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Society For Risk Analysis Annual Meeting 2009

Risk Analysis: The Evolution of a Science

Session Schedule & Abstracts

* Disclaimer: All presentations represent the views of the authors, and not the organizations that support their research. Please apply the standard disclaimer that any opinions, findings, and conclusions or recommendations in abstracts, posters, and presentations at the meeting are those of the authors and do not necessarily reflect the views of any other organization or agency. Meeting attendees and authors should be aware that this disclaimer is intended to apply to all abstracts contained in this document. Authors who wish to emphasize this disclaimer should do so in their presentation or poster. In an effort to make the abstracts as concise as possible and easy for meeting participants to read, the abstracts have been formatted such that they exclude references to papers, affiliations, and/or funding sources. Authors who wish to provide attendees with this information should do so in their presentation or poster.

Common abbreviations

M2-H Symposium: Formaldehyde Exposure and Human Leukomogenesis Room: Kent   10:30 AM-Noon

Chair(s): Gail Charnley

M2-H.1  10:30  Meta-Analysis of risks associated with occupational formaldehyde exposure. Mundt KA*, Mundt DJ, Montgomery R; ENVIRON International Corporation   kmundt@environcorp.com Abstract: The human health effects of formaldehyde have been studied extensively both toxicologically and epidemiologically. The International Agency for Research on Cancer (IARC) classified formaldehyde as a known nasopharyngeal carcinogen, and possibly a leukemogen in 2004. Additional cancers such as Hodgkin’s lymphoma, brain cancers and other cancers are inconsistently reported to be associated with occupational formaldehyde exposure. However, several recent reviews and meta-analyses – largely based on the same published literature – arrive at somewhat different and even contradictory conclusions regarding the specific cancers for which formaldehyde may increase risk. Furthermore, the exposure levels at which risks are increased remain poorly understood. To help summarize the latest available epidemiological evidence and to clarify which of these associations are most strongly and consistently reported, we conducted a meta-analysis comprehensively considering all case-control and cohort studies presenting statistical results for nasopharyngeal cancer, leukemias and various other cancers among workers known to be occupationally exposed to formaldehyde. This analysis of lymphohematopoietic cancers included the latest update of the single largest cohort study, conducted by the National Cancer Institute and published in May, 2009. Overall meta-relative risks as well as analyses of study results by study year, study design, exposure certainty or level, length of follow-up, degree of control for confounding and avoidance of bias, etc., will be presented and discussed. The results of this updated assessment also should be helpful in identifying specific cancers for which epidemiological data may be adequate for risk assessment purposes.

M2-H.2  10:50  Genomic evidence for dose-dependent transitions in the respiratory epithelium following formaldehyde exposure. Andersen ME*, Thomas RS, Clewell HJ; The Hamner Institutes for Health Sciences   mandersen@thehamner.org Abstract: Formaldehyde is a nasal irritant, and inhalation exposure to formaldehyde has been associated with nasal lesions and tumors in rats. Due to the equivocal nature of the human epidemiology data on formaldehyde, any quantitative risk assessment for formaldehyde that attempts to consider the mode of action and make use of formaldehyde-specific mechanistic data would need to be based primarily on the animal data. A suite of studies has been performed to provide critical information on the mode of action and quantitative dose-response for the nasal effects of formaldehyde. The goal of these studies was to improve the scientific basis for conducting a biologically realistic risk assessment for formaldehyde that is health protective without unnecessarily restricting the use of this important commodity chemical. Formaldehyde inhalation exposures were conducted in F344 rats for up to 90 days to provide information on the time-course and concentration dependence of genomic changes produced by formaldehyde in the nasal respiratory mucosa, the tissue in which formaldehyde-induced tumors arise. Exposures were conducted from 0.7 to 15 ppm, and genomic evaluations were conducted at several time points. The results of these initial experimental evaluations of the genomic changes induced by inhaled or formaldehyde demonstrate a highly concentration- and time-dependent response, with clear indications of changes in the mode of action for the cellular effects of formaldehyde. These data indicate the existence of important dose-dependent transitions in the mode of action for the carcinogenicity of formaldehyde that need to be carefully considered in future risk assessments.

M2-H.3  11:10  Nose-associated lymphoid tissue (NALT) and local lymph nodes in Fischer rats and B3C3F1 mice upon 28-day exposure to formaldehyde vapor . Kuper CF*, Ma-Hock L, Durrer S, Woutersen RA; Department of Toxicology and Applied Pharmacology, TNO Quality of Life, 3704HE, Zeist, the Netherlands (1,4); BASF SE, Department of Product Safety, 67056 Ludwigshafen, Germany (2, 3)    frieke.kuper@tno.nl Abstract: An association between formaldehyde (FA) and hematopoietic malignancies is under debate (IARC Monographs, 2004). A mode of action was not established, because (lympho)hematopoietic tissues distant from the exposure site have not been found target of FA. To investigate if local lymphoid tissues are a target of FA, Nose-associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer344 rats and B6C3F1 mice. Paraffin-embedded tissues were sectioned and stained with H&E or stained immunohistochemically for cell proliferation (BrdU incorporation). Light microscopy revealed slight to moderate simple hyperplasia of NALT lymphoepithelium of rats exposed to 15 ppm and increased proliferation rate of the epithelial cells. NALT may also have been slightly less active (decreased size, decreased cellularity, decreased germinal centre development), but this was not confirmed statistically. Principal component (discriminant) analysis of rat NALT and lymph nodes data did not reveal other effects or effects at lower exposure levels. Mice tissues were not affected. The available data either supporting or refuting these hypotheses will be discussed, including results from a 28-day inhalation study in rats and mice that investigated the nasal-associated lymphoid tissue (NALT) and cervical lymph nodes.

M2-H.4  11:30  Clinical and hematotoxicologic evaluation of current evidence does not support classifying formaldehyde as a human leukemogen. Goldstein BD*; Univ Pittsburgh Graduate School Public health   bdgold@pitt.edu Abstract: Epidemiological findings suggesting that formaldehyde exposure is associated with a higher risk of acute myelogenous leukemia (AML) have led to consideration of the potential mechanism of action by which inhalation of this rapidly reactive agent can cause bone marrow cancer. It is difficult to envision inhaled formaldehyde penetrating to the bone marrow. The lack of evidence that high-dose formaldehyde produces pancytopenia in humans or laboratory animals, and the longer latency period for its reported epidemiological association with AML, distinguish formaldehyde from the broad variety of known human leukemogens, indicating that if formaldehyde is a myeloid leukemogen it does not follow a known leukemogenic mechanism of action. One recently proposed mechanism for formaldehyde leukemogenesis suggests that myeloid precursors within the nasal mucosa may be the site for leukemogenesis. If that proposal is true then chloromas, which are local collections of myeloid tumor cells, would be expected to be found in the nose. However, nasal tissues appear rarely to be a site for a chloroma. Review of known nasal carcinogens found only mustard gas as having epidemiological findings of an elevated, but not statistically significant, leukemia risk. But mustard gas produces pancytopenia in exposed humans and laboratory animals. Dose issues at the interface between the epidemiologic and hematotoxicologic findings also detract from an evidence-based acceptance of a causal association between formaldehyde and AML.

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