons, dose is the only parameter determining overt toxicity [“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” (Paracelcus)] (see ). Science Versus the Regulators Unfortunately, by the edicts of regulatory authorities rather than the discoveries of science, any compound designated as a carcinogen is held not to act in the same way as a non-carcinogen. The mode of action of a carcinogen is judged to be that there is no threshold of effect. Since the mid-1970s risk assessment of carcinogens has been based on an unsubstantiated belief in such a „linear no threshold‟ (LNT) model . This model continues to be used in spite of the fact that there is very limited scientific evidence to support it. The model assumes a linear relationship which goes through the origin although this is generally qualified by inclusion of terms such as „multistage‟ and by ignoring the fact that even at the zero point conventional use of a 95% confidence interval can give a positive figure for carcinogenicity. The model is not mechanism-based and makes no distinction between compounds that are genotoxic and those that are non-genotoxic or acting through an epigenetic mechanism. The origin of this way of thinking is the US EPA and their overall view has been well reviewed . It is unfortunate that the views of the EPA have become global opinion but it is comforting that today the best criticism of this way of thinking is coming from America  and 2 some of the critics are in the EPA. A major problem is that by exaggerating risks of the effects of low doses leads to undue amounts of societal resources being used to reduce human exposure. There are considerable cost and other adverse implications for this at all levels of society . Applying the LNT model gives a result that is contrary to experience and has the consequence that it generates any number of „asbestos myths‟ such as the infamous and ludicrous claim that „one fibre can kill‟ . Since life in a large city may mean inhaling about one chrysotile fibre with every breath the validity of the statement must be in doubt. The „myths‟, unfortunately, raise public concern even if this is unwarranted and not based in reality. Whether or not the LNT model should be scrapped depends upon the toxic agent under consideration. The evidence is good that it should be for chrysotile but the case is more arguable for radiation . Environmental Exposure to Chrysotile Chrysotile is a ubiquitous component of all air samples taken indoors or out. Most of the fibres are the results of decades of mining but there is a background derived from natural sources. There are several sources of chrysotile in urban outdoor air, from motor vehicle brakes, weathered or friable building materials, as releases from industrial operations and from clearance and disposal operations. The use of chrysotile asbestos for brakes has decreased considerably in recent years in Western countries and the result has not always been positive. It is arguable that more people have died from accidents consequent on this decision than would ever have suffered an asbestos related disease had we continued to use chrysotile. Spurny  demonstrated that fibres are released into the air in the vicinity of weathered asbestos cement products. Air near buildings containing such weathered products could contain between 0.2 and 1.2 f.L-1 from this source. In addition, there was also the contribution from industries working with asbestos minerals. While Marconi et al.  studying the concentrations of airborne fibre in the vicinity of an asbestos cement plant in 1989, found peak levels of up to 19 f.L-1 at 0.4 km from the plant today it would be considered a serious breach of occupational hygiene if levels exceeded those of an urban background.. Human Exposure What levels are chrysotile are we exposed to today? Spot measurements of ambient levels have their uses but give little or no indication of long-term levels, nor long-term dose to those exposed, because of variations in point or local sources. It is better for the purposes of argument to use the figures of the World Health Organisation which has concluded  that, allowing for the great variations in fibre counts and counting techniques, levels of asbestos in outdoor ambient air are usually less than 1 f.L-1 in rural areas and up to 10 f.L-1 in towns. Low-level occupational exposure could be 10 to 100 times this value. Other inorganic fibres can be found at 10 times these levels. Air sampling can define the maximum possible exposure but only if it is personal air sampling. Static sampling can wrongly estimate personal dose by perhaps two orders of magnitude. Regardless of how exposure is measured the dose that can enter the body is limited by the daily inhalation volume which is about 10 m3 or more of air. If the WHO figures are used that corresponds to 10,000 to 100,000 chrysotile fibres per day and perhaps one tenth that amount of amphibole fibres. At this level of exposure the chrysotile fibres are largely cleared while the amphibole fibres are retained . Extending this calculation over a lifetime gives