Talc and human cancer: a systematic review of the experimental animal and mechanistic evidence.

The potential carcinogenicity of talc has been evaluated in many studies in humans and experimental animals published in the scientific literature over the last several decades, with a number of these studies reporting no associations between talc exposure and any type of cancer. In order to fully understand the current state of the science regarding the potential for talc to induce human cancers, we conducted a comprehensive and systematic review of the available experimental animal and mechanistic evidence (in conjunction with a systematic review of the epidemiology evidence in a companion analysis) to evaluate whether it supports talc as being carcinogenic to humans. We considered study quality and its impact on the interpretation of results and evaluated all types of cancer and all exposure routes. We also evaluated the evidence on the potential for talc to migrate in the body to potential tumor sites. We identified seven experimental animal carcinogenicity studies and 11 mechanistic studies of talc to systematically review. We found that several of the experimental animal carcinogenicity studies of talc have limitations that preclude their sensitivity to detect increases in tumor incidence. Regardless, the studies cover multiple exposure routes, species, and exposure durations, and none indicate that talc is a carcinogen in experimental animals except in rats under conditions of extremely high exposure that likely resulted in lung particle overload, a nonspecific effect of high exposures to poorly soluble particles, and not from any carcinogenic properties of talc. Lung particle overload leading to lung tumor formation has only been observed in rats and not in any other species, including humans. The mechanistic studies indicate that talc is not genotoxic or mutagenic, but can induce some effects that could be events on a possible pathway to carcinogenicity, mainly at high exposures or in in vitro studies with exposures of unclear relevance in vivo, but these effects are not consistent across studies and cell types. This systematic review of the experimental animal carcinogenicity and mechanistic evidence for talc indicates that an association between talc exposure and cancer is not expected in humans. Talc carcinogenicity is not plausible in any species except rats, and only when the exposure conditions are high enough to induce lung particle overload, which is not relevant to human exposures.

Perspectives on recent reviews of aspartame cancer epidemiology.

Aspartame is a dipeptide non-sugar sweetener that was first marketed in the US in carbonated beverages in 1983, before gaining prominence globally. The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) and the WHO International Agency for Research on Cancer (IARC) completed evaluations of aspartame and cancer in July 2023. JECFA reaffirmed the safety of aspartame, stating that epidemiology evidence is "not convincing," and that there are no consistent associations between aspartame and cancer (JECFA/IARC, 2023; JECFA, 2023). JECFA also noted "reverse causality, chance, bias and confounding by socioeconomic or lifestyle factors, or consumption of other dietary components, could not be completely ruled out" in relevant epidemiology studies (JECFA/IARC, 2023). In contrast, IARC stated that there are three "high quality" studies on liver cancer (Riboli, 2023), but that the evidence is limited because "chance, bias or confounding could not be ruled out as an explanation for the positive findings" (JECFA/IARC, 2023). IARC does not provide an explanation as to how these studies can be both high quality and have these weaknesses, most notably potential exposure misclassification, or how inconsistent associations from studies with these weaknesses constitute limited evidence. Further, when IARC concludes an agent has limited or inadequate human evidence (and no sufficient animal or strong mechanistic evidence), it classifies that agent as either Group 2B, a possible human carcinogen, or Group 3, not classifiable as to its carcinogenicity. Ultimately, the interpretations of Group 2B and Group 3 classifications are intended to be similar. However, a Group 2B designation may make it appear to scientists and non-scientists alike that the evidence is pointing in the direction of causality. This can lead to unnecessary confusion with respect to the evidence, as well as a perception of a disagreement within WHO regarding aspartame. This apparent contradiction could have been avoided by assigning the IARC classification most consistent with the conclusion that the human evidence for cancer is inadequate: Group 3.

The role of study quality in aspartame and cancer epidemiology study reviews.

Toews et al. [1] and the World Health Organization (WHO) [2] reviewed observational epidemiology studies of non-sugar sweeteners (NSSs) and various health effects. The former used the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool and the latter used both the ROBINS-I tool and the Newcastle-Ottawa Scale to evaluate study quality. Both reviews concluded that there were no associations between NSS or aspartame consumption and cancer (except possibly between saccharin and bladder cancer) but indicated that the certainty of the evidence for all cancer types was "very low." While we agree with this conclusion, the support for the confidence in the evidence generally was not transparently documented, as the results of the study quality assessment were only provided in scores or ratings. An examination of illustrative case studies shows that some important aspects of study quality domains specific for NSSs generally or aspartame specifically (i.e., issues with the exposure and outcome assessments, the consideration of confounding/covariates, and selection bias) may have been overlooked or not given appropriate consideration, while other aspects that were less likely to have a large impact on overall study quality dominated the results in the two assessments. Our review of other studies published after the WHO [2] review further demonstrates this point. While this may not seem important given the overall lack of associations, it impacts the degree to which evidence supports a lack of effects as opposed to not being adequate to evaluate associations. In the future, aspartame and cancer outcome reviews should focus on those study quality domains that are most likely to impact the interpretation of results and discuss them in a transparent, systematic manner. If there is very low certainty in the evidence as a result of low study quality, reviewers should conclude the evidence is inadequate for making a causal determination.