Guseva Canu Irina, Gaillen-Guedy Alan, Antilla Ahti, Charles Sandrine, Fraize-Frontier Sandrine, Luce Danièle, McElvenny Damien Martin, Merletti Franco, Michel Cecile, Pukkala Eero, Schubauer-Berigan Mary K, Straif Kurt, Wild Pascal, Richardson David B
Department of Occupational and Environmental Health, Unisanté, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
Department of Occupational and Environmental Health, Unisanté, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Occup Environ Med. 2022 May 2. doi: 10.1136/oemed-2021-108030.
Animal bioassays have demonstrated convincing evidence of the potential carcinogenicity to humans of titanium dioxide (TiO), but limitations in cohort studies have been identified, among which is the healthy worker survivor effect (HWSE). We aimed to address this bias in a pooled study of four cohorts of TiO workers.
We reanalysed data on respirable TiO dust exposure and lung cancer mortality among 7341 male workers employed in TiO production in Finland, France, UK and Italy using the parametric g-formula, considering three hypothetical interventions: setting annual exposures at 2.4 (U.S. occupational exposure limit), 0.3 (German limit) and 0 mg/m for 25 and 35 years.
The HWSE was evidenced. Taking this into account, we observed a positive association between lagged cumulative exposure to TiO and lung cancer mortality. The estimated number of lung cancer deaths at each age group decreased across increasingly stringent intervention levels. At age 70 years, the estimated number of lung cancer deaths expected in the cohort after 35-year exposure was 293 for exposure set at 2.4 mg/m, 235 for exposure set at 0.3 mg/m, and 211 for exposure set at 0 mg/m.
This analysis shows that HWSE can hide an exposure-response relationship. It also shows that TiO epidemiological data could demonstrate an exposure-effects relationship if analysed appropriately. More epidemiological studies and similar reanalyses of existing cohort studies are warranted to corroborate the human carcinogenicity of TiO. This human evidence, when combined with the animal evidence, strengthens the overall evidence of carcinogenicity of TiO.
动物生物测定已证明有令人信服的证据表明二氧化钛（TiO₂）对人类具有潜在致癌性，但队列研究存在局限性，其中之一是健康工人幸存者效应（HWSE）。我们旨在通过对四组TiO₂工人的汇总研究来解决这一偏差。
我们使用参数化g公式重新分析了芬兰、法国、英国和意大利7341名从事TiO₂生产的男性工人的可吸入TiO₂粉尘暴露和肺癌死亡率数据，考虑了三种假设干预措施：将25年和35年的年暴露量设定为2.4（美国职业暴露限值）、0.3（德国限值）和0 mg/m³。
证实了健康工人幸存者效应。考虑到这一点，我们观察到TiO₂的滞后累积暴露与肺癌死亡率之间存在正相关。随着干预水平越来越严格，各年龄组的肺癌死亡估计数减少。在70岁时，35年暴露后队列中肺癌死亡的估计数，暴露量设定为2.4 mg/m³时为293例，暴露量设定为0.3 mg/m³时为235例，暴露量设定为0 mg/m³时为211例。
该分析表明健康工人幸存者效应可能掩盖暴露-反应关系。还表明，如果进行适当分析，TiO₂的流行病学数据可以证明暴露-效应关系。需要更多的流行病学研究和对现有队列研究进行类似的重新分析，以证实TiO₂对人类的致癌性。这一人体证据与动物证据相结合，加强了TiO₂致癌性的总体证据。