a maximum dose that is far less than the 10 5 to 106 fibers/g. (dry weight) of lung tissue found post mortem in non-occupationally exposed people. In fact levels up to 3 x 106 /g (dry weight) of lung tissue in non-occupationally exposed people have been measured . Clearly environmental monitoring and lung measurements do not give the same type of information: air samples give the concentration at the time of sampling whereas the retained lung dose reflects historical levels of exposure confounded by clearance and by losses during preparation. The actual human exposure to fibres has to be assessed by the surrogates of either examining fibres in autopsy lung samples or measuring the levels in broncho-alveolar fluid (BAL). Post-mortem studies of lung burden give an integrated measure of lifetime exposure whereas BAL studies show more recent exposure . Autopsy samples can only show exposure to durable materials and chrysotile is not particularly durable in vivo. Examination of the lungs of Canadian chrysotile miners shows that tremolite rather than chrysotile constitutes the bulk of the fibre burden in their lungs [45,46]. 3 Risk Analysis All good data regarding the development of disease following exposure to chrysotile comes from people who have experienced heavy occupational exposures. To relate this to low-level exposures the question becomes whether heavy occupational exposure is a paradigm for non-occupational urban exposure or indeed the low-level occupational exposure now found in the Western world . Also, it is important to establish whether urban non-occupational exposure (continuous) is a paradigm for low- level occupational exposure (intermittent but at a higher exposure level)? If the first of these relationships were to hold it would be tantamount to saying that a linear dose-response model for chrysotile exposure is acceptable. However, as discussed above I do not believe that the evidence we have today sufficiently supports such a paradigm but the reasons for rejecting the LNT should be explored. The estimate for lung cancer risk from low level chrysotile exposure exceeds the one in one million which some people have suggested as the limit for an "acceptable risk". But, it must be stated that there is insufficient evidence to give much support to this figure, or other, more quantitative estimates of risk for the environmental effect of the fibre . Chrysotile is not a potent carcinogen for rodents or humans . Experiments on animals exposed to pure short fibre chrysotile have shown that they do not develop tumours even at any of the „high‟ doses tested , only long fibre chrysotile produces a carcinogenic response [50, 51] and that towards the end of the (healthy, specific pathogen free (SPF)) animals normal lifespan. Before the development of SPF animals carcinogenicity could not be demonstrated due to the comparatively short lifetime of „dirty‟ animals. In human studies those heavily exposed may be compared with a cohort exposed to environmental levels or low occupational levels. This is an acceptable model in which the difference in the levels of exposure between the two groups maybe several orders of magnitude. However, when the object of the experiment is to determine the effects of environmental levels on people there is a problem since the difference in exposure level between cohorts with high environmental, or low occupational, exposure and low environmental exposure is too small for any pathological or epidemiological method to differentiate between them. Since there is no scientific way to study low level exposure and so measure risk, the best that can be achieved is to calculate it. The classic paper by Hughes and Weill  and discussion that has arisen from this  and similar work  illustrates the problem. To take one example; from a cohort of one million people without any asbestos exposure 32,000 would be expected to die from lung cancer. Extrapolation from studies of people with heavy occupational exposure show that if this cohort had been exposed to 1 f.L-1 of chrysotile (over 6 years - a school population was modelled) an additional 0.6 lung cancers would be expected. The relative risk at this exposure is therefore 32,000.6/32,000 = 1.000019. To test this by a prospective study to show whether the observed risk is this high would require two cohorts which would have to number in total nearly 1,000 times the population of the Earth. In the light of this it is not surprising that animal experiments show no effect at low levels of exposure (similar numbers of animal would be required for a positive result) and so such experiments, if they are done and with necessarily modest numbers of animals, produce „negative results‟ and are very rarely reported (resulting in publication bias). Consequently no human relevance from such studies will ever become clear. This is unfortunate since there would be an objective if such studies could be done which would be to validate existing control measures and demonstrate their safety. Mechanism of Action Mechanistic studies on the development of cancer suggest