Table 2.

Evidence integration summary judgment: lung cancer and mesothelioma.

Summary of animal, human, and mechanistic evidence					Inference across evidence streams
Evidence from studies of exposed humans					Suggestive Evidence of no association • Several medium or high-quality epidemiological studies demonstrate no positive association between talc and LC or mesothelioma. • Three of four studies show no evidence of increased lung tumors • Single positive finding in one species exposed to doses associated with particle overload • Other inferences: • Talc is not DNA reactive • Insufficient evidence supporting a MOA
Studies, outcome and confidence	Key findings	Factors that increase certainty	Factors that decrease certainty	Summary strength of evidence judgment
Lung Cancer and Mesothelioma fifteen medium quality prospective cohort studies: and one cohort study each in the high and low quality categories	• No elevated risk of LC largely consistent across studies • Few sporadic mesothelioma cases • Include both cosmetic and industrial talc	• Medium quality studies • Highly-exposed millers and miners in several countries • Semi-quantitative exposure characterization in some studies	• Smoking not adequately considered in LC studies • Previous employment not often considered in LC studies	Evidence against
Evidence from in vivo animal studies
Studies, outcomes, and confidence	Key findings	Factors that increase certainty	Factors that decrease certainty	Summary strength of evidence judgment
Four high-quality studies in rats and mice	• Three studies with no lung tumors or mesothelioma • One study with > lung tumors in female rats	• High quality studies	• Particle overload/ exceedance of MTD in positive study • Micronized talc not relevant to human exposure	Indeterminate Micronized talc causes lung tumors in one species and sex of animals at doses >MTD conditions
Mechanistic Evidence or Supplemental Information
Biological events or pathways (or other information category)	Primary evidence evaluated	Key findings, interpretation, and limitations	Evidence stream summary
Genotoxicity, chronic inflammation	• Three GLP/guideline (K = 1) genotoxicity studies • Two medium quality (K = 2) in vivo studies	• Rapid clearance of talc from lungs • Increased macrophages and markers of inflammation in vitro and in vivo • One study used intratracheal instillation, not relevant to humans	• Available mechanistic evidence is insufficient to support any mode (or modes) of action for talc and lung cancer