Meeting report: mode(s) of action of asbestos and related mineral fibers.

BACKGROUND: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood. OBJECTIVES: A workshop was held to discuss the state of the science of the MOA for asbestos-related disease. The objective was to review the range of asbestos-induced health effects (including those at sites remote to the respiratory tract). We sought to identify existing knowledge gaps and define what research is needed to address these gaps and advance asbestos research. DISCUSSION: Discussions centered on areas of uncertainty in the field, including the ways asbestos is defined and characterized, the role of different fiber characteristics (e.g., length and mineralogy) in disease, and the impact of low-dose exposures on human health. Studying the dosimetry and mode of action of multiple fiber types would enhance our understanding of asbestos-related disease. To better elucidate the MOA of specific asbestos fibers, the risk assessor requires data as to specific characteristics of asbestos in determining fiber toxicity (e.g., surface area, mineral type), which may inform efforts to assess and control exposures and prevent adverse human health outcomes for the diverse range of fiber types. Specific research aims were defined for these topics and for overarching issues to be addressed, including the use of standardized terminology, test materials, and better experimental models to aid in data extrapolation to humans. CONCLUSION: To resolve these and other issues, participants agreed that diverse scientific disciplines must coordinate to better understand the MOA leading to the various asbestos-related disease end points.

Uncertainties in biologically-based modeling of formaldehyde-induced respiratory cancer risk: identification of key issues.

In a series of articles and a health-risk assessment report, scientists at the CIIT Hamner Institutes developed a model (CIIT model) for estimating respiratory cancer risk due to inhaled formaldehyde within a conceptual framework incorporating extensive mechanistic information and advanced computational methods at the toxicokinetic and toxicodynamic levels. Several regulatory bodies have utilized predictions from this model; on the other hand, upon detailed evaluation the California EPA has decided against doing so. In this article, we study the CIIT model to identify key biological and statistical uncertainties that need careful evaluation if such two-stage clonal expansion models are to be used for extrapolation of cancer risk from animal bioassays to human exposure. Broadly, these issues pertain to the use and interpretation of experimental labeling index and tumor data, the evaluation and biological interpretation of estimated parameters, and uncertainties in model specification, in particular that of initiated cells. We also identify key uncertainties in the scale-up of the CIIT model to humans, focusing on assumptions underlying model parameters for cell replication rates and formaldehyde-induced mutation. We discuss uncertainties in identifying parameter values in the model used to estimate and extrapolate DNA protein cross-link levels. The authors of the CIIT modeling endeavor characterized their human risk estimates as "conservative in the face of modeling uncertainties." The uncertainties discussed in this article indicate that such a claim is premature.

Evaluation of evidence for infection as a mode of action for induction of rat lymphoma.

The European Food Safety Authority (EFSA) released a 2006 report questioning the relationship of aspartame exposure with increased incidence of lymphomas/leukemias in a European Ramazzini Foundation (ERF) rat study. The EFSA report suggested that the lymphoma/leukemia findings were most likely explained by infection in the rat colony. The ERF has also conducted the only available long-term oral study of methyl tertiary-butyl ether (MTBE). Thus, using the EFSA report as support, some have now raised questions about the human relevance of MTBE-associated hemolymphoreticular tumors reported by the ERF in female rats as well as whether their incidence was elevated above background levels. In this report, we discuss the hypothesized mode of action (MOA) of infection-induced lymphoma and its relevance to MTBE-associated lymphomas. We address the relationship of rat strain and study duration to lymphoma susceptibility and review evidence of low background rates of this tumor in control animals at the ERF, similar survival rates for female rats at the ERF and National Toxicology Program (NTP), and chemical- and gender-specificity of tumor induction for this type of tumor in studies at the ERF. We find that the background incidence of hemolymphoreticular tumors in female rats in the MTBE study is consistent with contemporaneous studies at the ERF and that there is an exposure-related effect, which is unlikely to be due to infections. We examine more recent tumor classification schemes for lymphomas, which support the combination of lymphoblastic leukemias and lymphomas reported by Belpoggi et al. ([1995] Toxicol Ind Health 11:119-149; [1998] Eur J Oncol 3:201-206).