The NTP Talc Inhalation Study: A Critical Appraisal Focused on Lung Particle Overload

Abstract

Recently published results in a NTP report of a 2-year inhalation study with talc in rats and mice seem to fit the category of being associated with particle overload quite well: Exposure concentrations of 6 and 18 mg/m 3 induced pulmonary inflammation and fibrosis in male and female rats and induction of lung tumors (in female rats only) of the high exposure group; mice of either sex showed an inflammatory response but did not show pulmonary fibrosis or lung tumors. Analysis of the particle accumulation kinetics in lungs of both rats and mice indeed shows that lung overload had been reached at both exposure concentrations in both species resulting in increased talc accumulation of high lung burdens, This and the chronic inflammatory response-indicate that the maximum tolerated dose (MTD) had been exceeded at both exposure levels. This result was predictable based on the outcome of a 4-week range-finding study prior to initiation of the chronic talc study; however, the short duration of the range-finding study may have been inadequate to give great confidence in the prediction and,therefore may have accounted for the failure to include a concentration below the MTD in the chronic study. Further analysis of the results of the chronic talc study show that talc particles behave like other low-toxicity particles such as TiO 2 and toner with respect to effects on lung clearance and chronic pulmonary inflammation, The conclusion of the NTP report that there is clear evidence of pulmonary carcinogenicity of talc in female rats should, therefore, be qualified by a statement that this is a secondary effect due to the high pulmonary particle load and its associated chronic toxicity. Accordingly, the relevancy of the tumors observed in the female high-exposure group for occupational human exposures may be questionable.