Review of Lung Particle Overload, Rat Lung Cancer, and the Conclusions of the Edinburgh Expert Panel-It's Time to Revisit Cancer Hazard Classifications for Titanium Dioxide and Carbon Black.

Chronic inhalation of titanium dioxide or carbon black by rats at concentrations which overload lung particle clearance can result in lung cancer. Based on this rat lung response, IARC, NIOSH, and ECHA classified titanium dioxide, and IARC classified carbon black, as potential human carcinogens. These classifications have been questioned based on an extensive data base demonstrating: the rat lung cancer occurred only under conditions of extreme lung particle overload; the lung cancer response in rats has not been seen in other animal species; and studies in titanium dioxide and carbon black exposed human populations have not shown an increased incidence of cancer. In 2019 an international panel of science and regulatory experts was convened to document the state of the science on lung particle overload and rat lung cancer after exposure to poorly soluble low toxicity particles. Regarding hazard identification, the expert panel concluded, in the absence of supporting data from other species, lung particle overload-associated rat lung cancer does not imply a cancer hazard for humans. Regarding high to low dose extrapolation, the expert panel concluded rat lung tumors occurring only under conditions of lung particle overload are not relevant to humans exposed under non-overloading conditions. The conclusions of the Edinburgh Expert Panel directly conflict with IARC, ECHA and NIOSH's extrapolation of lung particle overload associated rat lung cancer to hazard for humans. The hazard classifications for titanium dioxide and carbon black inhalation should be assessed considering the state-of-the-science on lung particle overload and rat lung cancer.