The carcinogenic action of crystalline silica: A review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism

Paul J. A. Borm, Lang Tran, Ken Donaldson

In 1987 the International Agency for Research on Cancer (IARC) classified crystalline silica (CS) as a probable carcinogen and in 1997 reclassified it as a Group 1 carcinogen, i.e., that there was sufficient evidence for carcinogenicity in experimental animals and sufficient evidence for carcinogenicity in humans. The Working Group noted that "carcinogenicity in humans was not detected in all industrial circumstances studied, carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs." This unusual statement that the physicochemical form of the CS influences its carcinogenicity is well understood at the toxicological level and arises as a consequence of the fact that CS activity depends on the reactivity of the CS surface, which can be blocked by a number of agents. We reviewed the literature on CS genotoxicity that has been published since the 1997 monograph, with special reference to the mechanism of CS genotoxicity. The mechanism of CS genotoxicity can be primary, a result of direct interaction of CS with target cells, or indirect, as a consequence of inflammation elicited by quartz, where the inflammatory cell-derived oxidants cause the genotoxicity. The review revealed a number of papers supporting the hypothesis that the CS genotoxic and inflammatory hazard is a variable one. In an attempt to attain a quantitative basis for the potential mechanism, we carried out analysis of published data and noted a 5-fold greater dose required to reach a threshold for genotoxic effects than for proinflammatory effects in the same cell line in vitro. When we related the calculated threshold dose at the proximal alveolar region for inflammation in a published study with the threshold dose for genotoxicity in vitro, we noted that a 60-120-fold greater dose was required for direct genotoxic effects in vitro. These data strongly suggests that inflammation is the driving force for genotoxicity and that primary genotoxicity of deposited CS would play a role only at very high, possibly implausible, exposures and deposited doses. Although based on rat studies and in vitro studies, and therefore with caveats, the analysis supports the hypothesis that the mechanism of CS genotoxicity is via inflammation-driven secondary genotoxicity. This may have implications for setting of the CS standard in workplaces. During the writing of this review (in May 2009), IARC undertook a review of carcinogenic substances, including CS. The Working Group met to reassess 10 separate agents including CS. This was not a normal monograph working group published as a large single monograph, but was published as a two-page report. This review group reaffirmed the carcinogenicity of "silica dust, crystalline in the form of quartz or cristobalite" as a Group 1 agent, with the lung as the sole tumor site. Of special relevance to the present review is that the cited "established mechanism events" for CS are restricted to the words "impaired particle clearance leading to macrophage activation and persistent inflammation." The lack of mention of direct genotoxicity is in line with the conclusions reached in the present review.