that it develops by one of two main pathways. Either the compound is genotoxic and directly interacts with DNA or its action involves an epigenetic mechanism where it is normally described as non-genotoxic. One problem is therefore to decide which of these two mechanisms best describes the case of chrysotile. The problem is confounded by the fact that the mineral chrysotile per se is not carcinogenic [12, 55]. Only chrysotile fibres exceeding a certain length have been associated with a carcinogenic response. The evidence for this from animal experiments and human epidemiology is compelling (see refs. in ). Carcinogenicity has only been elicited by longer fibres (> 8 µm say) while fibres shorter than 5 µm 4 seem, from the evidence we have available, to be neither carcinogenic nor fibrogenic . Therefore, in spite of many proposals for a genetic mechanism it seems most likely that chrysotile exerts its carcinogenic effects by a non-genotoxic mechanism. In support of this it is widely accepted that in the case of lung cancer chrysotile acts as a promoter of carcinogenesis. If this is so there is no need for it to have a direct effect on DNA. There is still the question of whether the carcinogenic mechanism is dependent on dose and what is the dose-response relationship. High exposures may have a different mechanism of action compared to low exposures although evidence is lacking for chrysotile. It has long been known, as noted above, that the development of the various asbestos-related diseases is related to dose. Also, the type of malignancy is apparently dose-dependent. Lung cancer is found only where exposure has been high and may be consequent upon the development of asbestosis although whether it is a sequela or a separate development is unknown (see above). Any effect of dose seems limited to whether or not the disease occurs which is de facto admission that there is a threshold. This is heretical thinking with regard to current regulatory practice but there is overwhelming evidence of a threshold for many carcinogens . Because chrysotile has so many uses there has been long-term(at least 50 years) low-level exposure of the populations in most, if not all, major cities. The number of people exposed is many millions. If there is no threshold, with this size of population, one would have expected excess rates lung cancer in the various groups of outdoor workers of both sexes in the cities. This does not seem to be the case. Where there have been increases in levels of disease this can be attributed to levels of occupational exposure but within Europe, at least, the only increased risk seems to have occurred in the UK . Conclusions An important principle governing regulatory agencies, particularly the EPA, is that by regulating the levels of environmental carcinogens a considerable health benefit would be gained. It was perceived that treatment of cancer was largely ineffectual; there was good evidence that there were a lot of carcinogens in the environment; geography seemed more important than ethnicity; and perhaps as many as 90% of all human cancers had an environmental origin . It was thought that reducing carcinogens in the environment would considerably reduce the level of cancer in the population. Unfortunately, underpinning these ideas with hard science was impossible. There are no observable data for individual materials at low levels of exposure and the only recourse is to rely on a mathematical model. Such data as are available, almost always resulting from high levels of exposure, have to be extrapolated to low levels. Early on this was a simple straight line through the origin, a model that has been modified with time to a multi-stage linearised (LNT) model that is equivalent to a series of straight lines which finally go through the origin. The reason for such a model is the belief that there is no threshold of effect: no dose is too small. The implication of this approach is that mammals have no defence against events that damage DNA which, in the light of what is known about DNA repair, does not seem credible . Even at higher doses, where definite effects can be elicited, experiments have shown that whereas at one dose tumours may be produced in a large number of the animals tested, dosing at even half that amount may produce no tumours at all. More than that it seems that low doses may even be protective and beneficial, which is the phenomenon known as hormesis. There is at present little evidence that ambient levels of mineral fibres pose a real risk to human health. The intense and costly effort to clear asbestos from buildings to reduce further this immeasurably small risk may cause more human exposure to mineral fibres and not less [60,61]. Vigilance will be necessary to ensure that these abatement related exposures do not become a real hazard. We have already found that they have become a serious financial burden . It is well established that exposure to low levels of chrysotile have no detectable carcinogenic effect in experimental animals. 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