Epidemiological evidence on the carcinogenicity of silica: Factors in scientific judgement [1] (multiple letters)

In view of the extended debate and differing opinions on whether crystalline silica is a human carcinogen, we have reviewed a selection of epidemiological reports, to identify the areas of uncertainty and disagreement. We have chosen to examine the papers which in a recent review were considered to provide the least confounded examinations of an association between silica exposure and cancer risk. We also refer to a study of the mortality of coalminers very recently reported by ourselves and colleagues.

We find that parts of the evidence are coherent but there are contradictions. On examination this resolves mostly into differences between types of studies. The three types of epidemiological study included are: (i) exposure–response studies, the most powerful for the confirmation of a relationship between a specific exposure and a health effect; (ii) descriptive studies in which incidence of disease in an exposed population is compared with that in a reference population; and (iii) studies of incidence of disease in subjects on silicosis case-registers.

Descriptive studies frequently though not invariably suggest an excess lung cancer risk in silica-exposed workers compared with the general population, but exposure–response studies consistently fail to confirm that the cause is exposure to quartz. A single exposure–response study of cristobalite suggests a positive relation. Both sets of evidence have weaknesses. There are uncertainties on whether the excess risks in the descriptive studies are related to silica exposure or to lifestyle, including smoking habits. There are doubts on whether the exposure estimates in some of the exposure–response studies were sufficiently reliable to detect a small risk or weak association, though they are unlikely to have missed a strong effect.

Studies of subjects on silicosis case registers consistently show an excess of lung cancer, but it is not clear to what extent these increased risks represent a direct effect of silica exposure, a secondary effect of the silicosis, preferential inclusion of subjects suffering from the effects of smoking, or bias in diagnostic accuracy.

This not unnaturally leads to differences in opinion, exacerbated by variations in the strength of proof required by different experts.

The main scientific uncertainties in the evidence are:
1.
Whether, in the descriptive studies, the excess lung cancer rates in silica-exposed workers are explicable in terms of smoking habits, socio-economic class differences and inappropriate comparison populations. Better smoking information and more carefully chosen comparison populations are needed;

2.
Whether the exposure–response studies could have missed a real relationship between silica exposure and lung cancer, if one exists. Many of the exposure–response studies were conducted with great care, but weaknesses, in the available data on which the exposure estimations were based, could have caused a real relationship of lung cancer and silica exposure to be missed. These studies were sufficiently powerful to demonstrate relationships of silica exposure with silicosis and silico-tuberculosis, so it is unlikely that they would have missed any but a small risk, or weak relationship, for lung cancer. Our own recent study of coalminers used uniquely detailed and reliable exposure data, and failed to demonstrate convincingly an increased risk. This negative finding, though, applies only to a dust in which the proportion of quartz in the dust is usually less than 10%. Exposure–response studies are needed, with high quality exposure estimates, in populations exposed to respirable dust of which crystalline silica comprises more than 10%;

3.
Whether the excess cancer risks in subjects on silicosis registers are the result of selection and diagnostic bias. Given these difficulties, case-register studies may not be capable of giving a reliable answer to the central question, though they have been useful in pointing to the possibility of a cancer risk;

4.
If silica exposure is associated with increased risks of lung cancer, whether or not the increased risk is found in subjects without silicosis; or is confined to subjects with silicosis, with the implication that such a secondary effect would be avoided by avoiding the exposures that cause silicosis. The limited evidence available suggests that any silica-related cancer risk may well be confined to subjects with silicosis. Studies of risks in silica exposed workers demonstrated not to have silicosis would be informative;

5.
Whether it is justifiable to assume that quartz and cristobalite have similar health effects. Laboratory studies could complement epidemiological studies helpfully in this respect.

We have not sought in this review to give our opinion on what conclusions the evidence overall justifies, but hope that this discussion of the strengths, weaknesses and conflicts in the evidence will help to clarify the debate.